Chiral terpene auxiliaries. Part 1: Highly enantioselective reduction of ketones with borane catalyzed by an oxazaborolidine derived from (-)-β-pinene

Article abstract of DOI:10.1016/j.tetlet.2005.09.172

(1R,2S,3R,5R)-3-Amino-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane was synthesized in three steps from (-)-β-pinene. It was used for the in situ generation of a B-methoxy-oxazaborolidine catalyst for the asymmetric reduction of alkyl-aryl ketones with borane-dimethyl sulfide complex. In the presence of 3 mol % of the catalyst, the product alcohols were obtained in high yields and with enantiomeric excesses in the range of 93-98%.

Full text of DOI:10.1016/j.tetlet.2005.09.172

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8299–8302
Chiral terpene auxiliaries. Part 1: Highly enantioselective
reduction of ketones with borane catalyzed by an
oxazaborolidine derived from (ꢀ)-b-pinene
*
´
Marek P. Krzeminski and Andrzej Wojtczak
Department of Chemistry, Nicolaus Copernicus University, 87-100 Torun´, Poland
Received 24 August 2005; revised 20 September 2005; accepted 28 September 2005
Available online 13 October 2005
Abstract—(1R,2S,3R,5R)-3-Amino-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane was synthesized in three steps from (ꢀ)-b-pinene.
It was used for the in situ generation of a B-methoxy-oxazaborolidine catalyst for the asymmetric reduction of alkyl–aryl ketones
with borane-dimethyl sulfide complex. In the presence of 3 mol % of the catalyst, the product alcohols were obtained in high yields
and with enantiomeric excesses in the range of 93–98%.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Boron reagents and catalysts derived from chiral ter-
penes, especially a-pinene have proved to be very valu-
able in asymmetric synthesis.1 Versatile pinane-based
reagents were developed and successfully applied to
many chiral transformations, for example, asymmetric
reduction,2a hydroboration,2a allylboration,2b homo-
logation,2c ring opening of epoxides,2d and others.2e
Among these processes, the enantioselective reduction
of prochiral ketones with stꢁoichiometric reagents
(DIP-ChlorideTM, Alpine-Borane )2a,f or catalyzed by
oxazaborolidines,3 are widely used methods.
and obtained their best results with the catalyst gener-
ated from 1,1-diphenylprolinol and trioctylborate.5
Consequently, we decided to synthesize a new terpene-
derived aminoalcohol starting from the readily available
optically pure (ꢀ)-b-pinene as shown in Scheme 1.
(+)-Nopinone6 (1), obtained by ozonolysis of (ꢀ)-b-
pinene, was transformed into ketoxime 2.7 Reduction
of 2 with lithium tetrahydridoaluminate produced
(1R,2S,3R,5R)-3-amino-6,6-dimethyl-2-hydroxy-bicyclo-
[3.1.1]heptane (3) in 87% yield.8 Its structure was con-
firmed by X-ray analysis of its p-tolunesulfonamide
derivative 49,10 (Fig. 1).
Over the past two decades, oxazaborolidines derived
from amino acids, for example, 1,1-diphenylprolinol
and 1,1-diphenylvalinol, have been extensively studied.3
In contrast to the numerous stoichiometric applications
of terpene-based organoboranes in asymmetric synthe-
sis, very little is known on the utilization of terpene-
derived oxazaborolidines as catalysts for the reduction
of ketones with borane.4 Masui and Shioiri used 2-
hydroxy-3-aminopinane, obtained from a-pinene,4a for
the preparation of oxazaborolidines, and simplified the
reduction protocol by the in situ generation of B-meth-
oxy-oxazaborolidines.4b Ponzo and Kaufmann extended
the methodology to other B-alkoxy-oxazaborolidines,
O
O
HON
b)
a)
76%
88%
(–)-β-Pinene
1
2
c)
87%
OH
OH
H
N
d)
H2N
Ts
92%
3
4
Keywords: Asymmetric reduction; 1,2-Aminoalcohols; Chiral oxaz-
Scheme 1. Reagents and conditions: (a) (1) O3, ꢀ78 ꢂC, (2) S(CH3)2;
(b) (1) t-BuOK, n-BuONO, (2) HCl(aq); (c) (1) LiAlH4, THF, reflux,
(2) 10% NaOH(aq), H2O; (d) p-TsCl, Et3N, CH2Cl2.
aborolidines; Terpenes.
