Enantioselective chlorinative aldol reaction of α-substituted acroleins catalyzed by chiral phosphine oxides

Tetrahedron: Asymmetry xxx (2017) xxx–xxx

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Enantioselective chlorinative aldol reaction of a-substituted acroleins catalyzed by chiral phosphine oxides Shunsuke Kotani a,b,⇑, Takuya Hanamure a, Hirono Nozaki a, Masaharu Sugiura a, Makoto Nakajima a a b

Graduate School of Pharmaceutical Sciences Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan

a r t i c l e

i n f o

Article history: Received 11 October 2016 Revised 17 December 2016 Accepted 21 December 2016 Available online xxxx

a b s t r a c t The enantioselective chlorinative aldol reaction of a-substituted acroleins with aldehydes catalyzed by chiral phosphine oxides is described. A hypervalent silicon complex-derived chloride adds to the a-substituted acroleins to form the corresponding silyl enol ethers in situ, which subsequently reacts with aldehydes to produce the a-chloromethyl aldol adducts bearing a quaternary stereogenic center in good yields and stereoselectivities. When activated by a phosphine oxide catalyst, trichlorosilyl triflate acts as an effective promoter for the chlorinative aldol reaction as well as the chloride source; this discovery enabled the enantioselective chlorinative aldol reaction of a-substituted acroleins. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction

2. Results and discussion

The asymmetric tandem reaction is one of the most efficient synthetic strategies leading to chiral complex molecules in a single operation, and has been an attractive research area in recent years.1 In particular, asymmetric tandem reactions involving nucleophilic addition/aldol reaction sequences, such as reductive aldol reactions2 and alkylative aldol reactions,3 have seen sustained interest because these reactions produce multiple stereogenic centers in a single operation. An asymmetric halogenative aldol reaction is a valuable tandem approach for introducing a halogen atom into substrates along with the stereoselective carbon–carbon bond formation.4–6 The highly functionalized products contain a carbonyl group, a hydroxy group, and a halogen atom, representing a marked increase in complexity when compared to the starting materials. However, there are few reports on enantioselective halogenative aldol reactions of a,b-unsaturated enones or enals because of ready conversion to Morita–Baylis–Hillman adducts or dehydrated adducts (Fig. 1-a). Reports describing enantioselective halogenative aldol reactions have been limited to a,b-unsaturated ynones.2q,6 Although a-alkylated acroleins appear usable as an aldol donor to furnish halogenative aldol adducts that cannot undergo a subsequent elimination reaction (Fig. 1-b), such a methodology has not yet been reported.

Our research group has explored chiral Lewis base catalysis7 and developed several stereoselective transformations using chiral phosphine oxide catalysts.8 A chiral phosphine oxide coordinates with a chlorosilyl reagent to form a chiral hypervalent silicon complex that consists of a highly electrophilic silicon center adjacent to the nucleophilic site.7,9 Such a chiral complex effectively promoted an addition of a chloride to a substrate aided by activation from the electrophilic silicon center, facilitating the ring-opening of meso-epoxides,10 the phosphonylation of aldehydes,11 and a Morita–Baylis–Hillman-type reaction.12 We herein describe chiral phosphine oxide as a chiral catalyst for the stereoselective chlorinative aldol reaction of a-substituted acroleins with aldehydes using trichlorosilyl triflate. Our research started with the chlorinative aldol reaction of methacrolein 1a and benzaldehyde 2a. The reaction was initially conducted using SiCl4 in the presence of 10 mol % of (S)-BINAP dioxide C1 (BINAPO) and N,N-diisopropylethylamine in CH2Cl2 at 0 °C; however, these reaction conditions gave no desired adducts. It seemed likely that the silyl enol ether intermediate was indeed generated in the reaction mixture,12 but the decreased nucleophilicity of the silyl enol ether because of the a-substituent of 1a rendered it unreactive with the aldehyde acceptor. We then applied the more reactive trichlorosilyl triflate 3 as a chlorosilyl reagent to the reaction (Table 1, entry 1),13 and the expected adduct 4aa was formed. Due to the ease of purification and analysis, the yields and stereoselectivities were quantified for diol 5aa after the reduction with NaBH4 in methanol.14 After screening

⇑ Corresponding author. http://dx.doi.org/10.1016/j.tetasy.2017.01.006 0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx (a) With α-enones or α-enals Addition of X–

