The reductive aldol reaction between an α,β-unsaturated carbonyl compound and an aldehyde or ketone is a powerful method for stereocontrolled C-C bond formation [1]. These tandem reactions generally proceed via conjugate reduction of an enone or enoate followed by aldol reaction of the in-situ generated enolate with an aldehyde or ketone electrophile. By this way, the β-hydroxy carbonyl products with several contiguous stereocenters can be directly constructed in a one-pot fashion, thus providing an attractive alternative approach for stereocontrolled synthesis of aldols. Following the seminal studies by Revis and Hilty in 1987 [2], a variety of catalysts based on Rh [3], Co [4], Cu [5, 6], Ni [7], In [8, 9], Sn [10], etc. [11], have been developed for inter- or intramolecular reductive aldol reactions, wherein mostly silanes or molecular hydrogen [12], sometimes diethylzinc [13], or trialkylborane [7] were used as the stoichiometric reductants. The first example of the asymmetric reductive aldol reaction was reported by Morken et al. in 2000 [14], and since then a number of chiral metal-ligand complexes based on Ir [15], Rh [16, 17, 18, 19, 20, 21], or Cu [22, 23, 24, 25, 26, 27, 28, 29] have also been used as the catalysts to control the stereochemistry of the reactions, delivering various chiral aldol products with synthetically useful diastereo- and enantioselectivities. A notable progress in this area was made recently by Nakajima and coworkers [30, 31, 32, 33], who have developed highly enantio- and diastereoselective asymmetric reductive aldol reactions using chiral bisphosphine oxides as Lewis base catalysts. It is also noteworthy that over the decades, Lewis base catalysis has been established as an attractive and highly competitive alternative to the methods employing metal complexes, providing elegant solutions to numerous challenging organic transformations in general [34], and including the Mukaiyama aldol reactions in particular [35]. In this context, we recently reported the successful development of a class of spiro[4,4]- 1,6-nonadiene-based phosphino-oxazoline ligands/catalysts [36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47] and bisphosphine oxides (SpinPO) [48], and the use of SpinPO as chiral Lewis base catalysts in the direct asymmetric double-aldol reaction of ketones with aldehydes. As an ongoing effort to develop efficient Lewis base catalyzed asymmetric synthesis, herein we report a highly enantio- and diastereoselective reductive aldol reaction of enones and aldehydes with SpinPO as the catalyst and trichlorosilane as the reductant.
Unless otherwise noted, all reactions and manipulations involving air- or moisture-sensitive compounds were performed using standard Schlenk techniques or in a glovebox. All solvents were purified and dried using standard procedures. Melting points were measured on an RY-I apparatus and uncorrected. 1H, 13C, 31P, and 19F NMR spectra were recorded on Varian Mercury 300 MHz or 400 MHz spectrometers. Chemical shifts (δ values) were reported in ppm downfield from internal TMS (1H NMR), internal CDCl3 (13C NMR), external 85% H3PO4 (31P NMR), and external CF3CO2H (19F NMR), respectively. Optical rotations were determined using a Perkin Elmer 341 MC polarimeter. The IR spectra were measured on a Bruker Tensor 27 FT-IR spectrometer. ESI-MS and HRMS (ESI) spectra were taken on a Shimadzu LCMS- 2010EV and an Agilent Technologies 6224 TOF LC/MS spectrometer, respectively. HPLC analyses were performed on a JASCO 2089 liquid chromatograph. Trichlorosilane, the α,β- unsaturated ketones, and aldehydes were purchased from commercial sources and used without further purification.
The chiral SpinPO (S)-1a-c, (R)-1d-e, (-)-1f, and (S)-1g (Fig. 1) were synthesized by following our previously reported procedures [48].
