Total synthesis of an antitumor antibiotic, fostriecin (CI-920)

Article abstract of DOI:10.1021/ja030133v

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, an

Full text of DOI:10.1021/ja030133v

Published on Web 06/17/2003
Total Synthesis of an Antitumor Antibiotic, Fostriecin (CI-920)
Kazuyuki Miyashita, Masahiro Ikejiri, Hitomi Kawasaki, Satoko Maemura, and
Takeshi Imanishi*
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received February 24, 2003; E-mail: imanishi@phs.osaka-u.ac.jp
Abstract: The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route
is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via
a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin,
corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the
stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment
B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers
at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric
dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C,
was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is
known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct
phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl
groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the
former route is basically the same as those reported by other groups, the latter route is novel and more
effective than the former one. The present total synthesis would serve as a versatile synthetic route to not
only fostriecin, but also its various analogues including stereoisomers.
Fostriecin (1, CI-920; Figure 1), isolated from Streptomyces
puluVeraceus with its accompanying analogues, PD113270 and
PD113271,1 is known to be active in vitro against leukemia
(L1210), lung, breast and ovarian cancer and is also known to
show in vivo antitumor activity against L1210 and P388
leukemia.2 Because of these potentialities, the phase I trial of
this compound had been conducted by the National Cancer
Institute, but was halted due to problems of purity and stability
of the natural material.3 Fostriecin is a weak topoisomerase II
inhibitor, the mechanism of which is not well-known, but was
reported to be different from that of known classical topo-
Figure 1. Structures of fostriecin (1) and its analogues.
isomerase II inhibitors, such as anthracyclins and podophyllo-
between the antitumor activity and the enzyme inhibitory
toxins.4 Fostriecin is also known to be the most selective
activities of fostriecin is of great interest. It is also noteworthy
inhibitor against protein phosphatase 2A and 4; hence, it has
that fostriecin, which promotes chromatin compaction, radio-
attracted much attention as a pharmacological reagent as well.5
sensitizes tumor cells.6 However, despite its interesting biologi-
Because other protein phosphatase inhibitors, such as okadaic
cal activities, as is obvious from the fact that the stereostructure,
acid, calyculin A, and so on, are generally known to have tumor-
including the absolute stereochemistry, of fostriecin was dis-
promotion activity rather than antitumor activity, the relation
closed in 1997,7 only limited chemical research had been done
and little about the mechanism of action of fostriecin is known.8
(1) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36, 1595.
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.
(5) Roberge, M.; Tudan, C.; Hung, S. M. F.; Harder, K. W.; Jirik, F. R.;
Anderson, H. Cancer Res. 1994, 54, 6115. Guo, X. W.; Th’ng, J. P. H.;
Swank, R. A.; Anderson, H. J.; Tudan, C.; Bradbury, E. M.; Roberge, M.
EMBO J. 1995, 14, 976. Ho, D. T.; Roberge, M. Carcinogenesis 1996, 17,
967. Walsh, A. H.; Cheng, A.; Honkanen, R. E. FEBS Lett. 1997, 416,
230. Hastie, C. J.; Cohen, P. T. W. FEBS Lett. 1998, 431, 357. Cheng, A.;
Balczon, R.; Zuo, Z.; Koons, J. S.; Walsh, A. H.; Honkanen, R. E. Cancer
Res. 1998, 58, 3611.
(6) Biade, S.; Stobbe, C. C.; Boyd, J. T.; Chapman, J. T. Int. J. Radiation
Biol. 2001, 77, 1033.
(7) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62, 1748.
(8) Hokanson, G. C.; French, J. C. J. Org. Chem. 1985, 50, 462.
(2) Jackson, R. C.; Fry, D. W.; Boritzki, T. J.; Roberts, B. J.; Hook, K. E.;
Leopold, W. R. AdV. Enzyme Regul. 1985, 23, 193. De Jong, R. S.; De
Vries, E. G. E.; Mulder, N. H. Anti-Cancer Drugs 1997, 8, 413. Scheithauer,
W.; Hoff, D. D. V.; Clark, G. M.; Shillis, J. L.; Elslager, E. F. Eur. J.
Clin. Oncol. 1986, 22, 921.
(3) De Jong, R. S.; Mulder, N. H.; Uges, D. R. A.; Sleijfer, D. Th.; Hoppener,
F. J. P.; Groen, H. J. M.; Willemse, P. H. B.; Van der Graaf, W. T. A.; De
Vries, E. G. E. Br. J. Cancer 1999, 79, 882.
