Practical synthesis of chiral ligands for catalytic enantioselective cyanosilylation of ketones

Article abstract of DOI:10.1016/S0040-4039(02)00450-1

A practical and more environmentally benign synthetic route of chiral ligands that are useful for catalytic enantioselective cyanosilylation of ketones is described. A key step is the regioselective S_N2 reaction to cyclic sulfate 12 with catech

Full text of DOI:10.1016/S0040-4039(02)00450-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2919–2922
Practical synthesis of chiral ligands for catalytic enantioselective
cyanosilylation of ketones
Shuji Masumoto,a Kazuo Yabu,a Motomu Kanaia,b and Masakatsu Shibasakia,*
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bPRESTO, Japan Science and Technology Corporation (JST), Tokyo, Japan
Received 4 February 2002; revised 27 February 2002; accepted 1 March 2002
Abstract—A practical and more environmentally benign synthetic route of chiral ligands that are useful for catalytic enantioselec-
tive cyanosilylation of ketones is described. A key step is the regioselective SN2 reaction to cyclic sulfate 12 with catechol
derivatives. A range of chiral ligands containing electronically tuned catechols has become available by this new route. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
efficiency, because it increases the Lewis acidity of the
metal. For example, benzoyl-containing ligand 2 syn-
thesized by a laborious route produced significantly
better results in reactions promoted by a Ti-complex.1b
We recently developed a catalytic enantioselective
cyanosilylation of ketones that affords chiral tertiary
cyanohydrins from a wide range of ketone substrates.1,2
Both (R)- and (S)-cyanohydrins can be synthesized
with generally high enantioselectivity by catalysts pre-
pared from chiral ligand 1: 1-Ti (1:1) complex is (R)-
selective and 1-Ln (Gd or Sm) (2:3) complex is
(S)-selective (Scheme 1). The synthetic importance of
chiral tertiary alcohols as building blocks for various
pharmaceutically significant compounds (e.g. camp-
tothecin, fostriecin, oxybutynin, pyruvate dehydroge-
nase kinase inhibitor, etc.)3 illustrates that 1 is an
extremely useful chiral ligand.
Ti(OiPr)4 + 1 or 2
(1 : 1)
(1~10 mol %)
TMSO CN
71–92%
84–97% ee (R)
O
+
RL
RS
RS
RL
Ln(OiPr)3 + 1
(1 : 2)
(5~15 mol %)
TMSO CN
TMSCN
85–97%
62%–97 ee (S)
RL
RS
Ar
O
O
Ar
P
O
1 was previously synthesized in high overall yield from
O
commercially available tri-O-acetyl-
-glucal (7).4 A key
D
H
chiral ligands
Ar
X
step was the introduction of the catechol moiety (X in
Scheme 1) by an aromatic substitution of the arene–
chromium complex.5 Use of a stoichiometric amount of
chromium, however, is environmentally problematic,
especially in a large-scale synthesis. Furthermore, tun-
ing the catechol moiety of 1 was very difficult using this
synthetic route, because arene–chromium complexes
containing electron-deficient aromatic groups are gener-
ally difficult to prepare. Introducing an electron-with-
drawing group on the catechol moiety, however, is an
attractive approach for improving the catalyst
X
Ph
Ph
Ph
R1, R2 = H
R1 = COPh, R2 = H
R1, R2 = F
1
2
3
4
R1
R2
HO
HO
p-CH3C6H4
R1, R2 = F
5
Ph
Cl
Cl
Cl
6
Ph
HO
Keywords: chiral ligand; catalytic enantioselective reaction; cyanosilyl-
ation; ketones; practical synthesis; cyclic sulfate; ligand-tuning.
