The Firs Enantioselective Synthesis of the cis-2-Carboxy-5-phenylpyrrolidine

Full text of DOI:10.1021/jo980396l

5680
J . Org. Chem. 1998, 63, 5680-5683
Sch em e 1
Th e F ir st En a n tioselective Syn th esis of th e
cis-2-Ca r boxy-5-p h en ylp yr r olid in e
Mansour Haddad, Hassan Imoga¨ı, and
Marc Larcheveˆque*
Laboratoire de Synthe`se organique, UMR 7573 du CNRS,
ENSCP, 11 rue Pierre et Marie Curie,
75231 Paris Cedex 05, France
Received March 2, 1998
Cholecystokynin (CCK) is a polypeptide hormone which
exists in several biologically active forms (CCK-4, CCK-
8, CCK-33, etc.) depending on the number of amino acids
contained in the structure.1,2 It plays an important role
in the digestive tract where it predominantly interacts
with CCK-A receptors,3-5 and also in the central nervous
system where it essentially acts as a neurotransmitter
through CCK-B type receptors.6
Sch em e 2a
Over the past years, a variety of nonpeptide CCK
antagonists have been synthesized, which demonstrates
a great interest in this area.1,2 In particular, the (+)-RP
66803 1, a pyrrolidine derivative, has been prepared
recently by resolution and has had a high affinity for the
CCK receptors.7 The pyrrolidine moiety was obtained by
a nonstereoselective arylation of an acyliminium derived
from proline by an anodic oxidation.
We thought that these substituted 2-carboxypyrro-
lidines would be furnished by the cyclization of stereo-
selectively substituted 1,4-amino alcohols such as 3 after
activation of the hydroxy function. One possible method
for accessing such compounds would be the use of the
Overman rearrangement of appropriate trichloroacetimi-
dates 5 derived from allylic alcohols (Scheme 1).8 This
rearrangement has been widely used for the synthesis
of nitrogen-containing compounds, especially for amino
acids,9 amino sugars,10 and other complex natural prod-
ucts.11
a
Reagents and conditions: (a) (i) DIBAL-H, 1/1 ether/pentane,
-78 °C, (ii) t-BuPh2SiOCH2CtCMgBr, Et2O; (b) Red-Al, ether,
-20 °C; (c) (i) CCl3CN, cat. HNa, Et2O, (ii) xylene, reflux, 6 h; (d)
Bu4NF, THF, 12 h; (e) H2, cat. PtO2, AcOEt; (f) 3 M HCl, MeOH,
40 °C, 30 h; (g) MsCl, Et3N, THF; (h) BnOLi, THF, 65 °C; (i) (i) 1
M J ones reagent, acetone, (ii) CH2N2, Et2O; (j) Me2S, BF3/Et2O,
CH2Cl2, 24 h.
To access the required cis-pyrrolidine by an intra-
molecular substitution, it was necessary to start from a
syn-1,4-amino alcohol. Since the Overman rearrange-
ment takes place through a highly ordered chair transi-
tion state, such a syn-amino alcohol could be obtained
from a syn-(E)-1,2-monoprotected diol with a 1R,2R
configuration.
* To whom correspondence should be adressed. Fax: (33) 143 25
79 75. E-mail: larchm@ext.jussieu.fr.
(1) Nadzan, A. M.; Kerwin, J . F. Annu. Rep. Med. Chem. 1991, 191.
(2) Bo¨hme, G. A.; Blanchard, J . C. Therapie 1992, 47, 541.
(3) Mutt, V. Gastrointestinal Hormones; Raven Press: New York,
1980; p 169.
(4) Morley, J . E. ISI Atlas Sci.: Pharmacol. 1987, 1, 49.
(5) Baile, C.; McLaughlin, C. L.; Della-Ferra, M. A. Physiol. Rev.
1986, 66, 172.
For this purpose, the methyl ester of (R)-mandelic acid
was protected as a MOM ether 6 and reduced into
(6) Grawley, J . N. ISI Atlas Sci.: Pharmacol. 1988, 2, 84.
(7) Manfre´, F.; Pulicani, J . P. Tetrahedron: Asymmetry 1994, 5, 235.
(8) (a) Overman, L. E. J . Am. Chem. Soc. 1974, 96, 597. (b) Overman,
L. E. J . Am. Chem. Soc. 1976, 98, 2901. (c) Overman, L. E. Acc. Chem.
Res. 1980, 13, 218. (d) Overman, L. E. Angew. Chem., Int. Ed. Engl.
