UBC Theses and Dissertations

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UBC Theses and Dissertations

Some aspects of natural product chemistry Comer, Frederick William 1966

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SOME ASPECTS OF NATURAL PRODUCT CHEMISTRY I.  CIRCULAR DICHROISM STUDY OF SOME 3 -  II.  AND 20-KETO  THE STRUCTURAL DETERMINATION OF HIRSUTIC  III.BIOGENETIC-TYPE  STEROIDS  ACID C  SYNTHESES OF ACETATE-DERIVED AROMATIC COMPOUNDS by FREDERICK WILLIAM COMER  B.Sc.  Honours,  A THESIS  University  of  British  Columbia,  SUBMITTED IN PARTIAL FULFILMENT OF  THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF  in  the  PHILOSOPHY  Department of  Chemistry  We a c c e p t required  this  thesis  as  c o n f o r m i n g to  standard  THE UNIVERSITY  OF BRITISH  August,  1966  COLUMBIA  the  1963  In  presenting  requirements Columbia, for  the  understood cial  and  copying Head  of that  gain  shall  Department  an  agree  reference  tensive by  I  for  of  thesis  in  partial  advanced  degree  at  the  that  the I  this  thesis  further  Department  copying not  be  or  or  for by  Columbia  it  that  scholarly his  fulfilment  University  make  agree  without  Chemistry  August 3, 1966  shall  publication  allowed  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada D a t e  Library  study.  of my  this  of  of  freely  British available  permission  purposes  may  representatives. of  this  thesis  my  written  for  ex-  be It  for  the  granted is  finan-  permission.  The  University of B r i t i s h Columbia FACULTY OF GRADUATE STUDIES  PROGRAMME OF THE FINAL ORAL EXAMINATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY of FREDERICK W„ COMER B.Sc.  (Hons.) University of B r i t i s h Columbia, 1963 TUESDAY, AUGUST 2nd, 1966 at 3:30 P . M . IN ROOM 261, Chemistry Building COMMITTEE IN CHARGE Chairman:  Dean Ian McT, Cowan  F„ McCapra T. Money L, D. Hayward M„ Smith  L. D. Hall J . Trotter C. A„ McDoweLl  V  External Examiner: Dr. J . K. Sutherland Department of Chemistry Imperial  College  London, SW 7 , England Research Supervisor:  Dr. Frank McCapra  STUDIES  IN  NATURAL  PRODUCT  CHEMISTRY  ABSTRACT  In Part I, the C . D „ spectra of a number of 3-keto and 20-keto steroids are reported. The 3-keto steroids were comprised of two series of compounds. For one series, the conformationally transmitted e f f e c t s of o l e f i n i c centers located i n , or exocyclic to, rings B and C were investigated. It was found that these effects were r e f l e c t e d i n the C D . spectra when the double bond was located i n r i n g B , but not when the double bond was located i n r i n g C , Further, no corr e l a t i o n could be made between the r e l a t i v e rates of a l k a l i - c a t a l y z e d benzaldehyde condensation and the C D . data. For the other series, the conformations of ring A i n a number of steroids substituted at the 2- and 4- positions are discussed. The C D „ r e s u l t s are in agreement with other evidence on t h i s subject, and suggest that a 1,3-diaxial methyl i n t e r a c t i o n leads to f l a t t e n i n g of r i n g A . For the A ^ -=• 4,4-dimethyl-3-keto steroids, a non-chair conformation is indicated, but a d i s t i n c t i o n between a boat and a f l a t chair conformation cannot be made . For 2 oL bromo-4 4-dimethylcholest-5-en-3-one, a conformational equilibrium i s suggested. The 20-keto steroids were comprised of a large number of 16-substituted pregnanone and 17 oC -pregnanone derivatives. The CD, spectra of the 16,17 trans compounds and the 16 , 17<* -cis-compounds were similar to those of the 16-unsubstituted parent compounds. Modifications i n rings A and B had l i t t l e effect upon the dichroism of the 20-keto group. The C„D„ spectra of the 16/3 , 1.7 P -compounds were very sensitive to the nature of the 16P -substituent, These r e s u l t s are interpreted i n terms of the preferred conformation of the 17P -acetyl group. F i n a l l y , the C D.. spectra of a number of 16, 17-epoxy~20=keto steroids are reported and discussed with reference to the "reversed octant rule". In Part I I , the structural determination of the mould metabolite, h i r s u t i c acid C , i s reported. The functional groups were established from chemical information; however the X-ray analysis of the p=bromophenacyl ester was required to reveal the novel r i n g system. During the X-ray i r r a d i a t i o n an unusual s o l i d phase rearrangement occurred, transforming the 5  0  <=C-epoxy hydroxyl system of p-bromophenacyl h i r sutate t o a ft -hydroxy ketone system without d i s r u p t i n g the c r y s t a l structure. The X-ray a n a l y s i s revealed a 50:50 mixture of s t a r t i n g material and rearrangement product. A combination of the X-ray and the chemical data was required to complete the s t r u c t u r a l determinations of both products. The g e n e r a l i t y of the rearrangement process was"invest i g a t e d . I t occurred w i t h methyl h i r s u t a t e and dihydromethylhirsutate, but not w i t h h i r s u t i c a c i d . I t could not be induced thermally. I t d i d not occur w i t h the steroids 3 <* - and 3 P -hydroxy-4 p> , 5-epoxy-5/2> -cholestane. The rearrangement process i s probably c o n t r o l l e d by the nature of the molecular packing and hydrogen-bond formation. In Part I I I , the biogenetic-type syntheses of a number of acetate-derived aromatic compounds are reported. A d i s c u s s i o n of the preparation of the condensed polypyrone intermediates i s given, and i n p a r t i c u l a r the synthesis of the tetrapyrone, 4-hydroxy-9-methyl-2,5,7,12=tetraketo 1,6,8,11-tetraoxachrysene from the condensation of" b i s (2,4-dichlorophenyl) malonate and the t r i p y r o n e , 7=methyll-hydroxy-3,5,10-triketo 4,6,9-trioxaphenanthrene i s reported. Treatment of the tripyrone w i t h methanolic potassium hydroxide s o l u t i o n r e s u l t e d i n r i n g opening to form a poly- P> -keto chain, and subsequent a l d o l type condensation t o give aromatic compounds representative of the n a t u r a l l y - o c c u r r i n g 6,8 dihydroxyisocoumarins and C - a c e t y l o r s e l l i n i c a c i d . Treatment w i t h methanolic magnesium methoxide s o l u t i o n gave aromatic compounds derivable from d i f f e r e n t c y c l i z a t i o n modes of the poly- /3 -keto chain. Among the compounds i s o l a t e d were two representative of the n a t u r a l l y - o c c u r r i n g c u r v u l i n i c a c i d and the 5,7~di= hydroxychromones r e s p e c t i v e l y . S t r u c t u r a l assignments were made l a r g e l y on the b a s i s of the charact e r i s t i c s p e c t r a l properties of the compounds.  GRADUATE STUDIES F i e l d of Study:  Organic Chemistry J  Topics i n Physical Chemistry Topics i n Inorganic Chemistry  Topics i n Organic, Chemistry , '--„•-•<  L  ••  •  - -  Seminar i n Chemistry Crystal Structures  A„ R Coop A. Brs? W. R. Cul<*• . .N'.' Bartl-i't. R. C. Thompso R„ S. Dickso '/ D. E. McGree J. P. Kutne ;, F. McCapr . A. Rosentha J. Trotte S. A . Melza R. Stewar R„ E„ Pincr-c F. McCapr "\ T. Mone J. P. Kutne' L. D. Ha-1 0  0  v  '  v  Physical Organic Chemistry Organic Reaction Mechanisms Heterocyclic Compounds Isoprehbid Compounds A l k a l o i d Chemistry Organic Stereochemistry  Related Studies: Linear Algebra Computer Programming and Numerical Analysis  R, C. Thompso; B„ Henderso!  PUBLICATIONS A, I. Scott, F. McCapra, F„ Comer, S. A. Sutherland, D. W. Young, G. A. Sim, and G. Ferguson, "Structure and Stereochemistry of Some Polycyclic D i terpenoids", Tetrahedron, 20, 1339 (1964). P. Crabbe, F. McCapra, F. Comer and A. I. Scott, "Study of the Cotton effect of 16-substituted 20-keto Pregnane and 17 oc -pregnane derivatives", Tetrahedron, 20, 2455 (1964). F. W. Comer, F. McCapra, I. H. Qureshi, A. I. Scott and J. Trotter, "The Structure and Stereochemistry of H i r s u t i c Acid C, a Novel Fungal Sesquiterpenoid", Chem. Comm. 310 (1965). F. W. Comer and J. Trotter, "The Structure of H i r s u t i c Acid. X-ray Analysis of the p-Bromophenacyl Ester", J . Chem. Soc. (B), 11 (1966). F. W. Comer and J. Trotter, "Crystal Data for monorden ( r a d i c i c o l ) " , Acta Cryst. 19, 681 (1965). T. Money, F. W. Comer, B. Webster, I. H. Qureshi, I. G. Wright and A. I. Scott, "Biogenetic-Type Synthesis of Phenolic Compounds", J . Chem. Soc. (C), 1966, i n press.  ABSTRACT In P a r t 20-keto  I,  steroids  p r i s e d of  exocyclic  that  to,  located  densation  the  located C.  relative  and t h e  formations  were  in ring  the  of  of  compounds. effects  ring  with other  the  F o r the o t h e r  discussed.  indicated,  chair  c o n f o r m a t i o n cannot  cholest-5-en-3-one, The 2 0 - k e t o 16-substituted CD.  spectra  of  compounds were compounds.  but  subject,  leads  the  be made.  were  to  For  comprised of  of  Modifications in rings the  20-keto  the  at  a boat  is  the  17P-compounds were v e r y s e n s i t i v e  that  conformflat  a large  suggested. number o f  derivatives.  The  16<x, 17°<- c i s -  A and B had l i t t l e group.  in  ring A.  and a  16-unsubstituted  d i c h r o i s m of  are  -bromo-4,4-dimethyl-  2  upon t h e 16P,  a non-chair  and 17c<-pregnanone  those  con-  f l a t t e n i n g of  16,17 t r a n s compounds and t h e  s i m i l a r to  the  and s u g g e s t  a conformational equilibrium  pregnanone  the  d o u b l e bond  substituted  a d i s t i n c t i o n between  steroids  found  when  The C D . r e s u l t s  - 4,4-dimethyl-3-keto s t e r o i d s ,  is  was  in,  c o u l d be made  series,  steroids  e v i d e n c e on t h i s  ation  con-  located  It  but n o t when t h e  com-  a l k a l i - c a t a l y z e d benzaldehyde con-  a 1 , 3 - d i a x i a l methyl i n t e r a c t i o n For  the  investigated.  no c o r r e l a t i o n  and  were  i n the C D . s p e c t r a  A i n a number o f are  steroids  F o r one s e r i e s ,  i n r i n g B,  C D . data.  3-keto  of o l e f i n i c c e n t e r s  reflected  r a t e s of  a number o f  The 3 - k e t o  Further,  2- and 4- p o s i t i o n s  agreement  of  r i n g s B and C were  these e f f e c t s  between  reported.  transmitted  d o u b l e bond was was  are  two s e r i e s  formationally or  the C D . s p e c t r a  parent  effect  The C D . s p e c t r a to  the n a t u r e  of  of the  iii These r e s u l t s  16P-substituent. preferred CD.  conformation of the 17P-acetyl  spectra  ported  are i n t e r p r e t e d  o f a number o f 16,  i n terms o f the  group.  Finally,  the  17-epoxy-20-keto s t e r o i d s  and d i s c u s s e d w i t h r e f e r e n c e  to the " r e v e r s e d  are r e -  octant  rule". In P a r t metabolite, were  II,  the s t r u c t u r a l  hirsutic  d e t e r m i n a t i o n o f t h e mould  acid C, i s reported.  The f u n c t i o n a l g r o u p s  e s t a b l i s h e d f r o m c h e m i c a l i n f o r m a t i o n ; however t h e X - r a y  a n a l y s i s o f t h e p - b r o m o p h e n a c y l e s t e r was r e q u i r e d t o r e v e a l t h e novel  ring  system.  solid-phase hydroxyl ketone X-ray  During  rearrangement  the X-ray occurred,  i r r a d i a t i o n an u n u s u a l t r a n s f o r m i n g t h e <* - e p o x y  system o f p-bromophenacyl h i r s u t a t e  system without d i s r u p t i n g the c r y s t a l analysis revealed  rearrangement  product.  to a  P-hydroxy  structure.  a 50:50 mixture of s t a r t i n g A combination of the X-ray  m a t e r i a l and and t h e  c h e m i c a l d a t a was r e q u i r e d t o c o m p l e t e  the s t r u c t u r a l  ions of both p r o d u c t s .  of the  process  was i n v e s t i g a t e d .  dihydromethylhirsutate, not  The g e n e r a l i t y  rearrangement  It  acid.  d i d not occur with the  3°<- and 3 P - h y d r o x y - 4 P, 5 - e p o x y - 5 P - c h o l e s t a n e . ment p r o c e s s cular  It  could  steroids  The r e a r r a n g e -  i s p r o b a b l y c o n t r o l l e d by t h e n a t u r e  of the mole-  p a c k i n g and h y d r o g e n - b o n d f o r m a t i o n . In P a r t  III,  acetate-derived of  determinat-  I t o c c u r r e d w i t h m e t h y l h i r s u t a t e and  but not w i t h h i r s u t i c  be i n d u c e d t h e r m a l l y .  The  the b i o g e n e t i c - t y p e  aromatic  syntheses  compounds a r e r e p o r t e d .  o f a number o f A discussion  the p r e p a r a t i o n of the condensed p o l y p y r o n e i n t e r m e d i a t e s  is  iv g i v e n , and i n p a r t i c u l a r the s y n t h e s i s of the t e t r a p y r o n e , 4-hydroxy-9-methyl-2,5,7,12-tetraketo from the condensation  1,6,8,11-tetraoxachrysene  of b i s ( 2 , 4 - d i c h l o r o p h e n y l ) m a l o n a t e and  the t r i p y r o n e , 7 - m e t h y l - l - h y d r o x y - 3 , 5 , 1 0 - t r i k e t o 4 , 6 , 9 - t r i o x a phenanthrene i s r e p o r t e d . methanolic  Treatment of t h e • t r i p y r o n e w i t h  potassium hydroxide  to form a p o l y - P - k e t o ion to g i v e aromatic  s o l u t i o n r e s u l t e d i n r i n g opening  c h a i n , and subsequent a l d o l - t y p e condensatcompounds r e p r e s e n t a t i v e o f the n a t u r a l l y -  o c c u r r i n g 6 , 8 dihydroxyisocoumarins Treatment w i t h methanolic aromatic  and C - a c e t y l o r s e l l i n i c  acid.  magnesium methoxide s o l u t i o n gave  compounds d e r i v a b l e from d i f f e r e n t c y c l i z a t i o n modes of  the p o l y - p - k e t o c h a i n .  Among the compounds i s o l a t e d were two  r e p r e s e n t a t i v e of the n a t u r a l l y - o c c u r r i n g c u r v u l i n i c a c i d and the 5,7-dihydroxychromones r e s p e c t i v e l y .  S t r u c t u r a l assignments  were made l a r g e l y on the b a s i s of the c h a r a c t e r i s t i c s p e c t r a l p r o p e r t i e s of the compounds.  V  TABLE OF CONTENTS PART I  Page  INTRODUCTION DISCUSSION  1 ,  21  EXPERIMENTAL  54  BIBLIOGRAPHY  64  L i s t of F i g u r e s and Tables Figure 1  17  2  25  3  32  4  44  1  24  2  31  3  43  4  46  5  47  6  49  7  53  Table  PART I I INTRODUCTION  70  DISCUSSION  79  EXPERIMENTAL Chemical Data  94  X-ray Data  108  D i s c u s s i o n o f X-ray Data  126  BIBLIOGRAPHY  130  vi List  of  Figures  Figure  Table  and T a b l e s  1  80  2  91  3  93  4  117  5  118  6  124  1  114  1A  116  2  121  3  122  4  PART  List  Page  .  123  5  125  6  127  III INTRODUCTION  132  DISCUSSION  155  EXPERIMENTAL  175  BIBLIOGRAPHY  198  of  Figures  Figure  1  135  2  140  3  143  4  151  5  159  6  161  7  163  vii  ACKNOWLEDGMENTS I wish Dr.  F.  willing  to  McCapra, advice  research.  express  my t h a n k s  to  Professor  D r . T . Money and P r o f e s s o r and e n c o u r a g e m e n t  during  the  J.  A.I.  Scott,  Trotter  course  of  for this  their  PART I CIRCULAR DICHROISM STUDY OF SOME 3-  AND 2 0 - K E T O  STEROIDS  1 INTRODUCTION The  e l u c i d a t i o n of  optically cent  active  advances  associated (O.R.D.)  of  for  left  circularly  of  and t h e  As a r e s u l t  right  molecular and  a property  of  circular  a rotatory  amplitude, cular  against  rotation  extremum In  of  the  coefficients polarized incident  the of  the  left, t  components, light  gives  the  incident The  L  R  against  a C D . curve.  by  polarized  of  the  length  light  the  moleat  100. an  optically  components  dichroism.  right, (  rot-  molecular  between  molecular  and t h e  i.e.£ -€ ,  path  t  birefringent,  circular  i n the ,  L  two  A plot  t o ot  ^ > divided  two c i r c u l a r l y  difference  bire-  l o n g e r w a v e l e n g t h fyl^, and  wavelength  d e f i n e d as  the  angles.  difference  being c i r c u l a r l y  a property  A£ , w h i c h i s  by t h e  proportional  of  unequally,  circular  i n the  the  the  components  which i n turn r e s u l t s  1  a c t i v e medium a b s o r b s  refract-  active  ( O . R . D . ) curve.' '  extremum  shorter  a d d i t i o n to  phenomena  dispersion  polarized  birefringence,  the wavelength A of  d e f i n e d ^ as  at  re-  an o p t i c a l l y  polarization  dispersion  is  at,  two  by  i n d i c e s of  d e f i n e d as  traverse  r o t a t i o n [(J)} , which i s  molarity,  gives  the  plane of  the  rotatory  different  circularly  p o l a r i z e d components  the  measuring  optical  a c t i v e medium has  medium w i t h u n e q u a l v e l o c i t i e s , ation  facilitated  of  dichroism (C.D.).  plane-polarized light,  fringence.  for  Cotton e f f e c t :  and c i r c u l a r  and s t e r e o c h e m i s t r y  been g r e a t l y  in instrumentation  w i t h the  the  structure  compounds has  An o p t i c a l l y ion  the  A plot  of  extinction R  ,  circularly  t h e w a v e l e n g t h >> o f  As a r e s u l t  of  circular  the  2 dichroism,  when c i r c u l a r l y  a c t i v e medium i t the  angle  of  is  ofA(  as V  .  proportional  d e f i n e d by t h e  used i n p l a c e  traverses  an  optically  e l l i p t i c a l l y polarized light,  , which i s  molarity,  often^  emerges as  e l l i p t i c i t y designated  ellipticity, and  polarized light  for  The  molecular  to  equation:  with  path  length  [ © ] •= 3 3 0 0 A £ ;  p l o t t i n g C D . curves.  and  is  However  it  5 should  be e m p h a s i z e d t h a t  d i c h r o i s m are than  changes It  bands  is  are  to  to  detect  i n the  regions  closely  correlate  for  absorption  measuring  differences  that  i n which o p t i c a l l y  O.R.D.  the  and t h e C D . c u r v e s  are  devices  circular rather  in e l l i p t i c i t y .  observed  character curves  designed  present  them:  related  curves  exhibit  acquire  maxima.  and an e x p r e s s i o n  a = 40.28A€ .  active  absorption  anomalous  The two t y p e s has  Although both  of  been  derived^>®  O.R.D.  and C D . 7  can o f t e n the  be u s e d i n t e r c h a n g e a b l y  latter  method i s  O.R.D.  anomalous  often  curve  is  contributions  from the  cule,  t a i l i n g of  the  and t h e  same c h r o m o p h o r e  Although  a specif-ic  the  extreme they  resolution active  of  other  the  and i s  is  they  can o b s c u r e anomalous bands.  due t o  asymmetric optically  are  c e n t e r s of active  effects  On t h e  due t o  other  i n the  the  bands o f i n the  be u s e f u l f o r  more o f t e n  moleeither  molecule.  characteriz-  a hindrance; or  the  region of  i n f l u e n c e d by s u b s t i t u e n t s  and i n  prevent  two o r more  hand,  the  rotational  a weak C o t t o n e f f e c t  only observed  largely  curve  can  problems,  S u p e r i m p o s e d upon  a d d i t i o n a l chromophores  compound,  absorption  a chromophore maxima,  a plain  these background e f f e c t s  ing  stereochemical  preferred.  various  or  for  the  optically  C D . effect  of  absorption and  asymmetric  3  centers  i n the  immediate v i c i n i t y of  properties  render  of  optically  several  most  configurational  vances in  C D . the  (700  mP  Two t y p e s uished:  the  type  to  of  active  190  absorption  mP )  optically  results  and  bands,  the  resolution  and i n f a c t  problems.  two  for  Recent  ad-  comparable  sensitivity.  active  chromophores  can  chromophore,  chromophore.  from the  for  These  now make b o t h methods  dissymmetric  perturbed  chromophore.  choice  and c o n f o r m a t i o n a l  inherently  asymmetrically first  method o f  in C D . instrumentation^  range  the  Optical  intrinsic  be d i s t i n g -  and  the  activity  geometry  of  the  in  the  chromo-  g phore,  classical  examples  are  hexahelicene  (1)  and  twisted  Q  biphenyl threne  derivatives,  (2,A€262  eg.  (R)-9,10-dihydro-4,5-dimethylphenan-  = +16.4).  Compounds i n t h i s  relatively  strong  Cotton  asymmetric  carbon  atoms f o r  should  be n o t e d  molecule  that  could affect  effects,  the  and do n o t  their  optical  presence of  the  chirality  class  necessarily  activity.  asymmetric of  exhibit  require  However  centers  an i n h e r e n t l y  in a  dissymmetric  chromophore. The most  important  saturated carbonyl  example  function.  of  the  second  The c a r b o n y l  type  is  group has  it  the two  4  orthogonal 6f  reflection  approximation  active.  molecular  of  of  molecule is  carbonyl rise  planes  of  carbonyl  group  lie  octant  rule  see  assignments if  the  octants  the  configuration  is  particular  asymmetry  of  the  elements  and i s  (For  reference can  of  be made  is  known i n f o r m a t i o n a b o u t  its  conformation  from the  resultant  of  the  various  substituents  group.  The i n f l u e n c e o f  determined  by i t s  final  individual  asymmetrically  sterip  if  will  nature,  octant  substance obtained.  be  d i s p o s e d about  a given substituent  of  conformation  be  sign w i l l  the  the  the  can  the  (absolute  its  of  of  the  known a b s o l -  contributions  and e l e c t r o n i c  has  orthogonal  details  of  compound o f  configuration  the  of  negligible  a ketone  the  rule,  full  basis  and s i m i l a r l y i f  octant  case  to  considered  known,  the  the  n —> TT*  according  is  In a p p l y i n g  In t h e  rest  The i n f l u e n c e o f  On t h e  configuration  available)  of  Cotton e f f e c t  nodal planes.  a suitable  asymmetric  empirical results  by a s i g n  in-  dissymmetric  i n v o l v e d i n the  11).  order  of  i n space.  located,  an  The t h r e e m u t u a l l y  s t r u c t u r e on t h e  reference  of  the  body o f  '  lowest  is  symmetry  orbitals  the  by a  Cotton e f f e c t .  rule.  are  through  chromophore  since  characterized  i n any o f  configuration ute  is  i n which they  they  rule,  molecular  of  a large  the  define eight  the  octant  of  to  i n the  octant  however,  type  the  s h o u l d be o p t i c a l l y  electrons  studies  revealed  symmetry  atoms o f  the  This  and t o  transition  chromophoric  in relation  the  symmetry  arises,  chromophore,  to  transition  if  the  of  —*TT*  in stereochemical  the  given  n  environment.  chromophore the  the  Optical activity  pertubation  value  planes  1 *3  obtained made by the  be  the  carbonyl  largely  and by  its  5  true position about  the  i n the  quantitative  although D j e r a s s i groups  has  the  most  are  a p p l i e d , eg.  group the p l a n e of rather  part  the  an i m p o r t a n t  nearer  its  tool  amenable  steroid  the  influences  to  framework  have on t h e  its  has  that  the  axial  atom.  Thus i t  substituents (ca.+  or  has  shift  the  nearer  it  is  of  the  the  the  of  the  octant  the data  rule  steroidal  class  of  developed  ketones.  compounds  studies.  carbonyl  for  studying centers  chromophore.  of°c-halocyclohexanones  that  have to  C - h a l o g e n and C=0  have  been u s e d  to  the ° c - h a l o g e n  e q u a t o r i a l <<-halogen  corresponding band.  makes  Consequently  and u n s a t u r a t e d  configuration  upon t h i s  a nodal  quantitative  and s u b s e q u e n t l y  the  to  Despite  i n f r a r e d c a r b o n y l band t o  whereas  carbonyl  studies.  this  properties  rules  found wide a p p l i c a b i l i t y  numerous  been o b s e r v e d ^  effect  between  to  substituents  equatorial  20cm~^),  little  is  been u s e d e x t e n s i v e l y  various  alkyl  empirical  effect.  basis of  substituents,  i s o p r o p y l ^ ^ and t - b u t y l . ^ - ^  stereochemical  i n some d e t a i l ;  assign  repulsion  studies  Cotton e f f e c t  been s t u d i e d  has  it  i s known  several  which a lack of  rule,  has  The s p e c t r o s c o p i c  uent  less  f u s e d - r i n g s t r u c t u r e of  the  uency  e f f e c t s of  and t h e  the  little  various  a substituent  empirical  Cotton e f f e c t  readily  of  in stereochemical  the  very  semiquantitative  effect,  octant  Historically  The r i g i d  the  methyl,"^  restrictions  upon t h e  from the  eg.  chromophore  rigorous  imposes  it  studied  a number o f  greater the  At p r e s e n t  contributions  i n some d e t a i l ,  For  as  octant.  The  higher  axial  freq-  substit-  electrostatic  dipoles,  which w i l l  be  6 g r e a t e s t when t h e this  halogen  observation.  atom i s  equatorial,  The u l t r a v i o l e t  adequately  maxima a s s o c i a t e d  explains  with  the 18  saturated of  about  c a r b o n y l chromophore undergoes 5 mp  moved t o  when t h e  the  axial  The C o t t o n e f f e c t very  sensitive  equatorial ion  to  shifts  of  I F)  the  the  28  equatorial,  mn when t h e  shift  but  is  bromine  orientation. <=£ - h a l o c y c l o h e x a n o n e s  the o r i e n t a t i o n  and a m p l i t u d e o f  + 20  by about  halogen substituent  substituent (ca.  - b r o m i n e atom i s  longer wavelengths  atom p o s s e s s e s  a hypsochromic  of  has  the  anomalous  halogen  little  Cotton e f f e c t ,  is  effect  atom.  effect  whereas to  An  upon t h e an a x i a l  higher  and p r o f o u n d l y i n f l u e n c e s t h e  similarly  posithalogen  wavelengths  amplitude.  These"  haloketone  ' -, ' - 1 9 rule", :  observations  were  a forerunner of example.- 1  (3,  and 4 ° c - b r o m o of  stated  octant  as w e l l  as  the  ive Cotton e f f e c t .  the  exhibit  The a x i a l  by an  exception  (3 , R i = B r ,R2=H) positive  2 P -bromo  a much e n h a n c e d  4 £ -bromo d e r i v a t i v e With  illustrated  2°c-bromo  derivatives  exhibits  best  \ • '  -acetoxyandrostan-3-one  equatorial  s i m i l a r amplitude. however,  "axial  which i s  compound 17 P  =  and t h e  i n the  rule,  (3jR^=H,R2 Br)  (4,Rj=Br,R2=H), amplitude,  the  The p a r e n t  Ri=R2=H)  effects  first  exhibits of  Cotton  derivative positive  a strong  fluorine,  negat-  halogen  7 substituents  obey  atom e x h i b i t s halogen is  observed Cotton  significant  is  rear  pronounced  attributed  in sign  to  in p  to  2 1  octant.  The two e x p l a n a t i o n s 2 1  ,  halogen  rule. to  axial  The f l u o r i n e * " * 2  that  of  the  °c-halogen  determine  the  other  substituents  sign of  and X - p o s i t i o n s  and  the  Cotton effect  R  2  =  H)  offered (b)  also  the  of  have  3-keto  6 P -halogen  substituents  location  the  The n e g a t i v e  ( 5 , Ri=X,  conformation  octant  effect.  c o n t r i b u t i o n of  negative  the  as  i n f l u e n c e upon t h e  substituents  but  opposite  substituents  The n e g a t i v e R2=X)  general  The c o n t r i b u t i o n o f  so  Halogen  more  an e f f e c t  atoms.  generally  the  is  of  c o n t r i b u t i o n of  more d i f f i c u l t  are:  (a)  ring  r i n g A maintains  atom a c t u a l l y  halogen  lies  to  in a f r o n t ^  steroids. (5,Ri=H,  atom i n  a  5 "TT-halogen  rationalize.  A adopts  a chair  a  a  boat-like  conformation negative  octant.  22 Experimental example  evidence  illustrates  position  of  been w e l l  the  have  localized lie  evidence  somewhat  plane of  siderable these  indicates  containing the  to  that  octant the or  C=0  has  vacant  been u s e d into  bond h a s  the  charge d e l o c a l i z a t i o n  is  are  not  oxiran  The d e believed  The o v e r l a p  p-orbital to  the  studies.  and  systems.  ring.  This  i.e.  empirical  these e l e c t r o n s  w i t h the  rule,  cyclopropane  three-membered  carbonium ions  this  the  explanation.  delocalized electron  charge d e r e a l i z a t i o n  ions;  of  by t h e o r e t i c a l  these d e l o c a l i z e d o r b i t a l s cyclopropyl  latter  plane perpendicular  orbitals  i n the  the  one w e a k n e s s  defined either  Spectral groups  favors  of  of  explain  the  cyclopropyl ring indicated  to  by  the  conof  8  large of  (c_a. 3 ppm.) d o w n f i e l d s h i f t  the r i n g hydrogen atoms.  als  i s also  of the proton  The p r e s e n c e  i n d i c a t e d by t h e u l t r a v i o l e t  resonances  of d e l o c a l i z e d spectra  orbit-  o f <>c - e p o x y ^ ^  25,26 and °£ - c y c l o p r o p y l  ketones.  band o f t h e c a r b o n y l c h r o m o p h o r e slightly  higher  indicates 27  studies  '  o f °c - e p o x y  the presence  of a large  to  and °c - c y c l o p r o p y l k e t o n e s  of d e l o c a l i z e d o r b i t a l s .  Recent  number o f compounds h a v e shown t h e  and °c - c y c l o p r o p y l r i n g s  to the Cotton e f f e c t  opposite  i s e n h a n c e d and s h i f t e d  28  cc -epoxy ions  the a b s o r p t i o n  wavelengths.  The C o t t o n e f f e c t also  In g e n e r a l  make s i g n i f i c a n t  contribut-  o f the c a r b o n y l group which are  i n s i g n t o t h o s e made by a l k y l  and h a l o g e n  groups.  27 Also  i t h a s been shown  makes no s p e c i a l  that  a nonconjugated  c o n t r i b u t i o n to the Cotton  When a d o u b l e bond i s p l a c e d  transition ketones  i s analogous  longer wavelengths described  as TT - > T T * ,  shows v e r y of  intense  region.  enhanced  ( Araax  330 rn y ) .  appears  absorption  t h e n —> TT * t r a n s i t i o n  effect.  ketone  i s characterized  transition  ( £ — 100)  of  saturated  and s h i f t e d  The o t h e r  to  transition,  i n t h e r e g i o n 260 t o 2 2 0 ^ ^ (€ — 1 0 , 0 0 0 ) .  i s very  by  The l o n g w a v e l e n g t h  to the n ~ » T T *  but i s n o t i c e a b l y  ring  i n c o n j u g a t i o n w i t h a keto  g r o u p t h e r e s u l t i n g <£, p - u n s a t u r a t e d two maxima i n t h e u l t r a v i o l e t  cyclopropyl  The C o t t o n  sensitive  to  and  effect  conformational  3 29 changes  '  and r e c e n t l y  a modified octant  r u l e h a s been p r o -  30 posed  to account  f o r the e m p i r i c a l d a t a .  w i t h p l a n a r chromophores  t h e atoms  For  cyclohexenones  l y i n g o f f the plane  determine  9 the C o t t o n e f f e c t , chromophores  whereas  the Cotton e f f e c t  of nonplanar  i s d o m i n a t e d by t h e o r i e n t a t i o n  The TT — * TT * t r a n s i t i o n  i s also  to  i n conjugated  a similar transition  oc,p - u n s a t u r a t e d  keto  optically  of the double  active  dienes.  g r o u p may be r e g a r d e d  planar  chromophore.  as an i n h e r e n t l y  o f <£, P - u n s a t u r a t e d  keto  — * TT * and TT —> TT * t r a n s i t i o n s  keto  '  1 , 3 - d i e n e s h a s been a p p l i e d t o d e t e r m i n e  conformation n  31 32 The h e l i c i t y r u l e  u  g r o u p s have C o t t o n e f f e c t s  circular  ed t h a t region  several  there  exceptions  The u l t r a v i o l e t unsaturated geometry  ketones  f o r non-  the  absolute  G e n e r a l l y the  o f n o n p l a n a r <£•> ^ - u n s a t u r a t e d sign;  i n the r e g i o n  to t h i s  a r e two o p t i c a l l y  (280 t o 200 my  groups.  of opposite  d i c h r o i s m measurements  indicated  analogous  Hence a n o n p l a n a r  in dissymmetric  and i s  bond.  rule,  active  however  400 t o 2 0 0 m p h a v e  and have  bands  recent^'  also  reveal-  i n t h e TT — T T *  ).  and c i r c u l a r  dichroism spectra of  are c r i t i c a l l y  of the system.  dependent  upon t h e m o l e c u l a r  Thus i t h a s been o b s e r v e d  that  34 phenylcholestanones  exhibit  an e n h a n c e d  300 ran and an e n h a n c e d C o t t o n e f f e c t g r o u p i s i n an a x i a l  position,  absorption  band a t  o n l y when t h e p h e n y l  e g . 3<C-phenylcholestan-2-one  (6).  35 The compound 4 , 4 - d i m e t h y l c h o l e s t - 5 - e n - 3 - o n e unenhanced  absorption  5-en-3-one  (8)**^ e x h i b i t s  ition  also  band ( A m a x 293 my , £ =38)  between  shows an whereas  a s l i g h t l y enhanced n — T T *  ( T^raax 289 mv , e = 5 9 , A € 290 = 2 . 9 5 ) .  overlap  (7)  t h e two u n s a t u r a t e d  i n d i c a t e d by t h e a p p e a r a n c e  Partial  cholesttrans-  orbital  g r o u p s o f compound (8)  o f a new o p t i c a l l y  active  is  10  0  P hv^ (6)  absorption  (7)  band  ( "Amax 217  37 of the  postulates  '  '  have It  A C 218 -  3  -6).  A number  t h e C=G g r o u p o v e r l a p s  of  the O O group.  This  n —> T T * t r a n s i t i o n  been p u t f o r w a r d as t o t h e n a t u r e  i s generally  of  transfer  mH,^ = 1300  38 39  orbital overlap.  charge  (8)  accepted  that a T T - o r b i t a l  with both a p - o r b i t a l  model e x p l a i n s  and a l s o  band ,TTc='C «*—»"TT* c=o .  and a T T * - o r b i t a l  the observed  rationalizes  of  enhanced  the appearance  of a  Cholest-5-en-3-one  (8)  36 is  an example  orientation ily  o f weak o r b i t a l  the r o t a t o r y  There  a r e , however,  where  strong  effect  power o f t h e n—>  numerous e x a m p l e s ^  o r b i t a l overlap  effect  double bond,  In such c a s e s  the  o f t h e d o u b l e bond i n f l u e n c e s b u t d o e s n o t n e c e s s a r -  dominate  Cotton  overlap.  TT* t r a n s i t i o n .  of P,Y-unsaturated  ketones  is indicated.  In these cases the  i s d o m i n a t e d by t h e a b s o l u t e  conformation of the  e g . norcamphor  (9)  ( A € 310=-0.30) whereas  exhibits  a v e r y weak  dehydronorcamphor  (10)  Cotton shows a  40 strong p o s i t i v e Cotton effect ( A € 305 = + 4 . 7 ) . When s t r o n g o r b i t a l o v e r l a p i s i n d i c a t e d i t i s convenient to t r e a t the ketone  A, f-unsaturated  system  as an i n h e r e n t l y  dissymmetric  41 chromophore. in  T h i s viewpoint has l e d to u s e f u l  the determination  of absolute  configuration  applications  and c o n f o r m a t -  11 ion.  41,42  .0  .0  (10)  (9)  When t h e d o u b l e bond i s moved s t i l l carbonyl  dichroism spectra androstan-17-one  n i l , e g . the u l t r a v i o l e t  (11,  "X max 294 mp, 6 = 4 3 , A € 295 = + 3 . 5 5 ) and ketone,  3P-hydroxyandrost-9(ll)-en-17-one  9\max 295 mp, € =43, A d 3 0 0 = + 3 . 7 0 ) _ the l a t t e r  are n e a r l y  transfer  0  H O  (11)  band.  identical;  compound shows no e v i d e n c e o f a  0  HO  and c i r c u l a r  o f t h e c a r b o n y l c h r o m o p h o r e o f 3P> - h y d r o x y -  t h e Y, £ - u n s a t u r a t e d  addition  the  o f o r b i t a l o v e r l a p between t h e two u n s a t u r a t e d  g r o u p s becomes v i r t u a l l y  in  away f r o m t h e  g r o u p i n a s y s t e m s u c h as t h e s t e r o i d n u c l e u s ,  possibility  (12,  further  (12)  charge  12 In t h e  case of  nonconjugated  t h o u g h t h e r e may be no d i r e c t the  unsaturated  electronic  o l e f i n i c and c a r b o n y l g r o u p s ,  atoms about ion of  the  Barton43 sation  i  of  partial  the  study of  structure  of  the  fact  r a t e s of  benzaldehyde with v a r i o u s  15,R=CH3). series  the  This  (13,  R=CHg)  to  The mechanism has reversible  interaction  steric  c a r b o n y l g r o u p may v a r y  o l e f i n i c center. n  the  ketones,  according was f i r s t  to  of  the  the  locat-  illustrated  alkali-catalyzed  3-keto  by  conden-  triterpenoids  give benzylidene  the  between  arrangement  been shown^4>45 t o  s t e p s up t o  even  of  derivatives consist  formation of  the  of  a  anion  Ph  (13)  from It  (14)  (14)  f o l l o w e d by an i r r e v e r s i b l e  was o b s e r v e d  that  as  positions  in rings  s t u d y was  extended'**''  (partial similar terms of  results the  that  of the  the  13,  to  47  of  r a t e of  p o s i t i o n of  group r a t e  reaction  reference each  an u n s a t u r a t e d for  changed.  3-keto  the  (15).  various The  steroids  of P -decalone  By e x p r e s s i n g  factors,  factors  also  of  and d e r i v a t i v e s  a saturated  yield  s h i f t e d to  include a series  R=H)  group r a t e  e l i m i n a t i o n to  d o u b l e bond was  being obtained.  rate of  the  B , C , D the  structure  by a s e r i e s istic  (15)  rate  with  in  compound m u l t i p l i e d  of which i s center,  structurally  it  characterwas shown  analogous  steroidal  13 and  triterpenoid  shows t h a t  ketones  i n the  buttressing"  of  triterpene  the  the  i n f l u e n c e of  t h e P - m e t h y l groups  (at  C4  conformational  to  ring  in  atomic  i s minor.  i n r a t e w i t h the  unsaturation  is  p o s i t i o n of  distortion  transmitted  coordinates.  through the angles  Such an e f f e c t  that  in the  of  for  d o u b l e bond i s  at  the that  the o r i g i n a l s i t e  molecule  and  and s l i g h t  of  ultimately  alterations  is described  t r a n s m i s s i o n would a l s o  Cotton effect  and t r i t e r p e n o i d  the O . R . D .  location  the  advanced  as  "con-  of  be e x p e c t e d  unsaturated,  the  curves  of  ketones.  Djerassi  s u c h compounds a r e  double bond.  An a t t e m p t e d  to  be  nonconjugated  4R  steroidal  "axial  transmission".  Conformational reflected  the  introduced  This  and C I Q ) on  The e x p l a n a t i o n  A v i a f l e x i n g of v a l e n c y  formational  related.  series  group r a t e f a c t o r s variation  were q u a n t i t a t i v e l y  4Q  '  has  shown  sensitive  to  correlation  the  with  AC  Barton's the  rate  studies,  however,  background c o n t r i b u t i o n  pounds, TT-*.7T*  due l a r g e l y transition  to of  the the  to  was u n s a t i s f a c t o r y . the O . R . D .  t a i l i n g of olefin,  is  the  curves  of  optically  large  Since  0  these  com-  active  and c r i t i c a l l y  depend-  49 ent  upon t h e  data  location  of  transmission  ween t h e  C D . spectra  a number o f this  thesis.  r a t e of  ketones  was f e l t  manifestation  E s t a b l i s h i n g the  and t h e  steroidal  the  it  i n the C o t t o n e f f e c t  benzaldehyde condensation.  of  double bond,  m i g h t be more u s e f u l i n r e l a t i n g  formational  for  the  and t h e  that C D . of  rate  relationship  benzaldehyde  was t h u s one o f  conof bet-  condensation the  objects  14 Another  i l l u s t r a t i o n of  conformational  transmission  is  50 provided  by a c o m p a r i s o n o f  lanostan-3-one tion  of  (16a)  (16a)  and l a n o s t - 8 - e n - 3 - o n e  a f f o r d e d o n l y the  acid-catalyzed or  16c)  ostan-3-one mixture  of  catalyzed similar  resulted (16b).  2°c -  spectra  indicate  (17)  e q u i l i b r a t i o n of  in a quantitative  either  concepts  (16&) the  yield (17a)  of  either  and  the of  (17b)  or  however,  (17c)  gave  afforded  demonstrating  the  concept  above example  has  an  and s i m i l a r l y o f  b r o m i n e atom i s  equatorial  a  (5%).  ring A conformation.  (16c),  isomer  2<< - b r o m o l a n -  and 2P - b r o m o l a n o s t - 8 - e n - 3 - o n e  transmission,  of  In a d d i t i o n  2  In a d d i t i o n t o  b e a r i n g on p r e s e n t  (17c),  (  e q u i l i b r a t i o n of  mixture.  (16b) .  2  Monobromination of  (95%)  Monobromina-  R, - H,R£- Br R = B r , R =H  (HBr/HOAc/CHClg)  conformational  U.V.  2<£ - i s o m e r  with  (17a).  Ri = R = H  (a) (b) (c)  (16)  (16b  bromination experiments  Acida of  important I . R . and  (17b)  in a l l  and cases.  