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Studies toward a total synthesis of digitoxigenin from thujone Somerville, John Wallace 1987

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STUDIES  TOWARD  A  TOTAL  OF DIGITOXIGENIN  SYNTHESIS  F R O M  by JOHN B.Sc,  The  A THESIS THE  WALLACE  University  SUBMITTED  SOMERVILLE  of  New  IN  1984  PARTIAL FULFILMENT  REQUIREMENTS MASTER  Brunswick.  FOR THE  DECREE  OF  O F SCIENCE  in THE  FACULTY  OF  G R A D U A T E STUDIES  (Department  We  accept to  THE  this  the  of  Chemistry)  thesis  required  UNIVERSITY  OF  August  © John Wallace  as  conforming  standard  BRITISH  COLUMBIA  1987  Somerville,  1987  OF  THUJONE  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at The University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.  (Department  of  Chemistry)  The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5  Date:  August  1987  ABSTRACT This thesis concerns studies digitoxigenin  3c  from  synthesized from synthesis  would  thujone  followed  in the  digitoxigenin  of  the  the  a mixture  respectively. C3-ketone  43  Wittig  reaction  C17-methylene the  of  Swern  89  the  methodology  or,  of  the  cross-conjugated A ketone  93  model in  was  required  to  converted  93  an ester to  the  86b.  available  C4,5-double  bond,  and  protection  resulted  in the  bromide selenium  of  Cl7-ketone  produced dioxide  to  achieved via  pyridinium resulted  89.  produce  ketone  was  the  the  ketone  93  to  88b,  a,/3-unsaturated  DDQ  the  thereof)  chromatography  with  of  known  commercially  the  by treatment with of  aldehyde  and  the  the  ketal.  the  oxidized with of  of  88a  a,^-unsaturated  alternatively,  completion  produce the  of  been  5  diastereomers  ketal derivative  which  previously  after deoxygenation  C3-ethylene  C5/3-H  small amounts  93. the  dichlorochromate. in  the  85.  study was  order  the  liquid  trimethylsilylenolether dienone  could be  methyltriphenylphosphonium  91  and  would  hydrogenation  and  ethylene  with  derivative  92  C5a-H  the  which,  synthesized from  by preparative  to  Oxidation  of  was  had  and glyoxylic acid (or  which  by catalytic  as the  allylic alcohol 92  Oxidation  6  85  of the  88b  87  86b  nitrile,  by hydrolysis of  analog  Separation of  aldehyde  85  envisaged for  by reduction  butenolide  steroid  strategy  a total synthesis of  analog  produce 86a  androst-4-ene-3,17-dione produce  of  steroidal  to  synthon  The  The  towards  85  condensation of result  1.  and the  involved alkylation  Cl6-ketone Aldol  thujone  directed  conducted at  develop  the  butenolide  ring. Thus akylation  of  which was  subsequently protected  93  this  time  utilizing  necessary chemistry produced the  as the  for  nitrile  the  elaboration 94,  the  corresponding ethylene  ii  a,/3-unsaturated of  the  C16-ketone ketal  of  derivative  to  provide both  94  the  required C17/3-nitrile  and 95a  confirmed that  17/3-configuration.  Reduction of  the  which was  to  aldehyde 95b produce the The  the  cross-conjugated diene of  isomers  proved  are  butenolide  approach to  mixture  95a.  Cl7-epimers to  consistent with  be the  98 the 85  (ratio  the  Overhauser difference  compounds had  the  and the  with mentholglyoxylate, trans  ester  2:1,  diethylaluminum on  and  the  basis of  iii  followed  resulted in  by  reduction  99. pursued by  cyanide to NMR).  NOE-difference  isomer having the  on  required  synthesis of digitoxigenin was with  experiments  nitrile with diisobutylaluminum hydride  alkylated  impractical major  both  Nuclear  alkylation  produce 86a  Separation  experiments  on  C17^-configuration.  of this  as a  these mixture  of  TABLE  Title  O F  C O N T E N T S  page  Abstract  .  Table  Contents  of  iv  List of  Figures  vi  List of  Schemes  vii  Acknowledgements  viii  Abbreviations 1.  ix  Introduction  1  1.1. 1.2. 1.3. 1.4.  1 3 6 10  the  digitoxigenin  2.  Scope  3.  Results and discussion 3.1. The C o m m o n Intermediate 3.1.1. 5/3-Androstane-3,17-dione 88b 3.1.2. Formation of the C3-ketal 89 3.1.3. a,/3-Unsaturated ketone 93 3.1.4. Cross-conjugated dienone 85 3.1.5. M o d e l studies of the aldol condensation of the C21-aldehyde 95b 3.2. Digitoxigenin formal synthesis 3.2.1. Hydrocyanation reaction  33 33 33 35 37 39  Experimental 4.1. General 4.2. 5|3-Androstane-3,17-dione 88b 4.3. 50-Androstane-3,17-dione-3,3-ethyleneketal 89 4.3.1. M e t h o d A 4.3.2. Method B 4.3.3. M e t h o d C 4.4. 17-Methylene-5/3-androstane-3-one-3,3-ethyleneketal 91 4.5. 16a-Hydroxy-17-methylene-50-androstane-3-one-3,3-ethyleneketal 4.6. 17-Methylene-5j3-androstane-3,16-dione-3,3-ethyleneketal 93 4.6.1. M e t h o d A 4.6.2. M e t h o d B 4.7. ^ ^ - C y a n o m e t h y l - S / S - a n d r o s t a n e - S ^ - d i o n e - S ^ - e t h y l e n e k e t a l 94 4.8. 170-Cyanomethyl-50-androstane-3,16-dione  55 55 56 57 57 58 58 60 60 62 62 62 63  4.  of  Thujone Cardiac active glycosides Problems associated with the synthesis of Review of the synthesis of digitoxigenin present work  28  -3,3,16,16-bis(ethyleneketal) 95a iv  40 50 50  92  64  4.9. 4.10. 4.11. 4.12. 5.  20-Oxo-5/3-pregnane-3,16-dione-3,3,16,16-bis(ethyleneketal) 95b 5/3-Card-20(22)-enolide-3,16-dione-3,3,16,16-bis(ethyleneketal) 98 17-Methylene-5|3-androst-14-ene-3,16-dione-3,3-ethyleneketal 85 17-CyanomethyI-5|3-androst-14-ene-3,16-dione-3,3-ethyleneketal 86a  References  65 66 67 68 70  v  List Figure  1: The  Figure  2:  Some  examples  of  Figure  3:  Some  common  steroidal  Figure 4:  chemistry  Intermediates  Figure  6:  2D-COSY-HETCOR  Figure  7:  NOE-difference  Figure  8:  1  Figure  9 : NOE-difference  Figure  10: The  synthesis of  Figure  11: The  aldol  Figure  12:  1  Figure  13:  NOE-difference  H-NMR  NMR  2  cardenolides  to  85  5: The  C-NMR  Figures  thujone  Figure  3  proton  of  of  precursors  spectrum  32  ( H, 1  1  3  C)  of  of  the  36  88b experiments  on  94  42 43  94 on  45  95a  cardenolide  condensation of  35  88b  of  decoupling  experiments  spectrum  7  87  spectrum  and  4  reaction  of  95b  49 51  86a  experiments  47  98  on  86a  vi  53  List of Scheme  1: The  Ruzicka  approach  Scheme  2: The  Engal and  Scheme  3: The  first synthesis of  Scheme  4: The  Pettit  Scheme  5: Synthesis  Scheme  6: Digitoxigenin  Scheme  7: The  Kreiser  Scheme  8: The  synthesis  Scheme  9: The  Wiesner  Scheme  10: The  Scheme  digitoxigenin  Bach approach  approach of  to  Schemes  the  digitoxigenin  cardenolide  of  3c  of  3c  9 11  3c  12  29  14  15a-hydroxycortexone  synthesis  8  digitoxigenin  digitoxigenin to  from  to  3c  39  30a  15 17  44  18  synthesis  of  digitoxigenin  3c  19  Wicha  approach  to  digitoxigenin  3c  22  11: The  Wicha  synthesis  of  43  Scheme  12: The  Harnisch  Scheme  13:  Scheme  14: The  Scheme Scheme  Intermediates  synthesis 75  and  synthesis  of  80  15: The  synthesis  on  16: The  synthesis of  of  of 76  25 43  from  26 thujone  29 30  2  31  93  38  vii  ACKNOWLEDGEMENTS I wish opportunity progress  to  to  of  pursue this  this  invaluable The  the  staff  of  their Last,  members  the  NMR must  infra-red but  (both  also go  definitely  past  Dr.  McHugh  criticism of  for  to  and  Mr  their  to  Dr.  this  in the  and  least, of  friendship. Malcolm  Dr.  to  mechanical  also particularly  advice and  this thesis.  viii  to  their  like  and  to  his research group  liquid  Finally I wish  for  thank  patience. for  the  chromatograph.  express my  for  the  project.  appreciation  Kutney's research group  Roberts  during  the  mass spectroscopy, and  glass blowing,  preparative  I wish  for  Krystyna Piotrowska  research  NMR,  I would  kind  advice, both  Professor Ed Piers and  and present) and  staff  Kutney  this thesis.  gratitude  appreciated.  not  of  throughout  the  spectrometers  discussions  and  much  his valuable  as well as the  laboratory  enlightening Michael  express my  of  Professor James P.  preparation  encouragement  is very  to  and for the  service laboratories  Thanks use  and  to  in  technical expertise  shops  of  project  also like  help  microanalytical electronics  appreciation  research and  I would her  express my  thank  Dr.  meticulous  to  for their Cam proof  the advice,  Boulet, reading  ABBREVIATIONS The  following  is a list  of abbreviations  that have  been  used  throughout  this thesis:  Ac  acetate  atm  atmosphere  bs  broad  bz  benzyl  d  doublet  dd  doublet  of  dt  doublet  of triplets  DDQ  2,3-dichloro-5,6-dicyanoquinone  CLC  gas liquid  h  hour  singlet  doublets  chromatography  high performance HPLC  liquid  chromatography infra red  IR  maxima  max.  minute  min.  multiplet  m  nuclear magnetic  NMR  nuclear Overhauser  NOE  phenyl  Ph q  quartet saturated  aqueous  sat. aq. singlet s tetrahydrofuran  THF ix  resonance effect  t  _  triplet  p-TSA  =  para-toluene sulphonic  UV  =  ultraviolet  v/v  =  ratio  x  by volume  acid  1. INTRODUCTION  1.1.  THUJONE  The  decline of  stimulated waste  of  termed  the  the any  search for  dry  red  cedar  industry more  which  often  is the  must  be  uses of leftover  in particular  the  available  bark,  removed  is steam  distilled, a leaf  on where  the  trees  steam distillation  can be  thus  serving the  purpose of  inexpensive  dual  source of  would  be  the  grown  done  thujone.  before  "on  and  any  site"  on the  leaves,  re-forestation  If  the  largest  generally  can  slash from  important  chemical synthesis of  amount  immediately  removing the  An  resources. The  begin  Western  oil that contains as much as 8 8 % thujone  are  This  British Columbia, has  branches and  slash can also pose a considerable fire hazard.  depending  thujone  in Canada, and  efficient  logging operation  "slash",  and  forest  left-over  use for  of  after  1,  rain, is o b t a i n e d . 1  a logging operation,  "slash",  and  providing an  a chiral monoterpenoid  biologically important  optically  like  active  molecules. A been  done  thujone and  great  of  a viable  biologically important 3  thujone, the  stereospecific, important  over  chiral  the  utilizing past few  synthon for  molecules such  sesquiterpenes", and  From  molecule,  synthetic work  in our laboratory  can be  insectides ,  from  deal  inspection of  steroidal  Figure  1,  thujone  years. This work  synthesizing a variety  as: juvenile  hormone  compounds  one  can notice  rather  unusual 5/3-configuration.  reaction  where  this  class of  producing only natural  chiral center one  was  diastereomer  products, most  of which  1  5  (see that  has the  thus  as a chiral synthon has  In  have the  natural 2  Figure  the  in very  of  analogs ,  the  created  has shown that products  pyrethroid  1).  steroid 2, synthesized synthesis of  was  this  completely  g o o d yield. An 5/3-configuration,  are  Introduction /  Figure 1  2  Introduction the  cardiac  modem  active  g l y c o s i d e s . Typical  medicine  purpurea  and  examples  6  are  digoxin  digitoxin  3a  isolated from  from  D.  lanata  3b  (see  of  7  cardiac active  the  Purple  Figure  / 3  glycosides used in  Foxglove  Digitalis  2).  