Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Studies in Marine Natural Products : Onchidoris bilamellata, Nanaimoal and Capnellene Hellou, Jocelyne 1985

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1985_A1 H44.pdf [ 8.23MB ]
Metadata
JSON: 831-1.0060516.json
JSON-LD: 831-1.0060516-ld.json
RDF/XML (Pretty): 831-1.0060516-rdf.xml
RDF/JSON: 831-1.0060516-rdf.json
Turtle: 831-1.0060516-turtle.txt
N-Triples: 831-1.0060516-rdf-ntriples.txt
Original Record: 831-1.0060516-source.json
Full Text
831-1.0060516-fulltext.txt
Citation
831-1.0060516.ris

Full Text

Studies Onchidoris  i n Marine  bilamellata,  Natural  Products:  Nanaimoal  and  Capnellene  by  JOCELYNE B.Sc,  University  M.Sc, University  A THESIS  SUBMITTED  HELLOU de M o n t r e a l , 1978  of British  Columbia,  IN PARTIAL  FULFILLMENT  THE REQUIREMENTS  FOR T H E  DEGREE  OF  DOCTOR OF P H I L O S O P H Y  in  THE  F A C U L T Y OF G R A D U A T E (Department  We  accept to  THE  this  of  UNIVERSITY  as  Jocelyne  conforming  standard  OF B R I T I S H  January ©  Chemistry)  thesis  the required  STUDIES  COLUMBIA  1985  H e l l o u , 1985  1980  OF  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of  requirements f o r an advanced degree a t the  the  University  of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make it  f r e e l y a v a i l a b l e f o r reference  and  study.  I further  agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may  be granted by the head of  department or by h i s or her  representatives.  my  It is  understood t h a t copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l gain  s h a l l not be allowed without my  permission.  Department of The U n i v e r s i t y of B r i t i s h 1956 Main Mall Vancouver, Canada V6T 1Y3  DE-6  (3/81)  Columbia  written  - ii-  Abstract The following thesis is divided into three chapters.  The f i r s t describes  the isolation and identification of a sphingol ipid 1_ from the methanol ic "skin extract of the British Columbia nudibranch Onchidoris bilamellata.  The long  chain base has been identified as (E)-l,3-dihydroxy-2-amino-16-methyl-4octadecene (1_3) and the fatty acid moiety as palmitic acid ( 1 2 J .  This  ceramide possesses antibacterial activity towards the microorganisms Bacillus subtilis and Staphylococcus aureus.  CH,(CH 2 ) u C00H  12 The second chapter presents our attempt to synthesize a hypothetical structure of nanaimoal (24), a marine sesquiterpenoid, isolated from the British Columbia nudibranch Acanthadoris nanaimoensis. The proposed route envisaged photolysis of a 2,2,10,10-tetrasubstituted  cyclodecanone. This  work lend to a study of the solution photochemistry of 2,2,10-trimethylcyclodecanone (35).  2 4  H  35  H  H  51  The last chapter outlines studies directed toward the synthesis of capnellene (51_), a tricyclopentanoid obtained by Djerassi and co-workers  -  from of  thesoft  t h e known  coral  Capnella 1  i i i -  imbricata.  Starting  5  ketone A ' - b i c y c l o [ 3 . 3 . 0 ]  with  octen-2-one  an improved  (138), an  synthesis  acylation  1 5 method was d e v e l o p e d [3.3.0]  octen-2-one  been e x t e n d e d a  Michael  for the preparation (160).  tb related  addition with  condensation  The p r o c e d u r e  ketones. methyl  o f t h emethyl  of A  This  vinyl  ketone  '  -3-carboethoxybicyclo-  i s o f general  unsaturated  ketone  produced A  produced  o f the unsaturated  ketone  '  and dehydration  Diels-Alder cyclization  tricarboxylic  ester  functionality  o f 182 f o l l o w e d  intermediate  182.  Selective  of the latter  octen-2-one  160  led  9  o  alcohol  derivative 181. afforded  t o 183,  173  H  the tetracyclic  \  ester a key ring  system.  0  ,9 o  COOMe  COOMe  182  Knoevenagal  (179).  of theallylic  f o r the ultimate construction o f the capnellane  138  underwent  Selective  hydrolysis o f themalonic  by d e c a r b o x y l a t i o n  and has  -3-carboethoxy-3-(dimethyl-  a 1,1,3,4-tetrasubstituted cyclopentadiene  Intramolecular  keto-ester  t o g i v e . 178. 1 5  3-methyl-3-butenyl-4,4-dicarboxylate)-bicyclo[3.3.0] Reduction  utility  183  -  Table  iv -  o f Contents page  Title  Page  i•  Abstract Table  i i  of Contents  i v  List  of Figures  v  List  o f Schemes  v i i  List  of Tables  List  of Abbreviations  i x x  Acknowledgements  xi  Chapter  1:  Onchidoris  bilamellata  1.1  Introduction  1  1.2  Results  9  1.3  Discussion  Chapter  2:  II. 1  Introduction  27  11.2  Results  33  11.3  Discussion  38  Chapter  3:  111.1  Introduction  111.2  Results  18  Nanaimoal  Capnellene 49  and D i s c u s s i o n  . .  59  -  Approach  t o 138  -  Approach  Using  138 and D i e t h y l  -  Approach  Using  1_38 a n d E t h y l  -  T h e U s e o f DEPC  -  Approach  -  Successful  -  Conclusion  Using  70 Oxalate  74  Chiorofornate  78 80  DEPC  Cyclopentadiene  83 Approach  87 99  Experimental Bibliography  121 . . . . .  177  -  List  v -  of Figures page  1.  Dorsal  2.  4 0 0 MHz  3.  IR S p e c t r u m  4.  4 0 0 MHz  5.  IR S p e c t r u m  6.  Some C o n f o r m a t i o n s  o f Cyclodecane  39  7.  Some C o n f o r m a t i o n s  o f Cyclodecanone  40  8.  IR S p e c t r u m  9.  8 0 MHz  10.  View  'H NMR  6 0 MHz  12.  IR S p e c t r u m octen-2-one  14. 15.  16.  Spectrum  Spectrum  3  o f Ceramide 1  23  1_  24  of Diacetylated  of Diacetylated  Derivative  Derivative  Spectrum 1  1  47 (35) .  (138)  5  of A ' -bicyclo[3.3.0]octen-2-one  6 0 MHz 'H NMR S p e c t r u m octen-2-one (160)  48 100  (138)  of A ' -3-carboethoxybicyclo[3.3.0](160) 1  25  (35_)  o f 2,2,10-trimethylcyclodecanone  5  Spectrum  . . . .  26  of A ' -bicyclo[3.3.0]octen-2-one  'H NMR  9  9_  o f 2,2,10-trimethyl cycl odecanone  'H NMR  IR S p e c t r u m  Nudibranch  o f Ceramide  'H NMR  11.  13.  o f a Dorid  101  102  5  of A ' -3-carboethoxybicyclo[3.3.0]103  1 5 IR S p e c t r u m o f A ' - 3 - ( b u t a n - 3 - o n e ) - 3 - c a r b o e t h o x y b i c y c l o [3.3.0]octen-2-one (178) 1  104  5  8 0 MHz 'H NMR S p e c t r u m o f A ' - 3 - ( b u t a n - 3 - o n e ) - 3 carboethoxybicyclo[3.3.0]octen-2-one (178)  105  1 , 5  8 0 MHz 'H NMR S p e c t r u m o f A -3-carboethoxy-3-dimethyl 2-methyl-1-butenyl-1,1-dicarboxylate)bicyclo[3.3.0] octen-2-one  17.  (179) 1 5 IR S p e c t r u m o f A -3-carboethoxy-3-dimethyl 2-methyl-1-butenyl-1,l-dicarboxy!ate)bicyclo[3.3.0] octen-2-one (179)  18.  6 0 MHz  'H NMR  (dimethyl  Spectrum  1  of  106  106  5  A ' -3-carboethoxy-3-  2-methyl-1-butenyl-1,1-dicarboxylate)  bicydo[3.3.0]octen-2-ol  (180)  107  1 5 19.  IR S p e c t r u m (dimethyl  of A  '  -3-carboethoxy-3-  2-methyl-1-butenyl-1,1-dicarboxylate)  bicyc1o[3.3.0]octen-2-o1 20.  IR S p e c t r u m  (180)  butenyl-1,1-dicarboxylate) octa-1,4-diene 21.  8 0 MHz  107  o f 3-carboethoxy-3-(dimethyl  'H NMR  bicyclo[3.3.0]  (181) Spectrum  108 of  3-carboethoxy-3-(dimethyl  2-methyl-1-butenyl-1,1-dicarboxylate) octa-1,4-diene  2-methyl-1-  (181)  bicyclo[3.3.0] 1  0  9  - vi -  page 22.  IR S p e c t r u m o f A  12  8  -6-carboethoxy-2-dicarbomethoxy-3-  methyltetracyclo[6.4.0 23.  400  MHz  'H  NMR  1 , 6  Spectrum  3  7  8  1 2  .0 ' .0 ' 8  of  A '  1 2  ]-dodecene  1  24.  25.  6  IR S p e c t r u m  400  'H  NMR  IR S p e c t r u m  MHz  80  MHz  Spectrum  of endo-1-carboethoxy-4-methyl-5  heptan-2-one  'H  'H  NMR  Spectrum  NMR  6  acid  1 1 , ] 2  of A  'H  of A  NMR  '  6  3 , 7  8  .0 '  Spectrum  60  MHz  'H  8  1 2  ]-  acid  ]-dodecene  116  6  3  7  8 , 1 2  ]117  of A  10 '  of A  NMR  1 2  1  tetracyclo[6.4.0 33.  7  -6-carboethoxy-2-  -6-carboethoxy-2-carboxylic 6  3  7  S-methyltetracyclotS^.O ' .0 ' .0 9 10 IR  3  .0 ' .0 '  in  of A  1  32.  1 , 6  S-methyltetracyclote^.O ' .0 ' .0 9  IR S p e c t r u m  115  -6-carboethoxy-2-  -6-carboethoxy-2-dicarboxylic  Spectrum  carboxylic acid dodecene (183) 31.  (173)  116  Q  HMz  114  12  S-methyltetracyclote^.O ' .0 80  (173)  nona-1,8-diene  3-methyltetracyclo[6.4.0  1  30.  nona-1,8-diene  o f6 - c a r b o e t h o x y - 8 - m e t h y l - 3 - d i m e t h y l  Spectrum  11 IR S p e c t r u m  1 1 3  (171)  o f6-carboethoxy-8-methyl-3-dimethyl  dicarboxylic didecene 29.  ]-  1 1 2  methylenedicarboxylatebicyclo[4.3.0^'^] 28.  1 2  (171)  1  60  8  ,0 '  of endo-1-carboethoxy-4-methyl-5 acetylbicyclo  heptan-2-one  methylenedicarboxylatebicyclo[4.3.0 ' ] 27.  110  I l l  acetylbicyclo[2.2.1] 26.  3 , 7  (182)  [2.2.1] MHz  . . .  -6-carboethoxy-2-dicarbo-  methoxy-3-methyltetracyclo[6.4.0 ' .0 dodecene  (182)  8 , 1 2  ]-dodecene  2,6-dicarboxylic 1 , 6  3  7  8  .0 ' .0 '  Spectrum  of A 1  1 2  ]  ' 6  acid  (183)  dodecene  7  8  3-methyltetracyclo[6.4.0 ' .0 ' .0 '  1 2  ]  . . . .  118  3-methyl119  2,6-dicarboxylic 3  acid  dodecene  acid 120  -  List  v i i -  o f Schemes page  1.  Classification  2.  Reactions  3.  Biosynthesis of Sphingolipids  4.  P o s s i b l e B i o s y n t h e s i s o f t h e Nanaimoane  5.  P o s s i b l e Robinson Nanaimoal  o f the Phyllum  Performed  Mollusca  on Ceramide  Annulation  2  1_  16 21 C Skeleton  28  or D i e l s - A l d e r Approach t o  (24)  30  6.  Possible Photochemical  7.  Reactions  8.  Photochemical cyclohexanone  Behaviour (45_)  of  2,6,6-tetramethyl-  9.  Photochemical  Behaviour  of  2,2,10-trimethyl-  cyclodecanone  (35)  Performed  Approach  t o Nanaimoal  (24)  on 2 , 2 , 1 0 - t r i m e t h y l c y c l odecanone  32 (35_) . . .  44  43  10.  Synthesis  11.  Biogenetic  12.  Synthesis  o f 51_, b y R . D .  13.  Synthesis  o f 5J_, b y L . A . P a q u e t t e  and K.E. S t e v e n s  14.  Synthesis  o f 5 J _ , b y L . H u g u e t , M.  Karpf  15.  Synthesis  o f 51_, b y T . F u j i t a ,  o f 5Jj, a D e r i v a t i v e o f Nanaimoal  (26_)  46  Relationship o f the Capnellanes Little  49  and G.L. C a r o l l  51 51  and A.S. D r i e d i n g  T. O h t s u k a , H. S h i r a h a m a  . . .  52  16.  Synthesis  o f 5 J _ , b y W.  17.  Synthesis  o f 5J_, b y A.M.  18.  Synthesis  o f 51_, b y G . M e h t a , D.R.  19.  Synthesis  o f 5J_, b y E. P i e r s  20.  Synthesis  of a C Skeleton  O p p o l z e r a n d K. B a t t i g  53  B i r c h a n d G. P a t t e n d e n Reddy and A.N. M u r t y  and V. Karumaratne  Related  53 . . . .  54 55  t o 51_, b y J . E . Paw a n d  A . C . Weddon  56  21.  Synthesis  22.  Enol  23.  Synthesis  24.  Cyclopentadiene  25.  Alkylation  26.  Synthesis  o f 1 2 0 b y M.S.  27.  Synthesis  o f 1_20 b y A . De M e i j e r e  28.  Reactions  o f 8-diketone  29.  Known A l k y l a t i o n  30.  52  and  T. M a t s u m o t o  Ether  34  o f 5 3 , b y G. P a t t e n d e n Approach  and S . J .  Teague  t o 5J_  59  o f 108  60 Approach  Cyclopentadiene  0-alkylation  57  o f 121  o f 121  t o 5_1  62  116  63  B a i r d and C.B. Reese  1J8  and L. Meyer  66 66 67 68 6  9  - viii -  page 31.  Synthesis of 138  72  32.  Known Reaction of Cyclohexanone  74  33.  Reactions Performed on 145  75  34.  Reactions Performed on 150  79  35.  The Use of DEPC  81  36.  Reactions Performed on 160  84  37.  Isomerization of 166  86  38.  Diels-Alder Approach to 176, 177  88  39.  Formation of Side Product U l  89  40.  Possible Rearrangement Reaction  90  41.  Formation of Side Product 17_3_  42.  Diels-Alder Reaction of 175  92  43.  Diels-Alder Approach to 182  95  44.  Diels-Alder Reaction of 181  96  45.  Model Studies of Oxidative Decarboxylation  98  . ,  91  -  List  ix -  of  Tables page  1. 2.  400  MHz  'H  NMR  Proton-Proton  Spin  Diacetylated MHz  1 3  Spectral  100.1  4.  Conditions  5.  Acylation  6.  Preparation  7.  Yields  Obtained  8.  60  MHz  'H  9.  IR  Spectral  10.  MS  Results  11.  60  MHz  12.  IR S p e c t r a l  13.  MS  H  Performed  on 14  Spectral  Data  f o r Ceramide  of  15  1  1_1_6  64  Reagents  Spectral  Data  NMR  NMR  15.  IR  Spectral  16.  MS  Results  17.  80  MHz  18.  IR  Spectral  19.  MS  Results  to  to  Spectral Data  to  Spectral  Data  to  Alkylations Related  to  of  189  and  190  149  192  150  192  151 152  Data  Related  to  19J_  153  t o 19J_  154  19J_ Data to  154 Related  to  193  157  193_  158  193  158  Data  Related  Related  to  82  192  Related  Related NMR  Data  Related  Related  MHz  keto-esters  Related  Spectral  Data  £  i n Various  Related  60  80  of Cyclic  NMR  14.  h"  NMR  Experiment  9  f o r the A l k y l a t i o n  Results 1  C  13  Decoupling  Derivative  3.  'H  Data  194  Related  t o 194  to  194  164 . .  165 165  - X -  List  of Abbreviations  mCPBA:  meta-chloroperbenzoic  DEPC:  diethyl  DMAP:  4-dimethylamihopyridine  DME:  pyrocarbonate  dimethoxyethane  DMF:  N,N-dimethylformamide  DMSO:  dimethyl  DNPH:  acid  sulfoxide  2,4-dinitrophenylhydrazine  Et:  ethyl  EuCfod)^:  1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctanedionatoeuropium  GLC:  gas-liquid  HMPA:  hexamethylphosphoramide  HPLC:  high  IR:  chromatography  pressure liquid  chromatography  infrared  LDA:  lithium diisopropylamine  Me:  methyl  MP:  melting  MS:  mass  MsCl:  methane s u l f o n y l  chloride  NMR:  nuclear magnetic  resonance  PTLC:  preparative  RT:  room  SFORD:  single  point  spectrum  thin  layer  temperature frequency  o f fresonance  THF:  tetrahydrofuran  TLC:  thin  TMS:  tetramethylsilane  pTsOH:  para-toluenesulfonic  UV:  chromatography  layer  ultraviolet  chromatography  acid  decoupling  (III)  -  xi -  Acknowledgements The of  research  British  indebted the  Columbia  to twice  members  University fellows, own  students,  throughout  especially  t o take this  Without into  help  University  conducted  o f Newfoundland.  a graduate  spectra.  student  from  am  the  the post-doctoral  and J . F . K i n g s t o n  "contributions"  I  usually i s :  and i n a d d i t i o n  I thank  Drs. S . J . Alward  at the University  during  the University  this  for their thesis.  de S h e r b r o o k e f o r  calculations.  UBC, and D r . A.G.  arrangement  was  laboratories,  and P. Deslongchamps  mechanics  I would at  a n d NMR  human a n d s c i e n t i f i c  C. B a y l y  thesis  t h e number o f p e o p l e  o f A l b e r t a f o r t w o NMR  graduate  molecular  in this  and a t Memorial  o f t h e t w o MS  special  Drs.  presented  like  t o thank  F a l l i s a t MUN,  my  who  place, f o r their  two s u p e r v i s o r s , D r . R . J . Andersen allowed  such  understanding,  an  inconvenient  advice  and  help  work.  the support  perspective, this  research  Last  and c e r t a i n l y  with  typing  this  o f my  husband would  not least,  thesis  over  who  knew  n o t have  Miss  Teresa  and over  how  t o put problems  taken Barker  again!  back  place. f o r her  continuous  -  1-  Chapter 1 Onchidoris bilamellata 1.1. Introduction^ This chapter describes the i s o l a t i o n and i d e n t i f i c a t i o n of a sphingolipid 1_ from Onchidoris bilamellata, a nudibranch collected in B r i t i s h Columbia. A short introduction to the biology of nudibranchs, preceeds an outline of the chemical aspects in the study of opisthobranch molluscs. Some examples of metabolites isolated from opisthobranch molluscs with novel structures and interesting biological properties are included. The work related to the i d e n t i f i c a t i o n of sphingolipid 1_ obtained from methanolic skin  extracts of 0. bilamellata i s then presented.  This i s  followed by a discussion of the chemistry, biochemistry and biology of molecules related to 1.  The phyllum Mollusca contains the second largest number of invertebrate species.  Gastropoda  represents i t s major class (see Scheme 1), with  specimens found in a large variety of marine and t e r r e s t r i a l  habitats.  Members of this class have an asymmetric body and only one shell  (univalve).  Scheme 1 Classification  of  the  Phyllum  Phyllum  Mollusca  Class  Amphineura  Subclass  Bivalvia  Gastropoda  Opisthobranchia  -I  Sacoglossa  Suborder  Arminacea  1  T~  Nudibranchia  Dendronotacea  Organisms  are  classified  according  to  1  Doridacea  Kozloff  Scaphopoda  Pulmonata  1  Cephalospidea  (Genus)  N.B.  Cephalaspidea  Prosobranchia  -T  Order  Mollusca  Eolidacea  ro  -  One  of  the  marine  three  members  absent.  The  including:  do  are  Figure  Their with on  shell  internal  g i l l s . Among  the  dorsal  1 shows  vary  color  a  shell be  the  dorsal 12  ranges  from  white  special  which  represent  shown  that  color  from  the  cm  and  cavity  subdivided  cavity  sea and  slugs as  assumes  by  the  presence  or  naked  indicated  an  of a  in size  eight  In the  by  the  order shellfish) their  name,  with  a  suborder  secondary  gill  of  a  dorid  i n length  and  t o numerous  pattern  modified tentacles  from  shades  ("spots")  line  up  the most  on  0.5  as  likely  site  Members cm  in  and  their mantle. o f more  mentioning sense  to 3  of yellow  to depths  worth  used  nudibranch.  organs.  this  thickness. orange, They  than  i s the  of  two  18  often  are  rhinophores,  Experiments  f o r chemoreception  have  in  .  tubercules rhinophores  gills mantle  Figure Dorsal  View  of  1  a Dorid  Nudibranch  found  m.  3 nudibranchs  or  orders,,  elongated form of  mainly  .  view  shore  reduced  into  Cephalospidea.  known as  body  Opisthobranchia, with  mantle  further  morphological feature  rhinophores are  i s the  N u d i b r a n c h i a , members  anus  1 to  rocky surfaces  also  Their  from  some p a r t i c u l a r  A  a  or mantle  characterized  encircling  suborder  no  symmetry.  Doridaceae ring  by  (nudibranchs are have  have  bilateral  characterized  S a c o g l o s s a , N u d i b r a n c h i a and  animals not  -  of gastropods  O p i s t h o b r a n c h i a can  Nudibranchia the  subclasses  3  - 4 Nudibranchs no  other  are  obvious  slow-moving  protective  organisms  feature.  without  Four groups  an of  exterior animals  shell  have  and  with  been  5 suggested  as  stars  fish.  and  interest  possible The  among  predators fact  that  :  o t h e r o p i s t h o b r a n c h s , c r u s t a c e a n s , sea  nudibranchs  avoid direct  the  of  p r e d a t i o n has  raised  biologists.  5 L.G.  Harris  nudibranch  has  reviewed  d e f e n s i v e mechanisms.  results He  grouped  several studies them  into  five  concerning  categories,  as  follows: 1)  Behavioral  2)  Spicules  3)  Nematocysts  4)  Color  5)  Chemical  camouflage  Experiments nudibranchs  shown  i s altered.  swimming  attacked,  i t does  escape  can not  of  species.  Paine^  shape  make  a  cells  when  animal  types  of  nematocyst  ability  to  select  are  are  these  containing  Stored  more  the  by  of  Although of  behavior  rhinophores  this  is a  nudibranchs  to  the  present  give  for other  i s disturbed^.  appear  retraction  i n comparison  difficult  coelenterates.  nudibranchs  slow  the  postulated that  are  d i s t u r b a n c e , the  observed^.  explain  ingested the  upon  calcareous nature  them  Nematocysts  that  Immediate be  is usually  Spicules  and  secretions  have  sometimes  their  response  the  stinging  type  effective  they  types  to  nudibranchs to  structures  of  store.  gills  response  to  since  speed.  a  of  some  rather  dorid  rigid  swallow. originating can  nematocyst  be  from  released  exist  It i s believed  against certain  and  being  survive  i n the mantle  some n u d i b r a n c h s , t h e y  Different  and  predator's  opisthobranchs  of  predators.  and  that Of  some some  the  - 5 -  four the  nudibranch  suborders, only three are  E o l i d a c e a , Dendronotacea  and  known  Arminacea.  to feed  Dorid  on  coelenterates;  nudibranchs  feed  5 predominantly utilize  on  nematocysts  Coloration nudibranchs  on  nudibranchs.  diet.  The  mechanism The  may  be  white  interpreted  coral),  on  other  remain  view  of  and are  most the  i s disturbed.  R  e c e n t  eolid ly>  a  a warning of  are  and  do  i s lacking.  i n some c a s e s  i n the  the  case  nudibranch  i s still  of  not  (white  brightly  varies  of  colored  with i t s g  uncertain  Hence, aspects  as  of  emanating  from  been  might  shown  be  they  some s p e c i e s  are  early  and  this  a  defensive  chemist's  glands.  usually  such  organic molecules  These  emitted  literature  strong acids  that  from  epidermal  reported i n the  nudibranchs  s e c r e t e d by  protection  d e f e n s i v e because  I t was  i t has  means  8 structures  tunicates  camouflage  perceive color  secretions  the  ^ 2 ^ 4 ^ '  as  interesting  designated  from  colonial  investigated.  are  secretions  to  predators  secretions animal  or  as  pigmentation  fish  t o be  and  defense.  Often, the  final  of  for  ability  information  point  sponges, bryozoans  as  that  HC1  when the  and  with  interesting  11 '  .  In  some c a s e s  the  defensive  Q  molecules A  are  critical  mechanisms  very  to a  study  of  available likely  dietary  the  i n nudibranchs  information seems  related  relative  i s difficult  concerning  that  source  chemical  .  importance due  to  the  predator-prey secretions  may  of  the  different  limited  amount  interactions. p l a y an  defensive of  However, i t  important  defensive  role. It  must  unequivocally  studies to  be  stated  proven  involving  to  other  hypothesize that  that  such  exist  defensive substances  in nudibranchs.  organisms  such  as  defensive secretions  have  not  been  H o w e v e r , on 12  the  basis  arthropods are  also  , i t would  operative  in  be  of  logical  nudibranchs.  -  Research advances edited  i n marine  i n the last  by P . J .  natural  products  ten years.  Scheuer  13  6 -  chemistry  The f i r s t  i n 1973,while  book  h a s made  t o appear  significant  i n this . review  one o f t h e f i r s t  field  was • was  papers  14 written other  i n 1974 by D . J . F a u l k n e r  review  published. in  papers, Among 5  symposia  these,  6  and  following  biological  from  The from  examples  illustrate  that  have  with  then,  papers  the chemistry  molluscs  the variety  been  Since  assigned  many  have  been  of the molluscs 7  i n particular^ .  o f novel  structures  t o compounds  isolated  molluscs.  rearranged  both  deal  .  and s t r u c t u r a l  the opisthobranch  properties  opisthobranch  proceedings  two r e v i e w s  g e n e r a l ^ ' ^ , and w i t h The  and R . J . Andersen  terpenoid  the nudibranch  9-isocyanopupukeanane  Phyllidia  varicosa  ( 2 J was  and i t s p r e y ,  isolated  a sponge  from t h e  o Hymeniacidon lethal  sp. .  t o small  certain  fish  specificity  A novel  The n u d i b r a n c h  was known  and c r u s t a c e a n s . i n killing  steroidal  ketone  small  t o produce  Allomone  a smelly  2_ w a s s h o w n 1g  substance  t o have  a  crustaceans  3_ i s o l a t e d  from  Aldisa  sanguina  cooperi  19 shows  antifeedant activity  believed  that the dorid  i n a standard  nudibranch  goldfish  bioassay  o b t a i n s an i n a c t i v e  .  I t i s  metabolite  from i t s  prey, the sponge Anthoarcurata qracea, and modifies i t to produce the two steroidal ketones 3 and 4.  R  Doridosine  (5_), the f i r s t purine base isolated from a nudibranch,  produces hypotension, bradycardia, coronary dilation and relaxation of smooth muscle in mammals for many hours. minutes.)  (Other analogs act for only a few  This new hypotensive N-methyl purine riboside 5_ has been isolated  from the aqueous extract of the digestive glands of Anisodoris nobilis.  H  HO  OH  5 Navanax inermis of the order Cephalospidea is known to be a voracious 21 predator on other opisthobranch molluscs chemoreception.  . It locates i t s prey by contact  N. inermis recognizes the mucus trail of an acceptable prey  - 8 -  and  follows  pheromone". individual  i tt o i t ssource.  When s e c r e t e d b y a n i n d i v i d u a l , o f t h e same  species t o turn  following  a t an angle  have  e x t r a c t e d from  been  N. i n e r m i s a l s o  g r e a t e r than  When p r e s e n t  they  the trai1-breaking  e l i c i t  Many o t h e r the  skin  molluscs.  away f r o m  90°.  a  "trail-breaking  pheromone t h e mucus  Navenones  i n a 4:2:1 m i x t u r e  structurally  extracts  this  the colored secretion  irritated.  produces  A  trail  an  i t i s  ( 6 J , B (7J and C (8)  emitted  (ratio  causes  when  found  the animals are  i n the extract)  response.  interesting  or the digestive  gland  molecules extracts  have  been  isolated  of the opisthobranch  from  -  1.2.  9  -  Results As  part  Columbia this  of a  n u d i b r a n c h s , we  organism  species  program  arose  possesses  Bacillus  are  have  w h e n we  at  only  studying the  examined  noticed  antibacterial  s u b t i l i s and  There  aimed  two  the methanolic  activity  studies  British  Onchidoris bilamellata.  that  Staphylococcus  chemistry of  towards  the  extract  Interest of  in  this  microorganisms  aureus.  directly related  to 0.  bilamellata  in  the  22 biological  or  chemical  population  ecology  of  literature. 0.  The  bilamellata  first  i s concerned  i n Robin  Hood's  Bay,  with  the  England.  The  23 second  study  on  chemosensory  the  University  i s related  of  to  the  behavior  Washington,  of  "effects 0.  of  aromatic  bilamellata",  and  petroleum i t was  hydrocarbons  done a t  the  south  shore  Seattle.  4" Onchidoris  bilamellata  Phyllum:  Order:  of  English  May  1980  were  and  usually  barnacles The in  Bay,  Nudibranchia  bilamellata  1981  found  the  on  they  an  average  After  low  tide 1981.  undersides feed  are  vary size  c o l l e c t i o n , the  several weeks.  collected  t o May  nudibranchs, which have  were  Vancouver, at  February  Following for  Doridacea  upon which  bands),  :  Opisthobranchia  Suborder: 0.  follows  Gastropoda  Subclass:  of  as  Mollusca  Class:  Specimens  is classified  of  by  during  hand, from the  These  abundant  November 1979  intertidal where  to  organisms  the  present.  1 cm  and  nudibranchs  thawing,  periods  rocks, especially  i n c o l o u r from of  the  the  an were  beige-tan average  dry  to  brown  weight  of  s t o r e d i n methanol  supernatant  was  filtered,  (present  at  75  mg.  -35°C  evaporated  -  to  one h a l f  acetate.  of the original  After drying  the  oily  residue  the  active fraction  increasing  solvent  antibacterial further  was  Ceramide  volume  the organic  purified from  brine  e x t r a c t and e v a p o r a t i o n  of the solvent,  by s i l i c a  The  a free  column  thin  primary  chromatography.  facilitated  fractions  The f r a c t i o n s  by p r e p a r a t i v e  1_, w i t h  and p a r t i t i o n e d between  t h e c o l u m n was  polarity.  activity.  purified  10 -  layer  gave  were  a positive  has been  b i l a m e l l a t a and i s r e s p o n s i b l e  f o r the antibacterial  of  spectral  correlations,  a n a l y s i s and chemical  characterized  as  and  acid moiety  the fatty  activity. chain  3  Appromixately  ( C H , )  2 0 mg  By  base  means  has  (13)  Ri  13  (yield  from  as p a l m i t i c a c i d ( 1 2 ) .  9  C H  the long  were  (PTLC).  (E)-l,3-dihydroxy-2-amino-16-methyl-4-octadecene  1  12  result  isolated  0.  of  screened f o r  chromatography  alcohol  ethyl  Elution of  by a g r a d i e n t  obtained  which  and  H  C0(CH,)uCH3  COCH  C0(CH2)  H  H  C H ,  C O O H  o f 1_ w a s  = 0.02% o f d r y weight  of  obtained  animals).  from  1200 t o 1500  nudibranchs  been  -n -  The m/z  MS  (Figure  = 533.5173  formula  4 ) o f 1_ g i v e s  (Exact  C^Hg^O,,.  Mass  A  a  parent  calculated  fragment  i o n o f weak  533.5155)  resulting  from  intensity at  corresponding o f r^O  the loss  to the  molecular  a t m/z  515 i s  observed. The ion  MS  a t m/z  ^39^73^5 acid  of the diacetylated = 635.5481  a n c  a t m/z  formula  ' f  r a  = 575  9  m e n  (Exact t  and  molecule  i o n was has  two  = 280  followed from  this  sites  latter 1_ w a s  i n t h e MS  by e l i m i n a t i o n  from  o f HgO,  cleavage  an  result  0  10  residues  indicated  1CJ.  A  acetic  molecular  that  the  isolated  4 and  7)  between C(2) -  fragment  o f H~0  to  functionalities.  9_ ( F i g u r e s  cleavage  molecular  of  the  Hence, the  two a l c o h o l  allylic  that  CggHggNO^ a n d  o f b o t h .]_ a n d  a  corresponding  o f two  i n t h e MS.  the loss  7) d i s p l a y s  635.5470)  the loss  and  to give  before  (Figure  therefore  of unsaturation  results  9  calculated  not a c t u a l l y observed  (ClgH34N0)  allylic  The  compound  A major ion observed m/z  Mass  r e s u l t i n g from  515.  of the parent  molecular  s  derivative  a t m/z  i s also  298  present.  at C(3)  resulting  The and  6)  IR  spectra  of  ceramide  show a b s o r p t i o n s  f u n c t i o n a l i t y , which The  upfield  indicated  the  at  region  presence  of  triplets,  J  =  J  7 Hz)  a  straight  and  experiments 6  between presence  = of  3.5  and  partial  bond) and  f o r the  of  an  SF0RD amide, a  oxygen  atoms.  carbons  (13.7  C  f o r the  relative  NMR  by  integrating  second  degree of  ( T a b l e 3)  the  double  Comparison  chemical  ppm  f o r C-16,  of  1_ ( F i g u r e  (at 6  the 10.8  ppm  =  = 0.86, 0.85  Proton-proton spin the  signals  f o r seven  of  Therefore  alcohol  f o r C-18,  of  ppm,  ppm,  doublet,  decoupling  two  ppm  the  partial (a t r a n s  double  functionalities.  the  presence  carbons  values of 18.8  0.89  resonating  unsaturation  bond and  1)  protons, suggested  1_ c o n f i r m e d  shift  the  attached  three  f o r C-19)  to  methyl  with  those  24 in for  the  literature  C - l , 19.3  ppm  unbranched  f o r n_-decane f o r C-8)  of  an  (  -CH(CH3)CH2CH3).  (13.9  showed t h a t  chain, while  ppm) one  t h e o t h e r had  and end  3  amide  2, Table  (at 6  groups  group  two  of  9_ ( F i g u r e s  unsaturation.  