Catalytic enantioselective borane reduction of arylketones with pinene-derived amino alcohols

Article abstract of DOI:10.1016/j.tet.2007.12.020

Both cis- and trans-1,2-amino alcohols 5 and their N-alkylated derivatives 6 were prepared from (-)-α-pinene 7 as chirality source and utilized in asymmetric borane reduction of arylketones 12 employing a one-pot multi-substrate screening. The oxazaborolidine catalysts were generated in situ from amino alcohols 5 and 6 and trimethyl borate.

Full text of DOI:10.1016/j.tet.2007.12.020

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1635e1640
www.elsevier.com/locate/tet
Catalytic enantioselective borane reduction of arylketones
with pinene-derived amino alcohols
*
Dennis Hobuß, Angelika Baro, Sabine Laschat , Wolfgang Frey
Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Received 9 November 2007; received in revised form 6 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
Both cis- and trans-1,2-amino alcohols 5 and their N-alkylated derivatives 6 were prepared from (ꢀ)-a-pinene 7 as chirality source and
utilized in asymmetric borane reduction of arylketones 12 employing a one-pot multi-substrate screening. The oxazaborolidine catalysts
were generated in situ from amino alcohols 5 and 6 and trimethyl borate.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Amino alcohols; Asymmetric catalysis; Boron; Pinene
1. Introduction
Terpenes such as camphor 3, fenchone, or pinene 4 (Scheme
1) were used to a much lesser extent for this purpose.5,6
We have recently evaluated a-pinene as a versatile chiral
scaffold for the synthesis of bisphosphinites and other phos-
phorus ligands.7e9 In this context we also prepared cis- and
trans-1,2-amino alcohols 5 and 6 from a-pinene (ꢀ)-7
(Scheme 2) and investigated their behavior in the enantioselec-
tive borane-mediated reduction of prochiral ketones. The
results toward this goal are reported below.
Since the first report by Itsuno1 and further development by
Corey2 that enantiomerically pure oxazaborolidines such as 1
efficiently catalyze the borane reduction of ketones to the cor-
responding secondary alcohols, the asymmetric CBS reduction
has been grown into a reliable synthetic method,3 which is
amenable even to industrial scale production.4 The majority
of oxazaborolidines were either formed in situ or prepared
separately from amino acid-derived amino alcohols (e.g., 2).
OH
OH
H
N
H
N
2
R1
1
6
3
4
Ph
Ph
Ph
OH
R1
and
Ph
O
H
N
7
9
5
8
cis-5, 6
trans-5, 6
(−)-7
NH2
2
B
1
R
Scheme 2.
OH
O
P
N
O
O
N
NH
OH
H
Ph
O
2. Results and discussion
3
4
RO
Scheme 1. Some potential catalysts in the asymmetric borane reduction of
ketones developed by Itsuno,1 Corey,2,3 Xie,5b and Basavaiah.5d
The synthetic approach to the amino alcohols 5 and their
N-alkylated derivatives 6 is depicted in Scheme 3. Following
a procedure by Pierce and Carlson10 (ꢀ)-a-pinene 7 was
treated with KMnO4 to give the a-hydroxyketone 8, which
was converted into the crystalline oxime 911a in 97% yield.
* Corresponding author. Tel.: þ49 711 685 64565; fax: þ49 711 685 64285.
E-mail address: sabine.laschat@oc.uni-stuttgart.de (S. Laschat).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.020

1636
D. Hobuß et al. / Tetrahedron 64 (2008) 1635e1640
OH
OH
the target amino alcohols trans-6a and trans-6b in 78 and 79%
H
N
for 6b
NH2
R1
yields, respectively, and high diastereoselectivity (cis/
trans¼1:99). The 3-aminopinan-2-ol trans-5 was obtained quan-
titatively by hydrogenation of trans-6b in MeOH (Scheme 3).
Prior to reduction of alkylarylketones 12 to secondary alco-
hols 13 (Table 1) using the chiral amino alcohols 5 and 6, the
racemic products rac-13, which were needed as a standard in
GC analysis, were prepared from ketones 12 by treatment with
NaBH4 in MeOH at 0 ꢁC.
For easier product analysis the ‘one-pot multi-substrate
screening’ was used, which was originally introduced by
Kagan.16 As shown in Figure 2, the starting ketones 12aed
and the resulting secondary alcohols 13aed were clearly sep-
arated in a single run on GC and unambiguously assigned.
Furthermore, as shown in Figure 3, a base line separation of
the four pairs of enantiomers 13aed on a chiral stationary
phase Bondex-unb by capillary GC was achieved.
