Pyrrolate-Catalyzed Conjugate Addition of Pyrrole to Electron-Deficient Alkenes

Abstract

The conjugate addition of pyrrole as a nitrogen nucleophile can be catalyzed by potassium pyrrolate in coordinating solvents or by lithium pyrrolate in the presence of coordinating ligands offering an efficient route to protected b-amino carbonyl compounds.b-Amino carbonyl compounds are key components in many biologically active natural and unnatural products such as taxol, 1 streptothricin F 2 and the renin inhibitor KR1 1314. 3 They are also useful precursors to the b-lactam motif found in the antibiotics penicillin and cephalosporin. 4 In recent years there has been much development in stereoselective methods of synthesis of bamino acids. 5 One of the most attractive and powerful strategies is the conjugate addition of nitrogen-centered nucleophiles to a,b-unsaturated carbonyl compounds and other electron-deficient alkenes. 6,7 Scheme 1 Proposed catalytic cycle Towards our aim of developing a conjugate addition of nitrogen nucleophiles using substoichiometric base for use in b-amino carbonyl synthesis, we focused on the conjugate addition of pyrrole (1) to enoates 2. 8 The reaction (Scheme 1) appeared to offer considerable scope for employment of substoichiometric base since, from studying the pK a values (quoted here in DMSO as a model aprotic solvent), it was predicted that pyrrole (1, pK a = 23) 9 would be rapidly deprotonated by the intermediate enolate 3 (pK a = 30), 10 regenerating the catalytic metal pyrrolate 4 and releasing the adduct 5. The results (Table 1) show that this was indeed the case for a range of a,b-unsaturated tert-butyl esters when substoichiometric potassium pyrrolate was used in the presence of excess pyrrole in chilled THF, giving excellent yields of the adducts 5a-e for all but the most hindered of substrates. 11,12 The lower yields for 5e (R = t-Bu) can be explained by increased steric hindrance at the b-carbon giving rise to reduced reaction rates. For the reaction with tert-butyl crotonate (entry a), it was found necessary to maintain the reaction temperature below 0°C, and reduce the reaction time, in order to prevent formation of an unwanted bisadduct 6 ( Figure 1) believed to arise from a competing carbonyl substitution pathway. Interestingly, this was not seen with any of the other tert-butyl ester substrates. However, with less sterically demanding ester groups, such as ethyl crotonate, ester aminolysis was a major pathway.The potassium pyrrolate-catalyzed conjugate addition of pyrrole is general to a range of a,b-unsaturated substrates ( Table 2). Of interest are the nitrile 7 and Weinreb amide 9 since they allow access to both aldehyde 13 and ketone 14

Enantiomeric impurities in chiral catalysts, auxiliaries, and synthons used in enantioselective syntheses. Part 4

“…39 (2) Used in the conjugate addition of aryl methyl ketone derived enamines to nitroalkenes. 40 (3) Used in the practical asymmetric syntheses of b-lactones. 41 (1) Used in the carbon dioxide and epoxides coupling reactions to form cyclic carbonates.…”

Highly Enantioselective Michael Addition of Aromatic Ketones to Nitroolefins Promoted by Chiral Bifunctional Primary Amine‐Thiourea Catalysts Based on Saccharides.

“…Then the reaction solution was concentrated in vacuo and the crude was purified by flash chromatography to afford the product. Compounds 3a, [2,3,4] 3b, [3] 3c, [3,4] 3d, [3] 3e, [3] 3f, [3,5] 3i, [3] 3j, [3] 3k [2,3] and 3n [3] were known.…”