Synthesis of Chiral Tritylpyrrolidine Derivatives and ... - ACS Publications

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Synthesis of Chiral Tritylpyrrolidine Derivatives and Their Application to Asymmetric Benzoyloxylation Mio Shimogaki, Hiroki Maruyama, Shingo Tsuji, Chihiro Homma, Taichi Kano,* and Keiji Maruoka* Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan S Supporting Information *

ABSTRACT: An efficient synthesis of novel chiral tritylpyrrolidine derivatives has been developed. Single stereoisomers of various tritylpyrrolidine derivatives can be readily obtained through diastereomer separation by simple silica gel column chromatography. Representative compounds of this class have been shown to be efficient amine organocatalysts for asymmetric benzoyloxylation.

D

Scheme 1. Synthetic Approaches to Chiral Tritylpyrrolidine Derivatives

evelopment of highly stereoselective asymmetric reactions using organocatalysts has become a research area of great importance, and a number of new organocatalysts have been devised for this purpose.1 In this area, chiral secondary amine catalysts have been frequently utilized in various asymmetric reactions via enamine and iminium intermediates.2 Most efficient chiral secondary amine catalysts are derived from proline, and diarylprolinol silyl ethers (Hayashi−Jørgensen catalyst) are known to be broadly applicable organocatalysts.3 Meanwhile, we have developed 2-tritylpyrrolidine (3a), and this novel chiral amine was found to be an efficient catalyst for the asymmetric benzoyloxylation and hydroxyamination of aldehydes.4 Tritylpyrrolidine 3a is readily prepared from nitrone 1 (Scheme 1).4a However, modification of the catalyst is not trivial, since the appropriate resolution condition for each racemic catalyst is not predictable. For instance, while the optical resolution of 3a (Ar = Ph) can be achieved by the preferential crystallization with malic acid, 3b (Ar = 3,5-xylyl) requires a chiral column for HPLC separation. Therefore, we became interested in use of a readily available chiral nitrone (R)-45,6 instead of 1 in the synthesis of chiral tritylpyrrolidine derivatives 7. Addition reaction of trityllithium derivatives 5 to (R)-4 would afford readily separable mixtures of diastereomers 6, which can be converted to the desired chiral tritylpyrrolidine derivatives 7 by the subsequent N−O bond cleavage under hydrogenation conditions. This simplified method without optical resolution would enable facile access to chiral pyrrolidines bearing various α-substituents. Herein we report an efficient synthesis of novel chiral tritylpyrrolidine derivatives and their application to asymmetric benzoyloxylation. The chiral nitrone (R)-4 was prepared from the readily available L-hydroxyproline via TBS protection of hydroxy group5 and the decarboxylative oxidation of 8 (Scheme 2).6 We then examined the addition of trityllithium (5a) to (R)-4 (Table 1). The reaction in THF at −40 °C gave the diastereomer mixture of the desired hydroxyamine 6a in low yield, along with the byproduct 9 (entry 1). The mixture of © 2017 American Chemical Society

diastereomers could be separated into single stereoisomers (S,R)-6a (trans) and (R,R)-6a (cis), respectively, by simple silica gel column chromatography as expected. To suppress the Received: October 10, 2017 Published: November 2, 2017 12928

DOI: 10.1021/acs.joc.7b02562 J. Org. Chem. 2017, 82, 12928−12932

Note

The Journal of Organic Chemistry Scheme 2. Preparation of Nitrone (R)-4

Table 2. Addition of Trityllithium Derivatives to Nitrone (R)-4a

entry

Ar2PhCLi 5

1 2 3 4

Ph3CLi (5a) 5b 5c 5d

Table 1. Addition of Trityllithium to Nitrone (R)-4a

a

entry

Lewis acid

time (h)

6a (%)b

9 (%)b

1 2 3 4 5 6c 7c,d,e 8c,d 9

− BF3·OEt2 MAD DAD Et2AlCl Et2AlCl Et2AlCl Ti(OiPr)4 ZnBr2

2 2.5 1 1 4 2 0.5 1 1

39 (2.9/1) not detected 51 (3.6/1) 62 (3.4/1) 61 (2.8/1) 82 (3.3/1) 78 (3.3/1) 36 (3.5/1) 62 (3.8/1)

15 not detected 32 12 trace trace trace not detected 10

trans (%) (S,R)-6a (S,R)-6b (S,R)-6c (S,R)-6d

cis (%) 54 30 64 62

(R,R)-6a (R,R)-6b (R,R)-6c (R,R)-6d

18 37 not detected trace

Reactions were performed under the standard conditions.

a Reactions were performed under the standard conditions. bDetermined by 1H NMR with mesitylene as internal standard. Numbers in parentheses represent trans/cis ratios. cUse of 2.2 equiv of Lewis acid. d Use of 5 equiv of Ph3CLi. ePerformed at −20 °C.

