Borane-mediated asymmetric reduction of acetophenone by enantiopure aminonaphthols and aminoalcohols as catalytic source

Article abstract of DOI:10.1002/chir.20812

Practical, cheap, and stereoselective synthetic methods were applied to the preparation of novel 1-(aminoalkyl)naphthol and γ-aminoalcohol tridentate ligands. The ligands obtained were conveniently applied with good results as catalytic sources in the bor

Full text of DOI:10.1002/chir.20812

CHIRALITY 22:655–661 (2010)
Borane-Mediated Asymmetric Reduction of Acetophenone
by Enantiopure Aminonaphthols and Aminoalcohols
as Catalytic Source
*
CRISTINA CIMARELLI, DAVIDE FRATONI, AND GIANNI PALMIERI
Department of Chemical Sciences, University of Camerino, Camerino, Italy
ABSTRACT
Practical, cheap, and stereoselective synthetic methods were applied to
the preparation of novel 1-(aminoalkyl)naphthol and g-aminoalcohol tridentate ligands.
The ligands obtained were conveniently applied with good results as catalytic sources in
the borane-mediated enantioselective reduction of acetophenone with borane dimethyl-
sulfide. Conformational analysis through molecular modeling allows the rationalization
C
VV
of observed stereochemical outcomes. Chirality 22:655–661, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: asymmetric catalysis; borane; ketones; secondary alchohols;
aminonaphthols; aminoalcohols
INTRODUCTION
function in the starting b-enaminoketone or b-enami-
noester, by choosing suitable aminoalcohols, allows the
direct application of these reductive methods to the prepa-
ration of tridentate g-aminoalcohols, potentially useful as
ligands.
Enantioselective reduction of ketones with borane, in
the presence of chiral oxazaborolidines has emerged as
standard method for the synthesis of chiral secondary
alcohols.
In this article, the application of such synthetic method-
ologies to the preparation of novel tridentate 1-(aminoal-
kyl)naphtols 4, and g-aminoalcohols 6 and the results
from the use of these new compounds as ligands in the
enantioselective reduction of prochiral ketones with bor-
ane are reported.
This reaction has been widely studied by Corey and
Helal1 and has found wide application in the synthesis of
natural products, nonnatural bioactive compounds and chi-
ral intermediates, ligands and building blocks including a
chiral alcohol functionality.2–4 In the original articles of
Itsuno and coworkers5 and Corey and Link,6 the reaction
is catalyzed by monocyclic oxazaborolidines.
In principle bicyclic oxazaborolidines, obtained from tri-
dentate ligands containing one nitrogen and two oxygen
atoms, can increase the differentiation of the enantiotopic
faces of the carbonyl compound and the affinity of the ke-
tone binding to boron, because of the rigidity of the bicy-
clic skeleton and to the increased Lewis acidity of the
coordinated boron atom.
So, it becomes interesting to prepare new tridentate chi-
ral ligands to be tested in the borane enantioselective
reduction of prochiral ketones.
EXPERIMENTAL
General Methods
1H and 13C NMR spectra were recorded at 400 and 100
MHz, respectively, with CDCl3 as solvent at ambient tem-
perature and were calibrated using residual undeuterated
solvents as the internal reference. Coupling constants are
given in Hertz. IR spectra were recorded using FTIR appa-
ratus. Optical rotations were measured in a 1 dm cell at
208C. GC-MS analyses were performed with an HP 59970
workstation formed by an HP-5890 gas chromatograph
equipped with a methyl silicone capillary column and by
an HP-5970 mass detector. Enantiomeric purities (% ee)
were determined by GC analyses of the resulting alcohols
on a MEGADEX DMP b capillary column (30% dimethyl-
pentyl-b-cyclodextrin on OV 1701, 25 m, 0.25 mm ID, 0.25
lm film). All reagents were commercially available, pur-
In literature, it is known that tridentate aminophenols,
derived from salicylaldehyde, catalyze the boron enantio-
selective reduction of ketones.7,8 In the past, several dia-
stereoselective, practical and cheap methods were devel-
oped to synthetize 1-(aminoalkyl)naphthol systems,9–11
analogous to aminophenols. Sometimes these compounds
were easily obtained, as single diastereomers, through the
aromatic Mannich reaction of 2-naphthol, aldehydes, and
chiral primary amines. These methods can be directly
applied to the preparation of tridentate 1-(aminoalkyl)naph-
thols using aminoalcohols instead of simple amines.
