Enantioselective synthesis of (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide, a key intermediate for 20(S)-camptothecin analogues, via asymmetric bromolactonization

Article abstract of DOI:10.1016/S0957-4166(00)00376-1

A new enantioselective synthetic method for enantiomerically pure (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide 5, a versatile key intermediate has been developed employing asymmetric bromolactonization using (S)-proline as the chiral auxiliary. C

Full text of DOI:10.1016/S0957-4166(00)00376-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3985–3994
Enantioselective synthesis of
(S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide,
a key intermediate for 20(S)-camptothecin analogues,
via asymmetric bromolactonization
Sang-sup Jew,* Eun-young Roh, Hee-jin Kim, Myoung Goo Kim and Hyeung-geun Park*
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 4 August 2000; accepted 18 September 2000
Abstract
A new enantioselective synthetic method for enantiomerically pure (S)-N,N-diethyl-2-formyl-2-
(methoxymethoxy)butyramide 5, a versatile key intermediate has been developed employing asymmetric
bromolactonization using (S)-proline as the chiral auxiliary. © 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Camptothecin 1, a pentacyclic alkaloid with potent antitumor activity, has a peculiar mode of
action trapping a cleavable complex between topoisomerase I and DNA.1 Several camptothecin
derivatives such as 2 (CKD 602),2 3 (lurtotecan),3 and 4 (DX8951f)4 developed through recent
SAR studies have been highlighted as potential candidates for anticancer agents. As only the
20(S)-enantiomer shows biological activity, efficient enantioselective synthetic methods have
been extensively studied. So far a few enantioselective syntheses of 20(S)-camptothecin have
been reported by employing chemical5 or enzymatic resolution,6 asymmetric alkylation7 with
chiral enolates, and catalytic asymmetric dihydroxylation8 as key reactions. Among them,
Ciufolini’s 3-cyanopyridone protocol6b,d,9 providing the best enantioselectivity is one of the most
attractive synthetic methods for 20(S)-camptothecin. (S)-Aldehyde 5 was the key synthetic
intermediate which was prepared by enzymatic (pig liver esterase) resolution.6b,d
* Corresponding author. E-mail: ssjew@plaza.snu.ac.kr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00376-1

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In connection with our development of an efficient synthetic process for CKD 602 2 in phase
II clinical trials, it was envisaged that the (S)-aldehyde 5 could be obtained from (S)-a,a-disub-
stituted-a-hydroxy acid 6 which would be accessible from a,b-unsaturated acid 8 by employing
an asymmetric bromolactonization10 as shown by retrosynthetic analysis (Scheme 1). In this paper,
a highly enantioselective synthetic method for 5 using asymmetric bromolactonization is described.
Scheme 1.
2. Results and discussion
a,b-Unsaturated acid 8, the substrate for asymmetric bromolactonization, was prepared from
dihydroxyacetone 9. Conversion of 9 to tert-butyldimethylsilyl ether 10 using tert-butyldimethyl-
silyl chloride (TBSCl) followed by a Wittig reaction with (ethyl)triphenylphosphonium iodide and
n-butyllithium gave di-tert-butyldimethyloxyalkene 11 in 83% from 9. Deprotection of the TBS
group of 11 with tetrabutylammonium fluoride, followed by acetal formation using benzaldehyde
dimethyl acetal and p-toluenesulfonic acid and subsequent reduction with DIBALH afforded
benzyloxyallylalcohol 14 as a mixture (E:Z=1:1) in 93% yield. Swern oxidation of 14 gave
(E)-a,b-unsaturated aldehyde 15 exclusively, which was converted to the corresponding acid 8
using NaClO2 in the presence of excess 2-methyl-2-butene in 80% from 14 (Scheme 2).
