Enantioselective synthesis of cyanohydrins by a novel aluminum catalyst

Article abstract of DOI:10.1055/s-2005-863716

The development of a new chiral aluminum catalyst is reported. This catalyst has been applied efficiently to the asymmetric cyanosilylation of aldehydes.

Full text of DOI:10.1055/s-2005-863716

LETTER
627
Enantioselective Synthesis of Cyanohydrins by a Novel Aluminum Catalyst
Enantioselective
Synthesis
o
r
f
Cyano
rhydrins
b
y
y
a
N
ove
l
A
luminu
M
m
C
atalyst . Trost,* Silvia Martínez-Sánchez
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA
Fax +1(650)7250002; E-mail: bmtrost@stanford.edu
Received 3 December 2004
ture in methylene chloride for 30 minutes. A little excess
of ligand was used to avoid traces of the metal complex,
which could also catalyze the reaction. Divalent metals
did not generate an effective catalyst (entries 1–4). Thus,
when the dinuclear zinc catalyst was used, the conversion
of the reaction at 4 °C (temperature of the reaction)6 was
very low and silylation of the ligand was observed (entry
1). Dibutylmagnesium (one or two equivalents per ligand)
or a mixed complex (one equivalent of both ZnEt2 and
MgBu2) generated the silylated cyanohydrin as a racemic
mixture (entries 3 and 4) or with very low ee (entry 2). A
complex derived from titanium, a tetravalent metal, was
also studied but the product was obtained with low ee
(entries 5, 6). Trimethylaluminum was found to be the
best metal source for this transformation. The addition
of one equivalent of AlMe3 per ligand led to an active
species, which catalyzed the formation of silylated cyano-
hydrin (S)-3a in 60% yield and 80% ee (entry 7). The re-
action did not proceed when two equivalents of AlMe3 per
ligand were used (entry 8) and only 26% ee was obtained
when Cl2AlMe was used instead of AlMe3 (entry 9).
Abstract: The development of a new chiral aluminum catalyst is
reported. This catalyst has been applied efficiently to the asym-
metric cyanosilylation of aldehydes.
Key words: aldehyde, cyanohydrin, trimethylsilylcyanide, asym-
metric addition, aluminum
In recent years, we developed a dinuclear zinc catalyst
based on the chiral ligand 1 (Figure 1). This system was
very effective in different asymmetric processes, for
instance the aldol reaction, a Mannich-type transfor-
mation, the nitro aldol reaction and the desymmetrization
of meso-1,3-diols.1 As part of our study on this chiral
ligand, we have explored other catalytic processes and we
report herein its effectiveness in the enantioselective
cyanosilylation of aldehydes, a highly atom economical
reaction.2
Ph
Ph
Ph
Ph
OH
HO
N
N
OH
1
Scheme 1
Figure 1
Table 1 Influence of the Metal in the Catalytic Enantioselective
Addition of TMSCN to Benzaldehyde with Ligand 1, in CH2Cl2, 4 °C
Cyanohydrins have a high synthetic potential as chiral
building blocks in organic synthesis and they can be easily
converted into a wide variety of compounds, including a-
hydroxy acids, b-amino alcohols and a-amino acids.3
Numerous methods, both enzymatic and chemical, have
been reported for the asymmetric synthesis of cyano-
hydrins.4 In particular, the development of new enantio-
selective catalysts has been extensively investigated; for
instance, chiral aluminum complexes catalyze the
addition of TMSCN to carbonyl derivatives, showing
excellent enantioselectivity in most cases.5
Entry
[M]
x [M]
(%)
Yield of 3a ee
(%)
4 b
44
43
39
32
50
60
3
(%)a
1
2
3
4
5
6
7
8
9
ZnEt2
20
10
20
–
MgBu2
MgBu2
15 (R)
0
ZnEt2 + MgBu2 20
0
Ti(Oi-Pr)4
Ti(Oi-Pr)4
AlMe3
10
20
10
20
10
21 (R)
31 (R)
80 (S)
0
Initially, we focused on the addition of TMSCN to benz-
aldehyde using different metal sources (Scheme 1,
Table 1). The catalyst was prepared always by stirring
ligand 1 with an organometallic reagent at room tempera-
AlMe3
Cl2AlMe
20
26 (S)
SYNLETT 2005, No. 4, pp 0627–0630
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-863716; Art ID: S11104ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
3.
2
0
0
5
a Enantioselectivity determined by HPLC analysis.
b Silylated ligand was isolated.

628
B. M. Trost, S. Martínez-Sánchez
LETTER
Table 2 Optimization of the Cyanosilylation of Benzaldehyde in
Table 3 Asymmetric TMSCN Addition to Aromatic Aldehydes
Presence of the Aluminum Catalyst ([M] = AlMe3).
