Synthesis of actiketal, a glutarimide antibiotic

Article abstract of DOI:10.1016/S0040-4039(00)00928-X

The first synthesis of actiketal (RK-441S), an antibiotic from Streptomyces pulveraceus subsp. epiderstagenes, was achieved from 5,7- dimethylbenzofuran and dimethyl glutaconate via palladium-assisted coupling reaction as a key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00928-X

Tetrahedron Letters 41 (2000) 5887±5890
Synthesis of actiketal, a glutarimide antibiotic
Hiromasa Kiyota,* Yuko Shimizu and Takayuki Oritani
Department of Applied Bioorganic Chemistry, Division of Life Science, Graduate School of Agricultural Science,
Tohoku University 1-1, Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Received 19 April 2000; revised 31 May 2000; accepted 2 June 2000
Abstract
The ®rst synthesis of actiketal (RK-441S), an antibiotic from Streptomyces pulveraceus subsp. epiderstagenes,
was achieved from 5,7-dimethylbenzofuran and dimethyl glutaconate via palladium-assisted coupling
reaction as a key step. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: acetals; antibiotics; glutarimides; polyketides.
Actiketal (RK-441S, 1) was isolated from the culture extracts of Streptomyces pulveraceus
subsp. epiderstagenes as a new acetal-type glutarimide antibiotic.1 This compound inhibited the
EGF-induced DNA formation in murine epithelial cell (100% at 1 mM) and the Con A-
induced blast formation in spleen cell (100% at 20 nM).2 It also showed the inhibitory activity
towards the incorporation of [3H]thymidine into epidermal growth factor-stimulated Balb/MK
cells (IC50 14.5 mM).1 Although these activities are much weaker than those of cycloheximide (2),
1 is expected to be a new anti-cancer agent and an immnosuppressant because of its low
cytotoxicity.1,2 To provide 1 in a sucient quantity for further biological studies, we began the
synthetic study and achieved the ®rst total synthesis (Fig. 1).
Figure 1.
* Corresponding author. Tel/fax: +81-22-717-8783; e-mail: kiyota@biochem.tohoku.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00928-X

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The natural actiketal (1) was reported to be optically inactive {‰aŠ2D6þ0ꢀ (c 0.1, MeOH)}2 and
the asymmetric center of 1 is made up of a hemiacetal carbon. It could therefore be presumed that
1 occurs in the racemic form, so we started the synthetic study for the racemate. Firstly, we tried
semi-synthesis of 1 from cycloheximide (2), which is well-known as a protein synthesis inhibitor
and commercially available. As shown in Scheme 1, cycloheximide (2) was converted to
actiphenol (3)3 according to Highet's procedure.3 However, the desired compound 4 could not be
obtained: oxygenation of the a-position to keto carbonyl function failed in various conditions
in the protected form of the phenolic hydroxy group. Next we examined the total synthesis.
2,4-Dimethylphenol THP ether (5) was coupled with glutarimide acetaldehyde (6)4 to give 7.
Dehydration of 7 with acidic conditions a€orded 8. Once the OH and NH groups of 8 had been
protected with the BOM group, the double-bond was oxidized to give diol 9. This diol was
unstable and the formation of undesired g-lactone 10 predominated during the next oxidation
step.
Scheme 1. Synthetic study of actiketal from cycloheximide. (a) NBS, CCl4, re¯ux (10%). (b) n-BuLi, TMEDA, DME,
THF, HMPA, ^78 to 0ꢀC (32%). (c) TsOH, toluene (85%). (d) i. BOMCl, i-Pr2NEt. ii. OsO4, NMO, t-BuOH (61%).
(e) Dess±Martin periodinane
Consequently, the vicinal oxygen function must be introduced in the ®nal step to prevent
the g-lactone formation. We thought that the corresponding benzofuran derivative would be a
good precursor, so we chose 5,7-dimethylbenzofuran5 (11) and dimethyl glutaconate (12) as the
starting materials, which would be coupled together by the key palladium-assisted reaction. As
shown in Scheme 2, the oxidative coupling reaction6 of 11 and 12 mediated by 1 equiv. of
Pd(OAc)2 in AcOH proceeded successfully to give 13 in 57% yield. An attempt of the catalytic
method [0.01 equiv. of Pd(OAc)2 and 1 equiv. of PhCO2t-Bu]7 resulted in the formation
of a bibenzofuran derivative as the major product. The double-bond conjugated with

