Enzymatic Bromocyclization of α- and γ-Allenols by Chloroperoxidase from Curvularia inaequalis

Abstract

Vanadate-dependent chloroperoxidase from Curvularia inaequalis catalyzes 5-endo-trig bromocyclizations of α-allenols to produce valuable halofunctionalized furans as versatile synthetic building blocks. In contrast to other haloperoxidases, also the more challenging 5-exo-trig halocyclizations of γ-allenols succeed with this system even though the scope still remains more narrow. Benefitting from the vanadate chloroperoxidase's high resiliency towards oxidative conditions, cyclization-inducing reactive hypohalite species are generated in situ from bromide salts and hydrogen peroxide. Crucial requirements for high conversions are aqueous biphasic emulsions as reaction media, stabilized by either cationic or non-ionic surfactants.

Keywords: allenes; cyclization; halogenation; haloperoxidase; heterocycles.

Scheme 1

Possible routes in enzymatic halocyclization of allenic alcohols.

Figure 1

Representative time course of the bromocyclization of 1 a catalyzed by CiVCPO. (▴)=c(bromodihydrofuran 2 a), (▪)=c(allenol 1 a). Conditions: allenol 1 a (25 mm), CiVCPO (0.015 nm), NaBr (75 mm), H₂O₂ (75 mm), CTAB (250 mm), 1 : 1 mixture of n‐hexane and citrate buffer (pH 5.0). Yields determined by NMR spectroscopy using dimethyl sulfone as internal standard.

Figure 2

Effect of pH on the bromocyclization of 1 a catalyzed by CiVCPO. Conditions: allenol 1 a (25 mm), CiVCPO (0.015 nm), NaBr (75 mm), H₂O₂ (75 mm), CTAB (250 mm), 1 : 1 mixture of n‐hexane and citrate buffer. Yields determined by NMR spectroscopy using dimethyl sulfone as internal standard.

Figure 3

Optimization of CiVCPO driven bromocyclization of allenic alcohol 1 a in micellar reaction medium consisting of 1 : 1 mixture of pH 5.0 citrate buffer and n‐hexane. Yields determined by NMR spectroscopy using dimethyl sulfone as internal standard. Conditions: c(allenol 1 a)=25 mm, c(CiVCPO)=0.015 nm, 18 h reaction time, [a] c(CTAB)=25 mm, c(H₂O₂)=75 mm, c(NaBr)=brown columns, [b] c(CTAB)=blue columns, c(H₂O₂)=75 mm, c(NaBr)=0 mm, [c] c(CTAB)=100 mm, c(H₂O₂)=green columns, c(NaBr)=0 mm.

Scheme 2

Substrate scope for CiVCPO catalyzed endo‐bromocyclization of α‐allenic alcohols. [a] The allenic substrate 1 e is 98 % syn.

Scheme 3

Substrate scope for CiVCPO catalyzed exo‐bromocyclization of γ‐allenols. Conditions: c(allenol)=25 mm, c(CTAB)=100 nm, [a] c(CiVCPO)=0.025 nm, c(H₂O₂)=75 mm, c(NaBr)=0 mm, [b] c(CiVCPO)=0.0625 nm, c(H₂O₂)=500 mm, c(NaBr)=500 mm. Parentheses indicate yields determined by NMR spectroscopy using dimethyl sulfone as internal standard.