Total synthesis of 15-deoxoclerocidin

Article abstract of DOI:10.1016/S0040-4039(99)02206-6

Enantiomerically pure 15-deoxoclerocidin (14), 15-dihydro-12-O- formylclerocidin (19) and 12-O-formyl-15,20-tetrahydroclerocidin (18) were synthesized from a methyl-substituted Wieland Miescher ketone (3). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02206-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 843–846
Total synthesis of 15-deoxoclerocidin
A. S. Kende,a,∗ J. J. Rustenhoven b and K. Zimmermann c
aDepartment of Chemistry, University of Rochester, Rochester, NY 14627, USA
bPharmacopeia Inc., 3000 Eastpark Blvd., Cranbury, NJ 08512, USA
cBristol-Meyers Squibb Inc., 5 Research Parkway, Wallingford, CT 06492, USA
Received 18 October 1999; revised 15 November 1999; accepted 16 November 1999
Abstract
Enantiomerically pure 15-deoxoclerocidin (14), 15-dihydro-12-O-formylclerocidin (19) and 12-O-formyl-
15,20-tetrahydroclerocidin (18) were synthesized from a methyl-substituted Wieland Miescher ketone (3). © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: clerocidin; 15-deoxoclerocidin; 15-dihydro-12-O-formylclerocidin; 12-O-formyl-15,20-tetrahydroclerocidin;
synthesis.
Clerocidin (1)1 is a clerodane diterpene which was isolated from Oidiodendron truncatum in the form
of its methanol adduct (2). Shown here in its open chain γ-hydroxyaldehyde form, clerocidin exists in
solution as an equilibrium of the corresponding ketolactols and their 1,4-dioxane dimers (Fig. 1).
Fig. 1.
Clerocidin is reported to have antibacterial activity and stimulates irreversible topoisomerase II-
mediated DNA cleavage.2 A recent total synthesis of clerocidin3a leads us to report here our total
synthesis of enantiomerically pure 15-deoxoclerocidin, di- and tetrahydroclerocidin and of 15, an
unexpected rearrangement product obtained by Jacquet upon reacting clerocidin with diazomethane.4
Our results also provide independent synthetic proof of the absolute configuration of these compounds.
Our synthesis proceeds from the known enantiopure monoketal 35 by Birch reductive alkylation to
give the ester 4 in 80% yield (Scheme 1). Wittig methylenation of the ketone gave a 75% yield of the
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02206-6
tetl 16134

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exo-methylene compound 5,6 which on hydrogenation over Rh–C gave the desired α-epimer 6 in 80%
yield. The configuration at the new established stereocenter was firmly established by comparison of
NMR data with literature values of similar compounds.3b,3c,7
Scheme 1. Reagents and conditions: (a) Li, NH3; 1 equiv. H2O; ICH2COOEt, 80%; (b) Ph3PCH3Br, KOtBu, 75%; (c) H2,
Rh/C, 80%; (d) 1 M aq. HCl, THF, 100%; (e) LDA, PhN(SO2CF3)2, 84%; (f) Pd(OAc)2, CO, Bu3SnH, 84%; (g) NaBH4, CeCl3,
MeOH; (h) TBDPSiCl, imidazole, 96%; (i) LAH, ether, 0°C; (j) PCC, CH2Cl2, 79%; (k) methyl vinyl ketone, PhSeTMS,
TMSOTf; (l) NaIO4, 20% (12-R)+45% (12-S); (m) tBuOOH, Ti(OiPr)4, 4 Å MS, 83%; (n) SeO2, aq. dioxane, reflux, 5 h, 43%;
(o) AcOCHO, pyr., 44%
Ketal hydrolysis of 6 gave ketone 7 in quantitative yield. Numerous attempts to convert 7 to the
aldehyde 9 through initial nucleophilic addition of a C1-unit to the ketone carbonyl failed due to
enolization. However, reductive carbonylation of the corresponding enol triflate 8 using modified Stille
conditions8 gave the unsaturated aldehyde 99 in 84% yield. The aldehyde was subjected to Luche
reduction and protected as the TBDPS ether 10. The ester side chain was then converted to the aldehyde
1110 by a reduction–reoxidation sequence in 79% yield over two steps.
Treatment of 11 with methyl vinyl ketone, PhSeTMS and TMSOTf (1.5:1.5: 0.2 equiv.) gave on
NaIO4 oxidation11 a 1:2.5 ratio of 1212 and its 12-S diastereoisomer which were easily separated by
flash chromatography. Both diastereoisomers of 12 were separately carried forward to 15 and 12-epi-15
to establish the configuration at this stereocenter.
Attempts to use the (S,S)-enantiomer of Barrett’s chiral Lewis acid13 derived from (−)-tartaric acid,