1.2. CARDIAC ACTIVE GLYCOSIDES Various  plant  Squilla,  an  4a,  was  extracts  extract  used  various  classic  Dropsy  and  cardiac  glycosides (in  heart  the  book  of  other  of  the  motion  did  not  of  heart  any  foxglove  the  secondary It beneficial failure.  effect  due  was  only  effects  of  All of  decreased  on  the  heart  to  to  in the  of  of for  these  size, venous  effects  of  these  on  Practical  therapeutic  of  but the  effects.  heart ("It  in  any  "An  Withering  abnormal  because  has  other  until  a few  Ferriar) realized  that  the  main  effect  of  dropsy)  efficient  to  pressure, and  pumping it  reduce  these  relief  became the  drugs blood  by the  years of  was  of  accepted  a  that  congestive  such as: increased cardiac volume;  he  heart.  generally  symptoms  over  medicine")  not  thus  of  power  was  (and  on  uses of  Although  always,  7  Remarks  dropsy (the  not  for  poison .  It  years that  of  types  as a rat entitled  7  Foxglove).  unobserved  diuresis  drugs were  beneficial  effects  yet  between  60  certain  even  With  the  Purple  tissues, usually, the  that  the  centuries.  Romans used it  Withering  description  a degree  last  by William  the  and  first  of  return  emetic  used for  glycoside Proscillaridin A  Egyptians, and  Uses:  physician (John  the  the  its Medical  body  heart and  been  of  only  aware  connection  another  1785  some  in the  contains  heart tonic,  in  effective  also was  later (1799) that was  ancient  case, extracts  was  the  glycosides have which  the  published  this  fluids  and  make  by  Diseases" is the  body  failure)  martima,  Foxglove and  that foxglove  retention  cardiac  such as: a diuretic,  Account  noted  Urginea  as a medicine  purposes A  of  containing  diuresis and  relief  the  heart output; of  33.  digitoxin  [R, =tridigitoxose  3b  digoxin  3C  digitoxigenin  [R, = tridigitoxose [R,=OH  R  R2 H] =  4a  proscillaridin A  R '=OH]  2  A""*]  fR = rhamnose,  2  =OH]  4  4b  scillaren [R, = O H ,  4C  bufalin  A"] 4  [R, = O H ,  5  C5/3-H)  Figure 2 edema the  can be  heart  explained  muscle (positive  The  units. There  are  a very  only in the  linkage  all the  The 2),  two  major  17/3-lactone  large  known  number  (aglycone)  of  portion  consisting of  naturally  from  of  one  contraction  of  8  C/D  cis ring junctions as well to  the  four  hexose  a butenolide  the glycoside  "backbone" as 3/3-  steroid at  steroids, depending on the  cardenolides have  to  via  few aglycones.  a c o m m o n steroidal  ring attached  attached  occuring cardiac active glycosides  p o r t i o n . Thus hydrolysis of  steroids all have  cardiac active  the  a steroidal  cardiac glycosides produces relatively  groups and a lactone  moiety:  force  a carbohydrate  having A/B and  classes of  an increase in the  effect).  carbohydrate  cardiac active  most  14/3-hydroxy  inotropic  at C3 to  that differ of  basis of  cardiac glycosides consist of  a glycoside linkage  Figure  on the  (see  and  C17. There  nature  ring and the  of  are  the  bufadienolides  Introduction (such  as scillaren 4b,  bufadienolides are  much  have  more  Most  of  glycosides  having  therapeutic digoxin  It  induced is very level  chemists  for  above  7  and  The  a-pyrone but,  ring .  The  6  in general,  cardenolides  the  and  bufadienolides  digitoxin  moiety  is necessary. Comparison of  moiety,  such  is in the  range  of  14-26  this  used cardioactive  drug  The  9  glycosides (in  this  the  physical condition  function)  and  so the  low  margin  is this  activity  for  the  digoxin  desired  ng/ml whereas  of  that  for  9  absolutely  have  a valuable  drug with an  develop  shown  highest  0.6).  patient  carefully  improved  therapeutic  of  drug dose)  the  administered  3b.  plasma with on  an  medicinal  safer analogs.  as digitoxigenin to  Also  has stimulated  that the  contribution  rates  (especially  17/3-butenolide  necessary for biological activity.  a c o m p o u n d such be  be  is digoxin  ratio (therapeutic/toxic  the  safety that to  of the  case only  of  dose must  attempt  studies  one  therapeutic  on  would  aforementioned  glycoside in medicine  is responsible for  admission and d e a t h .  studies o n  cardiac  7  commonly  It  as the  two  the  ng/ml .  groups are  type  cardiac glycosides is associated with  plasma concentrations required  pharmacologists to  features  an heart  of  same carbohydrate  dependent  basis .  cardenolide  carbohydrate  all cardiac active  Structure  synthetic  biological activity  0.8-1.6  kidney  14/3-hydroxy  the  said that  is very  individual  on  for  hospital  to  effects  the  most  low  respect  similar  is interesting.  is only  has been  have  the  effect  The  4c)  the  although  digitoxin  bufalin  toxic.  aglycone,  and  and  / 5  the  3c,  which  3/3-  and  Therefore, incorporates  development  ratio.  ring,  of  a  the  Introduction  / 6  1.3. PROBLEMS ASSOCIATED WITH THE SYNTHESIS OF DIGITOXIGENIN All of such  the  approaches to  as: progesterone  because  these  possible  synthetic  which  must  are  be  cardenolides so far  5, androstenedione  readily routes  available to  overcome  introduction  in such  The  2.  Introducing  the  thermodynamically  3.  Introducing  the  14/3-hydroxy  4.  In  the  been  3j3-hydroxy  and  7 (see  one  from  unfavourable and  the  precursors Figure  3),  can envisage  necessary functionality.  group  group  steroidal  testosterone  expensive)  the  from  a partial synthesis are  1.  cis ring  of  6, and  (although  incorporate  have  The  problems  as follows:  a 3-keto  steroid.  A/B cis ring  junction.  thermodynamically  unfavourable  C/D  junction.  C/D  cis steroids, it  thermodynamically Most  of  the  is generally  favoured steroidal  true that  in .the  a side chain  at  position  C17  is  a-configuration.  precursors (such  as the  examples  given  above)  have  4 the of  A -3-keto the  C4,5  experimental complete these  functionality double  bond  stereoselectivity  is very  a mixture  problems generally really  syntheses proceed via a catalytic  producing a mixture  isomers. Similarly, with  not  most  conditions can often  3/3-configuration,  was  and  be  modified  rare,  thus,  reduction  of  3a-  caused low  of  and  if  to  5a-  it will  the  these  the  and  favour  the  desired  to  The  5/3-isomer  necessary to  the  but  separate  desired  compounds often 4  starting  reactions  50-isomers.  usually be  3-ketone  3/3-hydroxy  yields from  a serious problem  of  hydrogenation  _ -3-keto  were done  at  resulted. These  steroid,  but  an early  this  stage  of  the synthesis. The  problems of  17/J-butenolide 3c.  The  most  ring  foiled  common  introducing the many  strategy  of  the  is to  14 ^-hydroxy  earlier  attempts  introduce  a 17j3  group, to  and  the  synthesize  side chain (for  digitoxigenin elaboration  of  Introduction  CH  / 7  3  Figure 3 the  butenolide  ring)  thermodynamically group  in the  reported Scheme  1).  later  yield about  20%  undesired  junction steroid  1 1  of  the  the with  is kinetically  (see  few  the  first  attempts  8  11.  hydrogen from  Scheme 2).  a different  Starting  from  above the  in ethanol  this case,  the  favoured, thus producing the  years later,  the  17/3-methyIester In  14/3-hydroxy  synthesize a cardenolide  peracid gave  platinum  14/3-hydroxy,  17a-methylester  to  illustrate  with  hydrogen over  of  17/3-configuration is  c o m p o u n d s , and introduce the  14,16-diene  desired  14/3-hydroxy,  of  precursor because the  and this serves to  6  becomes cis, attack  A Bach  al.  treated of  in these  stages. O n e  Oxidation then  a 14<z-steroid  favoured  by Ruzicka e(  which was  the  on  (see  14,15/3-epoxide  or acetic acid and  10 once  less hindered  points  the  about C/D  ring  /3-face of  the  reported  14-dehydrodigitoxigenin  by 12,  Engel and attack  of  the  9,  to  70%  17a-stereochemistry.  approach was  was  of  Introduction  11  / 8  10 Scheme 1  C14,15  double  intermediate conditions) treatment chloride  b o n d with  140-hydroxy-15a-bromide cyclized to  with  dry  was then  the  group  of  it  14,15/3-epoxide  reduced with  have  into cardenolides.  14.  give  the  in  situ,  gave  the  spontaneously (under This epoxide  the  yields were standard way  was  not to  to  desired  these  then  reaction  opened  14|3-hydroxy-15a-chloride  tri-(n-butyl)tin hydride  Although the become  generated  which  13,  hydrochloric acid to  3/3-acetoxydigitoxigenin. or variations  hypobromous acid,  15.  by The  yield  high, either introduce  this  the  methodology  14/3-hydroxy  Introduction  Scheme 2  /  9  Introduction  1.4.  REVIEW OF THE SYNTHESIS OF DIGITOXIGENIN  The  first  from in  synthesis of  methyl  12  to  45%.  hydroxy  can see, this starting  already  14/3-hydroxy  solved,  20a  19  a Meyer-Shuster " in a total yield  to  yield  dioxide the  16  An  of  45%  approach to  Scheme 4).  the  (see  presence of  Treatment  of  this  based on  2N  and  18%  hydrolyzed,  be  which  starting  2  was  synthesized  the  in a total yield of  built  the  above  up without  from  16  mentioned  the  ring. of  loss  of  the  the  boron trifluoride  using 0.6N  the  followed,  nitrile  reaction pregnane  resulted  anion  ether,  of  then  after  removal  resulted  23a.  The  hydrochloric acid/methanol,  to  obtained  to ester  20a  with  was  cyclized  in 24%  a  overall  3/3-acetoxy-20-oxo-  reported  22a  with lead  in  1970  by  tetraacetate  3,21-diacetate  in  22b.  from of  the of  lactone the  solvent, the  in  21.  was  in 47% imino  which  from  in the  derived  of  compound  c o m p o u n d starting  etherate  c o m p o u n d with the  ^-unsaturated  3/3-acetate  was  produce  a,/3-unsaturated  Allylic oxidation  18.  to  sulphuric acid  allylic alcohol 20b  a Wittig-Horner of  dilute  producing the  Digitoxigenin  the  ethoxyacetylene  treatment with  intermediate  hydrochloric acid/diethyl of  by  compound  Treatment  diethylcyanomethylphosphonate with  C3,  with lithium  18  a cardenolide  Pettit  ,  from  by saponification  22a  5  1 3  at  1  This c o m p o u n d was  17 .  has most  must  rearrangement  butenolide  pregnan-5-ene 1  3)  by saponification to  18  acetylated  lactone  followed  produced the  required  from  acetate  material  reacting  type  1  selenium situ  involved  carbinol  a-acetylenic  effect  only the  (Scheme  al.  10  group.  This method the  acid, which was  by Sondheimer et 16  5/3-androstane-3/3-ol-17-one  As one  problems  reported  14/3-hydroxy-5/3-pregnan-20-one  corresponding of  was  3/3-acetoxy-14/3-hydroxy-5/3-etianate  steps from  converted  digitoxigenin  /  imino  24  lactone  by  treatment  lactone  could then 25a  in  24 be  90%  yield  introduction  19  18  20a  R=H  20b  R=OH  21 Scheme 3  / 11  Introduction / 12  25a  25b  R=OAC R=H  26 Scheme 4  accompanied  Lenz but  1 6  by  10%  of  This  same  The  diacetate  .  instead  workup,  of  the  observed.  22b,  Treatment  same  deoxycortexone  could not  the  of  be  resulted  reported  produce lactone  However  digitoxigenin Ruschig in  the 31.  C14,15  Pyrolysis of  double  ester  to  C4,5  double  to  28, the  the  produce the  was  in 75%  later (1978)  by  years  reagent  used  used as a solvent. yield  and  no  acid resulted  lactone of  1969  1 7  .  