Other convenient synthetic methodologies are available
for the preparation of enantiopure g-aminoalcohols, by
reduction of the corresponding b-enaminoketones12 or b-
Contract grant sponsor: University of Camerino.
*Correspondence to: Cristina Cimarelli, Department of Chemical Scien-
ces, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
E-mail: cristina.cimarelli@unicam.it
Received for publication 24 November 2008; Accepted 15 October 2009
DOI: 10.1002/chir.20812
Published online 10 December 2009 in Wiley InterScience
enaminoesters.13 Also in this case introducing an hydroxy (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

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CIMARELLI ET AL.
TABLE 1. Borane-mediated asymmetric reduction of acetophenone by enantiopure tridentate aminonaphthols 4 and
aminoalcohols 6 as catalytic source
Entry
1
4 or 6
Ligand (yield %)a
Time (h)
2
Yieldb (%)
96
e.e. (%)
Alcohol config.
(S,R)-4a10 (63)
55
(S)
2
(R,R)-4a10 (12)
2
98
8
(S)
3
4
5
6
(S,R)-4b (61)
(R,R)-4b (11)
(S,R)-4c (58)
(R,R)-4c (14)
4
4
2
2
75
65
41
6
(S)
(S)
(S)
(S)
>98
>98
31
7
7
8
(S,S)-4d (52)
(S,R)-4d (29)
2
2
97
95
17
9
(S)
(S)
9
(S,S)-4e (57)
5
83
0.6
(S)
10
11
(S,S)-4f (28)
(R,S)-4f (49)
2
2
97
21
10
(S)
(S)
>98
12
(R)-4g14 (88)
6
>98
62
(S)
Chirality DOI 10.1002/chir

BORANE ASYMMETRIC REDUCTION
657
TABLE 1. Continued
Entry
13
4 or 6
Ligand (yield %)a
Time (h)
1
Yieldb (%)
e.e. (%)
Alcohol config.
(R,R)-4h9 (93)
>98
0.5
(R)
14
(S,S,R)-6a (53)
4
>98
38
(S)
15
16
(R,S,R)-6b (63)
(R,R,S)-6c (54)
4
4
>98
6
(S)
(R)
93
43
17
(R,R)-6d (62)
4
16
9
(S)
aYield of the isolated pure ligand.
bGascromatographic yield.
chased at the highest quality, and were purified by distilla-
tion when necessary prior to use.
1-{(S)-[(R)-2-Hydroxy-1-phenylethylamino](phenyl)me-
thyl}naphthalen-2-ol (S,R)-4a:10 colorless oil 1H NMR
(400 MHz, CDCl3): d3.88 (dd, 1 H, J 5 15.1, 6.0 Hz); 3.93
(m, 1 H), 3.94 (dd, 1 H, J 5 15.1, 4.3 Hz), 5.55 (s, 1 H),
6.20 (br s, 3 H), 7.15–7.75 (m, 16 H).
Preparation of the Chiral Ligands 4 and 6
1-(Aminoalkyl)naphthols 4a–h,9–11 1-(aminoalkyl)phenol
1-{(R)-[(R)-2-Hydroxy-1-phenylethylamino](phenyl)me-
4g14 and g-aminoalcohols 6a–d12,13 were prepared accord- thyl}naphthalen-2-ol (R,R)-4a: compound (R,R)-4a10 col-
ing to the literature methods. Spectral data of ligands 4b–f orless oil (R,R)-4a 1H NMR (400 MHz, CDCl3): d3.83
and 6a–d follow.
(dd, 1 H, J 5 11.0, 4.8 Hz); 3.97 (dd, 1 H, J 5 4.8, 4.0 Hz),
Chirality DOI 10.1002/chir

658
CIMARELLI ET AL.
4.10 (dd, 1 H, J 5 11.0, 4.0 Hz), 5.40 (br s, 3 H), 5.91 (s, 1 0.55, CHCl3); IR (neat): mmax 3304, 1721, 1626, 1254, 1229,
1
H), 7.15–7.75 (m, 16 H).