Scheme 3. Reduction of Hydroxyamines 6 to Tritylpyrrolidine Derivatives 7

formation of 9 and improve the yield of 6a, we investigated effects of Lewis acids as additives.7 Among the Lewis acids tested, aluminum Lewis acids were found to increase the yield of 6a (entries 3−5).8 Addition of diethylaluminum chloride (1.1 equiv) was especially effective in suppressing the formation of 9 (entry 5). When the amount of diethylaluminum chloride was increased to 2.2 equiv, the yield of 6a was improved (entry 6). The amount of trityllithium (5a) could be reduced to 5 equiv without affecting the product yield (entry 7). With the optimized reaction conditions in hand, the reaction of several trityllithium derivatives 5 with (R)-4 was examined (Table 2). While the reaction of trityllithium (5a) gave (S,R)6a (trans) as a major diastereomer (entry 1), (S,R)-6b (trans) was obtained as a minor diastereomer in the reaction of trifluoromethyl-substituted trityllithium 5b (entry 2). On the other hand, use of trityllithium derivatives 5c and 5d generated from 9-phenylfluorene and 9-phenylxanthene resulted in exclusive formation of (S,R)-6c (trans) and (S,R)-6d (trans), respectively (entries 3 and 4). The Rf values of diastereomers of 6 are sufficiently different, and the diastereomer mixture of 6 could be readily separated into two diastereomers (S,R)-6 (trans) and (R,R)-6 (cis) by simple silica gel column chromatography. The separated hydroxyamines 6 were converted to chiral tritylpyrrolidine derivatives 7, respectively, by hydrogenation in acetic acid in the presence of Pd/C (Scheme 3).

The present method is also applicable to the addition reaction of other nucleophiles than trityllithium derivatives 5. The reaction of (R)-4 with the lithium enolate generated from methyl diphenylacetate gave the cyclic acyloxyamine (S,R)-10 and hydroxyamine 11 (Scheme 4). Isolated uncyclized 11 was cyclized to 10 gradually with releasing methanol. Interestingly, the major trans diastereomer (S,R)-11 was selectively cyclized to give (S,R)-10 in 78% yield in this spontaneous reaction, and the amount of the minor cis diastereomer (R,R)-11 remained unchanged. Hydrogenation of (S,R)-10 afforded the novel βamino acid (S,R)-12 in 81% yield. In order to evaluate the potential of the newly synthesized chiral tritylpyrrolidine derivatives 7, we decided to focus on the asymmetric benzoyloxylation of 3-phenylpropanal with benzoyl peroxide (BPO),4a,9,10 and the results are shown in Table 3. Trityl-substituted catalyst (S,R)-7a afforded the α-benzoylox12929

DOI: 10.1021/acs.joc.7b02562 J. Org. Chem. 2017, 82, 12928−12932

The Journal of Organic Chemistry

■

Scheme 4. Synthesis of β-Amino Acid (S,R)-12

catalyst

time (h)

yield (%)

1 2 3 4 5 6 7 8 9 10

(S)-3 (S,R)-7a (S,R)-7a (R,R)-7a (S,R)-7b (R,R)-7b (S,R)-7c (S,R)-7d (S,R)-12 (S)-14c

