Enantioselective annulation of enals with 2-naphthols by triazolium salts derived from l-phenylalanine

The annulation reaction between enals and 2-naphthols catalyzed by a novel NHC affords enantioenriched β-arylsplitomicins in good yields and enantioselectivity.

The naphthopyran-3-one core is a characteristic structural motif existing in a variety of biologically active natural products and pharmaceuticals ( Fig. 1). 1 Specically, b-arylsplitomicin and its analogues have recently been extensively investigated and they were found to exhibit highly interesting biological activities such as recombinant SIRT2 inhibition, antiproliferative properties and tubulin hyperacetylation in MCF7 breast cancer cells. 1c-e,g Moreover, they are also important synthetic intermediates in both organic synthesis and medicinal chemistry. Consequently, various approaches to access these b-arylsplitomicin scaffolds have been established. Although the synthesis of racemic b-arylsplitomicin derivatives has been extensively carried out, 2 limited progress on the synthesis of enantioenriched b-arylsplitomicins has been reported. 1g, 3 In 2008, Jung and coworkers reported a cyclization of b-naphthol with propiolic acid, followed by a chiral rhodium-catalyzed conjugated addition of arylboronic acids to benzo [f]chromen-3-one, delivering the b-arylsplitomicin in excellent enantioselectivity but with poor yield (18%). 1g Lately, Zhang and Feng employed a chiral bifunctional thiourea-tertiary amine-catalyzed annulation between b-naphthols and akylidene Meldrum's acids to afford b-arylsplitomicins in good yields but with moderate enantioselectivity. 3a Recently, N-heterocyclic carbene (NHC) 4 -catalyzed reactions involving a,b-unsaturated acyl azolium intermediates generated from enals, 3b,5 ynals, 6 a-bromoenals, 7 a,b-unsaturated acyl uorides, 8 a,b-unsaturated esters, 8a,9 and a,b-unsaturated carboxylic acids 10 have received great attention and enjoyed rapid development. In 2009, Bode and coworkers reported an elegant work on the NHC-catalyzed enantioselective Claisen rearrangement of ynals and 2-naphthols, affording b-phenylsplitomicin in 79% yield with 68% ee. 3b,c Later, the asymmetric annulation of 2-bromoenals and b-naphthols was also realized by Biju and coworkers to deliver b-phenylsplitomicin in moderate yield and enantioselectivity. 3d Despite these pioneering studies, highly enantioselective synthesis of b-arylsplitomicins by NHC catalysis remains to be an unsolved project (Fig. 2). In particular, the chemoselectivity of annulation over ester byproduct formation is responsible for the low yield of the desired splitomicin product. As part of our continuous interest  in NHC catalysis, 5d,11 we envisioned that the introduction of novel chiral triazolium salts might provide a solution for this highly challenging but interesting reaction. In this paper, we report the synthesis of novel NHCs derived from L-phenylalanine and their excellent performance in the annulation reaction of enals with 2-naphthols. 5 Our study began with the preparation of a series of triazolium salts from the commercially available methyl L-phenylalaninate hydrochloride (Scheme 1). The synthesis commenced with the transformation of L-phenylalaninate hydrochloride to the lactam. 12 The addition of a Grignard reagent to the ester group in lactam 1 and protection of the hydroxyl group by TMSOTf or TBSOTf afforded the corresponding silyl ethers. 13 Several homologous triazolium salts 4a-4g were then prepared by following the procedures developed by Rovis and coworkers. 14 Desilylation of 4a-4b under acidic reux conditions gave triazolium salts 5a-5b bearing a free hydroxyl group. 15 Furthermore, the structure of 4a was conrmed by an X-ray crystallographic analysis as shown in Scheme 1.
With these triazolium salts in hand, we began to test their catalytic activity in the annulation reaction between 3-methylnaphthalen-2-ol (6a) and (E)-3-(4-methoxyphenyl)acrylaldehyde (7a). To our delight, in the presence of 10 mol% N-Mes substituted triazolium salt 4a, 20 mol% DBU and 1 equivalent of quinone 8 as oxidant in THF, the reaction proceeded smoothly to afford the corresponding b-arylsplitomicin in 68% yield and 78% ee, along with 24% yield of byproduct ester 10a (Table 1,  entry 3). Interestingly, the enantioselectivity obtained by 4a is much higher than those obtained by previously reported NHC precursors A and B (Table 1, entries 1-2). The ee value of the product could be further increased to 84% ee when 1 equivalent of 7a was used (Table 1, entry 5). However when 7a was used in excess, it was difficult to isolate 9a from the reaction mixture due to the similar R f value between 7a and 9a. Other NHC precursors with different substituents were then investigated. As summarized in Table 1, NHC precursors 4b and 4c, bearing 4-MeOC 6 H 4 and C 6 H 5 groups on the N atom, respectively, gave moderate enantioselectivity and low conversions (Table 1, entries 7-8). In the presence of NHC precursors either bearing an electron-withdrawing group such as 3,5-(CF 3 ) 2 C 6 H 3 (4d) and C 6 F 5 (4e) or a TBS-protected hydroxyl group (4f, 4g), this annulation reaction became sluggish and only gave trace amounts of the desired product (Table 1, entries 9-12). Notably, NHC precursor 5a bearing a free OH group gave comparable results (Table 1, entry 5 vs. entry 13). 15 With 4a as the NHC precursor, further optimization of the reaction conditions was carried out. The results are summarized in Table 2. Various solvents such as THF, toluene, CH 2 Cl 2 , ether and dioxane were tolerated well, providing the desired product in moderate to good yields and enantioselectivity. The reaction in THF gave the highest ee (Table 2, entry 1, 61% yield, 84% ee), although toluene gave a higher yield (Table 2, entry 2, 83% yield, 74% ee). Lowering the reaction temperature to 0 C led to an increased yield and ee ( Table 2, entry 8, 72% yield, 85% ee).
In order to determine the absolute conguration of the products, a crystal of enantiopure 9h was obtained and X-ray crystallographic analysis determined its conguration as R.
To our great delight, when an ynal or 2-bromoenal was used, this annulation reaction occurred without external oxidant to give comparable results by running the reaction at room temperature (eqn (1) and (2)).
(1) (2) In order to shed light on the reaction mechanism, 16 compound 10o was synthesized and subjected to the identical reaction conditions. Product 9o was isolated in 22% yield with 48% ee aer 7 days at room temperature, along with 6h in 44% yield (eqn (3)). In addition, real time monitoring of the reaction of 6a with 7a by 1 H NMR showed that there was little change in the ratio of product 9a to byproduct 10a during the progress of the reaction, which suggested that an a,b-unsaturated acyl azolium intermediate is directly generated from the enal with the NHC and oxidant rather than from byproduct 10a (see the ESI † for details).
A gram-scale reaction between 6h and 7a was carried out to give the desired product in 85% yield and 93% ee without any

Conclusions
We have synthesized a series of novel chiral triazolium salts derived from L-phenylalanine. The NHC derived from 4a is found to be a highly efficient catalyst for annulation of enals with 2-naphthols under oxidative conditions. Structurally diverse b-arylsplitomicins were formed in good yields with up to 96% ee. Understanding the excellent performance of these novel triazolium salts and further exploration of their application in asymmetric reactions are currently underway in our lab.