Enantioselective borane reduction of ketones catalyzed by tricyclic 1,3,2-oxazaborolidines

Article abstract of DOI:10.1016/j.tetlet.2016.04.091

Two novel tricyclic 1,3,2-oxazaborolidines were synthesized in seven steps from methyl Boc-l-pyroglutamate. They are characterized by an ortho- and peri-fused 5/5/6-ring system with the B-N bond forming one ring junction. In the asymmetric borane reduction of ketones, the B-alkoxy bridged derivative permits excellent enantioselectivities of up to 98% ee and its activity is comparable to that of the standard CBS catalyst. The closely related, B-alkyl bridged derivative is less enantioselective and less active, as determined by competition experiments.

Full text of DOI:10.1016/j.tetlet.2016.04.091

Tetrahedron Letters 57 (2016) 2492–2495
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective borane reduction of ketones catalyzed by tricyclic
1,3,2-oxazaborolidines
⇑
Johannes Kaldun, Alexander Krimalowski, Matthias Breuning
Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel tricyclic 1,3,2-oxazaborolidines were synthesized in seven steps from methyl Boc-L-pyroglu-
Received 7 March 2016
Revised 22 April 2016
Accepted 25 April 2016
Available online 26 April 2016
tamate. They are characterized by an ortho- and peri-fused 5/5/6-ring system with the B–N bond forming
one ring junction. In the asymmetric borane reduction of ketones, the B-alkoxy bridged derivative per-
mits excellent enantioselectivities of up to 98% ee and its activity is comparable to that of the standard
CBS catalyst. The closely related, B-alkyl bridged derivative is less enantioselective and less active, as
determined by competition experiments.
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
CBS reduction
Oxazaborolidine
Enantioselective catalysis
Pyrrolidine
Amino diol
The catalytic enantioselective reduction of prochiral ketones is
one of the most valuable transformations in asymmetric synthe-
sis. A milestone in this field was reached in 1987 when Corey
O
OH
BH
3
•THF
or
cat.*
r.t.
+
1
R
R'
3
BH •SMe
R
*
2
R'
2
1
and coworkers introduced the prolinol-derived 1,3,2-oxazaboro-
(
up to 99% ee)
2
,3
lidine 3,
which efficiently catalyzes the borane reduction of
Ph
H
R
ketones 1, providing the secondary alcohols 2 in high yields, pre-
H
Ph
H
dictable configuration, and with excellent levels of stereocontrol
Ph
Ph
O
N
O
4
Ph
N
B
(
Scheme 1). The tremendous impact of this reaction, called CBS
N
(
O
B
N
O
B
O
reduction, is obvious from the plethora of successful applications
B
O
5
,6
Me
reported.
Me
R
In the last three decades, factors that affect the efficiency and
chirality transfer of CBS reductions were intensively studied. In-
depth investigations were done on the borane source, rate of
ketone addition, reaction temperature, solvent, additives, and, with
respect to the catalyst, on the loading, dimerization tendency, sta-
bility, structure of the chiral backbone, and nature of the exocyclic
substituent at the boron atom.4,7 A large number of highly stereod-
ifferentiating oxazaborolidines with monocyclic, bicyclic, fused
and bridged tricyclic cores had been prepared, but among all these
there are, as yet, just a few derivatives in which the NBO-unit is
part of an ortho- and peri-fused tricyclic ring system or in which
S)-3
4
5 (R = Me, Ph)
6
H
Ph
O
2
CO Me
Ph
NBoc
N
H
B
X
R
8 (X = O)
9 (X = CH )
2
7
Scheme 1. The CBS reduction, the known catalysts 3–6 and the targeted tricyclic
oxazaborolidines 8 and 9 derived from the proline derivative 7.
