FLUXlONAL NORBORNYL CATlONS SYNTHETIC APPROACHES TO TRICYCLO [6, 2., 1, 01: 5 lUNDECA - 2, 4 - DiENYL CAT‘ONS AND 3. 3 - ,DIMHHYLTRICYCLD “[4, 2, 1, Dissertation for the Degree of Ph. D. , M\CH\GAN STATE uuwmsm " SAMRAN BHU - ANANTANONDH 1975 . o LHNONAN- 2 - ONE ’ m 3 F. H ABSTRACT FLUXIONAL NORBORNYL CATIONS SYNTHETIC APPROACHES TO TRICYCLOI6,2,1,01'6] UNDECA-2,4-DIENYL CATIONS AND 3,3-DIMETHYLTRICYCLO BY Samran Bhu-anantanondh Synthetic approaches to 2,3,4,S-tetramethyltricyclo- [6.2.1.01’61undeca-2,4-dienyl cation gfi, tricyclo- [6.2.1.01’6]undeca-2,4-dienyl cation gx’and 3,3-dimethy1- 1: tricyclo[4,2,l,0 4lnonan-Z-one Ql’were investigated. 9% #1 u The cations zfi’and zx,were predicted to undergo thermally allowed-suprafacial [1,6] sigmatropic migration with re- tention of configuration of the shifting centers. Due to the accelerating effect of the norbornyl skeleton, it was Samran Bhu-anantanondh expected that the cation gfi’might exhibit the thermally forbidden [1,4] sigmatropic migration with retention. The synthetic pathways to the compounds zg’and QR, which were proposed to form the cations gfiland zX’in strong acid media are outlined below. The alcohol QR,re‘ acted with fluorosulfonic acid to form a protonated ion H + + Q. w—n .0 “2—032 *— \ H MR. 5)» RR fila’or filbiat -60°, and consisted of a rapidly equilibrat- ing pair ions at -40° to -20°. The alcohol Qereacted with fluorosulfonic acid to form the ion 41, (The solutions were observed by both C-13 and proton nmr spectroscopy.) CH —OH 4K. The synthetic approach to the ketone QAXproposed precursor for the cation Zfl) is shown. Attempts to cy- clize the keto tosylate figlwith various bases under various conditions were unsuccessful. Besides the intermediates shown.avariety'of compounds containing the bicyclo [3,2,0] skeleton were prepared. Samran Bhu-anantonondh \ H / H O J . o O 9 O H + C—chg 10 %Pd/C m-OCH3< H *0 —OCH CH CH fi—OCH3 H 3 3 O 0 o 10%Pd/C LiAlH4 CH2:PH LlAlH4 CHZ-OH 0 Mg,ngc12 H on H2504 a» 3. benzene kz COZCH3 O C H —Br 2 H3 CH3 Br2 2 Zn, I )' t€> CH3 CHZ-Br DMF LiAlH4 ”CW iR (\9 Samran Bhu-anantanondh 0 HO—CHZ—CHZ-OH o... MCPBA C? L> CO ———> 'rson, c6116 7 tBuLi o 0 Q; 9 .. .. Q _]:>=cn_&_OCH3 ;C2H50)P—CH2—C—OCH3 ‘0 T— ‘ 7 5R L'/NH /c H on if)“ 1) HZ/Pd/C l 3 2 5 ) LiAlH 0+ 1) H3 2) TsCl, Pyridine CHZ-CHZ-OTS 4 0.. \1 CHZ-CHz-OH 501R, .4. ) H30 2) TsCl, Pyridine F:O—CHZ-CH2—o'rs W llj¢3 FLUXIONAL NORBORNYL CATIONS SYNTHETIC APPROACHES TO TRICYCLOI6,2,1,01'6]UNDECA-2,4-DIENYL CATIONS AND 3,3-DIMETHYLTRICYCLO[4,2,l,01'4]NONAN-2-ONE BY Samran Bhu-anantanondh A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1975 To my parents, sister, brother and Sirina Phisanbut for their encouragement ii ACKNOWLEDGEMENTS The author wishes to express his gratitude to Professor Donald G. Farnum for his advice, interest and friendship throughout the course of this study. Thanks to the Royal Thai Government for financial support and also to the Department of Chemistry for partial support during the time in the United States. Thanks also go to the Farnum group: Botto, Chambers, Duhl, Geraci, Hagadorn, Lindsey, Mader, Raghu, Reitz and Wle whose friendship made the life bearable while away from home. Finally, thanks to Miss Mallika Thammakosala and Mrs. Carol Smith for their help in typing this dissertation. iii TABLE OF CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . RESULTS AND DISCUSSION A . . . . . . . . . . . . . . RESULTS AND DISCUSSION B . . . . . . . . . . . . . . EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . General . . . . . . . . . . . . . . . . . . . . 3,4-Dimethylhexane-3,4-diol Ia. . . . . . . . . 1,2,3,6-Tetrahydro-3,4,5,6-tetramethylphthallic anhydride 3". . . . . . . . . . . . . . . Dimethyl-l,2,3,6-tetrahydro-3,4,5,6-tetramethyl- phthallate a. O O O O O O O O O O O O O O Dimethyl-3,4,5,6-tetramethylphthalate QR, . . . 3,4,5,6-Tetramethylphthallic anhydride ax,. . . 1,2-Bis(hydroxymethyl)-3,4,5,6-tetramethyl- benzene QR,. . . . . . . . . . . . . . . . a) Lithium aluminum hydride reduction Of 3R 0 O I O O O O O O O O O O O O O O b) Two successive reductions of fixlwith lithium aluminum hydride. . . . . . . . 1,2-Bis(bromomethyl)-3,4,5,6-tetramethy1- benzene QR’. . . . . . . . . . . . . . . . 2-Carbomethoxy-l,2,3,4-tetrahydro-5,6,7,8- tetramethylnaphthalene 4R, . . . . . . . . a) The preparation of activated zinc . . . b) Reaction of Qg’with methylacrylate in the presence of activated zinc. . . . . iv Page 21 33 59 59 60 61 62 63 63 64 64 65 65 66 66 66 TABLE OF CONTENTS (Continued) Page 2-Hydroxymethyl-l,2,3,4-tetrahydro-5,6,7,8- tetramethylnaphthalene 29,. . . . . . . . . . 68 1,2-Bis(bromomethyl)benzene $§ . . . . . . . . . . 68 2-Carbomethoxy-l,2,3,4-tetrahydronaphthalene 4R, . 69 2-Hydroxymethyl-l,2,3,4-tetrahydronaphtha- lene QR! O O O O O O O I O O O O O O O O O O O 70 7,7-Dimethylbicyclol3,2,0lhept-2-ene-6-one SR, . . 71 7,7-Dimethyl-6,6—ethylenedioxybicyclo[3,2,0]- hept-z-ene 5A, 0 o o o o o o o o o o o o o o o 72 7,7-Dimethyl-6,6-ethylenedioxy-exo-bicyclo- [3,2,0]heptan-2-ol fig, Reaction of with diborane and by rogen peroxide . . . . . 73 Reaction of the mixture of and QA’with acetyl Chloride in pyri ine. Formation of exo-Z- -acetoxy- -7, 7-dimethy1- 6,6-ethylenedioxybicyclol3,2,0lheptane 65, and 3-acetoxy-7,7-dimethyl-6,6-ethylene- dioxybicyclol3,2,0lheptane Q6 . . . . . . . . 74 Reaction of the mixture of §§,andm “with chromium trioxide-pyri 1ne complex. Formation of 7,7-dimethyl-6, 6-ethylene- dioxybicyclo[3,2,0lheptan-2-one fix,and 7,7-dimethyl-6,6-ethylenedioxybicyclo- [3,2,0]heptan-3-one SQ. . . . . . . . . . . . 76 7,7-Dimethylbicyclo[3,2,0]heptane-2,6-dione ZR’. . 77 7:7-DimethylbiCYC1OI3,2.Olheptane-3,6-dione 2%,. . 73 7,7-Dimethyl-6,6-ethylenedioxy-l,3,3- trideuterobicyclol3,2,0lheptan-2-one ZR,. . . 79 7,7-Dimethyl-6,6-ethylenedioxy-exo-bicyclo- [3,2,0]heptane-2,3-oxide lRA, . . . . . . . . 79 Reaction of the epoxide lRA,with lithium aluminum hydride. Formation of 7, 7-dimethyl-6,6-ethylene- dioxy-exo-bicyclo[3,2,0lheptan-2-ol QR' . . . 80 TABLE OF CONTENTS (Continued) 7,7-Dimethyl-6,6-ethylenedioxy-exo-bicyclo- [3,2,0]hept-3-ene-2-ol le, Reaction of the epoxide lRllwith lithium diisopropylamide . . . . . . . . . . . . . Reaction of the epoxide lgllwith t-butyllithium 3-Carbomethoxymethylene-7,7-dimethyl-6,6- ethylenedioxybicyclo[3,2,0lheptane 56, . . a) Preparation of methyl diethylphospho- noacetate IRS . . . . . . . . . . . . . b) Reaction of lRfi’with the ketone 55, . . 3—exo-endo-Carbomethoxy-7,7-dimethyl-6,6- ethylenedioxybicyclol3,2,0lheptane IRR’. . a) Reduction of the conjugated ester with magnesium metal in methanol. . . . b) Catalytic hydrogenation of the conjugated ester SQ . . . . . . . . . . 7,7-Dimethyl-6,6-ethylenedioxy-3-exo-endo- (2-hydroxyethyl)-bicyclo[3,2,0] heptane . Reduction of the ester lRR’with ' lithium aluminum hydride . . . . . . . . . 7,7-Dimethyl-3-exo-endo-(2-hydroxyethyl)- bicyclo[3,2,0lheptan-6-one Qwi . . . . . . 7,7-Dimethyl-3-exo-endo-(2-ethyltosylate)- bicyclol3,2,0lheptan-6-one 53R.° . . . . . 7,7-Dimethyl-6,6-ethylenedioxy-3-exo-endo- (2-hydroxyethy1)-bicyclo[3,2,0lheptane . Reduction of the conjugated ester gééwith lithium-ammonia. . . . . . . . . . 7,7-Dimethyl-3-exo-endo-(2-hydroxyethyl)- bicycloI3,2,0lheptan-6-one QRR,. . . . . . 7,7-Dimethyl-3-exo-endo-(2-ethyltosylate)- bicyclol3,2,0lheptan-6-one QRR'. . . . . . vi Page 81 82 83 83 84 85 85 86 86 87 88 88 89 90 TABLE OF CONTENTS (Continued) Page S-Deutero-7,7-dimethyl-3-exo-endo- (2-hydroxyethyl)-bicyclo[3,2,0]- heptan’O-One m o o o o o o o o o o o o o o 90 5-Deutero-7,7—dimethyl-3—exo-endo- (2-ethyltosylate)-bicyclo[3,2,0]- heptan-G-one 52R.° . . . . . . . . . . . . . 91 Attempted synthesis of 3,3-dimethyl- tricyclol4,2,l,0‘"lnonan-Z-one 3k . . . . . 92 Reaction of the tosylate with sodium hydride and t-butanol in glyme . . . . . . . 92 Reaction of the tosylate Sgaiwith t-butyllithium in tetrahydrofuran. . . . . . 93 Reaction of the tosylate QRR’with methylsulfinyl carbanion . . . . . . . . . . 93 Reaction of the tosylate Sgb,with sodium ethoxide in ethanol . . . . . . . . . 94 Reaction of the tosylate QRR’with t-butyllithium in HMPA and tetrahydrofuran. . . . . . . . . . . . . . . 95 General procedure for attempted cyclization of the tosylate Qg . . . . . . . 96 BIBLIOGRAPHY o o o o o o o o o o o o o o o o o o o o o 9 7 APPENDIX.......................104 vii TABLE LIST OF TABLES Page Selected Norbornyl-fused Cyclic Sigmatropic Systems . . . . . . . . . . . . . . . 18 Study of Base Catalyzed Rearrangement of EPOXide W O O O O O O O O O O O O O O O O O O O 49 Attempted Cyclization of Tosylate 53’ with Various Bases and Conditions . . . . . . . . 56 viii FIGURES 1. 2. 8. 9. 10. 11. 12. 13. LIST OF FIGURES Classification of [i,j]Sigmatropic Shifts Suprafacial and Antarafacial Migration on n and 0 Systems. . . . . . . . . . . . Selection Rules for Sigmatropic Reactions of Order [i,j] with i and j >1 and Migration Occurs with Retention . . . . . Thermal Rearrangement of (S)-Cis, Trans- 3-methyl-7-deuteroocta-4,6-diene. . . . . Transition State for Thermally-Allowed Sigmatropic Shifts in Benzenonium and Cyclobutenium Ions. . . . . . . . . . . . Dihydropyrazines Subjected to Study under Photochemical and Thermal Conditions. . . Pathways Proposed to Obtain Ions %§,,%1 and ZR. 0 O O O O I O O I O O O O O O O 0 Synthetic Pathways to Alcohol QR, . . . . Synthetic Pathways to Alcohol QR, . . . . C-13 NMR Chemical Shift Assignment of gg,and QR’. . . . . . . . . . . . . . . . Proposed Synthetic Pathways to %k . . . . Various Pathways for Conversion of Epoxides to Alcohols or Ketones . . . . . Base Catalyzed Rearrangement of Epoxides to Some Ketones . . . . . . . . ix Page 10 12 16 20 22 26 27 34 42 43 LIST OF FIGURES (Continued) FIGURE Page 14. Proposed Mechanism for Rearrangement of an Epoxide to Ketones. . . . . . . . . . . . . . . 44 15. Synthetic Pathways to the Tosylate 52R, . . . . 51 16. Apparatus Used for Preparation of Ketone 59’. . 103 17. Proton NMR Spectrum of 7,7-Dimethyl-6,6- ethylenedioxybicyclol3,2,0lhept-2-ene a4. . . . 104 18. Proton NMR Spectrum of 7,7-Dimethyl-6,6- ethylenedioxy-exo-bicyclol3,2,0lheptan- 2-01 a O O O O O O O I O O O O O O C C I O O O 105 19. Proton NMR Spectrum of 7,7-Dimethyl-6,6- ethylenedioxy-exo-bicyclo[3,2,0lheptane- 2,3-oxide 1&1 . . . . . . . . . . . . . . . . . 106 20. Proton NMR Spectrum of 7,7-Dimethyl-6,6- ethylenedioxybicyclo[3,2,0lheptan- z-one a. O O C O C O C C C C O O O O O O O O O 107 21. Proton NMR Spectrum of 7,7-Dimethyl-6,6- ethylenedioxybicyclol3,2,0lheptan- 3-one QR. O O O O O C O O O O C O O O O O O O 0 lo 8 22. Proton NMR Spectrum of 7,7-Dimethylbicyclo- [3,2,0]heptane-2,6-dione 22'. . . . . . . . . . 109 23. Proton NMR Spectrum of 7,7-Dimethylbicyclo- [3,2,0]heptane-3,6-dione LI . . . . . . . . . . 110 24. Proton NMR Spectrum of 7,7-Dimethyl-3-exo- endo-(2-ethy1tosylate)-bicyclo[3,2,0]- heptan-6-one 52R, . . . . . . . . . . . . . . . 111 25. Proton NMR Spectrum of 7,7-Dimethyl-3-exo- endo-(2-ethy1tosylate)-bicyclol3,2,0]- heptan-6-one 52R, . . . . . . . . . . . . . . . 112 X INTRODUCTION The uncatalyzed thermal intramolecular rearrangement was first detected by Claisen1 in 1912. The required structural feature of the Claisen rearrangement is a vinyl (or phenyl) allyl ether which rearranges to the isomeric 7,6-unsaturated carbonyl system according to equation 1. The gross mechanistic picture was described by Claisen2 as a cyclic process involving simultaneous bond-breaking and -forming, accompanied by relocation of f 1 A (x “10 \0 \/j ——-—> [ j —————> (1) \ \V/ / the double bond in the allylic system. Since then, the details of this mechanistic pathway have been studied. A great deal of evidence collected, such as the absence 3'4 the first- of mixed products in crossing experiments, order kinetics, and the negative entropy of activations support the proposed mechanism as a concerted one—step reaction. The all-carbon analog of the Claisen rearrangement was first discovered by Cope and Hardy.6 They found that when the ester l’was heated at 150-160° for four hours, it completely rearranged into ester 2Iwhich is formed by migration of an allyl group as shown in equation 2. N CH CH / 3 ,”A“\ CN CH 3 \ (C): C H CO C H g : OZCZHS 2 2 5 1—5—5—9 ————> ‘~ 2 \\\ ‘V§§;>’ ./’ k z, (2) Cope-type rearrangements have been extensively studied to date.7 The absence of ”cross over” products, the first- order kinetics, and the negative entropy of activation again were interpreted as evidence that the reaction pro- ceeds through a concerted process with a cyclic transition state as proposed by Cope. Another thermal isomerization involving [l,5]hydrogen transfer with migration of both carbon-carbon double bonds 9 as described in equation 3 has been observed.8 Borg had shown that rearrangement of deuterated cycloheptatriene Q, / \ J/ (3) ’l to Qiupon heating occurred through [l,5]hydrogen migration. 