Pd/C, H2
MeOH, rt, 18 h
trans-5 (quant.)
trans-6a (78%, R1 = i-Pr)
trans-6b (79%, R1 = Bn)
1) NaBH4/HOAc
for
8
2) R2NH2 (10), CH2Cl2, rt, 15 h
OH
KMnO4
acetone, H2O
X
−10 °C→−5 °C, 18 h
(−)-7
8 (52%, X = O)
NH2OH, EtOH
reflux, 24 h
b
9 (97%, X = NOH)
cis-6,11
a
R2
Me Ph
Me
LiAlH4, Et2O
reflux, 18 h
R3
H
R3
for 9
R2
O
OH
OH
1)
(11)
R2 R3
NH
NH2
EtOH, rt, 1 h
R2
R3
Thus, this methodology was applied to the asymmetric
borane-catalyzed reduction of ketones 12 (Table 1). An equi-
molar mixture of the four substrates acetophenone (12a),
propiophenone (12b), 2-methylpropiophenone (12c), and
2-chloroacetophenone (12d) (0.25 mmol each) was added
over 75 min to a solution of the respective amino alcohols
O
cis-6a (71%)
cis-6b (62%)
cis-5 (65%)
NH
2) LiAlH4, Et2O, reflux, 12 h
Scheme 3.
Reduction of 9 with LiAlH4 in Et2O yielded selectively
cis-3-aminopinan-2-ol cis-511 in 65%. Following the reductive
alkylation by Saavedra,12 compound cis-5 was treated with
acetone (11a) or benzaldehyde (11b) in EtOH to give the cor-
responding intermediate oxazolidines, which were reduced
with LiAlH4 in Et2O. After chromatographic purification on
silica gel, N-isopropyl-13 and N-benzyl-substituted cis-amino
alcohols cis-6a,b were isolated in 71 and 62% yields, respec-
tively. Derivative cis-6a was converted into the hydrochloride,
which gave single crystals being suitable for X-ray crystal
structure analysis (Fig. 1).14 In this way, the absolute configu-
ration of 6a was determined to be 1R,2R,3S,5R.
Table 1
Catalytic borane reduction of a mixture of ketones 12 to alcohols 13 with
cis-amino alcohols 5 and 6 using the one-pot multi-substrate screeninga
cis-5 or cis-6a,b
B(OMe)3, THF, rt, 30 min
OMe
B
O
NR1
O
O
OH
OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
b
a
b
O
O
OH
OH
BH3 · THF
Cl
Cl
THF, 0 °C, 75 min
R1 = H, i-Pr, Bn
c
d
c
d
Direct reductive amination15 of a-hydroxyketone 8 with
isopropyl- (10a) and benzylamine (10b) and NaBH(OAc)3,
which was formed in situ from NaBH4 and HOAc, afforded
mixture of ketones 12
Entry Substrate 12 Catalyst Product 13 Conv.
mixture of alcohols 13
[%] % eeb,c Config.d
b,c
1
a
b
c
cis-5
cis-5
a
b
c
100 (100)
100 (98)
96 (93)e
93 (90)
61 (57)
91 (83)
6 (24)f
6 (20)
2 (2)
R
R
2
3
cis-5
cis-5
100 (100)
100 (100)
100 (100)
98 (100)
R
4
d
a
b
c
d
a
b
c
S
5
cis-6a
cis-6a
cis-6a
cis-6a
cis-6b
cis-6b
cis-6b
cis-6b
R
R
6
7
30 (100)
d
S
d
d
d
d
8
d
a
b
c
d
a
b
c
100 (100)
100 (100)
100 (100)
100 (100)
100 (100)
3 (22)
7 (3)
9
10
11
12
a
d
6 (d)
6 (2)
d
d
Reaction conditions: ketone solution (1 mL), THF (1 mL), B(OMe)3
(1 mL, 0.1 M solution), BH3$THF (1 mL, 1 M solution), 0 ꢁC/rt, 75 min.
Conversions determined by capillary GC on an achiral phase and enantio-
selectivities on a chiral Bondex-unb phase.
b
c
Conversion and ee values of reactions without B(OMe)3 additive in
parenthesis.
d
Assignment by comparison of optical rotation values with literature data.
For comparison see Refs. 13 and 17.
For comparison see Ref. 13.
e
Figure 1. ORTEP plot of (1R,2R,3S,5R)-3-(isopropylamino)-2,6,6-trimethyl-
bicyclo[3.1.1]heptan-2-ol hydrochloride (cis-6a$HCl).
f

D. Hobuß et al. / Tetrahedron 64 (2008) 1635e1640
1637
found for the branched alcohol 13c (entries 3 and 7) combined
with low conversion in the case of cis-6a (entry 7). Marko-
wicz13 also reported a decrease of enantioselectivity upon us-
ing the antipode ent-cis-6a instead of ent-cis-5. However, the
effect was much less pronounced as compared to our results.
The corresponding trans-amino alcohols trans-5 and trans-
6a,b did not show enantioselectivity, resulting not only in
racemic products 13 but also in low conversions.
3. Conclusion
Starting from (ꢀ)-a-pinene 7 a series of cis- and trans-
amino alcohols 5 and 6 were conveniently prepared. The in
situ formed oxazaborolidines from compounds 5 and 6 and tri-
methyl borate and BH3$THF are capable of catalyzing the
reduction of arylketones 12 to the secondary alcohols 13.
