Catalytic Enantioselective Michael Addition of α‐Aryl‐α‐Isocyanoacetates to Vinyl Selenone: Synthesis of α,α‐Disubstituted α‐Amino Acids and (+)‐ and (−)‐Trigonoliimine A

Abstract

a-Isocyanoacetates are well-known glycine templates for the synthesis of racemic a,a-disubstituted a-amino acids. [1] However, catalytic enantioselective alkylation of a-isocyanoacetates remains underexploited. Ito, Hayashi, and co-workers pioneered the field by discovering the first palladiumcatalyzed enantioselective allylation of methyl a-phenyl-aisocyanoacetate [Eq. (1), Scheme 1; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene]. [2] The enantioselectivity of this reaction was, however, moderate (< 39 % ee). In contrast, a number of Lewis-acid-and small-organomolecule-catalyzed enantioselective [2+3] cycloadditions of a-isocyanoacetates with aldehydes, [3] imines, [4] azodicarboxylates, [5] and polarized carboncarbon double bonds, such as nitroalkenes, [6] a,b-unsaturated ketones, [7] and maleimides, [8] have been developed to access enantioenriched five-membered heterocycles. In contrast, catalytic enantioselective Michael addition of a-isocyanoacetates was met with only limited success. Indeed, it has been established that any Lewis acid catalyzed nucleophilic addition of a-isocyanoacetates to polarized double bonds inevitably provided the [2+3] cycloadducts. The same trend holds true for organocatalytic processes. [8] However, a recent paper from Xu, Wang, and co-workers [9] on a tertiary amine thiourea catalyzed enantioselective Michael addition of aphenyl-a-isocyanoacetate to N-aryl maleimides demonstrated that the aforementioned reaction can be stopped at the Michael adduct stage under appropriate reaction conditions [Eq.(2), Scheme 1].In connection with our ongoing total synthesis project, we needed rapid access to enantiomerically enriched a-aryl-a-(2'-FG-alkyl)-a-amino acids (FG = functional group). [10] We were aware of the seminal contributions of Deng and coworkers on the enantioselective Michael addition of aphenyl-a-cyanoacetate to vinyl phenylsulfone and the subsequent conversion of the enantiomerically enriched adduct into a,a-disubstituted amino acids [Eq. (3), Scheme 1]. [11] However, six steps were needed to convert both the cyano and sulfone groups into other organic residues. Stimulated by this observation, we became interested in examining the chiral Brønsted base catalyzed nucleophilic addition of aaryl-a-isocyanoacetates (1) to vinyl phenyl selenone (2) [12][13][14] for the synthesis of the enantiomerically enriched a-aryl-a-(2'-FG-alkyl)-a-amino acids 3 [Eq. (4), Scheme 1]. [15] The advantage of this approach is that the resulting adduct can be readily converted into an array of functionalized amino acids. Indeed, phenylselenonyl is an excellent leaving group, [16] while the isocyano group is easily hydrolyzed under mild acidic conditions into the free amino function. We report herein the successful development of an organocatalytic enantioselective Michael addition of 1 to 2 for the synthesis of the enantiomerically enriched a,a-disubstituted a-isocyanoacetates 3 and their subsequent transformations into the linear and the cyclic quaternary a-amino acids. Enantioselective total synthe...

Catalytic enantioselective addition of isocyanoacetate to 3-methyl-4-nitro-5-styrylisoxazoles under phase transfer catalysis conditions

“…4, Scheme 2). 17 On the contrary, the enantioselective addition of unsubstituted 2 to activated alkenes (eq. 5, Scheme 2, this work) is undeveloped and remains a significant challenge, as it involves 70 controlling the stereoselectivity of the Michael addition and suppressing a potential second Michael reaction.…”

Enantioselective Synthesis of Quaternary α‐Amino Acids Enabled by the Versatility of the Phenylselenonyl Group

“…On the other hand, reaction of α‐phenyl substituted α‐nitroacetate with 2 a afforded the Michael adduct 5 p with low enantioselectivity (entry 14). The present method is therefore complementary to that based on α‐aryl α‐isocyanoacetates . Finally, the nature of the aryl group of the selenonyl function had no obvious effect on the reaction efficiency (entries 15–17).…”

“…We have recently described a Cinchona alkaloid‐catalyzed Michael addition of methyl α‐aryl‐α‐isocyanoacetates 1 to phenyl vinyl selenone ( 2 a , Ar=Ph) for the synthesis of enantioenriched quaternary α‐isocyanoacetates 3 (Eq. 1, Scheme ) . Unfortunately, the protocol cannot be applied to the α‐alkyl substituted counterpart due most probably to the reduced acidity of its α‐CH.…”

“…Chemical transformations taking advantage of the phenylselenonyl and nitro groups are illustrated in Scheme . Reaction of 5 m with NaN 3 afforded the azido derivative 8 , which, upon Staudinger reduction and lactamization cascade, furnished the pyrrolidinone 9 . The latter was further reduced to the amino derivative 10 , a constrained analogue of phenylalaninamide, the enantioselective synthesis of which remained unknown .…”

Recent studies on the chemical constituents of Trigonostemon plants

“…The key step involves a carbanion-triggered intramolecular cyclization of a seven-membered ring and a subsequent tetrahydropyrimidine ring formation in one pot. 73 In 2011, Hao's group also reported the biomimetic oxidative rearrangement of the bistryptamine framework into the ring system of trigonoliimine C (169) (Scheme 16) after their discovery of these alkaloids. 71 One year later, Zhu's group reported a seven-step synthetic route to trigonoliimine B (168) (Scheme 14), in which they started with the functionalization of commercially available α-isocyanoacetate (219) and 2-fluoronitrobenzene (220), and ended with the unprecedented Bischler-Napieralski reaction implemented for the construction of a seven- membered ring with an overall yield of 12%.…”