*
Corresponding author. Tel.: +48 56 6114531; fax: +48 56 6542477;
e-mail: mkrzem@chem.uni.torun.pl
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.172

8300
M. P. Krzemin´ski, A. Wojtczak / Tetrahedron Letters 46 (2005) 8299–8302
Table 2. Asymmetric reduction of selected ketones
1) 3 (3 mol%),
B(OMe)3 (3.3 mol%),
O
OH
Alk
BH3*SMe2, THF, rt
2) MeOH
Ar
Alk
Ar
Entry
Ketone
Product
Yielda (%)
98
eeb (%), (conf.)c
O
Ph
O
1
98 (S)
2
3
4
99
93 (S)
96 (R)
97d (R)
Ph
O
Figure 1. X-ray structure of 4.10
96
Cl
Ph
O
We used commercially available trialkyl borates for the
in situ generation of the active catalyst. Aminoalcohol 3
was treated with trimethyl, triisopropyl and tri-n-butyl
borates and the corresponding B-alkoxy-oxazaboroli-
dines were used without isolation from the reaction mix-
ture to catalyze the reduction with borane at room
temperature and at 0 ꢂC. Initial studies were focused
on the asymmetric reduction of acetophenone with bor-
ane in the presence of the catalyst (Table 1). Experi-
ments with 10 mol % of 3 and 11 mol % of B(OMe)3
proceeded smoothly to give (S)-1-phenylethanol of
97% ee in 99% yield (Table 1, entries 1 and 2). An
increase in the steric bulk on boron using triisopropyl
borate led to a lower enantiomeric excess probably
due to an uncatalyzed side reduction reaction, especially
at 0 ꢂC (entries 3 and 4). Tri-n-butyl borate gave similar
result to B(OMe)3 (entry 5). Lower catalyst loadings (5
and 3 mol %) did not decrease the enantiomeric purity
of the product alcohol. Even 1 mol % of 3 efficiently cat-
92
Br
Ph
O
5
6
97
94
96 (S)
95 (S)
O
Br
O
7
95
95 (S)
OMe
O
8
9
96
97
97 (S)
97 (S)
OMe
MeO
Table 1. Asymmetric reduction of acetophenone with BMSa catalyzed
O
b
by oxazaborolidines generated from 3 and B(OR)3
OH
O
3, B(OR)3, BH3*SMe2
THF
O
(S)
10
11
99
98
98 (S)
93 (S)
Entry 3 (mol %)
R
Temp (ꢂC)
Productc
Yield (%)d ee (%)e
O
1
2
3
4
5
6
7
8
10
10
10
10
10
5
Me
Me
i-Pr
i-Pr
0
20
0
98
99
98
97
99
97
98
96
96
97
84
94
98
97
98
92
a Isolated yields after flash chromatography.
20
b Enantiomeric excess was established by GC analysis of the product
alcohol on a Supelco b-dex 325TM column.
n-Bu 20
Me
Me
Me
20
20
20
c Configurations were established by comparing signs of rotation with
literature reports: entries 1, 2, 6, 8 see Ref. 12a, entry 3 see Ref. 12b,
entry 4 see Ref. 12c, entries 5, 9 see Ref. 12d, entry 7 see Ref. 12e,
entry 10 see Ref. 12f, entry 11 see Ref. 12g.
3
1
a Borane–dimethyl sulfide complex (BH3 S(CH3)2).
*
b For the typical procedure see Ref. 11.
d B(OBu)3 was used instead of B(OMe)3, which gave 86% ee.
c Configuration was established by comparing the sign of rotation with
an authentic sample (Aldrich).
d Isolated yields after flash chromatography.
e Enantiomeric excess was established by GC analysis of the product
alcohol on a Supelco b-dex 325TM column.
alyzed the reduction producing 1-phenylethanol with
92% ee (entry 8).

M. P. Krzemin´ski, A. Wojtczak / Tetrahedron Letters 46 (2005) 8299–8302
8301
New York; pp 395–576; (d) Wallbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1992, 3, 1475–1504.
4. (a) Masui, M.; Shioiri, T. Synlett 1996, 49–50; (b) Masui,
M.; Shioiri, T. Synlett 1997, 273–274; (c) Markowicz, S.
