m: SYNTHESIS or TRICYCLOUSQflSHI; DonEcA-zs,7,10-mma Thesis former Degree otmm [7 s - ‘MICHIGAN:STAIE,UmvERsm_g-:; * ALFRED» ARTHUR HAGEDORN m. £_ ‘ 219-74. ~ m. il; _. L I B R A R Y Michigan 5' r; *r University This is to certify that the thesis entitled THE SYNTHESIS OF TRICYCL0[7.3.0.04’12]- DODECA-2,5,7,lO-TETRAENE presented by Alfred Arthur Hagedorn III has been accepted towards fulfillment of the requirements for Ph.D. Chemistry degree in Major professor Date W73 0-7639 ABSTRACT THE SYNTHESIS OF TRICYCLOE7.3.0.0”’121- DODECA-2,5,7,lO-TETRAENE by Alfred Arthur Hagedorn III The title compound, I, has been synthesized using the reaction sequence shown. This compound is predicted to under- go a series of structurally degenerate Cope rearrangements which scramble the (CH) units into one set of eight equiv- alent positions, and another set of four. Although the rigid geometry of I appears ideal for the Cope rearrange- ment, no changes in the proton nmr spectrum of I were ob- served up to 1u10. It is concluded that the absence of a small ring, with its accompanying strain, is the cause of this result. In addition to the intermediates shown, a variety of other compounds containing the bicyclo[3.3.0]octane skeleton has been prepared. Alfred Arthur Hagedorn III CH 3C(OC 25H )3 Sea» O C) O2C2H5 ‘0 Na, ClSi(CH3)3 NaBHLl #— C Hr OH, OSi(CH3 )3 2 5 H20 CO2C2H5 OSi(CH3 )3 \ CH3307C1;; KOC(CHL)3 f / 7’ __. / H,12 THE SYNTHESIS OF TRICYCLOE7.3.0.0 J- DODECA-2,5,7,lO-TETRAENE By Alfred Arthur Hagedorn III A THESIS Submitted to Michigan State University in Ixartial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1974 9‘5“?" DEDICATION To my parents; without their aid and guidance this work could never have begun, and To my wife Myrna; without her love this work could never have been so happily ended. ii ACKNOWLEDGMENTS I am deeply indebted to Professor Donald G. Farnum for suggesting this project, and for his many valuable sugges- tions. His chemical knowledge and warm friendship have made my stay at Michigan State richly rewarding. The other members of the Chemistry Faculty of Michigan State University have made a great contribution to this work - and thereby to my scientific maturity - through their lectures and numerous informal discussions. I am especially grateful to Professors J. F. Harrison, T. J. Pinnavaia and w. H. Reusch for serving on my committee, and to Professor E. LeGoff for many important tactical suggestions. To the members of "the Farnum group", past and present, I offer my thanks for their technical assistance and good fellowship, and my apologies for all the heavy photochemistry, "borrowed" glassware, and off-key singing. Contrary to Professor Hart's suggestion, they should not all be drowned. I acknowledge with pleasure the honor of having held a National Science Foundation Fellowship during most of my stay in East Lansing. Finally, I should thank the members of the Cornell University Chemistry Department, 1965-1969, for their patience and encouragement during my undergraduate education. iii TABLE OF CONTENTS INTRODUCTION. SELECTION OF A SYNTHETIC APPROACH - A PRELUDE . . . . . . . . RESULTS AND DISCUSSION. Synthesis of Bicyclo[3.3.0]octa- 3 , 7-diene-2 , 6-dione o o o o 0 Reduction of Bicyclo[3.3.0]octa- 3,7-diene-2,6—dione. . . . Orthoester Claisen Reaction of Bicyclooctadienediol Completion of the Synthesis. Properties of Tricyclododeca- tetraene 11. SUMMARY EXPERIMENTAL. General. Dimethyl Glutarate 11. Tetramethyl Hexane-1,3,H,6- tetracarboxylate 1 . Free Radical Induced Coupling o Dimethyl Glutarate BicycloES.3.0]octane-2,6-dione Dieckmann Cyclization of Tetraester 55 and Hydrolysis-decarboxylation of the Product, Ketoester 16. 2, 6- Diacetoxybicyclo]3.3.0]octa-2,6— diene 11. Enol Acetylation of Dione 11. . . . . . . . . . . . . 3,7-DibromobicycloE3.3.0]octa—2,6- dione . Bromination of Enol Acetate 11 2, 2, 6, 6- Bis(ethylenedioxy)- -3, 7- dibromob1cycloE3. 3. 0]octane Ketalization of Bromoketone iV Page 21+ 36 36 US 53 68 8M 92 96 96 98 99 102 106 106 107 TABLE OF CONTENTS (Continued) 2, 2, 6, 6- -Bis(ethylenedioxy)bicyclo- [3. 3. 0]octa- 3, 7- diene 11. Dehydro- bromination of Bromoketal 11 with Ethanolic Potassium Hydroxi 2, 2, 6, 6- -Bis(ethylenedioxy)bicyclo- [3. 3. 0]octane 11. Ketalization of Bicyclooctanedione 11. . 2, 2, 6, 6- -Bis(ethylenedioxy)- 3, 7- dibromobicyclo[3. 3. 0]octane 11. Bromination of Ketal 11. 2, 2, 6, 6- -Bis(ethylenedioxy)- 3, 7- dibromob1cyclo[3. 3. 0]octane Direct Bromination of Dione §% in Ethylene Glycol 2, 2, 6, 6- -Bis(ethylenedioxy)bicyclo- [3. 3. 0]octa- 3, 7- diene . De- hydrobromination of Bromoketal 11. Bicyclo[3. 3.0]octa-3,7-diene-2,6- dione 11. Deketalization of Ketal QR Cis, endo- 2, 6- -dihydroxybicyclo- t3—3. Olocta- 3, 7- diene H1. Diisobutyl Aluminum Hydride Reduction of Diene- dione 11. Temperature Dependence of the Reduction of Dienedione 118 with Diisobutyl Aluminum Hydr1 Epimerization of Cis, endo- 2, 6- dihydroxybicycloEB. 3. Olocta- 3, 7- diene. . . . . . . Cis, endo- 2, 6- -diacetoxybicyclo- t“3. Olocta- 3, 7- diene 11 and the Trans- isomer . Acety ation of Blcyclooctadienediols 11 and 11. Chromium Trioxide-Pyridine Oxida- tion of the Epimeric Bicyclo- octadienediols . . . . . Page 108 109 110 113 11H 115 116 119 120 121 122 TABLE OF CONTENTS (Continued) Cis,endo-bicyclo[3.3.0]octa-3,7- diene-2,6-diacetic Acid, Diethyl Ester , and Endo-8-hydroxybicyclo- [3.3.0 octa-3,6-d1ene-endo-2-yl- acetic Acid Lactone . Orthoester Claisen Rearrangement of Dienediol 11 . . . . 2,6-Bis(carboethoxymethylene)bi- cyclor313.0]-octane . Acid Catalyzed Wittig Reaction of D1one 1h and Carbo- ethoxymethylenetriphenyl-p osphorane Bicyclo[3.3.0]octane-2,6-diacetic Acid, Diethyl Ester . Catalytic Reduction of Unsaturated sters 11 and 11. . . . 6,7-Bis(trimethylsiloxy)tricyclo- [7.37570”a12]-dodec-6-ene . Acyloin- type Cyclization of the Saturated Diester 11 . . . . . . 6,7-Bis(trimethylsiloxy)tricyclo- [7.37670”.123dodeca-2,6,1o-triene Acyloin Cyclization of Un- saturated Diester 11 . . 7-Trimethylsiloxytricyclo[7.3.0.0u’12]- dodeca-2,lO-diene-6-one 11 . . Strong Acid Catalyzed Hydrolysis of Bis(trimethylsiloxy)olefin 1 . Formation of Tetracyclic Ketol 1 orm11. . . . . . . . . . . . Tricyclo[7.3.0.0q’121dodeca-2,10- diene-6,7-diol . Reduction of Bis(trimethylsi yl)ether 11. . . Periodic Acid Cleavage of Diol Formation of Ci§,endo- b1cyclo[3.3.0]octa-3,7-d1ene- 2,6-diacetaldehyde 11. . . gig-6,7-diacetoxytricyclo[7.3.0.Ou’121- dodeca-2,lO-diene 111. . . vi Page 123 129 131 132 IBM 135 137 138 IMO 1u3 TABLE OF CONTENTS (Continued) Page Trans— 6, 7- -diacetoxytricyclo- [7. §. 0. Oua123dodeoa—2,10-diene (lgg or lQé. . . . . . . . . . . 1H5 Cis- 6, 7- -dihydroxytricyclo[7. 3. 0. OH’ 12]- dodeca- 2, lO- diene Dimethanesulfonate . . 1H5 Distillation of Tricyclododeca- dienediol gg from Alumina. . . . . . . . 1H7 Tricyclo[7. 3. 0. 0H, ’12]dodeca- 2, 5, 7, 10- tetraene §§ and Tricyclo[7. 3. 0. 0” 12]- dodeca-Z, diene- 6- -one {i 8. Potassium t- butoxide Elimination o imesylate Igz. . . . . . 1u7 Determination of Temperature Dependence of the NMR Spectrum of gz. . . . . . . . 150 REFERENCES. . . . . . . . . . . . . . . . . . 151 APPENDIX. . . . . . . . . . . . . . . . . . . 158 vii TABLE LIST OF TABLES Some Fluxional Molecules Interatomic Distances in Cope Systems Temperature Study of the Diisobutyl Aluminum Hydride Reduction of gz Additions to Bicyclooctyl Derivatives viii Page 13 50 51 FIGURES l 10 Al A2 A3 Au LIST OF FIGURES Degenerate Cope12 Rearrangement of Tri- cyclo[7.3.0.0. 2]dodeca-2, 5, 7,10- tetraene . . . . . Possible Degenerate Rearrangements of Tricyclododecatetraene 22. Claisen—type Rearrangements. Proposed Route to Tricyclododeca- tetraene 22 Original Route to Dienedione 62. New Synthesis of Dienedione £2 . Proton NMR Spectrum (60 MHz) of Tetraene 2%. . . . . . . . . . . . . . Olefinic Region of the Proton NMR Spectrum (100 MHZ) of Tetraene 22 . . . . . . Synthesis of Tricyclododecatetraene 22 . Apparatus for Preparation of Tetraester éé Proton NMR Spectrum (60 MHz) of Cis, exo- 3, 7- dibromo- 2, 2, 6, 6- bis(ethylenedioxy 5- bicyclo[3. 3. 0]octane— gag. . . . . Proton NMR Spectrum (60 MHz) of Trans- 3, 7- dibromo- 2, 2, 6, 6- bis(ethylenedioxy)- bicyclo[3. 3. 0]octane— égk' . . . Proton NMR Spectrum (60 MHz) of Cis,endo- 2, 6- dihydroxybicyclo[3. 3. 0]octa- 3,7-d1ene mg' . . Proton NMR Spectrum (60 MHz) of Cis, endo- bicyclo[3. 3. O]octa-3, 7- diene— 2, 6- d1acet1c Acid, Diethyl Ester 71. . . . ix Page 15 21 32 35 37 39 87 90 93 100 160 162 IBM 166 FIGURES A5 A6 A7 A8 A9 LIST OF FIGURES (Continued) Proton NMR Spectrum (6OMHz) of 6,7— Bls(tr1meth¥ls1loxy)tr1cyclo- l7 3. 0. 0” ]dodeca 2, 6,10 triene kté Proton NMR Spectrum (60 MHz) of Tri- cyclo[7. 3. 0. 0”12]dodeca-2,10-diene- 6, 7- -cis diol g6 . . . . Proton NMR Spectrum (60 MHz) of Cis- 6,7-diacetoxytricyclo[7.3.0.0u’lzjdodeca- 2,10-diene kgg o o o o o o o o Proton NMR Spectrum (60 MHz) of Trans- 6, 7— diacetoxytricycloE7. 3.0.0u’lzldodeca- 2,10—diene . . . . . . . . . . . . Proton NMR Spectrum (60 MHz) of Cis- 6, 7- dihydroxytricyclo[7. 3. 0. 0L} 12Id dodeca- 2,10-diene Dimethanesulfonate Igz. Page 168 170 172 17H 176 INTRODUCTION The design and synthesis of new compounds to test chemical theories has long been a favorite pastime of chemists. Willstatter's synthesis of cyclooctatetraene, which had been predicted to be aromatic since it was a fully conjugated cyclic system, is probably the best known exam- ple of this kind of research (the experimental fact that Willstatter's compound showed olefinic properties led the chemists of that time to suspect the experiment — a not infrequent situation)l. After Huckel's enunciation of the "Mn + 2" rule, a large number of syntheses were attempted to test this theoryz. Much more recently, the concept of "orbital symmetry" has led many chemists to design systems to explore concerted reactions. This thesis describes the synthesis of a compound of such "theoretical interest". The Cope rearrangement, shown in its simplest form 3. , below, has been extensively studied its intramolecular nature was deduced from A / ————r \ ‘\. ./’ l the first-order kinetics and the absence of "crossover" products when a mixture of reactants was heated. The rather large negative entropy of activation (22' - l2 e.u.) interpreted as evidence that the reaction proceeds through a cyclic "complex" l. According to Woodward and Hoffmannu, the reaction is a [3,3]-sigmatropic rearrangement (alternatively, a n28 + 02S + n28 reactions), and therefore a concerted pro- cess is "allowed" by orbital symmetry considerations. The remainder of this discussion will be in terms of a concerted reaction, but it should be realized that other mechanistic options are available, and that these are some- times employed. For example, a cleavage—recombination mechanism is operative (probably in competition with the 8 concerted mechanism) in the diphenylhexadiene 2, below . At the other extreme, formation of a l,u-cyclohexylene Ph Ph Ph :[::i: A __+ + //' .// Ph Ph Ph % I — _ I Ph intermediate (biradical) % has been suggested for the derivatives 3 (R = H or Ph)9 and may be involved (at least, f10 is energetically feasible) for 1,5-hexadiene itsel A recent calculationll suggests that this latter possibility is indeed the case, although this can not be taken as proof. Clearly a spectrum of mechanisms is available, ranging Ph Ph F _ Ph ‘\\ _____* _____' ,/’ / \ R - R - R 6 kt from bond-breaking preceding bond-making to the opposite, formation of the new o-bond preceding rupture of the old one. The concerted mechanism lies between these extremes. 12’13 demonstrated The classic study by Doering and Roth that this "complex" (more precisely, the transition state in the step determining the stereochemistry of the product) had a "chair-like" four-center arrangement 6 and not the alternative boat-like (six center) geometry 6; the energy difference between the two geometries was estimated to be "at least 5.7 kcal/mole." A "qualitative quantum mechanical explanation" was advanced to account for this preference. More recently, Woodward and Hoffmann have used a similar argument, treating it as a "secondary effect" of orbital symmetrylu. Thus, although a concerted reaction is "allowed" for a Cope rearrangement proceeding through either transi— tion state 6 or 6, there is an .antibonding interaction between the central atoms of the two allyl units; clearly, this effect would be greater in the boat geometry, and the 15 reached the same conclu- chair would be preferred. Pukui sion with a slightly different approach, and estimated an energy difference of 5-6 kcal/mole from a Huckel-type calcu- lation. Although the chair geometry is preferred, a number of compounds constrained to react gig the boat geometry do in fact rearrange very easilyls. Qis-divinylcyclopropane Z and Eig-divinylcyclobutane Q rearranged at -50° and 120° respectively. The corresponding trans isomers, g and 1Q, \ . \ 1 Q g 19 in which the formation of a cyclic "complex" introduces prohibitive strain, required much higher temperatures for reaction; the trans-divinylcyclobutane gave different prod- ucts as well. In the next homolog, the strain-free divinyl- cyclopentane ll, rearrangement to the monocyclic product was not observed; cis—trans isomerization was the only re— action noticed. Strain may have a thermodynamic effect in this case - the strain of the medium sized ring would cause ‘\\ ‘// the divinylcyclopentane to be favored. Similarly, in the cyclodecadiene—divinylcyclohexane system, the reaction pro- ceeds to give the unstrained cyclohexane derivative. Thus, ring strain may affect both the rate and equilibrium in Cope systems. This importance of strain was clearly recog- 16 nized by Vogel (who studied most of the examples just given), and Doering and Roth13’17. The latter authors proposed to counteract the unfavor- able entropy of activation by connecting the ends of a di- vinylcyclopropane with a methylene group, thus holding the vinyls in a geometry suitable for a cyclic process. The resulting molecule, bicyclo[5.l.0]octa-2,5-diene lg (homo- tropilidene), is set up for a degenerate Cope rearrangement; the reactant and product have the same structure. That this degenerate rearrangement was indeed occurring was evident from the temperature dependent nmr spectrum of 1213’17. It was estimated that rearrangement took place about once per second at -50°, and about 103 times per second at 180°. This "fluxional" behavior could be further enhanced by tying together the two ends of the homotropilidene, as in ketone lg (barbaralone)13’18. This has the effect of 13 mm eliminating the unreactive conformation kg of homotropilidene, leaving only the reactive conformer l6. In an inspired 1H 15 ’Vb "VI: 0 o o o 0 13,17 0 o fl1ght of 1mag1natlon, Doer1ng and Roth proposed jo1n- ing the "ends" of the homotropilidene by means of another double bond, giving structure 16. This molecule could U3 undergo a series of Cope rearrangements leading to the equivalencing of all ten protons, and the interconversion of the more than 1.2 million (10!/3) "isomers" (connectiv- ities) of 16; thus, every carbon atom becomes bonded to every other. In discussing this hypothetical compound, Doering and Roth declared "...all ten carbon atoms inevit- ably wander over the surface of a sphere in ever changing relationship to each other. Such a fluxional structure will have had no precedent in organic chemistry." IQ is, of course, bullvalene; the synthesis by Schroder in 196319, with the demonstration of its fluxional nature, fully con- firming Doering and Roth's speculations, is among the most dramatic discoveries in modern organic chemistry. A number of other fluxional molecules are known, with varying tendencies to rearrange. Several of these are shown in Table l with their measured energies of activationzo. As can be seen, the activation energies span a considerable range. The values for 1,5-hexadiene and benzene are appended for comparison (benzene may be regarded as a "transition state" for Cope rearrangement of cyclohexatriene, with an energy below that of the starting material20). The molecules shown in Table l all contain a homotro- pilidene unit, and the question arises whether this struc- tural feature is essential for rapid rearrangement to occur. To this writer's knowledge, the only neutral molecule not containing a homotropilidene which exhibits rapid fluxional behavior is the (CH)10 hydrocarbon lg ("hypostrophene")23. Although the Cope rearrangement is too slow to be detected _——*’ etc. 4—— «1% by collapse of the nmr spectrum (vide infra), its opera- tion was demonstrated by deuterium labelling. High tempera- ture nmr studies were not possible, as 12 rearranges to another (CH)10 hydrocarbon, 2Q, at temperatures over 80°. The diradical 21 was suggested as an intermediate in this "forbidden" reaction. This rearrangement clearly shows Table 1 (a) Some Fluxional Molecules 1 Compound AG , kcal/mole 12.8 Mi 1% (D 11 (b) (calculated 2.3 , 3.6(0) ) a 1% Octamethyl lg 6.H D 35.5 D negative (a Taken in part from Ref. 20. (b) Cal ulated (MINDO/2) AB , Ref. 21. (c) Calculated (MINDO/2)AE , Ref. 22. Jog—fig} that 1g is strained; steric acceleration of the Cope re— arrangement is probably operating here, as in the homo- tropilidene derived cases, although there may be a decelerat— ing effect due to closing a cyclobutane ring. Recently, this idea of strain being the principal factor in the low activation energies for Cope rearrangement of tropilidene "derivatives" has received theoretical support. Dewar and coworkers used the MINDO/2 approximation to cal- culate the energy of the ground and transition states for l,5-hexadiene and several homotropilidene-based mole- cu18821,22,2u. This approximate theory gave rather poor agreement with the experimental activation energies for 1,5-hexadiene, the calculated energies being 23. 10 - 11 kcal/mole low; Dewar attributed this to "a known failing of MINDO/2... a tending to over-estimate the stability of cyclic compounds"21. The ca, 6 kcal/mole preference for the chair-type transition state was reproduced very well, however, and much better agreement was obtained for the homotropilidene derivatives ("...errors due to the presence of rings should cancel"21). In the original MINDO/Z calculations on the homotropil- idene derivativele, Dewar and Schoeller indicated that the 10 rate enhancement in bullvalene 16 compared to a boat form of l,5-hexadiene is probably due to ring strain being re- lieved in the former case. A later study22 included "energy partitioning , whereby the total molecular energy is ap— portioned among the bonds and atoms of the molecule. Al- though the results were not completely clear, the same conclusion was drawn - the greater reactivity of molecules containing a homotropilidene unit is "primarily due to ring strain". Although not really relevant to this discussion, the proposed eXplanation for the sequence of reactivity bull- valene lg //AL~!!!;>, I: \ obvious. Clearly, the other Cope system could equally well U react, and a cycle of Cope rearrangements becomes possible. The complete cycle is shown in Figure 1, using Doering and Roth's convenient schemela’l7 for indicating which bonds are made and broken. "As can be seen in Figure l, a considerable amount of position scrambling occurs in this cycle of rearrangements, leading to two sets of equivalent positions, (1,3,H,6,7,9, 10,12) and (2,5,8,ll). This is represented in 2%, the group of eight equivalent positions being marked (0), the other group (of four) being unmarked. 