Enders reagent

D. Enders, M. Klatt, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 1, 178 ... 

It is worth mentioning that chiral N,N-dialkylhydrazones (SAMP, RAMP) had been introduced by Enders for asymmetric a-alkylation of carbonyl compounds [29], and addition of organometallic reagents to the C=N bond had also been demonstrated ([30] selected organometallic additions to other chiral hydrazones [31-34]). However, the SAMP and RAMP hydrazones require a multistep preparation, and lacked a carbonyl function for two-point binding, which we regarded as a key design element (see below). 

Since Kagan s first report of N-N bond reduction using Sml2,39 the reagent is now routinely used for the transformation. The reaction has been used widely in asymmetric synthesis to reduce the products of asymmetric additions to, or reductions of,47 hydrazone derivatives. For example, Enders reported the nucleophilic addition of alkyllithiums to trifluoroacetaldehyde SAMP and RAMP hydrazones in an asymmetric approach to a-trifluoromethyl-sub-stituted amines.48 After activation of the adducts by benzoylation, Sml2-mediated N-N bond cleavage proceeded in high yield (Scheme 4.41). 

Enders and coworicers have shown that deprotonation of chiral SAMP/RAMP hydrazones (or their substituted analogs) derived from ketones or aldehydes, followed by reaction with Davis oxaziridine reagent provides the a-hydroxy hydrazones in moderate yield but with high diastereoselectivity. Direct unmasking or protection followed by unmasking provides the corresponding a-hydroxy ketones or aldehydes respectively (Scheme 24). Both antipodes of the hydroxylated compounds are available by appropriate choice of (5)- or (R)-proline-deiived auxiliaries. The direction of induction is predictable, if not wholly uniform (R substitution alters the a-stereochemistry for aldehyde hydrazones). The process clearly provides a valuable approach to both systems. 

Enantiosekctive a-alkylation of cyclohexanone. A polymeric form of this chiral amine (1) has been prepared as shown in equation (I). The reaction of 1 with cyclohexanone leads to the polymer-bound chiral alkoxyimine (2). Alkylation of the anion of 2 followed by mild acid cleavage results in an (S)-2-alkylcyclohexanone (4). When methyl iodide is the alkylating reagent, the optical yield is 95% it is somewhat less when isopropyl iodide is used. These results compare favorably with those obtained by Enders and Eichenauer by alkylation of a chiral hydrazone of cyclohexanone (7, 10-11). For a related reaction, see Benzyl(methoxymethyl)methyl-amine, this volume. 

Enders, D. Reinhold, U. Asymmetric Synthesis of Amines by Nucleophilic 1,2-Addition of Organometallic Reagents to the CN-Double Bond, Tetrahedron Asymmetry 1997, 8, 1895-1946. 

High enantioselectivity and good yields have been obtained in asymmetric epoxidation of enones. Roberts modification of the Julia epoxidation using an immobilized polyleucine catalyst now represents a simple, practical method for enone epoxidation. Of the metal-based systems, the most economical and practical method is probably Enders protocol, despite the fact that it uses stoichiometric amounts of metal and hgand, as all the reagents are commercially available and cheap. It is difficult to compare the polypeptide-based catalysts with the metal based catalysts in terms of overall efficiency. 

More recently, Enders group has described the X-ray crystal structure of the chiral hydrazone anion (19). This internally chelated chiral hydrazone crystallizes as the bis(tetrahydrofuran) monomeric adduct. The lithium in this structure is 17° out of the C—C— N plane and is predominantly associated with the anionic nitrogen (and the chelating methoxy group). Interactions with the =CH2 carbon are minimal. Earlier studies by Bauer and Seebach had examined the association behavior of (19). They found that in THF this azaallyllithium reagent was monomeric. While there is no or ri -interaction with the azaallyl anion, the lithium in this structure is tetracoordinate and prochiral. Preferential coordination of lithium to an electrophile such as a carbonyl oxygen with selective replacement of one THF moiety could be involved in some of the asymmetric aldol reactions discussed below. 

Corey, Enders and Bock were among the first to describe the utility of lithium dimethylhydrazone anions for crossed aldol reactions. In the reaction shown in equation (14), an azaallyllithium reagent derived from an aldehyde dimethylhydrazone was first silylated with trimethylsilyl chloride to yield a silyl aldehyde dimethylhydrazone. Subsequent lithiation using lithium diethylamide at -20 C for 1 h generated the silylated azaallyllithium reagent (29). Subsequent addition of one equivalent of an aldehyde or ketone at -78 C and warming to -20 C then yielded the product a,p-unsaturated aldehyde dimethylhydrazone in yields of 85-95%. Hydrolysis produced the unsaturated aldehyde in 75% overall yield. 

The 1,2-addition of simple azaallyllithium reagents derived from ketone and aldehyde dimethylhydra-zones to aldehydes and ketones was also first described by Corey and Enders.Regioselective deprotonation of 2-pentanone dimethylhydrazone with Bu"Li followed by addition of an aldehyde or... 

---