Asymmetric total synthesis of (+)-fostriecin

Article abstract of DOI:10.1021/ol025537r

(equation presented) The title compound, a potent protein phosphatase inhibitor and anticancer agent, was prepared by an efficient, multiconvergent asymmetric synthesis. Key transformations include a ring forming olefin metathesis leading to the α,β-unsat

Full text of DOI:10.1021/ol025537r

ORGANIC
LETTERS
2002
Vol. 4, No. 6
969-971
Asymmetric Total Synthesis of
(+)-Fostriecin†
Y. Krishna Reddy and J. R. Falck
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center,
Dallas, Texas 75390-9038
j.falck@utsouthwestern.edu
Received January 10, 2002
ABSTRACT
The title compound, a potent protein phosphatase inhibitor and anticancer agent, was prepared by an efficient, multiconvergent asymmetric
synthesis. Key transformations include a ring forming olefin metathesis leading to the r,â-unsaturated lactone and creation of the triene
moiety via Suzuki cross-coupling.
Fostriecin (1, CI-920), a novel secondary metabolite of
Streptomyces pulVeraceus,1 displays potent antineoplastic
activity in vitro against a diverse panel of tumor cell lines
and in vivo toward lymphoid leukemias.2 More recent
investigations revealed that 1 (i) inhibits DNA topoisomerase
II by a unique, non-DNA strand cleavage mechanism;3 (ii)
selectively blocks the catalytic subunit of type 2A4 and 45
protein phosphatases (IC50 1.5 and 3 nM, respectively); (iii)
ameliorates myocardial infarct size;6 and (iv) partially
protects cardiomyocytes from ischemic injury.7
degradative9 studies culminating in total syntheses by Boger
et al.10 and Chavez and Jacobsen.11 Herein, we describe an
efficient and conceptually distinct asymmetric total synthe-
sis12 of 1 utilizing a multiconvergent strategy designed to
postpone introduction of the sensitive unsaturated lactone,
phosphate, and triene subunits until advanced stages of the
work plan (Scheme 1). Anticipating that natural 1 would be
Scheme 1. Retrosynthetic Analysis
The relative and absolute stereochemistries of 1 were
established by a series of elegant spectroscopic1,8 and
† Presented in part at the 217th National Meeting of the American
Chemical Society, Anaheim, CA, March 21-25, 1999; MEDI-040.
(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.; Willmer,
N. E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J.
Antibiot. 1983, 36, 1601-1605.
(2) (a) Review: Murray, A. W. Nature 1992, 359, 599-604. (b) De
Jong, R. S.; De Vries, E. G. E.; Mulder, N. H. Anti-Cancer Drugs 1997, 8,
413-418.
(3) Boritzki, T. J.; Wolfard, T. S.; Besserer, J. A.; Jackson, R. C.; Fry,
D. W. Biochem. Pharmacol. 1988, 37, 4063-4068.
(4) Walsh, A. H.; Cheng, A.; Honkanen, R. E. FEBS Lett. 1997, 416,
230-234.
(5) Hastie, C. J.; Cohen, P. T. W. FEBS Lett. 1998, 431, 357-361.
(6) Weinbrenner, C.; Baines, C. P.; Liu, G.-S.; Armstrong, S. C.; Ganote,
C. E.; Walsh, A. H.; Honkanen, R. E.; Cohen, M. V.; Downey, J. M.
Circulation 1998, 98, 899-905.
(7) Armstrong, S. C.; Gao, W.; Lane, J. R.; Ganote, C. E. J. Mol. Cell.
Cardiol. 1998, 30, 61-73.
(8) Hokanson, G. C.; French, J. C. J. Org. Chem. 1985, 50, 462-466.
10.1021/ol025537r CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/20/2002

