Synthesis of novel taxoid analogue containing sulfur group on C-13 side-chain: 2′-deoxy-2′-epi-mercaptopaclitaxel

Article abstract of DOI:10.1016/S0040-4020(03)01098-6

Paclitaxel analogues with a thiol group in place of the hydroxyl group on the C-13 side-chain constitute an interesting avenue of research for the study of new taxoid compounds. A synthetic route for the preparation of 2′-deoxy-2′-epi-mercaptopaclitaxel w

Full text of DOI:10.1016/S0040-4020(03)01098-6

Tetrahedron 59 (2003) 7409–7412
Synthesis of novel taxoid analogue containing sulfur group on
C-13 side-chain: 20-deoxy-20-epi-mercaptopaclitaxel
b
Xin Qi,a,b Sang-Hyeup Lee,b Juyoung Yoonc and Yoon-Sik Lee
,
,
*
*
aSchool of Chemical Engineering, Dalian University of Technology, Dalian 116012, People’s Republic of China
bSchool of Chemical Engineering, Seoul National University, Seoul 151-742, South Korea
cDepartment of Chemistry, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Ku, Seoul 120-750, South Korea
Received 24 May 2003; revised 14 July 2003; accepted 14 July 2003
Abstract—Paclitaxel analogues with a thiol group in place of the hydroxyl group on the C-13 side-chain constitute an interesting avenue of
research for the study of new taxoid compounds. A synthetic route for the preparation of 20-deoxy-20-epi-mercaptopaclitaxel with high ee has
been developed. The key step is the regio-controlled ring-opening reaction of the trans-oxazoline derivative with thiolacetic acid, which
allows the introduction of the sulfur-containing group onto the side-chain.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
mercaptopaclitaxel 2b through the coupling of (4S,5R)-
2,4-diphenyloxazoline-5-carboxylic acid 3 with suitably
protected baccatin III 4, followed by the ring-opening
reaction of the oxazoline intermediate with thiolacetic acid
as a key step.
Paclitaxel (taxolw) 1, a complex diterpenoid natural product
first isolated from the bark of the western yew tree, Taxus
brevifolia, has proved to be one of the most important new
anticancer agents to appear during last decade.1 In contrast
with other common anticancer drugs, paclitaxel inhibits cell
replication in the mitotic phase of the cell cycle by
promoting tubulin assembly and stabilizing the microtu-
bules formed, thus inducing cell death.2 Although numerous
efforts have been made to determine its structure–activity
relationship and elucidate its unique mechanism, the
specific roles of its various functional groups on the
molecular level remain unclear.1–3 Some research studies
have shown that the 20-hydroxyl functionality plays a crucial
role in its biological activity by interacting directly with a
protein residue in the paclitaxel–microtuble complex,4
perhaps acting as a hydrogen bond donor.5 In light of this
hypothesis, the synthesis of the 20-sulfur analogue (2a or 2b)
(Fig. 1) would be of great interest for the investigation of
paclitaxel binding site on the microtubules, and thus for the
development of new compounds with more desirable
properties than paclitaxel itself. Although the synthesis of
the 7b-sulfur analogue of paclitaxel was recently reported,6
to our knowledge, the synthesis of taxoid compounds
bearing thiol group at the C-13 side-chain has not yet been
demonstrated to date.
2. Results and discussion
Recently we reported the asymmetric syntheses of both syn
and anti, suitably protected b-phenylisocysteine.7 However,
the direct coupling of S-acetyl-N-benzoyl-phenylisocysteine
with 7-(triethylsilyl)baccatin III 4 was unsuccessful,
presumably because of the congested location of the C-13
hydroxy group. Thus, we decided to use an oxazoline
derivative for the coupling reaction.
Among the available hands of attaching a b-phenylisoserine
side-chain onto the C-13 hydroxy group of the baccatin III
moiety, the coupling of oxazoline derivatives with the
corresponding baccatin compound constitutes an attractive
We report herein the preparation of 20-deoxy-20-epi-
Keywords: taxol; mercaptopaclitaxel; oxazoline.
