Formal catalytic asymmetric total synthesis of fostriecin.

Article abstract of DOI:10.1021/ol027528o

The common synthetic intermediate of a potent and promising anticancer agent, fostriecin, was synthesized using a unique method that combines four catalytic asymmetric reactions as shown above.

Full text of DOI:10.1021/ol027528o

ORGANIC
LETTERS
2003
Vol. 5, No. 5
733-736
Formal Catalytic Asymmetric Total
Synthesis of Fostriecin
,†
Kunihiko Fujii,† Keisuke Maki,† Motomu Kanai,†,‡ and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and PRESTO, Japan Science and
Technology Corporation
mshibasa@mol.f.u-tokyo.ac.jp
Received December 21, 2002
ABSTRACT
The common synthetic intermediate of a potent and promising anticancer agent, fostriecin, was synthesized using a unique method that
combines four catalytic asymmetric reactions as shown above.
Fostriecin (1, CI-920) is a structurally interesting novel
metabolite of Streptomyces pulVeraceus that was first isolated
in 1983 by a research group at Warner Lambert-Parke Davis.1
Fostriecin displays antitumor activity against a broad range
of cancerous cell lines in vitro that is suggested to be
intimately related to the potent and highly selective inhibitory
activity against serine/threonine phosphatase PP2A.2 There-
fore, fostriecin is a novel lead compound for anticancer drugs,
as well as an important biological tool.
In 1997, Boger’s group determined the relative and
absolute configuration of fostriecin on the basis of synthetic
and degradation studies.3 They later reported the first total
synthesis.4 Since then, five elegant total syntheses have been
reported, reflecting the highly focused interest in this
compound.5,6 In this communication, we report our contribu-
tion to this field. Our synthetic route is characterized by the
fact that all the stereocenters of 1 are constructed by catalytic
asymmetric reactions promoted by external chiral asymmetric
catalysts. This route might be advantageous for rapid
synthesis of stereoisomers of 1.
Our retrosynthetic plan is shown in Scheme 1. Efforts to
synthesize 1 should focus mainly on the following three
points: (1) construction of the four chiral stereocenters
(including one tetrasubstituted carbon at C-8), (2) construc-
tion of the configurationally labile cis-cis-trans-conjugated
triene, and (3) selective phosphate ester construction at the
C-9 secondary alcohol. To access point 2, we chose a cross-
coupling reaction between cis-vinyl iodide 2 and cis-vinyltin
3 at a late stage.7 During the course of our studies, Imanishi
reported that 2, containing the proper protection pattern to
* Corresponding author.
† The University of Tokyo.
‡ PRESTO.
(1) (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983,
36, 1595-1600. (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.;
Willmwe, N. E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French,
J. C. J. Antibiot. 1983, 36, 1601-1605.
(5) (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40,
3667-3670. (b) Reddy, Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969-971.
(c) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T.
Chem. Commun. 2002, 742-743. (d) Wang, Y.-G.; Kobayashi, Y. Org.
Lett. 2002, 4, 4615-4618. (e) Esumi, T.; Okamoto, N.; Hatakeyama, S.
Chem. Commun. 2002, 3042-3043.
(6) For synthetic studies of 1, see: (a) Cossy, J.; Pradaux, F.; BouzBouz,
S. Org. Lett. 2001, 3, 2233-2235. (b) Kiyotsuka, Y.; Igarashi, J.; Kobayashi,
Y. Tetrahedron Lett. 2002, 43, 2725-2729.
(2) For reviews, see: (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.;
Boger, D. L. Curr. Med. Chem. 2002, 9, 2005-2032. (b) McCluskey, A.;
Sim, A. T. R.; Sakoff, J. A. J. Med. Chem. 2002, 45, 1151-1175. (c) De
Jong, R. S.; Mulder, N. H. Anti-Cancer Drugs 1997, 8, 413-418.
(3) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62,
1748-1753.
(4) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123,
4161-4167.
10.1021/ol027528o CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003