10 Roth also studied the [1,5] shift in 1,3—pentadiene. 0 100-140 ‘ H n (4) D V H l & He found that when deuterated compounds 5iand fitwere heated at 200°, they isomerized to SR, 5R’and 6R, 6R,re- spectively. A more beautiful example by the same author11 m I m : mm C02 CH3 HCD2 CH2 HCD CHZD 5. 5R. RR. \ / \ | | ‘ (6) V——" F— CH2 CD3 HZCD CD2 HCD CHD2 5, RR, RR. demonstrated the preference for a [1,5] shift over a [1,3] shift under thermal conditions. Thus, heating compound 1’ scrambled deuterium over all nonaromatic positions through [1,5] shifts even though they have to proceed through the unfavorably nonaromatic isoindene 8, Also, on heating 03: on: 7,8-dideutero cycloocta-1,3,5-triene IR, deuterium scrambling was found only in positions 3, 4, 7 and 8. (D (D) (D) (D) D (D D) 1,3 1,5 f:;;::; -————e> (D (D) D‘ (D D) (D)(D) 19. This proves that migration through a sequence of [1,5] shifts is preferred over [1,3] shifts under thermal con- ditions. Alkyl migration in a charged species has also been known for a long time. Meerwein13 demonstrated that cationic carbon intermediates were involved in the cam- phene hydrochloride-isobonyl chloride (11,-:;12) isomeri- zation. This simple [1,2] alkyl shift is commonly known as the Wagner-Meerwein rearrangement. [- '1 *3 .___> <- 0

(C=C)n-—-C shift when the bond migrates from position [1,1] to posi— tion [i,j] as shown in Figure l. Figure 1 Classification of i,j sigmatropic shifts R / \ %\ 1 3 shift\ 1,5 Shift\ \ 3, 3 shift / \ 1,6 shift ‘_ f 4 Shift\ x 1,4 shift \ \ at \ )I * = Charges species / \ \ Dependent on the steroechemical results, there are two different types of sigmatropic rearrangements: supra- facial shifts and antarafacial shifts. A suprafacial shift is one where a group migrates on the same face of the pi-system. An antarafacial shift is one where the migrating group flips from one face to the opposite face of the conjugated system. If a migrating group can undergo inversion of configuration, suprafacial and antarafacial additions to a sigma bond can be defined in terms of re- taining or inverting configuration of the atoms that form the migrating bond. A suprafacial addition arises when both atoms retain or invert configuration. An antara- facial addition arises when one atom retains and the other inverts configuration, as shown in Figure 2. For sigmatropic Changes of order [i,j] in which both i and j are greater than 1 and migration occurs with re- tention of configuration at the shifting site, the orbital symmetry rules for the neutral, cationic and anionic species are summarized in Figure 3. However if migration proceeds with inversion of configuration at the shifting center, the selection rules are precisely reversed. The Woodward-Hoffman rules make unambiguous predic- tions in pericyclic reactions. The experimental results are all in accord with prediction: rapid methyl or 16,17 an hydrogen migration found in benzenonium ion d Figure 2 Suprafacial and antarafacial migration on w and 0 systems 0. ‘\ suprafacial \ on 0 system A / 4 n \ antarafacial ‘ ,I R B\/ r on n system C D suprafacial addition to 0 bond retention at R suprafacial addition to o C D bond inversion at R antarafacial ‘ addition to 0 bond retention at R antarafacial A addition to 0 bond inversion at R Figure 3 Selection rules for sigmatropic reactions of order [i,j] with i and j >1 and migration occurs with retention; q is an integer. i+j ground state excited state neutral cation anion 4q 4q+1 4q+3 antara-supra supra-supra supra-antara antara-antara 4q+2 4q+3 4q+l supra-supra antara-supra antara-antara supra-antara very slow methyl or hydrogen migration, if any, found in cyclobutenium ion18 agree with thermally allowed [1,6] sigmatropic shift and thermally forbidden [1,4] sigma- tropic shift in cationic species respectively. In addi- tion, a number of cases which were not known before, particularly concerning the stereochemistry of sigmatropic shifts, have been tested and seem to support the predic- tive value of orbital symmetry rules. In his study of the 19 showed stereochemistry of thermal rearrangements, Roth that at 2503 diene lg,proceeded by way of [1,5] supra- facial sigmatropic hydrogen shift to a mixture of lfiland l§,as predicted. Berson15 also demonstrated that bicyclic 10 Figure 4 Thermal Rearrangement of (S)-Cis,Trans- 3-methyl-7-deuteroocta-4,6-diene Et suprafacial Et 11 compound lfilunderwent [1,3] thermal sigmatropic shift to lx’with inversion of configuration of the migrating group, which is completely consistent with the orbital symmetry 1,3 shift ' 1) with inverfium s1on rules. OAc 33D It would be worthwhile to discuss the geometric and steric requirements of the transition state of sigmatropic shifts. For example, in [1,6] migration of heptamethyl- benzenonium ion, suprafacial migration with retention of configuration of the shifting carbon would allow maximum bonding overlap throughout the transition with little ad- justment. However, the transition state for antarafacial shift with inversion of the migrating center would be unfavorably distorted in order to assure optimum overlap. Thus this would require higher activation energy. As predicted, suprafacial [1,6] migrations in benzenonium ions were rapid but antarafacial migration did not occur. In contrast to the benzenonium ions, the symmetry rules pre- dict thermally allowed-antarafacial [1,4] sigmatropic shift with retention of configuration of the migrating center and allowed-suprafacial [1,4] shift with inversion of configuration of the migrating center in 12 pentamethylcyclobutenyl cation. Antarafacial migration in such a small ring would result in a severe distortion in the transition state and highly strained product and will require a prohibitively high activation energy. Suprafacial migration with inversion of the shifting carbon also faces severe steric hindrance which still causes an energetic disadvantage in the transition state as shown in Figure 5. Thus the [1,4] sigmatropic shifts did not proceed in cyclobutenyl cations. suprafacial-retention antarafacial-inversion (Q L CDNIP suprafacial-inversion antarafacial-retention Figure 5 Transition State for Thermally-Allowed Sigmatropic Shifts in Benzenonium and Cyclobutenium Ions. It is well known that [1,2] sigmatropic shifts or commonly called Wagner-Meerwein rearrangements in nor- bornyl cations are so facile that they require relatively 13 19 0 small activation energy. Schleyer2 showed that the 1,2- dianisyl-Z-norbornyl cation lglpossessed a rapidly equili- brating ions at room temperature. More recently Olah showed . room temp.> \ CH O OCH u. that both 1,2—dimethyl-2-norbornyl cation21 lg’and 1,2- diphenyl-Z-norbornyl cation22 QR’were rapidly equili- brating ions having low energy barriers for the 1,2- Wagner-Meerwein shifts. CH CH In the crystal studies of some norbornyl derivatives, Macdonald and Trotter23 found that there was a considerable 14 strain in norbornyl skeleton. The carbon-carbon single bonds are all of normal length with the average distance of 1.54 A. However all the angles are less than tetra- hedral value ranging from 101° to 108° except the bridge angle being 96-97°. Estimating from a molecular model of the rigid norbornyl system,24 if Sp2 hybridization at C-2 is assumed, the deviation of the vacant p orbital from the C6-Cl-C2 plane is approximately 20°. Furthermore the C6-Cl bond is nearly parallel to the empty p-orbital, this deviation being approximately l7-21°. Such a suit- / ,/;’ \ l\ H 20° able stereo-electronic arrangement in the norbornyl skeleton allows maximum overlap in the transition state with little adjustment and thus helps accelerate the allowed process for sigmatropic rearrangements. The accelerating effect of the norbornyl system was shown by Farnum and Carlson?5 in their study of sigma- tropic shifts in 1,2,3,4,4a,6,7,8,9,9a-decahydro-syn- 2,4a,7,9a-dimethanophenazine 22, a compound which is predicted to undergo two simultaneous sigmatropic shifts photochemically. According to the orbital symmetry rules, 15 if the synchroneous rearrangement of 22’proceeds with retention of configuration at both migrating centers, then it will be a [as2 + n52 + 0a2 + Hazl or entirely suprafacial or entirely antarafacial process. As ex- pected, the optically active compound zgldid undergo %& 22a racemization upon irradiation. Under thermal condition ggldid not racemize. The same study26 was also carried out on dihydro- pyrazines 23, 2Aland 2;,1isted in Figure 6, none of which showed such a rearrangement under photochemical or thermal conditions. It is very interesting that in the study of these synchroneous sigmatropic shifts, only the norbornyl system promoted the rearrangement. The stereoelectronic factor that enhances or retards the rate of sigmatropic reaction is receiving increasing 27'28 Berson and coworkers29 attention in the literature. showed that violation of conservation rules in a reaction could be permitted if the structural features of the sub- strates interfered with the concerted-allowed pathway. Thus rearrangements occurred through a concerted-forbidden process. 16 Figure 6 DihydrOpyrazines subjected to study under photochemical or thermal conditions. {DEE at: 3:7; 3191 dog) 215. KER. It was our interest to design a system that provides a unique framework in such a way that maximum stereo- electronic efficiency could be obtained in order to super- accelerate an already facile sigmatropic process or perhaps to permit the concerted-forbidden reactions to occur. As described earlier, the norbornyl skeleton should be one that is well suited for rearrangement. Furthermore it has already been known to accelerate a 17 photochemically allowed process. Thus if the norbornyl skeleton could be fused into previously known systems where sigmatropic migrations are predicted to be allowed or forbidden processes, the resultant compounds should allow an excellent opportunity for the rate enhancement of sigmatropic Shifts and the possible detection of re- arrangement in a forbidden process. A few examples of the designed-fused norbornyl sys- tems30 for neutral, carbonium ion and carbanion species as well as their thermal and photochemical orbital symme- try selection rules (assuming retention of configuration of migrating carbon) are summarized in Table 1. None of these has been explored to date, therefore it would be worthwhile to investigate this area of sigmatrOpic shifts. The initial goal of this study was to synthesize the cations 26, 2x’and 28, The cations 2R’and 2X’were pre- dicted to Show thermally allowed-suprafacial shifts with retention, and the rate of rearrangement was expected to 2R 2,1 m be faster than that of benzenonium ions. The cation 28 18 TABLE I Selected Norbornyl-fused Cyclic Sigmatropic Systems. Woodward-Hoffmann Rearrangement type Compound selection rules A hv forbidden allowed 1,4 sigmatropic shift ‘) allowed forbidden 1,5 sigmatropic shift .) . allowed forbidden 1,6-sigmatropic shift allowed forbidden forbidden allowed 1.7 sigmatropic shift forbidden allowed 19 was predicted to Show a thermally allowed-suprafacial shift with inversion. Since inversion would cause a severe strain in the transition state and because of the accelerating effect of the norbornyl skeleton, the reac- tion might proceed through a forbidden—suprafacial- retention pathway. We proposed to make the cations 26, 2X,and zg’from alcohols 29, QR’and ketone 31,as shown in Figure 7. Thus the main part of this project was simply to synthesize the compounds 29, QR’and QAIand to investigate their chemical properties in strong acid media. Figure 7 Pathways proposed to obtain ions 26, 2X’and 28 21 RESULTS AND DISCUSSION A Synthesis of 2-hydroxymethy1-l,2,3,4-tetrahydro-5,6,7,8- tetramethylnaphthalene 2R’and 2-hydroxymethy1-l,2,3,4- tetrahydronaphthalene QRIand their reactions with fluoro- sulfonic acid. As mentioned previously, we proposed to make cations 2fi’and 2R’from alcohols 29’and QR’respectively. Therefore our intention was to prepare compounds 2R’and QR, The synthesis of the alcohol 2R’was carried out as outlined in Figure 8. The first step was the formation of dimethyl- hexane diol 32, This compound was obtained according to Berkoff's procedure31 by the coupling reaction of 2- butanone. The diol 22’showed diastereotopic ethyl groups in the nmr spectrum with centers at 6 1.41 and 0.90 for the methylene and methyl protons respectively. Conversion of the diol 22’to the diene QR’was achieved in poor yield by distilling 22Iwith concentrated sulfuric acid. The nmr spectrum showed that the distillate contained another unidentified diene which is believed to be 22, The diene qglcould be purified by redistillation. CH2 fl CH3-CH2-C-C-CH-CH3 CH 3 4k 22 Figure 8 Synthetic Pathways to Alcohol 22 / 2 Mg, HgCl ;% H+ % / \ (36116“:—9 42, H313. I)? 