15 12 ll Figure 1 Degenerate Cope Rearrangement of Tricyclo- [7.3.0.0”’121dodeca-2,5,7,lO-tetraene 16 88‘, This pattern may be derived in other, less involved ways. For example, the view shown in 22 reveals that the indicated Cope rearrangement reflects the molecule through a mirror plane passing through atoms 5 and 11 and bisecting bond 1—9. Thus, position u reflects into 6, 3 into 7, etc. The other Cope system similarly generates another plane (not shown), passing through positions 2 and 8 and the H-12 bond, reflecting 7 into 9, 6 into 10, and so on. These re- flections lead to four groups of equivalent positions, group A = (H,6,lO,l2), B = (l,3,7,9), C = (2,8), and D = (5,11). The two—fold axis of rotation present in the mole- cule then makes groups A and B equivalent giving the eight equivalent positions marked in 22. Similarly, groups C and D are interchanged by the C2 axis, giving the other group of four positions. This argument can be condensed even further, by con- sidering the result of simultaneous rearrangement of both l7 Cope systems. Structure 22 illustrates the transition state (or intermediate) for the hypothetical - and unlikely — reaction; .a biradical is used for illustrative purposes 85’. only. By virtue of the considerable symmetry (D2d) which 22 possesses, the eight "bonded" atoms are made equivalent, as are the four "radical centers". The scrambling pattern is the same as that derived earlier, as of course it must be. Thus, the series of degenerate Cope rearrangements in 22 could be detected by observing the scrambling of positions into the two sets (1,3,u,6,7,9,10,12) and (2,5,8,ll). Indeed, this is the usual test for fluxional behavior. If the rate of rearrangement were sufficiently high, this could be detected by observing the temperature dependence of the nmr spectrum of 22; at low temperatures a pattern consistent with structure 22 - eight vinyl and four aliphatic protons - would obtain, but this would be transformed at higher temperatures into a new pattern, with four vinyl pro- tons and eight protons "averaged" between vinyl and ali- phatic. If the rearrangement were too slow to be observable at temperatures accessible in the nmr experiment, or if some other reaction were to intervene, the position scramb— ling could still be detected by introducing a label (ideally 18 deuterium) specifically at a certain site (or sites)in 22. For instance, deuterium placed at the bridgeheads of the bicyclooctyl nucleus (positions 1 and 12 of the tricyclo- dodecyl system) would ultimately appear uniformly distributed over the eight marked positions in structure 22 (p.16). By one or the other of these techniques, the rate of equival- encing the positions, and thereby, the rate of Cope rear- rangement,cou1d be determined. Tricyclododecatetraene 22 has another unusual feature which has not been discussed - namely, it is chiral (point group C2)2u. The effect of Cope rearrangement on this property of 22 is easily determined "by inspection". As shown, each Cope rearrangement converts the starting struc- ~ m 1(§)-22 1(§)-22 ture into its enantiomer; this can also be seen by consider— ing view 22. This provides a second means of observing the degenerate Cope rearrangement, as this reaction would lead to racemization of initially resolved 22 (only partial resolution would be necessary). As two Cope rearrangements are needed for complete scrambling while only one is needed for racemization, the rates of these two "reactions" should be in the ratio of 1:2. In the event that rearrangement is slow on the nmr time scale, racemization studies could provide 19 information on the rate, without having to prepare the labelled compound. The price of this, of course, is that 22 would have to be resolved. Although position scrambling is the usual test for a degenerate rearrangement, such as stereochemical proof has been used occasionally. For example, Cope rearrangement in hydrocarbon 22 was followed by monitoring the loss of —> *—_— 8'7. optical activity in the partly resolved compound32. In a non—Cope system, the photolytically induced racemization of the dihydropyrazine derivative 22 demonstrated that the . . . . . . 3 indicated degenerate photo1somerizat1on was occurr1ng 3. gig: h“ (.3 Another amusing possibility based upon the enantiomeriza- tion which accompanies Cope rearrangement in 22 is complete conversion of the racemic mixture to a single enantiomer. It is possible (though unlikely) that this could be achieved by crystallization of 22, by analogy to the results of Pin- 3”. A somewhat more probable means cock with l,1'-binapthyl of such "resolution" requires the intervention of another chiral influence. Thus, treatment of racemic 22 with an 20 optically active complexing agent, such as Cope's platinum complex35 , might lead to complete formation of the more stable diastereomer. A similar result can be imagined to result from chromatography on a chiral adsorbent. Such a result would be most unusual, and the possibility deserves mention, even though it seems remote. The final comments in this section are devoted to an even less likely possible behavior of ag, one which has a startling result. The simultaneous rearrangement of both Cope systems was mentioned previously (p.15) and the result in terms of position scrambling was shown to be identical to that resulting from sequential Copes. When the stereo- chemical outcome of this "double Cope" is determined, how- ever, a difference appears: "double Cope" “~ - _ #7 — <4! ““\\\ This mechanism predicts scrambling without racemization! This possibility may be added to the cycle of COpe rear- rangements, resulting in the pattern shown in Figure 2. The operation of this mechanism could be detected by accu- rately measuring the rates of racemization and scrambling; if racemization takes place with any rate less than twice the rate of scrambling, the "double Cope" must be involved. The probability of observing this unusual reaction is of course determined by the activation energies of the "single" 21 single Cope V (— double Cope Figure 2 Possible Degenerate Rearrangements of Tricyclododecatetraene 3% 22 and "double" Cope rearrangements. To the extent that there is no interaction between the two Cope systems, the activa- tion energy for the double rearrangement would be roughly twice that for the single. Assuming an activation energy for the simple Cope rearrangement comparable to that in bull- valene, 23' 12 kcal/mole, this puts the double Cope prac- tically out of reach, at least as far as detection is con- cerned. Although the operation of the double Cope probably will not be observable in 22, it might be found in some deriva- tive; application of perturbation theory and approximate calculations may lead to the design of such derivatives, as was done in designing semibullvalenes predicted to have 20’21." Similarly, the struc— "negative activation energies tural features in 22 might be translated into some other molecule which would be more likely to show the simultaneous double rearrangement. To summarize this section, tricyclododecatetraene 22 appeared to be an interesting molecule for the following reasons: (1) 22 is a potentially fluxional molecule, the twelve (CH) units being scrambled into groups of eight and four by a series of degenerate Cope rearrangements. (2) The molecule is held rigidly in a geometry cor- responding to a boat-like transition state for the Cope. However, the strain is considerably less for 22 than for molecules - bullvalene, barbaralane, etc. — containing a homotropilidene unit. The importance 23 of release of ring strain in accelerating the Cope rearrangement could thus be estimated. (3) 22 is chiral, and the Cope rearrangement should lead to enantiomerization. This could be observed by following the racemization of resolved 22, which should occur twice as fast as position scrambling. (H) Other unusual properties might result from the relationship between the Cope rearrangement and the chirality of 22. For these reasons, and because it looked like fun, the synthesis of compound 22 was undertaken. SELECTION OF A SYNTHETIC APPROACH - A PRELUDE Our interest in the synthesis of the (CH)12 tetraene 22 was due in part to the recognition that it might arise from the combination of cyclopropenyl cation and cyclonon- atetrenyl anion: //\\- + ___, /[>\> /:.’.\ (\J D“ Q Q9 9 , %% However, preliminary results on this reaction have not been 36, and in a more heavily functionalized case a different sequence occurs37. In view of the difficulties promising inherent in this reaction, and the multitude of products which would probably arise, a tactical synthesis of 22 was desirable. In designing such a synthesis, a number of approaches came to mind. Several of these are outlined in this section; the advantages and disadvantages of each are briefly con- sidered, and the scheme finally chosen is presented in some detail. 2” 25 The first approach considered has as its key step a fragmentation reaction of a tetracyclic precursor, gag or gap, as illustrated: G ['Y __.. a: .— ’ I f' (' X ;::_ Cope (j; X 23a rearrangement 2gb Inspection of molecular models suggests that the orbitals involved are favorably aligned for this reaction to occur. The indicated interconversion of gag and {fig gig a Cope re- arrangement is an amusing feature of this scheme. However, the attractive features of this approach are more than bal- anced by the complexity of the necessary precursor 22. Design of a reasonable synthesis of just the carbon skeleton of 2% is not easy, and the necessary stereochemistry of the substituents further complicates the situation. Another approach which was considered involved fusing an additional five membered ring onto a bicyclo[5.2.l]decane derivative (Xn represents "necessary functionality"): A C Xn x “’ 5‘ n _’ “I Q In particular, an intramolecular alkylation (3Q + QT) or an intramolecular Michael addition ($2 + ég) appeared likely. 26 However, attack might take place at the wrong position, to give a derivative of the known38 0' 0 compound Qa. 2% .2; In any event, these routes were not pursued experimentally, mainly because reasonably straightforward synthesis of the necessary precursors, such as gQ and g2, were not obvious. The preceding two ideas are basically traditional in approach, using classical methods of bond formation. Two other synthesis were devised, which utilized more modern reactions. The first required photoaddition of acetylene (or its synthetic equivalent) to the knownag’”0 (CH)10 hydro- carbon gg, "lumibullvalene". Opening (disrotatory and there- fore photochemical) of the resulting cyclobutane gQ would then give 22. The problem evident here is that the other double bonds in SS might react with the acetylene, giving unwanted products. There is no obvious way of preventing 27 \ , HCECH,hv$ hv £2, / 3% I322 this side reaction. The known”1 photocyclization of éé to 81 would be another problem, although this might be suppressed by having a sufficiently high concentration of acetylene present. A less compelling objection is purely personal. I This route appears rather dry; the results would be deter- mined largely by what the molecules "want to do", and the amount of interesting chemistry might be small. As gé is quite readily available from cyclooctatetraeneuo, this route might well deserve further consideration. Another "moderd'synthesis is outlined below: :_\/ Xn XII w 1&3 —» - ~__ '\\ é»? £3 __’E__. gg @ 33,9, 28 Thus, sensitized photocyclization of a cyclododeca-l,5-diene ”2 to give a product of type derivative SQ would be expected Q3. Four double bonds would then be introduced (giving g9), which might rearrange thermally to 22 as shown. The rear- rangement is an "allowed" l,5-shift, and might be facilitated by release of strain and the reasonably good geometry of Q2- The objections to this rather intriguing approach to 22 mainly revolve around introducing the necessary unsatura- tion, that is, the SQ + $9 transformation. There is some evidence that the monocyclic precursor gg could not have any additional double bonds. Thus, 1,5,9-cyclododecatriene gl, when photolyzed in aromatic hydrocarbons, gives a low yield of the divinylbicyclo[3.3.0]octane g2 (cis-trans isomerism of gl is the main photoreaction, and only the minor all-cis isomer goes on to g2)u3; the proposed mechanism \ hv PhCH .24” is shown. This implies that a considerable amount of func- tionality (Xn) would be needed in 駰 Furthermore, all of 29 this functionality would have to survive the photocycliza- tion, which might exclude halogen substituents. Although this problem probably could be solved, the multitude of possible approaches at such an early stage in the synthesis seemed very undesirable. The rejection of the four schemes just discussed, and of other, more arcane routes, was assisted by the conception of another, to our minds far superior plan. This required the coupling of the termini of two 2-carbon bridges attached "cis, endo" to the underside of a bicyclooctadiene: :f s flié _._.z: ’.' Y Y \l‘- I X In particular, an acyloin condensationuu , or the Bloomfield- Rfihlmann modification thereofus, appeared ideally suited for this transformation. By these procedures, the diester gg would be converted to the tricyclic a-ketol g%, or the bis(trimethylsiloxy)triene H ; further elaboration to give 22 appeared straightforward. 30 l)Na -—co R 2)H+ / 2 A 0H 0 fit CO2R \\\ Na ClSi(CH3):_ . g; OSi(CH3)3 Si(CH3)3 Of these two possible reactions, the modified acyloin”5 appeared preferable. This method has the advantage that side reactions (particularly Dieckmann cyclization) are greatly reduced, and even strained systems such as %Q and i1 can be made in this wayus. In addition, the bis(trimethyl- OSi(CH3)3 031(CH3)3 081(CH3)3 3% #52. silyl)enediol ethers which result from this reaction can be subjected to a variety of further reactionsus. The necessary synthetic intermediate then becomes di- ester kg, or some other compound easily transformable into kg. It is at this stage, then, that the gigfgngg disposition of the two—carbon side chains must be established. Once this orientation is established, it is very unlikely that 31 it would be lost, as no easily epimerizable centers are present in kg. The most serious problem that we imagined was antarafacial Cope rearrangement, which would take kg into the gig-259 isomer fig. However, as the antarafacial Cope rearrangement now appears? to be nonexistent, this R CO R CO 2 2 CO2R CO2R At»: a: reaction did not seem very likely. After some consideration, we decided that the method of choice for introducing the two-carbon chains was a Claisen rearrangementus-u8 (the oxa-analogue of the Cope), or one of the many modifications of that reaction. The well knownu'8 stereospecificity of the Claisen rearrangement insures that a vinyl ether starting "under" the bicyclic skeleton will appear as an acetaldehyde chain, again "under" the [3.3.0] system. For example, thermolysis of the enol ether fig, derivable from the gisfgngg diol kg, should give dialdehyde ST. The conversion of the dialdehyde into the diester %% would probably be easy. As just mentioned, a number of u -—-» (fool ~ variations on the Claisen theme are also known. Several which have been useful in synthesis are shown in Figure 3; 32 Claisen Rearrangementus—ug OH _ —-o CHz-CHO-CZHS \f A .> CH0 Hg(II) 7 / OH CHO (Ref. Hg) Meerwein — Eschenmoser Reactionso-52 OHCH C(OR) NR' 0 /’ 3 2 Z x A, -ROH CON(CH3)2 5 (f (Ref. 51) NHCOCH NHCOCH 3 3 Orthoester Claisen53 ‘OH :2 CH3C(OR)3 OR H+,A, -ROH CO R V (\ J, N (A) (D OH HO (Ref. 53) 2C3H5 Figure 3 Claisen-type Rearrangements 33 an example of each is included. Several points about these deserve mention. The Claisen sequence proper, giving the aldehyde, is quite sensitive to steric effects, particularly in the step of forming the vinyl ether. Also, the yield (for the two steps) varies widely. The Meerwein-Eschenmoser reaction is suitable for hindered systems, but again the yields vary over a considerable range. As our synthetic route called for the diester i3, the orthoester modification53 of the Claisen rearrangement appeared ideal. At the time this project was begun, no examples of the orthoester Claisen in cyclic systems had been reported, and the effects of steric hindrance were completely unknown. We decided to try the orthoester procedure, fully expecting that some problems might develop in putting two substituents under the bicyclooctadiene framework. Whether the reaction could be done on the diol %g was unknown, but we believed that, if necessary, the side chains could be put on sequentially, with appropriate protecting steps along the line. Thus, the necessary compound for this approach is gig- ggdg-bicycloE3.3.0]octa-3,7-diene-2,6-diol ag. The obvious Precursor to this diol is the knownzg’su’55 dienedione £2 - reduction of the carbonyl groups would be expected to give the desired gndg orientation of the hydroxyls, provided a reasonably bulky reducing agent was used. Although Dauben and his students had been unable to reduce the carbonyls-of 32 without partially reducing the carbon-carbon double bonds55 3Q —-* O O H O 5% #93 22% we anticipated that some reagent could be found which would give usable yield of the diol $3. In particular, diisobutyl aluminum hydride appeared a likely candidate, as this reagent had been found to give clean reduction of a,B-unsaturated ketones to allylic alcoholsss. The bulkiness of this re- agent would also be expected to lead to the necessary gig- gndg stereochemistry. A final point which helped us choose this approach to 22 was the availability, from other research in this labora- tory, of bicyclooctanedione g3. As a procedure for convert— ing 3% to 32 had been worked out by the Dauben groung’su’ss, this simplified the planning necessary. Figure u shows the proposed synthesis of tetraene 22. The reasons for choosing this scheme can be condensed into the following. First, the sequence appeared promising, with no really bad steps. At the same time, the chemistry involved would not be trivial, and the use of some new re- agents and procedures might lead to improved knowledge of them. Having the starting material in hand was an added bonus. Finally, most of the synthetic intermediates possess the same 02 symmetry as the final product, and as each step transforms the symmetry-related functional groups in the same way, a certain economy of steps is maintained. 35 0 OH [H] CH3C(OR)3 o ;— + ; ((1-CuH9)2AlH?) H , A O HO gg %% c0212 6 o Na, ClSi(Cqu)3> ._, _, OSi(CH3)3 oSi(CH3)3 002R g3 £3 %% Figure u Proposed Route to Tricyclododecatetraene 22 RESULTS AND DISCUSSION Synthesis of Bicyclo[3.3.0]octa-3,7-diene-2,6-dione The synthetic plan just outlined required bicyclo- [3.3.0]octa—3,7-diene-2,6-dione 52 as the starting material. As mentioned previously, Dauben and coworkers had reported 0 O «53% 22% the preparation of this compound in 19525”, from the dione 29,55 53, and had subsequently improved the procedure Our first preparations of the dienedione utilized the most re- cent (1966) recipe of the Dauben group, that of Simpsonss. The precursor, dione 53, was prepared by Glen R. Elliott, also using Simpson's procedure. The entire scheme, with yields we obtained, is presented in Figure 5; the details are given in the Experimental section. For comparison, the yields reported by Simpson are given in parenthesis. Although this sequence afforded 52, albeit in rather low yield (22-23% from 53), the time required (10 days minimum for the £3 + 52 conversion) appeared excessive. COnsidering the number of synthetic steps beyond 52 which We contemplated, we were sure to need large quantities of :§% and a sequence affording higher yields and permitting Sc1aling up appeared desirable. Accordingly, a considerable 36 37 C02CH3 t-BuOO-t—Bu CH O 0 CH — 'i_.__, 3 2 2 3 KOt-Bu —t=§UUH—** CO2CH3 CH30QC. CO2CH3 SH 55 ’b’b 'b’b O o + H+,H20 >F02CCH3,H CHBOZC 02CH3 g 30-u0% 89% (80-8u%) from,b5 O 55 (ca.60 ) O 53 "J’b — "VD 0 CCH3 0 Br OH OH H+ -—l¥-8—96L—> B . 'I‘ "' .5 .. 9 (82-9u%) 93% (88 92.) o éQ dfi\' 0 ’ H+ KOH, EtOH Br“' Br ea; —4r 8;: 73%) 75'85% ‘ (77-100%) ‘\1 32 sq Figure 5 Original Route to Dienedione 52 38 effort was expended in developing a more efficient large scale synthesis of i2. Figure 6 presents the results of this effort, which also led to a substantial improvement in the preparation of bi- cyclooctanedione 53. The synthesis largely parallels that of the Dauben group2g’5u’55; the main differences are in the preparation of the bromoketal 5%, and in the conditions for the double dehydrobromination of 5% to 3Q. The full details are given in the Experimental section; only the results - and some interpretation - are presented here. Tetramethyl 1,3,”,6-hexane tetracarboxylate 53 was prepared by the free radical induced coupling of dimethyl glutarate 5%, using essentially the procedure developed by 29 55 Osborne and used by Simpson As reported by Osborne, both diastereomers of 55 are formed in this reaction. It was noted long ago by Ruzicka57 that both isomers undergo Dieckmann cyclization to give the same product, bi§(ketoester) SQ with the gig ring fusion. Thus, separation of the iso- mers is not necessary. However, an additional product was formed, amounting to about 15% of the distilled product. This compound has not been identified, but is almost surely the isomeric tetraester 32. The relative rates of abstrac- tion of the a- and B- hydrogens of propionic acid by methyl CO CH A t- BuOO— t- Bu, CH30-2 C CO2CH3 NaOCH us— 555 c; o c (CH3)230 COZCH3 3,2 CO2CH3 5% ii 0 I \ + H20 ’ CH HO GAN‘ wvco WCH o OH OH, H ,A 3 70— 850 969 from 55 o O 53 EA; ’Vb <0 QNH Br3 ,THF 0 o NaOCHq _..