Efficient synthesis of a configurationally stable L-serinal derivative

Article abstract of DOI:10.1021/jo026653a

An efficient synthesis of a configurationally stable L-serinal derivative 8 was achieved using an N-hydroxymethyl group in about 50% overall yield in four steps from L-serine. Not more than 1% racemization was observed during the preparation of 8. Its enantiomeric integrity was maintained for at least 15 days at room temperature, and it was stable on silica gel. The orthogonal protective groups of 8 would make it a useful chiral synthon.

Full text of DOI:10.1021/jo026653a

Efficien t Syn th esis of a Con figu r a tion a lly
Sta ble L-Ser in a l Der iva tive
Dongwon Yoo, J oon Seok Oh, Dong-Whal Lee, and
Young Gyu Kim*
School of Chemical Engineering, College of Engineering,
Seoul National University, Seoul 151-744, Republic of Korea
ygkim@plaza.snu.ac.kr
F IGURE 1. Known configurationally stable serinals in the
literature.
Received November 4, 2002
Abstr a ct: An efficient synthesis of a configurationally
stable L-serinal derivative 8 was achieved using an N-
hydroxymethyl group in about 50% overall yield in four steps
from L-serine. Not more than 1% racemization was observed
during the preparation of 8. Its enantiomeric integrity was
maintained for at least 15 days at room temperature, and
it was stable on silica gel. The orthogonal protective groups
of 8 would make it a useful chiral synthon.
SCHEME 1. Syn th esis of th e L-Ser in a l Der iva tive 8
R-Amino aldehydes are useful compounds in asym-
metric synthesis and widely used as either chiral syn-
thons or chiral auxiliaries.1 N-Protected serinal, among
others, has been of particular importance because it has
served as a key starting material for the synthesis of
many biologically important molecules such as sphingo-
sine,2a hydroxy-L-glutamic acid,2b kainic acid,2c destomic
acid,2d and hydroxyleucine.2e In addition, the hydroxyl
group in serinal can be utilized for further transforma-
tion.3 However, R-amino aldehydes have been well-known
to be both chemically and configurationally labile because
of the rather acidic proton positioned R to the carbonyl
group.1a,4 Among the configurationally stable serinals
1-4 reported to date (Figure 1),5 the popular Garner
aldehyde (1) and Reetz serinal (2) have been reported to
be problematic in a few cases.6 We report herein an effi-
cient preparation of another configurationally and chemi-
cally stable L-serinal derivative with an N-hydroxymethyl
group and a study of its stability under different condi-
tions. We have shown previously that attachment of the
N-hydroxymethyl group to N-Boc-L-phenylalaninal en-
hanced greatly its configurational stability.7 Particularly,
the enduring stability over two weeks at room temper-
ature was notable. The N-hydroxymethyl group used to
enhance the stability has also been utilized for the ster-
eoselective introduction of the â-hydroxyl group of (-)-
statine.8
First, N-Boc-L-serine (5) was prepared from L-serine
(> 97% ee) under basic conditions, although it is com-
mercially available (Scheme 1). Orthogonal protection of
the hydroxyl group was done with TBDMSCl in DMF to
give a better yield of 6.9 The N-hydroxymethyl group of
oxazolidinone 7 was introduced by heating 6 with
paraformaldehyde in the presence of a catalytic amount
of (()-10-camphorsulfonic acid (CSA).10 The yield in the
two-step sequence was 68%. The use of p-toluenesulfonic
acid (p-TsOH) in place of (()-CSA as an acid catalyst
reduced the yield of 7 by about 15%, probably because of
the more facile deprotection of the Boc or TBDMS group
with p-TsOH.
The reduction reaction of 7 with DIBALH in CH2Cl2
or toluene gave 8 in 70-80% yield. Slow addition of
DIBALH was essential for obtaining good yields of 8 on
a multigram scale. Production of the overreduced diol 9
(see Scheme 2) was significant with large-scale reactions,
and some of the starting compound was also recovered.
