Effective asymmetric synthesis of the key chiral building blocks of 20(S)- and 20(R)-camptothecins

Article abstract of DOI:10.1007/s00706-011-0617-0

An effective diastereoselective synthesis of (S)- N,N-diethyl-2-formyl-2- (methoxymethoxy)butanamide and (S)-2-formyl-2-(methoxymethoxy)butanoic acid ethyl ester, which are two key chiral building blocks for the synthesis of 20(S)-camptothecins, has been

Full text of DOI:10.1007/s00706-011-0617-0

Monatsh Chem (2012) 143:675–681
DOI 10.1007/s00706-011-0617-0
ORIGINAL PAPER
Effective asymmetric synthesis of the key chiral building blocks
of 20(S)- and 20(R)-camptothecins
•
•
•
Sanbao Yu Xiangjun Feng Yu Luo
Wei Lu
Received: 4 September 2010 / Accepted: 5 August 2011 / Published online: 7 September 2011
Ó Springer-Verlag 2011
Abstract An effective diastereoselective synthesis of (S)-
N,N-diethyl-2-formyl-2-(methoxymethoxy)butanamide and
(S)-2-formyl-2-(methoxymethoxy)butanoic acid ethyl ester,
which are two key chiral building blocks for the synthesis
of 20(S)-camptothecins, has been developed by employing
an asymmetric bromolactonization using (R)-proline. The
(R) compounds were also synthesized to obtain 20(R)-
camptothecin.
gimatecan (4) and belotecan (5), have been highlighted as
potential candidates for anticancer agents [7–10].
Structure–activity relationship studies have shown that
only the (S)-1 enantiomer exhibited biological activity [2].
Many successful asymmetric syntheses of pentacyclic
alkaloids have been reported since Corey et al. first
described the enantioselective total synthesis of 20(S)-
camptothecin by enzymatic resolution [11–21]. Among
these methods, one of the most successful enantioselective
total syntheses of 20(S)-camptothecin is Ciufolini’s 3-cy-
anopyridone protocol. In this method, the key chiral
building block (S)-N,N-diethyl-2-formyl-2-(methoxyme-
thoxy)butanamide (6) (Fig. 2), was prepared from pig liver
esterase [15, 16, 22, 23].
Keywords 20(S)-Camptothecins Á (R)-Proline Á
Asymmetric bromolactonization Á Diastereoselective
synthesis Á (S)-N,N-Diethyl-2-formyl-2-(methoxymethoxy)-
butanamide
In 2000, Jew et al. reported another synthesis of the (S)-
aldehyde 6 employing asymmetric bromolactonization
using (S)-proline as the chiral auxiliary [14]. In this method
(Scheme 1), a-unsaturated acid 8 was used as the key
intermediate, which was prepared from dihydroxyacetone
(9) through seven steps. However, the method exhibits
several disadvantages: (1) expensive organometallic
reagents were used (n-BuLi, DIBAL-H, and n-Bu3SnH),
(2) low temperature was required (-78 °C), and (3) the
reaction time was very long.
Introduction
The pentacyclic alkaloid 20(S)-camptothecin (1) (Fig. 1),
which was isolated from Camptotheca acuminata by
Wall et al., exhibited antitumor activity by trapping a
cleavable complex between topoisomerase I and DNA
[1–3]. Topotecan (2) was approved by the Food and Drug
Administration (FDA) for ovarian cancers and small-cell
lung cancer treatments, and irinotecan (3) was approved
for colorectal tumors [4–7]. Other derivatives, such as
As a part of our efforts toward a new synthetic process of
20(S)-camptothecin and its analogues, we envisioned that the
key chiral building units of (S)-aldehyde 6 could be obtained
from (R)-ethyl 2-bromomethyl-2-hydroxybutanoate (16),
which could be accessible from 2-methylenebutyryl chloride
(12), as shown by retrosynthetic analysis (Scheme 2).
