Formal total synthesis of fostriecin via 1,4-asymmetric induction using cobalt-alkyne complex

Article abstract of DOI:10.1021/ol800195g

(Chemical Equation Presented) The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. Two of the four chiral centers are controlled by an external chiral auxiliary and the other two are synthesized stereoselectively, one by a novel 1,4-asymmetric induction using cobalt-alkyne complex, and the other by 1,3-asymmetric induction.

Full text of DOI:10.1021/ol800195g

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1405-1408
Formal Total Synthesis of Fostriecin via
1,4-Asymmetric Induction Using
Cobalt-Alkyne Complex
Yujiro Hayashi,* Hirofumi Yamaguchi, Maya Toyoshima, Kotaro Okado,
Takumi Toyo, and Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received January 28, 2008
ABSTRACT
The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. Two of the four chiral
centers are controlled by an external chiral auxiliary and the other two are synthesized stereoselectively, one by a novel 1,4-asymmetric
induction using cobalt-alkyne complex, and the other by 1,3-asymmetric induction.
Fostriecin (1, CI-920), a novel secondary metabolite of
Streptomyces pulVeraceus, is a selective inhibitor of protein
phosphatase 2A (PP2A) that displays antitumor activity
against a diverse panel of tumor cell lines and in vivo activity
toward lymphoid leukemias.1 This important biological
activity has attracted the attention of many synthetic chemists.
Both the absolute and the relative stereochemistry were
determined by Boger,2 who also accomplished the first total
synthesis in 2001.3 Since then, several excellent asymmetric
syntheses have appeared,4 as well as a number of synthetic
studies.5
(1) (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L. Curr.
Med. Chem. 2002, 9, 2005. (b) McCluskey, A.; Sim, A. T. R.; Sakoff, J.
A. J. Med. Chem. 2002, 45, 1151. (c) DeJong, R. S.; Mulder, N. H. Anti-
Cancer Drugs 1997, 8, 413.
(2) Boger, D. L.; Hirota, M.; Lewis, B. M. J. Org. Chem. 1997, 62,
1748.
Structurally fostriecin has four chiral centers and con-
tains a conformationally labile cis-cis-trans triene moiety.
Shibasaki4g,i,k and Falck4b constructed all the stereo-
centers using four different catalytic asymmetric reactions,
while three of the four chiral centers were constructed
using asymmetric catalytic reactions by Jacobsen,4a Imanishi,4c,d
Kobayashi,4e and Trost.4h In these syntheses, asym-
metric catalytic reactions have been utilized at least twice.
Yadav employed D-glucose as a chiral starting material,
(3) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123,
4161.
(4) (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)
Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T.
Chem. Commun. 2002, 742. (d) Miyashita, K.; Ikejiri, M.; Kawasaki,
H.; Maemura, S.; Imanishi, T. J. Am. Chem. Soc. 2003, 125, 8238.
(e) Wang, Y. G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615. (f) Esumi, T.;
Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002, 3042. (g) Fujii,
K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733. (h)
Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Harrington, P. E.
J. Am. Chem. Soc. 2005, 127, 3666. (i) Maki, K.; Motoki, R.;
Fujii, K.; Kanai, M.; Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 17111. (j) Yadav, J. S.; Prathap, I.; Tadi,
B. P. Tetrahedron Lett. 2006, 47, 3773. Reviews, see. (k) Shibasaki, M.;
Kanai, M. Heterocycles 2005, 66, 727. (l) Miyashita, K.; Ikejiri, M.;
Tsunemi, T.; Matsumoto, A.; Imanishi, T. J. Syn. Org. Chem. Jpn. 2007,
65, 874.
(5) (a) Just, G.; Oconnor, B. Tetrahedron Lett. 1988, 29, 753. (b) Liu,
S. Y.; Huang, D. F.; Huang, H. H.; Huang, L. Chin. Chem. Lett. 2000, 11,
957. (c) Cossy, J.; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3, 2233. (d)
Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2002, 43, 2725.
(e) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197. (f)
Ramachandran, P. V.; Liu, H. P.; Reddy, M. V. R.; Brown, H. C. Org.
Lett. 2003, 5, 3755.
10.1021/ol800195g CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/04/2008

