Chiral terpene auxiliaries III: Spiroborate esters from (1R,2S,3R,5R)-3-amino-apopinan-2-ol as highly effective catalysts for asymmetric reduction of ketones with borane

Article abstract of DOI:10.1016/j.tetasy.2015.10.018

New spiroborate esters, derived from terpene amino alcohols, (S)-prolinol, and 2-aminoethanol, were employed as catalysts in the borane reduction of acetophenone and other aryl alkyl and halogenated ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to 98% ee. The influence of the amino alcohol and the diol moieties of spiroborate on the reaction selectivity was examined. The catalyst load, the nature of the solvent, the borane source, and the reaction conditions were also investigated.

Full text of DOI:10.1016/j.tetasy.2015.10.018

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral terpene auxiliaries III: spiroborate esters from (1R,2S,3R,5R)-3-
amino-apopinan-2-ol as highly effective catalysts for asymmetric
reduction of ketones with borane
⇑
´
´
´
Marta Cwiklinska, Marek P. Krzeminski , Agnieszka Tafelska-Kaczmarek
Faculty of Chemistry, Nicolaus Copernicus University in Torun´, 7 Gagarin St., Torun´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New spiroborate esters, derived from terpene amino alcohols, (S)-prolinol, and 2-aminoethanol, were
employed as catalysts in the borane reduction of acetophenone and other aryl alkyl and halogenated
ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to
98% ee. The influence of the amino alcohol and the diol moieties of spiroborate on the reaction selectivity
was examined. The catalyst load, the nature of the solvent, the borane source, and the reaction conditions
were also investigated.
Received 8 October 2015
Accepted 21 October 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
O3BN framework, where the B–N coordinative bond makes the
molecule stable toward moisture and air. Consequently, spirobo-
Spiroborate esters, derived from chiral 1,2-amino alcohols or
amino acids, exhibit high catalytic activity in the asymmetric
rates are easier to prepare, purify, store, and handle compared to
organoboronic catalysts, especially oxazaborolidines. One advan-
tage over other catalytic systems employed in asymmetric reduc-
tions of the carbonyl group is by-passing the need for highly
air/moisture-sensitive and precious metal catalysts or expensive
reducing agents, as well as excellent enantioselectivities and
almost quantitative yields of the products. Thus, the asymmetric
reduction involving spiroborates is a convenient, inexpensive
method suitable for industrial applications.
Previously, we described a series of chiral spiroborate esters
derived from (1R,2R,3S,5R)-3-amino-pinan-2-ol and various diols.
Except for the catechol derivative, all of them turned out to be effi-
cient and selective catalysts in the reduction of acetophenone with
borane.8 In continuation of our studies, we herein describe a com-
prehensive study of the asymmetric reduction of prochiral ketones
with borane catalyzed with new spiroborate esters.
reductions of prochiral ketones,1–8
a
-haloketones,9 and oxime
ethers with borane.10–13 They have also been successfully applied
in asymmetric aldol condensations.14 The spiroborate ester
obtained from (S)-1,1-diphenylprolinol and ethylene glycol,15
described by Ortiz-Marciales et al., proved to be an excellent
catalyst for the asymmetric reduction of various aryl alkyl and aro-
matic heterocyclic ketones,2–6,9 comparable in enantioselectivity to
the CBS oxazaborolidine. Its analogue, obtained from (S)-1,1-
diphenylvalinol, achieves outstanding stereoselectivity in the
reduction of aryl alkyl and heterocyclic benzyloxime ethers to
the corresponding primary amines and amino ethers.10–12 These
two spiroborates were applied in the syntheses of mexiletine,6,12
nicotine,11 and their analogues, a group of ligand-gated ion channel
receptors, which play a vital role in biological processes, such as
neurotransmission. Later investigations revealed their high
effectiveness in the preparation of duloxetine16 and calcimimetic
agents.17 Spiroboranes are also effective catalysts for the selective
reduction of esters, amides,18 and are excellent synthetic templates
for other asymmetric transformations.19,20
2. Results and discussion
Terpene spiroborate esters 1–10 are derived from various
diols and (1R,2S,3R,5R)-3-amino-apopinan-2-ol,21,22 (1S,3S,4R,6R)-
4-amino-caran-3-ol,23,24 (1S,2S,3S,4S,5R)-4-amino-2-methoxy-
pinan-3-ol (Fig. 1).25 Commercially available (S)-prolinol and achi-
ral 2-aminoethanol were also utilized in the synthesis of 8–10 for
the sake of comparison with the terpene amino alcohols. This
approach gives novel prospects for the application of terpenes,
which are a natural source of chirality.
