Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (−)-Preussin B, and 3‑Deoxy-(+)-preussin B

Efficient de novo
asymmetric syntheses of (+)-preussin B, the C(2)-epimer
of (−)-preussin B, and 3-deoxy-(+)-preussin B have been developed,
using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)­amide
to tert-butyl 4-phenylbut-2-enoate and diastereoselective
reductive cyclizations of γ-amino ketones as the key steps to
set the stereochemistry. Conjugate addition followed by enolate protonation
generated the corresponding β-amino ester. Homologation using
the ester functionality as a synthetic handle gave the corresponding
γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied
by diastereoselective reductive cyclization in situ; reductive N-methylation
then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product.
Meanwhile, the same conjugate addition but followed by enolate oxidation
with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization
by oxidation and diastereoselective reduction then gave access to
the corresponding syn-α-hydroxy-β-amino
ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino
esters gave the corresponding β-hydroxy-γ-amino ketones.
N-Debenzylation and concomitant diastereoselective reductive cyclization,
followed by reductive N-methylation, provided the C(2)-epimer of (−)-preussin
B and (+)-preussin B as the major diastereoisomeric products, respectively.
The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin
B over seven steps, 8% for the C(2)-epimer of (−)-preussin
B over nine steps, and 7% for (+)-preussin B over eleven steps.