Synthetic studies of viridenomycin. Construction of the cyclopentene carboxylic acid part

Article abstract of DOI:10.1016/S0040-4039(00)00013-7

A highly functionalized cyclopentene carboxylic acid derivative, as an advanced synthetic intermediate of viridenomycin, was synthesized. The synthesis commenced with the previously reported highly functionalized tetrahydrofuran derivative prepared from D-glucose. The stereochemical confirmation of the present final compound was conducted by comparison with a compound synthesized very recently by the Meyers group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00013-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1771–1774
Synthetic studies of viridenomycin. Construction of the
cyclopentene carboxylic acid part
Jun Ishihara,† Koji Hagihara, Hiroyuki Chiba, Kouichi Ito, Yumiko Yanagisawa,
Kiichiro Totani and Kin-ichi Tadano ∗
Department of Applied Chemistry, Keio University, Hiyoshi, Yokohama 223-8522, Japan
Received 24 November 1999; revised 15 December 1999; accepted 17 December 1999
Abstract
A highly functionalized cyclopentene carboxylic acid derivative, as an advanced synthetic intermediate of
viridenomycin, was synthesized. The synthesis commenced with the previously reported highly functionalized
tetrahydrofuran derivative prepared from D-glucose. The stereochemical confirmation of the present final com-
pound was conducted by comparison with a compound synthesized very recently by the Meyers group. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: antitumor compounds; polyenes; cyclopentenes; cyclization; regiocontrol.
Viridenomycin (1) (Fig. 1) was first isolated from the culture broth of Streptomyces viridochromogenes
in 1975 as a weakly acidic and lipophilic substance, which showed strong inhibitory activity against
Trichomonas vaginalis and gram-positive bacteria.1 In 1991 compound 1 was isolated from the culture
broth of Streptomyces gannmycicus as an agent for prolongation of the survival periods of mice infected
with B16 melanoma. Its gross structure and relative stereochemistry (except the benzylic carbon) were
fully elucidated by spectral means.2,3 The antibiotic 1 is classified into a 24-membered polyene macrolide
containing a lactam and an enol ester linkage. Another structural characteristic is a tetrasubstituted
β-ketocyclopentane carboxylic acid substructure existing as the enol form. One of the consecutive
stereogenic carbons in the five-membered ring is an asymmetric quaternary one. Quite recently, Arrington
and Meyers reported the asymmetric synthesis of the cyclopentane part of 1.4 We wish to disclose herein
our synthesis of the cyclopentene carboxylic acid equivalent of 1.
The retrosynthesis of A, a synthetic equivalent of the cyclopentene carboxylic acid part of viride-
nomycin with differentiable protecting groups, is summarized in Scheme 1. Our approach features a
Dieckmann cyclization of a tetrahydrofuran derivative such as C bearing two ester functionalities both
as side chains (C to B). The substrate C includes a methoxy group with the correct stereochemistry and
∗
†
Corresponding author. Fax +81-45-563-0446; e-mail: tadano@applc.keio.ac.jp (K. Tadano)
Present address: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00013-7
tetl 16293