Both 7 and 9 could be easily separated from 8 with silica
gel chromatography. Thus, the desired L-serinal deriva-
tive 8 was obtained in about 50% overall yield from
L-serine according to the four-step reaction scheme
(Scheme 1).
(1) For reviews, see: (a) J urczak, J .; Golebiowski, A. Chem. Rev.
1989, 89, 149-164 and references therein. (b) Fisher, L. E.; Muchowski,
J . M. Org. Prep. Proced. Int. 1990, 22, 399-484. (c) Reetz, M. T. Chem.
Rev. 1999, 99, 1121-1162.
(2) (a) Herold, P. Helv. Chim. Acta 1988, 71, 354-362. (b) Garner,
P. Tetrahedron Lett. 1984, 25, 5855-5858. (c) Barco, A.; Benetti, S.;
Pollini, G. P.; Spalluto, G.; Zanirato, V. J . Chem. Soc., Chem. Commun.
1991, 390-391. (d) Golebiowski, A.; Kozak, J .; J urczak, J . J . Org.
Chem. 1991, 56, 7344-7347. (e) Williams, L.; Zhang, Z.; Ding, X.;
J oullie, M. M. Tetrahedron Lett. 1995, 36, 7031-7034.
(3) Bergmeier, S. C.; Seth, P. P. J . Org. Chem. 1997, 62, 2671-2674.
(4) (a) J urczak, J .; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz,
P. Tetrahedron 1998, 54, 6051-6064. (b) Myers, A. G.; Zhong, B.;
Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron
Lett. 2000, 41, 1359-1362 and references therein.
(5) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-1546
and references therein. (c) Lubell, W.; Rapoport, H. J . Org. Chem. 1989,
54, 3824-3831. (d) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc.
1993, 115, 5021-5030.
The reduction of several oxazolidinones similar to 7 in
structure was claimed to give better results with NaBH4
in MeOH or Li(OtBu)3AlH in THF.11 The reduction
(7) Hyun, S. I.; Kim, Y. G. Tetrahedron Lett. 1998, 39, 4299-4302.
(8) Yoo, D.; Oh, J . S.; Kim, Y. G. Org. Lett. 2002, 4, 1213-1215.
(9) Kim, Y.-A.; Oh, S.-M.; Han, S.-Y. Bull. Korean Chem. Soc. 2001,
22, 327-329.
(10) Freidinger, R. M.; Hinkle, J . S.; Perlow, D. S.; Arison, B. H. J .
Org. Chem. 1983, 48, 77-81.
(6) (a) Meffre, P.; Durand, P.; Branquet, E.; Le Goffic, F. Synth.
Comm. 1994, 24, 2147-2152 and references therein. (b) Roush, W. R.;
Hunt, J . A. J . Org. Chem. 1995, 60, 798-806. (c) Aida, M.; He´naff, N.;
Whiting, A. Tetrahedron Lett. 1997, 38, 3101-3102. (d) La¨ıb, T.;
Chastanet, J .; Zhu, J . J . Org. Chem. 1998, 63, 1709-1713.
10.1021/jo026653a CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/08/2003
J . Org. Chem. 2003, 68, 2979-2982
2979

SCHEME 2. Tr a n sfor m a tion of 7, 8, a n d 14 in to th e Mosh er Ester Der iva tive 13
TABLE 1. HP LC Assa y of th e Mosh er Ester 13 fr om th e
Differ en t Sou r ces
TABLE 2. Stor a ge Test of th e L-Ser in a l Der iva tive 8
no.
temp (°C)
time (days)
dr [(S,R)-13:(S,S)-13] (% de)
starting
compound
1
2
3
4
5
-22
2
2
rt
30
15
30
15
30
85.5:1 (97.7)
90.6:1 (97.8)
89.3:1 (97.8)
88.5:1 (97.8)
40.0:1 (95.1)
no.
dr [(S,R)-13:(S,S)-13] (% de)
1
2
3
8
7
14
90.6:1 (97.8)
133:1 (98.5)
1:162 (98.8)
rt
reaction with Li(OtBu)3AlH gave results similar to those
with DIBALH on a small scale. However, the NaBH4
reduction gave mostly a methyl ester derivative of 6 with
the N-hydroxymethyl group (R1 ) TBDMS, R2 ) CH2-
OH, R3 ) Me in Scheme 1) in our hands that was derived
from the opening of the lactone ring with MeOH.
