A Short Diastereoselective Synthesis of 2,3-Disubstituted Succinates

Beckett, R.Paul; Crimmin, M.; Davis, Mark H.; Spavold, Zoë M.

doi:10.1055/s-1993-22378

Cited by 39 publications

(20 citation statements)

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“…As opposed to standard alkylations with alkyl halides which gave only the syn isomer (ref ), reaction of the dianion of 7 with disulfides gave a mixture of syn and anti diastereoisomers, presumably due to partial formation of the sulfur stabilized anion followed by reprotonation.…”

Section: Referencesmentioning

confidence: 87%

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New α-Substituted Succinate-Based Hydroxamic Acids as TNFα Convertase Inhibitors

et al. 1999

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Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).

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Section: Referencesmentioning

confidence: 87%

“…The inhibitors of the present study were prepared using the following sequences. Synthesis of the thioether-based inhibitors 2 started from succinate 7 (Scheme ) . The dianion of 7 was reacted with disulfides to give thioethers 8 and 9 as a mixture of two diastereoisomers, which were separated at this stage.…”

Section: Chemistrymentioning

confidence: 99%

New α-Substituted Succinate-Based Hydroxamic Acids as TNFα Convertase Inhibitors

et al. 1999

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“…Martin 6 showed that an Ireland-Claisen route (6 to 2) can provide anti-selective products, but this method is limited to functionalities that can be derived from an allyl group. Crimmin 7 showed that only syn-selective products could be obtained upon alkylation of ester 7. Recently, Baran 8a reported an efficient method for generation of 2,3-disubstituted succinic acids via a copper-mediated oxidative eno-…”

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confidence: 99%

A Practical Approach for Enantio- and Diastereocontrol in the Synthesis of 2,3-Disubstituted Succinic Acid Esters: Synthesis of the pan-Notch Inhibitor BMS-906024

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Gill

Kim

et al. 2016

Synlett

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“…Encouraged by literature precedent, we hoped that synthesis of b-lactone 3 would be possible via stereoselective chlorination of the monosubstituted succinate 18 7,8 followed by cyclisation. Synthesis of 18 commenced with hydrodeamination of L-isoleucine with a slight modification to the literature procedure (Scheme 3), 9 followed by conversion to the oxazolidinone derivative 16 and a highly diastereoselective alkylation using tert-butyl bromoacetate to afford 17 in 82% yield and 93 : 7 d.r.…”

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confidence: 99%

“…Synthesis of 18 commenced with hydrodeamination of L-isoleucine with a slight modification to the literature procedure (Scheme 3), 9 followed by conversion to the oxazolidinone derivative 16 and a highly diastereoselective alkylation using tert-butyl bromoacetate to afford 17 in 82% yield and 93 : 7 d.r. 7 Recrystallisation followed by hydrolysis using LiOH/H 2 O 2 then furnished the desired acid 18 in 92% yield and > 95 : 5 d.r. The key chlorination step was achieved by prior conversion to the dianion using LiHMDS followed by treatment with 1 equivalent of carbon tetrachloride.…”

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confidence: 99%