69451 Weinheim, Germany - Wiley-VCH · To a cold solution of 2-hydroxymethylenecyclic ketones (12.0 mmol) in 15 mL of dry dichloromethane at 0 °C, under nitrogen, DMAP (0.06 mmol)

Supporting Information

© Wiley-VCH 2007

69451 Weinheim, Germany

Enantioselective Radical Reactions. Stereoselective Aldol Synthesis from Cyclic Ketones

Mukund P. Sibi and Sukanya Nad Department of Chemistry North Dakota State University Fargo, ND 58105-5516 (USA) E-mail: [email protected] Fax: (+1) 701-231-1057 General: Dichloromethane was distilled from calcium hydride under nitrogen prior to use. Diethyl ether was distilled from

sodium benzophenone ketyl under nitrogen. Scandium triflate, Samarium triflate, Silver triflate, Silver hexafluoroantimonate

Magnesium perchlorate, Magnesium iodide, and (R, R)-N,N’-Bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexane-

diaminoaluminium(III) chloride were purchased from Aldrich chemicals. (R, R)-N,N’-Bis(3,5-di-tert-butyl-salicylidene)-1,2-

cyclohexane-diaminoaluminium(III) triflate, (R, R)-N,N’-Bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexane

diaminoaluminium(III) triflimide, (R, R)-N,N’-Bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexane diaminoaluminium(III)

hexafluoro antimonate, Cyclopropyl bisoxazoline ligand {3aS-[2(3’aR, 8’aS), 3aa, 8aa]}-2,2’-(cyclopropylidene)-bis{3a,8a-

dihydro-8H indeno[1,2d]-oxazole}, (-)-2,6-Bis[2-{3aS-(2(3’aR*, 8’aS*), 3a, 8a)-3a alpha, 8a alpha-dihydro-8H-indendo[1,2-

d]oxazole}]pyridine and were prepared according to literature procedure.

Flash chromatography was performed using EM Science silica gel 60 (230-400 mesh) or on an ISCOTM CombiFlash

Companion with AnaLogixTM RS-4 columns. All glassware was oven dried, assembled hot and cooled under a stream of

nitrogen before use. Reactions with air sensitive materials were carried out by standard syringe techniques.

Melting points were measured with a Fisher-Johns melting points apparatus and are uncorrected 1H-NMR were recorded

on a Varian Unity/Inova-500 NB (500 MHz) and Varian Unity/Inova-400 NB (400 MHz) or Varian Unity/Inova-400 NB (300

MHz). Chemical shifts are reported in parts per million (ppm) down field from TMS, using residual CDCl3 (7.26 ppm) as an

internal standard. Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet), coupling constant and integration. 13C-NMR was recorded in a Varian Unity/Inova-500 NB (125 MHz) or Varian

Unity/Inova-400 NB (100 MHz) spectrometers, using broadband proton decoupling. Chemical shifts are reported in parts per

million (ppm) downfield from TMS, using the middle resonance of CDCl3 (77.23) as an internal standard. HPLC analyses

were carried out on Waters 515 HPLC pump and a 2487 dual λ absorbance detector connected to a PC with Empower

workstation. Optical rotations were recorded on a JASCO-DIP-370 instrument. FT-IR spectra were recorded on a Mettler-

Toledo ReactIR-4000. High Resolution Mass Spectra (HRMS) (ESI+) were obtained from the Mass Spectrometry Laboratory,

North Dakota State University, Fargo, North Dakota.

2-Hydroxymethylenecyclic ketones were prepared by following the literature procedures.1

General procedure for the synthesis of α-methylene cyclic ketones:

(CH2)n

O

OH

(CH2)n

O

O

O

R+ R

n = 1, 2, 3.

Cl

ODMAP, Pyridine

DCM, 0 oC-RT

To a cold solution of 2-hydroxymethylenecyclic ketones (12.0 mmol) in 15 mL of dry dichloromethane at 0 °C, under nitrogen,

DMAP (0.06 mmol) was added followed by addition of acid chloride (14.4 mmol) and pyridine (18 mmol) respectively. The

mixture was slowly warmed from 0 °C to room temperature under nitrogen atmosphere for overnight. The solvent was

removed under reduced pressure to give the crude unsaturated ketone, which was finally purified by silicagel chromatography

(Hexane/EtOAc 4:1).

Benzoic acid 2-oxo-cyclohexylidenemethyl ester:

This was obtained in 81% yield as a white solid m.p. = 81 °C. 1H-NMR (400 MHz, CDCl3) δ 1.78

(m, 2H), 1.87 (m, 2H), 2.45 (t, J = 6.7 Hz, 2H), 2.73 (dt, J = 6.5 Hz, 2.3 Hz, 2H), 7.48 (t, J = 7.5

Hz, 2H), 7.62 (m, 1H), 8.11 (dd, J = 7.5 Hz, 1.5 Hz, 2H), 8.31 (t, J = 2.2 Hz, 1H). 13C-NMR (100

MHz, CDCl3) δ 22.9, 23.3, 24.7, 40.5, 122.2, 128.5, 128.9, 130.3, 134.4, 141.9, 162.8, 200.6. IR

(neat, cm-1): 2953, 2867, 1735, 1680, 1446, 1287, 1108, 699. HRMS Exact mass calcd. for

C14H15O3H+ 231.1021 found 231.1032.

4-Methoxy-benzoic acid 2-oxo-cyclohexylidenemethyl ester:

This was obtained in 75% yield as a white solid m.p. = 70 °C. 1H-NMR (400 MHz, CDCl3) δ

1.78 (m, 2H), 1.87 (m, 2H), 2.45 (t, J = 6.7 Hz, 2H), 2.72 (dt, J = 6.5 Hz, 2.3 Hz, 2H), 3.87 (s,

3H), 6.96 (dd, J = 7.0 Hz, 2.0 Hz, 2H), 8.06 (dd, J = 7.0 Hz, 2.0 Hz, 2H), 8.31 (t, J = 2.2 Hz,

1H). 13C-NMR (100 MHz, CDCl3) δ 22.2, 23.3, 24.6, 40.5, 55.7, 114.2, 121.7, 132.6, 133.0,

142.2, 162.5, 164.6, 200.7. IR (neat, cm-1): 2925, 2877, 1769, 1683, 1603, 1262, 1162, 761.