The used ‘one-pot multi-substrate screening’ allowed the anal-
ysis of the product mixture by GC in a single run on a chiral
stationary phase. The reagent from cis-5/trimethyl borate
afforded the secondary alcohols (R)-13aec and (S)-13d in
high enantiomeric excesses (up to 96% for (R)-1-phenyletha-
nol 13a), which are slightly higher than those obtained by
Rao for related camphor-derived endo- and exo-amino alco-
hols.5e Furthermore, while Rao reported decreased enantiose-
lectivities upon addition of trimethyl borate, we found
improved selectivities for cis-5 in the presence of trimethyl
borate as compared to parent system without any additives.
The N-alkylated amino alcohols cis-6a,b gave poor ee values
thus indicating the deleterious effect of steric hindrance on
the enantioselectivity. The oxazaborolidines from the corre-
sponding trans-amino alcohols and trimethyl borate gave
low conversion and only racemic products 13.
Figure 2. Capillary GC trace of a mixture of arylketones 12aed and the result-
ing alcohols 13aed.
cis-5 or cis-6a,b (10 mol %) and BH3$THF (1 equiv) in abs
THF at 0 ꢁC. As catalytic borane reductions are known to be
improved by the addition of trimethyl borate resulting in the
in situ formation of an oxazaborolidine with a BeOMe rather
than a BeH moiety,3,17 reactions were also carried out in the
presence of 10 mol % trimethyl borate in order to study the
effect on our catalytic system. After workup, the product mix-
ture was analyzed in a single run by capillary GC with regard
to conversion and enantioselectivity (Table 1).
As shown in Table 1, in the case of cis-5, B(OMe)3 addition
led to higher enantiomeric excesses as compared to the results
without additive with the highest effect for product 13d (entry
4). The best ee values were achieved for alcohol 13a (entry 1).
This result is in good agreement with findings by Markowicz13
and Shioiri17 who obtained similar enantioselectivities for the
enantiomeric ligand ent-cis-5 from (þ)-a-pinene. In contrast,
B(OMe)3 lowered the ee values when cis-6a was used (entries
5, 6, and 8). The N-benzylated amino alcohol cis-6b, however,
was not effected, giving nearly racemic mixture in all cases
despite of complete conversions (entries 9e12). Both the
size of the substrate and the bulkiness of substituent R1 in
the oxazaborolidine influenced the enantioselectivity. The ee
values of alcohol 13a decreased from 93 (R1¼H) to 24%
(R1¼i-Pr) and 3% (R1¼Bn) (entries 1, 5, and 9). Within the
product mixture 13aed the lowest enantiomeric excess was
4. Experimental section
4.1. General
Melting points (uncorrected) were determined on a Buchi
¨
510 melting point apparatus. Optical rotations were determined
with a PerkineElmer 241 LC polarimeter. IR spectra: Bruker
Vektor 22 FT-IR spectrometer. Mass spectra: Finnigan MAT
95 and Varian MAT 711 spectrometers. NMR spectra: Bruker
AC-250F and Bruker ARX 500 spectrometers. The spectra
were recorded with TMS as an internal standard. 13C NMR mul-
tiplicities were determined by DEPTexperiments. Column chro-
matography: Macherey-Nagel Kieselgel 60 (230e400 mesh).
GC: Hewlett Packard HP 5890 with capillary column HP-5MS
(30 mꢂ0.32 mm); temperature program: starting temperature
80 ꢁC, then 8 ꢁC minꢀ1 gradient to 280 ꢁC. GC condition for
ee determination is given in the appropriate preparation. Deriva-
tives 8, 9, cis-5 were prepared according to the literature.10,11
4.2. (1R,2R,3S,5R)-3-(Isopropylamino)-2,6,6-trimethyl-
bicyclo[3.1.1]heptan-2-ol (cis-6a) via benzoxazole
(a) To a solution of cis-5 (338 mg, 2.0 mmol) in abs EtOH
(5 mL) at room temperature was added acetone (11a)
Figure 3. Capillary GC trace of a mixture of racemic secondary alcohols
13aed on a chiral stationary phase Bondex-unb.

