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Use of camphor in terpenoid syntheses Lamb, Nancy Ching-Yun 1979

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USE OF CAMPHOR IN TERPENOID SYNTHESES by NANCY CHING-YUNf^LAMB B.Sc. U n i v e r s i t y o f Hong Kong, 1974  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s t h e s i s as conforming to the required  standard  THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1979  (c) Nancy Ching-Yun Lamb, 1979  In presenting t h i s thesis in p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I further agree that permission for extensive copying of t h i s thesis f o r s c h o l a r l y purposes may be granted by the Head of my Department or by his representatives.  It i s understood that copying or p u b l i c a t i o n  of t h i s thesis f o r f i n a n c i a l gain s h a l l not be allowed without my written permission.  Department n f Chemistry The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5  D a t e  DE-6  BP  7 5 - 5 11 E  8th June, 1979,  - ii -  ABSTRACT  Camphor has been f u n c t i o n a l i s e d at the C(5), C(6), C(8) and C(9) positions by procedures previously developed and the corresponding d e r i v a t i v e s have subsequently been u t i l i s e d as key intermediates in mono- and sesquiterpenoid syntheses. The monoterpenoid analogues of the plant growth-promotor ( - ) - c i s sativenediol and the g r o w t h - i n h i b i t o r (-)-helminthosporal, (-)-5-exo, 6exo-dihydroxycamphene and (+)-!,4-diformyl-2,3,3-trimethylcyclopentene r e s p e c t i v e l y , have been prepared from (-)-camphor by a synthetic route i n v o l v i n g the 'remote o x i d a t i o n ' of (+)-isobornyl acetate to a mixture of 5- and 6-oxoisobornyl acetates.  The t r a n s - d i o l (-)-5-endo, 6-exo-  dihydroxycamphene was also obtained during t h i s study.  The synthetic  monoterpenoids and t h e i r enantiomers were found to be devoid of growthpromoting or g r o w t h - i n h i b i t i n g properties on two v a r i e t i e s of r i c e (Oryza sativa). The 'remote o x i d a t i o n ' technique has also been applied to the synthesis of n o j i g i k u alcohol [(+)-6-exo-hydroxycamphene], Chrysanthemum japonense, from (+)-camphor.  a metabolite of  The s t r u c t u r e , absolute  c o n f i g u r a t i o n , and physical constants of t h i s monoterpenoid alcohol and i t s d e r i v a t i v e s have thus been e s t a b l i s h e d . (+)-9-Bromocamphor was used as a s t a r t i n g material f o r two unsuccessful synthetic approaches to the t r i s n o r s e s q u i t e r p e n o i d albene, a metabolite of plants of the genera Petasites albus (L.) Gearth and Adenostyles a l l i a r i a e (G.) Kern.  One of these routes was based on the proposal that e p i - B -  - iii -  santalene, a natural sesquiterpenoid which had previously been synthesised in our laboratory, could be a biosynthetic precursor of albene.  However,  during these investigations the original structure of albene was revised and a third synthetic route to this compound using (+)-8-bromocamphor as starting material was therefore studied. (+)-8-Bromocamphor has also been u t i l i s e d as the starting material in a synthetic approach to clausantalene, a sesquiterpenoid isolated from Clausena indica 01iv. (Rutaceae). A synthesis of dehydroclausantalene and epidehydroclausantalene T_9-hydroxy-9-(3' -methyl-V -butenyl )camphenes] has been accomplished but the regio- and stereoselective hydration of these two compounds to clausantalene and i t s epimer respectively i s s t i l l under investigation.  - iv TABLE OF CONTENTS  Page ABSTRACT  ii  TABLE OF CONTENTS  iv  LIST OF TABLES  .  vi  ;  LIST OF FIGURES  vii  LIST OF SCHEMES  ix  ACKNOWLEDGEMENT  xii  PART I  SYNTHESIS AND BIOLOGICAL A C T I V I T I E S OF MONOTERPENOID ANALOGUES OF cis.-SATIVENEDJ.OL AND HELMINTHOSPORAL  INTRODUCTION A. B.  R e g u l a t i o n o f P l a n t Growth by Phytohormones B i o l o g i c a l and Chemical Remote O x i d a t i o n o f Bicyclo[2,2,l]heptane Derivatives  1 15  DISCUSSION  24  EXPERIMENTAL  60  BIBLIOGRAPHY  87  PART I I  SYNTHESIS AND ABSOLUTE CONFIGURATION OF NOJIGIKU ALCOHOL  INTRODUCTION  92  DISCUSSION  94  EXPERIMENTAL  107  BIBLIOGRAPHY  120  -  V  -  Page PART III  SYNTHETIC APPROACHES TO ALBENE  INTRODUCTION  122  DISCUSSION  132  EXPERIMENTAL  183  BIBLIOGRAPHY  217  PART IV  SYNTHETIC APPROACHES TO CLAUSANTALENE  INTRODUCTION  221  DISCUSSION  224  EXPERIMENTAL  237  BIBLIOGRAPHY  243  - vi -  LIST OF TABLES  PART I Page Table  I  T a b l e II  E f f e c t o f S y n t h e t i c M o n o t e r p e n o i d s on R i c e S e e d l i n g s ( O r y z a s a t i v a ) ( e s t i m a t e d by t h e a g a r medium method)  57  E f f e c t o f S y n t h e t i c M o n o t e r p e n o i d s on R i c e S e e d l i n g s ( O r y z a s a t i v a ) ( e s t i m a t e d by t h e m i c r o d r o p method)  58  - v i i-  LIST OF FIGURES  PART I Figure  Page  1  N.M.R. Spectrum (100 MHz) o f 6-exo-Hydroxy-5-oxocamphene  2  I.R. Spectrum o f 6^exo-Hydroxy-5-0xocamphene  3  N.M.R. Spectrum (TOO MHz) o f (-)-5-exo, 6 - e x o - D i h y d r o x y -  (83)  (83) ... 31 32  camphene (66)  37  4  I.R. Spectrum o f (-)-5-exo, 6-exo-Dihydroxycamphene  5  N.M.R. Spectrum (100 MHz) o f (-)-5-endo, 6 - e x o - D i h y d r o x y camphene (87) I.R. Spectrum o f (-)-5-endo, 6-exo-Di hydroxycamphene (87)  39 40  7  N.M.R. S p e c t r u m (100 MHz) o f ( + ) - l , 4 - D i f o r m y l - 2 , 3 , 3 T r i m e t h y l c y c l o p e n t e n e (67)  54  8  I.R. S p e c t r u m o f ( + ) - l , 4 - D i f o r m y l - 2 , 3 , 3 T r i m e t h y l c y c l o p e n t e n e (67)  55  6  (66)  38  PART I I Figure  Page  1 ( a ) N.M.R. S p e c t r u m Hydroxycamphene (b) N.M.R. S p e c t r u m Hydroxycamphene 2 3 (a) (b) (c)  (60 MHz) o f S y n t h e t i c (+)-6-exo(1) (60 MHz) o f N a t u r a l (+)-6-exo(1)  I.R. Spectrum o f (+)-6-exo-Hydroxycamphene (Nojigiku A l c o h o l ) (1) N.M.R. Spectrum o f (-)-6-exo-Hydroxycamphene N.M.R. Spectrum o f (-)-6-exo-Hydroxycamphene N.M.R. Spectrum o f (+)-6-exo-Hydroxycamphene  101 101 102  (25) 104 (25) w i t h TFMC-Eu .. 104 (1) w i t h TFMC-Eu ... 104  - viii  PART  -  III  Figure  Page  1  N.M.R. Spectrum (100 MHz) of O l e f i n (A)  140  2  I.R. Spectrum of O l e f i n (A)  141  3  N.M.R. Spectrum (100 MHz) of Compound (B)  145  4  I.R. Spectrum of Compound (B)  146  5  N.M.R. Spectrum (100 MHz) of Compound (C)  149  6  N.M.R. Spectrum (100 MHz) of Compound (G)  154  7  N.M.R. Spectrum (100 MHz) of Compound (H)  160  8  I.R. Spectrum of Compound (H)  161  9  N.M.R. Spectrum (100 MHz) of Compound (J)  163  10  I.R. Spectrum of Compound (J)  164  11  N.M.R. Spectrum (100 MHz) of Compound (K)  165  12  I.R. Spectrum of Compound (K)  166  13  N.M.R. Spectrum (100 MHz) of Compound (85)  170  14  I.R. Spectrum of Compound (85)  171  15  N.M.R. Spectrum (100 MHz) of Compound (86)  172  16  I.R. Spectrum of Compound (86)  173  17  Stereodiagram of 2-exo, 3-exo-Dihydroxy-2,3-Dimethyl4-endo-Vinylbicyclo"[372,l]octane (86)  174  PART IV Figure 1  P a  N.M.R. Spectrum (100 MHz) of 9-Hydroxy-9(3'-Methyl-2'-Butenyl)camphenes (26)  9  e  234  -  ix  -  LIST OF SCHEMES  PART I Scheme  Page  1  3  2  5  3  7  4  io-n  5  16  6  17  7  19  8  20  9  21  10  26  11  34  12  35  13  43  14  45-46  15  47  PART II Scheme  Page  - x -  Scheme  Page  4  103  5  106  PART  Scheme  III  Page  1  123  2  125  3  126  4  127  5  128  6  130  7  133  8  134  9  135  10  137  11  138  12  143  13  147  14  148  15  150  16  153  17  155  18  156  19  158  20  168  -  Scheme  21  xi  -  Page 1 7 8  22  179  23  182  PART  IV  Scheme 1  Page  223 2  2  5  2  3  229  - xii -  ACKNOWLEDGEMENT  I would l i k e to extend my sincere g r a t i t u d e to Professor Thomas Money f o r his guidance and encouragement during my research and preparation of this thesis.  Stimulating discussions with Dr. Nicholas Darby, Dr. Malcolm  A l l e n and other members of the Department of Chemistry at the U n i v e r s i t y of B r i t i s h Columbia have also been most valuable. Much of my research would not have been possible without the generosity of members of t h i s department in providing me with t h e i r equipments and f i n e technical s e r v i c e .  In p a r t i c u l a r , I wish to thank  Professor Edward Piers f o r a g i f t of ( + ) - c i s - s a t i v e n e d i o l , Dr. P h i l i p Salisbury f o r conducting the b i o l o g i c a l t e s t s , Professor James T r o t t e r , Dr. Steve R e t t i g and Miss S y l v i a Spencer f o r performing the X-ray c r y s t a l l o g r a p h i c analyses.  Furthermore, I am most g r a t e f u l to Professor  Shingo Marumo, Nagoya U n i v e r s i t y , Japan, who has generously provided us with samples of ( - ) - c i s - s a t i v e n e d i o l and r i c e seeds, and who has confirmed our bioassay r e s u l t s .  Technical assistance from Mr. A l i s t a i r Fyfe during  the summer of 1978 i s also much appreciated. I am also indebted to Mrs. Thomas Money f o r kindly helping with the formidable task of t y p i n g , Mr. Paul Cachia, Dr. Michael Dabson and Dr. Wolfgang Appel f o r painstakingly proof-reading the t y p e s c r i p t , and Miss S h i r l e y Chow and Mr. John Kwong f o r t h e i r invaluable assistance during the preparation of t h i s t h e s i s . F i n a l l y r e c e i p t of a U n i v e r s i t y of B r i t i s h Columbia Graduate Fellowship (1978-79) i s acknowledged.  -  xiii  -  PART I  S y n t h e s i s and B i o l o g i c a l  Activity  of Monoterpenoid Analogues of c i s - S a t i v e n e d i o l and H e l m i n t h o s p o r a l  -  1  -  INTRODUCTION  A.  R e g u l a t i o n o f P l a n t Growth by Phytohormones P l a n t growth i s a s e r i e s o f p h y s i o l o g i c a l p r o c e s s e s  regulated  by hormones p r o d u c e d i n the p l a n t and t r a n s p o r t e d t o a c t i v e s i t e s v i a the v a s c u l a r system.  Phytohormones, as they a r e c a l l e d , a r e  u s u a l l y e f f e c t i v e i n v e r y s m a l l q u a n t i t i e s and e x h i b i t a f a i r l y broad s p e c t r u m o f a c t i v i t y .  C o n t r o l o f p l a n t growth i s  determined  by the p r e c i s e a d j u s t m e n t o f the r e l a t i v e amounts o f t h e s e hormones, as w e l l as the i n t e r p l a y o f t h e i r f u n c t i o n s . ' ' T h e r e are f o u r i m p o r t a n t c l a s s e s o f phytohormones:The  Auxins The most i m p o r t a n t member i n t h i s group i s i n d o l e - 3 - a c e t i c a c i d  (IAA) (1), a compound which i s p r o b a b l y b i o s y n t h e s i s e d from  trytophan  i n p l a n t s , e s p e c i a l l y i n the y o u n g e r p a r t s such as the t i p o f the main s h o o t .  The d i v e r s i f i e d f u n c t i o n s o f IAA i n c l u d e p r o m o t i o n o f .CH^COOH  (1)  l o n g i t u d i n a l growth, c e l l d i v i s i o n , c e l l e l o n g a t i o n , and a p i c a l dominance, i n h i b i t i o n o f s h e d d i n g o f l e a v e s and f r u i t , i n d u c t i o n o f  parthenocarpy  ( f r u i t f o r m a t i o n w i t h o u t ' f e r t i l i z a t i o n ) , and s t i m u l a t i o n or i n h i b i t i o n o f  -  2 -  some enzymes. Compounds with structures s i m i l a r to IAA have been synthesised in the hope of f i n d i n g more e f f e c t i v e growth regulators and f a c i l i t a t i n g better understanding of s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s . The synthetic compounds shown in Scheme 1 a l l e x h i b i t plant growth regulatory a c t i v i t y and some of them are even more a c t i v e than IAA i t s e l f I t  was observed that in the monochlorophenoxyacetic acid  series the a c t i v i t y increases with the s u b s t i t u t i o n p o s i t i o n of c h l o r i n e in the order 2>3>4.  In the dichlorophenoxyacetic a c i d s , the  2,3-, 2,4-, and 3,4-isomers are a c t i v e but the 2,6- and 3,5-derivatives are not.  Introduction, of a l k y l grouDS into the side-chain of  phenoxyacetic acids revealed the f o i l owing:-  H PhO-C-COOH  PhO-C-COOH  H  H  Active  Active  PhO-C-COOH  PhO-C—COOH  H Active  Inactive  It seems very l i k e l y that the carbon atom « to the carbonyl group has to have at l e a s t one hydrogen atom f o r the compound to be b i o l o g i c a l l y active.  In general, with c h i r a l hormones, only one enantiomer shows  -  3  -  Cl 2,4-Dichlorophenoxy-  1 - N a p h t h y l a c e t ic  acetic  acid  ac i d  12,4-D)  CO OH  OCH COOH 2  Cl 2-Methyl-A-chl  2,3,6-Trichlorobenzoi c  orophenoxyacetic  acid  acid (MCPA)  2,6-Dibromophenol SCHEME  1  -  growth r e g u l a t i n g  4  -  activity.  Cytokinins Phytohormones  o f t h i s t y p e are 6 - s u b s t i t u t e d adenine  derivatives  and some o f the b e s t known examples a r e shown i n Scheme 2. (2) was i s o l a t e d from a u t o c l a v e d y e a s t or h e r r i n g sperm DNA, (3)  is synthetic.  IPA  (4) and z e a t i n  Kinetin whereas  (5) were d i s c o v e r e d i n a wide  v a r i e t y o f p l a n t s and a r e b i o s y n t h e s i s e d i n the r o o t s from adenine and mevalonic a c i d J 3 ' ' 3 As the name suggests ( c y t o k i n e s i s = c e l l elongation, cell  division),  cytokinins  promote  cell  shoots.  They a l s o break the dormancy o f s e e d s , d e l a y s e n e s c e n c e , and  induce the s y n t h e s i s o f  d i v i s i o n , and growth of main and s i d e  enzymes.  Abscisic Acid  Abscisic  acid  A b s c i s i c a c i d i s a s e s q u i t e r p e n o i d p l a n t growth i n h i b i t o r .  It  was f i r s t i s o l a t e d from c o t t o n f r u i t s and l a t e r found i n sycamore l e a v e s and l u p i n p o d s J 9 ' ' 3 kingdom.  In f a c t i t i s u b i q u i t o u s i n the  plant  I t p r o t e c t s p l a n t s from p h y s i o l o g i c a l s t r e s s by s t i m u l a t i n g  the shedding o f l e a v e s and f r u i t s under d r o u g h t ,  as w e l l as by  i n d u c i n g the dormancy o f buds and i n h i b i t i n g seed g e r m i n a t i o n autumn.  in  - 5 -  HK1  HKJ  CH.  CH2  •0'  N  N  Kl  N  N 3  H  H  9  6-Benzylaminopunne  Kinetin (2)  (3)  .  HM  C H  N  2  .CH 2 OH  'CH,  H^  HN  ^ C H ,  'NI  M  "M  H  H 6-Isopenteny laminopurine  Zeati n  (I P A )  (5)  (4)  SCHEME 2  N:H;  CH2  -  Studies  on  the  violaxanthin  (6)  (the  of  bending  respectively) oxidation three  main  inactive that  (Scheme the  and  of  3)  shoot  the  products.  of  third  one  abscisic  acid.  It  was  found  and  was  named  mixture  to  an  explanation  toward  of  and  plant  these,  (7)  away  growth  extracted  from and  to  be  be  responsible  for  light  l i g h t . ^ peel,  Photoprovided  were  biologically  effect  comparable  a mixture  pentadienal,  compound phototropism  from  by  (8),  was  shown  for  orange  inhibitory  of  (9a)  a closely related  exhibited  2-trans-4-trans-isomers  isomer  root  (6),  the  on  provided  inhibition  Two  -  light  and  violaxanthin  and  of  and  of  effect  6  (9a)  and  the  high  of  to  2-cis-4-trans-  (9b).  The  activity  of  the  xanthoxin.  Gibberel1 ins The  g i b b e r e l l i n s are  gibbane  skeleton  diterpenoids  or  norditerpenoids  They  are  with  closely similar structures  the  fungus of  rice  group,  in  the  almost  all  higher  gibberellic acid  Gibberel!a in  the  acid  (GAg)  fifty  gibberellins  (ID  (10)  of  on  (10).  Gibberellic  found  based  Far  fujikuroi, E a s t .  l a  '  are (GA3)  and b  plants now  and  over  known.  The  (11),  causes  is  best  known  a metabolite  vigorous  of  longitudinal  member the growth  - 7 -  SCHEME 3  -  The  functions  As  mentioned  in  dwarf  cell  of  above,  mutants,  induce  gibberellins  they  by  elongation.  requirements  the  application  They  result  of  aleurone  enhance  synthesised  some  and  to  the  formation  of  gibberellins where  and  of to  a  very  the  or  apical  before The  being  proteases  stimulate  uniformly  then  also  IAA,  level  cell  can  of  the  is  be  of  of  IAA  or  is  and  short-  One  by  broken  into  the  a  enzymes  which  leading  as  the  of  ^-amylase  i s made  and  replaced  embryo  produced  IAA.  division  seeds  occurs.  of  especially  effect  respectively.  germination  high  by  endosperm  and  those  (low-temperature)  dormancy  are  of  dominance  released  the  cytokinins  both  to  growth,  flowering  hydrolases  into  similar  longitudinal  vernalization  of  released  are  either  species  synthesis  -  the  gibberellins.  Nucleases  industry  The  gibberellic acid where  starch.  of of  promote  stimulating  parthenocarpy.  day  8  degrades  eventually  This  ability  use  of  in  the  germination  of  barley  brewing is  desired. Consideration reminds  us  of  of  the  another  important  to  compounds  are  class  plants.  In  toxins  and  Helminthosporium  economic of  compounds  contrast growth  sativum  is  a  s i g n i f i c a n c e of  to  the  that  phytohormones,  produced  which  acid  pathologically  endogenous  regulators fungus  are  gibberellic  produces  by a  these  microorganisms. seedling  blight,  2 foot  and  root  This  disease  rot, is  head  blight,  wide-spread  in  and  leaf  North  spot  America  of and  cereals is  and  grasses.  responsible  for  3 tremendous  losses  produces  toxin  a  organism.^ Now  In  in  cereal  which  renders  particular,  classified  as  crops. the  It host  was  demonstrated  susceptible  the  respiration  Bipolaris  sorokimana  in  the  to  root  that  the  invasion tissues  by of  fungus the  -  barley was  and  wheat  isolated  are  by  found  de Mayo  to  9  be  -  inhibited.  et_ a l _ a n d  its  The  toxin  sesquiterpenoid  (-)-helminthosporal structure  5 was  established  investigation in  the  was  acid,  the  but  base,  the  The  in  or  the as  heat  of  helminthosporal  the  of  diethyl  both  of  and  from  cultures  with  its  of  (18).  (-)-prehelminthosporol dwarf  rice  (-)-helminthosporol H_.  sativum.^  the  growth  leaf in the  the  sheaths  light,  of  and  growth  is  of  certain  leaf  the  roots  both  of  gave  compound  Unlike  of  has  as  such  This  7  on m i l d  treatment  (17).  Like (15)  another  acetal,  has  (20)  is  of  and  for  the  isolated  together  of  from  but  no  the  hypocotyls  seeds.  It  effect  of  stimulates  elongates-  seedling  has  a culture  which  seedlings,  tobacco  wheat  of  affords  a regulator  rice  (15),  elongation  isolated  lettuce  germination  been  sativus  (18)  been  and  rice  active  also  of  also  prehelminthosporal  acetal  sheath  grasses  enhances  (15).  helminthosporal  sativum  slightly  which  second  exist  which  (Helminthosporium)  (-)-Helminthosporol  of  not  seedlings.  This  Hydrolysis  (20)  Further  (-)-prehelminthosporal  H_.  (19).  (18)  seedlings.  and  of  *  derivative  '  7  COchliobolus  hydroxy  did  (16)  toxin  wheat  6 (-)-prehelminthosporol  acetal  the  (+)-  growths  (17)  6  prehelminthosporal  provided  rice  extract  s p e c t r o s c o p i c means.  form  (-)—(17),  growth  same  and  that  isolated  dialdehyde  inhibit  chemical  revealed  culture,  precursor with  by  (17)  grown  inhibits on  the  11-13 shoots  of  dwarfing acid,  wheat of  seedlings.  lettuce  stimulates  acetate,  benzene,  seedlings  sugar  Helminthosporol or  In  release  (20) ether  by  some  from  dissolved is  addition,  slowly  it  also  chemicals and,  de-embryonated in  organic  and  reverses like  the  gibberellic  barley.^  solvents  spontaneously  such  as  converted  ethyl to  - 10 -  R = H, ( - ) - P r e h e l m i n t h o s p o r o l  >  R = 0H  SCHEME  A  (-)-Helminthosporol  -  11  -  (13) R=OH, Isosativenetriol  SCHEME  (24)  4 (Continued)  -  helminthosporic The  (-)-isomer  precursor  acid of  (21)  (21)  embryoless  rice  barley.  -  trend  (32)  room  temperature.  t h e same b i o l o g i c a l  seedlings,  lettuce  activity  13  as i t s  seedling hypocotyls  and  ' (20) has been  helminthosporic acid  (27)  at  13  Helminthosporol and  -  by a i r o x i d a t i o n  exhibits  (20) towards 11  12  on r i c e  to  converted  (28) -  and l e t t u c e  (32).  chemically to diol  The e f f e c t s  s e e d l i n g s were  tested  in the s t r u c t u r e - a c t i v i t y relationships in this  of  (27),  compounds  b u t no g e n e r a l series  of  growth  13 regulators  could  be d e d u c e d  from  this  study. Activity  (27)  Another sativum  of  v i c t o r i n which  )  (28)  CH20Ac  COOH  )  (29)  CH20H  C00CH3  (30)  COOH  CHO  (31)  COOH  COOH  (32)  COOH  C00CH.,  related  i s an a l k a l o i d ,  (22)  the non-toxin  non-specific  Promote inhibit  }  Inactive  Inactive Inactive  from  (-)-victoxinine  potent  complex  producing  and c o m p l e t e l y  the culture ( 2 2 ) . I t from  base  isolates of  filtrate is a  component  known.  i n the culture  H.  of  Helminthosporium  host-specific toxin  occurs as a f r e e  shoot growth, root growth  Inactive  structure  i s a polypeptide  and i s t h e most  (-)-Victoxinine from  CHo0H 2  closely  H_.  victoriae  CH90H 2  filtrate  v i c t o r i a e . I t  inhibits the root  growth  of  both  is  toxin-4  susceptible Other  and t o x i n - r e s i s t a n t tricyclic  compounds  oats  at  a concentration of  i s o l a t e d from  the culture  2.5 x  broth  of  10  M,  -  H.  sativum  include  13  (-)-sativene  (-)-isosativenediol  (23),  -  ( 1 2 ) J  7  (-)-cis-sativenediol  isosativenetriol  (24),  (cf.  The  (13),  1 8  '  1 9  (-)-longifolene  (25)  21 and  i t s  seco-derivative  interest  to  compound  promotes  rice  of  agricultural  seedlings,  but  (26)  inhibits ^-amylase  the elongation  Oryza  sativa  the growth in  chemists  of  L.  is of  4).  compound  (-)-cis-sativenedio! the second  cv.  variety  the embryoless  Scheme  leaf  Tan-ginbozu, Indica.  barley  It  prime  (13).  This  sheath  variety  enhances  endosperm,  of  and i s  of  dwarf  Japonica,  the  induction  slightly 8  active  18  for barnyard grass, but completely inactive f o r l e t t u c e . ' The ( + ) - i s o m e r s o f c i s - and t r a n s - s a t i v e n e d i o l s have been s y n t h e s i s e d Piers  and I s e n r i n g  Another  synthesis  McMurry  and  22  of  and were  demonstrated  (*)-cis-sativenediol  to  be b i o l o g i c a l l y  has been  by  inactive.  accomplished  8  by  23  Chemical  Silvestri. transformations  within  this  family  of p  have of  been  these  reported molecular  and a r e  indicated  structures  i n Scheme  reveals  a close  4.  related -If) TA  '  '  compounds  20  1Q  '  resemblance  ' between  Examination the 24  helminthosporin  skeleton  (33)  and t h e C / D - r i n g s  ( 33)  of  the g i b b e r e l l i n s  (10).  -  Mander and  et  compounds  properties  al_ has (35)  towards  -  14  -  synthesised (37),  the  all  (±)-14-norhelminthosporic  of  which  barley-endosperm  displayed essay,  acid  (34)  gibberellin-like  with  potency  comparable  24 with  that  that  the  of  helminthosporic  hydroxymethyl  group  acid in  (21).  (21)  is  It  is  structural acid  (21)  (17)  is  even  more  intriguing  similarity, exhibit  a growth  for  its  concluded activity.  (36)  to  note  that,  (-)-helminthosporol  gibberellin-like inhibitor.  therefore  superfluous  (35)  It  is  activity,  in  (20)  spite and  whereas  of  their  (-)-helminthosporic (-)-helminthosporal  -  B.  Biological  and  Chemical  Remote  15  -  Oxidation  of  Bicyclo[2,2,l]heptane  Derivatives  The H_.  sativum  Scheme or  biosynthetic has  5 is  not  at  The  assumption  that  the  the  would  (43).  then  Further  C(5)  Some  this  support  the  for  in  which  H.  sativum  converted  at  C(2),  to  helminthosDoral  by  asterisks in  the  gained  with  and  from  the  or  cleavage  (17),  an  oxidase  or  ylangoisoborneol  derivative  could  produce  related  work  of  compounds.  de Mayo  labelled with  labelling  (40)  5-hydroxysativene  other  the  an  in  oxygen  (38)  (42)  (±)-mevalonic acid,  (17)  contains  oxygenated  compound  oxidative  is  fungus  the  in  s e q u e n c e shown  introducing  of  helminthosporal proposal  helminthosporal  ylangoborneol  5-keto  and/or  and  proposed  capable of  rearrangement  oxygenation (13),  is  position of  provide  cis-sativenediol  sativenediol  elucidated.  Wagner-Meerwein  (41)  to  system which  functionality  or  been  b a s e d on  hydroxylase  (39).  route  pattern  et  a l ,  carbon-14  indicated  26 By  Scheme  analogy,  the  5.  b i o s y n t h e s i s of  culmorin  (45)  by  Fusarium  culmorum  26-28 could  involve  5-erido-hydroxylation  Consideration suggested systems  the  of  of  the  monoterpenoid Indeed,  recent  acetate  (46)  fungi  H_.  longiborneol  biosynthetic  p o s s i b i l i t y that  the  of  sativum  the  proposals  postulated  and  of  longiborneol  research  in  our  fed  to  (44)  laboratory  cultures of  outlined  H_.  been  (47)  and  i d e n t i f i e d as  bornane-diols  is  has  shown  that  a mixture  obtained. (48),  or  6).  hydroxylase  functionalise  and y l a n g o b o r n e o l  sativum,  5-exo-hydroxyborneol  (Scheme above  C(5)-oxidase  25 (-)-borneol  "  culmorum c o u l d a l s o  analogues  is  (44)  when  (38). (-)-bornyl  consisting  of  29 '  The  diols  have  5-endo-hydroxyborneol  (49),  -  Mevalonic acid  16  -  Farnesyl pyrophosphate  Helminthosporal  (17) OPP = pyrophosphate *  = ' " C label SCHEME 5  -  (44)  R = H,  Longiborneol  (45)  R = 0H,  Culmorin  17  -  OPP = p y r o p h o s p h a t e *  = C U  label SCHEME 6  -  6-exo-hydroxyborneol yield and  of  diols  2,6-  is  isomers  chromatography at  the  C(5)  The  have  of  was  The  their  £_.  relative  estimated  diacetates,  efficient  (53)  and  to  be  (51).  The  proportions  5:2:1  signifying  with  to  and  by a  of  overall  the  2,5-,  2,3-  gas-liquid  preferential  (55).  7:1.-  ratio  The  C(5)  degree  of  occurred  hydrolysis  product  The  hydroxylation  also  (+)-bornyl  of  the  (54)  was  of  A  a  oxidation  (52)  under  mixture was  5-exo-  of  amount  to  identical  5-exo-  obtained  small  hydroxylation  in  53-64%  (about  2%)  5-endo-hydroxyborneol  process  had  therefore  stereoselectivity.  of  at  acetate  regiospecific.  significant  a variable  culmorum  of  5-endo-hydroxyborneol  other  2.5:1  concomitant H_.  the  transformation  Regiospecific of  been  more  only  from  occurred  3-exo-hydroxyborneol  55% a n d  3-exo-hydroxyborneol  varied  and  -  position.  hydroxyborneol  of  about  microbial  conditions  yield.  (50),  18  the  (+)-  or  (-)-bornyl  acetate  C(5)-exo-position  acetoxy  group  but  and w i t h  with  cultures  without  lower  efficiency  than  sativum. An  overall  summary  and  previous  results  are  depicted  in  on  of  the  the  above  observations  biological  oxidation  is of  provided camphor  in  and  Scheme  7  borneol  30-32  These  biological  consider  the  chemical  means.  of has  bornyl  Schemes  acetate,  of  9,  of  respectively.  achieving  literature isobornyl  re-investigated Oxidation  and  functionalisations  possibility The  8  two  of  (-)-bornyl  unactivated  similar  contains acetate,  these  of  'remote  several and  sites  led  oxidation  reports  camphor.  on  the  Our  1  us by  oxidation laboratory  reactions.  acetate  (46)  with  a mixture  of  to  chromium  = R =H  (47)  R  (48)  RT = O H , R = H  (49)  R. =H, R = O H  1  •  2  (50)  2  2  (53)  R^ =OH,  (54)  R^ =H,  SCHEME  R R  2  =H zOH  2  7  ( 55)  SCHEME  8  - 21  Pseudomonad H.  H  OH (-)- Borneol  (47)  Pseudomonas pseudomal lei  H.  Pseudomonad  H. •»  0  0 Pseudomonas pseudomal lei H_.  SCHEME  - 22 -  trioxide-acetic or  with  anhydride-acetic  acid  for  seven  trioxide-acetic  acid  for  two hours  chromium  25 a mixture  of  identified products  products  i n 35-45% y i e l d .  as 5-oxobornyl  obtained  6-oxobornyl  were  acetate  acetate  (10-13%),  at  The major  (40-50%  5-exo-acetoxybornyl  (61)  at  room  temperature,  reflux  provided  product  was  29 '  (59)  days  of mixture).  acetate  and 3 - o x o b o r n y l  (60)  Three  (2-3%),  acetate  (62)  (61) Similarly, oxidation days  of  affords  chromium  trioxide-acetic  (+)-isobornyl  acetate  a 4:1  of  mixture  (63)  room  5-oxoisobornyl  acetate  (65)  i n about  acetate  55% y i e l d .  acid  temperature  34 6-oxoisobornyl  (1-3%).  (62)  anhydride-acetic at  minor  (64)  for  and  seven  -  It  is  pertinent  microbiological  to  hydroxylation 36  by  chemical  note  oxidation.  23  that of  -  (64)  is  also  (+)-isobornyl  available acetate  through  (63)  the  followed  -  24  -  DISCUSSION  It  has  been  pointed  out  in  the  Introduction  that  the  structure 1  activity  relationships  However,  it  seems  is  with  attached  therefore of  (13),  these  to  compounds  stimulated  our  monoterpenoid  their  is  (69)  (21)  that  and  interaction or  possibility  not  analogues  assume  bicyclic  the  interest  (66)  acid  enzymic  considered  to  still  remain the  (-)-helminthosporal  (-)-helminthosDoric  associated  groups  phytohormones  reasonable  (-)-cis-sativenediol (20),  of  in  -essential the  (66)  -  obscure.  biological (17),  the  tricyclic that for  the  their  potential  '  '  activity  (22)  accessible carbon  total  37  of  (-)-helminthosporol  (-)-victoxinine with  24  -  (Scheme functional  skeletons.  We  carbocyclic  biological  phytohormone  activity.  activity  (  of  This the  ( 68)  70)  have  framework  (70).  (67)  4)  -  To  test  the  monoterpenoid converted  validity  5-exo,  to  of  25  this  s p e c u l a t i o n we  6-exo-dihydroxycamphene  cycl opentene  2,3,3-trimethylcyclopentene  (69),  sequence  similar  of  transformations  (Scheme  compound  is  necessary  4  )  8  10  .  °  14 .  generally  for  us  and  (-)-isomers  our  synthetic  (-)-isomer  decided  (66)  which  1,4-diformyl-2,3,3-trimethylcyclopentene  hydroxymethyl-2,3,3-trimethyl  series  -  to of  '  °  ^  devise  can  a  the  reduction  In  of  literature  then  be  l-formyl-4-  derivative in  (70)  the  by  a  sesquiterpenoid  -  from  activity  one  enantiomers,  of  its  which  (70).  would  The  starting  (71)  of  a  it  was (+)-  materials  (63)  and  chiral  pure  Drovide  acetate  (-)-camphor  by  reports or  biological  (+)-isobornyl  followed  hydride  (67),  achieved  route  (66)  10),  prepared  by  only  synthetic  (Scheme  be  could  the  1-carboxyl-4-hydroxymethyl-  nitrogen  those  i nee  S  monoterpenoids  trimethoxyaluminum  to  synthesise  20  »  respectively, spite  the  associated with  sequence  (76),  18  and  (68),  to  and  in  its  (+)-camphor  (75),  acetylation.  that  reduction  L-Selectride  of  (lithium  camphor  with  lithium  tri-sec-butylborohydride) 38  affords  99% i s o b o r n e o l  hydride  reductions  preparative aluminum  scale  hydride  a mixture  of  contaminated  provided  us  with  reactions  it  was  as  the  reducing  (+)-isoborneol  (72)  (g.l.c.)  product  be  92%  n.m.r. a  spectrum  doublet  of  endo-proton 6.12  T (J  of  this  doublets of  = 9.0  of  Hz,  3.0  T (J  6.49  isoborneol Hz,  in  (72), 2.0  1%  more  analysis  carbon  of  (47)  (10%  (72)  and  in  and  a doublet  Hz)  for  the  of  use  (71)  gave  solution  doublets  of  C(2)-exo-proton  yield.  indicated (47).  assigned  to  the  The  exhibited the  doublets of  In  lithium  quantitative  8% b o r n e o l  Hz)  borneol.  to  DEGS c o l u m n )  and  2.0  2-5%  bulky  (-)-camphor  tetrachloride Hz,  these  convenient  Reduction  (-)-borneol  = 7.0  borneol,  isoborneol  therefore  isoborneol  mixture  at  95-98%  and  chromatographic a mixture  only  agent.  Gas-liquid to  with  borneol  C(2)at (47).  - 26 -  -  The  integrated  two  alcohols  on  silica  process  areas  could  gel  but  until  of  be i t  from  (overall  96%).  (-)-isoborneol  yield  after  showed  of  of  of  5.44x  doublets)  column  give  the  20:1.  The  chromatography  rigorous  Instead to  of  purification crude  isoborneol  product of  98%  of  (+)-camphor  (75)  afforded  to  (+)-acetate  (63)  proceeded  (72)  the  the  product.  half-width  acetate.  for  such  ratio  was purity  (58).  with  isobornyl  the  tedious  (30-60)  d i s t i l l a t i o n of  at  in  synthesis.  (+)-isoborneol  a multiplet  by  postpone  reduction  (+)-borneol  fractional  doublets  to  ether  Similar  of  C(2)-endo-proton  separated  the  petroleum  and  Acetylation  of  -  s i g n a l s were  decided  stages  recrystallised  two  partially was  later  yield  these  27  12  No  The  Hz,  n.m.r.  which  detectable  C(2)-exo-methine  of  was  in  spectrum  assigned  signal  (5.14T,  bornyl  96%  to  the  doublet  acetate  was  observed. Chromium and  acetic  oily  trioxide  acid  product  5-  and  also  in  that  as  by  basis  ing  diketones,  of  of  the  called  on  a  of  The  identity  signals  exo-acetate),  at  and  5.14 7.98  procedure  have  acetate  of  (64)  and  column,  of  each  and  (doublet (singlet,  of 3H,  that  but  3  4  not on  b  '  on  J  been  8.89,  9.01  a mixture (3%  of  0V17)  keto-acetates can  be  petroleum  ether  established  with  an  workers.  They  acetate = 7.0  is  two  with  correlation  afforded  a  early  3% S E 3 0 .  has  anhydride  analysis  These  Florisil  IH,  the  product  c  5-0xoisobornyl  CH3C00-),  by  g . l . c .  compound  doublets,  acetic  e_t a l _ ^  this  and  4 : l .  chemical  diacetates.  Toivonen  (65),  was  in  acetate1  shown  chromatography  spectroscopic data diols  isobornyl  (64):(65)  2 0 % DEGS  column  of  'ketoisobornyl  laboratory  ratio  eluent.  to  acetates,  careful  the  n.m.r.  our  the  resolved  separated (30-60)  was  6-oxoisobornyl  indicated are  according  which  Investigations  oxidation  the  on  correspond-  (64)  exhibits  Hz,  4.5  Hz,  and  9.05T  -CH00CCH3 (three  - 28 -  singlets, acetate  tertiary  9H,  shows  (65)  a doublet  the  C(2)-endo-methine,  and  three  A  s i n g l e t s at  small  amount  of  isolated  from  the  6-oxoisobornyl starting  *  8.86,  acetates  9.15  product were  n.m.r.  doublets  a singlet  crude  at  at  6-oxoisobornyl  = 7.5  Hz,  acetate  its  tertiary  of  in  this  about  for  protons,  methyl  was  oxidation.  Hz)  4.0  methyl  bornane-2,6-dione  mixture  obtained  the  for  9.16x and  5.36T ( J  for  8.01T  and  spectrum of  groups.  also  The  and  5-  40-55% y i e l d b a s e d o n  the  consumed.  5-0xoisobornyl  methanol.  of  The  starting material  material  quantitative  methyls).  acetate  yield  by  treatment  Wagner-Meerwein  was  (64)  with  converted  to  5-oxoisoborneol  sodium carbonate  rearrangement  of  (73)  to  in  (73)  refluxing  in  aqueous  5-oxocamphene  (74)  Attempt to h y d r o l y s e 6 - o x o i s o b o r n y l a c e t a t e (65) under i d e n t i c a l conditions resulted in decomposition. It i s possible that 6 - o x o i s o b o r n e o l (79) produced by h y d r o l y s i s underwent r e t r o - a l d o l f i s s i o n to y i e l d a cyclopentanone d e r i v a t i v e (80).  H ( 65) #  This  compound  eight-step +  Our is  laboratory most  2-6). is  was  as  has  commonly However,  shown  previously  prepared  by  Werstiuk  e_tal_ u s i n g  an  synthesis.39  in  adopted  used  in  the  the  according to structure  camphene  literature the  numbering  system  (cf.  II,  I.U.P.A.C.  (66a).  (66a)  Part 1975  (66)  p.120,  Rules,  the  which References numbering  -  was or  achieved  by  methanesulphonyl  analysis  of  a major  peak  (74)  and  the  minor  product  crystalline be  gel  the  (74)  olefinic  The  homogeneous  as  in  n.m.r.  spectrum,  and  spectrometry,  basis was  of  the  observed  proton  alpha  together  with  (73)  to  the  a  890  of  group  an  compounds ether  n.m.r.  were (30-60)  spectrum  5.24x,  of  characteristic  infrared ketone  which  150.1044,  empirical  (i.r.)  (1750  group  of  (73), C(6)  8.79,  determined  formula  by  three  cm~^)  the  of  resulting  in  to  by  and the  high  C-|QH^0.  evidence loss  tertiary  8.98  contributed  analytical  formed  -  had  singlets at  is  C(2)  ring  reaction  which  the  The  the  and  cnf^).  s p e c t r o s c o p i c and  formation  and  group.  rearrangement  to  5.03  five-membered  a carbonyl  carbonyl  Both  the  singlets at  ratio  and  in  the  (81),  (74)  distinctive feature  molecular weight,  assigned structure  of  the  petroleum  i n d i c a t e d by  corresponds  in  or  and  this  areas  5-oxocamphene  hexane  presence of  structure  mass  in  exo-methylene  its  The  soluble  indicated  desired  analysis.  the  of  the  g . l . c .  by  chloride G.l.c.  100°C,  samples  of  (1665  at  provided  broad  in  absorption.  too  to  (p_-tosy1) pyridine.  integrated  two  group  i . r .  with  the  groups its  minutes  dry  column  due  most  the  product  minutes  The  was  minor  3% 0V17  chromatography  protons  exo-methylene  refluxing  a  2.33  which were  confirmed  in  using  2.87  column  recrystallised.  spectrum an  at  -  n-toluenesulphony1  chloride  time  which were  5-oxocamphene of  peak  solids  either  product,  retention  a minor  Silica  (mesyl)  crude  of  9:1.  to  reaction with  29  this  9.01T 1760  an  an  overall  On  acidic  the product methylene  dehydration  bond.  (74)  cm"^  resolution  minor  of  methyl  (81)  -  Attempts of  to  functionalise  5-oxocamphene  isoamyl  (74)  42  nitrite  ,  using  and  30  the  -  C(6)  position 40  selenium dioxide  bromination  under  alpha  ,  lead  basic or  to  the  ketone 41  tetraacetate  group , 43  neutral  conditions'  all  44 failed  to  give  easily  on  the  hydroxylation  to  apply  this  identifiable of  enolates  reaction  to  products.  