1772
Fig. 1.
other functionalities for transformation into the cyclopentene carboxylic acid A. Cleavage of the tetrahy-
drofuran ring in the cyclized product B and transformation of further functional groups would eventually
provide A. The synthesis of C could be achieved by conventional functional group-transformation of the
D-glucose-derived building block 2. The efficient preparation of 25 and its synthetic utility6 have been
reported by our group.
Scheme 1.
The synthesis of the substrate 11 for the Dieckmann cyclization is shown in Scheme 2. Mild acid
hydrolysis of 2 gave an inseparable mixture of a diol and its δ-lactone, which was silylated with t-
butyldiphenylsilyl chloride (TBDPSCl) to give 37 and 4. Mesylation of the major product 3 gave 5.
Treatment of 5 with 4 M KOH aqueous solution and acidification of the solution afforded the δ-lactone
6 quantitatively. Spectral comparison of 6 with 4 verified the stereochemical inversion of C-5. This
reaction is likely to proceed through the saponification of the ester followed by the attack of the resulting
carboxylate to C-5 in an SN2 fashion. Furthermore, the δ-lactone 4 was converted to 6.8 Reduction of
the lactone ring in 6 with NaBH4 in t-BuOH in the presence of MeOH9 afforded the diol, in which the
primary hydroxyl group was selectively protected as the TBDPS ether providing 7. Compound 7 was
converted to 8 in three steps [O-methylation, de-O-silylation, then di-O-pivaloylation]. Ozonolysis of
the vinyl group in 8 followed by NaBH4 reduction gave 9. The hydroxyl group in 9 was protected as
a t-butyldimethylsilyl (TBS) ether. The pivaloyl groups in the resulting silyl ether were deprotected to
give diol 10. The hydroxyl groups in 10 were simultaneously oxidized to carboxylic acids in a two-step
oxidation.10,11 The resulting two carboxylic acids were esterified with CH2N2 to give the substrate 11.
The Dieckmann cyclization of 11 was investigated under a variety of basic conditions. We found that
excess (2.2 molar equivalents) of potassium hexamethyldisilazide (KHMDS) was the base of choice,
which provided the desired cyclopentene carboxylic acid exclusively (Scheme 3).12 The enol in the
cyclization product was protected as the pivaloyl ester providing 12. An exchange of the silyl ether
in 12 to the acetate 13 was required for the advanced step, which was achieved by desilylation and
successive acetylation. Acid hydrolysis of the acetal in 13 and glycol cleavage of the resulting hemiacetal
14, followed by dithioacetalization provided 15 after methanolysis of the intermediary formyl ester.
Desulfurization of 15 with Raney nickel and protection of the hydroxyl group provided the TBS ether

1773
Scheme 2. (a) 60% AcOHaq.; (b) TBDPSCl, Et3N, DMAP, CH2Cl2 (3: 63%, 4: 27%); (c) MsCl, pyr.; (d) 4 M KOHaq., MeOH
then 4 M HClaq.; (e) NaBH4, t-BuOH:MeOH (5:1), reflux; (f) TBDPSCl, Et3N, DMAP, CH2Cl2 (76% from 3); (g) NaH, MeI,
THF; (h) n-Bu4NF, THF; (i) PivCl, pyr. (80% from 7); (j) O3, MeOH, −78°C then Ph3P; (k) NaBH4, MeOH (87% from 8);
(l) TBSOTf, 2,6-lutidine, CH2Cl2; (m) DIBAL-H, CH2Cl2, −78°C (98% from 9); (n) (COCl)2, DMSO, CH2Cl2, −78°C then
Et3N; (o) NaClO2, NH2SO3Haq., Na2HPO4aq., t-BuOH; (p) CH2N2, Et2O, CH2Cl2, 0°C (68% from 10)
16.13 This compound 16 is an enantiopure synthetic equivalent of the cyclopentene carboxylic acid part
of viridenomycin.
Scheme 3. (a) KHMDS, THF −78°C; (b) PivCl, pyr., DMAP (68% from 11); (c) AcOH:H2O:THF (8:1:1); (d) Ac2O, pyr. (90%
from 12, 3% recovery of 12); (e) 60% TFAaq., 0°C (92%); (f) NaIO4, MeOH:H2O (5:3); (g) EtSH, BF3·Et2O, CH2Cl2, 0°C;
(h) Et3N, MeOH (94% from 14); (i) Raney Ni T-4, acetone, reflux; (j) TBSOTf, 2,6-lutidine, CH2Cl2 (82% from 15)
Finally, compound 16 was converted to Meyers’ product 194 as shown in Scheme 4 for confirmation
of our stereochemical assignment. Our synthetic 1914 {[α]20D +25.1 (c 0.22, CHCl3)}was identical with
Meyers’ synthetic {[α]D +24.4 (c 1.05, CHCl3)} by comparison with the 1H and 13C NMR spectra.
Scheme 4. (a) 14 M NH3aq., MeOH; (b) MOMCl, iPr2NEt, CHCl3 (94% from 16); (c) NaOMe, MeOH; (d) BnOC(_NH)CCl3,
TfOH, CH2Cl2, 0°C (formation of a mixture of 18 and its O-MOM enol form); (e) TfOH, CH2Cl2 (72% from 17); (f) TBSCl,
2,6-lutidine, CH2Cl2 (80%)