Next, pure 8 obtained after chromatographic separa-
tion was converted into the Mosher ester derivative 13
to check the possibility of racemization during the
DIBALH reduction and the following purification (Scheme
2). The N-hydroxymethyl group (R1) of 9 produced from
the LAH reduction of 8 was removed with 1 N aqueous
NaOH in MeOH in good yield to give 10. Efficient
protection of 10 with 2,2-dimethoxypropane (DMP) in the
presence of (()-CSA gave 11, and desilylation of 11 with
tetrabutylammonium fluoride (TBAF) hydrate resulted
in 12 in excellent yield. It appears that no significant
migration of the TBDMS group takes place during the
formation of 9, 10, or 11 unlike the report in the
literature.6d
The free hydroxyl group of 12 was then coupled with
(S)-R-methoxy-R-(trifluoromethyl)phenylacetic acid (MTPA)
to give (S,R)-13 in the presence of DCC and a catalytic
amount of DMAP in quantitative yield.5a,12 Its diaster-
eomeric purity is shown in Table 1. The diastereomeric
purities of other Mosher esters, (S,R)-13 and (S,S)-13
derived from 7 and 14, respectively (see Scheme 2), are
also given for comparison. Note here that the known ester
14 is prepared from L-serine5a,13 and it is in an enantio-
meric relationship with 12. Careful HPLC analysis of 13
prepared from 8 indicated that not more than 1%
racemization occurred during the preparation of pure 8
(entry 1). The loss of enantiomeric purity seems to be
originated mainly from the DIBALH reduction and the
following purification steps.7 A ca. 0.3% decrease in the
diastereomeric purity was observed with the Mosher
TABLE 3. Sta bility Test of th e L-Ser in a l Der iva tive 8
u n d er Ha r sh Con d ition s
no.
conditions
time (h)
dr [(S,R)-13:(S,S)-13] (% de)
1
2
3
4
5
SiO2/rt
TEA/rt
reflux
SiO2/reflux
TEA/reflux
3
3
3
3
3
97.7:1 (98.0)
50.6:1 (96.1)
82.8:1 (97.6)
66.8:1 (97.1)
30.4:1 (93.6)
ester produced from 7 when compared to that produced
from 14 (Table 1, entry 2 vs entry 3).
Finally, the configurational stability of 8 was tested
under different conditions, and the results are shown in
Tables 2 and 3. In the storage test, 8 obtained after
storage for a certain period at different temperatures was
converted to 13 by applying the same protocol as shown
in Scheme 2 (Table 2). It is evident that the L-serinal
derivative 8 is quite stable both chemically and configu-
rationally at low temperature and shows no racemization
even at room temperature for at least 15 days (entry 4).
However, significant racemization was detected after a
month at room temperature (entry 5).
The stability test under harsh conditions was under-
taken by either stirring at room temperature or heating
a solution of 8 in THF under reflux in the presence of
silica gel or triethylamine (TEA) for 3 h (Table 3). The
same method used for the storage test was employed for
the assay of the enantiomeric purities. At room temper-
ature, it was quite stable with silica gel (entry 1) but
showed about 2% erosion in enantiomeric excess with
base, TEA (entry 2). Its enantiomeric purity remained
practically the same even after refluxing for 3 h in THF
without SiO2 or TEA (entry 3). The presence of SiO2 in
refluxing THF resulted in a little racemization (entry 4).
The racemization was significant with TEA at the re-
fluxing temperature of THF (entry 5). The chemical
stability, however, was sufficiently robust to tolerate all
of the harsh conditions, and no significant decomposition
was observed for any sample. We have also tried to utilize
commercially available N-Boc-O-benzyl-L-serine as a
starting material for the other serinal derivative. How-
(11) (a) Reddy, G. V.; Rao, G. V.; Iyengar, D. S. Tetrahedron Lett.