with  Reports  molybdenum  5-oxocamphene  (74).  by  Vedejs  peroxide  Addition  et  MoO^  of  al  prompted  the  us  molybdenum ,44-46  peroxide-hexamethylphosphoramide-pyridine to  the  enolate  product and  which  ion was  of  DEGS,  all  at  efficiency product 4.88  and  which  (t.l.c.)  100°C).  temperature,  nor  of  exhibited  J =  3 Hz  was  was  obtained  was  and Neither  the  to  provide  homogeneous  on  of  to  a  broad  at  with  also  of  The  i . r .  spectrum  absorptions  at  3500  stretching),  1760  (C  data  indicated  was  one  group). of  the  (83)  The  above  ".hydroxy  soectral  ketones  (84)  (83)  -  at  (86).  -78°  (82) 1)  = 0)  and  of  1665  that  Structures  (85)  and  or  of  coupling  (Figure  material  20%  room  increased the  oily at  constant  to 2)  assignment one  proton,  showed  and  the  the  singlets  this  integrating  addition  CH^  crude  layer  3% S E 3 0  Confirmation  on  (C =  thin  o l e f i n i c proton  6.54x  6.69T,  gave  (Figure  disappeared  (OH  D20.  at  gel  time  spectrum  -CH0H m e t h i n e . signal  a  -78°C  (3% 0 V 1 7 ,  characteristic terminal  assigned  at  MoOg.HMPA.Py  n.m.r.  doublet  (82)  silica  reaction  amount  MoO^.HMPA.Py  crystalline starting  analyses  prolonged  The  one-proton  a  tetrahydrofuran  g . l . c .  reaction.  A  when  dry  i n c r e a s i n g the  this  5.14T.  in  chromatographed  a colorless oil  chromatography  (74)  complex  900  oily  (83)  and  cm"1 product (84)  (86)  were  Figure  2  I.R.  Spectrum of  6-exo-Hydroxy-5-0xocampherie  (83)  -  the  expected  products  could  formed  (86)  reaction  be  conditions  from by  33  -  <*-hydroxylation  i s o m e r i s a t i o n of  employed.  However,  of  ketone  (83)  and  acyloin  (74),  (84)  whereas  under  the  (85)  and  basic  i s o m e r i s a t i o n has  not  been  44 observed  during  (85)  (86)  and  molybdenum  would  and  (84)  the  endo-hydrogen  and  (86)  that  because of  were  the  be  expected  the  or  peroxide  hydroxylation  to  be  thermodynamically  1,3-interaction  hydroxyl  therefore  between  function  at  proceeds  by  an  the  C(5).  considered improbable.  ^-hydroxylation  and,  in  addition,  less  stable  C(10)  methyl  Alternative Vedejs  electrophilic  ketols  than  group  and  structures  e_t a l _ h a v e attack  of  (83)  (85)  proposed  MoOg.HMPA.Py  44 (82)  on  the  framework  enolate  followed  m o l e c u l a r model  preferentially  attack  by  cleavage of  suggested  from  the  that  an  the  sterically  0-0  bond.  peroxide  less  Examination  complex  hindered  exo  (82)  side  of  would  of  the  22 enolate  (83) is  of  been  leading  The  n.m.r.  for  the  within  the  (74)  spectrum  doublet  the  at  expected  C(6)-endo-methine ketol  exo-methine  (84), and  to  the the  (Figure 6.54x  range and  J  hydroxy-ketone  the  value  1)  of  (-CH0H) of  J  (83).  the has  values  hydroxy-ketone  a coupling constant for  the  C(7)-anti-proton for  the  C(l)-bridgehead  supports  vicinal proton  in  long-range  the  c o u p l i n g between  the  have  4 7  been  3 Hz  coupling If  would  (83).  of  structure  about  which between  product  had  C(6)6 Hz.  For  - 34 -  The s p e c t r a w e r e recorded in CDCI3 s o l u t i o n s s =singlet bs = broad s i n g l e t t =triplet  S C H E M E 11  -  comparison  about  support  7.8  signal.  -  gives  a list  for structure  of  chemical  shifts  allylic  molybdenum  oxocamphene  (83).  When  hand,  methine  the methylene  peroxide  no s u c h e f f e c t signal  a t 6.54T  of  It  provided  envelope  collapsed to a  at  broad  on i r r a d i a t i o n o f  can therefore  (74)  constants  experiments proton  was o b s e r v e d  at 6.99x.  "-hydroxylation  and c o u p l i n g  Decoupling  8 . I T was i r r a d i a t e d , t h e d o u b l e t  On t h e o t h e r  bridgehead that  11  -  r i 48-50 for bicyclo [ 2,2,1J heptanols.  observed further  Scheme  35  provided  the  be c o n c l u d e d  6-exo_-hydroxy-5-  (83).  Mo05-HMPA-Py (82 ) LiN(C3H7)2 (83)  (74) SCHEME  Reduction provided  of  a mixture  (83) with of  5-exo,  6-exo-dihydroxycamphene chromatography  (silica  (87)  12  l i t h i u m aluminum hydride 6-exo-dihydroxycamphene (83%) w h i c h were  i n dry ether (66)  separated  (7%)  at -15°C  and  5-endo,  by column  gel).  LiAlH^  , ether  H  +  -15°C  (83)  (66)  (87)  -  (66)  The  structure  was  established  (Figure  3)  protons  while  as  two  two  is  The  signal  The  i . r .  at  in  the  at  probably at  its  7.60T  3350  the  and  a  6.21T  5.31T at  C(5)  the  the  3350  expected  to  at  890  bonding  cm"''  The the In  is  major  in  the  product  particular, of  a  vicinal  3570  of  presence  doublet  of  the  of  positions  appeared of  the  on  addition strong  of  absorptions  hydrogen-bonded in  a  0-H  slight  and  D£0.  decrease  this  over  was  intermolecular  52 '  Finally,  exo-methylene  on  the  basis  of  (J^  the  absorption  band  group. of  ketol  its  a C(5)-exo-hydrogen 5.95T  olefinic  intramolecular  reduction  at  the  absorptions  the  doublets  to  broad  and  from  (87)  spectrum  C(7)-ajrti_-proton.  resulted  cm~^  cis-dio!.  obtained  structure  the  showed  solution  n.m.r.  broadening  disapoeared  4)  predominence  c h a r a c t e r i s t i c of  (-)-trans-diol  presence  the  C(6)  coupling with  51 hydrogen  and  The  proton  its  assigned  (J = 6 Hz).  (Figure  of  In  were  non-hydrogen-bonded  Dilution  6-exo-dihydroxycamphene  properties.  and  hydroxy!  the  of  (-)-5-exo,  hydrogens  solution)  for  ratio  with  5.07  long-range  to  (CHCl^ cm~^  intensity  to  due  respectively.  consistent  product,  at  5.76  due  -  spectroscopic  singlets  doublets  and  groups,  by  minor  -CHOH m e t h i n e  spectrum  3570  the  broad the  broad  doublets  of  36  was  spectroscopic  was  ^ =  (83)  Jg  consistent g =  3 Hz)  assigned properties.  with  in  the  its  n.m.r.  CO  spectrum the  cis-diol  Other (66).  absorption  intensity the  5).  The  C(6)-endo-proton.  observed.  0-H  (Figure  of  signals The  at  the  corresponding  hydrogen  bond  in  No  long in  i . r .  3560  the  and  (87)  was  6.37T  ( J = 3 Hz)  coupling  n.m.r.  with  spectrum  (CHCl^  for  the  were  solution)  hydrogen-bonded  decreased  observation  at  range  spectrum  cnf^  latter  doublet  0-H  intermolecular  (66). in  similar  band  at  dilution This  nature,  attributed  to  C(7)-anti_-proton  (Figure  d r a s t i c a l l y with cis-diol  was  to  6)  those  in  cm"''.  contrast  indicated  providing  of  exhibited  3350  that  further  was  free The to the  4000 100  3600  2800  3200  i  n  2400  F R E Q U E N C Y (CM') 2000 1800  1 6 0 01 4 0 0  1200  i 3.5  Figure 4  I.R.  S p e c t r u m o f (-)-5-exo_, 6 - e x o - D i h y d r o x y c a m p h e n e  (66)  1000  800  600  4000  3600  Figure  6  3200  I.R.  2800  2400  Spectrum of  F R E Q U E N C Y (CM') 2000 1800 1600  (-)-5-endo,  1400  6-exo-Dihydroxycamphene  1200  (87)  1000  800  600  -  support  for  groups.  the  The  assignment  structure  crystallographic  of  41  trans-orientation  of  the  trans-diol  analysis  but  detailed  has  bond  to  been  the  vicinal  confirmed  lengths  and  hydroxyl  by  bond  X-ray  angles  still  54 remain  to  be  prepared data  from  ketol  to  hindered  was  exo  face  of  increased  agent.  An  making  the  reduction major  by  or  due  the  to  sodium  an  the  to  increase  both  (66)  (87).  and  lithium  The  aluminum  sodium  steric  derivative  borohydride  (88)  cis  provided  also  showed  :  were  spectral  reduction  the  of  sterically  trans  diols  less  could  (temperature,  borohydride  hindrance was  and  from  conditions  using  the  of  trans-diols  hydride  attack  ratio  reaction by  c i s - and sequence  preferential  the nor  of  analogous  for  molecule.  varying  6-exo-acetoxy with  of  solvent)  attempt  by  observed  probably  concentration,  the  those  (75)  stereoselectivity  (83)  be  Enantiomers  (+)-camphor  identical The  not  calculated.  on  as  the  the  exo  face  unsuccessful  5-endo-hydroxy  reducing by  since  acetate  (89)  as  product.  NQBH  (89)  (88)  It  was  hoped  that  trimethoxyaluminum exo  attack  by  a  tetrahydrofuran  the  alkoxide  hydride  would  second molecule solution  of  formed  between  provide of  ketol  the (83)  Minor product  ketol  ample  (83)  steric  and  bulk  reducing  agent.  with  equivalents  two  lithium  to  discourage  Refluxing of  a  lithium  - 42  -  trimethoxyaluminum hydride f o r 20 hours f a i l e d to give any r e a c t i o n . Addition of two equivalents of l i t h i u m aluminum hydride to t h i s reaction mixture followed by 6 hours of r e f l u x i n g afforded a 1:3 mixture of s t a r t i n g material and t r a n s - d i o l (87).  It was f i n a l l y concluded that  the C(10) methyl group of the r i g i d camphene skeleton almost completely  * r e s t r i c t s endo approach of hydride reducing agents.  R=H  , Ac,  or  Al(OCH3)3  It was highly desirable to have a more e f f i c i e n t synthesis of 5-exo, 6-exo-dihydroxycamphene  (66) and i t s enantiomer (77) so that t h e i r  b i o l o g i c a l a c t i v i t y could be evaluated.  Since manipulation of the  oxocamphene system had not been too successful in t h i s respect, we turned our a t t e n t i o n to the p o s s i b i l i t y of e s t a b l i s h i n g the desired o r i e n t a t i o n of the two hydroxy! groups in the bornane framework. dihydroxyisoborneol  The protected  (90) was chosen as an appropriate precursor since  Wagner-Meerwein rearrangement followed by removal of the protecting groups R would provide the exo, exo-diol  (66)  (90) *  (66).  Attempts to reduce the ^-hydroxy ketone (83) with l i t h i u m and isopropanol in t o l u e n e " provided a mixture of compounds which had not been i d e n t i f i e d but no c i s - d i o l (66) could be detected. 56  3  -  The (91)  literature  contains  many  t o 3-endo-hydroxycamphor  microorganisms  o r by z i n c  43  -  reports  on t h e r e d u c t i o n  and a c e t i c  a c i d . ^  ketones alcohols  pointed  t o note  in t h e zinc i s also  norcamphors  R  (94)  R  1  (95)  R  1  (96)  R  ]  -  the preferential  acetic  observed  i n converting  2  3  =R zR  3  2  3  = R =R 4  =CH , R = R 3  2  3  5  reduction.  5  3  A  (96). 2 sp  = R =H 5  =H  =R  =R =R =CH , R A  ( 9 3 )  formation  the planar  A  2  =R =H 5  = R =H 3  SCHEME  13  (93) by  ' ^  of the  endo-hydroxy  A preponderance  i n t h e d i s s o l v i n g metal  =R =R =CH , R  ]  acid  (94) and ( 9 5 ) ,and fenchone  out that  (71)  8  (92)  i s pertinent  camphorquinone  (92) and 2-endo-hydroxyepicamphor  (91)  It  of  reductions Coulombeau  carbonyl  group  of  endo-  o f camDhor and Rassat to thesp  (71), have  3  - 44 -  tetrahedral torsional  arrangement  13).  decreases exo of  side  of  energy  (71),  of  this  C-0  there  will  moiety  and  norcamphor the  of  the  oxygen  be the  atom  interaction, while  increase.  Moreover,  a  change  was  or  reported  with  Similar (100).  3 4 a  desired The  the  Such (95)  an  and  exo-oxygen  effect  R-|  towards  side  will  the  endo  displacement towards  i s more  fenchone  (96)  prominent  where  interact with  hydride  reduction  to  a majority  give  trans-diols  reductions might  We t h e r e f o r e  5-exo,  virtue  the  C(l)-substituent  the  R-|  in  are  the  the  cases  methyl  C(7)-syn-methy1  of of  a  1:2  mixture  cis-diol  of  (97)  ketols  (about Cl  together  in  (71).  Hydrogenation (93)  the  Displacement  c a u s e s an  camphor  and  alcohol,  57a '  the  camphor  groups.  an  i n t e r a c t i o n between 56c  (Scheme  of  of  (98)  be  and  (99)  a c h i e v e d on  considered the  6-exo-dihydroxycamphenes this  route  was  that  (about  i t  made  use  '  3  /  a  5,6-dioxoisobornyl  modified (66)  30%).  C7-,  synthetic  (92) 70%)  CO  '  D  O  acetates  strategy  and  (77)  shown  of  the  mixture  in of  to  the  Scheme  14.  5-  and  SCHEME  H  - 46  SCHEME  U  -  (Continued)  - 47 6-oxoisobornyl material by  column  acetates,  by f r a c t i o n a l  dioxide  gave  could  Tedious  was t h e r e f o r e  oxidation  5,6-dioxoisobornyl  stereoselective  be s e p a r a t e d  distillation.  chromatography  Selenium acetates  which  unreacted  separation  of  starting  the  keto-acetates  avoided.  of a mixture acetate  and r e g i o s p e c i f i c z i n c  6-endo-hydroxy-5-oxoisobornyl  from  acetate  -  of  5 - and  (100)^  a  acetic  acid  (101).  which  6-oxoisobornyl underwent  reduction  to  provide  The s t e r e o c h e m i s t r y  of the  5-A3t  A-72T  (110)  (63)  SCHEME hydroxyl  group  in  (101)  was a s s i g n e d  15  on t h e b a s i s  of  n.m.r.  data  and chemical  i evidence. constant for  The -CH0H m e t h i n e 1.5  Hz.  chemical  2-endo-hydroxyepicamphor  C(3)-exo-proton 11^48-50 the  This  T  h  downfield  e  absorption p  r  e  s  shift  e  n  c  exhibited  e  of  0  f  shift  (93) (5.78T)  a  a doublet was a l m o s t  (6.13T)  at 6.15x with identical  and d i f f e r e d  the C(2)-endo-proton  group  signal  that  markedly  i n 3-endo-hydroxycamphor  c(6)-end£-hydroxyl  to  coupling  (4.75T)  from  (92)  was a l s o of  observed the  (Scheme  supported (101)  by  compared  - 48  -  with the -CHOAc of the diketone precursor (100) C(6)-endo-hydroxyl  (5.26T).  This e f f e c t of a  on the neighbouring C(2)-endo-hydrogen  has also been 29  observed i n other bornane systems as shown i n Scheme 15.  The C(6)-exo-  hydrogen of (101) was probably coupled to the C(4)-bridgehead methine, thus giving r i s e to the doublet with J = 1.5 Hz. Chemical evidence f o r the structure of (101) was obtained by 44-46 " - h y d r o x y l a t i o n of 5-oxoisobornyl  acetate (64) using MoOg.HMPA.Py (82).  The ketol obtained i n low y i e l d (12%)  (together with recovered s t a r t i n g  material) e x h i b i t e d spectral data and melting point i d e n t i c a l to those of (101).  The C(6)-endo-hydroxyl  group was expected to be introduced from the  s t e r i c a l l y less hindered endo side of the enolate of (64) by the molybdenum 44_46 peroxide complex (82). Careful examination of the n.m.r., g . l . c . (3% SE30 at 130°C, 20% DEGS at 150°) and t . l . c . ( s i l i c a gel) of the crude reduction product revealed the absence of other hydroxy-ketones, i n p a r t i c u l a r , that of  5-endo-hydroxy-6-  oxoisobornyl acetate (102) which has also been synthesised i n low y i e l d by the molybdenum peroxide hydroxylation of 6-oxoisobornyl s t e r e o s e l e c t i v i t y of the z i n c - a c e t i c acid reduction of  acetate (65).  The  5,6-dioxoisobornyl  acetate (100) could be explained by the t o r s i o n a l i n t e r a c t i o n argument of Coulombeau and Rassat discussed above.  However, the r e g i o s e l e c t i v i t y of t h i s  reaction was t o t a l l y unexpected as the analogous reduction of camphorquinone (91) provided a 1:2 mixture of 3-endo-hydroxycamphor hydroxyepicamphor  (93).^ ' 8  5 7  (92) and 2-endo-  We could only conclude that the  r e g i o s p e c i f i c i t y of the zinc - a c e t i c acid reduction of (100) was probably due to some unknown d i r e c t i n g e f f e c t of the C(2)-acetate group. Sodium borohydride reduction of 6-endo-hydroxy-5-oxoisobornyl (101) afforded a 1:1 mixture of 5-endo, 6-endo-dihydroxyisobornyl  acetate acetate (103)  -  and by  5-exo,  6-endo-dihydroxyisobornyl  silica  (106) cis  gel  column  followed :  side  trans of  49  by  ketol  ratio  (101)  acetate  chromatography  or  chromatography.  diols  by  -  by  An  attempt  protection  which  selective  i n c r e a s i n g the  through  (104),  of  has  could  formation  of  separated  acetonide  made  to  increase  s t e r i c hinderance  on  the  the  been  be  hydroxyl  the  endo  functionality  with  59 a  bulky  group  keto-ether The  less  s u c h as  so  formed  to to  formed  ketol  if  The  note  n.m.r.  that  were  of  The  6.57T  3 Hz)  (J = was  acetate  absorptions that  each  5-exo, for  very  (103)  n.m.r.  130°C)  and  the  was  group,  giving  was  spectra.  acetoxy  oxygen  the  was  t . l . c .  in  No  group  sodium  of  to  doublets at  which  It  would  in  this  5.84T  (J = 9 Hz,  ( J = 9 Hz)  exhibited  two  for  reduction.  to  be  is  also  have  been  reduction. acetate 4  the  doublets  Hz,  1  (103) Hz)  for  C(6)-exoat  6.10  and  methines. note  that  at  by  the  (104)  the  of  analyses.  hydrogen  such -  and  was  two  1735  of  cm"''.  extra  at  a  the  lower  both  possibility  formed -CHOAc by  that  cis-diol  carbonyl The  reasonable  a conformation to  of  strong  detected  Another  bonded  a C = 0 absorption  spectra  diol-acetates  absence  material  assume  i . r .  showed  1750  a mixture  starting gel)  at  6.17T  (104)  acetate  fact  appeared  conditions.  detected  the  borohydride  ether  (105),  not  However,  6-endo-dihydroxyisobornyl  intensity  intramolecularly to  was  5-endo,  -CH0H  could  to  reduction  6-exo-diol  eliminated  (silica  rise  the  6-endo-diol  comparable  compound  to  a doublet  trans-diol  trans-acetylation their  of  intriguing  and of  and  resistant  present,  doublets  C(5)-exo-proton,  be  moiety.  keto-trimethylsilyl  5-endo,  spectrum  a doublet  It  to  exposure  (102)  hydrogen.  that  proved  prolonged  pertinent  the  t-butyldimethylsilyl  s t e r i c a l l y hindered  unstable  showed  the  by signals  g.l.c.  {3%  in SE30,  explanation the  is  carbonyl  C(6)-endo-hydroxyl frequency.^  Examination  -  of  m o l e c u l a r models  Base  showed  hydrolysis  acetonide  (106)  pyridine)  provided  of  (108)  (50% y i e l d )  (111)  as  a minor  two  (104)  R1 =OH,  by  possible.  R2 = 0H R2  =H  6-endo-dihydroxyisobornyl  Wagner-Meerwein  desired  5-exo,  with  6-exo-  5-endo,  rearrangement  acetate (mesyl  dihydroxycamphene  6-endo-dihydroxybornene  (107)  compounds  could  characteristic  terminal  an  geometrically  chlorideacetonide acetonide  product.  (silica  of  was  R] = H,  together  chromatography  n.m.r.  -  (103)  (106)  The  this  5-endo,  followed the  that  50  spectrum,  as  exo-methylene  be  gel).  well  partially The  olefinic as  group.  (108)  the  separated  camphene proton  i . r .  by  (111)  careful  acetonide  signals at  absorption  at  (108)  5.24  and  895 cm"1  column exhibited 5.40x  in  the the  characteristic  - 51 The  minor  chloride the (J  -  pyridine  basis =  C(2)  of  3  Hz,  6  product  was  formed  reaction.  its  n.m.r.  Hz)  and  The  data,  1,2-elimination  bornene  i.e.  a doublet  olefinic protons,  by  structure  a doublet  of  respectively.  Three  ion  of  methyls  m/e  assigned  in  208  the  bornene  catalytic readily  on  conversion on  room  of  the  two  8.84  s i n g l e t s at  r e s o l u t i o n mass  the  with  C(3)  the  and and  9.17  bornene  8.86x.  and  on  4.16x  of  s p e c t r u m was  the  c a r r i e d out acid.  corresponding  hours  at  room  A  and  the  molecular  consistent with  acetonide  material  consumed)  refluxing of  Similar  the  the  5-ehdo,  was  a  the  trace  containing  acetonide  a was  (111)  6-endo-dihydroxybornene However,  very  the  6-exo-di hydroxycamphene  (66)  (77%  was  days  at  achieved  added  every  methanol  in  sluggish.  analogous 70%  desired diol  reluctance  bornene  by  Only  hydrochloric acid or  i n methanol  The  (108)  (-)-5-exo,  6N  contaminated  temperature.  desired  low y i e l d  products.  was  (108),  acetonide  hydrochloric  6N to  temperature in  camphene  camphene  starting  resulted side  to  (111),  isomer  several  to  •temperature at  low  the  hydrolysed  reaction  based  of  amount  within  (112)  the  rise  assigned  8.96,  groups  mesyl  structure.  Hydrolysis of  gave  at to  singlets at  9.20T w e r e a s s i g n e d t o t h e t h r e e t e r t i a r y m e t h y l acetonide  due  the was  (111)  doublets  4.40T ( J = 6 H z ) ,  at  during  after  four  day.  Longer  solution  together  acetonide  for  with  several  was  room  reaction  formation  hydrolysis  yield  hours of  time only  other  reported  by  23 McMurry Column  and  co-worker  in  the  synthesis  chromatography  of  our  hydrolysis  acetonide  (108), ( - ) - 5 - e x o ,  dihydroxybornene of  acetonides  (112).  (108)  and  racemic c i s - s a t i v e n e d i o l .  products  afforded  6-exo-di hydroxycamphene  Incidentally, (111)  of  served  to  the  (66)  difference  provide  pure  in (108)  recovered  camphene  and  5-endo,  the  rates  without  of  6-endohydrolysis  contamination  - 52 -  (108)  (111).  by  (111)  T h e (-)-5-exo,  data  and s p e c i f i c r o t a t i o n  from  the reduction  enantiomeric the  same  characterised J  identical  (Scheme  14).  by i t s n . m . r .  of doublets,  Oxidative sodium and  provided oil  cleavage  periodate  acetals.  J = 7 Hz, of  However,  J  signals  of the minor  using  product  obtained  (83) ( s e e a b o v e ) .  (-)-isobornyl  acetate  6-endo-bornenediol a t 3.83T ( d o u b l e t  4 Hz)  a n d 5.98T  (doublet,  The (76) b y  (112) w a s of  doublets,  J = 7 Hz).  6-exo-dihydroxycamphene  provided  a solution  a complex  mixture  of periodic  acid  (+)-!,4-diformyl-2,3,3-trimethylcyclopentene  of  (66) w i t h dialdehydes  H^IOg i n d r y  ether^  (67) a s a c o l o r l e s s  i n 67% y i e l d .  (66)  spectral  = 6 H z ) , a n d t h e -CH0H m e t h i n e s a t 5.49  (-)-5-exo,  i n 95% e t h a n o l  from  The 5-endo,  -CH=CH-  = 6 H z , 3 H z ) , 4.12x ( d o u b l e t ,  (doublet  to those  (77) w a s p r e p a r e d  (112)  (66) h a d m e l t i n g p o i n t ,  6-exo-camphenediol  o f 6-exo-hydroxy-5-oxocamphene  (+)-diol  sequence  (66)  (67)  - 53 -  The  dialdehyde  oxidation [cf.  the  Section  nitrogen to  to  was  unstable  acid  (A),  atmosphere  turn  grade  pink The  for An  ether  within  diacid  as  three  or  to  is  at  observed  give  two  by  for  minutes  at  in  support  cm"1),  while  ultraviolet  was  too  the  conditions  provided  Having  x i u a t  "  the  activity  i . r .  an  respectively.  Bioassays  growth-inhibiting and  (67),  xj^jj to  effect  Japonica,  cv.  of  the  of  their  to  A  singlet methyl  aldehyde (e  at  but  high  7.99x  groups  and  confirmed  The  dialdehyde  resolution  expected  (77) u n d e r  a  8) p r o v i d e s  was  11 ,200).  and  mass  for  identical  reaction  (78). goal  we  proceeded  (-)-5-exo,  (87),  (dwarf)]  two of  evaluate  the  6-exo-dihydroxycamphene  (77),  by m e a s u r i n g on  to  (+)-1,4-diformyl-2,3,3-  enantiomers  compounds  Tan-ginbozu  in  proton,  (Figure  166.0989 a s  (+)-cis-diol  conducted  the  led  (67) (2750, 1730, 1680  performed  monoterpenoids  were  13  observed  aldehyde  spectrum  249 nm  be  synthetic  and  was  tertiary  B-unsaturated  (-)-dialdehyde  the  storage  compound  hydrogen. two  structure  (-)-5-endo,6-exo-di hydroxycamphene  trimethylcyclopentene  Patna  of  of  the  B-unsaturated  a molecular weight  cleavage  i v e  of  (20)  1,4-diformyl-2,3,3-trimethylcyclopentene  The  microanalysis  air  under  -20°C  tetrachloride  The  at  at  prolonged  solution  protons.  of  to  temperature.  8.95x.  presence  but  C(4)-formyl  assigned  accomplished our  phytohormone (66),  the  indicated  0  and  due  helminthosporol  stored  carbon  the  the  absorption  for  ^10 14°2* H  of  for  be  months,  of  7)  methyl  8.71  (u.v.)  unstable  spectrometry  vinyl  at  could  room  presumably  case of  colorless  (Mgure  = 2 Hz)  the  singlets  evidence 1640  (J  the  s p e c t r a l 1 grade  spectrum  0.31x  in  four  (67) s h o w s a s i n g l e t a t 0.06x f o r doublet  temperature,  It  initially  five  n.m.r.  room  Introduction].  decomposition.  reagent  or  at  the  (113)  (78)  growth-promoting  varieties rice  and  (Oryza  [Indica, sativa)  cv.  or Century  using  both  WAVELENGTH  Figure  8  I.R.  Spectrum of  ( M I C R O N S )  (+)-!,4-Diformyl-2,3,3-Trimethylcyclopentene  (67)  -  the  agar  medium  and  (-)-cis-sativenediols  gibberellic estimated the  acid  by  treated  Tables  1  convenience,  (87),  comparing  The (68), and  It  their  confirmed  using  the  and  stage  activity  (17)  is  in  our  acetate  could  form  of  this  will  be  carried  out  devoid  of  growth-  tested.  Nagoya  we  conclude  (13)  laboratory. that  the  and  carbocyclic the  Our  University,  investigation  by  for  (-)-trans-diol  Marumo,  total  in  lengths  our  the  of  shown  100  concentrations  S.  in  the  (20),  framework  monoterpenoid  remote of  (cf. our  monoterpenoid  helminthosporic to  synthetic  basis (13)  into  remains  example,  cis-sativenediol  the  by  the  (66), were  are  in  (67)  similar  the  results  was  laboratory.  respectively,  For  sheath  represent  represented  helminthosporol  area.  synthesis  not  of  sesquiterpenoid  leaf  (-)-cis-sativenediol  dialdehyde  a  second  synthesised  associated with  Furthermore,  (114)  our  of  (22),  at  with compound  indicated  enantiomers  (+)-  each  The  not  Professor  in  of  sub-unit  (70)  do  monoterpenoids  preliminary  the  of  of  (-)-cis-diol  by  conversion  area  that  further  synthesised  4).  and  of  activity  comparison,  arbitrarily  effects  victoxinine  Scheme  is  The  activity  control.  numbers  clear  (67),  structural  (69)  is  length  the  for  The  growth-inhibiting  helminthosporal  compounds  of  other  that  biological  a  that  the  Japan,  with  to  average  62  method.  studied  standard.  so  Nagoya,  reported  the  also  control  were  this  were the  -  microdrop  the  results  At  the  2 where  (+)-dialdehyde or  and  as  measured.  promoting  or  (11)  seedlings  and  actually  method  56  be  may  oxidation  a potential  laboratory  5) in  acid  investigated  route  Scheme  analogues  be  of  useful  (21),  (cf. in  the  ylangoisobornyl  biogenetic-type  and the  investigation near  future.  in  -  Table  I.  Effect  of  Synthetic  (Oryza  sativa)  57  -  Monoterpenoids  on  Rice  Seedlings cl C  (estimated  Indica  Compound  the  agar  medium method)  cv. Tan-ginbozu (dwarf)  (+)-cis-diol  94  -  234  (+)-cis-sativenediol  200  432  gibberellic  100  control  (-)-cis-sativenediol  Japonica cv. Tan-ginbozu (dwarf)  -  101  -  100  200  432  100  100  (77)  _  (66)  5  Indica cv. Century Patna  Compound  Japonica  cv. Century Patna  (_)_cis-diol  by  (13)b gibberellic  acid  acid  (11)  (11) 100  control (+)-dialdehyde  (67)  -  (-)-trans-diol  (87)  89  Germinated  seedlings  mixed  test  was  In  with  measured  this  Test  case  results.  94 101  (3-day-old)  solution  after  the  solutions  .  of  6-7  test  (2.5  days  of  solution  other  (-)-dialdehyde  (78)  -  (+)-trans-diol  (113)  89  were  ml;  supported  3xlO" M). 4  on  Length  0.75% of  the  96 104  agar-water second  (2.5  leaf  ml)  sheath  growth.  was  2x10"  concentrations  M.  (6xlO"4M  and  12xl0"4M)  gave  similar  -  Table  II.  Effect  of  Synthetic  (Oryza  sativa)  (-)-cis-diol  "  Monoterpenoids  (estimated  by  the  on  Rice  microdrop  Compound  97  95  (+)-cis-diol  106  105  142  Seedlings 62 a method )  Indica cv. Century Patna  Japonica cv. Tan-ginbozu (dwarf)  100  102  (+)-ci s-sativenediol  103  105  252  gibberellic  142  252  100  100  control  100  100  -  (-)-dialdehyde  (78)  106  98  104  (+)-trans-diol  (113)  99  106  (66)  (-)-cis-sativenediol  -  Japonica cv. Tan-ginbozu (dwarf)  Indica cv. Century Patna  Compound  58  (77)  (13)  gibberel1ic  acid  acid  (11)  (11) control (+)-dialdehyde  (67)  -  (-)-trans-diol  (87)  98  a The were  rice  s e e d l i n g s were  determined  5 days  after  4-day-old  by  measuring  addition  test  supported  plants.  of  the  the  on wet average  compound  f i l t e r  length of Q  (0.4x10"  or agar.  paper the  mole)  to  second the  Activities leaf  sheath  coleoptile  of  - 59 -  -  60  -  EXPERIMENTAL  General  Unless (m.p.)  otherwise  were  capillary  determined  melting  chromatography gas  gas.  was  using Model  following  Column  Dimensions  •  6'  a  the  following  Kofler  micro  apparatus  (g.l.c.)  Aerograph The  on  point  chromatograoh  Varian  stated  and  6'xl/8" 90-P  with  columns  were  Stationary  on  columns 5'  x  implied.  heating  are  performed  are  Melting  stage  or  uncorrected. either  a Thomas  Hoover  Gas-liquid  a Hewlett-Packard  and.nitrogen  1/4"  points  columns  as  and  carrier helium  Model  gas,  as  employed:-  Mesh  Support  Phase  Chromosorb  W  (HP)  80/100  0V17  n  3%  0V101  II  80/100  C  II  3%  0V210  II  80/100  D  H  10%  DEGS  II  80/100  n  10%  II  80/100  B  E F  5'  1/8"  x  3%  1/4"  II  G H  x  Carbowax SE30  20%  DEGS  Varaport  3/3"  30%  SE30  Carrier  gas  flow-rate  for  1/4"  columns  about  spectra  were  recorded  on  a  spectra  were  recorded  on  Varian  Signal  35 m l / m i n .  positions  are  The  given  columns 6 0 MHz  Varian  in  was  muclear  Associates  Associates  the  about  Tiers  tau  60/80  60 m l / m i n  magnetic Model  Model scale  Varian 90-P  80/100  W  II  x  HewlettPackard 5831A  100/120  30  Chromosorb  10  a  carrier  3%  A  or  5831A  for  resonance  T-60  HA-100 (x)  and  while or  with  100  Model  1/8"  (n.m.r.) MHz XL-100.  tetramethylsilane  -  (TMS)  as  proton were  an  internal  assignments  recorded  Solution  on  reference.  are  spectra  were  Elmer  mm t h i c k n e s s .  Absorption  and  are  by  calibrated  Ultraviolet photometer either  a  (u.v.)  on  were  performed  refers  distillate were by  and  refluxing  and  by  to  as  methylene  calcium hydride  the  Spectral were  before  Dry  diethyl or  (CH^Cl^)  followed  a  were  MS50  model  SP.800  on  unit  spectro-  model  a  spectra  instrument.  with  241  MC  Varian/Mat were  determined  Microanalyses  Laboratory, used  of  measured  Perkin-Elmer  mass  cm"1  for  University  n.m.r.,  of  i . r . ,  u.v.,  grade. either use.  Reagent The  grade  term  Reagent  solvents  or  reagents,  by  sieves  (ether)  and  aluminum  grade  indicated,  tetrahydrofuran  hydride  4A);  ether  petroleum  where  followed  d i s t i l l a t i o n from (Type  Certified  "petroleum  of  ether  or  chloroform  d i s t i l l a t i o n from  phosphorous  and  dimethylsulfoxide  (DMS0)  storage  over  molecular  by  sieves  (THF) by  barium  by  by  (i.r.)  cell  the  were  fraction  (DMF)  and  polystyrene.  recorded  solvents  lithium  molecular  (HMPA)  of  of  in  rotations or  spectra  solution  given  a Unicam  Microanalytical  dimethylformamide  chloride  on  band  resolution  model  boiling  sodium w i r e  hexamethylphosphoramide from  or  30-60°).  over  spectra  High  used  low  Optical  All  of  cm"1  polarimeter  distilled  follows:  storage  1601  recorded  Borda,  were  the  ca.  over  distillation;  are  mass  Vancouver.  were  (b.p.  prepared  followed  P.  reagents  Solvents  (30-60)"  Mr.  rotations  Solvent grade.  by  Columbia,  optical  ("max)  the  area  spectrophotometer.  positions  141  MS902  chloride  chloride  spectrometer. model  Infrared  sodium  were  resolution  Kratos-AEI  British and  Low  sodium  integrated  a  of  model  multiplicity,  parenthesis.  using  solutions.  Perkin-Elmer  CH4B m a s s  the  spectra  i n methanol  polarimeter. model  means  in 137  performed  0.2  -  Signal  indicated  a Perkin  61  oxide  (CHCl^) pentoxide;  distillation (Type  4A);  -  diisopropylamine  and t r i e t h y l amine  potassium  hydroxide  sulfate;  benzene  storage  over  distilled  under  oxide  (Woelm  types  of  activity with  pellets;  distilled  acetone  just  was S i l i c a  neutral)  Grade  by d i s t i l l a t i o n f r o m  hydroxide.  nitrogen  packing  -  by  by d i s t i l l a t i o n from  potassium  chromatography  62  for  were  purchased  I material water  and were  according  Silica aktiv  to  ICN  etherate  gel  for  instructions  the  Aluminum  employed. Inc.  various  from  by  was  mesh).  was a l s o  to  magnesium  column  Pharmaceuticals,  deactivated  over  and p y r i d i n e  (70-150  chromatography from  anhydrous  trifluoride  use.  100-200,  column  over  calcium hydride;  Boron  before  Woelm  storage  and s t o r a g e  as  Both the  activity  grades  manufacturer.  D Florisil  used  chromatography t . l . c .  was f r o m  the  ( t . l . c . )  plates  according  neutral  t . l . c .  to  for  Pharmaceuticals, lengths with  thin  Inc.  ultraviolet  eerie  Preparative Silica  Stahl  Gel  sulfate t . l . c . 6 0 PF  Floridin were  (Type  layer Plates  were  of  from  E.  about  254 + 366 from  E.  Analytical from  Merck  visualised  and were  concentrated  plates  prepared  chromatography  radiation in  6)  Company.  Co.,  (without under  developed  sulfuric  Silica  acid  by  Co.  Gel  layer  GF-254  and Alumina binder  long  iodine  were  or by  by  for  Woelm  ) from  and s h o r t  followed  1 mm i n t h i c k n e s s Merck  thin  ICN wavespraying  heating.  prepared  with  -  (+)-Isobomeo1  and 0.26  mole)  was  added  0.26  (Aldrich  mole) THF  then  (100  ml)  hydroxide  by (10  removed  with  was  magnesium  minutes)  for  doublets  of  shown time  crude  the  by  J  of  at  singlets,  Hz,  9H,  6.12x  borneol  crystals  of  2.0  Hz,  tertiary  (47), the  (38.7  analyses  (J  g)  ml),  m l ) . ^  The  white  and  the  and  8%  of  methyls);  solvent  flow of  = 9.0 with  Hz,  1.61,  3.0  integrated  92%  areas  at  Hz) in  which were  over  98%  u  m = v  ( C C l J ,  9.02, 3790  dried  crystals  6.49x  and  petroleum  exo_-alcohol),  was  formed  (retention  from  time  for the  and  Hz,  of  the ratio  ether  (sharp,  = 7.0  a doublet  (doublet  9.16  N.m.r.  (J  20:1.  (72)  of  9.21  weak)  of  (30-60)  (+)-isoborneol  6.49  was  sodium  38 m l / m i n u t e ) .  (72),  (CC14),  2N  white  (47)  2.0  was  (+)-isoborneol  product  x  in  hydride  precipitate  doublets  Hz,  g,  CHC13))  by  gave  rate  (+)-isoborneol  g,  (40.0  filtrate  (-)-borneol  a doublet  (71)  followed  contain  c a r r i e r gas  (96% y i e l d ) ,  -CH0H  of to  (10.0  l i t h i u m aluminum  ether,  stirrer,  reaction mixture  (10  analysis  crude  The  wire  nitrogen  41.93°(c  hour.  Removal  of  -  4  excess  with  showed  C(2)-endo-proton  n.m.r.  = 7.0  120°C,  product  doublets  white  and  (40  minutes)  D,  Recrystallisation  g.l.c.  water  g . l . c .  (-)-Camphor ^  sodium  hydride  s t i r r e d under  1  water  sulfate.  3.49  (Column  C(2)-exo_-proton  afforded  of  f i l t r a t i o n , washed  4.17  Hz)  and  over  from  a mechanical  aluminum  bath.  before  then  by  the  hours  distilled  a condenser,  Inc.,[«]  dropwise  ml),  (retention  of  4  was  Lithium  Co.,  addition  (72)  IH,  with  ice-water  added for  ml)  s u s p e n s i o n was  dropwise  which were  (CCl^)  the  Chemical  0°C  anhydrous  (40g)  and  c o o l i n g by  s t i r r e d at  hydrolysed  2.0  fitted  100  pressure-equalising funnel.  with  was  (about  flask  atmosphere  dry  (THF)  a three-necked a  -  (72)  Tetrahydrofuran into  63  by  doublets, (three  and  3500  -  (broad, 1070  (c  weak)  (OH),  strong,  Reduction  (+)-camphor  (+)-Isobornyl  of  under  Acetate  A solution anhydride  washed  with  bicarbonate,  give [*]p5 1  H,  9.21  + 42.0°  (c  -CH00CCH3 (three  (Eastman-Kodak  11  (72)  Co.,  provided  o i l  hours.  The with  and 2850  (broad,  strong,  Similarly, (76),  [«]jj  8  -  (CH),  [ « ] " + 41.2°  over  anhydrous  (63)  water,  magnesium  sulfate.  as a c o l o r l e s s o i l  exo-acetate),  8.10  tertiary  5.44  50°C,  (45.0 g,  methyls);  (sharp, C-0);  medium)  m/e 194  acetylation  5 1 . 8 ° (c  1.29,  of  (CH),  (M+),  1740  154,  of  solvent  0.05 Torr)  to  96% y i e l d ) ; half-width  3 H,  CHgCOO-),  u  ( C C l J ,  12  Hz,  9 . 0 6 , 9 . 2 0 and  2900  (sharp,  H"  (sharp,  strong,  C = 0),  1245 cm"  136.  (-)-isoborneol  CHC13)  extract  sodium  Removal  (multiplet,  (singlet,  ether  saturated  (43 -  to  was c o o l e d ,  The combined  acid,  T (CC14),  and a c e t i c  120 m l ) was h e a t e d  mixture  w h i c h was d i s t i l l e d  CHC13);  9 H,  0.24 mole)  IT! a X  strong)  medium)  (-)-isoborneol.  (about  ether.  hydrochloric  (52 g)  g,  reaction  2 N  acetate  singlets,  (37.0  in dry pyridine  and e x t r a c t e d  1.34,  of  (75)  similar conditions  for  and d r i e d  (+)-isobornyl  (sharp,  (63)  water,  a yellow  and 2800  C-0).  0 . 4 2 mole)  water,  -  strong)  (+)-isoborneol  nitrogen  with  afforded  of  (43.0 g,  under  diluted was  (sharp,  cm"^ ( s h a r p ,  0 . 6 0 , CHClg))  100°C  2850  64  ( l i t .  6  5  provided |>]20  -  (-)-isobornyl  50.2°  acetate  (C^OH)).  34 Chromium  Trioxide  Isobornyl of  glacial  Oxidation  acetate  acetic  acid  (63)  of  Isobornyl  (45.0 g,  (200 ml)  Acetate  0 . 2 3 mole)  and a c e t i c  (63)  was d i s s o l v e d  anhydride  (100 m l ) .  in a The  mixture reaction  -  flask  was  cooled with  trioxide  (80.0  over  a period  then  allowed  The  heavy  g, 2  The  through  Celite.  slurry  and  then  by  other  volatile  (Column  and  A,  acetate  and  Torr),  and  6-oxoisobornyl 0.01  Torr).  (600  fractions other  g)  were  of  (5.2  5-  with  extract  of  solvent  be  a mixture  acetate flow  by  Droduct  petroleum in  the (2.0  ether order g),  6-oxoisobornyl  dried  up  g.l.c.  oil  (36  time  was  as  listed:-  acetates(l.l  g),  which  was  acetate time  7.19  of  isobornyl  8.0 of  g)  5-  (b.p.  and  (b.p.  62-73°C,  by  column  chromatographed  eluent.  acetate  The  on  following  acetate (65)  24-62°  (63)  (2.0  5-oxoisobornyl  and  g),  acetate  (65),  T  (CC14),  5.36  (doublet  of  a  acetate  g).  