Hydrazidation, enantioselective

An auxiliary controlled enantioselective route to generate seven-membered ring lactams 75 used the a-alkylation of cyclic hydrazide derivatives 74. Initially, 6-chloro hydrazides 73,bearing the chiral information in the M-amino-pyrrolidine function underwent amidocyclization in the presence of a base. A subse-... 

Allenyltitanium intermediates have also been found to react with diazo dicarboxy-lates to afford propargylic hydrazides (Table 9.25) [41]. The reaction proceeds with overall retention of configuration. The enantioselectivity of the process decreases with increasing steric demands of the propargylic substituent of the phosphate precursor (Eq. 9.36). 

For resolution of the racemate 12 two different procedures can be applied 124 the en-antioselective enzymatic deacylation of chloroacetyl-DL-a-aminosuberic acid at pH 7.2 with Taka-acylase or the enantioselective salt precipitation of Z-dl-Asu-OH with D-tyrosine hydrazide according to the method of Vogler et alJ25 Complete enzymatic digestion is achieved in about ten days at 37 °C, and the optically pure L-enantiomer is obtained in 80% yield but the overall efficiency is lower than that of the chemical method. Fractional crystallization affords in good yields the Z-l-Asu-OH derivative 13 which is then used directly as a suitably protected intermediate in subsequent derivatization steps (see Scheme 6). Moreover, the recovery of the D-enantiomer from the mother liquors is also easy in this case. 

The enantioselective amination of iV-acyl oxazolidinones has been studied as part of a general approach to the synthesis of arylglycines. In this case, the enolization is initiated by a chiral magnesium bis(sulfonamide) complex. The oxazolidinone imide enolates are generated using catalytic conditions (10 mol% of magnesium complex) and treated in situ with BocN=NBoc to provide the corresponding hydrazide. 20 mol% of iV-methyl-p-toluensulfonamide are added to accelerate the reaction (equation 117). 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

Having learned this, Dupont workers [52] have added a temporary auxiliary donor atom to an unsaturated substrate in order to be able to steer adduct formation, and so the enantioselectivity of the hydrogenation. For example, asymmetric hydrogenation of imines or ketones was a reaction that yielded rather low enantiomeric excesses. However, by converting these first into acyl hydrazones the hydrazide oxygen can function as the secondary complexation function and now extremely high enantiomeric excesses can be obtained (Fig. 6.23). 

In 2013, the Smith group reported asymmetric a-amination through an NHC-catalyzed redox reaction of a-aroyloxyaldehydes with A/-aryl-AI-aroyldi-azenes to form a-hydrazino esters with high enantioselectivity (up to 99% ee). The hydrazide products are readily converted into enantioen-riched A -aryl amino esters through Sml2-mediated N—N bond cleavage (Scheme 7.83). 

A highly enantioselective aza-Michael reaction of Af-protected benzyloxy-amines with a,p-unsaturated ketones, catalysed by 9-amino-9-deoxy-epz-quinine, was described by Deng et al. The reaction is effective for a broad range of alkyl vinyl ketones with both aryl and alkyl p-substituents, affording products in up to 90% yield and 96% ee (Scheme 15.21). Protected hydrazides were also used as nucleophiles in an aza-Michael reaction with aliphatic a,p-enones. ... 

Maruoka and co-workers reported the first catalytic asymmetric three-component 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using CuOAc/Ph-pybox and axially chiral dicarboxylic acid cocatalysts (Scheme 27) [48]. This transformation has abroad tolerance with regard to the substrates, affording diverse chiral 3,4-disubstituted pyrazolines with high enantioselectivities. The role of the axially chiral dicarboxylic acid is to generate the protonated acyclic azomethine imine, which then reacts with chiral Cu-acetylide. 

List [86] and Jorgensen [87] have recently independently described a novel application of L-proline (107) for catalysis of enantioselective hydrazidation of aldehydes [88]. For example, when aldehyde 106 is allowed to react with di-tert-butyl azodicarboxylate (95) in the presence of 10 mol% 107, adduct 108 is isolated in > 90% yield and 93% ee (Scheme 10.18) [87]. The product hydra-zides can be transformed into protected amino acid derivatives through a sequence that involves oxidation of the aldehyde to the corresponding carboxylic acid, esterification, deprotection, and N-N bond cleavage with Raney-Ni [86, 87]. The observed selectivity has been attributed to the intervention of transition state 111 [86]. This structure incorporates a hydrogen bond between proline s carboxyl group and the azodicarboxylate as a key organizing feature. The transition state structure has parallels to that proposed for the proline-cata-lyzed aldol addition reactions and is supported by quantum mechanical studies by Houk [89]. 

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