To obtain 20(R)-camptothecin and its analogues, we also
synthesized (R)-N,N-diethyl-2-formyl-2-(methoxymethoxy)-
butanamide (6) and (R)-2-formyl-2-(methoxymethoxy)-
butanoate (7), replacing only (R)-proline with (S)-proline
as the chiral auxiliary. In this paper, we describe a highly
S. Yu Á X. Feng Á Y. Luo (&) Á W. Lu
Department of Chemistry, East China Normal University,
Shanghai 200062, China
e-mail: yluo@chem.ecnu.edu.cn
W. Lu (&)
Institute of Drug Discovery and Development,
East China Normal University, Shanghai 200062, China
e-mail: wlu@chem.ecnu.edu.cn
123

676
S. Yu et al.
R2 R3
Fig. 1 20(S)-Camptothecin,
topotecan, irinotecan,
gimatecan, and belotecan
R1 = R2 = R3 = H
R1 = OH; R2 = CH2N(CH3)2; R3 = H
1
2
R1
O
N
R1 = NOCO ; R2 = H; R3 = Et
N
3
N
4 R1 = R2 = H; R3 = NOC(CH3)3
O
5 R1 = R2 = H; R3 = CH2CH2N(CH3)3
OH O
Fig. 2 The key chiral building
blocks of 20(S)- and 20(R)-
camptothecins
CHO
NEt2
CHO
OEt
CHO
CHO
NEt2
OEt
MOMO
MOMO
MOMO
MOMO
O
O
O
O
(S)-6
(S)-7
(R)-6
(R)-7
Scheme 1
H
O
7 steps
O
4 steps
HOOC
N
O
HO
OH
O
OBn
9
8
BnO
10
OH
6 steps
HOOC
(S)-6
OBn
11
Scheme 2
O
O
BnO
OH
OMOM
Br
OEt
(S)-6
OH
(R)-16
COCl
(S)-20
12
diastereoselective synthetic method for the key chiral
building blocks of 20(S)- and 20(R)-camptothecins (S)-6
and (S)-7, and (R)-6 and (R)-7, respectively (Fig. 2).
To synthesize compound (S)-18 from (R)-16, we firstly
attempted to use NaH in THF with benzyl alcohol, but
failed. To complete the conversion, we prepared an epox-
ide from (R)-ethyl 2-bromomethyl-2-hydroxybutanoate
(16) and then opened the epoxide using benzyl alcohol. In
the epoxidation reaction, we first used K2CO3 as the
reaction reagent, but failed to synthesize the epoxide
(S)-17. Then, CsF was chosen as the reagent and the
reaction was performed at room temperature in a mixed
solvent of THF and CH3CN, and we successfully obtained
the desired compound (S)-17 in a 98% yield. Finally, the
epoxide (S)-17 was opened using benzyl alcohol in the
presence of Mg(ClO4)2 at 50 °C to give (S)-18.
Results and discussion
The synthetic route to (S)-6 is depicted in Scheme 3. The
(S)-aldehyde 6 was obtained from 2-methylenebutyryl
chloride (12), which was accessible according to a known
literature procedure [24]. The condensation of 12 with (R)-
proline as a chiral auxiliary afforded (R)-prolinamide 13,
which was then reacted with N-bromosuccinimide (NBS) in
anhydrous dimethylformamide (DMF) to give the bromo-
lactone 14. Compound 14 was heated under reflux in 40%
HBr to give bromohydrin acid 15. The esterification of 15
under acidic conditions afforded the compound (R)-16.
Next, compound (S)-18 was treated with excess MOMCl
in the presence of diisopropylethylamine to afford (S)-19.
Then, (S)-19 was hydrolyzed to give acid (S)-20 in a
yield of 80% from (S)-17. The conversion of (S)-20 to
123

Effective asymmetric synthesis of the key chiral building blocks
677
Scheme 3
O
O
a
c
b
N
d
N
COOH
Br
OH
O
OH
COCl
O
O
O
Br
15
13
14
12
O
O
O
BnO
OEt
OMOM
e
f
g
Br
OEt
OH
OEt
BnO
OEt
OH
O
16
(R)-
(S)-17
(S)-18
(S)-19
O
O
O
k
h
j
i
BnO
OH
OMOM
BnO
NEt2
OMOM
HO
NEt2
OMOM
(S)-20
CHO
NEt2
MOMO
O
(S)-6
Reagents and conditions: (a) (R)-proline, 2 N aq. NaOH, acetone, -5 - 0 °C, 1 h, then r.t.,
4 h; (b) NBS, DMF, r.t., 16 h; (c) 40% aq. HBr, reflux, 10 h; (d) EtOH, conc. H2SO4
(cat.), reflux, 10 h; (e) CsF, THF:CH3CN = 1:1, r.t., 12 h; (f) benzyl alcohol, Mg(ClO4)2,
50 °C, 12 h; (g) MOMCl, i-Pr2NEt, CH2Cl2, 40 °C, 6 h; (h) 2.5 M NaOH, reflux, 2 h; (i)
Et2NH, TEA, 2-chloro-1-methylpyridinium iodide, CH2Cl2, 0 °C - r.t., 5h; (j) Pd/C, H2,
EtOH, r.t., 6 h; (k) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C to r.t.