6-oxoisobornyl  (63),  minutes)  separated  and  acid,  Fractional  isobornyl  6-oxoisobornyl  g)  7.79  40% y i e l d )  g)  with  sodium  (retention  be  days.  filtration  isobornyl  analysis)  could  was  anhydrous  a mixture  g,  added  hydrochloric  (colorless o i l ,  (30-60)  8  by  over  (65)  gave  (14  for  extracted  3 N  ml/minute).  acetates  mixture  water,  19.6  slowly  neutralised with  (retention  compounds 4:1  and  broken  acetate  column  was  reaction mixture  unreacted  41  chromium  stirred  a yellow  of  (64)  Vigreux  was  of  ml)  water  and  gave  rate  was  was  water,  (colorless o i l ,  compounds  and  extraction  ether  (about  crude  with  and  diluted  6-oxoisobornyl  obtained  non-polar  mixture (64)  A  temperature  volatile  acetates  chromatography. Florisil  5-inch  other  and  The  gas  a mixture  5-  stirring.  6-oxoisobornyl  carrier  solution  vigorous  successively with  to  a  (140  was  5-oxoisobornyl  a  while  anhydride  bicarbonate,  compounds,  using  bath  during  washed  analysis  distillation  0.01  formed  -  acetic  room  Removal  110°C,  (63)  to  sodium  g . l . c .  minutes),  with  combined  sulfate.  shown  in  formed  The  saturated  magnesium  mole)  up  emulsion  carbonate,  ice-water  hours  warm  green  ether.  water,  0.80  of to  an  65  doublets,  -  1  H,  J  = 7.5  (singlet, v  Hz,  3 H),  (CC1.),  strong,  4.0 9.15  2900  C = 0),  5-oxoisobornyl 1  H,  J  9.01  = 7.0  and  Hz,  9.05  Hz,  -CHOOCCh^),  and  9.16  (sharp,  1235  (three  8.01  (broad,  strong,  (64),  x  2750  6 H)  9 H,  3 H,  CH3COO-),  (tertiary  (sharp,  methyls);  weak)  (CH),  (doublet  of  1750  7.98  5.14  (sharp,  C = 0),  medium)  1235  cm  - 1  5-0xoisoborneol  (singlet,  tertiary  3 H,  CH3C00-),  v  methyls);  (25  diluted was  of  carbonate  ml)  was  washed  sodium  (CC1„),  m = v  7.77  _  provided  44.5°  (broad  singlets, 3500  for and  strong,  18  C -  c  hours.  (CH),  0);  as  m/e  with  1750  (sharp,  1  H,  x  strong,  169,  1745 168  g,  The  crude y i e l d )  (30-60) m.p.  to  244.5  6.21  (broad  give -  8.86,  (CCl^),  3750  strong,  C = 0),  139,  cooled, extract  Removal  which  of  were  pure  246.5°(sealed  8.98,  (sharp,  135,  (1:1)  saturated  multiplet,  v  150,  OH),  water  then  sulfate.  D20,  153,  was  :  and  combined o r g a n i c  with m g x  mmole)  chloride, water,  100%  ether  (sharp, (M+),  11.9  i n methanol  magnesium  (CC14),  methyls);  (OH),  ether.  needles,  exchanged  g,  reaction mixture  ammonium  (2.05  (2.50  mmole)  anhydrous  colorless CHC13);  tertiary  medium)  over  (64)  22.1  The  dilute  crystals  o.69,  signal,  g,  ether-petroleum  (73)  (  acetate  extracted  dried  white  from  9 H,  (broad,  weak)  H  C-0).  (2.74  successively with  5-oxoisoborneol ^  strong,  decahydrate  water,  recrystallised  2  (sharp,  5-oxoisobornyl  c h l o r i d e , and  solvent  [ c c ]  (broad,  refluxed  with  2750  8.89,  (73)  A mixture sodium  and  (sharp,  doublets,  Mia X 2900  8.86  C-0).  (CCl^),  -CH00CCH3),  singlets,  (singlet,  singlets, and  acetate Hz,  (two  -  medium)  cm"^  4.5  66  1  and  H,  cm  125,  124,  - 1  -CH0H),  9.09  medium)  1040  tube),  (three  and  (broad, 123,  122,  -  121,  111,  110,  109  168.1150.  Found  calcd.  C ^ H . ^  for  Removal which  were The  (c  of  (base  (High  C,  solvent  107.  71.39; from  H,  the  of  (73)  Mole.  mother  was  Found  liquor  (73)  also  Wt.  calcd.  spectrometry)  9.59.  5-oxoisoborneol  enantiomer  0.57,  108,  -  r e s o l u t i o n mass  :  93% p u r e  peak),  67  by  :  :  prepared  71.30;  white  g . l . c .  C  1 0  168.1147.  C,  gave  for  H  H,  and  showed  and  p-tosyl  A,  :  2  Anal, 9.66.  crystals  (Column  0  1 6  (1.40  g)  140°C). + 3 7 . 5 °  [<*]n  CHC13).  39 5-0xocamphene  (74)  5-0xoisoborneol (recrystallised were  refluxed  water, 2 N  for  12  extracted  over  (1.06  g)  and  (Column  A,  100°C,  silica  gel  ether  retention  time  product  (0.038  soluble  in  The desired  The  dark  brown  ether.  The  g)  water,  magnesium g . l . c .  one  (30-60)  hexane  major  hours.  at  with or  product  5-oxocamphene  Removal  flow  rate  III)  (30  (71%  time  ether  exhibited  was  of  of  and  by  spectral yield),  to  data  m.p.  afforded  a  time  areas  10% g)  with and  Column  ml) with  water,  retention  (0.78  (60  diluted  washed  integrated  yellow 2.33  9:1)  chromatography ether  with  +  90%  g . l . c .  colorless crystalline  minutes.  (30-60)  cooled,  elution with  another  2.87  pyridine  was  at  35 m l / m i n u t e ) . g)  dry  solvent  a peak  (ratio  chloride  bicarbonate,  colorless crystals  followed  retention  (74)  showed  in  extract  sulfate.  minutes  petroleum  mixture  sodium  provided  minutes,  mmole)  saturated  2.87  grade  20.0  combined  analysis  c a r r i e r gas  2.33  mmole) g,  (activity  petroleum  7.4  (3.8  on  another  g,  chloroform)  acid,  which  (1.25  with  anhydrous  minutes  on  from  hydrochloric  dried oil  and  (73)  Both  compounds  were  be r e c r y s t a l l i s e d . in  accordance with  59-61°C  (hot  stage)  the  too  -  ( l i t .  3 9  (two  singlets,  M p  61-63°C), IH  each,  bridgehead  a l l y l i c  methyls);  v  = 0),  -  methine),  A  -  1.14,  CHC13);  6 . 9 4 (broad  T (CCl^),  signal,  IH,  half-width  8 . 8 5 and 8 . 9 4 (two s i n g l e t s ,  2900  (broad,  strong,  CH),  C = C),  890 c m  1750  5 . 0 3 and 5 . 2 4  6 H,  8  Hz,  tertiary  (sharp,  strong,  *T  1665 ( s h a r p ,  medium,  m/e  150 ( M + ) , 1 3 5 , 1 2 1 ,  for  C-|oHi4u  119,  150.1045.  :  130.1°(c  = CH,,),  (CC1«), I lid  C  5  68  108, 107,  Found  (High  (sharp,  - 1  93 (base  strong,  peak).  resolution  mass  = CH2);  Mole.  wt.  calcd.  spectrometry)  :  150.1037. The 8.79,  (sharp,  = 0);  for  product  8 . 9 8 and 9.01  2900 C  minor  (three  strong)  m/e 1 5 0  C^QH^O  :  was a s s i g n e d singlets,  and 2850  9H, tertiary  (sharp,  (M+), 135, 122,  150.1045.  as 2,6-cyclocamphanone  Found  medium)  (High  methyls);  (CH),  1 0 9 , 1 0 8 , 107  mass  ( 8 2 )  The adding mole)  4 4 b  '  peroxide  complex  30% hydrogen  peroxide  (250 m l ) t o molybdenum  persisted  stirring. over  (CC1J,  (sharp,  Mole.  wt.  spectrometry)  MoOr  strong,  :  .HMPA.  calcd.  150.1046,  Py  4 5  molybdenum  with  (CCl^),  T  v  - 1  peak).  Oxodiperoxvmolybdenum(hexamethylphosphoramidepyridine Complex  u  1760 c m  (base  resolution  (81):-  1.5  ice-water  An e x o t h e r m i c  hours  water  or  bath  After  the exothermic  during so that  reaction  MoOg  .HMPA^O  reaction  which  was p r e p a r e d trioxide  occurred  after  the reaction mixture  i t s temperature  had s u b s i d e d  by  slowly  (50 g , 0 . 3 5 1  hour and  was c o o l e d  did not rise  above  by  40°C.  t h e s u s p e n s i o n was warmed  to  40°C  46 for  4 hours,  ice-water with was  giving  bath,  vigorous stirred  HMPA  an o r a n g e - c o l o r e d (64 g ,  stirring  f o r another  0 . 3 5 mole)  to give  a heavy  15 m i n u t e s  solution. was added yellow  before  After  cooling  dropwise  precipitate.  the precipitate  over  with  an  40 minutes  The s u s p e n s i o n was c o l l e c t e d by  - 69 -  suction from  f i l t r a t i o n , washed  methanol.  temperature a yellow  under  powder  Dry  crystals  (77  (65.5 of  g, (22  g,  g,  ether. for  8  0.27  (THF)  (2.4  in  M solution  mixture  was  (74)  (0.348  over  (82)  (2.44  formed room color  g,  was  5.6  temperature changed  organic  and  aqueous  ether  over  anhydrous  (0.42  g)  Elution  over  through  with  and  the  with  ether  added  to  were  to  dried  provide  a  stirred (150  collected  by  at  room  MoOg.KMPA  solution ml).  as  (room  complex  (82)  of  The  filtration  pentoxide  anhydrous  ml,  0.5  ml,  dry  5.0  mmole)  cooled to 4.8  THF  for  1  hour  was  yellow  and  temperature, (75  g,  96%  yield).  were  to  sulfate  chromatographed  ether  n-Butyllithium added  and  the  reaction  5-oxocamphene  added,  followed  by  Mo0g.HMPA.Py  4 4  which  extract  on  dry  of  green.  and  in  solution  separated.  organic  dissolved  A  '4^  and was  during  pale yellow  petroleum  was  was  0°C.  mmole)  30 m i n u t e s .  hours  combined  g,  ice-acetone bath.  after  layers  :  hours  tetrahydrofuran  and was  in  1.5  dry  the  (2.0  -78°C  magnesium  w h i c h was  (0.7  mmole)  s t i r r e d at  .HMPA.H^O were  twice  (83)  a dry  mmole)  15  phosphorous  provided  hexane)  2.32  was  formed  (5 m l )  c o o l e d by g,  in  (82)  diisopropylamine  tetrahydrofuran  for  mole)  mole)  6-exo-Hydroxy-5-0xocamphene  Dry  Torr)  MoOg  recrystal1ised  yield).  Drying  hours  a i r - d r i e d and  c r y s t a l s of  50%  0.18  water,  (0.01  Mo0g.HMPA.Py  washed w i t h Torr)  yellow  vacuum  pyridine  MoOg.HMPA  0.01  The  with  removal silica (30-60)  The then  i t  reddish-brown allowed  turned  Saturated The  aqueous  was  washed  of  (1:4)  warm  homogeneous brine  was  layer with  solvent  gel  to  f i r s t  up  The  extracted Drying  a brown  afforded  the  added.  was  grade  to  and  water.  gave  (activity  suspension  III)  oil (20  g).  colorless  -  crystals (83)  of  as  a  T  (CC14),  1  H,  J  6.99  starting  colorless 4.88  =  and  3 Hz,  (broad  singlets,  material  (16  (263  mg,  5.15  (two  broad  signal,  1  6.69 H,  tertiary  -  mg),  oil  -CH0H),  6H,  70  72%  (broad  provided  yield),  1  signal,  H,  1  allylic  v , m  medium,  1055  (broad,  (M+,  base  CH),  strong,  peak),  C-|QH-|402  :  1760  (sharp,  C - 0 ) ,  151,  900  138,  166.0993.  Found  strong,  124,  (High  60.0°  0.50,  = CH2),  exchanged  3500  (c  6.54  (doublet,  D20,  OH),  8.99  (two  with  8.82  and  (broad,  strong,  C =  0),  (broad, 123,  1665  (sharp,  (c  0.53,  strong,  110,  109.  r e s o l u t i o n mass  = CH2); Mole.  m/e  wt.  (+)-6-exo-hydroxy-5-oxocamphene,  CHC1^)>  prepared  Reduction  A in A  dry  of  solution  of  ether  ml)  added  allowed  (5  warm  up  was and  gave  white  crystals  (1:4)  afforded  reaction  analogous  dried  III)  (44  dry  ice  hydride  The  :  Elution  material  (4.3  for  166.1005. o  [=]n  (83)  carbon mg,  +  56.8  layer  0.31  mg),  :  followed  0.24  bath. ether  3  hours,  saturated  from  the  organic  extract  was  washed  Removal on  mmole)  dry  for  with  silica  petroleum by  in  -15°  organic  sulfate.  ether  at  separated  chromatographed with  mg,  mmole)  quenched  was  combined  (40  tetrachloride  stirred  then  magnesium  which were  g).  -  was  and  aqueous  ether.  C),  conditions.  (12  mixture  anhydrous  mg)  (1.5  starting  The  with  with  a  =  (83)  temperature,  solution.  water  by  aluminum  room  extracted  grade  cooled  The to  with  (activity  was  lithium  chloride  and  under  (-)-6-exo-hydroxy-5-oxocamphene  dropwise.  to  ammonium layer  s  6-exo-Hydroxy-5-oxocamphene  suspension of  was  a  2900  166  calcd.  spectrometry)  enantiomer, w  OH),  medium,C  25 The  CHC13);  *t  cm~^  137,  -  H each,  ( C C l J ,  v  6-exo-hydroxy-5>oxocamphene  methine),  IIIQ A  (broad,  [~]*S  singlets,  bridgehead  methyls);  then  of  gel  ether  colorless  solvent  (30-60)  crystals  -  of  5-exo,  elution  6-exo-dihydroxycamphene  with  ether  :  petroleum  6-exo-dihydroxycamphene The  5-exo, to  H p  5 3 . 6 ° (c  IH  -  each,  7.36  give  =  exchanged v  m  C = C),  1060  m/e  (M+),  168  168.1150. C  1 Q  H  and  1030  137,  Found  1 6  reduction The ether  0  :  2  of  8.96  -  (30.0  92.0°C  5.07  and IH  5-erido,  mg,  5.31  each,  yield). ether  stage),  (two J  =  7.60  singlets,  83%  petroleum  (hot  methine),  (two  Further  provided  6H,  non-hydrogen-bonded  121 ,  C,  109  fine  broad  singlets,  6 Hz,  -CH0H),  (broad  signal,  tertiary  methyls);  OH),  3350  (sharp,  (doublet  H,  6.37  (doublet,  exchanged  with  methylene),  cm"1  (sharp,  890  108.  Mole.  wt.  spectrometry)  Found +  0),  (broad,  :  :  C,  71.61;  52.8°  (c  0.57,  then  (87)  sublimed m.p.  T (CDC13), doublets, J  = OH),  97.0 5.09  IH,  3 Hz,  (bath  J  =  -CH0H  7.38  temperature  -  99.0°C  and  5.26  3 Hz, of  (broad  IH,  C(4)-bridgehead  and  8.90  (two  recrystal1ised  calcd.  (two  3 Hz,  C(6)-exo-0H), signal,  IH,  methine),  singlets,  6H,  was  ether  singlets, of  6.81  C(5)  -  (broad  (broad  -  760  tube),  tertiary  H  1 6  0  (+)-5-exo,  9.65.  bridgehead  8.33  1 ( )  H,  from  -CH0H  C  CH0);  Anal,  CHC13),  broad  for  =  168.1155.  100-110°C,  (sealed  medium,  strong,  was  Do0,  8.70  9.59.  1660  6-exo-diol  IH,  (multiplet,  peak),  (77),  needles,  of  (base  C -  CH),  (+)-6-exo-hydroxy-5-oxocamphene.  CHC13);  5.95  strong,  strong,  corresponding  and  white  (broad,  r e s o l u t i o n mass  71.39;  5-endo,  2900  (sharp,  (High  the  (30-60)  0.35,  7.96  90.0  a l l y l i c  strong,  OH),  6-exo-Di hydroxycamphene  (c  (4:1)  doublets,  bridgehead  (broad,  yield).  crystals  (CDC13),  and  7%  r e c r y s t a l l i s e d from  (two  8.91  mg,  (30-60)  m.p.  T  6.21  (2.3  3  hydrogen-bonded  give  was  needles,  and  strong,  for  (66)  colorless  3  OH),  3570  as  CHC1 );  IH,  D,,0,  (CHClo),  v  5.76  signal,  with  iTl3X  0.55,  -  ether  (66)  colorless  CH2),  (broad  (87)  6-exo-diol  (30-60) 7  71  calcd.  obtained  by  petroleum Torr)  to  -  45.1°  IH  each,  =  CH2),  endo-OH), signal,  allylic signal,  methyls);  :  2  v  2H,  methine), 2H,  m a x  (CHC13),  -  3560  (sharp,  bonded  OH),  (broad, 151,  2900  150,  168.1151.  Anal,  9.50.  The  +  138,  51.7°  890  137,  C]o^l6^2  for  strong,  C - 0 ) ,  139,  :  CH),  cm"1  135,  for  121,  enantiomer, 0.42,  C  1 0  1660  0  1 g  was  strong,  hydrogen-  (sharp,  medium,  C = C),  1030  108  C,  (+)-5-endo,  CHC13),  (broad,  = CH2);  (base  (High  :  2  3350  strong,  109, Found  H  OH),  (broad,  168.1151.  calcd.  (c  -  non-hydrogen-bonded  (broad,  strong,  calcd.  H,  strong,  72  m/e  peak),  107.  H,  9.59.  prepared  by  153,  wt.  spectrometry)  Found  6-exo-dihydroxycamphene  also  (M+),  Mole.  r e s o l u t i o n mass  71.39;  168  :  C,  :  71.48;  (113),  reduction  of  (+)-6-exo-  hydroxy-5-oxocamphene.  6-exo-Acetoxy-5-0xocamphene  A  solution  of  acetic  anhydride  reflux  for  which  on  15  (88)  6-exo-hydroxy-5-oxocamphene  (0.15  hours.  g,  1.4  Normal  distillation  (CC14),  signal, 4  Hz,  IH,  4.79  and  half-width  IH,  (two  3 Hz,  IH,  C(4)-bridgehead  (two  singlets,  6H,  aqueous  (88)  5.06  bridgehead  in  broad  pyridine gave  a colorless singlets,  methine),  methine),  7.95  6.98  7.72  methyls);  v  m = v  (sharp,  C = C),  1220  m/e  209,  for  C  n o  H  208 1 c  0  o  strong,  C = 0),  1745  (broad,  strong,  C-0-C),  (M+), :  166,  208.1099.  165  (sharp,  (base  Found  890  peak),  (High  ml)  Torr)  0.6  (0.105  g,  signal,  signal,  g)  84%  yield),  5.55  (broad  half-width  half-width  CH3C00-), 2900  (0.12  under  afforded  (broad  ( C C l J ,  and  heated  oil  = CH2),  3H,  mmole)  was  each,  (broad  (singlet,  (5  g,  a yellow  oil  IH  mo x 1760  (0.10  90-100°C, 0.05  -CHOOCCHg),  allylic  tertiary  as  dry  work-up  (bulb-to-bulb,  6-exo-acetoxy-5-oxocamphene T  mmole)  (83)  8.82  and  (sharp,  4  Hz,  8.93  medium,  CH),  H  strong,  C = 0),  cm"1  (broad,  151,  138,  137.  r e s o l u t i o n mass  1655  strong  =  Mole.  (broad,  weak,  CH2); wt.  spectrometry)  calcd. :  208.1089.  -  -  Sodium  Borohydride  Reduction  A  solution of  6-exo-acetoxy-5-oxocamphene  in  ether  :  methanol  (30  mg,  0.8  mmole)  for  1  hour  work-up  and  (bulb-to-bulb, which  were  t . l . c . that  (89) T of  b a s e d on  two  the  5.09  and  IH,  J  (two  singlets,  = CH,,),  (broad,  wt.  the  (two  2 Hz,  allylic  8.74  product  mixture  181,  calcd.  strong,  168,  151,  for  spectrometry)  :  the  1730  150,  210.1254.  s i n g l e t s , IH  7.95  (CCl^), (two  210.1256.  crystals G,  (96  mg)  130°C)  and  indicated of  signal  reduction;  = CH2),  (broad  5.92  signal,  The  component  minor  and  5.32  109,  (two  observed (broad, 1655  strong, 108,  (High  107  (doublet half-width  CH3C00-),  tertiary  C = 0),  Found  hydride  3H,  (broad,  121,  distillation  crystals  each,  6.27  3580  strong,  132,  0°C  aqueous  (singlet,  5.16  v  890 c m ' 1  Usual  integration  s i n g l e t s , 6H,  (CC1.),  at  6-exo-acetoxy-5-endo-hydroxycamphene  c o r r e s p o n d i n g ones  135, :  by  mmole)  borohydride  Column  the  5:1  methyls).  (sharp,  C-0-C),  C^H^gOg  T  8.94  of  CH),  of  of  0.5  stirred  hours.  120°C;  N.m.r.  methine),  epimer;  to  medium,  was  colorless  -CH00CCH3),  tertiary  and  F,  a s s i g n e d as  broad  mg,  P u r i f i c a t i o n by  afforded  ratio  2  (88)  Sodium  stereochemical course of  similar  (broad,  (M+),  in  were  I.r.  1250  isomers  6H,  (100  0°C.  another  (Column 254).  5-exo-hydroxy  signals  for  GF  = 2 Hz,  8.92  each,  cooled to  (98 mg).  g.l.c.  (88)  reaction mixture  gel  5.25  bridgehead  IH  on  preferred  IH,  the  oil  i s o m e r was  4 Hz,  as  The  temperature  (silica  major  doublets,  was  100-115°C, 0.05 Torr)  were  The  (CC14),  room  6-exo-Acetoxy-5-0xocamphene  ml)  added.  homogeneous  there  (8  a colorless  analyses  areas.  was  at  provided  (1:1)  of  73  8.68  was  broad  assigned  singlets,  methyls),  for  the  OH),  (sharp,  weak,  (base  other  major  medium,  = CH2);  and  m/e peak).  r e s o l u t i o n mass  product.  2900 C =  211,  C), 210  Mole,  -  5,6-Dioxoisobornyl  A mixture dissolved (1.63  of  14.6  5 - and 6 - o x o i s o b o r n y l  mmole)  stirring.  dried  After  was washed  over  crystals grade  III)  provided  pure  97.5  x  (three  strong, 108,  from [a]  sharp  peak).  Mole.  (c  1.35,  of  m.p.  3 4 a  of  (CC1,),  m a v  (100)  m.p.  101.0  95-96°C),  J  IH,  J  -  orange  ether  (30-60) (0.36 g, petroleum  103.0°C  (hot  3 6 . 5 ° (c  = 8 . 0 Hz,  8 . 8 0 , 8 . 8 9 and 9.11  4.0  Hz,  singlets,  (broad,  weak,  absorptions,  C = 0),  1230 and 1220 c m  wt. :  (100)  154,  calcd.  136,  for C  1 2  H  127,  l g  0  4  121, :  1825,  115,  224.1049.  1780 - 1  111,  and  (broad, 109,  Found  (High  224.1050. prepared  enantiomeric CHC13).  141,  1.22,  C(4)-bridgehead  (three  CH),  stage),  Hz,  2900  196,  and  (activity  -  1.0  hours  combined  crystals  [-]25  = 5 . 0 Hz,  18  water,  r e c r y s t a l l i s e d from  doublets, IH,  as y e l l o w  for  gave  gel  dioxide  The  solvent  + 70% p e t r o l e u m  prisms,  CH3C00-),  (M+),  (+)-enantiomer  + 37.3°  3H,  spectrometry)  the corresponding 2 5  yellow  of  was  precipitate  ether.  on s i l i c a  was f u r t h e r  doublets,  and s t r o n g  m/e 2 2 4  mass  acetate  ( l i t .  of  Selenium  bicarbonate,  Removal  30% e t h e r  (doublet  v  methyls),-  99 ( b a s e  The  5.26  (doublet  C-0);  resolution  sulfate.  with  tube)  3 . 7 5 mmole)  the black  with  sodium  chromatographed  give  8.00 (singlet,  tertiary  1760  (sealed  7.31  methine),  to  g,  10 m m o l e ) .  and washed  saturated  the product  ether  (CC14),  CH00CCH3),  9H,  -  99.5°C  CHC13);  water,  Elution  of  g,  (0.79  temperature,  by f i l t r a t i o n  which were  Part  m l , 1.0  room  5,6-dioxoisobornyl  (30-60) -  to  magnesium  (20 g ) .  53% y i e l d ) . ether  g)  acetates  and t h e s u s p e n s i o n was r e f l u x e d  cooling  with  anhydrous  (0.72  (1.0  was added  s e l e n i u m was removed  filtrate  -  (100)Jttd  i n acetic anhydride  g,  with  of  Acetate  74  under  similar reaction  5 - and 6 - o x o i s o b o r n y l  conditions  acetates  had  -  6-endo-Hydroxy-5-0xoisobornyl  (-)-5,6-Dioxoisobornyl in  a mixture  solution 48 added 10  of  w h i c h was  '  and  zinc  organic  dust  was  with  (12  and w a t e r  acid  Removal  as  yellow  ml)  0°C.  Zinc  120.0  -  4.75  (doublet 0 = 1 . 5  of  (0.3  g,  1.65  (3 m l )  dust  (0.40  from  of  mmole)  to  g,  give  6.15  was a  dissolved  yellow  mmole)  -CH0H),  methyls);  vm  ( C C l J ,  12H18°4  strong,  167, :  151, - l  2 2 6  calcd.  2  for  Analogous  gave  6.75  138  1 2  (broad,  (base  l g  0  reduction  hydroxy-5-oxoisobornyl  4  : of  C,  over  yellow  oil  was  Hz,  and  9.03  129,  H,  OH),  g)  water,  combined  which  on  short-  gave  purification colorless  CHC13);  0);  Mole.  wt.  spectrometry) Found  :  C,  acetate  0.50,  gave  OH),  7.99  tertiary  medium, m/e  :  CH),  226  calcd.  (M+),  for  226.1204.  63.59;  CHC13).  (CC14), (doublet,  Do0,  (sharp, C -  x  9H,  by  crystals,  6.15  with  singlets,  109.  (c  which  magnesium  -CH00CCH3),  strong,  8.02.  -68.0  (0.04  2900  (+)-5,6-dioxoisobornyl  acetate,  after  The  anhydrous  exchanged  r e s o l u t i o n mass  63.70;  within  diluted with  ether.  0.60,  (three  123,  hour,  was  ether  Hz,  (broad,  1  Further  (c  IH,  medium,  cm"1  -  4.5  disappeared  6-endo-hydroxy-5-oxoisobornyl  + 68.3°  signal,  peak),  (High  dried  (30-60)  = 7.0  3520  with  82% y i e l d ) .  [<*]27  for  filtrate  afforded  ether  8.91,  1240  and  g,  8.85,  Found H  J  0°C  extracted  Torr)  (broad  C = 0),  ° 4 C  IH,  The  a pale  (0.31  gradually  s t i r r e d at  and  stage),  doublets,  CH3C00-),  184,  was  water  petroleum  (hot  solution  filtration.  crystals  3H,  198,  the  (120-160°, 0.05  (singlet,  (broad,  by  solvent  122.0°C  Hz,  1760  of  washed w i t h  colorless  m.p.  color  removed  was  recrystal1isation  Anal,  (100)  sodium c a r b o n a t e ,  distillation  acetate  C  (101)  acetate  reaction mixture  extract  sulfate.  IH,  Acetate  cooled to  the  The  neutralised  path  -  57  minutes.  the  acetic  75  H,  7.94.  (-)-6-endo-  -  g-Hydroxylatidh  A (THF)  solution was  added  (86  mg,  and  diisopropylamine 0°C.  mixture  and  a  material  by  crystals  (12  dry  Mo05  .  THF  crystals  (95.5  (3  colorless n.m.r. mg,  oil  and  12%  retention  g . l . c .  yield  time  and  mg,  1.0  at  spectral  acetate  (100).  Mo05  .  HMPA  (65)  Py  (82)  (434  diisopropylamide  (0.9  mmole)  acetate  .  acetate  (64).  crude  product  ether  :  Column gave  petroleum  petroleum  ether  g,  ether  (30-60)  by  the  shown  petroleum to  be  to  by  (64)  stirred  for  introduced.  then  on  gel  silica  ether  0.5 in  the  was  presence  (1:1)  starting  with  m.p.,  (-)-6-endoreduction  of  °=_hydroxylated with of  lithium  described for gel,  material Further  activity  (49.3  mg)  elution  a colorless  oil  5-oxoisobornyl grade  III)  by  elution  with  ether  (8.3  mg)  4  pale  (30-60)  zinc-acetic acid  mmole)  '  colorless  consumed) of  4 4  room of  gave  those  at  a mixture  recovered  elution  mmole)  (65)  (silica  provided  and  afforded  material  procedure  (1:9).  :  identical  mmole)  hour  0.9  acetate  was  chromatographed  Further  mg,  starting  (30-60) (1:1)  was  mmole)  1  usual  ether  Acetate  (105  1.0  for  obtained  chromatography  recovered  was  data  (+)-5,6-dioxoisobornyl  6-0xoisobornyl  as  starting  (101)  6-0xoisobornyl  up  analyses. on  5-0xoisobornyl  -78°C  with  acetate  of  ml,  (434  (82)  hydroxy-5-oxoisobornyl  ' g-Hydroxylation  (0.4  hexane)  s o l u t i o n was  which  based  tetrahydrofuran  the  which  mg)  in  dry  and  Elution  (28  (2.4M  in  added  Working  g).  mmole)  -78°.  Py  mg)  1.0  to  stirred  hour.  III)  .  mg,  lithium  was  HMPA  (64)  (100  cooled  another  grade  provided  in  was  -  Acetate  n-Butyl  s u s p e n s i o n was  for  oil  (activity  to  before  temperature  g . l . c .  of  mmole)  red-brown  yellow  5-0x6isobornyl  the  0.41  30 m i n u t e s The  of  cooled  was  76  of  the  with :  with  spectral  - 77 -  data  i n accordance with  acetate  (102)  the structure  (21% y i e l d  based  of  5-endo-hydroxy-6-oxoisobornyl  on s t a r t i n g m a t e r i a l  consumed);  5.49  (doublet  of  doublets,  IH,  J  = 8 Hz,  4 Hz,  -CHOOCCHj o f  5.90  (doublet  of  doublets,  IH,  J  = 5 Hz,  2 Hz,  -CHOH  7.99  (singlet,  (tertiary strong, m/e  1760  226 ( M + ) ,  Sodium  v  166  (base  226.1195.  :  3500  strong,  C = 0),  peak),  Found  151,  (High  :  borohydride  (0.30 g,  8 . 0 mmole)  reaction  mixture  the usual  silica  gel  (30-60)  crystals -  (activity  5.84  1230 c m " 1 ( b r o a d , 138,  123.  r e s o l u t i o n mass  gave  (2:1)  allowed  5-endo,  III)  (total  yield  petroleum  of  ether  (doublet  C(5)-endo-0H),  of  wt.  acetate  o i l  a period  calcd. :  up t o  room  226.1205.  (1.03  1.5  (101)  g,  bath.  hours.  temperature.  Sodium The  Working  ( 0 . 9 9 g) w h i c h was c h r o m a t o g r a p h e d  (40 g ) .  Elution  acetate  78%).  for  Acetate  (101)  of  C-0-C);  with  Both  (104)  ether  :  acetate ( 0 . 3 8 g)  products  were  petroleum (103)  as  up on  ether  ( 0 . 3 5 g)  colorless  recrystal1ised  from  (30-60). (103)  (fine  4.92 (doublet  doublets  6.17  strong,  spectrometry)  6-endo-dihydroxyisobornyl  diols  6-endo-diol  T (CC14),  over  t o warm  a yellow  grade  Mole.  6H)  (broad,  was c o o l e d by an i c e - w a t e r  was added  6-endo-di hydroxyi sobornyl  5-endo, stage);  was t h e n  2900  6-endo-Hydroxy-5-0xoisobornyl  methanol  way a f f o r d e d  (9:1)  5-exo,  ether  141,  (singlet,  medium,OH),  6-endo-hydroxy-5-oxoisobornyl  i n ether  and  (broad,  exo-acetate),  endo-alcohol),  and 9.11  solution  of  of  3H)  Reduction  mmole)  in  (singlet,  (CCT„),  v  (broad,  8.81  Borohydride  A 4.55  CH3C00-),  methyls);  CH),  ^12H18^4  3H,  of  (CCl^),  T  of  (doublet,  of  white  doublets,  doublets, IH,  J  c r y s t a l s ) , m.p.  IH,  = 9 Hz,  J  IH,  J  = 9 Hz, -CHOH  of  83-85°C  = 8 Hz, 4 Hz, C(6)  4 Hz, 1  -  Hz, OH),  (hot -CH00CCH3),  -CHOH 8.00  of  -  (singlet,  3H,  (tertiary  methyls);  strong,  CH),  C-O-C),  1070,  186,  171,  wt.  CH3C00-),  1750  spectrometry)  stage), 4.87 IH, of  139,  ]2H20°4  C  :  subl.  :  (104)  (sharp,  3  ^  '  2  C = 0),  strong,  125,  124,  Found  8.00  [«]jj8  half-width  -CHOH o f  C(5)-exo-0H),  2900  (broad, 186, C  strong,  12H20°4  (singlet,  14  Hz,  (c  Anal, The  calcd.  for  5-endo,  A  1080  150, -  CH),  u  and  (broad, strong,  228  (base  (M+),  peak).  Mole,  mass  Found  (High  :  C  '  6 3  '  cm"1  (sharp,  (base  H  »  8  -  8 3  6-endo-diol  (103)  could also  formation  solution of  5-endo,  Acetate  -  H ^  showed  acetonide  sulfuric  and  (CC14), (doublet,  9.15  -CHOH (three  strong,  (see  -  be  (1  :  52.0°  C  '  (c  separated  C-0); wt.  6 3  -  2 9  m/e  228  calcd.  for  :  (M+),  228.1368.  '»  0.50, from  1260  H  >  8  -  9 6  -  CHOlg). the  5-exo,  below).  Acetonide  acid  Mole.  C = 0),  spectrometry)  F o u n d  4  strong,  strong,  6-endo-dihydroxyisobornyl  concentrated  (hot  = 3 Hz,  (broad,  peak).  (104)  by  J  9.03  3500  x  6.10  IH,  (sharp,  trans-diol  (104)  and  1735  124  1 3  CHCI3);  8.95,  r e s o l u t i o n mass -  121-123°C  f  and  1030  m.p.  (doublet,  ( C C l J ,  a  135,  6-endo-Dihydroxyisobornyl  mmole)  m/e  -CH00CCH3),  CH3C00-),  1750  139,  C-|2H20°4  of  5-endo,  6-endo-diol  0.61  1 3 6 1  enantiomer The  strong,  153, -  2 2 8  2900  resolution  0.52,  IH,  6.57  3H,  methyls);  C-O-C),  168, :  108  6H)  (broad,  C-0);  (High  + 51.2°  C(6)-endo-0H),  tertiary  (broad,  171,  OH),  1250  121,  max OH),  (singlet,  strong,  (colorless needles),  in-112°C,  multiplet,  9H,  strong,  135, * ^  2 2 8  (broad,  9.70  228.1379.  pt.  = 3 Hz,  singlets,  150,  cm"1  and  3H)  3450  (sharp,  1030  6-endo-Diol  (broad J  1735  -  (singlet,  (CC1J,  m a v  and  153,  for  5-exo,  and  1050  168,  calcd.  v  8.99  78  drop)  (106)  acetate in  dry  (103) acetone  (140 was  mg,  -  refluxed cooled  for  3 hours.  The d a r k  and n e u t r a l i s e d w i t h  removed  under  extracted sodium  with  ether.  bicarbonate,  Removal  of  120°C,  0.5  afforded  acetonide  84% y i e l d ) ,  m.p.  51-55°C,  [ « ] ^  too  i n hexane  soluble  (CC14),  T  (doublet  4.87 of  5.72  (doublet,  8.48  and 8 . 7 2  8.94,  (broad,  Found  C  15H24°4 The  '  7  Instead  employed. separated  1  4  ;  cis_-diol, of  the s t a r t i n g  reduction  -  H  >  9  of  using  -  of  1  *  material,  o  u  n  d  acetonide  had pure  F  wt.  5-endo,  C  »  from  cis-diol trans-diol  (103) (104)  saturated  of  could  sulfate.  (bulb-to-bulb,  6  1 Hz,  of  1  4  ;  H  »  CH3C00-),  v  C-O-C); C  H  1 5  2 4  0  Anal,  9  form  by column  group), (CCl^),  m g x  -  0  2  (strong,  m/e 2 6 8 4  :  (M+),  268.1675.  calcd.  for  -  from  the  corresponding  CHC13). acetate  c i s - and t r a n s - d i o l s acetate  were  5.43  1380 and 1375  for  prepared  (c 0 . 6 5 ,  3H,  methyls);  strong,  -  mg,  -C(5)H-0-),  isopropylidene  268.1691.  7  (137  -CHOOCCHg),  6-endo-dihydroxyisobornyl  6-endo-hydroxy-5-oxoisobornyl  Only  :  (106),  74.0°  a mixture  and  The c r y s t a l s  3 Hz,  C = 0),  calcd.  was  be r e c r y s t a l l i s e d .  4 Hz,  tertiary  (broad,  :  to  methyls  spectrometry)  0  with  8.03 (singlet,  strong,  Mole.  water  magnesium  = 8 Hz,  = 8 Hz,  9H,  (sharp,  168.  mass  (-)-enantiomer  enantiomeric  as  6  1750  226, 193,  J  tertiary  singlets,  CH),  resolution  C  6H,  1250 and 1230 c m " 1  peak),  :  (three  IH,  J  -C(6)H-0-),  (two s i n g l e t s ,  1260,  (High  doublets,  with  on d i s t i l l a t i o n  (30-60)  then  the solvent  (c 0 . 5 6 , CHC13).  IH,  was  as c o l o r l e s s c r y s t a l s  ether  doublets,  = 8 Hz,  strong,  CH3-C-CH3), (base  of  J  9 . 0 4 and 9 . 1 0  2900  253  IH,  of  anhydrous  (106)  and p e t r o l e u m  (doublet  doublets  over  + 78.9°  7  of  was washed  o i l which  Torr)  formed  Part  was d i l u t e d  extract  and d r i e d  a yellow  mixture  bicarbonate.  The o r g a n i c  gave  reaction  The r e s i d u e  water,  solvent  brown  sodium  an a s p i r a t o r .  -  79  (101)  an a c e t o n i d e  from  could  which  chromatography.  For  the  also  was  (103)  be  readily  example,  a  -  mixture in  of  dry  (103)  acetone  provided  grade  gave  :  cooled  residue washed  (107)  as  H ,  +  5.97  J  (30-60)  (1:1)  and  for  part  g).  Elution (0.36  pale  yellow  to  IH,  1 Hz,  medium,  strong,  124  peak),  m=v  5-endo,  121-122°C  x  (CC14),  8.64  and  group), ( C C l J ,  108,  at  mg,  85°C  0.76  for  107.  m/e  Mole.  10%  (106)  (126  mmole)  24  in  hours.  The  mixture  pressure.  ether  and  extract  the  sulfate.  were  mg,  The  was  Removal  recrystal1ised  of from acetonide  (sealed  110°C,  tube),  (doublet  (two  subl.  of  9.13  medium,  IH,  calcd.  of  3H  each,  doublets,  -C(6)H-0-)» tertiary  singlets,  3H  non-hydroqen-bonded strong,  208, for  ^  J = 8 Hz,  (three  (broad,  211,  pt.  doublets  singlets,  and  2900  (M+), wt.  and  6-endo-di hydroxyi soborneol  (sharp,  226  90% e t h e r  reduced  which  9.09  OH),  (30-60)  under  magnesium  8.81  3710  gel  ether  acetonide  (220  5.54  8.98,  hydrogen-bonded  CH3-C-CH3); 109,  mg)  before  silica  with  -C(5)H-0-)» 5 . 8 2 ( d o u b l e t ,  -CH0H),  v  methyls);  m.p.  CHC13);  4 . 5 Hz,  (100  on  drops)  (107)  with  anhydrous  provide  needles,  0.75,  (doublet,  over  as  (5  (104).  removed  extracted  up  petroleum  acetate  heated was  crystals  isopropylidene  (broad,  (base  solvent  (30-60)  (multiplet,  tertiary  the  dried  and  colorless  of  of  were  :  elution  decahydrate  ml)  water  50.7°(c  Further  Acetonide  (15  Working  ether  trans-diol  carbonate  s u l f u r i c acid  chromatographed  with  g).  provided  in water,  ether  3 hours.  w h i c h was  dissolved  gave  concentrated  6-endo-Dihydroxyisobornyl  water  = 8 Hz,  methyls  3550  g)  -  with  refluxed  (106)  sodium  with  petroleum  IH,  (50  and  was  solvent  6  was  g)  6-endo-Dihydroxyisoborneol  methanol  2  (0.75  (0.92  III)  ether  mmole)  was  ml) oil  (+)-5-endo, 0.47  (104)  acetonide  petroleum  5-endo,  (70  a yellow  (activity (1:4)  and  80  183, C  1 3  H  CH),  153, 2 2  0  3  151, :  1380 135,  226.1569.  each, OH),  -  Found  C  (High  13H22°3  :  r e s o l u t i o n mass  C >  -  6 8  Hydrolysis  9 9  '  of  H  »  similar conditions  [.c]25  _ 4 i j °  5-exo,  (2.65  g,  dry  then  11.7  of  pyridine  formed  was  combined  F  under  cooled,  chromatographed ether  obtained G.l.c.  + and  minutes, gas  was  with  flow  provided  a pure  Spectral  data  of  d  :  »  C  6  226.1553. -  9  1  ;  3  H  Anal,  >  9  6-endo-di hydroxyi sobornyl the  corresponding  calcd.  for  -81acetate  acetonide  (-)-alcohol,  Acetonide  diluted  stirred for  of  gel  sample this  with  0.15  in  the  to  was  with  30 m i n u t e s reaction  ether. over  a dark  brown  liquid  III)  (200  provide  peaks  at  ratio  with in  for  g)  oil  (107)  mmole)  dried  Repeated  colorless oil  70.0  brown  A yellow  the  component  g,  and  grade  indicated  areas  dark  water  Torr)  (8.0  extracted  (30-60).  39 m l / m i n u t e ) . of  The  gave  (activity  acetonide  temperature  and  solvent  product  integrated  room  water,  ether  chloride  hours.  washed  (75°C,  this  at  20  with  was  silica  rate  (108)  6-endo-dihydroxyisoborneol  nitrogen  distilled of  n  methanesulphonyl  90% p e t r o l e u m  analysis  carrier  and  Removal  on  u  :  CHC13).  extract  sulfate.  o  provided  (50 ml)  organic  magnesium  1.99  -  (+)-5-endo,  mmole)  refluxed  10%  8 0  6-exo-Dihydroxycamphene  A mixture  in  0.73,  -  spectrometry)  (-)-5-endo,  under  (c  -  9  81  mixture  The  anhydrous  and  which eluted  (1.47  g)  of  1:5  times  (Column  chromatography  retention  time  accordance with  A,  on  with  (1.23 1.50  g). and  120°C,  silica  1.99 the  was  was  a colorless oil retention  and  gel  minutes.  structure  of  26 5-exo, (c  6-exo-dihydroxycamphene  0.70,  5.79  and  CHC1 ); 3  6.13  (two  T (CC14), broad  acetonide  5.28  and  doublets,  IH  5.40  (108) (two  each,  J  (about broad = 5 Hz,  50% y i e l d ) , singlets, -CH-0-  at  IH  0  [=]n  -  67.4  each,  =  CH2),  C(5)  and  C(6)),  - 82 7.42  (broad  signal,  1H,  bridgehead  singlets,  3H e a c h ,  9.01  s i n g l e t s , 3H e a c h ,  (two  tertiary  allylic  methyls  of  tertiary  methine),  and  8.84  (two  isopropylidene group),  8.97  and  2900  (sharp,  methyls);  v  m  8.69  =  (CC1-),  v  Ilia X  strong,  CH),  1675  CH3-C-CH3), (broad, 119,  1270,  medium,  107.  prepared  and  colorless assigned  J  (50  the  of  for  C  of  its  3 Hz,  had  methine),  = 7  8.84,  methyls);  Hz,  weak,  1160, m/e  C = C),  1110, 208  5-exo,  1070  (M+),  0.18  and  193,  10%  mmole)  was  strong,  0.50,  peak),  150,  the  (+)-isomer  same  solvent  retention  4.40  time  4.16  2900  133,  121,  (High  of  (108)  was  afforded  1.5  also  IH,  7.52  J  9.20  Hz,  (broad,  (five  strong,  of J  (multiplet,  and  It  acetonide  IH,  = 7  a  minutes.  (doublet  (doublet,  doublets,  9.17  135,  cm"1  CHC13).  T (CCl^)  8.96,  895  Found  6-endo-di hydroxybornene  of  strong,  C-O-C),  208.1463. The  (111)  doublets,  = 6 Hz, 4  Hz,  IH,  IH,  C(2)-  -C(5)H-0-),  bridgehead  singlets,  CH),  was  1650  15H,  (broad,  1  and  1360  (doublet,  (broad,  150,  133,  strong, 121  in  C-O-C),  CH3-C-CH3), 875  peak),  cm"1  107,  1240,  (broad,  1190, strong,=CH);  100.  (66)  acetonide  6-endo-di hydroxybornene  dissolved  strong,  (base  6-exo-Di hydroxycamphene  5-endo,  (doublet,  H  1060  179,  :  -C(6)H-0-),  6-exo-Dihydroxycamphene  (-)-5-exo, about  1370  1385  (base  2  g . l . c .  ( C C l J , I lid A  very  0  proton),  8.86,  v  2 Q  (c  spectral data:-  J  193  208.1466.  5-endo,  (doublet  and  (broad,  column w i t h  which  5.21  IH,  H  1 3  70.2°  the  of  :  C(3)-olefinic  (doublet,  •tertiary  calcd.  mg)  proton),  allylic  (M+),  structure  basis  olefinic  208  +  1380  1040  m/e  C*]2,4  elution  C=C),  and  spectrometry)  showed  oil  = 6 Hz,  5.60  wt.  weak,  1060  =CH2);  mass  Further  the  1210,  Mole.  resolution  on  (sharp,  *t  methanol  (5  (108)  acetonide ml).  (111)  contaminated ( 3 9 mg  Hydrochloric  acid  with  mixture, (6N,  4  drops)  -  was  added  days, was  and  with  then  4 drops  under  with  ether  over  anhydrous  the  A,  30% e t h e r  +  colorless oil  (b)  mass  mass  (12.2  (g.l.c.  mg)  identical  to  compound provide  identified  following  H,  J  = 6 Hz,  C(2)-olefinic  of  mixture  was  extracted and  dried  a yellow  oil  peak  A,  retention  15%;  peak  C,  4.58  minutes,  The  crude (3  the  g)  product and  starting  peak  C),  spectral  and  g . l . c .  peak  C was  (c)  with  fractions  material  ( g . l . c .  was  elution  following  exhibiting  of  water  4  :-  III)  gave  water,  gave  for  reaction  solvent  with  analysis  A)  The the  solvent  grade  those  to  optical  to  provide  data  :(n.m.r.,  (108),  colorless  recrystallised  c o l o r l e s s needles  rotation  crystals  identical  to  with  those  of  m.p.,  from  n.m.r.,  (-)-5-exo,  i . r . ,  6-exo-  (66). corresponding  to  g . l . c .  colorless needles, as  5-endo,  3 Hz,  :-  C(3)-olefinic  proton), 5.98  5.49  m.p.  peak  B was  75-79°C  sublimed  (hot  6-endo-di hydroxybornene  spectroscopic data  C(5)-endo-0H),  washed  minutes,  peak  of  nitrogen  B).  (30-60)  and  was  (30-60)  to  mg)  corresponding  was  the  (12.9  product  Torr)  of  ether  day.  part  36 m l / m i n u t e s ) .  petroleum  under  diluted with  g . l . c .  (activity  The  The  It  gel  on  2.99  rate  peak  dihydroxycamphene  1  flow  each  and  Removal  B,  (g.l .c.  spectrum  added  extract  peaks  peak  silica  spectrum)  ether  acid  temperature  r e s i d u e was  ether  mg)  petroleum  room  sulfate.  50%;  colorless crystals  (4.5  The  three  120°C,  70%  at  sodium carbonate  combined  on  -  hydrochloric  magnesium  chromatographed  i . r . ,  stirred  aspirator.  