MFR-.113 LIBRARY Michigan State University 'I‘hisistocertifythatthe (fimwflnfionenfiflai 4 12 PART I. An Approach to Tricyclo[7.3.0.0 ’ Dodeca-2,5,7,10-Tetraene PART II. An Approach to Dodecahedrane PART III. Lithium Bromide-Lithium Diethylamide Induced Rearrangment of Epoxides pmmmfialby ]_ Peter Yain-Tain Gur hasbanumxzpmdtummflsfiufiflnmmt of the requirements f0: Ph.D. degreein Chemistry 4.105% Major professor Date May 6, 1987 MS U 'u an Affirmative Action/Equal Opportunity Institution 0- 12771 MSU LIBRARIES ——. 5 RETURNING MATERIALS: Place in book drop to remove this checkout from your record. FINES will be charged if book is returned after the date stamped below. PART I. AN APPROACH To TRICYCLO[7.3.0.O4'12]DODECA- 2,5,7,10-TETRAENE PART II. AN APPROACH TO DODECAHEDRANE PART III. LITHIUM BROMIDE-LITHIUM DIETHYLAMIDE INDUCED REARRANGEMENT OF EPOXIDES BY Peter Yain-Tain Gur A DISSERTATION Submitted to _ Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1987 ABSTRACT PART I. AN APPROACH TO TRICYCLO[7.3.O.O4'12]DODECA- 2,5,7,10-TETRAENE PART II . AN APPROACH TO 0003mm PART III. LITHIUM BROMIDE-LITHIUM DIETHYIAHIDE INDUCED REARRANGEHENT OP EPOXIDBS BY Peter Yain-Tain Gur 4’lz]dodeca-2,5,7,10-tetraene has Tricyclo[7.3.0.0 been made in low yield. It is predicted to undergo a series of structurally degenerate Cope rearrangements. Alternate syntheses through the key intermediate tricyclo[7.3.o.o4'12 ]dodeca-2,6,10-triene using sulfide contraction/elimination, titanium-induced intramolecular dicarbonyl-coupling, or big-ylide autoxidation, were unsuccessful. Dodecahedrane is a carbon representative of the five Platonic solids. Cis,endo-2,6-bi§(iodomethyl)bicyclo- [3.3.0]octa-3,7-diene and cis,egdo-2,6-bis- Peter Yain-Tain Gur (mercaptomethyl)bicyclo[3.3.0]octa-3,7—diene were synthesized, corresponding to two halves of dodecahedrane. However, coupling of the diiodide with dithiol could not be achieved. The rearrangement of gig-cyclooctene oxide with lithium bromide-lithium diethylamide gave a higher yield than with lithium diethylamide alone. The ratio of gi§,gngQ-bicyclo[3.3.0]octan-2-ol, the major product, to 2-cyclooctenol was also increased. The generality of this effect of lithium bromide was examined with some other epoxides. In most cases added lithium bromide improved the yield and purity of the final product. To My Parents and to My Wife, Phoebe Wei-Tsu, for Their Love and Understanding ii ACKNOWLEDGMENTS The author wishes to express his deepest appreciation to Professor Donald G. Farnum for his support and guidance during the pursuit of my degree. Appreciation is extended to Professor Chang Chi-Kwong who served as second reader. I also thank the remainder of my committee for their interest and suggestions concerning this work. Thanks are extended to Miss Tonya Acre and my colleagues for their friendship and many helpful discussions during the past years. Finally, The author would like to thank Michigan State University for a teaching assistantship and M. S. U. Synthesis Laboratory for financial support. iii Chapter LIST OF LIST OF PART I. TABLE OF CONTENTS TABLESOOOCOOOOOOOOOOOOO ..... O ..... O... ...... FIGURESOOOOOOOOOOOOOOOOOOO000...... ......... AN APPROACH TO TRICYCLO[7.3.O.O4'12]- DODECA-2’5’7’lo-TEMENE................... INTRODUCTION.OOOOOOOOOOOOOOOOOOOOO. OOOOOOOOOOOOOOOO 0 RESULTS AND DISCUSSIONOOCOOOCOOO00.... OOOOOOOOOOOOOO 1. 2. 3. 4. EXPERIMENTAL...OOOOOOOOOCOOOOO ..... O. OOOOOOOOOOOOOOO GeneraIOOOOOOOOOOOOOOOOOCOOO0......0.. ......... O 4-Thiatricyclo[8.3.0.0 The Fate of the Sulfide Contraction/ Elimination Approach.................. ...... The Fate of the Titanium-Induced Intramolecular Dicarbonyl-Coupling ReactionOOOOOOOOOOOOOOOO0.0.0.0....0.0.00.0. The Fate of the fiig-Ylide Autoxidation...... Reduction of Dienedione 18 and Oxidation of the Epimeric Dienediol 19.. .............. 7'111trideca- 8,12-diene 3. Reaction of Dibromoethyl- diene 11 with Sodium Sulfide...... .............. gig, n o-2,6-b;§(hydroxyethyl)bicyclo- [3.3.0]octa-3,7-diene Dimethanesulfonate 13...0....0.0000000000000000C000...... .......... Qis,ggg_-2,6-bi§(iodoethyl)bicyclo- [303.010Cta-3'7-diene 14000000000000 oooooooooooo Qis,gngQ-2,6-bis(chloroethyl)bicyclo- [3.3.0]Octa-3,7-diene 15. Reaction of Biol 7 with Carbon Tetrachloride/ Triphenylphosphine................ .............. iv 13 15 17 19 19 20 21 22 23 Chapter Page Reaction of Dimesylate 13 with Sodium su1fideoooooooooooooooooo oooooooo co ooooooooooooo 24 Reaction of Diiodide 14 with Sodium su1fide0000000.000.00.00...000...... 000000000000 24 §1§,gngQ-bicyclo[3.3.0]octa-3,7- diene-2,6-diaceta1dehyde 8. Aliphatic Claisen Rearrangement of Vinyl Ether 16 with Diethylaluminum Chloride/ Triphenylphosphine..................... ......... 25 Oxidation of g1§,gngQ-2,6-dihydroxy- ethylbicyclo[3.3.0]octa-3,7-diene 7 with Pyridinium Chlorochromate.... .............. 25 Oxidation of 91§,gngg-2,6-dihydroxy- ethylbicyclo[3.3.0]octa-3,7-diene 7 with Pyridinium Dichlorochromate...... ..... ..... 26 Titanium-Induced Reductive Coupling of DialdehYde 80.0.0000000000000000......O...0.00.0 27 91s. sage-2 . 6-Pis( 2-triPheny1- phosphoniumethyl)bicyclo[3.3.0]octa- 3,7-diene dibromide 17........... ............... 27 Approach to Tricyclo[7.3.0.04’12]- dodeca-2,6,10-triene 4.......... ........... ..... 23 Pyridinium Chlorochromate Oxidation of the Epimeric Dienediols 19 and 20.... ........... 29 Pyridinium Dichromate Oxidation of the Epimeric Dienediols 19 and 20.. ............. 3o gi§,gngg-2,6-dihydroxybicyclo- [1.3.0]octa-3,7-diene 19. Reduction of dienedione 18 with Cerous Chloride Mediated Sodium Borohydride..................... 31 PART II. AN APPROACH TO DODECAHEDRANE .............. 32 INTRODUCTION............ ........... . ................ 33 RESULTS AND DISCUSSION................. ............. 42 The Fate of The Coupling Reactions.... ...... .... 42 Chapter Page EXPERIMENTAL. C C O O O C O O O OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO 47 General.........OOOOOOCOCOOO ...... O 0000000000000 47 Qis.ende-2.6-bis(bromomethyl)- bicyclo[3.3.0]octa-3,7-diene 38. Reaction of Diol 37 with Carbon Tetrabromide/Triphenylphosphine ................. 48 Qis.enQ2-2.6-Pis(hydroxymethyl)- bicyclo[3.3.0]octa-3,7-diene Dimethanesulfonate 43............... ....... ..... 49 'l _,/ Qis,endQ-2,6-b1§(iodomethyl)- bicyclo[3.3.0]octa-3,7-diene 42... ........... ... 50 Qi§,endo-2,6-b1§(amidinothio)- methylbicyclo[3.3.0]Octa-3,7-diene Dimethanesulfonate 44. The Addition of Thiourea to Dimesylate 43........ ............ 50 91§,gnQQ-2,6-bi§(mercaptomethyl)- bicyclo[3.3.0]octa-3,7-diene 39. Hydrolysis of fiig-thiouronium DimeSYIate 440.000.00.00000000000 OOOOOOOOOOOOOOO 51 The Coupling Reaction of Diiodide 42 and DithiOI 39.00.00.000000000000000. ....... O... 52 5,9 3-Thia-tricyclo[6.3.0.0 Jundecane 51. Reaction of §1§,gndQ-2,6-b1§- (bromomethyl)bicyclo[3.3.0]octane 48....... ..... 53 PART III. LITHIUM BROMIDE-LITHIUM DIETHYLAMIDE INDUCED REARRANGEMENT OF EPOXIDES........ 55 INTRODUCTION............. ........................... 56 RESULTS AND DISCUSSION..... ......... .. .............. 59 EXPERIMENTAL.......................... .............. 69 General............................ ....... I ...... 69 General Procedure for Base—Promoted Rearrangements.......OOOOOOOOOOOO0......O ....... 70 Rearrangement of Cis-Cyclooctene Oxide 52 ....... 70 vi Chapter Page a) with five equiv of lithium bromide ......... 70 b) without lithium bromide..... ...... .. ....... 71 c) with half equiv of lithium bromide. ........ 72 d) with one and one quarter equiv of lithium bromide................... ......... 72 e) with two equiv of lithium bromide .......... 72 f) with two & half equiv of lithium bromide... 72 g) with ten equiv of lithium bromide.......... 72 h) with five equiv Of lithium perchlorate ..... 73 i) with five equiv of tetrabutylammonium bromide ......... ......OOOOOOOOOO ........... 73 Rearrangement of 3,4-Epoxycyclooctene 59........ 73 Rearrangement of Cyclopentene Oxide 62 .......... 74 Rearrangement Of -Pinene Oxide 65 .............. 74 Rearrangement of Cyclohexene Oxide 55........... 75 Rearrangement of 1,2-Epoxy-5,9-cyclododecadiene 67 and Hydrogenation of its Products............ 75 Rearrangement of egg-2,3-Epoxy-norbornane 72.... 77 Preparation of Cycloheptene Oxide 74 ......... ... 77 Rearrangement of Cycloheptene Oxide 74 in Ether. 78 Rearrangement of Cycloheptene Oxide 74 in Benzene. ...... .... .................. 79 Rearrangement of 1,2-Epoxy-5-hexene 78..... ..... 79 Rearrangement of 1,2-Epoxyhexane 83.. ........... 80 APPENDIX.... ................. . ...................... 81 REFERENCES .................. ... ........ . ............ 96 vii Table LIST OF TABLES Page Synthesis of Sulfides...................... 12 LiBr-LiN(C2 Induced H5’2 Rearrangement of Epoxide 52................ 59 LiClO4-L1N(C2H5)2 or (n-C4H9)4NBr- LiN(C2H5)2 Induced Rearrangement of Epoxide 52.............................. 60 viii Figure A1 A2 A3 A4 LIST OF FIGURES Page Proposed route to 4 from 3....... ........... 7 The Platonic solids : (top) tetrahedron, cube, dodecahedron, (bottom) octahedron, icosahedron................................. 33 1§_gggpg_du_rgi--The King's Cut...... ....... 36 The Linear Approach to 21 by Paquette ....... 37 41 is a Biogenetic-like Precursor of 21................ ....... ..... ........... 41 Proton NMR spectrum (CDClB, 60 MHz) Of gi§,eng-2,6-91§(hydroxyethyl)bicyclo- [3.3.0]octa-3,7-diene Dimethanesulfonate 13.. ........ .. ........... 82 Proton NMR spectrum (CDC13, 60 MHz) of §i§,gndQ-2,6-bi§(iodoethyl)bicyclo- [3.3.0]octa-3,7-diene 14......... ........... 84 Proton NMR spectrum (CDC13, 60 MHz) of Cis,endQ-2,6-bis(chloroethyl)bicyclo- [3.3.0]octa-3,7-diene 15.................... 86 Proton NMR Spectrum (CDCl 60 MHz) of 3' §i§,end_-2,6-bi§(bromomethy1)bicyclo- [3.3.0]octa-3,7-diene 38.... ........ . ....... 88 ix Figure A5 A6 A7 Page Proton NMR spectrum (CDCl3, 60 MHz) of Q1§,gngQ-2,6-_1§(mercaptomethyl)- bicyclo[3.3.0]—octa-3,7-diene 39 ...... . ..... 90 Proton NMR spectrum (CDC13, 60 MHz) of Qi§,§ndQ-2,6-bi§(iodomethyl)bicyclo- [3.3.0]octa-3,7-diene 42............ ........ 92 Proton NMR spectrum (CDClB, 60 MHz) of gi§,gngg-2,6-b1§(hydroxymethyl)- bicyclo[3.3.0]octa-3,7-diene Dimethanesulfonate 43 ...... . ................ 94 PART I. All APPROACH TO TRICYCIO[7.3.O.O4'12]DODECA- 2,5,7,10-TETRARNE INTRODUCTION 4'121dodeca-2,5,7,lo-tetraene 1 was Tricyclo[7.3.0.0 synthesized in 1974 by Hagadorn and Farnum1 in order to test the Cope rearrangement theory. The Cope rearrangement,2 shown below, has been 3 extensively studied. It is a suprafacial [W2+02+,2] concerted reaction which proceeds through a cyclic complex.4 2 2 3 \ 1 3 / 1 /\ ¢————— . : : m E‘. ...: 4 ’//’ 6 4 ‘\\‘ 5 \\<3?