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UBC Theses and Dissertations

An aspect of pyrone chemistry Webster, Godfrey Robin Barrie 1965

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AN ASPECT OP PIRONE CHEMISTRY  by  GODFREY ROBIN BARRIE WEBSTER ' B.Sc  University  of B r i t i s h Columbia  1963  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OP SCIENCE  i n the  Department of  Chemistry  We accept t h i s t h e s i s as conforming required  to  standard  THE UNIVERSITY OF BRITISH COLUMBIA September  1965  the  In p r e s e n t i n g the  fulfilment  of  requirements f o r an advanced degree at the U n i v e r s i t y  of  British  Columbia,  available  this  thesis  I agree that  in p a r t i a l  the L i b r a r y s h a l l  f o r r e f e r e n c e and study,  I f u r t h e r agree that  m i s s i o n f o r e x t e n s i v e copying o f t h i s purposes may be granted his  representatives,,  cation of t h i s  thesis  without my w r i t t e n  Department of  thesis  for  freely per-  scholarly  by the Head o f my Department o r by  It  i s understood that copying o r p u b l i -  for financial  gain shall  permission.  CfjgM I  The U n i v e r s i t y o f B r i t i s h Vancouver 8, Canada Date  make i t  JT^X  Columbia  Je^t&**U^  f^bi'  not be allowed  ii.  ABSTRACT Since 1893,  acetate has been regarded as a very important  p r e c u r s o r of n a t u r a l l y o c c u r r i n g phenolic compounds. intensive  work has been d i r e c t e d at the complete  this biogenetic  pathway,  a satisfactory  i n the acetate scheme.  e l u c i d a t i o n of  method has y e t  devised f o r the synthesis of the p o l y k e t i d e intermediates  Although  to be  chains proposed as  L a b e l l i n g s t u d i e s with such  compounds would provide information r e g a r d i n g t h e i r r o l e i n the acetate route to aromatic compounds. to synthesize these extended poly-|3-ketone  intermediate  E f f o r t s to  date  chains have been un-  successful. Polypyrones, to o f f e r  a feasible  containing potential polyketide chains, solution.  Synthesis  f u s i n g successive C^ u n i t s to t r i a c e t i c and by t h i s method,, b i s - , constructed.  tris-,  appeared  of these compounds by lactone proved  successful,  and tetrapyrone systems were  Basic h y d r o l y s i s of these fused pyrone systems,  followed by i n t r a m o l e c u l a r a l d o l condensation,  demonstrated  that  n a t u r a l l y o c c u r r i n g phenolic compounds could be synthesized by the c y c l i z a t i o n of a p o l y k e t i d e  intermediate.  iii.  TABLE OF CONTENTS  Introduction . . . . . .  Discussion  1  . . . . .  53  Experimental  Bibliography . . . . . . . .  21  •»  77  iv.  LIST OP TABLES  Table I  Attempts to Synthesize Bispyrone  . . . .  34  . . .  38  Table I I  Attempts to Synthesize Trispyrone  Table I I I S p e c t r a l Tables  74  LIST OP FIGURES  Figure  II  FxgUI*©  XXX*  Figure  IV  11  Figure  V  13  Figure  7 • e « «• • • e e o 0 c . «  VI . . . .  « o ••  .  3  16  Figure  VII  19  Figure  VIII  24  Figure  IX  Figure  X  28  Figure  XII .  44  Figure  . . . . . . . .  25  XIII  46  XV  50  Fi Figure  vi.  A CKN 0 ¥LEDGMEN T  I would and P r o f e s s o r  like  t o e x p r e s s my  gratitude  A. I . S c o t t f o r c o n t i n u e d  and i n s p i r a t i o n  during  also  H. H a n n i f o r t e c h n i c a l  due t o Mr.  to Dr. T. Money  guidance,  t h e c o u r s e o f t h i s work.  forbearance Thanks a r e  assistance.  " The attempt to  artificially  produce n a t u r a l l y o c c u r r i n g substances and to i m i t a t e  i n the l a b o r a t o r y some of  the many processes which are  perpetually  being c a r r i e d on around us i n n a t u r e , always been one of the c h i e f organic  aims of  has the  chemist . . . " J.  Norman C o l l i e ,  1893.  INTRODUCTION  In recent y e a r s , i n t e n s i v e i n v e s t i g a t i o n has been d i r e c t e d at the e l u c i d a t i o n of b i o s y n t h e t i c pathways to n a t u r a l products,, This work has l e d to the d i s c o v e r y t h a t many c l a s s e s of n a t u r a l l y o c c u r r i n g compounds are d e r i v e d from simple s t r u c t u r a l u n i t s .  Prom  t h i s d i s c o v e r y , s e v e r a l b i o g e n e t i c r u l e s have been formulated which c o n s i d e r a b l y s i m p l i f y the task of the n a t u r a l product they i n d i c a t e p r e v i o u s l y undetected of substances;  chemists  r e l a t i o n s h i p s between c l a s s e s  they l i m i t the number of p o s s i b l e formulas  i n struct-  u r a l s t u d i e s ; they very o f t e n serve as a guide to elegant l a b o r a t o r y syntheses;  and they a s s i s t the biochemical approach by p o i n t i n g  to l i k e l y l i n e s of i n v e s t i g a t i o n . Long before i t became p o s s i b l e to f o l l o w b i o s y n t h e t i c processes with p r e c i s i o n , attempts were made to determine something of t h e i r nature p u r e l y from s t r u c t u r a l r e g u l a r i t i e s w i t h i n , and resemblances between, groups of n a t u r a l products.  Such consider-  a t i o n s l e d Ruzicka^" to propose the isoprene r u l e s t a t i n g that t e r penoids  are formed by h e a d - t o - t a i l condensation  of isoprene u n i t s .  2  The hypothesis, which was enlarged by Robinson , has stimulated a great deal of r e s e a r c h i n t h i s f i e l d . i c a n c e of the acetate d e r i v e d mevalonic  The d i s c o v e r y of the s i g n i f a c i d ( l ) marked a milestone  i n the h i s t o r y of the t e r p e n o i d f i e l d . . Mevalonic  a c i d has only one  3 biochemical r o l e , that of t e r p e n o i d p r e c u r s o r . .  Phosphorylation  converts i t to the A - i s o p e n t e n y l pyrophosphate ( 2 ) intermediate (the a c t i v e s y n t h e t i c u n i t ) , which forms, by the appropriate number of h e a d - t o - t a i l condensations, (C-J^Q, ^159 ^20 ^30 9  9  ^40' ^ °)« E  C  a s e r i e s of f a m i l i e s of terpenoids  2.  OH 3 CH COOH  CH CHk0H  CH-C  3  J  o  i  z  CH C00H  z  2  C = CH CH 0 PP  TERPENOIDS  2  CH,  Robinson or  shikimic  such  introduced another (3)  acid  as aromatic  pathway,  amino  acids  (e.g. 4),  (e.g. 6),  anthocyanins  sstilbenes  (e.g. 9),  lignanes  by elegant  biochemical  concept,  the  leading to the formation  flavonoids  forced  useful  indole  ( e . g . 7),  ( e . g . 10),  and l i g n i n ^ ,  investigation  of  alkaloids  coumarins  such  carbohydrate compounds  ( e . g . 5),  (e.g. 8), a route  as t h a t  of  rein-  Davis  5 and  Sprinson  and t h e i r  collaborators.  COOH CM,  HO' (3)  MH  OH  shikimic  C H C O O H  (4)  acid  phenylalanine  CH.CH C O O H 1  H O (5)  tryptamine  (6)  O H  5 , 7 - d i h y d r o x y f l avone  3.  OG,H„05  OC HA fc  (7)  (8)  cyanin  coumarin  OH  w OH (9)  pinosylvin  CH3O  -a OH OCH(lO)  pinoresinol  4.  Aromatic compounds d e r i v e d from shikimic a c i d are e a s i l y guishable from those d e r i v e d from polyacetate of the oxygen s u b s t i t u t i o n p a t t e r n on the J u s t as terpenoids head-to-tail  distin-  condensation because  ring.  can be considered to be constructed by  l i n k a g e s between isoprene u n i t s ,  so can many phenolic  compounds be shown to r e s u l t from l i n k i n g between acetate u n i t s ranged i n a chain and subsequently modified by r e a c t i o n s ring closure,  reduction, C - a c y l a t i o n , dehydration, methylation,  and o x i d a t i o n . to-tail  such as  C o l l i e ^ ' ^ was the f i r s t to suggest that the head-  condensation of acetate u n i t s was i n v o l v e d i n the b i o s y n -  t h e s i s of many n a t u r a l l y o c c u r r i n g phenolic compounds. the c y c l i z a t i o n s  and condensations  of synthetic  He studied  poly-P-ketones,  and was struck by the resemblance of some of the products to natural products.  Thus, as e a r l y as 1893,  C o l l i e made the r a t h e r  astounding proposal that i t might be p o s s i b l e chemical r e a c t i o n s  on the b a s i s of l a b o r a t o r y  C o l l i e ' s acetate hypothesis years.  certain  to e x p l a i n b i o analogies.  l a y dormant for almost  fifty  I t was not u n t i l several years a f t e r B i r c h had. proposed an  essentially brought to  i d e n t i c a l hypothesis 5  that C o l l i e ' s work was again  light., g  Birch synthesis,  considered what might happen i n a f a t t y a c i d type  proceeding v i a h e a d - t o - t a i l  the (3-oxygen atoms,  the residues  linkage of acetate u n i t s ,  of the a c e t i c  groups, were not s e r i a l l y reduced out.  if  a c i d carboxyl  He and h i s colleagues had  n o t i c e d that the oxygen s u b s t i t u t i o n p a t t e r n i n many n a t u r a l l y o c c u r r i n g phenolic compounds corresponded to that expected i f  these  5. compounds were d e r i v e d i n such a f a s h i o n .  A c e t i c a c i d u n i t s had  a l r e a d y been e s t a b l i s h e d as b u i l d i n g u n i t s i n f a t t y a c i d s and steroids. Poly-p-ketones r i n g compounds.  can be shown to l e a d to many n a t u r a l l y occur-  F i g u r e I shows a schematic r e p r e s e n t a t i o n of  condensations of these p o l y - P - k e t o n e s l e a d i n g to p h l o r o g l u c i n o l s , o r c i n o l s , and pyrones, which form the b a s i s of a l a r g e number of n a t u r a l products.  Thus, we see that, given a poly-P-ketone;.  chain ( l l ) , condensation, proceeding through C - a l k y l a t i o n or O-alkylation to  , leads v i a path ( a ) , a C l a i s e n - t y p e condensation,  a c y l p h l o r o g l u c i n o l s (12); v i a path (b) to a-pyrones (13); v i a  path ( c ) , an a l d o l condensation, to compounds of the o r s e l l i n i c a c i d f a m i l y (14); and v i a path (d) (with t e r m i n a l d e c a r b o x y l a t i o n ) to Y-pyrones (15).  I f one of the carbonyl groups not i n v o l v e d i n  c y c l i z a t i o n were reduced to a hydroxyl group,  r i n g c l o s u r e through  C - a l k y l a t i o n would be accompanied by dehydration.  The products  from p o l y - 3 - k e t o n e m o d i f i e d i n t h i s way, f o l l o w i n g paths (c)  (a) and  above, would l e a d to compounds o f the a c y l r e s o r c i n o l type (16)  and the 6-methyl s a l i c y l i c  a c i d type (17) r e s p e c t i v e l y , F i g u r e I I .  I t i s known t h a t these types of condensations occur i n nature; indeed, two or more co-occur i n some i n s t a n c e s .  For example  many pine heartwoods c o n t a i n , i n a s s o c i a t i o n , compounds such as p i n o s y l v i n (9) and 5,7-dihydroxyf lavone((6). of  The b a s i c carbon s k e l e t o n  each could be c o n s t r u c t e d ( F i g u r e I I I ) from the same p r e c u r s o r  (18)** i f the p o l y - P - k e t o n e chain s t a r t e d from cinnamic a c i d a b l y as the coenzyme-A e s t e r ) .  The involvement  (presum-  of cinnamic a c i d i n the  Figure  I  Figure  II  (c)  / /  /  /  (a)'  (c)  /  \  o •O H  (17)  8. Figure III  9o  b i o s y n t h e s i s of these compounds has been confirmed by  tracer  - experiments. Tangonin ( 1 9 )  and i t s  analogues could be d e r i v e d i n a  s i m i l a r fashion by a v a r i a t i o n of  the flavone  condensation  CW30( 1 9 )  which leads to c y c l i z a t i o n carbon atoms to The f i r s t  to oxygen,  since there are  insufficient  complete an o r d i n a r y carbon 6-membered r i n g . s t r i k i n g confirmation  of  the  c o r r e c t n e s s of r  9  a c e t a t e hypothesis was B i r c h ' s work demonstrating  the i  14  that [ 1 -  CJ  a c e t i c a c i d was i n c o r p o r a t e d by P e n i c i l l i u m griseofulyum  Dierckx  into 6-methyl s a l i c y l i c  label  shown i n  a c i d to give the d i s t r i b u t i o n of  (20).  KL  CM3COOH  COOH  lOo  I t has of  s i n c e been shown, u s i n g t r a c e r methods, t h a t a number  rather diverse structures arise  griseofulvin  (21)  O  ?  alternariol  OCH  by  t h i s route i n c l u d i n g  ( 2 2 ) , and  citromycetin  (23).  3  HO\ — /  Ci (22)  (21)  X  HOOC  Cl CH:  (23) r  Griseofulvin, was  the  thetic is  which i s formed from  s u b j e c t o f one investigation.  of the The  In the  diagram,  assumed to r e p r e s e n t atoms, and degradation  on  the  CJ  examples o f a c e t a t e  labelled  expected t o t a l of  closely  r e c e n t l y confirmed  given  biosyn-  i n Figure  seven l a b e l l e d  corresponding  activities  of  f o l l o w the p r e d i c t e d v a l u e s .  