2-{(S)-[(R)-2-Hydroxy-1-phenylethylamino](phenyl)me- H, J 5 6.2 Hz), 2.40 (br s, 3 H), 3.00 (m, 1 H), 3.59 (dd, 1
1041, 712 cm21; H NMR (400 MHz, CDCl3): d1.31 (d, 3
thyl}naphthalen-1-ol (S,R)-4b:10 colorless oil: [a]2D0
1
H, J 5 11.4, 4.8 Hz), 3.73 (dd, 1 H, J 5 11.4, 4.0 Hz), 5.88
109.77 (c 1.0, CHCl3); IR (neat): mmax 3285, 1751, 1426, (s, 1 H), 7.14–7.82 (m, 11 H). 13C NMR (100 MHz,
1
1354, 1231, 1038, 762 cm21; H NMR (400 MHz, CDCl3): CDCl3): d 17.1, 54.5, 61.7, 64.4, 114.4, 120.4, 121.3, 122.6,
d.2.40 (brs, 3 H), 3.76–4.00 (m, 3 H), 5.57 (s, 1 H), 7.20– 126.5, 126.7, 129.0, 129.3, 131.1, 132.5, 141.9, 154.4, 157.4,
7.80 (m, 16 H); 13C NMR (100 MHz, CDCl3): d 60.1, 62.7, 162.0; Anal. Calcd. for C20H21NO2, (MW 307.39): C, 78.15;
66.5, 113.2, 120.35, 121.2, 122.6, 127.8, 127.9, 128.0, 128.2, H, 6.89; N, 4.56. Found: C, 78.12; H, 6.97; N, 4.72.
128.5, 128.8, 129.0, 129.2, 129.3, 130.0, 132.7, 139.0, 141.3,
1-{(S)-[(S)-1-Hydroxy-3-methylbutan-2-ylamino](phenyl)-
156.9; Anal. Calcd. for C25H23NO2 (369.46): C, 81.28; H, methyl}naphthalen-2-ol (S,S)-4e:10 colorless oil; [a]2D0
1
6.27; N, 3.79. Found: C, 81.23; H, 6.37; N, 3.97.
134.3 (c 0.23, CHCl3); IR (neat): mmax 3315, 1631, 1359,
2-{(R)-[(R)-2-Hydroxy-1-phenylethylamino](phenyl)me- 1231, 711 cm21; H NMR (400 MHz, CDCl3): d0.95 (d, 3
thyl}naphthalen-1-ol (R,R)-4b:10 colorless oil; [a]2D0 1 4.87 H, J 5 6.8 Hz), 1.00 (d, 3 H, J 5 6.8 Hz), 1.80 (br s, 3 H),
(c 1.3, CHCl3); IR (neat): mmax 3294, 1783, 1371, 1233, 1.96 (sept d, 1 H, J 5 6.8, 5.5 Hz), 2.63 (dt, 1 H, J 5 5.5, 3.8
1
1
1019, 760 cm21; H NMR (400 MHz, CDCl3): d1.60 (brs, 3 Hz), 3.74 (dd, 1 H, J 5 11.5, 3.8 Hz), 4.04 (dd, 1 H, J 5 11.5,
H), 3.87 (dd, 1 H, J 5 10.8, 4.6 Hz), 3.98 (dd, 1 H, J 5 4.6, 3.8 Hz), 6.00 (s, 1 H), 7.15–7.50 (m, 8 H), 7.70–7.80 (m, 3
4.0 Hz), 4.15 (dd, 1 H, J 5 10.8, 4.0 Hz), 5.92 (s, 1 H), H). 13C NMR (100 MHz, CDCl3): d 19.4, 19.7, 30.0, 59.6,
7.10–7.75 (m, 16 H); 13C NMR (100 MHz, CDCl3): d 60.7, 65.5, 64.7, 109.6, 118.1, 123.6, 126.5, 126.6, 128.0, 128.5,
61.7, 64.6, 109.6, 118.2, 120.2, 122.7, 123.5, 127.8, 127.9, 128.8, 129.2, 129.8, 131.0, 141.7, 153.9, 162.5. Anal. Calcd. for
128.0, 128.5, 128.8, 129.0, 129.3, 130.0, 130.7, 131.5, 141.3, C22H25NO2, (MW 335.44): C, 78.77; H, 7.51; N, 4.18. Found:
154.2, 163.1; Anal. Calcd. for C25H23NO2 (369.46): C, C, 78.51; H, 7.56; N, 4.01.
81.28; H, 6.27; N, 3.79. Found: C, 81.19; H, 6.48; N, 3.92.