1638
D. Hobuß et al. / Tetrahedron 64 (2008) 1635e1640
(0.18 mL, 3.0 mmol). After 2 h, additional 11a (0.18 mL,
3.0 mmol) was added and the reaction mixture stirred for a
further 30 min. The solvent was removed under vacuum to
give (3aS,5R,7R,7aR)-2,2,6,6,7a-pentamethyloctahydro-5,7-
methano-1,3-benzoxazole as a colorless liquid (386 mg,
95%). [a]2D0 þ18.4 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) d¼0.87 (s, 3H, 7a-CH3), 1.28 (s, 3H, 9-H), 1.36
(d, J¼10.9 Hz, 1H, 7-H), 1.37 (s, 3H, 8-H), 1.44 (s, 3H,
C(CH3)2), 1.47 (s, 3H, C(CH3)2), 1.57 (dd, J¼3.6, 1.0 Hz, 1H,
10-H), 2.01 (t, J¼5.2 Hz, 1H, 4-H), 1.93 (mc, 1H, 5-H), 2.15
(mc, 1H, 4-H), 2.30 (dd, J¼6.0, 8.7 Hz, 1H, 10-H), 3.41 (d,
J¼8.4 Hz, 1H, 3a-H), 7.28 (s, 1H, NH); 13C NMR (125 MHz,
CDCl3) d¼23.9 (7a-CH3), 25.7 (C-4), 27.4 (C(CH3)2), 28.4
(C-8), 29.9 (C-9), 32.9 (C-10), 38.0 (C-6), 40.4 (C-5), 52.1
(C-7), 59.1 (C-3a), 84.8 (C(CH3)2), 93.6 (C-7a); IR (film)
3320 (br), 2977 (s), 2908 (s), 2870 (s), 1970 (br), 1455, 1428,
1373 (s), 1269, 1233, 1204, 1173, 1142, 1073, 1052, 1018,
993, 951, 931, 916, 872, 795 cmꢀ1; MS (EI): m/z (%)¼210
(1) [MþþHþ], 209 (7) [Mþ], 196 (1), 195 (14), 194 (100),
177 (1), 167 (1), 166 (6), 153 (3), 152 (25), 140 (1), 139 (14),
135 (34), 120 (2), 119 (5), 113 (11), 109 (18), 99 (2), 98 (32),
93 (51), 85 (10), 84 (64), 71 (16), 60 (61), 44 (41), 41 (33),
28 (9), 18 (17). Anal. Calcd for C13H23NO: C, 74.59; H,
11.07; N, 6.69. Found: C, 74.58; H, 11.03; N, 6.71.
(b) To a suspension of LiAlH4 (759 mg, 20.0 mmol) in abs
Et2O (75 mL) at 0 ꢁC was added dropwise a solution of the
benzoxazole (2.09 g, 10.0 mmol) in abs Et2O (10 mL) and the re-
action mixture heated at reflux for 14 h. The reaction mixturewas
then hydrolyzed with EtOAc (2 mL) and 1 N NaOH solution
(6 mL). The precipitate was filtered off and washed with Et2O
(3ꢂ50 mL). The combined organic layers were concentrated un-
der vacuum to give cis-6a as a colorless liquid (1.91 g, 90%). 1H
NMR (250 MHz, CDCl3) d¼0.98 (s, 3H, 2-CH3), 1.10 (dd,
J¼4.6, 4.8 Hz, 6H, CH(CH3)2), 1.21 (s, 3H, 9-H), 1.23 (mc,
2H, 4-H), 1.26 (s, 3H, 8-H), 1.85 (mc, 1H, 5-H), 1.99
(t, J¼5.7 Hz, 1H, 1-H), 2.13 (mc, 1H, 7-H), 2.54 (mc, 1H, 7-H),
2.83 (mc, 1H, CH(CH3)2), 2.91 (mc, 1H, 3-H); 13C NMR
(63 MHz, CDCl3) d¼23.3 (2-CH3), 23.9 (C-9), 24.1 (C-8), 28.0
(CH(CH3)2), 31.2 (C-4), 38.4 (C-7), 39.6 (C-5), 40.5 (C-6),
48.9(C-1), 53.7(CH(CH3)2), 54.3(C-3), 71.4 (C-2). Thespectro-
scopic data were in accordance with those in the literature.13
methano-1,3-benzoxazole as a pale yellow liquid (2.14 g,
83%). 1H NMR (500 MHz, CDCl3) d¼0.92 (s, 2.1H,
7a-CH3*), 0.99 (s, 3.9H, 7a-CH3), 1.32 (s, 6H, 9-H, 9*-H),
1.34 (s, 3.9H, 8-H), 1.42 (s, 2.1H, 8*-H), 1.44 (d, J¼10.0 Hz,
1.3H, 4-H), 1.58 (mc, 1.3H, 5-H), 1.76 (mc, 0.7H, 5*-H), 1.95