* Corresponding author. Tel.: +81-3-5841-4830; fax: +81-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Cl
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00450-1

2920
S. Masumoto et al. / Tetrahedron Letters 43 (2002) 2919–2922
Herein, we report a new and practical synthetic route of
chiral ligands that is more suitable for large-scale syn-
thesis (Scheme 2). The direct introduction of electron-
deficient catechols allows for a facile synthesis of
electronically tuned chiral ligands (2–6).
methyl ether15 gave chiral ligands 1–6 [total 12 steps
from 7 for 1, 2, 3, 5, and 6. 1: 17% yield (10 steps in
44% yield, previously). 2: 17% yield (13 steps in 10%
yield, previously). 3: 19% yield. 4: 14% yield (total 15
steps). 5: 17% yield. 6: 25% yield.]. Ligands 3–6 cannot
be synthesized by the former route using arene–
chromium complexes.
2. Practical synthetic route of chiral ligands
In conclusion, we developed a practical and environ-
mentally more benign (i.e. no chromium) synthetic
route of chiral ligands that are very useful for catalytic
enantioselective cyanosilylation of ketones. This syn-
thetic route made it possible to readily prepare an array
of chiral ligands containing different catechol moieties.
The advantages of these new ligands will be discussed
in a following paper.
We attempted to introduce the key catechol via a
regioselective SN2 attack of catechol derivatives to
cyclic sulfate 12. To do so required inversion of the
3-OH group of the
D
-glucose derivative 8 to the
D-
allose derivative 10. Although there are several reports
on the synthesis of 10,6 none of them were satisfactory
for our purpose. Therefore, we planned to develop an
original method to synthesize 10 through an oxidation-
stereoselective reduction sequence from 8. Previous
reports using related ketones indicated that the reduc-
tion with NaBH4 should proceed mainly via an equato-
rial hydride attack to give the desired a-OH.7
3. Experimental
General procedure for the inversion of 3-OH (8–10):
DMSO (0.21 mL, 2.96 mmol) was added dropwise to a
solution of (COCl)2 (0.13 mL, 1.49 mmol) in CH2Cl2 (5
mL) at −78°C. After 15 min, 8 (278 mg, 1.18 mmol) in
CH2Cl2 (2 mL) was added dropwise for 10 min, and the
resulting suspension was stirred at the same tempera-
ture for 1 h. Then, Et3N (0.85 mL, 6.10 mmol) was
added at −78°C and the dry ice–acetone bath was
removed to allow the reaction temperature to reach
room temperature. After 30 min, H2O was added and
the product was extracted with CHCl3. Evaporation of
the organic solvent gave crude ketone 9, which can be
Precursor ketone 9 was synthesized via Swern oxidation
of 8,8 which was readily obtained from commercially
available 7 through three steps. Reduction of 9 with
NaBH4 in MeOH, however, resulted in low stereoselec-
tivity (8:10=1.5:1) and undesired 8 was obtained as the
major isomer.9 After several attempts, reduction with
L
-selectride gave the desired 10 with complete selectivity
in 93% yield from 8 (two steps).10 It is advantageous,
especially for a large scale synthesis, that column chro-
matography was not necessary through 7–10, and all
