Synthesis of Chiral α-Amino Tertiary Boronates via the Catalytic Enantioselective Nucleophilic Borylation of Dialkyl Ketimines

Abstract

The catalytic enantioselective nucleophilic borylation of ketimines is reported. A series of acyclic dialkyl ketimines reacted efficiently with bis(pinacolato)diboron in the presence of a copper(I)/chiral N-heterocyclic carbene catalytic system to furnish optically active α-amino tertiary boronates with high enantioselectivity (up to 99% ee). The products can be converted into peptidylboronic acid derivatives that bear bulky aliphatic substituents, compounds that are difficult to synthesize by other methods. Density functional theory calculations indicated that the enantioselectivity-determining step involves noncovalent interactions that recognize the prochiral dialkyl ketimine, leading to highly efficient enantiodiscrimination.

Recent Advances in Nonprecious Metal Catalysis

“…While several asymmetric methods have been developed for the Cucatalyzed addition of nucleophilic boron to imines, Kubota, Ito, and co-workers reported the first catalytic enantioselective version for dialkyl ketimines (Scheme 32). 79 Ketimine substrates have traditionally been challenging for this reaction, limiting the scope of available derivatives. The optimized reaction conditions employ a chiral NHC ligand precursor and CuCl in a 1:1 ratio.…”

Primary trifluoroborate-iminiums enable facile access to chiral α-aminoboronic acids via Ru-catalyzed asymmetric hydrogenation and simple hydrolysis of the trifluoroborate moiety

“…Many of the existing methods are either racemic, allow limited scope of substrates, or do not enable the synthesis of N -unprotected derivatives. 11,18–33,35…”

“…11,18 In recent years, this eld has continued to ourish with many exciting methods being developed. [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Among recent methodologies, discoveries of Yudin 32 and Bode 33 caught our attention. Namely, in these reports triuoroborate-iminiums (TIMs) and MIDA-protected iminoboronates were prepared from acylboranes, 34 and converted to racemic N-substituted a-aminoboronic acid derivatives with borohydride reagents (Scheme 1).…”

“…Many of the existing methods are either racemic, allow limited scope of substrates, or do not enable the synthesis of N-unprotected derivatives. 11,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]35 Based on our recent research, 35 we envisioned that unsubstituted primary TIMs (pTIMs) could provide access to chiral aaminoboronic acids using asymmetric hydrogenation. Moreover, the use of pTIMs would eliminate the N-deprotection step to obtain the free amino group, thereby shortening the overall synthetic sequence.…”

Copper-Catalyzed Enantioselective Synthesis of α-Aminoboronic Acid Derivatives

“…The enantioselective synthesis of chiral α-aminoboronic acids and their derivatives is an important goal in organic chemistry, since they are subunits in an array of bioactive compounds (antibacterial, anticancer, antiviral, etc., including Velcade; Figure 1A 1,2,3 ) 4,5,6,7 and serve as versatile intermediates in synthesis. 8,9,10,11,12,13 Whereas early approaches to controlling the α stereocenter relied on diastereoselective processes via, for example, chiral auxiliaries, 14,15,16 methods wherein a chiral catalyst controls that stereocenter have begun to emerge, including the hydroamination of alkenylboronates, 17,18 borylation of aldimines 19 and ketimines, 20 hydroboration of enamides, 21 and tandem hydroboration-hydroamination of terminal alkynes. 22 Figure 1B outlines a complementary approach to the catalytic asymmetric synthesis of αaminoboronic acid derivatives, starting with commercially available linchpin A.…”