1_1_ i n t h e m o l e c u l e .  1,2-disubstituted of  of  irradiating  position  spectrum  methyl  derivative  c o r r e s p o n d i n g t o an  spectrum  hydrocarbon.  and  structure  ]_]_ a c c o u n t s  A  ppm  cm" ,  degree  NMR  secondary  chain  1  1660  primary methyl  performed  6.0  structure  'H  two  Hz); a  ( T a b l e 2)  and  i t s diacetylated  f o r one  the  of:  two =  7  3400  accounts  and  1  3-methyl heptane of  the molecule  a methyl  at  the  (11.3  ppm  consisted  anteiso  position  -  400  H on  Ceramide  C#  3.93  2H-1  MHz  'H  13  -  Table  1  NMR  1_  (m)  Spectral  Data  diacetyl ated  triacetylated  derivative  d e r i v a t i v e ]3_  9  4.05  (dd,4.5,12)  4.05  (dd,4.5,12)  4.32  (dd,6,12)  4.31  (dd,6,12)  (m)  4.44  (m)  1H-2  3.71  (m)  4.49  1H-3  4.33  (m)  5.30  1H-4  5.53  (dd,15,7)  5.40  (dd,15,7)  5.39  (dd,15,7)  1H-5  5.79  (dt,15,7)  5.82  (dt,15,7)  5.80  (dt,15,7)  2H-6  2.06  (q,7)  2.06  (q,7)  (CH2)p  1.26  (s)  1.26  (s)  2'  2.23  (t,8)  2.12  (t,8)  16*  0.86  (t,7)  0.86  (t,7)  18*  0.89  (t,7)  0.88  19  0.85  (d,7)  NH  6.24  (bd,9)  5.28  (t,7)  (t,7)  1.26  (s)  (t,7)  0.88  (t,7)  0.85  (d,7)  0.85  (d,7)  5.63  (bd,9)  5.66  (bd,9)  NHC0CH3*  2.00  (s)  OCOCH3*  2.06  (s)  2.07  (s)  * interchangeable Numbers  represent the chemical  constants  shifts  (Hz) a r e i n p a r a n t h e s e s .  6  (ppm).  Multiplicities  and  coupl  -  Proton-Proton  Spin  14  -  Table  2  Decoupling  Diacetylated  6 J  5.82  a  b  5.63  (dt,15,7)  I D  E  E  X  c  5.40  (bd,9)  "  D  D  I  (t,7)  D  (dd,15,7)  d  Experiment  Derivative  Performed  on  9_  5.30  4.49  4.32  4.05  (t,7)  (m)  (dd,6,12)  2.06  (dd,4.5,12)  (d.7)  D  D  dm  C P 0  E  U  R  I  D  P L  'I  1  M  N  E  D  I  D  G T  (s)  (d,7)  I  D  (d,12)  D  I  D  (bdd,  D  I  S  8,6)  a.  chemical  b.  original multiplicity  c.  irradiated  d.  indicates on  the  shift  of  o r i g i n a l spectrum  (in  observed, coupling  ppm) constants in  Hertz  signal distorted  chemical  signal  shift  scale  (q,7)  due or  to due  proximity to a  real  to  the  irradiated  coupling  signal  - 15 -  Table 3 100.1 MHz 1 3 C NMR Spectral Data for Ceramide 1 C #  6 (multiplicity)  1  61.9 (t)  2  53.8 (d)  3  74.0 (d)  4*  133.5 (d)  5*  128.8 (d)  6+  31.6 (t)  r  172.3 (s)  ,t  36.3 (t)  16'  13.7 (q)  16  33.8 (d)  18  10.8 (q)  19  18.8 (q)  2  interchangeable  -  In o r d e r  t o determine  amide f u n c t i o n reaction out  under  fatty The  basic  acid,  long  1_6.  showing  This  remaining  long  chain unit  with molecular experiment  hetero-atoms  as t h e i r  formulas  confirmed  o f a C-15  into  of the  unit  Scheme  o f ^21^34^4^4  on one s i d e  a C-16  2  on C e r a m i d e  2  U  3  R ,R = H  14  R,,R = C0CH  1  K  ^  o r  —  2  3  a n c  ' ^26^43^5^7  of the double a n d a C-20  1  1  12  2  m e t h y l , 1_3.  reductive  | NaOH /MeOH ^ 13  chain  d e r i v a t i v e ]_4_  2  R, = H , R =C0(CH )CH  carried  straight  the anteiso  NO  1  of the  hydrolysis  hydrolysis  side.  Performed  side  2,4-dinitrophenylhydrazone  the position  on t h e o t h e r  Reactions  The  possessing  products  on e a c h  methyl, a  and t h e t r i a c e t y l  The  isolated  atoms  performed.  the molecule  acetylated  were  the presence  were  cleaved  ( M S , I R , 'H N M R ) .  reaction  derivatives, for  conditions  c h a i n b a s e was  ozonolysis  of the secondary  reaction  1_2 a n d a C - 1 9  characterized  t h e number o f c a r b o n  and t h e l o c a t i o n  and o z o n o l y s i s  16 -  CrL(CH  b o n d , by  unit  and  -  To of  the  ascertain isolation  nudibranchs  was  obtained several  It  when  or  2 20  min  and  under  the  ceramide  exists  with  a free  order to  primary  learn  more  antifeedant  defense  small  c r a b s and  bilamellata.  does  surprising  Unfortunately,  25  29  about  not  '  1M  enough  of  the crude and  i n methanol dry  at  artifact  fifty  collection  'H  i s very similar  (see extract,  NMR)  was  to the  -35°C  one  for  weight).  that  12  h  i s needed  conditions:  1M  skin  to  2M  I t seems  extracts  hydrolyze  HCl/Me0H/100°C;  conditions:  Na0H/Me0H/37°C. the  of  the  bioligical 38  test  .  encourage  purposes  since  surface  not  of  activity  f o r chemical  under the  their  and  an  of  0.  HC1/100°C, safe  to  bilame!lata,  alcohol.  is  living  (0.02%  1_ o b t a i n e d f r o m  X  so  stored  1_ was  hundred  t o 9_ ( C o - T L C  of dry weight)  conditions:  covered with  maybe n o t  identical  under a c i d i c  pellets used  of  sphingomyelins under a c i d i c  basic  ceramide  purification  literature  glycolipids  hydrolyze  an  (0.015%  from  that  performed  compound  and  of  o f one  ten minutes  nudibranchs were  assume  In  within  before extraction  i s known  h to  primary alcohol  acetylation  yield  the  weeks  cerebrosides and  After  This  -  procedure, the extraction  of a diacetylated  isolated.  the  performed  Experimental). 2 mg  whether  17  0.  The us  towards  bilamellata  role  of  response  to believe fish. i s an  ceramide  of  the  that  fish  crustaceans found  of  1_ w a s  available  i n the natural  However, t h i s intertidal  to  food  result  organism,  to perform  environment  we  sphingolipid  r o c k s , where m a i n l y c r u s t a c e a n s are  sample  1_,  of  present. tests  on  Onchidoris  1_ i s  -  1.3.  skin  molecule  extract  molecules  of  responsible  the  called  sphingolipids  the  '  .  The  There  have  in  plants,  elegantissima with  twenty 29  rubens  .  27  two  activity  bilamellata  of  belongs  the  to  organic  a  class  of  been  the  source  of  a wide  variety  these  lipids  derivatives are  N-acyl  a  phosphate  derive  of  mainly  phytosphingosine  derivatives  (cerebroside),  ester  from  of a  1_7  (18) and  1_8  or  complex  (sphingomyelin)  is  attached  alcohol.  been  few  by  have  have  ceramides  or  illustrated 20  plants  animals,  Nevertheless,  and  Onchidoris  In  organisms.  19  antibacterial  Often, a monosaccharide  (ganglioside)  primary  and  isolated  molecules.  glycoside  the  pc  (17_), w h i l e  predominate. related  nudibranch  animals  pc  sphingosine  for  sphingolipids.  Terrestrial  to  -  Discussion The  of  18  the  investigations a  variety  following  been  isolated  and  Metridium  carbon  bases  of  examples. from  the  senile were  of  structures The sea  28  sphingolipids have  ceramide anemones  from  the  been  marine  found  as  aminoethylphosphonates  Anthopleura  respectively.  obtained  from  Various sea  star  cerebrosides Asteria  - 19 -  C H^C H ),  O-P-CHfC H -MH  2  2  3  n = 13 to  18  0 u  CH (CH ) 3  0-P-CH C H NH  2 7  2  2  3  n= 13-15 n 2n+2 H  Caulerpicin (21_) is a toxic constituent of the marine algae 30 Caulerpa sp.  and aplidiasphingosine (22_) is an antimicrobial and anti-  tumor terpenoid derivative of sphingosine isolated from a marine tunicate 31 of the Aplidium sp. .  CH (CH 3  C_Q  r  22  H =  2U-26  - 20  The  long  bilamellata  chain  has  been  base  -  1_3 o f t h e s p h i n g o l i p i d  previously  identified  as  isolated  being  one  from  Onchidoris  o f 31  long  chain  32 bases  obtained  phosphorous were  and  extracted  corresponding product sodium These  from  bovine milk  choline from  containing  buttermilk  ceramides, which  rehydrolyzed periodate  into  oxidation  aldehydes were  .  were  reduced  experiment sphingomyelins,  sphingolipids  powder.  fatty and  In t h a t  These were  i n turn  acids  and  hydrolyzed  hydrogenated  bases.  the resulting  and  of the general formula  the alcohols  These  and  also  to the the  bases  aldehydes were  23,  latter  underwent  a n a l y z e d by  a n a l y z e d by  GLC.  a GLC.  -  The believed  biosynthesis to occur as  21  o f the long shown  -  chain  i n Scheme  fatty  3 through  base, sphingosine the condensation  (1_7) > i s of  33 palmitaldehyde The has  with  t h e amino a c i d  stereochemistry  the D configuration,  while  the double  bond  serine  of sphingosine carbon  i s the E  has a l s o  3 has an e r y t h r o  been e s t a b l i s h e d .  Carbon  r e l a t i o n s h i p to carbon  isomer.  Scheme Biosynthesis  Palmitic  .  of  acid  3 Sphingolipids  CH3(CH2)14C00H  f Palmitoyl  Palmitic  CoA  aldehyde +  serine  Dihydrosphingosine  t CH  Sphingosine +fatty  Ceramides  CH3(CH2)14CH(0H)CH(NH2)CH20H  acid  +  3  (CH2)12CH:CHCH(OH)CH(NH2)CH2OH  R COS  CoA  CH3(CH2)12CH:CHCH(0H)CH(NHC0R)CH20H  2,  2  - 22 -  Sphingolipids lipid the  bilayer  presence  permeable  For  of sphingolipids  biological  been  properties  associated with  with Na  +  mainly  34  of cells  i n t h e membrane  p o l a r and n o n - p o l a r  example, sphingolipids  have  t o be l o c a t e d  o f t h e s u r f a c e membranes  t o both  Several  a r e known  i n the upper h a l f .  I t has been  makes  i t more  of the  suggested  d e n s e , more  that ..  substances.  have  been  reported i n the  p o l a r head groups  transport  i n cells  34  literature.  composed o f .  carbohydrates  Sphingosine  was  found  35 to  inhibit  blood  clotting,  , while N-acetyl  s p h i n g o s i n e and  sphingomyelins  3fi have  effects  similar  have  immunological  to cortisone  i n guinea  pigs  , and  glycosphingolipids  37 activity  .  29 It  has a l s o  sphingolipids Obtaining  a complex  organism.  indicate  their  postulated  extracted  example, would or  been  different  the difference sources  m i x t u r e , as i n t h e case  indicate A  from  that  their  origin  from  from  a simpler  indicate  o f sea star  a functionally  s i m p l e r m i x t u r e , however, as origin  might  i n the complexity of origin.  cerebrosides f o r disparate  i n the present  structure.  their  study,  organ would  Figure 400  MHz  'H  NMR  2  Spectrum of  Ceramide  1  (CDCI3)  Figure 400  MHz  'H  NMR  Spectrum  of  4  Diacetylated  Derivative  9  (CDCI3)  - 26 -  -  27 -  Chapter  2  Nanaimoal II.1.  Introduction The  sequel ation from to  synthetic  t o my  M.Sc. t h e s i s  o f the marine a British  outlined  1  natural  Columbia  product  This  A  structures  obtained  of the chemistry  section partly  nanaimoal  nudibranch.  by t h e r e s u l t s  discussion  i n this  research.  one o f t h e h y p o t h e t i c a l  followed a  studies  arose  concerned  straightforward  pursuing  o f medium  ring  logical  the  identific-  ( 2 4 _ ) , (25_) o r ( 2 6 ) ,  24_ o f n a n a i m o a l  from  as a  that  synthetic  isolated approach  i s proposed.  synthetic  molecules.  This i s  route  The work  and  that  enabled  39 the of  s t r u c t u r a l e l u c i d a t i o n o f nanaimoal British  Columbia  i s then  briefly  24 As  part  Columbia  o f a program  n u d i b r a n c h s , we  The  Interest  while 'H NMR  A. n a n a i m o e n s i s  26  at studying  examined i n that  the skin  organism  s o r t i n g specimens  reduction  product  nanaimoal  of  H  extract  ratio.  ^  r o m  t  h  e  s  P  British  noticed  d a t a  of  of this  mixture  sesquiterpenoid  o f compounds,  to a molecular  formula f o r  a v a i l a b l e ( I R , MS,  13 C NMR)  several  features  of this  molecule  could  i t s sweet  expedition.  o f two c l o s e l y r e l a t e d  T h e MS  e c t r a l  of  Acanthadoris  of the extract  a n d DNPH d e r i v a t i v e p o i n t e d  -j5 20°'  of  w h e n we  after a diving  indicated the presence i n a 4:1  the chemistry  arose  o f the major constituent(s)  aldehydes, present  c  aimed  at the University  reported.  25  nanaimoensis. fragrance  (26_) b y c o l l e a g u e s  be  discerned:  'H, a n d  i t s  -  1.  four  sites  double  of unsaturation:  b o n d , and two  2.  a sesquiterpenoid  3.  fragment  4.  three  X-ray  methyl  did  not permit  the  proposed  decanes As  groups  attached  reasoning  attach  three  hypothetical  a suitable  and o t h e r  derivative f o r  spectral  measurements  structural assignment, a synthesis  o f one o f  undertaken. have  e i t h e r Robinson  i n Scheme 5  carbons.  to prepare  unsuccessful  approaches  an a p p r o p r i a t e  subsequently  As a t t e m p t s  an u n a m b i g u o u s  (decalins);  to quaternary  (Scheme 4) s u g g e s t e d  a n a l y s i s were  conventional  with  a tetrasubstituted  framework  s t r u c t u r e s 24 was  illustrated  start  (aldehyde),  rings.  2 4 , 25_ a n d 26_.  diffraction  Two  a carbonyl  -C-CH2-CH0  Biosynthetic structures  29 -  been  used  annulations  to prepare  or Diels-Alder  ( f o r s t r u c t u r e 24) these s i x membered  the required  second  ring,  bicyclo[4.4.0]  such  reactions.  two approaches  a s 2_7 o r 2 8 , a n d  s i x membered  ring.  could  -  30  Scheme Possible  Robinson  -  5  Annulation  and  Diels-Alder  Approach  to  27 /  •CHO 24  28  ^•CH CH(OEt) 2  2  /  /  24  -  The by  photochemical  Barnard  132  hours  trans). Our  and  afforded No  sequential  give  as  .'  the  route  They  alcohol study  (Scheme  cyclodecanone  32.  give  Provided of the  the  the  of  found 30  of 6)  -  cyclodecanone that  i r r a d i a t i o n of  (Scheme  was  based  alkylations  6)  by  on  product  target molecule  i n 52%  studied  would the  introduce  yield  requisite  24.  33  and  that  a  has  appeared.  that carbon  of  chain  substituents, to  cyclodecanone  deprotection  1959  ( 4 2 % c i s _ , 10%  two  methyl of  in  29_ i n c y c l o h e x a n e  the expectation  photolysis paralleled  alcohol  (29_) w a s  substituted cyclodecanones  -Ch^ChKOEt^), followed  dehydration would  4 0  subsequent  synthetic  (such  Yang  behaviour  31  the  (29),  aldehyde  for  - 32 -  Scheme Proposed  6  Photochemical Approach  t o Nanaimoal  CHfcCH (OEt)j  — 0%  29  34  qp H  33  24  based  on  CO  Op 0  H  29  (24)  30  -  II.2.  preparation of  order  to  ascertain (29)  methyl  afforded,  iodide  reaction  was  198  =  the  trisubstituted  Additional  the  isomer  NMR  and  J  ketone  was  =  32_, a n d  2.5  Hz  the  and  6  there would  of  35_, a l s o  irradiation  of  this  (Figure  a  presence  of  single  the  10)  formula  Lanthanide  by  of  =  J  5.10  have  1.5  of  indicated  a  f o r the  a  the methyl  at  parent  (Eu(fod)3) (35_)  'H  ppm 4 1  displayed  f o r the  major  (6:1).  These  tetrasubstituted  isomer.  The  3.31  (m).  ppm  doublet at  NMR  lithium  =  the  1.04  'H  NMR  spectrum  Upon  ppm  collapsed  13 to  a  singlet.  between being CO  6  =  22  The  SFORD  C  and  40  the  detected only  group  appeared  at  ppm,  in a 292  NMR  spectrum signal  concentrated nm  (log e =  due  of  35  to  the  showed e l e v e n  solution. 1.77)  i n the  CO The uv  at  structure  7 ) , which  isomer  ion  represents  Scheme 4.60  This  derivative  C-j-^gO, which  minor  from  o n l y one signal  35,  excess  product.  tetramethyl  shift  at 6  Hz  doublets  been  displayed  multiplet,  =  ppm  as  new  a c e t a t e 43_ ( o b t a i n e d b y  acetylation  doublet  appeared  12)  Although  MS  35.  h,  undertaken of  i n the  for 5  was  Treatment  2,2,10-trimethylcyclodecanone  a  at  have  GLC.  a molecular  reduction  not  by  provided  spectrum,  would  (Figure  the  i n THF  refluxing  derivative  evidence  hydride  to  behaviour.  hydride  expected,  confirmed  'H  signals  after  corresponding  experiments  in  sodium  monitored  was  m/z  aluminum  with  easily  cyclodecanone  2,2,10,10-tetramethylcyclodecanone  i t s photochemical  cyclodecanone  of  -  Results The  in  33  group band  at  signals 220.85  ascribed  spectrum.  ppm to  a  -  34 -  Scheme 7 Reactions  Performed  on 2,2,10-trimethylcyclodecanone ( 3 5 )  a:hv; b:03, MeOH or KMnO^, benzene; c: BH^, H202; d:Jones oxidation; e:LiAlH 4 , ether; f:Ac~0, pyridine, DMAP  The  photochemical  Photolysis  of  3_5  appearance  of  the  and  TLC  (one as  'H  between  NMR  about of  a  vinyl  alpha to  of  those  (Exact  starting  by  35  and  at  double  displayed  the major NMR  ppm  by  ppm.  also  for C  ] 2  H  2 4  p r o d u c t was  not  a  of  these  These (44)  ppm,  three and  ppm  in  The  the  presence  triplet,  signals  were  together with  168.1872, observed:  peak)  represented  signals.  (2.0  32.  single  appeared  a t 4.64  a methylene  indicated.  :  (one  singlet  5-bromo-2-methyl-hexene  calculated  GLC  signals  of  dis-  by  Olefinic  intensity  absence  complete  "homogeneous"  broad  of  i n the  i n the  photolysis  A  ( s ) and  b o n d was  resulted  spectrum.  6.0  investigated  Although  integrated  1.70  was  for 5 h  ketone.  'H  combined  methyl  Mass  the  6 = 4.6  the  to the  of  i n cyclohexane  implied  70%  -  behaviour  spot) analysis,  olefin  - 35  J  =  7  identical  the  MS  168.1860) p e r m i t t e d 42  the  identification  presence at  880  of cm  - 1  a  of  this  major o l e f i n  1,1-disubstituted  double  as  2-methyl-1-undecene  b o n d was  also  revealed  (36_). i n the  The  IR  .  44 The  structure  following fraction  series with  of  of  this  major  reactions  potassium  olefin  (Scheme  permanganate  36  7).  was  proved  Oxidation  i n benzene  by of  i n the  performing the  the  olefinic  presence  of  crown  42 ether  , gave  obtained sulfide ketone (1715  a  single  ketone  in better yield reductive  (2.07 1  cm" )  ppm, and  This  same m e t h y l  when o z o n o l y s i s  work-up. singlet)  t h e MS  39_.  The the  'H IR  ( E x a c t Mass  NMR  was  performed,  indicated  confirmed  ketone  the  calculated  the  followed  presence  presence  for C  n  product  H  ? ?  of a  0:  by  of a  was a  dimethyl  methyl  carbonyl  170.1665,  Hz)  group  -  observed: proved  36  -  170.1622) and  b.p.  (228-230° observed,  2-undecanone  (39)  was  that  the  literature  231-232  H J  )  product.  44 Hydroboration basic of  hydrogen 4Jj  alcohol  had  a  band a t  identical  of  a doublet  3300-3400  cm" .  of  readily  lost  from  the  alcohol  was  further  The  'H  bands  On chemical (IR,  'H  MS) the  synthesize  a  derivative  of  conditions  both  4 4  chlorine cases  higher  rate  by  yield  Jones  of  this  from  6  alcohol  Hz)  of  followed  at  by  40.  3.31  treatment  The  ppm,  'H  and  spectrum  the  IR  (40)  (36_)  H^O  ion.  indicating  The 44  primary  to  the  with  NMR  2-methyl-l-undecanol  oxidation  the  same  the  h y d r o b o r a t i o n and  fraction  that nature  spectrum  was  almost  is  of  the  corresponding  to  this  a more  minor  starting  Since the  the  leaving  a  =  164  hydroxyl  (C-^H^).  of  the  nitrogen having  ( C l , I ) , i t seems alkylation.  was  photolysis omitted  the  right  was  that This  prepared of  the  (38)  elimination i s deduced  d i d not  conterpart of  HC1  from  or  the  was HI  MS '  photo-  properties  isolated.  attempted  catalytic  cyclodecanone iodine  the  to  tetrahydropyranyl  under  the  reaction.  before  was  IR  3_7 i s  spectral  s t u d y , we  The  the  and  Structure  was  under  cyclodecanone.  group,  was  reactions.  or  reaction  group,  ozonolysis  carbonyl  product  alkylation  material  deshielded signals,  product  2-chloro-l-ethanol  than  the  f o r 2,10-dimethyl-10-undecene-l-al  tetrasubstituted  as  as  no  bubbling of polar  R^  showed  i o n a t m/z  photochemical  .  MS  parent  having  a molecular  reaction,  While  the  20%  o c c a s i o n when  NMR,  The  expected  fraction  assigned  one  (J =  corresponding to a  displayed  tentatively  primary  2-methyl-l-undecene  proved  spectrum  no  1  fraction  41_.  i n about  NMR  showed still  acid  non-polar  isolated  a  displayed  that  A  olefinic  peroxide afforded  to  carboxylic  the  (THP)  acidic take  place  prepared.  takes  presence  with In  place at of  three  a  - 37 -  new o l e f i n i c pattern)  signals  alkyl  spectrum  (typical  of the tetrahydropyranyl derivative  cyclodecanone. as  i n t h e 'H NMR  Various cyclodecanone  iodide,  cinnamyl  iodide  g r o u p , ABX  and t h e r e c o v e r y o f  alkylations  and benzyl  vinyl  with electrophiles  bromide,  followed  such"  by methyl  iodide,  using  bases  such  a s N a H , K H , L D A , K C H 2 S 0 C H 3 , K N H 2 , KOR, a n d a  variety  of solvents  such  a s T H F , DMSO, HMPA, DME, DMF, N H ^ , R O H , w e r e  investigated Unfortunately Subsequent  under various none o f t h e s e  attempts  cyclodecanone inconclusive.  also Thus  temperature experiments  t o prepare met w i t h this  enol  conditions, gave  including  sealed  a tetrasubstituted  tubes.  product.  ethers and acetates o f 2,2,10-trimethyl-  no s u c c e s s , w h i l e  photochemical  a D20 quenching  approach  t o nanaimoal  experiment ( 2 4 J was  was abandoned.  -  II.3.  38 -  Discussion 45 In  spite  reactivity related still  o f medium-ring  molecules  lacking.  failure the  of important  of  the molecule.  of  47 '  to the conformation  cycloalkanes, cycloalkanones twenty years  reaction  reactions  i s largely The  to follow  c a n be t e n t a t i v e l y  t e n membered  ring  deduced  based  on  and  understanding  of this  study  the anticipated cyclodecanone.  of  i s  are the path, The  of the conformational  conformation  and  and  course preferences  2,2,10-trimethylcyclodecanone  the present  work  and e a r l i e r  studies  molecules.  the cyclodecane  conformations  a consequence  preferred  detailed  aspects  i n preparing a tetrasubstituted  these  Although  '  two s i g n i f i c a n t  of the photochemical  of  of  Cg t o C ^  i n the last  Clearly,  difficulty  (35)  made  contributions  46  (Figure  molecule 48  i s capable  6 ) , t h e BCB  of existing  conformation  having  in a  a l l  number  staggered  47 linkages  possible with the more  i s preferred.  BCB  of cyclodecanone, 49  ("diamond-lattice") conformations  the carbonyl hydrogen stable  In t h e case  atoms  i n an e n d o c y c l i c p o s i t i o n , on t h e o p p o s i t e  according  to strain  side  energy  there  (Figure  h a s no  7).  steric  of the ring. 50 calculations  are three  Only  BCB-3,  hindrance  with  I t i s significantly and  1  H  NMR  51 measurements . This conformation relieves a p a r t i c u l a r l y serious " t r a n s a n n u l a r non-bonded r e p u l s i o n " . This i s also consistent with the 40 photochemical partially  located  transannular more  results  with  and Yang  the ring  stable  .  The  carbonyl  and p a r t i c i p a t e s  readily  group i s i n the observed  The  BCB-1 c o n f o r m a t i o n h a s b e e n p r o p o s e d a s 52 C-13 m e a s u r e m e n t s , w h i l e d i p o l e moment 45  f a v o r an e n d o c y c l i c c a r b o n y l  Other more substituted  inside  reaction.  i n accordance  calculations  of Barnard  conformations  c y c l o d e c a n e s , a n d some  have  as i n been  examples  being  BBC-1  found  follow.  or proposed f o r T h e TBC  conformation  - 39 Figure  6  Some C o n f o r m a t i o n s  B: C:  boat chair  L:  long  T;  twisted  of  Cyclodecane  BCC  CCC  TBCC  - 40 Figure  7  Some C o n f o r m a t i o n s o f  -:ReFers  Cyclodecanone  to n u m b e r i n g u s e d For c y c l o d e c a n e , F i g u r e 6  - 41  has  been  suggested  as  more  stable  -  i n the  case  of  4,4,8,8-tetramethylcyclo-  54 55 decanone  .  Through  1-carboxylic molecule  a c i d , the  i n the  solid 47  several of  studies  seems  t o be  indicated  a  two  which  solid  of  indicate  state  trying  phenylhydrazone)  of  4,4,7,7-tetramethylcyclodecane-  TBC  and  TBCC w e r e  Cyclodecane-1,6-dione  liquid  distorted  that  '  conformations  state.  i n the  i n the  analysis  has  assigned  been  the  a  state  difference  ( I R , UV,  (IR, X-ray).  "decalin-1ike"  to obtain  3_5  reactivity  example, reaction The or  products  a  probably  'H  The  or  solid  would  of molecules  rates  obtained  vary  from  also  between and  major  derivative  not  1 3  C  the  be  and  conformer  in  This  (such  as  the  intermediate also  a d d i t i o n , as  has  been  the  of  the  solution  latter  depends  on or  photolysis  change w i t h 40 59  previously  reaction  vary  study  2,4-dinitro-  their ring  '  the 60 '  with  size  and the  of  a  i n the  size  and  .  For  performed .  through  size  '  1  reductions are going  57  a  carbanion  ring.  In  present the  study,  substitution  ring.  Three indicate from  a  observed  same  warranted.  transannular reactions  ion  of  of  conformation  NMR)  TCCC m o l e c u l e .  when o x i d a t i o n s  carbonium  products  this  subject  46 The  to  56 '  the molecule  molecule  X-ray  different studies,  that  what  "the  structures  i s suggested  by  the  and  especially  of medium-ring floppy  X-ray  diffraction  molecules  necklaces  of  are  atoms  analysis^,  very  different  produced  by  fi? fi 3  conventional In  view  molecular of  the  models".  '  conformational  studies  outlined  2,2,10-trimethylcyclodecanone  (35)  in solution  which  from  carbon-10  abstraction  of  a  proton  1  adopts  a  conformation  i s extremely  that in  difficult.  CO  Comparison benzyl h  of  the  alkylation  bromide/NaH/THF.  alkylated 48  above, i t appears  product,  10%  After  product,  15%  gave:  starting  cyclohexanone  and  cyclodecanone  h r e f l u x , cyclohexanone  dialkylated  r e f l u x , cyclodecanone  dialkylated  of 5  product 70%  and  no  62%  starting material.  monoalkylated  material.  gave:  product, <  1%  using monoAfter  - 42 -  A the a  recent  effect  new a s y m m e t r i c  pseudoaxial 6.6  the  means  axial  that  to introduce  required  this  gives  w o r k was  for sites  into  existing  a t C-2  2 , 5 , 7 a n d 10  substituent.  the energy  a methyl  o f cyclodecane  i s no e n e r g e t i c  methyl  actually  A table  a t C - l , 0 kcal/mole  BCB, t h e r e  energy is  needed  after  finished,  s u b s t i t u e n t on t h e " s t e r e o s e l e c t i v e  centre".  positions  kcal/mole  This  , published  o f a methyl  calculations)  an  paper  penalty  (molecular  mechanics  .  a t C-3.  ( F i g u r e 8) a t t h e f o u r  the introduction  of  conformation:  kcal/mole  associated with  with  non-equivalent  i n t h e BCB  corners  of  the introduction  of  However, f o r t h e remaining  i s so l a r g e that  formation  the three  a n d 9.2  deals  s i x positions, the  o f an a x i a l  substituent  forbidden.  Therefore conformation,  i f we  consider  "tub shaped"  above), the introduction  2,2,10-trimethylcyclodecanone  like  the cyclooctanes,  o f t h e f o u r t h group  must  (based  (35) i n a  TBC  on t h e arguments  be t a k i n g  place  at a  64 position In  equivalent  our opinion  photochemical  t o C-4  and i s e f f e c t i v e l y  energetically  a twisted-boat-chair conformation and s p e c t r a l data  obtained  i s best  forbidden.  suited to the  f o r 3 5 , where:  0  TBC 1.  The p h o t o c h e m i c a l proton  2.  b y t h e CO  The c h e m i c a l a  methylene a  indicated H-10  reaction indicated that group  shift  transannular  i s not preferred.  o f t h e C-10  t o t h e CO  abstraction of a  proton,  6 = 3.31  o f a s i x membered  t h a t , i n the average  i s i n t h e d e s h i e l d i n g cone  conformation  ring  ppm  to that of  l a c t o n e , 6 = 3.31  adopted  o f the carbonyl  (similar  i n solution  group.  This  ppm  4 1 a  )  by 3 5 ,  requirement  - 43 -  implies  3.  that  the substituted  obtain  an angle  proton  a t C - 1 0 , a TB  The e l e v e n 12  alkyl  close  alkyl  C)  of the molecule  t o 0 ° between conformation  signals  indicate  side  obtained  an a b s e n c e  t h e CO  i s partly  flat.  To  a t C-l and t h e methine  i s necessary. i n t h e SFORD  o f symmetry  1 3  C  NMR  (C13H220:1  i n the average  CO  and  conformation  65 adopted The  results  comparison rather  b y 35_  .  of the photolysis  to the behaviour  than  related  medium  o f small ring  2,2,6,6-tetramethylcyclohexanone to  49_, w e r e  diradical positions. molecular  identified  reaction  (Scheme  ring  c a n be e x p l a i n e d by  ketones  k e t o n e s ^ ' ^ ' ^ .  (45_) w a s 8).  such  , four  reactions  Photochemical  o f carbon  ( d i s p r o p oS c r ht ei moen a8t e  Behaviour  monoxide w i t h  and c o m b i n a t i o n )  of 2,2,6,6-tetracyclohexanone  i n t h e a a n d a' subsequent was  intra-  promoted  69 (45)  + 46  47  CHO  + 48  46  alkyl  0  45  7 ,  when  products,  of the acyl  i n t e r m e d i a t e i s i n c r e a s e d by t h e s u b s t i t u e n t s Therefore, the loss  cyclohexanone^  For example, 69  photolysed  The s t a b i l i t y  as  49  i n 45_.  - 44 -  In cleavage  the case  ( o n t h e more  decarbonylation Norrish gem  o f 35_, m i n o r  type  product  substituted  and c y c l i z a t i o n  I cleavage  dimethyls.  side  3_7 r e s u l t e d  from  o f t h e CO  group)  (Scheme 9 ) .  f o l l o w e d by a p r o t o n  The m a j o r  product  36  of  !35_.  anticipated  i s not favored  T h e r e f o r e , no d e c a l i n  Photochemical  behaviour  38_ r e s u l t e d  abstraction.  from  The  was  from  type  Norrish  •  I  type  requirements  obtained.  9  of 2,2,10-trimethylcyclodecanone  a  one o f t h e  a Norrish  due t o t h e g e o m e t r i c a l  product Scheme  from  type. I  f o l l o w e d by a  abstraction  i s obtained  c l e a v a g e , a d e c a r b o n y l a t i o n and a p r o t o n cleavage  Product  a Norrish  35  II  - 45  As  mentioned  synthesis proposed structure  of  i n the  24_, o n e  of  f o r nanaimoal. of  nanaimoal  -  introduction, the  three  p r e s e n t s t u d y was  (24_, 25_ o r  Subsequent (26_) w a s  the  to this  successfully  26_)  hypothetical  study, the  directed  by  the  structures  elucidation  accomplished  at  of  the.  Andersen  39 and  collaborators  synthesis outlined  of  , at  50_, t h e  i n Scheme  the  University  of  British  p-bromophenylisocyanate  10.  Columbia.  