Efficient and Scalable Diastereoselective Synthesis of ((2<i>R</i>,7a<i>S</i>)-2-fluorotetrahydro-1<i>H</i>-pyrrolizin-7a(5<i>H</i>)-yl)methanol Hydrochloride

An efficient large-scale synthesis of 2a·HCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl3/NaIO4, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of 35a or 35b via a stable chelate with lithium cation 38 to give a stereoselective product, bicyclic scaffold 36a, with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester 37a afforded 2a·HCl without the need for chiral separation utilized in the first-generation approach.

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Publication Details

Journal
Organic Process Research & Development
Published
2025-03-11
DOI
https://doi.org/10.1021/acs.oprd.4c00462
Primary Topic
Fluorine in Organic Chemistry
Type
article
Field-Weighted Citation Impact
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article

Efficient and Scalable Diastereoselective Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol Hydrochloride

Anuradha Gupta, Pravin S. Shirude, Roshan Y. Nimje, Joseph Pawluczyk et al.
Organic Process Research & Development
Fluorine in Organic Chemistry
article

Efficient and Scalable Diastereoselective Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol Hydrochloride

Anuradha Gupta, Pravin S. Shirude, Roshan Y. Nimje, Joseph Pawluczyk, Arvind Mathur, Daniel Smith, Brian E. Fink, James Kempson, Bharti P. Koli, Zhenqiu Hong, Shishir Chourey, Bei Wang, Rulin Zhao, M. V. Chidambaram, Ramakrishna Panchakharla
article en

Abstract

An efficient large-scale synthesis of 2a·HCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl3/NaIO4, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of 35a or 35b via a stable chelate with lithium cation 38 to give a stereoselective product, bicyclic scaffold 36a, with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester 37a afforded 2a·HCl without the need for chiral separation utilized in the first-generation approach.

Organic Process Research & DevelopmentVol. 29(3)
Bristol-Myers Squibb (Germany) (DE), Bristol-Myers Squibb (India) (IN), Biocon (India) (IN), Syngene International (India) (IN)
Clean water and sanitation
Openalex Percentile: Top 97%
Fluorine in Organic Chemistry
DOISourceOpenAlex
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Efficient and Scalable Diastereoselective Synthesis of ((2<i>R</i>,7a<i>S</i>)-2-fluorotetrahydro-1<i>H</i>-pyrrolizin-7a(5<i>H</i>)-yl)methanol Hydrochloride — Anuradha Gupta, Pravin S. Shirude, et al. · Organic Process Research & Development (2025) | TGRS Research Map | TGRS