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group at the allylic position in triol 26 was attempted. The Ley
oxidation procedure14 using tetra-n-propylammonium perruthe-
nate as the oxidant afforded compound 27 in 22% yield. However,
the spectral data of 2715 are also not identical with those of the
natural product.11 The results of this study indicated that the
originally proposed structure of natural polyketide isolated from
Phialomyces macrosporus requires revision.
In summary, total synthesis of the proposed structure of
the polyketide 1, isolated from the culture of Phialomyces
macrosporus, was achieved. This synthesis featured the chemo-
selective epoxidation of the 1,4-cyclohexadiene portion of 13,
regioselective epoxide ring opening of 12, chemo- and diastereo-
selective dihydroxylation of the conjugated dienone derivative
16, and vinylation of lactone 10 accompanied by furan ring
formation. Unfortunately, the NMR spectra of synthetic samples
1 and 27 were not identical to those reported for the natural
product. This synthetic methodology contributes to the synthetic
research of related polyketide asperfuranone (7) isolated from
Aspergillus nidulans. This should lead to the actual structure of
the natural product isolated from Phialomyces macrosporus.
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Scheme 4 Synthesis of the proposed structure of polyketide 1.
Surprisingly, both the 1H and 13C NMR spectral data of the
synthetic polyketide 1 were not identical to those of the natural
product.11 However, the structure of synthesized 1 was identified by
X-ray crystallography.12 These results suggest that the structure of
natural polyketide differs from the originally proposed structure.
To resolve this discrepancy, the synthesis of 27, a diastereomer
of 1, was conducted as shown in Scheme 5. The synthesis of 27
containing a cis-oriented vicinal diol, was started from lactone 18,
which was the minor product obtained from the stereoselective
dihydroxylation of 16. Using a procedure similar to that used for
the synthesis of 21 (Schemes 3 and 4), compound 25 was
produced in 41% overall yield in 5 steps from 18 via the Weinreb
amide intermediate 24. The stereochemistry of 25 was confirmed
using X-ray crystallographic analysis.13 Selective removal of the
acetonide group did not occur under the same conditions used
for the synthesis of 22 from 21, and the triol 26 was obtained in
91% yield as the sole product (the corresponding diol was not
obtained). Therefore, chemoselective oxidation of the hydroxy
Notes and references
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Angew. Chem., Int. Ed., 2009, 48, 4688.
2 M. Furui, T. Komatsubara, J. Kimura, N. Chiba and T. Mikawa, Jpn
Pat., JP 09143118 A 19970603, Kokai Tokkyo Koho, 1997.
3 (a) Y.-M. Chiang, E. Szewczyk, A. D. Davidson, N. Keller, B. R. Oakley
and C. C. C. Wang, J. Am. Chem. Soc., 2009, 131, 2965; (b) C. C. C.
Wang, Y.-M. Chiang, M. B. Praseuth, P.-L. Kuo, H.-L. Liang and Y.-L.
Hsu, Basic Clin. Pharmacol. Toxicol., 2010, 107, 583; (c) S. Bergmann,
A. N. Funk, K. Scherlach, V. Schroeckh, E. Shelest, U. Horn,
C. Hertweck and A. A. Brakhage, Appl. Environ. Microbiol., 2010,
76, 8143; (d) Y.-M. Chiang, C. E. Oakley, M. Ahuja, R. Entwistle,
A. Schultz, S.-L. Chang, C. T. Sung, C. C. C. Wang and B. R. Oakley,
J. Am. Chem. Soc., 2013, 135, 7720.
4 (a) S. Nahm and S. T. Weinreb, Tetrahedron Lett., 1981, 22, 3815;
(b) S. Balasubramaniam and I. S. Aidhen, Synthesis, 2008, 3707.
5 J. R. Falck, A. He, H. Fukui, H. Tsutsui and A. Radha, Angew. Chem.,
Int. Ed., 2007, 46, 4527.
6 This Diels–Alder reaction of the alkyne and isoprene proceeded with
complete regioselectivity, and the 6-methyl-dihydroisobenzofuran-1-
one derivative that was a regioisomer of the desired bicyclic compound
13 was not detected.
7 CCDC 1039794 contains the supplemental crystallographic data of
17 for this paper.
8 S. Yamada, D. Morizono and K. Yamamoto, Tetrahedron Lett., 1992,
33, 4329.
9 A. Basha, M. Lipton and S. M. Weinreb, Tetrahedron Lett., 1977, 48, 4171.
10 Data for 1. Colorless needles; mp 91–92 1C; IR (KBr) 3446, 2966,
2935, 1704, 1695, 1682, 1593, 1532, 1446, 1404, 1372, 1293 cmÀ1
;
1H NMR (400 MHz, CD3CN) d 0.96 (3H, t, J = 7.4 Hz), 1.28 (3H, s),
1.63–1.72 (2H, m), 2.81 (2H, t, J = 7.3 Hz), 2.88 (1H, dd, J = 17.8, 8.1
Hz), 3.25–3.50 (2H, m, including 1H, dd, J = 17.8, 4.8 Hz, at d 3.37),
3.60–3.90 (1H, br s), 4.05 (1H, dd, J = 8.1, 4.8 Hz), 8.16 (1H, s); 13C
NMR (100 MHz, CD3CN) d 13.9, 17.6, 18.4, 28.2, 41.7, 74.1, 78.2,
124.9, 129.5, 147.6, 149.4, 191.5, 195.7; HRMS (ESI–TOF) calcd for
C13H17O5 ([M + H]+) 253.1076, found 253.1070.
11 The detailed comparison for 1H and 13C NMR spectra data of
synthetic 1 and 27 with those of natural polyketide is described in
the supporting information. In addition, comparison of 13C NMR
Scheme 5 Synthesis of the cis-isomer 27.
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