derivative  of  The  Diels-Alder  nanaimoal  is  3.0  i  35 1  ',  ,- 4 0 MOONS I  1  j  I ,' ' !.' •' I _ 1  1  1  1  5  .1  MICRONS ,o.o I K  L  0  H  I I  WOO  1200  1000  MtOutNCV C". 'I  Figure  IR  spectrum  8  of 2,2,10-trimethyl c y c l odecanone  (^near)  -481  i  I  i  I  1  1  1  1  1  1  100  MOO  WO  1200  600  t Hi  MO  1200  «K)  800  300  0  '50  600  460  300  ISO  0  Figure 9 80 MHz  'H NMR Spectrum of 2,2,10-trimethyl cycl odecanone (35_ CDCL)  - 49  -  Chapter  3  Capnellene III.l.  Introduction 9  12  A isolated New  Capnellene from  Guinea.  (51_) i s a m e m b e r o f a f a m i l y  the soft The most  coral  Capnel!a  abundant alcohol  imbricata, 52 was  o f seven  sesquiterpenoids  c o l l e c t e d i n Indonesia  first  isolated in 1974  7 0  and  ,  f o l l o w e d b y t h e s t r u c t u r e d7 e1 t- e7 r3m i n a t i o n of our other alcohol representatives T h e t r i c y c l i c h y d r o c a r b o n c a p n e l l e n e (5J_) 53 t o 5 6 , i n 1976 and 1977 74 was  identified  i n 1978  and  the unstable  and  volatile  bicyclic  hydrocarbon  75 precapnelladiene  (57_) i n 1 9 7 9  . Scheme  Biogenetic  Relationship  11 of the  Capnellanes  HH  H  58  57  h um uI • n •  51  Pr  OH  52 53 54 55 56  capn«M«n •  H  l At  "t,4.8  1,2  " 3,4,5,6  I A3  R  4,5,6  1,2,5  R  3,4,6  1,2,4,6  R  3,5  capnilloli  - 50 -  It  has  7  been  suggested **  defense mechanism,  "to ward  that  compounds  off algal  and  51_  to  5_7  microbial  could  serve  growth  and  11  been  in a  chemical  prevent  the  71 settlement The the  of  larvae"  biogenetic  capnellane  (59)  on  capnellanes  and  coriolin  soft  relationship  f a m i l y  The  the  7 1  '  and  (60_))  7 4  '  7 5  7 7  '  outlined  hirsutanes are  two  attention  arrangement.  from  i n Scheme  has  proposed  for  . (which  comprise  f o r example  tricyclopentanoid families  4??  cis-trans-cis  coral.  These  synthetic chemists  triquinanes  have  in  few  the  last  hirsutene  fused  received  in  a  considerable  years.  H  59  When we dealing  decided  with  the  literature. syntheses  synthetize  synthesis  Since  79 8fi  to  , the  then,  of  51_  carbon  capnellene  (5j_)  only  epi-precapnelladiene  has  been  skeleton  the has  subject been  of  had  one  communication  appeared  several  prepared  87  and  in  78  the  total diol  53_  op has  also  outlined The  been  synthesized  .  In  the  next  few  pages, these  syntheses  are  briefly. key  steps  i n these  syntheses  are  shown  i n Schemes  12  to  21.  involved  Diels-Alder  The  79 first  total  reaction  synthesis  (0°, 3  h;  azodicarboxylate.  of  51_  by  >91%  yield  This  was  Little's of  62J  followed  group  between by  a  the  novel  fulvene  a 6j_  and  1,3-diyl t r a p p i n g  dimethylreaction  -  (dropwise related 2  addition  51  o f 6_3, 6 6 h , r e f l u x i n g  a z o c o m p o u n d 63_, w i t h  isomers) a t r i c y c l i c  elimination  T H F , >56% y i e l d of nitrogen,  o f 51_, b y R.D.  61 dienone  synthesis  65 underwent  68%  yield)  Little  and G.L.  the  resulting  79%  yield)  64_ ( a n d .  ketone  i n Scheme  cyclization 66_.  13.  64 Initially  ( 8 % P2°5»  Further alkylation  y - k e t o - a l d e h y d e 6_7 u n d e r  l e d t o 68^, a d i f f e r e n t  Carroll  63  i s shown  a Nazarov  to bicyclic  t o produce  12  62 Paquette's  o f 64) o f t h e  p r e c u r s o r o f 5J_. Scheme  Synthesis  -  basic  the  CH3S03H,  sensitive  20°, 2 min,  and c y c l i z a t i o n  conditions  of  ( 5 % KOH, e t h e r ,  THF,  p r e c u r s o r o f 5J_.  Scheme  13  80 Synthesis  In  o f 5J_, b y L . A . P a q u e t t e a n d K . E .  Drieding's  synthesis  2-oxocyclopentanecarboxylate. the  unsaturated ketone  , the a-alkynone  69_ w a s  Thermolysis (620°,  70, which  was  Stevens  prepared  78% y i e l d )  converted t o a second  from  methyl  o f 69_ a f f o r d e d  a-alkynone 7l_.  - 52 -  Thermolysis (620°, 33% yield) of 7]_ gave 68_ (and one isomer). Scheme 14 Synthesis of 51_, by L. Huguet, M. Karpf and A.S. Drieding  Fujita et al's synthesis  started with the preparation of a humulene  derivative 72^ which after several transformations led to t r i c y c l i c epoxide 73.  The key steps in this synthesis involved an i n i t i a l rearrangement  (TMSOTf, toluene, RT; IN HCl; 54% yield of 73) with migration of a methyl, followed by solvolytic rearrangement (MsCl, CH2C12, DMAP, 0° to RT, 20 min; NaOAc, AcOH, 7 0 ° , 6 h; 93% yield of 74, plus 1 isomer).  Another series of  steps afforded capnellene (and an isomer). Scheme 15 Synthesis of 51_, by T. Fujita, T. Ohtsuka, H. Shirahama and T. Matsumoto  72  73  82  74  83  In Oppolzer's synthesis  rings A and B were formed through two  "magnesium-ene" reactions. The linear a l l y l i c chloride 75, and the monocyclic  -  allylic 60°, 70% 67  c h l o r i d e 77_ w e r e  23 h; a c r o l e i n ; yield)  which  t o 78.  53 -  cyclized  57% y i e l d )  Subsequent  underwent an a l d o l  under mild  t o 76 a n d  Scheme  (Mg p o w d e r ,  (Mg p o w d e r , e t h e r ;  transformation  condensation  conditions  o f 78 a f f o r d e d  ether;  RT, 2 h;  02;  y-keto-aldehyde  t o g i v e 51_.  16 83  Synthesis  o f 51_, b y W.  75  Oppolzer  a n d K.  76  Battig  77  78 84  The (Scheme This 450  first 17).  aromatic w,  (KOH,  biogenetic In t h i s  type  case,  molecule  was  h e x a n e , >90% y i e l d )  synthesis  the starting converted  81_ l e d t o e p i p r e c a p n e l l a d i e n e o f 51_.  trifluoride  Synthesis  material  t o 79_.  gave  was  B i r c h a n d G.  cyclization  by f r a g m e n t a t i o n 8J_.  isomer),  cyclization  Pattenden  1,3-dimethoxybenzene.  was  Further  (6 h ,  i n base  reaction of  the biosynthetic accomplished  (benzene, r e f l u x , 1 h, 50% y i e l d , Scheme 17  o f 5 j _ , b y A.M.  by  Photochemical  diketone  (82_ a n d o n e  The t r a n s a n n u l a r  etherate  undertaken  o f 7 9 t o 80_, f o l l o w e d  EtOH, 48 h , 2 5 ° , 36% y i e l d )  precursor  was  plus  Pattenden  two  using  boron  isomers).  -  Mehta's  synthesis  between methyl chemical  dione  86  to  led  the  Isomerization double  cyclopentadiene  86.  bond  in  and  ( E t O A c , 450  Flash  column  A  very  addition molecular  of  Diels-Alder  of  the  ring  double A  gave  bond 68,  a  in  of  51_,  by  G.  w,  85^ a f f o r d e d  75%  vinylic  alkylation  Grignard (KH,  THF,  y i e l d ) of 0.1  C  of  87  and  precursor  of  RT)  intramolecular  mm  cis-cisoid-cis  ring  known  by  (THF,  An  Hg,  60%  fused  the  photo-  penta-  yield)  of  rings.  reduction  of  the  51_.  18  M e h t a , D.R.  synthesis  reaction  p-benzoquinone.  t r i c y c l o p e n t a n o i d 87_ w i t h  recent a  a  pyrolysis (530°,  Scheme Synthesis  -  started with  cycloaddition  cyclic  54  Piers  Reddy  and  is outlined  reagent  afforded  RT,  y i e l d ) of  75%  A.N.  Murty  i n Scheme  chloroketone 88  gave  89.  8 5  19. 88.  Conjugate Intra-  After  -  further  preparation  performing yield),  55 -  of chloroketone  a second methylene  and deoxygenation  90, the second  cyclopentane  key step  annulation  was  achieved  by  ( K H , THF, RT, 69%  t o a f f o r d 9J_. Scheme  19  Rfi Synthesis  Two shown 96 A  other  o f 51_, b y E . P i e r s  syntheses  r e l a t e d t o 51_ s h o u l d  i n Scheme 2 0 c o n s i s t s o f t h e s y n t h e s i s  that  could  be a d a p t e d  photochemical  addition  cyclohexane-1,3-dione Coupling only  a n d V.  o f 94 u s i n g  product)  gave  to a synthesis  92^ a n d c y c l o p e n t e n e  olefin  96_.  be m e n t i o n e d .  The  f i r s t  of a tricycloundecane  of the capnellanes  (MeOH, uv l i g h t  a low valence  Karumaratne  o f 2 5 4 nm,  hirsutanes.  90% y i e l d )  (93) afforded  titanium species  or  bicyclic  (TiCl^,  skeleton  involving diketone  94.  K, T H F , 5 m i n ,  -  56  Scheme Synthesis  -  20  of a C skeleton  related  to 51,  87 b y J . E . Paw  A-  and A.C.  Weedon  °  +  o  i  93  92  94  OH 95  96 88 Finally,  another  (Scheme  21).  of  acetate  enol  keto  acetylene  naphthalene oxidation  A  synthesis  stannic chloride 97  produced  99_.  radical  step, diol  The  last  anion 53_.  by P a t t e n d e n (moist  (THF, 2 5 ° ,  53 f o r i t s t a r g e t  C F ^ C ^ , 63% y i e l d )  bicyclooctanone cyclization  has d i o l  was  98.  Further  accomplished  26% y i e l d )  induced  cyclization  reactions l e d to the with  and a f f o r d e d  sodium  after  an  -  57 -  Scheme Synthesis  o f 5_3, b y G .  21  Pattenden  and  S . J . Teaque'  summary, the ten syntheses presented in  In  Schemes  12  to 21 can be  divided into 3 categories. I n the first, the rings were assembled one at a time.  example, in  For  then ring  added; in  C  Schemes  Schemes  1 3 , 14 1 2 , 19  and 1 6 , ring  B  was attached to ring  and 2 1 , rings  A  and C were joined to  ring B . T h e second group consists of the biogenetic type syntheses. I n one case,  Scheme  (humulene)  15,  the "starting material" was a medium ring molecule  possessing the  15  carbons necessary for 1  8  2  51_.  After  4  several  transformations via t r i c y c l o L e . 3 . 0 ' . 0 ' ] and tricyclor.6.3.0 undecanes, the triquinane system was obtained.  I n Schemes  17  1  1 1  ]-  and 2 0 , the  key intermediate was a bicyclo[6.3.0]undecane molecule (related to precapnelladiene). T h e required tricyclopentanoid was then obtained through an intramolecular cyclization.  7  ^.O '  A;  - 58 -  Scheme 18 represents another special approach.  Starting with a 5 and  a 6 membered r i n g , a t r i c y c l i c intermediate was formed, followed by a pentacyclic  ring system and f i n a l l y the t r i c y c l i c  target.  -  III.2.  Results  This  and  discussed present  natural  aimed  at  product,  chronologically in order  first  disconnection the  marine  studies  to  the  total  capnellene  show  the  synthesis  (5J_).  logical  The  of  the  results  development  of  are the  work.  Our  of  -  Discussion  section describes  tricyclopentanoid  59  C-10,  retrosynthetic analysis of  the  C-5,  C - l l bond.  C-6  bond  of  Therefore,  (Scheme ring  the  B,  22)  of  51_ e n v i s a g e d  preceded  synthesis  by  the  begins  the  disconnection  with  the  preparation  89 of  the  appropriate  ring  A,  which  would  Scheme Enol  ether  numbered according to capnellene  later  be  joined  to  ring  C  .  22  approach  to  51  1 0 0  Eto  103  As  illustrated  cyclopentanone  102  i n Scheme  (104).  After  23,  our  first  formation  of  approach  methyl  to  ring  A  started  with  2-oxocyclopentanecarboxylate 90  (105), alcohol from is  t r i m e t h y l a t i o n of 108  105).  assigned  was The to  obtained 1  H  the  NMR  the with  of  methine  B-keto-ester a  very  alcohol proton.  108  and  reduction  good o v e r a l l y i e l d displays a The  presence  of  ketone  (30%  singlet  at  of  one  only  from 4.05 new  107_  ,  104,  or  ppm,  which  singlet,  56%  -  indicates  that  probably  only  one  60  -  alcohol  isomer  i s formed.  The  orientation  91 is  uncertain  isomer a  108b  bromine  of  but  i f the  would  or  be  reagent  obtained.  showed  that  due  to  steric  hindrance,  was  appreciated hindered,  related  the  that  encountered  regardless resulting  of  1 1  the  Grignard were  ester  ,  d i s p l a c e the  unsuccessful .  however t - b u t y l groups  experiments  to  the  1  be  difficulty  the  with  A l l attempts  c h l o r i n e seemed t o  108  quite  coordinates  A  (or  alcohol  space-filling  in displacing  alcohol  then  isomer  the  by  model  alcohol  considered.  l i t h i u m ) reagent would  s u c c e s s f u l l y added  to  103  is It be  in  . Scheme  23  Synthesis  of  O  O  104  108  Q  105  108  O Q  106  107  o:« b:—OH O H  c: Br I  Hydroxyl group displacements t r i e d : • triphenylphosphine, bromine, DMF; phosphorus t r i b r o m i d e , ether; p-toluenesulfonyl c h l o r i d e , p y r i d i n e ; h y d r o b r o m i c a c i d ( g ) , THF; phosphorus dibromide, p y r i d i n e , sodium bromide; t h i o n y l c h l o r i d e , p y r i d i n e , r e f l u x , or sodium c h l o r i d e i n benzene; aluminum t r i c h l o r i d e , e t h e r ; methanesulfonyl c h l o r i d e , p y r i d i n e ; phosphorus pentachloride, calcium carbonate, chloroform. No MS w a s a v a i l a b l e a t t h e time. I I  S . J . A l w a r d , unpublished r e s u l t s , r e a c t i o n between 3-ethoxy-2-methyl-2-cyclopentenone (103).  t-butyl  lithium  and  While  these  experiments  -  61  -  were  in  progress  cyclopentenone  annulation  93 results  became  laboratory forward.  indicated  prove more  The  second  Diels-Alder oxidation  allylic  would  a  bond) t o  double  several  of  potential  to  ring  capnellanes.  be  prepare  ring  to  closure.  stereocontrol As  will  and be  possible i n the  colleagues  would  route  (Scheme  110  24)  was  not  be  towards  would  opening  be  in  our  straight-  the  synthesis  of  of  lactone  accomplished  The  be  The  proposed  I t was  hoped  triquinanes (Scheme  was  by  T_T_1_  by  the  would  a  presence  intermediate  112  and  by  ketone  access could  base  since  of  hydro(later  oxidation  provide  selected  intramolecular  followed  allylic  via ozonolysis  24)  an  i n t r o d u c t i o n of  route  that  on  Baeyer-Villiger  directed  C  could  based  anticipated that  51_.  outlined  of  bonds  another  by  at to  eventually  catalyzed  i t allows  good  versatility.  related to  double  22)  capnellene  approach  derivative several  that  I t was  Ring  related  This  undertaken  " f " (Scheme  ketone  points.  oxygenated used  109.  bond.  lead  work  selected  tetracyclic  genation  step  decided  approach  double  The  rewarding.  reaction  of  .  that  T h u s , i t was  5J_ m i g h t  the  available  109  below, the has  proved  preparation  of  particularly  starting  materials  and  routes  required  position represented  a  cyclopentadiene  challenging. to  109,  a major  In  spite  establishing task.  the  -  62  -  Scheme Cyclopentadiene  115  24  Approach  to  Capnellene  114  -  Our f i r s t the  opportunity  reactivity  carbon  bicyclopentadiene  of cyclopentadiene  chain, followed  by an  bicyclo[3.3.0]octadiene structural  isomer  illustrated The  preferred.  favoured.  t o be d i r e c t ,  of the behaviour  This  119 o r 1 2 0 .  ( 1 1 6 , Scheme  second  (Only  and  systems. 25) w i t h  intramolecular alkylation,  120.  and o f f e r e d  step  could  one p o s i t i o n a l  a suitable was  produce  expected  three to give  either  i s o m e r o f 120 i s  i n Scheme 2 5 ) .  spiro  possessing  t o 109 a p p e a r e d  t o increase our understanding  of fused  Alkylation  approach  63 -  system  Also,  1_1_9 i s k n o w n  1  t o be u n s t a b l e , and t h u s  i f Y i n s t r u c t u r e 118  a carbonyl  group, a product  120^ s h o u l d  (Scheme 25) r e p r e s e n t s such  as 120 s h o u l d  a  species  be even  more  1 1  Scheme Alkylation  116  25  of cyclopentadiene  117  118 ^ J y  116  ^  120  Spiro  molecule  controversy 1 1  1_1_9_ w a s  surrounds  reported  i t s first  over  t h i r t y years 95_97 synthesis  ago  , and  some  A c c o r d i n g t o Baldwin's r u l e s , 5-exo-tet and 4-exo-tet processes a r e f a v o u r e d , however " f i v e and s i x membered r i n g compounds a r e f o r m e d more 98 e a s i l y than t h e i r analogues with smaller or l a r g e r r i n g s " .  be  - 64 -  Table Conditions  f o rthe alkylation Temperature  117 X  4  •  Y  (°C)  Cl  C00CH3  C0C1  Cl  o f 1_1_6 Time  Yield  (h)  of  (%)  118  0  4  75  -78  1  i  0  1  ii  20  2  i i i  CHO  Cl  Cl  CH(0CH2)2  0  16  82  Cl  CH(0CH3)2  20  4  89  Br  CH20C0CH3  0  4  90  Br  CH2C1  -78  6  65  Br  CH2Br  -45  1  88  I  CH,I  0  .5  91  -40%, y i e l d  of possibly  1,3:1,1  diacetylated  cyclopentadiene (1:4)  -40%, y i e l d  of possibly  1,3:1,1  diacetylated  cyclopentadiene (1:1)  -5%,  possibly  product  with  alcohol a to the cyclopentadiene  -  As  expected,  straightforward  the  in a  first  obtained.  proceeded  number o f  cases  Products alumina.  could  118  I t was  but  be  readily with  tentative,  as  to  to  1  conditions .  (Y  converted  118i  (Y  =  to  solvents,  the  cyclopentadiene  to  by  i f not  column  distill  reduced  to  Only  This  118d step  100°C).  starting  No  kept  in  solution).  u s e d , more  65  to  products  of  the  and  products  3-chloropropanal  chromatography  on  neutral  decomposition  products  90%.  (in  Most  reaction  products of  3-chloropropanal  and  (Y  NaH  not  =  or  DMF,  was  (mild  118e  (acetals) be  cyclo-  are  i t was  achieved  annulations of  DME,  product  material  with  from  118g  using  THF,  However,  diacylated  these  could  Cyclopentane  (ether,  4).  proved  4.  products  attempted  (116)  Table  some o f  20%  the  C H 2 0 T s , CHO),  CH2I) were  and  c h r o m a t o g r a p h y was  i n Table  aldehyde.  118f  Usually  were  cyclize  the  to  of  25  u s e d , two  3-chloropropionyl chloride  of  -78°C  ( 1 1 7 b ) was  possible  identified.  variety  different  also  cyclopentadiene  (Scheme  purified  flash  indicated  order  deprotect  (from  best  the y i e l d s  pentadiene  In  were  of  (unstable product  When s t a n d a r d  occurred. vacuo),  Also, reaction  i n poor y i e l d  -  alkylation  when 3 - c h l o r o p r o p i o n y l c h l o r i d e were  65  necessary  cleanly  under  118a  (Y  =  C00CH3),  C H 2 C 1 ) , 118h  (Y  =  CH2Br),  KH  (1  or  DMSO) a n d  detected  from  conditions) or  2 equivalents), at  different  any  some  of  these  insoluble  in  temperatures reactions. product  99 was  recovered.  ethyl was  There  a c e t a t e and  tried  on  118a  a  to 1  heat  and  precedent  catalytic  and  unsuccessful, which  i s a  other  amount o f  for alkylating base  modifications.  i s probably  partly  due  (NaOEt). A l l these  to  the  high  cyclopentadiene This  mild  reactions  with  procedure were  sensitivity  of  120,  base.  Deprotections t aluminum t r i c h l o r trimethylsilyl ch c h l o r i d e , sodium  a  ried: 1% h y d r o c h l o r i c a c i d ; o x a l i c a c i d a n d acetone; i d e , dichloromethane; boron t r i f l u o r i d e e t h e r a t e , e t h e r ; l o r i d e , sodium i o d i d e , a c e t o n i t r i l e ; trimethylsilyl i o d i d e , a c e t o n i t r i l e and butadiene.  - 6b Scheme 26 Synthesis of 120, by M.S. Baird and C.B. Reese  120  Q  Compound 120 has been previously synthesized as shown in Schemes 26 and 27.  However these procedures are not of preparative value. Scheme 27 Synthesis of 120, by A. De Meijere and L. Meyer  97  9 0 — O O —CO ° +120  0  120b  119  Since molecule 1_20 was elusive, a modified approach to 1_26 (Scheme 28), which bears a methyl substituent was examined. The enol ether 103 formed from 2-methyl-1,3-cyclopentanedione (121) has been converted by Koreeda, 1  Liang and A k a g i ^ into bicyclic enol ether 122. followed by hydrolysis and reduction of 122.  This sequence was repeated, 1  Several dehydrations of  a l l y l i c alcohol 124 were attempted, but no dehydrated product of type 126 1  Dehydrations tried: hydrogen chloride (g), chloroform; phosphorus oxychloride; thionyl chloride; N-phenylselenophthalimide, n-tributylphosphine; phosphorus pentachloride, chloroform; trifluoroacetic anhydride, dimethylaminopyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene; p-toluenesulfonyl chloride, pyridine, dichloromethane. In retrospect, the Burgess reagent or methanesulfonyl chloride and the sulfur dioxide dehydrations (see experimental) might have given a better result.  - 67 could be isolated.  Thus, alternative step "e" (Scheme 28) which would  introduce a second substituent in ring B before dehydration was explored. 101  It i s known  that 3-diketones such as 121_ can be alkylated using methyl  vinyl ketone. The product of this Michael addition depends on the reaction conditions (Scheme 29). afforded 128.  Under neutral conditions (reaction in water), 121  Under catalytic basic conditions (chromatography of 128_ on  alumina, or standing of 128 at 20°C for a few days), ketol 130 was produced. In contrast, when 128 was submitted to acidic conditions, 129 was obtained. Scheme 28 Reactions of 8-diketone 121  121  122  103  •  JOH  0  e  0  0  -  68 -  Scheme 2 9 Known a l k y l a t i o n  121  o f 121  0  \  127  0  128  1 29  A Michael satisfactorily 'H NMR s p e c t r u m product. proceed dione  addition t o give (CH3>  Selective  between  123 and methyl  125, as indicated  vinyl  ketone  by t h e IR spectrum  s , 0.94 and 2.02 ppm), c h a r a c t e r i s t i c  functionalization  asexpected.  1  o fthe methyl  ketone  T h e r e f o r e a 1 , 6 - a d d i t i o n between  121 o r b i c y c l i c k e t o n e  123 a n d 144b was a t t e m p t e d .  proceeded ( n o OH)  and  o fa non-cyclized i n 125 d i d n o t  2-methyl-1,3-cyclopentaneThel a t t e r  reaction  102 did  n o ta f f o r d  Since  these  skeleton  t h er e q u i r e d  attempts  were  product  even  though  l i t e r a t u r e precedent  unsuccessful a different  approach  exists  t ot h eb i c y c l i c  was a d o p t e d .  Q  R2lR3=H,COOEf  b  R2=R3=COOMe  1U as  Reactions attempted: Wittig, well asGrignard additions.  Horner-Emmonds  and Knoevenagal  condensations,  .  One  of  3-diketone  the 121  results  obtained while  i s presented  i n Scheme  investigating 30.  In  the  keeping  alkylation  with  of  literature  103 precedent  , 0  an a l k y l i o d i d e (K2C03),  r a t h e r than i n an  C-alkylation  aprotic  o c c u r r e d when  polar solvent  Scheme  (DMF  or  121  was  HMPA) a n d  treated  a mild  base  0  0  30  O-alkylation  of  121  it  121  » K>  132  The  IR  and  'H  identification. and 'H J  these were NMR  =  7 Hz);  The  The MS  NMR  Two  4.30  132  bands  ppm  (2H,  of  the t , J  a  O-alkylated product  i n the  carbonyl  and  following =  s i x protons  displayed  the  appeared  to a  displayed  remaining  of  spectra  assigned  spectrum  bs).  with  7Hz);  a  spectrum  3.92  (3%)  at  conjugated  signals  appeared  v e r y weak  IR  ppm  as  at: (4H,  1700  double  6 =. 5 . 0 0 bs)  a multiplet  parent  enabled i t s  and  and bond. ppm  i o n a t m/z  =  The  (IH,  1.58  between  cm~\  1640  ppm 2.1  t ,  (3H, and  2.8  212.  104 A  p a p e r by  variant  to  enolizable  the  Coates Michael  carbonyl  observed  that  the  acrolein  acetal  and  Hobbs  which  reaction.  appeared  It involves  compounds w i t h a , 3 - e n o l s  reaction  between  (CH9CHCH(OEt)9)  the or  in early reaction  1984, of  place neat  ethoxyallenes.  in a  a  readily  2-methyl-1,3-cyclopentanedione  takes  offers  It  was (121)  sealed tube, at  and  200°C  ppm.  -  in  33 h ( 8 2 % ) o r i n r e f l u x i n g  This  r e a c t i o n may p r e s e n t  Approach  70 -  1,2-dichloroethane,  another  possible  85°,  i n 0.25 h  (67%).  approach.  t o 138  The  results  described  above  influenced the next  route  examined  which  1 5 starts  with A  prepared has in  ' bicyclo[3.3.0]octen-2-one  by s e v e r a l  a precedent Scheme 3 1 .  alcohol  groups  1 0  ^'  1 0  ^.  ( f o r and against Diol  (138),  Another  approach  133 was p r e p a r e d  from  Grignard (100).  rearrangement) acid-catalyzed rearrangement 133 t o o k  identified  place  through  isolated.  (137) the  were  'H NMR  Although  similar  1 0 7 , 1 0 8  addition of Although  which  i s outlined propargyl  t h e (Meyer  of the tertiary  a-acetylenic  a n d IR s p e c t r a , s e e E x p e r i m e n t a l ) ,  partially the sensitive  t h e Nazarov c y c l i z a t i o n . I n s t e a d , k e t o n e 137 formed by decomposition of the Grignard product  t h e I R a n d 'H NMR  t o those  DNPH d e r i v a t i v e  ketone  ( s i n c e 1 3 4 , 135 a n d t r a c e s o f 136 w e r e  d i e n o n e 136 d i d n o t undergo (self-condensation o f 104), was  previously  to this  i t ! ! )i n the l i t e r a t u r e  (ClMgCCCH2OMgCl) t o cyclopentanone  alcohol  a ketone  of A  o f 1_37 ( M  +  spectra  of  bicyclopentyliden-2-one  1 5 ' -bicyclo[3.3.0]octen-2-one  = 330 C  1 6  H  1 8  1_38, t h e MS o f  N40c, therefore the  molecular  13 formula  o f t h e ketone  observed 158.66  at:  Scheme  31  The ester the  105 w i t h  primary  reported  C NMR  spectrum  (10 s i g n a l s  left  no d o u b t  as t o t h e d i m e r i c  according  t o t h e known  nature route  128.69, of this  product.  shown i n  .  approach  performing  ppm)  138 was s y n t h e s i z e d 1 0 5  and t h e  20.09, 25.23, 26.94, 29.52, 32,55, 34.30, 39.79,  and 207.39  Therefore,  i s C^H^O)  illustrated  methyl  ester  i n Scheme 3 1 , c o n s i s t s o f a l k y l a t i n g  acrylate;  decarboxylating  o f 139_ i n o n e s t e p . .  a Meyer rearrangement.  to give  Reducing  The f o u r  9 2 , 9 0 , 97 a n d 7 7 % y i e l d ,  B-keto-  t h e B-keto-ester and h y d r o l y z i n g t h e ketone  steps  of this  respectively.  o f 1_40 a n d  finally  synthesis  were  The f i r s t  three  steps  -  could the  be r e p r o d u c e d  cyclization  polyphosphoric Easton,  Carlson  proceeded (f^Og,  and Lee's  followed.  This  continuous  extraction  cyclization  According 1 , 5  mixture  procedure  -  i n t h e same q u a n t i t a t i v e  step acid  71  improved  a  s  i n  e a s i e r t o handle  i n t h e work-up was  t o t h e IUPAC  Kiilkarni  alternative  Nomenclature  Therefore, and Dev's  1 1 0  (^2^5'  yield),  however  instead of  synthesis  C^SO^rl)  1 0 5  using  ;  was  and d i d not r e q u i r e a  procedure.  used, the yields  (73% overall  1  i n 30-40% y i e l d .  "3^4)  was  way  When t h i s  increased  o f Organic  modified  to 60%.  Chemistry  A bicyclo[3.3.0]octen-2-one ( 1 3 8 ) c a n a l s o be named b i c y c l o [ 3 . 3 . 0 ] oct-1(5)-en-2-one or 1(5)-bicyclo[3.3.0]octen-2-one. These two v a r i a t i o n s a p p l y t o t h e m o l e c u l e s where t h e d e l t a n o m e n c l a t u r e has been used.  - 72 Scheme Synthesis  of  1 , 5  -bicyc1o  140  31 3.3.0  octenone  (138)  141  -  The of  next  138.  142  was  steps  i n the  H o w e v e r , due chosen  formation  and  as  to  o f an  troublesome.  138.  to minimize  necessary (<  to  perform  20°C), using  Therefore,  an  facilitate  the  later  the  compound  converted  into  dimethyl  carbonate  ( C 0 ( 0 M e ) 2 ) was  diethyl  oxalate  described  i n the  a methyl  too  next  side  group. not  reactive,  ( ( C 0 0 E t ) 2 ) and  reactions.  142  was  ethyl  as  a  the  chain. A  these  diethyl  first  a'  sensitive  low  in a  few  reactive,  ( H C O O E t ) c o u l d be  138  to  (DEPC, used  could  examined:  methyl  pyrocarbonate  0  minutes).  group  r e a g e n t s were  0  than  temperatures  substituent  This activating  pages.  142  was  at  (reacting  number o f  formate  selective  k e t o n e s , i t was  carbanion)  sufficiently  but  The  even more  of  electrophiles needed  alkylations  1  cyclopentenones  (involving  the  be  (CICOOMe) was  these  a  3-methyl-2-cyclopentenone  self-condensation  g r o u p was of  sequential  next  Model  reactive  introduction  the  from  reactions  activating  formate  of  anion  the  relatively  require  availability,  f o r most  experimentally In o r d e r  -  synthesis  i t s ready  a model  reaction  73  chloro0(C00Et)2) as  - 74 -  Approach It hexanone  Using  138  has been with  and Diethyl  reported  diethyl  Decarbonylation  of  Oxalate  oxalate,  143, u s i n g  powdered  the related B-keto-ester  with  a n d 142,  literature  and thus  under t h e reported  (including  sealed  tubes)  alkylation  o f 145  was s t u d i e d  (65%).  known  upon  i n 65%  and i r o n  proved  conditions  yield  reaction  of cyclo-  (Scheme  powder, a t  165-175°C  were  according  32).  expected to the  o f t h e cyclopentenone  and higher  impossible.  (Scheme  reaction  T h e same r e a c t i o n s  Decarbonylation  Scheme A  glass  that  t h e a c y l a t i o n was c o n d u c t e d  (95% a n d 65% y i e l d ) .  derivatives,  ,  143_ i s o b t a i n e d  produces 138  1 1 1  i n the literature  Therefore,  temperatures t h e reduction and  33).  32  o f cyclohexanone  143 Reduction  o f 145  (76%).  carbonyl  The  signal  chemical  unsaturated chain  represented  of this  alcohol  reduced  the unsaturated  146 w a s f o r m e d  f o r 146  was s u p p o r t e d  b y i t s 'H NMR  appeared  i n t h e 'H NMR  spectrum  shift  of this  carbonyl  carbonyl  i n MeOH), c l e a n l y  The t r i f l u o r o e s t e r  structure  deshielded  NaBH^  (98%, u p o n a d d i t i o n o f T F A A , DMAP i n CH 2 C1 2 a t 2 0 ° C ) .  quantitatively proposed  (with  4 1  (6  4 1  (6  methine expected:  expected:  a vicinal  coupling  -6.1  corresponded -v5.6 ppm).  between  a n d IR s p e c t r a .  a t 5.40  The s m a l l  H - l a n d H-8  A  ppm ( d , J = 3 H z ) .  t o the reduction  ppm), rather  The  than  coupling  o ft h e  to the side observed  (0 f t _ Q e x p e c t e d t o b e  -  7  Hz).  1  and to  The IR s p e c t r u m  1630 cm" . the ethyl  bond.  reduction  took  A DNPH s p r a y 145,  The f i r s t  ester,  Another  of this  place  ester  displayed  band was a s s i g n e d  the third  observation  75 -  supported  a t the unsaturated  was u s e d  to visualize  a r e d c o l o u r was o b s e r v e d  and t h e l a s t  this  1750,  on T L C .  t h e second  from  double  that the  TLC  analysis.  In t h e case  f o r 1 4 6 , an orange  1700  possibly to a  interpretation,  c a r b o n y l , comes  the spots  while  a t 1800,  to the trifluoroester,  t o t h e ketone  that  bands  c o l o u r was  o f compound produced.  