What distinguishes spiroborates from other well-known oxaz-
aborolidines is their unique structure containing a characteristic
⇑
Corresponding author.
E-mail address: mkrzem@chem.umk.pl (M.P. Krzemin´ ski).
http://dx.doi.org/10.1016/j.tetasy.2015.10.018
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
´
´
Please cite this article in press as: Cwiklinska, M.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.018

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M. Cwiklinska et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
2
O
N
O
O
O
N
O
N
O
O
O
O
O
N
O
O
B
B
O
B
B
H2
H2
H2
H2
2
3
4
1
OMe
O
O
O
O
O
N
O
O
O
O
O
B
B
B
B
O
NH
N
O
N
H2
H2
H2
6
7
8
5
O
O
O
O
O
B
B
NH
O
N
H2
9
10
Figure 1. Terpene spiroborate esters 1–10.
Spiroborate esters 1–10 were prepared by the reaction of an
using a syringe pump. When the reduction was completed, metha-
nol was added, the mixture was concentrated, and 1-phenyletha-
nol was isolated by column chromatography on silica gel. The
results are summarized in Table 2.
appropriate amino alcohol, triisopropyl borate, and a diol, according
to the reported procedure.8 Amino alcohols, (1R,2S,3R,5R)-3-amino-
apopinan-2-ol, (1S,3S,4R,6R)-4-amino-caran-3-ol, (1S,2S,3S,4S,5R)-
4-amino-2-methoxy-pinan-3-ol, (S)-prolinol, and 2-aminoethanol
were used for the reaction with the following diols: ethylene glycol,
(1S,2S,3R,5S)-pinane-2,3-diol,26
(1R,2R,3S,5R)-pinane-2,3-diol,26
Table 2
Borane reduction of acetophenone catalyzed by spiroborate esters 1–10
(1S,3S,4R,6R)-carane-3,4-diol,27 and the commercially available
1,4-anhydroerythritol, and cis-1,2-cyclopentanediol. All terpene
spiroborates were formed as white precipitates in high yields, and
showed excellent stability after being exposed to air for a short per-
iod of time, as was evidenced by the unchanged 11B NMR spectra.
They could be stored under an inert atmosphere for prolonged peri-
ods. In all cases, the 11B NMR spectra recorded in CDCl3 exhibited a
characteristic singlet at 9–13 ppm for the central boron atom, thus
confirming the unique O3BN framework. However, minor signals
at 22.37, 22.07, and 22.14 ppm, for 2, 3, and 8, respectively, were also
noticed. These indicate an equilibrium between spiroborate and
boratelacking complexationbetween the nitrogen and boron atoms.
Representative data of spiroborate esters 1–10 are summarized in
Table 1.
1. Catalyst / BH3.SMe2
O
OH
*
THF, rt, 1h
Ph
Ph
2. MeOH
Entry
Catalyst (mol%)
Yielda (%)
eeb (%)
Conf.c
1
2
3
4
5
6
7
8
1 (10)
1 (1)
1 (0.5)
2 (5)
3 (10)
3 (5)
93
91
96
96
98
97
96
93
94
90
93
95
96
98
94
90
97
96
80
86
95
92
94
94
98
97
95
96
34
46
24
1
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
—
4 (1)
5 (1)
9
6 (10)
6 (5)
10
11
12
13
14
15
16
6 (1)
7 (5)
8 (5)
Table 1
Synthesis of spiroborate esters 1–10
20
Ester
Yielda (%)
Mp (°C)
11B NMRb,c
[a]
D
9 (10)
9 (5)
10 (5)
(d ppm)
1
2
3
4
5
6
7
8
9
10
95
79
42
87
78
73
50
46
69
74
110–113
146–148
149–152
223–228
197–200
79–83
164–166
105–107
144–146
123–124
10.24
12.90
12.86
10.80
11.04
9.17
10.40
10.74
10.98
11.04
ꢀ23.8 (c 0.5, THF)
ꢀ20.6 (c 0.6, THF)
ꢀ17.5 (c 0.6, THF)
ꢀ28.5 (c 0.6, THF)
ꢀ17.0 (c 0.5, THF)
ꢀ2.1 (c 0.5, THF)
+33.3 (c 0.6, THF)
+22.95 (c 0.6, THF)
+22.0 (c 0.5, THF)
ꢀ26.4 (c 0.5, THF)
a
Isolated yield.
a ,
chiral column, Supelco Beta-DEX 325TM
b
Determined by GC analysis on
30 m ꢁ 0.25 mm.
c
Assigned by comparison of the rotation sign with the literature data.