___'~._.’ 88— 91% B Br (CH3)230 ?\Jo 89—92% Qt $2 In 0 + 0 2X20, H , A 93—94% 60 52 ’V‘b ’Vb Figure 6 New Synthesis of Dienedione 52 ¥g 40 radical are 7.8 and 1.0, respectively (on a per—hydrogen basis)58. Dimethyl glutarate has four a- and two "B-like" hydrogens; applying the relative reactivities of the prop- ionic acid hydrogens to dimethyl glutarate, and assuming that the coupling of the resulting radicals is random, about 12% of the "wrong" tetraester 62 should be formed. The agreement with the observed result, 15%, is embarrassing, considering the assumptions made in the "calculation". Osborne2g had concluded that isomers of 55 were formed in only small amounts; our results are in contrast to that conclusion. In any event, this impurity is removed quite easily by recrystallization from methanol. If this is not done, the product from the Dieckmann cyclization of 55 to 56 is quite impure, and usually liquid. We found that this cycli- zation may be carried out using sodium methoxide in dimethyl- sulfoxide (DMSO), provided water is excluded. This gives a somewhat higher yield than the old reagent, potassium t—butoxide in t-butanol. In addition, the hazards of hand- ling potassium are avoided, and large scale preparations (0.5-0.6 mole) can be run without difficulty. The product, ketoester 56, was obtained as a finely divided solid. This material can be used directly in the next step, hydrolysis - decarboxylation to 5%, without purification. Dione 5% is quite soluble in water, and extraction with ether requires an extended continuous extraction. We observed that the use of chloroform permits nearly complete extraction of ul ' the dione with only a few separatory funnel extractions. The crude dione is suitable for use in the next step; it can be purified by sublimation (97% recovery) if desired. The use of DMSO as a solvent for Dieckmann cyclizations is not new; in some cases it has been found to give faster reaction and higher yieldssg. However, side reactions have also been reportedsgb; these have been attributed to oxida— tion of the reactants by the solvent. In this regard, we have noticed that high reaction temperatures (over 90°) lead to extensive darkening of the product. In these cases, the odor of dimethyl sulfide was easily detected. The rest“ of the synthesis of dienedione 52 required introducing the two double bonds. The sequence of ketaliza- tion, bromination, elimination, and deketalization as used by Eaton in the structurally similar transformation 6% + 6&60, appeared suitable for the conversion 53 + 52. After some 0 o 3% «53% fitnitial trials, an efficient synthesis of 52 was developed along these lines . Ketalization of 53 proceeded cleanly and in nearly quan- titative yield. The liquid diketal 6k was then brominated “’5Jth.pyridinium tribromide ("pyridinium hydrobromide per- t>15 %% (Mo / Kg 0A1::O gg.———> Wm: O-—Al \ \——* ma 2% id 6 . . . 5, such a sequence 18 reasonable. The activation alcohols energy for the intramolecular reduction would probably be low, and hence the influence of temperature would probably be small. The observed temperature dependence of the reduc— tion is probably the result of decreasing the amount of ini- tial attack on the gndg—face of 82. In any event, the diisobutyl aluminum hydride reduc— tion has been shown to give a high yield of allylic diols, demonstrating the applicability of this reagent in a very difficult case, where other reagents fai155. Also, it provided the necessary stereoisomer, gi§,gngg—diol %%a in quite good yield, although isolation of this material was initially troublesome. 53 Orthoester Claisen Reaction of Bicyclooctadienediol. The introduction of two acetic ester side chains to the "underside" of the bicyclooctadiene system was the next prob- lem to be faced. As discussed previously, the intended ap- proach was to utilize the orthoester modification of the Claisen rearrangement53 ; thus, dienediol #8 would be con- verted into a diester g3, formally via the intermediates orthoacetate lg and ketene acetal 78. For several reasons - a fairly high boiling point, commercial availability, and the fact that it had been used previously53 - triethyl orthoacetate was chosen as the orthoester component in the reaction mixture. The ethyl ester 71 was thus the desired product of this reaction. As described in the previous section on the reduction of dienedione 82 to $8, the isolation of the pure Cis,endo- diol %g was a problem of some severity. Accordingly, pre- liminary studies on the orthoester Claisen step were carried out using the distilled mixture of diol isomers g8, 88 and fig (approximately 77%, 21% and 2%, respectively). In these early studies several problems became apparent. Technically, the most troublesome were the complexity of the mixture of products, and the lack of a really good method for analyzing this mixture. Gas chromatography of the product mixtures from the early trials (starting with the mixture of diols) showed over twenty "significant" components; these were eluted too closely to permit collect- ing the individual components. Similarly, thin layer 5H -2 ROH \ 17 OR O‘.(;.OR CH3 BBC 1% CH3CCOR)3 ‘. H+, OH R0 R 2 O C R 2 1% O um C 5 H 2 C 2 O C 9 A R DY, odd RNu 7N COZCZHS 1% 55 chromatography showed that clean separations could not be obtained in this way either. Although the shower of prod- ucts was partly the result of the impurity of the starting material, we were faced with the problem of not knowing which components needed to be maximized. The most useful analytical technique found was nmr spectroscopy; the appearance of a quartet near 6 ”.0 was evidence that an ethyl ester was formed. This method ob- viously had the defect that the desired product 71 could not be distinguished from other compounds containing an ethyl ester unit. Nevertheless, this technique was better than nothing, and was used until pure 11 finally was iso— lated;at that time the go analysis became practical. It quickly became apparent from the early studies that the very mild conditions used by Johnson, 33 £1.53 in acyclic cases - several hours at 138° with continuous removal of ethanol - were woefully inadequate for the transformation gg + 11. This situation was not unexpected in view of the considerable steric congestion "underneath" the bicyclic framework. However, as more and more vigorous conditions were tried, all without success, we concluded that some factor or factors were operating to our disadvantage. In particular, the nmr spectra of the distillates from these early experiments suggested that the main compounds formed were the mixed orthoacetate lg (R = C2H5). That Zé could survive such treatment as several weeks in refluxing acidified xylene was taken to mean either (1) the intermediate 56 ketene acetal 218 was not being formed, or (2) ZR was fail— ing to undergo the Claisen-type rearrangement to a. As ketene acetals were formed under the mild conditions of Johnson, SE £353, and there appeared to be no reason for elimination of ethanol from 7,5] to be unfavorable by compari— son, we concluded that the problems involved the rearrange— ment itself. Thus, a ketene acetal probably fl being formed, but the temperature was too low to force rearrangement; under- these circumstances, polymerization of the ketene acetal would probably become dominant. Although these con- clusions are in fact incorrect, they led to the development of conditions which did produce the desired product, diester 71. Having convinced ourselves that a higher temperature was needed, the reaction was attempted using g-dichloro- ben2ene (bp 178°) as solvent. Pivalic acid (trimethyl acetic acid) was chosen as the acid catalyst for several r‘eaSons: (1) its high boiling point — 163° — should reduce the amount lost by distillation. (2) The bulk of the :— butyl group should minimize the incorporation of the pivaloyl unit into the bicyclooctadienyl system (esterification of the diol by the catalyst appeared to be a problem when pr‘OIDj-Ol'lic acid was used). Finally, (3), any such pivalate— der‘iVed products should be easily identified, the nine-proton singlet of the t—butyl group being readily recognizable. Using a fourfold excess of triethyl orthoacetate in bOiling g-dichlorobenzene, occasional additions of pivalic ‘_ 57 acid, and removal of material boiling below 100°, a four day reaction period afforded the usual plethora of products. Of these, the two of longest retention times predominated, each comprising about 35% of the mixture. The nmr spectrum of this mixture showed a vinylzester methylene ratio of about 5:3. Assuming the only ethyl esters present to be 2.2, and epimers, this represents about 60% rearrangement in the product mixture. Further data on this mixture showed that diester 7'1 (and epimers) definitely was formed. The mass spectrum of the mixture showed a very intense peak at m/e 278, as expect— ed for a (or isomers). The two major components mentioned above (the "longest retention time" products) showed gas chromatographic behavior similar to the structurally related compounds 18 and 2.3. (see below). Finally, the following Chemical transformations definitely prove that, at the least, the desired skeleton 80 had been formed. c0202H5 0020 H CO2C2H5 o 00 ”o CHC02C2H5 C02C2H5 C02C2H5 Z8 1% £8 The mixture of stereoisomeric a,8-unsaturated diesters 1% Was prepared in fair yield (60-70%) by Wittig reaction Of biCYClooctanedione 53 and carboethoxymethylenetriphenyl- phOSPhOranesg; the addition of benzoic acid as catalyst?0 was fOund to increase the reaction rate significantIY- 58 18 was separated from the two isomers of ketoester 81 and an assortment of other products by column chromatography. 0 CHCO C H 2 2 5 benzene- - dioxan . + Ph3R-CHCO2C2H5 S 7% + PhCOzH cat. O 5% 33% The isomer of 18 which was eluted first (and which had the shortest retention time on a QF-l gc column) proved to be crystalline; further characterization of 18 was carried out on this isomer. Several recrystallizations (two from pentane, three from ethanol-water) gave fine white needles, mp 5Q.6-55.0°, raised to 55.0-55.2° by sublimation. The combustion analysis and spectral data were in complete ac- cord with structure 18. Certain features of the nmr spectrum suggest that this compound is the isomer 18a. In particular, C2H502 I C / C02C2H5 1% the two-proton multiplet at 6 M.0-3.5 is presumably due to the bridgehead protons. The mixture of the three isomers (in the ratio 35:50:15) showed this peak in diminished amounts (22' l.” proton), while the series of multiplets at higher field (62.7-2.0) increased in intensity (from 8H to 8.6H) and spread to lower field (63.3-2.1). Deshielding 59 of the bridgehead protons in ZR?) by the proximate ester groups is the most likely origin of this shift; this argument, which has been used before71 , leads to the assigned stereochemistry. (Zatalytic reduction of either 18a or the mixture of isomers of 78 gave all three isomers of the saturated diester 18,.No attempt was made to separate these isomers, but the $——C02C2H5 HZ/Pd H /Pd 1% ' ‘L— Orthoester Claisen ( mixture (,1 \ CO2C2H5 R gross structure was evident from the spectra, as well as from the unambiguous synthesis. Reduction 9_f_ the product m frfl ES orthoester Claisen fl fle fl saturated m (as well as an assortment of minor products of ShOrter retention time). Thus, the Claisen-type reaction was working, producing from the mixture of epimeric diols SeVeral compounds of the desired gross structure 810’. With the knowledge that the reaction was working, and PeaSOnable certainty that the two major "longest retention time" products were u and its m isomer, the best condi- tiOTIS for this reaction were worked out, still starting with the mixture of diols. It was found that several days re— actiOn in neat boiling triethyl orthoacetate, followed by Several days more in dichlorobenzene, gave improved yields 0f CliGESter u. Fortunately, the development of suitable conditions for this reaction coincided with the discovery 60 of a method for obtaining the pure Cis,endo-diol 1%, and the orthoester Claisen could be tried on this material. After some minor adjustments, a productive method was developed which gave 11 in good purity and fair yield (35-H0% isolated). The procedure used is described in the Experimen- tal section, together with full characterization of the gig, saga-diester 11. This material, an oil, had the anticipated spectral properties, although, as was the case with the diol 18, positive assignment of the Cis,endo-stereochemistry could not be made on the basis of the nmr spectrum. That it should be the Cis,endo-isomer followed from the mechanism; evidence that this assignment was correct came from the catalytic hydrogenation mentioned before. Pure 11 gave a single isomer of 12, with only a small amount of epimers of 1% being formed. This product had the longest retention time on QF-l of the three isomers of 11; significantly, this isomer was the major isomer formed in the catalytic hydrogenation of 18. As the latter reduction should involve hydrogen transfer to the less hindered exo-face of 18, the Cis,endo-product should predominate. It was mentioned previously that the use of dichloro- benzene as solvent resulted from the belief that the Claisen rearrangement step itself was not proceeding at 1u0-1u5°. This conclusion is in fact wrong; the problem with the early trials was that the necessary ketene acetal intermediates (g5 15) were not being formed efficiently. By using neat triethylorthoacetate as solvent, but forcing the removal 61 of evolved ethanol by slow, continuous distillation of the solvent, substantially improved yields of 11 (and much less polymer) were obtained. Using this procedure, the isolated yield (after chromatography) of 11 was increased to 50-55%; the go yields were around 60%. Taking into account the byproducts (vide infra), 85-90% of the starting diol could be accounted for. The higher yields were somewhat offset by the necessity of monitoring the distillation rate quite closely, which made the process rather tedious. As was the case with reactions run in g—dichlorobenzene, it was neces- sary to add the pivalic acid catalyst in portions throughout the reaction period, as various side reactions consumed the catalyst. That elimination of ethanol from 11 to give ketene ace- tal 15 should be so difficult - or, alternatively, that capture of ethanol by 16 should be so easy - is quite un- usual. In cases where intermediates have been isolated72, they have been ketene acetals (analagous to 15) and not the mixed orthoacetates (analagous to 15). In our case, one CH3 0 2 5 X vow y Y C H O 2H5 CH3 OCZH5 OC2H5 1% 18 62 would expect that 11 would be destabilized (relative to 16) by virtue of the additional steric interactions present in the former; in 11, the lesser bulk of the pendant groups should relieve the crowding underneath the bicyclic skeleton. Reluctance of 11 to undergo rearrangement would be easily understandable, as the preferred chair-type transition state is impossible, and the boat-like geometry is still severely hindered. However, a relatively strain-free conformation is available, with the attached groups extended away from the bicyclic nucleus. The reasons for our original isola- tion of 15 and not 16, in spite of the availability of this strain-free conformation, are not clear. Some gyproducts of the Orthoester Claisen. As has been stated repeatedly, a variety of products was formed in addition to the desired diester 11. Although the complexity of the mixture decreased when only the pure Cis,endo-diol 11 was used, quite a few products were still formed. In this section the structures of several of these are presented. The most abundant product after diester 11 was the lac- tone 11. This material is a solid, permitting nearly quanti- tative separation from the other products by simply adding hexane. The substance was obtained in yields of 22' 20% as fine needles, mp 8H.8-85.2°. The structure was deduced from the (spectral) data, which are given in the Experimen- tal section. The stereochemistry was not apparent from the 63 nmr spectrum; however, inspection of models convinced us that the only possible stereochemistry for the ring fusions is that indicated in structure 11. The only other product formed to any significant degree had a structure basically similar to 11 - this is the pivalate ester 11. This material, formed in about 12% yield, was isolated in the course of the chromatographic purification of diester 11; 11 was eluted before the diester. This material was obtained as a pale yellow oil with an odor "73. The structure was estab- "reminiscent of musty places lished by the spectra, particularly the nmr; the nine-proton singlet at 6 1.20 demonstrated the presence of the pivaloyl unit. Again, the stereochemistry was not obvious from the spectra; however, the nmr spectrum of 11 closely resembled that of 11, supporting their stereochemical similarity. Another product of similar structure was 81, the acetate analogue of 11. This material was isolated in trace amounts (%l%) during the chromatography of 11; 11 was eluted after .3 (0.) CO CH Co 0 (CH3)3CC02 C02C2H5 3 2 O C H 2 2 5 O 3% 8% 8% the diester. As was the case with 11, the gross structure followed from the spectra, and the stereochemistry is anal- agous to that of the other products. 64 Two other products of somewhat different structure have also been isolated (again in trace quantities) from the re- action mixture. In the chromatography of the reaction mix- ture a purple band was eluted very early; this material possessed a strong, rather pleasant, sweet odor. As gc analysis showed it to contain three components in roughly equal amounts, preparative gc was used to isolate them. The component of shortest retention time was too close to the solvent peak to permit effective isolation, but the second and third main components were cleanly separated from each other and from the numerous very minor impuri- ties. The component of intermediate retention time was ob- viously the source of the strong odor. However, the small amount of material obtained prevented accurate integration of the nmr spectrum. An ethyl ester and considerable un- saturation were present, and mechanistic considerations led us to consider structure 11 (or a double bond isomer) for this compound. However, the mass spectrum showed a parent 0“ 8’2 0 C H 2 5 peak at m/e 192, which demands that this product be a di- hydroderivative of 81 - that is, 86 or an isomer. 