50 This for  can  best  be e x p l a i n e d  r i n g A i n the  t h e work r e p o r t e d compounds o f obtained, detail  by p o s t u l a t i n g  2P -bromo i s o m e r s in this  thesis  controversial  and t h u s  i n the next  this  ring  subject  section.  (16c  a boat  conformation  and 1 7 c ) .  the C D . s p e c t r a  As p a r t of  A c o n f o r m a t i o n have will  be d i s c u s s e d  in  several been some  of  Aliphatic because of  the  ketones  e x h i b i t weak C o t t o n  conformational mobility destroys atomic  environment of  ational mobility is the  generally  conformations  be e n h a n c e d , activity  the  the  carbonyl group.  predominates  and s t r u c t u r e rotation  the  the  c a n more e a s i l y is  when one  Cotton effect  between  will  observed  be made.  hindered i s  asymmetry  When c o n f o r m -  h i n d e r e d , o r more p r e c i s e l y ,  and c o r r e l a t i o n s  a s y s t e m where  much o f  effects  of  generally  optical  An example  p r o v i d e d by t h e  of  17-acetyl  51 steroids.  It  has  been o b s e r v e d  t h e P - c o n f i g u r a t i o n as effect  is  acetyl  group i n the  effect.  positive,  As p a r t  of  t h a t when t h e  i n 17-acetylpregnanone  whereas  17=c - p r e g n a n o n e  spectra were  of  a large  measured.  relate  to  preferred  the  t h e work r e p o r t e d  in this  been t h e  group  the  Cotton  w h i c h has  a negative thesis  has  the  Cotton  the C D .  (19) number o f  16-substituted,  A d i s c u s s i o n of  these r e s u l t s  problem o f d e t e r m i n i n g the  the  (19),  exhibits  conformation of  One o f  (18)  "^-configuration,  (18)  acetyl  the  17-acetyl  problems a s s o c i a t e d  interpretation  of  17-acetyl and how  configuration sidechain w i l l  with c i r c u l a r  C D . spectra  steroids they and  the  be g i v e n .  d i c h r o i s m has  e x h i b i t i n g two maxima  16 of o p p o s i t e  sign for  Examples of  such curves  300  mp  region of  particularly  a single optically are  active  p r o v i d e d by t h e  a number o f  steroidal  3-ketotriterpenes;  transition.  C D . spectra  in  and t r i t e r p e n o i d  and even by more  the  ketones,  conformation-  53 ally  rigid  structures,  Three proposals curves.  For  the  e q u i l i b r i u m has is  have  w o u l d be e x p e c t e d  species curve  is  the  is  rigid  solvent  these  molecules,  eg.  (20),  accepted,  expected  Fundamental to  dependence of  i n the  to  then  transition  the  short  increase  at  solvational  this  hence  hypothesis  the  expense  of  if  the  the  Such an e q u i l i b r i u m w o u l d and t e m p e r a t u r e  methylcyclohexanone  solvated  l o n g waveSfi  (21b)  sign is also  '  the C D .  3  account  (see  for  a curve  a conformational  be e x p e c t e d  dependent, '  the  solvent and t e m p e r a t u r e " d e p e n d i s o f e n c h o n e (20) is observed.  A s e c o n d phenomenon w h i c h c a n opposite  In species  w a v e l e n g t h band o f  (21a)  (20)  solvent  a  solvated  due t o  1.  irregular  55  length band. The e x p e c t e d ence o f the C o t t o n e f f e c t of  two maxima o f  the  is  figure  C D . curve.  temperature;  54  ing  the  p o p u l a t i o n of  energy  , see for  on l o w e r i n g t h e  higher  (20)  account  been p o s t u l a t e d .  an i n c r e a s e  view t h a t  isofenchone  been made to  case of  a considerable  addition  eg.  eg.  to  be  exhibit-  equilibrium.  considerably  (+)-trans-2-chloro-5-  figure  1),  which i s  present  17  240  260  280  300  Figure Circular  Dichroism curves  320  340  1  of:  i s o f e n c h o n e (20): ethanol, 25° (+)trans-2-chloro-5-methylcyclohexanone (21) e t h e r : i s o p e n t a n e : e t h a n o l , 5:5:2 (EPA) 2 5 ° e t h e r : i s o p e n t a n e : e t h a n o l , 5:5:2 (EPA) - 1 9 2 ° carbon t e t r a c h l o r i d e 25°  360  18 In s o l u t i o n as a mixture o f the d i e q u a t o r i a l (21b) for  forms.  The octant  (21a) and d i a x i a l  r u l e p r e d i c t s a p o s i t i v e Cotton e f f e c t  (21a) and a n e g a t i v e Cotton e f f e c t f o r (21b). In both o f the e x p l a n a t i o n s above the s i m p l i f y i n g assumpt-  ion has been made that  the e q u i l i b r i u m  involves only  two s p e c i e s .  54 On the b a s i s o f t h i s assumption, c a l c u l a t i o n s the s u p e r p o s i t i o n  have shown that  o f two Cotton e f f e c t s o f s i m i l a r amplitude  but  opposite sign with a separation  mP  r e s u l t s i n a r e l a t i v e l y weak C D .  maxima separated by about 30  IIIP  .  o f t h e i r maxima o f 1 to 20 curve w i t h apparent  E m p i r i c a l l y i t i s observed  that u s u a l l y one and o f t e n both of the maxima o f an a l t e r n a t i n g s i g n curve have very low i n t e n s i t y .  I t i s obvious from the  above arguments based on the s o l v e n t  and temperature dependence  of the C.D. curve that  be d i f f i c u l t  i t w i l l often  to d i s t i n g u i s h  between a s o l v a t i o n a l o r c o n f o r m a t i o n a l e q u i l i b r i u m , 3-one ' 5 2  5 6  (22), *X ( A O , E P A : 25°, 330(-0.06), 295(+0.7) ; -192°,  330(-0.21), 290(+0.18). the vapor s t a t e then only eg.  eg. lupan-  (-)-carvone  59  (22)  When the i r r e g u l a r curve p e r s i s t s i n the l a t t e r e x p l a n a t i o n  (23) , A ( A € ) :  i s justified,  370(-0.5), 330(+2.6).  (23)  A further  19 weakness to  of  the  rationalize  solvational hypothesis the  s o l v a t i n g power o f  Low t e m p e r a t u r e  o  enhancement  with  an o p t i c a l l y a c t i v e  structuring" account  for  arguments magnetic arising  of  has the  the  of  the  power  if  l e d to  the  it  is  originating  that  i.e.  |A&| < 1 . 0 .  at  the  of  0-0  the  1200  (22,  at  p r o p o s a l have n o t expected  to  From t h e exhibiting  nearly  -192°)  and s o l v e n t  the  On t h i s  composed w h i c h a r e  and  latter  b e i n g the  basis,  900  dich-  the  features  i n terms  (-)  carvone to  cm  - 1  ,  negative,  at  be e x p e c t e d  even  chosen  two maxima o f  it  at can  alternating  very  curves  25°).  on t h e  low  be s e e n sign for  "forprog-  - 1  "non-totally have  been  of  The  lupan-  tempera-  basis  been d e f i n e d , however v i b r a t i o n a l  be i m p o r t a n t  cm  the C D . c u r v e s  (23,  of  frequency  same 1200  hypothetical  i d e n t i c a l to  dependence  examples  the  b a n d , complemented by a p o s i t i v e ,  i n combination with a s i n g l e mode.  and  components  symmetric,  cm~^ s t r e t c h  ression  symmetric"  may  may a l t e r n a t e when  Most o f  a totally  it  Theoretical  s i g n of  and i n f a c t  band s y s t e m ;  is  "vibrational  both e l e c t r i c  then the  bidden"  ture  of  a C D . band.  assumed t h a t  c o n s i s t i n g of  progression  considerassociated  c a r b o n y l d i c h r o i s m band c a n be r a t i o n a l i z e d  "allowed"  3-one  proposal  i n s i g n of  be i n v a r i a n t  i s weak,  a v i b r o n i c scheme  difficult  solvents.  produce  A consideration  from molecular v i b r a t i o n s ,  rotary  often  is  d i p o l e moments have s i g n i f i c a n t  r o i s m band n e e d n o t the  band.  alteration  transition  it  vibrational fine structure  recently  show t h a t  that  hydrocarbon  C D . measurements  able  is  of  this  structuring  temperatures. that  a C D .  a single  curve  chromo-  20 p h o r e may be r a t i o n a l i z e d lated  phenomena.  During  thesis,  several  A brief  d i s c u s s i o n of  t h r e e phenomena: brium,  by o n e , the  course of  C . D . s p e c t r a of these w i l l  solvational  vibrational  two o r  three of  the  t h e work r e p o r t e d  alternating  s i g n were  be made w i t h r e s p e c t  equilibrium,  structuring.  all  postuin  this  obtained. to  conformational  the equili-  21 DISCUSSION The and  intense  ketones  ization  ultraviolet  has proved u s e f u l f o r the d e t e c t i o n  o f these chromophores.  fundamental c r i t e r i a are  elemental  satisfactory purity,  analysis elemental  a sufficient 1%)  analysis  steroidal point U.V.  i s a necessary  absorption,  however,  but w i l l  A  can not  have  in either  With  criterion  amounts  i n a sample o f a  for  is  (ca.  saturated the m e l t i n g  a profound e f f e c t  on t h e  spectrum o f the sample. In  a consideration  of the e f f e c t s  bonds on t h e U . V . and C . D . s p e c t r a originally  postulated*^'^  interaction jugation"  between  that  was b a s e d  largely  band at 239 mp  could occur  carbon  on the o b s e r v a t i o n  ( £ =70,  =0.2)  3P -hydroxyandrost-5-en-17-one i s that  trace 17-one  atoms.  charge  v i a weak This  "con-  postulate  C O  '  o f a weak  i n the e l e c t r o n i c (24a).  transfer  absorption  spectrum of  An a l t e r n a t i v e  explanat-  t h i s weak a b s o r p t i o n band i s due t o t h e p r e s e n c e  amounts o f a d i e n e (25),  double  o f t h e c a r b o n y l g r o u p , Mason  a long range,  t h e two g r o u p s  through the saturated  of nonconjugated  CO  ion  neither  Thus t r a c e  may n o t be r e f l e c t e d  o r the a n a l y s i s ,  compounds  requirement  though d e s i r a b l e ,  for purity.  impurity present  ketone  organic  f o r a l l c l a s s e s o f compounds.  requirement  of a diene  and most  and m e l t i n g p o i n t d e t e r m i n a t i o n .  but a sharp m e l t i n g p o i n t ,  to u l t r a v i o l e t  olefins  and c h a r a c t e r -  The two t r a d i t i o n a l  f o r p u r i t y of c r y s t a l l i n e  be c o n s i d e r e d n e c e s s a r y respect  absorption of conjugated  i m p u r i t y such  ~ \ max 290 mp (€ 9 0 ) ,  as a n d r o s t - 3 ,  236 my  (£ 22,400).  of  5-dieneThe U . V .  22 spectrum of  a c o m m e r c i a l sample of  l e n g t h band at  236  mn  (€=143).  ion  scheme o f  recrystallization,  the  corresponding acetate  (24b),  (24a)  also  showed a s h o r t  However by a s t e p w i s e followed the  purificat-  by c h r o m a t o g r a p h y  peak a t  236  my  wave-  was  of  elimin-  36 ated.  S u b s e q u e n t l y Mason has  (24a, (24b, also  has  R=H) R=OAc)  suggested  demonstration  that  reported  a similar result  (25)  that  the  (24a)  and  (26)  i m p u r i t y was t h e  does not  exhibit  diene  (25).  a charge  The  transfer  36 band,  plus a d d i t i o n a l evidence provided  by M a s o n ,  substant-  iates  the  interaction  is  latively  view t h a t short  the  range  charge  transfer  and o p e r a t e s  through  The q u e s t i o n o f w h e t h e r o ~ - b o n d s c a n transfer  interaction  observation  of  unsaturated  ketones,  (€  1330).  systems  This  has  the  6 4  transfer eg.  is  shown t o  been i n t e r p r e t e d the  central  do n o t  a charge  The a p p e a r a n c e  such  allowing  has v e r y r e c e n t l y  c o u p l i n g of  (26), of  the  a T T c c —*  307  mP  TT * co  (€  the  geometry  in  of  charge the  V, 6  79),  a favorable  in  geometry.  geometry  twoTT-systems through o v e r l a p  In g e n e r a l T, c> - u n s a t u r a t e d defined  in  (26)  -  224 mH  transition  be c r i t i c a l l y d e p e n d e n t on  C 3 - C 4 <3 - b o n d .  possess  be i n v o l v e d  been r e o p e n e d by  A max:  re-  space.  band i n a number o f  i n terms  of  and h e n c e  with  ketones do  not  23 show t h i s  type of o v e r l a p .  The r e s u l t s  o f a study o f the long range e f f e c t s  c e n t e r s on t h e C . D . s p e c t r a o f 3 - k e t o s t e r o i d s  of o l e f i n i c  are summarized i n 5  Table 52  1.  Some r e c e n t l y  published results  of V e l l u z  and O u r i s s o n  65 '  are also  are  i n c l u d e d i n the t a b l e ,  given i n f i g u r e  2.  and a l l s t r u c t u r a l  Most o f t h e s a m p l e s  e x h i b i t e d weak U . V . a b s o r p t i o n maxima in  a d d i t i o n t o t h e 290 mH  Tt  is felt  ional  absorption  amounts not  bands  explanation  are, i n every  t o have  study  i n t h e r e g i o n 260 t o 230 mp  case,  of h i g h l y absorbing i m p u r i t i e s .  be e x p e c t e d  used i n t h i s  band o f t h e c a r b o n y l  the o n l y s a t i s f a c t o r y  formula  any m e a s u r a b l e  chromophore.  i s that  the a d d i t -  i n d i c a t i v e of  These  trace  i m p u r i t i e s would  i n f l u e n c e upon t h e C . D .  spectra. An e x a m i n a t i o n series  (27 t o 36)  groups.  reveals  that  at Cy ( 3 0 , 3 1 )  of the saturated  the i n t e n s i t y  analogues  when t h e d o u b l e bond i s l o c a t e d at  C T 2 (36)  the unsaturated  upon t h e c i r c u l a r These r e s u l t s the  i n T a b l e 1.  4-demethylated i n t o two  i n r i n g B (29,32)  (27,28).  On t h e o t h e r  i n r i n g C (33,34,35)  center  appears  t o have  that  exocyclic  little  effect  rates of  which are  i n contrast  i s quite  hand,  group.  benzaldehyde c o n d e n s a t i o n ^ c a n be s e e n  from  or  c a n be compared w i t h t h e r e l a t i v e  It  or  o f t h e maxima v a r i e s  dichroism of the carbonyl  alkali-catalyzed  listed  f o r the  t h e compounds f a l l  When t h e d o u b l e bond i s l o c a t e d  exocyclic that  of the C . D . r e s u l t s  also  to the C . D .  results,  the r a t e of condensation  sensitive  location  o f t h e d o u b l e bond f o r a l l o f t h e compounds.  to the In  this  24 TABLE 1 46 Compound  17P  7v max  -hydroxyandrostan-3-one  (27)  ref.  294 (+6.96) 295  cholestan-3-one  (A€. )  Relative rate  188  (+0.90)  5  295 (+1.13)  5  295 (+1.56)  65  325(-0.04),294(+0.39)  65  (28)  182  17 p> - h y d r o x y - 7 - m e t h y l e n e a n d r o s t an-3-one  (30)  cholest-6-en-3-one  (29)  7-methylenecholestan-3-one ergost-7-en-3-one ergost-8  (32)  (14)-en-3-one  (33)  A9(1D-dehydrotigogenone A^-dehydrotigogenone  *  calculated  (36)  (16a)  lanost-8-en-3-one  (34)  (35)  12-methylenetigogenone lanostan-3-one  (31)  (17a)  from O . R . D .  295 (+1.54)  365  295 (+0.67)  47  295 (+1.15)  94  295 (+0.88)  221  294 (+0.93)  380  295 (+0.90)  218  c a . 300 ( - 0 . 3 4 ) * 318(-0.11),290(+0.13) 320(-0.13),290(+0.14)  amplitude,  645  '  49  55 100  52  o f . ( 4 6 ) , Table 2.  25  (36)  (16a)  Figure  2  26 regard  it  s h o u l d be n o t e d  that  the  relative  rates  for  ergostan-3-  46 one  (37,  188)  for  the  other  for  the  ring  and t i g o g e n o n e saturated  (38,  174)  analogues  B unsaturated  are  (27,  28).  rates  maxima,  and the  and c i r c u l a r  Despite of  but  latter  (29) the  d i c h r o i s m can not  between  be made,  and e r g o s t - 7 - e n - 3 - o n e  former  compound e x h i b i t s  a much d e p r e s s e d  this  measurements  the  rates  re-  (38)  cholest-6-en-3-one C.D.  to  In a d d i t i o n even  compounds a c o r r e l a t i o n  (37)  lative  similar  l a c k of  reflect  r a t e of  correlation,  the  i.e.  both  show a d i m i n i s h e d a much e n h a n c e d  condensation. it  phenomenon o f  is  felt  that  both  conformational  sets  trans66  mission.  The r e l a t i v e  by c o n s i d e r i n g t h e a suitable  r a t e s have r e c e n t l y  A ^-enolate  model f o r  the  anion  transition  been  (partial state  (14a)  (15)  structure  i n the  7\ /  (32a)  rationalized  rate tl  14a)  as  determin-  27 ing  step to form the benzylidene d e r i v a t i v e  (15).  By t h e u s e  67 of D r e i d i n g models of  it  c a n be d e m o n s t r a t e d  a C 7 8 d o u b l e bond c a u s e s  deformation Cej-C in  This distortion  and r e s u l t i n g  a x i s of the groups  i n  turn  produces  strain  atom.  attached  rotation  at t h e s e c e n t e r s  by c o n v e r s i o n  Thus t h e f o r m a t i o n  of the  the tendency  for A^-enol  diminished,  i n a reduced  rate  the  d o u b l e bond i s l o c a t e d  upon r i n g A i s r e v e r s e d enhanced  rate  i s observed  The C . D . r e s u l t s the  octant  positive  octant  towards  w o u l d be e x p e c t e d  (32),  Cg i s displaced  Cotton  effect.  the  methylene  group  e x p e c t e d enhancement explanations grossly  a  facilitatis  (32).  When  a t C7 t h e e f f e c t  formation,  and an  by c o m p a r i n g  and u n s a t u r a t e d  (29)  a nodal plane. as i s o b s e r v e d .  towards  t h e major  3-keto  change  i n the  Thus a d i m i n i s h e d C . D . In e r g o s t - 7 - e n - 3 - o n e  a nodal plane,  again  F o r the 7-methylene-3-keto i s located  in a positive  o f t h e C . D . maxima  diminishing  steroids  octant  the subtle  w h i c h a D r e i d i n g model i s u n a b l e  (30,31).  and t h e  i s observed.  f o r t h e C . D . s p e c t r a o f compounds  o v e r s i m p l i f i e d and n e g l e c t  conformation  The  Cy i s d i s p l a c e d from i t s p o s i t i o n i n a  curve  the  is  can. s i m i l a r l y be r a t i o n a l i z e d  i s that  This  (29,30,31).  For cholest-6-en-3-one  diagram  the  of C^  of Cg.  as o b s e r v e d  A^-enol  D r i e d i n g models o f the s a t u r a t e d  steroids.  (32a) .  formation  at C g y o r e x o c y c l i c  to f a v o r  about  of C^ into  A^-enol  ed and s i m u l t a n e o u s l y resulting  angle  (<-direction)  an upward d i s p l a c e m e n t  be r e d u c e d  o f Cg i n t h e  t o C5 c a u s i n g  i n an a n t i c l o c k w i s e  causes  may e f f e c t i v e l y  trigonal  i s relayed  a downward d i s p l a c e m e n t  which s i m u l t a n e o u s l y  introduction  an upward d i s p l a c e m e n t  (  -direction.  that  (29) ; t o changes t o show;  These (32)  are  in ring A in addit-  28  | j i  (29)  (30, R-OH) (31, R = C H )  (32)  8  17  i ion the i n f l u e n c e o f the T T - b o n d bonds that i t r e p l a c e s  as compared to the two C-H  i s not known.  conformation i t i s worth n o t i n g would lead t o diminished  With r e s p e c t  to r i n g A  that any f l a t t e n i n g o f the r i n g  p o s i t i v e c o n t r i b u t i o n s from Cg and C . ?  When the double bond i s l o c a t e d i n r i n g C i t becomes more difficult  t o r a t i o n a l i z e the r e s u l t s .  By an extension  o f the  above arguments, however, the r e l a t i v e r a t e s o f compounds (33) to  (36) can be i n t e r p r e t e d i n terms of the s t r a i n induced i n  r i n g A.  S i m i l a r l y the C D . r e s u l t s f o r these compounds suggest  e i t h e r the atomic c o o r d i n a t e s or they vary effect.  of r i n g s A and B vary n e g l i g i b l y  i n such a way as t o g i v e a n e g l i g i b l e r e s u l t a n t  I f the arguments used to e x p l a i n the two s e t s o f meas-  urements are v a l i d ,  then i t f o l l o w s that a c o r r e l a t i o n between  the r a t e s o f benzaldehyde condensation and c i r c u l a r  dichroism  i s not expected. It i s p e r t i n e n t t o note that the C D . s p e c t r a o f 3-keto 52  t r i t e r p e n e s are more s e n s i t i v e eg.  taraxasterone  (39),  to u n s a t u r a t i o n  A(A£):  rone (40), "X(Ae): 293(+0.30).  i n r i n g C,  293 (+0.75), whereas  P -amy-  T h i s i s not unexpected as the  29  (39) positions  of  the  (40) 4«s  by c o n f o r m a t i o n a l  4P and 8 P - m e t h y l  transmission.  A comparison of spectra one  of  (17a,  effects quite  the see  likely  dichroism  is  groups  C^.  at  either  latter  that  is  opposite also  of  type of least  sign.  curve,  tenable  the  of  it  known t h a t  is  chair-boat  and  the  these e f f e c t s  presence  fact of  that  of  there  lanost-8-en-3transmitted  the  by  is  lanost-8-en-3-one are  to  conversion  to  see  two maxima (29)  explain  why t h e s e  so d i f f e r e n t l y f r o m t h e  A conformational the  difficult  equilibrium  exocyclic  keto  i n cyclohexane  is  group ring  is  gem-dimethyl  solvational equilibrium hypothesis it  it  circular  cholest-6-en-3-one  three hypotheses  the C . D .  triterpenes,  the C . D . spectrum of  by t h e  pounds s h o u l d s o l v a t e 1.  of  by t h e  Of t h e  since  Table  (16a)  As f o r  detection  The C . D . c u r v e  type.  rates or  suggests conformationally  facilitated  complicated  this  condensation  compound.  the  The e x p l a n a t i o n (17a)  the  compounds l a n o s t a n - 3 - o n e T a b l e 1)  i n the  g r o u p s w o u l d be i n f l u e n c e d  others  the  systems,  is  this is  the  two comlisted  more p l a u s i b l e lowers  of  since  barrier  and  in  the  to  30 conformationally possibly  lower  difficult  to  transmitted  this  see  barrier  why t h e s e  others with respect structuring (17a)  and  in  substituted  ion.  pounds and i t with  present  Table  measurements  since  the  will  the  2 includes  a large  subject, of has  the  again  be shown t h a t  alternative. i n accord  might  Both  with  this  help d i s t i n g u i s h  temperature  variation  conformation of  a number o f  such  are  recently  attentcom-  consistent  To s u b s t a n t i a t e  results  ring A  considerable  these r e s u l t s  subject.  a number o f  the  The v i b r a t i o n a l  received  C D . maxima o f  views on the  is  equilibrium.  3-keto steroids  Table 2 l i s t s  However i t  an a t t r a c t i v e  a conformational years  d o u b l e bond c o u l d  further.  weak C o t t o n e f f e c t s  two h y p o t h e s e s  In r e c e n t  the  A flexibility.  Low t e m p e r a t u r e  would support  of  two compounds s h o u l d d i f f e r f r o m  ring  (29) e x h i b i t  latter  still  hypothesis offers  hypothesis. the  to  effects  o u r own  data,  p u b l i s h e d by  52  Ourisson, listed  £t.al.  i n the  The s t r u c t u r a l  table  A number o f of  an a x i a l  saturated believed  displacement lieving  the  given i n figure  studies  have  m e t h y l g r o u p at  3-keto the  are  formulae f o r  steroid  indicated  the  leads  2Pto  or  that 4P-  of  (or  steric  determinations  of  and 4P  interaction the  the  )  2P  between  structures of  introduction  p o s i t i o n of  f l a t t e n i n g of  concurrently  10P  compounds  3.  f l a t t e n i n g occurs the  the  ring  w i t h the  methyl groups these  groups.  a  A.  It  is  lateral in  re-  X-ray  3B-iodoacetoxylanost-8-ene  68  and 3 P - a c e t o x y - 7 c c ,  (55)  ll«:-dibromolanostane-8cc,  9°c-epoxide  69  (56)  showed t h a t  the  bonds to  the  4P  and 10P  methyl  groups  TABLE 2 \max  Compound  (Ap  ref .  294  (+0.96)  295  (+1.17)  295  (+0.75)  2,2-dimethyl-17P -hydroxyandrostan3 - o n e (42)  303-290  (+1.52)  2,2-dimethylcholestan-3-one  3 0 2 - 295  (+1.93)  3 0 3 - 290  (+2.78)  294  (+1.37)  52  305  (-0.30)  52  295  (+0.96)  294  (+1.28)  303-295  (+2.11)  307-297  (+1.84)  52  301  (-0.47)  52  309  (+0.70)  312  (+1.07)  17P  -hydroxyandrostan-3-one  cholestan-3-one  (27)  (28)  2«c - m e t h y l c h o l e s t a n - 3 - o n e  (41)  (43)  2,2,17^ - t r i m e t h y l - 1 9 - n o r a n d r o s t a n 3 - o n e (44) 17P - h y d r o x y - 1 9 - n o r a n d r o s t a n - 3 - o n e 4,4-dimethylcholestan-3-one  (46)  4,4-dimethylcholest-5-en-3-one  (47)  4,4-dimethyl-17p 5 - e n - 3 - o n e (48)  -hydroxyandrost-  4,4-dimethyl-17P drost-5-en-3-one  -hydroxy-19-noran(50)  4,4-dimethyl-17p drost-5-en-3-one  -acetoxy-19-noran(51)  >  (45)  4,4-dimethyl-17P -acetoxy-19-norand r o s t a n - 3 - o n e (52) 2^ -bromo-4,4-dimethylcholest-5-en3 - o n e (53) 2 oc - b r o m o - 4 , 4 , 6 - t r i m e t h y l c h o l e s t - 5 - e n 3 - o n e (54)  52  52  32  Figure 3  33  (55) were  not  parallel,  c e n t e r s of 3.28  i  radius?  of  15°,  1.7  and a r e  of  the  steroids  studies  71  '  72  these s t u d i e s  has  and e n e r g y the  to  a lateral  been f o u n d f o r effects  of  carbon  3.2  w i t h an the  steric  chair  boat  forms of which the suggest  r i n g A conformation facilitated  calculations  7*3  (57a),  that  the  flat  chair  of  (57b)  two e x t r e m e s a r e  conformation  (57b)  ,  74  '  possible conformations  the  (57a)  correspond  been g r e a t l y  were  results  the  atom  +_ 0 . 1  A and  displace-  interference methyl  group  interactions  spectra.  Our u n d e r s t a n d i n g o f keto  between  i n agreement  A w h i c h has  from a c o n s i d e r a t i o n upon U . V .  difference  A; these values  about 0  and t h e  t h e s e m e t h y l g r o u p s was r e s p e c t i v e l y  0.03  ment o f  (56)  (57b)  by t h e of  d i p o l e moment  Allinger.  and t h e  is  3-  In  ring A considered  (57c)  (57c)  i n saturated  and  flexible (57d).  f a v o r e d when a  (57d)  The  34 1,3-dimethyl eg.  d i a x i a l methyl i n t e r a c t i o n  2P - m e t h y l ,  3-one  (R=CH„).  interaction  4I  -methyl,  3  Similarly  stituents  are e q u a t o r i a l ,  stretch  conformation  and 4 , 4 - d i m e t h y l c h o l e s t a n -  conformation  (57a)  data  i s expanded and h e n c e  frequency  is  i s f a v o r e d when t h e s u b -  also  In going from conformation  angle  (57a)  e g . 2<« - a n d 4 c C - c h o l e s t a n - 3 - o n e .  and N.M.R. s p e c t r a l  assignments.  i n r i n g A,  I n t h e c o r r e s p o n d i n g 1 9 - n o r compounds (R=H) t h i s  favored.  C2-C3-C4  2,2-dimethyl  i s l a c k i n g and t h e c h a i r  Infrared  i s present  75  i s expected.  support  (57a)  to  a decrease  these  (57b)  the  i n the carbonyl  This decrease  (c_a.6cm  1  )  is  72 observed  f o r cholestanone  d e r i v a t i v e s w i t h an a x i a l  methyl  g r o u p at Cg o r C ^ , b u t i s n o t o b s e r v e d f o r t h e c o r r e s p o n d i n g nor  compounds.  several about vent. axial  The p r o t o n r e s o n a n c e  19-nor-3-keto  0.2  steroids^  o f t h e 2P - m e t h y l g r o u p i n  suffers  an u p f i e l d  s h i f t of  ppm. on g o i n g f r o m d e u t e r i o c h l o r o f o r m t o b e n z e n e  This  i s i n agreement  methyl group adjacent The most  19-  w i t h the r e p o r t e d ^  shift  sol-  f o r an  to a carbonyl group.  convincing spectral  evidence  f o r these  assignments  72 is  p r o v i d e d by O . R . D .  and C . D . d a t a .  The r e s u l t s  T a b l e 2 o v e r l a p c o n s i d e r a b l y w i t h the O.R.D.  given i n  results  previously  72  reported  , and i n t h i s  measurements group  (41,  case a r a t i o n a l e  i s equally v a l i d .  partial  structure  b a s e d on e i t h e r  The p r e s e n c e  41a)  a C . D . maximum o f  diminished amplitude  negative  c o n t r i b u t i o n of the e q u a t o r i a l methyl group. compounds  (42,43,  27,28)  2cc-methyl  slightly  2,2-dimethyl  (cf.  produces  of a  partial  set of  due t o t h e weak  structure  42a)  The show  35 enhanced by t h e  C D . curves  but n o t  corresponding  19-nor  is  since  positive  contribution  ring  of  the  as  of  the it  For  structure  ring  flattening  the the  2 P -methyl  46a)  flattening  gem-dimethyl  the  groups  situation  decreases  of  the  the  pounds a r e  compatible  is  the  44a).  of  compounds  as  it  -methyl  positive  contrib-  become  the  the  2  compounds is  former  i n t h r e e ways:  the  less (16a,  complicated  negative  curve  probably  opposite  r i n g B methylene  Nevertheless  52a)  structure  as  the  17a,  46,  by t h e  contribution  fact  of  the  (52a)  positive.  more n e g a t i v e  shown  group d e c r e a s e s  axial;  4,4-dimethyl  groups which i s  contributions  for  negative, contribution  becomes more  the  that  partial  C D . amplitude  (46a)  ure  (44,  as  (44a)  Cg and C7 m e t h y l e n e  flattens.  partial that  axial;  increases  utions  with ring  would d i m i n i s h  becomes l e s s group  enhanced  (42a)  compatible  this  as  compound  (41a)  This  nearly  the  the  19-nor  indicative  of  the  groups,  weak C o t t o n  with a f l a t  of  to  effect  upon  the  w h i c h become  effects  of  these  r i n g A conformation; compound  (52,  a more  axial  partial 4I  3  less  com-  and  the  struct-  -methyl  \  36 g r o u p as i n t h e c h a i r  conformation  The C . D . r e s u l t s of  a flat  (42,43)  chair  since,  (57a).  provide strong  conformation  support  to the 2 , 2 - d i m e t h y l  from the octant  rule,  it  conformations would e x h i b i t  Cotton  Conversely,  forms o f the 4 , 4 - d i m e t h y l  one o r s e v e r a l  compounds  expected  t o g i v e weak C o t t o n e f f e c t s ;  a choice  between  not  the f l a t  be made on t h e b a s i s The e v i d e n c e  dimethyl-3-keto the  5-en-3-one  (49,  '  7 9  '  8 0  partial  1 9 - n o r compound ( 5 1 ,  positive  1 7 a , 46) w o u l d be  thus  i n the l a t t e r  and t h e b o a t  case  conformations can alone. A in A  -4,4-  i s less  conclusive.  o f 17P  -acetoxy-4,4-dimethylandrost-  structure  partial  47a)  structure  A comparison of  and t h e c o r r e s p o n d i n g 50a)  shows t h e f o r m e r  compound h a s an unenhanced c a r b o n y l band ( £ = 30) w h e r e a s latter  (51)  ( € = 75)  exhibits  but a l s o  T T c c — » T T * co b a n d . . h y d r o x y compounds n o r sample ing  (50)  suggest  8a)  that  compounds  also ring  (50,51,  an e n h a n c e d n —^ TT *  end a b s o r p t i o n  Our r e s u l t s  (48,50)  a trace  the spectrum.  structure  not o n l y  strong  that  of the f l e x i b l e  f o r the conformation of r i n g  7 8  unlikely  an e n h a n c e d  of the C . D . r e s u l t s  steroids  U.V. s p e c t r a  chair  (16a,  assignment  compounds  i s highly  any o f t h e b o a t effect.  f o r the  the  transition  i n d i c a t i v e o f a new  f o r the c o r r e s p o n d i n g  are s i m i l a r except  that  17p> -  f o r t h e 19-  amount o f i m p u r i t y i s p r o b a b l y d o m i n a t -  Since cholest-5-en-3-one  (8,  partial  shows e n h a n c e d U . V . a b s o r p t i o n , A i s i n a chair partial  conformation  structure  c o n f o r m a t i o n f o r t h e compounds  50a),  (47,48,49,  the  results  f o r the 19-nor  but i n a n o n c h a i r partial  structure  47a).  37  H  0'  0'  0"  (47a)  0'  (50a)  (8a)  (52a)  (28a)  0 (46a)  The d e c r e a s e d  infrared  carbonyl stretchy frequency  of the l a t t e r  81 compounds  i s also  compatible with a nonchair  conformation.  The p r o t o n r e s o n a n c e o f t h e C m e7t 8 h -y8l 1 g r o u p i n compounds ( 4 7 , 48,49) i s at r e l a t i v e l y h i g h f i e l d again suggesting a i  nonchair  conformation  for ring  q  A.  Finally  a slight  temperature 81  dependence  of t h i s  a conformational adequately ion.  r e s o n a n c e may o r may not^ be i n d i c a t i v e  equilibrium.  d i s t i n g u i s h between  The C D . r e s u l t s comparison (52,  None o f t h e s e  (Table  a flat  2)  chair  spectral  data can  o r a boat  are equally  conformat-  inconclusive.  of the C D . s p e c t r a o f the 19-nor s a t u r a t e d  partial  structure  partial  structure  50a)  double  bond r e s u l t s  Cotton  effect  52a) shows  and t h e 1 9 - n o r that  i n a large  and a l s o  A 5 ketones  A  ketone (50,51,  the i n t r o d u c t i o n of the P , Y -  positive  produces  of  contribution  a broadened  maxima.  to the This  same  5 effect (28,  h a s been o b s e r v e d  partial  5-en-3-one  structure  (8,. p a r t i a l  f o r t h e compounds  28a),  A(A6):  structure  8a),  cholestan-3-one  295 (+1.13) X(A€)  :  and c h o l e s t -  304-295  (+2.52).  38 Hence t h e r e s u l t s the  are consistent  1 9 - n o r compounds  octant where  (50,51)  dominating the e f f e c t  dichroism).  (cf.  the saturated  results  suggested  groups.  since  o r b i t a l overlap  4-dimethyl-3-keto  shows t h a t  bond r e s u l t s (47,48) pounds  again  steroid  between  t h e two u n s a t u r a t e d  (46,  (50,51)  partial  (47,48,  much weaker C o t t o n e f f e c t s  for (47,48).  A d i s t i n c t i o n between  any one o f s e v e r a l Cotton  boat  since  structure  However  the 19-nor These  a nonchair  the v a r i o u s  A i n 2-bromo-4,  chair  com-  results  conformatnonchair conformation  to give a  o f t h e b r o m i n e atom,  or  double bond.  A  4  dimethy1-3-keto  82 — 85 ~ t o be dependent, n o t o n l y on t h e  °c - o r P - o r i e n t a t i o n of a  46a)  P > , Y -double  than  the f l a t  satur-  effect.  h a s been shown  absence  partial  f o r m s w o u l d be e x p e c t e d  The c o n f o r m a t i o n o f r i n g steroids  structure  and do n o t show b r o a d e n e d maxima.  the U . V . evidence which suggested  positive  of the  i n sign of the Cotton e f f e c t .  f o r m s c a n n o t be made h o w e v e r , or  of the P , ^ -double  the i n t r o d u c t i o n o f the  i n a change  exhibit  support ion  dominates the  A s i m i l a r comparison of the C . D . s p e c t r a  4,  (52)  the p r e v i o u s l y mentioned U . V .  and t h e c o r r e s p o n d i n g A ^ compounds 47a)  analogue  octant  The p r o n o u n c e d e f f e c t  bond i s n o t u n e x p e c t e d  conformation f o r  w i t h t h e d o u b l e bond i n a p o s i t i v e  t h e 4P - m e t h y l g r o u p i n a n e g a t i v e  circular  ated  with a chair  but a l s o  on t h e  For the s a t u r a t e d  presence  series,  I.R.  82 and U . V . s p e c t r a l both the 2°c flattened ure  58),  data  show t h e b r o m i n e atom i s e q u a t o r i a l f o r  and 2P - i s o m e r s .  chair)  This  conformation f o r the  and a boat  indicates  oc-isomer  a chair (partial  conformation f o r the P - i s o m e r  (or struct-  (partial  39 structure energy  59).  T h e s e c o n c l u s i o n s have  calculations,  stants  '  between  74  been s u b s t a n t i a t e d  and a c o n s i d e r a t i o n  the protons  on  by  of the c o u p l i n g c o n -  and C  2  .  F o r the A  -  82 85 series, is  I . R . and U . V . s p e c t r a l  equatorial  axial  f o r t h e 2P - i s o m e r  f o r t h e 2cc - i s o m e r  (58) both  data  have r i n g  show t h e b r o m i n e  (partial  (partial  structure  structure  (59)  isomers  '  53a).  A i n a boat  6 0 ) , but This  (60)  atom  suggests  (53a)  conformation. 1  The c h e m i c a l protons  f o r the 2 ° c - b r o m o x  53a,  shifts  54a)  and c o u p l i n g c o n s t a n t s o f t h e C compounds  (53,54,  partial  and C  n  2  structures  83 are almost  identical,  conformation.  Furthermore,  concluded  that  the p r e f e r r e d  classical  boat  w i t h Co and C ,  suggesting  t h e same r i n g A  from the c o u p l i n g c o n s t a n t s  i t was  c o n f o r m a t i o n was q u i t e c l o s e n  at  the stem-stern  to a  positions  (57c).  0  (53a)  (54a)  From an e x a m i n a t i o n seen  that  (57c)  of the C D . s p e c t r a  the 4 , 4 , 6 - t r i m e t h y l  p o s i t i v e Cotton effect  ( s e e T a b l e 2)  compound (54)  relative  (57d)  exhibits  i t c a n be an e n h a n c e d  t o t h e d i m e t h y l compound  (53).  40 If  it  is  assumed  conformation, classical  boat  distortion group of ment. is  then  the  formation  or  bond and Cy a l s o  give the  a positive strong  groups only  slight  makes  upon t h e  exists.  the  this  a mixture noting  of  that  a chair  of  studies chair  In  both the  N.M.R.  the  the  the  in a  4<=c  and  and C . D . d a t a  (53)  regard  are  and  to  also  6-methyl It  can  an u n u s u a l equilibrium  unpublished  r i n g A of In t h i s  (57d)  be e x p e c t e d  highly unlikely.  that  con-  double  evidence  explanation,  forms.  the  the  a conformational  latter  effect  negative  for  d o u b l e bond h a s  else  enhance-  Cotton  might  the N . M . R .  between  suggest  and b o a t  for  Conformation  positions  but  either  the  from i t ,  minor  Cg m e t h y l  addition,  octant.  conformation  dichroism or  account  the  the  b r o m i n e atom i s  stem-stern  same r i n g A  incompatible with  a positive  deviations  interaction  In s u p p o r t  d i p o l e moment  to  in a negative  be c o n c l u d e d t h a t  effect  axial  the  However a r e l a t i v e l y  octant  Cotton e f f e c t ;  steric  (54)  (57c).  conformations.  lie  w i t h Cg and C,. at  have  are  compound e x h i b i t s  a l l boat (57c)  (54)  c o n f o r m a t i o n would p l a c e  s u r p r i s i n g because the for  and  C.D. results  in a positive  That e i t h e r  octant  (53)  conformation  from t h i s  (54)  that  exists it  is  consistent  as  worth with  conformation.  The 17-acetyl  stereochemical steroids  configurations  at  are  problems  three-fold:  C ^ g and C ^ y ;  conformation  of  r i n g D;  conformation  of  the  associated  (iii)  17-acetyl  (i)  (ii) the  the  the  with  assignment  of  the  determination  of  the  determination  sidechain.  16-substituted,  of  the  preferred  41 Assignments o f the c o n f i g u r a t i o n s largely  been made o n t h e b a s i s  volving  the p r e p a r a t i o n  compounds. the  A  These  precursor  include:  (partial  n  of chemical  and s u b s e q u e n t  arguments  at C g and Cny have arguments  transformations  preferential  structure  87,88  61a)  of  these  a t t a c k ^ of 0  from the  least  R'  (61a)  (61b)  hindered,  <=c - f a c e o f t h e m o l e c u l e  compound  (partial  vice-versa),  structure  trans  position, isomers,  formation,  greater  figurational configuration  formation have  isomers,  where  changes  also  effects  steric  have  also  C g,17 n  been u s e f u l i n m a k i n g c o n Correlations  upon t h e p r o t o n  except  9 0  > -*9  proved u s e f u l ,  between resonance  the a d d i t i v i t y  f o r t h e 16 P ,  crowding probably r e s u l t s  i n r i n g D and 17P - a c e t y l  measurements  to  (61c).  been m a d e ; >  h a s been shown t o h o l d  9 2  s t a b i l i t y of the  a t C-^g and C17.  t h e C g m e t h y l g r o u p have  principle  al  87  and s u b s t i t u e n t  n  a c a r b o n y l group adjacent  o f t h e c i s - c o n f i g u r a t i o n by r i n g  methods  assignments  16-substituted  e p i m e r i z a t i o n a t C^y and a t  thermodynamic  eg. V -lactone  the  6 1 b , R=H., R^=" f u n c t i o n a l g r o u p o r  contains  attainment  Spectroscopic  of  to g i v e  acid or base-catalyzed  C , „ when t h e s u b s t i t u e n t lb this  (61c)  sidechain.  17 P  i n conformationO.R.D.  a p o s i t i v e Cotton  and C D . e f f e c t 51  42  being with not  w i t h a 17 P - a c e t y l  associated  a 17<< - a c e t y l alter  " group,  group.  g r o u p and a n e g a t i v e  In g e n e r a l ,  substituents  the s i g n of the Cotton e f f e c t  but the a m p l i t u d e does  of the C 2 0  a t C i g do carbonyl  v a r y w i t h b o t h t h e n a t u r e and 93  configuration  o f the C^g s u b s t i t u e n t .  and C . D . ^ , 9 6  studies  9  effect  Several O . R . D .  of 16-substituted  20-keto  94 '  steroids  have  96 appeared this  recently,  7.  have  A general little  group.  dichroism results feature  effect  forming part  steroids.  