synthesis of some naturally occurring sesquiterpenes

Abstract

Syntheses of Some Naturally Occurring Sesquiterpenes” consists of six chapters. Chapter 1 describes the first total syntheses of marmelerin (10) (isolated from Croton sonderianus Muell. Arg.), its positional isomer 12, and the linear isomer 7. Acylative cyclization of m-cresol methyl ether with crotonic acid afforded indanone 1, which upon Clemmensen reduction yielded 1,4-dimethyl-6-methoxyindane (2). Demethylation of 2, followed by alkylation of phenol 3 with methyl ?-bromopropionate, gave ester 4. Intramolecular acylation of the acid chloride derived from acid 5 furnished furanone 6 as the sole product. Treatment of furanone 6 with methylmagnesium iodide afforded the linear isomer 7 of marmelerin (10). In an alternate approach, 2,3,6-trimethylbenzofuran (8) was prepared from m-cresol in four steps, following the procedure used for converting 3 to 7. Acylative cyclization of 8 with crotonic acid gave a mixture of ketones 9 and 11. Modified Clemmensen reduction of 9 and 11, after separation, afforded marmelerin (10) and its positional isomer 12, respectively. Chapter 2 details the conversion of (S)-(+)-ar-turmerone (13) (available from turmeric oil) to (+)-?-cuparenone (26) (isolated from the essential oil of Mayur pankhi). Curcumone (14), obtained from ar-turmerone (13), was subjected to bromination followed by Favorskii rearrangement to yield ester 16 in poor yield. Alternatively, conversion of curcumone (14) to methyl curcumate (15), followed by alkylation (CH?I/LDA), gave ester 16 in good yield. Re-alkylation of 16 (CH?I/LDA) afforded ester 17. Attempts to homologate 17 to 24 via alcohol 18 and bromide 19 were unsuccessful. Alkylation of ester 16 with allyl bromide and LDA afforded ester 20, which was converted to hydrocarbon 23 via alcohol 21 and aldehyde 22. Ozonolysis of hydrocarbon 23, followed by oxidation with silver oxide, furnished acid 24. Rhodium-catalyzed intramolecular C–H insertion of diazomethyl ketone 25, prepared from chiral acid 24, gave (+)-?-cuparenone (26). Chapter 3A presents the synthesis of the naturally occurring bicyclic 1,4-naphthoquinone cadalenquinone (33) (isolated from Stahlianthus campanulatus). Treatment of tetralone 27 with acetic anhydride and perchloric acid led to an inseparable mixture of unchanged tetralone 27 and its enol acetate 28. Action of DDQ on this mixture furnished cadalenquinone (33) in poor yield. In an alternate route, DDQ treatment of hydroxymethylene ketone 30, obtained from tetralone 29, gave 5-hydroxycadalenal (31). Reduction of 31 with NaBH? afforded 5-hydroxycadalenene (32), which upon iodoxylbenzene oxidation yielded cadalenquinone (33) in good yield. Chapter 3B deals with a model study on one-step iodoxylbenzene oxidation of hydroxy-3-naphthol 37 to 1,2-naphthoquinone (38) and its application to the total synthesis of mansonone E (44) (isolated from Mansonia altissima Chev.). Reformatsky reaction of 6-methoxy-1-tetralone with methyl ?-bromopropionate gave unsaturated ester 34, which upon aromatization with DDQ furnished naphthyl ester 35. Reduction of 35 with LAH gave alcohol 36, which was demethylated to furnish hydroxy-3-naphthol 37. Iodoxylbenzene oxidation of 37 afforded 1,2-naphthoquinone (38) via a one-pot oxidation, conjugate addition, and reoxidation sequence. Treatment of 7-methoxy-6-methyl-1-tetralone (39) with methylmagnesium iodide, followed by dehydration, gave dihydronaphthalene 40. Metal-ammonia reduction of 40 yielded tetralin 41, which upon oxidation with Na?Cr?O? afforded tetralone 42. Hydroxy-3-naphthol 43 was prepared from 42 following the procedure described above for 37. Oxidation of 43 with iodoxylbenzene furnished mansonone E (44). Chapter 4 describes the total synthesis of a naturally occurring pterosin-type sesquiterpene alcohol (54) (isolated from the cultured mycelium of Fomitopsis insularis). Reformatsky reaction of 3,5-dimethylbenzaldehyde (45) with methyl ?-bromopropionate, followed by dehydration, gave unsaturated ester 46, which was hydrogenated to saturated ester 47. Alkylation of 47 (CH?I/LDA) afforded dimethyl ester 48. The dicarboxylic acid 51 was prepared by subsequent steps. Chloromethylation of 48 afforded 49, which upon cyanide exchange furnished 50, followed by acidic hydrolysis. Cyclodehydration of 51 with HF, followed by esterification, gave the keto ester 52. Modified Clemmensen reduction of 52 yielded ester 53, which on reduction with LAH afforded the sesquiterpene alcohol 54. Chapter 5 consists of the total syntheses of two rearranged oxycadalenes: 4-methoxyisocadalene (63) (isolated from Heterotheca species) and 6-hydroxyisocadalene (68), both of analogous biogenetic interest. Condensation of ethyl cyanoacetate with aldehyde 55 gave alkylidene cyanoacetate 56. Treatment of 56 with concentrated acid furnished amino ester 57. However, its amino function was inactive toward either diazotization or Bucherer reaction for conversion to naphthyl ester 60. Thermal cyclization of 56, on the other hand, gave cyanonaphthol 58, which was methylated to 59. Hydrolysis of 59, followed by esterification, afforded methoxy ester 61. Treatment of 61 with methylmagnesium iodide gave 62, which upon hydrogenation yielded 4-methoxyisocadalene (63). Action of methylmagnesium iodide on 8-isopropyl-5-methyl-1-tetralone (29) followed by dehydration gave dihydronaphthalene 64. Epoxidation of 64, followed by rearrangement of the resulting epoxide, afforded tetralone 65. Dehydrogenation of its enol acetate 66 with DDQ gave naphthyl acetate 67, which upon hydrolysis furnished 6-hydroxyisocadalene (68). In the Appendix, the mechanism of formation of dimeric indane 72, obtained as a byproduct during the synthesis of acid 71 by the action of 2-methoxy-5-methylphenylmagnesium bromide (69) on ethyl isopropylidene cyanoacetate (70), is elucidated. The intermediates 73 and 75, proposed in the mechanism leading to 72, were synthesized and separately treated with acid to yield dimeric indane 72. It was shown that 74 and 76, under identical experimental conditions, do not undergo fragmentation similar to 73. The former is recovered unchanged, while the latter gives indene 77 by cyclodehydration.