65 It is hard to account for the formation of structure such as 11. Compounds such as 11 might well be expected, arising from Claisen rearrangement in one ring and dehydra- tion in the other. No such obvious pathway to 11 is avail- able. It may arise gig reduction of 11, or more likely by cleavage of an intermediate such as 11, followed by hydrogen atom abstraction from solvent. -R0- 801- H m Ro co 2c 25H co2 c 25H £1 The component of the purple band with the longest retention time was easily identified as 1,3,5—triethoxy- benzene 11 from the nmr and ir spectra. This was confirmed by the melting point (needles from methanol-water, mp Hl.0- ul.3°)which agreed with that reported long ago7u. The origin of this aromatic compound is left as an exercise for the reader. The structural similarity of compounds 11, 11, and 11 suggests a common mode of formation, and speculation along 66 these lines is amusing. It is possible that all arise from Claisen rearrangement in one ring, followed by some sort of capture of the remaining hydroxyl: -C2H50H \ (CH ) cco H 3 3 2 ~——> co > o c H HO Q2 C02C2H5 (CH3 ) 3cco2 2 2 5 \fi CH3CO2H 0‘ (from CH 3C(OC 2H:)3) CH3co2 02c2H5 However, an alternate mechanism is possible, as shown below: ”9 __> @H‘t ___> m“ ~Er:~ -C 25H OHL 2% \ H C 3 oczH5 67 This mechanism involves formation of the bridged orthoace— tate 11. Loss of ethanol would give the bridged ketene acetal 11, which could yield lactone 11 directly upon Claisen re- arrangement. Inspection of models suggests that neither 11 nor 11 is excessively strained; furthermore, Claisen re- arrangement of 91 appears reasonable, a slightly distorted chair-like transition state being available. Our failure to prepare any cyclic derivatives of diol 11 may be taken as evidence against this second mechanism, but this argu- ment must face the caveat applying to any statement based upon negative evidence. In any event, this second mechanism is an interesting possibility. No attempts have been made to increase the yields of any of these byproducts, as they represent an unwanted diversion of the rather precious diol 11 from our goal. However, it appears that formation of lactone 11 is favored by the use of relatively small amounts of excess triethyl orthoacetate, and by the use of the dichlorobenzene cosol- vent from the start of the reaction. The amount of pivalate 11 could probably be increased by using larger amounts of pivalic acid. In the event that either 11 or 11 were desired, it could probably be made the major product by finding the right conditions. This concludes the discussion of the key reaction in the synthesis of tetraene 11, the attachment of the two 2- carbon chains. Although the discussion has been rather lengthy, the crucial importance of this step and the 68 interesting results finally obtained justify this much detail. Completion of the Synthesis With the diester 11 finally in hand, it remained to join the ends of the two-carbon chains and introduce the necessary unsaturation into the resulting four carbon bridge. As outlined earlier, we chose to use the acyloin condensa- tion1m , or the chlorotrimethylsilane modification of the acyloin, to achieve the cyclization. The expected products, ketol 11 and bis(trimethylsiloxy)olefin 11, appeared well suited for further transformations to 11. “\ 1) Na 2) H+ CO2C2H5 OH ”’/ 84: 841‘ O2C2H5 Z1 \ Na, ClSi(CH3)3' -081(CH3)3 081(CH3)3 $92 A single attempt was made to achieve the cyclization to 11 using the "traditional" acyloin procedure - that is, running the reaction at high dilution without the addition of the chlorosilane. This procedure gave, in a low recovery, 69 a mixture of four "major" products and a host of minor components. Due to the complexity of this mixture, and the low yield, this procedure was not investigated further, and we turned our attention to the chlorosilane modification. For a model, the cyclization of the saturated diester 11 was attempted. Starting with a mixture of stereoisomers of 11, containing about 50% of the Cis,endo-isomer (vide supra), the reaction gave a fair yield (22' 60% on the basis CO2C2HS Na,C1Si(CH§}. / . PhCH3, // 381(CH3)3 OSi(CH ) C02C2H5 3 3 1% 2% of 50% purity of 11) of the trimethylsiloxy product 11. Although a mixture of products was formed, the spectral data of this mixture supported the assigned structure 11. With the knowledge that the cyclization was successful for the saturated case, we tried the unsaturated diester 11 and soon worked out a useful procedure for converting 11 ”‘0 A92- Treatment of 11 with finely divided sodium and chloro- trimethylsilane in hot (SO-110°) toluene gave a complex mixture of volatile products; the desired bi§(trimethyl— siloxy)olefin 11 was the major (65-85%) component. The yield of 11 was only fair (HO-55%), and varied without 70 any obvious relationship to the experimental parameters. The only consistent pattern observed was that larger scale reactions gave slightly higher yields. That the main component was indeed 11 was apparent from the spectral properties of the mixture (summarized in the Experimental section). An attempt was made to purify '11 by preparative go, but it decomposed badly under the go conditions, giving two new products. As the crude (distilled) 11 was quite sensitive, no attempts at purification using other techniques were tried. Fortunately, as described later, the impure distillate was suitable for the subse- quent steps. While monitoring the reaction by go, it was noted that the composition of an aliquot changed quite drastically upon exposure to moist air; 11 was rapidly converted to a new product of longer retention time. The distilled product did not show this reaction, suggesting that it was catalyzed by some very volatile component in the crude mixture. This conversion was carried out on a larger scale by overnight exposure of the reaction mixture to the air, followed by distillation and preparative go. The new compound was assigned the structure 11 on the basis of the spectral data. Thus, the molecular weight, the carbonyl stretch in the ir, and the nine proton Si-CH3 signal left little doubt as to the gross structure. The stereochemistry is not known, as molecular models show that either epimer of 11 can adopt a conformation which should give the observed 71 OSi(CH ) O 3 3 532% couplings of the methine hydrogen alpha to the ketone. Siloxyketone fig is a hydrolysis product of the siloxyolefin gg, the reaction being catalyzed by hydrogen chloride form- ed by hydrolysis of the chlorosilane in the reaction mixture. Originally, we planned to hydrolyze gé completely to ketol g& and proceed to the final product tetraene gg using H20 ‘ii \I A " / Si(CH3)3 OH - o 081(CH3)3 kté rlikt fairly standard reactions. However, although one trimethyl- silyl group was lost very easily (giving siloxyketone fig), the removal of both proved to be extremely difficult. The standard procedures for such transformationsu5’75 gave either no reaction, or led to the formation of complex mixtures and polymer. The only reaction which gave a single product in reasonable yield was treatment of gé with a trace of concentrated hydrochloric acid. Via the intermediacy of fig, this gave a tetracyclic ketol, which we believe to be 72 either 3% or fig. Structure QR is supported by the 5.73u absorption in the ir, which suggests a cyclopentanone; however, such an assignment of ring size may not be valid in such a highly condensed polycyclic system. In any event, this material was definitely tetracyclic, showing that the double bonds in the bicyclic nucleus had gotten into the act in an un- fortunate way. The sensitivity of acyloins, particularly towards base, is well knownuu ; oxidation and polymerization are very facile under these conditions. Initially, this fact led us to avoid basic conditions for the "hydrolysis". In fact, treatment of kg with methanolic base did give a complex mixture. However, LeGoff and Kovar had discovered that methanolic borohydride (which is surely quite basic) could be used to reduce bi§(trimethylsilyl)enediol ethers to the corres- ponding diols, albeit in rather low yield76. For example, the conversion fig + g1 was accomplished in this manner in 23° 30% yield. Preliminary trials of this method on our 73 - H 81(CH3)3 F9 ———» 081(CH3)3 OH fié %% material appeared promising, and a satisfactory procedure was worked out. Slow addition of a benzene solution of gfi to a huge excess (20-60 fold) of sodium borohydride in 80% aqueous ethanol containing a little alkali afforded, after acidi- fication, extraction and distillation, fairly good yields of a gummy product rich (22° 90%) in the desired diol g0. Yields assuming 100% purity of the starting bis(trimethyl- i I, OH OH 2% silyl)ether were in the range 55-70%. As g2 was known to be impure, the actual yields are considerably higher (70- 85%). Further purification of diol gg was achieved by chroma- tography on silica gel with ethyl acetate as the eluent. The material so obtained was a colorless, very thick goo which tenaciously retained solvent. After the last traces of solvent were removed in a stream of dry nitrogen or in high vacuum, the material slowly solidified to a hard white 7H wax, which decomposed without melting. All attempts at re- crystallization were unsuccessful; sublimation could be achieved, but led to some decomposition. As the material isolated in this fashion was 22° 98% pure (gc), it was used without further purification. The yield of pure diol was in the neighborhood of 60%. That this compound had the gross structure 3% was clear from the spectra (molecular weight 192; hydroxyl but no carbonyl in the ir; four vinyl protons and a two proton singlet exchangeable with D20 in the nmr); the stereochemistry will be discussed shortly. Further proof of the structure was obtained by chemical means. Thus, Malaprade-type oxida- tion of fig with periodic acid in dry ether77 gave a high yield of the dialdehyde 33; for comparison, this dialdehyde was prepared unambiguously from diester Z1 as shown (60% yield, not optimized). The formation of 32 was observed by CHO 4L?) LlAlHu, 11 2) CrO3 (pyr)2 gc, ir, and by an even more sensitive technique, smell. Amounts of fig barely detectable by gc could be easily de- tected in a small room; as the odor is quite pleasant, this was an enjoyable analytical tool. gg was very unstable, decomposing upon standing overnight in the air. Sublima- tion gave wet-looking needles, mp 53-58°, but further puri- fication was deterred by the instability of the compound. 75 The structure was obvious from the spectral data, which are summarized in the Experimental section. To return to the structural arguments, the periodic acid cleavage left no doubt that this compound was in fact the desired 6,7-dihydroxytricycloE7.3.0.0L"12 ]dodeca-2,10- diene 30. This conversion establishes that the acyloin cyclization had occurred as intended, thereby confirming the gis,gndg-stereochemistry of diester xx. The final comments here deal with the stereochemistry of the diol. As indicated in structure 3%, this compound has the hydroxyls gig. This assignment follows from the nmr spectrum of the diol, and, more convincingly, from the spectra of several derivatives. Thus, the vinyl protons of fig appear as a three proton multiplet accompanied by a one-hydrogen doublet of doublets. Furthermore, the two methine protons on the hydroxyl-bearing carbons are not equivalent, appearing as distinct multiplets. Of the three possible diastereomeric structures g0, IQQ and lQl, only the first would be expected to show such nonequivalence. As shown, IQQ and IQI both possess a two-fold axis, at least in the "flattened out" conformation shown. Molecular models confirm these conclusions; the preferred conforma- tion of both trans isomers IQQ and IQ; would be symmetrical and show equivalent methines (a- to the hydroxyls). Also, the C2 symmetry of the trans isomers would influence the vinyl region of the nmr spectrum, and a pattern markedly simpler than that observed would be expected. 76 5 I OH i / 0“ III III e 2% HQ UR These arguments are greatly strengthened by the nmr data of several derivatives of the diol, namely the dimesyl- ate IQZ and the diacetate lgg. In both of these, the methyls are clearly nonequivalent, appearing as distinct, equally 02CCH3 i /. so 23CH o CCH 0802 2GB: 2 3 UR \ intense singlets. Again, the methine protons alph - to the oxygens give rise to two separate multiplets, and the vinyl protons give the same complex pattern - a broad two-proton singlet and two l-proton multiplets - observed for the diol . \ v 77 itself. Although this evidence is quite convincing, the argu- ment suffers slightly from being based upon data for only one isomer. Fortuitously, we have obtained one of the trans-diacetates Igg or lgé. Chromatography of the pot i l o CCH O CCH 2 3 I 02CCH3 «Wt MR residue from distillation of the diol afforded a small O2CCH3 amount of material which on cursory chromatographic analysis (tlc and vpc on a single column) behaved identically to the purified diol fig. Acetylation of this material, however, gave the "old" diacetate lgg in only 23. 20% yield. The major product (93. 75%) was a new diacetate, shown to be isomeric with $00 by its mass spectrum. However, the nmr was strikingly different; the vinyl hydrogens appeared as an extreme AB-quartet type pattern, the methines alpha- to the acetoxyls gave a single multiplet, and the acetate methyls gave a sharp singlet. These data clearly support a symmetrical structure, that is, one of the two trans- isomers %Q% and lgg; which isomer we obtained is not known. The nmr spectra of the gis- and trans- diacetates are shown in Figures A7 and A8 to permit visual comparison; these results demonstrate the gig-stereochemistry of lgg, and hence of the diol g0. 78 With the structure of the diol firmly established, we were faced with double dehydration (or its equivalent) of the compound. Several problems of unknown severity were envisioned for this step, the most serious being the pos— sibility of elimination the "wrong" way to give an enol (I01, X = OH) or an enol derivative (gg., an enol tosylate, IQZ, X = OTs). This possibility appeared quite likely in view of the cis-stereochemistry of diol 3% and hence of a .\ 44>» ./ // #853 Ml x derivative IQQ - the preferred conformations of I00 both are set up for a trans-elimination in this "wrong" way. Molecu- lar models show that the desired eliminations (E2) to gg cannot both proceed via the preferred trans elimination pathway; one of the double bonds must be formed with a proton and the substituent (X) leaving in a gig—manner. This suggested that rather vigorous conditions might be needed for this reaction. The use of strongly basic conditions for this elimina- tion appeared to offer the solution to both of these prob- lems. With a sufficiently strong base, the fact that elim- ination must be gig would not be a serious problem. At the same time, if the "wrong" elimination were to take place first, two reasonable pathways appeared open which 79 would still lead to the desired tetraene gg. Thus, IQZ could be equilibrated to the allylic isomer IQQ, from which elimination to gg is possible. Alternatively, lgz might undergo elimination to the allene lgg, which should iso- merize to the desired isomer gg. Molecular models show that allene lgg is not impossibly strained, but that it is less stable than the "1,3-diene" KK- i / I /' X \ .\ Mg ‘6 / / m m x \ /' zz / ,,C m The first attempt at dehydration of diol 2Q utilized \ distillation from alumina, a brute force method which has, in fact, been successful in some rather unpromising situa- tions. Atmospheric pressure distillation of 20 from alumina treated according to von Rudloff78 (Woelm, neutral, Activity I, plus 2% pyridine) gave a complex mixture; only a trace component of this mixture showed gas chromatographic behavior 80 consistent with a C12 hydrocarbon. The major component of the mixture was clearly a car- bonyl compound, as shown by its behavior on the carbonyl- specific gc liquid phase QF-l; on this fluorosilicone the major product had by far the longest retention time of any of the products, while on SE-30 it appeared in the midst of the other peaks. The ir spectrum of the mixture showed strong carbonyl absorption (5.90u); the nmr spectrum of the mixture was practically incomprehensible, but showed no ob- vious aldehyde or ester peaks. These results led us to suspect that this major product was ketone ITO, formed by dehydration the "wrong" way to an enol (IQZ, X = OH) and i / O 3&9 tautomerization. Further support of this structure came when it was isolated in another reaction, and spectral data obtained on a fairly pure sample; these results will be dis- cussed shortly. When the reaction was repeated using strongly basic alumina, no compounds behaving like a C12 hydrocarbon were formed; under these conditions the amount of the ketonic PPOduct llg increased slightly. As it was apparent that direct dehydration was taking an undesired course we examined the possibility of achieving 81 base catalyzed elimination of a sulfonate ester. Attempts to prepare the ditosylate were unsuccessful, as only one of the hydroxyl groups of 3% reacted with p—toluenesulfonyl chloride. As the gig-configuration of the diol results in one very hindered hydroxyl, this result is not surprising. In contrast, reaction with the smaller reagent methanesul- fonyl chloride took place at both hydroxyls, affording the dimesylate Igg in 62% yield after recrystallization. This material, mp 99.5-lOl° (dec), exhibited the expected spec- tral properties. As was mentioned previously, the methyl groups were nonequivalent, in accord with the gig-stereochem- istry. This dimesylate was somewhat unstable, gradually SO2CH3 0802CH3 Mé yellowing even at -35°, we suspect that considerable decom- POsition accompanied this discoloration, as the next step gave cleaner products when freshly prepared kgz was used c 6H 53CH // OSi(CH3 )3 C 2H50H‘ 3H20 . OSi(CH3)3 52.1 R5. (SO-60%) (HO-55% crude) KOC(CH3)3 CH3302Cl (CH3)230 . . + » OH Pyridine / OSOZCH3 OH 0802CH3 2% %Q% (SO-60%) (60%) 22 ’Vb (5-9%) Figure 9 Synthesis of Tricyclo[7.3.0.0q’121dodeca— 2,5,7,ll-tetraene 9M deuterated selectively at the bridgehead position862, this is an attractive option, although the rearrangement may well be too fast to permit isolation of %% before extensive scrambling has occurred. Finally, as the Cope rearrange- ments of ii interconvert the enantiomeric forms of this chiral structure, resolution of ag and observation of its racemization deserve attention. Resolution of one of the precursors of gz is surely possible, although, as with the deuterium labelling, this may not yield the desired informa- tion. The possibility of resolving the tetraene itself, gig formation of an optically active complex or chromatography on an optically active adsorbent, was mentioned in the Intro- duction, and certainly merits experimental effort. The conception of tetraene gaze, and this synthesis, were motivated by curiosity about the structural require- ments for rapid Cope rearrangement. From the nmr results which we have obtained, it is clear that gg does not meet those requirements, at least in contrast to fluxional mole- cules such as bullvalene. As discussed in the Introduction, the main feature lacking in gg is a small ring, with its accompanying strain. In light of the arguments about the importance of strain effects on Cope rearrangement given earlier, the failure of £2 to show fluxional behavior is not surprising. More exact statements about the effects operating in gz must await activation data, which in turn depend on finding a means of observing the rearrangement. Thus, regrettably, this project is not finished; the 95 characterization of the final product is just begun. In addition to measuring the rate of rearrangement, the chemis- try of the tetraene, and indeed of the tricyclic ring system itself, deserves further study. The relationship of this compound to other (CH)12 isomers is but one area that may prove fruitful. Lest the impression be given that this project was un- successful, it should be emphasized that our concern was synthetic. In addition to the success of our synthetic plan, several other results, of greater practical value, have come out of this research. Among these may be men— tioned (l) the success of diisobutyl aluminum hydride in achieving a previously "impossible" reduction; (2) the demonstration that the orthoester Claisen procedure is applicable to cyclic systems, even when steric effects are very unfavorable; (3) the synthesis of a number of functionalized bicyclo[3.3.0]octane derivatives in synthet- ically useful quantities; and (H), a reasonably efficient u,12 entry into the new tricyclo[7.3.0.0 ]dodecane ring system. EXPERIMENTAL General. All melting points were measured in open capillaries with a Thomas-Hoover apparatus and are uncor- rected; boiling points are also uncorrected. Combustion analyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan. Unless noted otherwise, reagents and solvents were reagent grade materials used as received. Solvents for chromatography were treated as follows: pentane and hexane were washed with concentrated sulfuric acid and distilled; ethyl acetate was distilled and passed through a column of neutral alumina (Activity I); chloroform was distilled and passed through basic alumina immediately before use. Proton nuclear magnetic resonance (nmr) spectra were run on Varian A—60, A-56/60, and T-60 instruments (60 MHz); variable temperature nmr spectra were recorded on a Varian HA-lOO spectrometer (100 MHz) by Mr. Eric Roach. Chemical shifts are reported in ppm downfield of internal tetramethyl- silane (60.0). For a few trimethylsilylated compounds, benzene (67.27) was used as the internal reference. Chem- ical shifts and coupling constants are believed accurate to 0.01 ppm and 0.5 Hz, respectively. Infrared spectra were measured on a Perkin-Elmer model 137 Spectrophotometer; absorption maxima are reported as wavelength (in microns), referenced to the 6.2Hu peak of 96 97 polystyrene, and are believed accurate to within 0.01p. Liquid samples were examined as neat films, and solids as Nujol mulls. Mass spectra (ms) were run on an Hitachi RMU—6 instru- ment with an ionizing voltage of 70 eV. A Perkin-Elmer model 881 gas chromatograph interfaced with the RMU-6 was used for coupled gas chromatography-mass spectrometry (gc- ms); the column used for these studies was a 1m x 2mm glass column packed with 3% SE-30 on 100-120 mesh Chromosorb W. All other gas chromatographic separations were achieved using an F 8 M model 700 chromatograph equipped with a thermal conductivity detector. Helium was used as the'car- rier gas at flow rates of 70-80 ml/min; an injector tempera— ture of 200° and a detector temperature of 270° were used in all cases. The compositions reported were calculated from the peak areas (determined by triangulation) without corrections for differing detector responses. The columns employed were 6' X 1/u" aluminum columns packed with the following materials: column A: u% QF-l on 60-80 mesh Chromosorb G, acid and base washed and silanized column B: 5% Carbowax 20M on 60-80 mesh Chromosorb G, acid and base washed and silanized column C: H% OV-l7 on 60-80 mesh Chromosorb G, acid and base washed and silanized column D: 1% SE-30 on 60—80 mesh Chromosorb G (un- treated). 