Scheme 2. Reagents and conditions: (a) TBSCl, TEA, CH2Cl2, rt; (b) Ph3PEtI, n-BuLi, THF, 0°C to rt; (c) n-Bu4NF,
THF, rt; (d) C6H5CH(OCH3)2, PTSA, CH2Cl2, reflux; (e) DIBALH, CH2Cl2, −78 to 0°C; (f) (COCl)2, DMSO, TEA,
CH2Cl2, −78 to 0°C; (g) 2-methyl-2-butene, NaClO2, NaH2PO4, t-BuOH, H2O, rt

S. Jew et al. / Tetrahedron: Asymmetry 11 (2000) 3985–3994
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The (S)-aldehyde 5 was obtained from the a,b-unsaturated acid 8 by asymmetric bromo-
lactonization using (S)-proline as the chiral auxiliary (Scheme 3). Compound 8 was coupled with
(S)-proline methyl ester using diethyl phosphorocyanidate in the presence of triethylamine to
give (S)-a,b-unsaturated acyl proline methyl ester 16, [h]2D0=−54 (c 1.0, CHCl3), which was
hydrolyzed to (S)-a,b-unsaturated acyl proline 17, [h]2D0=−97 (c 1.0, CHCl3) in 90% from 8.
Bromolactonization of 17 was performed with n-butyllithium and N-bromosuccinimide in
dimethylformamide to give enantiomerically pure bromolcatone 18, [h]2D0=−29 (c 4.2, CHCl3)
(51%) (vide infra). The bromolactone 18 was debrominated with n-Bu3SnH to provide lactone
7, [h]2D0=−65 (c 1.4, CHCl3) in 95%. The hydrolysis of both the lactone and lactam groups under
basic condition gave (S)-a-hydroxy acid 6, [h]2D0=+12 (c 1.0, CHCl3), in 73% yield. Esterification
of 6 with excess CH2N2 gave (S)-a-hydroxy acid methylester 19, [h]2D0=−3.1 (c 0.78, CHCl3),
which was treated with MOMCl to afford (S)-a-MOMoxy methyl ester 20, [h]2D0=+29 (c 1.0,
CHCl3) in 94% from 6. The methyl ester 20 was hydrolyzed to (S)-a-methoxymethoxy acid 21,
[h]2D0=+18 (c 1.0, CHCl3) in 94% yield. Coupling of 21 and diethylamine using 2-chloro-1-
methylpyridinium iodide afforded (S)-a-methoxymethoxy amide 22, [h]2D0=+33 (c 1.0, CHCl3) in
92% yield. Removal of benzyl group of the (S)-amide 22 by hydrogenolysis led to (S)-a-hydroxy-
methyl amide 23, [h]2D0=+33 (c 1.4, CHCl3). The diastereoselectivity of the asymmetric bromo-
lactonization step (18, >99% ee) was determined by HPLC (Chiral OD column) of 23, which
showed no detectable R enantiomer. Swern oxidation of 23 provided the enantiomerically pure
(S)-aldehyde 5,11 [h]D20=−55 (c 8.0, CHCl3); lit.6a [h]D20=−40.8 (c 10.25, CHCl3) in 95%. The
absolute configuration of C(1%) of 18 was assigned as S by chemical correlation with 5.
Scheme 3. Reagents and conditions: (a) (S)-proline methyl ester, DEPC, TEA, DMF, 0°C–rt; (b) KOH, MeOH–
H2O=1:1, rt; (c) NBS, n-BuLi, DMF, 0°C–rt; (d) n-Bu3SnH, AIBN, benzene, reflux; (e) 3N KOH, reflux; (f) CH2N2,
ether, 0°C–rt; (g) MOMCl, NaH, THF, 0–60°C; (h) KOH, MeOH:H2O=1:1, rt; (i) Et2NH, TEA, 2-chloro-1-
methylpyridinium iodide, CH2Cl2, 0°C–rt; (j) Pd/C, H2, EtOH, rt; (k) (COCl)2, DMSO, TEA, CH2Cl2, −78°C to rt
3. Conclusion
In summary, a new enantioselective synthetic method for enantiomerically pure (S)-N,N-
diethyl-2-formyl-2-(methoxymethoxy)butyramide 5 has been developed via asymmetric bromo-
lactonization using (S)-proline as the chiral auxiliary from a,b-unsaturated acid 8 in 11 steps
(25%, >99% ee). Because of high enantioselectivity, we believe that this new synthetic method
can be applied to prepare various potential 20(S)-camptothecin derivatives 2, 3, and 4 in
enantiomerically pure form.