(mc, 2.0H, 7-H, 7*-H), 2.24 (mc, 2.7H, 4*-H, 10-H, 10*-H),
2.42 (mc, 2H, 4-H, 4*-H), 3.32 (dd, J¼9.0, 1.7 Hz, 0.7H,
3a*-H), 3.57 (dd, J¼9.5, 5.5 Hz, 1.3H, 3a-H), 5.38 (s, 0.7H,
2*-H), 5.69 (s, 1.3H, 2-H), 7.30e7.55 (m, 10H, aromat); 13C
NMR (125 MHz, CDCl3) d¼23.9 (7a-CH3*), 24.0 (7a-CH3),
25.6 (C-4*), 26.3 (C-4), 27.3 (C-9*), 27.6 (C-9), 27.8 (C-8*),
29.5 (C-8), 33.8 (C-6*), 35.1 (C-6), 38.1 (C-10*), 39.4 (C-10),
40.4 (C-5*), 40.6 (C-5), 51.2 (C-7*), 52.9 (C-7), 59.3 (C-3a*),
59.5 (C-3a), 83.8 (C-7a*), 86.0 (C-7a), 89.3 (C-2*), 92.9
(C-2), 126.2 (C-40*), 126.3 (C-40), 128.2e134.5 (C-20, C-20*,
C-3, C-30*), 138.5 (C-10*), 140.1 (C-10) (* signal of the minor
diastereomer); IR (film) 3314, 3061 (w), 2978, 2951, 2917 (s),
2865, 1953 (w), 1889 (w), 1809 (w), 1739 (w), 1704 (w),
1601 (w), 1547 (w), 1494, 1470, 1447, 1430, 1386, 1367,
1345, 1306, 1273, 1245, 1223, 1206, 1170, 1159, 1145, 1123,
1113, 1082, 1029, 1011, 998, 972, 945, 937, 918, 907, 883,
867, 838 cmꢀ1; MS (EI): m/z (%)¼258 (14) [MþþHþ], 257
(78) [Mþ], 242 (3), 214 (8), 187 (8), 180 (18), 161 (26), 145
(8), 144 (21), 132 (100), 119 (31), 105 (52), 94 (8), 93 (41),
79 (14), 77 (23), 67 (10), 55 (8), 43 (13), 41 (18), 28 (25).
(b) To an ice cold suspension of LiAlH4 (759 mg,
20.0 mmol) in abs Et2O (65 mL) was added dropwise a solution
of benzoxazole (2.57 g, 10.0 mmol) in abs Et2O (10 mL) and
the reaction mixture heated at reflux for 18 h. It was then hydro-
lyzed with EtOAc (2 mL) and 1 N NaOH solution (4 mL). The
precipitate was filtered off and washed with Et2O (3ꢂ50 mL).
The combined organic layers were dried (MgSO4) and concen-
trated under vacuum. The residue was chromatographed on
SiO2 (200 g) with CH2Cl2/MeOH/NH3 (100:10:1) to give cis-
6b as a light yellow liquid (2.10 g, 81%). [a]2D0 ꢀ41.1 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3) d¼0.94 (s, 3H, 2-CH3),
1.25 (s, 3H, 9-H), 1.26 (s, 3H, 8-H), 1.28 (mc, 2H, 7-H), 1.87
(mc, 1H, 5-H), 1.99 (t, J¼5.8 Hz, 1H, 1-H), 2.14 (mc, 1H,
4-H), 2.48 (mc, 1H, 4-H), 2.96 (dd, J¼9.8, 5.9 Hz, 1H, 3-H),
3.87 (d, J¼12.8 Hz, 1H, CHaHbPh), 3.92 (d, J¼12.8 Hz, 1H,
CHaHbPh), 7.31 (mc, 5H, aromat); 13C NMR (125 MHz,
CDCl3) d¼24.1 (2-CH3), 27.9 (C-9), 28.1 (C-4), 31.4 (C-8),
38.1 (C-7), 38.3 (C-6), 40.5 (C-5), 54.2 (C-1), 54.3 (CH2Ph),
56.9 (C-3), 71.7 (C-2), 127.3 (C-40), 128.2 (C-20), 128.6
(C-30), 139.9 (C-10); IR (film) 3315 (br), 3063, 3028, 2985,
2905 (s), 2868, 1604, 1495, 1452, 1383, 1368, 1325, 1272,
1219, 1166, 1120, 1095, 1017, 949, 937, 922, 899, 859, 738,
697, 653 cmꢀ1; MS (EI): m/z (%)¼259 (2) [Mþ], 244 (2), 216
(8), 188 (3), 160 (4), 134 (25), 133 (100), 104 (3), 91 (68), 72
(8), 43 (6), 28 (14). Anal. Calcd for C17H25NO: C, 78.72; H,
9.71; N, 5.40. Found: C, 78.36; H, 9.68; N, 5.43.