0 Co CH CO CH O 2 3 2 3 4510% Pd/C 4/ ‘ ‘ V Co CH COZCH3 CH 30H 2 3 o QR QR, 3,4, L1AlH4 10% Pd/C 1 _ O HZOH LiAlH4 o LiAlH e—__‘ 6—____.4__ CH CH 2 J 0 51/3. 4% QR. PHr3 C6H6 /Coz CH3 Cflzgr H COZCH3 H on n, . 2 .___DMF1> L1A1H4 CH '—“————— 2 1 42, AR 219, 23 However, the impure diene QR’could be used without further purification. Treatment of the diene QR’with maleic anhy- dride formed the Diels-Alder adduct, tetrahydrophthallic anhydride 3A’(m.p. 91.5-94°). The overall yield of 34 from the diol Qz’was 23%. The spectral data were consis- tent with the assigned structure. The nmr spectrum showed two types of methyl proton absorptions at 6 1.42 (d, J = 7 Hz, 6H) and 1.67 (s, 68). Esterification of 3A’on refluxing with a catalytic amount of concentrated sulfuric acid in excess methanol gave the diester QRIin 74% yield, m.p. 50-52°. The sing- let absorption of six protons at 6 3.63 in the nmr spectrum and the ir absorption at 1745 cm-1 supported the diester structure. Dehydrogenation of the tetra- hydroester QR’was carried out on direct heating with 10% palladium-charcoal under a nitrogen atmosphere to afford the aromatic ester 3§Iin fair yield (60%). The two singlet signals with the same ratio of protons at 6 2.20 and 2.23 in the nmr spectrum gave evidence that four methyl groups are now attached to an aromatic ring. Other spectral properties were also in accord with the aromatic ester 36. Treatment of the ester 3fi’with lithium aluminum hydride in refluxing ether produced a clean diol QK'in 90% yield. The ir spectrum of the purified alcohol 3% 24 (m.p. l7l.5-l73°) showed the hydroxy absorption at 3330 cmfl. The nmr spectrum exhibited the methylene proton signal at 6 4.70. The mass spectrum had the parent peak at m/e 194 (calc. mass of 38, 194). The alcohol Qfi’could be obtained by an alternative pathway from the tetrahydrophthallic anhydride 3A, De- hydrogenation of 3AIupon heating with 10% palladium- charcoal afforded the desired phthallic anhydride 3x,in 50% yield. Again, two singlet signals in the nmr spectrum at 6 2.33 and 2.63 were clearly evidence that the aromatic ring was formed. The ir spectrum showed absorptions at 1851 and 1785 cm-1 which were characteristic of an anhydride. Attempts to reduce QX.t° the alcohol QR’with lithium aluminum hydride in one step were unsuccessful. In all trials, the isolated material had the same relative in- tensity of signals in the nmr spectrum. This material was not identified and it was believed to be a mixture of two compounds. One of these was suggested to be the lactone 42, However, when this material was reacted with 25 lithium aluminum hydride again, it proceeded smoothly and cleanly to the alcohol QK’in 95% yield from.3}, The dibromide QR’which served as a key intermediate for the synthesis of the alcohol 29, was obtained from the reaction of the diol 38,with phosphorus tribromide. The white, needle-like solid was obtained in greater than 80% yield, m.p. 163-164° after recrystallization from hexane. All spectral properties were in accord with the assigned structure. Conversion of the dibromide 391to the ester 4RIwas achieved in 72% yield by reaction with activated zinc and methyl acrylate in dimethylformamide. The spectral data of this solid ester, m.p. 91-92.5°, fully supported the proposed structure. The course of this reaction probably involved debro- mination by zinc to form a 1,3-diene intermediate QR, followed by Diels-Alder reaction with methyl acrylate to the desired ester. t L g _1 02CH3 H23rzzn / H2 COZCH3 crrg'ar \ H £22. 48‘. AR. Finally, reduction of the ester QRlusing lithium aluminum hydride provided the alcohol 32.13 95% yield (m.p. 101-102°). The mass spectrum showed the parent 26 peak at m/e 218 (calc. mass for alcohol 29, 218). Both ir and nmr spectra were consistent with the expected structure. The synthesis of the alcohol 3R,was carried out in a similar way to that of the alcohol 29’(Figure 9). Bro- mination of o-xylene Qfilafforded the dibromo compound $5 in 48% yield. This lachrymal compound 4;, m.p. 92-93° was then converted to the bicyclic ester Qfilin the same fashion as described for the preparation of the ester QR, Finally, treatment of the ester 4§,with lithium aluminum hydride gave the desired alcohol QR’cleanly and smoothly. The spectral data of all compounds were in accord with assigned structures. CO2 CH3 H 2Br (0 C02 CH3 H 20H bE—z—m 2,, ———Lbe be H2 Br LiAlH4 1% 1R, Figure 9 Synthetic Pathways to Alcohol 3R, The C-13 nmr spectra showed that both alcohols zg’and 3R,possess partially symmetrical structures. The alcohol 29’showed only four aromatic carbon signals at 6 132.4, 132.1, 132.8 and 131.6 and two signals for the methyl groups at 16.5 and 15.5. The alcohol QRlshowed five 27 aromatic carbon signals at 5 136.7, 135.9, 129.2, 128.8 32 and and 125.6. On the basis of some model compounds coupled spectra of both alcohols, the chemical shifts were assigned as shown in Figure 10. 15.5 B6 16 132.4 67 5 132.1 CH Z-OH 131.8 131.6 37 02 25. 9 ER 129.2 32.4 128.8 28.7 27 67.5 Hz—OH 25.6<<: 37'0 25.9 ‘136.7\ 135.9 %8 Figure 10 C-13 nmr Chemical Shift Assignment of gg’and 30 28 At this point, we had both alcohols zgland QRIin hand. The next step was to look into their reactions in fluorosulfonic acid solution. These reactions were fol- lowed by both H-nmr and C-13 nmr spectroscopy. The compound 3leas slowly added into a solution of fluorosulfonic acid and fluorosulfuryl chloride at -78°. The mixture was observed by C-13 nmr spectroscopy at various temperatures. The temperature-independent (-50° to -lO°) spectrum consisted of aromatic absorptions at 6 136.6, 134.6, 130.1, 127.0 and 126.5 along with saturated carbon absorptions at 79.4, 34.4, 31.4, 29.0 and 25.0. All saturated carbon peaks were broad at -50° and only slightly sharpened up at -10°. When the solution of the ion was warmed to higher temperature, it slowly decom- posed. The C-l3 nmr data suggested the structure a. The charge distribution in the ion remained about the same as CH -OH RR. in the neutral compound except for the methylene carbon attached to the hydroxy group. The change in the chemical shift of this methylene carbon was likely to be expected for a protonated alcohol. The difference of 12 ppm (79.4 29 ppm in ion 4X,and 67.5 ppm in QR) was comparable to that of 15 ppm between methanol and its protonated form (62.0 ppm in CH3OH2 and 47.4 ppm in CH3OH).33 The nmr data rules out the desired static classical ion 2}, since, for this, a cationic carbon peak in the nmr spectrum should be expected. Besides that, the posi- 1 _,_: 2g 6% 0 2X, MR tive charge should be built up in the aromatic ring as in 34 the case of ion QR, Rapidly equilibrating pairs of classical ions (QXR’¢=2XR) were also rules out, because the C-13 nmr would exhibit a simpler spectrum. 152.5 \ 125.2 131.8 165.5 193.8 0‘ —=— 4R. Charge Distribution in Cation $8 Protonation on the aromatic ring to form the classical ion 49,could be excluded since the nmr data did not show any significant positive-charge distribution which is a 30 + + H —OH CH2“”‘2 H 2 2 H H bbb ARR, characteristic of a carbocation ion such as benzenium ion ion 54.34 180.8 138.8 180.8 88 C-13 Chemical Shift in Benzenium Ion The HNMR spectra of 30,1n FSO H—FSOZCl solution 3 showed resonances at 6 7.5 (m), 4.6 (bs) and 1.43-3.56 (m). The broad signal at 6 4.6 was consistent with the chemical shift of methylene protons alpha to oxygen in a protonated 35 The relative integral ratio of signals at 6 alcohol. 7.5 and 4.6 of 2 and no other signal at 6 4.0-6.0 as expec- ted for the added proton ruled out ion 49, Thus both HNMR and CNMR spectra were in accord with the proposed ion 41, When the alcohol gg’was dissolved in fluorosulfonic acid, a purple solution was formed. The CNMR spectrum, at -50°, showed a signal at 6 77.7 and two other broad 31 absorptions at 6 20-25 and 29-34. Aromatic carbon absorp- tions were not detected. The broad signals gradually sharpened as the solution was slowly warmed up to -20° to -15°. At -15°, the two broad signals resolved into sev— eral sharp peaks. Chemical shifts were recorded as fol- lowed: 77.7, 33.9, 31.9, 31.5, 23.7, 21.2, 20.7 and 20.2 ppm. The aromatic signals could not be obtained again, possibly due to relaxation time. However, the spectrum showed a very broad absorption at 6 140-170. When the solution was warmed above -10°, the spectrum began chang- ing with the appearance of several saturated carbon signals, presumably from decomposition. The HNMR spectra of the solution also showed broad signals at lower temperatures (-600 to -40°). At -60°, the spectrum possessed broad absorptions at 6 4.75, 4.21 and 3.48-1.39. When the solution was warmed up to -40°, the signal at 6 4.21 became broader while the other became sharper. However at -20°, methyl absorptions were re- solved. The spectrum showed three singlet peaks at 6 2.46, 2.41 and 2.10 with relative area of 1:1:2. Other absorptions were at 6 4.73 (broad doublet), 4.31 (multi- plet) and 3.38-1.40 (multiplet). The HNMR spectrum at -60° indicated that either ion 51R,or filb'was formed. At -40° to -20°, it indicated that rapid equilibration of ions (51R,#=51R) occurred resulting 32 in broadening of the added proton at 6 4.21 due to coupling with more different protons. The C-13 chemical shift study indicated protonation of hydroxy group. However due to poor resolution of the aromatic signals, the CNMR could not confirm protonation on the aromatic ring as suggested by the HNMR spectrum. 33 RESULTS AND DISCUSSION B Synthetic Approach to 3,3-Dimethyltricyclol4,2,1,01’4] nonan-Z-one 31 We proposed to achieve the synthesis of tricyclic ketone 31’by means of cyclization of the bicyclic keto tosylate 52. The total synthetic plan is outlined in ‘% CH —-CH —OTS % 41 Figure 11. This route required 7,7-dimethylbicyclol3,2,0] hept-2-ene-6-one figlas a starting material. This compound is well suited as a starting material in many ways. First, it provides two functionalities, ketone and olefin, in which each function could be easily transformed to the desired structure. Second, it has been known in the lit- erature36 and can be synthesized without much difficulty. Finally, it is a very stable compound and can be kept under nitrogen atmosphere at room temperature for at least nine months. 