/’ 5 5 2 2 3 1 1 3 /// /// --//--> or 6 ‘\\\ 4 4 \\\ 6 5 5 Tetraene 1 contains two 1,5-hexadiene units, so it is predicted to undergo a series of structurally degenerate Cope rearrangements. gm =69 The degenerate Cope rearrangement might be detected from the proton NMR spectrum. Thus, at low temperature, if the rate of equilibration of 1 is slow enough, the spectrum would consist of eight olefinic protons and four allylic protons. If the temperature is raised and the rate of equilibration increases sufficiently, it is predicted that four of the olefinic protons would remain unchanged in respect to their chemical shift, while the remaining eight protons (markedv) would coalesce. / However, the nmr spectrum of 1 was unchanged from 350 to 1410. Therefore, the Cope rearrangement of 1 is slow on the nmr time scale. This slow rate is probably due to the absence of a small ring and its accompanying strain. The goal of this project was to explore an alternate synthesis in order to obtain sufficient material easily, and to use another method to study the kinetics and mechanism of the Cope rearrangement. Our strategy for the synthesis Of 1 is outlined below: Br 5 Cyclization of dihalide 2 with sodium sulfide might afford sulfide 3. Ring contraction of 3 via a Stevens rearrangement,5 followed by Hofmann elimination6 might yield triene 4. Treatment Of 4 with NBS might give halide 5. Removal of the halide in 5 with a base might produce 1. Triene 4 might also be produced by another way: HO OHC 7 8 Treatment of dihalide 2 with triphenyl phosphine might produce his ylide 6. Cyclization of 6 through an autoxidation process might afford triene 4. Oxidation of dialcohol 7 might afford dialdehyde 8. Coupling Of 8 with titanium (III) chloride might also give triene 4. Since the Cope rearrangement of 1 is slow on the nmr time scale, racemization studies might provide information on the rate. Thus, treatment of racemic 1 with an Optically active complexing agent, such as Cope's platinum complex 9,7 might lead to complete formation of the more stable (or less soluble) diastereomeric complex. Repeated crystallization of the diastereomeric Pt complexes 10 might give the Optically pure 1: [PtC12(C2H4)(+)-CGR CHZCH(CH3)NH2] + racemic 1 9 5 --> [PtC12(1)(+)-C6H CHZCH(CH3)NH2] + C H 5 2 4 10 10 + 4 KCN --> optically pure 1 + Kth(CN)4 + 2 KCl + (+)-C6H SCHZCH(CH3)NH2 As shown below, each Cope rearrangement converts the starting molecule into its enantiomer, so the Cope rearrangement could be observed by monitoring the loss of Optically activity in the initially resolved 1: D fl/K/g :: G\$ 1(R) 1(8) RESULTS AND DISCUSSION 4'121dodeca-2,6,1O-triene 4 was the Tricyclo[7.3.0.0 key intermediate in our approach toward 1. Therefore, firstly we concentrated our effect to produce 4. 1. The Fate of the Sulfide Contraction/Elimination Approadh Triene 4 might be produced by treating dibromide 11 with sodium sulfide, then eliminating the sulfide in 3 (Figure 2). 4. - Br Na S09}! 0 (M60) 2CHBF I 2 2 4 ’ EtOH ‘ NaH CO --------- > ----------- > ; S (Ref.8) Brr‘ 11 3 CHBI s K+O-C489 s ....... > I SCH3 THF (Ref.9) 4 Figure 1. Proposed route to 4 from 3. 10 3: Mirmohammad had reported the preparation of sulfide Succcessful synthesis albeit in low yield (1%). of sulfide rings via cyclization of dibromide normally requires high dilution conditions. Br Br 0 C C(CH2)88r Na S (CH2)BBr (CH2)SBr Na S EtOH 43% 2 Alumina ¥ I NaZS EtOH 23% Some examples are shown below: S (Reference 11) (Reference 12) (Reference 13) We modified Mirmohammad's procedure and treated dibromide 11 with sodium sulfide in absolute ethanol in concentrated solution.14 After twenty hours the reaction was complete and gave a mixture. The major product was a white solid, identified as sulfide dimer 12 (74% yield, m.p. 110-1120). The minor product was the wanted sulfide 3 (18% yield) which was a yellow Oil. We believed that 12 was two isomers. r“ :0: + s «no ion» ...: O. b 10 Because the yield of sulfide 3 from dibromide 11 was very low, we synthesized other dihalides and treated them with sodium sulfide in the hope of producing higher yield of sulfide 3. Treatment of diol 7 with mesyl Chloride in pyridine15 gave a 90% yield of the dimesylate 13, which slowly solidified on standing. Exposure of this material to sodium iodide in refluxing acetone provided diiodide 14 in 54% yield after chromatography. OH CH3SOZC1 OMS .1 , .—-’ ’ Pyridine I I ’ r o t o ' 2 h ' l“ {—4 HO 90% M50 7 13 NaI I ' ..J Acetone reflux, 18 h I H 54% I 14 11 Biol 7 was converted to the dichloride 15 by reacted with triphenylphosphine/carbon tetrachloride.16 After flash chromatography, dichloride 15 was Obtained as a yellow Oil in 52% yield. OH Ph P, CC14 Cl ...! 3 ,—-J ' CH3CN I, rote; 3 h " f- f"- H0 52% Cl 7 15 However, reaction of dimesylate 13 with sodium sulfide still gave sulfide 3 in low yield (22%). There was no trace of sulfide dimer 12. OMs Na28°9H20 0...] EtOH *; I r.t., 22 h 5 M50 22% 13 3 Reaction of diiodide 14 with sodium sulfide gave a mixture. The major product still was sulfide dimer 12 (81%, m.p. 95-97 0), and the minor product was the desired sulfide 3 (15%). 12 I Na S°9H O ..J 2 2 ' EtOH ' rote, 6 h I 96% 14 3 12 The results of cyclization are summarized in Table Table 1. Synthesis of Sulfides Reactant Product Yield, % (ratio) Dibromide 11 Sulfide 3 & 92 (1 o. b V Sulfide dimer 12 Diiodide 14 Sulfide 3 & 96 (1 UI b Sulfide dimer 12 13 2. The Fate of the Titanium-Induced Intramolecular Dicarbonyl-Coupling Reaction Intramolecular couplings of dicarbonyl compounds have been Obtained by the McMurry reagent17, TiCl3-Zn-Cu, as shown in the following examples: 0 O TiCl3,Zn-Cu R R. II II \ / RC CR' ; (Czc 3 (CH2)n (CH2)n n = 2-14, 20 Yield 3 65-90% TiCl3 ,Zn- Cu f I><;i\/kN/\/k\ (Ref. 19) CHO TiC13,Zn-Cu /// —: (Ref. 18) 40% (CH)4CHO TiCl3 ,ZR-Cu 0cm eye (Ref. 20) \__J 24% 14 Since there are relatively few other methods of carbocyclic ring synthesis, this titanium-induced coupling reaction might be useful for our synthesis. Dialdehyde 8 was produced from vinyl ether 16 by 1 EtzAlCl-PPh3 in methylene chloride2 in 53% yield. For comparison, 8 was also prepared from diol 7 by pyridinium 22 Chlorochromate, CSHSNHCrO3C1, in 49% yield, and pyridinium dichromate,23 (CSHSNH‘I‘)2Cr207-'2 in 50% yield. 0 4/ Et2A1C1-PPh3 CH0 0 CH2C12 r.t. 0.5 h O J ' o; 16 53% OHC 8 OH PCC, AcONa . CH2C12 4; 8 ' r.t., 2 h r HO 7 49% PDC, CHZCI2 r.t., 24 h 7 ; 8 50% 15 However intramolecular coupling of dialdehyde 8 by TiCl3-Zn-Cu, did not work: neither the starting material, nor the desired product was found. We only got elimination products. CHO '__ ' TiCl:3 , Zn-Cu 6 ----- //----—> OHC 8 4 3. The Fate of the nigrYlide Antoxidation Cycloolefins can be Obtained by autoxidation of pig(alkylidenephosphoranes).24 CH=P(C6H5)3 CH (c?2)n + O2 > (CH2)n I + 2 OP(C6H5)3 CH=P(C6H5)3 CH n = 3,4,5 Yield : 58-61% Treatment of dibromide 11 with triphenylphosphine in a sealed tube afforded the 2,6-bistriphenylphosphonium bromide 17 in 91% yield. 16 + - Br Ph3P, CH3CN PPhBBr r—/ ..l ’ Sealed tube ’ . 100°, 24 h ’ f—J r" Br 11 91% -BrPh P+ 17 gig-ylide 6 was produced by adding 17 dropwise into a NaH/DMSO base solution. Passing the oxygen gas through the solution, however, did not afford any trace of the desired triene 4. DMSO, NaH I O 17 > ————//-———> Although we tried many methods such as cyclization with sodium sulfide, intramolecular coupling with McMurry reagent TiCl3-Zn-Cu, and autoxidation of is- ylide, triene 4 was never realized. 17 4. Reduction of Dienedione 18 and Oxidation of the Epileric Dienediol 19 Dienedione 18 was our starting material.la Reduction of 18 by cerous chloride mediated with sodium borohydride25 gave dienediols 19 and 20 in 35% yield. 0 CeC13°6H20 OH OH CH OH ' / NaBH4, 3 W + r.t., 5 min . - O 35% HO H0 18 19 20 However, Mirmohammad found at 00 this reaction gave a mixture in 100% yield, and the ratio of 19 : 20 was 5 : 1 (GLC analysis). After crystallization from acetone, 19 was isolated in 78% yield.10 The residual Oil from the crystallization of 19 still contained a certain amount Of 19 and 20, and could be recycled to 18. Oxidation Of the residual Oil with PCC in methylene chloride afforded 18 in 35% yield. PCC, NaOAC CH2C12 Residual Oil Of 19 and 20 18 ‘7 r.t., 2 h 35% 18 Oxidation of the residual oil with PDC in methylene chloride afforded 18 in 36% yield. PDC, CH2C12 4A sieves Residual Oil of 19 and 20 V 18 r.t., 24 h 36% The recycled 18 was a white solid and pure enough to use in the next step. EXPERIMENTAL General. Melting points were measured in open capillaries with a Thomas-Hoover apparatus and are uncorrected. Proton nuclear magnetic resonance (H NMR) spectra were obtained on Varian T-60 or Bruker WM-250 spectrometers at 60 MHz and 250 MHz, respectively. Chemical shifts are reported in parts per million downfield from tetramethylsilane internal standard. Infrared spectra (IR) were measured on a Perkin-Elmer 137 spectrometer and a Perkin-Elmer 599 spectrometer, and were calibrated with the polystyrene 1601 cm-1 peak. Mass spectra (MS) were obtained on a Finnigan 4000 instrument with ionizing voltage of 70eV, or, when noted, with ionized methane (CI). Gas liquid chromatography (GLC) was performed on an F 8 M model 700 chromatograph equipped with a thermal conductivity detector. Component ratios were determined by a comparison of peak areas (determined by triangulation) and are uncorrected for detector response. Columns used for analysis were 6' x 1/4" _aluminum columns packed with the following stationary phased on Chromosorb G (acid and base washed and silanized, 60/80 mesh): column A, 5% Carbowax 20 M: column B, 4% QF-l: column C, 3% SE-30. Thin layer chromatograms (TLC) were run on Machery-Nagel Polygram SIL G/UV 254 precoated 0.25 mm silica gel plates, and were 19 20 developed with either iodine vapor, or an anisaldehyde spray reagent, or identified under UV light. Flash column chromatography was accomplished with either Watman LPS-2 (37-53 um) or EM 9385 (40-63 um) silica gel. Normal column chromatography was performed on EM reagents silica gel 60, 70-230 mesh (EM Cat. #7734) rated at activity 2- 3. Unless otherwise noted, reagents and solvents were reagent grade materials and were used as received. Ether and THF were dried by distillation from sodium or potassium benzophenone ketyl. Diisopropylamine, DMSO and UHF were dried by distillation from calcium hydride. g- Butyllithium was Obtained from Aldrich as a 2.6 M solution in hexane, and was titrated according to the method Of Watson and Eastham.26 7'11]trideca-8,12-diene 3. 