3
two atoms of the X B unit form one ring junction of a bi- or oligo-
and other ketones.8,9 Just a few bicyclic derivatives with the N–B
cyclic system. The only example of the former type is Corey’s
constraint catalyst 4 (5/5/5-ring system), which provides superb
enantioselectivities in the reduction of acetophenone (98% ee)
bond as the fusion bond are currently known, such as the B-alkoxy
1
0
11
oxazaborolidines 5 and 6 developed by Kagan and Lee, respec-
tively. The asymmetric inductions reached with 5 and 6 were
moderate (<69% ee).
⇑
Corresponding author. Tel.: +49 921 55 3396.
E-mail address: matthias.breuning@uni-bayreuth.de (M. Breuning).
In the course of our work on chiral ligands derived from 5-cis-
substituted prolines of type 7, we wondered whether it will be
1
2
http://dx.doi.org/10.1016/j.tetlet.2016.04.091
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

J. Kaldun et al. / Tetrahedron Letters 57 (2016) 2492–2495
2493
possible to synthesize the novel tricyclic oxazaborolidines 8 and 9,
which are based on the highly stereodiscriminating standard CBS
1
. LiBHEt
3
2. TsOH, MeOH
PhMgBr
skeleton 3 (upper part of 8 and 9), but possess an additional oxy-
O
CO Me
2
CO Me
N
2
N
THF, 0°C to r.t.
3
. allyl-TMS,
BF •OEt
ethano or propano bridge between the boron atom and the
bon of the pyrrolidine moiety. The rigid ortho- and peri-fused
/5/6-ring system and the incorporation of the N–B bond into
a
-car-
Boc
Boc
3
2
8
9%
6
5% (acc. to ref. 16)
10
18 (dr = 2.9:1)
5
one ring junction should create a stereochemically well-defined
environment, thus giving rise to high asymmetric inductions upon
application of 8 and 9 as catalysts in borane reductions. Further-
more, we anticipated that the concave, bowl-like shape of 8 and
Ph
TFA
Ph
+
Ph
Ph
Ph
N
CH
2
r.t.
Cl
2
,
N
N
Ph
O
Boc
OH
O
O
O
9
will reduce the double bond character in the N–B bond and, in
1
9 (dr = 2.9:1)
cis-20 (62%)
trans-20 (22%)
consequence, enhance the Lewis-acidity of the boron atom and
the Lewis-basicity of the nitrogen atom, which might increase
1
3
the catalytic activity. Herein we present the synthesis of the
Ph
Ph
KOH, MeOH
new tricyclic B-alkoxy oxazaborolidine 8 and its B-alkyl analogue
Δ
N
H
9, their efficiency in the CBS-type reduction of ketones, and
OH
97%
investigations on their activities in comparison to the standard
CBS catalyst 3.
21
The synthesis of the amino diol 17, precursor to the oxazaboro-
Scheme 3. Synthesis of the amino alcohol 21 from the pyroglutamate 10.
lidine 8, started from commercially available methyl Boc-
L-pyrog-
lutamate (10), which was converted into the cis-5-vinylprolinate
1
4
hydroboration–oxidation of 12 provided the diol 16 as the domi-
nating product, which was directly subjected to N-deprotection,
giving the amino diol 17 in acceptable 51% yield after purification.
The unsaturated amino alcohol 21, precursor to 9, was synthe-
sized from 10 using a related sequence (Scheme 3). Introduction of
the 5-cis allyl substituent according to a known three-step proto-
col afforded the alkene 18 as a 2.9:1 mixture of cis/trans-diastere-
omers (65% yield), which could not be separated on this stage.
