Chinese Chemical Letters  2018, Vol. 29 Issue (11): 1625-1628   PDF    
Organocatalytic asymmetric cascade cyclization reaction of o-hydroxy cinnamaldehydes with diphenylphosphine oxide
Haiyun Suna, Yuan Lia, Wei Liua, Yang Zhenga, Zhengjie Hea,b    
a The State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China;
b Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Tianjin 300071, China
Abstract: A highly stereoselective asymmetric cascade cyclization reaction between o-hydroxycinnamaldehydes and diphenylphosphine oxide has been achieved with 84%-99% ee and 7:1-20:1 dr under the catalysis of L-diarylprolinol silyl ether. This reaction provides a facile access to highly enantioenriched 4-diphenylphosphinyl chroman-2-ols. It also represents a novel organocatalytic asymmetric phosphaMichael addition of α, β-unsaturated aldehydes with pentavalent P-nucleophiles.
Keywords: Organocatalysis     Asymmetric catalysis     Cyclization reaction     Phospha-Michael addition     Cascade reaction    

Asymmetric organocatalysis has experienced rapid development since the beginning of this century. It has therefore been established as the third pillar of asymmetric catalysis [1-5]. The expansion of the field has led to a large number of efficient types of catalysts. Among them, one group of chiral secondary amines, diarylprolinol silyl ethers, which was first introduced in 2005 [6], has been recognized as one of the most frequently used in asymmetric aminocatalysis. By the number of publications on chiral amine-catalyzed asymmetric reactions, diarylprolinol silyl ethers are undoubtedly the most popular and efficient catalysts for highly enantioselective transformations of common carbonyl compounds such as aldehydes and ketones [7, 8]. Accordingly, the diarylprolinol silyl ether-catalyzed asymmetric reactions provide effective access to optically active functionalized carbonyl compounds that are a class of basic and versatile materials in organic synthesis.

Organophosphorus compounds are widely found in nature and possess significant, and in many cases, very specific biological activity that is often related to their absolute stereochemistry [9, 10]. Also, chiral organophosphorus compounds are very useful in asymmetric synthesis as ligands, catalysts, and reagents [11-14]. Thus, there is a great need for the development of methods enabling their preparation in an asymmetric fashion. The asymmetric phospha-Michael addition reaction constitutes one of the most important synthetic methods for enantioenriched phosphorus compounds containing P—C bond [15-17]. In the last decade, besides in the metal-catalyzed asymmetric phospha-Michael reactions [17-19], remarkable progress has also beenmade in the organocatalytic asymmetric phospha-Michael reactions by utilizing both trivalent and pentavalent phosphorus species as Michael donors [16]. As the first example of organocatalytic, enantioselective phospha-Michael addition, the reaction of nitroalkenes and trivalent diphenylphosphine was developed by Melchiorre et al. with the cinchona alkaloid derived thiourea employed as the catalyst [20]. Under the catalysis of diarylprolinol trimethylsilyl ethers, a highly enantioselective hydrophosphination of α, β-unsaturated aldehydes with diphenylphosphine was also subsequently achieved independently by two research groups [21, 22]. This catalytic protocol was even successfully extended to the enantioselective β-phosphonylation of α, β-unsaturated alde hydes with trivalent trialkylphosphites [23]. However, the asymmetric phospha-Michael addition of α, β-unsaturated aldehydes with pentavalent phosphorus species has met little success yet [24], although its analogues of nitroalkenes with pentavalent diarylphosphine oxides or diphenoxyphosphine oxide were successfully achieved by using basic chiral guanidines [25, 26], quinine [27] or squaramide [28] as the catalysts.

Recently, asymmetric Michael addition-cyclization cascade reactions of o-hydroxycinnamaldehydes with C-nucleophiles like nitromethane and malonates were realized under the catalysis of diphenylprolinol trimethylsilyl ether by Kim et al. [29, 30]. These reactions afforded 4-substituted chroman-2-ols in high enantioselectivities (up to >99% ee for the reduced products) but low diastereoselectivities (dr values < 2:1) (Scheme 1, Eq. (1)). Inspired by Kim's work, and also as part of our continuous efforts to develop new cascade reactions [31, 32], we recently developed a highly enantio- and diastereoselective phospha-Michael additioncyclization cascade reaction of o-hydroxycinnamaldehydes with diphenylphosphine oxide by using the similar diarylprolinol silyl ether catalyst (Scheme 1, Eq. (2)). Herein we report the relevant results.

