Efficient asymmetric synthesis of (S)- and (R)-N-Fmoc-S-trityl-α- methylcysteine using camphorsultam as a chiral auxiliary

Article abstract of DOI:10.1021/jo049622j

(1R)-(+)-2,10- and (1S)-(-)-2,10-camphorsultam were acylated with ethyl 2-phenylthiazoline 4-carboxylate to afford (+)- and (-)-2- phenylthiazolinylcamphorsultam, which were stereoselectively alkylated with MeI in the presence of n-BuLi. Alkylation of the

Full text of DOI:10.1021/jo049622j

Efficien t Asym m etr ic Syn th esis of (S)- a n d
(
R)-N-F m oc-S-Tr ityl-r-m eth ylcystein e Usin g
Ca m p h or su lta m a s a Ch ir a l Au xilia r y
Satendra Singh,* Samala J . Rao, and
Michael W. Pennington
There are mainly three strategies for synthesizing R-meth-
Bachem Bioscience Inc., 3700 Horizon Drive,
King of Prussia, Pennsylvania 19406
ylcysteine: (1) thiolation of bromomethyl bislactim ether
9
10
3
, (2) regioselective ring opening of chiral aziridine 4
1
1,12
or â-lactone 5,
with thiolate nucleophile, and (3)
ssingh@usbachem.com
Received March 8, 2004
utilization of Seebach’s “self-reproduction of chirality”
approach to thiomethylate oxazolidinone 6 derived from
1
3
alanine or methylate a thiazolidine derivative 7 of
cysteine.1
4,15
Recently, R-methylcysteine has been syn-
Abstr a ct: (1R)-(+)-2,10- and (1S)-(-)-2,10-camphorsultam
were acylated with ethyl 2-phenylthiazoline 4-carboxylate
to afford (+)- and (-)-2-phenylthiazolinylcamphorsultam,
which were stereoselectively alkylated with MeI in the
presence of n-BuLi. Alkylation of these phenylthiazolinyl-
camphorsultams occurred from the â-face rather than R-face,
resulting in the formation of (S)-R-methylcysteine from (1R)-
thesized from dimethyl 2-methylmalonate 8 via enzy-
matic resolution followed by Curtius rearrangement.
1
6
(
(
+)-2,10-camphorsultam and (R)-R-methylcysteine from (1S)-
-)-2,10-camphorsultam after acidic hydrolysis. Subsequent
protection of the side chain thiol group with trityl alcohol
and R-amine function with Fmoc-OSu furnished fully pro-
tected (S)- and (R)-N-Fmoc-S-trityl-R-methylcysteine in
overall 20% yield.
Optically pure modified amino acids are valuable
building blocks for the preparation of biologically active
peptidomimetics since they can be utilized to confer
1
stability to peptides against enzymatic degradation. In
R
addition, C -alkylated amino acids are not prone to
racemization under basic or acidic conditions because of
Several groups have utilized chiral auxiliaries to direct
a lack of abstractable or enolizable R-hydrogen. Further-
17-23
an incoming alkyl group stereoselectively.
In these
R
more, C -alkylation severely restricts rotation around the
reactions, alkylation occurs from the least shielded face
of the enolate. Furthermore, in successive dialkylation
reactions, the second alkyl group comes in from the
opposite side of the sterically demanding group(s) present
on the chiral auxiliary. In this publication, we report a
short and efficient synthesis of R-methylcysteine using
R
R
N-C (φ) and C -C(O) (ψ) bonds of the amino acid in a
peptide sequence and stabilizes preferred conformations
of the peptide backbone.
Among C -alkylated amino acids, R-methylcysteine (1)
2
R
is an interesting molecule because it can impart con-
strained cyclic structure to the peptide via disulfide
bridge formation. Furthermore, R-methylcysteine occurs
naturally in the thiazoline rings (2) of a number of
21
Oppolzer’s camphorsultam chiral auxiliary. We chose
(
9) Groth, U.; Sch o¨ llkopf, U. Synthesis 1983, 37-38.
(10) Shao, H.; Zhu, Q.; Goodman, M. J . Org. Chem. 1995, 60, 790-
791.
11) Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 1035-1037.
12) Fukuyama, T.; Xu, L. J . Am. Chem. Soc. 1993, 115, 8449-8450.