Scheme 2a
a Reagents and conditions: (a) (+)-Ipc2BOMe, allylmagnesium bromide, Et2O, -100 °C, 1 h; 30% H2O2, 3 N NaOH, 0 °C, 12 h; (b)
t-BuPh2SiCl, ImH, CH2Cl2, 23 °C, 4 h; (c) OsO4, NMO, Me2CO/H2O (9:1), 0 °C, 4 h; NaIO4/SiO2, CH2Cl2, 23 °C, 4 h; (d) EtO2CC(Me)PPh3,
C6H6, 23 °C, 12 h; (e) AD-mix-â, t-BuOH/H2O (1:1), 4 °C, 48 h; (f) 2-methoxypropene, PPTS (cat.), CH2Cl2, 23 °C, 8 h; (g) NBS, AgNO3,
Me2CO, 23 °C, 2 h; (h) (KO2CN))2, AcOH, THF, 23 °C, 24 h; (i) LiAlH4, THF, 0° to 23 °C, 3 h; (j) (ClCO)2, DMSO, Et3N, -78 °C, 2
h; (k) OHCCHPPh3, CH2Cl2, 40 °C, 8 h; (l) (+)-Ipc2BOMe, allylmagnesium bromide, Et2O, -100 to 23 °C, 1.5 h; 30% H2O2, pH 7 buffer,
23 °C,12 h; (m) acryloyl chloride, DIPEA, CH2Cl2, 0 °C, 2 h; (n) Grubbs’s cat., CH2Cl2, 23 °C, 12 h; (o) Montmorillonite K 10, CH2Cl2,
23 °C, 10 h.
chemically and metabolically labile, we also sought ready
access to more robust analogues.13
and LAH reduction of the ester gave rise to alcohol 7 in
good overall yield. The final two carbons of the central, linear
fragment 9 were added by (triphenylphosphoranylidene)-
acetaldehyde homologation of aldehyde 8, obtained from 7
by Swern oxidation. To construct the R,â-unsaturated lactone
moiety, 9 was allylated14 as described above, creating the
fourth and final stereocenter at C(5) (≈ 98% de). Acylation
of the newly created alcohol with acryloyl chloride evolved
10 and set the stage for a ruthenium-catalyzed ring closing
metathesis.20 Removal of the acetonide using Montmorillo-
nite K 1021 yielded diol 11, representing the C(1)-C(13)
segment of the total carbon skeleton.
The remaining C(14)-C(18) unit 13 was efficiently
secured from 2-(E)-penten-4-yn-1-ol (12)22 by alcohol silyl-
ation followed by Rh-mediated trans-addition23 of pina-
colborane to the terminal acetylene (Scheme 3).
Suzuki-Miyaura24 cross coupling of 11 and 13 afforded
Z,Z,E-diol 14 as the sole product and finalized assembly of
As envisaged in the retrosynthesis above, the C(11)-alcohol
was introduced via asymmetric allylation14 of 3-trimethyl-
silyl-2-propynal 215 using (+)-B-methoxydiisopinocampheyl-
borane and allylmagnesium bromide at low temperature
(Scheme 2). Protection of the resultant alcohol 316 (≈ 98%
ee) provided silyl ether 4 which was homologated to (E)-
R,â-unsaturated ester 5 by selective oxidative cleavage of
the terminal olefin and Wittig condensation with commercial
(carbethoxyethylidene)triphenylphosphorane. The stereo-
centers at C(8) and C(9) were conveniently established via
Sharpless asymmetric dihydroxylation17 (SAD) of the trisub-
stituted olefin in 5. Diol protection as the corresponding 1,2-
isopropylidene furnished a chromatographically separable
mixture (3:1) of 6 and its (S),(R)-diastereomer. Subsequent
terminal alkyne bromination,18 diimide cis-hydrogenation,19
(9) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62,
1748-1753.
Scheme 3a
(10) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001,
123, 4161-4167.
(11) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40,
3667-3670.
(12) Other synthetic studies directed toward 1: (a) Just, G.; O’Connor,
B. Tetrahedron Lett. 1988, 29, 753-756. (b) Cossy, J.; Pradaux, F.;
BouzBouz, S. Org. Lett. 2001, 3, 2233-2235.
(13) Clinical trials were halted early due to concerns over the stability
and purity of 1: De Jong, R. S.; Mulder, N. H.; Uges, D. R. A.; Sleijfer,
D. T.; 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, 882-887.
(14) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-
2093.
a Reagents and conditions: (a) t-BuPh2SiCl, ImH, CH2Cl2, 0 °C,
2 h; (b) [Rh(cod)Cl]2, Cy3P, Et3N, pinacolborane, C6H12, 23 °C,
4.5 h.
(15) Bertus, P.; Pale, P. Tetrahedron Lett. 1997, 38, 8193-8196.
970
Org. Lett., Vol. 4, No. 6, 2002

with NaHCO3 completed the synthesis of 1, identical in every
respect with natural (+)-fostriecin.
Scheme 4a
Acknowledgment. Financial support was provided by the
Robert A. Welch Foundation and NIH (GM-31278). Natural
1 was kindly provided by the Drug Synthesis & Chemistry
Branch, Developmental Therapeutics Program, Division of
Cancer Treatment, National Cancer Institute, NIH.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL025537R
a Reagents and conditions: (a) Pd(PPh3)4, Ag2O, THF, 65 °C, 8
h; (b) 2,6-lutidine, t-BuMe2SiOTf, CH2Cl2, -20 °C, 1 h; (c) PCl3,
pyridine, 0 °C, 10 min; Me3SiCH2CH2OH, 23 °C, 1 h; 30% H2O2,
1 h; (d) HF‚py, CH3CN/H2O (9:1), 23 °C, 5 d.
(16) (a) Smith, A. B., III.; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935-
3948. (b) Glanzer, B. I.; Faber, K.; Griengl, H. Tetrahedron 1987, 43, 5791-
5796.
(17) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(18) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 727-729.
the carbon backbone (Scheme 4). Unexpectedly, all efforts
to selectively phosphorylate the secondary C(9)-alcohol in
14 resulted in significant amounts of cyclic phosphate
involving the tertiary C(8)-alcohol. This was circumvented
as recommended by Boger et al.10 by prior silylation of the
interfering hydroxyl using tert-butyldimethylsilyl (TBDMS)
triflate and 2,6-lutidine to give 15, thus allowing Evans’
three-stage protocol25 to proceed resulting in bis(2-trimeth-
ylsilylethyl)phosphate triester 16. Global desilylation with
excess HF‚pyridine at ambient temperature and quenching
(19) Duffault, J.-M.; Einhorn, J.; Alexakis, A. Tetrahedron Lett. 1991,
32, 3701-3704.
(20) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(21) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 1881-1884.
(22) Rama Rao, A. V.; Reddy, E. R.; Sharma, G. V. M.; Yadagiri, P.;
Yadav, J. S. Tetrahedron Lett. 1985, 26, 465-468.
(23) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000,
122, 4990-4991.
(24) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(25) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
Org. Lett., Vol. 4, No. 6, 2002
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