Development and Applications of Amino Acid Derived Organometallics

Abstract

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.

Fluorescent carbazole-derived α-amino acids: structural mimics of tryptophan

“…12 Various strategies were considered and it was proposed that the Negishi coupling of halo-substituted carbazoles with an organozinc reagent derived from a β-iodoalanine derivative would allow rapid access to the amino acid targets. 13 Precedent for the use of this type of β-alanine anion reagent, developed by Jackson and co-workers, has been shown with coupling to various halogenated N-heterocycles such as pyridines and N -protected indoles. 13,14 Initially, a series of carbazoles ( 10 ) were prepared in a two-step approach by Suzuki–Miyaura coupling of 1-bromo-2-nitrobenzenes with various arylboronic acids, 15 followed by Cadogan cyclisation performed using triphenylphosphine (see ESI†).…”

“…13 Precedent for the use of this type of β-alanine anion reagent, developed by Jackson and co-workers, has been shown with coupling to various halogenated N-heterocycles such as pyridines and N -protected indoles. 13,14 Initially, a series of carbazoles ( 10 ) were prepared in a two-step approach by Suzuki–Miyaura coupling of 1-bromo-2-nitrobenzenes with various arylboronic acids, 15 followed by Cadogan cyclisation performed using triphenylphosphine (see ESI†). 16 Regioselective bromination using N -bromosuccinimide (NBS) then gave bromocarbazoles 11a–d in 75–91% yields (Scheme 1).…”

“…Organozinc reagent 9 was prepared in three steps from commercially available serine derivative 7 by activation of the primary alcohol as a mesylate, displacement with iodide and then treatment with iodine-activated zinc dust. 13,17 Using SPhos as a ligand, 18 which Jackson and co-workers propose forms a monoligated palladium species, the Negishi cross-coupling of bromocarbazoles with organozinc reagent 9 was investigated. Surprisingly, N -protection of the carbazoles was not required and with a Pd 2 (dba) 3 loading of 2.5 mol%, successful coupling was observed to give adducts 12a–e in moderate to good yields from β-iodoalanine 8 .…”

Total Synthesis of Virgatolide B via Exploitation of Intramolecular Hydrogen Bonding

“…Methyl ketone 9 contains an α-chiral β-arylated ketone side chain, a motif posing some synthetic challenges. There are few direct methods for the construction of such subunits, − which have to date been accessed by benzylation of enolates, , conjugate addition of aryl organometallics, Negishi cross-coupling, − or catalytic asymmetric hydrogenation of α,β-unsaturated carbonyl compounds. − Each of these methods suffer from nontrivial drawbacks . Our synthetic strategy sought to employ methodology developed by Molander et al for the Suzuki cross-coupling of enantiomerically enriched potassium β-trifluoroboratoamide 10 with a suitable aryl halide coupling partner 11 .…”

Synthesis of C3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

“…The Negishi cross coupling [37–38] is a reliable synthetic method, which involves palladium or nickel-catalyzed coupling of organozinc reagents [39–40] with various halo derivatives (e.g., aryl, vinyl, benzyl, or allyl) and has a broad scope to assemble diverse targets. This reaction was first reported in 1977, and it is an elegant and versatile method that allows the preparation of biaryls and olefins in good yields.…”