Catalytic enantioselective oxa-hetero-Diels–Alder reactions of enones with aryl trifluoromethyl ketones

Tetrahydropyranones and tetrahydropyrans are important structures found in bioactive natural products and pharmaceutical leads. Incorporation of the triuoromethyl group has been shown to favour bioactivity, therefore concise routes to tetrahydropyranone and tetrahydropyran derivatives bearing a triuoromethyl group are of interest. To synthesize functionalized tetrahydropyranones, we have recently developed enantioselective oxa-hetero-Diels–Alder reactions of enones with isatins that are catalyzed by amine-based catalyst systems. In the reactions, enamines of enones are formed in situ, and the enamines act as dienes of the [4 + 2] cycloaddition resulting in the formation of the tetrahydropyranones under mild conditions. Based on these studies, we reasoned that oxa-heteroDiels–Alder reactions of enones with triuoromethyl ketones would provide access to triuoromethyl-substituted tetrahydropyran derivatives. However, direct use of enones as diene precursors to form tetrahydropyranones is still a challenge; reported reactions of enones with ketones or aldehydes oen give aldol products as the main product or as a signicant byproduct. That is, formation of oxa-hetero-Diels–Alder reaction product is not promised in the reactions of enones with ketones or aldehydes as dienophiles either in racemic or highly enantioselective versions. Here, we report enantioselective oxahetero-Diels–Alder reactions of enones with aryl triuoromethyl

Tetrahydropyranones and tetrahydropyrans are important structures found in bioactive natural products and pharmaceutical leads. 1,2 Incorporation of the triuoromethyl group has been shown to favour bioactivity, 3 therefore concise routes to tetrahydropyranone and tetrahydropyran derivatives bearing a triuoromethyl group are of interest. To synthesize functionalized tetrahydropyranones, we have recently developed enantioselective oxa-hetero-Diels-Alder reactions of enones with isatins that are catalyzed by amine-based catalyst systems. 2 In the reactions, enamines of enones are formed in situ, and the enamines act as dienes of the [4 + 2] cycloaddition resulting in the formation of the tetrahydropyranones under mild conditions. 2 Based on these studies, we reasoned that oxa-hetero-Diels-Alder reactions of enones with triuoromethyl ketones would provide access to triuoromethyl-substituted tetrahydropyran derivatives. However, direct use of enones as diene precursors to form tetrahydropyranones is still a challenge; reported reactions of enones with ketones or aldehydes oen give aldol products as the main product or as a signicant byproduct. 4 That is, formation of oxa-hetero-Diels-Alder reaction product is not promised in the reactions of enones with ketones or aldehydes as dienophiles either in racemic or highly enantioselective versions. 2,5 Here, we report enantioselective oxahetero-Diels-Alder reactions of enones with aryl triuoromethyl ketones that afford triuoromethyl-substituted tetrahydropyranones (Scheme 1).
First, we screened catalyst systems for the reaction of enone 1a with ketone 2a to form triuoromethyl-substituted tetrahydropyranone product 3aa (3aa-1 and/or 3aa-2). Selected results are shown in Table 1. Previously reported catalyst systems (such as A-B, A-B-C, and D-B) for the reactions of enones with isatins to afford tetrahydropyranones in high enantioselectivity 2 did not work efficiently for the reaction with ketone 2a; the use of these catalysts signicantly generated aldol product 4aa with oxa-hetero-Diels-Alder product 3aa (Table 1, entries 1-3). The best results for the formation of 3aa with high enantioselectivity (er 97 : 3 for 3aa-2) were obtained when the reaction was performed in the presence of proline-derived catalyst L and DABCO (K) in toluene at rt (25 C) ( Table 1, entries 11 and 12). The reaction using less loading of L (0.1 equiv.) with K (0.2 equiv.) gave essentially the same results as the reaction using L (0.2 equiv.) and K (0.2 equiv.) (Table 1, entry 12 versus entry 11). The major diastereomer (i.e., 3aa-2) obtained under the catalysis by L-K differed from that obtained under the catalysis by A-B (Table 1, entries 11 and 12 versus entry 1).
products, and tetrasubstituted carbon centers were concisely constructed ( Table 2). The reactions of phenyl triuoromethyl ketones bearing electron-withdrawing substituents on the phenyl group (such as the formation of 3ad) were faster than the reactions of those bearing electron-donating groups (such as the formation of 3af). In all cases shown in Table 2, the formation of the aldol product was negligible (3 : 4 were >95 : 5 or 95 : 5).
The catalyst system was useful for the reactions of b-alkyl substituted enones and also b-aryl substituted enones to afford the hetero-Diels-Alder reaction products with high enantioselectivities for the major product diastereomers. This is signicant because previously reported conditions for the hetero-Diels-Alder reactions of b-alkyl substituted enones oen do not work for the b-aryl substituted enones. 2,5c Further, the reaction using the L-K catalyst system was easily scaled up: a 1.0 mmol-reaction to form 3bb gave the major isomer, 3bb-2, as a single diastereomer (purity >95%) in 61% yield with er 92 : 8.
When a mixture of 3aa and 4aa (racemic, 3aa/4aa ¼ 2.5 : 1, 3aa-1 : 3aa-2 ¼ 3 : 1) was treated under the hetero-Diels-Alder reaction conditions with the L-K catalyst system, no decomposition of the compounds and no changes in the ratios were detected. This indicates that product 3aa is stable under the L-K catalyst system and that aldol 4aa is not converted to 3aa in the presence of this catalyst system. Thus, the formation of 3aa under the L-K catalyst system is likely a kinetically controlled [4 + 2] cycloaddition reaction of in situ-generated enamine of enone 1aa with ketone 2aa. Table 1 Screening of catalyst systems in the hetero-Diels-Alder reaction of 1a and 2a a
To demonstrate the use of the hetero-Diels-Alder reactions, the product tetrahydropyranones were transformed into tetrahydropyran derivatives (Scheme 2). Oxime formation, reductive amination, and allylation gave the corresponding products 5-8. The triuoromethyl-substituted tetrahydropyranones and tetrahydropyran derivatives that can be synthesized by the methods described here may be useful in the search for biofunctional molecules.
In conclusion, we have developed an organocatalytic enantioselective oxa-hetero-Diels-Alder reaction of enones with aryl triuoromethyl ketones that afford triuoromethyl-substituted tetrahydropyranones, which uses novel amine-based catalyst systems. Tetrasubstituted carbon centers bearing a tri-uoromethyl group were concisely constructed with the formation of the tetrahydropyranone ring. We have also demonstrated that the hetero-Diels-Alder products can be transformed further to various triuoromethyl-substituted tetrahydropyran derivatives.