(4) Boritzki, T. J.; Wolfard, T. S.; Besserer, J. A.; Jackson, R. C.; Fry, D. W.;
Biochem. Pharmacol. 1988, 37, 4063.
9
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J. AM. CHEM. SOC. 2003, 125, 8238-8243
10.1021/ja030133v CCC: $25.00 © 2003 American Chemical Society

Total Synthesis of Antitumor Antibiotic Fostriecin
A R T I C L E S
coupling reaction, which would stereoselectively provide various
geometrical isomers, including a natural Z,Z,E-isomer.
An unsaturated δ-lactone system is seen as a part of a number
of biologically active natural products as well as fostriecin. This
structural unit was sometimes connected by the Horner-
Emmons reaction employing the lactone moiety as an aldehyde
part in syntheses of such natural products,14 including fostriecin,9
or, recently, was constructed by ring-closing olefin metathesis.
The latter method involves an asymmetric allylation procedure
and was also employed in syntheses of natural products15 and
their analogues, including fostriecin.10b,c,13b In contrast, we
expected that this structural unit would be conveniently con-
structed by the Horner-Emmons reaction employing the lactone
moiety as a Horner-Emmons reagent. Stereoselective reduction
of the resultant unsaturated ketone would give both stereoiso-
mers relative to the C-5 position at this stage, allowing a more
versatile synthetic route. According to this idea, we employed
the Horner-Emmons reagent16 as segment A.
Concerning segment B having a series of stereogenic centers,
we planned to construct the C-8 and C-9 stereogenic centers
by Sharpless asymmetric dihydroxylation17 of the E-olefin. The
C-11 stereogenic center was assumed to be made from the
starting material, (R)-malic acid.
Results and Discussion
Synthesis of Segment A-B. Synthesis of segment B was
achieved as follows. Alcohol 2 (Scheme 1), which was prepared
from (R)-malic acid according to a literature procedure,18 was
oxidized by Swern oxidation and treated with a Wittig reagent
4 19 to give E-olefin 3a in 86% yield from 2. In contrast, it was
also found that the reaction with 5 20a gave Z-olefin 3b as a
major product under conditions reported by Ando et al.,20,21
showing that both E- and Z-isomers of 3 are stereoselectively
obtained. Reduction of 3a and subsequent benzoylation gave
olefin 7 in 86% yield. Stereoselective introduction of two
hydroxyl groups was achieved as follows. At first, dihydrox-
ylation of 7 without a chiral ligand was examined, affording a
mixture of anti- and syn-isomers (Table 1, entry 1). From the
proposed model for asymmetric dihydroxylation by Sharpless
and co-workers,17 DHQD as a chiral ligand was expected to
give the desired anti-isomer 8a. In fact, asymmetric dihydrox-
ylation with DHQD gave the anti-isomer 8a as a main product
(entry 2). It is noteworthy that the reaction with (DHQD)2PHAL
as a chiral ligand improves the stereoselectivity (entry 3) and,
Figure 2. Retrosynthetic analysis of fostriecin (1).
Therefore, fostriecin has the potential to be, or to open the door
to, a novel type of antitumor agent that is based on a novel
mechanism of action.
For the reasons described above, a number of synthetic studies
have been conducted, particularly since its stereostructure was
revealed by Boger’s group in 1997,7 and the first total synthesis
was achieved by his group in 2001.9 Subsequently, some
groups,10 including ours,11 have reported its total synthesis.12
Synthetic studies including the formal total synthesis also have
been reported.13 In this paper, we would like to report details
of our total synthesis of fostriecin.11
In considering a synthetic strategy for fostriecin, we paid
attention particularly to take account that not only fostriecin
but also its various analogues can be synthesized efficiently
according to the same strategy. For the purpose, we planned to
take a convergent route in which the fostriecin molecule is
divided into three segments A, B, and C as shown in Figure 2.
Because the triene moiety was easily expected to be unstable,
plans were made to couple segment C after the construction of
the segment A-B moiety. The triene moiety was expected to
be synthesized by Wittig reaction and/or a Pd(0)-catalyzed
(14) For example: Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto,
M.; Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349. Crimmins, M. T.;
King, B. W. J. Am. Chem. Soc. 1998, 120, 9084. Kalesse, M.; Quitschalle,
M.; Khandavalli, C. P.; Saeed, A. Org. Lett. 2001, 3, 3107. Vicario, J. L.;
Job, A.; Wolberg, M.; Mu¨ller, M.; Enders, D. Org. Lett. 2002, 4, 1023.
