Toward the synthesis of the antibiotic tetrodecamycin

Article abstract of DOI:10.1016/S0040-4039(00)01809-8

We report here a short approach to a tricyclic substructure of tetrodecamycin exhibiting a unique ring skeleton utilising an acid catalysed ring closure as the key step. In addition an efficient three-step synthesis of 5-alkylidene 4-methoxy-2(5H)-furanones starting from 4-methoxy-2(5H)-furanone is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01809-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9977–9980
Toward the synthesis of the antibiotic tetrodecamycin†
Franz F. Paintner,* Gerd Bauschke and Marion Kestel
Institut fu¨r Pharmazie–Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstraße 5–13, Haus C, D-81377, Germany
Received 12 September 2000; accepted 11 October 2000
Abstract
We report here a short approach to a tricyclic substructure of tetrodecamycin exhibiting a unique ring
skeleton utilising an acid catalysed ring closure as the key step. In addition an efficient three-step synthesis
of 5-alkylidene 4-methoxy-2(5H)-furanones starting from 4-methoxy-2(5H)-furanone is described. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: antibiotics; furanones; cyclisation.
Tetrodecamycin 1 is a novel tetronic acid based antibiotic isolated from the culture broth of
Streptomyces nashvillensis MJ885-mF8. It shows distinct activity against Gram-positive bacteria
including Bacillus anthracis as well as methicillin resistant Staphylococcus aureus (MRSA).1 On
the other hand dihydrotetrodecamycin 2, isolated together with 1 from the Streptomyces strain,
does not show such an effect revealing the crucial role of the exo-methylene moiety in 1 for
antibacterial activity.2 The unique ring skeleton and absolute stereochemistry of compound 1
were fully elucidated by spectral means and X-ray crystallography.3,4 However, so far no
approach to the total synthesis of 1 or 2 has been reported.
Our retrosynthetic analysis of the skeleton of 1 is outlined in Scheme 1. The tetracyclic
intermediate 3 was envisioned to arise from two key operations: (a) the hydroxyalkylation of the
known 4-methoxy-5-methylene-2(5H)-furanone (6a)5 with chiral aldehyde 5 followed by an
* Corresponding author. Fax: (+49) 089-2180-7247; e-mail: ffpai@cup.uni-muenchen.de
†
Dedicated to Professor Dr. Dr. h.c. F. Eiden on the occasion of his 75th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01809-8

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Scheme 1.
oxidation step to give 4,6 and (b) deprotection of the allylic hydroxyl group followed by ring
closure. Having compound 3 available stereoselective cis dihydroxylation should provide the
target molecule 1 in a single step. In this letter we describe our approach to a tricyclic
substructure of 3 (bold type in Scheme 1) containing the crucial seven-membered ring.
We selected 4-methoxy-5-phenylseleno-2(5H)-furanone (8), readily prepared from commer-
cially available 4-methoxy-2(5H)-furanone (7), as the key intermediate for a new, short and
efficient approach to building block 6a as well as to 5-alkylidene 4-methoxy-2(5H)-furanones in
general (Scheme 2).7 Alkylation of 8 and subsequent oxidative removal of the phenylseleno
group using MCPBA gave the 5-alkylidene derivatives 6a–c8 in good overall yields (56–68%
from 7). The success of the alkylation reactions to form 9a–c, however, was strongly dependent
on the bases employed. Generating the enolate with n-BuLi resulted in the cleavage of the C5ꢀSe
bond to a considerable extent.9 Thus in the case of the methylation reaction compound 9a was
obtained in only moderate yield (52%). This side-reaction could be avoided using tert-BuLi as
the base, resulting in substantially higher yields of the alkylation products (9a: 82%).
Scheme 2. (a) (i) n-BuLi, THF, −78°C; (ii) PhSeCl, −78°C (90%); (b) (i) tert-BuLi, THF, −78°C; (ii) RCH2X, −78°C
to rt [9a: (R=H, X=I) 82%; 9b: (R=Me, X=I) 65%; 9c: (R=Ph, X=Br) 76%]; (c) MCPBA, CH2Cl2, 0°C [6a: 92%;
6b: 95%; 6c: 91%]; (d) LDA, THF, −78°C