Catalyzed by (S,S)-1
Entry
x AlMe3 Solvent
(%)
Temp
(°C)
Yield of 3a ee
Entry ArCHO
Prod- Yield of 3 ee
(%)
60
42
79
60
76
50
38
59
70
(%)a
uct
3a
3b
3c
3d
3e
3f
(%)
76
72
68
80
76
78
74
74
54
68
56
73
68
50
66
75
(%)a
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
PhCl
4
–25
25
4
80
58
55
27
86
33
0
1
2
Benzaldehyde
86
3-Tolualdehyde
80
3
3,5-Dimethylbenzaldehyde
3-Chlorobenzaldehyde
3-Bromobenzaldehyde
3,5-Dichlorobenzaldehyde
3,5-Dibromobenzaldehyde
3-(Hex-1-ynyl)benzaldehyde
4-Tolualdehyde
57b
86
4
4
5
82
Toluene
THF
4
6
80b
85b
82b
77
4
7
3g
3h
3i
MeCN
PhCl
4
5
8
7 b
4
77
9
a Enantioselectivity determined by HPLC analysis.8,9
10
11
12
13
14
15
16
4-Anisaldehyde
3j
62
b 7.8 mol% of 1.
Biphenyl-4-carboxaldehyde
2-Naphthaldehyde
3k
3l
60
84
The addition of TMSCN to benzaldehyde in presence of
the aluminum catalyst (generated at r.t.) was then opti-
mized (Scheme 1, Table 2). First, it was observed that any
change in the temperature of reaction produced lower ee
(see entries 1–3). On the other hand, the choice of solvent
influenced the degree of enantioselectivity (entries 4–8).
Chlorobenzene was the most effective solvent, generating
the product in high yield and 86% ee (entry 5). Finally, a
1-Naphthaldehyde
3m
3n
3o
3p
73
2-Furaldehyde
60c
71
3-Furaldehyde
3-Thienylcarboxaldehyde
84
a Enantioselectivity determined by HPLC analysis. Absolute configu-
lower catalyst loading was also tested, but poorer ee was ration assigned as S by comparison to known compounds unless
otherwise indicated.
observed (entry 9).
b Absolute configuration assigned by analogy.
c R-isomer as a result of a change in the priority of the substituents.
The scope of the reaction was then investigated with dif-
ferent aldehydes using the optimized conditions (11 mol%
catalyst generated at r.t., 4 °C, chlorobenzene).7 Aromatic
aldehydes gave better results, with high yields and up to
86% ee, as shown in Scheme 2 and Table 3. In general,
alkyl, alkynyl and halogen groups at the meta-position of
the aromatic ring were tolerated well (entries 2–8), where-
as substituents at the para-position gave slightly lower ee
(entries 9–11). Among the heterocyclic aldehydes studied
(entries 14–16) 3-thienylcarboxaldehyde performed best,
forming the silylated cyanohydrin in 75% yield and 84%
ee (entry 16).
Scheme 3
In order to examine the structure of the catalyst, we stirred
an equimolecular amount of ligand 1 and trimethylalu-
minum in deuterated methylene chloride (distilled from
calcium hydride) for 30 minutes and obtained a 1H NMR.
Based on this spectrum, we suggest that the precatalyst
could have the structure I represented in Scheme 4. There
is a peak at d = –1.18 ppm assigned to a methyl group still
remaining on the aluminum atom. In addition, two aro-
matic protons at d = 6.24 and 6.33 ppm, and two AB sys-
tems at d = 3.41 (1 H, d, J = 12.3 Hz), 2.96 (1 H, d,
J = 12.9 Hz), 2.85 (1 H, d, J = 12.9 Hz) and 2.23 (1 H, d,
J = 12.3 Hz), corresponding to the diastereotopic methyl-
ene groups, suggest a non-symmetrical structure. The real
nature of the active catalyst awaits further investigation.
Scheme 2
An aliphatic aldehyde was also studied (Scheme 3). Cy-
clohexanecarboxaldehyde reacted well with TMSCN in
presence of our aluminum catalyst, leading to the silylated
cyanohydrin in 70% yield and moderate ee. The absolute
configuration of the products was determined by compar-
ison of optical rotations to known products8 and by analo-
gy in the other cases.9
Synlett 2005, No. 4, 627–630 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Cyanohydrins by a Novel Aluminum Catalyst
629
(4) For reviews on enantioselective synthesis and applications
of cyanohydrins: (a) Effenberger, F. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1555. (b) Gregory, R. J. H. Chem. Rev.
1999, 99, 3649. (c) North, M. Tetrahedron: Asymmetry
2003, 14, 147. (d) Brunel, J.-M.; Holmes, I. P. Angew.
