Total synthesis and stereochemistry of the antitumor antibiotic PD 113,271

Article abstract of DOI:10.1021/ol062111u

A total synthesis of PD 113,271, an antitumor fostriecin analogue isolated from Streptomyces pulveraceus, was achieved by the chiral pool approach starting with D-galactose and L-tartaric acid. The synthesis of PD 113,271 led to unambiguous assignment of

Full text of DOI:10.1021/ol062111u

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5307-5310
Total Synthesis and Stereochemistry of
the Antitumor Antibiotic PD 113,271
Toshifumi Takeuchi,† Kouji Kuramochi,† Susumu Kobayashi,‡ and
Fumio Sugawara*,†
Department of Applied Biological Science and Faculty of Pharmaceutical Sciences,
Tokyo UniVersity of Science (RIKADAI), 2641 Yamazaki, Noda-shi,
Chiba 278-8510, Japan
sugawara@rs.noda.tus.ac.jp
Received August 28, 2006
ABSTRACT
A total synthesis of PD 113,271, an antitumor fostriecin analogue isolated from Streptomyces pulveraceus, was achieved by the chiral pool
approach starting with -galactose and -tartaric acid. The synthesis of PD 113,271 led to unambiguous assignment of the relative and absolute
stereochemistry of its stereocenters.
D
L
PD 113,271 (1), which is a 4-hydroxy analogue of fostriecin
(CI-920, 2), was isolated in 1983 by Tunac and co-workers
from a fermentation broth of Streptomyces pulVeraceus
subsp. fostreus ATCC 31906 (Figure 1).1,2 Compound 1
(HCT-8, IC50 ) 9.0 µM) in vitro, and it also exhibits potent
antitumor activity against L1210 and P388 leukemia in vivo.3
It has been reported that PD 113,271 inhibits the enzyme
topoisomerase II with an MIC of 12.5 µM in an in vitro
assay.4 There have been several reports of total synthesis of
fostriecin (2) as well as many biological studies on 2,
including descriptions of its mechanism of action.5-7 How-
ever, little is known about PD 113,271 (1). Since there are
neither synthetic nor degradation studies reported for 1, the
complete relative and absolute configurations of 1 have not
(3) (a) Lewy, D. S.; Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr.
Med. Chem. 2002, 9, 2005. (b) Jackson, R. C.; Fry, D. W.; Boritzki, T. J.;
Roberts, B. J.; Hook, K. E.; Leopold, W. R. AdV. Enzyme Regul. 1985, 23,
193. (c) Scheithauer, W.; von Hoff, D. D.; Clark, G. M.; Shillis, J. L.;
Elslager, E. F. Eur. J. Clin. Oncol. 1986, 22, 921.
Figure 1. Structures of PD 113,271 (1) and fostriecin (2).
exhibits excellent cytotoxic activity against a mouse leukemia
(4) (a) Boritzki, T. J.; Wolfard, T. S.; Besserer, J. A.; Jackson, R. C.;
Fry, D. W. Biochem. Pharmacol. 1988, 37, 4063. (b) de Jong, R. S.; de
Vries, E. G. E.; Mulder, N. H. Anti-Cancer Drugs 1997, 8, 413.
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Chem. Soc. 2001, 123, 4161. (b) Chavez, D. E.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2001, 40, 3667. (c) Reddy, Y. K.; Falck, J. R. Org. Lett.
2002, 4, 969. (d) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.;
Imanishi, T. Chem. Commun. 2002, 9, 742. (e) Wang, Y.-G.; Kobayashi,
Y. Org. Lett. 2002, 4, 4615. (f) Esumi, T.; Okamoto, N.; Hatakeyama, S.
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(L1210, IC50 ) 1.8 µM) and a human ileocecal carcinoma
† Department of Applied Biological Science.
‡ Faculty of Pharmaceutical Sciences.
(1) (a) Tunac, T. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983,
36, 1595. (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N.
E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J.
Antibiot. 1983, 36, 1601. (c) Hokanson, G. C.; French, J. C. J. Org. Chem.
1985, 50, 462. (d) Mamber, S. W.; Okasinski, W. G.; Pinter, C. D.; Tunac,
J. B. J. Antibiot. 1986, 39, 1467.
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R. H. U.S. Patent 447,544, 1986. (b) Stampwala, S. S.; French, J. C.; Tunac,
J. B.; Hurley, T. R.; Bunge, R. H. European Patent Appl. 87021 A2, 1983.
10.1021/ol062111u CCC: $33.50
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Published on Web 10/14/2006