To a Schlenk tube containing a stirred solution of the enone 2 (0.25 mmol), chiral phosphine oxide (S)-1c (15.1 mg, 0.025 mmol), and the aldehyde 3 (0.30 mmol) in anhydrous THF (1.0 mL) was added dropwise trichlorosilane (0.17 mL, 0.5 mmol) at -78 °C. The resultant yellowish emulsion was stirred at -78 °C for 24 h, and the reaction was quenched by saturated aqueous sodium bicarbonate solution (5.0 mL). The mixture was stirred for 0.5 h at this temperature, warmed to r.t., and stirred for further 0.5 h, and the solids were removed by filtration through a pad of celite. The filtrate was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and filtered. After removal of the volatiles under reduced pressure, the residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (15/1-10/1) as the eluents, to give the aldol product 4 as a diastereomeric mixture. The diastereomeric ratio (dr, syn/anti) and the enantiomeric excess (ee) values of the optically enriched 4a-q were determined by chiral HPLC, whilethe 1H, 13C, and 19F NMR spectral data were recorded on the diastereomeric samples of 4a-q obtained from the corresponding reductive aldol reactions catalyzed by racemic BINAP dioxide (BINAPO) or achiral triphenylphosphine oxide.
Nakajima et al. [30] have shown that trichlorosilane can be activated by an appropriate Lewis base to undergo conjugate reduction with an enone, and the in situ generated trichlorosilyl enolate may react with a coexisting aldehyde to give the reductive aldol product. Denmark et al. [49, 50, 51, 52] have extensively investigated the aldol additions of trichlorosilyl enolates derived from various carbonyl compounds and demonstrated that the reactions proceeded via the catalysis of some hypervalent silicon species stabilized by a suitable Lewis base. Inspired by these pioneering studies, we initiated the study by examining the viability of SpinPO catalysts of asymmetric reductive aldol reaction, using substoichiometric (S)-1a in the reaction of chalcone (2a) and benzaldehyde (3a) with two equivalents of trichlorosilane as the reductant. As shown in Table 1, a large variation in reactivity and stereoselectivity was observed, depending on the temperature, solvent, and/or catalyst loading used in the reactions. For the reactions performed in dichloromethane in the presence of 10 mol% of (S)-1a, varying the temperatures from -78 to -40 °C raised the yield of the aldol adduct 4a, but the diastereoselectivities (dr) were only modest (entries 1-3). Replacing dichloromethane with other types of aprotic polar or nonpolar solvents (entries 4-11) has been found to improve the dr values in most cases, but sometimes at a cost of poor conversion (entries 5, 9, and 10) or moderate ee values (entries 4 and 6). The coordinating ether THF and DME turned out to be the most favorable solvents for the reaction, affording preferentially syn-4a in good yields and high levels of diastereo- and enantioselectivities (entries 8 and 11). Further attempts to optimize the reaction by reducing the catalyst loadings of (S)-1a from 10 to 5 or 1 mol% were unsuccessful, resulting in poor yields and decreased dr and ee values (entries 12 and 13 vs 8). Thus, the optimized conditions as in entry 8 were used in subsequent catalyst survey studies.
To further optimize the reaction results, the family of SpinPO catalysts 1a-g was screened against reductive aldol reaction of chalcone (2a) and benzaldehyde (3a) using trichlorosilane as the reductant. The reactions were allowed to proceed in THF for 24 h at -78 °C in the presence of 10 mol% of 1a-g, and the relevant results are summarized in Table 2. Generally moderate to high yields (41%-86%) were obtained for the β-hydroxyketone 4a, whereas the sense and level of stereoselection fluctuated to some degree depending upon the SpinPO structure (entries 1-7). Both the steric effects and the skeleton flexibility in SpinPO structure appeared to be important for the diastereo- and enantioselectivity. While high diastereoselectivities (syn/anti ca 96/4) and excellent enantioselectivities (92%-94% ee) for syn-4a were reached in the cases of (S)-1a-c (entries 1-3), considerable losses in stereoselectivities were observed for the reactions catalyzed by (R)-1d-e with bulkier aryl substituents (entries 4 and 5). In contrast to flexible 1a-c with two methylene moieties between the spiro scaffold and the Ar2PO units, their structurally more rigid analogs 1f-g bearing only one or no flexible methylene group led to a substantial decline in enantioselectivities (entries 6 and 7 vs 1). Among the SpinPO family, (S)-1c was identified as the optimal Lewis base catalyst for the reaction, affording preferentially syn-4a in high levels of diastereo- and enantioselectivities (dr 96/4, 94% ee, entry 3).
