Toward the creation of NMR databases in chiral solvents: bidentate chiral NMR solvents for assignment of the absolute configuration of acyclic secondary alcohols.

Article abstract of DOI:10.1021/ol0171160

The absolute configuration of acyclic secondary alcohols can be established from analysis of the chemical shift behaviors of the adjacent carbons in bidentate chiral solvents (R,R)- and (S,S)-1d as formulated in the boxed illustration.

Full text of DOI:10.1021/ol0171160

Supporting Information
Toward the Creation of NMR Databases in Chiral Solvents:
Bidentate Chiral NMR Solvents for Assignment of the Absolute Configuration of
Acyclic Secondary Alcohols
Yoshihisa Kobayashi, Nobuyuki Hayashi, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University
Oxford Street, Cambridge, Massachusetts 02138
Synthesis of chiral NMR solvents 1a~d
Chiral NMR solvents 1a, 1b and 1d were prepared, with small modifications of
the literature known methods [(a) Horner, L.; Dickerhof, K. Liebigs Ann. Chem. 1984,
1240-1258; (b) Mimoun, H.; Laumer, J. Y. S.; Giannini, L.; Scopelliti, R.; Floriani, C. J. Am.
Chem. Soc. 1999, 121, 6158-6166].
General procedure for 1a, 1b and 1d: Dibromopropane (2.08 g, 10.3 mmol,
1equiv.) was added dropwise over 5 min to (R)-α-phenetylamine (5.00g, 41.3 mmol, 4
equiv.) at 130 °C. After stirring for 30 min, the mixture was cooled to 80 °C and then
poured into aqueous 50 % NaOH solution (300 mL). The resulting free amines were
extracted with EtOAc (300 mL) and the organic layer was washed with brine, dried over
anhydrous K2CO3, filtered and evaporated to give the crude oil. The crude product was
distilled by Kugelrohr to give pure 1a (2.56 g 82%).
Dibromoethane (1.94 g) was used for synthesis of 1b (2.39g, 86%) according to
the procedure shown above.
1,3-Dibromo-2-methylpropane used for synthesis of 1d was prepared, according
to the procedure reported by B. Török and Á. Molnár (J. Chem. Soc. Perkin Trans. 1 1993,
801-804).
- 1 -

Chiral NMR solvent 1c was prepared by LAH-reduction of the literature known
amide N,N'-bis-(1-phenylethyl)-succinamide (Potapov, V. M.; Koval', G. N.; Solov'eva,
L. D. J. Org. Chem. USSR 1985, 21, 705-708).
For spectroscopic data of 1a,b, see: Hulst, R.; de Vries, N. K.; Feringa, B. L.
Tetrahedron:Asymmetry 1994, 5, 699-708.
Spectroscopic data of chiral NMR solvents 1c,d:
1c ([α]D25 = +60 (c 1.1 CHCl3)): 145.7 (x2), 128.3 (x4), 126.8 (x2), 126.5 (x4), 58.3 (x2),
47.6 (x2), 28.0 (x2), 24.3 (x2).
1d ([α]D25 = +68 (c 1.0 CHCl3)): 146.0, 145.9, 128.3 (x4), 126.7 (x2), 126.5 (x4), 58.6,
58.4, 53.9, 53.8, 33.8, 24.5, 24.4, 17.3.
13C NMR Data of 2, 3, 6, 8a and 8b (100 MHz, CDCl3)
2: 72.0, 37.2 (x2), 27.8 (x2), 22.8 (x2), 14.1 (x2).
3: 72.8, 41.6 (x2), 27.0, 26.1 (x2), 23.3 (x2), 14.1 (x2).
6: 74.6, 29.8 (x2), 9.8 (x2).
8a: 82.2, 46.8, 39.7 (x2), 35.1 (x2), 32.1, 27.5 (x3), 19.0 (x2).
8b: 74.5, 47.6, 37.4 (x2), 32.3, 28.4 (x2), 27.6 (x3), 18.7 (x2).
Synthesis of alcohols 9, 10, 13 and 14
The alcohol 10 was obtained from valeraldehyde by Brown's asymmetric
allylation (Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org. Chem. 1986, 51,
432-439). Hydrogenation (H2/Pd on C/MeOH) of 10 gave the alcohol 9.
13C NMR (100 MHz, CDCl3) of 9: 71.7, 39.6, 37.2, 27.8, 22.7, 18.8, 14.10, 14.06.
13C NMR (100 MHz, CDCl3) of 10: 134.9, 118.0, 70.6, 41.9, 36.5, 27.8, 22.7, 14.0.
Optically active 11 and 12 were obtained from Aldrich.
- 2 -

