Catalytic enantioselective synthesis of (20s)-camptothecin intermediates using cyanosilylation of ketones promoted by D-glucose-derived lanthanide catalyst

Article abstract of DOI:10.3987/com-02-s49

An efficient catalytic enantioselective synthetic route was developed for Curran's versatile camptothecin intermediate (5). The key step is the catalytic enantioselective cyanosilylation of ketone (7) using a chiral samarium (Sm) complex. The target ketone cyanohydrin (6) was obtained with 90% ee using 2 mol % of the catalyst. A gadolinium (Gd) complex derived from the same chiral ligand could also be used as an enantioselective catalyst to synthesize Corey's intermediate (11).

Full text of DOI:10.3987/com-02-s49

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 369 - 385, Received, 2nd August, 2002
CATALYTIC
ENANTIOSELECTIVE
SYNTHESIS
OF
(20S)-
CAMPTOTHECIN INTERMEDIATES USING CYANOSILYLATION OF
KETONES PROMOTED BY D-GLUCOSE-DERIVED LANTHANIDE
CATALYST
Kazuo Yabu,a Shuji Masumoto,a Motomu Kanai,a,b Wu Du,c Dennis P. Curran,c
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)
cDepartment of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
15260, USA
Dedicated to Professor Yuichi Kanaoka on the occasion of his 75th birthday.
Abstract – An efficient catalytic enantioselective synthetic route was developed
for Curran’s versatile camptothecin intermediate (5). The key step is the catalytic
enantioselective cyanosilylation of ketone (7) using a chiral samarium (Sm)
complex. The target ketone cyanohydrin (6) was obtained with 90% ee using 2
mol % of the catalyst. A gadolinium (Gd) complex derived from the same chiral
ligand could also be used as an enantioselective catalyst to synthesize Corey’s
intermediate (11).

Introduction
Camptothecin (Figure 1, 1) and its analogues are very important anti-cancer agents, especially for the
treatment of solid tumors.1 Topotecan (2) and irinotecan (3) have been approved as anti-cancer drugs, and
several other derivatives are now in pre-clinical and clinical development. The mechanism of action of 1
is to interfere with the unwinding of supercoiled DNA by the cellular enzyme topoisomerase I.2
Accumulated data on the structure–activity relationship of 1 indicate that, in general, substitution on C, D,
and E rings is not well tolerated; however, substituents on A and B rings, especially at C7, C9, and C10,
often have good biologic activity and improve physical or pharmacologic activity. Therefore,
development of an efficient and flexible synthetic route to make various analogues is currently under
intensive investigation.3
One of the authors’ groups (Curran’s group) developed a flexible synthetic route using radical cyclization
to connect the A ring moiety and the DE ring moiety at the final stage of synthesis (Scheme 1).3a This
route made it possible to introduce a fairly wide range of substituents on the A and B rings using
substituted isocyanide (4). Therefore, the DE ring moiety (5) containing chiral α-hydroxy lactone is a
common and versatile synthetic intermediate. Another flexible synthetic route was reported by Corey,
connecting the ABC ring moiety (8) and E ring moieties (9) and (10) (Scheme 2).4 In this case, the chiral
α-hydroxy lactone derivative (11) is the versatile intermediate.
To synthesize these intermediates for camptothecin synthesis, we expected that our catalytic
enantioselective cyanosilylation of ketones would be a powerful methodology.5,6 We developed a
catalytic enantioselective cyanosilylation of ketones using chiral ligand (14) derived from D-glucose.

Both (R)- and (S)-ketone cyanohydrins can be synthesized from a wide range of substrates using either
the titanium complex or the lanthanide complex. Herein, we describe the details on the application of the
(S)-selective catalytic cyanosilylation of ketones to synthesize two versatile synthetic intermediates for
camptothecin.7
R9
R10
A
radical
cyclization
NC
1
and
its analogues
TMS
4
catalytic enantioselective
cyanosilylation of ketone
+
O
OMe
OMe
HN
O
N
OTBS
N
OTBS
D
E
CN
I
O
TMS
TMS
HO
TMSO
O
7
5
6
Scheme 1. Retrosynthesis based on Curran's route
O
Cl
O
O
O
O
O
O
O
E
E
NH
+
1
A
B
C
and
O
O
Cl
O
O
O
MeOCO2
8
9
10
11
MeO
O
MeO
O
catalytic enantioselective
cyanosilylation of ketone
OTBS
CN
OTBS
O
O
TMSO
O
12
13
Scheme 2. Retrosynthesis based on Corey's route
Catalytic Enantioselective Synthesis of Curran’s Intermediate
Ketone (7), the substrate for the catalytic enantioselective cyanosilylation, was synthesized from the
known aldehyde (20),3a as shown in Scheme 3. The ethyl ketone was introduced to the pyridine ring using
Knochel’s procedure.8
When we started this project, we had only (R)-selective catalytic cyanosilylation of ketones using Ti-14.
Therefore, we first used the Ti-14 complex for the cyanosilylation of ketone (7). With 20 mol % of Ti-14,
however, the reaction proceeded very slowly even at room temperature and the product, cyanohydrin (6),
was obtained in 34% yield with only 18% ee (Table 1, entry 1). As expected, the major enantiomer was