the purifications could be performed by recrystalliza-
tion.11 Deprotection of the benzylidene acetal, selective
tosylation of the primary alcohol, and introduction of
the phosphine oxide gave 11.12 The key cyclic sulfate 12
was synthesized following the reported procedure.13
From 12, a variety of catechol moieties were introduced
in an SN2 manner with complete regioselectivity at the
less hindered position (C-3).14 Deprotection of the
used for the next step without purification. L-Selectride
(1.0 mol L−1 in THF, 467 mL, 0.47 mmol) was added to
a solution of ketone 9 (0.44 mmol) in THF (4 mL) at
−78°C. After 50 min, 30% H2O2 aq. (0.32 mL) was
added at the same temperature and the mixture was
stirred at 4°C for 20 min. The mixture was then slowly
poured into sat. Na2S2O3 aq. and the aqueous layer was
O
O
O
O
O
AcO
AcO
O
O
O
a, b, c
d
e
2
3
Ph
O
Ph
O
Ph
O
OAc
OH
OH
7
8
9
10
Ar
Ar
Ar
O
O
O
O
O
Ar
Ar
Ar
P
P
P
f, g, h
i, j
k, l
O
O
O
O
O
O
H
H
S
OH
O
X
O
11
12
1–6
Scheme 2. Reagents and conditions: (a) Pd/C, H2, MeOH, rt; (b) NaOMe (0.25 equiv.), MeOH, rt; (c) PhCH(OMe)2 (1.2 equiv.),
p-TsOH·H2O (0.3 equiv.), toluene, reflux, 57% (three steps); (d) DMSO (2.5 equiv.), (COCl)2 (1.3 equiv.), Et3N (5 equiv.), CH2Cl2,
−78°C to rt; (e) L-Selectride (1.03 equiv.), THF, −78°C, 93% (two steps); (f) Pd/C, H2, MeOH–AcOH (1:1), rt, 92%; (g) TsCl (1.1
i
equiv.), pyridine, 78%; (h) Ph2PK (2.5 equiv.), THF, 0°C; H2O2, 94% (Ar=Ph), [Ar=p-CH3C6H4: MOMCl (2.5 equiv.), Pr2NEt
(3 equiv.), CH2Cl2, reflux, 72%; Ar2PLi (2 equiv.), THF, 0°C; H2O2; cat. HCl aq.–MeOH, reflux, 85% (three steps)]; (i) SOCl2 (1.2
equiv.), CH2Cl2; (j) RuCl3·3H2O (1 mol%), NaIO4 (1.5 equiv.), CCl4–CH3CN–H2O, 90% (Ar=Ph), 98% (Ar=p-CH3C6H4) (two
steps); (k) catechol derivatives (1.3 equiv.), K2CO3 (2 equiv.), DMF; 20% H2SO4 aq., Et2O/CHCl3, 65–86% (two steps); (l) EtSH,
AlCl3, CH2Cl2, 82–100% (two steps).

S. Masumoto et al. / Tetrahedron Letters 43 (2002) 2919–2922
2921
4. Selected spectral data of new ligands
extracted with Et2O. The combined organic layer was
washed with brine and dried over Na2SO4. Evapora-
tion and purification by SiO2 column chromatography
(eluent: AcOEt/hexane=1/2) gave pure 10 in 93%
yield as white powder. In a large scale synthesis, the
crude product was purified by recrystallization
(AcOEt–hexane).
1
3: H NMR (500 MHz, CDCl3) l 1.94 (dddd, J=5.1,
12.9, 12.9, 12.9 Hz, 1H), 2.09 (m, 1H), 2.67 (ddd,
J=9.7, 15.0, 15.0 Hz, 1H), 2.85 (ddd, J=2.5, 9.7, 15.0
Hz, 1H), 3.24 (ddd, J=1.8, 12.3, 12.9 Hz, 1H), 3.33 (m,
1H), 3.50 (ddd, J=5.1, 8.6, 12.9 Hz, 1H), 3.69 (brt,
J=8.6 Hz, 1H), 3.91 (m, 1H), 6.77 (ddd, J=8.2, 10.7,
19.8 Hz, 1H), 7.53 (m, 6H), 7.76 (m, 4H), 7.85 (s, 1H),
9.16 (d, J=1.2 Hz, 1H). 13C NMR (125 MHz, CDCl3)
l 31.56, 36.04 (d, J=69 Hz), 65.39, 74.70 (d, J=3 Hz),
75.93, 85.57, 105.58 (d, J=21 Hz), 110.93 (d, J=18
Hz), 129.03 (d, J=12 Hz), 129.07 (d, J=12 Hz), 130.20
(d, J=101 Hz), 130.71 (d, J=10 Hz), 131.17 (d, J=10
Hz), 131.62 (d, J=100 Hz), 132.58 (d, J=4 Hz), 132.61
(d, J=3 Hz), 141.14 (dd, J=3, 7 Hz), 142.60 (dd,
J=14, 239 Hz), 146.58 (dd, J=3, 10 Hz), 147.37 (dd,
J=13, 243 Hz). 31P NMR (202 MHz, CDCl3) l 33.3.