t h i s work by u s i n g  IV  atoms i n p h e n o l i c  r  has  acetate units  the r a d i o a c t i v i t y o f g r i s e o f u l v i n  t h i s b a s i s , the  products  -  method o f d e g r a d a t i o n  a g e n e r a l method f o r i d e n t i f y i n g  nuclei"^.  seven [ 1  finest  i  14  [2 -  14  carbon the Rickards  i  CJ  is  acetate.  11. F i g u r e IV  C H  3  O  o  9 ^ CI  =0  7 CH COOH 3  (21)  OH"  I  OCM, -COOH CH3O  ^ 0 cs  -OH  u  4.05'  2.93' HNO,  C 0  OCH,  2  HO^  v  BaC0  ,L .Ol•NO,  NO,  3  ' 3  NO,  I  1.04"  CH  3  2.94° NaOBr 3BaC0 < 3  3C0 -*~  3Br CN0  2  3  2  2C0, (c +c )  0.01*  3  (c  2 +  c  4 +  c ) 6  2BrC0, 0.97'  5  12. From the beginning, of work on the acetate hypothesis,  it  was necessary to assume that almost any organic a c i d found i n Nature (presumably as i t s initiate  a polyacetate  an a c e t y l acids,  coenzyme-A ester) might  chain by condensing with the methyl end of  coenzyme-A u n i t .  Among such acids are v a r i o u s  branched chain a c i d s ,  nicotinic  conceivably  cinnamic a c i d (as mentioned  a c i d , and p o s s i b l y glutamic a c i d .  fatty above),  5  The number of a c e t i c a c i d u n i t s which w i l l condense headto-tail  i n such a chain v a r i e s from one to eight or more, but  with the exception that other a c i d s  of p r o p i o n i c a c i d , there i s no c l e a r  can be i n v o l v e d i n chain b u i l d i n g as  from , chain i n i t i a t i o n .  I t has been shown, however,  evidence  distinct  that  the  a c e t i c a c i d u n i t i n v o l v e d i n chain b u i l d i n g i s  first  malonyl coenzyme-A, by c a r b o x y l a t i o n of a c e t y l  coenzyme-A.^"!'  c o n s t r u c t i o n of poly-P-ketone  converted  to The  chains may then be summarized as  shown i n F i g u r e V. Several r a c t i o n s are a v a i l a b l e whereby the are modified from simple poly-p-ketone of a carbonyl i s  cyclization.  a poly-P-ketone intermediate  (24)  end products The r e d u c t i o n  leads to^the removal  (25)  13.  of the oxygen from the r i n g on aromatization by dehydration.  The  l i k e l i h o o d t h a t such routes are c o r r e c t i s i n c r e a s e d by the n a t u r a l occurrence  of compounds such as f l a v o s k y r i n (24) .  This',- or the  anthrone 'precursor,;, could very l i k e l y aromatize. to -' chrysophanol 1  Figure V  CQ  2  CH COSCoA  >  3  b i o t i n etc.  H-0. R - CO  f  R»  R»  C0 H 2  ^  CsCoA  R'  I  >  2  H-0 CH - CO  CsCoA  CH C0SCoA  l  CH - CO R»  SCoA  B' I  R - CO - CH - CO - CH - CO - CH . . . C0 H 2  59-  p h e n o l i c compounds, pyrones,  macrolide  R = CH , CH CH -, 3  R» = H, CH  2  3  only.  antibiotics  NH COCH , PhCH = CH; 2  2  (25).  14.  The i n t r o d u c t i o n of oxygen i n t o organic molecules w e l l known p r o c e s s ,  and operates i n phenolic compounds by i n t r o -  d u c t i o n of oxygen at ortho or para p o s i t i o n s oxidative  cleavage r e a c t i o n s  acid  on t h e . ' r i n g .  Several  of r i n g s are also becoming apparent  and i t i s known that p e n i c i l l i c a c i d (26) a c i d (27)  is a  and that p a t u l i n (28)  comes from o r s e l l i n i c  i s derived from 6-methyl  salicylic  (29). Structure analysis  shows that  and C,_ u n i t s are i n t r o -  duced by d i r e c t biochemical attachment at carbon i n .'addition to the w e l l known r e a c t i o n s  on oxygen,  nitrogen,  the biochemical p r e c u r s o r s of these groups are other members of the C-^ pool)  and sulfur;,  That  methionine,(or  and the terpenoid p r e c u r s o r s has  been proved by t r a c e r experiments.  Further work has shown that  these carbon groups are most l i k e l y added at the poly-{3-ketone intermediate  stage.  5  C o l l i e was the f i r s t  to propose the biochemical  cance of poly-P-ketone c h a i n s .  7  He discovered  12  signifi-  that dehydro-  13 acetic  a c i d (30)  , which he recognized as a condensed poly-j3-  ketone  (although he d i d not a s s i g n i t the c o r r e c t  structure),  formed the n a t u r a l l y o c c u r r i n g compound o r c i n o l (31') with weak base. 2,4,6-trione  In a s i m i l a r experiment,  (diacetyl  acetone)  (32),  he found that  (33).  heptane  a w e l l known poly-P-ketone,  which he had prepared from dehydroacetic a c i d (30), with a second molecule of (32)  on treatment  to form a naphthalene  condensed derivative  This r e a c t i o n also y i e l d e d a small q u a n t i t y of o r c i n o l .  (See F i g u r e VI)  -O  OCH (26)  5  16. F i g u r e VI  14  B i r c h and h i s co-workers  re-examined  along with B e t h e l l and M a i t l a n d  positively  condensation  products.  the naphthalene  (34).  identified  the  They agreed with C o l l i e ' s s t r u c t u r e  compound ( 33),  r i n g intermediate.  C o l l i e ' s work, and  for  but disagree with h i s proposed mono-  C o l l i e h e l d the benzenoid intermediate  to be  The modern workers pointed out the i m p r o b a b i l i t y of  this  s t r u c t u r e because i t would i n v o l v e r e a c t i o n of a carbonyl group with the anion from -CO-CH^ i n preference  to the e q u a l l y a v a i l -  able but more r e a d i l y formed anion from -CO-CH^-CO-. 1  counter with s t r u c t u r e chemical and s p e c t r a l  (35)  which condenses to  evidence to prove  Although heptane 2 , 4 , 6 - t r i o n e i s  (33)  They and present  it. a poly--|3-ketone,  it  differs  from those which f i t  phenols  i n t h a t both ends of the chain are "blocked" by methyl  groups; i . e . ,  i n t o the b i o g e n e t i c scheme l e a d i n g  both ends are " s t a r t i n g ends" f o r a c h a i n .  p-ketone chain of the type u s e f u l must have one end f r e e had  as a b i o s y n t h e t i c  to form a coenzyme-A e s t e r .  obtained a l i m i t e d y i e l d of o r c i n o l (3l)  heptane 2 , 4 , 6 - t r i o n e  to  A poly-  intermediate Still,  Collie  from condensation  of  (32).  B i r c h ' s attempted b i o g e n e t i c type synthesis of p i n o s y l v i n  (9)14 i s the only attempt i n recent times to synthesize a n a t u r a l product u s i n g a p o l y k e t i d e  chain.  OH  \ (9)  OH  18,  By Knoevenagel condensation of benzaldehyde with dehydroacetic a c i d (30);, he obtained the b e n z i l i d e n e d e r i v a t i v e (36).  Acid  h y d r o l y s i s followed by d e c a r b o x y l a t i o n y i e l d e d the pyrone which y i e l d e d the t r i o n e (38)  by way of i t s barium s a l t .  a l i n e h y d r o l y s i s of each of these compounds (36,  37,  (37) Alk-  38)  gave  r e a c t i o n mixtures i n which paper chromatography r e v e a l e d no i n d i c a t i o n of p i n o s y l v i n . B i r c h then attempted to condense the hydrogenated t r i o n e (39)  under a l k a l i n e c o n d i t i o n s to o b t a i n d i h y d r o p i n o s y l v i n (40)  i n a c l o s e r analogy to C o l l i e ' s conversion of heptane (32)  to o r c i n o l ( 3 l ) .  Both the t r i o n e (39)  pyrone c y c l i z e d to d i h y d r o p i n o s y l v i n (40). was also i s o l a t e d and i d e n t i f i e d as ( 4 l ) , 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.  and the corresponding A second component,  produced by the  alter-  A t h i r d component,  detected by paper chromatography, was t e n t a t i v e l y naphthalene d e r i v a t i v e analogous to (42).  2,4,6-trione  i d e n t i f i e d as a  This work i s summarized  i n Figure V I I . The highest members of the poly-P-ketone s e r i e s known at time were d i f o r m y l acetone (43), acetone (44),  heptane  and 3,5-dioxohexanoic  o o o (43)  0 o (44)  acid  2,4,6-trione  (32),  (45).  o o o (32)  o o o (45)  this  formyl  Figure V I I  20, 16 B i r c h and h i s c o l l e a g u e s , ' " thus, ketones longer than these. of cyclohexa-1,4-dienes added the o z o n o l y s i s  set out to synthesize  He had already shown that  l e d to (3-diketones.  poly-|3ozonolysis  To t h i s method he  of 4,7-dihydroindan-2-one d e r i v a t i v e s .  The  products produced by these pathways were red o i l s which decomposed soon a f t e r i s o l a t i o n . from the pentaketone  Attempts to prepare c r y s t a l l i n e (46)  f a i l e d although the k e t a l  (47)  derivatives was  isolated.  o o o o o (46)  (47) Thus, u n t i l  the beginning of our work poly-P-ketone chains  c o n t a i n i n g greater than three carbonyl groups had not been synthesized,  and the longest p o l y k e t i d e chain known with a terminal  carboxyl group was 3,5-dioxohexanoic  acid,^  21.  DISCUSSION The study of the s t r u c t u r e , s y n t h e s i s ,  b i o s y n t h e s i s , and  chemical p r o p e r t i e s of n a t u r a l products has r e s u l t e d i n important and f a r - r e a c h i n g c o n t r i b u t i o n s to the development of organic chemistry.  N a t u r a l products are a l s o of immense importance i n the  pharmaceutical i n d u s t r y and are e x t e n s i v e l y used as chemotherapeutic agents. Various b i o s y n t h e t i c proposals have been made to account f o r the formation of a wide v a r i e t y of n a t u r a l p r o d u c t s , and i n many cases,  experimental c o n f i r m a t i o n of these b i o s y n t h e t i c  has been o b t a i n e d . biosynthesis  The e f f i c i e n c y and e s s e n t i a l  routes  s i m p l i c i t y of the  of s t r u c t u r a l l y complex n a t u r a l products has r e s u l t e d  i n attempts to d u p l i c a t e these processes term " b i o g e n e t i c - t y p e  i n the l a b o r a t o r y .  The  synthesis" has thus been a p p l i e d to those  syntheses which f o l l o w c l o s e l y the presumed or known b i o s y n t h e t i c route,  Robinson's c e l e b r a t e d tropinone synthesis may be quoted  as the f i r s t s u c c e s s f u l l a b o r a t o r y synthesis time,  a p p l i c a t i o n of b i o s y n t h e t i c ideas to  of complex n a t u r a l p r o d u c t s .  the  Since that  and e s p e c i a l l y w i t h i n the past decade, many syntheses have i  been announced which are e q u a l l y s t r i k i n g and have provided simple s y n t h e t i c routes to complex n a t u r a l p r o d u c t s . account of recent work i n t h i s f i e l d ,  For a more complete  see the review by Van Tamelen.  In t h i s work, we have set out to develop a new b i o g e n e t i c type synthesis  of n a t u r a l l y o c c u r r i n g phenolic compounds.  I t can  be seen from i n f o r m a t i o n presented i n the i n t r o d u c t i o n that present  22. evidence  supports the acetate o r i g i n of many phenolic n a t u r a l  products and s t r o n g l y i n d i c a t e s  the intermediacy of a poly-|3-  k e t o a c i d d e r i v a t i v e i n the b i o g e n e t i c  pathway.  As y e t ,  however,  there i s no d i r e c t proof of the existence of such an i n t e r m e d i a t e . Efforts  to synthesize p o l y - P - k e t o a c i d chains i n v i t r o have so f a r 18  f a i l e d except f o r the work of W i t t e r and Stotz 3 5-dioxohexanoic s  acid (triacetic  heptane 2 , 4 , 6 - t r i o n e  (32)  acid)  (45).  who  synthesized  This compound and  were the longest p o l y k e t i d e chains known  at t h a t time." "^ 1  6 An examination of work done over seventy years ago by C o l l i e ' provided a clue to the s o l u t i o n of t h i s problem.  When C o l l i e  synthesized  (30),  o r c i n o l (31)  from dehydroacetic  acid  HO.  O H  (30)  (31)  he showed that a n a t u r a l l y o c c u r r i n g phenol could be sythesized  from  7 an a - p y r o n e  e  During h i s work, C o l l i e  acid a c y c l i z e d polyacetate  recognized i n  chain and p o s t u l a t e d  dehydroacetic  that h i s  synthesis  of o r c i n o l somewhat resembled the pathway followed i n Nature. p e r c e i v e d that a p o l y a c e t a t e  chain could be c y c l i z e d to an a-pyrone,  then h y d r o l y z e d , r e g e n e r a t i n g an a c t i v e polyacetate could subsequently o c c u r r i n g phenol.  He  chain which  undergo a l d o l condensation to y i e l d a n a t u r a l l y  23. An cx-pyrone r i n g system such as that i n dehydroacetic (30)  and i n t r i a c e t i c lactone  (48)  provides a c y c l i z e d form of  two longest s t r a i g h t chain p o l y k e t i d e s known, a c i d (45)  and heptane 2 , 4 , 6 - t r i o n e  acid  (32)  the  3,5-dioxohexanoic  mentioned above,,  OH O  O  O  (48)  ( 4 5 )  O  H O  O  C H ^ ^  O  O  -  2>  ^  C  ^  (32)  (30)  These s t r a i g h t chain compounds are r e l a t i v e l y easy to prepare and are r e l a t i v e l y s t a b l e  following i s o l a t i o n .  