Thiourea-type organocatalysts

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. 

Sohtome, Y, Tanatani, A., Hashimoto, Y. and Nagasawa, K. (2004) Developmentofbis-thiourea-type organocatalyst for asymmetric Baylis-Hillmanreaction. Tetrahedron letters, 45,55, 9-5592. 

Tsogoeva et al. described the use of the primary amine thiourea-based organocatalyst 73 in an asymmetric Mannich-type reaction of unmodified aldehydes and ketones 7 with readily available and stable a-hydrazonoesters 74 (Scheme 5.35) [46]. Moderate to good yields and excellent enantioselectivities (90-99% ee) were reported. However, the anti-diastereoselectivity appeared generally poor (8-72% de). 

Takemoto et al. were the first to report that hifunctional organocatalysts of the thiourea - tert-amine type efficiently promote certain Michael-reactions, e.g., the addition of P-dicarhonyl compounds to nitro olefins (Scheme 6) [43 5],... 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

Interestingly, completely different types of organocatalyst have been found to have catalytic hydrocyanation properties. Among these molecules are chiral diketo-piperazine [4, 5], a bicydic guanidine [6], and imine-containing urea and thiourea derivatives [7-13]. All these molecules contain an imino bond which seems to be beneficial for catalyzing the hydrocyanation process. Chiral N-oxides also promote the cyanosilylation of aldimines, although stoichiometric amounts of the oxides are required [14]. 

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 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... 

Besides the use of bifunctional thioureas containing a chiral cyclohexane-type linker like catalyst 487, the use of Cinchona alkaloid-derived (thio)-ureas has found to be highly popular and fruitful 366, 367, 417-420). In these cases, the easily obtainable well-defined spatial arrangement of the naturally occurring Cinchona alkaloids can be exploited efficiently to build up highly selective and versatile bifunctional organocatalysts. 

In 2009, the Jorgensen group developed the organocatalytic asymmetric addition of P-keto-benzothiazole-sulfones to N-Boc aromatic imines based on the thiourea organocatalyst 61 and using as solvent, unusually, propionitrile (Scheme 29.33) [70]. The reaction proceeds with moderate yields, and stereoselectivities from moderate to excellent The initially formed adducts 62 were easily transformed into different types of protected amines like the aUyHc amines 63, or P-amino ketones 64 and 65. 

Takemoto and coworkers [32] elaborated bifunchonal catalyst 27, which was found, after this initial report, to be highly versahle in promohng a large variety of trans-formahons. The combinahon of a thiourea and a terhary amine separated by a chiral scaffold, (l ,l )-l,2-cyclohexyldiamine, was studied to build a new type of organocatalyst. Aminothiourea 27 was first examined as catalyst for the enanhose-lective addition of malonate to nitroaUcenes (Scheme 34.5). The thiourea moiety of catalyst 27 guides and activates the nitroolefin while the terhary amine part deprotonates the malonate. 

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