1-{(S)-[(S)-1-Hydroxy-3-methylbutan-2-ylamino](phenyl)
1-{(S)-1-[(R)-2-Hydroxy-1-phenylethylamino]heptyl}naph- methyl}naphthalen-2-ol (R,S)-4e:10 1H NMR (400 MHz,
thalen-2-ol (S,R)-4c:10 colorless oil; [a]D20 1 3.83 (c 0.73, CDCl3, obtained from an enriched mixture of the two dia-
CHCl3); IR (neat): mmax 3309, 1622, 1601, 1269, 1038, 736, stereomers): d1.02 (d, 3 H, J 5 6.8 Hz), 1.03 (d, 3 H, J 5
1
699 cm21; H NMR (400 MHz, CDCl3): d0.85 (t, 3 H, J 5 6.8 Hz), 1.70 (br s, 3H), 2.16 (sept d, 1 H, J 5 6.8, 5.1 Hz),
6.6 Hz), 1.00–1.80 (m, 10 H), 1.95 (br s, 3 H), 3.73 (t, 1 H, 2.72 (td, 1 H, J 5 5.1, 3.8 Hz), 3.64 (dd, 1 H, J 5 12.0, 5.1
J 5 5.1 Hz), 3.83 (dd, 1 H, J 5 11.0, 5.1 Hz), 3.93 (dd, 1 H, Hz), 3.73 (dd, 1 H, J 5 12.0, 3.4 Hz), 5.81 (s, 1 H), 7.13–
J 5 11.0, 5.1 Hz), 4. 48 (dd, 1 H, J 5 7.9, 5.7 Hz), 7.00–8.03 7.80 (m, 11 H).
(m, 11 H). 13C NMR (100 MHz, CDCl3): d 14.2, 22.8, 26.3,
1-{(S)-[(S)-2-Hydroxypropylamino](phenyl)methyl}naph-
29.2, 31.8, 35.1, 54.8, 61.7, 66.6, 115.8, 119.9, 121.1, 122.5, thalen-2-ol (S,S)-4f:10 colorless oil; [a]D20 1 66.9 (c 0.43,
126.3, 127.7, 128.3, 128.9, 129.0, 129.1, 129.3, 132.9, 139.5, CHCl3); IR (neat): mmax 3297, 1633, 1391, 1222, 1041, 705
156.2. Anal. Calcd. for C25H31NO2, (377.52): C, 79.54; H, cm21; H NMR (400 MHz, CDCl3): d1.24 (d, 3 H, J 5 6.2
1
8.27; N, 3.71. Found: C, 79.71; H, 8.12; N, 3.51.
Hz), 1.95 (br s, 3 H), 2.76 (dd, 1 H, J 5 12.8, 7.0 Hz), 2.90
1-{(S)-1-[(R)-2-Hydroxy-1-phenylethylamino]heptyl}naph- (dd, 1 H, J 5 12.8, 3.3 Hz), 4.15 (dqd, 1 H, J 5 7.0, 6.2, 3.3
thalen-2-ol (R,R)-4c:10 colorless oil; [a]D20 2 47.1 (c 0.15, Hz), 5.75 (s, 1 H), 7.14–7.80 (m, 11 H); 13C NMR (100 MHz,
CHCl3); IR (neat): mmax 3305, 1738, 1626, 1354, 1268, 1038, CDCl3): d 21.6, 55.4, 63.3, 65.7, 113.5, 120.3, 121.3, 122.7,
1
735, 700 cm21; H NMR (400 MHz, CDCl3): d0.84 (t, 3 H, 126.7, 128.0, 128.1, 128.3, 129.1, 129.3, 130.0, 132.9, 141.6,
J 5 6.6 Hz), 1.10–1.58 (m, 10 H), 1.95 (br s, 3 H), 3.79 (dd, 156.9. Anal. Calcd. for C20H21NO2, (MW 307.512): C, 78.16;