and three of the four chiral centers are derived from this
chiral source.4j
Next is the critical 1,4-asymmetric induction. As allyl
metal reagents such as allylMgBr gave no selectivity, the
Hosomi-Sakurai allylation was investigated, with the results
summarized in Table 1. Lewis acid mediated allylation11 and
Mukaiyama aldol reaction12 of dicarbonylhexacarbonyl cobalt
of R,â-acetylenic aldehyde is known, and BF3‚Et2O is
reported to be a suitable promoter in the reaction of allyl
stannane.11 Although low selectivity was observed with
HfCl4, ZnCl2, TiCl3(O-i-Pr), TiCl(O-i-Pr)3 and BF3‚OEt2,
moderate selectivity (73:27) was obtained when MgBr2‚OEt2
was employed. Good selectivity (80:20) was obtained in the
presence of TiCl2(O-i-Pr)2, which increased to 92:8 when
the reaction was performed at lower temperature (-40 °C).
The bulkiness of the allyltin reagent is important, because
Ph3SnCH2CHdCH2 gave a excellent result whereas the
corresponding Bu3Sn analogue gave poor selectivity (entry
9). The relative configuration of newly generated C5
of 24 was determined by the advanced Mosher’s MTPA
method13 after conversion to (R)- and (S)-mono MTPA esters
of 25.
Our synthetic strategy has been to control stereochemistry
using pre-existing stereogenic centers as much as possible.
Thus, the stereogenic center at C11 was to be constructed
via 1,3-asymmetric induction using the C9 chiral center,
whereas the stereochemistry at C5 was to be controlled
by the chiral center at C8 via 1,4-asymmetric induction
using a cobalt-alkyne complex, methodology recently dev-
eloped in this group.6 The only reaction requiring use of an
external chiral auxiliary is the asymmetric dihydroxy-
lation of a homoallylic alcohol. Another noteworthy feature
is the construction of the labile triene unit, which we plan-
ned to synthesize by reduction of the more stable dieneyne
at a late stage of the synthesis. Herein we report the
realization of this scenario for the synthesis of protected
dephosphofostriecin 2, Imanishi’s key intermediate (Scheme
1).4c,d
No selectivity was observed using the parent aldehyde 22
under the same reaction conditions. Thus, the cobalt-alkyne
complex is the key for achieving high selectivity.
Scheme 1. Retrosynthesis of Fostriecin (1)
The angle of the alkyne triple bond is 180°, whereas that
of the alkyne cobalt complex is about 140° (see 7 of Scheme
1). Complexation forces the stereogenic and prestereogenic
centers closer, which makes the highly stereoselective 1,4-
asymmetric induction possible. C5 stereochemistry has been
constructed by the reagent-controlled allylation; Ipc2B-allyl14
was used by Falck,4b Hatakeyama,4f Trost,4h and Yadav,4j
whereas Shibasaki4g,i,k used the catalytic method of Yama-
moto allylation.15
As the crucial 1,4-asymmetric induction had been suc-
cessfully achieved, the cobalt was removed by treatment with
NMO, then reduction with Red-Al gave trans-alkene 26 in
good yield. The unsaturated lactone moiety was constructed
by acylation with acryloyl chloride, followed by exposure
to Grubbs’ second generation catalyst,16 affording 28 quan-
titatively.
Our synthesis (Scheme 2) commenced with the prepara-
tion of cobalt-alkyne complex 7. 1,3-Propanediol was mono-
protected with PMBCl to give 10, which was oxidized
with SO3‚pyridine7 to give the aldehyde. Wittig reaction,
followed by reduction and oxidation, gave 13. The Corey-
Fuchs alkyne synthesis8 afforded alkyne 14, which on
Sharpless dihydroxylation9 gave diol 15 in good yield
with excellent enantioselectivity (93% ee).10 Protection of
the diol 15 with TESCl gave 16. Treatment of 16 with BuLi
and ClCO2Me gave ester 17. Changing the protecting group
from TES to BOM gave 19. Reduction with DIBAL-H,
followed by treatment with TBAF, gave diol 21. Oxidation
with MnO2 then gave aldehyde 22. On treatment with
Co2(CO)8 22 provided cobalt-alkyne complex 23 in good
yield.
The next task is installation of the triene moiety via 1,3-
asymmetric induction. The protecting group of the diol unit
and nucleophile were found to be important for obtaining
high selectivity. Cleavage of the BOM group afforded the
diol 29, which is Hatakeyama’s intermediate.4f The diol 29
(11) Balduzzi, S.; Brook, M. A.; McGlinchey, M. J. Organometallics
2005, 24, 2617.
(12) Review, see: Mukai, C.; Hanaoka, M. Synlett 1996, 11.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(14) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(15) Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.;
Matsumoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38,
3701.
(6) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Nasu, S.; Ochiai, K.;
Shoji, M. Organometallics 2008, 27, 163.
(7) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(16) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(17) (a) Chan, K.-K.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1978,
43, 3435. (b) Jones, T. K.; Denmark, S. E. Org. Synth. Col. 7, 524.
(18) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003,
123, 4048.
(10) The enantioselectivity of 15 was determined by chiral HPLC analysis
(19) For an excellent review of 1,3-asymmetirc induction, see; Evans,
D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118,
4322.
(chiralcel OD-H column, l ) 254 nm, iPrOH/hexane 1/20, 1.0 mL min-1
tR ) 24.1 min (major), 20.7 min (minor)).
;
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Org. Lett., Vol. 10, No. 7, 2008