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Acknowledgements
We thank Professor Albert I. Meyers (Colorado State University) for providing us with copies (1H and
13C NMR) of 19 and experimental details of their work. This work was supported by the CIBA-GEIGY
Foundation (Japan) for the Promotion of Science, to whom our thanks are due.
References
1. Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J. Antibiot. 1975, 28, 167.
2. Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1991, 32, 659.
3. Nakagawa, M.; Toda, Y.; Furihata, K.; Hayakawa, Y.; Seto, H. J. Antibiot. 1992, 45, 1133.
4. Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999, 1371.
5. Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52, 1201.
6. For recent natural product synthesis starting from 2, see: Ishihara, J.; Nonaka, R.; Terasawa, Y.; Shiraki, R.; Yabu, K.;
Kataoka, H.; Ochiai, Y.; Tadano, K. J. Org. Chem. 1998, 63, 2679.
7. All new compounds were fully characterized by spectroscopic means [1H (270 or 300 MHz) and 13C (67.5 or 75 MHz) NMR,
IR] and gave satisfactory HRMS except for some unstable intermediates. Yields refer to homogeneous samples purified by
chromatography on silica gel.
8. The conversion of 4 to 6 was carried out as follows: (1) DIBAL-H, CH2Cl2, −78°C; (2) NaBH4, MeOH (89% for two steps);
(3) PivCl, pyr., DMAP (96%); (4) MsCl, pyr. (88%); (5) DIBAL-H, CH2Cl2, −78 °C; (6) Jones’ reagent, acetone, 0°C; (7)
CH2N2, Et2O, 0°C (95% for three steps); (8) 4 M KOHaq. MeOH then 4 M HClaq.; (9) TBDPSCl, Et3N, DMAP, CH2Cl2
(80% for two steps)
9. Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem. Soc. Jpn. 1984, 57, 1948.
10. Muncuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
11. For NaClO2 oxidation, see: Kraus, G. A.; Tashner, M. J. J. Org. Chem. 1980, 45, 1175; Dalcanale, E.; Montanari, F. ibid.
1986, 51, 567.
12. We also synthesized an acyclic diester i (see below). The Dieckmann cyclization of i provided three products, i.e., the
desired ii, undesired cyclization product iii, and a β-eliminated product iv. The results were as follows: (1) KHMDS, THF,
−78°C (iii, 30%; iv, 33%); (2) KHMDS, DMF, −78°C (ii, 23%; iv, 39%); (3) LiHMDS, THF/HMPA, −78°C (ii, 41%; iv,
26%); (4) t-BuOK, DMF, rt (decomposition).
1
13. Spectral data for 16: [α]21 +52.4 (c 0.96, CHCl3); H NMR (270 MHz) δ 0.06, 0.11 (2s, 3H×2), 0.91 (s, 9H), 1.14 (s,
D
3H), 1.33 (s, 9H), 2.02 (s, 3H), 3.47 (s, 3H), 3.69 (s, 3H), 3.88, 4.38 (ABq, 1H×2, J=11.0 Hz), 4.10 (d, 1H, J=6.7 Hz), 4.32
(d, 1H, J=6.7 Hz). 13C NMR (75 MHz) δ −5.2, −4.6, 16.9, 18.0, 20.8, 25.7, 26.9, 39.1, 46.6, 51.2, 59.1, 65.3, 76.8, 86.2,
121.9, 155.7, 162.9, 170.8, 174.9; HRMS calcd for C23H40O8Si (M+) m/z: 472.2492; found: 472.2501.
1
14. Spectral data for 19: H NMR (300 MHz) δ 0.00, 0.08, 0.167, 0.174 (4s, each 3H), 0.87, 0.95 (2s, 9H×2), 1.00 (s, 3H),
3.22, 3.65 (2d, 1H×2, J=8.8 Hz), 3.34 (s, 3H), 3.64 (s, 3H), 4.07 (d, 1H, J=6.3 Hz), 4.31 (d, 1H, J=6.3Hz), 4.44 (s, 2H),
7.20–7.32 (m, 5H); 13C NMR (75 MHz) δ −4.8, −4.5, −4.4, −4.3, 17.2, 18.1, 18.4, 25.5, 25.8, 47.2, 50.5, 55.2, 72.1, 72.9,
73.5, 87.1, 114.6, 127.2, 127.5, 128.1, 138.9, 159.4, 165.0; HRMS calcd for C29H49O6Si2 (M+−H) m/z: 549.3068; found:
549.3045.