OMe
OMe
i
OMe
1) PrMgCl
CuCN, LiCl
NaBH4
EtOH
TBSCl
CHO
I
imidazole
OH
N
OTBS
N
N
7
78%
2) EtCOCl
DMF
TMS
I
TMS
I
TMS
20
21
22
82% (3 steps)
Scheme 3. Synthesis of ketone (7)
Table 1. Catalytic enantioselective cyanosilylation of ketone (7
)
: synthesis of Curran's intermediate
MeO
OMe
Metal–ligand
N
OTBS
N
OTBS
CN
TMSCN
S
TMS
TMS
TMSO
O
7
6
entry
ligand
solvent
Metal (mol %)
ligand/Metal
°C
25
h
%
%ee
S/R
Ti(OiPr)4
THF
THF
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
1
2
(20)
14
14
14
14
14
14
14
14
14
14
15
16
17
18
18
19
19
19
1
144
24
24
24
24
44
18
44
18
44
96
65
16
14
38
12
19
36
34
88
92
92
96
95
92
84
98
18
20
62
72
56
26
52
21
84
82
38
42
83
91
83
90
89
90
Sm(OiPr)3 (5)
Sm(OiPr)3 (5)
Sm(OiPr)3 (5)
1
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
THF
3
1.5
1.8
2
4
THF
Sm(OiPr)3
THF
5
(5)
6
La(OiPr)3 (5)
Gd(OiPr)3 (5)
Yb(OiPr)3 (5)
Sm(OiPr)3 (5)
Sm(OiPr)3 (2)
Sm(OiPr)3 (5)
Sm(OiPr)3 (5)
Sm(OiPr)3 (5)
Sm(OiPr)3 (5)
Sm(OiPr)3 (2)
Sm(OiPr)3 (5)
Sm(OiPr)3 (2)
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
THF
THF
7
8
THF
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
9
10
11
12
13
14
15
16
17
18
100
100
90
94
100
95
94
95
Sm(OiPr)3
EtCN–MeCN
(2)
93
Ph
Ph
Ph
Ph
Ph
P
Ar
Ar
O
O
O
O
O
Ph
P
P
P
O
O
O
O
O
H
O
H
Cl
O
O
H
O
H
O
X
Cl
Cl
O
F
F
HO
HO
HO
17
HO
18: Ar = Ph
19: Ar = p-tol
14: X = H
15: X = COPh
16
Cl
the opposite of the desired one (R). After screening the Lewis acid metal, we found that the lanthanide

complex was more reactive than the titanium complex. Thus, when we used a samarium complex
prepared from Sm(OiPr)3 and 14 in a 1:1 ratio in THF, the reaction was completed at –40 °C, and 6 was
obtained in 88% yield with 20% ee (entry 2). Gratifyingly, the absolute configuration of the major
product was switched to the desired one (S). There was an interesting dependency of the
enantioselectivity on the ligand/metal ratio (entries 2–5). Increasing the ligand/metal ratio, improved the
enantioselectivity to a maximum 72% ee at ligand/metal = 1.8 (entry 4). Other lanthanide metals gave less
satisfactory results (entries 6–8).9
We next investigated the effect of the ligand structure (entries 9–18). Propionitrile was a better solvent
than THF for this reaction with regard to enantioselectivity. Propionitrile improved the enantiomeric
excess to 84% (entry 9) compared to 72% (entry 4) in THF. To quickly screen the ligand effect,
development of a practical synthetic route of the ligands using a regioselective opening of the cyclic
sulfate intermediate (23) by various catechols was essential (Scheme 4).10 We synthesized a variety of
ligands containing catechol of different electronic and steric demands using this route. The best ligand
Ar
O
Ar
P
X
KO
O
14–19
+
O
MeO
O
S
O
23
O
Scheme 4. Key step for the ligand synthesis
was determined to be 19, containing a difluorocatechol moiety and a di-(p-tolyl)phosphine oxide. The
increased Lewis acidity by the electron-withdrawing groups (the fluorine atoms) on the catechol, as well
as the increased Lewis basicity by the electron-donating groups (the methyl groups) on the phosphine
oxide might be key for the improved enantioselectivity of ligand (19) compared to the original ligand (14).
The shortened reaction time was probably also due to this type of dual enhancement of the Lewis acidity
and the Lewis basicity of the catalyst. Under the optimized conditions, the cyanohydrin product was
obtained in 93% yield with 90% ee using 2 mol % of catalyst prepared from Sm(OiPr)3 and 19 in a 1:1.8