6 4 24 24 72 72 24 24 90 6

68 61 77 71 27 34 63 59 15 45

ee (%)b 94 94 94 97 93 93 89 97 84 93

EXPERIMENTAL SECTION

General Information. Infrared (IR) spectra were recorded on a Shimadzu IRPrestige-21 spectrometer. 1H NMR spectra were measured on a JEOL JNM-FX400 (400 MHz) spectrometer and a JEOL JNM-ECA500 (500 MHz) spectrometer. Chemical shifts were reported in ppm from tetramethylsilane as an internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br = broad, and app = apparent), coupling constants (Hz), and integration. 13 C{1H} NMR spectra were measured on a JEOL JNM-FX400 (100 MHz) and a JEOL JNM-FX500 (125 MHz) spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as an internal standard. High-performance liquid chromatography (HPLC) was performed on Shimadzu 20A instruments using Daicel Chiralpak AD-H 4.6 mm × 25 cm column. High-resolution mass spectra (HRMS) were performed on Thermo SCIENTIFIC Exactive Plus. Optical rotations were measured on a JASCO DIP-1000 digital polarimeter. For thin-layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used. The products were purified by flash column chromatography on silica gel 60N (Kanto Chemical Co. Inc., 40−50 μm). Tetrahydrofuran (THF), methanol (MeOH) and dichloromethane (DCM) were purchased from a commercial source. (4R)-4-(tert-Butyldimethylsilyloxyproline (S,R)-8,4b (4R)-4(tert-butyl dimethylsilyloxy)-1-pyrroline N-oxide (R)-4,6b 1-((3,5bis(trifluoromethyl)phenyl)(phenyl) methyl)-3,5-bis(trifluoromethyl)benzene,11 9-phenyl-9H-fluorene,11 and 9-phenyl-9H-xanthene11 were synthesized according to the literature procedures. The commercially available aldehydes were distilled and stored under argon atmosphere at −17 °C. Benzoyl peroxide (BPO) and hydroquinone were purchased and used without purification. Typical Procedure for Preparation of Hydroxyamine 6. To a solution of triarylmethane (10 mmol) in THF (15 mL) at 0 °C was added 1.6 M hexane solution of n-butyllithium (6.25 mL), and the mixture was stirred for 2.5 h. In another round-bottom flask, 1 M hexane solution of Et2AlCl (4.4 mL) was added to a solution of nitrone (R)-4 (431 mg, 2 mmol) in THF (15 mL) at −40 °C, and the mixture was stirred for 30 min. To a solution of the deprotonated triarylmethane was added the solution containing (R)-4 at −40 °C. After stirring for 2.5 h, the mixture was quenched by aqueous NH4Cl and aqueous Rochelle salt and extracted with ether. The organic phase was dried with Na2SO4 and concentrated in vacuo. The crude mixture was purified by SiO2 column chromatography to give hydroxyamine 6, which was immediately used for the next reaction to prevent the decomposition. Reduction of Hydroxyamine 6 to Tritylpyrrolidine 7. General Procedure A. A mixture of 6 (0.2 mmol), palladium 10% on carbon (18 mg) in acetic acid (2 mL) was stirred under an atmosphere of hydrogen at room temperature for 24 h. The mixture was filtered through Celite with ethyl acetate, and the filtrate was evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo. General Procedure B. The reaction was carried out as indicated general procedure A (reaction time was 15 h when using (S,R)-6d). After extraction, the crude mixture was purified by SiO2 column chromatography using the indicated solvent. The stereochemistry of 7 was determined by the stereochemical outcome of asymmetric benzoyloxylation using 7.4a Hydroxyamine (S,R)-6a and (R,R)-6a. Following the procedure for the preparation of 6, the reaction of nitrone (R)-4 (431 mg, 2 mmol) and triphenylmethane (2.44 g, 10 mmol) was carried out. The crude mixture was purified by SiO2 column chromatography (hexane/ ethyl acetate = 20:1 as eluent) to give hydroxyamine (S,R)-6a (495.3 mg, 1.08 mmol, 54% yield) as the former fractions (Rf: 0.26, Hex/ EtOAc = 4:1 as eluent) and (R,R)-6a (169.5 mg, 0.37 mmol, 18% yield) as the latter fractions (Rf: 0.20, Hex/EtOAc = 4:1 as eluent). Tritylpyrrolidine (S,R)-7a. Following the general procedure A for the preparation of 7, the hydrogenation of (S,R)-6a (234 mg, 0.51

