Synthesis of an enantiomerically pure serine-derived thiazole

Article abstract of DOI:10.1021/jo961408a

Previously reported methods for preparing enantiomerically pure thiazoles are inadequate for the synthesis of inherently labile O-alkyl serine-derived thiazoles. The intermediate N-Boc-(O-methylseryl) thiazolines are very susceptible to tautomerization, e

Full text of DOI:10.1021/jo961408a

J . Org. Chem. 1996, 61, 7671-7676
7671
Syn th esis of a n En a n tiom er ica lly P u r e Ser in e-Der ived Th ia zole
J ennifer A. Sowinski and Peter L. Toogood*
Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-1055
Received J uly 23, 1996X
Previously reported methods for preparing enantiomerically pure thiazoles are inadequate for the
synthesis of inherently labile O-alkyl serine-derived thiazoles. The intermediate N-Boc-(O-
methylseryl) thiazolines are very susceptible to tautomerization, even under neutral conditions
(Scheme 5). Herein, it is demonstrated that the choice of N-protecting group is critical to the
preservation of enantiomeric purity. Thus, using an N-trityl protecting group, O-methyl serine
was converted to the corresponding N-Boc-(O-methylseryl) thiazole 3 with no appreciable epimer-
1
ization as indicated by 19F and H NMR of the corresponding Mosher’s amide.
In tr od u ction
In recent years, many thiazole-containing secondary
metabolites from marine sources have been isolated and
characterized.1 These compounds include the potent
antineoplastic agent dolastatin 10,2 the cytotoxin bistatra-
mide C,3 the antifungal pateamine,4 and the antitumor
agent ulithiacyclamide.5 Several of these peptides con-
tain a chiral 2-(1-aminoalkyl)thiazole possessing either
the R or S configuration. A number of methods for the
synthesis of these optically active amino acid-derived
thiazoles have been described. Examples include the fol-
lowing: (a) condensation of an amino acid-derived thioa-
mide with ethyl bromopyruvate (Hantzsch reaction);6 (b)
conversion of aminoaldehydes into thiazoles via the
thiazolidine;7 and (c) cyclodehydration of â-hydroxythioa-
mides using Burgess reagent,8 followed by oxidation of
the intermediate thiazoline.9 While each of these general
methods has been used in the synthesis of 2-(1-ami-
noalkyl)thiazoles, none of these methods has been applied
successfully to the preparation of chiral serine-derived
thiazole amino acids due to extensive epimerization at
the R-carbon. As part of our ongoing investigation into
the synthesis of the marine cyclic peptides keramamide
F (1)10 and keramamide J (2),11 we needed a way to
prepare (O-methylseryl) thiazole derivative 3 in enan-
F igu r e 1.
tiomerically pure form (Figure 1). Herein, we describe
the first synthesis of a serine-derived thiazole with
preservation of stereochemical integrity.
X Abstract published in Advance ACS Abstracts, October 15, 1996.
(1) For leading reference, see: Davidson, B. S. Chem. Rev. 1993,
93, 1771.
(2) Pettit, G. R.; Kamano, Y.; Heralk, C. L.; Tuinman, A. A.;
Boettner, F. E.; Kizu, H.; Schmidt, U.; Baczynskyj, L.; Tomer, K. B.;
Boetems, R. J . J . Am. Chem. Soc. 1987, 109, 6883.
Resu lts a n d Discu ssion
(3) Foster, M. P.; Concepcion, G. P.; Caraan, G. B.; Ireland, C. M.
J . Org. Chem. 1992, 57, 6671.
(4) Northcote, P. T.; Blunt, J . W.; Munro, W. M. G. Tetrahedron Lett.
1991, 32, 6411.
(5) Ireland, C.; Scheuer, P. J . J . Am. Chem. Soc. 1980, 102, 5688.
(6) For recent examples, see: (a) Kelly, R. C.; Gebhard, I.; Wicnien-
ski, N. J . Org. Chem. 1986, 51, 4590. (b) Schmidt, U.; Utz, R.;
Lieberknecht, A.; Griesser, H.; Potzolli, B.; Bahr, J .; Wagner, K.;
Fischer, P. Synthesis 1987, 233. (c) Bredenkamp, M. W.; Holzapfel, C.
W.; van Zyl, W. J . Synth. Commun. 1990, 20, 2235. (d) Hamada, Y.;
Hayashi, K.; Shioiri, T. Tetrahedron Lett. 1991, 32, 931. (e) Pattenden,
G.; Thom, S. M. J . Chem. Soc., Perkin Trans. 1 1993, 1629. (f) Martin,
B. J .; Clough, J . M.; Pattenden, G.; Waldron, I. R. Tetrahedron Lett.
1993, 34, 5151.
(7) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J . Org.
Chem. 1987, 52, 1252.
(8) Atkins, G. M.; Burgess, E. M. J . Am. Chem. Soc. 1968, 90, 4744.
Burgess reagent is commercially available from Aldrich and Fluka.
(9) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397.
(10) Itagaki, F.; Shigemori, H.; Ishibashi, M.; Nakamura, T.; Sasaki,
T.; Kobayashi, J . J . Org. Chem. 1992, 57, 5540.
We have reported previously our progress toward the
total synthesis of the cytotoxic cyclic peptide keramamide
F (1).12 In this communication, we described a synthesis
of thiazole 3 via a modified Hantzsch reaction which
provided 3 as a 4:1 mixture of enantiomers, as deter-
mined by 1H and 19F NMR analysis of the corresponding
(-)-R-methoxy-R-(trifluoromethyl)phenylacetyl deriva-
tive13 (Mosher’s amide). Upon further investigation, it
was determined that the starting acid we had used was
a mixture of enantiomers due to epimerization (ca. 33%)
during the saponification of N-Boc-O-Me-L-serine methyl
ester. To circumvent this problem, enantiomerically pure
acid 6 was prepared from serine benzyl ester as il-
lustrated in Scheme 1. However, use of enantiomerically
(11) Kobayashi, J .; Itagaki, F.; Shigemori, H.; Takao, T.; Shimonishi,
Y. Tetrahedron 1995, 51, 2525.
(12) Sowinski, J . A.; Toogood, P. L. Tetrahedron Lett. 1995, 36, 67.
