Jacobsen thiourea

Another important type of transformation, which is has inspired the above developments, is the nitro-Mannich (or aza-Henry) reaction catalyzed by Jacobsen thiourea catalysts (Scheme 4.16) [77]. The reaction is highly 5yn-selective, and the corresponding products were isolated in high yields and ees. 

Enantioselective homologation can also be a powerful approach. Benjamin List of the Max-Planck-Institute, Miilheimhas foimd (Angew. Chem. Int. Ed. 2007, 46, 612 Organic Lett. 2007, 9, 1149) that three-component coupling of acetyl cyanide, an aldehyde and benzylamine under the influence of the Jacobsen thiourea catalyst 10 delivered the one-carbon homologated nitrile 12 in high ee. 

New organocatalysts prepared by the Jacobsen group showed that alkylation of the final amide bond increased the enantioselection (Scheme 38, compare R2 = Me, 98% ee to R2 = H, 91% ee). Thus, the reaction performed with N-allyl benzaldimine and with the dimethylamide-ending thiourea (Scheme 38 with Ri = R2 = Me) gave up to 99% ee. This compound is a structural analogue of the urea depicted in Scheme 36 [148,152,154]. 

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... 

The Jacobsen group also studied the thiourea-catalysed enantioselective hy-drophosphonylation of imines (Scheme 44) [160]. Many examples were de-... 

Jacobsen (1998), Corey (1999) chiral ureas/thioureas and guanidine Enamine Cataiysis... 

Since Curran and Kuo and Schreiner and coworkers reported that urea and thiourea derivatives act like Lewis acid catalysts, several chiral urea and thiourea catalysts have been designed by Jacobsen et al. and Takemoto et al. ... 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

In addition to the activation of carbonyl compounds and imines, Schreiner studied on thiourea-catalyzed acetalization reaction, in which ortho esters were activated by hydrogen bond [19]. Jacobsen has utilized the hydrogen-bond catalysis in reactions with acyliminium ions, wherein hydrogen bond activates the acylim-inium salt through complexation with chloride [20]. 

Wenzel and Jacobsen, in 2002, identified Schiff base thiourea derivative 48 as catalyst for the asymmetric Mannich addition [72] of tert-butyldimethylsilyl ketene acetals to N-Boc-protected (hetero)aromatic aldimines (Scheme 6.49) [201]. The optimized structure of 48 was found through the construction of a small, parallel... 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

The computations suggested that the enantioselectivity of the cyanosilylation arose from direct interactions between the ketone substrate and the amino-acid derived unit of the catalyst type represented by thiourea 72. On the basis of this insight, the Jacobsen group designed thiourea catalysts 73 and dipepetide thiourea catalyst 74 [67]. These optimized catalysts gave access to a broader spectrum of silylated cyanohydrins (e.g., 1-6) and proved to be more active (88-97% yield) and more enantioselective (98-98% ee) than 72 (Scheme 6.85) [242]. 

The Jacobsen group independently focussed on the development of primary amine-functionalized thiourea derivatives and published, in 2006, the thioureas 100-103 incorporating the established tert-leucine (amide) motif (Figure 6.14) and the diaminocyclohexane or diphenylethylenediamine chiral backbone, respectively (Figure 6.31) [262]. The catalyst screening was carried out in the asymmetric Michael addition [149-152] of 2-phenylpropionaldehyde, an a,a-disubstituted aldehyde, to 1-nitrohex-l-ene (at 20mol% loading, DCM, rt, variable equiv. of H2O)... 

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004,126, 10558) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2. 

A very efficient method for hydrocyanation of aldimines and ketimines has been developed by the Jacobsen group. Chiral urea or thiourea derivatives containing an imine bond of type 9 and 10 were used as organocatalysts [7-13]. The core... 

The Jacobsen group have also focused on optimization of the organocatalyst, and the design of new, simpler catalysts [37], by systematic variation of each modular component of the catalyst, for example the salicylaldimine, diamine, amino acid, and amide. A new catalyst was found, a simple amino acid derivative 42 with less than half the molecular weight and fewer stereogenic centers than the thiourea catalyst 41. In the presence of this organocatalyst 42, benzaldimine was converted into the corresponding //-phenylalanine derivative (R)-40a with 100% conversion and 94% ee (Scheme 5.24) [37]. 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

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... 

The groups of Tsogoeva, Tang and Jacobsen each pioneered the development of the bifunctional catalyst, combining the nucleophilic amine and thiourea... 

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