Addition of PhMgBr delivered the alcohol 19 in 89% yield
1
1 in four steps following a literature sequence (Scheme 2). Addi-
tion of PhMgBr to 11 occurred chemoselectively at the ester group
and afforded the -diphenyl prolinol 12 in good 90% yield. Stan-
a,a
dard N-Boc deprotection with TFA did not provide the desired
amino alcohol 14, but delivered the cyclic carbamate 13 in 56%
yield. Thus, the intramolecular trapping of the protonated Boc
group by the neighboring alcohol is considerably faster than its
1
6
cleavage, which probably is a consequence of the steric pressure
of the two geminal phenyl groups (Thorpe–Ingold effect15). Under
(
2
dr = 2.9:1), which was treated with TFA to give the carbamates
0. The rigid bicyclic system of 20 permitted a separation of the
basic conditions in refluxing methanolic KOH, however, the N-Boc
protective group could be cleanly removed to give the amine 14 in
high 94% yield. Introduction of the terminal alcohol function was
attempted by hydroboration–oxidation. Unfortunately, an insepa-
rable 55:45 mixture of the unwanted secondary alcohols 15 and
the required amino diol 17 resulted. We therefore changed the
order of the last two steps, anticipating that the bulky N-Boc group
in 12 will strongly enhance the regioselectivity. And indeed,
cis/trans-diastereomers by chromatography, giving desired cis-20
in 62% isolated yield. Final cleavage of the carbamate in methanolic
KOH under reflux afforded the unsaturated amino alcohol 21 in
9
7% yield.
The tricyclic, B-alkoxy oxazaborolidine 8 was accessible by
simple heating of 17 with a slightly overstoichiometric amount
of BH in toluene for 1 h at 50 °C (Scheme 4). The formation
3
ꢀSMe
2
+Å
11
of 8 was confirmed by GC-MS (EI, m/z = 305, [M] ) and B NMR
spectroscopy. The chemical shift of d = +5.1 ppm is in the typical
1
. TMSC≡ CMgCl
1
0
2
. NaBH(OAc)
3
range for B-alkoxy oxazaborolidines, but in the region of higher
PhMgBr
field, due to the tetrahedral arrangement at the boron center.17
O
CO
2
Me
6
CO
2
Me
N
N
THF, 0°C to r.t.
90%
3
4
. TBAF
. H , Lindlar
2
Boc
Boc
Treatment of 21 with BH
afforded an inseparable mixture of boron-containing species. With
an excess of BH in toluene at 90 °C, compound 22 was
ꢀSMe
formed as the main species, in which, according to H, B NMR
3 2
ꢀSMe under the conditions above
1
0
11
1% (acc. to ref. 14)
3
2
1
11
+Å
BH
3
•SMe
2
,
and MS (EI, m/z = 319, [M] ), hydroboration of the double bond
and borylation of the alcohol function had taken place. Heating
of 22 under high vacuum to >200 °C enforced the desired ring
closure of 22 to 9. The structure of 9 was confirmed by MS (EI,
Ph
Ph
the n H
2
O
2
, KOH
Me
Ph
Ph
+
17
N
H
N
H
15
56%
OH
OH
OH
14
55 : 45
+Å
11
18
m/z = 303, [M] ) and B NMR spectroscopy (d = 20.4 ppm).
KOH,
MeOH, Δ
9
4%
Ph
TFA
Cl , r.t.
6%
H
Ph
O
BH
3 2
•SMe
Ph
Ph
13
Ph
Ph
Ph
Ph
(1.1 equiv.)
N
CH
2
2
N
Boc
N
H
N
OH
5
O
toluene, 50 °C, 1 h
OH
H
B
12
O
OH
O
BH
3
•SMe
2
,
17
8
then H
2
2
O , KOH
H
Ph
3 2
BH •SMe
Ph
Ph
Ph
Ph
Ph
Ph
Ph
>200 °C
1 h
(5.0 equiv.)
Ph
KOH, MeOH
Δ
Ph
N
H
N
H
N
O
N
N
H
toluene,
90 °C, 16 h
OH
OBH
H
B
Boc
2
OH
OH
OH
1
51% from 12
OH
6
17
21
BH
2
22
9
Scheme 2. Synthesis of the amino diol 17 from the pyroglutamate 10.
Scheme 4. Preparation of the tricyclic oxazaborolidines 8 and 9.