by previous workers, and t h e o r e t i c a l  Difficulties  considerations  conclude t h a t longer poly-P-ketone chains would be difficult  to prepare and i s o l a t e .  system o f f e r e d a p o s s i b l e  f o r c e d us to exceedingly  The expansion of an cx-pyrone  s o l u t i o n to the d i f f i c u l t i e s  involved i n  s y n t h e s i z i n g and i s o l a t i n g these more complex polyacetate One way i n which t h i s  R  systems.  could be achieved was considered! i t  thought that c o n s t r u c t i o n of the bispyrone (49) with a p o t e n t i a l C  encountered  p o l y k e t i d e chain (see  would present us  Figure V I I I ) .  was  24.  F i g u r e VIII  o  0  C O O H  OH  CHC^O (49)  This would r e q u i r e f u s i o n of a second pyrone r i n g to lactone  triacetic  (48). The s y n t h e s i s of polypyrones through f u s i o n of a d d i t i o n a l  a-pyrone r i n g s to an i n i t i a l a-pyrone r e q u i r e s the condensation of the a-pyrone with a s u i t a b l e malonic a c i d .  species such as a d e r i v a t i v e of  Each malonate u n i t added to the i n i t i a l r i n g  rep-  resents an a d d i t i o n a l acetate u n i t i n the p o t e n t i a l p o l y k e t i d e so c o n s t r u c t e d ,  and i s  By simple extension, of p o t e n t i a l  chain  i n c o r p o r a t e d as p a r t of a new a-pyrone r i n g .  this  polyketides  approach could be used f o r the  synthesis  of v a r y i n g l e n g t h .  Polypyrones had been a l r e a d y synthesized by at l e a s t two 19 methods.  Z i e g l e r and h i s coworkers  formed members of an aromatic  based polypyrone s e r i e s (Figure IX) i n an e s s e n t i a l l y manner, by condensing 4-hydroxycoumarin (50)  uncontrolled  with carbon s u b o x i d e ( C - 0 ) . 9  25.  F i g u r e IX  26. This work provided a route to polypyrones, but i n v o l v e d  difficulties  i n the p r e p a r a t i o n of carbon suboxide ( p y r o l y s i s of d i a c e t y l t a r t a r i c 20 anhydride at 600 ), In a d d i t i o n , carbon suboxide b o i l s at 7 and 0  is  therefore  a gas at room temperature.  These f a c t s coupled with  the observation by Z i e g l e r t h a t the r e a c t i o n could not be c o n t r o l l e d easily  to y i e l d d i s c r e t e polypyrones,  pyrones to be regarded with reserved  caused t h i s pathway to p o l y enthusiasm.  21 Yoods et a l .  developed,  i n c o n t r a s t to the work of Z i e g l e r ,  a method whereby d i s c r e t e malonate u n i t s could be fused to the cxpyrone r i n g of 4-hydroxycoumarin. bispyrone (5l)  They synthesized  the aromatic  by r e a c t i n g 4-hydroxycoumarin (-50) with  a c i d i n t r i f l u o r o a c e t i c a c i d (TFA).  (50)  (51)  cyanoacetic  27. Both cyanoacetic  a c i d and t r i f l u o r o a c e t i c  a c i d are commercially  a v a i l a b l e and can be used conveniently i n the l a b o r a t o r y without special  equipment. That polypyrone systems can be synthesized with an a l i -  p h a t i c group at C-6 on the i n i t i a l a-pyrone r i n g was  demonstrated  19 by Z i e g l e r  when he synthesized  the tetrahydrocoumarin (52) carbon  the polypyrone s e r i e s based on  by r e a c t i o n of cyclohexanone  with  suboxide.  OH  (52)  As b e f o r e ,  he was not able to c o n t r o l the r e a c t i o n s u f f i c i e n t l y  obtain d i s c r e t e triacetic  polypyrones i n h i s r e a c t i o n product.  lactone  (48)  had a methyl group ( a l i p h a t i c )  However,  to since  at C - 6 ,  Z i e g l e r ' s work provided a stepping stone between the work of Woods 2  et a l . , i n which aromatic s u b s t i t u t e d polypyrones were  synthesized,  and the p u r e l y p o l y k e t i d e d e r i v e d polypyrones l i k e bispyrone and higher members of t h i s  series.  To complete our proposed b i o g e n e t i c pounds,  (49)  pathway to phenolic com-  the polypyrones must be hydrolyzed to s t r a i g h t chain i n t e r -  mediates (Figure X) which can undergo i n t r a m o l e c u l a r a l d o l conden22 sation. Edwards et a l . hydrolyzed the s t y r y l pyrone t r i - O - m e t h y l -  28  a  Figure X  o cr  O H  h i s p i d i n (52)  o  CH^""'"  o OM  with N e t h a n o l i c potassium hydroxide, and obtained  potassium s a l t of the s t y r y l p o l y - p - k e t o a c i d (53). this  '  o  An approach of  s o r t was considered to provide a method f o r the opening of our  polypyrones.  C y c l i z a t i o n to form phenolic compounds might then proceed spontan-r eously,  since the c o n d i t i o n s used to hydrolyze the polypyrone r i n g  systems are also those which would promote i n t r a m o l e c u l a r a l d o l condensation.  29  I t must b e p o i n t e d o u t t h a t , a l t h o u g h p o l y p y r o n e s rather ingenious ketideSj,  units  chain,  provide a  to the problem of i s o l a t i o n s t a b l e p o l y -  t h e y do n o t r e t a i n  the s t r i c t b i o g e n e t i c c h a r a c t e r  Triacetic  which c y c l i z e without d e s t r o y i n g the b i o g e n e t i c  char-  j u s t as p o l y - P - k e t o a c i d malonate u n i t s ,  F u r t h e r p y r o n e r i n g s a r e b u i l t up,  c h a i n s a r e b u i l t up, b y a d d i n g  b u t i n the case of p o l y p y r o n e s ,  successive  t h e second  g r o u p o f each m a l o n a t e g r o u p must b e r e t a i n e d t o f o r m each pyrone  a three  a c t e r o f the p o l y a c e t a t e chain.  lactone  of  (48) i s formed from  poly-|3-ketoacid  acetate  solution  c  ring.  OH 3 CH COOH 3  CH^Cr'^o (48)  carboxyl successive  30. In the acetate theory, the condensation of a c e t y l  polyacetate  chains are b u i l t up by  coenzyme-A with successive u n i t s of  onyl coenzyme-A, themselves formed by c a r b o x y l a t i o n of a c e t y l enzyme-A.  Each malonyl group l o s e s t h i s added C 0 u n i t 2  condensation i s  complete  (see  after  14  experiments with l a b e l l e d carbonate. p h e n o l i c product so s y n t h e s i z e d .  No  C is  r e t a i n e d by the  Opened polypyrones r e t a i n t h e i r  carboxyl (corresponding to a l a b e l l e d carboxyl above)  condensation to phenolic compounds. with the acetate h y p o t h e s i s , an elegant v e h i c l e  In s p i t e of t h i s  for biogenetic-type  inconsistency  s y n t h e s i s of  acetogenins.  the goal i n t h i s work was to prepare  polypyrones of a p p r o p r i a t e s i z e and to study t h e i r p o s s i b l e the s y n t h e s i s of phenolic compounds. triacetic  on  polypyrones as d e s c r i b e d h e r e i n provide  As mentioned p r e v i o u s l y ,  proposed s e r i e s ,  co-  F i g u r e V ) , a f a c t born out by feeding 3  terminal  raal-  lactone  use i n  Only the f i r s t member of  (48),  the  had p r e v i o u s l y been p r e -  23 pared.,  and was considered a convenient  starting material for  s y n t h e s i s of the d e s i r e d polypyrone s t r u c t u r e s .  Triacetic  was prepared i n the l a b o r a t o r y by the d e a c e t y l a t i o n a c i d (30),  synthesized  from e t h y l a c e t o a c e t a t e ^ ,  lactone  dehydroacetic  or obtained  commercially.  (30)  of  (48)  the  31. The r e a c t i o n of t r i a c e t i c  lactone with an equimolar amount  21 of  cyanoacetic  acid  y i e l d e d only s t a r t i n g m a t e r i a l .  r e a c t i o n times made no d i f f e r e n c e  to the  Longer  results.  Further work l e d to the d i s c o v e r y that the r e a c t i o n of an excess of cyanoacetic  a c i d with t r i a c e t i c  lactone  formation of a new product, mp. 2 9 9 - 2 3 2 ° , from s t a r t i n g m a t e r i a l by TLC„ of  than that of t r i a c e t i c r i n g methyl at 7.44T, respectively, lactone  distinquished  spectrum (328,269 mjx)  f o r a longer chromophoric system  (283 m\i).  The NMR spectrin showed a  and two aromatic hydrogens at 4.02T and 3.30T5,  and was e s s e n t i a l l y the same as that of  (7.53,  metric analysis  3.79,  3.48T).  This d a t a ,  triacetic  combined with mass s p e c t r o ™  and m i c r o a n a l y s i s , was c o n s i s t e n t with the  bispyrone s t r u c t u r e the presence  lactone  initially  The u l t r a v i o l e t  the product provided evidence  r e s u l t e d i n the  (49).  A positive  of an e n o l i z a b l e  ferric  fused  c h l o r i d e t e s t confirmed  |3-diketone.  (48)  (49)  Simultaneously,  alternate  routes  to bispyrone were examined.  25 Voods et a l .  d i s c o v e r e d that t r i a c e t i c  amounts of a c e t y l  lactone with equimolar  c h l o r i d e , benzoyl c h l o r i d e , p h e n y l a c e t y l  and p - n i t r o b e n z o y l c h l o r i d e , r e s p e c t i v e l y ,  chloride,  a c y l a t e d the pyrone r i n g  32. at C-3 i n every case.  Based on these o b s e r v a t i o n s , - t r i a c e t i c  lactone was reacted with e t h y l c h l o r o f o r m y l a c e t a t e  under s i m i l a r  conditions.  Examination of the r e a c t i o n product by TLC i n d i c a t e d  the presence  of a new compound.  the  successful  cyanoacetic  Mixed TLC with the product from  a c i d r e a c t i o n showed that the two  products were i d e n t i c a l .  (48)  (49).  This new method, being a one step r e a c t i o n provided a higher y i e l d of bispyrone (49)  than d i d the two step cyanoacetic  acid  method. The r e l a t i v e inconvenience ethylchloroformylacetate in his heterocyclic  i n v o l v e d i n the p r e p a r a t i o n of  coupled with the success of E l v i d g e et a l .  synthesis i n v o l v i n g malonyl c h l o r i d e and e n o l i c  ketones and d i k e t o n e s ,  l e d to i n v e s t i g a t i o n s  a v a i l a b l e malonyl c h l o r i d e . c h l o r i d e was necessary,  Although a two-fold excess of malonyl  the product of t h i s  i d e n t i c a l with the bispyrone i s o l a t e d esting  with commercially  r e a c t i o n was again  above.  This provided an i n t e r 25  c o n t r a s t to the f i n d i n g s of Woods et a l .  r e a c t i o n of t r i a c e t i c  lactone with a two-fold  :  i n t h e i r work,  excess of the a c i d  33c  c h l o r i d e r e s u l t e d i n each case i n the formation of the ated product  3,5-diacyl-  (54).  ( 5 4 )  For a summary of these and other attempts towards the t h e s i s of b i s p y r o n e ,  see  Table I .  Having achieved a s a t i s f a c t o r y  synthesis of the fused  pyrone ( 4 9 ) we could now proceed with the c o n s t r u c t i o n of s u i t a b l e pyrone s t r u c t u r e s .  A simple extension  of the  s a t i o n of bispyrone with a c e t y l  potential  ( 4 9 )  chloride.  o  ( 5 5 )  bis-  other  poly-|3-ketone chain could be v i s u a l i z e d as o c c u r r i n g by the  o  syn-  o  conden-  34 c  Table I  ATTEMPTS TO SYNTHESIZE BISPYRONE  reaction medium  unit  result  acid  1:1  TFA  starting  cyanoacetic a c i d  2:1  TPA  bispyrone  ethylcyanoacetate  1:1  TPA  starting  ethylchloroformylacetate  1.3:1  TPA 25  bispyrone  malonyl  chloride  2:1  TPA  b i spyrone  d i e t h y l malonate  1:1  monoethylmalonate  1:1  ethylchloroformylac etate  1:1  pyridine  1:1  ZnCl„/HCl  cyanoacetic  cyanoacetic  acid  EtOH/HCl  25  TFA  material  t r i a c e t i c lactone methyl ether starting  27  material  material  tar  28 starting  material  35„ Examination of the r e a c t i o n product from the condensation equimolar p o r t i o n s of bispyrone and a c e t y l  of  c h l o r i d e by TLC revealed  a new m a t e r i a l (mp, 2 4 5 - 2 5 2 ° ) , showing intense fluorescence ultraviolet light.  This new compound d i d not r e a c t with  c h l o r i d e and had an u l t r a v i o l e t  225 mu. (€ = .12,800) ; (€ = 1 0 , 4 0 0 ) ) »  confirmed t h i s  Initial  an a d d i t i o n a l  Examination by mass spectrometry  that  (55),  and the  elemental  conclusion.  attempts to synthesize a fused t r i s p y r o n e  the next higher member of the fused  series,  pyr3ne  using  s i m i l a r to those above were s u r p r i s i n g l y u n s u c c e s s f u l . bispyrone (49)  showed  This evidence was c o n s i s t e n t with  expected p r o d u c t , a c e t y l bispyrone  analysis  expected  and the r i n g proton at 3.45T? ( c o r r e s p -  the molecular weight was 236. the  269 mu.  i n a d d i t i o n to the  s i m i l a r protons i n b i s p y r o n e ) ,  methyl group at 7 , 1 7 T .  