1984, 23, 579.
(9) (a) Takano, S.; Akiyama, M.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1984, 770. (b) Mehmandoust, M.; Petit, Y.; Larcheveˆque, M.
Tetrahedron Lett. 1992, 33, 4313. (c) Imoga¨ı, H.; Petit, Y.; Larcheveˆque,
M. Tetrahedron Lett. 1996, 37, 2773. (d) Imoga¨ı, H.; Petit, Y.;
Larcheveˆque, M. Synlett 1997, 615.
(10) (a) Dyong, I.; Weigand, J .; Merten, H. Tetrahedron Lett. 1981,
22, 2965. (b) Roush, W. R.; Straub, J . A.; Brown, R. J . J . Org. Chem.
1987, 52, 5127. (c) Takeda, K.; Kaji, E.; Konda, Y.; Sato, N.; Nakamura,
H.; Miya, N.; Morizane, A.; Yanagisawa, Y.; Akiyama, A.; Zen, S.;
Harigaya, Y. Tetrahedron Lett. 1992, 33, 7145. (d) Takeda, K.; Kaji,
E.; Nakamura, H.; Akiyama, A.; Konda, Y.; Mizuno, Y.; Harigaya, Y.
Synthesis 1996, 341.
(11) For example, see: Danishefsky, S.; Lee, J . Y. J . Am. Chem. Soc.
1989, 111, 4829. (b) Chida, N.; Tsutsumi, N.; Ogawa, S. J . Chem. Soc.,
Chem. Commun. 1995, 793.
S0022-3263(98)00396-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/09/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5681
aldehyde by DIBAL-H at low temperatures. However,
it was not necessary to isolate this, and the magnesium
acetylide derived from a silylated ether of propargylic
alcohol was directly reacted at low temperatures with the
intermediate aluminoxi acetal without hydrolysis accord-
ing to a procedure previously described by Burke.12 Such
a strategy allowed us to obtain the acetylenic alcohol 7
in a 98/2 syn/anti ratio.13 Reduction of this alcohol with
RedAl in ether14 afforded the purely (E)-allylic alcohol 8
in 72% yield. It must be noted that it was necessary to
carry out these reactions at -20 °C to avoid the cleavage
of the silyl ether.
genation in the presence of palladium on charcoal was
unsuccessful and only afforded the opening of the pyr-
rolidine due to the hydrogenolysis of the benzylic C-N
bond. This cleavage was then achieved by reaction with
dimethyl sulfide in the presence of boron trifluoride
according to the method described by Fujita16 and gave
the pyrrolidine 2 which proved to be identical in all
respects to the previously described compound.7
In summary, this synthesis demonstrates that the [3,3]
sigmatropic rearrangement of trichloroacetimidates de-
rived from monoprotected allylic diols allows access to
2,5-disubstituted pyrrolidines by an approach which
offers the potential to functionalize the 3,4-positions of
the pyrrolidine ring.
The alcohol 8 was then reacted with trichloroaceto-
nitrile in the presence of a catalytic amount of sodium
hydride, and the resulting trichloroacetimidate was
submitted to thermal rearrangement by refluxing in
anhydrous xylene. The trichloroacetamide 9 was thus
Exp er im en ta l Section
1
obtained as a single diastereomer as judged by H and
Gen er a l Meth od s. Infrared spectra were taken on a FT-IR
instrument using KBr film. 1H NMR and 13C NMR spectra were
recorded at 200 and 50 MHz, respectively, in CDCl3 unless
specified otherwise. Chemical shifts are expressed in parts per
million from internal TMS. Mass spectra were recorded with a
70 eV ionizing voltage; ammonia was used for chemical ioniza-
tion. Melting points were determined on a Kofler apparatus and
are uncorrected. Flash chromatography was performed using
Merck Kieselgel 60 silica gel (230-400 mesh).
13C NMR. The silyl group was then removed by reaction
with tetrabutylammonium fluoride. A concomitant cleav-
age of the trichloroacetamide resulting from an intra-
molecular nucleophilic addition of the intermediate al-
coholate followed by an elimination of the trichloromethyl
anion afforded the oxazolidinone 10 in one step in
accordance with previous results.9b To effect the cycliza-
tion, the double bond was reduced. Due to the presence
of the OMOM group in both the allylic and benzylic
positions, this reduction was difficult to achieve by
catalytic hydrogenation, and products resulting from
hydrogenolysis were obtained in the presence of pal-
ladium. However, the use of platinum oxide as a catalyst
allowed us to isolate the oxazolidinone 11 in a nearly
quantitative yield.