*
Corresponding authors. Tel.: þ82-2-3277-2400; fax: þ82-2-3277-2384;
e-mail: jyoon@ewha.ac.kr;Tel.: þ82-2-880-7073; fax: þ82-2-888-1604;
e-mail: yslee@snu.ac.kr
Figure. 1. Structures of paclitaxel and 20-deoxy-20-mercaptopaclitaxels.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01098-6

7410
X. Qi et al. / Tetrahedron 59 (2003) 7409–7412
alternative, and this is followed by simple hydrolysis, to
obtain the desired taxol with good yield.8 However, unlike
the hydrolysis procedure with dilute hydrochloric acid
producing no change0 at the C-5 configuration of the
oxazoline ring (5R!2 R), complete inversion at the C-5
configuration (5R!2S or 5S!2R) was observed during the
ring-opening reaction of oxazoline derivatives with thiola-
cetic acid in our previous experiments.07,9 Thus, the
methodology applied to the preparation of 2 -deoxy-20-epi-
mercaptopaclitaxel 2b involved the coupling of (4S,5R)-2,4-
diphenyloxazoline-5-carboxylic acid 3 with 7-(triethylsi-
lyl)baccatin III 4 first, then ring-opening with thiolacetic
acid to generate the sulfur-containing side-chain, followed
by two subsequent deprotection steps, as shown in
Scheme 1.
hydrolyzing methyl ester with lithium hydroxide, which
leads to there being less of the cis-isomer actually present in
the hydrolysis product.7 The ring-opening reaction of
coupling product 5 with thiolacetic acid was performed at
relatively simple conditions (708C and 12 h) to afford
compound 6 (20S,30S) with the thioacetyl group introduced
at the 20-position, without any of the (20R,30S)-isomer being
produced. Dilute rather than neat thiolacetic acid was used
during this process to help reduce the possibility of acid-
catalyzed cleavage of the 7-triethylsilyl group.12 The 7-
triethylsilyl group was then removed by means of hydrogen
fluoride–pyridine in dry THF to afford compound 7 using
the method described in the literature.13 The S-acetyl group
on the side-chain was able to be selectively removed under
aqueous basic conditions, based on the differences in
reactivity between the thioester and other ester groups in
the structure. However, it was found that the final product
2b (20S,30S) was always accom0panied by a small amount of
its diastereoisomer 2a (20R,3 S) based on its 1H NMR
spectrum.14 This small amount of epimerization ca0n
probably be attributed to the acidic thiol geminal 2 -
methane, under the basic reaction conditions, whose acidity
is enhanced by the presence of the adjacent ester bond. Four
kinds of bases such as LiOH, K2CO3, KHCO3 and NH3·H2O
were examined. Among them, KHCO3 proved to be the
best, whereas LiOH was too strong and resulted in the
hydrolysis of other ester bonds of the taxane and in more
severe epimerization. The use of a less than stoichiometric
amount of KHCO3 and the slow addition of the base
solution were adopted in order to obtain the best result. In
our experiment, a ratio of 9:1 (2b/2a) was obtained when
0.9 equiv. of KHCO3 was used.14
(4S,5R)-2,4-Diphenyloxazoline-5-carboxylic acid 3, gener-
ated from the corresponding methyl ester by hydrolysis,7
was coupled to 7-(triethylsilyl)baccatin III 410 in the
presence of DCC and 4-pyrrolidinopyridine, as shown by
Kingston,8 giving the coupling product 5. Excess carboxylic
acid 3 (3.5 equiv. in our methods) was used to ensure the
complete conversion of the baccatin compound. Although
this trans-oxazoline derivative 3 should in fact be mixed
with a small amount of its cis-isomer [(4S,5R):
(4S,5S)¼25:1, in the form of methyl esters7], the resulting
1
coupling product was quite pure based on the H NMR
spectrum. This is likely due in part to the difference of steric
hindrance between the trans- and cis- structures, when they
approached the C-13 hydroxy group hidden in the concavity
of the baccatin skeleton,11 and also because of the
epimerization of the cis-oxazoline methyl ester when
Scheme 1. Preparation of 20-deoxy-20-epi-mercaptopaclitaxel 2b. (i) DCC, 4-pyrrolidinopyridine, toluene, rt, 1 h. (ii) Thiolacetic acid, dioxane, 708C, 12 h. (iii)
HF–pyridine (70:30), THF, rt, 5 h. (iv) KHCO3, MeOH–H2O, rt, 2 h. (v) KHCO3, K2CO3 or LiOH, MeOH–H2O, rt.

