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IIII',, I 1:"1'I1' 1W II-11,,,,,1,,I"' "I" m' 1“" : ..'. ' WI, i ,fil'wmfl'fl' "'I'fi'I" "'1". . . I 1.‘ . - I N" , - 'I"" ..I ' ""l' J 1 11".” ‘ "..’ "ml ""' ""'N'W'OI IIII.'-I'""-"' :- .., , If ‘EIBRARY ‘ uichiganSuw University rHEBl’ This is to certify that the thesis entitled PART I STUDIES TOWARD THE TOTAL SYNTHESIS OF A ”Ia-METHYL ANALOG 0F VITAMIN D PART II TYPE I PHOTO-REACTIONS 0F BICYCLIC KETONES presented by JUNG-HWA SHAU has been accepted towards fulfillment of the requirements for [ID/4'0 degreejn //I€/"/5tr// 77% 24. W ijor professor Date M WM FINE§z 25¢ 9'!- day per It. RETUMIN LIBRARY MTERIAL§: Place in book atom to move charge fro. circulation records PART I STUDIES TOWARD THE TOTAL SYNTHESIS OF A ind-METHYL ANALOG OF VITAMIN D PART II TYPE I PHOTO-REACTIONS OF BICYCLIC KETONES By Jung-Hwa Shau A DISSERTATION Submitted to Michigan State University in partial fullfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1979 ABSTRACT PART I STUDIES TOWARD THE TOTAL SYNTHESIS OF A lad-METHYL ANALOG OF VITAMIN D PART II TYPE I PHOTO-REACTIONS OF BICYCLIC KETONES By Jung-Hwa Shau PART I Two strategies have been tried to synthesize the 14a-methyl analogvi of vitamin D, 2; In the first approach, reaction between perhydroindene-dione 2’and trimethyl- silylated aldimine Q'followed by acid hydrolysis gave d,B-unsaturated aldehyde 2; 5 N $R=CH3,R=O Li R = H, R2: 0 H (CH3)BSiCHCH=N-t-Bu or C8H17 it Jung-Hwa.Shau 6 R N 8 R = CH N Aldol condensation of é’with 4-hydroxycyclohexanone provided dienone g and a small amount of bis-condensation product. Photoisomerization of the central double bond ended up with a 1:1 mixture of é’and Z; Treatment of 2’ with triphenylphosphonium methylide gave olefin g, which is a lua-methyl analog of 5,6—trans-vitamin D. In the second approach, acetylenic ketal Z’was pre- pared from 1,3-cyclohexanedione by four steps. There was no significant reaction between dione z’and anion of 2’ under conditions established by model studies. This pro- blem has finally been solved by complexation of the carbonyl function in.2'with lithium iodide prior to the addition of nucleophile. Adduct £9 obtained from this reaction was a precursor of if {\O J ung-Hwa S hau Jung-Hwa.Shau PART II In order to synthesize cis-1,6-dimethyl[4c3-Olnonane- 2,7-dione l, Norrish type I reactions of diketone g, alcohol z’and acetate fi'have been studied. Photolyses of these compounds in various solvents yielded the corresponding cis-isomers and products via ketene intermediates, such as ester 2’ lactone é, amide 3, etc. It was surprising to find out that a-cleavage of the six-membered ketone is favored in the photolysis of 53 Since the cis-isomer of acetate fi’was obtained in highest yield, it was hydrolyzed, and then oxidized to give the desired compound A; The chromatographic and spectroscopic properties of these epimers were compared. DEDICATION This dissertation is dedicated to my parents. ii ACKNOWLEDGMENTS The author is deeply grateful to Professor William H. Reusch for his guidance, enthusiasm and encouragement during the course of this work. Appreciation is extended to my colleagues for their friendship and discussion. Special thanks are also extended to my sisters and other friends for their love and concern. The author acknowledges the financial support from the National Institutes of Health and the Department of Chemistry at Michigan State Univer- sity. iii TABLE OF CONTENTS Page PART I INTRODUCTION ........................................ 1 RESULTS AND DISCUSSION .............................. 11 EXPERIMENTAL ........................................ 22 General ........................................ 22 Preparation of epoxyaldehyde 26 ................ 24 Reaction of epoxyaldehyde 26 with triphenyl— phosphine ................................... 24 Reaction of epoxyaldehyde 26 with zinc dust in acetic acid .............................. 25 Preparation of enol ether 31 ................... 25 Preparation of imine 32 ........................ 26 Preparation of trimethylsilylated aldimine 33 .. 26 Preparation of unsaturated aldehyde 25 ......... 27 Preparation of dienone 34 ...................... 28 Preparation of keto selenide 3Q ................ 29 Reaction between keto selenide 36 and allylic chloride 3 ................................. 30 Preparation 0 olefin 39 ....................... 30 Reaction of dienone 34 with Wittig reagent in.DMSO ..................................... 31 Isomerization of 34 to 41 ...................... 31 Preparation of en6I ether 4 ................... 32 Preparation of unsaturated etone 45 ........... 33 Preparation of ketal 46 ........................ 33 Preparation of alcohol ~43 ...................... 34 Preparation of alcohol 59 ...................... 35 Reaction of ketone 2 with acetylide 43(a) ...... 35 Transformation of ketal 46 to alcohol 51 ....... 36 Reaction of ketone 3 with Grignard reagent from 46 ..................................... 36 Attempt to trap enolate from 3 with t- -butyl- dimethylchlorosilane ........................ 37 Preparation of alcohol 48 ...................... 38 APPENDIX ......................... ........... ...;.... 39 iv TABLE OF CONTENTS --Continued Page PART II INTRODUCTION ................... .............. ..... 65 RESULTS AND DISCUSSION ............ ........ ........ 71 EXPERIMENTAL ... ............ . ............ . ......... 81 General ...................................... 81 Irradiation of dione 2 in ether .............. 81 Irradiation of dione Z:in methanol ........... 82 Preparation of lactone 14 by irradiation of alcohol 12 ................................ 82 Reduction of lactone 14 to diol 15 ........... 83 Short irradiation of alcohol 12 .............. 84 Irradiation of alcohol 12 with added t-butyl- amine ..............?7..................... 84 Preparation of acetate 23 .................... 85 Preparation of acetate 25 .................... 85 Hydrolysis of acetate 25 ..................... 86 Oxidation of alcohol 13 ...................... 87 APPENDIX ... .............................. . ........ 88 REFERENCE OOOOOOOOOOOOOOOOOO 000000 0.00.... ........ 106 Figure # CD\)O\U\-F’\ONH ...—l 00 11. 12. Infrared Infrared Infrared Infrared Infrared . Infrared Infrared Infrared Infrared Infrared Infrared PMR spectrum of Spectrum spectrum spectrum Spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum LIST OF FIGURES N of 59 . of 13. PMR 14. 15. 16. 17. 18. 19. PMR PMR PMR PMR PMR PMR spectrum spectrum spectrum spectrum spectrum spectrum spectrum of of of of of of of 25;: 26:? at”. 2‘11 2‘0". er: {8 281 Page 39 4O 41 42 43 44 us 46 47 48 1+9 50 50 51 51 52 52 53 53 LIST OF FIGURES-~continued Figure # 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 3o. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. PMR PMR PMR PMR PMR Mass Mass Mass Mass Mass Mass Mass Mass Mass Mass Mass Mass Mass CMR spectrum of 2 spectrum spectrum spectrum Spectrum Spectrum spectrum Spectrum spectrum Spectrum Spectrum Spectrum spectrum Spectrum Spectrum Spectrum spectrum spectrum Spectrum 0 O O O Pb ts Pb 1w U1 kn -: c— 4? N ZH {o be Zoo 20x 0\ o o o C) o C) o o C) <3 0 o C) It Pb It Pb It Pb It Pb It Pb It Pb It U1 -p c' I: -P c— C) kn \» n: k» “2‘82... 30 Zoo Zmem2u2©em N: am (we of N Infrared Infrared Infrared Infrared Spectrum spectrum Spectrum Spectrum of 13 ..... ~ Of in 000000... N vii Page 54 54 55 55 56 56 57 58 58 59 59 6O 60 61 61 62 62 63 64 88 89 9O 91 LIST OF FIGURES--Continued Figure # 43. 44. 45. 46. 47. 48. 49. 5o. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. Infrared spectrum Infrared Spectrum Infrared spectrum Infrared spectrum PMR PMR PMR PMR PMR PMR PMR Mass Spectrum Mass Mass Mass Mass Mass Mass Mass Spectrum Spectrum spectrum Spectrum Spectrum Spectrum Spectrum Spectrum spectrum spectrum Spectrum Spectrum spectrum Spectrum of of of of of of viii Page 92 93 94 95 96 96 97 97 98 98 99 99 101 102 102 103 104 105 Table I. II. III. LIST OF TABLES Page Irradiation of 12 in benzene, using phenyl ether as internal standard ................... 76 Irradiation of 13 and 10 equiv. of t-BuNH2 inether ......OIOOOOCIOOOOOOOO.....OOOOIOOOOO 78 Comparison of‘%,and crude product with trimethy1-1,3, -benzenetricarboxylate 26 byGLPC OOIOOOIOOOODOIIOOIOOOOOOIOOOOOO0...... 81 ix PART I STUDIES TOWARD THE TOTAL SYNTHESIS OF A 14a-METHYL ANALOG 0F VITAMIN D INTRODUCTION Vitamins are essential dietary factors required by an organism in small amounts and whose absence results in deficiency diseases. Among them, vitamin.D is the only one derived from steroids. Vitamin D promotes the absorption of calcium and phosphorous from the intestine into the bloodstream, so that it reaches a level high enough to permit proper bone mineralization. R U N '21 II M '0 I Vitamin D It has been found that vitamin.D3(cholecalciferol) is metabolized to 25-hydroxycholecalciferol 1} in the liver and then to 1(S),25-dihydroxycholecalciferol 23’3 in the kidney. Both metabolites exhibit much greater physiological activity than the vitamin itself. 1 $9 ZP‘ w :1 In order to study the relationship between struc- ture and reactivity in vitamins, much effort has been directed to the synthesis of structural analogs. To this end, the availability of perhydroindene-dione 2’has prompted us to explore the synthesis of a 14a-methyl analog 4 of vitamin.D. This dissertation describes our efforts to join ring A and two bridging carbon atoms onto 3. 2 Triene 4 is interesting for at least two independent reasons. First, the possibility of a [1,7] SigmatrOpic hydrogen Shift followed by an electrocyclic ring closure would, if realized, generate tetracyclic intermediates 2’ related to lanostane and euphane triterpenes. This would 5, 19 provide an alternative synthetic route to such compounds which has precedent in vitamin D chemistryé. Second, the precursor of vitamin.D has the 14a-methyl group. In the biosynthesis of steroids from squalene via lanosterol, the 14a-methyl group appears to be removed 4 before the C-4 methyl groups and before the appearance of a AS-double bond7. Indeed, no sterol having a 14a-methyl group in the absence of a gem-dimethyl unit at C-4 has ever been found in mammalian tissues. Compound 4,therefore is a vitamin.D analog that nature either chose to by-pass entirely, or may have abandoned in as yet undiscovered earlier organisms. Five pathways have been employed in the total synthe- sis of vitamin D. Inhoffen8 used a Wittig reaction to introduce the sensitive triene system in the last step. In this synthesis alcohol 6 was converted to a,B-unsaturated aldehyde Z by a bis-homologation requiring five steps. Aldol condensation between.Z and 4-hydroxycyclohexanone gave trans-dienone‘g as a mixture of CB-epimers. A Wittig reaction followed by photochemical isomerization then led to vitamin.D (Scheme I). Lythgoe used an acetylene unit as a precursor of the two bridging carbon atoms between ring A and C9. Chloro- ketone 8 and the lithium derivative of enyne 19 were combined to give chlorohydrin 11. Reductive elimination of 11 generated dienyne 12, which on controlled hydrogenation of the acetylene link gave precalciferol 13 (Scheme II). . CrO3 . Ph3P=CH-CH=CH2 > I O 3 . MnOu Q, R 1. Ph3P=CH2 1 2. hv \ H 3. chromatography 0 OH HO. 8 N Scheme I ch1+' Ill ether, 0°C \ .7 bis-(ethylenediamine)\ chromium(II), DMF H Lindlar Catalyst 2' _\ Scheme II 10 In Okamura's approach , 3-deoxy-1-hydroxyvitamin D 3 18 was synthesized via a vinylallene intermediate. The key step involved coupling of the cuprate complex 16 with the ethynyl acetate 15. This coupling followed by deprotection afforded vinylallene 17 as a mixture of C -epimers, which 1 were converted to 18 by a thermal SigmatrOpic rearrangement (Scheme III). In the above methods, the triene system of vitamin D has been established by photochemical or thermal isomeriza- tion processes. Recently, Lythgoe reported a direct total 11 synthesis of vitamin.D by adding the optically active phosphine oxide 19 to the Widaus-Grundmann ketone 13. R PPhZO —>, 2. 14 N 0” 3. dilo HOAC 13 R = 09H17 or C8H17 In this reaction, the original Z-allyl geometry of the phosphine oxide was completely preserved in the 5,6- double bond of the product, and the new 7,8-double bond was formed with exclusive E-geometry. 1. LiCECH N7 2. AcZO, pyridine L1+ C H -CaC-Cu- OSi(CH 3 7 O 3’2 t-Bu N7 23 [1.5] H-shift A _I Scheme III Lythgoe has also deveIOped a modification of this synthesis, in which the reactivities of the intermediates 2 are reversed1 . Thus 8a-phenylsulfonyl-des-AB-ergostane 21, prepared from 29, formed a lithium derivative which reacted with the benzoyloxy-aldehyde 22 to give, after treatment with trimethylchlorosilane, a mixture of B-silyloxy-sulfones 23. Reduction with lithium amalgam, followed by removal of the benzoyl group, gave vitamin.D”. 9 19 ' C9H19 . 6 steps . ‘—‘—‘€> -—+-9’ H 1% PhS02 ‘ 2,8 21 N 0 2- c Phcoé' 22 2 N 3. Me SiCl 3 10 The approaches to the synthesis of a 14a-methyl analog of vitamin.D described in this thesis are based on the first two strategies noted here. RESULTS AND DISCUSSION The bicyclic a,B-unsaturated aldehyde Z served as a key intermediate in Inhoffen's vitamin.D synthesis, and the corresponding methyl homolog 25 is a necessary inter- mediate in a parallel route to 14a—methyl vitamin D derivatives. Recently, several facile new methods for converting aldehydes or ketones to a,B-unsaturated aldehydes with simultaneous chain extension have been reported. However, not all of these proved effective with perhydroindene-dione 2f For example, addition of vinyl magnesium chloride to 3’followed by oxidative pyridinium chlorochromate 11 12 13 rearrangement with pyridinium chlorochromate gave a,B- epoxyaldehyde 28 instead of 2;. This deviation from the 13c expected reaction has been noted previously for hindered allylic alcohols. Attempts to convert 28 to 25 by 14 . . . or z1nc dust 1n acet1c heating with triphenylphosphine acidls failed. A second approach involved the addition of a nucleo- philic acetaldehyde equivalent, (Z)-2-ethoxyvinyl lithium 2816, to 2; Although 28 reacted with cyclohexanone to produce enol ether 29 in excellent yield, there was only modest reaction between 28 and 2’below the decomposition temperature of 28 (ca. -4OOC). Compound 31 was stable to silica 2, gel 13 chromatographic purification on silica gel while 22 was completely converted into 29 under the same conditions. The acid hydrolysis of enol ether 21 was not tried because a better method of preparation of aldehyde 2; was found. By using the lithium derivative of trimethylsilylated aldimine 2217 as a nucleophile. aldehyde 2; was prepared in 66% yield (based on recovered starting material): 1. ILDA CHBCH=N-t-Bu «% (CH3)BSiCH2CH=N-t-Bu 2. (CH3)38101 32 33 IV 'V 1. LDA 5% 25 M 2. 2 3. (COOH)2, H20 The next few steps in this synthesis followed Inhoffen's procedure8. Thus aldol condensation of 25 with 4-hydroxycyclohexanone in the presence of sodium ethoxide gave the desired adduct 24 along with a small amount of bis-condensation product 25 (5.8:1). Since formation of 25 consumed two equivalents of 25 and caused problems in the purification of 24, an effort was made to minimize this product. Unfortunately, the use of excess 4-hydroxy- cyclohexanone did not prevent the formation of 25 under conditions that still yield 24. 