2
494
J. Kaldun et al. / Tetrahedron Letters 57 (2016) 2492–2495
Table 1
exceeded 0.33 in the reaction mixture under these conditions. By
keeping this ratio, the amount of 8 can be reduced to 2.5 mol %
Optimization of the reaction conditions for oxazaborolidine 8a
(
addition time of 1a: 120 min), giving (R)-2a in high 98% yield
and excellent 98% ee (entry 6). Increasing the catalyst loading to
0 mol % (addition time of 1a: 30 min) or dilution of the reaction
from 0.25 M to 0.13 M exerted no effect on the enantioselectivity
entries 7 and 8). Finally, variation of the temperature revealed,
again in good agreement with other CBS reductions, that higher
or lower temperatures cause a loss in enantioselectivity and/or
yield (entries 9 and 10).
A short study on the scope of our new catalyst 8 is given in
Table 2, entries 1–7. Under optimized conditions (see Table 1, entry
4), the aryl alkyl ketones 1a–d were smoothly reduced in the pres-
ence of 8 delivering the secondary alcohols (R)-2a–d in high 92–
99% yield and high to excellent 93–98% ee (entries 1–4). 4-Acetyl-
pyridine (1e), which is one of the more problematic aryl methyl
ketones due to the strongly Lewis basic and deactivating nitrogen
atom in the heteroaromatic ring, was also reduced in high 94% ee
O
OH
*
8
(cat.)
+
3 2
BH •SMe
Ph
Me
tolue ne
Ph
Me
1
1a
(R)-2a
(
Entry 8 (mol
Temp
(°C)
Addition time of 1a
(min)
Yield
(%)
ee
(%)
7g
b
c
%
)
1
2
3
4
5
6
7
8
9
1
5
5
5
5
20
20
20
20
20
20
20
20
40
10
0
0
93
99
80
95
95
98
89
81
94
15
91
82
97
97
97
98
97
97
96
92
d
30
60
90
120
30
60
60
60
5
2.5
10
e
5
5
5
0
a
A solution of 1a (500 lmol) in toluene (1 mL) was continuously added over the
indicated time to a solution of catalyst 8, prepared in situ, and BH
in toluene (1 mL).
(
98% yield, entry 5). This result is clearly superior to that reached
3
ꢀSMe
2
(1.0 equiv)
with the well-known CBS catalyst (52% ee under similar condi-
b
20,21
Isolated yield.
Determined by HPLC on chiral phase.
Reaction in THF as the solvent.
Reaction at half concentration (2 + 2 mL toluene).
tions).
As examples for dialkyl ketones, pinacolone (1f) and
c
benzylacetone (1g) were chosen (entries 6 and 7). While the for-
mer one afforded (R)-2f in 97% yield and superb 98% ee, the reduc-
tion of 1g delivered (R)-2g with just 65% ee. The mediocre
enantioselection, presumably caused by the lower steric differenti-
ation between the two aliphatic substituents at the ketone, seems
d
e
The performance of 8 and 9 as chiral catalysts in the enantios-
elective ketone reduction with borane was studied next. The reac-
2
2
to be typical for Oxazaborolidine-type catalysis.
tion conditions were first optimized using catalyst
acetophenone (1a) as the model substrate (Table 1). The oxaz-
aborolidine 8 (5 mol %) was prepared prior to use (vide supra) as
8
and
The borane reduction of 1a in the presence of the tricyclic B-
alkyl catalyst 9 provided the alcohol (R)-2a with good 89% ee
(entry 8). Since 8 and 9 only differ in the atom next to the boron
atom (oxygen vs methylene), the lower stereocontrol of 9 must
be related to it. Either steric or electronic reasons (8: boric ester
vs 9: boronic ester) may account for this. In all reactions, the R-con-
figured alcohols were obtained as the major enantiomers.