112 Since red  DNPH d e r i v a t i v e s  rather  would  tend  than  o f unsaturated  orange  t o support  (qualitative  carbonyls  test,  a r e known  t o be  not quantitative),  this  coloured result  the spectral data. Scheme 33  Reactions  performed  on 145  COOMe The to for  give  trifluoroester the diene.  alcohol  dehydration  o f 146 c o u l d  Since  148 (which  alcohol  riot  be r e a d i l y  146 does  eliminated  not represent  has a t e t r a s u b s t i t u t e d  a carbon,  o f 146 was n o t e x t e n s i v e l y s t u d i e d .  a very Scheme  (using good  DBU) model  33), the  -  In  view  attention  o f the encouraging  was t u r n e d  76 -  results  to the alkylation  of the reduction o f 145_.  the  alkylation  o f 5-carboxy-2-cyclopentenones  131  (a or b).  This alkylating  In  reagent  the present case, displacement  abstraction compete. the  o f the y proton  C o n d i t i o n s were  side  reaction.  insoluble  anion  reacted the  halide,  When r e a g e n t  a t a higher  alkyl  chloride  work-up.  o f using  followed  used  c a s e , 1.1  by e l i m i n a t i o n  mixture  and  may  reduced  i n a  t h e E isomer  adding  pre-warmed  (trans)  T h e r e f o r e , two e q u i v a l e n t s ( c i s ) recovered  o f 131b were  an  7, f o r several  the dehydrohalogenated  equivalents  however  i n e t h e r a t 20°C,  and t h e Z isomer  1 3 1 b was u s e d ,  manners.  sodium ethoxide t o generate  the reaction  the Z isomer.  s u c h as-  was a n t i c i p a t e d ,  (seeExperimental, Table  than  ester  favored the alkylation  and s t i r r i n g  131a were  In t h i s  a chloro  1 3 1 a ( 1 : 1 , E;Z) was u s e d ,  rate  When r e a g e n t  recovered.  which  was d e v e l o p e d f o r  i n two competing  o f the 5-carboxy-2-cyclopentenone  b a t h , f o rtwo hours  examples).  with  of the chlorine  These c o n s i s t e d  DMSO a n d t h e a l k y l (75-80°C)  found  A method  can react  (y t o t h e e s t e r )  study, our  of  after  diester  was  used.  Cl  131 The During  bicyclic  this  conjugation from  molecule  alkylation,  1_45_ w a s a l k y l a t e d  t h e double  ( a s i n 1 4 7 , Scheme  t h e 'H NMR  spectrum.  bond  33).  with  diester  i n the side  chain isomerized outof  The i s o m e r i z a t i o n  The c h e m i c a l  shift  131b ( 9 0 % y i e l d ) .  was e a s i l y  of the signal  identified  assigned tothe  -  vinyl  methyl  while  a  new  presence more  changed  from  olefinic  of  base  stable  signal  i n the  double  2.01  bond  77  ppm  -  ( s ) i n 131b  appeared  solution isomer  at  5.04  appeared  to  ppm  to  1.68  ppm  ( t , J  promote  (non-conjugated!).  in  147,  1  =  7 Hz) .  the  This  (bs)  The  formation of behaviour  the  has  also  113 been  observed After  ethoxy The in  by  alkylation  g r o u p was  reduction methanol  was  149_  reduction  product  to  an  NMR  structure  the  33)  and  and  the  of  side  has  the  IR  147,  a  product  with  expected  alcohol  (Scheme  borohydride  of  or  sodium  ammonium c h l o r i d e  product  been  149  could not  tentitatively 1:4),  spectrum  a l c o h o l 148  then  based  which  on  the  showed  or  be  assigned  no  no 33).  cyanoborohydride at  pH  4.  eliminated. to  lack  of  the  side  13,1b),  and  the  trifluoroester  t o an  of  0C0CF3  appeared  at  in  the  isolation  to  eliminate  mainly OH  1800  1  cm" .  H0C0CF3, only  not  lead  to a  Other  at  of  had A  the  this of  band  major  OEt  group  in  corresponding  a n h y d r i d e , dimethyl amino-  5.06  dehydration  (back  from  of  into  i t s IR  disappeared  ppm  achieved  due  (s). the  to  procedures  148.  a  new  band  H C ( 0 C 0 C F 3 ) was  When a  ester  of  spectrum.  and  was  partial  c o n j u g a t i o n as  trifluoroester  signal  hydrolysis  cyclopentadiene  bond  deduced  group  isomerized derivative  elimination).  trifluoroacetic  chain double  was  assigned  (no  with  1,5-diazabicyclo[5.4.0]undec-5-ene,  band  1  presence  of  the  sodium  (alcohol:lactone,  spectrum  isomerization  -1  reduction  with  i n the  Levine  OH.  pyridine,  cm  and  and  together with  performed  (Scheme  Treatment  of  145  formation of  Structure  'H  of  isolated  or water  However t h e  the  D a n i s h e f s k y , Koppel  The The  performed  on  presence  3300-3500  observed  upon  was  used  work-up  a l c o h o l 148  did  derivative.  Ethyl 3-methyl-2,4-pentadienoate 144a has a l s o been used experiments (Michael a d d i t i o n , see Table 7 i n experimental w h i c h w i l l n o t be d i s c u s s e d ) . An i s o m e r i z a t i o n o f t h e s i d e was a l s o o b s e r v e d . The c h e m i c a l s h i f t o f t h e v i n y l m e t h y l a r e d i f f e r e n t f o r 1 4 4 a ( 2 . 1 8 p p m , C H 3 , s f o r E i s o m e r ; 5.71 f o r t h e p r o d u c t (1.71 ppm, C H V b s ; 5.06 ppm, I H , t , J = 7  ,  characteristic  s t r o n g e r base observed  in  in later alkylation f o r model r e a c t i o n s c h a i n double bond and o l e f i n i c p r o t o n ppm, IH, bs) and Hz).  -  Approach  Using  Due  to  138  the  and  Ethyl  -  Chloroformate  complications  (COCOOEt), another  78  encountered  known a c t i v a t i n g  group  with  the  (CHO)  first  was  activating  chosen.  group  Reaction  of  .  114 ethyl  chloroformate  anticipated and  that  (45  and  60%  In  into  performed  as  derivative carbonyl  of  a  the  and  of  the  the  reaction of  142  1  the  i n the  hydrazone  and  leading  to  150  give  a  the  cyclopentenones  138),  but  the  the  section  prepared. an  It  of  Therefore,  was  g-keto-aldehyde  c a r b o x y l i c a c i d would  previous  aldehyde  B-keto-aldehydes.  unsaturated  acylation  B-keto-ester .  described  152  produces  resulting  practice,  yield,  converted  ketones  o x i d a t i o n of  esterification  B-keto-ester.  with  aldehyde  alkylation (58%)  and  of  the  Simultaneous  unsaturated  alcohol  was (Scheme  34)  stable took  could 1_50  place  not  be  with  131b  was  tosylhydrazone  reduction  and  methyl  of  the  group  115 was  expected  tried  at  several  hydrazone the of  'H the  NMR  did  not  and  IR  Sodium borohydride temperatures.  spectral data.  No  acid;  to  to  a  diol,  a methyl  tried:  Jones  silver  oxide,  was  methyl  group  also  but  observations  derivative  was  of  the  primary  did  not  give  manganese  water.  reductions  obtained,  These  tosylation  reagent; THF,  catecholborane  alcohol  group.  reduction  Oxidations  The  and  a f f o r d a methyl  B-keto-aldehyde  subsequent  acetic  .  the are  were tosyl-  based  isolated. alcohol  encouraging  d i o x i d e , sodium  on Reduction  and results.  cyanide,  -  79  Scheme Reactions  -  34  performed  o n T_50  COOMe 152  - 80 -  The  Use o f D i e t h y l At  this  unsaturated  of our investigations,  i t seemed  desirable from  to construct the requisite  ketone.  indicated  literature these  point  (DEPC)"°:  3 - k e t o - e s t e r s 1_59 a n d l_6fJ_ ( T a b l e 6 ) d i r e c t l y  unsaturated As  Pyrocarbonate  i n Table  t o encourage  require  C acylation  additional  Acid  chlorides  this  may  display  solution  employed  ketones  catalyzed  enol  of a total  been  cyclic  excess  i nthe  b u t many o f  condensation.  derivatives  a 2-3 f o l d  i n the middle  Reaction  t h e base  to yield  by e m p l o y i n g  Acylation  have  of various  Table  RCOOET  reagents  steps after  a tendency  be s u p p r e s s e d  impractical  5 several  although  of ketone  1 1 7  ,  an  synthesis.  5  Reagents  conditions  Yield  Reference  NaOEt  70-80%  114  Ph3K  29%  118  NaH  92%  1  R=H  Ether,  2  R=C1  DME,  3  R=0Et  Benzene,  4  R=C00Et  E t O H , 10°C  NaOEt  65%  123  n-Bu20,  NaH  80%  124  Mg  45%  125  5  R=P0(0Et)2  6  Mg(0C00Me)2  In the  ated  unsymmetrical  ketones  both  at different ketones  23°C  Me2NCH0,  generation of  react  0-22°C  Base  80°C  30-60°C 130°C  an a d d i t i o n a l  kinetic  rates  and thermodynamic  and a f f o r d  are particularly  complication  complex  challenging  often  119-122  arises  due t o  enolate anions which  product  since  (enol)  mixtures,  double  a;  may  g-Unsatur-  b o n d m i g r a t i o n may  1 pc also  occur  position  .  usually  Selective requires  introduction a strong  of a carboethoxy  nonnucleophi1ic base,  group  a t t h e a'  an a p r o t i c  solvent,  - 81 -  and at  a reactive  acylation  low temperature.  (DEPC) f u l f i l l s saturated  reagent  i n order  Our i n v e s t i g a t i o n s  these  requirements  that  the reaction  revealed that  providing  diethyl  a convenient  and u n s a t u r a t e d 3 - k e t o - e s t e r s as i l l u s t r a t e d  may  be  conducted  pyrocarbonate  route t o both  i n the general  scheme  below. Scheme The  The cyclic  results  ketones  conditions acylation (entries  of this  35  U s e o f DEPC  study  a r e summarized  153 a n d 104 t h e r e a c t i o n  to give  either  (80°C, b e n z e n e ) a-h).  the 0 acylation products  Of t h e bases  diethyl  ether as the solvent  ketones  i n which  self  was  For the saturated  by v a r y i n g  (-78°C, d i e t h y l  lithium  preferred,  condensation  controlled  6.  the  ether) or C  154 a n d 156 o r 155 a n d 105 a s  examined was  i n Table  desired  dicyclohexylamide (LiNCy^)  particularly  c o u l d be a p r o b l e m .  attack  o f the base  o n DEPC w a s m i n i m i z e d  by a d d i n g  ketone  t o t h e base  and c o n d u c t i n g t h e a c y l a t i o n  with  f o r the unsaturated The  nucleophilic  a mixture  a t -78°C.  o f DEPC  The  and t h e  conditions  Table Preparation  6  of Cyclic  Product  3-Keto Esters Entry  Base  Procedure (see  I  1 04  KH  A  98%  KOtBu  A  50%  LiNCy2  A  47%  KH  B  72%  KOtBu  A  52%  KOtBu  B  62%  LiNCy2  B  60%  KH  B  61%  KOtBu  A  0%  LiNCy2  A  LiNCy2  B  I 1 05  LDA  160  R = Et  161  R-Me  (50%)  58%(25%) .  64%(14%)  60%  LiNCy2  A  64%(15%)  LiNCy2  B  71%(8%)  LDA  138  Yield  experimental)  35%  LiNCy2  A  37%  LiNCy2  B  78%(15%)  LiNCy2  B  46%(22%)  - 33  employed were m i l d Isolated yields material detail  are  were e s p e c i a l l y  indicated followed  in parentheses.  i n the  Diethyl  The  experimental  studies  useful  with  by  amount of  procedures  the (A  or  B)  sensitive  used  compounds.  recovered are  starting  described  in  section.  pyrocarbonate 127  enzyme  and  -  has  been  used  previously for N acylation  in  128 '  and  i t s reactivity  with  n i t r o g e n , o x y g e n , and  sulphur  129 nucleophiles been  compared  examined.  but  Recently  i t s use  dimethyl  f o r carbon  pyrocarbonate  a c y l a t i o n s appears  not  became c o m m e r c i a l l y  to  have  avail-  130 able  and  although arsenal  the of  an  yields  were  unsaturated  Our prepared  group  ketone  using next by  alkylation  lower.  r)  i t behaved  These  synthetic organic  paper d e a l i n g  Approach  (entry  reagents  chemist  f o r the  i n analogous are  useful  fashion  additions  preparation  of  to  the  B-keto-esters  reaction conditions. 131  activating  (76%,  anticipated,  the  under m i l d  A  as  with  an  alternative  (using methyl appeared  procedure  cyanoformate)  after  the  work  at  f o r the  the  described  i n t r o d u c t i o n of  position  a'  of  an  above  was  completed.  keto-ester  160  (Scheme  DEPC: approach  the was  started with  method d e s c r i b e d performed  Scheme 3 6 ,  as  between  described  Next, reduction  of  the  unsaturated  i n the  previous  bicyclic  f o r the  ketone  section.  molecule  alkylation  i n 162  was  160  of  and  Then,  36)  an  chloro  ester  131b  150)'.  considered.  The  reduction  was 132  accomplished The  most e f f e c t i v e l y  a d d i t i o n of  observed with shown  that  the  cerous  cyclopentenones, presence  a  increases  of  acidity  sodium  c h l o r i d e minimizes  methanol, f a c i l i t a t e s the  using  of  complexation the  1,4-proton  including  lanthanoid  medium.  borohydride  this  case.  the  The  solvent  reducing  cerous  chloride  a d d i t i o n which Gemal and  chlorides with  of  and  the  by  Luche  sodium +3  Ln  species  .  is  often  have  borohydride  This  in this  in  combination case  is  not  - 84  BH4~  -  but the derived alkoxyborohydrides  reactive Also,  than  BH^",  consistent with  the substitution  of hydrides  NaBH4_n(0R)n.  t h e enhancement i n BH^"  by  These  s p e c i e s a r e more  of the reaction  alkoxy  groups  rate.  increases the-  132 hardness higher the  of the reagent  selectivity  cyclopentenones  site,  which  (hard  and  soft  (1,2-reduction) (and conjugate  acid-base  observed enones  with  theory) this  i n general)  i s the carbonyl. Scheme Some r e a c t i o n s  164  36  performed  on  160  163  , this  system.  The  i s enhanced  explains the attack at the  of hard  - 85 -  The  dehydration  step  was  performed  DMAP, p y r i d i n e i n C H 2 C 1 2 , 1 h , 2 0 ° C 60%).  These  below),  different  as deduced  obtained  from  olefinic  region  11:4:2  procedures  from  'H NMR  the second  ratio,  integrating  procedures  a n a l y s i s o f 164.  ( b s ) , 6.22  protons. displayed  (bs), 4:1, integrating  olefinic  f o r three  1 3 4  ,  (shown  product  signals i n the  ( b s ) , present  The p r o d u c t  20°C  products  The  three  ppm  (MsCl.SC^,  ( g ) , 2 h,  dehydration  (HC1) d i s p l a y e d  ( m ) , 5.77  chloride dehydration  ( b m ) a n d 5 . 7 7 ppm  different  spectral  f o r three  several  , 7 0 % ; o r C H C 1 3 , HC1  gave  dehydration  a t 6 = 5.21  methanesulfonyl  1 3 3  using  in a  of the  signals at 6 =  protons.  The  5.36  Burgess  1 oc reagent a  could  one proton  indicates  also  singlet  that  be u s e d  (30%).  a t ~ 4 . 0 0 ppm,  the double  A l l these  'H NMR  characteristic  bond o f t h e s i d e  chain  spectra  also  o f (MeOOC^CFU n  i s '  J  displayed  which  ' conjugation.  or order is  required  Although  t o examine  i n the side  the Diels-Alder r e a c t i o n , a conjugated c h a i n , as well  i t had p r e v i o u s l y been  (of the trifluoro  ester  with  pyridine or other  bases, higher  give  reflux, 3:2:5  the required  18 h , 8 0 % ) t h r e e  ratio.  'H NMR signals  studies,  double  The p r e s e n c e  spectrum  o f 148) w i t h  product.  B o f 164  the side  temperatures,  longer  of three  a t 1 . 6 5 , 1.87  (Scheme 3 6 ) .  chain  double  r e a c t i o n times  F o r e x a m p l e , on one o c c a s i o n , bond  bond  b a s e , r e a c t i o n o f 162_, 163_ o r 1 6 4  isomers olefinic  a t 4 . 5 2 , 5.00 a n d 5.52 ppm.  (bs) appeared  i n ring  possible to isomerize  bond  not  as a diene  double  and 2.06  o f 162 w e r e signals  Also, three ppm.  t h e i s o m e r i z a t i o n o f 165 d i d n o t t a k e  i n a  observed  possible  Earlier  place  ( D B U , THF  obtained  (m) w a s  did  i n the  methyl  i n our synthetic  under a c i d i c  conditions  - 86 -  (using  ( C O O H ) 2 , pTsOH o r CH3COOH  Diels-Alder  reaction  i n refluxing  ethanol).  Therefore,the  ( o n a m i x t u r e o f 1_64 i s o m e r s ) w a s t r i e d ,  while  hoping  136 for  a favorable  also  tried  various where  thermal  using  isomerization  a Lewis  acid  t o take  place  .  (BF^.Et^O) o r a c a t a l y t i c  The D i e l s - A l d e r was amount o f base a t  t e m p e r a t u r e s , b u t m a i n l y d e c o m p o s i t i o n was o b s e r v e d .  N,N,N',N'-tetramethylethylenediamine  decarboxylation 110° t o 1 9 0 ° ,  (-COOMe  4 days,  from  164,Scheme  was used  36 s e a l e d  as a c a t a l y s t ,  tube  2 5 % ) was o b s e r v e d , a c c o r d i n g  In one c a s e ,  reaction,  a  i n toluene  t o MS a n d 'H NMR  spectral  analysis.  0  0  6^  ^OEr  MeOOC  165 COOMe  137 A uses  recent paper  which  polyphosphoric acid  silica  appeared  (1 e q ) i n r e f l u x i n g  g e l , f o r24 h t o c o n v e r t  conditions  reveal  (isomerization  thedifficulty  into  after  these  attempts  dichloromethane,  166 t o 167 (Scheme  37).  i n a c c o m p l i s h i n g such  c o n j u g a t i o n ) , even  were  i n a "simple"  These a  ^•^CCOEt 166  system  unusual  such  o f 166  Q^COOEt 167  containing  transformation  Scheme 37 Isomerization  undertaken,  as 166.  - 87  Successful In be  Diels-Alder  the  next  discussed f i r s t , The  159  not  new  route  w i t h methyl  under  "very  kept  from  enolized  a  Although  J  =  ketone 171  was  5.92  (bs)  and  2.22  ( C 0 C H 3 ) ppm  groups.  7 Hz,  CH3)  6.12  The are  the  deduced or  the  with  the  the  addition  t i m e was  unsaturated from  ketone  ppm), NMR  a t 4.22  assigned proton  be  long,  the  two  to  performed base  side  constants  =  7  ethyl  appeared  (Scheme  and  MS  (Figure  at  Hz,  (vicinal  and  the 39).  at  signals 1.45  be  1.30  Another  set  (ddd, J  =  ppm  at  (-C-CH3)  assigned  0 C H 2 ) and  ester. 3.02  product  spectra.  34,  appearing  was  (171)  between  could definitely  (q, J the  IR  singlets  spectrum, ppm  NMR,  170  will  B-keto-ester  amount o f  too  of  present  coupling  to  1,4-intramolecular-addition  was  f o r one  of  142  1_38.  Bicyclo[2.2.1]heptan-2-one  decomposition  'H  had  I f the  'H  i n the  compound  alkylation  conditions. reaction  on  bicyclooctenone  MHz  (bs)  easily  on  400  signals  integrating Because  and  performed  This Michael  amounts.  catalyzed  study  performed  starts  catalytic  in varying  impurity  Hz).  38)  ketone.  some  signals 12  (Scheme  base  methyl  Structure  methyl  the work  t o a minimum, and/or  results  and  then  controlled"  obtained  =  approach  p a g e s , t h e model  vinyl  V7J_ w a s  6  few  -  long-range)  ppm  to ( t ,  of  2,6, in  norbornane  41 systems  have  been  well  studied  , interpretation  of  this  coupling  was  possible.  -  88  Scheme  -  38  Diels-Alder Approach  176  to  176,  177  177  - 89 -  Scheme Formation  39  of Side  Product  171  COOEt  It  are J  i s known  =  3  4  "  Therefore, H-7),  allows  Z  '  J  2D-3D  1-2D  =  =  6  °"  -  7  2 H z  t h e 2 Hz c o u p l i n g  t o an exo-exo  H z ;  '  J  J  such =  2X-3X  3X-5X  =  ]  9  "  i n 171 w a s  t o an endo-exo coupling  as  2  -  H  169, the coupling 1  z  0  ;  H  J  z  ;  J  2X-*-»-3D  5D-7B  due t o a W coupling  (H-5, H-6).  =  K  5  =  "  2  5  ,  constants 5  H z  H  z  ;  "  long-range  coupling  ( H - 5 , H - 6 ) , a n d t h e 12  Interpretation of this  (H-5, Hz  coupling  us t o p l a c e  proton  5 i n t h e e x o p o s i t i o n a s s h o w n f o r 171  i n Scheme  and t h e methyl  ketone  substituent  IR o f  indicated addition The  H  i n molecules  t h e 6 Hz c o u p l i n g  coupling  39;  J  as f o l l o w s :  1-2X  that  MS  that  a strained  to other  displayed  ketone  carbonyls a molecular  i n t h e endo  (CO b a n d  (broad  CO  position.  a t 1765 cm  - 1  ) 1  band a t 1715 cm" ,  i o n a t m/z  = 238  (C^H-igO^).  B 7/A v  D«Endo X«Exo 169  was  The  171  present i n  C0CH3  and  COOEt).  - 90  from  The d e s i r e d  product  t h e 'H NMR,  IR a n d MS.  ketone  i n 1 7 0 was  ketone  was  performed  -  170 o f t h e M i c h a e l In t h e next  reacted selectively.  selectively i n acetic  formed  acid  1 OR  addition  easily  identified  step of the synthesis,  the methyl  Although  (BF-j.Etp^O, 2 0 ° ,  was  the dithioketal  o f the methyl  1 h , 70%) when t h e r e a c t i o n  , the deprotection  c o u l d n o t be a c c o m p l i s h e d  •;  was on  139 this  derivative,  the corresponding alcohol,  reaction  o f 170 p r o c e e d e d  spectrum  o f the major  and an  a methine internal  proton  product  usual  was  not selective  giving  rearrangement  i n very  indicated  ( 2 . 8 2 ppm,  reaction,  the  selectively  or d i o l .  A  low y i e l d  the presence  a 6-membered-ring  (30% of the direacted  The  to phosphorus.  lactone  Also,  (10%).  of three ethoxy  d , J = 20 Hz) c o u p l e d  o f the phosphonate.  Horner-Emmonds  predominated  a Wittig  reaction  p r o d u c t , a c c o r d i n g t o MS  and  'H  NMR  groups Probably over o f 170 'H  NMR  analysis). Scheme Possible  A  Knoevenagel  malonate when 1  reaction  time  water,  using  titanium  12 h .  tetrachloride  172.  silver  Side  and  product  dimethyl  1_73 w a s  formed  (Scheme 4 1 ) .  mercury(II) chloride,  reflux;  trifluoroacetate,  Reaction  12 h ) , g a v e  exceeded  Deprotections tried:  acetonitrile, thai l i e  Rearrangement  (CH,(COOMe), a t 2 0 ° ,  the reaction  40  nitrate,  tetrahydrofuran.  potassium  c a r b o n a t e , 80%  acetonitrile,  water;  - 91 -  H, a: R b :R Triunsaturated intramolecular the  carbonyl  rapidly.  be u n s t a b l e .  protons H-2  R  p l a c e between  of 170),  3  3  = H,COOEr = COOMe result  to silica  the enolized  ketone  a t 6.58 ( s ) a n d 6.02 ( b s ) ppm.  methyl  These were  o f the chemical  shift  H-4, 6 . 7 0 ppm;  ^ - 5 , 5 . 2 8 ppm) a n d t h e l i t e r a t u r e  tentatively  6.02  as a broad  coupling signal  between  appeared  this  proton  a t 1.91  at  4 . 1 0 ( C H 2 , q , J = 7 H z ) a n d 1.21  173  was C  1 8  H  2 2  while  a t m/z  signals  assigned  methyl.  from  Scheme Formation  of Side  0  be  two  olefinic  assigned to  Also,  the signal of  at  long-range  The v i n y l i c  methyl  a t 3 . 7 0 a n d 3 . 7 3 ppm w e r e  t o the ethoxy  that  group  appeared  formula  o f H20.  41 173  MeOOC  due  The p a r e n t i o n  the molecular  172 by t h e l o s s  Product  expected  = H a t 5 . 7 9 ppm;  ( C H 3 , t , J = 7 H z ) ppm.  = 334, confirmed  0 g , and d i f f e r e d  .  and  t o 144b ( H - 4 , 7.00  i s characteristic  ( b s ) ppm; t w o s i n g l e t s  t h e methyl  i n t h e MS  which  and t h e v i n y l i c  to  observed  esters;  singlet,  4 1  ketone  PTLC, and  also  spectrum,  values  catalyzed  condensation.  precursor would  p p m ; H £ - 5 , 5 . 4 3 p p m ; H z ~ 5 , 5 . 6 8 p p m ) ; 1 4 4 a ( R 2 = C O O E t ; R~  ppm a p p e a r e d  an a c i d  chromatography, e s p e c i a l l y  1 7 3 d i s p l a y e d i n i t s 'H NMR  a n d H-4, by c o m p a r i s o n  from  f o l l o w e d by a Knoevenagel  The u n s a t u r a t e d  Product  2 3  R  1_73 ( S c h e m e 4 1 ) c o u l d  (taking  1 7 3 was s e n s i t i v e  decomposed to  addition  unsaturated  Compound  triester  2 5  COOMe  COOEt  of  - 92  Scheme rDi e l s - A l d e r  -  42  Reaction  of  175  R  -  The through  product  172 f r o m  i t s 'H NMR,  MS  93 -  t h e Knoevenagel  a n d IR s p e c t r a l  condensation  data.  was  Compound  characterized  172 was  then  reduced  140 using  zinc  borohydride  yields  when  of  (MsCl.S02  174  . This  t h e r e a c t i o n was  intermolecular  reduction  performed  procedure  on a l a r g e  resulted i n better  scale.  After  dehydration  o r M s C l , no S 0 2 ) t h e D i e l s - A l d e r was a t t e m p t e d .  example  cyclopentadiene-as  A related  t o our intramolecular Diels-Alder (diactivated  dienophile)  has been  described  by L e v i n a  and  diene,  Godovikov,  141 in  1955  .  I t takes  place  malonate  (CH2=HC(C00Et)2)  reaction  o f 175 t o o k  between  cyclopentadiene  i n refluxing  place  benzene  i n toluene,  and d i e t h y l  for 6 h  (60%).  a t 140° (sealed  tube)  methylene The D i e l s - A l d e r  during  10 h  (40%). As  i n d i c a t e d i n Scheme 4 2 , two r e g i o i s o m e r s  Diels-Alder  step.  product would assigned doubled The  series  Knoevenagel  similar 179  for  vinyl  to indicate  (Scheme ketone  triester  179.  t o 173 were  181  took  the presence  and present  43).  of U 8  place  In t h i s  a b o v e was  case,  dimethyl only  of alcohol one d o u b l e  of alcohol  180 bond  1 6 3 , p.- 8 5 ) .  a t 140°C  and o l e f i n i c  (sealed  reaction  proton  are  ratio. next  performed  product  malonate  traces  the  The s i g n a l s  a d d i t i o n performed  on one o c c a s i o n .  than  i n toluene,  o f two a d d u c t s .  1 7 8 , a n d no s i d e with  during  on t h e p u r i f i e d  i n a 5:4  The M i c h a e l  produced  obtained  (more  obtained  ( 2 . 0 2 a n d 2 . 0 4 ppm)  and d e h y d r a t i o n  the dehydration  Alder  methyl  condensation  diene  spectrum  of reactions described  160  (Zn(BH4)2)  produced  'H NMR  ( 6 . 2 0 a n d 7 . 1 0 ppm)  methyl  afforded  tend  to the vinyl  3-keto-ester and  The  c a n be f o r m e d  (MsCl.SOg  between  160  detected.  of a side  h)  product  o f the ketone i n o r M s C l , no  i s o m e r , as mentioned The i n t r a m o l e c u l a r tube)  bicyclic  (20°C, 20 t o 24  (< 1%)  Reduction  was  on  during  10  h.  S02) earlier  Diels-  - 94  In product plane the  the  present case, the D i e l s - A l d e r  (two  of  e n a n t i o m e r s , Scheme 4 4 ) .  symmetry  newly  formed  i n the double  ring bond  tri:tri:tetra-substituted spectrum. one  Alder de the  ppm  exo 188  i s less  none  of  f o r X-ray  are grateful  two  olefinic  exo  187  and  the  endo  Derivatives dianilide  and  that  This of  i s due  181.  bond  to  the  H o w e v e r , an  i s observed.  signal  188)  A  4:1:3  only  at  5.45  ppm  give  presence  one of  a  isomerization mixture  i s present, according appears  can  stable  of  stable (~  187,  5.5 an  be  drawn  f o r the  calculations  structure  more  structure  The  I I  (187  indicate  accuracy of  We  double  olefinic  is slightly  satisfactory  i n 182  M o l e c u l a r mechanics  Sherbrooke ring  moiety  c y c l i z a t i o n can  of  of  to the  'H  ( m ) , and  the  NMR minor  (m).  adduct.  Unfortunately  I  major  structures  structure the  The  a t 5.76  Two  -  187 (~  1.5  kcal)  X-ray  the d e r i v a t i v e s  with  performed the  kcal)  than  double than  182.  diffraction  prepared  isomerized  1  at  Diels-  the  bond  adduct  University  a t C-9 182,  In o r d e r t o analysis  to date  1 1  i s  have  and  and that  establish  required.  proved  analysis.  t o C.  signals  B a y l y and observed  P.  Deslongchamps  i n the  'H  NMR  f o r the  spectrum  calculations.  could  be  due  to  187.  183  prepared:  derivative.  dicarboxylic  acid, diol,  di-p-bromobenzoate,  - 95 Scheme  43  D i e l s - A l d e r Approach  186  to  182  185  -  96  Scheme Diels-Alder  -  44  Reaction  R  of  181  - 97 -  Several in  key  routes  molecule  can  1_82  to  be  envisaged  the  required  to  convert  ketone  the  malonic  functionality  ester  (as  functionality  i n 184,  Scheme  43).  142 A  conventional  consists  the  applied  in  the  1960  s  f o l l o w i n g s i x step  procedure:  decarboxylation  of  treatment  methyl  conversion  the  of  method  lithium,  acetate  reactions ethyl  a malonic  acid,  of  the  of  would  convert  a malonic  acid  into  bond w o u l d  also  be  double  the  alcohol.  oxidation  and  of  ketone  finally  the  perform  this  hydrolysis of  methyl  and  ester  to  a  to  transformation  a malonic  carboxylic acid an  acetate,  Although  ketone,  with  hydrolysis  this  i n our  ester,  sequence  case  of of  the  affected. 143  Another  possibility  unfortunately  gives  which  rise  to  has  been  different  applied  side  in several  products  cases  i n the  case  , of  but  the  144 norbornane  system  decarboxylation different ester the  , involves  leads  approach  (NaCN  methyl  would  i n HMPA ester  directly  1 4 5  use  from  c o n s i s t of  or  (AlCl^  the  LiCl  in  a  of  lead  malonic  the  1 4 7  )  acid  to  a  and  1 4 6  This  ketone.  decarboxylation  in H20-DMS0  EtSH  tetraacetate.  of  ), followed  the  by  oxidative  A malonic  hydrolysis  oxidative decarboxylation  of  (see  below). Decarboxylation chloride  was  aluminum  trichloride  presence  of  the  unsuccessful  the  crude  product  ppm.  The  i n our  ester,  displayed of  only  the  ester  case.  using  hydrolyzed  in acceptable one  Lewis  singlet acid  was  accomplished  for  The  'H  methyl that  singlet,  the  exo  from  NMR  1.23  spectrum to  carboxylic acid  1.10 has  the  refluxing of  ppm. been  cyanide  183  (>  or  182  in  The  'H  region  at  isomerized  the  C-9  bond.  the  double  malonic an  result  acid  upfield would  lithium with  esters  40%).  olefinic  showed  This  of  methyl  yields  apparently  Decarboxylation hours.  the  i n the  D i e l s - A l d e r adducts, to by  sodium  However t r e a t m e n t  the  two  of  malonic  in ethanethiol  ethyl  presence  bond m i x t u r e  of  eliminated, therefore  the  NMR  of  5.85  double  in  shift  tend  the  to  toluene for  the  indicate  effect  due  this  -  " to this  substituent  reported  98 -  has d i s a p p e a r e d .  t o be more  stable  than  Endo  the exo  substituted  isomers  norbornanes  have  been  146  1 no Wasserman  and  Lipshutz's  oxidative  decarboxylation  (LDA, 0^;  DMF-  149 acetal)  as w e l l  as T r o s t  and Tamaru's  procedure  N - C l - s u c c i n i m i d e ) w e r e a t t e m p t e d , h o w e v e r no in  either  were  case  performed  indicated  that  20°C, and t h a t intermediate  20°C w a s  of  an e s t e r ,  attempts the of did  this not  and  product  i n THF-HMPA).  184 c o u l d  (Scheme  the carboxylic  only  the methyl  acid  dianion  disulfide acid  procedure  could  N-chlorosuccinimide.  be  reaction  conditions,  dicarboxylic  showed  the ester  acid  was  then  was  that was  45).  to take  also  place  showed and  as e x p e c t e d .  the ethyl hydrolyzed.  generated,  ester The  Model  Studies  Since  C00H  studies  at 0°to  since  that  that  the  before a  temperature  i n the our  d i d not  survive  however the s u l f e n y l a t i o n  Decarboxylation  C00H R=00H,SMe  °  presence  earlier  trianion  45  of the Oxidative  reactions  These  reliable,  proceed. Scheme  isolated  be g e n e r a t e d  more  These r e s u l t s  d i d not proceed  183  be  i s o l a t e d and c h a r a c t e r i z e d  needed f o r the s u l f e n y l a t i o n this  could  NaHC03,  T h e r e f o r e , model  on 4 - c a r b o x y b i c y c l o [ 2 . 