The  30c  which  28  the  in  the  required  enol  authors. Their cyclize to  as above,  above After  £-nitrile  in 95%  but  23a  yield  was  of  the  29  in  69%  dimesylate the  an imino  30a,  30b  the  hydrolysis and  butenolide  ring 32  in  28  was  methanol  (Scheme  was  acid benzyl  in the  of  acid  which  yield.  spontaneously cyclized to  elimination  to  lactone  saponification of  derivative  malonic  of  initial plan was  15a-hydroxycortexone  of  ether  with p-toluenesulfonic  c o m p o u n d in collidine  as well as the  b o n d was  same  saponify and  synthesis from  this  used on  cardenolide  acid resulted bond,  resulted  by the  potassium salt  intermediate  p-toluenesulfonic  5)  treatment  A  by the  23b  a few  same Wittig  1,2-dimethoxyethane  nitrile  conversion to  transesterified  dramatically  sequence was  (Scheme  in  by  13  25b.  hydrolyzed  successful.  improved  with p-toluenesulfonic  reaction  27,  /  26.  treated with the  nitrile  23b  unsaturated  then  was  tetrahydrofuran,  Z-unsaturated  This  diene  sequence was  3/3-hydroxy-cardenolide  produce  the  Introduction  prepared  half  produce  of  was and  to  the  of  mesyl group  decarboxylation  stereospecifically hydrogenated  ester  presence  in a yield  6)  to of  25%  produce the  from  with hydrogen  over  the  benzyl 30a.  The  palladium  14 on  charcoal to  reduced  with  compound  produce the  lithium  33b  A  -3-ketone  tri(f-butoxy) aluminum  in 81%  yield. This hydroxy  33a  in  hydride  79% to  yield. The produce the  c o m p o u n d was  ketone  was  then  3a-hydroxy  epimerized  at  C3  by  Introduction  /  14  29 Scheme 5 solvolysis required  (in  sodium acetate/acetic  3/3-acetoxy  product  34.  The  method  developed  derivative  14/3-hydroxy by  yield.  in  group  Engel and  N,N-dibromobenzosulfonamide Raney  33c  acid)  gave  nickel®/palladium chloride  of  26% was  Bach  1  the  mixture  1  the yield  corresponding tosylate accompanied  introduced .  gave  the  35,  of  then  33c  give  the  elimination  using a modification  Thus, treatment  bromohydrin  by  to  of  the  with  catalytic  3/3-acetoxy-digitoxigenin  reduction 21,  in  19%  over  Introduction  /  15  Introduction A very (from  a C21  C21  convenient  aldehyde)  aldehyde  dehydroepiandrostane monohydrate acid  was  was  37  was  (heating 68  studied. hours  acidic conditions  hours  at  sodium yields  of  the  synthesized much  in  more  at  and  al.  in  20  58%.  intermediate  than  their  which,  Horner-Emmons  for  synthesis of (Scheme  Reduction  of  the  the  latter after  first  glance, this  to  be  no  of  solving this  developed presence  of  to  3-ketone  the  the  afforded  c o m p o u n d would method problem  Breslow ef  iodobenzene  to  al.  required the  to 2  1  .  utilize  the  be  therefore  and  a  acid,  Although  procedure  yield  group  with  "dead  end"  14/3-hydroxy  functionalization 43  was  in the  43  is  by  mixed  the  from  Wittig  or  40.  L-Selectride® and, in  89%  because  yield. At  there  group. Their of  the  reactions.  employed  acid gave  70%  36  with  with the  cardenolide  resulted  and  by an intramolecular  in  methodology this  yield  series of  40  of  acetic  ring is  this  Treatment  required  remote  Via this  dichloride  cardenolide  from  3/3-hydroxy  to  39.  synthesis was  3/3-acetoxy  seem  introduce  was  cardenolide  a lengthier  42  This  acid  glacial  in 27%  digitoxigenin  cardenolide  in  subsequently reduced  cyclized  7).  with glyoxylic  acetate  diethylphosphonoacetic  isolation, was  give to  acetylation,  facile  by  acid and  8).  system  Scheme  in glacial acetic  and  involving  ring  16  from  9  high, the  aldehyde,  (see  1 8  obtained  the  a digitoxigenin  formal  without  reaction  the  not  1  acid  was  a butenolide  Nazir  sodium  produce  are  of  aldehyde  was  38  lactol  to  a method  strategy  trifluoroacetic 41  this  hydrochloric  step  1  of  of  lactol  The  steps from  and  methods  the  21-hydroxy-5p -pregnane-3,20-dione anhydride  Kreiser  67°C),  deacetylated  two  interesting  ef  by  basic conditions,  condensation  only  construction  Under  (concentrated  convenient  An McMurry  aldol  developed  yield was  borohydride  the  Aldol condensation  36.  the  for  synthesized via known  under  60°C)  method  /  seems method  steroids as  photolyzed production  in of  the  Introduction  39  /  17  38 Scheme 7  3/3-acetoxy-5/3-carda-14,20(22)-dienolide of  dehydrohalogenating  small amounts allylic C 1 7  was  after  into  intermediate of  digitoxigenin,  by Wiesner was  protection  this  et  22  the  C17  to  hydroxy  a formal strategy  Scheme  group  9).  mainly (as  the  necessity  c o m p o u n d . Surprisingly,  c o m p o u n d 44  novel  produce  yield without  derived from  45  constitutes  (see  in 55%  14a-chloro  product  a rather  al.  hydrogenated of  the  directly  observed. Since the  synthesis employing  reported  testosterone  10%)  position was  transformed A  (about  the  44  of  the  had p r e v i o u s l y  synthesis from starting  The  the  oxidation  only  C4,5  required  from  been  40.  testosterone  double  bond  5/3-isomer  a tetrahydropyranyl  17  tertiary  ether),  7  of  46, and the  C3  Introduction  44  45 Scheme 8  /  18  Introduction / 19  46  50  47a  R  I=H,  47b  Ri=OH,  51 Scheme 9  R =OH 2  R =H 2  Introduction  55  /  54 Scheme 9-continued  ketone and  was  47b.  then  The  3/3-hydroxy  a,/3-unsaturated of  the  followed  ketone  molecule  Treatment  of  reduced  this  48.  resulted  using a Meerwein-Ponndorf c o m p o u n d 47b Attack in the  of  in acetone  transformed  ketone  tertiary allylic  alcohol with acetic  by refluxing  this  was  anhydride  reaction  in the  pyridine  the  alcohols  6 steps to  1,2-sense  alcohol 49 in  in  to  from  47a  the the  with a yield of  a-face  93%.  to  give the  acetate,  containing calcium carbonate,  resulted  in allylic  20  Introduction rearrangement  to  the  palladium  on  saturated  alcohol 51  Oxidation  of  chloroform, which,  calcium carbonate  this  without  effected  with  the  in ethanol  was  in 87%  acid,  and  desired Cl7/3-configuration  sodium acetate  isolation, was  cardenolide  by treatment  in  87%  sodium  yield.  with  mesyl chloride  85%  yield. The  in  Hydrogenation  a yield  of  hydroxy  borohydride  Dehydration  of  in pyridine  to  this  of  give  hydroxy  produce  the  92%.  lactone  to  21  over  producing  acid in a mixture  produced the  reduced with  53  yield.  stereospecific, thus  c o m p o u n d with m-chloroperbenzoic  acetic  15/3-hydroxy  secondary allylic alcohol 50  /  52,  the group  was  the  14 A  - c o m p o u n d 54  in  modification  of  treated with  N-bromoacetamide  produce  intermediate  the  reduced with potassium group  the  to  An  Kabat (see of  2 3  in their  Scheme  40%,  strategy  The  58  tetrahydropyranyl  the  unsaturated  The  mixture  was  with  in  91%  ether,  trimethylsilylacetate  for  the  and  ester  the of  n-butyllithium  59a  (as  reduced with  give  hydrogen  a mixture  of  water  chloride,  and  the  isolation,  methanol  in a  butenolide  was  employed  prepared  peroxide of  to  the  from  produce  geometric  The  hydride  in ether  benzyl  yield.  ring based  on  by Wicha  and 56  yield  the group  as  the  methyl  a Peterson isomers at  to  and  in overall  3/3-hydroxy  treated with  effect  56  was  was  3/3-acetoxy-androst-5-ene-17-one  57,  to  3c  olefin  acetone  93%  epoxide  aluminum  Thus the  digitoxigenin  c o m p o u n d was ether  .  55.  protection  in  1  introduced via a  3/3-benzyldigitoxigenin  from  ketone  1  then  which, without  methylene  an allylic  lithium  acid,  construction of  yield. After resulting  method  acetic  the  digitoxigenin  alkaline  Bach of  of  yield  a,/3-unsaturated  oxidized  14,15/3-epoxide  78%  rearrangement  synthesis of  10).  was  a mixture in  group was  15a-bromide,  by hydrogenolysis to  interesting  a palladium-induced  in a mixture  in  provide  removed  Engel and  14/3-hydroxy,  Raney nickel©  acetate  was  aforementioned  14/3-hydroxy  olefination,  C20) at  in 75%  -40°C  to  giving yield. give  Introduction  Scheme 10  / 22  Introduction  65  /  23  64 Scheme 10-continued  mainly  (80%)  resulting in the yield.  the  from  ring  presence Treatment  allylic alcohol 59b, of  the  epoxide.  of  dicyclohexylcarbodiimide  of  the  palladium(O)  at  The  double  C16,17  opening  accompanied  40°C  ester  with  10  in tetrahydrofuran b o n d was  mol%  by some  Esterification gave of  solution  stereospecifically  the  (10%)  of  the  diol  with (phenylthio)acetic  isomeric esters  61  in  60 acid  92%  tetrakis(triphenylphosphine) resulted reduced  in  60%  of  the  using diimide  lactone  generated  62. in  Introduction situ  from  dipotassium azodicarboxylate  produce  the  C17p'-lactone  effected  by oxidizing to  the  cardenolide  the  usual way  75%  yield  (mesyl mild  digitoxigenin  years later  in 80%  above  a formal  research g r o u p " 2  17  presence  resulted  Reduction  ammonium  of  the  acetate  double  group  Diisobutyl aluminum  which  when  room  temperature  yield.  Acetylation of  C22  acetate  group to and  treated with  hydride  gave the  hydroxy  lithium  cardenolide McMurry  ef  al.  the  chloride  which  the  reaction  has already  been  11).  give  transformed  1 7  reported  Treatment  in refluxing  of  toluene  nitrile 66  in  a few  the the  in 89%  yield.  molecule with sodium of  the  saturated  nitrile 67a  96%  the  nitrile  gave the  in  aldehyde  in the by  yield.  hydroxy lactone  and  selective hydrolysis of Elimination of  by addition refluxing,  transformed  to  in  at of  this  room lithium  resulted  in  a digitoxigenin  the  67b,  hydrochloric acid in methanol  in dimethylformamide  mixture  in  65  by protection  resulted  in 92%  to  in  followed  groups followed 68  eliminated  ester  gave of  give  56.  unsaturated  corresponding chloride, followed  chloride to 43,  ether  reduction  mono-acetate  by treatment with thionyl  produce the  Scheme  to  derivative  an androstane was  (see  was  toluene  ether  24  to  ether  c o m p o u n d has b e e n  a-face of the of  by refluxing,  unsaturated  tetrahydropyranyl  potassium cyanide and  followed both  the  thio  group was  synthesis from  in the  reduction  as a tetrahydropyranyl  yield.  the  the  with cyanoacetate  bond from  borohydride with simultaneous hydroxy  give  a cardenolide from  3p'-acetoxy-5/3-androstane- 17-one of  15/3-hydroxy  to  the  solution  pyrolysis in refluxing  yield. Since this  constititutes  approach to  by the  pyridine)  acid in pyridine  Elimination of  and  63b  acid hydrolysis removed  this  Another  yield.  yield. The  chloride in  14-anhydrodigitoxigenin into  sulfoxide  in quantitative  64  and  in 70%  63a  the  and acetic  /  at  79% the  hydroxy temperature carbonate  the synthon  by  Introduction  /  25  Scheme 11 Another was  reported  by  synthesis of  the  Harnisch ef  al.  trifluoromethanesulfonate  G9  was  f-3-(methoxycarbonyl)-2-propenyl acetate  triphenylphosphine to  Treatment butenolide  of 71  2  digitoxigenin synthon 43 5  (see  formed  Scheme 12). in 46%  tetrahydropyranyl produce the  ether  intermediate  37%  strategy  enol  yield from  this with an ion exchange resin (acid in  The  utilizing a novel  in the  and alkylated  17  presence of  with  palladium  a,j3-unsaturated ester  70.  