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Chiral complexes formed by phosphoramidites such as (S a ,R,R)-9 and Cu(OTf) 2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.Substituted prolinates 1, obtained from the corresponding 1,3-dipolar cycloadditions (1,3-DC) 1 between glycine ester aldimines and nitroalkenes, are important inhibitors of α 4 β 1 -integrin-mediated hepatic melanoma metastasis. 2 The most simple prolines exo-2 have been recently used as chiral organocatalysts in aldol reactions. 3 In particular, for the asymmetric 1,3-DC of nitroalkenes as dipolarophiles chiral copper(I) complexes, formed from ferrocenyl-type phosphanes, have been mainly used as catalysts. 3,4 Copper(I) complexes 3, 4a,c 4, 4b,e and 5, 3 generally afforded exo 5 -cycloadducts, whereas the corresponding endodiastereomers have been prepared using complex 6. 3 However, when copper(II) triflate and chiral ligand PyBidine 6 were combined the resulting catalyst 7 afforded

ABSTRACT:The synthesis of constrained spirocycles is achieved effectively by means of 1,3-dipolar cyclodditions employing α-imino γ-lactones as azomethine ylide precursors and nitroalkenes as dipolarophiles. The complex formed by (R,R)-Me-DuPhos 18 and AgF is the most efficient bifunctional catalyst. Final spiro-nitroprolinates cycloadducts are obtained in good to moderate yields and both high diastereo-and enantioselections. Density functional theory (DFT) calculations supported the expected absolute configuration as well as other stereochemical parameters.The importance of having a wide number of enantiomerically enriched sterically congested polysubstituted organic compounds is continuously increasing. Many scientific areas need all these functionalized structures for their specialized researches. Along this line, optically active polysubstituted nitroprolinates have emerged since 2005 as promising therapeutic agents.1 For example, molecules 1 (Figure 1) are important inhibitors of 41-integrin-mediated hepatic melanoma and in a murine model of colon carcinoma metastasis, as well as potent antiadhesive properties in several cancer cell lines.2,3 Bicyclic heterocycles 2, containing an atropane scaffold have been found as novel inhibitors of skin cancer. 4 Spirooxindoles 3 increased the mortality of zebrafish embryos 5 whilst molecules 4 with benzopyran skeleton were successfully tested as antimycobacterials against M. tuberculosis H37Rv strain.6 Besides, the most simple 4-nitroprolines exo-5, and endo-6 have been recently used as chiral organocatalysts in aldol reactions.7 Michael-type addition of ketones to nitroalkenes was successfully run in the presence of exo-5b (X=H),8 obtaining good to excellent diastereoselections and high enantiomeric ratios. A family of enantiopure tetrasubstituted nitroprolinate surrogates has been designed as scaffolds for proteasome inhibitors with high medicinal prospects.9 In addition, the NH-D-EhuPhos ligand 6 has been efficiently employed in the 1,3-dipolar cycloadditions (1, 10 to yield nitroprolines and structurally rigid spirocompounds from chiral γ-lactams. 11,12Grigg and co-workers reported in 2008 the silver-promoted racemic and diastereoselective 1,3-DC involving homoserine derived imino esters 7 13 and nitroalkenes 8 obtaining spirolactones 9 as major products (Scheme 1).14 The asymmetric approach to this molecules was performed by the employment of organocatalysts. Michael adducts could be isolated in a first step. A second treatment with DBU afforded enantiomerically enriched endo-cycloadducts 9 in good yields.15 These homoserine-lactone surrogates are a class of signaling molecules involved in the so called bacterial quorum sensing. In this work, with the idea of combining structural rigidity and enantiomerically enriched nitroprolinates, we report the direct enantioselective synthesis of these attractive intermediates 9. 17,18,19 For the optimization of the reaction privileged ligands 20 11-20 were tested in the silver-catalyzed 1,3-DC between imino lactone 7a...