A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine.

Abstract

BACKGROUND:

Spiroketals and the corresponding aza-spiroketals are the structural features found in a number of bioactive natural products, and in compounds possessing photochromic properties for use in the area of photochemical erasable memory, self-development photography, actinometry, displays, filters, lenses of variable optical density, and photomechanical biomaterials etc. And (1R,8aS)-1-hydroxyindolizidine (3) has been postulated to be a biosynthetic precursor of hydroxylated indolizidines such as (+)-lentiginosine 1, (-)-2-epilentiginosine 2 and (-)-swainsonine, which are potentially useful antimetastasis drugs for the treatment of cancer. In continuation of a project aimed at the development of enantiomeric malimide-based synthetic methodology, we now report a divergent, concise and highly diastereoselective approach for the asymmetric syntheses of an aza-spiropyran derivative 7 and (1S,8aR)-1-hydroxyindolizidine (ent-3).

RESULTS:

The synthesis of aza-spiropyran 7 started from the Grignard addition of malimide 4. Treatment of the THP-protected 4-hydroxybutyl magnesium bromide with malimide 4 at -20 degrees C afforded N,O-acetal 5a as an epimeric mixture in a combined yield of 89%. Subjection of the diastereomeric mixture of N,O-acetal 5a to acidic conditions for 0.5 h resulted in the formation of the desired functionalized aza-spiropyran 7 as a single diastereomer in quantitative yield. The stereochemistry of the aza-spiropyran 7 was determined by NOESY experiment. For the synthesis of ent-3, aza-spiropyran 7, or more conveniently, N,O-acetal 5a, was converted to lactam 6a under standard reductive dehydroxylation conditions in 78% or 77% yield. Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine 8 in 95% yield. Compound 8 was then converted to 1-hydroxyindolizidine ent-3 via a four-step procedure, namely, N-debenzylation/O-mesylation/Boc-cleavage/cyclization, and O-debenzylation. Alternatively, amino alcohol 8 was mesylated and the resultant mesylate 12 was subjected to hydrogenolytic conditions, which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8.

CONCLUSION:

By the reaction of functionalized Grignard reagent with protected (S)-malimide, either aza-spiropyran or (1S,8aR)-1-hydroxyindolizidine skeleton could be constructed in a concise and selective manner. The results presented herein constitute an important extension of our malimide-based synthetic methodology.

• Authors: Jian-Feng Zheng, Wen Chen, Su-Yu Huang, Jian-Liang Ye, Pei-Qiang Huang
• Journal: Beilstein journal of organic chemistry (Beilstein J Org Chem) Vol. 3 Pg. 41 (Nov 08 2007) ISSN: 1860-5397 [Electronic] Germany
• PMID: 17996045 (Publication Type: Journal Article)