Metal‐Triflate‐Catalyzed Synthesis of Polycyclic Tertiary Alcohols by Cyclization of γ‐Allenic Ketones

Abstract

It has been established that bismuth(III) triflate catalyzes the cyclization of g-allenic ketones under mild reaction conditions. This reaction allows the selective formation of polycyclic tertiary alcohols from cyclic ketone derivatives. The resulting dienols can engage in stereoselective cycloadditions to efficiently afford complex polycyclic systems.Complex polycyclic molecules have always fascinated organic chemists, and their rapid, reliable, and efficient synthesis constitutes a motivating challenge to accept. Cycloisomerization reactions are undoubtedly powerful and provide a sustainable means to generate molecular complexity with good control of selectivity.[1] In this context, the intramolecular carbonyl-ene reaction represents a very useful tool for the efficient formation of substituted cyclohexanols, [2] and has been widely used in natural product synthesis. Because of the relatively high energetic barrier, carbonyl-ene processes often require high temperatures or the employment of Lewis acids, usually in excess (Prins reaction). Despite its reliability, this reaction presents some important limitations, such as the difficulty in forming five-membered rings because of the higher cyclization energy requirement induced by geometric factors. In addition, ketones are intrinsically much poorer enophiles than aldehydes in these reactions. Cyclizations involving ketone derivatives have been reported [3] and include highly activated ketones such as trifluoromethylketones [4] or a-ketoesters.[5]The cyclization of carbonyl-allene compounds has been mainly studied under thermal, [6] radical, [7] and transitionmetal-catalyzed [8] processes. Herein we present our results concerning the metal-triflate-catalyzed cyclization of g-allenic ketones. We anticipated that allenes could be used as ene components to bias the geometric cyclization for the formation of five-membered rings. Moreover, the higher reactivity of allenes, as compared to alkenes, should allow the reaction with ketones to proceed under mild reaction conditions. We first used the acyclic b-ketoester 1 bearing a pendant trisubstituted allene as a model and assessed its reactivity towards various metal triflate catalysts in nitromethane (Table 1, entries 1-4). A rapid screening highlighted nonexpensive bismuth(III) triflate [9,10] as a very active catalyst at low loading with the total conversion of 1 occurring at À20 8C. Switching solvents from nitromethane to CH 2 Cl 2 considerably slowed down the reaction rate and led to the isolation of the cyclopentadienes 2 b and 2 c in good yield (88 %) at room temperature by using only 1 mol % of bismuth(III) triflate (entry 5). The formation of 2 b could arise from the elusive ene product 2 a undergoing an elimination reaction. Hydration of compound 2 b could lead to the tertiary alcohol 2 c.To prevent the elimination of the alcohol in 2 a, a reaction which is possibly favored by the position of OH group b to the ester, the reactivity of the allenic cyclohexanone derivative 3 was examined (Scheme 1)....

Calcium‐Catalyzed Formal [2+2+2] Cycloaddition

“…The second mechanistic proposal then proceeds with a carbonyl allene ene reaction yielding alcohol 10. [8] This alcohol assumes a helical conformer in which the alcohol moiety hovers either above or below the double bond depending on its stereocenter, so that a protonation of the double bond by the alcohol hydrogen atom, the acidity of which is significantly enhanced by coordination of the Ca 2 + Lewis acid, happens on the same side of the molecule (see Figure 1). Subsequent ring closure then yields the observed diastereomer via the all equatorial flattened chair-like transition state TS alkoxy .…”