34 Figure 11 Proposed Synthetic Pathways to 3,1, D l 5 ‘CH-C—OCH O HZ—CHZ—OH —————> CHZ-CHZ-OH <——$ //O <""““"" H —CH ~0Ts 35 The synthesis of 7,7-dimethyl-6,6-ethylenedioxybicyclo- [3,2,0]heptan-3-one 55, According to the literature, the ketone 53,was pre- pared by means of addition of dimethylketene generated by direct pyrolysis of 2,2,4,4-tetramethyl-l,3-dione 5237 to cyclopentadiene. With some modification, we generated °\\ 56% QR. C\\ b +8 ———> -5, 5R, dimethylketene QR’by pyrolyzing its dimer 52,30d passed it directly into a solution of cyclopentadiene in aceto- nitrile. This reaction afforded a 56% yield of 53, The nmr and ir spectra were consistent with those reported previously. The chemical shift of the methine proton (H-S) at 6 3.38 and its multiplicity (doublet of triplet, J = 7, 3 Hz) appear to distinguish the ketone QR’from its isomer fil’which has never been observed from such a reaction. 36 5636 The next step of the synthesis requires protection of the carbonyl function in the compound figtfollowed by transformation of the olefinic function to another. Hydroboration and oxidation appears to be a suitable pathway to convert an olefin to an alcohol. \ (\L‘ (\ (K / ———9 / 6% +0 3011 OAc O 8/5. ‘83. Q1 52, The ketone fig’was therefore protected as an ethylene ketal 5A, This ketalization proceeded cleanly and in quantitative yield. The presence of the ketal function 37 moved chemical shifts of all protons to higher field as expected especially that of the methine proton (H-S), which moved from 6 3.83 in 5R’to 6 2.96 in 5A, Treat- ment of QA’with diborane in tetrahydrofuram followed by oxidation with hydrogen peroxide in basic solution afforded a mixture of alcohols in more than 95% yield. Gas chromatographic analysis showed that the mixture consisted of two alcohols with a ratio of 7:3. These two alcohols were presumed to be alcohols fig’and fifllrespective- 1y. The proof of this was given later. Attempts to sep- arate these two isomers on column chromatography were unsuccessful. Separation by preparative vpc gave only pure fig’which is the major isomer. Reinjection of the other collected fraction still showed the presence of 63, The proton magnetic resonance spectrum allowed a decision about the stereochemistry of 63, The spin-spin coupling of the proton (6 3.96) alpha to the hydroxy group showed a broad doublet with a coupling constant of 4 Hz. This was consistent with that expected from the egg alcohol 63; Although the ketal alcohol QAIcould not be separated, it could be characterized as an acetate. Treatment of the mixture of alcohols QR’and QA’with excess acetyl chloride in pyridine afforded a mixture of acetates fifiland QR,in 92% yield and a ratio of 2:1 respectively as analyzed by 38 gas chromatography. Conversion of the ketal alcohol Q4 to the acetate fifitwas complete but 7.2% of the ketal a1- cohol fig’remained. Separation of acetate isomers was achieved by column chromatography. The spin-spin coupling of the proton alpha to the acetyl group in the nmr spectra permitted the isomeric acetates to be identified as fik’and fifi’respectively. The broad doublet at 6 4.88 (J = 4 Hz) was consistent with the assigned structure fig’as well as its stereochemistry. A triplet at 6 5.17 (J = 7 Hz) was also in accord with the acetate 66, The stereochemistry of fifi,could not be established from the nmr or ir spectra. However, the stereochemistry of this compound was sug- gested to be an exo acetate fifia’on the basis of attack of borane on the less hindered side. It is very interesting that hydroboration of 5A,gave fig,as a major product. Brown38 also observed that hydro- boration of fifllgave a mixture of alcohols fig’and ZR’with a ratio of 6:4. The reason for this is not clear. 39 1 h, ._. u. . 0H QR 69, OH %Q The structural assignment of alcohols fig'and fiklwas confirmed by oxidation of the mixture of alcohols to ke- tones according to Dauben's procedure39 followed by de- ketalization. The mixture of fig,and fiAlwas subjected to oxidation using chromium trioxide-pyridine complex to afford a clean mixture of ketones fifiiand fix,in a ratio of 3:7 according to gas chromatographic analysis. This ke- tone mixture was then separated by column chromatography. Both ir and nmr spectra of these ketones are quite differ- ent. The ir spectrum of 55’showed a carbonyl absorption 1 and that of 6R,at 1739 cm-1. The nmr spectra at 1750 cm- were markedly different in the spin-spin coupling. The ethylene ketal protons in QRIshowed a broad singlet while those of figlshowed a multiplet. The signals for the pro— tons at C-1, C-2 and C-4 of 5§,were less complex than those for the protons at C-1, C-3 and C-4 of 6}, However, the evidence collected from nmr and ir spectra would not permit a definite structural assignment for ketones fig’and 6}, Therefore both ketones 5§,and 62,were subjected to further reactions. Deketalization of 5§,and QXIProduced diketones Zl’and 72,respectively. 4O 0 0 RX, 12. The spin-spin coupling of the methine (H-l) proton resolved the conflict between the two structures. A doublet for the H-1 proton at 6 2.60 (j = 8 Hz) which was split by the H—5 proton was consistent only with the diketone 22, A complex signal at 6 2.70 split by 2H-2 and H-5 protons was consistent with the diketone 21, Additional evidence to confirm the structure of 6x,was obtained from proton-deuterium exchange. Thus stirring fiztwith sodium methoxide in deuterium ethoxide for two hours exchanged up to three protons as determined by the nmr spectrum. The signal of a broad triplet at 6 3.12 6 3.12 bd) 6 3.12(bt) ( CL: ‘1 NaOCH3 CZHSOD 41 (J = 8 Hz) in fix’changed to a broad doublet (J = 8 Hz) in 7}, Comparison of the integration ratio based on the methyl protons or ethylene ketal protons revealed that $3 possessed a multiplet of approximately two protons at 6 1.90. This is consistent with the deuterated ketone ZR. It is very unfortunate that the desired ketone fifi’was a minor product from hydroboration and oxidation reactions. Since the synthesis of Qllrequired many reactions, it was clear that a large amount of 5§Iwas required in order to complete the final step. Therefore a new route to 5§,was designed. A thorough search of the chemical literature provided several routes for the conversion of epoxides to ketones or alcohols as shown in Figure 12. Even though acid or salt catalyzed rearrangement of an epoxide to a ketone is well known, base catalyzed transformation may also be possible. In general, the dominant pathway for the reac— tion of a simple alkyl-substituted epoxide with a strong base is a rearrangement into an allylic alcohol.46 How— 47 and coworkers found that ketones were ever Crandrall also formed upon treatment of some epoxides with lithium diethylamide as shown in Figure 13. iPr 42 Figure 12 Various Pathways for Conversion of Epoxides to Alcohols or Ketones. mfk (CH ) /° QDO 113. .g M 049...... g g 40 O HCl, Etzo, H20; iPr ZR. 41 BF3. EtZO ‘\ benzene O u 42 fl 0 MgBrZ, EtZO X» (CH2)14 I \\_,.CH2 ZR. 43 Bu3PO, L1ClO4 5%> benzene O 816 . 44 L1A1H4 \ OH {273. R 45 C LiBr, HMPA \CH €> 3 benzene Figure 13 Base Catalyzed Rearrangement of Epoxides to some Ketones Et 2NLi ———> 86. 42 Ft 2NLi v. 88 28'” Ft NLl Gay—4905+ 030+ 24 8:. QROH In some cases, rearrangement to ketones was found to predominate over that to allylic alcohols. For example,48 the reaction of the epoxide 9x,with lithium diethylamide gave ketones afiland QR,as major products while the OH QR. QR. QR. U29. 44 allylic alcohol lRR’was found in a small yield. Crandall suggested that the steric effect of the methyl group in- fluenced the course of the transformation. The mechanism for the base catalyzed conversion of an epoxide to a ketone was pr0posed by Crandall48 to involve a-proton abstraction followed by rearrangement as depicted in Figure 14. Figure 14 Proposed Mechanism for Rearrangement of an Epoxide to Ketones. \ / x I Eje— / -—-> /c—' .- ——-> /C= C\ ———> /CH'C\ H H H l H R. H R .. , __ o R' C') ’R 0‘ '41— CH R/IC—C .- —_> fi -——-9 R / \ H H R H It appears to be very promising that the ketone 55 could be obtained as a major product from rearrangement of the epoxide 1R1, Thus treatment of the olefin 5AIwith metachloroperbenzoic acid yielded the epoxide lRlIin quantitative yield. The product appeared to be a single isomer as shown from the nmr spectrum and gas 45 O {V C :/>——> :206 it iii chromatography. The nmr data permitted the stereochemis- try of lRllto be established. A doublet at 6 2.13 (J = HcJP63.23, dd, J = 8,2 Hz 6 2.13, d,J = 8 Hz MAR. 8 Hz) and a doublet of doublet at 6 3.23 (J = 8, 2 Hz) confirmed the structure as well as stereochemisty as exo epoxide lRlR, Reaction of the epoxide 1R1,with lithium aluminum hydride gave only the alcohol 63, This is not very surprising since the less hindered position was attacked LiAlH ether 46 by the hydride ion. This reaction also confirmed the stereochemical assignment of fig’obtained from hydro- boration. When the epoxide lRl’was treated with lithium diisopropylamide in ether at reflux temperature, two products were formed in a ratio of 85:15. The minor (\L {\(L (\0 01 3‘ \+ O H’OH o W W 571 85% 15% product was found to be 6}, The spin-spin coupling in the nmr spectrum allowed us to assign the structure and stereochemistry of the major product to be an era allylic alcohol 1R2, A broad doublet at 6 3.37 (J = 7 Hz), a doublet at 6 1.95 (J = 7 Hz) and a broad singlet at 6 4.45 were consistent with those expected from the assigned structure. 47 6 3.37, bd, J = 7 Hz e 6 5.78 6 4.45, bs 6 1.95, d,J = 7 Hz 1% Treatment of the epoxide lRAIwith t-butyllithium at low temperature afforded the desired ketone 55, as well as 61, 102, 1R3, lRfi’and another in 71, 3.4, 15.4, 3.4, CE ———>O / O /+W'%”“” 7—— w, W W 3.4% 4.5% 15.4% 3.4% 71% 4.5 and 2.3% yield as analyzed by gas chromatography. Separation of QR, SRIand lRR’from a mixture of Lg; &‘UW% was achieved by column chromatography. However, separa- tion by preparative vpc afforded pure lRR,and 1R4, Struc- tures of both lRRland lRA’were assigned mainly on the basis of nmr spectra. However, further evidence to support the correctness of the proposed structures was obtained from nmr decoupling experiments. Irradiation of 48 62. 95 (dt, J = 7, 3 Hz) 6 3.63 )'<;;+> 6 1.00 (s) the methylene protons at 6 2.20 in the compound 1R3, changed the spin-spin coupling of the olefinic proton at 6 5.05 (m) to a doublet (J = 2 Hz). Similarly, irra- diation of the methylene protons at 6 2.40 in lRA’changed the triplet at 6 5.37 (J = 2 Hz) to a singlet. This was completely consistent with expected results from the proposed structures. The ketone fifi’was also found to predominate over the allylic alcohol le,and the ketone fix’in a variety of 49 solvents and butyllithium base catalyzed reactions as shown in Table 2. TABLE II Study of Base Catalyzed Rearrangement of Epoxide L01. % product base solvent 55’ 6,1, m others t-BuLi THF 71.1 3.4 15.4 10.1 t-BuLi pentane 33.5 13.5 31.3 21.7 n-BuLi pentane 40.7 10.2 29.8 19.8 n-BuLi THF-pentane 56.7' 2.6 21.9 18.8 n-BuLi THF 56.0 2.3 22.6 19.1 n-BuLi ether 59.6 6.7 18.0 15.7 Synthesis of 7,7-dimethyl-3-(2-ethyltosylate)-bicyclo- [3,2,0]heptan-6-one 52, Establishing a carbon sidechain at the C-3 site of the ketone 55Iwas the next synthetic step. The modified Wittig reaction seemed to be well suited for this trans- formation. Thus the ketone 55’was converted to the con- jugate ester §§,in 67% yield using methyldiethylphos- phonoacetate in a Wadsworth-Emmons phosphonate reaction.49 The nmr spectrum showed a broad singlet for the olefinic 50 proton and a sharp singlet for the methoxy protons at 6 5.52 and 3.50 respectively. Catalytic hydrogenation of the conjugated ester 5fitover 5% palladium-charcoal afford- ed the saturated ester lRfi1in 94% yield. Gas chromato- graphic analysis showed two isomers present in a ratio of 4:1. The saturated ester 1R§,was also obtained in a similar ratio of isomers from reduction of the conjugated ester fifi’with magnesium metal in methanol. The stereo- chemistry of the isomers could not be established on the basis of nmr and ir spectra. Transformation of the saturated ester lgfi,to a mix- ture of ketal alcohols 5XR'was achieved by lithium alu- minum hydride reduction in quantitative yield. The nmr spectrum of this material showed four different methyl groups at 6 1.03, 1.00, 0.80 and 0.75 with relative in- tensity 4:1:4:1. The ketal alcohols 5kg,underwent deketalization very cleanly to a mixture of the keto alcohols age. .Attempts to separate the isomers as the acetates on column chromatograph by varying the flowrate of eluting solvent, solvents and even the load of solid supports were unsuccessful. Tosylation of the keto alco- hols QQR furnished the bicyclo keto tosylates 52R,in greater than 90% yield. Accomplishing the synthesis of the keto tosylates 52g,provided an intermediate for cyclization to the tri- cyclic ketone 31. However this material was a mixture of 51 Figure 15 Synthetic Pathway to the Tosylate §&R° o o 0 " iLocn 0 0 o (C2350)2P‘C32 3 M 0+ 9 H—C-OCH NaH, glyme S? 34271 ii Hz/Pd/C —+2NLi THF, 25‘5 10 hrs. starting material 52a ()—+2NLi THF, 70°, 24 hrs. starting material + uniden- tified 52a NaH + 1 glyme, 25°, 10 hrs. 11% 93% drop 45°, 2 hrs. tBuOH 52a NaNH2 THF, 25°, 18 hrs. starting 3 material 52a CH3SCH2 DMSO, 25°, 1/2 hr. + 30% uniden- tified 3. 