X. Qi et al. / Tetrahedron 59 (2003) 7409–7412
7411
Another route was also explored from 6 to 8, and then 2b, as
shown in Scheme 1, but attempts to obtain the desired
product 8 were unsuccessful. Surprisingly, the S-acetyl
group was tolerated under KHCO3 or K2CO3 conditions,
and a mixture of several products was obtained from starting
material 6 when LiOH was employed. It would appear that
the low reactivity observed can be attributed to the existence
of the protective 7-triethylsilyl group. Similar observations
were reported by another research group regarding the
removal of the 10-acetyl group.15
temperature. The reaction mixture was then passed through
a short silica gel plug (,5 g) and further eluted with 50 mL
of EtOAc. The combined eluent was concentrated under
reduced pressure. A 1:1 mixture of EtOAc and hexane
(20 mL) was added to the residue and the suspension was
filtered through a cotton plug. The filtrate was concentrated
again. Purification of the residue by flash chromatography
(EtOAc–hexane, 1:3) afforded 5 as a pale yellow solid
(164 mg, 0.173 mmol, 93%). An analytical sample was
obtained by recrystallization (distilled EtOAc–hexane) as
white needles: mp 211–2128C; [a]2D0¼249.98 (c¼1.00,
CHCl3); IR (KBr) 3471, 2958, 2873, 1753, 1726, 1710,
1
1657 cm21; H NMR (CDCl3, 300 MHz) d 0.58 (m, 6H),
3. Conclusions
0.91 (t, J¼8.1, 7.7 Hz, 9H), 1.19 (s, 3H), 1.23 (s, 3H), 1.69
(s, 3H), 1.77 (s, 1H), 1.84–1.93 (m, 1H), 1.99 (s, 3H), 2.07
(s, 3H), 2.16 (s, 3H), 2.10–2.42 (m, 2H), 2.49–2.60 (m,
1H), 3.83 (d, J¼7.1 Hz, 1H), 4.14 (d, J¼8.2 Hz, 1H), 4.29
(d, J¼8.2 Hz, 1H), 4.50 (dd, J¼6.8, 10.3 Hz, 1H), 4.94 (d,
J¼6.6 Hz, 2H), 5.60 (d, J¼6.4 Hz, 1H), 5.68 (d, J¼7.0 Hz,
1H), 6.18 (m, 1H), 6.42 (s, 1H), 7.36–7.64 (m, 11H), 8.07
(d, J¼7.1 Hz, 2H), 8.24 (d, J¼7.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 5.20, 6.65, 9.93, 14.43, 20.72, 21.61,
26.47, 35.54, 43.09, 46.90, 58.38, 71.84, 72.23, 74.74,
74.89, 76.32, 77.21, 78.88, 80.80, 83.28, 84.11, 126.37,
126.62, 128.18, 128.50, 128.80, 128.92, 128.96, 129.23,
129.25, 129.98, 123.03, 133.63, 133.98, 139.73, 140.72,
166.86, 169.04, 169.76, 170.08, 201.58; HRMS (FAB)
m/z¼972.3966 [MþNa]þ, calcd for C53H63NO13-
SiNa¼972.3949.
4.1.2. 20-Deoxy-20-epi-acetylmercapto-7-(triethylsilyl)pa-
clitaxel 6. Compound 5 (140 mg, 0.147 mmol), thiolacetic
acid (1 mL) and dioxane (3 mL) were added in a 6 mL
pressure vial at room temperature. The vial was then closed
tightly with a Teflon disk lid, and was heated at 708C for
12 h. After concentration under reduced pressure, the sticky
yellowish oil was purified by flash chromatography
(EtOAc–hexane, 1:3) to afford 6 as a white solid
In conclusion, we have stereoselectively synthesized 20-
deoxy-20-epi-mercaptopaclitaxel through the coupling of
(4S,5R)-2,4-diphenyloxazoline-5-carboxylic acid with suit-
ably protected baccatin III, followed by the ring-opening
reaction of the oxazoline intermediate with thiolacetic acid
as a key step. Since we have shown the ring-opening
reactions of the oxazoline intermediates,9 our approach can
be used for the syntheses of taxol derivatives bearing
various C-13 side-chains.
