Chiral guanidine

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

It was not until 1994 that Chinchilla and co-workers identified a synthesized a chiral guanidine for asymmetric catalysis [115],... 

The authors reported the first chiral guanidine catalyzed addition of nitro-olefms to aldehydes (Scheme 62, Table 3). While reactivity and selectivity were not optimal, the discovery led to great developments in the field of asymmetric Brpnsted base catalysis. 

The chiral guanidine s role as a strong Brpnsted base for the reactions of protic substrates has been proposed. In 1999, Corey developed a C -symmetric chiral guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition of HCN to imines was promoted high yields and high enantioselectivities for both electron-withdrawing and electron-donating aromatic imines (Scheme 64). 

Fig. 9 Corey s proposed catalytic cycle for chiral guanidine promoted hydrocyanation...

Ma and co-workers extended use of chiral guanidine catalysts to the addition of glycine derivatives to acrylates [121], Addition products were achieved in high yield with modest enantioselectivity (Scheme 67). The ferf-butyl glycinate benzophenone imines generally provided better enantiomeric ratios than the ethyl glycinate benzophenone imines. Based on this observation, the authors hypothesized that an imine-catalyst complex determines the stereochemical outcome of the product. 

Corey, E. J. Ohtani, M. Enantiospecific Synthesis of a Rigid C2 Symmetric, Chiral Guanidine by a New and Direct Method, Tetrahedron Lett. 1989, 30, 5227-5230. 

Enantioselective a-animation of carbonyl compounds has been promoted by l-azetidinecarboxylic acid,159 axially chiral guanidine derivative,160 and chiral palladium complexes.161... 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

Scheme 7. Asymmetric Strecker synthesis with chiral guanidine catalyst 19 (Corey and Grogan).

Asymmetric esterification of benzoic acid with racemic (l-bromoethyl)benzene was performed with chiral cyclic guanidines as stoechiometric bases4 the ester was obtained with ee below 15%. The chiral guanidines 6 were obtained from a chiral diamine of C2 symmetry which was tranformed first to urea and then to several guanidines through an intermediate chloroformamidinium chloride (Figure 4). 

Figure 4 Chiral guanidines from C2 symmetry diamines...

S)-2(N,N-dialkylaminomethyl)pyrrolidines react with diisopropylcarbodiimide to give chiral guanidines. ... 

Corey EJ, Ohtani M. Enantiospecitic synthesis of a rigid, C2-symmetric, chiral guanidine by a new and direct method. Tetrahedron Lett. 1989 30 5227-5230. 74. 

TBDMSCl, DMAP, EtjN, DMF, 25°C, 12 h. These conditions were used to silylate selectively a primary over a secondary alcohol. In the silylation of carbohydrates, it was shown that these conditions inhibit silyl migration whereas the use of imidazole as base causes migration." Besides DMAP, other catalysts such as 1,1,3,3-tetramethylguanidine, l,8-diazahicyclo[5.4.0]undec-7-ene (83-99%), l,5-diazabicyclo[4.3.0]non-5-ene, and ethyldiisopropyl-amine have also been used. A chiral guanidine has been used to give modest kinetic resolution of chiral secondary alcohols with TBDMSCl and TIPSCl. ... 

There are reports that extend the nature of the catalyst beyond an oxazaborolidine framework. One such example made use of a chiral guanidine catalyst.11 Proline-derived 25 was converted to guanidine 26 in good yield. This species was capable of reducing ketones 27 to alcohols 28 by the addition of BH3-SMe2. 

A series of chiral guanidines, either symmetrical or nonsymmetrical, was newly synthesized from commercial amino alcohols using a concise and efficient aziridine-based synthetic methodology [25]. 

Axially chiral guanidines with an external guanidine unit such as dinaphthoazepineamidine are effective catalysts for the enantioselective addition of p-oxoesters and a 1,3-diketone to di-ferf-butyl azodicarboxylates to yield cx-hydrazino-p-oxoesters and a-hydrazino-p-dike-tones in 54-99% yields and in 15-98% ee [44]. For example, stirring 2-oxocyclopenta-necarboxylate and di(tert-butyl) azodicarboxylate in THF in the presence of 0.05 mol% catalyst for four hours at —60° C provides an adduct in quantitative yield and in 97% ee (Scheme 4.15). The (R)-catalyst was prepared from (/ )-2,2 -dimethyl-3,3 -binaphthalene-diol ditriflate, 4-methoxyphenylboronic acid and 3.5-di(rert-butyl)phenylboronic acid in six steps. 

Figure 4.6 The structures of representative axial chiral guanidines 78 with an internal...

Chinchilla, R., Najera, C. and Sanchez-Agullo, P. (1994) Enantiomerically pure guanidine-catalysed asymmetric nitroaldol reaction. Tetrahedron Asymmetry, 5, 1393-1402 Ma, D. and Cheng, K. (1999) Enatioselective synthesis of functionalized a-amino acids via a chiral guanidine-catalysed Michael addition reaction. Tetrahedron Asymmetry, 10, 713. 

Kohn, U., Klopfleisch, M., Gorls, H. and Anders, E. (2006) Synthesis of hindered chiral guanidine bases starting from (5)-(7/,7/-dialkylaminomethyl)pyrrolidines and BrCN. Tetrahedron Asymmetry, 17, 811-818. 

Terade, M., Nakano, M. and Uhe, H. (2006) Axially chiral guanidine as highly active and enantioselelctive catalyst for electrophilic amination of unsymmetrically substituted 1,3-dicarbonyl compounds. Journal of the American Chemical Society, 128, 16044-16045. 

Terada, M., Ikehara, T. and Ube, H. (2007) Enantioselective 1,4-addition reactions of diphenyl phosphite to nitroalkenes catalysed by an axially chiral guanidine. Journal of the American Chemical Society, 129, 14112-14113. 

Koehn, U., Guenther, W., Goerls, H. and Anders, E. (2004) Preparation of chiral thioureas, ureas and guanidines from (S)-2-(7V,7V-dialkylaminomethyl)pyrrolidines. Tetrahedron Asymmetry, 15,1419-1426 Koehn, U., Schulz, M., Goerls, H. and Anders, E. (2005) Neutral zinc (II) and molybdenum(O) complexes with chiral guanidine ligands synthesis, characterisation and applications. Tetrahedron Asymmetry, 16, 2125-2131. 

Surprisingly, there have been only few synthetic studies on polymer-supported asymmetric superbase reagents. Recently, Wannaporn and Ishikawa prepared a new chiral guanidine based polymer catalyst and applied it to the asymmetric Michael addition reaction of iminoacetate with methyl vinyl ketone [39] (Scheme 6.7). Although the catalyst shows only moderate levels of reactivity and enantioselectivity, the result demonstrates the possibility of expanding an exciting field of asymmetric synthesis using polymer-supported chiral superbase catalysts. 

Scheme 6.7 Chiral guanidine catalysed asymmetric Michael addition reaction of t-butyl diphenyliminoacetate with methyl vinyl ketone...

Wannapom, D. and Ishikawa, T. (2005) Polymer-supported and polymeric chiral guanidines preparation and application to the asymmetric Michael reaction of iminoacetate with methyl vinyl ketone. Molecular Diversity, 9, 321-331. 

Scheme 4.33 Chiral guanidine-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to enones.

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