14 An alternative approach involving coupling18 between keto selenide lg and allylic chloride 2319 was considered as a model for vitamin D synthesis; however, no alkylation products were obtained in these experiments. SePh 1 o IDA, TIE-MFA \L 3 W‘ 7 O 01 37 38 N Reaction of 23 with triphenylphosphonium methylide gave olefin 23, which exhibited UV absorption 15 + _ 34 PhBPCHBBr, n-BuLl% N ether 39 N (Amaxz 270 nm, 6 = 22000) very close to that reported for 5,6-trans-vitamin D2 (Amaxz 272-273 nm, E = 22700)8. In order to improve the yield of the above Wittig reaction, a modification using a stronger base and different solvent was studied. Although Corey and Chaykovsky reported that Wittig reactions proceeded more rapidly and gave better yields with dimsyl sodium in dimethylsulfoxidezo, none of olefin 22 was obtained under these conditions. Since vitamin D has a cis configuration at the 5,6- position, 23 had to be isomerized through irradiation. When a methanol solution of dienone é’was irradiated with light filtered to give 365 nm21, the photoequilibrium favored %9 by at least 0:1. The same conditions were applied to 23, but the photoequilibrium was only 1:1, 23:33. Apparently the ind-methyl group has an effect on the photoisomerization equilibrium. 16 hv Vi methanol A second approach to ind-methyl vitamin.D analog was patterned after Lythgoe's synthesis of precalciferolg. This synthesis required the preparation of acetylenic ketal e3 as a key intermediate. Scheme IV shows the way in which this was accomplished. Thus the enol ether22 of 1,3-cyclohexanedione was alkylated regiospecifically23 to give a; by treatment with lithium diis0propylamide and methyl iodide. Reaction of a; with lithium acetylide- ethylenediaminezu gave ethyl carbinol Q3, which proved unstable and easily lost ethanol giving conjugated ketone 29. Direct ketalizationzs of a; by ethylene glycol led to many undesired products, so exchange ketalization26 was used instead. The acetylene intermediate«&§ is especially attractive because it does not have any asymmetric carbon atoms. Thus addition of anion fig to 3 should not generate N 17 o o . EtOH/ p-TSOH \ .' '1. LDA \ I 7 0 benzene, reflux OEt 2. CHBI LL? 0 H0 /// + LiCz-CHWH CH OH NH H o C1 U as OEt ' OEt 5‘9 5‘3 V O Scheme IV 18 m H2 \ :3 i \ 7 Lindlar Catalyst ‘03 Co / Scheme V 19 diastereoisomeric mixtures as was the case in 23. The hydroxyl group at the C-3 position would then be intro- duced at a later stage in the synthesis. The approach is outlined in Scheme V. To establish conditions for the reaction between 2’ and a3, the following two model systems were studied: ether ~v 3 + PhCECLi N as: o T. +va ——> ------- (2.) o "’ H0 \\\ i" .J 50 N Although reactions (1) and (2) proceeded smoothly to give adducts &? and Q9, respectivelyg, no product was obtained from a? and 2’under the same conditions. Various 20 bases and solvents, such as NaH/DMSO, NaH/ether, CHBMgBr/ ether, were tried without success. Indeed, forcing condi— tions led to the transformation.of'eg(b) to 2}' which may proceed via sigmatrOpic rearrangement and proton transfer as illustrated in Scheme VI. 0‘ III %- ' H C . H C + 3 O [1,5]}I-sh1ft \ 2 H. -transferL I7 0 \ [5 (J & E2 Ox) 0) (strong'base) H H \[r H /CH2 H C 2 base HZC _ . . > _ O’A\«’° (H -transfer) o’“\u/° 1. base ’ 7 2. H20 work-up Scheme'VI 21 A possible reason for the failure of addition may be competitive enolate anion formation on the six-membered ring. This has been ruled out by trapping experiments with t-butyldimethylsilyl chloride, which are known27 to give O-silylated derivatives on reaction with ketone enolates. No silyl ether 22 was obtained in the following reaction: \V 47(b) N 1. \\ _4;] ’T\ 2.+SiCl I Complexation of the carbonyl function in 2’with certain electrOphiles overcomes the sluggishness of this reactiona When 2’was treated wtih lithium iodide prior to reaction with 23(a), a 12% of adduct fi§ was obtained. EXPERIMENTAL GENERAL All reactions in which strongly basic reagents were used were conducted under nitrogen or argon, using sol- vents purified by distillation from suitable drying agents. Magnetic stirring devices were used for most small scale reactions: larger reactions were agitated by paddle stirrers. Organic extracts were always washed with water and brine and dried over anhydrous sodium sulfate or anhydrous magnesium sulfate before being concentrated or distilled under reduced pressure. The progress of most reactions was followed by thin layer chromatography (TLC) and/or gas liquid phase chromatography (GLPC). Visualiza- tion of the thin layer chromatograms was effected by spray reagents such aS 3% p-anisaldehyde in ethanol and 30% sulfuric acid with subsequent heating. Analysis by GLPC was conducted with A-90-P3 or 1200 Varian-Aerograph instruments. Preparative layer chromato- graphy was carried out on 2 mm silica gel or 1.5 mm alumina F-254 adsorbent on 20 x 20 cm glass plates. Visu- alization of the preparative plates was effected by ultraviolet light and/ or charring with a hot wire. Melting points were determined on either a Hoover-Thomas 22 23 apparatus (capillary tube) or on a Reichert hot-stage microsc0pe and are uncorrected. Infrared spectra (IR) were recorded on a Perkin-Elmer 237B grating spectrophotometer. Proton magnetic resonance spectra (PMR) were taken in deuterochloroform or carbon tetrachloride solutions with a Varian T-60 spectrometer and are calibrated in parts per million (6) downfield from tetramethylsilane as an internal standard. Ultraviolet spectra (UV) were recorded on a Unicam SP-800 spectrOphotometer. Mass spectra (MS) were obtained with a Hitachi RMU 6 mass spectrometer. Carbon magnetic resonance spectra (CMR) were taken in deutero- chloroform solution with a Varian CFT-20 spectrometer and are calibrated in parts per million (5) downfield from tetramethylsilane as an internal standard. Microanalyses were performed by Spang Microanalytical Laboratories, Eagle Harbor, Michigan. 24 Preparation of epoxyaldehyde 26; A solution of 816.7 mg (3.9 mmole) of alcohol 24273 in 14 ml of methylene chloride was added to a suspension of 3.2 g (15.6 mmole) pyridinium chlorochromate in 10 ml of methylene chloride. The mixture was stirred at room tem- perature under nitrogen overnight, diluted with 80 ml of ether and filtered through Florisil. After removal of solvent, 790 mg of yellow oil was obtained. Crystalliza- tion in ether gave 274 mg of 26 (34%), which displayed the following properties: mp 95.5-96.50: IR (CDC13) 1735, sh 1715, 1256 cm‘1; PMR (69013) 5 1.05 (s, 3H), 1.17 (s, 3H), 1.4-2.6 (m, 10H), 3.07 (d, 1H, J=5 Hz), 9.37 (d, 1H, J=5 Hz): MS (70 eV) m/e (rel intensity) 222(4), 207(8), 121(25.5), 110(100), 84(67.5). AQQLL Calcd. for 0 H180 : C, 70.27; H, 8.17 13 3 Found: C, 70.25, H, 8.16 Reaction of epoxyaldehyde 26 with triphenylphosphine. A solution of epoxyaldehyde 2g (97 mg, 0.44 mmole), triphenylphosphine (119 mg, 0.45 mmole) and hydroquinone (19 mg, 0.17 mmole) in 10 ml of triethyleneglycol was heated at 160°C for 5 hr and 190°C for 2 hr. The tarry residue showed the same chromatographic prOperties as the starting materials. 