The synthesis of the monomeric moiety of disorazole C1

Article abstract of DOI:10.1016/S0040-4039(00)00271-9

The stereocontrolled synthesis of the monomeric subunit of the macrolide dimer disorazole C₁ (1) has been accomplished by convergent coupling of 3 and 4 using the Stille method. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00271-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2821–2824
The synthesis of the monomeric moiety of disorazole C1
M. C. Hillier, D. H. Park, A. T. Price, R. Ng and A. I. Meyers ∗
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Received 6 December 1999; accepted 26 January 2000
Abstract
The stereocontrolled synthesis of the monomeric subunit of the macrolide dimer disorazole C1 (1) has been
accomplished by convergent coupling of 3 and 4 using the Stille method. © 2000 Elsevier Science Ltd. All rights
reserved.
Disorazole C1 (1) was isolated in 1994 from the fermentation broth of Sorangium cellulosum by Jansen
et al.1 and its crude structure was identified (Scheme 1). As part of our general interest in the synthesis
of oxazole-containing natural products, we became intrigued with a synthetic route to this molecule.
Unfortunately, though 1 was found to be optically active, none of the stereocenters (C6–C60, C14–C140,
and C16–C160) were assigned in either a relative or an absolute sense.1 With this in mind, we set out to
devise a synthesis of disorazole C1, via the monomeric subunit 2, which would be both stereocontrolled
and convergent. In this way, we could access all of the stereochemical possibilities present in 1. By direct
comparison of our synthetic samples with the reported [α]D and 1H NMR spectral data1 for disorazole
C1 we might then obtain correct stereochemical information regarding this macrolide. We feel that this
is the best way to determine the structure and stereochemistry of disorazole C1, since none of the natural
product remains2 and, therefore, chemical degradation or X-ray techniques cannot be employed to obtain
this information. Retrosynthetically, we envisioned that the synthesis of disorazole C1 might involve
a cyclodimerization of the hydroxyacid 2 (Scheme 1), which, in turn, could be assembled via a Stille
coupling of the dienyl iodide 3 and the stannane 4.3 Furthermore, a successful synthesis of 2 would
potentially allow access to 17 of the 29 known disorazole variants, which have this subunit in common.1
Synthesis of the oxazole fragment 3 began from the readily available ester 54 which was saponified
(2N LiOH, THF) and coupled to the methyl ester of racemic serine with 1,10-carbonyl diimidazole5
(1,10-CDI) to give 6 in 67% combined yield (Scheme 2). Cyclodehydration of 6 was accomplished
using diethylaminosulfur trifluoride (DAST) in CH2Cl2 at −78°C, and the resulting oxazoline was taken
on without purification and treated with DBU and BrCCl3 in CH2Cl2 at 0°C to give the oxazole 7 in
79% overall yield for the two steps.6 Subsequently, the acetal in 7 was cleaved and the diol selectively
converted into the hydroxy-methoxy oxazole 8 in 56% overall yield from 7. Homologation of 8 to the
α,β-unsaturated aldehyde was affected by oxidation of the primary alcohol (SO3·Pyr, DMSO, Et3N,
CH2Cl2) to the aldehyde, which was treated with triphenylphosphoranylidene acetaldehyde in refluxing
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00271-9
tetl 16551

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Scheme 1.
benzene to afford 9 in 62% yield. This enal 9 was converted to the (Z)-vinyl iodide 3 (R=Me) in 71%
yield (Z:E=18:1) using a modification7 of the Wittig coupling (I−Ph3P+CH2I,8 NaHMDS, HMPA, THF,
−78°C).
Scheme 2. Reaction conditions: (i) 2N LiOH, THF; (ii) D,L-serine·OMe, 1,10-CDI, THF, 67% for two steps; (iii) DAST, CH2Cl2,
−78°C; (iv) DBU, BrCCl3, CH2Cl2, 0°C to rt, 79% for two steps; (v) (a) Dowex-H+, MeOH; (b) TIPSOTf, 2,6-lutidine, CH2Cl2
(0.05 M), −78°C, 74% for two steps; (vi) (a) MeI, Ag2O, CH3CN, ∆; (b) TBAF, THF, 75% for two steps; (vii) SO3·Pyr, DMSO,
Et3N, CH2Cl2; (viii) Ph3P_CH2CHO, benzene, ∆, 62% for two steps; (ix) I−Ph3P+CH2I, NaHMDS, HMPA, THF, −78°C, 71%
The first step in the reaction sequence leading to 4 (Scheme 3) involved a modified9 Mukaiyama
aldol between (E)-crotonaldehyde 10 and the O-silyl ketene acetal 1110 thus furnishing 12 in 73% yield
and 92–93% ee.11 The hydroxy-acetal 12 was protected with 2-(trimethylsilyl)ethoxymethyl chloride
(SEMCl) in the presence of diisopropylethylamine (DIEA) and the t-butyldimethylsilyl (TBS) ethyl
acetal was hydrolyzed to give the aldehyde 13 in 79% yield for the two steps. This aldehyde was subjected
to a Horner–Emmons reaction to install an (E)-α,β-unsaturated ester, which was immediately reduced
with Dibal at −78°C affording the allylic alcohol 14 (76% from 13). Sharpless epoxidation12 (D-(−)-