4.3. (1R,2R,3S,5R)-3-(Benzylamino)-2,6,6-trimethylbicyclo-
[3.1.1]heptan-2-ol (cis-6b) via benzoxazole
(a) Benzaldehyde (11b) (1.52 mL, 15.0 mmol) was added to
a solution of cis-5 (1.69 g, 10.0 mmol) in abs MeOH (15 mL)
and the reaction mixture stirred for 1 h. The solvent was re-
moved under vacuum, the residue dissolved in EtOH (25 mL)
and adjusted to pH 5 with concd HCl. After removal of the sol-
vent under vacuum, the residue was washed with acetone
(3ꢂ10 mL). The obtained hydrochloride was dissolved in H2O
(50 mL) and alkalized with 10 N NaOH solution. The precipi-
tate was extracted with EtOAc (3ꢂ50 mL), the combined
organic layers successively washed with H2O (2ꢂ50 mL) and
brine (50 mL), dried(MgSO4), and concentratedtogivea diaste-
reomeric mixture of 6,6,7a-trimethyl-2-phenyloctahydro-5,7-
4.4. General procedure for the preparation of trans-amino
alcohols (6) by reductive amination
To a suspension of finely powdered NaBH4 (980 mg,
26.0 mmol) in abs CH2Cl2 (60 mL) was added dropwise glacial

D. Hobuß et al. / Tetrahedron 64 (2008) 1635e1640
1639
acetic acid (4.80 mL, 84.0 mmol) and the suspension heated at
4.5. (1R,2R,3R,5R)-3-Amino-2,6,6-trimethylbicyclo[3.1.1]-
heptan-2-ol (trans-5)
reflux for 30 min. The reaction mixture was cooled to room tem-
perature and a solution of 8 (1.68 g, 10.0 mmol) in abs CH2Cl2
(10 mL) was added followed by a solution of isopropylamine
(10a) (2.22 mL, 26.0 mmol) or benzylamine (10b) (2.84 mL,
26.0 mmol) in abs CH2Cl2 (10 mL). After stirring at room tem-
perature for 15 h, the reaction mixture was hydrolyzed with 2 N
NaOH solution (11 mL) and adjusted to pH 10 with 2 N NaOH
solution. The layers were separated and the organic layer ex-
tracted with 1 N HCl (7ꢂ25 mL). The extracts were alkalized
with NaOH, the precipitate filtered off and extracted with
Et2O (3ꢂ50 mL). The combined organic layers were washed
with brine (50 mL), dried (MgSO4), and concentrated under
vacuum. The residue was chromatographed on SiO2 with
Et2O/MeOH/NH3.
To a solution of trans-6b (519 mg, 2.0 mmol) in abs MeOH
(10 mL) at room temperature was added 10% Pd/C (20 mg) and
the suspension stirred for 18 h under 1 atm of H2. The catalyst
was filtered through Celite and the solvent removed under vac-
uum to give trans-5 as a crystalline powder (338 mg, quant.).
Mp 72 ꢁC (66e67 ꢁC);18 [a]2D0 ꢀ31.2 (c 1.0, MeOH); 1H
NMR (500 MHz, CDCl3) d¼0.88 (s, 3H, 2-CH3), 1.25 (s, 3H,
9-H), 1.30 (s, 3H, 8-H), 1.41 (q, J¼5.2 Hz, 1H, 5-H), 1.58 (d,
J¼10.5 Hz, 1H, 1-H), 1.73 (br, 3H, NH2, OH), 1.93 (sext,
J¼5.4 Hz, 2H, 4-H), 2.13 (mc, 1H, 7-H), 2.31 (sept, J¼5.0
Hz, 1H, 7-H), 3.33 (t, J¼9.2 Hz, 1H, 3-H); 13C NMR
(125 MHz, CDCl3) d¼23.2 (2-CH3), 24.9 (C-8), 24.5 (C-9),
27.7 (C-4), 34.9 (C-7), 39.2 (C-5), 40.5 (C-6), 54.6 (C-1),
55.3 (C-3), 77.6 (C-2); IR (film) 3374 (NH), 3317 (NH), 3191
(br, NH), 2988, 2915 (s), 2902 (s), 2868, 1577 (s), 1459,
1382, 1372, 1325, 1268, 1240, 1156, 1108, 1061, 983, 929,
920, 895, 838, 739 (br), 698 (br), 659 (br), 578 cmꢀ1; MS
(EI): m/z (%)¼169 (1) [Mþ], 151 (2), 136.1 (3), 127 (3), 126
(30), 112 (4), 111 (41), 99 (11), 93 (12), 71 (48), 58 (8), 56
(15), 44 (100), 30 (19).