minutes,  (Column  (a)  of  w h i c h , showed  2.05  35%  an  and  mg)  time  mixture  neutralised with  removed  (32.8  the  83  x  proton),  (doublet  (doublet,  1  (CDClg),  H,  of J  3.83  4.12  Hz,  (112)  on  (doublet  (doublet,  doublets, = 7  stage),  1  H,  -CH0H  J of  1  = 7  (100-110°C, subl. the  pt.^70°C.  basis  of  of  doublets,  H,  J  Hz,  = 6 4  0.5  Hz,  Hz,  C(6)-endo-0H),  -CH0H  -  7.34  (doublet  8.86  (singlet,  3450  (broad,  C = C), 108  of  doublets,  3H)  and 9 . 1 5  strong,  OH),  peak),  resolution  mass  93.  (singlet,  wt.  spectrometry)  C -  for C  ether  (4 m l ) a t  solution (66) the  acid  starting column  of  ether  for 1  A fine (^  (30-60))  material  remained.  alumina  (activity  with  ether  a colorless  0.06  (singlet,  (singlet,  white  m si x of  :  150,  weak,  137,  168.1151.  was powdered The c l e a r (-)-5-exo,  t . l . c .  135,  121,  Found  (High  grade  III)  ether  0.31  on a l u m i n a  (30-60)  -C-CH0),  [ = c ]  (doublet,  8.71 (broad,  i m m e d i a t e l y and  g e l GF  2  5  (1:1)  gave  + 3.1°  IH,  solvent  (activity  CH),  (c 1 . 3 7 ,  J = 2 Hz,  2850  that  through provided  grade  -CH-CH0),  (7  g).  (67) T  (CC14),  7.99  6H, t e r t i a r y  and 2750  short  a yellow  III)  CHCI3);  (sharp,  methyls); medium,  T *  aldehydes),  (sharp, C = C of  strong,  1730  (sharp,  C = 0 of  -,6-unsaturated  strong,  C = 0 of  <*,g-unsaturated aldehyde)  ;  X^J  saturated  aldehyde), 0H  249  aldehyde),  1680  1640 c m " 1 ( s h a r p ,  nm ( e  11 , 2 0 0 ) ;  +  no  a  the dialdehyde  and 8 . 9 5 (two s i n g l e t s , strong,  2 5 4 , 80% e t h e r  showed  was f i l t e r e d of  in dry  supernatent  the reaction mixture  and removal  IH,  and s t i r r e d  6-exo-dihydroxycamphene  (silica  The r e a c t i o n m i x t u r e  ( 2 2 m g , 67% y i e l d ) ,  3000 and 2900  (M+),  p r e c i p i t a t e developed  analysis of  petroleum  methyl),  of  1 ml) until  o i l  3H, vinyl  (CC1,),  v  :  1660 ( b r o a d ,  i602  hour.^1  to a solution  was c o n t i n u e d  (CClJ,  v  (67)  ( 3 5 . 5 mg) w h i c h w a s c h r o m a t o g r a p h e d  Elution  CH  temperature  droowise  H  methine),  168.1151.  (990 m g , 3 . 5 mmole)  (34 mg, 0 . 2 0 mmole).  20% p e t r o l e u m  as  room  was added  addition  oil  H^IOg  1 0  allylic  methyls);  CH),  m/e 168  1,4-Diformyl-2,3,3-Trimethylcyclopentene  Periodic  bridgehead  strong,  0);  calcd.  :  4 Hz,  6H, t e r t i a r y  (broad,  strong  Mole.  -  J = 3 Hz,  2900  1065 c m " 1 ( b r o a d ,  (base  IH,  84  m/e 166  medium, (M+),  -  151 ,  137,  Found  123,  (High  95  peak).  r e s o l u t i o n mass  Oxidative analogous  (base  cleavage  conditions  85  Mole.  -  wt.  calcd.  spectrometry)  of  (+)-5-exo,  :  for  C-|0H1402  :  1  6  6  -  0  9  9  3  -  166.0989.  6-exo-dihydroxycamphene  provided  (-)-dialdehyde  could  stored  (78),  -  (77)  under  2.0°  (c  1.00,  nitrogen  at  -4°C  CHC13). The for  dialdehyde  3 months,  decomposed  and  on  could  storage  be  be  in  distilled  under  darkness  under  ( 9 0 - 1 0 0 ° C , 0.1  nitrogen  at  room  Torr).  temperature  However,  or  on  i t  repeated  distillation.  Bioassay  of  the  Sativenediols  Two  of  washing  with  1  rice  hour,  occurred  after  Agar  (Oryza  followed  in  2-3  day-old the of  (2.5  (3  growth  at  were  thorough and  of  x  10~4M)  water. ml)  germinated  lengths  Century  hypochlorite  water  Rice  Patna  used. NaOCl  and The  in  Japonica seeds were  solution  rinsing with kept  (+)-  and  (-)-cis-  cv.  Tan-ginbozu  Seedlings  in  water.  darkness  at  sterilised  by  distilled  water  They were  then  30°C.  Germination  Method:-  distilled  a mixture  Monoterpenoids,  on  days.  Solutions using  cv.  sativa)  by  distilled  Medium  Synthetic  Indica  5% s o d i u m  immersed  (A)  of  Gibberellic Acid  varieties,  (dwarf),  for  Effects  and  the  30°C  of  of  Each agar  rice  test  test  (0.75%)  leaf  compounds  solution  sheaths  fluorescent  (2.5  and w a t e r  s e e d l i n g s were  second under  the  to  supported were  light.  were ml) form on  measured  prepared  was  mixed  a cake. the  medium  after  6-7  with Threeand days  - 86 -  Microdrop  Method^:-9  Test the or  solutions  coleoptile of agar  using  measuring addition  the of  (0.4  x  10  4-day-old  mole  per  plant)  seedlings supported  were  applied  on wet  f i l t e r  a micro-syringe.  A c t i v i t i e s were  determined  average  the  sheath  the  length  compounds.  of  second  leaf  to paper  by  5 days  after  -  87  -  BIBLIOGRAPHY  1.  (a)  D.  Hess,  (b)  R.L.  "Plant  Wain,  Physiology",  Chem.  Soc.  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I I C , S. Coffey ( E d . ) , E l s e v i e r , ( 1 9 6 9 ) , p. 226-231 and r e f e r e n c e s c i t e d t h e r e i n .  - 91a -  PART  Synthesis  II  and A b s o l u t e of  Nojigiku  Configuration  Alcohol  - 92  -  INTRODUCTION  N o j i g i k u a l c o h o l , a m e t a b o l i t e o f Chrysanthemum j a p o n e n s e , has been a s s i g n e d t h e s t r u c t u r e o f (+)-6-exo-hydroxycamphene (1) on t h e b a s i s o f i t s s p e c t r a l d a t a and chemical c o n v e r s i o n t o t h e c o r r e s p o n d i n g a c e t a t e ketone ( 3 ) , d i h y d r o - a l c o h o l ( 4 ) , and d i h y d r o - k e t o n e  (5)  (4)  SCHEME  * c f . F o o t n o t e t, p.28, derivatives.  (5) (Scheme l ) .  1  P a r t I , f o r t h e numbering system o f camphene  1  (2),  -  93  -  The a b s o l u t e c o n f i g u r a t i o n o f (1) was deduced from the n e g a t i v e e f f e c t i n the o p t i c a l r o t a t o r y d i s p e r s i o n (ORD)  Cotton-  curve of dihydro-ketone  (5).  However, t h e r e were some d i s c r e p a n c i e s i n the s p e c i f i c r o t a t i o n s r e p o r t e d f o r the a c e t a t e ( 2 ) . The compound o b t a i n e d from a c e t y l a t i o n o f n o j i g i k u a l c o h o l was r e p o r t e d t o e x h i b i t [<*] + 1 1 . 6 ° (c 1.20, C H C l ^ ) , whereas the D  a c e t a t e i s o l a t e d from the p l a n t i n small q u a n t i t y showed OJrj +20.0° (c 0.58,  CHC1 ).  ]  3  (±)-6-exo-Hydroxycamphene and the (+)-isomer s y n t h e s i s e d i n low y i e l d s from c a m p h e n e  2-4  (1) have p r e v i o u s l y been  and t r i c y c l e n e . ^ ' ^ A l l the  s y n t h e t i c p r o d u c t s had m e l t i n g p o i n t s ( r a n g i n g from 54° t o 6 0 . 5 ° C ) s l i g h t l y h i g h e r than t h a t o f n o j i g i k u a l c o h o l ( 5 2 - 5 3 ° C ) J Racemic 6-oxocamphene has 3 5 7 8 a l s o been p r e p a r e d by s e v e r a l r e s e a r c h groups, * ' ' and a g a i n the r e p o r t e d m e l t i n g p o i n t s ( r a n g i n g from 65° t o 78°C) are much h i g h e r than t h a t o f the ketone (3) (47-48°C) o b t a i n e d from o x i d a t i o n o f n o j i g i k u a l c o h o l .  1  -  94  -  DISCUSSION  The  discrepancies in the l i t e r a t u r e  question  the authenticity  physical  constants  a  synthetic  Scheme  route  2 leading  application Part  I)  to  of the  of  reported to  to  this  data  the structure, for  nojigiku  compound.  The  oxidation  synthesis  of  (1)  (+)-6-exo-hydroxy-5-oxocamphene  isobornyl  acetate  (p.26  by the r o u t e s  epimeric  of  alcohols  the  n.m.r.  The  major  (9)  compound  hydride  acetate  (8)  confirmed  (7)  spectrum  because  followed  and (10)  of  outlined  B,  Introduction,  was p r e p a r e d i n Schemes  10  in  further  since the  give  attack  from  subsequent  to  dry  crystalline  the  under  borohydride  relative  mixture  yield  starting  from  (-)-  and 1 2 ,  reduction  (5:1)  Part  I  of  (12).  prolonged  product  with  (see  alcohols  (11),  which  This  (9)  spectral  and  (10)  data  (13  I,  p.73).  (9)  exo s i d e  of  keto-  a s s i g n m e n t was  of  proceeded  aluminum  provided  treatment  refluxing  from  below).  on l i t h i u m  3 hours)  Further  structural  Part  epimer  hindered  provided  was d e d u c e d  (see Experimental,  s t e r i c a l l y less  be f a v o r e d .  tetrahydrofuran,  sulphonyloxycamphene hydride  whose  investigation  acetoxy-mesylate  (refluxing  sodium  was a s s i g n e d a s t h e C ( 5 ) - e n d o - h y d r o x y  was e x p e c t e d  by  by  the product  Methanesulphonylation  the  (7),  depicted  devise  and 3 5 ) . Acetylation  to  (see Section  to  and  us t o  illustrate a  and s e s q u i t e r p e n o i d s ,  material,  (6)  sequence  would  l e d us  configuration  and prompted  proposed  techniques  mono-  absolute  alcohol  6-exo-hydroxycamphene  remote  (see Introduction)  i n 60% y i e l d  hydride  6-exo-hydroxy-5-methane-  hydroxy-mesylate  hours)  and t . l . c .  reduction  resulted Rf  value  (12)  with  in a colorless (silica  gel)  SCHEME 2  -  identical (87),  to  those  Discussion,  presence  of  the  of  5-endo,  Part  I,  desired  96  -  6-exo-dihydroxycamphene  p.35 ] .  No  evidence  could  6-exo_-hydroxycamphene  (1)  (13) be  in  [cf.  obtained  Compound for  the  product.  also  followed  the  (1 ) Reduction  of  (11)  with  course  leading  sodium  cyanoborohydride,  mesylates  and  to  the  lithium  triethylborohydride  familiar  tosylates  hexamethylphosphoramide  was  trans-diol  reported  without  to  used  Another  mild  effect  hydride  displacement  as  (11)  *  and  an  HMPA s o l u t i o n  sodium  of  bond  the  6-exo-hydroxy-5-methanesulphonyloxycamphene (110°C)  the  (13).  sulphur-oxygen  (HMPA) was  3  (12)  cleavage  solvent. was  1 0  reducing  agent, of  when  However,  obtained  same  on  only heating  6-exo-acetoxy-5-methanesulphonyloxycamphene  cyanoborohydride  for  7  days.  *  We w e r e a w a r e o f t h e h y d r o g e n o l y s i s o f m e s y l a t e s a n d h a l i d e s w i t h t h e c o p p e r (I) c o m p l e x p r e p a r e d b y M a s a m u n e e t a l _ u s i n g t w o e q u i v a l e n t s o f -|-| l i t h i u m t r i m e t h o x y a l u m i n u m h y d r i d e and one e q u i v a l e n t o f c u p r i c i o d i d e . H o w e v e r , we h a v e n o t i n v e s t i g a t e d t h i s p r o c e d u r e w i t h m e s y l a t e (11).  -  Deoxygenation dethioketalisation was  lost  the  Lewis  during acid  S-methyl  of  -  6-exo-acetoxy-5-oxocarophene  was  the  97  not  successful  thioketalisation  catalyst  boron  dithiocarbonate  (14)  s i n c e the step,  (8)  camphene  presumably  trifluoride  etherate.  followed  free  by  via  thioketalisationterminal  due  to  reaction  Formation  radical  olefin  of  reduction  with  the  0-alkyl-  with  12 tri-n-butyltin  hydride  was  also unsuccessful.  C9) + (10)  Other (15)  with  (H)  possible mild sodium  procedures  cyanoborohydride,  13  (2)  such  as  or  with  reduction  of  the  catecholborane  tosylhydrazone 14  were  considered.  or  (7)  R =H  (8)  R = Ac  However, camphor and with  no  i t  R =H  has  (1)  (15)  been  reported  tosylhydrazone identifiable  fenchone  or A c  (16)  product  tosylhydrazone  that  is  sodium  very  could (17).  or  cyanoborohydride  inefficient  be  detected  Steric  in  even an  hindrance  under  (2)  reduction acid  analogous from  R = H  the  R=Ac  of  conditions  reaction methyl  groups  -  98  -  N-NHTs TsNH-N  (17)  (16)  was  suggested  considered of  as  that  route  was  at  (Scheme  cause of  similar  oxocamphene It  the  the  problems  i n e f f i c i e n c y of  would  tosylhydrazone  (15).  this  we  3)  stage  to  that  nojigiku  decided  alcohol  (-)-6-endo-hydroxy-5-oxoisobornyl acetate  (6)  by  the  reaction  Thioketalisa^ion followed acetate  by  Raney  (20)  in  of  nickel  occur  (1)  during  to  the  reactions. proposed  investigate  an  80% o v e r a l l  (18)  prepared  from  outlined  with  alternative  deoxygenation  in  provided  yield,  reduction  involved  Scheme  of  (-)-isobornyl  14,  Part  (-)-6-endo-hydroxy-5-oxoisobornyl reduction  We  which  acetate  sequence  these  I  (p.  acetate  45).  (18)  (-)-6-hydroxyisobornyl  melting  point  and  spectral  data  15 identical (20) to  the  the  signal This  those  signal  at  reported 4.72T  C(2)-endo-hydrogen (5.43T)  downfield  hydroxyl was  to  group  further  compound oxidation  shift to  the  was  Teresa  (doublet was  isobornyl  confirmed  whose to  of  by  at  of  lower  (6)  due  to  structure  hydrolysis has  been  to  the  n.m.r.  = 8 Hz, than  Scheme  the in  J  field  (cf.  C(2)-endo-hydrogen by  In  doublets,  much  acetate  probably  ejt a l _ .  The  of  assigned  I,  the  p.  structure  n.m.r.  47).  C(6)-endo-  6-endo-hydroxyisoborneol  e s t a b l i s h e d by  of  corresponding  Part  proximity (20).  4 Hz) the  15,  spectrum  evidence  of  (20)  (21),  a  and  2,6-bornanedione.1^  (-)-6-endo-Hydroxyisobornyl t-butyldimethylsilyl  (TBDMS)17  acetate ether  (22)  (20) and  was  converted  subsequently  to  the  hydrolysed  to  -  99  -  (1) SCHEME 3  -  hydroxy-ether  (23)  in  100  95% o v e r a l l  using  mesyl  c h l o r i d e and  silyl  ether  (24).  yield.  refluxing  Deprotection  -  Wagner-Meerwein  pyridine,  of  the  provided  hydroxyi  with  tetra-n-butylammonium  (THF)  or with  a mixture  of  (silica  gel)  chromatography afforded  nojigiku  needles,  m.p.  l i t . [ = e ]  (c  4  2  '  6  '  1  1.1,  point  1.33,  CHC13), and  the  acetic of  l i t .  (n-Bu^NF)  crude  (sealed l i t .  m.p.  3  subl.  58-59°C, 1.16,  3  H  in  +9°).  D  specific rotation  on  two  different  instruments  of  our  synthetic  product  It  is  and  dry  (Perkin  were  F.lmer  (1)  as  52°(lit.  l i t .  5  m.p. ( l i t .  clear  and  sublimation  colorless m.p.  1  52-53°C,  54-55°C); [«]  1  that  different  141  Column  1 7  subsequent  CHCI3)  at  accomplished  tetrahydrofuran  pt.  therefore  [measured  was  (3:1:1).  product  tube),  CHC1 ), + 6 0 . 4 ° (c  4  '  acid-water-THF  the  t-butyldimethyl-  18  [(+)-6-exo-hydroxycamphene]  59.5-60°C,  + 5 8 . 6 ° (c  5  alcohol  67.5-69.5°C  m.p.  9  fluoride  the  function 17  rearrangement,  +12°  Q  the  melting  concentrations  241  MC  significantly different  and  Polarimeters)]  from  the  values  1 quoted  for  nojigiku  alcohol  However,  the  n.m.r.  those  the  natural  of  product  was  variety  of  and  by Matsuo  i . r .  alcohol  e s t a b l i s h e d by columns  spectra  over  ert a l _  a wide  Julia  and  co-workers.  our  compound  were  1  and  2).  homogenity  (silica  range  and  of  (Figures  t . l . c .  4  of  gel)  The  1  and  identical  g . l . c .  temperatures  of  our  analyses  (cf.  to  on  Experimental,  p.115). Acetylation corresponding [«]  +20.9° In  (+)-6-exo-hydroxycamphene  acetate  ( 2 ) ,  0.58,  CHC1 ),  (c  order  of  to  +11.6°  3  obtain  [«]p5  1 , 3  further  +37.6° (c  (1)  (c  1.20,  provided  1.11,  the  CHC1 ) 3  ( l i t .  1  CHC1 )). 3  comparison  with  the  literature  data,  20 alcohol  (1)  was  6-oxocamphene 4 0 ° C , H n  5  oxidised with  (3),1>  +155.3°  3  >  (c  5  '7'  8  0.91,  pyridinium  m.p.  chlorochromate  73.5-75.5°C  CHCI3).  Again  (sealed  a  to  tube),  discrepancies with  provide subl.pt. reported  101  9  i i l i  ( b )  TMS  i  •  ....  I  Figure  1  •  .  (a)  l  — i — i — i  N.M.R.  i  >  •  Spectrum  Hydroxycamphene (b)  N.M.R.  Spectrum  Hydroxycamphene  i  .  .  ( 6 0 MHz)  t i l l  of  Synthetic  of  Natural  (+)-6-exo-  (1) ( 6 0 MHz) (1)  (+)-6-exo-  15 W A V E L E N G T H  Figure  2  I.R.  Spectrum  of  ( M I C R O N S )  (+)-6-exo-Hydroxycamphene  (Nojigiku  Alcohol)  (1)  -  data l i t  7  were '  8  noted  m.p.  ( l i t .  77-78°;  1  l i t .  6-exo-hydroxycamphene from  acetate  oxidised further  to  (2)  recorded  for  [ « ]  1  (1),  H  these  D  2  l i t .  +33.7°  +158.2°  5  the authenticity  m.p.  3  (c  +58.9°  5  carbonate  ( 3 ) , H p  for  -  47-49°,  by sodium  ketone  support  m.p.  103  65-70°,  l i t .  CHCI3)).  0.86,  (c 0 . 7 9 , of  and was  CHClg),  the physical  75-76°,  Furthermore,  (c 0 . 8 8 , CHC13),  hydrolysis  m.p.  5  was  regenerated  subsequently  thus  providing  constants  we  have  compounds.  (2)  (1)  (3)  SCHEME A (-)-6-exo-Hydroxycamphene (-)-6-oxocamphene (28)  by  the  rotations  of  (1)  chiral  reaction  were  the o p t i c a l  outlined  purity of  and i t s enantiomer reagent  (-)-6-exo-acetoxycamphene  synthesised  equivalent  by the absence  shift  also  sequence  numerically  Furthermore, confirmed  (27)  (25),  to of  common  (25)  i n Schemes  those our  of  (+)-isobornyl 3 and 4  and had  the enantiomers  3),  shifts  in  recorded  the  specific  (1)-(3).  the n.m.r.  in  and  acetate  (+)-6-exo-hydroxycamphene  chemical  (Figure  from  (26),  (1)  was  spectra  presence  of  the  tris[3-(trifluoromethylhydroxymethylene)-d-camphorato]-  21 europium (25)  were  seemed more  (TFMC-Eu).  reasonable  prominent  molecule. 3(b)  complexed  to  to  It to  was assumed  europium  expect  lanthanide  We h a d t h e r e f o r e  via their  that  shifts  assigned of  alcohol  (1)  and i t s  C(6)-exo-hydroxyl  the C(6)-endo-hydrogens  induced  the C(6)-endo_-proton  that  (25)  than  the broad with  enantiomer  groups  would protons  signal  3.35T  TFMC-Eu,  i t  experience  the other at  and  in  in  the  Figure  and t h e m u l t i p l e t  at  ( b )  (a)  -••I • •:• 2 3 4 Figure  3 (a) (b) (c)  N.M.R. N.M.R. N.M.R.  Spectrum of Spectrum of Spectrum of  • !':M ;..i:.:M....i:..:L.::i::.:l::::l^:=rt^,~-*^^ 5 6 7 8 9 10T (-)-6-exo-Hydroxycamphene (-)-6-exo-Hydroxycamphene (+)-6-exo-Hydroxycamphene  (25) (25) w i t h TFMC-Eu (1) w i t h TFMC-Eu  -  105  -  3.75T in Figure 3(c) to the -CH0H of (1) with the same lanthanide reagent. Both have been s h i f t e d downfield by the europium from t h e i r o r i g i n a l p o s i t i o n at 6.29x i n Figure 3(a).  It i s proposed, t h e r e f o r e , that the s p e c i f i c r o t a t i o n of (+)-6-exohydroxycamphene ( n o j i g i k u alcohol) (1) f a l l s w i t h i n the range +55° to o 22 +61 .  This conclusion i s relevant to the report by J u l i a and co-workers  on the copper (I) s a l t catalysed oxidation of (+)-camphene (29) with 1>butyl perbenzoate.  4  Nojigiku alcohol (1), M ^  0  + 9 ° , was obtained in  low y i e l d together with other products (32)-(34) (Scheme 5). A free r a d i c a l mechanism was proposed f o r t h i s reaction and i t was assumed that the r a d i c a l intermediate (30), formed by hydride abstraction of camphene was captured by copper (II)  benzoate to give (31), which on base  (29),  hydrolysis  provided alcohol (1). Based on the assumption that the s p e c i f i c r o t a t i o n of pure (+)-6-exo-hydroxycamphene (1) i s approximately + 1 2 ° , J u l i a et al 1  considered t h e i r product as o p t i c a l l y pure and therefore excluded the p o s s i b i l i t y of the i n t e r v e n t i o n by the symmetrical n o n - c l a s s i c a l r a d i c a l intermediate (35), which would have resulted in considerable racemisation. However, i f indeed the s p e c i f i c r o t a t i o n of (1) i s about +55°, then the n o j i g i k u alcohol obtained by the French group was almost completely racemic. This would then i n d i c a t e that the mechanism of the perbenzoate oxidation involved a symmetrical intermediate such as  (35).  PhCOO-OBu* • C u d )  106  -  > Bu*0. • C u d D ( O O C P h )  (35)  SCHEME  5  -  107  -  EXPERIMENTAL  General  See  Experimental,  Preparation  of  Oxocamphene  (8),  See  Part  I  (p.60).  (+)-6-exo-Hydroxy-5-0xocamphene  Experimental,  Part  I  0.14 (4  mmole)  drops)  minutes the  of  in dry  tetrahydrofuran  and a t  mixture  followed  was f o r m e d . room  The  washed  successively with  sodium  bicarbonate, solvent  reaction mixture for  to  ether.  water,  3 N  over  anhydrous  provide  6-exo-acetoxy-5-methanesulphony!oxycamphene  2  (singlet, bridgehead methine),  3 H,  CH3S02-0-),  allylic 7.98  7.30  methine),  (singlet,  3 H,  (10)  7.72  (10)  (30 mg,  chloride A  white  0°C for  was t h e n  added  extract  water,  magnesium  5  2H,  (two  broad  -CH0S02CH3  (broad  singlet,  (multiplet,  CH^COO-),  8.30  1  (11)  saturated sulphate. to  (colorless o i l ,  singlets,  1  H each,  and -CHOOCCHg), half-width H,  and  was  o i l - ( 3 4 . 5 mg) w h i c h w a s d i s t i l l e d  5 . 0 5 and 5 . 1 5  =CH ), 5 . 3 0 and 5 . 6 0 ( m u l t i p l e t s ,  at  The combined o r g a n i c  of  T(CC14),  and  (8 d r o p s ) .  Water  Removal  24 m g , 60% y i e l d ) ,  and  0 ° C . Mesyl  hydrochloric acid,  and d r i e d  a colorless  (9)  was s t i r r e d  15 m i n u t e s .  with  water, gave  was c o o l e d  by d r y t r i e t h y l a m i n e  temperature  was e x t r a c t e d  (9)  (11)  6-exo-acetoxy-5-hydroxycamphenes  was a d d e d ,  precipitate  6-exo-Acetoxy-5-  (p.69-73).  6-exo-Acetoxy-5-Methanesulphonyloxycamphene  A solution  (7),  and 6-exo-Acetoxy-5-Hydroxycamphenes  4 Hz,  7.10 1  H,  C(4)-bridgehead  (multiplets,  2 H,  methylenes),  -  8.71  and  8.86  (two  singlets,  108  6 H,  -  tertiary  methyls);  u  ( C C l J , !T!ct X  (broad, 1370,  medium,  1350  CH),  and  1330  (sharp,  strong,  Lithium  Aluminum  camphene  1755  (sharp,  (strong,  strong,C=0),  S02),  1235  (broad,  Hydride  Reduction  of  aluminum  hydride  (30 mg,  0.8  mmole)  in  dry  tetrahydrofuran nitrogen  chloride  and  layer with  dried  over  structure  of  and  5.36  -CH0S02CH3), 8.80  and The  (100  mg,  was  8.90  (two 6.20  chloride,  which  broad  The  was  with  layers  added (100  mixture  sulphate.  1175  cm"1  organic  1  singlets,  6 H,  oil  mmole)  spectral  data  was  further  in  refluxing  crystals  identical (87),  singlets,  to  (84  1  H,  H each,  -CH0H), tertiary  treated THF mg)  those  Experimental,  of  with  13  for  I,  3  hours  ammonium and  extract  solvent  the was  water,  gave  a  accordance with  5.53  (12);  x  (singlet,  3 H,  the  (CCl^),  (multiplet,  1  H,  -0S02CH3)f  lithium hours.  t . l . c .  Rf  aluminum  Working value  up  hydride as  (silica  5-endo,6-exo-dihydroxycamphene  Part  mmole)  methyls).  with  for  =CH2),  7.00  0.34  bicarbonate,  of  in  solution  separated,  sodium  data  mg,  a  refluxed  were  Removal  n.m.r.  to  saturated  combined  saturated  exhibited  (multiplet,  (two  colorless  Compound  ether.  magnesium  (11)  quenched  organic  was  6-exo-hydroxy-5-methanesulphonyloxycamphene  crude 2.6  and  and  with  ammonium  mg)  reaction  cooled  extracted  (100  The  aqueous  anhydrous  provided  (cf.  The  dilute  oil  (THF).  atmosphere,  solution.  colorless  5.15  C-O-C),  C=C),  6-exo-Acetoxy-5-Methanesulphony!oxy-  6-exo-acetoxy-5-methanesulphonyloxycamphene  washed  strong,  weak,  S02).  of  aqueous  (broad,  (11)  Lithium  under  1670  2900  T *  p.70).  before gel)  and  (13)  -  Reduction  of  109  -  6-exo-Acetoxy-5-Methanesulphonyloxycamphene  (11)  with  Lithium  Triethyl borohydride  Lithium Co.)  (0.2  triethylborohydride  ml,  0.2  mmole)  was  (1  M  added  to  in  tetrahydrofuran,  a tetrahydrofuran  6-exo-acetoxy-5-methanesulphonyloxycamphene cooling 10  by  minutes  the  an  ice-water  and  then  organo-boranes  peroxide. was  The  saturated  Removal  n.m.r.  to  be  of  crude  mmole) (10 with  in  mg)  (Column  G,  oxidised with  2 N  gave  15  15.3  hours.  with  water,  and  0.08  product  on  (12)  with  short-path  t . l . c . 140°C),  Rf  value  and  35 h o u r s  distillation (silica  n.m.r.  gel  gave  spectral  data  0°C  for and  added  hydroxide  and  30%  and  saturated over oil  identical  sodium  (12).  magnesium  (0.4 a  shown  by  Treatment ml,  0.4  colorless  crystals  retention to  hydrogen  extract  w h i c h was  afforded  g.l.c.  the  anhydrous  colorless  GF254),  at  with  was  mg c o l o r l e s s  for  of  Water  lithium triethylborohydride  tetrahydrofuran  Chemical  mmole)  stirred  ether,  dried  those  (4  oil  mg)  time of  5-endo,  (13).  Reduction  of  6-exo-Acetoxy-5-Methanesu1phonyloxy-  (11)  6-exo-Acetoxy-5-methanesu1phonyloxycamphene and  mg,  was  sodium  extracted  sodium c h l o r i d e ,  Cyanoborohydride  camphene  for  hydrochloric acid,  6-exo-dihydroxycamphene  Sodium  reaction mixture  temperature  solvent  (24  solution  6-exo-hydroxy-5-methanesulphonyloxycamphene  refluxing  which  m.p.,  of  The  s o l u t i o n was  dilute  sulphate.  the  room  were  aqueous  washed w i t h  bicarbonate,  at  bath.  (11)  Aldrich  sodium cyanoborohydride  hexamethylphosphoramide The  reaction mixture  and  extracted  with  (40.0  were  was  ether.  then The  mg,  heated  0.63  to  organic  mmole)  110°C  cooled to  (11)  room  extract  under  in  (27.8  0.09  for  7  mmole)  dry  nitrogen  temperature, was  mg,  days.  diluted with  washed w i t h  water  and  water  - no dried  over  yellow  oil  Torr) of  anhydrous (26  mg)  afforded  magnesium  which  on  a colorless  sulphate.  distillation oil  with  See  Experimental,  Part  6-endo-Hydroxyisobornyl  Freshly solution  0.91  extracted  for  with  sodium  ether  (60-75°C, residue  on  (20)  22  before  hours  ether.  The  in  etherate  the  0.5  Torr) mg,  over  followed  provided  dithioethylene  85%).  r e c r y s t a l l i s e d from  5.22  (doublet  of  (19),  doublets,  half-width  -SCH2CH2S-),  ketal  10 8.09  Hz,  was  1 1  H, H,  J  was  3 H,  pale 0.5 those  (M+),  drops)  150.  precipitate  was  was  excess as  5 Hz,  9.00  Removal  colorless was  oily  distilled which  to  stage);  6.70-7.00  8.85,  sodium  crystals  -CH00CCH3),  water,  ethanedithiol  (30-60)-ether  endo-OH),  CH3C00-),  a  product  colorless  ether  was  sulphate.  (19)  crude  mixture  saturated  of  to  room  washed w i t h  magnesium  the  (18)  added mg,  the  water,  ketal  was  (205  1 0 2 . 5 - 1 0 3 . 5 ° C (hot  of  246  s t i r r e d at  and  extract  give  = 8 Hz,  -CHOH  (singlet,  to  of  petroleum m.p.  (4  distillation  Part  m/e  white  added  dithioethylene  150-160°C, 0.05Torr)  pure  fine  anhydrous by  a  120-130°C,  acetate  hydrochloric acid,  crude y i e l d  further  A  combined o r g a n i c  dried  aspirator  ml).  water  gave  accordance with  (12),  reaction mixture  2 N  and  (4  solvent  (18)  trifluoride  The  were  H,  Acetate  minutes.  water,  (bulb-to-bulb,  signal,  p.75.  boron  hydroxide,  (233  Acetate  1,2-ethanedithiol  15  bicarbonate,  4  data  (-)-6-endo-hydroxy-5-oxoisobornyl  in  after  temperature  2 M  distilled  of  mmole)  formed  of  n.m.r.  I,  of  (bulb-to-bulb,  6-exo-hydroxy-5-methanesulphonyloxycamphene  (-)-6-endo-Hydroxy-5-oxoisobornyl  a  Removal  6.14  T  afford (CC14), (broad  (multiplets, and  9.16  -  (three OH),  singlets,  2900  strong, 159,  9 H,  (sharp,  C-0);  134,  strong,CH),  m/e  131 ,  302  126,  Found  (High  for  03S2:  C,  S,  1 4  H  2 2  258,  109.  resolution  55.60;  H,  mass  7.33;  214,  wt.  3500  C=0),  186  calcd.  21.20.  1245  (base for  spectrometry):  S,  (sharp,  medium,  i  strong,  242,  Mole.  (CClJ,  ll i d A  (sharp,  274,  111,  u  Found:  cm"1  (broad,  peak),  173,  168,  C - ^ H ^ O ^ :  302.1002.  Anal,  C,  H,  55.37;  calcd.  7.56;  21.10. The  without  rest  the  Co.)  catalyst  (106  mg,  in  was of  ethanol  of  pt. 1 5  1  H,  J = 8.0  J  = 9.5  9.05  [«]  Hz,  and  (broad,  cm"1  119,  108  (High  (base  The  gave  Hz,  1 5  (c  m.p. 1.49,  Hz,  -CH0H  (two  2900  strong,  peak). mass  mg,  of  (sharp, C-0);  Mole.  wt.  strong,  m/e  212  calcd.  spectrometry)  :  provide  for  m.p.  4.72  of  methyls);  Z- 20°3 H  :  Anal,  212  (hot  155,  - 1412  calcd.  stage),  CHC13) of  doublets, 1  H,  CH3C00-),  (CC14),  (sharp,  [2  212.1401.  3 H,  170,  with  6-endo-  0.55,  m a x  removal  sulphate.  doublets,  u  1755  by  the  washed  94.5°C  (c  (singlet,  194,  and  were  (doublet  (doublet  (M+),  ether,  pure  -70.9°  CH),  cooled,  which  of  (19)  magnesium  to  8.06  tertiary  in  mg)  2 5  slurry  concentrated  (74.6  (CC14),  6.05  endo-OH), 9 H,  H  A  ketal  hour,  was  80% y i e l d ) ,  94-94.5°C); T  1  anhydrous  (56.2  CHC13));  for  dissolved  (30-60)  -CH00CCH3),  singlets,  OH),  over  Davidson  95% e t h a n o l .  filtrate was  desulphurised  Grace  dithioethylene  ether  (20)  was  water,  with  colorless crystals  petroleum  (19)  in  refluxed  dried  4.0  resolution  was  and  Hz,  (broad,  the  chloride,  ( l i t .  medium,  mixture  to  filtration.  acetate  3.5  added  twice  residue  -59.7°  9.18  1250  by  washed  the  from  ^80°C  ( l i t .  was  ketal  (immersed  and  solvent  hydroxyisobornyl  nickel  was  The  solvent  sodium  dithioethylene  Raney 3 g)  removed  recrystallised  subl.  crude  mmole).  the  saturated Removal  the  (about  0.35  catalyst most  of  purification.  Chemical  of  methyls); 1750  (M+),  119,  302.1011. C  tertiary  I l l  3580  strong,  C=0),  152, F  for  o  137, u  n  d  C  1 ?  H  ? f )  03:  -  C,  67.89;  H,  9.50.  Found  :  C,  112  68.07;  (+)-6-endo-Hydroxyisobornyl also  prepared  from  -  H,  9.53. H  acetate,  2  +68.0°  5  (+)-6-endo-hydroxy-5-oxoisobornyl  (c  0.65,  acetate  CHClj),  by  the  was  same  sequence.  (-)-6-endo-Hydroxyisoborneol  A mixture 0.35  mmole)  of  and  (1:1)  work-up  provided  part  of  w h i c h was  give  short  268-270.5 Hp  carbonate  (5  ml)  was  J  = 7  Hz,  needles,  4  Hz,  -CHOH o f  0.95,  5 Hz,  monohydrate refluxed  r e c r y s t a l l i s e d from  C°(sealed tube)); (c  acetate (100.0  for  22  (-)-6-endo-hydroxyisoborneol  colorless  -56.4°  5  6  (-)-6-endo-hydroxyisobornyl  sodium  methanol:water  (21  m.p.  [-1  CH3CN));  -CHOH o f endo-OH),  8.96,  o  254-256 -48.6°  x  (CDClg), 5.94  9.02  mg,  (21)  as  C  (c  (sealed 0.80,  5.66  and  9.12  ether  crystals,  (30-60)  tube)  ( l i t . of  to  16  ( l i t .  m.p.  1 6  doublets,  doublets,  (three  in  aqueous  colorless  CH3CN)  of  mg,  mmole)  Normal  (doublet  (doublet  (74.5  0.80  hours.  ether-petroleum  2 5  exo_-0H),  (20)  1  H,  1  J  H,  = 9  s i n g l e t s , 9 H,  tertiary  methyls).  6-endo-t-But.vldimethyl si lyloxyisoborneol  A 1.88  solution  mmole)  (Aldrich  of  with  Chemical  dimethylformamide reaction mixture  mixture (1:1)  of  (23)  (-)-6-endo-hydroxyisobornyl  jb-butyldimethylsilyl Co.) was was  and  imidazole  heated cooled  ether  and  to ,  85°C  chloride (510 under  diluted with  petroleum  ether  mg,  acetate (470 7.50  mg,  for  and  (30-60).  (400  3.11  mmole)  nitrogen water,  (20)  20  dry  hours.  extracted  The  mg,  mmole)  in  combined  Hz,  The  with  a  organic  -  layer  was  Removal was  washed  of  solvent  and  H,  acetate  J = 7  3.5  Hz,  H,  Hz,  (400  mg,  After an  3000  The  combined  to  (563  mg)  (16  g).  6.06  Elution  (hot  with  doublets, J  (oil  stage),  = 10  Hz,  1  singlets,  CH),  1760  (sharp,  of  crude  3.5  of  which  with  10%  which  t-butyldimethyl of 1  doublets,  H , J = 9.0  (singlet,  methyls),  3  9.20  6 H,  Hz,  H,  (singlet,  -SiCH3);  strong,  t>butyldimethyl s i l y l o x y A mixture  95% e t h a n o l  temperature,  extract  10%  (15  was  ether  part  of  Hz,  ^50°C;  Hz,  4 Hz,  -CHOSi-),  x  of  C=0),  1250cm"1  -CH0H), 9.12,  760  6.10  with  gave  Torr),  of  m.p.  TMS),  (doublet and  9.21  and  ether.  dried  a yellow grade  oil  III) afforded  crystals was  obtained  77.0-78.0°C  5.68 of  under  with  (30-60)  (23)  hours.  removed  water  was  hydroxide  1.5  extracted  colorless  sample  9.15  was  ether  as  without  for  (activity  90% p e t r o l e u m  (CDC13,  9.01,  and  (22)  potassium  solvent  gel  (23)  acetate  refluxed  solvent  silica  90°C,  and  thoroughly  analytical  temperature  pt.  J = 7  An  was the  Removal on  (22)  in water  washed  and  of  ml)  dissolved  sulphate.  yield).  bath  subl. H,  9.04  (two  strong,  Elution  doublets,  10.02  chromatographed  95% o v e r a l l  sublimation  of  10.01  and  portion  (doublet  12  magnesium  w h i c h was  mg,  4.60  tertiary  sulphate.  colorless oil  CH3C00-),  H,  III).  desired  TMS),  6 - endo-1^-butyl d i m e t h y l s i l y l o x y i s o b o r n e o l (509  a  (doublet  3 H,  a small  grade  the  magnesium  (singlet,  r e s i d u e was  organic  anhydrous  mg),  provided  without  (singlet,  in  room  The  over  (768  accordance with  purification.  mmole)  aspirator.  (30-60)  -CH00CCH3),  portion  cooling  anhydrous  (activity  (CDC13§  (sharp,  without  7.14  over  C-0).  major  hydrolysed  x  9.13  strong,  The  in  methyl),  ( C C l J ,  dried  gel  ether  8.02  methyl),  (broad,  silica  (22):  4 Hz,  tertiary  u  on  data  -CHOSi-),  tertiary 3  spectral  and  -  a colorless oil  90% p e t r o l e u m  exhibited silyloxy  water  gave  chromatographed  ether  1  with  113  (doublet  doublet, (four  1  of H,  singlets,  by  - 1 1 4 -  18  H,  tertiary  u  (CC1.), II\cX A  methyls),  3700  10.02  (sharp,  and  weak,  10.04  (two  non-hydrogen-bonded  C-0);  m/e  calcd.  284  for  284.2184. 67.52;  OH),  (M+),  3000 269,  ^-|6^32^2^n Anal,  H,  227,  :  calcd.  (broad,  strong, (base  peak),  284.2171.  Found  (High  for  c  -]  6  H  3  2  °2  S i  :  C  '  chloride  pyridine  (15  ml).  nitrogen  for  15  (920  magnesium  3500  (broad,  weak,  mg,  8.07  mmole)  ether  (30-60) oil  broad  tertiary (CC14),  on  109.  H  »  "11.34.  strong,  Mole.  wt.  spectrometry):  Found  silica  1260  (sharp,  251,  209  gel  (23)  for  :  and  1.79  C,  and  room  III).  The  1  (two of  H each, 7.46  =CH,,),6.30  (broad  (1.76  Elution  2900  strong, peak),  (broad, C-0), 191,  10.00  strong,  890 cm"1 179,  H,  tertiary  group),  165,  methyls),  strong  135.  6 H,  (broad,  (24)  wt.  as  and 1  m/e  a 5.40  H,  J  u  9 m a x  C=C), 266  calcd.  =  methine),  (singlet,  weak,  was  petroleum  -SiCH3);  =CH2);  Mole.  which  allylic  9.15  dark  ether.  with  5.18  under  anhydrous  g)  doublets,  bridgehead  1650  (broad,  TMS),  of  (singlet,  CH),  153,  without  (doublet  signal,!  s i n g l e t s , 6 H, t-butyl  (CDC13,  with over  40% y i e l d ) ;  x  dry  resulting  (192  mg,  in  temperature  dried  oil  of  mmole)  extracted  a brown  grade  solution  hours.  water  gave  (activity  10  water,  washed w i t h  a  (509 mg,  s t i r r e d at  refluxed  solvent  to  6-exo-t-butyldimethyl silyloxycamphene  and  (base  of  added  provided  methyls 2950  then  was  Removal  -CHOSi-),  9.05  and  extract  singlets,  3 Hz, and  123,  (broad,  r e s o l u t i o n mass  was  was  cooled, diluted with  sulphate.  colorless  Hz,  135,  cm"''  (24)  reaction mixture  minutes,  chromatographed  (two  The  s o l u t i o n was  combined  ether  1250  -54">  6 7  6-endo-t-butyldimethyl silyloxyisoborneol  9.00  OH),  11.21.  Mesyl  brown  CH),  151  6-exo-t-Butyldimethyl silyloxycamphene  7  -s|iCH3);  6 H,  *T  hydrogen-bonded  The  singlets,  (M+),  for  H,  -  C  16H30  0 S l  :  2  Further product  (10  6  6  -  2  0  6  -  5  elution  of  mg) w i t h  time  identical  (see  below).  to  Found  of  (+)-6-exo-Hydroxycamphene  Method  A  r e s o l u t i o n mass  data,  ether  t . l . c .  Rf  spectrometry)  gave  value  a colorless and g . l . c .  (+)-6-exo-hydroxycamphene  (Nojigiku  Alcohol)  (1)  1  -  :  266.2065.  crystalline  retention  (nojigiku  alcohol)  (1)  according to  the  6  :-  Tetra-n-butylammonium procedure (Fisher  (High  -  the column w i t h  n.m.r.  those  115  i n Reference  fluoride  18.  S c i e n t i f i c Co.)  (n-Bu^NF)  was p r e p a r e d  C o m m e r c i a l l y a v a i l a b l e 48% h y d r o f l u o r i c  was d i l u t e d to  5% w i t h  distilled  water.  tetra-n-butylammonium  hydroxide  (0.4 M  solution  was added  dropwise  solution  in water,  Eastman-Kodak)  to  about  acid  (50 ml) w i t h  stirring until  This  t h e pH o f  the  o mixture  was 7 . 0 5 .  The  crystals  were  formed.  crystals  were  dried  n_-Bu^NF Dry a  as a w h i t e  Most  under  the  with  at  water  fluoride  (10  ml)  under  room  water  Removal  of  a yellow  ether  (30-60)  for  to  4 C until  liquid 7  colorless  was d e c a n t e d  hours  to  gave  (silica  gel  as e l u e n t ) ,  (200 mg, 0.76  and t h e  give  anhydrous  mmole)  was added  with  and d r i e d o i l  (activity followed  to  6-exo-t-butyldimethyl silyloxycamphene  helium atmosphere  and e x t r a c t e d  was washed w i t h  chromatography  of  temperature  extract  solvent  supernatant  a freeze-drier  solution  was s t i r r e d  hydrolysed  cooled  powder.  (139 m g , 0 . 5 2 mmole)  mixture  of  tetra-n-butylammonium  tetrahydrofuran  (24)  s o l u t i o n was t h e n  for  in a dry-box.  15 m i n u t e s  ether. over  The  and was  combined  anhydrous  1 7  then  organic  magnesium  ( 1 6 5 mg) w h i c h w a s p u r i f i e d grade  III),  by s u b l i m a t i o n  10% e t h e r (oil  bath  The  sulphate. by  column  and 90% p e t r o l e u m temperature  -  70°C, (62  760  Torr)  to  mg,  78%  yield).  (silica  gel  GF254,  and on to  g . l . c .  200°C),  200°C),  10%  10%  0V210  l i t .  4  (c  2  '  6  1  +58.6°(c  5  1.11,  1  -CHOH o f allylic  (from  (from  1.33,  120°to  120°to  200°C), sub!.  l i t .  4  H  +9°);  n  =CH2),  6.29  exo-OH),  7.48  (broad  methine),  8.98  and  3700  (sharp,  hydrogen-bonded  C=C),  1060  (sharp,  (M+),  137,  135,  134,  (two  weak,  OH),  2900  119,  prepared  Method  from  B  1  2  0  for  1  -  F  o  u  n  ( 9  d  C1()H160  the  :  and  singlets,  4  1  108  (base  6 H,  peak).  ^ s o l u t i o n mass H, H ^  10.59.  H  1  1670  wt.  :  corresponding enantiomeric  starting  broad  = 6 Hz,  C,  3  Hz,  bridgehead methyls). (broad,  (sharp,  =CH2);  m/e  calcd.  for  spectrometry) Found  +12°  3400  :  medium, 152  152.1209.  79.00;  -59.3°(c 1.00,  5  J  H,  OH),  200°C).  52-53°C,  n  tertiary  Mole.  90°to  (two  H,  Hz,  120°  54-55°C);  5.43  doublets,  half-width  120°to  1  strong,  (25),  calcd.  -  ( l i t .  (broad,  (-)-6-exo-Hydroxycamphene  2  5.21  from  m.p.  5  eluent),  m.p.  890 cm"1  78.90;  5  l i t .  as  t . l . c .  from  1  CH),  C,  Anal,  1  ( l i t .  