Multigram scale, chiron-based synthesis of sacubitril

Wang, Yun; Chen, Fen‐Er; Shi, Yong; Tian, Weisheng

doi:10.1016/j.tetlet.2016.11.078

Cited by 7 publications

(3 citation statements)

References 12 publications

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“… [1–5] As versatile building blocks, chiral substituted γ ‐butyrolactones can be facilely utilized as intermediates for the synthesis of many blockbuster drugs and bioactive agents. For instance, the hydrolysis product of α , γ ‐disubstituted γ ‐butyrolactones could be transformed to sacubitril (an enkephalinase inhibitor used for heart failure) and geodiamolide A–F [6–9] . Its functionalized tetrahydrofuran derivatives could be effectively converted to orlistat (treatment for obesity) and (+)‐cryptophycin 52 (a potent antimitotic antitumor agent) [10–13] …”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5] As versatile building blocks, chiral substituted γ-butyrolactones can be facilely utilized as intermediates for the synthesis of many blockbuster drugs and bioactive agents. For instance, the hydrolysis product of α, γ-disubstituted γ-butyrolactones could be transformed to sacubitril (an enkephalinase inhibitor used for heart failure) and geodiamolide A-F. [6][7][8][9] Its functionalized tetrahydrofuran derivatives could be effectively converted to orlistat (treatment for obesity) and (+)-cryptophycin 52 (a potent antimitotic antitumor agent). [10][11][12][13] Intrigued by the great importance, significant efforts have been made on the development of concise and efficient approaches toward diastereo-and enantioselective construction of α, γ-disubstituted γ-butyrolactones.…”

Section: Introductionmentioning

confidence: 99%

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Double Asymmetric Hydrogenation of (E)‐2‐Substituted‐4‐oxo‐2‐alkenoic Acids: An Efficient Synthesis of Chiral α, γ‐Disubstituted γ‐Butyrolactones

et al. 2022

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Optical pure α, γ‐disubstituted γ‐butyrolactones moieties are versatile building blocks for the synthesis of many drugs and natural products. Herein we report a straightforward and efficient approach to afford a series of chiral α, γ‐disubstituted γ‐butyrolactones with excellent results (up to 98 % yield, up to >99 : 1 d.r., and up to >99 % ee) through the double asymmetric hydrogenation of the (E)‐2‐methyl‐4‐oxo‐2‐alkenoic acids utilizing the rhodium/JosiPhos catalytic system.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Double Asymmetric Hydrogenation of (E)‐2‐Substituted‐4‐oxo‐2‐alkenoic Acids: An Efficient Synthesis of Chiral α, γ‐Disubstituted γ‐Butyrolactones

et al. 2022

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“…Upon stereoselective addition of a Grignard reagent to the obtained chiral intermediate 8, the biphenyl motif is installed and 3 more steps finally give the active pharmaceutical ingredient 1 (Scheme 1, d). Secondly, the group of Wang [8] developed a chiron-based approach relying on the protected triol 9. The key transformations of their process are epoxide formation as well as an one-flask Staudinger reduction/succinic amide formation, which facilitate formation of sacubitril 1 in a total of 7 steps (Scheme 1, e).…”

Section: Introductionmentioning

confidence: 99%

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

et al. 2019

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The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical "Design of Experiments" (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield. Keywords Continuous flow chemistry. Heterogeneous catalysis. Multistep reaction cascade. Palladium. Sacubitril Highlights • Development of a multistep setup for the integrated synthesis of a latestage sacubitril precursor in continuous flow. • Intensification of Suzuki coupling in continuous flow employing a heterogeneous palladium catalyst implemented in a packed-bed reactor. • Optimization of Boc-deprotection as well as N-amidation using the "Design of Experiments" approach.

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