4. Experimental
4.1. General methods
Unless otherwise noted, materials were obtained from
commercial suppliers and were used without further
purification. 7-(Triethylsilyl)baccatin III 4 was prepared
from 10-deacetylbaccatin III using the method described in
the literature.9 (4S,5R)-2,4-Diphenyloxazoline-5-carboxylic
acid 3 was synthesized by the procedure described in the
literature.7 THF, toluene and dioxane were freshly distilled
over sodium-benzophenone ketyl. The CHCl3 and MeOH
were distilled from CaH2. Flash chromatography was
carried out on silica gel 60 (230–400 mesh ASTM;
Merck). Thin layer chromatography (TLC) was carried
out using Merck 60 F254 plates with a thickness of 0.25 mm.
Preparative TLC was performed using Merck 60 F254 plates
with a thickness of 1 mm.
(107 mg,
0.105 mmol,
71%);
mp
165–1678C;
[a]1D5¼297.88 (c¼0.532, CHCl3); IR (KBr) 3483, 3425,
3300, 3026, 2952, 2873, 1747, 1726, 1710, 1663,
1610 cm21; H NMR (CDCl3, 300 MHz) d 0.49–0.63 (m,
1
6H), 0.93 (t, J¼8.0, 7.9 Hz, 9H), 1.12 (s, 3H), 1.15 (s, 3H),
1.17 (s, 3H), 1.64 (s, 3H), 1.69 (s, 1H), 1.81–1.90 (m, 1H),
2.03–2.28 (m, 2H), 2.15 (s, 3H), 2.33 (s, 3H), 2.44 (s, 3H),
2.39–2.56 (m, 1H), 3.64 (d, J¼7.0 Hz, 1H), 4.09 (d,
J¼8.4 Hz, 1H), 4.30 (d, J¼8.0 Hz, 1H), 4.35 (m, 1H), 4.86
(d, J¼3.8 Hz, 1H), 4.93 (d, J¼10.0 Hz, 1H), 5.61 (d,
J¼6.9 Hz, 1H), 5.73 (dd, J¼3.6, 9.3 Hz, 1H), 6.06 (m, 1H),
6.27 (s, 1H), 7.39–7.64 (m, 11H), 7.92 (m, 2H), 8.08 (m,
2H), 8.20 (d, J¼9.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
5.29, 6.75, 9.98, 20.81, 20.91, 22.11, 26.44, 30.38, 34.91,
37.14, 43.18, 46.82, 49.83, 54.46, 58.40, 72.11, 72.21,
74.80, 75.00, 76.45, 77.26, 78.75, 80.85, 84.21, 126.18,
127.12, 128.35, 128.60, 128.75, 129.20, 130.14, 131.93,
133.63, 133.70, 133.81, 127.80, 139.58, 166.92, 167.04,
169.12, 169.77, 171.44, 192.37, 201.65; HRMS (FAB)
m/z¼1026.4130 [MþH]þ, calcd for C55H68NO14-
SSi¼1026.4111.
Melting points were measured using a Bu¨chi 530 melting
point apparatus, and are uncorrected. 1H NMR spectra were
recorded using JEOL JNM-LA 300 or Bruker Avance 500
spectrometers with TMS as the internal standard. Chemical
shifts were expressed in ppm and coupling constants (J) in
Hz. 13C NMR were recorded using JEOL JNM-LA 300,
Bruker Avance 300 or 600 spectrometers. Infrared spectra
were recorded on a JASCO FTIR-200 Spectrometer. Mass
spectra were obtained using JEOL JMS AX505WA or JMS-
700 Mstation spectrometers. Optical rotations were
measured using a JASCO 3100 polarimeter.
4.1.1. Compound 5. A solution of DCC (134 mg,
0.651 mmol) in dry toluene (10 mL) was added to a
suspension of 7-(triethylsilyl)baccatin III 4 (130 mg,
0.186 mmol), carboxylic acid 3 (174 mg, 0.651 mmol) and
a catalytic amount of 4-pyrrolidinopyridine in 5 mL of dry
toluene at 08C under N2 while stirring. After 10 min, the
reaction mixture was stirred for a further 1 h at room
4.1.3. 20-Deoxy-20-epi-acetylmercaptopaclitaxel 7. To a
solution of compound 6 (90 mg, 0.088 mmol) in dry THF
(9 mL) was added HF–pyridine (70:30) at 08C. After

7412
X. Qi et al. / Tetrahedron 59 (2003) 7409–7412
10 min, the reaction mixture was then stirred for a further
5 h at room temperature. Water (10 mL) was added to
quench the reaction and the mixture was extracted with
EtOAc (4£20 mL). The combined organic layer was
subsequently washed with 5% aqueous NaHCO3 (30 mL)
and brine, dried over Na2SO4, and concentrated in vacuo.