ratio (entry 18). This reaction could be conducted on an 11-g scale.
Conversion of the cyanohydrin to the enantiomerically pure Curran’s intermediate (5) was achieved as
shown in Scheme 5. Iododesilylation with ICl, direct lactone formation under acidic conditions, and
demethylation gave 5 in high overall yield, which was then recrystallized from MeOH-CHCl3 to give the
enantiomerically pure 5.
Sm(OiPr)3 + 19
(1:1.8) (2 mol %)
OMe
1) ICl
CH2Cl2–CCl4
0 °C
TMSI
H2O (cat.)
N
O
TMSCN (1.2 equiv)
5
7
6
I
O
MeCN
97%
2) HCl–EtOH
90 °C
77% (2 steps)
EtCN–MeCN
–40 °C, 34 h
11–g scale
91%
90% ee
> 99% ee (y. 68%)
after recryst. from
MeOH–CHCl3
HO
24
Scheme 5. Catalytic enantioselective synthesis of Curran's intermediate
Catalytic Enantioselective Synthesis of Corey’s Intermediate
To demonstrate the usefulness of the catalytic enantioselective cyanosilylation of ketones, we applied the
reaction to another convergent synthesis of camptothecin, previously reported by Corey.4 In this first
synthesis of naturally occurring (20S)-camptothecin, an optically pure synthetic intermediate was
obtained through optical resolution. We first developed a convenient and reproducible route for the
synthesis of ketone (13) (Scheme 6), modifying the original synthetic route. The results of catalytic
enantioselective cyanosilylation of 13 using three selected ligands (14, 18, and 19) are summarized in
Scheme 6. In this case, the Gd-catalyst gave better results than the Sm-catalyst,11 and cyanohydrin (12)
was obtained with up to 94% ee using 2 mol % of catalysts. From 12, enantiomerically pure Corey’s
intermediate (11) was obtained in high overall yield as follows. Reduction of the cyanide with DIBAH
followed by acidic desilylation gave lactol (27), which was then oxidized to lactone (28). Direct acid
hydrolysis of 12 to 28 was not successful in this case. Enantiomerically pure 28 was obtained by
recrystallization from a CHCl3-Et2O-hexane mixture. Methoxycarbonylation of the tert-alcohol through a
lithium alkoxide gave enantiomerically pure Corey’s intermediate (11).

1) NaOH (1 equiv.), MeOH, 79%
i
1) DIBAH, CH Cl , 99%
2) BuOCOCl, Et N, THF;
2
2
3
CO Et
2
2) MnO , CH Cl
NaBH , H O, 85%
OTBS
CO Me
2
2
2
OTBS
4
2
O
O
O
3) EtMgBr, THF, 66%
3) TBSCl, imidazol, DMF, 100%
CO Et
2
2
4) Dess-Martin periodinane
25
26
13
O
CH Cl , 85%
2
2
Catalytic Asymmetric Cyanosilylation
i
1) DIBAH, toluene
2) TsOH•H O,
Gd(O Pr) + ligand (14, 18, or 19)
3
(1:2) (2 mol %)
OTBS
CN
2
O
O
14: 94%, 93% ee
18: 100%, 94% ee
19: 96%, 94% ee
O
THF-H O, 89%
TMSCN (1.5 equiv.)
2
OH
EtCN
–40 °C, 18~24 h
HO
TMSO
12
27
O
> 99% ee (y. 77%)
after recryst. from
BuLi; MeOCOCl, THF
76%
NIS, TBAI
CH Cl
O
11
O
2
2
CHCl –Et O–hexane
3 2
HO
28
85%
Scheme 6. Catalytic enantioselective synthesis of Corey's intermediate
Conclusion
We developed two efficient catalytic enantioselective synthetic routes of camptothecin intermediates. The
present work clearly demonstrates the power of our catalytic enantioselective cyanosilylation of ketones.
Because camptothecin and its analogues are extremely important anti-cancer drugs, studies toward the
development of a truly practical synthetic route are currently in progress in our laboratory.
EXPERIMENTAL
General: NMR spectra were recorded on a JEOL JNM-LA500 spectrometer, operating at 500 MHz for
1H NMR, 125.65 MHz for 13C NMR, and 202 MHz for 31P NMR. Chemical shifts were reported
downfield from TMS ( = 0) for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative
to the solvent used as an internal reference. 31P NMR were carried out with phosphoric acid (85%) as an
external standard. Optical rotations were measured on a JASCO P-1010 Polarimeter. Column
chromatographies were performed with silica gel Merck 60 (230-400 mesh ASTM). The enantiomeric
excesses (ee’s) were determined by HPLC analysis. HPLC analysis was performed on JASCO HPLC

systems consisting of the following: pump, 880-PU or PU-980; detector, 875-UV or UV-970, measured at
254 nm; column, DAICEL CHIRALPAK AS, AD, or DAICEL CHIRALCEL OJ, OD; mobile phase,
hexane-2-propanol. In general, reactions were carried out in dry solvents under an argon atmosphere,
unless noted otherwise. Tetrahydrofuran (THF) and toluene were distilled from sodium benzophenone
ketyl. Dichloromethane (CH2Cl2) was distilled from calcium hydride. Other reagents were purified by
usual methods. Lanthanide alkoxide was purchased from Kojundo Chemical Laboratory Co., Ltd. (Fax:
+81-492-84-1351).
[4-Iodo-2-methoxy-6-(trimethylsilyl)pyridin-3-yl]methanol (21): To a solution of NaBH4 (1.1 g, 26.4
mmol) in EtOH (100 mL) at –40 °C was slowly added a solution of known aldehyde (20) (31.8 g, 94.9
mmol)3a in EtOH (50 mL). After stirring for 1 h, the reaction mixture was carefully quenched with brine
and then extracted three times with Et2O. The combined organic extracts were dried over MgSO4. The
solvent was removed under reduced pressure and the residue was purified by flash chromatography
1
(gradient hexane to hexane/AcOEt 91/9) to afford 21 (25.1 g, 78%) as a clear oil. H NMR (300 MHz,
13
CDCl3) δ 0.28 (s, 9H), 2.52 (br s, 1H), 4.01 (s, 3H), 4.81 (s, 2H), 7.53 (s, 1H); C NMR (75 MHz,
CDCl3) δ –1.99, 53.78, 65.32, 11.65, 125.34, 133.19, 160.90, 165.81; IR (film, NaCl, cm-1) 3485, 2960,
1580, 1450, 1039, 839; LRMS (70 eV, EI) m/z (rel int %) 337 (M+), 322 (100), 306, 194, 180, 73. HRMS
m/z calcd for C10H16NO2ISi (M+) 336.9995, found 337.0002.
1-[3-(tert-Butyldimethylsilyloxymethyl)-2-methoxy-6-(trimethylsilanyl)pyridin-4-yl]propan-1-one
(7): To a solution of 21 (2.2 g, 6.5 mmol) and imidazole (1.1 g, 16 mmol) in DMF (3.2 mL) at 0 °C was
added TBDMSCl (1.34 g, 8.9 mmol). The mixture was then heated at 35 °C. After heating for 30 h, the
reaction mixture was quenched with water and then extracted with hexane. The combined organic layers
were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 3.19 g of the
1
crude product (22). The crude product was sufficiently pure for the subsequent reaction. H NMR (300
MHz, CDCl3) δ 0.15 (s, 6H), 0.31 (s, 9H), 0.99 (s, 9H), 3.97 (s, 3H), 4.82 (s, 2H), 7.52 (s, 1H).

