Stereoselective Synthesis of the C9–C19 Fragment of Peloruside A

Abstract

A concise synthesis of the C9-C19 fragment of peloruside A that is both highly stereoselective and efficient is described. Achieving an overall yield of 23% over 14 steps, this synthesis not only is high yielding but also involves four chromatography steps. This approach is based on the addition of metal enolates of chiral auxiliary scaffolds generated by either catalytic or stoichiometric amounts of nickel(II) or titanium(IV) Lewis acids.

Function-Oriented Synthesis toward Peloruside A Analogues

“…The crystallographic structure of a PelA/tubulin complex was resolved in 2014, as well as dually bound PelA/Taxol to microtubules, providing structural information on the binding mode. Despite this propitious context, synthetic studies toward new PelA analogues have been scarcely reported since 2014. , The lack of SAR study is undoubtedly due to the structural complexity of PelA, requiring challenging synthetic work for each single analogue.…”

“…Despite this propitious context, synthetic studies toward new PelA analogues have been scarcely reported since 2014. 10b, 12 The lack of SAR study is undoubtedly due to the structural complexity of PelA, requiring challenging synthetic work for each single analogue. In this context, the development of a convergent synthetic strategy, allowing the late-stage functionalization of a synthetic platform, would be of high value.…”

Stereoselective and Catalytic Synthesis of anti-β-Alkoxy-α-azido Carboxylic Derivatives

“…More recently, Kumagai and Shibasaki have described a highly diastereoselective and enantioselective catalytic aldol reaction of α-azido 7-azaindolinylacetamide, but this is restricted to ortho -substituted aromatic aldehydes . In the face of this lack of experimentally simple and broad ranging synthetic methods, we envisaged that the direct addition of chiral N -glycyl thiazolidinethiones to dialkyl acetals catalyzed by nickel­(II) complexes might afford anti -β-alkoxy-α-amino carboxylic derivatives. , Herein, we report that (Me 3 P) 2 NiCl 2 triggers the stereocontrolled addition of a chiral N -2-azidoacetyl thiazolidinethione (NPG: N 3 in Scheme ) to aromatic and propargylic dialkyl acetals to give anti -β-alkoxy-α-azido adducts which, in turn, can be easily converted into a plethora of enantiomerically pure intermediates.…”

Diastereoselective and Catalytic α-Alkylation of ChiralN-Acyl Thiazolidinethiones with Stable Carbocationic Salts

“…As part of our studies aimed at the development of new catalytic and stereoselective carbon–carbon bond-forming reactions, we have recently described a nickel-catalyzed alkylation of chiral N -acyl-4-isopropyl-1,3-thiazolidine-2-thiones with diarylmethyl methyl ethers, which provide the corresponding adducts in high yields and with absolute stereocontrol . Considering that the reaction involves the addition of a nickel­(II) enolate to a cationic intermediate generated in situ, we thus envisaged that a related procedure based on the direct addition to naked carbenium cations would avoid the need to activate the electrophile, greatly simplifying the experimental procedure and attaining a more atom-economic process, and might also provide a way to introduce sterically hindered groups, a challenge that still remains elusive.…”

“…Applying small changes to the conditions previously employed , where the electrophile required activation, we initially assessed the addition of ( S )-4-isopropyl- N -propanoyl-1,3-thiazolidine-2-thione ( 1a ) to the stable tropylium cation, a model for naked carbenium ions, promoted by (Me 3 P) 2 NiCl 2 in the presence of 2,6-lutidine. Remarkably, this nickel­(II) complex is structurally simple, robust, and can be handled without any special care; furthermore, this is easily activated in the reaction mixture by TESOTf to form the true catalyst, (Me 3 P) 2 Ni­(OTf) 2 .…”