Assignment of the structure of petrocortyne A by mixture syntheses of four candidate stereoisomers

Abstract

Two different mixture synthesis routes have been used to make the four stereoisomers of petrocortyne A. A first quick and dirty route provided a mixture of the four isomers in nonselective fashion. Mosher and 2-naphthylmethoxyacetic acid (NMA) ester methods were developed to identify the components, and the mixture was partially resolved on analytical chiral HPLC to give the two pure enantiomers of petrocortyne A and the racemate of its diastereomer. A second fluorous mixture synthesis produced all four isomers of petrocortyne A in individual pure form. Comparison of spectra of Mosher derivatives of the synthetic isomers with two supposedly different natural products showed that both natural samples were instead identical and had the (3S,14S) configuration. Likewise, petrocortynes B, D, and F-H are (3S,14S) and petrocortyne D is (3R,14S). Having access to all possible candidate isomers of both petrocortyne A and its Mosher derivatives provided a secure structure assignment not so much because one of the isomers matched the natural product, but because all of the other isomers did not.

Figure 1

Proposed structures of petrocortyne A

Figure 2

Retrosynthetic plan for the synthesis of a mixture of true diastereomers of 1

Figure 3

Plan for the fluorous mixture synthesis

Figure 4

Expansions of portions of the ¹H NMR spectra of the bis-(S)-Mosher esters of (3S,14S)-1 (top) and (3S,14R)-1 (bottom) with proton assignments.

Scheme 1

Synthesis of alkynyl alkenyl carbinol 3 and derived MTPA and 2-NMA esters

Scheme 2

Synthesis of dialkynyl carbinol fragment 8 and derived MTPA and 2-NMA esters

Scheme 3

Fragment couplings and production of a mixture of the four stereoisomers of petrocortyne A.

Scheme 4

Synthesis of alcohols R,S-18

Scheme 5

Fluorous mixture synthesis of petrocortyne isomers