(1R ,2R )-5-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-1-(m e t h oxy-
m eth oxy)-1-p h en ylp en t-3-yn -2-ol (7). Compound 6 (3.15 g,
15 mmol) was dissolved in Et2O/pentane (1/1, 60 mL) under an
argon atmosphere, cooled to -78 °C, and treated dropwise with
18 mL of DIBAL-H (1 M in hexanes). The mixture was stirred
for 1 h before addition, through cannula, of a Grignard solution
of magnesium acetylide, prepared as follows. An ethereal
solution (30 mL) of protected propargyl alcohol (6.62 g, 22.5
mmol) was treated with 15.46 mL of n-BuLi (1.6 M in hexanes)
at -20 °C under an inert atmosphere. The mixture was stirred
for 1 h at this temperature, warmed to 0 °C, and recooled to
-30 °C. An ethereal magnesium bromide solution, obtained
from magnesium (1.44 g, 60 mmol) and 1,2-dibromoethane (11.16
g, 60 mmol), was then cannulated, and the reaction mixture was
allowed to warm to 23 °C while stirring was continued overnight.
On the next day, the solution was cooled to -20 °C and the
reaction quenched by addition of a 10% HCl solution (30 mL),
and the mixture was diluted with water (50 mL). The organic
extract was washed with brine, dried over MgSO4, and concen-
trated. Flash chromatography (4/1 cyclohexane/EtOAc) gave 7
With 11 in hand, we could then investigate the cy-
clization to pyrrolidine. This cyclization was achieved
in two ways. In the first experiment, the alcohol 12
resulting from the cleavage of the MOM ether was
reacted with diethylazodicarboxylate in the presence of
triphenylphosphine under the conditions of Mitsunobu.15
The corresponding pyrrolidine was obtained, but it was
extremely difficult to separate it from triphenylphosphine
oxide. Alternatively, we decided to activate the alcohol
as a mesylate, and we were pleased to isolate the
cyclization product 13 directly by reaction with mesyl
chloride in THF in the presence of triethylamine without
isolating the intermediate mesylate.
The oxazolidinone was then cleaved with sodium
hydroxide in refluxing methanol to give the free amino
alcohol in 80% yield. However, after several attempts,
we were unable to selectively protect the secondary amine
as a tert-butyl carbamate. Therefore, we set out to modify
our strategy. The oxazolidinone 13 was reacted with
lithium benzylate in refluxing THF to afford the N-
protected pyrrolidine 14 which was in turn oxidized with
J ones reagent into acid and esterified with diazomethane
to give the N-protected proline derivative 15. The
cleavage of the benzyloxycarbamate by catalytic hydro-
(6.2 g, 87%) as an oil: [R]20 ) -66 (c 0.7, CHCl3); IR (film) ν
D
3430 (br), 2955, 2930, 2890, 2860, 1425 cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.07 (s, 9H), 2.72 (d, J ) 5 Hz, 1H), 3.41 (s, 3H), 4.25-
4.38 (m, 2H), 4.48-4.58 (m, 1H), 4.62-4.80 (m, 3H), 7.26-7.50
(m, 10H), 7.65-7.80 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 19.07,
26.60, 52.48, 55.83, 66.49, 80.85, 82.54, 84.90, 94.67, 127.65,
127.90, 128.19, 128.34, 129.74, 132.95, 135.56, 137.14; MS (CI,
NH3) m/z (relative intensity) 492 (M + NH4+, 22%), 198 (100%).
Anal. Calcd for C29H34SiO4: C, 73.38; H, 7.21. Found: C, 73.10;
H, 7.29.