(15) For example: Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. J.
Ind. Chem. Soc. 1999, 739. Reddy, M. V. R.; Yucel, A. J.; Ramachandran,
P. V. J. Org. Chem. 2001, 66, 2512. Ramachandran, P. V.; Reddy, M. V.
R.; Rearick, J. P.; Hoch, N. Org. Lett. 2001, 3, 19. Reddy, M. V. R.;
Ramachandran, P. V.; Brown, H. C. J. Organomet. Chem. 2001, 624, 239.
(16) Wenkert, E.; Guo, M.; Lavilla, R.; Porter, B.; Ramachandran, K.; Sheu,
J.-H. J. Org. Chem. 1990, 55, 6203.
(9) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161.
(10) (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667.
(b) Reddy, Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969. (c) Esumi, T.;
Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002, 3042.
(11) A part of this work appeared as a preliminary communication: Miyashita,
K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. Chem. Commun.
2002, 742.
(12) For review article about chemistry and biology of fostriecin: Lewy, D. S.;
Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr. Med. Chem. 2002, 9,
2005.
(13) (a) Just, G.; O’Connor, B. Tetrahedron Lett. 1988, 29, 753. Liu, S. U.;
Huang, D. F.; Huang, H. H.; Huang, L. Chin. Chem. Lett. 2000, 11, 957.
Cossy, J.; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3, 2233. Kiyotsuka,
Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2002, 43, 2725. (b) Wang,
Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615. (d) Fujii, K.; Maki, K.;
Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733.
(17) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(18) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933. Smith, A.
B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J.
Am. Chem. Soc. 1997, 119, 10935.
(19) Isler, O.; Gutmann, H.; Montavon, M.; Riiegg, R.; Ryser, G.; Zeller, P.
HelV. Chim. Acta 1957, 40, 1241.
(20) (a) Ando, K. J. Org. Chem. 1998, 63, 8411. (b) Ando, K. Tetrahedron
Lett. 1995, 36, 4105. Ando, K. J. Org. Chem. 1997, 62, 1934. Ando, K.;
Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745.
(21) Tang, J.; Brackenridge, I.; Roberts, S. M.; Beecher, J.; Willetts, A. J.
Tetrahedron 1995, 51, 13217.
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J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003 8239

A R T I C L E S
Miyashita et al.
Scheme 1 a
1
Figure 3. Selected H and 13C NMR data for 14a,b.
acetonide 14a as a main product (78% yield) with accompanying
five-membered acetonide 15a (10% yield).22 Less polar isomer
8b was also transformed into 13b by the same procedures, and
acetonidation gave six-membered acetonide 14b exclusively.22
As shown in Figure 3, 1H NMR and 13C NMR analyses revealed
that 14a derived from the more polar isomer 8a has a half-
chair conformation, while 14b derived from the less polar isomer
8b has a chair conformation.23 These results clearly show that
the more polar isomer 8a has anti-stereochemistry and the less
polar one 8b has syn-stereochemistry, as expected.
To transform into segment B, the diol 8a was protected with
an acetonide group, giving a bisacetonide, the terminal acetonide
group of which was selectively removed under Vijayasaradhi’s
conditions24 to give 9. The primary hydroxyl group of 9 was
protected with an MPM group via stannoxane,25 and the residual
secondary hydroxyl group of 10 was protected with a TBS group
to give 11, corresponding to segment B.
a Conditions: (i) Swern oxidation -78 to 0 °C, then 4, rt, 86%, or (1)
Swern oxidation, (2) 5, DBU, NaI, THF, -78 to 0 °C, 40% (3b), 11%
(3a); (ii) LAH, Et2O, 0 °C to rt, 98%; (iii) BzCl, Et3N, CH2Cl2, 0 °C, 86%;
(iv) Table 1, entry 3; (v) (1) 2,2-dimethoxypropane, p-TsOH, rt, (2)
Zn(NO3)2‚6H2O, MeCN, 50 °C, 81%, 2 steps; (vi) Bu2SnO, toluene, reflux,
and then MPMCl, Bu4NI, reflux, 84%; (vii) TBSOTf, 2,6-lutidine, CH2Cl2,
0 °C.