HRMS Exact mass calcd. for C15H16O4H+ 261.1127 found 261.1115.

2,4,6-Trimethyl-benzoic acid 2-oxo cyclohexylidenemethyl ester:


(m, 2H), 1.86 (m, 2H), 2.30 (s, 3H), 2.33 (s, 6H), 2.45 (t, J = 6.7 Hz, 2H), 2.73 (dt, J = 6.5 Hz, 2.3

Hz, 2H), 6.89 (s, 2H), 8.32 (t, J = 2.2 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 20.5, 21.4, 22.9,

23.3, 24.7, 40.5, 122.1, 129.1, 136.7, 140.9, 141.8, 165.9, 200.8. IR (neat, cm-1): 2921, 2870, 1737,

1684, 1610, 1443, 1272, 1096, 855. HRMS Exact mass calcd. for C17H20O3Na+ 295.1310 found

295.1305.

Phenylacetic acid 2-oxo-cyclohexylidenemethyl ester:

This was obtained in 81% yield as colorless oil. 1H-NMR (400 MHz, CDCl3) δ 1.72 (m, 2H),

1.84 (m, 2H), 2.42 (t, J = 6.7 Hz, 2H), 2.53 (dt, J = 6.5 Hz, 2.3 Hz, 2H), 3.77 (s, 2H), 7.33 (m,

5H), 8.07 (t, J = 2.2 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 22.8, 23.3, 24.5, 40.5, 41.2, 127.7,

128.8, 129.0, 129.5, 129.6, 141.7, 167.9, 200.8. IR (neat, cm-1): 2933, 2859, 1740, 1693, 1610,

1450, 1170, 1096, 933. HRMS Exact mass calcd. for C15H16O3Na+ 267.0997 found 267.0990.

O

O

O

C14H14O3

Exact Mass: 230.0943

Mol. Wt.: 230.2592

5

O

O

O

OMe

C15H16O4


Mol. Wt.: 260.2851

16

O

O

O

C17H20O3


Mol. Wt.: 272.3389

17

O

O

O

C15H16O3


Mol. Wt.: 244.2857

18

(2,4,6-Trimethylphenyl)-acetic acid 2-oxo-cyclohexylidenemethyl ester:


1.72 (m, 2H), 1.84 (m, 2H), 2.26 (s, 3H), 2.30 (s, 6H), 2.42 (t, J = 6.7 Hz, 2H), 2.50 (dt, J = 6.5

Hz, 2.3 Hz, 2H), 3.79 (s, 2H), 6.88 (s, 2H), 8.07 (t, J = 2.2 Hz, 1H). 13C-NMR (100 MHz,

CDCl3) δ 20.3, 21.0, 22.8, 23.3, 24.4, 34.9, 40.4, 121.6, 127.2, 129.2, 137.2, 141.8, 167.7, 200.6.

IR (neat, cm-1): 2950, 2861, 1715, 1690, 1612, 1415, 1272, 1096, 933. HRMS Exact mass calcd.

for C18H23O3H+ 287.1647 found 287.1627.

Naphthalene-1-carboxylic acid 2-oxo cyclohexylidenemethyl ester:


(m, 2H), 1.90 (m, 2H), 2.49 (t, J = 6.7 Hz, 2H), 2.75 (dt, J = 6.5 Hz, 2.3 Hz, 2H), 7.57 (m, 2H),

7.66 (m, 1H), 7.90 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.34 (dd, J = 7.3 Hz, 1.2 Hz, 1H),

8.44 (t, J = 2.2 Hz, 1H), 9.0 (d, J = 8.5 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 22.9, 23.4, 24.8,

40.5, 122.0, 124.6, 125.8, 126.8, 128.5, 128.7, 129.0, 131.6, 131.9, 134.1, 135.2, 142.1, 163.0,

200.7. IR (neat, cm-1): 2910, 2840, 1731, 1668, 1611, 1466, 1104, 870. HRMS Exact mass calcd.

for C18H16O3Na+ 303.0997 found 303.1011.

Naphthalene-2-carboxylic acid 2-oxo-cyclohexylidenemethyl ester:


1.83 (m, 2H), 1.91 (m, 2H), 2.49 (t, J = 6.7 Hz, 2H), 2.80 (dt, J = 6.5 Hz, 2.3 Hz, 2H), 7.59 (m,

2H), 7.90 (t, J = 8.2 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 8.07 (dd, J = 8.0 Hz, 1.8 Hz, 1H), 8.39 (t,

J = 2.2 Hz, 1H), 8.67 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ 22.9, 23.4, 24.8, 40.5, 122.2,

125.3, 125.7, 127.2, 128.1, 128.8, 129.2, 129.7, 132.4, 132.6, 136.2, 142.1, 163.0, 200.7. IR

(neat, cm-1): 2941, 2867, 1739, 1688, 1614, 1470, 1188, 1126, 1085, 773. HRMS Exact mass calcd. for C18H16O3Na+ 303.0997

found 303.1012.

4-Methoxy-benzoic acid 2-oxo-cyclopentylidenemethyl ester:


2.01 (quintet, J = 7.6 Hz, 2H), 2.39 (t, J = 7.61 Hz, 2H), 2.83 (m, 2H), 3.89 (s, 3H), 6.97 (d, J =

9.0 Hz, 2H), 8.07 (d, J = 9.0 Hz, 2H), 8.34 (t, J = 2.6 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ

20.2, 25.7, 39.4, 55.8, 114.2, 120.5, 121.8, 132.6, 140.1, 162.7, 164.6, 208.0. IR (neat, cm-1):

2910, 2844, 1734, 1653, 1601, 1256, 1147, 712. HRMS Exact mass calcd. for C14H14O4+

246.0892 found 246.0880.

