Lipase/Oxovanadium Co-Catalyzed Dynamic Kinetic Resolution of Propargyl Alcohols: Competition between Racemization and Rearrangement

Abstract

Quantitative conversion of racemic propargyl alcohols into optically active propargyl esters with up to 99% ee has been achieved by lipase/oxovanadium co-catalyzed dynamic kinetic resolution, which combines the lipase-catalyzed enantioselective esterification of the racemic substrates and the in situ racemization of the remaining enantiomers. The success is owed to our discovery of a magic solvent, (trifluoromethyl)benzene, that accelerated the racemization while sufficiently suppressing the common oxovanadium-catalyzed rearrangement of propargyl alcohols to irreversibly produce enals.

Diastereoselective Synthesis of Terminal Bromo-Substituted Propargylamines via Generation of Lithium Bromoacetylide and Addition to Chiral N-tert-Butanesulfinyl Aldimines

“…Prior to further optimization, we confirmed the stereochemistry of the major diastereomer of 2a through conversion to known terminal alkyne 3a via reaction of 2a with nBuLi to affect lithium−halogen exchange, followed by an acidic quench (see Scheme S2). Comparison of 1 H/ 13 C NMR spectra and optical rotation value to previously reported experimental data 17 confirmed the stereochemical assignment shown in Table 1.…”

“…11 Finally, as shown in Scheme 1c, even reported syntheses of racemic terminal bromo-substituted propargylamines require multiple steps. For example, Honda and co-workers utilized a synthetic route starting from the corresponding propargylic alcohol, 5 which is typically prepared in one 12 or two 13 steps from commercially available materials. Transformation of propargylic alcohol to propargylamine was accomplished via FeCl 3 -catalyzed nucleophilic substitution with p-toluenesulfonamide, 14 which was followed by bromination with NBS in the presence of catalytic AgNO 3 .…”

Progress on the Stereoselective Synthesis of Chiral Molecules Based on Metal-Catalyzed Dynamic Kinetic Resolution of Alcohols with Lipases

“…Stepwise addition of both the catalysts during the reaction allowed to overcome the inactivation of the enzyme due to long reaction times (312 h). The DKR of propargylic alcohols carried out in (trifluoromethyl)benzene or MeCN as solvents, led to the corresponding (R)-esters with high selectivity (15 examples, 70-99%, 81-99% ee) (Scheme 9) [44]. The choice of the solvent was crucial to reduce or totally suppress the formation of the unsaturated aldehyde which can form as a by-product.…”

Direct Nucleophilic Substitution of Alcohols Using an Immobilized Oxovanadium Catalyst

“…[20] VMPS4 was highly compatible with lipase and also exhibited excellent activity in the DKR of allyl, propargyl, and benzyl alcohols (Figure 1b). [21][22][23][24][25][26][27][28] We speculated that the racemization by VMPS4 in these reactions proceeded via a cationic intermediate generated due to CÀ O bond cleavage in the substrate alcohols. [21] Considering this, we envisioned that VMPS4 could also catalyze the direct substitution of alcohols in the presence of an appropriate nucleophile in the reaction medium.…”