BINOLAM, a recoverable chiral ligand for bifunctional enantioselective catalysis: The asymmetric synthesis of cyanohydrins

Article abstract of DOI:10.1021/ol0262338

(Matrix presented) A new bifunctional catalytic system based on a monometallic aluminum complex is used for the efficient enantioselective cyanation of aldehydes. The ligand (S)- or (R)-2,2′-bis(diethylaminomethyl)-substituted binaphthol (BINOLAM) used is

Full text of DOI:10.1021/ol0262338

ORGANIC
LETTERS
2
002
Vol. 4, No. 15
589-2592
BINOLAM, a Recoverable Chiral Ligand
for Bifunctional Enantioselective
Catalysis: The Asymmetric Synthesis of
Cyanohydrins†
2
‡
,‡
‡
,§
Jes u´ s Casas, Carmen N a´ jera,* Jos e´ M. Sansano, and Jos e´ M. Sa a´ *
Departamento de Qu ´ı mica Org a´ nica, UniVersidad de Alicante, Apartado 99,
03080-Alicante, Spain, and Departament de Qu ´ı mica, UniVersitat de les Illes Balears,
07071-Palma de Mallorca, Spain
cnajera@ua.es
Received May 23, 2002
ABSTRACT
A new bifunctional catalytic system based on a monometallic aluminum complex is used for the efficient enantioselective cyanation of aldehydes.
The ligand (S)- or (R)-2,2′-bis(diethylaminomethyl)-substituted binaphthol (BINOLAM) used is recovered for recycling. This methodology is
used for the synthesis of a precursor of epothilone A.
1
A new generation of chiral bifunctional catalysts that try to
imitate nature’s enzymatic processes have been designed in
center to which the prochiral substrate should bind. Among
others, the most representative examples of this concept are
3
2
search for high efficiency in asymmetric synthesis. At the
the chiral oxazaborolidine-mediated (CBS) reduction of
4
very least, these catalysts must contain an acid center and a
basic functional group capable of simultaneously binding a
basic substrate and an acidic reactant in a proper manner,
so as to facilitate control over the three main issues of
asymmetric catalysis, namely, kinetics of the rate-determining
step, stereochemistry, and overall kinetics. In contrast with
nature, however, the acid in most man-made catalysts is a
Lewis acid metal properly designed so as to become a chiral
ketones and the addition of dialkylzinc reagents to carbonyl
5
compounds by means of chiral amino alcohols, developed
by the groups of Corey and Noyori, respectively. Very
recently, Shibasaki et al. reported a series of bifunctional
Lewis acid-Lewis base (LALB) catalysts 1 (Figure 1)
derived from BINOL as the chiral scaffold, where an
aluminum atom of a bisaryloxyaluminum chloride moiety
should act as the Lewis acid center (LA) and an appropriate
functionality at the 3,3′-positions should work as the Lewis
†
Dedicated to Prof. Marcial Moreno-Ma n˜ as on the occasion of his 60th
6
birthday.
base (LB) unit. In particular, the phosphane oxide-derived
‡
Universidad de Alicante.
Universitat de les Illes Balears.
§
(
1) For a recent review, see: Rowlands, G. J. Tetrahedron 2001, 57,
865-1882.
2) (a) Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.
(3) Gr o¨ ger. H. Chem. Eur. J. 2001, 7, 5246-5251.
(4) For a review, see: Corey, E. J.; Helal, C. J. Angew. Hem. Int. Ed.
1998, 37, 1987-2012.
(5) Relevant reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92,
833-856. (c) Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (d) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101,
757-824.
1
(
Houben-Weyl Methods of Organic Chemistry, StereoselectiVe Synthesis;
Thieme: Stuttgart/New York, 1995; Vol. E21. (b) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000.
c) ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
(
1
0.1021/ol0262338 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/02/2002

recoverable chiral ligand for the preparation of new bifunc-
tional monometallic catalysts 3 capable of achieving the
7,14
enantioselective cyanation of aldehydes, for the synthesis
1
5
of enantiomerically pure cyanohydrins. Expectations were
that the C -symmetric BINOL template would impart chiral-
2
ity unto the aluminum atom, which should act as a Lewis
acid center to ligate the aldehyde, while the amino grouping
could work as a Lewis base, activating the nucleophile
(Figure 1). In this model system, recycling of the precious
ligand would be facilitated by its eventual extraction with
an aqueous acid.