form) produced the  yield. Stereospecific hydrogenation of  the  C16,17  double  bond  Introduction  /  26  OTHP  71 Scheme 12 produced  the The  the  problems  can be of  the  reducing  desired C17/3-cardeno!ide above  literature review  associated with the  overcome. C3-ketone agents  For example, of  (eg.  5/3-steroids  43  in  has shown  synthesis of as was can be  L-Selectride®) to  shown  quantitative yield. several  examples  cardenolides from by McMurry  et  of  how  common al.  2 0  ,  the  achieved stereospecifically utilizing  produce  mainly  the  many  of  steroids reduction complex  3/3-hydroxy-5/J-steroidal  Introduction precursor. The introduction of type  the  precursors (as o p p o s e d to  17/3-configuration)  is most  17/3-configuration  the  often  /  27  from androstane or testosterone  progesterone type  that already  accomplished by taking  advantage  have of  the  the kinetically  14 favoured  attack  the  hindered  less  group  of  however,  hydrogen (or a-face of the  some other  reducing species) on A  molecule. The  is done essentially by the  introduction of the  method  of  Engel and  -steroids from  14/3-hydroxy Bach  1  1  14 corresponding  A  -steroid and  often  proceeds with a rather  modest yield.  from  the  2. SCOPE OF THE The chemistry  of  past  and, as mentioned  10 years  been  shown to  molecules. the  thujone  be  a viable  As a result  analog  1, has been  2 (Figure  the  6,7-unsaturated  tricyclic  with methyl isomeric in the  (Scheme  acrylate  keto-esters enol  ketone in  with the  79  and 80, respectively in 65%  80  by catalytic of  80  reagent  79. Birch reduction  60%  yield  resulted  of  the  Cl7-epimers)  yield from wish to  this  of  yield  yield  bond at  the  the  the  and  synthesis of  14/3-steroidal  the  C8,14  15),  resulting  thujone.  double enone  followed  5/3-steroid  was  in  of  as an ethylene steroid  by utilizing  14  overall  of  compounds converted  the  of  this  steroidal  converted  28  to  aldol  in  bond ring of  ozonolysis of  in 46%  overall  research, we  analog 2 as a  cardiac active steroids.  analog 2 was  to  yield  a mixture  analog 2  and  77  catalyzed  ketal,  74  resulted  C4,5-double  (as  yield  the  Base catalyzed  the  82. As a continuation  thujone  to  by cyclization resulted  in c o m p o u n d 84  in the  and  readily  70%  methyl  Alkylation of  in the  analog 83. Acid  C3-ketone  dione  74. Alkylation  bond.  81  with  scheme  resulted  has  active  thujone  as shown in  the  steroids such as  carboxylic acid 75  hydrogenation  resulted  ketone  chemistry of  the  yield from  thujone  biologically  Alkylation of  Scheme 14)  tetracyclic  the  C16  of  each. C o m p o u n d 79  of  of  the  in 45%  (Scheme  81  introduction,  yield from  mixture  shown in  in the  a,/3-unsaturated  extend  The  (as  and, after protecting  the  substrate for  of  of  cyclopropane ring resulted  exocyclic double  a variety  in 48%  74  steroid analog 82  in a quantitative  opening of  the  the  of this  cyclization of  a mixture  reduction  resulted  from  by  and 78, both  78  2  for  this research group for  research, a total synthesis of  followed  76. Treatment  (H /Pd)  part  5  resulted  Grignard  first  focus of  achieved as f o l l o w s .  13)  lactones 77  condensation  in the  above  1) was  72  a major  chiral synthon  of the  vinyl ketone  PRESENT WORK  the cross-conjugated  Scope  of  the  present  work  /  76 Scheme 13 dienone  85  (Figure  dichlorobenzene methylene produce  2  group an  6  .  4) If  via elimination the  dienone  with some  intermediate  like  with benzeneselenic  85,  type  of  86a,  then  can  be  aldehyde  selectively synthon  a direct  anhydride alkylated  (such  cardenolide  in at  the  exocyclic  as a nitrile),  to  synthesis can  be  29  Scope  of  the  present work  75 + 76  1. O H " , reflux  25°C  2. Pd/C, H 3. A c O , N a O A c , 2  z  80 Scheme 14  reflux  /  30  Scope  Scheme 15  of  the  present work  /  Scope  86  of  present  work  /  32  g7  aR=cN, x = o  86bR = C H O ,  the  X=H  2  Figure 4 envisaged suited  possibly via the  as a cardenolide  aldehyde  or  86b.  bufadienolide  This c o m p o u n d would synthon  because it  be  particularly  already  has  well  the  14 A C21  -functionality aldehyde  can be  method  used by  possible  to  group, into  necessary for  Kreiser  1 8  produce the  would  yield  digitoxigenin.  achieved.  used in  the In  to  the  introduction  an aldol  ketone  this  33a  manner,  87 the  the  14/3-hydroxy  condensation type  construct the  cardenolide  of  lactone  which, latter  a formal  after having  group  reaction,  ring. Therefore removal  of  and  the  similar to  the  it  the  should  be  ring-A ketal  been  already  transformed  synthesis from  thujone  would  be  1  7  3.  3.1.  THE  As  COMMON  discussed  from  C21-aldehyde lengthy  steroid  confirm shown  the in  3.1.1.  at  this research project  possibly via the  synthesis of  the  decided to  was  to  synthesize  cross-conjugated dienone  steroidal  produce  this  analog  85  from  of  the  the  is a  rather  a commercially  This synthetic  stereochemistry  and  thujone  c o m p o u n d from 6.  85  route  would  also  chiral centers as  85.  the  some  isomers  at  C5  involve  Since this  (5/3-  first. Thus catalytic  and  5a-)  88a  point  and  circular  dichromism  results in a mixture  the  and  best of  6,  the  Although spectrum  spectrum would  specific rotation) 2 6  stategy over  make  series, this  spectrum was  be  to  bond of  the  perform  obtain  two  this  distinguished on  the  88b  the  possible  reaction  on calcium carbonate  similar physical properties were  to  6  resulted  28%  and  (such as basis of  NMR.  discussed  it easier to  would  double  desired 5/3-androstane-3,17-dione  5/3-androstane-3,17-dione been  C4,5  palladium  so they  and carbon-13  has not  androst-4-ene-3,17-dione  reaction  often  the  the  of  respectively. These isomers have  melting  from  hydrogenation  hydrogenation  5a-androst-3,17-dione yields  88b  cross-conjugated dienone  point,  5/3-isomer.  in this  DISCUSSION  such as androst-4-ene-3,17-dione  desired  NMR  of  previously assigned absolute  synthesis of  60%  objective  5j3-Androstane-3,17-dione  must,  in  The  process so we  available  A  the  thujone  86b.  AND  INTERMEDIATE  earlier,  digitoxigenin  RESULTS  is a known  in the  assign the studied  literature. spectra of  in detail  33  compound  (Figure  Since the the 5).  2 7  , the  proton  analysis of  this  subsequent compounds The  two  methyl  group  Results and  discussion  /  spectrum  to  34  88aC5a-H 88bc5/3-H signals  (at  that of methyl  0.90  the  singlets at  respectively.  singlets (1.21 unchanged, group.  to  therefore  There  are  2.47  these  protons  and  basis of  However  it  were  are their  is not  shift  the  three  2.68  0.92  and  assigned by comparison of  1.21  Hydrogenation  ppm)  2.32,  the  ppm)  substrate, androst-4-ene-3,17-dione.  group  groups,  and. 1.06  not  the  at  1.06  in the  coupled to  chemical shift, possible to  they  (Figure  6)  multiplets  and  say which  spectrum has been  as: 2.32  (C4a-hydrogen).  double  C18  be  each  (see  be  to  proton  the  (C2/3-hydrogen),  Figures 5b,  was  in the of  the  remains  proton,  (O6a-hydrogen),  and  and  this  5d) 4  and  or  16.  carbon. T o  Since the experiment  assignment of 2.68  at  showed that  2 D - H E T C O R spectrum  coupling constants allows 2.47  one  which  8  the  C19-methyl  performed. 2  of  other  for  5c,  to  literature  the  methyl  carbons 2,  is attached  experiment  discussed  to  C19  the  integrating  attached  two  causes one  while  due  shows  and  bond,  must  signals. Examination  consideration of  the  ppm),  ppm  must  NMR  assign these  to  (1.06  each other  carbon-13  to  latter spectrum  spectrum. Decoupling experiments  problem, a 2 D - C O S Y - H E T C O R  help  C4,5  resolved multiplets,  solve this  would  due  a higher field  singlet  well  ppm  to  of  ppm  The  this  ppm  these  on  Results  1  H-NMR a) b) c) d)  (400 M H z , C D C I normal 400 M H z homonuclear spin homonuclear spin homonuclear spin  and  discussion /  ) of 5/3-androstane-3.l7-dione spectrum. decoupling at 2.32 p p m . decoupling at 2.47 p p m . decoupling at 2.68 p p m .  35  88b  3  Figure 5 3.1.2. Formation of the C3-ketal 89 The  C3-ketone  as in the presence  10%  of  (on  the  5|3-androsiane-3,17-dione  thujone-derived of  azeotropic  of  a catalytic  removal  the  of  diketal  basis of  90  steroid  amount water, and  2. Treatment  was of  protected  88b  as an  with ethylene  of p-toluenesulfonic acid in refluxing  resulted 5%  88b  in  76%  yield  of  the  the  C3-ketone  ketal,  glycol in  the  benzene  desired monoketal  recovered substrate. Therefore,  steric arguments),  ethylene  as one  is much more  might  reactive  than  with 89, expect the  Results and discussion /  36  U  F2 (PPM)  2 6  2.8  2.4  2.2  2.0 F1 ( P P M )  Heteronuclear ( C , H) 2D C O S Y 5/3-androstane-3,17-dione 88b. 1  3  spectrum (300  MHz,  CDCI ) 3  of  Figure 6 C17-ketone. diones  A  more  resulting from  of  trimethylsilyl  In  our  hands,  regioselective method the  use of  trifluoromethane this method was  for  the  formation  of  1,2-bis[(trimethylsilyl)oxy]ethane  sulfonate was not  recently reported  a significant improvement  ethylene  ketals  of  and catalylic amounts in the of  the  literature . 29  above  method.  Results and discussion /  CH  P  3  CH  o  ketalization  years  90  we  thought  solution  it would  3 0  ,  attempts were  6.  in steroidal  This method  monoketal  89  acid  at reflux,  and the diketal  convenient  used  in the next  subsequent  for large  Wittig  to accomplish the selective  worked  example,  very  well on some  method  on our system.  and the dione  resulted  in complete  5a-steroids, so Heating  of the desired  scale preparations  reaction,  and the diketal  reaction  with  a  in the presence of  88b  conversion to the desired  in 70% and 30% yields, respectively.  90  did not increase the yield  most  made  diones, for  be useful to try this  of 2-butanone-2,2-ethyleneketal  p-toluenesulfonic  method  ago  of the C3-ketone  androst-4-ene-3,17-dione  O  3  H  89 Several  37  product,  it proved  because the crude was easily recovered  Although  this  to be the  product  could be  unchanged  after the  89.  3.1.3. a,^-unsaturated ketone 93 Following  similar  procedures to those  was  treated with  dry  tetrahydrofuran  oxidation  of this  hydroperoxide,  used by Trost  methyltriphenylphosphonium to yield  resulted  bromide  94% of the desired  c o m p o u n d with selenium  ef a / .  olefin  dioxide,  in the allylic alcohol  92,  3 1  ,  the C l 7 - k e t o n e  and potassium 91  (Scheme  in the presence  f-butoxide  89 in  16). Allylic of  and the a, /^-unsaturated  f-butyl ketone  93  Results and  discussion /  38  Scheme 16 in 75%  and  18%  yields, respectively.  treatment with a solution the  a,/3-unsaturated  involved of  92  in the  above  with pyridinium  a,/3-unsaturated it  ketone  ketone  is obviously the  of  The  oxalylchloride 93  reaction,  in  86%  the  allylic alcohol 92, was in dimethylsulfoxide  yield.  