Table 3. Asymmetric Benzoyloxylation of 3-Phenylpropanala

entry

Note

(S) (S) (S) (R) (S) (R) (S) (S) (S) (S)

a

Reactions were performed under the standard conditions. HQ = hydroquinone. bDetermined by HPLC analysis using a chiral column after conversion to the corresponding primary alcohol. c(S)Diphenylprolinol trimethylsilyl ether.

yaldehyde 13 with 94% ee, which is similar to that observed with original catalyst (S)-3 and (S)-diphenylprolinol trimethylsilyl ether ((S)-14) (entry 1 vs 2 and 10). Use of the diastereomeric catalyst (R,R)-7a led to increased enantioselectivity (entry 4). Introduction of trifluoromethyl groups to the catalyst resulted in a significant decrease in yield (entries 5 and 6). While tethering two phenyl groups of the catalyst resulted in reduced enantioselectivity (entry 7), the catalyst (S,R)-7d having an oxygen linker between two phenyl groups gave 13 with excellent enantioselectivity (entry 8). The reaction catalyzed by β-amino acid (S,R)-12 proceeded slowly due to the low solubility of the catalyst (entry 9). In summary, we have developed the novel tritylpyrrolidine derivatives as chiral amine catalysts for enamine catalysis. These chiral amine catalysts are readily synthesized from readily available L-hydroxyproline through diastereomer separation by simple silica gel column chromatography without laborious optical resolution of racemic catalysts. A series of catalysts are evaluated in the asymmetric benzoyloxylation and are comparable in terms of reactivity and selectivity to 2tritylpyrrolidine itself and the frequently used proline derivative. The present study offers opportunities for the new design and application of chiral amine catalysts. 12930

DOI: 10.1021/acs.joc.7b02562 J. Org. Chem. 2017, 82, 12928−12932

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The Journal of Organic Chemistry