different  c f . b i spyrone: 328 mu. (6 = 6800),  The NMR spectrum showed,  to  and with a  (347 mu. (€ =.14,300), 261 mu,.(€ = 6400),  methyl protons at 7.48T, onding c l o s e l y  ferric  spectrum which i n d i c a t e d a chromo-  p h o r i c system longer than that i n b i s p y r o n e , p a t t e r n of i n t e n s i t i e s  under  was reacted with a t w o - f o l d  structure, conditions Thus,  excess of malonyl  c h l o r i d e i n t r i f l u o r o a c e t i c a c i d y i e l d i n g a product which resembled in  every way the product obtained by the r e a c t i o n of bispyrone with  acetyl  c h l o r i d e ; that i s ,  acetyl  that the malonyl c h l o r i d e was,  bispyrone  indeed,  bispyrone with an e i g h t - f o l d a yellow ferric  evident  c y c l i z a t i o n could take  However the r e a c t i o n of  excess i n t r i f l u o r o a c e t i c  c r y s t a l l i n e product (mp. 2 5 5 - 2 5 7 ° )  chloride test,  I t was  condensing with the b i s p y r o n e ,  but was undergoing d e c a r b o x y l a t i o n before p l a c e to y i e l d a t h i r d pyrone r i n g .  (55).  acid yielded  which gave a p o s i t i v e  TLC showed a new m a t e r i a l at Rf  =0.3  36. (cf.  bispyrone Rf = O . 7 5 a c e t y l b i s p y r o n e Rf = 0 . 6 5 ) .  violet  spectrum (373,  282,  The u l t r a -  255 mjj,) r e v e a l e d an extended  type chromophore at a wavelength  reasonable  f o r the lengthening  the pyrone system by an a d d i t i o n a l fused pyrone r i n g „ spectrum was s i m i l a r to that f o r b i s p y r o n e , at 7.42,  3.96,  3.30T„  weight to be 262,  Mass spectrometry  which,  bispyroneof  The NMR  and e x h i b i t e d  bands  showed the molecular  combined with the m i c r o a n a l y t i c a l d a t a ,  was c o n s i s t e n t with the c o n c l u s i o n that t h i s new compound was trispyrone  (56).  O OH O H  (49)  (56)  P u r i f i c a t i o n of t r i s p y r o n e i n v o l v e d repeated r e c r y s t a l l i z a t i o n and c h a r c o a l treatments. was f i n a l  column chromatography was used  p u r i f i c a t i o n e f f e c t e d and s i n g l e - s p o t m a t e r i a l  (TLC examination). duct,  Only a f t e r  TLC r e v e a l e d ,  before  obtained  p u r i f i c a t i o n of the  a s e r i e s of spots at Rf values lower than that of  pro-  trispyrone  and c o n s i s t e n t with those expected f o r extended polypyrones and a c e t ylpolypyrones i f i o r of b i s p y r o n e ,  they followed  the p a t t e r n apparent i n the  a c e t y l b i s p y r o n e and t r i s p y r o n e .  behav-  37. A number of a d d i t i o n a l attempts were made to trispyrone,  but y i e l d e d i n c o n c l u s i v e r e s u l t s .  these and the above r e a c t i o n s ,  trispyrone reaction,  For a summary of  see Table I I .  Because of TLC evidence pyrones and acetylpolypyrones  synthesize  f o r the existence of higher p o l y i n the r e a c t i o n product of  the  attempts were made to synthesize higher  members of the polypyrone s e r i e s . with a s i x - f o l d excess of a c e t y l  Thus,  treatment of  trispyrone  c h l o r i d e i n the manner p r e v i o u s l y  d e s c r i b e d f o r the s y n t h e s i s of a c e t y l b i s p y r o n e y i e l d e d the product,  acetyltrispyrone  (57).  I t may be noted that the  desired diffi-  c u l t y of o b t a i n i n g a c e t y l t r i s p y r o n e i n t h i s way i n d i c a t e s  a re-  duced r e a c t i v i t y at the a c t i v e methylene p o s i t i o n at C - 3 .  This  was a l s o confirmed by the d i f f i c u l t i e s s y n t h e s i s of the tetrapyrone  encountered during the  (58).  (58) Thus, r e a c t i o n of t r i s p y r o n e with an e i g h t - f o l d chloride yielded acetyltrispyrone,  excess of malonyl  A twelve-fold  excess of malonyl  c h l o r i d e was r e q u i r e d before a compound having p r o p e r t i e s i n d i c ative  of a t e t r a c y c l i c polypyrone was formed. The new product was extremely d i f f i c u l t to p u r i f y ,  efforts  to t h i s  end reduced the y i e l d c o n s i d e r a b l y .  and  Further work  38  o  Table II  A T T E M P T S TO S Y N T H E S I Z E  TRISPYRONE  reaction medium  unit  malonyl  chloride  2:1  TP A'  malonyl  chloride  2:1  refluxing  malonyl  chloride  8:1  ethylchloroformylacetate  7:1  ethylchloroformylacetate  7:1  result  acetylbispyrone TPA  TPA TPA  TFA  acetylbispyrone t r i spyrone  25  starting  (120°)  27  ethylchloroformylacetate  5:1  pyridine  ethylchloroformylacetate  2:1  DMP/pyridine  material  a c e t y l b i spyrone, starting material, and a t r a c e o f trispyrone starting  material  starting  material  39. is  i n progress  pyrone  to o b t a i n a s a t i s f a c t o r y  y i e l d of the d e s i r e d  tetra-  (58). Having achieved the  pyrone s t r u c t u r e s ,  synthesis of some of the  desired  we were now i n a p o s i t i o n to i n v e s t i g a t e  u s e f u l n e s s i n the p r o d u c t i o n of p h e n o l i c be seen that the pyrone s t r u c t u r e s disguised polyacetate  compounds.  It  their  can r e a d i l y  so f a r c o n s t r u c t e d are i n  chains of v a r y i n g l e n g t h .  (See page 40.)  Basic h y d r o l y s i s of the fused pyrone systems was c a r r i e d out with the hope that r i n g opening would o c c u r , by i n t r a m o l e c u l a r a l d o l condensation  fact  therefore followed  of the p o l y - P - k e t o a c i d chain  so produced. Bispyrone was h y d r o l y z e d with hydroxide and y i e l d e d three from s o l u t i o n at pH 6. a positive  linic  phenolic  (300,  triester /  trimethylester  potassium  Compound A p r e c i p i t a t e d  and melted at 1 1 2 ° .  not an a c i d ,  The u l t r a v i o l e t  232 m[x) d i s t i n g u i s h e d  a c i d (27)  methanolic  I t gave a negative sodium bicarbonate  therefore,  (3-dicarbonyl system. 247 sh,  compounds.  f e r r i c chloride test,  m a t e r i a l was,  N  test,  T h i s new  but possessed an e n o l i z e d spectrum (315,  260  sh,  compound A from the expected o r s e l -  260 mu) and i n d i c a t e d i t s  s i m i l a r i t y to  3,5-dihydroxy-2,4 - dicarboxyphenylacetic  the  acid  \ 29  (59)  which has u l t r a v i o l e t  spectrum 314,  260  sh,  30 250,  228 mu..  The NMR spectrum of compound A showed a r i n g methyl  group at 7.53T, two carbomethoxy groups at 5.91T and 5.85T, and only one aromatic p r o t o n . spectrum with the present.  exception  The t r i e s t e r  (59)  had an i d e n t i c a l NMB  that a t h i r d carbomethoxy group was  Examination by mass spectrometry  showing that the molecular  (58)  41  COOH  COOCM  HO.  HQ-  0  5  •COOCH3  CH3OOC OH  OH  (27)  weight was 240,  (59)  coupled with m i c r o a n a l y s i s  A was d i m e t h y l - 2 , 4 - o r c i n o l The i s o l a t i o n  dicarboxylate  of the d i e s t e r  (60)  confirmed that compound (60),  from the  hydrolysis  r e a c t i o n of bispyrone i n d i c a t e d that both pyrone r i n g s were attacked by methoxide  i o n (See page 0  42,)  E x t r a c t i o n of the mother l i q u o r s from compound A with chloroform y i e l d e d compound B (mp. 1 3 8 - 1 4 0 ° ) acteristics  whose s p e c t r a l  and chromatographic behavior i n d i c a t e d that i t  methyl o r s e l l i n a t e  (61).  charwas  Comparison of these p r o p e r t i e s with those 31  of  an authentic  sample of methyl o r s e l l i n a t e  confirmed t h i s  conclusion. ' Here a g a i n , oxide,  the bispyrone was i n i t i a l l y attacked by meth-  but only i n one r i n g .  The other carboxyl group  (non-terminal)  was l o s t through d e c a r b o x y l a t i o n . The mother l i q u o r s were adjusted to pH2 and r e - e x t r a c t e d chloroform, y i e l d i n g compound C (mp, 1 5 7 - 1 6 7 ° ) positive  sodium bicarbonate t e s t and a p o s i t i v e  with  which gave both a f e r r i c chloride  test.  42. This compound t h e r e f o r e P-dicarbonyl  system,,  ultraviolet  spectrum was an o r s e l l i n i c  a c i d spectrum and the NMR spectrum showed a r i n g methyl at  7 43T,an  ether methyl at 6 0 I 6 T ,  and two aromatic protons at 3 „ 6 4 T  Mass  spectrometric  showed the molecular weight to be  analysis  TLC d i s t i n g u i s h e d :  Its  contained a free a c i d and an e n o l i z e d  a c i d (27)  and d i m e t h y l - 2 , 4 ~ o r c i n o l d i c a r b o x y l a t e  above evidence orsellinic The  compound C from methyl o r s e l l i n a t e (60)  0  c  182,  (61),orsellinic Prom the  o  i t was concluded that compound C was p-0-methyl  acid (everninic  acid) ( 6 2 ) „  formation of an o r s e l l i n i c  a c i d methyl ether  from the  h y d r o l y s i s of bispyrone i n d i c a t e d attack on the p o l y k e t i d e chain by methoxide For  f o l l o w i n g h y d r o l y s i s and preceding r i n g  closure.  a summary of the h y d r o l y s i s of bispyrone i n methanolic  potassium hydroxide see  Figure X I , 32  The work of C a l d i n and Long quite  provides a very i n t e r e s i n g and  simple explanation of the predominance of methoxide  i n the  methanolic h y d r o l y s i s media as evidenced by the p r o d u c t i o n of methyl e s t e r s and methyl e t h e r s . made by d i s s o l v i n g hydroxide i o n i s 0H~ + EtOH water i n the  C a l d i n and Long showed t h a t ,  in  sodium hydroxide i n e t h a n o l , much of  r e p l a c e d by ethoxide,  0Et~ + H 0 l y i n g w e l l 2  ethanol,  94°/o  I t i s not s u r p r i s i n g , then,  solutions  the  the e q u i l i b r i u m  to the r i g h t .  of the b a s i c  Even with 2 ° / o  species were  ethoxide.  that methyl e s t e r s and methyl  ethers  were produced from the h y d r o l y s i s of bispyrone i n both methanolic and  10 percent aqueous methanolic potassium h y d r o x i d e .  43o  F i g u r e XI  Compound C  44.  The most a t t r a c t i v e the  synthesis of o r s e l l i n i c  a common mould m e t a b o l i t e ,  goal i n the h y d r o l y s i s of bispyrone was acid i t s e l f .  O r s e l l i n i c a c i d (27)  produced f o r instance  is  by P e n i c i l l i u m  33 madriti  and was the most obvious product expected from the  r e a c t i o n of bispyrone with d i l u t e base. the c o n c e n t r a t i o n of hydroxide i o n s , changed from  N  methanolic  In an attempt  to  increase  the r e a c t i o n medium was  potassium hydroxide to  N 10°/o  aqueous methanolic potassium h y d r o x i d e . H y d r o l y s i s of bispyrone i n t h i s new b a s i c medium y i e l d e d two compounds.  (See F i g u r e X I I . )  (61)  (62)  F i g u r e XII  45. The f i r s t p r e c i p i t a t e d from s o l u t i o n at pH 2 and was shown by U.V.,  I . R . , N.M.R.,  mass spectrometry,  TLC to be i d e n t i c a l with compound p~0-methyl  orsellinic  acid  C  mixed melting p o i n t and mixed isolated  above;  that  is,  (62).  E x t r a c t i o n of the mother l i q u o r s with chloroform y i e l d e d the second product which was shown by U . V . , I . R . , N . M . R . ,  mixed  m e l t i n g p o i n t and mixed T„C to be i d e n t i c a l with compound B isolated  above;  Clearly,  that i s ,  methyl o r s e l l i n a t e  i f orsellinic  (6l).  a c i d were to be produced,  c o n c e n t r a t i o n of hydroxide i o n must be d r a s t i c a l l y The r e a c t i o n medium was therefore  the  increased.  changed to t o t a l l y aqueous  N  potassium h y d r o x i d e . Bispyrone (49)  9  hydrolyzed i n t h i s new medium, y i e l d e d no  product through p r e c i p i t a t i o n at pH 2.  E x t r a c t i o n of the pH 2  s o l u t i o n with chloroform y i e l d e d only a trace amount of brown t a r , which n e v e r t h e l e s s contained a very minor amount of m a t e r i a l r e sembling o r s e l l i n i c aqueous s o l u t i o n , (see  Figure X I I l )  a positive  (300,  however,  on TLC.  Freeze d r y i n g o f . t h e  y i e l d e d a new product (mp.  which gave a p o s i t i v e  f e r r i c chloride test.  contained a f r e e ultraviolet  a c i d (27)  180-188°)  sodium bicarbonate t e s t and  The new compound  therefore  carboxyl group and was presumably p h e n o l i c ,  spectrum was i d e n t i c a l  to that of o r s e l l i n i c  The  acid  260 mu.). The NMR spectrum revealed only a r i n g methyl at  two aromatic prtotons  at 3.73T.  7.47T  and  Mixed melting p o i n t and mixed TLC  46c  with authentic o r s e l l i n i c  acid  34  confirmed our  Accompanying the o r s e l l i n i c q u a n t i t y of o r c i n o l ( 3 l )  conclusion  a c i d i n t h i s product was a small  which was detected and c h a r a c t e r i z e d by  TLC.,  COOH  T  II  (27)  ( 3 1 )  KOAc  F i g u r e XIII  47c  Also i s o l a t e d as a r e s u l t of the freeze a q u a n t i t y of potassium a c e t a t e .  