Among nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes, more so sesquiterpenes, with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionality. This phenomenal structural diversity of this class of natural products makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The present thesis entitled "Synthesis of sesquiterpenes containing two vicinal quaternary carbon atoms" describes the synthesis of a number of herbertane sesquiterpenoids, antimicrobial sesquiterpenes enokipodins A and Bf and spirocyclic sesquiterpenes acorone and isoacorones based on ring-closing metathesis reaction. In the thesis, the compounds are sequentially numbered (bold), and references are marked sequentially as superscript and listed at the end of thesis. All the figures included in-the thesis were obtained by DIRECT XEROX OF THE ORIGINAL NMR SPECTRA, and in some of them uninformative areas have been cut to save the space.
The herbertane sesquiterpenes are relatively a new class of aromatic sesquiterpenes, containing sterically crowded l-aryl-l,2,2-trimethylcyclopentane carbon framework incorporating two vicinal quaternary carbon atoms on a cyclopentane ring. The sterically crowded molecular framework coupled with the novel biological properties associated with the phenolic herbertanes made the herbertenoids challenging synthetic targets. In the present investigations, to begin with, a formal total synthesis of (±)-herbertenediol and (±)~ mastigophorenes A-D was developed starting from vanillin, based on a combination of Wacker oxidation and intramolecular aldol reactions.
A general ring-closing metathesis (RCM) based methodology was developed for a-cuparenone and the herbertane sesquiterpenes herbertene, a-herbertenol, f)~herbertenol and herbertenediol starting from the appropriately substituted acetophenones. The acetophenones on Horner-Wadsworth-Emmons reaction followed by regioselective reduction generated 5-arylbut-2-enols, which on Claisen rearrangement furnished 3~aryl-3-methylpent-4-enals. Grignard reaction with vinylmagnesium bromide followed by RCM reaction and oxidation transformed 3-aryl-3-methylpent~4-enals into 4~aryl-4-methylcylopentenones, which were further transformed into 3-aryl-2,2,3-trimethylcyclopentanones, thus, completing the formal synthesis of the sesquiterpenes (±)-a-cuparenone, (±)-herbertene, (±)-a-herbertenol, (±)-pherbertenol and (±)'herbertenediol.
In continuation of the synthesis of herbertane sesquiterpenes, a Claisen rearrangement and RCM reaction based strategy was developed for the synthesis of (±)~lt14-herbertenediol and (±)-71-epi-herbertenolide, and marine sesquiterpenes {£)-tochuinyl acetate and (±)-dihydrotochuinyl acetate. Ortho ester Claisen rearrangement of 3-arylbut-2~ enols generated 3-aryl~3-methylpent-4-enoates, which on allylation and RCM reactions generated 2~methyl-2-arylcyclopent-3-encarboxylates. Stereoselective alkylation followed by functional group manipulations transformed 2-methyl'2-arylcyclopent'3-encarboxylates into the marine sesquiterpenes (±)-tochuinyl acetate and (±)-dihydrotochuinyl acetate, (±)-ll-epiherbertenolide and (±)~l,,14-herbertenediol.
Total synthesis of (±)-lt13-herbertenediol has been accomplished employing an RCM reaction as the key step. The requisite starting material 2-methoxy-5-methylphenyl acetate was obtained from p-cresol. Two sequential allylation reactions followed by RCM reaction transformed 2-methoxy-5-methylphenyl acetate into 1 -arylcyclopent-3-en-l-carboxylate. Allylic oxidation and alkylation followed by functional group manipulation transformed I-arylcyclopent-3-en-l-carboxylate into (±)-U3-herbertenediol.
For the enantiospecific synthesis of (+)-a-herbertenol, an aromatic Claisen rearrangement based strategy was developed starting from the readily available monoterpene (R)-limonene. To begin with, limonene was converted into 5-isopropenyl-2-methylcyclopent-l-enemethanol which on Mitsunobu reaction with p-cresol followed by Claisen rearrangement of the resultant aryl ether generated a mixture of3-isopropenyl-3a,7,8b-trimethyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofurans. Degradation of the isopropenyl group and cleavage of the central ether ring transformed the major cyclopentabenzofuran into 3-aryl-2,3-dimethylcyclopentanone, which was further elaborated into (+)-a-herbertenol.
The general RCM reaction methodology developed for the herbertenoids has been further extended to the first total synthesis of the antimicrobial sesquiterpenes (±)~ enokipodins A andB, and a formal total syntheses of (±)-cuparene-l,4-diol, (±)-cuparene-lt4-quinone and (±)~HM-1 methyl ether star*w« from 2,5~dimethoxy~4-methylacetophenone. It has been further extended to the formal synthesis of spirocydic sesquiterpenes (±)-acorone and (±)-isoacorones starting from cyclohexane-1,4-dione.
| Identifer | oai:union.ndltd.org:IISc/oai:etd.ncsi.iisc.ernet.in:2005/333 |
| Date | 05 1900 |
| Creators | Rao, M Srinivasa |
| Contributors | Srikrishna, A |
| Source Sets | India Institute of Science |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Rights | I grant Indian Institute of Science the right to archive and to make available my thesis or dissertation in whole or in part in all forms of media, now hereafter known. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. |
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