Synthesis of novel isoxazole-linked steroidal glycoconjugates-an application of a novel steroidal nitrile oxide

Article abstract of DOI:10.1016/j.tetlet.2008.01.130

Isoxazole-linked steroidal glycoconjugates are prepared by 1,3-dipolar cycloaddition reactions of an in situ generated and hitherto unknown steroidal nitrile oxide with appropriate propargyl ethers of sugars. The methodology provides a novel vector in the

Full text of DOI:10.1016/j.tetlet.2008.01.130

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2069–2073
Synthesis of novel isoxazole-linked steroidal
glycoconjugates—an application of a novel steroidal nitrile oxide
Karuna S. Wankhede b, Vipraja V. Vaidya b, Prajakta S. Sarang b,
Manikrao M. Salunkhe a,*,1, Girish K. Trivedi b,*
a Shivaji University, Vidyanagar, Kolhapur 416 004, Maharastra, India
b Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400 032, India
Received 29 October 2007; revised 17 January 2008; accepted 31 January 2008
Available online 6 February 2008
Abstract
Isoxazole-linked steroidal glycoconjugates are prepared by 1,3-dipolar cycloaddition reactions of an in situ generated and hitherto
unknown steroidal nitrile oxide with appropriate propargyl ethers of sugars. The methodology provides a novel vector in the form
of an easily accessible nitrile oxide having the ability to couple with many biomolecules, thus offering a new pathway to construct
biologically significant novel steroidal conjugates.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Bioconjugation; Glycoconjugates; Cycloaddition; Isoxazole; Steroid; Propargyl ethers of sugars
Bioconjugation has emerged as a fast growing techno-
logy providing a simple method to couple two or more
molecular entities with distinct properties to form novel
conjugates possessing the combined properties of its indi-
vidual components.1 The medicinal applications of this
are based on the fact that several new conjugates arising
through such bioconjugation have been found to exhibit
unusual biological properties and activities as the different
molecular segments act cooperatively.
Steroids, due to their rigid framework and potential
for varying levels of functionalization, broad biological
activity profile and ability to penetrate the cell mem-
brane and bind to specific hormonal receptors, have
become preferred synthons for the development of diverse
bioconjugates. Several conjugates derived from diverse
steroids through integration and/or linkage with other
biomolecules, drugs and other functional molecules along
with their pharmacological applications have been
reported.2 Some steroidal framework conjugates are
steroid–polyamine conjugates,3 steroid–anthraquinone
hybrids,4 steroid–carbohydrate conjugates5 and many
other steroidal conjugates.6 Steroidal glycosides are used
as agents for combating cholesterol, microbes, fungi,
viruses, tumours and molluscs.7 Amongst several steroidal
glycosides one well-known example is digitoxin, a cardiac
glycoside.
Recently, the so-called ‘Click chemistry’ has been used
in the synthesis of a wide variety of glycoconjugates.8–10
This has been attributed to the ease of reaction and relative
stability of the 1,2,3-triazole linker. However, the use of an
isoxazole moiety in a similar sense has yet to be realized
fully. Based on the stability of nitroalkanes and in view
of the availability of several efficient methods of transform-
ing nitroalkanes into their respective nitrile oxides11 and
the utility of carbohydrates in cycloaddition reactions,12
it appeared of interest to employ an isoxazole moiety in
the aforementioned sense. In the present Letter, we report
the application of a novel steroidal nitrile oxide, as a
*
Corresponding authors. Tel./fax: +91 231 2691533 (M.M.S.); tel./fax:
+91 22 22816750 (G.K.T.).
E-mail addresses: mmsalunkhe@hotmail.com (M. M. Salunkhe),
snehgkt@yahoo.com (G. K. Trivedi).
1
Vice-Chancellor.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.130

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K. S. Wankhede et al. / Tetrahedron Letters 49 (2008) 2069–2073
O
O
OSugar
NO2
N
O
+
OSugar
AcO
2
AcO
4
3
O
AcO
1
Scheme 1. Retrosynthetic analysis.
variant in ‘Click’-like chemistry, for the synthesis of isoxaz-
ole-linked steroidal glycoconjugates.