4-Methoxy-benzoic acid 2-oxo-cycloheptylidenemethyl ester:

This was obtained in 75% yield as a white solid m.p. = 79 °C. 1H-NMR (400 MHz, CDCl3)

δ 1.73 (m, 6H), 2.63 (m, 4H), 3.86 (s, 3H), 6.96 (dd, J = 8.6 Hz, 2.0 Hz, 2H), 8.04 (dd, J =

8.6 Hz, 2.0 Hz, 2H), 8.31 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ 25.4, 29.7, 31.6, 44.4,

O

O

O

C18H22O3


Mol. Wt.: 286.3655

19

O

O

O

C18H16O3


Mol. Wt.: 280.3178

20

O

O

O

C18H16O3


Mol. Wt.: 280.3178

21

O

O

O

OMe

C14H14O4


Mol. Wt.: 246.2586

34

O

OO

OMe

C16H18O4


Mol. Wt.: 274.3117

35

55.7, 114.2, 120.7, 125.9, 132.5, 142.3, 162.6, 164.5, 204.1. IR (neat, cm-1): 2921, 2855, 1734, 1692, 1604, 1454, 1256, 1150,

1065, 1022, 765. HRMS Exact mass calcd. for C16H18O4Na+ 297.1103 found 297.1109.

Naphthalene-2-carboxylic acid 2-oxo-cycloheptylidenemethyl ester:


1.77 (m, 6H), 2.64 (m, 2H), 2.71 (m, 2H), 7.59 (m, 2H), 7.87 (t, J = 8.4 Hz, 2H), 7.96 (d, J =

8.0 Hz, 1H), 8.05 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 8.37 (s, 1H), 8.63 (s, 1H). 13C-NMR (100 MHz,

CDCl3) δ 25.4, 25.5, 29.7, 31.6, 44.4, 125.3, 125.7, 126.4, 127.2, 128.1, 128.8, 129.2, 129.7,

132.4, 132.6, 136.2, 142.1, 163.2, 204.0. IR (neat, cm-1): 2925, 2848, 1738, 1688, 1618, 1443,


Representative experimental procedure for chiral Lewis acid catalyzed conjugate addition of radicals to α-methylene

cyclic Ketones:

(CH2)n

O

O

O

R1

(CH2)n

O

O

O

R1

RRI, Lewis AcidBu3SnH (3 equiv)

Et3B/O2 (4 equiv)

CH2Cl2, -78 °C A mixture of Chiral Lewis acid (0.03 mmol) and α-methylene cyclic ketone (0.1 mmol) was stirred vigorously in 5.0 mL of

dichloromethane at room temperature for 45 min, and then cooled at –78 °C for 20 min. The reaction was initiated by

sequential addition of alkyl halide (0.5 mmol), tributyltin hydride (0.3 mmol), triethylborane (0.4 mmol 1 M solution in

hexane) and oxygen (introduced via syringe). The reaction was monitored by TLC (hexane/EtOAc 4:1), and after completion

was quenched with silica gel, evaporated, washed with hexanes. Finally the silicagel (containing product) was washed with

ethyl acetate and the crude product (ethyl acetate layer) was purified by silica gel chromatography (hexane/EtOAc 4:1).

Racemic standards were prepared using Sc(OTf)3 as a Lewis acid in the absence of a chiral ligand.

Benzoic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:

This was obtained in 80% yield as colorless oil. Enantiomeric purity was determined by HPLC (254

nm, 25 °C) tR 32.8 min (minor); tR 35.8 min (major) [Chiralcel ODH (1.0 cm x 25 cm) (from Daicel

Chemical Ind., Ltd.) hexane/i-PrOH, 96/4, 1.0 mL/min] as 77% ee. [α]D25 = -37.1 (c 0.77, CHCl3).

1H-NMR (500 MHz, CDCl3) δ 0.95 (d, J = 2.7 Hz, 3H), 0.97 (d, J = 2.7 Hz, 3H), 1.68 (m, 2H), 1.78

(m, 1H), 1.88 (m, 2H), 2.03 (m, 1H), 2.19 (m, 1H), 2.29 (m, 1H), 2.50 (m, 1H), 2.79 (m, 1H), 5.40

(dd, J =7.2 Hz, 5.0 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.53 (m, 1H), 8.01 (dd, J = 8.0 Hz, 1.3 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 17.2, 20.3, 24.1, 27.9, 29.6, 30.4, 42.2, 52.7, 77.7, 128.7, 130.1, 131.2,

133.2, 166.2, 210.1. IR (neat, cm-1): 2966, 2939, 2869, 1713, 1451, 1272, 1108, 712. HRMS Exact mass calcd. for

C17H22O3Na+ 297.1467 found 297.1460.

O

OO

C19H18O3


Mol. Wt.: 294.3444

35a

O

C17H22O3


Mol. Wt.: 274.3548

O O

6

Benzoic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 7.12 min (minor); tR 11.06 min (major) [Chiralcel OJ (0.46 cm x 25 cm) and OJH

(0.46 cm x 25 cm) were connected (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 99/1, 1.0

mL/min] as 85% ee. [α]D25 = -43.5 (c 0.21, CHCl3). 1H-NMR (300 MHz, CDCl3) δ 1.00 (s, 9H), 1.64

(m, 2H), 1.85 (m, 4H), 2.24 (m, 2H), 2.95 (q, J = 5.0 Hz, 1H), 5.29 (d, J = 5.6 Hz, 1H), 7.43 (t, J =

7.7 Hz, 2H), 7.53 (m, 1H), 8.01 (dd, J = 8.0 Hz, 1.3 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 22.0,

26.4, 27.3, 32.6, 36.7, 41.9, 51.0, 80.4, 128.7, 129.9, 130.2, 133.4, 166.3, 210.1. IR (neat, cm-1): 3050,

2966, 2949, 1710, 1700, 1250. HRMS Exact mass calcd. for C18H24O3Na+ 311.1623 found 311.1599.