acetate = 5:1 as eluent) to give hydroxyamine (S,R)-6c (292.9 mg, 0.64 mmol, 64% yield, Rf: 0.42, Hex/EtOAc = 5:1 as eluent). Triarylmethylpyrrolidine (S,R)-7c. Following the general procedure A for the preparation of 7, the hydrogenation of (S,R)-6c (146.5 mg, 0.32 mmol) using Pd/C (35 mg) in AcOH (3 mL) was performed to give the tritylpyrrolidine derivative (S,R)-7c (135.5 mg, 0.31 mmol, 96% yield) as a sticky pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.35−7.12 (m, 9H), 4.80 (app t, J = 7.7 Hz, 1H), 3.94−3.89 (m, 1H), 2.80 (dd, J = 11.1, 4.6 Hz, 1H), 2.75 (dd, J = 11.1, 2.9 Hz, 1H), 1.82−1.67 (m, 1H), 1.34−1.24 (m, 1H), 0.81 (s, 9H), −0.08 (s, 3H), −0.09 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 150.5, 148.8, 144.1, 142.0, 140.1, 128.4, 127.53, 127.5, 127.4, 127.21, 127.18, 127.1, 126.4, 124.4, 119.8, 119.5, 73.0, 62.7, 62.4, 56.0, 37.1, 25.9, 18.1, −4.8, −4.9; HRMS (ESI-Orbitrap) m/z calcd for C29H36ONSi (M + H)+ 442.2561, found 442.2524; [α]27 D = −161.1 (c = 1.4, CHCl3). Hydroxyamine (S,R)-6d. Following the procedure for the preparation of 6, the reaction of nitrone (R)-4 (215 mg, 1 mmol) and 9-phenyl-9H-xanthene (1.29 g, 5 mmol) was carried out. The crude mixture was purified by SiO2 column chromatography (hexane/ ethyl acetate = 10:1 as eluent) to give hydroxyamine (S,R)-6d (294.6 mg, 0.62 mmol, 62% yield) as the former fractions (Rf: 0.30, Hex/ EtOAc = 10:1 as eluent) and a trace amount of (R,R)-6d as the latter fractions (Rf: 0.19, Hex/EtOAc = 10:1 as eluent). Triarylmethylpyrrolidine (S,R)-7d. Following the general procedure B for the preparation of 7, the hydrogenation of (S,R)-6d (91.5 mg, 0.19 mmol) using Pd/C (17 mg) in AcOH (1.2 mL) was performed to give the tritylpyrrolidine derivative (S,R)-7d (58.1 mg, 0.13 mmol, 67% yield) as a sticky pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.7 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.24−7.15 (m, 3H), 7.09 (t, J = 7.7 Hz, 2H), 6.93−6.87 (m, 3H), 6.72 (d, J = 7.7 Hz, 1H), 4.32 (app t, J = 7.7 Hz, 1H), 3.84−3.79 (m, 1H), 2.62 (dd, J = 11.3, 2.8 Hz, 1H), 2.47 (dd, J = 11.3, 5.1 Hz, 1H), 1.54−1.48 (m, 2H), 0.80 (s, 9H), −0.07 (s, 3H), −0.09 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 151.8, 150.9, 148.0, 131.6, 130.4, 130.1, 127.84, 127.8, 127.6, 127.2, 126.1, 125.2, 122.7, 122.5, 115.8, 115.6, 72.5, 66.0, 55.8, 51.4, 38.5, 25.9, 18.0, −4.8, −4.84; HRMS (ESI-Orbitrap) m/z calcd for C29H36O2NSi (M + H)+ 458.2510, found 458.2511; [α]25 D = −13.3 (c = 1.8, CHCl3). β-Amino Acid (S,R)-12. To a solution of diisopropylamine (0.84 mL, 6 mmol) in THF (7 mL) at −78 °C, 1.6 M hexane solution of nbutyllithium (3.75 mL) was added and stirred for 40 min to prepare LDA. Methyl diphenylacetate (1.36 g, 6 mmol) in THF (7 mL) was added to the mixture and stirred for additional 1.5 h. In another roundbottom flask, 1 M hexane solution of Et2AlCl (3.3 mL) was added to a solution of nitrone (R)-4 (323 mg, 1.5 mmol) in THF (7 mL) at −78 °C and stirred for 20 min. To the solution prepared from methyl diphenylacetate was added the solution containing nitrone at −78 °C and warmed to 0 °C over 2 h. The mixture was quenched with aqueous NH4Cl and aqueous Rochelle salt and extracted with ether. The organic phase was dried with Na2SO4 and concentrated in vacuo. The crude mixture was purified by SiO2 column chromatography (hexane/ethyl acetate = 5:1 as eluent) to give acyloxyamine (S,R)-10 (0.31 g, 0.76 mmol, 50% yield) and the mixture of hydroxyamine (S,R)-11 (180.4 mg, 0.44 mmol, 27% yield) and (R,R)-11 (30.1 mg, 0.07 mmol, 4% yield). (S,R)-11 was spontaneously cyclized to (S,R)10 and 85% of (S,R)-11 was converted to (S,R)-10. A mixture of (S,R)-10 (0.31 mg, 0.76 mmol) and palladium 10% on carbon (76 mg) in acetic acid (5 mL) was stirred under an atmosphere of hydrogen at room temperature for 24 h. The mixture was filtered through Celite with ethyl acetate, and the filtrate was evaporated under reduced pressure. To the residue was added saturated NaHCO3 to adjust pH 6 and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to give β-amino acid (S,R)-12 (0.25g, 0.61 mmol, 81% yield) as a tan powder. 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 7.7 Hz, 1H), 7.25−7.15 (m, 5H), 4.69 (dd, J = 11.6, 6.0 Hz, 1H), 4.64−4.59 (m, 1H), 3.45 (dd, J = 11.9, 4.0 Hz, 1H), 3.18−3.12 (m, 1H), 2.23 (ddd, J = 13.6, 11.6, 4.0 Hz, 1H), 2.00−1.91 (m, 1H), 0.88