O

O

OH

RCHO

O

R X

X enolate –H2 O

–HX Elimination OH

O

O

R

R

X

Morita-Baylis-Hillman adduct

Dehydrated adduct

(b) With α−substituted acroleins O

Addition of X–

O

OH

RCHO H

H

R

X

O H

X

α-substituted acrolein

halo aldol adduct

Figure 1. Halogenative aldol reactions of a,b-unsaturated carbonyl compounds with aldehydes.

several amine bases, sterically congested amine, N,N-dicyclohexylisobutylamine13b dramatically improved the diastereoselectivity of the reaction to produce 5aa (entry 2). The steric hindrance of the amine could suppress the coordination to highly electrophilic trichlorosilyl triflate preventing excess formation of chloride in situ. Varying the stoichiometry of the substrates led us to increase the product yield to 55% at 0 °C (entry 3). Lowering the reaction temperature to
40 °C improved both the yield and enantioselectivity (entry 4). However, precipitation of N,N-dicyclohexylisobutylamine at
60 °C decreased the yield and diastereoselectivity (entry 5). We therefore switched to N,N-diisopropylisobutylamine, a sterically congested amine that is soluble even at
60 °C, and this allowed

us to obtain product 5aa in 91% yield and with good enantioselectivity (entry 6). We then examined various chiral phosphine oxide catalysts other than (S)-BINAPO (Fig. 2). (R,R)DIOPO C2 was ineffective for the reaction (entry 7), and (S)SEGPHOSO C3 and (S)-H8-BINAPO C4, both bearing a biphenyl skeleton, provided results slightly inferior to (S)-BINAPO C1 (entries 8 and 9). (S)-4,40 -Br2-BINAPO C5 afforded the chloro aldol adduct 5aa in similar yield and stereoselectivities to those with (S)-BINAPO C1 (entry 10).15 With the optimized reaction conditions in hand, we set out to investigate various substrates for the enantioselective chlorinative aldol reaction (Table 2). a-n-Alkylated acroleins 1a–c gave the corresponding adducts 5aa–ca with good enantioselectivities, but increasing steric hindrance of alkyl substituents decreased the diastereoselectivity (entries 1–3). a-Isopropylated acrolein 1d showed lower reactivity, resulting in low yield, and the syn-isomer syn-5da was predominantly produced (entry 4). The reversal of diastereoselectivity indicates that the geometry of silyl enol ether intermediates was inverted and this inversion was observed absolutely in the reaction of a-benzylacrolein 1e, producing only syn-5ea (entry 5). We then performed the reaction with various aldehyde acceptors 2 to react with methacrolein 1a (entries 6–10). p-Bromobenzaldehyde 2b gave the similar yields and stereoselectivities to the parent aldehyde 2a (entry 6), whereas the yield decreased in the reaction of p-anisaldehyde 2c. 2-Naphthaldehyde 2d afforded product 5ad in good yield and stereoselectivities (entry 8), but 1-naphthaldehyde 2e produced 5ae in decreased yield and diastereoselectivity (entry 9). Cinnamaldehyde 2f reacted smoothly to afford adduct 5af, albeit in low enantioselectivity (entry 10). The absolute configuration of the major product of 5ae was assigned to be (1S,2R) based on single-crystal X-ray analysis (Fig. 3).16 The proposed reaction mechanism is shown in Fig. 4. Chlorosilane 3 coordinates to acrolein 1 and then a chloride anion attacks the b-carbon atom to form silyl enol ether intermediate 6. The chloride attacks the acrolein 1 in the s-trans conformation to give (E)-6, whereas (Z)-6 is obtained from the s-cis conformation. (E)- and (Z)-6 react with aldehyde 2 via 6-membered chair-like transition state to produce anti-7 and syn-7, respectively.7,8 Therefore, the E/Z ratio of the silyl enol ether intermediates 6 directly determines the

Table 1 Optimization of enantioselective chlorinative aldol reactions of methacrolein 1a and benzaldehyde 2a catalyzed by chiral phosphine oxidesa &&  PRO  DPLQH  HTXLY

2 0H

+



3K&+2 D

D  HTXLY

Entry d

1 2d 3 4 5 6 7 8 9 10 a b c d

Catalyst

Amine

C1 C1 C1 C1 C1 C1 C2 C3 C4 C5

i

Pr2NEt Cy2NiBu Cy2NiBu Cy2NiBu Cy2NiBu i Pr2NiBu i Pr2NiBu i Pr2NiBu i Pr2NiBu i Pr2NiBu



