Synthesis of α,β‐Unsaturated δ‐Lactones by Vinyl Acetate Mediated Asymmetric Cross‐Aldol Reaction of Acetaldehyde: Mechanistic Insights

Abstract

A tandem asymmetric cross‐aldol reaction involving the in situ generation of acetaldehyde from vinyl acetate has been developed that may resolve the challenges associated with the handling of acetaldehyde. The simple protocol, mild reaction conditions and unique harmony of an organocatalyst with a biocatalyst make this method a valuable tool for the synthesis of asymmetric β‐hydroxy aldehydes. By using this methodology we have accessed α,β‐unstaurated δ‐lactones as well as isochromenones with high enantioselectivities from both asymmetric β‐hydroxy aldehydes and ketones. Systemic density functional theory (DFT) studies were also performed to gain mechanistic insights into the role of hydrogen bonding in the asymmetric cross‐aldol reaction of acetaldehyde and in the key cis/trans isomerisation step in the synthesis of δ‐lactones.

Acetaldehyde in asymmetric organocatalytic transformations

“…To further explore the use of vinyl acetate as an alternative 35 source of acetaldehyde our group have recently employed vinyl acetate in for highly enantioselective cross-aldol reaction 63 (Scheme 24). The reaction apparently involves in situ generation of acetaldehyde from vinyl acetate through lipase Novozym 435 followed by the cross aldol reaction in the presence of bis-trifluoro 40 substituted diphenylprolinol (18).…”

Design and synthesis of a new class of cryptophycins based tubulin inhibitors

“…To synthesize the enantioselective cross-aldol product we followed our methodology wherein the reaction involves lipase-catalysed in situ generation of acetaldehyde from vinyl acetate which in presence of organocatalyst (R-a,a-Bis[3,5-bis (trifluormethyl) phenyl]-2-pyrolidinemethanol) reacts with aromatic aldehydes to give highly enantiopure cross-aldol products 4aef [14,15]. The hydroxy groups of cross aldol products were protected as their TBS ethers using TBDMSCl and imidazole in DCM at 0 C to give 5aef.…”

“…This may have been a reason that analogues without epoxide chain haven't been reported so far. We reasoned that our method employing vinyl acetate as a precursor to acetaldehyde to access b-hydroxy aldehyde could prove handy [14,15].…”

Synthesis, Crystal Structure and in vitro DNA Binding Studies of Combretastatin A-4 Analogue

“…Computational studies through molecular docking are an attractive tool to probe the mechanistic details [33] and mode of interaction between biopolymers and bioactive compounds. Docking studies were attempted to establish the type and the magnitude of interaction between the compound 1 and the CT DNA.…”