General Approach to the Synthesis of the Chlorosulfolipids Danicalipin A, Mytilipin A, and Malhamensilipin A in Enantioenriched Form

Abstract

A second-generation synthesis of three structurally related chlorosulfolipids has been developed. Key advances include highly stereocontrolled additions to α,β-dichloroaldehydes, kinetic resolutions of complex chlorinated vinyl epoxide intermediates, and Z-selective alkene cross metatheses of cis-vinyl epoxides. This strategy facilitated the synthesis of enantioenriched danicalipin A, mytilipin A, and malhamensilipin A in nine, eight, and 11 steps, respectively.

Catalytic, stereospecific syn-dichlorination of alkenes

“…In recent years, the state-of-the-art in stereoselective chlorination methods have been showcased in synthetic efforts toward the chlorosulfolipids (e.g., 1–5 ) 10,11,12,13,14 – a class of stereochemically-complex, polychlorinated natural products isolated from marine sources (Figure 1, left). The daunting synthetic challenge of constructing such densely functionalized arrays of chlorinated stereogenic centers has provided impetus for the study of (external) diastereocontrol in the dichlorination of chiral alkene substrates, 12 as well as more recent efforts to effect enantioselective dichlorinations of allylic alcohols.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…(several examples failed) [234]. Ruthenium mediated asymmetric and Z-selective RO-CM using catalyst 28 in enantiomerically pure form was demonstrated with several cyclobutene-3,4-diol derivatives (e.g.…”

[1,3]‐Sigmatropic Shift of an Allylic Chloride

“…[1 -3] Numerous syntheses have showcased diverse strategies, which include unanticipated anchimeric assistance by chlorides in openings of allylic epoxides. [4][5][6][7][8][9][10][11][12][13] Yet, despite the extensive work that has been documented, this natural product class harbors additional surprises in store. Herein we report one such discovery, i. e. a [1,3]-sigmatropic shift of an allylic chloride.…”

“…when the reaction was performed 10-fold more dilute under otherwise identical conditions, in accordance with an intramolecular, suprafacial shift of the chlorine atom. 7 The fact that only 3 and 7 afforded single stereoisomeric products suggests the importance of the hydrophobic, sterically demanding domain in the starting allylic chloride.…”

“…6 Configurations were assigned based on the configuration of 5. 7 Other sigmatropic rearrangements, for example Kwart's shift of allylic phenylthioethers [29] showed a strong dependence of the reaction outcome on concentration and was explained through bimolecular mechanisms for rearrangement. 8 For a recent example of an epimerization on a similar time scale as [1,3]-sigmatropic rearrangement, see [30].…”