Scheme 4
O
O
CHO
OEt
a
b
BnO
OEt
OMOM
HO
OEt
OMOM
MOMO
O
(S)-19
(S)-21
(S)-7
Reagents and conditions: (a) Pd/C, H2, EtOH, r.t., 8 h; (b) (COCl)2, DMSO, TEA,
CH2Cl2, -78 °C to r.t.
(S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butanamide
(6) was achieved according to a reported literature proce-
dure [14].
(R)-19, as depicted in Scheme 6, according to the synthetic
route used for (S)-7.
In conclusion, we have developed an efficient diaste-
reoselective synthetic method for (S)-N,N-diethyl-2-
formyl-2-(methoxymethoxy)butanamide (6) and (S)-2-for-
myl-2-(methoxymethoxy)butanoic acid ethyl ester (7), and
their (R)-enantiomers (R)-6 and (R)-7, respectively, by
employing an epoxidation and ring-opening reaction from
the (R)- and (S)-ethyl 2-bromomethyl-2-hydroxybutanoates
in excellent overall yields. Our total route is highly dia-
stereoselective, the reaction conditions are mild, and the
work-up procedures are simple, thus, we believe that our
new synthetic procedure is suitable for the preparation of
20(S)- and 20(R)-camptothecins in enantiomerically pure
forms.
The key chiral building blocks of (S)-2-formyl-2-
(methoxymethoxy)butanoate (7) were obtained from (S)-
a-MOMoxy ethyl ester 19. Removal of the benzyl group of
(S)-19 using hydrogenolysis led to the (S)-a-hydroxy-
methyl ethyl ester 21. Swern oxidation of (S)-21 provided
the enantiomerically pure (S)-aldehyde 7 (Scheme 4).
(R)-6 was synthesized according to the synthetic route
used for (S)-6 using (S)-proline as the chiral auxiliary.
(S)-Ethyl 2-bromomethyl-2-hydroxybutanoate (16) could
be obtained according to a known literature procedure [24],
and (R)-20 was synthesized from (S)-16, as shown in
Scheme 5. At the same time, (R)-7 was synthesized from
123

678
S. Yu et al.
Scheme 5
O
O
O
b
a
c
OEt
OEt
Br
BnO
OEt
OH
OH
O
(S)-16
(R)-17
(R)-18
O
O
CHO
NEt
Ref. 12c
d
BnO
OEt
OMOM
BnO
OH
OMOM
2
MOMO
O
(R)-19
(R)-20
(R)-6
(a) CsF, THF:CH3CN = 1:1, r.t., 12 h;
Reagents and conditions:
(b) benzyl alcohol, Mg(ClO4)2, 50 °C, 12 h; (c) MOMCl, i-Pr2NEt, CH2Cl2, 40 °C, 6 h;
(d) 2.5 M NaOH, reflux, 2 h.
Scheme 6
O
O
CHO
OEt
a
b
BnO
OEt
OMOM
HO
OEt
OMOM
MOMO
O
(R)-21
(R)-19
(R)-7
Reagents and conditions: (a) Pd/C, H2, EtOH, r.t., 8 h; (b) (COCl)2, DMSO, TEA,
CH2Cl2, -78 °C to r.t.
pale-yellow solid (65.00 g, 90% yield). M.p.: 101–103 °C;
[a]2D0 = ?143.5° cm3 g-1 dm-1 (c = 1.0, CHCl3); 1H
Experimental
NMR (500 MHz, CDCl3): d = 1.06 (t, J = 7 Hz, 3H),
1.87–1.92 (m, 1H), 2.00–2.04 (m, 1H), 2.17–2.20 (m, 1H),
2.30–2.37 (m, 3H), 3.55–3.65 (m, 2H), 4.59–4.61 (m, 1H),
5.11–5.30 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.69, 24.79, 26.40, 28.65, 49.42, 58.88, 114.88,
146.23, 171.979, 174.68 ppm; HRMS-FAB: m/z calcd. for
C10H15NO3 [M]? 197.1052, found 220.0944 [M?Na]?.
