Development of an approach towards the stereoselective synthesis of the cyclobutyl isomer of presqualene pyrophosphate

Chang, Jane Liao

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https://hdl.handle.net/2142/19157 Copy

Description

Title

Development of an approach towards the stereoselective synthesis of the cyclobutyl isomer of presqualene pyrophosphate

Author(s)

Chang, Jane Liao

Issue Date

1989

Doctoral Committee Chair(s)

Coates, Robert M.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Chemistry, Organic

Language

eng

Abstract

• Studies towards the synthesis of the cyclobutyl isomer of presqualene pyrophosphate, proposed by Popjak as an intermediate in squalene biosynthesis from presqualene pyrophosphate, were conducted mainly on C$\sb{10}$ models. The key steps in the synthesis are conjugate addition-alkylation, ring contraction of the cyclopentanone, stereoselective reduction of the resulting cyclobutanone, and conversion of benzyloxymethyl moiety to a methyl group. Synthesis of the C$\sb{10}$ cis cyclobutanol analog of the target molecule from 2-methyl-2-cyclopentenone was completed over 18 steps in 8% overall yield. Although the desire trans C$\sb{10}$ cyclobutanol was not obtained by this approach, it is believed that the chemistry involved in the synthesis of the trans isomer should be very similar. Part of the studies were conducted on C$\sb{20}$ models and the results were compatible with C$\sb{10}$ models. Methods for synthesis of the starting materials 2-homogeranyl-2-cyclopentenone and (1E,5E)-1-iodo-2,6,10-trimethyl-1,5,9-undecatriene have also been developed. The estimated yield for the synthesis of the C$\sb{30}$ cyclobutanol is 5% from 2-homogeranyl-2-cyclopentenone.
• Carboxylation of endocyclic enolate anions with methyl cyanoformate and carbon dioxide proceeds in fair to good yields (25 to 76%). When methyl cyanoformate is used, the enol carbonate is a major side product (8 to 34%) with six-membered ring enolates, and enolate hydrolysis ketone is the major side product (11 to 22%) when carbon dioxide is used. In general, both the methyl cyanoformate and carbon dioxide approach trans to the other substituent on the enolate ring. Although the stereoselectivity of C-carboxylation of six-membered ring enolates is greater with methyl cyanoformate than with carbon dioxide, the actual isolated yields of the major $\beta$-keto esters are similar owning to the formation of substantial amounts enol carbonates with the former reagent. The stereoselectivity for the two reagents is about equal for five- or seven-membered ring enolates and is usually $\geq$93:7 with Mander's reagent. The stereochemistry of the methyl cyanoformate carboxylations is rationalized by a stereoelectronic effect and a late transition state while carbon dioxide carboxylation is proposed to proceed through an earlier and less sterically demanding transition state. The carboxylation reaction with both reagents appears to be irreversible and product stability seems to be unimportant. The carboxylation stereoselectivity of the enolate of 2,6- dimethylcyclohexanone with carbon dioxide is anomalous, attack occurring predominantly cis to the C-6 methyl group. Steric interactions between the tetracoordinated lithium ion and the C-6 methyl group together with an anti S$\sb{\rm E}\sb{\sp\prime}$ mechanism are involked to rationalize the stereoselectivity in this case.

Type of Resource

text

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Copyright 1989 Chang, Jane Liao

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