4-Thiatricyclo[8.3.0.0 Reaction of dibronoethyldiene 11 with sodiun.su1fide. Dibromoethyldiene 11 (1.37 g, 4.3 mmol) dissolved in 21 mL of absolute ethanol was stirred with sodium sulfide (Na28-9H20, 2.06 g, 8.6 mmol) at room temperature for 20 hours. Then, the solution was diluted with 50 mL of distilled water. The aqueous solution was extracted with pentane (2 x 50 mL). The organic phase was washed with saturated aqueous NaCl solution (1 x 10 mL), and dried over anhydrous NaZSO4. Removal of solvent left a purple 21 oil (0.166 g) with a somewhat sharp sulfur containing smell. A substantial amount of sulfide dimer 12 remained in the aqueous phase as a white solid (1.065 g), and it was collected by suction filtration. The crude Oil and white solid were combined and flash chromatographed on a 1 cm diameter column containing silica gel (20 g, Whatman LPS-2) pack with 4% ethyl acetate/hexane. Elution of the column led to sulfide 3 (0.146 g, 17.6%) and sulfide dimer 12 (0.621 g, 74.5%, m.p. 110-1120). The spectral properties of both materials were identical to those reported earlier.10 Elfingnggrz,6€h1§(hydroxyethyl)bicyclo[3.3.0]octa-3,7- diene Dimethanesulfonate 13. 0101 7 (0.97 g, 0.005 mol) was dissolved in dry pyridine (10 mL) in a 25 mL round bottom flask, and cooled to 0°C. Methanesulfonyl chloride (3.9 mL, 0.05 mol, previously distilled (b.p. 54.5-550C/10 mm)), was added to the stirred solution. The reaction was stirred for 2 h, and then poured onto ice. Extraction with chloroform (2 x 10 mL) was followed by multiple extractions of the combined organic phase with cold 5% NaOH (3 x 10 mL), cold 1 M HCl (4 x 10 mL), saturated NaHCO3 (1 x 10 mL), and saturated NaCl solution (1 x 10 mL). The extract was dried over M9804 and the solvent removed to afford dimesylate 13 (1.57 g, 90%) as a brown Oil which solidified on standing. This material 22 was not Characterized or purified further, but was used directly in the next step. A 1H NMR of this material (CDC13, 60 MHz) was as follows: 65.15 (4H, s), 4.38 (4H, d, J=7 Hz), 3.60-3.40 (4H, m), 3.05 (6H, s), 2.30-1.70 (4H, m): MS m/e 350 (M+, 0.06%), 254 (5.94%), 158 (55.94%), 143 (58.39%), 130 (67.9%), 79 (100%). ,Q1§,gnggr2,67bi§(iodoethyl)bicyclo[3.3.0]octa-3,7- diene 14. To a solution of crude dimesylate 13 (1.40 g, 4.0 mmol) in acetone (18 mL) was added sodium iodide (1.80 g, 12 mmol). The reaction was refluxed with stirring for 16 h, after which time an additional portion Of sodium iodide (0.45 g) was added and refluxing continued for an additional 6 h. The reaction was cooled, filtered free of precipitated salt, and the solvent removed under reduced pressure. The brown residue was taken up in ether (150 mL) and washed with saturated sodium sulfite (2 x 20 mL) and saturated NaCl solution (20 mL). The organic phase was dried over MgSO4 and the solvent removed to give crude diiodide 14 as a brown oil. Flash chromatography on silica gel packed with 3% ethyl acetate/hexane yielded diiodide 14 (0.90 g, 54%, m.p. 63-650) as a white solid. The spectral .characteristics were as follows: 1H NMR (CDC13, 60 MHz) 65.58 (4H, s), 3.40-3.05 (4H, t, J=10 Hz), 3.04-2.40 (4H, m), 2.10-1.70 (4H, m): MS m/e 415 (n+1, 1.23%), 414 (M+, 23 12.55%), 287 (36.44%), 259 (47.26%), 155 (24.09%), 131 (37.71%), 117 (55.05%), 91 (100%). §1§,gng9r2,6-h1§(chloroethyl)bicyclo[3.3.0]octa-3,7- diene 15. Reaction of 0101 7 with Carbon Tetrachloride/ Triphenylphosphine. Diol 7 (0.97 g, 5 mmol) was dissolved in acetonitrile (100 mL) in a 250 mL three necked flask equipped with a good magnetic stir bar, a condenser with a drying tube, a thermometer, and a stopper. Carbon tetrachloride (10 mL) was added, and the solution stirred until it was all in solution. Triphenylphosphine (1.45 g, 5.5 mmol) was then added all at once, causing the reaction to warm up to 40°C. The solution immediately became a dark red, and was refluxed for 3 h. The flask was then cooled to room temperature and 10 mL of pentane was added to precipitate the bulk of the triphenylphosphine oxide. The solution was filtered through celite packed in a fritted funnel, and the filtered precipitate washed thoroughly with cold pentane. The solvent was removed under reduced pressure and the remaining Oil was flash chromatographed on silica gel (Whatman) packed with hexane. The dichloride 15 (0.58 g, 52%) was isolated as a yellow oil with the following spectral properties: 1 H NMR (C0C13, 6o MHz)65.58 (4H, s), 3.46 (6H, t), 3.20-2.60 (2H, m), 2.05-1.80 (4H, m): MS m/e 231 (M+, 0.65%), 195 (35.16%), 167 (31.11%), 159 24 (14.27%), 153 (37.08%), 131 (100%). Reaction of Dimesylate 13 with Sodium, Sulfide. Dimesylate 13 (1.05 g, 3.0 mmol) dissolved in absolute ethanol (15 mL) was stirred with sodium sulfide (Na28-9H20, 1.44 g, 6.0 mmol) at room temperature for 22 h. Then, the solution was added with H20 (15 mL), and extracted with pentane (2 x 10 mL). The combined organic layer was washed with distilled H20 (10 mL) and saturated NaCl (10 mL), then was dried over MgSO4. Removal of solvent with the rotovap yielded sulfide 3 (0.13 g, 22.5%) as a pink oil. The spectral properties of the material were identical to those reported earlier.10 Reaction of Diiodide 14 with Sodium Sulfide. Diiodide 14 (0.414 g, 1 mmol) suspended in absolute ethanol (25 mL) was stirred with sodium sulfide (Nazs-9H O, 0.48 g, 2 2.0 mmol) at room temperature for 6 h. Then, the solution was diluted with distilled H20 (50 mL), and extracted with pentane (2 x 50 mL). The combined organic layer was washed with distilled H20 (20 mL), saturated NaCl (20 mL), and dried over MgSO4. Removal of solvent with the rotovap yielded sulfide 3 (0.028 g, 14.6%) as a pink Oil. Suction filtration of the aqueous product mixture yielded sulfide dimer 12 as a white solid (0.156 g, 81.3%, m.p. 95-970). The spectral properties of 25 both materials were identical to those reported earlier.10 §fl§,gn§9rbicyclo[3.3.0]octa-3,7-diene-2,6- diacetaldehyde 8. Aliphatic Claisen Rearrangement of Vinyl Ether 16 with Diethylaluminum Chloride] Triphenylphosphine. A solution of diethylaluminum chloride (25 wt% (1.8 M) solution in toluene, 2.2 mL, 4.0 mmol) was added to a solution of triphenylphosphine (1.16 g, 4.4 mmol) in methylene chloride (7.8 mL) at room temperature under nitrogen and the whole reaction was stirred for 15 min. Vinyl ether 16 (0.38 g, 2 mmol) in methylene chloride (5 mL) was added to the solution and stirred for another 30 min. The mixture was diluted with ether (30 mL) and poured into 1 N HCl (15 mL). The organic layer was washed with saturated sodium chloride (10 mL), dried over M9804, and concentrated with the rotovap. The residue (0.282 g) was purified by flash chromatography on 20 g silica gel packed in 33% ethyl acetate/hexane. Dialdehyde 8 was Obtained as a clear, colorless oil (0.20 g, 53%). The spectral properties of this material were identical to those reported earlier.1a Oxidation of ,§1§,§n§9r2,6-dihydroxyethy1bicyclo— [3.3.0]octa-3,7-diene 7 with Pyridinium.Chlorochromate. A 25 mL round bottomed flask was fitted with a reflux 26 condenser. Pyridinium Chlorochromate (0.646 g, 3 mmol, 1.5 eq.) and sodium acetate (0.049 g, 0.6 mmol, 0.3 eq.) was suspended in methylene chloride (2.6 mL). Dienediol 7 (0.194 g, 1.0 mmol) in methylene chloride (2.6 mL) was added in one portion to the magnetically stirred solution. After 2 h ether (10 mL) was added and the supernatant decanted from the black gum. The insoluble residue was washed thoroughly with ether (3 x 5 mL) whereupon it became a black granular solid. The combined organic solution was passed through a short pad of Florisil, and was washed with 5% aqueous NaHCO (15 mL) 3 and saturated NaCl (15 mL). The organic solution was dried over MgSO4 and concentrated at the rotovap. The residue was purified by flash chromatography packed in 33% ethyl acetate/hexane and afforded dialdehyde 8 (0.094 g, 49%) as a colorless Oil. The spectral properties of this material were identical to those reported earlier.1a Oxidation of .§1§,gnggrz,6-dihydroxyethylbicyclo— [3.3.0]octa-3,7-diene 7 with Pyridinium.Didhlorochronate. Diol 7 (0.388 g, 2 mmol) was dissolved in methylene chloride (5.6 mL). Pyridinium dichlorochromate (2.26 g, 6 mmol) was added in one portion. The solution was stirred at room temperature for 24 h, then diluted with ether (25 mL). The supernatant was decanted, the residue was washed with ether (3 x 25 mL), and the combined 27 solution was washed with saturated NaI-ICO3 (3 x 10 mL) and saturated NaCl (10 mL). The extract was dried over MgSO4 and the solvent removed to afford a yellow Oil. The crude oil was purified by flash chromatography packed in 33% ethyl acetate/hexane and afforded dialdehyde 8 (0.187 g, 50%) as a clear oil. The spectral properties of this material were identical to those reported earlier.1a Titaniu-rInduced Reductive Coupling of Dialdehyde 8. The Zn-Cu couple was prepared from zinc dust and CuSO4 following the procedure of McMurry.18 A stirred slurry of TiCl3 (1.03 g, 6.7 mmol) and Zn-Cu (1.0 g, 15.4 mmol) in 1,2—dimethoxyethane (20 mL) was refluxed under nitrogen for 1 h. Dialdehyde 8 (0.171 g, 0.90 mmol) in 1,2- dimethoxyethane (20 mL) was added through an addition funnel over 3 h, followed by a further 24 h period of reflux. The reaction mixture was then cooled to room temperature and filtered through a Florisil pad. Concentration at the rotorvap gave only 1,2- dimethoxyethane. Neither starting material nor product was found in the solvent. 