Alcohol 13 was prepared in 2 steps: (1) Jacobsen's hydrolytic kinetic resolution of
( )-isobutyloxirane (Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science,
1997, 277, 936) and (2) LAH/THF.
13C NMR (100 MHz, CDCl3) 13: 66.1, 48.6, 24.8, 24.0, 23.2, 22.3.
Alcohol 14 was obtained by CBS reduction of pinacolone (Corey, E. J.; Bakshi, R.
K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-5553).
13C NMR (100 MHz, CDCl3) 14: 75.6, 34.9, 25.3 (x3), 17.9.
Synthesis of alcohols 16~19 was carried out as summarized below.
1. TrCl, Et3N, DMAP
1. (-)-Ipc2BOMe
CH2Cl2, quant.
AllylMgBr
Me
Me
BnO
CHO
HO
TrO
2. H2, Pd/C, EtOH
2. MPMCl, tBuOK
TBAI, DMF, quant.
OH
OMPM
67% for 2 steps
1. TsOH•H2O
MeOH/CH2Cl2 ,89%
2. SO3•Py, Et3N
DMSO, 93%
1. (+)-Ipc2 BOMe
AllylMgBr
OH
OH
Me
Me
Me
2. H2, Pd/C, EtOH
56% for 2 steps
OH
OH
18
OHC
Me
1. (-)-Ipc2BOMe
AllylMgBr
OMPM
Me
2. H2, Pd/C, EtOH
53% for 2 steps
18'
Scheme S1. Synthesis of diols 18 and 18'
The synthesis of meso-diols 16, 17 and 19 and optically active diols 16', 17' and 19'
was carried out under the same conditions given for 18 and 18', respectively. Also see
Figure 1 and 2 in the Supporting Information.
13C NMR (100 MHz, CD3OD) of 16: 72.49 (x2), 40.75 (x2), 34.70 (x2), 19.94 (x2),
14.48 (x2).
13C NMR (100 MHz, CD3OD) of 17: 72.12 (x2), 40.68 (x2), 38.51 (x2), 22.95, 19.93
(x2), 14.51 (x2).
13C NMR (100 MHz, CDCl3) of 18: 71.64 (x2), 39.70 (x2), 37.39 (x2), 25.71 (x2),
18.81 (x2), 14.10 (x2).
- 3 -