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4. Experimental
4.1. General
Optical rotations were measured with a JASCO DIP-1000 digital polarimeter. Infrared spectra
were taken on a Perkin–Elmer 1710 FTIR spectrometer. Mass spectra were obtained on a VG
Trio-2 GC–MS instrument; high-resolution mass spectra were obtained on a HP 5890 Series II
1
spectrometer. H and 13C NMR spectra were measured with a JEOL JNM-LA 300, a JEOL
JNM-GCX 400, or a Bruker AMX-500 spectrometer using TMS as the internal standard. All
reactions were carried out under an argon atmosphere, using anhydrous solvents except for
those involving hydrolysis. Most reagents were obtained from commercial suppliers and used
without further purification unless noted. Tetrahydrofuran was distilled from Na0 and ben-
zophenone, and methylene chloride from CaH2.
4.2. 1,3-Bis-(tert-butyl-dimethyl-silanyloxy)-propan-2-one 10
To a methylenechloride solution (100 mL) of dihydroxy acetone (5 g, 55.51 mmol) and TBSCl
(18.5 g, 122.12 mmol) was added triethylamine (17 mL, 55.51 mmol) at 0°C. The reaction
solution was stirred at room temperature (24 h) and diluted with ethyl acetate (500 mL). The
organic solution was washed with sat. aq. NaHCO3 (2×100 mL), water (2×100 mL), and brine
(100 mL), then dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue
was purified by column chromatography (SiO2, hexane–EtOAc (30:1)) to give 10 as a colorless
1
oil (16.84 g, 95% yield): IR (neat) 1744 cm−1; H NMR (CDCl3, 300 MHz) l 4.42 (s, 4H), 0.92
(s, 18H), 0.09 (s, 12H); 13C NMR (CDCl3, 75 MHz) l 214.80, 67.88, 25.71, 18.37; MS (EI) m/e
319 [M++1], HRMS (EI) calcd for C15H34O3Si2 [M++1] 319.2125, found 319.2115.
4.3. 1-(tert-Butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-but-2-ene 11
To a tetrahydrofuran solution (200 ml) of ethyltriphenylphosphonium iodide (42.09, 100.62
mmol) was added n-BuLi (1.6 M in hexane, 63 mL, 100.8 mmol) at −78°C under nitrogen. The
solution was allowed to warm to room temperature and stirred for 20 min, after which it was
recooled to −78°C, and tetrahydrofuran solution of 10 (16 g, 50.31 mmol) was added slowly.
The reaction mixture was allowed to warm to room temperature over 1 h and quenched with
water (100 mL) and extracted with pentane (3×100 mL). The organic layer was washed with
water (2×50 mL), and brine (100 mL), then dried over anhydrous MgSO4. The solvent was
removed in vacuo and the residue was purified by column chromatography (SiO2, hexane–
1
EtOAc (30:1)) to give 11 as a colorless oil (14.85 g, 89% yield): IR (neat) 1074 cm−1; H NMR
(CDCl3, 300 MHz) l 5.56 (q, J=6.8 Hz, 1H), 4.21 (s, 2H), 4.16 (s, 2H), 1.67 (d, J=6.8 Hz, 3H),
0.90 (s, 9H), 0.89 (s, 9H), 0.06 (s, 12H); 13C NMR (CDCl3, 75 MHz) l 138.26, 121.25, 64.86,
58.22, 25.71, 18.40, 12.83; MS (EI) m/e 330 [M+], HRMS (EI) calcd for C17H38O2Si2 [M+]
330.2411, found 330.2434.
4.4. 2-Ethylidene-propane-1,3-diol 12
To the tetrahydrofuran (200 mL) solution of 11 (14 g, 42.42 mmol) was added TBAF (1 M
in THF, 84.84 mL, 84.84 mmol) dropwise at 0°C. The dark reaction mixture was stirred for 1
h at room temperature. 1N aq. HCl (100 mL) and EtOAc (600 mL) were added to the reaction

S. Jew et al. / Tetrahedron: Asymmetry 11 (2000) 3985–3994
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mixture and the organic layer was washed with water (2×50 mL) and brine (100 mL), then dried
over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by
column chromatography (SiO2, EtOAc) to give 12 as a brown oil (4.33 g, 100% yield): IR (neat)
1
3333 cm−1; H NMR (CDCl3, 300 MHz) l 5.65 (q, J=6.8 Hz, 1H), 4.33 (s, 2H), 4.20 (s, 2H),
2.01 (br s, 2H), 1.70 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 137.79, 124.94, 66.12,
58.32, 13.39; MS (EI) m/e 102 [M+], HRMS (EI) calcd for C5H10O2 [M+] 102.0681, found
102.0676.
