Functionalizing the γ-Position of α-Diazo-β-ketoesters

Abstract

Although α-diazo-β-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed into a β-ketoester, with the diazo group being subsequently added with a diazo transfer reagent. While introducing this highly functional moiety in a convergent one step process would be ideal, such an objective is limited by the relatively few studies which address functionalization of the α-diazo-β-ketoester at the γ-position. In the present investigation, we evaluate strategies, both new and established, for functionalizing α-diazo-β-ketoesters, particularly with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapenems. We report the first δ-aldehydo-α-diazo-β-ketoester as well as a method for its oxidation to the corresponding methyl ester, and the formation of a new substituted pyrazole under basic conditions.

Keywords: Diazo; carbapenem; pyrazole; β-ketoester.

Figure 1

Crystal structure of 23.

Scheme 1

Merck carbapenem synthesis.

Scheme 2

Non-catalytic reactions of α-diazo-β-dicarbonyl compounds with electrophilic reagents.

Scheme 3

Stepwise introduction of α-diazo-β-ketoester moiety.

Scheme 4

Proposed single-step introduction of α-diazo-β-ketoester moiety.

Scheme 5

Initial efforts to functionalize α-diazo-β-ketoesters.

Scheme 6

Successful efforts to functionalize a C4 α-diazo-β-ketoester synthon.

Scheme 7

Synthetic utility of γ-iodo-α-diazo-β-ketoester 15.

Scheme 8

Attempted utilization of 20 in the synthesis of C1 substituted carbapenems.

Scheme 9

Attempted Pinnick oxidation of 20.

Scheme 10

Successful oxidation of 20 and attempt to utilize α-diazo-β-ketodiester 26 in the synthesis of C1 substituted carbapenems.

Scheme 11

Mechanistic rationale for observed product 23.