a solution in toluene (1 mL) and the achiral reductand BH
3
ꢀSMe
2
(
1.0 equiv) was added. If the ketone 1a (1.0 M in toluene) was
introduced at 20 °C in one batch, the R-configured alcohol (R)-2a
was obtained in 93% yield and acceptable 91% ee (entry 1). Chang-
ing the solvent to THF lowered the asymmetric induction signifi-
cantly (82% ee, entry 2). Continuous addition of 1a over a period
of 30–90 min permitted enhanced levels of stereocontrol (97% ee,
entries 3–5). Thus, as for other CBS reductions, a too large excess
of the ketone in the reaction mixture has to be avoided, in order
to efficiently suppress the non-stereoselective background reac-
Finally, we decided to get some information about the activities
of 8 and 9 relative to the standard CBS catalyst (R)-3 (Scheme 5).
The reduction of acetophenone (1a) under our optimized condi-
tions (see Table 2), in which (R)-3 provided (S)-2a in 91% yield
2
3
and excellent 98% ee, was chosen as the model reaction. Since
catalysts 8 and 9 provided, compared to (R)-3, the enantio-comple-
mentary products with good to high stereocontrol, their relative
reaction rates can be judged from the sense of the asymmetric
induction and the level of the enantiomeric excess in the product,
by using a competition experiment with equimolar amounts of 8/
1
9
tion. Considering yield and reaction time, addition of 1a within
0 min provided the best result. The ratio ketone/catalyst never
6
2
4
Table 2
(R)-3 and 9/(R)-3, respectively. The high 85% ee (S) in the reaction
with 9/(R)-3 reveal that the standard CBS catalyst (R)-3 accelerates
the borane reduction of 1a by far more efficiently than the tricyclic
B-alkyl oxazaborolidine 9. This observation is in contrast to our ini-
tial assumption that the reduced N–B double bond character,
caused by the bowl-like shape of 9, might increase the Lewis acid-
ity/basicity of the boron and nitrogen atom and, thus, enhance the
activity of the catalyst. It might be possible that the coordination of
both reactants to the catalyst and the following internal hydride
transfer is indeed, as anticipated, faster for 9, but this acceleration
is overcompensated by other rate-reducing effects. For example, a
higher dimerization tendency of 9, which would reduce the
amount of active catalyst, or a slower release of the product due
to tighter binding might be a consequence of the increased Lewis
Reduction of prochiral ketones in the presence of 8 and 9a
8
or 9
O
OH
(
5 mol%)
+
BH
3
•SMe
2
R
R'
toluene, 20 °C
R
*
R'
1
(R)-2
0
Yield (%)b
ee (%)c
Entry
Cat.
Ketone
R
R
1d
2
3
8
8
8
8
8
8
8
9
1a
1b
1c
1d
1e
1f
Ph
Ph
4-O
a
4-Py
tBu
CH
Ph
Me
Et
Me
95
99
96
92
98
97
81
96
97
96
f
2
N-Ph
-Indanone
98
4
5
93
94
e
Me
Me
Me
Me
f
6
7
8
98
1g
1a
2
Bn
65
89
a
A solution of the ketone 1 (500
over a period of 60 min to a solution of catalyst 8 or 9 (5 mol %), prepared in situ,
and BH (1.0 equiv) in toluene (1 mL).
lmol) in toluene (1 mL) was continuously added
cat.
(R)-3: 91%, 98% ee (S)
9/(R)-3 (1:1): 99%, 85% ee (S)
8/(R)-3 (1:1): 95%, 22% ee (S)
3
ꢀSMe
2
O
OH
(
5 mol% in sum)
b
Isolated yield.
Determined by HPLC on chiral phase.
See Table 1, entry 4.
c
d
e
f
Ph
Me toluene, 20 °C
Ph
*
Me
1a
2a
2
.0 equiv of BH
3
ꢀSMe
2
were used.
Determined by GC on chiral phase.