25 Reaction of epoxyaldehyde 26 with zinc dust in acetic acid. To a stirred solution of 26 (25 mg, 0.11 mmole) in 10 ml of THF was added zinc dust, followed by dropwise addi- tion of 2 ml (30 mmole) of acetic acid. After refluxing for 6 hr, the solution was filtered, and the filtrate was extracted by ether and water, washed with sat. sodium bicarbonate, water, brine and dried. Removal of solvent gave 23.4 mg crude product which proved to be a mixture of 26(30%) and 2’(70%) by GLPC analysis. The latter was collected by GLPC (4% QF-l, 180°C) and exhibited an infra- red spectrum identical to that of an authentic sample of 3. N Preparation of enol ether 23; To a solution of cis-1-ethoxy-2-tri-n-butylstannyl- ethylene 2716 (410.8 mg, 1.14 mmole) in 6 ml of THF was added 2.42M n-BuLi (0.46 ml, 1.11 mmole) at -78°0. After 1 hr, the solution was treated with a solution of ketone;1 (90 mg, 0.5 mmole) in THF. The mixture was stirred at this temperature for 2 hr, warmed up to room temperature, and quenched by sat. sodium bicarbonate solution. Work-up of the reaction mixture by the previously described procedure gave 421 mg of crude product, which was chromatographed on HPLC (silica gel) with 20% ethyl acetate-hexane to afford 47.1 mg (41% based on the recovered 2) of 31: IR (CD013) 3520, 1733, 1667 cm'l; PMR (00013) 0 0.85 (s, 3H), 1.30 (s, 3H and t, 3H, J=7 Hz), 1.4-2.4 (m, 10H), 3.77 (q, 2H, 26 J=7 Hz), 4.07 (s, 1H), 4.37 (d, 1H, J=7 Hz), 5.87 (d, 1H, J=7 Hz): MS (70 eV) m/e (rel intensity) 252(0.30), 237 (1.35). 235(1.61), 206(1.65), 165(11.94), 140(76.78), 71 (100). An analytical sample was crystallized from ether, mp 52-55°. Preparation of imine 2228. A three neck, round bottom flask, fitted with a reflux condenser and a dr0pping funnel, was packed in an ice bath and charged with 41 ml (0.39 mole) of t-butylamine and 22 ml (0.39 mole) of acetaldehyde. The mixture was stirred for 20 min., 2 g of potassium hydroxide was added, and the reaction mixture was allowed to stand until separation into two layers appeared complete. The organic layer was dried over crushed potassium hydroxide in the refrigerator overnight, and then distilled from fresh potassium hydroxide at 70-7400 to afford 29.88 g (77%) of acetalde- hyde t—butylimine 32. Preparation of trimethylsilylated aldimine 23; To a stirred solution of n-butyllithium (55 ml, 0.12 mole) in 80 ml of THF at -78°C was added dropwise 32 (14 ml, 0.11 mole). This solution was stirred for 20 min. and then treated with trimethylchlorosilane (15.2 ml, 0.12 mole). After the reaction mixture had warmed to 0°C, it was poured into 250 ml of water and extracted with ether. The combined organic extracts were washed with brine, dried over 27 potassium carbonate and concentrated. The residual liquid was distilled at 69-71°C (9 mm) to afford 12.9 g (69%) of 33: MS (70 eV) m/e (rel intensity) 171(9.5), 156(21.5), 147(100), 100(37). Preparation of unsaturated aldehyde 2;; To a stirred solution of LDA (made in situ from 8 ml of 2.42 M n-BuLi and 3 ml of diis0pr0pylamine) in 40 ml of THF at 0°C was added imine 33 (3.24 g, 18.9 mmole) over a 5 min. period. This reaction mixture was stirred for 15 min., cooled to -78°C and treated with a solution of 2’(1.5 g, 8.3 mmole) in 10 ml of THF._The resulting mixture was stirred at -78°C for 2 hr, -20°C for 0.5 hr, and then quenched with aqueous oxalic acid to bring the pH of the solution to 4.5. After another 2 hr at room temperature, the mixture was poured into brine and extracted with ether and ethyl acetate. The organic layer was washed with sat. sodium bicarbonate, water and brine. After dring and remo- val of the solvent, 2 g of yellow oil was obtained. Crys- tallization from ether gave 493 mg of 25, mp 72.5-740. The mother liquid was chromatographed on HPLC (silica gel) with 20% Et0Ac-hexane to afford 198.6 mg of 2’and 806 mg of 23, from which 488 mg of 2é'was crystallized from ether. Aldehyde 25, obtained in 66% yield (based on the recovered starting material), had the following pr0perties: IR (CDC13) 1729, 1657 cm‘1; Pmr (00013) 6 0.99 (s, 3H), 1.13 (s, 3H), 1.33-2.07 (m, 6H), 2.33 (m, 4H), 5.83 (dd, 1H, J=8, 2 Hz), 28 9.67 (d, 1H, J=8 Hz): CMR (00013) 18.03, 21.06, 23.08, 23.81, 25.24, 28.43, 33.21, 48.78, 53.56, 125.2, 169.0, 190.4, 217.5; MS (70 eV) m/e (rel intensity) 206(65), 191 (11). 177(10). 163(56). 149(26). 135(49). 121(40). 107(42). 41(100). ‘Angl; Calcd. for C13H1802: 0, 75.69; H, 8.80 Found: c, 75.77; H, 8.85 Preparation of dienone 34; To a solution of sodium (0.23 g, 0.01 mole) in 14 ml of absolute ethanol was added dr0pwise a solution of 4-hydroxycyclohexanone29 (2.97 g, 0.026 mole) in 7 ml of ethanol. This mixture was stirred for 5 min. and then treated with a solution of 25 (537 mg, 2.6 mmole) in 7 ml of ethanol. The resulting mixture was stirred for 30 min. and then neutralized with 10% HOAc-EtOH. After removal of ethanol, the residue was worked up and the excess 4-hydroxy- cyclohexanone was removed by Kugelrohr distillation (5 x 10.!"L mm, 110°C, 40 min.). The residual dark red oil (0.99 g) was chromatographed on alumina (50 g, neutral, activity grade I): eluting with CHCl3 gave 148 mg of 33 and then 525 mg (67%) of 34. Analytical samples of 34 and 35 were crystallized from ether—ethyl acetate: 34: mp 145—1470; IR (00013) 3601, 1733, 1673, 1612, 1573 cm‘l; PMR (00013) 6 0.94 (S, 3H), 1.17 (8, 3H), 1.41-3.75 (m, 17H), 4.24 (m, 1H), 5.97 (d, 1H, J=12 Hz), 7.45 (d, 1H, J=12 Hz); UV (CH30H) lmax= 312 nm, 6: 29000; MS (70 eV) m/e (rel 29 intensity) 302(37), 287(37), 190(34.5), 178(30), 164(100). Anal; Calcd. for C19 3: C, 75.46: H, 8.67 Found: 0, 75.55; H, 8.76 35; mp 214-2170, IR (00013) 3583, 1734, 1651, 1618, 1591 cm‘l; PMR (00013) 6 0.99 (s, 6H), 1.23 (s, 6H), 1.45-3.45 (m, 25H), 4.28 (m, 1H), 6.08 (d, 2H, J=12 Hz), 7.74 (d, 2H, J=12 Hz): MS (70 eV) m/e (rel intensity) 490(58), 475(51), 378(25). 352(100): UV (CHBOH) km H260 ax: 360 nm, €= 29000. Preparation of keto selenide 234 A three neck, round bottom flask, equipped with addi- tion funnel, was cooled to +7800 and charged with diiso- pr0pylamine (1.8 ml, 12.8 mmole), 2.3M of n-BuLi (5.2 ml, 12 mmole) and 20 ml of THF. The mixture was stirred for 15 min. and treated with a solution of cyclohexanone (1 ml, 9.7 mmole) in 8 ml of THF. Into the funnel was added PhZSe2 (1.8 g, 5.8 mmole) and 10 ml of THF. Bromine (0.3 ml, 5.5 mmole) was then added dropwise to the solution. After 10 min. the PhSeBr solution was added to the enolate solution in one portion. The resulting mixture was stirred for 15 min., poured into 50 ml of 0.5 N HCl and extracted with 50% ether-pentane. The organic layer was washed with. sat. NaHC03, water and brine. After dring and removal of solvent, 3 g of crude product was obtained. An analytical sample of 3é,was crystallized from ether-pentane: mp 57- 58°: PMR (0014): 6 1.4—3.1 (m, 8H), 3.7 (br t, 1H, J=5 Hz), 6.85—7.48 (m, 5H). 30 Reaction between keto selenide 29 and allylic chlorideAzz; To a solution of 1 equiv. LDA (made in situ from 0.6 ml of 2.42M n-BuLi and 0.22 ml of'diisopropylamine) at 0°C, was added 0.3 ml of HMPA followed by drOpwise addition of keto selenide 36,(360 mg, 1.42 mmole). The mixture was stirred for 5 min. and allylic chloride 3319 (280.5 mg, 1.24 mmole) was added in one portion. After stirring at room temperature for 3 hr, this reaction mixture was quenched with water and worked-up to give 613.8 mg of a brown oil. However, the PMR and MS showed that this oil was a mixture of starting materials, and no 28 could be detected. Preparation of olefin 39. To a 10 ml, three neck, round bottom flask equipped with a condenser and argon inlet was added 4 ml of ether and 0.2 ml of 2.42M n—BuLi (0.48 mmole) followed by methyl- triphenylphosphonium bromide (239 mg, 0.67 mmole) in two portions. After 2.5 hr, a solution of 34 (30.2 mg, 0.1 mmole) in 2 ml of THF was added and the mixture was heated to 50°C for 1.5 hr. After cooling to room temperature, the precipi- tate was removed by suction filtration and washed with ether and ethyl acetate. The combined filtrates were washed with water and brine, dried and stripped of solvent. The residue (150 mg) was chromatographed on a preparative alumina plate, elution with 45% ethyl acetate-hexane giving 5 bands. The first band gave 4 mg of 25 and the second band 31 gave 5 mg of 23. The latter material had the following properties: UV (ethanol) Amax=270 nm, 6:22000: MS (70 eV) m/e (rel intensity) 300(21), 267(95), 149(100). Reaction of dienone 24'with Wittig reagent in DMSO. Sodium