Chemoenzymatic Synthesis of (+)-Xyloketal B

Abstract

Xyloketal B is a pentacyclic fungal marine natural product that has shown potential for the treatment of diseases such as Alzheimer’s disease and atherosclerosis. Herein, we describe the first asymmetric synthesis of this natural product, which relies on a chemoenzymatic strategy. This approach leverages a biocatalytic benzylic hydroxylation to access to an ortho-quinone methide intermediate which is captured in a [4 + 2] cycloaddition to stereoselectively yield a key cyclic ketal intermediate enroute to (+)-xyloketal B. The relative configuration of this intermediate was rapidly confirmed as the desired stereoisomer using MicroED. To complete the synthesis, a second ortho-quinone methide was accessed through a reductive approach, ultimately leading to the stereoselective synthesis of (+)-xyloketal B.

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“…The total synthesis of (+)-xyloketal B (28), a pentacyclic fungal marine natural product, has been reported using an enzymatic benzylic hydroxylation as the key step. 30 Whole-cell, preparativescale hydroxylation of a 3-methylbenzaldehyde intermediate was achieved using an a-ketoglutarate (a-KG)-dependent nonhaem iron (NHI) oxygenase, ClaD, in excellent yield (Scheme 3). An ortho-quinone methide intermediate was generated from this product and captured in a [4 + 2]cycloaddition reaction to generate three rings of (+)-xyloketal B (28).…”

Lewis acid-catalyzed one-pot thioalkenylation of donor–acceptor cyclopropanes using in situ generated dithiocarbamates and propiolates

“…8 More recently, the Werz group also demonstrated 1,3-sulfonylation-fluorination using sulfinate salts as nucleophiles (eqn (2)). 9 Considering the scarce existing literature on sulfur-based nucleophilic triggers to open D-A cyclopropanes, we conceived a one-pot thioalkenylation method for D-A cyclopropanes (eqn (3)). This method involves the in situ generation of dithiocarbamates (from amines and CS 2 ) as nucleophilic triggers and the use of alkyl propiolates as electrophiles.…”