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Scheme 1. Organocatalytic asymmetric Michael addition-cyclization cascade reaction of o-hydroxycinnamaldehydes with nucleophiles.

We started our investigations with the model substrates o hydroxycinnamaldehyde 1a and diphenylphosphine oxide 2a (Table 1). Gratifyingly, an expected cyclization product 3a was obtained from the reaction of 1a (0.5 mmol) and 2a (0.75 mmol) under the catalysis of diphenylprolinol trimethylsilyl ether (10 mol %) in 71% isolated yield and 92% ee (Table 1, entry 1). Also, 31P NMR measurement indicated that the diastereomeric ratio (dr) of 3a was greater than 20:1 (Table 1, footnote d). This reaction thus unveiled a novel asymmetric phospha-Michael addition of α, β-unsaturated aldehydes with pentavalent phosphorus species. It also disclosed an easy access to 4-diphenylphosphinyl chroman-2-ols. The conditions of the model reaction were therefore screened further. According to previous reports [25-28], the phospha-Michael addition reactions of pentavalent phosphorus nucleophiles generally required a basic reaction condition. The basic additives sodium carbonate and sodium acetate were then tested. Additions of such bases (0.25 mmol) enhanced the yields but slightly lowered the ee values (Table 1, entries 2–3). Running the reaction at a low temperature (-10 ℃) resulted in a substantially lowered yield although the enantioselectivity was to some degree improved (Table 1, entry 4). Other catalysts (Ⅱ–Ⅳ) with varied R groups were further evaluated (Table 1, entries 5–8). Under the similar conditions, the catalyst diphenylprolinol triethylsilyl ether afforded product 3a in 88% yield and 91% ee; while the catalyst diphenylprolinol tert-butyldimethylsilyl ether gave 3a in 73% yield and 95% ee (Table 1, entries 5 and 6). The use of the additive sodium acetate further enhanced the yield and enantioselectivity (Table 1, entry 7). Finally, the precursor of catalysts , diphenylprolinol (), was proven to be completely ineffective in this cyclization reaction, presumably due to its free hydroxyl-involved concomitant formation of an oxazolidine species [6].

Table 1
Screening of the reaction conditions of the model reaction of 1a and 2a a.

With the catalyst and the additive sodium acetate employed, several solvents were further examined (Table 1, entries 9–13). All reactions run in a solvent like CHCl3, CH3CN, toluene, or i-PrOH uneventfully delivered the cyclization product 3a in 67%–77% yields and 91%–95% ee (Table 1, entries 9–12). It was surprising that solvent THF was detrimental for this reaction; the reaction run in THF failed to give any expected product 3a under otherwise similar conditions (Table 1, entry 13). Notably, in the Kim's work, the use of solvent THF was also avoided [29, 30]. According to the above results, the reaction conditions for Table 1, entry 7 were chosen as the preferred with regard to the enantioselectivity.

Under the preferred conditions, the substrate scope of the cascade cyclization was further investigated with respect to o-hydroxycinnamaldehydes 1 (Table 2). A series of differently substituted o-hydroxycinnamaldehydes 1 with electron-donating or electron-withdrawing groups at the benzene ring smoothly afforded the corresponding 4-diphenylphosphinyl chroman-2-ols 3 in moderate to good yields and in high stereoselectivities (Table 2, entries 1–11). In all cases, the enantioselectivity varied from 84% ee to >99% ee and the diastereoselectivity was in the range of 7:1 dr to >20:1 dr. Thus, this organocatalytic asymmetric cascade cyclization reaction of o-hydroxy cinnamaldehydes 1 with diphenylphosphine oxide 2a provides a highly enantio- and diastereo-selective access to 4-diphenylphosphinyl functionalized chroman-2-ols. In a sharp contrast, those similar asymmetric cascade cyclization reactions of o-hydroxycinnamaldehydes with C-nucleophiles like nitromethane and malonates were poorly diastereoselective with dr values being lower than 2:1 [29, 30]. Since product 3 has a hemiacetal structure that is unstable under the HPLC measurement conditions, product 3 was transformed into its corresponding stable acetate by acetylation with acetic anhydride (vide infra) before it was subjected to chiral HPLC measurement (Table 2, footnote c). The dr of product 3 was conveniently determined by 31P NMR assay.