845
which has been described for closely related examples of Baylis–Hillman-like reactions, led to much
lower yields of a mixture favoring the same (wrong) diastereoisomer. Obviously, stereocontrol by the
substrate in this case cannot be overcome by the chiral catalyst.
Epoxidation of allylic alcohol 12 with t-BuOOH/Ti(OiPr)4 gave the single epoxide 1314 in 83%
yield.15 Oxidation of 13 with SeO2 for 5.5 h gave 43% of deoxyclerocidin (14);16 longer oxidations
gave inhomogeneous products.4 Treatment of 14 with formacetic anhydride gave 15, which was identical
to the rearrangement product obtained by Jacquet from clerocidin and diazomethane.4 ([αD](obsd)=+44°,
c=0.165, CHCl3, ([αD](ref.)=+49°, c=0.25, CHCl3, identical NMR spectra; 9.30 ppm, s, 1H; 8.01 ppm, s,
1H; 6.56 ppm, bs, 1H; 5.37 ppm, dd, 1H, J=8.8 Hz, ∼2 Hz; 3.05 ppm, AB-system, 2H; HRMS [M+NH4]+
calcd: 384.2437, obsd: 384.2437).
To avoid the harsh SeO2 conditions, we coupled aldehyde 11 with 1-TBDPSilyloxy-3-buten-2-one17 as
above to isolate, after NaIO4 oxidation, a 1:4 ratio of 1618 and its C(12)-epimer (Scheme 2). Treatment
of 16 with t-BuOOH/Ti(OiPr)4, followed by O-formylation, gave 17 in 74% yield. Desilylation with
HF/pyridine gave 90% of the selectively protected tetrahydroclerocidin 18.19 Treatment of 18 with
Dess–Martin reagent at 0°C gave dihydroclerocidin 19.20
Scheme 2. Reagents and conditions: (a) 1-TBDPSiO-but-3-en-2-one, PhSeTMS, TMSOTf, 10% (12-R)+40% (12-S); (b) NaIO4;
(c) tBuOOH, Ti(OiPr)4, MS; (d) AcOCHO, pyr., 79%; (e) HF–pyridine, reversed phase FCC, 90%; (f) 2.4 equiv. Dess–Martin
periodinane, 0°C, 5 min, 50%
Subsequent attempts to achieve the final oxidation of the α-hydroxyketone 19 using Dess–Martin
reagent led in our hands to intractable mixtures. Our route thus comprises an independent total synthesis
of the Jacquet compound, provides synthetic confirmation of absolute configuration in this series, but has
not attained access to clerocidin itself.
References
1. (a) Anderson, N. R.; Lorck, H. O. B.; Rasmussen, P. R. J. Antibiot. 1983, 36, 753–759; (b) Anderson, N. R.; Rasmussen, P.
R. Tetrahedron Lett. 1984, 25, 465–468; (c) Anderson, N. R.; Rasmussen, P. R. Tetrahedron Lett. 1984, 25, 469–472.
2. (a) Kawada, S.-z.; Yamashita, Y.; Fujii, N.; Nakano, H. Cancer Res. 1991, 51, 2922–2925; (b) Binaschi, M.; Zagotto, G.;
Palumbo, M.; Zunino, F.; Farinosi, R.; Capranico, G. Cancer Res. 1997, 57, 1710–1716.
3. (a) Xiang, A. X.; Watson, D. A.; Ling, T.; Theodorakis, E. A. J. Org. Chem. 1998, 63, 6774–6775. For other syntheses
of advanced intermediates, see: (b) Almstead, J.-I. K.; Demuth, T. P.; Ledoussal, B. Tetrahedron: Asymmetry 1998, 9,