We began our synthesis by finding the optimum reaction
conditions for the catalytic asymmetric cyanosilylation of
ketone 9 (Table 1). On the basis of previous studies,14 the
Scheme 1. Retrosynthetic Analysis
Table 1. Catalytic Asymmetric Cyanosilylation of Ketone 9a
entry catalyst (mol %) temp, °C time, h yield, %b ee, %c
1
2
3
4
11 (10)
11 (5)
12 (5)
12 (2.5)
12 (5)
-40
-20
-20
-20
-25
120
36
48
72
48
58
94
93
91
93
86
71
85
81
85
5d
a For detailed experimental procedures, see Supporting Information.
b Isolated yield. c Determined by chiral HPLC analysis after conversion to
14. d Scale of reaction ) 50 g.
access point 3, can be synthesized from 4.5c Thus, we
employed 4, which contains all the chiral stereocenters of
fostriecin, as a key intermediate for our synthesis. Partial
conformational constraint by the acetonide in 4 should be
helpful for purification from other possible contaminating
isomers. The chiral secondary alcohol at C-11 should be
constructed using a Noyori reduction8 of the corresponding
acetylenic ketone 5, followed by iodination and diimide
reduction of the acetylene.9 The chiral secondary alcohol at
C-9 of 5 should be constructed through a catalytic asym-
metric direct aldol reaction10 of aldehyde 6 and ketone 7
promoted by a Lewis acid-Bro¨nsted base two-center asym-
metric catalyst, which was developed in our group.11,12 R,â-
Unsaturated lactone 6 should be synthesized through catalytic
asymmetric allylation of aldehyde 8, followed by ring-closing
olefin metathesis (RCM) using Grubbs’ catalyst.13 Finally,
the tetrasubstituted chiral center at C-8 should be constructed
using the catalytic asymmetric cyanosilylation of ketones
promoted by the Lewis acid-Lewis base two-center asym-
metric catalyst (11 or 12) developed in our group.14
titanium complex of a D-glucose-derived ligand (catalyst 11
or 12) generally gives (R)-ketone cyanohydrins, which is
required for natural fostriecin synthesis. First observed was
a significant protecting-group effect of the substrate allylic
alcohol on the reactivity and enantioselectivity.15 Among the
ketones studied, benzyl-protected 9 gave the most promising
results and cyanohydrin 10 with 86% ee was obtained in
58% yield using 11 as the catalyst (Table 1, entry 1).16 To
improve the yield, the reaction was performed at a higher
temperature; however, the enantioselectivity decreased sig-
nificantly (entry 2). Next, we employed the tuned catalyst
12 containing a benzoyl group at the catechol moiety14b under
high concentration (>12 M to THF), and the product was
obtained in synthetically acceptable reaction time, yield, and
enantioselectivity (entry 3). The reaction was performed
using 5 mol % of the catalyst on a 50 g scale without any
difficulty (entry 5). The chiral ligand was recovered in 95%
yield after silica gel column chromatography, which could
be used at least several times without any loss of catalyst
activity.
The next task was to enrich the enantiomeric excess and
construct the C-5 chiral carbon through allylation of aldehyde
8 (Scheme 2). Ethanolysis of 10 followed by a two-step
reduction gave diol 13. Enantiomerically pure compound was
obtained by recrystallization of the corresponding p-nitroben-
zoyl ester 14 in 78% yield. After hydrolysis, selective
(7) Jacobsen, Imanishi, Hatakeyama, and Falck utilized Stille or Suzuki
cross-coupling for the triene construction. Compound 2 is the common
intermediate of Jacobsen, Imanishi, Hatakeyama, and Kobayashi.
(8) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738-8739.
(9) Same strategy was employed in Jacobsen’s synthesis.
(10) For a review, see: Alcaide, B.; Almendros, P. Eur. J. Org. Chem.
2002, 67, 1595-1601.
(11) (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168-4178. (b) Yamada, Y. M. A.;
Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 1871-1873.
(14) (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 7412-7413. (b) Hamashima, Y.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2001, 42, 691-694.
(12) For a recent review on two-center asymmetric catalysis, see:
Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989-
1999.
(15) See Supporting Information for details.
(16) The absolute configuration of 10 was determined by conversion to
the known triol: Partridge, J. J.; Shiuey, S.-J.; Chadha, N. K.; Baggiolini,
E. G.; Blount, J. F.; Uskokovic J. Am. Chem. Soc. 1981, 103, 1253-1255.
(13) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
734
Org. Lett., Vol. 5, No. 5, 2003