98 Dimethyl glutarate 5%. This material was prepared at various times by Glen R. Elliott, E. Irene Pupko and Myrna Sult Hagedorn using Elliott's modification79 son's proceduress. Glutaric anhydride (Aldrich technical of Simp- grade, labelled 70% pure; 2.5 kg) was added slowly to 2 liters of methanol (exothermicl), pftoluenesulfonic acid (l-Zg) added, and the mixture refluxed for 20-30 hrs. The reaction mixture was cooled, l l of water added, and the mixture made slightly basic by the addition of 10% sodium hydroxide solution. This mixture was extracted with ether (u x l 1), and the combined ether layers washed with satu- rated aqueous sodium chloride solution, dried over Drierite, and freed of solvent on the rotary evaporator. Distillation of the residue afforded impure dimethyl glutarate, bp 90- 110°/l7 mm. This material was redistilled through a lm Vigreux column and the fraction boiling at 99-101°/l7mm collected. This product, a water-white oily liquid, was 22° 99.5% pure by gc (column A, 150°); yields were in the range M5-55%. The ir showed ester carbonyl absorption at 5.72u; nmr (6,CClu): 3.64 (6H, s), 2.33 (UH, distorted t, J = 6 Hz), 2.15—1.63 (2H, distorted quintet with further splittings, J = 6 Hz). The aqueous solution from the above extraction was acidified with hydrochloric acid. Extraction of this mix- ture with ether afforded, after removal of the solvent, 22° 500 ml of very crude monomethyl glutarate. This mater- ial was added with the glutaric anhydride at the start of l 99 the next preparation. Tetramethyl hexane-1,3,£,§etetracarboxylate 55. Free radical induced couplingg£_dimethyl glutarate. This pro- cedure, a slight modification of those of Osborne29 and Simpsonss, was run with the aid of Glen R. Elliott, Charles A. Geraci, and E. Irene Pupko. The reaction vessel was a 5 2 three-necked flask equipped as shown in Figure 10. The flask was charged with 2500 ml of dimethyl glutarate (DMG), which was heated to boiling, with stirring, while nitrogen was passed through the apparatus. After 15 min boiling the DMG was cooled to 175°, and the nitrogen flow adjusted to #5-50 ml/min. A mixture of di-t-butyl peroxide (Columbia, #00 m1, 22° 2.17 mole) and DMG (160 ml) was then added to the vigorously stirred DMG, maintaining the tempera- ture at l70-175°; the addition rate was 1 ml/min. After addition was completed, heating was continued until gas evolution ceased (this was determined by temporarily stop- ping the nitrogen flow and inspecting the gas bubbler at the outlet of the system); this typically required an addi- tional hour. When no more gas was evolved, the contents of the flask were rapidly heated to vigorous boiling until DMG (bp 21u°) just began to distill over. The flask and contents were allowed to cool overnight, and the reaction mixture transferred to a 5 2 round bottom flask. Unreacted DMG was then removed by vacuum distilla- tion through a 50 cm Vigreux column; everything boiling up to 1u0°/17 mm was collected in one fraction; the last drop 100 50° thermometer cold finger condenser constant :dg;:ion sealed u mechanical stirrer —> N2 out (via bubbler to hood) fir ‘V ‘K\E>> N2 in-——€> L~/ 2 x 70 cm Vigreux (cheesecloth wrapped) ’////"250° thermometer heating mantle Figure 10 Apparatus for Preparation of Tetraester £5 101 of this material contained 22' 40% DMG, ”0% numerous uniden- tified compounds, and 20% of the desired product. Nearly all of this fraction distilled at 95-110°/l7 mm. The volume of recovered DMG was 2180 m1, so #80 ml (23. 520 g, 3.23 mole) of DMG had been consumed. The residue in the pot was cooled to around 80°, and transferred while hot to a 1 2 round bottom flask. Distil- lation was then continued through the 50 cm Vigreux; three fractions were collected: fraction 1, 20 g, bp 80—135°/ 0.02 mm; fraction 2, 290 g, bp 135°/0.02 mm-155°/0.03 mm (most of this material boiled at 1H0-1M3°/0.02 mm), and fraction 3, 20 g, bp 155-180°/0.03 mm. The dark pot residue was discarded. All of these fractions eventually solidified to give mushy white crystals. Fraction 2 contained about 85% of the desired product (two barely separated peaks) and about 15% of an additional compound (go on column A, 210°). Fur- ther purification was achieved by recrystallization from methanol. Fraction 2 was dissolved in an equal volume of methanol (warming necessary) and cooled to 10°, affording 165 g of white crystals (a mixture of needles and tablets). Two more crops, 5H g and 6.5 g, were obtained by cooling the mother liquor to -10° and then to -60°. Fractions 1 and 3 were combined and crystallized in the same manner to give 11 s more 55 (two crops, 10° and -60°). Thus, the total recrystallized product came to 236.5 g (0.745 mole). This corresponds to a yield of approximately #6% based on 102 the DMG consumed, or 3H% based on the di—E-butyl peroxide. Subsequent runs were made in the same manner, using the recovered DMG; after four or five batches, the DMG was refractionated, as described previously, to remove the impurities which had accumulated. The apparatus and still were not cleaned between runs, so as to minimize losses due to hold-up. A number of preparations afforded recrystallized 55 in yields of 42-55% based on reacted DMG. The mother liquors from the recrystallization of several preparations were combined and the methanol removed in 23229. Distillation of the residue afforded fractions similar to those obtained in the distillation of the reaction mixture; that distilling at 135-1H5°/0.02 mm was recrystallized, as described above, yielding an additional amount of pure tetraester 55. The recrystallized tetraester exhibited mp H8-59°; the broad melting range is undoubtedly due to the presence of a mixture of the meso and d,l diastereomerszg. This was con- firmed by gc (column A, 210°), which showed two barely separated components in roughly equal amounts. The other data on this mixture are in complete agreement with struc- ture 55: ir (neat melted £5), 5.75u; nmr (6, CClu); 3.70 (6H,s), 3.65 (6H, s), 2.68 (2H, broad t, J = H Hz), 2.50- 2.06 (NH, m), 1.8% (RH, broad m). Bicyclo[3.3.0]octane-2,6-dione 53. Dieckmann cycliza- tion of tetraester 55, and hydrolysis-decarboxylation of the product, ketoester 56. fl.§.! The success of this 103 procedure depends crucially upon the strict exclusion of water and other sources of hydroxide ion. The use of dry glassware, dry dimethylsulfoxide (DMSO), and fresh sodium methoxide is essential; if these precautions are not taken, the yield drops substantially, even to the point of no product being formed. It should be noted that even freshly opened bottles of commercial reagent grade DMSO usually gave unsatisfactory results. DMSO was purified by stir- ring with calcium hydride for several days, then vacuum distillation from the same drying agent: bp 77-78°/15 mm. A 1 liter three-necked flask was fitted with a mechani- cal stirrer, addition funnel, thermometer, and provision for an inert atmosphere, and the apparatus dried by flaming while evacuated. Sodium methoxide (Matheson Coleman 8 Bell, freshly opened, 60 g, 1.1 mole) and dry DMSO (22° 300 ml) were then added, and a nitrogen atmosphere established by repeated cycles of evacuation and bleeding in nitrogen. Tetraester 55 (159 g, 0.50 mole), dissolved in 22° 150 ml warm DMSO, was then added to the stirred slurry of sodium methoxide. Addition took 15 min, during which the internal temperature rose to 50-60°. An additional portion of sodium methoxide (H0 g, 0.7% mole) was added after all the ester had been added. The reaction mixture, which had become deep orange during the ester addition, was then heated at 70-80° for 1.5 hr. The nearly black mixture was then cooled to 20-25° with an ice bath, and ice-cold 6M_hydrochloric acid (320 ml) added slowly, with continued stirring. Ice bath 10% cooling was used to keep the temperature below 30°. As the acid was added, the mixture lightened in color, becoming yellow-brown and finally pink; a finely divided solid pre- cipitated towards the end of the addition. The final slurry was poured into 2500 ml of ice water, and the pH checked to make certain it was acidic. When the temperature of this mixture reached 10° the solid was collected by filtra- tion through a large Buchner funnel, washed several times with cold water, and washed once with cold methanol-water (1:1) and sucked as dry as poSsible. The crude bi§(ketoester) was then dried, first at room temperature and finally in an oven at 85—90°. The oven drying led to considerable sinter- ing and some darkening of the initially yellow or pink, powdery product, but did no harm; the sintering was in fact beneficial in the next step. The crude ketoester 56 weighed 109.5 g (86.3% crude) and showed mp 91-98° (dec). Further purification was not necessary, but could be achieved by crystallization from methanol (5 ml/g) in 80% recovery. The recrystallized product melted at 93-96°; a second re- crystallization, this time from acetone-hexane, gave color- 29 90.n-92.u°). less prisms, mp 92-93° (lit The entire crude product from the above Dieckmann cyclization was added to 300-900 ml of 6M_hydrochloric acid, containing one small drop of Dow-Corning "Antifoam C" de- foamer, in a 2 2 erlenmeyer flask (the benefits of the defoamer may have been largely psychological). Several Carborundum boiling stones were added, and the mixture 105 heated on the steam bath with frequent swirling (gas evolu— tion and foamingl); the temperature was kept below 70°, as considerable darkening occurred at higher temperatures, and the foaming became inconveniently vigorous. When gas evolu- tion had ceased (typically, after about one hour of heating), the solution was cooled and filtered with suction through two thicknesses of filter paper. The filtrate was then extracted six times with 200 ml portions of chloroform. The chloroform layers were combined and washed with 5M aqueous sodium hydroxide solution (2 X 25 ml), and con- centrated to ca. 500 ml by distillation; this also effected azeotropic drying of the solution. The chloroform solution was filtered through a Drierite cone (to catch the fine particles), whereupon removal of the solvent on the rotary evaporator gave a golden yellow oil which slowly solidified to a pale yellow mass. The yield of crude dione 53 was 57.1 g (96.1% based on the crude ketoester; 82.9% from tetraester £6). yellowish granules mp 43-H6°. Again, further purifica- tion was not necessary. If desired, purer material could be obtained by sublumation (35—H0°/0.01 mm) onto a cold finger kept at 0°. Recovery was about 97%. The sublimed product was in the form of blocky crystals, mp ”5.1-u6.3° (litss, us-u6.5°) with the expected spectral properties: iP (Nujol): 5.73u; nmr (6, CClu): 2.90 (2H, broad s), 2.20 (8H, broad s). 106 2,6:DiacetoxybicycloE3.3.0]octa-2,§-diene 51. Enol 29,55 acetylation of dione 53 Purified bicyclooctanedione 23 (13.8 g, 0.1 mole) was dissolved in isopropenyl acetate (Aldrich, redistilled, 100 ml) containing 125 mg of sulfo- salicylic acid, and the mixture refluxed under nitrogen for 2H hr. The excess isopropenyl acetate was removed on the rotary evaporator and the black residue vacuum distilled through a 10 cm Vigreux. The fraction boiling at 95—1050/0.3-0.u mm was collected as a yellow oil which solidified upon scratching. Crystallization from pentane afforded 19.7 g (89%) of white needles, mp 60-62° (lit29 62.0-62.5). Two other preparations on a somewhat smaller scale gave yields of 78% (recrystallized) and 85% (distilled only). 3,1—Dibromobicyclo[3.3.0]octane-2,§fdione 58. Bro- 29,55 mination of enol acetate 51 The bis(enol acetate) 51 (19.6 g, 0.089 mole) was dissolved in carbon tetrachloride (100 ml) and the solution cooled in an ice bath. Bromine (29 g, 0.181 mole) in 30 ml carbon tetrachloride was then added dropwise over about 15 min. The bromine color faded rapidly throughout the reaction, in contrast to Simpson's observation55 that it lingers when the reaction nears completion. The precipitated solid was collected by filtration and washed twice with cold carbon tetrachloride 107 to give 12.5 g (”8%) of a yellow-brown powder, mp 120- 1250 (dec) (lit, 122-125° (dec)55; 130.5-131° for re- 29 crystallized material ). The ir spectrum showed carbonyl 55 absorption at 5.75u (lit 5.7Hu). 2,2,§,§-Bis(ethylenedioxy)-§,ledibromobicyclo[3.3.0]- octane 59. Ketalization of bromoketone 5855. The crude dibromodione 58 (12.0 g, 0.0405 mole if pure) was added to a mixture of ethylene glycol (2” ml), p-toluenesulfonic acid (175 mg) and benzene (300 ml) in a 500 ml flask equipped with a Dean-Stark water separator. The mixture was then heated to boiling with vigorous magnetic stir- ring to mix the layers. After 2 days, an additional portion (8 m1) of ethylene glycol was added. The re- action was stopped when no more water separated (3 l/H days). The brown solution was cooled, washed with 100 ml portions of 5% aqueous bicarbonate, water, and satu- rated sodium chloride solution, and dried over Drierite. The product solidified spontaneously when the benzene solvent was removed on the rotary evaporator. Yield, 19.5 g (93% if pure) of hard, yellow-white granules, mp not determined (but see p. 113, below). The ir spec- trum showed some residual carbonyl absorptions in the 5.75 region, suggesting that ketalization had not been complete. 108 2,Z,§,§—§i§(ethylenedioxy)bicyclo[3.3.01933373,7- diene 60. Dehydrobromination of bromoketal 59 with ethan— glig potassium hydroxidess. Crude bromoketal 59 (19.5 g, 0.038 mole), prepared as just described, was added to a freshly prepared solution of potassium hydroxide (25 g) in absolute ethanol (500 ml). This mixture was heated to reflux for four days. The brown mixture was then cooled, filtered with suction, and freed of solvent on the rotary evaporator to give a dark brown mass. This was broken up and refluxed for 1 hr with #00 ml benzene. The resulting red-brown solution was cooled, filtered, and washed, twice with cold water containing a little sodium bicarbonate and twice with saturated sodium chlor— ide solution. Drying (Drierite), filtering and removal of the solvent on the rotary evaporator yielded an orange oil (7.5 g). This was taken up in the minimum volume of boiling cyclohexane and the solution cooled, whereupon pale yellow needles, mp 101-103° were formed (5.12 g, 61%). An additional crop of yellow granules, mp 9u-97° (0.51. g, 6%) was obtained by concentrating the mother liquorj. The reported mp is 101-103°55. The ir spectrum (NujOJ_) showed C=C absorption at 6.13u and other strong bands .at 7.93, 8.69, 9.28, 9.80, 10.15 and 12.22u; the Carbonyfll region was free of absorptions. The nmr spec— trum was; in complete accord with structure 60: (6, CClu): 109 5.91 (2H, dt, J = 5.6 Hz, J' = 1.1 Hz), 5.42 (2H, dd, J = 5.6 Hz, J' = 0.9 Hz), 3.89 (8H, 8), 3.18 (2H, m). Ketalization g: bicyclooctanedione 5%. The crude dione (209 g, 1.5 mole) was added to a mixture of ethylene glycol (220 ml, ca. 3.95 mole, 32% excess), p—toluenesulfonic acid hydrate (3.8 g, 0.02 mole) and benzene (1500 ml). This mixture was refluxed with separation of water (Dean—Stark trap) and magnetic stirring for HR hr. The volume of water collected was 6H ml (118% of the theoretical, assuming that all the reactants were dry and that the water was free of ethylene glycol); nearly all of the water distilled over during the first 12 hrs. The brownish solution was cooled and washed as follows: 1 X 100 ml saturated aqueous sodium bicarbonate, 2 X 200 ml water, and 2 X 200 ml saturated aqueous sodium chloride solution. The combined aqueous washings were extracted four times with 200 ml portions of ether, and the combined ether layers washed once with saturated sodium chloride solution. This ether extract was combined with the original benzene layer, and the solution filtered through a Drierite cone. Removal of the solvent on the rotary evaporator gave a brownish, oily liquid, which was distilled in vacuum; the volatile material was collected in a single fraction, bp 93—95°/0.15 mm, which was homo— geneous by gc (column A, 170°; column B, 190°). The yield was 327 g (96.5%) of a colorless, oily liquid. An analytical 110 sample was obtained by repeated fractional freezing of this liquid in an ice—acetone bath. The spectra of this puri- fied material (mp ca. -l°), which were superimposable on those obtained from the distillate, were as follows: ir (neat): 3.u1, 3.u9, 6.82, 7.u7, 8.2a, 8.6-9.15, 9.5u, and 10.53u, and other, weaker bands; nmr (6, CClu): 3.87 (8H, s), 2.37 (2H, broad m), 1.62 (8H, broad m). Anal. Calc for C12H180u: C, 63.70; H, 8.02. Found: C, 63.67; H, 8.02. Other preparations, on 0.2 - 0.6 mole scales, gave yields of 96.1-96.u%. In view of the ca. 97% purity of the crude dione 53, the yield must be close to quantitative. Other boiling points observed were 100°/0.2 mm, 88°/0.05 mm, and 8H°/0.015 mm. Z,2,§,6-Bis(ethylenedioxy)-§,Z-dibromobicyclo[3.3.0]- octane 59. Bromination of ketal 61. Pyridinium tribromide 80 was prepared according to Fieser and Fieser , starting with approximately 1 lb of bromine and scaling the other reac- tants accordingly. During the recrystallization of the product from acetic acid, the mixture was stirred frequently 81 have found to keep the crystals small. We and others that finely divided tribromide gives better results than coarse material. Yields of the purified tribromide were in the range 72-78%. The diketal 61 (US.2 g, 0.2 mole) was dissolved in dry tetrahydrofuran (#00 ml, distilled from CaHZ) in a 1 liter three-necked flask equipped with a mechanical stirrer and 111 a drying tube; the unused neck was stoppered. This solution was cooled, with stirring, to 23' -70° in a Dry Ice - ace- tone bath, and pyridinium tribromide (1H0 g, 0.u38 mole) added in one portion. The mixture, which rapidly decolorized, was stirred at 23' -70° for 1 hr, then allowed to warm to room temperature. The pale yellow suspension was then poured slowly into 2500—3000 ml of vigorously stirred cold water, whereupon the product precipitated. After 5 min more stirring, the solid was collected by filtration and washed repeatedly with water, and sucked fairly dry. This yellow- ish product was then covered with methanol (33. 200 ml), the lumps broken up, and the stirred mixture gently boiled for a few minutes; it was then cooled to —10° for several hours, and the white product collected, washed once with cold methanol, and air dried. Yield, 69 g (90%) of white crystals (needles and granules), mp 152-156° (sinters 128°, further softens 192-1950, with gradual darkening from 128° on). Other runs on a similar scale (0.2—0.25 mole) gave yields in the range 88—91%. Although not necessary for the next step, this material could be further purified by recrystallization from a va— riety of solvents. For example, the product was dissolved in hot acetone (10—12 ml/g); treated with Norite, filtered and cooled. A second crop was obtained by concentrating the mother liquor; addition of water and cooling afforded two more crops of crystals. The overall recovery of the bromoketal was about 85—90%. 