Optical rotations were measured with a JASCO DIP-1000
1
digital polarimeter. H NMR spectra were recorded on a
Bruker DRX-500 (500 MHz). 13C NMR spectra were
obtained on a JNM-EX400 (100 MHz). MS spectra were
determined on a Finnigan MAT-95 mass spectrometer. All
reagents were used directly as obtained commercially,
unless otherwise noted. THF was distilled from Na, and
CH2Cl2 and DMF from CaH2.
(3R,8aR)-3-(Bromomethyl)-3-ethyltetrahydro-1H-pyrrolo-
[2,1-c][1,4]oxazine-1,4(3H)-dione (14, C10H14BrO3)
To a solution of 30.00 g 13 (0.15 mol) in 500 cm3
anhydrous DMF was added 54.00 g NBS (0.30 mol) in
portions at r.t. under nitrogen. The reaction mixture was
stirred for 16 h, and then the solvent was removed in vacuo.
The residue was dissolved with 500 cm3 EtOAc and washed
with 5% aq. NaHCO3 (100 cm3 9 2), H2O and brine, and
dried over Na2SO4. Evaporation of the solvent in vacuo
gave compound 14 as a pale-yellow solid (33.50 g, 81%
yield). M.p.: 104–106 °C; [a]2D0 = ?128° cm3 g-1 dm-1
(R)-1-(2-Methylenebutanoyl)pyrrolidine-2-carboxylic acid
(13, C10H15NO3)
To a stirred solution of 42.00 g (R)-proline (0.36 mol) in
220 cm3 2 N aq. NaOH and 220 cm3 acetone, 64.50 g 12
(0.54 mol) in 220 cm3 acetone at -5 to 0 °C was added
dropwise. Aq. NaOH (2 N) was simultaneously added into
the reaction mixture to keep the pH at 10–11. After stirring
at r.t. for 4 h, the acetone was removed under reduced
pressure; the aqueous layer was acidified to pH 2 with
conc. HCl and extracted with EtOAc (300 cm3 9 4). The
combined organic layer was washed with H2O and brine,
and dried over Na2SO4. The solvent was concentrated
under reduced pressure to provide compound 13 as a
1
(c = 1.0, CHCl3); H NMR (500 MHz, CDCl3): d = 0.93
(t, J = 7 Hz, 3H), 1.81–1.85 (m, 1H), 1.97–1.99 (m, 2H),
2.09–2.10 (m, 1H), 2.20–2.24 (m, 1H), 2.49–2.50 (m, 1H),
123

Effective asymmetric synthesis of the key chiral building blocks
679
3.60–3.64 (m, 2H), 3.73–3.76 (m, 1H), 3.88–3.90 (m, 1H),
4.50–4.54 (m, 1H) ppm; 13C NMR (100 MHz, CDCL3):
d = 8.12, 21.40, 29.83, 30.98, 37.81, 1 44.88, 57.81, 89.04,
163.39, 166.53 ppm; HRMS-FAB: m/z calcd. for
C10H14BrO3 [M]? 275.0157, found 276.0230 [M?H]?.
(m, 3H), 1.74–1.78 (m, 1H), 2.08–2.12 (m, 1H), 2.79 (d,
J = 6 Hz, 1H), 3.03 (d, J = 6 Hz, 1H), 4.20–4.30 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3): d = 7.50, 14.03,
24.13, 50.85, 61.80, 67.58, 170.26 ppm; HRMS-FAB: m/z
calcd. for C7H12O3 [M]? 144.0786, found 167.0679
[M?Na]?.
(R)-2-Bromomethyl-2-hydroxybutanoic acid (15)
(R)-enantiomer (R)-17: according to the above procedure,
colorless oil, 97% yield; [a]2D0 = ?12° cm3 g-1 dm-1
(c = 1.0, CHCl3), [26]: [a]2D0 = ?10.7° cm3 g-1 dm-1
A mixture of 16.50 g 14 (0.06 mol) and 150 cm3 40% aq.