The substrate adaptability of the protocol was evaluated with the reductive aldol reactions of chalcones (2a and 2c) or (E)-1- phenylbut-2-en-1-one (2b) and various aromatic, aliphatic, α,β-unsaturated, and heteroaromatic aldehydes (3a-p) using trichlorosilane as the hydride source. The reactions were performed in THF at -78 °C for 24 h using 10 mol% of (S)-1c as the catalyst, and the representative results were presented in Table 3. The β-hydroxyketone products 4a-r were obtained in 45%-88% yields, generally good to excellent diastereo- and enantioselectivities (dr 8/92-100/0, up to 95% ee for the syn-isomers). For the reactions of chalcone (2a) with the aromatic aldehydes 3a-j, steric properties of the aldehyde component seem to be less significant, as aldehydes 3a-f and 3j afforded the corresponding aldol products 4a-f and 4j with comparable stereoselectivities (dr 90/10-97/3, 78%-94% ee for the major syn-diastereomers), regardless of the o-, m-, or p-locations of the electron-donating substituent on their phenyl rings (entries 1-6 and 10). On the other hand, the electronic nature of the aldehydes appears to play a major role in determining the stereoselectivities. Compared to their electron- rich homologues, aldehydes 3g and 3i bearing strongly electron-withdrawing p-nitro or p-trifluomethyl groups, respectively, gave the products 4g and 4i in drastically reduced stereoselectivities (syn/anti 46/54 and 53/47, 15%, and 44% ee for the syn- and racemic for anti-isomers, respectively) (entries 7 and 9), probably as a result of less favorable interaction with the hypervalent silicon species. The reaction of 2a and 3h is an exception, therein a high level of diastereo- and enantioselectivity was attained (dr 95/5, 94% ee for syn-4h) despite the presence of electron-withdrawing F atom on the aldehyde reactant (entry 8). Aldehydes 3k-m containing heteroaromatic or naphthyl groups also reacted smoothly with 2a (entries 11-13), to deliver β-hydroxyketone products 4k-m in good yields (73%-86%) with a strong preference for the syn- diastereomers (dr 92/8-99/1) and high enantioselectivities (84%-93% ee). High levels of diastereoselectivity were also observed in the reactions involving α,β-unsaturated aldehydes 3n and 3o (entries 14 and 15), but only the reaction of cinnamaldehyde 3o gave the corresponding adduct syn-4o with excellent enantioselectivity as well (94% ee, entry 15). The reaction of 2a with alkyl aldehyde was examined using 3p as a substrate, to result in the exclusive formation of syn-4o albeit with a modest ee value (entry 16). Enone 2b with an aliphatic vinyl substituent (Me) was also used as the nucleophilic partner in the reductive aldol reaction with 3a, giving the high levels of stereoselectivity (dr 87/13, 95% ee) for the syn-aldol product 4q (entry 17). Finally, the chalcone derivative 2c also underwent a smooth reductive aldol reaction with 3a under the standard conditions, affording the corresponding aldol product 4r in good yield (87%) with high diastereo- and enantioselectivities (syn/anti = 94:6, 88% ee for syn, entry 18).
We have developed a highly diastereo- and enantioselective synthesis of optically enriched β-hydroxyketones. Using the spiro bisphosphine oxides SpinPO as chiral Lewis base catalysts, the asymmetric reductive aldol reactions of enones and a range of aldehydes proceeded smoothly with trichlorosilane reductant, to afford the corresponding aldol adducts 4a-r in 45%-88% yields, generally high syn-diastereoselectivity, and good to excellent enantioselectivity (up to 95% ee). Substrates with diverse stereoelectronic natures were tolerated, generally affording good yields and high stereoselectivities.
2015, Vol. 36 Issue (1): 100-105
PDF (7207 KB)
2015, Vol. 36 Issue (1): 100-105
PDF (7207 KB)