Enders alkylation hydrazones, cleavage

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

Electrophilic substitution. A number of chiral nucleophilic species have been described that result in optically active a-alkyl aldehydes, ketones, acids, and acid derivatives upon alkylation and (usually) subsequent hydrolytic cleavage. Enders provides a number of examples (Figure 3) one of which results in the ant alarm pheromone, 4-methyl 3-heptanone (26 2 7). Studies by A. I. Meyers of the chemistry of anions of chiral oxazolines (Figure 4) were the first of the genre, however ( 8 ). Related reactions of chiral anions of metalloenamines and hydrazones (29, 30, 31) have in common with the alkylation of oxazolines metallated azaenolate intermediates that predispose one face of an azaenolate double bond to reaction with the electrophile. 

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 and Jegelka [88] have used l,3-dioxan-5-one 122, a protected dihydroxyacetone derivative, to construct enantiomerically pure C5- to C9-deoxycarbohydrates. For example, reaction of 122 with SAMP gives the hydrazone 123, which is deprotonated and alkylated with methyl iodide to yield 124. The monoalkylated hydrazone is then alkylated in the same manner with chloromethyl benzyl ether to form 125. Cleavage of the hydrazone with ozone furnishes the protected ulose 126 (>98% de, >98% ee), which is deprotected to (—)-5-deoxy-L-r/ir o-3-pentulose 127. Reduction of 126 with L-Selectride, followed by deprotection, provides 5-deoxy-D-arabinitol 128 (>95% de, >95% ee) (Scheme 13.46). 

The total synthesis of (-)-denticulatin A, a polypropionate metabolite, was accomplished in the laboratory of F.E. Ziegler. To establish the absolute stereochemistry at C12, they utilized the Enders SAMP/RAMP hydrazone alkylation. To this end, the RAMP hydrazone of 3-pentanone was successfully alkylated with 1-bromo-2-methyl-2( )-pentene. Hydrolysis of the hydrazone under standard acidic conditions led to loss of the enantiomeric purity. This problem was avoided by using cupric acetate for the cleavage. 

Concerning the hydrolytic cleavage conditions, one method was reported by Enders in his seminal study in 1976 [8]. The latter consists in the alkylation of the nitrogen with an excess of iodomethane to form the corresponding ammonium salt, which is hydrolyzed in a biphasic HCl 1 M/n-pentane system. In 1998, Enders described very mild conditions using a saturated aqueous solution of oxalic acid in ether, which allowed to hydrolyze the hydrazones without racemization [12]. This protocol has also the advantage of recycling the chiral SAMP hydrazine. 

In 1999, Enders used this method in an iterative fashion to synthesize fl ti-l,3-polyols (Scheme 2.33). The sequence required two diastereoselective alkylations at the a- and a -positions of the hydrazone before cleavage of the chiral auxiliary using an aqueous solution of oxalic acid in ether. The reduction of the resulting ketone followed by a Barton-McCombie deoxygenation furnished the corresponding acetal 17, which was converted to the iodide intermediate 18 upon three additional steps. The latter was then used as an... 

The synthesis of the spiroketal core represented the major challenge of this work (Scheme 2.59). It started with an Enders diastereoselective alkylation using the SAMP hydra-zone 48 to afford the alkylated product 86 in good yield and high diastereoselectivity. An oxidative cleavage under ozon-olysis conditions of the hydrazone provided the corresponding aldehyde, which was subsequently engaged in a Brown... 

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