The reduction of acetophenone was very fast (<1 h) and gave
the product almost quantitatively in all cases. Catalysts 1, and 4–
7 gave the highest enantioselectivities (Table 2) and with low cat-
alyst loading, 10–1 mol %, the enantiomeric excess of the product
still remained above 90% (Table 2, entries 1, 2, 7, 8, 10, and 11).
In the case of 1, lowering its amount up to 0.5 mol % decreased
the ee value of the product to 80% (Table 2, entry 3).
a
b
c
Isolated yield.
Spectra were recorded in CDCl3.
Co-existing signals in the 11B NMR spectra and their percentage: 2 (22.37 ppm,
21%), 3 (22.07 ppm, 35%), 8 (22.14 ppm, 63%).
Initially, we examined the catalytic activity of spiroborate esters
1–10 in the asymmetric borane reduction of prochiral ketones. The
reduction of acetophenone as a model compound was carried out
with 1 mol equiv of borane–dimethyl sulfide adduct and 10, 5,
and 1 mol % of 1–10 in dry THF at room temperature. The THF
solution of acetophenone was added dropwise to the reaction flask
Reductions catalyzed with 1–7, obtained from terpene amino
alcohols, were more enantioselective than reductions in the pres-
ence of catalysts derived from (S)-prolinol (Table 2, entries 13–
15). Spiroborate ester 10, obtained from achiral 2-aminoethanol
and chiral terpenyl diol, led to a racemic product (Table 2, entry
16). Spiroborates 7–9, in which the configuration on the carbon
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M. Cwiklinska et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
atom bonded with amino group was (S) gave (R)-1-phenylethanol
(Table 2, entries 12–15), whereas those with an (R)-configuration
1–6 gave the (S)-product (Table 2, entries 1–11). The configuration
of the product alcohol is independent of the chirality of the diol-
moiety of the catalysts. The chiral diol moiety in spiroborate struc-
ture did not improve the ee value of the alcohol. On the contrary, in
all cases it led to decrease in the enantioselectivity. This fact is
more noticeable for the results obtained with lower amounts of
catalysts (Table 2, entries 4, 6, 13, and 15). A lower amount of cat-
alyst containing the chiral diol moiety resulted in a decreased
enantioselectivity, whereas this effect was negligible for analogues
containing the ethylene glycol moiety. Spiroborate catalysts 4 and
5, derived from 1,4-anhydroerythritol and cis-1,2-cyclopentane-
diol, of similar shapes and dimensions, resulted in identical ee val-
ues of the product (Table 2, entries 7 and 8). It seems that the most
significant factor for the enantioselectivity of the reduction is the
size of the diol moiety, not its chirality. Clearly, the amino alcohol
fragment induces the enantioselectivity of these spiroborate cata-
lysts. This explains the highest selectivity gained for the reduction
in the presence of 1, 6, and 7.
catalyst. The reactions were carried at room temperature, first in
THF. Thus, the THF solution of acetophenone was added dropwise
at a rate of 3.0 mL/h to the reaction flask containing the catalyst
and borane–dimethyl sulfide adduct in THF (Table 3, entry 1). Next,
reversing the reagent addition, borane–dimethyl sulfide adduct in
THF was added to the acetophenone solution by syringe pump at
the same rate as above (Table 3, entry 2). The simultaneous drop-
wise addition of acetophenone and borane solutions in THF to the
catalyst was also examined (Table 3, entry 3). The concentration
and the volume of borane and ketone solution was the same, but
the rate of borane addition was slightly faster (3.2 mL/h) than ace-
tophenone (3.0 mL/h). Optimal selectivity was achieved when bor-
ane and ketone were added simultaneously to the catalyst solution
(90% ee). Changing the manner and the sequence of reagents addi-
tion decreased the enantioselectivity from 90% to 72% ee. Clearly,
the way of conducting the reduction affects its enantioselectivity.