1999, 40, 2653-2656. (b) Liu, L. T.; Huang, H.-L., Wang, C.-L. J .
Tetrahedron Lett. 2001, 42, 1329-1330.
(12) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(13) Dondoni, A.; Perrone, D. Synthesis 1997, 527-529.
2980 J . Org. Chem., Vol. 68, No. 7, 2003

partitioned between Et2O (2 × 25 mL) and 1 N aqueous HCl
(20 mL), and the phases were separated. The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified with SiO2 column
chromatography eluting with 4:1 hexane/EtOAc to give 6 (1.32
ever, the N-Boc-O-benzyl-L-serinal derivative with the
N-hydroxymethyl group, similar in structure to 8, was
not so stable, and about 3-4% racemization was realized
after the DIBALH reduction and the purification steps
(not shown). The reason the N-Boc-O-benzyl-L-serinal
derivative is less stable than 8 is not clear at the present
time.
g, 85%) as a colorless oil: Rf ) 0.6 (9:1 CH2Cl2/MeOH); [R]26
D
+20.1 (c 0.63, CHCl3); 1H NMR δ 0.08 (s, 6H), 0.89 (s, 9H), 1.46
(s, 9H), 3.80 (dd, 1H, J ) 9.9 and 5.0), 4.10 (dd, 1H, J ) 9.9 and
3.3), 4.35 (m, 1H), 5.36 (d, 1H, J ) 7.7); 13C NMR δ -5.6 (two
peaks), 18.2, 25.7, 28.3, 55.4, 63.5, 80.1, 155.6, 175.8. Anal. Calcd
for C14H29NO5Si: C, 52.63; H, 9.15; N, 4.38. Found: C, 52.35;
H, 9.36; N, 4.27.
In conclusion, an efficient synthesis of the configura-
tionally stable L-serinal derivative 8 was achieved in
about 50% yield in four steps from L-serine, and its
configurational stability was firmly established by the
HPLC analysis of its Mosher ester derivatives. A serinal
derivative of 98% ee could be easily produced, starting
from L-serine of >99% ee according to the present
scheme. Its stability on silica gel would facilitate its
purification with column chromatography, which is often
desirable in the synthesis of complex natural products.
Its durable stability would add more flexibility in syn-
thetic design, too. In addition, use of the L-serinal deriv-
ative of high enantiomeric purity will enhance diaster-
eoselectivity in reactions with other chiral reagents.6b The
orthogonal protective groups on 8 would make it a
versatile chiral synthon as well. The reactivity and
stability of the aldehyde group in its hemiacetal form of
8 have been demonstrated in previous reports.7,8
(4S)-4-[(t-Bu tyld im eth ylsilyloxy)m eth yl]-3-[(1,1-d im eth -
yleth oxy)ca r bon yl]-5-oxa zolid in on e (7). To a solution of 6
(1.32 g, 4.1 mmol) in toluene (40 mL) were added paraformal-
dehyde (1.09 g, 34.1 mmol) and (()-10-camphorsulfonic acid
(CSA, 0.113 g, 0.487 mmol). The reaction mixture was heated
under reflux for about 25 min with azeotropic removal of water.
The reaction mixture was cooled and washed with 1 N aqueous
NaHCO3 (40 mL). The organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
was done with silica gel column chromatography (8:1 hexane/
EtOAc) to give 7 (1.10 g, 80%) as a colorless oil: Rf ) 0.6 (2:1
hexane/EtOAc); [R]26 +121.4 (c 0.85, CHCl3); IR (KBr) 1800,
D
1700 cm-1; 1H NMR (DMSO, 100 °C) δ 0.01 (s, 6H), 0.82 (s, 9H),
1.42 (s, 9H), 3.88 (d, 1H, J ) 10.5), 4.04 (d, 1H, J ) 10.5), 4.22
(br s, 1H), 5.03 (d, 1H, J ) 3.8), 5.36 (d, 1H, J ) 3.8); 13C NMR
δ -5.8, -5.7, 18.0, 25.6, 28.2, 57.7, 61.8, 78.9, 81.7, 151.5, 171.6;
MS (CI) 332 ([M + 1]+, 54), 276 (47), 260 (26), 232 (100), 174
(31), 57 (58); HRMS (CI) calcd for C15H30NO5Si 332.1893 ([M +
1]+), found 332.1902. Anal. Calcd for C15H29NO5Si: C, 54.35; H,
8.82; N, 4.23. Found: C, 54.61; H, 8.80; N, 4.12.