the desired isomer 16 was obtained in 80% isolated yield
after separation of the diastereomer (dr ) 28:1).19 Esterifi-
cation with acryloyl chloride and RCM using Grubbs’
catalyst gave lactone 17, which was desilylated and oxidized
by Dess-Martin periodinane (DMP) to give aldehyde 6, the
substrate for the catalytic asymmetric aldol reaction.
Scheme 2a
Despite the versatility of acetylenes, there has been no
previous use of an acetylenic ketone as a donor in direct
catalytic enantioselective aldol reactions.10,20 Mechanistic
studies revealed that deprotonation of the ketone is the rate-
determining step.11a Therefore, the reaction rate of acetylenic
ketones should be higher than that using aromatic ketones.
As expected, the reaction between 6 and 7 proceeded
smoothly at -20 °C for 4 h (ca. 50% isolated yield) in the
presence of the second generation (S)-LLB (19 + KOH
+H2O, 10 mol %), the optimum asymmetric heteropolyme-
tallic complex for direct aldol reaction using phenyl ketones.
The diastereoselectivity was low (2:1), however, giving the
desired 18a as the preferred isomer.21 Due to the high acidity
of the R-proton of 7, the enolate concentration should be
higher than that of phenyl ketones. As a result, the
background reaction independent of the asymmetric catalyst
might be more problematic in the case of 7 than that of
phenyl ketones. Thus, we examined less basic conditions
using first generation (S)-LLB.11b As expected, the selectivity
was improved to 3.6:1 (16 h, 65% yield).22 Further decreasing
the basicity of the bimetallic complex using the substitution
effect of BINOL (catalysts 20 and 21) did not produce any
beneficial results.23 Although the selectivity was not satisfac-
tory even in the optimized case, the effect of the chiral
catalyst is significant considering that the reaction did not
proceed with 10 mol % La(OiPr)3.
a Reagents and conditions: (a) 6 N HCl/EtOH, 60 °C, 83%; (b)
DIBAH, CH2Cl2, from -78 °C to 0 °C; (c) NaBH4, MeOH, 93%
(two steps); (d) p-NO2C6H4COCl, py, CH2Cl2, 100%; recrystallized
from CH2Cl2/hexane, 78% (>99% ee); (e) K2CO3, MeOH-CH2Cl2,
i
100%; (f) TIPSCl, imidazole, DMF, 96%; (g) MOMCl, Pr2NEt,
The mixture of 18a and 18b was directly converted to the
corresponding acetonide 22 (Scheme 3). Then, the asym-
metric transfer hydrogenation was performed following
Noyori’s procedure.8 The stereoselectivity from the desired
isomer was extremely high (>97:3), and stereochemically
pure 23 was obtained in 49% isolated yield after silica gel
column chromatography.24 Protection of the propargylic
alcohol, iododesilylation of the acetylene,25 and diimide
CH2Cl2, 88%; (h) LiDBB, THF, -78 °C, 73%; (i) TPAP (5 mol
%), NMO, CH2Cl2, 87%; (j) AgF (20 mol %), (R)-p-tol-BINAP
(20 mol %), CH2dCHCH2Si(OMe)3, MeOH, 80% (dr ) 28:1); (k)
acryloyl chloride, Et3N, CH2Cl2, 76%; (l) (Cy3P)2RuCl2(dCHPh)
(15 mol %), CH2Cl2, 94%; (m) 3HF‚NEt3, THF, 90%; (n) DMP,
CH2Cl2, 92%; (o) 19 (10 mol %), 7 (6 equiv), THF, 65% (18a/18b
) 3.6/1).
protection of the diol, reductive debenzylation using lithium
di-t-butyl biphenylide (LiDBB), and TPAP-catalyzed oxida-
tion gave aldehyde 8. For the synthesis of 16, we first tried
Keck allylation17 using allyltributyltin (2 equiv) and 20 mol
% catalyst prepared from Ti(OiPr)4 and (R)-BINOL. The
reaction, however, did not proceed well, and the product was
obtained in only 39% yield with a diastereomeric ratio (dr)
of 7:1. On the basis of the hypothesis that the low catalyst
activity is due to the coordination of the MOM oxygen to
the Lewis acid, Yamamoto’s silver-catalyzed asymmetric
allylation was tried next.18 The use of a soft metal should
minimize adverse effect of the oxygen coordination to the
catalyst. As expected, using 20 mol % AgF-(R)-p-tol-BINAP
complex, the reaction proceeded smoothly at -20 °C and
(19) All the relative configurations, including C-5, were confirmed after
1
conversion to 4 and comparison of the H and 13C NMR with Imanishi’s
NMR chart. The stereoselectivity matches that of Yamamoto’s transition-
state model. AgF-catalyzed reaction in the absence of the chiral ligand
resulted in no reaction. Addition of allylmagnesium bromide gave a 1:1
diastereomixture.
(20) The aldol reaction using 7 as a donor proved to be difficult possibly
due to a fast retro-aldol reaction. Using 2,2-dimethyl-3-phenylpropanal as
a model substrate in a reaction with the lithium enolate derived from 7
gave the product in only 28%. The reaction did not proceed with the zinc
enolate. LLB (10 mol %), however, promoted the reaction efficiently, and
the product was obtained in 72% yield.
(21) Diastereoisomers could not be separated at this stage. The relative
configuration of C-8 and C-9 was determined by NOE measurement on
acetonide 22.
(22) Preliminary studies on the reaction of 7 and a simple aldehyde (2,2-
dimethyl-3-phenylpropanal) had a similar tendency: 60% ee with LLB-
KOH-H2O and 72% ee with LLB.
(23) For a beneficial effect of BINOL substitution on a catalytic
asymmetric nitroaldol reaction, see: Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256.
(17) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993,
58, 6543-6544.
(18) Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.;
Matsumoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701-
3703.
(24) Other diastereomers ((9S,11S)- and (9S,11R)- derived from 18b)
were separable at this stage (14 and 4%, respectively). The relative
configuration of C-9 and C-11 was determined by NOE measurement. See
Supporting Information for details.
Org. Lett., Vol. 5, No. 5, 2003
735