d r y i n g process  was  This m a t e r i a l could only r e s u l t  by the h y d r o l y s i s of the opened p o l y k e t i d e c h a i n , reducing i t its  parent acetate u n i t s .  to  I t was not determined whether any s i m i l a r  h y d r o l y s i s occurred i n the cases where methanolic and lO^/o aqueous methanolic media were used,  since freeze  d r y i n g of the  aqueous  s o l u t i o n was not used i n the i s o l a t i o n of the products from these reactions. The h y d r o l y s i s of bispyrone ( 4 9 ) ,  it  can be seen,  yields  a p o l y k e t i d e chain which can undergo a l d o l condensation to y i e l d several o r s e l l i n i c acid derivatives. which i s  essentially  is possible final  By u s i n g a r e a c t i o n medium  one hundred percent methoxide i n methanol,  f o r the mid-chain carboxyl group to be r e t a i n e d i n the  phenol.  Methyl e s t e r s and methyl ethers are produced i n a  h y d r o l y s i s medium r i c h i n methoxide.  In methoxide-free  only o r s e l l i n i c a c i d i s produced and w i l l extent to y i e l d o r c i n o l ( 3 l ) . reactions  in vitro  0  closely  hydrolysis,  decarboxylate to some  We have thus performed a s e r i e s of  r e l a t e d to those p o s t u l a t e d by the  acetate theory and have e s t a b l i s h e d for  it  a new b i o g e n e t i c  type  synthesis  o r s e l l i n i c a c i d and r e l a t e d compounds. The next fused pyrone compound to be h y d r o l y z e d was  b i s p y r o n e ( 5 5 ) . Reaction of a c e t y l b i s p y r o n e with  N  potassium hydroxide y i e l d e d only one p r o d u c t , (mp. which gave a p o s i t i v e hydroxide t e s t .  ferric  chloride test,  methanolic 1 5 7 . 5 - 1 5 8 ° )  but a negative  sodium  This new compound c l e a r l y contained no f r e e  group, but contained an e n o l i z e d 6 - d i c a r b o n y l violet  acetyl-  s pec tra were v i r t u a l l y i d e n t i c a l  system.  with those of  acid  The u l t r a orcaceto-  48 \ phenone X  , i.e.  (base)  ^  m  a  315 sh,  283,  233 sh mu.;  262 mu; X  335,  max A (n-hexane) 324, methyl at 7 . 4 8 T ,  (acid.) 315 sh, 284, 234 sh mu; max ~ ma.v ' • ' ~ 276 mu. The NMR spectrum showed a r i n g 7  an a c e t y l methyl at 7 „ 4 0 T ,  protons at 3.73T. material  (ethanol)  x  and two aromatic  Mixed melting p o i n t and mixed TLC with  confirmed t h a t i h i s  Since a c e t y l b i s p y r o n e  compound was orcacetophenone contains  a potential  with no t e r m i n a l carboxyl group, condensation one product  (see  can r e s u l t  Figure XIV).  KOH/MeOH -CO,  (55)  or  (b)  (63)  F i g u r e XIV  (63).  polyketide  o o  (a)  authentic  chain  i n only  49,  Bispyrone (49), sation,  on h y d r o l y s i s and subsequent a l d o l  cyclized in a specific  orsellinic contains  acid derivatives.  a polyketide  therefore,  (Figure XV"); that i s ,  Under s u i t a b l e bicyclic  one malonate u n i t longer  three  C-acetyl  compounds or orsellinic  or 2 - m a l o n y l o r c i n o l (66)  conditions,  than  s t r u c t u r e s by e n o l - l a c t o n e  acid  (64),  or r e l a t e d  compounds.  formation i n v o l v i n g the  Thus, C - a c e t y l o r s e l l i n i c  form 3-methyl-6,8-dihydroxyisocoumarin compound (68),  derivatives  these three compounds could each become  chains on the o r c i n o l r i n g .  form the  on the other hand,  H y d r o l y s i s and subsequent i n t r a m o l e c u l a r  condensation may y i e l d ,  c u r v u l i n i c a c i d (65),  the compounds were  T r i s p y r o n e (56),  chain which i s  the chain i n b i s p y r o n e .  thereof  way; that i s ,  conden-  (67),  side  a c i d would  c u r v u l i n i c a c i d would  and 2 - m a l o n y l o r c i n o l could form 4 , 7 36  dihydroxy-5-methyl-coumarin (69). (65)  3 7  ,  (67) , 3 6  2  Since o r s e l l i n i c  from bispyrone h y d r o l y s i s , type of condensation  acids had been  i t was reasonable  to occur with  Trispyrone (56)  to expect a s i m i l a r  N  methanolic  A major component appeared at Rf  separated from the other r e a c t i o n  by p r e p a r a t i v e TLC.  This compound (mp. 2 5 0 - 2 5 3 ° )  sodium bicarbonate  test,  and a p o s i t i v e  compound contained no f r e e The u l t r a v i o l e t  288,  potassium  and y i e l d e d a number of compounds as evidenced by p r e l i m -  and was conveniently  (327,  isolated  trispyrone.  was hydrolyzed i n  i n a r y examination by TLC.  nature.  ,  and (69) * , are known compounds and were a v a i l a b l e  f o r comparison purposes.  hydroxide,  Of these s i x compounds,(64)  277,  257,  244,  0.5,  products  gave a negative  f e r r i c chloride test;  carboxyl groups, but was phenolic  the in  spectrum revealed a chromophoric system 237 mu) very s i m i l a r to that c f  3-methyl-  50,  Figure XV  51c  6 , 8 - d i h y d r o x y i socoumarin  ( 6 9 ) ( 3 1 7 , 2 7 6 , 2 6 0 , 2 4 4 , 2 3 7 mu)  isolated  36  by  Hassall  and  coworkers  at  7.778T,  and  three  mass  spectrometry, Pyrolysis  192.  .  aromatic  showed  of  T h e NMR s p e c t r u m  a  protons  that  small  the  sample  at  new of  revealed  a ring  Examination  3C62T.  methyl by  compound h a d m o l e c u l a r  authentic  C-acetyl  weight  orsellinic  38  acid  yielded  identical is  to  that  therefore  of  the  new  an u l t r a v i o l e t  compound a b o v e .  spectrum  almost  This  compound  new  3-methyl-6,8-dihydroxyisocoumarin ( 6 9 ) .  Freeze product,  a compound w i t h  drying  of  the  acetylbispyrone  aqueous  solution yielded,  w h i c h was  (55)  as  characterized  a  by  major mixed  TLC.  O  o  O H  (56)  (55)  A second pyrone the  that  and had of the  at  6  to  be  o  methanolic  (56) yielded  isocoumarin  1 5 2 ° )  0 6 T  220.  as  ( 6 9 ) .  It  ( 6 0 ) .  6.02T,, In  spite  compound i s  not  solve  structure.  this  the  potassium major was  an u l t r a v i o l e t  diester  and  o  Mass of  known.  hydroxide  product  isolated spectrum  this  by p r e p a r a t i v e  Vork i s  tris-  showed the  two the  similar  methoxyl molecular  structure  c o n t i n u i n g i n our  from  TLC (mp. 1 5 0 -  ( 3 1 6 , 2 4 8 , 2 3 1 mu)  information,  of  a compound d i s t i n c t  T h e NMR i n d i c a t e d spectrometry  hydrolysis  of  to  groups weight this  laboratories  to  52.  Aqueous a  complex  mixture  appeared. coupled  as  Our  mixed  work  provide  an  of  TLC  has  hydroxide  shown by  Examination  with  pyrones  potassium  hydrolysis  TLC.  this  demonstrated elegant  trispyrone  yielded  H o w e y e r , .a, m a j o r . ' c o m p o n e n t  i t s ultraviolet,  showed  of  infrared,  compound  that  vehicle  to  be  the  NMR  spectra  orcacetophenone  polypyrones  for  and  ;  and  biogenetic  (63).  acetylpolytype  synthesis  39 of  phenols.  w i l l  ever  I t would be  enabled  us  In  way,  this  studied.  readily  to  the  mode  stabilized  by  u t i l i z e d  similar  of  in  i s  knowledge biogenetic  these  of  idea  such,  the 40  surface to  that  handle  of  long  but  compounds  i n Nature,  chain  our  approach  disguised  that,  these  as"  i n  can  chain  effect,  intermediates  has  polypyrones.  poly-(3-ketoacids  poly-p-ketoacid  so  poly-P-ketoacids  we i n  be  i s  have our  study  synthesis.  continuing of  as  cyclization  enzyme  biogenetic-type Vork  our  the  unlikely  accessible  synthesize  Presumably  a  seem  the  i n  our  laboratories i n  a p p l i c a t i o n of  studies.  these  fused  order pyrone  to  extend  structures  53.  EXPERIMENTAL A l l melting p o i n t s were determined using a R e i c a e r t hot stage m e l t i n g p o i n t apparatus, and are u n c o r r e c t e d . The microanalyses were performed by Dr. A l f r e d Berhnardt and h i s a s s o c i a t e s , M i k r o a n a l y t i s c h e s Laboratorium im Max- P l a n c k Institut  fur Kohlenforschung, 433 Mulheim (Ruhr), Vest Germany,  and by Mrs. C. J e n k i n s , Chemistry Department, U n i v e r s i t y of B r i t i s h Columbia. The u l t r a v i o l e t s p e c t r a were recorded on a Unicam SP 800 r e c o r d i n g spectrophotometer igation,  during the  e a r l y p a r t of the  and on a Cary 11 or Cary 14 r e c o r d i n g  invest-  spectrophotometer  during the l a t t e r p o r t i o n of the work. I n f r a - r e d spectra were recorded on a P e r k i n Elmer 137 spectrophotometer d e s c r i b i n g the v  and on a P e r k i n Elmer 21 spectrophotometer. , s = sharp, m = medium, b = broad,  The muclear magnetic resonance megacycles  sh = shoulder.  spectra were measured at 60  on a V a r i a n A60 instrument.  used as the i n t e r n a l standard i n a l l  In  Tetramethyl s i l a n e  was  cases.  The mass spectrometric analyses were performed by Mr. Prank Bloss u s i n g an MS9 and an A t l a s high r e s o l u t i o n mass All  spectometer.  pH measurements were made with u n i v e r s a l i n d i c a t o r paper.  54. Dehydroacetic a c i d  (30):  Dehydroacetic (a)  Initially,  (30)  a c i d from two sources was was synthesized  used.  from e t h y l a c e t o a c e t a t e by the 24  established  method of Horning as., given i n ^Organic ' Syntheses":  Freshly d i s t i l l e d and  sodium bicarbonate  e t h y l acetoacetate ( l O O g . , 0.77  (0.05g,  moles)  c a t a l y s t ) were combined and heated  c a r e f u l l y u n t i l the r e a c t i o n mixture had reached 2 0 0 - 2 1 0 ° hours).  During the r e a c t i o n ,  p r i n c i p a l l y ethanol, dark brown.  was c o l l e c t e d  distillate,  and the r e a c t i o n mixture became  D i s t i l l a t i o n i n vacuo of the r e a c t i o n mixture y i e l d e d  dehydroacetic acetate.  approximately 43 m l . of  (5.25  a c i d at 1 4 0 ° (18mm.) a f t e r  Y i e l d 14g.,  ethylaceto-  2 2 ° / o ; mp. 1 0 9 ° .  Spectral Properties: 224 mu. (€ = 9770).  a forerun of  X  (ethanol)  (chloroform)  v  1745,  309 mix ( € = 11,200), 1735,  1650,  1620,  1560 cm" . 1  NMR ( t r i f l u o r o a c e t i c a c i d) 7 . 6 0 T ( 3 H ) , 7 . 1 6 T ( 3 H ) , 3 . 7 0 T ( 1 H ) . Reaction with f e r r i c c h l o r i d e i n ethanol y i e l d e d an orange complex. (b)  Dehydroacetic a c i d s u p p l i e d by Eastman Organic Chemicals,  mp.  108"-  above.  110 ', was e q u i v a l e n t u  i n every way to the product  A l l f u r t h e r work used dehydroacetic  T r i a c e t i c lactone  source.  (48):  Dehydroacetic a c i d (30)  (lOOg.,  90 per cent s u l f u r i c a c i d (165 m l . ) . bath y i e l d e d a yellow bath ( 1 5 0 ° )  a c i d from t h i s  (30)  solution.  0.59  moles) was d i s s o l v e d  in  S l i g h t warming on the steam  The s o l u t i o n was heated i n an o i l  and s t i r r e d under n i t r o g e n u n t i l the temperature  of  the  55. s o l u t i o n had reached 1 3 0 ° . 136° The in  The temperature was maintained at 130  f o r f i v e minutes at which p o i n t the s o l u t i o n was removed from the b a t h ,  s o l u t i o n was deep r e d . cooled r a p i d l y by s w i r l i n g  an i c e b a t h , and poured i n t o i c e - w a t e r  minuted,  (700 m l . )  c r y s t a l l i z a t i o n was e s s e n t i a l l y complete.  s o l i d was c o l l e c t e d (500 m l . ) ,  Within  five  The white  i n a Buchner f u n n e l , washed with c o l d water  and allowed to  stand o v e r n i g h t .  The moist p r e c i p i t a t e was d i s s o l v e d i n e t h y l acetate by vigorous b o i l i n g f o r ten minutes. for  two hours,  Yield:  the white  48.6g.,  -  65°/o;  (500ml.)  A f t e r c o o l i n g i n an i c e bath  c r y s t a l l i n e product was  collected.  mp. 1 8 9 ° .  Spectral Properties:  X  (ethanol) 283 mu. (€ = 6750).  m£tx (Nujol)  V  7.53T(3H),  1700,  1645,  1575  cm" .  3.79T(1H), 3.48T(1H).  284 mu. ('€ = 7800).  1719,  v  NMR ( t r i f l u o r o a c e t i c  1  Reported v a l u e s :  chloroform + minimum of methanol)  1620,  7.76,  1594 cm" .  4.61,  1  R e c r y s t a l l i z a t i o n of t r i a c e t i c  in  ethyl  ethanol.  from e t h y l a c e t a t e  a c i d because of i t s  greater  solubility  (49):  Three experimental pathways  (a)  NMR (deutero-  acetate.  