4§1§,gnggr2,67915(2-tripheny1phosphoniunethyl)- bicyclo[3.3.0]octa-3,7-diene dibromide 17. Bi - bromoethyldiene 11 (0.24 g, 0.75 mmol) was dissolved in acetonitrile (10 mL) in a glass tube. Triphenylphosphine 28 (0.49 g, 1.88 mmol, 1.12 eq.) was added into the mixture and the glass tube was sealed under vacuum. After heating in an autoclave for 24 h, the glass tube was cooled and Opened, and the bloody red solution was taken up in chloroform (30 mL). By addition of ether, a heavy red precipitate was formed. The mixture was filtered by suction filtration. The amorphous red precipitate (0.57 g, 91%), was washed several times with ether. Its decomposition point was 205-2350C. The spectral properties of this material were identical to those reported earlier.10 4'12]dodeca-2,6,10-triene Approadh to Tricyclo[7.3.0.0 4. Sodium hydride (0.054 g, in 50% mineral Oil, 1.125 mmol) was weighed out in a dry 250 mL three necked flask. A magnetic stirrer, addition funnel, nitrogen inlet adapter, reflux condenser and thermometer were fitted to the flask, and a nitrogen atmosphere established. The sodium hydride was washed free of mineral Oil with pentane (3 x 20 mL), and then suspended in dry DMSO (50 0 mL). The mixture was heated at 70-80 C for 45 min, then cooled in an ice bath. Big-phosphoniumbromidediene 17 (0.45 g, 0.53 mmol) in DMSO (20 mL) was added dropwise, and rinsed in with DMSO (5 mL). The mixture was heated to 50°C, and oxygen (dried over P205, conc. H2504 and KOH) passed through a bubbler in the solution at 50°C for 29 three days. The deep red color of the solution turned gradually to deep brown and then lighter brown. The solution was poured into distilled H20 (50 mL) and extracted with pentane (3 x 75 mL). The combined organic layer was washed with 1 : 1 HZO-DMSO (100 mL), distilled H20 (100 mL) and dried over MgSO4. Removal of solvent left a clear solution, whose proton NMR showed only the DMSO proton absorptions. Since the residue contained material other than the expected triene, the experiment was repeated at room temperature for four days. The deep red color of the solution turned to deep brown after one day and then light brown after four days. The result was similar to the above experiment. Pyridinium Chlorochromate Oxidation of the Epileric Dienediols 19 and 20. In a 250 mL round bottomed flask fitted with a reflux condenser was suspended pyridinium Chlorochromate (16.15 g, 75 mmol) and sodium acetate (1.23 g, 15 mmol) in methylene chloride (100 mL). The residual dienediols from crystallization of 19 (6.9 g) in methylene chloride (10 mL) was added in one portion to the magnetically stirred solution. After 2 hours dry ether (100mL) was added and the supernatant decanted from the black gum. The insoluble residue was washed thoroughly with ether (3 x 25 mL) whereupon it became a 30 black granular solid. The combined organic solution was passed thorough a short pad Of Florisil, and was washed with 5% NaOH (2 x 10 mL), 5% HCl (2 x 10 mL), 5% NaHCO3 (10 mL), and saturated NaCl (10 mL). Removal of the solvent gave a thick brown residue, which was sublimed (using a kugglrgh; apparatus) to give 18 as a white solid (2.36 g, 35.2%, m.p. 77-790). The spectral properties of this material were identical to those reported earlier.1a Pyridinium. Dichromate Oxidation of the Epineric Dienediols 19 and 20. The residue diols 19 and 20 from crystallization of 19 (4.14 g,) was dissolved into methylene chloride (85 mL). Pyridinium dichromate (33.84 g) and 4A molecular sieves were added into the solution. After stirring at room temperature for 24 hours the solution was diluted with ether (170 mL) and the supernatant decanted. The residue was washed with ether (3 x 170 mL), and the combined organic solution was filtered through a small amount of silica gel in order to remove last traces of Cr species. Then, the organic solution was washed with 5% NaOH (2 x 10 mL), 5% HCl (2 x 10 mL), 5% NaHCO3 (10 mL), and saturated NaCl (10 mL). Removal of the solvent gave brown needles, which was sublimed (using a kugglrghr apparatus) to give 18 as a white solid (1.44 g, 35.8%, m.p. 77-790). The spectral properties of this material were identical to those 31 reported earlier.la ‘91:,gnggr2,6-dihydroxybicyclo[3.3.0]octa-3,7-diene 19. Reduction of dienedione 18 with Cerous Chloride Mediated Sodium Bordhydride. Dienedione 18 (1.34 g, 10 mmol) was dissolved in a 0.4M CeCl3-6H20 methanol solution (25 mL, 10 mmol) in a 100 mL erlenmeyer flask and NaBH4 (0.378 g, 10 mmol) was added within five minutes with stirring. The mixture was allowed to react at room temperature for thirty minutes. Water (10 mL) was added to the flask and the mixture was stirred for five more minutes. The aqueous solution was extracted with chloroform (2 x 25 mL). The combined organic solution was washed with water (10 mL), saturated aqueous NaCl (10 mL), and dried over Na2S04. Removal Of solvent left a yellow Oil which was recrystallized from acetone (10 mL) to give dienediol 19 as a white solid (0.477 g, 34.6%, m.p. 92-930). The spectral properties of the material were identical to those reported earlier.1a PART II . AN APPROACH TO DODECAHEDRANE 32 INTRODUCTION Dodecahedrane 21 was realized by Paquette in 27'28 Plato wrote in Timaeus "... of the earth 1983. arising from the cubane, fire from the tetrahedrane, air from the octahedrane, water from the icosahedrane, and the sphere of the universe from the dodecahedrane" (Figure 2). For the organic chemist, it is a great challenge to translate the Platonic solids into real molecules.29 Q .0 O CO 0*...0... Figure 2. The Platonic solids : (top) tetrahedron, cube, dodecahedron, (bottom) octahedron, icosahedron. 33 34 Indeed, Maier succeeded in 1978 in preparing tetra- tert-butyl tetrahedrane 22,30’31 and Schleyer prepared tetralithiotetrahedrane 23.32 t-Bu Li _t_-Bu 4> t-Bu Li 4} Li t-Bu Li 22 23 33 Cubane 24 was achieved by Eaton as early as 1964, and the perfluorooctamethylcubane 25 was obtained by Miller34 in 1976. 4' (“3’3 .1 I L.-. O 24 25 , 35 36 In the 1960 s, Woodward and many other groups began to pursue 21. However, octahedrane and icosahedrane are excluded because they exceed the valence of carbon. Dodecahedrane 21 is a highly symmetric and rigid 1H and 13 molecule. The C NMR of 21 (in CDC13) are characterized by singlets, the former atM63.38 and the latter at 66.93 ppm. Although 21 is very rigid, the 35 angle strain is minimal. Dodecahedrane 21 and all other above moleculars are achiral molecules, but 21 can be bisected into two isomeric homochiral halves. This kind Of disection is called lg coupe g0 :91, the King's cut, (Figure 3).37 21 is cut halfway from the top, then perpendicularly out another halfway from the bottom. Two horizontal quarter-cuts give two homochiral halves which have an identical absolute stereochemical configuration. However, a left-handed segment and a right-handed segment cannot be reassembled to form an apple. To synthesize 21 is a tough task, because it requires placing twenty identical methine units, thirty C-C bonds, and twelve five-membered rings together properly. Besides, each of the thirty ring fusions must be gig and syn to one another. The strategy to synthesize 21 can be divided into the linear approach and the convergent approach. Paquette has synthesized 21 by a linear approach (figure 4).28 The domino Diels-Alder reaction Of 9,10- dihydrofulvalene 26 with dimethyl acetylene dicarboxylate provided the cornerstone intermediate 27, in which fourteen carbon atoms were already installed into proper position. For the next step, he introduced the remaining six carbon atoms. The so-called closed dilactone 28 contained all requisite twenty carbon 37 atoms and had twelve of the all-important gig-locked methine stereocenters properly installed. Treatment of 28 with methanolic hydrogen chloride provided dichloro diester 29. Firstly, he shelved 29 for about 30 months while he pursued other aspects. Lately, however, 29 was shown to be a pivotal intermediate. Finally, 21 was realized in twenty-three steps. Q + MeOOC-CEC-COOMe ---> III Figure 4. The Linear Approach of 21 by Paquette. 38 For the convergent approach, dodecahedrane 21 has been pursed by dimerizing of triquinacene 30,38 coupling of peristylane 31 with a five-membered ring,39 and dimerizing of bivalvane 32.40 2 1 ====> 39 Recently, Roberts completed 33 from dibromide 34 and dimercaptan 35.41 His target molecule is the doubly annelated dodecahedrane 36. Br Br ? I‘ ....> (n, ‘20:, () n—2,3 We are interested in the convergent synthesis, because it will take fewer steps to realize 21. Diol 37 was available in our labratories. Following Monego's model study, we might couple 38 and 39 together to give 40.42 40 ----> 41 Treatment of 41 with a small, cationic species,43 such as H+, or Li+, might give a stable inclusion compound of 21. 41 21 has four isoprene units, and 41 is a biogenetic-like precursor (Fig. 5).44 Connecting two bicyclo[3.3.0]Octa-3,7—diene fragments Of the dodecahedrane framework by two trans double bond bridges will give 41. 21 41 Figure 5. 41 is a Biogenetic-like Precursor of 21. RESUDTS AND DISCUSSIONS The Fate of The Coupling Reactions Our immediate goal of this project was to synthesize hexaene 41. Based upon Monego's model study, we could easily make dibromide 38 and dithiol 39. Thus, treatment of diol 37 with triphenylphosphine/ carbon tetrabromide in THF gave dibromide 38 in 50% yield. However, 38 was easily decomposed and hard to purify. Therefore, we decided to make another compound such as diiodide 42 to replace dibromide 38. Br OH PPhB, CBr4 2’ ' THF .' rote, 2 hr ' 2’ /’ H0 50% Br 37 38 Treatment of diol 37 with mesyl chloride in pyridine afforded dimesylate 43 in 95% yield. Treatment of 43 with sodium iodide in refluxing acetone gave diiodide 42 in 53% yield after chromatography. 42 43 OH CH 80 Cl OMs / 3 2 K I Pyridine ' , 00, 2 hr / O H0 95% M50 / 37 43 NaI I /’ Acetone ‘ reflux, 18 hr } z’ 53% I 42 Now, we have succeeded in producing one half segment Of 21. We needed to make the other half segment. The reaction of dimesylate 43 with thiourea in 95% ethanol afforded the pig-thiouronium mesylate 44 in quantitative yield. Alkaline hydrolysis of 44 followed by acidification gave dithiol 39 in 80% yield. NH2 OMs (NH2)2CS SC=NH2+ / / -... ' 95% EtOH ' 0 ' 100 , 18 hr HZN / I MsO 100% +H2N=Cs” Ms- 43 44 44 1) NaOH, reflux SH 2) H+ . 80% 39 It's time to do the coupling reaction. However, we never succeeded. A 1:1 mixture of diiodide 42 (<0.1M) and dithiol 39 (<0.1M) in benzene was added dropwise over 72 hours to 2.5 molar equivalents of potassium hydroxide in 95% ethanol buffered with 4 equivalent of phenol under 41 The reaction was nitrogen at room temperature. monitored by GC every twelve hours. However, we only recovered some starting materials and got some decomposed compounds. If we increased temperature, we only got I SH KOH ‘ 95% EtOH Phenol \. \C I HS r.t., 72 hr 42 39 45 45 46 elimination products, such as 45 and 46. We changed the base from potassium hydroxide to potassium hydride, the solvent from benzene and 95% ethanol to DMF, and even the starting material from diiodide 42 to dimesylate 43. However, when we ran this coupling reaction again and again, we still could not get sulfide dimer 40. In Monego's model study, the target molecule was sulfide dimer 47. However, coupling of dibromide 48 with dithiol 49 gave disulfide 50 in 1% yield. There was no trace of sulfide 47. Br SH ./ ./ so + co s / / Br HS 48 49 47 46 Ce CO DMF 48 + 49 W 95 1% 50 Curiously, we treated dibromide 48 with sodium sulfide. If the product was the sulfide dimer 47, we would use sodium sulfide in our project to approach dodecahedrane 21. Unfortunately, the product was sulfide 51. NaZS°9H20 . 