Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols

Abstract

Although chiral allene preparation via formal S_N2' nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown. Here, we show that a highly enantioselective synthesis of tetrasubstituted allenes from racemic propargylic alcohols has been realized by organocatalysis with good efficiency (up to 96% yield and 97% ee). The intermolecular C-C and C-S bond formation was achieved efficiently with simultaneous stereocontrol over the axial chirality. Furthermore, an adjacent quaternary stereocenter could also be constructed. Mechanistically, the reaction may involve efficient stereocontrol on the propargylic cation by its chiral counter anion or 1,8-conjugate addition of para-quinone methides. In sharp contrast to previous central chirality construction, this process employs quinone methides for axial chirality construction.Axially chiral allenes that are normally present in natural products, bioactive molecules, organocatalysts, and functional materials are usually produced from propargylic derivatives. Here, the authors show direct use of propargylic alcohols for catalytic asymmetric allene synthesis.

Fig. 1

Strategies for the asymmetric synthesis of allenes and representative axially chiral allenes. a Previous approaches to the enantioselective synthesis of allenes, which are largely limited to the formation of di- or trisubstituted allenes. Compared with other methods, organocatalytic approaches still remain underexplored and are largely limited to allenaoates. b Useful chiral tetrasubstituted allenes and an allene bearing adjacent quaternary stereocenter

Fig. 2

Chiral allene synthesis from propargylic compounds. a Well-established formal SN2′ reactions from enantioenriched propargylic derivatives. b A rare metalyzed-catalyzed example from racemic propargylic derivatives. c Our design of an organocatalytic approach from racemic propargylic alcohols

Fig. 3

Allene formation with 1,3-dicarbonyl nucleophiles. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol for 3a–3j; 0.6 mmol for 3k–3p), (R)-A1 (0.01 mmol), CCl₄ (4.0 mL), −20 °C (3a–3g) or 0 °C (3k–3p), 0.5–30 h. *Isolated yield. ^†Determined by ¹H NMR analysis. ^‡Determined by HPLC with a chiral stationary phase. ^§Run at room temperature with anhydrous MgSO₄ (200 mg) as additive. ^#Run at −15 °C. ^¶Run at 0 °C. PMP p-MeOC₆H₄

Fig. 4

The rate difference between 1i and 1i’ with thioacetic acid nucleophile and the proposed intermediates. When R≠H, the reaction may proceed via ion pair OX, while when R=H, the para-quinone methide QM activated by hydrogen bonding might be involved

Fig. 5

Formation of allenes 5w–z. Reaction was carried out with 1 (0.3 mmol), 4 (0.6 mmol), catalyst B1 (5 mol%), and 3 Å MS (90 mg) in solvent (6.0 mL, CCl₄ for 5w, x and CH₂Cl₂ for 5y, z) at −5 °C. *Run without 3 Å MS. ^†Run with A7 at −15 °C

Fig. 6

Representative product transformations and mechanistic studies. a Triflation of the free hydroxy group (Eq. 2), transformation of the thioacetate moiety to a sulfone unit (Eq. 3), and NIS-mediated cyclizations of the chiral tetrasubstituted allenes proceed via the axial-to-central chirality transfer (Eqs. 4–5). b Important molecules bearing chiral indene or indane units. c Control experiments and possible mechanism. The reactions suggest that the 1,8-addition to p-QM is rate-determining (Eq. 6) and the conjugate addition step is irreversible (Eq. 7). The product stereochemistry was purely determined by the chiral catalyst, regardless of the absolute configuration of substrate (Eqs. 8–9), which rules out the possible S_N2’ pathway (via TS1). d Kinetic study indicated that the reaction is first-order in catalyst, suggesting that one catalyst molecule is involved in the rate-determining transition state