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DIPT, t-BuOOH, Ti(OiPr)4, 3 Å mol sieves, CH2Cl2, −30°C) of 14 gave the epoxy alcohol 15 (95%
yield, ≥15:1 de) which was reduced with Red-Al,13 and protected as the p-methoxybenzylidene acetal
16 in 79% overall yield for the three steps. The acetal 16 was selectively ring opened with Dibal at
−78°C,14 followed by oxidation of the primary hydroxyl group with Dess–Martin periodinane15 to afford
the aldehyde 17 (76%). Subsequent reaction of this aldehyde with iodomethyl triphenylphosphonium
ylide according to the Stork/Zhao modification7 of the Wittig method and oxidative removal of the p-
methoxybenzyl group (DDQ, CH2Cl2:H2O) led to the (Z)-vinyl iodide 18 in 53% (Z:E=18:1) for the two
steps. This iodide was converted to the stannane 4 in 74% yield by reaction with hexamethylditin in THF
in the presence of catalytic Pd(PPh3)2Cl2 at rt.16–18
Scheme 3. Reaction conditions: (i) BH3·THF, N-Ts-L-valine, CH2Cl2, −78°C, 73%; (ii) SEMCl, Hünigs base, CH2Cl2,
−78°C; (iii) 80% AcOH, 79% for two steps; (iv) (EtO)2P(O)CH2CO2Et, NaH (oil-free), toluene, THF, >95%; (v) Dibal,
CH2Cl2, −78°C, 76%; (vi) D-(−)-DIPT, t-BuOOH, Ti(OiPr)4, CH2Cl2, −30°C, 95%; (vii) Red-Al, THF, −20°C; (viii)
p-methoxybenzylidene dimethyl acetal, PPTS, CH2Cl2, 83% for two steps; (ix) Dibal, CH2Cl2, −78°C, 92%; (x) Dess–Martin
periodinane, pyridine, t-BuOH, CH2Cl2, 83%; (xi) I−Ph3P+CH2I, NaHMDS, HMPA, THF, −78°C, 67%; (xii) DDQ, CH2Cl2,
H2O, 79%; (xiii) Pd(Ph3P)2Cl2, (Me3Sn)2, Li2CO3, THF, rt, 74%
With both coupling partners 3 and 4 in hand, a Stille coupling was attempted in order to assemble the
target monomer 2 (R=Me, P=SEM). In practice, this was accomplished by addition of the stannane 4 to
a solution of the dienyl iodide 3 in DMF in the presence of a catalytic amount of Pd(CH3CN)2Cl2 to give
2 in 76% yield.19 1H NMR of this monomeric product 2 (Scheme 1) revealed that this material contained
many of the signals found in the natural product 1, particularly in the olefinic region.20
In conclusion, we have constructed the monomeric moiety 2 of the natural product disorazole C1 (1)
in a convergent and stereocontrolled fashion. It is hoped that this methodology will provide access to
a number of diastereomeric derivatives of 2, which may then be dimerized and compared to 1 via the
reported [α]D and spectral data for this compound. However, early attempts at double lactonization of 2
(R=H, P=SEM) to provide disorazole C1 have not been promising. We continue to address this final key
step.

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Acknowledgements
The authors are grateful to the NIH and NSF for financial support and to the American Cancer Society
for a postdoctoral fellowship (M.C.H.). We thank Professor R. Jansen (Gesellschaft für Biotechnologi-
sche Forschung mbH) for providing spectral data of natural disorazole C1 for comparison.
References
1. Jansen, R.; Irschik, H.; Reichenbach, H.; Wray, V.; Höfle, G. Liebigs Ann. Chem. 1994, 759.
2. According to the isolation team (Ref. 1), the stereochemical identity of disorazole C1 can no longer be obtained by chemical
degradation, since the only known sample of 1 has since decomposed: Jansen, R. Gesellschaft für Biotechnologische
Forschung mbH, personal communication.
3. For a general review, see: Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions; Paquette, L. A., Ed.; John Wiley
& Sons: New York, 1997; Vol. 50, Chapter 1.
4. For preparation of this derivative, see: Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48,
4067.
5. Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82, 4596.
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transformation of oxazolines to oxazoles, see: Tavares, F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2481.
7. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
8. Seyferth, D.; Heeren, J. K.; Singh, D.; Grim, S. O.; Hughes, W. B. J. Organometallic Chem. 1966, 5, 267.
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10. Rathke, M. W.; Sullivan, D. F. Syn. Commun. 1973, 3, 67.
11. The enantiomeric excess (ee) of the Mukaiyama aldol reaction was determined by Mosher’s ester anaylsis of 19 via HPLC
and 19F NMR:
12. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
13. (a) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719. (b) Viti, S. Tetrahedron Lett. 1982, 23, 4541.
14. Schreiber, S.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29, 4085.
15. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Ireland, R. E.; Liu, L. ibid. 1993, 58, 4155.
16. Farina, V.; Hauck, S. I. J. Org. Chem. 1991, 56, 4317.
17. We found that conversion of the iodide 20 to the vinyl tin species, followed by removal of the p-methoxybenzyl group with
DDQ resulted in destannylation, thus providing 21:
18. Elevated reaction temperatures for this transformation resulted in lower reaction yields (ca. 45%). Use of the less toxic
hexabutylditin (Bu3Sn)2 in this reaction did not provide product.
19. The Stille coupling also resulted in the formation of a small of amount (<5%) of the homocoupled byproduct 22:
20. Unfortunately, the monomer 2 is somewhat unstable and slowly isomerizes even when stored at −20°C.