Stereoselective Synthesis of 3-Aryloctahydroindoles and Application in a Formal Synthesis of (−)-Pancracine

Abstract

A stereoselective synthesis of 3-aryloctahydroindoles from enantiomerically enriched gamma-nitroketones has been developed. Reduction of imines derived form the nitroketones provides the trans-fused octhaydroindole motif selectively. The cis-octahydroindole skeleton is accessible by an invertive cyclization strategy involving a diastereomerically pure nitromesylate intermediate. This approach was employed in the synthesis of an advanced intermediate to (-)-pancracine. The gamma-nitroketone starting materials are readily available via an organocatalytic Michael reaction.

Organocatalytic Conjugate Addition in Stereoselective Synthesis

“…55 As mentioned, the diaryl prolinol silyl ethers, general catalysts for aldehyde, do not work in the case of ketones because of the steric constraint of the requisite transition state. A good 89% ee and >19 : 1 dr was obtained using catalyst 89.…”

One‐Step Stereospecific Strategy for the Construction of the Core Structure of the 5,11‐Methanomorphanthridine Alkaloids in Racemic as well as in Optically Pure Form: Synthesis of (±)‐Pancracine and (±)‐Brunsvigine

“…Most of the asymmetric approaches known for the synthesis of montanine alkaloids are mainly based on chiral-pool strategies except for two recent reports on the formal synthesis of pancracine [17,18] based on organocatalytic approaches. The asymmetric 1,3-dipolar cycloaddition of azomethine ylides to a variety of alkenes has emerged as one of the most powerful strategies for the construction of enantiopure pyrrolidine ring systems.…”

“…Overman, [11] Pearson, [12] Ikeda, [13] Sha, [14] Banwell, [15] Chang, [16] Hashimoto [17] and Pansare [18] and their co-workers all used precursors of type 9 in their respective elaborations of these alkaloids. However, in all these strategies, the syntheses were elaborated from a precursor having the desired stereochemistry at C-4a and C-11a and relative disposition of the methylene bridge of 8, which involved its construction in a stepwise manner.…”

Construction of Chiral 2‐Substituted Octahydroindoles from Cyclic Ketones and Nitroolefins Bearing only One α‐Substituent

“…It was envisaged that the development of a general method for the synthesis of chiral octahydroindoles bearing a non-functional group at their 2-position would provide a facile access to a broad range of chiral analogues that could exhibit potentially interesting biologically activities. Pansare et al [5] reported the stereoselective synthesis of 3-aryl-A C H T U N G T R E N N U N G octahydroindoles from g-nitro ketones via the organocatalytic Michael reaction of cyclohexanone with bmonosubstituted nitroolefins [Scheme 1, Eq. (1)].…”

“…Nitroolefins bearing a variety of different electron-donating and electron-withdrawing substituents on their phenyl ring behaved as suitable substrates for the asymmetric Michael addition with cyclohexanone. High enantioselectivities (94 to > 99% ee) were achieved in all cases with good diastereoselectivities (84:16-94:6 dr) and yields (67-93%) ( Table 2, entries [1][2][3][4][5][6][7][8]. The position of the substituent appeared to have a significant influence on the yield (73-85%) and diastereoselectivity (88:12-94:6 dr) of the transformation, although the effect of the substituent on the enantioselectivity was only minor (94 to > 99% ee) ( Table 2, entries 4-6).…”