Initial studies were carried out by treating benzaldehyde
with trimethylsilyl cyanide in the presence of the selected
Lewis acid under different reaction conditions (Table 1). The
Table 1. Cyanation of Benzaldehyde Catalyzed by Preformed
Lewis Acid-(S)-3 Complexes
Figure 1.
4a (%)a
er (%)b
run
Lewis acid
solvent
t (h)
i
1
2
3
4
5
6
7
8
9
TiCl2(OPr )2
CH2Cl2
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
PhCH3
24
24
1
26
3
20
6
14
8
65
83
99
87
99
99
99
99
99
55/45
88/12
78/22
67/33
88/12
75/25
>99/1
77/23
90/10
i
TiCl2(OPr )2
catalysts 1 (R ) H; X ) POAr
2
) were found to be very
i
Ti(OPr )4
7
efficient for the asymmetric cyanosilylation of aldehydes
AlClMe2
8
AlClMe c
and imines (Strecker synthesis) as well as for the addition
2
AlClMe2d
of cyanide to quinoline or isoquinoline derivatives (Reissert-
9
AlClMe2
c
type reaction). An additional requirement for high efficiency,
1
0
AlClMe2c
AlClEt2c
at least for industrial batch processing, is catalyst recovery
11
and reusability. Catalyst recovery is meant here to describe
the recovery not of the usually unstable organometallic
species but of the chiral organic ligand. A polymer-supported
a
Isolated yields given refer to the cyanohydrin obtained after acidic
hydrolysis. b Enantiomeric ratios were determined by chiral HPLC analysis
(
Chiralcel OD-H). c Triphenylphosphane oxide (40 mol %) was added.
Reaction was performed with 40 mol % triphenylphosphane oxide, though
d
2
catalyst 1 [R ) linker-polymer; X ) P(O)Ph ] was developed
in the absence of 4 Å MS.
by Shibasaki et al. for the Strecker-type reaction though,
8
unfortunately, with some loss of enantioselectivity. There-
fore, the development of recoverable ligands in enantio-
selective catalysis is also an important additional goal for
achieving overall efficiency in asymmetric synthesis.
We disclose herein our preliminary results on the use of
a bifunctional catalyst for the enantioselective synthesis of
cyanohydrins by means of the addition of HCN to aldehydes.
We envisaged that 3,3′-bis(diethylaminomethyl)-1,1′-bi-2-
naphthol (BINOLAM) 2 (Figure 1),1 easily available in
both enantiomeric forms, could be a good candidate as a
catalysts were prepared by mixing the ligand (S)-2 and the
Lewis acid at room temperature for 1 h in the appropriate
(12) Diethylamino-substituted (S)- and (R)-BINOLAM 2 were the most
suitable phase-transfer catalysts for the enantioselective alkylation of the
aldimine Schiff bases of alanine esters: Casas, J.; N a´ jera, C.; Sansano, J.
M.; Gonz a´ lez, J.; Sa a´ , J. M.; Vega, M. Tetrahedron: Asymmetry 2001, 12,
6
99-702. For addition of diethylzinc to aldehydes, see: Kitajima, H.; Iti,
K.; Katsuki, T. Chem. Lett. 1996, 343-344.
13) BINOLAM 3 was easily prepared from methyl 3-hydroxy-2-
2,13
(
naphthalenecarboxylate employing a chemical resolution using L-leucine
methyl ester hydrochloride following a known procedure. (a) Feringa, B.;
Wynberg, H. Tetrahedron Lett. 1977, 4447-4450. (b) Brussee, J.;
Groenendijk, J. L. G.; Koppele, J. M.; Jansen, A. C. A. Tetrahedron 1985,
41, 3313-3319. (c) Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan,
L. J.; Domeier, L. A.; Moreau, P.; Koga, K.; Mayer, J. M.; Chao, Y.; Siegel,
M. G.; Hoffman, D. H.; Sogah, G. D. Y. J. Org. Chem. 1978, 43, 1930-
1946.