48 > 29 h, r.t. S 83% 51 EXPERIMENTAL General. Melting points were measured in Open capillaries with a Thomas-Hoover apparatus and are uncorrected. Proton nuclear magnetic resonance (H NMR) spectra were obtained on Varian T-60 or Bruker WM-250 spectrometers at 60 MHz and 250 MHz, respectively. Chemical shifts are reported in parts per million downfield from tetramethylsilane internal standard. Infrared spectra (IR) were measured on a Perkin-Elmer 599 spectrometer, and were calibrated with the polystyrene 1601 cm.1 peak. Mass spectra (M8) were Obtained on a Finnigan 4000 instrument with an ionizing voltage of 70 eV. Gas liquid chromatography (GLC) was performed on a Hewlett Packard 5880 instrument. Thin layer chromatograms (TLC) were run on Machery-Nagel Polygram SIL G/UV254 precoated 0.25 mm silica gel plates, and were developed with either iodine vapor, or an anisaldehyde spray reagent, or identified under UV light. Flash column chromatography was accomplished with Watman LPS-2 silica gel. Normal column chromatography was performed on EM reagents silica gel 60. Unless otherwise noted, reagents and solvents were reagent grade materials and were used as received. Ether, THF and benzene were dried by distillation from 47 48 sodium or potassium benzophenone ketyl. DMF was dried by distillation from calcium hydride. n-Butyllithium was Obtained from Aldrich as a 2.6 M solution in hexane, and was titrated according to the method Of Watson and Eastham.26 §i§,§ndQ-2,6¢bi§(bromomethyl)bicyclo[3.3.0]octa-3,7- diene 38. Reaction of Biol 37 with Carbon Tetrabromide/ Triphenylphosphine. D101 37 (0.51 g, 3.1 mmol) was dissolved in THF (20 mL) in a 50 mL three necked flask equipped with a magnetic stir bar, thermometer, stopper and under a nitrogen atmosphere. Carbon tetrabromide (4.13 g, 12.4 mmol, 2 eq.) was added, and the solution stirred until it was all dissolved. Triphenylphosphine (3.27 g, 12.4 mmol, 2 eq.) was added all at once, causing the reaction to warm up to 500. The solution immediately became a dark red, and began to turn brown as triphenylphosphine oxide precipitated. After stirring at room temperature for 2 hr, the solution was filtered through a fritted funnel, and the filtered precipitate washed thoroughly with hexane. The TLC of this mixture indicated that it contained carbon tetrabromide which is visible on TLC only under UV light, the dibromide 38, and triphenylphosphine oxide. The solvent was removed under reduced pressure. The remaining product was flash chromatographed on silica gel packed with hexane. When 49 carbon tetrabromide and triphenylphosphine oxide were no longer detected in the eluate, the solvent was changed to 20% ethyl acetate/hexane whereupon the dibromide 38 eluted and was isolated as a very pale yellow liquid (0.45 g, 50.2%). Dibromide 38 was very unstable and decomposed into a dark green solution at room temperature on standing. Dibromide 38 had the following properties: 1H NMR (CDCl3, 60 MHz) 65.70 (4H, q), 3.60-3.00 (4H, d), 2.10-1.85 (4H, m); MS m/e 294 (M+2, 1.12%), 292 (M+, 2.30%), 290 (M-2, 1.44%), 131 (82.11%), 117 (52.11%), 91 (100%), 55 (57.52%), 39 (89.07%). §i§,endo2,6ebig(hydroxynethyl)bicyclo[3.3.0]octa-3,7- diene Dimethanesulfonate 43. Biol 37 (0.102 g, 0.614 mmol) was dissolved in dry pyridine (10 mL) in a 25 mL round bottom flask, and cooled to 00. Methanesulfonyl Chloride (0.5 mL, 6.4 mmol) previously distilled (b.p. 54.5-550/10 mm), was added to the stirred solution. The reaction was stirred for 2 h, and then poured onto ice. Extraction with chloroform (2 x 10 mL) was followed by multiple extractions of the combined organic phases with cold 5% NaOH (3 x 10 mL), cold 1 M HCl (4 x 10 mL), saturated NaI-ICO3 (10 mL), and saturated NaCl (10 mL). The extraction was dried over M980 and the solvent 4 removed to afford dimesylate (0.190 g, 95%) as a brown Oil which solidified on standing. A 1H NMR of this 50 material (CDC13, 60 MHz) was as follows: 65.70 (4H, q), 4.20 (4H, d), 3.70-3.20 (4H, m), 3.00 (6H, s). §1§,gn§Q-2,6-hi§(iodo-ethyl)bicyclo[3.3.0]octa-3,7- diene 42. To a solution of crude dimesylate 39 (1.26 g, 4.0 mmol) in acetone (18 mL) was added sodium iodide (1.80 g, 12 mmol). The reaction was refluxed with stirring for 16 h, after which time an additional portion of sodium iodide (0.45 g) was added and refluxing continued for an additional 6 h. The reaction was cooled, filtered free of precipitated salt, and the solvent removed under reduced pressure. The brown residue was taken up in ether (150 mL) and washed with saturated sodium sulfite (2 x 20 mL) and saturated NaCl solution (20 mL). The organic phase was dried over MgSO4 and the solvent removed to give crude diiodide 42 as a brown oil. The crude product was recrystallized from pentane to give diiodide 42 (0.90 g, 53%, m.p. 61-640) as a white solid. The spectral characteristics were as follows: 1H NMR (CDClB, 60 MHz) 65.85-5.40 (4H, q), 3.60-2.50 (12H, m): MS m/e 386 (M+, 1.77%), 259 (29.31%), 181 (6.09%), 132 (80.23%), 117 (63.99%), 91 (86.6%), 39 (100%). g1§,engQ-2,6-bi§(amidinothio)methylbicyclo[3.3.0]- octa-3,7-diene Dimethanesulfonate 44. The Addition of 51 Thiourea to Dimesylate 43. Dimesylate 43 (0.161 g, 0.5 mmol) and thiourea (0.114 g, 1.5 mmol, 50% excess) were placed in a screw-capped reaction tube, and 95% ethanol added (1.7 mL, i.e., to make the solution 0.3 M in dimesylate). The tube was filled with nitrogen gas, tightly capped and heated on a steam bath for 18 h. The color of the solution became blood red. The solution was allowed to cool to room temperature, and then chilled to -150 for 4 h. The resultant solid was filtered, washed with cold ethanol, and air dried to give a yellow solid (0.227 g, 95.6%, m.p. 104-1090). §i§,gnggrz,6791§(lercaptonethyl)bicyclo[3.3.0]octa- 3,7-diene 39. BYdrolysis of gig-thiouroniun.Dimesylate 44. The crude thiouronium salt 44 from last step (0.227 g, 0.5 mmol) was placed in a 50 mL round bottom flask, and suspended in aqueous NaOH (10 mL of a 1.5 N solution). A serum cap was fitted to the flask and the suspension stirred as nitrogen was bubbled through the solution with a syringe needle (another needle served as a vent). After 5 minutes, a nitrogen purged condenser was fitted to the flask, and the whole system kept under nitrogen for the duration of the reaction. The solution was refluxed for 12 h, whereupon the suspension 0 dissolved. After cooling to 0 , the reaction was acidified to pH 1-2 with cold HCl (4 N) in the hood. The 52 mixture was transferred to a separatory funnel, and extracted with ether (2 x 20 mL). The organic phase was washed with water (2 x 10 mL), saturated aqueous NaCl (10 mL), and dried over Nazso4. Removal of solvent left a yellow oil which was then flash chromatographed on silica gel with 5% ether in hexane. Dithiol 39 was obtained as a clear colorless oil (0.076 g, 80%). Dithiol 39 had the following properties: 1H NMR (CDC13, 60 MHz) 5.60 (4H, s, two isotope satellite peakes, J = 18 Hz), 63.30 (2H, t), 3.00-2.60 (2H, m), 2.40 (4H, t), 1.20 (2H, t); MS m/e 199 (n+1, 4.34%), 198 (M+, 23.83%), 165 (38.8%), 117 (95.44%), 105 (66.71%), 91 (77.47%), 85 (100%). The Coupling Reaction of Diiodide 42 and Dithiol 39. Potassium hydroxide (0.126 g, 2.25 mmol) and phenol (0.338 g, 3.6 mmol) were dissolved in 95% ethanol (45 mL) in a 250 mL round bottom flask equipped with a magnetic stir bar, condenser, addition funnel, and nitrogen inlet. A 1:1 mixture of diiodide 42 (0.350 g, 0.9 mmol) and dithiol 39 (0.180 g, 0.9 mmol) in dry benzene (90 mL) was slowly added over a period of three days under a nitrogen atmosphere at room temperature. Then, potassium iodide was removed by filtration, and solvent removed by the rotovap. The residue was flash chromatographed on silica gel with 10% ether/pentane. Removal of solvent afforded a yellow oil (0.409 g) which contained starting material 53 42 (0.090 g, 21.8% GC yield), decomposed compound 45 (0.093 g, 23.2% GC yield) and other unidentified compounds. There was no trace of the desired sulfide dimer 40. If the base was changed from potassium hydroxide to potassium hydride and the reaction was run without phenol it gave diiodide 42 (0.031 g, 7.61% GC yield) and decomposed compound 45 (0.016 g, 3.94% GC yield). If we changed the solvents to DMF and ran the reaction without phenol, we got diiodide 42 (0.120 g, 29.2% GC yield) and decomposed compound 45 (0.049 g, 12.3% GC yield). 5’9]undecane 51. Reaction of 3-Thiatricyclo[6.3.0.0 §1§,ggggr2,6-b1§(brononethyl)bicyclo[3.3.0]octane 48. Dibromide 48 (0.148 g, 0.5 mmol) dissolved in absolute ethanol (5 mL) was stirred with sodium sulfide (Nazs-QHZO, 0.24 g, 1.0 mmol) at room temperature for 29 h. The solution was added to distilled H20 (10 mL), and extracted with pentane (2 x 25 mL). The combined organic layer was washed with distilled H20 (10 mL), saturated NaCl (10 mL), and dried over MgSO4. Removal of solvent with the rotovap yielded sulfide 51 (0.07 g, 83%) as a pale yellow oil. The spectral characteristics were as follows: 1H NMR (c0013, 60 MHz) 62.40 (4H, d), 2.38-0.90 (12H, two m centered at 2.36 and 1.50); MS m/e 169 (n+1, 54 6.36%), 168 (M+, 28.23%), 135 (100%), 121 (59.55%), 93 (53.65%), 79 (60.02%). PART III. LITHIUM BROKIDE-LITHIUHCDIETHYLNHIDE INDUCED REARRANGEHENT OF EPOXIDES 55 INTRODUCTION In a project for the MSU Synthesis Laboratory, we required 2-methylbicyclo[3.3.0]octane with cis- cyclooctene oxide 52 as the starting material. 0 Q-BULi OH —’ Cor—”Cb EtZNH 52 53 However, the yield of gndQ-gig-bicyclo[3.3.0]octan-2- 01 53 (39%) was far below the reported yield (70%).45 From the literature, Cope prepared n-butyllithium from n- butyl bromide and lithium wire, and there was a substantial amount of lithium bromide left in the solution. Our n-butyllithium was bought from Aldrich Chemical Company and was free from lithium bromide. Therefore, it seemed likely that lithium bromide influenced the reaction. A more detailed experimental study showed to be the case. The base-induced rearrangement of epoxides was first discovered by Cope,46 47-52 then extensively studied by 53-58 Crandall and Rickborn. 56 57 Generally, this rearrangement produces four kinds of products: allylic alcohols, ketones, saturated alcohols, and amino alcohols. Cope reported that treatment of gig-cyclooctene oxide 52 with lithium diethylamide45 gave gngQ-gig- bicyclo[3.3.0]octan-2-ol 53 as the major product, and a small amount of 2-cyclooctenol 54. 