O
O
Towards a target such as 4, a retrosynthetic analysis
(Scheme 1) was carried out by taking into account the
ready access to propargyl ether sugars 2 and steroidal
nitroalkane 3.
NO2
a
90%
AcO
AcO
1
3
The synthetic phase of our investigation started with the
synthesis of 3b-acetoxy-16a-nitromethyl-5-pregnen-20-one
3, starting from readily available 16-dehydropregnenolone
acetate (16-DPA) (1) using 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base and nitromethane in dry dichloro-
methane. The reaction was complete in 12 h affording the
desired product in 90% yield as shown in Scheme 2.13 To
the best of our knowledge, the only report available for
the preparation of this compound is by employing piperi-
dine as a base and the reaction takes 5 days to complete.14
The propargyl ethers of the sugars were prepared from
readily available sugars such as D-glucose, D-mannitol
and D-galactose. All the monosaccharides were trans-
formed into the respective alcohols followed by treatment
with NaH, propargyl bromide and tetrabutylammonium
bromide in THF as a solvent affording the respective pro-
pargyl ethers 2a, 2b, 2c and 2e. Propargyl ether 2d was
obtained by conversion of D-glucose into the D-glucal,
which on Ferrier rearrangement with propargyl alcohol
using bismuth nitrate in acetonitrile, following a literature
procedure,15 afforded the required product.
Scheme 2. Reagents and conditions: (a) DBU, CH3NO2, CH2Cl2, ꢀ15 °C
to rt, 12 h.
O
OSugar
b
N
O
3
+
OSugar
AcO
2a-e
4a-e
Scheme 3. Reagents and conditions: (b) PhNCO, Et3N, dry benzene, rt.
13C NMR signals were observed17 at d 102 ppm for C-40,
d 167 ppm for C-50, d 168 ppm for C-30, d 170 ppm for
the acetate carbonyl and at d 207 ppm for C-20, which lent
further support to the assigned structures.16 Since the
stereochemical outcome of the conjugate addition has been
shown to be dependent on the nature of the nucleophile
employed and the stereoselectivity varies from highly syn
selective to highly anti selective,18 it was expedient to ascer-
tain the stereostructure of steroidal nitroalkane 3 on the
one hand, and that of the derived cycloadduct on the other.
Therefore, single crystal X-ray analysis of the cycloadduct
derived from propargyl ether 2a and nitroalkane 3 was per-
formed. The ORTEP diagram of the steroidal glycoconju-
gate 4a is given in Figure 1.19 From the molecular geometry
of 4a it can safely be concluded that the conjugate addition
of nitromethane to 16-DPA is anti-selective and that the
1,3-dipolar cycloaddition is regioselective.
In our approach, nitroalkane 3 was treated with propar-
gyl ethers 2a–e in the presence of phenyl isocyanate
(PhNCO) and triethylamine in dry benzene at room
temperature utilizing Mukaiyama’s conditions.11a The
one-pot reaction proceeds completely regioselectively
affording 3,5-disubstituted isoxazoles 4a–e as shown in
Scheme 3.16 All the newly formed glycoconjugates (Table
1) were purified by column chromatography over silica
gel to furnish the desired products in 58–65% yield.