i
To a solution of crude 22 (6.5 mmol) in THF (25 mL) at –40 °C, PrMgCl (7.0 mL, 2.0 M in THF) was
added dropwise. The mixture was stirred at –40 °C for 1 h, and then CuCN•2LiCl [prepared from CuCN
(1.2 g, 13.4 mmol) and LiCl (1.16 g, 27.4 mmol)] in THF (30 mL) was added. After 15 min, propionyl
chloride (2.7 mL, 31.5 mmol) was added, and then the reaction was stirred for 1 h at –40 °C and 15 min at
rt. The reaction was quenched with brine and extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified
by flash chromatography (gradient hexane to hexane/Et2O 95/5) to afford 7 (2.04 g, 82%) as a pale yellow
oil. 1H NMR (300 MHz, CDCl3) δ 0.09 (s, 6H), 0.29 (s, 9H). 0.91 (s, 9H), 1.18 (t J = 7.1 Hz, 3H), 2.85 (q,
J = 7.1 Hz, 2H), 3.99 (s, 3H), 4.78 (s, 2H), 6.90 (s, 1H); 13C NMR (75 MHz, CDCl3) δ –1.95, 7.69, 18.59,
25.95, 36.52, 53.36, 57.62, 118.35, 118.97, 148.31, 160.23, 164.4, 207.17; IR (film, NaCl, cm-1) 840.7,
1076.6, 1343.5, 1455.2, 1715.8, 2957.1; LRMS (70 eV, EI) m/z (rel int %) 392 (M+-tBu), 324, 256, 192,
160, 128, 96, 64 (100). HRMS m/z calcd for C15H26NO3Si2 (M+-tBu) 324.1451, found 324.1452.
(S)-1-[3-(tert-Butyldimethylsilyloxymethyl)-2-methoxy-6-(trimethylsilyl)pyridin-4-yl]-2-
(trimethylsilyloxy)butyronitrile (6): Sm(OiPr)3 (0.60 mmol, 0.2 M stock solution in THF) in THF (3.0
mL) was added to a solution of chiral ligand (19) (528 mg, 1.08 mmol) in THF (12 mL) in an ice bath and
the mixture was stirred for 30 min at 45 °C. Cooling to rt, THF was evaporated and the residue was dried
for 1.5 h under vacuum (5 mmHg). Dissolving the residue in propionitrile (5 mL) and acetonitrile (5 mL)
mixture, TMSCN (4.8 mL, 36.0 mmol) was added at –40 °C. After 20 min, a solution of 7 (11.5 g, 30.0
mmol) in propionitrile (5 mL) and acetonitrile (5 mL) mixture was added slowly over 30 min and the
mixture was stirred for 34 h at –40 °C. H2O was added to quench the reaction (caution: HCN is
generated.), and the product and the ligand were extracted with AcOEt. The combined organic layer was
washed with sat. NaCl aq and dried over Na2SO4. Evaporation of the solvent gave a crude oil, which was
purified by SiO2 column chromatography (hexane/Et2O = 400/1 to 200/1) to give pure 6 as colorless oil
(13.2 g, 91%). Enantiomeric excess of 6 was determined by chiral HPLC after conversion to 24 (DAICEL

