Total Synthesis of Proteasome Inhibitor (−)-Omuralide through Asymmetric Ketene [2 + 2]-Cycloaddition

Abstract

The total synthesis of (-)-omuralide, a potent specific proteasome inhibitor, has been achieved through an unprecedented route. The C3 and C4 chiral centers of the natural product have been selectively installed by an asymmetric [2 + 2]-cycloaddition between an unusual oxadisilinane ketene and a chiral enol ether, while the γ-lactam core was prepared by a single-pot two-step Beckmann transposition. The C5 quaternary center was eventually defined by an original selective oxidative desymmetrization of a spiro cyclic oxadisilinane thanks to the anchimeric assistance of a proximal hydroxyl group.

Oxetanes and Oxetenes: Fused-Ring Derivatives

“…<Scheme 49 near here> 2.06.9.6 Dehydration of Hydroxy Acids Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) proved to be a reliable and efficient reagent for the synthesis of fused b-lactones within densely functionalized scaffolds. It has been applied to the ring closure of numerous b-hydroxyacids in the context of total synthesis of natural products, such as (+)-lactacystin, 130 a rocaglate-derived b-lactone, 131 (-)-7-methylomuralide, 132 (-)-omuralide, 133 or salinosporamide A [134][135][136] to cite only a few. As an example, Burton reported a high-yielding sequence from b-hydroxyester 188 to salinosporamide A in 3 steps (61% overall), using BOPCl as the key coupling agent.…”

Strategies and methodologies for the construction of spiro-γ-lactams: an update

“…In the same year, Poisson and co-workers employed a two-step Beckmann transposition for the construction of the -lactam scaffold, as part of a strategy for the total synthesis of proteasome inhibitor (−)-omuralide (Scheme 66). 97 The direct Beckmann rearrangement of stericolsubstituted cyclic oxadisilane spiro-cyclobutanone (+)-256 using MSH was attempted, however low yields and regioisomeric lactams were obtained. The replacement of the bulky chiral auxiliary by a TBS ether via diastereoselective DIBAL-H reduction of 256 followed by TBS protection, stericol cleavage and subsequent Dess-Martin oxidation of the obtained alcohol, afforded cyclobutanone 258 as a suitable substrate for lactam formation.…”

Synthesis of γ-Lactams by Formal Cycloadditions with Ketenes

“…Due to their high ring strain, cyclobutanones can in turn undergo ring expansion to diversely substituted five-membered carbo- and heterocycles such as cyclopentanones (with diazoalkanes), γ-lactams (through a Beckmann transposition), and γ-lactones (via a Baeyer–Villiger oxidation) . In the past several decades, our group has been involved in the synthesis of a variety of γ-butyrolactams using the ketene [2+2] cycloaddition and ring expansion strategy in the context of the total synthesis of natural products (Scheme a) . During these syntheses, we often faced difficulties at the ring expansion step, particularly with the Beckmann transposition: yields and selectivities were highly sterically and electronically dependent.…”