Stereoselective Synthesis of Polyhydroxylated Quinolizidines from C-Glycosides by One-Pot Double-Conjugate Addition

Abstract

An effective one-pot synthesis of polyhydroxylated quinolizidines from 1-C-(2'-oxo-4'-pentenyl)-5-azido-C-glycofuranosides was developed. Reduction of the 5-azido group using triphenylphosphine followed by base treatment produced quinolizidines in good yield. The base-mediated ring-opening beta-elimination produced an acyclic alpha,beta-conjugated ketone as a Michael acceptor, which was followed by an intramolecular nitrogen conjugate addition to form an aza-C-glycopyranoside intermediate. Meanwhile, the beta,gamma-double bond of the aglycon migrated under the basic conditions to form another alpha,beta-conjugated ketone. The subsequent intramolecular conjugate addition by the azasugar nitrogen led to the formation of the quinolizidines in a highly stereoselective manner. The stereoselectivity of the first conjugate addition giving azasugar is affected by the stereochemistry of the monosaccharide substrate, whereas the stereoselectivity in the second conjugate addition was likely directed entirely by steric repulsion from the azasugar.

Triazole-fused sugars from nitroalkene-containing C-glycosides by a tandem 1,3-dipolar cycloaddition and intramolecular Michael addition

“…The open-chain intermediate, a conjugated ketone containing a triazole moiety, then underwent an intramolecular Michael addition to give a triazole-fused sugar. The stereochemistry of the reaction was controlled similarly by thermodynamic stability of the transition state as previously reported, 14 which led to the formation of a fused triazole (14) from nitroalkene 4 and an anomeric mixture of 15 and 16 from nitroalkene 7. The low chemical yield was likely the result of a series of side-reactions, including intermolecular couplings similar to that reported in Scheme 4 as indicated by a significant amount of very polar byproducts observed on TLC.…”

“…The triazole product obtained (14)(15) N) was analyzed by 1 H and 13 C NMR. Because of the 15 N label at N-1 and N-3 of the triazole, based on 15 N-13 C and/or 15 N-1 H couplings one would be able to definitively assign the structure of 14.…”

Tactics and strategies for the synthesis of iminosugar C-glycosides: a review

“…Steric repulsion resulting from metal ion (Na + ) chelation or hydrogen bonding between the 4-axial OH group and the amino group may destabilize the favorable 4 conformation of the putative transition state in which all the substituents are equatorial except the OH group at C-4. 62 It is noteworthy that in the strategy reported by Zou, the imino-C-glycosides are synthesized via a C-glycoside intermediate. Access to polyhydroxylated quinolizidines following a similar approach as well as access to pyrrolidine C-glycosides was also reported by the same group, 62 (Section 3.1.4., Scheme 88).…”

Synthesis of N-substituted iminosugars from 2′-carbonyl-C-glycofuranosides

“…Recently, many such methods attempting to synthesize N-substituted iminosugars have emerged, [14][15][16][17][18][19][20] which may lead to superior inhibitors when the anomeric carbon in the piperidine rings is substituted. 21,22 In view of the high therapeutic and industrial potential of N-alkylated iminosugars, and as a part of our continuing interest in their synthesis, [23][24][25][26][27][28] we hereby report a practical approach for the synthesis of hitherto unknown N-substituted iminosugars.…”

“…[25][26][27][28] Thus, we hypothesized that 1-C-(2 0 -oxoalkyl)-glycosides with an N-substituted amino group could also undergo a similar intramolecular Michael addition to produce N-substituted iminosugars. Additionally, iminosugars with different N-substituted amino groups could be further prepared for various iminosugar library constructions.…”