2 . 1 ] h e p t e n e  to sulfenylate  reaction  i n THF  sulfenylated  treatment with of  (reaction  (LDA, Me2S2;  -  99  -  Conclusion: These  studies  may  be  for  cyclic  and  reactions  been  feasible.  revealed They  ketones  have  and  that  C i e l s - A l d e r approach  resulted  enones.  which w i l l  a  In  permit  in a  useful  new  a d d i t i o n , the  further  capnellene  acylation  types  development  to  of  of  (51)  procedure  intermediates  this  strategy  have  delineated., It  is anticipated  oxidation  (mCPBA) w o u l d  185  preferentially.  186  with  carbon  the  step  in  the the  followed  by  are  possible.  also  Wittig  be  upon g e n e r a t i o n directed  Reduction  capnellane  represents  earlier  that  carbon  the  (LiAlH^)  of  skeleton,  exocyclic  synthesis,  by  double possibly  condensation.  of  ketone  double this  except  bond  to  the  Baeyer-Villiger  afford  lactone  would  for  carbon.  bond w h i c h by  184,  allylic  one  could  be  of  give  triol  This  introduced  oxidation  Other m o d i f i c a t i o n s  lactone  this  (SeG^) route  missing at  an  1  Figure 5  10  IR S p e c t r u m o f A ' - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e (1 38 , neat) 1  - 101 -  Figure 60  MHz  'H  NMR  Spectrum of  A  1  5  11  ' -bicyclo[3.3.0]octen-2-one  (1_38,  C C I J  o  Figure  IR  Spectrum of A  1  12  ' 3-carboethoxybicyclo[3.3.0]octen-2-one 5  (1_60, neot)  - 103 -  Figure IR  Spectrum of  5  ^  A1' -3-(butan-3-one)-3-carboethoxybicyclo[3.3.0]octen-2-one  -  -  105  Figure 80 1 A  MHz  'H  NMR  15 Spectrum  of  5 ' -3-(butan-3-one)-3-carboethoxybicyclo[3.3.0]octen-2-one  (178,  CDCI 3 )  - 106 -  Figure 80  MHz  'H  NMR  Spectrum  of  16 5  A ' -3-carboethoxy-3-(dimethyl 1  3-methyl-3-butenyl-^-dicarboxylate)bicyclo[3.3.0]octen-2-one  1 IR S p e c t r u m  of  A  (179,  Figure 17 5 ' -3-carboethoxy-3-(dimethyl  3-methyl-3-butenyl-c, i.-dicarboxylate )bicyclop.3.0]octen-2-one  f 1 7 9.  neat)  -  107  -  Figure 5  18  1 60  MHz  'H  NMR  Spectrum  of  A  ' -3-carboethoxy-3-(dimethyl  3-butenyl- i,c-dicarboxylate)bicyclo[3.3.0]octen-2-ol  4000  3-methyl( 1 8 0 , CO/  )  m o  Figure IR  Spectrum  of A  5  1  19  ' -3-carboethoxy-3-(dimethyl  3--methyl-  3-butenyl-t,a-dicarboxylate)bicyclo[3.3.0]octen-2-ol  (180;  neat)  Figure IR S p e c t r u m o f  20  3-carboethoxy-3-(dimethyl  2-methyl-1-butenyl-1,  l-dicarboxylate)bicyclo[3.3.0]octa-l,4-diene  (181, neat)  Figure 80  MHz  'H  NMR  Spectrum  of  21  3-carboethoxy-3-(dimethyl-2-methyl-l-  b u t e n y l - 1 , l - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t a - l ,4-diene  (181,CDC L)  Figure Q  IR S p e c t r u m  of  A '  22  10 -6-carboethoxy-2-dicarbomethoxy-3-methyl1  6  3  7  8  tetracyclo[6.4.0 ' .0 ' .0 '  1 2  ]-dodecene  (l_B_2,neat)  - Ill  -  L  i l  Figure 400  MHz  'H  NMR  Spectrum  of  8  A '  methyltetracyclote^.O  1  1 2  6  23  -6-carboethoxy-2-dicarbomethoxy-3-  ' .0  3 , 7  .0  8 , 1 2  ]-dodecene  (1_B2,CDC  U)  -  113  -  f i  1  Figure 400  MHz  'H  NMR  Spectrum  of  25  endo-1 - c a r b o e t h o x y - 4 - m e t h y l - 5 -  acetylbicyclo[2.2.1]heptan-2-one  (17], CDC  13)  Tfl  S  Figure IR  Spectrum of  26  6-carboethoxy-8-methyl-3-dimethyl  methylenedicarboxylatebicyclor.4.3.0  1  6  ' ]nona-l ,8-diene  (173,  neat)  - 115  -  I ;  hi  A  Figure 60  MHz  'H  NMR  Spectrum  of  ' i  v  i •  J  27 6-carboethoxy-8-methyl-3-  di methyl methyl enedicarboxylatebicyclo[4.3.0]nona-l ,8-diene  (1_7_3  CCf,  -  116  -  29  Figure  11 12 IR S p e c t r u m acid  of  A  -6-carboethoxy-2-dicarboxylic 1  6  3  7  8  S-methyltetracyclole.A.O ' .0 ' .o '  1 2  ]-dodecene  (neat)  - 117 -  Figure q IR  Spectrum of A  31  1n '  -6-carboethoxy-2-carboxylic acid  3-methyltetracyclo[6.4.0  1 , 6  3  7  .0 ' .0  8 , 1 2  ]dodecene  (l_BJ, n e a t )  32  Figure Q  IR  Spectrum of A  ] n  2,6-dicarboxylic 1  6  3  7  8  3-methyltetracyclo[6.4.0 ' .0 ' .0 '  1 2  acid  ]dodecene  (C  HC1 3 )  -  120  -  33  Figure  q MHz  'H  NMR  Spectrum  of  i n  2,6-dicarboxylic  A 1  6  3  7  8  -methyltetracyclo[6.4.0 ' .0 ' .0 '  1 2  ]dodecene  acid (CDC  13 )  -  121  -  Experimental Infrared 12  and  13J,  s p e c t r a were  237B  (compounds  spectrophotometers. polystyrene indicated recorded  film.  (s: on  calibrated  a  or  Brucker  or Brucker  positions  are reported  as an  constants Low  internal  s p e c t r a were  from  a t m/z  The  mass  and  o f 3%  other  low and  high  Micromass  7070-HS  instrument  volts.  ( I n some c a s e s ,  Optical using  a  1 dm  and v a l u e s conducted column  rotations cell.  on  (3m x 6mm  mass  using  an  Gas  band  spectra and  of  and  were  were  182  a t U.  a A.E.I.  (delta  on  gas  i . d . ) c o n t a i n i n g 1.5%  mass  higher  from  M  are  9,  were the  indicated.  o f 70  on  a  V.6.  electron  i s indicated.)  on  141  a  chromatograph supported  polarimeter,  Fisher-Johns  chromatographic  0V-17  coupling  1,  with  determined  a Perkin-Elmer obtained  scale)  spectro-  spectra  starts  energy +  MS-902  (compounds  Plotting  and  Signal  parentheses.  MS-50  ionization  liquid  402B  i n  of  a t MUN).  tetramethylsilane  on  were  N i c o l e t - O x f o r d H-270  ( o t h e r compounds  s p e c t r a were  lost  were measured  Packard  171  spectra.  M e l t i n g p o i n t s were  a Hewlett  13_ a t U B C ;  f o r the plotted  the fragment  are uncorrected.  1  f i l t e r . on  obtained  intensity  resolution  cm"  or the intensities  oxide  are indicated  intensities  peaks  t h e 1601  recorded  from  9_,  compounds)  Ultraviolet  s p e c t r a on A . E . I .  the low r e s o l u t i o n  = 32  (other  1_,  number o f p r o t o n s , m u l t i p l i c i t y ,  mass  calculated  The  The  (compounds  spectrophotometer  EM-360  resolution  a n d 16).  and  downfield  standard.  resolution  weak).  9 , 12  70B  possible  s p e c t r a were  WP-80 o r V a r i a n i n ppm  with  o f a Holmium  assignment  1 3 , 15  peak  band  proton  high  when  uv-visible  (Hz) and  meter and 12,  nm  resonance  Alberta),  used  202  Elmer  o r 1320  calibrated  assigned  (compounds 1,  400  Perkin  m e d i u m , w:  t h e 279.4  magnetic  on  t o 4 3 ) , 451  were  Bands were  Perkin-Elmer  WH  35  Spectra  s t r o n g , m:  with  Proton  recorded  analyses  equipped on  Gas  apparatus  were  with  a  Chrome Q  (noe)  -  using in  helium  stoppered quartz  pressure  mercury  Thin silica  layer  plates  BDH  thin  ether  (ether),  Dry  size  was  Hanovian  conducted  450W m e d i u m  HPLC  grade  with  lithium  used  6  0  Kodak  (  M e r c k  ) -  precoated silica  flash  range  used f o r  chromatography  f o r a l l other  using  columns.  reagent grades.  30-60°C.  hydride  dried  or  glass silica  Petroleum  Anhydrous  dimethoxyethane and d i o x a n e were  were  gel 13181).  Merck  mesh ASTM) was  or distilled  boiling  o u t on  (Eastman  t y p e  (70-230  aluminum  and methanol  carried  c o n d u c t e d o n 2 0 x 2 0 cm  1_, 9_, 1_2 a n d 1 3 J , w h i l e  from  ethanol  were  + 366  0 . 0 6 3 - 0 . 2 0 0 mm  tetrahydrofuran,  distillation  diethyl obtained  potassium/benzophenone.  by d i s t i l l a t i o n  from  magnesium.  hexamethylphosphoramide, dimethylformamide, dimethyl sulfoxide  Solutions  were  i n organic  the solvent  water  was  aspirator.  aqueous  saturated  solutions. an  gel PF254  to a fraction  diisopropylamine  and  chromatography  used were  refers  a water-cooled  indicator  g e l 6 0 , 2 3 0 - 4 0 0 mesh was  ether  Absolute  using  fluorescent  silica  (compounds  Solvents  by  with layer  60, particle  silica  containers  Photochemical experiments were  chromatographic analyses  coated with  columns  gas.  a r c lamp.  gel plates  Preparative  gel  as t h e c a r r i e r  122 -  Unless  atmosphere  p r e p a r e d by d i s t i l l a t i o n solvents  removed  Sodium  were  using  dried a Blichi  bicarbonate  solutions, otherwise  while  calcium  over anhydrous rotary  a n d ammonium  5 a n d 1 0 % HC1  indicated  of dry nitrogen.  from  chloride refers  a l l reactions  hydride.  magnesium  evaporator  sulfate  connected to a refer to  to  were  and  aqueous  conducted  under  -  Extraction  and Crude  Following soaked  #1  volume.  ethyl  filter  acetate.  This  phase was d r i e d  an  residue.  The Elution of  crude  fractions eluting by  extract  of the active  increasing  solvent  ethyl  preparative  0.05  i n ethyl  compound was  extraction sodium  was p u r i f i e d  screened  C  layer  MS  procedure  was  (yield 4):  2 0 mg  shown  (Table  (m/z, r e l a t i v e  one h a l f  partitioned  repeated  between  three times.  by s i l i c a  column  chromatography.  t h e c o l u m n was f a c i l i t a t e d  (PTLC).  to inhibit  activity. a n d was The band  1_ w e r e  obtained  The  The  fraction  further  purified  having  of the  from  an Rf  ]_.  1)  2) 533(3), 515(3),  298(10),  280(12) Exact  Mass  calculated  f o rC35H67N02:  This  1200 t o 1500  1  Figure 4):  533.5155, obtained:  of  microorganisms  of dry weight).  % intensity,  The  by a g r a d i e n t  t o ceramide  the growth  brine  to give  aureus.  ( N H ) , 1660 (CO) cm"  2, Table  of the  and evaporated  result  and  filtered  filtered  a positive  o f ceramide  =0.02%  3420  then  sulfate,  chromatography  subsequently  (Figure  NMR:  was t h e n  acetate:chloroform (1:1) corresponded  Approximately  1 3  t o about  f o rantibacterial  1  'H NMR:  was  (dichloromethane-ethyl acetate).  Ceramide  (Figure  The s u p e r n a t a n t  i n methanol  polarity  s u b t i l i s and Staphylococcus  IR  immersed  from  Bacillus  nudibranchs  were  fraction  a c e t a t e gave  thin  bilamellata)  paper and evaporated  over  o b t a i n e d were  with  the nudibranchs  The c o n c e n t r a t e d e x t r a c t  organic oily  (Onchidoris  f o r several weeks.  Whatman  original and  collection,  a t -35°C  through  Separation  123 -  533.5173.  -  MP [a]  =  77-78°C =  D  -ll°(c  Acetylation A  1.0, CHC13)  of 1  sample  solution  o f ceramide  containing  acetic  dimethylaminopyridine at  20°C.  (Rf  Removal  1_ ( 1 0 m g ,  1 0 mg  (2 mg).  IR  (Figure  'H NMR:  6):  2  3400  (Figure  mixture  ( 0 . 2 mL)  was  stirred  and p u r i f i c a t i o n  1:1) g a v e  to a  by  diacetylated  and f o r 18 h  PTLC  derivative  mmole,8 7 % ) . ( N H ) , 1720 ( C O ) , 1660 (CO)  5, Table  (m/z, r e l a t i v e  i n vacuo  acetate,  mmole) was added  (0.2 mL), pyridine  The r e a c t i o n  of the solvents  (1.5 x 10"  1.8 x 1 0  anhydride  = 0.58, chloroform:ethyl  9,  MS  124 -  cm  - 1  .  1)  % intensity,  Figure  7):  635(3), 575(3),  515(5),  280(85),  43(100). Exact MP: [a]  Mass  calculated  635.5470, obtained:  635.5481.  8 8 - 90°C -40°(c  =  D  Hydrolysis A  mixture  o f 1_ ( 1 0 m g ,  i n methanol  (1 m L ,  was p a r t i t i o n e d  acidified  solvents  a c i d 12_.  1 N) w a s  with  and r e e x t r a c t e d , evaporated  1.8 x 1 0  between water  and r e e x t r a c t e d  neutralized  fatty  1.5, CHC13)  of 1  solution  hydroxide  the  f o r C3qH73N05:  ether.  mmoles), dioxane refluxed  i n vacuo  f o r 48 h r s .  and e t h e r ,  to give  layers  The  reaction  and t h e aqueous  The two o r g a n i c  the organic  (0.2 mL), sodium  dried  t h e long  extracts over  chain  layer were  sodium  base  sulfate  1_3 a n d t h e  and  -  The  fraction  purified  by  containing  PTLC  triacetylated  125  1_3 w a s  -  acetylated  a s d e s c r i b e d f o r 1_ a n d  ( R ^ = 0 . 5 3 , e t h y l a c e t a t e : c h l o r o f o r m , 1:1)  derivative  1_4, 2 mg  (4.5 x  10  mmole, 25%)  to give  and  starting  _p material IR:  3400  'H NMR: MS  1_, 6 mg  (1.1 x  ( N H ) , 1720 (Table  10  mmoles, 6 0 % ) .  ( C O ) , 1660  (CO)  cm"  1  1)  (m/z, r e l a t i v e  •% i n t e n s i t y ) :  439(3),  397(3), 380(5), 278(5),  144(85),  43(100).  Exact  Mass  Ozonolysis Ozone 3.6  x  calculated  was  passed  through  dimethylsulfide residue  was  was  were  purified  15,  MS  by  PTLC  before  %  calculated  %  two  stirred  suspension  (1 mL)  mixture  a  439.3304  solution  maintained to flush After  compounds  containing  a t -78°C.  the remaining  the solvent-was  Oxygen ozone  HC1). 1_5 a n d  products  1_6 h a v i n g  537(1), 429(1),  resolution  MS  intensity):  A  A  could  406(5),  f o r C,,,H? H 0 : A  R^  be  335(2),  was  then  and  evaporated, ( 5 mg  of this values  mg,  of  the  in reaction 0.20  280(3),  250(3).  obtained.  308(5),  235(6), 206(50),  406.2572, observed:  181(12).  406.2571.  (35)  ( 2 . 0 g , 13 m m o l , A l d r i c h ) o f d r y THF  The  1_ ( 2  collected.  intensity):  2,2,10-trimethy1cyclodecanone Cyclodecanone  through  of concentrated  and  a high  (m/z, r e l a t i v e Mass  439.3287, observed:  a 2,4-dinitrophenylhydrazine solution  1 drop  (m/z, r e l a t i v e  MS  :  i n excess.  i n c h l o r o f o r m were  Decomposed  Exact  added  reacted with  methanol and  0.72  5  f o r ten minutes  the reaction  1 mL  and  N 0  of 1  10"^ m o l e s ) and m e t h a n o l  bubbled  16,  H  for C25 45  ( 8 0 mL)  was  containing  added  to a magnetically  sodium hydride  (3.6  g,  -  60%  i n o i l ,  dropwise was  93 mmol).  and s t i r r i n g  complete.  wise  solution  excess  filtered,  flask  ether  t o g i v e 3 5 , 2.56 g  UV  (Xmax  (log E)):  IR  (neat, Figure  'H NMR  (CDC13,  CH3), MS  2):  added  organic  by c h r o m a t o g r a p h y  as a viscous  the reaction drop-  and t h e aqueous  The c o m b i n e d  and p u r i f i e d  (99%y i e l d )  1700 cm"  1  extracts (dichloro-  o i l .  (CO)  1 . 0 3 ppm  ( s , 3 H , C H 3 ) , 3.31  (m/z, r e l a t i v e  t o 0 ° and methanol  f o l l o w e d by w a t e r ,  (5 x 30 m l ) .  until  added  290(1.3)  Figure 3):  1 . 1 7 ppm  ( 1 5 g , 105 mmol) was  GLC m o n i t o r i n g  was c o o l e d  concentrated  methane)  iodide  f o r4 h with  sodium hydride  extracted with  dried,  15 m i n , m e t h y l  continued  The r e a c t i o n  to destroy  were  After  126 -  % intensity,  ( s , 3 H , C H 3 ) , 1 . 0 4 ppm  ppm  Figure  (D, J = 7 Hz, 3H,  (m, IH) 1):  196(30),  178(5),  163(3),  69(72),  56(100) Exact SF0RD  Mass 1 3  C  calculated NMR  f o r C-^H^O:  (CDCl-j):  cyclohexane  ( 1 8 0 mL)  stoppered.  This  5 h  ether  placed  ( s ) ppm  f o r t h e CO.  solution  evaporated  t o 15% e t h y l  (35_) ( 0 . 9 0 g , 4 . 6 m m o l ) w a s d i s s o l v e d i n  i n a quartz  was  irradiated  ( f o l l o w e d by GLC, u n t i l  solvent  ( t , each) and 220.85  o f 35  2,2,10-trimethylcyclodecanone  for  196.1835  2 2 . 2 4 , 2 2 . 5 8 , 23.11 , 2 5 . 5 4 , 26.41 , 2 7 . 2 3 ,  2 7 . 8 2 , 2 9 . 7 6 , 3 5 . 3 0 , 3 8 . 5 5 , 38.69  Photolysis  196.1821 , o b s e r v e d :  container flushed with ( 4 5 0 w, m e d i u m  cyclodecanone  n i t r o g e n and  pressure  (29_) w a s n o l o n g e r  Hanovia) present) the  and t h e residue p u r i f i e d  by c h r o m a t o g r a p h y ( 1 0 0 % p e t r o l e u m  acetate-petroleum  to give  ether)  an  "olefinic  mixture"  (40%). 36,  IR ( n e a t ) :  'H NMR 1.70  (CDC13):  ppm  1 6 4 0 , 1 4 7 0 , 1 4 6 0 , 1 4 5 0 , 8 8 0 cm" 4 . 6 4 ppm  ( s , 3H, CH3C0)  1  ( b s , 2 H , = C H 2 ) , 2 . 0 ppm  ( a l l m  intensity  peaks)  ( t , J = 7 Hz, 2H,  CH2-C0),  -  MS  (m/z, r e l a t i v e  Exact 37_,  Mass  % intensity):  calculated  IR ( n e a t ) :  127 -  168(5),  f o rC12H24:  70(72),  56(100)  168.1872, observed:  1 4 6 0 , 1 4 5 5 , 1 4 4 5 , 1 3 7 5 , 1 2 6 0 , 1240 cm"  168.1860. 1  ( a l l m  intensity  •  peaks) 1  H  MS  NMR  (CC14):  0.8-2.0  (m/z, r e l a t i v e  43(100),  38,  1.96 MS  mixture  % intensity):  168(10),  9 . 5 4 ppm  (m/z, r e l a t i v e  % intensity):  ether  ( 5 mL)  suspension  m m o l ) a t 22°C a n d s t i r r i n g the solution  42,  0.190 g  196(20),  ( 3 5 ) ( 0 . 2 1 5 g , 1.1  of lithium  continued  aluminum  f o r 0.85 h. ether  and concentrated  3300-3500  (CDC13):  mmol) was a d d e d  hydride  After  (0.042 g ,  dropwise  1.1  addition  ( 3 x 25 m l ) , t h e c o m b i n e d  to give  to a  of  organic  2,2,10-trimethylcyclodecanol  cm"  0.80-1.15  1  ppm  (OH) (m, 9 H , 3 C H 3 ) , 1.20-2.00  ppm  (m, 1 6 H ) , 3.14  (m, I H ) . The  and  56(100).  (43)  was e x t r a c t e d w i t h  filtered  178(3), 69(68),  (82%).  IR ( n e a t ) :  'H NMR ppm  dried,  ( b s , 2H, =CH2),  ( s , 3H, CH3)  2,2,10-trimethylcyclodecanone  (42J,  55(96),  consisted of the  ( d , J = 2 H z , I H , C H O ) , 4 . 5 4 ppm  2,2,10-trimethylacetoxycyclodecane  extracts  57(100),  (40%).  ( t , J = 6 H z , 2H., C H 2 ) , 1 . 6 6  water,  69(75),  1725(C0)  (CC14):  stirred  166(6),  o f N^ w a s o m i t t e d , t h e p r o d u c t s ( 2 5 % ) and 38  IR ( n e a t ) :  'H NMR  (m)  41(100)  When t h e b u b b l i n g olefinic  ppm  a l c o h o l 42_ w a s d i s s o l v e d  pyridine  ( 0 . 1 mL)  (30 mL) was a d d e d  added  i n CC14 (2 m L ) , a c e t i c  and t h e s o l u t i o n  and t h e s o l u t i o n  washed  stirred  with  anhydride  (0.2 mL),  a t 2 2 ° f o r 15 h .  5% aqueous  Ether  HC1, b r i n e , t h e  -  organic 43:  layer  dried  IR ( n e a t ) :  'H NMR  and concentrated  1725 cm"  (CDC13):  1  0 . 8 3 ppm  and  2.5 H z , I H , CH(OAc)  Potassium  18-Crown-6-ether 1.6 m m o l ) w e r e (100  added  filtered,  'H NMR MS  1715 cm"  (CC14):  t o a benzene  Exact  Mass  mixture  The  2 h.  hydrogen  (3  2 h.  ketone  43(100).  photolysis  permanganate  of the olefinic  f o r 120 h a t 2 3 ° . ether  1.5  o f 35)  ( 2 5 2 mg, mixture  Water  was  ( 3 x 25 m L ) , d r i e d , purified  by PTLC  (5% ethyl  39_, 1 0 mg ( 9 % ) .  C O ) , 2.10 ( t , J = 7 H z , 2 H , CH2C0) 170(11),  f o rC^H^O:  58(100),  43(83)  170.1665, observed:  (obtained from  photolysis  170.1682.  o f 35)  (4 ml) c o n t a i n i n g t h e o l e f i n i c mixture  solution  and t h e s o l u t i o n  o f sodium hydroxide added  and s t i r r i n g  was a d d e d , t h e r e a c t i o n  x 20 m l ) , t h e combined o r g a n i c  ( 1 0 0 mg, 0.56  ( 0 . 6 4 mL, 0.6 mmol, A l d r i c h )  was r e m o v e d  ( 0 . 0 8 mL) w e r e Water  stirred  (d, J =  ..  (CO)  5 min t h e i c ebath  peroxide  additional  to give  t o 0 ° a n d BH3~THF  A 3N a q u e o u s  ( 1 5 mL)  extracted with  % intensity):  THF s o l u t i o n  After  (obtained from  and t h e n e u t r a l m a t e r i a l  of Olefins  mmol) was c o o l e d wise.  1  calculated  Hydroboration  for  solution  2.07 ( s ,3 H , C H 3 >  (m/z, r e l a t i v e  181(72),  ( 3 0 mg, 0.08 mmol) a n d p o t a s s i u m  concentrated  (neat):  225(28),  Oxidation of Olefins  acetate:dichloromethane) IR  239(55),  mg, 5.6 mmol) a n d t h e r e a c t i o n  added, the reaction  (85%).  ( s , 3 H , C H 3 ) , 0 . 9 7 ppm  ( s , 3 H , C H 3 ) , 4 . 5 6 a n d 5 . 1 0 ppm  % intensity):  Permanganate  t h e a c e t a t e 4 3 , 0.185 g  ( s , 3 H , C H 3 ) , 0 . 9 3 ppm  J = 7 H z , 3 H , C H 3 ) , 2 . 0 7 ppm  (m/z, r e l a t i v e  to give  (CO)  (d,  MS  128 -  extracts  stirred  ( 0 . 0 8 mL)  and 30%  continued  f o r an  mixture  dried,  added  extracted with  filtered,  dropat 23°  ether  concentrated  and  -  the  resulting  2 0 mg 40:  (20%) and primary IR ( n e a t ) :  'H NMR MS  o i lpurified  Mass  Jones  O x i d a t i o n o f 40  Jones This  an acetone  mixture  added  solution  was s t i r r e d  acid  (neat):  'H NMR  filtered 41_, 1 5 mg  3400-2800  (CDC13):  Ozonolysis Ozone  was p a s s e d  dropwise  again  .8-1.4  1_5,  (m, 22H)  43(95)  168.1878, observed:  precipitate  was  15 m i n a n d 2 - p r o p a n o l  reagent.  168.1875.  a l c o h o l 40 ( 1 5 mg, 0.08  a green  The r e a c t i o n  and t h e s o l v e n t  mixture  concentrated  mmol),  obtained. ( 2 mL) was  was  then  to give the  1  ( b s , I H ) , .8-2.0  Mixture during  through  sulfide  ( 0 . 5 mL) was a d d e d .  the solution  200(10),  ppm  5 min through  to flush After  hydrocarbon  (m, ~23H)  140(12),  ( o b t a i n e d from  74(100).  photolysis  a solution  any remaining  Oxygen  ozone and  for 1 h at 20°,  b y PTLC  3_7, 2 0 mg  o f 35)  containing  (2 m L ) , a t -78°C.  stirring  and t h e r e s i d u e p u r i f i e d  data  hydrocarbon  (93%).  bubbled  Spectral  containing  5.6 mmol) i n m e t h a n o l  to afford  - H20)  until  Jones  (100 mg,  methane)  +  f o r an a d d i t i o n a l  mixture  concentrated  (M  ( 2 mL)  % intensity):  of Olefinic  168(5%), 57(100%),  ( O H ) , 1700 (CO) cm"  1 0 . 2 ppm  (m/z, r e l a t i v e  to give  (OH)  f o rC12H24:  was a d d e d  dried,  carboxylic  MS  7  1  ( d , J = 5 Hz, 2H, CH2-0H),  t o d e s t r o y any excess  filtered,  IR  calculated  reagent  cm"  % intensity):  Exact  (dichloromethane)  a l c o h o l 4 0 , 6 0 mg ( 6 0 % )  3 . 3 0 ppm  (m/z, r e l a t i v e  To  by PTLC  3600-3300  (CC14):  129 -  (5% ethyl  (20%) and ketone  reported i n previous experimental  the olefinic was  then  dimethyl  the solution  was  acetate:dichloro39_, 6 0 mg  sections.  (54%).  -  130 -  MethyT-2-oxocycl opentanecarbox.yl a t e (105) Sodium carbonate solution wise (5%  hydride  (20 g , 220 mmol, Eastman) were refluxed.  HCl) and e x t r a c t e d  after  distillation,  97-100°C/12  IR  (CC14): NMR  Methyl A  ppm  solution  'H NMR  MS  s,  containing  A  added  drop-  acidified  were washed  with  f i l t e r e d and c o n c e n t r a t e d , t o a f f o r d  105  cm"  1  ( I H ,s , e n o l ) ,  3 . 7 8 ppm  (3H, s ,  CH30C0),  was  (106)  3 - k e t o - e s t e r 1 0 5 ( 1 . 8 g , 13 mmol) i n acetone  ( 2 5 mL)  was  added d r o p w i s e ,  heated  dried,  potassium  t o 40°C.  and t h e m i x t u r e  c o o l e d , f i l t e r e d , w a t e r added were  and  stirred  and e x t r a c t e d  f i l t e r e d and c o n c e n t r a t e d  to  with give  (98%). 1 7 2 5 ( s ) , 1 6 7 5 ( m ) , 1 6 2 5 (w)  (CC14):  6 = 3 . 5 0 ppm  cm"  1  ( 3 H , s , C H 3 0 C 0 ) , 1 . 5 - 2 . 5 ppm  ( 6 H , m ) , 1.18  ppm  CH3)  (m/z, r e l a t i v e  Methyl  (0°C) was  The combined e x t r a c t s  ( 3 . 8 g , 26 mmol, A l d r i c h )  (CC14):  (3H,  6 = 7 . 5 0 ppm  The r e a c t i o n  g  reaction  was  and t h e  Torr  The combined e x t r a c t s  1.8  ( 5 0 mL)  (55%).  ( 7 . 3 g , 5 3 m m o l , BDH)  1 h.  ether.  IR  dried,  The c o l d  and d i m e t h y l -  (6H, m).  Iodomethane  106,  added t o benzene  1-methyl-2-oxocyclopentanecarboxylate  carbonate  for  g  ether.  1 7 5 0 ( s ) , 1 6 6 0 (m)  (CC14):  1.5-2.5  2.1  6 3 m m o l , BDH)  ( 2 . 4 7 g , 29 m m o l , A l d r i c h )  f o r 2 h.  with  bicarbonate, brine,  bp  H  Cyclopentanone  and s t i r r i n g continued  sodium  1  (2.46 g, 60% o i l d i s p e r s i o n ,  % intensity):  142(38),  1 1 0 ( 5 2 ) - MeOH.  1,3,3-trimethyl-2-oxocyclopentanecarboxylate (107) potassium-t-amyloxide  solution  was  prepared  by r e f l u x i n g  DME  (200 mL),  -  t-amyl mol,  alcohol  (22.52  g , 0.256 m o l , F i s h e r ) and p o t a s s i u m  BDH) f o r 2 d a y s .  phthalein, with Ketone  Titration  HC1, determined  mmol, A l d r i c h ) ' w a s added  for  10 m i n . ether.  purified  IR  mg  (each,  borohydride  o f ketone  ether),  (CC14):  (0.93 g,  was a d d e d , a n d t h e s o l u t i o n  extracted  dried,  solution,  potassium-t-  continued  filtered,  concentrated and ether)  to afford  107,  1  3500  and p u r i f i e d  to afford  et a l  (CC14):  from 1 5 0  After ether.  1 0 8 , 2.4 g  t o a methanol  ( 1 0 mL)  f o r 1 h, the solution  The c o m b i n e d  extracts  (10%ethyl acetate-  1  ( I H , s , C H ( 0 H ) ) , 3 . 8 3 ppm  ( 3 H , s , C H 3 0 C 0 ) , 3.20  (each, 3H, s , C H 3 ) .  (117a)  (97%). 1  dried,  (83%).  3-chloropropionyl chloride,  1740 (CO) cm"  stirring  by c h r o m a t o g r a p h y  ( O H ) , 1725 (CO) cm"  3-chloropropanoate  Prepared  4H, m), 1.23,  cyclopentanecarboxylate (108)  ( 0 . 9 0 g , 2 4 m m o l , BDH) w a s a d d e d  6 = 4 . 0 5 ppm  (CC14):  ppm  3H, s , C H 3 ) .  ( I H , b s , O H ) , 1 . 1 8 , 1 . 0 2 a n d 0 . 9 2 ppm  Carpino  Iodomethane  (1.2 M).  and s t i r r i n g  ( 5 % HCL) and e x t r a c t e d w i t h  petroleum  IR  a t -20°C.  1 0 7 ( 3 . 1 g , 17 m m o l ) .  concentrated  Methyl  phenol-  containing  ( 3 H , s , C H 3 0 C 0 ) , 1.5-2.5  1,3,3-trimethyl-2-hydroxy  filtered,  ppm  ( 3 mL)  (5%ethyl acetate-petroleum  6 = 3 . 6 9 ppm  acidified  'H NMR  extracts  1 7 5 0 ( w ) , 1 7 3 0 (w) cm"  (CC14):  solution  IR  containing  0.306  (70%).  Sodium  was  The c o m b i n e d  a n d 1 . 0 2 ppm  Methyl  t o DMF  t o t h e orange  ammonium c h l o r i d e  by chromatography  (CC14):  'H NMR 1.10  Excess  ( 2 mL)  (11.9[ g ,  the concentration of the solution  ( 2 . 2 mL, 2.6 mmol) a n d s t i r r e d  6.5  155  o f an a l i q u o t  1 0 6 ( 2 1 0 m g , 1.3 m m o l ) w a s a d d e d  amyloxide  with  131 -  based  on t h e p r o c e d u r e  of  -  'H NMR  (CC14):  6 = 2 . 7 8 ppm  C O O M e ) , 3 . 7 3 ppm MS  3-Chloropropanal  (CC14):  *H NMR ppm  1725 (CO)  cm"  with  6 = 8 . 4 2 a n d 5 . 0 7 ppm  followed The  glycol  was t h e n  dried,  ether. filtered  bp  40-42°C/0.07  IR  (CC14): NMR  C H 2 0 ) , 3 . 4 7 ppm  CH2CH2C1.  was o b t a i n e d a s a  analysis.  (117d)  condenser  addition  removed  = CHOH), 3.56  (2H, d t , J = 4, 7 Hz, CH2CH0).  was  and d r y i n g  extracts  into  ( 2 3 . 8 mL,  and t h e r e a c t i o n  i n a flask  t u b e , a t 0°C.  was b u b b l e d  of acrolein  The combined  placed  stirred  equipped  Gaseous flask,,  0.4 m o l , A l d r i c h ) . f o r 4 h and  washed w i t h  and c o n c e n t r a t e d t o a f f o r d  the  extracted  sodium b i c a r b o n a t e ,  1 1 7 d , 55.6 g  (CH) cm"  (83%).  6 = 4 . 8 6 ppm  1  (IH, t , J = 4 Hz, HC(0CH2)2),  ( 2 H , t , J = 7 H z , C H 2 C 1 ) , 2 . 0 2 ppm  3 . 8 4 ppm  (m/z, r e l a t i v e  % intensity):  137(8), 73(100)  -  (4H, s ,  (2H, d t , J = 4, 7 Hz,  CH2CH(0CH2)2 MS  -  Torr  2950, 2850  (CC14):  The p r o d u c t  ( I H , b s : t , J = 4 H z , CH  (16 g , 0.42 m o l , F i s h e r )  by t h e d r o p w i s e  petroleum  water,  (85%).  (30 g , 0.49 m o l , F i s h e r )  stirrer,  acid  i c e bath  with  ethylene acetal  a mechanical  hydrochloric  - H C l , 63(100)  1  ( 2 H , t , J = 7 H z , C H 2 C 1 ) , 2 . 1 0 ppm  Ethylene  H  123(22), 87(85)  ( 1 0 : 1 ) , a c c o r d i n g t o 'H NMR  (CC14):  (3H, s,  (117c)  3-Chloropropanal  1  % intensity):  a s 1 1 7 d , n e a t , no s o l v e n t  trimer:monomer IR  ( 2 H , t , J = 7 H z , C H 2 C O O ) , 3 . 6 9 ppm  ( 2 H , t , J = 7 Hz, CH2C1)  (m/z, r e l a t i v e  Prepared  132 -  HC(0CH2)2>  -  3-Chloro-l,1-dimethoxy Prepared glycol IR  (CC14):  =7  (117e)  as above, using methanol  (1.25 mol) instead  of ethylene  (75%).  'H NMR J  propane  133 -  2 9 7 5 , 2 9 4 0 , 2810 (CH)  (CC14):  6 = 4 . 7 5 ppm  Hz, CH2C1),  3 . 2 8 ppm  cm'  1  ( I H , t , J = 4 H z , H C ( 0 M e ) 2 ) , 3 . 5 4 ppm  (6H, s, CH30),  1.9  Lppm  (2H,t ,  (2H, d t , J = 4, 7  Hz,  CH_2CH(0Me)2) MS  (m/z, r e l a t i v e  Exact  Mass  calculated  3-Bromopropanol Prepared acetic CC14  and IR  alcohol  1740 (CO)  (CC14):  ( 1 4 g , 0.1  (11 g , 0.11 m o l , F i s h e r ) ,  138.0380.  m o l ) ,s t i r r e d  pyridine  cm"  6 = 4.11  = 7 H z , C H 2 0 ) , 2 . 2 8 ppm  were  washed  1 1 7 f , 14.3 g  with  a t 20°C  with  ( 8 . 8 g , 0.12 m o l ) i n  Cold water and c h l o r o f o r m were  concentrated, to afford  'H NMR J  the related  The c h l o r o f o r m e x t r a c t s  (CC14):  138.0444, observed:  (117f)  ( 1 0 m L ) , f o r 16 h .  solution.  107(100) M -0Me, 103(15) - C l  f o r CgH^OgCl:  acetate  from  anhydride  +  % intensity):  then  added  to the  10% HC1, d r i e d ,  filtered,  (83%).  1  ppm  ( 2 H , t , J = 7 H z , C H g B r ) , 3 . 4 3 ppm  (2H, quint.,  (2H,t ,  J = 7 H z , C H 2 C H _ 2 C H 2 ) , 2 . 2 0 ppm  (3H, s ,  CH3C0).  Typical  Alkylation  Freshly (2  mL)  was  Aldrich) 5-10 was  of Cyclopentadiene  distilled  added  i n THF  cyclopentadiene  dropwise  (15 mL), s t i r r i n g  a t 0°C.  reagent  117  (5 mmol, A l d r i c h ,  t o sodium hydride  m i n , and t h e a l k y l a t i n g stirred  using  i n THF  (5.5 mmol, 60% o i l d i s p e r s i o n , The s o l u t i o n  1J_7 ( 5 m m o l ) w a s  a t the appropriate temperature,  bp 38-40°C)  stopped  added.  f o r the requisite  bubbling  The time  after  reaction (Table 4 ) .  -  The  solution  ether.  The  was  cooled, acidified  combined  concentrated  and  ether-petroleum  the  product  ether).  spectral  The  chromatography  reaction  of  117b  ( C C 1 4 ) : . 300-2810, 1615,  1605  'H  NMR  ppm  4.27  ppm  b s , CH2  (IH, t , J  =  4  Hz,  of  117i  was  f o r products  <5 = 6 . 3 - 5 . 8  brine,  by  IR  (CCl^):  washed w i t h  and  purified  reaction data  -  (5% HCl, dropwise)  ether extracts  cyclopentadiene, while Typical  134  (CH) (m,  3H,  and  dried,  alumina, -  using  i n THF:DME,  in this  filtered,  (neutral  performed  case,  with  4  equiv.  of  1:1.  118e.  1  olefinic  C H ( 0 M e ) 2 ) , 3.23  i n c y c l o p e n t a d i e n e ) , 2.35  done  118, cm"  was  extracted  1.84  cyclopentadiene  ppm  (6H,  ppm  (each, CH2,  protons),  s , C H 3 0 ) , 2.85 m,  ppm  (2H,  CH_2CH(0Me)2  or  CH2-cyclopentadiene) MS  (m/z,  Exact  relative  Mass  ppm  ( 4 H , m,  J  =  ppm 7  product  H z ) , 2.70  "118b",  CHgCl),  (IH, t , J  =  ppm  168(13),  for C,0H1602:  product  1,3-diacylated 6.32  intensity):  calculated  1,1-diacylated 3.68  %  3.0  'H  ppm  "118b",  4' H z ) , 3 . 8 2 (IH, t , J  = 4  NMR:  House  et a l  IR  (CC14):  'H  NMR  9  from 1  ppm  C H 2 C H 2 ) , 1.56  6.3  - 2Me0H,  *  168.1135.  ppm  (4H,  bs,  olefins),  CH2C0) (CC14) 6 =  (4H,  t , J  =  7.30  ppm  (2H,  7 H z ) , 3.30  ppm  d,  J  (4H,  =  4  Hz),  t ,  Hz).  (103)  2-methylcyclopentane-1,3-dione,  based  on  the  procedure  of  (90%).  