Scheme 2. Synthesis of Fostriecin (1)
was protected as its dimethylacetal 30. Removal of the PMB
protecting group, followed by TEMPO oxidation, afforded
key intermediate 32.
methylsilylacetylene successively to generate ene diyne
derivative 38 in good yield. Stereoselective reduction with
Red-Al,17 followed by protection of hydroxy group and
deprotection of trimetylsilyl group, afforded 5 in good
yield.
The other coupling partner 5 was easily prepared stereo-
selectively from cis-1,2-dichloroethene via successive
Sonogashira reactions (Scheme 3). That is, cis-1,2-dichlo-
roethene (36) was reacted with 2-propyne-1-ol and tri-
(20) (a) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452. (b) Chou, W. N.;
Clark, D. L.; White, J. B. Tetrahedron Lett. 1991, 32, 299.
Org. Lett., Vol. 10, No. 7, 2008
1407

Scheme 3. Synthesis of Alkynediene Moiety (5)
Table 1. Effect of the Lewis Acid on 1,4-Asymmetric
Induction with 23 Using Allyltin
entry
R
lewis acid
condition
yield[%]a R:S b
1
2
3
4
5
6
7
8
9
Ph HfCl4
Ph ZnCl2
-78 °C, 30 m
-78 °C, 4 h
-78 °C, 10 m
-78 ∼ 0 °C, 8 h
-78 °C, 30 m
-78 ∼0 °C, 8 h
15
45
40
86
20
78
60
60
86
50:50
55:45
64:36
73:27
60:40
60:40
80:20
92:8
Ph BF3‚OEt2
Ph MgBr2‚OEt2
Ph TiCl3(O-i-Pr)
Ph TiCl(O-i-Pr)3
Ph TiCl2(O-i-Pr)2 -20 °C, 4 h
Ph TiCl2(O-i-Pr)2 -40 °C, 46 h
Bu TiCl2(O-i-Pr)2 -45 °C, 12 h
45:55
a Isolated yield. b Diastereomer ratio of C5 of 24 was determined by
HPLC analysis.
controlled by an external chiral reagent and the other two
are synthesized stereoselectively, one by a novel 1,4-
asymmetric induction using cobalt-alkyne complex deve-
loped by our group6 and the second by 1,3-asymmetric
induction.
After extensive experimentation, the diastereoselec-
tive coupling of 32 and 5 was successfully accomplished
using Fukuyama’s protocol.18,19 The higher order alkynyl Zn
reagent reacted smoothly to yield 33 in good yield with
excellent diastereoselectivity. Treatment of 33 with TFA
removed both the acetal and TBDPS groups to yield tetraol
34. Protection of the primary alcohol with TBDPSCl gave
35. The labile triene unit was successfully constructed using
Rieke Zn20 in the presence of buffer solution, affording the
protected dephosphofostriecin 2 in good yield. The conver-
sion of 2 to fostriecin has been demonstrated by Imanishi
and co-workers.4c, d
Acknowledgment. This work was partially supported by
a Grand-in-Aid for Scientific Research on Priority Areas
16073219 from MEXT.
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, and copies of H
and 13C NMR and IR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have accomplished the synthesis of
a protected dephosphofostriecin, and thereby a formal
synthesis of fostriecin. Two of the four chiral centers are
OL800195G
1408
Org. Lett., Vol. 10, No. 7, 2008