The regioselective formation of the cycloadduct was
1
confirmed by the appearance of characteristic H NMR
In conclusion, we have developed a very simple and con-
venient [3+2] cycloaddition route for the synthesis of a new
class of steroidal conjugates 4a–e, featuring an isoxazole
moiety between the sugar and the steroid entities. We have
in turn, provided a novel vector in the form of an easily
signals at d 6.03–6.10 ppm as singlets for 40-H. Other
signals such as that at d 5.36–5.37 ppm (broad singlet for
6-H), d 3.00 ppm as a doublet (17-H) and the remaining
signals were in accordance with the assigned structures.16

K. S. Wankhede et al. / Tetrahedron Letters 49 (2008) 2069–2073
2071
Table 1
Cycloaddition of steroidal nitrile oxide 3 with sugar propargyl ethers
Entry
Sugar propargyl ethers
Cycloadduct
Yielda (%)
O
5''
21
20
O
6''
4''
O
O
18
O
O
12
17
16
O
O
11
4'
6'
3''
19
1
1''
13
5'
1
65
O
O
3'
O
O
O
9
2''
2
14
15
8
7
N
2'
O
10
O
1'
2a
AcO
3
5
6
4
4a
O
O
O
4'
6'
5"
4"
O
2"
2
3
4
62
60
58
64
O
1''
5'
3'
O
BnO
O
N
O
1'
2b
2'
3"
BnO
O
4b
4c
4d
AcO
AcO
O
3'
2''
O
O
6'
7'
4'
O
O
O
1''
5'
O
H
H
N
2'
O
1'
2c
6"
OAc
O
3'
5''
O
O
O
OAc
OAc
6'
4'
4''
3''
O
1''
5'
OAc
2''
N
2'
O
1'
2d
AcO
AcO
O
O
O
O
O
6"
O
1"
6'
4'
O
4"
O
O
5
5"
5'
3'
O
2"
O
N
2'
O
3"
1'
O
O
2e
4e
a
Yields after column chromatography.
accessible nitrile oxide having the ability to couple with a
host of biomolecules, thus offering a new pathway to
construct novel molecular entities bearing the pregneno-
lone framework. The developed methodology may prove
beneficial in the synthesis of other biologically significant
steroidal conjugates, studies on which are in progress.
Fig. 1. ORTEP representation of the X-ray structure of 4a.

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K. S. Wankhede et al. / Tetrahedron Letters 49 (2008) 2069–2073
acetyl-Me), 2.16 (s, 3H, 21-H3), 2.31–2.33 (m, 2H), 2.48 (d, 1H,
Acknowledgements
J = 9 Hz, 17-H), 3.37 (m, 1H, 16-H), 4.28 (d, 2H, J = 6 Hz,
nitromethyl), 4.58 (m, 1H, 3-H), 5.37 (br s, 1H, 6-H) ppm. 13C
NMR (75 MHz, CDCl3): d 13.79 (C-18), 19.26 (C-19), 20.79, 21.44
(acetyl-CH3), 27.64, 28.95, 31.48 (C-21), 35.34, 36.52, 36.88, 37.97,
38.67, 44.96, 49.60, 55.32, 67.36 (C-17), 73.68 (C-3), 79.59, 121.93
(C-6), 139.66 (C-5), 170.57 (acetate-CO), 206.89 (C-20) ppm.
14. Dodson, R. M. United States Patent, Patent No. US2794815
19570604, 1957; Chem. Abstr. 1957, 51, 91139.
The authors thank UGC, DRDO, New Delhi (India) for
financial support .V.V.V. thanks UGC, New Delhi (India)
for the award of JRF. P.S.S. thanks CSIR, New Delhi
(India) for the award of SRF.
References and notes
15. Naik, P. U.; Nara, S. J.; Harjani, J. R.; Salunkhe, M. M. J. Mol.
Catal. A: Chem. 2005, 234, 35.
1. (a) Singh, Y.; Spinelli, N.; De Francq, E.; Dumy, P. Org. Biomol.
Chem. 2006, 4, 1413; (b) Virta, P.; Katajisto, J.; Niittymaki, T.;
Lonnberg, H. Tetrahedron 2003, 59, 5137. For reviews see: (c) Dedola,
S.; Nepogodiev, S. A.; Field, R. A. Org. Biomol. Chem. 2007, 5, 1006;
(d) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org.
Chem. 2006, 51; (e) Wu, P.; Fokin, V. V. Aldrichim. Acta 2007, 40, 7;
(f) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid Commun. 2007,
28, 15; (g) Wang, Q.; Chittaboina, S.; Barnhill, H. N. Lett. Org.