The nature of the solvent is also a critical factor affecting the
enantioselectivity of the reductions with borane.2,28–30
Consequently, THF, chloroform, and toluene were compared as
the solvents for our reduction reaction, and the results are summa-
rized in Table 3 (entries 3–5). THF proved to be the most effective
solvent in terms of chemical yield and enantioselectivity (Table 3,
entry 3). Chloroform or toluene led to a dramatic in the ee and the
reduction yield. Apparently, the complexing properties and higher
Next, the reaction conditions, solvent, and the borane source
were examined to improve enantioselectivity of reductions
conducted with the catalyst load of 0.5 mol %. For this purpose,
acetophenone was used as the model compound and 1 as the
Table 3
Influence of the borane source, solvent, and reaction conditions on the reduction of acetophenone catalyzed by 1
1. 1 (0.5 mol %)
O
OH
BH3.L, rt, 1h
2. MeOH
(S)
Ph
Ph
Entry
Rate of PhCOMe addition (mL/h)
BH3ꢂL
Rate of BH3–L addition (mL/h)
Solvent
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
3.0
BH3ꢂSMe2
BH3ꢂSMe2
BH3ꢂSMe2
BH3ꢂSMe2
BH3ꢂSMe2
BH3–THF
In flask with 1
THF
THF
THF
CH3Cl
Toluene
THF
THF
THF
96
87
94
61
56
88
92
47
80
72
90
9
In flask with 1
3.2
3.2
3.2
3.2
3.2
3.2
3.5
3.0
3.0
3.0
3.0
3.0
3.0
7
77
52
0
BACH-EITM
Catecholborane
a
Isolated yield.
Determined by GC analysis on a chiral column, Supelco Beta-DEX 325TM, 30 m ꢁ 0.25 mm.
b
Table 4
Asymmetric borane reduction of prochiral ketones catalyzed by 1
1.
/ BH3.SMe2
THF, rt, 1h
1
OH
*
O
R1
R2
R1
R2
2. MeOH
Entry
R1
R2
1 (mol %)
Yielda (%)
ee (%)
Conf.b
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
Me
CF3
Me
Me
1
1
2
2
2
5
2
2
2
5
2
91
90
94
93
92
97
97
96
81
67
95
96c
94c
95c
88c
96c
6c
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
4-MeC6H4
3-MeOC6H4
3,4-(MeO)2C6H3
3-CF3C6H4
Ph
1-Naphtyl
2-Benzofuryl
Ph
91d
92d
37d
13d
50d
e
9
10
11
2-Benzofuryl
2-Benzofuryl
Me
—
—
e
4-MeOC6H4
n-Hexyl
(S)
a
b
c
Isolated yield.
Assigned by comparison of the sign of the specific rotation with the literature data.
Determined by GC analysis on a chiral column, Supelco Beta-DEX 325TM, 30 m ꢁ 0.25 mm.
Determined by HPLC analysis on a chiral column, Daicel Chiralcel OD-H, 250 ꢁ 4.6 mm, 5
Absolute configuration not determined.
d
e
l
m.
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4
Table 5
Asymmetric borane reduction of halogenated ketones catalyzed by 1
/ BH3.SMe2
THF, rt, 1h
1
1.
O
OH
R
(CH2)nX
R
(CH2)nX
2. MeOH
Entry
1
Halogenated Ketone
1 (mol %)
Yielda (%)
ee (%)
97c
Conf.b
O
Br
1
1
91
(R)
O
Cl
2
3
94
92
93c
90d
(R)
(R)
O
Cl
1
Cl
O
4
5
1
5
96
82
80d
96d
(S)
(R)
Cl
O
O
O
O
Br
Br
6
5
87
92d
(R)
a
b
c
Isolated yield.
Assigned by comparison of the sign of the specific rotation with the literature data.
Determined by GC analysis on a chiral column, Supelco Beta-DEX 325TM, 30 m ꢁ 0.25 mm.
Determined by HPLC analysis on a chiral column, Daicel Chiralcel OD-H, 250 ꢁ 4.6 mm, 5
d
l
m.
polarity of THF play a key role. The coordination of its oxygen atom
to boron atom exerts a significant effect on the catalytic cycle of
borane reduction of ketones.
3. Conclusion
Terpene spiroborate esters 1–10 have been synthesized in a
simple way and in good yields. All are stable solids and except
for 8–10 catalyze asymmetric reductions of various prochiral
ketones and their halogenated derivatives with borane with high
enantioselectivities. The spiroborate ester 1 can be successfully
used as a highly efficient chiral transfer reagent employing only
0.5 mol % of the catalyst. The amino alcohol moiety of spiroborane
molecule is the predominant factor affecting the enantioselectivity
of the reduction. The selectivity of the borane reduction of prochi-
ral ketones catalyzed by spiroborate esters depends on the order
and the rate of the reagents addition, solvent, and borane source.
The reduction procedure is simple and convenient for scaling up,
and suitable for synthetic applications.