hydride (40 mg as a 57% dispersion in mineral oil, 0.95 mmole) in a 25 ml three neck flask was washed with several portions of pentane to remove the oil. The system was alternatively evacuated and filled with argon: 3.5 ml of DMSO was added, and the mixture was heated to 7500 until the evolution of hydrogen ceased (about 45 min.). The resulting solution of dimsyl sodium was cooled to room temperature and treated with methyltriphenylphosphonium bromide (31? mg, 0.89 mmole) in 3 ml of DMSO. The resulting yellow solution was stirred at room temperature for 15 min. and then mixed with 34'(45 mg, 0.15 mmole) in 2 ml of DMSO. This mixture was heated at 50°C overnight, cooled to room temperature and poured into water. The usual work-up followed by chromatography on a preparative alumina plate with 45% ethyl acetate-hexane gave 18 mg of 34'and 9 mg of side products. No olefin 33 could be detected. Isomerization of 34 to 41. N .v- A solution of 34 (8.4 mg, 0.028 mmole) in 22 ml of methanol was irradiated at 0°C with a medium pressure mercury lamp, the light from which was filtered through aqueous 13% copper sulfate. The reaction was followed by 32 reverse phase analytical HPLC; eluting with 45% MeOH-HZO. After irradiation for 20 min., the solution changed to a 1:1 mixture of 33 and 43. Longer reaction times did not change the equilibrium concentration, but caused decomposi- tion of both isomers. The UV absorption of the reaction mixture did not shift to shorter wavelength as reported in 21 vitamin D chemistry , but the extinction measured at 305 nm had decreased by 12% after 3.3 hr. Preparation of enol ether 434_ To a solution of 2.42M n-BuLi (10 ml, 24.2 mmole) in hexane at 0°C was added drOpwise 3.65 ml of TMEDA (24.2 mmole), followed by 3.6 ml of diis0pr0pylamine (25.8 mmole). After 10 min. this solution was cooled to -78°C and formed some precipitate which was dissolved by adding 5 ml of THF. A solution of 43_(3.3 g, 23.8 mmole) in 3 ml of THF was added over a 5 min. period. After stirring for 40 min., 1.56 ml of methyl iodide (25 mmole) was added and the resulting turbid solution was stirred overnight, quenched by water and extracted with ether. The organic layer was washed with 2N HCl, water and brine. Drying and removal of solvent gave 3.21 g (88%) of 43, which had the following prOperties: PMR (CClu) 6 1.05 (d, 3H, J=6 Hz), 1.33 (t, 3H, J=7 Hz), 1.5-2.5 (m, 4H), 3.81 (q, 2H, J=7 Hz), 5.1 (s, 1H); MS (70 eV) m/e (rel intensity) 154(36), 112(68), 84(100), 68(76). 33 Preparation of unsaturated ketone 45; To a suspension of lithium acetylide-ethylenediamine complex (400 mg, 4.35 mmole) in 5 ml of THF at 38°C was added dropwise a solution of 43(643 mg, 4.17 mmole) in THF. The mixture was stirred at room temperature overnight and TLC indicated there was still some starting material left. However, addition of more lithium acetylide and a longer heating period did not complete the reaction. After cooling to room temperature, water was added slowly to quench the reaction, and the usual work-up gave 640.8 mg crude product which showed 70% addition from PMR (80% addition can be obtained by using 1.7 equiv. of lithium acetylide in 50% benzene-THF). During separation by HPLC (25% ethyl acetate -hexane, silica gel) the acetylenic alcohol 43 lost ethanol giving 305 mg (55%) of 43 along with 160 mg of 43. Ketone gé’had the following prOperties: IR (neat) 3234, 2084, 1673, 1575 cm’1; PMR (00013) a 1.38 (d, 3H, J=6.8 Hz), 1.59-2.95 (m, 5H), 3.59 (s, 1H), 6.24(d, 1H, J=2 Hz): MS (70 eV) m/e (rel intensity) 134(53), 119(46), 117(48), 106(100), 78(56). A 2,4-DNP derivative of 43 was prepared and crystallized from ethanol: mp 147-1480. Anal. Calcd. for 015H14N4O4‘ C, 57.32; H, 4.49; N, 17.83 Found: C, 57.44; H, 4.51: N, 17.89 Preparation of ketal 46. A mixture of ketone 45 (1.1 g, 8.2 mmole), p-toluene- sulfonic acid monohydrate (82 mg, catalytic amount) and 34 2-methyl-2-ethyl-1,3-dioxolane (18 ml, excess) was heated and the liberated butanone distilled slowly. The mixture was stirred at 100°C overnight in order to get the thermo- dynamically more stable isomer 46. The cooled reaction mixture was diluted with ether, washed successively with 5% aqueous sodium bicarbonate and water. Drying and removal of solvent gave 1.34 g crude product, which was chromatographed on HPLC (silica gel) with 17% ethyl acetate-hexane to afford 0.71 g of 49 (49%): IR (neat) 3218, 2084, 1089, 1067 cm‘1; PMR (C014) 0 1.5-1.8 (m, 4H), 1.88 (br s, 3H), 2.23 (m, 4H), 2.83 (s, 1H), 3.84 (s, 4H): MS (70 eV) m/e (rel intensity) 178(63), 163(13), 86(100). Preparation of alcohol 43;_ A solution of phenyl acetylene (0.26 ml, 2.4 mmole) in 8 ml of ether was treated with 2.42M n-BuLi (0.84 ml, 2 mmole). This mixture was stirred at room temperature for 1 hr, cooled to 0°C, and a solution ofI2’(180 mg, 1 mmole) in 5 ml of ether was then added. After stirring for 2.5 hr at 0°C followed by overnight at room temperature, the reaction was quenched with water and worked up as usual. The residue was chromatographed on HPLC (silica gel) with 25% ether-hexane to give 177.6 mg (63%) of 43. Crystalli- zation from ether afforded 80 mg of analytical sample: IR (0014) 3630, 1735, 863 cm‘1; PMR (0014) a 1.03 (s, 3H), 1.2 (s, 3H), 1.3-2.5 (m, 11H), 7.15 (s, 5H): MS (70 eV) m/e (rel intensity) 282(2), 281(12), 267(7.5), 260(1.5), 35 239(7). 170(100). 169(100)- Preparation of alcohol 59; Sodium hydride (65 mg, 52%, 1.54 mmole) was washed with pentane to remove the mineral oil and heated with 3 ml of DMSO at 50°C until hydrogen evolution was complete. After cooling, a solution of 46 (230 mg, 1.29 mmole) in ' 1 ml of DMSO was added dr0pwise. The resulting deep blue mixture was stirred for 0.5 hr and then treated with cyclo- hexanone (0.13 ml, 1.25 mmole). This reaction mixture was stirred at room temperature overnight and quenched with water. The usual work-up gave 230.8 mg of a red oil, which was chromatographed on HPLC (silica gel) with 20% ethyl acetate-hexane to give 160.6 mg (47%) of 58. An analytical sample was crystallized from ether and displayed the following properties: mp 79.5-80.5O: IR (CDClB) 3608, 3485, 1070 cm‘1; PMR (00013) 6 1.0-1.8 (m, 10H), 1.87 (br s, 3H), 2.07—2.47 (m, 4H), 3.75 (s, 4H): MS (70 eV) m/e (rel inten- sity) 276(4.6), 261(2.1), 86(100). Anal. Calcd. for C17H2403: C, 73.88: H, 8.75 Found: C, 73.86; H, 8.72 Reaction of ketone 3 with acetylide.47(a)4_ Isl—L AIM To a solution of 2.42M n-BuLi (0.39 ml, 0.94 mmole) and TMEDA (0.15 ml, 1 mmole) in THF at 10°C was added dr0pwise a solution of 49 (184 mg, 1.03 mmole) in THF. The resulting brown solution was stirred for 25 min., then 36 cooled to -78°C and treated with a solution of ketone 2’ (81 mg, 0.45 mmole) in THF. After stirring for 1 hr at -78°C, followed 1.5 hr at 0°C, the reaction mixture was worked up in the usual way. The crude product (0.23 g) was chromatographed on HPLC (silica gel) with 23% ethyl acetate -hexane to afford 88.1 mg of 49 and 60 mg of 2; Transformation of ketal 4é_to alcohol 53;_ To 3 ml of a dimethyl sulfoxide solution of dimsyl- sodium (1.28 mmole) was added a solution of 49 (192 mg, 1.08 mmole) in 2 ml of DMSO. This solution was then treated with ketone 21(82 mg, 0.46 mmole) in DMSO and the mixture was heated at 50°C for two days. After cooling, the usual work-up gave 110 mg of crude product. This oil was spread on a preparative silica gel plate: eluting with 20% ethyl acetate-hexane gave four bands. The third band yielded 15.2 mg of 53: IR (CD013) 3590, 1601, 1567, 1490, 1283, 1243, 1071, 1037 cm-1:PMR (0014) 0 1.85 (s, 1H), 2.24 (s, 3H), 3.6-4.2 (m, 4H), 5.17 (dd, 1H, J=10.4, 2 Hz), 5.47 (dd, 1H, J=17.6, 2 Hz): MS (70 ev) m/e (rel intensity) 178(66.5), 134(100), 133(88.5). Reaction of ketone 3 with Grignard