Scheme 5. Single catalyst and competition experiments with (R)-3, 8 and 9.

J. Kaldun et al. / Tetrahedron Letters 57 (2016) 2492–2495
2495
3
.
(a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553;
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926; (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861–2863; (d) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209–1216.
Ph
Ph
X
O
23
B
R
R
S
L
N
(X = O, CH
2
)
O
H
B
4. Reviews: (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012;
b) Cho, B. T. Chem. Soc. Rev. 2009, 38, 443–452; (c) Deloux, L.; Srebnik, M.
H
2
(
Chem. Rev. 1993, 93, 763–784.
Figure 1. Proposed transition states 23.
5. (a) Cho, B. T. Tetrahedron 2006, 62, 7621–7643; (b) Wallbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1992, 3, 1475–1504.
6.
For some newer applications of CBS reductions, see: (a) VanHeyst, M. D.; Oblak,
E. Z.; Wright, D. L. J. Org. Chem. 2013, 78, 10555–10559; (b) Chang, C.-W.; Chein,
R.-J. J. Org. Chem. 2011, 76, 4154–4159; (c) Tamura, S.; Tonokawa, M.;
Murakami, N. Tetrahedron Lett. 2010, 51, 3134–3137.
acidic/basic character, too. In the competition experiment with 8/
(
R)-3, only a weak preference for the S-enantiomer (22% ee) was
7
.
For some newer mechanistic studies, see: (a) Saavedra, J.; Stafford, S. E.; Meyer,
M. P. Tetrahedron Lett. 2009, 50, 1324–1327; (b) Alagona, G.; Ghio, C.; Persico,
M.; Tomasi, S. J. Am. Chem. Soc. 2003, 125, 10027–10039; (c) Xu, J.; Wei, T.;
Zhang, Q. J. Org. Chem. 2004, 69, 6860–6866; (d) Nettles, S. M.; Matos, K.;
Burkhardt, E. R.; Rouda, D. R.; Corella, J. A. J. Org. Chem. 2002, 67, 2970–2976;
observed, indicating that the activities of the two catalysts are in
the same range, with (R)-3 being just slightly more reactive than
8
. The B-alkoxy derivative 8 possesses therefore a higher activity
than its B-alkyl counterpart 9, which goes along with the better
stereodifferentiation of 8. The order of activity is (R)-3 > 8 ꢁ 9.
The sense of asymmetric induction with 8 and 9 is the same as
with the CBS catalyst (S)-3. Since the stereochemical environment
around the active site of 8 and 9 is similar to that of (S)-3, the tran-
sition states 23 (Fig. 1) are proposed in analogy to literature mod-
els.
reductand BH
convex side, with the smaller substituent R
(
e) Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043–2047; (f)
Kawanami, Y.; Mikami, Y.; Kiguchi, K.; Harauchi, Y.; Yanagita, R. C. Tetrahedron:
Asymmetry 2011, 22, 1891–1894; (g) Salunkhe, A. M.; Burkhardt, E. R.
Tetrahedron Lett. 1997, 1997, 1523–1526. G. B. Tetrahedron: Asymmetry
1
994, 5, 465–472; (h) Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472;
i) Jiang, B.; Feng, Y.; Zheng, J. Tetrahedron Lett. 2000, 41, 10281–10283.
Corey, E. J.; Chen, C.-P.; Reichard, G. A. Tetrahedron Lett. 1989, 30, 5547–5550.
(
8.
3
,7a,7b
Coordination of the ketone to the boron atom and of the
to the nitrogen atom occurs from the unhindered
of the ketone being
9. For applications of N-protonated 3 and 4 (R = o-Tol) as the chiral catalyst in
Diels-Alder reactions, see: (a) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc.
3
2004, 126, 5984–5986; (b) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
S
1
26, 13708–13713; (c) Reddy, K. M.; Bhimireddy, E.; Thirupathi, B.; Breitler, S.;
directed toward the oxyethano and propano bridge, respectively.