4.5. 5-Ethylidene-2-phenyl-[1,3]dioxane 13
A methylene chloride solution of 12 (4 g, 39.2 mmol), benzaldehydedimethylacetal (11.77 mL,
78.43 mmol), and catalytic amount of p-toluenesulfonic acid was refluxed for 3 h under
nitrogen. The reaction solution was washed with sat. aq. NaHCO3 (2×20 mL), water (20 mL)
and brine (20 mL), then dried over anhydrous MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography (SiO2, hexane–EtOAc (10:1)) to give 13 as
a colorless oil (7.30 g, 98% yield): IR (neat) 1558 cm−1; 1H NMR (CDCl3, 300 MHz) l 7.51–7.30
(m, 5H), 5.64 (s, 1H), 4.90 (AB q, J=12.7 Hz, 1H), 4.54–4.34 (m, 3H), 1.67 (dt, J=6.8 Hz,
J=1.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 138.18, 133.62, 130.10, 128.41, 126.04, 101.61,
72.41, 65.96, 12.24; MS (EI) m/e 190 [M+], HRMS (EI) calcd for C12H14O2 [M+] 190.0994, found
190.0985.
4.6. 2-Benzyloxymethyl-but-2-en-1-ol 14
To a methylene chloride solution (150 mL) of 13 (7 g, 36.84 mmol) was added DIBAL (1 M
in CH2Cl2, 184 mL, 184 mmol) dropwise at −78°C. It was allowed to warm to 0°C, and stirred
for 2 h. The reaction mixture was quenched with Rochell solution (150 mL) and stirred for 1 h
at room temperature, then poured into EtOAc (300 mL). The organic layer was washed with
water (50 mL) and brine (50 mL), then dried over anhydrous MgSO4. The solvent was removed
in vacuo and the residue was purified by column chromatography (SiO2, hexane–EtOAc (3:1))
1
to give 14 as a mixture of isomers (6.72 g, 95% yield): IR (neat) 3443 cm−1; H NMR (CDCl3,
300 MHz) l 7.35–7.28 (m, 5H), 5.76–5.63 (m, 1H), 4.71, 4.50, 4,28 (3d, 2H, J=6.0 Hz, J=6.0
Hz, J=5.9 Hz, 2H), 4.54, 4.52 (2s, 1H), 4.19, 4.09 (2s, 2H), 2.19, 2.09 (2t, J=5.9 Hz, 6.0 Hz,
1H), 1.73, 1.67 (2d, J=7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 137.87, 135.52, 128.51,
127.61, 127.17, 126.45, 74.78, 72.22, 67.10, 66.59, 59.54, 13.28; MS (EI) m/e 192 [M+], HRMS
(EI) calcd for C12H16O2 [M+] 192.1150, found 195.1133.
4.7. 2-Benzyloxymethyl-but-2-enal 15
To a methylene chloride (150 mL) solution of oxalyl chloride (9.13 mL, 104.69 mmol) was
added Me2SO (14.86 mL, 209.38 mmol) at −78°C. After 30 min, the CH2Cl2 (60 mL) solution
of alcohol 14 (6.7 g, 34.9 mmol) was added at −78°C and stirred for 1 h. Et3N (48.64 mL, 349
mmol) was added and the reation mixture was allowed to warm to room temperture over 1 h.
After the reaction was complete, the methylene chloride was removed in vacuo and the residue
was diluted with EtOAc (400 mL). The organic solution was washed with water (50 mL) and
brine (50 mL), then dried over anhydrous MgSO4. The solvent was removed in vacuo and the
residue was purified by column chromatography (SiO2, hexane–EtOAc (5:1)) to give 15 as a

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1
yellow oil (5.55 g, 80% yield): IR (neat) 1693, 1496 cm−1; H NMR (CDCl3, 300 MHz) l
9.42 (s, 1H), 7.38–7.28 (m, 5H), 6.85 (q, J=7.1 Hz, 1H), 4.53 (s, 2H), 4.25 (2, 2H), 2.09 (d,
J=7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 193.74, 154.86, 140.96, 138.02, 128.34,
127.82, 126.92, 72.81, 60.72, 15.27; MS (EI) m/e 191 [M++1], HRMS (EI) calcd for C12H14O2
[M++1] 191.1072, found 191.1092.