Bispyrone  lactone  lactone  (ethanol)  4.10T.  No r e a c t i o n occurred with f e r r i c c h l o r i d e i n  removes unreacted dehydroacetic  X  4 1  1661,  acid)  to bispyrone from t r i a c e t i c  proved workable.  T r i a c e t i c lactone  (48)  (l0.06g.,  8.0 mmoles)  and cyanoacetic  21 acid  (l2.11g.,  14.0 mmoles) were d i s s o l v e d  in trifluoroacetic  acid  56., (30 m l . )  and r e f l u x e d under n i t r o g e n f o r s i x hours.  Water (10  was added and the orange r e a c t i o n s o l u t i o n heated to r e f l u x f i v e minutes,  and allowed to c o o l .  of  l8°/o;  but  and subsequent c o o l i n g at 0 °  two hours y i e l d e d a q u a n t i t y of c r y s t a l l i n e m a t e r i a l . red-orange powder: 2 . 8 1 g . ,  for  No c r y s t a l s were evident,  treatment with e t h y l a c e t a t e (40 m l . ) for  ml.)  mp. 200 -  Yield  220°,  E e c r y s t a l l i z a t i o n from chloroform y i e l d e d a r e d d i s h m a t e r i a l (mp. 227 - 2 3 1 ° ) . oil  Alternatively,  sublimation i n vacuo at 1 5 0 ° and  pump vacuum y i e l d e d a s o l i d which on c r y s t a l l i z a t i o n - ^ rom  chloroform y i e l d e d white c r y s t a l s  (mp. 225 -  232°).  25 (b)  Ethylchloroformylacetate (prepared from d i e t h y l malonate by 42 43 p a r t i a l hydrolysis , and subsequent r e a c t i o n with o x a l y l c h l o r i d e , 44 \ or,  alternatively,  with phosphorus p e n t a c h l o r i d e  /  \  ) (1.02g.,  was added over a 30 minute p e r i o d to a s o l u t i o n of t r i a c e t i c (48)  (646 mg., 5.12  mmoles)  in trifluoroacetic  at 1 1 2 ° i n an o i l bath f o r three hours.  acid ( l ml.)  and allowed to cool to room temperature.  occurred y i e l d i n g , 228 - 2 3 0 ° . in  d r y i n g i n vacuo,  acid,  held evolved.  excess a c i d Crystallization  206 mg., 2 1 ° / o; mp.  Comparison by TLC with the product from the  (a) with cyanoacetic  to be (c)  after  mmoles)  lactone  Hydrogen c h l o r i d e was  The r e a c t i o n mixture was heated to r e f l u x to destroy chloride,  6.7  showed the product from the  reaction two sources  identical.  T r i a c e t i c lactone  (48)  (l„38g.,  11.0 mmoles)  and malonyl chloride^"*"  ( A l d r i c h Chemical Company; also, from malonic a c i d by r e a c t i o n with thionyl chloride  ) were combined w i t h t r i f l u o r o a c e t i c  a c i d (4 ml.)  and  s t i r r e d at room temperature for ten minutes,  then p l a c e d i n an  oil  bath ( 8 0 ° ) .  A f t e r 90 minutes,  a precipitate  Hydrogen c h l o r i d e was evolved.  formed.  A f t e r 4.5 hours, the  temperature was r a i s a d  5t. to 1 3 0 ° over f i v e minutes, had  ceased,  and, when hydrogen c h l o r i d e  evolution  the r e a c t i o n mixture was cooled to room temperature,  the product separated by f i l t r a t i o n , and d r i e d i n vacuo. 1.27g«,  60°/o;  mp. 223 - 2 3 2 ° .  was accomplished by 1.) tallization;  or 2.)  convenient  F u r t h e r p u r i f i c a t i o n of bispyrone  recrystallization,  s u b l i m a t i o n , and r e c r y s -  chromatography ( s i l i c a  recrystallization.  Yield:  gel/chloroform)  The second method proved to be the  on a p r e p a r a t i v e s c a l e , a n d was e s p e c i a l l y  the removal of dark c o l o r e d polymeric i m p u r i t i e s . sample was prepared by s u b l i m a t i o n ( 1 4 0 ° ,  and  most efficient  in  An a n a l y t i c a l  o i l pump vacuum),  followed by three r e c r y s t a l l i z a t i o n s , from c h l o r o f o r m - e t h y l a c e t a t e . Analysis:  C, 55.90; H , 3.19;  Found:  r e q u i r e s C, 55.68; H , 3.12;  0,  Spectral Properties: 269 mu (€ = 10,400).  0,  41.28. C g H ^  41.21.  A  (ethanol)  328 mu (€ = 6800),  No s h i f t was observed on a d d i t i o n of  sodium hydroxide; however,  the i n t e n s i t y  dilute  of the peak at 328 mu  was decreased and of that at 269 mu enhanced.  v  (chloroform)  rn&x 1770  sh,  1747 s,  (trifluoroacetic spectrometric (cf.  1705 v s ,  sh,  1570  a c i d) 7 . 4 4 T ( 3 H ) , 4 . 0 2 T ( 1 H ) ,  analysis  194.15 f o r  1645 m, 1640  s cm" . NMR 1  3.30T(1H).  Mass  showed the parent peak at 194 mass u n i t s  C H 0 ). 9  6  5  R e a c t i o n with f e r r i c c h l o r i d e i n ethanol y i e l d e d a red complex. For p r e p a r a t i o n purposes, was used: in  T r i a c e t i c lactone  trifluoroacetic  acie  the f o l l o w i n g r e a c t i o n  (20.Og.,  O.I5( moles) was  sequence dissolved  (70 m l . ) and malonyl c h l o r i d e ( 4 5 g . , 0.32  moles)  58. was added. for  The r e a c t i o n s o l u t i o n was r e f l u x e d on the  three hours with a d r y i n g tube i n p l a c e .  was removed from the b a t h , and, a f t e r (30 m l . ) ,  The dark  the a d d i t i o n of  solution ethylacetate  c r y s t a l l i z a t i o n commenced and was completed by c o o l i n g  under the c o l d t a p .  The crude product was f i l t e r e d o f f  with a small a d d i t i o n a l volume of e t h y l a c e t a t e . 65°/o.)  steam bath  This m a t e r i a l was d i s s o l v e d  through a column of s i l i c a gel  and  A v a s h e d  ( Y i e l d : 20g. ,  i n chloroform and f i l t e r e d  (75g.) y i e l d i n g the white  crystalline  p r o d u c t , mp. 228 - 2 3 1 ° . A c e t y l Bispyrone  (55):  A c e t y l b i s p y r o n e was the p r i n c i p a l product i n at l e a s t two attempts to synthesize t r i s p y r o n e (56). however,  a c e t i c a c i d (4.0  ml.),  0.01  moles) was d i s s o l v e d i n t r i f l u o r o -  acetylchloride  (2.2  the mixture heated on a steam b a t h .  evolved and a f t e r ice-water  two hours,  (20 m l . ) .  washed with water.  m l . , 0.03  245 - 252 .  moles) added,  Hydrogen c h l o r i d e was  the r e a c t i o n mixture was poured i n t o  The p r e c i p i t a t e d s o l i d was f i l t e r e d o f f and Yield:  " 2 . 8 g . ; mp. 245 - 2 5 2 ° .  from chloroform y i e l d e d l i g h t brown c r y s t a l s mp.  scale,  the f o l l o w i n g r e a c t i o n was used:  Bispyrone ( l . 9 g . ,  and  On a p r e p a r a t i v e  (l.2g.,  Recrystallization 52°/o),  TLC showed no s t a r t i n g m a t e r i a l .  The product was d i s s o l v e d i n chloroform and f i l t e r e d a column of s i l i c a gel  (60g.).  c o n c e n t r a t i o n of the c o l o r l e s s mp.  245 -  247°.  ,  through  E l u t i o n with chloroform (2 1.) eluate gave c o l o r l e s s  and  needles (675 m g „ ) ,  59. Analysis:  Found:  C, 55.76; H, 3.50;  r e q u i r e s C, 55.95; H , 3.41;  0,  261 mu (€ - 6,400), 1730  s,  (ethanol)  225 mu (€ = 12,800).  1650 m, 1550  s cm" . 1  v  1  Mass spectrometric  236 mass u n i t s  (cf.  v  m Q Y  H 1 : L  (Naijol) 1765  acid):  0 8  6  analysis  s,  sh,  1638  s,  7,48T(3H), 7 . 1 T ( 3 H ) ,  showed the parent peak at  236.18 f o r C^HgOg).  No r e a c t i o n occurred with f e r r i c c h l o r i d e i n Trispyrone  C  3.47 mu (€ = 14,300),  (KBr) 1765 m, 1730  1550 b cm" . . NMR ( t r i f l u o r o a c e t i c 3.45f(lH).  40.74.  40.64.  X  Spectral Properties:  0,  ethanol.  (56):  Attempts were made to s y n t h e s i z e t r i s p y r o n e from bispyrone (49)  by condensation with malonyl c h l o r i d e and e t h y l c h l o r o f o r m y l -  acetate under a v a r i e t y of c o n d i t i o n s . the one used f o r p r e p a r a t i v e purposes,  The most s u c c e s s f u l  method,  was c a r r i e d out i n the  f o l l o w i n g way: B i spyrone (49) acetic  a c i d (15 m l . )  was added. 1.5  (5.0g.,  0.02  moles) was d i s s o l v e d i n t r i f l u o r o -  and malonyl c h l o r i d e ( 2 9 . l g . ,  The r e a c t i o n s o l u t i o n was r e f l u x e d on a steam bath f o r  hours with a d r y i n g tube i n p l a c e .  evolved.  0.206 moles)  A f t e r heating f o r 30 minutes,  Hydrogen c h l o r i d e was the s o l u t i o n t u r n e d i t o r a  dark brown t a r which p a r t i a l l y s o l i d i f i e d on f u r t h e r r e f l u x i n g . The mixture was allowed to c o o l ,  and ether  (30 m l . ) was added,  c o n v e r t i n g the t a r to a brown powder which was i s o l a t e d by f i l t r a t i o n and washed with an a d d i t i o n a l volume of ether. ( p a r t l y polymeric m a t e r i a l ) .  Yield:  13.lg.  60. The s o l i d m a t e r i a l and t h e  solution  resulting 47°/o,  solid  This  thus was  16°/o  was  42,85.  c  i2 6°7 H  e  <  u  i  r  e  s  C,  filtered,  a yellow  c  »  5495,  1.)  The  Yield:  3,2g,,  ethylacetate,  and c r y s t a l l i z e d .  powder.  54,44;  54,9.7$. H ,  Properties:  282 mu,(€ = 8 , 7 5 0 ) , s,  l  dryness.  (2  Yield:  This  l,05g,.  268°d,  Pound: r  evaporated to  t a k e n up i n h o t  charcoal,  mp, 262 -  Spectral  1730  was  repeated y i e l d i n g  Analysis.  ethylacetate  r e c r y s t a l l i z e d from a c e t o n e .  crude m a t e r i a l  overall}  e x t r a c t e d with hot  o b t a i n e d was  treated with a c t i v a t e d process  was  >-  mav  2.31$  v  1  m n v  sh,  (KBr)  2,59,  0,  (ethanol)  255 mu. ( 6 = 6,700)  1640 m, 1540 s c m " .  H,  2,71;  0,  42,46.  42,72,  373 mu ( 6 a . v  10,100),  „. ( N u j o l )  1750 b,  1710  1775  s,  s,  1640  sh,  ill A A  1622 m, 1565 (3H),  sh,  3,96T(1H),  1535  s cm" . 1  3,30T(1H),  t h e p a r e n t peak a t  NMR ( t r i f l u o r o a c e t i c Mass s p e c t r o m e t r i c  262 mass u n i t s  Reaction with  ferric  (cf,  analysis  262,17 f o r  chloride in  acid):  7.42T showed  C]_2^6^7^*  e t h a n o l gave an  orange  complex.  Several (a)  Bispyrone  acetic was  acid  added.  a drying  other (49)  (1.5  attempts  (0,79g,,  ml.)  solution.  The r e a c t i o n  ethyl acetate Solid  4 , 0 7 mmoles)  and m a l o n y l  tube i n p l a c e .  four hours,  were made to  0,83g,,  86°/o,  a light  red c r y s t a l l i n e  was  chloride  dissolved  (l.23g.,  trispyrone: in  8.73  trifluorommoles)  solution  was  Hydrogen  c h l o r i d e was  e v o l v e d , and,  (6 m l . )  added to t h e  dark  p r e c i p i t a t e d from the  Yield:  synthesize  r e f l u x e d on a steam b a t h  solution  on  with  after  red-brown cooling.  Recrystallization  from c h l o r o f o r m y i e l d e d  powder, rap, 255 -  257,  61. Examination of the product by TLC showed no material, Rf value  but showed that the product behaved d i f f e r e n t l y , and i n fluorescence  expected t r i s p y r o n e , be a c e t y l  bispyrone  s i l i c a gel) (b)  under u l t r a v i o l e t l i g h t ,  (55).  from the  TLC (10 per cent a c e t i c a c i d - c h l o r o f o r m / conclusion.  was repeated with bispyrone  and malonyl c h l o r i d e ( 2 . 3 0 g . ,  16.30  mmoles)  The r e a c t i o n was run at r e f l u x  (49)  (l.55g.,  of  Yield:  t h i s product showed i t  with a c e t y l (c)  1.68g.,  89°/o,  mmoles) acid  for 2 hours and the product  mp. 255 - 2 5 7 ° .  was  A l l properties  to be i d e n t i c a l with that from (a)  and  bispyrone.  Bispyrone (49)  ( 0 , 9 2 g . , 4.84  mmoles)  was d i s s o l v e d i n t r i f l u o r o -  a c e t i c a c i d (4ml.) and e t h y l c h l o r o f ormyl acetate mmoles)  800  in trifluoroacetic  which p r e c i p i t a t e d without the a d d i t i o n of e t h y l a c e t a t e , collected.  both i n  U . V . and NMR spectra showed the compound to  confirmed t h i s  Reaction (a)  (4 ml,'),  starting  )5..16g.,  31.2  was added and s t i r r e d overnight i n an o i l bath at 6 0 ° with  a d r y i n g tube i n p l a c e ,  then at room temperature for a f u r t h e r day.  Hydrogen c h l o r i d e was evolved. a pale y e l l o w ,  The r e a c t i o n s o l u t i o n ,  became dark orange.  initially  On c o o l i n g to room temperature,  a white s o l i d p r e c i p i t a t e d which proved to be p r i n c i p a l l y s t a r t i n g material. (d)  Reaction (c)  was repeated with the m o d i f i c a t i o n that the  s o l u t i o n was h e l d at 1 2 0 ° f o r three hours, then allowed to overnight at room temperature.  stand  The s o l i d which p r e c i p i t a t e d  room temperature was i s o l a t e d by f i l t r a t i o n , mp. 2 2 7 - 2 3 1 ° ,  reaction  at  245°.  TLC examination of t h i s product (10 per cent a c e t i c a c i d - c h l o r o f o r m / s i l i c a gel)  r e v e a l e d a s e r i e s of spots corresponding to  and a c e t y l b i s p y r o n e . was also  present.  