Table 2
Organocatalytic asymmetric cascade cyclization reaction of o-hydroxy cinnamaldehydes 1 with diphenylphosphine oxide 2a a.

Under the standard conditions as shown in Table 2, the reaction of asymmetric (o-anisyl)phenylphosphine oxide (2b) with o-hydroxycinnamaldehyde 1a was further investigated, readily delivering the corresponding cyclization product 3l in 84% yield as a pair of separable diastereomers 3l-1 and 3l-2 with a 1:1 ratio and 85%–94% ee (Scheme 2). Although the absolute configuration of the chiral phosphorus in 3l has not been identified yet, this reaction certainly discloses a facile access to functionalized Pchiral phosphine oxides.

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Scheme 2. An organocatalytic cascade cyclization of 1a and 2b.

The structures of products 3 were identified by 1H, 13C NMR and HRMS analyses. The structural assignments of products 3 were further confirmed by the single-crystal X-ray analysis of compound 3a (CCDC 1814256). On the basis of its X-ray diffraction structure, product 3a has the (2R, 4S) absolute configuration (the crystal structure and data of 3a are available in the Supporting information).

According to the previous reports [7, 8, 29] and our results obtained in this study, a plausible mechanism for this organocatalytic asymmetric cascade cyclization reaction is depicted in Scheme 3. It is most likely that this cyclization proceeds through a sequence of phospha-Michael addition-intramolecular hemiacetalization. Initially, o-hydroxy-cinnamaldehyde like 1a is activated by the chiral secondary amine catalyst to form an iminium ion intermediate A. Under the aid of the in situ generated base hydroxyl anion, intermediate A engages in a stereoselective phospha-Michael addition with diphenylphosphine oxide 2a to generate enamine intermediate B. Through a proton transfer, intermediate B is subsequently transformed into intermediate C, which undergoes an intramolecular nucleophilic addition followed by hydrolysis to furnish product like 3a and regenerate the catalyst (Scheme 3).

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Scheme 3. A plausible mechanism for the cascade cyclization.

Derivatization of the cyclization products 3 was further investigated (Scheme 4). As mentioned above, compound 3 was acetylated prior to its HPLC measurement of ee value (a typical procedure of the acetylation is provided in the Supporting information). As demonstrated in Scheme 4, Eq. (1), compound 3a was readily converted into its corresponding acetate 4a in 80% isolated yield. 31P NMR assay of 4a indicated that the dr value almost kept intact in this course.

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Scheme 4. Derivatization of products 3.

Considerring the biological importance of indole derivatives [33], we intended to prepare 2-(3-indolyl)chromans from the cyclization products 3 by a BF3-catalyzed Friedel-Crafts alkylation reaction [34]. Following a reported procedure [34], selected 3a and 3g (0.1 mmol) were respectively treated with 1-benzyl-5-methoxy indole (0.3 mmol) in the presence of BF3 etherate (0.1 mmol) at r.t. for 10 h. Unexpectedly, two ring-opening products 5a and 5g were collected in high yields (Scheme 4, Eq. (2)). For relevant experimental details, see the Supporting information). Presumably, these two compounds were generated from double FriedelCrafts alkylations.

The characterization data of compounds 3, 4a, and 5 are also provided in the Supporting information.

In conclusion, an organocatalytic asymmetric phospha-Michael addition-hemiacetalization cascade cyclization reaction of o-hydroxycinnamaldehydes with pentavalent diphenylphosphine oxide was developed for the first time, producing 4-diphenylphosphinyl chroman-2-ols in high enantio- and diastereoselectivities. Through easy derivatization of the cyclization products, this reaction also provides an effective route to synthesize other chiral organophosphorus compounds.

Acknowledgment

Financial support from the National Natural Science Foundation of China (Nos. 21472096, J1103306) is gratefully acknowledged.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.cclet.2018.01.026.

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