This sets the stage for a Si-face selective hydride transfer in 23,
which leads to the experimentally observed R-configured alcohols.
In conclusion, the novel oxazaborolidines 8 and 9 were synthe-
Yu, S.; Corey, E. J. J. Am. Chem. Soc. 2016, 138, 2443–2453.
0. (a) Dubois, L.; Fiaud, J.-C.; Kagan, H. B. Tetrahedron: Asymmetry 1995, 6, 1097–
1
1
1104; (b) Dubois, L.; Fiaud, J.-C.; Kagan, H. B. Tetrahedron 1995, 51, 3803–3812.
1. (a) Lee, D.-S. Chirality 2007, 19, 148–151; For related B-alkoxy
oxazaborolidines, see: (b) Cimarelli, C.; Fratoni, D.; Palmieri, G. Chirality
2010, 22, 655–661.
sized in overall seven steps from methyl Boc-L-pyroglutamate (10).
1
2. (a) Scharnagel, D.; Prause, F.; Kaldun, J.; Haase, R. G.; Breuning, M. Chem.
Commun. 2014, 6623–6625; (b) Prause, F.; Kaldun, J.; Arensmeyer, B.;
Wennemann, B.; Fröhlich, B.; Scharnagel, D.; Breuning, M. Synthesis 2015, 47,
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They are characterized by a tricyclic, ortho- and peri-fused 5/5/6-
ring system with the N–B bond forming one of the ring junctions
and differ from the well-known CBS catalyst 3 by an additional
oxyethano or propano bridge between the boron atom and the a-
1
carbon of the pyrrolidine. In the borane reduction of ketones, the
B-alkoxy catalyst 8 provided excellent asymmetric inductions of
up to 98% ee, while the stereodifferentiation with the B-alkyl
derivative 9 reached 89% ee. The catalytic activity of 8 is compara-
ble to that of the standard CBS catalyst 3, but significantly higher
than that of 9.
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Acknowledgment
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1
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Financial support by the DFG (German research foundation) is
gratefully acknowledged.
1
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1
8. For 11B NMR chemical shifts of B-alkyl 1,3,2-oxazaborolidines (typical range
d = 30–35 ppm), see: (a) Ortiz-Marciales, M.; Gonzalez, E.; De Jesus, M.;
Espinosa, S.; Correa, W.; Martinez, J.; Figueroa, R. Org. Lett. 2003, 5, 3347–3349;
Supplementary data
(
b) Ref. 3b.
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21. It should be noted that the B-methoxy analogue of 3 and a spiroborate ester
reached 99% ee in the reduction of 1e, see: (a) Masui, M.; Shioiri, T. Synlett
1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
2
2
0
91.
1
997, 273–274; (b) Stepanenko, V.; De Jesús, M.; Correa, W.; Guzmán, I.;
Vásquez, C.; Ortiz, L.; Ortiz-Marciales, M. Tetrahedron: Asymmetry 2007, 18,
738–2745.
References and notes
2
1
.
.
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9
58.
23. The 98% ee found are in good agreement with the enantiomeric excess reached
under standard literature conditions (98% ee).3b
2
For preliminary work by Itsuno et al. on oxazaborolidine catalyzed borane
reductions of ketones, see: (a) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N.
J. Chem. Soc. Chem. Commun. 1981, 315–317; (b) Itsuno, S.; Hirao, A.;
Nakahama, S.; Yamazaki, N. J. Chem. Soc. Perkin Trans. 1 1983, 1673–1676; (c)
Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem. Commun. 1983,
24. In approximation, the competition experiment can be treated as two parallel
reactions in which one catalyst delivers the S-configured product and the other
one the R-enantiomer. From this follows [S]/[R] = kcat1/kcat2
.
4
69–470; (d) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.;
Nakahama, S. J. Chem. Soc. Perkin Trans. 1 1985, 2039–2044.