(13) Walker, M. A.; Heathcock, C. H. J . Org. Chem. 1992, 57, 5566-
5568.
14) Pattenden G.; Thom, S. M.; J ones, M. F. Tetrahedron 1993, 49,
131-2138.
(15) Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. Tetrahedron
3
,4
5
natural products including mirabzoles, tantazoles, and
thiangazole,6 which exhibit antitumor and anti-HIV-1
activities.
,7
(
(
Synthesis of R-methylcysteine is rather challenging as8
a result of the labile nature of the sulfhydryl group.
(
2
(
(
1) Ma, J . S. Chim. OGGI 2003, 21, 65-68.
2) Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug
1993, 49, 5359-5364.
Discovery, 5th ed.; Wolff, M. E., Ed.; J ohn Wiley & Sons: 1995; Vol. 1,
Chapter 20, pp 803-861.
(16) Kedrowski, B. L. J . Org. Chem. 2003, 68, 5403-5406.
(17) Williams, R. M. In The Synthesis of Optically Active R-Amino
Acids; Pergamon Press: Oxford, 1989, and references therein.
(18) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650.
(19) Berkowitz, D. B.; Smith, M. K. J . Org. Chem. 1995, 60, 1233-
1238.
(
3) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35,
1
379-1382.
4) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35,
383-1384.
5) Carmeli, S.; Paik, S.; Moore, R. E.; Patterson, G. M. L.; Yoshida,
W. Y. Tetrahedron Lett. 1993, 34, 6680-6684.
6) Parsons, R. L.; Heathcock, C. H. J . Org. Chem. 1994, 59, 4733-
734.
(
1
(
(20) Seebach, D. Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708-2748.
(
(21) Oppolzer, W.; Moretti, R.; Zhou, C. Helv. Chim. Acta 1994, 77,
2363-2380.
4
1
2
(7) Boyce, R. L.; Mulqueen, G. C.; Pattenden, G. Tetrahedron Lett.
(22) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J . Org. Chem.
1999, 64, 3322-3327.
994, 35, 5705-5708.
(8) J eanguenat, A.; Seebach, D. J . Chem. Soc., Perkin Trans. 1 1991,
(23) O’Donnell, M. J .; Drew, M. D.; Cooper, J . T.; Delgado, F.; Zhou,
C. J . Am. Chem. Soc. 2002, 124, 9348-9349.
291-2298.
1
0.1021/jo049622j CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/29/2004
J . Org. Chem. 2004, 69, 4551-4554
4551

SCHEME 1
this chiral auxiliary because of low cost, ease of attach-
ment and removal, excellent enantioselectivity, and scal-
ability. Furthermore, it was visualized that deprotonation
of thiazolinylcamphorsultam should result in a Z-enolate
transition state, which upon alkylation with methyl
iodide from the R-face would afford (R)-R-methylcysteine
from (1R)-(+)-2,10-camphorsultam and (S)-R-methylcys-
teine from (1S)-(-)-2,10-camphorsultam. However, our
results indicated reverse stereochemical outcome.
As shown in Scheme 1, (R)-ethyl cysteine hydrochloride
Sultam 14 was refluxed in 6 N aqueous HCl for 8 h,
followed by treatment with trityl alcohol in the presence
of boron trifluoride etherate27 to afford (S)-S-trityl-R-
methylcysteine (15) in 49% yield (isolated yield over two
steps), [R]24
) -32 (c 0.5, MeOH). Protection of the
D
R-amino function of 15 with Fmoc-OSu in the presence
of sodium carbonate28 overnight afforded (S)-N-Fmoc-S-
2
4
trityl-R-methylcysteine (16) in quantitative yield, [R]
) -29.3 (c 0.15, MeOH).