W.; Pokrzeptowicz, K.; Karolak-Wojciechowska, J.; Czyl-
Me
OMe
H2 B
H
B
Ph
H
N
O
O
´
kowski, R.; Omelanczuk, J.; Sobczak, A. Tetrahedron:
Asymmetry 2002, 13, 1981–1991; (d) Santhi, V.; Mad-
husudana Rao, J. Tetrahedron: Asymmetry 2000, 11,
3553–3560.
Figure 2. The chair-like transition state.
5. Ponzo, V. L.; Kaufman, T. S. Synlett 2002, 1128–1130.
6. Brown, H. C.; Weismann, S. A.; Perumal, P. T.; Dhokte,
U. P. J. Org. Chem. 1990, 55, 1217–1223.
7. Heiwald, J.; Gassman, P. G. J. Am. Chem. Soc. 1960, 61,
5445–5450.
The optimal reaction conditions, 3 mol % of 3 and
B(OMe)3 at room temperature, which gave the highest
yield for acetophenone and an excellent ee value (Table
1, entry 7), were applied for the reduction of other alkyl–
aryl ketones (Table 2). As the results in Table 2 indicate,
all the ketones were reduced with high enantioselectivi-
ties regardless of the substitution pattern or substituent.
8. (1R,2S,3R,5R)-(ꢀ)-3-Amino-6,6-dimethyl-2-hydroxy-bi-
cyclo1[3.1.1]heptane (3): A three-necked flask, equipped
with a reflux condenser, a dropping funnel and magnetic
stirring bar, was charged with THF (250 ml) and LiAlH4
(11.40 g, 0.3 mol). A solution of (+)-isonitrosonopinone
(2) (16.70 g, 0.1 mol) in THF (100 ml) was then added and
stirred at room temperature under a nitrogen atmosphere.
The mixture was stirred under reflux for 24 h. The solution
was cooled in an ice bath and ethyl acetate (11.4 ml), 10%
NaOH(aq) (11.4 ml) and water (34.3 ml) were added
carefully. After stirring the mixture at room temperature
for 4 h, it was filtered under reduced pressure through a
small pad of Celite. The filtrate was dried with anhydrous
magnesium sulfate. Removal of the solvent provided a
In the generally accepted mechanism of the oxazaboroli-
dine catalyzed reduction of ketones with borane, a cyclic
transition state for the hydride transfer is proposed.3a,13
In the case of the B-methoxy-oxazaborolidine prepared
from 3 and B(OMe)3, the stereochemistry of the reduced
product can be explained by the transition state model
depicted in Figure 2.
In conclusion, aminoalcohol 3 is conveniently prepared
from (ꢀ)-b-pinene in three steps, and in a good yield.
B-Methoxy-oxazaborolidine generated in situ from 3 is
a superior catalyst for the asymmetric reduction of alkyl
aryl ketones with borane. The optical purities of the
product alcohols are as high as those obtained in reduc-
tions catalyzed by oxazaborolidines prepared from
1,1-diphenylprolinol, and are higher than those in the
reported reactions catalyzed by other terpene-derived
oxazaborolidines.
crude product, which was crystallized from diethyl ether to
22
afford 3 (13.5 g, 87%), mp 77–78 ꢂC, ½aŠ ꢀ13.9 (c 2.4,
D
1
1
CHCl3). H, H · 1H COSY NMR (300 MHz, CDCl3) d
(subscript c or t means, that the proton is cis or trans to
the dimethyl bridge) 0.99 (s, 3H, CH3), 1.19 (s, 3H, CH3),
1.19 (d, J = 10.2 Hz, 1H, H7c), 1.51 (ddt, J1 = 13.2 Hz,
J2 = 7.8 Hz, J3 = 1.5 Hz, 1H, H4c), 1.89 (q, J = 5.5 Hz,
1H, H5t), 2.13 (dt, J1 = 10.2 Hz, J2 = 6.0 Hz, 1H, H7t),
2.28 (m, 1H, H1t), 2.34 (ddd, J1 = 13.4 Hz, J2 = 9.6 Hz,
J3 = 5.0 Hz, 1H, H4t), 2.50 (br s, 3H, OH, NH2, exchange-
able with D2O), 3.50 (dt, J1 = 9.6 Hz, J2 = 7.9 Hz, 1H,
H3t), 4.08 (dd, J1 = 7.8 Hz, J2 = 4.8 Hz, 1H, H2t). 13C
NMR (75 MHz, CDCl3) d 22.45, 25.09, 27.35, 36.42, 38.29
(C–(CH3)2), 40.97, 43.52, 46.31, 71.79. HETCOR 1H · 13C
NMR cross peaks: 0.99 (s)–22.45 (CH3); 1.19 (d), 2.13
(dt)–25.09 (CH2); 1.19 (s)–27.35 (CH3); 1.51 (ddt), 2.34
(ddd)–36.42 (CH2); 1.89 (q)–40.97 (CH); 3.50 (dt)–43.52
(CHNH2); 2.28 (m)–46.31 (CH); 4.08 (dd)–71.79 (CHOH).