1 H, J 5 10.6, 4.8 Hz), 3.86 (dd, 1 H, J 5 4.8, 3.8 Hz), 4.03 H, 6.88; N, 4.55. Found: C, 77.87; H, 6.90; N, 4.46.
(dd, 1 H, J 5 10.6, 3.8 Hz), 4.87 (t, 1 H, J 5 6.6 Hz), 6.97–
1-{(R)-[(S)-2-Hydroxypropylamino](phenyl)methyl}naph-
7.90 (m, 11 H). 13C NMR (100 MHz, CDCl3): d 14.2, 22.8, thalen-2-ol (R,S)-4f:10 colorless oil; [a]2D0 1 155.8 (c 0.30,
26.4, 29.5, 31.8, 35.2, 55.9, 61.4, 64.1, 116.5, 120.0, 121.0, CHCl3); IR (neat): mmax 3317, 1602, 1429, 1237, 1052, 722
122.4, 126.4, 127.2, 127.8, 128.7, 128.7, 128.9, 129.1, 132.7, cm21; H NMR (400 MHz, CDCl3): d1.19 (d, 3 H, J 5 6.2
1
139.5, 156.0. Anal. Calcd. for C25H31NO2, (377.52): C, Hz), 1.70 (br s, 3 H), 2.75 (dd, 1 H, J 5 11.7, 9.2 Hz), 2.85
79.54; H, 8.27; N, 3.71. Found: C, 79.66; H, 8.08; N, 3.48.
(dd, 1 H, J 5 11.7, 3.0 Hz), 4.07 (dqd, 1 H, J 5 9.2, 6.2, 3.0
1-{(S)-[(S)-1-Hydroxypropan-2-ylamino](phenyl)methyl}- Hz), 5.66 (s, 1 H), 7.11–7.80 (m, 11 H). 13C NMR (100
naphthalen-2-ol (S,S)-4d:10 colorless oil; [a]D20 1 157.1 (c MHz, CDCl3): d 22.1, 56.8, 64.7, 67.6, 113.6, 120.2, 121.4,
1.05, CHCl3); IR (neat): mmax 3297, 1621, 1266, 1231, 765 122.7, 126.7, 128.0, 128.3, 128.9, 129.0, 129.3, 129.9, 132.8,
1
cm21; H NMR (400 MHz, CDCl3): d1.12 (d, 3 H, J 5 6.6 141.6, 156.9.Anal. Calcd. for C20H21NO2, (MW 307.39): C,
Hz); 1.70 (br s, 3 H), 3.10 (qdd, 1 H, J 5 6.6, 5.5, 3.7 Hz), 78.16; H, 6.88; N, 4.55. Found: C, 77.99; H, 6.73; N, 4.61.
3.54 (dd, 1 H, J 5 10.8, 5.5 Hz), 3.95 (dd, 1 H, J 5 10.8,
(1S,3S)-3-[(R)-2-Hydroxy-1-phenylethylamino]-1-phenyl-
3.7 Hz), 5.82 (s, 1 H), 7.12–7.90 (m, 11 H); 13C NMR (100 butan-1-ol (S,S,R)-6a:12 colorless oil; [a]D20 2 26.9 (c 3.08,
MHz, CDCl3): d 17.2, 54.4, 61.7, 64.5, 114.3, 120.5, 121.3, CHCl3); IR (neat): mmax 3294, 1493, 1453, 1062, 758, 700
122.6, 126.7, 127.9, 128.2, 128.8, 129.0, 129.3, 129.8, 132.5, cm21; H NMR (400 MHz, CDCl3): d1.06 (d, 3 H, J 5 6.2
1
141.9, 157.5; Anal. Calcd. for C20H21NO2 (MW 307.39): C, Hz), 1.59 (dd, 1 H, J 5 14.3, 9.8 Hz), 1.74 (dt, 1 H, J 5 14.3,
78.15; H, 6.89; N, 4.56. Found: C, 78.41; H, 7.06; N, 4.48.
3.4 Hz), 3.22 (dqd, 1 H, J 5 9.9, 6.2, 3.3 Hz), 3.36 (bs, 3 H),
1-{(S)-[(S)-1-Hydroxypropan-2-ylamino](phenyl)methyl}- 3.60–3.96 (m, 3 H), 4.98 (dd, 1 H, J 5 9.9, 2.9 Hz), 7.00–
naphthalen-2-ol (S,R)-4d:10 colorless oil; [a]D20 2 19.8 (c 7.50 (m, 10 H); 13C NMR (100 MHz, CDCl3): d 22.5, 46.3,
Chirality DOI 10.1002/chir

BORANE ASYMMETRIC REDUCTION
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Scheme 3. Diastereoselective reduction of b-enaminoester 7 to g-ami-
noalcohol 6d.
Scheme 1. Aromatic Mannich reaction for the synthesis of ligands 4a–f.
