A General Approach to 1‐Hydroxymethylquinolizidine and 8‐Hydroxymethylindolizidine Stereoisomers: Synthesis of (+)‐Epitashiromine and Formal Syntheses of (+)‐Epilupinine and (+)‐Tashiromine

Abstract

A general strategy for the synthesis of structurally and stereochemically related indolizidine and quinolizidine alkaloids was developed. The methodology involves regio‐ and stereoselective 1,3‐dipolar cycloadditions of simple nitrones with ephedrine‐derived alkylidenemorpholinones. The intermediate isoxazolidines can be converted into either the indolizidine or the quinolizidine motif depending on the nitrone and the substituent on the dipolarophile. The approach was applied to the synthesis of (+)‐epitashiromine and to the formal syntheses of (+)‐epilupinine and (+)‐tashiromine.

Novel stereocontrolled syntheses of tashiromine and epitashiromine

“…Similarly to the cis isomer, this unstable dialdehyde intermediate was subjected without isolation to catalytic hydrogenolysis, followed by reductive cyclization, to give the corresponding indolizidine ester (±)- 9 in 40% yield. Finally, ester reduction with LiAlH 4 in THF resulted in epitashiromine (±)- 10 [ 32 , 34 , 39 ] in 53% yield after isolation by chromatography ( Scheme 3 ). The stereochemistry of (±)-epitashiromine was assigned by NMR data, which were in agreement with those reported [ 32 , 34 , 39 ].…”

“…Finally, ester reduction with LiAlH 4 in THF resulted in epitashiromine (±)- 10 [ 32 , 34 , 39 ] in 53% yield after isolation by chromatography ( Scheme 3 ). The stereochemistry of (±)-epitashiromine was assigned by NMR data, which were in agreement with those reported [ 32 , 34 , 39 ].…”

“…(+)-Tashiromine has been synthetized from a pyrrolidinone derivative through chiral Lewis acid-catalysed cyclization to substituted pyrrolidinones [ 17 ], by the intramolecular cyclization of a chiral alkenylated pyrrolidinone, followed by hydroxylation [ 32 ], or by the intramolecular ring closure of chiral pyrrolidine diesters followed by ester and oxo group reduction [ 33 ], while the syntheses of (+)-epitashiromine starts from a chiral morpholine derivative, with nitrone 1,3-dipolar cycloaddition and reduction [ 34 ] ( Fig. 3 ).…”

Regio and diastereoselective multicomponent 1,3-dipolar cycloadditions between prolinate hydrochlorides, aldehydes and dipolarophiles for the direct synthesis of pyrrolizidines

“…For instance, chain elongations of proline derivatives followed by cyclization, 10 transanular iodoamination 11 using lactams, 12 from other natural products, 13 etc. However, the most important and straightforward route is to employ a 1,3-dipolar cycloaddition (1,3-DC) 14,15,16 using mainly nitrones 17,18,19,20 or azomethine ylides. 21,22,23,24,25,26,27,28 Figure 1.…”

Enantioselective synthesis of polyhydroxyindolizidinone and quinolizidinone derivatives from a common precursor

“…1 ) [ 4 ] and castanospermine ( 2 ) [ 5 ] obtained from natural sources have potent inhibitory effects towards various glycosidase enzymes and also exhibit anti-HIV, antimetastatic, immunoregulating, antitumor, and anticancer activities [ 6 – 9 ]. Although naturally occurring polyhydroxylated quinolizidines are less documented, several synthetic derivatives have been prepared in the quest for analogues of the more abundant indolizidines [ 10 – 15 ]. Ring-size variation and/or stereochemical manipulation of the hydroxy groups have been adequately practiced for such purpose [ 16 – 17 ].…”