846
3179–3183; (c) Marko, I. E.; Wiaux, M.; Warriner, S. M.; Giles, P. R.; Eustace, P.; Dean, D.; Bailey, M. Tetrahedron Lett.
1999, 40, 5629–5632.
4. Jacquet, J. P.; Bouzard, D.; Remuzon P. Tetrahedron Lett. 1993, 34, 823–826.
5. Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
6. Compound 5: 1H NMR (CDCl3, ppm) 4.82 (s, 1H); 4.80 (s, 1H); 4.12 (q, 2H, J=7 Hz); 3.98–3.82 (m, 4H); 2.51 (s, 2H); 2.38
(m, 1H); 2.20 (m, 2H); 1.80–1.35 (m, 8H); 1.26 (t, 3H, J=7 Hz); 1.17 (s, 3H); 1.10 (s, 3H).
7. (a) Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1982, 47, 1727; (b) Sarma, A. S.; Gayen, A. K. J. Indian Chem. Soc.
1985, 24B, 1208.
8. Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
9. Compound 9: 1H NMR (CDCl3, ppm) 9.32 (s, 1H); 6.58 (m, 1H); 4.12 (AB part of ABX3 system, 2H) 2.60–2.30 (m, 3H);
2.40 (d, 1H, J=15 Hz); 2.16 (d, 1H, J=15 Hz); 2.00 (m, 2H); 1.70–1.20 (m, 5H); 1.24 (s, 3H); 1.28 (t, X3 of ABX3, 2H, J=7
Hz); 1.19 (s, 3H); 1.00 (d, 3H, J=7 Hz). IR (cm−1) 1735, 1695.
1
10. Compound 11: H NMR (CDCl3, ppm) 9.93 (t, 1H, J=2.5 Hz); 7.70 (m, 4H); 7.50–7.37 (m, 6H); 5.72 (bs, 1H); 4.18 (s,
2H); 2.42–0.85 (m, 10H); 1.20 (s, 3H); 1.06 (s, 12H); 1.00 (d, 3H, J=7 Hz). IR (cm−1) 1725.
11. Oxidation of crude aldol products was necessary to suppress retro-aldol fragmentation.
1
12. Compound 12: H NMR (CDCl3, ppm) 7.75–7.66 (m, 4H); 7.48–7.36 (m, 6H); 6.12 (s, 1H); 6.04 (s, 1H); 5.68 (bs, 1H);
4.58 (m, 1H); 4.18 (s, 2H); 2.80 (bs, 1H), 2.40 (s, 3H); 2.25–0.80 (m, 15H); 1.06 (s, 12H); 0.98 (s, 3H). HR-MS (DCI)
[M+NH4]+ calcd: 576.3873, obsd: 576.3859
13. Barrett, A. G. M.; Kamimura, T. J. Chem. Soc., Chem. Commun. 1995, 1756.
14. Bailey, M.; Marko, I. E.; Ollis, W. D.; Rasmussen, P. R. Tetrahedron Lett. 1990, 31, 4509–4512.
15. Compound 13: HRMS (DCI) [M+NH4]+ calcd: 592.3822, obsd: 592.3831.
1
16. Compound 14: H NMR (CDCl3, ppm) 9.32 (s, 1H); 6.76 (m, 1H); 3.72 (m, 1H); 3.10 (AB-system, 2H); 2.45–0.85 (m,
13H); 2.13 (s, 3H); 1.25 (s, 3H); 1.05 (s, 3H); 1.04 (d, 3H, J=7 Hz).
17. Prepared from 2-TBDPSilyloxy-N-methyl-N-methoxy-acetamide, analogous to Nemoto, H.; Shiraki, M.; Fukumoto, K.
Tetrahedron 1994, 50, 10391.
18. Compound 16: 1H NMR (CDCl3, ppm) 7.70 (d, 8H, J=7 Hz); 7.50–7.37 (m, 12H); 5.85 (s, 1H); 5.81 (s, 1H); 5.66 (bs, 1H);
4.63 (AB-system, 2H); 4.47 (m, 1H); 4.18 (bs, 2H); 2.75 (bs, 1H); 2.25–0.80 (m, 21H); 1.14 (s, 9H); 1.08 (s, 9H). IR: 1685,
1425 cm−1; HRMS (FAB) [M+Na]+ calcd: 835.4554, obsd: 835.4591.
19. Compound 18: 1H NMR (CDCl3, ppm) 8.05 (s, 1H); 5.55 (bs, 1H); 5.39 (dd, 1H, J=8.9 Hz, 2.8 Hz); 4.28 (AB-system, 2H);
4.15 (s, 2H); 3.18 (d, 1H, J=4.8 Hz); 3.03 (d, 1H, J=4.8 Hz); 2.25–0.85 (m, 14H); 1.18 (s, 3H); 1.07 (s, 3H); 1.03 (d, 3H,
J=7.0 Hz). HRMS (DCI) [M+NH4]+ calcd: 398.2543, obsd: 398.2541.
20. Compound 19: 1H NMR (CDCl3, ppm) 9.35 (s, 1H); 8.06 (s, 1H); 6.57 (bs, 1H); 5.38 (bd, 1H, J=9 Hz); 4.26 (AB-system,
2H); 3.17 (d, 1H, J=4.7 Hz); 3.01 (d, 1H, J=4.7 Hz); 2.25–0.85 (m, 13H); 1.18 (s, 3H); 1.07 (s, 3H); 1.03 (d, 3H, J=7.0 Hz).