Mechanism of Enantioselective Ti-Catalyzed Strecker Reaction:  Peptide-Based Metal Complexes as Bifunctional Catalysts

Abstract

Kinetic, structural, and stereochemical data regarding the mechanism of Ti-catalyzed addition of cyanide to imines in the presence of Schiff base peptide ligands are disclosed. The reaction is first order in the Ti-ligand complex; kinetic studies reveal DeltaS(dagger) = -45.6 +/- 4.1 cal K(-1) mol(-1), indicating a highly organized transition structure for the turnover-limiting step of the catalytic cycle. A mechanistic model consistent with the kinetic and stereochemical data is presented, where the Ti center is coordinated to the Schiff base unit of the ligand and the AA2 moiety of the peptidic segment of the chiral ligand associates and delivers HNC to the activated bound substrate. Thus, these studies illustrate that these non-C2-symmetric catalysts likely operate in a bifunctional fashion.

Bifunctional Organometallic Catalysts Involving Proton Transfer or Hydrogen Bonding

“…The second catalyst type includes Al III , In III , or Ti IV centers held by ligands containing Brønsted-Lowry bases near enough to act on intermediates, but far enough from the metal to prevent coordination. For examples, see the work of Shibasaki, [28][29][30][31][32] Saa, [33,34] Leckta, [35,36] Snapper and Hoveyda, [37] and Kozlowski. [38] In some systems, even a transition metal (for example, Ru II [39,40] ) may act simply as a Lewis acid, not forming metal-carbon bonds.…”

New Developments in Enantioselective Brønsted Acid Catalysis: Chiral Ion Pair Catalysis and Beyond

“…Consequently, various attempts to develop asymmetric Strecker reactions have been made (for reviews, see : Gröger 2003;Yet 2001;Spino 2004). In addition to metal-catalyzed hydrocyanations using chiral metal catalysts (Al catalysts: Sigman and Jacobsen 1998a; Takamura et al 2000;Krueger et al 1999;Byrne et al 2000;Josephsohn et al 2001;Ishitani et al 1998;Kobayashi and Ishitani 2000;Chavarot et al 2001;Masumoto et al 2003), promising metal-free, enantioselective variants of this reaction have recently been disclosed. These processes are based on chiral guanidines (Corey and Grogan 1999), ureas and thioureas (Sigman and Jacobsen 1998b; Sigman et al 2000;Vachal and Jacobsen 2000;Vachal and Jacobsen 2002;Wenzel et al 2003;Tsogoeva et al 2005), bis-N-oxides [for the application of stoichiometric amounts of bis(N-oxides), see : Liu et al 2001;Jiao et al 2003] and ammonium salts (Huang and Corey 2004).…”

Efficient Solid‐Phase Synthesis of Peptide‐Based Phosphine Ligands: Towards Combinatorial Libraries of Selective Transition Metal Catalysts

“…Peptides have been applied for asymmetric azidation and for regioselective functionalisation of carbohydrates by Miller and co-workers. [3,4] Functionalised peptides complexing transition metals, have been utilised for a number of asymmetric addition and substitution reactions in the group of Hoveyda, [5][6][7][8][9][10][11][12] and peptidic catalysts for the Strecker reaction have been developed by Jacobsen and co-workers. [13][14][15] However, because of the expected high chemo-, regioand stereoselectivity of peptide-based catalysts, there is a need for the development of a method for the identification of the most efficient catalyst for any specific reaction.…”

“…A solution of Fmoc-Phe-OH (3 equiv) and methylimidazole (2.25 equiv) in dry dichloromethane was added to MSNT (3 equiv), and the resulting solution was added to the dry resin and reacted for 1 h. The resin was washed with dry dichloromethane ( 3) and the MSNT coupling repeated to give 2. Resin 2 was washed with dichloromethane ( 6) and N,N-dimethylformamide ( 6), whereupon the Fmoc groups were removed. Fmoc-Phe-OH, Boc-Dap-(Fmoc)-OH and Fmoc-Phe-OH were coupled successively to the resin by using TBTU activation followed by Fmoc cleavage, to obtain resin bound peptide 5.…”

“…The resin was washed with N,N-dimethylformamide ( 6) and dichloromethane ( 6) and the Boc group was removed by treating the resin with TFA-dichloromethane 1:1 (v/v) for 15 min, which yielded ligand precursor 6. The resin was washed with dichloromethane ( 6), N,N-dimethylformamide ( 6), methanol ( 2) and dichloromethane ( 2), whereupon it was dried in vacuo overnight. A sample of 6 (100 mg resin, 0.019 mmol) was cleaved for analysis, affording an amorphous colourless solid (11 mg, 89 %).…”