Finally, a borane–dimethyl sulfide adduct, a borane solution in
THF, a borane N-ethyl-N-isopropylaniline complex (BACH-EITM),
and catecholborane were examined as borane sources. Results are
summarized in Table 3 and differ significantly. The reduction of
acetophenone with the borane–dimethyl sulfide adduct produced
(S)-1-phenylethanol with the highest enantioselectivity (90% ee)
and yield among the above reagents (Table 3, entry 3). Catecholbo-
rane produced the racemate in low yield (Table 3, entry 8).
With the standardized conditions for the borane reduction
catalyzed by 1 in hand, the enantioselectivity of the reduction of
various prochiral ketones was explored. The corresponding
optically active alcohols were obtained almost quantitatively and
with high enantiomeric excesses for aryl–alkyl alcohols, except
for (R)-2,2,2-trifluoro-1-phenylethanol (Table 4, entry 6). The
reduction of benzofuryl phenyl ketones provided the product
alcohols with lower enantioselectivities, whereas 2-octanol was
obtained in excellent yield and with 50% ee (Table 4, entries 9–11).
Halogenated acetophenones and benzofuryl halomethyl
ketones were also reduced with borane–dimethyl sulfide adduct
in the presence of 1–5 mol % of 1 producing the corresponding
alcohols with high enantioselectivity (90–97%), except for (S)-3-
chloro-1-phenylpropan-1-ol (80% ee, Table 5, entry 4). The chiral
halohydrins obtained in this way, can serve as useful synthetic
intermediates for further asymmetric transformations. For
example, (R)-2-bromo-1-(7-ethylbenzofuran-2-yl)ethanol (Table 5,
entry 6) was applied in the synthesis of bufuralol, a potent
non-selective b-adrenergic receptor antagonist.31,32
4. Experimental
4.1. General
Experiments with air and moisture sensitive materials were
carried under a nitrogen atmosphere. Glassware was oven dried
for several hours, assembled hot, and cooled in a stream of nitrogen.
1H, 13C, and 11B NMR spectra were recorded on a Varian Gemini 200,
Bruker AMX 300 MHz, Avance III 400 MHz, and Avance 700 MHz
instruments. Optical rotations were measured on an automatic
polarimeter, PolAAr 3000, Optical Activity Ltd. GC analyses were
performed on a Perkin–Elmer AutoSystem XL chromatograph, and
HPLC analyses on a Shimadzu LC-10AT chromatograph. Melting
points were determined in open glass capillaries and are
´
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M. Cwiklinska et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
uncorrected. Elemental analyses were performed on Vario MACRO
CHN, ELEMENTAR Analysensysteme GmbH instrument.
41.10, 45.00, 45.06, 52.41, 76.02, 76.71, 82.40; 11B NMR (CDCl3):
d = 12.90 (79%), 22.37 (21%); Anal. calcd for C19H32BNO3: C,
68.47, H, 9.68, N, 4.20; found: C, 68.55, H, 9.42, N, 4.08.
4.2. Materials
4.3.3. (1R,2S,3R,5R)-2-(10,30,20-Dioxaborolan-(40-3,50-4-(1S,3S,4R,
6R)-caran)-20-yloxy)-apopinan-3-amine 3
Silica Gel 60, Merck 230–400 mesh, was used for preparative col-
umn flash chromatography. Analytical TLC was performed using
Merck TLCSilicagel 60F254 0.2 mmaluminum plates. THF was freshly
distilled from sodium benzophenone ketyl. Chloroform, methanol,
and toluene were dried over 4 Å molecular sieves. (S)-Prolinol, 2-ami-
noethanol, ethylene glycol, 1,4-anhydroerythritol, cis-1,2-cyclopen-
tanediol, triisopropyl borate, borane–dimethyl sulfide adduct,
borane tetrahydrofuran complex, BACH-EITM, catecholborane, ace-
tophenone, and substituted acetophenones, 1-(naphthalen-1-yl)
ethanone, octan-2-one, 2-bromo-1-phenylethanone, 2-chloro-1-
phenylethanone, 2-chloro-1-(4-chlorophenyl)ethanone, and 3-
chloro-1-phenylpropan-1-one were commercial products (Aldrich).