4-Methoxy-benzoic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 46.0 min (minor); tR 51.9 min (major) [Chiralpak ADH (1.0 cm x 25 cm) (from Daicel



(m, 1H), 2.25 (m, 2H), 2.48 (m, 1H), 2.77 (m, 1H), 3.84 (s, 3H), 5.37 (dd, J =7.2 Hz, 5.0 Hz, 1H),

6.91 (dd, J = 7.0 Hz, 2.0 Hz, 2H), 7.98 (dd, J = 7.0 Hz, 2.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ

17.0, 20.1, 23.8, 27.7, 29.4, 30.2, 41.9, 52.5, 55.6, 79.4, 113.7, 122.9, 131.9, 163.5, 166.1, 210.1. IR

(neat, cm-1): 2960, 2951, 2869, 1714, 1440, 1265, 1108, 712. HRMS Exact mass calcd. for

C18H24O4Na+ 327.1572 found 327.1565.

4-Methoxy-benzoic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 36.5 min (major); tR 40.8 min (minor) [Chiralpak ADH (1.0 cm x 25 cm) (from Daicel


1H-NMR (500 MHz, CDCl3) δ 0.99 (s, 9H), 1.68 (m, 2H), 1.95 (m, 4H), 2.23 (m, 2H), 2.98 (m, 1H),

3.84 (s, 3H), 5.25 (d, J = 5.5 Hz, 1H), 6.93 (dd, J = 8.5 Hz, 1.3 Hz, 2H), 7.97 (dd, J = 8.5 Hz, 1.3 Hz,

2H). 13C-NMR (125 MHz, CDCl3) δ 21.6, 26.2, 27.0, 32.4, 36.5, 41.6, 50.7, 55.4, 79.9, 113.7, 122.4,

131.7, 163.5, 165.7, 210.7. IR (neat, cm-1): 3050, 2966, 2850, 1720, 1438, 1108, 708. HRMS exact

mass calcd. for C19H26O4Na+ 341.1729 found 341.1734.

2,4,6-Trimethyl-benzoic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:





(m, 5H), 2.26 (s, 3H), 2.33 (s, 6H), 2.45 (m, 1H), 2.81 (m, 1H), 5.51 (dd, J = 7.2 Hz, 4.4 Hz, 1H),

6.84 (s, 2H). 13C-NMR (125 MHz, CDCl3) δ 20.1, 20.4, 24.3, 25.6, 27.7, 28.9, 29.8, 41.9, 52.9, 67.9,

74.8, 128.6, 134.6, 135.6, 139.1, 165.9, 210.1. IR (neat, cm-1): 3044, 2960, 2850, 1724, 1260, 711.

HRMS Exact mass calcd. for C20H28O3Na+ 339.1936 found 339.1928.

O O O

C18H24O3


Mol. Wt.: 288.3814

7

O O O

OMe

C18H24O4


Mol. Wt.: 304.3808

22

O O O

OMe

C19H26O4


Mol. Wt.: 318.4073

23

O O O

C20H28O3


Mol. Wt.: 316.4345

24

2,4,6-Trimethyl-benzoic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 64.1 min (major); tR 87.0 min (minor) [ChiralPak ADH (1.0 cm x 25 cm)(from Daicel


1H-NMR (500 MHz, CDCl3) δ 1.01 (m, 9H), 1.65 (m, 3H), 1.85 (m, 3H), 2.15 (m, 1H), 2.26 (s, 3H),

2.33 (s, 6H), 2.45 (m, 1H), 2.81 (m, 1H), 5.40 (d, J = 4.4 Hz, 1H), 6.84 (s, 2H). 13C-NMR (125 MHz,

CDCl3) δ 21.0, 21.2, 24.1, 27.2, 27.5, 28.0 31.8, 42.2, 53.1, 80.8, 129.1, 136.3, 139.6, 165.9, 210.1. IR

(neat, cm-1): 3040, 2960, 2850, 1720, 1260, 1108, 712. HRMS Exact mass calcd. for C21H30O3Na+

353.2093 found 353.2080.

Phenyl-acetic acid 2-methyl -1-(2-oxo-cyclohexyl)-propyl ester:





(m, 4H), 2.25 (m, 1H), 2.45 (m, 1H), 2.61 (m, 1H), 3.58 (s, 2H), 5.14 (dd, J = 7.2 Hz, 4.4 Hz, 1H),

7.27 (m, 5H). 13C-NMR (125 MHz, CDCl3) δ 16.3, 19.9, 23.9, 27.7, 28.9, 30.0, 41.8, 41.9, 52.3, 76.6,

127.1, 128.6, 129.5, 129.6, 133.1, 169.4, 210.1. IR (neat, cm-1): 2966, 2954, 2850, 1711, 1257, 1110,

709. HRMS Exact mass calcd. for C18H24O3Na+ 311.1623 found 311.1635.

Phenyl-acetic acid 2,2-dimethyl -1-(2-oxo-cyclohexyl)-propyl ester:





3.60 (s, 2H), 5.12 (d, J = 6.0 Hz, 1H), 7.25 (m, 5H). 13C-NMR (100 MHz, CDCl3) δ 22.1, 26.4, 27.5,

32.3, 36.2, 41.7, 42.1, 51.3, 80.2, 127.3, 128.7, 129.7, 129.6, 133.4, 170.2, 210.1. IR (neat, cm-1):

2965, 2950, 2900, 1711, 1250, 1108, 719. HRMS Exact mass calcd. for C19H26O3Na+ 325.1780 found

325.1790.

(2,4,6-Trimethyl-phenyl)-acetic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:

This was obtained in 85% yield as colorless oil. Enantiomeric purity was determined by HPLC

(254 nm, 25 °C) tR 32.0 min (minor); tR 48.6 min (major) [Chiralpak ADH (1.0 cm x 25 cm)(from

Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 96/4, 1.0 mL/min] as 94% ee. [α]D25 = -40.4 (c 0.35,

CHCl3). 1H-NMR (300 MHz, CDCl3) δ 0.78 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 1.63 (m,

3H), 1.77 (m, 2H), 1.89 (m, 2H), 2.01 (m, 1H), 2.24 (m, 3H), 2.27 (m, 6H), 2.43 (m, 1H), 2.58 (m,

1H), 3.61 (s, 2H), 5.14 (dd, J = 7.2 Hz, 4.4 Hz, 1H), 6.83 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ

16.4, 20.2, 20.6, 21.3, 24.0, 27.9, 29.1, 30.2, 35.4, 21.9, 52.7, 76.6, 129.1, 129.2, 136.7, 137.4,

171.4, 211.0. IR (neat, cm-1): 3054, 2950, 2870, 1724, 1270, 1108, 708. HRMS Exact mass calcd.

for C21H30O3Na+ 353.2093 found 353.2085.