1680  (CC14):  ( C C 1 4 ) <5 =  NMR:  3-Ethoxy-2-methy1-2-cyclopentenone Prepared  - MeOH, 1 0 4 ( 6 2 )  168.1146, observed:  ( 4 H , m, 'H  136(74)  (CO), 6 =  ppm  1620  4.23  (3H,  ppm  (C=C) (2H,  cm" q,  1  J =  b s , C H 3 C = C ) , 1.40  7  Hz,  ppm  CH_2CH3), 2.8-2.3  (3H,  t , J  =  7  Hz,  ppm  (4H,  CH_3CH2).  m,  -  135 -  4-Ethoxy-3-methylbicyclo[3.3.0]oct-3-en-2-one (122) Prepared  from  bp  9 0 - |B°C/0.5  IR  (CC14):  'H NMR  enol  ether  103 by t h e method  o f Koreeda  et a l  1  1  0  (68%).  Torr  1700 ( C O ) , 1645 (C=C) cm'  (CC14):  1  6 = 4 . 2 8 ppm ( 2 H , q , J = 7 H z , 0 C H _ 2 C H 3 ) , 3 . 2 0 ppm ( I H ,  C H C = C ) , 2 . 7 3 ppm  ( I H , m , C H C O ) , 1 . 5 8 ppm  ( 9 H , b s ) , 1 . 3 6 ppm  m,  (3H, 5, J = 7 Hz,  CH3CH2) MS  ( m / z ,r e l a t i v e  124(83) Exact  % intensity):  181(30)M  +  + 1, 180(100),  152(48)- E t ,  -CH2CH2C0  Mass  calculated  f o rC ^ H ^ O ^  180.1146, observed:  180.1158.  2-Methy1-2,4-bicyclo[3.3.0]octadione (123) Enol  ether  122 ( 1 . 8 g , 10 mmol) was h y d r o l y z e d u s i n g  3.5  mL, 70 mmol) a n d w a t e r  was  cooled  methane. brine,  dried,  filtered  recrystallized mp  158-160°C  IR  (CHC13):  'H NMR 2.20 MS  ( 7 mL, 70 mmol) a t 100°C, f o r 18 h .  t o 20°C, a n d e x t r a c t e d The combined  The  (cone.  reaction  acetate and h o t d i c h l o r o -  were washed w i t h  and concentrated  to afford  1 7 0 0 ( C O ) , 1645 (C=C) cm"  ( m / z ,r e l a t i v e  6 = 7 . 1 0 a n d 4 . 1 8 ppm  & intensity):  calculated  sodium  1 2 3 , 0.6-1.2  bicarbonate, g  (40-80%),  aluminum  ( I H , b s , O H ) , 2 . 6 0 ppm ( I H , s , C H - O C ) ,  152(54),  f o r CQH,o09:  hydride  1  (3H, s , CH3)  3-Methy1bicyc1o[3.3.0]-3-octen-2-ol Lithium  hot ethyl  acid  i n hot dichloromethane.  (CDC13-):  Mass  with  organic extracts  ppm ( I H , s , C H C O ) , 1 . 2 6 ppm  Exact  sulfuric  124(63)  -CO, 2 8 ( 1 0 0 )  152.0834, observed:  -CO  152.0833.  (124)  ( 4 2 m g , 1.1 mmol o r 4 . 4 e q u i v . , A l d r i c h )  was  -  added  t o enol  ether  122  ( 1 8 0 mg,  reaction  stirred  the  (0°C) r e a c t i o n .  cold  washed w i t h the  a t 20°C.  ether.  products  The  purified  After The  polar product,  IR  (CC14):  3600  'H  NMR  MS  (m/z,  relative  124b, more IR 1  H  (CC14): NMR  (2H, MS  ( w , OH) 6 =  5.20  %  (CC14):  7 0 mg cm"  extracts  (0.1  then  mL,  5.6  dried,  ( 1 0 mL)  and  mmol) was  filtered,  and  filtered,  (8% ethyl  the  the  added  to  residue  concentrated  and  acetate-dichloromethane).  (40%),  138(57),  8 8 mg  ( s , OH), 5.10  was  ( I H , b s ) , 4.0  intensity):  6 =  h, water  i n ether  1  ppm  polar product, 3600  2  chromatography  124a, l e a s t  (CC14):  -  1 mmol) d i s s o l v e d  mixture  combined  by  136  3450 ppm  ppm  ( I H , b s ) , 3.10  120(38)  ppm  -Hp_0, 1 2 3 ( 3 8 )  ( I H , bs)  -CH3>  109(100)  (49%), (m)  cm"  1  ( I H , b s ) , 4.36  ppm  (IH, bd, J =  7 H z ) , 2.80  ppm  m)  (m/z,  relative  %  intensity):  138(60),  123(30)  -CHy  120(20)  -H20,  109(100).  3-Methyl-3-(3-oxobutyl)-2,4-bicyc1o[3.3.0]octadione Prepared procedure (neat):  'H  NMR  1760  (CDC13):  ppm  3-methyl-2,4-bicyclo[3.3.0]octadione,  of Hajos  IR  2.57  from  (125)  and  ( m ) , 1725 6 =  (2H, t , J  3.68  =  1 0 1 a  Parrish (s) ppm  cm"  based  on  the  (85%). 1  (2H, t , J =  7 Hz, CH2C0),  2.05  7 H z , C H 2 C H 2 C 0 ) , 3.30  ppm  (3H, s , C0CH3),  0.96  ppm  (2H,  ppm  (3H,  m), s,  CH3) MS  (m/z,  relative  %  intensity):  222(20),  152(77)  - C ^ O ,  124(100)  CO Exact  Mass  calculated  for C  ] 3  H  1 8  03:  22.1251, observed:  222.1249.  -  C ^ O ,  -  3-(Propyloxy-3-al  e t h y l e n e a c e t a l ) - 2 - m e t h y l - 2 - c y c l o p e n t e n o n e(132)  3-iodopropanal Aldrich), (1  by  extraction  (CC14):  'H NMR J  ( 2 e q u i v . , BDH) w e r e system  for  used,  a:  1700(C0),  (CDC13):  The combined  extracts  Purification  by  T H F , 0 % ; b: 1640(C=C) cm"  5 . 0 ppm  % intensity):  ketone.  The p r o d u c t  use.  bp  80-82°C/15  IR  (neat):  followed  washed,  chromatography  ( 4 H ,b s , C H 2 0 ) ,  -CH3C0,  4-chlorobutanone  obtained after  (3H,  t ,  b s , CH3)  124(36).  was r e p l a c e d by m e t h y l  extraction  (90%)  was p u r e  enough  distilled,  Torr (19%) 1 6 3 5 , 1 6 1 0 , 1605 ( O C ) cm"  6 = 7 . 6 2 ppm a n d 6 . 1 7 ppm  m,  1 o f C H 2 = C ) , 3 . 8 6 ppm  (3H,  s : s , 1 : 1 , C H 3 C = C ) , 1 . 0 0 ppm  (m/z,r e l a t i v e Mass  1 . 6 2 ppm  (2H,  (131a)  However, i t c o u l d be  1715 (CO),  (CC14):  1  J = 1 0 , 1 8 H z , 1 : 1 , C H = C H 2 ) , 5 . 4 9 ppm  Exact  were  refluxed  HMPA a t 1 5 0 ° C , 3 5 % .  2 1 2 ( 2 ) , 168(34)  except  (IH,  MS  was  ( I H , t , J = 4 H z , C H ( 0 C H 2 ) 2 ) , 4 . 3 0 ppm  as f o r144a,  further  and  m i x t u r e was  acetate.  Prepared  'H NMR  The r e a c t i o n  (catalytic,  t o diketone 121'  (20°), t h i s  3-methyl-2,4-pentadienoate  vinyl  added  the reaction  and c o n c e n t r a t e d .  (m/z,r e l a t i v e  Ethyl  a , b.  18-crown-6  t o quench  = 7 H z , C H _ 2 C H 2 ( C H 2 0 ) 2 ) , 3 . 9 0 ppm  MS  (2 e q u i v . , A l d r i c h ) ,  afforded 132.  Solvents IR  added  with ethyl  filtered  (ether)  carbonate  i n solvent  18 h a n d w a t e r  dried,  ethylene acetal  and sodium  equiv.), present  for  137 -  ( I H , d d , J = 1 2 , 1 8 H z a n d HC=C (2H,  b s , 1 o f C H _ 2 = C ) , 5 . 1 5 ppm  ( 2 H , q , J = 7 H z , 0 C H 2 C H 3 ) , 2 . 0 0 a n d 1 . 7 2 ppm  % intensity):  calculated  1  ( 3 H ,t , J = 7 H z , CH3CH2) 140(3), 111(18)  for CgH1202:  - E t , 95(63)  140.0834, observed  -OEt,  140.0843.  43(100)  -  138 -  3-Methyl-4,4-dicarbomethoxy-1,3-butadiene Alkyl solution  chloride  o f sodium  After and were for IR  1 4 4 b ( 3 g , 17 mmol) was ( 0 . 4 g , 17 m m o l , BDH)  stirring  t h e aqueous  (neat):  layer  extracted  with  acetate.  to afford  1710 C O ) , 1 6 1 0 , 1575 (C=C)  (CC14):  6 = 7 . 0 0 ppm  s , CH3C00),  2 . 1 0 ppm  Methyl was  added  magnesium  slowly  28-30°C/10  to a  stirred  (50 mL). neutralized  (10% H C l ) ,  The combined  1 3 1 b , 2.1  g  extracts  (90%) pure  enough  chloride  (13.1 mL,  to freshly distilled  30 m i n a t 20°C.  filtered  through  concentrated (neat):  'H NMR (8H,  added  to the cold  celite,  extracted  to afford 3500-3400  (CDC13):  1 3 3 , 2.2 g (OH)  cm"  6 = 4 . 2 7 ppm  39 m m o l , 2.99 M s o l u t i o n ,  propargyl  (25 mL).  alcohol  The s o l u t i o n was  Cyclopentanone (0°C) s o l u t i o n . with  ethyl  (1 g , 1 8  Mass  Aldrich)  stirred for  ( 1 . 5 g , 18 m m o l , The m i x t u r e  acetate,  dried,  Aldrich)  was  filtered  and  ( 2 H , b s , O H ) , 1.88  ppm  (87%).  1  ( 2 H , s , C H 2 0 H ) , 4 ppm  intensity):  calculated  ppm  mmol,  bs)  (m/z, r e l a t i v e ' %  Exact  10 H z , C H = C H , Z ) , 3 . 7 0  (133)  10 m i n a t 0 ° C , t h e n was  1 0 , 1 6 H z , H O C ) , 5 . 6 8 ppm ( I H ,  (3H, s , CH3C=C).  A l d r i c h ) . i n THF  ( 2 mL)  1  (IH, bd, J =  Torr,  THF  cm"  ( I H ,d d , J =  l-(prop-1-yn-3-ol)-1-cyclopentano1  MS  i n methanol  ethyl  and c o n c e n t r a t e d  J = 1 6 H z , C H = C H , E ) , 5 . 4 3 ppm  (6H,  IR  dropwise  further use.  bd,  in  added  f o r 1 h a t 0°C, t h e s o l u t i o n was  dried, filtered  'H NMR  bp  (131b)  140(2),  f o r CgH1202:  79(100)  140.0834, observed:  140.0832.  -  "Intermediates" Diol was  133  treated  134  t o 136  or acetylated  with  sulfuric  20°C), f o r d i f f e r e n t 137  were  134, 'H  IR  NMR m)  135,  IR  'H  NMR  ppm  (neat):  'H  10  137,  ppm  NMR  (CC14):  (neat):  6.50  1700  MS  (m/z, r e l a t i v e  (CC14):  Mass  NMR  6 =  ppm  cm"  (CO)  cm'  137  117f),  temperatures  (0°.to  I n t e r m e d i a t e s 1_34  to  (-30-40%).  1  ppm  (2H, s , OH),  1.8  ppm  1  s, HOC),  (2H, m),  %  (CDC13):  ( C O ) , 1630  intensity):  Ketone hydrazine  137  4.20  ppm  (2H, s , CH20H),  6.10  ppm  (IH,  m),  5.80  (IH,  A  and  207.39  ( 3 0 0 mg,  226-228°C  2.5  1.5-2.5  dd, J  =  1  (m) 150(18),  149(100),  +  M -l  150.1041 , o b s e r v e d :  150.1041.  (98%).  39.79,  ppm.  derivative  2 mmol) was  mmol, A l d r i c h )  precipitate  recrystallized  1 3 7 , 6 5 0 mg  cm"  6 = 20.09, 25.23, 26.94, 29.52, 32.55, 34.30,  ( 5 0 0 mg,  2 drops).  (C=C)  f o r C1()H140:  2,4-Dinitrophenylhydrazone  mp  product  (CO)  (IH,  1 . 5 - 2 . 8 ppm  calculated  128.69, 158.66  and  and  to 2 h).  ( 2 H , s , C H 2 0 H ) , 3.20  1700  ppm  (5 min  for  m)  NMR  C  a c i d : m e t h a n o l , 1:1, a t v a r i o u s  (OH)  6 = 5.92  'H  1 3  ( p r e p a r e d as d e s c r i b e d p r e v i o u s l y  ( O H ) , 1730  3500  137  Hz) IR  Exact  133  5 t o 30%)  <5 = 4 . 1 8  (neat):  (8H,  (from  -  product  lengths of time  3500  (CC14):  136, 2,  isolated  (CC14):  (8H,  and  139  formed  of  137  added  to a  solution  i n methanol  instantaneously,  i n chloroform:methano!,  ( 5 mL) i t was  to afford  of and then  2,4-dinitrophenylHC1  (cone.  filtered o f f  t h e DNPH d e r i v a t i v e  of  -  IR  (CHC13):  'H NMR 7.80 MS  9 . 1 0 ppm  , 5 1  Mass  1.7-3.0  % intensity):  ppm  N  f o rC-|6 i8 4°5  :  8 . 3 0 ( I H , d d , J = 2 , 10 H z ) ,  (10H,  330(8),  H  calculated  1  (IH, d, J = 2 Hz),  ( H , d , J = 10 H z ) ,  (m/z, r e l a t i v e  Exact  A  1 6 5 0 , 1 6 0 0 , 1520 cm"  (CDC13):  ppm  140 -  m)  149(100)  -  C6H3N304  330.1328, observed:  330.1372.  -bicyclo[3.3.0]octen-2-one (138) Prepared  from  methyl-2-oxocyclopentanecarboxylate  by t h e method o f  115 Kulkarni  a n d Dev  (30-40%).  Also  prepared  from  83_, b a s e d  on t h e p r o c e d u r e  of  120 Easton could  C a r l s o n and Lee be p e r f o r m e d  phosphorus  (-60%).  i s 0.11 m o l e  pentoxide  i n the literature  IR  1700 (CO),  'H NMR MS  (CC14):  Exact  Mass  (X m a x  UV  (log  1640 (C=C) cm"  e)):  122(100),  f o rCgH^O:  107(5),  ethoxide  solution  (10%  an e x t e r n a l i c e b a t h .  added, followed after  immediate  of tenequivalents  93(20),  79(95)  122.0713.  (145)  (prepared  from  d r y e t h a n o l , 1.8 m L , 3 0 m m o l ) w a s d i s s o l v e d  was  equivalents of  (189)and  5  0° w i t h  five  reaction  241 ( 3 . 5 )  1  to  instead  122.0729, observed:  A ' -ethoxa1y1bicyclo[3.3.0]octen-2-one  and  using  this  1  5-Ethoxalyl-3-methyl-2-cyclopentenone  A sodium  on w h i c h  (m)  % intensity):  calculated  acid,  scale  (58%).  2 . 2 t o 2 . 8 ppm  (m/z, r e l a t i v e  of hydroxy-acid  and methanesulfonic  recommended (neat):  The l a r g e s t  precipitate.  HCl), extracted with  a further  BDH,  i n - e t h e r ( 1 0 mL) a n d c o o l e d  Diethyl oxalate  5 m i n by ketone  After  s o d i u m , 0 . 1 1 5 g , 5 mmol  (0.73 g , 5 mmol, A l d r i c h )  138 o r 142 ( 5 m m o l ) , r e s u l t i n g  10 m i n , t h e s o l u t i o n  e t h y l a c e t a t e , t h e combined  was  extracts  i n an  acidified  dried,  -  filtered, ethyl  concentrated  acetate  1 8 9 , 6 0 0 mg 145 cm 1  IR ( C H C 1 3 ) :  purified  to afford  145, 1 g  ( 9 0 % ) , mp  65-67°C; o r  60-62°C.  1760 ( m ) , 1725  NMR  6 = 1 1 . 8 0 ppm  (CDC13):  0 C H 2 C H 3 ) , 3 . 3 8 ppm  ( s ) , 1700 ( w ) , 1660 ( s ) , 1625 ( w ) , 1600  (w)  ( I H ,b s , e n o l ) ,  4 . 3 3 ppm  ( 2 H , b s , ( C = C ) 2 - C H 2 ) ; 2 . 4 8 ppm  (2H, q, J = 7  ( 6 H , m ) , 1.38  ppm  Hz,  (3H, t ,  = 7 Hz, CH3CH2)  MS  (m/z, r e l a t i v e  149(100) 189  ppm  intensity): -  223(12)  +  6 =  ppm  +  1, 2 2 2 ( 1 3 ) ,  1 2 . 3 2 ppm  ( s ) , 1 6 1 0 (w)  ( I H ,bs, enol),  % intensity):  - COOEt, 95(55)  -  197(9)  6 . 0 6 ppm  bicyclo[3.3.0]octen-2-one ethoxide  dry ethanol, 0°C w i t h  resulting  i n an  solution  was  extracts  dried,  ethyl  5.1  M  +  +  1, 1 9 6 ( 1 0 ) ,  (189) and A  (prepared  9 0 mmol) was i c e bath.  immediate  from  2 . 2 0 mmp  (3H, s ,  -  CO,  precipitate.  concentrated  petroleum ether)  s o d i u m , 0 . 3 5 g , 1 5 mmol i n ether  of ethyl  After  stirring  with  ethyl  and p u r i f i e d  to afford  (20 m L ) , and  f o r m a t e ( 1 . 3 mL,  ( 1 5 mmol) i n e t h e r  (10% HC1), extracted  filtered,  168(3)  5 ' -3-formyl  dissolved  A mixture  and k e t o n e 138 o r 142  acidified  acetate-  ( I H , b s , HC=C), 4.28  (150)  solution  mL,  an e x t e r n a l  mmol, A l d r i c h )  - 1  (2H, bs, (OC)2-CH),  1  and  cm  COCOOEt.  5-Formyl-3-methyl-2-cyclopentenone  sodium  - Et,  (3H, t , J = 7 Hz, CH3CH2)  (m/z, r e l a t i v e  A  194(4)  COCOOEt.  ( 2 H , q , J = 7 H z , C H 2 C H 3 ) , 3 . 3 7 ppm  123(100)  M  1740 ( m ) , 1720 ( s ) , 1660  (CDC13):  C H 3 C 0 ) , 1.37 MS  %  - COOEt, 121(31)  IR ( C H C 1 3 ) :  'H NMR  to  by c h r o m a t o g r a p h y ( 1 5 %  - 1  H  J  -  and t h e product  petroleum ether)  ( 6 2 % ) , mp  141  ( 5 mL)  was  BDH, cooled 16.5  added,  f o r 30 m i n , t h e acetate,  the  combined  by c h r o m a t o g r a p h y ( 2 0 %  1 5 0 , 1.3 g  ( 5 8 % ) , mp 1 2 0 ° - 1 2 2 ° C ;  -  or  1 8 9 , 8 3 0 mg  (45%),  1 5 0 , IR ( N u j o l ) : 1560  (m)  'H NMR bs,  cm"  2800-2600  (CDC13):  189,  Mass  %  (m/z, r e l a t i v e  Mass  General  mixture in  ether  10% HCl  extracted  with  silica  cm"  1  (3H, s, bs, s, bs, bs,  1 : 3 : 3 : 2 : 2 ) , 3 . 0 3 ppm  +  + 1, 124(55), 96(100)  124.0522, observed  (KH), Procedure ( 1 0 mL)  hydride  ( 1 5 mL)  was  cooled  i n ether  ( 3 0 mL) ether,  was  was  A:  (2H, bs,  -  CO,  124.0526.  Cyclohexanone (153) (0.490 g , 5  added  dropwise  over  20 m i n t o a  ( 1 . 2 5 g , 11 m m o l , 3 5 % o i l d i s p e r s i o n ,  under n i t r o g e n .  After  t o -78°C a n d d i e t h y l ( 2 mL)  added  removed  under  an a d d i t i o n a l pyrocarbonate  i n one a l i q u o t .  added, the reaction  t h e combined ether  (MgSO^) a n d t h e s o l v e n t on  protons,  125(22) M  f o r C-,H802:  ether  of potassium  mmol, A l d r i c h )  aqueous  150.0680.  C0CH).  Hydride  mixture  CO,  Procedures  i n diethyl  reaction 5.5  calculated  refluxing  122(59) -  1 7 0 0 ( s ) , 1 6 9 5 ( s ) , 1 6 2 0 (m)  olefinic  % intensity):  Acylation  Aldrich)  (2H,  (3H, b s , CHg-OC)  67(59) -  Potassium  + 1 , 150(100),  5 = 9 . 7 2 , 8 . 8 0 , 7 . 1 0 , 6 . 0 2 , 5 . 8 4 ppm  ( C = C ) 2 C H 2 ) , 2 . 1 2 ppm  Exact  +  150.0680, observed:  (enol),  aldehyde, enol,  - CHO,  151(12) M  f o r CgH1Q02:  3300-3500  (CDC13):  95(68)  2 . 9 8 ppm  (6H, bs)  intensity):  calculated  representing  ( I H ,b s : s : s , e n o l ) ,  C0CH0  IR ( N u j o l ) :  'H NMR  1 7 0 5 ( s ) , 1 7 0 0 (m) 1 6 1 5 ( s ) ,  6 = 7 . 7 0 , 7 . 2 2 , 7 . 0 ppm  (m/z, r e l a t i v e  Exact  (w, e n o l ) ,  1  94(90), 93(40) -  (1)  70-80°C.  ( C = C ) 1 - C H 2 ) , 2 . 4 0 ppm  MS  MS  mp  142 -  was  extracts  reduced  washed  pressure.  g e l (400-230 m e s h , 5% e t h e r - p e t r o l e u m  ether)  Aldrich)  0.5 h t h e  brine,  Flash afforded  g,  1 h a t -78°C  t o warm  with  stirred  (DEPC, 0.890  After  allowed  mmol,  t o 22°C, dried  chromatography 1-cyclo-  -  hexenyl IR  ethyl y  (neat):  'H NMR 2.10  carbonate  ( 1 5 4 ) 9.820 g  = 1 7 5 3 , 1695  (CC14):  143 -  6 = 1.30  cm"  (98%).  1  ( t , 3H, CH2CH3,  J = 7 H z ) , 1.70  (m, 4H, C H 2 C H 2 ) ,  (m, 4 H , C H 2 C H 2 ) , 4.20 ( q , 2 H , - 0 C H 2 C H 3 , J = 7 H z ) , 5.38 ( b r s , I H ,  HOC-0). (2)  Potassium  t-Butoxide (KOtBu),  5 mmol, A l d r i c h ) potassium After  an a d d i t i o n a l worked  0.410  (52%).  g  (neat):  'H NMR  dropwise  t - b u t o x i d e (0.615  reaction  IR  was added  0 . 5 h a t -78°C  y = 1758, 1688 5 = 1.27  over  cm"  ( t , 3H, CH2CH3>  (3)  Potassium  over  5.5  mmol)  t-Butoxide (KOtBu),  HC1  ( 3 0 mL)  pentenyl (4)  5 min t o a s t i r r e d  was  ethyl  Potassium  added  Hydride  5 mmol, A l d r i c h ) added  rapidly  ice 22°C  B:  ( 2 mL)  b a t h , aqueous after  1 0 % HC1 work  After  worked  g  and t h e  carbonate (156)  B:  mixture  CH2CH2CH2);  (104) (0.420  ( 2 mL)  and  added  t - b u t o x i d e (0.615  1 h a t -78°C  Cyclohexanone DEPC  aqueous  to give  g, 10%  1-cyclo-  hydride  benzene  g, was  (1.25 g ,  ( 1 5 mL)  m i x t u r e was  and t h e r e a c t i o n  and f l a s h  (153) (0.490  ( 1 . 2 2 g , 7.5 mmol)  o f potassium  i n refluxing  added  up a s a b o v e  i n ether  up a s a b o v e  0.5 h t h e r e a c t i o n  ( 3 0 mL)  (m, 6H,  (62%).  containing  Aldrich)  an a d d i t i o n a l  was a d d e d  Cyclopentanone  of potassium  under, n i t r o g e n .  (1 m i n ) t o a s t i r r e d  After  t o give  mixture  (KH),Procedure  11 m m o l , 3 5 % o i l d i s p e r s i o n , nitrogen.  Procedure  ( 1 5 6 ) 0.480  i n benzene  nitrogen.  ( b r s , I H , HC=C-0).  and t h e r e a c t i o n  carbonate  ( 3 0 mL)  g,  mixture of  under  J = 7 H z ) ; 1.6-2.6  ( 1 . 2 0 g , 7.5 mmol) was d i s s o l v e d  i n e t h e r a t -78°C  (104) (0.420  1  ( q , 2 H , 0 C H 2 C H 3 , J = 7 H z ) ; 5.32  dropwise  1 0 % HC1  1-cyclopentenyl ethyl  4.13  5 m m o l ) a n d DEPC  Cyclopentanone  i n e t h e r a t -78°C  aqueous  to give  A:  20 m i n t o a s t i r r e d  g , 5.5 mmol)  up a s a b o v e  (CC14):  Procedure  under  cooled  i n an  a l l o w e d t o warm t o  chromatography  (5% ether-  g,  -  petroleum IR  ether) 2-carboethoxycyclohexanone  (neat):  'H NMR 2.10  y = 1 7 4 0 , 1 7 2 2 , 1 6 6 0 , 1620 cm"  (CC14):  6 = 1.31  (m, 4H, CH2CH2);  H0-OCC0). (5)  rapidly  (KH),Procedure  i n benzene  ( 2 mL)  After  to give  petroleum IR  an a d d i t i o n a l  DEPC  added  up as above  6 = 1.23  (104) (0.420  hydride  i n r e f l u x i n g benzene  and f l a s h  ( t , 3H, CH2CH3,  ( 1 5 mL)  chromatography ( 1 0 5 ) 0.472 cm"  g (61%)  1  J = 7 H z ) ; 2.22 (m, 6 H , C H 2 ) ;  (6)  Lithium  Dicyclohexylamide (LiNCy2),  prepared  from  4 . 2 mL  dicyclohexylamine After in 10%  one a l i q u o t . citric  above  acid  11 m m o l ) )  0 . 5 h DEPC  After ( 1 0 mL)  and f l a s h chromatography  (neat):  ( 2 . 5 M, i n ether  (0.890  1 h a t -78°C allowed  i n ether  A:  3-Methyl-2-cyclo-  ( 1 0 mL) was a d d e d  dropwise  of lithium dicyclohexylamide (LiNCy2>  of n-butyllithium  3-methyl-2-cyclohexenone IR  solution  ( 2 . 1 5 mL,  an a d d i t i o n a l  Procedure  g , 5 mmol, A l d r i c h )  20 min t o a s t i r r e d  i n an  (5% ether-  ( b r t , I H , C0-CH-C0); 4.14 ( q , 2H, -0CH2CH3, J = 7 H z ) .  over  under  a l l o w e d t o warm t o  3.02  (157) (0.550  g,  (1.25 g ,  m i x t u r e was c o o l e d  and t h e r e a c t i o n  y = 1 7 6 5 , 1 7 3 5 , 1 6 6 0 ( w ) , 1 6 2 0 (w)  (CC14):  hexenone  IH,  ( 1 . 2 2 g , 7.5 mmol) was  mixture o f potassium  ether) 2-carboethoxycyclopentanone  (neat):  'H NMR  (m, 4 H , C H 2 C H 2 ) ; -  Cyclopentanone  0.5 h t h e r e a c t i o n  1 0 % H C l ( 3 0 mL)  a f t e r work  B:  containing  (1 m i n ) t o a s t i r r e d  b a t h , aqueous  22°C  (72%).  1  ( t , 3 H , C H 2 C H 3 , J = 7 H z ) ; 1.61  11 m m o l , 3 5 % o i l d i s p e r s i o n , A l d r i c h )  ice  g  4.20 ( q , 2H, -0CH2CH3, J = 7 H z ) ; 12.12 ( s ,  Hydride  5 mmol, A l d r i c h )  nitrogen.  ( 1 5 5 ) 0.602  .  Potassium  added  144 -  10.5 mmol, A l d r i c h ) , ( 1 5 mL)  g , 5.5 mmol)  the reaction  t o w a r m t o 22°C  a t -78°C  i n ether  y = 1 7 4 0 , 1 6 7 0 , 1630 cm"  g 1  (58%).  ( 2 mL) was  was q u e n c h e d w i t h t o give  a f t e r work  (15% ether-petroleum ether)  (158) 0.530  under  nitrogen. added  aqueous up a s  6-carboethoxy-  -  •H NMR 2- 2.4  6 = 1.21  (CC14):  ( m , 4 H ) ; 3.21  ( b r s , 1H, =CH).  (7)  Lithium  Dicyclohexylamide (LiNCy2),  cyclohexenone  (157) (0.550  mmol) was a d d e d  d i c y c l o h e x y l amide mmol, A l d r i c h ) ,  flash  acid  (8)  After  mmol, A l d r i c h ) ,  aqueous as  and f l a s h  (neat):  'H NMR  y  (CC14):  11 m m o l ) )  solution  of  i n ether  after  (1.2 g,  lithium  ( 2 . 5 M, 1 0 . 5  ( 1 5 mL)  was q u e n c h e d w i t h  to give  i n ether  4 . 2 mL  workup  a t -78°C  aqueous  as above  10% and  6-carboethoxy-3-methyl-2-  B:  3-Methyl-2-  ( 1 0 mL)  containing solution  o f n_-butyll ithium  11 m m o l ) )  i n ether  the reaction  a l l o w e d t o warm  g  DEPC of  t o 22°C  (1.2 g,  lithium  ( 2 . 5 M, 1 0 . 5  ( 1 5 mL) a t  was q u e n c h e d to give  (15%ether-petroleum ether)  = 1 7 3 0 , 1 6 9 0 , 1615 cm"  with  after  work  up  5-carboethoxy-  (71%).  1  ( t , 3 H , C H 2 C H 3 , J = 7 H z ) ; 2.19 ( b r s , 3 H , = C C H 3 ) ;  5.80  ( b r s , I H , =CH).  (m/z, r e l a t i v e  DEPC  o f n_-butyll ithium  Procedure  from  (159) 0.590  ( m , 2 H , C H 2 ~ C = ) ; 3.31  HCOOEt.  t o 22°C  1 h a t -78°C  chromatography  6 = 1.27  containing  ( 5 m i n maximum) t o a s t i r r e d  ( 1 0 mL)  2.80  MS  4 . 2 mL  the reaction  g , 5 mmol)  After  acid  3-Methyl-2-  (64%).  (LiNCy2, prepared  3- m e t h y l - 2 - c y c l o p e n t e n o n e IR  from  d i c y c l o h e x y l a m i n e ( 2 . 1 5 mL,  10% c i t r i c  above  g  rapidly  nitrogen.  B:  ( 1 0 mL)  (15%ether-petroleum ether)  (142) (0.480  d i c y c l o h e x y l amide  under  i n ether  Dicyclohexylamide (LiNCy2),  mmol) was a d d e d  -78°C  prepared  1 h a t -78°C  ( 1 5 8 ) 0.580  cyclopentenone  1.90 ( s , 3 H , = C C H 3 ) ;  ( 5 m i n maximum) t o a s t i r r e d  a l l o w e d t o warm  chromatography  Lithium  7.5  rapidly  (LiNCy2>  ( 1 0 mL)  cyclohexenone  g , 5 mmol)  Procedure  d i c y l c o h e x y l a m i n e ( 2 . 1 5 mL,  under n i t r o g e n . citric  ( t , 3H, CH2CH3, J = 7 Hz):  (m, 1H, C0-CH-C0); 4.10 ( q , 2H, OCH2CH3, J = 7 H z ) ;  5.70  7.5  145 -  (m, I H , C0-CH-C0); 4.12 ( q , 2 H , 0 C H 2 C H 3 , J = 7 H z ) ;  % intensity):  169(28) M  +  +  1, 123(64)  - O E t , 96(100)  -  -  Exact (9)  Mass  calculated f o rCgH1203:  Lithium  Dicyclohexylamide  cyclopentenone (24.3  168.0783, observed:  ( L i N C y 2 ) , Procedure  ( 1 4 2 ) ( 9 . 6 0 g , 100 mmol) i n e t h e r  g , 150 mmol) was a d d e d  solution  146 -  of lithium  rapidly  ( 2 . 5 M, 2 0 0 m m o l , A l d r i c h ) ,  mmol) i n e t h e r  ( 2 0 0 mL)  to  was q u e n c h e d w i t h  22°C, e x t r a c t e d w i t h  dried the  tography  (15%ether-petroleum  cyclopentenone (10)  Lithium  en-2-one  ( 1 5 9 ) 7.56 g  di c y c l ohexyl amide  10.5 m m o l , A l d r i c h ) , -78°C 10%  acid  i n ether  prepared  After  ( 1 0 mL)  from  stirred  21 mL o f ( 4 1 . 8 mL, 210  A f t e r 1 h a t -78°C t h e  acid  ( 1 0 0 mL)  allowed  e x t r a c t s washed  reduced Torr)  pressure. followed  t o warm  with  brine,  Distillation by f l a s h  of  chroma-  5-carboethoxy-3-methyl-2-  ( L i N C y 2 ) , Procedure  4 . 2 mL  ( 2 . 1 5 mL,  1 h a t -78°C  allowed  ( 1 0 mL)  B:  A '^-Bicyclo[3.3.0]oct1  c o n t a i n i n g DEPC  to a stirred  from  dicyclohexylamine  under n i t r o g e n .  citric  gave  ( 5 m i n maximum)  (LiNCy2,  DEPC  (45%).  ( 1 3 8 ) ( 0 . 6 1 0 g , 5 mmol) rapidly  under  (40-60°C/0.1  ether)  Dicyclohexylamine  mmol) was a d d e d  20% c i t r i c  removed  and k e t o - e s t e r  containing  d ic y c l o h e x y l amine  e t h e r , t h e combined ether  (MgSO^) a n d t h e s o l v e n t  r e s i d u a l DEPC  ( 5 0 mL)  under n i t r o g e n .  aqueous  3-Methyl-2-  (LiNCy2), prepared  ii-butyl lithium  reaction  B:  ( 5 m i n maximum) t o a m e c h a n i c a l l y  dicyclohexylamide  a t -78°C  168.0787.  solution  of  ( 1 . 2 g , 7.5 lithium  o f rv-butyl 1ithium 11 m m o l ) )  ( 2 . 5 M,  i n ether  t h e r e a c t i o n was q u e n c h e d  t o w a r m t o 22°C  to give  after  work  ( 1 5 mL) a t with up a s  aqueous above  1 5 and  flash  chromatography (15% ether-petroleum  [3.3.0]octen-2-one IR  (neat):  'H NMR (br MS  ( 1 6 0 ) 0.760  (CC14):  6 = 1.28  (m/z, r e l a t i v e - HCOOEt.  A  '  -3-carboethoxybicyclo-  (78%).  y = 1 7 3 5 , 1 7 0 0 , 1640 cm"  1  ( t , 3H, C H 2 C H 3 , J = 7 H z ) ; 2.1-2.9  t , I H , J = 5 H z , C0-CH-C0);  120(86)  g  ether)  % intensity):  ( m , 8 H ) ; 3.61  4.18 ( q , 2H, 0 C H 2 C H 3 , J = 7 H z ) . 195(100) M  +  + 1, 194(39),  149(73) - OEt,  -  Exact  Mass  calculated  (A m a x  UV The  (log e)):  same p r o c e d u r e  147 -  f o rC^H^Cy 245  194.0939, observed:  (3.6).  employing  dimethyl  pyrocarbonate  5  A ' -3-carbomethoxybicyclo[3.3.0]octen-2-one 1  IR  (neat):  *H NMR  y = 1 7 4 5 , 1 7 1 0 , 1640 cm"  (CC14):  194.0931.  6 = 2.1-2.9  i n place  o f DEPC  afforded  (161) i n 46% y i e l d .  1  (m, 8 H ) ; 3.59 (m, I H , C0-CH-C0); 3.63 ( s ,  3H,  0CH3). (11)  Lithium  octen-2-one (9.7  Dicyclohexylamide (LiNCy2),  ( 1 3 8 ) ( 4 . 8 8 g , 40 mmol) i n e t h e r  g , 6 0 mmol) was a d d e d  solution  of lithium  ii-butyll ithium in was  ether  aqueous  ether,  20% c i t r i c  t h e combined  (MgSO^) a n d t h e s o l v e n t residual  under n i t r o g e n .  removed  DEPC a n d t h e k e t o - e s t e r  acid  1  from  d i c y c l ohexyl amine After  DEPC  to a mechanically  ( 1 8 mL, 88 mmol)) the reaction  ( 1 0 0 mL) a l l o w e d t o warm  reduced  (40-60°C/0.1  washed w i t h  pressure.  stirred  8 . 6 mL o f  1 h a t -78°C  ether extracts  under  5  A ' Bicyclo[3.3.0]-  ( 2 0 mL) c o n t a i n i n g  (-5 m i n m a x i m u m  ( 9 . 5 M, 8 0 m m o l , A l d r i c h ) ,  quenched with with  rapidly  B:  dicyclohexylamide (LiNCy2, prepared  ( 7 0 mL) a t -78°C  extracted  Procedure  t o 22°C,  brine,  Distillation  Torr) followed  by  dried o ft h e  flash  1 5 chromatography  ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) gave A ' - 3 - c a r b o e t h o x y b i c y c l o -  [3.3.0]octen-2-one  Alkylation Method  ( 1 6 0 ) 5.58 g  o f t h e 5-carboxy-2-cyclopentenone  derivatives  189 and 1 9 0 ,  A  5-Carboxy-2-cyclopentenone solution ether  (72%).  (prepared from  sodium,  ( 4 m L ) , a t 20°C, r e s u l t i n g  mixture  was l o w e r e d  added, followed stirring  into  ( 5 mmol) was added  5 m m o l , BDH a n d d r y e t h a n o l , i n an immediate  an o i l bath  by t h e a l k y l  continued f o r 2 h.  t o a sodium  halide  precipitate.  (75-80°C), dimethyl  ethoxide  30 mmol) i n The r e a c t i o n  sulfoxide  ( 1 0 mL)  ( 6 mmol o f 1 3 1 a o r 1 0 mmol o f 1 3 1 b ) , a n d  The s o l u t i o n  was t h e n  cooled  (0°), a c i d i f i e d  -  (10%  HC1)  and  with  brine,  extracted with  dried,  chromatography Yields data  10 a n d  Alkylation Method  ethyl  8 and  a l c o h o l 4 mL,  aqueous  layer  with  dried,  chromatography Yields Tables  8 to  (prepared  alcohol  (0°) a n d ethyl  i n Table  'H NMR  9 and  7,  1 2 , and  MS  derivatives  by  spectral  results  189  filtered,  Fisher),  ( 2 mL)  constant  from  was  acidified  potassium, a t 20°C.  added  (20°C).  alcohol  at a  After  and  in  190,  ( 1 % HC1).  concentrated  (ether-petroleum  and  After  the product  ( 2 mL)  0.01 The  rate  stirring  a c e t a t e , the combined e x t r a c t s  are reported  was  m m o l , BDH  purified  and  activated  diene  that  the  kept  f o r 16  extraction were  added  h, the of the  washed  with  by  ether).  i n Table  7,  ' H , NMR,  IR a n d  MS  data  are  reported  13.  -3-Carboethoxy-3-methylbicyc1o[3.3.0]octen-2-one Prepared  by a l k y l a t i o n  described  Method  IR:  ( C O ) , 1705  1740  'H NMR  MS  purified  (5 mmol) i n t - b u t y l  i n e t h e r , 2 mL,  of the reaction cooled  1.33  solution  (10 mmol) i n t - b u t y l  was  > 5  the product  washed  13.  reaction  A~*  i n Tables  of the 5-carboxy-2-cyclopentenone  temperature  in  and  combined e x t r a c t s  B  t-butyl  brine,  The  are reported  1 1 , IR d a t a  potassium-t-butoxide  144b  acetate.  ether).  reactions  5-Carboxy-2-cyclopentenone a  -  concentrated  (ether-petroleum  of various  i n Tables  Tables  filtered,  148  (CC14):  ppm  A  (R-j = O E t , R^  = Me)  by  the previously  (82%). ( C O ) , 1640  6 = 4.13  (3H, s , CH3),  (m/z, r e l a t i v e  o f 160  %  ppm  1.23  C=C)  cm  - 1  (2H, q, J = ppm  intensity):  7 H z , 0 C H 2 C H 3 ) , 2.45  (3H, t , J = 208(28),  7 Hz,  ppm  (8H, b s ) ,  CH3CH2)  1 8 0 ( 5 9 ) - CO,  135(92) -  COOEt,  to  - 149 -  Table Yields R  Starting material  Obtained  l = H  R4  i n Various  7 Alkylations  Product  Method  R  o f 189 a n d 190  2  R  3  %  Yield  190  COOEt  A  192  COOMe  COOMe  90  189  COOEt  A  191  COOMe  COOMe  62  189  H.  A  191  COOMe  COOMe  58  189  H  A  192  COOMe  COOMe  45  189  OEt  A  192  H  COOEt  76  190  OEt  A  192  COOMe  COOMe  65  190  OMe  A  192  H  COOEt  45  190  OEt  B  192  H  COOEt  86  189  OEt  B  191  H  COOEt  90  190  OEt  C  190  R  4  =  190  OEt  D  190  R  4  =  190  OEt  D  190  a:  See t e x t  (Chapter  3) f o r v a r i a t i o n  RA =  75-95  A  40-95  3  i n yield.  M e t h o d A:  alkylation  u s i n g 131  Method  B:  alkylation  u s i n g j_44  M e t h o d C:  alkylation  using  methyl  iodide  Method  alkylation  using  methyl  vinyl  D:  82  Me  (Mel) ketone  (CH =CHC0CH ) 2  3  o o.  -  150 -  Table 60  R  1)  'H NMR S p e c t r a l D a t a  R2  l  H  MHz  R  COOMe  3  COOMe  OEt  COOMe  COOMe  Related  t o 192  H-2'  3H-5'  H-4  5.22  1.80  (t, 2)  8  7)  5.18 (t,  7)  1  l  R2  4.04  9.50  3.72  3.72  (s)  (s)  (s)  (s)  (s)  1.78  3.93  1.27  3.70  3.70  (bs)  (s)  (s)  (s)  3.70  3.70  R  (t,  7)  R  3  4.14 (q. 3)  COOEt  COOMe  COOMe  5.04 (t,  7)  1.68  3.83  (bs)  (s)  7)  1.27 (t,  7)  (s)  4.15 (q, 4)  OEt  H  COOEt  5.06 (t,  7)  1.72  7)  1.14  (bs)  (t,  1.14  7)  4.06* (q, 5)  OMe  H  COOEt  5.01 (t,  7)  7)  1.73  3.66  (bs)  (s)  Parentheses Values  represent the chemical  indicate  them u l t i p l i c i t y  a r einterchangeable.  shift  4.11* (q,  (t,  7)  7)  4.04  (s)  i n Table  7)  1.18  3.68  Numbers  (t,  (q.  7)  (6 i n p p m ) .  and t h e coupling  constants  ( i n Hz).  -  151 -  Table  IR  R1  Spectral  R2  Data  9  Related  R3  t o192  bands  (cm  - 1  )  1)  H  COOMe  COOMe  1 7 4 5 ( s ) , 1 7 0 0 ( s ) , 1 6 3 0 (m)  2)  OEt  COOMe  COOMe  1 7 4 5 ( s ) , 1 7 0 0 ( s ) , 1 6 4 0 (m)  3)  COOEt  COOMe  COOMe  1 7 4 0 ( s ) , 1 7 0 0 ( s ) , 1 6 4 0 (m)  4)  OEt  H  COOEt  1 7 4 5 ( s ) , 1 7 0 5 ( s ) , 1 6 4 5 (m)  5)  OMe  H  COOEt  1 7 4 5 ( s ) , 1 7 0 0 ( s ) , 1 6 3 5 (m)  -  152 -  Table  10  MS R e s u l t s R e l a t e d  R  "2  "1 1)  COOMe  H  t o 192  m/z  3  COOMe  150(100) 2)  OEt  COOMe  COOMe  +  335(4) M  OEt  H  COOEt  OMe  H  COOEt  - C g H ^ O ^ , -186 (rearrangement  b  - CgH^Ogj  151, entry  1 :  +  335(11)  M  261(48)  - COOEt, 215(50)  Mass  observed: 1 6 2 , e n t r y 2:  Exact  Mass  observed: entry  3:  Exact  Mass  observed:  with with  calculated  + 1, 334(4), 288(7)  +  + 1, 288(6)  loss  - COOMe  o f side  loss  for C  334.1792.  EtOH, -  EtOH,  of side  - MeOH,  chain), chain)  06:  334.1410,  for C^H^O^:  378.1671 ,  for C ^ H ^ O ^  334.1694,  1 8  H  - MeOH, 2 6 1 ( 2 0 )  2 2  378.1725. calculated  -  - COOEt  334.1407. calculated  - COOEt,  b  (100)  321(3) M  - 140 (rearrangement  Exact  - COOMe, 3 0 5 ( 7 )  a  COOMe, 2 1 5 ( 3 3 )  a  intensity)  + 1 , 3 3 4 ( 5 ) , 3 0 5 ( 1 2 ) - CHO,  378(2), 316(3)  194 4)  %  a  194(112) 3)  (relative  -  180(100)  b  -  153 -  Table 60  R]  MHz  'H NMR S p e c t r a l  R2  R3  H-2  11 Data  3H-6  1  Related  H-2'  t o 191  3H-5'  H-4'  R]  R2  R3  4.06  3.67  3.62  ( q , 7)  (s)  (s)  9.60  3.68  3.68  (s)  (s)  (s)  1.08 (t, COOEt  COOMe  COOMe  OEt  H  COOMe  COOMe  COOEt  5.73  2.00  (bs)  ( b s ) ( t , 7)  (bs) (s)  5.68  2.12  1.68  (bs)  ( b s ) ( t , 7)  (bs) (s)  2.12  1.70  '5.72 (bs)  5.08  5.06  5.00  ( b s ) ( t , 7)  1.58  3.73  3.80  2.86  7)  , 1.22  b  ( b s ) ( b s ) ( t , 7) 4.02 (q,  Numbers  i n Table  Parentheses  indicate  tosylhydrazone values  represent  t h e chemical  them u l t i p l i c i t y  derivative  are interchangeable.  shift  1.26  b  ( t , 7) 4.05  7)  ( q , 7)  (6 i n p p m ) .  and t h e c o u p l i n g  constants  ( i n Hz).  154  Table IR S p e c t r a l  R  a  l  1)  COOEt  COOMe  2)  H  COOMe  3)  OEt  a  R  R2  tosylhydrazone  Data  -  12  Related  bands  3  COOME  2)  OEt  COOMe  COOMe  1740  ( s ) , 1705 ( s )  COOEt  1740  ( s ) , 1 7 1 0 ( s ) , 1 6 3 0 (m)  COOMe  COOMe  a  Exact  COOEt  OEt  tosylhydrazone  Mass  1 6 2 0 (m)  derivative  13  Related  t o 191  (relative  549(12)  M  %  intensity)  + 1, 531(8)  - C H 3 , 489(5) -  COOMe, 3 9 3 ( 3 0 )  - CgH6S02  352(3),  - OMe, 2 8 8 ( 1 0 )  321(6)  168(100)  3)  )  COOMe  m/z  COOEt  - 1  ( s ) , 1700 ( s ) , 1 6 2 5 ( m ) , 1600 (w)  MS R e s u l t s  a  (cm  1740  Table  l )  t o 191  309(3) M  - side  +  chain,  + 1, 262(5)  - CH3  CgH  ] 2  0  - 2MeOH, 4  - EtOH, 235(50)  - COOEt  derivative  f o r 188, entry  2:  no p a r e n t  i o n , b u t base  calculated:  168.0786,  peak  f o r CgH^203,  observed:  168.0811.  -  134(100) Exact  A  1 , 5  - HCOOEt  Mass  calculated  f o rC  1 2  H  l g  03:  208.1094, observed:  water  1_60 ( 3 5 0 m g ,  (1 m L )  h.  1.68 mmol) was a d d e d  and methanol  I t was t h e n  (1 m L ) .  cooled  This  to a solution  reaction  (0°C) a n d e x t r a c t e d  mixture  extracts  dried,  filtered  [3.3.0]octen-2-one, (heat):  'H NMR MS  (CC14):  Mass  1 6 0 mg  6 2 . 3 2 ppm  Tosylhydrazone  20° f o r 4 h. extracts  dried,  derivative,  l' g  IR  3200  (neat):  'H NMR  bs, MS  ppm  ' -3-methylbicyclo-  ( 3 H , d , J = 7 H z , CH3CH)  121(100) - CH3, 93(69) - CH3  -  was  then  t o 151  ( 6 4 0 mg, 2 mmol) and s t i r r e d  extracted  and c o n c e n t r a t e d  dissolved i n  with  to afford  6 = 9 . 0 ppm  the hydrazone  1 6 4 0 ( m ) , 1 6 0 5 (m)  ( I H , b s , N H ) , 7 . 8 0 ppm  cm"  1  (2H, d, J = 8 Hz,  ( 2 H , d , J = 8 H z , a r o m a t i c ) , 5 . 1 0 ppm  ( I H , s , C H ( C 0 0 M e ) 2 ) , 3 . 7 5 ppm  (m/z, r e l a t i v e chain,  at  e t h e r , t h e combined  ( I H , t , J = 7 Hz,  ( 6 H , s , C O O M e ) , 1 . 7 0 ppm ( 3 H ,  CH3C=C)  side  CO.  136.0868.  ( 3 6 0 mg, 2 mmol, A l d r i c h )  ( N H ) , 1750 ( s ) ,1700 ( s ) ,  7 . 3 0 ppm  H C = C ) , 3 . 9 2 ppm  5  (96%).  (CDC13):  aromatic),  solution  filtered,  A  136.0885, observed:  ( 5 mL, 7:3) was a d d e d This  was r e f l u x e d f o r  o f 151  p-Toluenesulfonylhydrazide methanol:water  1 mL),  1  136(86),  f o rCgH120:  derivative  to afford  ( 9 H , b s ) , 1.11  % intensity):  calculated  (cone.  (70%).  1700 ( C O ) , 1635 (C=C) cm"  (m/z, r e l a t i v e  Exact  and c o n c e n t r a t e d  o f HC1  w i t h e t h e r , t h e combined 1  IR  208.1091.  -3-Meth,ylbicyc1o[3.3.0]octen-2-one Ketone  24  155 -  % intensity):  CQH,,0«,  91(100).  503(8) M  +  + 1 , 4 4 3 ( 6 ) - COOMe, 3 1 8 ( 1 0 ) -  -  Exact  Mass  Alcohols  calculated  -  f o r C25H3()07N2S:  502.1765, observed:  borohydride  m e t h a n o l , a t 20°C.  (1 m o l e  After  - e q , BDH)  stirring  was  f o r 16  and  extracted with  ethyl acetate.  filtered  and  concentrated.  In t h e case  cyanoborohydride methanol  or  ( 1 e q , BDH)  i n aqueous  different  alcohol  petroleum  ether)  A  1 , 5  used  isomers  (0.1  were  HC1)  40  IR  (neat):  'H  NMR  1.32  3500  (CC14):  separated  ppm  (m/z, r e l a t i v e  123(10) Exact  -  %  Mass  Aldrich)  dried,  145, sodium  On  (2 e q ) , i n  one  occasion  the  chromatography (ethylacetate Later,  the  -  mixture  ( C O ) , 1710  ppm  (146)  alcohols  ( 3 H , m,  (70%).  ( C O ) , 1635  (C=C)  cm"  0 C H 2 , C H ( 0 H ) ) , 3.30  1  ppm  ( 2 H , m,  CH2),  CH3CH2)  intensity):  225(7) M  calculated  of  for  C^ieV  +  +  1, 2 2 4 ( 5 ) ,  151(25) -  224.1044, observed:  COOEt,  to alcohol and  146  ( 5 0 mg,  trifluoroacetic  dichloromethane  224.1050.  146  1,5-diazabicyclo[5.4.0]undec-5-ene added  acidified  extracts  ammonium c h l o r i d e  by  in  COCOOEt  Trif1uoroacetate  was  was  (1 e q )  and 7 0 % ) .  ( O H ) , 1750  (3H, t , J = 7 Hz,  combined  the dehydrations.  f o r previous  6 = 4.20  t o ketone  for hydrolysis.  -3-ethoxaly1bicyclo[3.3.0]octen-2-o1 as  The  o f ketone  u s e d , and  attempting  between  Same p r o c e d u r e  MS  acid  before  (yields  was  added  h, the s o l u t i o n  HC1)  was  502.1745.  146:  Sodium  (5%  156  (5 mL),  0.25  anhydride  stirred  ( 0 . 0 4 mL,  mmol),  mmol, 96%,  N,N-dimethyl  ( 0 . 0 4 mL,  a t -78°C.  0.27  The  0.27  Aldrich)  aminopyridine  mmol, A l d r i c h )  reaction  was  (2  in  warmed t o 0°C,  -  157 -  Table 60  R  'H NMR S p e c t r a l D a t a  R2  l  COOEt  MHz  14  R  COOMe  3  COOMe  Related  t o1 9 3  a  3H-5'  H-4'  4.98  1.70  3.88  (m)  (bs)  (s)  H-2'  H-l  4.37 (s)  R  l  "2,3  1.30  3.62  (t,  7)  (s)  4.20 (m) H  b  COOMe  COOMe  4.50 (m)  OEt  COOMe  COOMe  5.00 (t,  7)  1.70  3.90  3.77  (bs)  (s)  (s)  4.70  5.36  1.76  3.98  (m)  (m)  (bs)  (s)  1.28 (t,  7)  3.70 (s)  4.12  (q. 7 ) OEt  C  COOMe  COOMe  5.35 (t,  7)  1.75  3.92  (bs)  (s)  1.17 (t,  7)  3.70 (s)  4.07  (q, 7 ) OMe  H  COOEt  4.70  5.18  1 .68  2.87  3.62  (m)  (m)  (bs)  (bs)  3.64 (s:s)  1 .25 (t,  7)  4.08  (q. 7 ) COOEt  193 r i Numbers  Spectral  1.70  2.90  (m)  (m)  (bs)  (bs)  represent t h e chemical  indicate  data  Tosylhydrazone Tosylate  5.20  1.27 (t,  7)  1.27 (t,  7)  4.08  4.08  (q. 7 )  (q. 7 )  2  i n Table  Parentheses  4.70  them u l t i p l i c i t y  i n Tables  (6 i n p p m ) .  and t h e coupling  1 4 , 1 5 , 16 f o r m a j o r  derivative.  derivative.  shift  isomer.  constants  ( i n Hz)  -  158 -  Table IR  R  S p e c t r a l Data  R2  l  1)  COOEt  2)  H  R  Related  -1  3500  (w),  1750 ( s ) , 1700 ( s ) , 1640  (m)  3500  (m),  1750 ( s ) , 1725 ( s ) , 1670  (m),  1625  (m)  COOMe  COOMe  3500  (m), 1 7 6 0 - 1 7 2 5  ( s ) , 1630 (w)  COOMe  COOMe  3500  (m),  1750-1720  ( s ) , 1 6 3 0 (m)  OMe  H  COOEt  3500  (m), 1 7 5 0 - 1 7 2 5  ( s ) , 1 6 4 0 (m)  OEt  H  COOEt  3500  (m),  OEt  4)  0Et  5) 6)  C  Table  "l  *2  OEt  COOMe  m/z  c  COOMe  COOMe  (relative  sidechain,  COOEt  OMe  533(12) M  322(3), 180(100)  4)  COOEt  OEt  264(14) C  190,  e n t r y 3:  observed:  Exact  322.1636.  Mass  intensity)  +  CgH-j^O^  + 1 , 4 7 4 ( 5 ) - HCOOMe, 3 6 2 ( 6 0 ) -  H O T s , 3 1 6 ( 8 0 ) - HOTs 3)  %  3 8 0 ( 2 ) , 362(2) - H 2 0 , 318(10) - 20Me, 177(32) -  OEt  (s)  t o 193  3 COOMe  1730  16  MS R e s u l t s R e l a t e d  2)  (cm )  bands  b  3)  1)  t o 193  3  COOMe  COOMe  15  - EtOH  2 8 8 ( 8 ) - HOMe, 2 6 1 ( 1 9 ) - COOMe, - sidechain,  CgH-|202  - COOEt, 195(32) -  sidechain,  H  8 13°2  calculated  f o r C 1 R H ? f i O,-:  322.1695,  -  in  ~  2  and  h,  and  extracted with  filtered  and  IR  (neat):  'H  NMR  J  =  A  1800  Hz,  =  7  6  =  Hz,  added.  5.40  The  afford  ppm  the  (CO),  ppm  (2H,  product,  J =  bs,  aqueous  combined  1700  ( I H , d,  The  (CO), 3  Hz,  CH2),  layer  extracts 78  mg  1630  was  were  ppm  dried,  (98%). (C=C)  cm"  C H C 0 C F 3 ) , 4.12  2.35  separated  (6H,  1  ppm  '  b s ) , 1.20  q,  ppm  CH3CH2).  -7-(3-methyl-4,4-dicarbomethoxy-2-butenyl)-10-oxatricyclo 1 , 5  .0  7 , 1 1  Lactone alkylation lactone The  149  of  149  ]undecen-8,9-dione was  145.  also  separated The  IR  separated  NMR  (neat): 6  (CC14):  CHO),  3.70  no  could  MS  1750  ppm  =  (6H,  be  5.20  solution  of  methanol  ( 2 mL)  It  was  to  afford  (100  1700  ppm  case  on  mg,  147  was  148  upon  ppm  the  to  be  ~  reduction of to  (C=C)  be cm"  ~  1:4.  derivative  HCl  and  purified  f o r the  The  ketone  147.  4:1.  1  C H ( C 0 0 M e ) 2 ) , 3.83  (10H,  b s ) , 1.68  ppm  ppm  (3H,  mmol)  of  (IH,  bs,  s,  CH3C=C)  147  i n methanol  drop). by  A  mg,  0.27  precipitate  chromatography  derivative  (1 m L )  147,  90  mg  was  (25%  was  added  DNPH d e r i v a t i v e  of  147  a in  instantaneously petroleum  ( 6 4 % ) ; and  and  to  mmol, A l d r i c h )  of  ether  149,  (30%). 146-148°C  after  149.  and  hydrazone  DNPH d e r i v a t i v e  7 Hz,  2 , 4 - d i n i t r o p h e n y l h y d r a z i n e (55  filtered  the found  found  1640  (IH, t , J =  0.25  (1  as  ratio  was  (CO),  C H 3 0 C 0 ) , 2.30  obtained  147  ketone  alcohol  in this  2,4-Dinitrophenylhydrazone Ketone  from  from  (CO),  s,  (149)  lactone:ketone  alcohol:lactone ratio  149,  mp  (2H,  5  [6.3.0  'H  to  ( C D C F 3 ) , 1750  C H 2 C H 3 ) , 3.30  t , J  was  -  dichloromethane.  concentrated  (CC14):  7  (3H,  1  ammonium c h l o r i d e  159  158-160°C  for  149  40  formed. mg  ether)  -  DNPH d e r i v a t i v e 1620  o f 1 4 7 , IR ( N u j o l ) :  ( m ) , 1 5 9 5 (m) c m "  'H NMR  (CDC13):  160 -  1760 ( m ) , 1740 ( s ) ,1700 ( s ) ,1645 ( m ) ,  1  6 = 9 . 0 0 ppm  ( I H , d , J = 2 H z ) , 8 . 4 0 ppm  Hz),  8 . 0 0 ppm  ( H , d , J = 1 0 H z ) , 5 . 4 0 ppm  (2H,  q , J = 7 H z , 0 C H 2 C H 3 ) , 4 . 0 2 ppm  (each, 3H, s , CH3C00),  1 . 8 3 ppm  ( I H , d d , J = 2 , . 10  ( I H , t , J = 7 H z , H C = C ) , 4 . 2 7 ppm  ( I H , s , C H ( C 0 0 M e ) 2 ) , 3 . 7 3 , 3 . 7 0 ppm  ( 3 H , b s , C H 3 C = C ) , 1.27 ppm  (3H,t ,J = 7 Hz,  CH3CH2) no  MS  could  be o b t a i n e d  DNPH d e r i v a t i v e 1590  (m) c m "  'H NMR 8.23 t,  ppm  n o MS  1755 ( m ) , 1740 ( m ) , 1600  6 = 1 1 . 2 5 ppm  ( I H , b s , N H ) , 8 . 9 5 ppm  ( I H , d d , J = 2 , 1 0 H z ) , 7 . 9 0 ppm  ( I H ,d , J = 2 H z ) ,  ( I H , d , J = 1 0 H z ) , 5 . 4 8 ppm ( I H ,  ( I H , s , C H ( C 0 0 M e ) 2 ) , 3 . 7 6 ppm  could  Ketone  be o b t a i n e d  stirred  afford  derivative  o f "monocyclic"  147 ( 1 4 2 as s t a r t i n g m a t e r i a l )  142 ( 9 0 mg, 0.24 mmol) i n m e t h a n o l  a t 15°C f o r 6 h .  After  (1 mL) w a s a d d e d  t h e "monocyclic" (18%).  hydrazone derivative  2 0 mg  1700  ( s ) , 1630 ( m ) , 1600 (w) cm' (CC14):  Tosylhydrazone  6 = 7 . 7 4 ppm  ( I H , s ) , 5 . 7 3 ppm  to a  solution  i n methanol  ( 2 mL)  concentration of the solution, the  was p u r i f i e d by c h r o m a t o g r a p h y ( 2 0 % p e t r o l e u m  149,  'H NMR  CH30C0),  (FAB o r E I ) .  p - t o l u e n e s u l f o n y l h y d r a z i d e ( 4 5 mg, 0.24 mmol, A l d r i c h )  product  (6H,s ,  ( 3 H , b s , CH3C=C)  Tosylhydrazone  and  ( s ) ,  1  J = 7 H z , H C = C ) , 4 . 0 8 ppm  1.85  of  o f J 4 9 , IR ( N u j o l ) :  (CDC13):  ppm  (FAB o r E I )  ether  1 4 7 , 1 0 0 mg  o f 1 4 7 , IR ( C H C 1 3 ) :  - ether) to  (79%) and  1740  ( s ) ,  1  ( 2 H , d , J = 8 H z ) , 7 . 2 2 ppm  7.02  ppm  ( I H , b s , H C = C ) , 5 . 0 8 ppm  (2H,  q , J = 7 H z , 0 C H 2 C H 3 ) , 3 . 7 3 ppm  ( 2 H ,d , J = 8 H z ) ,  ( I H , m,  H C = C ) , 4 . 0 6 ppm  ( I H , s , C H ( C 0 0 M e ) 2 ) , 3 . 6 2 ppm  (6H,s ,  -  COOMe), 2.00,  1.58  ppm  ( e a c h , 3H,  161  -  b s , C H 3 C = C ) , 1.08  ppm  (3H, t , J  =  7  Hz,  CH3CH2) MS  (m/z,  relative  Tosylhydrazone 'H  NMR  of  (CC14):  %  intensity):  1491R  6 =  (CHC13):  7.79  7.10  ppm  (IH,  s , C H ( C 0 0 M e ) 2 ) , 3.70  MS  ( I H , s ) , 5.82  (m/z,  449,  relative  389(8)  %  549(3)  ppm  ppm  M  +  +  1750-1680  (2H, d,  J =  8  (6H, s ,  intensity):  - HCOOMe f r o m  449,  A '^-3-Hydroxymethyl-3-(3-methyl-4,4-di 1  5.18  ppm  - COCOOEt, 91(100)-. (m),  ppm  1605  (m)  (2H, d, J  ( I H , m,  HOC),  1  cm" =  8  Hz),  3.89  ppm  COOMe)  449(12) 293(28)  ( s ) , 1630 H z ) , 7.24  (IH, bs, HOC), ppm  1, 447(2)  M  +  - 55, 417(5)  - C7HgS02  from  - HOMe  449,  from  91(100).  carbomethoxy-2-butenyl)  bicyclo[3.3.0]octen-2-ol This  alcohol  was  in  methanol  as  IR  (neat):  3500-3400  'H  NMR  prepared  described  (CDC13):  C H ( C 0 0 M e ) 2 ) , 3.68 (3H, b s ,  CH3OC)  MS  (m/z,  relative  C9H  1 3  ppm  ppm  %  1735  (CO)  ( 2 H , m,  cm"  of  151,  using  sodium  borohydride  1  CH-(OH) and  ( 6 H , s , C H 3 0 C 0 ) , 3.35  intensity):  C H O C ) , 4.92  ppm  ppm  (IH, s,  ( 2 H , b s , C H 2 0 H ) , 1.70  3 3 8 ( 5 ) , 302(12)  - 2H20, 185(20)  side  ppm  chain,  04.  3-Carboethoxy-3-(3-methyl-4,4-di bicyc1o[3.3.0]octadiene Alcohol a)  reduction  previously.  (OH),  5.22  by  1_63  Tosylation Alcohol  was  (164)  or  dehydrated  carbomethoxy-2-buteny1) (194) using  several  methods,  method  163  p-toluenesulfonyl-  ( 7 6 0 mg, chloride  2 m m o l ) was (380 mg,  added  t o THF  ( 2 mL)  2 mmol, A l d r i c h ) ,  containing  pyridine  (0.4  mL,  -  162 -  5 mmol) and N , N - d i m e t h y l a m i n o p y r i d i n e  (10 mg, A l d r i c h ) .  stirred  (10% HCl) and e x t r a c t e d with  The  a t ~ 20°C f o r 1 6 h , a c i d i f i e d  combined  e x t r a c t s were  dried,  filtered,  purified  by chromatography  (ether  - petroleum  tosylate  derivative,  diene b)  isomer),  4 0 mg  Hydrochloric Alcohol  solution This  sodium The  which  hydrogen  extracts dried, (10% ether  isomer),  (60%).  chloride  f o r 2 h.  and'the  aqueous  filtered,  - petroleum  ether)  163 ( 1 9 0 mg, 0.5 mmol) i n b e n z e n e  preparation  o f Burgess  with by  isomer),  (1 m L )  (10% ether  Aldrich)  and p u r i f i e d product  a  cold  chloroform. by  164 ( o r d i e n e  salt  (Et^l^SO^'NCOOMe,  and P e n t o n was  1 4  heated  0  ^ ,  150 mg, 0.55  t o 50°C f o r 1 h .  The aqueous  l a y e r was  filtered,  concentrated  - petroleum  t o methyl  ether), to afford  extracted and  product  purified 164 ( o r  5 0 mg ( 3 0 % )  sulfur  solution  to water.  extracts dried,  Methanesulfonylchloride Gaseous  into  (1 mL) w a s a d d e d  inner  The r e a c t i o n m i x t u r e  and added  e t h e r , t h e combined  diene d)  on t h e p r o c e d u r e (1 m L ) .  chromatography  f o r 10 m i n .  method  hydroxide  cooled  bubbled poured  to afford  Alcohol  was t h e n  ( 5 mL)  layer extracted with  concentrated  (carboxysulfamoyl)triethylammonium  It  164 ( o r  to a chloroform  I t was t h e n  reagent  mmol) i n b e n z e n e  product  ( F i s h e r ) had been  Burgess  based  and t h e products-  ether), to afford the  (68%) and a dehydrated  a t 20°C  solution,  chromatography  c)  ether.  method  was s t i r r e d  5 5 mg  was  (5%).  acid  bicarbonate  combined  concentrated  163 ( 1 0 0 mg, 0.26 mmol) was a d d e d  into  mixture  6 8 5 mg  The s o l u t i o n  dioxide  method ( F i s h e r ) was b u b b l e d  containing methanesulfonyl  f o r 10 m i n , a n d a d d e d  to alcohol  into  chloride  a  dichloromethane  ( 0 . 4 8 mL, 6 mmol,  1_63 ( 2 0 0 m g , 0 . 6 m m o l ) , p y r i d i n e  -  (0.56 in  mL,  7.2  and by  water  combined  extracts  chromatography  diene  A  solution  in  a  to  180-190°C, by  20  mg  IR  (neat):  'H  NMR  (3H,  were  164,  dried,  ether  then  stirred extracted  filtered,  - petroleum  This  with  ( 8 0 mg,  procedure  at  20°C  with  dissolved  for 1  ether) was  also  h,  dichloromethane,  c o n c e n t r a t e d and to afford used  0.24  mmol) i n t o l u e n e  purified  1_64  (or  omitting  (2.0 mL),  t e t r a m e t h y l e t h y l e n e d i a m i n e (80 mg, h.  The  chromatography  1730-1725  t , J  (m/z,  6  =  7  solution  (12% ether  the  was  then  0.69  ether),  heated  mmol,  c o n c e n t r a t e d and  - petroleum  was  Aldrich)  the  product  to afford  164,  1  ( 2 H , m,  (3H,  THF M,  ether  ( 5 0 mL)  was  Aldrich)  signals), ppm  (3H,  4.11 bs,  ppm  (2H,  CH3C=C),  q, 1.26  CH3CH2)  C  H 8  - HOEt, 231(42)  -  COOEt,  13°2*  for C 215  304(9), 258(7)  l g  H  2 4  (3.4),  04:  304.1668, observed:  250  (3.2)  5-ch1oro-3-methyl-2-pentenoate Ethynyl  olefinic  s , C H 3 0 C 0 ) , 1.68  intensity):  calculated ( l o g e)):  cm"  ppm  ppm  Hz, %  (CO)  5.30  - sidechain,  max  Ethyl  =  relative  Mass  (A  2.99  of  0 C H 2 C H 3 ) , 3.62  Exact  in  164  f o r 96  (CC14):  Hz,  a)  I t was  was  Aldrich)  (25%).  177(100)  UV  added.  (70%).  of  sealed tube  purified  MS  mg  solution  ( 2 mg,  dioxide.  Decarboxylation  ppm  The  (8 t o 30%  i s o m e r ) , 130  sulfur  7  (3 mL).  t o 0°C a n d  the  -  mmol), N,N-dimethylaminopyridine  dichloromethane  cooled  163  (144a)  (18.5  g,  added  to methylmagnesium  dissolved  0.26  i n THF  304.1672.  mmol, F a r c h a n , f r e s h l y  (250  mL)  chloride at  22°C.  distilled,  ( 8 . 3 mL, The  0.24  resulting  bp  49-50°C)  mol, mixture  -  164 -  Table H ' NMR S p e c t r a l  Dehydration  R]  R2  Data  Related  R3  t o 194 ( i s o m e r s )  3 olefins  OEt  COOMe  COOMe  1: 5 . 7 7 (bs) 4:: 5 . 3 6  3H-5'  H-4'  R]  2.02  4.27  1.24  (s)  (s)  OEt  COOMe  COOMe  (t,  1.75  R2>  R3  7)  3.70 (s)  4.46  (q.  (bs)  On) (b)  o r 164  ratio:6  Method (a)  17  2:: 6 . 2 2  1.68  3.85  (bs)  (bs)  (s)  7)  1.22 (t,  7)  3.66 (s)  4.02  4:: 5 . 7 7  (q.  (bs)  7)  11 :5.21 : (m) (b)  OEt  H  COOEt  1:: 6 . 2 0  1.64  3.50  (s)  (bs)  (s)  2:: 5 . 7 2  1.69  (bs)  (bs)  1 .18 (t,  7)  4.03*  (q.  7)  1.18 (t,  7)  3.98*  (q.  7)  4:: 5 . 1 8 (m) (c)  OEt  COOMe  COOMe  1 ::5 . 6 9  1.67  3.68  (bs)  (bs)  (s)  1.18 (t,  8 :5.18  OEt  H  COOEt  (s)  4.06  (q.  (m) (d)  7)  3.65  1 ::5 . 6 2  1.64  (bs)  (bs)  -  7)  1.20 (t.  3 :5.22  7)  4.02  (q.  (m)  7)  1.20 (t,  7)  4.02  (q.  7)  194 Numbers  i n Table  Parentheses values  represent  indicate  t h e chemical  them u l t i p l i c i t y  are interchangeable  shift  (6  i n ppm)  and t h e coupling  constants  ( i n Hz)  -  165 -  Table IR  R1  R2  Spectral Data  18 R e l a t e d t o 194  R3  bands  OEt  COOMe  COOMe  1755-1730  OEt  H  COOEt  1 7 2 5 (COO)  Table  R1 OEt  R2 COOMe  t o 194  R3 COOMe  m/z  OEt  H  COOEt  (relative  362(3), 289(8) chain,  2)  (COO)  19  MS R e s u l t s R e l a t e d  1)  1  (cm" )  intensity)  - COOEt, 177(100)  -  side  Cg^-jO^  318(6), 244(13) side  %  chain,  CgH-j  - HCOOEt, 177(100) -  -  was  stirred  was  added over  reaction  5 min and s t i r r i n g  ceased.  IR  extracts  20 g  dried,  (5%ether  33-3500  (m/z, r e l a t i v e  b)  Mass  added  addition  % intensity):  dropwise  t o 5% s u l f u r i c  added  acid  the reaction  to the solution,  ether extracts  were  orange  144a,  bp  65-68°C/0.5  IR  (neat):  15 g  ( 7 5 % )w h i c h  (3H,s,  - OEt - H 2 0 , 85(100) 176.0604.  - ethanol  (20 mL), kept  sodium  purified  a t 0°C.  After  f o r 20 h a t 0 t o 10°C.  extracted  with  ether.  bicarbonate, dried,  by c h r o m a t o g r a p h y  c o u l d be f u r t h e r  ( 2 0 mL)  purified  by  (as above)  distillation.  Torr  1710 (CO),  (CC14):  ( 2 H , m,  ( 2 0 g , 0.11 m o l ) i n e t h a n o l  washed w i t h  afford  1655 ( O C ) cm  6 = 5 . 7 0 ppm  0 C H 2 C H 3 ) , 3 . 6 3 ppm  - 1  ( I H , b s , H O C ) , 4 . 1 0 ppm  (2H,t , J = 7 Hz, CHgCl),  = 7 H z , 2 : E , C H g - O ) , 2 . 1 8 a n d 1 . 9 9 ppm  (2H,q , J = 7 Hz,  3 . 0 2 a n d 2 . 6 7 ppm  ( 2 H , t : t , 1:1,  (3H, s : s , 1:1, C H 3 O C ) ,  1 . 2 7 ppm  t , J = 7 Hz, CH3CH2)  (m/z, r e l a t i v e  131(100)  The  purified  ( 2 H , m , C H 2 C ( 0 H ) ) , 1 . 4 8 ppm  and t h e product  to  MS  with ether.  1,  m i x t u r e was s t i r r e d  c o n c e n t r a t e d and t h e product  (3H,  gas  The  168 as an  176.06005, observed:  filtered,  J  extracted  to give  176(6), 113(45)  f o rCgH^OgCl:  was c o m p l e t e ,  combined  'H NMR  Celite.  The  ( 3 H , t , J = 7 Hz, CH3CH2)  calculated  Water was t h e n The  through  ( 2 H , q , J = 7 H z , 0 C H 2 C H 3 ) , 3 . 6 0 ppm  4-chloro-2-ethynyl ether 2-butanol  was  ether),  (C=C) c m "  ( I H , s , O H ) , 1 . 9 6 ppm  C H 3 C ( 0 H ) ) , 1 . 3 8 ppm  Exact  dropwise, until  c o n c e n t r a t e d and t h e product  - petroleum  ( O H ) , 2250  6 = 4 . 0 8 ppm  (CC14):  C H 2 C 1 ) , 3 . 0 4 ppm  MS  filtered,  layer  20 h a t 22°C.  (88%).  (neat):  'H NMR  continued f o ra f u r t h e r  T h e n , t h e m i x t u r e was f i l t e r e d  chromatography  o i l ,  ( 1 4 g , 0 . 1 3 m o l ) i n THF ( 1 0 mL)  l a y e r was s e p a r a t e d a n d t h e aqueous  combined by  f o r0.5 h , 4 - c h l o r o b u t a n o n e  m i x t u r e w a s c o o l e d t o 0°C a n d w a t e r w a s a d d e d  evolution organic  166 -  % intensity):  - OEt, 113(91)  - OEt -  177(17) M HQ.  +  + 1, 1 7 6 ( 1 7 ) ,  141(83)  - C l ,  -  167 -  4- C h l o r o - 2 - m e t h y l - l , 1 - d i c a r b o m e t h o x y - l - b u t e n e 1 3 1 b Titanium slowly  added  stirrer,  t e t r a c h l o r i d e (11 mL, 0.10 m o l , (45 min) t o a 1 L three  condenser and dropping  precipitate  was p r e s e n t .  dimethyl  malonate  followed  by p y r i d i n e  resulting mixture layer  dark  filtered, pure 5.5 IR  g  with  a  ethyl  f o rf u r t h e r  water,  mechanical  was c o m p l e t e , a  added  dropwise  The combined  to afford  1 4 4 b , 6.6 g  I t could  also  f o r 24 h.  layer  acetate.  use.  yellow  (5.3g , 0.05 mol) and  a t 20°C  the organic  were  over  separated  extracts (60%).  be d i s t i l l e d ,  30 min.  The  The  reaction  and t h e aqueous  were  This  15 m i n ,  dried,  p r o d u c t was  bp 9 6 - 9 8 ° C / 0 . 3  Torr,  (50%).  (neat):  'H NMR  1725 (CO),  (CC14):  Exact  1  ( 6 H , s , C O O M e ) , 3 . 5 8 ppm  ( 2 H , t , J = 7 H z , C H 2 C = ) , 1 . 9 8 ppm  (m/z,r e l a t i v e  121(12)  1640 (C=C) cm"  6 = 3 . 6 3 ppm  C H 2 C 1 ) , 2 . 7 6 ppm MS  addition  Eastman) were  s o l u t i o n was s t i r r e d  and concentrated  enough  After  equipped  Then, 4-chlorobutanone  t o cold  with  flask  ( 1 6 g , E a s t m a n , 0 . 2 m o l ) i n THF ( 4 0 mL) o v e r  orange  extracted  funnel.  (6.6 g , 0.05 mol,  was a d d e d  neck  BDH) a n d C C 1 4 ( 2 5 mL)  % intensity):  221 ( 2 ) , 1 8 8 ( 5 )  ( 2 H ,t , J = 7 H z ,  ( 3 H ,s , CH3C=)  - MeOH, 1 5 3 ( 2 8 )  - MeOH  - HC1,  - 2MeOH - H C 1 .  Mass  calculated  f o rC g H - ^ C l  +  (M -MeOH):  188.0237, observed:  188.0223.  5- C a r b o e t h o x y - 5 ( 3 - o x o b u t y l e t h y l e n e t h i o k e t a l ) - 3 - m e t h y l - 2 - c y c l o p e n t e n o n e Ethanedithiol (2  drops, Aldrich)  in  acetic  cold  acid  ( 5 0 mg, 0.55 mmol, A l d r i c h ) were  added  extracts  were washed w i t h  purified  by chromatography  120  mg  (70%).  t o V70 ( 1 0 0 mg, A l d r i c h ,  ( 2 mL) a t 20°C.  water and t h e aqueous  and boron  layer sodium (12%  0.42 mmol)  The s o l u t i o n was s t i r r e d extracted  with  bicarbonate, ethyl  ethyl  trifluoride  dissolved  f o r1 h, poured  acetate.  dried, filtered,  acetate-hexane)  etherate  to afford  into  The combined concentrated and the thioketal,  -  IR  (neat):  'H NMR  1750 ( s ) , 1705 ( s ) , 6 = 5 . 7 5 ppm  (CC14):  0 C H _ 2 C H 3 ) , 3 . 2 2 ppm  (m/z, r e l a t i v e  119(100)  - C6H  1 0  1 6 3 0 (C=C)  ppm  cm'  1  ( I H , b s , C H = C ) , 4 . 1 2 ppm  ( 4 H , s , C H 2 S ) , 2 . 1 8 ppm  C H 3 - C ( 5 C H 2 ) 2 ) , 1.22 MS  168 -  (2H, q, J = 7  Hz,  ( 3 H , b s , C H 3 C = C ) , 1 . 7 0 ppm  (3H, s,  ( 3 H , t , J = 7 H z , CH_3CH2)  % intensity):  S2, side  314(2),  chain, -  168(28) - C g H 1 0 S 2 , side  chain,  CO.  5-Carboethoxy-5(3-oxobutylethylenethioketal)-3-methyl-2-cyclopentenol Sodium product BDH)  dissolved  i n methanol  I t was  then  alcohol,  1 1 0 mg  (neat):  'H NMR  3500-3400  MS  added  was  stirred  ( 5 % HC1) and e x t r a c t e d w i t h dried,  filtered,  t o t h e above  ( C e C l 3 . 7 H 2 0 , 1.3 g , 4 . 7 7  The s o l u t i o n  acetate-hexane)  to afford  the  mmol,  a t 20°C f o r  ethyl  concentrated  ( O H ) , 1730 ( C O ) , 1625 (C=C)  6 = 5 . 8 2 ppm  (CC14):  chloride  was  acetate.  and p u r i f i e d  by  corresponding  (76%).  C H ( O H ) ) , 4 . 1 3 ppm ppm  (25 mL).  washed,  (25% ethyl  4 . 7 7 m m o l , BDH)  and cerous  acidified  combined e x t r a c t s  chromatography  IR  ( 1 8 0 mg,  ( 1 . 5 g , 4.77 mmol)  30 m i n . The  borohydride  1  ( I H , b s , H C = C ) , 5 . 3 8 , 4 . 7 8 ppm  ( 2 H , q , J = 7 H z , 0 C H 2 C H 3 ) , 3 . 2 7 ppm  ( 3 H , b s , C H 3 C = C ) , 1.73 (m/z, r e l a t i v e  cm"  (3H, s , CH3C0),  % intensity):  316(3),  1.27  298(8),  ppm  ( I H ,bs:bs,  (4H, s, CH2S),  1:1,  2.20  ( 3 H , t , J = 7 Hz, CH3CH2)  168(25),  119(100).  5-Hydroxymethyl-5(3-oxobutylethylenethioketal)-3-methyl-2-cyclopentenol Prepared  by l i t h i u m  aluminum  8 - k e t o - e s t e r , as d e s c r i b e d above IR  (neat):  'H NMR ppm MS  3300-3500  (CDC13):  (OH)  ( 2 H , b s , C H 2 0 H ) , 3 . 3 0 ppm (m/z, r e l a t i v e  %  reduction of the  corresponding  (50%).  1  cm"  6 = 6 . 2 0 ppm  hydride  ( I H , m, (4H, s ,  intensity):  H C = C ) , 4 . 8 ppm  ( I H , m,  CH2S)  256(13) M  +  - H 2 0 , 119  (100).  C H ( 0 H ) ) , 3.42  -  169 -  1-(3-0xobutylethylenethioketal)-l-carboethoxy-4-inethy1cyclopentadiene Prepared  by t h e methanesulfonyl  corresponding (neat):  IR  'H NMR 4.10,  alcohol  (68%) as d e s c r i b e d  1725 ( C O ) , 1625 (C=C) cm'  d e h y d r a t i o n method, o ft h e  above.  1  6 = 6 . 1 0 ppm ( 2 H , m , o l e f i n s ) ,  (CC14):  4 . 8 0 ppm ( I H , m,  4 . 0 6 ppm ( 2 H , q : q , 1 : 1 , J = 7 H z , 0 C H 2 C H 3 ) , 3 . 7 5 ppm  3.27  ppm  (3H,  t : t ,1:1, J = 7 Hz, CH3CH2)  MS  chloride  ( 3 H , b s , C H 3 C = C ) , 1 . 7 3 ppm ( 3 H , s , C H 3 C ( S C H 2 ) 2 ) ,  ( m / z ,r e l a t i v e  Exact  Mass  % intensity):  calculated  for C  1 5  H  298(18),  2 2  S202:  225(6)  298.1060,  Prepared  by a l k y l a t i o n  170  e x a m p l e , f o r 2 0 mmol o f k e t o n e , depended  (neat):  IR  'H NMR  on t h e c a t a l y t i c  observed:  J = 7 Hz, CH3CH2)  MS  (m/z,  168(46)  one IR  was a l s o (neat):  "H NMR J  amount o f base  % intensity):  - C4H60, side  Product  1 71  catalytic  The  amount  The y i e l d  of  (40 t o 95%). 1  (2H, q , J = 7 Hz,  chain,  239(2)  43(100)  M  +  + 1, 238(1), 192(4)  - HOEt,  - CH3C0.  endo-l-carboethoxy-4-methyl-5-acetylbicyclo[2.2.l]heptan-2-  obtained  i n varying  1 7 7 5 (CO s t r a i n e d ) ,  (CDC13):  Method B.  ( 3 H , b s , C H 3 C = C ) , 2 . 1 0 ppm ( 3 H , s , C H 3 C 0 ) , 1 . 2 2 ppm ( 3 H ,  t,  relative  (170)  0 . 2 mmol o f p o t a s s i u m ) .  6 = 5 . 8 7 ppm ( I H , b s , H C = C ) , 4 . 1 1 ppm  0 C H 2 C H 3 ) , 2 . 1 9 ppm  298.1038.  t o a minimum  1 7 3 0 ( s ) , 1 7 0 0 ( s ) , 1625 (C=C) cm"  (CC14):  119(100).  o f 142 a s d e s c r i b e d p r e v i o u s l y ,  amount o f p o t a s s i u m - t - b u t o x i d e used was k e p t (for  (4H, s , CH2S), 1 . 2 5 , 1 . 2 3 ppm  - COOEt,  5-(3-0xobuty1)-5-carboethoxy-3-methyl-2-cyclopentenone  olefin),  6 = 4 . 2 1 ppm  amounts  (0 t o 5 0 % ) .  1725 ( C O ) , 1625 (C=C) cm"  (2H, q , J = 7  1  H z , 0 C H 2 C H 3 ) , 3 . 0 3 ppm ( I H , d d d ,  = 2 , 6 , 1 2 H z , H-5 e x o ) , 2 . 2 1 ppm ( 3 H , s , C H 3 C 0 ) , 1 . 4 5 ppm ( 3 H , s , C H 3 - C - ) ,  1.30  ppm ( 3 H , t , J = 7 H z , C H 3 C H 2 )  -  MS  relative  (m/z!  125(100) Exact UV  %  intensity):  (X max  calculated ( l o g e)):  for C 224  Prepared 144b, except products  by  afforded  173  NMR  3.72  by  +  1,  238(3), 193(9)  -  OEt,  Knoevenagal  168(100)  5.78  (6H, s , CH30C0), ppm  relative  238.1200,  was  170  observed:  ppm  (using  reduced  238.1211.  170)  t o 12  ethyl  h.  ppm  Purification  (C=C)  cm"  of  the  ether)  1  ppm  (2H, q , 7 Hz,  ( 3 H , b s , C H 3 C = C H ) , 2.03  7 Hz,  intensity):  described for  acetate - petroleum  ( I H , b s , H C = C ) , 4.11  2.22  as  (12%).  ( C O ) , 1630  (3H, t , J = %  04:  (20% t o 50%  1750-1700 6 =  ] 8  condensation  ( 7 % ) , 172_ ( 5 3 % ) ,  (CC14):  (m/z,  H  time  chromatography  (neat):  ppm  1 3  (172)  the reaction  C H 3 C = C ) , 1.23 MS  +  3-methyl-3-butenyl-4,4-dicarboxylate)  3-methyl-2-cyclopentenone  'H  239(3) M  (3.3)  5-Carboethoxy-5-(dimethy1  IR  -  C7H100.  Mass  172,  170  ppm  (3H,  0CH2CH3), s,  CH3CH2)  352(2), 321(6)  - OMe,  288(12)  -  HCOOMe,  CgH1203.  173, 6-carboethoxy-8-methyl-3-(dimethyl  methylenedicarboxylate)  bicyclo[4.3.0]  nona-1,8-diene IR  (neat):  'H  NMR  (2H,  1740-1710  (CC14):  q, J =  MS  (m/z,  Exact UV  ppm  (3H, t , J %  ( l o g e)):  =  ppm  7 Hz,  intensity):  calculated  1570  cm"  (4.2)  1  ppm  (6H, s, CH30C0),  ( I H , b s , HC=C), 4.07 1.91  ppm  ppm  (3H, b s ,  CH3CH2)  334(8), 302(18)  for C18H220g: 226  (C=C)  ( I H , s , HC=C), 6.03  0 C H 2 C H 3 ) , 3.68  ppm  relative  Mass  (X max  6 = 6.57  7 Hz,  C H 3 C = C ) , 1.23  (CO), 1610,  334.1414,  - HOMe, 1 1 9 ( 1 0 0 ) ,  observed:  334.1196.  117(100).  -  5-Carboethoxy-5(dimethyl  3-methyl-3-butenyl-4,4-dicarboxylate)  3- m e t h y l - 2 - c y c l o p e n t e n o l Sodium ( 1 0 mL) chloride The  reaction  and  mixture  afford  'H NMR  3300-3500  (CC14):  0.31  ketone  m m o l , BDH)  172  ( 1 0 0 mg,  was a d d e d  to a  0.28 mmol)  and  0.31 m m o l , B D H ) , a n d s t i r r e d  then  acidified  extracts  were  methanol cerous  a t 20° f o r 1  ( 5 % H C l ) , and e x t r a c t e d w i t h  washed, d r i e d ,  by chromatography  (62% best  filtered,  h.  ethyl-  concentrated,  (25% ethyl acetate-hexane)  to  yield).  ( O H ) , 1725 ( C O ) , 1625 (C=C)  6 = 5 . 8 7 ppm  C H ( 0 H ) ) , 4 . 2 0 ppm ppm  was  purified  1_74 6 5 mg  (neat):  (12 mg,  115 mg,  The c o m b i n e d  the product  (174)  containing  (CeCl3.7H20,  acetate.  IR  borohydride  solution  171 -  cm"  1  ( I H , b s , H C = C ) , 5 . 3 5 , 4 . 9 0 ppm  ( 2 H , q , J = 7 H z , 0 C H . 2 C H 3 ) , 3 . 7 8 ppm  ( 3 H , b s , C H 3 C = C H ) , 2 . 0 8 ppm  ( 3 H , s , C H 3 C = C ) , 1.29  ( I H , m,  1:1,  (6H, s , CH30C0), ppm  2.27  (3H, t , J = 7 Hz,  CH3CH2).  l-Carboethoxy-1(dimethyl  3-methyl-3-butenyl-4,4-dicarboxylate)  4- m e t h y l  (175),  cyclopentadiene  Prepared  by d e h y d r a t i o n  method d e s c r i b e d above. mesylate afford IR  derivative  1_75  (neat):  'H NMR 4.07,  The r e a c t i o n  dehydrated  was  the methanesulfonyl purified  chloride  by c h r o m a t o g r a p h y ( t h e  on t h e c o l u m n , 3 0 % e t h e r - p e t r o l e u m  ether) to  (53%). 1725 ( C O ) , 1635 (C=C)  (CDC13): 4 . 1 2 ppm  6 = 6 . 1 0 ppm  cm"  ( 2 H , m,  1  olefins),  4 . 8 0 ppm  ( I H , m,  ( 2 H , q : q , 1 : 1 , J = 7 H z , 0 C H _ 2 C H 3 ) , 3 . 6 5 ppm  2.01  ppm  t:t,  1:1, CH3CH2)  MS  o f 174 u s i n g  ( 3 H , s , C H 3 C = C ) , 1.82  (m/z, r e l a t i v e  % intensity):  ppm  (6H, s , CH30C0),  ( 3 H , b s , C H 3 C = C H ) , 1 . 2 3 , 1.26  336(3),  304(5)  olefin),  - HOMe, 19 1(60),  ppm  (3H,  91(100).  -  A  2 > 3  172 -  -5-Carboethoxy-9-dicarbomethoxy-2>8-dimethyl-tricyclo[4.3.0  1 , 5  .Q  4 , 8  ]  nonene (176) A a  s o l u t i o n o f 175 ( 3 0 mg, 0.089 mmol) i n t o l u e n e  s e a l e d tube  concentrated afford IR  ( o i l b a t h ) t o 140°C  and p u r i f i e d  by chromatography  1 7 6 a n d 1 7 7 , 1 4 mg  (neat):  'H NMR J  and heated  1730 (CO) cm"  (CDC13):  (1 m L ) w a s p l a c e d i n  f o r 10 h .  The s o l u t i o n was  then  (6% ether-petroleum ether) to  (40%). 1  <5 = 7 . 1 0 a n d 6 . 2 0 ppm  = 7 H z , 0 C H 2 C H 3 ) , 3 . 7 0 ppm  ( I H , b s , H C = C , 5 : 4 ) , 4.11  ( 6 H , s , C H 3 0 C 0 ) , 2 . 0 2 a n d 2 . 0 4 ppm  ppm  (2H, q,  (3H,bs,  CH3C=C, 5:4) MS  (m/z, r e l a t i v e  226(75) Exact  A  % intensity):  - EtOH, 2H0Me,  Mass  calculated  336(7), 209(23)  - HOEt, 258(43)  - H O E t , HOMe,  29(100). f o r C-jgH^Og,:  336.1572,  observed:  336.1561.  ' -3-(3-oxobutyl)-3-carboethoxybicyc1o[3.3.0]octen-2-one (178) Prepared  IR  (neat):  •H NMR  by a l k y l a t i o n  1750-1700  (CDC13):  C H 3 C 0 ) , 1 . 2 3 ppm MS  (m/z, r e l a t i v e  Exact  Mass  o f 160, as d e s c r i b e d p r e v i o u s l y ,  ( C O ) , 1645 (C=C) cm"  6 = 4.11  ppm  Method  B  (95%).  1  ( C H 2 , q , J = 7 H z , 0 C H 2 C H 3 ) , 2.11  ppm  (3H, s ,  ( 3 H , t , J = 7 H z , CH_3CH2) % intensity):  calculated  f o rC  1 6  H  264(3),  2 2  0c:  194(9)  264.1360,  - C4Hg0, 43(100) observed:  CH3C0.  264.1331.  1 5 A  ' -3-Carboethoxy-3-(dimethyl  3-methy1-3-butenyl-4,4-dicarboxylate)  bicyclo[3.3.0]octen-2-one (179) Prepared 151b,  except  reaction  by Knoevenagal that  condensation  the reaction  by c h r o m a t o g r a p h y  (60%) and 178 ( 3 0 % ) . IR ( n e a t ) : 1755-1725  time  (using  1 7 8 ) , as d e s c r i b e d above f o r  was 20 t o 24 h .  Purification  ( 2 0 % t o 30% ether-petroleum  ( C O ) , 1650 (C=C) cm"  1  ether)  of the  a f f o r d e d 1_79  -  'H  NMR  s:s,  6  (CC14):  1:1,  = 4.12  C H 3 0 C 0 ) , 2.02  ppm  173  -  (2H, q, J =  ppm  7 Hz,  OCH_2CH3), 3 . 7 3 ,  ( 3 H , s , C H 3 C = C ) , 1.24  ppm  3.70  (3H, t , J =  ppm  7  (6H,  Hz,  CH3CH2) MS  (m/z,  CgH  1 2  relative  %  intensity):  240(3) M  +  - 138,  194(16)  M  +  - side  chain",  04. On  one  IR  (neat):  'H  NMR  occasion a 1730  (CO), 1620, 6  (CDC13):  0CH_2CH3), 3.74  cyclized  = 6.52  and  3.77  1575  ppm  ppm  product  of type  (C=C)  cm"  173  isolated  (<  1%).  1  ( I H , s , H C = C ) , 4.11  (3H e a c h ,  was  ppm  (2H, q, J =  s , C H 3 C 0 0 ) , 1.22  ppm  7  Hz,  (3H, t , J =  7  Hz,  CH3CH20). MS  (m/z,  relative  %  intensity):  3 6 0 ( 6 ) , 328(13)  -MeOH, 2 5 5 ( 2 8 )  -MeOH,  COOEt.  1 A  5 ' -3-Carboethoxy-3-(dimethyl-3-methyl-3-butenyl-4,4-dicarboxylate)  bicyc1o[3.3.0]octen-2-ol Prepared best  (neat):  'H  NMR  3500  (CC14):  0CH_2CH3), 3.64  This  of  179  ( 4 0 mL)  After  stirring  This  g  = 4.60  ppm  as  described previously  by  (58%).  ppm  was  ( 6 0 mL,  was then  -0.16  containing  M  dried,  dropwise  ppm  also  f o r 172  (67%:  filtered,  ppm  zinc  1_79_ ( 3 g ,  (-1.5  1  (2H, q, J =  (3H, t , J =  using  30 m i n  cm"  4.05  i n e t h e r , 8.8  ketone  a t 0°C, and  added  chromatography  (C=C)  ( I H , b s , CH(OH)),  accomplished  f o r 30 m i n  was  ( C O ) , 1650  ( 6 H , s , C H 3 0 C 0 ) , 1.27  solution  tartrate  solution  purified  6  solution  ether  sodium  (OH), 1750-1705  reduction  borohydride  1.6  reduction  yield).  IR  of  by  (180)  Hz,  m m o l ) was 7.9  until  added  .  A  to  an  zinc  mmol) a t 0°C. saturated  bubbling  c o n c e n t r a t e d and  (30% ether-petroleum ether)  Hz,  CH_3CH2). 151  borohydride  a t 20°C, a mL)  7  7  the  solution  ceased.  product  to afford  180,  -  174 -  3-Carboethoxy-3-(dimethyl-3-methyl-3-butenyl-4,4-dicarboxylate) bicyclo[3.3.0]octa-l,4-diene Prepared method IR  by d e h y d r a t i o n o f 180 u s i n g  d e s c r i b e d above  (neat):  'H NMR  (181)  cm"  1  6 = 5 . 7 3 , 5 . 3 5 , 5 . 2 0 ppm  (2H, bs:bs:bs,  4.06  ppm  ( 2 H , q : q , - 2 : 1 , 0 C H _ 2 C H 3 ) , 3 . 7 2 , 3 . 6 4 ppm  2.01  ppm  ( 3 H , s , C H 3 C = C ) , 1 . 5 1 , 1 . 4 8 ppm  MS  (m/z, r e l a t i v e  %  chloride  (60%).  1730 ( C O ) , 1635 (C=C)  (CDC13):  the methanesulfonyl  intensity):  olefins),  4.10,  (6H, s : s ,-2:1, CH30C0),  ( 3 H , t : t , - 2 : 1 , CH_ 3 CH 2 )  362(4), 257(5)  - HOMe, COOEt o r H C O O E t ,  OMe,  117(38).  8  9  A ' -6-Carboethoxy-2-dicarbomethoxy-3-methyltetracyclo[6.4.0 dodecene  (181) (also  Prepared above IR  8 , 1 2  181  and  'H NMR  1735 (CO)  (CDC13):  olefin),  cm"  reaction  ppm  MS  intensity):  Exact  A  1 1  '  1 2  calculated  4:4:1:1,  CH30C0),  363(15) M  +  +  2 6  06:  aluminum  182  (1 mL)  1.25  ppm  1, 3 6 2 ( 1 5 ) ,  362.1727,  -6-Carboethoxy-3-methy1tetracyclo[6.4.0  Triester  ]-  as d e s c r i b e d  (50%).  - H C O O E t , HCOOMe, 1 5 3 ( 5 9 ) ,  f o r C2QH  dodecene-2-dicarboxylic  1 2  of IH; bs:bs,  (3H, t , J =  ( 3 H , s , CH3~C-)  - HCOOEt, 228(19)  Mass  8  .0 '  ( 2 H , 4 : 1 , q : q , J = 7 H z , 0 C H 2 C H 3 ) , 3 . 7 1 , 3.65  7 H z , C H 3 C H 2 ) , 1.17  288(17)  o f 175  i n toluene  ( 4 : 1 , 5/8 o f t h e i n t e g r a t i o n  (6H, s:s:s:s,  %  3 , 7  1  4 . 1 4 a n d 4 . 1 5 ppm  (m/z, r e l a t i v e  .0  )  0.081 mmol)  5 . 4 5 , 5 . 2 6 ppm  3 . 6 9 , 3 . 6 6 ppm  9 , 1 0  A  (30 mg,  f o r the Diels-Alder  (neat):  and  using  A  1 , 6  1 > 6  - HCOOMe,  117(100).  observed:  3  302(19)  362.1720.  7  .0 ' .  acid  ( 2 0 0 mg,  trichloride-(140  0.55 mmol) mg,  1.1  was  added  mmol, F i s h e r )  to a solution  containing  i n e t h a n e t h i o l (2  mL,  -  Eastman).  Immediately  continued acid  ( 1 % HC1)  extracts (94%) IR  a t 20°C  were  used  viscous  f o r 20 h.  The  and e x t r a c t e d  with  dried, filtered,  i n the next  (neat):  'H NMR  a very  p r e c i p i t a t e was  reaction  ( O H ) , 1725  6 = 8.80  ppm  (CO)  ( 2 H , b s , C 0 0 H ) , 5.85  1.23  ppm  (3H, s , CH3).  1  ppm  The toluene  above  evaporated ether)  acid  acid  and t h e s o l u t i o n  and t h e product  to obtain  cold  p r o d u c t , 170  mg  ppm  (IH,  s,  1 , 6  3  HC=C), CHgCHg),  7  .0 ' .  (183)  dicarboxylic  ( 2 mL)  into  combined  (3H, t , J = 7 Hz,  °-6-Carboethoxy-3-methy1tetracyclo[6.4.0  dodecene-2-carboxylic  stirring  1  cm"  ( 2 H , q , J = 7 H z , C H . 2 C H 3 ) , 1.25  »  and  poured  The  c o n c e n t r a t e d and t h e crude  ppm  9  then  e t h e r and c h l o r o f o r m .  4.08  A  m i x t u r e was  formed  reaction.  3700-2800  (CDC13):  175 -  ( 1 7 0 mg, refluxed  0 . 5 0 mmol) was f o r 2 h.  The  p u r i f i e d by c h r o m a t o g r a p h y  the monocarboxylic  acid  product  dissolved  solvent  i n  was  (20% ether-petroleum  1 8 3 , 6 5 mg  ( 3 8 % f o r two  steps). IR  (neat):  'H NMR  3700-2800  (CDC13):  (OH), 1720  6 = 5.85  ppm  (CO)  (IH,  cm"  b s , C 0 0 H ) , 5.82  4.09  ppm  ( 2 H , q , J = 7 H z , C H _ 2 C H 3 ) , 1.25  1.10  ppm  (3H, s , CH3).  MS  (m/z, r e l a t i v e  217(45)-C00Et, (35%  f o r two Spectral  % intensity):  172(98)-C00Et,  i n next  ppm  291(13) M  C00H  +  ppm  (IH,  paragraph.  s,  (3H, t , J = 7 Hz,  +  1, 2 9 0 ( 6 ) ,  and d i c a r b o x y l i c a c i d  steps). data  1  HC=C), CH_3CH2),  246(45)-0Et, 1 8 3 , 60  mg  -  A  9 , 1 Q  -3-Meth.y1tetracyc1or6.4.O Ester  (10%  cooling  ethyl  acetate.  to  afford  IR  (CHC13):  MS MP:  8  .0 '  1 2  ]dodecene-2,6-dicarboxylic  t h e s o l u t i o n , i t was a c i d i f i e d The combined  - 1 0 0 mg  extracts  were  t o a sodium mixture  hydroxide  refluxed  for2  solution h.  ( 1 0 % H C l ) and e x t r a c t e d  dried, filtered  206-208°C.  with  and c o n c e n t r a t e d  ( C 0 0 H ) , 1720 (CO) cm'  6 = 1 0 . 8 0 ppm  1  ( I H , b s , C00H),  5 . 8 5 ppm  (IH, s, HOC),  (3H, s , CH3).  (m/z, r e l a t i v e  acid  (99%).  3500-300  (CDC13):  ppm  3 , 7  NaOH, 1 mL, - 2 . 5 mmol) a n d t h i s  After  1.10  .0  183 ( 1 1 0 mg, 0 . 3 8 mmol) was a d d e d  aqueous  'H NMR  1 , 6  176 -  % intensity):  262(5), 217(18)-C00H,  172(28)-2C00H.  -  177 -  Bibliography 1.  (Some  paragraphs  University 2.  i n section  of British  1.1  Columbia,  a r e taken  R.D. B a r n e s .  Invertebrate Zoology,  Philadelphia,  London and T o r o n t o , 1 9 6 8 .  W.B.  Saunders  Company.  A . J . Khon.  4.  E.N. K o z l o f f . Keys t o t h e M a r i n e I n v e r t e b r a t e s o f P u g e t S o u n d , San Juan A r c h i p e l a g o and A d j a c e n t R e g i o n s , U o f Washington P r e s s , S e a t t l e and L o n d o n , 1 9 7 4 .  5.  L.G. H a r r i s . (1973).  Current  6.  D.R.  Veliger,  7.  R.J. Paine.  8.  R.E. J o h a n n e s .  9.  J.£. Bardash. Chemoreception pp. 104-141.  The Chemical Senses o f F i s h , i n G r a n t , M a c k i e , i n M a r i n e O r g a n i s m s , A c a d e m i c P r e s s , N.Y., 1 9 7 4 ,  10.  M.J. Edmunds.  J . L i m . S o c . L o n d o n , 4 6 , 46  11.  L.B. Arey  12.  R.H. W h i t t a k e r  and P.P. Feeny.  P . J .Scheuer.  Chemistry  Wobber.  Veliger,  7 , 291  M.Sc. T h e s i s ,  3.  13.  Amer. Z o o l . ,  from) J . H e l l o u .  1980.  (1961).  Topics' i n Comparative  1_2, 3 8 3 6, 1  Veliger,  P a t h o b i o l o g y , 2_, 2 1 3 - 3 1 5  (1970).  (1963).  5_, 1 0 4  a n d W.J. C o z i e r .  (1963).  (1966).  J . E x p . Zoo., 3 2 , 443  (1921).  S c i e n c e , 171 , 3 9 7 3 , 7 5 7 ( 1 9 7 1 ) .  o f Marine  Natural  Products, Academic  Press,  N.Y., 1 9 7 3 . 14.  D.J. Faulkner  and R . J . Andersen.  The S e a , V o l . 5 ,  Wiley-Interscience,  N.Y., 1 9 7 7 . 15.  P . J .Scheuer.  16.  G.R.  17.  D.J. Faulkner  19. 20.  S.W.  a n d W.  Fenical,  52  (1977).  Tetrahedron, Eds.  Marine  3 8 , 1857  Natural  Products  4763  Chemistry,  Ayer  P . J .Scheuer,  J . Finer  and J . C l a r d y .  193  J . Am. C h e m . S o c . ,  (1975). and R . J . Andersen.  Tetrahedron  Lett.,  2 3 , 1039  F.A. Fuhrman, G . J . Fuhrman, Y.H. Kim and L.A. P a v e l k a . 207,  (1982).  P r e s s , N.Y., 1 9 7 7 .  B.J.Burreson, 97,  J . C h e m . , ]6_,  S c h u l t e and P.J. Scheuer.  Plenum 18.  Israel  (1980).  (1982).  Science,  -  21.  G.M.  Blair  22.  C D .  Todd.  23.  J . F . Gardner.  24.  G.L. Levy Organic  25.  a n d R.R. S c a p y .  178 -  Veliger,  J . Exp. Mar. B i o l . Diss.  Abst.  Ecol.,  Carbon-13  John-Wiley  (1972).  4J_, 2 1 3  I n t . B, 4 0 , 2489  and G.L. N e l s o n .  Chemists,  1_5, 1 1 9  (1979).  (1979).  Nuclear  Magnetic  Resonance f o r  a n d S o n s , N.Y., 1 9 7 2 .  For example, see D.J. Hanachan.  Lipid  Chemistry,  John  Wiley  and  S o n s , N.Y., C h a p . 5 , 1 9 6 0 . 26.  R.M. B u r t o n a n d F . C . G u e r r a , E d s . F u n d a m e n t a l s o f L i p i d C h e m i s t r y , BI S c i e n c e P u b l i c a t i o n s D i v i s i o n , M i s s o u r i , C h a p . 1 3 , 1 9 7 4 .  27.  G. Simon  28.  K.A. K a r l s s o n a n d B . E . S a m u e l s o n .  a n d G. R o u s e .  Lipids,  2_, 5 5  (1967).  Biochim.  B i o p h y s . A c t a , 3 3 7 , 204  (1974). 29.  K.A. K a r l s s o n .  30.  G. A n g u i l a r - S a n t o s a n d M.S. Rhode I s l . 1 9 6 7 , p. 1 7 3 .  31.  G.T. C a r t e r a n d K . L . R i c h a r d , J r .  32.  W.R.  33.  E . J .Masoro. Physiological S a u n d e r s C o , N.Y., 1 9 6 8 .  34.  S. Abrahamsson and I. P a s c h e r , E d s . P l e n u m P r e s s , L o n d o n , N.Y. 1 9 7 6 .  35.  E. Hecht  36.  N. F i s h e r ,  37.  R.0. Brady.  38.  H.H.  39.  S.W. 25,  40.  Morrison.  Ayer,  Pergamon  Doty  Chem. P h y s . Fenical.  J . Hellou,  5, 6  (1970).  i n T r a n s a c t i o n s , Drugs  J . Am.  Chemistry  of Lipids  Structure  S c i e n c e , 1 2 5 , 1041  Lipids,  Long.  Tetrahedron  M. T i s h l e r  the Sea,  (1978).  (1969). i n Mammals.  of Biological  W.B.  Membranes,  (1957).  L a n c e t , 2, 5 2 2  5 , 261  from  Chem. S o c , 1 0 0 , 7441  B i o p h y s . A c t a , 1 7 6 , 537  C . H a r i n g t o r i a n d D.A.  a n d N.C. Y a n g .  4 1 . a L.M. J a c k m a n 10  Lipids,  (1951).  (1970).  Lett.,  685  (1979).  and R . J . Andersen.  Tetrahedron  Lett.,  (1984).  M. B a r n a r d  Vol.  Biochim.  a n d D. S h a p i r o .  S u n a n d W.  141  Chem. P h y s .  P r o c . Chem. S o c , 302  and S. S t e r n h e l l .  Applications  o f NMR  P r e s s , N.Y., 1 9 7 8 .  International  Spectroscopy  (1958).  Series  i n Organic  Chemistry,  i n Organic  Chemistry,  2nd Ed.,  -  179 -  4 1 . b R.M. S i l v e r s t e i n , G . C . B a s s l e r a n d T . C . M o r r i l l . Spectroscopic I d e n t i f i c a t i o n o f O r g a n i c Compounds, 3 r d E d . , John W i l e y and Sons,  N.Y.,  1974. 42.  D . J . Sam a n d H . E . S i m m o n s .  43.  Aldrich  44.  Catalog  L.F. Fieser John-Wiley  45.  Chem. S o c , 9 4 , 4024  Handbook o f F i n e C h e m i c a l s ,  a n d M.  Fieser.  and Sons,  Reagents  I n c . , N.Y.,  (1972).  1983-84.  i n Organic  S y n t h e s i s , V o l . 1,  1967 and r e f e r e n c e s  therein.  P . M a u r e t , J . P . F a y e t , D. M e r m i l l o d - B l a r d e t , P . M a z e r o l l e s a n d A. Faucher. J . Chim. Phys., Phys.-Chim. B i o l . , 7 7 , 325 (1980) and references  46.  J . Am.  therein.  J . Casanova  and B. W e g e l l .  Bull.  S o c . C h i m . F r . , 911  (1974) and r e f e r e n c e s  therein. 47.  F . A . L . A n e t , M. S t - J a c q u e s , P . M . H e m i c h s , A . K . C h e n g , J . K r a n e a n d L. Wang. T e t r a h e d r o n , 3 0 , 1629 (1974) and r e f e r e n c e s t h e r e i n .  48.  J . Sicher.  49.  N . L . A l l i n g e r , M.T. (1972).  50.  G. S a m u e l  51.  F.A.L. A n e t ,  A.K. Cheng  52.  F.J. Weigert  and J.D. R o b e r t s .  53.  J . Dale.  54.  J.D. Dunitz  55.  J . D . D u n i t z , H . E s e r , M. B i x o n 1572  Progress  i n S t e r e o c h e m i s t r y , 3 , 202 Tribble  a n d R. W e i s s .  Pure  a n d M.A.  Miller.  Tetrahedron,  (1962).  Tetrahedron,  2 6 , 3005  and J . Krane.  J . Am.  J . Am.  2 8 , 1173  (1970). Chem. S o c . , 9 5 , 7877  Chem. S o c . , 9 2 , 1347  (1973).  (1970).  a n d A p p l . Chem., 2 5 , 4 6 9 (1971 ) .  a n d H. E s e r .  Helv.  Chim. A c t a , 5 0 , 1565 and S. L i f s o n .  Helv.  (1967). Chim. A c t a , 50,  (1967).  56.  T. A l i r k ,  G. B o r g e n  57.  R.A. R a p h a e l .  58.  Personnal  59.  W.H.  60.  T . M o r i , K. M a t s u i  and J . Dale.  Acta  P r o c . Chem. S o c , 97  C h e m . S c a n d . , 26_, 1 8 0 5  (1972).  (1962).  results.  Urry, D.J. Trecker  a n d D.A. W i n e y .  a n d H. N a z a k i  Tetrahedron  Tetrahedron  Lett.,  L e t t . , 609 1175  (1962).  (1970).  -  180 -  61.  For example  62.  W.C.  63.  A m o d i f i e d m o l e c u l a r model has been proposed by J . D a l e . J . Chem. S o c , 93 ( 1 9 6 3 ) . With t h a t m o d e l , t h e bonds o f two a d j a c e n t carbons c a n o n l y t a k e a l i m i t e d number o f v a l u e s , w h i c h a r e m u l t i p l e s o f IT/3...  64.  H.O.  65.  See r e f . 24 a n d 5 2 .  66.  O.L. C h a p m a n , D.S. W e i s s V o l . 3 , Chap. 3 , 1973.  67.  N . L . A l l i n g e r , M.P. C a v a , D.C. D e J o n g h , C R . J o h n s o n , N.A. L e b e l L.C. S t e v e n s . Chimie Organique, E d i s c i e n c e , McGraw-Hill, 1975.  68.  D.S. W e i s s i n O r g a n i c P h o t o c h e m i s t r y , A . P a d w a , E d . ; V o l . 5 , C h a p . 1981 a n d r e f e r e n c e s t h e r e i n .  69.  R.H. E a s t m a n  70.  M. K a i s i n , Y . M . S h e i k h , L . J . D u r h a m , C . D j e r a s s i , B . T u r s c h , B . D a l o z e , J . C . B r a e k m a n , D. L o s m a n , a n d R . K a r l s s o n . T e t r a h e d r o n L e t t . , 2239 (1974).  71.  Y . M . S h e i k h , G . S i n g y , M. K a i s i n , H . E g g e r t , C.' D j e r a s s i , B . T u r s c h , D. D a l o z e , a n d J . C . B r a e k m a n . T e t r a h e d r o n , 3 2 , 1171 ( 1 9 7 6 ) a n d references therein.  72.  Y.M. S h e i k h , C . D j e r a s s i , J . C a n d R. K a r l s s o n . Tetrahedron,  73.  R.  74.  E. A y a n o g l u , T. G e b r e y e s u s , C M . T e t r a h e d r o n L e t t . , 1671 ( 1 9 7 8 ) .  B e e c h a n , C. D j e r a s s i ,  E. A y a n o g l u ,  Beechan, and C. D j e r a s s i .  75.  Still  b. 77.  a n d I. G a l y n k e r .  H o u s e , M. G a l l  a n d H.D.  Acta  Tetrahedron,  Ohnstead.  i n Organic  and J . Beard.  Karlsson.  35_, 1 0 3 5 76a.  s e e r e f . 54 a n d 5 5 . (1981).  J . O r g . Chem., 3 6 , 2361  Lett.,  3029  B 3 3 , 1143  and  4,  (1970).  B r a e k m a n , D . D a l o z e , M. 3 3 , 2115 (1977).  CM.  (1971).  P h o t o c h e m i s t r y , O.L. Chapman, E d . ;  Tetrahedron  Crystallogr.,  T. G e b r e y e s u s ,  3 7 , 3981  Kaisin,  B.  Tursch,  (1977). a n d M.  Kaisin.  Tetrahedron,  (1979).  L.S. Cierszko.  Trans.  N.Y. A c a d .  S c i . , 2 4 , 502  P.R. B u r k h o l d e r , a n d L.M. B u r k h o l d e r .  (1962).  S c i e n c e , 1 2 7 , 1174  (1958).  For recent discussions related to similar biosyntheses, refer to a) K. H a y a n o , Y . O h f u n e , H. S h i r a h a m a , a n d T. M a t s u m o t o . Helv. Chim. A c t a , 6 4 , 1347 ( 1 9 8 1 ) . b) Y . M u r a t a , T. O h t s u k a , H. S h i r a h a m a , a n d T. M a t s u m o t o . Tetrahedron L e t t . , 2 2 , 4313 (1981).  -  78.  A.M. B i r c h ,  79a.  R.D. L i t t l e ,  a n d G. P a t t e n d e n .  J . C h e m . S o c . , C h e m . Comm., 1 1 9 5 ( 1 9 8 0 ) .  and G.L. C a r r o l l .  b . R.D. L i t t l e , 105,  181 -  G.L. C a r r o l l ,  Tetrahedron  Lett.,  and J.L. Petersen.  22_, 4 3 8 9  (1981).  J . Am. C h e m .  Soc.,  928 (1983).  80.  A. P a q u e t t e , and K.E. S t e v e n s .  Tetrahedron  81.  J . H u g u e t , M. K a r p f , a n d A . S . D r i e d i n g .  Lett.,  2 2 , 4393  (1981).  Helv. Chim. A c t a , 6 5 ,  2413  (1982) . 82.  T. F u j i t a , Lett.,  T. O h t s u k a , H. S h i r a h a m a , a n d T. M a t s u m o t o .  Tetrahedron  2 3 , 4091 ( 1 9 8 2 ) .  83.  W. O p p o l z e r , a n d K . B a t t i g .  Tetrahedron  Lett.,  2 3 , 4669  84a.  A.M. B i r c h ,  a n d G. P a t t e n d e n .  Tetrahedron  b. A.M. B i r c h ,  a n d G. P a t t e n d e n .  J . Chem. S o c , P e r k i n  Lett.,  (1982).  2 3 , 991  (1982).  Trans.  1,  1913  (1983) . 85.  G. M e h t a , D.S. R e d d y , a n d A . N . M u r t y . 824  86.  E. P i e r s ,  87.  J . E . Paw, a n d A.C. Weedon.  88.  G. P a t t e n d e n ,  89.  Prepared according t o a procedure O r g . S y n . , 4 0 , 41 ( 1 9 6 0 ) .  90a.  Prepared Murty.  and V. Karumaratne.  C a n .J . Chem., 6 2 , 6 2 9 ( 1 9 8 4 ) .  Tetrahedron  and S . J . Teague.  S. B e n e t t i ,  Lett.,  Tetrahedron  2 3 , 5485  Lett.,  (1982).  2 3 , 5471 ( 1 9 8 2 ) .  i n W.F. G a n n o n , a n d H.O.  according t o a procedure C a n . J . Chem., 5 6 , 2508  b. A. B a r c o , c.  J . C h e m . S o c , C h e m . Comm.  (1983).  i n R.B. K e l l y ,  House,  S . J .A l w a r d ,  and K.S.  (1978).  a n d G.P. P o l l i n i .  Synthesis,  316 ( 1 9 7 3 ) .  H.N. E d w a r d s , A . F . W y c p a l e k , N.C. C o r b i n , a n d J . O . M c C h e s n e y .  Synth.  Commun., 8 , 5 6 3 ( 1 9 7 8 ) . 91.  H.O. H o u s e , H . B a b a d , R . B . T o o t h i l l , 27,  92. 93.  W. L e n h e r t . K. A n t c z a k , 62,  94.  a n d A.W. N o l t e s .  J . O r g . Chem.,  4141 ( 1 9 6 2 ) . Tetrahedron  2 9 , 635 (1973).  J . F . K i n g s t o n , S . J .A l w a r d ,  and A.G. F a l l i s .  C a n .J . Chem.,  829 (1984).  R.Y. L e v i n a , a n d T . I . T a n t s y r e v a . (1953).  D o k l . A k a d . Nauk. S.S.S.R., 8 9 , 697  -  95a.  R.D. M i l l e r ,  182 -  M. S n e i d e r , a n d D . L . D o l c e .  J . Am. C h e m . S o c . , 9 5 , 8 4 6 8  (1973). b.  C F . Wilcox  J r . , and G.C  96.  M.S. B a i r d ,  and C B . Reese.  97a.  A . De M e i j e r e , a n d L . M e y e r .  b.  ibid.  Whitney.  J . O r g . Chem., 3 2 , 2933  Tetrahedron  Lett.,  2895  Angew. Chem. I n t e r n a t .  (1967).  (1976). E d . , 1_2, 8 5 8 ( 1 9 7 3 ) .  Chem. B e r . ,1 1 0 , 2561 ( 1 9 7 7 ) .  98.  S e e f o r e x a m p l e , R . K . M a c k i e a n d D.M. S m i t h . Guidebook t o Organic S y n t h e s i s , The P i t m a n P r e s s L t d . , B r i t a i n , 1982 pp 129-131 a n d J.E. Baldwin. J . C h e m . S o c . , C h e m . Comm., 7 3 4 , ( 1 9 7 6 ) .  99.  T. F u j i s a u a ,  100.  M. K o r e e d a , Y . L i a n g , a n d H . A k a g i .  a n d K. S a k a i .  Tetrahedron  Lett.,  3331 ( 1 9 7 6 ) .  J . C h e m . S o c , C h e m . Comm., 4 4 9  (1979). 101a. b.  Z.G. H a j o s , J .Cripsin,  a n d D.R. P a r r i s h .  J . O r g . Chem., 3 9 , 1612 ( 1 9 7 4 ) .  A.E. Vanstone, and J . S . Whitehurst.  (1970) and r e f e r e n c e s c.  V. Eder,  d.  G. B a u d u i n , (1973).  e.  C.B.C. B o y c e , a n d J . S . W h i t e h u r s t .  102a. b.  G. S a v e r ,  a n d R. W i e c h e r t .  H. C h r i s t o l ,  J.W. R a l l s .  J . Chem. S o c . , C  Angew. Chem. I n t . E d . , I C 496 ( 1 9 7 1 ) .  and Y. P i e t r a s a n t a .  Bull.  S o c . C h . F r . , 359  J . Chem. S o c , 2022  (1959).  Chem. R e v . , 5 9 , 329 ( 1 9 5 9 ) .  S . D a n i s h e f s k y , W.E. H a t c h , M. S a x , E . A b o l a , a n d J . P l e t c h e r . Chem. S o c , 9 5 , 2 4 1 0 ( 1 9 7 3 ) .  103.  H.O. H o u s e . Modern S y n t h e t i c 1972 p . 4 9 6 , 4 9 7 , 5 2 0 , 5 2 1 .  R e a c t i o n s , W.A. B e n j a m i n ,  104.  R.M. C o a t e s ,  J . O r g . C h e m . , 49_, 1 4 0 ( 1 9 8 4 ) .  105a. b. 106a.  b.  and S . J . Hobbs.  S.B. K u l k a r n i ,  and S. Dev.  S . D e v , a n d R. C h a r a n j i t . A. Lorenzi-Riatsch, 67,  Tetrahedron,  J . Am.  I n c . , N.Y.,  2 4 , 553 ( 1 9 6 8 ) .  J . I n d . Chem. S o c , 3 4 , 2 6 6 ( 1 9 5 7 ) .  Y. N a k a s h i t a , a n d H. H e s s e .  Helv.  Chim.  Acta,  249 ( 1 9 8 4 ) .  E. P i e r s , 2965  10  therein.  J .Banille,  (1982).  C.K. L a u , a n d I . N a g a k u r a .  C a n . J . Chem., 6 0 ,  -  c.  K. S a s a k i , T . K u s h i d a , M. 2117  183 -  I y a d a , a n d M. O d a .  Tetrahedron  (1982).  d.  C . R e e s e , a n d H.P. S a n d e r s .  e.  F . C o o k e , R. M o e r c k , J . S c h w i d e r m a n , a n d P . M a g n u s . 1046  107.  Lett.,  S y n t h e s i s , 276  (1980) and s e v e r a l o t h e r  Examples  o f Nazarov  a.  M.  b.  T . H i y a m a , M.  (1981). J . O r g . Chem., 4 5 ,  groups.  cyclizations:  K a r p f , and A.S. D r i e d i n g . Shinoda,  Helv.  C h i m . A c t a , 5 9 , 1226  a n d H. N o z a k i .  J . Am.  (1976).  Chem. S o c . , 1 0 1 , 1599  (1979). c. 108.  C. S a n t e l l i - R o u v i e r , Examples  of difficult  a n d M. S a n t e l l i .  S y n t h e s i s , 429  cyclizations:  a.  B.B. S n i d e r , a n d P.C. C a r t a y a - M a r i n .  b.  r e f . 90  c.  r e f 47b Spectrochim.  J . O r g . Chem., 4 9 , 153  109.  H. J u n g e .  110.  P.E. E a t o n ,  111.  E.M.  112.  D.J. Pasto and C R . Johnson. Organic Structure Englewood C l i f f s , N.J. P r e n t i c e - H a l l , 1969.  113.  S . D a n i s h e f s k y , G. K o p p e l ,  (1984).  A c t a , 24A, 1965 (1968) and r e f e r e n c e s  G.R. C a r l s o n , a n d J . T . L e e .  Bottorff,  (1983).  and L . L . Moore.  therein.  J . O r g . Chem., 3 8 , 4071  Org. Synth.,  a n d R. L e v i n e .  Coll.  (1973).  V o l . 5 , p. 687  (1973).  Determination,  Tetrahedron  Lett.,  2257  (1968). 114.  S . B o a t m a n , T.M.  Harris,  and C R .  Hauser.  J . Am.  Chem. S o c . , 8 7 , 82  (1965). 115.  G.W.  116.  J . Hellou,  117.  C R .  118.  H.O. 514  119.  120.  Kabalka,  J.D. Baker,  a n d G.W.  Neal.  J . F . K i n g s t o n , and A.G. F a l l i s .  H a u s e r , and B.P. L i n n .  J . Am.  H o u s e , R . A . A u e r b a c h , M. G a l l ,  J . O r g . Chem., 4 2 , 512 S y n t h e s i s , (1984)  C h e m . S o c . , 79_, 7 3 1 a n d N.P. P e e t .  (1977).  i n press.  (1957).  J . O r g . Chem., 3 8 ,  (1973).  A . P . K r a p c h o , J . D i a m a n t i , C . C a y e n , a n d R. B i n g h a m . Vol.  5 , 198  F.W.  Swamer, and C R .  Org. Synth.  (1973). Hauser.  J . Am.  Chem. S o c , 7 2 , 1352  (1950).  Coll.,  -  121. 122.  G. Z v i l i c h o v s k y ,  methyl  H.R. 531  124. 125.  esters  Synder,  with  dimethyl  L.A. B r o o k s ,  S.W.  Tetrahedron  Pelletier,  Proc.  Org. Synth., carbonate  I n t . , 6, 5  5 4 , 151  a n d S.H. S h a p i r o .  Lett.,  K. W i e d h a u p , A . J .  1747  (1974).  Preparation  Org. Synth.  Coll.  V o l . , 2,  Nollet,  J.G. Korsloot,  128.  H. S h o u n , a n d T. B e p p u .  129.  S. Osterman-Golkar, 215  Sigma and  a n d H.O.  Hulsman.  B i o c h e m . , 21_, 7 3 7  (1982).  J . Biol.  Chem., 2 5 7 , 3422  L. Ehrenberg,  and F. Solymosy.  C o . , S t . L o u i s , MO, U S A :  hazardous  than  (1982). Acta  Chem. S c a n d . [ B ]  note  that  L.N. Mander and S.P. S e t h i .  Tetrahedron  132.  A.L. Gemal, and J . C . Luche.  J . Am. C h e m . S o c . , 1 0 3 ,  133.  G.G. H a z e n , a n d D.W.  134.  J . F . K i n g s t o n , Ph.D. T h e s i s , U n i v e r s i t y  135.  E.M. B u r g e s s ,  H.R.  5 6 , 40  A . J .Hubert,  DMPC  i s less  stable  DEPC.  131.  Synth.,  Lewin.  (1974).  Chemical  more  2201.  (1968).  H.H. D a r o n , a n d J . L . A u l l .  28,  1966,  (1966).  127.  136.  (1974).  (NaH/KH/THF).  R . L . C h a p p e l l , P . C . P a r t h a s a r a t h y , a n d N.  O r g . C h e m . , 31,  T e t r a h e d r o n , 2 4 , 771  130.  Org. Prep.  (1943).  I. Shahak.  J. 126.  a n d U. F o t a d a r .  P. Deslongchamps, and L. R u e s t . of  123.  184 -  Rosenburg.  Penton,  Lett.,  2 4 , 5425 3434  J . O r g . Chem., 2 9 , 1930 of British  J r . , E.A. T a y l o r ,  (1983). (1981 ) . (1964).  Columbia, 1974.  a n d W.M.  Williams.  Org.  (1977).  a n d H. R e i m l i n g e r .  S y n t h e s i s , 405 (1970)  and r e f e r e n c e s  therein. 137.  T. S u g a h a r a , 214  Y. Komatsu, and S. Takano.  J . C h e m . S o c . , C h e m . Comm.  (1984).  138.  J.R. Williams,  139.  W.S.  a n d G.M.  W a d s w o r t h , a n d W.D.  Sarkisian.  S y n t h e s i s , 32  Emmunds.  Org. Synth.  (1974).  Coll.  V o l . , 5 , p. 547  (1973). 140.  Better yields F. (b) 810  Johnson,  were  obtained  a n d D.B. S l o a n .  P . G r a b b e , G.A. G a r c i a , (1973).  using  this  J . Am.  procedure:  ( a ) W.G.  Chem. S o c . , 8 2 , 6075  and C. R i u s .  Gensler,  (1960).  J . Chem. S o c . , P e r k i n  I,  -  141.  185 -  N.Y. L e v i n a , a n d N.N. G o d o v i k o v . Chem. A b s . , 5 0 , 3458c  Zh. Obshch.  Khim., 2 5 , 986  (1955).  (1956).  142.  F o r e x a m p l e s e e a ) N . L . A l l i n g e r , M. N a k a z a k i a n d V . Z a l k o w . J . Am. C h e m . S o c , 81_, 4 0 7 4 ( 1 9 5 9 ) . (b) J . Meinwald, J . J . T u f a r i e l l o , and J.J. Hurst. J . O r g . Chem., 2 9 , 2914 ( 1 9 6 4 ) . '  143.  R.A. S h e l d o n  144a.  and J.K. K o c h i .  W.J. K i s s e l .  O r g . R e a c t i o n s , 1 9 , 279  Ph.D. T h e s i s , S t a t e U n i v e r s i t y  o f New  (1972). York  i n  Buffalo,  1968. b.  R.M.  Moriarty,  H.G. W a l s h  a n d H. G o p a l .  Tetrahedron  Lett.,  4363  (1966). c.  J . Meinwald, J . J . T u f a r i e l l o 2914  145a. b.  P. M u l l e r and B. S i e g f r i e d . P. M u l l e r a n d B. S i e g f r i e d .  146.  P. K r a p c h o .  147.  M.  Nodi,  46, 148. 149a. b. 150.  J . O r g . Chem., 2 9 ,  1991  B.M.  Tetrahedron Helv.  Lett.,  3565  (1973).  Chim. A c t a , 5 7 , 987  (1974).  S y n t h e s i s , 805 and 893 (1982) and r e f e r e n c e s  K. N i s h i d e , M. S a i , K. F u j i  a n d E. F u j i t a .  therein.  J . O r g . Chem.,  (1981).  H.H. W a s s e r m a n  B.M.  and J . J . H u r s t .  (1964).  a n d B.H. L i p s h u t z .  T r o s t a n d Y. T a m a r u . Trost  and Y. Tamaru.  J . Am.  Tetrahedron  Lett.,  C h e m . S o c , 92,  4611  3528  J . Am. C h e m . S o c . , 9 9 , 3101  (1975).  (1975). (1977).  L . A . C a r p i n o , B . A . C a r p i n o , C A . G i z a , R.W. M u r r a y , A . A . S a n t e l l i P.H'. T e r r y . O r g . S y n t h . C o l l . V o l . , 5 , p. 168 ( 1 9 7 3 ) .  and  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060516/manifest

Comment

Related Items