4.8. 1-(2-Benzyloxymethyl-but-2-enoyl)-pyrrolidine-2-carboxylic acid methyl ester 16
To the tert-butanol (300 mL) and 2-methyl-2-butene (58.8 mL, 555.0 mmol) solution of
aldehyde 15 (5.3 g, 27.75 mmol) was added an aqueous solution of sodium chlorite (22.59 g,
249.75 mmol) and sodium dihydrogen phosphate (30.30 g, 194.25 mmol) dropwise over 10
min. The pale yellow reaction mixture was stirred at room temperature for 1 h. After the
solvent was removed in vacuo, the residue was dissolved in water (100 mL) and extracted
with two 20 mL portions of hexane. The aqueous layer was acidified to pH 3 with 1N aq.
HCl and extracted with ether (3×100 mL). The combined ether layers were washed with
water (30 mL), brine (30 mL), dried and concentrated to give 8 as a colorless oil (5.75 g),
which was not purified further. To an N,N-dimethylformamide solution (60 mL) of the crude
acid 8 (5.7 g, 27.54 mmol) and (S)-(−)-methyl prolinate (3.91 g, 30.29 mmol) were added
diethyl phosphorocyanidate (4.60 mL, 30.29 mmol) and triethylamine (4.22 mL, 30.29 mmol)
at 0°C. The reaction mixture was stirred at room temperature for 5 h. The reaction solution
was diluted with ethyl acetate (200 mL) and the ethyl acetate solution was washed with 5%
aq. HCl (30 mL), sat. aq. NaHCO3 (30 mL), water (30 mL) and brine (30 mL), then dried
over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by
column chromatography (SiO2, hexane–EtOAc (2:1)) to give 16 as a colorless oil (7.88 g,
1
90% yield): [h]2D0 −54 (c 1.0, CHCl3); IR (neat) 1746, 1621 cm−1; H NMR (CDCl3, 300 MHz)
l 9.42 (s, 1H), 7.36–7.24 (m, 5H), 6.08 (q, J=6.9 Hz, 1H), 4.59–4.54 (m, 3H), 4.29 (s, 2H),
3.78–3.56 (m, 5H), 2.30–1.70 (m, 7H); 13C NMR (CDCl3, 75 MHz) l 172.79, 170.33, 138.31,
134.69, 131.63, 128.34, 128.23, 127.46, 72.64, 63.54, 58.58, 52.05, 49.17, 29.33, 25.12, 16.08;
MS (EI) m/e 318 [M++1], HRMS (EI) calcd for C18H23NO4 [M++1] 318.1706, found
318.1703.
4.9. 1-(2-Benzyloxymethyl-but-2-enoyl)-pyrrolidine-2-carboxylic acid 17
The methanol–water (1:1, 160 mL) solution of 16 (7.8 g, 24.61 mmol) and 85% potassium
hydroxide (3.25 g, 49.22 mmol) was stirred at room temperature for 3 h. After the methanol
was removed in vacuo, the water layer was acidified to pH 4 with 5% aq. HCl solution (60
mL) and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate solution was
washed with water (50 mL) and brine (50 mL), then dried over anhydrous MgSO4. The
excess solvent was removed in vacuo to give crude 17 as a colorless oil (7.46 g, 100% yield):
[h]2D0 −97 (c 1.0, CHCl3); IR (neat) 1731, 1586 cm−1; H NMR (CDCl3, 300 MHz) l 7.37–
1
7.28 (m, 5H), 6.01 (q, J=7.1 Hz, 1H), 4.64 (m, 1H), 4.53 (s, 2H), 4.28 (s, 2H), 3.69–3.52 (m,
2H), 2.51–2.45 (m, 1H), 2.11–1.78 (m, 6H); 13C NMR (CDCl3, 100 MHz) l 178.18, 174.23,
137.97, 134.46, 128.95, 128.32, 127.73, 72.80, 64.96, 60.42, 49.65, 29.50, 24.91, 14.12; MS (EI)
m/e 304 [M++1], HRMS (EI) calcd for C17H21NO4 [M++1] 304.1549, found 304.1539.