(1R ,2R ,3E )-5-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-1-(m e t h -
oxym eth oxy)-1-p h en ylp en t-3-en -2-ol (8). In a four-necked,
500 mL, round-bottomed flask fitted with a mechanical stirrer,
a thermometer, an addition funnel, and an argon inlet was
placed the propargylic alcohol 7 (4.75 g, 10 mmol) in 100 mL of
anhydrous Et2O. The solution was cooled to -25 °C and treated
via a syringe with a 3.2 M solution of bis(methoxyethoxy)-
aluminum hydride in toluene (4.8 mL, 15 mmol). The reaction,
monitored by HPLC (column, Merck LichroCART 250-4, 100RP-
18.5 mm), was generaly complete within 5 h. The reaction was
quenched by dropwise addition of 1 M H2SO4 (30 mL). The
organic layer was separated and washed with H2O (2 × 50 mL)
and brine (50 mL). After drying (MgSO4), the ethereal phase
was concentrated in vacuo, and the residual oil was chromato-
(12) Burke, S. D.; Deaton, D. N.; Olsen, R. J .; Armistead, D. M.;
Blough, B. E. Tetrahedron Lett. 1987, 28, 3905. For a mechanical aspect
of this reaction, see: Polt, R.; Peterson, M. A.; DeYoung, L. J . Org.
Chem. 1992, 57, 5469.
(13) A similar ratio may be obtained by condensation of a zinc
acetylide; however, this reaction is not compatible with the presence
of a MOM protection which is partially cleaved during the reaction:
Mead, K. T. Tetrahedron Lett. 1987, 28, 1019.
(14) Denmark, S. E.; J ones, T. K. J . Org. Chem. 1982, 47, 4595.
(15) Bernotas, R. C. Tetrahedron Lett. 1990, 31, 469.
(16) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J . Org. Chem. 1979,
44, 1661.

5682 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
graphed (4/1 cyclohexane/AcOEt) to afford the ethylenic com-
The solution was heated at 40 °C for 30 h (reaction monitored
by TLC). The mixture was cooled, diluted with water (40 mL),
and extracted with EtOAc (3 × 30 mL). The combined organic
phases were washed with brine. The usual workup gave a white
pound 8 (3.43 g, 72%): [R]20 ) -40.8 (c 1.24, CHCl3); IR (film)
D
ν 3445, 2955, 2930, 2890, 2855, 1700, 1425 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.12 (s, 9H), 3.16-3.24 (m, 1H), 3.48 (s, 3H),
4.18-4.52 (m, 3H), 4.58 (d, J ) 7.6 Hz, 1H), 4.71 (s, 2H), 5.71-
6.01 (m, 2H), 7.33-7.56 (m, 10H), 7.65-7.82 (m, 5H); 13C NMR
(50 MHz, CDCl3) δ 19.05, 26.64, 55.66, 63.34, 75.11, 82.33, 94.35,
126.81, 127.50, 127.82, 128.01, 128.21, 129.47, 131.18, 133.43,
135.31, 137.90; MS (CI, NH3) m/z (relative intensity) 494 (M +
NH4+, 18%), 342 (100%). Anal. Calcd for C29H36SiO4: C, 73.07;
H, 7.60. Found: C, 73.37; H, 7.75.
solid (0.77 g, 92%): mp 137-138 °C (from CH2Cl2); [R]20
)
D
-53.3 (c 0.92, MeOH); IR (CHBr3) ν 3278 (br), 3128 (br), 3019,
1746 (br) cm-1 1H NMR (200 MHz, DMSO-d6) δ 1.2-1.9 (m,
;
4H), 3.6-4.0 (m, 2H), 4.33 (t, J ) 8.2 Hz, 1H), 4.45-4.65 (m,
1H), 5.23 (d, J ) 4.6 Hz, 1H), 7.1-7.6 (m, 5H), 7.75 (s(br), 1H);
13C NMR (50 MHz, DMSO-d6) δ 31.40, 34.70, 51.61, 69.18, 71.78,
125.75, 126.67, 127.98, 146.15, 158.83; MS (CI, NH3) m/z
(relative intensity) 239 (M + NH4+, 9.1%), 222 (100%). Anal.
Calcd for C12H15NO3: C, 65.14; H, 6.82; N, 6.33. Found: C,
65.01; H, 6.90; N, 6.40.
