Aldol reactions of glycine Schiff base

LLB, LiOH, and H2O promoted the direct aldol reaction of glycinate Schiff bases 12 with aldehydes 3, providing access to p-hydroxy-a-amino acid esters 13 (Scheme 4,bottom) [7],... 

Direct Asymmetric Aldol Reaction of Glycine Schiff Base... 

Maruoka and coworkers recently developed an efficient, highly diastereo- and enantioselective direct aldol reaction of glycine Schiff base 2 with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt li as a key catalyst, as shown in Table 5.12 [41a]. 

Scheme 17.32 Aldol reaction of glycine Schiff base with acetaldehyde.

The spiro-type phase-transfer catalyst (188, Ar = H) possessing a C2-symmetry axis provides a single type of asymmetric environment in contrast, a newly designed spiro-type phase-transfer catalyst (188, Ar H) has two different asymmetric environments. The substituents of the binaphthyl subunits affect enantioselectiv-ity, and the 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl group is the best substituent of those evaluated in the anti-selective aldol reactions of glycine SchifF base 186 with aldehydes (35) (Scheme 28.21) [94]. Similarly, simpMed chiral phase-transfer catalyst 189 bearing the 3,5-bis[3,5bis(trifluoromethyl)phenyl] phenyl substituent, which is prepared in a combinatorial approach from the readily available (S)-l,l -binaphthyl-2,2 -dicarboxylic acid, effectively catalyzes syn-selective aldol reactions [95]. 

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

Quaternary Ammonium Salt-Mediated Asymmetric Direct Aldol Reaction of Glycinate Benzophenone Schiff Base with 3-Phenylpropanal Under Phase-Transfer Conditions [6] (p. 145)... 

Side chain cleavage (Group c). In a third type of reaction the side chain of the Schiff base of Fig. 14-5 undergoes aldol cleavage. Conversely, a side chain can be added by (3 condensation. The best known enzyme of this group is serine hydroxymethyltransferase, which converts serine to glycine and formaldehyde.211-21313 The latter is not released in a free form but is transferred by the same enzyme specifically to tetrahydrofolic acid (Eq. 14-30), with which it forms a cyclic adduct. 

The reaction of a glycine Schiff base (159) with aldehydes can be catalyzed by cinchona-derived salts, though the stereoselectivity is rather low [171]. Maruoka reported that this reaction proceeded well with a C2-symmetric chiral quarternary ammonium salt (160) as a phase-transfer catalyst [172]. The reaction generated tz fi -(3-hydroxy-a-aminoacids with reasonable yields and stereoselectivities (Scheme 3.28). Further modifications of the catalyst structure led to a salt which provided predominantly jy -aldols [173]. 

SCHEME 3.28. syn- And a ti-selective quartemary ammonium salts as catalysts for the aldol reaction of a glycine Schiff base 159 with aldehydes. 

The combinational use of inorganic base and chiral phase-transfer catalyst provides an efficient process for the synthesis of -hydroxyl-a-amino acids via the aldol reaction (260-262). A representative and successful example was reported by Maruoka and co-workers (319) that a highly efficient direct asymmetric aldol reaction of a glycinate Schiff base with aliphatic aldehydes has been achieved under mild organic/aqueous biphasic conditions with excellent stereochemical control activity (Scheme 67) (96 99% ee). 

The influence of the coordination of lithium and sodium enolates on the stereochemical outcome of their aldol reactions has been reviewed. The alkylation of the ambident enolates of a methyl glycinate Schiff base with ethyl chloride have been studied at B3LYP and MP2 levels. The transition states for the alkylation of the free ( )/(Z)-enolate with ethyl chloride have energy barriers of 13kcalmol However, with a lithium ion, the ( )-enolate behaves as an ambident enolate and makes a cyclic lithium complex in bidentate pattern, which is more stable by 11-23 kcal mor than the (Z)-enolate-lithium complexes. The results suggest that the alkylation of ambident enolates proceeds with stable cyclic bidentate complexes in the presence of metal ion and solvent. 

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