4.4.1. (1R,2R,3R,5R)-3-(Isopropylamino)-2,6,6-trimethyl-
bicyclo[3.1.1]heptan-2-ol (trans-6a)
Colorless liquid (1.65 g, 78%), cis/trans¼1:99; [a]2D0 ꢀ23.4
1
(c 1.0, CH2Cl2); Rf (Et2O/MeOH/NH3¼150:10:1)¼0.52; H
NMR (500 MHz, CDCl3) d¼0.87 (s, 3H, 2-CH3), 1.07 (dd,
J¼6.2, 6.3 Hz, 6H, CH(CH3)2), 1.24 (s, 3H, 9-H), 1.32 (s, 3H,
8-H), 1.36 (mc, 1H, 4-H), 1.60 (d, J¼10.4 Hz, 1H, NH), 1.63
(mc, 1H, 4-H), 1.87 (t, J¼5.7 Hz, 1H, 1-H), 1.92 (mc, 1H,
5-H), 2.27 (mc, 1H, 7-H), 3.01 (mc, 1H, 7-H), 3.02 (mc, 1H,
CH(CH3)2), 3.21 (t, J¼9.1 Hz, 1H, 3-H); 13C NMR
(125 MHz, CDCl3) d¼23.0 (2-CH3), 23.2 (C-8), 23.2 (C-9),
24.7 (CH(CH3)2), 27.7 (C-4), 33.6 (C-7), 39.2 (C-5), 40.4
(C-6), 46.2 (C-1), 55.8 (CH(CH3)2), 57.2 (C-3), 78.1 (C-2);
IR (film) 3411 (br, NH), 2956 (s), 2908 (s), 2867 (s), 2548
(br), 2361 (s), 2342, 2159, 1975, 1661, 1458, 1381, 1366,
4.6. General procedure for the preparation of racemic
alcohols (rac-13)
To a stirred solution of the respective 12 (5.0 mmol) in abs
MeOH (10 mL) at 0 ꢁC was added NaBH4 (95.0 mg,
2.50 mmol) over 15 min, and the reaction mixture was stirred
for a further 2 h. After hydrolysis with a satd NH4Cl solution
(15 mL), the reaction mixture was extracted with EtOAc
(3ꢂ15 mL). The combined organic layers were washed with
brine (50 mL), dried (MgSO4), and the solvent was removed
under vacuum. The enantiomers were separated by GC on a col-
umn Bondex-unb (20 mꢂ0.30 mm) and H2 as carrier gas; tem-
perature program: 5 min at 40 ꢀꢁC1 , then 2 ꢁC minꢀ1 gradient to
140 ꢁC followed by 10 ꢁC min gradient to 200 ꢁC.
1267, 1227, 1164, 1126, 1066 (s), 1030, 921, 891, 846 cmꢀ1
;
HRMS (ESI) calcd for C13H25NO 212.2014 [Mþ], found
212.2013 [MþþHþ]. Anal. Calcd for C13H25NO: C, 73.88; H,
11.92; N, 6.63. Found: C, 73.84; H, 11.83; N, 6.65.
4.4.2. (1R,2R,3R,5R)-3-(Benzylamino)-2,6,6-trimethyl-
bicyclo[3.1.1]heptan-2-ol (trans-6b)
Colorless oil (2.05 g, 79%), cis/trans¼1:99; [a]2D0 ꢀ42.6
1
(c 1.0, CH2Cl2); Rf (Et2O/MeOH/NH3¼100:10:1)¼0.73; H
4.6.1. rac-1-Phenylethanol (rac-13a)
tR(R)¼30.0 min, tR(S)¼31.3 min.
NMR (500 MHz, CDCl3) d¼0.91 (s, 3H, 2-CH3), 1.24 (s, 3H,
9-H), 1.40 (s, 3H, 8-H), 1.48 (mc, 1H, 5-H), 1.54
(d, J¼10.4 Hz, 1H, 4-H), 1.87 (t, J¼5.7 Hz, 1H, 1-H), 1.94
(mc, 1H, 4-H), 2.11 (mc, 1H, 7-H), 2.31 (mc, 1H, 7-H), 3.14
(t, J¼8.6 Hz, 1H, 3-H), 3.90 (d, J¼12.6 Hz, 1H, CH2Ph), 4.01
(d, J¼12.6 Hz, 1H, CH2Ph), 7.24 (mc, 1H, 40-H), 7.32 (mc,
2H, 30-H), 7.37 (mc, 2H, 20-H); 13C NMR (125 MHz, CDCl3)
d¼23.1 (2-CH3), 24.7 (C-9), 24.8 (C-8), 27.7 (C-4), 33.2
(C-7), 35.4 (CH2Ph), 39.2 (C-6), 40.3 (C-5), 52.9 (C-1), 60.3
(C-3), 77.9 (C-2), 126.9 (C-40), 128.1 (C-30), 128.4 (C-20),
140.9 (C-10); IR (film) 3402 (br, NH), 3025, 2990, 2907 (s),
2866, 1603 (w), 1494, 1453, 1384, 1366, 1212, 1159, 1129,
1091, 1070, 1028, 921, 891, 732, 696 (s) cmꢀ1; MS (EI): m/z
(%)¼259 (2) [Mþ], 254 (7), 216 (3), 188 (2), 160 (4), 135 (4),
134 (30), 133 (100), 118 (5), 104 (6), 92 (7), 91 (71), 65 (6),
43 (8), 28 (13). Anal. Calcd for C17H25NO: C, 78.72; H, 9.71;
N, 5.40. Found: C, 78.38; H, 9.62; N, 5.44.
4.6.2. rac-1-Phenylpropanol (rac-13b)
tR(R)¼35.7 min, tR(S)¼36.5 min.
4.6.3. rac-2-Methyl-1-phenylpropanol (rac-13c)
tR(R)¼39.3 min, tR(S)¼39.8 min.