(5R,7a S)-5-P h en yltetr ah ydr o-1H,3H-pyr r olo[1,2-c]oxazol-
3-on e (13). Alcohol 12 (1 g, 4.52 mmol) and triethylamine (1.26
mL, 9.04 mmol) were dissolved in THF (30 mL), and the mixture
was cooled to 0 °C under argon. Mesyl chloride (525 mL, 6.72
mmol) was added dropwise via a syringe through a septum. The
mixture was allowed to reach 23 °C and stirred for 48 h. The
mixture was partitioned between Et2O and water and extracted
once more with Et2O. The combined organic layers were washed
with brine, dried (MgSO4), and concentrated to give a solid
residue which was flash chromatographed (2/3 cyclohexane/
(1S,2E,4S)-N-[5-[(ter t-Bu t yld ip h en ylsilyl)oxy]-1-(m et h -
oxym eth oxy)-1-p h en ylp en t-2-en -4-yl] 2,2,2-Tr ich lor oa ceta -
m id e (9). A suspension of sodium hydride (116 mg of a 60%
dispersion in mineral oil, 2.89 mmol), which had been previously
washed three times with pentane, was placed into 40 mL of
anhydrous ether and treated dropwise with an ether solution of
8 (2.76 g, 5.79 mmol). The mixture was stirred for 15 min before
being cooled to -5 °C, and trichloroacetonitrile (0.87 mL, 8.68
mL) was added dropwise. The solution was allowed to warm to
23 °C and then concentrated. Pentane [30 mL containing
methanol (0.117 mL, 2.89 mmol)] was added and the mixture
stirred vigorously for 2 min before being filtered through a pad
of Celite. Evaporation of the solvent gave the crude imidate
which was used without purification. Thus, the above imidate
was dissolved in xylene (40 mL) and heated at reflux for 6 h.
After cooling, the solvent was evaporated in vacuo and the dark
residue purified by flash chromatography (9/1 cyclohexane/
AcOEt) to afford the compound 9 as a pale yellow solid (2.5 g,
EtOAc) to give a white crystal (551 mg, 60%): mp 145 °C; [R]20
D
) +23.4 (c 0.9, CH2Cl2); IR (CHBr3) ν 3020, 1725, 1140 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.8-2.25 (m, 3H), 2.52-2.8 (m,
1H), 4.12-4.30 (m, 1H), 4.31-4.52 (m, 1H), 4.52-4.67 (m, 1H),
4.72 (dd, J ) 8.85 Hz, 1H), 7.12-7.47 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 28.66, 39.0, 58.56, 61.03, 69.51, 126.33, 127.71,
128.67, 140.05, 155.06; MS (CI, NH3) m/z (relative intensity) 204
(M + H+, 100%). Anal. Calcd for C12H13NO2: C, 70.92; H, 6.44;
N, 6.89. Found: C, 70.86; H, 6.45; N, 6.98.
70%): mp 98 °C; [R]20 ) +7.4 (c 1.11, CH2Cl2); IR (CHBr3) ν
D
3420, 3020, 1715, 1500, 1140, 1120, 1030 cm-1
;
1H NMR (200
MHz, CDCl3) δ 1.14 (s, 9H), 3.46 (s, 3H), 3.90 (AB part of ABX
system, J AB ) 10.4 Hz, 2H), 4.57-4.87 (m, 1H + AB system,
J AB ) 6.7 Hz, 2H), 5.26 (d, J ) 4.6 Hz, 1H), 5.88-6.08 (m, 2H),
7.29-7.58 (m, 10H), 7.63-7.8 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 19.06, 26.61, 53.67, 55.33, 65.04, 76.83, 92.62, 93.49,
126.98, 127.77, 128.03, 128.37, 129.90, 132.22, 132.33, 132.96,
133.24, 134.67, 135.31, 135.36, 140.00, 160.90; MS (CI, NH3) m/z
(relative intensity) 637 (M + NH2-, 100%). Anal. Calcd for
(2S,5R)-N-(Ben zyloxyca r b on yl)-2-(h yd r oxym et h yl)-5-
p h en ylp yr r olid in e (14). To a stirred solution of benzyl alcohol
(383 mg, 3.54 mmol) in THF (20 mL) at 0 °C (ice bath) was added
a 1.6 M hexanes solution of n-butyllithium (2.2 mL, 3.54 mmol).
The bath was removed, and the solution was stirred for 30 min.
Bicyclic compound 13 (480 mg, 2.36 mmol) diluted in THF (3
mL) was then added via a syringe, and the mixture was refluxed
for 15 h. After cooling, the solution was diluted with water (40
mL) and extracted with CHCl3 (2 × 30 mL). The usual workup
gave a crude oil which was purified by flash chromatography
(3/2 cyclohexane/EtOAc) giving a colorless oil (397 mg, 54%):
C
31H36Cl3NO4Si: C, 59.95; H, 5.83; N, 2.25. Found: C, 59.94;
H, 5.84; N, 2.21.
