Epimerization of Diastereomeric α-Amino Nitriles to Single Stereoisomers in the Solid State

Sakurai, Rumiko; Suzuki, Shuji; Hashimoto, Junichi; Baba, Manabu; Itoh, Osamu; Uchida, Akira; Hattori, Tetsutaro; Miyano, Sotaro; Yamaura, Masanori

doi:10.1021/ol049256q

Cited by 41 publications

(17 citation statements)

References 13 publications

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“…得益于这一有用的差向异构化, 可从非对映立体异构体混合物 5a/5b (2,5-trans∶2,5-cis＝69∶31)直接高立体选择性地得到(＋)-2-别-bulgecinine 衍生物 16b (2,5-trans∶2,5-cis＝10∶90). α-氰胺高立体选择性差向异构化的运用文献已有记载 [36] .…”

Section: 结果与讨论unclassified

Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group: A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine

高燕娇¹,

肖振华²,

刘良先³

et al. 2017

Chin. J. Org. Chem.

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The direct reductive cyanation of N-benzyl-4-benzyloxy-5-hydroxymethyl-2-pyrrolidinone (3a), a lactam bearing a free hydroxyl group, has been achieved with the LiAlH 4 /KCN combination. The reaction afforded 2,5-trans-2-cyano-5hydroxylmethyl-4-benzyloxy-pyrrolidine (5a) and its cis-diastereomer 5b in a ratio of 69∶31 with a combined yield of 63%. The observed 2,5-trans-stereoselectivity is suggested to be resulted from both stereoelectronic effect and allylic 1,3-strain between the hydroxymethyl group at C(5) and the incoming cyanide anion on the presumed Δ-1 pyrrolinium ion intermediate. The subsequent hydrolysis of the cyano group of the diastereomeric mixture 5a/5b (trans∶cis＝69∶31) under basic conditions afforded the corresponding 5-hydroxymethyl-4-benzyloxyproline with 2,5-cis-diastereomer as the major diastereomer (trans∶cis＝10∶90). This result implies that a synthetically useful epimerization at C(2) has occurred concomitantly. This unexpected result afforded a concise and highly stereoselective synthesis of 2,5-cis-(-)-N-methyl-2-epi-bulgecinine. Keywords amides; nitriles; iminium ion; stereoselective synthesis; epimerization α-氰胺是一类多用途的复合官能团 [1] , 其多样的化学已在 Husson 著名的氰基调控构型方法学中全面展示 [2]. 此外, α-氰胺结构单元存在于许多药物和活性天然产物及其类似物中 [3] (图 1), 例如 , 沙格列汀 (Saxagliptin, D-1) 和地格列汀甲苯磺酸盐 (Denagliptin tosylate, D-2)均为四型二肽酶(DPP IV)抑制剂, 前者作为高效地治疗二型糖尿病的药物于 2009 年获批准上市 [4] , 后者正在被开发为治疗二型糖尿病的药物 [5]. 化合物 D-3 是一种苯并二氮杂受体拮抗剂 [3]. Lahadinine A (N-1) [6] 和 Cyanosafracin B (N-2)均为天然产物, 后者被用作合成抗癌药 Ecteinascidin 743 工业生产的原料 [7]. DX-52-1 (N-3)表现出显著的抗肿瘤活性 [1b] .

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Section: 结果与讨论unclassified

Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group: A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine

高燕娇¹,

肖振华²,

刘良先³

et al. 2017

Chin. J. Org. Chem.

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“…[31] We then prepared [D 6 ]DMSO solutions of isolated pure diastereoisomers 37a and 37b, and heated them at 80°C for 24 h. 1 H NMR spectra of both of the samples showed the formation of traces of benzaldehyde and l-proline methyl ester, and also of epimerization products with a final diastereomeric ratio of 68:32 (37a/37b) starting from 37a, and 65:35 (37a/37b) starting from 37b. Sakurai, for instance, observed isomerization of diastereomeric α-aryl aminonitriles when the compounds were dissolved in DMSO, or after heating.…”

Section: Secondary Chiral Aminesmentioning

confidence: 99%

Asymmetric Strecker Reaction with Chiral Amines: a Catalyst‐Free Protocol Using Acetone Cyanohydrin in Water

et al. 2013

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The synthesis of a series of new chiral α‐aminonitriles was achieved in a diastereoselective Strecker reaction in a one‐pot procedure with aldehydes, enantiopure amines, and acetone cyanohydrin in water. Primary and secondary amines derived from L‐α‐amino acids were used as sources of chirality. The reactions proceeded efficiently without any catalyst at room temperature. The diastereoselectivity of the process, and the configurational stability of new chiral α‐aminonitriles were investigated. The identification of labile intermediates by NMR analysis, and a proposed mechanism and a model for the asymmetric induction are reported. The chemical transformation of proline‐derived chiral α‐amino‐nitriles into chiral amino‐diacids, aminols, and amides is reported.

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“…We observed an additional interesting finding with regard to the partial epimerization on the atropic axis that a diastereomer isomerized toward the more stable another diastereomer in a ratio of 5 to 1 after standing in the solid state at room temperature for two months. 25 The ideal rotational barrier on the atropisomers and the related structures were investigated by the Density Functional Theory, as mentioned above. 17 The results are illustrated in Figure 4.…”

Section: ((Arasrs)-19) and (Mpsr)-19 ((Arassr)-19)mentioning

confidence: 99%

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Yokoyama¹,

Matsumoto

Nomura

et al. 2009

Tetrahedron

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Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12.However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed so that the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.

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Epimerization of Diastereomeric α-Amino Nitriles to Single Stereoisomers in the Solid State

Cited by 41 publications

References 13 publications

Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group: A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine

Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group: A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine

Asymmetric Strecker Reaction with Chiral Amines: a Catalyst‐Free Protocol Using Acetone Cyanohydrin in Water

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

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