0 on g-BuLi 0" -—-> 00 + EtZNH 52 53 54 Bicyclic alcohol 53 was proposed to arise from a- elimination, followed by a transannular carbene insertion (eq. 1).59 Allylic alcohol 54 was proposed to arise from fi-elimination (eq. 2).60 O 0 Li 0H 52 53‘ o (‘0 a on Bu H ufiV _———> —" ‘: (eq. 2) 52 54 58 Crandall reported that reaction of cyclohexene oxide 55 with lithium diethylamide produced 2-cyclohexenol 56, cyclohexanone 57, and 2-(N,N-diethy1amino)cyclohexanol 47,56 58. Allylic alcohol 56 could be derived from fi-elimination, ketone 57 by isomerization of allylic Q-BuLi OH O HO NEt 5 + + EtzNH 55 56 57 58 alcohol 56, and amino alcohol 58 from nucleophilic ring opening. However, we found that when lithium bromide was added to the lithium diethylamide solution, the yield of the rearrangement was improved and the ratio of products was changed. RESULTS AND DISCUSSION The rearrangement of epoxide 52 was reinvestigated. Lithium bromide was suspended in 2.5 equiv of lithium diethylamide solution, and 1 equiv of epoxide 52 was added dropwise into this cold solution. The results are shown in Table II. Table II. LiBr-L1N(CZHS)2 Induced Rearrangement of Epoxide 52 ‘_EIBf__—__T5tal Yield Recovered - RaEio of (equiv) (%) 52 (%) 52 : 53 : 54 0.0 72 15 0.4 : 1 : 1 0.5 63 28 1 : 1 : l 1.25 68 23 1 : 2 : 1 2.0 74 17 1 : 4 : 1 2.5 75 16 1 : 5 : 1 5.0 90 3 0.4 : 9 : 1 10.0 80 10 l : 9 : 1 As the amount of lithium bromide was increased, the total yield was improved, the yield of the major product 53 was increased, and the yields of the minor product 54 and the recovered starting material 52 were decreased. With 5 equiv of lithium bromide added, the rearrangement of 52 gave the best result. Then we suspended 5 equiv of lithium perchlorate or tetra-n-butylammonium bromide in 2.5 equiv of 59 60 lithium diethylamide solution. The results are shown in Table III. Our purpose was to investigate the role of lithium cation and bromide anion in this reaction. The lithium cation apparently could influence the rearrangement. However, the reaction of 52 with a tetra- g-butylammonium bromide-lithium diethylamide solution only gave recovered 52, so the role of bromide anion in this reaction was not clear. Table III. LiClO -LiN(C n ) or (nee H ) unr- LiN(Czfis)2 I u Rearranaeaefit of Epoxide 52 =7 ToEanYield Recovered* Ratio of (%) 52 (%) 52 : 53 : 54 LiClO 48 42 8 3 8 3 1 (g-c4fi9)4NBr 0 95 1 : o : o Because the treatment of 52 with a cold (5 equiv) lithium bromide-(2.5 equiv) lithium diethylamide solution gave the best result, other epoxides were also treated with the same solution in order to test the generality of the reaction 3,4-Epoxycyclooctene 59 was reacted with lithium diethylamide to produce bicycloalcohol 60 (44%), cyclooctenone 61 (14%), and recovered starting material 59 (7%).48 However, with the lithium bromide-lithium diethylamide, the transformation of 59 gave exclusively 60 (60%) and a small amount of unreacted 59 (2%). 61 was not found. 61 O on 0 ——->C.+ 59 60 61 Total Yield Recovered Ratio of (%) 59 (%) 59 : 60 : 61 LiN(C H ) 58 7 1 : 6 : 2 LiBr-ii§(52H5)2 60 2 1 : 28 : o The rearrangement of cyclopentene oxide 62 with lithium diethylamide was carried out to give 2- 7 With cyclopentenol 63 (10%) and cyclopentanone 64 (2%).4 the lithium bromide-lithium diethylamide solution, however, 62 afforded 63 (22%) and 64 (1%) in higher total yield. 0 OH 0 o “7 D *0 62 63 64 Total Yield Ratio of (%) 63 : 64 LiN(C H ) 12 5 : 1 LiBr-ii§(52H5)2 23 22 : 1 The reaction of a-pinene oxide 65 with lithium diethylamide afforded allylic alcohol 66 in 91% yield.47 62 With lithium bromide-lithium diethylamide, 65 produced more 66 in 96% yield with a small amount of recovered 65 (4%). jg:::ld :§::::i O OH 65 66 Yield Recovered (%) 65 (%) LiN(C H ) 91 o LiBr-ii§(52H5)2 96 4 Treatment of cyclohexene oxide 55 with lithium diethylamide produced 2-cyclohexeno1 56 (59%), cyclohexanone 57 (2%), and 2-(N,N-diethylamino)cyclo- hexanol 58 (8%).47'56 But, with lithium bromide—lithium diethylamide, 55 gave a lower amount of major product 56 (50%) and a higher amount of by-product 58 (11%). Ketone 57 was not present. 0 on o no NBtZ 55 56 57 58 Total Yield Ratio of (%) 56 : 57 : 58 LiN(C H ) 69 7 : 0.2 : 1 LiBr-fii§(52H5)2 61 5 : o : 1 63 With lithium diethylamide, 1,2-epoxy-5,9- cyclododecadiene 67 produced a mixture of allylic alcohol 68 and unsaturated ketone 69. The starting material 67 was complete consumed. After hydrogenation on 10% Pd-C under hydrogen atmosphere, the mixture afforded cyclododecanol 70 (37%) and cyclododecanone 71 (42%). Isomerization of epoxide 67 with lithium bromide- lithium diethylamide, followed by hydrogenation, produced alcohol 70 (61%) and ketone 71 (19%). Apparently, the lithium bromide—lithium diethylamide solution increased the yield of allylic alcohol 68 and decreased the yield of unsaturated ketone 69. 0 OH 0 l1 67 68 69 OH O 3 + 10% Pd-C 70 71 64 Total Yield Ratio of (%) 70 : 71 LiN(C H ) 79 1 : 1 LiBr—ii§(52H5)2 80 3 : 1 Egg-2,3-epoxynorbornane 72 produced nortricyclanol 73 as a single product.61 With lithium diethylamide or lithium bromide-lithium diethylamide, the results were the same (55% yield). Therefore, lithium bromide had no influence upon 72. 72 73 Yield (%) LiN(C H ) 55 LiBr-ii§(52H5)2 55 The rearrangement of cycloheptene oxide 74 in ether with lithium diethylamide gave allylic alcohol 75 (20%), ketone 76 (7%), amino alcohol 77 (3%), and a lot of recovered starting material 74 (47%).47 With lithium bromide-lithium diethylamide, the starting material was complete consumed to give 75 (17%), 76 (24%), and 77 (32%). The rearrangement of cycloheptene oxide 74 with lithium diethylamide was repeated in benzene, instead of 65 ether, to give amino alcohol 77, and two minor products in 36% yield.47 There was no trace of the starting material 74. With lithium bromide-lithium diethylamide, the rearrangement of 74 in benzene gave amino alcohol 77 and two minor products in 46% yield. 0 OH O HO NEt2 74 75 76 77 Total Yield Recovered Ratio of (%) 74 (%) 74 : 75 : 76 : 77 (Ether was used as the solvent) LiN(C H ) 30 47 7 : 3 : 1 : 0.5 LiBr-£i§(0 H ) 73 0 0 : 2 : 3 : 4 .......... 2-52-2--_-__-.._-----------_-_------_----..-..--..-- (Benzene was used as the solvent) LiN(C H ) 36 0 0 : 0 : 0 : 1 LiBr-fii§(52H5)2 46 0 o : 0 : o : 1 Treatment of 1,2-epoxy-5-hexene oxide 78 with lithium 55 We did diethylamide produced a mixture in 64% yield. not separate the mixture, but the major product was quite possibly the amino alcohol 79 (26%) and the minor products were gis- and trans-1,5-decadiene 80 (23%), 1- decen-S-ol 81 (12%), and 2,5-hexa-dien-1-ol 82 (3%) based upon the spectra of GC-MS and 1H NMR of the mixture. With lithium bromide-lithium diethylamide, 78 gave 79 (50%), 80 (27%), 81 (4%), and 82 (2%). 66 OH O NEtz 4H9 \\ -—————> + + /" 2” 2” 78 79 80 OH C4H9 0H ./’ .... / / 81 82 Total Yield Ratio of (%) 79 : 80 : 81 : 82 LiN(C H ) 64 9 3 8 3 4 3 1 LiBr-Ei§(EZHS)2 83 25 : 14 : 2 : 1 Lithium diethylamide transformed 1,2-epoxyhexane 83 into a 83% yield of a mixture which was not separated. 1H NMR of the Based upon the spectra of GC-MS and mixture, the major product was probably the amino alcohol 84 (49%) and the minor products were 2-hexen-1-ol 85 (10%), 1,2-hexanediol 86 (9%), and 5-decanol 87 (15%). Lithium bromide-lithium diethylamide transformed 83 into a mixture of amino alcohol 84 (73%), 2—hexen-1-ol 85 (10%), and 5-decanol 87 (5%). O H OH 0 NEtz / 5 + + 83 84 85 OH OH OH C4H9 + 86 87 Total Yield Ratio of (%) 84 : 85 : 86 : 87 LiN(C H ) 83 5 : 1 : 1 : 2 LiBr-fii§(EZH5)2 88 7 : 1 : 0 : 0.5 Lithium bromide is a useful modification in the rearrangement of epoxides. It can improve the yield, increase the ratio of the major product, and increase the amount of bicyclic products. However, sometimes it may increase the yield of the undesired amino alcohol for simple epoxides. It can complement the use of HMPTA reported by Apparu62 which tends to inhibit the formation of bicyclic products and favor unsaturated alcohol products. The role of lithium cation in effecting these changes is confirmed by Apparu's results. 68 The lithium bromide-lithium diethylamide solution should have some synthetic potential. Bicyclo[3.3.0]oct- 7-en-engQ-2-ol 60 has served as the starting material for Whitesell's synthesis of sarracenin,63 Ikegami's 64 and Trost's synthesis of 65 synthesis of dl-coriolin, plumericin, allamcin, and allamandin. EXPERIMENTAL General. Proton nuclear magnetic resonance (NMR) spectra were obtained on Varian T-60 or Bruker WM-250 spectrometers at 60 MHz and 250 MHz, respectively. Chemical shifts are reported in parts per million downfield from tetramethylsilane internal standard. Infrared spectra (IR) were measured on a Perkin-Elmer 599 spectrometer, and were calibrated with the polystyrene 1601 cm-1 peak. Mass spectra (MS) were obtained on a Finnigan 4000 instrument with an ionizing voltage of 70 eV. Gas liquid chromatography (GLC) was performed on a Hewlett Packard 5880 instrument. The INJ TEMP was 250°, and the DET TEMP was 300°. Unless otherwise noted, reagents and solvents were reagent grade materials and were used as received. Ether and benzene were dried by distillation from sodium or potassium benzophenone ketyl. Diethyl amine was dried by distillation from lithium aluminum hydride. n- Butyllithium was obtained from Aldrich as a 2.6 M solution in hexane. Lithium bromide and lithium perchlorate were dried in a drying pistol heated with refluxing xylene under vacuum pressure. 