HBr was refluxed for 10 h, and then the system was cooled
to r.t., extracted with EtOAc (80 cm3 9 4), and the organic
phase was washed with 200 cm3 sat. aq. NaHCO3. The
alkaline extract was acidified to pH 2 with conc. HCl, and
then extracted with EtOAc again (200 cm3 9 4). The
organic layer was washed with H2O and brine, and dried
over Na2SO4. The solvent was concentrated under reduced
pressure to provide compound 15 as a pale-yellow solid
(8.30 g, 71% yield); [a]2D0 = ?29° cm3 g-1 dm-1 (c = 1.0,
CHCl3). The 1H NMR spectrum was found to be identical to
the one described in [25].
1
(c = 0.67, CHCl3). The H NMR spectrum was found to
be identical to the one described in [26].
(S)-Ethyl 2-[(benzyloxy)methyl]-2-hydroxybutanoate
((S)-18, C14H20O4)
To a mixture of 6.00 g benzyl alcohol (55.60 mmol) and
4.00 g (S)-17 (27.80 mmol) was added 1.60 g magnesium
perchlorate (7.20 mmol) at r.t. The reaction mixture was
stirred at 50 °C for 12 h, and then cooled to r.t. Water
(40 cm3) was added to the reaction solution, and extracted
with EtOAc (40 cm3 9 3). The combined organic extracts
were washed successively with H2O and brine, and then
dried over anhydrous Na2SO4. The solvent was removed in
vacuo and the residue was purified by column chromatog-
raphy (hexane–EtOAc (30:1)) to give (S)-18 as a colorless
oil (4.6 g, 66% yield); [a]2D0 = -5° cm3 g-1 dm-1 (c =
1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d = 0.88
(t, J = 7 Hz, 3H), 1.24–1.31 (m, 3H), 1.59–1.63 (m, 1H),
1.67–1.73 (m, 1H), 3.67 (d, J = 9 Hz, 1H), 3.69 (d,
J = 9 Hz, 1H), 4.20–4.28 (m, 2H), 4.50 (d, J = 8 Hz, 1H),
4.61 (d, J = 8 Hz, 1H), 7.26–7.28 (m, 3H), 7.31–7.34 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3): d = 7.28, 14.17,
27.95, 61.70, 73.41, 75.33, 78.27, 127.47, 127.58, 128.28,
137.85, 174.60 ppm; HRMS-FAB: m/z calcd. for C14H20O4
[M]? 252.1362, found 275.1254 [M?Na]?.
(R)-Ethyl 2-bromomethyl-2-hydroxybutanoate
((R)-16, C7H13BrO3)
A mixture of 8.00 g 15 (0.04 mol), 200 cm3 anhydrous
EtOH, and 0.3 cm3 conc. H2SO4 was refluxed for 10 h, and
then the mixture was cooled to r.t. After the removal of
EtOH under reduced pressure, the residue was diluted with
H2O and extracted with EtOAc (60 cm3 9 3). The com-
bined organic layer was washed successively with 50 cm3
sat. aq. NaHCO3, H2O, and brine, and then dried over
Na2SO4. The solvent was concentrated under reduced
pressure to provide compound (R)-16 as a pale-yellow oil
(8.20 g, 90% yield); [a]2D0 = -5° cm3 g-1 dm-1 (c = 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3): d = 0.89 (t, J =
7 Hz, 3H), 1.29 (t, J = 7 Hz, 3H), 1.68–1.74 (m, 1H),
1.80–1.85 (m, 1H), 3.45 (d, J = 5 Hz, 1H), 3.52 (s, 1H),
3.64 (d, J = 5 Hz, 1H), 4.23–4.31 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 8.23, 14.19, 27.88, 39.46, 61.78,
78.24, 174.62 ppm; HRMS-FAB: m/z calcd. for
C7H13BrO3 [M]? 224.0048, found 246.9940 [M?Na]?.