6L&O 27I

&+ &O

  HTXLY

+2

2

+2

1D%+  3K

+

0H2+

&O

Temp (°C)

Time (h)

0 0 0
40
60
60
60
60
60
60

2.5 2.5 2.5 20 24 24 24 24 24 24

3K &O

DD

Yield (%) 22 27 55 65 25 91 14 81 86 93

2+

DD

drb

eec (%)

53/47 98/2 86/14 95/5 63/37 91/9 68/32 83/17 85/15 97/3

38 42 46 66 66 75 14 67 74 75

Unless otherwise noted, the reaction was conducted with 1a (2.0 equiv) and 2a (0.5 mmol), 3 (2.0 equiv), amine (2.2 equiv), and a phosphine oxide (10 mol %) in CH2Cl2. Ratio of anti/syn was determined by 1H NMR and HPLC analysis. Ee of anti-5aa. 1a (1.0 equiv), 2a (1.2 equiv).

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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx

O P P O

O Ph Ph Ph Ph

O

P

O

P O

(S)-BINAPO C1

O

O

Ph

P

O

Ph Ph

O

P

Ph

O

O

(R,R)-DIOPO C2

Ph Ph Ph Ph

(S)-SEGPHOSO C3 Br

O P P O

O

Ph

P

Ph Ph

P

Ph

O

Ph Ph Ph Ph

Figure 3. X-ray crystal structure of 5ae. Thermal ellipsoids are shown at 20% probability.

Br (S)-H8 -BINAPO C4

(S)-4,4'-Br2 -BINAPO C5

Figure 2. Chiral phosphine oxides used in this study.

the transition state bearing the R2 group in axial position leading to decrease the diastereoselectivity. After the formation of the CAC bond, the product remains in the silylated form 7, preventing a retro-aldol reaction and resulting in a high-yielding transformation.

diastereoselectivity in the chlorinative aldol reaction. This assumption is supported by the results in Table 2. Methacrolein 1a, bearing a small methyl group, may prefer an s-trans conformation to produce the anti-isomer (Table 2, entry 1), whereas a bulky a-substituent, such as an isopropyl group, forces the acrolein to be in the s-cis conformation, resulting in the formation of the syn-isomer (Table 2, entry 4). The decrease of the diastereoselectivity in the investigation of aldehydes might be explained by the steric environment around the carbonyl in aldehydes in the chair-like six-membered transition state. The hindered aldehyde makes it hard to make the cyclic transition state, undergoing the reaction via acyclic transition state to decrease the diastereoselectivity. On the other hand, a less hindered aldehyde around the carbonyl could form

3. Conclusion We have demonstrated the enantioselective chlorinative aldol reaction of a-alkylated acroleins with aldehydes, which has never before been described in the literature. The combination of trichlorosilyl triflate and chiral phosphine oxide catalysts effectively facilitated the reaction to furnish highly functionalized aldol adducts bearing a quaternary stereogenic center in good yields and stereoselectivities. Further research is currently ongoing to both improve the stereoselectivity and develop different transformations.

Table 2 Enantioselective chlorinative aldol reactions of a-substituted acroleins and aldehydes catalyzed by C1a  & PRO L3U

2 5

+

 5 &+2 \

[  HTXLY  5 0H  D

 6L&O 27I   HTXLY

L

1 %X HTXLY

+2

&+ &Oದr& K

2+

5

  1D%+ 0H2+

&O

5 [\

5

3K  D

5 (W  E

5  %U & +   E

5 Q 3HQW  F

5  0H2 & +    F

5 L3U  G

5  QDSKWK\O  G

5 &+ 3K  H

5  QDSKWK\O  H 5  3K&+ &+  I

Entry

1x

2y

5xy

Yield (%)

1 2 3 4 5 6 7 8 9 10

1a 1b 1c 1dd 1e 1a 1a 1a 1a 1a

2a 2a 2a 2a 2a 2b 2c 2d 2e 2f

5aa 5ba 5ca 5da 5ea 5ab 5ac 5ad 5ae 5af

91 90 95 17 83 94 56 82 32 56

drb

eec (%)

91/9 66/34 62/38 28/72 0/100 87/13 73/27 87/13 59/41 71/29

75 61 69 61 41 73 74 72 78 4

a The reaction was conducted with an acrolein 1 (2.0 equiv) and an aldehyde 2 (0.5 mmol), silyl reagent 3 (2.0 equiv), N,N-diisopropylisobutylamine (2.2 equiv), and C1 (10 mol %) in CH2Cl2. b Ratio of anti/syn was determined by 1H NMR and HPLC analysis. c Ee for major isomer. d 4.0 equiv.