Chem. Int. Ed. 2004, 43, 2752.
(5) For aluminum-catalyzed TMSCN enantioselective addition
to aldehydes see: (a) Iovel, I.; Popelis, Y.; Fleisher, M.;
Lukevics, E. Tetrahedron: Asymmetry 1997, 8, 1279.
(b) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.;
Shibasaki, M. Tetrahedron 2001, 57, 805. (c) Casas, J.;
Nájera, C.; Sansano, J. M.; Saá, J. M. Org. Lett. 2002, 4,
2589. (d) For aluminum-catalyzed TMSCN enantioselective
addition to ketones see: Deng, H.; Isler, M. P.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2002, 41, 1009.
(6) Temperature of a cold room.
Tentatively, we propose an initial reaction of TMSCN to
the aluminum alkoxide followed by hydrogen bonding of
the aldehyde to the free hydroxy group, leading to struc-
ture II (Scheme 4). An internal delivery of the cyanide to
the re face of the aldehyde to adduct III, followed by
silylation of the alkoxy group would lead to the final
product.
(7) Typical Procedure
Catalysis Generation: A 2 M solution of trimethylalu-
minum in toluene (25 mL, 0.05 mmol) was added dropwise
to a solution of ligand 1 (36 mg, 0.056 mmol) in 1.0 mL of
chlorobenzene at r.t. After stirring for 30 min at the same
temperature, the resulting solution was cooled to 4 °C to be
used as catalyst.
TMSCN Addition: Aldehyde 2 (0.5 mmol) was added in
one portion to the catalyst solution at 4 °C and after 10 min
TMSCN (73 mL, 0.55 mmol) was added over 2 min. The
reaction mixture was stirred at the same temperature for 24
h. Then the reaction was quenched with 2.0 mL of pH 7
buffer phosphate solution (Na2HPO4/NaH2PO4) and
extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with brine (5 mL), dried over MgSO4
and concentrated to give a colorless oil. The crude was
purified by flash chromatography on silica gel (petroleum
ether–EtOAc, 5:1) to yield the corresponding silylated
cyanohydrins.
Scheme 4 Mechanism rationale
In summary, we have developed a novel aluminum
catalyst based on our chiral ligand 1, which lets us to carry
out the enantioselective addition of TMSCN to aldehydes
with reasonable yields and enantioselectivity. More
experiments to determine the nature of the active catalyst
and the mechanism of the reaction are currently under-
way.
(8) (a) Brusse, J.; Roos, E. C.; Van der Gen, A. Tetrahedron
Lett. 1988, 29, 4485. (b) Almsick, A.; Buddrus, J.;
Hoenicke-Schmidt, P.; Laumen, K.; Schneider, M. J. Chem.
Soc., Chem. Commun. 1989, 18, 1391. (c) Effenberger, F.;
Hörsch, B.; Förster, S.; Ziegler, T. Tetrahedron Lett. 1990,
31, 1249. (d) Effenberg, R.; Gutterer, B.; Ziegler, T. Liebigs
Ann. Chem. 1991, 269. (e) Dhanoa, D.; Bagley, S. W.;
Chang, R. S. L.; Lotti, V. J.; Chen, T.-B. J. Med. Chem.
1993, 36, 3738. (f) Effenberger, F.; Eichhorn, J.
Tetrahedron: Asymmetry 1997, 8, 469. (g) Hwang, C. D.;
Hwang, D.-R.; Uang, B.-J. J. Org. Chem. 1998, 63, 6762.
(h) Yang, W. B.; Fang, J. M. J. Org. Chem. 1998, 63, 1356.
(i) Abiko, A.; Wang, G. Tetrahedron 1998, 54, 11405.
(j) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702.
(k) Nogami, H.; Motomu, K.; Shibasaki, M. Chem. Pharm.
Bull. 2003, 51, 702.
Acknowledgment
We thank the National Science Foundation and the National Insti-
tute of Health, General Medical Sciences (GM13598), for their
generous support of our programs. S.M.S thanks Fundación Ramón
Areces for a postdoctoral fellowship.
(9) Characterization of the New Compounds:
Compound 3c: 1H NMR (300 MHz, CDCl3): d = 7.32 (s, 2
H), 7.26 (s, 1 H), 5.66 (s, 1 H), 2.59 (s, 3 H), 0.48 (s, 9 H)
ppm. 13C NMR (300 MHz, CDCl3): d = 138.8, 136.2, 131.0,
124.2, 119.5, 63.8, 21.3, –0.1 ppm. IR (neat): 2960, 2921,
1612, 1464, 1255, 1159, 1101, 846, 754, 692 cm–1. Anal.
