Chiral N-phosphonyl imine chemistry: asymmetric additions of glycine enolate to diphenyl diamine-based phosphonyl imines

Abstract

Diphenyl diamine-based phosphonyl imines attached by the N-isopropyl group in the auxiliary have been synthesized in good yields under convenient reaction conditions. These new chiral N-phosphonyl imines can react with glycine enolate smoothly to give chiral α-β diamino esters in good yields (72%-90%) and up to excellent diastereoselectivity (>99:1 dr). By treatment with HBr, the chiral auxiliary can be readily removed. The absolute structure has been unambiguously determined by converting a product to a known sample. chiral N-phosphonyl imine, chiral phosphoramide, glycine enolate, α-β diamino ester

N,N-Diisopropyl-N-phosphonyl imines lead to efficient asymmetric synthesis of aziridine-2-carboxylic esters

“…The advantages of using chiral N -phosphonyl imines would be showed by the following factors: higher thermolytic stability, modification and flexibility at their multiple sites, inertness of phosphonyl group to oxidative conditions, the 31 P NMR determination of diastereoselectivity and easy recycling of diamine auxiliary precursors. 9–12 Importantly, our N -phosphonyl and N -phosphinyl imine-based work has resulted in a new concept called GAP chemistry (Group-Assisted Purification chemistry) 14 which can enable organic synthesis to be performed without using traditional purification techniques such as column chromatography and recrystallization, albeit a few non-GAP exceptions were encountered including the present aziridine formations in which there is no N-H moiety in the products. 15 In our first aza-Darzens synthesis, we utilized N -benzyl as the protection group on phosphonyl imine auxiliary.…”

“…In several of our previous systems, the combination of N,N -diisopropyl and diaminocyclohexyl scaffolds have been proven to be superior to others in several nucleophilic addition reactions and syntheses, such as aza-Henry reaction, 9b the addition reaction of allyl magnesium bromide, 9c the synthesis of β-amino weinreb amides, 11a α,β-diamino esters 11d chiral propargyl amines, 12a and umpolung reaction with lithium 1,3-dithianes. 12c Therefore, this combination was considered to enhance the present synthesis of aziridine-2-carboxylic esters.…”

“…12c Therefore, this combination was considered to enhance the present synthesis of aziridine-2-carboxylic esters. We now found that (1 R , 2 R )-diaminocyclohexyl derived N,N -diisopropyl- N -phosphonyl benzaldimine ( 5c ) can react with β-bromo lithium enolate smoothly to completion within 8 hours.…”

“…7,8 Although a great progress has been made on this synthetic topic, it is still remained challenging to develop more efficient and facile approaches to a broad range of structurally diverse aziridines in enantio- and diastereoselective manner. In the past several years, we have designed and synthesized new chiral reagents of N -phosphonyl and N -phosphinyl amides and imines; we have successfully utilized them in various asymmetric reactions such as asymmetric aza-Darzen reaction, 9a asymmetric aza-Henry reaction, 9b asymmetric addition of allylmagnesium bromides, 9c asymmetric synthesis of N -phosphonyl β-amino Weinreb amides, 11a asymmetric synthesis of N -phosphonyl propargyl amines, 12a and asymmetric synthesis of α-amino-1,3-dithianes. 12c In our preliminary work on asymmetric aza-Darzens reaction, we utilized N,N -dibenzyl N - phosphonyl imines as the electrophiles to react with pre-generated β-bromo lithium enolate to give the aziridine products in good yields and diastereoselectivities.…”

“…In the past several years, we have designed and synthesized new chiral reagents of N -phosphonyl and N -phosphinyl amides and imines; we have successfully utilized them in various asymmetric reactions such as asymmetric aza-Darzen reaction, 9a asymmetric aza-Henry reaction, 9b asymmetric addition of allylmagnesium bromides, 9c asymmetric synthesis of N -phosphonyl β-amino Weinreb amides, 11a asymmetric synthesis of N -phosphonyl propargyl amines, 12a and asymmetric synthesis of α-amino-1,3-dithianes. 12c In our preliminary work on asymmetric aza-Darzens reaction, we utilized N,N -dibenzyl N - phosphonyl imines as the electrophiles to react with pre-generated β-bromo lithium enolate to give the aziridine products in good yields and diastereoselectivities. 9a The important feature of these chiral N -phosphonyl imines is shown by the fact that the steric and electronic properties can be optimized by making modifications on different positions of the imine auxiliaries.…”