General procedure for the introduction of the phosphine
oxide (11): A solution of the tosylate (8.57 g, 28.3
mmol) in THF (30 mL) was added to a commercially
available Ph2PK solution in THF (0.5 M, 142 mL,
71.0 mmol) over 10 min in an ice bath. After stirring
for 30 min at the same temperature, sat. NH4Cl aq.
was added, followed by the addition of 30% H2O2 aq.
(16 mL) under vigorous stirring. The mixture was then
poured slowly into sat. Na2S2O3 aq. in an ice bath.
Evaporation of THF, extraction of the aqueous layer
with CHCl3, and concentration gave a crude oil that
was purified by SiO2 column chromatography (eluent:
MeOH/CHCl3=1/30). The resulting solid was recrys-
tallized from CHCl3–Et2O to give white powder in
94% yield. The corresponding diol containing di-(p-
tolyl)phosphine oxide was synthesized from the MOM
protected tosylate in a similar way using (p-tolyl)2PLi
prepared following the reported procedure.16
1
4: H NMR (500 MHz, CDCl3) l 1.93 (dddd, J=5.2,
12.8, 12.8, 12.8 Hz, 1H), 2.08 (m, 1H), 2.40 (s, 3H), 2.41
(s, 3H), 2.63 (ddd, J=10.1, 15.3, 15.3 Hz, 1H), 2.79
(ddd, J=2.8, 9.8, 15.3 Hz, 1H), 3.23 (ddd, J=2.1, 11.9,
12.8 Hz, 1H), 3.30 (m, 1H), 3.49 (ddd, J=5.2, 8.9, 11.3
Hz, 1H), 3.67 (brt, J=8.9 Hz), 3.91 (m, 1H), 6.74 (dd,
J=7.9, 11.6 Hz, 1H), 6.78 (dd, J=8.3, 10.7 Hz, 1H),
7.29 (dd, J=2.8, 8.3 Hz, 2H), 7.32 (dd, J=2.8, 8.3 Hz,
2H), 7.58 (dd, J=8.3, 11.9 Hz, 2H), 7.62 (dd, J=8.3,
11.9 Hz, 2H), 7.97 (s, 1H), 9.24 (s, 1H). 13C NMR (125
MHz, CDCl3) l 21.71, 21.73, 31.55, 36.42 (d, J=69
Hz), 65.38, 74.72 (d, J=3 Hz), 76.01, 85.66, 105.58 (d,
J=22 Hz), 110.99 (d, J=20 Hz), 126.80 (d, J=103 Hz),
128.36 (d, J=108 Hz), 129.74 (d, J=12 Hz), 129.83 (d,
J=13 Hz), 130.71 (d, J=10 Hz), 131.19 (d, J=9 Hz),
141.17 (dd, J=3, 8 Hz), 142.55 (dd, J=14, 239 Hz),
143.19 (d, J=2 Hz), 143.20 (d, J=2 Hz), 146.67 (dd,
J=2, 10 Hz), 147.38 (dd, J=13, 243 Hz). 31P NMR
(202 MHz, CDCl3) l 33.7.