Chem. 2005, 2, 293.
16. General procedure for the cycloaddition: To 25 mL of dry benzene
containing 1 mmol of PhNCO and 0.55 mmol of propargyl ether 2
were added a solution of 0.55 mmol of nitro compound 3 and 10
drops of Et3N in 15 mL of dry benzene. The reaction started, evolving
CO2 and diphenylurea precipitated. After stirring the reaction mixture
overnight, the solution was filtered. The brownish yellow benzene
solution was evaporated under reduced pressure, the residue was
dissolved in diethyl ether and filtered and the filtrate washed with dil
HCl and then with water and dried over anhydrous Na2SO4. The
product was purified by column chromatography over silica gel using
a mixture of petroleum ether and ethyl acetate (70:30).
2. For a review see: Salunkhe, D. B.; Hazra, B. G.; Pore, V. S. Curr.
Med. Chem. 2006, 13, 813.
3. (a) Bellini, A. M.; Quaglio, M. P.; Guarneri, M. Eur. J. Med. Chem.
1983, 18, 185; (b) Bellini, A. M.; Quaglio, M. P.; Guarneri, M. Eur. J.
Med. Chem. 1983, 18, 191; (c) Chitkul, K.; Arash, B.; Bradley, M.
Tetrahedron Lett. 2001, 42, 6211.
4. De Riccardis, F.; Izzo, I.; Di Filippo, M.; Sodano, G.; D’Acquisto, F.;
Carnuccio, R. Tetrahedron 1997, 53, 10871.
5. Gargiulo, D.; Blizzard, T. A.; Nakanishi, K. Tetrahedron 1989, 45,
5423.
6. Mehta, G.; Singh, V. Chem. Soc. Rev. 2002, 31, 324.
Spectral data of compounds: (i) Compound 4a: White crystalline solid,
mp 168–170 °C. IR (CHCl3):
mmax = 3100, 1734, 1710, 1240,
760 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.74 (s, 3H, 18-H3), 1.03
.
(s, 3H, 19-H3), 1.15 (m, 2H), 1.31 (s, 3H), 1.36 (s, 3H), 1.43 (s, 3H),
1.49 (s, 3H), 1.57–1.90 (m, 13H), 2.04 (s, 3H, acetyl-Me), 2.18 (s, 3H,
21-H3), 2.33 (m, 2H), 3.00 (d, 1H, J = 9Hz, 17-H), 3.92–4.11 (m, 5H,
16-H, 600-H2, 400-H, 300-H), 4.29 (m, 1H, 500-H), 4.54 (d, 1H, J = 3.6 Hz,
200-H), 4.59 (m, 1H, 3-H), 4.69 (s, 2H, 60-H2), 5.36 (br s, 1H, 6-H), 5.88
(d, 1H, J = 3.6 Hz, 100-H), 6.10 (s, 1H, 40-H) ppm. 13C NMR
(75 MHz, CDCl3): d 13.67 (C-18), 19.30 (C-19), 20.87, 21.44 (acetyl-
CH3), 25.41, 26.22, 26.79, 26.87, 27.67, 31.37, 31.55, 31.64, 31.69 (C-
21), 34.30, 36.57, 36.94, 38.01, 38.59, 45.11, 49.67, 55.68, 63.51, 67.50
(C-17), 69.02, 72.23, 73.72 (C-3), 81.11, 82.47, 82.75, 102.60 (C-40),
105.22 (C-10), 109.21 (˜C(CH3)2, sugar), 118.98 (˜C(CH3)2, sugar),
122.08 (C-6), 139.66 (C-5), 167.50 (C-50), 168.46 (C-30), 170.55
(acetate-CO), 207.70 (C-20) ppm. HRMS (TOF, ES+): calcd for
C39H56NO10: 698.3904 [M++H]; found, 698.3910 [M++H].
7. Mbadugha, B. N. A.; Menger, F. M. Org. Lett. 2003, 5, 4041 and
references cited therein.