h y d r o x y l , methoxyl  amplitude,  whereas  and a c e t y l  result  i s that  the r e s u l t s  are c o l l e c t e d  substituents  i n Tables 3  i n rings  that  and m e t h y l r e s u l t  cyano,  substituents,  in a slightly  eg. isopropyl, carboxamido,  certain  carboxy,  i n an e n h a n c e d C o t t o n e f f e c t .  carbomethoxy Table 3  a number o f compounds c o n t a i n i n g two o p t i c a l l y  carbonyl  chromophores.  i s t h e sum o f t h e two C o t t o n e f f e c t s ,  and t h e e f f e c t s  are w e l l  upon t h e C 2 0  the C . D . curve of the A  resolved  ( 6 2 q , +6.82) i a -  chromophore  compounds c o n t a i n i n g t h e A ^ - 3 - k e t o  two C o t t o n e f f e c t s  as  eg. the large  20-dione  the c o n t r i b u t i o n from the A ° - 3 - k e t o  those  active  F o r t h e s e compounds t h e o b s e r v e d C . D .  amplitude of 16°c -cyanopregn-5-en-3, eludes  diminished  dicarboxymethyl,  includes  curve  A and B  f o r the 16°c - s u b s t i t u t e d ,  I t c a n be s e e n  others,  dicarbethoxymethyl,  For  of  upon t h e d i c h r o i s m o f t h e C - 2 0 c a r b o n y l  Table 3 l i s t s  17P - a c e t y l eg.  comprehensive  thesis. The c i r c u l a r  to  t h e most  (+2.52).  chromophore,  ( s e e f i g u r e 4,  the  62o, 6 2 p ) ,  c a r b o n y l C . D . maxima a r e s l i g h t -3-keto  chromophore  i s o n l y weakly  43  TABLE 3  Compound  P o s i t i o n of s u b s t i t u e n t s 3RT  62a b c d e f g h i j k 1 m n o P q r s t u  P -OH  ketone POAc POAc POAc POH POAc POH POH ketone POH POAc POAc POAc POH ketone ketone POH ketone ketone ketone  4,5,6,7  16R  5*H 5*H  A* ,  5«H,  5<n  5  A  s  H H OH OCH3 OCH* CH CH CH(CH )^ CH(CH ) CH(CH \ CH(COz H)a CH(CO Et)z C==N C==N Cs=N C==N 3  s  3  3  3  3  3  z  5<cH A A A* A5 A* A A A* B  s  1  4 ,  4-  C . D . max. 20-keto-group  A max (mM)  2  3  5<H A A ,6CH A*, 6 * C H A 5  of  C=HN  CONH C0 H C0^CH COCH-i 2  2  3  a  293 292 293 293 292 292 292 293 294 293 290 292 289 286 287 287 290 288 288 288 288  A£  + 3 .50* + 3 .74* + 3.48 + 3.50 + 3 .00 + 3 .05 + 3.10 + 4.44 + 5.00 +4.23* + 4.90 +4.47* +4.40* +4.57* + 4.52 + 3.80 (+6.82) + 5.00 + 3.70 + 4.12 (+4.35)  * T h e s e compounds were p r o v i d e d by D r . P. C r a b b e , b u t t h e C . D . s p e c t r a were r u n i n t h e l a b o r a t o r i e s o f G . O u r i s s o n , U n i v e r s i t y of S t r a s b u r g .  44  4.0-  3.0  2.0 •  V.  .0  AE  0  2.0-  3.0  250  270  290  Figure Circular  Dichroism curves  310  370  4  of:  3 P - h y d r o x y - 16<*-cyanopregn-5-en-20-one (62o) 16*-cyanoprogesterone (62p) 3P-acetoxy-16P-carbornethoxy-17<-pregn-5-en-20-one 16P-C ar borne t h o x y - 1 7 « i - p r o g e s t e r one (63t) 3f -acetoxy-16P-methyl-pregn-5-en-20-one (65i) 3  350  330  (63q)  •+  + • s •  45 negative  9 7  in this  region.  The e x c e l l e n t  r e s o l u t i o n of  these  two c h r o m o p h o r e s by c i r c u l a r d i c h r o i s m c a n be c o n t r a s t e d the O . R . D .  curves *^ which 9  the C o c a r b o n y l group.  the observed C D . curve  two i n d i v i d u a l known t o  and  electronic  interactions  Table 4 l i s t s acetyl  steroids.  methyl,  the  the It  have  as  it  effect  be a sum o f  the  that  group  possible  two c h r o m o p h o r e s . 160-substituted,  most  17*-  substituents,  cyano,  carboxy  and How-  g r o u p p r o d u c e s a d e f i n i t e enhancement  dichroism.  The C o t t o n e f f e c t s  with  d o m i n a t e d by t h e C o t t o n e f f e c t  chromophore.  eg.  upon t h e C D . a m p l i t u d e .  and a g a i n t h i s may be c o n t r a s t e d  which are  exsteric  of  4  The A ^ - 3 - k e t o  (63d)  the O . R . D .  of  and t h e  the  of  the A - 3 - k e t o  C20 c a r b o n y l c h r o m o p h o r e s a r e w e l l - r e s o l v e d ( f i g u r e  63t)  the  is  However t h i s  0  i g n o r e s the  for  c a n be s e e n  to  lG^-acetyl  between t h e  results  little  carboxamido  the n e g a t i v e and  the  hydroxymethyl, acetoxymethyl,  carbomethoxy ever  as  a weak p o s i t i v e e f f e c t .  is oversimplified  of  1 6 ° c , 1 7 P - d i a c e t y l compound  again appears  Cotton e f f e c t s ,  exhibit  planation  d o m i n a t e d by t h e C o t t o n e f f e c t  F o r the  2  (62u)  are  with  4,  63q,  curves ^ 9  unsaturated  3,5-cyclo-6-keto  27 (63s)  compounds e x h i b i t C D . c u r v e s w h i c h a r e  Cotton is  effects  due t o  an example o f  the  individual  the  chromophores;  sums o f the  the  latter  an °c - c y c l o p r o p y l k e t o n e w h i c h o b e y s a " r e v e r s e d *  1  27 octant 16P,  rule.  This  17°c-diacetyl  viously  s i m p l e summation a l s o  compound ( 6 3 u ) ,  0  a p p l i e s to  a l t h o u g h as m e n t i o n e d p r e -  t h i s may be an o v e r s i m p l i f i c a t i o n i n t h i s  Table  5 lists  the  results  the  f o r the  case.  16*-substituted,  17 -acetyl o c  46  TABLE 4  CD. Compound  P o s i t i o n of  3RT 63a b c d e f g h i j k 1  m n o P q r s t u  pOAc ketone ketone ketone ketone POH ketone ketone POAc POAc POAc ketone POAc pOAc POH POAc pOAc 3 ,5 -cyclo 3 ,5 -eye lo ketone ketone  substituents  of  max.  20-keto-group  Xmax (mp)  Ae  4 , 5 , 6  1 6 R  A A*  H • H H H CH CH2.OH CH2.OH  2 8 9  - 2 . 7 0  2 8 9  - 2 . 3 0  CHJLOAC  2 9 2  - 2 . 5 2 *  C=N  2 8 6  - 2 . 8 6  5  1  A*  A* A A* 5  A* A 5  5°cH  A A* A 5  5  5«H  A A A  J s 5  6 P> OH 6-ketone  A* A* 1  2  3  2 9 2  - 2 . 3 6 *  2 9 4  ( + 0 . 3 0 )  2 9 4  -2.  2 8 5  - 2 . 6 6  5 8 *  2 9 2  - 2 . 3 1 *  2 9 0  - 3  CONH2.  2 9 0  - 3 . 1 8 *  CONHj CONEt* C0 H CO^H CO^H COzCH  2 9 0  - 3 . 1 3  2 8 7  - 3 . 3 3 *  2 8 9  - 2 . 8 0  2 8 9  - 2 . 6 4  2 9 0  - 2 . 7 4  2 8 9  - 2 . 8 9  CO2.CH3  2 9 0  - 2 . 9 4  291  ( - 4 . 4 0 )  C0NH  2  2  3  CO2CH3 C0Z C H 3  COCH3  . 1 5  2 9 0  - 2 . 7 5  2 8 8  ( - 4 . 3 0 )  * T h e s e compounds were p r o v i d e d by D r . P . C r a b b e but t h e C D . s p e c t r a were r u n i n t h e l a b o r a t o r i e s o f G . O u r i s s o n , U n i v e r s i t y of S t r a s b u r g .  47 steroids.  Several of  the  substituents,  methyl  and d i c a r b e t h o x y m e t h y l have  effect  of  not  the  17°^ - a c e t y l  distinguish  progesterones  between t h e  (63e)  .  finitely  enhances  tinguish  between t h e  17<* - a c e t y l  group.  little  methyl,  effect  dicarboxy-  upon t h e C o t t o n  Hence c i r c u l a r  16«=* (64c)  d i c h r o i s m can  and 16 P - m e t h y l - 1 7 = ^ -  The 16<=c-carbomethoxy g r o u p ,  the negative  steroids  eg.  dichroism;  16«*:  (64g,  64h,  64i)  (63q,  63r,  63s,  63t) .  however,  and t h u s C . D . c a n and 1 6 P  P o s i t i o n of 3R-L  63a b 64c d e f g h i  POAc ketone ketone POH POAc POAc POAc POAc ketone  substituents  4,5  16fl  A A* A* 5  A 5*C1 r  A  of  5  5«H  A* A*  H H CH CH(C02.H)2. CH(CO Et)j. CH(CO Et)2. 3  z  e  CO2CH3  CO2.CH3 C0iCH 3  max.  20-keto  7 \ m a x (mp)  2  289 289 295 285 286 290 290 292 290  dis-  -carbomethoxy-  C.D. Compound  de-  group A€  -2.70 -2.30 -2.70 -3.06 -3.00 -2.30 -3 .85 -4.06 -3 . 54  48 Table 6 l i s t s  the r e s u l t s f o r the 16P - s u b s t i t u t e d ,  17 P - a c e t y l s t e r o i d s .  In each case the 16P  s u b s t i t u t e d com-  pound has a C D . curve d i f f e r e n t from the c o r r e s p o n d i n g 16<* compound  (Table 3 ) .  T h i s i s not unexpected  as s t e r i c and e l e c t -  r o n i c i n t e r a c t i o n between the C^g methyl group and the 16P 17P  and  s u b s t i t u e n t s can lead to c o n f o r m a t i o n a l changes i n e i t h e r  r i n g D o r the 1 7 P - a c e t y l group.  Thus e l e c t r o s t a t i c  between the cyano and c a r b o n y l d i p o l e s i n compound ably r e s u l t s i n a r e o r i e n t a t i o n o f the C account compound  f o r the d i m i n i s h e d d i c h r o i s m .  2  interaction  (65c) prob-  Q c a r b o n y l a x i s to  For the 1 6 P - c a r b o x y  (65d), hydrogen bonding between the c a r b o x y l and c a r -  bonyl groups may account  f o r the weak Cotton e f f e c t ; the c o r r e s -  ponding carbomethoxy compounds (65e, 65f) e x h i b i t C D . curves s u p p o r t i n g t h i s h y p o t h e s i s .  undiminished  The s t e r i c  induced by the i n t r o d u c t i o n o f a 16P -methyl  interaction  group r e s u l t s i n  a dramatic change i n the Cotton e f f e c t o f the C o c a r b o n y l group 2  ( 6 5 i , see f i g u r e 4 ) . To i n t e r p r e t  the r e s u l t s i n Table 6, both the conformation  of r i n g D and the p r e f e r r e d o r i e n t a t i o n of the 17P must be c o n s i d e r e d .  - a c e t y l group  Three f a v o r a b l e r i n g D conformations have  been c o n s i d e r e d : the envelope form  (67a) w i t h C-j^ below the plane  of the o t h e r f o u r carbon atoms, the h a l f - c h a i r form  (67b) w i t h  C i g and C14 e q u i d i s t a n t above and below the C i s C i g C i y and the envelope form four carbon atoms. substituted steroids  plane,  (67c) w i t h C13 above the plane of the other  Energy  calculations  suggest that f o r 17P -  (Rn=CH3 o r OH, R =R3=R4 = H) conformations 2  49  TABLE 6  Compound  P o s i t i o n of  of  substituents  Tvmax (mH)  31^  4,5  16R  POH ketone POAc POH POAc ketone POAc  5*H  5*H  H H C=N CO*H COaCH* C0 CH CH  h  POH  A*  CH  3  i  POAc  A*  CH  3  j  ketone  A*  CH  3  62a b 65c d e f g  A* A A* A A* 1  5  FF  2  3  C.D, max. 20-keto group  2  a  293 292 290 290 290 290 320-307 280-271 344 326 314 285 321 280-271 307 296  A€  +3.50* +3.74* +2.23* + 1.40 + 3.68 + 3.40 + 0.21 -0.26 -0.034* +0.103 +0.062 -0.207 + 0.22 -0.25 -0.72* -0.49  * These compounds were provided by Dr. P. Crabbe but the C.D. s p e c t r a were run i n the l a b o r a t o r i e s o f G. O u r i s s o n , U n i v e r s i t y of S t r a s b u r g .  50  (67a)  (67b)  (67c)  (67b) and (67c) are favored over (67a) by about 2 k.cal./mole, whereas f o r 17««. - s u b s t i t u t e d s t e r o i d s ( R = C H 2  conformations  o r OH, Ri= R3=R = ,  3  ,  4  (67a) and (67b) are favored over (67c) by a  s i m i l a r amount.  An N.M.R. s t u d y  of 16-carbomethoxy-17-acetyl  9 0  of the f o u r p o s s i b l e  androst-4-en-3-one  isomers  (62t, 63t, 6 4 i ,  65f) has been c a r r i e d out i n which the c o u p l i n g c o n s t a n t s between the protons at C^g calculated 67b,  a n <  * C]_7 have been compared w i t h those  f o r the three probable r i n g D conformations (67a,  6 7 c ) . F o r the 16,17-trans  isomers, the r e s u l t s support  the energy c a l c u l a t i o n s mentioned above with conformations (67b) and  (67c) being f a v o r e d f o r the 16"^-carbomethoxy-17P - a c e t y l  steroid R  2  (62t, p a r t i a l s t r u c t u r e 67, R i = CH3CO, R  =» R3 = H) , and conformations  made. it  = C0 CH , 2  3  (67a) and (67b) being f a v o r e d  f o r the c o r r e s p o n d i n g 17°c - a c e t y l t r a n s isomer unately, f o r the c i s isomers  4  (63t) .  Unfort-  ( 6 4 i , 65f) no d i s t i n c t i o n could be  N e v e r t h e l e s s , from a c o n s i d e r a t i o n o f the o c t a n t r u l e ,  i s h i g h l y u n l i k e l y that the dramatic e f f e c t o f a 1 6 P -methyl  group on the d i c h r o i s m of 17(3 - a c e t y l s t e r o i d s (Table 6)  is  caused simply by v a r i a t i o n s i n r i n g D conformation. In c o n s i d e r i n g the o r i e n t a t i o n o f the 1 7 - a c e t y l group,  51 D r e i d i n g models are u s e f u l s i n c e they p r o v i d e a h a l f - c h a i r  (67b)  conformation f o r r i n g D, which i s probably q u i t e c l o s e to the p r e f e r r e d conformation  (see above).  A c o n s i d e r a t i o n of the  s t e r i c i n t e r a c t i o n s suggested by D r e i d i n g m o d e l s  (68a)  1 0 0  has  (68b)  indicated  (68c)  that the p r e f e r r e d conformation f o r the 17«c - a c e t y l group i s (68c) , whereas f o r the 17P> - a c e t y l group two a t i o n s (68a) and Tables 3,4,5 (68b)  and  (68b)  are p r o b a b l e .  low energy  The C.D.  are c o n s i s t e n t w i t h the p r e f e r r e d  conform-  results in conformations  (68c) f o r the 17P and 17°c - a c e t y l groups r e s p e c t i v e l y .  In a d d i t i o n , d i p o l e moment s t u d i e s * * and h y d r i d e r e d u c t i o n 0  experiments* ^ 0  on the u n s u b s t i t u t e d 17P - a c e t y l compound,  pregnan-20-one (69), and the O.R.D. curves of 17°£ -halopregnan103 20-ones (70) group. steric  support conformation  (68b) f o r the 17P  -acetyl  With the 16P - s u b s t i t u t e d - 1 7 P - a c e t y l compounds however, (eg. R^CH^j) o r e l e c t r o n i c  (eg. Ri=CN) i n t e r a c t i o n would  d e s t a b i l i z e conformation  (68b) w i t h r e s p e c t to (68a).  a n e g a t i v e Cotton e f f e c t  i s p r e d i c t e d f o r the l a t t e r  d i c h r o i s m would be expected  as has been observed  Since a diminished  (Table 6 ) .  L6w  52  AcO' (69) temperature C.D. w h i l e the C.D. acetyl  (63a)  (70) studies  100  support  these c o n c l u s i o n s ;  curves of the u n s u b s t i t u t e d  s t e r o i d s 104  17 P  (62a)  thus and  17<*-  remain e s s e n t i a l l y unchanged on c o o l -  i n g to -192°C, the c u r v e s  of both the 16P  1 0 0  -cyano (65c)  and  16P -methyl (65i) 17P - a c e t y l compounds change d r a m a t i c a l l y on cooling  (A£ -192°  = 0.8  and  -1.6  the weak, a l t e r n a t i n g s i g n C.D. conveniently  respectively). curve of  Consequently  (65i, f i g u r e d ) i s  e x p l a i n e d on the c o n f o r m a t i o n a l  e q u i l i b r i u m hypoth-  esis . Table 7 l i s t s the C.D.  r e s u l t s f o r v a r i o u s 16,  and c y c l o p r o p y l 20-keto s t e r o i d s . i z e d by weak Cotton a c e t y l group has  effects.  17-epoxy  These compounds are  character-  I f i t i s assumed that the 17p  the p r e f e r r e d conformation  (68b)  (or c y c l o p r o p y l ) group l i e s i n a n e g a t i v e octant  -  then the epoxy ( c f . 17°* - h a l o -  103 pregnan-20-one  ); thus the observed Cotton  e f f e c t s would  17 appear to be i n c o n t r a d i c t i o n to the " r e v e r s e d " octant r u l e p o s t u l a t e d f o r <*-epoxy and  <* - c y c l o p r o p y l ketones.  However i t  i s d o u b t f u l that the r e s u l t s i n Table 7 can be used e i t h e r to e s t a b l i s h a p r e f e r r e d conformation  f o r the 1 7 - a c e t y l group, o r  to v e r i f y the " r e v e r s e d " o c t a n t r u l e because the e l e c t r o n i c i n t e r a c t i o n between the c a r b o n y l and  epoxy (or c y c l o p r o p y l )  groups would be expected to be unique f o r each p o s s i b l e o r i e n t a t -  53 i o n o f the s i d e c h a i n ,  i . e . a conformation o f low  population  might have a profound i n f l u e n c e upon the r e s u l t a n t effect  through s t r o n g  Cotton  e l e c t r o n i c i n t e r a c t i o n o f these two groups.  TABLE 7  Compound  66a b c d e f  C.D. max. o f 20-keto group  P o s i t i o n bf s u b s t i t u e n t s  3R-L  4,5  POH POH POAc PTHP POH POH  A 5*H A 5  5  A  A A  5  5 5  R  2  16PH 16PH 16PH 16PH 16PCH l&cH  R  3  "Amax ( m M )  <* - c y c l o p r o p y l "t-epoxy <*-epoxy <* -epoxy «-epoxy P-epoxy  278 300 301 302 304 310  A£  + 0.92 -0.38 -0.33 -0.38 +2.13* -0.16  * T h i s compound was p r o v i d e d by Dr. P . Crabbe but the C.D. spectrum was run i n the l a b o r a t o r i e s o f G. O u r i s s o n , U n i v e r s i t y of S t r a s b u r g .  54 EXPERIMENTAL M e l t i n g p o i n t s were microscope. ethanolic  U l t r a v i o l e t spectra  solutions  maxima a r e  reported  r e g i o n ,260  to  of  d e t e r m i n e d on a K o f l e r  230  unsaturated  ( U . V . ) were  u s i n g a C a r y 14  are  determined  in and  The maxima i n  b e l i e v e d i n d i c a t i v e of  impurities.  stage  spectrophotometer,  i n m i l l i m i c r o n s (mp).  mp  hot  trace  the  amounts  C i r c u l a r d i c h r o i s m measurements  were 105  made i n d i o x a n s o l u t i o n s assembled ion,  according  C . D . values  4  starting  point of  (inflections C.D,  values  are are  millimicrons; f  P.  Crabbe of  steroids  the  to  236  and t h e n m.p.  '  for  with  the  following  final  p o i n t of  when t h e  o f most  of  circular  band i s n o t w e l l  McCapra o f the  S . A . Mexico f o r  3-keto  this  supplying  1 5 3 ° .  1  0  8  the  m.p.  1  0  9  halfresolved.  and D r .  20-keto  from benzene:  ,  (24a):  145-150°,  was r e c r y s t a l l i z e d o n c e  '  in  dichroism study.  androstenolone,  times  curve.  department  steroids,  3  143)  inflections  *X(A6) w i t h t h e w a v e l e n g t h s  thank D r . F .  three  the  b a n d w i d t h ( i n m i l l i m i c r o n s ) at  (Upjohn)  convent-  wavelengths:  maxima and  (3 f - h y d r o x y a n d r o s t - 5 - e n - 1 7 - o n e )  (€  apparatus  A c c o r d i n g to  p o s i t i o n s of  as  reported  used i n the  (£ 45),  reported  curve,  Syntex  Commercial  water  the  samples  Androstenolone ,  293  reported  reported  is  supplying  Mitchell.  d e n o t e d by " s " ) ,  I would l i k e for  room t e m p e r a t u r e  are  is  maximum and rk  to  at  from e t h a n o l :  n-hexane,  The i n t e n s i t y o f  the  A max:  m.p.  peak a t  151-153°, 236  mP  55 decreased the  peak  i n a stepwise at  293  my  manner f r o m €-115  remained c o n s t a n t  Androstenolone acetate, 1.5 hrs.  g.  recrystallized  dilute  (10  sulphuric,  subsequently dried  m.p.  extracted with ether  i n vacuo.  60-80°)  the U.V.  Fraction  most  final  was u s e d f o r  =  spectrum  13  at  a c i d i f i e d with  m.p.  this  peak  at  layer  solution,  38  (£54).  mH  at  (583  170-171°. my  (€36);  had c o m p l e t e l y  1 1 0  the  ether  being  mg.)  from ethanol:water  293  on a  Petroleum  largest  reported  peak  the  236(£150).)  by c h r o m a t o g r a p h y  be t h e  g.  (When  androstenolone  x 2 cm.dia.)  168-169°,  236  washed,  w a t e r gave 1.2  e l u t i o n w i t h 50 ml f r a c t i o n s  showed a s i n g l e  Lanost-8-en-3-one 5g.  (€ 4 3 ) ,  Recrystallization  product,  v i o u s l y observed (€  293  5 proved to  pure.  acetic  C r y s t a l l i z a t i o n from ether  u s i n g commercial  (120g,  and  (16  and t h e o r g a n i c  p u r i f i c a t i o n was e f f e c t e d  g r a d e HI a l u m i n a column  the  was  from e t h a n o l :  a c e t a t e had Amax:  Further  also  ml.)  1 6 6 - 1 6 8 ° , A m a x : 293 (€ 36) , 236sh  was r e p e a t e d  crystallized  collected.  mixture  (24b):  acetylated  e x t r a c t e d w i t h sodium b i c a r b o n a t e  reaction  (b.p.  was  d r y p y r i d i n e (10  by r e c r y s t a l l i z a t i o n  acetate,  whereas  at 6 = 3 3 .  androstenolone  The r e a c t i o n  and c o n c e n t r a t e d  followed  the  ml.).  £ =76,  -acetoxyandrost-5-en-3-one),  2 5 ° ) with a s o l u t i o n of  anhydride  of  (3ft  to  and gave The pre-  disappeared  wavelength). (17a).  commercial  (K & K)  lanosterol,  m.p.  1 3 5 - 1 3 8 ° , Amax:  56 251  (e 1630) , 243  (£ 2 0 8 0 ) ,  235  (€ 1 8 5 0 ) ,  i n 200 m l . e t h y l a c e t a t e  was h y d r o g e n a t e d f o r 4 h r s . o v e r 0 . 5 g . crystallization m.p.  f r o m e t h y l a c e t a t e gave 4 . 5 g .  142-145°,  ported m.p.  > max: 252  145-146°.  (6 8 5 4 ) ,  (3g.)  i n acetone  lanost-8-en-3-one m.p. 252 M  118-120°, (6693), +  D  243  78°.  D  (£ 1 0 7 0 ) ,  (Jones'  as p l a t e s  gave  gel.  235 (£ 9 2 5 ) ;  re-  of  lanost-  i n the usual w a y , ^ ^ 1  from acetone:methanol,  + 8 1 ° ( c h l o r o f o r m , C - 2 . 6 ) , > m a x : 286  (G 1010) , 236  (€926);  (£35),  reported m.p. 1 1 9 - 1 2 0 ° ,  1 1 1  F u r t h e r p u r i f i c a t i o n was a t t e m p t e d silica  Re-  lanost-8-enol,  reagent**^'*^)  (150 m l . ) g a v e ,  (2.1g)  [oc]  243  catalyst.  1 1 1  Chromic a c i d o x i d a t i o n 8-enol  Adams  by c h r o m a t o g r a p h y on  However e l u t i o n w i t h e t h e r : p e t r o l e u m e t h e r  lanost-8-en-3-one  which s t i l l  1:19  showed t h e U . V . maxima b e -  l i e v e d due t o t h e d i e n e i m p u r i t y  lanost-7,9(ll)-dien-3-one.  17P-hydroxyandrostan-3-one  U . V . : 367sh  283sh  (52),  252sh  270(+0.32),  (68),  (27):  237sh  7-methylenecholestan-3-one  P = 38  308s(+0.99),  (20),  (0),  294(+0.96) ,  (31):  U . V . :285(26);  301s(+1.40),  C D . : 330(0),  295(+1.54) ,  256(+0.14),  (c=1.74) .  ergost-7-en-3-one 252  C D . : 330  330sh  (c=1.24 g . / l O O m l . ) .  T=37  311sX+0.82),  (74);  (9),  (109),  241sh  262(+0.13) , P=37  (32): (117);  U.V.:  360sh  C D . : 324(0),  (c=1.25).  (24),  320sh  (49),  297-293(+0.67),  287  (65),  280s(0.48),  57 ergost-8(14)-en-3-one 330(0), A  9 ( 1 1 )  (33):  U.V.:  288sh  298-292(+1.15) , 268(+0.40) ,  T =37  dehydrotigogenone  282(37),  252(41),  (34):  242(42);  A  1  1  dehydrotigogenone  256(27),  246(27),  294(+0.93) , 258(+0.11), 12-methylenetigogenone 285sh(114),  254(216),  236(926);  (36):  268(+0.04),  303s(+0.73),  (c=1.68). U . V . :365sh(40), 345sh(57), 330sh(68),  T=38  U.V.:  303s(+0.80),  (c=0.78). 286(35),  318(-0.11),  (41):  252(693),  308(0),  243(1010),  296-280(+0.13),  U . V . : 365sh(12) , 340sh ( 1 5 ) ,  282sh(43), 265sh(54), 255(65);  298- 292(+0.75) , 256(+0.05),  T =36  C.D.:328(0),  (42):  CD.:  306s(+1.31),  336(0), 312s(+1.02),  260(+0.18), T = 4 0  310sh(+0.49),  (c=1.57).  2,2-dimethyl-17P-hydroxyandrostan-3-one 309s(+1.18),  U.V.:288(31); 303-290 (+1.52) ,  (c=2.64).  2,2 ,17cc-trimethyl-19 nor-androstan-3-one CD.:  304s(+0.75),  (c=2.77).  2<*-methylcholestan-3-one 330sh(16),  310s(+0.51),  240sh(205); C . D . : 328(0),  C . D . : 336(0),  (15),  U . V . :365sh(4), 325sh(13),285(31),  P =37  (17a):  325sh  311s(+0.48),  C . D . : 328(0),  297- 294(+0.90) , 270(+0.31), lanost-8-en-3-one  (6),  (c-2.24).  (35):  239(26);  (c=2.21).  U . V . : 365sh  C . D . : 330(0),  2 9 5 ( + 0 . 8 8 ) , 2 5 6 ( + 0 . 0 9 ) , T=39  (36), 251(172); C . D . :  334(0), 315s(+1.28),  312s(+1.65),  (44):  U . V . : 286(35);  309s(+1.84),  3 0 3 - 2 9 0 ( + 2 . 7 8 ) , 287s (2 . 4 0 ) , 285s (+2 .30) , 2 6 6 ( + 0 . 2 2 ) ,  306s(+2.24), P =37 (c=0. 83) .  58 4,4-dimethylcholest-5-en-3-one 242sh(242),  reported:  293(38)  297-292(+0.96) , 262(+0.05),  (47): 3 5  U . V . : 325sh(46),  ; C . D . : 324(0),  P =39  328(0),  309s(+0.77),  310s(+0.52),  (c=0.61).  4,4-dimethyl-17P-hydroxyandrost-5-en-3-one C D . :  283sh(98) ,  303s(+1.14),  (48):  U.V.:287(44);  294(+1.28) ,  260(+0.16),  T=37(c=1.46). 4 4-dimethyl-17l -hydroxy-19-nor-androst-5-en-3-one 285sh(443),  230(2160); C . D . : 3 3 0 ( 0 ) ,  264(+0.08),  T=39  3 1 5 s ( + l . 18) , 303-295(+2 .11) ,  (c=0.25).  2°c-bromo-4,4-dimethylcholest-5-en-3-one 314(167);  C D . : 344(0),  300s(+0.60),  335s(+0.14),  284s(+0.37),  (53):  352(0),  286s(+0.37),  337s(+0.38),  272(+0.05),  P =44  325s(+0.69),  2 7 8 ( + 0 . 0 5 ) , T=40  3 2 8 ( 0 ) , 293(+3.48) , 255(+0.36),  330(0),  (54) :  328(0),  P =35  330(0),  299s(+0.77),  292 (+3.50) , 2 6 9 ( + 0 . 3 0 ) ,  (c=0.34).  (62d) : P =39  292 (+3.00) , 2 8 7 s ( + 2 . 9 0 ) ,  3ft-hydroxy-16<*-methyl-5oc-pregnan-20-one C D . :  U . V . : 321(169);  (62c) :  3P-acetoxy-16<*-methoxy-5<x-pregn-7-en-20-one C D . :  (c=0.76).  (c=0.93).  3p-acetoxy-16<*-methoxypregn-5-en-20-one C D . :  309(+0.70) ,  312(+1.07) ,  3ft-acetoxy-16<*-hydroxy-5<*-pregnan-20-one C D . :  U . V . : 365sh(26) ,  324s(+0.47),  2*-bromo-4,4,6-trimethylcholest-5-en-3-one C D . :  (50): U . V . :  3  >  (c=0.29). (62e) :  267 ( + 0 . 2 0 ) ,  T-34  (62f) :  292 (+3.05) , 252 (+0.20) , P =40  (c=1.40).  (c=0.20).  59 3P-acetoxy-16«*-methyl-5og-pregnan--20-one CD.:  326(0),  (62g):  P =39  292(+3.10) , 269(+2.10),  3P-hydroxy-16*-isopropylpregn-5-en-20-one CD.:  (62h):  2 9 3 ( + 4 . 4 4 ) , 2 6 6 ( + 1 . 3 4 ) , P=37  328(0),  (c=0.71).  (c=0.78).  3P-hydroxy-6-methyl-16 c-isopropylpregn-5-en-20-one  (62i) :  CD.:  P - 3 7 ( c - 0 . 56) .  o  330(0),  294(+5.00) , 2 9 1 s ( + 4 . 9 3 ) ,  267(+1.03),  3ft-hydroxy-16<-dicarboxymethylpregn-5-en-3-one CD.:  326(0),  305s(+2.45),  290 (+4. 90) , 264 (+1. 05) , P=34  3ft-hydroxy-16«-cyanopregn-5-en-20-one CD.:  326(0),  332(-0.88), 270(+2.40),  318(0),  (62p):  C D . : 372(0),  303s(+2.90),  326(0),  328(0),  290(+6.82),  274 ( + 2 . 6 0 ) ,  252(+0.60),  (62s):  P =40  (c=0.24). (62r) :  P =38  (c=0.31).  C D . : 372(0), 362s(-0.30),  330(-1.14), 316(0), 301s(+2.74),  288(+3.70),  (c=1.50).  16*-carbomethoxyprogesterone 343s(-1.10),  287 (+3.80) ,  (62q) :  288(+5.00) , 2 5 3 ( + 0 . 6 0 ) ,  16*-carboxyprogesterone 344s(-0.74),  362(-0.28), 345(-0.66),  295s(+3.66),  3P-hydroxy-16*-carboxamidopregn-5-en-20-one CD.:  (c=1.51).  (c=1.47).  16°c-cyanopregn-5-en-3 ,20-dione CD.:  (c=0.49).  (62o):  287 (+4. 52) , 2 5 0 ( + 0 . 4 0 ) , P =39  16«-cyanoprogesterone  (62k) :  (62t) :  C D . : 376(0), 360s(-0.36),  330(-1.50), 323s(-1.00), 316(0),  288(+4.12) , 2 7 0 ( + 2 . 3 6 ) ,  ( c - l . 50).  301s(+3.00),  60 16<-aeetylprogesterone 344(-1.10),  (62u):  C.D.:  330(-1.31) , 316(0),  372(0),  303s(+2.80),  361s(-0.30), 288(+4.35) ,  270(+2.50),  (c=1.50). 3P-acetoxy-17°c-pregn-5-en-20-one C.D.:  336(0),  303s(-2.10),  17 ° c - p r o g e s t e r o n e 331(-1.16),  (63b) :  (63a) :  289(-2.70), C . D . 376(0),  303s(-2.04),  295s(-2.26),  256(-0.40),  P =40  360s(-0.30),  346(-0.90),  289(-2.30),  (c-l.5Q).  270(-1.05),  (c=1.50). 17*-pregn-5-en-3,20-dione CD.:  320(0),  (63d):  294(+0.30) , 266(+0.05) ,  P =32  (c=0.30) .  3p-hydroxy-16P - h y d r o x y m e t h y l - 1 7 * - p r e g n - 5 - e n - 2 0 - o n e (63f) : CD.:  326(0),  286(-2.66) , 251(-0.49),  (c=0.37).  P=36  3P-acetoxy-16P - c y a n o - 1 7 ° < - p r e g n - 5 - e n - 2 0 - o n e CD.:  326(0),  3P-acetoxy-16P CD.:  330(0),  2 8 6 ( - 2 . 8 6 ) , 271 (-2 .00) , P / 2 = 17 -carboxamido-5**. ,  (c =  33K-1.33),  (c=0.46).  17°t-pregnan-20-one (63j) :  290(-3.15) , 250(-0.26),  16P-carboxamido-17o< - p r o g e s t e r o n e 345s(-1.02),  (63i) :  P =37  (631) :  314s(-1.80),  (c=1.51).  C D . :374(0),  288(-3.13) ,  360s(-0.26),  261(-1.23),  0.18).  3P-acetoxy-16P-carboxy-5<*,  17°<-pregnan-20-one  CD.:  289(-2.80) , 250(-0.26),  330(0),  317s(-0.31),  3P-hydroxy-16P-carboxy-17 <-pregn-5-en-20-one <  (63n) :  (63o) :  P =39  (c=1.52).  61 CD.:  330(0),  280s(-2.15),  319s(-0.33), 250(-0.33),  309s(-1.80),  P =37  295s(-2.20),  (c=1.51).  3P-acetoxy-16P-carboxy-17°<-pregn-5-en-20-one CD.:  328(0), 307s(-1.25), 294s(-2.56),  250(-0.24),  T =38  (63p) :  290(-2.74) ,  285s(-2.59),  (c=1.49).  3P-acetoxy-16P-carbomethoxy-17o<-pregn-5-en-20-one CD.:  289(-2.64),  328(0), 289(-2.89) , 2 5 4 ( - 0 . 5 0 ) ,  P =39  (63q) :  (c=1.51).  3 , 5 ° < - c y c l o - 6 P - h y d r o x y - 1 6 l - c a r b o m e t h o x y - 1 7 < < - p r e g n a n - 2 0 - o n e (63r) : 3  CD.:  330(0), 290(-2.94),  250(-0.33),  P=39  (c=1.51).  3 , 5oc-cyclo-16P-carbomethoxy-17<^-pregnan-6,20-dione CD.:  330(0), 29K-4.40) , 260(-0.90),  16P-carbomethoxy-17°<-progesterone 344(-0.86),  332(-1.24),  270(-1.80),  (c-l.50).  346(-1.10), 272(-2.80),  331(-1.40),  (c=1.50).  C D . : 3 7 6 ( 0 ) , 361(-0.33) ,  297s(-2.46) / 290(-2.75) ,  (63u) :  303s(-2.80),  C D . : 374(0), 288(-4.30),  279s(-3.90),  (64c) :  C D . : 372(0),  314s(-2.42), 295(-2.70),  269(-1.14),  340s(-1.28), P=52 (c=0.11).  3P-hydroxy-16<*-dicarboxymethyl-17°<-pregn-5-en-20-one CD.:  360(-0.40),  (c=1.50).  16*-methyl--17<*-progesterone 325s(-1.78),  (63t) :  317s(-1.26),  16P-acetyl-17o<-isoprogesterone  T=37  (63s) :  330(0), 285(-3.06) , 266(-1.79),  P / 2 =18  (64d) :  (c-0.88).  3 P - a c e t o x y - 5 * - c h l o r o - 1 6 ^ - d i c a r b e t h o x y m e t h y 1-17<* - p r e g n a n - 2 0 - o n e (64e) : CD.:  3 2 8 ( 0 ) , 286(-3.00) , 2 6 7 ( - 1 . 7 6 ) ,  P/2 -  19  (c  =0.88).  62 3P-acetoxy-16°(-dicarbethoxy-17°<-pregn-5-en-26-on.e CD.:  328(0),  290(-2.30) , 254(-0.53),  P =39  (c=1.51).  3 P - a c e t o x y - 1 6 < * - c a r b o m e t h o x y - 5 ° < , 17<*-pregnan-20-one CD.:  332(0),  301s(-2.93),  290(-3.85) , 250(-0.33),  3P-acetoxy-16°<-carbomethoxy-17 CD.:  328(0),  o <  -pregn-5-en-20-one  2 9 2 ( - 4 . 0 6 ) , 2 5 1 ( - 0 . 6 2 ) , p =39  16P-carbomethoxy-17^-progesterone 345(-1.00),  330(-1.40),  263(-1.00),  (64i):  309s(-2.20),  328(0),  290(+1.40) , 260(+0.10),  328(0),  298s(+3.52),  346(-0.96),  332(-1.31),  290(+3.40),  270(+1.80),  332(0),  362s(-0.40),  290(-3.54),  (c=0.21).  344(0),  (65e):  290(+3.68) , 251(+0.30), (65f):  323s(-0.73),  C D . : 378(0), 317(0),  T=43  (c=0.36).  360(-0.44),  297s(+3.13),  (c=1.51).  3 2 0 - 3 0 7 (+0 .21) , 2 9 7 ( 0 ) ,  321(+0.22),  313s(+0.18),  (65g) :  2 8 0 - 2 7 1 (-0 .26) ,  3P-acetoxy-16P-methyl-pregn-5-en-20-one  (c=1.30).  (64h) :  (65d):  p =39  3P-acetoxy-16P-methyl-5°<-pregnan-20-one  CD.:  (c=1.50).  (c=1.50).  16P-carbomethoxyprogesterone  CD.:  P =37  C D . : 374(0),  3P-acetoxy-16P-carbomethoxy-pregn-5-en-20-one CD.:  (64g) :  (c=0.23).  303s(-2.83),  3ft-hydroxy-16P-earboxy-pregn-5-en-20-one CD.:  (64f) :  (c=0.67).  (65i) : 301(0),  280-271 (-0.25) ,  63  3 p - h y d r o x y - 1 6 , 17<*-cyclopropy l p r e g n - 5 - e n - 2 0 - o n e CD.:  300(0),  278(+0.92) , 265(+0.48),  P/2  3ft-hydroxy-16,17o<-epoxy-5<*-pregnan-20-one CD.:  336(0),  300(-0.38) , 276(-0.13),  CD.:  338(0),  301(-0.33) , 266(-0.14),  <  CD.:  338(0),  302(-0.38) , 268(-0.14),  (66b) : ( c - l . 50).  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Chem. 13, 542 (1948).  PART  II  THE STRUCTURAL DETERMINATION OF HIRSUTIC ACID C  70 INTRODUCTION In  Part  specific  I some a p p l i c a t i o n s o f  stereochemical  many l i m i t a t i o n s o f of  the  given.  method were  revealed.  has  organic  chemistry.  provide  a p o w e r f u l means o f  problems.  a l i m i t e d or  In t h e  the  organic  chemistry,  f o r m an i n t e g r a l  of  modern a p p r o a c h .  are to  this  p r o v e d by s y n t h e s i s , compounds o f  nature  or  orientations  a molecule  are  integration  aspect of  of  the  has still  structures  transformation  various  established  and  the  functional by a c o m b i n a t i o n  methods.  chemical  modern s t r u c t u r a l  or  Many  stereochemistry,  of  generally  b o t h p h y s i c a l and c h e m i c a l The  or  stereochemical  c h e m i c a l methods  by d e g r a d a t i o n  known s t r u c t u r e  and r e l a t i v e  groups of of  part  and  to  tools  p h y s i c a l methods  modernized s t r u c t u r a l  each  application  physical  solving structural  a p p l i c a t i o n of  discussion  In g e n e r a l ,  specific  C o l l e c t i v e l y , however,  Although the  d i c h r o i s m to  p r o b l e m s were  this  p h y s i c a l methods  circular  and p h y s i c a l methods  organic  chemistry;  the  is  one  application  1-4 of  X-ray  other of  d i f f r a c t i o n methods  is  another.  p h y s i c a l and c h e m i c a l m e t h o d s ,  fragmentary  nothing  evidence,  approach  unique f e a t u r e  to  of  the  correct  ion  r e q u i r e d to  formula;  molecular  this  dimensional picture  X-ray  of  absolute carry  structural that  molecule,  configuration. out  which p r o v i d e a  d i f f r a c t i o n presents  method i s the  In c o n t r a s t  an X - r a y  a p r e v i o u s knowledge o f  it  collection an  determination. provides  including,  a  structural  is  i n many  the  data  all-orAnother  three-  The o n l y c h e m i c a l analysis  to  cases, informat-  empirical  can  often  7 1  greatly  f a c i l i t a t e the X-ray a n a l y s i s ;  i o n of i n c o r r e c t  s t r u c t u r a l i n f o r m a t i o n i n t o the a n a l y s i s  lead to time-consuming d e l a y s . proceed w i t h the a n a l y s i s , out  Thus i t i s u s u a l l y  best to  I t should be emphasized  i t i s v i r t u a l l y i m p o s s i b l e to d e r i v e an i n c o r r e c t  structure  from a s a t i s f a c t o r y X-ray a n a l y s i s ;  i s very d i f f i c u l t  X-ray  As f o r the o t h e r p h y s i c a l  molecular  at the same time,  to d e r i v e any p a r t i a l s t r u c t u r a l  i o n from an u n s a t i s f a c t o r y  will  at l e a s t i n the e a r l y stages, w i t h -  the a i d of any s u p p o r t i n g evidence.  that  it  however the i n c o r p o r a t -  informat-  analysis.  methods, there are c e r t a i n  l i m i t a t i o n s to the use o f X-ray d i f f r a c t i o n i n s t r u c t u r a l organi c chemistry; the major r e s t r i c t i o n i s that c r y s t a l l i n e form must be a v a i l a b l e . which i s g e n e r a l l y  a satisfactory  Another r e s t r i c t i o n ,  met, but has p a r t i c u l a r r e l e v a n c e to the  s t r u c t u r a l determination described i n t h i s thesis, c r y s t a l structure regards to n a t u r a l  must be s t a b l e  to X-ray i r r a d i a t i o n .  With  products chemistry, the use of X-ray d i f f r a c t -  ion i s l a r g e l y l i m i t e d to a p p l i c a t i o n method,  i s that the  i . e . the X-ray a n a l y s i s  o f the "heavy-atom"  i s c a r r i e d out on a d e r i v a t i v e  c o n t a i n i n g a heavy atom, eg. I, Br, C l , S, Fe, Zn.  Before des-  c r i b i n g some o f the s a l i e n t f e a t u r e s of t h i s method i t i s important to note that heavy atom d e r i v a t i v e other physical  the s t r u c t u r a l c o r r e l a t i o n between the and the parent compound must be made by  and chemical methods.  72 The  Heavy-Atom Method of X-ray A n a l y s i s : Experimentally  the X-ray d i f f r a c t i o n p a t t e r n , which con-  s i s t s of a s e r i e s of d i f f r a c t e d beams of v a r y i n g recorded p h o t o g r a p h i c a l l y  intensities, is Each beam i  or by counter t e c h n i q u e s .  i s d i f f r a c t e d by a set of p a r a l l e l planes i n the c r y s t a l r e f e r r e d to by M i l l e r i n d i c e s h k l .  The  group of the c r y s t a l s t r u c t u r e ; and ies  pattern defines  the  more important, the i n t e n s i t -  are r e l a t e d to the s t r u c t u r e amplitudes  |F(hkl)| .  The  s t r u c t u r e amplitudes are r e l a t e d to the e l e c t r o n d e n s i t y t r i b u t i o n i n the u n i t c e l l , P(xyz),  the u n i t c e l l . f a c t o r and  The  x, y ,  dis-  by the t r i p l e F o u r i e r s e r i e s :  f ( x y z ) - g ^ i l F ( h k l ) exp [-2ni where V i s the volume and  space  (hx +ky  +lz)]  z the f r a c t i o n a l c o o r d i n a t e s  function F(hkl)  i s known as the  of  structure  i s the r e s u l t a n t of the waves s c a t t e r e d by each of  the N atoms w i t h f r a c t i o n a l c o o r d i n a t e s pressed by the  X j , y j , Z j .  I t i s ex-  summation:  F ( h k l ) - £ f j exp[2TTi (hx^ + k y j +  IZJ)]  where f . i s the s c a t t e r i n g f a c t o r of atom j .  The  complex  J  quantity  F(hkl)  | F ( h k l ) | and  i s characterized  a phase angle  ions:  by the s t r u c t u r e  (hkl) a c c o r d i n g rz  |F(hkl)| (hkl)  = JA* =  amplitude  to the two  express-  s+ BT  arctan  (B/A)  where A = ^ f j cos 2TT (hxj + ky^ + I Z J ) B The  f j s i n 2TT (hx^ + ky^ +  e l e c t r o n d e n s i t y can  replacing F(hkl)  be put  Izj)  i n a more convenient form by  by i t s amplitude and  phase:  73 P(xyz) - ^ 22S|F(hkl)| c o s [ 2 T T ( h x + ky + lz) - <*(hkl)] This last equation illustrates the phase problem in X-ray 0  crystallography, i.e. in the recording of the X-ray data the structure amplitudes |F(hkl)| are obtained, but unfortunately the phase angles °<(hkl) are lost.  Before the electron density  distribution can be revealed the phase angles must be recovered by some indirect,method.  The heavy-atom method i s the one most  commonly used. The f i r s t step of this method i s the location of the heavy atom.  Generally this i s accomplished by using the structure 7 8 amplitudes to evaluate the Patterson function: ' P(uvw) - -JlIIl|F(hkl)| cos 2TT (hu + kv + lw) e  where u,v,w  are fractional coordinates.  The peaks of a Patterson  map occur at the ends of vectors starting from the origin of the unit c e l l , which correspond to the vectors between every pair of atoms in the c e l l .  If a l l of these vectors could be found i t  would be theoretically possible to derive the atomic positions from this vector distribution.  However for n atoms in the unit  c e l l there are (n -n)/2 independent peaks, and for most organic 2  structures the interpretation of the Patterson map i s extremely d i f f i c u l t due to overlap of the numerous peaks.  The relative  intensity of a Patterson peak i s determined by the product of the atomic numbers of the two atoms involved.  Thus i t i s  usually possible to locate the heavy atom in a Patterson distribution.  74 It  is  p o s s i b l e to  derivative  carry  too  is  c o m p l i c a t e d even f o r  is  p a r t i c u l a r l y true  of  many h e a v y atoms  since  vectors  the  coordinates  used to  possible  evaluate  many o f  from the  repeated,  atoms  the  of  are  ability  of  the  This atomic  s t r o n g peaks formed of  vectors  bet-  atoms,  i.e.  then u s i n g  and t h e  series  calculated  is  summed.  C,N,0 is  usually  d e n s i t y map.  coordinates  angle c a l c u l a t i o n s ,  established,  angles <*(hkl);  resulting electron  until  of  the  a l l of  The  The  process  light  atoms  the non-hydrogen  located. t h e h e a v y - a t o m method d e p e n d s on  an atom o f  r e l a t i v e l y high s c a t t e r i n g  The c h o i c e  of  a useful guide. 5  been d e f i n e d :  For 2  Z H Z  phases  to  initiate  the  power t o the  b u t some n u m e r i c a l e s t i m a t e this  purpose a " h e a v i n e s s  deter-  Fourier  a h e a v y atom i s o f t e n r e s t r i c t e d  chemical considerations,  numbers o f  atoms.  characteristic  h e a v y atom a r e  phase  light  mine a s u f f i c i e n t number o f analysis.  presence  map w h i c h ,  different  s t r o n g peaks  there  the  i n c o r p o r a t i n g the  phase  are  heavy  of  amplitudes |F(hkl)|  the  The s u c c e s s o f  as  are  b a s e d on t h e h e a v y atom a F o u r i e r  l o c a t i o n of  into  atoms  the  many p e a k s c h a r a c t e r i s t i c  the observed s t r u c t u r e  is  atoms  the  the  in a Patterson  l o c a t i o n of  when t h e s e  but  atoms.  After  phases  the  between h e a v y  ween l i g h t  are  h e a v y - a t o m method w i t h a  could result  i n a d d i t i o n to  from the o v e r l a p of  they  the  c o n t a i n i n g more t h a n one h e a v y a t o m ;  of  species,  out  can  index"  by serve has  2 where Z J J  t h e h e a v y and l i g h t  and Z L r e f e r  atoms  to  respectively.  the  atomic  F o r com-  pounds o f used, the  moderate  complexity  although values  index i s  atom may n o t  too  because  of  f r o m 0.2  low t h e r e  be l o c a t e d  electron-density  a value of  is  i n the  hand,  if  the  light  atoms a r e  In g e n e r a l  amount o f  |Fo| -  p l o t t e d where  usually  |Fo|  generally  structure  a c c u r a t e d a t a was  heavy the  results  and  large  amplitudes  then  that  electron-density  not  resolved  in  X-ray 5  been l o c a t e d ,  available,  synthesis"  |Fc|are the  located  and  i n which the  basis  to  of  observed  and  Although the  i n an X - r a y  analysis w i l l  accurate  too  a the  function:  |Fc| ) c o s r 2 T T ( h x + ky + l z ) - o<(hkl)1  be p l a c e d on t h e  sufficiently  index i s  t h e y have  amplitudes r e s p e c t i v e l y .  