O O O

C21H30O3


Mol. Wt.: 330.4611

25

O O O

C18H24O3


Mol. Wt.: 288.3814

26

O O O

C19H26O3


Mol. Wt.: 302.4079

27

O O O

C21H30O3


Mol. Wt.: 330.4611

28

(2,4,6-Trimethyl-phenyl)-acetic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:

This was obtained in 75% yield as a colorless oil. Enantiomeric purity was determined by HPLC

(254 nm, 25 °C) tR 20.2 min (minor); tR 24.7 min (major) [Chiralpak ADH (1.0 cm x 25 cm)(from


CHCl3). 1H-NMR (500 MHz, CDCl3) δ 0.85 (s, 9H), 1.57 (m, 2H), 1.74 (m, 1H), 1.85 (m, 3H),

2.18 (m, 2H), 2.24 (m, 3H), 2.27 (m, 6H), 2.67 (m, 1H), 3.62 (s, 2H), 5.02 (d, J = 6.2 Hz, 1H),

6.84 (s, 2H). 13C-NMR (125 MHz, CDCl3) δ 20.4, 21.1, 22.1, 26.4, 27.5, 28.2, 32.3, 35.5, 41.6,

51.4, 80.0, 128.3, 129.1, 136.4, 137.2, 171.2, 210.9. IR (neat, cm-1): 3050, 2988, 2875, 1720, 1211,

1100, 708. HRMS Exact mass calcd. for C22H32O3Na+ 367.2249 found 367.2258.

Naphthalene-1-carboxylic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:





(m, 1H), 1.90 (m, 2H), 2.07 (m, 1H), 2.24 (m, 1H), 2.32 (m, 1H), 2.52 (m, 1H), 2.84 (s, 1H), 5.54 (dd,

J = 7.5 Hz, 4.5 Hz, 1H), 7.50 (m, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 8.00 (d, J =

8.0 Hz, 1H), 8.11 (d, J = 7.1 Hz, 1H), 8.91 (d, J = 8.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3) δ 17.5,

20.9, 24.7, 28.5, 30.0, 30.9, 42.7, 53.3, 78.2, 125.4, 126.8, 127.0, 128.5, 128.6, 129.3, 130.6, 132.3,

133.9, 134.7, 168.0, 211.5. IR (neat, cm-1): 3054, 2970, 1711, 1700, 1266. HRMS Exact mass calcd. for C21H24O3Na+

347.1623 found 347.1630.

Naphthalene-1-carboxylic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 47.2 min (major); tR 51.8 min (minor) [Chiralcel ODH (1.0 cm x 25 cm) (from Daicel



5.45 (d, J = 6.0 Hz, 1H), 7.50 (m, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 8.00 (d, J =

8.0 Hz, 1H), 8.11 (d, J = 7.1 Hz, 1H), 8.91 (d, J = 8.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3) δ 22.7,

27.1, 27.9, 33.1, 37.2, 42.5, 51.8, 80.6, 125.4, 126.4, 126.9, 127.3, 128.6, 129.3, 131.0, 132.4, 134.3,

134.6, 167.4, 211.5. IR (neat, cm-1): 3055, 2970, 1711, 1700, 1265. HRMS Exact mass calcd. for

C22H26O3Na+ 361.1780 found 361.1786.

Naphthalene-2-carboxylic acid 2-methyl-1-(2-oxo-cyclohexyl)-propyl ester:


nm, 25 °C) tR 80.9 min (major); tR 88.9 min (minor) [Chiralpak ADH (1.0 cm x 25 cm) (from Daicel


1H-NMR (400 MHz, CDCl3) δ 1.00 (t, J = 7.3 Hz, 6H), 1.72 (m, 4H), 1.95 (m, 1H), 2.15 (m, 1H),

2.23 (m, 2H), 2.52 (m, 1H), 2.83 (m, 1H), 5.46 (dd, J = 7.1 Hz, 5.1 Hz, 1H), 7.55 (m, 2H), 7.86 (d, J =

8.2 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 8.67 (s, 1H). 13C-NMR (100 MHz,

CDCl3) δ 17.1, 20.1, 24.0, 27.7, 29.5, 30.3, 42.0, 52.6, 77.5, 125.6, 126.7, 127.8, 127.9, 128.3, 128.4,

O O O

C22H32O3


Mol. Wt.: 344.4877

29

O O O

C21H24O3


Mol. Wt.: 324.4135

30

O O O

C22H26O3


Mol. Wt.: 338.4400

31

O O

C21H24O3


Mol. Wt.: 324.4135

O

32

129.6, 131.3, 132.7, 135.7, 166.5, 211.5. IR (neat, cm-1): 3042, 2965, 1720, 1700, 1263. HRMS Exact mass calcd. for

C21H24O3Na+ 347.1623 found 347.1635.

Naphthalene-2-carboxylic acid 2,2-dimethyl-1-(2-oxo-cyclohexyl)-propyl ester:



Chemical Ind., Ltd.) hexane/i-PrOH, 99/1, 1.0 mL/min] as 94% ee. [α]D25 = -14.8 (c 0.32, CHCl3). 1H-

NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.65 (m, 2H), 2.01 (m, 4H), 2.25 (m, 2H), 3.01 (m, 1H), 5.37

(d, J = 5.5 Hz, 1H), 7.55 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz,

1H), 8.67 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ 22.0, 26.5, 27.3, 32.6, 36.8, 41.9, 51.1, 80.6, 125.4,

125.6, 126.8, 127.9, 128.5, 129.7, 131.5, 132.7, 133.0, 135.8, 166.5, 211.5. IR (neat, cm-1): 3041, 2966,

1722, 1700, 1265. HRMS Exact mass calcd. for C22H26O3Na+ 361.1780 found 361.1799.