reagent from 46. N IV— To a three-neck, round bottom flask containing magne- sium turnings (24 mg, 1mmole) and ether was added dropwise an ether solution of methyl iodide (0.036 ml, 0.58 mmole). After this mixture became turbid, it was stirred for 37 30 min. to complete the methyl magnisium iodide formation and then a solution of 46 (104 mg, 0.58 mmole) in ether was added dr0pwise. The reaction mixture was stirred for 1 hr and then treated with a solution of 21(47 mg, 0.26 mmole) in ether. After stirring at room temperature overnight, this solution was quenched with sat. ammonium chloride and worked up in the usual way. The crude product (147.5mg) displayed spectral and chromatographic pr0perties identical with a mixture of 46 and 3. N Attempt to trap enolate from 2’with t-butyldimethylchloro- silane. - To a solution of dimsylsodium (0.57 mmole) in 3 ml of DMSO was added dr0pwise a solution of 49 (100.7 mg, 0.56 mmole) in.DMSO. The mixture was stirred for 30 min. and combined with a solution of 2’(47 mg, 0.26 mmole) in DMSO. After 3.5 hr, this solution was mixed with a solution of t-butyldimethylchlorosilane (135 mg, 0.90 mmole) in THF. The resulting mixture was stirred overnight, quenched with water and extracted with ether. The usual work-up yielded 199 mg of crude product which proved to be a mixture of 2’ and some unidentified isomers of 48. The GLPC analysis and mass spectrum of the crude product showed that no silyl ether 52 was formed. AJ 38 .ErenarafiebLef_eleehel_fig; To a solution of 4é’(200mg, 1.12 mmole) in THF was added dropwise 2.42M n-BuLi (0.42 ml, 1.02 mmole) at room temperature. This mixture was stirred for 1 hr, cooled to 0°, and then treated with a solution of 2J(90 mg, 0.5 mmole) and lithium iodide (160 mg, 1.20 mmole) in THF. After stirring for 2.5 hr at 0°C, followed by overnight at room temperature, the reaction was quenched with water and extracted with ether and ethyl acetate. This extract gave 250 mg of crude product, and 205.7 mg of the residual oil was chromatographed on two preparative silica gel plates. Elution with 25% ethyl acetate-hexane gave 18 mg (12%) of 48. IR (0014) 3605, 1738, 1065 cm-1: PMR (001“) a 0.92 (s, 3H), 1.12 (S, 3H), 1.28-2.45 (m, 20H), 3.75 (8, 4H): MS (70 eV) m/e (rel intensity) 358(3.5), 340(2.5), 246(12), 180(21), 110(31), 88(67), 86(70), 70(100). An analytical sample of 4é'was crystallized from ether-ethyl acetate, mp 134.5-135°. APPENDIX 39 ...). ‘1‘.Ilalll.1u . a ally-VII. III! 1"".QIIIII.’ \l. ‘11.!- : H L . . _ w l -f: - .1 ..; - -2. ..v-.-fi: _ _ . _ . _ . . . _ . . - a . : . . L L .--.x -:.-.. r- 1..-..--.- - :-.r--l--;L-;. -:-+-:.+: _ W .4 + 1 1 . _ * - - 2-9T- --I-rl .. 1:.-11s-qt- - --------.-I!!|h..-:.--. . - - - .- w . . H H 1 _ . L T: ... .-O -1.--“ Y - a- - .o o... . -1 . ....... 51.-.; ......... :.. u *- _ _ H w _ H IT...: 1 70.: .4. ..... r0. 9: u ..I ll .H: C!» I w ......... p ....... .W . H . - . . W M m. . a . h 1 ....... ....<.. Lvlilnwbl-Lv.I-:«vl‘lp ...sz 1 F1-.. L--- .. H . w -v: Ir. .... . ...... :5. In...4 (I)! (I n: III-fillllu-.n.lx 1 _ . . . ,;.. L;_ H :7 lri M _ . _ ” ...! 1. - ..ol , _ . - 1|-- 0 ..- u :_.. f M L. w . . . _ . . . . . . [41.-Ti..- I till»- ..i --- .- . n - _ . p _ :5. .l Illllwul. (A -A rl0.9..|0h.l L l m 0 _ _ a . .. a a _ . H rw - w- 4 r i I !% - - 804 O .O Aoamoz . *5 8 r I, I :0 ”I 1:“: I“ A l I 1 ' £0 go me Ito M: m/e Figure 31. Mass Spectrum Of i3. fit I“ E 0 0a ”0 C: a) +3 .5 4o ~+ _ ‘1’ . 54 )c . . 1 :l 1 9o [00 no 40 m/e Figure 32. Mass spectrum of i3” 61 9 8‘ l I rel intensity(%) t 3’ j IIIHTII [L l ,. L . Figure 33. Mass spectrum of 29. m I'D H0 m Q V9. :>. P . or! 2.. Q) +3 :3 "a“. H G) s. h . . Am I lit fly “a I ’20 If? Figure 34. Mass spectrum of fig. g.” l "I ’ ’7‘: 9% ‘30 62 rel intensity(%) l , 5. i.’ 5 [I ! - gig l I ' d 3!, Judi"?! J: "I ' ...” LII!“ ll m/e Figure 35. Mass spectrum of E2. "3° A K. .5 ‘.' rel intensity(%) J 1:“! [U] MIJII “I “J m/e Figure 36. Mass spectrum of i3' HO Ibo : 5” 63 'lL . 1...: 2. __ __ AA La 3.; - rug. 2.. . . - n“; :2 V. add _= 01 an“ x95. L mo eznpommm mmmz .mm mndmwm — $fi m\t I a T— To u q? 9 u .8 ”To 0.9,. m“) % 0.00— wo .m/m... mo 85.3.0QO 520 .mm mhzwflm EEEEEEEEEEEEE.EEr.EEE..E Fl 61+ ; E...E.EE .EE EEEE , E . EEEEE ......E EEEEEE EEEEEEEE. E E EEEEE.EEE.E EEEEEEEE EEE. EEEE EEEEEEEEEEEEE EEEEEEEE . E EEEEEEEEEEEEE EEEE EEE EEEEEEEE EEEEEEEEEEEEEE AEEA Leg... PART II TYPE I PHOTO-REACTIONS OF BICYCLIC KETONES INTRODUCTION Ring opening reactions of 6—methyl-5-hydroxy-tricy- clolfl-u-O-QJdecane-9-oneIi have been studied in our laboratoryu. The formation of trans-1,6-dimethylbicyclo- [4-3-Q]nonane-2,7-dione é, a versatile intermediate in synthesis, from reaction of l'with methanolic base]+ was particularly interesting. OH 0 $ + 0 CH3OH-H20 O 1 N 20% O . I. O trace 65 66 In connection with our published study of this reaction, it was important to find out whether the cis- isomer 3 was also present among the products. To this end an independent synthesis of ’3’ from 3’ was developed, and the chromatographic and spectroscopic properties of these isomers were compared. Compoundtg held additional interest as a potential intermediate for a synthesis of pinguisoneBl. 2: Pinguisone It is known that n.» n* photoexcitation of saturated ketones causes homolytic cleavage of a bond a to the excited carbonyl function (Norrish type I process)37, The biradicals derived from cyclopentanones and cyclohexanones then undergo subsequent reaction to: (1) form ketenes through transfer of Ha; (2) form unsaturated aldehydes through transfer of Hb: and (3) recyclize to the starting ketone or a stereoisomer thereof (Scheme I). 67 0 O {5&0 Ha .' E:V/J g 11) _i§l__9 Hb Scheme I The third process has been used to epimerize 17-keto steroids to analogs having an unnatural configuration. For 32 example : estrone 1 . 5.5 In 1971 N. C. Yang33 reported a study of the photo- chemistry of 8-methyl-1-hydrindanones tga and fib) and 9-methyl-1-decalones (2a and 2b). 68 ##“® 5a 5b N ~ ~ Irradiation of these compounds in hexane yielded the corresponding configurational isomers and an unsaturated aldehyde é’as the only products detectable by GLPC. The 6 IV (CH2)ncHo following conclusions were drawn: 1. The rate of a-cleavage decreased as the internal strain of these molecules decreased. 2. The quantum efficiencies of isomerization depended on the stereochemistry of ring closure of the biradical intermediate Z'(Scheme II). Thus photoisomerization occurred much more efficiently from trans-ketones than cis-ketones (e.g., ¢4b~fig=°'“6' ¢ia~fib=o'02)' This suggests preferentiaI ring closure of the biradical intermediate from the axial side. 69 ~o H 4b N equatorial closure hV O “V —‘ flfi o . <: H axial closure _.1 . H 4a 7 A, AJ H ~a 0 hv \ <— o equatorial closure g, + [ketenes] {—— Scheme II 70 In this dissertation, type I reactions of diketone 3’ and some derivatives have been studied. RESULTS AND DISCUSSION Irradiation of dione g’in.ether gave the cis-isomer 2' as the major product detectable (>90%) by GLPC, but the actual yield of 2’was only 16% when compared to an inter- nal standard. When this reaction mixture was washed with 5% aqueous sodium hydroxide, only 53% of neutral product was obtained from the organic layer. This result suggested that the poor yield of epimerization was due to formation of a carboxylic acid via a ketene intermediate. + acids 2 rv This ketene intermediate was trapped as a methyl ester by irradiation of g,in.methanol. Two pathways of this kind can be envisaged, as illustrated in Scheme III. The isolated ester is assigned as é'rather than 2 because of the absence of a 1710 cm-1 absorption band in its IR spectrum. Additional support for this assigned structure was provided by its mass spectrum. The m/e 112 and m/e 7h 71 72 O ‘ 0 hv 3 ‘B H-transfer; I . H ' .5 o7 H o ' . CH OH hv 3 Scheme III 73 fragments were formed by McLafferty rearrangements involving ketone and ester groups of g, Hydrogen transfer and bond rupture from the initial a-cleavage product 18 generated the m/e 82 and m/e 55 fragments. M+ of 8 m/e 112 m/e 97 c>+ . COZCH3 H-transfer 3 COZCH3 H ‘E; o n” OH .