(R)-enantiomer (R)-18: according to the above proce-
dure, colorless oil, 70% yield; [a]2D0 = ?6° cm3 g-1 dm-1
1
(c = 1.0, CHCl3); H NMR (500 MHz, CDCl3): d = 0.89
(t, J = 8 Hz, 3H), 1.22–1.29 (m, 3H), 1.54–1.63 (m, 1H),
1.68–1.74 (m, 1H), 3.45 (s, 1H), 3.49 (d, J = 8 Hz, 1H),
3.69 (d, J = 8 Hz, 1H), 4.22–4.27 (m, 2H), 4.55 (d,
J = 8 Hz, 1H), 4.61 (d, J = 8 Hz, 1H), 7.27–7.29 (m, 3H),
7.30–7.35 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d = 7.30, 14.16, 29.07, 61.62, 73.35, 75.36, 78.23, 127.50,
127.55, 128.26, 137.90, 174.55 ppm; HRMS-FAB: m/z
calcd. for C14H20O4 [M]? 252.1362, found 275.1278
[M?Na]?.
(S)-2-Ethyloxiran-2-carboxylic acid ethyl ester
((S)-17, C7H12O3)
To a solution of 6.00 g (R)-16 (26.70 mmol) in 100 cm3
anhydrous THF and 100 cm3 anhydrous acetonitrile was
added 13.40 g cesium fluoride (88.20 mmol) at r.t. The
reaction solution was stirred at r.t. for 12 h. Anhydrous
MgSO4 was then added to the reaction mixture. Evapora-
tion of the solvent under reduced pressure gave compound
(S)-17 as a colorless oil (3.7 g, 98% yield), which was used
directly in the next step without purification. A small
sample of (S)-17 was purified by column chromatography
on silica gel (hexane–EtOAc (40:1)) and characterized;
(S)-Ethyl 2-[(benzyloxy)methyl]-2-(methoxymethoxy)-
butanoate ((S)-19, C16H24O5)
To a solution of 3.50 g (S)-18 (13.90 mmol) and 6.5 cm3
MOMCl (85.50 mmol) in 70 cm3 CH2Cl2 was added
20 cm3 diisopropylethylamine (114.50 mmol) in 60 cm3
CH2Cl2 dropwise at r.t. It was heated to 50 °C and stirred
for 8 h, and then cooled to r.t. The mixture was acidified to
[a]2D0 = -12° cm3 g-1 dm-1 (c = 1.0, CHCl3); H NMR
1
(500 MHz, CDCl3): d = 1.01 (t, J = 7 Hz, 3H), 1.26–1.33
123

680
S. Yu et al.
pH 5 with 1 N aq. HCl, the organic phase was washed with
H2O and brine, and dried over MgSO4. The solvent was
removed in vacuo to yield compound (S)-19 as a pale-
yellow oil (3.90 g, 95% yield), which was used directly in
the next step without purification. A small sample of (S)-19
was purified by column chromatography on silica
3H), 3.74–3.78 (m, 2H), 4.53 (s, 2H), 4.84 (d, J = 8 Hz,
1H), 4.91 (d, J = 8 Hz, 1H), 7.24–7.36 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3): d = 7.53, 26.60, 56.23, 71.90,
73.48, 83.10, 92.74, 127.69, 128.31, 130.14, 137.59,
176.12 ppm; HRMS-FAB: m/z calcd. for C14H20O5 [M]?
268.1311, found 291.1210 [M?Na]?.
gel (hexane–EtOAc (30:1)) and characterized; [a]D20
=
(S)-Ethyl 2-(hydroxymethyl)-2-(methoxymethoxy)butanoate
((S)-21, C9H18O5)
?36° cm3 g-1 dm-1 (c = 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3): d = 0.86 (t, J = 7 Hz, 3H), 1.24 (t,
J = 7 Hz, 3H), 1.82–1.88 (m, 2H), 3.39 (s, 3H), 3.71–3.76
(m, 2H), 4.16–4.20 (m, 2H), 4.47–4.55 (m, 2H), 4.78
(d, J = 6 Hz, 1H), 4.90 (d, J = 6 Hz, 1H), 7.25–7.35 (m,
5H) ppm; 13C NMR (100 MHz, CDCl3): d = 7.38, 13.97,
26.77, 55.80, 60.73, 71.67, 73.20, 82.14, 92.83, 127.33,
127.36, 128.08, 137.80, 171.96 ppm; HRMS-FAB: m/z
calcd. for C16H24O5 [M]? 296.1624, found 319.1516
[M?Na]?.