8. (a) Chittaboina, S.; Xie, F.; Wang, Q. Tetrahedron Lett. 2005, 46,
2331; (b) Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos,
J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J. A.;
Isac-Garcia, J.; Santoyo-Gonzalez, F. Org. Lett. 2003, 5, 1951.
9. Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitan-Vallvey, L. F.;
Santoyo-Gonzalez, F. Org. Lett. 2004, 6, 3687.
10. (a) Kuijpers, B. H. M.; Groothuys, S.; Keerweer, A. R.; Quaedflieg, P.
J. L. M.; Blaquw, R. H.; Van Delft, F. L.; Rutjes, F. P. J. T. Org. Lett.
2004, 6, 3123; (b) Dondoni, A.; Giovannini, P. P.; Massi, A. Org.
Lett. 2004, 6, 2929; (c) Hotha, S.; Kashyap, S. J. Org. Chem. 2006, 71,
364.
11. (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339; (b)
Chen, Y.-J.; Li, C.-N. J. Chin. Chem. Soc. 1993, 40, 203; (c)
Kantorowski, E. J.; Brown, S. P.; Kurth, M. J. J. Org. Chem. 1998,
63, 5272; (d) Kumaran, G.; Kulkarni, G. H. Tetrahedron Lett. 1994,
35, 5517; (e) Shimizu, T.; Hayashi, Y. Bull. Chem. Soc. Jpn. 1984, 57,
2531; (f) Shimizu, T.; Hayashi, Y.; Shibafuchi, H.; Teramura, K. Bull.
Chem. Soc. Jpn. 1986, 59, 2827.
12. (a) Gallos, J. K.; Koumbis, A. E. Curr. Org. Chem. 2003, 7, 397; (b)
Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 771.
13. Procedure for the preparation of 3b-acetoxy-16a-nitromethyl-5-pre-
gnen-20-one (3): To a stirred solution of 16-DPA (0.178 g, 0.5 mmol)
and freshly distilled nitromethane (0.25 mL, 5 mmol) in dry dichloro-
methane (10 mL), DBU (0.37 mL, 2.5 mmol) was added at ꢀ15 °C.
The reaction mixture was then stirred at room temperature. After 12 h
2 N HCl (10 mL) was added, the layers were partitioned, and the
acidic layer was extracted with dichloromethane (3 ꢁ 15 mL). The
combined extracts were dried over anhydrous Na2SO4 and the solvent
was evaporated under reduced pressure. The product obtained was
purified by recrystallization using petroleum ether and dichloro-
methane (9:1) to afford nitro compound 3 in 90% yield.
(ii) Compound 4b: Yellowish sticky mass. IR (CHCl3): mmax = 2932,
1732, 1707, 1372, 1243, 760 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
0.73 (s, 3H, 18-H3), 1.03 (s, 3H, 19-H3), 1.15 (m, 2H), 1.31 (s, 3H),
1.48 (s, 3H), 1.55–1.89 (m, 13H), 2.03 (s, 3H, acetyl-Me), 2.16 (s, 3H,
21-H3), 2.34 (m, 2H), 3.00 (d, 1H, J = 9Hz, 17-H), 3.78(d, 1H,
J = 5.4 Hz), 3.91–3.95 (m, 2H), 4.36 (m, 1H), 4.47–4.68 (m, 6H), 5.36
(br s, 1H, 6-H), 5.94 (d, 2H, J = 3.6Hz, 100-H), 6.03 (s, 1H, 40-H),
7.28–7.33 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3): d 13.67 (C-18),
19.29 (C-19), 20.86, 21.42 (acetyl Me), 26.27, 26.79, 27.67, 31.35,
31.53, 31.62, 31.70 (C-21), 34.24, 36.55, 36.91, 38.00, 38.56, 45.07,
49.64, 55.65, 64.25, 68.73 (C-17), 69.07, 71.93 (–OCH2Ph), 73.76
(C-3), 79.08, 81.65, 82.15, 102.49 (C-40), 105.12 (C-100), 111.76
(˜C(CH3)2, sugar), 122.13 (C-6), 127.64 (Ar-C), 128.00 (Ar-C),
128.52 (Ar-C), 137.33 (Ar-C), 139.58 (C-5), 167.47 (C-50), 168.94
(C-30), 170.55 (acetate-CO), 207.73 (C-20) ppm. HRMS (TOF, ES+):
calcd for C42H56NO9: 718.3955 [M++H], found, 718.3953 [M++H].