(13) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
S0022-3263(96)01408-9 CCC: $12.00 © 1996 American Chemical Society

7672 J . Org. Chem., Vol. 61, No. 22, 1996
Sowinski and Toogood
Sch em e 1
Sch em e 3
Sch em e 2
procedure in which the thiazole ring is formed quickly
and under near-neutral conditions should reduce the
extent of epimerization.
Shioiri has reported the convenient and efficient
conversion of N-Boc and N-Z R-aminoaldehydes into their
corresponding 2-(1-aminoalkyl)thiazole-4-carboxylic ac-
ids, with no appreciable racemization, by condensation
with cysteine followed by oxidation of the resulting
thiazolidine.7 Following this approach, N-Boc-O-Bn-D-
serine17 was converted to the corresponding methyl ester
which was reduced with sodium borohydride-lithium
chloride in methanol-THF to give the amino alcohol
derivative 10 (Scheme 3). O-Methylation using trim-
ethyloxonium tetrafluoroborate, followed by hydrogenoly-
sis, afforded methyl ether 12 as a single enantiomer as
determined by 1H NMR analysis of the corresponding
(1S)-(-)-camphanate ester. Oxidation of compound 12
under Swern conditions and immediate condensation
with L-cysteine methyl ester smoothly afforded the thia-
zoline derivative 13 as a mixture of C-2 epimers with no
apparent epimerization of the R-center. Oxidation of
thiazolidine 13 (MnO2, benzene, 55 °C, 4 h) afforded the
corresponding thiazole 14 as a 1.6 to 1 mixture of
enantiomers, as determined by Mosher’s amide analysis
(1H and 19F NMR). Epimerization presumably results
from the relatively harsh conditions required to perform
the oxidation step.
pure 6 in the preparation of thiazole 3 via a modified
Hantzsch synthesis similarly produced an enantiomeric
mixture of products. Thus, N-Boc-L-serine benzyl ester
was methylated using trimethyloxonium tetrafluorobo-
rate and proton sponge (PS). Hydrogenolysis provided
acid 6, which was converted to the thioamide 8 via
treatment of amide 7 with Lawesson’s reagent (LR).
Subsequent reaction of thioamide 8 with ethyl bromopy-
ruvate under the conditions reported by Meyers and co-
workers14 afforded thiazole 3 as a 4.4:1 mixture of
enantiomers, as determined by Mosher’s amide analysis
(1H and 19F NMR). Further modifications of the Hantz-
sch reaction, including those reported by Holzapfel15 and
Schmidt16 also afforded thiazole 3 as a mixture of
enantiomers (2-4:1).
Wipf and co-workers have developed a mild and reli-
able method for the preparation of 2-(1-aminoalkyl)-
thiazoline-4-carboxylic acids with high diastereomeric
excess.9,18 These thiazolines may be oxidized to the
corresponding thiazoles with MnO2 at room temperature.
Since this procedure does not require the use of elevated
temperatures during the oxidation step, it represented
an attractive option for the synthesis of thiazole 3. Thus,
It has been proposed that epimerization during the
Hantzsch reaction occurs through an acid-catalyzed
imine-enamine tautomerization of the intermediate
hydroxythiazoline 9, as illustrated in Scheme 2.15 Since
a long lifetime of this intermediate presumably would
result in complete racemization, we reasoned that a
(14) Meyers, A. I.; Aguilar, E. Tetrahedron Lett. 1994, 35, 2473.
(15) Bredenkamp, M. W.; Holzapfel, C. W.; Snyman, R. M.; van Zyl,
W. J . Synth. Commun. 1992, 22, 3029.
(16) Schmidt, U.; Gleich, P.; Griesser, H.; Utz, R. Synthesis 1986,
992.
(17) Commercially available from Bachem (California).
(18) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267.

Enantiomerically Pure Serine-Derived Thiazole
J . Org. Chem., Vol. 61, No. 22, 1996 7673
Sch em e 4
Sch em e 5
Sch em e 6
N-Boc-O-Me-L-serine (6) was converted into the necessary
thiazoline 18 as outlined in Scheme 4. Acid 6 was
condensed with L-serine ethyl ester, and the alcohol was
protected as its tert-butyldimethylsilyl ether affording
dipeptide 15 which was smoothly converted to the thioa-
mide 16 with Lawesson’s reagent.19 Subsequent removal
of the silicon protecting group and reaction with Burgess
reagent yielded thiazoline 18. Oxidation of thiazoline 18
(MnO2, CH2Cl2, rt, 36 h) afforded thiazole 3 as a mixture
of enantiomers (3:1) as determined by Mosher’s amide
analysis (1H and 19F NMR).
Interestingly, upon standing at 4 °C (ca 7 days),
thiazoline 18 underwent complete conversion to the
didehydro peptide 19 (Scheme 5). We propose that this
elimination occurs via an imine-enamine tautomeriza-
tion with subsequent loss of methanol. Εlimination
reactions are a well-documented problem commonly
associated with serine derivatives. For example, reaction
of O-tosyl and â-halo N-Boc or N-Z L-serine derivatives
with organocuprates or amines affords the corresponding
didehydroalanine.20 Furthermore, attempts to methylate
N-Boc or N-Z L-serine derivatives have resulted in high
yields of the corresponding â-elimination products.21
While Mitsunobu reactions of N-Boc or N-Z L-serine
derivatives also commonly afford the elimination prod-
uct,22 Cherney recently reported that neither N-phe-
nylfluorenyl nor N-trityl (Tr) serines undergo elimination
under Mitsunobu conditions.23 This result followed
previous work demonstrating that the phenylfluorenyl
and trityl protecting groups protect the R-center of amino
acids from deprotonation.24,25 We postulated that the use
of such a protecting group also might suppress epimer-
ization of serine-derived thiazolines (Scheme 5).
To test whether using the N-trityl protecting group
would preserve enantiomeric purity in our chemistry, we
prepared the N-Tr protected thioamide 22 as illustrated
in Scheme 6. N-Tr-O-Me-L-serine26 was coupled to L-
serine ethyl ester and protected as its tert-butyldimeth-
ylsilyl ether (20). Compound 20 was subsequently
converted into the thioamide 21. Conversion of dipeptide
20 to thioamide 21 proceeds in poor yield, presumably
due to instability of the N-trityl group during treatment
with Lawesson’s reagent.27 Furthermore, variations in
solvent (THF, DME, HMPA) and thionation reagent
(19) Clausen, K.; Thorsen, M.; Lawesson, S. O.; Spatola, A. F. J .