4-Methoxy-benzoic acid 2-methyl-1-(2-oxo-cyclopentyl)-propyl ester:




NMR (500 MHz, CDCl3) δ 0.92 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 1.60 (m, 1H), 1.78 (m,

2H), 1.99 (m, 1H), 2.20 (m, 2H), 2.40 (m, 1H), 2.58 (m, 1H), 3.85 (s, 3H), 5.15 (dd, J = 7.5 Hz, 4.5 Hz,

1H), 6.92 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 18.4, 19.6, 20.9,

27.4, 30.1, 39.4, 49.0, 55.6, 78.6, 113.8, 122.8, 131.8, 163.5, 166.2, 217.9. IR (neat, cm-1): 2960, 2877,

1724, 1717, 1451, 1272, 1108, 712. HRMS Exact mass calcd. for C17H22O4Na+ 313.1416 found

313.1425.

4-Methoxy-benzoic acid 2,2-dimethyl-1-(2-oxo-cyclopentyl)-propyl ester:




NMR (500 MHz, CDCl3) δ 1.03 (s, 9H), 1.71 (m, 1H), 2.00-2.31 (m, 5H), 2.52 (m, 1H), 3.85 (s, 3H),

4.85 (d, J = 4.3 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H). 13C-NMR (125 MHz,

CDCl3) δ 21.1, 26.6, 31.2, 35.8, 39.1, 48.5, 55.6, 82.2, 113.9, 122.9, 131.9, 163.6, 166.5, 216.9. IR

(neat, cm-1): 2964, 2878, 1712, 1714, 1450, 1270, 1109, 712. HRMS Exact mass calcd. for C18H24O4+

304.1675 found 304.1645.

4-Methoxy-benzoic acid 2-methyl-1-(2-oxo-cycloheptyl)-propyl ester:




1H-NMR (500 MHz, CDCl3) δ 0.92 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 1.49 (s, 3H), 1.92

(m, 5H), 2.07 (m, 1H), 2.39 (m , 1H), 2.66 (m, 1H), 2.83 (m, 1H), 3.84 (s, 3H), 5.15 (t, J = 6.5 Hz,

1H), 6.91 (d, J = 8.5 Hz, 2H), 7.97 (dd, J = 8.5 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 17.5, 20.2,

O O O

C22H26O3


Mol. Wt.: 338.44

33

O

C17H22O4


Mol. Wt.: 290.3542

O O

OMe

36

O O O

OMe

C18H24O4


Mol. Wt.: 304.3808

37

O O

OMe

C19H26O4


Mol. Wt.: 318.4073

O

38

26.5, 27.8, 28.4, 30.0, 30.6, 43.1, 55.3, 55.9, 79.7, 114.1, 122.9, 132.1, 163.9, 166.3, 214.5. IR (neat, cm-1): 2966, 2950, 2860,


4-Methoxy-benzoic acid 2,2-dimethyl-1-(2-oxo-cycloheptyl)-propyl ester:


nm, 25 °C) tR 30.7 min (major); tR 45.6 min (minor) [Chiralpak ADH (1.0 cm x 25 cm)(from Daicel



2.05 (m, 1H), 2.20 (m, 1H), 2.54 (m, 1H), 2.87 (m, 1H), 3.84 (s, 3H), 5.05 (d, J = 3.7 Hz, 1H), 6.91 (d,

J = 8.5 Hz, 2H), 7.97 (dd, J = 8.5 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 26.3, 26.9, 27.3, 28.1, 30.6,

31.2, 36.4, 42.4, 54.2, 55.6, 82.6, 114.0, 121.3, 132.0, 163.8, 166.1, 214.3. IR (neat, cm-1): 2966, 2950,

2869, 1720, 1265, 1108, 712. HRMS Exact mass calcd. for C20H28O4Na+ 355.1885 found 355.1990.

Naphthalene-2- carboxylic acid 2-methyl-1-(2-oxo-cycloheptyl)-propyl ester:


nm, 25 °C) tR 207.7 min (major); tR 229.0 min (minor) [Chiralpak ADH (1.0 cm x 25 cm) (from


CHCl3). 1H-NMR (500 MHz, CDCl3) δ 0.99 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 1.35-1.60 (m,

3H), 1.91 (m, 5H), 2.15 (m, 1H), 2.41 (m, 1H), 2.72 (m, 1H), 2.95 (m, 1H), 5.26 (t, J = 6.4 Hz, 1H),

7.59 (m, 2H), 7.87 (d, J = 6.4 Hz, 2H), 7.96 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 8.63

(s, 1H). 13C-NMR (125 MHz, CDCl3) δ 17.4, 20.1, 26.2, 27.7, 28.2, 29.8, 30.4, 43.0, 55.2, 80.0, 125.6,

126.9, 127.6, 128.0, 128.5, 128.6, 129.7, 131.5, 132.8, 135.9, 166.6, 214.3. IR (neat, cm-1): 3040, 2965,

1720, 1265. HRMS Exact mass calcd. for C22H26O3H+ 339.1960 found 339.1968.