Corey  3 3  chlorochromate  resulted  93. Therefore,  although  method  of  choice.  Because of the method in only the  was 74%  Swern  oxidized  (Swern technical  tried.  Thus  yield reaction  of  by method)  3 2  to  difficulties treatment  the  is more  difficult,  Results 3.1.4. Cross-conjugated d i e n o n e The  last step  in the  we  synthesis of  decided to  case however, substrate.  this dienone  try this method  this very  a synthesis of  intermediates  the  2 and it was  our  ketone  was  tetrahydrofuran the  observed that two Therefore  generated at  -40°C,  and  quenching  resulted  with recovery  of  in the almost  this yield were not  the  Oxidation  the of  this  successful,  the  remaining  so we  substrate.  decided to  in this  desired cross-conjugated dienone  substrate. While  many  examples  result  and  in the  enol  this  oxidized " 3  reaction  literature for  proceed with the  next  this  step.  with  of  of the  the  ether 85  this  steroidal to  could serve as a of  In  .  the  introduced  produce model  a,)3-unsaturated disilylamide  in  chloride  with palladium  in only  about  Several attempts  search for  to  an alternative  gave  (II)  5%  yield,  improve method.  2,3-dichloro-5,6-dicyanoquinone,  and  85  57%  is far from reaction,  93.  2 6  alternative.  one  hexamethyl  desired cross-conjugated dienone all of  an  D-ring  yield  recovered  latter with trimethylsilyl  have also been  recovered  work  enolate  Enol silyl ethers case the  the  lithium  of  sought  bonds were  this synthetic  dehydration  ketone  no  3  similar to  by treatment with  with  ( ± ) - c o r i o l i n ",  double  the  bonds in a g o o d  20%)  result, we  methodology,  was  a,/3-unsaturated  about  tricyclopentanoid  corresponding silylenol ether.  acetate  (only  thujone  double  on the  disappointing  system. Employing this 93  low  from  both  possesses a ring system very  a cross-conjugated dienone. for  produce  yield was very  Because of In  analog  the  39  85  using benzeneselenic anhydride- to Therefore  and discussion /  resulted  ideal,  so we  the  in  32%  yield and  yields are  decided to  similar  accept  this  to  Results and discussion / 40  3.1.5. Model studies of the aldol of  the  C21-aldehyde  In order to evaluate  95b the application  synthesis of the required  of the Kreiser method  butenolide  condensation of a C21-aldehyde. 14a-steroid  condensation  93. To elaborate  For this purpose we decided to p r o c e e d with the  this  a,|3-unsaturated  a one carbon aldehyde  appeared  desirable.  was  done  using the method  ketones . 3 6  ketone resulted (Figure epimers  Thus treatment  93 with  The  effect  chemical shifts  (Figure  two protons  is increased ( % N O E =  interactions  this  enhancement.  distance  must  Examination  nitrile 95 shows that the distance  C20-protons  simplifying  is much less than  3.7  7a) and carbon-13 NMR  isomer,  not a mixture of  be used to determine  the interpretation,  This method  in regions of the spectrum where decreases rapidly  chloride  molecules. The NOE-difference  of very small enhancements.  of enhancement  measurable  of organic  a,/3-unsaturated  and ammonium  (NOE) can often  the enhanced signals thereby  the  the  Overhauser  at specific centers  measurement  3  solution of the  94. The proton  expect.  the  CH :H  ef al. for a,/3-unsaturated  8) spectra show that this c o m p o u n d is a single  shows only  the  by Nagata  1 / R , where 6  be less than of a molecular  the  experiment  and allowing  can also aid in assigning  several multiplets  as the d i s t a n c e  3 7  through  R = distance).  model  overlap. The  space  between  In the case of  3.7 A in order  to observe a  of the Cl7/3-isomer of  between the Cl8-methyl  A and similarly,  group  of the a,j3-unsaturated ketone  of potassium cyanide  (at C17) as one might  to the required  synthon, and the nitrile  of a dimethylformamide  in 80% yield of the nitrile  configuration  amount  ketone  Hydrocyanation  developed  a water solution  nuclear  earlier for  it was necessary to study the aldol  C21 -aldehyde, we needed to be the most  mentioned  group  if the C17a-isomer  and the is examined,  Results  the  distance between  Therefore  irradiation  configuration  at  the of  to  one  at  of  resulted which The  in the  observation at  0.75  ppm  ppm  (see  heating glycol  collapse of  removal  of  9).  and  This result  41  is also very small.  the  determination  of  the  ppm  but  not  AB quartet  2.17  of  ppm  the  the  2.72  enhancement  7c)  of  the  signal at  ppm  to  a doublet  (/ = 4  due  to  the  C20-proton.  signals (at  2.17  2.72  other  ppm)  is consistant with the  ppm  of  at  signal being  group)  in the  AB quartet  Figure  at  C20-proton  (C18-methyl  resulted  (due  2.17  ppm  Hz)  is enhanced compound  by  having  Cl7/3-configuration. ketone  at  C16  was  amount  water,  yield  at  to  C17  Irradiation at 2.35  ppm  protected  solution  a catalytic  stereochemistry Figure  that one  7b)  group)  Decoupling (see  the  a toluene/benzene and  C17/3-hydrogen  signal should enable  (Cl8-methyl  Figure  C20-protons).  0.75  required The  2.25  C18-methyl  is consistant with the  irradiation the  2.17  the  the  and the  discussion /  C17.  Irradiation at a quartet  C18-methyl  and  was 0.75  quartets  of  the  as the nitrile  ethylene  94  of p-toluenesulfonic  95%  of  the  investigated ppm  protected by  (C20-hydrogens)  is consistent with the  nitrile  95a  acid for nitrile  resulted  but  not  having  derivative  with an excess of h,  by  ethylene  with  azeotropic  As above,  the  spectroscopy (see  in enhancement  the  the  48  95a.  NOE-difference  (C18-methyl)  ketal  C17-proton  desired  of  both  the  resonance.  C17/3-configuration.  ID  Nuclear Overhauser difference and homonuclear spin decoupling experiments 170-cyanomethyl-5p -androstane-3,3-ethyleneketal 94 (400 M H z , C D C I ) . a) off resonance spectrum b) irradiation at 0.75 ppm c) homonuclear spin decoupling (irradiation at 2.17 ppm)  on  ,  3  n  c  Figure 7 ro  Results  and  discussion /  cu c  >-  o  <v  c re ~o  ,_ i  O  -o  C  ro  LT)  CD  E o c ro > u  - U N  X — I m  'n  2  I  U  43  Results  and  discussion /  44  95aR=cN 95bR=cHo The  nitrile 95a  was  reduced to  treatment with  diisobutylaluminum  done  temperature  at  proceed  room to  completion.  by chromatography even  at  the With  elaboration et  al.  1  the  of  conditions be  decided are be  to  quite  We  involved.  used in  try  preparation  a lower 95b  butenolide  could,  on  and  a variation  of  Fortunately,  rapidly  this ester  if  in  temperature.  66%  reaction  not  could not  to  ensure  by was  the  aldehyde  yield  This reduction  the  important  hand  we  were  synthesis of not  al.  3  this  on  method.  in the  would  be  separated  a complete  In  to  reaction  method  pregnane  from  general,  methyl  glyoxylate  menthol  ester  of  "Kugelrohr"  indirect  the  free  distillation  The route.  Thus,  esters  ketones  can  so  and  can  not  can  be  it  too,  procedure  for  treatment  of  we  esters  aldehyde  although,  literature  drastic  acids and  glyoxylic acid is stable  moisture.  a  because of  type  easily (often the  proceeds via an  ring  for  Kreiser  shown, that glyoxylate  very  exposed to  methods  introduction,  hydrates  by  study  butenolide  this  have  8  ready  the  employ  Pettit ef  in an anhydrous form  hydrate of  the  95b  temperatures,  ring. As mentioned  however,  However,  room  lower  nitrile  aldehyde  yield.  a short  unstable, and form  easily prepared the  of  C21  at  an aldol condensation reaction  isolated).  forms  Since the  developed  C21 -aldehyde.  because at  aldehyde  the  have  8  hydride  on silica-gel, it was  expense  the  3 9  the  menthol  ?ooo  1500  1000  Nuclear Overhauser difference experiments on 17/3-cyanomethyl-5/3-androstane-3,3,16,16-bis(ethyleneketal) a) off resonance spectrum b) irradiation at 0.75 ppm  Figure 9  son  95a  (400  MHz,  CDC! ). 3  Results bromoacetate  with silver  treatment with glyoxylate  sodium acetate  is k n o w n " ,  often  the  enolate  potassium  the  the  chloride  are  using potassium hydride.  hydride  reaction  was  (saturated  freshly  yielded  mass spectometry) attempts to  by the  Work-up  a UV-active of  obtain  the  was  hydrolyzing to  acid  catalysis by silica-gel). Treatment  methanol 70%,  resulted  respectively.  decided to  borohydride ester  99  produce the  in the  reduce the  directly.  borohydride  ester .99, in  17%  saturated  over  lactone  hydroxy  of  46  by  menthol  and  isolate  palladium 100,  thus  by  column  the  correct 10),  in  were  32%  not  successful,  menthol  trans-ester  99  difficulties  in working  with the  crude  resulted  98  reaction in the  calcium carbonate  providing indirect  reaction  compound  product  to  borohydride  in yields of  hydroxy-lactone with sodium  reduced  trans  mixture  (without  work-up)  trans  menthol  cyclized to  evidence that it was  in  17%  and the  cardenolide  and  and  (possibly due  and the  the  yield.  indicating that the  and  about  molecular weight  98  yields, respectively. The on  followed  odor  cardenolide  min, a  added. After  this c o m p o u n d with sodium  the  of  30  ammonium  (Figure  97  was  a slurry of  of  sample  lactone  after  make  a solution  mixture,  pure  to  of  the  in methanol  24%  of  96  and  unreactive,  decided to  added  glyoxylate  crude, aldol condensation  Thus treatment  with sodium  hydrogenated  to  this  a menthol-like  cardenolide  Because  in methanol  of  addition  rather  so we  was  95b  menthol  analytically  consistently exhibited  reactive,  c o m p o u n d having  product  we  followed  crystalline  aldehydes are  temperature,  desired ester  an  of  more  room  distilled  quenched  aqueous).  enolates  much  at  the  and  produces the  The aldehyde  in tetrahydrofuran  solution of  chromatography  Repeated  lithium  potassium enolates  tetrahydrofuran  (from  corresponding nitrate  dimethylsulfoxide,  that the  0  but  h,  in  produce the  discussion /  monohydrate. It  2  nitrate to  and  98, and ester  the  could  99  produce indeed  trans be  the  the  trans  Results  100 Figure 10  and  discussion  /  47  Results ester  2  6  molecular  of  models leads  favourable from  C18-methyl  group  the  so that the  C20,21  bond is rotated groups are  enolate  transition  attacks  state  the  Cl6-ketal  the  trans  rings  B and  the  as shown the  from  above  to  the  and the  the  the  enolate the  the  and the plane E  the  is not  two  (see  then  the  Also,  plane  Examination  enolate  would  The  11),  menthol  bond,  double  the  relieving  ester should both  the  the  be  menthol  If  the  result.  In  repulsions state  ester  leading  and to  transition  condensation synthesis of  above of  synthesis has provided some experience with  a C21-aldehyde, and we  digitoxigenin  from  thujone.  decided to  the  to  the  the  state  aldol  proceed with the  the  between  cis product. The  the  Similarly, if  repulsions due  favour the  the  would  reaction  result.  bond will  would  of  hydrogen and  carbonyl oxygen. The transition between  the  in opposite  a plane.  