52a CHBSCH2 DMSO, 25°, 2 hrs. 11% + 40% uniden- tified 52a tBuLi hexane, -100°, starting + 1 1/2 hrs. material TMEDA 52a tBuLi THF, —78°, 15 min 113 80% 25°, 12 hrs. 57 starting condition . material base solventjtemp.,time product % yield 52a tBuLi THF, -100°, 2-3 hrs. 11g 80% 52a tBuLi THF, -100°, 2 hrs. 11% ? 25% + + HMPA uniden- tified 52b tBuOK tBuOH, 25°, 14 hrs. starting material 52b NaOCH3 THF, 25°, 6 hrs. starting 40°, 12 hrs. material 50°, 12 hrs. 52b ()—+2NLi THF, 25°, 18 hrs. starting material 52b NaOC2H5 CZHSOH’ 25°, 108 hrs. 115* ~100% *structural assignment based on only nmr and ir spectra. 0 Q0 m - - H = CH CH2 CH2 OCH3 2 «1.4.1 11% OH O :>CH2-CH2-OTS O . HZ-CHz-OTS 6.6% «1110?, 06 CHZCHZ-OCZHS 115 mmm 58 It was very unfortunate that the tosylate fig’did not undergo cyclization to the tricyclic ketone 31tunder the conditions shown. However it is quite understandable because the transformation may have to proceed through a prohibitively high activation energy in order to achieve the formation of 31’which is a highly strained compound. EXPERIMENTAL General All melting points were measured in open capillaries with a Thomas-Hoover apparatus and were uncorrected; boiling points were also uncorrected. Combustion analysis were per- formed by Spang Microanalytical Laboratory, Ann Arbor, Michigan. Infrared spectra were recorded on a Perkin—Elmer model 137 spectrophotometer; absorption maxima are reported as frequency (in cm-l), referenced to 1601 cm".1 peak of polystyrene. Liquid samples were taken as neat films, and solids as nujol mulls. Proton nuclear magnetic resonance spectra (HNMR) were run on Varian T-60 instrument (60 MHz); variable tempera- ture nmr spectra were recorded on a Varian A-56/60 spectro- meter; Carbon nuclear magnetic resonance spectra were taken on a Varian CFT-ZO spectrometer. Chemical shifts are reported in ppm downfield of tetramethylsilane (TMS) or relatively to tetramethylammoniumtetrafluoroborate (TMA) as standard. Mass spectra were run on a Hitachi RMU-6 instrument with an ionizing voltage of 70 eV. Gas chromatographic Separations were run on an F & M model 700 chromatograph. 59 60 The percentage of compositions reported were calculated from the peak areas. Most of the solvents used for reactions were dried in usual manners. For examples: acetonitrile was dried over calcium chloride and refluxed with phosphorus pentoxide overnight and distilled; glyme was refluxed with lithium aluminum hydride and distilled; ether, tetrahydrofuran, and benzene were dried over sodium metal. Hexane used for column chromatography was washed with concentrated sulfuric acid and distilled over calcium chloride. 3,4-Dimethylhexane-3,4-diol 3% Dry magnesium turnings (48 g, 2 moles) and anhydrous benzene (400 ml) were placed in a 2 liter-three necked round bottom flask fitted with mechanical stirrer, reflux condenser and addition funnel. A solution of 43 g (0.15 M) of mercuric chloride dissolved in 437 ml (4.4 moles) of dry ethylmethylketone was slowly added to the stirred mixture at such a rate to maintain a gentle reflux. When the addition was completed, another 200 m1 of benzene was added and the mixture was heated on a steam bath for two hours. The solution was then cooled down and added to ice- water containing 120 g of sodium hydroxide. The organic layer was separated, dried over sodium hydride and dis- tilled to remove benzene and unreacted ethylmethylketone. The residue was then distilled under reduced pressure. 61 The fraction of boiling point 124-126°/10 nm (142 g, 48.6%) was collected. The product has the following spectral properties: nmr (6, CC14): 0.90 (a pair of triplet, J = 7 Hz, 6H), 1.03 (singlet, 6H), 1.41 ( a pair of quartet, J = 7 Hz), 2.23 (singlet, 2H); ir (neat): 3465, 1464, 1130, 995 cm'1 and others. l,2,3,6-Tetrahydro-3,4,5,6-tetramethy1phthallic anhydride 34 One drop of 20% sulfuric acid was added into 90 grams of 3,4-dimethylhexane-3,4-diol 3R’and the solution was then distilled. The distillate which was collected at 980 con- sisted of two layers, organic and water layers. The mixture was poured into a separatory funnel and the oil was separ- ated and dried over anhydrous calcium chloride. The oil was then redistilled and the fraction of boiling point 72- 78°/90-100 mm was collected (37.3 g). The nmr spectrum of this material showed that it was a mixture of olefins. One of these was 33, This mixture was used without further purification. To a cooled solution of 5 g of maleic anhydride in 20 ml of ethyl acetate and 20 m1 of petroleum ether, the mixture of dienes (5.74 g) was added slowly. After the addition was completed, the mixture was then refluxed for an hour and cooled to room temperature. The solid was filtered through aspirator, and washed with petroleum (ether, giving the crude anhydride QAIin 23% yield (4.51 g) 62 from the diol 32, The product which was recrystallized from hexane has the melting point 91.5-94°. The spectral data were consistent with the assigned structure: nmr (6, CC14), 1.40 (d, 6H, J = 7 Hz), 1.65 (s, 6H), 2.40 (m, 2H), 3.05 (dd, 2H, J = 3,2!Hz); ir (nujol) 1850, 1780, 1192 and 1180 cm.1 and others; ms, m/e: 208 (parent peak), 136, 121, 105, 95, 91, and 77 among others. Dimethy1—1,2,3,6-tetrahydro—3,4,5,6-tetramethy1phtha11ate 35 The anhydride 34, (2.2 g, 10.6 mm) was dissolved in 10 m1 of methanol containing one drop of concentrated sulfuric acid. The mixture was boiled under reflux for an hour. The excess of alcohol was removed. The residue was then poured into sodium bicarbonate solution and ex- tracted with ether. The extract was dried over anhydrous sodium sulfate. The solvent was removed on the rotary evaporator to give the crude diester 35, This was then recrystallized from petroleum ether to give 2.0 g (74%) of the white solid of 35, m.p. 50-52°. The spectral pro- perties were in accord with the expected structure. The nmr spectrum showed the following absorptions (6, CC14): 1.07 (d, J = 7 Hz, 6H), 1.67 (s, 6H), 2.50 (m, 2H), 3.00 (d, J = 5 Hz, 2H) and 3.63 (s, 6H). The ir spectrum 1 exhibited one carbonyl absorption at 1745 cm- and others at 1215, 1178, and 1190 cm'l. 63 Dimethy1-3,4,5,6-tetramethy1phtha1ate 36 The tetrahydroester 3§,(2.0 g, 0.78 mm) and 10% palladium-charcoal (1 g) were placed in a round bottom flask fitted with a refluxing condenser. The flask was flushed with nitrogen and inert atmosphere was maintained. The mixture was then heated at 220° for two hours. After cooling, the reaction mixture was washed several times with ether. Removal of the ether yielded 1.28 g of dimethyltetramethylphthallate, 3R’(60%). The purified aromatic diester 3§’(petroleum ether, m.p. 124-125°) showed the following spectral properties: nmr (6, CDC13): 2.20 (s, 6H), 2.23 (s, 6H), 3.77 (s, 6H); ir (nujol), 2899, 1730, 1460, 1379 and 1212 cm"1 and other weak bands; ms, m/e: 250 (parent peak), 119, 118, 190, 160 among others. 3,4,5,6-Tetramethy1phthallic anhydride 3% A 100 m1 round-bottom flask equipped with a refluxing condenser were placed 7.73 g (3.72 mm) of the tetrahydro anhydride 3Aland 3.54 g of 10% palladium-charcoal and inert atmosphere was provided. The flask was then heated in an oil bath at 220-2300 for four hours. After cooling, the product was extracted with warm chloroform several times. Removal of solvent on rotary evaporator provided a clean desired-anhydride QX’in 50% yield (3.83 g). The product could be used immediately for the next reaction 64 or recrystallized from ether. The purified 3X,has spectral data as follows: ms, m/e: 204 (parent peak); ir (nujol): 1851, 1785, 1219, 913 and 749 cm-1 and other weak bands; nmr (CDC13): 2.33 (s, 6H), 2.63 (s, 6H). 1,2-Bis(hydroxymethyl)-3,4,5,6—tetramethylbenzene 38 a) Lithium aluminum hydride reduction of 36. In a 100 ml three-necked flask fitted with condenser and provided with nitrogen atmosphere, were placed excess lithium alu- minum hydride and 40 m1 of dry ether. The solid diester 36 (1.52 g, 6.1 mm) was added slowly and carefully. After the addition was completed, the reaction mixture was re- fluxed overnight (15-20 hours). At the end of the period, the reaction was cooled to room temperature, and water was slowly added to destroy excess lithium aluminum hydride. The solution was then extracted several times with ether. The combined ether layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of ether on the rotary evaporator afforded 1.06 g (90%) of the clean alcohol 38; The spectral data of recrystallized product (CC14, m.p. 171.5-173°) were as followed: ms, m/e: 194 (parent peak); ir (nujol): 3330 cm-1; nmr (6, c0013): 2.16 (s, 6H), 2.28 (s, an), 3.13 (ha, 2H) and 4.72 (s, 4H). Anal. Calc. for C H O 12 18 2‘ Found : C, 74.27; H, 9.26 C, 74.23; H, 9.28 65 b) Two successive reductions of QX’with lithium aluminum hydride. To a stirred solution of excess lithium aluminum hydride in 200 m1 of ether, the solid anhydride 3; (5.51 g, 27.0 mm) was added slowly and carefully at room temperature. After the addition, the mixture was refluxed for ten hours. At the end of the reaction, the solution was cooled to room temperature and water was added. The solution was extracted several times with ether. The com- bined ether layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The ether was removed on rotary evaporator to give a solid mixture which was not identified. This solid mixture was repeatedly reduced in a solution of lithium aluminum hydride. At the end of the reaction, 5.02 g (96%) of the diol 3R’was collected. 