Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates and Trifluoromethyl Ketones by Carbonyl Catalysis

Cheng, Aolin; Zhang, Liangliang; Zhou, Qinghai; Liu, Tao; Cao, Jing; Zhao, Guoqing; Zhang, Kun; Song, Guanshui; Zhao, Baoguo

doi:10.1002/anie.202104031

Cited by 40 publications

(29 citation statements)

References 78 publications

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“…[21] A plausible mechanistic pathway has been proposed for the reaction (Scheme 3). [13,15,18] Chiral pyridoxal 8 a condenses with glycinate 1 a to form Schiff base 15, which is deprotonated at the α-position of the ester to generate delocalized carbanion 16. [23] Asymmetric addition of carbanion 16 to the quaternary ammonium salt intermediate 17, which formed through the nucleophilic addition of DMAP to MBH acetate 2, produces species 19 with the elimination of DMAP.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Gao

Song

et al. 2022

Angew Chem Int Ed

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Owing to the strong nucleophilicity of the NH2 group, free‐NH2 glycinates react with MBH acetates to usually deliver N‐allylated products even in the absence of catalysts. Without protection of the NH2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N‐allylation to α‐C allylation. The reaction formed chiral multisubstituted glutamic acid esters as SN2′–SN2′ products in good yields with excellent stereoselectivity (up to 86 % yield, >20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo‐ and enantiocontrol of the pyridoxal catalysts.

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Section: Methodsmentioning

confidence: 99%

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Gao

Song

et al. 2022

Angew Chem Int Ed

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“…[21] A plausible mechanistic pathway has been proposed for the reaction (Scheme 3). [13,15,18] Chiral pyridoxal 8 a condenses with glycinate 1 a to form Schiff base 15, which is deprotonated at the α-position of the ester to generate delocalized carbanion 16. [23] Asymmetric addition of carbanion 16 to the ammonium salt intermediate 17, which is formed through the nucleophilic addition of DMAP to MBH acetate 2, produces species 19 with the elimination of DMAP.…”

Section: Zuschriftenmentioning

confidence: 99%

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Gao

Song

et al. 2022

Angewandte Chemie

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Owing to the strong nucleophilicity of the NH 2 group, free-NH 2 glycinates react with MBH acetates to usually deliver N-allylated products even in the absence of catalysts. Without protection of the NH 2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N-allylation to α-C allylation. The reaction formed chiral multisubstituted glutamic acid esters as S N 2'-S N 2' products in good yields with excellent stereoselectivity (up to 86 % yield, > 20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo-and enantiocontrol of the pyridoxal catalysts.Organocatalytic allylic substitution of Morita-Baylis-Hillman (MBH) adducts is a very useful synthetic transformation, which is capable to transfer various nucleophiles into optically active compounds bearing multiple functional groups. [1][2][3][4][5] When glycinates, a type of important synthons [6] for constructing non-natural amino acids, serve as the nucleophiles, N-addition products 4 and/or 5 are easily formed due to the high nucleophilicity of NH 2 group (Figure 1a). [7] Protecting of the NH 2 group leads to α-C allylation to give S N 2' products 4-alkylidenyl glutamic acid derivatives 7 or S N 2'-S N 2' products 4-methylene glutamic acid derivatives 7' when in the presence of chiral organo-

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“…[10d,e] Inert primary amines bearing more basic α CÀ H bonds such as propargylic amines are still highly challenging for the transformation. In continuation of our ongoing interest in this area, [7,9,12] herein, we disclose our success on chiral pyridoxal catalyzed asymmetric α-CÀ H addition of Nunprotected propargylic amines 1 to trifluoromethyl ketones 2, which provided chiral alkynyl β-aminoalcohols [1] 3 in good yields (54-84 %) with excellent enantioselectivities (85-99 % ee) and high diastereoselectivities (7 : 1-> 20 : dr) (Figure 1c).…”

mentioning

confidence: 98%

“…Initially, the studies were carried out by examining the reaction of propargylic amine 1 a with trifluoromethyl ketone 2 a in the presence of 5 mol % of chiral pyridoxal [9] 4 a as the carbonyl catalyst (Table 1). To our delight, the reaction occured as expected with diisopropylethylamine (DIPEA) as the base, affording the chiral alkynyl β-aminoalcohol 3 a in high diastereomeric ratio (> 20 : 1 dr), albeit in only 14 % yield with moderate enantioselectivity for the Table 1: Optimization of reaction conditions.…”

mentioning

confidence: 99%

Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

Liu

et al. 2022

Angewandte Chemie

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Direct asymmetric functionalization of the inert α C−H bonds of N‐unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pKa≈42.6) of the α C−H bonds and interruption of the nucleophilic NH2 group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric α‐C−H addition of N‐unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl β‐aminoalcohols in 54–84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The α C−H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 1022 times (from pKa 42.6 to pKa 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C−H bonds enabled by an organocatalyst.

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Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates and Trifluoromethyl Ketones by Carbonyl Catalysis

Cited by 40 publications

References 78 publications

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

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