Synthesis and evaluation of guanidinyl pyrrolidines as bifunctional catalysts for enantioselective conjugate additions to cyclic enones

Abstract

Guanidinyl pyrrolidines derived from 'S'-proline are effective catalysts for the enantioselective conjugate addition of malonate, nitroalkane and other carbon and heteroatom nucleophiles to cyclohexenone and cyclopentenone in the absence of basic additives. The stereoselectivity is strongly dependent on catalyst loading as well as reaction concentration.

Novel guanidinyl pyrrolidine salt-based bifunctional organocatalysts: application in asymmetric conjugate addition of malonates to enones

“…Moreover, the presumed ability of guanidinium ion to efficiently complex a malonate by both electrostatic interaction and two-directional hydrogen bonds would be suitable for the efficient orientation of nucleophilic attack of malonate. Consequently, the attack of the nucleophile could occur syn with respect to the pyrrolidine substituent, During the final course of this work, the report of Pansare and Lingampally 16 based on a similar working hypothesis 17 was published and it prompted us to report our preliminary results. It should be noted that the use of acyclic guanidine catalysts is rare compared to that of their cyclic or bicyclic counterparts.…”

Enantioselective Conjugate Addition of Nitro Compounds to α,β‐Unsaturated Ketones: An Experimental and Computational Study

“…[1] One of the most studied Michael acceptors are a,bunsaturated ketones, because the adducts obtained contain interesting functionalities suitable for their further transformation into relevant products, such as pyrrolidines, aminoalkanes, and aminocarbonyl compounds. Organocatalytic enantioselective conjugate addition of nitroalkanes to cyclic and acyclic aliphatic a,b-unsaturated ketones has been extensively studied by using proline derivatives, [2] imid-A C H T U N G T R E N N U N G azolines, [3] guanidines, [4] and spiro-ammonium salts as catalysts. [5] Bifunctional thioureas bearing a primary amine have also been described as useful catalysts for this reaction, [6] and even aluminum and magnesium complexes have been reported to promote that enantioselective transformation.…”

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…The poor enantioselectivity observed in malonate as the reaction medium, supports this proposal. Lowering the concentration of malonate, the rate of malonate deprotonation by free catalyst is reduced to allow iminium ion formation [25].…”

“…Under Pansare group's conditions (entry 9, Table 2), the trend of nitroalkane addition in stereoselection was less predictable than with malonate, since lowering the catalyst loading, and increasing dilution, did not always increase enantioselectivity [25]. However, only in this reaction, nitromethane adduct does not react further, suggesting that these reaction conditions are mild enough to avoid further deprotonation of the substrate.…”