Chem. Soc., Perkin Trans. 1 1984, 785. Lawesson’s reagent is com-
mercially available from Sigma and Aldrich.
(20) (a) Bajgrowicz, J . A.; El Hallaoui, A.; J acquier, R.; Pigiere, Ch.;
Viallefont, Ph. Tetrahedron 1985, 41, 1833. (b) Photaki, I. J . Am. Chem.
Soc. 1963, 85, 1123.
(21) (a) Cheung, S. T.; Benoiton, N. L. J . Can. Chem. 1977, 55, 906.
(b) Olsen, R. K. J . Org. Chem. 1970, 35, 1912.
(22) Wojciechowska, H.; Pawlowicz, R.; Andruszkiewicz, R.; Grzy-
bowska, J . Tetrahedron Lett. 1978, 4063.
(24) Christie, B. D.; Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(25) Guthrie, R. D.; Nicolas, E. C. J . Am. Chem. Soc. 1981, 103, 4638.
(26) Barlos, K.; Papaioznnou, D.; Cordopatis, P.; Theodoropoulos,
D. Tetrahedron 1983, 39, 475.
(23) Cherney, R. J .; Wang, L. J . Org. Chem. 1996, 61, 2544.

7674 J . Org. Chem., Vol. 61, No. 22, 1996
Sowinski and Toogood
afforded the title compound (1.87 g, 98%) as a colorless oil: Rf
) 0.42 (1:1 hexanes/EtOAc); IR (film) 3426, 2977, 1717, 1505,
1165, 1061; 1H NMR (360 MHz) δ 7.39-7.32 (m, 5H), 5.52 (d,
1H, J ) 8.6 Hz), 5.20 (s, 2H), 4.44-4.38 (m, 1H), 3.97 (dd, 1H,
J ) 3.8, 11.1 Hz), 3.89 (dd, 1H, J ) 3.5, 11.1 Hz), 2.53-2.45
(m, 1H), 1.43 (s, 9H); 13C NMR (90 MHz) δ 170.7, 155.7, 135.1,
128.4, 128.2, 128.0, 80.1, 67.1, 63.1, 55.7, 28.1; MS m/z (rel
int) 296 (21, M + H), 257 (100), 240 (31), 196 (66); HRMS (CI)
calcd for C15H22NO5 (M + H) 296.1498, found 296.1484; [R]25
) +0.5 (c 1, CH2Cl2).
D
N-Boc-O-Meth yl-L-ser in e Ben zyl Ester (5). Compound
4 (1.74 g, 5.89 mmol) was dissolved in CH2Cl2 (50 mL) and
cooled to 0 °C under nitrogen in the dark. Trimethyloxonium
tetrafluoroborate (1.13 g, 7.67 mmol) was added. After 5 min,
proton sponge (1.64 g, 7.67 mmol) was added and the resulting
solution was allowed to reach ambient temperature over 18
h. The solution was filtered through a pad of Celite and the
filtrate washed with 1 M HCl and brine. The organic layer
was dried (MgSO4), filtered, and concentrated. Purification
by flash chromatography (2:1 hexanes/EtOAc) afforded 5 (1.52
g, 84%) as a colorless oil: Rf ) 0.47 (2:1 hexanes/EtOAc); IR
(film) 2980, 2933, 1718, 1498, 1163; 1H NMR (360 MHz) δ
7.38-7.30 (m, 5H), 5.40 (d, 1H, J ) 8.6 Hz), 5.27 (d, 1H, J )
12.3 Hz), 5.14 (d, 1H, J ) 12.4 Hz), 4.47-4.45 (m, 1H), 3.81
(dd, 1H, J ) 3.0, 9.1 Hz), 3.60 (dd, 1H, J ) 3.2, 9.3 Hz), 3.29
(s, 3H), 1.44 (s, 9H); 13C NMR (90 MHz) δ 170.4, 155.3, 135.8,
128.3, 128.1, 127.9, 79.9, 72.3, 66.9, 59.0, 53.9, 28.1; MS m/z
(rel int) 310 (51, M + H), 254 (87), 210 (100); HRMS (CI) calcd
for C16H24NO5 (M + H) 310.1654, found 310.1654; [R]25D ) -4.3
(c 1, CH2Cl2).
F igu r e 2. 19F-NMR (282 Hz, CDCl3) spectra of (R)-(-)-
Mosher’s amide of (A) 3 as a mixture of enantiomers (δ -69.69
and -70.06), and (B) enantiomerically pure 3 (δ -69.69).
Chemical shifts (δ) reported in parts per million (ppm) with
respect to a C6F6 external reference (δF -162.90).
(P2S5) did not increase the yield of thioamide 21. Re-
moval of the silyl protecting group and treatment with
Burgess reagent provided the thiazoline, which was
oxidized to afford the enantiomerically pure N-trityl
protected thiazole 23. Thiazole 23 was smoothly depro-
tected (TFA, CHCl3/MeOH, -10 °C), and the resulting
amine was reprotected as its tert-butyl carbamate 3 in
high yield and with no loss of stereochemical integrity
as determined by 1H and 19F NMR analysis of the
corresponding Mosher’s amide (Figure 2). Thus, the
N-trityl group does indeed appear to prevent removal of
the adjacent proton providing access to enantiomerically
pure product under conditions which otherwise yield
product mixtures.
In summary, we have shown that previously over-
looked serine-derived thiazole amino acids may be pre-
pared enantiomerically pure by judicious choice of the
N-protecting group. Due to the inherent lability of the
R-proton of O-alkylated serines, very bulky, non-urethane
protecting groups (e.g. trityl) appear to be the N-protect-
ing groups of choice. This observation may be extended
to other cases where epimerization is a problem during
thiazole ring formation.
