Electrophilic and Nucleophilic Reactivities of the Azomethine Carbon of SAMP-Hydrazones:  Stereoselective Synthesis of γ-Amino Ketone Derivatives

Abstract

A novel methodology for the asymmetric synthesis of secondary N-Boc-protected γ-amino ketones is described. After the highly diastereoselective nucleophilic 1,4-addition of formaldehyde SAMPhydrazone 1 to prochiral conjugated enones 2, the carbonyl group of the resulting 4-oxo aldehyde SAMP-hydrazones 4 was protected as ethylene ketals 5. The stereoselective (de 58-88%) addition of organometallic reagents to the CN double bond of the latter was then performed, and the unstable intermediate hydrazines obtained were either trapped as Moc-protected hydrazines 8 in good yields (65-87%) or reduced by Raney nickel-catalyzed hydrogenolysis of the N-N bond to afford the corresponding amines, which were isolated as their corresponding N-Boc derivatives 11. Noteworthy, the azomethine carbon of SAMP-hydrazones, not being essentially modified during the process, sequentially serves as a nucleophilic and an electrophilic center, acting as a nexus between the conjugated enone (electrophile) and the organometallic reagent (nucleophile) and helping in the creation of two adjacent stereogenic centers.

ChemInform Abstract: Formaldehyde N,N‐Dialkylhydrazones as C‐1 Building‐Blocks in Asymmetric Synthesis

“…It is also worth to mention that many of the products obtained along the routes described along this account retain the hydrazone moiety and, therefore, their usefulness depends not only on the palette of functional group transformations available, but also on the many possibilities available for further C-C bond forming processes. Thus, in addition to well established tools as the SAMP/RAMP methodology, 49 and the addition of organometallics, 32 the increasing number of applications recently reported for N,N-dialkylhydrazones 50 could be applied to expand the synthetic potential of these adducts.…”

“…Considering the whole process, an aminomethine fragment would then be inserted between the enone skeleton and the organic rest from the organometallic reagent. 32 In other words, SAMP-hydrazone 6 could be viewed as an ambiphilic chiral aminomethine synthon, being able to suffer sequential electrophilic and nucleophilic attacks.…”

Stable synthetic equivalents of N-unsubstituted imines: Part 1. Synthesis

“…The N-O bond in the resultant hydroxylamines can be cleaved by reduc tion with molecular hydrogen over Pd/C [177,178] or Raney nickel [179], zinc in aqueous acetic acid [180], Мо(СО) 6 [181][182][183], and various one electron reducing agents: sodium or aluminum amalgam [184], TiCl 3 [185], and SmI 2 [186]. The cleavage of the N-N bond also occurs upon hydrogenation on palladium catalysts [187,188], PtO 2 [189,190], and Raney nickel [191][192][193][194] (sometimes with preliminary acylation [195] or ultrasound assistance [196]), as well as on reduction with SmI 2 [197], refluxing with ВН 3 · THF complex [198,199], and by means of other reducing systems [200].…”

New Developments in Enantioselective Brønsted Acid Catalysis: Chiral Ion Pair Catalysis and Beyond

“…Hydrazones have proven to be important synthetic intermediates that can be readily derivatized to many useful chiral blocks, including amino-aldehydes, amino-nitriles, or diamines without any racemization (Scheme 6; Pareja et al 1999;Enders et al 1999;Enders and Schubert 1984;Diez et al 1998Diez et al , 1999review: Job et al 2002). Given the value of these products we decided to develop an enantioselective Brønsted acid catalyzed synthesis of amino hydrazones.…”