yet been established.1c,2,8 To confirm the configurations and
examine the structure activity relationships, total synthesis
of 1 is required. Herein we report the synthesis of PD 113,-
271 and establish that its stereochemistry is 4S,5S,8R,9R,-
11R in 1.
(JH-3/H-4 ) 2.7 Hz, JH-4/H-5 ) 8.7 Hz, 4,5-anti). Thus we
deduced that the absolute configuration at C4 might be S.
Our retrosynthetic analysis of 1a is outlined in Figure 3.
In this strategy, two unstable units, phosphate monoester and
In planning the synthesis, we drew from knowledge of
the structurally related natural products fostriecin (2),2,5,6,8
phomalactone (3),9 and 4-epi-phomalactone (4),10 whose
absolute and relative configurations have been determined
by NMR spectroscopy, degradation studies, and total syn-
thesis (Figure 2). Since 1 should be synthesized via biosyn-
Figure 3. Retrosynthetic analysis of (4S)-4-hydroxyfostriecin (1a).
triene, should be introduced at the late stages of the synthesis.
Further disconnection of the R,â-unsaturated lactone 5 at the
C6-C7 bond would lead to an aldehyde 7 and a ketophos-
phonate 8. The aldehyde 7 would be derived from alcohol
9, prepared from L-tartaric acid according to a published
method.11 The ketophosphonate 8 would be prepared from
the optically active lactone 10, which is derived from
D-galactose.12
Synthesis of the aldehyde 7 is outlined in Scheme 1. The
alcohol 9, which can be readily produced in three steps from
dimethyl L-tartrate,11 was oxidized by a Swern oxidation13
to give the corresponding aldehyde. Without any further
purification, the aldehyde was directly subjected to the
Z-selective Horner-Emmons reaction14 to produce the
unsaturated ester 11 in 93% yield from 9. Next was a DIBAL
reduction of ester 10 (98% yield) and oxidation of the
corresponding allylic alcohol with MnO2, followed by
treatment of the resulting aldehyde with CSA in EtOH to
provide 12 (69% yield in two steps). A Swern oxidation of
12 furnished aldehyde 7 with a 97% yield.
Figure 2. Speculations about the absolute configuration of PD
113,271 (1) based on the NMR data for phomalactone (3) and 4-epi-
phomalactone (4).
thetic pathways that are similar to 2, the absolute configu-
rations at C5, C8, C9, and C11 of 1 might be S, R, R, and R,
respectively, the same as the stereochemistry of 2. The syn
relationship between C4 and C5 of 1 was deduced based on
the reported coupling constants (JH-3/H-4 ) 6.3 Hz, JH-4/H-5
) 2.7 Hz) of 1,1c which are similar to those of 3 (JH-3/H-4
)
5.3 Hz, JH-4/H-5 ) 3.1 Hz, 4,5-syn) versus those of 4
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I.; Pedersen, C. Acta Chem. Scand. B 1981, 163. (c) Nicolaou, K. C.;
Fylaktakidou, K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.; Mitchell,
H. J.; Wei, H.; Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc.
2003, 125, 15433.
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Org. Lett., Vol. 8, No. 23, 2006