Table 1. Asymmetric Dihydroxylation of 7a
entry
ligand
ratio (8a:8b)
yield (%)
1
2
3
4
noneb
DHQD
(DHQD)2PHAL
(DHQ)2PHAL
57:43
72:28
95:5
95
80
92
90
17:83
a The reactions were performed in t-BuOH-H2O at 0 °C with 2 mol %
of K2OsO2(OH)4, 3 equiv of K3Fe(CN)6, 3 equiv of K2CO3, 1 equiv of
MeSO2NH2, and 5 mol % of the ligand. b The reaction was carried out in
acetone-H2O at room temperature with OsO4 and NMO.
Scheme 2 a
It is noteworthy that, theoretically, the present synthetic
strategy for segment B can provide all of its possible stereo-
isomers bearing three stereogenic centers by choosing the proper
starting material [(R)- or (S)-malic acid], the geometrical
selectivity of the Wittig reaction (3a or 3b), and the chiral
ligand for asymmetric dihydroxylation [(DHQD)2PHAL or
(DHQ)2PHAL]. In addition, segment B (11) has a characteristic
feature in that either segment A or C can be coupled with it by
selective removal of one of the two terminal protecting groups,
the benzoyl group and the MPM group. In the case of the
synthesis of fostriecin, segment A rather than segment C was,
at first, coupled with segment B by taking account of the labile
property of the triene moiety.
Construction of segment A-B was achieved as shown in
Scheme 3. The benzoyl group of 11 was removed by hydrolysis
to give alcohol 16, which was oxidized to aldehyde 17, and
treated with the Horner-Emmons reagent 18 16 corresponding
to segment A to give 19, selectively. The stereochemistry at
the C-5 position was introduced as follows. As reduction of 19
with NaBH4-CeCl3 afforded a mixture of diastereomers, 20a,b,
a Conditions: (i) 60% AcOH, rt; (ii) TBDPSCl, DMAP, py, rt, 62% from
(()-8a, 57% from (()-8b; (iii) (1) 2,2-dimethoxypropane, p-TsOH, rt, (2)
Ac2O, py, rt.
as expected, the syn-isomer 8b was stereoselectively obtained
by employing enantiomeric (DHQ)2PHAL (entry 4).
Although the stereochemistries of 8a and 8b were expected
to be as shown from the proposed model for the asymmetric
dihydroxylation,17 it was eventually confirmed by NMR analysis
of six-membered acetonides 14 derivatized as shown in Scheme
2. Acidic treatment of the more polar isomer of 8a, which was
expected to be an anti-isomer, afforded tetraol 12a, the primary
hydroxyl group of which was protected with a TBDPS group
to give triol 13a. Acetonidation of 13a gave the six-membered
(22) To obtain six-membered acetonide selectively, it was important to protect
the primary hydroxyl group with a benzoyl group.
(23) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945. Evans,
D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
(24) Vijayasaradhi, S.; Singh, J.; Aidhen, I. S. Synlett 2000, 110.
(25) Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi, S. J. Org. Chem. 1990,
55, 5132. Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39, 1972.
Boons, G.-J.; Castle, G. H.; Clase, J. A.; Grice, P.; Ley, S. V.; Pinel, C.
Synlett 1993, 913.
9
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Total Synthesis of Antitumor Antibiotic Fostriecin
A R T I C L E S
Scheme 3 a
Scheme 4 a
a Conditions: (i) PdCl2(MeCN)2, 26, DMF, rt; (ii) DIBAl-H, CH2Cl2,
-78 °C, 86%, 2 steps; (iii) NBS, Me2S, CH2Cl2, -20 °C to rt, 68%; (iv)
Ph3P, MeCN, rt, 96%.
Scheme 5 a
a Conditions: (i) 3 M KOH(aq):MeOH:THF (1:2:2), rt, 87%; (ii) TPAP,
NMO, MS4A, CH2Cl2, rt; (iii) (MeO)2OPCH2CO(CH2)3CO2Et (18), DBU,
LiCl, MeCN, rt, 79%, 2 steps; (iv) 20a, Table 2, entry 4, and 20b, Table 2,
entry 5; (v) p-TsOH, benzene, reflux, 92%; (vi) TMSCl, NaHMDS, THF,
-78 °C, and then PhSeBr, -78 °C, 94%; (vii) 30% H2O2(aq), NaHCO3,
AcOEt:THF (1:1), rt, 95%; (viii) DDQ, CH2Cl2:H2O (10:1), rt, 96%.