Exp er im en ta l Section
O-t-Bu tyldim eth ylsilyl-N-[(1,1-dim eth yleth oxy)car bon yl]-
N-h yd r oxym eth yl-L-ser in a l (8). To a stirred solution of 7 (0.75
g, 2.26 mmol) in dry CH2Cl2 (35 mL) at -78 °C was added
dropwise a 1.0 M solution of DIBALH in CH2Cl2 (2.49 mL, 2.49
mmol) under a nitrogen atmosphere, and the resulting mixture
was stirred for 30 min. The rate of addition was adjusted so as
to keep the internal temperature below -75 °C. The reaction
was quenched by slowly adding cold MeOH (10 mL). Cold 1 N
aqueous HCl solution (20 mL) was added to the resulting white
emulsion, and the aqueous layer was then extracted with EtOAc
(2 × 50 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification was performed with silica gel column chromatog-
raphy (16:1 hexane/EtOAc) to give a diastereomeric mixture of
8 (0.56 g, 75%) as a white solid: Rf ) 0.5 (2:1 hexane/EtOAc);
Gen er a l Meth od s. Materials were obtained from commercial
suppliers and were used without further purification. Methylene
chloride was distilled from calcium hydride immediately prior
to use. Likewise, THF, benzene, ether, and toluene were distilled
from sodium benzophenone ketyl. DMF was dried with molecular
sieves (4 Å). Air- or moisture-sensitive reactions were conducted
under a nitrogen atmosphere using oven-dried glassware and
the standard syringe/septa technique. The reactions were moni-
tored with a SiO2 TLC plate under UV light (254 nm) followed
by visualization with a molybdenum stain solution. Column
chromatography was performed on silica gel 60 (70-230 mesh).
Optical rotations were determined at ambient temperature with
a digital polarimeter and are the average of five measurements.
1H NMR spectra were measured at 300 MHz in CDCl3 unless
stated otherwise, and data were reported as follows in parts per
million (δ) from the internal standard (TMS, 0.0 ppm): chemical
shift (multiplicity, integration, coupling constant in hertz.).
HPLC analyses were done with a µPorasil silica column.
N-[(1,1-Dim eth yleth oxy)ca r bon yl]-L-ser in e (5). To an ice-
cold solution of L-serine (0.54 g, 5.14 mmol) in a mixture of water
(12 mL), t-BuOH (12 mL), and NaOH (0.23 g, 5.65 mmol) was
added di-tert-butyl dicarbonate (1.23 g, 5.65 mmol) with stirring.
After 1 h at 0 °C, the mixture was warmed to room temperature
and stirred for 10 h. The mixture was concentrated to half its
original volume with vacuum evaporation, and the resulting
concentrate was extracted with pentane. The aqueous phase was
acidified to pH 1-2 by slow addition of cold 1 N KHSO4. The
resulting mixture was extracted with EtOAc (3 × 50 mL). The
combined organic layers were dried over MgSO4, filtered, and
1
IR (KBr) 3400, 1680 cm-1; H NMR (DMSO, 100 °C) δ 0.05 (s,
6H), 0.89 (s, 9H), 1.44 (s, 9H), 3.50 (dd, 1H, J ) 7.9 and 9.5),
3.58 (dd, 1H, J ) 7.9 and 3.3), 3.72 (dd, 1H, J ) 9.0 and 3.3),
4.73 (d, 1H, J ) 3.3), 4.93 (d, 1H, J ) 3.3), 5.36 (d, 1H, J ) 4.4),
6.45 (d, 1H, J ) 5.1); 13C NMR (a mixture of diastereomers) δ
-5.8, -5.5, 17.9, 18.1, 25.6, 25.8, 28.3, 28.4, 61.3, 63.3, 78.1, 80.5,
80.8, 98.9, 152.6; MS (CI) 334 ([M + 1]+, 8), 278 (38), 248 (17),
216 (100), 57 (52); HRMS (CI) calcd for C15H32NO5Si 334.2050,
found 334.2058. Anal. Calcd for C15H31NO5Si: C, 54.02; H, 9.37;
N, 4.20. Found: C, 54.18; H, 9.52; N, 4.16.