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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx (S)-BINAPO (S)-BINAPO

R

1

H

OSiCl2OTf

(S)-BINAPO SiCl3 OTf

O

R1

R 2CHO 2

H

H

TfOCl2SiO SiCl2OTf

O

Cl

Cl s-trans-1

R2

O

HO 1) workup

R

Cl

H

R 2) reduction

R1

OH

2

R1

Cl

anti-7

R1

(E)-6

O

2

anti-5

(S)-BINAPO (S)-BINAPO O

(S)-BINAPO SiCl3 OTf H

R1 s-cis-1

H

OSiCl2OTf Cl

H

R2 CHO 2

R2 R1

R1 (Z)-6

Cl

TfOCl2SiO SiCl2OTf

O O

O

2

R

Cl syn-7

HO H

R1

1) workup 2) reduction

R

OH

2

Cl

R1 syn-5

Figure 4. Proposed reaction course of the chlorinative aldol reaction.

4. Experimental 4.1. General Melting points (mp) are uncorrected. 1H and 13C NMR spectra were measured in CDCl3 with JEOL JNM-ECX400 spectrometer. Tetramethylsilane (TMS) (d = 0 ppm) and CDCl3 (d = 77.0 ppm) served as an internal standard for 1H and 13C, respectively. Infrared spectra were recorded on Perkin Elmer Frontier or JEOL JIR-6500W. Mass spectra were measured with JEOL JMS-700MStaion. Optical rotations were recorded on JASCO P-1010 polarimeter. High-pressure liquid chromatography (HPLC) was performed on JASCO P2080 and UV-2075. Thin-layer chromatography (TLC) analysis was carried out using Merck silica gel plates. Visualization was accomplished with UV light, phosphomolybdic acid and/or anisaldehyde. Column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, 63–210 lm). Dehydrated stabilizer-free dichloromethane (CH2Cl2) was purchased from Kanto Chemical Co. Inc. All reactions were performed under argon atmosphere. Chiral phosphine oxides were prepared by oxidation of the corresponding phosphine with hydrogen peroxide in acetone.17 Methacrolein derivatives 1c–e were synthesized according to the literature.18 All other chemicals were purified based on standard procedures or used as received otherwise noted. 4.2. Preparation of trichlorosilyl triflate 313,19 Trifluoromethanesulfonic acid (2.66 mL, 30.0 mmol, 1.0 equiv) was added to phenyltrichlorosilane (5.05 mL, 31.5 mmol, 1.05 equiv). After stirring for 4 h at 60 °C, the reaction mixture was diluted with dry CH2Cl2 and the solution was stocked in a screw-top test tube with a Teflon packing. 4.3. Typical procedure for asymmetric chlorinative aldol reaction A solution of trichlorosilyl triflate 3 in CH2Cl2 (2.0 M, 0.5 mL, 1.0 mmol, 2.0 equiv) was added dropwise to a solution of N,Ndiisopropylisobutylamine (0.22 mL, 1.1 mmol, 2.2 equiv) and methacrolein 1a (2.0 M, 0.5 mL, 1.0 mmol, 2.0 equiv), in CH2Cl2 (5.0 mL) at
60 °C. After being stirred for 0.5 h, (S)-BINAPO (32.7 mg, 0.05 mmol, 10 mol %), and a solution of benzaldehyde 2a in CH2Cl2 (2.0 M, 0.25 mL, 0.5 mmol) were added to the resulting solution. After being stirring for 24 h at the same temperature, the reaction was quenched with aqueous 1.5 M KF/3.0 M HCOOH (5.0 mL), and then the slurry was stirred for 1 h at room temperature. The aqueous layer was extracted with EtOAc (3  30 mL). The combined organic layers were washed with 10% HCl (20 mL), satd

NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. After filtration and concentration, the crude material was obtained and used in the next step without any purification. The crude material was dissolved in methanol (3 mL), and then NaBH4 (94.6 mg, 2.5 mmol, 5.0 equiv) was added to the solution. After being stirred for 30 min at 0 °C, the reaction was quenched with H2O (5 mL). The two layer mixture was extracted with CH2Cl2 (3  20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Evaporation of the solvent furnished the crude product, which was purified by column chromatography (SiO2, hexane/EtOAc = 5:1) to give the diol 5aa (97.8 mg, 91% yield, anti/syn = 91/9, 75% ee (anti), 68% ee (syn)). 4.3.1. 2-(Chloromethyl)-2-methyl-1-phenyl-1,3-propanediol 5aa Data for the anti-isomer: State; 97.8 mg, 91% yield (anti/syn = 91/9); TLC: Rf 0.40 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); [a]28 D =
7.6 (c 1.00, EtOH) for 75% ee, 1 [a]28 435 =
16.4 (c 1.00, EtOH) for 75% ee; H NMR (400 MHz, CDCl3): d 0.75 (s, 3H), 3.15 (br s, 1H), 3.40 (d, 1H, J = 3.7 Hz), 3.52–3.77 (m, 4H), 4.87 (d, 1H, J = 3.7 Hz), 7.21–7.44 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): d 16.6, 43.4, 50.4, 66.6, 78.2, 127.4, 128.0, 128.1, 140.2; IR (film): 3346 cm
1; LRMS (EI): m/z 214 (M+), 196, 107, 77; HRMS (EI): Calcd for C11H15ClO2 214.0761, found 214.0764. The enantiomeric excess was determined to be 75% ee (anti) and 68% ee (syn) by chiral HPLC with Daicel Chiralpak AD-H column and Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 92:8; flow rate: 1.0 mL/min; detection: 220 nm; tR: 29.5 min (anti-major), 31.0 min (syn-major), 33.7 min (anti-minor), 39.8 min (syn-minor)]. 4.3.2. 2-(Chloromethyl)-2-ethyl-1-phenyl-1,3-propanediol 5ba Data for the anti-isomer: State; 103.0 mg, 90% yield (anti/syn = 66/34); TLC: Rf 0.27 (hexane/EtOAc = 4:1, stained blue with phosphomolybdic acid/EtOH); [a]29 D =
3.9 (c 0.70, CHCl3) 1 for 61% ee, [a]29 H NMR 435 =
7.5 (c 0.70, CHCl3) for 61% ee; (400 MHz, CDCl3): d 0.85 (t, 3H, J = 7.6 Hz), 1.03–1.22 (m, 2H), 3.01 (br s, 1H), 3.12 (br s, 1H), 3.69 (d, 2H, J = 4.1 Hz), 3.82 (d, 1H, J = 11.5 Hz), 4.02 (d, 1H, J = 11.5 Hz), 5.00 (d, 1H, J = 4.6 Hz), 7.15–7.48 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): d 7.2, 22.3, 45.3, 47.1, 65.1, 78.4, 127.4, 128.0, 128.1, 140.3; IR (ATR): 3307 cm
1; LRMS (EI): m/z 228 (M+), 210, 107, 79; HRMS (EI): Calcd for C12H17ClO2 228.0917, found 228,0920. The enantiomeric excess was determined to be 61% ee (anti) and 62% ee (syn) by chiral HPLC with Daicel Chiralpak IE-3 column [eluent: hexane/ IPA = 30:1; flow rate: 1.0 mL/min; detection: 220 nm; tR: 30.0 min (syn-major), 32.5 min (anti-major), 38.9 min (syn-minor), 51.7 min (anti-minor)].