(R)-3-[(R)-2-Hydroxy-1-phenylethylamino]-3-phenylpro-
pan-1-ol (R,R)-6d13 colorless oil; [a]2D0 - 158.9 (c 0.69,
CHCl3); IR (neat): mmax 3287, 1736, 1493, 1341, 1147, 1032,
758, 700 cm21; 1H NMR (400 MHz, CDCl3): d1.70 (dq, 1H,
J 5 14.6, 3.4 Hz), 2.04 (ddt, 1H, J 5 14.6, 10.8, 7.0 Hz),
3.64 (dd, 2H, J 5 10.6, 3.4 Hz) 3.77 (dd, 4H, J 5 6.6, 3.4
Hz), 3.90 (br s, 3H), 7.16–7.91 (m, 10H). 13C NMR (100
MHz, CDCl3): d 39.5, 60.7, 61.8, 63.2, 67.4, 126.8, 127.1,
127.5, 127.9, 128.4, 128.9, 139.7, 142.9. Anal. Calcd. for
C17H21NO2 (271,35): C, 75.25; H, 7.98; N, 5.16%. Found: C,
75.33; H, 7.70; N, 5.21%.
54.0, 62.8, 66.9, 75.1, 125.7, 127.3, 127.4, 128.1, 128.5, 129.0,
142.0, 145.0; EI-MS m/z (%): 254 (57), 132 (100), 105 (21),
91 (23), 77 (27); Anal. Calcd. for C18H23NO2, (285.38): C,
75.76; H, 8.12; N, 4.90. Found: C, 75.77; H, 7.91; N, 4.88.
(2R,4S)-4-[(R)-2-Hydroxy-1-phenylethylamino]pentan-2-
ol (R,S,R)-6b12 colorless oil; [a]2D0 1 15.5 (c 5 2.84,
CHCl3). IR (neat): mmax 3304, 1741, 1454, 1376, 1234, 1038,
1
762, 702 cm21; H NMR (400 MHz, CDCl3): d0.94 (d, 3 H,
J 5 6.2 Hz), 1.09 (d, 3 H, J 5 5.9 Hz), 1.22 (dt, 1 H, J 5
14.3, 10.3 Hz), 1.45 (ddd, 1 H, J 5 14.3, 3.1, 2.0 Hz), 2.97
(dqd, 1 H, J 5 10.3, 6.2, 3.3 Hz), 3.40 (br s, 3 H), 3.86–4.09
(m, 2 H), 4.06–4.24 (m, 2 H), 7.20–7.40 (m, 5 H). 13C NMR
(100 MHz, CDCl3): d 22.2, 23.9, 45.8, 53.6, 59.0, 67.3, 68.7,
127.2, 127.9, 128.8, 141.2. EI-MS m/z (%): 192 (100), 163
(26), 134 (56), 132 (56), 106 (85), 91 (45), 77 (25); Anal.
Calcd. for C13H21NO2, MW 223.31: C, 69.93; H, 9.47; N,
6.27%. Found: C, 69.81; H, 9.33; N, 6.50%.
General Procedure for the Reduction of Acetophenone
with Borane-Dimethylsulfide Catalyzed by Ligands
4a–h and 6a–d
Ligands 4a–h or 6a–d (0.2 mmol) were poured into a
three-necked round-bottom flask equipped with magnetic
stirring. Borane dimethyl sulfide 1 M in toluene (2.2
mmol, 1.1 mL) was added dropwise to the ligand at room
temperature, under nitrogen atmosphere. After 30 min,
the mixture was cooled to 08C and acetophenone was
added (0.240 g, 2 mmol in 2 mL toluene); the reaction mix-
ture was allowed to stand until the reaction was complete,
according to the reaction times reported in Table 1. Then
the reaction mixture was quenched with 2 M NaOH (10
mL) and extracted twice with CH2Cl2 (10 mL). The or-
ganic layer was dried with anhydrous sodium sulfate and
the solvent removed under reduced pressure. The crude
mixture obtained was filtered on a thin pad of silica gel
with AcOEt/cyclohexane (20:80 v/v) and then submitted
to gaschromatographic analysis.