a satisfactory  and  the  few c a s e s t h a t  a "difference  D =—  not  If  an i n s u f f i c i e n t number o f  h y d r o g e n atoms a r e  quite  method u s e d was  are  the  inconclusive  p o o r l y r e s o l v e d on t h e  the  In the  structure  either  d i s t r i b u t i o n , or  the h e a v i n e s s  h e a v y atom may so d o m i n a t e  is  usually  have been u s e d .  that  Patterson  is  1.0  angles.  the  large  danger  d i s t r i b u t i o n may g i v e  On t h e o t h e r  analysis.  above 2.0  the  the d e t e r m i n a t i o n of  a c c u r a t e phase  map.  to  about  analysis,  calculated  h y d r o g e n atoms they  can  chemical considerations,  g i v e bond l e n g t h s  d e f i n e atom t y p e ,  and  since  angles  bond m u l t i p l i c i t y  type of h y b r i d i z a t i o n . After  refinement  a l l of  t h e n o n - h y d r o g e n atoms have  of  structure  the  generally  proceeds  been f o u n d , by t h e  further  method o f  9 least find  squares. the  atomic  The o b j e c t parameters  of  the  refinement  which give  the  best  procedure agreement  is  to  bet-  76  ween t h e o b s e r v e d least  squares  where w i s  and c a l c u l a t e d  method t h e  in  |Fo|,  crystallographically that  the  that  it  least is  included  i n the  isotropic a scale  free  or  and t h e  refinement  anisotropic  factor  summation e x t e n d s  method has o v e r  from s e r i e s  i s : Zw  One o f  (|Fo|  the  over the  positional  thermal parameters  the  -|Fc|)  2  the all  the  advantages  t h e F o u r i e r method  termination errors. are  In  i n v e r s e l y p r o p o r t i o n a l to  independent p l a n e s .  squares  amplitudes.  f u n c t i o n minimized  a weighting factor  probable error  structure  The  is  parameters  parameters,  for  each  r e l a t i n g t h e o b s e r v e d and c a l c u l a t e d  atom,  and  structure  amplitudes. As p a r t ions of  the  be u s e d t o and  of  the  least  parameters calculate  angles.  squares  are  the  process  calculated,  the  standard  and t h e s e c a n  standard d e v i a t i o n s of  The s t a n d a r d d e v i a t i o n 6 ( A B ) o f  the  the  deviat-  subsequently bond  bond  lengths  length  4 between  the  two atoms <S  where  tf(A)  and C(B)  A and B i s 2  (AB)  are  =  the  given by:  C (A) 2  +  6  2  standard d e v i a t i o n s of  o f A and B a l o n g t h e d i r e c t i o n o f  the bond.  viation  between  (in radians)  of  the  (B)  angle  the  coordinates  The s t a n d a r d  the  de-  bonds AB and BC  4 is  g i v e n by: ^0)  =  <* (A) + AB a  2  The is and  structure  c* (B)/1 ^-AB 2  2  revealed  2cose + 1 \ + AB-BC BC -/ 2  by t h e  (5 (C) BC 2  2  electron-density distribution  g e n e r a l l y c o n f i r m e d by a s u i t a b l e r e f i n e m e n t o f thermal parameters.  correctness  of  i  A p o p u l a r means o f  a structure  is  by use o f  the  the p o s i t i o n a l  expressing discrepancy  the factor,  77 R, which i s d e f i n e d by: R = Z ( |Fo| - |Fc| )/I|FOI Not  too much s i g n i f i c a n c e should be attached to the R value  s i n c e i t i n d i c a t e s the accuracy o f the i n t e n s i t y measurements as w e l l as the c o r r e c t n e s s  of the s t r u c t u r e ; and the l a t t e r  i s determined by the extent as w e l l as the accuracy o f the empirical data.  A f t e r a s u i t a b l e refinement procedure, a  necessary but i n s u f f i c i e n t c o n d i t i o n f o r a c o r r e c t s t r u c t u r e i s that R <d 0.25. As a f i n a l step  i n a s t r u c t u r e a n a l y s i s by the heavy atom  method, i t i s o f t e n p o s s i b l e to determine the a b s o l u t e c o n f i g u r a t i o n o f the m o l e c u l e . ^  Normal s c a t t e r i n g o f X-rays by a  0  non-centrosymmetric c r y s t a l r e s u l t s i n the e q u a l i t y :  |F(hkl)|  =»  |F(hkI)| , i . e . the i n t e n s i t y of r e f l e c t i o n s (hkl) and ( h k l ) are the same ( F r i e d e l ' s Law).  The consequence o f t h i s law i s  that normally i t i s not p o s s i b l e to d i s t i n g u i s h between two enantiomers by X-ray d i f f r a c t i o n .  However i t has been o b s e r v e d ' 1 1  that some atoms s c a t t e r X-rays anomalously; t h i s anomalous s c a t t e r i n g i s g r e a t e s t when the frequency of the i n c i d e n t r a d i a t i o n i s near but s t i l l frequency of the atom.  greater  than an a b s o r p t i o n  edge  The s c a t t e r i n g f a c t o r s f o r atoms which  s c a t t e r X-rays anomalously are d e f i n e d by: f = fo + A f  1  + iAf  1 1  where f o i s the normal s c a t t e r i n g f a c t o r , and A f r e a l and imaginary c o r r e c t i o n s . TT/2  1  and i A f ^ ^ are  The imaginary part  ahead of the phase of the r e a l p a r t  (fo + A f ^ )  i s scattered resulting i n  78  the breakdown of Friedel's Law.  Thus i f a molecule contains two  or more atomic species, one of which i s an anomalous scatterer, i t should be possible to distinguish between the two enantiomers. Empirically i t i s observed that the commonly available radiations, eg.  Cu-Koc,  Mo-K , x  are scattered anomalously by most  heavy atoms. In order to distinguish between two enantiomers, structure amplitudes based on the coordinates of one enantiomer and using the anomalous scattering factor for the heavy atom are calculated for the reflection pairs (hkl) and (hkl).  These  amplitudes are compared with the observed intensities I(hkl) and I (Tiki) ; and i f i t i s found that when |F(hkl)| > |F(hkl)|, I(hkl)>  I (hkl), and similarly when |F(hkl)| <  |F(hkl)| ,  I (hkl)< I (hkl) , then the correct enantiomer has been chosen. If the inequalities do not agree then the mirror image of the assumed structure has the correct -absolute configuration.  Care  must be taken to choose a right-handed system of coordinates while indexing the reflections since the formula for the 4 structure amplitudes coordinates.  are given for a right-handed system of  Usually only a few pairs of reflections exhibit  a significant intensity difference, and even for these very accurate intensity measurements may be required; however only one pair of reflections i s necessary to establish the absolute configuration, and accurate intensity measurements can be made by counter techniques.*^  79 DISCUSSION Hirsutic  a c i d C i s one o f t h e m e t a b o l i t e s  isolated  from  14 Stereum h i r s u t u m elucidation  and h a s t h e m o l e c u l a r  of i t s structure  has  been a c c o m p l i s h e d  and  X-ray The  ° methods  hirsutic most  (1)  1700  of  of the s u b s t i t u e n t s .  (carbonyl),  exocyclic  a t 3520  methylene ester  spectra of  and (3)  at  peaks  methyl resonance  4.72,  peaks 5.00  at  (1)  (hydroxyl), - 1  at  trans-  properties the  suggested  (1)  showed o n l y e n d -  and e x h i b i t e d  3200-2400  (exocyclic  nature  peaks i n  (carboxyl),  methylene);  I.R. absorption  - 1  .  as t h e The N . M . R .  were i d e n t i c a l w i t h t h e e x c e p t i o n methyl h i r s u t a t e  8.66  and 8 . 9 7 t  (tertiary  (Ha,Hb)  and 6 . 5 5 X  (Hd) as w e l l  the  bands f o r t h e  as w e l l  1720 and 1160 c m  (6.34t);  of  (3)  and h y d r o x y l f u n c t i o n s ,  characteristic  singlet  spectrum,  showed s i m i l a r  v i a the  The s p e c t r a l  1655 and 890 c m  (3)  (1)  1.  The a c i d  i n the u l t r a v i o l e t  m e t h y l esl^er  ester  stereochemistry  analysis.  and i t s m e t h y l e s t e r  infrared region  The  by a n e c e s s a r y c o m b i n a t i o n o f c h e m i c a l * * *  outlined in figure  acid  absorption  the  and a b s o l u t e  f u n c t i o n a l g r o u p s were c h a r a c t e r i z e d  formations  of  formula C ^ ^ g C ^ -  (3)  methyls)  of the  a l s o had and d o u b l e t s  as a m u l t i p l e t  at  80  R=pBrC H COCH 6  4  2  (8)  (9) Figure  1  81 Ha  5 . 4 0 t (He). exocyclic  The l o n g range  whereas  JHaHb -  0 and JHcHd =» 1 . 9 c . p . s .  t h e mass s p e c t r u m o f m e t h y l h i r s u t a t e  parent  peak  methyl,  between t h e  m e t h y l e n e p r o t o n s H a , H b and t h e C5 p r o t o n He were  and 2 , 7 c . p . s . , ally  coupling constants  (m/e - 278)  as w e l l  2.1  Fin-  showed a s t r o n g  as p e a k s due t o t h e l o s s o f  h y d r o x y l and c a r b o m e t h o x y  groups  (m/e =» 2 6 3 , 2 6 0 , 2 1 9 and  201) . The p r e s e n c e  of a secondary  h y d r o x y l g r o u p was c o n f i r m e d by  the  f o r m a t i o n o f the monoacetate  (6)  showed no a b s o r p t i o n above 3000 c m  at  1735,  s p e c t r u m showed a s i n g l e t  (3),  but the c o u p l i n g  The a l l y l i c  (7) 1727  of the acetoxy group.  a t 7 . 8 5 T. due t o t h e  C15  were d i f f e r e n t  constants  g r o u p was e s t a b l i s h e d a f t e r gave  5350); > c a l c :  1 7  manganese  an <^,P-unsaturated 230 mp) .  t h e same.  - 1  characteristic  dioxide oxidation  ketone  (7, Amax:  The i n f r a r e d s p e c t r u m o f  showed no a b s o r p t i o n above 3000 c m and 1645 c m  were  from the parent  r e l a t i o n s h i p between t h e d o u b l e bond and t h e  methyl h i r s u t a t e  231 my (€  , but e x h i b i t e d peaks  i n a d d i t i o n the chemical s h i f t s of the protons  on c a r b o n atoms C5,Cg,Ci4 and  of  - 1  -  acetate protons;  hydroxyl  The i n f r a r e d s p e c t r u m o f  1375 and 1210 c m * c h a r a c t e r i s t i c  The N . M . R .  compound  (6).  - 1  but e x h i b i t e d peaks  o f t h e u,0-unsaturated  at  ketone  82  MeO^C  OH  (7) system.  (8)  The v a l u e f o r the c a r b o n y l s t r e t c h frequency (1727 cm" '' 1  suggested a five-membered  ring.  The N.M.R. spectrum showed that  the keto group s h i f t e d the protons on C15 d o w n f i e l d by 0.15T, and more important Ha,Hb and Hd appeared as s i n g l e t s , thus conf i r m i n g the assignment o f long range c o u p l i n g i n methyl (3) and a l s o c o n f i r m i n g the presence o f oxygen  hirsutate  f u n c t i o n s on  adjacent carbon atoms. The presence o f the e x o c y c l i c double bond was confirmed by s e v e r a l experiments.  Formaldehyde,  as the 2 , 4 - d i n i t r o p h e n y l -  hydrazone, was i s o l a t e d by the o z o n o l y s i s o f methyl (3).  C a t a l y t i c r e d u c t i o n o f (3) r e s u l t e d i n the uptake o f one  mole o f hydrogen (8).  hirsutate  and the i s o l a t i o n o f the dihydromethyl h i r s u t a t e  The N.M.R. spectrum o f (8) was c o n s i s t e n t w i t h the r e -  placement o f an e x o c y c l i c methylene methyl group  group by a secondary  (9.05T, d o u b l e t , J = 6.0 c . p . s . ) ; and again the  chemical s h i f t s o f the protons at Cg,Cg and C-^g had a l t e r e d . F i n a l l y o x i d a t i o n o f (3) w i t h osmium t e t r o x i d e gave a t r i o l ( 9 ) , The epoxide f u n c t i o n was the most d i f f i c u l t By e l i m i n a t i o n , the remaining oxygen  to e s t a b l i s h .  f u n c t i o n had to be i n an  e t h e r l i n k a g e , and as suggested above, probably was a t t a c h e d to a carbon atom adjacent t o the secondary h y d r o x y l group.  The  83 p r e s e n c e o f an e p o x i d e chlorohydrin absorption  (4).  was c o n f i r m e d by t h e f o r m a t i o n  The i n f r a r e d  spectrum  o f (4)  at 3500 c m " * as w e l l  as p e a k s  at  showed p e a k s in  of the e t h y l  ester.  due t o t h e e t h y l at  -  He and Hd c o n s i d e r a b l y  (T 5.86q,  field  (4)  uct  (10)  strong  to the a c e t a t e peaks  spectrum  clearly  (7.87T,  c.p.s.).  c.p.s.);  The  by t h e f a i l u r e periodate  The a c e t y l a t i o n  absorption  test prod-  a t 3480 c m * i n -  1735 and 1370 c m * . -  showed t h e p r e s e n c e o f a s i n g l e  evidence  methyl h i r s u t a t e  reduction  product  as p e a k s  f o r the epoxide  (3)  (5)  at 3500 cm""*,  The mass s p e c t r u m well  J=7  (4)  The N . M . R .  acetoxy  group  3H) .  Further  spectrum  at  (J=9  of  with the coupling  a negative  (10).  infrared  addition  8.76t,  was s u p p o r t e d  of a monoacetate  exhibited  spectrum  (6.04t)  enhanced  f o r m an i s o p r o p y l i d e n e d e r i v a t i v e ,  and t h e f o r m a t i o n  of  The N . M . R .  ester  lower  s t r u c t u r e of the c h l o r o h y d r i n to  enhanced  (10)  a d d i t i o n Hd a p p e a r e d  between  showed  1720 and 1190 c m *  (4)  characteristic  of the  with  lithium  showed s t r o n g  was p r o v i d e d by r e d u c t i o n aluminum h y d r i d e .  absorption  b u t no a b s o r p t i o n  showed a s t r o n g  due t o t h e l o s s  parent  The  i n the i n f r a r e d  i n the carbonyl peak  o f one h y d r o x y l ,  (m/e = 252)  region. as  two h y d r o x y l  and  hydroxymethyl groups  (m/e = 2 3 4 ,  a h y d r o x y m e t h y l g r o u p was a l s o by  a two p r o t o n s i n g l e t  appeared the  at 8.66 T  range  Both t e r t i a r y  at  since  as q u a r t e t s  the C  of 0.5  c.p.s.  methyl groups this  1  ,(4.82,  3  suggested  methyl group  5.03 t ) c.p.s.  The C5 p r o t o n He a p p e a r e d  methylene  with  long  and a g e m i n a l as a broad  peak b u t a d d i t i o n o f a d r o p o f a c i d t o a d e u t e r i o a c e t o n e ion  resulted  sistent ing  in a triplet  w i t h a s p l i t t i n g o f 1.8 c . p . s .  of 6 c . p . s .  N.M.R. 6.19,  -  Acid  of the r e d u c t i o n product  The C  1  2  protons  p e a k s due t o t h e t e r t i a r y  appeared  as i n t h e p a r e n t  (5).  con-  treatment  of the  of peaks  at  to hydroxyl protons.  at  spectrum e s t a b l i s h e d the presence 6H).  (121,242,121)  i n the disappearance  i n a d d i t i o n to the a c e t a t e peaks  (T 7 . 9 4 s ,  solut-  w i t h H a , Hb and a s p l i t t -  The i n f r a r e d s p e c t r u m showed s t r o n g  N.M.R.  and  resulted  and 7 . 1 5 T a s s i g n e d  Acetylation  cm *  pattern  w i t h the p r o t o n s on C g .  sample a l s o 6.53  (11).  of t r i p l e t s  of  spectrum  The e x o c y c l i c  c o u p l i n g c o n s t a n t s w i t h He o f 1 . 8 , 1 . 9  splitting  The p r e s e n c e  i n the N.M.R.  i n methyl h i r s u t a t e .  p r o t o n s H a , Hb a p p e a r e d  221).  o n 100 Mc s p e c t r u m ) ;  gem-substitution pattern  appeared  revealed  at 6 . 7 0 T .  at 8 . 9 0 T ( r e s o l v e d  216,  appeared  (5)  gave a d i a c e t a t e  a b s o r p t i o n a t 3500  1725 and 1365 c m " * . The o f two a c e t o x y as a s i n g l e t  methyl groups  groups  at 6 . 1 8 T ,  and e x o c y c l i c  The p r o t o n He a p p e a r e d  methylene  as t e n  85  peaks  in a triplet  sistent on  quartet  with s p l i t t i n g s  Cg as w e l l  as  of  triplet  and. 7 . 7  5.8  a l o n g range  pattern  (121  c.p.s.  s p l i t t i n g of  1331  121)  w i t h the  1.9  c.p.s.  con-  protons with  Ha,Hb. Other catalytic pyridine  transformations h y d r o g e n a t i o n of  o x i d a t i o n of  P-unsaturated ized  by i t s  (T4.8s, ation  ketone  be a s c r i b e d  to  (12)  and  also  the  (13b).  can  reduction  double bond,  secondary  mp),  product  and c h r o m i c  the  latter  (12)  was  I.R.  (1720,  1640  cm )  The N . M . R .  at  peak  at  and N . M . R . the  which could  the  chemical  two p a r t i a l  evid-  structures  f u n c t i o n a l groups  are  it  (13a) contained  i n these p a r t i a l  oxid-  Cg.  be s u m m a r i z e d by t h e a l l of  The  character-  - 1  7.48X  acid/  C5.  spectrum of  i n f o r m a t i o n p r o v i d e d by t h e  Although  (5) i n c l u d e d  h y d r o x y l g r o u p at  showed a s h a r p  two p r o t o n s  structural  e n c e g i v e n above (13a)  the  = Ha,Hb) s p e c t r a .  product  the  system of  U . V . (Araax 234  4.0s  The  the  of  (13b) structures,  very  little  of  the  86 hirsutic alkali in  acid ring  system  i s revealed.  In a d d i t i o n ,  or selenium treatment of methyl h i r s u t a t e  complex m i x t u r e s  l a c k i n g i n any d i s t i n c t i v e  Since our o r i g i n a l supply of h i r s u t i c few g r a i n s ,  and s i n c e  the s t r a i n  (3)  acid only consisted  metabolite  h a s n o t been r e d i s c o v e r e d ,  apparent  that  a complete  chemical degradation  acyl  ester  (2)  analysis  i t was  of h i r s u t i c  acid  of the p-bromophen-  was c a r r i e d o u t .  The p - b r o m o p h e n a c y l e s t e r ized  of a  o f Stereum h i r s u t u m which  this  Thus an X - r a y  resulted  chromophore.  produces  was n o t p o s s i b l e .  acid,  by s p e c t r a l  of h i r s u t i c  and a n a l y t i c a l d a t a .  acid  (2)  The e s t e r  was c h a r a c t e r -  g r o u p was  (2)  . w e l l - d e f i n e d by t h e U . V . (Amax: 1705, at  4.71X)  ation the  1590 c m  ),  N.M.R.  (4 a r o m a t i c  and mass s p e c t r a  from benzene-ethanol  space group Initially  estimated *  - 1  P2 2 2 1  1  255 mp ( £ 1 5 , 5 0 0 ) ,  (parent  phenacyl  m/e = 4 6 0 , 4 6 2 ) .  gave c o l o r l e s s  (1735, methylene  Crystalliz-  prisms b e l o n g i n g to  1 >  a set of i n t e n s i t i e s  visually.  protons,  I.R.  On t h e f i r s t  was c o l l e c t e d  electron-density  o n f i l m and distribution,  I w o u l d l i k e t o t h a n k D r . N.G. H e a t l e y f o r p r o v i d i n g u s w i t h his t o t a l supply of h i r s u t i c acid C .  87 w h i c h was c a l c u l a t e d 28 o f that  the  a n a l y s i s would g i v e  any c h e m i c a l d a t a . oxygen)  more a c c u r a t e the  In t h e  was  located;  intensities  very w e l l .  The c o m p l e t e d  tions  full  27  the  of  the  resolved,  structure  subsequent  and i t  without  analysis  however,  bromine  the  in spite  of  thermal  the  atoms and 4 " h a l f - a t o m s "  as  aid  of  m i s s i n g atom a new s e t  nature  of  counter,  parameters d i d not  a n a l y s i s d e f i n e d the  atom,  appeared  measured on a s c i n t i l l a t i o n  p o s i t i o n a l and i s o t r o p i c  of  coordinates  29 n o n - h y d r o g e n atoms were  X-ray  (epoxide  u s i n g the  refine  and  shown by  posi-  the  HO (14)  structural Cj. and Cj  formula are  irradiated  (14)  where  "half-atoms" .  crystals  the  f o u r oxygen  The X - r a y  contained  result  an a l m o s t  appeared  that  rearrangement essentially  d u r i n g the  had o c c u r r e d ,  but  two n o n - h y d r o g e n atoms a l t e r i n g  chemical evidence ure of  the  the  (partial  suggested  the  the  X-ray  crystal  that  of  two  molecules.  i r r a d i a t i o n an u n u s u a l  unchanged w i t h o n l y the  A combination of  to  equal mixture  r a n d o m l y d i s t r i b u t e d and c h e m i c a l l y d i s t i n c t it  atoms a t t a c h e d  Thus  solid-phase  structure  remained  p o s i t i o n a l parameters  of  significantly. evidence  structure  p -bromophenacyl e s t e r of  13b)  (structure  14)  established  hirsutic  acid  (2),  with  the  the  struct-  and  88 suggested the rearrangement product had the s t r u c t u r e c o n f i r m the l a t t e r assignment, a sample of hirsutate  (2) was  irradiated,  separated from the unchanged chromatography. s p e c t r a l data.  (15).  p-bromophenacyl  and the rearrangement product (15) ester  (2) by p r e p a r a t i v e  thin-layer  C h a r a c t e r i z a t i o n o f (15) f o l l o w e d from the The t e r t i a r y h y d r o x y l group was  (2)  R - BrC H COCH 6  4  2  indicated  <*,P-unsaturated ketone system was 1  .  c h a r a c t e r i z e d by I.R.  and N.M.R. (X4.72s, a 9 6 s Ha,Hb) s p e c t r a .  ion the rearrangement product e x h i b i t e d enhanced the u l t r a v i o l e t r e g i o n , 9\max:255 m p  (e 18,500).  by  (15)  s t r o n g a b s o r p t i o n i n the i n f r a r e d spectrum at 3480 cm  1625 cm" )  To  The (1720,  In a d d i t -  absorption i n The Cg  methylene  group appeared i n the N.M.R. spectrum as a two proton s i n g l e t at 7.48T. As a f i n a l s t e p i n the X - r a y a n a l y s i s the a b s o l u t e conf i g u r a t i o n s of both p-bromophenacyl arrangement  (2) and the r e -  product (15) were determined by the anomalous  dispersion method. of h i r s u t i c  hirsutate  11  The s t r u c t u r e and a b s o l u t e s t e r e o c h e m i s t r y  a c i d C (1) f o l l o w s from the c h e m i c a l c o r r e l a t i o n  between the a c i d and the e s t e r ( 2 ) .  89  From an examination of the X-ray r e s u l t s i t was that  the rearrangement p r o c e s s was  strongly  apparent  influenced  by the  n a t u r e of the m o l e c u l a r p a c k i n g and the hydrogen bonding scheme. A discussion arrangement  of the X-ray r e s u l t s and the mechanism of the r e are given i n the Experimental s e c t i o n f o l l o w i n g  the  X-ray d a t a . The g e n e r a l i t y of the X-ray-induced rearrangement was investigated. hirsutate  I r r a d i a t i o n of methyl h i r s u t a t e  then  (3) and dihydromethyl  (8) gave r e s p e c t i v e l y about 30% and 70% rearrangement.  A n a l y t i c a l l y pure samples of the rearrangement p r o d u c t s were not  o b t a i n e d ; however s p e c t r a l data o b t a i n e d i n each case from  samples c o n t a i n i n g about 70% rearrangement product were cons i s t e n t w i t h a rearrangement p r o c e s s analogous to the one served w i t h p-bromophenyl h i r s u t a t e  (2).  ob-  Thus the r e a r r a n g e -  ment product from e t h y l h i r s u t a t e i s b e l i e v e d  to have  structure  (16) and the one from dihydromethyl h i r s u t a t e , s t r u c t u r e (17). I r r a d i a t i o n of h i r s u t i c a c i d (1) i t s e l f r e s u l t e d i n no r e arrangement.  In the f r e e a c i d  ( 1 ) , hydrogen bonds i n v o l v i n g the  c a r b o x y l group, p r o b a b l y dominate the m o l e c u l a r p a c k i n g . to induce the rearrangement t h e r m a l l y i n the e s t e r s a l s o were u n s u c c e s s f u l .  Attempts  (2) and  (3)  90  MeOiQ  :0  OH  OH  (17)  (16)  Further to the investigation of the generality of the rearrangement process, the model compounds 4P, 5-epoxy-5P-cholestan3P-ol (21)  and 4P, 5-epoxy-5P-cholestan-3<*-ol (23),  and the  -expected rearrangement product, 5P-hydroxy-cholestan-3-one (2"5) were synthesized (see figure 2). (23)  bears l i t t l e  however the  -hydroxy-epoxy functional groups were expected to Irradiation of the 3P-hydroxy  for 2 days resulted in no degradation, and a similar *  bombardment of the 3°<-isomer (23) position.  and  resemblance to the hirsutic acid skeleton;  dominate the molecular packing. isomer (21)  The ring system of (21)  A sample of (23)  produced only slight decom-  which had been irradiated for 7  days showed four components on T.L.C. in addition to ca.90-95% starting material.  Of the new products, the major one (ca.5%)  could not be identified.  Of the minor components, T.L.C. and  U.V. (Amax 236 nu-0 evidence suggested that one was cholest-4-en3-one (19)  and T.L.C. evidence suggested that another could  possibly be the expected rearrangement product  (25).  The results of the irradiation of the two model compounds (21,23) suggests that the unusual solid phase rearrangement observed with p-bromophenacyl hirsutate (2)  does not generally  apply to other ring systems containing the ot-hydroxy-epoxy  91  Figure 2  92 f u n c t i o n a l groups. p-bromophenacyl  Thus the n a t u r e o f the m o l e c u l a r p a c k i n g i n  h i r s u t a t e (2) and the r e l a t e d methyl e s t e r s  (3,8)  might be a unique f e a t u r e o f the p e c u l i a r r i n g system. S i n c e h i r s u t i c a c i d C possesses a n o v e l r i n g system i t i s i n t e r e s t i n g to s p e c u l a t e on i t s b i o s y n t h e t i c o r i g i n . culaa* formula, Ci5H2o°4i  suggests that i t i s a  and hence d e r i v a b l e from f a r n e s y l pyrophosphate  The mole-  sesquiterpene (26).  Hirsutic 20  a c i d a l s o bears a s t r u c t u r a l resemblance to humulene (28) t h i s suggests a p o s s i b l e b i o s y n t h e t i c scheme as o u t l i n e d i n f i g u r e 3.  A O ,  ;  °  93  Figure 3  94 EXPERIMENTAL Chemical Data: M e l t i n g p o i n t s were d e t e r m i n e d o n a K o f l e r h o t microscope. ethanolic frared  U l t r a v i o l e t spectra  (I.R.)  spectrophotometer cells were  unless  were  tubes.  instrument  and h i s  and i n -  Elmer Model  137B  at  measurements  resonance  spectra  the  (N.M.R.)  in deuteriochloroform  The mass  spectra  MS 9 D o u b l e F o c u s i n g Mass  m i c r o a n a l y s e s were  mm.  i n chloroform solutions with  indicated otherwise.  associates  rotation  A60 Mc i n s t r u m e n t  d e t e r m i n e d o n an A . E . I . Elemental  Optical  Nuclear magnetic  t a k e n on a V a r i a n unless  t a k e n on a P e r k i n  otherwise.  t a k e n on a R u d o l p h  solutions  spectrophotometer;  i n c h l o r o f o r m s o l u t i o n s u s i n g matched 0 . 1  stated  one d e c i m e t e r were  ( U . V . ) were d e t e r m i n e d i n  s o l u t i o n s u s i n g a C a r y 14  spectra  stage  c a r r i e d out  Spectrometer.  by D r . A.  Max P l a n c k I n s t i t u t e ,  were  Bernhardt  Mulheim,  Ruhr,  West-Germany. The U . V . maxima a r e I.R.  peaks  ported  in  reported  constants  the are  as m / e ;  functional  ;  and t h e N . M . R .  of  the N . M . R .  in brackets.  a rationale however,  s t r o n g peaks which are  J  in millimicrons;  coupling constants,  assignments  enclosed  been a t t e m p t e d ;  reported;  i n cm  X u n i t s w i t h the  cycles/sec;  reported  are  reported  of  the  The mass complete  i n a d d i t i o n to  the  suggested  spectra  fragment  that  is  the  the  re-  reported  and t h e  the parent  of  are  spectra  probably i n d i c a t i v e of  groups without rearrangement  peaks J,  peaks  pertinent  coupling  data has  peak loss  skeleton  eliminated is  in  are  not several  of are enclosed  95 in  brackets.  and shape  Standard  (N.M.R.)  abbreviations  f o r peak i n t e n s i t y  are used.  The u s u a l w o r k - u p i n c l u d e d w a s h i n g t h r e e d r y i n g w i t h sodium s u l f a t e rotary phrase  evaporator  unfiltered  and r e m o v a l o f t h e s o l v e n t  at 4 5 ° , the l a t t e r  molybdenum r a d i a t i o n .  i n a thin-walled, soft  placed  i n the c a v i t y  attached  silica  tube  by t h e  +  from ethanol  C 68.30,  block.  The b l o c k was  plates  unless  indicated  U.V. irradiation,  sulfate/10%  out with otherwise.  i o d i n e vapor  s u l f u r i c acid  to give c o l o r l e s s  H 7.47,  -  prisms;  890 m; U . V . : end a b s o r p t i o n ; JHa , H b : He = 1 . 9 ,  d ( H d : JHcHd = 2 . 0 ) , 7.4  1 4  3  d , 5.00 d (Ha,Hb:  (C^g m e t h y l ) ,  steel  I . R . ( C H C 1 ) : 3520 w, 3200-2400  1660 w, 920 s ,  6.54  c a p s u l e w h i c h was t h e n  sample p r o v i d e d by D r . N . G . H e a t l e y  1 1 6 ° (c=1.05);  1700 v s ,  (up t o 50mg) was  spray.  (1)  The c r u d e crystallized  out using  ( T . L . C . ) was c a r r i e d  out w i t h :  and c h a r r i n g w i t h a 5% e e r i e acid  carried  outlet.  to Stahl)  D e t e c t i o n was c a r r i e d  Hirsutic  glass  chromatography  g e l G (acc.  were  The sample  of a stainless  to the X - r a y  Thin-layer  (He),  on a  being designated  i r r a d i a t i o n experiments  placed  4.73  times w i t h water,  i n vacuo. The X - r a y  M§3  (I.R.)  8.2  - 9.0  C-,,-H 0. 9 0  8.62  s  2.6,  requires:  protons);  C 68.16,  m.p. 1 7 9 - 1 8 0 ° ; b , 2950  H 7.63.  s,  N.M.R.:  JHaHb =• 0 ) ,  (C13 m e t h y l ) ,  (8 s k e l e t o n  was r e -  5.39m  8.97s Anal.  Found:  96 X-ray i r r a d i a t i o n : 30mg. was an undepressed  m.p.,  bombarded f o r 42 hours, but  an i n f r a r e d spectrum  i d e n t i c a l with s t a r t -  i n g m a t e r i a l and o n l y end a b s o r p t i o n i n the u l t r a v i o l e t r e g i o n i n d i c a t e d that no rearrangement p-Bromophenacyl h i r s u t a t e 150 mg.  of h i r s u t i c  had o c c u r r e d .  (2) acid  (0.57 mmoles) and 160 mg.  of  p-bromophenacyl bromide (0.62 mmoles) were d i s s o l v e d i n 15 ml. of potassium c a r b o n a t e - d r i e d acetone c o n t a i n i n g 1 g. of p o t a s s ium carbonate.  The mixture was  r e f l u x e d f o r 50 min.  anhydrous c o n d i t i o n s , then f i l t e r e d vacuo.  from ether-petroleum e t h e r , f o l l o w e d by  recrystallizations  from benzene-ethanol  c o l o r l e s s prisms; m.p. (benzene:ether, 2920 m,  1735  129-130°; H , 2  1:1): R  = 0.5;  f  444  1 3  methyl), 8.95  (-H 0), 263 2  CH COCgH Br), 201 2  + 97°  (c - 1.55); T.L.C.  (CHClg): 3600 m, 3500 w,  nq, 2.37  nq  s, 890 m;  U.V.:  (4 aromatic protons,  b (He), 6.52  s (C  1 5  2 3  H  2 5  d (Hd, JHcHd - 2.1),  methyl), 7.3 462  2  +  - H 0); 2  - 8.2  +  - H 0),  i r r a d i a t i o n product  (15)  2  (8  447 219  A n a l . Found: C 60.08, H  0 B r r e q u i r e s : C 59.88, H 5.46, 5  - 9.0  ( p a r e n t ) , 445,  (-CH C0C6H4Br),245 (263  (219  4  Br 17.44, C X-ray  gave a 50% y i e l d of  1590 vs, 920  s k e l e t o n p r o t o n s ) ; mass spec.: 460, 442,  two  s (phenacyl methylene), 4.70 d, 498 d (Ha,Hb, JHaHb -  0, JHa,Hb : He = 2.1), 5.36 s (C  2  I.R.  vs, 1705 vs, 1660 w,  ( 15,500); N.M.R.: 2.18  J=9), 4.71  8.57  and the s o l v e n t removed i n  T.L.C. i n d i c a t e d g r e a t e r than 95% r e a c t i o n had o c c u r r e d .  Crystallization  255 my  under  (-CH3),  (-C0 5.78,  Br 17.30,  2  97 ( i ) 3 mg.  of a n a l y t i c a l l y pure p-bromophenacyl e s t e r was  bombarded and the r a t e of r e a c t i o n f o l l o w e d by T.L.C. about 10 hours the r e a c t i o n was e s t e r being converted. m.p.  70-100°,  The  complete w i t h about 60% of the  i r r a d i a t e d sample showed a depressed  an enhanced U.V.  maximum 255  (£=17,900) and  hanced a b s o r p t i o n i n the i n f r a r e d r e g i o n at 3500 (ii)  en-  cm . -1  S i n g l e c r y s t a l s were^mounted on both the Weissenberg  camera and the Spectrogoniometer conditions).  (X-ray s t r u c t u r e d e t e r m i n a t i o n  A f t e r 15 hours i r r a d i a t i o n  crushed s e p a r a t e l y . m.p.  After  (Cu-K«) they were  P i e c e s from both c r y s t a l s had  depressed  and e x h i b i t e d a spot on T.L.C. p l a t e s c o r r e s p o n d i n g to the  rearrangement product (iii) e s t e r was  On  (15).  a p r e p a r a t i v e s c a l e , 200 mg.  i r r a d i a t e d f o r 60 hours.  30-40% c o n v e r s i o n was  obtained.  For t h i s impure e s t e r o n l y  S e p a r a t i o n of the s t a r t i n g  m a t e r i a l and rearranged products was T.L.C. u s i n g two t a i n i n g G.E.  c a r r i e d out by p r e p a r a t i v e  s i l i c a g e l p l a t e s (20 x 60 x 0.05  phosphor and developed  benzene:ether,  of c_a. 95-98% pure  1:4  f o r 24 hours.  cm.)  con-  along the long a x i s w i t h  The compounds were e l u t e d from  the s i l i c a w i t h e t h e r ; the recovered e s t e r c r y s t a l l i z e d  instantly;  however the rearrangement product d i d not c r y s t a l l i z e .  It  appears  from  silica. oil  that the l a t t e r decomposes p a r t i a l l y on e l u t i o n  T h e r e f o r e the s p e c t r a l data were a c q u i r e d u s i n g the  (ca. 95% p u r e ) . ["*lp + 30° 9  e t h e r , 1:1): 1720  vs, 1705  R  f  - 0.45;  I.R.  (c = 1.10); T.L.C. (benzene:  (oil):  vs, 1625 ra, 1585  3480 s, 2920 s, 1735  s, 910 m;  U.V.:  s (sh),  255 mp (€18,500);  98 N.M.R.: 2.20 nq, 2.40 nq (4 aromatic protons, J •= 9) , 4.72 s (phenacyl methylene), (Cg methylene),  3.96s, 4.72 s (Ha,Hb, JHaHb - 0 ) , 7.48 s  8.58 s ( C  1 3  methyl), 8.85 s ( C  1 5  methyl), 7.3-  8.3-9.0 (8 s k e l e t o n p r o t o n s ) . Methyl h i r s u t a t e (3) 1 g. o f h i r s u t i c a c i d was d i s s o l v e d i n 30 ml o f ether and c o o l e d to 0 ° . was  F r e s h l y prepared diazomethane/ether  added dropwise  solution  at 0° u n t i l an excess was c l e a r l y  2 1  indicated.  The excess reagent was destroyed w i t h d i l u t e a c i d and the e t h e r l a y e r washed, d r i e d , f i l t e r e d  and removed i n vacuo.  Recrystall-  i z a t i o n from e t h a n o l gave a q u a n t i t a t i v e y i e l d o f the methyl e s t e r as c o l o r l e s s prisms; m.p.  161-162°;[°0j)  T.L.C. (benzene:ether,  - 0.4; I.R. (CHClg): 3660 m,  1:1): R  f  O+  119° (c = 2.25);  3500 w, 3000 s, 1720 vs, 1655 w, 1160 vs, 915 s, 885 m; N.M.R. (100 Mc): 4.72 d, 5.00 d (Ha,Hb, JHaHb = 0, JHa,Hb:He =• 2.1, 2.7), 5.40 b(Hc), 6.55 d (Hd, JHcHd - 1.9), 6.34 s ( e s t e r methyl), 8.66  s (C13 methyl), 8.97 s ( C  on p r o t o n s ) ; mass s p e c : 219 C  1 5  methyl), 7.4-8.2-9.0 (8 s k e l e t -  278 ( p a r e n t ) , 263 (-CH3) , 260 (-HgO),  (-C0 CH ), 201 (219+ - H 0 ) ; A n a l . Found: C 69.09, H 7.98, 2  3  2  1 6 2 2 ° 4 r e q u i r e s : C 69.04, H 7.97. H  X-ray  irradiation:  barded f o r 150 hours.  100 mg. o f methyl h i r s u t a t e was bomThe i r r a d i a t e d sample had a depressed  m.p. 105-140° and T.L.C. i n d i c a t e d c_a. 30% c o n v e r s i o n to a new product had o c c u r r e d .  The u l t r a v i o l e t  spectrum o f the i r r a d i a t e d  sample e x h i b i t e d a maximum at 238 my; but the new product was shown t o be d i f f e r e n t from the manganese d i o x i d e o x i d a t i o n  99 product  (7) by comparative  T.L.C.  The new product  (16) was  separated from s t a r t i n g m a t e r i a l by p r e p a r a t i v e T . L . C , however c o n s i d e r a b l e decomposition i t s e l u t i o n and subsequent  o f the former r e s u l t e d d u r i n g  handling.  acquired w i t h c_a. 70% pure product. to be dominated by the i m p u r i t i e s  The s p e c t r a l data were The U.V. spectrum  appeared  (Amax 246 mp,6 11,000, eg.  A® - 5 - keto chromophore); however the i n f r a r e d and N.M.R. data were c o n s i s t e n t w i t h s t r u c t u r e  (16); I.R. ( o i l ) :  3400 m,  1725 vs, 1620 s, 1160 v s , 880 m; N.M.R.: 4.12 s, 4.82 s (Ha,Hb, JHaHb = 0 ) , 6.35 s ( e s t e r methyl), 8.61 s ( C (C  1 5  1 3  methyl), 8.82 s  methyl), 7.2 - 8.4 - 9.0 (8 s k e l e t o n p r o t o n s ) ; T . L . C  (benzene:ether,  1:1): R j = 0.6.  E t h y l h i r s u t a t e c h l o r o h y d r i n (4) 100 mg. o f h i r s u t i c a c i d was d i s s o l v e d i n 20 ml. e t h a n o l and 2 ml. cone. HC1 added.  The s o l u t i o n was r e f l u x e d on a  steam bath f o r 5 hours; the e t h a n o l was removed i n vacuo, e t h e r added and the e t h e r l a y e r washed, d r i e d and evaporated.  Cry-  s t a l l i z a t i o n from ether-petroleum ether f o l l o w e d by two r e c r y s t a i l i z a t i o n s from benzene-petroleum c o l o r l e s s prisms; m.p.: 95-96; [<*]p  3  (benzene:ether,  e t h e r gave a 50% y i e l d o f + 67° (c = 2.42); T . L . C  1:1): Rf = 0.4; U.V.: end a b s o r p t i o n ; I.R.: 3610 m,  3480 m, 2980 s, 1720 vs, 1665 w, 1190 vs, 910 s; N.M.R.: 4.68 d, 4.81 d (Ha,Hb, JHaHb = 0, JHa,Hb:He = 2.0, 2.0), 5.7b (He), 6.04 d (Hd, JHcHd = 9 ) , 5.86 q, 8.76 t ( e s t e r e t h y l , J = 7 ) , 8.67 s ( C  1 3  methyl), 8.87 s ( C  1 5  methyl), 7.4 - 8.4 - 9.0 (8  s k e l e t o n p r o t o n s ) ; A n a l . Found: C 62.32, H 7.48, C l 10.34,  100  C  17 25°4 H  C 1  R  Q  E  U  I  R  E  S  C 62.09, H 7.67,  -  Three r e a c t i o n s supported (i)  the s t r u c t u r a l assignment (4):  Attempted i s o p r o p y l i d e n e 30 mg.  d i s s o l v e d i n 15 ml.  dry  g. anhydrous copper s u l p h a t e , and  mixture shaken f o r 2 days. occurred,  formation:  of the c h l o r o h y d r i n was  acetone c o n t a i n i n g 1.5  C l 10.80.  the  T.L.C. showed t h a t no r e a c t i o n had  and s t a r t i n g m a t e r i a l was  recovered.  22 (ii)  Negative p e r i o d a t e t e s t  (iii)  Monoacetate formation 30 mg.  1 ml,  a c e t y l a t e d ( 2 ml. p y r i d i n e +  a c e t i c anhydride) f o r 3 days.  l a y e r was  i n d i c a t e d a s i n g l e product monoacetate of  v s . 1655  R  f  which was  w,  I.R.  1370  s, 915  8.5),  q, 8.75  8.67  i n vacuo.  - 0.7;  JHa.Hb - He  methyl),  (oil): s, 870  - 2.1),  organic  T.L.C. o f the  was  residue  c h a r a c t e r i z e d as  5.8  3480s, 2940 s, 1735 m;  N.M.R.: 4.81  b (He), 5.81  t ( e s t e r e t h y l , J °> 7) , 7.87  s ( C 1 3 methyl),  (8 s k e l e t o n  8.86  s (C  1 5  the  d (Ha,Hb,  d (Hd, s  vs,  JHcHd -  (acetate  methyl),  7.3  - 8.4  -  protons).  L i t h i u m aluminum h y d r i d e r e d u c t i o n product The  The  added to  (4) from I t s s p e c t r a l p r o p e r t i e s ; T.L.C. (benzene:  JHaHb - 0, 5.85  s o l u t i o n was  removed i n vacuo; the p y r i d i n e  o f f w i t h toluene  e t h e r , 1:1):  The  then e x t r a c t e d w i t h c h l o r o f o r m .  washed, d r i e d and  azeotroped  9.0  (10):  of c h l o r o h y d r i n was  c o l d water and  1725  *  experiments c o n c e r n i n g  t r a n s f o r m a t i o n s of  (5)  the p r e p a r a t i o n and  (5) were c a r r i e d out w i t h Dr.  whose a s s i s t a n c e i s g r a t e f u l l y  acknowledged.  subsequent  I.H.  Qureshi,  101 500 mg. o f methyl h i r s u t a t e i n 25 ml. t e t r a h y d r o f u r a n was added dropwise t o a r e f l u x i n g s o l u t i o n o f 2g. L i A l H t e t r a h y d r o f u r a n , and the mixture LiAlH  i n 100 ml.  4  r e f l u x e d f o r 5 hours.  Excess  was decomposed c a u t i o u s l y w i t h e t h y l a c e t a t e f o l l o w e d by  4  a s a t u r a t e d s o l u t i o n o f ammonium c h l o r i d e .  The product was  e x t r a c t e d with e t h e r and the o r g a n i c l a y e r washed, d r i e d and r e moved in vacuo.  R e c r y s t a l l i z a t i o n from e t h a n o l gave a 30%  y i e l d o f c o l o r l e s s prisms; I.E.  m.p. 117-118°; M^  (CHC1 ): 3500 s, 2900 s, 1655 3  w, 910 s; N.M.R. (100  CDCI3: 4.82 q. 5.03 q (Ha,Hb, JHaHb = 0.5, 5.50  b (He), 6.70 s ( C  methyls, 4.91  1 2  Mc),  JHa,Hb:He - 1.8,  methylene), 8.90 d (6H, C  1 3  1 cps) , 7.4 - 9.0 (8 s k e l e t o n p r o t o n s ) ,  and C  1.9), 1  5  (CD )2CO: 3  q, 5.10 q, 5.6 b, 6.76 s, 8.92 d (6H), 7.4 - 9.0 (8H), and  broad  peaks at 6.19,  protons,  6.53,  7.15 b e l i e v e d due to three  (CD3)gCO/HCl: h y d r o x y l peaks d i s a p p e a r  as a t r i p l e t o f t r i p l e t s mass s p e c : 31  + 54° (c - 1.13);  9  (121 242 121)  252 ( p a r e n t ) , 234 (-H 0), 221 (-CH OH) , 216 (-2H 0) , 2  +  2  The several (i)  and He appears  p a t t e r n , (J - 1.8, 6 ) ;  (CH OH ); A n a l . Found: C 70.92, H 9.09,  C 71.39, H  hydroxyl  2  2  C H240 1 5  3  requires:  9.59.  