Table 2. Asymmetric Reduction of 19
a Conditions: (i) Dess-Martin periodinane, NaHCO3, CH2Cl2, rt; (ii)
NaHMDS, 30, THF, -78 to 0 °C, 76%, (E:Z ) 12:1).
entry
conditions
ratio (20a:20b)
yield of 20 (%)
1
2
3
4
NaBH4, CeCl3‚7H2O, MeOH, -78 °C
(S)-CBS, BH3‚THF, THF, 0 °C
1:2
3:1
3:1
80
95
96
report of a Wittig reaction with that conjugated with a Z-olefin,
like segment C, has been reported. Expecting formation of a
Z-olefinic bond, we at first selected a Wittig reaction with Wittig
salt 30, which was prepared alternatively as shown in Scheme
4. Vinylstannane 2530 was coupled with alkenyl iodide 2631
under Pd(0)-catalyzed conditions32 to give 27 stereoselectively,
which was reduced to yield alcohol 28. Bromination and
quartenalization with triphenylphosphine afforded the Wittig salt
30.
The alcohol 24 was oxidized with Dess-Martin reagent33 and
then reacted with the Wittig salt 30 to give E-isomer 32 as a
major product (Scheme 5). We examined several conditions of
the Wittig reaction to obtain the Z-isomer, but the results were
unsuccessful, probably due to serious steric repulsion of the
Z,Z,E-geometry. In addition, deprotection of the acetonide group
of 32 was also examined to introduce a phosphate moiety to
the hydroxyl group at the C-9 position, but this attempt failed,
forming a complex mixture. Therefore, it was found that the
desired Z-selectivity cannot be obtained by the Wittig reaction
of the phosphorus ylide conjugated with a Z-olefinic bond and
that the acetonide group should be removed before formation
of the triene moiety.
(S)-CBS, BH3‚DMS, THF, 0 °C
(R)-BINAl-H, THF, -100 to -78 °C
>20:1
73
(21: 12%)a
5
(S)-BINAl-H, THF, -100 to -78 °C 20b only
70
(5-epi-21: 9%)a
a The ratio was determined after conversion to 20 with K2CO3 and EtOH.
in a ratio of ca. 1:2 (Table 2, entry 1), we examined asymmetric
reduction of 19. Although the desired (R)-isomer 20a was
obtained as a major product on treatment with a chiral borane
reagent,26 the stereoselectivity was unsatisfactory (entries 2 and
3). In contrast, the reduction with (R)-BINAl-H27 afforded good
stereoselectivity (entry 4) in good chemical yield. As expected,
the isomer 20b was almost exclusively obtained by the reduction
with (S)-BINAl-H (entry 5). Although the stereochemistry at
the C-5 position of 20 was expected to be as shown from the
proposed transition states for the reduction,26,27 it was eventually
confirmed by modified Mosher’s method (see Supporting
Information).28 Lactonization and dehydrogenation via R-phenyl-
selenide 22 afforded unsaturated lactone 23, the MPM group
of which was removed by oxidative treatment to give 24,
corresponding to segment A-B. The present method to construct
the unsaturated lactone moiety is straightforward and is char-
acterized by the fact that both stereoisomers are distinctly
obtained by choosing the asymmetric reducing agent, (R)- or
(S)-BINAl-H.
Considering the facts described above, we consequently
utilized the Stille coupling reaction after formation of the
Z-olefinic bond between the C-12 and C-13 positions by Wittig
reaction, to introduce the triene moiety to segment A-B.
Synthesis of Fostriecin by Direct Phosphorylation. Some
examples have been reported that the Wittig reaction of a
phosphorus ylide conjugated with an E-olefin affords Z-
stereoselectivity.29 However, to the best of our knowledge, no
(29) Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem. Soc. 1980, 102,
7984. Niwa, H.; Watanabe, M.; Inagaki, H.; Yamada, K. Tetrahedron 1994,
50, 7385.
(30) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851. Bansal, R.;
Cooper, G. F.; Corey, E. J. J. Org. Chem. 1991, 56, 1329. Lai, M.; Li, D.;
Oh, E.; Liu, H. J. Am. Chem. Soc. 1993, 115, 1619. Oddon, G.; Uguen, D.
Tetrahedron Lett. 1998, 39, 1153.
(26) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(27) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc.
1984, 106, 6709. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J.
Am. Chem. Soc. 1984, 106, 6717.
(31) Marek, I.; Meyer, C.; Normant, J. F. Org. Synth. 1997, 74, 194.
(32) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
(33) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899. Frigerio, M.; Santagostino, M.;
Sputore, S. J. Org. Chem. 1999, 64, 4537.
(28) Kusumi, T. J. Synth. Org. Chem. Jpn. 1993, 51, 462.
9
J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003 8241

A R T I C L E S
Miyashita et al.
