Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units

Abstract

As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a range of homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding beta-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral alpha,beta-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral alpha,beta-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the beta-amino ester products of conjugate addition gives access to polyoxygenated beta-amino acid derivatives.

Highly Diastereoselective anti-Dihydroxylation of 3-N,N-Dibenzylaminocyclohex-1-ene N-Oxide

“…They have found use as intermediates in, for example, [1,2]- and [2,3]-Meisenheimer rearrangements, Cope eliminations, and Polonovski reactions and are well-known in alkaloid chemistry (e.g., within the strychnos, ergoline, and opium families), often facilitating structure elucidation or promoting interesting skeletal rearrangements . Nonetheless, their utility in synthesis remains underdeveloped. , As part of our ongoing research program directed toward the synthesis of the amino diol motif, − and recognizing that N -oxidation of allylic amines competes with oxidative functionalization of the olefin, we recently achieved the highly chemo- and diastereoselective, ammonium-directed epoxidation of 3- N , N -dibenzylaminocyclohex-1-ene 1 with m CPBA employing a strategy reliant on in situ N -protection against oxidation via protonation with Cl 3 CCO 2 H. Epoxide ring opening by Cl 3 CCO 2 H, followed by transesterification, gave 3- N , N -dibenzylaminocyclohexane-1,2-diol 2 in 90% de (Scheme ) . We hypothesized that an alternative diastereoselective olefin functionalization protocol would be available through N -oxidation of 3- N , N -dibenzylaminocyclohex-1-ene 1 to give the corresponding N -oxide followed by further oxidation of the olefin.…”

Stereospecific Cyclization Strategies for α,ε-Dihydroxy-β-amino Esters: Asymmetric Syntheses of Imino and Amino Sugars

“…Attempted aminohydroxylation of (4 S ,5 S , E )- 8 using lithium amide ( S )- 1 and (−)-CSO 4 gave rise to a complex mixture of products, along with returned (4 S ,5 S , E )- 8 . However, conjugate addition of ( S )- 1 to (4 S ,5 S , E )-8 and quenching with (+)-CSO 4 gave complete conversion to a single diastereoisomer of α-hydroxy-β-amino ester 16 , which was isolated in 66% yield.…”

“…As part of an ongoing research program aimed at the development of asymmetric syntheses of imino and amino sugars, we have recently examined the conjugate addition of the antipodes of lithium amide 1 to enantiopure α,β-unsaturated esters (4 S ,5 S , E )- 8 and (4 R ,5 S , E )- 9 (β-substituted with trans - and cis -dioxolane units, respectively). We determined that the combinations of ( S )- 1 /(4 S ,5 S , E )- 8 and ( S )- 1 /(4 R ,5 S , E )- 9 are the doubly diastereoselective “matched” reaction pairings, and proceed in >99:1 dr in both cases to give, after protonation of the intermediate enolates, the corresponding β-amino esters. , We anticipated that these highly diastereoselective conjugate addition reactions could be coupled with our enolate oxidation protocol (using CSO 4 ) , to give the corresponding α-hydroxy-β-amino esters 10 as key intermediates en route to a range of imino and amino sugars. The presence of several heteroatoms within α-hydroxy-β-amino esters 10 was expected to render them ideal precursors to either pyrrolidine or tetrahydropyran scaffolds via O -desilylation and activation of the resultant ε-hydroxyl group, followed by cyclization of 11 .…”

Asymmetric Synthesis of Polyhydroxylated Pyrrolizidines via Transannular Iodoamination with Concomitant N-Debenzylation

“…An improved synthesis of tert -butyl (4 S ,5 R , E )-4,5- O -isopropylidene-2,7-dienoate 11 from d -ribose 8 was developed . Treatment of d -ribose 8 with acetone and methanol in the presence of HCl gave 9 , which underwent reaction with I 2 and PPh 3 to give iodide 10 .…”