Thiourea Strecker reaction

Schiff base thiourea catalysts (2 mol%) first enantioselective (polymer-bound) thioureas, Strecker reactions (92% yl. 91% ee)... 

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

Similar organocatalytic species to those successfully used for the Strecker reaction were used for the asymmetric Mannich reaction. Catalyst structure/ enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were compared by the Jacobsen group [160]. The efficient thiourea... 

In screening a library of these molecules with a variety of metal ions, it was found that the ligand in the absence of added metal was more active than the metal complexes tested. Three libraries were synthesized where sequential changes were made in the structures contained in each library. Ultimately, ligand 64, with a thiourea linker, was found to catalyze the Strecker reaction between benzaldehyde and HCN in 91% ee (Scheme 8). This system also catalyzed the addition of HCN to aliphatic aldehydes with selectivities of > 80% ee. 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

Figure 6.15 Polymer-bound Schiff base thiourea catalyst 41 bearing 5-pivaloyl-substitution and its nonimmobilized urea analog 42 optimized for the asymmetric Strecker reaction of aromatic and aliphatic aldimines.

Scheme 6.43 Recycling study Polymer-bound Schiff-base thiourea 41 catalyzed the Strecker reaction of pivalaldimine without loss of activity or enantioselectivity even after 10 catalytic cycles.

This tertiary amide-functionalized Schiff base thiourea was found to efficiently catalyze the asymmetric Strecker reaction [157] of N-benzyl-protected aldimines and also one ketimine in high enantioselectivities (86-99% ee) and proved superior to 42 examined under the same conditions (1 mol% loading, toluene, -78 °C, HCN) (Scheme 6.46) [198]. 

Figure 6.16 Structure optimization of 42 in the asymmetric Strecker reaction of N-benzyl-protected 2-methylpropionaldehyde imine identified tertiary amide-functionalized Schiff base thiourea 47 as the most enantioselective catalyst stmcture.

Tsogoeva and co-workers explored the catalytic potential of pyridyl- and imida-zoyl-containing thiourea derivatives (e.g., thiourea 92 and 93) in the asymmetric model Strecker reactions [157] of N-benzyl- and benzhydryl-protected benzaldi-mine with HCN [258], The observed enantioselectivities were consistently very low (4—14% ee) for all catalyst candidates and were far below synthetically useful levels, while imidazoyl-thiourea 93 was reported to be highly active and displayed 100% conversion (at 7% ee) of the N-benzhydryl-protected benzaldimine (Scheme 6.99). X-ray structure analysis of a pyridyl-thiourea revealed an intramolecular hydrogen-bond between the basic ring nitrogen and one amide proton. This could make this... 

Scheme 6.99 Typical pyridyl- and imidazoyl-thioureas evaluated for bifunctional catalysis in the asymmetric Strecker reaction of aldimines.

The modification of thiourea catalyst 93 through incorporation of the (S,S)-diaminocyclohexane backbone as an additional chirality element and a Schiff base imidazoyl-moiety led to the bifunctional catalyst 94 that, in contrast to 93 in the Strecker reaction (Scheme 6.99), exhibited enantioinduction (83-87% ee) in the nitro-Michael addition of acetone to trons-P-nitrostyrenes. The desired adducts were isolated in moderate yields (46-62%) as depicted in Scheme 6.100) [259]. 

The asymmetric catalytic Strecker reaction is an elegant means of synthesis of optically active a-amino acids. The Jacobsen group developed optimized organocata-lysts [21, 44-48], optically active urea or thiourea derivatives, which were found to be the most efficient type of catalyst yet for asymmetric hydrocyanation of imines (see also Section 5.1 on the hydrocyanation of imines). Because of its high efficiency, Jacobsen hydrocyanation technology has already been used commercially at Rodia ChiRex [49]. The concept of the reaction is shown in Scheme 14.7. In the presence of a catalytic amount (2 mol%) of the readily available organocatalyst... 

Scheme 6.7 Thiourea-catalyzed Strecker reactions of ketoimines.

Scheme 4.3 The thiourea-catalyzed Strecker reaction reported by Jacobsen.

Scheme 10.37 Three-component acyl-Strecker reaction catalyzed by thiourea.

A pioneer in the field of the asymmetrie (thio)urea organocatalysis was Eric Jacohsen, who first reported a chiral (polymer-hound) Schiff base thiourea derivative for asymmetric Strecker reactions optimised from parallel synthetic libraries/ These catalysts can be used either in solution or immobilised to a polystyrene resin, with the latter retaining efficiency, after repeated recycling/ The key factors responsible for high enantioselectivities were the presence of bullqr substituents at both the amino acid position and at the 3-position of the aromatic ring (Scheme 19.3). 

In 2002, Jacobsen s group reported an improved analogue for the as5mimetric Strecker reaction based on detailed mechanistic studies. Both aldimines and ketimines underwent hydrocyanation with high enantioselectivities utilising thiourea 4 in just 1 mol% catalyst loading (Scheme 19.4). 

Scheme 19.4 Sustainable thiourea 4 for oiganocatalytic Strecker reaction.

Scheme 105 Thiourea-catalyzed Strecker reaction in the s oitheses of (—)-calycotomine (476), (—)-salsolidine (477), and (—)-camegine (478)...

The first organocatalytic asymmetric three-component Strecker reaction was reported by List and Pan using Jacobsen s thiourea catalyst 75. Diverse a-aminonitriles 76 and 77 were formed in excellent yields and enantioselectivities from aliphatic and aromatic aldehydes, different amines, and acyl cyanides by using 5mol% of catalyst 75 (Scheme 10.33) [97]. 

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