mmol) using Pd/C (47 mg) in AcOH (4 mL) was performed to give the tritylpyrrolidine (S,R)-7a (221.3 mg, 0.50 mmol, 98% yield) as a sticky pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 6H), 7.27−7.14 (m, 9H), 5.02 (app t, J = 7.6 Hz, 1H), 3.65−3.59 (m, 1H), 2.72 (dd, J = 10.6, 5.3 Hz, 1H), 2.64 (dd, J = 10.6, 5.3 Hz, 1H), 1.97 (ddd, J = 13.0, 8.2, 5.3 Hz, 1H), 1.59 (app quint, J = 6.8 Hz, 1H), 0.83 (s, 9H), −0.06 (s, 3H), −0.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.9 (br), 130.1 (br), 127.6, 126.0, 72.4, 61.9, 61.0, 54.7, 39.0, 25.9, 18.1, −4.8, −4.9; HRMS (ESI-Orbitrap) m/z calcd for C29H38ONSi (M + H)+ 444.2717, found 444.2725; [α]27 D = +26.7 (c = 1.1, CHCl3). Tritylpyrrolidine (R,R)-7a. Following the general procedure A for the preparation of 7, the hydrogenation of (R,R)-6a (169.5 mg, 0.37 mmol) using Pd/C (34 mg) in AcOH (3 mL) was performed to give the tritylpyrrolidine (R,R)-7a (152.4 mg, 0.34 mmol, 93% yield) as a sticky pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 6H), 7.28−7.14 (m, 9H), 4.48 (app t, J = 8.5 Hz, 1H), 4.32−4.25 (m, 1H), 2.79 (dd, J = 11.6, 4.3 Hz, 1H), 2.61 (dd, J = 11.6, 2.9 Hz, 1H), 2.27 (ddd, J = 13.8, 7.7, 6.8 Hz, 1H), 1.52 (app quint, J = 4.3 Hz, 1H), 0.77 (s, 9H), −0.07 (s, 3H), −0.08 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 145.9 (br), 130.1 (br), 127.7, 126.1, 72.8, 64.6, 60.1, 56.0, 40.0, 25.8, 18.0, −4.77, −4.8; HRMS (ESI-Orbitrap) m/z calcd for C29H38ONSi (M + H)+ 444.2717, found 444.2725; [α]24 D = +14.6 (c = 0.67, CHCl3). Hydroxyamine (S,R)-6b and (R,R)-6b. Following the procedure for the preparation of 6, the reaction of nitrone (R)-4 (151 mg, 0.7 mmol) and 1-((3,5-bis(trifluoromethyl)phenyl)(phenyl)methyl)-3,5bis(trifluoromethyl)benzene (1.81 g, 3.5 mmol) was carried out. The crude mixture was purified by SiO2 column chromatography (hexane/ ethyl acetate = 20:1 as eluent) to give hydroxyamine (S,R)-6b (151.8 mg, 0.21 mmol, 31% yield) as the former fractions (Rf: 0.44, Hex/ EtOAc = 10:1 as eluent) and (R,R)-6b (189.5 mg, 0.26 mmol, 37% yield) as the latter fractions (Rf: 0.39, Hex/EtOAc = 10:1 as eluent). Triarylmethylpyrrolidine (S,R)-7b. Following the general procedure B for the preparation of 7, the hydrogenation of (S,R)-6b (137.7 mg, 0.19 mmol) using Pd/C (18 mg) in AcOH (1.5 mL) was performed to give the tritylpyrrolidine (S,R)-7b (84.9 mg, 0.12 mmol, 62% yield) as a sticky pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.84−7.73 (m, 6H), 7.35 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 5.14 (app t, J = 7.6 Hz, 1H), 3.55−3.47 (m, 1H), 2.70 (dd, J = 10.2, 5.1 Hz, 1H), 2.60 (dd, J = 10.2, 5.1 Hz, 1H), 2.05 (ddd, J = 13.0, 8.2, 5.1 Hz, 1H), 1.31 (app quint, J = 6.5 Hz, 1H), 0.82 (s, 9H), −0.07 (s, 3H), −0.09 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 147.7 (br), 146.5 (br), 143.6 (br), 131.2 (q, JC−F = 32 Hz), 131.1 (q, JC−F = 32 Hz), 130.5 (br), 129.8 (br), 129.0 (two peaks overlap), 127.4, 123.3 (q, JC−F = 272 Hz, two peaks overlap), 120.9 (q, JC−F = 4 Hz), 120.6 (q, JC−F = 4 Hz), 71.9, 61.6, 61.4, 54.1, 38.7, 25.7, 18.1, −5.05, −5.1; IR (neat) 1274 (CF3) cm−1; HRMS (ESI-Orbitrap) m/z calcd for C33H34F12ONSi (M + H)+ 716.2213, found 716.2218; [α]27 D = +44.3 (c = 1.1, CHCl3). Triarylmethylpyrrolidine (R,R)-7b. Following the general procedure B for the preparation of 7, the hydrogenation of (R,R)-6b (309.1 mg, 0.42 mmol) using Pd/C (38 mg) in AcOH (3 mL) was performed to give the tritylpyrrolidine (R,R)-7b (217 mg, 0.30 mmol, 72% yield) as a sticky pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.89−7.72 (m, 6H), 7.40−7.27 (m, 3H), 7.17 (d, J = 7.7 Hz, 2H), 4.66 (app t, J = 8.2 Hz, 1H), 4.34−4.28 (m, 1H), 2.87 (dd, J = 11.4, 5.6 Hz, 1H), 2.41 (dd, J = 11.4, 4.3 Hz, 1H), 2.34 (app quint, J = 6.8 Hz, 1H), 1.33−1.19 (m, 1H), 0.74 (s, 9H), −0.09 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 147.8 (br), 146.8 (br), 142.4 (br), 131.3 (q, JC−F = 33 Hz), 131.1 (q, JC−F = 33 Hz), 130.5 (br), 129.7 (br), 129.2, 128.9, 127.6, 123.23 (q, JC−F = 273 Hz), 123.21 (q, JC−F = 273 Hz), 121.0 (q, JC−F = 4 Hz), 120.9 (q, JC−F = 4 Hz), 72.4, 62.9, 60.9, 54.9, 39.0, 25.6, 17.9, −4.9, −5.0; IR (neat) 1275 (CF3) cm−1; HRMS (ESI-Orbitrap) m/z calcd for C33H34F12ONSi (M + H)+ 716.2213, found 716.2222; [α]26 D = −8.1 (c = 0.73, CHCl3). Hydroxyamine (S,R)-6c. Following the procedure for the preparation of 6, the reaction of nitrone (R)-4 (215 mg, 1 mmol) and 9-phenyl-9H-fluorene (1.21 g, 5 mmol) was carried out. The crude mixture was purified by SiO2 column chromatography (hexane/ethyl 12931