Purification of the crude product by flash chromatography
(EtOAc–hexane, 1:1) afforded the corresponding product 7
as a white solid (72 mg, 0.079 mmol, 90%); mp 180–
1828C; [a]1D8¼298.98 (c¼0.431, CHCl3); IR (KBr) 3536,
3515, 3415, 2984, 2947, 1715, 1678, 1610 cm21; 1H NMR
(CDCl3, 300 MHz) d 1.05 (s, 3H), 1.08 (s, 3H), 1.18 (s, 3H),
1.63 (s, 3H), 1.69 (s, 1H), 1.80–1.88 (m, 1H), 2.05–2.41
(m, 3H), 2.22 (s, 3H), 2.32 (s, 3H), 2.44 (s, 3H), 2.44–2.59
(m, 1H), 3.65 (d, J¼7.0 Hz, 1H), 4.11 (d, J¼8.2 Hz, 1H),
4.30 (d, J¼8.6 Hz, 1H), 4.34 (m, 1H), 4.81 (d, J¼3.9 Hz,
1H), 4.94 (d, J¼8.4 Hz, 1H), 5.60 (d, J¼7.1 Hz, 1H), 5.72
(dd, J¼4.0, 9.3 Hz, 1H), 6.08 (m, 1H), 6.10 (s, 1H), 7.33–
7.65 (m, 11H), 7.90 (m, 2H), 8.08 (m, 2H), 8.14 (d,
J¼9.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 20.80, 21.78,
22.05, 24.70, 26.61, 28.46, 29.29, 29.66, 30.35, 34.84,
35.19, 35.42, 71.93, 71.97, 74.99, 75.43, 76.32, 77.20,
79.16, 80.76, 84.39, 126.09, 127.09, 128.60, 128.73, 129.08,
129.17, 130.12, 131.94, 132.82, 133.74, 137.82, 141.88,
166.84, 166.97, 169.89, 171.15, 171.33, 192.33, 203.57;
HRMS (FAB) m/z¼912.3265 [MþH]þ, calcd for
C49H54NO14S¼912.3250.
74.81, 75.49, 76.38, 78.98, 81.02, 84.32, 126.06, 127.03,
127.09, 128.50, 128.64, 128.69, 128.80, 128.96, 129.02,
129.15, 130.05, 132.07, 132.99, 133.58, 133.81, 138.51,
141.78, 166.98, 167.01, 169.66, 171.16, 172.91, 203.51;
HRMS (FAB) m/z¼892.2977 [MþNa]þ, calcd for C47H51-
NO13SNa¼892.2965.
Acknowledgements
We thank Hanmi Pharmaceutical Co., Ltd for the generous
donation of 10-deacetylbaccatin III. Financial support from
the Brian Korea 21 Program is gratefully acknowledged.
References
1. For recent review, see: Kingston, D. G. I. Chem. Commun.
2001, 867.
2. Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665.
3. Ojima, I.; Bounaud, P.; Ahern, D. G. Bioorg. Med. Chem. Lett.
1999, 9, 1189.
´ ´
´
4. (a) Lozynski, M.; Rusinska-Roszak, D. Tetrahedron Lett.
´
1995, 36, 8849. (b) Jimenez-Barbero, J. A.; Souto, A. A.; Abal,
´
M.; Barasoain, I.; Evangelio, J. A.; Acuna, A. U.; Andreu,
J. M.; Amat-Guerri, F. Bioorg. Med. Chem. 1998, 6, 1857. (c)
Kant, J.; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina,
4.1.4. 20-Deoxy-20-epi-mercaptopaclitaxel 2b. To a sol-
ution of 7 (40 mg, 0.044 mmol) in MeOH (3 mL) was added
dropwise a solution of KHCO3 (4.0 mg, 0.040 mmol) in
H2O (0.2 mL) over a period of 1.5 h at room temperature
under N2 with vigorous stirring. After another 30 min the
reaction mixture was poured into a 1:1 mixture of CHCl3–
H2O (30 mL), and acidified with 2–3 drops of 1N HCl to pH
1–2. The organic layer was collected, and the water layer
was extracted with CHCl3 (3£10 mL). The combined
organic layer was washed with water (15 mL), dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by preparative TLC (EtOAc–hexane, 1:1) in a dark
place, followed by flash chromatography with a small silica
gel column wound with aluminum foil (EtOAc–hexane,
1:2, containing 0.5% MeOH, all distilled and degassed
under N2 before use) to afford final product 2b (mixed with
´
V. Bioorg. Med. Chem. Lett. 1993, 3, 2471. (d) Guenard, D.;
´
Gueritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26,
160.