(
6) For a review, see: Shibasaki, M.; Kanai, M. Chem. Pharm. Bull.
001, 49, 511-524.
7) (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am.
2
(
Chem. Soc. 1999, 121, 2641-2642. (b) Hamashima, Y.; Sawada, D.;
Nogami, H.; Kanai, M.; Shibasaki, M. Tetrahedron 2001, 57, 805-814.
(8) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652.
(14) For recent selected examples, see: (a) You, J. S.; Gan, H.-M.; Choi,
M. C. K. Chem. Commun. 2000, 1963-1964. (b) Belokon, Y. N.; Caveda-
Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.;
Moscalenko, M. A.; North, M.; Orizn, C.; Tararov, V. I.; Tasinazzo, M.;
Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968-
3973. (c) Hwang, C. D.; Hwang, D.-R.; Uang, B. J. J. Org. Chem. 1998,
63, 6762-6763. (d) Mori, M.; Imma, H.; Nakai, T. Tetrahedron Lett. 1997,
38, 6229-6232.
(
9) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 6327-6328.
(
10) Gladysz, J. A. Pure Appl. Chem. 2001, 73, 1319.
(11) Sophisticated strategies are being developed for recovery and
recycling of chiral catalysts: Chiral Catalyst Immobilization and Recycling;
De Vos, D. E., Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2000.
2590
Org. Lett., Vol. 4, No. 15, 2002

solvent. Then, benzaldehyde and trimethylsilyl cyanide
TMSCN) were added in one portion at 0 °C in the presence
(
Table 2. Enantioselective Synthesis of Cyanohydrins Catalyzed
by Complexes 3
of 4 Å molecular sieves (MS). Preliminary studies with
titanium(IV) salts as Lewis acids were not completely
satisfactory as it was found that chemical yields did not
parallel those of enantioselection (Table 1, entries 1-3).
In contrast, aluminum catalysts offered better prospects.
Thus, when dimethylaluminum chloride was used as the
Lewis acid, the reaction took place quantitatively in 3 h in
T
t
yield configuration,
b
1
6,17
entry
aldehyde
PhCHO
3
(°C) (h)
4
(%)a
er
8
8:12 er, though only when both MS
and triphenylphos-
1
8
1
2
3
4
5
6
7
8
9
(S) -20
6
6
6
4a
4a
4a
4a
4a
4d
4e
4e
4f
99
99
99
99
99
99
70
45
99
99
99
99
99
99
(R) >99/1
(S) >99/1
(R) >99/1
(R) >99/1
(S) 98/2
(R) >99/1
(R) 85/15
(R) 89/11
(R) 88/12
(R) 96/4
phane oxide were employed as additives (Table 1, cf.
PhCHO
PhCHO
4-(MeO)C
(R) -20
entries 4-6). Lowering the temperature to -20 °C (Table
(S)c -20
1
, entry 7) led to a significant leap forward in enantioselec-
tivity (er higher than 99:1) while keeping the reactivity high
quantitative chemical yield in 6 h). Using diethyl instead
of dimethylaluminum chloride gave somewhat poorer results
Table 1, entry 9). The presence of both 4 Å MS (200 mg/
6
H
4
CHO (S) -20 20
2-ClC
4-ClC
6
H
H
4
CHO
CHO
(R) -20
8
6
4
(S) -20 21
(
4-(PhO)C
4-(PhO)C
6
H
H
4
CHO (S) -20 48
6
4
CHO (S) -40 48
2-FurylCHO
2-FurylCHO
PhCHdCHCHO
PhCHdCHCHO
(S) -20
(S) -40 12
(S) -20
(R) -40 12
5
(
1
0
4g
4h
4h
16
mmol of aldehydes, ca. 1 equiv) and triphenylphosphane
oxide was crucial for achieving high enantioselectivities in
all cases studied (Table 1, entries 4-6). On the other hand,
in coping with solvent effects, we found that operating with
toluene (the reaction mixture is somewhat heterogeneous
under these conditions) yielded higher ers than when
dichloromethane (the reaction mixture is homogeneous) was
employed as the solvent (Table 1, entries 7 and 8). In
contrast, operating without 4 Å MS but in the presence of
water (the same amount determined to be present in the
molecular sieves) gave a very low yield and a poor
enantiomeric ratio of the resulting cyanohydrin 4. So, we
can reckon that 4 Å MS are an excellent carrier of a limited
11
6
(R) 91/9
(S) >99/1
(S) 94/6
1
1
2
3
PhCH
2
CH
2
CHO
CHO
(R) -40 4.5 4i
(R) -40 3.5 4j
14
CH (CH
3
2
)
5
(S) 83/17
a
Isolated yields of the cyanohydrin after acidic hydrolysis. b Enantiomeric
ratios were determined by chiral HPLC analysis (Chiralcel OD-H and
Chiralpak AD and AS). c Reaction was performed with recovered ligand
by extractive workup and recrystallization.
