Beta-amino alkylzinc iodides are intrinsically unstable toward beta-elimination and protonation. The aim of this study was to determine the rates of these processes and also to understand how the reactivity of a range of beta-amino alkylzinc iodides in Negishi cross-coupling reactions is influenced by the presence of functional groups within the zinc reagent. Decomposition of beta-benzamido alkylzinc iodides occurs by protonation, and the first-order rate constant for the self-protonation of the carbon-zinc bond in reagent 4b was determined to be 5.2 x 10(-6) s(-1) (at 291 K). In contrast, the carbamate derivative 2 decomposes by a first-order elimination process. The homologous reagent 3, derived from glutamic acid, decomposes more quickly by beta-elimination, with a first-order rate constant of 24 x 10(-6) s(-1) (at 291 K). Reagents 23 and 25, in which the Boc group has been replaced with a trifluoroacetyl group, are more stable toward beta-elimination than the corresponding reagents 2 and 3, a striking outcome given that the trifluoroacetamido group is a better leaving group. Moreover, this replacement also changes the mechanism of the elimination to a second order process. Pseudo-second-order rate constants for the Negishi cross-coupling of reagents 2, 3, 23, and 25 with iodobenzene have been determined, revealing the higher reactivity of the glutamic acid-derived reagents 3 and 25. The main factor influencing reactivity, therefore, is determined to be the proximity of the ester group, rather than the nature of the nitrogen protecting group. Finally, beta-amino alkylzinc iodides 46-48 containing Weinreb amides have been prepared, rate constants for their decomposition through elimination determined, and their synthetic potential for the preparation of beta-amino ketones established.

Replacing the N-Boc-protecting group on a beta-amino organo-zinc reagent with a trifluoroacetyl group, which would be expected to make the nitrogen a better leaving group, results in a reagent that is more stable towards elimination.

Palladium-catalysed reaction of unprotected 2-, 3-, and 4-iodophenols with a range of amino acid derived organozinc reagents (not used in excess) gives the expected products in good to excellent yield, demonstrating that carbon-zinc bonds are not protonated by acidic phenols under the conditions of palladium-catalysed coupling reactions.

This Account describes the discovery and development of a family of organometallic reagents derived from naturally occurring a-amino acids that have found widespread use in the stereocontrolled synthesis of non-natural analogues of proteinogenic amino acids. The general approach that we have taken involves the conversion of the side chain of enantiomerically pure naturally occurring amino acids, such as serine, aspartic acid and glutamic acid, into the corresponding primary alkyl iodide, followed by conversion into the corresponding organozinc reagents. Subsequent palladium-or copper-catalysed reactions of these reagents allow the synthesis of a wide variety of functionalised a-, b-and g-amino acid derivatives, without loss of stereochemical integrity. Insights gained from spectroscopic and kinetic studies into the stability of functionalised organozinc reagents are included.

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