P r oced u r e for La r ge-Sca le P r ep a r a tion of 8 by DIBALH
r ed u ction of La cton e 7. To a stirred solution of 7 (5.52 g, 16.7
mmol) in dry CH2Cl2 (167 mL) at -78 °C was added dropwise a
1 M solution of DIBALH in CH2Cl2 (26.6 mL, 26.6 mmol) under
a nitrogen atmosphere with a syringe pump. The addition rate
was 30 mL/h, and the total reaction time was 1 h. The reaction
was quenched with the sequential slow addition of cold MeOH
(25 mL) and water (13 mL). After warming to room temperature,
the reaction mixture was stirred for 1 h (a white gel was formed).
After dilution with EtOAc (100 mL) and MgSO4, the resulting
mixture was stirred for 1 h to facilitate filtration. The mixture
was filtered and concentrated under reduced pressure. Purifica-
tion was performed with silica gel column chromatography (16:1
hexane/EtOAc) to give a diastereomeric mixture of 8 (4.08 g,
74%) as a white solid. The overreduced product diol 9 was
obtained in 10% yield (0.56 g), and the starting material 7 was
recovered in 7% yield (0.38 g).
concentrated to give the crude product as
a colorless oil.
Crystallization in hexane/Et2O afforded 5 (1.00 g, 95%) as a
white solid: mp 90 °C (dec.); Rf ) 0.7 (8:1:1 BuOH/H2O/AcOH);
1H NMR δ 1.45 (s, 9H), 3.86 (d, 1H, J ) 10.5), 4.06 (d, 1H, J )
10.5), 4.34 (br s, 1H), 5.69 (br s, 1H); 13C NMR δ 28.3, 55.5, 62.9,
80.6, 156.2, 174.0. Anal. Calcd for C8H15NO5: C, 46.82; H, 7.37;
N, 6.83. Found: C, 46.64; H, 7.32; N, 6.76.
O-(t-Bu tyld im eth ylsilyl)-N-(1,1-d im eth yleth oxy)ca r bo-
n yl-L-ser in e (6). To an ice-cold solution of 5 (1.00 g, 4.90 mmol)
in DMF (10 mL) were added TBDMSCl (0.96 g, 6.30 mmol) and
imidazole (1.00 g, 14.6 mmol) with stirring under a nitrogen
atmosphere. After 1 h at 0 °C, the mixture was warmed to room
temperature and stirred for 10 h. The reaction mixture was
J . Org. Chem, Vol. 68, No. 7, 2003 2981

O-t-Bu tyldim eth ylsilyl-N-[(1,1-dim eth yleth oxy)car bon yl]-
N-h yd r oxym eth yl-L-ser in ol (9). To an ice-cold suspension of
LiAlH4 (37.8 mg, 1.00 mmol) in ether (3 mL) was added dropwise
a solution of 7 or 8 (150 mg, 0.45 mmol) in ether (2 mL) under
a nitrogen atmosphere. After the mixture was stirred for 20 min
at 0 °C, the reaction was quenched with 1 N aqueous NaOH
(1.5 mL). After MgSO4 was added, the reaction mixture was
stirred for 10 min. The resulting mixture was filtered and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (2:1 hexane/EtOAc) to give
pure diol 9 (106 mg, 70%) as a colorless oil. The yield of this
step was consistently between 50 and 70%: Rf ) 0.25 (2:1
hexane/EtOAc); [R]26D +20.4 (c 0.6, CHCl3); IR (KBr) 3419, 1698,
Rf ) 0.75 (2:1 hexane/EtOAc); [R]30 +33.1 (c 0.7, CHCl3; IR
D
(KBr) 1703 cm-1; H NMR δ 0.06 (s, 6H), 0.89 (s, 9H), 1.47 (s,
1
9H), 1.39-1.54 (m, 6H), 3.39 (m, 1H), 3.68 (m, 2H), 3.76-4.10
(m, 2H); 13C NMR (a mixture of two conformational isomers) δ
-5.3, 18.2, 23.1, 24.6, 25.9, 26.7, 27.4, 28.4, 28.6, 58.4, 58.6, 61.4,
62.2, 64.9, 65.1, 79.7, 80.1, 93.4, 93.9, 151.9, 152.3; MS (CI) 346
([M + 1]+, 100), 246 (95), 232 (46); HRMS (CI) calcd for C17H36
-
NO4Si 346.2395, found 346.2404. Anal. Calcd for C17H35NO4Si:
C, 59.09; H, 10.21; N, 4.05. Found: C, 59.44; H, 10.26; N, 4.20.
