ENDERS Chiral reagent

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). 

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. 

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. 

Chronologically, the successful and efficient asymmetric alkylation of enolates was preceded by the development of chiral azaenolates indeed, the meanwhile classic reagents hke Meyers oxazolines [4], Enders hydrazones RAMP and SAMP [5], and Schollkopf s bislactim ethers [6] were the first auxiharies to enable carbon-carbon bond formation with high (overall) enantioselectivity. 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

One of the most successful classes of chiral auxiliaries for asymmetric synthesis is that of Enders proline-based hydrazines, namely (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 74) and its (R)-enantiomer RAMP (Scheme 11.11) [68]. Enders has reported that chiral hydrazones such as 75 undergo diastereoselective additions with organolithium reagents. The facile removal of the auxiliary by reductive cleavage of the N-N bond enables it as a versatile tool for the synthesis of a wide range of chiral secondary amines [69, 70]. As shown in Scheme 11.11, the secondary amine 77 was thus prepared in 73 % overall yield and 93 % ee [69]. 

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