N-Boc-O-Meth yl-L-ser in a m id e (7). Compound 5 (1.50 g,
4.85 mmol) and Pd/C (150 mg) were combined and methanol
(30 mL) was added. The resulting heterogeneous mixture was
stirred under hydrogen (1 atm) for 1 h. The palladium was
removed by filtration through Celite and the filtrate concen-
trated in vacuo. The resulting residue was dissolved in water,
adjusted to pH 9 with 1 M NaOH, and washed with diethyl
ether. The aqueous layer was adjusted to pH 4 with 10% citric
acid and extracted with EtOAc. The combined organic layers
were dried (MgSO4), filtered, and concentrated to afford 6 (952
mg, 90%) as a white foam; Rf ) 0.57 (10% MeOH/CH2Cl2). A
solution of the crude acid 6 (952 mg, 4.37 mmol) in THF (25
mL) was cooled to -15 °C, and 4-methylmorpholine (0.48 mL,
4.37 mmol) was added. Isobutyl chloroformate (0.57 mL, 4.37
mmol) was added and the resulting solution stirred 15 min at
-15 °C. Ammonia gas was bubbled through the reaction and
condensed using a dry ice/acetone cold finger. After 10 min,
the flask was allowed to warm to room temperature over 30
min. The reaction mixture was purged with nitrogen, diluted
with EtOAc, and washed with 5% aqueous NaHCO3, 1 M HCl,
and then brine. Flash chromatography (EtOAc) afforded the
title compound (790 mg, 83%) as a white solid: Rf ) 0.38
(EtOAc); IR (film) 3400, 2986, 2914, 2386, 2314, 1772, 1736,
Exp er im en ta l Section
1
1701, 1664; H NMR (300 MHz) δ 6.45 (br s, 1H), 5.69 (br s,
Gen er a l P r oced u r es. Anhydrous ether and tetrahydro-
furan (THF) were distilled from sodium and benzophenone.
Dichloromethane (CH2Cl2), benzene, and acetonitrile (CH3CN)
were distilled from calcium hydride (CaH2). Other solvents
used were HPLC or reagent grade. Organic acids and bases
were reagent grade. Triethylamine and diisopropylethylamine
were distilled and stored over 4 Å molecular sieves. All other
reagents were commercial compounds of the highest purity
available.
N-Boc-L-Ser in e Ben zyl Ester (4). L-Serine benzyl ester
(1.50 g, 6.47 mmol) was dissolved in CH2Cl2 (50 mL) under
nitrogen and cooled to 0 °C. Triethylamine (2.70 mL, 19.41
mmol) was added followed by a solution of di-tert-butyl
dicarbonate (1.40 g, 6.47 mmol) in CH2Cl2 (5 mL). After 2 h,
the solution was washed with 1 M HCl followed by brine. The
organic layer was dried (MgSO4), filtered, and concentrated.
Purification by flash chromatography (1:1 hexanes/EtOAc)
1H), 5.43 (d, 1H, J ) 7.0 Hz), 4.25-4.22 (m, 1H), 3.76 (dd,
1H, J ) 4.1, 9.3 Hz), 3.47 (dd, 1H, J ) 4.7, 9.0 Hz), 3.35 (s,
3H), 1.48 (s, 9H); 13C NMR (90 MHz) δ 173.1, 155.4, 80.0, 72.0,
58.9, 53.4, 28.1; MS m/z (rel int) 219 (55, M + H), 163 (100),
119 (45). Anal. Calcd for C9H18N2O4 C, 49.53; H, 8.31; N,
12.84. Found: C, 49.50; H, 8.46; N, 12.84. [R]25 ) +19.6 (c
D
1, CHCl3).
N-Boc-O-Meth yl-L-ser in e Th ioa m id e (8). Amide 7 (700
mg, 3.21 mmol) was dissolved in ethylene glycol dimethyl ether
(20 mL) at ambient temperature. Lawesson’s reagent19 (779
mg, 1.93 mmol) was added, and the mixture was stirred
overnight under an atmosphere of dry nitrogen. The solvent
was evaporated in vacuo. The resulting residue was dissolved
in CH2Cl2 and washed with 1% aqueous NaOH. The aqueous
layer was further extracted with CH2Cl2. The combined
organic layers were dried (MgSO4), filtered, and concentrated
to yield a residue which was purified by flash chromatography
(1:1 hexanes/EtOAc). The title compound (563 mg, 75%) was
obtained as a white solid: Rf ) 0.38 (1:1 hexanes/EtOAc); IR
(film) 3336, 2854, 2818, 1640, 1619; 1H NMR (300 MHz) δ 7.94
(br s, 1H), 7.79 (br s, 1H), 5.63 (d, 1H, J ) 6.5 Hz), 4.55 (dt,
1H, J ) 4.4, 6.5 Hz), 3.86 (dd, 1H, J ) 4.7, 9.0 Hz), 3.56 (dd,
(27) Attempts to form the thioamide from N-Tr-O-methyl-L-serina-
mide were unsuccessful. The polarity of the primary thioamide formed
prohibited its separation from decomposition products; consequently,
the Hantzsch method was not investigated using the N-trityl protecting
group.

Enantiomerically Pure Serine-Derived Thiazole
J . Org. Chem., Vol. 61, No. 22, 1996 7675
1H, J ) 4.4, 9.0 Hz), 3.38 (s, 3H), 1.45 (s, 9H); 13C NMR (90
MHz) δ 205.9, 155.1, 80.3, 74.0, 58.9, 28.1; MS m/z (rel int)
235 (43, M + H), 219 (31), 195 (12), 179 (100), 163 (75). Anal.
Calcd for C9H18N2SO3: C, 46.30; H, 7.34; N, 12.0. Found: C,
and the aqueous layer was extracted several times with EtOAc.
The combined organic layers were dried (MgSO4), filtered, and
concentrated to afford the corresponding aldehyde (64 mg,
99%) as a colorless solid. The aldehyde was immediately
dissolved in benzene (2.5 mL) at room temperature under
nitrogen. A solution of L-cysteine methyl ester (43 mg, 0.32
mmol) in benzene (2.5 mL) was added. After stirring 18 h,
the mixture was diluted with EtOAc and washed with NH4Cl
(aqueous saturated) and then brine. The organic layer was
dried (MgSO4), filtered, and concentrated. Purification by
flash chromatography (3:2 hexanes/EtOAc) afforded 13 (67 mg,
66%) as a colorless oil: Rf ) 0.17 (3:2 hexanes/EtOAc); IR (film)
2979, 2929, 1744, 1714, 1505, 1368, 1166; 1H NMR (360 MHz)
δ 5.18-5.12 (m, 1H), 4.77-4.79 and 4.73-4.71 (m, 1H), 4.27-
4.24 and 4.03-4.01 (m, 1H), 3.73 and 3.72 (s, 3H), 3.75-3.71
and 3.63-3.59 (m, 1H), 3.55-3.48 (m, 1H), 3.31 and 3.30 (s,
3H), 3.29-3.27 (m, 1H), 3.24-3.20 (m, 1H), 2.81 and 2.68 (t,
1H, J ) 10.3 Hz), 1.40 (s, 9H); 13C NMR (90 MHz) δ 171.1,
155.5, 79.8, 73.5, 73.1, 71.8, 65.3, 65.0, 59.1, 59.0, 52.3, 52.3,
50.6, 37.7, 37.5, 28.1 (diastereomers present in NMR); MS m/z
(rel int) 321 (42, M + H), 265 (56), 233 (32), 221 (58), 172 (20),
146 (100), 86 (20); HRMS (CI) calcd for C13H25N2SO5 (M + H)
321.1484, found 321.1470.