D
It is important to note that alkylation of glycylsultam
under similar reaction conditions occurs via a kinetically
controlled Li-chelated Z-enolate (17), which is attacked
by the alkylating agent from the face opposite to the lone
electron pair on the nitrogen atom. The stereospecific
formation of Z-enolate occurs as a result of the presence
(
9) was treated with ethyl benzimidate hydrochloride (10)
in ethanol at reflux for 2 h to afford 2-phenylthiazoline
11) in 87% yield.24 Thiazoline 11 has been previously
(
synthesized using phosphorus pentachloride mediated
cyclization in 80% yield.25 Thiazolines are highly reactive
molecules with a labile acidic proton at C-4 and undergo
facile electrophilic alkylation to yield racemic 4-meth-
ylthiazolines, a precursor of R-methylcysteine.2 However,
we exploited (+)-camphorsultam (12) as a chiral auxiliary
to conduct alkylation, stereospecifically. Thus, camphor-
sultam 12 was acylated with thiazoline 11 in the presence
of trimethylaluminum to afford 2-phenylthiazolinylcam-
phorsultam 13 in 71% yield.21 Some racemization (<10%)
occurred during acylation possibly as a result of enoliza-
tion of ester 11 prior to nucleophilc addition, which was
easily separated by silica gel column chromatography.26
Alkylation of sultam 13 with methyl iodide in the
presence of n-butyllithium afforded alkylated sultam 14.
Enolate generation at -78 °C followed by quenching with
methyl iodide at the same temperature and continuing
the reaction either at -78 or -50 °C up to 24 h resulted
in poor yield. Furthermore, use of lithium diisopropyla-
mide or lithium bis(trimethylsilyl)amide as a base re-
sulted in poor alkylated product. Treatment of 13 in
tetrahydrofuran at -78 °C with n-butyllithium for 1 h,
followed by quenching the resulting enolate with methyl
iodide in hexamethylphosphoramide (both 3 molar equiv)
at the same temperature and allowing the reaction to
warm to ambient temperature over the period of 2 h gave
the alkylated product 14 in 49% yield.
of the bulky camphorsultam skeleton and sterically
21,29
demanding SO
2
group.
However, in the present case,
4
the Z-enolate derived from 2-phenylthiazolinylcamphor-
sultam (18) was attacked by the electrophile from the
â-face and furnished (S)-R-methylcysteine as confirmed
by optical rotation. High performance liquid chromatog-
raphy and NMR spectrometry were used to determine
the diastereomeric excess (asymmetric induction) during
1
the alkylation step. The H NMR spectrum exhibited a
relatively downfield shift for the R-methyl protons (2.52
ppm) in agreement with the â-alkylation product (14).
Compound 14 was the only alkylation product isolated
from the reaction mixture, and there was no R-alkylated
product formed as checked by HPLC. Furthermore, the
13
C NMR spectrum exhibited resonances corresponding
to a single isomer only.
To explain the unexpected stereochemical outcome on
electrophilic alkylation of 13, it can be speculated that
the enolate assumes E-configuration (19), which upon
alkylation from the R-face could result in the formation
of product 14. However, in the E-enolate transition state
(19) increased steric interactions between the camphor-
(
27) Bodanszky, M.; Bodanszky, A. In The Practice of Peptide
Synthesis, 2nd ed.; Springer-Verlag: Berlin Heidelberg, Germany,
1
994; pp 68-69.
(24) Pattenden, G.; Thom, S. M. J . Chem. Soc., Perkin Trans. 1 1993,
(28) Atherton, E.; Sheppard, R. C. In Solid-Phase Peptide Synthesis;
1
629-1636.
IRL Press: Oxford, England, 1989; p 61.
(
25) Ino, A.; Murabayashi, A. Tetrahedron 1999, 55, 10271-10282.
26) Martin, S. F.; Dwyer, M. P.; Lynch, C. L. Tetrahedron Lett.
(29) Anne, C.; Turcaud, S.; Quancard, J .; Teffo, F.; Meudal, H.;
Fournie-Zaluski, M.-C.; Roques, B. P. J . Med. Chem. 2003, 46, 4648-
4656.
(
1
998, 39, 1517-1520.
4
552 J . Org. Chem., Vol. 69, No. 13, 2004

HPLC was performed on a C18, reversed phase column (Vydac,
50 mm × 4.6 mm, 5 µ). A linear gradient from 5% buffer B to
5% buffer B in 45 min was used. Buffer A consisted of 0.1%
2
9
TFA in water, and buffer B was MeCN containing 0.1% TFA.
Flow rate was 1.5 mL/min.