Anal. Calcd for C9H17NO (155.24): C, 69.63; H, 11.04.
Found: C, 69.59; H, 11.21.
Acknowledgements
We gratefully acknowledge financial support by the
Nicolaus Copernicus University, Grant Ch-341.
9. (+)-p-Toluenesulfonamide 4: p-TsCl (210 mg, 1.1 mmol)
was added in one portion to a stirred solution of (ꢀ)-3
(155 mg, 1 mmol) and Et3N (0.28 ml, 2 mmol) in CH2Cl2
(10 ml) at 0 ꢂC under an argon atmosphere. After 24 h,
water was added, and stirring was continued for 15 min.
The layers were separated and the organic layer was
washed with 5% aqueous NaHCO3 (5 ml), brine (5 ml) and
then dried over magnesium sulfate. Evaporation of the
solvent provided a crude product, which was crystallized
References and notes
1. (a) Brown, H. C.; Zaidlewicz, M. Recent Developments. In
Organic Syntheses via Boranes; Aldrich Chemical Com-
pany: Milwaukee, 2001; Vol. 2; (b) Matteson, D. S.
Stereodirected Synthesis with Organoboranes; Springer:
Berlin, Heidelberg, 1995; (c) Deloux, L.; Srebnik, M.
Chem. Rev. 1993, 93, 763–784.
2. (a) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res.
from cyclohexane/toluene to afford 4 (255 mg, 92%), mp
´
1992, 25, 16–24; (b) Ramachandran, P. V.; Krzeminski,
20
D
131–132 ꢂC, ½aŠ
+16.1 (c 5.3, CHCl3). 1H NMR
M. P.; Ram Reddy, M. V.; Brown, H. C. Tetrahedron:
Asymmetry 1999, 10, 11–15; (c) Matteson, D. S.; Man,
H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996, 118, 4560–4566;
(d) Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14,
(300 MHz, CDCl3) d (subscript c or t means, that the
proton is cis or trans to the dimethyl bridge) 0.99 (s, 3H,
CH3), 1.14 (d, J = 10.2 Hz, 1H, H7c), 1.17 (s, 3H, CH3),
1.69 (ddt, J1 = 13.8 Hz, J2 = 8.4 Hz, J3 = 1.5 Hz, 1H,
H4c), 1.86 (q, J = 5.4 Hz, 1H, H5t), 1.97 (br s, 1H, OH),
2.08–2.14 (m, 3H), 2.43 (s, 3H, CH3), 3.77 (dt, J1 = 9.3 Hz,
J2 = 8.4 Hz, 1H, H3t), 4.12 (dd, J1 = 7.8 Hz, J2 = 4.8 Hz,
1H, H2t), 5.25 (br s, 1H, NH), 7.31 (d, J = 7.8 Hz, 2H,
2·CH), 7.80 (d, J = 8.4 Hz, 2H, 2·CH). 13C NMR
(50 MHz, CDCl3) d 21.48 (CH3), 22.60 (CH3), 24.82
´
645–647; (e) Zaidlewicz, M.; Krzeminski, M. P. Tetrahe-
dron Lett. 1996, 37, 7131–7134; (f) DIP-Chloride is a
trademark of the Aldrich Chemical Company.