13C NMR (100 MHz, CDCl3) of 19: 71.69 (x2), 39.69 (x2), 37.39 (x2), 29.70, 25.60
(x2), 18.82 (x2), 14.11 (x2).
13C NMR (100 MHz, CD3OD) of 16': 72.16 (x2), 40.76 (x2), 34.44 (x2), 19.96 (x2),
14.48 (x2).
13C NMR (100 MHz, CD3OD) of 17':72.10 (x2), 40.71 (x2), 38.48 (x2), 23.00, 19.92
(x2), 14.49 (x2).
13C NMR (100 MHz, CDCl3) of 18': 71.57 (x2), 39.70 (x2), 37.37 (x2), 25.62 (x2),
18.81 (x2), 14.10 (x2)
13C NMR (100 MHz, CDCl3) of 19': 71.68 (x2), 39.68 (x2), 37.40 (x2), 29.73, 25.60
(x2), 18.81 (x2), 14.11 (x2).
Synthesis of alcohols 20 and 21 was prepared by Brown's aymmetric
crotylboration (Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923) of
valeradehyde and hydrogenation (H2/Pd on C/MeOH)).
13C NMR (100 MHz, CDCl3) of 20: 75.7 (C4), 40.5 (C3), 33.3
OH
Me
8
Me
1
4
(C5), 31.9 (C7), 25.7 (C6), 24.5 (C2), 22.6 (C8), 14.7 (C10), 14.0 (C9),
11.7 (C1).
Me
20 and 21
13C NMR (100 MHz, CDCl3) of 21: 74.8 (C4), 39.9 (C3), 34.4 (C5), 31.9 (C7), 26.0
(C6), 25.9 (C2), 22.6 (C8), 14.0 (C9), 13.1 (C10), 11.8 (C1).
Synthesis of alcohols 22~25
1. Myers alkylation
O
Me
BnO
I
Me
Ph
CHO
Me
N
BnO
2. LiAlH(OEt)3
Me OH
S1
S2
S3
63 % for 2 steps
1. Brown's Crotylboration
2. Ac2O, Py, 69% for 2 steps
1. NaOH, MeOH
95%
OH
OAc
HO
Me
BnO
2. H2, Pd/C, MeOH
85%
Me Me
Me Me
23
Scheme S2. Synthesis of alcohol 23
- 4 -

Aldehyde S2. To a solution of diisopropylamine (5.04 mL, 36.0 mmol) and LiCl
(4.07 g, 96.0 mmol) in THF (20 mL) was added n-BuLi (2.5 M in Hexane, 14.8 mL, 33.3
mmol) at -78 °C. The suspension was stirred for 30 min at 0 °C, then recooled to -78 °C.
A solution of propionamide S1 (Myers, A. G.; Yang, B. H.; Chen, H.; Mckinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511) (3.54 g, 16.0 mmol)
in THF (40 mL) was added to the reaction flask at -78 °C via cannula. The reaction
mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min and at rt for 5 min and finally
cooled to 0 °C. A solution of 5-benzyloxy-1-iodopantane (Sargent, M. V.;
Wangchareontrakul, S. J. Chem. Soc. Perkin Trans. 1 1990, 129-132) (9.73 g, 32.0 mmol) in
THF (20 mL) was added to the reaction flask over 15 min. The mixture was stirred at 0
°C for 1 h and then quenched by the addition of satd aq. NH4Cl. The resulting mixture
was diluted with EtOAc (750 mL) and washed with satd aq. NH4Cl (250 mL) and brine
(250 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The
resulting residue was purified by flash chromatography to give amide (6.36 g, >99%).
To a suspension of LAH (118 mg, 3.11 mmol) in hexane (7.2 mL) was added
AcOEt (0.45 mL, 4.6 mmol) at 0°C over 2 min. The resulting suspension was cooled to -
78 °C. A solution of the amide (537 mg, 1.35 mmol) in THF (4.7 mL) was added to the
reaction flask via cannula over 5 min. The reaction mixture was stirred at 0 °C for 1 h,
and then 1N HCl was added to the reaction flask at 0 °C. The resulting mixture was
diluted with EtOAc (70 mL), and washed with a solution of TFA (1.04 mL) in 1N HCl
(17 mL), satd aq. NaHCO3 (30 mL X 2) and brine (30 mL). The organic layer was dried
over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash
chromatography to give aldehyde S2 (198 mg, 63%).
Acetate S3. To a solution of KOtBu (158 g, 1.41 mmol) in THF (10 mL) was
added cis-2-butene (2 mL) and n-BuLi (2.5 M in hexane, 0.56 mL) at -78 °C. This mixture
was stirred for 10 min at -45 °C, and recooled to -78 °C. To this solution was added a
solution of (+)-(Ipc)2BOMe in THF (5 mL). After stirring for 30 min at -78 °C, BF3·Et2O
(0.250 mL, 1.92 mmol) and a solution of aldehyde S2 in THF (2 mL). The solution was
stirred for 3 h at -78 °C. After addition of 3N NaOH (1.2 mL) and 30% H2O2 aqueous
solution (0.5 mL) at rt, the mixture was stirredd overnight at rt, diluted with EtOAc (150
mL), and washed with brine (100 ml). The organic layer was dried over Na2SO4 and
concentrated in vacuo to give a mixture of alcohol and isopinocampheol. The mixture
- 5 -

