Note pubs.acs.org/joc
Au-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of Isocyanoacetates with Maleimides Silvia Padilla, Javier Adrio,* and Juan C. Carretero* Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain S Supporting Information *
ABSTRACT: An efficient protocol for the AuI-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with phenylmaleimide has been developed. In the presence of cationic AuI/DTBM-segphos complex, excellent diastereoselectivity and high levels of enantioselectivity (up to 97% ee) have been attained with a variety of α-substituted isocyanoacetates. The synthetic potential of the resulting enantioenriched 1pyrrolines has been demonstrated by the preparation of highly substituted pyrrolidines bearing a quaternary stereocenter.
T
OH-Mop complex as catalyst led to the corresponding 2pyrrolines with high yields and excellent enantioselectivities (up to 98% ee), albeit with moderate diastereoselectivities (3:1 to 5:1 trans/cis mixtures). Shortly after, Escolano and co-workers demonstrated that the combination of a cinchona alkaloid derived bifunctional catalyst and a silver salt is able to promote the cycloaddition of isocyanoacetates and α,β-unsaturated ketones in moderate enantioselectivities.7 Despite these significant advances, the scope of the enantioselective reaction with regard to both reaction partners is still rather limited. For example, as far as we are aware, cyclic activated alkenes such as maleimides have not been yet applied in this asymmetric formal [3 + 2] cycloaddition.8 It is interesting to note that this type of alkenes led to 1-pyrrolines instead of the 2-pyrrolines obtained in the previously reported catalytic asymmetric versions. Herein, we describe the AuI/DTBM-segphos9,10 catalyzed highly diastereoselective and enantioselective synthesis of 1pyrrolines by reaction of isocyanoacetates with phenylmaleimide. Some aspects of the synthetic utility of the resulting 1-pyrrolines are also presented. As model reaction we chose the cycloaddition of methyl isocyanoacetate (1a) with N-phenylmaleimide (2). After screening a variety of metal salts and chiral ligands,11 we found that the reaction catalyzed by 10 mol % of (R)-DTBMsegphos(AuCl)212 (4a) and 10 mol % of AgSbF613 in CH2Cl2 as solvent and Et3N as base, afforded the desired adduct 3a with moderate yield, a relatively good diastereoselectivity (cis/trans 80/20), and a promising 50% ee (Table 1, entry 1). Further optimization of the reaction conditions was then carried out. After surveying different solvents (entries 2−4), we observed a significant improvement in the reactivity and selectivity in THF (71% yield, excellent cis-selectivity and 70% ee, entry 4).
he cyclization reaction of isocyanides with carbon−carbon and carbon−heteroatom multiple bonds has proved to be a powerful tool for the preparation of substituted aromatic fivemembered heterocycles, such as pyrroles, 1,3-azoles, and 1,2,4triazoles.1 In particular, isocyanoacetates, which contain a more acidic proton in the α-position, offer additional synthetic possibilities. For instance, the formal [3 + 2] cycloaddition of isocyanoacetates with electron-deficient olefins can be envisaged as one of the most convergent approaches for the preparation of pyrrolines (Scheme 1), which are versatile building blocks in the synthesis of natural products and biologically active compounds.2 Scheme 1. [3 + 2] Cycloaddition of Isocyanoacetates with Electron-Deficient Olefins
This reaction can be greatly accelerated either in the presence of a base or a metal complex. However, since the pioneering work by Saegusa in 1971, using Cu2O as catalyst,3 this type of formal [3 + 2] cycloaddition has received limited attention.4 Regarding the development of catalytic asymmetric protocols, the first procedure was described by Gong and co-workers in the reaction of α-phenyl isocyanoacetate with nitroolefins catalyzed by cinchona alkaloids.5 Very recently, in 2011, the same research group succeeded in performing the silvercatalyzed enantioselective reaction of α-aryl isocyanoacetates with α,β-unsaturated ketoesters.6 The use of a chiral silver− © 2012 American Chemical Society
Received: February 20, 2012 Published: March 29, 2012 4161
dx.doi.org/10.1021/jo3003425 | J. Org. Chem. 2012, 77, 4161−4166
The Journal of Organic Chemistry
Note
Table 2. Scope of the Process with α-Substituted Isocyanoacetates
Table 1. Optimization of the Reaction Conditions for the Model Reaction
entry 1 2 3 4 5 6 7 8 9d 10e 11f,d 12d 13g,d
base Et3N Et3N Et3N Et3N i
Pr2EtN DBU Cs2CO3 Et3N Et3N Et3N Et3N Et3N
Au complex
solvent
cis/transa
yieldb (%)
ee (cis)c (%)
4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4b 4b
CH2Cl2 CH3CN toluene THF THF THF THF THF THF THF THF THF THF
80/20 80/20 >95/95/95/95/95/95/95/