on  (from  strong,  n  :  carbowax  needles  (90°C,  (90°C,  (broad,  Hi  10H16°  3% 0 V 1 7  non-hydroqen-bonded  C-0),  121,  (30-60)  CHC13)  of  colorless  homogeneous  52.0°C  x (CC14),  signal,  :-  10%  1.16,  as  ether  58-59°C,  (doublet  9.03  strong,  pt.  +60.4°(c  be  3% 0V101  and  m.p.  3  (1)  to  columns  170°C),  tube),  CHC13),  H each,  (CC1,), medium,  shown  + 80% p e t r o l e u m  59.5-60°C, l i t .  CHC13),  singlets,  c r y s t a l s were  (sealed  m.p.  9  6-exo-hydroxycamphene  20% e t h e r  DEGS  67.5-69.5°C '  The  -  analysis using various  M.p.  H  C  afford  116  H,  CHC13),  10.72.  was  also  material.  :-  6-exo-t-Butyldimethyl silyloxycamphene stirred  with  (3:1:1)  at  a mixture  room  (10  temperature  ml) for  of 11  acetic hours.  (24)  acid 1 7  (116.8 :  The  water  mg, :  0.43  mmole)  tetrahydrofuran  s o l u t i o n was  then  was  -  neutralised organic  extract  sulphate. were 10%  with  sodium carbonate was washed w i t h  Removal  of  solvent  chromatographed ether  (62.0  and  mg,  t . l . c .  R^  with  which  value,  optical  and  hydroxycamphene  (1)  and  to  provided  100°C  ether  (30-60)  oil  III)  gave  yield),  CHC13), 1  grade  -CH00CCH3  of  bridgehead 8.99  (two  medium,  1740  150  peak),  (High  anhydrous  (activity  g).  grade  data,  i d e n t i c a l to A  describe  combined magnesium  (116.4  mg)  Elution  colorless  with  crystals  retention  those  which  of  time,  (+)-6-exo-  above.  0 . 9 9 mmole) for  in  9 hours.  w h i c h was  Elution  (1)  (21.4  dry  Normal  as  CHC13)); (doublet  6 H,  ( l i t .  x (CC14), of  7.30  1  on  90%  H,  J  5.35  (singlet,  3 H,  CH3C00-),  tertiary  methyls);  u  (CC14),  strong,  895 cm"1 119.  r e s o l u t i o n mass  C=0),  (broad,  Mole.  Wt.  1240  medium, calcd.  spectrometry)  a  and  1230  =CH2); for  :  x  C  1 2  l g  194.1320.  0.58, singlets, 3.5  Hz, 1  8.97  H,  and  2900  (broad,  (sharp,  strong,  m/e H  gel  (19.6  4 Hz,  8.09  m  oil  Hz,  half-width  was  petroleum  (two  = 8.0  ml)  silica  +20.9°(c  D  and  signal,  and  mmole)  work-up  a colorless H  1  5.08  doublets,  (broad  (10  chromatographed  (2)  CHCI3)  0.14  aqueous  6-exo-acetoxycamphene 1.11,  mg,  pyridine  ether  134,  The  III).  g.l.c.  10%  (sharp,  C-0),  crystals  provided  spectral  Method  mg)  methine),  singlets,  and  over  dried  with  5.56  allylic  CH3-C-CH3  Found  (23.6  exo-acetate),  CH),  (base  mg,  +37.6°(c  =CH2),  and  colorless  rotation  nitrogen  (2  +n.6°(c 1.20,  H each,  ether.  (30-60)  showed  by  with  (2)1  (100  under  a yellow  (activity  gel  extracted  (+)-6-exo-hydroxycamphene  a c e t i c anhydride  heated  72%  of  afforded  prepared  6-exo-Acetoxycamphene  and  ether  94% y i e l d )  -  water  silica  90% p e t r o l e u m  A mixture  117  0  194 2  :  Anal,  (M+),  179,  194.1306. calcd.  for  mg,  -  C  12H18°2  :  '  C  7  4  J  9  Acetylation (-)-acetate  ;  of  (26),  6-0xocamphene  '  9  1  3  4  '  F  o  u  n  d  -  :  '  C  7 4  -  1 7  "'  H  (-)-6-exo-hydroxycamphene  [*]25  ( 3 )  Pyridinium  '  H  118  »  '  3  -37.4°(c  '  5  '  7  0.80,  >  9  -  (25)  2  0  -  gave  the corresponding  CHC13).  8  chlorochromate  (132  mg, 1.44  mmole)  prepared  by t h e  method  20 of  Corey  et  al_  was s u s p e n d e d  (+)-6-exo-hydroxycamphene (3  m l ) was a d d e d ,  The  the  filtered filtrate  (activity  gave  grade  afforded  yield).  Part  to  colorless  give  ^40°C  2  ( l i t .  7  of  '  +33.7°  D  H,  =CH2),  8.88  7.04  CH),  (broad,  strong,  :  C,  (3 g ) .  =CH2);  -|QH1 4 °  Elution (3)  H  150.1033.  79.72;  H,  9.25.  with  0  -  1  Anal,  (bath  +155.3°  T (CC14),  0  brown  for  1  H,  4  5  -  F °  u n d  calcd.  and was  solvent  on s i l i c a  gel  ether  ( 2 0 . 4 mg, 80%  temperature tube),  (c 0 . 7 9 ,  from  CHC13)  50°C,  760  subl.  pt.  ( l i t .  Torr)  1  5 . 0 0 and 5 . 2 5 (two s i n g l e t s ,  methyls); 1660  ( M + , base  chloride  + 90% p e t r o l e u m  (sealed  of  precipitate.  of  crystals  bridgehead  C=0),  solution  2 hours  Removal  10% e t h e r  as c o l o r l e s s  2 5  strong,  5  temperature  73.5-75.5°C  tertiary  1  a dark  Florisil.  was s u b l i m e d  m/e 1 5 0 :  of  of  o i l w h i c h was c h r o m a t o g r a p h e d  signal,  6 H,  room  column  77-78°C);  (sharp,  c  :  at  needles, m.p.  (broad  1750  for  spectrometry) Found  i n methylene  yellow  the product  (two s i n g l e t s ,  calcd.  mmole)  (c 0 . 8 6 , CHC13));  strong,  wt.  ( 2 6 . 5 mg, 0.17  6-oxocamphene  m.p.  8  (3 m l ) . A  i n the formation  a short  a pale  III)  chloride  was s t i r r e d  through  (30-60)  H  resulting  reaction mixture  then  (1)  i n methylene  u  allylic v  ( C C l J ,  (sharp,  peak), (High  methine),  135,  2850  weak,  107,  resolution  mass  for C^H^O  :  C,  79.95;  and  (sharp,  C=C),  121,  8.81  895 cm"1  106.  H,  Mole,  9.39.  -  Oxidation conditions  gave  of  119  -  (-)-6-exo-hydroxycamphene  (-)-6-oxocamphene  (27),  (25)  25 [<*]_.  under  similar  reaction  o -157.6  (c  0.85,  CHCK).  - 1 2 0 -  BIBLIOGRAPHY  1.  (a) A.  Matsuo,  Y.  Uchio,  M. Nakayama,  Y.  Matsubara  and S.  Tet. L e t t . , 4219 (1974). We a r e g r a t e f u l t o D r . A . workers, Hiroshima University, Japan, f o r providing n.m.r. spectra of nojigiku alcohol. (b)  Y.  Uchio,  2.  B.H.  Jennings  3.  H.G. 3095  Richev, (1964);  4.  M. J u l i a ,  5.  M.  Gaitonde,  6.  P.  Lipp,  7.  8.  Y.  9.  H.C.  Mansuy P.A.  R.O. 1097  (b)  R.O.  (a)  S.  J .  and P.  Detraz,  B e r . , 8 0 , 165  Org. Chem.,  Tet.  and S .  (1937);  and S.  Krishnamurthy, B.E.  3 0 , 3902  (1965).  2141  (1976).  Lett.,  2007  (1964).  (1947).  Tukamoto,  Hutchins,  Lett.,  Dev, Tet.  and A . S . Z a b r o d i n a . B u l l . 1015  (1978).  D.C. Dull and J . E . G r a n t , J . Org Chem., 2 9 , 3 0 , 3909 (1965) and r e f e r e n c e s c i t e d t h e r e i n .  and T.  acad.  Chem.  Chem.  B e r . , 7 0 / 584 J.  Maryanoff  s c i .U.R.S.S.  A b s . , 3 2 , 2920  Am. Chem.  and C A .  Classe s c i .  (1938).  (1937).  S o c . , 9 5 , 1669  Milewski,  J.C.S.  (1973).  Chem.  Comm.,  (1971). Hutchins,  Maryanoff, 11.  Herschbach,  Vatakencherry  Ser. Chim.,  Brown  S o c . J a p . , 51_, 2 3 4 2  T.L. Garbacik, J . Org. Chem.,  Chem.  Asahina  (a)  Chem.  and G . B .  S . S . Nametkin math.,  10.  D.  Bull.  Hayashi,  Matsuo and c o us w i t h i . r . and  J.  Masamune,  D.  Kanclasamy,  Org. Chem.,  C A .  4 2 , 82  Milewski,  D.  Masilamani  and B . E .  (1977).  G.S.  Bates  and P . A .  Rossy,  J.  G.S.  Bates  and P . E .  Geoghiou,  Am. Chem.  S o c , 95,  6452,  (1973). (b) 12. 13.  D.H.R. R.O. 3662  14.  S.  Masamune, Barton  Hutchins,  and S.W. McCombie, C A .  Milewski  J.C.S.  and B . E .  Perkin  Maryanoff,  ibid.,  9 £ , 3686  1,1574 J.  (1974).  (1975).  Am. Chem.  S o c , 95,  (1973).  (a) G.W.  Kabalka  (b)  Kabalka,  G.W.  Synthesis,  and J . D .  124  D.T.C.  Baker, Yang,  (1977).  J r . ,  J.H.  J .  Org. Chem.,  Chandler  and J . D .  4 0 , 1834 Baker,  (1975). Jr.  -  15.  J.  De  P.  Teresa,  560  (1976).  M.S.  Allen,  Can.  J.  17.  E.J.  Corey  18.  (a)  16.  (b)  I.  D.  20.  E.J.  21.  (a)  22.  N.  and A.  Fowler, 62,  Corey M.D.  and  T.  J.  Chem.  K.A.  Kime  Darby,  N.  and  E.R.  Barrueco,  Anal,  Sigurdson  and  de  T.  Quim.,  72^,  Money,  J.  and  Loebenstein,  Am.  E.  Chem.  S o c ,  Nakamura, D.B.  Pall  94,  6190  Synthesis,  and  CA.  (1972).  602  Kraus,  (1976). J.  Am.  (1940). Gen.  J.W.  J.F.S.  Salisbury,  Murofushi  W.V.  -  (1979).  Venkateswarlu,  McCreary,  Am.  P.  733  1140  Tishchenko,  J. (b)  57,  Kuwajima,  D.L.  B e l l i d o and  Darby,  Chem.,  Soc., 19.  N.  I.S.  121  Chem.  Suggs, D.W.  Soc., R.E.  Lamb a n d  U.S.S.R.,  Tet.  Lewis, 96,  1030  Sievers, T.  Money,  Lett., D.L.  23, 2647  Wernick  (1974)  and  1051  (1953).  (1975). and  G.M.  Whitesides,  references  cited  therein.  Aldrichimica Acta,  J_0,  54  Can.  742  (1979).  J.  Chem.,  57,  (1977).  Chem.  - 121 a -  PART  Synthetic  III  Approaches  to  Albene  -  122  -  INTRODUCTION  Albene isolated  C-^IS'  from  Adenostyles years  Sorm  based  ystalline  of  (G.)  on s p e c t r a l  data  a s shown  (1)  and the exo o r i e n t a t i o n rotatory  degradation amplitude display Cotton from of  a -258.  the  the enantiomer  sign  of  by Novotny  that  proposed  of  curve  a negative  The enantiomer a +258.  (2), of  this  Sorm  of  of  t h e ORD c u r v e .  were  ketonitrile  Cotton  this  displayed  effect  only  Ketonitrile  value  that  contributes  deduced (8).  of  from  of  the  This  anticipated  based  the  to  positive  (13)  prepared group  on t h e  the amplitude  (8) was t h e r e f o r e  The o c t a n t p r o j e c t i o n f o r the enantiomer c a m p h e n i l o n e ( 1 3 ) i s a s shown b e l o w .  for  a t 2 8 6 nm w i t h  with  to  (1)  (+)-camphene  the cyanoethylene  octant  Ten  configuration  by camphenilone  e_t a l _ c o n c l u d e d  (8) was i n a n e g a t i v e  in 1962.1  structure  the absolute groups  was  Gearth and  correlation with  (8) was t h e r e f o r e  Comparing  functionality  (L.)  the t r i c y c l i c  the methyl  (ORD)  albus  and co-workers  and chemical  a t 2 8 0 nm ( a + 3 8 0 )  (+)-camphene  Petasites  In p a r t i c u l a r ,  exhibited  the amplitude  assumption  1.  dispersion  product  effect  Kern  and co-workers  i n Scheme  trisnorsesquiterpenoid hydrocarbon,  the genera  (2)  optical  *  plants  c r  alliariae  later,  albene  a  but not  a s s i g n e d an  ketonitrile  (8)  ChLCN,  enantiomer of  2  H,  or  (8)  camphenilone (13)  to  -  123  -  SCHEME  1  -  exo-methyl (16)  or  group  124  -  and t h e p o s s i b i l i t y o f  i t s enantiomer  (17)  was  albene  being  structure  rejected.  (16)  Sorm  the t r i c y c l i c  (17)  and c o - w o r k e r s  relationship  between  also  pointed  out that  proof  of  trimethylbicyclo[2,2,1]heptanes  the  (12)  enantiomeric  and  (15)  (Scheme p  1)  had n o t been  The H  2  albene  degradation  product  - 0 . 5 ° (c 0 . 4 3 , C H C 1 3 ) ,  0  was  s u c c e s s f u l due t o  a solid,  n.m.r. they  m.p.  and i . r .  were  both  69-70°C,  spectra  (12)  2  0  (12)  levorotatory  was r e p o r t e d  whereas  H  of  the low q u a n t i t y  (15)  to  obtained  and p u r i t y  be a l i q u i d from  - 3 . 7 ° (c  0 . 5 5 , CHC13).  and  were  and t h a t  (15) (12)  of  of  (+)-camphene Although  identical,  was a l i q u i d  (12).  the  the fact  while  (15)  (2)  that was a  4 solid  was q u e r i e d  photochemical as  well  as  decarbonylation  i t s epimer  A synthetic same w o r k e r s and  by Lansbury  route  (18)  leading  in order  i t s degradation  to  and B o d e n , of  (cf.  ketone Scheme  to  ketone  gain  more  products  (5)  suggested  (albanone)  could  that provide  (9)  1).  (5)  was t h e r e f o r e  insight  (Scheme  who a l s o  2 ) .  4  into There  proposed  by  the  the structures  of  albene  w a s no i n d i c a t i o n  whether  -  the  starting  material,  racemic.  The  i . r . ,  mass  of  and  albanone  that  a  ketone  (5)  carbonyl  spectral  infrared  five-membered  at  cm  -1  enone for  (4)  (*  and  to  u s e d was  demonstrated be  ketones  at are  However,  1712  cm  -1  expected  optically by  homogeneous  co-workers.  absorption  ring  -  (13),  was  analyses  Sorm  whereas 1745  camphenilone  so o b t a i n e d  from  125  and it  was to  g . l . c ,  t . l . c ,  identical is  to  pertinent  reported  exhibit  or n.m.r., a to  for  (5),  carbonyl  sample note 2  stretching  5 .  Furthermore,  the  m a x  227  also  o  a six-membered  nm)  was  ring  ultraviolet  more  absorption  consistent with  «,B-unsaturated Cl  maximum  the  value  ketone.^  (19)  (13)  HCOOH  1.  Ac20,  1.  Baeyer-Villiger  2.  (5)  active  3.  HC10A  reaction  "OH Cr03-H2SO^  S C H E M E  (20)  2  observed  expected  for  -  126  ( 19  )  2,3 Me  exo — e x o - 2 , 3 - m e t h y 1 s h i f t  2,3 Me  endo — e n d o - 2 , 3 - m e t h y l  -  shift  SCHEME  3  -  Lansbury ketone  and  (20),  and  well-documented endo-shifts ketone  (5)  Boden hence  assigned to  those  preference  in  norbornyl  revealed  by  127  of  -  the of  exo  orientation  synthetic  albanone  exo-2,3-methy1  cations.  spectral  The  7  and  to  shifts  homogeneity  chromatographic  the  methyl  (5),  over of  based  the  groups  on  of  the  corresponding  their  synthetic  evidence  led  them  to  p conclude cation  that  (27)  involved ketone  (1)  (23)  were  that  loss  the  (22)  from  acid  and/or  its  by  similar of  an  the  (28)  would  endo-2,3-methyl  derivative (19)  structure  of  this  synthetic  sequence.  from  group  (Scheme  (26),  (Scheme  have  the  c y c l i s a t i o n of  isopropyl  by  c y c l i s a t i o n of  biosynthesised  to  (21)  tricyclene  enantiomer  established is  from  viia  catalysed  that  (1)  formed (24)  concluded  albene  pathway by  formed  in  therefore  cation  been  albanone  (5),  shift, were  7  3).  not Otherwise  4  obtained. and  They  hence  Moreover,  i t  of  was  (29).  (19)  involved  (20)  may  be  albene proposed  (+)-epi-B-santalene to  and  A  4  followed  4).  SCHEME U In racemic  1977,  Kreiser  tricyclic  and  alkene  Janitschke (1)  vi_a a  reported  that  Di e l s - A l d e r  they  reaction  had  synthesised  between 9  cyclopentadiene of  (1)  was  and  dimethylmaleic  established  by  X-ray  anhydride  crystallographic  (Scheme  5).  analysis  of  The the  structure precursor  -  thioenolether and  proton  n.m.r.  different of  (1)  (30).  from  However,  spectrum  those  provided  the  of  reported dihydro  128  -  these  workers  their  synthetic  for  albene  derivative  by  (3)  noted  that  product  Sorm  et  whose  the (1)  melting were  al_.  inner  point  markedly  Hydrogenation symmetry  was  13 indicated much  by  higher  therefore al  was  its than  C n.m.r. that  concluded  wrong.  of  that  Instead,  spectrum,  the  proposed  formula"  (31)  mentioned  spectral  data  concerned with  dihydro  derivative  contradicts n.m.r.  O  if  spectral  that  natural  Sorm's  structure  based  they  that  would  in  on  "an  Sorm's his  not  observed  additional  have  the  on his  the  to  albene  have  of  the  structure  optical  (31),  SCHEME  inactivity  (1)  5  Sorm  et  natural  details  then  symmetry,  dihydro-albene.  (3)  by  However,  +  (31)  again  "omitted  experimental  inner  was  Janitschke  reported.  p o s s e s s e d any  based for  had  was  point  synthesis  should  Neither  synthesis  and  assigned  compound  really  melting  Kreiser (1)  paper.  the  albene  deduction  data  whose  dihydro-albene.  albene",  obvious  but  and  nor  it  is  its  which proton  -  One on  "the  year  later,  real  detail  on  structure  the  reported.  Kreiser of  and  route  the  -  Janitschke  albene  Diels-Alder  Furthermore,  129  and to  its  published  total  structure  structure  and  another  synthesis (1)  (now  absolute  two  J°  papers  Further  named  isoalbene)  configuration  was  (17)  which  2 had  been  result Using of  rejected  of  to  that  et_'al_  albene  was  now  reassessment  of  (+)-camphenilone  described  tricyclic of  and  pure  reactions  obtained  Sorm  repetition  optically  the  by  ketone (Scheme  by  and  6).  In  to  Lansbury's  (13)  Lansbury  (34),  assigned  as  et  aj_,  alkene  (17)  natural  e a r l i e r work4  starting Kreiser with  addition,ketone  albene  material and  the  (Scheme  and  2).  some  Janitschke  melting  (34)  as  was  point shown  identical to  be  * identical  to  However,  albanone  our  laboratory  cyclopentane cyclisation  would  as  from  EtOH)  allylic  albene  Kreiser  and  occurring excluded of  by  neither  (23) a  by  (19)  would  be  previous nor  1).  a l _ , £ was Ac^O) If  absolute  enantiomeric  oxidation  investigation. Kreiser's  of 1 1  the  albanone  and/or  shift,  of  structure  particular, been  does  (34)  occur  derived  proposed  by  racemisation  seem t o the  (H^,  not  albanone  p o s s i b i l i t y of  has  by  hydrogenation  not  this  skeletal  albene  migration  does  a  that  Wagner-Meerwein  from  by  sequence.  exo-fused  7  bond  albene In  the  shift  derived  the  of  We c o n s i d e r  configuration to  identical  6).  followed  double  an  formation  (Scheme  Unfortunately,  allylic  the  2,3-exo-methyl  et  HOAc,  the  on  e_t a l _ v i a  2,3-endo-methyl  Sorm  Scheme  co-worker.  Sorm's  from  rare  oxidation  during  Lansbury  speculated  (K^CrO^,  (cf.  (17)  by  c o n s i s t i n g of  described  oxidation  Pd-SrCO^, during  involve  process  Albanone, allylic  has  intermediate  rearrangement  *  prepared  have  optical  reported.  been purity  - 130 -  WM=Wagner-Meerwein  rearrangement  2,6 H - 2 , 6 - h y d r i d e  2, 3 M e = 2, 3 - m e t h y l s h i f t SCHEME  6  shift  -  rearrangement, two  pathways  would  respectively, racemic that  for  and  product  the  optical been  and  purity  considered albene  absolute  shift  lead  intermediate  be  (cf.  (17)  the  these  of  It  (34)  these  (23) a  and  Thus, are  3).  its  racemic  or  the  (28)  was  of  to  note  low  rearrangement structures  certainly  remain  these  partially  interesting  carbocation  almost  of  enantiomer  Janitschke  although  compounds  Operation  and  therefore  p o s s i b i l i t y of  albanone of  is  Kreiser  workers.  configurations  Scheme  occurred  obtained.  that  and  the  sequences  albene  by  (17)  to  both  would  and  -  2,6-hydride  if  synthetic  131  correct,  has  proposed the  doubtful.  Addendum  After  submission of  (-)-albene  (17)  albene  reported  natural  was  4 7  compound  and  has  to  this  thesis  (+)-isoalbene on have  [<*]n -9.2°  full  papers  (l)4^ -6.5°  (c  (c  0.54,  were  on  Kreiser's  published.  1.17, CHClj).  CHC13)  syntheses  Synthetic  whereas  the  of  -  132  -  DISCUSSION  Recent s t u d i e s i n our l a b o r a t o r y have r e s u l t e d i n the development s i m p l e s y n t h e t i c r o u t e s from camphor (35) sesquiterpenoids.  of  to a v a r i e t y o f mono- and  In the s e s q u i t e r p e n o i d a r e a (Scheme 7)  the general  s t r a t e g y was based on the s t r u c t u r a l s i m i l a r i t i e s between camphor and 12 each s p e c i f i c compound,  and on the development o f an e f f i c i e n t 13  procedure f o r b r o m i n a t i o n camphor a t the C ( 8 ) - p o s i t i o n  (cf.  three-step  p.  177).  ( + ) - E p i - g - s a n t a l e n e (29) was one o f the s e s q u i t e r p e n o i d s s y n t h e s i s e d d u r i n g these i n v e s t i g a t i o n s and when Lansbury et_al_ suggested t h a t  this  compound c o u l d be a b i o s y n t h e t i c p r e c u r s o r o f a l b e n e , whose s t r u c t u r e and 2 4 a b s o l u t e c o n f i g u r a t i o n (1) (cf.  p. 122),  had been determined by Sorm and c o - w o r k e r s  '  we d e c i d e d to s t u d y the p o s s i b i l i t y o f a c h i e v i n g t h i s  c o n v e r s i o n i n the  laboratory.  (1 )  (29) Our i n t e r e s t i n t h i s p o t e n t i a l  b i o g e n e t i c - t y p e s y n t h e s i s o f albene  was f u r t h e r s t i m u l a t e d by the unconfirmed f o r m a t i o n o f t r i c y c l i c (38) when a m i x t u r e o f <*-santalene  (36),  3-santalene (37), 12a  s a n t a l e n e (29) was t r e a t e d w i t h f o r m i c a c i d (Scheme  8).  (1)  alkene  and e p i - g -  -  -  133  (+)-£-Santalene (+)- S a t i v e n e  R] =H, R 2 = O H ,  (+)-Campherenol  R=OH,R=H,  (*)-Isocampherenol  )-Ylangocamphor  (+ ) - C a m p h o r ( 35)  (+ )-Epicampherone  (+ ) - C o p a c a m p h e n e  RpH,  R2=OH,  R-)=OH, R 2 = H ,  (O-Epicampherenol (O-Isoepicampherenol  (+ )-Epi-£-santalene (29) SCHEME  7  -  134  -  SCHEME As  a result  possibility precursor  of [eg_.  of  Scheme  9  earlier  transforming (38)]  (+)-Epi-6-santalene in  these  which (29)  previously  8  observations  we  (+)-epi-B-santalene could  was  subsequently  synthesised  developed  in  our  by  decided  (29) be  the  to  to  a  the  tricyclic  converted reaction  study  to  albene  sequence  (1).  outlined  laboratory.12a,e,f *14  Bromination  *  of  commercially  (+)-3-Bromocamphor (35)  with  bromine  (39) in  had  glacial  available  been  (+)-3-bromocamphor  prepared  acetic  acid."  by 1 4  treatment  of  (39)  (+)-camphor  SCHEME  9  -  136  provided  (+)-3,9-dibromocamphor  product,  (+)-3,9,9-tribromocamphor  mechanisms 10.  )  involved  Purification  followed  by  in  the  of  (40)  (41).  formation  of  these  with  Subseauent  1 5  a recently  J30'1'7  3,9-dibromocamphor  '  1 4  and  | I + - I n  (47)  selective debromination  9-bromocamphor  -  (A  proposal  products  (40)  identified  is  for  minor  the  shown  in  Scheme  by r e c r y s t a l l i s a t i o n  zinc-hydrogen  conversion  of  bromide  (41)  to  gave  the  (+)-  corresponding  1p iodoketal  (43)  followed  by  19 allylnickel  complex  epicampherenone  '  in  the  highly  and  acid  35% o v e r a l l  hydrolysis  y i e l d .  1 2 a  '  e  provided  conversion  of  iodoketal  via  a  Applying  the  alkylation  s l i g h t l y more  iodoketal  (43)  Subsequent  with  by  ethylene  ketal  tedious  epicampherenone also  (45)  but  (+)-epicampherenone less  reported  ethylene  of  sulphone  1 i t h i u m - d i e t h y l amine (44),  to  ketal  toxic  by  which in  was  (48)  (48)  then  from  the  in  dry  was  (Scheme Masaki,  prepared  by  also  11). 2 1 a  heating  hexamethylphosphoramide.  afforded  hydrolysed yield.  was  and  (45)  l-bromo-3-methyl-2-butene  reduction  30% o v e r a l l  synthesised  with  route  Grieco  sodium p_-toluenesulphinate  alkylation  followed  (43)  procedure  9-p_-toluenesulphonylcamphor  was  (+)-  (45)  achieved  (49)  TT-  ' ^  (43)  The  toxic  20  (a)  (45)  condensation with  to  The  corresponding  epicampherenone  provide  (+)-  9-benzenesulphonyl sodium  salt.  ketal  Alkylation  -  137 -  WM = W a g n e r - M e e r w e i n rearrangement 2,3 Me =2,3-methyl shift  SCHEME  10  -  138  -  (45)  SCHEME  11  (48)  R=CH  (49)  R =H  3  -  of  (49)  and  reduction  epicampherenone Lithium sterically displayed  (45)  of in  aluminum  hindered spectral  (51)  139  followed  higher y i e l d  hydride  endo-side data  -  (cf.  by  acid  (41%)  hydrolysis  and w i t h  gave  fewer  side  products.  (45)  from  reduced  (+)-epicampherenone  to  (+)-isoepicampherenol  give  Experimental,  p.190)  (+)-  (46)  identical  to  the  less  which  those  of  the  22 natural  alcohol.  Treatment  methanesulphonyl Meerwein n.m.r.  chloride  rearrangement  spectrum :-  5.57  singlets,  in  to  the  following (two  T  of  refluxing  4.95  (two  (singlet,  3 H,  tertiary  methyl).  the  o l e f i n i c C-H  (29) of  had  the  natural  As  cm-1  H  2  +23.3°  that  a mixture  an  broad  in  of  (A)  and  our  of  work  (Scheme  product  in  9).  Wagner-  1 2 a  showed  6 H,  1  (c  H,  vinyl  at  laboratory  "  d  f  he  T  the 5.33  and  bridgehead  (CCl^)  880 and  2.6,  >  methyls),  spectrum  synthetic  +26.9  with  resulted  (multiplet,  Our  CHCI3).  (46)  olefinic proton),  absorptions  of  previous  (29)  infrared  bending.  4.12,  alkene  H,  singlets, The  isolated (c  indicated above,  demonstrated  and  rotation  compound  9  broad  out-of-plane  a specific  displayed  when  1650  1  =Cttr,), 7 . 3 4  H each,  and 8 . 3 8  at  pyridine  (alumina)  (multiplet,  8.32  stretch  dry  (+)-epi-$-santalene  methine),  C=C  (+)-isoepicampherenol  chromatographed  (CCl^), 1  of  allylic  and  8.97  exhibited  835 c m " 1  due  to  (+)-epi-6-santalene  CHC13) from  whereas  sandalwood  a  sample  oil  1 2 A  by  G.  L.  undetermined  epi-B-santalenes  Hodgson  in  structure (relative  our was  laboratory obtained  ratio  4.4:1.0:3.0  12a respectively) same  product  formic  acid,  spectrum J  = 3 Hz,  was (A)  heated when  boron  (CDC13) which  with  pure  c o u l d be  1)  acid  (Scheme  (+)-epi-6-santalene  trifluoride  (Figure  formic  of  etherate, (A)  assigned  or  showed to  an  a  8).  (29)  stannic  was  We o b t a i n e d treated  chloride.  a one-proton  triplet  o l e f i n i c hydrogen,  and  the  with The at a  n.m.r. 4.66T, doublet  Figure  2  I.R.  Spectrum  of  Olefin  (A)  - 142 -  (2 H , J = 3 H z ) a t 7.85x t h a t The  two s i g n a l s  components  a t 8.91  a n d 8.98x  of a doublet,  secondary  methyl  indicated  two t e r t i a r y  could  J  groups.  be due t o an a l l y l i c  ( 6 H) w e r e  = 7 Hz,  centred  The two sharp  methyl  groups.  C-H o u t - o f - p l a n e  spectrum  (Figure  2).  The mass  204 i m p l y i n g  that  ( A ) h a d t h e same  m/e  (+)-epi-B-santalene spectral The  data,  formation  santalene (Scheme routes  were  structures which  However,  also  Our before  structures with  to exhibit  ion at  C ^ H ^ as i t s precursor  o f the observed  n.m.r.  assigned  a n d mass  t o compound  cyclisation of  (+)-epi-3-  or double  migration  bond  by more  diastereotopic  two t h r e e - p r o t o n  than  a six-proton  initial  task  was t o e s t a b l i s h a possible  doublet  •  Furthermore,  secondary  doublets  (A).  circuitous  the spectroscopic evidence.  rather  with  composition  (6 H )  i n the infrared  a molecular  (52) a n d (53) f o r m e d  (38), (52) a n d (53) h a v e  proceeding  displayed  shift  by two  C=C s t r e t c h i n g n o r  was o b s e r v e d  acid-catalysed  by 1,3-hydride  consistent  are expected  spectrum,  spectrum  as the  a t 9.05 a n d 9.07T  (38) w a s t e n t a t i v e l y  (A) i n v o l v e s  (29) f o l l o w e d  singlets  group.  assigned  a t 8.95T c o n t r i b u t e d  absorption  On t h e b a s i s  (29).  the structure of  12).  bending  tentatively  No p r o m i n e n t  olefinic  methylene  methyl  groups  in the n.m.r.  a t 8.95x.  the correct  synthesis  structure  o f albene  of olefin Treatment  (1).  (A) of  23 (A)  with  hydrogen in  borane  complexes  bromide,  aqueous  hydrogen  dioxane,  BH^.tetrahydrofuran chloride,  ' osmium  or B H ^ C H - ^ S ,  bromine,  N-chlorosuccinimide-perchloric  tetroxide,  nitrosyl  chloride  or  acid  iso-amyl  25 nitrite-hydrochloric  acid,  and 2,4-dinitrophenylsulphenyl  chloride  O f  CgH-^NO^SCl  in glacial  derivatives  or products  encouraging  result  acid.  The n . m . r .  acetic that  could  was o b t a i n e d spectrum  acid  be e a s i l y  when  (CDCl^)  a l l failed  to provide  identified.  (A) was t r e a t e d  (Figure  with  A  crystalline more  m-chloroperbenzoic  3) o f t h e c o l o r l e s s  oily  product  -  143  -  (38)  <y  WM =Wagner-Meerwein 1,3 H = 1 , 3 - h y d r i d e  shift  2,6 H = 2 , 6 - h y d r i d e  shift  rearrangement  SCHEME  12  -  (B)  showed  a broad  one-proton  -  144  signal  at  6.68x  which  could  be a s s i g n e d t o  the  i -CH-0-  methine  integrating methyl  infrared  the  molecular  1255  a t m / e 57  the epoxides  with  the precursor  (54),  (52) and (53)  from  while  (Fiqure  of  (A),  those 4).  (55),  or  (Scheme  (56)  13).  methyl  9.13  at 950,  920,  of  formed  due to  two  The  the  data  9.17T  tertiary  weak  symmetric  a n d 895 c m  were  - 1  of  (B)  was  a t m / e 220 w h i c h w a s  composition  a n d m/e 4 3 .  four  to  spectral  was o b s e r v e d  and  groups.  attributed  The mass  f o r an e p o x i d e peak)  9.05,  to a doublet  two t e r t i a r y  low i n t e n s i t y  (base  9.03,  c o u l d be a s s i g n e d t o  c m " 1 was t e n t a t i v e l y  stretching A peak  signals at  protons  ring,  ion expected  fragments  (38),  at  the epoxide  informative.  also  twelve  and two s i n g l e t s  absorption of  of  The f o u r  by a n a l o g y  to asymmetric  more  of  or,  methyls  stretching due  an e p o x i d e .  to a total  groups  secondary  of  C-^^O-  Compound  (B)  There  could  were  be one  from  the corresponding  olefins  Rearrangement  and f r a g m e n t a t i o n  of  either  27 (54)  or  would  (55)  lead  to  i n the fashion both  generally  t h e m / e 57  a n d m/e 43  the  m / e 43 f r a g m e n t  c a n be d e r i v e d  the  m / e 57  this  molecular  i o n from models  was  more  the  exo-epoxides It  liable  compound  revealed to  attack  that  that  from  ions  to  for alicyclic as d e p i c t e d  epoxide  cannot  (56)  the s t e r i c a l l y less  be f o r m e d  the well-known  acid  epoxides  i n Scheme  13.  Only  and t h e f o r m a t i o n  be r a t i o n a l i s e d .  by t h e p e r b e n z o i c  are l i k e l y  was d e c i d e d  observed  of  Examination  hindered  exo-side  of  of  whereas  both  the endo-  i n the cases of  (52)  and  boron  trifluoride  (38) and  (53).  etherate  catalysed  28 fission-rearrangement provide  more  size  an a l i c y c l i c  of  absorption  insight  frequency  of  epoxides  into  carbonyl  the structure  epoxide of  to  of  (B).  c a n be d e d u c e d  the corresponding  compounds  from  ketone  (Scheme  In p a r t i c u l a r , the infrared formed.  14) the  might ring  carbonyl  Figure  4  I.R.  Spectrum of  Compound  (B)  -  147  -  m  SCHEME  / e S7  13  -  |  148  -  3  R = H  or  alkyl group  SCHEME Contrary  to  our  benzene  with  aqueous  work-up  expectation,  boron  The  presence  broad  one-proton  methylenes,  tertiary  methyl  solution  stretching  to  1640  vinyl  and  an  product  (C)  and  was  could  be  The  therefore  isolated  n.m.r.  and  of  as  (D)  its  n.m.r. and of  cm"1,  a  in  the  in  C=C at  spectral  shown  two  (C)  C-H  epimer.  from  and  two  spectrum  its  identified  by  olefinic  are  (C)  5.72x  at  i . r .  by  terminal  in  3350  at  and  assigned  (C) and  enols  8.22x  infrared  dry  followed  two  occurred  bending  in  witnessed  at  absorption  exhibited  enols  was  singlet  out-of-plane  (D)  provided  (C)  (B)  10 m i n u t e s  multiplet  OH  compound  c h a r a c t e r i s t i c of  9.12x.  weak  (57)-(59) f o r  compound  in  of  for  gel)  methyl  and  and  0°C  5.29x  -CH0H  8.96  at  a broad  second of  the  at  entity  and  saturated  cm"1,  structures  data  Some Scheme  15.  crude  mixture.  Jones' a  A  singlets  those  carbonyl  product  5).  4.99  at  solution  (silica  CH^-C^Hg  with  showed  The  possible No  at  cm"1.  similar  the  together  (Figure  900  of  a  etherate  chromatography  singlets  spectrum  CCl^  trifluoride  and  (D).  stirring  14  oxidation  colorless oil  which  (chromic showed  acid-water-acetone)^  two  spots  on  t . l . c .  of  enol  (silica  gel)  (C)  provided  analysis. i  The  n.m.r.  spectrum  group  had  width  3 Hz)  feature  of  of  the  product  e s s e n t i a l l y remained was the  probably infrared  due  to  mixture  intact. an  A  allylic  s p e c t r u m was  a  indicated broad  signal  methine.  sharp  and  that at  The  strong  the  CH^-C^H^^  7.25x (1 most  H,  half-  prominent  absorption  at  Figure  5  N.M.R.  Spectrum  (100  MHz)  of  Compound  (C)  - 150 -  (61)  (63)  SCHEME  15  -151-  cm"'  1745 the  with  carbonyl  shoulder  a weak  stretch  at  lower  <*,g-unsaturated  =CH  the  of  and  enol  i . r .  ketone  data  olefin  oxidation  part  ground,  alumina  (activity  Removal  of  gave  oily  an  values  7.80  at  tertiary  a  conjugated  -1  cm  that  the  ring  ketone  those  of  8.08x  band  major  the  were  of  same  15)  which would  rejected  as  two  the  spots  observed  at  8.80  at  1705  cm  - 1  ,  ^-unsaturated on  a and  give  To  place a  a  this  structure  for  ring  1745  cm-1  15  to  ketones (C).  of  the  The  basic hours.  with  It basic  (64)  R^  protons while i . r .  two spectrum  corresponding  C=C  ring  spectrum  five-membered  5  the  solvent  gel)  groups,  a strong  (E)  of  (three  8.94x.  strong  compound  for  n.m.r.  methyl and  to  c o n c l u s i o n on  (silica  singlets  and  the  five-membered  (F) d e s c r i b e d p r e v i o u s l y .  six-membered  cm"1  oxidation  suspension of  The  the  ring  1640  medium  evaporation  ketones.  subjecting  at  acidic  t . l . c .  vinyl  stretch,  while  unconjugated  to  by  on  at  (E)  five-membered  temperature  Two  intensity  a  the  material.  protons.  carbonyl  to  room  followed  clearly  ketone  observed  (E)  with  to  obtained  led  at  was  speculation that  under  attibuted  * , £ - u n s a t u r a t e d ketone have  ketone  treated  starting  medium  absorption  the  product.  ether  olefinic  ketone  product  wet  showed  characteristic of  the  therefore  which  to  band  c o r r e l a t i o n between  conjugation  was  former  saturated  The  ring  filtration  s i n g l e t s were  sharp  five-membered  1600  and  cm"1.  a minor  in  by  absence of  methyl  exhibited  I)  The  s t r e t c h was  However,  mixture  .  presence of  support  undergone  ketone  product  the  full  (F) a s  grade  to  900  at  CH^-C^H^. had  - 1  ring  C=C  a five-membered  alumina  similar  indicated each)  the  A weak  provided  ketone  cm  1705  i n d i c a t e d the  bending  (E)  the  at  five-membered  (F).  entity of  <*,£-unsaturated  a  frequency  afforded  (C)  terminal  firmer  of  out-of-plane  2  n.m.r.  shoulder  at  seemed most conditions  and  However,  a  ring  stretch  Enol  to  (59) (65) both  likely was (Scheme  was  -  structures  (57)  and  (58)  corresponding  enones  show  spectral  data  When  reaction  was  the  allowed  to  with  and  (Scheme  (67)  from  6).  vinyl  8.32T  the  distinct  C=C  stretch spectrum  246  nm  that  (e  Fieser  weight  (G)  of  202.1721, for  the  and  was  which  composition  (63),  discussed (B)  and for  10  doublets  at  would  3.79  account  methyls  could  observed  be  of  a methanol  10  ) while  Fieser  and  for  trifluoride  hours for  in  the  solution  a diene  both  H,  as  their  will  (G)  etherate  (G)  was  structures double J  (66)  bond  was  = 6 Hz)  (Figure  singlets  at  and  8.97  9.09T.  and  infrared  of  8.26  NO  spectrum.  displayed the  an  The absorption  correlation  of  o n riu  predicted by  at  (2  c a l c u l a t i o n according to  on  '  the  those  (C)  above.  4.73T  for  for  respectively,  boron  appropriate  tertiary  in  and  c i s - d i s u b s t i t u t e d carbon-carbon  determined  is  those  were  representations  (62)  temperature  room  c Woodward,  and  at  groups  two  likely  compound  The  methyl  and  at  (61),  -  between  n.m.r.  H),  maximum  and  data  16).  (6  ultraviolet  equally  consistent with  spectral  inferred Two  (60)  proceed  obtained  are  152  high  £  239  nm.  r e s o l u t i o n mass  c l o s e agreement  with  the  The  molecular  spectrometry  value  of  202.1709  to  be  expected  C-^H^* 31  Treatment methanol  of  provided  compound  (B)  with  6 N  the  compound  (G).  same  atmospheric  pressure with  olefin  n.m.r.,  (A)  with  (Scheme  occurred. double  16).  g . l . c .  by  using  data  1,4-addition  effect the  t . l . c .  selective  homogeneous  acid  Hydrogenation  p a l l a d i u m on  and  Presumably  Attempts to  bond  10%  hydrochloric  charcoal  as  identical of  catalyst  of  this  catalyst  to  hydrogen  reduction  of  in  to  the  those the  of  refluxing diene  at  afforded compound  diene  had  disubstituted  tris-(triphenylphosphine)-  32 rhodium hydrogen  chloride pressure  (Ph3P)3RhCl also  failed  in and  dry only  benzene  under  starting  one  material  atmosphere was  of  recovered.  an  -  153  -  (38)  (52)  SCHEME  16  -  1  54 -  -  In  spite  conclusion  of  all  could  particular,  it  the  not  [ endo-fused. synthetic to  is  project  possess  The  It  the  suspend  2  the  could  be  firmly  studies  on  this  to  61 Idecane  '  to  discussed above,  structures  possible  note  skeleton,  that  an  (41)  starting  as  alternative  which (61)  and  desired  (+)-9-Acetoxycamphor  if  been  the  diene  Failing  to  was (68)  to  biogenetic-type  albene  the  exo-  of  considered  Lansbury  therefore  (Scheme prove  or  our  was  by  would  cyclopentane  was  albene  In  17)  this  synthesis  if we  of  et  a l .  be their  decided  albene  to  (1).  17  (1)  considered was  (A)-(G).  stage  'confirmed' (66)  definite  formed,  this  de-isopropylation  potential  material  whether  t i l l  had  established.  route  up  no  compounds  determine  SCHEME  Instead  of  trisnorsesquiterpenoid  (1)  ketone  for  the  natural  structure  precursors  formation  been  pertinent  *,e-unsaturated  useful  about  5,2,1,0  the  -  investigations  be made  had  155  again  using  (Scheme  initially  (+)-9-bromocamphor  18).  prepared  by  refluxing  a  33 solution  of  (distilled achieved used  as  (+)-9-bromocamphor from  after solvent  Reduction  of  acetic 7  days the  (41)  anhydride). of  reaction.  substitution  (+)-9-acetoxycamphor  Wagner-Meerwein  rearrangement  of  and  potassium  acetate  Only  50% c o n v e r s i o n  When  dry  reaction (68)  alcohols  of  acetic  (41)  to  acid (68)  hexamethylphosphoramide  was  with  in  completed  sodium  (69)  in  24  borohydride  afforded  was  was  hours. followed  by  10-acetoxycamphene  -  (41)  156  -  (68)  (69a) (69b)  exo-OH endo-OH p-TsCl C H N 5  7  (74)  (75)  (76)  (1)  SCHEME  18  5  - 157  which  (70)  singlets  exhibited  the  c h a r a c t e r i s t i c camphene  5.18 a n d 5.43x, a s w e l l  at  (C=C)  and  cm"1  basic  conditions  895  -  as  infrared  (=CHr, o u t - o f - p l a n e  provided  n.m.r.  olefinic  proton  absorptions  at  1660 c m "  Hydrolysis  of  (70)  bending).  (+)-10-hydroxycamphene  which  (71)  was  1  under  oxidised  34 with  the  pyridine-sulphur  10-oxocamphene  (72),  trioxide  complex  c h a r a c t e r i s e d by  the  1 H, -CH0), 5.16 a n d 5.56 ( t w o  broad  (broad  allylic  signal,  tertiary  methyl  The  reacting  an  allylic  n.m.r.  signals  at  to (singlet,  x 0.50  1 H e a c h , =CH ), 7.30  singlets,  2  methine),  10-hydroxy-10-vinylcamphene  aldehyde alcohol  Designating  dimethylsulohoxide  and  (singlet,  8.98  3  H,  ).  desired  by  bridgehead  1 H,  in  the  with  (72)  entity  protons  in  vinyl  (73)  magnesium  was  evident  was  (73)  obtained  bromide. from  its  The  in  83%  presence  n.m.r.  yield of  spectrum.  as  HO  the  following  doublets, Hz),  of  doublets  BM  at J  A X  at  =  and  1 7  was  1 H)  10  J  assignments  H z  the  doublets  a n c  '  a  ^ -  4.85x ( d o u b l e t =  2 Hz).  5.91x  spectrum  to  methine  of '  due  The  (1 H, showed  J  v  of  l "  could H^  l c  two  :-  to  ( J ^  H^  4.08x ( d o u b l e t  protons  H  = 4 Hz).  g  ( J ^  of  = 17  Another  doublets  of  J  g x  = 2 Hz,  doublets,  while  1 H, J  A M  doublets Hz),  -  the  H^  =  10 H z ,  signal JftB  terminal  x  = 2 Hz, methylene  J  g x  = 2 Hz).  singlets  at  of ( J ^  Furthermore  occurred =  =  doublet  2 Hz,  -CH 0H m e t h i n e d i s p l a y e d a d o u b l e t o f  = 4 Hz,  H^  one-proton  4.67x w a s a s s i g n e d t o Hg w i t h  coupling  allylic  M X  coupled  proton at  be made  2 Hz,  multiplets the  5.13 a n d 5.21x, a  -  bridgehead  allylic  9.05T.  A C=C  1660  - 1  c m  930 c m  - 1  reagent. epimeric  in  alcohol  (1)  of  medium  (73)  and t h a t  mixture  of  albene  of  by  -CH=CH2 at  high  the value  s u s c e p t i b l e to spectral  was f o r m e d ,  data  singlet  was o b s e r v e d occurred at  900 c m  - 1  .  attack did not  995 and  spectrometry  calculated  that  at  and t h e  r e s o l u t i o n mass  revealed  both  for  faces  by the v i n y l  of  was a  the  Grignard  i n d i c a t e whether  there  at  The low  i o n o f m/e 178  178.1358  or whether  methyl  an  predominance  other.  (73)  (1)  intensity  -C=CH2  molecular models  the above  the  of  and a t e r t i a r y  indicated a molecular  were  as a s u i t a b l e of  bending  was d e t e r m i n e d  of  (72)  over  Acetylation considered  absorption  i n accordance with  However,  one i s o m e r  framework  of  Examination group  7.32,  spectrum  be 1 7 8 . 1 3 5 2 ,  aldehyde  at  strong),  weight  C-|2H^g0.  of  mass  -  signal  the out-of-plane  (broad,  molecular to  infrared  , while  resolution  methine  1 58  gave  (+)-10-acetoxy-10-vinylcamphene  precursor (Scheme  for  the cyclisation  to  the  (74)  carbon  19).  (75) SCHEME  (76) 19  w h i c h was  -  Treatment temperature  of  for  2 hours  chromatography by  (5:1 the  allylic  provided  weight).  expected  acetate  a  acetate-formate  in  by  with  98-100%  formic  aqueous  work-up  and  c o l o r l e s s waxy spectral  product  which  -  (74)  followed  N.m.r.  cyclised  159  the  data or  (75)  allylic  retained.  singlet  at  observed An  2.15T  The  8.00.  The  ester  H  the  analogous  of  doublets,  (doublet  of  multiplets,  5.25x and  the  sharp  intense and  two  singlets  strong  bands  at  a formate,  assigned  to  absorptions and  to  the  H^),  1 H,  one at  8.90  (Figure  carbonyl  therefore  8)  was  out-of-plane  showed  7)  (H)  product  methyl  was  1 H,  = 6 Hz.  A  two  to  a  (I)  nor  (H)  (I)  was  was  an  hydrogen  singlet  s i m i l a r to  observed be  allylic  that  at  methyl  -CH=CH . ?  The  at  these  977  mass  at methine  groups.  to  cm"1  The  analyses.  The of  4.82  H^),  -CH00CR  1735 c m - ' ' .  band  1 H,  multiplet  C-O-C absorptions  and medium  of  x  saturated  support  (74).  RC00CH -),  multiplets, broad  at  (doublet  x 4.18  tertiary  further  could  of  :-  of  to  was  broad  bending  offered  (doublet  provided  stretch  A  a colorless oil  a formate  acetate  4.0-5.Ox  assigned  9.11  1170 cm"1  respectively.  column  chain  (doublet,  and  and  gel  neither  major  room  (+)-10-acetoxy-10-vinylcamphene  Hg), 4.85  proton  1240 and  between  4.53  J g ^ = 17 H z ,  integrating  infrared A  10 H z ,  1 H,  was  silica  at  B  (Fiqure  material  interpretation  side  and  that  The  a three-proton  signals  starting  of  =  with  the  doublets  where  spectrum  together  pattern  for  n.m.r.  (H)  indicated (76).  RCOO  was  solid  acid  broad  an was  spectrum  acetate  Figure  8  I.R.  Spectrum of  Compound  (H)  -  exhibited  a  molecular  weights  m/e  224,  peak  220,  M+-CH3C00H, The except 9.llx  low  of  206,  intensity  formic  178  and  M+-(CH3C00H  minor  that for  of  product  the  The  acid 160  (I)  m/e  266 w h i c h  and  the  starting  were  had  interpreted and  n.m.r.  methyl  same  -  at  + CH2=C=0),  tertiary  (H)].  162  singlets  products  (H)  (74)  acid  (1:1),  amount  acid  and  or  The  (H)  (95%)  n.m.r.  indicated  to  that  carbon-carbon n.m.r.  hydrolysed  was  i . r . an  the  double  doublet  9.02  were  2 N  (74).  Peaks  to  and  of  respectively.  those 9.10T  obtained  of  (H)  [cf.  on  formic  sulphuric  at  M+-HC00H,  + CH3C00H),  a mixture  of  with  potassium  colorless crystals  9),  of  with  (I)  the  M+-CH2=C=0,  similar  at  sum o f  and  heating  acid  acid  8.90  in  and  acetic  formic  (1:3).  give  it  one  catalytic  was  (Figure  particular,  an  a  chloroform  Compound ethanol  with  were  and  (+)-10-acetoxy-10-vinylcamphene  as  very  the  material  M+-(HC00H  data  was  10)  unsaturated  hydroxyi  bond  of  (Figure  such  doublets  and  diol  groups that of  (J),  the  m.p. mass  with  was  hydroxide  in  99-101°C spectra  allylic  to  a  at  5.76x,  stage).  (J)  clearly  weight  196.  In  monosubstituted  -CH^OH-CH^CH^Hg  doublets  (hot  of  molecular  refluxing  methine  with  =  exhibited  5 Hz  and  i  ^AX  =  ^BX  multiplet In acids  =  2  H z  at  employed  T  ^  e  o t  *  i e r  a  ''coh0"'  w a s  to  attain  better  understanding  (+)-l0-acetoxy-l0-vinylcamphene as  saturated,  showing  a  -CH0H  6.47x.  order  on  '  the  catalyst.  An  oily  of  (74),  the  action  of  trifluoroacetic  acetate-trifluoroacetate  (K)  carboxylic acid  was  was  obtained.  i  Again as 11).  a  the  presence  saturated The  most  of  the  R'COOCH-  entity  prominent  trifluoroacetate  allylic  carbonyl  was  features  ester  side  evident of  absorption5  chain  from  the  RC00-CHx-CHM=CHAHB n.m.r.  spectrum  the  i . r .  spectrum  (Figure  at  1780  cm"1  an  and  12)  acetate  as  well  (Figure were  a  carbonyl  4000  3000  2000  1500  CM-  mill M ill I I I i | I I I I 1 I I I , 1 I I ,1 I I, I 1.1 L _ l 1  1000  1  i  900  111111111111111  800  12 WAVELENGTH Figure  10  I.R.  Spectrum  of  Compound  (J)  (MICRONS)  700  i i i i I i i i i i | i i.i 1 \  13  14  i i ,  15  4000 100  3000  • ••<!•• , .1  1500  2000  CM-'  I i • • i I i I i 1 i I ,i I i. I 1 . 1 1 , 1 1  1 | I  ,1  1000 i  i i i I i i  900  ii I  ft  80  i  i  i i I i l  800 l  l  700 i i I I  I  i i ' I I l  L  TO  ttSK  Z 60 <  S  40  < 20 1  0  8 WAVELENGTH  F i g u r e 12  I.R. Spectrum o f Compound (K)  10 (MICRONS)  1  12  13  14  15  -  absorption a  at  colorless  diol  cm"1.  Hydrolysis  c r y s t a l l i n e product  c a n be  concluded that  trifluoroacetic acid  acid  molecule  (cf.  Scheme  with  instead  19).  resulted  of  the  Diesters  under  spectral  anion  CF^)  in  R=H (H),  compound  or  depicted  and  (K)  have  not  been made.  (82).  In  or  with  98% f o r m i c data  in  a  acid  but,  similar to  basic  data  conditions  identical  allylic  overall  and  (K)  (Scheme  as y e t , Diol  20  to  fashion,  (73)  of  a  provided  those  of  most  to  or  reasonable  have  the  10-hydroxy-lO-vinylcamphene  with  in  low y i e l d which  structures  (83)  and  (83)  When  chloride Careful  6 drops)  in  chloroform  a c r y s t a l l i n e compound examination  of  the  or  (85),  n.m.r.  formed  (76) by  CF^)  and  structures to  each  structure (73)  reacted  displayed (84).  (84)  (+)-10-acetoxy-10-vinylcamphene  (70%,  and  assignments  therefore  formic  and n u c l e o p h i l i c  R=H  structural  might  (75)  probably  (79,  be  with  carboxylic  compounds  Both  appear  a diformate  agreement  to  (74)  rearrangement  20).  definite (J)  acetate  addition  were  skeletal  Scheme  provide  reasonable  of  an  subsequent  (I),  (81)  spectral  with  in  (I)  a carboxylate  from  (74)  (H),  attack  acid  (K)  desired cyclisation  of  for  of  treatment  protonation  (80,  -  (J). It  or  1740  167  (74)  with m.p.  spectrum  was  boron  treated  with  trifluoride  85-89°C  (hot  of  (Figure  (85)  in  stage), 13)  perchloric methylene was  obtained.  revealed  the  -  168  -  (82) SCHEME  20  - 169 -  presence 1 H,  of  three  olefinic  J  = 17 H z ,  12 H z ,  2 Hz),  a n d 4.99  (doublet  protons  6 Hz), of  :-  x4.04 ( d o u b l e t  (doublet  4.94  triplets,  of  1 H,  J  of  doublets  triplets,  = 17 H z ,  1 H,  2 Hz).  of  J  doublets,  = 12  An  Hz,  acetate  i  methyl  singlet  detected. tertiary proton  was o b s e r v e d  The t h r e e - p r o t o n methyl  group.  singlet  CHg-C-O-  at  7.96T b u t n o - C H O A c m e t h i n e  singlet  The most  a t 8.50x w h i c h  functionality.  a t 8.97x w a s r e a d i l y  interesting  might  feature,  indicate  The m u l t i p l e t  at  a vinyl  signal  could  assigned  however, methyl  to  a  was a  group  6.75x c o u l d e i t h e r b e  be  three-  or a attributed  i  to  an a l l y l i c  (Figure  methine  or to  a -CHOH p r o t o n  14) d i s p l a y e d h y d r o x y i  definitive (74) w e r e analysis  evidence  a molecular results  Hydrolysis afforded  for  at  a crystalline diol  product  i n t h e mass  in accord with  (85) w i t h  the infrared  potassium (86), m . p .  spectrum  3600 a n d 3500 c m  a hydrated  a t m / e 238  which were of  absorptions  (85) b e i n g  peak  since  of  hydroxide  The  most  acetate  and t h e  micro-  C^H^gO^.  in refluxing  79-84°C, w i t h  .  allylic  spectrum  the formula  - 1  the  ethanol  composition  i C  12 20^2* H  inferring  15) at  signal  ^°  tertiary  that  the hydroxyi  positions.  (8.50x) i n (85) s h i f t e d (cf. group  Figures  could  be o b s e r v e d groups  of  in the n.m.r.  (86), a n d h e n c e  Moreover,  the position  up-field  t o 8.87x a f t e r  13 a n d 15), a n d t h i s  indicated  of  one o f  spectrum that  (85), w e r e  the methyl  hydrolysis  the presence  of  (Figure  to diol  of  a  signals  (86)  CHo-C-OAc  i n (85). X-ray  crystallographic  analysis  of  diol  (86) d e m o n s t r a t e d  that  2-exo,3-exo-dihydroxy-2,3-dimethyl-4-endo-vinylbicyclo[3,2,1]octane  i t was (86)  oc (cf.  stereodiagram  intramolecularly  analysis  17).  The two v i c i n a l  h y d r o g e n - b o n d e d a s e i t h e r C(2)-0-H  C(2)-0----H-0-C(3). X-ray  i n Figure  Precursor  was t h e r e f o r e  (85) w h o s e most  likely  crystalline  hydroxyi  groups  were  0-C(3) o r form  was t o o f i n e  for  the corresponding 2-exo-acetoxy-3-  A-9A-C A-OAT  6 HzFt H  ^ • 9 9 T  17 Hz  17 H z 12  12 H z r i  f?^ A  F i g u r e 13  N.M.R. Spectrum (100 MHz) o f Compound (85)  Figure  14  I.R.  Spectrum of  Compound  (85)  Figure  15  N.M.R.  Spectrum  (100  MHz)  of  Compound  (86)  4000  2000  3000 ''i  ' ' ' ' ' ' '  I  I  u  i  1500 i  i  i  i  i  i  .1  i  CM'  i  i  i  i  1000  700  800  900  l , i  (JO  7  8  WAVELENGTH F i g u r e 16  I.R.  Spectrum o f Compound (86)  9  10 (MICRONS)  11  12  13  14  15  -  174  -  - 175  -  e x o - h y d r o x y compound formed by a c i d - c a t a l y s e d  r e a r r a n g e m e n t o f the  b i c y c l o [ 2 , 2 , l ] framework o f 1 0 - a c e t o x y - 1 0 - v i n y l c a m p h e n e (74) t o the bicyclo[3,2,l] skeleton.  O t h e r i s o m e r s o f (85) m i g h t a l s o be  i n the p r o d u c t m i x t u r e o b t a i n e d  by a c i d t r e a t m e n t o f  present  (74).  (86)  ( + ) - 1 0 - A c e t o x y - 1 0 - v i n y l c a m p h e n e (74) remained i n t a c t on t r e a t m e n t w i t h 36 a c e t i c acid or p i c r i c acid-nitromethane, m i x t u r e s were o b t a i n e d  while intractable  polymeric  with stannic c h l o r i d e , p_-toluenesulphonic  acid,  p h o s p h o r i c a c i d , o r boron t r i f l u o r i d e e t h e r a t e as c a t a l y s t . Our p e r p l e x i t y a t the r e l u c t a n c e o f (74) to undergo a c i d - c a t a l y s e d 2  c y c l i s a t i o n to the t r i c y c l o [ 5 , 2 , 1 , 0 by the.-timely  6  ' J d e c a n e framework was  quickly dispelled 37  p u b l i c a t i o n of Baldwin's empirical r u l e s f o r r i n g c l o s u r e .  In terms o f B a l d w i n ' s n o t a t i o n s , the d e s i r e d c y c l i s a t i o n o f c a t i o n (77)  to  -  (78) on  is  a 5-endo-trig  stereochemical  In  the  plausible this since  allowed  the  amendment  conversion  to  application the  scheme of  enyne-acetate  this  5-endo-dig  of  synthetic  compound  cyclisation  (72)  *  which  -  is  disfavored  for  the  first-row  to  Baldwin's route (87) the  rules0'  involving was  albene  provided  number  the  breaking  5 refers  and  dig  the  carbon  refer  bond to  atom  is the  to  the  considered framework  as  an  would  with  a  (74).  In  intermediate involve  an  process.  (88)  size  of  the  ring  endocyclic  to  the  smallest  trigonal  undergoing  us  diene-acetate  (87)  The  elements  grounds.  event,  alternative  process  176  the  and  digonal  closure.  formed.  Endo  so-formed  geometries,  indicates cycle.  respectively,  that Trig of  -  177  -  At t h i s stage of our synthetic s t u d i e s , however, the a l t e r n a t i v e 9  structure (31) f o r albene was proposed by Kreiser and Janitschke l a t e r revised to (17) by the same w o r k e r s  10  ( c f . Introduction).  and was We decided  therefore, to synthesise enyne-acetate (89) and evaluate i t s potential as a synthetic precursor of albene (17).  OAc  (89)  (90)  (17)  The b i c y c l i c enyne-acetate (89) was prepared from (93) by the route o u t l i n e d in Scheme 21. camphor d e r i v a t i v e s in synthetic  38  (+)-8-bromocamphor  The importance of 8-substituted  and mechanistic  38b 39 ' studies has been  f u l l y recognised and the quest f o r t h i s group of compounds was launched as e a r l y as the end of the nineteenth century.  Although racemic 8-bromo- and 39a c  8- iodo-camphors have been synthesised by tedious routes,  '  step conversion of (+)-camphor (35) into (-)-8-iodocamphor  has been  achieved,  1 2 a  '  f , 3 8 a  '  4 0  and a twelve-  our laboratory f u l l y r e a l i s e d the necessity f o r a  more e f f i c i e n t synthesis of o p t i c a l l y a c t i v e 8-substituted camphor.  By  considering the mechanistic r a t i o n a l i s a t i o n which can be made to explain 9- bromination (and the absence of 8-bromination) when  (+)-3-bromocamphor  (39) i s treated with bromine and chlorosulphonic acid ( c f . Scheme 10), an e f f i c i e n t three-step synthesis of (+)-8-bromocamphor 1o accomplished in our laboratory. a v a i l a b l e (+)-3-bromocamDhor  14  (93) has been  According to t h i s scheme, commercially was converted to (+)-3,3-dibromocamphor  (91),  -  (97)  178  -  (96)  (95)  (94)  C H N-Cr0 -HCl 5  5  3  OH (17)  (100)  OAc (90) R = H or HCO  SCHEME  21  -  which  was  then  treated  3,3,8-tribromocamphor latter  bromination  Reduction a c i d  1 3 b  '  yield.  of  1 8  The  (92)  with  bromine  (92).  reaction with  provided  chlorosulphonic acid  [A  proposal  for  is  shown  Scheme  desired  of  -  and  zinc-hydrogen  the  structure  179  (93)  in  the  bromide  mechanism 22,  a  or  (+)-8-bromocamphor  has  been  confirmed  by  to  involved  (cf.  Scheme  zinc-glacial (93)  in  X-ray  provide  about  in  the  10).] acetic 38%  overall  crystallographic  42 analysis.  WM=Wagner-Meerwein rearrangement 2,3 Me = 2,3-methyl shift SCHEME 8-Acetoxycamphor with 72  potassium  hours.  point  of  obtained  If HMPA  (94)  acetate this  in  was dry  prepared  accompanied  for by  24  by  heating  (+)-8-bromocamphor  hexamethylphosphoramide  substitution  (220°C)  22  r e a c t i o n was  hours  a mixture  only of  (HMPA)  to  110°C  (93) for  c a r r i e d out  at  the  negligible yield  of  (94)  was  products  (cf.  preparation  decomposition  boiling  -  of  (+)-9-acetoxycamphor  of  (94)  dry  followed  pyridine)  (68),  180  Experimental).  by Wagner-Meerwein  gave  -  Sodium  rearrangement  9-acetoxycamphene  borohydride  reduction  (methanesulphonyl  (96) w h i c h was t h e n  chloride-  hydrolysed  to  the  46 corresponding  alcohol  Oxidation  of  (97)  i n 46% o v e r a l l  (+)-9-hydroxycamphene  yield  (97)  to  (Scheme  21).  9-oxocamphene  (98) was  43 achieved  using  pyridinium chlorochromate.  Treatment  of  aldehyde  (98)  with  44 the  lithium acetylide  the  crude  75%  overall  the  structure  addition  propagylic 1  presence  of  (3320  - 1  H,  J  a n d C^C  spectrum.  expected  the product  (silica Having  structure  (90)].  to  unsaturated (L)  interpreted  :-  T 4.70 1  H each,  (singlet,  (89) was f u r t h e r  3 H,  a mixture  of  1  H,  =CH0),  by  observed  by  g . l . c .  (Column  A,  = 2  The C=C-H  in  the was  130°C)  and  analyses.  Treatment n.m.r.  to  of  to  investigate  the albene  (89) w i t h  was h y d r o l y s e d ,  which  without  framework  97% f o r m i c  [eg.  acid  had two t e r t i a r y  :-  n.m.r.  4 5  (M) w h o s e  (CC14),  tricyclic gave  methyl  spectral  T 5 . 9 0 (broad  of  an  oily  the structure  p u r i f i c a t i o n , under  a c r y s t a l l i n e hydroxyketone  9-acetoxy-9-  the p o s s i b i l i t y  s p e c t r u m was c o n s i s t e n t w i t h  acetate-formate  as f o l l o w s  of  of  groups.  basic data  singlet,  conditions were 1  H,  in  with  7.79  the  epimeric enyne-acetates  (89) was homogeneous  J  CH3C00-).  supported  of  (89)  agreement  (doublet,  (2150 c m " 1 ) s t r e t c h i n g a b s o r p t i o n s  enyne-acetate  whose  (L)  provide  in  ( 8 9 ) was i n f u l l  singlets,  and 8 . 0 4  ( 8 9 ) we p r o c e e d e d  this  Compound  group  by a c e t y l a t i o n  9-acetoxy-9-ethynylcamphene  spectrum of  CEC-H),  followed  s y n t h e s i s e d and e s t a b l i s h e d t h e s t r u c t u r e  cyclising  an  provided  and 5 . 4 5 (two  Although  gel)  ethynylcamphene  product  5.27  = 2 Hz,  infrared  t . l . c .  complex  the desired enyne-acetate  an e t h y n y l  )  (99)  The n . m . r .  -CHOAc),  (doublet,  cm  product  yield. of  ethylenediamine  Hz,  -  -CHOH), and  6.90  9.13  (OH),  (two  1715  at  signal,  singlets,  (C=0),  absorption to  (broad  and  1715  a five-membered  group.5  Thus  both  formates  (90)  and  structures would acid  for  involve  rearrangement  could  ring  ketone  (102)  of  (M)  with  formate  was  Formation  cyclisation  followed  converted  the  (N)  showed  would by  to  ring  (CCl^),  u  of  be  ring a  infrared  ketone  of  albanone  ketone  was  (34)'which  reported is  (cf.  Introduction),  (N).  Establishment  is  being  pursued  in  the  to  structure  could also of our  have  the  be  a  a  ketone  formate  enyne-acetate  (N)  oxidation  by  via  a  ketone  in  the  (Scheme  absorption  carbonyl  assigned to a  reasonable  structures  laboratory.  of  or  enol  (90)  (89)  under  Wagner-Meerwein  at  sequence 23).  1718  structure  The  cm-1  (104).  which  stretch albanone  at by  1712  cm  (M)  2 ,  Kreiser et  representation for  hydroxyketone  and  is  However, -1  since  3500  x  reasonable  enol  formed  a  hydroxyl  hydrolysis  of  m  carbonyl  to  are  8.87  cyclisation.  a carbonyl  six-membered  by  respectively,  (102)  OH),  six-membered  formed  23).  D20,  the  hydrogen-bonded  (103),  (L)]  a  of  i . r .  particular,  d e s u l p h u r i s a t i o n , and  spectrum of  consistent  and  (Scheme  (101)  In  w h i c h was  addition  methyls);  assigned to  5-endo-dig  enol  cation  dithioketalisation,  be  [compound  desired  while  tertiary  (C-0).  (100)  (M)  -  d i s a p p e a r e d on  cm"1  cm"1  Hydroxyketone  infrared  1090  compound  conditions  H,  3 H each,  ketols  the  1  181  al  compound  ketone  (N)  -  (104)  W M =Wagner~Meerwein  182  -  (103)  (34)  rearrangement  SCHEME  23  -  183  -  EXPERIMENTAL  General  See  Experimental,  Part  (+)-3,9-Dibromocamphor  The  procedure  bromocamphor  (39)  (21g,  0 . 0 9 mole)  water  bath.  of  I  (40)  Corey  (p.60).  1 2 - 1 6  etal_  (Aldrlch,  1 4  m.p.  Bromine  ( 7 m l , 20 g ,  stirring.  The e x o t h e r m i c  bath  f o r T hour  and then  quenched  by p o u r i n g  stirring  until  onto  sodium  and washed  with  (300  The crude  ml).  chloride, part  of  crystals  the methylene  dibromocamphor  (40)  m.p.  l i t .  M+107,60). white  solid  crystals  recrystallised  anhydrous  (14.2 1  2  a  g,  m.p.  Concentration (6%), m.p. from  After  provided  50% y i e l d ) ,  of  I*]*  the mother  153-156°C.  methylene  m.p.  Part  3  It  by an was  then  Methanol  of  156-158°C  chloride-methanol  (hot  afforded  to  give  been  water  methylene was added  and  until  (+)-3,9-  (c 1 0 . 1 ,  the f i r s t  had  filtration  an a s p i r a t o r  needles  +136°  with  (50 m l ) , and in  portions ice-water  bromine  dissolved  under  liquor of  in several  excess  sulphate.  white  CH30H))  by an i c e -  was c o l l e c t e d by  pressed dry,  (+)-3-  i c e was added  hydroxide  sodium  of  (c 5 . 3 ,  was c o o l e d  Additional  the product  151-156°);  +132°  0  for 3 hours.  c h l o r i d e was e v a p o r a t e d  Filtration  solution  was added  mixture  granular.  was then  2  A  m l ) was c o o l e d  mole)  ( 3 0 0 m l ) , 5% s o d i u m  over  appeared.  became  (16  bath  ice.  bisulphite,  water  and d r i e d  152-156°,  by a w a t e r  the product  with  0.13  reaction  crushed  M  75-78°C,  in chlorosulphonic acid  with  destroyed  was f o l l o w e d .  1 5  stage)  ( l i t .  1 4  CHC13),  ( l i t .  1 4  another  1.8  g  c r o p was colorless  needles,  -  m.p. J  158.0-158.5°C  = 5 Hz,  and  1.5  6.76  C(4)  Hz,  (hot  methine),  stage);  -CHBr),  (doublet,  1  H,  8.75  184  J  and  -  (CDC13),  x  6.36  (doublet  =  Hz)  10  9.00  5.53  of  doublets,  (-CH^Br),  (two  (doublet  7.30  singlets,  6 H,  1  of  H,  doublets,  J  =  10  Hz,  (triplet,  1  H,  J  tertiary  =  methyls):  1  H,  1  Hz)  5  Hz,  u  v  ma X  (CC14), (M+),  2950  310  (broad,  (M+),  A minor  medium,  308  (M+),  product  of  232, this  tribromocamphor  (47),  camphor  sublimation  of  the  ["I25  (40)  by  residue +82.6°  (doublet, 8.64  1  and  (C=0);  3.35;  (c H,  for Br,  392  The  dibromocamphor (20  ml)  and  was  bubbled  resulting  in  to  x  C,  30.85;  structure  (41  the  (40)  )  1  2  (5  g,  the  1  4  ,  16 zinc  exothermic  filtration.  The  filtrate  bicarbonate,  saturated  69,  3.74  J  methvls);  3.35;  Br,  was  198-199.5°C;  H,  -CHBr2),  5 Hz, „  C(4)  309, Found  5.29  methine),  (CHClJ,  311,  61.65.  compound  1  =  u  (M+),  peak).  crystallisation  had m . p .  H,  312  (+)-3,9-dibromo-  (singlet,  386  (base  subsequent  (47)  1  41  m/e  (+)-3,9,9-  of  and  (triplet,  of.this  1  1754  307.  cm"1  Anal,  :  C,  30.95;  confirmed  by  X-ray  H,  5  of  Corey  mmole) powder  reaction  an  removal  torr)  (M+),  H,  81,  C=0);  1 7  procedure  stirred with through  '  by  ),  3  strong,  r e a c t i o n was  tertiarv 388  122,  tribromide  (CDCT 7.19  (sharp,  202,  0.01  The  (M+),  analysis.  (+)-9-Bromocamphor  According  :  204,  (140°C,  -CHBr),  390  cm"1  obtained  s i n g l e t s , 6 H,  C^H-^OB^  crystallographic  was  CH.C13);  (M+),  61.40.  230,  acetone.1"^  = 5 Hz,  (two  1750  bromination  which  1.45, J  8.78 m/e  calcd.  from  CH),  brine,  washed and  (7.3  g, for  The with  dried  co-workers,  dissolved  mixture  reaction. was  was  and  112 4  zinc  hours  (+)-3,9-  methylene  g-atom). with  powder  water,  over  in  1 5  was  saturated  anhydrous  chloride  Hydrogen vigorous then  bromide stirring,  removed  sodium  sodium  sulphate.  by  -  Removal  of  solvent  (30-60)  afforded  m.p.  94-95  m.n.  94.0-94.5°C  (c x  0.93,  (doublet,  C°(hot  tertiary  stage)  ( l i t .  1 5  (doublet  1  J  =  10  strong,  u  of  Hz) m  a  m/e  Ethylene  refluxed  with  toluenesulphonic 40  hours.  bicarbonate sulphate which  and  colorless  oil  1.5 J  Hz)  = 1.5  109,  1  1  8.98  2950  crystals  (M+),  l i t .  230  1  2  [-]23  4  J  and  9.26  q,  56%  Hz,  (two  strong, 109,  [ « ]  (c  0.93,  1.5  Hz)  108,  +110°  3 2  and  1750 107,  of  CHC13));  singlets, CH),  yield),  crystals  95-95.5°);  a  = 10  (M+),  (2  provided  +109°  H,  (broad,  mixture  saturated by  6.84  6  H,  cm-1  81  (base  (0.91  g,  4.8  mmole)  was  glycol  (4  ml,  4.4  70  g,  mmole)  2.3  was  cooled,  sodium of  on  solvent  alumina  provided  (CC14),  6.47  (doublet  and  6.93  1  J  Hz,  tertiary 2950  87,  41.  and  methyl), 2870  strong,  H,  9.20  (broad, C-0);  Drying  (activity  x  = 10  of  Hz)  m/e  276  and  over  CH), (M+),  separator  (0.97  Elution (42)  (multiplet,  4 H,  8.70  tertiary  J  = 10  (doublet,  g)  with as  a  halfHz, 3  H,  methyl);  1200-1000  cm"1  274  195  (M+),  sodium  sodium  ketal  (-CHgBr), 3 H,  liquid  H,  and  p_-  saturated  III).  ethylene  6.21  benzene  anhydrous  a yellow  grade  in  water  with  multiplets, 1  (singlet, strong,  mmole)  washed  9-bromocamphor  83% y i e l d ) ,  dissolved  a Dean-Stark  was  chloride.  afforded  (doublet,  g,  under  and  -0-CH2CH2-0-),  absorptions, 95,  g,  1 2 a > 1 8  (1.0  removal  (30-60)  (42)  Hz,  (neat), broad  (0.4  chromatographed ether  7  acid  followed  was  (41)  ethylene  The  petroleum  width  232  Ketal  (+)-9-Bromocamphor  for  l i t .  multiplets,  (CCl^),  white  ether  41.  9-Bromocamphor  was  +115°,  D  as  93-95°,  1 5  (-CHgBr),  x  C=0);  (41)  petroleum  recrystal1isation  ( l i t .  [ « J  -  r e c r y s t a l l i s a t i o n from  Further  (hot  methyls);  (sharp, peak),  stage).  6.41 H,  by  (+)-9-bromocamphor  C2H50H)  (CC14),  followed  185  (several (base  peak),  -  9-Iodocamphor  Ethylene  A mixture sodium (50  iodide  of  (28.0  was  heated  mixture  was  then  extract anhydrous  (5.1  g)  with  petroleum  a  which  colorless  (Column  magnesium was  (4.55  -0-CH CHo-0-),  6.58  (doublet,  J  O  methyl), (broad, 109 I,  H,  9.19  =  10  peak),  39.39.  Found  87, :  67,  C,  by  a  with  41.  44.90;  similar  which  8.83  H,  was  procedure  4  1  H, J  (doublet,  calcd. I,  and  3 H,  u  C  1 2  yellow  pale III).  Hz,  H  02I  i g  6 Hz)  = 1  Hz,  bands,  C,  oil  as  analysis  Hz, and  7.08  tertiary  2950  C-0); :  (43)  g.l.c.  1  dried  Elution  ketal  on  J  combined  a  (neat),  v  broad  for  10  reaction  The  half-width =  (HMPA)  and  ethylene  H,  and  water,  grade  homogeneous  methyl);  6.03;  mmole)  cooled  gave  (activity  (several  Anal,  18  ether.  solvent  (multiplet,  cm"1  g,  The  with  9-iodocamphor  tertiarv  and m/e  44.73;  2870 195, H,  5.94;  39.21. (41)  was  was  then  first  converted  ketalised  to  to  9-  9-iodocamphor  ketal.  reaction  (45)  was  1 2 a  Derformed i n  apparatus  which  had  been  round-bottomed  flask  was  fitted  stopper.  of  alumina  (+)-9-bromocamohor  (+)-Epicampherenone  This  on  (-CH0Br),  3 H,  4 days.  extracted  multiplets,  1200-1000  Alternatively,  ethylene  Hz)  (5.0  sodium m e t a b i s u l p h i t e ,  provided  of  for  Removal  6.20  (42)  hexamethylphosphoramide  and  dilute  (CC14),  (doublet  CH),  (base  water  88% y i e l d )  (singlet,  strong,  iodocamphor  g,  x  dry  sulphate.  (30-60)  ketal  nitrogen  chromatographed  ether  £ d  in  under  with  -  ethylene  mmole)  100°C  washed  175°C).  1  182  diluted with  oil  F,  g, to  was  over  (43)'  9-bromocamphor  ml)  ether  Ketal  186  A  solution  of  dried with  the at  fume 140°C  hood  under  overnight.  a condenser,  1-bromo-3-methyl-2-butene  a  nitrogen A  rubber  atmosphere  three-necked septum,  (distilled  from  and  a  anhydrous  -  magnesium  sulphate)  (15  ml,  19.2 in  the  flask.  Nickel  syringe  while  45-55°C  for  and  deep  A  the  solution  DMF 24  was  the  2 hours. red  of  by  after  syringe.  which  it  was  (30-60).  The  saturated  brine  and  with  oil  w h i c h was The  (10  yellow  oil  activity 0.01  at  to h  proton),  (singlet,  room  grade  35% y i e l d ) ; vinyl  ketal  (3.5  Torr)  6 H,  crude  hydrolysed  crude  droos)  the  which  III,  8.39  and  tertiary  (c 8.34  diluted  1730  109  (base  peak),  10.98.  Found  H,  (broad,  for  24  purified ether  4.88, (two  95, :  C,  81,  C=0), 69,  82.00;  67, H,  was  mixture  was  g,  11  was  in  water,  to  and was  ethylene  (40  ml).  in  dry  55-60°C  for  extracted  (44)  as  with  with  Removal  ketal  to  Torr)  (DMF)  washed  sulphate.  by  heated  mmole)  heated  extract  sodium  added  d i s t i l l a t i o n (0.5  (3.55  with  organic  acetone  hours. by  (30-60))  water,  of a  yellow  broad u  v  840  10.94.  work-up  afforded  (90-110°C,  a  colorless oil  (CC14),  4.91  6 H,  2950  and  (0.8  (multiplet,  vinyl  acid  a  distillation  singlets,  g, 1  H,  methyls),  9.17  (broad,  strong,  2875  X  (broad,  41.  hydrochloric  (alumina,  as  (neat),  6 N  chromatography  and  (45) T  and  Usual  column  CHC13);  methyls);  strong,  placed  purification.  Mia  CH),  was  dimethylformamide  mixture  (+)-epicampherenone  +84.4°  7  benzene  230 mmole)  by  (43)  stirred with  petroleum  provide 2  was  dry  reaction  dry  ketal  anhydrous  temperature  g)  in  epicampherenone  was  g,  removed  combined  without  (44)  in  39.6 The  reaction  cooled,  ether  afforded  then  dissolved  petroleum  solvent  ml,  ethylene  was  mmole)  stirred.  The  dried  130  (30  was  was  -  on  Benzene  residue  g,  '  9-iodocamphor  added  hours  carbonyl solution  187  Anal  medium, calcd.  =CH);  for  C  1 5  m/e H  2 4  0  220 :  C,  (M+), 81.76;  135,  -  9-p_-Tol u e n e s u l p h o n y l camphor  A mixture  of  Ethylene  9-iodocamphor  sodium £ - t o l u e n e s u l p h i n a t e  (4.5  (20  for  ml)  diluted was  (30-60)  on  hours.2'' with and  over  Elution  drying  g, at  room  2.25  7.17 7.57  tertiary  which  temperature  anhydrous  g)  (doublet,  turned  which  2 H,  J  protons),  6.30  (multiplet,  (doublet,  1  J  (singlet, methyls),  H,  = 10  Hz)  3 H,  -PhCH3),  u  (neat),  v  8.63  and and  extract sulphate.  petroleum ketal  (0.01  (48)  Torr)  a  16  H,  Hz,  (doublet,  2800  for  2  5  (two  as  m.p.  (doublet,  9.30  ether  solid,  half-width  7.46  was  chromatographed  a waxy  2.72  H,  and  2850  :  vacuum  and 4  and  mixture  magnesium  ethylene  into  = 8 Hz)  mmole)  organic  was  ether  high  12.5  reaction  combined  with  under  g,  hexamethylphosphoramide  cooled  The  (4.69  (4.03  dry  The  ether.  oil  III).  in  9  dried  (43)  93% y i e l d ) ,  (aromatic  each,  25 mmole)  a brown  grade  ketal  (3.63  (-CH2S02-),  3 H,  22  (48)  9-p_-tol uenesul phonyl camphor  -0-CH2CH2-0-), Hz)  g,  water  provided  Ketal  afforded  (CC14),  = 8 Hz)  with  -  ethylene  extracted  (activity  oil  x  40°C  and  solvent  (3:7)  56-66°C,  J  brine  gel  colorless  to  thoroughly  of  silica  hours,  heated  with  washed  Removal on  was  188  1  H,  J  =  10  singlets,  (broad,  strong,  Mid X  CH),  1600  strong,  (sharp,  medium,  C-C  aromatic  procedure  in  comparable  sulphone  (49)  aromatic  protons),  (two  doublets,  3 H,  each,  2  and  1130  ketal  (49)  was  prepared  was  1  yield  ethylene using  c h a r a c t e r i s e d by 6.20  H each,  tertiary  x  (multiplet, J  = 8 Hz,  methyls),  u  sodium  cm"1  2900  and  2850  (sharp,  4  H,  2.11  and  2.50  -0-CH2CH2-0-),  -CH2S02-), v  strong,  benzenesulphinate.  (CCl^),  (CC1.),  (broad,  8.63  3050  and  7.07 9.30  (shoulder,  by The  the  ketal-  (multiplets, and (two  same  5  7.43 singlets,  weak,  aromatic  t  Hid A  so ).  1300  S02).  9-Benzenesulphonylcamphor  CH),  ring),  CH),  1320  and  1150  cm"1  (broad,  strong,  H,  -  Conversion  of  Ketal-Sulphone  189  (48)  to  9-p_-Toluenesul phony!camphor was  dissloved  (HMPA) (0.7 The  (1:1)  ml,  1.24  over  deepened  with  to  mixture  was  kept  orange.  After  (0.12  allowed  ml, to  washed  by at  the 0.15 up  dilute  water,  solvent  colorless crystals  which  was  reduced  without  Diethylamide flask  containing  condenser. Lithium  wire  reaction room the  was the  crude  added  until  kept  temperature  for  1  and  extract  the  was  washed  to  room  temperature  extracted  anhydrous the  in  mmole)  in  a yellow and  was and  to  warmed the  over  2 hours,  water,  to  l-bromo-3-  the  The  up  color  -78°,  ether.  hexane)  suspension.  Then  magnesium  alkylated  M  added.  with  acid,  0.67  (1.71  cooled  was  water,  and  solvent  a pale  yellow  from  potassium  at  product  reaction hydrolysed  organic  saturated  sulphate.  ketal-sulphone  vigorously  -78°C  hour,  The  dried oil  for  Lithium  1 was  reaction was  was  sodium Removal  (50)  g)  was  of  (0.33  color  then  at  during  was  0°  g)  carefully  acid,  water,  magnesium n.m.r.  to  1  a  dry-ice  -78°C.  and  so  quenched  at  that with  organic  saturated sulphate. i . r .  The  hour  stage  The  and  a  formed.  for  each  into  with  cooled  ether.  with  pellets  fitted  with  anhydrous  (0.105  blue  then  extracted  and  and  added  hydrochloric over  hydroxide (50)  deep  dilute  bicarbonate, gave  mmole)  a permanent  solution  with  again  g,  hexamethylphosphoramide  homogeneous  1.03  of  :  minutes  g,  stirred  hour.  persisted. aqueous  10  turned  alkylation  was  was  color  for  was  over  distilled  solution  was  (THF)  mixture  and  (0.24  purification.  mixture  blue  water  The  dried  (48)  resulting  hydrochloric  bicarbonate, gave  and  syringe  it  (45)  n-Butyllithium  -78°C  chloride  with  ketal  -78°C.  which  warm  ammonium  ethylene  to  added  saturated was  cooled  during  Epicampherenone  tetrahydrofuran  was  30 m i n u t e s  was  extract  was  of  mmole)  methyl-2-butene mixture  a mixture  which  reaction  -20°C  in  -  sodium Removal  spectral  of  data  -  consistent Acid  with  the  hydrolysis  chromatography spectral  structure of  the  provided  data  of  to  those  conditions  (+)-Isoepicamphereno1  Lithium  tetrahydrofuran THF  was  under  nitrogen  colorless  oil  III)  g).  (150  for (14  (3.0  syringe.  which  was  (+)-isoepicampherenol  (46)  as  H,  8.36  CHC13)  olefinic proton), and  8.39  methyls), (broad, 835  5.1,  (two  9.12  and  strong,  cm-1  (broad,  solution  methanesulphonyl refluxed  for  4  (  6.46  The  up  a  l i t .  :  2  2  H  the  30% y i e l d )  alkylated (45)  (broad,  suspended  (10.6  J =  1  on  with  and  in  reduced  41%  g,  1.5  );  yield.  Hz  6 H,  strong,  2 Hz,  tertiary  CH),  1060  dry  refluxed  (activity (15:85)  80%  -CHOH  in  afforded  gel  (CC14),  6 Hz,  and  then  (30-60) g,  dry  48 mmole)  was  silica  x  in  fashion  (8.44  J=  H,  usual  ether  +6°  N  a grade  provided  yield), 4.92 of  (multiplet,  exo-alcohol),  respectively,  methyls); (broad,  u  m  a  x  strong,  vinyl 3400 C-0),  =CH).  1 2 a  (+)-isoepicampherenol  chloride  hours.  in  colorless oil  singlets,  (29)  was  was  (45)  petroleum  (triplet,  (two  2950  (49)  reaction mixture  9.18  medium,  of  ketal  80 mmole)  6 H,  (+)-Epi-g-Santalene  A  g,  doublets,  OH),  mg,  column  previously.  chromatographed  ether  (c  (45  (44).  alumina  (+)-epicampherenone  Working  with  +7.0°  (45)  by  ketal  1 2 a , Z 2  hours.  g)  ethylene  followed  (+)-Epicampherenone  by  17  ethylene  Elution  HQ0 1  added  (44)  observed  provide  hydride  (THF).  slowly  to  ( 4 6 )  aluminum  ketal  (+)-epicampherenone  identical  identical  -  epicampherenone  crude  9-Benzenesulphonylcamphor under  190  The  (8.2  ml,  12.1  (46) g,  reaction mixture  (8.11  104 was  g,  mmole)  3 6 . 5 mmole) in  cooled,  dry  and  pyridine  diluted  with  was water,  -  and  extracted  hydrochloric over  with  ether.  acid,  water,  anhydrous  which with  yield)  ether  (30-60)  as a c o l o r l e s s 1  =0^),  (multiplet,  broad  methyl); 880 94  singlets, u _ , max  (broad, (base  Reaction  olefinic  strong)  proton),  6 H,  2950  at  of  (+)-Epi-e-Santalene  50°C  cooled, The  for  diluted  combined  water,  chromatography ether  (30-60)  analysis peak  I)  (two  allylic  (broad,  (29)  weak)  g)  73%  4.95  1 H  each,  8 . 3 2 and 8 . 3 8 3 H,  tertiary  (sharp,  (=CH);  (10  (5.45 g,  singlets,  1650  oil  Elution  T (CC14),  (singlet,  CH),  a brown  (200 g ) .  methine),  8.97  strong,  F,  with  was washed  weak,  m/e 2 0 4  Separation  evaporative  distillation  homogeneous  colorless  grade o i l  contain  by p r e p a r a t i v e gave  a sample  o i l which  I,  C=C),  (M+),  122,  brown  turbid  petroleum  saturated  of 100  g)  g.l.c.  98% f o r m i c  s o l u t i o n was  ether  (30-60).  sodium  Removal  the crude  one m a j o r  exhibited  1 2 a  was s t i r r e d w i t h  ( 2 . 4 5 g)  of  Acid  sulphate.  Purification  a colorless to  with  magnesium  activity  150°C)  mmole)  and e x t r a c t e d  (3.8 g).  afforded  17  Formic  The  anhydrous  (alumina,  (Column  area).  oil  with  nitrogen.  extract  over  (29)  (3.5 g,  under  water,  organic  a brown  (29)  40 hours with  and d r i e d  provided  dried  and  3 N  peak).  (+)-Epi-B-santalene acid  water,  CHC13);  5 . 3 3 and 5.57  (broad,  with  gave  grade  (c 2 . 6 ,  methyls),  and 835 c m " 1  solvent  was washed  (+)-epi-B-santalene  bridgehead  vinyl  of  (activity  +26.9°  2 9  1 H,  (neat),  v  alumina  extract  bicarbonate,  Removal  provided  o i l , H  (multiplet, 7.34  H,  with  organic  sodium  sulphate.  