(1R,2S,3R,5R)-3-Amino-apopinan-2-ol,21,22 (1S,3S,4R,6R)-4-amino-
caran-3-ol,23,24 (1S,2S,3S,4S,5R)-4-amino-2-methoxy-pinan-3-ol,25
White solid; mp 149–152 °C; [
a
]
D
20 = ꢀ17.5 (c 0.6, THF); 1H NMR
(CDCl3): d = 0.54–0.77 (m, 3H), 0.79–0.88 (m, 1H), 0.97 (s, 3H), 1.03
(d, J = 10.4 Hz, 1H), 1.07 (s, 3H), 1.08 (s, 3H), 1.22 (s, 3H), 1.25 (s,
3H), 1.71 (dd, J = 13.9, 6.4 Hz, 1H), 1.87–2.03 (m, 2H), 2.10 (ddd,
J = 15.3, 7.2, 1.7 Hz, 1H), 2.19–2.28 (m, 1H), 2.38–2.44 (m, 1H),
2.47–2.59 (m, 1H), 3.26 (br s, 2H), 3.69 (q, J = 8.1 Hz, 1H), 4.00 (s,
1H), 4.53 (dd, J = 8.3, 4.5 Hz, 1H); 13C NMR (CDCl3): d = 14.60,
16.44, 18.21, 18.98, 22.58, 25.28, 25.99, 27.42, 28.64, 29.75,
31.00, 34.89, 38.04, 41.05, 45.03, 45.09, 76.16, 77.46, 79.38; 11B
NMR (CDCl3): d = 12.86 (65%), 22.07 (35%); Anal. calcd for C19H32
-
BNO3: C, 68.47, H, 9.68, N, 4.20; found: C, 68.73, H, 9.04, N, 4.33.
4.3.4. (1R,2S,3R,5R)-2-(10,30,20-Dioxaborolan-(40-3,50-4-tetrahyd-
(1S,2S,3R,5S)-pinane-2,3-diol,26
(1S,3S,4R,6R)-carane-3,4-diol,27
(1R,2R,3S,5R)-pinane-2,3-diol,26
rofuran)-20-yloxy)-apopinan-3-amine 4
1-(benzofuran-2-yl)ethanone,33
White solid; mp 223–228 °C; [
a
]
D
20 = ꢀ28.5 (c 0.6, THF); 1H NMR
benzofuran-2-yl(phenyl)methanone,34 benzofuran-2-yl(4-methoxy-
phenyl)methanone,35 1-(benzofuran-2-yl)-2-bromoethanone,36 and
2-bromo-1-(7-ethylbenzofuran-2-yl)ethanone31 were prepared
according to the literature.
(CDCl3): d = 1.01 (d, J = 10.6 Hz, 1H), 1.06 (s, 3H), 1.24 (s, 3H), 1.73
(ddt, J = 13.8, 5.8, 1.4 Hz, 1H), 1.99 (q, J = 5.0 Hz, 1H), 2.26–2.32 (m,
1H), 2.36–2.40 (m, 1H), 2.61 (ddd, J = 14.1, 9.6, 4.8 Hz, 1H), 3.36 (td,
J = 10.8, 2.9 Hz, 2H), 3.76 (s, 1H), 3.98 (dd, J = 15.1, 10.6 Hz, 4H),
4.53 (dd, J = 8.1, 4.4 Hz, 1H), 4.67–4.73 (m, 2H); 13C NMR (CDCl3):
d = 22.16, 26.34, 27.35, 34.68, 37.75, 40.96, 44.66, 45.13, 76.30,
76.46, 76.68, 78.45, 78.54; 11B NMR (CDCl3): d = 10.80; Anal. calcd
for C13H22BNO4: C, 58.45, H, 8.30, N, 5.24; found: C, 58.37, H, 8.42,
N, 5.15.
4.3. General procedure for the synthesis of terpene spiroborate
esters 1–10
To a solution of the corresponding diol (5 mmol) in dry toluene
(10 mL), under a nitrogen atmosphere, was added triisopropyl
borate (1.17 mL, 5.1 mmol) via syringe and the mixture stirred
under mild reflux conditions for approximately 20 min. When
the mixture became homogeneous, a solution of amino alcohol in
dry toluene (10 mL) was added. The mixture was refluxed for
20 min and during this time a portion of toluene along with evolv-
ing isopropanol was removed by distillation (about 10 mL). Next,
toluene (10 mL) was added to the distillation flask and the contents
evaporated again to make sure all the isopropanol had been
removed. After stirring for 20 min, the mixture was cooled to room
temperature and a white precipitate of the spiroborate ester
appeared. The product was filtered and recrystallized from toluene
as a white crystalline powder.
