Catalyst chiral urea

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

Abstract After an overview of chiral urea and thiourea synthetic methods, this review describes the main applications of urea and thiourea complexes in asymmetric catalysis. Some recent examples of thioureas as catalysts are also presented. Coordination chemistry of ureas and thioureas is briefly discussed. 

TABLE 12. The asymmetric reduction of prochiral ketones under catalysis of chiral urea derivative 8173 (in all reactions 5% catalyst was used)... 

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 asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

Cyclohexanediamine-derived amine thiourea 70, which provided high enantio-selectivities for the Michael addition [77] and aza-Henry reactions [78], showed poor activity in the MBH reaction. This fact is not surprising when one considers that a chiral urea catalyst functions by fundamentally different stereoinduction mechanisms in the MBH reaction, and in the activation of related imine substrates in Mannich or Streclcer reactions [80]. In contrast, the binaph-thylamine thiourea 71 mediated the addition of dihydrocinnamaldehyde 74 to cyclohexenone 75 in high yield (83%) and enantioselectivity (71% ee) (Table 5.6, entry 2) [79]. The more bulky diethyl analogue 72 displayed similar enantioselectivity (73% ee) while affording a lower yield (56%, entry 3). Catalyst 73 showed only low catalytic activity in the MBH reaction (18%, entry 4). 

Over the past half-dozen years, many laboratories have focused their efforts on the development of chiral hydrogen bond donors that function as catalysts for enantioselective organic reactions. One of the earliest successes in this area came from Jacobsen and co-workers, who reported the use of peptide-like chiral urea-based catalysts for the hydrocyanation of aldimines and ketoimines [40, 41]. Several other laboratories have also reported highly enantioselective transformations catalyzed by a chiral hydrogen bond donor. The following sections provide a summary of the many developments in hydrogen bond-catalyzed enantioselective reactions, along with a discussion of mechanisms and selectivity models. 

Many noticeable examples of chiral Lewis base catalyzed allylation of carbonyl compounds have also appeared. Iseki and coworkers published a full paper on enantioselective addition of allyl- and crotyltrichlorosilanes to aliphatic aldehydes catalyzed by a chiral formamide 28 in the presence of HMPA as an additive [41]. This method was further applied to asymmetric allenylation of aliphatic aldehydes with propargyltrichlorosilane [40]. Nakajima and Hashi-moto have demonstrated the effectiveness of (S)-3,3 -dimethyl-2,2 -biquinoline N,AT-dioxide (29) as a chiral Lewis base catalyst for the allylation of aldehydes [42]. In the reaction of (fs)-enriched crotyltrichlorosilane (54 , E Z=97 3) with benzaldehyde (48), y-allylated anfi-homoallylic alcohol 55 was obtained exclusively with high ee while the corresponding syn-adduct was formed from its Z isomer 54Z (fs Z= 1 99) (Scheme 6). Catalytic amounts of chiral urea 30 also promote the asymmetric reaction in the presence of a silver(I) salt, although the enantioselectivity is low [43]. 

Cook reported that a 3,3 bis(trifluoromethyl) BINOL catalyzed asymmetric addition of allylindium to hydrazones proceeds in modest to good enantioselec tivities (10 92% ee) [90]. The stoichiometric version of this reaction yields much higher enantioselectivities (84 97% ee). Jacobsen later found that a chiral urea catalyst is effective in catalyzing a similar transformation [96]. The bifunctional catalyst 55 bearing a hydrogen bond donor and a Lewis base that are properly... 

Tan, K.L. and Jacobsen, E.N. (2007) Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angewandte Chemie - International Edition, 46, 1315-1317. 

Another application of this concept, in this case to an intermolecular process, the Povarov reaction, was reported by Jacobsen s group in 2010 [150]. The reaction was efficiently catalyzed by o-nitrobenzenesulfonic acid in the presence of a chiral urea derivative. The authors performed a detailed experimental and computational analysis of this catalyst system, which supported the mechanism shown in... 

The catalytic potential of base functionalities has been referred to in the previous chapter (see Sect. 7.4), wherein the interplay between an acidic (thio-)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such brfunctional thiourea-containing acid-base catalysts, chiral catalysts containing Lewis or Br0nsted-) base functionality as the sole catalyticaUy active group as weU as those having another H-bond donor like a hydroxy group e.g. Cinchona alkaloids) have found widespread applications in asymmetric catalysis (443-449). 

Jacobsen investigated cooperative catalysis for the Povarov reaction by combining a chiral urea catalyst (84) with a Brpnsted acid (o-nitrobenzenesulfonic acid) to induce highly enantioselective syntheses of tetrahydroquinolines and their fused derivatives [66]. Unusually for a Povarov reaction, the final product 85 is trans, with the absolute configuration shown in Scheme 3.25. This strategy was applied to the generation of compound libraries for drug discovery [67]. 

In 2010, the Jacobsen group further advanced this chemistry to the combined use of strong achiral acid components with chiral urea and thiourea catalysts for Povarov reaction (Fig. 21) [77]. Different types of electron-rich alkenes, such as 2,3-dihydrofuran, various enamides and enecarbamates, can be used for the Povarov reaction with imine substrates. Detailed kinetic, as well as computational studies, led to the picture of inducing high enantioselectivity with protio-iminium... 

A new class of chiral bifunctional cinchona-alkaloid catalyst with urea moiety at C5 has recently been reported by Connon and coworkers, and successfully applied in enantioselective nitroaldol reaction of nitromethane with aromatic... 

A hydrogen-bond-mediated asymmetric [4,l]-annulation/rearrangement cascade of stable sulfur ylides and nitroolefins has been developed in the presence of a C2-symmetric chiral urea catalyst This reaction provides a facile route to enantioenriched 4,5-substituted oxazolidinones with excellent stereocontrol (up to more than 95 5 dr and 97 3 er). The stereocontrolled modes and mechanism have been proposed to explain the origin of this stereochemistry. 

Jacobsen pioneered a number of chiral ureas and thioureas that function as chiral hydrogen-bond donors [40, 41], These were first showcased in enantioselective Strecker reactions in 1998 (see Chapter 10) [160]. The highly modular nature of these catalysts provided ready access to structural variants and facilitated the identification of thiourea 235 as an optimal catalyst in catalytic enantioselective Mannich reactions (Equation 20) [161]. Thus, a broad range of N-Boc-protected aromatic aldimines such as 233 afforded the corresponding products (cf 236) with excellent yield and enantioselectivity. 

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