General procedure for the cyclic sulfate synthesis (12):
SOCl2 (0.27 mL, 3.70 mmol) was added to a solution
of diol 11 (1.03 g, 3.10 mmol) in CH2Cl2 (20 mL), and
the mixture was stirred for 30 min at room tempera-
ture. Then, the reaction mixture was concentrated, fol-
lowed by co-evaporation with toluene two times. The
resulting crude cyclic sulfite was dissolved in a CCl4
(15 mL)/CH3CN (15 mL)/H2O (30 mL), and NaIO4
(994 mg, 4.65 mmol) and RuCl3·nH2O (7.3 mg, 1
mol%) were added in an ice bath. After stirring vigor-
ously for 1 h, H2O was added and the aqueous layer
was extracted with AcOEt. The combined organic
layer was washed with sat. NaCl aq., followed by
1
5: H NMR (500 MHz, CDCl3) l 1.99 (dddd, J=4.9,
12.8, 12.8, 12.8 Hz, 1H), 2.23 (m, 1H), 2.73 (ddd,
J=9.5, 15.0, 15.0 Hz, 1H), 2.84 (ddd, J=3.1, 9.5, 15.0
Hz, 1H), 3.24 (ddd, J=1.9, 12.2, 12.8 Hz, 1H), 3.39 (m,
1H), 3.71 (ddd, J=4.9, 8.9, 11.0 Hz, 1H), 3.79 (t like,
J=8.9 Hz, 1H), 3.91 (m, 1H), 7.25 (brt, J=7.0 Hz,
1H), 7.30 (s, 1H), 7.33 (brt, J=7.0 Hz, 1H), 7.36 (s,
i
stirring with PrOH (5 mL) at room temperature for 1
h. Drying with Na2SO4, filtration through celite, and
concentration gave a crude powder, which was recrys-
tallized from AcOEt–Et2O to give 12 as fine needles
(1.10 g, 90%).
1H), 7.5–7.66 (m, 8H), 7.77 (m, 4H), 8.98 (brs, 1H). 13
C
NMR (125 MHz, CDCl3) l 31.42, 35.95 (d, J=69 Hz),
65.49, 74.82 (d, J=4 Hz), 76.05, 84.16, 111.55, 117.54,
123.41, 125.10, 126.32, 126.86, 128.36, 128.98 (d, J=12
Hz), 129.01 (d, J=12 Hz), 130.60 (d, J=101 Hz),
130.78 (d, J=10 Hz), 131.23 (d, J=9 Hz), 131.97 (d,
J=103 Hz), 132.04, 132.44 (d, J=2 Hz), 146.88,
149.15. 31P NMR (202 MHz, CDCl3) l 33.3.
General procedure for the SN2 reaction by catechol
derivatives: K2CO3 (1.32 g, 9.56 mmol) and guaiacol
(0.68 mL, 6.21 mmol) were added to a solution of 12
(1.86 g, 4.78 mmol) in DMF (10 mL) and the mixture
was stirred for 14 h at room temperature. After 12
had disappeared on TLC, 20% H2SO4 aq. (100 mL)
and Et2O (50 mL)–CHCl3 (50 mL) were added and
the mixture was vigorously stirred for 12 h. The
aqueous layer was extracted with CHCl3 and the com-
bined organic layer was washed with H2O and sat.
NaCl aq. Drying over Na2SO4, followed by concentra-
tion, gave a crude oil that was purified by SiO2
column chromatography (eluent: AcOEt/hexane=1/1
to 100/0). The methylated ligand was obtained as a
white solid (65%).
1
6: H NMR (500 MHz, CDCl3) l 2.11 (dddd, J=4.9,
12.5, 12.5, 12.5 Hz, 1H), 2.26 (m, 1H), 2.69 (ddd,
J=10.1, 15.3, 15.3 Hz, 1H), 2.85 (m, 1H), 3.21 (brt,
J=12.5 Hz, 1H), 3.36 (m, 1H), 3.70 (ddd, J=4.9, 8.9,
11.3 Hz, 1H), 3.81 (t like, 8.9 Hz, 1H), 3.90 (m, 1H),
7.49–7.63 (m, 6H), 7.72 (dd, J=7.3, 12.2 Hz, 2H), 7.78
(dd, J=7.3, 11.9 Hz, 2H), 8.47 (s, 1H), 10.9 (s, 1H). 13
C
NMR (125 MHz, CDCl3) l 32.93, 36.02 (d, J=69 Hz),

2922
S. Masumoto et al. / Tetrahedron Letters 43 (2002) 2919–2922
65.39, 74.85 (d, J=3 Hz), 75.67, 87.03, 120.58, 121.92,
126.81, 128.73, 129.06 (d, J=11 Hz), 129.10 (d, J=12
Hz), 129.90 (d, J=101 Hz), 130.62 (d, J=10 Hz),
131.20 (d, J=10 Hz), 131.57 (d, J=100 Hz), 132.65 (d,
J=3 Hz), 142.78, 147.77. 31P NMR (202 MHz, CDCl3)
l 33.4.
