Highly Enantio‐ and Diastereoselective Reactions of γ‐Substituted Butenolides Through Direct Vinylogous Conjugate Additions

Abstract

The strength of the weak: An L‐tert‐leucine‐derived amine–thiourea catalyst (see scheme, green box) promotes the asymmetric vinylogous conjugate addition reaction between γ‐aryl‐ and alkyl‐substituted butenolides with the butenamides and enoates shown. Computational studies show the preference for the observed stereochemistry is a result of favourable weak non‐bonding interactions, which stabilize the transition state.

Kinetic Evidence of an Apparent Negative Activation Enthalpy in an Organocatalytic Process

“…The bond indices were calculated from canonical molecular orbitals in the atomic orbital basis and can be used to analyze the covalent bonding between atoms. The computed bond orders of 0.057 and 0.032 for these α-C-H···O bonding interactions are more significant with reference from our recent DFT studies with different derivatives of thiourea for catalytic organic transformation4546. The N-H···O hydrogen bonding interactions showed similar to prominently higher bond orders of 0.040, 0.098, and 0.155.…”

Diastereodivergent organocatalytic asymmetric vinylogous Michael reactions

“…Reactions of a variety of g-substituted butenolides and benzalacetone derivatives also proceeded smoothly giving uniformly excellent enantioselectivities, regardless of the position and electron-donating or electronwithdrawing nature of the substituent on the aromatic ring (Table 3, entries 24-32). However, with respect to the diastereoselectivity, the result varies with the type of substituent at the g-position of the butenolides; those with alkyl groups (Table 3, entries 27-29, 31-32) performed relatively better than those with an aryl group (Table 3, entries [24][25][26]30). As for cyclic Michael acceptors, excellent enantioselectivities were observed in moderate-to-good yields; however, 2-cyclopentenone gave a relatively poor diastereoselectivity compared with 2-cyclohexenone or 2-cycloheptenone (Table 3, entries 33-37).…”

“…These compounds contain quaternary stereogenic centres and are important motifs in biologically active natural compounds and medicinally important agents [13][14][15][16][17][18] . The organocatalytic asymmetric synthesis of g, g-disubstituted butenolide derivatives has attracted much attention in the past few years [19][20][21][22][23][24][25][26] . However, the key limitation encountered with the previous asymmetric vinylogous reactions using b, g-butenolides was that only one diastereoisomer was accessed, therefore making it relevant to this study.…”

Acyclic Amino Acid Based Bifunctional Chiral Tertiary Amines, Quaternary Ammoniums and Iminophosphoranes as Organo­catalysts

“…22 In 2012, we reported the direct asymmetric vinylogous conjugate additions of γ-aryl-and alkyl-substituted butenolides, respectively, to (E)-4-oxo-4-arylbutenamides possessing an oxazolidinone motif (49), (E)-oxazolidinone and (E)-/(Z)-β-trifluoromethyl oxazolidinone enoates (51) by employing 1.0 mol% of L-tert-leucine-derived thiourea-cyclic tertiary amine 50 as the catalyst (Scheme 11). 23 Various γ,γ-butenolide-substituted α-(52) and β-stereogenic amides (53), containing a quaternary chiral center, were obtained in up to 93% yield, 99% ee and >99:1 dr. From experimental observations and DFT calculations, it was determined that the carScheme 9 Asymmetric Michael addition of 5H-oxazol-4-ones 39 to trans-β-nitrostyrenes 8, the proposed mechanism and the synthetic advantages of the Michael adducts …”