The mass spectra of crude and purified samples were obtained
using in-house MALDI-MS and ESI-MS. R-Cyano-4-hydroxy-
cinnamic acid (CCA) was used as matrix for MALDI-MS. ESI-
MS spectra were collected from samples dissolved in methanol
1
13
as a solvent. The H and C NMR spectra were obtained at 600
MHz with CDCl or d -DMSO as solvent (Emory University,
3
6
Atlanta, GA). Micro Analysis Inc. (Wilmington, DE) performed
elemental analysis.
Diastereoisomeric excess (asymmetric induction) during the
alkylation step was measured using HPLC and NMR spectrom-
etry. Optical rotation measurements on purified samples were
obtained from Bachem AG, Bubendorf, Switzerland.
(
4R)-Eth yl 2-p h en yl-4,5-d ih yd r oth ia zole-4-ca r boxyla te
(
11). Triethylamine (21.21 g, 210 mmol) was added dropwise
over the period of 15 min to a stirred solution of (R)-cysteine
ethyl ester hydrochloride (9, 37.13 g, 200 mmol) and ethyl
benzimidate hydrochloride (10, 37.13 g, 200 mmol) in EtOH (250
mL).24 The mixture was refluxed for 2 h. The reaction mixture
was diluted with isopropyl ether (500 mL) and washed with 0.5
N aqueous HCl (1 × 150 mL), water (4 × 150 mL), and brine (1
sultam skeleton and the phenylthiazoline ring, as well
as electronic repulsions between the lone electron pair
on the nitrogen atom of thiazoline ring and the lone pair
×
4
150 mL). The organic layer was dried over MgSO and
2
electrons on the nitrogen and SO groups of camphor-
concentrated in vacuo to afford 41.0 g (87%) of light yellow oil.
It was used in the next step without further purification. ESI-
sultam moiety, are expected. On the contrary, the Z-
enolate transitions state (18) has minimum steric inter-
actions. Furthermore, formation of the Li-chelated
MS analysis gave a molecular ion peak at 236 (C12
H
14NO
2
S) (M
+
+ 1
+
H) and 258 (M+Na) . H NMR (CDCl
3
): δ 7.86 (2H, d, J )
7
4
Hz).
.5 Hz), 7.47 (1H, m), 7.41 (2H, m), 5.27 (1H, t, J ) 6.9 Hz),
.29 (2H, q, J ) 6.9 Hz), 3.71-3.64 (2H, m), 1.33 (3H, t, J ) 6.9
Z-enolate transition state under the similar reaction
conditions has been demonstrated previously.2
1,29
There-
fore, deprotonation of 13 should result in the formation
of the Z-enolate transition state (18), which upon alky-
lation from the â-face furnishes compound 14.
(
1R)-(+)-2,10-N-(2-P h en ylth iazolin e-4-car bon yl)cam ph or -
3
su lta m (13). A 2 M solution of Me Al (35 mL, 70 mmol) was
added dropwise to a suspension of sultam 12 (12.6 g, 58.6 mmol)
in toluene (100 mL).21 The mixture was heated to reflux. After
Having realized the reverse stereochemical outcome
from alkylation of enolate 18 and to confirm this finding,
we utilized (1S)-(-)-2,10-camphorsultam (enantiomer of
5
min of refluxing, the clear solution was allowed to cool to
ambient temperature over the period of 30 min, and stirring was
continued for additional 30 min. A solution of thiazoline 11 (21.3
g, 90.8 mmol) in toluene (60 mL) was added. The reaction
mixture turned bright yellow immediately upon addition. It was
stirred at 55 ( 5 °C for 24 h. The mixture was cooled in an ice
bath, and MeOH (50 mL) was added dropwise. After 30 min of
stirring, water (40 mL) was added dropwise. After 60 min of
stirring, the mixture was filtered through Celite and washed
with EtOAc (750 mL). The filtrate and the washings were
1
2) for alkylation of thiazoline 11. As observed above,
alkylation of the enolate derived from thiazolinylsultam
0 with methyl iodide occurred from the â-face and
afforded the â-alkylated product 21 as shown in Scheme
. The stereochemistry of alkylation was confirmed by
2
2
checking the optical rotation. After treatment with 6 N
aqueous HCl, protection of the side chain thiol group with
trityl alcohol furnished S-trityl-R-methylcysteine (22;
4
combined, dried over MgSO , and concentrated in vacuo to afford
a syrup (30 g). Purification of the crude product by silica gel
chromatography (EtOAc/hexane 5:95 to 20:80) afforded 16.8 g
2
4
[R]
D
) +28.5 (c 0.15, MeOH), and protection of the
R-amino function then afforded (R)-N-Fmoc-S-trityl-R-
(71%) of white solid. Mp 174-175 °C. RP-HPLC: t
[R]24
) +152.34 (c 0.5, MeOH). ESI-MS analysis gave a
molecular ion peak at 405 (C20
R
) 28.65 min.