1,2-Bis(bromomethy1)-3,4,5,6-tetramethylbenzene 3R, In a 250 ml three-necked flask equipped with a mechanical stirrer, condenser and dropping funnel, were placed 3.0 g (15.5 mm) of the diol QR’and 100 m1 of dry benzene. The reaction flask was cooled to 10° and a solu- tion of 4.5 g of phosphorus tribromide in 50 ml of dry benzene was slowly added to the stirred solution of the diol 38, After the addition was completed, the reaction mixture was stirred for additional 20 minutes. The solution was then filtered and poured into a beaker 66 containing ice-water. The benzene layer was separated and washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. Removal of benzene gave 4.51 g (86.6%) of the dibromide Qlehich was recrystallized from hexane (m.p. l63-164°). The spectral data were in accord with the expected structure. The mass spectrum showed peaks at m/e 322, 320, 318 and others (Calc. mass of 39, 1 and 320). The ir spectrum showed absorptions at 1195 cm- several other weak bands. The nmr spectrum exhibited signals at (6, CC14) 2.27 (s, 6H), 2.32 (s, 6H) and 4.67 (s, 4H). Anal. Calc. for C12H16Br2: C, 45.00, H. 5.00 Found : C, 45.09; H, 5.17 2-Carbomethoxy-l,2,3,4-tetrahydro-5,6,7,8-tetramethyl- naphthalene 4Q a) Thegpreparation of activated zinc. Zinc powder (10 g) was put in 50 ml of 10% hydrochloric acid solution and stirred for 15 minutes. The metal was then filtered through suction funnel, washed with water, methanol, acetone and ether and dried under vacuum. This activated zinc was kept under nitrogen before use. b) Reaction of QRIwith methylacrylate in the presence of activated zinc. In a three-necked flask equipped with a mechanical stirrer, dropping funnel and condenser provided with nitrogen atmosphere were placed 5.0 g of 67 freshly distilled methylacrylate (excess), 200 ml of dry dimethylformamide and 3 g of activated zinc. To the stirred solution, a mixture of 6.1 g (19 mm) of the dibromide 3a in 150 m1 of dimethylformamide was added slowly over a period of three hours. During addition time, 1.5 g more of activated zinc was added. After the addition was com- pleted, the reaction was stirred for additional six hours. The solution was then filtered and the residue was washed with ether. The combined filtrates were poured into a solution of 20 ml of concentrated hydrochloric acid in 300 ml of water. The organic layer was separated, washed with water, sodium bicarbonate solution, saturated sodium chloride and dried over anhydrous sodium sulfate. Re- moval of solvent on the rotary evaporator gave a white solid. The solid was then sublimed very slowly at 60- 65°/0.5 mm to afford 3.4 g of the methylester 4R’(72%, m.p. 91-92.5°). The spectral properties were consistent with the expected structure. The mass spectrum exhibited the parent peak at m/e 246 (calc. mass for QR, 246). The ir spectrum showed the carbonyl absorption at 1740 cm-1 and C—0 stretching band at 1176 cm.1 and other bands. The nmr spectrum had the following peaks (6, CC14), 3.70 (s, 3H), 2.16 (bs, 12H) and 1.10-3.20 (m, 7H). 68 2-Hydroxymethyl-l,2,3,4-tetrahydro-5,6,7,8-tetramethyl- naphthalene @g In a round bottom flask equipped with a refluxing condenser, were placed 2.5 g (10 mm) of the methylester 40, 0.82 g of lithium aluminum hydride and 50 ml of ether. The flask was refluxed for a period of six to eight hours. At the end of reaction, the solution was cooled to room temp- erature and water was added. The reaction mixture was extracted with ether twice. The combined ether layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of ether yielded 2.95 g of the clean alcohol 2R’(95%). The sublimed white-solid alcohol 2R’(m.p. 101-102°) possessed the following spectral properties: ms, m/e 218 (parent peak, calc. mass for 29, 218); ir (nujol) 3323 cm‘l, nmr (6, cc14): 1.40-2.67 (m, 8H), 2.07 (s, 6H), 2.13 (5, 6H) and 3.15 (d, J = 7 Hz, 2H). 1,2-Bis(bromomethyl)benzene $5 In a three-necked flask equipped with a long condenser, addition funnel and magnetic stirrer was placed 50 g (0.47 mole) of ortho-xylene. The flask was heated at 110-120° with an oil bath. Bromine (160 g) was very slowly added through drOpping funnel to maintain an almost colorless liquid till the end of the Operation. Hydrogen bromide evolved was carried out by a stream of nitrogen into a 69 dilute solution of sodium hydroxide. The time used for addition of bromine was approximately seven to eight hours. As soon as the reaction was over, the crude dibromide Afilwas poured into a small beaker and allowed to stand for 24 hours to solidify. The solid crystal was then spread over paper towels. The solid compound obtained (60 g, 48%) was now almost colorless and sufficiently pure. The pure dibromide was obtained by recrystallizing from hexane, m.p. 92-93°. The spectral data were in accord with the assigned structure. The mass spectrum showed the follow- ing peaks, m/e 266, 264, 262, 185, 183, 104, 91 and 78 and others (calc. mass for $5, 264). The nmr spectrum ex- hibited two singlet signals at 6 6.33 and 7.37 with the same ratio of protons. 2-Carbomethoxy-l,2,3,4-tetrahydronaphthalene 46, In a 500 ml three—necked flask fitted with mechanical stirrer and additional funnel provided with an inert at- mOSphere were placed 17 g of freshly distilled methylacry- late, 100 ml of dry dimethylformamide and 4 g of activated zinc. To the stirred solution, a mixture of 20.0 g (7.6 mm) of the dibromide Afi’in 200 ml of dry dimethylformamide was added dropwise for a period of 3-4 hours. Every hour, 2 g of zinc was added. After the addition was completed, the reaction mixture was stirred for ten more hours. When the reaction period was over, the solution was then 70 filtered through celite. The filtrate was poured into a solution of 30 m1 of concentrated hydrochloric acid in 1 liter of water. The solution was extracted twice with ether (2 x 150 ml). The combined organic layers were washed with water, sodium bicarbonate solution, saturated sodium chloride and dried over anhydrous magnesium sulfate. Removal of ether on the rotary evaporator gave an oily liquid. Molecular distillation at 68-70°/0.5 mm gave 6.93 g of the ester 46 (48.2% yield). The spectral data of this material were as followed: nmr, (6, CC14): 1.70-3.13 (m, 7H), 3.66 (s, 3H) and 7.00 (s, 4H); ir (neat): 1739, 1497, 1190 and 746 cm‘1 among other bands; ms, m/e: 190 (parent peak), 158, 130, 115, 91, 77 and others (calc. mass of 46, 190). 2-Hydroxymethyl-1,2,3,4-tetrahydronaphthalene 3R, To a round bottom flask containing 0.7 g of lithium aluminum hydride and 30 ml of ether, was added slowly the ..mixture of 1.98 g (10 mm) of ester Qfi’in 5 m1 of ether. The reaction mixture was then stirred at room temperature for eight hours after which water was added slowly to destroy excess lithium aluminum hydride. The solution was extracted with ether. The ether was separated and washed with water, saturated sodium chloride and dried over anhy- drous sodium sulfate. Removal of ether on the rotary evap- orator gave 1.60 g of the crude alcohol QRI(95%) which was 71 molecular distilled at 70°/0.5 mm. The spectral properties were consistent with the assigned structure: ms, m/e: 162, 144, 129, 119, 104, 91, 77 and others; ir (neat) 3333, 1494, 1069, 1031 and 743 cm”1 and other bands; nmr (6, CC14): 1.15-3.03 (m, 8H), 3.58 (d, J = 6 Hz, 2H) and 7.00 (s, 4H). Anal, Calcd. for C H O: C, 81.48; H, 8.64 ll 14 Found : C, 80.26; H, 8.39 7,7-Dimethylbicyclo[3,2,0lhept-2-ene-6-one 53 The apparatus used for this reaction is shown in Figure 16. Tetramethyl-l,3-butanedione 5RIwas used as dimethylketene precursor. The dione 5R’(25 g) was placed in the ketene generator which was heated at 110-120° with an oil bath and the heating coil was heated to just red- ness. The dione which was heated to sublime was pyrolyzed to dimethylketene in this region. Over a period of 10-12 hours, dimethylketene was carried by nitrogen stream into a rapidly stirred solution of 50 ml of freshly distilled cyclopentadiene in 100 ml of acetonitrile at 0°. At the end of the period, the reaction mixture was kept under nitrogen at -40° overnight. The excess cyclopentadiene and acetonitrile were then distilled at atmospheric pressure. The residue was distilled under reduced pressure through a 12 inch vigreux column giving 26 g of adduct 53,(57%), b.p. 66-67°/15 mm. The spectral data were in accord with that 72 expected from 5}, The nmr spectrum exhibited the following signals: (6, CC14): 0.90 (s, 3H), 1.30 (s, 3H), 2.30- 2.77 (m, 2H), 3.07 (bd, J = 7 Hz, 1H), 3.83 (dt, J = 7, 3 Hz, 1H), and 5.50-5.87 (m, 2H). The ir spectrum showed absorptions at 1775, 1358, 743 cm_1 and other several bands. 7,7-Dimethy1-6,6-ethy1enedioxybicyclo[3,2,0lhept-2-ene 54 In a one liter round bottom flask was placed a mixture of 16.925 9 (124 mm) of ketone 53, 75 m1 of ethylene glycol, 100 mg of p-toluenesulfonic acid and 300 ml of benzene. The mixture was stirred vigorously in order to mix the two layers. The flask was connected to a Dean-Stark trap and a condenser along with a drying tube. The solution was then heated to reflux for twenty hours (an approximately equivalent amount of water was collected). At the end of the period, the reaction mixture was cooled to room temp- erature and 5 ml of saturated sodium bicarbonate solution was added and stirred. The benzene layer was separated and washed twice with water. The organic layer was also washed with 200 ml saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled at atmospheric pressure. The residue was then distilled under reduced pressure yielding 21 g of the ketal 5A, (94%, b.p. 74-75°/15 mm). The spectral properties of 54 were as follows: ms, m/e: 180 (parent peak), 165, 137, 114, 99 and others (calc. mass of 54, 180); (neat): 1212, 73 1177, 1134, 1053 and 718 cm‘1 and other bands; nmr, (6, CC14): 0.77 (s, 3H), 1.10 (s, 3H), 2.07-2.67 (m, 3H), 2.96 (dt, J = 7, 3 Hz, 1H), 3.67 (m, 4H) and 5.27-5.73 (m, 2H). Anal. Calcd. for C11H1602° C, 73.33; H, 8.89 Found : C, 73.25; H, 8.88 7,7-Dimethyl-6,6-ethylenedioxy-exo-bicyclo[3,2,0lheptan- 2-ol 6}, Reaction of 5A,with diborane and hydrogen peroxide. Into a 500 m1 three-necked round bottom flask provided with a nitrogen inlet, dropping funnel, reflux condenser and magnetic stirrer, was introduced a solution of 6.19 g (34 mm) of olefin 5AIin 130 ml of tetrahydrofuran. Com- mercial borane solution (38 m1, 1 M in T.H.F.) was added to the stirred solution of olefin. After the addition was completed, the reaction mixture was stirred for an addi- tional hour. water was then added to destroy residual borane. After hydrogen evolution had ceased, 8 ml of 6 N sodium hydroxide was added, followed by 8 m1 of 30% hydro- gen peroxide. The solution was stirred for two hours and 50 m1 of water was added. The organic layer was separated and the aqueous layer was extracted with ether for three times (3 x 100 ml). The combined organic solvents were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the ether gave 6.32 g of a clear liquid (93% yield). Gas chromatographic analysis (4% QF-l, 6 ft column, 150°) showed that only two 74 alcohols were obtained with an approximate ratio of 7:3. Attempts to separate these alcohols by preparative gas chromatograph gave only one pure isomer, the major 63, Reinjection of the minor fraction still showed the presence of the major isomer. The spectral data obtained from the major alcohol were in accord with the structure 6}; ms, m/e: 198 (parent peak), 183, 165, 153, 141, 125, 114, 99 and other (calc. mass for 63, 198); ir (nujol): 3247, 1316, 1176, 1031 and others; nmr, (6, CC14): 0.80 (s, 3H), 1.40 (s, 1H exchanged with D20), 1.33-2.33 (m, 5H), 2.87 (bt, J = 7 Hz, 1H), 3.67 (m, 4H) and 3.96 (bd, J = 4.5 Hz, 1H). The minor isomer could not be obtained in pure form. However, it was suggested to have the structure 6A, Reaction of the mixture of figland QA’with acetyl chloride in pyridine. Formation of exo-2-acetoxy-7,7-dimethyl- 6,6-ethylenedioxybicyclol3,2,0lheptane 6§,and 3-acetoxy- 7,7-dimethyl-6,6-ethy1enedioxybicyclo[3,2,0lheptane 66, The mixture of alcohols figiand 6A,(358 mg, 1.8 mm) was dissolved in 2 ml of dry pyridine and cooled to 0°. Acetyl chloride (1 ml, Ca. 6 fold excess) was added and the reaction was stirred for 15 minutes. The reaction mixture was then poured into 10 m1 of water and the solution was extracted with ether (3 x 10 ml). The 75 combined ethers were washed with diluted hydrochloric acid, saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed on the rotary evaporator to give 370 mg of an oil. Gas chromatographic analysis showed that the mixture contained 63% of 66, 29% of 66, 7.2% of unreacted alcohol 66’and 0.8% of olefin 66. This material was adsorbed on alumina column (15 g, activity 2-3). The eluting solvent was gradually changed from pure hexane to 7% ether-hexane. The major acetate 66Ihad the following spectral properties: ms, m/e: 240 (parent peak 4.08%), 197 (14.64%), 180 (38.40%), 165 (34.78%), 114 (98.55%), 99 (100%) and others; ir (neat): 1738, 1246, 1016 cm"1 and other bands; nmr, (6, CC14): 0.80 (s, 3H), 1.12 (s, 3H), 1.83 (s, 3H), 1.40-2.23 (m, 5H), 2.90 (bt, J = 7 Hz, 1 Hz), 3.70 (m, 4H) and 4.88 (bd, J - 4.5 Hz, 1H). The minor acetate 66’had spectral properties as followed: ms, m/e: 240 (parent peak, 0.34%), 197 (1.19%), 180 (48.57%), 165 (24.29%), 114 (80.7%), 99 (100%) and others; ir (neat): 1739, 1247, 1033 cm’1 and other bands; nmr, (6, CC14): 0.85 (s, 3H), 1.08 (s, 3H), 1.10-2.27 (m, 5H), 2.90 (dt, J = 8, 2 Hz, 1H), 3.73 (m, 4H) and 5.17 (t, J = 7 Hz, 1H). 