1,3-Stereoinduction in Radical Additions to Glyoxylate Imines

Abstract

Addition of alkyl radicals to the acyclic glyoxylate imine 1 proceeded with a 70 : 30 stereoinduction, even at -78 °C. Addition to the cyclic imine 4b resulted in complete stereocontrol at -40 °C.If one excepts spin-trapping techniques using nitrones, 1 the field of radical addition to C=N bonds 2 has expanded slowly compared to that of radical addition to C=C bonds. Among the various classes of nitrogen containing radical acceptors, imines have received much less attention than for instance oxime-ethers or hydrazones. To our knowledge, studies conducted with imines have been mainly devoted to intramolecular reactions involving either aryl radicals, 3 or alkyl radicals. 4 Few articles refer to the use of glyoxylate derivatives as substrates. 5 High yielding and highly selective radical additions to glyoxylic oxime ethers have recently been reported. 5b,c We report in this article our preliminary studies on intermolecular addition of alkyl radicals to glyoxylate imines bearing a chiral auxiliary on nitrogen. Glyoxylate imines provide routes to non proteinogenic α-aminoacids through ene reactions 6 and cycloaddition reactions, 7 or through the addition of various nucleophilic species. 8,9 It is noteworthy that the addition of organometallic species suffers a major drawback which is the absence of regioselectivity. Most of the synthetically useful reactions are restricted to the use of allylating reagents (allyl zinc, allyl boronates, or allyl stannanes). 9 While this work was in progress, the enantioselective addition of silyl enol ethers catalysed by Pd complexes has been reported. 9k We investigated first the addition of primary, secondary, and tertiary alkyl radicals, generated from alkyl iodides and Bu 3 SnH/AIBN to imine 1 derived from methyl glyoxylate and 1-phenylethyl amine. The results are given in Scheme 1. Scheme 1The adducts were isolated in satisfactory yield for primary and secondary radicals. The overall yield decreased while the steric bulk of the radical increased. The diastereomeric ratio exhibited the opposite trend, however, the diastereomeric excess was only slightly enhanced on going from the primary to the tertiary radical. 10 As shown in Figure 1, these results might be rationalized according either to the model of 1,3-(2-aza)-allylic strain (A), 11 or to the model developed by Yamamoto et. al 9d for allylmetalation (B). The lowest energy conformation of 1 is (A). This is supported by molecular mechanics calculation (GenMol) 12 and by 1 H NMR data. 7c If the radical attacks conformer (A), little differentiation between the two diastereotopic faces is to be expected. On the contrary, one would predict higher diastereomeric excess from the radical attacking conformer (B).Attempts to influence stereocontrol by changing the conformation of the substrate through chelation with a Lewis acid were unsuccessful in the presence of MgBr 2 ; the competitive hydrostannylation of C=N bond was the only observed pathway.Within one exception, 7a all the studies mentioned in the introduction were conducte...

Tin-Free Radical Reactions Mediated by Organoboron Compounds

“…By using a triethylborane as a chain transfer reagent, the reaction could be extended to alkyl iodides as radical precursors. Bertrand [94,114] and Naito [95,97] reported both the use of triethylborane for the tin-free addition of alkyl iodides to imines. A typical example for a tentative of asymmetric addition to a glyoxylate imine is depicted in Scheme 50 (Eq.…”

Radical Chain Reactions: Organoborane Initiators

“…Bertrand et al reported diastereoselective radical addition to glyoxylate imines 33 [26]. Compared with the "Bu3SnH/AlBN system, stereoselectivity of the products is higher when EtjB and no "BulSnH were employed at -40°C (Scheme 19).…”

Diethylzinc Mediated Radical Additions to Glyoxylate Imines

“…3 We have reported recently that triethylborane could promote the radical reaction between alkyl iodides and glyoxylic imines in a procedure which avoids completely the use of any tin derivative. 4 Concomitantly the group of Naito has investigated Et 3 B mediated intermolecular additions onto oxime ethers. 3g-j It must be underlined that contrary to our observations on imines, these reactions could not be performed in the absence of tributyltin hydride except for the addition of ethyl radical.…”