3. (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 1987–1990; (b) Cho, B. T. Aldrichim. Acta 2002, 35, 3–
16; (c) Itsuno, S. In Organic Reactions; Paquette, L. A.,
Ed.; Enantioselective Reduction of Ketones; John Wiley:

8302
M. P. Krzemin´ski, A. Wojtczak / Tetrahedron Letters 46 (2005) 8299–8302
(CH2), 27.02 (CH3), 36.57 (CH2), 38.14 (C(CH3)2), 40.36
charged with (ꢀ)-3 (23 mg, 0.15 mmol), THF (1 ml), and
B(OMe)3 (18.5 ll, 0.165 mmol). This mixture was stirred
for 1 h at room temp. Next, THF (4 ml) and BMS(10 M,
0.5 ml, 5 mmol) were added via syringe, followed by slow
addition of acetophenone (0.60 g, 5 mmol) in THF (5 ml)
using a syringe pump. The reaction mixture was then
stirred for 0.5 h. Methanol (4 ml) was cautiously added,
and after 3 h, volatiles were removed under vacuum on a
rotary evaporator. The residue was flash chromato-
graphed through a small pad of silica gel using petroleum
ether–ethyl acetate (9:1) as solvent. 1-Phenylethanol
(CH), 46.34 (CH), 47.04 (CH), 71.79 (CHOH), 127.11
(2·CH), 129.68 (2·CH), 137.49 (C), 143.44 (C). Anal.
Calcd for C16H23NO3S(309.43): C, 62.11; H, 7.52. Found:
C, 62.11; H, 7.57.
10. Crystallographic data for the structure in this letter has
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
279066. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk). Crystal data: Com-
pound 4: The diffraction data was collected at 293 K,
single crystal 0.58 · 0.32 · 0.31 mm, Oxford Diffraction
KM4 CCD diffractometer, MoKa radiation k =
(0.60 g, 98%) was isolated, and was analyzed by GC
22
on a Supelco b-dex 325TM column 98% ee, ½aŠ ꢀ53.2 (c
D
25
D
1.2, CHCl3). Lit.12a: ½aŠ ꢀ55.1 (c 1.63, CHCl3) for >99%
ee.
˚
0.71073 A. Structure refined with SHELX97 package
12. (a) Nakamura, K.; Matsuda, T. J. Org. Chem. 1998, 63,
8957–8964; (b) Kamal, A.; Sandbhor, M.; Ramana, K. V.
Tetrahedron: Asymmetry 2002, 13, 815–820; (c) Imuta, M.;
Kawai, K.; Ziffer, H. J. Org. Chem. 1980, 45, 3352–3355;
(d) Palmer, M.; Walsgroue, T. J. Org. Chem. 1997, 62,
5226–5228; (e) Davies, S. G.; Goodfellow, C. L. J. Chem.
Soc., Perkin Trans. 1 1989, 192–194; (f) Ma, Y.; Liu, H.;
Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett. 2003, 5,
2103–2106; (g) Kasai, M.; Froussios, C.; Ziffer, H. J. Org.
Chem. 1983, 48, 459–464.
(Sheldrick, G. M.; Schneider, T. M. Methods Enzymol.
1997, 277B, 319). C16H23N1O3S1, crystal system mono-
clinic, space group, C2; a = 18.453(2), b = 9.638(1), c =
3
˚
˚
8.752(1) A, b = 93.64(1)ꢂ, V = 640.50(9) A ; Z = 4;
F(000) = 664; l = 0.218 mmꢀ1
;
R1 = 0.0432, wR2 =
0.1175; S = 1.092. The relative positions of the tosyl and
pinene ring systems is described by the torsion angle
values:
O2–C2–C3–C4
ꢀ101.6(2);
C2–C3–N3–S1
ꢀ136.17(14); C3–N3–S1–C10 61.26(15); N3–S1–C10–C20
ꢀ107.23(16); the hydrogen bond N3ꢁ ꢁ ꢁO4 [ꢀxꢀ1/2, yꢀ1/
13. (a) Jones, D. K.; Liotta, D. C.; Shinkai, I.; Mathre, D. J. J.
Org. Chem. 1993, 58, 799–801; (b) Quallich, G. J.; Blake,
J. F.; Woodal, T. M. J. Am. Chem. Soc. 1994, 116, 8516–
8525.
˚
2, ꢀzꢀ1] distance is 3.096 A.
11. Typical procedure for the reduction: A round bottom
flask, dried at 120 ꢂC and cooled in a stream of argon, was