was c h r o m a t o g r a p h e d  -  combined  saturated  magnesium  petroleum  (two  The  191  bicarbonate, of  solvent  product  and e l u t i o n  with  w h i c h was shown component  (Column  the major  H,  (70%  the following  by of  250°C)  compound  by  column petroleum g.l.c.  total  followed  (A)  as a  spectral  data  :-  by  -  x  (CDC13),  J  = 3 Hz,  4.66 (triplet, allylic  9.05  and 9 . 0 7  2850  cm"1 (broad,  136,  121,  of  was  followed  formic  of  to  of  under  (see  :  1.1  4 . 2 mmole)  f o r 20 h o u r s .  with  petroleum  gave  (alumina,  with  g.l.c.  u  (CC1„),  v  159,  (doublet,  secondary  138,  137  Trifluoride  ( 5 5 . 2 mg, 0.27 (0.1  ml)  18 h o u r s .  oil  (41  product  (A)  (29) w i t h  (0.53 g,  (30-60)  was added  2  H,  methyls),  2950 and (base  peak),  Etherate  mmole)  and  i n d r y benzene  Usual  aqueous  activity  grade  mg) w i t h  g.l.c.  obtained  (3:1).  I,  (5 m l )  work-up petroleum  and n . m . r .  by t r e a t i n g  data  (29)  with  oil  grade  over  data  stannic  was s t i r r e d  quenched extract  anhydrous  magnesium  with  petroleum  similar  ether  product to  those  chloride  under water  was washed  w h i c h was p u r i f i e d  the chromatographed  and n . m . r .  was d i s s o l v e d i n d r y  The o r g a n i c  ( 0 . 5 5 g) I,  Chloride  Anhydrous  and t h e m i x t u r e  (30-60).  and d r i e d  Stannic  2 . 6 mmole)  The r e a c t i o n was t h e n  a brown  of  (29)  ether  ether  activity  distillation  (29)  (alumina,  the o l e f i n i c  petroleum  35°C  solvent  = 7 Hz,  161,  Boron  etherate  for  a colorless  (+)-Epi-g-Santalene  brine,  7.85  above).  benzene  saturated  J  methyls):  (29) w i t h  chromatography  of  6 H,  m/e 2 0 4 , 1 8 9 ,  nitrogen  (+)-Epi-e-santalene  g,  CH);  tertiary  trifluoride  provided  those  acid  Reaction  6 H,  proton),  105, 95.  boron  by column  olefinic  8.95 (doublet,  (+)-epi-B-santalene  to 45°C  (30-60))  similar  107,  -  = 3 Hz,  (+)-Epi-B-Santalene  distilled  heated  ether  strong,  117,  A solution freshly  J  methylene),  (two s i n g l e t s ,  119,  Reaction  1 H,  192  sulphate.  nitrogen and  Subsequent  provided  a colorless  olefin  (A)  water,  Removal  by column  at  extracted  with  (30-60)).  of  (0.5 ml,  of  chromatography evaporative oil  described  ( 0 . 3 5 g) above.  -  Reaction  A in  of  Olefin  solution  dry  benzene  (0.40  g)  stirred excess  in at  of  sodium  for  until  ether.  sodium  of  eluent) 145°C)  to of  the  data  that  (broad  CH), 895 205,  could  signal,  be 1  singlets,  cm-1 153,  57(base  H,  (sharp,  149,  137,  peak),  55,  symmetric  43,  127, 41.  119,  g).  oil to  u  of  (B) an  chromatographed (30-60)  which  exhibited  9.05,  3000 and  99,  x  9.13  95,  spectral 6.68  and  9.17 strong,  950,  ring);  93,  of  150°C)  (broad,  ring),  epoxide  97,  G,  G,  (70%  (CDCl^),  2850  epoxide  as  (Column  (Column  9.03,  extracted  component  :-  was  sulphate.  analysis  a major  Saturated  saturated  magnesium  ether  the  sodium  and was  w h i c h was  was  Then  which  washed w i t h  stretching of 111,  mixture  epoxide  (A)  hours.  g.l.c.  stretching of  113,  10  separated  g)  mmole)  reaction mixture  for  the  G.l.c.  ( C C l J ,  v  3.3  olefin  saturated  petroleum  -CH-0-),  antisymmetric  135,  (0.48  preparative  Hz,  methyls);  weak, weak,  4  was  presence  assigned  half-width H,  (0.20  g,  iodine-starch test.  anhydrous  III,  a colorless  tentatively  12  (broad,  oil  P u r i f i c a t i o n by as  layer  grade  of  neutralise  over  i n d i c a t e d the  compound  temperature  (0.69  while  The  addition  oil  85%)  bath  minutes.  f r a c t i o n s were  a yellow  (activity  product  to  dried  a colorless  area).  major  1255  gel  (Aldrich,  a negative  aqueous  and  afforded  provide this  peak  gave  silica  water,  15  room  added  Acid  ice-water  dropwise  combined o r g a n i c  solvent  with  The  an  at  gave  slowly  acid  over  and by  mixture  ether.  by  added  destroyed  bicarbonate,  Removal  total  The  cooled  was  b i c a r b o n a t e was  with  m-Chloroperbenzoic  30 m i n u t e s  the  diluted with  twice  was  benzene  then  (four  ml)  p e r a c i d was  bisulphite  with  -  m-chloroperbenzoic  (30  dry 0°C  (A)  193  85,  920 m/e  83,  81,  and 220, 71,  -  Reaction  of  Compound  Compound an  ice-water  (B)  separated were  bath.  Freshly  a  the reaction  with  gel,  ether  product the  (C)  methyl), 3350  cm  (broad,  - 1  H each,  vinyl u  methyl), (CC1J,  weak,C=C), Other separation If etherate  3500  (broad,  non-polar  to  -CHOH),  (broad,  ( 1 0 mg)  :-  m l , 0.1  afford  data  of  strong,  CH),  fractions  solvent  provided  t . l . c .  (silica  colorless  (C)  tertiary  (R^=0.2)  It  weak,  medium,  were  oily  consistent singlets,  singlet,  3 H,  u  methyls).  1640 ( b r o a d ,  with 1 H  vinyl (CCl^),  m a x  weak,  C=C),  was a l s o  was a s s i g n e d  1  H,  OH),  recovered  from  the  as an e p i m e r i c  enol  (D)  5 . 0 2 and 5 . 2 6 (two broad -CHOH),  2950  8.27  (doublet,  3 H each,  (broad,  strong,  C - 0 ) , 890 cm"1 (broad, (R^  0.7-0.9)  recovered  CH),  medium, from  singlets,  3 H,  tertiary  as  J = 1  Hz,  methyls), 1640  (sharp,  =CH).  the  t . l . c .  identified.  between g,  of  8 . 2 2 (broad  6 H,  T (CDC13)  compounds  n o t been  the reaction (0.1  (1:9))  and 9 . 3 8 (two s i n g l e t s ,  1060 ( b r o a d ,  have  1 H,  5.95 (multiplet,  9.12  Removal  for  l a y e r was  organic  by p r e p a r a t i v e  The s p e c t r a l  separation.  the following  =CH0),  the combined  (0.05 m l ,  nitrogen  The aqueous  by  =CH).  colorless o i l  exhibited  etherate  T ( C C l ^ ) , 4 . 9 9 and 5 . 2 9 (two broad  2950  medium,  and was c o o l e d  0°C under  water.  sulphate.  (two s i n g l e t s ,  OH),  t . l . c .  Then  (30-60)  :-  with  was p u r i f i e d  (multiplet,  weak,  preparative  1  an enol  trifluoride  s t i r r i n g at  magnesium  (Rf=0.5).  Etherate  i n d r y benzene  boron  ether.  ether  8 . 9 6 and 9 . 1 2  Another  it  of 5.72  (broad,  After  ( 5 4 mg) w h i c h  ( 1 5 mg)  =CH2),  distilled  with  petroleum  structure  each,  900  :  Trifluoride  was quenched  anhydrous  colorless o i l  Boron  was a d d e d .  and e x t r a c t e d  dried  with  -  ( 5 5 . 7 mg) w a s d i s s o l v e d  55 m g , 0 . 4 mmole) 10 m i n u t e s ,  (B)  194  0.7  compound mmole)  (B)  ( 8 5 mg) a n d b o r o n  was a l l o w e d  to  proceed  trifluoride under  nitrogen  at  -  room  temperature  chromatography of  the  crude  assigned 1  as  = 6 Hz)  8.32  (  two  CH„0H  (silica  diene  J  x  10  product  H,  tertiary  for  methyls);  n  (  m  £  usual  mg)  u  m a v  1 0 } 0 0 0  ).  grade  provided  on  its  (broad  6 H,  -  aqueous  activity  based  4.73  singlets,  2 4 6  gel,  (80.5  (G)  and  hours,  195  2900,  1  data  H,  J  8.97  2850  /  (M ), 201,  e  :-  and  column  ether  (17  (30-60))  mg)  which  3.79  (two  cm"1  159,  145,  calcd.  for  was  (doublet,  (-CH=CH-),  9.09  2800  187,  by  T (CC14),  = 6 Hz)  and  +  m  petroleum  III,  spectral  methyls),  ( C C l J ,  followed  a colorless oil  doublet,  vinyl  work-up  8.26  and  singlets,  (broad,  6  H,  strong,  136,  135  CH);  (base  iMaX  peak),  134,  Found  (High  133,  column w i t h  (21  mg)  two  broad  which  showed  of  drops)  Compound  in  of  mixture  provided  a yellow  the  crude  colorless described  oil  of  oil  no  on  with  which  showed  :  202.1709.  (30-60)  t . l . c .  intensity  the  was  (31.4  i . r .  at  and  mg)  refluxed  spectral  ether data  gave  H  :  2 2  202.1721 .  elution  a yellow gel)  1715  spectral  and  cm"1  structure(s)  n.m.r.  and  6 N  of  oil displayed  in  of  the  this  data.  hydrochloric  3 hours.  followed  Preparative  petroleum  the  and  1 5  Further  (silica  1740  C  Acid  for  bicarbonate  mg).  (1:9)  analysis  Hydrochloric  (B)  sodium (26  ether  wt.  c o n c l u s i o n about  with  product  above.  on  medium  compound  Mole.  spectrometry)  based  (B)  with  105.  spots  95% e t h a n o l  reaction  of  119,  petroleum  However, be made  A mixture  : two  absorptions  could  Reaction  (10  ether  spectrum.  product  120,  r e s o l u t i o n mass  the  i . r .  121 ,  t . l . c .  (30-60) identical  acid  Neutralisation  by  usual  (silica as to  eluent those  aqueous gel)  of  work-up  separation  afforded of  the  diene  a (G)  -  Catalytic  Hydrogenation  A solution atmospheric 13 ml o f to  of  of  diene  hydrogen  had been  solvent g.l.c.  through from  a short  data  (+)-epi-3-santalene  Oxidation  Enol was  Enol  (C)  added  oxidising green.  of  dissolved  the  extract  with  was t h e n  in water.  saturated  two s p o t s  (R^-0.2,  crude  singlets,  1  methine),  8.32  J  methyl),  (broad,  product  H each,  strong,  those  up-take  of  After  the gas  grade  III).  (A)  was  Removal  ( 3 0 mg) w i t h  olefin  about  dropped  and t h e m i x t u r e  (activity  of  removed  of  =CH2),  ( broad  of  n.m.r.,  obtained  singlet,  1745  persisted.  by  with  provided  treating  3 H,  (sharp,  vinyl  3 H,  by  drying  over  of  half-width  C=0 o f  methyl).  anhydrous  5-membered  m g x  ketone  (E).  broad  3  allylic H,  (CC14),  ring  which  spectral  3 Hz,  (doublet, u  was  residue  a  1  8.97  the  The  and 5 . 4 0 (two  methyl),  ml o f  (9 mg)  5.11 H,  M )  washing  gel).  the presence  tertiary  strong,  followed  (silica  (1.05  the mixture  a colorless o i l  analysis  signal,  0.005  and t h e green  water,  consistent with  (broad  until  chloroform,  bicarbonate,  reagent  About  was added  ( F ) :- x ( C C l ^ ) ,  7.25  and Jones'  by e v a p o r a t i o n  solvent  9.06 (singlet,  CH),  color  on t . l . c .  were  ketone  i n acetone  Isopropanol  0.3)  an * , 8 - u n s a t u r a t e d  = 1 Hz,  to  sodium  showed  and  as c a t a l y s t .  a colorless o i l  Extraction  and removal  this  of  at  acids.  was r e q u i r e d .  with  was h y d r o g e n a t e d  was s t o p p e d  alumina  the yellow  sulDhate,  of  of  provided  sodium  data  reaction  identical  until  solvent  was  the rate  mg) w a s d i s s o l v e d  dropwise  The  consumed  column  (29)  i n hexane  (C)  (10  agent  (G)  ( 3 0 mg)  The  the f i l t r a t e  and t . l . c .  -  10% p a l l a d i u m o n c h a r c o a l  0 . 5 ml p e r 3 0 m i n u t e s .  filtered  Diene  (G)  pressure with  196  2900  ketone),  -  1705  (shoulder,  (sharp,  weak,  The alumina of  the  the  3  crude  alumina  on  was  methyls), ( C C l J ,  ring  <*,B-unsaturated  (broad,  (4  room  mg)  at  followed o i l  before,  2850  ketone),  and  x  1600  wet  by  ether  and  which  (CCl^),  7.80  (two  strong,  for of  the  showed and  15  1640  two  (two  CH),  (sharp,  strong,  of  C=C  from  spots  3 H each,  C=0  Removal  solvent  8.08  1745  basic  hours.  singlets,  strong,  (sharp,  ketone),  stirred with  temperature evaporation  (sharp,  cm"1  ,B-unsaturated =CH).  ( 8 mg)  8.94  (broad, 1705  a  medium, in  8.80  ketone),  ring  dissolved  a colorless  a n a l y s i s as  m a v  5-membered  I)  -  5-membered  filtration  afforded  vinyl u  of  900 cm"1  grade  by  t . l . c .  methyls).  C=0  product  (activity  H each,  of  C=C),  filtrate  0.3)  weak,  197  (R^=0.2,  singlets, tertiary  medium,  5-membered of  C=0  ring  B-unsaturated  ketone).  (+)-9-Acetoxycamphor  A mixture acetate under  (16.3  g)  165.4 24  hours.  ether.  The  magnesium  w h i c h was  123°C  (6.55 (two  g,  (5  9.10  (broad,  to  86% y i e l d ) ,  (two  2 H,  J  3 0  = 12  CH),  1750  g,  34.9  mmole)  hexamethylphosphoramide  It  was  then  by  0.04  cooled,  extract  was  Removal  column Torr)  washed w i t h  of  solvent  chromatography ( l i t .  1 2 a  b.p.  (c  0.88,  -CH20Ac), tertiary  (sharp,  CHC13);  7.99  C=0),  u  m a x  1240  (0.05 as  (CC14),  (singlet,  methyls);  strong,  x  3 H,  (CC14), cm"1  refluxed  and  a brown  (silica  (68)  potassium  water,  water  gave  70°C  and  was  diluted with  (+)-9-acetoxycamphor  +53.2° Hz,  (8.08  dry  provide  [ « ]  (41)  in  sulphate.  s i n g l e t s , 6 H,  medium,  1 4 , 3 3  organic  purified  Torr))  doublets,  '  mmole)  d i s t i l l a t i o n (66-68°C,  b.p.  and  with  1 2 a  (+)-9-bromocamphor  for  anhydrous  (7.27 by  g,  nitrogen  extracted over  of  ( 6 8 )  gel)  and dried  oil  followed  Torr);  l i t .  a colorless 5.85  3  3  oil  and  6.10  CH3C00-),  9.08  2950 and  2900  (broad,  strong,  -  C-O-C); 43  m/e  (base  peak).  resolution 68.54;  210  H,  ( M  Mole.  mass 8.63.  mixture  Found  g,  29.7  bath.  solution was  stirred  at  and  9-acetoxyborneol(69b)  chloride up  in  (3.9  the  usual  (36-38°C, (1.92  g,  1.2  H each,  1  H,  Torr)  half-width  CH3C00-),  8.93  medium,  1240  (broad,  134,  121  C,9H  1 Q  0  o  fashion  =CH0),  to  :  6.10 8 Hz,  H  H,  108,  i8°3  :  Anal,  107,  95,  93,  79,  210.1256.  Found  calcd.  C-j 2 ^ 1 8 ^ 3  for  67,  (High ^'  :  8.80.  CH),  peak),  194.1306.  (1.92  a  product  was  provided  oil  signal,  3 H,  allylic  tertiary  (sharp,  106, Found  91,  (High  89,  (2.87  and  (broad, 43.  17.7  mmole)  mixture  was  in then  hydrochloric  w h i c h was  for g)  acid  (69a)  used  in  5.43  (two  the  1660  medium, Mole.  was  distilled  broad  multiplet,  singlet, ),  2950  (broad,  weak,  4  =CH2);  m/e  calcd.  spectrometry)  oil  singlets,  (broad  (  (CCl  wt.  Working  a colorless  7.30  8.00 m a x  hours.  which as  u  r e s o l u t i o n mass  15  (70)  -CH20Ac),  methyl);  87,  g)  pyridine  C=0),  ice-water  an  p-toiuenesulphonyl  methine),  strong,  895 cm"1  93,  2 H,  g,  ammonium  purification.  with  5.18  by  dilute  (3.43  oil  and  9-acetoxyisoborneol  without  a yellow  bridgehead  C-O-C),  of  treated  (CC14),  x  broad  1755  (3.71  10-acetoxycamphene  yield); (  cooled  before  dry  mmole)  reaction  a mixture  refluxing  afford  (68)  30 m i n u t e s  colorless  50.9 was  The  rearrangement  in  g,  95% e t h a n o l  provided as  (singlet,  strong,  (base  1 2  stirring.  for  20 mmole)  56% o v e r a l l  1  (sharp,  work-up  reduction g,  in  with  Wagner-Meerwein  crude  C  122,  210.1251.  borohydride  added  added.  The  137,  for  68.59;  temperature  Usual  150,  (+)-9-acetoxycamDhor  of  slowly room  C,  :  mmole)  was  subsequent  calcd.  -  (70)  sodium  (1.59  ethanol  :  of  chloride A  wt.  164,  spectrometry)  10-Acetoxycamphene  A  ) , 167,  +  198  3 and  H, 2850  C=C), 194  ( M  +  ) ,  for :  194.1305.  -  Anal,  calcd.  f o r C ~\8°Z H  10-Hydroxycamphene  A mixture hydroxide It  of  combined  sulphate.  (bath  (c  =CH2),  H,  6.51  C=C),  OH),  152  for  C-jgH^gO  1  H,  ;  :  '  -  9  3  half-width  4  -  F  o  u  n  d  :  c  gave  m.p.  122,  calcd.  121  3 N  »  - ">  74  >  10  H  9  over  to  -  3  3  -  7  Hz,  (1.37  (base  C-0),  peak),  (High  for C ^ g O  :  C,  water,  magnesium  which  and  were  subsequently  +88.6°  Hz,  (sharp,  signals, -CH^OH),  medium,  93, 91,  - 1  1670  (sharp,  79, mass H,  1  77.  H  each,  7.33  methine),  OH),  890 c m  78.90;  g)  The  tube);  allylic  resolution  acid,  hours.  10-hydroxycamphene  hydrogen-bonded  strong,  Found  3700  for 4  provide  = 11  bridgehead  potassium  ether.  anhydrous  5 . 2 5 and 5 . 5 6 (two broad J  with  pressure)  (sealed  2 H,  and  hydrochloric  crystals  (30-60)  93-95°C  10 mmole)  m l ) was r e f l u x e d  and d r i e d  yellow  ether  g,  (15  atmospheric  medium,  (broad,  (1.9  and e x t r a c t e d  with  ( C C l J ,  u  (broad,  (70)  water,  petroleum  152.1201 .  Anal,  H  water,  110°C,  T (CC14),  124,  (broad  8.93  non-hydrogen(sharp,  medium,  strong,  =CH0);  Mole.  wt.  spectrometry)  10.59.  (singlet,  Found  calcd. :  :  C,  78.50;  10.47.  10-Oxocamphene  A solution (25  with  solvent  methyl);  3500  (M+),  152.1203.  9  was washed  needles,  1045 and 1025  m/e  J  and 6 . 6 5 (two d o u b l e t s ,  tertiary  bonded  H,  from  CHC13);  multiplet, 3  of  as c o l o r l e s s 1.00,  diluted  temperature  recrystal1ised  4  i n 95% e t h a n o l  bicarbonate,  Removal  sublimed  (71)  35 mmole)  extract  sodium  7  -  (71)  cooled,  organic  saturated  '  C  1O-acetoxycamphene  (2.0 g,  was t h e n  :  12  199  (72)  of  m l ) was c o o l e d  dry pyridine  (32 m l , 400 mmole)  to  nitrogen  0°C under  while  i n carbon  tetrachloride  chlorosulphonic  acid  (4.6 m l ,  -  8 g,  6 9 . 4 mmole)  allowed and  was s l o w l y  t o warm  dissolved  up t o  t r i e t h y l amine at  extracted  over  t . l . c .  ether.  acid,  accordance  g)  water,  half-width  7  crude  aldehyde  purification  (72)  (see  (about  10  magnesium the  turnings  vigorously fitted  with g,  0.1  stirred  solvent  bridgehead  x  (CCl^),  allylic  2  and  a yellowish F,  N. dried  volatile  liquid  115°C)  as  and  data  in  0.50 (singlet,  =CH0),  7.30  methine),  was  and  and o t h e r  spectral  IH e a c h ,  mixture  water,  water,  (Column  n.m.r.  :-  singlets,  was u s e d  1  H,  (broad  8.98  (singlet,  mole)  i n the subsequent  (1.3  reaction  (73)  g,  0.054  g-atom)  in dry tetrahydrofuran  i n d r y THF the yellow  was removed  Grignard  below).  a dry-ice-acetone  had d i s s o l v e d  condenser  bicarbonate,  provided  (72)  and d r y  water  with  n-hexane,  (+)-10-  The r e a c t i o n with  f o r m e d was  with  of  (30 ml)  was washed  on g . l . c .  washed  solution  quenched  of  solid  methyl).  Magnesium  was  40 T o r r )  aldehyde  Hz,  then  and e x h i b i t e d  and 5 . 5 6 (two broad  1 H,  was a d d e d .  Removal  was homogeneous  A  i n d r y DMSO  sodium  sulphate.  the desired  15 m i n u t e s ,  extract  saturated  The w h i t e  (DMSO).  for 2 hours,  10-Hydroxy-10-Vinylcamphene  were  over  mmole)  395 mmole)  gel) analyses,  tertiary  without  stirring.  The o r g a n i c  which  with  5.16  The  27.6  by d i s t i l l a t i o n ( 3 5 ° C ,  (2.7  signal,  g,  magnesium  (silica  -CHO),  (4.2  temperature  anhydrous  residue  with  temperature  (55 m l , 40 g ,  with  compounds  3 H,  (71)  room  hydrochloric  room  -  in dry dimethylsulphoxide  hydroxycamphene  stirred  added  200  and i o d i n e (THF).  (1  The  condenser  and a s o l u t i o n  was added  over  vinyl  bromide  crystal)  reaction  flask  of  vinyl  bromide  After  a l l  30 m i n u t e s .  s u s p e n s i o n was s t i r r e d  and excess  small  for 1  was a l l o w e d  hour to  the  before  evaporate.  -  A solution  of  added  10 m i n u t e s ,  was  over  stirred  crude  at  10-oxocamphene  room  resulting  temperature  dilute  ammonium  washed  successively with  water,  sodium  chloride.  with  removal  of  0.03-0.04  Torr)  oil  (2.5  g,  J  = 10  Hz,  A M  doublets  chloride  gave  provided  of  = 17  B M  -CHx0H-CHM=CHAHg), J  = 2 Hz,  A 5  2  H,  J  =CH2),  2 Hz,  H,  4.85  (broad,  (broad,  medium,  strong,  -C=CH0);  91 ,  77.  79,  resolution  mass  J  wt.  15  hours.  of  (broad  3100,  3 H, 2900  (M ), 160, +  calcd.  bicarbonate, sulphate  which  :  (3.22 g,  (73)  doublets  HZ,  of  5.13  1  H,  signal,  J 1  tertiary and 2830  150,  :  of  = 2  X  and 5.21  1  by  H,  half-width  doublets,  (doublet  H,  J  u  m  A X  JftM  a  -CH=CH0), (base  1  singlets, J  =  g x  bridgehead  (CCl^),  x  CH),  1660  900 cm"1  peak),  Found  Hz,  105,  (broad, 94, 93,  (High  178.1352.  (74)  31.5  (73)  mmole)  up i n t h e u s u a l  (2.36 g,  14  in refluxing  fashion  gave  mmole) dry  a brown  was t r e a t e d  pyridine o i l  H,  of  = 10  = 2 Hz, 8 Hz,  strong,  178.1358.  (43-45°C,  (two broad  = 4 Hz,  121  saturated  Hz,  M X  (sharp,  was  as a c o l o r l e s s  4.67  methyl);  122,  extract  followed  doublets,  strong,  with  and  doublets  Jg  was  mixture  on d i s t i l l a t i o n  of  = 17  g M  The  The o r g a n i c  -CH^H-CH^CH^g), J  i n d r y THF  was h y d r o l y s e d  ether.  (doublet  for C-^H^O  spectrometry)  Working  4.08  multiplets,  10-Hydroxy-10-vinylcamphene anhydride  then  g)  mole)  reaction.  magnesium  995 and 930 ( b r o a d ,  10-Acetoxy-lO-Vinylcamphene  acetic  0.017  sodium  (3.1  = 2 Hz,  A g  7.32  m/e 178  Mole.  oil  = 4 Hz,  M X  of  OH),  C=C),  with  anhydrous  9.05 (singlet,  medium,  g,  hours,  -CHx0H-CHM=CHAHB),  (doublet  methine),  15  saturated  ( doublet  = 2 Hz,  5.91  J  -CHx0H-CHM=CHAHB),  allylic 3650  A X  for  (CC14),  x  1  (2.6  10-hydroxy-10-vinylcamphene  Hz,  doublets,  (72)  i n an e x o t h e r m i c  a yellow  83% y i e l d ) ; J  -  and e x t r a c t e d  Drying  solvent  201  (15  (3.13  g)  with ml)  for  which  -  was  distilled  (74) T  as  a colorless  (CC14),  5 Hz,  (49-53uC,  4.16  signal,  (singlet, 3130,  1  3 H,  weak,  (broad,  medium,  161 ,  ^•]4^20^2  of  (two  220.1464.  2 H,  CH),  Found  2  (base  1  H,  singlets,  (c  4.86  1  (sharp,strong,  =CH0),  970,  89,  r e s o l u t i o n mass  u  1  7.97  m  a  (CClJ,  v  1650  940 and  925  43.  m/e  220  Mole.  H,  7.31  C=0),  -C=CH2);  93,  Hz,  methine),  1750  peak),  10  methyl);  980,  CHCI3);  (multiplet,  tertiary  medium,  Hz,  H each,  allylic  C-O-C),  1.13,  = 16  J  -Cf^CH^),  (sharp,  (High  +17.7°  5  3 H,  strong,  121  H  bridgehead  (singlet,  895 c m " 1  1 3 2 , . 122,  10-acetoxy-10-vinylcamphene  doublets,  broad  8 Hz,  (broad,  -CH=CH2), 145,  '  5.38  8.96  1240  provide  84% y i e l d ) ,  (sharp,medium,  C=C),  160,  to  doublets  half-width  2850  (broad,  g,  -  (multiplet,  and  CH,C00-),  2900 and  194,  H,  of  4.70  5.27  Torr)  (2.53  (doublet  -CHOAc),  (broad  for  oil  -CH0Ac-CH=CH2),  allylic  0.01  202  (M+),  wt.  spectrometry)  calcd. :  220.1464.  Reaction  A  of  solution  in  formic  It  was  oil  acid  then  extract dried  10-Acetoxy-10-Viny1camphene  of  (168  (98-100%)  starting  material  ratio  1:4  major  Column  G,  in  with (74)  the  component 160°C).  ml)  water water,  s t i r r e d at extracted  saturated  ether  :  petroleum  (38 mg).  (90%)  n.m.r.  and  i . r .  (159  room  temperature  with  on  mg,  ether.  of  a silica  ether  the  g.l.c.  gel  oil  :  spectral  data  2  hours.  organic water,  and  gave  yellow  gave  a  grade  which  (Column  III)  recovered  petroleum  ( 9 0 mg)  analysis  mmole)  for  (activity (1:9)  ether  0.72  The  solvent  (30-60)  a colorless  according to  Acid  (74)  Removal  Increasing  afforded  Formic  sodium b i c a r b o n a t e ,  sulphate.  chromatographed  eluent  The  was and  magnesium  w h i c h was  Elution  one  with  anhydrous  column.  to  (4  diluted with  mg)  with  10-acetoxy-10-vinylcamphene  was washed  over  (74)  ether contained  F,  indicated that  120°C; it  was  -  an  acetate-formate.  (Column on  G,  150°C)  analysis with (CC14),  T  1  H,  J  (doublet,  1  = 10  A M  3  H,  1  Hz,  977 145,  2900  139,  134,  Further colorless to  those  were  M X  = 6Hz,  (I)  2 days  in  the  Hydrolysis  A mixture  3 mmole)  was  then  cooled,  (broad  medium,  (sharp,  1735  1170  (broad,  266,  peak),  224, 79,  (H)  with  and  (I)  formic  a formic of  were acid  acid  a catalytic  of  of  multiplets, 8.00  tertiary  220,  1  H,  (singlet,  methyls);  C=0),  C-O-C  of  206,  178,  43,  (3:7)  two  of  -CH00C-),  spectral  the  doublets  strong,  55,  ether  recorded:-  1240 formate), 161,  160,  41. afforded  data  another  (CCl^)  tertiary  similar  methyl  singlets  with  :  :  obtained acetic  acid  chloroform amount  of  on  treating  10-acetoxy-  (1:1)  50°C  (1:3)  2 N  at  solution  sulphuric  for  of  24  (74)  for  acid.  (H)  95% e t h a n o l  diluted  petroleum  67,  were  (doublet  strong,  221,  homogeneous  9.10T.  acetate-formate in  CH),  that  and  H,  3 H each,  except  (H)  4.82  1  g.l.c.  -COOCH^CH^C^Hg),  (doublet  multiplet,  n.m.r.  9.02  of  6 Hz,  4.85  w h i c h was  (doublet  singlets,  m/e  (base  Acetate-Formate  mg,  =  M X  showed  presence  (170  J  (H)  preparative  data  -COOCH^-CH^CH^g),  (two  95  Hz,  which  (74)  of  17  by  spectral  4.18  mg)  (18  refluxing  of  =  B M  HC00-),  :  compounds  by  H,  solid  following  ether  The  or  purified  with  at  hours,  The  1  =CH);  105,  was  - C H ^ C H ^ ) ,  9.11  medium,  observed  10-vinylcamphene  G.  5.25  acetate-formate  same  product  of . a c e t a t e ) ,  elution  oil of  and  J  Hz,  (broad,  121,  and  Hz,  17  -  a c o l o r l e s s waxy  10  C-O-C  (broad,  the  singlet,  =  g M  8.90  strong,  cm"1  J  J  F  -CH^CH^Hg),  CH3C00-),  (sharp,  =  H,  H,  (CClJ,  u  Columns  A M  of  provide  (broad  multiplets, J  to  2.15  doublets, 4.53  Part  203  (H) was  water,  (71  mg)  and  potassium  refluxed  for  4  and  extracted  hours. with  hydroxide The  ether.  solution The  organic  -  extract  was w a s h e d  washing  to avoid  magnesium  thoroughly  204  with  possible allylic  sulphate  and removal  of  provide  colorless  data of  consistent with  doublets,  4.78  1 H,  (doublet  2 Hz,  of  J  those  doublets  -CHx0H-CHM=CHAHe),  10  Hz,  J  = 2 Hz,  of  doublets,  A B  (multiplet,  IH,  J  1 H,  methyls);  u_  3 V  0  A X  of  J  -CHOH), (CHC1,),  J  A X  3700  (broad,  medium,  overtone  (sharp,  strong,  C-0),  Reaction  of  acid at  organic  and  dried  brown  o i l  of  995 c m  OH),  over  J  B M  = 17  of  doublets  J  2900  - 1  (broad,  peak),  The m i x t u r e  and washed  magnesium  J  = 2 Hz,  A B  J  H,  of  g x  =  JftM  =  doublets  3 H each,  (sharp,  tertiary OH),  strong,  weak,  3550  CH),  C=C),  m/e 1 9 6 ,  6.47  1720  1070  178,  163,  139,  41.  with  Trifluoroacetic  (74)  with  was c h r o m a t o g r a p h e d  1  (doublet  Acid  (100 m g , 0 . 4 5 mmole)  at  bath.  sodium  Removal  0°C for  on s i l i c a  1  hour  solvent  gel  and  was then  bicarbonate, of  in  Trifluoroacetic  sodium b i c a r b o n a t e  sulphate.  (doublet  -CH_x0H-CHM=CHAHB),  =CH);  was s t i r r e d  was s e p a r a t e d  ( 1 4 0 mg) w h i c h  5.76  by an i c e - w a t e r  Saturated  4.04  non-hydrogen-bonded  55,  (74)  spectral  doublets.  1650 ( b r o a d ,  for 4 days.  anhydrous  of  and 2830  67,  with  to  -CHx0H-CH^=CHAHB),  Hz,  = 2 Hz,  B X  strong,  79,  m l ) was c o o l e d  was a d d e d .  layer  H,  1  =CH b e n d i n g ) ,  95 (base  (15  temperature  The  = 5 Hz,  10-acetoxy-10-vinylcamphene  chloride  (5 d r o p s )  room  of  M X  anhydrous  0.2 Torr)  (CDCl^),  J  medium,  10-Acetoxy-10-Vinylcamphene  A solution methylene  121,  x  Hz,  = 2 Hz,  (sharp,  hydrogen-bonded  122,  :-  for  crystalline  110°C,  8 . 8 8 and 8 . 9 9 (two s i n g l e t s ,  medium,  123,  17  over  (hot stage),  -C^OH-CH^D^Hg),  (broad,  138,  =  m  was n o t used  Drying  temperature  for a diol  4.88 (doublet  = 2 Hz,  acid  a yellowish  99-101°C  doublets,  = 5 Hz,  M X  m.p.  Hz,  gave  (bath  expected  = 10  A M  (Dilute  solvent  ( 5 0 mg) w h i c h w a s s u b l i m e d (J),  water.  rearrangement.)  product  crystals  -  water,  gave  (activity  added.  a grade  -  III) a  (6.5 g).  colorless  (K)  based  o i l  1  = 11  A M  (two  = 11  doublet,  multiplets, J  IH,  Hz,  singlets,  strong,  C=0 o f  cm"1  145,  J  H,  = 18  B M  CH),  119,  Jg  J  :  petroleum  :-  (CCl^),  = 18  M  ether  Hz,  J  4.18  (30-60)  8.01  (singlet,  tertiary (sharp, 1240,  95, 94,  3 H,  strong, 1170  m/e 3 3 4 ,  93, 91,  81,  CH3C00-),  of  290, 273, 79,  of  77,  of  (doublet  of  multiplets,  1  H,  8 . 9 2 and 9 . 0 9 2850  CF3C00-),  and 1140  doublets  4.80  (CC1,),  C=0 o f  provided  -COOCH^CH^C^Hg),  (doublet  u  methyls);  1220,  (doublet  -C00CHx-CHM=CHAHR), 4.82  (1:9)  acetate-trifluoroacetate  = 6 Hz,  M X  - C H ^ C H ^ ) ,  medium,=CH);  105,  x  = 6 Hz,  M X  Hz,  1780  CH3C00-),  (broad,  121,  1  Hz,  3 H each,  medium,  ether  data  -CH^CH^Hg),  (sharp,  976  spectral  H,  (broad  with  -  ( 9 4 . 8 mg) w h i c h w a s i d e n t i f i e d a s a n  on i t s  doublets, 4.53  Elution  205  (broad,  1740  2800  (sharp,  strong,  2 3 5 , 221 ,  69, 67,  and  178,  5 5 , 43  C-O-C),  161 , (base  160, peak),  41.  Hydrolysis  of  Acetate-Trifluoroacetate  A mixture hydroxide It  (80 mg,  was t h e n  organic  1.4  to  mmole)  diluted  was washed  sulphate.  product  identical  acetate-trifluoroacetate  cooled,  extract  magnesium crude  of  of  water,  thoroughly of  (J)  by  and  potassium  (5 m l ) was r e f l u x e d  water,  followed  crystals  obtained  ( 9 4 . 8 mg)  and e x t r a c t e d  with  solvent  colorless di ol  (K)  i n 95% e t h a n o l with  Removal  provided those  (K)  (31  with  and d r i e d  ether. over  by s u b l i m a t i o n  mg) w i t h  hydrolysis  spectral of  for  2  hours.  The anhydrous  of  the  data  acetate-formate  (H).  -  Reaction  A in  of  formic  of  acid  (3  aqueous  work-up  crude  product  by  mg)  which  diformate of  :-  1  = 17  H,  (two  J  B M  singlets,  medium,  was  Elution (115  mg)  of  identified.  H,  (doublet  Perchloric  of  4  10-acetoxy-10-vinylcamphene  c o o l e d by drops)  hour.  was  It  hours.  ether  178,  (doublet  Hz,  x  of  -CH00CH),  with  189,  a  a  4.12  = 6  M X  (74)  strong,  m  of  oil  HC00CH_x-CHM=CHAHB),  4.76 1  the  (CC14),  strong, 135,  multiplets,  8.90  2850  4.70  and  9.10  (broad,  C-O-C); 134,  m/e  121,  119,  peak).  was  :  acetates, Further  (74)  (274  Acid  mg,  1.25  a dry  ice-carbon tetrachloride bath.  added  and  then  Usual  chromatographed  with  (multiplet,  J  IO-Acetoxy-10-Vinylcamphene  206,  (base  (6  for  Hz,  = 6 Hz,  M X  -CH^=CHAHB),  5.24  tertiary  J  = 17  B M  HC00-),  145,  (sharp,  209,  solution  stirred  = 5 Hz,  H,  J  2 H,  those  160,  c h l o r o f o r m was  which  3 H each,  singlets  hours.  a colorless  161,  95  1  A M  1  afforded  163,  105,  for  J  (two  2  mmole)  P u r i f i c a t i o n of  accordance with  = 5 Hz,  (doublet,  gel)  0.56  for  (broad,  107,  -20°C  4.40  H,  temperature  1180  223,  (70%)  1  2.03  mg,  C=0),  235,  acid  and  in  Acid  (100  (80 mg).  (silica  data  (73)  room oil  Formic  u  252,  A  a yellow  t . l . c .  -CHM=CHAHg),  1730  of  with  methyls);  CH),  Reaction  2.00  multiplets, Hz,  s t i r r e d at  spectral  doublets,  HC00CHx-CHM=CHAHB), of  was  provided  displayed  of  (doublet  ml)  preparative  T(CC14),  doublets  (73)  10-hydroxy-10-vinylcamphene  Usual  (17  -  10-Hydroxy-10-Vin,y1camphene  solution  97%  206  the  allowed  aqueous  with  petroleum carbonyl  reaction mixture  gel  ether  :  up  to  afforded  (activity  (30-60)  compounds,  elution with  warm  work-up  silica ether  to  or  (1:9)  was  room  gave  oil  ether  (1:4)  and  (326  (4.5  a complex  diacetates which  petroleum  at  temperature  III)  in  Perchloric  stirred  a yellow grade  mmole)  have  mg)  g). mixture not  been  provided  -  white  crystals  (doublet  of  proton),  4.94  4.99  (multiplet, (two  (74  doublets  mg),  of  (doublet  (doublet  8.97  (85)  1  m.p.  of  1  H,  triplets,  triplets,  H,  allylic  1  H,  J  1  =  methine),  3 H each,  -  85-89°C  doublets,  of  singlets,  207  (hot  J  =  17  H,  J  =  17  Hz,  7.96  stage); Hz,  12  12  Hz,  2 Hz,  (sharp, 910  strong,  cm"1  106,  98,  9.30.  C=0),  3500  1640  (broad,  medium,  79,  43  Found  Reaction  OH),  of  67, :  C,  (broad,  (sharp,  =CH);  (base  70.37;  H,  olefinic  proton),  6.75  3 H,  solution  room oil  (100  until  was  temperature (195  activity  mg)  provide  to  those with  of  for  III)  of  acetate  perchloric of  ethanol  one m a j o r  Purification  (sharp,  hydrogen-bonded  C=C),  1240 195,  calcd.  (74)  (200  Boron  saturated 10  purified by  crystals  and  medium,  for  (broad, 178,  C  OH),  1 4  H  strong,  153, 2 2  0  3  1745  137, :  C,  C-O-C),  135,  107,  70.65;  H,  with  mg,  Boron  0.94  trifluoride  and  the  Trifluoride  mmole) gas  was  Aqueous  by  chromatography  short-path  (42.5  obtained  mg)  by  work-up  distillation  which  showed  treating  dissolved  bubbled  reaction mixture  minutes. column  was  was  gave  a  (silica  through  stirred yellow gel,  (130-150°C, 5  spectral  at  data  Torr)  identical  10-acetoxy-lO-vinylcamphene  acid.  the (95%)  component by  (74)  ml).  another  (85)  3600  8.50  9.17.  followed  colorless  Hydrolysis refluxing  i t  w h i c h was  grade  to  (74)  chloride  CH3C00-),  *T  (M+),  10-Acetoxy-lO-Vinylcamphene  methylene  the  238  Anal  10-Acetoxy-10-vinylcamphene in  weak,  m/e  peak).  weak,  olefinic proton),  (CCl*),  v  6 Hz,  olefinic  II I d A  non-hydrogen-bonded  Hz,  4.04  2 Hz,  (singlet,  methyls);  (CC14),  x  c r y s t a l l i n e product provided (80%)  preparative  with  potassium hydroxide  yellowish needles  according to g.l.c.  (Column  g . l . c . G,  (23.2  analysis  110°C)  gave  mg)  which  (Column  in consisted  G,  colorless  130°C). needles  -  (86),  m.p.  78-84°C  Column  G.  11  4 Hz,  Hz,  olefinic  (hot stage),  T (CC14),  and 8 . 9 4  3500  (broad,  strong,  OH),  1645  (sharp,  medium,  C=C),  (M+), C,  178,  73.43;  (two s i n g l e t s ,  163, H,  153  (+)-3,3-Dibromocamphor  bromine the  (40 m l , 120  reaction mixture  destroyed and  with  Removal  of  ice-water  3,3-dibromocamphor m.p.  56-58°C  +37.1°  (c  methine), methyls),  c=o).  1 3  '  73.42;  H,  (100 g ,  brine,  (hot stage)  J = 16  as v e r y  8.75,  8.87  and 2850  H,  J = 16  J = 11  u  m  a  (broad,  strong,  calcd.  using  proton),  (CC14),  x  strong)  =CH);  for C  Hz,  Hz,  olefinic  methyls);  1 2  H  (CH),  m/e 196 2 Q  0  :  2  10.20.  20 h o u r s  i n the dark.  water  layer  were  with  oil  washed over  (148  pale  1 3 a  g)  T (CC14),  (broad,  60°C, 7.27  magnesium  ether  m.p.  g,  1770  1  cm  with  ether  sodium  cooling provided  96% y i e l d ) ,  54-55°C);  1 H each,  CH),  cooling  sulphate.  (30-60)  (129  (multiplet,  singlets, medium,  4 1  with  saturated  s o l i d i f i e d on  crystals l i t .  After  was e x t r a c t e d  anhydrous which  52°C  b r o m i n e was  water,  petroleum  yellow  m.p.  to  and the e x c e s s  The aqueous  and 9 . 0 0 ( t h r e e 2950  Hz,  was h e a t e d  and d r i e d  ( l i t .  1  multiplets,  0 . 4 3 mole)  for  into  a yellow  95% C 2 H 5 0 H ) .  ( C C l J ,  doublets,  Anal,  R e c r y s t a l l i s a t i o n from (91)  on a n a l y s i s  1 4  fractions  1.67,  u  weak)  135.  bisulphite.  gave  of  tertiary  137,  0.75 mole)  saturated  bath.  C,  (39)  organic  solvent  :  was p o u r e d  sodium  the combined  bicarbonate,  in  g,  3 H each,  of  985 and 915 c m " 1 ( b r o a d ,  (91)  (+)-3-Bromocamphor  (doublet  of multiplets,  peak),  Found  homogeneous  doublets  3100 ( s h a r p ,  (base  10.27.  were  of  4.94  4.98 (doublet  8.87  -  which  4.09 (doublet  olefinic proton),  proton),  208  H,  H  2  5  bridgehead  tertiary - 1  (sharp,  strong,  (+)-8-Bromocamphor  A  solution  of  chlorosulphonic (30 m l ,  90 g ,  ( 9 3 )  acid  0.56 mole)  bromine  destroyed  with  bisulphite chloride, gave was  crude  A  A  : -  bromide which the  over  either  of  was  was  was  organic  was  the  extract  hydroxide,  bath  then  poured  and  magnesium  0.35 mole)  ice-water  mixture  bisulphite  stirred  onto  sulphate.  at  room Excess  solution  washed  water,  bromine  ice.  aqueous was  in  while  was  with  sodium  saturated  sodium  Removal oil  of  as  a viscous  brown  Method  B without  purification.  (92)  or  an  carefully  by  saturated  sodium  distilled  of  twice solid  by  Hp  8.90 2950  (c  +76.7° and  9.10  (broad,  the at  (92)  zinc  and  the  solvent g)  (120  g,  m.p.  1.24,  filtrate  water, a  which  (two  medium,  singlets,  to  was  T  [«]  brown  oil  (CC1 ), 4  3 H each,  C H ) , 1740 c m " 1  6.98  (sharp,  anhydrous  g)  which as  Torr).  95%  singlet,  methyls);  strong,  a  (30-60)  1.17,  (broad  was  (0.005  ether (c  tertiary  successively  (93)  70-110°C  +73.1°  5  during  over (69  Hydrogen  temperature  washed  dried  petroleum 2  added.  room  and  b.p.  chloride  5 hours  (+)-8-bromocamphor  83-85°C;  3  was  for  cooling  19% y i e l d ) ,  CHC1 ).  in methylene  mixture  afforded  provide  g)  (200 g)  After  50°C.  solvent  (18.8  dust  reaction  bicarbonate,  to  (120  r e c r y s t a l 1 i s a t i o n from  C H 0H),  5  while  filtration,  Removal  followed  tribromide  kept  colorless crystals,  (CC1.),  A  by  The  sodium  through  provided  -CHoBr),  i t  2 N  vigorously  crystalline  Sublimation  crude  bubbled  sulphate.  5  added.  (108 g ,  (91)  cooled  anhydrous  Method  the  removed  fractionally  2  was  combined  water,  stirred  was  colorless  8  sodium  The  temperature  water,  sodium  3  1 3 a  gas  zinc  with  dried  by  was  the  »  3  before  with  ether.  solution  (200 ml)  1  3,3,8-tribromocamphor  reduced  Method  was  14 h o u r s  solution, and  »  f  (200 ml)  for  extracted  2  (+)-3,3-dibromocamphor  temperature was  1  C=0);  u m/e  2  H,  m a x  232  -  (M+),  230 ( M + ) ,  34.60.  Found  151.  :  C,  Anal,  52.05;  210  calcd.  H,  -  for C  6.50; Br,  l n  H  0Br  1 5  34.80.  :  C,  51.95;  H,  The s t r u c t u r e  6.54; Br,  of  (+)-8-  4? bromocamphor  Method  B : -  1  Crude  ( 9 3 ) was c o n f i r m e d  3  (+)-3,3,8-tribromocamphor  acid  slowly  added w i t h  (250 ml)  The a c i d  vigorous  stirring.  was a l l o w e d  with  saturated  sodium b i c a r b o n a t e ,  distillation to  ether.  Removal  of  g,  110°C  under  diluted were  170  with  washed  mmole) nitrogen water, with  (93)  extract over  o i l  (93)  ( 2 9 . 4 g) was  had been  temperature  was washed anhydrous  g,  added  over  water,  (33 g) w h i c h (18.2  glacial  1.5  and  with  water,  magnesium  on f r a c t i o n a l  55% y i e l d )  identical  A.  (18.2  atmosphere  water,  solvent  gave  a brown  Vigreux  column  (silica  g e l , activity  1  N  79 mmole)  and p o t a s s i u m  and d r i e d o i l  (15.3  g,  grade  with  over g). Torr)  III)  were  heated  The m i x t u r e  ether.  