(1R,3R)-3-[(S)-1-Hydroxymethyl-2-methyl-propylamino]-
1-phenylbutan-1-ol (R,R,S)-6c12 colorless oil; [a]D20 1 1.84
(c 0.68, CHCl3); IR (neat): mmax 3304, 1740, 1454, 1370,
1
1216, 1038, 762, cm21; H NMR (400 MHz, CDCl3): d0.95
(d, 3 H, J 5 6.8 Hz), 0.99 (d, 3 H, J 5 7.3, Hz), 1.15 (d, 3
H, J 5 6.0 Hz), 1.69 (dt, 1 H, J 5 14.5, 10.7 Hz), 1.77 (dt, 1
H, J 5 14.5, 3.0 Hz), 1.93 (sept d, 1H, J 5 6.8, 3.8 Hz), 2.72
(dt, 1 H, J 5 9.0, 3.8 Hz), 3.12 (dqd, 1 H, J 5 10.2, 6.4, 2.6
Hz), 3.43 (dd, 1 H, J 5 10.7, 9.0 Hz), 3.72 (dd, 1 H, J 5
10.7, 3.4 Hz), 3.85 (m, 3H), 4.90 (dd, 1 H, J 5 10.2, 2.6
Hz), 7.20–7.40 (m, 5 H). 13C NMR (100 MHz, CDCl3): d
17.4, 19.7, 20.9, 28.9, 46.1, 53.0, 61.7, 61.8, 75.5, 125.7,
127.2, 128.5, 145.0. Anal. Calcd. for C15H25NO2, (251.36): C,
71.67; H, 10.02; N, 5.57. Found: C, 71.53; H, 10.08; N, 5.39%.
(S,S)-3-[(S)-1-Hydroxymethyl-2-methyl-propylamino]-
1-phenylbutan-1-ol (S,S,S)-6c12: colorless oil; 1H NMR
(400 MHz, CDCl3, obtained from an enriched mixture of
the two diastereomers): d0.96 (d, 3H, J 5 6.8 Hz), 0.98 (d,
3H, J 5 6.8, Hz), 1.13 (d, 3H, J 5 6.4 Hz), 1.59 (dt, 1H, J 5
14.5, 10.7 Hz), 1.78 (dt, 1H, J 5 14.5, 3.0 Hz), 1.85 (oct,
1H, J 5 6.4Hz), 2.54 (q, 1H, J 5 5.0 Hz), 3.18 (dqd, 1H, J
5 9.4, 6.4, 3.0 Hz), 3.66 (dd, 1H, J 5 11.5, 5.5 Hz), 3.75
(dd, 1H, J 5 11.5, 3.8 Hz), 3.85 (m, 3H), 4.94 (dd, 1H, J 5
10.7, 2.1 Hz), 7.20–7.40 (m, 5H). 13C NMR (100 MHz,
CDCl3): d 18.9, 19.6, 21.6, 29.4, 45.9, 53.5, 62.4, 75.5, 125.8,
127.3, 128.5, 145.2.
RESULTS AND DISCUSSION
The aromatic Mannich reaction has been applied to the
preparation of (aminoalkyl)naphtols 4a–g by reaction of a-
or b-naphthols 1 with aldehydes 2 and several b-aminoal-
cohols 3.9–11 The three-component reaction simply takes
place by mixing the reagents and allowing the mixture to
stand at 608C for 5–48 h, as depicted in Scheme 1.
Secondary g-aminoalcohols 6a–c were instead prepared
by diastereoselective reduction of b-enaminoketones with
sodium borohydride in acetic acid,12 as depicted in
Scheme 2.
Scheme 2. Diastereoselective reduction of b-enaminoketones 5 to g-
aminoalcohols 6a–c.
Scheme 4. Enantioselective borane reduction of acetophenone cata-
lyzed by ligands 4 or 6.
Chirality DOI 10.1002/chir

660
CIMARELLI ET AL.
Fig. 3. Structures of oxazaborolidines (S,R)-10a, (S,S)-10e and
(R,R,S)-11c and ee obtained in the corresponding reductions.
Fig. 1. Structures of the byciclic oxazaborolidines formed by ligands
10a–c,f,g and 11a,b,d.
(entry 1) the ee is ꢀ100 times larger in this last case, in
which the ligand (S,R)-4a differs from (R,R)-4h only in
the presence of the second hydroxy group.
Finally, primary g-aminoalcohol 6d was prepared by
reduction of the corresponding b-enaminoester with so-
dium in THF, in the presence of isopropanol,13 as reported
in Scheme 3.