bond will  there  have  bulk  glyoxylate  and after  can occur, (the  a trans  of  it is reasonable to assume  possible because the  a cis double  cis double ester  aldehyde  carbonyls define  Figure  elimination  2  is interesting.  carbonyl groups oriented  ester  steroid. Therefore, of  the  enolate.  has steric crowding  bulk  detail  in Figure 11.  of  anti-periplanar)  bond  of  this  so that  oxygens and  C  of  aldehyde  below  leading  double  C16-ketal, to  from  in more  conclusion that  conformation with  attacks  the  the  /3-face  enolate  hydroxy  to  reaction  blocks this face  a preferred  directions,  this  geometry  that attack  have  48  . Consideration  most  and discussion /  total  leading  Results  Figure 11  and  discussion  /  49  Results and discussion / 3.2.  DIGITOXIGENIN  FORMAL  3.2.1. Hydrocyanation The work produce to  try  of  in  Very  benzene  solution  at  room  addition,  of the best  of  results  proton  product  NMR  86,  consists  G L C peaks were  the  2:1,  signals in the  NMR  Figure  this  of  some  stereoselective  cyanide. Thus treatment  5 ° C , resulted  in  50%  resulted  in lower  were obtained  of  of  led us  the  the  cyanide)  yields  by fast  of  to  the  yield  (diethylaluminum  dienones  addition,  solution, with a solution of  reagent  85,  (75%)  12)  of  difficult  mixture,  to  be  phase  proportion by  of  NMR  a mixture it was  not were  shows due  accurately  Extensive attempts reverse  of  although  spectrum  signal is presumed to  so the  this  reaction  addition  desired  to  the  a  dilute  desired  of  spectrum, as well as gas chromatographic  because  detected  at  dienone  about  The  in some cases,  benzene  isomers was  on  and  hydrocyanation  the  reagent  temperature.  that this  it  the  using diethylaluminum  slow addition  The  The  make  on  cyanide in toluene  product.  86.  ,  1  an anhydrous  diethylaluminum  product  ef al."  procedure  85  SYNTHESIS  reaction  regioselective  their  dienone  Nagata  50  to  to  (see  minor Figure  epimers  impossible to  well resolved. In also poorly one  of  the  the  at C17. provide  resolved. The C20  of  determine  the  relative  amounts  separate  these  isomer was 13a)  physical and spectral data  but are  ratio  the  of  an accurate  NMR  protons, and  proton  C18,  The  similar fashion, the  same  HPLC columns ( C N , the  of  analysis, showed  of  spectrum  reduced  were only  enough  was still detected  reported  for  this  the  two  partially  so that by gas  mixture.  (see  resolved  isomer. These  it was  data  isomers.  isomers on silica-gel columns and C8)  analysis  proton  a poorly  minor  these  and  even  successful. not  chromatography,  Results and Since decided  to  isomer,  using  resulted  and  2.45  at  2.49  ppm  multiplet  sprectrum  molecular  to of  the  models  of  the  doublet  C17-H of  the  and  95,  of  of  doublets  the  96a,  their  of  results  (at are  at  one  ppm  the 2.45  ppm  it  about  ppm)  the  two  the  smaller  large  One  coupling  coupled,  and  the  having  one  C20-proton. than  C18-methyl  side chain  therefore,  is assigned to  other  than  of  basis of  and  the  larger  the  ppm  Cl7-hydrogen.  to  ppm  NMR  2.46  the  bond,  signals are  2.26  is  Examination  the  is much  between  with the  and  the  proton  a signal at  on  of  two  proton  the  that group  distance the  of  Another  (9%)  these  because this  07,20  to  (6%).  enhancement  is equal  at  13b),  a doublet  ppm  reasonable,  is due  is much  Figure  can conclude that  shows  multiplet  signal (8%)  in  major  above  Hz),  2.49  assignment.  Since the  distance  consistent  this  multiplet  (see  52  we  the  the  Comparison to  which  makes  on  signals. From  C20-hydrogens  ppm.  the  2.26  model  85,  86  the  C20-H  therefore  C20-hydrogens These  the  other  of  y=18,12  resulted  the  confirms  2.26  at  done  (8%,  a multiplet  rotation  2.45  doublets  ppm  C*19-methyl.  or  chemical shift,  of  (4%),  at  those  spectrum  C17  (Cl8-methyl)  13c)  dienone  the  at  allylic C8/3-hydrogen  C8j3-hydrogen,  enhancement  /3-configuration.  be  and  a molecular  constants between  resonance  Cl7-proton.  must  2.26  not  NMR  configuration  ppm  (Figure  assume restricted  C20-protons  the  of  at  but  in the  similar to  Hz)  as above,  constants  basis of  of  y = 12,4  either  the  1.24  a quartet  (Cl9-methy!)  the  of  coupling coupling  amount  of  cross-conjugated  grounds, to  the  Irradiation at  Cl8-methyl  the  the  one  ppm  detected  experiments  examination  2.49  of  of  of  multiplet,  is assigned to  the  determination  (4%,  ppm  and  at  equidistant  unequal  not  96a.  ppm  1.05  experiments,  steric  was  NOE-difference  95  at  irradiation  on  the  isomer  in enhancement  doublets  that  minor  attempt  compounds  the  the  discussion /  The  of  the  and to  the  JOno  I 500  Nuclear Overhauser difference experiments on 17/3-cyanomethyl-5/3-androst-4-ene-3,3ethyleneketal a) off resonance spectrum b) irradiation at 1.24 ppm c) irradiation at 1.05 ppm  Figure 13  1 000  86  (400  500  MHz,  CDCI ). 3  Results and In relating  to  conclusion, the  intermediates. further  shown  It  is clear  the  of  via the  intermediate  for  this  studies  target  information  Indeed,  methodology  purpose  and  have  the  provided  considerable  c o m p o u n d , digitoxigenin,  thujone-derrived  cardenolide.  85,  the  that the  the  that  hand.  above  synthesis of  elaboration  synthesis of  the  other  derived  steroid  can  analog  researchers  completion  of  now 85  be  for  in our  described in this  from  54  chemistry thujone-derived  applied  completing  laboratory  thesis, is a  the  discussion /  to  the  the  have  total  already  suitable  total synthesis is near  at  4.  4.1.  GENERAL  The  c o m p o u n d s were  solvents given unless  (using were  in brackets)  otherwise  71 OB and  cells of  coefficients  on  are  nanometers.  KRATOS-MS-50 ionization  are  rotations cell  at  0.1  spectrometer  in  The  1  H-NMR  in ppm on  temperature  formulae  of  all  the  was  relative  to  using the  following  the  performed  done  or  141  solvents recorded  with  rotation  flow  rate.  of  Large  pressure  "Prep  by  or  and  the  combustion  scale and  The  g/100  optical cm  mL)  molecular  analysis Small  (Merck  chemical  in a 10  (in  values. The  silica gel  liquid  impact  following  chromatography  by Mr  P.  scale column  60G)  more  PAK-500/silica" columns).  55  resolution)  polarimeter  Columbia.  spectra  in  concentrations  British  using columns  using medium  and  solution  maxima  electron  the  710,  extinction  (internal standard).  automatic  determined of  on  Elmer  ultraviolet  the  Bruker XHS-270  tetramethylsilane  University  a suitable  (equipped  recorded  XL-300  a Perkin-Elmer  Laboratory,  obtain  instrument  Varian  compounds were  Microanalytical  were  spectra were  the  uncorrected,  chloroform  AEl-MS-9 (low  employing  are  cells the  on  parenthesis  gas pressure to  quartz  recrystallization  Perkin  The  recorded  recorded  chromatography  1 cm  spectrometers,  a  in either  as KBr pellets.  the and  on  mass spectra were  Bruker WH-400,  ambient  apparatus  wavelength(s) of  in  LC-500  or  (with  recorded  spectrometers  length)  (high resolution)  were  point  spectra were  I.R.)  path  15  melting  points  and, the  reported  separations  infrared  mm  a Cary  indicated  Borda,  a Nalge  melting  parenthesis  method.  spectrometers:  by their  Transform  given in  The  on  The  (Fourier  recorded  shifts  noted.  1710  NaCl  characterized  EXPERIMENTAL  with  N  2  difficult on  a  Petroleum  Waters ether  Experimental /  refers to  the  prepared  by distillation from  Anhydrous CaH .  20°C).  The  to  acetate  The  (500  3  methanol. The  yield a viscous  [95:5, v/v  until  mg)  was  a mixture  the  g,  stirred  by filtration  Ujohn  of  eluted,  then  88a  and  physical characteristics of  88a  are  (ligroin)  benzene  and  chemical company.  20  mmol)  under  through  in 2-propanol (500  1 atm.  of  (corrected  H  2  for  5 h.  concentrated  liquid chromatography using C H C I 2  80:20 to  elute  3.84g (67%)  mL) (at  Celite which was subsequently  combined filtrate and washings were  5a-androstane-3,17-dione  m.p. = 1 3 3 . 5 - 1 3 4 . 0 ° C  from  from  (5.72  6  oil. Preparative  88a  was  88b  catalyst was removed  washed with vacuo  Pd/CaC0  °C. Anhydrous tetrahydrofuran  containing sodium and benzophenone.  was obtained  androst-4-ene-3,17-dione  10%  30-60  by distillation  5/3-ANDROSTANE-3,17-DIONE  containing  range  a mixture  benzene was prepared  A solution of  pure  boiling in the  Androst-4-ene-3,17-dione  2  4.2.  fraction  88b]  to  yield 1.60g  5|3-androstane-3,17-dione  2  in /ethyl (28%) 88b.  as follows: value)  [literature"  2  value  132-134°C  24 (ether/pentane)].  [al  (0.4-0.8,CHCl )].  IR  3  =+116+2.5°  D  v  max.(CHCI ): 3  1735(C = 0,stretch,C17-ketone), 1  H-NMR  (400  MHz,  CDCL )5: 3  (1.0266, 2930,  288.2093.  Elemental analysis calculated for  found:  78.96,  cm'  0.89(3H,s,C18-H),  ms m/z:  mass measurement:  9.69.  [literature value  3  +105°  2815(C-H,stretch),  0.81(1H,m),  resolution  H  CHCI )  1705(C = O,stretch,C3-ketone)  1.05(3H,S,C19-H), 1.21-2.56(20H,m).  C  56  calculated for  288(M+), C  C ,  9  1  9  H  H  2  2  8  8  0  273,  0 2 :  2  :  1  .  1.00(1H,m), 244,  229,  217.  High  288.2089 and found:  C 79.12,  H  9.79;  Experimental /  The  physical characteristics of  m.p. = l 3 1 . 0 - 1 3 2 . S ° C 5  max.(CHCI ):  v  2950,  3  1705(C3  ketone)  cm  1.06(3H,s,C19-H),  -  1  .  are  CHCI )  1  H-NMR  (400  21.865(C15),  31.710(C12),  35.124(00),  35.173(C8),  47.872(03),  288(M"t),  273,  288.2089  and found: 288.2086.  C  ,H  79.12  9.79;  5  1  22.692(C19), 35.942(06),  51.417(04),  3  C-NMR  (75  24.802(C6),  CHCI ). 3  36.996(C2), 212.632(C3),  H  MHz,  CDCI )5: 3  26.408(C7), 37.202(0),  41.039(C9),  220.200(07).  calculated for C  Elemental analysis: calculated for  78.86,  (1.0,  0.90(3H,s,C18-H),  3  resolution mass measurement:  found: C  ].  ketone),  CDCI )6:  2.68(1H,t,/=16,C4a-H).  20.564(C11),  High  MHz,  =+87.4  [a]^  1725(C17  129-131°C  2 7  2.32(1H,dt,/ = 4,14,C2a-H),  13.910(C18),  255.  [literature v a l u e  [literature value  3  1.15-2.23(16H,m),  44.233(C5),  value)  2875(C-H,stretch),  2.47(1H,dd,y = 8 , 2 0 , C l 6 a - H ) ,  42.296(C4),  as follows:  (corrected  = +106.2 + 2 ° C (1.0165,  [a]^ IR  (ligroin)  88b  57  C  1  9  H  2  ms  1  9  H  8  0  2  2  8  m/z: 0 : 2  :  9.80.  4.3. 5/3-ANDROSTANE-3,17-DIONE-3,3-ETHYLENEKETAL 89  4.3.1. M e t h o d To (50  a solution of mg)  heated for  at  reflux, with mixture  (200  3  MgSO ,  was  v/v)  to  (4.3g,  give the  mmol) g,  in benzene  (200  mL) was added p-TSA  14.9  The  resulting mixture  azeotropic removal was  and the  purified  15  glycol (0.923  cooled,  mL, saturated  filtered,  f l  residue  88b  and ethylene  3 h. The  NaHC0  (1:4,  A  mmol).  