Stereochemical Control of the Passerini Reaction

Abstract

A catalytic asymmetric Passerini reaction using tridentate indan (pybox) Cu(II) Lewis acid complex 4 with substrates capable of bidentate coordination has been achieved. The reaction occurs via ligand-accelerated catalysis.Strategies, reagents, and catalysts that enable systematic stereochemical and skeletal variation are central to effective diversity-oriented syntheses (DOS). [1][2][3][4] The Passerini threecomponent coupling reaction (P-3CCR) (coupling of a carbonyl compound and an isocyanide with a carboxylic acid to form an α-acyloxycarboxamide) increases structural complexity; however, methods to control the stereochemical outcome of the carbon-carbon bond when simple achiral substrates are used are currently limited. Although several diastereoselective examples have been described that use chiral auxiliaries or chiral substrates to direct the α-addition of isocyanides, 5 analogous enantioselective examples using chiral catalysts, which involve only one step, are less common. 6,7 Herein, we report the development of a catalytic asymmetric P-3CCR giving rise to α-acyloxycarboxamides enantioselectively.Passerini reactions performed in organic solvents are often sluggish and afford products in low yields unless either highly acidic carboxylic acids or unusually electrophilic carbonyl compounds are used. In contrast, electrophilic iminium ions, formed in situ from the corresponding four-component Ugi reactions undergo a more facile α-isocyanide addition. Since these findings underscore the importance of carbonyl activation we initially sought to use chiral Lewis acid chelation control with Cu(II)-derived Lewis acids to control the © 2004 American Chemical Society Correspondence to: Stuart L. Schreiber, stuart_schreiber@harvard.edu. Supporting Information Available: General experimental procedures, characterization data, and an X-ray crystallographic file (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. Our approach uses a Cu(II) complex and bidentate coordination with carbonyl substrates as a means to invoke stereocontrol of the newly formed C-C bond. Initial studies used bidentate (S,S)-bis(oxazolinyl) (box) (1 and 2)-Cu(II) and tridentate bis(oxazolinyl)pyridine (pybox) (3 and 4)-Cu(II) complexes. 8,10 The reactions were performed in the presence of benzoic acid (5), (benzyloxy)acetaldehyde (6), and p-methoxyphenyl isocyanide (7) ( Table 1). The ligand screen revealed that bispybox 4, derived from (1S,2R)-aminoindanol, was able to control the α-addition of the isocyanide with superior enantioselectivity and yield (entry 7, Table 1). NIH Public AccessThe Cu(II) complex was stirred in methylene chloride until a homogeneous solution was obtained. When the SbF 6 − complexes 1b, 2b, and 3b were used, a homogeneous solution was difficult to achieve, even after filtration through a GHP Acrodisc 13 0.20 μm filter.(Benzyloxy)acetaldehyde (6) was then added to the solution, which was cooled to 0 °C. AW-300 MS (molecular sieves) were added to this solution followed by c...

Theoretical investigation on enantioselective Biginelli reaction catalyzed by natural tartaric acid

“…Introduction M ulticomponent reaction (MCR) [1] which combines more than two components in a vessel to generate complex molecule is of particular importance in organic and medicinal chemistry [2,3] because of its high synthetic efficiency and molecular diversity. One-pot cyclocondensation of aldehyde, b-ketoester, and urea, known as Biginelli reaction (Scheme 1) [4], is a very useful MCR to access multifunctionalized 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs).…”

Catalytic Enantioselective Passerini Three‐Component Reaction

“…[8] Schreiber and coworkers demonstrated that an indan-pybox-Cu II complex (pybox = pyridinebis(oxazoline)) could catalyze the P-3CR. [9] Nevertheless, the enantiomerically enriched Passerini adduct was obtained only when a chelating aldehyde was used.…”

A Marriage of Convenience: Combining the Power of Isocyanide‐Based Multicomponent Reactions with the Versatility of (Hetero)norbornene Chemistry

“…The number of possible applications of this strategy has yet to be exhausted, as demonstrated by recent papers published on this subject. [14][15][16][17][18] However, because of the poor reactivities of pyrrole derivatives in Diels-Alder reactions, this approach is so far essentially limited to the synthesis of oxanorbornene compounds, although one exception is represented by Paulvannan's report [19] in which the highly reactive N-nosylated pyrrole-2-carbaldehyde 8 is employed with formation of the desired cycloadduct 9 in two steps in a completely diastereoselective manner (Scheme 4). The relative configuration of the Ugi-derived stereocentre, also determined in this case by X-ray crystallography, again parallels the results obtained for 3.…”