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The synthesis of our tricyclic target molecule 16 was initiated by opening the known bicyclic
lactone 11, readily available from 1-methyl-3-cyclohexenoic acid10 using NaOMe to obtain the
corresponding alcohol which was protected as a tert-butyl-dimethylsilyl ether to form 12 in 70%
overall yield (Scheme 3). DIBAL reduction of the ester 12 yielded the primary alcohol which was
converted to the aldehyde 13 by Swern oxidation (84% from 12). Hydroxyalkylation of 6a was
achieved by converting 6a first into the a-lithio derivative 10a6b,c and then by reacting it with the
aldehyde 13 to form 14 in 73% yield (1:1 mixture of diastereomers). Swern oxidation of the
hydroxyalkylation product 14 gave acyl tetronate 15 in satisfactory yield (78%) whereas use of
other oxidants (e.g. MnO2, PDC) resulted in distinctly lower yields. Finally the key step in our
synthesis—deprotection of the tert-butyldimethylsilyl protected hydroxyl group in 15 followed
by cyclisation to give 16—was carried out in a one pot reaction by treating 15 with 2.5 equiv.
H2SO4 (96%) in CH2Cl2 at 0°C for 1 h. Thus compound 16 was isolated in good yield (70%).11
Application of the more ‘classic’ silyl ether cleavage conditions, 5–10% HF (48%) in acetonitrile
at 0°C, led to the formation of 16 in varying yields (up to 55%). In these cases the product was
also accompanied with considerable amounts of the regioisomeric cyclisation product 17 (ꢀ1:1
mixture of E–Z isomers).12
Scheme 3. (a) NaOMe, MeOH, rt; (b) TBDMSCl, imidazole, DMF, rt (70% from 11); (c) DIBAL, THF, −78°C; (d)
oxalyl chloride, DMSO, Et3N, CH2Cl2, −60°C to rt (84% from 12); (e) 10a, −78°C to −40°C (73%); (f) oxalyl chloride,
DMSO, Et3N, CH2Cl2, −60°C (78%); (g) H2SO4, CH2Cl2, 0°C (70%)
In conclusion, we have developed an efficient approach to a substructure of the tetrode-
camycin 1 ring skeleton (seven steps, 23% overall yield). Further investigations toward the total
synthesis of 1 are now in progress in our laboratory.
Acknowledgements
We are greatly indebted to Professor Dr. Klaus Th. Wanner for his generous support.

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References
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5). However, this strategy is not applicable to 5-alkylidene 4-methoxy-2(5H)-furanones in general. For a prior
synthesis of 5-alkylidene 4-methoxy-2(5H)-furanones starting from 7, see: Pelter, A.; Al-Bayati, R. I. H.; Ayoub,
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9. This reaction is likely to proceed by attack of n-BuLi on the selenium atom to form i and the lithium enolate of
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comparison with authentic material.
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1
11. All new compounds were characterised by H and 13C NMR spectra and gave satisfactory elemental analyses.
1
Compound 16: H NMR (400 MHz, CDCl3) l=1.22 (s, 3H, CH3), 1.98 (m, 1H,), 2.13 (dd, J=6.4/16.5 Hz, 1H),
2.47 (m, 1H), 2.71 (m, 1H), 5.23 (d, J=2.8 Hz, 1H), 5.31 (d, J=2.8 Hz, 1H), 5.34 (m, 1H), 5.76 (m, 1H), 6.18
(m, 1H);13C NMR (100 MHz, CDCl3): l=25.91, 34.42, 37.38, 44.82, 76.10, 96.10, 102.61, 121.47, 135.17, 148.17,
164.19, 164.45, 198.59.
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