4.3.5. (1R,2S,3R,5R)-2-(10,30,20-Dioxaborolan-(40-1,50-2-cyclopen-
tan)-20-yloxy)-apopinan-3-amine 5
White solid; mp 197–200 °C; [
a]
20 = ꢀ17.0 (c 0.5, THF); 1H NMR
D
(CDCl3): d = 0.98 (d, J = 10.6 Hz, 1H), 1.06 (s, 3H), 1.20 (s, 3H), 1.44–
1.57 (m, 3H), 1.67–1.83 (m, 4H), 1.94 (q, J = 5.2 Hz, 1H), 2.22–2.26
(m, 1H), 2.34–2.38 (m, 1H), 2.54 (ddd, J = 14.1, 10.5, 4.7 Hz, 1H),
3.69 (q, J = 7.9 Hz, 1H), 4.44 (dd, J = 8.3, 4.5 Hz, 1H), 4.48 (br s, 2H),
4.51 (dd, J = 3.5, 1.6 Hz, 2H); 13C NMR (CDCl3): d 22.16, 22.64,
26.20, 27.34, 34.29, 35.12, 35.20, 37.84, 40.96, 44.76, 45.29, 76.78,
79.24, 79.31; 11B NMR (CDCl3): d = 11.04; Anal. calcd for C14H24
-
BNO3: C, 63.42, H, 9.12, N, 5.28; found: C, 63.27, H, 9.41, N, 5.41.
4.3.6. (1S,3S,4R,6R)-3-(10,30,20-Dioxaborolan-20-yloxy)-caran-4-
4.3.1. (1R,2S,3R,5R)-2-(10,30,20-Dioxaborolan-20-yloxy)-apopinan-
3-amine 1
amine 6
White solid; mp 164–166 °C; [a]
20 = +33.3 (c 0.6, THF); 1H NMR
D
White solid; mp 110–113 °C; [
a
]
20 = ꢀ23.8 (c 0.5, THF); 1H NMR
(CDCl3): d = 1.24 (s, 3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.37 (d, J = 8.0,
1H), 2.05 (t, J = 5.4 Hz, 1H), 2.14–2.34 (m, 3H), 3.17 (s, 3H), 3.87
(s, 4H), 4.25 (d, J = 8.8 Hz, 1H), 4.43 (br s, 2H); 13C NMR (CDCl3):
d = 19.18, 22.98, 25.94, 28.87, 37.32, 44.16, 48.85, 51.47, 56.37,
64.27 (2 ꢁ C), 73.98, 80.90; 11B NMR (CDCl3): d = 10.40; Anal. calcd
for C13H24BNO4: C, 58.01, H, 8.99, N, 5.20; found: C, 58.14, H, 9.07,
N, 5.27.
D
(CDCl3): d = 0.95 (d, J = 10.6 Hz, 1H), 1.04 (s, 3H), 1.18 (s, 3H), 1.72
(dd, J = 13.3, 5.8 Hz, 1H), 1.93 (q, J = 5.2 Hz, 1H), 2.21–2.24 (m, 1H),
2.31–2.33 (m, 1H), 2.51–2.54 (m, 1H), 3.64–3.71 (m, 1H), 3.83 (s,
4H), 4.40–4.47 (m, 1H), 4.92 (br s, 2H); 13C NMR (CDCl3): d = 22.20,
26.32, 27.48, 34.16, 38.04, 40.98, 44.84, 45.82, 64.22 (2 ꢁ C),
77.16; 11B NMR (CDCl3): d = 10.24; Anal. calcd for C11H20BNO3: C,
58.69; H, 8.96; N, 6.22; found: C, 58.24; H, 8.67; N, 6.59.
4.3.7. (1S,2S,3S,4S,5R)-3-(10,30,20-Dioxaborolan-20-yloxy)-2-methoxy-
4.3.2. (1R,2S,3R,5R)-2-(10,30,20-Dioxaborolan-(40-2,50-3-(1R,2R,3S,
5R)-pinan)-20-yloxy)-apopinan-3-amine 2
pinan-4-amine 7
White solid; mp 123–124 °C; [
a
]
D
20 = ꢀ26.4 (c 0.5, THF); 1H NMR
White solid; mp 146–148 °C; [
a
]
20 = ꢀ20.6 (c 0.6, THF); 1H NMR
(CDCl3): d = 0.85 (s, 3H), 1.29 (d, J = 10.4 Hz, 1H), 1.31 (s, 3H), 1.42
(s, 3H), 1.86–1.98 (m, 2H), 2.06 (t, J = 5.2 Hz, 1H), 2.23–2.31 (m,
1H), 2.36 (ddt, J = 14.8, 8.4, 2.0 Hz, 1H), 3.66 (t, J = 7.6 Hz, 2H),
4.28–4.39 (m, 1H), 4.49 (t, J = 7.6 Hz, 2H), 6.89 (br s, 2H); 13C
NMR (CDCl3): d = 23.98, 26.34, 27.08, 28.53, 35.70, 38.40, 39.46,
51.55, 66.98, 73.74, 77.21, 84.78; 11B NMR (CDCl3): d = 11.04; Anal.
calcd for C12H22BNO3: C, 60.27, H, 9.27, N, 5.86; found: C, 60.25, H,
9.33, N, 5.76.
