Structure reassignment and synthesis of Jenamidines A1/A2, synthesis of (+)-NP25302, and formal synthesis of SB-311009 analogues

Abstract

The proposed structures of jenamidines A, B, and C (1-3) were revised to jenamidines A1/A2, B1/B2, and C (8-10). Jenamidines A1/A2 (8) were synthesized from activated proline derivative 43 by conversion to 26 in two steps and 50% overall yield. Acylation of 26 with acid chloride 38d gave 39d, which was deprotected with TFA and then mild base to give 8 in 45% yield from 26. (-)-trans-2,5-Dimethylproline ethyl ester (49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (51) and methyl vinyl ketone (50) using modified dihydroquinine 60 as the catalyst. Further elaboration converted 49 to natural (+)-NP25302 (12). A Wittig reaction of proline NCA (76) with ylide 79 gave 72 as a 9/1 E/Z mixture in 27% yield, completing a one-step formal synthesis of SB-311009 analogues.

FIGURE 1

Proposed structures of jenamidines A, B, and C.

SCHEME 1

Synthesis of Model 6

FIGURE 2

Bohemamine, NP25302, and revised structures of jenamidines A₁/A₂, B₁/B₂, and C.

SCHEME 2

Possible Late Steps in the Biosynthesis of Jenamidines A₁/A₂, B₁/B₂, and C

SCHEME 3

SCHEME 4

SCHEME 5

Synthesis of Intermediate 26

SCHEME 6

Synthesis of Jenamidine A₁/A₂ Model 31

SCHEME 7

Synthesis of Side-chain Acid Chlorides

SCHEME 8

Synthesis of Jenamidines A₁/A₂

SCHEME 9

Improved Synthesis of 26

SCHEME 10

Retrosynthesis of NP25302

SCHEME 11

Feringa's Synthesis of 53 and 54

SCHEME 12

Synthesis of trans-2,5-Dimethylproline Ethyl Ester (49)

SCHEME 13

Completion of the Synthesis of (±)-NP25302 (12)

FIGURE 3

Dihydroquinidine-based catalysts 59 and 60.

SCHEME 14

Synthesis of (+)-NP25302

FIGURE 4

¹H NMR spectral data of Mosher amides 61-64.

SCHEME 15

Oxidative Acetoxylation of 26

SCHEME 16

Pinto's Synthesis of SB-311009 Analogue 74

SCHEME 17

One Step Synthesis of Intermediate 72