A very minor spot corresponding, to  bispyrone trispyrone  : 62. (e)  Bispyrone (49)  (15 m l . ) ,  ( l . O g . , 5.50  i n which i t  mmoles)  was added to p y r i d i n e  only p a r t i a l l y d i s s o l v e d ,  a l i g h t green s l u r r y which subsequently  giving  initially  became p u r p l e - g r e y  s t i r r i n g for three hours at room temperature.  E t h y l chloroformyl  acetate ( 4 g „ , 26.6 mmoles) was added, the r e a c t i o n mixture i n an ice-water erature  bath f o r 15 minutes,  after  cooled  then s t i r r e d at room temp-  overnight. The r e a c t i o n mixture was poured i n t o ice-water  and adjusted to pH 2 with 6N h y d r o c h l o r i c a c i d . s o l u t i o n was extracted with ether  (4 x 50 m l . ) .  (100  ml.)  This a c i d i f i e d Evaporation of  the ether i n vacuo y i e l d e d a red-orange powder which proved to be p r i n c i p a l l y bispyrone (f)  Bispyrone (49)  (UV, TLC, and f e r r i c c h l o r i d e t e s t ) .  (2.1g.,  0.018  moles) was d i s s o l v e d  mixture of dimethyl formamide (30 m l . )  and p y r i d i n e (20  The s o l u t i o n was kept i n an o i l bath at 9 0 ° . c h l o r o f ormylacetate  (4„8g.,  0.031  i n a hot ml.).  A s o l u t i o n of  ethyl-  moles) i n dimethyl formamide  (10ml.) was added dropwise to the s t i r r e d , hot r e a c t i o n mixture. N i t r o g e n was passed through the apparatus and a d r y i n g tube was used. The r e a c t i o n mixture was s t i r r e d at 9 0 ° f o r 2.5 hours, time the brown s o l u t i o n was poured i n t o with concentrated h y d r o c h l o r i c a c i d .  ice-water  and a c i d i f i e d  solvent y i e l d e d a  small amount of a dimethylformamide s o l u t i o n from which  methanol. identical  The c r y s t a l s  were c o l l e c t e d  on a f i l t e r  crystals  and washed with  Examination of the product by TLC showed that i t to s t a r t i n g m a t e r i a l .  which  E x t r a c t i o n of the aqueous  s o l u t i o n with choroform and evaporation of the  separated.  after  was '  ' Acetyltrispyrone  (57):  Trispyrone (56) a c e t i c a c i d (3 m l . ) added.  63.  (517 mg. 2 mmoles was d i s s o l v e d  and a c e t y l  c h l o r i d e (1.9  in trifluoro-  m l . , 12 mmoles)  was  The mixture was heated on a steam bath f o r 24 hours.  Hydrogen c h l o r i d e was evolved. i n t o ice-water f i l t e r e d off  (25 m l . ) p r e c i p i t a t i n g a yellow  s o l i d which was  and washed s e v e r a l times with c o l d w a t e r .  m a t e r i a l was d i s s o l v e d activated  The r e a c t i o n mixture was poured  i n hot e t h y l a c e t a t e (600 m l . ) ,  t r e a t e d with  c h a r c o a l , and f i l t e r e d through a c e l i t e f i l t e r .  pale yellow  filtrate  was concentrated i n vacuo u n t i l  occurred at which p o i n t the s o l i d was f i l t e r e d o f f with c o l d e t h y l a c e t a t e . Analysis:  Yield:  Pound:  Spectral Properties:  0, X  NMR ( t r i f l u o r o a c e t i c  v  m  (Nujol)  acid)  and washed twice  0, 42.48.  C  H 1  4  C 8  8  (ethanol) 430 mu (€ = 2 , 0 0 0 ) 373 mu (€ = 16,  1750 b, 1640  7.45T (3H)',  s,  1600  7.18T(3H),  s,  000), 1540 b cm" . 1  3.40T(1H)  No r e a c t i o n occurred with f e r r i c c h l o r i d e i n Acetyl  285-300°.  42.08.  390 mu (€ = 12,000) shoulder,  269 mu (€ = 9000).  The  crystallization  410 mg., 6 8 ° / o ; mp.  G, 55.02; H, 2.50;  r e q u i r e s C, 55.27; H , 2.65;  shoulder,  The crude  C  ethanol.  t r i s p y r o n e was also obtained when the molar r a t i o of  t r i s p y r o n e to a c e t y l  c h l o r i d e was 1:1  and 1:2;  however,  some  s t a r t i n g m a t e r i a l remained i n each case, as was shown by TLC and UV (1:1, 275 mu).  A  (ethanol) 375,.278 mu; 1:2,  X  (ethanol)  377,  Only a small amount of t r i s p y r o n e remained when the  r a t i o was used.  1:4  64, A c e t y l t r i s p y r o n e was the major product furing. i n i t i a l attempts to synthesize tetrapyrone  (58),  Tetrapyrone (58,) ' Two attempts were made to synthesize tetrapyrone from t r i spyrone: (a)  Trispyrone (56)  (0,7g,,  2,67 mmoles)  was d i s s o l v e d  a c e t i c a c i d (5 ml,)' and malonyl c h l o r i d e ( 3 , 0 g , , added.  and the r e s u l t i n g Yield:  850 mg, , ( p a r t l y polymeric m a t e r i a l ) . i n hot e t h y l acetate (500  and c o n c e n t r a t i o n of the yellow  acetate and ether.  Yield:  270mg.,  charcoal.  filtrate  l i z a t i o n occurred the s o l i d was f i l t e r e d o f f  T r i s p y r o n e (56)  a c e t i c a c i d (2 m l . )  (0.4g.,  1,53  3.33°/o,  mmoles)  After  until  crystalethyl  A l l properties acetyltrispryone,  was d i s s o l v e d  and malonyl c h l o r i d e ( 3 . 0 g . ,  in trifluoro-  21.3 mmoles)  was  The mixture was heated on the steam bath for 90 minutes  y i e l d i n g a thick black t a r .  On treatment with e i t h e r ,  was obtained which was f i l t e r e d o f f and washed with Yield:  ml.)  and washed with  i n d i c a t e d t h a t t h i s product was i d e n t i c a l with  added.  ether  and washed s e v e r a l times with  and the brown s o l u t i o n t r e a t e d with a c t i v a t e d filtration  was  hours.  The s l u r r y was t r e a t e d with  s o l i d f i l t e r e d off  The product was d i s s o l v e d  (b)  21,3 mmoles)  The mixture was heated on the steam bath f o r three  Hydrogen c h l o r i d e , was evolved.  ether.  in trifluoro-  a brown s o l i d  ether.  l . O g , ( p a r t l y polymeric m a t e r i a l ) . The s o l i d s o l i d was d i s s o l v e d  i n hot e t h y l a c e t a t e  y i e l d i n g a dark brown s o l u t i o n which was t r e a t e d with charcoal and f i l t e r e d concentrated  through c e l i t e .  The yellow  (300ml,)  activated  filtrate  in vacuo u n t i l c r y s t a l l i z a t i o n commenced,  was  and the  solid  65. isolated TLC  by  filtration.  (50 p e r  cent acetic  Only  a few  = 0,3  Generation  of P o l y a c e t a t e Chains  Opening  N  (cf, acetyl  trispyrone,  and  Rf  resulted.  gel) revealed  =  a  0,35),  Subsequent  Aldol  Condensation  of Bispyrone (49):  (a) Bispyrone in  of m a t e r i a l  acid-chloroform/silica  spot a t Rf  1.  milligrams  ( 3 . 0 g . , 0 . 0 1 5 5 m o l e s ) was  methanolic potassium hydroxide  almost  (1200  completely  ml.  1.20  dissolved  moles)  and  2?  stirred this  a t room t e m p e r a t u r e  time, a  reaction  small  flask.  became o r a n g e , m i x t u r e was  amount o f  The and  finally  reduced  m l . ) , and  paper)  a t 0°  (ice-water  feathery white  Yield  200  mg.,  ether y e i l d e d to  be  C,  Spectral  X NMR  mu  Found:  C,  Properties:  ^  Mass  mass u n i t s ,  V  21  and  ice  (indicator  acid.  A  quantity free.  acetone-petroleum  T h i s c o m p o u n d was  ( c o m p o u n d A)  5.24;  m  a  x  0,  ( e t h a n o l ) 315 mu 1650  (€ = b,  7.53T(3H),  spectrometric analysis ( c f . 240.  water  shown  (60)„  39.49.  C  i2°ll°6  39.95.  (Nujol)  acid):  but  were f i l t e r e d  from  112-113°.  5 5 . 2 7 ; H, 0,  mu,  which  the  reaction  to 6  hydrochloric  of  yellow,  The  i n vacuo,  dicarboxylate  5.05;  (trifluoroacetic  3.48T(1H). 240  289  hours.  Recrystallization  (€ = 1 2 , 4 0 0 ) s h o u l d e r , 247  (base)  6N  precipitated  w h i t e n e e d l e s , mp.  5 5 . 0 0 ; H,  ml.  was  adjusted carefully  bath with  dimethyl-2,4-orcinol  requires  35  At  i n the bottom  initially  after  t o 250  t h e pH  crystals  5.4°/o.  Analysis:  260  brown  f o r 35 h o u r s  remained  solution  i n volume  ( t o 500  nitrogen  solid  reaction  added  of  under  5580), 1620  (€ =  232  mu  s, 1570  5.91T(3H),  s  5580), (€. =  33,300);  cm" . 1  5,85T(3H),  showed t h e p a r e n t peak  f o r C, H,,0..) LZ 11 D o  mu  at  6.6. Reaction with f e r r i c complex.  c h l o r i d e i n ethanol y i e l d e d a dark red  No r e a c t i o n with sodium bicarbonate was observed.  The mother l i q u o r s from compound A were extracted with chloroform (900 m l . ) .  The very pale yellow  s o l u t i o n was  to dryness i n vacuo y i e l d i n g a c r y s t a l l i n e s o l i d . little white mpt, mp.  Washing with a  benzene removed the yellow o i l y contamination l e a v i n g a crystalline solid,  100-128°. 138 -  140 .  orsellinate  compound B.  (6l). (ethanol)  X  v (KBr) 1645 b, 1617 s, max 7.54T(3H),  acetone):  301 mu, (€ = 9,600),  (base) 305 mu (€ = 12,700),  m six  (€ = 8050).  6.11T(3H),  Mass spectrometric a n a l y s i s 1 0  18°/o;  This compound was shown to be methyl  265 mu (€ = 25,600); X  9  0.5g.,  Sublimati on under h i g h vacuum y i e l d e d white  Spectral Properties:  C H  Yield:  R e c r y s t a l l i z a t i o n from benzene y i e l d e d white prisms  p r i s m s , mp. 138-139. 5 ° .  for  evaporated  1585 s cm" .  3.73T(2H),  1  240 mu NMR (deutero-  1.03T(1H), -1.58T(1H).  showed the parent peak at 182 ( c f .  182.  0 ). 4  R e a c t i o n with f e r r i c green complex.  c h l o r i d e i n ethanol y i e l d e d a brown-  No r e a c t i o n with sodium bicarbonate was observed.  TLC (50 per cent a c e t i c  a c i d - c h l o r o f o r m / s i l i c a gel)  showed  compound B to be i d e n t i c a l with authentic methyl o r s e l l i n a t e . other p r o p e r t i e s agreed with t h i s  All  conclusion.  This aqueous l a y e r from the chloroform e x t r a c t i o n y i e l d i n g compound B was c a r e f u l l y taken to pH 2 with d i l u t e h y d r o c h l o r i c a c i d and the red s o l u t i o n e x t r a c t e d with chloroform (900 m l . ) . deep yellow s o l u t i o n was taken to dryness i n vacuo y i e l d i n g a  The  67, yellow t i n t e d crude c r y s t a l l i n e  solid.  Washing with benzene and  r e c r y s t a l l i z a t i o n from benzene y i e l d e d a pale yellow compound C, mp. 1 4 0 - 1 6 3 ° with effervescence,  tinted  Recrystallization  from benzene y i e l d e d c r y s t a l s m e l t i n g at 1 5 7 - 1 6 7 ° with TLC showed t h i s  to be one compound.  effervescence,  Sublimation at high vacuum  y i e l d e d white p r i s m s , mp, 1 6 6 ° needles form; 1 9 0 - 1 9 0 . 5 ° with  solid,  melting  effervescence. This compound was shown to be the para-methyl ether of  linic  acid,  p-0-methyl o r s e l l i n i c a c i d  orsel-  (62).  Spectral Properties: 260 mu (€ = 7,410); X (€ = 8,650)  shoulder,  X (ethanol) 302 mu (€ = 2,620), max (base) 300 mp, (€ = 7,170) shoulder, 270 mu.  f f l a x  249 mu (€ = 11,820).  v  (KB ) 1640 b, nicix  1585 m c m " . 1  NMR (deuteroacetone)  Mass s p e c t r o m e t r i c a n a l y s i s (cf.  182.17 f o r  C H 9  1 0  1L  7.43T (3H), 6.16x  (3H), 3.64T  (2H).  showed the parent peak at 182 mass u n i t s  0 ). 4  R e a c t i o n with f e r r i c c h l o r i d e i n ethanol y i e l d e d a brown-green complex.  R e a c t i o n with sodium bicarbonate produced  TLC d i s t i n g u i s h e d authentic (b) N  (62)  o r s e l l i n i c acid Bispyrone (49)  34  from authentic methyl  , and  (l.47g.,  effervescence. orsellinate,  / \ (60). 0.00758 moles) was d i s s o l v e d  in  10 per cent aqueous methanolic potassium hydroxide (150 m l . ,  0,150 days.  moles) and s t i r r e d at room temperature under n i t r o g e n f o r two The r e a c t i o n s o l u t i o n ,  c o l o r e d as i n the 100 per  methanolic case, was concentrated to 40 m l . i n vacuo.  cent Ice and water  68. •were added to b r i n g the volume to 100 ml. and the pH was adjusted at 0° to 2 with 6N h y d r o c h l o r i c a c i d . became t u r b i d and a t pH 2 a q u a n t i t y of s o l i d Yield:  65 mg,  4.7°/o; mpt.  precipitated.  ether y i e l d e d white  152-160° with e f f e r v e s c e n c e .  i d e n t i c a l i n every way  At pH 3, the s o l u t i o n  150-167° with e f f e r v e s c e n c e .  l i z a t i o n from acetone-petroleum mpt.  carefully  Recrystal-  crystals  This compound was  shown to be  with compound B (62) from the previous :  reaction. The mother l i q u o r s from the above s o l i d were e x t r a c t e d with chloroform (200 ml.)  and the s o l u t i o n taken to dryness i_n vacuo.  A q u a n t i t y of c r y s t a l l i n e m a t e r i a l remained which, a little  chloroform, y i e l d e d white c r y s t a l s , mp.  R e c r y s t a l l i z a t i o n from chloroform-benzene Yield:  251 mg,,.18,2°/o; mp.  110-135°.  vacuum y i e l d e d white prisms, mp.  on washing with 100-135°.  y i e l d e d white prisms. Sublimation under high  126-135°.  