r e d u c t i o n product  (5) was c h a r a c t e r i z e d f u r t h e r by  transformations:  D i a c e t a t e formation  (11):  A c e t i c a n h y d r i d e / p y r i d i n e a c e t y l a t i o n o f (5) gave an o i l which was shown to be the d i a c e t a t e (11) from i t s s p e c t r a l p r o p e r t i e s ; I.R. (CHCI3): 3560 m, 3460 m, 2910 1655  w, 1365  s, 1725  vs,  s, 910 s, 865 w; N.M.R. (100 Mc) : 4.80 d, 4.91 d  (Ha,Hb, JHaHb = 0, JHa,Hb:Hc - 1.9,1.9), 4.47 m (He,  121 1331 121  102 p a t t e r n , J » 7.7, 7.94  5.8,  1.9 ( t r i p l e t ) ) ,  6.18  s (6H, two a c e t a t e m e t h y l s ) , 8.89  s (Ci  d (6H, C  2  methylene),  and C  1 3  1 5  methyl  <5= 1.5 c p s ) ; 7.4 - 9.0 (8 s k e l e t o n p r o t o n s ) . ( i i Chromic a c i d o x i d a t i o n product 33 mg. o f (5; 0.13 a s o l u t i o n o f 13 mg. pyridine.  (12):  m moles) i n 1 ml. p y r i d i n e was  chromic  acid  (0.13 mmoles) i n 0.5 ml.  A f t e r 16 hours the mixture was  d i l u t e HC1,  added t o  then e x t r a c t e d w i t h e t h e r .  pourred i n t o i c e and  The o r g a n i c l a y e r was  washed, d r i e d and removed i n vacuo t o y i e l d  18 mg.  o f a gum.  The s p e c t r a l p r o p e r t i e s of the r e s i d u e suggest o x i d a t i o n of the secondary h y d r o x y l (Cg) has o c c u r r e d ; I.R. (CHCI3): 3400 s, 2900 s, 1720  vs, 1640  m; U.V.:  (Ha,Hb, JHaHb =• 0 ) , 6.65 8.85  (C  1 5  234 mP; N.M.R.: 4.0 s, 4.8 s  s (C  methyl), 8.90 ( C  1 3  1 2  methylene),  7.48  s (C  g  methylene  methyl), 7.2 - 8.5 (8 s k e l e t o n  protons). (iii)  Catalytic 28 mg.  hydrogenation  o f (5) i n 30 ml. e t h a n o l was hydrogenated  platinum oxide.  The s p e c t r a l data of the r e s i d u e was c o n s i s t e n t  w i t h r e d u c t i o n of the e x o c y c l i c methylene group; 3400 vs; N.M.R. (CD ) CO: 6.0 b (He), 6.55 3  2  protons, removed w i t h D 0 ) , 2  (C  1 3  7.4  using  methyl), 9.06  s (C15  6.75  s (C^  methyl), 9.05  2  I.R. ( o i l ) ;  b (2 o r 3 h y d r o x y l  methylene), d (C  1 4  8.95 s  methyl, J » 6 ) ,  - 9.0 (8 s k e l e t o n p r o t o n s ) . A c e t y l a t i o n of the hydrogenation product above gave a  103  r e s i d u e which by i t s s p e c t r a l p r o p e r t i e s was a d i a c e t a t e , (oil):  3450 m, 2900 s, 1720  (He), 6.19 s ( C methyls),  vs, 1370  vs;  N.M.R. (CD ) CO: 5.0 b 3  methylene), 7.92 s, 7.99 s (6H,  1 2  8.95 s ( C  1 3  methyl),  I.R.  9.05 s ( C  1 5  2  two acetate  methyl),  9.05 d ( C  1 4  methyl, J =» 4) , 7.4 - 9.0 (8 s k e l e t o n protons) . Methyl h i r s u t a t e a c e t a t e (6) 145 mg. o f methyl h i r s u t a t e was d i s s o l v e d i n 2 ml. p y r i d i n e and 2 ml.  a c e t i c anhydride added.  dry  The s o l u t i o n was  l e f t s t a n d i n g f o r 4 days w i t h o c c a s i o n a l s w i r l i n g , and then the o r g a n i c reagents  were removed under high vacuum; ethanol was  added t o remove t r a c e s o f a c e t i c anhydride.  The r e s i d u e appear-  ed t o be at l e a s t 95% homogeneous by T . L . C , however c r y s t a l l i z a t i o n c o u l d not be induced. (0.02 was  mm Hg)  The r e s i d u e was sublimed at 85°  t o g i v e a homogeneous, c o l o r l e s s o i l .  c h a r a c t e r i z e d as the monoacetate;["^ID^ + 106°  11.1); T.L.C. (benzene: ether,  1:1):- R  2990 s, 1735  w, 1375  875 w; 2.2,  1 5  vs, 1675  (c =  - 0.75); I.R. s, 1210  1.78,  (CHC1 ) : 3  vs, 1170  s, 915 s,  N.M.R.: 4.29 d, 4.92 d (Ha,Hb, JHaHb - 0, JHa,Hb:Hc =  2.2),  methyl), (C  s, 1725  F  This o i l  4.98  m (He), 6.44 d (Hd, JHcHd - 2.0),  7.85 s ( a c e t a t e methyl),  methyl),  8.65 s ( C  1 3  6.33 s ( e s t e r  methyl),  8.91 s  7.4 - 8.2 - 9.0 (8 s k e l e t o n p r o t o n s ) ; Anal. Found:  C 67.87, H 7.59,  C H C> 18  24  5  r e q u i r e s : C 67.48, H 7.55. '  Manganese d i o x i d e o x i d a t i o n product (7) 1 g. o f a c t i v e manganese d i o x i d e  was added to a s o l u t i o n  of 155 mg. methyl H i r s u t a t e i n 15 ml. c h l o r o f o r m  and  the mixture  104 was s h a k e n f o r 1 d a y . removed  in. v a c u o .  followed gave  The s o l u t i o n was f i l t e r e d  C r y s t a l l i z a t i o n from e t h e r - p e t r o l e u m  by two r e c r y s t a i l i z a t i o n s  a 50% y i e l d  of colorless  (c = 2 . 2 3 ) ;  T.L.C.  (€  I.R. ( C H C l g ) :  =• 5 3 5 0 ) ;  1170 s , 6.58 (C  s  methyl),  1 5  C  (benzene:ether, 2980 s ,  69.61,  s  7.3  H 7.34,  C  8.1  -  H  0  1 6  2 ( )  Dihydromethyl h i r s u t a t e  9.0  R  f  -  0.8;  ether - 96°  2  U . V . : 231 mp  1727 v s , 1720 v s , 1645 m, s,  4.69  8.62  s  s  C  (Ha,Hb,  (C  (8 s k e l e t o n  requires:  4  ether,  m.p. 1 0 3 - 1 0 4 ° ; [ « ] ^  1:1):  (ester methyl), -  solvent  from benzene-petroleum  prisms;  915 m, 885 m; N.M.R.:3*92  ( H d ) , 6.34  and t h e  1 3  methyl),  protons); 69.54,  JHaHb =  0),  8.82  Anal.  s  Found:  H 7.30.  (8) i  70 mg. o f 5% P d / c h a r c o a l acetate  and h y d r o g e n a t e d ;  hirsutate reaction being and  was i n t r o d u c e d was o v e r  absorbed.  acetate  119 -  120°;[<*]g  R  f  = 0.4;  1 4  removed  3  requires:  3  X-ray  C  i_n v a c u o .  8.70  J = 6.0); 68.54,  H  irradiation:  T.L.C.  b ( H e ) , 6.77  (C  1 3  Anal.  methyl), Found:  of hydrogen a d e l i t e pad  Two r e c r y s t a i l i z a t i o n s  (benzene: e t h e r ,  1:1):  1720 v s , 1165 v s ,  d ( H d , JHcHd = 2 . 0 ) ,  9.10 C  from  prisms; m.p.:  3600 w, 3460 w, 2980 s ,  5.9 s  through  of c o l o r l e s s  + 2 5 ° (c « 1 . 7 0 ) ;  I.R. ( C H C 1 ) :  methyl,  and s h a k i n g c o n t i n u e d f o r 35 m i n . ; t h e  gave a 25% y i e l d  (ester methyl),  45 m i n . 50 mg. o f m e t h y l  i n 3 m i n . w i t h 1 mole e q u i v a l e n t  920 m, 885 w; N . M . R . :  (C  after  was added t o 6 m l . e t h y l  The s o l u t i o n was f i l t e r e d  the s o l v e n t  ethyl  catalyst  s  (C  67.99,  1 5  methyl),  H 8.48,  C  1 6  6.40  9.05 d H  2 4  0  4  8.64. 45 mg. o f d i h y d r o m e t h y l h i r s u t a t e  was  s  105 bombarded f o r 50 h o u r s . liquid  and T . L . C .  starting is  had o c c u r r e d .  material  t h e sample was a  indicated  The s p e c t r a l  and 70% r e a r r a n g e m e n t  Hd),  I.R/ (oil):  s  ( I H ) , 6.36  methylene),  8.69 s  methyl  and C  6.59  s  (2H), 7.74  (6H  J-7).  5  (CHCI3):  915 w; N . M . R .  6.34  1  4  3450 s , 5.9  2960 s ,  J -  8),  s  was  allowed to stand  black  through  6.94  U.V.:  s  d (1/3 H ,  (4/3 H ,  9.09 s  d (1/3H),  (6 H , C 6.54  1  5  s (IH), s  (9)  ( 1 . 0 5 mmoles)  (0.72  mmoles) and  i n 10 m l . d r y d i o x a n  f o r 14 d a y s p r o t e c t e d  t h e osmium s u l f i d e p r e c i p i t a t e a celite  pad.  After  frpm l i g h t .  The  from ethanol  colorless  m . p . 1 6 5 - 1 7 3 ° ; [o<]  3500 s , s  powder;  2970 s , (ester  8.4  C 60.94,  -  9.0  H 7.44,  gave a 10% y i e l d  1725 v s , 1180 s ,  methyl),  8.61 s  (other protons C  1 6  H  2  0  fi  removed by f i l t r a t i o n  removal of the solvent  recrystallization  -  (16).  s o l u t i o n was s a t u r a t e d w i t h h y d r o g e n s u l f i d e f o r 30 m i n .  and t h e n  6.35  7.62  8.96,  A s o l u t i o n o f 200 mg. m e t h y l h i r s u t a t e mg. o f osmium t e t r o x i d e  The l a t t e r  (3H), 8 . 9 5 , 9 . 0 4 , 9 . 0 6 , 9 . 1 5  product  267  to  30%  1730 v s , 1720 v s ,  methyl),  CgHg:  (4/3 H ) , 8.74  Osmium t e t r o x i d e o x i d a t i o n  5.7  (17).  b (1/3 H , H e ) , 6.77  s (2H, e s t e r  about  sample c o n t a i n s product  (3H, C13 m e t h y l ) ,  methyl,  that  d a t a c a n be  b e l i e v e d t o be t h e d i h y d r o compound a n a l o g o u s  1165 s ,  6  CHCI3)  by a s s u m i n g t h e i r r a d i a t e d  288 s h (€ = 2 5 ) ;  C  irradiation  (alumina p l a t e ,  70% r e a r r a n g e m e n t rationalized  After  (C  22  i n vacuo,  o f t r i o 1 as a  0 ° (c = 1 . 2 7 ) ,  I.R.  915 m, 875 w; N . M . R . 1 3  methyl),  9.08  poorly resolved);  requires:  C  61.52,  s  (C  Anal.  H 7.75.  (CHCI3) :  (DMF): 1 5  methyl),  Found:  106 Ozonolysis This  experiment  was c a r r i e d  o u t by D r . I . . H . Q u r e s h i .  To a s o l u t i o n o f 53 m g . m e t h y l h i r s u t a t e methane hour.  a t - 7 8 ° was b u b b l e d a s t r e a m o f o z o n i z e d o x y g e n T h e o z o n i d e was decomposed  reaction with  mixture  2,4-dinitrophenylhydrazine.  authentic  The d i s t i l l a t e  Cholest-4-en-3-one  (19)  by o x i d a t i o n w i t h J o n e s '  undepressed  from  ethanol  mixed m . p . w i t h  4-dinitrophenylhydrazone  5-epoxy-5ft-cholestan-3P-ol  and t h e  was t r e a t e d  Recrystallization  m.p. 1 6 2 - 1 6 3 ° ,  formaldehyde 2,  for 1  by warming w i t h w a t e r  steam d i s t i l l e d .  gave y e l l o w c r y s t a l s ;  4ft,  i n 20 m l . d i c h l o r o -  derivative.  (21)  was p r e p a r e d  Reagent  from c h o l e s t e r o l  (18)  2 4 , 2 5 f o l l o w e d by i s o m e r i z a t i o n 26  with oxalic  acid  according  Cbolest-4-en-3P-ol hydride  reduction  to  (20)  Fieser. was. p r e p a r e d  of cholest-4-en-3-one  f r o m t h e <*-isomer v i a t h e d i g i t o n i d e Gaffney  2 7  .  Oxidation of  (20)  crystallized  from methanol less  prisms;  3450 s ;  (cf.  X-ray 3P-ol  (21)  (19)  f o l l o w e d by  according  gave a homogeneous  from methanol.  Plattner  2 8  irradiation:  :  0  +  2  Two r e c r y s t a i l i z a t i o n s  5 . 7 ° (c -  m.p. 9 5 - 9 6 ° , [ < O a few mg. o f 4 p ,  was bombarded f o r 2 d a y s .  a c i d ® in^  o i l which  gave 4 p , 5 - e p o x y - 5 P - c h o l e s t a n - 3 0 - o l (21) m.p. 9 5 - 9 7 ° , M f )  separation  t o M c K e n n i s and  with m-chloroperbenzoic  c h l o r o f o r m a t 0 ° f o r 36 h o u r s eventually  by l i t h i u m aluminum  d  3.14), +  I.R.  as  color-  (nu'jol) :  5.4°).  5-epoxy-5p-cholestan-  However,  T.L.C.  evidence,  107  an undepressed m.p. and negligible absorption in the.U.V. spectrum confirmed that no rearrangement had occurred. 4P, 5-epoxy-5P-cholestan-3*-ol ( 2 3 ) 4 p , 5-epoxy-5P-cholestan-3-one ( 2 2 ) was prepared from cholest-4-en-3-one ( 1 9 ) by alkaline hydrogen peroxide epoxidation according to Plattner.  Catalytic hydrogenation of ( 2 2 )  gave  a crude mixture which failed to yield a sharp melting compound by successive recrystallizations from methanol.  However column 30  chromatography with grade III Woelm neutral alumina  and elution  with benzene, followed by recrystallization from methanol gave 4P, 5-epoxy-5P-cholestan-3o<-ol ( 2 3 ) as colorless prisms; m.p. 163-164°, H  )  2  (cf. P l a t t n e r 162°,  [o<]  D  +  +  0  29  25°  m.p.  (c «  I.R. (nujol):  0.41),  158-159°,  [«0  +  D  31.4°;  3450  Collins  s (sharp); 3 0  m.p.  161-  25°) .  X-ray irradiation: a few mg. of 4P, S-epoxy-Sp-cholestan-S*ol ( 2 3 ) was bombarded for 2 days yielding material of depressed m.p.  154-161°.  i a l of m.p.  30  mg. was irradiated for,  140-157°.  1  week yielding mater-  Comparative infrared spectra (KBr) of  starting material and the irradiated sample showed broad absorption in the carbonyl region of the latter with a weak maximum at 1715 cm" . 1  The U.V. spectrum of the irradiated sample also  possessed a maximum at 2 4 0 my (€  m  236).  T.L.C. (alumina,  benzene:ether 4:1) showed the major component was starting material, ca. 9 0 - 9 5 % , R^ =  0.52,  but at least four new products  also were indicated: Rj = 0.03, c_a. 5%; R^ = 0.82, ca. 1%;  108 R  f  = 0.35,  c a . 0.1%; R  t h e m a j o r component (Rj = 0.10) is and  (ca.  5%)  c a . 0.1%.  as w e l l  remain u n i d e n t i f i e d .  U.V. evidence.  expected  as one o f t h e . m i n o r o n e s  (19)  (From t h e U . V . d a t a  (/\max 240 mp,€ = 1 6 , 0 0 0 )  other  Of t h e new p r o d u c t s ,  The 1% component  b e l i e v e d t o be c h o l e s t - 4 - e n - 3 - o n e  en-3-one The  = 0.10,  f  3 1  by c o m p a r a t i v e  t h e amount o f  product,  Sft-hydroxycholestan-S-one  (22)  Jones'  2  and  reagent * 0  n-hexane  gave  isomers.  gave  (25).  a mixture of the 3,  m.p. 1 5 9 - 1 6 1 ° , (^l ,  1720 s ;  (cf. Plattner  2  4  5P-  with  r e c r y s t a i l i z a t i o n s from methanol °  5P-hydroxycholestan-3-one  plates;  m.p.  as t h e  5-epoxy-5P-cholestan-  O x i d a t i o n of the mixture  and s u c c e s s i v e  3 3  (0.35)  1.5%.)  (25)  a c c o r d i n g to P l a t t n e r ®  dihydroxycholestane  cholest-4-  5P-hydroxycholestan-3-one  L i t h i u m aluminum h y d r i d e r e d u c t i o n o f 4 P , 3-one  T.L.C.  c o u l d n o t be more t h a n  m i n o r component h a s t h e same R j v a l u e rearrangement  (R^ =» 0 . 8 2 )  + 4 5 ° , I.R.  (25)  as  colorless  ( n u j o l ) : 3400 s  m.p. 1 5 2 - 1 5 3 ° , M  D  + 62.3°;  (sharp),  Burgess  3 2  158-159°).  X-RAY DATA: Crystals are  colorless  developed.  of the p-bromophenacyl e s t e r prisms elongated  a l o n g a., w i t h  (001)  and (010)  The d e n s i t y was measured by f l o t a t i o n i n aqueous  potassium i o d i d e ;  and t h e u n i t - c e l l  d i m e n s i o n s and s p a c e  were d e t e r m i n e d f r o m v a r i o u s r o t a t i o n , ion  of h i r s u t i c acid C  group  W e i s s e n b e r g and p r e c e s s -  p h o t o g r a p h s and o n t h e G . E . s p e c t r o g o n i o m e t e r .  During the  109 analysis  i t became a p p a r e n t  a molecular  rearrangement,  minor changes  in crystal  that which,  of  dimensions corresponding  the u n i r r a d i a t e d  relatively measured  short  produced o n l y  One m a n i f e s t a t i o n  as p o s s i b l e  c r y s t a l s were d e t e r m i n e d  exposures,  very  of  this  i n u n i t - c e l l parameters;  as c l o s e l y  and t h e f i n a l  on t h e S p e c t r o g o n i o m e t e r  intensity  however,  structure.  r e a r r a n g e m e n t was a s m a l l change cell  i r r a d i a t i o n was i n i t i a t i n g  after  unit-  to those  from f i l m s w i t h  cell  d i m e n s i o n s were  the completion o f the  measurements.  Crystal  Data  (A, C u - K « = 1 . 5 4 1 8  p-bromophenacyl ester Orthorhombic,  of h i r s u t i c  S; "A, Mo-K« =0.7107 X)  acid,  C23H25Oj.Br; M =» 4 6 1 . 3 .  initial:  a = 6.49 + 0.03,  b = 9.14 + 0 . 0 3 ,  c =»  3 5 . 6 4 + 0 . 0 8 X, f i n a l :  a = 6.56 + 0 . 0 3 ,  b = 9.38 + 0.03,  c  35.14 D  + 0 . 0 8 8 . U = 2114 %  '=» 1 . 4 6 + 0 . 0 1  3  (initial),  (unirradiated  2162 X  crystal),  Z -  3  (initial), p(Cu-K«) absent  1.42  (final).  = 31 c m " . 1  spectra:  Absorption coefficient  F (000) -  952.  Space  (final);  4 , D  va  -  c  » 1.45  f o r X-rays,  group P 2 2 2 1  ]  hoo when h i s o d d , o k o when k i s o d d ,  1  (D^);  ool  when 1 i s o d d . T h r e e c r y s t a l s were u s e d t o o b t a i n three-dimensional dimensions pectively. film,  data.  One c r y s t a l  intensity  I n t h e f i l m measurements,  l k l . . . 4 k l layers  t o a , b and c  was u s e d t o r e c o r d  for direct  sets of  The two main c r y s t a l s h a d  0 . 0 2 and 0 . 1 mm. p a r a l l e l  and t h e o t h e r  techniques. Okl,  1.1,  intensity  two c o m p l e t e  were r e c o r d e d  res-  the i n t e n s i t i e s on  measurement  by c o u n t e r  the i n t e n s i t i e s  of the  on e q u i - i n c l i n a t i o n  110 Weissenberg f i l m s w i t h Cu-K^ r a d i a t i o n , and were estimated visually. posures.  The l a y e r s were s c a l e d i n i t i a l l y A third,  by t i m i n g the ex-  l a r g e r c r y s t a l was used f o r r e c o r d i n g the  weakest r e f l e x i o n s .  A t o t a l o f 800 r e f l e x i o n s was  observed,  150 of these being very weak and v i s i b l e o n l y on the f i l m s of  the l a r g e r  crystal.  For the counter data, the c r y s t a l was s i m i l a r l y mounted about the a a x i s .  The i n t e n s i t i e s of a l l r e f l e x i o n s w i t h 2 ©  ( C u - K « ) ^ 1 0 2 ° (corresponding to a minimum i n t e r p l a n a r s p a c i n g d =» 0.99 °0 were measured on a General E l e c t r i c XRD-5 S p e c t r o goniometer, w i t h S i n g l e - c r y s t a l O r i e n t e r , s c i n t i l l a t i o n approximately  monochromatic Cu-K^  radiation  counter,  ( n i c k e l f i l t e r and  p u l s e - h e i g h t a n a l y s e r ) and u s i n g the moving c r y s t a l - m o v i n g counter t e c h n i q u e .  1 3  Of the 1379 r e f l e x i o n s i n the range 0 <•  2 © < 1 0 2 ° , 798 had i n t e n s i t i e s g r e a t e r than twice the background, and these were used ment.  i n the s t r u c t u r e d e t e r m i n a t i o n and r e f i n e -  F i n a l s t r u c t u r e f a c t o r s were c a l c u l a t e d a l s o f o r the 186  r e f l e x i o n s w i t h i n t e n s i t y between one and two times the background, and f o r the 395 unobserved r e f l e x i o n s .  F o r both the  v i s u a l and counter data, the a p p r o p r i a t e L o r e n t z and p o l a r i z a t ion  f a c t o r s were a p p l i e d and the s t r u c t u r e amplitudes d e r i v e d .  No a b s o r p t i o n c o r r e c t i o n s were c o n s i d e r e d necessary. Structure Analysis: The v i s u a l data, obtained f i r s t , ary  stages o f the s t r u c t u r a l a n a l y s i s .  bromine atom was determined  was used  i n the p r e l i m i n -  The p o s i t i o n o f the  from the three Harker  s e c t i o n s of  Ill the  three-dimensional Patterson  f u n c t i o n as  (0.101,  0.216,  0.146),  « *  and a t h r e e - d i m e n s i o n a l F o u r i e r s e r i e s b a s e d o n t h e b r o m i n e atom. distribution were ing  On t h e r e s u l t i n g  28 o f t h e 29 n o n - h y d r o g e n atoms  resolved, atom.  was summed w i t h  t h e epoxide oxygen  Structure  atom  (atom  phases  electron-density i n the molecule 17)  factors  were c a l c u l a t e d  factors  f o r B r , C , 0 of the  being the miss-  f o r t h e 28  atoms  M Br—2i  using the s c a t t e r i n g Tables  f o r X-ray Crystallography,  factor, phases not in  was 0 . 4 4 .  A second F o u r i e r  b a s e d on a l l 28 atoms,  reveal  the f i n a l  atom,  d e n s i t y near recalculated, phasing,  but t h i s  suggested  some  errors  o f r i n g C ; atom  and t h e r e was c o n s i d e r a b l e The e l e c t r o n - d e n s i t y  electron-  map was  only confirmed the p o s i t i o n s already deduced.  by ( b l o c k - d i a g o n a l )  cycles  d e n s i t y map d i d  w i t h a l l t h e atoms o f r i n g C o m i t t e d f r o m t h e  IBM 1620 c o m p u t e r . ^  Four  discrepancy  was summed w i t h  and s u b s t i t u e n t s  16 and 6.  The p o s i t i o n a l and i s o t r o p i c fined  series  but the e l e c t r o n  poorly defined, atoms  and R, t h e u s u a l  and i n f a c t  t h e l o c a t i o n o f t h e atoms  16 was r a t h e r  4  International  4  thermal parameters  least-squares  were  u s i n g a program f o r the  The f u n c t i o n m i n i m i z e d was Zw  reduced R to 0.34.  then r e -  The s c a l e  factor  (|F | - |Fc| ) 0  o f each  layer  ,  112 was  then  k|Fo|  adjusted  =  |Fc| exp ( A B S i n  squares  cycles  At  this  counter  stage  were  greater  reliable  and  |Fo | / 2 5 when  with  r e m a i n i n g atom t h r e e phases  than  background.  /w~ =• 1 when stage  the  were  d e v i s e d by P r o f e s s o r  u s i n g the coordinates  to 0.170.  I n an e f f o r t  a l l 28 a t o m s ,  series  (ii)  o f the  to  were  a l l atoms  except  ( i i i ) atoms o f t h e p - b r o m o p h e n a c y l g r o u p o n l y .  addition,  a difference  synthesis  5 , 6 , 7 , 1 6 was c a r r i e d  density d i s t r i b u t i o n s obtained were  a l l very s i m i l a r ;  already atoms"  found,  pretation. Attempts positions  16,  synthesis  16,  16 ,  meters f o r these  1  1  The t h r e e  from the F o u r i e r  be i n t e r p r e t e d  and 1 7 ,  17  provided further  Four cycles  to r e f i n e  16  out.  1  of least-squares  atoms,  17  1  of a l l  electron-  series  summations  by p l a c i n g  for this  reduced R to  larger  The inter-  0.124.  atoms i n any o f t h e  gave a n o m a l o u s l y h i g h  and gave  "half-  (see F i g u r e 4 ) .  support  structures with f u l l 17,  In  c o n f i r m e d t h e p o s i t i o n s o f t h e atoms  and c o u l d b e s t  at p o s i t i o n s  difference  they  b a s e d on t h e p h a s e s  locate  summed,  5,6,7,16,  atoms e x c e p t  Since  |Fo| ^ - 2 5  also,  and t h e c o m p u t a t i o n s  separate Fourier  based o n : ( i )  u s i n g t h e 798  twice  At t h i s  cycles  28 atoms r e d u c e d R f r o m 0 . 1 9 6 the  proceeded  i v programmes  Two l e a s t - s q u a r e s  least-  measured w i t h t h e  u s e d was  Fo « < 2 5 .  out using F o r t r a n  three  f o r a l l b u t t h e v e r y weak r e -  IBM 7040 c o m p u t e r was a v a i l a b l e  Trotter.  were  and t h e a n a l y s i s  t h e w e i g h t i n g scheme  carried  and a f u r t h e r  ) ,  0.26.  flexions, v/w" =  2  the i n t e n s i t i e s  with intensities  measurements  by a p p l i c a t i o n o f t h e r e l a t i o n :  Q / ^  2  reduced R to  equipment,  reflexions the  separately  R values.  thermal  para-  The c h e m i c a l  113 nature of them  (discussed  final  set  with 2e the  these " h a l f  of  later)  are  was summed,  taken  through  5; a p e r s p e c t i v e  Figure  4.  Refinement  less  was  also  cycles R to  i n the  The in  0.214; when " f u l l  the  atoms.  all  the  values for  are  to  is  shown i n  four  16, 16 , 1  the  preference  least-squares 17, 1 7  positions  latter  similar  favored  reduced  1  16,17, R  0.216, i n s i g n i f i c a n t l y  data f o r  984  shown i n  This  16, 17.  at  the  electron-density  distribution  positions  for  series  a c c u r a t e v i s u a l d a t a gave  value:  A  planes  Fourier  molecule  atoms" were used  reduced  for  centers  positions  at  visual structure factor  different.  case are  given  Table IA. At  and  atomic  discrepancy  using "half-atoms"  was c o r r e s p o n d i n g l y  oxygen  R b e i n g 0.136  1,  electron-density  s t r u c t u r e w i t h atoms at  involving  and c a l c u l a t e d  s e c t i o n s of  the  the  revealed  are  three-dimensional  drawing of  w i t h the  However t h e  they  measured  A final  Figure  results.  the  and s u p e r i m p o s e d  distribution  that  g i v e n in. T a b l e  reflexions.  bond d i s t a n c e s  f a c t o r s was c a l c u l a t e d  ^102°;  1379 p l a n e s  and t h e  indicate  structure  (Cu-Ko<)  observed  atoms"  this  point,  some c h e m i c a l  anomalies  i n the  the  X-ray  structure  i n f o r m a t i o n was r e q u i r e d X-ray  results.  pure p-bromophenacyl  ester,  suggested  irradiation  that  after  two compounds  i n the  appeared  the  that  a n a l y s i s was  but  crystal,  molecular  to  complete,  clarify  the  The o r i g i n a l c r y s t a l s the  results  t h e r e was  distributed  structure,  of  the  X-ray  a mixture randomly.  but n o t  the  were  of  analysis at  Thus crystal  least it  114 Table  1  h  0 0 0 0 0 0 p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 I 1 1 i 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I t [ I 1 1 1 1 1 1 1 1 1 ,L.  k  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 6 6 4  1.  C  2 4 6 a 10 12 14 16 1» 20 22 24 26 20 30 32 34 0 2  6 a 10 12 14 16 ia 20 22 24 26 28 30 32 34 0 2 4 6 S 10 12 14 16 16 20 22 24 26 2a 30 32 0 2 4 6 a 10 12 14 16 ia 20 22 24 26 0 2 4 6 a 10 12 14 16 ia i 3 3 7 9 11 13 13 i> I» 21 23 23 27 29 31 33 1 3 3  ft ft ft ft ft 6  A 6 6  0 8 0 6 8 0 8 8 8 8 1 1 1 1 1 1 1 I 1 1 1 1 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 5 _L  »  9 11 13 13 17 19 21 23 23 27 29 31 33 1 3 > 7  c rv  9 33.0 22.6 83.4 10.0 108.4 40.2 61.8 25.6 49.7 32.4 6.0 26.6 6.T 20.8 6.3 0. 8.2 211.7 123.7 104.0 66.0 18.2 132.6 13*6 12.3 35.0 48.4 21.8 9.2 12.2 17.1 12.3 8.9 0. 0. 60.6 48.1 21.1 36. T 30.1 58.2 39.1 40.4 9.5 12.1 10.8 0. 11.7 12.0 9.7 0. 0. 0. 3.3 10. I 7.0 14.3 8.0 4.7 9.1 21.4 6.2 0. 0. 0. 0. 3.1 0. 9.2 0. 0. 0. 0. 0. 0. 0. 94.9 91.1 144.6 41.9 51.0 23.6 23.3 32.2 8.4 29. T 16. T 16.6 6.1 13.4 16.1 0. 0. 16.0 52.9 37.B S1.0 23.8 23.3 39.3 10.6 29. a  M e a s u r e d and c a l c u l a t e d IT  i\  11.4 11.6 13.5 9.3 0. 10.9 9.1 0. 10.7 53.3 11.6  52.9 22.5 99.0 26.6 121.4 66.5 71.1 26.8 54.6 35.2 3.9 28.4 4.2 22.9 2.2 0.1 6.2 240.4 126.1 109.4 60.7 26.4 130.6 16.6 22.2 41.5 54.1 26.2 9.1 16.3 15.2 11.0 7.a a.9 6.3 97.0 47.6 23.3 33.9 29.0 90.2 31.4 44.9 11.6 19.0 9.4 2.3 14.7 14.3 9.8 9.1 4.9 4.0 7.B 6.7 9.0 13.5 ft.9 3.4 6.6 19.4 3.0 0.1 3.1 0.7 3.3 0.7 1.4 1.9 3.1 0.9 0.1 3.9 3.0 2. a 3.1 48.0 09.7 119.3 39.6 49.9 17.a 29.3 32.7 2.4 34.1 16.9 21.3 7.3 16.2 11. 7 1.0 0.9 12.5 49.4 42.1 78.9 24.9 23.0 10.0 19.5 26.9 16.4 16.2 14.9 12.7 9.3 19.2 7.3 1.2 20.0 91.1 11.9  *Tlr.  J M  1 1 1  5 5  1 I I I 1 1 I 1 I | I 1 I I I I | I 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2  5 5 5 5 5 3 5 7 7 7 7 7 f 7 7 7 7 7 9 9 9 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2  2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4  2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 j 3 3 3 3 3 3 3 3 3 3 1 3 3 3 3  4 4 4 4 4 4 6 6 6 6 6 6 6 6 6 6 6 ft 6 0 6 8 6 8 8 0 0 i i i I i i | i i i i i l | i 1 3 3 3 3  1  5  9 11 13 13 17 14 21 23 25 27 29 1 3 5 7 9 11 13 15 17 19 21 \ 3 5 7 0 2 4 6 8 10 12 14 16 10 20 22 24 26 26 30 32 0 2 4 6 6 10 12 14 16 18 20 22 24 26 20 30 32 0 2 4 6 0 10 12 14 16 10 20 22 24 26 28 30 0 2 4 6 8 10 .2 14 16 ia 20 2* 24 0 2 4 6 0 to 12 14 1 3 3 7 9 11 13 19 17 19 21 23 23 27 29 11 1 3 9 7 _ 2 _  13.2 IB. 3 10.6 10.3 19.a 13.0 10.7 10.3 0.2 6.1 0. 6.9 20.7 10.9 23.1 6.2 7.2 0. 1.7 7.4 0. 6.2 0. 0. 9.1 0. 0. 21.9 24.9 21.7 9.0 20.9 27.2 19.7 3.8 7.1 0. 0. 7.6 11.2 0. 7.4 0. 27.6 30.1 10.9 91.3 22.4 24.9 29.1 0. 17.0 9.0 6.1 0. 0. 6.2 0. 0. 0. 9.9 42.7 24. B 49.3 25.2 16.4 30.1 20.9 15.2 16.3 10.4 14.2 5.1 8.2 0. 0. 0. 21.3 la.a 18.7 17.7 11.3 25.4 15.2 0. 9.7 5.2 9.0 0. 0. 7.4 6.4 0. 0. 0. 14.2 0. 37.0 39.5 62.6 26.3 23.1 33.6 24.3 29.2 0. IS.6 11.1 12.7 11.0 0. 8.1 6. 15. 5 40.9 34.9 28.9 WM  12.3 19.4 16.9 6.9 14.6 11.9 13.3 9.0 9.1 5.2 4.9 7.9 17.0 8.7 21.6 7.2 9.1 4.8 6.3 11.2 3.9 7.5 1.3 2.6 4.0 9.4 6.9 11.6 18.0 27.1 1.0 17.7 29.9 16.9 7.7 1B.1 1.7 0.7 6.6 14.1 0.8 9.9 9.0 26.9 27.0 6.6 47.3 22.0 27.4 26.4 2.9 17.7 11.0 12.9 6.1 7.7 11.1 4.9 1.0 1.6 1.5 41.1 24.4 40.0 22.6 16.2 28.6 20.9 19.7 14.9 12.1 16.6 8.4 12.1 0.5 2.5 5.7 19.6 17.0 16.6 19.9 10.9 24.6 10.5 6.2 7.4 6.4 10.2 1.4 1.2 9.9 7.9 4.3 5.8 7.5 13.2 3.7 28.3 37.4 53.0 21.7 20.4 37.4 24.9 33.6 4.3 16.1 13.8 14.4 14.4 3.1 9.7 4.1 28.6 38.7 31.1 29.6 23.2  structure  19.3  14.5  16. 15.  19.6 13.2 It.6 6.4 3.1 3.0 9.8  20.7 24.2 6.4  7.8 29.6  31.7 19.4 10.6 12.3 0. 0. 0. 6.2 4*.6 13.9 19.0 13.8 22.7 20.6 9.4 21.3  9.6 _19i7_  12.2 0. 6.1  9.0 0.  3.2 0.  ~TY7F 0. 9.2 6.2 3.7 10.4 5.2  14.5 11.8 11.8 11.9 11.2 12.4 9.1 18.6 21.4 5.1 2.9 2.6 3.7 6.2 5.0 12.6 6.8 5.9 7.6 3.3 7.7 36.4 10.9 25.9 I. 9 20.5 17.9 3.1 31.7 23.0 10.3 15.4 0.7 5.5 3.5 4.7 39.6 10.B 17.0 9.9 22.1 20.4 6.1 16.0 12.0 17.9 11.0 7.6 7.1 21.9 9.9 !+ 5.0 16.0 11.3 5.3 7.3 »r» 8.9 1.9 3.1 3.5 7.9 4.3 4.3 7.9 3.4 2.3 3.3 2.7 6.4 11.8 9.2 2.4 4.1 2.9 ?.* 4.9 1.5 1.1 ' 4.2 3.2 II. 9 6.a 3.4 5.7 3.0 4.5 1.6 3.7 2.9 4.0 3.2 4.4 11.7 2.a 6.0 2.5 10.2 12.3 TTio.s 5.7 8.0 1.5 L±P_  6 6 6 6 6 6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 I 1 I 1 I t 1 1 1 1 1 1 1 1 t I 1 1 1 1 I I I 1 1 1 1 I 1 1 1 I 1 1 1 1 1 1 1 1 1 \ \ 1 1 1 1 1 I 1 1 1 1  2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 6 6 6 6 6 6 6 6 6 6 6 6 6 6 0 8 6 B 8 8 8 6 8 1 1 I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 3 3 1 i 1 1 1 3 3 3 1 3 1 3 3 1 5 5 5 5 5 5 5 5 5 5 5 5 5 5 9 7 7 7 7 7  0. 0 6.4 2 0. 4 0. 6 0. a 5.1 10 a. 12 1 74.0 3 17.5 5 15.0 7 a.2 9 17.3 19.5 11 38.6 13 13 29.a 17 12.9 19 18.4 16.4 21 21 10.0 9.4 25 27 0. 29 0. 5.2 31 13 0. 1 13.4 3 25.3 5 46.5 7 11.8 9 39.5 11 26.9 11 15.5 15 12.2 17 16.7 19 5.5 21 q. 23 11.0 6.2 25 27 8.9 29 12.7 31 0. 1 16.4 3 31.0 5 13.3 5.3 7 28.1 9 30.3 11 13 0. 15 16.7 17 0. 19 8.9 21 0. 23 0. 25 11.5 27 0. 25.3 1 0. 1 3 0. 7 0. 9 0. 6.4 11 0. 13 5.2 15 17 0. 116.0 0 2 64.3 4 44.9 86.4 6 115.7 8 10 40.3 12 36.0 14 28.3 16 42.7 IB 39.5 20 10.3 9.2 22 10.2 24 14.4 26 B.7 28 30 0. 32 7.3 34 0. 35.6 0 17.5 2 4 46.1 31.2 ft 17.7 a 35.0 10 26.3 12 19.5 14 16 17.0 18 31.1 20 11.7 15.8 22 24 0. 2ft 10.6 0. 20 0. 10 0. 12 36.9 0 11.7 2 27.4 4 38.2 6 13.7 8 10 25.6 12 0. 14 17.6 16 s.y IB 0. 10.0 20 14.6 22 ' 24 0. 6.4 26 28 5.1 12.9 0 2 0. 4 16.7 16.6 6 a 0.  amplitudes 1.4 4.3 5.0 2.9 0.9 3.9 1.9 81.9 12.9 22.3 12.5 14.2 20.1 19.7 19.8 18.4 22.9 16.6 11.9 19.5 0.2 6.7 7.8 0.3 9.1 18.1 49.6 17.0 42.1 26.1 14.3 32.7 16.4 8.2 2.1 15.7 13.0 9.6 13.0 1.6 16.1 29.4 12.5 4.4 22.1 30.9 5.0 16.1 6.4 12.a 0.9 4.3 14.6 0.9 23.4 2.6 3.0 1.4 7.6 7.3 2.8 7.6 1.1 112.1 60.7 44.0 92.4 113.4 51.6 43.4 23.4 90.4 44.5 9.9 13.2 10.1 18.6 9.5 2.9 6.0 4.5 37.9 40.3 46.2 27.4 24.5 51.7 2».B 26.4 21.9 30.8 13.7 21.8 9.6 11.9 9.4 7.7 6.0 43.3 14.2 21.7 36.6 11.9 21.9 7.1 16.9 6.9 2.4 11.9 12.4 5.7 7.6 5.5 12.9 0.5 16.6 16.9 4.3  1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Z 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 3 3 3 3 3 3 3  7 7 7 7 7 7 7 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 6 6 6 ft ft 6 6 ft 6 6 6 6 a 8 6 8 8 8 B a 1 I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 5 9 9 5 9 5 5  10 12 14 16 IB 20 22 0 2 4 6 8 1 3 5 7 9 11 11 13 17 19 21 23 29 27 29 31 33 1 3 9 7 9 11 13 15 17 19 21 23 25 27 29 31 1 3 5 7 9 11 11 15 17 19 21 23 25 27 29 1 3 5 7 9 11 13 13 17 19 21 21 1 3 5 7 9 11 13 15 0 2 4 6 8 10 12 14 16 IB 20 22 24 26 28 10 0 2 4 6 6 10 12 14 16 18 26 22 24 26 28 0 2 4 6 0 10 IZ  0. 0. 0. 13.3 5.2 0. 0. 0. 0. 7.3 0. 0. 25.6 137.2 25.4 00.8 21.6 86.9 63.6 25.4 19.0 11.1 22.2 21.4 6.0 0. 0. 0. 0. 42.1 91.0 16.3 47.1 20.1 37.5 50.0 6.2 33.3 6.9 12.1 21.4 7.0 5.1 0. 5.1 23.7 36.4 18.6 12.1 0. 22.9 22.7 22.1 13.1 4.8 12.6 11.4 0. 6.3 0. 5.7 13.6 17.0 0. 6.9 0. 19.5 17.7 0. 0. 0. 0. 0. 3.7 5.2 0. 0. 0. 0. 0. 0. 19.1 21.7 37.a 36.9 14.8 a.4 6.3 0. 8.5 7.4 0. 5.0 0. 0. 0. 45.9 17.4 17.5 9.0 0.3 32.3 6.9 11.9 10.9 21.8 15.7 0. 7.3 6.1 0. 11.9 17.3 20.9 14.2 16.9 20.4 0.  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A.2 28.8 19.0 2T.2 A.6 16.1 5.9 13.6 5.1 6.3 12.3 0. 0. 0. 12.7 8.2 16.5 5.2 6.4 0. 0. 0. 83.0 2T.0 10T.1 16.0  P-*  62.0 94.T 14.3 1A.0 4.5 30.5 4.0 14.0 0.6 5.1 5.5 4T.9 41.0 54.3 36.1 23.6 24.3 10.4 20.T 17.3 22.1 21.8 7.4 12.6 9.2 29.6 1T.6 13.2 26.5 3.7 23. 7 6.7 14.2 3.6 6.2 10.4 9.2 9.1 2.2 8.0 3.0 108.1 72.5 72.2 46.8 135.0 14.9  k  14. 63.0 3.5 63.6 27.9 18.1 17.5 1.5 17.2 3.6 3.7 09.4 89.5 54.1 28.4 86.7 76. 3 30.3 40*9 14.3 44.3 15.1 5.0 22.3 6.1 9.8 7.3 2.4 46.8 25.9 40.3 30.6 59.1 19.3 6.1 32.6 16.7 9.3 21.9 6.9 11.7 3.2 6.3 2.1 4.4 2T.6 18.5 26.1 9.6 14.8 a.o 18.6 6.1 a.5 12.5 3.A A.I 2.2 10.4  T.l  14.A B.2 8.7 2.A 7.8 3.3 61.5 24.9 103.2 12.0 17.2  2  2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 ' 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4  |  10 12 14 IA \B 20 22 24 2A 26 30 l 32 3 0 3 2 3 4 3 6 3 6 3 10 9 12 3 14 3 16 3 18 3 20 3 22 3 24 3 26 3 26 3 30 5 0 5 2 5 4 3 6 3 a 5 10 5 12 5 ~ 14 ~ 5 16 5 16 5 20 5 22 5 24 S 26 7 0 7 2 7 4 7 6 7 8 7 16 7 12 7 14 7 16 7 16 7 20 1 .0 3 0 0 3 0 7 0 9 0 .11 13 0 0 15 0 17 0 19 0 21 0 23 0 25 0 27 29 31 2 I 2 3 2 5 2 T 2 9 2 11 2 13 2 15 2 17 2 19 2 21 2 23 2 25 2 27 2 29 4 1 4 3 9 4 4 T 4 9 4 11 4 13 4 19 4 17 4 19 4 21 4 23 4 25 4 27 6 1 6 3 £ S £ 7 A 9 6 6 13 6 15 6 IT 6 19 A 21 e 1 g 3 6 5 8 7 9 6 1 0 1 2 1 4 6 1 1 1 1 1 1 1 1 1 1  l  o o  tl  49.A 25.9 99.3 29.2 33.9 22.0 6.4 24.6 9.3 11.4 0. 6.3 81.6 24.4 40.6 34.9 24.2  t  50. 32.5 90.6 19.9 19.7 9.T 10.8 T.9 T.2 6.2 0. 33.2 10.3  l$.A  O 7.0 25.1 8.0 11.7 9.2 13.6 0. 0. 0. 0. 0. 6.2 0. 0. 0. 6.1 6.4 0. 0. 8.2 0. 6.3 26.0 24.1 29.6 52.0 1A.T 0. 22.2 12.9 16.2 4.6 10.A 0. 3.2 0. 0. 3. A 28.9 33.1 30.9 32.3 24.5 14.3 13.1 21.6 10.5 6.0 6.2 0. 5.2 0. 12.0 24.8 21.9 30.4 11.5 17.3 12.5 6.9 20.1 14. T 9.6 0. 0. 5.1 13.1 16.5 5.0 17.9 12.0 8.4 0. 0. 16.1 0. 0. 0. 6.9 0. 8.9 0. 25.9 26.1 28.5 28.2  48.1 27.9 AO. 8 36.3 37.A 25.1 11.9 ZT.e 11.8 12.7 2.0 10.0 69.1 23.0 36.2 29.1 21.2 4T.3 34.9 92.9 21.9 16.9 9.1 9.9 6.3 T.6 8.1 3.0 30.9 9.2 11.8 3.7 9.8 29.3 6.8 11.6 6.9 10.3 3.8 9.6 4.1 1.9 3.6 5.4 4.1 3.7 4.6 1.2 9.6 6.0 3.9 6.1 2.2 4.9 27.8 20.1 29.5 46.9 17.7 8.3 24.2 17.0 21.5 6.7 9.3 3.0 8.7 6.7 0.8 19.8 24.3 27.8 28.5 32.3 2T.T 12.4 10.4 22.T 9.9 10.2 3.9 3.8 T.T 4.1 13.9 23.2 26.6 31.2 16.1 IT.3 10. 1 T.6 21.4 13.2 8.2 3.4 3.9 4.7 10.A 10.8 3.8 1A.1 7.7 7.9 7.4 3.0 12.2 7.0 4.8 4.9 7.2 3.9 6.2 2.6 19.9 22.3 25.0 24.4  4 ' t 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 5 4 5 4 5 4 5 4 5 4 5 4 5 4 3 4 S 4 5 4 S 4 7 4 T 4 T 4 7 4 7 5 0 5 0 5 0 S 0 5 0 5 0 5 0 5 0 5 6 5 0 5 0 9 2 5 2 5 2 5 2 9 2 5 2 5 2 9 2 3_ 2 5 2 5 2 5 4 5 4 9 4 9 4 5 4 5 4 9 4 5 4 9 4 5 6 5 6 6 1 6 1 6 1 6 1 6 1 6 1 6 1 6 3 6 3 6 3 6 3 6 3  6 10 12 14 16 18 20 22 24 26 0 2 4 A 6 10 12 14 IA 18 20 22 24 0 2 4 A 8 10 ii 14 16 18 20 0 2 4 A 8 1 3 5 7 9 11 13 15  IT  19 21 1 3 5 7 9 11 13 15 IT 19 21 1 3 5 7 9 11 13 13 17 1 3 0 2 4 A a 10 12 0 2 4 6 8  14.2 14.8 0. 13.T A. 8 0. 5.1 5.1 0. 0. 19.8 29.7 20.9 17.4 18.A 12.7 17.4 5.0 7.1 5.1 7.3 8.2 5.1 0. 17.8 13.5 8.9 7.3 14.7  U.8  11.1 0. 0. 0. 7.3 6.3 S.2 0. 0. 22.3 10.9 16.3 6.1 20.1 13.4 9.6 9.0 0. 0. 0. 12.7 15.9 18.9 0. 8.0 0. 5.2 8.2 0. 8.1 0. 5.2 7.4 7.4 5.2 0. 0. 0. 0. 0. 0. 0. 23.3 12.3 6.4 3.2 0. 7.2 0. 7.3 0. 5.2 0. 0.  14.7 14.0 5.2 17.2 5.3 l.A 1.9 5.5 2.0 9.0 10.3 2T.0 16.0 12.8 13.) 11.) IT.4 4.6 4.2 5.0 8.7 8.) 6.T 1.2 15.5 9.T 10.) 12.1 6.2  14.4  10.3 0.9 2.6 4.5 6.9 S.T 5.4 5.2 7.8 19.2 T.3 15.6 4.3 14.8 14.1 8.7 8.9 5.3 0.2 0.) 10.7 12.4 15.8 4.9 6.6 6.4 3.0 A.8 4.0 t.3 l.A 1.4 7.7 3.8 4.5 5.0 5. A t.S 3.0 2.4 2.1 1.8 14.7 8.3 4.1 2.2 3.0 5.1 2.1 A.l 2.1 6.0 1.5 4.3  116 Table  IA.  Measured 31 35 37 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 3 13 15 19 21 25 27 27 33 1 3 7 - 15 2 4 6 8 10 12 14 16 IB 20 20 22 22 24 26 26 20 28 30 30 2 4 4 6 8 10 12 14 . 16 18 18 20 22 74 24 26 2 4 6  £  IcX K» o 0 0 0 0 0 0 0 Q 0 0 0 0 0 g 0 0 0 2 2 j 2 2 2 ' 2 2 2 2 2 2 2  4 4 4 4 4 4 4 4 4 4 4 4 4 4  ft  2 2 2 2 2 2 2 2 2 2  2 2 4 4 4  2 4 6 S 10 12 14 IA 16 20 22 24 2ft  ?ff 30 30 34 0 2 4  ft  8 10 12 14 IA 18 20 22 24 2ft 28 32 0 2 4 6  ff  10 12 14 1ft 1ft ia 20 22 24 24 26 ?fi 2 8 10 14 m 22 24 1 3 3 7 9 11 13 13 17 19 21  ?\  1 I I I I  23 27 1 3 3 7 9 11 13 15 17 19 19 21 23 23 25 25 27 27 29 1 3 7 9 13 15 17 23 1 1 3 5 7 9 11  I I 1 I I | 1 1  17 19 21 23 23 27 29  4 4 4 4 4 4 4 4 4 4 4 4 4  ft ft ft ft ft 6 6 B  n 15  0. 39.5 112.4 17.7 148.3 77.6 65.3 26.6 60.1 33.6 0. 35.5 0. 22.a 0. 9.1 11.9 269.6 131.5 129.2 80.9 19.5 159.9 17.3 21.6 37.0 71.9 23.2 10.1 15.0 7.1 11.6 12.0 50.2 34.0 24.4 29.6 20.0 56.4 30.7 41.5 0. 4.4 10.2 10.7 7.0 7.3 11.5 11.8 17.0  20.2 21.0 21.4 11.2 9.2 5.4 9.3 00.9 7.4 11.1 5.9 15.7 25. 8 47.0 35.7 21.0 22.4 23.9 10.1 6.9 O.J 3.4 15.3 39.8 O.  31.2 17.4 12.8 26.9 19.9 0. 4.7 6.9 7.2 12.4 0. 9.0 0. 9.2 12.0 7.8 14.3 A.O 21.2 11.1 16.0 5.2 5.4 11.9 H . A  17.6 55.2 32.3 25.5 65.6 41.5 64.6 30.5 6.8 18.6 10.0 24.1 15.6 0.  50.2 74.7  103.9 21.5 123.0 57.6 76.3 23.2 45.7 30.4 6.3 27.9 2.8 17.9 0.1 0.1 3.9 250.5 120.4 103.1 74.7 24.7 125.9 19.4 23.4 35.7 45.6 21.0 9.4 16.6 10.0 10.2 6.1 53.3 32.0 25.6 33.7 11.9 51.7 27.0 32.6 6.0 6.0 13.a 4.6 1.2 a.3 8.3 a.a 5.7 4.0 4.2 3.7 5.1 4.0 1.0 1.1 78.2 17.2 15.3 a.4 12.2 25.3 14. A 31.4 20.3 16.6 16.1 1Q,9_ 7.3 1.9 6.3 11.0 36.2  S  10 12 14 16 IB 20 22 24 26 32 2 4 6 6 12  4.3  32.3 14.7 11.9 27.0 18.3 3.1 3.1 4.2 10.3 10.3 9.4 9.4 3.3 3.3 6.3 4.3 19.2 4.B  14.0 0.3 10.6  1.3  2.8 10.0 46.7 25.4 91.0 31.4 24.7 48.7 23.1 47.6 23.5 0.6 15.6 7.1 21.3 13.2 0.0  h= 1  and c a l c u l a t e d  16.9 11.8 10.1 76.6 77.9 6.7 27.8 14.6 7.7 fl.2 17.3 16.4 0. 25.2 0. 22.6 11.7 5.3 35.6 10.1 10.4 5.0 16.3 9.3 7.6 10.7 4.8 15.9 11.2 5.1 7.5 47.9 101.5 99.6 5.4 22.5 36.2 58.7 15.7 12.0 0. 4.1 0. 10.7 0. 6.9 9.8 0. 8.9 7.5 10.6 71.6 0. 2.9 45.0 28.4 28.1 48.9 51.9 B.9 0. 6.0 0. 29.8 0. 4.9 11.5 35.4 33.a 40.7 34.9 23.3 24.3 10.3 21.3 B.5 1A.1 16.5 11.9 12.0 5.0 11.2 11.3 11.4 11.5 7.4  10.2 7.5 6.5 65.1 68.9 5.9 31.9 11.5 2.7 2.6 19.3 18.3 1.5 17.5 2.5 16.3 B.l 1.7 32.5 0.5 5.2 6.1 7.1 6.4 1.6 1.6 0.7 6.5 3.1 1.6 0.9 43.0 91.9 74.5 6.3 28.3 31.9 36.6 15.6 18.6 5.9 5.9 8.6 a.6 5.0 2.5 2.5 1.6 1.6 3.0 3.0 63.3 10.8 10.8 44.0 30.0 27.4 55.1 51.2 12.6 10.1 10.1 1.5 23.5 4.7 4.7 7.9 38.0 33.3 41.9 77.9 20.7 22.1 10.0 16.0 12.4 12.9 14.3 4.2 7.6 1.9 16.8 12.8 11.3 16.7 15.5  1 1 1  1 3 5  34.9 67.7 109.6  1 1 1 1 1 1 1 1 1 1 1  3 3 3 3 3  9 11 13 IS 17 19 21 23 25 27 29 1 3 5 7 9 11  50.9 15.5 24.0 26.1 3.5 10.4 17.8 19.0 2.6 B.6 6.3 B.5 29.6 28.2 61.8 17.9 13.4  39.1 B1.4 141.5 27.1 47.6 17.6 26.4 31.2 1.0 31.7 12.6 19.4 6.2 12.0 10.1 10.B 36.3 40.5 73.1 20.4 20.7  3 3 3 3 3 3 3 3 5  15 17 19 21 23 25 27 29 1  6.7 22.5 13.0 5.6 11.8 8.7 4.9 9.1 13.7  12.2 22.6 11.5 11.6 10.9 9.0 6.0 9.3 22.0  )  5 5 5 5 5 5 5 5 5 5 5 7 7 1 1 1 1 1 I 1 1 1 1 1 I 1 1 1 I 3 3 3 3 3 3 3 3 3 3  ^ 3 5 5 5 5 5 5 5 5 5 5 5 5 5 7 7 7 0 0 0 0 0 0 0 Q 0 0 0 0 0 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4  ft ft ft ft ft 6 6  8 8 8 0 0  o  0 0 0 0 0  o  0 0 0.  3 7 11 13 15 17 19 21 2? 25 27 3 7 0 2 4 6 8 10 12 14 16 18 20 24 26 26 32 0 2 4 6 a 10 12 14 16 18 20 22 ?4 26 0 2 4 6 in 12 14 16 20 22 74 26 28 0 4 6 2 4  32.3 16.8 7.5 11.0 5.7 8.3 6.1 6.3 8.1, 6.3 2.9 8.6 a.a 69.4 43.7 32.7 76.7 107.3 53.5 33.2 31.7 42.9 37.1 7.0 10.6 13.8 11.9 4.8 5.0 14.6 23.7 34.0 25.2 9.5 41.1 23.a 17.7 13.B 35.0 13.4 11.3 7.7 7.9 1B.1 4.B 15.5 18.6 14.A 4.2 11.2 4.5 7.a a.9 2.9 2.9 5.0 2.7 8.7 8.7 19.3 157.8  39.6 21.4 10.7 14.0 5.0 8. 3 7.7 7.7 6.7 5.2 1.4 15.9 12.2 91. B 56.9 35.7 96.8 112.9 53.6 38. 8 22.3 48.9 35.9 6.3 12.6 9.6 10.2 3.9 1.7 22.9 29.4 42.2 26.0 17.9 46.1 22.2 18. B 14.6 25:7 i i . a 15.3 1.9 6.7 29.5 7.5 IB.3 25.6 15.4 3.3 12.6 5.7 7.3 10.2 1.9 3.6 2.6 9.6 10.5 9.B 23.5 170.0  a 10 12 14 IA 18 22 26 30 32 0 2 4 6 a 10 12 14 16 IB 20 22 26 28 32 0 2 4 6 B 10 14 18 20 22 24 0 4 10 14 16 20 22 0 2 6 1 3 5 7 9 11 13 15 1? 21 23 25  22.7 7.8 49. B 17.3 14.6 15.8 14.9 a.7 9.0 9.1 17.1 39.7 65.7 BO.6 62.6 10.3 31.4 23.9 6.4 16.8 5.2 19.0 8.6 6.3 5.0 29.9 18.6 13. a 55.9 20.0 5.9 25.9 5.6 5.B 6.0 7.9 11.0 11.1 11.7 7.7 6.2 2.9 4.1 4.1 2.9 4.1 38.6 57.3 56.0 29.9 120.8 4.7 16.5 57.1 61.0 12.5 10.9 B.l  26.0 2.0 57.3 14.0 15.2 19.7 14.9 9.2 5.8 12.1 20.3. 44.9 78.3 85.6 69.6 12.5 79.9 22.8 4.3 14.6 7.9 1B.1 6.1 5.0 4.9 35.4 33.4 32.0 56.5 29.6 11.2 25.7 10.8 6.0 11.1 5.3 15.3 16.5 11.6 11.9 5.4 4.6 2.4 a.o 2.0 4.2 84.5 74.3 67.8 32.1 121.1 7.6 16.4 51.0 57.6 18.2 16.5 14.7  ??  