S. Jew et al. / Tetrahedron: Asymmetry 11 (2000) 3985–3994
3991
4.10. 3-Benzyloxymethyl-3-(1-bromo-ethyl)-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione 18
To an N,N-dimethylformamide solution (30 mL) of 17 (5 g, 16.50 mmol) was added n-BuLi
(1.6 M in hexane, 10.3 mL, 16.5 mmol) dropwise at 0°C and then an N,N-dimethylformamide
solution (30 mL) of NBS (11.75 g, 66 mmol) was added. The reaction mixture was stirred at 0°C
for 2 h and room temperature for 24 h. The reaction mixture was quenched with water (5 mL)
and diluted with ethyl acetate (500 mL) and the organic layer was washed with sat. aq. NaHCO3
(2×50 mL), water (5×50 mL), and brine (100 mL), then dried over anhydrous MgSO4. The
excess solvent was removed in vacuo and the residue was purified by column chromatography
(SiO2, hexane–EtOAc (2:1)) to give 18 as a yellow oil (3.21 g, 51% yield): [h]2D0 −29 (c 4.2,
CHCl3); IR (neat) 1723, 1667 cm−1; 1H NMR (CDCl3, 300 MHz) l 7.29–7.18 (m, 5H), 4.49–4.42
(m, 3H), 4.31–4.25 (m, 1H), 3.92 (AB q, J=9.3 Hz, 1H), 3.79–3.70 (m, 2H), 3.43–3.35 (m, 1H),
2.30–2.26 (m, 1H), 1.85–1.59 (m, 7H), other diastereomer was not detected; 13C NMR (CDCl3,
75 MHz) l 165.76, 162.09, 137.14, 128.31, 127.84, 127.69, 90.38, 74.26, 73.79, 58.04, 50.00,
45.47, 29.58, 21.41; MS (EI) m/e 381 [M+], HRMS (EI) calcd for C17H2079BrNO4 [M+] 381.0573,
found 381.0571.
4.11. 3-Benzyloxymethyl-3-ethyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione 7
To a benzene solution (100 mL) of 18 (5 g, 10.09 mmol) was added n-Bu3SnH (10.6 mL, 39.28
mmol) and the reaction mixture was refluxed for 3 h. After the benzene was removed in vacuo,
the crude residue was purified by column chromatography (SiO2, hexane–EtOAc (1:1)) to give
1
7 as a yellow oil (3.77 g, 95% yield): [h]2D0 −65 (c 1.0, CHCl3); IR (neat) 1755, 1650 cm−1; H
NMR (CDCl3, 300 MHz) l 7.37–7.26 (m, 5H), 4.59–4.42 (m, 2H), 4.23–4.09 (m, 1H), 3.94 (AB
q, J=9.8 Hz, 1H), 3.87–3.31 (m, 3H), 2.41–2.27 (m, 1H), 2.17–1.60 (m, 5H), 0.98 (t, J=7.4 Hz,
3H); 13C NMR (CDCl3, 75 MHz) l 167.04, 164.83, 137.60, 128.27, 128.09, 127.65, 89.90, 73.64,
73.54, 57.79, 45.31, 29.58, 27.27, 21.76, 7.66; MS (EI) m/e 303 [M+], HRMS (EI) calcd for
C17H21NO4 [M+] 303.1471, found 303.1497.
4.12. 2-Benzyloxymethyl-2-hydroxy-butyric acid methyl ester 19
A mixture of 3N aq. KOH solution (80 mL) and 7 (3.7 g, 12.21 mmol) was refluxed for 1 day.
The reaction solution was acidified to pH 4 with 1N aq. HCl (250 mL) and extracted with ethyl
acetate (3×300 mL). The combined ethyl acetate solution was washed with water (100 mL) and
brine (100 mL), then dried over anhydrous MgSO4. The excess solvent was removed in vacuo to
give 6 as a yellow oil (2.00 g), which was not purified further. To an ether solution (20 mL) of
the crude acid 6 (1.9 g, 8.48 mmol) was added the ether solution of excess diazomethane at 0°C.