(iii) Compound 4c: Yellowish sticky mass. IR (CHCl3): mmax = 2932,
1734, 1710, 1240, 760 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.73 (s,
.
3H, 18-H3), 0.86 (m, 2H), 1.03 (s, 3H, 19-H3), 1.25 (s, 6H, ˜C(CH3)2),
1.52–1.89 (complex m, 13H), 2.03 (s, 3H, –COCH3), 2.17 (s, 3H,
21-Me), 2.34 (m, 2H), 3.00 (d, 1H, J = 9 Hz, 17-H), 3.57 (m, 2H,
70-H), 3.72 (t, 1H, J = 7 Hz, 200-Ha-H), 3.92 (t, 1H, J = 9.3 Hz, 16-H),
4.05 (t, 1H, J = 7.2 Hz, 200-Hb-H), 4.28 (m, 1H, 100-H), 4.59 (br s, 3H,
3-H, 60-H2), 5.37 (br s, 1H, 6-H), 6.04 (s, 1H, 40-H) ppm. 13C NMR
(75 MHz, CDCl3): d 13.65 (C-18), 19.28 (C-19), 20.86, 21.39 (acetyl
CH3), 25.32, 26.73, 27.67, 31.39, 31.52, 31.62, 31.66 (C-21), 34.34,
36.54, 36.91, 38.00, 38.57, 45.07, 49.66, 55.67, 64.24, 66.44 (C-17),
69.11, 71.92, 73.72 (C-3), 74.55, 102.59 (C-40), 109.58 (˜C(CH3)2,
sugar), 122.09 (C-6), 139.61 (C-5), 167.48 (C-50), 168.64 (C-30), 170.48
Spectral data of compound 3: White crystalline solid, mp 149 °C. IR
(CHCl3): mmax = 2938, 1729, 1701, 1552, 1438, 1381, 1363 cmꢀ1 1H
.
NMR (300 MHz, CDCl3): d 0.68 (s, 3H, 18-H3), 1.02 (s, 3H, 19-H3),
1.11–1.29 (m, 2H), 1.33–1.65 (m, 10H), 1.85–1.94 (m, 3H), 2.04 (s, 3H,

K. S. Wankhede et al. / Tetrahedron Letters 49 (2008) 2069–2073
2073
(acetate-CO), 207.67 (C-20) ppm. HRMS (TOF, ES+): calcd for
C33H48NO7: 570.3431 [M++H]; found, 570.3424 [M++H].
