Hanessian et al.
Table 2. Reduction of ketones using
887
Table 3. Comparison between reduction of ketones with amino
acid 6 and amino alcohol 7.
thiazolidine 6.
CO2H
CO2H
S
S
S
or
OH
NH
NH
NH
6
6
7
O
(10 mol%)
OH
(10 mol%)
R
R
Ketone
Alcohol
Ph
Ph
BH3·THF, Additive
1.5 equiv BH3·THF
THF, r.t.
THF, r.t.
Entry
R
Ligand
Additive (10 mol%)
ee (%)a
Ketone
Yield (%)a
75
60
85
72
71
83
ee (%)b
1
2
3
4
5
6
7
8
H
H
H
H
Br
Br
Br
Br
6
6
7
7
6
6
7
7
None
N,N-Dimethylaniline
None
N,N-Dimethylaniline
None
N,N-Dimethylaniline
None
81 (S)
81 (S)
54 (S)
83 (S)
74 (R)
77 (R)
54 (R)
81 (R)
PhCOMe
81 (S)
80 (S)
59 (S)
74 (R)
65 (S)
70 (S)
p-FC6H4COMe
p-MeOC6H4COMe
PhCOCH2Br
ꢁ-Tetralone
8-Methoxytetralone
aKetone added over 1 h (see Experimental).
N,N-Dimethylaniline
bDetermined by HPLC.
aDetermined by HPLC.
catalyst in the latter case is the oxazaborolidine 9 which is
formed directly (Scheme 2).
(300 MHz, CDCl3) ꢂ: 4.26 (AB system, 2H, J = 9.9 Hz),
3.71 (dd, 1H, J= 4.2 Hz and J = 10.5 Hz), 3.57 (dd, 1H, J =
10.5 Hz and J = 9.3 Hz), 2.99 (dd, 1H, J = 4.2 Hz and J =
9.3 Hz), 2.35–2.10 (br s, 2H), 1.51 (s, 3H), 1.30 (s, 3H). 13C
NMR (75 MHz, CDCl3) ꢂ: 73.9, 59.9, 56.5, 52.3, 30.7, 25.7.
In conclusion, we have demonstrated that penicillamine 2
and its thiazolidine derivative 6 may be used as a ligand in
the catalytic reduction of ketones with borane at room tem-
perature. Up to 81% ee was observed with acetophenone and
related ketones in the presence of 10% mol catalyst. Compa-
rable ee values were observed with the corresponding amino
alcohol 7, in the presence of N,N-dimethylaniline as an addi-
tive.
Representative reductions
Reduction of ketones in presence of amino acid 6 or
amino alcohol 7
To a solution of thiazolidine 6 (8) (30 mg, 0.19 mmol,
0.1 equiv) or amino alcohol 7 (27.9 mg, 0.19 mmol,
0.1 equiv) in 1 mL THF were added 2.8 mL of BH3·THF
(1 M THF, 1.5 equiv) at 0°C. After stirring 10 min, the cool-
ing bath was removed and a solution of ketone (1 equiv) in
1 mL of THF was added over 60 min via a syringe-pump.
After 10 min, the mixture was quenched at 0°C by adding
5 mL of 2 N HCl diluted with water (10 mL), the organic
phase was extracted with AcOEt (3 × 10 mL), dried over
MgSO4, and the product was purified by flash chromatogra-
phy (AcOEt–hexane). Enantiomeric excesses were measured
by HPLC. PhCHOHMe: OB column, ꢃ: 210 nm, flow:
1 mL min–1, hexane–isopropanol 90:10, Rt1: 6.44 min (S)
and Rt2: 9.73 min. p-FC6H4CHOHMe: OB column, ꢃ:
210 nm, flow: 1 mL min–1, hexane–isopropanol 98:2, Rt1:
17.77 min (S) and Rt2: 19.89 min. p-MeOC6H4CHOHMe:
OB column, ꢃ: 210 nm, flow: 1 mL min–1, hexane–
isopropanol 90:10, Rt1: 13.54 min (S) and Rt2: 18.56 min.
PhCHOHCH2Br: OB column, ꢃ: 210 nm, flow: 1 mL min–1,
hexane–isopropanol 90:10, Rt1: 8.02 min and Rt2: 10.38 min.
(S). 8-methoxytetralol: OB column, ꢃ: 210 nm, flow:
1 mL min–1, hexane–isopropanol 90:10, Rt1: 6.61 min and
Rt2: 10.50 min (S).
Experimental
[(4S)-5,5-Dimethyl-1,3-thiazolidin-4-yl]methanol (7)
To a solution of 0.5 g (3.10 mmol, 1 equiv) of thiazolidine
6 in 10 mL THF were added 15.5 mL (5 equiv) of BH3·THF
(1 M THF). After 1 h stirring at room temperature (r.t.), the
mixture was quenched with 2 N HCl. The mixture was di-
luted with water (10 mL) and the organic phase was ex-
tracted with dichloromethane (3 × 10 mL) and dried over
MgSO4. Concentration in vacuo, afforded the corresponding
oxazaborolidine hydride 8 as a colorless oil. Rf: 0.9
(AcOEt). MS (FAB): 176 ([M + H]+, 7%), 160 (M+.-Me.,
100%), 158 (M+.-HO., 24%), 157 (M+.-H2O., 8%), 146
.
(M+.-[BHOH]., 25%), 116 (146-CH2 , 17%). 1H NMR
(300 MHz, CDCl3) ꢂ: 4.90–4.75 (br s,1H), 4.31 (dd, 1H, J =
11.1 Hz and J = 3.3 Hz), 4.15 (dd, 1H, J = 12.6 Hz and J =
3.0 Hz), 4.02 (t, 1H, J = 10.5 Hz), 3.80 (dd, 1H, J = 12.6 Hz
and J = 3.0 Hz), 2.76 (dt, 1H, J = 11.1 Hz and J = 3.3 Hz),
2.55–2.40 (br s,1H), 1.52 (s, 3H), 1.42 (s, 3H). 13C NMR
(75 MHz, CDCl3) ꢂ: 76.1, 57.4, 54.7, 54.4, 29.5, 27.8. This
compound was dissolved in 50 mL of MeOH in presence of
1 mL of triethylamine. After 3 h stirring at 70°C, the mix-
ture was concentrated in vacuo, then purified by flash chro-
matography (AcOEt–MeOH, 95:5), to give 0.31 g of amino
alcohol 7. Yield: 69%. Rf: 0.2 (AcOEt–MeOH 95:5, silica).
[ꢁ]D: –29.4 (c 0.18., CHCl3). HRMS (EI) m/z calcd. for
C6H13NOS: 148.0796; found: 148.0799. 1H NMR
Reduction of ketones in presence of amino alcohol 7 and
N,N-dimethylaniline
To a solution of amino alcohol 7 (28 mg, 0.19 mmol,
0.1 equiv) and 0.24 mL of N,N-dimethylaniline in 1 mL
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