The excess solvent was removed in vacuo and the residue was purified by column chromatogra-
phy (SiO2, hexane–EtOAc (3:1)) to give 19 as a colorless oil (1.98 g, 70% yield): [h]2D0 −3.1 (c
1
0.78, CHCl3); IR (neat) 3519, 1739 cm−1; H NMR (CDCl3, 300 MHz) l 7.32–7.21 (m, 5H),
4.56, 4.46 (AB q, J=12.2 Hz, 2H), 3.73 (s, 3H), 3.65, 3.43 (AB q, J=9.3 Hz, 2H), 3.35 (s, 1H),
1.72–1.51 (m, 2H), 0.83 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 175.10, 137.79,
128.32, 127.65, 127.50, 78.51, 75.23, 73.41, 52.61, 28.00, 7.38; MS (EI) m/e 238 [M+], HRMS
(EI) calcd for C13H18O4 [M+] 238.1205, found 238.1211.

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4.13. 2-Benzyloxymethyl-2-methoxymethoxy-butyric acid methyl ester 20
To a tetrahydrofuran suspension (40 mL) of 95% NaH (403 mg, 15.96 mmol) was added a
tetrahydrofuran solution (10 mL) of 19 (1.9 g, 7.98 mmol) and MOMCl (1.82 mL, 23.94 mmol)
at 0°C. The reaction mixture was refluxed for 4 h. After the solvent was removed in vacuo, the
residue was diluted with ethyl acetate (200 mL). The ethyl acetate solution was washed with
water (20 mL) and brine (20 mL), then dried over anhydrous MgSO4. The solvent was removed
in vacuo and the residue was purified by column chromatography (SiO2, hexane–EtOAc (2:1))
to give 10 as a colorless oil (2.16 g, 96% yield): [h]2D0 +29 (c 1.0, CHCl3); IR (neat) 1747, 1454
1
cm−1; H NMR (CDCl3, 300 MHz) l 7.31–7.24 (m, 5H), 4.88, 4.77 (AB q, J=7.1 Hz, 2H), 4.54,
4.49 (AB q, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.71 (s, 3H), 3.39 (s, 3H), 1.88–1.81 (m, 2H), 0.84 (t,
J=7.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 172.74, 137.89, 128.27, 127.57, 127.54, 92.93,
82.41, 73.35, 71.53, 56.06, 52.00, 26.79, 7.58; MS (EI) m/e 282 [M+], HRMS (EI) calcd for
C15H22O5 [M+] 282.1467, found 282.1459.
4.14. 2-Benzyloxymethyl-N,N-diethyl-2-methoxymethoxy-butyramide 22
A methanol–water (1:1, 40 mL) solution of 20 (2 g, 7.09 mmol) and 85% KOH (936 mg, 13.18
mmol) was stirred at 50°C for 3 h. After the methanol was removed in vacuo, the water layer
was acidified to pH 4 with 1N aq. HCl (20 mL) and extracted with ethyl acetate (3×100 mL).
The combined ethyl acetate solution was washed with water (20 mL) and brine (20 mL), then
dried over anhydrous MgSO4. The excess solvent was removed in vacuo to give 21 as a colorless
oil (1.9 g), which was not purified further. To the methylene chloride (40 mL) solution of the
crude acid 21 (1.8 g, 6.72 mmol), Et2NH (1.39 mL, 13.43 mmol), and Et3N (3.75 mL, 26.88
mmol) was added 2-chloro-N-methylpyridinium iodide (2.58 g, 10.08 mmol) at 0°C. The
reaction solution was stirred for 5 h. After the addition of sat. aq. NaHCO3 (20 mL), the
solution was extracted with EtOAc (3×50 mL). The combined ethyl acetate was washed with
water (20 mL) and brine (20 mL), then dried over anhydrous MgSO4. The solvent was removed
in vacuo and the residue was purified by column chromatography (SiO2, hexane–EtOAc (2:1))
to give 22 as a colorless oil (2.0 g, 92% yield): [h]2D0 +33 (c 1.0, CHCl3); IR (neat) 1622, 1455
1
cm−1; H NMR (CDCl3, 300 MHz) l 7.27–7.19 (m, 5H), 4.68, 4.63 (AB q, J=6.8 Hz, 2H), 4.52,
4.43 (AB q, J=12 Hz, 2H), 3.75 (s, 2H), 3.45–3.17 (m, 7H), 2.16–2.04 (m, 1H), 1.70–1.58 (m,
1H), 1.12–1.02 (m, 6H), 0.74 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 170.30, 138.43,
128.19, 127.54, 127.38, 92.69, 85.01, 73.10, 69.99, 56.38, 41.44, 41.24, 26.30, 14.14, 12.48, 8.07;
MS (EI) m/e 324 [M++1], HRMS (EI) calcd for C18H29NO4 [M++1] 324.2176, found 324.2148.