46.01; H, 7.61; N, 11.83. [R]25 ) +38.0 (c 1, CHCl3).
D
(S)-(-)-N-Boc-O-Ben zylser in ol (10). N-Boc-O-Bn-D-Ser-
ine17 (1.18 g, 4.00 mmol) was treated with Diazald (1.00 g, ca.
4 mmol) in a typical diazomethane procedure to yield the
corresponding N-Boc-O-Bn-D-serine methyl ester (1.12 g, 99%)
as a colorless oil: Rf ) 0.30 (4:1 hexanes/EtOAc). The ester
was dissolved in THF (6 mL), and LiCl (339 mg, 8.00 mmol)
was added. The solution was cooled to -10 °C. After 30 min,
NaBH4 (303 mg, 8.00 mmol) was added. Methanol (11 mL)
was added dropwise over 15 min and the mixture allowed to
warm to ambient temperature with stirring. After 2 h, the
solution was cooled to 0 °C and adjusted to pH 4 by addition
of 10% citric acid. The volatile components were removed in
vacuo, the resulting residue was dissolved in water, and the
product was extracted with CH2Cl2. The combined organic
layers were dried (MgSO4), filtered, and concentrated. Puri-
fication by flash chromatography (1:1 EtOAc/hexanes) afforded
the title compound (1.06 g, 95%) as a colorless oil: Rf ) 0.34
(1:1 hexanes/EtOAc); IR (film) 3393, 2977, 2932, 2869, 1695,
1
1501, 1363, 1169; H NMR (360 MHz) δ 7.35-7.29 (m, 5H),
N-Boc-O-Meth yl-L-ser yl-O-TBDMS-L-ser in e Eth yl Es-
ter (15). L-Serine ethyl ester hydrochloride (773 mg, 4.56
mmol), acid 6 (994 mg, 4.56 mmol), and HOBt (678 mg, 5.01
mmol) were dissolved in CH2Cl2 (35 mL) and cooled to 0 °C.
Triethylamine (0.64 mL, 4.45 mmol) was added, followed by a
solution of DCC (941 mg, 4.56 mmol) in CH2Cl2 (5 mL). The
resulting mixture was allowed to reach ambient temperature
with stirring over 4 h. The solution was filtered through a
pad of Celite, and the filtrate was washed with 1 M HCl,
NaHCO3 (aqueous), and brine. The organic layer was dried
(MgSO4), filtered, and concentrated to yield the dipeptide (1.44
g, 95%) as a white solid. The dipeptide (495 mg, 1.1 mmol)
was dissolved in DMF (30 mL) at ambient temperature. tert-
Butyldimethylsilyl chloride (1.43 g, 9.53 mmol) was added,
followed by imidazole (1.30 g, 19.05 mmol). After stirring 18
h, the mixture was diluted with benzene/EtOAc (1:1) and
washed with 10% citric acid and brine. The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography (3:1 hexanes/EtOAc) afforded the title com-
pound (1.90 g, 98%) as a colorless oil: Rf ) 0.50 (1:1 hexanes/
EtOAc); IR (film) 2928, 2856, 1723, 1684, 1490, 1390, 1366,
5.19-5.17 (m, 1H), 4.52 (s, 2H), 3.81-3.79 (m, 2H), 3.69-3.62
(m, 3H), 1.44 (s, 9H); 13C NMR (90 MHz) δ 155.9, 137.6, 128.3,
127.6, 127.5, 79.4, 73.2, 70.0, 63.1, 51.5, 28.2; MS m/z (rel int)
282 (7, M + H), 226 (80), 208 (60), 182 (90), 91 (100); HRMS
(CI) calcd for C15H24NO4 (M + H) 282.1705, found 282.1699;
[R]25 ) -8.5 (c 1, CH2Cl2).
D
(S)-(-)-N-Boc-O-Ben zyl-O-m eth ylser in ol (11). Alcohol
10 (400 mg, 1.42 mmol) was dissolved in CH2Cl2 (10 mL) at
room temperature in a foil-covered flask. Trimethyloxonium
tetrafluoroborate (315 mg, 2.13 mmol) was added, followed by
the portionwise addition of proton sponge (456 mg, 2.13 mmol).