112 The first crop obtained from the acetone recrystal- lization was recrystallized from cyclohexane giving the "a—isomer" (the gi§,gxg isomer 59a), white prisms, mp 157- 159° (slight darkening); an additional recrystallization from cyclohexane raised the melting point to 160—160.5°. The spectral properties of this material are as follows: ir (Nujol): 7.51, 8.22, 8.58, 9.18, 9.55, 10.5u, 12.38, 12.57 and 13.07u, among others; nmr (6, CDC13): H.25 (2H, t, J = 6.7 Hz), 9.10 (8H, broad 8, Av = 2H2), 3.10-2.70 1/2 (2H, m), 2.90-1.98 (4H, m). The first crop of crystals obtained after addition of water to the acetone mother liquor (gigg Egpgg) was recrystal— lized twice from cyclohexane to give the "B—isomer" (trans bromines, 59R), colorless needles mp 1H4—1H5°. This com- pound gave the following spectra: ir (Nujol): 7.72, 8.33, 8.59, 8.79, 9.58, 9.85, 9.97, 10.H5-10.53, 10.98, 11.97, 12.96, 13.51, 13.810, and others; nmr (6, CDC13): H.55- 3.75 (10H, extremely complex multiplet), 2.83-2.u5 (2H, m), 2.90-1.75 (HH, complex). The nmr spectra of this material, and the "a-isomer" just described, are given in the Appendix as Figures Al and A2. The complexity of the spectrum of the "B-form" shows it to be the unsymmetrical, trans-isomer 929- The proportions of the isomers formed in this reaction are not accurately known; inspection of the ir spectrum of the crude (methanol washed) material (comparison of the absorbances at 13.07 and 11.97 for 59a and 592, respectively) 113 suggested a ratio of about 10:1, the gi§,gxg-isomer 59a predominating. Although the isomers could be separated by gc (column A, 220°) (the irggg-isomer 59b is eluted first), the peaks overlapped enough to prevent accurate measure— ment of the composition. A yggy rgugh estimate would be 5— 10% of 828- Having pure samples of two of the isomers of 59, the 29 and Simpsonss, which was reported to sequence of Osborne give a third isomer, was repeated. The preparation, carried out by Miss Barbara A. Duhl, followed exactly the procedure given earlier (pp 106—107). The crude bromoketal was re— crystallized twice from cyclohexane to give needles, mp l28-130° (lit55 123-125°). The ir and nmr spectra of this material, however, were essentially a superposition of the spectra of the other two isomers. In particular, the ir spectrum of the alleged "y-isomer" contained every band found in the spectra of 59a and 592, and no new bands. With this evidence that the "y-form" was really a mixture, the material was analyzed by gc using conditions (column A, 220°) under which 59% and 59b could be barely, but un- equivocally separated. Thig analysis showed ihg presence EE.EQ£E 59a and 59b, in a ratio (peak heights) of SE- 1.3:1. Thus, the "y—form" is not the third isomer, but a mixture of the other two. 3,2,§,§—§i§(ethyelendioxy)—_,Z—dibromobicyclo[3.3.0]- octane 59. Direct bromination 9i dione 53 ig ethylene 61 glycol Sublimed bicyclooctanedione 5% (1.38 g, 0.01 11W mole) was dissolved in about 50 ml of warm (93. 80°) ethyl— ene glycol. Bromine (1.5 ml) was then added dropwise at such a rate that the bromine color never completely dis— appeared; about 30 min was required for this addition, during which the mixture was gently heated to maintain a temperature of u0—500. The pale yellow reaction mixture was then poured into 200 ml of water, stirred for several minutes, and the product collected, washed with water, and dried. This gave 3.06 g (80%) of white granules, mp 122- 13H° (dec). The spectra of this material showed no hydroxyl or carbonyl absorbtions, but did show the characteristic peaks of both the gi§,e§97guujthe iggng—isomers 59a and gap. This was confirmed by gc (column A, 220°) which showed the 59% : 59R ratio to be about 1.6 : 1. 2,2,6,6—Bis(ethyelendioxy)bicyclo[3.3.0]octa-§,Z-diene QR. Dehydrobromination 9i bromoketal 59. The methanol wash- ed mixture of isomeric bromoketals (87 g, 0.227 mole) pre- pared by bromination of 61 was added in one portion to a stirred slurry of sodium methoxide (73.5 g, 200% excess) in dimethylsulfoxide (H00 m1); a 1 liter, three-necked flask equipped with a mechanical stirrer, thermometer and a gas bubbler (to reduce entry of air into the flask, thus reducing autoxidation of the solvent) was used for the reaction vessel. Occasional cooling (ice bath) was used to keep the reaction temperature below 60°. After the exothermic reaction had ceased (£3. 30 min) the mixture 115 was heated to 70° for 2 hrs. It was then cooled to room temperature and poured into 2500 ml of stirred water and ice; the flask was rinsed with an additional 100 ml of water. Solid sodium chloride was added to nearly saturate the solution, and the crude solid product was collected by filtration. The filtrate was then extracted eight times with 500 ml portions of ether; each ether layer was roughly dried by washing with 50 m1 of saturated sodium chloride. To keep the volume manageable it was best to evaporate each 500 ml portion as it was obtained. The solvent was removed and the residue combined with the solid product originally filtered off. This product was dissolved in cyclohexane (33. 1200 ml) and refluxed with water separa— tion (Dean-Stark trap). When water ceased to distill over, the hot cyclohexane solution was filtered, concentrated by distillation to a volume of about 500 m1 and allowed to cool. The product, ”9.8 g (89%) of fine colorless needles, mp 101-102°, was then collected. Concentration of the mother liquor afforded an additional crop (1.5 g, 3%) of slightly yellowish needles, mp 97-100°. The total yield of crystal- line 60 was thus 92%; other runs on the same scale gave yields of 89-93%. The spectral data for this material were identical with those reported previously (pP- 108‘109)- Bicyclo[3.3.0]octa-3,7-diene-2,6-dione 52. Deketaliza- tion 9: ketal 60. The dienediketal 60 (48.5 g, 0.2 mole) and sulfosalicyclic acid (0.3 g) were dissolved in acetone 116 (500 ml) with gentle warming, and the solution allowed to stand at room temperature for 1-12 hrs. The acetone, to- gether with the ethylene ketal of acetone, was then removed on the rotary evaporator; the residue was taken up in ace- tone, allowed to stand for 30 min, and the volatile material again removed. After a third acetone treatment, the solid residue was sublimed at 70°/0.01 mm onto a carbon tetra- chloride-slush cooled condenser, yielding 25.2 g (99%) of white, blocky crystals, mp 76.5—78.5°. Recrystallization of this material, although not necessary, could be achieved using cyclohexane as solvent. This gave colorless or white needles, mp 78-79° (lit55 mp 78-79.5) in nearly quantitative recovery (three crops). The spectra of this material were entirely consistent with the structure 52: ir (Nujol), 5.88 (strong and broad), 6.35u, and others; nmr (6, CClu), 7.66 (2H, d of m, J = 5.6 Hz), 6.08 (2H, d of d with additional fine structure, J = 5.6 Hz, J' = 1.u Hz), 3.67 (2H, m). Cis,endo-i,g-dihydroxybicyclo[3.3.0]octa-§,Z—diene a9. Diisobutyl aluminum hydride reduction 2i dienedione 52. Caution! As diisobutyl aluminum hydride is pyrophoric and reacts explosively with protic solvents, due care should be exercised in its use. ii i§_strongly recommended that this preparation not be run 9g 3 scale larger than that described below, as the destruction of the excess reagent can be treacherous. A 1 liter three-necked flask equipped with a sealed 1 1'7 mechanical stirrer, constant addition funnel, low tempera- ture thermometer and gas inlet/outlet was dried by flaming under vacuum and purging with dry nitrogen. A nitrogen atmosphere was established, and the flask charged with diisobutyl aluminum hydride in toluene (250 ml of a 2.0 M solution, 0.5 mole). This solution was cooled with stirring to -H5°, and the dienedione 52 (16.7 g, 0.125 mole) in toluene (300 m1) added dropwise over H hr, during which time the temperature was kept between -HO and -50°. The reaction mixture, which had become quite yellow and viscous during the addition, was stirred for an hour more at £3. -u5°, then allowed to warm to 0° over an additional hour; the mixture lightened to a very pale yellow during this time. Saturated sodium sulfate solu- tion (35 ml) was then added, yggy slowly at first; cooling with an ice bath was used to keep the internal temperature below 10°. Due to the rather vigorous gas evolution, this addition required about one hour (when about half of the sulfate solution had been added the mixture became very gummy, but with continued stirring it reliquified). Methanol (50 ml) was then added, and the mixture slowly brought to room temperature. When the gas evolution slackened an additional 200 m1 of methanol was added, and the contents of the reaction flask transferred to a 2 liter Erlenmeyer. More methanol was added to bring the volume to 22° 1.5 liter, and the flask heated on the 118 steam bath with swirling (bumping and considerable gas evolutionl). When the temperature of the white suspension reached 65° it was boiled for an additional ten minutes, cooled, and filtered with suction. The white solid resi- due was then extracted twice with boiling methanol, boil- ing for 15 min each time. The combined filtrates were stripped of solvent on the rotary evaporator to give a very thick brown oil which was taken up in acetone (”00 ml), filtered, and again freed of solvent. Kugelrohr distillation (”0-70°/0.01 mm) of the brown residue afford- ed the mixture of epimeric dienediols ”g, 65, and 66 as a waxy solid (15.2 g, 88%). Analysis by gc (column B, 210°) showed these three components to be present in amounts of 77.7% 20.3%, and 2% of the product, respec- tively; this is also the order of increasing retention times on Carbowax 20 M. Several runs on a 0.05-0.125 mole scale gave yields of 80-88% of distilled material. "Sublimation" in a large sublimation apparatus with magnetic stirring of the "subli- mand" could also be used for purification, but was slower and less convenient than kugeirohr distillation. Separation of the desired Cis,endo-isomer Hg was achieved by dissolving the entire crude product from the above reduc- tion in 22° ”0 m1 of warm acetone and cooling to 0° overnight; a second crop was obtained by further cooling of the mother liquor to -30° for several days. This process afforded H2 in excellent purity (>99% by gc on column B, 210°); yield, 119 9.86 g of white prisms, mp 93.0-93.7° (57% yield based on dienedione 52, 8”% recovery of the desired epimer). The spectra were in agreement with the assigned structure; ir (Nujol): 3.08, 6.12 (weak), 9.”2u inter alia; nmr (6, CDCl3 + trace of conc. HCl to cause rapid exchange): 5.89 (”H, broadened AB quartet, J = 6 Hz), ”.95-”.62 (2H, m), 3.62-3.22 (2H, m), 2.72 (2H, s, exchangeable with D20); this nmr spectrum is reproduced as Figure A3; ms: m/e 138 (very weak), 120 (36%), 10” (11.5%), 91 (100%), 79, 78, 77, 76 (93° 15% each), 70 (2”%), 66 (25%), 65 (”2%), ”l (31%), 39 (79%), among others. Good combustion analyses were not obtained on the diol, but the diacetate gave satisfactory analytical results (vide infra). The mother liquor from the above crystallization was freed of solvent on the rotary evaporator, and the result— ing yellowish oil oxidized back to dienedione 52, as subse- quently described (p 122). Temperature Dependence 9i the Reduction pi Dienedione 52 with Diisobutyl Aluminum Hydride. A solution of diiso- butyl aluminum hydride (10 ml of 2.0 M solution) was cooled to the appropriate temperature and dienedione 52 (0.670 g) in a 33. 10 m1 toluene added dropwise, with stirring, over 1.5 hr. A nitrogen atmosphere was maintained throughout. The mixture was stirred at the appropriate temperature for 1-2 hrs, then warmed (or cooled) to 0°. Saturated sodium sulfate solution (2 ml) was then added dropwise, followed by 50 m1 of methanol. The resulting suspension was briefly 120 boiled, filtered and the precipitate washed twice with boiling methanol. The combined filtrates were freed of solvent on the rotary evaporator, taken up in acetone, filtered, and analyzed by gas chromatography (column B, 210°); the results (averages of three separate analyses, uncorrected for different detector responses) are given in Table 3, p 50. Epimerization pi Cis,endo-i,6—dihydroxybicyclo[3.3.0]- octa-§,Z-diene. Recrystallized Cis,endo diol 66 (6” mg, 0.5nmmfltfl was dissolved in acetone (93. 1 ml) containing 1 drop of water and a tiny crystal of p—toluenesulfonic acid. The mixture was then heated to gentle reflux, and was analyzed by gc (column B, 210°). After 8 hrs the starting material had decreased to about ”0% of the mixture, while peaks for the ipgpp and pi§,g§p-diols 66 and 66 respectively had ap- peared, in amounts of 23° ”5% and 15%. After 12 hrs the com- position was roughly 15% 66, ”5% 66, 35% 66 and about 5% of a new product of slightly longer retention time (16?). Finally, after 2” hr reflux, time starting material was undetectable, 66 and 66 comprised about ”0% of the mixture each, and the new, fourth component came to about 20%. The mass balance could not be checked, as no internal stand- ard was present. However, the amount of solvent lost was very small, and as the same amount of the mixture was analyzed each time, the total area of the product peaks established that little material was being destroyed. The mixture was decidedly yellow, but about 80% of the starting material 121 could still be accounted for. Cis,endo-i,6—diacetoxybipycloE3.3.0]octa-i,lfdiene 66 and the Trans-isomer 66. Acetylation pi bipyclooctadi- enediols 66 ppp 66. The distilled mixture of epimeric diols (100 ml, 0.725mmole containing about 77% 66, 21% 66 and 2% 66) was dissolved in dry pyridine (6 m1), cooled to 0°, and acetic anhydride (1 ml, pp. 7-fold excess) added. The mix- ture was allowed to stand at room temperature for 1 hr, then heated on the steam bath for an additional hour. The yellow brown reaction mixture was then cooled to 0° and poured into 30 m1 of cold water with vigorous stirring. The aqueous solution was then extracted five times with 10 m1 portions of ether, and the combined ether layers washed with 2M HCl until the odor of pyridine could not be detected. The ether layer was then washed with 5% sodium hydroxide (2 X 10 ml), with water (15 ml), and with saturated sodium chloride, and filtered through Drierite. Removal of the solvent gave l”0 mg (87%) of a pale yellow oil which gradually solidified. Gas chromatographic analysis (column A, 170°) showed the presence of two components in a ratio of about ”:1; the minor component was eluted first. 120 mg of this material was recrystallized from pentane to give 72 mg of 66, white needles, mp 92-93.5°. An analyt- ical sample was obtained by 2 more recrystallizations from hexane and sublimation (50-60°/0.01 mm). This material had mp 93.6-9”.l° and gave the following spectra: ir (Nujol): 5.75, 6.1”, 8.05u, among others; nmr (6, CClu), 5.71 (”H, 122 broad s), superimposed on 5.80—5.50 (2H, m), 3.83-3.”5 (2H, broad m), 2.0” (6H, s). Appi: Calc for Cl2H1”O” : C, 6”.85; H, 6.35 Found : C, 6”.80; H, 6.”6 The mother liquor from the above crystallization was freed of solvent and the nmr spectrum of the residue taken. Most of the spectrum was indecipherable, but the acetate region showed the 62.0” singlet of the pip,pppp-isomer 66, and two singlets of equal intensity at 62.03 and 2.02. Careful integration of these signals gave a ratio of 62.0”: (62.03 + 62.02) = 38:3”, hence a 66:66 ratio of 1.12:1. The ratio determined by gc (column A, 170°) was 1.15:1 (average of three analyses). Chromium Trioxide-Pyridine Oxidation pi EDS Epimeric Bicyclooctadienediols. The chromium trioxide-pyridine com— plex was generated ip piip according to Ratcliffe and Rode— hurst82. Thus, pyridine (19 g, 0.2” mole, dried by distil- lation from calcium hydride) was dissolved in dry methylene chloride (pp. 350 m1), and chromium trioxide (12 g, 0.12 mole, ground, dried by overnight heating at 50°/0.01 mm and stored over P205) added with magnetic stirring. After 15 min stirring the red-orange solution was cooled in an ice bath, and the residual dienediols from crystallization Of the pip,pppp—isomer (1.38 g, 0.01 mole) in methylene chloride (30 ml) were added rapidly; the magnetic stirrer usually stopped a few seconds after mixing, and swirling was 11sed to effect mixing. After a reaction periodof 2 min 1.23 the black mixture was poured into 200 m1 of 2M HCl. The black polymeric residue in the reaction flask was rinsed with 50 m1 of 2M HCl and 100 ml methylene chloride, and these washes combined with the rest of the mixture. The organic layer was separated and the aqueous layer extracted one with 100 ml of methylene chloride. The combined organic layers were washed once with 100 ml 2M HCl, twice with water (100 m1 portions), saturated sodium chloride solution (100 m1), and filtered through a Drierite cone. Removal of the solvent gave a thick brown residue, which was sublimed (using a kugelrohr apparatus) to give dienedione 66, 0.95 g (71%), mp 77-790. Other runs on a similar scale gave yields of 62—78%. The short reaction period was used to minimize the destruction of the very base-sensitive product by any pyri- 86 dine present. For the same reason, the usual step of Vvashing the organic extract with strong aqueous base was IIOt used. pip,pppp-bicyclo[3.3.0Jppip—i,l—pippp—i,6-diacetic pipip, diethyl ppipp 16, and pppp-g-hydroxy bicyclo[3.3.0]- gppip-B,6—diene-endo—2-ylacetic ppip lactone 66. Orthoester (Zlaisen rearrangement53 pi dienediol 66. Method A: p- Ciichlorobenzene solvent. Dienediol 66 (5.300 g, 3.95 mmole) vvas added to freshly distilled triethyl orthoacetate (pp. 50 ml) in a 100 m1 three-necked flask equipped with a mag— Iietic stirrer, heating mantle, thermometer, nitrogen inlet, and a take-off condenser with a gas bubbler attached to the '12” top of the condenser. A nitrogen atmosphere was established, and a gentle nitrogen sweep (5 ml/min) employed to carry the more volatile products into the condenser. The mix- ture was warmed until the diol had all dissolved, then 60 mg of pivalic acid in 1 ml triethyl orthoacetate was added. The mixture, which began to turn yellow almost immediately, was then heated to a gentle boil; heating was adjusted so that the orthoester condensed before it reached the take— off condenser. Collection of the volatile distillate (mainly ethanol, together with some ethyl acetate and triethyl orthoacetate) was begun immediately. Gentle boiling was continued for ”8 hrs; approximately every 12 hours during this period an additional 25—35 mg of pivalic acid (dis— solved in a little triethyl orthoacetate) was added. After the ”8 hr reflux, the reaction mixture was cooled, a short path still head attached, and pp. 35 m1 of triethyl ortho- acetate removed by distillation (aspirator pressure). p— Dichlorobenzene (pp. ”0 ml) was then added, along with an additional 100 mg of pivalic acid, and the deeply colored solution heated to boiling, again with removal of lower boiling products, for an additional 72 hours. Four times during this period additional 10-20 mg portions of pivalic acid were added. The nearly black solution was then cooled, most of the solvent removed by distillation (aspirator pres— sure), and the residue passed through a 12 X 2.5 cm. column of Activity III acidic alumina. 250 ml of benzene was used to elute the products from most of the polymer. The eluted 125 material was concentrated, first on the rotary evaporator to remove benzene, then by trap-to-trap removal of the re- maining p-dichlorobenzene. The residue was then kugelrohr distilled at ambient to 110°/0.01 mm to give 6.213 g of yellow oil which partly crystallized. Based on gc analysis (column A, 210°), this material was estimated to contain 72% diester 66, 21% lactone 66, and 7% numerous (unidenti- fied) minor products. This corresponds to a pp. ”1% yield of 66. The entire product was dissolved in warm hexane (30 ml), then cooled to -10° for several hours for crystal- ' lization of the lactone 66. This material, after a second crystallization from hexane, showed the following properties: white needles mp 8”.8-85.2°; ir (Nujol): 5.79m; nmr (6, CDC13): 6.3-5.1 (5H, complex m), 3.73 (1H, broad s), 3.52- 2.95 (2H, m), 2.62-2.33 (2H, m); ms: m/e 162 (19%), 13” (10%), 117 (100%), 115 (25%), 91 (70%), 78 (52%), 39 (50%) inter alia. The sample submitted for combustion analysis was recrystallized a third time from hexane and sublimed (50°/0.01 mm). pppi. Calc for C10H1002 : C, 7”.05; H, 6.22. Found : C, 73.91; H, 6.20. The desired diester 61 was isolated by chromatography of the mother liquor from the initial crystallization of lactone 66. The hexane solution, containing pp. 90% of 66, was placed on a dry packed column (2.5 X 70 cm) of acidic alumina (Fisher, 80—200 mesh, deactivated to Activity III) and eluted with purified hexane; fractions averaging about 126 10 ml were collected. When gc analysis showed that diester 11 was beginning to appear in the eluent (typically around fraction #80), the eluting solvent was switched to hexane- 5% ether (v/v), and collection of fractions was continued until 11 stopped coming off the column. Those fractions containing >98% 11 were combined and the solvent removed, to give 3.163 g (29%) of diester 11 as a pale yellow oil. The less pure fractions were combined and chromatographed again; this raised the yield of diester to 3.828 g (35%). An analytical sample of 11 was obtained by preparative gc (column C, 220°). This material gave the following data: ir (neat): 3.25, 3.3”, 3.H2, 5.76, 8.50—8.66, and 9.67u, among others; nmr (5, C01”): 5.50 (HH, 8), H.08 (HH, q, J = 7.5 Hz), 3.70-3.37 (2H, m), 3.35—2.95 (2H, m), 2.26 (HH, broad d, J = 7.5 Hz), 1.27 (6H, t, J = 7.5 Hz); ms: m/e 278 (11%), 233 (8%), 205 (9%), 190 (20%), 159 (12%), 131 (19%), 117 (76%), 91 (92%), 57 (”9%), H3 (21%), H1 (26%), 39 (19%), and 29 (100%), among others. The nmr spectrum is shown in Figure AH. 