D
(CDCl3): d = 0.84 (s, 3H), 1.05 (d, J = 10.8 Hz, 1H), 1.07 (s, 3H), 1.22
(s, 3H), 1.26 (s, 3H), 1.33 (s, 3H), 1.46 (d, J = 10.4 Hz, 1H), 1.72 (dd,
J = 13.7, 6.5 Hz, 1H), 1.81–1.90 (m, 2H), 1.91–2.04 (m, 2H), 2.09–
2.28 (m, 2H), 2.28–2.45 (m, 2H), 2.45–2.57 (m, 1H), 3.38 (br s,
2H), 3.70 (q, J = 8.1 Hz, 1H), 4.12 (dd, J = 8.6, 1.7 Hz, 1H), 4.52 (dd,
J = 8.5, 4.5 Hz, 1H); 13C NMR (CDCl3): d = 22.48, 24.19, 26.09,
27.07, 27.36 (2 ꢁ C), 29.69, 34.76, 37.15, 37.99, 38.18, 40.03,
´
´
Please cite this article in press as: Cwiklinska, M.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.018

´
´
M. Cwiklinska et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
6
4.3.8. (S)-2-[(1,3,2-Dioxaborolan-(4-20,5-30-(10S,20S,30R,50S)-pinan)-
Subsequently, the solvents were evaporated under vacuum and the
product was isolated by column chromatography using hexane/
EtOAc (4:1) as the eluent.
2-yloxy)-methyl]pyrrolidine 8
White solid; mp 105–107 °C; [a]
20 = +22.95 (c 0.6, THF); 1H
D
NMR (CDCl3): d = 0.85 (s, 3H), 1.28 (s, 3H), 1.30 (s, 3H), 1.51 (d,
J = 10.2 Hz, 1H), 1.65–1.76 (m, 1H), 1.78–2.09 (m, 6H), 2.19–2.40
(m, 2H), 2.84–3.00 (m, 1H), 3.21–3.38 (m, 1H), 3.46–3.60 (m,
1H), 3.76–4.01 (m, 2H), 4.11 (br s, 1H), 4.24–4.37 (m, 1H); 13C
NMR (CDCl3): d = 23.97, 25.16, 26.34, 26.59, 27.09, 28.93, 35.71,
38.35, 39.47, 45.74, 51.59, 60.59, 65.59, 76.09, 84.57; 11B NMR
(CDCl3): d = 10.74 (37%), 22.14 (63%); Anal. calcd for C15H26BNO3:
C, 64.53, H, 9.39, N, 5.02; found: C, 64.72; H, 9.61; N, 5.09.
Acknowledgements
Financial support from the Ministry of Science and Higher
Education, Poland, grant
Financial support from the European Social Fund and National
Budget, grant ‘Krok w przyszłos´c´—stypendia dla doktorantów
V edycja’, is also acknowledged.
N N205 268338, is acknowledged.
4.3.9. (S)-2-[(1,3,2-Dioxaborolan-(4-20,5-30-(10R,20R,30S,50R)-pinan)-
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2-yloxy)-methyl]pyrrolidine 9
White solid; mp 144–146 °C; [
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20 = + 22.0 (c 0.5, THF); 1H NMR
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4.3.10. 2-(1,3,2-Dioxaborolan-(4-20,5-30-(10R,20R,30S,50R)-pinan)-
´
2-yloxy)-ethanamine 10
White solid; mp 79–83 °C; [
a
]
D
20 = ꢀ2.2 (c 0.5, THF); 1H NMR
(CDCl3): d = 0.59 (q, J = 8.4 Hz, 1H), 0.73 (dd, J = 15.3, 8.5 Hz, 1H),
0.89–0.99 (m, 1H), 0.94 (s, 3H), 1.00–1.09 (m, 1H), 1.05 (s, 3H),
1.21 (s, 3H), 1.99–2.08 (m, 2H), 3.18 (s, 1H), 3.83 (s, 4H), 4.96 (br
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28.04, 30.09, 31.67, 56.80, 63.96 (2 ꢁ C), 74.05; 11B NMR (CDCl3):
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´
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Please cite this article in press as: Cwiklinska, M.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.018