Protection of 15a as a TBS ether, then deprotection of
the ethyl acetal followed by MnO2 oxidation of the resulting
hemiacetal furnished lactone 16 with a 54% yield in three
steps (Scheme 4). After deprotection of the acetonide 16,
Scheme 1. Synthesis of the Aldehyde 7 from 9
Scheme 4. Synthesis of the C1-C13 Fragment of PD 113,271
The synthesis of ketophosphonate 8 is outlined in Scheme
2. TBS protection of an optically active lactone 10, produced
Scheme 2. Synthesis of the Phosphonate 8 from the
Lactone 10
the resulting diol was oxidized with sodium periodate to give
an aldehyde, which was subsequently converted into the vinyl
iodide 17 by a Wittig reaction17 as an inseparable mixture
(E:Z ) 2:1) with a 58% yield in three steps. Deprotection
of the TBS ether with in situ generated Et3N‚2HF18 in
acetonitrile afforded triol 18. TBS protection of the C11
hydroxyl group and sequential TES protection (C8 and C9)
of two hydroxyl groups afforded vinyl iodide 19 with an
89% yield in two steps. Deprotection of the MPM ether with
DDQ,19 TBS protection of the C4 hydroxy group, and
selective removal of the C8 TES group followed by separa-
tion of the Z-isomer by silica gel column chromatography
furnished the vinyl iodide 20 with a 31% yield in three steps.
A Stille coupling reaction20 of the vinyl iodide 20 with
the known stannane derivative 6,21 followed by phosphory-
lation22 of the resulting alcohol, gave 21 (Scheme 5).
Deprotection of the allyl ester and deprotection of the silyl
ether with in situ generated Et3N‚2HF18 in acetonitrile
provided 1a as a sodium salt with a 92% yield in two steps.
1H and 13C NMR spectral data for 1a were in good agreement
with those reported for natural PD 113,271(1).1c,2
in five steps from D-galactose,12 then addition of dimethyl
methylphosphonate to the lactone, followed by TBS protec-
tion15 of the hemiketal 13 produced the ketophosphonate 8
with an 88% yield in three steps.
A Horner-Emmons reaction of ketophosphonate 8 with
aldehyde 7 yielded enone 14. Addition of MeLi to enone 14
5a,16
in the presence of CeCl3
gave the desired (8R)-alcohol
15a and the undesired (8S)-alcohol 15b in 75% and 17%
yields, respectively (Scheme 3). The major diastereomer 15a
Scheme 3. Synthesis of the C1-C12 Fragment of PD 113,271
Unfortunately, the optical rotation of natural PD 113,271
(1) has not been reported and the authentic sample of natural
PD 113,271 (1) is no longer available. To confirm the
(17) (a) Seyferth, D.; Heeren, J. K.; Singh, G.; Grim, S. O.; Hughes, W.
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2001, 123, 9694.
is derived from a Felkin-Anh addition mechanism. The
relative configuration of C8 and C9 was determined by
NOESY experiments of the corresponding acetonide deriva-
tive (see the Supporting Information).
(15) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325.
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Org. Lett., Vol. 8, No. 23, 2006
5309

Scheme 5. Total Synthesis of PD 113,271
Figure 4. The proposed and revised structure of PD 116,251.
absolute configuration of 1, synthetic 1a was converted into
PD 116,251 by acetylation according to the reported
procedure,2b and the spectral data for synthetic PD 116,251
(22a) were compared with those of the authentic natural PD
116,251 sample (Scheme 6). 1H NMR data for our synthetic
acetylating step.24 The optical rotation of our synthetic PD
116,251 ([R]24 +28 (c 0.02 in H2O)) was identical with
D
that of the authentic one ([R]23D +29 (c 0.04 in H2O)). Thus
we confirmed the structural and stereochemical assignments
(4S,5S,8R,9R,11R) of 1.
In summary, we have accomplished the first total synthesis
of PD 113,271 from readily available starting materials using
a chiral pool approach, thereby establishing its relative and
absolute stereochemistry. The natural product was obtained
in a 23-step sequence with an overall yield of 2.9%, starting
from the known and easily accessible alcohol 9. Further
synthetic studies to improve the synthetic efficiency as well
as biological studies are currently ongoing. Our synthesis
and structural determination of 1 now open up opportunities
to develop new tools for biological studies and to design
new drugs to treat or prevent cancer.
Scheme 6. Acetylation of 1a
22a were in excellent agreement with those of the natural
sample. However, the 31P chemical shift of PD 116,251 was
observed at 14.5 ppm, which is characteristic of a five-
membered phosphate (10-15 ppm) against phosphate mo-
noester (-1 to 6 ppm),23 indicating that PD 116,251 contains
a cyclic phosphate. Furthermore, the molecular formula of
22a, C25H30O12NaP, was established by HRESIMS (calcu-
lated for C25H30O12Na2P ([M + Na]+) to be 599.1264,
observed value 599.1258). Although the proposed structure
of PD 116,251 is phosphate monoester as depicted in 22,
the structure and the absolute configuration of PD 116,251
were determined to be those shown in 22a (Figure 4). The
formation of a cyclic phosphate might occur during the
Acknowledgment. We are especially indebted to Pfizer
Inc. for providing us the authentic sample of PD 116,251.
We gratefully acknowledge Prof. Imanishi and Dr. Miyashita
of Osaka University for giving us helpful advice. We thank
Prof. Soai and Dr. Kawasaki of Tokyo University of Science
for giving us technical support for high-resolution NMR
examination.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL062111U
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