76 Reaction of the mixture of 66’and 8A.With chromium trioxide- pyridine complex. Formation of 7,7-dimethyl-6,6-ethy1ene- dioxybicyclol3,2,01-heptan-2-one 6K, and 7,7-dimethyl-6,6- ethylenedioxybicyclol3,2,01heptan-3-one 66. A l-liter three-necked flask was equipped with a mechanical stirrer, and a dropping funnel, and provided with an inert atmosphere. Chromium trioxide (30 g) was added to the stirred solution of 60 m1 of pyridine in 500 ml of methylene chloride. After the addition was completed, the deep-red solution was stirred for additional 15 minutes at room temperature. At the end of this period, a solution of 6.39 g of the alcohol mixture in 50 ml of methylene chloride was added in one portion. ~After stirring for an additional 15 minutes, the solution was left standing for a period of 6-8 hours to complete oxidation. The solution was decanted and the residue was washed with methylene chloride. The combined methylene chloride solutions were then washed with dilute sodium hydroxide, quickly washed with dilute hydrochloric acid, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent on the rotary evaporator gave 5.77 g of a crude material. Gas chromatographic analysis showed that con- version of alcohols to ketones was completed and two ketones were obtained in a ratio of 7:3 (4% QF-l, 6 ft column, 150°). 77 Separation of these two ketones was achieved on column chromatography using alumina a adsorbent (activity 3) and ether-hexane as eluting solvent which was gradually changed from 5% to 10% ether. The ketone 6X’which was the major product had the following spectral properties: ms, m/e: 196 (parent peak), 181, 140, 114, 99 and others; ir, (neat): 1739, 1163, 1031 cm.1 and several other bands; nmr (6, CC14): 0.86 (s, 3H), 1.20 (s, 3H), 1.70-2.67 (m, 5H), 3.12 (bt, J = 8 cps, 1H) and 3.87 (m, 4H). Anal. Calc. for C H 0 ° C, 67.35: H, 8.16 11 16 3' Found : C, 67.26; H, 8.27 The ketone 66, which was the minor product, showed the following spectral data: ms, m/e 196 (parent peak, calc. mass for 56, 196); ir (neat): 1750 cm-1; nmr (6, CC14): 0.90 (s, 3H), 1.23 (s, 3H), 2.20 (m, 5H), 3.20 (dt, J = 8, 3 Hz, 1H) and 3.87 (bs, 4H). anal. Calc. for C H O - C, 67.35; H, 8.16 11 16 3' Found : C, 67.32; .H, 8.27 7,7-Dimethy1bicyclo[3,2,0]heptane-2,6-dione L6 In a round bottom flask, 174 mg of ketone QX’in 5 m1 of benzene was mixed with 3 m1 of 5% of hydrochloric acid solution. The mixture was stirred vigorously for six hours. After the reaction time, the mixture was slowly poured into a solution of sodium bicarbonate. The benzene layer was separated. The aqueous layer was extracted again 78 with benzene. The combined benzene layers were washed with water, saturated sodium chloride and dried over anhydrous sodium sulfate. Gas chromatographic analysis showed that 94% of the diketone zglwas formed. Separation of zg’was achieved by preparative gas chromatography (20% SE 30, 1369. The spectral data of zglwere as followed: ms, m/e: 152 (parent peak), 124, 109, 95, 83, 70 and others (calc. mass for 7,2“ 152); ir (neat): 1785 and 1739 cm-1 and other bands; nmr, (6, CC14): 1.03 (s, 3H), 1.40 (s, 3H), 1.93 (m, 4H), 2.60 (d, J = 8 Hz, 1H), and 3.93 (bt, J = 8 Hz, 1H, 1H). Anal. Calc. for C H O ' C, 71.05; H, 7.89 9 12 2’ Found : C, 70.96; H, 7.78 7,7-Dimethylbicyclol3,2,0]heptane-3,6-dione 66 The ketone 66’(92 mg) was subjected to deketalization according to the procedure used for deketalization of 6}, The diketone Zl’which was obtained in 95% yield was separ- ated by preparative gas chromatography. The spectral properties were consistent with 66, The mass spectrum showed the parent peak and the base peak at m/e 152 and 70 respectively (calc. mass for 71, 152). The nmr spectrum exhibited the following signals (6, CC14), 1.05 (s, 3H), 1.37 (s, 3H), 1.95-3.01 (m, 5H), and 3.98 (m, 1H). 79 7,7-Dimethyl-6,6-ethylenedioxy-l,3,3-trideuterobicyclo- [3,2,0]heptan-2-one 76, A mixture of 72 mg of the ketone 6X, 30 mg of sodium methoxide and 5 ml of deuterium ethoxide was stirred at room temperature for two hours. At the end of the re- action, 1 ml of deuterium oxide was added, with stirring, followed by 10 m1 of ether. The organic layer was separ- ated and washed with water, saturated sodiumchloride and then dried over sodium sulfate. Removal of the solvent afforded 70 mg of a clean product. The nmr spectrum showed absorptions at 6 0.83 (s, 3H), 1.20 (s, 3H), 1.56-2.10 (m, 2H), 3.03 (bd, J = 8 Hz, 1H) and 3.85 (m, 4H). 7,7-Dimethy1-6,6-ethylenedioxy-exo-bicyclol3,2,0]heptane- 2,3-oxide 666. In a 300 ml three-necked flask fitted with a condenser and dropping funnel were placed 4.64 g (23.6 mm) of 6R’and 150 m1 of dry methylene chloride. To the stirred solution at 0°, 5.23 g of 85% metachloroperbenzoic acid in 40 ml of methylene chloride was added. After the addition was com- pleted, the reaction was stirred for two hours. At the end of this period, the solution was filtered through a suction funnel. The filtrate was washed with dilute sodium hydroxide, water, saturated sodium chloride and dried over anhydrous sodium sulfate. Methylene chloride was removed on the rotary evaporator to give 4.81 g of the crude 80 epoxide 666 (95%). G. C. analysis showed quantitative conversion of the olefin 6A’to the epoxide 1R1, This epoxide was purified on column chromatography (alumina, act 3) using 7% ether-hexane as eluting solvent. The spectral data supported the assigned structure: ir (neat): 1380, 1050, 835 cm"1 and others; ms, m/e: 196, 195, 181, 167, 153, 137, 114, 99 (base) and others (calc. mass for 666, 196); nmr, (6, CC14): 0.97 (s, 3H), 1.07 (s, 3H), 1.88 (m, 2H), 2.13 (d, J = 8 Hz, 1H), 2.60 (dt, J = 8, 3 Hz, 1H), 3.23 (dd, J 8, 2 Hz, 2H) and 3.72 (bs, 4H). Reaction of the epoxide lRllwith lithium aluminum hydride. Formation of 7,7-dimethyl-6,6-ethylenedioxy-exo-bicyclo- [3,2,0]heptan-2-ol 66, In a round bottom flask fitted with a condenser were placed 674 mg (3.4 mm) of the epoxide 161, excess lithium aluminum hydride (150 mg) and 30 m1 of ether. The mixture was stirred at room temperature for 51 hours, and water was added. The ether layer was separated and the aqueous layer was extracted again with ether. The combined extracts were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The g.c. analysis showed that the epoxide lRllwas converted to a single alcohol 66’in 91% yield. The nmr spectrum of the crude material was compar- able to that of the pure alcohol 66, 81 7,7-Dimethyl-6,6-ethylenedioxy-exo-bicyclo[3,2,0]hept-3- ene-2-ol 1R2, Reaction of the epoxide lRAIwith lithium diisopropylamide. A 25 ml three-necked flask was equipped with a con- denser and a mercury bubbler connected to an aspirator. The flask was flame-dried and an inert atmosphere was pro- vided. Through a syringe, 1 ml of n-butyllithium (15.03% of n-butyllithium in hexane) was injected and the flask was cooled to 0°. Diisopropylamine (0.2 ml) was added slowly and the mixture was stirred. After the addition was completed, the hexane was evaporated under reduced pressure to dryness. A nitrogen atmosphere was again provided, and the mercury bubbler was removed. The base was then dissolved with 5 ml of dried ether. To the stirred solution, a mixture of 260 mg of the epoxide 1R1, in 1 m1 of ether was added and the reaction mixture was refluxed for four hours. When the solution was cooled to room temperature, water was added. The organic layer was separated and the aqueous layer was extracted again with ether. The combined extracts were washed with dilute hydrochloric acid, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the ether yielded 252 mg of a crude material. Gas chromatographic analysis showed two major peaks (ratio, 85:15). Separation was achieved on column chromatograph using alumina as adsorbent 82 and 20% ether-hexane as eluting solvent. The major product had spectral properties consistent to the allylic alcohol 166, nmr (6, CC14): 0.88 (s, 3H), 1.10 (s, 3H), 1.95 (d, J = 7 Hz, 1H), 2.13 (bs, 1H), 3.37 (bd, J = 7 Hz, 1H), 3.70 (m, 4H), 4.45 (bs, 1H) and 5.78 (m, 2H); ir (neat): 3438 cm.1 and others; ms, m/e: 196 (parent peak, calc. mass for 66%, 196). The minor product was identified as the ketone 66. Reaction of the epoxide lRA’with t-butyllithium. A 200 ml three-necked flask fitted with a condenser was flame-dried and a nitrogen atmosphere was provided. Tetrahydrofuran (120 ml) was introduced, cooled to -78° and 16 ml of t-butyllithium (0.96 M) was slowly added. To the stirred solution, a mixture of 2.719 g (13.3 mm) of the epoxide lRA’in 5 m1 of tetrahydrofuran was slowly added. After stirring for 15 minutes at -78°, the solu- tion was allowed to warm up slowly to room temperature and stirred for an additional 30 minutes. The reaction was then quenched with water. The solvent was separated, washed again with water, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of solvent afforded a mixture of compounds which were assigned as 1R}, 16A, 162, 6R,and 66,and others. Analysis by gas chromatograph (4% QF-l, 6 ft, 150°) showed that these components presented in amounts of 3.4%, 4.5%, 15.4%, 3.4% 83 and 71.1% respectively. The mixture was adsorbed on alumina (activity 2-3) and eluted with hexane and gradually changed to 7% ether-hexane and up to 40% ether-hexane. The com- pounds 666, 66A’and unidentified came out in the same fractions. Separation of 666’and 6RA’was achieved by pre- parative gas chromatography (4% QF-l, 6 ft, 110°). The spectral data of 6RAlwere as followed: ms, m/e: 236 (9.2%), 221 (2.8%), 193 (3.1%), 179 (32.4%), 114 (100%), 99 (62.9%), and others (calc. mass for 666, 236); ir (neat): 1190, 1139 cm’1 and others; nmr (6, cc14): 0.83 (s, 3H, 1.00 (s, 9H), 1.07 (s, 3H), 2.10-3.07 (m, 4H), 3.70 (bs, 4H) and 5.37 (t, J = 2 Hz, 1H). Irradiation of the signal at 6 2.40 changed the spin-spin coupling of the olefinic proton at 6 5.37 from a triplet to a singlet. The compound 666’showed the following spectral properties: ms, m/e: 236 (2.2%), 221 (1.6%), 179 (27.8%), 114 (100%), 99 (38.9%) and others (calc. mass for 666, 236 ), nmr (6, CC14): 0.75 (s, 3H), 1.05 (s, 12H), 2.10-2.70 (m, 3H), 2.95 (dt, J = 7, 3 Hz, 1H), 3.63 (m, 4H) and 5.05 (m, 1H). Irra- diation of the signal at 6 2.20 changed the spin-spin coupling of the olefinic proton at 6 5.05 from a multiplet to a doublet (J = 2 Hz). 84 3-Carbomethoxymethylene-7,7-dimethy1-6,6-ethy1enedioxy- bicyclol3,2,0]heptane 66. a) Preparation of methy1diethylphosphonoacetate 666. In a three-necked flask equipped with a condenser and a dropping funnel and provided with a slow stream of nitrogen was placed 35.5 g (21.4 mm) of triethyl phOSphite. The flask was heated with an oil bath at 110-120°. To the stirred solution, methylbromoacetate (28.5 g, 18.6 mm) was added dropwise to maintain a slow refluxing rate. After the addition was completed, the reaction was heated for an additional three hours. The mixture was then distilled and the fraction of b.p. 130-131°/0.08 mm was collected (34.3 g, 89%). The nmr spectrum showed the following absorptions: (6, CC14): 1.33 (t, J = 7 Hz, 6H), 2.83 (d, J = 22 Hz, 2H), 3.73 (s, 3H) and 4.10 (q, J = 7 Hz, 4H). b) Reaction of 666lwith the ketone 66, In a 250 m1 three-necked flask equipped with a condenser and provided with a nitrogen atmosphere were placed 1.32 g of sodium hydride (57% dispersion) and 150 ml of glyme. To the stirred solution, 6.5 ml of 666Iwas added at 0°. After the evolution of gas had ceased, a solution of 3.57 g (18 mm) of 66’in 2 m1 of glyme was added. The solution was then heated under reflux for six hours. The reaction mixture was then cooled to room temperature and water was added. The solution was extracted with ether. The 85 organic layer was separated, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent gave a liquid mixture which was adsorbed on alumina and eluted with 7% ether-hexane to afford 3.04 g of the conjugated ester 66’(67%). The spectral properties were as followed: ms, m/e: 252., 237, 221, 220, 193, 179, 114, 99 and others; ir (neat): 1719, 1666, 1205, 1129 and 1031 cm'1 and other bands; nmr, (6, CC14): 0.80 (s, 3H), 1.08 (s, 3H), 1.83-3.37 (m, 6H), 3.53 (s, 3H), 3.67 (m, 4H) and 5.57 (bs, 1H). Exo-endo-B-carbomethoxymethyl-7,7-dimethyl-6,6-ethylene- dioxybicyclol3,2,0lheptane 666, a) Reduction of the conjugated ester 66’with magnesium metal in methanol. In a round bottom flask fitted with condenser were placed 2 ml of methanol, 72 mg of the con- jugated ester 66 and 61 mg of magnesium metal. The mixture was stirred for 3 hours during which time most of the magnesium was consumed and a gelatinous precipitate was formed. To dissolve the precipitate and the remaining magnesium, 5 ml of dilute hydrochloric acid was added. The solution was extracted with three 10 ml portions of ether. The combined solvents were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The sol- vents were removed to afford 70 mg of a clean mixture of exo— and endo- ester 666 (96%). 