(4R)-2,2-Dim et h yl-3-[(1,1-d im et h ylet h oxy)ca r b on yl]-4-
h yd r oxym eth yloxa zolid in e (12). To a solution of 11 (51.5 mg,
0.149 mmol) in THF (5 mL) was added tetrabutylammonium
fluoride (TBAF‚3H2O, 56.4 mg, 0.179 mmol). After 30 min, the
resulting mixture was partitioned between H2O (2 × 50 mL) and
EtOAc (2 × 50 mL), and the phases were separated. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (2:1 hexane/EtOAc) to give
1682 cm-1 1H NMR δ 0.07 (s, 6H), 0.89 (s, 9H), 1.49 (s, 9H),
;
1.70 (br s, 1H), 3.17 (br s, 1H), 3.60-4.10 (m, 5H), 4.20-5.20
(m, 2H); 13C NMR (a mixture of two conformational isomers) δ
-5.7 (two peaks), 18.1, 25.7, 28.2, 59.6, 61.3, 61.7, 61.8, 68.3,
69.7, 80.3, 80.5, 80.8, 80.9, 155.4, 156.1; MS (CI) 336 ([M + 1]+,
4), 318 (77), 262 (94), 218 (100), 160 (32), 57 (48); HRMS (CI)
calcd for C15H34NO5Si 336.2207, found 336.2209. Anal. Calcd for
C15H33NO5Si: C, 53.70; H, 9.91; N, 4.17. Found: C, 53.55; H,
10.08; N, 4.11.
12 (31.7 mg, 92%) as a colorless oil: Rf ) 0.5 (2:1 hexane/EtOAc);
1
[R]30 +24 (c 0.46, CHCl3); IR (KBr) 3458, 1698 cm-1; H NMR
D
δ 1.50 (s, 9H), 1.55-1.69 (br s, 6H), 3.50-4.20 (m, 5H); 13C NMR
δ 24.6, 27.1, 28.4, 59.5, 65.2, 65.3, 81.1, 94.1, 154.2.
