synthetic investigations in terpenoids

Abstract

The thesis entitled “SYNTHETIC STUDIES IN TERPENOIDS” consists of three chapters.

Chapter I Chapter I deals with experiments involving the construction of spiro[4.5]decanes, which led to the total synthesis of (+)-hinesol (1) and 10?epi?(+)-hinesol (2), and is divided into two sections. Section I An overview of current developments in the synthesis of spiro[4.5]decane and spiro[5.5]undecane frameworks. Section II Begins with a brief introduction to the chemistry of hinesol, a naturally occurring sesquiterpene—its isolation, structure, biosynthesis, and previous syntheses—followed by discussion of a new, efficient, stereoselective strategy for constructing the spiro[4.5]decane core. This method successfully furnished (+)-hinesol and its 10?epimer. Regiospecific addition of ??chloroacrylonitrile to the diene (5)—obtained by metal–ammonia reduction of 6?methoxy?1?methyltetralin (3)—followed by base?catalysed conjugation of the diene (4) gave the adduct (6) as a 5:2 mixture of endo? and exo?isomers. Hydrolysis with aq. KOH/DMSO afforded the ketone (7). Reduction with NaBH? produced a 3:1 mixture of endo? and exo?alcohols (8) and (9). Rearrangement of the endo?alcohol (8) with BF?·Et?O gave a 3:2 mixture of enone (10) and ketone (11). Oxidation of (10) with RuCl?·3H?O/NaIO? yielded the keto acid (12). Addition of MeMgI followed by esterification produced hydroxy ester (13). Dehydration gave a mixture of olefins (14) and (15), separated by AgNO??impregnated silica. The exo?olefin (15) was isomerised to the endo?olefin (14) using PTS. Grignard reaction of (14) with MeMgI afforded a mixture of (+)-hinesol (1) and 10?epi?(+)-hinesol (2). The structure of ketone (11) was assigned via spectral data and confirmed through degradation. Deoxygenation via thioacetalisation followed by Raney?Ni desulfurization afforded compound (16). Oxidation (RuCl?·3H?O–NaIO?) yielded the dione (17). Aldol condensation furnished unsaturated ketone (18), confirming the double?bond position in (11). The mechanism involves rearrangement of a bicyclo(2.2.2) system into an isomeric bicyclo(2.2.2) structure.

Chapter II Begins with an introduction to the Eremophila species native to Australia and discusses synthetic investigations of sesquiterpenes (19) and (20) isolated from Eremophila georgei. Diels–Alder reaction of diene (24)—prepared from aromatic precursor (22) by metal–ammonia reduction and isomerisation—with ??chloroacrylonitrile yielded adduct (25). Hydrolysis furnished tricyclic ketone (26). Grignard reaction with MeMgI produced alcohol (27), which underwent a stereospecific Wagner–Meerwein rearrangement on refluxing with BF?·Et?O to yield enone (30). Intermediate (30) was transformed to target molecules (19) and (20). Reduction of ketone (26) with NaBH? gave isomeric alcohols (28) and (29) (1:3). The endo?alcohol (29) rearranged smoothly to enone (31), which was elaborated into compound (21).

Chapter III Covers synthetic studies on diterpenoids:

calyone (32) calyenone (33) precalyone (34)

isolated from Roylea calycina. These compounds show anticancer activity against P?388 lymphocytic leukaemia in mice. The total synthesis of nordrimane (35) from Lepista glaucocana is also reported. An attempted synthesis of compound (36), a key intermediate toward calyenone, was carried out from ketone (37):

Woodward alkylation ? ketone (38) NaBH? reduction ? alcohol (39) Acetylation ? acetate (40) Allylic oxidation ? enone (41) Metal–ammonia reduction ? alcohol (42a) (A/B trans junction) Acetylation ? (42b) Carbomethoxylation ? ester (43) Introduction of ??(?) double bond ? enone (44) via PhSeCl Reduction of ketal (45) yielded a mixture of undesired products

Reduction of (38) under Huang–Minlon conditions gave (46). Oxidation ? (47); metal–ammonia reduction ? saturated ketone (48) (A/B trans). Reaction with dimethyl carbonate/NaH gave 8?ketoester (49), subsequently converted into the natural product possessing the ??(?) double bond via phenylselenenyl?oxide elimination.