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Scheme 2. Synthesis of actiketal (1). (a) 12 (1.4 equiv.), Pd(OAc)2 (1 equiv.), AcOH, 60ꢀC (57%). (b) H2, Pd powder,
EtOAc (98%). (c) i. KOH, MeOH. ii. Ac2O, heat. iii. NH3 gas, Et2O. iv. NaOAc, Ac2O, heat (62%). (d) OsO4 (1.3
equiv.), Py, Et2O, 20ꢀC, then aq. NaHSO3 60ꢀC (33%)
methoxycarbonyl group was selectively hydrogenated over Pd powder to a€ord 14 in 98% yield.
Formation of glutarimide function was performed in the conventional manner, similar to that of
Matsuda et al.8 to give the desired precursor 15. Finally, oxidation of the electron rich double
bond with OsO4,9 followed by hydrolysis of the resulting osmate with aq. NaHSO3 at 60ꢀC gave
over-oxidated product,10 actiketal (1). 11 The total yield was 11.4% in six steps. 1H and 13C NMR
data12 were in good accordance with those reported.1
In conclusion, the ®rst synthesis of actiketal (RK-441S), an antibiotic from Streptomyces
pulveraceus subsp. epiderstagenes, was achieved.
Acknowledgements
1
We thank Prof. Hiroyuki Osada (Riken Institute) for kindly sending us the copies of the H-
and 13C-NMR spectra of the natural actiketal.
References
1. Sonoda, T.; Osada, H.; Uzawa, J.; Isono, K. J. Antibiot. 1991, 44, 160±163.
2. Isono, K.; Osada, H.; Sonoda, T. Jpn Kokai Tokkyo Koho 1991, JP 03,255,082 (Chem. Abstr. 1992, 116, 126985).
3. Highet, R. J.; Prelog, V. Helv. Chim. Acta 1959, 42, 1523±1526.
4. Egawa, Y.; Suzuki, M.; Okuda, T. Chem. Pharm. Bull. 1963, 11, 589±596.
5. Stoermer, R.; Gohl, Fr. Chem. Ber. 1903, 36, 2873±2877.
6. Kasahara, A.; Izumi, T.; Yodono, M.; Saito, R.; Takeda, T.; Sugawara, T. Bull. Chem. Soc. Jpn. 1973, 46, 1220±
1225.
7. Tsuji, J.; Nagashima, H. Tetrahedron 1984, 40, 2699±2702.
8. Matsuda, F.; Kawasaki, M.; Terashima, S. Tetrahedron Lett. 1985, 26, 4639±4642.
9. Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M. Chem. Pharm. Bull. 1992, 40, 1148±1153.
10. According to Ref. 9, hydrolysis of the osmate derived from a benzofuran with aq. NaHSO3 gave the diol, while
that with aq. Na2SO3 gave the ketol. In our case, treatment with aq. Na2SO3 failed in decomposition of the
product.
11. 1; amorphous powder, mp 79.5±80.5ꢀC (Ref. 1 96±100ꢀC). The mixed melting point could not be measured
because the natural sample was absent. However, the value of the synthetic product is reliable for its smaller
melting range (Á 1ꢀC).

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12. 1H-NMR (500 MHz, CDCl3, all protons and carbons were assigned according to Ref. 1) d: 2.27 (s, 3H, 12-Me),
2.33 (s, 3H, 4-Me), 2.55 (dd, 1H, J=17, 10 Hz, 14-H), 2.66 (dd, 1H, J=17, 4 Hz, 14-H), 2.65±2.71 (m, 1H, 9-H),
2.75 (dd, 1H, J=17, 10 Hz, 10-H), 2.91 (dd, 1H, J=17, 4 Hz, 10-H), 4.42 (br, s, 1H, OH), 7.22 (s, 1H, 5-H), 7.33
(s, 1H, 3-H), 8.03 (s, 1H, NH). 13C-NMR (125 MHz, CDCl3) d: 14.1 (2-Me), 20.6 (4-Me), 30.9 (C-10), 31.5 (C-14),
35.7 (C-9), 103.2 (C-8), 118.2 (C-6), 121.6 (C-5), 123.1 (C-2), 132.7 (C-4), 142.0 (C-3), 167.5 (C-1), 171.3 (C-11),
171.6 (C-13), 198.6 (C-7). HR-FABMS (glycerol-PEG) m/z calcd for C15H16NO5, 290.1029; found, 290.1029.