of water  (using a "Dean-Stark"  diluted with ethyl  aqueous solution), water  solvent removed in  by preparative  acetate (200  vacuo to  (300  (3.77  g, 76%)  apparatus)  mL), washed with  mL) then  dried over  yield a yellow  liquid chromatrography using ethyl  desired product 89  was  and diketal  oil. This acetate/hexanes  90  Experimental / (0.58  g,  4.3.2. To  10%)  in  Method  addition  to  5p'-androstane-3,17-dione  1,2-bis[(trimethylsilyl)oxy]ethane was  added trimethylsilyl  the  solution for  the  addition  of  6  h.  an  (3X,  3  filtration, product  the  90  mixture  mL, sat.  separated  acetate/petroleum diketal  at - 7 8 ° C  solvent was  was  starting  (47.9  ether mg,  88b  ketone  (0.22  88b  mL, 2.5  (606.71 mg,  mmol)  trifluoromethanesulfonate  The  15  (0.62  under  equal volume  temperature.  NaHC0  unreacted  g,  5%).  B  a solution of  room  the  58  of  was  aq.),  on  a short  to  yield  diluted (15 vacuo  with mL)  0.0421  the  aq.)  3  2  to  (30  2  over  a white  desired monoketal  recovered substrate  (3  mL)  After  was  stirring  quenched by  to  mL)  -78°C  warm  up  to  and washed with  MgSO„.  After  foam. This crude ethyl  (544  mg,  78.0%),  (20.6  mg,  3.4%).  89  88b  and at  mmol).  reaction  dried  yield  mmol)  and allowed  CH CI and  2  silica-gel column using 10%  the  6.05%) and  2  (8.14/u,  NaHC0 (sat.  in  CH CI  Ar atmosphere,  water  removed  in  2.107  the  4.3.3. Method C To  a solution of  2-butanone-2,2-ethyleneketal  5/3-androstane-3,17-dione 5.63x10" *  moles)  bicarbonate was  and the  (about  distilled  off  500  under  re-dissolved  in ethyl  drying over  MgSO , t t  (7.08  88b  g,  mg)  was  reduced  acetate filtering  added  89  plus some of  and the  and p-TSA (107  refluxed excess  pressure (water aspirator).  (500 and  the  added  mloes)  resulting solution was  mL)  for  vacuo  product showed that  corresponding diketal  1.25  mg, h. Sodium  2-butanone-2,2-ethyleneketal The  and washed with water  concentrating in  layer chromatography of this crude monoketal  0.025  was  resulting oil (3X,  a brown it  100 oil  contained  90, so the  was  mL).  After  resulted. Thin mainly  the  crude product  Experimental / 59 was  used  recovered  in the  next reaction, as is. The unreacted diketal (about  from the next reaction unchanged,  step was about 70% of the 30% of the The  desired  m.p. = 1 3 0 . 5 - 1 3 1 . 0 ° C  therefore the yield of the ketalization  5/3-androstane-3,17-dione-3,3-ethyleneketal 89  0.87(3H,s,C18-H),  (hexanes). [a]^  13.855(C18), 30.082(0),  31.758(C12),  40.123(C9),  40.852(C5),  resolution  1  21.823(C15), 32.195(C2),  1  51.484(04),  ms m/z: 332(M+),  317,  found:  76.00,  IR  v  (methanol),  max. ( C H C I ) :  0.85(3H,s,O8-H), ketals).  3  2  2  1  H  0  3  :  26.480(C7),  35.693(C16),  35.904(C4),  and 64.184(C3-ethyleneketal),  276,  =-6.19 + 0 . 7 ° (1.115,  [a]^  5  0.96(3H,s,O9-H), +  ),  7  for C  2  3  H  3  2  6  3  0  H 3  -  1  .  1  125(C H 0 ), 7  3  2  0  3  :  9  99(C H O ).  2  5  332.2350  C 75.92,  H  7  9  3  :  6  2  0  3  :  9.71;  5  376.2614  7  2  MHz,  CDCL )6:  3.80-4.00(8H,m,C3  99(C H 0 ).  C 73.47,  2  2  High  and found:  H 9.65; found:  3  and C17  resolution  mass  376.2614. Elemental C  73.75,  z  and found:  CH CI ).  H-NMR (400  1.00-2.10(22H,m),  125(C H 0 ),  calculated for C  analysis: calculated  MHz, CDCI )5:  are as follows:  2965(C-H, stretch) c m  ms m/z: 376(M  measurement:  3  9.76.  properties of 90  3  3  MHz, C D C I ) 6 :  25.187(C6),  64.035  2  m.p. = 5 8 . 0 - 5 9 . 0 ° C  (75  34.76KC10), 35.233(C8),  47.820(C13),  v max.(KBr):  2.04-2,13(1 H , m , O 6 0 - H ) ,  23.076(C19),  Elemental analysis: calculated for C i H  physical  H-NMR (400  mass measurement: calculated for C  H  ethanol). IR  C-NMR  3  332.2350.  The  1  1.00-2.04(20H,m),  3.93(4H,s,C3-ketal).  220.788(07).  (0.2035,  ketone) c m " .  0.98(3H,s,C19-H),  20.384(C11),  109.686(C3),  = +96±4°  5  2.43(1H,dd,/=8,20,Cl6a-H),  C  and  are as follows:  2980(C-H,stretch), 1725(C17  High  was  g)  5/3-androstane- 3,17-dione-3,3,17,l7-bis(ethyleneketal) 90.  physical properties of 89  2945,  2.6  H  9.16.  Experimental /  60  4.4. 17-METHYLENE-5/3-ANDROSTANE-3-ONE-3,3-ETHYLENEKETAL 91 To  a bright  yellow  (15.70 g, 43.98 (60  mL) was  refluxing (300  for  mmol)  added 3  h,  mL). The  brine  (300  viscous ethyl  mixture  and potassium <-butoxide (5.42  ketone  the  methyltriphenylphosphonium  89  (7.30g,  mixture  was  22.0  mmol)  partitioned  dried  over M g S O / , ,  oil. This oil was  acetate/petroleum  ether  filtered  purified  (5:95, v/v)  bromide  g, 48.4  mmol)  in dry THF (100  between  organic layer was washed with  mL),  brown  of  in dry THF mL).  hexanes (400  methanol  (300  mL)  mL, 50%  and concentrated in  After and  aq.)  vacuo to  water  and yield a  by preparative  liquid chromatography using  to  (94%)  yield  6.86g  pure  91  as a colorless  oil. The  physical properties  b.p. = 2 2 0 ° C  (at  0.22  of  mm  91 Hg).  are  as follows:  [a]^  2942(C-H,stretch),  1655(C = C,stretch),  0.77(3H,s,C18-H),  0.98(3H,s,Cl9-H),  2.24(1H,m,Cl6/3-H),  cm" . 1  ms m/z:  330(Mt),  resolution  mass measurement:  330.2559.  Elemental  C  H  1  (0.2120,  H-NMR  1.0-1.98(19H,m),  2.48(1 H,m,C16a-H),  4.63(1H,bs,C20-H').  80.20,  =+38±2°  4  ethanol).  (400  MHz.  268,  calculated for  analysis: calculated  for  C C  2  2  2  7  H  H  3  (KBr):  CDCI )5: 3  4.60(1H,bs,C20-H),  125(C H 0 ),  2  max.  v  2.00(1H,t,/= 1 2 , C l 5 a - H ) ,  3.94(4H,s,C3-ketal), 315,  IR  3  U  1  |  0  0  2  2  9  :  :  2  99(C H 0 ). 5  330.2559 C  80.01,  7  2  High  and found: H  10.38; found:  10.50.  4.5. 16a-HYDROXY-17-METHYLENE-5^-ANDROSTANE-3-ONE-3,3-ETHYLENEKETAL 92 To  a suspension of  room 70% olefin  temperature aq.).  The  91  (3.30  selenium dioxide  was  mixture g,  10  added was mmol)  (558  mg,  a solution of  stirred  at  room  in C H C I 2  2  (55  5 mmol)  in C H C l 2  t-butylhydroperoxide temperature mL) was  for then  (25  2  (1.93  1 h. The added  mL,  mL) 20  at mmol,  steroidal  and stirring  was  Experimental / continued  for  5 h. The  reaction mixture  and washed with sodium hydroxide (2X, dried  over M g S O , t t  Separation (3:7,  94  by preparative  v/v)  gave the  (0.61  The  filtered  g,  are  92  (ethanol).  2960,  0.77(3H,S,C18-H),  10%  aq.)  vacuo to  (2.59  g,  75%)  ether  and water  (500 (250  yield a white  and the  mL) mL),  foam.  ether/petroleum  ether  a,/3-unsaturated  ketone  as follows:  ta]^ =+2.4±0.3°  2980(C-H,stretch)  0.97(3H,s,Cl9-H), 4.63(1H,bs,  ms  328(M-H O),  326(M+),  (2.852,  &  3.92(4H,s,C3-ketal),  H  mL,  diethyl  18%).  3580(O-H,stretch),  C16-H), 313,  z  cm" . 1  1  2  125(C H 0 ), 7  2  2  H  2  2  H  3  3  u  4  0  0  3  3  9  :  2  C  IR  MHz,  v  max.  (KBr):  CDCl )6: 3  1.92(1H,t,/=12,Cl5j3-H), 5.02(1 H,d,/= 2,C20-H).  99(C H 0 ). 5  330.2499  :  2  (400  4.83(1 H,d,/ = 2,C20-H),  C  analysis: calculated for C  CH CI ).  H-NMR  1.06-1.91(20H,m),  measurement: calculated for  Elemental  250  and concentrated in  allylic alcohol 92  m.p. = 1 6 7 . 0 - 1 6 8 . 0 ° C  mass  diluted with  liquid chromatography using diethyl  physical properties of  m/z:  was  76.37  7  2  High resolution  and found: 330.2503. ,H  9.91;  found: C  76.13,  9.88.  The  physical properties of  m.p. = 9 9 . 5 - 1 0 0 . 0 ° C UV  Xmax:  226  93  are  (isopropanol).  nm  (4567,  1720(C = O,stretch,Cl6)  as follows: [a]^  ethanol).  cm" . 1  1  1.09-2.07(19H,m),  5.00(1H,s,C20-H),  5.79  125(C H 0 ), 9  (1H,s,C20-H').  99(C H 0 )-.  2  5  7  2  5  IR  H-NMR  1.01(3H,S,C18-H),  7  =-119±0.3° v  max.  (400  ms m/z:  and found: 324.2351.  C  C  H  H  3  2  0  3  :  76.71,  (CHCI ):  2950(C-H,stretch),  3  MHz,  CDCI )6: 3  324(M"t),  ethanol).  329,  0.94(3H,s,Cl9-H), 3.94(4H,s,C3-ketal), 287,  High resolution mass measurement:  324.2351  2  (0.2771,  2.24(1H,dd,y = 8,18,C15a-H),  C22H32O3:  2  61  9.36;  found: C  195, calculated for  Elemental analysis calculated for  76.49,  H  9.35.  Experimental / 4.6.  17-METHYLENE-5|3-ANDROSTANE-3,16-DIONE-3,3-ETHYLENEKETAL  4.6.1. To  Method  added  and  the  92  stirring  for  then  water The to  yield  4.6.2.  min,  6.90  mL),  with  After ml  dried  15.36  at  mmol)  added was  (50  mL)  and  MgSO„,  (1:4,  v/v)  to  -78°C.  for  HCl (50  After  3 h. The mL,  yield  pure  93  on  mL)  solution was  10%  and concentrated purified  (5  2  reaction aq.),  once again with water  filtered  -78°C  allylic  added. The  this temperature  at  2  (5  mL) was  mL)  in C H C I  2  foam. This crude product was  acetate/hexanes  mmol)  the  mL), washed with  over  (15  2  min. A solution of  mL, 2.07  (75  3  pyridinium 0.132  immediately  stirring for  which was  2  2  5  and held at  NaHC0 (aq)  then  mL,  in C H C I  (50 in  mL). vacuo,  a short silica-gel  (2.04  g,  86%).  B  (0.011 g,  diethyl  2  -20°C  2  for  (2.85  mmol)  (1.7  in C H C I  CH CI  a yellow-brown  allylic alcohol 92  mixture  mmol)  saturated  using ethyl  at - 7 8 ° C  triethylamine  diluted  7.68  dimethylsulfoxide  warm to  a solution of  the  50  g,  to  Method  acetate  chloride (670/il,  stirred  organic layer was  column  To  15  was (50  was  (2.39  allowed  mixture  oxalyl  a solution of  mixture  alcohol  93  A  a solution of  was  62  mmol)  (1.176 turned  1 h at  ether.  chlorochromate (1.465  The  g,  in C H C I  3  3.399 mmol)  black due to  room black  (5  the  mL) in  at 5  6.796 mmol) room  ml  the  3  precipitation  was  reaction  ether  (5X,  The  of the mixture  removed  and sodium  temperature  CHCl .  precipitation  temperature,  subsequently washed with diethyl  g,  was  added  orange  reaction  reduced  reagent.  was added  to  by filtration through  5 mL)  and the  solvents  florisil  Experimental  removed short  vacuo  to  mg,  a white  using ethyl  foam. This  crude  acetate/hexanes  product  (1:4,  v/v)  was  to  yield  pure  of  the  dimethylformamide mmol)  resulting water.  product (3:7, The  and  (83  v/v)  to  mL), was  was  solution  filtered, was  a,/3-unsaturated  ammonium  mixture  The  MgSO„,  was  and  on  max.  94 of  (2.72 94  (ethanol).  (CHCI ): 3  h,  in  cm" . 1  g,  of  93  [a]^  H-NMR  (400  yield  (5X,  a brown  using ethyl  MHz,  mL).  an  equal  100  ml),  foam.  The  dried  This  over  crude  acetate/hexanes  34.550(00), 50.066(04),  ethanol).  CDCL )6:  1 3  C-NMR  22.879(09),  35.477(C4),  (75  2.12-2.35(4H,m,C3-ketal), MHz,  26.242(C6),  37.147(C7),  58.773(07),  0.77(3H,s,C18-H),  3  2.01(1H,t,/=12,C15a-H),  20.217(02),  41.776(03),  acetate  with  (17  g,  2275(CN,stretch),  12.113(01),  40.422(C5),  to  diluted  in  cyanide (1.56  in water  = - 1 2 6 . 3 ± 0 . 1 ° (1.3796,  5  3.94(4H,s,C3-ketal).  33.678(C2),  ethyl  mmol)  90%.).  2.72(1H,dd,y=18,4,C20-H),  32.493(C8),  and  7.99  potassium  mmol)  cooled with  of  g,  94  as follows:  1.12-1.95(17H,m),  13.158(C18),  15  silica-gel column  are  1  g,  vacuo  2950(C-H,stretch),  1740(C = O,stretch,C16) 0.99(3H,S,C19-H),  3  extracted  a short  pure  m.p. = 1 6 2 . 0 - 1 6 2 . 5 ° C  for  (2.75  93  a solution  (0.86  concentrated  purified yield  then  ketone  added  chloride  refluxed  physical properties  v  volume  on a  74%).  a solution  24  63  purified  17/3-CYANOMETHYL-5/3-ANDROSTANE-3,16-DIONE-3,3-ETHYLENEKETAL  To  IR  yield  silica-gel column  (859.4  4.7.  in  /  CDCL )6:. 3  29.886(d),  37.404(C20),  63.826(05),  63.885  39.723(C9),  and  Experimental / 64  64.016(C3-ethyleneketal), 356,  314,  125(C H 0 ), 7  9  C23H33O3N:  for  C2 3  H  109.380(C3),  3 30 N: 3  99(C H 0 ).  2  5  371.2460  C  74.36,  118.434(C21),  7  High  2  and found:  H  8.95,  N  214.07KC16). ms m/z:  resolution  371.2460.  