synthesis of some terpenic and other natural products of plant and marine origin

Abstract

The thesis entitled, "Synthesis of Some Terpenic and Other Natural Products of Plant and Marine Origin", consists of eight chapters.

Chapter 1 describes the first synthesis of two naturally occurring dehydrothymol derivatives (6 and 1), isolated from the roots of Calea pilosa Baker. The bromo compound 2, obtained by the NBS bromination of the key intermediate 1, was transformed into the corresponding acetate. Grignard reaction of the acetate 3 with excess MeMgI gave the diol 4, which underwent oxidation, concurrently with dehydration, using active MnO? to produce the monoterpenoid 6. The second monoterpenoid 2 was prepared from 1 in essentially two steps: Grignard reaction of the ketone 1 with MeMgI, followed by dehydration of the resulting carbinol 5 with p-toluenesulphonic acid.

Chapter 2 describes the synthesis of the monoterpenoids 2,3,6-trimethylbenzaldehyde (2) and 2,3,6-trimethylbenzoic acid (10), isolated from Molopospermum peleponnesiacum. Single-step degradation by ozonolysis of the bisnorsesquiterpenic unsaturated ketone (the synthesis of which is described in Chapter 4) gave the monoterpenicaldehyde 9. Silver oxide oxidation of 9 afforded the acid 10.

Chapter 3 gives an account of the synthesis of two meroterpenoids (16 and 18), isolated from Helianthella uniflora and Senecio graveolens, respectively. The key intermediate 13 required for their synthesis was obtained by the Friedel-Crafts reaction of 11 with acetyl chloride. The alcohol 13, obtained by sodium borohydride reduction, was subjected to Grignard reaction with MeMgI to produce the diol 14, which on oxidation with active MnO? afforded the keto carbinol 15. Dehydration of 15 with p-toluenesulphonic acid furnished the rare meroterpenoid 16. The phenolic diol 17 was obtained in a single step by treatment of 13 with excess MeMgI in refluxing xylene. Oxidation of 17 with active MnO? furnished the second related meroterpenoid 18.

Chapter 4 presents an efficient, high-yield synthesis of 4-(2,3,6-trimethylphenyl)butan-2-ol (6), 4-(2,3,6-trimethylphenyl)butan-2-one (7), and 4-(2,3,6-trimethylphenyl)but-3-en-2-one (8), all artifacts isolated from Vitis vinifera, and the sesquiterpene alcohols 26 and 27, isolated from Laurentia nidifica and Laurencia intricata, along with its dehydro analog. The common intermediate from which these compounds are derived was synthesized in a four-step sequence from dihydronaphthalene 20. Ozonolysis of 20 afforded the keto aldehyde 21, which was reduced using sodium borohydride to provide the diol. Metal-ammonia reduction of the diol 21 produced the secondary alcohol 22, which upon oxidation with Jones reagent furnished the saturated ketone. Selective monobromination of 23 at the ?-methylene position was achieved using pyridinium bromide perbromide to give 24. Its dehydrobromination was effected using LiBr/Li?CO? in DMF to provide 8. Grignard reaction of 7 and 8 with excess vinylmagnesium bromide generated the sesquiterpene alcohols 26 and 27, respectively.

Chapter 5 deals with the first synthesis of acetyl-dehydrorishitinol 35, a recently isolated sesquiterpenic stress metabolite from potatoes. The intermediate 30 required for its synthesis was prepared by two routes. In the first route, dehydrogenation of 29 to 30 was effected with Pd-C (10%). Acylation of 30 with acetyl chloride under Friedel-Crafts conditions gave predominantly 2-acetyl-5,8-dimethylnaphthalene 30. In the second route, dehydrogenation with DDQ of the known aldehyde 31, a precursor of the dihydronaphthalene (19) used earlier, provided the naphthaldehyde. Grignard reaction of 31 with MeMgI, followed by Jones oxidation of the resulting secondary alcohol, produced the ketone 30. Lithium-liquid ammonia reduction of 30 in the presence of ferric chloride gave the unsaturated ketone 34, which was transformed in one step into the natural product 35. With a tertiary acetate function, using excess MeMgI followed by quenching with acetic anhydride and sodium acetate, Grignard reaction of 35 with excess MeMgI followed by quenching with ammonium chloride gave, on the other hand, the tertiary alcohol. This chapter illustrates the generality of the one-step preparation of tertiary acetates with another example (37 ? 38).

Chapter 6 describes the first total synthesis of isoparvifolin 51, a sesquiterpenic benzocyclooctene. The key intermediate 44 required for its synthesis was obtained by two routes. In the first route, the keto acid 40, obtained by the Friedel-Crafts reaction of toluene with adipic anhydride, reacted with MeMgI under inverse Grignard conditions to produce exclusively the hydroxy ester. The hydroxy acid 42 was subjected to metal-ammonia reduction to give the saturated acid 43, which was transformed into the methoxy acid 45 in a four-step sequence of nitration, reduction, diazotization, and methylation. In the second route, the keto acid 36 was converted to the methoxy acid 45 by nitration, reduction, diazotization, and methylation. The keto ester 46 was converted to 47 by inverse Grignard, followed by hydrogenolysis (metal in liquid ammonia). Polyphosphoric acid (PPA) cyclization of 44 afforded the keto compound 47. The alcohol 48, obtained from 47 by borohydride reduction, was subjected to Vilsmeier reaction to produce the aldehyde 49. Modified Wolff-Kishner reduction of 49 gave 50, which was demethylated with boron tribromide to furnish isoparvifolin (51).

Chapter 7 presents the synthesis of 1,1-dimethyl-7-t-butyl tetralin (57), a rearrangement product of 10-methylene-longibornane. The keto ester 53 was obtained by the Friedel-Crafts reaction of 52 with isobutyryl chloride. The keto function of 53 was reduced with borohydride. Treatment of the resulting alcohol with MeMgI afforded the diol. The keto carbinol obtained by Jones oxidation of 53 was cyclodehydrated with p-toluenesulphonic acid to produce the ketone. Lead tetraacetate oxidation of 56 produced the ester. The ester function in 56 was converted to the methyl group by the standard sequence of reactions (56 ? 57) to give a C?? member of the interesting class of 1,1-dimethyltetralins.

Chapter 8 describes the synthesis of the bromo-phenol metabolites isolated from marine algae. Compounds 60 and 61 were demethylated using HBr-HOAc to give 62 and 63, respectively. Borohydride reduction of 62 and 63 produced the bromophenols 66 and 68, respectively. DDQ oxidation of 62 afforded 63, which was reduced by borohydride to furnish 68.