Total synthesis of piericidin A1 and B1 and key analogues

Abstract

Full details of the total synthesis of piericidin A1 and B1 and its extension to the preparation of a series of key analogues are described including ent-piericidin A1 (ent-1), 4'-deshydroxypiericidin A1 (58), 5'-desmethylpiericidin A1 (73), 4'-deshydroxy-5'-desmethylpiericidin A1 (75), and the corresponding analogues 51, 59, 76, and 77 bearing a simplified farnesyl side chain. The evaluation of these key analogues, along with those derived from their further functionalizations, permitted a scan of the key structural features providing new insights into the role of the substituents found in both the pyridyl core as well as the side chain. A strategic late stage heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain permitted ready access to the analogues in which each half of the molecule could be systematically and divergently modified. The pyridyl cores were assembled enlisting inverse electron demand Diels-Alder reactions of N-sulfonyl-1-azabutadienes, while key elements of side chain syntheses include an anti selective asymmetric aldol to install the C9 and C10 relative and absolute stereochemistry (for natural and ent-1) and a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chains.

Figure 1

Structure of Piericidin A1 and B1

Figure 2

Retrosynthetic Analysis

Scheme 1

Scheme 2

Figure 3

X-ray crystal structures of 13 and 17

Scheme 3

Scheme 4

Scheme 5

Synthesis of Piericidin A1 and B1

Scheme 6

Synthesis of Analogues 43, 44, 45 and 46

Scheme 7

Synthesis of Analogues 51 and 53

Scheme 8

Synthesis of Analogues 54 and 55

Scheme 9

Synthesis of Analogues 57 and 59

Scheme 10

Scheme 11

Synthesis of Analogues 73, 75, 76, and 77

Figure 4

Key Comparisons

Figure 4

Key Comparisons