After stirring 24 h, the solution was concentrated, the residue
dissolved in EtOAc, and the solution filtered through a pad of
Celite. The filtrate was washed with 1 M HCl and brine. The
organic layers were dried (MgSO4), filtered, and concentrated
in vacuo. Flash chromatography (3:2 hexanes/EtOAc) afforded
the methyl ether (214 mg, 51%) as a colorless oil: Rf ) 0.42
(2:1 hexanes/EtOAc); IR (film) 2979, 2923, 1716, 1497, 1457,
1
1366, 1167; H NMR (360 MHz) δ 7.37-7.27 (m, 5H), 4.92-
4.89 (m, 1H), 4.52 (s, 2H), 3.94-3.91 (m, 1H), 3.79-3.77 (m,
1H), 3.58 (dd, 2H, J ) 4.1, 9.4 Hz), 3.44 (dd, 1H, J ) 5.9, 9.3
Hz), 3.34 (s, 3H), 1.44 (s, 9H); 13C NMR (90 MHz) δ 155.4,
138.1, 128.3, 127.8, 127.5, 79.3, 73.1, 71.2, 68.9, 58.9, 49.5, 28.3;
MS m/z (rel int) 296 (2, M + H), 240 (21), 196 (100), 91 (84);
HRMS (CI) calcd for C16H26NO4 (M + H) 296.1863, found
1
1251, 1169, 1116; H NMR (360 MHz) δ 7.36-7.33 (m, 1H),
5.42-5.40 (m, 1H), 4.58 (dt, 1H, J ) 2.7, 8.4 Hz), 4.26-4.21
(m, 1H), 4.17 (q, 2H, J ) 7.2 Hz), 4.06 (dd, 1H, J ) 2.5, 10.0
Hz), 3.80-3.73 (m, 2H), 3.45 (dd, 1H, J ) 7.3, 8.9Hz), 3.36 (s,
3H), 1.42 (s, 9H), 1.24 (t, 3H, J ) 7.2 Hz), 0.87 (s, 9H), 0.00 (d,
6H, J ) 6.0 Hz); 13C NMR (90 MHz) δ 170.2, 169.9, 155.5, 79.9,
72.0, 63.3, 61.3, 58.9, 54.3, 53.3, 28.2, 25.5, 18.0, 14.0, -5.6,
-5.7; MS m/z (rel int) 449 (56, M + H), 393 (84), 375 (61), 349
(100), 317 (10), 178 (15), 164 (13), 134 (15), 119 (51); HRMS
(CI) calcd for C20H41N2SiO7 (M + H) 449.2688, found 449.2664;
296.1862; [R]25 ) -6.8 (c 1, CH2Cl2).
D
(R)-(-)-N-Boc-O-Meth ylser in ol (12). To compound 11
(200 mg, 0.678 mmol) was added 10% Pd/C (20 mg) followed
by methanol (10 mL). The resulting heterogeneous solution
was stirred under a hydrogen atmosphere for 24 h. The
palladium was removed by filtration through Celite and the
filtrate concentrated in vacuo. Purification by flash chroma-
tography (1:1 hexanes/EtOAc) afforded the title compound (122
mg, 88%) as a colorless oil: Rf ) 0.21 (1:1 hexanes/EtOAc); IR
(film) 3351, 2976, 2934, 1693, 1512, 1364, 1248, 1172, 1062;
1H NMR (360 MHz) δ 5.26-5.21 (m, 1H), 3.76-3.73 (m, 2H),
3.64-3.62 (m, 1H), 3.53 (dd, 1H, J ) 3.8, 9.5 Hz), 3.49 (dd,
1H, J ) 4.2, 9.5 Hz), 3.34 (s, 3H), 2.99-2.96 (m, 1H), 1.42 (s,
9H); 13C NMR (90 MHz) δ 156.0, 79.6, 73.0, 63.7, 59.1, 51.4,
28.3; MS m/z (rel int) 206 (37, M + H), 150 (100), 132 (14),
106 (82); HRMS (CI) calcd for C9H20NO4 (M + H) 206.1392,
[R]25 ) +44.3 (c 1, CH2Cl2).
D
Th ioa m id e 16. To a stirred solution of 15 (240 mg, 0.536
mmol) in benzene (3 mL) was added Lawesson’s reagent19 (130
mg, 0.321 mmol), and the mixture was stirred at 80 °C for 1
h. After cooling to ambient temperature, the reaction mixture
was poured into a solution of saturated NaHCO3 (aqueous
saturated, 4 mL, 0 °C). The aqueous layer was extracted
several times with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4), and concentrated in vacuo.
Flash chromatography (4:1 hexanes/EtOAc) afforded the title
compoud (235 mg, 94%) as a yellow oil: Rf ) 0.43 (4:1 hexanes/
EtOAc); IR (film) 2929, 2857, 1724, 1522, 1471, 1366, 1251,
1163, 1113; 1H NMR (200 MHz) δ 5.72-5.65 (m, 1H), 5.17 (dt,
1H, J ) 2.6, 7.7 Hz), 4.52 (dt, 1H, J ) 4.0, 9.2 Hz), 4.23 (q,
2H, J ) 7.2 Hz), 4.12 (dd, 1H, J ) 2.4, 10.2 Hz), 4.02 (dd, 1H,
J ) 2.8, 10.2 Hz), 3.89 (dd, 1H, J ) 4.0, 9.2 Hz), 3.57 (dd, 1H,
J ) 9.1, 9.2 Hz), 3.37 (s, 3H), 1.46 (s, 9H), 1.28 (t, 3H, J ) 7.2
Hz), 0.86 (s, 9H), 0.00 (s, 6H); 13C NMR (50 MHz) δ 201.2,
168.9, 160.7, 80.3, 74.3, 62.3, 61.6, 59.8, 59.0, 28.2, 25.6, 18.1,
14.1, -5.6, -5.7; MS m/z (rel int) 465 (11, M + H), 437 (10),
409 (46), 391 (22), 365 (100), 333 (21), 307 (18), 277 (21), 259
found 206.1390; [R]25 ) -3.3 (c 1, CH2Cl2).
D
Th ia zolid in e 13. To a -78 °C solution of oxalyl chloride
(0.24 mL, 0.48 mmol) in CH2Cl2 (3.5 mL) was added DMSO
(0.07 mL, 1.0 mmol). After 15 min, a solution of alcohol 12
(66 mg, 0.32 mmol) in CH2Cl2 (2.5 mL) was added via cannula.
The resulting solution was stirred for 15 min and then treated
with triethylamine (0.26 mL, 1.90 mmol). The dry ice/acetone
bath was removed, and the solution allowed to gradually warm
to ambient temperature over 2.5 h. The reaction was quenched
by the addition of NH4Cl (aqueous saturated, 4.7 mL) and
transferred to a separatory funnel. The layers were separated,

7676 J . Org. Chem., Vol. 61, No. 22, 1996
Sowinski and Toogood
(23), 233 (34), 173 (27); HRMS (CI) calcd for C20H41N2SiSO6
) 6.3 Hz), 7.47-7.40 (m, 6H), 7.31-7.20 (m, 9H), 5.02-4.99
(m, 1H), 4.38-4.32 (m, 4H), 3.94 (d, 1H, J ) 10.7 Hz), 3.79
(dd, 1H, J ) 2.7, 8.9 Hz), 3.71 (dd, 1H, J ) 2.6, 8.9 Hz), 3.08
(s, 3H), 2.27-2.24 (m, 1H), 1.32 (t, 3H, J ) 7.1 Hz); 13C NMR
(90 MHz) δ 203.8, 169.5, 145.3, 128.7, 128.1, 126.8, 75.8, 71.9,
65.5, 62.1, 61.2, 59.2, 59.1, 14.2; MS m/z (rel int) 493 (2, M +
H), 459 (1), 415 (1), 316 (3), 243 (100), 165 (6); HRMS (CI)
(M + H) 465.2437, found 465.2437; [R]25 ) +66.7 (c 1, CH2-
D
Cl2).