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4.3.3. 2-(Chloromethyl)-2-pentyl-1-phenyl-1,3-propanediol 5ca Data for the anti-isomer: State; 128.5 mg, 95% yield (anti/syn = 62/38); TLC: Rf 0.31 (hexane/EtOAc = 4:1, stained blue with phosphomolybdic acid/EtOH); [a]17 D =
10.9 (c 1.14, CHCl3) for 69% ee; 1H NMR (400 MHz, CDCl3): d 0.86 (t, 3H, J = 7.1 Hz), 0.96–1.10 (m, 2H), 1.11–1.38 (m, 6H), 2.89–3.01 (m, 1H), 3.02– 3.14 (m, 1H), 3.69 (d, 2H, J = 5.0 Hz), 3.84 (d, 1H, J = 11.5 Hz), 3.99 (d, 1H, J = 11.5 Hz), 4.99 (d, 1H, J = 5.0 Hz), 7.29–7.45 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): d 14.0, 22.3, 22.5, 29.7, 32.4, 45.4, 47.7, 65.4, 78.6, 127.4, 128.0, 128.2, 140.4; IR (ATR): 3304 cm
1; LRMS (FAB): m/z 293 (M+Na)+; HRMS (FAB): Calcd for C15H23ClNaO2 293.1284, found 293.1297. The enantiomeric excess was determined to be 69% ee (anti) and 68% ee (syn) by chiral HPLC with Daicel Chiralpak ID-3 column [eluent: hexane/ IPA = 30:1; flow rate: 1.0 mL/min; detection: 220 nm; tR: 14.4 min (syn-minor), 15.4 min (anti-minor), 18.7 min (syn-major), 22.3 min (anti-major)]. 4.3.4. 2-(Chloromethyl)-2-isopropyl-1-phenyl-1,3-propanediol 5da Data for the diastereomeric mixture: State; 20.7 mg, 17% yield (anti/syn = 28/72); TLC: Rf 0.28 (hexane/EtOAc = 4:1, stained blue with phosphomolybdic acid/EtOH); [a]30 D = +4.7 (c 0.70, CHCl3) for 61% ee (syn), 51% ee (anti), anti/syn = 21/79; 1H NMR (400 MHz, CDCl3): d 0.78 (d, 3H(anti), J = 6.9 Hz), 0.91 (d, 3H(anti), J = 6.9 Hz), 0.99 (d, 3H(syn), J = 6.9 Hz), 1.16 (d, 3H(syn), J = 6.9 Hz), 1.78 (sep, 1H(anti), J = 6.9 Hz), 2.25 (sep, 1H(syn), J = 6.9 Hz), 2.77 (br s, 1H(anti)), 2.85 (br s, 1H(syn)), 3.18 (br s, 1H (anti)), 3.23 (br s, 1H(syn)), 3.28 (d, 1H(syn), J = 11.5 Hz), 3.64 (d, 1H(syn), J = 11.5 Hz), 3.67–3.79 (m, 2H(syn), 1H(anti)), 3.83 (d, 1H (anti), J = 12.4 Hz), 4.00 (d, 2H(anti), J = 2.3 Hz), 5.04 (d, 1H(anti), J = 4.1 Hz), 5.16 (d, 1H(syn), J = 2.7 Hz), 7.05–7.59 (m, 5H(syn), 5H (anti)); 13C{1H} NMR (100 MHz, CDCl3): d 17.8, 18.0, 18.06, 18.13, 28.9, 29.7, 45.7, 46.7, 46.8, 47.1, 64.2, 64.8, 77.86, 77.90, 127.6, 128.1, 128.3, 128.4, 140.7, 141.2 (two carbons overlapped); IR (ATR): 3305 cm
1; LRMS (EI): m/z 224, 118, 107, 105; HRMS (EI): Calcd for C13H17ClO 224.0968, found 224.0961. The enantiomeric excess was determined to be 61% ee (syn) and 51% ee (anti) by chiral HPLC with Daicel Chiralpak AD-H column and Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 24:1; flow rate: 1.0 mL/min; detection: 220 nm; tR: 47.5 min (syn-major), 51.0 min (syn-minor), 54.5 min (anti-major), 65.6 min (anti-minor)]. 4.3.5. 2-Benzyl-2-(chloromethyl)-1-phenyl-1,3-propanediol 5ea Data for the syn-isomer: State; 120.6 mg, 83% yield (anti/syn = 0/100); TLC: Rf 0.30 (hexane/EtOAc = 4:1, stained blue with phosphomolybdic acid/EtOH); mp: 157.0–159.0 °C; 1 [a]29 D =
21.3 (c 1.00, CHCl3) for 41% ee; H NMR (400 MHz, CDCl3): d 2.61 (br s, 2H), 2.83–2.94 (m, 2H), 3.39 (d, 1H, J = 11.0 Hz), 3.64 (dd, 1H, J = 5.5 Hz, 11.7 Hz), 3.75 (dd, 1H, J = 5.5 Hz, 11.7 Hz), 3.97 (d, 1H, J = 11.0 Hz), 5.25 (d, 1H, J = 3.7 Hz), 7.11–7.18 (m, 2H), 7.18–7.28 (m, 3H), 7.34–7.46 (m, 3H), 7.47–7.54 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): d 35.4, 46.2, 47.3, 65.6, 78.2, 126.7, 127.7, 128.28, 128.33, 130.5, 136.0, 139.9 (one carbon overlapped); IR (ATR): 3271 cm
1; LRMS (FAB): m/z 313 (M+Na)+, 289, 255, 107; HRMS (FAB): Calcd for C17H19ClNaO2 313.0971, found 313.0970. The enantiomeric excess was determined to be 41% ee (syn) by chiral HPLC with Daicel Chiralcel OD-H column [eluent: hexane/IPA = 19:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 19.9 min (syn-major), 26.1 min (syn-minor)]. 4.3.6. 1-(4-Bromophenyl)-2-(chloromethyl)-2-methyl-1,3-propanediol 5ab Data for the anti-isomer: State; 138.5 mg, 94% yield (anti/syn = 87/13); TLC: Rf 0.35 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); mp: 107.0–109.0 °C; [a]33 D =