mass measurement: calculated  Elemental  3.77; found:  C  37KM+),  74.24,  analysis: calculated for H  9.02,  N  3.99.  4.8. 17|3-CYANOMETHYL-5/3-ANDROSTANE-3,16-DIONE -3,3,16,16-BIS(ETHYLENEKETAL) 95a To  a solution  (200  of the  mL) was added  ketone 95a  (1.67  g, 4.5  (3.1  g, 50  ethyleneglycol  mixture was heated at reflux with of  the  solvent  (all  except  azeotropic  about 50  was diluted with ethyl acetate (300 10% aq.) followed by water (100 filtered  and concentrated in  silica-gel column (1.77 The  g,  mmol) and p-TSA  removal of water  mL) was distilled  mL). The organic  vacuo. The crude  (50  for 48  NaHC0  3  v/v)  h, then the  (100  solution was dried  product  (1:1,  mg). The  off. After cooling,  mL) and washed with  with ethyl acetate/hexanes (3:7,  most  solution  ml,  over  MgSO , t t  was purified on a short  v/v) to  yield  pure 95a  95%).  physical characteristics  m.p. = 1 4 9 . 0 - 1 4 9 . 5 ° C (CHCI3):  mmol) in toluene/benzene  of 95a  (ethanol).  are as follows:  [a)^ =+21.4 + 5  0.8°  (2.9192,  2937(C-H,stretch), 2252(CN,stretch) c m " . 1  0.76(3H,s,C18-H),  0.95(3H,s,Cl9-H), 1.00-2.20(21H,m),  2.35(1 H,dd,/=20,4,C20-H'),  3.94(4H,s,C3-ketal).  11.804(C11),  20.376(C12),  12.753(C18),  1  3  30.029(C1),  33.99KC2), 3 4 . 6 7 5 ( 0 0 ) ,  34.798(C8),  39.893(C9),  40.729(C5),  51.953(04),  41.984(03),  2  IR  MHz,  v max. CDCL )6: 3  2.25(1H,dd,7 = 20,4,C20-H),  C-NMR  23.062(C19),  2  H-NMR (400  1  3.75(1 H,q,7= 16,8,06-ketal),  4.00-4.06(1 H,m,Cl6-ketal),  CH CI ).  3.88-3.97(2H,m,Cl6-ketal), (75  MHz,  26.187(C6),  35.628(C4),  CDCL )6:  26.518(C7),  37.775(05),  55.422(07),  3  39.385(C20),  Experimental 63.456(C16-ethyleneketal),  64.028  65.266(C16-ethyleneketal),  115.543(C16),  375,  125(C H 0 ), 7  C  2  5  H  C  2  5  H  3  7  3  9  and  99(C H 0 ).  2  5  7  109.716(C3),  u  N :  415.2722  and found: 415.2722.  0  4  N :  C  H  72.26,  8.97,  N  119.635(C21).  resolution  O  7  65  64.156(C3-ethyleneketal),  High  2  /  3.37;  ms m/z:  mass measurement:  415(MT),  calculated  for  Elemental analysis: calculated for  found: C  72.36,  H  9.10,  N  3.40.  4.9. 20-OXO-5 0-PREGNANE-3,16-DIONE-3,3,16,16-BIS(ETHYLENEKETAL) 95b To a  a solution of 1M  18.9  solution mmol)  quenched the  of  at  25  with  preparative (1.73 The  g,  1  The  the  6.3  mmol)  hydride  (in  aq.).  yield  After  chromatography  on  stirred  was  for  oil. The  silica-gel to  mL) was  (18.89  0.5  h,  ethyl  extracted  dried  (50  solution)  diluting with  aqueous layer  a brown  in benzene  benzene  solution was  ml, sat.  and  vacuo to  liquid  over M g S O „ ,  crude yield  product pure  ml,  then  acetate  with  was  added  (50  ethyl  acetate  filtered purified  aldehyde  mL)  and by  95b  66%).  max.  H-NMR  g,  combined organic layers were  physical properties  v  (25  3  separated  m.p. = 1 4 3 . 0 - 1 4 4 . 0 ° C IR  temperature.  NaHC0  in  (2.61  95a  diisobutylaluminum  mL). The  concentrated  nitrile  room  layers were  (5X,  the  are  95b  (Hexanes).  (CHCI ):  (400  of  3  MHz,  as follows:  [a]^ = - 1 0 . 7 ± 0 . 9 °  2937(C-H,stretch), CDCL )5:  1695(C = 0,stretch),  0.74(3H,S,C18-H),  3  2.00(1H,t,/=12,Cl7-H),  3.67-3.90(4H,m,C16-ketal),  ms m/z:  390,  418(f),  measurement:  403,  128,  calculated for  analysis: calculated for  C  2  5  C H  3  (1.3567,  5  2  8  125(C H 0 ), 7  5  H  0  5  3  :  8  0 : 5  C  9  2  H  2  2  cm" . 1  0.96(3H,S,C19-H), 3.93(4H,s,C3-ketal), 99(C H 0 ). 5  418.2719  71.74,  CH CI ).  7  2  1.03-1.92(9H,m), 9.71(1 H,m,C21-H).  High  resolution mass  and found: 418.2719.  9.15;  found: C  71.92,  Elemental H  9.27.  Experimental 4.10.  5/3-CARD-20(22)-ENOLIDE-3,16-DIOIME-3,3,16,16-BlS(ETHYLENEKETAL)  To  a suspension of  oil)  in dry THF (6  aldehyde  the  distilled  anhydrous and  ml)  (418  95b  ceased,  added,  potassium hydride  turbid  the  at  mg,  room  solution was  stirred  quenched with water (0.5 borohydride  (190  temperature,  the  mixture  concentrated  was  (200  ml)  (100  mL). The  separated to  yield  ml),  excess NaBH in  on the  2 h at  u  vacuo  to  a short  for  After  mg,  1.5  room  mmol)  The  ml)  ml,  then  mg,  mixture.  residue was 1M),  and  over  oil (970  mL)  reaction  30  using diethyl  The  (5  mL)  at  and  ml, sat.  crude  hydroxy  then  acetate  aq)  and  water  and  ether  ester  room the  product  ether/petroleum  17.0%) and the  was  min.  M g S O i , , filtered  mg).  was  sodium  After  (100  3  had  freshly  re-dissolved in ethyl  NaHC0  dried  a brown  (78  the  (5  then  in THF (2  temperature.  the  evolution  min,  d e c o m p o s e d with acetone The  to  15  suspension in  a solution of  hydrogen  another  66  98  22%  added  was  H C l (200  98  ml).  with methanol  silica-gel column  cardenolide  slowly  of  added  vacuo.  yield  mmol,  was  organic layers were  in  stirred (318  diluted  mg, 5 mmol)  and washed with  concentrated  for  1.22  was  in dry THF (6  R(-)-menthylglyoxylate  mixture  mg,  temperature  1mmol)  yellow  (224  /  was (2:3,  (147  99  v/v)  mg,  24%). The  physical properties  of  the  cardenolide  [a] ^ 2  98  m.p. = 9 4 . 0 - 9 5 . 0 ° C  (Hexanes).  2932(C-H,stretch),  1747(C = 0,stretch) c m " .  0.87(3H,c,Cl8-H),  0.97(3H,s,C19-H),  = -17.5°  as follows:  (1.2505,  1  3.72-3.95(4H,m,Cl6-ketal), ms m/z:  r  are  1  ethanol).  H-NMR  1.05-2.03(20H,m),  (400  IR  MHz,  7  9  2  99(C H 0 ). 5  7  2  High  resolution  calculated for  C  2  7  H  3  6  0 :  458.2970 and found: 458.2969.  calculated for  C  2  7  H  3  6  0 :  C  6  6  70.74,  H  8.30;  max.  (CHCU):  CDCL )6: 3  2.64(1H,s,C17-H),  3.93(4H,s,C3-ketal), 4.77(2H,d,/ = 2,C21-H),  458(M~t), 1 2 5 ( C H 0 ) ,  v  found: C  6.04(1H,s,C22-H). mass  measurement:  Elemental analysis:  70.98  H  8.49.  Experimental The  physical properties  m.p. = 1 9 7 . 0 - 1 9 8 . 0 ° C IR  1  1  H-NMR  =-11.3 + 0.7°  [a]^  3610, 3415(0-H,stretch),  3  cm" .  of the ester 99 are as follows:  (Heptane),  max. ( C H C I ) :  v  (400 M H z , C D C L ) 5 :  7  3  7  H  calculated for C  3  7  H  4.11.  5  5  1700(C = O,stretch)  9  0.80-2.10(29H,m),  4.20(1 H,dd,/=16,8,C21-H),  99(C H 0 ).  2  5  7  High  2  B  0  7  :  614.4196  and found: 614.4196.  8  0  7  :  C 72.32,  H 9.51; found: C 72.12,  6.19(1H,s,C22-H).  resolution mass  Elemental analysis: H 9.38.  17-METHYLENE-5/3-ANDROST-14-ENE-3,16-DIONE-3,3-ETHYLENEKETAL 85  A solution of lithium (9.07  mmol)  (CH CN/C0 3  solution  hexamethyldisilylamide  was prepared  of a solution of n-butyllithium  hexamethyldisilazane 2  (3.34 ml, 15.1 mmol)  bath),  excess of TMS-CI temperature. benzoquinone  After  ketone  (4.8 ml, 38 mmol)  (2.06 g, 9.07 mmol)  stirring for 1 h the resulting acetate  to a solution of  93 (2.60 g, 7.56 mmol)  and allowed  in C H C N 3  to warm  up to  room  2,3-dicyano-4,5-dichloro temperature.  After  to dryness, re-dissolved  (3X, 100 ml, 10% aq) and brine  dried over M g S O ,  foam. This crude  added to a  in dry THF (15 mL)  (150 mL) at room  NaOH  -40°C  was quenched with an  black solution was evaporated  and washed with  a brown  the reaction  added to a solution of  100 mL). The solution was then  in vacuo to yield  hexanes)  in dry THF (15 mL) at  15 min at - 4 0 ° C  This solution was then  in 200 ml ethyl  (1.6M,  by adding 5.67 ml  under Ar atmosphere. This solution was then  of the a,/3-unsaturated  under Ar atmosphere.  (2X,  2  4.78(1H,dt,/ = 4,10,C3'-H),  552, 476, 1 2 5 ( C H 0 ) ,  C  2  0.95(3H,s,C19-H),  3.72-3.97(8H,m,C3+ C16-ketals),  4.47(1H,S,C17-H), 4.48(1 H,dd,/= 16,8,C21-H'),  measurement:  CH CI ).  2950(C-H,stretch),  0.89(6H,t,/ = 6,C9'-H + C l O ' - H ) , 0.94(3H,s,C18-H), 2.28(1 H , U = 8 , C l 5 a - H ) ,  (2.26293,  0.75(3H,d,y= 8,C7'-H),  3  ms m/z: 614(MT),  / 67  t t  filtered  product was then  and concentrated purified o n a short  Experimental silica-gel column using ethyl  acetate/toluene  the  cross-conjugated diene  85  and  The  physical properties  85  are  of  1.48  g  (Hexanes).  [a]^  UV  (2.32x10*,  ethanol).  249  nm  1692(C16,C = 0,stretch), 1  H-NMR  (400  MHz,  1647,  ms m/z:  342(M"t),  5  =+221 + 6° IR  9  2  5  for  C  2  2  H  3  0  O  3  :  342.2194  and  calculated  for  C  2  2  H  3  0  O  3  :  C  H  (34%)  of  substrate.  77.21,  CH CI ). 2  (KBr):  2  292KC-H,stretch),  1  1 .26(3H,S,C1 9-H),  5.21(1H,s,Cl5-H),  7  High  2  found: 8.83;  5.95(2H,s,C20-H).  resolution  342.2197.  1.32-2.06(16H,m),  mass  measurement:  Elemental analysis:  found: C 76.92,  H  8.72.  17-CYANOMETHYL-5j3-ANDROST-14-ENE-3,16-D!ONE-3,3-ETHYLENEKETAL 86a  A solution prepared of  mg  cm" .  99(C H 0 ).  calculated  4.12.  max.  v  3.93(4H,s,C3-ketal),  125(C H 0 ),  87.6  recovered  (0.2320,  1 .07(3H,C,C1 8-H),  3  7  of  l599(C = C,stretch)  CDCL )S:  2.46(1H,dt,y = 4,10,Cl8/3-H),  (57%)  to yield  68  as follows:  m.p. = 1 4 5 . 5 - 1 4 6 . 0 ° C Xmax.:  (5:95, v/v)  /  of  at  the  room  a solution  of  diethylaluminum about  30  orange  (100  mL)  over  MgSO ,  product  a light reaction  color to  was  (1:4,  v/v)  to  C17  epimers.  yield  130  mmol)  this was  cyanide  (1M,  solution turned  was  and on  360  (2X,  concentrated a short  mg  (75%)  C L C analysis of  toluene).  50 in  for  NaOH  (2  was ml,  then 10%  vacuo to  silica-gel column of  the  this mixture  orange  and  min  ml,  10%  diluted  (1.30 of  at aq.)  (2X,  yield a white  mmol)  the (in  room which  with ethyl  brine  50  caused  acetate mL),  foam. This  dried crude  acetate/hexanes  nitrile 86a  showed that the  ml  was  quickly faded  using ethyl  unsaturated  mL)  addition  30  aq.),  (12  1.30  Upon  stirring  quenched with  NaOH  in dry benzene  quickly added  deep  color. After  disappear. This mixture  filtered purified  mg,  and to  orange  and washed with t t  (443  temperature  cyanide the  the  the  85  diethylaluminum  sec) to  temperature,  diene  ratio  as a mixture of  of  isomers was  Experimental / 69 about was  2:1. Repeated  only  isomer could  partially  attempts  successful.  enough that be detected  The  physical properties  (9.64x10 , 3  of the nitrile  (Hexanes).  ethanol).  1  H-NMR  3.93(4H,s,C3-ketal),  found:  resolution 369.2298.  IR  v  2944,  CDCL )5:  1  in the  major  H-NMR  (but  given here  are for  2874(C-H,stretch),  3  2360,  c m " . U V ymax.: 1  233nm  1.05(3H,C,C18-H),  2.26(1H,q,/=18,16,C20-H).  2.49(1 H,m,C8/3-H),  mass measurement:  The data  1605(C = C,stretch)  (400 M H z ,  5.80(1 H,s,C15-H).  by  chromatography  86 are as follows:  max. (KBr):  0.83-2.35(17H,m),  2.45(1 H,dd,y=16,4,C17-H),  High  isomer could not be detected  1703(C = O,stretch),  1.24(3H,s,C19-H),  isomers by column  by capillary gas chromatography).  mixture.  2342(CN,stretch),  these  It was possible to enrich the mixture  the minor  this  m.p. = 5 4 . 0 - 5 5 . 0 ° C  to separate  2.92(1 H,dd,/=18,4,C20-H'),  ms m/z: 3 6 9 ( M ) , +  calculated  for C  2  3  H  125(C H 0 ), 7  3  1  0  3  N :  9  2  99(C H 0 ). 5  369.2292 and  7  2  5. REFERENCES 1.  W.J. Leyten Thujone"  2.  3.  4.  "Synthesis of Some  juvenile  J.P. Kutney,  J. Balsevich, R. Carruthers,  and  B.R. Worth.  M.J.  McCrath,  Bioorganic Chemistry,  A. Markus,  Analogues From  R.N. Young, and B.R. Worth.  M.K. Choudhury, J.M. Decesare,  B.R. Worth.  Can. J. 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