Part I

TERPENOIDS

Sesquiterpenoids

BY J. S. ROBERTS

1 Farnesane

The continuing search for new marine natural products has led to the discovery of the farnesic acid glycerides (1) — (3) in the nudibranch Archidoris odhneri and the two hydrocarbons (4) and (5) from the gorgonian Plexaurella grisea Kunze. Other new farnesyl/nerolidyl sesquiterpenoids include (6)–(11) and the interesting acetal eremoacetal (12) from Eremophila rotundifolia.

Epi-7-hydroxymyoporone (13) has been synthesized by a route which makes use of the dianion (14) as a crucial intermediate. Dendrolasin (15) has been prepared by reaction of homogeranyl iodide with lithium di-(3-furyl)cuprate.

β-Sinensal (18) and β-farnesene (19) have both been synthesized from the thioncarbamate (16), which undergoes a [3,3] sigmatropic rearrangement to produce the allylic thiolcarbamate (17) (Scheme 1). The Grignard reagent from homogeranyl bromide has been added to 3-methyl-β-propiolactone in the presence of copper(1) iodide to produce dihydrofarnesic acid (20) which could be elaborated in two steps to farnesol.

One mechanism which has been advanced for the 1'–4 condensation between isopentenyl pyrophosphate and an allylic pyrophosphate is that shown in Scheme 2. This mechanism involves an enzyme-assisted coupling with nucleophilic attack at C-3 followed by a subsequent elimination reaction. By using 2-ftuoroisopentenyl and 2,2-diftuoroisopentenyl pyrophosphate as substrates Poulter and Rilling sought to intercept an X-containing intermediate (either bound or unbound to avian liver farnesyl pyrophosphate synthetase). In neither case was this detected and hence it is suggested that the X-group mechanism is an unlikely process (see Ref. 12 for a comprehensive review of allylic pyrophosphate metabolism). In a continuing investigation of the substrate specificity of farnesyl pyrophosphate synthetase, Ogura et al. have studied the enzyme-catalysed condensation of homologues of isopentenyl pyrophosphate (21) with dimethylallyl and geranyl pyrophosphate. As a result of varying the parameters R1 — R3 and n, it has been shown that for pig liver farnesyl pyrophosphate synthetase R1 can be Me or Et, R2 and R3 can be H, Me, or Et, R1 and R2 can be part of a five- or six-membered ring system, and n should be 1 or 2.

A method for the asymmetric synthesis of R-(-)-[1- R2H]farnesol has been described, based on the reduction of [1-2H]farnesal with the optically active hydride reagent (22). The cyclic analogue (23) of juvenile hormone-II has been synthesized starting from R-(+)-limonene. This compound is less active than the natural hormone.

2 Mono- and Bi-cyclofarnesane

Full details of the structural determination of nigakialcohol (24) have been published. Co-occurring with aplysistatin (25) in Laurencia cf. palisada Yamada are the marine sesquiterpenoids palisadin A (26) and B (27), 5- acetoxypalisadin B (28), 12-hydroxypalisadin B (29), and palisol (30). 3β-Bromo-8-epi-caparrapi oxide (32) has been synthesized by a procedure which involves brominative cyclization of the hydroxy-ester (31) as a key step. The marine sesquiterpenoid (33), in which a methyl migration has taken place, has been synthesized in four steps. All eight racemic diastereoisomers of the marine metabolite dactyloxene-B have been synthesized and this work shows that natural dactyloxene-B has the relative configuration (34) whereas dactyloxene-C is considered to be (35). Interestingly all eight compounds have individually different odours. In a related area of olefaction eight stereoisomeric sesquirose oxides, which have yet to be discovered in nature, have been synthesized. These compounds correspond to the eight possible stereoisomers (36) according to the chiralities at C-2 and C-4 and to the E/Z configuration of the Δ-double bond. The same authors have also methodically synthesized eighteen sesquiter-penoid theaspirane derivatives, of which (37)–(39) are representative examples.

New drimane sesquiterpenoids include polyonal (40), isodrimeninol (41) (from the seeds of Polygonum hydropiper), uvidin A (42), uvidin B (43) (from Lactarius uvidus Fries), and 7 α, 8β,11-trihydroxydrimane (44) (from Fomes annosus). Three new indolosesquiterpenoids, polyavolensin (45), polyavolensinol (46), and polyavolensinone (47), have been identified in the stem extract of Polyathia suaveolens.

A second synthesis of the marine sesquiterpenoid pallescensin A (49) has been achieved by acid-catalysed cyclization of the furanodiene (48). Continued interest in the synthesis of warburganal (52) has resulted in two very similar syntheses (Scheme 3). In both cases the troublesome step was the homologation of the bicyclic keto-aldehyde (50). In Kende's synthesis this was solved by using the Magnus reagent, lithium methoxy(trimethylsilyl)methylide, which ultimately led to both warburganal (52) and isotadeonal (51). In the other synthesis by Goldsmith the extra carbon was introduced by methyl-lithium followed by dehydration with the Burgess reagent. Additional routes to confertifolin (53), isodrimenin (54), in namodial (55), and cinnamosmolide (56) have also been reported.

The dihydro-derivative (58) of the unique sesquiterpenoid spiniferin-1 (57), which incorporates the novel 1,6-methano[10]annulene skeleton, has been synthesized (Scheme 4) and this confirms beyond doubt its precise structure.

3 Bisabolane

New bisabolane sesquiterpenoids include (59), (60), and the perezone derivatives (61)–(63). Based on mass spectral evidence structures (64) and (65) have been assigned to two minor constituents of Chinese cinnamon oil; both ketones have been synthesized from α-curcumene. Dihydroxydeodactol (66), a derivative of deodactol, has been isolated from the mollusc Aplysia dactylomela. A related metabolite, 8-desoxy-isocaespitol (67), is a minor constituent of the marine alga, Laurencia caespitosa. This compound has been synthesized from farnesol acetate in low yield (Scheme 5).

A careful study of the mechanism of the oxy-Cope rearrangement of 1,5-diene alkoxides has provided a neat synthesis of erythro-juvabione (68) (Scheme 6). This work has shown that the (3,3] sigmatropic process proceeds in a concerted fashion predominantly via a chair transition state.

A number of relatively short and straightforward syntheses of bisabolane sesquiterpenoids have been reported ; these include E- and Z-α- bisabolene, (69) and (70) (together with the isopropenyl analogues), α-curcumene (71), β-curcumene (72), ar-turmerone (73), iso-α-curcumene (74), and...