Alcoh ol 17. A solution of 16 (235 mg, 0.51 mmol) in THF
(3 mL) at 0 °C was treated with tetrabutylammonium fluoride
(146 mg, 0.56 mmol). After stirring 1 h at 0 °C, the solvent
was evaporated and the residue partitioned between CH2Cl2
and water. The aqueous layer was extracted three times with
CH2Cl2, and the combined organic layers washed with brine,
dried (MgSO4), and concentrated in vacuo. Flash chromatog-
raphy (3:2 hexanes/EtOAc) afforded 168 mg (94%) of the title
compound as a light yellow oil: Rf ) 0.23 (1:1 hexanes/EtOAc);
IR (film) 3338, 2980, 2932, 1721, 1693, 1519, 1392, 1166, 1118;
1H NMR (360 MHz) δ 5.66 (d, 1H, J ) 5.7 Hz), 5.16 (dt, 1H, J
) 3.6, 7.1 Hz), 4.55 (dd, 1H, J ) 5.3, 11.3 Hz), 4.27 (q, 2H, J
) 7.2 Hz), 4.20-4.17 (m, 1H), 4.01 (dd, 1H, J ) 2.7, 11.6 Hz),
3.86 (dd, 1H, J ) 4.7, 9.4 Hz), 3.60-3.56 (m, 1H), 3.36 (s, 3H),
1.43 (s, 9H), 1.29 (t, 3H, J ) 7.2 Hz); 13C NMR (50 MHz) δ
201.4, 169.4, 155.2, 80.6, 74.4, 62.0, 61.2, 60.4, 59.7, 59.1, 28.1,
14.0; MS m/z (rel int) 351 (11, M + H), 333 (10), 317 (41), 295
(14), 261 (21), 251 (54), 233 (20), 217 (62), 201 (17), 187 (20),
162 (18), 145 (20), 135 (100); HRMS (CI) calcd for C14H27N2-
calcd for C28H33N2SO4 (M + H) 493.2161, found 493.2169; [R]25
D
) -67.7 (c 1, CH2Cl2).
Th ia zole 23. Compound 22 (55 mg, 0.11 mmol) was
dissolved in THF (4 mL) under nitrogen. Burgess reagent8
(29 mg, 0.12 mmol) was added and the resulting solution
heated to 65 °C for 10 min. The mixture was cooled to room
temperature, concentrated in vacuo, and purified by flash
chromatography (3:2 hexanes/EtOAc) to yield the thiazoline
(51 mg, 98%) as a colorless solid: Rf ) 0.36 (3:2 hexanes/
EtOAc). The thiazoline (40 mg, 0.074 mmol) was dissolved in
CH2Cl2 (3.0 mL), and manganese(IV) oxide (73 mg, 0.84 mmol)
was added. After 24 h, the mixture was filtered through a
pad of Celite and concentrated in vacuo. Purification by flash
chromatography (3:1 hexanes/EtOAc) afforded compound 23
(26 mg, 74%) as a white foam: Rf ) 0.44 (2:1 hexanes/EtOAc);
IR (film) 2929, 2821, 1733, 1716, 1491, 1450, 1237, 1208, 1104;
1H NMR (360 MHz) δ 8.13 (s, 1H), 7.55-7.53 (m, 6H), 7.28-
7.18 (m, 9H), 4.41 (q, 2H, J ) 7.1 Hz), 4.32-4.29 (m, 1H), 3.49
(dd, 1H, J ) 2.3, 9.1 Hz), 3.51-3.45 (m, 1H), 2.95 (s, 3H), 1.96
(dd, 1H, J ) 3.9, 8.9 Hz), 1.40 (t, 3H, J ) 7.1 Hz); 13C NMR
(90 MHz) δ 179.2, 161.7, 146.9, 145.9, 128.6, 128.4, 127.9,
126.6, 74.2, 71.8, 61.1, 58.7, 55.6, 14.3; MS m/z (rel int) 473
(1, M + H), 427 (1), 395 (1), 243 (100), 231 (12), 185 (5); HRMS
SO6 (M + H) 351.1590, found 351.1583; [R]25 ) +32.6 (c 1,
D
CH2Cl2).
Th ia zolin e 18. A solution of compound 17 (159 mg, 0.45
mmol) in THF (3 mL) was treated with Burgess reagent8 (118
mg, 0.50 mmol) and heated for 15 min at 65 °C. The reaction
mixture was cooled to room temperature and concentrated in
vacuo, and the residue was chromatographed (1:1 hexanes/
EtOAc) to afford 131 mg (88%) of the title compound as a
colorless solid: Rf ) 0.30 (1:1 hexanes/EtOAc); IR (film) 2978,
2932, 1719, 1621, 1507, 1367, 1237, 1165; 1H NMR (360 MHz)
δ 5.49 (d, 1H, J ) 6.5 Hz), 5.11 (t, 1H, J ) 9.5 Hz), 4.69-4.66
(m, 1H), 4.24 (q, 2H, J ) 7.2 Hz), 3.81-3.77 (m, 1H), 3.62-
3.59 (m, 1H), 3.55-3.46 (m, 2H), 3.35 (s, 3H), 1.44 (s, 9H), 1.29
(t, 3H, J ) 7.2 Hz); 13C NMR (90 MHz) δ 175.6, 170.4, 155.1,
105.3, 80.0, 78.3, 61.7, 59.2, 53.1, 35.21, 28.2, 14.1; MS m/z
(rel int) 333 (100, M + H), 301 (23), 277 (81), 245 (72), 233
(88), 201 (17), 187 (9); HRMS (CI) calcd for C14H25N2SO5 (M +
(CI) calcd for C28H28N2SO3 473.1899, found 473.1890; [R]25
-260.8 (c 1, CH2Cl2).