Scheme 6 a
Scheme 7 a
a Conditions: (i) POCl3, py, 0 °C, and then ROH, 0 °C; (ii) Table 3,
method A-D; (iii) Pd(PPh3)4, HCO2NH4, THF, rt, 87%.
Table 3. Partial Hydrolytic Cleavage of Cyclic Phosphate 41
entry
41
methoda
yield from 40 (%)
ratio (42:43:44)
1
2
3
4
5
6
a
a
a
a
b
c
A
B
C
D
D
D
81
78
75
83
72
81
54:15:31
57:14:29
66:15:13
70:17:13
77:14:9
a Conditions: (i) Ph3P+CH2I‚I-, NaHMDS, HMPA, THF, -100 to 0
°C, 61% from 24 (Z:E ) 4:1); (ii) 1 M HCl(aq):MeOH (1:9), rt, 89%; (iii)
(1) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, and then TESOTf, -78 °C,
(2) separation 56% (Z-isomer); (iv) 1 M HCl(aq):THF:MeCN (1:3:6), -10
°C, 70% (18% recovery of 35); (v) PdCl2(MeCN)2, 37, DMF, rt, 84%; (vi)
PCl3, MPMOH, py, 0 °C to rt, and then t-BuOOH, CH2Cl2, rt, 56%; (vii)
HF(aq)-MeCN and then py, rt, 38%.
72:14:14
a Method A: MeCN:H2O:Et3N (20:1:1), room temperature. Method B:
THF:H2O:Et3N (20:1:1), room temperature. Method C: t-BuOH:H2O:Et3N
(20:1:1), room temperature. Method D: CF3CH2OH:H2O:Et3N (20:1:1),
room temperature.
Iodomethylenation34 of the aldehyde 31 gave Z-isomer 33 as a
major product (Z:E ) ca. 4:1; Scheme 6). Because the geometric
isomers were difficult to separate at this stage, the mixture was
employed for the subsequent transformation. Deprotection of
the acetonide group of 33 was successfully achieved, affording
triol 34. To introduce a phosphoryl group regioselectivey, the
hydroxyl groups of 34 were selectively protected as follows.
One of the two secondary hydroxyl groups was selectively
protected with a TBS group, and the resultant two hydroxyl
groups were protected with a TES group. These protection
procedures could be accomplished in one pot, and the Z-isomer
could be separated at this stage by silica gel column chroma-
tography to give 35 in 53% yield. Selective removal of the TES
group at the C-8 position was achieved by acidic treatment to
give 36,35 which was coupled with organostannane 37 36 under
Pd(0)-catalyzed conditions32 to afford 38.35 Phosphorylation of
38 according to Evans’ procedure37 gave 39, which is a fully
protected derivative of fostriecin. Deprotection of 39 by fluoride
treatment9 afforded fostriecin (1), which was identified by
comparison of the spectral properties (IR, 1H NMR, 13C NMR,
[R]D, and TLC behavior) with those of an authentic sample.
Synthesis of Fostriecin via Cyclic Phosphate. Not only in
our synthesis described above, but also in those reported by
other groups,9,10 the tertiary hydroxyl group at the C-8 position
was protected with a silyl group on phosphorylation. It occurred
to us that it would be more convenient if the hydroxyl group at
the C-9 position could be phosphorylated without protecting
the tertiary hydroxyl group. Choosing 40, which was easily
obtained from 8a, as a model compound, we alternatively
examined the posphorylation without protecting the tertiary
hydroxyl group. Several attempts to phosphorylate the secondary
hydroxyl group of 40 failed, forming diphosphate or cyclic
phosphate. We focused on the cyclic phosphate, which would
be an intermediate for selective phosphorylation by selective
cleavage of the P-O bond. Although some reports concerning
hydrolytic cleavage of cyclic phosphates have been reported,38
regioselectivity of the cleavage of cyclic phosphates has not
been known. Cyclic phosphate 41a (Scheme 7 and Table 3)
was obtained as a diastereomeric mixture by treatment with
POCl3 in pyridine and then with deuterated methanol, which
was employed to simplify the 1H NMR spectrum of the products.