(1′E,3′S,4S)-4-[3-(Meth oxym eth oxy)-3-p h en ylp r op en yl]-
oxa zolid in -2-on e (10). To a stirred solution of compound 9
(2.51 g, 4.04 mmol) in THF (30 mL) at 23 °C was added n-Bu4-
NF in THF (1 M, 6 mL, 6.0 mmol). The mixture was stirred
overnight and diluted with water (50 mL). The product was
extracted with Et2O (2 × 40 mL) and dried over MgSO4, and
the solvent was evaporated in vacuo. Flash chromatography (3/7
cyclohexane/AcOEt) yielded the title compound (0.85 g, 80%) as
an oil: [R]20D ) -28.1 (c 1.12, CH2Cl2); IR (CHBr3) ν 3010, 1750,
[R]20 ) +23.3 (c 1.455, CH2Cl2); IR (CHBr3) ν 3440 (br), 3140,
D
1690 (br), 1460, 1420, 1360, 1150 cm-1
;
1H NMR (200 MHz,
CDCl3) δ 1.6-2.15 (m, 3H), 2.17-2.45 (m, 1H), 3.65-4.05 (m,
2H), 4.1-4.32 (m, 1H), 4.6-5.2 (m, 4H), 6.7-7.45 (m, 10H); 13
C
NMR (50 MHz, CDCl3) δ 26.82, 33.91, 62.02, 62.87, 66.17, 66.98,
125.38, 126.62, 127.14, 127.51, 128.02, 128.23, 135.88, 143.22,
157.18; MS (CI, NH3) m/z (relative intensity) 312 (M + H+,
100%). Anal. Calcd for C19H21NO3: C, 73.29; H, 6.79; N, 4.5.
Found: C, 73.78; H, 6.88; N, 4.33.
1400, 1140 cm-1 1H NMR (200 MHz, CDCl3) δ 3.35 (s, 3H),
;
3.95-4.2 (m, 1H), 4.3-4.7 (m, 2H + AB system, J AB ) 6.6 Hz,
2H), 5.11 (d, J ) 5.8 Hz, 1H), 5.71, (dd, J ) 6.6, 15.4 Hz, 1H),
5.88 (dd, J ) 6, 15.4 Hz, 1H), 6.22-6.45 (m, 1H), 7.25-7.45 (m,
5H); 13C NMR (50 MHz, CDCl3) δ 54.14, 55.47, 69.94, 76.62,
93.63, 126.99, 127.99, 128.56, 129.18, 134.68, 139.67, 159.48; MS
(CI, NH3) m/z (relative intensity) 281 (M + NH4+, 14.7%), 202
(100%). Anal. Calcd for C14H17NO4: C, 63.87; H, 6.50; N, 5.32.
Found: C, 63.75; H, 6.58; N, 5.21.
Meth yl (2S,5R)-N-(Ben zyloxyca r bon yl)-5-p h en ylp yr r o-
lid in e-2-ca r boxyla te (15). Alcohol 14 (380 mg, 1.22 mmol) in
acetone (20 mL) was treated with J ones reagent, prepared from
CrO3 (10 g), H2SO4 (14 g), and H2O (100 mL), while the mixture
was being stirred at 23 °C until a lasting orange color was
obtained. Total disappearance of the starting material was
checked by TLC (3/7 cyclohexane/EtOAc). The mixture was
diluted with MeOH (30 mL), and the solvents were removed.