The combined o r g a n i c  anhydrous  followed  water,  magnesium  Fractional  provided  70% y i e l d ) ;  (100 ml)  acetate  hours.  hydrochloric acid,  ( 6 2 - 7 2 ° C , 0.01  (10.6  g,  f o r 72  and e x t r a c t e d  water,  o i l  dust  diluted with  i n dry hexamethylphosphoramide  bicarbonate,  colorless  Zinc  in  (94)46  (+)-8-Bromocamphor (16.2  a brown  by Method  room  and d r i e d  (+)-8-bromocamphor  obtained  8-Acetoxycamphor  gave  was d i s s o l v e d  a l l the zinc  up t o  organic  water,  solvent  bath.  decanted,  The combined  provided  the product  ( 5 4 . 8 g)  After  t o warm  s o l u t i o n was t h e n  extracted  sulphate.  (92)  and c o o l e d by i c e - w a t e r  reaction mixture  hours.  crystallographic analysis. '  b  acetic  the  by X - r a y  saturated  distillation  by column  6.26  cooled, layers  sodium  sulphate.  Removal  using  a  5-inch  chromatograDhy  8-acetoxycamphor  x (CC14),  was t h e n  (broad  (94)  to  as a  singlet,  2  H,  of  -  -CH2OAc),  8.04  tertiary  (singlet,  methyl);  u  calcd.  C=0), for  :  9-Acetoxycamphene  A solution  C,  ammonium  cooled  by an i c e - w a t e r  was  added,  followed  The  reaction  1  with  saturated  sodium  sulphate. in  g,  Normal  65.1  silica  (30-60) give  It  reduction  work-up  afforded  (CC14),  5 Hz,  8.93  (singlet,  2850  (sharp,  gave  product  gave  :  C,  singlets, 1750  3  H,  (sharp,  (M+),  68.66;  (96)  (94)  150.  H,  Anal,  8.70.  (5.0 g,  into  organic  rearrangement was t r e a t e d (70 m l )  o i l  g)  Elution (5 g)  as a c o l o r l e s s  J  = 11  bridgehead  3 H,  medium)  tertiary (CH),  reflux  ether  o i l 1  for  :  (2.36 g,  H each,  methine),  8.04  (singlet,  1745  (sharp,  (CC14),  strong,  2900  C=0),  24  used  chloride  hours.  ether  distilled  to  55% o v e r a l l  =CH2),  allylic  x  was  petroleum  (broad  g  magnesium  chromatographed  7.35  m  and  water,  methanesulphonyl  -CH20Ac),  u  acid  purification.  Hz,  methyl);  ethanol.  with  which  w h i c h was f u r t h e r  5 . 2 4 and 5 . 4 8 (two s i n g l e t s , 2 H,  g)  w h i c h was  with  in  room  anhydrous  without  under  (7.2  and a t  mmole)  hydrochloric  (4.79  with  51.0  was washed  over  o i l  g,  2 3 . 8 mmole)  N  extract  and d r i e d  o i l  1  i n 95% e t h a n o l  (1.94  30 m i n u t e s  poured  III).  a yellow  5 1 . 0 mmole)  borohydride  a yellow  a brown  grade  g,  0°C f o r  brine,  in dry pyridine  (two d o u b l e t s ,  half-width  at  Wagner-Meerwein  9-acetoxycamphene x  (0.74  was t h e n  solvent  (activity  (1:9)  pure  yield); 6.38  gel  CH),  m/e 2 1 0  Found  Sodium  The combined  of  mmole)  aqueous  bath.  bicarbonate,  the subsequent  (7.5  on  ether.  crude  C-O-C);  8.63.  chloride  was s t i r r e d  hour.  Removal  The  H,  by 8-acetoxycamphor  mixture  extracted  strong,  (two  (96)4^  of  for  (broad,  strong,  68.55;  was  temperature  2900  9 . 0 0 and 9.12  T"  A  1235 c m " 1 ( b r o a d ,  C ^ g O ^  -  CHgCOO-),  ( C C l J ,  v  IMG  strong,  3 H,  211  6.15  signal,  1  3 H,  (sharp,  and  H,  CH3C00-), strong)  1650 ( s h a r p ,  weak,  and  -  C=C),  1240  (broad,  (M+),  152,  134,  H,  9.34.  strong,  121  Found  C-O-C),  (base  peak),  C,  74.00;  (+)-9-Hydroxycamphene  (97)  A mixture potassium 2.5  of  H,  (1.8  Working-up  g,  (silica  provided  (+)-9-hydroxycamphene  (two 7  ™,„ max  u  bridgehead (CHCK), o  weak,  J  allylic  3650  (97)  (broad,  m/e  (M+),  124,  121  :  C  '  7  9-0xocamphene  8  '  9  0  '  H  '  -  =CH0); H  1 2  1 8  F  grade  0  m/e :  o  2  7.38  III)  C,  74.19;  (broad  u  n  (sharp,  :  c  >  78.77;  H,  product  g , 83%  CHC13);  6 . 6 9 and 6.91 1  H,  half-width  tertiary  OH),  strong,  8 9 , 87.  3400 CH),  methyl); (broad,  1650  (broad,  strong,=CH,,);  Anal.calcd.  for  10.40.  chlorochromate  (225 mg, 1.04  mmole)  prepared  according  43  (2  procedure ml).  chloride  g).  pressure)  (1.55  signal,  3 H,  (2.15  the crude  1.53,  885 cm"1 (broad,  93, 91,  d  (c  =CH0),  (singlet,  C-0),  of  o i l  for  (98)  Pyridinium  the  194  and  was r e f l u x e d  crystals  +95.4°  3  mmole)  atmospheric  H each,  and 2800  °  12.2  a brown  non-hydrogen-bonded  peak),  -  1  8.94  strong,  5 9  afforded  80°C,  H  -CHo0H),  2850  (base 1 0  for C  (2.36 g,  as c o l o r l e s s  tube);  weak,  OH),  1020  10H16°  temperature  Hz,  (sharp,  C=C),  C  fashion  methine),  medium,  calcd.  i n 95% e t h a n o l  g e l , activity  (sealed  = 11  hydrogen-bonded  152  (96)  5 . 2 9 and 5 . 5 8 (two s i n g l e t s , 2 H,  strong,  9.18.  (bath  68.0-69.5°C  doublets,  Hz,  Anal,  4 5 . 0 mmole)  by s u b l i m a t i o n  T (CC14),  106.  (broad,  4 6  followed  m.p.  890 cm"1  i n the usual  chromatography  yield),  -  (+)-9-acetoxycamphene  hydroxide  hours.  Column  :  212  of  Corey  and Suggs  (+)-9-Hydroxycamphene was a d d e d .  The  was s u s p e n d e d  (97)  solution  (87.1  turned  i n methylene  mg, 0.57 brown  with  mmole)  in  chloride methylene  the formation  of  to  precipitates. filtered  through  anhydrous  5.04  product  m.p.  of  8 Hz,  bridgehead  ( C C l J ,  1650 ( s h a r p ,  m/e  (M+),  136,  Found  led  to  Florisil from  and t h e r e s i d u e was washed  the f i l t r a t e  (98) as c o l o r l e s s T (CC14),  1 H each,  =CH0),  (sharp,  gave  a  crystals 0.74  30°C,  (73.2  strong,  CH),  0.1  1 H,  signal,  8.88 (singlet,  with  mg, 86%  (singlet,  (broad  was  colorless  (bulb-to-bulb,  7.30  methine),  and 2800  the reaction mixture  1  3 H,  1725  -CH0), H,  tertiary  (sharp,  weak,  (base  C=C),  peak),  890 c m  105,  r e s o l u t i o n mass  storage  under  (broad,  Mole.  f o r 3-4 days  medium,  wt.  spectrometry)  (98) c o u l d be s t o r e d  However,  93.  - 1  :  for C  1 0  H  1 4  0  oxidation  yield  of  (+)-9-hydroxycamphene  (65%) u s i n g  (97)  the pyridine-sulphur  - 4 ° C under  days  at  nitrogen  room  temperature  could  trioxide  also  be e f f e c t e d  complex  in  in dry  34 dimethylsulphoxide.  9-Acetoxy-9-Ethyny1camphene  A  solution of  (89)  9-oxocamphene  (98)  (108 mg. 0 . 6 8 mmole)  in dry  ether 44  (12  m l ) was added  (140  was  a solution  m g , 1 . 5 2 mmole)  mixture it  to  was s t i r r e d  was p o u r e d  into  washed w i t h  of  lithium acetylide  i n dry hexamethylphosphoramide under  water  water  nitrogen  at  room  and e x t r a c t e d  and d r i e d  over  with  ethylenediamine (3 m l ) .  temperature ether.  anhydrous  :  150.1043.  at  a i r for several  calcd.  =CH2);  decomposition.  The lower  121  (High  aldehyde  atmosphere.  of  allylic  2850  C=0),  The  temperature  H  strong,  150.1044.  room  mg) w h i c h w a s d i s t i l l e d  9-oxocamphene  l l i Q A  150  at  solvent  (two s i n g l e t s ,  vm3V  methyl);  -  2 8 . 5 - 3 1 . 5 ° C (hot stage);  and 5.41  half-width  (77  213  column  Removal  to provide  yield),  2 . 5 hours  a short  ether.  crystalline Torr)  After  -  f o r 17  The  hours  The o r g a n i c  magnesium  reaction before  extract  sulphate.  Remova  -  of  solvent  gave  a yellow  o i l  chromatographed  on s i l i c a  petroleum  (30-60)  as  ether  214  -  (150 m g ) , a small  gel  (1:9)  (activity provided  grade  (silica  =CH2),  5 . 8 3 (broad  (broad  signal,  (multiplet,  x  gel) analyses; signal,  1 H,  =CH),  7  Hz,  1  H,  Elution  on g . l . c .  (CCl^),  half-width  half-width  III).  o f w h i c h was with  ether  9-ethynyl-9-hydroxycamphene  a c o l o r l e s s o i l w h i c h was homogeneous  t . l . c .  portion  5.18  6 Hz,  1  3 H,  A,  (99)  130°C)  and  and 5 . 2 6 (two s i n g l e t s , H,  bridgehead  8.86 (singlet,  (Column  propargylic allylic  tertiary  2  -CHOH),  methine), u  methyl);  :  7.34  7.70 (CClJ,  m a v  Ii Id A  3610,  3570  (broad,  and 3490  weak,  (broad,  C^C),  900  cm"1 (sharp,  77,  67,  1660 ( s h a r p ,  strong,  65, 55, 53, 51,  176.1201. In  Found  general  without  (High  hours.  Torr)  afforded  (111  m g , 75% o v e r a l l  propargylic  (doublet, H,  1  tertiary  J  m/e 176  (M+),  121  43, 41,  of  Mole.  5.27  x  alcohol  (99)  =CH), u  v  1  H,  8.04  ( C C l J ,  and 2900  C=C),  (sharp,  strong,  C=0),  C-O-C),  900 c m '  93,  79,  67,  1  (sharp,  4.70  peak),  C-0),  93, 91,  for C  (99) was  was heated  1 2  H  (singlet, 3320  to  medium,  3 H,  H,  H each,  1 6  0  :  acetylated  100°C  for 6  medium, (CH),  medium,  41,  = 2  100°C,  Hz,  =CH2),  7.33 7.79  8.81  =CH),  (singlet,  3100  (sharp,  2150 (broad,  C=C),  m/e 2 1 8  peak),  J  methine),  CH3C00-),  medium)  =CH2);  (base  1  1  allylic  (sharp,  (broad,  79,  (89) as a c o l o r l e s s o i l  bridgehead  43  strong,  176.1197.  (doublet,  1665 ( s h a r p ,  65, 55, 53, 51,  2140  ( 1 5 0 mg) a n d a c e t i c  and 5 . 4 5 (two s i n g l e t s , 8 Hz,  =CH),  calcd.  :  .  by d i s t i l l a t i o n ( b u l b - t o - b u l b ,  (CC14),  strong)  strong,  wt.  spectrometry)  followed  yield);  methyl);  77,  39.  in dry pyridine  (broad,  91,  40,  (base  9-ethynyl-9-hydroxycamphene  work-up  = 2 Hz,  strong,  1060 ( s h a r p ,  weak),2980 1760  (sharp,  C=C),  r e s o l u t i o n mass  half-width  H,  3310  9-acetoxy-9-ethynylcamphene  -CHOAc),  signal,  OH),  medium,  A mixture  aqueous  0.05  3  44,  (510 m g , 5 . 0 mmole)  Normal  (broad  =CH2);  the crude  purification.  anhydride  medium,  H,  1240  (M+), 39.  weak,  (broad,  176,  158,  121,  -  Reaction  of  for  acid  2  with  proton  water  allylic  sodium were by  washed  silica  of  gel  overall 5.90  (broad  exchanged  D^O,  3500  1715  (sharp,  strong,  base  peak),  for  spectrometry)  :  i2  H  crude  organic  mmole)  3 H,  and  oil  98%  at  mixture  over (L)  100°C was  was  washed  anhydrous  (96  (multiplets,  CH3C00-),  in  then  extract  dried  a yellow  H,  mixture  over  to  mg),  2 H,  8.90  olefinic  and  194.1307.  was  then  the  (87  (sealed  hydrolysed in  9.12  combined  6 Hz,  subl.  -CH0H),  6.90  9.13  (two  singlets,  medium,  OH),  2950  and  1  9  1090  cm-1  (broad,  161,  151,  138,  4  -  1  3  0  6  -  F  fractions  sulphate  o u n d  137,  2875  medium, 136,  (High  by  subsequent (M)  (24  74-76°C; (broad  (broad, C-0);  resolution  T  m/e  194  122.  mass  25%  (CC14), 1  H,  methyls);  strong,  133,  mg,  signal,  3 H each,  135,  followed  purified  and  pt.  water  organic  colorless crystals  tube),  :  saturated  w h i c h was  chromatography  refluxing  with  magnesium  mg)  by  methanol  diluted  and  165, :  oil  was  mmole)  anhydrous  provide  half-width  (L)  3.1  and  column  8.87  mg,  ether,  III)  C=0),  18°2  product  (394  a yellow  Torr)  (broad,  176, c  gave  OH),  ( C C l J ,  calcd.  (singlet,  0.50  reaction  and  4.70-4.90  150-153°C 1  u  wt.  water,  HC00-),  Drying  0.05  signal,  179,  The  H,  with  grade  m.p.  with  the  gave  reaction  water.  solvent  yield),  ether.  mg,  Acid  30 m i n u t e s  solvent  the  extracted  (80°C,  for  of  7.96  Formic  (111  temperature,  with  monohydrate The  (activity  sublimation  with  methyls).  hours.  with  room  bicarbonate,  1  -CHOAc),  6 H,  chloride,  removal  sodium Removal  carbonate  12  to  temperature  extracted  purification,  sodium for  room  (multiplet,  singlets,  (1:1)  and  sulphate.  and  at  cooling  saturated  Without with  stirred  2.10  (B9)  9-acetoxy-9-ethynylcamphene  After  water,  (CC14),  (two  was  with  magnesium T  of  hours.  diluted  -  9-Acetoxy-9-Ethynylcamphene  A mixture formic  215  CH), (Mf, Mole,  -  Deoxyqenation  of  A mixture distilled was  of  boron  of  the  a yellow  provided A  solvent  oily  refluxing  room  etherate  temperature  for  was  by  removed  (95%)  colorless  solution  of  (45  (M)  r e s i d u e w h i c h was  ethanol  -  (M)  hydroxyketone  trifluoride  s t i r r e d at  most  Hydroxyketone  216  (4 17  drops)  then  treated  hours.  crystals  (15  mg)  mmole)  in  freshly  washing  (80°C,  with  0.1  with  Torr)  Raney-nickel  Working-up  which were  and  1,2-ethanedithiol  After  distillation  1.5  crude  0.23  hours.  for  the  mg,  in  the  (^5  usual  in  methylene  ml)  water, to  give g)  in  fashion  oxidised without  c r y s t a l l i n e product  (5  purification.  chloride  was  43 added in  to  the  a  suspension of  same  solvent.  Florisil  after  filtrate  followed  (activity (9  mg),  grade  m.p.  9.17  (two  2800  (broad,  178  2  by  III)  at  mixture room  strong, 150,  calcd.  spectrometry)  :  for  chlorochromate  was  column  136,  178.1360.  tube),  cm"1  135,  123, :  through  afforded  (sharp,  178.1357.  121,  strong, 108,  Found  mg,  m  a  solvent  from  by  silica  (CCl^),  (High  94,  of the  gel  crystals  T (CC14),  x  mmole)  column  C=0);  107,  1.12  short  colorless  pt.^60°C; u  a  of  product  methyls);  122,  (242  Removal  crude  subl.  tertiary  1718  C^H-^O  the  chromatography  (sealed  CH),  filtered  temperature.  p u r i f i c a t i o n of  singlets, 3 H each,  +  wt.  hours  183-188°C  (M ), 163,  Mole.  The  pyridinium  9.12  2850  m/e  179  93  (base  resolution  (N) and  and (M  +  +  peak).  mass  1),  -  217  -  BIBLIOGRAPHY  1.  J . Hochmannova, 2711 ( 1 9 6 2 ) .  2.  K.  3.  D.E.  Bays,  4.  P.T..  Lansbury  5.  K.  Vokac,  Z.  L.  Novotny  Samek,  G.W.  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Kreiser,  Janitschke,  112,  397  L.  (1979).  Janitschke, W.  Chem.  Ber.,  Voss,  L.  112,  Ernst  408  (1979).  and W.S.  Sheldrick,  ibid.,  - 220a -  PART IV  Synthetic Approaches to Clausantalene  -  221  -  INTRODUCTION  An  oxygenated  isolated from  of  ClaUsena  clausantalene.  clausantalene homoallylic which  with  as a c o l o r l e s s c r y s t a l l i n e  the roots  named  sesquiterpenoid  indicated  was a t t a c h e d  structure  (1)  The n . m . r .  1  secondary to  indica  compound,  Oliv.  alcohol  of  bearing  w a s  1.9, et  CHCl^),  al_ and  characteristics  an i s o p e n t e n y l methyl  a hydroxyi  (c  by J o s h i  spectral  and two t e r t i a r y  a carbon  was t h e r e f o r e  [°=]n + 2 7 . 7 °  (Rutaceae)  and mass  the presence  ^-j5^26^2  the composition  chain with groups,  function.  one The  of  a of partial  proposed.  HO.  "CH3  H3C'  (1 )  Catalytic  hydrogenation  (2)  C15H 0 ,  any  unsaturation.  2 g  2  clausantalene not  completely  X-ray  m.p.  102°, [«] Although  was t h e r e f o r e determined  crystallographic  although  the absolute  of  clausantalene  +16.6°  (c  the b i c y c l i c apparent  nature  of  structure  remained  dihydroclausantalene  which (2)  did not  and hence  possess of  c a r b o c y c l i c framework  and s p e c t r a l  provided  configuration  CHC13),  the total  by c h e m i c a l  analysis  2,  provided  in  means. (3)  doubt.  for  was  Subseouent clausantalene  -  222  -  H  2  (2)  (3)  It  is  obvious  resemblance Indian  to  santalol  clausantalene  (-)-e-santalene  sandalwood  (5),  3-santalol  oil  (Santalum  B-santalic  album  (6),  acid  santalene  (11) (Scheme  (7) h a v e  (lauraceae).  It  stereoselective involved  also  l ) .  been  therefore  in  the  2  "  and  has  Linn)  close  been where  structural  isolated it  from  co-occurs  (9), (+)-epi-8-santalene (-)-B-Santalene  5  from  reasonable  regiospecific  biosynthesis  of  with  ( 1 0 ) , and  (4) and  Cinnamomum to  East  ( 7 ) , (+)-«-  (+)-*-santalene  isolated  seems  hydroxylation  (3) b e a r s  (4) w h i c h  (8), t r i c y c l o e k a s a n t a l a l  epi-3-santalol  (4) a r e  that  (+)-—  camphora  speculate  Siebold  that  hydration  clausantalene (3).  of  6-santalene  - 223 -  (A)  ( 7 )  (6)  (9)  SCHEME 1  (10)  -  224 -  DISCUSSION  The  sesquiterpenoid  (-)-8-iodocamphor Scheme  Part  7,  clausantalene not  yet  camphor latter of a  III).  established,  compound  from  2)  enol  butyl  hydroperoxide  However, (sodium  benzene  (13)  pure  of  as  synthesis,  to  has  8-substituted  Thus,  on s e s q u i t e r p e n o i d  7  was c o n v e r t e d to  the  an we  extension considered  clausantalene  III,  and c a t a l y t i c  did not afford Droduct  p.178.  The  n.m.r.  and  two d o u b l e t s  C10H  spectrum at  1 8  and  (3)  amount  could  product  be reduced  hydride)  two t e r t i a r y  to M  methyl  6.12 a n d 6.80x, J = 11 H z ,  epoxidation  the t r a n s i t i o n of  olefins  metal  2  of  sequence of  group with  (15)  t-  hexacarbonyl10  after  aaueous  in situ provide  1  '  hydration  the exo-methylene Treatment  8 9  (14)  by t h e  (15)  o f molybdenum  any u s e f u l  o  showed  (+)-8-bromocamphor  stereoselective  of  0 , m . p . 189.5-191°C,  the mechanism of  hydroperoxide  The  reduction.  bis(2-methoxyethoxy)aluminum diol  to  9-hydroxycamphene  vi_a e x o e p o x i d a t i o n  the epoxidation  crystalline  Although  and  (4)  precursor  III).  (13)  Discussion,  configuration  as a s y n t h e t i c  p.132, P a r t  by r e g i o s e l e c t i v e h y d r i d e  refluxing  absolute  an o p t i c a l l y  (+)-3-bromocamphor  21, P a r t  was e f f e c t e d  followed  whose  that  be used  was t r a n s f o r m e d  i n Scheme  (15)  also  (cf.  2)  from  (18).  in turn,  outlined  suggests  Discussion,  (+)-3-Bromocamphor which,  1  (Scheme  synthesised  s i m i l a r i t y between  metabolite  investigations  (Scheme  epimer  could  (cf.  our previous  its  structural  a plant  derivative  route  The  h a s been  (4)  in our laboratory6  (12)  (3),  been  (-)-B-santalene  with a  in  work-up.  Redal  colorless  - 3 5 . 2 ° ( c 0 . 6 5 , CHC1 ). 3  singlets for  8.78 a n d 9.01T,  t h e -CH^OH  catalysed  has n o t been  at  protons.  t-butyl  confirmed,  "^a,c  the  reaction  w a s known  stereoselective that  both  state  complexing  to  from  the exo side Thus  crystalline  i t  group of  diol  atom. in  (15)  reasonable  obtained  by  as h i g h l y  enols.  group  Examination will  the molecule  appears  as w e l l  direct  leading to  assign  in situ  to  regiois  in  its directive  m o l e c u l a r models  the reagents transition  structure  regioselective  and  believed  are involved  exerts of  It  1 0  and the hydroperoxide  the hydroxyi  the metal  the 9-hydroxyl  efficient  and h o m o a l l y l i c  catalyst  and t h a t  that  (20).  be more  for allylic  the metal  transition by  to  to  state  the effect  revealed  attack (19)  (16) t o  the  reduction  of  or  exo-  27 epoxide  (21).  (16) R= t - C H A  (21)  9  Oxidation sulphoxide  of  diol  (DMSO)11  aldehyde  proton  infrared  absorption  (16) w i t h  gave  singlet at  pyridine  hydroxy-aldehyde at  1725  0.60x cm"1.  sulphur  trioxide  -  (17) c h a r a c t e r i s e d  i n the n.m.r. The compound  spectrum could  dimethylby  and the  be s t o r e d  the carbonyl at -4°C  -  under  dry  exposure via  nitrogen to  air  atmosphere  at  a retro-aldol  room  227  for  1-2  temperature  mechanism as  expected  3-methyl-2-butenyl  at  of  3.91x  the  the  (1  5.00T  carbon  H,  (1  J  H,  double  (22)  (3)  reaction  = J  18 =  bonds  with  and  18  storage  decomposition,  Hz)  hydroxy-aldehyde bromide  epimer did  proton  11  Hz)  were  its  product  Hz,  of  magnesium  olefinic  6,y-unsaturated  reagent  in  prolonged  or  presumably  depicted.  treatment  (prenyl)  trisubstituted  and  that  clausantalene  spectrum and  but  (17)  was  provide  days,  resulted  (16)  It  -  not  (18).  two  doublets  alcohol(s)  The  (23).  9-oxocamphene  (24),  at  (22)  the  expected  Instead  c h a r a c t e r i s t i c of  observed.  the  with  chloride)  However,  show  signals.  and  (or  (17)  n.m.r.  vinyl  a doublet 4.96  would  (1  H,  monosubstituted  product  was  therefore  Reacting  the  allylic  prepared  by  methyl  of J  doublets = 11  Hz)  carbonmost  likely  Grignard  pyridinium  1o chlorochromate Part  III),  also  oxidation provided  of  the  9-hydroxycamphene corresponding  (15)  alcohol(s)  (cf.  Compound  (25).  (98),  -  (15)  X = Br  228  -  (2A) or  (25)  Cl  S i m i l a r attacks by the y - s i t e of a l l y l i c organometallic reagents in nucleophilic a d d i t i o n  1 3  '  1 4 b  and s u b s t i t u t i o n  1 4  reactions have been well  documented although these reagents are known to e x i s t in s o l u t i o n as a r a p i d l y e q u i l i b r a t i n g mixture of the forms (A) and (B) with the e q u i l i b r i u m l y i n g well to the side of the primary form (A). It was 13f suggested by Benkeser et a |  15  and Young and Roberts  t h a t , in the case  of unhindered aldehydes or ketones, the unsaturated alcohol (C) i s formed v i a a six-membered c y c l i c t r a n s i t i o n state in which the metal atom of form (A) i s complexed to the carbonyl oxygen (Scheme 3 , S ^ i ' ) . and Frajerman  16  and Holm  1 3 a <  However, F e l k i n  considered that formation of alcohol (C) from  - 229 -  R] , R , R 3 , 2  R = alkyl , H 4  M = MgX , ZnX , Li  SCHEME  3  -  (A)  proceeds  studies  and  When formed  via  an  and  of  and  ketones  prompted  to  reagent.  However,  (24)  magnesium  and  bromide the none  (22,  which  attempt  no  X = Br)  in  prenyl  coupling  of  desired  the  MgBr  an  reported  S^i'  route  of  on  had a  in  been  recently  ore-mixed  observed  benzene-ether  tetrahydrofuran. product  and  alcohol(s)  a  ^-attack  carbanion  with  was  a  (26)  could  be  was  an  kinetic  added  to  the  of  were  reacted  with  bromide,"'7  allylic  solution  Refluxing low y i e l d  of  products  magnesium  using  when  bases  symmetry.  that  similar reaction was  the  orbital  1-trimethylsilylallyl  reaction  bromide  of  -  conservation  co-worker  regioselectively if  we w e r e  but  instead  consideration  Chan  aldehydes  gave  S ^ '  230  Rrignard  of  9-oxocamphene  prenyl  magnesium  mixture  for  20  9-hydroxycamphene  hours (15)  detected.  2  (26)  It  has  been  organometallic proportion be  of  reagents the  increased at  temperature  of  demonstrated  e x D e n s e  reaction  reactions  involving  reversible.13a-g,18  thermodynamically  the the  are  that  of and  the by  more  stable  kinetic using  j  p  a r  ti  ^-attack  product  allylic  n  allylic  (C)  by  C  ular,  product  the (D)  can  i n c r e a s i n g the '  organozinc  reagents.  -  Indeed  model  prenyl  zinc  studies bromide  provided  yield)  dry  hexamethylphosphoramide  24  analogous  were  bromide  (29)  (67°C,  However,  in  a complex  less HMPA  alcohol  r e a c t i o n was  alcohol  refluxing  (17)  the  was  (100°C,  mixture  thermodynamically  (HMPA)  of  (28)  as  using  to  stable  the  the  hours)  of  at  In  compound  product  115°C  (24  contrast,  r e a c t i o n was  and  (over  90%,  hours)  in  only  the  performed  in  (THF).  (24)  provided  alcohols.  carbonyl  major  proceed  9-oxocamphene  o l e f i n i c compounds  more  the  solvent.  when  Treatment  24-60  as  as  tetrahydrofuran  reactions  successful.  (27)  allowed  obtained  hours)  -  benzaldehyde  70%  isomeric  if  using  231  with  or  (24)  or  (17)  with  hydroxy-aldehyde prenyl  some y - a t t a c k no  trace  of  the  zinc  product  and  -  232  -  other compounds  other compounds  Aldehyde prenyl  (24)  p-toluenyl  remained s u l phone"'9  intact in  on  treatment  refluxing  with  THF-HMPA  the  anion  (1:1).  (30)  of  Preliminary  20 studies (27)  on  the  action  indicated  Li*  that  of  only  the  ir-allylnickel  alcohol  (29)  was  complex  benzaldehyde  of  carbonyl  j  -  recent  compounds  on  formed.  ( 31)  (30)  A  (31)  report  with  by  Sakurai  allylsilane  et  a l / '  catalysed  by  on  the  allylation  t e t r a - n _ - b u t y l ammonium  fluoride  22 rv-Bu^NF  provided  the  solution  to  our  problem.  Prenyl  trimethylsilane  23 (32)  was  the  (22,  X = Br)  only  with  product  obtained  trimethylsilyl  on  reacting  chloride.  prenyl  Treatment  of  magnesium  bromide  9-oxocamphene  (24)  -  with  silane  work-up a  (32) and a c a t a l y t i c  and column  colorless oily  and  t . l . c .  product  product  (silica  indicated  singlets  -CH=C(CH^)2 e n t i t y .  n-Bu^NF f o l l o w e d g e l , activity  w h i c h was homogeneous The n . m . r .  i t was a m i x t u r e The broad  (26).  ( 6 H)  of  (silica  gel) analyses. that  -  amount  chromatography  butenyl)camphenes broad  233  of  The e x o - m e t h y l e n e  aqueous III)  (Column  (Figure  provided  A,  130°C)  1) o f  this  9-hydroxy-9-(3'-methyl-2'-  triplet  a t 8 . 3 5 and 8.44x  grade  on g . l . c . spectrum  by  (1 H )  at  4.74x  and t h e two  are characteristic of singlets  of  the  the epimeric  alcohols  i were the  observed epimers  a doublet provided showing 1060 be  5.21 and 5 . 4 0 x ,  showed  a doublet  of doublets further  detected  Only  of  at 6.76x  confirmation  a n OH a b s o r p t i o n  cm"''.  product  at  a trace  by c a r e f u l  at  and 5 . 1 7 and 5 . 5 2 x . doublets  (J to  group  of  t-butyl (cf.  6.66x  4 Hz).  the presence  of  (J  = 10 H z ,  The i . r .  amount  (^5%) o f  examination  of  the y-attack  the n.m.r.  group  of  o f (26)  by at  (25) could the  crude  mixture.  (26)  was hoped dienols  that  (26) could  hydroperoxide  p.224).  selective  be a c h i e v e d  and molybdenum  The s u c c e s s o f  this  (25) traces  exo e p o x i d a t i o n  of  by t h e p r o c e d u r e  hexacarbonyl10  regio-  the terminal  olefin  employing  described  and s t e r e o s e l e c t i v e  of  and  absorption  product  spectrum  3 Hz),  spectrum  an a l c o h o l  3500 cm"'' and a C - 0 s t r e t c h i n g  (24)  It  = 9 Hz,  at  The -CHOH p r o t o n s  above epoxidation  -  would  depend  complexed chain  in  on w h e t h e r  to  the  (26)  to  attack  on  the  the  the  C(9)-hydroxyl  hydroperoxide  and  the  attain  exo-methylene  group  of  (26)  with  t-butyl  (0.1  equivalent)  hexacarbonyl reduction  with  the  (see  in  a colorless oily  product  olefinic  proton  methyl  dienols  (26)  and  vinyl  other  olefin.  catalyst,  undesired  *^  1 0  (1.3  refluxing  preparation  group,  as  imposing  hydroperoxide  provided  nor  while  trisubstituted  Redal  metal  such a conformation  attack  dienols  -  not  could  or  235  of  whose  to  which and  geometric  benzene  n.m.r.  the  reagents  constraints  and  followed  (16),  prenyl  treatment  equivalents)  diol  the  direct  However,  was  of  molybdenum  by  in  situ  Experimental,  spectrum  signals.  Obviously  reactions  had  showed  p.237)  neither  bis-epoxidation  of  occurred.  (3) In  the  event  clausantalene or  ester  *  Some  (3)  an  alternative  and  derivative  appropriate  its of  the  acetate  catalyst.  (18)  leading would  hydroxy-aldehyde  protecting  3-methoxyethoxymethyl and  epimer  route  entity  ether  groups?|or (MEM),  formed  with  (17)  to  the  involve with  tertiary  synthesis  treatment prenyl  an  ether  trimethylsilane  alcohols  methylthiomethyl  of  of  include  ether  (MTM),  4-(N,N-dimethylami no)pyridine  as  -  (32) under  and n-Bu^NF, the basic  Investigation  in  as compound  condition this  of  236  (17)  -  itself  may u n d e r g o  the a l l y l a t i o n  direction  i s being  reaction  pursued  or  protecting  group  (cf.  in our  R =H R = H  retro-aldol  (3)  cleavage  p.227). laboratory.  EXPERIMENTAL  General  See  Experimental,  Part  I  (p.60).  Preparation of (+)-9-Hydroxycamphene (+)-3-Bromocamphor (13)  See  Experimental,  Part  III  (15)  and 9-0xocamphene  (24)  from  (p.208-213).  (-)-2-endo,3-endo-Dimethyl-2-Hydroxy-3-Hvdroxymethylbicyclo[2,2,l]heptane (16)27 — — '  A mixture molybdenum (6.46 for  of  (+)-9-hydroxycamphene  hexacarbonyl  mmole/ml)  2.5 hours.  ( 8 m g , 0 . 0 3 mmole)  ( 0 . 2 0 m l , 1 . 2 9 mmole) After  1 0  cooling  bis(2-methoxyethoxy)aluminum (0.29  g,  1.61  exothermic After was  hydride,  i n d r y benzene occurred  and washed  and w a t e r .  Drying  a colorless  activity  grade  provided  pure  with  anhydrous  crystalline solid.  III) diol  with (16)  ether  :  petroleum  as c o l o r l e s s  A to  the  crystals  The  were  bicarbonate,  and removal  (30-60)  It  aqueous  fractions  sodium  chromatography ether  mixture.  f o r 2 hours.  The o r g a n i c  sulphate  Aldrich)  violent  chloride.  saturated  refluxed  (sodium  i n benzene,  color  ammonium  water,  Column  Redal  was r e f l u x e d  ether.  magnesium  hydroperoxide  slowly.  a yellow  dilute  successively with over  70% s o l u t i o n  mmole),  (4 m l ) was  temperature,  the solution  and e x t r a c t e d  mg, 0.51  and t - b u t y l  was added  imparting  had s u b s i d e d  (77  i n d r y benzene  t o room  cooled and hydrolysed with  was s e p a r a t e d  combined  gave  reaction  the reaction  then  layer  mmole)  (15)  of  solvent  (silica g e l ,  (3:7)  as  ( 3 2 m g , 37% y i e l d ) ,  eluent m.p.  -  189.5-191°C  (sealed  homogeneous  on  t . l . c .  6.12  and  T  (CDC13),  8.78  and  9.01  (two  tube),  [-]21  (silica 6.80  238  singlets,  -36.2°  gel)  (two  -  and  (c  0.65,  g . l . c .  doublets, 3 H each,  1  CHC13),  (Column  H each,  tertiary  J  which  G,  were  140°C)  = 11  Hz,  methyls):  analyses.  -CHo0H),  •  (CHClJ,  u m ci x  3440  (broad,  strong, C,  strong,  OH),  Anal,  calcd.  C-0).  70.28;  H,  2850  (broad,  for  c  strong,  -jQHI8°2  :  C  '  CH),  7 0  *  1050  >  5 5  H  »  cm"1  1 ° '  6 6  (broad,  -  Found  Chlorosulphonic to  a  acid  solution  tetrachloride  (2  ml)  removed  to  form  in  dry  dimethylsulphoxide  of  di ol  (63.4  mmole)  in  temperature  for  ml).  20 m i n u t e s  bicarbonate,  and  sulphate  removal  was  of  of  the  0.60  (singlet,  methyls);  desired  u  m ci x  (sharp,  strong,  C=0).  1  H,  it  brine.  hexane  8.71  3400  dry  to  a  (0.48  ml,  diluted with  over  9.01  m.p.  singlets,  carbon  dissolved mixture 351  at  mg, room  and  washed sodium  magnesium  ( 5 5 mg)  crystals  92-94°C  with  saturated  anhydrous  colorless  (two  ether  solid  which  (42.7  (subl.);  OH),  2850  (sharp,  weak)  (CH),  1725  cm"1  ( C C l J ,  T  3 H each,  medium,  mg,  tertiary  strong),  T  and  2750  (sharp,  2 7  in  a  stirred  water,  colorless  (17),  (broad,  and  triethylamine  afford  and  hexane  was  )  supernatant  to  Drying  gave  mmole)  added  hydrochloric acid,  solvent  -CHO),  with  3.65 The  1 1  (17  dropwise  s o l u t i o n was  was  hydroxy-aldehyde  ( C C l J ,  medium)  and  added  288 mg,  reaction mixture  before  2 N  saturated  r e c r y s t a l l i s e d from  68%)  2700  water,  washed  This  mmole)  ml,  was  precipitate.  was  The  mmole)  (0.29  (DMS0).  (1  with  1.74  a white  solid  0.37  successively  and  the  mg,  DMS0  mg,  pyridine  was  (16)  and  (203  of  liquid  3.48  :  10.75.  2 - endo, 3-e_ndo-Dimethyl -3-Formyl - 2-Hydroxybi c y c l o [ 2 , 2 , 1 ] heptane  stirring  j  (sharp,  -  The at  -4°C  to  air  hydroxy-aldehyde for  at  Reaction  1-2  room  of  Aldehyde  stirred  in  dry  by  (85  0.5  mg,  at  room  which  (3  ml,  0.47  spots  provided  T (CDC13), and  CH^CH-),  6.63  (broad  tertiary  oil  (doublet  5.00  (two  of  1  H,  or  at  then  Chloride  and  one  ether  on  exposure  small  added  of  gave  which  doublets, 2 H,  -CH0H),  H,  III)  with  8.80,  Hz,  (150  mg)  CH^OH-CHCl^). chloroform  Hz,  18  8.88  stirred  oil  displayed  J = 18  J = 11  (17)  saturated  2%  still 1  was  gel,  grade  with  aldehyde  a colorless  (silica  activity  with  crystal  l-chloro-3-  dropwise  reaction mixture  work-up  X=C1)27  iodine  temperature  hydrolysed  (23)  (22,  solution  was  room  The  doublets,  signal,  an  analysis  gel,  storage  atmosphere  tv/o 11  Hz,  t . l . c . Hz,  respectively,  and 8 . 9 0  (singlets,  methyls).  solution  of  1,2-dibromoethane magnesium  powder  evolution  of  (24)  mg,  (102  aqueous  )  mmole)  added.  nitrogen  hours.  hour  and  under  prolonged  mmole  4.4 1  t . l . c .  R e a c t i o n o f 9-0xocamphene and Magnesium Bromide  A  while  (silica  3.91  4.96  H,  ml) g,  stored  Magnesium  17  a colorless  CH2=CIH-),  12  on  on  Prenyl  hour  Normal  be  several  After  1  -  mg,  slowly  for  chromatography  eluent  spots;  two  (430  ether  was  chloride.  for  with  bath.  mmole)  showed  Column as  a water  temperature  ammonium  (17)  (0.5  could  decomposed  turnings  methyl-2-butene cooling  but  temperature  Magnesium were  days  (17)  239  magnesium (294  (46  ethene 0.68  (24)  mg,  mg,  with  bromide  1.56  1.91  were  was  mmole) mmole)  had c e a s e d d r y mmole)  Prenyl  prepared  in in  Magnesium  added.  by  dry  ether  ether  (9  benzene This  (3  ml)  Bromide  X=Br)  adding to  a  ml). and  mixture  (22,  suspension After  the  9-oxocamphene  was  then  added  of  -  dropwise  to  a tetrahydrofuran  (22,  X=Br)  gel)  analysis of  occurred for  (1.1  after  20 hours  (silica and  mmole)  of  hour  prepared  at  followed  g e l , activity solid  of  Aldehyde  (70  mg, 1.07  ice-water in  mmole  for  grade  provided  with  fashion  followed  III)  the crude which  to  was added i n THF  The  (silica  no r e a c t i o n the  had  solution  chromatography coupling  identical  product  to  those  Bromide  solution of  with  to  vigorous  at  before  120°C  not  data  bromide  T . l . c .  the prenyl  0 ° C , aldehyde  dry  21  (17)  was s t i r r e d a t  hours.  diol  The  (23)  by  in  (HMPA)  the  with  was  HMPA usual  g e l , activity  together  mmole)  room  remaining  Working-up (silica  dust  (84 mg, 0 . 5  hexamethylphosphoramide  chromatography provided  zinc  s t i r r i n g and c o o l i n g  by d i s t i l l a t i o n .  for  been  l-bromo-3-methyl-2-butene  a suspension of  reaction mixture  by column  have  that  and column  Zinc  dropwise  2 hours  product  fashion.  Refluxing  spectral  Prenyl  (THF)  was removed  was h e a t e d  compounds  III)  magnesium  (15).  (17)  0 . 5 hour  mixture  showed  work-up  ( 3 0 mg) w i t h  After  a n d t h e THF  of  )  was a d d e d .  temperature added  mmole)  bath.  d r y THF  i n the usual  by aqueous  A dry tetrahydrofuran (100 mg, 0 . 6 7  prenyl  room t e m p e r a t u r e .  (+)-9-hydroxycamphene  Reaction  -  solution of  the reaction mixture  1  a colorless  240  other  grade olefinic  identified.  9-Hydroxy-9-(3'-Methyl-2'-Butenyl)camphenes  (26)  23 Prenyl solution to  of  a mixture  trimethylsilane  (32)  was p r e p a r e d  l-chloro-3-methyl-2-butene of  magnesium powder  (2.00 g,  (0.60 g,  25.1  by s l o w l y 19.2  adding  mmole)  mmole),  a  in dry  iodine  (1  ether  small  -  crystal),  and t r i m e t h y l s i l y l  mixture  was s t i r r e d a t  water.  Working  of  the crude  o i l ,  b.p.  1  J  H,  8.42  76-77°C  (doublets,  -Si(CH3)3); CgH-jgSi  :  2 H,  J  m / e , 142  142.1178.  17.1  overnight  way f o l l o w e d  prenyl  torr);  -CH=C-),  (1.94 g,  temperature  provided  (110  -  chloride  up i n t h e n o r m a l  product  = 8 Hz,  room  241  mmole) and then  allylic  ( M + ) , 127,  without  TMS), 4.76  Found  -CH0-Si-),  9 9 , 73  (High  hydrolysed  with  (base  9.78  peak).  r e s o l u t i o n mass  distillation  (32) as a  8 . 3 5 and 8 . 5 0 (two s i n g l e t s , 6 H, = 8 Hz,  The  by f r a c t i o n a l  trimethylsi lane  x (CDC13,  in ether.  colorless  (broad vinyl  triplet,  methyls),  (singlet, Mole.  9 H,  wt.  calcd.  spectrometry)  :  for  142.1165.  22 A mixture  of  Experimental, (Type  4A)  was with  oil  refluxed ether.  Elution was  Prenyl  elution  (40 m g , 0 . 1 5 mmole)  trimethylsilane (24)  cooled,  water,  magnesium  petroleum  likely with  10% e t h e r  (30-60)  yield)  w h i c h was homogeneous  130°C)  analyses,  and  x (CC14),  5 . 4 0 (two broad  ethers  of  ether  solvent  silica  4.74  (broad  and 5.17  was added  water,  and d r i e d  provided  gave  1  yellow grade  (26).  III).  Further  9-hydroxy-9-  o i l ( 3 4 . 5 m g , 40%  g e l ) and g . l . c .  triplet,  a  o i l ( 1 2 mg) w h i c h  hydroxycamphenes  (silica  2 N  gel (activity  (30-60)  mixture  and e x t r a c t e d  water  a colorless  (26) as a c o l o r l e s s  on t . l . c .  singlets),  with  afforded  + 90% p e t r o l e u m  (3'-methyl-2'-butenyl)camphenes  water,  sodium b i c a r b o n a t e , of  nitrogen  The r e a c t i o n  was washed w i t h  Removal  the t r i m e t h y l s i l y l  with  sieves  under  ( 2 0 0 m g , 1 . 4 0 mmole)  extract  sulphate.  ether  was s t i r r e d  hydrolysed  saturated  (see  and m o l e c u l a r  (94 mg, 0 . 6 2 mmole).  The combined o r g a n i c acid,  (THF)  (32)  mg) w h i c h w a s c h r o m a t o g r a p h e d with  most  p.115)  f o r 40 h o u r s ,  anhydrous (119  II,  by 9-oxocamphene  hydrochloric over  Part  f l u o r i d e jn-Bu^NF  ( 3 6 mg) i n d r y t e t r a h y d r o f u r a n  atmosphere. followed  tetra-n-butylammonium  H,  -CH=C-),  and 5 . 5 2 (two broad  (Column 5.21  singlets)  A,  -  (2  H,  3 Hz)  =CH2 and  epimeric allylic 8.44  two  6.76  broad u  „ max  (broad,  =CH2);  98,  94  220.1827.  of  7.37  doublets,  (broad  7.85-8.10  singlets, (CC1.), f  weak,  strong, 95,  (doublet  methine),  (two  -  epimeric alcohols),  alcohols),  methyl); 1650  of  242  m/e  C=C), 221  (base  peak),  Found  (High  vinyl  (M++l),  1  81,  79,  H,  2 H,  weak,  70.  r e s o l u t i o n mass  4 Hz)  allylic  OH),  medium,  (M+),  of  202, Mole.  doublets,  (1  half-width  methyls),  (sharp, 220  (doublet  = 9 Hz,  signal,  (broad,  1060  93,  J  (multiplets  6 H,  3600  6.66  H, 7  Hz,  2900  (broad,  wt.  133,  123,  calcd.  spectrometry)  :  two  8.35  3 H,  for  and  tertiary  strong,  895 cm"1  Hz,  bridgehead  methylene), (singlet,  151,  = 10  -CHOH o f  9.02  C-0),  J  CH),  (broad, 122, C  ] 5  220.1846.  121, H  2 4  0  109, :  -  243  -  BIBLIOGRAPHY  1.  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