After several attempts, we found that cleavage of the cyclic
phosphate 41a smoothly took place by treatment with aqueous
acetonitrile (method A) or aqueous THF (method B) in the
presence of triethylamine to give hydrated products 42a, 43a,
and 44. The desired product 42a was obtained as a main product
in both cases, and the respective ratios obtained by the 1H NMR
spectra were almost the same (entries 1 and 2). Although the
same reaction in a methanolic solvent afforded a complex
mixture, the reaction in tert-butyl alcohol (method C) success-
fully took place. In this reaction, the ratio of 42a increased,
while that of 44 decreased (entry 3 vs entries 1 and 2). As a
consequence, it was also found that the reaction in a 2,2,2-
trifluoroethanol (method D) gave the best results with respect
to both chemical yield and regioselectivity (entry 4). Taking
into account application of this method to the synthesis of
(34) Seyferth, D.; Heeren, J. K.; Singh, G.; Grim, S. O.; Hughes, W. B. J.
Organomet. Chem. 1966, 5, 267. Stork, G.; Zhao, K. Tetrahedron Lett.
1989, 30, 2173.
(35) This compound 36 was employed as an intermediate in the total synthesis
of fostriecin by Jaconsen’s group10a and Hatakeyama’s group10c as well.
Kobayashi’s group reported formal total synthesis of fostriecin by the
synthesis of 36.13c The compound 38 was also synthesized by Shibasaki
and co-workers in their formal total synthesis of fostriecin.13d
(36) Heathcock and co-worker reported the synthesis of a compound having a
TBS group in place of the TBDPS group of 37: Mapp, A. K.; Heathcock,
C. H. J. Org. Chem. 1999, 64, 23. Hatakeyama’s group reported alternative
synthesis of 37.10c
(38) (a) Gorenstein, D. G.; Taira, K. J. Am. Chem. Soc. 1982, 104, 6130. Kluger,
R.; Taylor, S. D. J. Am. Chem. Soc. 1990, 112, 6669. (b) Taira, K.; Fanni,
T.; Gorenstein, D. G. J. Org. Chem. 1984, 49, 4531.
(37) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114,
9434.
9
8242 J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003

Total Synthesis of Antitumor Antibiotic Fostriecin
A R T I C L E S
Scheme 8 a
alcohol to give the cyclic triester 47 as a diastereomeric mixture.
Without purification, 47 was immediately hydrolyzed, and the
P-O bond of 47 was regioselectively cleaved under the same
conditions as those described above, affording 48a as a major
product [δH, 1.14 ppm (C-8-Me); δP, 1.0 ppm]. The minor
components were not isolated but were assigned to be C-8-
phosphate 48b and cyclic phosphate diester 48c from the 31P
1
NMR and H NMR spectra of the crude product, similarly to
the reaction of the model compound 41. The ratio of 48a:48b:
48c was estimated to be 80:12:8. After deprotection of the allyl
group of 48a,40 the resultant phosphate 49 was further treated
with fluoride to afford fostriecin after chromatographic purifica-
tion. Spectral properties of the product were identical with those
of an authentic sample and of 1 prepared by the method
described above. On comparing the two methods, the route from
34 via direct phosphorylation of 38 afforded fostriecin in 7%
yield, while that via cyclic phosphate 47 resulted in 23% yield
from the same compound 34, showing that the latter route is
obviously more effective.
a Conditions: (i) (1) PdCl2(MeCN)2, 37, DMF, rt, (2) separation, 52%
(Z-isomer); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 88%; (iii) POCl3,
py, 0 °C, and then CH2dCHCH2OH, 0 °C; (v) CF3CH2OH, Et3N, H2O, rt,
81%, 2 steps (80% selectivity); (vi) (1) Pd(PPh3)4, HCO2NH4, PPh3, THF,
rt, (2) HF-py, MeCN, H2O, rt, 63%, 2 steps.
In conclusion, we have successfully synthesized fostriecin
via a highly convergent route involving a three-segment coupling
procedure. Introduction of the phosphate moiety was achieved
via two routes, direct phosphorylation and partial hydrolytic
cleavage of cyclic phosphate. The latter method was shown to
be more efficient than the former method. Our present synthetic
methodology would be of great use for the synthesis of various
fostriecin analogues including stereoisomers and natural products
belonging to the fostriecin family41 as well, and synthetic studies
on fostriecin analogues according to the present strategy are in
progress toward efforts to reveal the structure-activity relation-
ship of fostriecin.
fostriecin, we next studied the reaction using cyclic phosphates
41b,c, both of which have deprotectable alkoxy groups under
mild conditions after introduction of the phosphate moiety. On
employing allyl derivative 41b, the ratio of 42b slightly
increased, and that of 44 slightly decreased, compared with the
result of the methyl derivative 41a (entry 5 vs entry 4). The
reaction of 2-(trimethylsilyl)ethyl derivative 41c afforded the
same result as that of 41b. Therefore, the alkoxy group of the
cyclic phosphate would not significantly affect the regioselec-
tivity of the cleavage.