the preparation of cyanohydrins (S)-4. In all studied cases,
the reaction conversions and chemical yields were both very
high, the title alcohol 4 being obtained after acidic treatment.
From the experimental viewpoint two noticeable aspects need
to be remarked, especially when compared with the proce-
19
amount of water, as recently demonstrated in a related case.
7
dure reported by Shibasaki et al. First, the procedure is
These optimized reaction conditions were used for the
cyanation of a number of other aldehydes (Table 2). Aromatic
aldehydes gave excellent results (Table 2, entries 1-10) with
the exception of furfural and p-phenoxybenzaldehyde. In
these cases, better ers were reached when operating at -40
extremely simple as reagents can be added at once (no slow
pump addition is needed); reaction times are short; and the
temperature of operation is quite high. In addition, the
process can be scaled-up without appreciable differences in
chemical and stereochemical yields. Thus, when the cyana-
tion of benzaldehyde was carried out in a 2.5 mmol scale, a
°C (Table 2, entries 9 and 10). A prototypic R,â-unsaturated
aldehyde such as cinnamaldehyde also yielded the cyano-
hydrin in excellent yield and er (Table 2, entries 11 and 12).
On the other hand, enatioselectivities of aliphatic aldehydes
were poorer than those of aromatic aldehydes at -20 °C
and were improved by working at -40 °C (Table 2, entries
9
8% isolated yield of cyanohydrin was obtained, after 12 h
at -20 °C, in a 98.5:1.5 er. Moreover, enantiomerically pure
S)-BINOLAM was almost quantitatively (>95% yield)
(
recovered after a simple acid-base workup and purification
and reused without a loss of efficiency (Table 2, entry 3).
The cyanation of the aldehyde containing a thiazole moiety
13 and 14). Alternatively, (R)-BINOLAM can be used for
7
b,20
deserved special attention,
as this asymmetric reaction
(15) Enantiopure cyanohydrins are important building blocks for the
constitutes one of the key steps in the synthesis of epothilone
synthesis of 1,2-bifunctional compounds such as R-hydroxycarbonyl
compounds, â-amino alcohols, and R-amino acids and also for the generation
of new materials: (a) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702-
2
1
A. Previously, compound (S)-4k was prepared at -40 °C
in 48 h by adding 1.5 equiv of TMSCN very slowly (syringe
2
708. (b) Gr o¨ ger, H. AdV. Synth. Catal. 2001, 343, 547-558. (c) Gregory,
7
b,21
pump).
In our case, slow addition of 2 equiv of TMSCN
R. J. H. Chem. ReV. 1999, 99, 3649-3682. (d) Effenberger, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1555-1564. (e) Kruse, C. G. In Chirality
in Industry; Collins, A. N., Schedrake, G. N., Crosby, J., Eds.; Wiley:
Chichester, UK, 1992; Chapter 14. (f) North, M. Synlett 1993, 807-820.
was not productive (Table 3, entry 3) because residual
unreacted 4k was observed in the crude reaction mixture.
Fortunately, when the reaction was carried out at -20 °C
and excess TMSCN (9 equiv) added in one portion,
(
16) Thermogravimetric analysis of “dry” MS (dried at 120 °C for 4 h)
revealed a 7.5% water content.
