A catalytic asymmetric version of the exo-selective [C+NC+CC] reaction is reported. This multicomponent reaction utilizes a readily prepared achiral glycyl sultam as the "NC" component and commercially available catalyst components. The method can be applied to a variety of aldehydes ("C" component) and activated alkenes ("CC" component) to provide substituted pyrrolidines in good yields and high enantioselectivities. Of particular note is the ability to employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.
a b s t r a c tA general synthesis of N-terminal aziridinyl-2-carbonyl (Azy) peptides has been developed aided by the photolabile o-nitrophenylethyl protecting group. This method enables the synthesis of unprotected Azy-terminated peptides incorporating ionizable groups using solid phase techniques followed by photorelease of the free N-terminal Azy moiety. The resulting Azy peptides undergo Cu(II)-mediated ligation with thioacids to give Azy-embedded peptides, providing a handle for site-specific modification of the peptide.Ó 2015 Published by Elsevier Ltd.The Cu(II)-promoted ligation of unprotected peptide thioacids 1 and aziridine-2-carbonyl (Azy) peptides 2 generates electrophilic N-acylated aziridines 3 that may be subjected to nucleophilic attack to give peptides corresponding to 4 (Scheme 1). 1 This aziridine-mediated ligation can be performed under denaturing aqueous conditions and has the potential, via the use of different nucleophiles, 2 to enable the site-specific modification of peptides and proteins. While access to C-terminal peptide 3 (and protein) 4 thioacids 1 is fairly well established, a general and reliable synthesis of Azy peptides 2 is not available. Relatively few examples of compounds that correspond to 2 have been reported in the literature. 5 The observations of Moroder and co-workers (Reference 5a) were particularly relevant in this regard wherein the propensity for unprotected Azy peptides 2 to decompose upon lyophilization or storage was duly noted. 6 This stability problem may be traced to the susceptibility of the aziridine moiety in 2 to undergo ringopening, a property that can be exacerbated by the presence of acidic functional groups in the peptide. The inability to prepare Azy peptides corresponding to 2 without imposing significant functional group restrictions would, of course, limit the utility of our aziridine-mediated ligation. We now report a general strategy for the synthesis of unprotected Azy peptides 2 and their in situ Cu(II)-promoted coupling to peptide thioacids 1.Since HPLC purification of 2 was out of the question due to its instability, we focused on a solid phase synthesis strategy (Scheme 2) that would allow for purification of the SPPS cleavage product 5 prior to ligation. This led us to search for an orthogonal protecting group (PG) that would not activate the aziridine ring thus enabling purification of 5 and that could be removed in situ to give a ligation-competent solution of 2. The known instability of both N-H and N-acyl aziridines complicated implementation http://dx.
The observations that 1,l-diphenylethylene and a series of related alkenes act as promoters for the formation of benzyne from benzenediazonium acetate even in the presence of furan, which otherwise promotes the competing radical reaction, leads also to an explanation of the hitherto puzzling promoting effect of tetraphenylc yclopen tadienone.
Experiments using l5N-labelled N-nitrosoacetanilide and related compounds have shown that the complex reaction leading to benzyne and/or phenyl radicals does not involve the reversible extrusion of nitrogen. The contrasting observation that nitrogen exchange did occur in the formation of benzenediazonium ions by the in situ nitrosation of 15N-labelled acetanilide is attributed to the generation of unlabelled benzenediazonium ions by the reaction of phenyl radicals with the nitrosating agent. The reactions of nitrosating reagents such as p-chlorobenzoyl nitrite with 1 -phenylazo-2-naphthoI and related hydroxyazo-compounds to give benzenediazonium ions have been investigated, and it is suggested that nitrosation of the hydrazone form of the hydroxyazo-compound followed by rearrangement and cleavage provides the primary source of the diazonium ions but that these are again regenerated in the system from phenyl radicals and the nitrosating reagent. In accord with this, azobenzene and 4-phenylazo-1 -methoxynaphthalene, which cannot exist as hydrazones do not so react, in contrast to phenylazotetrachlorocyclopentadiene, which does exist in the hydrazone form. Reactions of p-chlorobenzoyl nitrite or pentyl nitrite with 1 -phenylazo-2-naphthol in benzene at 50" lead to biphenyl, via phenyl radicals, in 30 and 41 % yield (82% based on azo-compound consumed).
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