Structures of the products were determined as follows. The
cyclic phosphate 44 which was alternatively prepared from 41b
by deallylation and was also differentiated from 42 and 43 by
31P NMR, showed a signal at 11.2 ppm, while 42a and 43a
showed signals at +1.5 ppm and -2.4 ppm, respectively.7 The
structures of 42a and 43a were assigned as shown by compari-
son of their 1H NMR spectra, in which the hydrogen at the C-3
position of 42a and the methyl group at the C-2 position of
43a shifted to lower field due to the phosphate moiety [42a,
4.42 (C-3-H) and 1.13 ppm (C-2-Me); 43a, 3.89 (C-3-H) and
1.34 ppm (C-2-Me)].
With regard to the reaction mechanism, it has been already
reported that, in hydrolytic cleavage of five-membered cyclic
phosphate, the endo-cyclic P-O bond is cleaved more easily
than the exo-cyclic P-O bond, because of a stereoelectronic
effect.38b The fact that 42, not 43, was a major product in every
case would be explained by taking account of the fact that the
sterically more hindered P-O bond is likely to be cleaved more
easily after attack of H2O on the phosphorus center of 41. The
fact that a less nucleophilic and more acidic alcohol, 2,2,2-
trifluoroethanol, afforded the best result suggests an important
role of hydrogen bonding, but the detail is unclear.
Encouraged by the results described above, we applied the
method to the synthesis of fostriecin as follows. Compound 34
was coupled with the organotin compound 37 to give 45
(Scheme 8),39 the hydroxyl group at the C-11 position of which
was selectively protected with a TBS group, giving diol 46.39
Diol 46 was phosphorylated by treatment with POCl3 and allyl
Experimental Section
Full experimental details are provided as Supporting Information.
Acknowledgment. We gratefully acknowledge Dr. Robert J.
Schultz of the Drug Synthesis and Chemistry Branch, Devel-
opmental Therapeutics Program, Division of Cancer Treatment
and Diagnosis, National Cancer Institute, for the kind gift of
natural fostriecin.
Supporting Information Available: Text describing complete
1
experimental details and figures showing H NMR spectra for
3a, 6, 7, 8a, 9, 10, 16, 19, 20a, 21, 23, 24, 35, 36, 38, 46, and
natural and synthetic fostriecin (1) and 13C NMR spectra for
natural and synthetic fostriecin. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA030133V
(40) Hayakawa, Y.; Kato, H.; Uchiyama, M.; Kajino, H.; Noyori, R. J. Org.
Chem. 1986, 51, 2400. Hayakawa, Y.; Wakabayashi, S.; Nobori, T.; Noyori,
R. Tetrahedron Lett. 1987, 28, 2259. Zhang, H. X.; Guibe, F.; Balavoine,
G. Tetrahedron Lett. 1988, 29, 623.
(41) Phospholine: Ozasa, T.; Suzuki, K.; Sasamata, M.; Tanaka, K.; Kobori,
M.; Kadota, S.; Nagai, K.; Saito, T. J. Antibiot. 1989, 42, 1331.
Leustroducsin: Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.;
Torikata, A.; Inukai, M.; Kaneko, I.; Kagasaki, T.; Sakaida, Y.; Satoh, A.;
Shiraishi, A. J. Antibiot. 1993, 46, 1503. Kohama, T.; Nakamura, T.;
Kinoshita, T.; Kaneko, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512. Shibata,
T.; Kurihara, S.; Yoda, K.; Haruyama, H. Tetrahedron 1995, 51, 11999.
Phoslactomycin: Fushimi, S.; Nishikawa, S.; Shimazu, A.; Seto, H. J.
Antibiot. 1989, 42, 1019. Tomiya, T.; Uramoto, M.; Isono, K. J. Antibiot.
1990, 43, 118. Cytostatin: Amemiya, M.; Ueno, M.; Osono, M.; Masuda,
T.; Kinoshita, N.; Nishida, C.; Hamada, M.; Ishizuka, M.; Takeuchi, T. J.
Antibiot. 1994, 47, 536. Sultriecin: Ohkuma, H.; Naruse, N.; Nishiyama,
Y.; Tsuno, T.; Hoshino, Y.; Sawada, Y.; Konishi, M. J. Antibiot. 1992,
45, 1239.
(39) The compounds 45 and 46 were employed as intermediates in the total
synthesis of fostriecin by Boger’s group.9
9
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