Reformatsky reaction chiral amino alcohols

The earliest enantioselective Reformatsky reaction was reported in 1973.52 Compound (-)-spartein was used as the chiral ligand, but the reaction gave rather low yield. Almost 20 years later, in 1991, Soai and Kawase53 reported an enantioselective Reformatsky reaction in which chiral amino alcohol 58 or 59 was used as the ligand. Aliphatic and aromatic //-hydroxy esters were obtained with moderate to good yields. 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

The indium-induced Reformatsky reaction with stoichiometric amounts of chiral amino alcohols such as cinnco-nine and cinchonidine gives optically active /3-hydroxy esters with 40%-70% ee (Table 19). In contrast to the smooth reaction with uncomplexed indium-based Reformatsky reagents, ketones do not react with the complexed indium Reformatsky reagents. Other chiral ligands, including (—)-spartein, (—)-norephedrine, (+)-(l-methylpyrrolidin-2-yl)diphenylmethanol, (+)-Dibutyl tartrate and (+)-l,l -bi-2-naphthol, are not effective for this reaction.324... 

In more recent work, germanium catalysts such as GeClq gave a highly diastereoselective Reformatsky reaction favoring the syn diastereomer.228 Another syn selective reaction was reported using TiCl2 and Cu.229 Enantioselective Reformatsky reactions have also used chiral amino alcohols as additives.220... 

Only a few enantioselective approaches to optically active 2,2-difluoro-3-hjrdroxy esters, key S)mthetic interme ates for a variety of important chiral fluorinated molecules, have been reported. Braun et al and Andrds et al. have independently reported that the Reformatsky reagents generated from bromodifluoroacetates react with aromatic aldehydes in the presence of stoichiometric amounts of chiral amino alcohols such as iV-methylephediine to afford the corresponding desired aldols in good optical yields (22,23). However, these methods are not catalytic, and the decrease in quantity of the chiral ligands dramatically suppresses the enantioselectivity. Thus, we became very interested in developing an unprecedented catalytic asymmetric aidol reaction of difluoroketene silyl acetals promoted by chiral Lewis acids. 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

As the dosage of air is hardly controlled in these protocols and oxygen causes undesired side reactions, Cozzi and coworkers elaborated a procedure that used t-butyl hydroperoxide as an oxidative additive. In addition, the readily available amino alcohol 323 was used as the chiral ligand. Again, the presence of triphenylphosphine oxide was required as shown in the Reformatsky reaction with aldehydes (Scheme 5.88) [166]. The long reaction times over more than 100 h required at -25 °C indicates a rather sluggish conversion. It may be abbreviated by running the reaction at 25 °C, however, at the expense of reduced enantiomeric excess of P-hydroxy esters 316. Enantioselectivity varied considerably, was fair for most aromatic aldehydes, but was low for aliphatic aldehydes, except for pivalalde-hyde that provided 93% ee. The procedure was also applied to prochiral ketones. 

Later, different amino alcohols were used for the same type of difluoro Refor-matsky reactions [158], and the extension to prochiral ketones was reported recently [171]. In addition, protocols for monofluoro Reformatsky reactions were disclosed that lead to products with moderate diastereoselectivity but remarkable enantioselectivity for the individual diastereomers [172]. All these protocols have in common that they are not catalytic and the chiral additive needs to be applied at least in stoichiometric amounts. Thus, it seems that protocols for an enantioselective catalytic difluoro Reformatsky as well as difluoro aldol reaction are still missing. 

Fujiwara, Y, Katagiri, T., and Uneyama, K. (2003). Trifluoromefhylated amino alcohols as chiral ligands for highly enantioselective Reformatsky reaction. Tetrahedron Lett., 44,6161-6163. 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

---