O-t-Bu tyldim eth ylsilyl-N-[(1,1-dim eth yleth oxy)car bon yl]-
L-ser in ol (10). To a solution of 9 (75.3 mg, 0.22 mmol) in MeOH
(5 mL) was added 1 N aqueous NaOH solution (1 mL). After
the mixture was stirred for 1 h at room temperature, MeOH
was evaporated. The residue was partitioned between water (2
× 50 mL) and EtOAc (2 × 50 mL), and the phases were
separated. The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (4:1 hexane/
EtOAc) to give pure 10 (48 mg, 70%) as a colorless oil: Rf )
(S)-(-)-MTP A Ester of (4R)-2,2-Dim eth yl-3-[(1,1-d im eth -
ylet h oxy)ca r b on yl]-4-h yd r oxym et h yloxa zolid in e [(S,R)-
13]. To a solution of 12 (30 mg, 0.13 mol), DMAP (1.6 mg, 0.01
mmol), and MTPA (36.4 mg, 0.16 mmol) in dry CH2Cl2 (3 mL)
was added a solution of DCC (53.5 mg, 0.26 mmol) in CH2Cl2 (2
mL). After the mixture was stirred at ambient temperature for
5 h, the resulting white suspension was filtered to remove N,N′-
dicyclohexylurea. The residue was purified by silica gel column
chromatography (9:1 hexane/EtOAc) to give quantitatively (-)-
MTPA ester (S,R)-13 as a colorless oil: Rf ) 0.6 (2:1 hexane/
EtOAc); IR (KBr) 1754, 1703 cm-1; 1H NMR (C6D6, 75 °C) δ 1.40
(br s, 12H), 1.54 (br s, 3H), 3.36 (s, 3H), 3.49 (dd, 1H, J ) 9.3
and 5.9), 3.62 (dd, 1H, J ) 9.3 and 2.0), 3.88 (m, 1H), 4.06 (m,
1H), 4.57 (dd, 1H, J ) 10.3 and 3.4), 7.00-7.40 (m, 4H), 7.60
(br d, 1H, J ) 7.3); 13C NMR (a mixture of two conformational
isomers) δ 23.0, 24.3, 26.6, 27.2, 28.3, 55.1, 55.2, 55.4, 64.1, 64.3,
64.8, 65.1, 80.5, 80.8, 84.7 (q, J ) 29.7), 93.8, 94.1, 123.2 (q, J )
288), 127.3, 128.5, 129.7 (two peaks), 132.0, 151.4, 152.1, 166.1,
166.2. Anal. Calcd for C21H28F3NO6: C, 56.37; H, 6.31; N, 3.13.
Found: C, 56.05; H, 6.42; N, 3.13.
0.45 (2:1 hexane/EtOAc); [R]26 +17.2 (c 0.75, CHCl3); IR (KBr)
D
3449, 3360, 1714, 1694 cm-1
;
1H NMR δ 0.07 (s, 6H), 0.89 (s,
9H), 1.44 (s, 9H), 2.87 (br s, 1H), 3.50-3.90 (m, 5H), 5.15 (br s,
1H); 13C NMR δ -5.6, 18.1, 25.8, 28.3, 52.6, 64.0, 64.1, 79.5,
156.0; MS (CI) 306 ([M + 1]+, 53), 250 (93), 234 (58), 206 (100),
192 (54), 57 (53); HRMS (CI) calcd for C14H32NO4Si 306.2101,
found 306.2098. Anal. Calcd for C14H31NO4Si: C, 55.04; H, 10.23;
N, 4.59. Found: C, 55.42; H, 10.31; N, 4.65.
(4S)-4-[(t-Bu tyld im eth ylsilyloxy)m eth yl]-2,2-d im eth yl-3-
[(1,1-d im eth yleth oxy)ca r bon yl]oxa zolid in e (11). To a solu-
tion of 10 (47.6 mg, 0.156 mmol) in benzene (25 mL) were added
2,2-dimethoxypropane (DMP, 211 mg, 2.03 mmol) and (()-CSA
(0.4 mg, 0.01 equiv). The mixture was heated under reflux for
30 min. After the mixture was concentrated, the same protection
procedure was repeated to complete the reaction as described
above for another 20 min. The resulting mixture was partitioned
between water (2 × 50 mL) and Et2O (2 × 50 mL), and the
phases were separated. The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(20:1 hexane/EtOAc) to give 11 (49 mg, 91%) as a colorless oil:
Ack n ow led gm en t. This work was supported by a
grant from the Korea Health 21 R&D Project, Ministry
of Health & Welfare, Republic of Korea (HMP-98-D-5-
0050), and the Brain Korea 21 Project. We thank also
Pacific Corporation for financial support and Professor
So-Yeop Han at Ewha Womans University for the
helpful discussion about the experimental procedure.
J O026653A
2982 J . Org. Chem., Vol. 68, No. 7, 2003