structure  0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 A— 4 4 4 4  29 8.9 1 80.8 3 86.9 42.9 5 7 16.4 9 85.8 11 67.6 13 32.5 15 40.1 17 4.7 19 40.7 21 13.0 23 3.6 25 11.9 29 B.l 1 33.2 3 16.B 5 21.8 7 13.9 9 52.4 11— 13 12.2 15 26.3 17 13.3 19 13.9  4 4 4 6 6 6 6 6 6 6  23 25 29 3 5 7 11 15 17 21  h*2  Q  0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4  12.2 26.3 12.6 10.6 ,15.3 3.5 7.0 3.0 15.7 10.4 17.5 10.2 12.5 4.3 8.0  10.2 IB.9 11.4 2.3 15.0 23.5 23.1 6. a 5.2 4.7 19.4 19.7 7 . ft 39.3 20.2  32.2 _5_*0_ 8.3 11.1 12.3 24.0 17.1 14.2_ 5.7 7.6 20.6 21.9 —l*X. 44.9 16.6  12 14  29.3 2.0  IA  1 1.7  24.7 5.8  -s-a-  0 0 0 0 0 0  4.8 11.0 5.0 11.1 7.9 11.3 4.6 8.7 2.8 6.4  12. B 78.6 ' B4.2 42.6 21.3 77.6 62.5 30.3 39.9 12.7 37.4 13.0 6.4 15.4 7.1 34.1 25.2 33.4 23.4 52.2  18 20 24 26 26 0 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 B 10 12 14 1 3 5 7 9 11 11 15 17 19 21 23 1 3 5 7 9 11 13 15 17 19 21 23 25 1 3 5 7 11  3.2 3.4 4.7 4.8 2.9 ?.n 29.2 20.0 37.1 17.7 15.5 22. A 18.4 11.1 11.6 8.5 8.8 2.9 11.2 10.9 8.2 8.3 8.4 6.0 14.5 6.3 9.2 101.7 15.3 67.5 20.0 90.3 89.7 27.0 13.1 2.2 16.B 13.9 26.9 74.2 11.1 40.7 18.1 54.4 42.9 2.1 25.1 4.1 13.7 16.6 4.7 12.4 25.0 11.1 9.3 17.3  15 17 21 23 25 3  18.8 13.9 11.6 8.9 2.9 7.3  ft  17. A  5.1 9.9 7.9 7.8 2.7 1. A 35.0 1B.1 29.a 15.6 9.9 25.a 13.A 11.4 11.0 8.6 10.2 4.4 8.9 10.9 11.5 9.9 12.2 7.1 14.0 7.9 lb.1 136.3 2.5 69.3 27.1 76.B H I . 1 28.7 IB.4 3.7 20.1 17.4 29.3 80.9 IB.9 41.9 13.3 52.5 49.8 6.1 26.3 4.3 19.0 17.4 9.6 14.5 29.2 16.2 B.3 11.9 _2.fi*3_ 16.8 11.3 11.1 9.1 2.9 9.6  6 6 ' 1 1 1 I 1 1 1 1 I I 1 3 3 3 3 3 3 1 3 3 3 3 3 9 5 5 5 5 5 5 1 1 1 1 i 1 1 1 1 1 I 1 1 1 1 3 3 3 3 3 3 3 3 3 3  5 13 1 3 5 7 9 11 13 15 17 19 21 1 3 5 7 9 11 11 15 19 21 25 27 t 5 9 11 13 15 19 0 2 4 6 a 10 12 14 16 IB 20 22 24 26 28 0 2 4 6 a 10 12 14 16 IB  J  20 22 24 26 2B 0 2 4 10 12 14 16 IB  3 ;j 3 3 5 5 5 5 5 5 5 9  h»3  1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 3 3 3 3 3 3 } t 3 3 3 3 3 5 5 5 5 9 5 5 5 5 5 5 1 1 1 1 1 1 1 1 1  1 3 5 7 9 11 13 15 19 21 23 25 27 29 1 3 5 7 9 11 13  ii 19 21 23 79 29 1 3 5 7 9 11 13 15 17 19 71 0 2 4 6 6 10 12 14 16  amplitudes B.2 8.1 B.3 11.9 28.2 34.6 22.3 23.1 9.3 10.5 53.6 53.5 26.9 27.7 33.5 41.6 21.8 22.7 19.6 19.5 21.0 17.2 10.1 7.3 2.4 5.8 24.4 24.8 10.A_ _19.4 21. B 20.2 13.9 13.4 38.7 38.9 49.0 51.2 1.0 6.6 14.3 19.9 8.3 15.7 7.8 5.4 8.B 6.3 4.1 4.3 79.9 7A.0 17.6 12.7 21.6 23.3 15.7 13.9 14.0 14.2 14.5 17.3 7.4 7.4 51.9 62.0 15.7 17.5 91.3 78. 9 10.4 2.9 22.0 19. B 35.2 39.1 24.B 24.3 57.0 53.9 25.3 23.1 29.0 31.6 19.5 20.9 5.6 8.5 20.7 16.6 4.8 8.5 6.4 9.5 59.1 60.2 20.9 22.0 33.6 28.a 26.1 24.a IB.4 20.1 39.7 36.1 23.3 27.4 48.4 47.2 13.1 16.2 18.7 16.2 8.0 6.2 4.0 4.1 20.3 2.3 2.3 15.5 2.5 3.7 2.7 4.R  6.7 3.9 3.B 5.9 23.6 9.1 10.4 17.7 4.1 13.7 2.7 6.B  20.7 23.7 42.6 14.6 16.3 25.3 19.6 23.5 13.4 9.0 9.4 9.a 1.6 1.6 22.4 27.0 27.8 19.6 20.6 11.9 6.9 19.6 11.6 12.2 4.8 4.4 1.6 1.6 10.4 7.4 7.5 a.a 11.9 2.5 4.7 4.8 15.6 15.9 7.1 1.8 14.5 11.A 25.3 27.1 9.4 4.6 3.5 6.6  32. B 27.5 53.4 17.0 14.4 28.1 21.7 25.7 12.5 9.9 7.9 5.2 3.ft 5.0 17.5 25.9 2ft.8 16.0 15.7 16.2 5.6 14.4 13.2 7.7 9.6 5.3 4.0 3.3 10.8 7.a 8.0 7.0 6.5 7.1 6.4 6.5 13.1 10.7 1.4 67? 20.7 71.2 30.5 31.6 14.1 13.7 4.1 7.6  ! 1 1 1 3 3 3 3 3 3 3 3 3 3 3 J 5 9 9 9 5 5 5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4  ft ft 6  2 2 2 2 7 2 2 2 2 2 7 2 2 2 2 2 * 4 4 4 4 4 4 4 4 4 4 6 6 6 6 6 ft  18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 24 26 20 0 2 4 6 8 10 12 14 16 IB 20 2 4 6 a to 12 14 16 IB 20 22 2A 2B 0 2 4 6  B.2 3.9 2.1 2.2 31.6 7.0 5.6 3.3 3.3 21.1 3.9 7.1 7.4 16.2 12.4 2.7 3.6 3.6 17.0 4.5 12.9 7.6 7.7 12.1 2.1 4.8 2.2 15.8 13.3 33.0 16.6 29.7 36.3 2.0 51.1 1.6 5.3 4.0 4.3 4.6 4.9 1.6 4.3 25.7 30.7 39.6  10 12 14 16 IB 70 22 24 26 28 30 0 2 4 6 8 10 12 14 16 18 20 22 ?t\ 6 8 10 16  19.4 22.8 9.2 20.1 17.1 a.4 17.0 3.5 5.0 1.6 1.6 5.7 8.3 3.B 3.9 15.9 a.2 9.A 9.9 12.2 12.6 3.5 3.5 4.5 4.6 2.2 2.2 3.6 5.9 17.2 12.9 13.6 40.9 5.2 2.3 13.0 5.5 13.2  1 3 5 7 9 11 13 13 17 19 71 23 25 27 29 31 1 3 5 7 9 11 13 17 19 21 27 , 1 3 7 9 11 17  9.1 16.8 27.7 19.0 11.4 19.2 11.5 12.3 19.4 8.a 9.7 4.3 3.5 3.6 1.6 1.6 5.7 11.8 10.1 17.5 7.0 9.4 3.1 14.8 11.8 5.0 2.2 3.3 3.4 1.5 1.5 1.6 3.6  (Visual 12.5 6.0 2.3 2.1 30.6 12.6 12.6 9.3 13.4 16.B 1.6 13.6 10.0 17.0 11.0 3.5 3.0 3.B 15.8 7.7 14.0 8.B 9.1 12.B l.B 7.0 3.6 11.5 6.8 39.1 21.7 39.a 38.3 6.2 44.5 3.6 11.9 11.4 10.4 16.7 9.9 1.1 0.7 25.1 32.B 34.7 37.iL 21.B 22.2 4. 7 17.3 10.3 7.7 13.9 5.1 6.1 1.3 2.3 11.2 13.4 12.1 14.7 17.3 9.7 10.7 4.6 6.5 9.0 5.8 4.0 3.9 3.6 4.7 2.4 1.9  K«4 0 0 0 e 0  o  0 0 0 0 0  0 0 0 0 0  1«  17 21 1 3 3 1 3 5 7 9 11 11  4.6 17.9 18.6  16.2 18.7 24.2 24.7 17.7 14.1 6.2 11.1 12.9 8.a 7.3 4.1 2.6 4.3 1.9 0.3 12.3 20.9 20.5 23.0 17.2 10.2 6.3 14.4 a.7 4.4 2.7 7.6 6.2 10.9 5.0 5.5 5.6  2 4 6 8 10 12 14 16 18 20 22 24 28 0 2 4 6 a 10 12 14 16 16 20 24 26 0 2 4 6 a 10 12 14 18 1 3 7 17 21 1 3 5 7 9 11 13 15 17 19 25 1 3 4 7 9 11 13  5 5  IS 17 19 21 1 3 7 9 11 13 17 19 21 23 1 3 7 9 11 0 7 4 6 a 10 12 1* 16 20 0 2 4 6 8 10 12 16 18 20 22 24 2 4 n 10 12  2.0 15.9 5.9 17.2 14.1 8.5 21.4 15.2 8.7 9.1 2.1 4.9 2.2 22.4 6.9 11.0 a.a 14.2 15.2 5.4 15.2 3.3 11.1 A.O 4.9 2.2 11.4 2.5 8.2 1.9 12.1 5.6 2.0 2.1 3.8 1.0 5.4 16.1 10.3 9.3 a.a 9.9 7.4 10.2 12.0 10.5 7.9 10.3 4.0 2.1 3.1 9.8 11.5 n.7 14.6 12.3 10.9 3.6 1.7 2.2 2.2 9.7 4.9 4.9 14.7 22.0 8.6 20.2 6.2 13.7 i*.q 3.7 17.0 2.0 6.6 11.9 12.1 12.9 1.7 12.9 13.5 5.9 6.0 4.9 3.1 9.0 3.5 6.6 6.0 6.8 8.6 12.6 14.3 16.3 8.4 9.2 2.3 10.9 5.8 2.9 9.7 17.6 11.2 11.6 12.0 B.O 13.2 5.7 4.7 1.1 3.1 3.a 9.0 6.4 4.7 4.7 4.a  data).  6.61 26.9 3.1 IS.5 13.0 5.2 20.6 13.9 B.l 7.6 0.5 3.5 2.3 24.7 6.2 9.8 10.1 IS.l 10.3 4.3 12.9 6.3 a.a 6.4 4.2 2.5 10.3 4.6 0.7 1.6 9.1 6.8 2.0 4.8 5.4 4.6 12.0 10.6 7.3 10.7 9.6 10.1 6.a 9.5 12.7 8.4 11.1 10.2 i.a 1.0 5.0 10.7 9.3 A.A  9.3 10.7 11.0 3.5 4.9 2.8 2.3 8.7 0.9 5.a 19.2 28.4 10.5 15.5 3.5 13.5 14.ft 11.3 16.3 2.1 6.5 19.1 16.1 14.9 3.1 12.2 12.9 6.5 5.8 5.6 3.6 9.6 6.0 4.6  ?.*  7.6 13.0 17.1 18.5 11.9 6.5 7.2 5.7 14.8 1.0 0.7 B.l 21.0 10.2 0.3 7.6 6.7 11.7 1.1 2.4 1.4 tti 3.3 9.5 3.5 6.9 2.8 8.2  Figure  4.  A p e r s p e c t i v e d r a w i n g o f t h e m o l e c u l e w i t h t h e atom n u m b e r i n g u s e d . The c o r r e c t a b s o l u t e c o n f i g u r a t i o n i s shown, t h e p o s i t i v e d i r e c t i o n o f t h e a - a x i s b e i n g towards t h e v i e w e r .  Figure  5.  Superimposed s e c t i o n s o f the t h r e e - d i m e n s i o n a l e l e c t r o n - d e n s i t y d i s t r i b u t i o n , t h r o u g h t h e a t o m i c c e n t r e s p a r a l l e l t o ( 1 0 0 ) ; c o n t o u r s f o r c a r b o n and o x y g e n atoms are a t i n t e r v a l s o f l e . A s t a r t i n g at l e . A " , and f o r t h e B r atom a t i n t e r v a l s o f 3e.A~* s t a r t i n g at 3 e . A . The c o r r e c t a b s o l u t e c o n f i g u r a t i o n i s shown, t h e p o s i t i v e d i r e c t i o n o f t h e a - a x i s b e i n g t o w a r d s t h e v i e w e r . - 3 ,  3  _ i  119 structure,  was d e c o m p o s i n g on e x p o s u r e  to  X-rays.  i o n was c o n f i r m e d by i r r a d i a t i n g s a m p l e s o f unfiltered  molybenum r a d i a t i o n .  was e s s e n t i a l l y w h i c h were (ca.  complete,  separated  40% y i e l d )  yield)  starting  was shown by I . R . ,  rearranged  product.  a mixture of  material,  U . V . and N . M . R .  As a f i n a l  check  when t h i s  melting point  w i t h the  irradiated  sample.  Two p i e c e s the  crystal  structures  of of  two s p o t s  both the  and t h e  rearrangement  uct,  but not  the  system;  The s t a r t i n g  starting  (ii)  each  material  rearrangement  to  on T . L . C .  is  be a  intensity  showed d e p r e s s e d '  plates  w h i c h were  p-bromophenacyl ester product: material,  (i)  the  therefore  (2,  is  (15,  fix  hirsutic  rearrangement  contains  compound c o n t a i n s  of  prod-  an <*p - u n s a t u r a t e d ?  a hydroxyl group.  R=p-bromophenacyl)  (15)  product  60%  was  c o n d i t i o n s of it  (ca.  o b t a i n e d w i t h the p r e v i o u s l y  (2)  the  spectroscopy  One  c h e m i c a l e v i d e n c e were now s u f f i c i e n t t o  acid  ketone  (T.L.C.).  and t h e o t h e r  was c r u s h e d  and g i v e two s p o t s  consistent  two compounds  a single crystal  i r r a d i a t e d w i t h C u - K ^ r a d i a t i o n under the measurement;  the d e c o m p o s i t i o n  by t h i n - l a y e r c h r o m a t o g r a p h y  was t h e  suspic-  the d e r i v a t i v e w i t h  A f t e r 10 h r .  yielding  This  R => p - b r o m o p h e n a c y l ) .  and  120 C o o r d i n a t e s and M o l e c u l a r Dimensions:Only the parameters from the f i n a l  least-squares c y c l e with  the counter data are g i v e n , s i n c e these are the most accurate results.  The  f i n a l p o s i t i o n a l and  i s o t r o p i c thermal  parameters  are given i n Table 2, t o g e t h e r w i t h t h e i r standard d e v i a t i o n s c a l c u l a t e d from the l e a s t - s q u a r e s r e s i d u a l s . The and  bond d i s t a n c e s and v a l e n c y angles are given i n Table 3;  the s h o r t e r I n t e r m o l e c u l a r d i s t a n c e s i n Table 4.  The  mole-  c u l a r packing, i n c l u d i n g p o s s i b l e hydrogen bonds, i s i l l u s t r a t e d i n F i g u r e 6. The three five-membered  r i n g s were examined f o r p l a n a r i t y .  The r i n g s were a l l non-planar,  and  i n each case i t was  that one of the f i v e p o s s i b l e four-atom  planes was  found  much b e t t e r  d e f i n e d than the o t h e r s ; but o n l y f o r the r i n g c o n t a i n i n g atoms 1,2,9,10,11 ( r i n g A) was fined.  an envelope  conformation  s h a r p l y de-  Table 5 summarizes the equations of v a r i o u s planes  ( i n c l u d i n g the aromatic r i n g ) , d e v i a t i o n s from the planes several pertinent dihedral  and  angles.  Absolute C o n f i g u r a t i o n : As a f i n a l s t e p i n the a n a l y s i s the a b s o l u t e c o n f i g u r a t i o n s of  the molecules  (both s t a r t i n g m a t e r i a l and rearrangement  uct) were determined  prod-  by the anomalous d i s p e r s i o n method. * 1  S t r u c t u r e f a c t o r s were c a l c u l a t e d f o r a l l the h k l and h k l r e f l e x i o n s , u s i n g a s c a t t e r i n g f a c t o r f o r Br of the form: f - (fBr + A f ^ r ) +  iAf'Br  121  T a b l e 2.  Fractional  p o s i t i o n a l p a r a m e t e r s and s t a n d a r d ; d e -  viations  (each x 1 0 ) ,  standard  deviations  4  Atom  X  y  C(l) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(ll) C(12) C(13) C(14) C(15) 0(16) 0(16') 0(17) 0(17') 0(18) 0(19) 0(20) C(21) 0(22) C(23) C(24) C(25) C(26) 0(27) C(28) Br(29)  3075 1897 3156 2486 0743 0540 2318 1706 0903 1549 1931 0134 3106 3588 5639 0717 -0513 2428 3806 -1641 0076 -1570 -1798 -0652 -3560 -5183 -6745 -6821 -5166 -3594 -8947  1321 0751 -0038 -1616 -1605 -0289 0539 2176 2118 3437 2801 2253 3672 -2745 0191 -2896 -2662 0313 0370 2865 1321 1042 2207 3260 2224 1121 1161 2062 3189 3129 2132  z 3699 4030 4357 4378 4624 4865 4705 4651 4229 4001 3627 3394 3332 4215 4297 4873 4651 5019 5083 3434 3114 2858 2584 2574 2321 2377 2121 1832 1768 2028 1463  isotropic  thermal  p a r a m e t e r s and  <T(x)  <5(y)  g(z)  42 51 50 51 63 60 56 54 47 46 41 47 54 63 61 97 73 80 85 32 31 52 48 33 42 52 47 41 43 46 7  29 32 35 34 40 39 36 41 33 30 32 37 35 43 41 67 55 53 , 45 23 23 33 37 21 31 35 32 33 32 31 5  7 9 8 9 10 10 10 9 7 8 7 8 9 10 10 14 13 13 11 5 5 9 8 5 7 8 8 7 8 7 1  !  B  <r(B)  5.22 7.31 7.20 8.34 11.58 10.15 9.24 10.16 6.50 6.10 6.39 8.44 7.71 12.09 10.74 14 .'75 11.39 9.88 8.39 8.67 7.00 7.46 8.05 8.03 5.45 7.67 6.42 5.79 6.21 6.11 9.58  0.78 0.97 0.91 1.02 1.27 1.18 1.15 1.06 0.73 0.83 0.79 1.01 0.98 1.21 1.20 1.89 1.51 1.52 1.28 0.60 0.60 0.91 0.93 0.62 0.71 1.00 0.84 0.77 0.84 0.77 0.09  122  Table 3 .  o Bond distances (A) and valency angles (degrees). Standard deviations are about 0.05 A and 3°.  c [1)-C(2) c [l)-C(ll) c [2)-C(3) c [2)-C(9) c [3)-C(4) c [3)-C(7) c [3)-C(15) c [4)-C(5) c [5)-C(6) c [6)-C(7) c [7)-C(8) c (8) -C(9) c (9)-C(10) c [lO)-C(ll) c [11)-C(12) c [11)-C(13) c [4)-C(14) c [5)-0(16) c [5)-0(16') c [6)-0(17) c [7)-0(17) c [7)-0(17') c (12)-0(18) c<[12)-0(19) 0 [19)-C(20) c<[20)-C(21) Cl[21)-0(22) C [21)-C(23) C [23)-C(24) c [23)-C(28) c [24)-C(25) c [25)-C(26) c [26) -C(27) c [27)-C(28) c [26) -Br (29) c [2)-C(l)-C(ll) c [1)-C(2)-C(3) c [1)-C(2)-C(9) c [3)-C(2)-C(9) c [2)-C(3)-C(4) c [2)-C(3)-C(7) c [2)-C(3)-C(15) Cl[4)-C(3)-C(7) c [4)-C(3)-C(15) c [7)-C(3)-C(15) c [3)-C(4)-C(5) c [3)-C(4)-C(14)  1.50 1.59 1.60 1.59 1.54 1.45 1.65 1.43 1.50 1.51 1.59 1.58 1.53 1.47 1.52 1.58 1.40 1.49 1.29 1.46 1.13 1.66 1.30 1.32 1.43 1.46 1.24 1.48 1.49 1.33 1.37 1.32 1.53 1.38 1.91 101.1 117.4 105.4 105.4 109.3 104.0 110.8 102.0 114.2 115.6 104.4 123.7  C (5) -C(4)-C(14) Cl[4) -C(5)-0(16) C [6) -C(5) -0(16) C [4) -C(5) -C(6) Cl[4) - C ( 5 ) - 0 ( 1 6 ' ) Cl[6) - C ( 5 ) - 0 ( 1 6 ' ) Cl[5) - C ( 6 ) - C ( 7 ) C [5) -C(6)-0(17) Cl[7) -C(6)-0(17) Cl[6) -0(17)-C(7) c [6) -C(7)-0(17) * c [3) - C ( 7 ) - C ( 6 ) c [3) - C ( 7 ) - C ( 8 ) Cl[3) -C(7)-0(17) Cl[3) - C ( 7 ) - 0 ( 1 7 ' ) Cl[6) - C ( 7 ) - C ( 8 ) Cl[6) - C ( 7 ) - 0 ( 1 7 » ) Cl[8) -C(7)-0(17) Cl[8) - C ( 7 ) - 0 ( 1 7 ' ) Cl[7) -C(8) -C(9) c [2) - C ( 9 ) - C ( 8 ) Cl[2) -C(9)-C(10) c [8) -C(9)-C(10) Cl[9) - C ( 1 0 ) - C ( l l ) Cl[ D - C ( l l ) - C Q O ) Cl[ D - C ( l l ) - C ( 1 2 ) Cl[1) - C ( l l ) - C ( 1 3 ) Cl[10 ) - C ( l l ) - C ( 1 2 ) c [10 ) - C ( l l ) - C ( 1 3 ) c [12 ) - C ( l l ) - C ( 1 3 ) c [11 )-C(12)-0(18) c [11 )-C(12)-0(19) 0 [18 )-C(12)-0(19) Cl[12 )-O(19)-C(20) 0 [19 )-C(20)-C(21) c [20 )-C(21)-0(22) c [20 )-C(21)-C(23) 0 [22 )-C(21)-C(23) c [21 )-C(23)-C(24) c [21 )-C(23)-C(28) c [24 )-C(23)-C(28) c [23 )-C(24)-C(25) c [24 )-C(25)-C(26) Cl[25 )-C(26)-C(27) c [25 )-C(26)-Br(29) c [27 )-C(26)-Br(29) c [26 )-C(27)-C(28) c [23 )-C(28) -C(27)  131.6 - 111.0 109.2 114.8 123.1 122.0 98.1 116.8 44.7 69.8 65.5 114.7 110.7 137.4 115.0 110.1 95.8 108.1 109.5 99.3 107.7 107.7 112.0 101.0 106.7 99.0 111.8 119.2 116.3 102.3 118.9 130.4 110.2 127.9 110.9 123.4 120.1 116.4 117.5 120.3 122.0 115.1 123.7 121.7 125.1 113.1 113.8 123.5  123  Table 4.  Shorter  intermolecular  distances.  ( A l l the c r y s t a l l o g r a p h i c a l l y - i n d e p e n d e n t c o n t a c t s <3.70 A* are l i s t e d )  Atom to (Molecule 1) 0(22) C(13) 0(22) C(27) C(13) C(13) 0(17) 0(17) C(7) C(4) C(5) C(6) C(15) C(14) 0(16) 0(16) 0(16) 0(17') 0(17') 0(17') 0(17')  Molecule 1 2 3 4 5  Atom  C(25) 0(18) C(20) C(l) C(24) C(25) 0(16) 0(16') 0(16) 0(16) 0(16') 0(16') 0(16) 0(16) C(6) 0(16) 0(16') 0(16) 0(16') C(9) C(8)  in  Molecule  2 2 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5  Coordinates x, y, z 1+x, y, z -x, ?+y, §-z |+x,-|-y, 1-z |+x, §-y, 1-z  o d(A)  3.60 3.56 3.35 3.63 3.60 3.64 3.14 3.05 3.64 3.41 3.61 3.64 3.63 3.55 3.70 3.47 3.03 2.63 2.74 3.64 3.12  F i g u r e 6.  P r o j e c t i o n of the s t r u c t u r e along (100), i l l u s t r a t i n g the p a c k i n g o f the molec u l e s and the hydrogen bonding between atom 17* and atoms 16 o r 16* .  o o o hydrogen bonding between molecules:  • • • hydrogen bonding between molecules  x,l+y, z and -|+x,£-y,l-z l - x , t + y , f - z and l - x , -y,£+z l - x , i + y , £ - z and £-x, -y,-£+z  x,l+y, z and i + x , £ - y , 1-z l - x , J + y , i - z and |-x, -y, J+z l-x,fr-y,£-z and \-x, -y,-|+z  125  Table  5.  Equations of  Atoms i n p l a n e  planes.  Equation  Symbol  C(1)C(2)C(9)C(10) 0.8096X+0.0972Y+0.5788Z 9.2875 C(3)C(2)C(9)C(8) 0.8051X+0.5230Y-0.2798Z - -2.6324 C(4)C(5)C(6)C(7) -0.5767X+0.3928Y-0.7163Z -12.5574 C(21)C(23)C(24)C(25)C(26)C(27)C(28)C(29) 0.4973X-0.6494Y-0.5753Z - -7.1831  Deviations Atom 1 2 3 7 8 9 10 11  A  B  -0.0005 0.0007  + 0.0280 -0.0168 -0.5183 0.0117 -0.0223 +  + +  -0.0007 0.0005 -0.6196  f r o m mean p l a n e s Atom 3 4 5 6 7 14 16' 16  Dihedral Angles Plane  C(3)C(7)  A A B C C and C ( 2 ) o r C ( 8 )  (A) (B) (C) (D)  o (A) .  C  Atom  D  0.3646 -0.0162 0.0255 -0.0240 0.0147 -0.4348 0.0445 -0.5247  21 23 24 25 26 27 28 29  0.0236 -0.0251 0.0018 -0.0109 0.0021 -0.0144 0.0066 0.0164  (degrees). Plane  C(1)C(11)C(10) B C(3)C(7)C(8) C(4)C(3)C(7) C(6)0(17)C(7) C ( 3 ) C ( 7 ) and C ( 4 ) o r C ( 6 )  * An a v e r a g e o f t h e f o u r d i h e d r a l  angles.  42.8 122.7 36.7 22.8 118.2 120 *  126 With Cu-K«>< |Fc(hkl)|  r a d i a t i o n the d i f f e r e n c e s between J F c ( h k l ) | were q u i t e s m a l l .  of p l a n e s w i t h r e l a t i v e l y  and  The i n t e n s i t i e s f o r twelve s e t s  l a r g e d i f f e r e n c e s were measured w i t h  the s c i n t i l l a t i o n counter, and the r e s u l t s (Table  6) i n d i c a t e  unambiguously that the parameters used to c a l c u l a t e the s t r u c t ure  f a c t o r s (those  o f Table 2 r e f e r r e d to a c o n v e n t i o n a l  handed s e t of axes) represent  the t r u e absolute  right-  configuration.  F i g u r e 4 and (2) and (15) t h e r e f o r e d e p i c t the c o r r e c t  absolute  configuration. Discussion The  of X-ray r e s u l t s : -  present X-ray a n a l y s i s has e s t a b l i s h e d , w i t h the  a s s i s t a n c e o f some c h e m i c a l evidence, the s t r u c t u r e and absolute c o n f i g u r a t i o n of the p-bromophenacyl e s t e r of h i r s u t i c a c i d as (2, R=p-bromophenacyl) . The  H i r s u t i c acid i s therefore  (2, R="H) .  e s t e r r e a r r a n g e s on i r r a d i a t i o n with X-rays to form a prod-  uct f o r which the X-ray a n a l y s i s g i v e s configuration  the s t r u c t u r e and absolute  as (15, R=p-bromophenacyl).  T h i s rearrangement  proceeds without d i s r u p t i n g the c r y s t a l s t r u c t u r e , and produces o n l y minor changes i n l a t t i c e parameters and i n the i n t e n s i t i e s of the r e f l e x i o n s . two  A f t e r i r r a d i a t i o n the c r y s t a l c o n t a i n s the  d i f f e r e n t molecules d i s t r i b u t e d randomly at the l a t t i c e  s i t e s , s i n c e no s u p e r l a t t i c e r e f l e x i o n s o r d i f f u s e n e s s were observed.  Each atomic p o s i t i o n determined by the X-ray a n a l y s i s  i s therefore  the mean o f the p o s i t i o n s i n the separate molecules,  which c o i n c i d e very c l o s e l y , except f o r the o u t e r atoms i n r i n g C . The  r e l a t i v e l y high  thermal parameters (Table 2) are probably a  127  T a b l e 6.  Determination of the absolute  configuration  (CuKc* r a d i a t i o n )  Io(hkl) h k  1 1 1 1 1 1 1 1 1 2 2 2  1  1 2 1 11 2 5 2 8 2 16 3 1 3 2 3 8 3 12 1 6 1 8 3 4  Io(hkl)  4102 338 2328 4601 30 173 814 225 267 205 226 773  Io(hkl)  6057 273 2220 5223 46 106 714 164 328 108 168 572  Fc(hkl)  Fc(hkl)  , Io(hkl)  57.6 19.9 54.3 82.6 5.9 14.4 41.2 26.0 24.4 12.7 17.8 37.4  65.2 16.9 50.3 86.4 8.6 10.1 37.3 22.2 27,. 9 9.2 15.0 33.6  0.68 1.24 1.05 0.88 0.65 1.63 1.14 1.37 0.81 1.90 1.35 1.35  |Fc(hkl)| |Fc(hk'  0.78 1.39 1.17 0.91 0.47 2.03 1.22 1.37 0.77 1.91 1.41 1.24  2  128 result  of t h i s  parameters position  disorder rather  are greatest  than  large  i n r i n g C where t h e c h a n g e s  accompanying the rearrangement  The g e n e r a l  shapes  e s t e r of h i r s u t i c  vibrations;  process  are  these  i n atomic largest.  of the molecules of the p-bromophenacyl  acid,  and o f t h e r e a r r a n g e m e n t  clear  f r o m F i g u r e s 4 and 5 .  rings  as e n v e l o p e s o r s l i g h t l y d i s t o r t e d  product,  are  Table 5 d e f i n e s the five-membered envelopes.  Not t o o  much s i g n i f i c a n c e s h o u l d  be a t t a c h e d  r i n g C g i v e n i n T a b l e 5,  as t h e r e  a r e u n d o u b t e d l y two c e n t e r s  at  and o n l y  a mean p o s i t i o n h a s been d e -  each  atomic  position,  t o t h e d e t a i l e d shape o f  rived . The measured bond d i s t a n c e s  and v a l e n c y  accurate  however t h e y  a r e a c c u r a t e enough t o d e f i n e u n a m b i g u o u s l y  an e x o c y c l i c  methylene  group,  o f the d i s o r d e r e d  are not  particularly  as  as a r e s u l t  angles  atom 1 6 '  and atom 16 as a h y d r o x y l o x y g e n , and atom 1 7 ' tertiary  Nearly  of h i r s u t i c  the 0(17')-•• 0(16) which represent does not c o n t a i n  ar  0-H---0  interactions.  i s 3 . 2 4 A*.  derivates.  ( T a b l e 4)  c o n t a c t s of 2.63  hydrogen bonds.  and 0 ( 1 7 )  and t h e two  The two e x c e p t i o n s  The o r i g i n a l  any h y d r o g e n bonds s i n c e  between 0 ( 1 6 )  distance  a c i d and i t s  and 0 ( 1 7 ' ) - - - 0 ( 1 6 ' )  oxygen  w i t h t h e c h e m i c a l and  a l l of the i n t e r m o l e c u l a r d i s t a n c e s  c o r r e s p o n d t o v a n d e r Waals  distance  These f e a t u r e s  m e t h y l g r o u p s a r e i n agreement properties  as a c a r b o n y l o x y g e n  atom 17 as an e p o x i d e  as a h y d r o x y l o x y g e n .  spectroscopic  arrangement;  and 2 . 7 4 A ,  crystal  the i n t e r m o l e c u l a r  i s 3.14 X,  However t h e n a t u r e  are  and t h e i n t r a m o l e c u l of the hydrogen-bonding  129 scheme  formed d u r i n g the i r r a d i a t i o n - i n d u c e d  p r o b a b l y has a s t r o n g The r e a r r a n g e m e n t at  ring.  During  i n f l u e n c e on the rearrangement  involves oxidation  C(5) to a ketone,  rearrangement  of the secondary  the rearrangement  at  least  t h r e e bonds a r e b r o k e n  and two h y d r o g e n atoms a r e s h i f t e d .  atom s h i f t s  p r o b a b l y i n v o l v e a 1,2 s h i f t  shift  tertiary of  of the secondary  starting ment  material  product  (0-16').  and t h e m o l e c u l a r mixture  can then form  w i t h the secondary or w i t h the keto  The n a t u r e  packing  (Figure  0(17')  an i n t e r m o l e c u l a r  c a n n o t be made.  x  to the  hydroxyl  group  intermolecular  h y d r o x y l group o f the group o f t h e r e a r r a n g e -  o f t h e h y d r o g e n bonds f o r m e d 6)  can account  (c_a. 60% r e a r r a n g e m e n t ) ; however  an i n t r a - a n d to  product  (0-16)  f r o m C ( 5 ) t o C ( 6 ) , and  The t e r t i a r y  x  h y d r o g e n bonds e i t h e r  The h y d r o g e n  hydroxyl proton 0 ( 1 6 ) - H  h y d r o x y l group 0 ( 1 7 ' ) - H .  the rearrangement  hydroxyl  together with r e d u c t i o n of the epoxide  and f o r m e d ,  the  process.  f o r the observed  a distinction  h y d r o g e n atom t r a n s f e r  between from 0(16)  130 BIBLIOGRAPHY 1.  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Acta,  PART III BIOGENETIC-TYPE SYNTHESES OF ACETATE-DERIVED AROMATIC COMPOUNDS  132 INTRODUCTION In  Part  II  the  structure  compound was c a r r i e d  out.  made on t h e  the  a  basis  of  logical rationale  the  terpenoid nature  successful farnesyl as  molecular  its  of  a terpene  precursor  terpene  the  basic  isoprene  CH3-CO-SC0A  unit  of  mevalonic  been e s t a b l i s h e d , *  f o r m e d by t h e  that of  2  is  3  acid acid  or (5)  and f a r n e s y l  head-to-tail  (6), '  units  condensation  b e l i e v e d to  The p r e c u r s o r s  of  be a  other of  (6) .  + CH2-CO-SC0A  CO2H  CH2-CO-SC0A  CH -CO-CH -CO-SCoA 3  2  (2)  CH3  (3)  OH  CH3  COSCoA  CO2H  * C02H  CH OH 2  (5)  (4) CH  Proof  s i m i l a r l y d e r i v a b l e from condensations  (1)  CO2H  fact  with l a b e l l e d mevalonic  sesquiterpenes.*  f a m i l i e s are  c o u l d be made.  The u n i q u e r o l e  three b i o l o g i c a l isoprene of  and on t h e  was  compound c o u l d be p r o v i d e d by  has  which i s  a sesquiterpenoid classification  formula,  biogenesis  the  pyrophosphate.  precursor  the  The b i o s y n t h e t i c  f e e d i n g experiments  pyrophosphate, of  of  e l u c i d a t i o n of  3  CH,  The  TERPENOIDS  ^C-CH2-CH2-OP2 (6) biogenetic  theory  invaluable  i n the  variety  structural  of  of  i s o p r e n o i d compounds  e l u c i d a t i o n and c o r r e l a t i o n types  characteristic  of  of  has  4  the  this  proved  great  class  of  1 3 3  natural  products.  been p r o p o s e d t o An i m p o r t a n t received  or  to  of  products.  biosynthetic  group of n a t u r a l are  compounds  pathways. pathway,  These c l a s s e s  the  have  p r o d u c t s w h i c h have aromatic  appears  1  One o f  can  schemes  t h e n o n i s o p r e n o i d compounds.  investigation  aromatic  (8)  other  many o f  and l a r g e  two d i s t i n c t  shikimic acid  natural  correlate  considerable  The b i o g e n e s i s fined  Similarly,  to  these,  compounds.  be l a r g e l y  the  carbohydrate  l e a d t o numerous c l a s s e s arise  con-  from e i t h e r  of  a Cg-C-^ o r  a  COiH  GLUCOSE  C«-Ci:  C 6 - C 3 :  benzoic acids eg. a n t h r a n i l i c tryptophan  phenylalanine-^ ALKALOIDS tyrosine cinnamic acids lignans, lignin coumarins Cg-Cg  aromatic  benzoic  a c i d s w h i c h can  anthranilic the  precursor;  acid  precursor  group are alkaloid coumarins  the  of  is the  the  precursor  for  example, is  i n c l u d e d i n the C g - C ^  (Cg-C^  the  the  tryptophan which i n turn  a c i d s which are  lignans  In a d d i t i o n t o  by t h e  Cg-C-^ g r o u p a r e  p h e n y l a l a n i n e and t y r o s i n e  and c i n n a m i c  compounds d e r i v e d f r o m t h e characterized  of  indole alkaloids;  ( C g - C g monomer),  (Cg-Cg p o l y m e r ) .  i n c l u d e d i n the  be m e t a b o l i z e d f u r t h e r ,  amino a c i d s  precursors,  INDOLE ALKALOIDS  dimer)  C^ or  shikimic acid  precursors and  pathway  patterns:  are of  lignin  C^ s i d e c h a i n ,  (8)  f o l l o w i n g oxygenation  which  are  aromatic usually  none,  4-,  134 3,4- o r 3,4,5- ( n u m b e r i n g w i t h r e s p e c t The o t h e r  well-established  compounds i s  the  1) commences  w i t h the  the  another occur  malonate  at  way,  whereas  intermediate  condensation  at  head-to-tail  the  the  c a r b o n y l groups w h i l e the  to  the  fatty are  These are can  l e a d to  several  illustrated  for  formation of  "orcinol-type"  condensation  The s i m p l e s t  of  been i s o l a t e d aromatic are  the  ion product,  (see  unit  figure  (2) w i t h  to  of  can  the  is  chain  compounds to  the  carbonyl  (12): O - a c y l a t i o n  acid  can  finally  phloroglucinols (15).  triacetic  1 0  leads  possible.  ( 1 4 ) ; and  acyl  derivable  orsellinic  and a c e t y l p h l o r o g l u c i n o l  Reduction  ( 1 3 ) ; a l d o l condensation  from P e n i c i l l i u m p a t u l u m .  (18) a r i s e  poly-  b u i l t - u p by  modes a r e  poly-P-keto  lead  path-  being constructed  d e r i v e d from three acetate u n i t s ,  orcinol  the  a  A c c o r d i n g to  However i f  the ot-pyrone s t r u c t u r e s ,  products;*  can  terpenoid  acetate u n i t s .  chain i s  of  group produces  a c e t a t e pathway.  pyrones  compounds, w h i c h a r e  natural  keto  condensation  aromatic  Claisen-type  (16), which i s  aromatic  group produces  and p o l y a c e t y l e n e s .  retained  l e a d to  ester  condensations  the  groups  to-  The c o n d e n s a t i o n  poly-p-keto chain  of  acids  the  (4) e s s e n t i a l  (11) i n t h e  acetate hypothesis  further  a malonate  CoA (1,9 R=»CHg) .  C o n d e n s a t i o n at  P~keto intermediate the  route  T h i s pathway  1 , - 9  of  sidechain).  u n i t w i t h a c e t o a c e t y l CoA ( 3 , 10 R=CHg)  two s i t e s .  branched-chain  condensation  acetyl  the  biosynthetic  acetate p a t h w a y  chain s t a r t e r ,  to  acid  has  lactone  recently  S i m i l a r l y the  simplest  from f o u r a c e t a t e (17) and t h e  from a l d o l - t y p e  (19) f r o m C l a i s e n - t y p e  units,  decarboxylat-  condensation, condensation  135  R-CO-SCoA  +  (9)  >  CH2-CO-SC0A C02H  R-CO-CH -CO-SCoA  (2)  CH -C0-SCoA 2  (10)  R-CO-CH2-CO-CH -CO-SCoA 2  COoH 4  2  CH2-CO-SC0A  C02H >  > ( I D  R-CO-CH2-CO-CH2-CO-CH2-CO-SC0A (12)  OH (18)  Figure 1  136 of the p o l y - p - k e t o  precursor  (12 R=CHg).  A l a r g e number of aromatic compounds can  be  accommodated  by the a c e t a t e  h y p o t h e s i s i f the f o l l o w i n g e x t e n s i o n s are  sidered.*  poly-p-keto c h a i n may  The  con-  be p a r t i a l l y reduced p r i o r  to c y c l i z a t i o n as i l l u s t r a t e d by the products, 6 - m e t h y l s a l i c y l i c acid  (20)  and  pelanjuoic  acid  (21).  Alternatively oxidation  (21)  occur as i n the m e t a b o l i t e and acid  (22).  (23).  Oxidation  may  (17)  In a d d i t i o n to o x i d a t i o n ,  O - a l k y l a t i o n w i t h a C - l u n i t may  C-  occur as i n c y c l o p a l d i c  also involve hydroxylation  and  sequent quinone formation as i n the product f u m i g a t i n  (22)  may  (23)  sub-  (24).  In  (24)  each of the above examples the c h a r a c t e r i s t i c a l k y l a t i o n and/or hydroxylation  p a t t e r n of o r s e l l i n i c  Another mode of o x i d a t i o n through o x i d a t i v e c o u p l i n g  a c i d (17)  has  been masked.  i s the formation of d i m e r i c  species  as shown by the c o u p l i n g of two  units  137  (25)  (26)  of methylphloroacetophenone (25) usnic acid (26). by Barton,  11  to form the lichen product,  This reaction has been carried out in vitro  u t i l i z i n g a one-electron oxidizing agent.  oxidative cleavage of the aromatic ring may by p e n i c i l l i c acid (27) (17)  Finally,  occur as illustrated  which is produced from orsellinic acid  by Penicillium cyclopium.  12  (17)  (27)  There are two important variants of the acetate hypothesis which result in the overlap of the terpenoid and shikimic acid pathways with the acetate route. 1  First, alkylation by an  isoprene unit can occur in a fashion analogous to the alkylation by a C-l unit; for example, euparin (28) acylphloroglucinols  and evodionol (29)  containing isoprenoid units.  are  Second, the  i n i t i a l acid of the poly-p-keto chain, i.e. the chain starter, need not always be acetic acid.  In fact a large number of nat-  ural products appear to be acetate-derived from cinnamic (Cg-Cg) or benzoic (Cg-C^) acids as chain initiators.  Important examples  138  (28) of  the  such  (29)  mixed s h i k i m a t e - a c e t a t e pathway  as  yangonln  phenones,  eg.  (30),  stilbenes,  maclurin  (32)  eg.  and t h e  i n c l u d e pyrone pinosylvin  flavanoids,  (32)  In e a c h o f  the  distinguishes illustrates With ation  in  the  the  examples the  shikimate  cyclization  longer  eugenone  1 are  eg.  benzo-  naringenin  hydroxylation  p a t t e r n not  and a c e t a t e - d e r i v e d r i n g s ,  but  mode o f  the  acetate-derived  poly-P-keto chains  the  possibilities  become more v a r i e d  figure  (31),  (33).  (33)  above  acetate units,  structures  and c o m p l e x .  cyclizations possible,  ( 3 4 ) and e u g e n i n  entirely  as  For  a chain of  analogous  illustrated  to  by t h e  (35) which c o - o c c u r  of  only also  part. cycliz-  five  those i  outlined  acylphloroglucinols,  i n the  species  139  (34)  (35)  Eugenia c a r y o p h y l l a t a . derivable  structure  (35)  is  formally  from the a c y l p h l o r o g l u c i n o l s t r u c t u r e  (34)  by  further  O-acylation. nature, (37).  eg.  1 3  The chromone  " O r c i n o l - t y p e " compounds a r e a l s o the isocoumarin  P y r o l y s i s or a c i d  (37)  corresponding  isocoumarin  modes,  other  1 4  yields  acid  the  (38)  (38). aldol  in  and t h e C - a c e t y l o r s e l l i n i c  treatment of the l a t t e r  (36)  cyclization  (36)  represented  In a d d i t i o n to the condensations  above  are p o s s i b l e  as  15 illustrated  by. t h e p r o d u c t ,  curvulinic acid  (39).  0, (39)  Chains of s i x to ten a c e t a t e The most  important  group d e r i v a b l e  units  a r e shown i n f i g u r e  from s i x a c e t a t e  units  1  2. are  140  (44) Figure  2  141 the  naphthalenes,  naphthoquinones. units  gives  rise  e g . <* - s o r i g e n i n  (40),*®  The c y c l i z a t i o n  of  to  a great  1 pounds, ures.  griseofulvin  the  units.  the  The m y c i n o n e s acid  monoamide o f are  The f i r s t hypothesis  derivable  3  acetate  polycyclic  com-  give  to  the  malonic  acid  the be  important  about  groups  chlorotetracycline (44).  The  tetra-  from a chain of  i n i t i a t i n g the  from a chain of chain.  struct-  largest  to  appears to  two  be d e r i v a b l e  ten  units  nine 18  chain.  with  a  direct  2  experimental  was p r o v i d e d by B i r c h ^  incorporated  many n a t u r a l l y  to  eg.  form the  The l i m i t  chain  rise  more u n u s u a l  C0 H  l a b e l l e d atoms i n t h e , l a b e l l i n g experiments  periments  poly-P-keto  i n i t i a t i n g the  CH  a c i d was  seven  (42),  e g . d -pyrromycinone  be c o n s i d e r e d  u n i t s w i t h the  endocrocin  tetracyclines,  mycinones,  the  acetate units.  Such l o n g c h a i n s  can  propionic  eg.  hypothetical  and t h e  cyclines  of n a t u r a l  b e i n g one o f  from eight  antibiotics,*  (43),  (41)  The a n t h r a q u i n o n e s ,  l e n g t h of  of  a c h a i n of  corresponding  17  group d e r i v a b l e  ten  variety  and t h e  into  verification  who showed t h a t  0  6-methylsalicylic  expected p o s i t i o n s . have v e r i f i e d t h e  occurring  compounds. 2  examples  of  acid  Since  the  the  acetate  l-C* -acetic 4  (20)  with  the  similar ^ g a c e t a t e pathway ' for  In a d d i t i o n ,  with labelled mevalonic*' *  have v e r i f i e d s e v e r a l  of  then,  feeding  and s h i k i m i c * '  2 2  ex-  acids  mixed a c e t a t e - t e r p e n o i d  and  142 acetate-shikimate  pathways  respectively. 1  have a l s o  established  Feeding  experiments  23  methionine  '  as  a source of  C-l  frag-  ments . The b i o g e n e s i s studied  2-C  2 4  1 4  -ethyl 27 A  coenzyme  acetate  an enzyme the  molecules  to  periments  and r e l a t e d  biogenesis* Birch's  reaction produce  original  if  not  compounds, building  of  for  biosynthesis  activity  of of  is  quite  the  CoA.  enzyme  mechanism o f  fatty  1  3)  acid  also  serves  o n l y major  f r o m one 28  i.e.  likely for  chain  acid  ex-  with f a t t y  acid  to  m a l o n y l CoA i s  that  the  These  modification  the  m a l o n y l CoA i s  acetate-derived believed  to  the  aromatic  be  the  ' ^  builder,  studies  description  Lynen  30  biosynthesis  in of  observed  s y n t h e t a s e " was  and t h u s he h a s  acid  as  (20).  in connection  Further,  "fatty  s u l f h y d r y l - c o n t a i n i n g enzyme. figure  labelled  CoA and t h r e e m a l o n y l CoA  macrolides.  d e f i n i n g the  by s u l f h y d r y l - b l o c k i n g a g e n t s ; detailed  acetyl  have p r o v i d e d a d e t a i l e d  the  derived  addition,  m e t h y l m a l o n y l CoA i s  acetyl  and  4  which  i n the  some o f to  is  2 6  1-C* -  from a P e n i c i l l i u m s p e c i e s  experiments  It  been  has  chain-builder  although  carboxylation  (20) In  has  experiments with  -acetate  1 8  6-methylsalicylic  unit. sole  unit  0  5  acetate hypothesis,  In a d d i t i o n  (see  2  (20)  Lynen  one  have r e s u l t e d  chain-building  the  malonate,  extract  acid  Feeding  have shown t h a t  catalyzes  acid  detail.  and t h r e e m a l o n a t e u n i t s .  isolated  major,  6-methylsalicylic  in considerable  acetate, acetyl  of  fatty the  that  quenched  postulated  a  involving a  A m o d i f i c a t i o n of  Lynen's  a u s e f u l working hypothesis  model* for  143  Figure 3  144  the biogenesis of acetate-derived aromatic compounds.  It w i l l  be noted that in this model the carboxyl groups of the malonate units are assumed to be lost during the build-up of the poly-P keto chain.  There i s direct support for this concept for the 1  31  biogenesis of fatty acids; '  and i t is quite likely that the  concept applies to acetate-derived aromatic compounds since there have been no verified examples of natural products which retain the residual carboxyl groups.  However i t i s important to real-  ize that the postulated poly-p-keto intermediates in the acetate pathway have never been isolated from nature with the exception of the C - 6 unit, 3, 5-diketohexanoic acid (45)* which i s the straight-chain form of triacetic acid lactone ( 1 6 ) .  Thus at  present there is no direct evidence of the. intermediate steps in the biogenesis of acetate-derived aromatic compounds; this  (45)  (16)  pertains not only to carboxyl loss but also to several of the variants of the acetate hypothesis, eg. reduction and alkylation, which probably occur at the poly-p-keto stage. In addition to the direct experimental verifidiation provided by feeding experiments, the acetate hypothesis i s supported by two other c r i t e r i a .  One of these i s the cooccurrence in a  single species of several compounds of similar structure, of  145 which there are numerous examples.* the r e a c t i o n s p o s t u l a t e d  should  Another c r i t e r i o n i s that  be c h e m i c a l l y  sound.  c r i t e r i o n i s p a r t i c u l a r l y important to the o r g a n i c it  forms the b a s i s of the " b i o g e n e t i c - t y p e  products. c a r r y out  This  latter  chemist  since  s y n t h e s i s " of n a t u r a l  In such a s y n t h e s i s , the chemist need not  attempt  the r e a c t i o n under p h y s i o l o g i c a l c o n d i t i o n s , but  to  can  choose any d e s i r a b l e set of l a b o r a t o r y c o n d i t i o n s to overcome the l a c k of an enzyme system. The  h i s t o r i c a l development of the acetate  remarkable i n that i t was  first  s t a t e d i n 1893  hypothesis i s and  again  i n more  5 d e t a i l i n 1907  by C o l l i e .  Unfortunately  C o l l i e ' s ideas remain-  ed dormant f o r over 50 years u n t i l the h y p o t h e s i s was  independ-  Q  ently rediscovered 7 the h y p o t h e s i s  B i r c h subsequently e l a b o r a t e d  on  8 '  al v e r i f i c a t i o n . his  by B i r c h .  and  i s r e s p o n s i b l e f o r much of the experiment-  What i s a l s o remarkable i s that C o l l i e developed  h y p o t h e s i s from a c o n s i d e r a t i o n of s e v e r a l  syntheses, whereas B i r c h d e r i v e d  biogenetic-type  the same h y p o t h e s i s from a  c o r r e l a t i o n of s t r u c t u r e s . 31 C o l l i e f i r s t observed acid  (46)  that treatment of  under weakly a l k a l i n e c o n d i t i o n s  (aqueous barium  hydroxide) y i e l d e d the n a t u r a l product, o r c i n o l 5 31 pected, s i m i l a r treatment also yielded o r c i n o l  (18), but  compounds were o b t a i n e d . been e s t a b l i s h e d  '  5 , 3 2 , 3 3  The as  dehydroacetic  (18).  of heptane-2,4,6-trione i n a d d i t i o n three other  As  ex-  (47) aromatic  s t r u c t u r e s of these compounds have  (48),  (49),  that they a r i s e from an i n t e r m o l e c u l a r  (50), and  i t i s obvious  condensation of  two  146  (46)  (18)  molecules o f heptane-2,4,6-trione  (48) w i t h subsequent  cyclizat-  ion (49) and d e h y d r a t i o n ( 5 0 ) .  (48)  (49)  Recently, B i r c h  (50)  has c a r r i e d out a b i o g e n e t i c - t y p e  synthesis of d i h y d r o p i n o s y l v i n  (53) by a l k a l i n e treatment of  the Y-pyrone (51) o r the c o r r e s p o n d i n g t r i o n e ( 5 2 ) . In a d d i t i o n the compound (54) was o b t a i n e d which would r e s u l t from the a l t e r n a t i v e i n t r a m o l e c u l a r a l d o l condensation. form p i n o s y l v i n  Attempts to  (55) by an analogous procedure f a i l e d however.  