4.15. N,N-Diethyl-2-hydroxymethyl-2-methoxymethoxy-butyramide 23
An ethanol (60 mL) suspension of Pd/C (10%, 8.83 g) and 22 (1.9 g, 5.88 mmol) was stirred
under hydrogen (1 atm) for 2 h. After filtration through celite, the solvent was removed in vacuo
to give 23 as a colorless oil (1.36 g, 99% yield): [h]2D0 +33 (c 1.4, CHCl3,); IR (neat) 3444, 1615
1
cm−1; H NMR (CDCl3, 300 MHz) l 4.75, 4.66 (AB q, J=6.6 Hz, 2H), 3.92–3.76 (m, 3H),
3.67–3.60 (m, 1H), 3.40–3.30 (m, 4H), 3.24–3.19 (m, 1H), 1.99–1.74 (m, 2H), 1.18–1.09 (m, 6H),
0.91 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 171.62, 93.24, 85.59, 64.16, 56.09, 41.08,
40.71, 26.73, 14.09, 12.54, 8.27; MS (EI) m/e 234 [M++1], HRMS (EI) calcd for C11H23NO4 [M+]
233.1628, found 233.1651; enantiopurity was determined by HPLC analysis using a chiral

S. Jew et al. / Tetrahedron: Asymmetry 11 (2000) 3985–3994
3993
column (Daicel Chiralcel OD) with n-hexane:i-propanol (98:2)(1 mL/min) at 254 nm. It was
established by analysis of racemic that the enantiomers were fully resolved (S, 17.4; R, 19.8 min).
Chiral HPLC analysis showed no detectable R enantiomer.
4.16. N,N-Diethyl-2-formyl-2-methoxymethoxy-butyramide 5
To a methylene chloride solution (20 mL) of oxalyl chloride (1.35 mL, 15.52 mmol was added
Me2SO (2.2 mL, 31.04 mmol)) at −78°C. After 30 min, a methylene chloride solution (10 mL)
of alcohol 23 (600 mg, 32.59 mmol) was added at −78°C. After 1 h, Et3N (7.2 mL, 51.72 mmol)
was added and the reaction solution was allowed to warm to room temperature for 1 h. After
the reaction was complete, the methylene chloride was removed in vacuo and the residue was
dissolved with EtOAc (100 mL). The organic solution was washed with water (20 mL) and brine
(20 mL), then dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue
was purified by column chromatography (SiO2, hexane–EtOAc (3:1)) to give 5 as a yellow oil
1
(574 mg, 96% yield): [h]2D0 −55 (c 8.0, CHCl3); IR (neat) 1715, 1644 cm−1; H NMR (CDCl3, 300
MHz) l 9.66 (s, 1H), 4.75, 4.70 (AB q, J=6.8 Hz, 2H), 3.59–3.23 (m, 7H), 2.28–2.23 (m, 1H),
1.16–1.09 (m, 6H), 0.88 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 195.97, 167.34, 92.80,
86.80, 56.10, 40.57, 40.14, 24.67, 13.45, 12.09, 7.63; MS (EI) m/e 231 [M+], HRMS (EI) calcd for
C11H21NO4 [M++1] 232.1549, found 232.1546.
Acknowledgements
This work was supported by the grants of the Ministry of Health & Welfare, Korea and the
Research Institute of Pharmaceutical Sciences in the College of Pharmacy of Seoul National
University.
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11. Enantiomeric excess of 5 was determined by chiral HPLC of the intermediate compound 23 (Chiral OD column).
Chiral HPLC analysis showed no detectable R enantiomer. n-Hexane:i-propanol (98:2),1 mL/min, 254 nm (S)
17.4 min, (R) 19.8 min.
.