1
CHIRALPAK AS, hexane/2-propanol = 20/1, 1.0 mL/min, tR 19.6 (minor) and 23.3 min (major)). H
NMR (CDCl3, 500 MHz) δ: 0.11 (s, 3H), 0.12 (s, 3H), 0.17 (s, 9H), 0.29 (s, 9H), 0.89 (s, 9H), 0.99 (t, J =
7.4 Hz, 3H), 2.25 (m, 2H), 3.98 (s, 3H), 4.85 (d, J = 11.0 Hz, 1H), 5.01 (d, J = 11.0 Hz, 1H), 7.34 (s, 1H);
13C NMR (CDCl3, 126 MHz) δ: -5.5, -5.4, -1.9, 0.9, 8.6, 18.5, 25.9, 37.3, 53.3, 55.6, 76.2, 118.5, 119.7,
120.4, 146.9, 153.0, 164.9; IR (neat) ν 2956, 1553, 1448, 1347, 1251, 1132, 1092, 840 cm-1; MS m/z 480
(M+), 423 (M+–tBu); [α]24 –7.87° (c 6.10, CHCl3) (72% ee); HRMS (M+–tBu) Calcd for C19H35N2O3Si3
D
423.1956. Found 423.1942. The ligand and the silylated ligand were eluted from the column with
MeOH/CHCl3, treated with HCl aq in THF, extracted, and purified by SiO2 column chromatography to
recover pure ligand (19) in > 90% yield.
(S)-4-Ethyl-4-hydroxy-6-iodo-8-methoxy-1,4-dihydropyrano[3,4-c]pyridin-3-one (24): To a solution
of 6 (9.13 g, 19.0 mmol) in CH2Cl2 (110 mL), ICl (3.81 mL, 76.0 mmol, 4 equiv) in CCl4 (90 mL) was
added dropwise at 0 °C. After 30 min, the reaction mixture was poured into 5% Na2SO3 aq. + satd. NaCl
aq. (1 L:1 L) at 0 °C. The water layer was extracted with AcOEt and the organic layer was washed with
satd. NaCl aq. The combined organic layer was dried over Na2SO4 and filtration followed by evaporation
gave the crude mixture. This resulting iodide was not stable on silica gel and was used without further
purification.
The crude mixture (10.5 g) was dissolved in half-saturated HCl (g) in EtOH (125 mL) and stirred at 60 °C
for 30 min. Cooled to ambient temperature, the reaction mixture was poured into AcOEt + satd. NaCl aq.
(1:1) at 0 °C. The water layer was extracted with AcOEt and the combined organic layer was dried over
Na2SO4. Filtration, evaporation, followed by purification by silica gel column chromatography
(hexane/AcOEt = 8/1~4/1) gave 24 in 77% yield (2 steps). For the spectroscopic data, see ref. 3a. [α]24
D
+25.2° (c 2.09, CHCl3) (52% ee); HPLC (DAICEL CHIRALPAK AS, hexane/2-propanol = 20/1, 1.0
mL/min) tR 19.6 (minor) and 23.3 (major) min.
(S)-4-Ethyl-4-hydroxy-6-iodo-3-oxo-1H-pyrano[3,4-c]-8-pyridone (5): The conversion of 24 to 5 was

originally reported in ref. 3a. To a solution of 24 (0.718 g, 2.06 mmol) in MeCN (7.5 mL), NaI (0.493 g,
3.29 mmol), TMSCl (0.42 mL, 3.29 mmol), and H2O (18.5 µL, 1.03 mmol) were added at 0 °C. The
mixture was stirred at 65 °C for 2 h and poured into 5% Na2SO3 aq. + brine (1:1). The water layer was
extracted with AcOEt (x4) and the combined organic layers were dried over Na2SO4. Filtration,
concentration, and purification by silica gel column chromatography gave 5 (0.593 g, 97%) as a white
powder. Enantiomerically pure 5 was obtained by recrystallization from MeOH (4 mL) and CHCl3 (0.5
mL) in 68% yield as colorless prisms. [α]29 +53.8° (c 1.01, MeOH) (> 99.5% ee); HPLC (DAICEL
D
CHIRALCEL OJ-H, hexane/2-propanol = 4/1, 0.5 mL/min) tR 22.0 (minor) and 23.7 (major) min.
4-(tert-Butyldimethylsilyloxymethyl)furan-3-carboxylic acid methyl ester (26): To a MeOH (60 mL)
solution of commercially available 25 (5.25 g, 23.5 mmol), NaOH (0.94 g, 23.5 mmol) was added and the
mixture was stirred at rt for 61 h.12 Et2O was added to the reaction mixture and precipitates were filtrated
off. The filtrate was then neutralized by the addition of 1 N HCl at 0 °C and the water layer was extracted
with AcOEt. The combined organic layer was dried over Na2SO4. Filtration, concentration, and
purification though silica gel column chromatography (hexane/Et2O = 4/1 to 1/1) gave the mono-ester in
78% yield (3.1 g). To the mono-ester (1.00 g, 5.88 mmol) solution in THF (10 mL), Et3N (0.9 mL, 6.47
i
mmol) and BuOCOCl (0.84 mL, 6.47 mmol) were added at –20 °C and the mixture was stirred for 15
min. Precipitates were filtrated off and the resulting filtrate was cooled to –20 °C. To the solution, a
solution of NaBH4 (0.334 g, 8.82 mmol) in H2O (4 mL) was added. After 30 min, satd. NH4Cl aq. was
added to quench the reaction, and the water layer was extracted with AcOEt. Concentration and
purification of the resulting crude mixture through silica gel column chromatography (hexane/Et2O = 2/1)
gave the mono-ol in 85% yield (0.782 g). To a solution of the mono-ol (2.56 g, 16.4 mmol) in DMF (7
mL), imidazole (3.35 g, 49.2 mmol) and TBSCl (3.71 g, 24.6 mmol) were added at 0 °C. After stirring for
1 h at rt, H2O was added to quench the reaction and the water layer was extracted with AcOEt.
Concentration and purification through silica gel column chromatography (hexane/Et2O = 80/1 to 40/1)