The b i o g e n e t i c - t y p e syntheses o f a c e t a t e - d e r i v e d aromatic compounds has been hindered by the d i f f i c u l t y i n p r e p a r i n g poly-l>-keto compounds.  P r i o r to work i n these l a b o r a t o r i e s the  147  (53)  (54)  (55)  l a r g e s t members i n t h i s s e r i e s were heptane-2,4,6-trione (47) 31 which  i s formed  pyrone  by a l k a l i n e h y d r o l y s i s  (56), and 3,5-diketohexanoic a c i d  (16) a s i m i l a r manner  o f the dimethyl-Y(45) which i s formed i n  (45) from t r i a c e t i c  a c i d l a c t o n e (16). The l a t t e r  reaction  has been r e v e r s e d by treatment o f (45) w i t h  acid.  Birch^  1 0  5  has attempted  hydrofluoric  to prepare l o n g e r poly-p-keto  c h a i n s by o z o n o l y s i s o f d i h y d r o a r o m a t i c compounds.  He succeeded  i n i s o l a t i n g the t e t r a k e t o n e (59) from the dihydroindanone (57).  However attempts to i s o l a t e the pentaketone  ketal  (59) were  u n s u c c e s s f u l ; and attempts to c y c l i z e (58) o r (59) by treatment  148  AXJJUL  (58)  (59)  w i t h base gave complex mixtures which were not i n v e s t i g a t e d further. a convenient s y n t h e s i s of t e t r a - P - k e t o n e s has been  Recently 36 reported.  The r e a c t i o n sequence i n v o l v e s the formation of a  diisoxazolylmethane  (61) from the a d d i t i o n of two molecules  of n i t r i l e oxide, RCNO, to diethynylmethane (60), f o l l o w e d by c a t a l y t i c r e d u c t i o n to form the imino d e r i v a t i v e (62), and subsequent a c i d h y d r o l y s i s to the t e t r a k e t o n e dibenzoylacetylacetone ,„  R-/  ,„  U  1^  (63).  \—R  J  R  —  T ^ w . (61)  0 v  v  way  (63, R = phenyl) has been s y n t h e s i z e d .  (60)  R^  In t h i s  0  R  v  (62) Dibenzoylacetylacetone  0  (63) (64) has a l s o been s y n t h e s i z e d from  a c e t y l a c e t o n e by s u c c e s s i v e a r o y l a t i o n with methyl benzoate i n a * sodium hydride:  1,2-dimethoxyethane  system.  the system sodium a m i d e - l i q u i d ammonia  38  37  Alternatively,  has been used f o r  149  ^  XX  W H  CcHs-  ^""^ ^"^^CJ-!*  s i m i l a r a c y l a t i o n s and proved very  alkylations.  carboxylation  '  T h i s l a t t e r system  has  t r i k e t o acids  by  39 '  of the corresponding  syntheses of the t r i k e t o a c i d s  liquid  CjHs  (64)  u s e f u l f o r s y n t h e s i z i n g d i k e t o and 10 38  generating  XXX  .  ketones (65).  (67) were c a r r i e d out  the anions (66), f o l l o w e d  by  a l l y the a d d i t i o n of dry  JUUL  first  by r a p i d removal of  ammonia w i t h simultaneous replacement by e t h e r ;  The  the  and  fin-  i c e e f f e c t e d the c a r b o x y l a t i o n .  By  JUUL °^ , C  NaNH^lNHs D * — »  R  R  ether  .  (65)  (66)  C0H 2  0  G  CO^H  R  pH 5 16 hr.  \AY"  0 H  25°  (67) (68) t h i s method the a c i d s nC H 3  ?  and  CH  3  nCAi^,  (67) w i t h R = CgH CH=CH, n C H , 5  7  1 5  have been formed i n y i e l d s o f 52%,30%,14%,2% and 39  trace respectively.  Treatment of these a c i d s  conditions  (aqueous b u f f e r , pH  conversion  (ca. 90%  5,  25°,  mild  r e s u l t e d i n the .  y i e l d ) to the r e s p e c t i v e aromatic a c i d s  p i n o s y l v i c , spheropherolcarboxylic, and o r s e l l i n i c .  16 hr.)  under very  (68)  olivetolcarboxylic, divaric  A l l of these a c i d s except p i n o s y l v i c  (68,  150 R = CgHr-CH=CH)  are  decarboxylated  to  completing  physiological i n the  products,  and t h e  latter  biogenetic-type  poly-P-keto  acid  (67)  synthesis.  cyclizes  b i o g e n e s i s of  acetate-derived  laboratories  overcoming the  it  was f e l t  d i f f i c u l t i e s i n the  p o l y - p - k e t o c h a i n s w o u l d be t o  the  (see  structures  by s u c c e s s i v e  units  i n a manner  p-keto chains,  w i t h the  analogous  exception  that  the the  retention  r e q u i r e d f o r pyrone f o r m a t i o n .  in  media,  of  the  triacetic  ' 3  of  '  lactone  and i n f a c t  the  ,  and B i r c h  were  of  four  units;  (69)  w o u l d be e x p e c t e d  acetate u n i t s ; and t h e  Unfortunately  the  tetrapyrone  to  figure 4);  lost  at  however,  some l a t e r  •for nomenclature mental s e c t i o n .  has  of  The of  with  poly-  the generation,  t h e mono-  already  been  biogenetic-type  syntheses  tripyrone (71)*,  stage  it  is  i n the  Thus,  alkaline  in basic  treat-  media,  generate a p o l y - P - k e t o (70),  a c h a i n of  a chain of  t h e s e c h a i n s do r e t a i n  (see  (16)  b a s e d on t h e  ment o f m o n o c y c l i c p y r o n e s t r u c t u r e s . dipyrone  form of  33  1  both C o l l i e  a c i d analogue  of  41  34 40 demonstrated.,  acid  compounds.  b i o g e n e s i s of  is  c y c l i c o( - p y r o n e ,  intermed-  condensations  groups  poly-P-keto  its  These p o l y p y r o n e  carboxyl basic  essentially  i n the  figure 4).  to  thus  and i s o l a t i o n  chains  condensed p o l y p y r o n e s t r u c t u r e s  malonate  (55),  a c o n v e n i e n t way o f  preparation  hold  c o u l d be c o n s t r u c t e d  for  aromatic  that  easily  The e a s e  under  c o n d i t i o n s ^ p r o v i d e s good s u p p o r t  In t h e s e  was  the n a t u r a l l y - o c c u r r i n g p i n o s y l v i n  a remarkable  w i t h which the  iacy  natural  quite  the  six  chain  five  acetate  that  biogenetic-type  b a s e d on c o n d e n s e d a r o m a t i c  they  acetate  units.  residual carboxyl  likely  the  groups  c o u l d be  synthesis.  systems  see  experi-  15.1  (16)  (45)  (71) Figure 4  152  ii A search  of the l i t e r a t u r e  revealed  that  condensed p o l y p y r o n e 42  structures  have  been s y n t h e s i z e d ,  n o t a b l y by Z i e g l e r  and  on t h e s t r u c t u r e  "red-carbon",  43 Mentzer.  In h i s i n v e s t i g a t i o n s  the  p o l y m e r i z a t i o n product  has  synthesized  ures. are  a large  The c l o s e s t  t h e two s e r i e s  thesized  suboxide  (CgO^),  number o f c o n d e n s e d p o l y p y r o n e  analogies  to the pyrones  (73),(74),(75)  i n a stepwise  (76)  of carbon  of  Ziegler struct-  shown i n f i g u r e 4  and ( 7 7 ) , ( 7 8 )  w h i c h were  manner f r o m t h e 4 - h y d r o x y c o u m a r i n  (77)  syn-  (72)  (78) 44  and t h e 4 - h y d r o x y t e t r a h y d r o c o u m a r i n syntheses  were  of  and t h e c o n d e n s i n g u n i t ,  pyrone  best  carried  (76)  respectively.  o u t by f u s i n g e q u i m o l a r b i s (2,  The  quantities  4-dichlorophenyl)  153  o m a l o n a t e at 250 . (79) by r e f l u x i n g  4 3  Mentzer has s y n t h e s i z e d t h e p h e n y l d i p y r o n e acetophenone i n d i e t h y l m a l o n a t e ; t h i s pyrone 44  (79) bis  has  also  been s y n t h e s i z e d  (2,4-dichlorophenyl)  independently  malonate  The a r o m a t i c d i p y r o n e  (73)  as  has  the  by Z i e g l e r  condensing  also  using  reagent.  been s y n t h e s i z e d  by  4 5  Woods (72)  by c o n d e n s i n g in refluxing  hydrolysis  of  the  cyanoacetic  trifluoroacetic imine  f o l l o w e d by  (80)  Woods a l s o was r e a d i l y back  acid,  4-hydroxycoumarin  had o b s e r v e d  acylated  with  dehydroacetic  (16)  acid  (80).  (72)  give  acid with  that  acetyl  acid  (46).  (73) triacetic chloride  at  acid the  lactone  3-position  In a d d i t i o n E l v i d g e ^ 4  (46)  (16) to  has  154 carried  out  dichloride; with  the  a number o f for  heterocyclic  example,  p-diketo  with malonyl  m a l o n y l d i c h l o r i d e condenses  compound,  hydroxy-2-methyl-4-pyrone  syntheses  acetylacetone,  to  (81) , an i s o m e r o f  readily  form 3 - a c e t y l - 6 -  dehydroacetic  acid  (81) (46).  It  is  pertinent  to note  b o t h C - and 0- a c y l a t i o n o f Utilizing  the  ideas  that  i n these  pyrones  listed  o u t l i n e d i n the  dipyrone  (69)  conditions,  laboratories  i n f i g u r e 4; and t h e  and have  compounds w h i c h were  of  (81)  involves  papers  have s y n t h e s i z e d  and i n a d d i t i o n have  isolated  mentioned  above,  49 '  tripyrone  formed.  synthesis  a c e t y l a c e t o n e by m a l o n y l d i c h l o r i d e .  48 workers  the  (70)  under  treated  a variety  and c h a r a c t e r i z e d  the  the  of  polythe basic  aromatic  155 DISCUSSION The  syntheses  outlined  of  the  polypyrones  listed  Triacetic  acid  of  Collie.  in  these  50  (16)  was p r e p a r e d  available  dehydroacetic  The d i p y r o n e  laboratories triacetic  fold  dipyrone  excess of  dipyrone  (69)  of  of  acid  method  (46)  by t h e  had p r e v i o u s l y been  lactone  (16)  The t r i p y r o n e  (69)  synthesized  (70)  had been  been c a r r i e d  acid  these reagents  sol-  that  an  The s y n t h e s i s  u s i n g the  of  eightof  condensing  and e t h y l c h l o r o f o r m y l a c e t a t e ,  but  could effect  tripyrone  (70).  In a d d i t i o n p r e v i o u s  pyrone  (71)  from t r i p y r o n e  out  51  synthesized  i n a s i m i l a r f a s h i o n except  had a l s o  acid  and a t w o - f o l d e x c e s s  a c i d c h l o r i d e was r e q u i r e d .  reagents cyanoacetic neither  (69)  by d e a c e t y l a t i o n  by r e f l u x i n g a t r i f l u o r o a c e t i c  acid  malonyl d i c h l o r i d e . from the  are  (71)  lactone  commercially  u t i o n of  4  below:  (70)  the  in figure  attempts  the to  synthesis synthesize  of the  tetra-  by t r e a t m e n t w i t h m a l o n y l d i c h l o r i d e  156 had  failed.  As part of the work r e p o r t e d  methods of s y n t h e s i s ,  and n o t a b l y  i n t h i s t h e s i s , the  the methods of i s o l a t i o n and  p u r i f i c a t i o n of the pyrones (36), (69) and (70) were improved; and  the s y n t h e s i s of the tetrapyrone As p a r t o f the s y n t h e s i s  preparation  of t e t r a p y r o n e ,  of t r i p y r o n e was i n v e s t i g a t e d .  increasing d i f f i c u l t y (70),(71),  (71) was  achieved. the method of  From the s t e a d i l y  i n the formation of the polypyrones (69),  i t was obvious that as the condensed polypyrone  s t r u c t u r e was b u i l t - u p the r e a c t i v i t y at the a c y l a t i n g p o s i t i o n s decreased. and  T h i s was a l s o r e v e a l e d  by the a c y l a t i o n of dipyrone 51  tripyrone with a c e t y l c h l o r i d e  acetyldlpyrone  t o give r e s p e c t i v e l y the  (82) and the a c e t y l t r i p y r o n e  (83); the s y n t h e s i s  of the l a t t e r r e q u i r i n g more v i g o r o u s c o n d i t i o n s .  Acetyltripyrone  51  (83)  has a l s o been i s o l a t e d  prepare tetrapyrone with tripyrone,  i n low y i e l d from the attempts to  from the condensation o f malonyl d i c h l o r i d e  and was an impurity  i n the analogous  preparat-  ion of t r i p y r o n e .  (82)  (83)  In the i n v e s t i g a t i o n of the reagent, malonyl d i c h l o r i d e , i t was observed that  i t s use was l i m i t e d by the  formation of a red-brown polymer.  heat-catalyzed  The d i e s t e r reagents  42  were  157 more s t a b l e and c o u l d be used f o r s y n t h e s i z i n g both t r i p y r o n e and t e t r a p y r o n e .  The formation o f a melt  (230°,  dipyrone and b i s (2,4-dichlorophenyl)malonate  10 min.) o f  y i e l d e d a mixture  of dipyrone, t r i p y r o n e and t e t r a p y r o n e i n the r a t i o o f about 2:1:0.4.  T h i s procedure  p r o v i d e s a u s e f u l s y n t h e s i s o f both of  the h i g h e r pyrones and has the advantages over the malonyl d i c h l o r i d e method o f i n c r e a s e d y i e l d s and the absence o f the acetylpolypyrone impurities.  Tetrapyrone was a l s o s y n t h e s i z e d  i n a s i m i l a r f a s h i o n from t r i p y r o n e and i s o l a t e d i n about 30% yield.  The o t h e r d i e s t e r reagents, diphenylmalonate  and  b i s ( 2 , 4 , 6 - t r i c h l o r o p h e n y l ) m a l o n a t e were l e s s e f f e c t i v e i n the p r e p a r a t i o n o f h i g h e r pyrones than b i s ( 2 , 4 - d i c h l o r o p h e n y l ) m a l o n a t e ; and d i e t h y l m a l o n a t e was  ineffective.  Tetrapyrone was c h a r a c t e r i z e d by a n a l y t i c a l and s p e c t r a l data.  The N.M.R. spectrum  was n e a r l y i d e n t i c a l w i t h the s p e c t r a  of the o t h e r two polypyrones trifluoroacetic  in this series exhibiting, in  a c i d , s i n g l e t peaks at 3.43 ( C H ) ,  and 7.45 T. (CgCHg) .  1 Q  The I.R. spectrum  3.99 (CgH)  i n the c a r b o n y l and  o l e f i n i c s t r e t c h r e g i o n s was a l s o s i m i l a r w i t h peaks at 1755, 1705,  1645, 1590 and 1555 c m . -1  As expected  the U.V. a b s o r p t i o n  was d i s p l a c e d to longer wavelengths than f o r t r i p y r o n e w i t h maxima at 398,385 and 272 my;  and f i n a l l y the mass spectrum  show-  ed a s t r o n g parent peak at m/e = 330. Treatment o f these condensed polypyrone r e s u l t s i n r i n g opening aromatic compounds.  s t r u c t u r e s w i t h base  and subsequent condensation  to form  The r e s u l t s which had p r e v i o u s l y been ob-  158 t a i n e d * * * f r o m the r i n g opening experiments w i t h dipyrone and a c e t y l d i p y r o n e (82) are summarized i n f i g u r e 5.  (69)  The open  form of dipyrone (69a) can c y c l i z e v i a e i t h e r a C l a i s e n o r a l d o l - t y p e condensation to g i v e r e s p e c t i v e l y compounds of the acetylphloroglucinol  (84) o r o r c i n o l - t y p e (85).  Compounds of  51 the l a t t e r type  were o b t a i n e d when dipyrone was  treated with  e i t h e r IN aqueous potassium hydroxide o r IN methanolic p o t a s s ium hydroxide s o l u t i o n s . product o r s e l l i n i c a c i d  Under aqueous c o n d i t i o n s , the n a t u r a l (17) was  o b t a i n e d , w h i l e from  potassium hydroxide s o l u t i o n s methyl o r s e l l i n a t e  methanolic  (86),  2,4-  d i c a r b o m e t h o x y o r c i n o l (87) and p - O - m e t h y l o r s e l l i n i c a c i d were i s o l a t e d .  (88)  The formation of methyl e s t e r s and e t h e r s under  the methanolic c o n d i t i o n s i s not s u r p r i s i n g s i n c e the predomin53 54 ant b a s i c s p e c i e s i s probably methoxide anion. condensation mode was methanol  '  The  Claisen  e f f e c t e d by the system magnesium methoxide-  to g i v e c a r b o m e t h o x y a c e t y l p h l o r o g l u c i n o l (89).  both of the c y c l i z a t i o n modes observed  Thus  i n nature f o r a p o l y -p -  keto c h a i n of f o u r a c e t a t e u n i t s have been c a r r i e d out i n v i t r o . The ring-open form of a c e t y l d i p y r o n e (82a) can  similarly  c y c l i z e v i a two condensation modes to g i v e compounds of the diacetylphloroglucinol  (90) and the a c e t y l o r c i n o l type (91).  Treatment of a c e t y l d i p y r o n e w i t h methanolic potassium hydroxide 51 solution gave the expected a l d o l condensation product, orcacetophenone (92); however from the methanol-magnesium 52 methoxide system orcinol  (87) was  o n l y the d e g r a d a t i o n product, isolated.  dicarbomethoxy-  160 The  styryldipyrone  (93) has a l s o been prepared by workers  55 In these l a b o r a t o r i e s  and base treatment has given  structures  r e p r e s e n t a t i v e o f the s t i l b e n e s (94) and the f l a v a n o n e s (95). The  selectivity  i n the condensation modes was achieved  the d i p y r o n e ( 6 9 ) . The d i h y d r o s t y r y l d i p y r o n e  as f o r  (96), when  s i m i l a r l y t r e a t e d , gave s t r u c t u r e s r e p r e s e n t a t i v e o f d i h y d r o s t i l 55 benes and d i h y d r o c h a l c o n e s . As p a r t o f the work r e p o r t e d  i n t h i s t h e s i s , t r i p y r o n e (70)  was t r e a t e d under the b a s i c c o n d i t i o n s d e s c r i b e d  above, and the  aromatic products formed were i s o l a t e d and c h a r a c t e r i z e d . ring-open form o f t r i p y r o n e  The  (70a) can c y c l i z e i n many ways, the  three a l d o l condensation modes (3 -> 9, 7 -H> 2, 10*4) and the three C l a i s e n - t y p e are i l l u s t r a t e d dehydration  condensation modes (3 -> 8, 5 — ^ 1 ,  i n f i g u r e 6.  10  From subsequent O - a c y l a t i o n  12) and  various oxygen-containing h e t e r o c y c l i c s t r u c t u r e s  are p o s s i b l e as shown i n f i g u r e 6.  E m p i r i c a l l y , a l a r g e number  of aromatic compounds were formed, and those which were i s o l a t e d  161  162 i n s u f f i c i e n t q u a n t i t y and p u r i t y to be c h a r a c t e r i z e d are given i n f i g u r e 7. From the treatment o f t r i p y r o n e w i t h IN aqueous potassium hydroxide at 25° o n l y one aromatic compound was i s o l a t e d , and t h i s was shown to be the d e g r a d a t i o n product, (92).  orcacetophenone  Proof of s t r u c t u r e was p r o v i d e d by comparison  p r o p e r t i e s , m.p. and undepressed e r i a l p r e v i o u s l y prepared  51  of spectral  mixed m.p. w i t h a u t h e n t i c mat-  by the method o f Hoesch.  56  This  51 compound has been i s o l a t e d  from base treatment o f a c e t y l d i p y r o n e  (82); i t i s q u i t e l i k e l y that i n the base treatment o f t r i p y r o n e it  formed  v i a a c e t y l d i p y r o n e (82) s i n c e t h i s degraded  pyrone was  a l s o i s o l a t e d from the r e a c t i o n mixture. From the treatment o f t r i p y r o n e w i t h IN methanolic p o t a s s ium hydroxide at 25° s e v e r a l aromatic compounds were i s o l a t e d and c h a r a c t e r i z e d  (see f i g u r e 7 ) .  The t o t a l y i e l d o f aromatic  products was c a . 15-20%, however about o n e - t h i r d o f t h i s was degraded m a t e r i a l .  Orcacetophenone  (92) was again i s o l a t e d , and  another d e g r a d a t i o n product, 2,4-dicarbomethoxyorcinol also i s o l a t e d .  (87) was  T h i s l a t t e r compound (87) had p r e v i o u s l y been  51 isolated  from base treatment o f dipyrone (69); the s t r u c t u r a l  assignment  was made on the b a s i s o f s p e c t r a l and a n a l y t i c a l data,  and on the s i m i l a r i t y o f the U.V. spectrum (>jnax:316,262sh, 247sh, 57 58 232 my) w i t h that o f the known compound,  '  3,5-dihydroxy-2,  4 - d i c a r b o x y p h e n y l a c e t i c a c i d t r i m e t h y l e s t e r (97) Amax: 314, 260  infl,  247sh, 228 my.  163  164  (87)  (97)  In a d d i t i o n t o t h e s e d e g r a d a t i o n compounds were o b t a i n e d appear  to a r i s e v i a the a l d o l  open f o r m o f t r i p y r o n e can  be g r o u p e d  (99),  (see f i g u r e  (101),  into  (103)  phenylpropanone acid work-up.  (70a,  products,  7).  A l l of these  cyclization figure  three pairs  6).  mode  10 -->  Further,  (98),  (100)  Compounds o f b o t h t y p e  of the  t h e compounds structures  corresponding  and (102) (98)  compounds 4,  with the isocoumarin  probably a r i s i n g v i a the  structures  s i x new a r o m a t i c  d u r i n g the  and (99)  occur  in  1 nature,  probably  a r i s i n g v i a t h e same c y c l i z a t i o n  The c h a r a c t e r i s t i c are  in excellent  compounds  exhibited  a positive weight  (98),  (100),  ferric  (102)  appeared  test,  by a s t r o n g  The s a t u r a t e d  compounds  assignments.  chloride  was i n d i c a t e d  i n t h e mass s p e c t r u m .  compounds  o f each o f t h e s e  agreement w i t h t h e s t r u c t u r a l  each the m o l e c u l a r peak  properties  modes.  carbonyl  All  and f o r parent  groups of  i n the i n f r a r e d  spectrum  -1 at  1700-1710 cm  ed a t  whereas t h e c o n j u g a t e d  1660-1670 cm  bonyls of  (99),  (101),  ester  and t h e h y d r o g e n - b o n d e d (103)  at  carbonyls isocoumarin  1675-1685 c m ' . 1  s p e c t r a d e f i n e d a l l of the protons  at very  low f i e l d  (-1.2  car-  The N.M.R.  f o r e a c h o f t h e compounds.  The . h y d r o g e n - b o n d e d h y d r o x y l g r o u p s were i n d i c a t e d signals  appear-  to - 2 . 8 T )  by s h a r p  whereas the f r e e  165  CH,0  (98) (100) (102)  R=R'=H R~CR ,R*-H R=H,R'=C0 CH 2  hydroxyls  (98,99)  methyl ethers ception on  (103)  m e t h y l peak  the  appeared  as w e l l  signals  appeared  system CHg-C-CH^-Ar  peak  (101,  6.68 T . ) .  (100),  The  The p r o t o n s  as t h e o l e f i n i c p r o t o n s  i n the r e g i o n 3.51-3.72 T .  at 7 . 8 2 - 7 . 8 4 X  and (103)  a t c a . + 0 . 5 T. .  a t 5.97-6". 17 T w i t h t h e e x -  methyl ether of  rings  was c h a r a c t e r i z e d  (102)  CH -8=C-Ar 3  respectively  peak of the  at 7.78  at  (99),  The C H g - C O -  was c h a r a c t e r i z e d  and a m e t h y l e n e  of  by a  6.00-6.371.  isocoumarins  and 7 . 7 5 T ,  whereas  of the methoxydihydroisocoumarin  by a m e t h y l peak a t  8.37 X  (101)  and a m e t h y l e n e  at 6.84 T . The  tic.  ultraviolet  s p e c t r a o f t h e s e compounds was a l s o  The p h e n y l p r o p a n o n e s  isocoumarin natural (€  vides  (101)  products 12,600)  (€ 6 2 0 0 ) ,  it  as b r o a d s i g n a l s  methyl group of the system  (99)  260  appeared  system o f (98),  2  (101) 3  3  of the k e t a l  exhibited  CH -Ar  2  and e s t e r s  the aromatic  The  (99) R=H (103) R = C 0 C H  3  OCH,  270  further  (98)  a l l exhibit orsellinic  and (100)  proof  has r e c e n t l y  acid  5 9  '  6 0  (17) , "Xmax: 300(6 acid  F o r compounds  of the l o c a t i o n  been shown  62  and t h e m e t h o x y d i h y d r o  U . V . spectra characteristic  and C - a c e t y l o r s e l l i n i c (G 1 2 , 9 0 0 ) .  diagnos  that  1 4  '  6 1  (100),  of the  4,000),  (37) , A m a x : (101)  this  305 pro-  of the methyl e t h e r s  since  compounds o f s t r u c t u r e  (104,  166 R=R'=H) and (104, R=Me, R'=H) have o r s e l l i n i c  (17)  a c i d U.V.'s whereas  (37)  (104)  compound (104, R=H, R'=Me) has a d i f f e r e n t U.V. s p e c t r a ( A max: 282,  245sh).  The presence o f a second  carbomethoxy group  attached t o the r i n g a l t e r s the U.V. s p e c t r a ; however the s p e c t r a of  (102, Tvmax: 316, 265sh, 248, 231 my) was very s i m i l a r to that  of  2,4-dicarbomethoxyorcinol  (87), thus s u g g e s t i n g the  carbomethoxy group was l o c a t e d o r t h o t o both h y d r o x y l A p o s i t i v e Gibbs ment.  test  The isocoumarin  spectrum  6  3  ,  6  4  ,  6  5  groups.  f o r (102) confirmed t h i s a s s i g n -  (99) i s a known compound and the U.V.  (Amax: 324, 289, 278, 257sh, 245, 237 mp) and m.p.  250-253° a r e i n agreement w i t h that r e p o r t e d . spectrum 257,  second  1 4  '  6 1  The U.V.  o f compound (103), ^raax: 340, 325sh, 303, 291, 274sh,  250sh, 214shrap,was t y p i c a l o f an isocoumarin s t r u c t u r e  d e s p i t e the e f f e c t o f the carbomethoxy group.  The l o c a t i o n o f  the carbomethoxy group was again e s t a b l i s h e d by a p o s i t i v e Gibbs  test. As f i n a l proof o f t h e isocoumarin s t r u c t u r e (103), i t was  converted to (102) 61 ing  to H a s s a l l ,  by aqueous sodium hydroxide  treatment  accord-  f o l l o w e d by m e t h y l a t i o n w i t h diazomethane.  61 Hassall  has e f f e c t e d a s i m i l a r c o n v e r s i o n o f the isocoumarin  (99) to C - a c e t y l o r s e l l i n i c a c i d  (37).  167  It i s not s u r p r i s i n g that isocoumarin and methoxydihydroisocoumarin formation has o c c u r r e d d u r i n g the a c i d work-up. 14 Raistrick acid  has converted the n a t u r a l product,  (37) to the isocoumarin  C-acetylorsellinic  (99), by a c i d treatment;  and on  a c i d work-up o f a methanolic s o l u t i o n c o n t a i n i n g t h i s a c i d (37) he o b t a i n e d the methoxydihydroisocoumarin  (37)  Treatment  (99)  (105).  (105)  o f t r i p y r o n e w i t h IM methanolic magnesium methoxide  s o l u t i o n . a t 25° a l s o r e s u l t e d i n the formation o f many aromatic compounds ( t o t a l y i e l d  10-15%); however d i f f e r e n t  cyclization  modes were p r e f e r r e d and d e g r a d a t i o n was more severe.  The com-,  pounds which were i s o l a t e d i n s u f f i c i e n t q u a n t i t y and p u r i t y to be c h a r a c t e r i z e d are shown i n f i g u r e 7. p r o p e r t i e s o f two o t h e r compounds however s t r u c t u r a l assignments  In a d d i t i o n  characteristic  (110) and (111) are g i v e n ;  f o r these two compounds c o u l d  not be made and i t i s q u i t e l i k e l y that the p r o p e r t i e s r e p o r t e d are not those o f homogeneous compounds.  Once again, 2,4-dicarbo-,  168 methoxyorcinol (87) was i s o l a t e d and i d e n t i f i e d by comparison 51 w i t h an a u t h e n t i c sample. orsellinate,  Another " d i p y r o n e product", methyl  (86) was a l s o i s o l a t e d and i d e n t i f i e d by comparison  of i t s s p e c t r a l p r o p e r t i e s , m.p. and undepressed mixed m.p. w i t h 51 an a u t h e n t i c sample. Four new compounds were c h a r a c t e r i z e d . of these c o n t a i n s carbomethoxy  U n f o r t u n a t e l y each  groups attached to the r i n g , thus  o b s c u r i n g the c h a r a c t e r i s t i c U.V. s p e c t r a o f orcacetophenone, a c e t y l p h o r o g l u c i n o l or 6,8-dihydroxychromones.  Nevertheless  the c h a r a c t e r i s t i c p r o p e r t i e s o f each o f the compounds 108,109) p r o v i d e good support f o r the s t r u c t u r a l  (106,107,  assignments  made. A l l o f the compounds e x h i b i t e d a p o s i t i v e f e r r i c  chloride  t e s t , and f o r each the molecular weight was i n d i c a t e d by a s t r o n g parent peak i n the mass spectrum.  Compound  (106)  is  b e l i e v e d t o be the " a c e t y l d i p y r o n e product", 3-acetyl-4-carbometh \  oxyorcinol.  The a c e t y l f u n c t i o n was d e f i n e d by the I.R. (1645 cm  and N.M.R. s p e c t r a (7.47 IT, 3H) , as was the carbomethoxy (1675 c m , 5 . 9 5 T ) . -1  hydrogen-bonded  The N.M.R. s p e c t r a a l s o c h a r a c t e r i z e d the  h y d r o x y l groups (-1.35, -0.10X),  methyl (7.70t) and the aromatic proton (3.68T). positive Gibbs  group  the r i n g Finally, a  t e s t suggested the l o c a t i o n o f the carbomethoxy  group. The U.V. spectrum o f compound (108), "Amax: 327, 265sh, 250, 236sh, was very s i m i l a r t o that o f compound (106).  In a d d i t i o n  169  (106) the  (108)  A r - C H ^ C O ^ M e g r o u p was d e f i n e d by t h e I.R. (1725 c m  N.M.R. s p e c t r a protons  (108)  (6.29,  6.31t).  The o t h e r c a r b o n y l  were d e f i n e d as f o r ( 1 0 6 ) ,  suggested  and  (39)  and a p o s i t i v e  t h e p o s i t i o n o f the carbomethoxy  arises  from the a l d o l c y c l i z a t i o n  is in fact  the 4-carbomethoxy d e r i v a t i v e  ) and  g r o u p s and Gibbs  group.  mode 3 ->  - 1  This  test compound  9 (figure  of the  6)  natural  15 product,  curvulinic acid  occurring"  cyclization  acetate units The  major  treatment (107).  (39).  Thus a n o t h e r o f t h e  modes f o r a p o l y - p - k e t o  h a s been d e m o n s t r a t e d product  of tripyrone  chain of  five  in vitro.  isolated  f r o m t h e magnesium  was t h e  dicarbomethoxyacetylphloroglucinol  A l l of the f u n c t i o n a l  methoxide  g r o u p s were e s t a b l i s h e d  I.R. and N.M.R. s p e c t r a .  Compound (107)  cleavage of the structure  (112,  f r o m t h e open f o r m o f t r i p y r o n e  (107)  "naturally-  (112)  probably arises v i a  R=C02Me) w h i c h i n t u r n (70a)  from the  v i a the C l a i s e n  (109)  i s formed cyclization  170 mode 10 — 1 2 further  O-acylation  rivatives The  (figure  6) .  and d e h y d r a t i o n  chromone  analogue  of  structure The  N.M.R.  isocoumarin  ion  between their  whereas  structural  (109)  was v e r y  isomer  isolated; analogue  (103);  s i m i l a r to that of  i n addition a  distinct-  However t h e U . V . a b s o r p t i o n was d i a g n o s t i c ;  (109)  similar 317sh,  has a spectrum  to that  280sh,  Thus a n o t h e r  in vitro.  chromone,  A negative  the carbomethoxy  condensation  (Amax:  parent  280sh,  257,  6 6  and n o t u n l i k e  eugenin test  group to complete type  of a chain of f i v e  that  of the  (35)  Gibbs  structural  of the  315sh,  (89)  naturally-occurring 67 2 4 8 , 2 2 8 mp.  that  of the carbomethoxyphloroglucinol  256 m p ,  (109)  out  R^CC^Me) was n o t  has a U . V . spectrum not u n l i k e  (99),  225 DIM) v e r y  of  de-  t h e s e two compounds c o u l d n o t be made o n t h e b a s i s  (103)  (89), A m a x :  of  dihydroxymethylchromones.  i s b e l i e v e d t o be t h e chromone  spectrum of  I.R. spectra.  isocoumarin  i s capable  ( 1 1 2 , R=H).  the  of  (112,  (112)  to form carbomethoxy  of the n a t u r a l l y - o c c u r r i n g  however compound (109) of  The s t r u c t u r e  (35),  Amax:  suggested  the p o s i t i o n  the s t r u c t u r a l  formed from the  acetate units  The n a t u r a l l y - o c c u r r i n g  318,288,257,  assignment.  intramolecular  h a s been  chromones,  carried  e g . eugenin  (35),  171 probably arise  v i a the  condensation  f o l l o w e d by s u b s e q u e n t carbomethoxychromone mode;  however  (109)  since  the  compound i s o l a t e d , cyclization 10 are  12; not  on t o  mode p o s s i b l e  is  units  is  inic  acid  in this  means o f  from a p o l y - p - k e t o  five  treatment  the  dipyrone  (69)  4  resulted  orsellinic  acid  this  field will  involve:  considerable  soluble  and t h u s  groups  major via  i.e.  C g and C  1  2  only Claisen  1  the  opening of of  six  the  to  arise  of  effort  more  larger since  d i f f i c u l t to  efficient  acetate four  have  been  showed t h a t two  four  curvul-  i n nature isolated.  base  structural  acetate Future  units,  work  tetrapyrone  acetate units,  polypyrone structures, effect  five  tripyrone  isocoumarin,  i n the  chain of  the  tripyrone  and a c e t y l p h l o r o g l u c i n o l .  which should generate a chain  quire  acid,  work ^'^  i.e.  The c o n s t r u c t i o n  the  groups,  acetate u n i t s ,  from a p o l y - p - k e t o  systems to  arises  show t h a t  believed  types d e r i v a b l e  new b a s i c  (109)  and t h e  thesis  which are  previously reported  larger  was  h o l d i n g a chain of  In a d d i t i o n ,  of  cyclization  (103)  carboxyl  base t r e a t m e n t o f  c h a i n of  struction  The  same  carboxyl  chain  C-acetylorsellinic  and c h r o m o n e ,  of  the  that  the  6)  11.  From t h e  types:  product  residual  poly-p-keto  reported  a convenient  structural  the  presumably,  5 ->  together.  could arise v i a  more p r o b a b l e  one o f  (figure  and d e h y d r a t i o n .  degradation  is  i n the  The r e s u l t s (70)  it  in nature,  present  O-acylation  mode 5 —> 11  and t h e  the  (71), con-  search  for  cyclizations.  polypyrone structures w i l l t h e s e compounds  handle.  in  are  An a t t e m p t  to  quite  rein-  prepare  172 the pentapyrone  (113) by condensation of b i s ( 2 , 4 - d i c h l o r o p h e n y l )  malonate w i t h t e t r a p y r o n e f a i l e d , pentapyrone  although t r a c e s of the  were i n d i c a t e d by T.L.C. evidence.  Acetyltetrapyrone  (114) was prepared by r e f l u x i n g a t r i f l u o r o a c e t i c a c i d of t e t r a p y r o n e and a l a r g e excess of a c e t y l c h l o r i d e .  (113)  (114) the s y n t h e s i s of the pentapyrone  solution Perhaps  (115)  (113) might be accomplished  a c y l a t i o n of (114) w i t h e t h y l c h l o r o f o r m a t e .  by  Alternatively, 67  a c y l a t i o n of a c e t y l t e t r a p y r o n e (114) w i t h a c e t i c might extend the poly-p-keto c h a i n by one u n i t ure 115).  The s y n t h e s i s of acetylpentapyrone  116) from tetrapyrone.might  anhydride  (partial (partial  a l s o be accomplished  structstructure  i n two s t e p s ,  eg. a c y l a t i o n w i t h e t h y l c h l o r o f o r m a t e f o l l o w e d by condensation •4  with e t h y l a c e t y l a c e t a t e .  (116) A more p r o f i t a b l e approach  to the problem of c o n s t r u c t i n g  l a r g e r polypyrone s t r u c t u r e s might be to couple two condensed  173  (119)  pyrone structures together.  For example, acylation of tripyrone  (70) with the tripyrone acid chloride (117) could give the bi_s-tripyrone (118) . In this regard, the monocyclic acid 72  chloride (119) has been prepared, are under investigation.  and i t s acylating properties  Base opening of (118) would give rise  to a poly-p-keto chain of ten acetate units, and thus the biogenetic-type synthesis of tetracyclic structures representative of the tetracyclines (43) and mycinones (44) would be possible.  Work towards this goal i s proceeding in these labora-  tories. Before attempting the syntheses of compounds such as (118) a more c r i t i c a l examination of systems for opening condensed polypyrones should be made. The real weakness in the biogenetictype synthetic scheme based on condensed polypyrones i s that the conditions for generating the poly-P-keto chains might preferably degrade these chains rather than promote intramolecular con39  densations.  Harris  has shown that poly-p-keto chains of four  acetate units cyclize to aromatic compounds under essentially  174  p h y s i o l o g i c a l c o n d i t i o n s , and he has p o s t u l a t e d that such c y c l i z a t i o n s may r e q u i r e no enzyme c a t a l y s i s . formation  and the r e t e n t i o n of poly-p-keto  However the  c h a i n s do r e q u i r e  enzyme c a t a l y s i s ; thus i t i s d o u b t f u l that chains much longer than f o u r acetate u n i t s w i l l proves to be the case,  a c t u a l l y be i s o l a t e d .  If this  then the polypyrone s t r u c t u r e s s t i l l  v i d e an a t t r a c t i v e a l t e r n a t i v e f o r the b i o g e n e t i c - t y p e of a c e t a t e - d e r i v e d aromatic  i  compounds.  pro-  syntheses  175 EXPERIMENTAL M e l t i n g p o i n t s were scope.  U l t r a v i o l e t spectra  solutions spectra  u s i n g a C a r y 14  (I.R.)  were  u s e d as  unless  the  Nuclear magnetic  internal standard.  by D r . A . B e r n h a r d t  Institute, this  Mulheim,  ethanolic  137B  spectra  (N.M.R.)  in deuteriochloroform  Tetramethyl s i l a n e  The mass s p e c t r a  were  associates  at  was  determined  E l e m e n t a l m i c r o a n a l y s e s were and h i s  micro-  and i n f r a r e d  resonance  indicated otherwise.  on an A t l a s s p e c t r o m e t e r . out  stage  i n n u j o l w i t h a Perkin Elmer  t a k e n on a V a r i a n A60 Mc i n s t r u m e n t  solutions  hot  ( U . V . ) were d e t e r m i n e d i n  spectrophotometer;  taken  spectrophotometer. were  d e t e r m i n e d on a K o f l e r  carried  t h e Max P l a n c k  R u h r , West Germany, and by M r . P B o r d a o f  department. The U . V . maxima a r e  refers  to  the  spectra  reported  in millimicrons;  obtained after  potassium hydroxide s o l u t i o n to  the  A(base)  adding 1 drop of ethanolic  aqueous  U . V . sample.  I.R.  -1 peaks  are  reported  i n cm  i n X u n i t s w i t h the the  assignments  are  enclosed  as m / e . shape  coupling  constants,  the N . M . R .  in brackets.  peaks  The mass  J,  and t h e  peaks  are  reported  Organic at  U . V . ) are  spectrum data  (in vacuo).  purposes  20  are  cycles/sec;  constants reported  (I.R.)  r o u t i n e l y removed on a r o t a r y Thin-layer  was c a r r i e d o u t w i t h s i l i c a g e l G ( a c c . preparative  in  and  used.  s o l v e n t s were  45°  reported  coupling  S t a n d a r d a b b r e v i a t i o n s f o r peak i n t e n s i t y  (N.M.R.,  porator  of  ; and t h e N . M . R .  x 60  x 0.10  chromatography to  Stahl)  cm p l a t e s  eva-  (T.L.C.)  plates.  For  were r u n a l o n g  176 the  60  cm a x i s w h i l e i n c l i n e d  The f e r r i c ferric  adding a small quantity  (-=^1  benzoquinone-4-chlorimine  Triacetic 100  g.  dissolved bath. bath;  pH 9 . 2 4 .  acid  lactone  of  of  (B.D.H.),  of  ethanolic  carried  compound i n  the  reagent,  3  2,6-dichloro-p-  and t h e n 2 m l . o f  (16) ,  50  sodium  (4-hydroxy-6-methyl°<-pyrone) :  acid  (46,  Eastman O r g a n i c )  f l a s k was p a r t i a l l y  flask.  up to  by  6 2  s o l u t i o n was s t i r r e d  blown t h r o u g h t h e  out  ethanol,*'  m l . 90% s u l f u r i c a c i d by warming on a  The r e a c t i o n  u r e was b r o u g h t  t e s t s were  mg.)  mg.)  dehydroacetic  i n 165  the  (<Cl  angle.  r u n u s i n g a 1%  The G i b b s  a small quantity  borate b u f f e r ,  a 15°  c h l o r i d e t e s t s were  chloride solution.  dissolving  at  was steam  immersed i n a 1 5 0 ° o i l  magnetically,  The t e m p e r a t u r e  1 3 0 ° and t h e n k e p t  of at  and n i t r o g e n  was  the  mixt-  reaction  130-136°  for  5 min.  The r e s u l t i n g deep r e d d i s h - b r o w n s o l u t i o n was c o o l e d r a p i d l y i n an i c e - b a t h  and t h e n  added t o  i z a t i o n was e s s e n t i a l l y cipitate 500  ml.  acetate  was c o l l e c t e d ice-water.  complete in a  but  191°;  T.L.C.  chloride:  m l . of within  Buchner  (45g.)  of  negative;  1630s,  1590m,  1540m,  1150m,  1040w,  990s,  I.R. 1510 880m,  acid  The w h i t e  crops)  lactone  1340m,  815m,  730w,  pre-  and washed w i t h from e t h y l  (16);  R =0.30; f  3 1 0 0 - 2 6 0 0 m,  1490m,  843s,  (3  acid 4:1):  (nujol): m,  5 min.  Crystall-  slightly discolored  sharp m e l t i n g t r i a c e t i c (chloroform:acetic  ice-water.  funnel  Recrystallization  gave a 60% y i e l d  tinge)  700  m.p.  190-  ferric  1720s,  1300s,  (orange  1660s,  1250s,  690w; U . V . :  1190m, 47  177 284(e 6 , 5 0 0 ) ;  N.M.R.  (trifluoroacetic  range c o u p l i n g w i t h methyl group 7.53s  (methyl);  Anal.  C 57.14,  H 4.76.  Dipyrone  (69),  Found:  trifluoroacetic moles)  then ing  H 4.90,  acid  (Matheson  (Aldrich). under  was c o o l e d  130 m l . o f c o l d e t h y l  acetate  added.  crude  The c r u d e 13 l i t e r s  g e l column  liters  per hour.  liters  of c h l o r o f o r m .  conditions  i n an i c e - b a t h and  After  10 m i n . c h i l l -  and washed  with  100 g .  d i p y r o n e was p u r i f i e d f u r t h e r  of chloroform  400 g . s i l i c a  chloroform  yield  was added 222 g :  anhydrous  was c o l l e c t e d  i n 300 m l .  The deep r e d -  mixture  acetate,  requires:  l a c t o n e . ( 0 . 