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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

None
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
See this image and copyright information in PMC

References

    1. Ahmad M., Bergstrom R.C., Cashen M.J., McClelland R.A., Powell M.F. “Phosphate extension”. A strategem for the stereoselective functionalization of acyclic homoallylic alcohols. J. Am. Chem. Soc. 1977;99:4829–4830.
    1. Angelo M.L., Moreira L.M., Ruela A.L.M., Morais A.L., Santos A.L.A., Salgado H.R.N., Magali B.A. Analytical methods for the determination of rosuvastatin in pharmaceutical formulations and biological fluids: a critical review. Crit. Rev. Anal. Chem. 2018;48:317–329. - PubMed
    1. Appel A.M., Bercaw J.E., Bocarsly A.B., Dobbek H., DuBois D.L., Dupuis M., Ferry J.G., Fujita E., Hille R., Kenis P.J.A. Frontiers, opportunities, and challenges in biochemical and chemical catalysis of CO2 fixation. Chem. Rev. 2013;113:6621–6658. - PMC - PubMed
    1. Bartlett P.A., Meadows J.D., Brown E.G., Morimoto A., Jernstedt K.K. Carbonate extension. A versatile procedure for functionalization of acyclic homoallylic alcohols with moderate stereocontrol. J. Org. Chem. 1982;47:4013–4018.
    1. Beck G., Jendralla H., Kesseler K. Practical large scale synthesis of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate: essential building block for HMG-CoA reductase inhibitors. Synthesis. 1995;8:1014–1018.