1
gave 26 in 100% yield (4.43 g). H NMR (CDCl3, 500 MHz) δ: 0.11 (s, 6H), 0.93 (s, 9H), 3.81 (s, 3H),
4.84 (d, J = 1.6 Hz, 2H), 7.39 (dd, J = 1.5, 1.6 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H); 13C NMR (CDCl3, 126
MHz) δ: -5.5, 18.3, 25.9, 51.4, 58.0, 116.7, 126.7, 141.3, 148.7, 163.8; IR (neat) ν 2954, 2858, 1731,
1541 cm-1; MS m/z 239 (M+–OMe), 213 (M+–tBu); HRMS Calcd for C9H13O4Si (M+–tBu) 213.0583.
Found 213.0589.
1-[4-(tert-Butyldimethylsilyloxymethyl)furan-3-yl]propan-1-one (13): To a CH2Cl2 solution (35 mL)
of 26 (3.34 g, 12.4 mmol), DIBAH (1.0 M in toluene, 37.1 mL, 37.1 mmol) was added dropwise for 30
min at –78 °C. After 30 min, H2O was added at –78 °C, followed by the addition of satd. Rochelle salt aq.
The water layer was extracted with AcOEt. The combined organic layer was concentrated and
purification through silica gel column chromatography (hexane/Et2O = 5/1) gave the mono-ol in 100%
yield (3.14 g). 1H NMR (CDCl3, 500 MHz) δ: 0.12 (s, 6H), 0.91 (s, 9H), 3.17 (t, J = 6.1 Hz, 1H), 4.52 (d,
J = 6.1 Hz, 2H), 4.64 (s, 3H), 7.31 (s, 1H), 7.36 (s, 1H); 13C NMR (CDCl3, 126 MHz) δ: -5.4, 18.3, 25.8,
55.2, 56.5, 124.2, 124.9, 140.2, 140.7; IR (neat) ν 3385, 2930, 2858, 1471 cm-1; MS m/z 185 (M+–tBu);
HRMS Calcd for C8H13O3Si (M+–tBu) 185.0634. Found 185.0625.
To the solution of this mono-ol (3.80 g, 15.7 mmol) in CH2Cl2 (60 mL), MnO2 (20.4 g, 0.235 mol + 6.80
g, 0.078 mol + 2.72 g, 0.031 mmol) was added and the mixture was stirred at rt for 18 h. The reaction
mixture was filtrated and concentrated to give the crude aldehyde, which was subjected to the next
1
reaction without purification. H NMR (CDCl3, 500 MHz) δ: 0.10 (s, 6H), 0.93 (s, 9H), 4.85 (d, J = 1.9
13
Hz, 2H), 7.43 (dd J = 1.8, 1.9 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 9.94 (s, 1H); C NMR (CDCl3, 126
MHz) δ: -5.5, 18.3, 25.8, 57.8, 125.7, 126.4, 142.0, 152.7, 185.1.
To a solution of the aldehyde (crude, 3.35 g, 13.9 mmol) in THF (70 mL), EtMgBr (1.0 M in THF, 22.3
mL, 22.3 mmol) was added at –78 °C for 20 min. After 15 min, satd. NH4Cl aq. was added and the water
layer was extracted with AcOEt. The combined organic layer was washed with satd. NaCl aq., dried over
NaSO4, and concentrated. Purification through silica gel column chromatograohy (hexane/Et2O = 20/1)

gave the alcohol in 66% yield (2.78 g) in two steps. 1H NMR (CDCl3, 500 MHz) δ: 0.12 (s, 6H), 0.91 (s,
9H), 0.99 (t, J = 7.3 Hz, 3 H), 1.83 (m, 2H), 3.56 (t, J = 5.5 Hz, 1H), 4.50 (dd, J = 5.5 Hz, 6.2 Hz 1H),
13
4.61 (d, J = 12.6 Hz, 1H), 4.64 (d, J = 12.6 Hz, 1H), 7.29 (s, 2H); C NMR (CDCl3, 126 MHz) δ: -5.4,
10.6, 18.3, 25.8, 29.3, 56.7, 67.6 123.6, 128.0, 140.0, 140.5; IR (neat) ν 3403, 2931, 2858, 1464 cm-1; MS
m/z 213 (M+–tBu); HRMS Calcd for C10H17O3Si (M+–tBu) 213.0947. Found 213.0943.
To a solution of the alcohol (2.73 g, 10.1 mmol) in CH2Cl2 (50 mL), Dess-Martin periodinane (5.57 g,
13.1 mmol) was added at 0 °C and the mixture was stirred for 40 min at rt. Then, satd. NaHCO3 aq. was
added to quench the reaction and precipitates were filtrated off through a celite pad. The water layer was
extracted with CH2Cl2 and the combined organic layer was dried over Na2SO4. Concentration and
purification through silica gel column chromatography (hexane/Et2O =50/1 to 20/1) gave ketone (13) in
93% yield. 1H NMR (CDCl3, 500 MHz) δ: 0.10 (s, 6H), 0.93 (s, 9H), 1.17 (t, J = 7.4 Hz, 3 H), 2.75 (q, J =
7.4 Hz, 2H), 4.87 (d, J = 1.6 Hz, 2H), 7.40 (dd, J = 1.6, 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H); 13C NMR
(CDCl3, 126 MHz) δ: -5.5, 8.1, 18.3, 25.9, 33.4, 58.6, 124.9, 126.9, 141.5, 148.2, 196.5; IR (neat) ν 2938,
1674, 1536, 1143 cm-1; MS m/z 268 (M+), 253 (M+–Me), 211 (M+–tBu, base peak); HRMS Calcd for
C10H15O3Si (M+–tBu) 211.0790. Found 211.0785.
(S)-2-[4-(tert-Butyldimethylsilyloxymethyl)furan-3-yl]-2-(trimethylsilyloxy)butyronitrile
(12):
Gd(OiPr)3 (0.015 mmol, 0.2 M stock solution in THF) in THF (75 µL) was added to a solution of chiral
ligand (19) (15 mg, 0.030 mmol) in THF (0.3 mL) in an ice bath and the mixture was stirred for 30 min at
45 °C. Cooling to rt, THF was evaporated and the residue was dried for 1.5 h under vacuum (5 mmHg).
Dissolving the residue in propionitrile (0.25 mL), TMSCN (0.15 mL, 1.13 mmol) was added at –40 °C.
After 20 min, a propionitrile solution (0.38 mL) of 13 (0.201 g, 0.75 mmol) was added and the mixture
was stirred for 24 h at –40 °C. Workup as described above and purification by column chromatography
gave 12 as colorless oil (0.27 g, 96%). 1H NMR (CDCl3, 500 MHz) δ: 0.09 (s, 3H), 0.10 (s, 3H), 0.18 (s,
9H), 0.91 (s, 9H), 0.98 (t, J = 7.6 Hz, 3H), 1.98-2.15 (m, 2H), 4.62 (d, J = 1.2 Hz, 2H), 7.37 (dd, J = 1.2,