69 70 General Procedure for Base-Promoted Rearrangements. To an ice-cold solution of 2.5 equiv of diethylamine and the required amount of lithium bromide in anhydrous ether in a three necked flask equipped with a rubber stopper, addition funnel, condenser, and nitrogen inlet was added 2.5 equiv of 2.6 M n-butyllithium in hexane under a nitrogen atmosphere. After 15 min a solution of 1 equiv of the appropriate epoxide in anhydrous ether was added and the mixture was heated to reflux for 2 days. The reaction mixture was cooled and poured into water, and the organic layer separated. .The aqueous layer was extracted with ether and the combined organic layers were washed with saturated aqueous ammonium chloride, water, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was removed from the product by distillation through a column and the residue was purified by distillation. Product identification was by comparison of spectral data with those in the literature. Rearrangement of gigrcyclooctene Oxide 52. a) with five equiv of lithium. bromide. The rearrangement of 52 was carried out as described in the general procedure. Thus, diethylamine (9.10 g, 0.125 mole) was dissolved in dry ether (100 mL) in a 500 mL three-necked flask equipped with a rubber stopper, addition funnel, condenser, and nitrogen inlet. Lithium 71 bromide (21.71 g, 0.250 mole) was suspended in the reaction mixture which was then cooled in an ice bath. 3- butyllithium (48.0 mL x 2.6 H, 0.125 mole) was added through a syringe during five minutes under a nitrogen atmosphere, and the ethereal solution was stirred for an additional fifteen minutes. A solution of gig- cyclooctene oxide 52 (6.30 g, 0.05 mole) in ether (100 mL) was added and the solution was stirred and refluxed under a nitrogen atmosphere for forty eight hours. The reaction mixture was cooled and poured into ice water (350 mL), and the organic layer was separated. The aqueous layer was extracted with ether (2 x 100 mL) and the ethereal solutions were combined and extracted with saturated ammonium chloride (4 x 75 mL) to remove diethylamine. After a final washing with water the ethereal solution was dried over magnesium sulfate and concentrated. The residue was distilled through a short path distillation unit to give a mixture (5.86 g, 93% wt. recovered). The spectral data were compared with those 45 reported before, and the distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 100o OVEN TEMP PRGM RATE lo/min OVEN TEMP FINAL VALUE 130° b) without lithiun.bronide. The rearrangement of 52 72 (6.30 g, 0.05 mole) without lithium bromide was carried out as described in the general procedure. The weight of the distilled product was 5.46 g (86.6% wt. recovered). c) with half equiv of lithium bromide. The rearrangement of 52 (6.30 g, 0.05 mole) with lithium bromide (2.17 g, 0.025 mole) was carried out as described in the general procedure. The weight of the distilled product was 5.75 g (91.2% wt. recovered). d) with one and one quarter equiv of lithium bromide. The rearrangement of 52 (6.30 g, 0.05 mole) with lithium bromide (5.43 9, 0.0625 mole) was carried out as described in the general procedure. The weight of the distilled product was 5.74 g (91.1% wt. recovered). e) with two equiv of lithium. bromide. The rearrangement of 52 (6.30 g, 0.05 mole) with lithium bromide (8.86 g, 0.200 mole) was carried out as described in the general procedure. The weight of the distilled product was 5.70 g, (90.5% wt. recovered). f) with two 8 half equiv of lithium. bromide. The rearrangement of 52 (6.30 g, 0.05 mole) with lithium bromide (10.86 g, 0.125 mole) was carried out as described in the general procedure. The weight of the distilled product was 5.71 g, (90.7% wt. recovered). g) ‘with ten equiv of lithium. bromide. The rearrangement of 52 with lithium bromide (43.42 g, 0.500 mole) was carried out as described in the general 73 procedure. The weight of the distilled product was 5.67 g, (90.0% wt. recovered). h) ‘with five equiv of lithium. perchlorate. The rearrangement of 52 with lithium perchlorate (26.60 g, 0.250 mole), in stead of lithium bromide, was carried out as described in the general procedure. The weight of the distilled product was 5.66 g, (89.8% wt. recovered). i) with five equiv of tetrabutylammonium. bromide. The rearrangement of 52 with tetrabutylammonium bromide (80.60 g, 0.250 mole), instead of lithium bromide, was carried out as described in the general procedure. The only product (5.99 g, 95.1% wt. recovered) was recovered cis-cyclooctene oxide 52. Rearrangement of 3,4-Epoxycyclooctene 59. The isomerization of 3,4-epoxycyclooctene 59 (1.24 g, 0.01 mol) in ether (70 mL) at reflux temperature for 22 hr was performed and worked up according to the general procedure. The spectral data was compared with those 48 reported before, and the distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 100o OVEN TEMP PRGM RATE lO/min OVEN TEMP FINAL VALUE 130° a) without lithium bromide. The weight of the 74 distilled product was 0.818 g, (66.0% wt. recovered). b) with five equiv of lithium bromide. The weight of the distilled product was 0.776 g, (62.6% wt. recovered). Rearrangement of Cyclopentene Oxide 62. A solution of cyclopentene oxide 62 (1.68 g, 0.02 mol) in ether (100 mL) was treated according to the general procedure. The spectral data were compared with those reported before,47 and the distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 40o OVEN PRGM RATE lo/min OVEN TEMP FINAL VALUE 60° a) without lithium. bromide. The weight of the distilled product was 0.202 g, (12.0% wt. recovered). b) with five equiv of lithium bromide. The weight of the distilled product was 0.428 g, (25.5% wt. recovered). Rearrangement of“ a-Pinene Oxide 65. The rearrangement of a-pinene oxide 65 (3.04 g, 0.02 mol) in ether (100 mL) was treated according to the general procedure. The spectral data were compared with those 47 reported before, and the product was analyzed by GLC under the following conditions: 75 OVEN TEMP INITIAL VALUE 100° OVEN TEMP PRGM RATE lo/min OVEN TEMP FINAL VALUE 1200 a) ‘without lithium. bromide. The weight of the distilled product was 2.982 g, (98.1% wt. recovered). b) with five equiv of lithium.bromide. The weight of the distilled product was 2.964 g, (97.5% wt. recovered). Rearrangement of Cycldhexene Oxide 55. The rearrangement of cyclohexene oxide 55 (1.963 g, 0.02 mol) in ether (100 mL) was treated according to the general procedure. The spectral data were compared with those 47 reported before, and the distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 100° OVEN TEMP PRGM RATE lo/min OVEN TEMP FINAL VALUE 120° a) ‘without lithium. bromide. The weight of the distilled product was 1.354 g, (69.0% wt. recovered). b) with five equiv of lithium.bromide. The weight of the distilled product was 1.197 g, (61.0% wt. recovered). Rearrangement of 1,2-Epoxy-5,9-cyclododecadiene 67 and Hydrogenation of its Products. Rearrangement of 1,2- 76 epoxy-5,9-cyclododecadiene 67 (3.56 g, 0.02 mol) in ether (100 mL) was treared according to the general procedure. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 1400 OVEN PRGM RATE lo/min OVEN TEMP FINAL VALUE 1600 a) ‘without lithium. bromide. The weight of the distilled product was 2.784 g (78.6% wt. recovered). The product (2.56 g, 14 mol) was hydrogenated with 10% Pd/C (250 mg) in 95% ethanol (150 mL) under a hydrogen atmosphere. After 36 mmol of hydrogen was consumed, the solid was filtered and the ethanol solution was added to 'water (50 mL). The aqueous solution was extracted with pentane (3 x 50 mL), and the combined organic layers were washed with water (2 x 20 mL), saturated aqueous NaCl (20 mL), and dried over MgSO4. Removal of solvent gave a white solid (2.51 g, 99%, m.p. 58-620), which was analyzed by GLC. The solid was flash chromatographied with 10% ether/pentane to give cyclododecanol 70 (R = 0.26, m.p. 59-610) and cyclododecanone 71 (R = 0.74, m.p. 75-770). The spectral data were identical with those of authentic samples Obtained from commercial source. b) with five equiv of lithium bromide. The yield of the distilled product was 2.847 g (80.0%), and the 77 product (2.56 g, 14 mol) was hydrogenated with 10% Pd/C (250 mg) in 95% ethanol (150 mL) under a hydrogen atmosphere. After 48 mmol of hydrogen was consumed, the solution was treated as above to give a solid (2.50 g, 99% wt. recovered, m.p.62-700) which was analyzed by GLC as above. Rearrangement of ngr2,3-Epoxynorbornane 72. Rearrangement of egg-2,3-epoxynorbornane 72 (2.20 g, 0.02 mol) in benzene (50 mL) was treated according to the general procedure. The spectral data were compared with 61 those reported before. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 30o OVEN PRGM RATE 250/min OVEN TEMP FINAL VALUE 250° a) without lithium. bromide. The only product was nortricyclanol 22 (1.217 g, 55.3% yield). b) with five equiv of lithium. bromide. The only product was nortricyclanol 73 (1.199 g, 54.5% yield). Preparation of cycloheptene Oxide 74. To an ice-cold mechanically stirred mixture of cycloheptene (9.61 g, 0.1 mol) and anhydrous sodium carbonate (31.8 g, 0.3 mol) in methylene chloride (90 mL) was added dropwise 8.6% 78 peracetic acid (100 g, 0.105 mol).66 The mixture was stirred at room temperature until the methylene chloride solution gave a negative test with starch-iodide paper. The solid salts were removed by suction filtration and washed well with additional methylene chloride (3 x 10 mL). The solvent was removed from the filtrate by distillation through a Vigreux column and the residue was redistilled through a short distillation unit to give cycloheptene oxide 74 as a colorless oil (5.714 g, 50.9%, b.p. 154-1560). Rearrangement of Cycloneptene Oxide 74 in Ether. The rearrangement of cycloheptene oxide 74 (2.24 g, 0.02 mol) in ether (100mL) was treated according to the general procedure. The spectral data were compared with those 47 reported before. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 350 OVEN PRGM RATE lo/min OVEN TEMP FINAL VALUE 550 a) without lithium. bromide. The weight of the distilled product was 1.298 g (77.3% wt. recovered). b) with five equiv of lithium.bromide. The weight of the distilled product was 1.622 g (72.4% wt. recovered). 79 Rearrangement of Cycldheptene Oxide 74 in Benzene. The rearrangement of cycloheptene oxide (2.24 g, 0.02 mol) in benzene (50mL) was treated according to the general procedure. The spectral data were compared with 47 those reported before. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 30° OVEN PRGM RATE lo/min OVEN TEMP FINAL VALUE 500 a) ‘without lithium. bromide. The weight of the distilled product was 0.869 g (38.8% wt. recovered). b) with five equiv of lithium bromide. The weight of the distilled product was 1.357 g (61.3% wt. recovered). Rearrangement of 1,2-Epoxy-5-hexene 78. The rearrangement of 1,2-epoxy-5-hexene 78 (1.963 g, 0.02 mol) in ether (100mL) was treated according to the general procedure. The spectral data were compared with 49 those reported before. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 35o OVEN PRGM RATE 1o°/min OVEN TEMP FINAL VALUE 200o 80 a) without lithium. bromide. The weight of the distilled product was 1.250 g (63.7% wt. recovered). b) with five equiv of lithium.bromide. The weight of the distilled product was 1.630 g (83.1% wt. recovered). Rearrangement of 1,2-Epoxyhexane 83. Rearrangement of 1,2-epoxyhexane 83 (2.00 g, 0.02 mol) in ether (100 mL) was treated according to the general procedure. The distilled product was analyzed by GLC under the following conditions: OVEN TEMP INITIAL VALUE 30o OVEN PRGM RATE loo/min OVEN TEMP FINAL VALUE 1600 a) ‘without lithium. bromide. The weight of the distilled product was 1.662 g (83.1% wt. recovered). b) with five equiv of lithium.bromide. The weight of the distilled product was 1.767 g (88.4% wt. recovered). 