4-Methoxy-benzoic acid 1-(2-oxo-cyclohexyl)-butyl ester:




NMR (400 MHz, CDCl3) δ 0.91 (d, J = 7.3 Hz, 3H), 1.42 (m, 2H), 1.64 (m, 5H), 1.88-2.15 (m, 2H),

2.13 (m, 1H), 2.30 (m, 1H), 2.41 (m, 1H), 2.79 (m, 1H), 3.84 (s, 3H), 5.51 (q, J =4.3 Hz, 1H), 6.91 (d,

J = 9.0 Hz, 2H), 7.98 (dd, J = 9.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 14.1, 19.2, 24.5, 27.5, 28.5,

33.1, 42.2, 53.8, 55.6, 73.2, 113.7, 122.3, 131.8, 163.5, 166.1, 210.1. IR (neat, cm-1): 2958, 2939, 2871,


4-Methoxy-benzoic acid 1-(2-oxo-cyclohexyl)-hex-5-enyl ester:




1H-NMR (400 MHz, CDCl3) δ 1.48 (m, 1H), 1.65 (m, 7H), 1.91 (m, 1H), 2.11, (m, 3H), 2.32 (m, 1H),

2.41 (m, 1H), 2.79 (m, 1H), 3.85 (s, 3H), 4.97 (m, 2H), 5.50 (m, 1H), 5.77 (m, 1H), 6.91 (d, J = 9.0 Hz,

2H), 7.98 (dd, J = 9.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 24.5, 25.2, 27.5, 28.4, 30.4, 33.6, 42.2,

O O

OMe

O

C20H28O4


Mol. Wt.: 332.4339

39

O OO

C22H26O3


Mol. Wt.: 338.4400

38a

O O O

OMe

C18H24O4


Mol. Wt.: 304.3808

40

O O O

OMe

C20H26O4


Mol. Wt.: 330.4180

41

53.7, 55.6, 73.3, 113.8, 114.9, 122.3, 131.8, 138.6, 163.5, 166.1, 210.1. IR (neat, cm-1): 2950, 2944, 2850, 1705, 1277, 1150,

785. HRMS Exact mass calcd. for C20H26O4Na+ 353.1729 found 353.1733.

4-Methoxy-benzoic acid 2-methoxy-1-(2-oxo-cyclohexyl)-ethyl ester:




NMR (500 MHz, CDCl3) δ 1.69 (m, 3H), 1.91 (m, 1H), 2.05, (m, 1H), 2.18 (m, 1H), 2.35 (m, 1H),

2.42 (m, 1H), 2.94 (m, 1H), 3.36 (s, 3H), 3.69 (m, 2H), 3.84 (s, 3H), 5.54 (q, J = 5.1 Hz, 1H), 6.91 (d, J

= 9.0 Hz, 2H), 7.97 (dd, J = 9.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 24.8, 27.9, 29.6, 42.4, 51.5,

55.6, 59.4, 71.8, 72.0, 113.7, 121.3, 132.0, 163.6, 165.9, 210.0. IR (neat, cm-1): 2960, 2939, 2780, 1720,

1275, 1141, 720. HRMS Exact mass calcd. for C17H23O5H+ 307.1545 found 307.1552.

4-Methoxy-benzoic acid cyclopentyl-(2-oxo-cyclohexyl)-methyl ester:


nm, 25 °C) tR 13.6 min (major); tR 18.4 min (minor) [Chiralpak ASH (0.46 cm x 25 cm) (from Daicel


NMR (500 MHz, CDCl3) δ 1.25 (m, 1H), 1.44 (m, 2H), 1.51 (m, 4H), 1.68 (m, 4H), 1.84 (m, 2H), 2.11

(m, 1H), 2.24 (m, 1H), 2.41 (m, 2H), 2.71 (m, 1H), 3.84 (s, 3H), 5.54 (t, J = 6.5 Hz, 1H), 6.91 (d, J =

9.0 Hz, 2H), 7.97 (dd, J = 9.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 24.0, 25.3, 25.6, 27.5, 28.1,

29.7, 30.3, 41.7, 42.1, 53.8, 55.6, 76.0, 113.8, 123.0, 131.9, 163.6, 166.2, 210.6. IR (neat, cm-1): 2946,

2867, 1710, 1509, 1449, 1243, 1190, 1130, 1127, 799. HRMS Exact mass calcd. for C20H26O4H+

331.1909 found 331.1898.

4-Methoxy-benzoic acid cyclohexyl-(2-oxo-cyclohexyl)-methyl ester:




1H-NMR (500 MHz, CDCl3) δ 1.10 (m, 2H), 1.23 (m, 1H), 1.61-1.74 (m, 10H), 1.87 (m, 3H), 2.01 (m,

1H), 2.29 (m, 1H), 2.47 (m, 1H), 2.80 (m, 1H), 3.84 (s, 3H), 5.33 (m, 1H), 6.91 (d, J = 9.0 Hz, 2H),

7.97 (dd, J = 9.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 24.0, 26.2, 26.4, 26.5, 27.6, 27.7, 30.3, 30.5,

39.2, 42.0, 51.8, 55.6, 76.6, 113.8, 123.0, 131.9, 163.5, 166.2, 210.6. IR (neat, cm-1): 2940, 2864, 1720,

1501, 1449, 1244, 1190, 1135, 1127, 789. HRMS Exact mass calcd. for C21H28O4H+ 345.2066 found

345.2076.

4-Methoxy-benzoic acid 5-chloro-2,2-dimethyl-1-(2-oxo-cyclohexyl)-pentyl ester:

This was obtained in 85% yield as colorless oil. Enantiomeric purity was determined by HPLC

(254 nm, 25 °C) tR 36.9 min (major); tR 50.0 min (minor) [Chiralpak ADH (1.0 cm x 25 cm)

(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 90/10, 1.0 mL/min] as 83% ee. [α]D25 = -44.4

(c 0.24, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.97 (s, 3H), 0.99 (s, 3H), 1.55 (m, 1H), 1.65 (m,

4H), 1.87, (m, 5H), 2.24 (m, 2H), 2.95 (m, 1H), 3.48 (m, 2H), 3.86 (s, 3H), 5.28 (d, J = 5.1 Hz,

1H), 6.91 (d, J = 9.0 Hz, 2H), 7.97 (dd, J = 9.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 21.9, 23.4,

O O

OMe

O

OMe

C17H22O5


Mol. Wt.: 306.3536

42

O O O

OMe

C20H26O4


Mol. Wt.: 330.4180

43

O O O

OMe

C21H28O4


Mol. Wt.: 344.4446

44

O O O

OMe

Cl

C21H29ClO4


Mol. Wt.: 380.9056

45

23.8, 27.2, 27.6, 32.8, 36.1, 42.0, 45.9, 50.6, 55.7, 79.3, 114.1, 122.4, 132.0, 163.5, 166.1, 210.1. IR (neat, cm-1): 2955, 2939,

2877, 1720, 1150, 780. HRMS Exact mass calcd. for C21H29ClO4Na+ 403.1652 found 403.1661.

