Simple and Efficient Asymmetric α‐Alkylation and α,α‐Bisalkylation of Acyclic Ketones by Using Chiral N‐Amino Cyclic Carbamate Hydrazones

Abstract

Ketone a-alkylation is fundamental to organic synthesis. Remarkably, however, only one effective asymmetric version of this transformation applicable to acyclic systems is available. [1][2][3] Introduced over 25 years ago, this method is based on the alkylation of metalated SAMP/RAMP hydrazones, and has enabled numerous total syntheses.[1] Unfortunately, its further development has been impeded as a result of certain inherent limitations. For instance, the dialkyl hydrazones used are only weakly acidic, so azaenolate formation requires exposure to lithium diisopropylamide (LDA) for 2-10 h.[1a] Alkylation must then be conducted at an extremely low temperature (À110 to À78 8C),[1a] making large-scale applications impractical. Moreover, removal of the costly auxiliary under recommended [1a] conditions (ozonolysis or quaternization/hydrolysis) limits functional group compatibility. The auxiliary itself is liberated in an altered form that hinders recycling.[4] Given these limitations, it is apparent that asymmetric a-alkylation of ketones remains an unsolved problem. Herein, we report a substantial advance in this field through the development of chiral N-amino cyclic carbamates (ACCs). These auxiliaries significantly diminish the drawbacks associated with the use of chiral dialkyl hydrazines, yet still provide excellent stereoselectivity. In addition, the auxiliaries exhibit a unique directing effect that overrides the inherent selectivity of LDA, thus enabling the asymmetric a,a-bisalkylation of ketones, a previously unattainable transformation.Hydrazones possessing an electron withdrawing group (1, Scheme 1), which we term activated hydrazones, are readily formed from the corresponding substituted hydrazines (e.g., hydrazides, sulfonyl hydrazides, etc.) and ketones under mild conditions, and are rapidly hydrolyzed under similarly mild conditions, making them excellent candidates for auxiliarybased synthetic methods. We anticipated that the enhanced acidity of these activated hydrazones would enable rapid metalation over a range of temperatures. Moreover, the substantial electron density imparted to the electron withdrawing group in the derived azaenolates (2) should lead to tight metal cation binding, in a manner analogous to, for example, chelation of hydroxamate anions. In the context of asymmetric transformations, this could potentially bring high facial selectivity during alkylation, even at temperatures well above À110 to À78 8C, as required of SAMP/RAMP systems. Collectively, these factors suggested that chiral hydrazines substituted with a conjugated electron-withdrawing group could provide the basis of a simple method for asymmetric ketone a-alkylation.We focused our initial studies along these lines on the easily accessible ACCs.[5] Thus, 3 was prepared by amination of the corresponding oxazolidinone and was then condensed with 3-pentanone to give 8 (Table 1). This activated hydrazone 8 was readily deprotonated with LDA at À78 8C and allylated in excellent yield (90 %). The auxiliary was also easily remo...

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

“…Reactivity and applications of N-acylhydrazones have been reviewed 5,6 and are outside the scope of this review, although they parallel to some extent those of N,N-dialkylhydrazones. 7 …”

“…ij][2,7]naphthyridin-7-one(275), an analogue of kuanoniamine A (marine alkaloid), 217 a regioisomer of the marine alkaloid meridine 9-hydroxybenzo[b]-pyrido[4,3,2-de](1,10)-phenanthrolin-8-one(276),218 diazaquinomycin A (277),219 dihydrofuroquinolinedione derivative 278, 220 substituted 1,8-diaza-9,10-anthraquinone 279,221 1,5-diazaanthraquinone derivatives 280,222,223 and tetracyclic compound 281 224. The Diels-Alder reaction of 282 (Scheme 53) was the key transformation in the synthesis of analogues of the marine pyridoacridines meridine and ascididemin.…”

The apratoxin marine natural products: isolation, structure determination, and asymmetric total synthesis

“…42 This strategy would require intermediate 113, which would carry the C-37 stereocenter, set using asymmetric ACC (amino cyclic carbamate) α,α-bisalkylation. [43][44][45][46] Scheme 23. Coltart's retrosynthesis of apratoxin D.…”

Asymmetric Methods for Radical Addition to Imino Compounds

“…Mixtures of E/Z isomers were usually obtained, although ketone N-acylhydrazones 14d and 15d, with highly branched tertiary butyl (tBu) substituents, were formed as single isomers. Others have recently used the amination and condensation procedures to prepare very similar chiral N-acylhydrazones from ketones with excellent results [23].…”