3.1 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ: -5.44, -5.40, 0.87, 8.7, 18.3, 25.8,
36.2, 56.7, 70.7, 120.2, 123.7, 124.6, 141.1, 142.5; IR (neat) ν 2956, 2858, 1464, 1255 cm-1; MS m/z 310
(M+–tBu); HRMS (FAB (PEG)) Calcd for C18H34NO3Si2 (M+H+) 368.2077. Found 368.2082. [α]21
D
–22.8° (c 1.00, CHCl3). Enantiomeric excess was determined after conversion to the corresponding
benzoylamido alcohol (1. LAH, THF; 2. BzCl, Et3N; 3. TBAF) by chiral HPLC (DAICEL CHIRALCEL
OJ-H, hexane/2-propanol = 9/1, 1.0 mL/min, tR 16.0 (minor) and 18.7 min (major)).
(S)-7-Ethyl-6,7-dihydro-4H-furo[3,4-c]pyran-6,7-diol (27): To a solution of 12 (41.7 mg, 0.113 mmol)
in toluene (0.8 mL), DIBAH (1.0 M in toluene, 0.23 mL, 0.23 mmol) solution was added at –78 °C and
the mixture was stirred for 1 h. Then, H2O was added followed by the addition of 1 N HCl (3 mL).
Extraction with AcOEt, drying over Na2SO4, and concentration gave crude aldehyde (41.2 mg), which
was subjected to the following lactol formation. 1H NMR (CDCl3, 500 MHz) δ: 0.08 (s, 6H), 0.15 (s, 9H),
0.89 (t, J = 7.3 Hz, 3 H), 0.92 (s, 9H), 1.88-2.08 (m, 2H), 4.52 (dd, J = 1.2, 13.5 Hz, 1H), 4.58 (dd, J =
1.2, 13.5 Hz, 1H), 7.31 (d, J = 3.1 Hz, 1H), 7.35 (dd, J = 1.2, 3.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz)
δ: -5.4, 2.0, 7.5, 18.3, 25.9, 28.6, 57.4, 82.3, 122.7, 125.0, 141.4, 141.7, 200.0.
To a solution of the crude oil in THF-H2O (9:1, 0.8 mL), TsOH•H2O (4.3 mg, 0.023 mmol) was added
and the mixture was stirred for 13.5 h at rt. Satd. NaHCO3 (3 mL) was added and the water layer was
extracted with AcOEt (x 6). The combined organic layer was dried over Na2SO4 and concentrated.
Purification through silica gel column chromatography (hexane/Et2O = 4/1) gave lactol (27) in 89% yield
(18.5 mg) in 2 steps. 1H NMR (CDCl3, 500 MHz, anomeric mixture, for major isomer) δ: 0.96 (t, J = 7.7
Hz, 3 H), 1.85 (m, 2H), 3.85 ( d, J = 8.9 Hz, 1H), 4.67 (dd, J = 1.5, 14.3 Hz, 1H), 4.86 (dd, J = 1.5, 14.3
Hz, 1H), 4.87 (d, J = 8.9 Hz, 1H), 7.17 (m, 1H), 7.52 (m, 1H); 13C NMR (CDCl3, 126 MHz) δ: 8.2, 29.8,
58.9, 70.0, 95.8, 118.8, 124.5, 134.8, 139.9.
(S)-7-Ethyl-7-hydroxy-4H,7H-furo[3,4-c]pyran-6-one (28): To a solution of 27 (0.344 g, 1.87 mmol)
in CH2Cl2 (15 mL), tetrabutylammonium iodide (1.03 g, 2.80 mmol) and NIS (1.26 g, 5.60 mmol) were