was treated with Ac2O, pyridine, and 4-dimethylaminopyridine. After removing excess
reagents in vacuo, the resulting residue was purified by flash chromatography to give
acetate S3 (0.297 g, 69% for 2 steps)
.
Alcohol 23. To a solution of acetate S3 (0.283 g, 0.850 mmol) in methanol (4 mL)
was added NaOH (one pellet). The mixture was stirred for 7 h at 50 °C, then diluted
with EtOAc (100 mL), and washed with 1N HCl (20 mL), satd NaHCO3 (20 mL), and
brine (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. the
resulting residue was purified by flash chromatography to give alcohol (0.200 g, 81%).
To a solution of the alcohol (41.9 mg, 0.144 mmol) in ethanol (3 mL) was added
Pd/C (10 wt%, 4.3 mg). The mixture was stirred under hydrogen atmosphere for 7 h at
rt, then filtered throuh Celite. The filterate was concentrated in vacuo to give alcohol 23
(24.6 mg, 85%).
The synthesis of 22, 24 and 25 was carried out under the same conditions given
for 23.
13C NMR (100 MHz, CD3OD) of 22: 78.7 (C7), 63.0
OH
(C1), 38.1 (C8), 36.3 (C6), 34.9 (C5), 33.7 (C2), 27.9 (C4), 27.4
1
5
10
Me
HO
(C9), 27.3 (C3), 14.9 (C11), 14.5 (C12), and 11.7 (C10).
Me Me
11
12
13C NMR (100 MHz, CD3OD) of 23: 79.3 (C7), 63.0
22~25
(C1), 37.9 (C8), 37.1 (C6), 33.5 (C5), 33.7 (C2), 28.1 (C4), 28.0 (C9), 27.4 (C3), 16.5 (C11),
13.2 (C12), and 12.1 (C10).
13C NMR (100 MHz, CD3OD) of 24: 79.1 (C7), 63.0 (C1), 38.7 (C8), 35.9 (C6), 35.6
(C5), 33.7 (C2), 28.2 (C4), 26.0 (C9), 27.3 (C3), 15.9 (C11), 13.4 (C12), and 11.6 (C10).
13C NMR (100 MHz, CD3OD) of 25: 81.4 (C7), 63.0 (C1), 38.4 (C8), 36.5 (C6), 31.7
(C5), 33.7 (C2), 28.3 (C4), 24.7 (C9), 27.4 (C3), 17.2 (C11), 16.4 (C12), and 11.9 (C10).
- 6 -