DOI: 10.1021/acs.joc.7b02562 J. Org. Chem. 2017, 82, 12928−12932

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The Journal of Organic Chemistry

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(s, 9H), 0.09 (s, 3H), 0.04 (s, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 177.8, 144.0, 143.3, 130.9, 129.8, 129.4, 128.6, 128.5, 127.8, 72.4, 65.2, 63.3, 54.9, 40.4, 26.2, 18.8, −4.87, −4.90; IR (neat) 1602 (CO) cm −1 ; HRMS (ESI-Orbitrap) m/z calcd for C24H33O3NNaSi (M + Na)+ 434.2122, found 434.2127; [α]24 D = −50.4 (c = 0.69, MeOH). General Procedure for the α-Benzoyloxylation Reaction. To a solution of 3-phenylpropanal (26 μL, 0.2 mmol), (S,R)-7 (0.02 mmol, 10 mol %), and hydroquinone (2.2 mg, 0.02 mmol, 10 mol %) in THF (1.5 mL) was added BPO (wetted with ca. 25% water) (71.1 mg, 0.22 mmol) at 0 °C. After stirring the reaction mixture at 0 °C for 24 h, H2O (36 μL) was added to the mixture and stirred at 0 °C for 30 min. The reaction mixture was cooled to −10 °C, and MeOH (1.5 mL) and CH2Cl2 (1.5 mL) were then added. To the reaction mixture, NaBH4 (95 mg, 2.4 mmol) was added portionwise at −10 °C. After stirring for 30 min, the reaction mixture was quenched with 1 N HCl aqueous solution slowly and extracted with ethyl acetate. The organic phase was then washed with saturated NaHCO3 aqueous solution and brine and dried over Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by SiO2 column chromatography (hexane/ethyl acetate = 4:1 as eluent) to give (S)1-hydroxy-3-phenylpropan-2-yl benzoate as a major isomer. Enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane/i-PrOH = 15:1; flow rate 1.0 mL/min, retention time: 15.2 (S) and 17.0 min (R)).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02562. 1 H and 13C{1H} NMR spectral data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Taichi Kano: 0000-0001-5730-3801 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI grant nos. JP26220803 and JP25708016. H.M. thanks the Japan Society for the Promotion of Science for Young Scientists for Research Fellowships.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02562 J. Org. Chem. 2017, 82, 12928−12932