17) The role of 4 Å MS as an H2O donor has been demonstrated for
(
the case of binaphthol-derived titanium complexes: Terada, M.; Matsumoto,
Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281-282.
(20) (a) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39,
209-213. (b) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 43, 10521-10532.
(21) (a) Nicolaou, K. C.; Hepworth, D.; King, N. P.; Finlay, M. R. V.;
Scarpelli, R.; Pereira, M. M. A.; Bollbuck, B.; Bigot, A.; Werschkun, B.;
Winssinger, N. Chem. Eur. J. 2000, 6, 2783-2800. (b) Bode, J. W.; Carreira,
E. M. J. Org. Chem. 2001, 66, 6410-6424.
(18) The influence of Ph3PO on prevention of oligomerization of the
catalyst and activation of trimethylsilyl cyanide has been pointed out: Vogl,
E. M.; Gr o¨ ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570-
1
577.
(19) Shimizu, M.; Ogawa, T.; Nishi, T. Tetrahedron Lett. 2001, 42,
5
463-5466.
Org. Lett., Vol. 4, No. 15, 2002
2591

Our catalyst has an efficiency similar to that of Shibasaki’s
LALB phosphine oxide catalyst while allowing work to be
performed at higher temperatures and with an easier setup.
In addition, we have demonstrated that chiral ligand (S)-
BINOLAM 2 can be easily recovered at the end of the
reaction and recycled, thus suggesting the possible applica-
tion of this methodology in large-scale processes. Experi-
mental and theoretical studies are currently underway in order
to clarify the mechanistic details of this reaction.
Table 3. Synthesis of Cyanohydrin (S)-4k
run
TMSCN (equiv)
3
T (°C)
t (h)
4k (%)a
er (%)b
Acknowledgment. This work has been supported by the
DGES of the Spanish Ministerio de Educaci o´ n y Cultura
(MEC) (PB96-0203, PB97-0123, and BQU2001-0724).
1
2
3
4
5
-20
-20
-20
-20
-40
22
48
24
36
48
33
52
0
>98
>98
96/4
88/12
c
1.5 + 1.5
d
2
9
9
96/4
96/4
OL0262338
a
Isolated yields given refer to the cyanohydrin obtained after acidic
b
(22) Typical Experimental Procedure. To a suspension of enantiopure
(S)-BINOLAM 2 (0.025 mmol, 11.4 mg), triphenylphosphane oxide (0.1
mmol, 28 mg), and 4 Å MS (0.25 mg/mmol, previously dried at 120 °C for
hydrolysis. Enantiomeric ratios were determined by chiral HPLC analysis
Chiralcel OD-H). Second 1.5 equiv of TMSCN was added after 1 day.
Slow (syringe pump) addition over 24 h.
c
(
d
4
h) in dry toluene (1 mL), under an inert atmosphere (argon), was added
dimethylaluminum chloride (1 M solution in hexanes, 0.025 mmol, 25 µL),
and the resulting suspension was stirred at room temperature for 1 h. This
mixture was cooled at -20 or -40 °C (see Table 2), and then freshly
distilled aldehyde (0.25 mmol) and TMSCN (0.75 mmol, 100 µL) were
the reaction was completed in 36 h in excellent chemical
yield and very good er (Table 3, entry 4). Lowering the
working temperature to -40 °C did not improve the
enantiomeric ratio of the product (Table 3, entry 5).
In summary, we have shown that our BINOLAM-derived
catalyst is more efficient that the otherwise simpler LA
1
added in one portion. The reaction was monitored by H NMR spectroscopy,
and when it was judged to be complete, a 2 M aqueous solution of
hydrochloric acid (2 mL) and ethyl acetate (2 mL) were added; the resulting
mixture was stirred vigorously for 1 h. The emulsion was filtered through
a Celite pad, and the organic layer was separated, dried (MgSO4), and
evaporated, affording a residue that was purified by flash chromatography
to obtain pure cyanohydrins 4.
2
2
catalysts in the enantioselective cyanation of aldehydes.
2592
Org. Lett., Vol. 4, No. 15, 2002