methylcysteine (23; [R]24
D
D
) +31.9 (c 0.25, MeOH)) in
+
1
H
25
N
2
O
3
S
2
) (M + H) . H NMR
overall good yield.
(
5
3
CDCl ): δ 7.90 (2H, d, J ) 7.5 Hz), 7.48 (1H, m), 7.41 (2H, m),
3
Thus, an efficient asymmetric synthesis of (S)- and (R)-
N-Fmoc-S-trityl-R-methylcysteine (16 and 23) from the
commercially available camphorsultam chiral auxiliaries
was successfully accomplished with excellent optical
purity (>95%) and in overall good yield (20%). Synthesis
was easy to perform as reactions could be monitored by
HPLC for transformation and diastereoselectivity. Fur-
thermore, alkylation of 2-phenylthiazolinylcamphorsul-
tams (13 and 20) occurred from the â-face. This reverse
stereochemical outcome was completely unexpected. It
is not known how other chiral auxiliaries will behave
under similar conditions.
.86 (1H, t, J ) 6.9 Hz), 3.99 (1H, m), 3.73 (1H, d, J ) 7.2 Hz),
.62-3.42 (3H, m), 2.18-2.06 (2H, m), 1.98-1.85 (3H, m), 1.50-
1
3
1.42 (1H, m), 1.40-1.32 (1H, m), 1.17 (3H, s), 0.99 (3H, s).
C
6
NMR (600 MHz, DMSO-d ): δ 170.3, 168.5, 132.1, 132.0, 128.9,
1
28.2, 64.2, 52.0, 48.7, 47.4, 44.5, 37.6, 31.8, 25.8, 20.1, 19.4.
Anal. Calcd for C20 C, 59.40; H, 5.94; N, 6.90.
Found: C, 59.04, H, 5.84; N, 6.50.
1R)-(+)-2,10-N-((4S)-Met h yl-2-p h en ylt h ia zolin e-4-ca r -
24 2 3 2
H N O S :
(
bon yl)ca m p h or su lta m (14). A 1.6 M n-BuLi solution in hexane
(28.5 mL, 45.6 mmol) was added over 30 min at -78 °C to a
stirred solution of 13 (12.85 g, 31.8 mmol) in dry THF (270 mL).
After 90 min of stirring at the same temperature, a solution of
MeI (5.94 mL, 94.5 mmol) and HMPA (16.6 mL, 94.5 mmol) in
THF (25 mL) was added over 30 min. After an additional 90
min of stirring at -78 °C, the reaction mixture was allowed to
warm to ambient temperature over 2 h. After cooling in ice bath
Exp er im en ta l Section
All reagents and solvents were used without further purifica-
tion unless otherwise stated. Methyl iodide was freshly distilled.
THF was dried over LAH and freshly distilled before use. HMPA
was dried over 4Å molecular sieves.
4
the reaction was quenched with 3.7 M aqueous NH Cl (50 mL).
The mixture was taken in 1 L of EtOAc and successively washed
with 10% aqueous citric acid (3 × 250 mL), saturated aqueous
NaHCO
3
(3 × 250 mL), H O (2 × 250 mL), and brine (2 × 250
2
J . Org. Chem, Vol. 69, No. 13, 2004 4553

SCHEME 2
mL). The organic layer was dried over MgSO
in vacuo to afford 13.0 g of a red oil. The crude mixture was
purified by silica gel chromatography (EtOAc/hexane 5:95 to 20:
4
and concentrated
J ) 6.0 Hz) 2.33 (1H, d, J ) 6.0 Hz), 1.13 (3H, s). Anal. Calcd
for C23 S: C, 73.21; H, 6.10; N, 3.71. Found: C, 73.01, H,
5.94; N, 3.38. C NMR (600 MHz, DMSO-d ): δ 170.3, 144.2,
6
129.1, 128.0, 126.7, 65.6, 58.9, 22.1.