+ 04 N m/e 82 m/e 74 The formation of ester Q'indicates a preferential a-cleavage of the six-membered ketone‘g, This is a surprising result since it is not consistent with the 74 strain effect noted earlier by N. C. Yang33. Furthermore, mass spectral studies of specifically labeled analogs (11a and 13b) of g'indicate that fragmentation of the methyl group adjacent to the six-membered ketone function is six times more facile than fragmentation of the other methyl groupsb’ 38- 0 CD3 11a N The most straightforward rationalization of this fragmentation selectivity assumes that opening of the strained five-membered ring is faster than the correspond- ing Opening of the six-membered ring. V/ 0 -CH- 75 In order to exclude the influence of the carbonyl group on the six-membered ring, dione g'was reduced selectively to alcohol 12 by the action of sodium boro- hydride27a . When a solution of alcohol 12 in ether was irradiated until all the starting material was consumed, the product proved to be lactone 14 rather than cis-isomer 13. Reduction of 14 with lithium aluminum hydride gave diol 15 providing additional support for the assigned structure. 50 min. In a second study of 13, it was found that both 13 and 14 were formed in the early stages of photolysis, and that 13 was consumed during a longer irradiation (Table I). IV Table I. Irradiation of 1% as internal stan ard. 76 in benzene, using phenyl ether time/percentage(%) 1g 12 14 ‘ totalI O min. 100 O O 100 25 min. 28 34 16 78 50 min. 5 38 28 71 85 min. 2 25 42 69 120 min. 0 18 43 61 A similar result has been reported by Huppi and co- workers34 (Scheme IV). In their study, a-acetoxy-B- hydroxyketone 19 was isomerized to acetoxylactone 12 in 88% yield on irradiation in benzene. The mechanism was presumed to involve.arcleavage to biradical 13, followed by an intramolecular hydrogen transfer and subsequent lactonization of ketene 18. In order to show whether lactone 13 was formed by a similar pathway, alcohol 13 was irradiated in methan0135: however, none of the expected ester 23 could be detected. Ketene 21 was subsquently trapped by adding t-butylamine (Scheme V and Table II). 7? OAc .. I M \ 7 o AcO 0“ 16 N \V I W 7‘ . lg ,. [0H AcO J 17 18 Scheme IV 78 Scheme V Table II. Irradiation of 12 and 10 equiv. of t-BuNH2 in ether time/perc entage (9%) 12 12 15 2'3 0 hr 100 O O O 1 hr 21.1 38.7 2.9 3.4 2 hr 4.2 44.2 7.1 8.4 3 hr 0 33.7 8.7 10.3 79 The experimental data showed that amide a; was formed along with lactone 14. Addition of more t-butylamine only slowed down the reaction, perhaps by forming a charge- transfer complex with biradical 2936. Since the isolated yield of epimerized alcohol 13 was low, the photo-epimerization of a derivative of 13 was examined. Irradiation of acetate 24, prepared from 1g’by reaction with acetic anhydride in pyridine, gave cis-isomer 23 in 43% yield. Alkaline hydrolysis of 25 followed by oxidation with pyridinium chlorochromate provided the desired cis-diketone 21(Scheme VI). KOH/CH3OH pyridinium 41 W chlorochromate Scheme VI 80 The three cis—isomers obtained from these photo- epimerizations, dione 3, alcohol 13 and acetate 25, were N N N easily distinguished from the correponding trans-isomers by PMR spectra and GLPC analyses. The two angular methyl groups of the trans-isomers are separated by a larger chemical shift than those of cis-isomers. The C-5 proton of acetate 24:3howed a broader PMR signal than that from acetate 25. This suggests that the former is axial and the latter equatorial. The same difference existed between 12 and 13. Compound 3, 13 and 25 have shorter N N ”I N N retention time on GLPC (4% QF—l) than their trans-isomers. From these results, we can show that 2’is not formed in the ring Opening reaction of’1. EXPERIMENTAL GENERAL In addition to the general described in Part I, all the irradiations were carried out under nitrogen at 000 with light from an ACE-Hanovia 450 W. medium-pressure mercury lamp. The reactions were followed by GLPC (4% QF-l, 160°C). _rradiation of dione 2 in ether. A solution of dione 2,(617.3 mg, 3.43 mmole) in 300 ml ether was irradiated through a corex filter until the ratio of cis—isomer‘g t°,§ was 30:1 (2hr). Removal of the solvent gave 701 mg crude product. The internal standard analysis indicated that the yield of 2’was 16% (Table III). Table III. Comparison of Q’and crude product with tri— methyl-l,3,5—benzenetricarboxylate 26 by GLPC. run sample weight integration ratio 1 2’(authentic) 4.5 mg 40.8 ' 26 4.9 mg 28.0 2 crude product 10.8 mg 42.5 88 4.2 mg 73-5 81 82 The ether solution of 649 mg of crude product was washed with 5% NaOH. The organic layer was concentrated to 349 mg of oil, which was chromatographed on HPLC (silica gel) with 0.5% CHBOH-CHZCl2 to afford 90.2 mg (15%) of 2; The aqueous layer was neutralized and then extracted with chloroform. Removal of solvent gave 198 mg of unidentified residue. Irradiation of dione gfiin methanol. A solution of 2’(115.5 mg, 0.64 mmole) in 75 ml of methanol was irradiated for 50 min. through a corex filter. Removal of the solvent gave 140 mg of crude product which proved to be a mixture of'8’(70%),‘2,(15%) and side products (15%). An analytical sample of esterig, collected by GLPC (4% QF-l, 175°C), showed the following properties: IR (neat) 1736, 1200 cm'lg MS (70 eV) m/e (rel intensity) 212(o.39). 181(2.27), 97(58.94), 82(38.89), 74(27.25), 55(71.uo), 41(100). Preparation of lactone 14 by irradiation of alcohol 13; A solution of alcohol 13 (801.8 mg, 4.4 mmole) in 74 ml of ether was irradiated for 5 hr through a corex filter. The solvent was removed with the aid of a roto- evaporator. Recrystallization of the residue from ether- pentane gave 129.8 mg (16%) of lactone 13. The mother liquid contained lactone 14 and some unidentified high 83 molecular weight compounds. Lactone 13 displayed the following prOperties: mp 73-73.5O; IR (C014) 1741, 1250, 1205, 1138 cm’l; PMR (00013) a 0.83 (d, 3H, J=8 Hz), 0.9 (8, 3H), 1.1-2.1 (m, 9H), 2.38 (d, 1H, J=6 Hz), 2.55 (dd, 1H, J=6, 2 Hz), 4.1 (t, 1H, J=3 Hz); MS (70 eV) m/e (rel intensity) 182(34), 164(7), 122(22), 110(44), 96(100). Aggl; Calcd. for C11H1802: C, 72.36; H, 9.88 Found: C, 72.49; H, 9.96 Reduction of lactone 13 to diol 15; To a refluxing suspension of lithium aluminum hydride (50 mg, 1.3 mmole) in 20 ml of ether was added dropwise a solution of lactone 14 (130 mg, 0.71 mmole) in 10 ml of ether. The reduction was followed by GLPC, and the reaction mixture was quenched by careful addition of 1.5 ml of water and 1 ml of 10% aqueous NaOH when 14 was consumed. The precipitated solids were filtered and washed with methanol. The combined filtrate and wash were evaporated at reduced pressure, and the resulting residue was extracted with ether. After the ether extracts were washed with brine and dried, removal of the solvent and crystallization from acetone—hexane gave 89.2 mg (68%) of 13. mp 109.5-1110; IR (00013) 3613, 1451, 1376 cm'l; PMR (00013) 0 0.77 (s, 3H), 0.8 (d, 3H, J=5 Hz), 1.1-1.8 (m, 11H), 1.84 (s, 2H), 3.4-3.7 (m, 3H); MS (70 eV) m/e (rel intensity) 186(4), 168(15), 156(21.5), 109(92), 84 41(100). Short irradiation of alcohol 12; A solution of alcohol 13 (240 mg, 1.32 mmole) in 250 ml ether was irradiated for 50 min. through a corex filter. The concentrated residue was dissolved in 5% methanolic sodium hydroxide and stirred for 1 hr. After the methanol was removed under reduced pressure, the residue was extracted with ether and the combined extracts were washed and dried. Removal of the solvent gave 167.5 mg of crude product from which 143.3 mg (60%) of 13 and 13 in 1:4 ratio was obtained as white solid by Kuglerohr distillation. The aqueous layer was acidified and extracted by chloroform to give 73 mg (30%) of lactone 14. Irradiation of alcohol 12 with added t—butylamine. A solution of alcohol 13 (25.8 mg, 0.14 mmole), t—butylamine (0.146 ml, 1.4 mmole) and tetracosane (13.9 mg, 0.042 mmole) in 5.5 ml ether was irradiated through a corex filter. The results are listed in Table II. An analytical sample of amide a; had the following pr0perties: mp 108.5-110.5O; IR (00013) 3600, 3419, 1650 cm'1; PMR (QDClB) 6 0.72 (S, 3H), 0.77 (d, 3H, J=7 Hz), 1.3 (s, 9H), 1.4-2.0 (m, 9H), 2.07 (d, 2H, J=6 Hz), 3.42 (br s, 2H), 5.5 (br s, 1H); MS (70 eV) m/e (rel intensity) 255(1.05), 237(0.36), 227(0.52), 222(0.37). 