5. Moyna, G.; Williams, H. J.; Scott, A. I. Synth. Commun. 1997,
27, 1561.
6. Mastalerz, H.; Zhang, G. F.; Kadow, J.; Fairchild, C.; Long,
B.; Vyas, D. M. Org. Lett. 2001, 3, 1613.
7. (a) Lee, S.-H.; Qi, X.; Yoon, J.; Nakamura, K.; Lee, Y.-S.
Tetrahedron 2002, 58, 2777. (b) For other preparation method
of 3, see: Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Ham, W.-H.
Tetrahedron Lett. 1998, 39, 8129.
8. Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483.
9. Lee, S.-H.; Yoon, J.; Nakamura, K.; Lee, Y.-S. Org. Lett.
2000, 2, 1243.
10. Kant, J.; O’Keeffe, W. S.; Chen, S. H.; Farina, V.; Fairchild,
C.; Johnston, K.; Kadow, J. F.; Long, B. H.; Vyas, D.
Tetrahedron Lett. 1994, 35, 5543.
1
10% 2a as shown by H NMR) as a white solid (16.3 mg,
0.019 mmol, 47%); mp 149–1518C; [a]2D5¼226.08
(c¼0.500, distilled EtOAc); IR (KBr) 3489, 3415, 2952,
2926, 2852, 2558, 1726, 1663, 1610 cm21 1H NMR
;
´
´
11. Denis, J. N.; Greene, A. W.; Guenard, D.; Gueritte-Voegelein,
F.; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917.
12. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis. 3rd ed. Wiley: New York, 1999.
(CDCl3, 500 MHz) d 1.10 (s, 3H), 1.14 (s, 3H), 1.18 (s,
3H), 1.64 (s, 3H), 1.74 (s, 1H), 1.82–1.89 (m, 1H), 2.03–
2.43 (m, 3H), 2.21 (s, 3H), 2.37 (s, 3H), 2.49–2.56 (m, 1H),
2.54 (d, J¼11.2 Hz, 1H), 3.68 (d, J¼6.9 Hz, 1H), 3.89 (dd,
J¼3.8, 11.1 Hz, 1H), 4.13 (d, J¼8.6 Hz, 1H), 4.30 (d,
J¼8.2 Hz, 1H), 4.32 (m, 1H), 4.94 (d, J¼8.0 Hz, 1H), 5.62
(d, J¼7.0 Hz, 1H), 5.78 (dd, J¼3.8, 9.5 Hz, 1H), 6.07 (m,
1H), 6.13 (s, 1H), 7.30–7.63 (m, 11H), 7.94 (m, 2H), 8.06
(m, 2H), 8.16 (d, J¼9.5 Hz, 1H); 13C NMR (CDCl3,
150 MHz) d 9.45, 14.09, 20.82, 21.49, 22.79, 26.66, 35.10,
35.53, 43.04, 44.55, 45.64, 56.53, 58.55, 71.19, 72.12,
13. (a) Ojima, I.; Slater, J. C.; Michaud, E.; Kuduk, S. D.;
Bounaud, P.; Vrignaud, P.; Bissery, M.; Veith, J. M.; Pera, P.;
Bernacki, R. J. J. Med. Chem. 1996, 39, 3889. (b) Jagtap, P. G.;
Kingston, D. G. I. Tetrahedron Lett. 1999, 40, 189.
14. The small peaks on the 1H NMR spectrum of 2b belong to 2a.
For example: d 7.03 (d, C30 –NHCO), 6.26 (s, C10–H), 3.74
(d, C3–H).
15. Zheng, Q. Y.; Darbie, L. G.; Cheng, X. Q.; Murray, C. K.
Tetrahedron Lett. 1995, 36, 2001.