α-Vinylic Amino Acids: Occurrence, Asymmetric Synthesis and Biochemical Mechanisms

Abstract

This report presents an overview of the family of naturally occurring 'vinylic' amino acids, namely those that feature a C-C double bond directly attached to the α-carbon, along the side chain. Strategies that have been brought to bear on the stereocontrolled synthesis of these olefinic amino acids are surveyed. The mechanistic diversity by which such 'vinylic triggers' can be actuated in a PLP (pyridoxal phosphate) enzyme active site is then highlighted by discussions of vinylglycine (VG), its substituted congeners, particularly AVG [4E-(2'-aminoethoxy)vinylglycine], and a naturally occurring VG-progenitor, SMM (S-methylmethionine).

Figure 1

PLP enzymes that α-deprotonate and α-vinylic AA structure.

Figure 2

Naturally occurring vinylglycine antipodes

Figure 3

β-substituted vinylglycines from natural sources.

Figure 4

γ-Substituted vinylic AA’s.

Figure 5

β,γ-Substituted vinylic AA’s.

Figure 6

Cofactor-AVG adducts bound in three PLP enzyme active sites (PDB codes: 1M7Y, 1C7O and 1CL2, respectively.

Figure 7

Evidence of Mechanism B for L-vinylglycine with ACC synthase (PDB 1YNU ) and for vigabatrin with GABA transaminase (PDB 1YHW ).

Scheme 1

Rapoport’s sulfoxide pyrolysis entry.

Scheme 2

Griesbeck’s photofragmentation route from L-methionine.

Scheme 3

Our use of phenylselenolate lactone-opening chemistry.

Scheme 4

Arylselenium introduction via the Grieco protocol.

Scheme 5

Hanessian’s oxidative decarboxylation of L-glutamate.

Scheme 6

Decarboxylative introduction of selenium via a Barton ester.

Scheme 7

Galvez’s Felkin Anh-vinylation route from D-glyceraldehyde.

Scheme 8

Lajoie’s Peterson olefination route from L-serine.

Scheme 9

Neber rearrangement/papain-based kinetic resolution.

Scheme 10

Schöllkopf’s formal vinylation of his chiral glycine enolate.

Scheme 11

Duhamel’s chiral acid dienolate protonation approach.

Scheme 12

Trost’s DYKAT asymmetric allylic amination route.

Scheme 13

Our Ni(0) -mediated asymmetric allylic amination route.

Scheme 14

Introducing the enol ether into E- and Z-MVG

Scheme 15

Enzymatic resolution of E- and Z-MVG

Scheme 16

Keith’s route to rhizobitoxine

Scheme 17

Kirihata’s approach to E-APPA

Scheme 18

Mechanism A: Vinylogous imidate formation from γ-alkoxy-α-vinyl AA’s via PLP enzyme-catalyzed azallylic isomerization.

Scheme 19

Mechanism B: Inactivation of ACC synthase by L-vinylglycine via enzyme-catalyzed azaallyllic isomerization-Michael addition.

Scheme 20

Fate of SAM and analogues in the ACC synthase active site.