4-Methoxy-benzoic acid adamantan-1-yl-(2-oxo-cyclohexyl)-methyl ester:



Chemical Ind., Ltd.) hexane/i-PrOH, 90/10, 1.0 mL/min] as 5% ee. 1H-NMR (500 MHz, CDCl3) δ 1.71

(m, 14H), 1.92 (m, 4H), 2.01 (s, 3H), 2.25 (m, 2H), 3.01 (m, 1H), 3.85 (s, 3H), 5.18 (d, J = 5.3 Hz, 1H),

6.91 (d, J = 9.0 Hz, 2H), 7.97 (dd, J = 9.0 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ 13.8, 17.6, 21.8,

27.0, 27.2, 28.0, 28.3, 32.8, 37.0, 38.3, 38.6, 42.0, 49.1, 55.6, 80.5, 114.0, 122.6, 132.0, 163.8, 166.1,

211.2. IR (neat, cm-1): 3050, 2867, 1711, 1500, 1445, 1190, 1130, 1127, 780. HRMS Exact mass calcd.

for C25H32O4Na+ 419.2198 found 419.2189.

Stereochemical analysis: It was found that the product from the radical reaction 6 contained anti (1S, 2S) stereochemistry (see below).

The relative stereochemistry was assigned by converting 6 into the corresponding benzilidine derivative, which has been

reported in the literature.2

OO

Hd

Hc

HbHa

Spectrum assigned by 2D-COSY at 400 MHz

nOe (Ha*) [Hb + Hc] 15.2%;

Hb and Hd did not show any nOe. Hb and Hd are anti

O

O

OLiAlH4, Et2O, RT, 15 min

80%

OH

dr 99:1

OH

OH

OH

+

dr 83:17

PhCHO

5 mol% p-TsOH

C7H8, 50 oC

O

He

O

Ha

Hc Hb

Hd

Flash column

6

A two-neck 100 mL flask was charged with lithium aluminum hydride (15 mg, 0.39 mmol) and 10 mL dry ether was added

under nitrogen at 0 °C. A solution of 6 (0.11 g, 0.39 mmol) in 5 mL dry ether was added to the lithium aluminum hydride

solution over 20 min under nitrogen at 0 °C. The reaction mixture was stirred for 15 min at room temperature. The mixture was

then quenched with 0.02 mL water, 0.02 mL 15% NaOH, and 0.04 mL water. The resulting white reaction mixture was stirred

for 1 h. The mixture was filtered under vacuum and the residue was washed with diethyl ether (3x10 mL). The combined

filtrates were concentrated under reduced pressure and purified by silicagel chromatography (cyclohexane/EtOAc 1:1) to give

0.06 g (80%) the corresponding diol as colorless oil (dr 83:17).

To a solution of diol (0.05 g, 0.29 mmol) in 8 mL of toluene at room temperature, benzaldehyde (0.037 g, 0.34 mmol) was

added followed by addition of p-toluenesulfonic acid monohydrate (3 mg, 0.01 mmol). The mixture was stirred at 50 °C for

overnight. The solvent was removed under reduced pressure to give the crude benzilidine derivatives and the major

diastereomer was finally separated by silicagel chromatography (Hexane/EtOAc 4:1). The structure was assigned by

comparing the known compound and the absence of nOe effects between Hb and Hd confirmed the formation of anti product.

The absolute stereochemistry was assigned by converting known alcohol in to the radical product 6.3

O O O

OMe

C25H32O4


Mol. Wt.: 396.5192

46

O

+ CHO30 mol% (S)-proline

DMSO, RT, 5 d

O OH

anti

97% ee

PhCOCl, DMAP

Pyridine, RT, 2 h

O OCOPh

HPLC analysis of this known stereochemical product shows that the radical adduct is thesame enantiomer

Chiral reaction (Al-salen/X=OTf):ODH 4%iPrOH:

major peak = tR = 35.8 min. From Known aldol

product (1S, 2S): major peak = tR = 35.8 min.

6

(S)-proline (35 mg, 0.3 mmol) in 10 mL of DMSO/cyclohexanone (4:1) was treated with isobutyraldehyde (1 mmol) at room

temperature. The mixture was stirred for 5 days and worked up in the usual manner using aq. ammonium chloride solution and

ethyl acetate. Chromatography on silica using hexane/ethyl acetate (5:1) furnished known aldol anti-alcohol as a single

diastereomer (116 mg, 0.68 mmol).

To a cold solution of anti-aldol (116 mg, 0.68 mmol) in 8 mL of dry dichloromethane at 0 °C, under nitrogen, DMAP (4 mg,

0.03 mmol) was added followed by addition of benzoyl chloride (0.1 mL, 0.74 mmol) and pyridine (0.1 mL, 1.02 mmol)

respectively. The mixture was slowly warmed from 0 °C to room temperature under nitrogen atmosphere for 2 h. The solvent

was removed under reduced pressure to give the crude aldol, which was finally purified by silicagel chromatography

(Hexane/EtOAc 4:1) to give 0.14 g (80%) of the corresponding ester 6 as colorless oil (dr 99:1).

References 1. a) C. Ainsworth, Organic Syntheses, 1963, 4, 536; b) P. E. Eaton, P. G. Jobe, Synthesis, 1983, 796; c) S. Brückner, E.

Abraham, P. Klotz, J. Suffert, Org. Lett. 2002, 4, 3391-3393.

2. D. H. Birtwistle, J. M. Brown, Michael, W. Foxton, Tetrahedron Lett. 1986, 27, 4367-4370.

3. S. Bahmanyar, K. N. Houk, H. J. Martin, B. List, J. Am. Chem. Soc. 2003, 125, 2475-2479.

Documents

69451 Weinheim, Germany - Wiley-VCH · To a cold solution of 2-hydroxymethylenecyclic ketones (12.0 mmol) in 15 mL of dry dichloromethane at 0 °C, under nitrogen, DMAP (0.06 mmol)