4.6.4. rac-2-Chloro-1-phenylethanol (rac-13d)
tR(R)¼45.1 min, tR(S)¼44.0 min.
4.7. General procedure for the one-pot multi-substrate
screening
To a solution of the respective amino alcohol 5 or 6
(0.10 mmol) in abs THF (1 mL) at 0 ꢁC were added 1 M
BH3$THF solution (1.0 mL, 1.00 mmol) in THF and 0.1 M

1640
D. Hobuß et al. / Tetrahedron 64 (2008) 1635e1640
Gong, L. Z.; Li, Z.; Yang, G. S.; Mi, A. Q. Chin. Chem. Lett. 1996, 7,
415e418; (l) Quallich, J. G.; Blake, J. F.; Woodall, T. M. J. Am. Chem.
Soc. 1994, 116, 8516e8525; (m) Tanaka, K.; Matsui, J.; Suzuki, H.
J. Chem. Soc., Chem. Commun. 1991, 1311e1312.
B(OMe)3 solution (1.0 mL, 0.10 mmol) in THF followed by
dropwise addition of the mixture of substrates 12 (1.0 mL,
1.00 mmol) [prepared from 2.50 mmol of each ketone 12 in
10 mL THF] over 75 min by syringe. The reaction mixture
was hydrolyzed with H2O (4 mL), the layers were separated
and the aqueous layer was extracted with Et2O (3ꢂ10 mL).
The combined organic layers were washed with H2O
(10 mL) and brine (10 mL), dried (MgSO4), and concen-
trated. The crude product mixture was taken up in CH2Cl2
and directly analyzed by GC as described for the racemic
mixture.
6. For the use of bicyclic terpene-derived amino alcohols in dialkylzinc
additions to aldehydes, see some selected examples: (a) Martinez,
A. G.; Vilar, E. T.; Fraile, A. G.; de la Moya Cerero, S.; Martinez Ruiz,
P.; Diaz Morillo, C. Tetrahedron: Asymmetry 2007, 18, 742e749; (b)
Szakonyi, Z.; Balazs, A.; Martinek, T. A.; Fulop, F. Tetrahedron: Asymme-
¨ ¨
try 2006, 17, 199e204; (c) Kasashima, Y.; Hanyu, N.; Aoki, T.; Mino, T.;
Sakamoto, M.; Fujita, T. J. Oleo Sci. 2005, 54, 495e504; (d) Goldfuss, B.;
Loschmann, T.; Rominger, F. Chem.dEur. J. 2004, 10, 5422e5431; (e)
¨
Garcia Martinez, A.; Teso Vilar, E.; Fraile, G. A.; de la Moya Cerero,
S.; Martinez-Ruiz, P.; Chicharro Villas, P. Tetrahedron: Asymmetry
2002, 13, 1e4; (f) Xu, Q. Y. ; Wu, T. X.; Pan, X. F. Chin. Chem. Lett.
2001, 12, 1055e1056; (g) Goldfuss, B.; Houk, K. N. J. Org. Chem.
1998, 63, 8998e9006; (h) Kitamura, M.; Okada, S.; Suga, S.; Noyori,
R. J. Am. Chem. Soc. 1989, 111, 4028e4036.
Acknowledgements
We gratefully acknowledge the Deutsche Forschungsge-
meinschaft, the Fonds der Chemischen Industrie and the Mini-
7. Hobuß, D.; Thone, C.; Laschat, S.; Baro, A. Synthesis 2003, 2053e2056.
¨
8. For other pinene-derived phosphorus ligands, see: (a) Gavryushin, A.;
Polborn, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 2279e2288;
(b) Bergner, E. J.; Helmchen, G. Eur. J. Org. Chem. 2000, 419e424.
9. For camphor-derived phosphorus ligands, see: (a) Monsees, A.; Laschat,
S. Synlett 2002, 1011e1013; (b) Sell, T.; Laschat, S.; Dix, I.; Jones,
P. G. Eur. J. Org. Chem. 2000, 4119e4124; (c) Alexakis, A.; Vastra, J.;
Burton, J.; Mangeney, P. Tetrahedron: Asymmetry 1997, 8, 3193e3196;
(d) Zhorov, E. U.; Gavrilov, K. N.; Pavlov, V. A.; Teleshev, A. T.;
Gorshkova, L. S.; Nifantev, E. E.; Klabunovskii, E. I. Russ. Chem. Bull.
1991, 871e876; (e) Morrison, J. D.; Masher, W. F.; Neuberg, M. K.
Adv. Catal. 1976, 25, 81e85; (f) Bogdanovic, B.; Henc, B.; Meister,
B. B.; Pauling, H.; Wilke, G. Angew. Chem. 1972, 84, 1070e1071;
Angew. Chem., Int. Ed. Engl. 1972, 11, 1023e1024.
sterium fur Wissenschaft, Forschung und Kunst des Landes
Baden-Wurttemberg for financial support.
¨
¨
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