81 APPENDIX 82 Figure Al. Proton NMR spectrum (CDC13, 60 MHz) of gis,gggQ-2,6-bi§(hydroxyethyl)bicyclo- [3.3.0]octa-3,7-diene Dimethanesulfonate 13. OIA 00m cub—4 . e s 0 I A 4- L . 1 _ 1-3.1 v . I s o 1 . m H. H .. .... 1.3-; . . .-J... - -u . ....»r . m .C,; . . . -46“... p . . .L b LP b b Figure A2. 84 Proton NMR spectrum (CDClB, 60 MHz) of gis,gngQ-2,6-bi§(iodoethyl)bicyclo- [3.3.0]octa-3,7-diene 14. V I I I I vv—fi l—T'W'Vfivrfi' T—f'rrTf—Uw—T fij' fi'fl 'vfwalw—Tff—v r‘r—l Tri'fifw—r—r hf: fw— ~T——.——. . _ I . . _ _ . . . _ . . . u 1 . — q 1 — . a q _ q q I v — l _ _ u . l . o .o n _ . . . _ u _ h .H .a. . n _ _ . W L . l . ii {iii-I — _ . . . . . e . , o . . . _ u. . . ._ . . .. o H ..U 5 . u .H 8 u . 2134-421? _ H : p e . _ , . 1 _ . H A . .. . . 1 O lllll I v! v'l olll’llill’l-II‘III‘: r'l I n . . w o . I.I l .... n 4.1;). . m . . l .4 . e u n .. .. I... I A . . 4. n._.~ I . m ....c..._. 4r: ... .... butllfisrwm 1 . L - . ~Io 00. 00m 00m 8 1 .. J... l . i — L L p p — L» LI - r P y b _ p t L p h — n pl — P ..L. h — b — b p p — — p p p — u b s p — — n s n F 86 Figure A3. Proton NMR spectrum (CDCl3, 60 MHz) of cis,gngQ-2,6-bi§(chloroethyl)bicyclo- [3.3.0]octa-3,7-diene 15. se or on on 66 Isl sea on so as as 1 i d 1 4 J — 4 d 1 q — d I d u — d n d d F 1 d 1 q u u j d — d d d d \F d o 1 fl — a q 1 d a 1 4 q q — 3 d 4 .4 M d 4 d J _ u a . d T q q . 4 q q d . u q q - q I J7 a — ..M. 4‘ ‘ .4” . _ m .;.; a ..r.mmw _ . n .m . “r ..C. . . . . .. w : g. . 0:4--. -. ..- .- m ...m . a ‘ _ H. o _. . -.. I . . . a . It . . . . . 7 I 8 . .-..-. _ u . M u _ llguv rd. 1 t 8 h . -. M :r-...:-. . - -- . - .z--:l:n.v; m _ _ .1 . .. .z o oo. 00m 06m 004 . ...tfln of ) lo- 88 Figure A4. Proton NMR Spectrum (CDCl 60 MHz) of Cis, 3’ endQ-z,6-bi§(bromomethyl)bicyclo[3.3.0]octa- 3,7-diene 38. 8 °. 0 jfi Y ' gene-.3 .. ~Mu— to-“ L.-~.--<-~r'-‘*-!r- - . o n 5‘ -—-o ~4p—i. ‘7 .. ”1;-..V Y O .‘o- '1 9 l L ‘. i . MT L.--._.'- y 4 -. mm—vw _ - . ~11! I _ .. , . . -. . O I '. , . ., . . - . , .. . .. v. Ayewvh—V‘” , ...... » I t ‘ . l.‘ c .... I - ”Av ... . a . .1 . . ”-..J -.—-—. .Y. ...—- q——- j l I A ‘r ‘3')!” I I . I I Y‘- -.- . _——-vm—«Q . l . -...-.- -- . a Y on. v . .. . . t '0. I. u u. .. . . —. 'PL . v. .10-: .. .. t b. I '0. o 3 o. o . ... _ ..... . . I I 1 I. . . .p .00. .. 1 -..-..tli 'tlevi'l t l ..... 1r.l- . ...... r—u- 90 Figure A5. Proton NMR spectrum (CDClB, 60 MHz) of 91s, gage-2,6-bi§(mercaptomethyl)bicyclo[3.3.0]- octa-3,7-diene 39. Of ml [3.3.0]- 0H1 ‘)H’ ‘.-.‘._. _. ._ ....--” L—. -»—.. --. .— “.--- ..- ...- .-—.—-.. ..- ..‘og—o— L a ('3 I- ‘ J r. -I q k 4 ‘ ‘ r- \ ‘ ‘ ..-- .... p .— L. a d I- . at I ‘ _ : 4 J _8.. ... -- ‘._. J:— _-_._._.__- . - 1 ... __ V I 3 a P . 4 I 5 I b - ..... . 9.1. . .-. . . - ‘Jfi - : . , 4 . i . | ‘ L .. ' ; . ; . J '2 . . . I . v .. .. , -‘ . » v kw..--...‘....s-----w*~M~-uow-------—-JL<..~.-._4__”.--... __.--...‘-——-~-~ .~--— -- ~ .-- ----r- ~—-—L—...-~.——o4ll , . “3 .... ‘ ; ‘ X. . ‘ ' 1 ' “ “i q , ., ..... . ,u . l . l- -- . I I I l P— . _ . , i I I .. a— . . . . ... . 6 I - I 4 .. . . .. . . , . v. . . . . 1 . I .. ‘ .. . . 1 A ‘ . . A. 0 .... A A .---I —-~o—-J--~-}>—----t~—-----.-I . . . . . - . . . . 3 . . L. ..f .' ‘1. I .5; . '4 L . .. ..... .. . ,, . ,. .. ... . I ' ' "' . . 2 .i: '..3. I: :1; .' '. . 2‘ El. '23; . .. .... .... a . . .... -... . . d ‘ I" 9.0- "' . .. .. .... --. U 4 ... LID! .. ..... . ..... . ..... -4 IQ-I --.- ... I< .- . - . m' . ~... .. ..... . .. . . - ... .’- . ... . . : . . . A q d d .1 . .._._.-.- .- 5-0 PPM H ) 4.0 3.0 2.0 1.0 6.0 7.0 8.0 92 Figure A6. Proton NMR spectrum (CDCl3, 60 MHz) of Gig, gndo-Z,6-21§(iodomethyl)bicyclo[3.3.0]octa- 3,7-diene 42. 93 S C I. O ] octa- 94 Figure A7. Proton NMR spectrum (CDC13, 60 MHz) of gig, endg-Z,6-bi§(hydroxymethyl)bicyclo[3.3.0]- octa-3,7-diene Dimethanesulfonate 43. °. N d H I L L L L L L L L . “...—‘L L.-«-.-a-‘—- .....- e e u . q 4 i 1 q ., ..L L .3 I .e . . L . . . . 1 ~ . -- — I _L ‘11.. m _ L I . ‘0... no. . ... o L .. _ . L . oo . ~ . . . . u 1». I. . L _ . . C . . II . . 40.1. - 10°-u1 IL till! .O.OII“I4 . L . o _ . . . .- ...... . -L.. I.“ _ . . . L . . 1 . I L 3 I ..I ,0 ... . L a . . ., L . . .9. .I»..:. III A e . u _ I I - IIIII 91.---.IIII notVIv YIIIIOI d — d d ‘ d ‘ d a d u. _ 4 q .4 a . . . . o . . . . , .. . _ — o .L . . . . . . . .L.. -....-.II.IIlw.IoIII:II_IIII-. L . M. ....r. .. L o . .. 05.1... o . .. . . ....Oo... 1 —. . ..—. . .....r-4. .4... _ - Asaaels. .... L ._ ...... . .. . ..4..... . . L; .--E...-.:.- . .. . ... . n. ... . ...... . .. . . . . _ . . .. . . w o. . ... . . .... u o - 1 ...... v! 1.0:.» 4 .I‘ T. , . . . . L . _. . . .. 1 o .o—. m I . . . .. . _ . . . .. . e . . . c . c u L _ . . . IIIIIII. 71". . L . . . . . . . i n L _ L . . . .0 I.II . . . .. ._ . .. . . .. . G . IV I . .L . .L . . ....... O .- .-I.1.I.I‘I.Iv I III . .... .. . ...... . .. . o. . . . .--T I. .I. . .. o. .o .. v. . ' IIOI" a. .. .. .. la. ..... . .. .. ...L...,.. . .. ...-... . . L . a I IOIOI o O D , - . . . ...:.I.. . .. .. .... . . . [’7‘ 0 O 0 . ... ....... . .. .. ..a.-I.. . .4 , .....4... . . . .. . ....... .. .0 IIIIIIII [ELI .0 I. — . o m .. ..... . v. . _. .. . . .. . . L L - 1 o . . . I .3 LI u .4 . .. . . .. . . . . . . ..... . . . L. . . . . .. . L. . . . ..... . q .. .. ..... II... .I IIII«III.I1IDI ‘It'434311000ln. . . .. . ........ .. ... L L .. i .. c . . L .. . . . .. _ L .. . . . .... . o O . 8‘ .I.-.l<4 ‘ ‘0' ’ . >4- i ., L L L L . L . L --.. -. . .,...-..L---.m-.—_.._...- . 5 . L I l ' . I 6 (L13: .3 N... _ .o . ...-..II 96 REFERENCE 10. 11. 12. 13. 14. 15. 16. 17. 97 a) Hagedorn, A. A. III Ph.D. Thesis, Michigan State _University, 1974. b) Farnum, D. G.: Hagedorn, A. A. III LELIQDQQLQELLQLLL 1975, 3987- Levy, H.; Cope, A. C. J. Am. Chem. Soc. 1944, §§, 1684. Gajewski, J. J. "Hydrocarbon Thermol Isomerization", Academic Press, New York, 1981, PP. 163-176. Woodward, R. B.: Hoffmann, R. "The Conservation of Orbital Symmetry", Verlag Chemie, Weinheim, 1970, P. 119. For reviews of the Stevens rearrangement, see House, H. O. "Morden Synthetic Reactions", W. A. Benjamin, Inc., Menol Park, 1972, PP. 712-713. Mitchell, R. H.: Boekelheide V. J. Am. Chem. Soc. 1973, 2;, 1547. Cope, A. C.: Ganellin, C. R.: Johnson, H. W. Jr.: Van Auken, T. V.: Winkler, H. J. S. J, Am, Qhem. Soc. 1963, 85, 3276. Mitchell, R. H.: Otsubo, T. : Boekelheide, V. TELLQDQQIQB_L§LLL 1975: 219- Boeckelheide, V. Age, Chem. Bee, 1980, 1;, 65. Mirmohammad M. Ph.D. Thesis, Michigan State University, 1983. Paquette, L. A.: Fischer, J. W.: Browne, A. R.: Doecke, C. W. J. Am, Chem. gec. 1985, 107, 686. Eaton, P. E. Michigan state University Colliquim, March 29, 1984. Friedman, P.; Allen, P. J, Org, Chem. 1965, 39, 780. Singh, A.: Mehrotra, A.: Regen, S. L. Syn. Commun. 1981, 11, 409. Fieser, L. F.: Fieser, M. "Reagents for Organic Synthesis", 1, John Wiley, New York, 1967, P. 667. Hooz, J.: Gilani, S. S. H. Ca J. C em. 1968, fig, 86. McMurry, J. E. ACQ, Chem, Res. 1983, 16, 404. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 98 Marshall, J. A.; Chung, K. H. J. O em. 1979, AA, 1566. McMurry, J. E.; Matz, J. R. et n et 1982, 2723. McMurry, J. E.; Haley, G. J.; Matz, J. R.; Clardy, J. C.; Duyne, G. V.; Gleiter, R.; Schafer, W.; White, D. H. J, Am. Chem. Soc, 1984, 106, 5018. Takai, K.: Mori, T.; Oshima, K.; Nozake, H. Temzahedmon Lett. 1981, 3985. Corey. E- J-: Suggs, J- W. Tetrahedron_Letti 1975. 2647. Corey, E. J.; Schmidt, G. et dr tt. 1979, 399. Bestmann. H. J. Angeui_§hemi_InLi_Edi__Engli 1965. 4. 583. Luche, J. L. m. Am. Chem. 809, 1978, 199, 2226. Watson, 8. C.; Eastham, J. F. J. e h m. 1967, 2, 165. Ternansky, R. J,; Balogh, D. W.: Paquette, L. A. gm Am, Qmem, Soe, 1982, 105, 4503. For a review on synthesis of dodecahedrane, see Lindberg, T. "Strategies and Tactics in Organic Synthesis", Academic Press, 1984, pp. 175-200. For a review on synthetic efforts directed towards dodecahedrane, see Eaton, P. E. Ietmemedgem 1979, ;§, 2189. Maier, G.; Pfriem, S.; Schaffer, U.; Matusch, R. m. n . d 1978, 11, 520. Maier, G.; Pfriem, S.; Schaffer, U.; Malsch, K-D.: Matusch, R. Qhem. Be;. 1981, 114, 3965. Rauscher, 6.; Clark, T.; Poppinger, D.; Schleyer, P.y.R. n ew. Chem. Int. Ed En . 1978, 11, 276. Eaton; P. E.; Cole, T. W., Jr. J, Am. cmem, Soc. 1964 86, 3157. Pelosi, L. F.; Miller, W. T. J. Am, cmem. Soc. 1976, 28, 4311. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 99 Woodward, R. B.; Fukunaga, T.; Kelly, R. C. J. Am. gmem, Sec. 1964, 88, 3162. a) Muller, D. M. cmem. Weekmlad 1963, 82, 334. b) Jacobson, I. T. Acta. Chem. Scand. 1967, 2;, 2235. Anet, F. A. L.; Miura, S. 8.: Siegel, J.; Mislow, K. e . O 1983, 105, 1419. a) Repic. O. Ph.D. Thesis, Harvard University, 1976. b) Deslongchamps, P.; Souey, P. Tetrahedron 1981, 81, 4385. Eaton, P. E.; Bunnelle, W. H.; Engel, P. Can. J. Chem, 1984, 82, 2612. Paquette, L. A.; Itoh, I.; Lipkowitz, K. B. J. Omg. Shemi 1975. $1. 3524- Roberts, W. P.; Shoham, G. Ietmahedmon Lett. 1981, 4895. Theresa, A. M. Ph.D. Thesis, Michigan State University, 1982. Schulman, J. M.; Disch, R. L. J Am h . o . 1978, 188, 5677. Pyrek. J. s. Wen. 1979. 2. 1557- a) Cope, A. C.; Lee, H. H.; Petree. H. E. 8. Am, Chem, 809, 1958, 89, 2849. b) Cope, A. C.; Brown, M.; Petree. H. E. ihid, 1958 88, 2852. Cope, A. C.; Tiffany, A. B. J. Am. Chem. Soc. 1951, 18, 4158. Crandall, J. K.; Chang, L. J. Org. Chem, 1967, 8;, 435. Crandall, J. K.; Chang, L. J. Org. Chem. 1967, 8;, 532. Crandall, J. K.; Lin, L. C. J. Am. Chem. Soc. 1967, 88, 4526. Crandall, J. K.; Lin, L. C. J. Am, Chem. Soc. 1967, 88, 4527. Crandall, J. K.; Lin, L. C. J. Org. Chem. 1967, 82, 2375. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 100 Crandall, J. K.; Crawley, L. C.; Banks, 0. B.; Lin. L. C. 8, Org. Chem. 1971, 88, 510. Rickborn, B.: Thummel, R. P. J. Org, Qhem, 1969, 85, 3585. Thummel, R. P.; Rickborn, B. J. Am. Chem. Soc. 1970, 88, 2064. Thummel, R. P.; Rickborn, B. J. Org. Chem. 1971, 88, 1365. Kissel, C. L.; Rickborn, B. J. Ozg, Qhem, 1972, 81, 2060. Thummel, R. P.; Rickborn, B. J. ng, Qhem, 1972, 81, 3919. Thummel, R. P.; Rickborn, B. 8. grg, Qhem. 1972, 81, 4250. Cope, A. c.; James, K. H. 19.151. 1965, L1, 3125. Cope, A. C.; Berchtold, G. A.; Peterson, P. E.: Sharman, S. H. ihig, 1960, 82, 6370. Crandall, J. K. J. O C 1964, 82, 2830. Apparu, M.; Barrelle, M. Ietrahedrom 1978, 88, 1541. Whitesell, J. K.; Matthews, R. S.; Wang, P. K. S. gymth. Commun. 1977, 1, 355. Iseki, K.; Yamazaki, M.; Shibasaki, M.; Ikegami, S. Tetrehedron 1981, 81, 4411. Trost, B. M.; Mao, M. K. T.; Balkovec, J. M.; Buhlmayer, P. J. Am. Chem. Soc, 1986, 108, 4965. L Greenspan, F. P. J . C . SO 1946, 88, 907. WWIWHHSIWIW IUIINWIIVITUWIIIWHW Miles 3 1293 03062 0029