| dc.description.abstract | By the hydrolysis of the oil derived from Abies sachalinensis Mast., Tuchihashi and Hanzawa (1940) isolated a sesquiterpene acid called todomatuic acid, and its structure, deduced by Momose (1941), was confirmed by Nakazaki and Isoe (1963), who also assigned the absolute configuration (1a). Very recently (1966 and 1967), highly active sesquiterpenoid juvenile hormones called Juvabione and dehydro Juvabione were isolated, the former identified as a methyl ester (1b) of todomatuic acid.
The synthesis of the keto acids* (2a), the methyl esters (2b), and their aromatic analogues, (+) 8d and (+) 3b, prepared by total synthesis and by conversion of the naturally occurring turmerone fraction from the essential oil of Curcuma longa L., are reported in this thesis.
This thesis, entitled “Synthetic Studies in Todomatuic Acids, Juvabiones and Analogues”, is divided into two parts.
Part I consists of a comprehensive survey of naturally occurring sesquiterpene acids. Such a survey, not previously described in literature, finds its relevance in the candidate’s synthetic investigations on a sesquiterpene acid and its analogues. The source of occurrence, structure, synthesis, absolute configuration and biogenesis of the individual acids, grouped into acyclic, mono , bi , tri , and tetracyclic members, are discussed briefly. The available information on members of as yet undetermined constitution is also summarised.
(The suffix S indicates a diastereomixture.)
Part II is divided into two chapters.
Chapter 1
In Chapter 1, the synthesis of the keto acids (2a), Juvabiones (2b), and the correlation of the former with desoxo and trans dihydro desoxo todomatuic acid are described.
p Methoxystyrylisobutyl ketone on conjugate addition with CH MgI furnished the 1,4 addition product 4a. Birch reduction of the anisyl alcohol (4b) and hydrolysis of the resulting dihydroanisole gave the unconjugated keto alcohol (5a). Its acetate (5b) was hydrogenated to 6a, which was then converted to the cyanohydrin acetate (6b) by an exchange reaction. The dehydration of 6b furnished the acetoacyl unsaturated nitrile (7a) as the major product, which on alkaline hydrolysis gave the hydroxy unsaturated acid (7b). On oxidation, it gave the keto acid (2a), m.p. 65-66° (as regenerated from its p-benzylthiuronium salt, m.p. 162°). Its IR spectrum (CCl ) was almost superimposable with that of natural todomatuic acid (1a).
The following route was also investigated for the synthesis of the keto acid (2a):
Unsaturated keto alcohol (5a) saturated keto alcohol (6c) cyanohydrin alcohol (6d) keto cyanohydrin (6e) keto unsaturated nitrile (7c).
The alkaline hydrolysis of the keto unsaturated nitrile (7c) gave a solid bicyclic non ketonic diene acid which is under investigation. Acid hydrolysis of 7c, however, furnished the required keto acid (2a).
Several attempts to separate the two epimers of the methyl esters (2b) by TLC, including Al O -SiO , GLC and VPC, were unsuccessful. Its spectrum showed good agreement with that reported for the natural keto ester (1b). It had an identical Rf on TLC and gave a superimposable IR spectrum with natural Juvabione (1b). It also exhibited juvenile hormone activity against Pyrrhocoris apterus L. and Dysdercus intermedius at 10 µg/bug dosage.
Chapter 2
In Chapter 2, the total synthesis of (+) ar Juvabione (3b) and its correlation with the synthetic keto acid (2a) described in Chapter 1, and the conversion of naturally occurring ar turmerone (9) to (+) ar Juvabione (3b), are described.
The synthesis of ar todomatuic acid arose from the consideration that the occurrence in nature of perhydroterpenoids and the corresponding aromatised compounds-either in different sources or often in the same source-is quite widespread. Several such examples from sesquiterpenoids are illustrated.
Conjugate addition of CH MgI to styrylisobutyl ketone furnished 2 phenyl 6 methylheptan 4 one (8a). Chloromethylation of 8a gave the chloromethyl ketone (8b), which was converted by standard procedures to the keto acid (8d) and (+) ar Juvabione (8e) via the aldehyde (8c). Dehydrogenation of the keto acid (2a) to give the ar keto acid (8d) provided mutually confirmatory support to both structures.
Alternatively, (+) ar turmerone (9), of known absolute configuration at C 7, appeared to be an attractive starting material for the preparation of optically active ar todomatuic acid (3a) and ar Juvabione (3b).
Aromatisation of the sesquiterpene ketonic fraction from the essential oil of Curcuma longa L., consisting chiefly of turmerone and ar turmerone, by the hydrogen transfer technique of Kindler and Lührs gave (+) ar turmerone (9). On oxidation with chromic acid, (+) ar dihydroturmerone (10) gave ar todomatuic acid (3a) contaminated with terephthalic acid. Intensive purification of the esterified material by successive chromatographic separations gave pure (+) ar Juvabione (3b). It also exhibited identical physiological effects as 1b and 2b.
Since the C 7 centre in ar turmerone is established as S, the same stereochemistry follows for (+) ar Juvabione. However, since naturally occurring todomatuic acid (1a) and Juvabione (1b) possess R chirality at C 7, they are expected to give, on aromatisation, the corresponding laevorotatory ar compounds. | |