128(24.38), 115(9u.42), 85 58(100). Preparation of acetate 24; To a solution of alcohol 15 (297.5 mg, 1.63 mmole) in 25 ml of pyridine was added 5 ml of acetic anhydride (excess). This solution was stirred for two days and quenched with ice water. Most of the pyridine was removed at reduced pressure and the residue was extracted with ether, washed with 5% HCl, 10% NaHC03, water, brine and dried. Removal of the solvent gave 246.6 mg (67%) of 24 which was crystallized from petroleum ether to give pure 23 (66%): mp 49.5-51.50; IR (0014) 1738, 1238 cm’1; PMR (CDClB) 0 0.94 (S, 3H), 1.22 (S, 3H), 1.33-1.95 (m, 8H), 2.07 (s, 3H), 2.25 (m, 2H), 4.93 (br t, 1H, J=2 Hz); MS (70 eV) m/e (rel intensity) 224(2), 182(1.06), 181(1.27), 164(1.62), 136(5.68), 122(10.11), 108(10.49), 43(100). Preparation of acetate 25; A solution of acetate 23'(128 mg, 0.57 mmole) in 75 ml of ether was irradiated for 9 hr through a pyrex filter. Removal of the solvent gave 140 mg of crude pro- ducts giving four components on GLPC, of which acetate 25 proved to be the major product (65%). Recrystallization from petroleum ether gave 32.8 mg of 23, The residue was purified by HPLC (silica gel), eluting with 15% HOAc- 86 hexane to give 29.3 mg of acetate (25:23=4.6:1). Acetate 25, obtained in 45% yield, had the following properties: mp 75-760; IR (0014) 1741, 1236 cm'1; PMR (00013) 0 0.92 (s, 3H), 0.99 (s, 3H), 1.2-1.9 (m, 8H), 2.0 (S, 3H), 4.8 (broad, 1H); MS (70 eV) m/e (rel intensity) 224(5), 182(9), 164(14), 145(19), 122(21), 111(32), 109(38), 44(100). Anal. Calcd. for C13H2003: C, 69.61: H, 8.99 (C:H=7.74) Found: C, 68.17; H, 8.86 (C:H=7.69) or C, 68.33; H, 8.87 (C:H=7.70) Acetate 25 is easy to sublimate, so that the found percentage of C and H is lower than the calculated value. However, the ratios of C to H are consistent. Hydrolysis of acetate 25; To a solution of KOH (0.4 g, excess) in 4 ml of methanol was added acetate 25 (202 mg, 0.90 mmole). This mixture was stirred for 30 min., following which the solvent was removed at reduced pressure. The residue was extracted with ether and water, washed with brine and dried. Evaporation of the ether yield 145 mg (89%) of alcohol 13: IR (00013) 3600, 1720, 1450, 1380, 1090 cm"1; PMR (CD013) 0 0.96 (s, 3H), 1.0 (s, 3H), 1.2-1.8 (m, 9H), 2.3 (br s, 2H), 3.58 (broad, 1H); MS (70 eV) m/e (rel intensity) 182(32.5), 167(36), 149(30), 122(42), 111(92), 109(100). 87 Oxidation of alcohol 13. f Ar «r- A solution of alcohol 13 (245 mg, 1.35 mmole, crude product) in CHZCl2 was added to a suspension of pyridinium chlorochromate (232.6 mg, 1.13 mmole) in 20 ml of CH Cl 2 The reaction mixture was stirred vigorously for 24 hr, 2. diluted with ether and filtered through Florisil. The filtrate was washed with water, brine and dried. Removal of the solvent followed by recrystallization from ether- pentane gave 74 mg (31%) of dione 2; mp 147-1500, IR (CClu) 1740, 1710 cm'1; PMR (00013) 0 1.0 (s, 3H), 1.17 (s, 3H) 1.3-2.9 (m, 10H); MS (70 eV) m/e (rel intensity) 180(2.78), 165(7.48), 137(7.00), 125(6.98), 110(8.93). 42(100). APPENDIX 88 1600 ----1.. wnnwwuwmw.-umwrmm~1 1--» 12.:1.Hum-1.-ww1u w“ .1m-w g..g - - - - m --w1.- 1 w - “lull-ad.1lll.1|l.11111. . . . H * . fl h. . 1 . . 1 ’ 1 _ _ 1 .1 ...-1118111111111111 5.31, . .1 P321..- 1 . 1 1 1 . .1 1 1 1 1 11.; . .. . 0 1 1 1 1 . _ . . 1 _ :1. _ - _ . .x:- . .1:.-11-111U f: r 1 1 . 1 1. 1 . 1 4 1 1 1 1 . w 1 , 1 1 1 1 1 1 u1..........-1|..1cl.h_11l1|1.1.1|.II-I_- ....... L f1..- '1. u “1-., 1 o 1.17. 311.17 .-. 2 (111((l‘11 . 1 1 . 1 . * ... ........ . -. )PHI’HMU'...‘ a.“ w .. M .. _. 1.15.1-.. 1 .1 m p , 10+ .. fl . .. ...o.» fir W11 . 11.. 7.91 . 1 . . . a . 1 . _..1_. T1 ..-..1- 1 . ..1. 1- .....1 - 1 1 1 m 1 . 1 1 ...1.- 0 1 -.-... -. 1 1 1 2 1 1 1 1 . . 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O 4000 2500 2000 1500 - m (Can't 3000 3500 . 1 9 ‘- o _ 1 _ u 0 _ . 1 I01 Ill ‘ .IOO'IIQI .‘0“1 0 o o . til: no.9l'QOIIIIA .. - . . 111.114 -1 . . ‘000 . 1 t .14 1,4-.- - 4L -‘-—.~--..-4 . . . --- J —..—._—.——4,.—-..—.. ..-—4 - . . . . y {ya—.— 0 +~ c . . . - - . - I - - o . 1 n - 1..___.“—0- H—.—4p ——-.—~ 0 -- u . . C u l . . ; ...—.4. . . o' . I 0 . o . . v.. I... 00! IOll.i'O‘O‘tIOOOOOO‘EnOOUO‘IVOQO ...-0.. I O 0 _ . 1 . . . . _ o - O . u .0 o .1 ‘ . o . . 7|... ? 0 009.10.100.01 '00-'01. O. I. ott|0-'-: - n t 1600 O O 6 4 1oc1wUZ<~Z< . .— . . . . —-—o-—0~ -—o——.uo-———-4 --— . . I . . l 21- [1‘01 1 -.'-I 0. 0 0| 0 II...‘ A ........ o o . — a I Q‘film". mu. -0» In. ............ to. . . .. I. u n o H a . . c........... v u. co .— o 0.. 10. .«. .... . . .m . . . h . I .-.TL!!.....L:-.+:.. . ... .. ... . .h. ” ... I .1”. I r; 00.0.? ...... VI '0 1.. 9s ..’ ........... ,o. N . . m r\. p M 4 “.0 a. C b. (A o -9 10.0 OV v. ..u ... Iv _ . . . . H . . _ {it a .104 v-6... 0... on. 00,.‘hnl‘b‘i\‘. . .o .o _ ~ . . .. .. . . . _ u I . . o .o'OJoOoOA c’Qvnao t ..'..o..u¢..o, .0. v o. I .V‘N.. ...... . fl . . . . ~ : ._ ... a ... . I u . _ , , , . .nvitoaO: OAo'IOO.9LI .-’..llaot ..... o ........ > ...... m .4 . I a ._ H m . _ ..’...a.v. o ov.,c~.~ .s . .. .. . _. . . a” . . n“ AMI! r- n. n;. AI. 6" 4 “I ‘ v II I - x p 1" . ‘ ...v .. v. a a .w u a _ ext mw ~14 c ~. . 1")" ‘(\'\f\ 1401‘C1A. Iii“! .1fi1!0|.|0¢ 9 , u - 0 O . 4— -—4__. n 1 a a I . 4 ... -..+ ‘.-. -fi.- .- ... ...... « ......~. ” _ . . a a . . . 0 fl . _ Q ....... M .. a . ....-. 0‘: .. o ‘lw: c. .o .. . m I a . . I . I I a . * . -h-- - . .- .- -.- . . _ . I 1600 1400 1200 1000 800 1800 .nuu 6 4 Ao.o.wUZ<»:< '5'. ...”! ,5 .4 ACC ‘ 9? r I m J 17.: “ a: 4 1:35 4 l ‘C I :3 4 | L | ‘5‘ 224 ' :49 19‘ ' 193 n ‘ 5“ "'9 150 m Figure 60. Mass spectrum of a3. 105 {at 35 : 5’ w ..—q Acc 9 “ B y C . OH 4‘ I 1 I 1 I I'u'I " 'I "E II M l! I 1321' '31 'g'l'l 1:": '1'! 'I'JL'11'I' 1'1 1", Figure 61. Mass spectrum of a3. LI S T OF REFERENC ES 1. 2. 3. 4. LIST OF REFERENCES J. W. Blunt, H. F. DeLuca and H. K. Schnoes, Biochemistry, Z; 3317 (1968)- D. R. Fraser and E. Kodicek, Nature, 238” 764 (1970). A. W. Norman, R. J. Midgett, J. F. Myrtle and H. G. Nowicki, Biochem. Biophys. Res. Comm., 43, 1082 (1971). W. Reusch, K. Grimm, J. Karoglan, J. Martin, K. P. ' Subrahamanian, and P. S. Venkataramani, J. Am. Chem. Soc., 10. 11. 12. 13. 23. 1958 (1977). . (a) R. B. Woodward, A. A. Patchett, D. H. R. Barton and R. B. Kelly, J. Chem. Soc., 1131 (1957); (b) J. Martin, Ph.D. Thesis, Michigan State University, 1976. (a) E. Havinga, Experientia, 22, 1181 (1973); (b) L. F. Fieser and M. Fieser, "Steroids", Reinhold Publishing Corporation, New York, 1959, pp. 146-150. (a) F. Gautschi and K. Bloch, J. Am. Chem. Soc., 23, 684 (1957); (b) M. Akhtar, K. Alexander, R. B. Boar, J. F. McGhie and D. H. R. Barton, Chem. Comm., 383 (1972). (a) H. H. Inhoffen, Angew. 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