J.; Tomaselli, H. C.; Islam, A.; Lozito, R. J.; Liu, X.;
Maniara, W. M.; Fillers, W. S.; Delgrande, D.; Walter,
R. E.; Mann, W. R. J. Med. Chem. 2000, 43, 236–249.
4. For the synthesis of 1, see Ref. 1a.
5. (a) Mahaffy, C. A. L. J. Organomet. Chem. 1984, 262,
33–37; (b) Loughhead, D. G.; Flippin, L. A.; Weikert, R.
J. J. Org. Chem. 1999, 64, 3373–3375.
6. (a) Still, I. W. J.; Banait, N. S.; Frazer, D. V. Synth.
Commun. 1988, 18, 1461; (b) Haga, M.; Tejima, S. Carbo-
hydr. Res. 1974, 34, 214.
Acknowledgements
7. For examples of selective a-OH formations, see: (a)
Hladezuk, I.; Olesker, A.; Cle´ophax, J.; Lukacs, G. J.
Carbohydr. Chem. 1998, 17, 869–878; (b) Nicolaou, K.
C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am.
Chem. Soc. 1987, 109, 2821–2822. These reports use
NaBH4 as the reducing reagent.
Financial support was provided by RFTF of Japan
Society for the Promotion of Science and PRESTO of
Japan Science and Technology Corporation (JST).
8. Nakamura, H.; Tejima, S.; Akagi, M. Chem. Pharm. Bull.
1966, 14, 648–657.
References
9. These results indicated that substituents on C-2 had a key
role in controlling the stereochemistry of the reduction in
previous cases.7
1. (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 7412–7413; (b) Hamashima, Y.;
Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42,
691–694; (c) Yabu, K.; Masumoto, S.; Yamasaki, S.;
Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908–9909.
2. For other examples, see: (a) Tian, S.-K.; Deng, L. J. Am.
Chem. Soc. 2001, 123, 6195–6196; (b) Belokon’, Y. N.;
Green, B.; Ikonnikov, N. S.; North, M.; Parsons, T.;
Tararov, V. I. Tetrahedron 2001, 57, 771–779.
3. For selected recent examples of enantioselective synthesis
of these compounds, see: (a) camptothecin: Comins, D.
L.; Nolan, J. M. Org. Lett. 2001, 3, 4255–4257, see also
Ref. 1c; (b) fostriecin: Chaves, D. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2001, 40, 3667–3670; (c) oxybu-
tynin: Grover, P. T.; Bhongle, N. N.; Wald, S. A.;
Senanayake, C. H. J. Org. Chem. 2000, 65, 6283–6287;
(d) pyruvate dehydrogenase kinase inhibitor: Aicher, T.
D.; Anderson, R. C.; Gao, J.; Shetty, S. S.; Coppola, G.
M.; Stanton, J. L.; Knorr, D. C.; Sperbeck, D. M.;
Brand, L. J.; Vinluan, C. C.; Kaplan, E. L.; Dragland, C.
10. For a use of L-selectride to synthesize an axial alcohol,
see: Kozikowski, A. P.; Xia, Y.; Rusnak, J. M. J. Chem.
Soc., Chem. Commun. 1988, 1301.
11. We routinely start from 100 g of 7 and obtain approxi-
mately 40 g of 10.
12. In the synthesis of 4 containing di-(p-tolyl)phosphine
oxide, it was necessary to protect the diol with MOM
groups at the tosylate stage for a reasonable yield of the
phosphine oxide introduction step.
13. (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988,
110, 7538–7539; (b) Lohray, B. B. Synthesis 1992, 1035.
14. Introduction of the catechol via a Mitsunobu reaction
from 10, as well as via an SN2 reaction of the triflate
derived from 10, failed.
15. Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem.
1980, 45, 4275–4277.
16. Ding, H.; Hanson, B. E.; Bakos, J. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1645–1647.