Water (30 mL) was added, and the product was extracted with
CHCl3 (2 × 30 mL). The extract was dried (MgSO4) and
evaporated to give a residue, which was used directly in the next
step. The crude acid was diluted with Et2O (25 mL) and treated
with a solution of diazomethane in Et2O until the yellow color
was maintained. After the mixture was stirred for 15 min and
in vacuo concentration, the crude oil was purified by flash
chromatography (7/3 cyclohexane/EtOAc) to give the correspond-
(3′S,4S)-4-[3-(Meth oxym eth oxy)-3-p h en ylp r op yl]oxa zo-
lid in -2-on e (11). The ethylenic compound 10 (1.07 g, 4.06
mmol) was dissolved in EtOAc (30 mL), and PtO2 (46 mg, 0.2
mmol) was added. Hydrogen (1 atm) was applied, and the
reaction mixture was stirred at 23 °C for 5 h. After filtration
through Celite, the solvent was evaporated to afford 11 (1.05 g,
97%) as a colorless oil: [R]20 ) -11.4 (c 1.25, CH2Cl2); IR
D
(CHBr3) ν 3020, 1710 (br), 1145 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.43-2.35 (m, 4H), 3.35 (s, 3H), 3.38-4.06 (m, 2H), 4.44 (t, J
) 8 Hz, 1H), 4.51 (s, 2H), 4.55-4.65 (m, 1H), 6.38 (s, 1H), 7.22-
7.42 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 31.49, 33.33, 52.39,
55.67, 70.06, 77.35, 94.12, 126.65, 127.85, 128.50, 141.13, 159.83;
MS (CI, NH3) m/z (relative intensity) 283 (M + NH4+, 40.6%),
266 (100%). Anal. Calcd for C14H19NO4: C, 63.38; H, 7.21; N,
5.28. Found: C, 63.29; H, 7.14; N, 5.24.
ing ester 15 (320 mg, 77%): [R]20 ) +15 (c 1.3, CH2Cl2); IR
D
(CHBr3) ν 3010, 1745 (br), 1700 (br), 1410, 1340, 1140 cm-1; 1H
NMR (200 MHz, CDCl3) (two conformers) δ 1.9-2.5 (m, 4H), 3.7
(s, 1H), 3.84 (s, 2H), 4.40-4.65 (m, 1H), 4.85-5.10 (m, 3H), 6.78-
6.98 (m, 1H), 7.05-7.45 (m, 7H), 7.47-7.65 (m, 2H); 13C NMR
(50 MHz, CDCl3) (two conformers) δ 28.45, 29.12, 34.39, 35.44,
52.19, 60.39, 60.77, 62.69, 66.94, 126.12, 126.80, 127.17, 127.48,
127.70, 128.08, 136.13, 142.39, 143.16, 154.36, 155.19, 173.04;
(3′S ,4S )-4-(3-H yd r oxy-3-p h e n ylp r op yl)oxa zolid in -2-
on e (12). The protected alcohol 11 (1 g, 3.77 mmol) was placed
in MeOH (30 mL), and concentrated HCl (3 drops) was added.

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5683
MS (CI, NH3) m/z (relative intensity) 357 (M + NH4+, 17.2%),
340 (M + H+, 100%). Anal. Calcd for C20H21NO4: C, 70.78; H,
6.23; N, 4.12. Found: C, 71.23; H, 6.44; N, 4.51.
tion in vacuo, a crude oil which was purified by flash chroma-
tography (3/2 cyclohexane/EtOAc) to furnish the pyrrolidine 2
(110 mg, 58%): [R]20D ) +15.3 (c 1.22, CH2Cl2); IR (neat) ν 2951
(br), 1735 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.55-1.74 (m, 1H),
1.97-2.24 (m, 4H), 3.70 (s, 3H), 3.87 (dd, J ) 8.36, 5.18 Hz, 1H),
4.13 (dd, J ) 9.24, 5.64 Hz, 1H), 7.15-7.45 (m, 5H); 13C NMR
(50 MHz, CDCl3) δ 29.67, 30.52, 52.15, 60.00, 63.53, 126.73,
127.17, 128.45, 143.29, 175.60; MS (CI, NH3) m/z (relative
intensity) 206 (M + H+, 100%). Anal. Calcd for C12H15NO2: C,
70.22; H, 7.36; N, 6.82. Found: C, 70.19; H, 7.31; N, 6.85.
Meth yl (2S,5R)-5-P h en ylp yr r olid in e-2-ca r boxyla te (2).
Compound 15 (316 mg, 0.93 mmol) was dissolved in dry CH2Cl2
(20 mL) and the mixture treated with dimethyl sulfide (1.9 mL,
26 mmol) and boron trifluoride etherate (1.8 mL, 9.3 mmol). The
mixture was stirred for 2 h at 23 °C before a second addition of
dimethyl sulfide (1 mL, 13.6 mmol). The reaction mixture was
stirred for another 24 h and poured into water (20 mL) and 10%
aqueous NH4OH (40 mL). Extraction with CHCl3 (2 × 30 mL),
washing (H2O, brine), and drying (MgSO4) gave, after concentra-
J O980396L