Stereochemistry
The stereochemistry of the ligand determines the pre-
ferred face of the ketone on which the reduction takes
place. In fact, all the ligands that achieve the major enan-
tioselectivitites show a similar structure of the byciclic oxa-
zaborolidine, with the substituents R1, R2, and R3 located
on the same side of the complex, as shown in Figures 1
and 3. In the majority of the chelants reported in Table 1,
the product is the bicyclic oxazaborolidine with the ReB
face of the chelated boron atom hindered by the substitu-
ents, whereas the SiB face is open to coordinate both bor-
ane and acetophenone for the subsequent reduction step.
This situation is common to both 1-(aminoalkyl)naphthols
and g-aminoalcohols (Fig. 1).
In the reduction step, acetophenone can approach to the
catalyst in two different ways, to give (R) or (S)-1-phenyle-
thanol. The molecular models of the two hypothetical tran-
sition states corresponding to the two situations are
depicted in Figure 2, in the case of ligand (S,R)-4a. The
transition state SiB-10a-(S)-TS, that affords the (S) alcohol,
is stabilized by 6.03 kJ/mol with respect to SiB-10a-(R)-TS
(PM3 semiempirical minimization*), reasonably because
the hydride transfer takes places through a six member
chair-like transition state in the first, whereas the second
presents a boat-like conformation (Fig. 2). This model is in
accord with the experimental data that show that the major
enantiomer obtained is (S)-1-phenylethanol in the majority
of the cases (Table 1).
These tridentate ligands were applied to the catalyzed
reduction of ketones with borane, as depicted in Scheme
4. The catalyst was prepared by dissolving ligands 4 or 6,
in 10% molar ratio with respect to the acetophenone, in a
solution of borane-dimethylsulfide in toluene, at room tem-
perature, under a nitrogen atmosphere. After 30 min, ace-
tophenone was added at 08C then the ee of the reaction
was determined at completion by gas-chromatography on
a chiral column. The ligands used and the results obtained
are reported in Table 1.
The yields are >95% in the majority of the cases. The
ligand reacts with a borane molecule forming the bicyclic
oxazaborolidine 10 or 11, that is the real catalytic specie.
In the subsequent step, this complex coordinates the ke-
tone at boron atom and borane at nitrogen atom. The sub-
sequent hydride transfer step takes place through a cyclic
six-membered transition state.
The reaction performed with ligand (R,R)-4h (entry 13)
shows the need of a tridentate chelating structure to make
the reduction enantioselective: although the yield of the
reduction is as high as that obtained with ligand (S,R)-4a
These results are relative to oxazaborolidines with struc-
tures like (S,R)-10a, depicted in Figure 3. On the con-
trary, the reduction with ligand (R,R,S)-6c produces the
(R) alcohol in 43% ee. Indeed the catalyst (R,R,S)-11c,
obtained with this ligand, presents R1 and R2 substituents
located on the SiB face, resulting in the ReB face being
open for the reduction step, in a situation opposite to the
previous (S,R)-10a (Fig. 3).
A confirmation of the hypothesis of induction mecha-
nism is the reduction performed with ligand (S,S)-4e, that
results in a very low ee with a slight preference for the (S)
alcohol. In the corresponding bicyclic oxazaborolidine
Fig. 2. Molecular modeling representations of the diastereoselective
transition state (TS) of the reduction step with ligand (S,R)-4a (PM3 semi-
empirical minimization). [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
*PM3 semiempirical minimization was performed with the Spartan ’06
1,1,1 – Wavefunction Inc 18401 Von Karman Avenue, Suite 370, Irvine, CA
92612.
Chirality DOI 10.1002/chir

BORANE ASYMMETRIC REDUCTION
661
was attributed to the major ligand 6c, the one used in the
reduction.
LITERATURE CITED
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1
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one was then used in the reduction reaction. The attribu-
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analysis of the two syn-g-aminoalcohols 6c. The more
populated conformations of the two syn isomers show a
significant difference in the relative position of the two
methine protons present on the side chain bonded to the
nitrogen atom. Compound (R,R,S)-6c presents three more
stable (more populated) conformations, the most stable of
which is depicted in Figure 4, and all have both anti (J 5
9.0 Hz) and syn (J 5 3.8 Hz) protons. On the other hand,
the more populated conformations of (S,S,S)-6c isomer
are equilibrating anti/gauche conformations and conse-
quently the coupling constants result lie between the anti
and gauche standard values (J 5 5.5, 6.4 Hz). According to
this experimental data, the (R,R,S) absolute configuration
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Chirality DOI 10.1002/chir