This compound was  shown  to be i d e n t i c a l i n every way with authentic methyl o r s e l l i n a t e ( 6 l ) . Mixed m e l t i n g p o i n t and mixed TLC confirmed t h i s c o n c l u s i o n . (c)  Bispyrone (49) (2.2g., 0.011  moles) was  aqueous potassium hydroxide (150 ml., 0.150  The  reaction  adjusted to pH 2 a t 0° with concentrated h y d r o c h l o r i c  acid.  The usual chloroform e x t r a c t i o n y i e l d e d only 53 mg.  erial,  and was  shown by TLC  of mat-  (50 per, cent a c e t i c a c i d - c h l o r o f o r m / .  s i l i c a g e l ) to contain a mixture of compounds. was  N  moles) and s t i r r e d at  room temperature under n i t r o g e n f o r 70 minutes. s o l u t i o n was  dissolved i n  Consequently, i t  decided to reduce the aqueous s o l u t i o n to dryness by f r e e z e  drying.  A q u a n t i t y of y e l l o w s o l i d remained and was  e x t r a c t e d with  hot acetone  (150 ml,).  The white s o l i d r e s i d u e , separated by  filtration,  on examination proved to be potassium a c e t a t e .  69. Further the  concentration  remainder  evaporation  of  the  of  the  potassium  y i e l d e d a red  acetate,  gum.  and  w a t e r y i e l d e d a mass o f  mp.  174-177° w i t h  acetone  effervescence  and  from water-acetone y i e l d e d needles effervescence orsellinic  and  acid  Spectral (€  =  7290);  v  (KBr)  green  A  (b a s e )  1643  b.  ferric  Reaction  be  compound t o  methanolic at  room  ution  bispyrone  potassium  The  solution  (initially  at  60°  reversed  and  mg.,  on  acetone 6°/o;  Recrystallization  c o m p o u n d was  with  shown t o  be  and with  mu,  (€ =  2740),  (€ = 4 4 2 0 ) ,  274  mu  (€ =  6060).  TLC  7.47T(3H),  with  the  (300  on  pH  0.30  f o r two light  a  concentrated The  ml.,  concentrated  finally  showed  acid  (pre-  of  Hoesch).  method  (55):  became  was  with  point  orsellinic  acid by  mu  brown-  proceed  mixed m e l t i n g  authentic  260  3.73T(2H).  yielded a  bicarbonate  and  orsellinic  and  occurred. the  300  under n i t r o g e n  reaction.  hydroxide,  by  hydroxide  orange  effervescence  with  180—188  ( l . 4 2 g . , 0 . 0 0 6 m o l e s ) was  clear  mixture  at  liquor  (ethanol)  sodium  Acetylbispyrone  temperature  was  gum  123  c h l o r i d e i n ethanol  identical  dicarbcmethoxy  Acetyl  mu  with  the  Opening of  mother  decomposition.  (deuteroac etone)  Examination  2.  the  Yield:  This  A  298  NMR  with  complex.  from  the  precipitated  (27)„  effervescence.  pared  of  melting  decomposition.  Properties:  Reaction  while  Treatment  crystals.  solution  was  reaction mixture  dissolved in  moles),  days.  brown  The  at  the  i n vacuo  steam b a t h )  and  and  to  end  with the  7 with  extracted with  stirred  reaction  hydrochloric acid, adjusted  N  of  sol-  the  heating pH  of  during 6N  the which,  sodium  chloroform  70.  (150 and  ml.).  This  crystals  chloroform needles.  formed  and  283  335  =  (€  mu =  (€  3440)  mg.,  shown  evaporated oily  residue.  5.4°/o:  to  to  mp.  in  mu  (€  Washing  with  262  shoulder,  X  (n-hexane)  1610  b,  b  324  mu  284 mu  (€ mu  (€  1  (€  =  NMR  cm" .  20, =  152-153°.  Further  recrys-  100);  7560),  889),  276  l i t t l e  white  needles,  orcacetophenone  =  a  yielded  X  mu  mu  =  (€  =  48  =  3440) X  315  (base)  mu  5960)  326).  7.48T  (deuteroacetone)  (€  '  157.5-158°.  shoulder;  mu  (€  47  (acid)  max  234  mp.  (63).  A. ( e t h a n o l ) 315 m ELX 7 5 6 0 ) , 2 3 3 mu ( € = 5 9 6 0 )  =  vacuo  chloroform  yielded white be  dryness  Properties:  6020),  1565  the  chloroform  was  Spectral shoulder,  from  65  from  compound  was  r e c r y s t a l l i z a t i o n from  Yield:  tallization This  solution  shoulder; (KBr)  v  (3H),  7.40T  =  10,000);  (3H),  .  3.73T ( 2 H ) , -0.13T ( I H ) , -3.99T ( l H ) . 35 Reported (base)  X X  values:  330  mu  (n-hexane)  (€  321  = (€  •  (ethanol)  X  11,700);  X  =  275  4170),  _  283  (acid) mu  =  (6  mu  (.6  283  (€•=  10,000);  10,200).  XX c L X  Reaction mixed  melting  be  identical  3.  Opening  open  gave  the  ferric  point,  and  with of  Several to  with  sets  trispyrone best  the  authentic  Trispyrone  of and  results  chloride  spectral  data  a dark red complex. showed  orcacetophenone  .  (63).  this  TLC,  compound  to  47  (56):  reaction obtain is  yielded  conditions a workable  outlined  below.  were  examined  product.  The  in  the  method  attempt which  71. Trispyrone (56)  (l.09g.,  0,0042 moles) was d i s s o l v e d i n N  methanolic potassium hydroxide (1000  m l . , 1.00  at room temperature under n i t r o g e n for 2 days. was i n i t i a l l y a b r i l l i a n t green, then pale y e l l o w ,  mole) and s t i r r e d The s o l u t i o n ,  which  q u i c k l y darkened and became  a p e r i o d of an hour.  The s o l u t i o n was  i n vacuo l e a v i n g a l i g h t brown syrup.  orange,  concentrated  Ice and water were added and  the s o l u t i o n adjusted to pH 2 with concentrated h y d r o c h l o r i c a c i d (final  volume 800 m l . ) .  This aqueous s o l u t i o n was extracted  chloroform (450 m l . ) and the chloroform evaporated to i n vacuo  y i e l d i n g a yellow  residue.  Yield:  dryness  291 mg.  r e s i d u e was separated on a p r e p a r a t i v e t h i n l a y e r p l a t e ( s i l i c a gel with organic phosphor; 10 per cent a c i d The p l a t e was d i v i d e d into and of  eluted.  with  The t o t a l (8 X 20  in,)  chloroform).  seven main bands which were scraped o f f  The c e n t r a l f r a c t i o n (Rf = 4 . 5 - 6 . 0 ) y i e l d e d 34.7 mg.  crystalline material.  F u r t h e r separation of t h i s f r a c t i o n on a  preparative thin layer plate minor f r a c t i o n s .  ( 2 X 8 in.)  y i e l d e d one major and two  The major f r a c t i o n y i e l d e d a compound which was  p u r i f i e d by r e c r y s t a l l i z a t i o n from water-acetone y i e l d i n g n e e d l e s . Yield:  17 mg., 2 . 3 ° / o ;  mp. 2 4 7 - 2 5 1 . 5 ° .  A f t e r d r y i n g i n vacuo,  m e l t i n g p o i n t was r a i s e d to 2 5 0 - 2 5 3 ° with s u b l i m a t i o n .  This  compound was shown to be 3-methyl-6,9-dihydroxyisocoumarin Spectral Properties. 288 mu ( 6 = 4000), (€ = 39,000), shoulder,  A  in ctx  the  (67).  (ethanol) 237 mu (€ = 4,900),  277 mu (€ = 5640), 257 mu ( 6 = 9000), 244 mu  237 mu (€ = 34,000); X  332 mu (€ = 14,300) shoulder,  (6 = 27,200) shoulder,  (base) 345 mu (€ = 11,500) 307 mu (€ = 19,900),  254 mu (€ = 43,700),  26o mu  243 mu (6 = 41,600).  72. v  (KBr) 1685 b, 1627 s cm" .  NMR (deuteroacetone):  1  3 . 6 2 T . ( 3 H ) , 0.47T  (IH), -1.17T  (lH).  Mass spectrometric  showed the parent peak at 192 mass u n i t s Reported v a l u e s :  A  7.78T  (cf.  192.2  (3H).  analysis,  f o r C^QHgO^).  (ethanol) 317 mu, (€ = 6,300), 276 mu  IBEX  (€ = 29,500) 260 mu (30,900), Reaction with f e r r i c  244 mu (€ = 56,200), 237 mu (€ = 44,600).  c h l o r i d e i n ethanol gave a brown complex.  T e s t i n g with sodium bicarbonate s o l u t i o n gave no  effervescence.  Freeze d r y i n g of the aqueous l a y e r from above y i e l d e d a yellow  s o l i d which, on e x t r a c t i o n with hot chloroform y i e l d e d a small  q u a n t i t y of gum.  Examination by TLC showed the major product to be  acetyl bispyrone,  a c o n c l u s i o n confirmed by i s o l a t i o n of  corresponding band from a p r e p a r a t i v e TLC p l a t e  the  (8 * 20 i n . )  and  examination by UT, IR, NMR and mixed TLC. A repeat of the above r e a c t i o n gave a d i f f e r e n t major product although (67) with Rf = 0 . 7 , mp.  was present as a minor product.  This new product  was not i d e n t i f i e d although i t was examined thoroughly;  150-152°. Spectral Properties:  A  (base) 348,  272,  1610 b, 1570 m . c n T . 1  3.64T  ^  249 mu.  m  a  x  V  (ethanol) 316,  265 sh, 248,  (KBr) 1712 m, 1670  NMR (deuterochloroforrn) :  probably 3:6:4:1 but not c l e a r .  7.28T,  s,  230 mu;  1650  sh,  6.11T, 5.97T,  Mass spectrometric  analysis  showed the parent peak at 220 mass u n i t s . Reaction with f e r r i c complex.  c h l o r i d e i n ethanol y i e l d e d a pink  A sodium bicarbonate t e s t y i e l d e d i n c o n c l u s i v e  Reaction with 2 , 4 - d i n i t r o p h e n y l hydrogen gave a yellow  results.  solid.  73. Other attempts  to open t r i s p y r o n e met with v a r y i n g  degrees  of success: (a)  This method was  i d e n t i c a l to the one above with the exception  that s e p a r a t i o n of the products was column ( l O g . ) .  attempted  using a s i l i c a gel  Only very crude s e p a r a t i o n r e s u l t e d and the f r a c -  t i o n s were combined f o r chromatrography on a p r e p a r a t i v e t h i n layer plate. (b)  T r i s p y r o n e (56) (300 mg,,  1.15  mmoles) was  aqueous e t h a n o l i c potassium hydroxide s t i r r e d at room temperature  dissolved i n N  (100 ml.,  100 mmoles) and  under n i t r o g e n f o r 2 days.  The  s o l u t i o n went from green through orange to yellow as b e f o r e . s o l u t i o n was  concentrated iri vacuo and adjusted to pH 7 with d i l u t e  h y d r o c h l o r i c a c i d and t h i s s o l u t i o n was The  chloroform l a y e r was  which was,  The  e x t r a c t e d with chloroform.  e x t r a c t e d with sodium bicarbonate  i n t u r n , e x t r a c t e d with ether.  TLC  examination  solution of t h i s  product showed a major spot corresponding to (67), but there  was  too l i t t l e m a t e r i a l f o r f u r t h e r work. (c)  A l a r g e s c a l e r e a c t i o n with t r i s p y r o n e (56) (2.47g., 0.0094  moles) i n N e t h a n o l i c potassium f a i l e d to produce encouraging  hydroxide  results.  (1000 ml.,  This was  1.0  mole)  l a r g e l y due to, the  s p a r i n g s o l u b i l i t y of t r i s p y r o n e i n t h i s r e a c t i o n medium. (d)  T r i s p y r o n e (56) (l06mg., 0.405 mmoles) was  aqueous potassium hydroxide  (60 ml.,  under n i t r o g e n at room temperature was  dissolved i n N  60 mmoles) and allowed to stand  f o r 75 minutes.  The  solution  adjusted to pH 2 at 0° with concentrated h y d r o c h l o r i c a c i d ,  and e x t r a c t e d with chloroform (200 ml.). to dryness i n vacuo.  Examination  This s o l u t i o n  was  reduced  of the residue by TLC showed that  the major component of the r e a c t i o n mixture was  orcacetophenone (63).  74. Table I I I SPECTRAL TABLES Compound Dehydroacetic a c i d (30)  UV mu.  -1 ., IR' m"  NMH :  T  309 (11,200)  1745  7.60 (3H)  224  1735  7.16 (3H)  1650  3.70 (IH)  (9,770)  1620 1560 Triacetic l a c t o n e (48)  Bispyrone (49)  283  328  (6,750)  (6,800)  269 (10,400)  1700  7.53 (3H)  1645  3.79 (IH)  1575  3.48 (IH)  1770 sh  7.44 (3H)  1745 s  4.02 (IH)  1705 vs  3.30 (IH)  1645 sh 1570 s Acetylbispyrone (55)  Trispyrone (56)  347 (14,300)  1765 m  261  (6,400)  1730 s  7.48 (3H)  225 (12,800)  1630 s  7.17 (3H)  1550  3.45 (IH)  373 (10,000)  1750 b  7.42 (3H)  282  (8,750)  1710 s  3.96 (IH)  205  (6,700)  1640 sh  3.30 (IH)  Compound  UV  mu  IR  m"  NMR  1  T  1622 m  Acetyl trispyrone  sh  1535  s  430  (2,000)sh  1750  b  7.45  (3H)  390  (12,000)sh  1640  s  7.18  (3H)  373  (16,000)  1600  s  3.40  (IH)  269  (9,000)  1540  b  315  (5,580)  1650  b  7.53  (3H)  260  (12,400)  sh  1620  s  5.91  (3H)  247  (16,200)  sh  . 1570 s  5.85  (3H)  232  (33,300)  3.40  (IH)  (57)  Dimethyl-2,4orcinol dicarboxylate (60)  (base)  Methyl orsellinate (6l)  Orsellinic methyl (62)  1565  acid ether  289  301  (9,600)  1645  b  7.54  (3H)  265  (25,600)  1617  s  6.11  (3H)  (base )305  (12,700)  1585  s  3.73  (2H)  240  (8,050)  1.03  (IH)  -1.58  (IH)  302  (2,620)  1640  b  7.43  (3H)  260  (7,410)  1620  b  6.16  (3H)  (base )300  (7,170)  sh  1585  m  3.64  (2H)  270  (8,650)  sh  249  (11,820)  76, Compound  UV  IR  NMR  300  (2,740  260  (7,290  (base)298  (4,420  274  (6,060  315  (3,440  283  (7,560  233  (5,960  (b ase )335  (6,020  3.73 (2H)  262 (20,100  -0.12 (IH)  Orsellinic a c i d (27)  Orcacetophenone (63)  1643 b  7.47 (3H) 3.73 (2H)  sh  1610 b  7.48 (3H)  1565 b  7.40 (3H)  sh  -3.99 (IH)  (acid)315  (3,440  284  (7,560  234  (5,960  (n-hexane)324  (889  276  (326  327  (4,900  1685 b  288  (4,000  1627 s  277  (5,640  3.62 (3H)  257  (9,000  0.47 (IH)  244 (39,000  -1.17 (IH)  3~Methyl-6,8dihydroxyisocoumarin (67)  237  sh  sh  (34,000  (base)345 (11,500  sh  332 (14,300  sh  307  (19,900  260 (27,200 254 (43,700 243 (41,600  sh  7.78 (3H)  77. 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