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. 2018 Nov 30:9:513-520.
doi: 10.1016/j.isci.2018.11.010. Epub 2018 Nov 9.

Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols

Guanxin Huang  1 , Minjie Liu  1 , Fangjun Xiong  1 , Ge Meng  1 , Yuan Tao  1 , Yan Wu  1 , Haihui Peng  2 , Fener Chen  3
Affiliations

Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols

Guanxin Huang et al. iScience. .

Abstract

Chiral syn-1,3-diols are fundamental structural motifs in many natural products and drugs. The traditional Narasaka-Prasad diastereoselective reduction from chiral β-hydroxyketones is an important process for the synthesis of these functionalized syn-1,3-diols, but it is of limited applicability for large-scale synthesis because (1) highly diastereoselective control requires extra explosive and flammable Et2BOMe as a chelating agent under cryogenic conditions and (2) only a few functional syn-1,3-diol scaffolds are available. Those involving halogen-functionalized syn-1,3-diols are much less common. There are no reported diastereoselective reactions involving chemical fixation of CO2/bromocyclization of homoallylic alcohols to halogen-containing chiral syn-1,3-diols. Herein, we report an asymmetric synthesis of syn-1,3-diol derivatives via direct diastereoselective carboxylation/bromocyclization with both relative and absolute stereocontrol utilizing chiral homoallylic alcohols and CO2 in one pot with up to 91% yield, > 99% ee, and >19:1 dr. The power of this methodology has been demonstrated by the asymmetric synthesis of statins at the pilot plant scale.

Keywords: Chemistry; Organic Chemistry; Stereochemistry.

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Figures

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Graphical abstract
Scheme 1
Scheme 1
1,3-Diol Polyketide Natural Products and Drugs
Scheme 2
Scheme 2
Methods for the Synthesis of syn-1,3-Diols (A–D) (A) Hydrogenation of 1,3-hydroxyketones to chiral syn-1,3-diols. (B) Cryogenic Narasaka-Prasad reduction to chiral syn-1,3-diols (currently dominates in the industry). (C) nBuLi-mediated iodocarboxylation to racemic syn-1,3-diols. (D) This work: substrate-induced diastereoselective bromocarboxylation to chiral syn-1,3-diols.
Scheme 3
Scheme 3
Pilot-Plant-Scale Synthesis of Statins
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