(S)-N-F m oc-S-tr ityl-R-m eth ylcystein e (16). Compound 15
(2.1 g, 5.57 mmol) was treated with Fmoc-OSu (2.27 g, 6.68
H23NO
2
1
3
8
0) to furnish 6.5 g (49%) of a white solid. Mp 135-136 °C. RP-
2
4
HPLC: t
R
) 30.65 min. [R]
D
) +51.07 (c 0.5, MeOH). ESI-MS
) (M +
): δ 7.95 (2H, d, J ) 7.5 Hz), 7.44 (1H, m),
.39 (2H, m), 4.18-4.10 (1H, m), 3.57-3.25 (3H, m), 2.93 (1H,
m), 2.52 (3H, s), 1.94-1.80 (5H, m), 1.46-1.40 (1H, m), 1.25-
.21 (1H, m), 1.15 (3H, s), 0.91 (3H, s). 13C NMR (600 MHz,
DMSO-d ): δ 172.8, 126.2, 132.5, 131.6, 128.5, 128.4, 67.7, 49.5,
8.4, 47.2, 43.7, 34.0, 31.5, 27.1, 26.5, 20.0, 19.6. Anal. Calcd
analysis gave a molecular ion peak at 419 (C21
H
27
N
2
O
3
S
2
+
1
H) . H NMR (CDCl
3
mmol) in the presence of Na
dioxane mixture overnight according to reported procedure.
After workup, 3.2 g (96%) of a white soild was obtained. Mp 192
2 3
CO (1.5 g, 14 mmol) in a water/
2
8
7
24
1
°C. RP-HPLC: t
R
) 35.4 min. [R]
D
) -29.3 (c 0.15, MeOH).
S)
): δ 7.90-7.85 (2H, m), 7.72-7.67
(2H, m), 7.40-7.35 (2H, m), 7.28 (15H, s), 7.22-7.15 (2H, m),
6
ESI-MS analysis gave a molecular ion peak at 600 (C38H34NO
4
+
1
4
(M + H) . H NMR (DMSO-d
6
for C21
26 2 3 2
H N O S : C, 60.28; H, 6.22; N, 6.69. Found: C, 59.94,
1
3
H, 6.02; N, 6.38.
S)-S-Tr ityl-R-m eth ylcystein e (15). Sultam 14 (4.7 g, 11.24
4.30-4.15 (3H, br, m), 2.88-2.68 (2H, m), 1.47 (3H, s). C NMR
(600 MHz, DMSO-d ): δ 174.4, 154.7, 144.4, 143.8, 140.7, 129.1,
127.9, 127.6, 127.1, 127.0, 126.7, 125.3, 120.1, 65.6, 65.5, 57.6,
46.6, 22.6. Anal. Calcd for C38 S: C, 76.12; H, 5.50; N,
(
6
mmol) was refluxed in 6 N HCl (85 mL) for 8 h. The mixture
was washed with EtOAc (3 × 50 mL) and evaporated under
reduced pressure. The syrup was taken in EtOH and treated
with MTBE to yield a white solid (5.1 g). Without further
purification, the solid was treated with trityl alcohol (3.12 g, 12
H
33NO
4
2.33. Found: C, 75.92, H, 5.39; N, 2.13.
Compounds 20-23 were prepared using similar procedures
as described above.
mmol) and BF
3
2
‚OEt (1.72 mL) in glacial acetic acid (30 mL) at
2
7
8
0 ( 5 °C for 30 min according to reported procedure. After
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures including characterization data for compounds 20-
workup and purification by silica gel chromatography, 2.2 g of
a white solid (49% over two steps) was obtained. Mp 188 °C.
2
3. This material is available free of charge via the Internet
2
4
RP-HPLC: t
R
) 21.01 min. [R]
D
) -32.0 (c 0.5, MeOH). ESI-
S) (M
6
H) . H NMR (DMSO-d ): δ 7.40-7.15 (15H, m), 2.40 (1H, d,
at http://pubs.acs.org.
MS analysis gave a molecular ion peak at 378 (C23
H
24NO
2
+
1
+
J O049622J
4
554 J . Org. Chem., Vol. 69, No. 13, 2004