'énal. Calc for C16H220u : C, 69.0”; H, 7.97. Found : C, 69.05; H, 8.01. Method B; neat triethyl orthoacetate procedure. Dienediol 9% (2.76 g, 20 mmole) was mixed with freshly distilled triethyl orthoacetate (60 ml) in a 100 m1 flask equipped with a thermometer, magnetic stirrer, and Claisen-Vigreux distillation column carrying a thermometer, condenser and receiver. A nitrogen atmosphere was established, and the 127 mixture warmed. When the diol had completely dissolved, 50 mg of pivalic acid in 1 m1 of triethyl orthoacetate was added, and the mixture heated to boiling. When the initial surge of ethanol evolution had subsided, the heating was adjusted to give a distillation rate of about 0.3 ml/hr. Additional 20-30 mg portions of pivalic acid in ca. 1 ml triethyl orthoacetate were added approximately every 6 hrs; after each such addition the temperature at the head of the column rose to 70 to 90°, but soon subsided to HD— 50°. The reaction was continued for 90 hrs, during which time about 25 ml of distillate had collected; the total amount of pivalic acid added was 0.52 g. The excess ortho— acetate was then removed by distillation at aspirator pres- sure, and the brown residue kugelrohr distilled to give H.75 g of yellow oil and crystals. This material showed (gc on column A, 210°) 69% diester 11, 15% lactone 92, 11% pivalate 83 (vide infra) and about 5% of numerous other pro— ducts. This composition suggests that diester 11 is formed in SE 60% yield. The lactone 82 was removed as described in method A, and the diester isolated using the same chromatographic procedure. After reworking the less pure fractions, a total of 2.89 g (52%) of 11 was obtained. Several of the byproducts from this reaction were isolated during the chromatographic separation. Thus, a purple band was eluted quite rapidly with hexane (well be- fore the diester 77). Gas chromatographic analysis of this ‘128 material (column A, 180°) showed three main components and a host of trace materials. Preparative gc (column A, 170°) permitted isolation of the second and third (in order of increasing retention time) of the major components. The second compound was a faint lavender color. On the basis of the following spectral data, it is assigned structure 86: ir (neat), 5.75u; nmr (6, CClu): 5.8”—5.3” (”H, m), ”.13 (2H, q, J = 7.” HZ), 3.73—2.90 (3H, m), 2.61-2.06 (”H, m, including a broad 2H d,J = 7 Hz), 1.27 (3H, t, J = 7.” Hz); ms: m/e 192 (”2%), 163 (13%), 1”7 (2”%), 119 (62%), 118 (75%), 117 (70%), 105 (99%), 10” (100%), 91 (79%), 79 (30%), 78 (27%), 77 (38%), 65 (27%), ”1 (56%), 39 (”6%), 29 (65%). The major component of the purple band with the long— est retention time was isolated as a colorless oil which solidified to give long white needles. The spectra suggest- ed that the structure was 1,3,5—triethoxybenzene 88: nmr (6, CClu): 5.93 (3H, 8), 3.95 (6H, q, J = 7 Hz), 1.38 (9H, t, J = 7 Hz); ir (neat): 3.3”, 3.”l, 3.”6, 6.25, 6.81, 7.19, 8.56, 8.95, 9.”0, and 12.28u. This structural assign- ment was confirmed by the melting point of recrystallized material: needles from methanol—water, mp ”3.0—”3.3° (lit7u, ”3°). Later in the chromatography, a band was eluted which Contained 22' 95% one component, pivalate 83; this material Was eluted shortly before the diester 77 appeared. The Spectral data left no doubt as to the structure: ir (neat): 129 5.75u; nmr (6, CClu): 6.10 (1H, d of d, J = 6 Hz, J' = 3 Hz), 5.85-5.5 (”H, complex), ”.13 (2H, q, J = 7 Hz), 3.85 (1H, m), 3.55-2.75 (2H, series of m), 2.5 (2H, pseudotriplet, J = 6 Hz), 1.27 (3H, t, J = 7.5 Hz), 1.20 (9H, s). A considerable time after diester 11 had eluted com- pletely, a small amount of acetate 8” was eluted from the column. The structure followed from the spectral data: ir (neat): 5.76u; nmr (6, CClu): 6.10 (1H, d of d, J = 5 Hz, J' = 2.5 Hz), 5.93-5.”5 (”H, complex), ”.11 (2H, q, J = 7 Hz), 3.8-2.9 (3H, series of m), 2.8-2.2 (2H, complex), 1.97 (3H, s), 1.27 (3H, q, J = 7 Hz). 2,6—Bis(carboethoxymethylene)bicyclo[3.3.0]octane 18. Acid catalyzed Wittig reaction of dione 53 and carboethoxy- 70 methylenetriphenylphosphorane The ylid component of the Wittig reaction was prepared using the method of Isler, 9.: 211-69 , and was purified by recrystallization from ethyl acetate-petroleum ether. Sublimed dione 53 (1.380 g, 10 mmole) and the ylid (7.66 g, 22 mmole, 10% excess) were dissolved in ”0 m1 of benzene-dioxane (3:1 v/v) and benzoic acid catalyst70 (300 mg) added. The mixture was then re- fluxed under nitrogen for ” days, during which time it became a deep red-brown color. The solvents were removed on the rotary evaporator and the resulting brown paste taken up in 20 ml carbon tetrachloride. This solution was filtered with suction through a ” x 3 cm bed of silica gel, and the silica gel washed with 100 ml of carbon tetrachloride. Removal of the solvent from the combined CClu layers afforded 130 6.” g of a mixture of white crystals in a yellow oil. This material was chromatographed on a 2 x 17 cm dry packed column of silicic acid (Mallinckrodt, 100 mesh), using carbon tetrachloride as the eluting solvent. The column runnings were discarded until evaporation of a drop left a visible residue; then six 20 ml fractions were collected. The first two fractions were pure diester 78 (a mix- ture of three stereoisomers) as shown by gc analysis (column A, 200°); together, they weighed 1.302 g (”7%). Fraction 1, which contained 22' 75% one isomer (that with the shortest retention time), crystallized on standing. Two recrystal- lizations of this material from pentane at -20° gave white prisms, mp 5”.2-55.0°, containing 22° 97% one isomer. An analytical sample was obtained by three more recrystalliza- tions from ethanol-water, giving needles mp 5”.6-55.0°; sublimation (”0°/0.005 mm) of this material raised the melting point to 55.0-55.2°. The spectral data showed this to be 18%: ir (Nujol): 5.80, 6.01u, inter alia; nmr (6, CD013): 5.77 (2H, pseudoquartet, J = 1.5 Hz), ”.16 (”H, q, J = 7.2 Hz), ”.0-3.5 (2H, broad m), 2.7—2.0 (6H, m, with maxima at 2.65, 2.6, and 2.”5), 1.8-l.” (2H, broad m), 1.27 (6H, t, J = 7.2 Hz); ms: m/e 278 (57%), 2”9 (100%), 233 (”3%), 203 (35%), 159 (16%), 131 (13%), 91 (1”%) and 29 (8%), among others. Fraction 2, contained the three isomers of 18 in the ratio 35:50:15, in order of increasing retention time. The nmr spectrum of this mixture was basically similar to 131 that of the pure isomer 18a, with the following differences: the bridgehead absorbtion at 6”.0-3.5 had decreased in in- tensity to l.”H, while a corresponding increase (to 8.6H) was apparent in the higher field absorbtions. Also, these higher field bands had spread out, beginning around 63.”, reflecting the contribution of the less shielded bridgehead protons in the other isomers. The ir spectrum (neat) was practically identical to that of pure 18a. Fractions 3-6 contained mostly a mixture of stereo- isomers of ketoester 81. The weight of this material came to 0.”8” g (23%): the ir of this material showed peaks at 5.7”, 5.83, and 6.02u, demonstrating the presence of both cyclopentanone and a,B-unsaturated ester functionality. The total recovery of identifiable organic material from this reaction thus is ca. 71%. In two later runs the amount of ylid was increased to ”0% excess, and more benzoic acid catalyst used. These gave yields (after a more frugal chromatographic separation) of 67% and 71% of diester 78 (isomer mixture); the ketoester 81 was not isolated. Bicyclo[3.3.0]octane-g,§ediacetic acid, diethyl ester 1%. Catalytic reduction of unsaturated esters 17 and 18. The mixture of isomeric diesters 18 obtained from the Wittig reaction just described (0.835 g, 3 mmole) was dissolved in ethyl acetate (25 m1), and 30 mg of 10% palladium on charcoal added. This mixture was hydrogenated at atmospheric pressure and 22° 0° (ice bath) until hydrogen uptake ceased. The catalyst was removed by centrifugation and washed with 132 additional ethyl acetate. Removal of the solvent and molec- ular distillation (80-100°/0.05 mm) afforded 0.795 g of color- less liquid (9”%). Gas chromatographic analysis (column A, 210°) showed this material to contain three components, in the ratio 10:”0:50. The spectral data indicate that this material is a mixture of stereoisomers of the saturated diester 19: ir (neat): 5.75u; nmr (6, CClu): ”.15 (”H, q, J = 7.3 Hz), 2.75-0.95 (22H, series of peaks, including a broad singlet at 2.3” and a triplet (J = 7.3 Hz) at 1.26). The purified diester 17 from the orthoester Claisen reaction (33. 5 mg) was dissolved in 1 ml ethyl acetate and a few mg of 10% Pd/C added. Atmospheric pressure hydrog- enation of this material was conducted on this mixture at 0° until hydrogen uptake ceased (SE: 20 min). Gc analysis (column A, 210°) of the solution showed that the starting diester was entirely consumed. The main product was the major saturated diester isomer (of longest retention time) in the preceding preparation. A small amount (9;. 3%) of the intermediate retention time isomer was also formed. 6,1-Bis(trimethylsiloxyhricyclo[7.3.0.0u’12 ]dodec-§- ene 92. Acyloin-type cyclization of the saturated diester 19. A 100 ml three-necked flask equipped with an addition funnel, thermometer, magnetic stirrer, reflux condenser and nitrogen inlet/outlet was charged with toluene (”0 ml, re- distilled and passed through a column of Activity I basic alumina). The toluene was heated to vigorous boiling so that the vapors flooded the entire apparatus; about 5 ml 133 of toluene was distilled from the top of the reflux con- denser to guarantee dryness. The apparatus was cooled to room temperature while a stream of dry nitrogen was passed through the flask, and clean sodium (0.20” g, 8.87 mg-atoms) added to the toluene. The mixture was heated to reflux with vigorous stirring to disperse the sodium, and cooled to room temperature. Chlorotrimethylsilane (0.985 g, 9.06 mmole) in toluene was added to the stirred sodium suspension, followed by the mixture of isomeric saturated diester 19 (0.556 g, 0.98 mmole; ES: ”0% of this material was the gig, endg-epimer) in an additional 10 ml toluene. The addition took 1 hr, after which the mixture was heated to reflux for 3.5 days. Twice during this period (after 2” and 70 hrs reflux) additional 0.1 g portions of sodium and 0.50 g portions of chlorotrimethylsilane were added. The reaction was stopped when all of the diester (all of the three iso- mers) had been consumed. The reaction mixture was filtered through a medium frit under a nitrogen atmosphere, the purple solid washed with 15 ml toluene, and the solvent removed from the combined toluene solutions on the rotary evaporator. Molecular distillation of the yellow, viscous residue afforded 0.178 g of a very pale yellow liquid; most of the material distilled at 115-125°/0.25 mm. Analysis of this material (gc on column A, 170°) showed one major com- ponent (93. 80%) and numerous minor products. The spectral data for this mixture support the structure 92 for the major component: nmr (6, CClu, referenced to benzene, 57.26): 13” 2.7—1.0 (16H, very broad), 0.12 (18H, 5); ir (neat): 5.99, 83) 3)3) and 13.l”-l3.33u (Si(CH3)3). The mass spectrum of the mix- ture showed a strong peak at m/e 338, the calculated molecu- lar weight of 92. EaZfBis(trimethylsiloxy)tricyclo[7,3.0,05,12 ]dodeca- 2,§,_07triene ”5. Acyloin cyclization g£_unsaturated diester 11. Sodium (0.77 g, 0.0335 g—atoms) was placed in 100 ml toluene (redistilled and passed through a 20 x 2.5 cm column of Activity I basic alumina) in a dry 250 ml three-neck flask fitted with an addition funnel, reflux condenser, thermometer and nitrogen inlet/outlet; a magnetic stir-bar and about twenty 5 mm glass beads were used for mixing. A nitrogen atmosphere was established and maintained through- out the following steps. The sodium was melted and dis- persed by heating the toluene to reflux while stirring. The mixture was then cooled to E2: 60° and 5.2 ml of chloro- trimethylsilane (”.”” g, 0.0”12 mole) (Aldrich, redistilled, bp 56.1-56.”°) added with stirring. While the temperature was maintained around 60°, the diester 11 (2.00 g, 0.0072 mole) in ”0 ml of toluene was added dropwise over 2.6 hrs. Upon completion of the addition, an additional 1.0 ml of chlorotrimethylsilane was added and the mixture heated to reflux. The reaction was monitored by periodic gc analysis (column A, 215°). After ” hrs reflux the diester had been consumed completely, and the reaction mixture was cooled to room temperature and filtered through a medium frit 135 using N2 pressure. The purple residue was washed three times with 25 ml portions of toluene, and the yellow fil- trate and washings combined and the toluene removed by dis— tillation (N2 atmosphere). The thick brown residue was then kugelrohr distilled at 80-100°/0.01 mm, yielding 1.16 g of a pale yellow liquid. The brown nonvolatile residue amounted to 0.9” g. Chromatographic analysis of the distillate (column A, 190°) showed it to contain three components of short re— tention time, totalling 11% of the mixture, one of inter~ mediate retention time (8”%), and another of longer reten— tion time (5%). Evidence is given below to show that this last component is the a—siloxy ketone 93 and that it is derived from the major component. Thus, the major component should be the expected bis- (trimethylsilyl)ether ”5. Attempts to purify this compound by preparative gc were unsuccessful, as reinjection revealed that decomposition to two new compounds had taken place. However, the spectral data obtained on the mixture are all in accord with structure ”5: ms: m/e 338 (calculated for ”5, 338) and nothing higher, and others; ir (neat): 7.99» 83), 10.62, (Si(CH3)383), 8.61, 9.10 and 9.”6 (both Si—O—C 11.”5, 11.82 (Si(CH3)383), 12.8” and 13.13-13.27u (Si(CH3)383); nmr (6, CClu, referenced to benzene 7.27): 5.77 (”H, nearly degenerate AB pattern, J = 22° 7 Hz), 3.”0-2.67 (”H, m), 2.22 (”H, slightly broadened d, J = ” Hz), and -0.01 (18H, 8). This spectrum is reproduced in Figure A5. 136 The yield of ”5 was ”0.5% on the basis of 8”% purity of the distillate. Including the 5% of 93 in the distil- late, the yield of cyclized product came to ”3.5%. In several other runs, starting with 1.0—2.8 g of diester 17, this total yield was in the range ”0-56%. ”,12 l—TrimethylsiloxytricycloE7.3.0.0 ]dodeca-2,10- 91222395922 93. The preceding reaction, acyloin cycliza— tion of the unsaturated diester 71, was repeated on the same scale using an identical procedure. When the diester was completely consumed (go on column A, 210°), the reaction mixture was cooled, filtered as before, and allowed to stand overnight exposed to the atmosphere; a glass wool plug permitted air, but not particulate matter, to enter the flask. The solvent was then removed by distillation at atmospheric pressure; removal of the last traces of solvent (aspirator vacuum) and kugelrohr distillation of the residue (70-110°/0.01 mm) gave 1.01 g of a light yel- low oil containing 31% ”5, 5”% of the desired product (the "longer retention time" material mentioned above), and a total of 15% of four other products of short retention time (analysis on column A, 190°). Thus, the yield of cyclized material (”5 and 93) was ”2%. Preparative gc (column A, 175°) of this mixture af- forded a pure sample of 93 as a white, waxy solid which sublimed without melting above 100°. As the material de- composed on standing, a combustion analysis was not obtained. The spectral data confirm structure 93 for this compound: 137 ms: m/e 262 (1”%), 2”7 (7%), 23” (9%), 219 (19%), 169 (22%), 129 (33%), 117 (5”%), 91 (23%), 73 (100%), and others; ir (neat): 5.82u; nmr (6, CClu, referenced to benzene): 5.98 (1H, d of d, J = 6 Hz, J' = 2H2), 5.81 (1H, broad d, J = 6 Hz), 5.66 (2H, broad s, AV1/2 = 23' 2 Hz), ”.”5 (1H, t, J = 7 Hz), 3.”3-2.68 (”H, m), 2.53 (1H, broad d, J = ” Hz), 2.25 (1H, m), 2.05-1.71 (2H, m), and -0.02 (9H, 5). Strong Acid Catalyzed Hydrolysis gf §i§(trimethylsiloxy) olefin ”5. Formation of tetracyclic ketol a” or 95. Dis- tilled acyloin product ”5 (100 mg, 8”% pure, ca. 0.25 mmole) was dissolved in benzene (3 m1) and one tiny drop of 12 M hydrochloric acid added. The mixture was vigorously shaken for 2 min, poured into 5 ml water, and made slightly basic by the addition of sodium bicarbonate. The organic phase was separated and the aqueous layer extracted twice with 5 m1 portions of chloroform. The combined organic layers were washed with 5 ml saturated sodium chloride solution, dried over MgSOu, and freed of solvent. Kugelrohr distil— lation of the residue at 60-100°/0.01 mm gave 38 mg of a thick oil containing 93. 80% one compound and at least four minor components. Preparative gc (column A, 190°) afforded a small amount of the major component as a white wax. The spectral data given below demand a tetracyclic structure, and suggest structure 9” or 95: ms: m/e 190 (100%), 172 (”9%), 162 (12%), 1”6 (73%), 10” (92%) among others; ir (neat film): 2.91, 3.27, 3.39, and 5.73u, among others; 138 nmr (5, CClu): 5.9-5.3 (2H, m), 3.9” (1H, broad d, J = 23' ” Hz), 3.75-l.l (11H, series of complex m, including a singlet whose shift varied from 3.” to 3.1 with a two-fold increase in concentration). Tricyclo[7.3.0.07’12]dodeca—g,lgfdiene-§,Zfdiol 99. Reduction of bis(trimethylsilyl)ether 99. A solution of distilled bis(trimethylsiloxy)olefin 99 (1.50 g, 80% pure (column A, 190°, 3.6 mmole) in 15 ml benzene was added dropwise over 2 hr to a gently boiling solution of sodium borohydride (1.6 g, ”2 mmole, Si: ”6-fold excess) and sodium hydroxide (SE: 100 mg) in 60 ml of 80% aqueous ethanol; a nitrogen atmosphere was maintained throughout the addition and a subsequent 2 hr reflux period. The solution, which had become dark orange during the addition of 99, lightened during this 2 hr period to a light yellow. The cooled mix- ture was then poured into 150 ml of water, and acidified to pH 3 by the cautious addition, with cooling, of 3H hydro- chloric acid (foaming!). The milky solution was heated on the steam bath for 10 min, cooled, and extracted three times with 50 m1 portions of chloroform. The combined chloroform extracts were washed with water (50 m1) and saturated sodium chloride solution, and dried (MgSOu). Removal of the solvent and kugelrohr distillation of the yellow residue at 70-120°/0.01 mm afforded 600 mg of a thick colorless oil which partly solidified on standing. Analysis of this material showed it to contain 22° 85% of one component, diol 99, and numerous trace components. 