Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2022-10-04 DOI:10.1021/acs.oprd.2c00200

Wenxing Guo, Tawfik Gharbaoui, Joseph R. Lizza, Fanfan Meng, Yuanxian Wang, Maoshu Xin, Yuanpeng Chen, Jing Li* and Cheng-yi Chen*,

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引用次数: 2

Abstract

The “butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8. This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de).

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双环吡咯烷醇的实用不对称合成

“蝴蝶形”双环吡咯烷醇((2R,7aS)-2-氟四氢- 1h -吡咯烷醇-7a(5H)-基)-甲醇(1)是候选药物的关键组成部分，其实际化学合成仍难以实现。因此，开发了一种适合规模化生产的((2R,7aS)-2-氟四氢- 1h -吡咯利嗪-7a(5H)-基)-甲醇(1)的不对称合成方法。新优化的工艺利用现成的n - boc -反式-4-羟基-l-脯氨酸甲酯(8)来建立具有挑战性的含氟立体中心。随后的非对映选择性α-烷基化是利用Seebach的自再生立体化学(SRS)方法实现的，该方法已用于脯氨酸衍生物的合成。最后，通过分子内环化/脱保护级联和羰基还原，从化合物8得到双环吡咯烷醇1。该工艺大大减少了整体生产顺序，并允许在数千克规模上制备产品1，总收率为40%，手性控制完美(ee和de均为99%)。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.