Total Synthesis of (−)-Incarvilline, (+)-Incarvine C, and (−)-Incarvillateine

Abstract

The first total syntheses of new monoterpene alkaloids (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine, corresponding to the natural enantiomers, have been accomplished. The strategy for the synthesis of these natural products utilized 6-epi-incarvilline as a common precursor, which was assembled by a three-component coupling reaction using (4S)-4-siloxy-2-cyclopenten-1-one to construct an appropriately trisubstituted cyclopentanone, followed by ring closure to the cis-perhydro-2-pyrindine skeleton by means of a reductive Heck-type reaction. Furthermore, topochemically controlled [2 + 2] photodimerization of cinnamic acid derivatives in the solid state for the stereospecific construction of a 1,2,3,4-tetrasubstituted cyclobutane ring was also investigated as a means to access (-)-incarvillateine.

[2+2] Photocycloaddition of Cinnamates in Flow and Development of a Thiourea Catalyst

“…[27] In batch, we observed similar results with and without thiourea 4 (27 %a nd 28 %c onversion) and both reactions favored the b isomer (2:1). In flow,t he conversion increased to 50 %and the selectivity remained the same.With addition of catalyst 4 in flow,the conversion increased to 67 % and we observed an increase in the d isomer 8 (d.r.…”

Cyclobutane-Containing Alkaloids: Origin, Synthesis, and Biological Activities

“…Deprotection of the tosyl groups using sodium amalgam in methanol provided (-)-incarvillateine ( 13 ) as colorless crystals. The optical rotation and spectroscopic properties ( 1 H and 13 C NMR) of synthetic ( 13 ) were in agreement with those reported for natural incarvillateine [44]. …”

Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

“…Although the absolute configuration and the optical rotation of fasicularin have not yet been determined (no literature data are available) and no original natural sample remains, 95) since the optical rotation value for 57 was first obtained by the present synthesis, determination of the absolute configuration of fasicularin will become possible by re-isolation of the natural product and optical rotation measurement. 96,97) Incarvillateine (91) is a member of a new class of monoterpene alkaloids carrying a characteristic cyclobutane ring (Fig. 5), first isolated from the aerial parts of Incarvillea sinensis LAM., which is a wild plant distributed in the northern area of China, that has been traditionally used in treating rheumatism and relieving pain as an ancient Chinese crude drug designated as "Jiaohao".…”

“…97,107) Condensation of the resulting a-truxillic acid 104 with 2 equiv of the above-described (ϩ)-6-epi-incarvilline (102) under Mitsunobu conditions, followed by deprotection of the tosyl groups provided (Ϫ)-incarvillateine (91) (Chart 14). The completion of the first total synthesis of incarvillateine firmly established the structure and absolute stereochemistry of this interesting antinociceptive monoterpene alkaloid as 91.…”