139 On this basis, the yield of 99 was 7”%. The brown, resin- ous residue from the distillation contained some of the diol, and was saved for later chromatographic separation. The above distillate was chromatographed on a column of Woelm silica gel (2.5 x 16 cm, slurry-packed in ethyl acetate) and eluted with ethyl acetate, collecting 5 m1 fractions. The desired diol appeared in fractions 20-”5; most of the material was in fractions 20-30. Removal of the solvent afforded pure 99 as an extremely viscous oil. As this material retained ethyl acetate tenaciously, a few drops of cyclohexane were added, and the solvents re- moved on the rotary evaporator (bath temperature ”0°). This cyclohexane treatment was repeated twice, and the residue, a colorless oil, freed of the last traces of sol- vents by application of high vacuum. This caused the material to froth up and gradually solidify to a white wax, which decomposed (blackened) without melting at 100- 120°. The yield of this material, which showed only a single component on all gc columns tried (column A, 200°, and programming at 1°/min from 180°; column B, 220°; column C, 220°; column D, 190°), was ”20 mg (61%). The acetyla- tion results (vide infra) show that, despite the homogeneity by gc, a small amount (EE- 5%) of one of the trans-isomers was present in this material. The spectral data obtained on this product which lead to the assignment of structure 99, were as follows: ir (neat): 2.9”, 3.27, 3.”3, 6.19 (weak), 7.01, 9.”3, 9.73, 1”0 10.69, 10.9”, 12.77u inter alia; nmr (6, CClu): 6.2” (1H, d of d, J = 6 Hz, J' = 2.6 Hz), 6.00-5.66 (3H, m), 3.93- 3.67 (1H, m), 3.66-2.62 (5H, m), 2.”8-2.0 (1H, m), 2.3” (2H, s, exchangable with D20), l.83-1.”3 (3H, m); ms: m/e 192 (”%), 17” (59%), 156 (27%), 1”5 (”0%), 117 (95%), 115 (50%), 105 (5”%), 91 (100%), 79 (82%), 67 (”7%), 39 (””%) and others. The nmr spectrum is reproduced in Figure A6. The glassy pot residue from the kugelrohr distillation was chromatographed in a similar fashion to that described above for the distillate. This afforded 51 mg of colorless oil; analysis of this material showed only one peak, with identical retention data to the material obtained above. Acetylation of the material recovered from the distillation residue showed it to be largely one of the trans-isomers (999 or 999), containing 23' 30% of the cis isomer 99 (3193 infra). Thus, the total yield of diols was 68.5%. Other runs on a similar scale, using a 20 to 60 fold excess of sodium borohydride, gave yields of chromatographed diol of 57-69%. Periodic Acid Cleavage g: Diol 99. Formation of cis, endo-bicyclo[3.3.0]octa-3,7-diene-2,6-diaceta1dehyde 99. A periodic acid solution in ether was prepared according to Ireland77 by stirring excess periodic acid with anhydrous ether for 1 hr at 25°. This solution, which is stated77b to contain "about 16 mg/ml" (= 22° 0.07 E), was added in 50 or 100 pl portions to a solution of diol 99 (3.8 mg, 0.02 mmole) in anhydrous ether. The mixture was analyzed l”l by gc (column A, 210°), after each addition of periodic acid; the volumes injected were increased each time in rough proportion to the increase in volume of the reaction mixture, permitting crude quantitative analysis. After 200 pl of periodic acid had been added, the amount of diol 99 had dropped to about half its original concentration, and a corresponding peak for the dialdehyde 99 had appeared. As more periodic acid was added, the formation of the di- aldehyde continued to mirror the disappearance of the diol; however, a new peak, of much shorter retention time than either 99 or 99, began to appear. After ”00 ul of periodic acid solution had been added, the diol peak had completely disappeared, the dialdehyde peak accounted for about 80% of the original diol concentration, and the new product came to about 10% of the dialdehyde. When the solution was allowed to stand, this new compound continued to be formed at the expense of the dialdehyde; addition of more periodic acid accelerated this transformation. A drop of the mixture obtained after all the starting material had disappeared was evaporated on a salt plate, and the ir spectrum recorded. This showed the aldehyde peak for 99 (5.78m) along with numerous other peaks. From the first addition of periodic acid on, the odor of the dialdehyde was readily noticable over the odor of the ether solvent. A sample of the dialdehyde was obtained for comparison gig the following unambiguous route. To a stirred solution 1”2 of diester 99 (0.361 g, 1.30 mmole) in anhydrous ether (8 ml) was added ethereal lithium aluminum hydride (”.0 m1 of a 0.80 g solution, 23' 150% excess). The mixture was stirred at room temperature for 15 min; saturated aque- ous sodium sulfate solution (0.5 ml) was then added drop- wise, followed by methanol (20 ml). The mixture was reflux- ed for 10 min and filtered. The precipitate was washed twice with boiling methanol, and the methanol layers con- centrated on the rotary evaporator. The thick yellow resi- due was taken up in chloroform, refluxed briefly, filtered through Drierite and freed of solvent (rotary evaporator) to give 0.226 g (90%) of thick yellowish oil. The nmr spectrum showed this material to be the gi§,endg-2,6-bi§- (2-hydroxyethyl)bicyclo[3.3.0]octa-3,7-diene (6, CDC13): 5.6” (”H, nearly degenerate AB pattern, J = 23' 6 Hz), 3.79 (”H, t, J = 7 Hz), 3.6”-3.25 (2H, m), 3.15-2.63 (2H, m), l.93-l.”5 (6H, series of peaks, including a 2H singlet exchanged with D20). This diol (63 mg, 0.325 mmole) in 3 ml methylene chloride was added to 6 mmole of chromium trioxide pyridine complex in methylene chloride, prepared according to Ratcliffe and Rodehurst82 from 0.95 g pyridine and 0.60 g chromium tri- oxide in 15 m1 methylene chloride. The reaction mixture was stirred at room temperature for 10 min, the orange methylene chloride solution, separated by decantation, and the gummy black residue washed with 25 m1 ether. The com- bined organic layers were washed with 5% aqueous sodium 1”3 hydroxide (6 X 5 ml), 5% aqueous hydrochloric acid (3 x 5 ml), 5% aqueous sodium bicarbonate (15 m1) and saturated aqueous sodium chloride solution (15 ml). Removal of the solvent in 33939 gave ”1 mg (66%) of faintly yellow dial- dehyde 99 as a waxy solid with a very powerful odor. The material showed a single peak upon gc analysis (column A, 210°); sublimation (”0°/0.02 mm) gave a mass of white, soft, wet-looking needles, mp 53-58°. Further purification was not attempted due to the instability of this compound; upon standing overnight in air it was converted to a yellowish, sticky gum. Dilute (£3. 1%) solutions in methylene chloride were stable for several months if kept at -10°, however, permitting storage. The spectral data, obtained on the crude material, fully support the structure 99: ir (neat): 3.26, 3.””, 3.52 (shoulder), 3.65 and 5.78u, among others; nmr (6, CClu): 9.87 (2H, t, J = 1.” Hz), 5.51 (”H, extreme AB pattern, J = 22° 6 Hz), 3.85-3.00 (”H, m), 2.50 (”H, d of d, J = 7.5 Hz, J' = 1.” Hz). ”,12 Cis-§,Z-diacetoxytricyclo[7.3.0.0 ]dodeca-2,ig-diene 999. Tricyclododecadienediol 99 (19.2 mg, 0.10 mmole), obtained by chromatography of the distillate from reduc- tion of 99, was dissolved in dry pyridine (2 ml), and acetic anhydride (0.2 ml, 22' 10-fold excess) added. After 15 min at room temperature, the yellow mixture was heated on the steam bath for 2 hr, during which it turned brown. The cooled reaction mixture was then poured into 10 ml of cold water, extracted with chloroform (3 x 5 ml); the chloroform In u layers were washed with 5 ml of 10% aqueous sodium hydroxide, washed with dilute hydrochloric acid until the odor of pyridine could not be detected, and dried over Drierite. The solvent was removed on the rotary evaporator to give a pale yellow oil (26 mg), which contained 2a. 90% gis- diacetate 103, 5% trans-diacetate (1Qg or 105) and small amounts of several other compounds. This material was adsorbed on alumina (l X 8 cm, Woelm Activity I, dry packed) and eluted with hexane; 2 ml frac- tions were then collected while the eluting solvent was gradually (over 20 ml) changed to chloroform—hexane (1:1), which was used for the rest of the separation. Fractions 13—15 contained the trans-diacetate (vide infra); the cis- isomer was eluted in fractions l7-25. These fractions were combined and freed of solvent to give 19 mg (E§° 69%) of 103 as a colorless oil, containing a trace (92° 2%) of an unknown contaminant (gc on column A, 200°). The spec- tral data obtained on this sample of 10% were as follows: ir (neat): 3.27, 3.92, 5.72, 6.19 (weak), 7.30, 8.09, 9.73, and 12.7lu, among others; nmr (6, CClu): 6.20-5.82 (3H, m), 5.67 (1H, broad d, J = 6 Hz), 5.15-H.7H (2H, two broad multiplets), 3.4-2.6 (NH, m), 2.28-l.u8 (MH, series of m), 2.02 (3H, s), 1.87 (3H, s). The material was purified by preparative gc (column C, 210°) prior to mass spectral analysis, to remove the small impurity present, ms: m/e 276 (very weak, E§° 0.03%), 261 (very weak, SE- 0.01%), 234 (3g. 0.3%), 206 (1%), 192 (2%), 17H (9%), 156 (26%), 195 91 (20%) and H3 (100%), inter alia. The compound was un- stable forming a tough clear resin on standing, and was not analyzed. The nmr spectrum is shown in Figure A7. Trans-6, -diacetoxytricyclo[7.3.0.01“12 ]dodeca-2,10- giggg (10% or 105). The diol mixture (51 mg, 0.266 mmole) obtained by chromatography of the distillation residues was dissolved in dry pyridine (H ml) and treated with acetic anhydride (1 m1). Heating and workup of this reaction fol- lowed the procedure just given for the gig-isomer. The crude product, 67 mg, contained 33. 30% gig—diacetate 10%, ca. 60% of the trans-isomer, and 22' 10% of four minor pro- ducts. Chromatography of this material in the manner des- cribed above afforded the trans-isomer (28 mg) as a soft solid, mp 86.5-88.5° after washing the cold hexane. Re- crystallization from hexane raised the mp to 88-89.8°. The spectral data for this compound show it to be a trans-isomer (10% or 105) of the gig-diacetate 103: ir (Nujol): 5.73, 8.00, 9.71, 12.50 and 13.07u, among others; nmr (6, CClu): 5.97 (MH, nearly degenerate AB pattern), 5.62 (2H, broad t, J = 93' H.5 Hz), 3.4H-2.83 (UH, m), 2.05-1.67 (HH, m), 1.90 (6H, 8); ms: m/e 276 (very weak), 261 (very weak), 234 (9%), 216 (1%), 192 (5%), 179 (93%), 156 (35%), 91 (35%) and H3 (100%). The nmr spectrum is reproduced in Figure A8. Cis-g,l-dihydroxytricyclo[7.3.0.OQ’IZJdodeca-2,_gediene dimethanesulfonate 102. Diol 98 (192 mg, 1.0 mmole) was dissolved in 8 m1 dry pyridine and redistilled methanesulfonyl 146 chloride (0.78 ml, S-fold excess) added with cooling. The mixture was allowed to stand at room temperature for 2 hr, then poured into 20 ml of ice and water. This mixture was extracted four times with 5 ml portions of chloroform, and the chloroform layers washed with cold 5% aqueous sodium hydroxide (3 x 5 ml), cold 5% hydrochloric acid (2 x 10 ml), 5% aqueous sodium bicarbonate (10 m1) and saturated sodium chloride (10 ml). The chloroform layer was then filtered and the solvent removed on the rotary evaporator to give 285 mg of crude dimesylate 102 as a colorless oil, which partly solidified on standing. Recrystallization from chloroform-hexane (or benzene-hexane) gave hard, white wedge-like plates, mp 99.5-101° (dec). The quantity of crystalline 10% obtained was 215 mg (62%). The spectral data on this crystalline material support the structure (and stereochemistry) assigned: ir (Nujol): strong bands at 7.52, 8.53, 11.17, and 12.65u and many weak bands; nmr (5, CDC13): 6.15 (1H, d of d, J = 6 Hz, J' = 2.2 Hz), 6.01 (2H, broad s, Avl/2 = E§° 2.5 Hz), 5.74 (1H, broad d, J = 6 Hz), 5.14-4.78 (2H, m), 3.46-2.65 (4H, m), 3.08 (3H, s), 3.03 (3H, s), 2.56-1.60 (4H, series of m); ms: m/e 348 (4%), 307 (6%), 279 (5%), 252 (15%), 173 (23%), 167 (33%), 156 (63%), 149 (100%), 141 (38%), 129 (47%), 117 (45%), 115 (40%), 91 (86%), 79 (45%), 77 (34%), 57 (44%), 55 (44%), 43 (44%), 41 (65%), 39 (34%), inter alia. The nmr spectrum is shown in Figure A9. The recrystallized dimesylate 10% appears to be unstable 147 even at —35°. After two weeks at that temperature, the melting point had increased to 103.5-106° (dec). Distillation of Tricyclododecadienediol 98 from Alumina. Alumina for dehydration was prepared according to von Rud- loff78 by adding 2% pyridine (by weight) to Woelm neutral alumina, Activity 1, and allowing the stoppered mixture to stand for several days. Diol 98 (50 mg) was adsorbed onto 1 g of this alumina by evaporation of an ether solu— tion, and the residue pyrolyzed at l70-220° at atmospheric pressure. A kugelrohr distillation apparatus was used for this distillation. The distillate,a yellow oil with a pronounced olefin-like odor, weighed 31 mg. Analysis of this material (column A, 150°) showed it to contain 93. 75% one component; the ir spectrum showed a strong band at 5.90u, suggesting ketone 110. This assignment was subse- quently confirmed by the isolation and characterization of this same product from the t—butoxide elimination of mesyl- ate 102. A very minor component (9a. 2%) of this mixture showed a retention time comparable to 1,5,9-cyclododecatriene on several columns (column A, 150°; column D, 130°). Tricyclo[7.3.0.0“’12]dodeca-2,§,Z,lQ-tetraene 22 and Tricyclof7.3.0.0”’12]dodeca-2,lg-diene-§-one 110. Potas- sium t—butoxide elimination of dimesylate 10%. Potassium t—butoxide was prepared by refluxing a large excess of :- butanol (distilled from calcium hydride) with potassium. The excess t-butanol was removed by bulb-to-bulb distilla- tion, and the residue sublimed at 170°/0.01 mm. The 148 sublimed potassium t—butoxide was stored under nitrogen in sealed glass ampoules until use. Dimesylate 102 (107 mg, 0.308 mmole) was added in one portion to a stirred solution of potassium tfbutoxide (0.72 g, E§° lO—fold excess) in dry dimethylsulfoxide (5 ml). The flask was stoppered tightly and kept at room temperature for 1 hr, and 60—70° for a second hr. The cooled mixture was then poured into 10 m1 of cold water and extracted with purified pentane (4 X 10 ml). The combined pentane extracts were washed once with water (10 ml) and most of the pentane removed on the rotary evaporator at a bath temperature of 5-10°. The last of the pentane was removed at 33. -10° (ice-acetone bath) with a stream of dry nitro- gen. The residue (52 mg) was a yellow oil with a strong olefin— like odor. Analysis of this material (column A, 150°) showed it to be a complex mixture containing at least six compon- ents. The component of shortest retention time (32. 15% of the mixture) showed a retention time comparable to 1,5,9- cyclodecatriene on several columns (column A, 150°; column C, 150°; column D, 130°). The major component (93. 30%) which was eluted last on QF-l (column A) was identical with the major product from the attempted alumina dehydra- tion. This mixture was analyzed further by gc-ms, programming the column temperature from 72° upwards at 8°/min, and the mass spectra of the first and last components eluted 149 determined. These showed parent ions at m/e 156 and 174, respectively, in accord with the structures 2% and 110. More complete mass spectra are given below. Tetraene 22 was isolated by chromatography of the mixture on alumina (0.4 x 4 cm dry packed, basic, Activity 1) with pentane as eluent; 0.5 ml fractions were collected. The first fraction was only pentane, but the second and third contained 22, contaminated with traces of other com— pounds. Removal of the solvent gave 4.5 mg of 22 of 23° 85% purity (23' 8% yield). This material, a soft white solid which sublimed at fairly low temperatures (SO-60°), exhibited the following properties: ir (neat): 3.31, 3.37, 3.45, 6.09 (weak), 6.20 (weak), 6.90 (weak), 7.45, 7.60, 9.17, 10.26, 10.91, 12.02, 12.50, 12.82, 12.99, 13.10, 13.70 and 14.0u; nmr (6, CS2): 6.02-5.03 (8H, complex), 3.21 (4H, broad s). This spectrum is shown on Figure 7. The mass spectrum, determined in the gc-ms experiment, showed the following peaks: m/e 156 (10%), 155 (18%), 153 (10%), 141 (16%), 128 (22%), 115 (28%), 91 (100%), 78 (25%), 77 (12%), 65 (8%), 63 (11%). Ketone 110 was obtained by elution of the column with chloroform-pentane (1:1) after the tetraene 22 had been eluted. Fraction 4 so obtained contained a variety of com- ponents and was not investigated further. Fraction 5 con- tained ketone 110 in ca 90% purity; fraction 6 was rich in 110 (22° 60%) but was discarded. Removal of the solvent from fraction 5 gave 10.3 mg of 110 of 90% purity (17% yield) 150 as a pale yellow waxy solid which decomposed (and sublimed) at temperatures above 100°. This material had an odor containing both olefin—like and camphor-like elements; the unpleasant olefin odor was the stronger. Spectral data obtained on this material support structure 110: ir (neat): 3.20, 3.44, 5.90, 12.66 and 13.87u, ingp Elia; nmr (6, CClu): 6.09-5.75 (4H, m), 3.5-3.23 (2H, m), 3.17-2.78 (2H, m), 2.76-1.73 (6H, complex). The mass spectrum, from the gc— ms experiment, showed the following ions: m/e 174 (19%), 146 (8%), 145 (21%), 131 (20%), 128 (17%), 117 (91%), 115 (49%), 104 (33%), 91 (100%), 79, 78, 77 (each about 60%), 65 (43%). Determination pf Temperature Dependence 9f the amp Spectrum pf 22. The nmr spectrum of the sample 2% prepared above was recorded at 100 MHz in tetrachloroethylene solu— tion at several temperatures between 35° and 141°. The solution of 2% was degassed and sealed under vacuum. Ethyl- ene glycol was used for temperature calibration. The nmr Spectra so obtained were independent of the sample tempera- ture; with only very minor differences, the 141° spectrum was superimposable on the 35° spectrum. LIST OF REFERENCES 10. 11. 151 REFERENCES L. F. Fieser and M. F. 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APPENDIX APPENDIX Included here are the proton nmr spectra of the key intermediates in this synthesis, and of several other com— pounds where the spectra permit stereochemical assignments. All of these spectra were recorded on a Varian T-60 spectrom— eter at 60 MHz (500 Hz sweep width) in the solvents indicated. 158 159 Figure A1 Proton NMR Spectrum (60 MHz) of Cis,exo—3,7-dibromo-2,2,6,6-bis(ethylenedioxy)- bicyclo[3.3.0]octane 59a 1150 ~< wgacwm I .lst oi 0.. OJ ad 0.0 0.? Ail. a u u - IE 1 u q u I d u HI I .. .... ...II I..III0 III III. II.|III.II.I I J u d 1 HI _.I- 1 . . . . . u . . . ¢ . . . ~ , . . . . . . I -.. - II I II. - II I I4. IIII .. .-. I I I . ...,I . I I I . ~ n _ . .. , _ u u N .7 n. . . I I - I I. II} I III . I III). II II....|II| I I . . I.| . I III. . . . , . m. . - . I. . ... . . - . w .1 _ . I . I I . . I I. . u M I I I I - IIIIIIiIII I I-IIIII ...I.--.IIII -III.I-II-I..II II . III I- ...I . v I h I I I I .. . . I l e . I I I a. I I I _ n — u. m: .: . . . t I- I I If-’ '1': l l.‘ 0 III ‘3: 0 I'l'-|l| .. . . . . . - I. . . .-. . - I n I I I . .r I . I . . . - _ . - I. I n. I -. .I. .II. III I L . I . I ,.II I I. III . . II I. t I. I .I I _ I . . I . .- -- II... ..1!. III- - I. I ...u I - In. I . I ”I: .ImHlIII .II. . I- a I II I I "I I I 'I l‘l I - . . I . - . .. I I. I I . - . . . .. I u I v I I I I I I .I I.III ...... II. III IIIIIIIIILIFIIIPII IIHIIII I. . . III I I.I IF I! III.II I - I.II I .... II . . . III II II II!I'II IIIII|III l I II. II I.-. II I .5. II I I 7' III II I III-..II . o ...l. I I I I . n I I I I-IIIII IIIII — I- I .. I .. - . I - I ,I . . p I. H . ... , I H .u I . . I -I I.III . - I I ... I - _ I .II I . I v , . I z... . . - . ... . II..I.. -.., . . -. “I II. . I. n, . .7. -.I..IIII..II I. II..- In..II.. I- - I, . I I - .I .l I I! III I .III-III .’ I.IIIII -IIIII IlIII..I II.) II I||.I.-II-I I I ...IIII. . .I. I II IIIII I.. I I I I II .I I. III nI . I- . - :MI I -H p . . . . . 7.- I. I I- . I ..- I.. I . . IIw.II . . .. I. u... I . - In. I- . .0” .I . -. . -I.I. u I I.I. - .IIII. m....--. I . . I «I- I- --- III - . o. .. - . .. - - I . H, . I . ...u... .. ”-n- -. . . T .. - I . . , I I . I II - I- In . .- I I- I .nHIIII .. II II.» 453' I.II.II- In...:.II. ..I- I. --I IwIHIui-Iu.Iu..I- .I..I..Iu. . .. 1.- - -m.» a ,h . .-.m..-ImmI...r. . ..- . - ..OIIII . ,I . . . Ow. - I I --I.I...I .I.III .I .I 9.? .HI ,I I- I. MIMI“ I . .I... H ”II. I IIIHI-... ..lIIIJHII II:..IHIH.|IH.I.I.IH.II.IIHI.”IIIIHI..I.II.I....lnuI- I .- . - -.. - .-n-..L-IwII.I . :III.;.-- .II III::.I:--II:I-I-IIIIIII.II1I.- I .- .I- I.(.I-I I- u- .- I .I II; .I...I -I I (.....II-I.I . I IIIII ' III. .. n" DON. "Innflnw 161 Figure A2 Proton NMR Spectrum (60 MHz) of Trans—3,7—dibromo—2,2,6,6-bis(ethylenedioxy)- bicyclo[3.3.0]octane égk ~< Pic—ml o 0.. oi od 9.. A o . it °.n oi 0.x 0.. 162 IMIII I I III I II I .l I II .. II I“- I III m 5.: r _. .I VIII I|I I HIII...uI. I.I .Iél I.IIIuI. I I . I hru I I I H II II. III. III...|I r. . .IIuHILIHI HHII — 163 Figure A3 Proton NMR Spectrum (60 MHz) of Cis,endo—2,6-dihydroxybicycloE3.3.0]octa— 3,7-diene kg 164 m< 0L3: PM o .... o.« oi. oi . . .Izt .... o... cg od 1 I I I I I 165 Figure AH Proton NMR Spectrum (60 MHz) of Cis,endo-bicyclo[3.3.0]oota—3,7-diene- 2,6-diacetic Acid, Diethyl Ester zz 166 ¢< szcrn— AIA .|,.....|II|.r||...|I||I 167 Figure A5 Proton NMR Spectrum (60 MHZ) of 6,7—Bis(trimethylsiloxy)tricyclo[7.3.0.0u’12J- dodeca-2,6,10-triene #3 168 m.< 9:6: I 3 fl . .ltt 0.. o... 169 Figure A6 Proton NMR Spectrum (60 MHZ) of H,l2 Tricyclo[7.3.0.0 ]dodeca-2,10—diene— 6,7-cis-diol 2% 170 w< 0.5:: o6 fl . .Ilzt a.“ o6 as ... .. I|I.I.|— I ”III II. ..l..II.I .—....I.. ,I I. .,4I.. ...I .—. .II . ...II. _ . . q a. — 171 Figure A7 Proton NMR Spectrum (60 MHz) of Cis-6,7-diacetoxytricyclo[7.3.0.0u’121- dodeca-2,lO-diene 1Q; 172 2 misc I oi 1 . .lst . . o; o.- 173 Figure A8 Proton NMR Spectrum (60 MHz) of Trans-6,7-diacetoxytricyclo[7.3.0.0u’12]- dodeca-2,lO-diene 174 AA- A. ‘- AIA 0.0 II * d _ I I! II III IonIoIIIOI‘l. ..ou. 96”}... d m< ”LDC wh' 0.. a n . s: q — d 4 u d II |o ‘ I.-"!!Il. ‘ ..I.‘._.' .. III I lull I III I. ' III lull... I t 0 II- I- III IO|.I lulull .l I III! II I I o II III I I l- l.ll I ' II . I..: 0 I III . ill 0 I‘ll-l I I I. .IIIIII O \ .9. I.IIIIII‘I I I. III III II I .- .. II III II'I- II: a Il‘l' I' I .ll II I. I '1 l. l I «I .l s I II .I'III .l l I I ->.o--- -.- on . ...—_-..——--I- ~" 175 Figure A9 Proton NMR Spectrum (60 MHz) of 4,12 Cis—6,7-dihydroxytricycloE7.3.0.0 ]dodeca- 2,lO-diene Dimethanesulfonate 19% 176 m< mtacwu .WEEQM- , N: 03 ..__,. .1” V.