3.98 (m, 2H), 4.23 (d, 1H, J = 9.1 Hz), 4.31 (m, 1H), 4.60 (m, 4H), 5.37
(br s, 1H, 6-H), 5.54 (d, 1H, J = 5.1 Hz, 100-H), 6.05 (s, 1H, 40-H)
ppm.13C NMR (75 MHz, CDCl3): d 13.68 (C-18), 19.30 (C-19), 20.88,
21.43 (acetyl CH3), 24.45, 24.92, 25.98, 26.09, 27.68, 31.38, 31.55,
31.65, 31.72, 34.28, 36.57, 36.94, 38.02, 38.59, 45.09, 49.68, 55.67,
64.25, 66.89 (C-17), 69.08, 69.90, 70.46, 70.64, 71.10, 73.76 (C-3),
96.33, 102.46 (C-40), 108.66 (anomeric C, sugar), 109.36 (˜C(CH3)2,
sugar), 122.14 (C-6), 139.62 (C-5), 167.47 (C-50), 169.19 (C-30), 170.55
(acetate-CO), 207.75 (C-20) ppm. HRMS (TOF, ES+): calcd for
(iv) Compound 4d: Yellowish sticky mass, IR (CHCl3): mmax = 2921,
2851, 1742, 1705, 1240, 760 cmꢀ1. 1H NMR (300 MHz, CDCl3): d 0.74
(s, 3H, 18-H3), 1.03 (s, 3H, 19-H3), 1.16–1.91 (complex m, 15H), 2.03
(s, 3H, acetyl-Me, steroid), 2.10 (s, 6H, acetyl-Me, sugar), 2.18 (s, 3H,
21-H3), 2.33 (m, 2H), 3.00 (d, 1H, J = 9 Hz, 17-H), 3.92 (t, 1H,
J = 9 Hz, 16-H), 4.13-4.24 (m, 3H, 60-H2, 500-H), 4.63–4.67 (m, 2H,
3-H, 600-Ha), 4.77 (d, 1H, J = 13.5 Hz, 600-Hb), 5.14 (s, 1H, 100-H), 5.32
(s, 1H, 6-H), 5.36 (s, 1H, 400-H), 5.84 (d, 1H, J = 10.2 Hz, 300-H), 5.93
(d, 1H, J = 10.2 Hz, 200-H), 6.06 (s, 1H, 40-H) ppm. 13C NMR
(75 MHz, CDCl3): d 13.64 (C-18), 19.28 (C-19), 20.78, 20.85, 20.95,
21.41 (acetyl-Me), 27.65, 31.28, 31.51, 31.60, 31.63 (C-21), 36.89,
37.99, 38.55, 45.07, 49.63, 55.67, 60.56, 62.66, 65.03, 67.20 (C-17),
69.09, 73.71 (C-3), 94.00, 102.78 (C-40), 122.07 (C-6), 126.90, 129.94,
139.62 (C-5), 167.50 (C-50), 168.41 (C-30), 170.23 (acetate-CO), 170.52
(acetate-CO), 170.73 (acetate-CO), 207.71 (C-20) ppm. HRMS (TOF,
ES+): calcd for C37H50NO10: 668.3435 [M++H]; found, 668.3435
[M++H].
C
39H56NO10: 698.3904 [M++H]; found, 698.3882 [M++H].
17. (a) Weinig, H. G.; Passacantilli, P.; Colapietro, M.; Piancatelli, G.
Tetrahedron Lett. 2002, 43, 4613; (b) Baskaran, S.; Baskaran, C.;
Trivedi, G. K. J. Chem. Res. (S) 1997, 394.
18. Patrocinio, V. L.; Costa, P. R. R.; Correia, C. R. D. Synthesis 1994,
474.
19. Crystallographic data for the structure in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Number CCDC 674216. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-
mail: deposit@ccdc.cam.ac.uk]. Some selected crystallographic data:
(v) Compound 4e: White crystalline solid, mp 90–92 °C. IR (CHCl3):
m
max = 2930, 1735, 1710, 1240, 760 cmꢀ1 1H NMR (300 MHz,
.
CDCl3): d 0.73 (s, 3H, 18-H3), 0.85 (m, 2H), 1.03 (s, 3H, 19-H3),
1.10–1.25 (m, 2H), 1.33 (s, 6H, ˜C(CH3)2), 1.44 (s, 3H), 1.54 (s, 3H),
1.59–1.86 (complex m, 11H), 2.03 (s, 3H, acetyl-Me), 2.17 (s, 3H,
21-H3), 2.34 (m, 2H), 3.00 (d, 1H, J = 9 Hz, 17-H), 3.67–3.69 (m, 2H),
empirical formula C39H55N O10, crystal system, space group:
monoclinic, P21; some of the important bond lengths: N(1)–
C(16), 1.302; C(14)–C(15), 1.335(7); O(7)–C(14), 1.354; O(7)–N(1),
1.414(4).