Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes

Abstract

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-a-aminob-hydroxy and a,b-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.Scheme 1. Direct and enantioselective carbon-carbon bond-forming reactions from carbonylic compounds.

Direct and Asymmetric Aldol Reactions of N‐Azidoacetyl‐1,3‐thiazolidine‐2‐thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of β‐Hydroxy‐α‐Amino Acids

“…We just hypothesize that it might be the result of the combination of several geometric and electronic contributions. Although no significant changes in molecular geometries are appreciated, it is important to note that the C•••C distances for the propanoyl-derivative are similar to a previous studied system, [16] but such distances are shortened in the N-azidoacetyl enolate by about 0.10 Å in all transition states, which indicates that it is a late transition state.…”

“…[19,20] Particularly, it was found that the N-azidoacetyl-1,3thiazolidine-2-thione (1 in Table 1) reacts with 1.1 equivalents of 4-methoxybenzaldehyde (a) in the presence of 2 mol% of [(S)-Tol-BINAP]NiCl 2 , TIPSOTf (1.5 equivalents), and lutidine (1.5 equivalents) to give anti aldol adduct 1 a in a 95 % yield with outstanding stereocontrol (dr > 95 : 5, ee 99 %). [16] Despite such an excellent result, we decided to examine in detail the influence of the endocyclic heteroatom as well as the size of the heterocycle. Thus, we tested parallel reactions with Nazidoacetyl-1,3-oxazolidine-2-thione (2 in Table 1) containing a five-membered oxygenated scaffold and the related six-membered counterparts (3-4 in Table 1).…”

“…[9][10][11][12][13] As part of our ongoing project towards the development of increasingly more efficient synthetic methods under the premises dictated by the atom economy [14] and catalytic principles, [15] we have recently reported a new direct and highly enantioselective aldol reaction catalyzed by structurally simple chiral nickel(II) complexes derived from commercially available Tol-BINAP (BINAP = 2,2'-bis(diphenylphosphino)-1,1'binaphthyl). [16] More specifically, we found that N-azidoacetyl-1,3-thiazolidine-2-thione is an outstanding platform from which carry out a highly stereocontrolled aldol addition to 4-methoxybenzaldehyde to produce the enantiomerically pure anti Oprotected derivative in a high yield. [17] Importantly, the resultant aldol adduct contains an easily removable thiazolidinethione scaffold, which enables the smooth formation of an amide bond, and also an azido group, which can be considered a masked amino group and thus permits the extension of the peptide sequence employing standard procedures (Scheme 1).…”

“…However, and despite the undeniable success of such approaches, most require stoichiometric amounts of the corresponding enolates and only a select number of methods hinge on direct, catalytic, and asymmetric transformations (Scheme 1). [9–13] As part of our ongoing project towards the development of increasingly more efficient synthetic methods under the premises dictated by the atom economy [14] and catalytic principles, [15] we have recently reported a new direct and highly enantioselective aldol reaction catalyzed by structurally simple chiral nickel(II) complexes derived from commercially available Tol‐BINAP (BINAP=2,2’‐bis(diphenylphosphino)‐1,1’‐binaphthyl) [16] . More specifically, we found that N ‐azidoacetyl‐1,3‐thiazolidine‐2‐thione is an outstanding platform from which carry out a highly stereocontrolled aldol addition to 4‐methoxybenzaldehyde to produce the enantiomerically pure anti O ‐protected derivative in a high yield [17] .…”

Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes

“…Finally, the azido thiazolidinethione 16 (R = N 3 ) proved especially successful and afforded in just 2 h the a-azido-b-silyloxy adduct 27 a virtually as a single stereoisomer (dr 95:5, 99 % ee) in a yield of 93 %. [13] The configuration of 5 a was established as the (2S,3R)anti-adduct through X-ray analysis of the benzyl amide derivative 28, [14] which was easily prepared by nucleophilic displacement of the scaffold of 5 a with (S)-1-phenyl-1ethylamine (Scheme 3). [15] Furthermore, amides 29 and 30 were isolated in up to 99 % yield after reaction with morpholine and N-methoxy-N-methylamine, respectively.…”