86 The ester mixture was adsorbed on alumina and eluted with 10% benzene-hexane. The spectral data of this exo- and endo-mixture were as followed: nmr (6, CCl4): 3.80 (m, 4H), 3.63 (s, 3H), 2.91 (bt, J = 8 Hz, 1H), 2.46—1.20 (m, 8H), 1.12; 1.07 (5,5; ratio 4:1, 3H) and 0.85 (S, 3H); ir (neat): 1742 and 1190 cm.1 and others; ms, m/e: 254 (parent peak). b) Catalytic hydrogenation of the conjugated ester 66, A solution of 2.73 g of the ester 66 in 150 m1 of ethanol was stirred over 1.0 g of 5% palladium-charcoal under a hydrogen atmosphere until hydrogen uptake ceased (1.5 hr). The solution was filtered and the residue was washed with ethanol. Removal of solvent on the rotary evaporator afforded 2.49 g of the ann-anQn_mixture of estern666. Gas chromatographic analysis showed that the ratio of ann-annn isomers obtained from catalytic hydro- genation was approximately the same as that obtained from magnesium metal reduction. 7,7-Dimethyl—6,6-ethylenedioxy-3-exo-endo-(2-hydroxyethyl)- bicyclo[3,2,0]heptane 66;, Reduction of the ester 666 with lithium aluminum hydride. Into a solution of lithium aluminum hydride (0.50 g) in 40 m1 of ether was added slowly a mixture of 1.16 g of the ester 666’in 2 ml of ether. After the solution was stirred at room temperature for four hours, water was 87 added. The ether layer was separated and the aqueous layer was extracted again with ether. The combined ether was washed with saturated sodium chloride and dried over an- hydrous sodium sulfate. Removal of the ether yielded an oil which was then chromatographed on alumina and eluted with 25% ether-hexane giving 1.02 g of 51a (99%). The spectral data were as followed: ms, m/e: 226 (parent peak); ir (neat): 3389, 1379 and 1041 cm”1 and others; nmr, (6, CC14): 3.67 (m, 4H), 3.45 (t, J = 6 Hz, 2H), 2.78 (bt, J = 8 Hz, 1H), 2.41 (bs, 1H, D20 exchangeable), 2.10-1.00 (m, 8H) and four methyl groups at 1.03, 1.00, 0.80 and 0.75 (total 6H). 7,7-Dimethyl-3-exo-endo-(2-hydroxyethyl)-bicyclol3,2,0]- heptan-6-one‘gga. The ketal alcohol‘EQQ (0.270 g) was dissolved in 7 ml of benzene and 5 m1 of dilute hydrochloric acid was added. The reaction was stirred vigorously to mix the two layers for 6 hours. The organic layer was separated and the aqueous layer was washed again with benzene. The benzene extracts were washed with sodium bicarbonate solution, saturated sodium chloride and dried over anhy- drous sodium sulfate. The benzene was removed on the rotary evaporator and the residue was chromatographed to give 0.213 g (98%) of 58%} ms, m/e: 182 (parent peak); ir (neat): 3425 and 1770 cm‘l; nmr (a, cc14): 3.57 (t, 88 underneath t at 3.47, 1H), 3.47 (t, J = 6 Hz, 2H), 2.66 (bs, 1H, D O exchanged), 2.60-1.10 (m, 8H) and four methyl groups at 1.23, 1.20, 1.00, 0.93 (total 6H). 7,7-Dimethyl-3-exo—endo-(2-ethyltosylate)-bicyclo[3,2,0]- heptan-6-one gag. The alcohol 58a (2.54 g) was dissolved in 20 ml of pyridine and the solution was cooled to 0°. Excess toluenesulfonyl chloride (3.0 g) was added in one portion and the mixture was stirred for 1-2 hours. At the end of the reaction, ice cold water was added and the solution was extracted twice with chloroform (2 x 20 ml). The combined extracts were washed with dilute hydrochloric acid, saturated sodium carbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. The chloroform was removed and the residue was chromatographed on an alumina column to give 4.21 g of,é%e (90%): ms, m/e: 336 (parent peak), 242, 181, 164, 155, 136, 121, 108, 93, 70 and others; ir (neat) 1776, 1610 cm’1 and several bands; nmr (6, CC14): 7.26 (ABq, J = 8 Hz, 4H), 3.76 (t, J = 6 Hz, 2H), 3.43 (bt, J = 8 Hz, 1H), 2.60-1.00 (m, 8H), 2.30 (s, 3H) and four methyl groups at 1.07, 1.03, 0.83 and 0.73 (total 6H). 89 7,7-Dimethyl-6,6-ethylenedioxy-B-exo-endo-(2-hydroxyethyl)- bicyclo[3,2,0]heptane 57R, Reduction of the conjugated ester 56 with lithium-ammonia. Into a 250 ml three-necked flask equipped with a mechanical stirrer and Dry Ice condenser was distilled 150 ml of ammonia. At ~78°, a solution of 3.0 g (12 mm) of the conjugated ester 56 in 5 ml of ethanol was added. The mixture was distilled to dryness. The residue was then dissolved with ether and water. The ether layer was separated and the aqueous layer was extracted again with ether. The combined organic extracts were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the ether gave a crude material which was then chromatographed (Alumina, 20% ether-hexane) to afford 1.92 g of the ketal alcohol 57b (70%). The spectral properties were as followed: ms, m/e: 226, 114, 99 and others; ir (neat): 3395, 1041 cm-1 and other bands; nmr (6, CC14): 3.63 (m, 4H), 3.43 (t, J = 7 Hz, 2H), 2.76 (bt, J = 8 Hz, 1H), 2.33-1.00 (m, 8H), 1.00 (s, 3H) and 0.73 (s, 3H). 7,7-Dimethyl-3-exo-endo-(2-hydroxyethyl)-bicyclo[3,2,0]- heptan-6-one,§@b. Procedure used according to preparation of 58a, ms, m/e: 182, 70 and others. 90 ir, (neat): 3448, 1774, 1058 cm‘1 and others. nmr, (6, CC14): 3.57 (t, J = 7 Hz, 2H), 3.46 (t, J = 7 Hz, 1H), 2.50-0.93 (m, 9H), 1.20 (s, 3H) and 1.00; 0.93 (both 5, total 3H). 7,7-Dimethyl-3-exo-endo-(2-ethyltosy1ate)-bicyclo[3,2,0]- heptan-6-one 52R, Procedure used according to preparation of 52a. ms, m/e: 336, 70 and others. ir (neat): 1775 cm.1. nmr (6, CC14): 7.26 (ABq, J = 8 Hz, 4H), 3.76 (t, J = 6 Hz, 2H), 3.43 (t, J = 8 Hz, 1H), 2.60-1.00 (m, 8H), 2.30 (s, 3H) and four methyl groups at 1.20, 1.16, 0.96, and 0.83 (total of 6H). 5-Deutero-7,7-dimethyl-3-exo-endo-(2-hydroxyethyl)-bicyclo- [3,2,0]heptan-6-one 58g. The alcohol 58R,(0.82 g) was dissolved in 5 ml of deuterium ethoxide and 0.27 g of sodium methoxide was added. After the reaction was stirred for two hours, 0.5 ml of deuterium oxide was added. The mixture was extracted with ether (2 x 15 ml) and the combined extracts were washed with saturated sodium chloride and dried over an- hydrous sodium sulfate. Removal of solvents on the rotary evaporator gave a clear liquid which was chromatographed on an alumina column (25% ether-hexane) to afford 0.72 g 91 of the deuterated alcohol 58R; nmr (6, CCl4): 3.47 (t, J = 7 Hz, 2H), 2.60-1.10 (m, 9H) and four methyl groups at 1.23, 1.20, 1.00 and 0.93 (total of 6H); ms, m/e: 183 (7.26%), 165 (7.26%), 138 (9.67%), 110 (14.51%), 94 (22.58%), 70 (100%) and others. Calculation from ms showed that 99% of one deuterium was incorporated into the molecule. 5-Deutero-7,7-dimethyl-3-exo-endo-(2-ethyltosylate)- bicyclol3,2,0]heptan-6-one, 52g, To the solution of the deuterated alcohol EQE (0.652 g, 3.5 mm) in 5 ml of pyridine at 0°, 0.70 g of toluene- sulfonyl chloride was added in one portion. After the reaction was stirred at 00 for two hours, ice-water was added and the mixture was extracted with cold chloroform (2 x 20 ml). The combined extracts were washed quickly with dilute hydrochloric acid, sodium bicarbonate solution, saturated sodium chloride and dried over anhydrous sodium sulfate. The chloroform was removed and the residue was chromatographed on an alumina column (25% ether-hexane) to give 1.05 g of the deuterated tosylate 52R (88%). The nmr spectrum of 523 was similar to that of QRRIexcept the broad triplet at 6 3.43 disappeared. The mass spectrum showed m/e at 337 (1.98%), 242 (1.95%), 182 (1.83%), 165 (7.73%), 155 (4.04%), 109 (33.87%), 91 (32.26%), 70 (100%) 92 and others. Again, calculation from ms showed 91% of deuterium incorporated in the molecule. Attempted synthesis of 3,3—dimethyltricyclol4,2,l,01’4] nonan-Z-one 31. Reaction of the tosylate QKR'with sodium hydride and t-butanol in glyme. To a suspension of 50 mg of 57% sodium hydride in 9 m1 of glyme was added slowly a mixture of 111 mg of the tosylate QRRIin 1 ml of glyme followed by a drop of t- butanol. The solution was stirred at room temperature for 15 hours and then heated at 45° for 3 hours. The reaction was followed by TLC until the starting material disappeared. After the reaction was completed the solution was cooled to room temperature and poured into ice-water. The mixture was extracted with methylene chloride (2 x 10 ml). The organic extracts were washed with water, saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed to give 60 mg of the clean methyl ether 111 (93%). The spectral data were in accord with the as- signed structure: ms, m/e: 196 (parent peak, calc. mass of 111, 196), 70 (base peak) and others; ir (neat): 1776, 1373 and 1124 cm'1 and others; nmr (6, cc14): 3.64 (bt, J = 8 Hz, 1H), 3.23 (t, J = 6 Hz, 2H), 3.17 (s, 3H), 2.57- 1.00 (m, 8H) and four methyl groups at 1.23, 1.17, 1.00 and 0.92 (total of 6H). 93 Reaction of the tosylate 52R with t-butyllithium in tetrahydrofuran. In a 25 ml three—necked flask equipped with condenser, stopper and serum cap was placed 5 m1 of tetrahydrofuran and 0.5 ml (0.96 M) of t-butyllithium was added slowly at -78°. To the stirred solution, a mixture of 156 mg of the tosylate an’in 1 m1 of tetrahydrofuran was added. The reaction mixture was stirred at -780 for 15 minutes and allowed to warm to room temperature. The solution was then quenched with water and extracted with ether (2 x 10 ml). The combined solvents were washed with saturated sodium chloride and dried over sodium sulfate. Removal of solvents gave a crude material which was adsorbed on an alumina column. The material was eluted with 25% ether- hexane to give 140 mg of the adduct 112 (77%): ms, m/e: 394 (very weak), 337 (8.8%), 222 (5.0%), 207 (3.7%), 194 (5.0%), 165 (16.2%), 155 (6.2%), 137 (51.2%), 128 (77.5%), 91 (45.0%), 57 (87.5%), 43 (100%); ir (neat): 3597, 1610, 1470, 1360, 1176, 1099 and others; nmr (6, CC14): 7.37 (ABq, J = 8 Hz, 4H), 3.90 (t, J = 6 Hz, 2H), 2.40 (s, 3H), 2.93-1.10 (m, 10H), 1.20 (s, 3H) and 0.90 (S, 12H). Reaction of the tosylate figalwith methylsulfinyl carbanion. A solution of methylsulfinyl carbanion was prepared by the method of Corey52 from 57 mg of 57% sodium hydride 94 p b t b L L b b L F b L b b L L (p L (I ) b F _ h b b b _ b h b b _ h h b b — h h b b h h b h H h h b b _ h b b h _ L h Figure 18 Proton NMR Spectrum of 7,7-Dimethyl-6,6-ethylenedioxy-exo- bicyclol3,2,0lheptan-2-ol QR, 105 I 1 ma shaman o-.. - I — 41(I‘I I d — _ . 1 m . .. _._ _ 1. _ _ _ _ . 1 ,. ._ . H. .z . . . . _ [\lxa m — - .IA _ .r a . p L h b — .1 Figure 19 Proton NMR Spectrum of 7,7-Dimethyl-6,6-ethylenedioxy-exo- bicyclol3,2,0]heptane-2,3-oxide 144 106 AIA ~10 h b — D P L (P A— r by L (Dr _ Figure 20 Proton NMR Spectrum of 7,7-Dimethyl-6,6-ethylenedioxy- bicyclol3,2,0lheptan-2-one 44 107 Figure 21 Proton NMR Spectrum of 7,7-Dimethyl-6,6-ethy1enedioxy- bicyclol3,2,0lheptan-3-one 44 108 Hm magmas H» Figure 22 Proton NMR Spectrum of 7,7-Dimethy1bicyclol3,2,0]heptane-2,6-dione 44 109 mm 0.33m O// Figure 23 Proton NMR Spectrum of 7,7-Dimethy1bicyclol3,2,0]heptane-3,6-dione 1*, 110 mm shaman a ..- - .vo—o / O/ Figure 24 Proton NMR Spectrum of 7,7-Dimethyl-3-exo-endo-(2-ethyltosylate)- bicyclol3,2,0lheptan-6-one 52R. 111 «N gunman Cd u» a .2 Mario Figure 25 Proton NMR Spectrum of 7,7-Dimethyl-3-exo-endo-(2-ethy1tosy1ate)- bicyclol3,2,0lheptan-6-one 52R, mm aromas 112 A..-.—..-.— . LAWm 1H 4 (I I — ‘ IIIJ I I . N . $16-6 _ no _ _ ~14 or: CON 00m. 00.. Dan _ r . . . . _ r , . . _ . r . _ L ) . . _ , _ - . _ p, _ . . r . . ,1_ . . . _ . . a , _ . . . 1 . .