added at 0 °C and the mixture was stirred at rt for 2.5 h. Then, satd. Na2S2O3 aq. was added and the water
layer was extracted with AcOEt. The combined organic layer was dried over Na2SO4 and concentrated.
Purification through silica gel column chromatography (hexane/Et2O = 4/1) gave pure lactone (28) in
85% yield (0.29 g). Enantiomerically pure compound was obtained by recrystallization from CHCl3-Et2O-
1
hexane in 77% yield (0.224 g). H NMR (CDCl3, 500 MHz) δ: 1.01 (t, J = 7.3 Hz, 3 H), 1.85 (m, 2H),
3.41 (s, 1H), 5.35 (dd, J = 1.6, 13.9 Hz, 1H), 5.38 (d, J = 13.9 Hz, 1H), 7.35 (dd, J = 1.5, 1.6 Hz, 1H),
7.51 (d, J = 1.5 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ: 7.3, 32.4, 64.6, 72.6, 115.8, 123.8, 136.3, 138.6,
174.9; IR (KBr) ν 3398, 2971, 1718, 1558, 1381 cm-1; MS m/z 182 (M+), 164 (M+–H2O), 153; mp 61-66
°C; Anal. Calcd for C9H10O4: C, 59.06; H, 5.49. Found: C, 59.34; H, 5.53. [α]21 +9.13° (c 1.01, MeOH);
D
HPLC: DAICEL CHIRALCEL OD-H, hexane/2-propanol = 9/1, 1.0 mL/min, tR 10.4 (minor) and 13.1
min (major).
(S)-2-Ethyl-2-methoxycarbonyloxy-3-oxo-4,8-dioxabicyclo[4.3.0]non-1(9),6-diene (11): To a solution
of enantiomerically pure 28 (40 mg, 0.22 mmol) in THF (3 mL), BuLi (1.55 M in hexane, 0.16 mL, 0.25
mmol) was added at –78 °C and the mixture was stirred for 1 h. To this solution, MeOCOCl (67.9 µL,
0.878 mmol) was added, and after 10 min the reaction temperature was raised to 0 °C. After 30 min, satd.
NaCl aq. was added and the organic layer was extracted with AcOEt. The combined organic layer was
washed with satd. NaCl aq., dried over Na2SO4, and concentrated. Remained 28 was removed by filtration
through a short-pad Al2O3 (neutral), and 11 was obtained by purification through silica gel column
1
chromatography (hexane/Et2O = 5:1) in 76% yield (40 mg). H NMR (CDCl3, 500 MHz) δ: 0.90 (t, J =
7.4 Hz, 3 H), 2.07-2.27 (m, 2H), 3.73 (s, 3H), 5.40 (dd, J = 1.2, 14.5 Hz, 1H), 5.56 (dd, J = 1.2, 14.5 Hz,
13
1H), 7.34 (dd, J = 1.2, 1.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H); C NMR (CDCl3, 126 MHz) δ: 7.6, 33.1,
55.2, 65.2, 116.7, 121.6, 135.6, 138.9, 154.3, 169.1; IR (neat) ν 2979, 1747, 1556, 1443 cm-1; MS m/z
240 (M+); HRMS Calcd for C11H12O6 (M+) 240.0634. Found 240.0624. [α]21D –92.9° (c 1.99, MeOH)

REFERENCES
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S. J. Froelich-Ammon and N. Osheroff, J. Biol. Chem., 1995, 270, 21429.
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5
E. J. Corey, D. N. Crouse, and J. E. Anderson, J. Org. Chem., 1975, 40, 2140. A drawback of their
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Kanai, and M. Shibasaki, J. Am. Chem. Soc., 2000, 122, 7412. (b) Y. Hamashima, M. Kanai, and M.
Shibasaki, Tetrahedron Lett., 2001, 42, 691. For our (S)-selective catalytic enantioselective
cyanosilylation of ketones, see: (c) K. Yabu, S. Masumoto, S. Yamasaki, Y. Hamashima, M. Kanai,
W. Du, D. P. Curran, and M. Shibasaki, J. Am. Chem. Soc., 2001, 123, 9908.
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Isler, M. L. Snapper, and A. H. Hoveyda, Angew. Chem., Int. Ed., 2002, 41, 1009. (b) S.-K. Tian and
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North, T. Parsons, and V. I. Tararov, Tetrahedron, 2001, 57, 771.
6
7
For the preliminary communication, see ref. 5(c) and: K. Yabu, S. Masumoto, M. Kanai, D. P.
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8
9
A. Boudier, L. O. Bromm, M. Lotz, and P. Knochel, Angew. Chem., Int. Ed., 2000, 39, 4414.
It is noteworthy that the optimum lanthanide metal is gadolinium in the catalytic enantioselective
cyanosilylation of simple ketones such as acetophenone.

10 S. Masumoto, K. Yabu, M. Kanai, and M. Shibasaki, Tetahedron Lett., 2002, 43, 2919.
11 For example, the Sm-catalyst (5 mol %) derived from ligand (14) gave 12 in 96% yield with 81% ee
(–40 °C, 20 h).
12 J. A. Edwards, A. Guzman, R. Johnson, P. J. Beeby, and J. H. Fried, Tetrahedron Lett., 1974, 2031.