8 moles)  gently  c.p.s.),  aa  1,6-dioxanaphthalene):  Coleman & B e l l )  t h e f i n e brown p r e c i p i t a t e  (CgH, J 2  CgHgO-j  The r e a c t i o n  ethyl  in  C57.28,  of malonyl d i c h l o r i d e  5 hours.  5  and C^H) , 3 . 7 9 d  acid  brown s o l u t i o n was r e f l u x e d for  3.48m ( C H , l o n g  (4-hydroxy-7-methyl-2,5-diketo  To 100 g . o f t r i a c e t i c  (1.6  acid):  by d i s s o l v i n g i t  and f i l t e r i n g t h e s o l u t i o n  through  (35 x 5 cm. d i a . ) a t t h e r a t e o f 2  The column was washed w i t h an a d d i t i o n a l  (2 c r o p s )  a  The d i p y r o n e was r e c r y s t a l l i z e d to give  82 g . d i p y r o n e  10  from  (53% y i e l d ) .  The  51 major  impurity,  acetyl  dipyrone  cence under U . V . i r r a d i a t i o n ) and t h e s e c o n d  crops.  sharp  melting;  m.p. 2 3 0 - 2 3 2 ° ;  4:1):  R =0.65;  ferric  f  (69)  (characteristic  was p r e s e n t  The e a r l i e r  i n the l a t e r  fractions  T.L.C.  fractions  were c o l o r l e s s  (chloroform-acetic  chloride:positive,  fluores-  dark r e d ; I . R .  , .  and  acid (nujol):  3200m,3050m,1755s,1690s,1625s,1560s,1340m,1285w,1200s,1170s, 1125m,1100m,1050s,990m,860m,793m,770m,740m,720m;  U.V.:329(5  7,300),  178 271  (C 1 1 , 8 0 0 ) ;  (C3H),  7.44s  C 55.90,  N.M.R.  (methyl);  H 3.19,  g.  c  9 6  5  c  of  collected  the form  C 55.65,  mole)  ( 1 0 0 ° o i l bath)  H  i n 20  for  Anal.  liters  trifluoroacetic  hr.  The  under  reaction anhydrous  black  sludge  brown powder was  of  by  The sample was  hot  benzene.  Recrystallization  gave 2 . 7  of  tripyrone.  chromatography  initially  Elution with  first  f o l l o w e d by t r i p y r o n e . yield)  4,6,9-trioxa-  mole).  further  y i e l d e d d i p y r o n e i n the  (20%  Found:  ether.  t r i p y r o n e was p u r i f i e d  liters)  4.02s  3.12.  ml.  1.5  The l i g h t  s i l i c a g e l column.  g.  g  f l a s k was c o o l e d and t h e  and washed w i t h  g.  3.30m ( C H ) ,  (parent);  m a l o n y l d i c h l o r i d e (0.4  w i t h 50 m l . e t h e r .  column w i t h 12 (7  (0.05  The r e a c t i o n  The c r u d e on a 100  requires:  dipyrone  m i x t u r e was r e f l u x e d  triturated  spec.:194  acid):  (l-hydroxy-7-methyl-3,5,10-triketo  a c i d was added 5 8 g .  conditions.  mass  C H O r t  T r i p y r o n e (70), phenanthreiieTl To 10  (trifluoroacetic  p u t on chloro-  fractions  from acetone  The m a j o r  (2g.) (2  crops)  i m p u r i t y was  51 acetyltripyrone crop  contained  which appeared  t i n y yellow needles;  (chloroform-acetic (weak); 1540s,  acid 4:1):  I.R.  (nujol):  1325m,  1290w,  1010W, 975w, (G 5 1 0 0 ) , (fe 5 , 6 0 0 ) ;  370  880w, (e  N.M.R.  (C2H) , 7 . 4 3 s  i n the  3200w, 1220m,  860w,  8,900),  1755s, 1185m,  mass  770w,  1635 1110m, 740m;  The  chloride: m,  positive  1570(sh)m,  1045m,  1028m,  U . V . : 392  infl.  255sh  3.30m ( C H ) ,  (parent);  first  T.L.C.  281(fe 8 , 7 0 0 ) ,  acid): 262  dec;  ferric  1170m,  (€ 8 , 9 0 0 ) ,  spec:  260°  1720s,  802m,  (trifluoroacetic  (methyl);  m.p.  R^ = 0 . 3 0 ;  830w, 360  second c r o p .  g  Anal.  3.96s Found:  179 C 54.95,  H 2.59,  For  C^HgC^  an a l t e r n a t e  which gives  better  requires:  synthesis  yields,  see  C  of  54.97,  H  tripyrone  under the  2.31.  from dipyrone  tetrapyrone  section.  Tetrapyrone (71), (4-hydroxy-9-methyl-2,5,7,12-tetraketo 1,6,8,11 tetraoxachrysene): Attempts  to  synthesize  tetrapyrone  from the  condensation  of  tripyrone with malonyl d i c h l o r i d e y i e l d e d only trace  of  the  desired product.  t h e s e a t t e m p t s was t h e dichloride (nujol):  to  1755vs,  since  dioxan or the  heat-catalyzed  1710(sh)s, a c i d d i d not  1625s,  m.p.  1540s,  appear  which  to  330°  800m,  catalyze  a s i m i l a r p r o d u c t was o b t a i n e d when c h l o r o f o r m was u s e d as  polymerization rather  aluminum c h l o r i d e was  than  solvent.  the  ineffective  a  dec;  I.R.  1300-850w. this  polymerizat-  tetrahydrofuran,  Pyridine  condensation as  accompanied  polymerization of malonyl  form a red-brown polymer;  Trifluoroacetic ion  The m a j o r r e a c t i o n  amounts  catalyzed  reaction;  and  catalyst. 42  The use o f  malonic  was more s u c c e s s f u l . carried of  A series  of  as  C3O2  condensing  u s i n g d i p y r o n e and a number o f  diesters.  diesters tripyrone diesters  resulted  The f u s i o n o f  i n the  was:  Treatment  solution  dipyrone with various  f o r m a t i o n of  and t e t r a p y r o n e .  were  ( 2 1 5 ° o i l bath),  r e f l u x i n g 10% s u l f u r i c a c i d / d i e t h y l m a l o n a t e  no c o n d e n s a t i o n .  units  p r e l i m i n a r y experiments  dipyrone with r e f l u x i n g diethylmalonate  with in  out  acid diesters  substantial  The o r d e r o f  bis(2,4,6-trichloropheny1)malonate  < b i s (2 , 4 - d i c h l o r o p h e n y l ) m a l o n a t e T h e  reactions  for  resulted aryl  amounts  reactivity  or  of  the  <diphenylmalonate were  carried  out  180 by  f u s i n g a mixture  i o n s were  o f d i p y r o n e and d i e s t e r  over w i t h i n  10 t o 30 m i n . when t h e m e l t  due t o t h e p o l y m e r i z a t i o n o f t h e d i e s t e r . pective and  at 2 3 0 ° .  phenols to m a i n t a i n the melt  The r e a c t -  solidified  The u s e o f t h e  repressed  res-  the condensation;  t h e u s e o f d i e t h y l c a r b i t o l f o r t h e same p u r p o s e d i d n o t  increase  the y i e l d .  The u s e o f an aluminum c h l o r i d e - s o d i u m  69 chloride  5:1 melt  experiment mmoles)  was as f o l l o w s :  unsuccessful. a mixture  The most  (230°  o i l bath)  f o r 10 m i n . ; T . L . C .  of dipyrone:tripyrone:tetrapyrone  On a l a r g e tripyrone  scale  this  reaction  and t e t r a p y r o n e .  A mixture  o f 300 mg. t r i p y r o n e  bis(2,4-dichlorophenyl)malonate T.L.C.  bath)  for 2 min.  the  ratio  of t r i p y r o n e : t e t r a p y r o n e  was  then chromatographed  both  tetrapyrone  mmoles)  mmoles)  of the r e a c t i o n  was  was about  was h e a t e d mixture 2:1.  (250°  indicated  The m i x t u r e  o f h o t benzene  eluted with 8 l i t e r s  manner.  and 550 mg.  on a 3 0 g . s i l i c a g e l c o l u m n .  was p u t on t h e column w i t h 4 l i t e r s were  2:1:0.4.  i n the f o l l o w i n g  (1.1  (1.4  oil  pyrone m a t e r i a l s  i n d i c a t e d the  c o u l d be u s e d t o p r e p a r e  and p u r i f i e d  (0.5  (1.3mmoles)  t o be about  For our purposes,  s y n t h e s i z e d from t r i p y r o n e  successful  o f 100 mg. d i p y r o n e  and 508 mg. b i s ( 2 , 4 - d i c h l o r o p h e n y l ) m a l o n a t e  was h e a t e d ratio  was a l s o  The sample  and t h e  of chloroform;  bis(2,4-dichlorophenyl)malonate  (175 mg.) was e l u t e d w i t h t h e  benzene.  (160 mg.) was e l u t e d w i t h t h e  first  Most o f t h e t r i p y r o n e  two l i t e r s  of chloroform;  p y r o n e was c o l l e c t e d (125 m g . ) . off  from the l a s t  The t e t r a p y r o n e  the t r i p y r o n e  a mixture  6 liters  was p u r i f i e d  i m p u r i t y (0.01  90-95% p u r e  in tetra-  of chloroform  further  by s u b l i m i n g  mm. H g , 1 9 5 ° , 4 h r . ) .  Charcoal-  181 ing  an a c e t o n e s o l u t i o n o f  ation 280°  f r o m a c e t o n e gave dec;  T.L.C.  the  tetrapyrone  I.R.  (nujol):  1555s,  1320w,  1290w,  1240m,  1030w,  1005w,  965vw,  860w,  398  (G 8 , 6 0 0 ) ;  N.M.R.  ( C ^ K ) , 7.45s C 54.67,  an a n a l o g o u s  lieved  C  to  be  1 5  H  mass  1 6  C>  prepare  (71)  (113)  collected I.R.  920m,  860m,  1055w, infl.  (£ 4 , 6 0 0 ) ,  3.43s  H  (C  1 Q  H),  Anal.  272  3.99s  Found:  1.83.  from t e t r a p y r o n e as T . L . C .  of  by  the  a compound b e -  (114): was added t o  a s o l u t i o n of  in 1 ml. t r i f l u o r o a c e t i c  The r e a c t i o n  acid,  20mg.  and t h e  810s,  1750vs,  -687m;  372  (parent).  the  common s o l v e n t s ;  1640s,  U . V .:  1600s,  "Xmax:  s u b l i m e d at  397,  the  1540vs, 265  was v e r y 230°  24  and a y e l l o w compound  m i x t u r e was c o o l e d ;  The a c e t y l t e t r a p y r o n e it  solution  under anhydrous c o n d i t i o n s f o r  precipitate  and washed w i t h w a t e r and t h e n a c e t o n e ;  (nujol):  slowly.  1120m,  amounts o f  H y d r o g e n c h l o r i d e gas was g i v e n o f f  dec;  332sh  C 54.56,  1590m,  U . V . : 420  (parent;  unsuccessful,  ( 1 0 0 ° o i l bath)  precipitated.  very  requires:  ferric  1645m,  1135w,  m.p.  pentapyrone.  was r e f l u x e d  \as  acid):  pentapyrone  1 ml. acetylchloride  hrs.  9  •» 0 . 1 5 ;  f  678w;  (G- 9 , 8 0 0 ) ,  330  R  1705s,  1165w,  700vw,  spec:  recrystalliz-  tiny yellow prisms;  acid):  indicated only trace  Acetyltetrapyrone  tetrapyrone  385  p r o c e d u r e were  mixture  to  1210w, 805m,  f o l l o w e d by  1755s,  (trifluoroacetic  (methyl);  Attempts  reaction  (G 9 , 8 0 0 ) ,  H 2.02,  as  (chloroform-acetic  c h l o r i d e : v e r y weak;  (G 6 , 0 0 0 ) ,  residue,  (0.1  m.p.  1130s,  mn; mass  330°  1000s, spec:  j  insoluble in mm H g ) j b u t  all  only  182 Bis(2,4-dichlorophenyl)malonate: A mixture 32.6  g.  mole)  (0.2  of  mole)  3 hr.  the  crystalline 600  ml. ether  f  = 0.9;  1150s, 698w, (4H, C  I.R.  organic  99-100°;  1095vs,  5.82s  layer  solvent  T.L.C.  1775vs, 1060m,  ice-water  bath) and  removed i n v a c u o .  gave a 70% y i e l d  1750m,  1585m,  940w,  C 46.08,  Found: H 2.05,  Re-  color4:1):  1215s,  845m,  (2H,  of acid  1245m,  872m,  (2H);  C 45.72,  (0.2  (120° o i l  (chloroform-acetic  965w,  Anal.  g.  e x t r a c t e d w i t h sodium  2.40q  1 K  and 3 0 . 6  The p r o d u c t was t a k e n up  (deuterioacetone):  H CvCl. requires: 15 8 4 4  (Eastman);  ( B . & A . ) was r e f l u x e d  d r i e d and t h e  (nujol):  685w; N . M . R . J=1.8),  (Eastman)  from benzene:n-hexane  m.p.  1135vs,  malonic a c i d  collected.  and t h e  washed,  needles;  mole)  m i x t u r e was p o u r r e d i n t o  material  crystallization  R  (0.1  2,4-dichlorophenol  The r e a c t i o n  bicarbonate,  less  g.  phosphorus o x y c h l o r i d e  for  in  10.4  J -  825m, 2,1),  H 2.19,  783s, 2.60d  C l 35.99,  C l 35.99.  Diphenylmalonate: A s o l u t i o n of  9.4  c h l o r o f o r m was h e a t e d s o l u t i o n of  14.0  g.  g. to  (0.1  (0.1  a gentle mole)  c h l o r o f o r m s l o w l y added o v e r a further  30  with water. 100  mole)  phenol  reflux  (B.D.H.)  i n 30  ( 7 5 ° o i l bath),  2 hr.  ether.  The o r g a n i c  washed,  d r i e d and t h e  aqueous  for  destroyed  in  vacuo,  solution extracted with  l a y e r was e x t r a c t e d w i t h s o d i u m solvent  and a  R e f l u x i n g was c o n t i n u e d  , The c h l o r o f o r m l a y e r was c o n c e n t r a t e d added and t h e  of  m a l o n y l d i c h l o r i d e i n 15 m l .  m i n . and t h e n e x c e s s m a l o n y l d i c h l o r i d e  m l . water  ml.  removed i n v a c u o .  bicarbonate,  Crystallization  183 from e t h a n o l  (3  crops)  Recrystallization  gave  1360s,  1005w,  965m,  m.p.  50  1340s, 955m,  );  I.R.  1255m,  940m,  (nujol):  910m,  of diphenylmalonate.  needles;  (deuterioacetone):  Anal.  Found:  C 70.33,  H 4.91,  m.p.  i5  H  1 2  760s,  2.74m  °4  r  e  (  *  1750vs,  1125vs,  820m,  2.68, c  1780vs,  1150s,  845m,  N.M.R.  46-47°  u  1060m,  750s,  (10H), i  r  e  s  :  c  1595m, 1025m,  705s,  6.05s  (2H);  70.30,  H  4.72.  (2,4,6-trichlorophenyl)malonate: A s o l u t i o n of  man)  i n 20  ml. of  a s o l u t i o n of  5.0g  ( 0 . 0 2 5 mole)  for  3.0  a further  g.  ( 0 . 0 2 1 mole)  benzene dried  and t h e  to  a gentle  reflux,  15 m i n .  excess malonyl d i c h l o r i d e  t a k e n up i n 150  crops)  gave  iri v a c u o .  a 65% y i e l d  (3.8  to  m l . benzene.  l a y e r was e x t r a c t e d w i t h s o d i u m b i c a r b o n a t e ,  and c o n c e n t r a t e d  and  R e f l u x i n g was c o n t i n u e d  The c h l o r o f o r m l a y e r was t a k e n  residue  (East-  m a l o n y l d i c h l o r i d e i n 5 ml  15 m i n . and t h e n t h e  destroyed with water. i n vacuo  2,4,6-trichlorophenol  c h l o r o f o r m was h e a t e d  c h l o r o f o r m added s l o w l y o v e r  (3  yield)  colorless  1200vs,  695s;  Bis  (80%  o  reported  1490s,  g.  f r o m e t h a n o l gave  70 (cf.  10.3  dryness  The washed,  C r y s t a l l i z a t i o n f r o m benzene g.)  of  diester.  Recrystallizato  ion  f r o m b e n z e n e gave c o l o r l e s s  prisms;  3100w,  1795s,  1780s,  1570m,  1420w,  1230s,  1195w,  1155m,  1135w,  1105vs,  1400w,  875w,  862s,  822s,  805m,  790m; N . M . R .  (4H),  5.95s  (2H);  Anal.  Found:  C  15 6°4 H  It  C 1  6  is  r  e  <  *  u  i  r  e  s  :  c  interesting  38.92,  H 1.31, that  154-156  1385m,  1075w,  960w,  ; I.R.  1330s, 938m,  H 1.21,  (nujol):  1255m, 920w,  (deuteriochloroform):  C 39.12,  to note  m.p.  2.59s  C l 45.92,  C l 45.95. bis  (2,4,6-trichlorophenyl)  184 malonate  is  unstable  in several  common o r g a n i c  e t h e r was u s e d i n t h e w o r k - u p v e r y isolated;  attempted  degradation of  the  of  the  diester  Base Treatment 1.  recrystallization diester;  of  of  in this  the  When  diester  from e t h a n o l  and t h e N . M . R .  in deuterioacetone  a t i o n had o c c u r r e d  little  solvents.  was  f a i l e d with  spectrum of  a  sample  indicated considerable  solvent  degrad-  also.  T r i p y r o n e (70) :  IN KOH ( a q u e o u s ) : A s o l u t i o n of  200  mg.  tripyrone  a s s i u m h y d r o x i d e was m a g n e t i c a l l y temperature f o r 2 h r .  2 hr.  the  15 mg. o f a c i d 4:1)  cluding  contain  a number o f  at  a dark  room  green  a few m i n u t e s .  (11 the  acidified ml.)  (pH2)  and t h e n  organic  w h i c h was shown by T . L . C .  aqueous  l a y e r was f r e e z e - d r i e d yield  w h i c h was shown by T . L . C .  contain  to  two components were s e p a r a t e d acid 9:1). (Rf=0.7,  benzene  over  (ice-bath),  ed w i t h r e f l u x i n g a c e t o n e t o  other  under n i t r o g e n  pot-  layer  (chloroform:  m i n o r components  in-  tripyrone.  The  acetic  IN aqueous  initially  E v a p o r a t i o n of  residue, to  ml.  hydrochloric acid  extracted with chloroform.  acetic  to orange  s o l u t i o n was c o o l e d  w i t h dropwise a d d i t i o n of  yielded  stirred  The s o l u t i o n was  c o l o r w h i c h g r a d u a l l y changed After  i n 120  to  One o f  crude  yield  give colorless  140  and t h e mg. o f  residue  crude  extract-  material,  two m a j o r c o m p o n e n t s .  by p r e p a r a t i v e  T.L.C.  (chloroform-  t h e s e components was t r i p y r o n e ; 30  mg.)  needles;  was r e c r y s t a l l i z e d m.p.  157-158°.  The  the  from  Comparative  185 T.L.C.,  I.R.,  U . V . and N . M . R .  spectra,  and u n d e p r e s s e d  mixed  51 m.p.  with authentic  material  was o r c a c e t o p h e n o n e The  above  tripyrone  in 1 liter  the  mg.  starting  of  dipyrone 2.  was r e p e a t e d  of  IN aqueous  material  before  a l o n g w i t h about  to  yield  50 mg. o f  After  over  500  acetyl-  (82) .  IN KOH/MeOH: of  1 g.  room t e m p e r a t u r e f o r bright  green  first  solution. acidified  tripyrone  color,  hour.  2 days.  in 1 liter  After  (pH2)  by d r o p w i s e  then c o n c e n t r a t e d  200  m l . water The  layers  above  T.L.C.  yield  and I . R .  Another major (benzene-ether  the  ca.  component 4:1);  hexane g a v e c o l o r l e s s  twice.  1 g.  crude  of  consist  isolated  during into  (ice-bath), acid  m.p.  The c o m b i n e d  extracted with  material, largely  (95  recrystallization needles;  a  (80  ml.)  chloroform.  residue  was  had gone  hydrochloric  and t h e  to  orange  at  The s o l u t i o n was d i l u t e d w i t h  was r e p e a t e d  spectra  initially  bright  solid  a d d i t i o n of  and t h e n e x t r a c t e d w i t h reaction  under n i t r o g e n  s o l u t i o n was c o o l e d  in v a c u o .  were f r e e z e - d r i e d  acetone to  the  IN m e t h a n o l i c  The s o l u t i o n was  1 day a l l o f  A f t e r 2 days  of  stirred  g r a d u a l l y c h a n g i n g to  and  by  1 g.  potassium hydroxide.  p o t a s s i u m h y d r o x i d e was m a g n e t i c a l l y  ing  component  with a s o l u t i o n of  s o l u t i o n was w o r k e d up as  A mixture  the  aromatic  (92).  reaction  3 days  proved the  mg.)  of  reflux-  w h i c h was  shown  tripyrone.  by p r e p a r a t i v e  from e t h y l  157-158°;  aqueous  acetate:  T . L . C  T.L.C.  n-  (benzene-  186 ether  4:1):Rf  = 0.55;  Gibbs  test:positive  1575s,  852m,  (€  5,000),  827m;  221  (e  (methyl).  chloride:  (purple);  U . V . : 315sh 7,400);  H-bonded OH), 0.93b 7.48s  ferric  I.R.  (nujol):  (€3,200),  N.M.R.  (1H,0H),  positive  282  (dark  3200s, (€  1620s,  6,700),  (deuterioacetone) :  3.76m  (2H,  Comparative T . L . C . ,  aromatic),  spectral  red);  231sh  -3.00b 7.40s  data  and  (IH,  (methyl),  undepress-  51 ed  m i x e d m . p . w i t h an a u t h e n t i c  component was o r c a c e t o p h e n o n e The solvent The  Further the  removed in v a c u o was  to  initially  fractionation systems:  yield  ca.  out  benzene-ether  the  t h e r e was  m.p.  tripyrone. residue  This data  from the  From t h e of  data.  indicated,  presented  data  mg. o f  T.L.C.  indicates  that  relatively  to in-  spectral  compound as evidence of ca.  a large  30%  number  t h e s e 7 were  the  starting  The y i e l d s g i v e n a r e  (ca.  isolated  be c h a r a c t e r i z e d  and p r o b a b l e s t r u c t u r e s  below.  using  mixture.  procedure  to  T.L.C.  In a d d i t i o n  identified this  and o f  solvents.  Comparative T . L . C ,  reaction  p u r i t y and q u a n t i t y  The s p e c t r a l  pounds a r e  i n the  fractionation  compounds were  sufficient  layers  material.  and c a r b o n  10:9:1.  120  the  by e l u t i o n f r o m a  ether,  combined w i t h the  aqueous  m a t e r i a l was p r e s e n t  acid  255-260 d e c .  and u n d e p r e s s e d mixed m . p .  crude  by p r e p a r a t i v e  4:1,  acetic  soluble material,  of  d r i e d and  c h l o r o f o r m and a c e t o n e  was c a r r i e d  material  2 g.  fractionated  tetrachloride:chloroform: fractionated  aromatic  (92).  g e l column w i t h benzene,  solvent  data  proved the  c o m b i n e d c h l o r o f o r m l a y e r s were w a s h e d ,  material  silica  sample  by  for the  20) in  spectral t h e s e comweights  187 of  the m a t e r i a l  and  collected  probably represent  from the  m.p.  108-110°;  (purple); 1240s, (e  I.R.  1200m,  6,300),  T^base): N.M.R. (IH,  1095m,  262sh 310sh  1670s,  970m,  8,000),  (deuterioacetone)  :  H-bonded h y d r o x y l ) ,  methyl),  6.09s  form):  -2.65s,  acetic  acid):  Anal.  Found:  (ester  3.48s,  By c o m p a r a t i v e m.p.,  the  -1.94b  H 5.24,  T.L.C,  above d i e s t e r  (87)  Gibbs  815m,  715w;  positive  1260s, U.V.:  232  250sh  re-  needles;  test:  1575m,  (£ 15,600),  (£  (£  316  21,600),  13,000);  (IH, H-bonded h y d r o x y l ) ,  (IH,  aromatic),  7.60s  +3.68s,  gave c o l o r l e s s  10,000),  (e  3.62s  f  1620m,  830m,  247sh  286  5.85s,  C 55.27,  1650s,  methyl),  -1.62s,  case.  4 : 1 ) : R =-0.60;  positive;  852w,  (£ 11,400), (€  n-hexane  chloride:  (nujol):  y i e l d s i n each  (benzene: e t h e r  from benzene: ferric  step  (87):  12 m g . ; T . L . C .  crystallization  chromatographic  minimum r e a c t i o n  2,4-dicarbomethoxyorcinol Yield:  last  (methyl),  6.01s,  5.91s,  6.09s,  7.53s;  C-QH^Og  spectral  5.98s  -l-.05b  (ester  (deuteriochloro-  7.56s,  (trifluoro-  mass s p e c :  requires:  C  240  (parent);  55.00,  H  5.05.  data  and u n d e p r e s s e d mixed  was shown t o  be i d e n t i c a l w i t h one  51 of  the  products previously i s o l a t e d  dipyrone The  (69)  structural  from the  treatment  of  w i t h IN m e t h a n o l i c p o t a s s i u m h y d r o x i d e s o l u t i o n . assignment  was made on t h e  basis of  the  above  d a t a , and on t h e s i m i l a r i t y o f t h e s p e c t r a l p r o p e r t i e s ( p a r t i , , x 57,58 c u l a r l y U . V . ) w i t h t h o s e o f t h e known compound 3,5-dihydroxy-2,4-dicarboxyphenyl U.V.:  314  (£ 7 , 6 0 0 ) ,  260  acetic infl.,  acid trimethyl ester 247sh  (€  15,000),  228  (97): (£  21,700);  188 I.R.  (nujol):  1200vs, 870vw,  1730s,  1175s, 828s,  1675s,  1600m, 1580m, 1310m, 1 2 7 0 v s ,  1100m, 1135vw,  755vw;  N.M.R.  1060vw,  990vw,  980w, 950vw,  (deuteriochloroform):  -2.92s  bonded h y d r o x y l ) ,  -2.00s  ( I H , H-bonded h y d r o x y l ) ,  aromatic),  6.12s,  6.30s  5.98s,  1260vs, 905vw,  (IH, H -  3.60s (IH,  (9H, e s t e r m e t h y l s ) ,  6.12s (2H,  methylene). 2-carbomethoxy-3,5-dihydroxyphenyl propan-2-one Yield:  30mg.;  crystallization prisms;  T.L.C.  from e t h y l  m.p. 1 2 6 - 1 3 1 ° ;  Gibbs  test:  1700s,  1670vs,  1100s,  1055m, 945m,  265  11,900)j  (€  (€  6,000),  N.M.R.  positive  305  1625s,  (€  3.66d,  methylene),  6.05s  224 C  1610s,  (parent);  58.92, The  1320s,  254sh -1.51s  (ester methyl), Found:  t h e known a c i d s ,  (37): 300  61  305  1260s,  1218s,  1190s,  1160s,  730m;  260  U . V . : 303  (20,700),  25,000),  246  (£  5,520),  A(base): (€  7.83s  C 58.97,  330sh  28,000);  ( I H , H-bonded h y d r o x y l ) ,  +0.5b  J=2.4 c p s ) , 6.00s (2H, (methyl);  H 5.48,  mass  LA  spec:  requires  C i i L A •  12 o  a s s i g n m e n t was made on t h e b a s i s o f t h e  2-carboxy-3,  (G 6 , 2 0 0 ) ,  (e 4 , 0 0 0 ) ,  (dark r e d ) ; 3290s,  above d a t a and by t h e s i m i l a r i t y o f t h e U . V . of  colorless  3410s,  H 5.40. structural  re-  (nujol):  215  (t  positive  3 . 7 3 d (2H, a r o m a t i c ,  Anal.  = 0.20;  f  I.R.  835w, 797m,  (€. 1 4 , 4 0 0 ) ,  (deuterioacetone):  (hydroxyl),  chloride:  (blue-purple);  9,000),  R  a c e t a t e : n - h e x a n e gave  ferric  853m,  225sh  (benzene-ether 4:1):  (98):  270  spectra with  5-dihydroxyphenyl  (£ 12,900), 60 ( 6 12,600).  that  propan-2-one  and o r s e l l i n i c  acid  (17):  189 6,8-dihydroxy-3-methyl  isocoumarin (99):  Y i e l d 40 mg.; T.L.C.  (benzene:ether 4:1): R  f  - 0.40; r e -  c r y s t a l l i z a t i o n from e t h y l a c e t a t e gave d i s c o l o r e d prisms, m.p. 216-243° dec,; r e c r y s t a l l i z a t i o n from acetone:water gave c o l o r l e s s n e e d l e s ; m.p. 250-253°; f e r r i c c h l o r i d e : p o s i t i v e Gibbs  test: positive  (blue);  (dark r e d ) ;  I.R. ( n u j o l ) : 3250m, 1685s,  1625s, 1580m, 1240s, 1180s, 1070m, 963m, 867m, 838m, 795m; U.V.: 324  (G 6,200), 289 (5,200), 278 (7,000), 257sh (12,000), 245  (49,000), 237 (42,000), 280sh  ^ ( b a s e ) : 344 (€ 8,600), 300(11,400),  (13,000), 263sh (28,000), 253sh (32,000), 245 (37,000);  N.M.R. ( d e u t e r i o a c e t o n e ) : -1.17b (IH, H-bonded h y d r o x y l ) , +0.47b ( h y d r o x y l ) , 3.62s (3H, aromatic, o l e f i n i c ) , 7.78s (methyl); mass s p e c :  192 ( p a r e n t ) ; A n a l . Found: C 61.90, H 4.41, C  1 0  H 0 g  4  r e q u i r e s : C 62.50, H 4.20. 6,8-dihydroxy-3-methyl  isocoumarin (99) i s a known compound  and the above data a r e i n agreement w i t h that r e p o r t e d : 2 4 4 - 2 4 8 ° , 245-248° 1 4  6 1  m.p.  ; U.V.: 317 (6,300), 276(29,000), 260  (31,000), 244 (56,000), 237 ( 4 5 , 0 0 0 ) .  61  2-carbomethoxy-3-hydroxy-5-methoxyphenyl propan-2-one (100): Yield:  8 mg; T.L.C.  (benzene:ether 4:1): R  f  - 0.45; sub-  l i m a t i o n at 85° (0.01 mm. Hg) f o l l o w e d by r e c r y s t a l l i z a t i o n benzene:n-hexane gave c o l o r l e s s n e e d l e s ; m.p. 101-103°; chloride:positive I.R.  (red-brown); G i b b s  test:positive  from  ferric  (purple);  ( n u j o l ) : 3400w, 1710s, 1660s, 1620m, 1585m, 1310s, 1270m,  1230s, 1165m, 1110s, 960w, 880w, 815s, 780m, 720m; U.V.: 315  190 315 (e 2,800), 258 (€ 11,300),  A(base): 350sh (€ 1,400),  303 (e 2,800); N.M.R. ( d e u t e r i o c h l o r o f o r m ) : -1.51s (IH, H-bonded h y d r o x y l ) , 3.51s (IH, a r o m a t i c ) , 3.72s  (IH, aromatic)*, 6.06s  (methyl), 6.15s (methyl), 6.37s (2H, methylene), 7.83s (methyl); mass s p e c : 238 (parent, C ^ H ^ O g ) . 3,6-dimethoxy-8-hydroxy-3-methyl-3,4-dihydroisocoumarin  (101):  Y i e l d : 23 mg.; T.L.C. (benzene:ether 4:1): R =0.55; r e f  c r y s t a l l i z a t i o n from n-hexane gave c o l o r l e s s cubes; m.p. 99-101°; f e r r i c chloride: (purple);  p o s i t i v e (dark r e d ) ; G i b b s  test: positive  I.R. ( n u j o l ) : 1675s, 1640m, 1590w, 1510m, 1315s, 1285m,  1245w, 1220m, 1190m, 1165s, l l l O v w , 1070s, 1040s, 970vw,•950vw, 935w, 915w, 855m, 815w, 785s, 755w, 725vw, 690w, 680w; U.V.: (G 5,800), 268 (13,300), 228sh (12,800), 216 (21,400), A(base):  303  337 (8,000), 268 (10,000), 237sh (28,000); N.M.R. ( d e u t e r i o a c e tone): -1.28s (IH, H-bonded 6.17s  h y d r o x y l ) , 3.65s (2H, a r o m a t i c ) ,  (methyl), 6.68s (methyl), 6.84s (2H, methylene), 8.37s  (methyl); mass s p e c : 238 ( p a r e n t ) ; A n a l . Found: C 60.49, H 6.12, C  12 14°5 H  r e a  .  u i r e s :  c  60.50, H 5.92.  2,4-dicarbomethoxy-3, 5^-dihydroxyphenyl propan-2-one (102): Y i e l d : 20 mg; T.L.C. (benzene:ether 4:1): Rf = 0.40; r e c r y s t a l l i z a t i o n from benzene:n-hexane gave c o l o r l e s s needles; m.p. 149-151°; f e r r i c c h l o r i d e : p o s i t i v e test:positive  (dark r e d ) ; Gibbs  ( b l u e - p u r p l e ) ; I.R. ( n u j o l ) : 1710m, 1665s, 1610m,  1570m, 1330s, 1255s, 1235s, 1215s, 1165m, 1095s, 975w, 950w, 840w, 820w, 720w; U.V.: 316 (€ 3,100), 265sh (9,800), 248 (11,800),  191 231  (14,600),  N.M.R.:  ^\(base):  -2.62s  aromatic),  (5,400),  (IH), -1.78s  5.97s  methylene),  348  (methyl);  (16,300),  mass  6.11s  thoxy  (87)  group i s l o c a t e d  also  at  spec:  284  suggests  95 mg. ; T . L . C .  crystallization 196-198°; positive 1280m, 815m, 291  785w;  (8,400),  (10,100), N.M.R.  I.R.  1225s,  274sh  1150m,  (£ 7 , 7 0 0 ) ,  (12,000), 352  3.72s  Found:  H 4.51,  The s t r u c t u r a l  R  colorless  (methyl); C  1 2  H  980w,  272  carbome-  (103): =» 0 . 5 0 ;  f  io°6  945vw,  (6,200),  3.86s  .  u i r e  test:  303(8,300), (34,000),  246  s:  250  1570s,  830m,  214sh  (27,000); ( I H , H-bonded  (IH, o l e f i n i c ) ,  mass s p e c . ; r e a  865m,  250sh  (IH), -2.42s  re-  needles; m.p.  1625(sh)m,  (25,000),  -2.78s  6.00s  (parent);  C 57.60,  Anal.  H 4.03.  a s s i g n m e n t was made o n t h e b a s i s o f t h e above  and by t h e c o n v e r s i o n o f (102).  4:1):  (39,000),  (IH, aromatic),  7.75s  propanone  the second  1650s,  325sh  257  (8,700),  (ester methyl),  data  and 2 , 4 - d i -  isocoumarin  1685s,  1080s,  (deuteriochloroform):  C 57.73,  that  (benzene: e t h e r  (nujol):  U . V . : 340  A(base):  hydroxyls),  (102)  Cj^HjgO ) .  c h l o r i d e : p o s i t i v e (dark r e d ) ; G i b b s  (blue);  1245m,  (parent,  of  f r o m e t h y l a c e t a t e gave  ferric  3.64s (IH,  the 4 - p o s i t i o n .  7-carbomethoxy-6,8-dlhydroxy-3-methyl Yield:  (17,200);  (5H, e s t e r m e t h y l ,  The s i m i l a r i t y o f t h e U . V . s p e c t r a carbomethoxyorcinol  249  ( I H , H-bonded h y d r o x y l s ) ,  (ester methyl),  7.84  272  (103)  to the corresponding phenyl  T h e r i n g o p e n i n g was c a r r i e d o u t ( s e e below)  by a method u s e d by H a s s a l l 6,8-dihydroxy-3-methyl  61  to e f f e c t  isocoumarin  (99)  a s i m i l a r conversion of r  to  2-carboxy-3,5-dihydro-  192 xyphenyl propan-2-one the  isocoumarin r i n g  the  ester  groups o f  carbomethoxy of  (37).  system but also (102)  group of  and (103)  (103)  the isocoumarin r i n g  The c o n v e r s i o n o f  The c o n v e r s i o n n o t o n l y  (103)  (see  vacuo. 246,  cooled  i n 2 m l . aqueous  ( 1 3 0 ° o i l bath)  f o r 20 m i n . The  d r i e d and t h e s o l v e n t  (TVniax:  was v e r y s i m i l a r t o t h a t o f compound  (ice-bath)  0.02 M  a c i d i f i e d and e x t r a c t e d w i t h 20 m l . e t h e r ;  l a y e r washed,  Three-quarters  at p o s i t i o n 7  above).  The U . V . spectrum o f t h e r e s i d u e  232)  Thus the  (102):  s o d i u m h y d r o x i d e was r e f l u x e d  and t h e e t h e r  t h e l o c a t i o n o f - •-.  a r e t h e same.  A s o l u t i o n o f 5 mg. compound (103)  s o l u t i o n was c o o l e d ,  that  i s probably located  system to  proves  establishes  o f t h e r e s i d u e was t a k e n  removed i n 323,  265 i n f 1. ,  (102).  up i n 2 m l . e t h e r ,  and t r e a t e d w i t h d i a z o m e t h a n e  at 0 ° .  The  e x c e s s r e a g e n t was i m m e d i a t e l y d e s t r o y e d w i t h d i l u t e h y d r o c h l o r i c acid  and t h e e t h e r  moved i n v a c u o .  l a y e r was w a s h e d ,  C r y s t a l l i z a t i o n from benzene:n-hexane  needles,  m.p. 1 4 5 - 1 5 0 ° .  compound  (102)  able  3.  I.R.  The r e a c t i o n  by T . L . C . ,  re-  gave  p r o d u c t was shown t o be  u n d e p r e s s e d mixed m . p . and s u p e r i m p o s -  spectra.  IM M g ( 0 C H ) / M e 0 H : 3  9  A magnesium m e t h o x i d e g.  d r i e d and t h e s o l v e n t  o f magnesium powder  methanol^  1  s o l u t i o n was p r e p a r e d  (B.D..-H.  reagent)  and r e f l u x i n g t h e m i x t u r e  by a d d i n g  6.0  t o 225 m l . a n h y d r o u s  for 1 hr.  The s o l u t i o n was  193 cooled 25  to  room t e m p e r a t u r e  m l . methanol  added.  ature under n i t r o g e n centrated cooled ca.  i n vacuo;  i n an i c e  and a s l u r r y o f  g.  The s o l u t i o n was s t i r r e d  f o r 2 days, 100  bath  1.0  and t h e n  m l . w a t e r was  the  added,  tripyrone at  room  solvent the  in  temper-  was  con-  s o l u t i o n was  and t h e n a c i d i f i e d by d r o p w i s e a d d i t i o n o f  40 m l . h y d r o c h l o r i c a c i d .  The aqueous  s o l u t i o n was  extract-  ed w i t h c h l o r o f o r m . The above r e a c t i o n layers ing  were  freeze-dried  acetone to  compounds were 4:1  solvent  was r e p e a t e d ;  yield  compounds were  c_a.  isolated  system.  and t h e 0.2  g.  and t h e  residue of  combined  extracted with  crude m a t e r i a l .  by p r e p a r a t i v e  T.L.C.  be m e t h y l o r s e l l i n a t e  and 2 , 4 - d i c a r b o m e t h o x y o r c i n o l  (87,  yield  aromatic  benzene:ether samples  (86,  8 mg.),  reflux-  Two  with  By c o m p a r i s o n w i t h a u t h e n t i c  shown t o  aqueous  yield  these 7  mg.)  both of which  51 had been p r e v i o u s l y o b t a i n e d Both of  t h e s e compounds were  extract  (see  20 (87)  mg.  below)  and t h e  by b a s e t r e a t m e n t o f also total  and 9 mg. r e s p e c t i v e l y .  was  also  treatment of  isolated tripyrone  from the  yields for  Since  from the its  isolated  (86)  dipyrone  (69).  chloroform  and (87)  were  2,4-dicarbomethoxyorcinol  methanolic  characteristic  potassium hydroxide properties  are  given  above. Recrystallization gave c o l o r l e s s R =0.60; f  Gibbs  prisms;  of  methyl o r s e l l i n a t e  m.p.  141-143°;  test:positive  1645s,  1620m,  1585m,  1495w,  1160s,  lllOw,  1060w,  955w,  T.L.C.  (purple);  1320s, 855w,  I.R.  1305s,  840w,  (86)  (benzene:ether (nujol):  1260s,  803m;  f r o m benzene  3340m,  1200m,  U . V . : 300  4:1):  1170s, (£  4,400),  194 264  (13,000),  217  (18,000),  A(base):  306  (21,000),  N.M.R. ( d e u t e r i o c h l o r o f o r m ) :  -1.71s  0.28bd  (2H, a r o m a t i c ) ,  7.53  (IH, hydroxyl),  (methyl),  7.54s;  deuterioacetone:  mass s p e c :  The solvent  3.75s  182  ( I H , H-bonded h y d r o x y l ) ,  -1.58s,  combined c h l o r o f o r m l a y e r s removed in v a c u o  systems:  form: a c e t i c  6.10s  +1.03s,  (ester  3.73s,  were w a s h e d ,  to give c a .  10:9:1.  1.2  4:1,  carbon  T.L.C.  u s i n g the  tetrachloride:chloro-  In a d d i t i o n to the f r a c t i o n a t e d  t h e r e was 50 mg. o f r e l a t i v e l y  insoluble material.  and  N.M.R. e v i d e n c e  m a t e r i a l was a 1:3  tripyrone  unidentified T.L.C; its  indicated  however  i t s s o l u b i l i t y and T . L . C .  suggest  that  3.26s  it  ( I H ) , 5.91s  From t h e f r a c t i o n a t i o n of  compounds were  cient  indicated,  p u r i t y and q u a n t i t y  As m e n t i o n e d a b o v e ,  layer most given  as w e l l . cases,  procedure of these  p u r i f i c a t i o n by  (3H), 7.29s  (3H),  perhaps  a large  number  8 were  isolated  t o be c h a r a c t e r i z e d  (87)  and 7.43s  the methyl  probable structures,  isolated  the s p e c t r a l  20)  in suffidata.  (86) and  f r o m t h e aqueous properties,  are given below.  of the m a t e r i a l  (ca.  by s p e c t r a l  methyl o r s e l l i n a t e  were  For the o t h e r s ,  are the weights  mixture  (82).  two o f t h e s e ,  2,4-dicarbomethoxyorcinol  T.L.C.  characteristics,  i s a new p y r o n e p r o d u c t ,  e t h e r of the a c e t y l d i p y r o n e  mater-  U n f o r t u n a t e l y the  decomposed upon a t t e m p t e d  N.M.R. s p e c t r u m :  (3H)  this  and an u n i d e n t i f i e d p r o d u c t . product  6.11s,  material.  ial  of  methyl),  d r i e d and t h e  g. crude  o u t by p r e p a r a t i v e  benzene:ether  acid  (8,200);  (parent).  F r a c t i o n a t i o n was c a r r i e d solvent  240  collected  and i n  The y i e l d s  from the  last  195 chromatographic ion  step,  and t h u s p r o b a b l y r e p r e s e n t  yields.  2-acetyl-4-carbomethoxyorcinol Yield:  12 m g . ; T . L . C .  crystallization ferric I.R.  (9,900),  from n-hexane  (methyl),  (C 3 , 9 0 0 ) ,  300  -1.35s  hydroxyl),  7.77s;  (benzene:ether  3420m ( s h a r p ) ,  U . V . : 325  form):  (106):  gave c o l o r l e s s  (8,600),  1675s,  265sh 266  1645m,  (8,100),  (11,100);  ( I H , H-bonded h y d r o x y l ) ,  3.68s 7.70s  (IH, aromatic), (methyl),  mass s p e c :  224  Yield:  benzene:n-hexane chloride: (nujol):  317  1640s,  815s,  690s;  (22,200),  277  1320s,  U . V . : 270sh (26,600);  H-bonded h y d r o x y l s ) ,  (6H,  2 ester methyls), Found:  R  C 50.49,  (purple);  1570m,  1165s,  1245m,  A(base):  (deuteriochloro( I H , H-bonded  (ester methyl), 3.66s,  7.47s  5.90s,  7.54s,  (  20,100),  1 2  tetrachloride:  r e c r y s t a l l i z a t i o n from  mp. 1 7 2 - 1 7 3 ° ;  980m,  970m, 256  ferric  (brown);  (41,700),  'A(base): -5.38bd  ( I H , H-bonded h y d r o x y l ) ,  H 0  I.R.  955m, 910m,  (deuteriochloroform):  (methyl); C  (carbon  test:negative  1240s,  -4.08bd  H 4.59,  = 0,  f  needles;  N.M.R.  7.29s  R  (107):  = 0.60;  f  dark r e d ; Gibbs  (2H,  Anal.  (ether):  gave c o l o r l e s s  1570s,  re-  (parent).  acid 10:9:1):  positive,  = 0.55;  249 ( 1 4 , 2 0 0 ) ,  deuterioacetone:  104 m g . ; T . L . C .  chloroform:acetic  f  test:positive  -0.10s  5.95s  R  prisms; m.p. 9 6 - 9 8 ° ;  N.M.R.  3,5-dicarbomethoxyacetylphloroglucinol  870m,  4:1):  c h l o r i d e : p o s i t i v e , dark r e d ; G i b b s  (nujol):  802m; 353  minimum r e a c t -  mass s p e c :  284  requires C 50.71,  6.02s  (parent); H 4.26.  196 4-carbomethoxymethyl Yield:  14 m g . ; T . L . C .  crystallization m.p.  110-112°;  positive  ferric  1645s,  327  5,650),  "X(base) :  353  1565m,  I.R.  (14,100),  1255s,  305  6.29s  (methyl);  (2H,  mass s p e c .  1170vs,  263  6.31s  (benzene:ether  crystallization  from benzene:  m.p.  ferric  negative 1330s, 257  (brown);  1180m,  (26,000),  I.R.  1130w, 225  n-hexane  chloride: (nujol):  970w,  860w,  (17,200),  3200w,  ^A(base):  -2.42s  ( I H , H-bonded h y d r o x y l ) , 3 . 6 8 s  250  +0.34s (ester 7.44s  -3.71s  methyl),  (109): R  -  f  0.45);  gave c o l o r l e s s dark r e d ;  1675s,  324  needles; Gibbs  1620m,  test:  1585m,  (€  (10,500),  re-  8,000),  279  (16,200);  (IH, H-bonded h y d r o x y l ) ,  7.60s  (IH,  aromatic),  (methyl);  mass  3.88  (IH,  spec.:  (parent). The  are  (ester  5.90s  805w; U . V . : 2 8 0 s h  (deuteriochloroform):  6.01s  4:1):  positive,  N.M.R.  aromatic),  N.M.R.  (parent).  8 mg.; T . L . C .  178° dec.;  (16,000),  methyl),  2-methyl-5,7-dihydroxy-8-carbomethoxychromone Yield:  1725vs,  (14,600);  (ester  test:  820m; U . V . :  236sh  aromatic),  re-  needles;  p u r p l e ; Gibbs  (19,200),  (IH,  methylene) 282  0.45;  ( I H , H-bonded h y d r o x y l ) ,  H-bonded h y d r o x y l ) , 3.61s  methyl),  -  f  gave c o l o r l e s s  1220s,  250  R  3400w ( s h a r p ) ,  (11,700),  -0.66s  4:1):  positive,  (nujol):  (11,400),  (deuteriochloroform): (IH,  n-hexane  chloride:  1330s,  265sh  (108):  (benzene:ether  from benzene:  (blue-purple);  1680s, (£  curvulinate  characteristic  given below.  properties  Both of  of  compounds (110)  and  t h e s e compounds were d i f f i c u l t  (111) to  197 purify  and a p p e a r  t o be u n s t a b l e ;  some i n c o n s i s t e n c i e s structural Compound  i n the reported p r o p e r t i e s ,  assignments  chloroform:  negative;  12 m g . ; T . L . C . acetic  Gibbs  1330w,  (ether):  acid 10:9:1):  6.25s  and a l s o no  1290m,  1240m,  (G 8 , 7 0 0 ) ,  Compound  f  R =0.30; f  I.R.  1155w,  (carbon  tetrachloride:  s u b l i m a t i o n at 6 0 °  (nujol): 995m,  228 ( 6 , 7 0 0 ) ,  (deuteriochloroform): (3H) , 7 . 7 1 s  R =0,  prisms; m.p. 9 2 - 9 3 ° ;  test:negative;  U . V . : 311  N.M.R.  -5.76s  (3H) ; mass s p e c :  1725s,  985w,  70 mg; T . L . C .  (ether):  c h l o r o f o r m : a c e t i c ) : . R^=0.55;  154-155°,  1310s,  1620m,  778w, 710w,  "X(base): 283  (9,500);  ( I H ) , 5.97s (2H),  (parent).  R =-0, ( c a r b o n f  tetrachloride:  r e c r y s t a l l i z a t i o n from e i t h e r d i -  m e t h y l s u l f o x i d e o r d i m e t h y l f o r m a m i d e gave c o l o r l e s s 161-162°  form);  negative  chloride:  1640s,  940w,  ( I H ) , +4.01s 250  ferric  (111):  Yield:  needles  may be  h a v e been made.  ( 0 . 0 1 mm. Hg) gave c o l o r l e s s  700w;  there  (110);  Yield:  1570m,  f o r these reasons  ferric  (brown);  (£ 7 , 0 0 0 ) ,  272  (23,400),  (nujol):  1105m,  270sh 258  154° crystal  1730s,  1090m,  (16,500),  (22,800);  N.M.R.  5.87s  (8 o r 9 H ) , 7 . 6 0 s  (IH),  ( d i m e t h y l f ormamide) : 2 . 8 2 b d 308  (perhaps  982m,  260  (IH),  (very weak),  structure  b r e a k s down and  c h l o r i d e : p o s i t i v e , dark r e d ; Gibbs  I.R.  1240-1225s,  307  (at  prisms; m.p.  1680s, 952m,  (26,200),  parent).  1640-1610s, 850m,  (IH) ,  350  acid):  -2.80bd  (6.07);  1550m,  820m; U . V . :  A(base):  (trifluoroacetic  (3H), (dioxan):  test:  (7,000), 2.65s  (IH), 3.15s  mass s p e c :  340  198 BIBLIOGRAPHY 1.  J.H. R i c h a r d s and J.B. Hendrickson, "The B i o s y n t h e s i s o f S t e r o i d s , Terpenes and Acetogenins", Benjamin, N.Y., 1964.  2.  K. B l o c h , S. Chaykin, A.H. P h i l l i p s and A. deWaard, J . B i o l . Chem. 234, 2595 (1959).  3.  F. 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