A suspension of 0.08 g Pd/C (10%) and 0.80 g (S)-19
(3.20 mmol) in 10 cm3 ethanol was stirred under hydrogen
for 6 h. After filtration, the solvent was removed in
vacuo to give 17 as a colorless oil (0.40 g, 71% yield);
[a]2D0 = ?46° cm3 g-1 dm-1 (c = 1.0, CHCl3); H NMR
1
(500 MHz, CDCl3): d = 0.84 (t, J = 8 Hz, 3H), 1.23 (t,
J = 7 Hz, 3H), 1.69–1.75 (m, 2H), 3.38–3.41 (m, 4H),
3.65–3.69 (m, 1H), 3.81–3.86 (m, 1H), 4.14–4.20 (m, 2H),
4.69 (d, J = 7 Hz, 1H), 4.96 (d, J = 7 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3): d = 7.57, 14.09, 27.53, 55.80,
61.01, 65.51, 84.57, 93.03, 171.97 ppm; HRMS-FAB: m/z
calcd. for C9H18O5 [M]? 206.1154, found 229.1046
[M?Na]?.
(R)-enantiomer (R)-19: according to the above proce-
dure, pale-yellow oil, 97% yield; [a]2D0 = -39° cm3
g-1 dm-1 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d = 0.98 (t, J = 4 Hz, 3H), 1.27 (t, J = 7 Hz, 3H),
1.80–1.90 (m, 2H), 3.44 (s, 3H), 3.77–3.82 (m, 2H),
4.18–4.23 (m, 2H), 4.52–4.57 (m, 2H), 4.78 (d, J = 7 Hz,
1H), 4.90 (d, J = 7 Hz, 1H), 7.26–7.34 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3): d = 7.60, 14.18, 29.12, 56.01,
60.92, 71.82, 73.38, 82.30, 93.02, 127.53, 127.56, 128.28,
138.01, 172.13 ppm; HRMS-FAB: m/z calcd. for C16H24O5
[M]? 296.1624, found 319.1547 [M?Na]?.
(R)-enantiomer (R)-21: according to the above proce-
dure, pale-yellow oil, 75% yield; [a]2D0 = -46° cm3 g-1
dm-1 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d = 0.88 (t, J = 8 Hz, 3H), 1.27 (t, J = 7 Hz, 3H),
1.74–1.79 (m, 2H), 3.40 (t, J = 7 Hz, 1H), 3.45 (s, 3H),
3.69–3.73 (m, 1H), 3.85–3.90 (m, 1H), 4.19–4.24 (m, 2H),
4.73 (d, J = 8 Hz, 1H), 5.00 (d, J = 8 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3): d = 7.89, 14.32, 27.86, 56.14,
60.83, 65.91, 84.89, 93.34, 172.27 ppm; HRMS-FAB: m/z
calcd. for C9H18O5 [M]? 206.1154, found 229.1065
[M?Na]?.
(S)-2-Benzyloxymethyl-2-(methoxymethoxy)butanoic acid
((S)-20, C14H20O5)
A mixture of 3.00 g (S)-19 (10.10 mmol) and 7.5 cm3
2.5 N aq. NaOH was refluxed for 3 h, and then cooled and
extracted with petroleum ether (30 cm3 9 2). The aqueous
layer was acidified to pH 4 with 1 N aq. HCl, and extracted
with ethyl acetate (60 cm3 9 4). The combined organic
extract was washed successively with H2O and brine, and
dried over Na2SO4. The concentration of the solvent under
reduced pressure gave compound (S)-20 as a pale-yellow
oil (2.30 g, 85% yield); [a]2D0 = ?23° cm3 g-1 dm-1 (c =
1.0, CHCl3) [14]; [a]2D0 = ?18° cm3 g-1 dm-1 (c = 1.0,
(S)-2-Formyl-2-(methoxymethoxy)butanoate
((S)-7, C9H16NO5)
To a cooled (-60 °C) solution of 0.60 cm3 DMSO
(8.70 mmol) in 20 cm3 CH2Cl2 was added a solution of
0.40 cm3 (COCl)2 (6.40 mmol) in 5 cm3 CH2Cl2, and the
mixture was stirred for 30 min. Then, a solution of 0.60 g
(S)-21 (2.90 mmol) in 10 cm3 CH2Cl2 was added drop-
wise, and stirring was continued for 30 min. Then, 2.4 cm3
triethylamine (17.50 mmol) was added slowly. After
stirring for 15 min, the mixture was allowed to reach r.t.