5


3.7 (c 0.90, EtOH) for 73% ee, [a]29 435 =
9.8 (c 0.40, EtOH) for 73% ee; 1H NMR (400 MHz, CDCl3): d 0.78 (s, 3H), 2.62 (br s, 1H), 3.12 (br s, 1H), 3.55–3.77 (m, 4H), 4.91 (s, 1H), 7.27 (d, 2H, J = 8.2 Hz), 7.50 (d, 2H, J = 8.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): d 16.5, 43.5, 50.1, 66.8, 77.5, 121.9, 129.1, 131.2, 139.3; IR (ATR): 3259 cm
1; LRMS (FAB): m/z 317, 315 (M+Na)+, 154; HRMS (FAB): Calcd for C11H14BrClNaO2 314.9763, found 314.9763. The enantiomeric excess was determined to be 73% ee (anti) and 74% ee (syn) by chiral HPLC with Daicel Chiralpak AD-3 column and Daicel Chiralcel OJ-H column [eluent: hexane/IPA = 24:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 71.8 min (anti-major), 78.9 min (anti-minor), 96.1 min (syn-major), 110.9 min (syn-minor)]. 4.3.7. 2-(Chloromethyl)-1-(4-methoxyphenyl)-2-methyl-1,3propanediol 5ac Data for the anti-isomer: State; 68.5 mg, 56% yield (anti/syn = 73/27); TLC: Rf 0.32 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); [a]29 D = +4.4 (c 0.40, CHCl3) for 1 74% ee, [a]29 H NMR 435 = +10.9 (c 0.40, CHCl3) for 74% ee; (400 MHz, CDCl3): d 0.79 (s, 3H), 2.63–2.74 (m, 2H), 3.61–3,80 (m, 4H), 3.82 (s, 3H), 4.91 (d, 1H, J = 3.2 Hz), 6.90 (d, 2H, J = 8.7 Hz), 7.32 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz, CDCl3): d 16.6, 43.6, 50.4, 55.3, 66.8, 77.9, 113.5, 128.5, 132.3, 159.3; IR (film): 3363 cm
1; LRMS (FAB): m/z 267 (M+Na)+, 227, 137; HRMS (FAB): Calcd for C12H17ClNaO3 267.0764, found 267.0769. The enantiomeric excess was determined to be 74% ee (anti) and 75% ee (syn) by chiral HPLC with Daicel Chiralpak AD-H column and Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 19:1; flow rate: 1.0 mL/min; detection: 220 nm; tR: 75.1 min (anti-major), 81.2 min (anti-minor), 83.6 min (syn-major), 88.1 min (synminor)]. 4.3.8. 2-(Chloromethyl)-2-methyl-1-(2-naphthyl)-1,3-propanediol 5ad Data for the anti-isomer: State; 108.1 mg, 82% yield (anti/syn = 87/13); TLC: Rf 0.39 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); [a]29 D =
4.5 (c 1.06, EtOH) for 1 72% ee, [a]29 H NMR 435 =
10.3 (c 1.06, EtOH) for 72% ee; (400 MHz, CDCl3): d 0.84 (s, 3H), 2.73 (t, 1H, J = 5.5 Hz), 2.98 (d, 1H, J = 4.4 Hz), 3.63–3.90 (m, 4H), 5.11 (d, 1H, J = 4.4 Hz), 7.44– 7.60 (m, 3H), 7.78–7.94 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): d 16.8, 43.8, 50.4, 66.8, 78.3, 125.3, 126.2, 126.3, 126.4, 127.6, 127.7, 128.0, 132.9, 133.1, 137.8; IR (film): 3350 cm
1; LRMS (FAB): m/z 287 (M+Na)+, 217, 157, 69; HRMS (FAB): Calcd for C15H17ClNaO2 287.0815, found 287.0824. The enantiomeric excess was determined to be 72% ee (anti) and 63% ee (syn) by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane/IPA = 9:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 13.4 min (antiminor), 15.3 min (anti-major), 18.1 min (syn-major), 20.1 min (syn-minor)]. 4.3.9. (1S,2R)-2-(Chloromethyl)-2-methyl-1-(1-naphthyl)-1,3propanediol 5ae Data for the anti-isomer: State; 42.2 mg, 32% yield (anti/syn = 59/41); TLC: Rf 0.41 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); mp: 146.0–148.0 °C; [a]30 D = +5.4 (c 0.46, CHCl3) for 78% ee (after recrystallization); 1H NMR (400 MHz, CDCl3): d 0.72 (s, 3H), 2.84 (br s, 1H), 2.99 (br s, 1H), 3.56 (dd, 1H, J = 6.4 Hz, 11.5 Hz), 3.83 (d, 1H, J = 11.0 Hz), 3.94 (d, 1H, J = 11.0 Hz), 4.00 (d, 1H, J = 11.5 Hz), 6.01 (s, 1H), 7.66–7.41 (m, 3H), 7.99–7.76 (m, 3H), 8.12 (d, 1H, J = 8.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): d 17.5, 44.7, 51.1, 66.4, 72.3, 123.1, 125.2, 125.4, 125.6, 126.2, 128.6, 129.0, 131.6, 133.5, 136.6; IR (ATR): 3255 cm
1; LRMS (EI): m/z 264 (M)+, 157; HRMS (EI): Calcd for C15H17ClO2 264.0917, found 264.0913. The enantiomeric excess was determined to be 78% ee (anti) and 81% ee (syn) by chiral HPLC