Calcd for C13H19NOSi: C, 66.90; H, 8.21; N, 6.00. Found: C,
66.67; H, 7.95; N, 5.95. Enantiomer separation by HPLC
(Daicel Chiralpak AD, l = 250 nm, heptane–i-PrOH =
99.95:0.05; 1.0 mL/min; 57% ee): tR = 6.83 (major) and 7.98
min. [a]D –16.28 (c 2.12, CHCl3).
References
(1) (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem. Int. Ed. 2002,
41, 861. (b) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc.
2003, 125, 338. (c) Trost, B. M.; Mino, T. J. Am. Chem. Soc.
2003, 125, 2410. (d) Trost, B. M.; Fettes, A.; Shireman, B.
T. J. Am. Chem. Soc. 2004, 126, 2660.
(2) Atom economy in organic synthesis: (a) Trost, B. M.
Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(3) (a) Gaucher, A.; Ollivier, J.; Salaün, J. Synlett 1991, 151.
(b) Schwindt, M. A.; Belmont, D. T.; Carlson, M.; Franklin,
L. C.; Hendrickson, V. S.; Karrick, G. L.; Poc, R. W.;
Sobicray, D. M.; Van de Vusse, J. J. Org. Chem. 1996, 61,
9564. (c) Effenberger, F.; Jäger, J. J. J. Org. Chem. 1997, 62,
3867.
Compound 3f: 1H NMR (300 MHz, CDCl3): d = 7.36 (m, 3
H), 5.43 (s, 1 H), 0.27 (s, 9 H) ppm. 13C NMR (300 MHz,
CDCl3): d = 139.5, 135.7, 129.6, 124.8, 118.3, 62.4, –0.2
ppm. IR (neat): 3083, 2961, 2901, 1592, 1574, 1435, 1259,
1202, 1119, 872, 805, 754 cm–1. Anal. Calcd for
C11H13Cl2NOSi: C, 48.18; H, 4.78; N, 5.11. Found: C, 48.61;
H, 5.17; N, 5.03. Enantiomer separation by HPLC (Daicel
Synlett 2005, No. 4, 627–630 © Thieme Stuttgart · New York

630
B. M. Trost, S. Martínez-Sánchez
LETTER
Chiralpak AD, l = 235 nm, heptane–i-PrOH = 99.5:0.5; 0.6
mL/min; 80% ee): tR = 9.80 and 10.48 (major) min.
[a]D –12.52 (c 2.91, CHCl3).
Compound 3h: 1H NMR (300 MHz, CDCl3): d = 7.49 (s, 1
H), 7.39–7.32 (m, 3 H), 5.45 (s, 1 H), 2.44 (t, J = 6.9 Hz, 2
H), 1.60–1.47 (m, 4 H), 0.98 (t, J = 6.9 Hz, 3 H) ppm. 13
C
Compound 3g: 1H NMR (300 MHz, CDCl3): d = 7.69 (m, 1
H), 7.55 (m, 2 H), 5.43 (s, 1 H), 0.27 (s, 9 H) ppm. 13C NMR
(300 MHz, CDCl3): d = 139.9, 135.1, 128.1, 123.5, 118.2,
62.2, –0.2 ppm. IR (neat): 3076, 2959, 1589, 1562, 1427,
1256, 1193, 1118, 1095, 848, 742 cm–1. Anal. Calcd for
C11H13Br2NOSi: C, 36.38; H, 3.61; N, 3.86. Found: C, 36.01;
H, 2.99; N, 3.94. Enantiomer separation by HPLC (Daicel
Chiralcel OD, l = 235 nm, heptane–i-PrOH = 99.8:0.2, 1.0
mL/min; 85% ee): tR = 11.69 (major) and 16.01 min.
[a]D –9.39 (c 2.53, CHCl3).
NMR (300 MHz, CDCl3): d = 136.4, 132.5, 129.5, 128.9,
125.4, 125.0, 119.0, 91.6, 79.9, 63.4, 30.8, 22.1, 19.1, 13.7,
–0.2 ppm. IR (neat): 2959, 2934, 2873, 2230, 1603, 1482,
1431, 1330, 1256, 1108, 1082, 860, 848 cm–1. Anal. Calcd
for C17H23NOSi: C, 71.53; H, 8.12; N, 4.91. Found: C,
70.98; H, 8.51; N, 5.05. Enantiomer separation by HPLC
(Daicel Chiralcel OD, l = 250 nm, heptane–i-PrOH =
99.7:0.3; 1.0 mL/min; 82% ee): tR = 18.16 (major) and 30.05
min. [a]D –9.11 (c 0.26, CHCl3).
Synlett 2005, No. 4, 627–630 © Thieme Stuttgart · New York