Scheme 3a
a Reagents and conditions: (a) 2,2-dimethoxypropane, PPTS, acetone, 80%; (b) Noyori’s catalyst (10 mol %)-KOH (10 mol %), iPrOH,
49% (other isomers: 18%); (c) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 73%; (d) NIS, AgNO3, acetone, 88%; (e) NBSH, Et3N, THF/
iPrOH, 40% (6% recovery); (f) 1 M HCl (aq)/MeOH, 47%, (g) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; TESOTf, from -78 °C to -10 °C,
52%; (h) 1 M HCl (aq)/THF/CH3CN (1:3:6), -10 °C, 52%; (i) PdCl2(CH3CN)2, 3, DMF, 85%.
reduction using o-nitrobenzenesulfonylhydrazide (NBSH)26
gave cis-vinyl iodide 4. Vinyl iodide 2 containing the
appropriate protection pattern was synthesized from 4, using
modified Imanishi’s procedure. Stille coupling between 2
and 327 under ligand-free conditions28 gave 24, which is the
common intermediate reported by Jacobsen, Imanishi, and
Hatakeyama.29 Thus, we achieved the formal catalytic
asymmetric total synthesis of fostriecin.
To demonstrate the uniqueness of our synthetic strategy,
we are currently attempting to synthesize other stereoisomers
of fostriecin. Initial results are promising as shown in Scheme
4. Thus, using the (S)-selective gadolinium catalyst for ketone
cyanosilylation30 afforded product with the unnatural con-
figuration in 90% ee.
the fact that all four stereocenters were selectively synthe-
sized by external chiral catalysts. Studies to improve the
synthetic efficiency and generate new potent analogues for
anticancer agents are currently ongoing.
Acknowledgment. This work was supported by RFTF
of Japan Society for the Promotion of Science and PRESTO
of Japan Science and Technology Corporation (JST). We
thank Professor Imanishi of Osaka University for providing
spectral data.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL027528O
Scheme 4
(25) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994,
485-486.
(26) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
(27) Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23-27.
(28) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817.
(29) Absolute configuration of 24 was confirmed comparing the sign of
the optical rotation to the reported data by Hatakeyama. Two steps
(phosphate ester formation and deprotection) are necessary from 24 to 1.
(30) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908-
9909. Ligands 11L and 12L are commercially available from Junsei
Chemical Co., Ltd. (fax: +81-3-3270-5461).
In summary, we achieved a formal catalytic asymmetric
total synthesis of fostriecin. Our strategy is characterized by
736
Org. Lett., Vol. 5, No. 5, 2003