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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx

with Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 29:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 32.0 min (anti-major), 35.9 min (anti-minor), 37.9 min (syn-major), 51.1 min (synminor)]. 4.3.10. 2-(Chloromethyl)-2-methyl-5-phenyl-4-pentene-1,3-diol 5af Data for the anti-isomer: State; 67.0 mg, 56% yield (anti/syn = 71/29); TLC: Rf 0.32 (hexane/EtOAc = 2:1, stained blue with phosphomolybdic acid/EtOH); mp: 105.0–107.0 °C; 29 [a]29 D =
1.4 (c 0.60, CHCl3) for 4% ee, [a]435 =
2.2 (c 0.60, CHCl3) 1 for 4% ee; H NMR (400 MHz, CDCl3): d 0.93 (s, 3H), 2.70 (br s, 1H), 2.78 (br s, 1H), 3.64–3.86 (m, 4H), 4.44 (d, 1H, J = 7.3 Hz), 6.32 (dd, 1H, J = 7.3 Hz, 16.0 Hz), 6.67 (d, 1H, J = 16.0 Hz), 7.20– 7.30 (m, 1H), 7.30–7.37 (m, 2H), 7.37–7.47 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): d 16.8, 43.5, 50.0, 66.8, 126.6, 127.4, 128.0, 128.7, 133.1, 136.2 (one carbon overlapped into CDCl3); IR (ATR): 3359 cm
1; LRMS (EI): m/z 240 (M)+, 222, 205, 192, 157, 133, 115, 91, 77; HRMS (EI): Calcd for C13H17ClO2 240.0917, found 240.0912. The enantiomeric excess was determined to be 4% ee (anti) and 14% ee (syn) by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane/IPA = 19:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 30.3 min (anti-major), 33.3 min (antiminor), 37.6 min (syn-major), 40.7 min (syn-minor)].

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Acknowledgments This work was partially supported by the Naito Foundation, JSPS KAKENHI Grant Number 16K08168, and a Grant-in-Aid for Scientific Research on Innovative Areas ‘Advanced Molecular Transformations by Organocatalysts’ from The Ministry of Education, Culture, Sports, Science, and Technology, Japan.

7. 8.

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A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.01. 006.

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