Benzhydryl group

This is by far the most versatile route to the synthesis of ester-substituted aziridines, especially as the benzhydryl group can easily be cleaved by hydrogenolysis. Wulff has applied this methodology to a short asymmetric synthesis of the antibiotic (-)-chloramphenicol in four steps from p-nitrobenzaldehyde (Scheme 1.34) [61]. In this case it was found that treatment of the aziridine 111 with excess dichloroacetic acid gave the hydroxy acetamide directly, so no separate deprotection step was required. 

The benzhydryl group from azasugars was removed in MeOH using Pd(OH2)/C (0.03 mol Pd/mol compound) at 60 psi hydrogen overnight (Scheme 4.85).334... 

The catalyst 6 can be recovered for re-use in 80-90% yield by extraction with oxalic acid. The a-amino nitrile products were easily transformed into the corresponding a-amino acids by removing the benzhydryl group by hydrolysis in HC1. 

The key cis stereochemical relationship is created by an alkylation reaction that sets a tram stereochemical relationship, which is then reversed in the subsequent ringopening and closing sequence. Although this route replaced both the quinuclidine and the benzhydryl group of CP-96,345 (2), it produced a very potent NKi receptor antagonist, CP-99,994 (17). This simplified structure then served as a starting point for many variants, including clinical candidates CP-122,721 (18)5 (Pfizer) and GR-205,171 (19)6 (GSK). 

The influence of the substitution pattern in the benzhydryl group follows very general patterns. In very broad terms, it may be said that ... 

The linker is also of importance, as becomes clear from the next examples. It seems that an oxygen or nitrogen attached to the benzhydryl group leads to better results than either an alkyl or alkylene function. The replacement of an oxygen by a sulfur reduces antihistamine activity drastically (though the influence of this latter change has a positive influence on the antimuscarinic efficacy of these derivatives) (Fig. 18.7). 

Table 99 lists kinetic data for the decomposition of various r-butyl peresters of unsaturated cyclic acids. Differences in delocalization energies between the perester and corresponding radical (R-) and ion (R-I-) are also given as ADE and ADHio . For further comparison the t-butyl peresters, where R is benzyl and benz-hydryl, are included. By the simple hmo calculation, that was employed for the benzyl and benzhydryl groups, there is no difference in the ADE values between the ions and radicals. However, a difference of one ]8-unit is calculated between the radical and ion of the cyclopropenyl group. The AH values for decomposition of peresters with R = benzhydryl and 2,3-di- -propylcyclopropenyl are approximately the same. Yet, the ADE value increases in energy from 1.55 / to 1.00 p. 

Poll and Sames [112] have converted L-serine into A -methylfucosamine (Scheme 13.63). The method relies on the diastereoselective addition of propenyllithium to the aldehyde derived from protected L-serine derivative 183, giving allylic alcohol 184. Catalytic osmylation of 184 gives a 6 1 mixture of anti,syn 185 and syn,syn-2iminotnols. Protection of the triol 185 as its triacetate, reductive methylation and desilylation provides 186. Successive Swern oxidation, methanolysis and benzhydryl group hydrogenation leads to A -methylfucosamine 187. 

In one case, the benzhydryl group was used to protect the hydrazino... 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

In recent years the reactions of basic reagents with quaternary ammonium salts containing the benzyl and benzhydryl groupings have received extensive study. It is useful to examine these reactions for the existence of ylids and to note the variety of ways in which they react. 

The high yield of 30 is ascribed to the displacement of the benzhydryl group by the lithio derivative of 29. The tetraphenylethane, 32, is reported to result from a displacement on 28 by benzhydryllithium which may have resulted from the decomposition of the methyl ylid to an immonium ion-pair. 

In the aforementioned syntheses of the nocardicins and their analogs the benzhydryl group (145 R = CHPh2) was removed by hydrogenolysis, and so was thep-nitro benzyl group (145 R = Pbn).l2lb... 

The ready formation of TV-substituted amino-phosphonic and -phosphinic acids through this route, and the facility with which A -substituents, particularly those of the aralkyl group, may be removed, makes the methodology particularly attractive. As already noted, the TV-(phenylmethyl) (benzyl) substituent is conveniently removed by hydrogenol-ysis over as is the A-diphenylmethyl (benzhydryl) group which, additionally, is... 

Asymmetric nitro-Michael reactions of methyl vinyl ketone (MVK) in the presence of bicyclic guanidine with a benzhydryl group led, disappointedly, to low asymmetric induction (9-12%) [21a] Trials for the reaction of 0 ,p-unsaturated y- or 8-lactones with pyrrolidine in the presence of the conjugate acids of a bicyclic guanidine [50] or the Murphy s guanidine [24a] (R = Me in Scheme 4.7) resulted in the production of racemic compounds. The latter phase transfer catalyst (PTC) catalyses the nitro-Michael addition of chalcone but with limited range (70% yield, 23% ee) [24c]. 

Borrowing from Ito s original work, smooth removal of the benzhydryl group was achieved in moderate yield (40-60%) after ozonolysis followed hy workup with 10 equiv of sodium horo-hydride in MeOH at low temperature (eq 43). Since there is no aziridine bond breaking in the reaction sequence, the deprotected aziridines are recovered without loss of enantiopurity. 

Ring opening of cyclic compounds containing an N—bond is readily accomplished to give amino alcohols. For isoxazolidines 49 and 51 the 0-benzyl, A-benzyl, and N-benzhydryl groups were also cleaved under the reaction conditions (Scheme... 

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