Figure 1. Difference in carbon chemical shifts of meso-diols (100 MHz) in between
(R,R)- and (S,S)-chiral solvent (1a and 1d) . The x- and y-axes represent carbon number
and δ(R,R)-δ(S,S) in ppm, respectively.
15 : meso-1,3-diol (n=1)
16 : meso-1,4-diol (n=2)
17 : meso-1,5-diol (n=3)
18 : meso-1,6-diol (n=4)
19 : meso-1,7-diol (n=5)
R
H
N
H
N
OH OH
2
Me
Me
Me
Me
4
3
1
n
(R,R)-BMBA-p (1a): R = H
(R,R)-BMBA-p-Me (1d): R = Me
BMBA-p (1a)
BMBA-p-Me (1d)
0.08
0.04
0
0.08
0.04
0
15
+17
-17
OH OH
4
OH OH
4
Me
Me
Me
1
Me
1
-0.04
-0.08
-0.04
-0.08
0.08
0.04
0
+46
-46
+57
-57
4
4
4
4
6
4
6
0.08
0.04
0
-33
-29
16
17
*
OH
OH
Me
Me
Me
Me
4
4
*
1
1
OH
OH
*
-0.04
-0.08
0.08
0.04
0
-0.04
+33
+29
*
-0.08
0.08
7
4
7
0.04
0
OH
4
OH
OH
4
OH
Me
Me
Me
1
Me
1
-0.04
-0.08
0.08
0.04
0
-0.04
-0.08
0.08
0.04
0
+38
-38
+43 -31 +31 -43
4
8
8
18
+42 -58
OH
-40
OH
OH
4
Me
Me
Me
1
Me
4
1
OH
-0.04
-0.08
-0.04
-0.08
0.08
0.04
0
+40
+58 -42
9
4
4
4
9
0.08
0.04
0
19
OH
4
OH
OH
OH
Me
1
Me
Me
1
Me
4
-0.04
-0.08
-0.04
-0.08
+45 -33
+33 -45
+52 -48
+48 -52
10
4
10
0.08
0.04
0.08
0.04
9
OH
4
OH
4
8
Me
8
Me
0
-0.04
-0.08
0
-0.04
-0.08
Me
1
Me
1
+56 -45
+36 -26
1
1
4
- 7 -

Figure 2. Difference in carbon chemical shifts of optically active diols (100 MHz)
in between (R,R)- and (S,S)-chiral solvent (1a and 1d) . The x- and y-axes represent
carbon number and δ(R,R)-δ(S,S) in ppm, respectively.
R
15' : dl-1,3-diol (n=1)
H
N
H
N
OH OH
16' : dl-1,4-diol (n=2)
17' : dl-1,5-diol (n=3)
18' : dl-1,6-diol (n=4)
19' : dl-1,7-diol (n=5)
2
Me
Me
Me
Me
4
3
1
n
(R,R)-BMBA-p (1a): R = H
(R,R)-BMBA-p-Me (1d): R = Me
BMBA-p (1a)
BMBA-p-Me (1d)
15'
0.2
0
0.2
0
OH OH
OH OH
4
4
Me
1
Me
Me
Me
1
-79
+166
-79
-87
-87
-0.2
-0.2
+210
4
6
4
6
0.08
0.04
0
0.08
0.04
0
-61
+81 -33
+22
16'
17'
OH
4
OH
4
Me
Me
Me
1
Me
1
OH
OH
-0.04
-0.08
0.08
0.04
0
-0.04
-33 +81
-61 +22
-0.08
0.08
4
4
4
7
4
7
0.04
0
OH
4
OH
OH
4
OH
Me
1
Me
Me
Me
1
-0.04
-0.08
0.08
0.04
0
-0.04
-0.08
0.08
0.04
0
-32 +39 +39 -32
-33 +36 +36 -33
8
4
8
18'
+53 -40
OH
+37 -17
OH
OH
4
Me
Me
Me
1
Me
1
4
OH
-0.04
-0.08
-0.04
-0.08
0.08
0.04
0
-40 +53
-17 +37
9
4
4
4
9
0.08
0.04
0
19'
OH
OH
OH
4
OH
Me
1
Me
Me
1
Me
4
-0.04
-0.08
-0.04
-0.08
-59 +45
+45 -59
-36 +57
+57 -36
10
4
10
0.08
0.04
0
0.08
0.04
0
9
OH
4
OH
4
8
Me
8
Me
Me
1
Me
1
-0.04
-0.08
-0.04
-0.08
+36 -26
+56 -45
1
1
4
- 8 -