for another 1 h. The reaction was then quenched with
15 cm3 aq. HCl (1 mol/dm3). The organic layer was
washed with brine, dried with Na2SO4, the solvent was
removed in vacuo, and the residue was purified by column
chromatography on silica gel (hexane–EtOAc (10:1)) to
1
CHCl3); H NMR (500 MHz, CDCl3): d = 0.90 (t, J =
7 Hz, 3H), 1.79–1.90 (m, 2H), 3.42 (s, 3H), 3.77–3.79 (m,
2H), 4.53 (s, 2H), 4.84 (d, J = 7 Hz, 1H), 4.92 (d,
J = 7 Hz, 1H), 7.26–7.34 (m, 5H) ppm; 13C NMR
(100 MHz, CDCl3): d = 7.44, 26.43, 56.27, 71.88, 73.48,
83.37, 92.65, 127.70, 128.32, 130.10, 137.45, 175.37 ppm;
HRMS-FAB: m/z calcd. for C14H20O5 [M]? 268.1311,
found 291.1203 [M?Na]?.
give (S)-7 as a yellow oil (0.40 g, 70% yield); [a]D20
=
-51° cm3 g-1 dm-1 (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 1.10 (t, 3H), 1.32 (t, 3H), 2.81–2.86 (m, 2H),
3.48 (s, 3H), 4.27–4.31 (m, 2H), 4.83 (d, J = 7 Hz, 1H),
5.05 (d, J = 7 Hz, 1H), 9.88 (s, 1H) ppm; 13C NMR
(R)-enantiomer (R)-20: according to the above proce-
dure, pale-yellow oil, 83% yield; [a]2D0 = -23° cm3
g-1 dm-1 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d = 0.91 (t, J = 9 Hz, 3H), 1.77–1.87 (m, 2H), 3.43 (s,
123

Effective asymmetric synthesis of the key chiral building blocks
681
6. Takimoto CH, Wright J, Arbuck SG (1998) Biochim Biophys
Acta 1400:107
7. Pommier Y (2009) Chem Rev 109:2894
8. Pratesi G, Beretta GL, Zunino F (2004) Anticancer Drugs 15:545
9. Cesare MD, Pratesi G, Veneroni S, Bergottini R, Zunino F (2004)
Clinical Can Res 10:7357
10. Jew SS, Kim HJ, Kim MG, Roh EY, Cho YS, Kim JK, Cha KH,
Lee KK, Han HJ, Choi JY, Lee H (1996) Bioorg Med Chem Lett
6:845
(100 MHz, CDCl3): d = 7.88, 14.34, 27.86, 56.11, 61.32,
93.29, 105.68, 172.21, 204.58 ppm; HRMS-FAB: m/z
calcd. for C9H16NO5 [M]? 204.0998, found 227.0906
[M?Na]?.
(R)-enantiomer (R)-7: according to the above procedure,
pale-yellow oil, 68% yield; [a]2D0 = ?53° cm3 g-1 dm-1
1
(c = 1.0, CHCl3); H NMR (500 MHz, CDCl3): d = 0.98
(t, 3H), 1.31 (t, 3H), 2.80–2.87 (m, 2H), 3.44 (s, 3H),
4.30–4.33 (m, 2H), 4.83 (d, J = 7 Hz, 1H), 5.06 (d,
J = 7 Hz, 1H), 9.89 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 7.86, 14.37, 27.85, 56.14, 61.38, 93.27,
105.66, 172.20, 204.60 ppm; HRMS-FAB: m/z calcd. for
C9H16NO5 [M]? 204.0998, found 227.0910 [M?Na]?.
11. Corey EJ, Crouse DN, Anderson JE (1975) J Org Chem 40:2140
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J Org Chem 62:6588
18. Imura A, Itoh M, Miyadera A (1998) Tetrahedron Asymmetr
9:2285
Acknowledgments We gratefully acknowledge the Shanghai
Municipal Natural Science Foundation (10ZR1409600). We also
thank the Laboratory of Organic Functional Molecules, the Sino-
French Institute of ECNU for the support.
19. Ejima A, Terasawa H, Sugimori M, Tagawa H (1990) J Chem
Soc Perkin Trans 1:27
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(1995) Tetrahedron Asymmetr 6:1245
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