)
D
Th ia zole 3. To a solution of thiazole 23 (10 mg, 0.021
mmol) in 1:1 chloroform/methanol (1.0 mL) was added TFA
(1.0 mL) with stirring at -10 °C. After 40 min, the volatile
components were removed in vacuo and azeotroped twice with
CH2Cl2. The resulting residue was dissolved in water and
washed with ether. The aqueous layer was lyophilized. The
crude TFA salt was dissolved in CH2Cl2 (1.0 mL) under
nitrogen and cooled to 0 °C. Triethylamine (0.01 mL, 0.063
mmol) was added, followed by a solution of di-tert-butyl
dicarbonate (4.5 mg, 0.021 mmol) in CH2Cl2 (1.0 mL). After 4
h, the solution was washed with 1 M HCl followed by brine.
The organic layer was dried (MgSO4), filtered, and concen-
trated. Purification by flash chromatography (3:2 hexanes/
EtOAc) afforded the title compound (6.8 mg, 98%) as a colorless
solid: Rf ) 0.24 (3:2 hexanes/EtOAc); IR (film) 3390, 2431,
2359, 2255, 2205, 1554, 1534, 1516; 1H NMR (360 MHz) δ 8.10
(s, 1H), 5.68-5.65 (m, 1H), 5.27-5.24 (m, 1H), 4.41 (q, 2H, J
) 7.1 Hz), 3.98-3.94 (m, 1H), 3.73 (dd, 1H, J ) 4.7, 9.0 Hz),
3.32 (s, 3H), 1.48 (s, 9H), 1.40 (t, 3H, J ) 7.1 Hz); 13C NMR
(90 MHz) δ 172.5, 161.1, 155.0, 147.1, 127.3, 80.1, 73.5, 61.1,
58.9, 52.8, 28.1, 14.1; MS m/z (rel int) 330 (3, M + H), 285
(14), 274 (38), 257 (19), 242 (10), 229 (40), 211 (18), 198 (11),
185 (63), 168 (9), 139 (33), 112 (8), 57 (100); HRMS (CI) calcd
for C14H23N2SO5 (M + H) 330.1249, found 330.1239. Anal.
Calcd for C14H22N2SO5: C, 50.90; H, 6.71; N, 8.48. Found: C,
H) 333.1484, found 333.1474; [R]25 ) +54.4 (c 1, CH2Cl2).
D
N-Tr -O-Meth yl-L-ser yl-O-TBDMS-L-ser in e Eth yl Ester
(20). Prepared from N-Tr-O-Me-L-Ser-OH26 as described for
compound 15. Purification by flash chromatography (2:1
hexanes/EtOAc) afforded compound 20 (84%, two steps) as a
colorless foam: Rf ) 0.26 (2:1 hexanes/EtOAc); IR (film) 2928,
2952, 2118, 1743, 1676, 1492, 1446, 1112; 1H NMR (360 MHz)
δ 8.72 (d, 1H, J ) 8.1 Hz), 7.57-7.54 (m, 6H), 7.29-7.12 (m,
9H), 4.72-4.69 (m, 1H), 4.31-4.22 (m, 3H), 4.18 (dd, 1H, J
∼2.4, 9.9 Hz), 3.83 (dd, 1H, J ) 2.8, 9.9 Hz), 3.38 (dd, 1H, J )
1.9, 8.9 Hz), 3.29-3.27 (m, 1H), 2.93 (s, 3H), 1.59 (d, 1H, J )
10.3 Hz), 1.31 (t, 3H, J ) 7.1 Hz), 0.91 (s, 9H), 0.06 (d, 6H, J
) 2.6 Hz); 13C NMR (90 MHz) δ 173.2, 170.1, 145.9, 128.6,
128.0, 126.5, 71.7, 71.3, 63.9, 61.3, 58.5, 57.5, 54.3, 25.6, 14.2,
-5.6, -5.7; MS m/z (rel int) 591 (2, M + H), 213 (1), 349 (25),
243 (100), 165 (8); HRMS (CI) calcd for C34H47N2SiO5 (M + H)
591.3254, found 591.3231; [R]25 ) -69.8 (c 1, CH2Cl2).
D
Th ioa m id e 21. Prepared from compound 20 as described
for compound 16. Purification by flash chromatography (3:1
hexanes/EtOAc) afforded the title compound (52%) as a color-
less oil: Rf ) 0.59 (3:1 hexanes/EtOAc); IR (film) 2927, 2858,
1745, 1503, 1440, 1251, 1204, 1113; 1H NMR (360 MHz) δ
10.41 (d, 1H, J ) 6.3 Hz), 7.50 (d, 6H, J ) 7.2 Hz), 7.32-7.19
(m, 9H), 5.29-5.26 (m, 1H), 4.33-4.28 (m, 3H), 4.18 (dd, 1H,
J ) 2.4, 10.1 Hz), 4.04 (dd, 1H, J ) 2.7, 10.1 Hz), 3.74-3.72
(m, 2H), 3.00 (s, 3H), 2.01-1.97 (m, 1H), 1.31 (t, 3H, J ) 7.1
Hz), 0.92 (s, 9H), 0.06 (d, 6H, J ) 1.4 Hz); 13C NMR (90 MHz)
δ 203.9, 169.1, 145.7, 128.7, 128.0, 126.7, 74.3, 71.9, 67.9, 62.9,
61.6, 59.6, 58.7, 25.6, 14.3, -5.6, -5.7; MS m/z (rel int) 607
(1, M + H), 529 (1), 350 (19), 243 (100), 165 (5); HRMS (CI)
calcd for C34H47N2SiSO4 (M + H) 607.3026, found 607.3018;
50.91; H, 6.77; N, 8.30; [R]25 ) -11.6 (c 1, CH2Cl2).
D
Ack n ow led gm en t. This work is supported by the
donors to the Petroleum Research Fund, administered
by the American Chemical Society, and by NSF grant
no. CHE-9321233.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3-5, 7, 8, 10-13, 15-18, and 20-23
(34 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
[R]25 ) -56.3 (c 1, CH2Cl2).
D
Alcoh ol 22. Prepared from compound 21 as described for
compound 17. Purification by flash chromatography (3:2
hexanes/EtOAc) afforded 22 (67%) as a colorless solid: Rf )
0.29 (3:2 hexanes/EtOAc); IR (film) 3258, 2931, 2886, 1741,
1507, 1451, 1204, 1114; 1H NMR (360 MHz) δ 10.41 (d, 1H, J
J O961408A