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

Abstract

SummaryChiral 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.

Development of a Practical, Biocatalytic Synthesis of tert-Butyl (R)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain

“…The combined EtOAc solution was dried and concentrated in vacuo to give ( R )- 2a (3.21 kg, 96.2% yield) with a GC purity of 80%, as well as an enantiomeric purity of >99.9% ee. Without further purification, thus obtained ( R )- 2a can be directly used in our reported synthesis of bromocarbonate 3a via a one-pot diastereoselective carboxylation/bromocyclization sequence …”

“…Moreover, extensive research studies in the field indicate that statins have many other pharmacological activities, including anti-inflammatory and anticancer activity, as well as antioxidative effects. ,− Given their pharmaceutical importance, tremendous efforts have been devoted to the efficient and sustainable synthesis of statins. ,, In particular, various methods have been developed to build the chiral syn -3,5-dihydroxy-6-heptenoic or heptanoic acid side chain, the common and pharmacologically important structural feature of statins . Within this context, our group has longtime interests in the efficient and asymmetric synthesis of statins. − Recently, we have demonstrated a pilot-plant-scale synthesis of bromocarbonate 3a via a one-pot diastereoselective carboxylation/bromocyclization of tert -butyl ( R )-3-hydroxyl-5-hexenoate (( R )- 2a ) (Scheme A) . The bromocarbonate 3a was transformed further to Kaneka alcohol 4a , the common synthetic intermediate to statin molecules, in three steps with high yields.…”

Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

“…Our group has long‐standing interests in the development of efficient synthesis of statins, [13] as exemplified by a recent success on a pilot‐plant‐scale synthesis of bromocarbonate 9 , an advanced intermediate to statin molecules, via a one‐pot diastereoselective carboxylation/bromocyclization of tert ‐butyl ( R )‐3‐hydroxyl‐5‐hexenoate ( 8 ) [14] . Our most recent work on statin synthesis was the development of a practical, sustainable, biocatalytic synthesis of 8 , therefore replacing the first‐generation chemical method which requires the cryogenic reaction conditions (−40 °C) [15] .…”

Continuous-Flow Asymmetric Synthesis of (3R)-3-Hydroxyl-5-hexenoates with Co-Immobilized Ketoreductase and Lactobacillus kefir Dehydrogenase Integrating Greener Inline Microfluidic Liquid–Liquid Extractors and Membrane Separators

“…Enantiomerically pure (3 R )-3-hydroxyl-5-hexenoates ( 1 ) are crucial chiral intermediates in the synthesis of a wide variety of biologically active compounds and chiral drugs, such as (−)-mycalolide A, lankacidins, (−)-spirofungins, ulapualide A, macrosphelides, (+)-leucascandrolide A, (+)-neopeltolide, and statins. − From a synthetic perspective, the control of the stereochemistry of the hydroxyl moiety presents a major challenge due to the simultaneous presence of multiple reactive functionalities. Therefore, a considerable amount of effort has been devoted to the development of efficient synthetic protocols to access ( 1 ). − …”

“…1,4,10,11 In the second approach, crotonoyl chloride (6) was transformed into β,γ-unsaturated ester (7). Then, a reaction with m-CPBA led to racemic epoxide (8), and a Jacobsen hydrolytic kinetic resolution of racemate (8) using the (R,R)-salen-Co(III) complex led to (9). The epoxide function of (9) was opened by attack of vinylmagnesium bromide, leading to the desired (1) (Route 2 in Scheme 1).…”