Total synthesis of fostriecin: Via a regio-and stereoselective polyene hydration, oxidation, and hydroboration sequence

Article abstract of DOI:10.1021/ol101340n

A total synthesis of the fostriecin has been achieved in 24 steps from enyne 11. The lactone moiety was installed by a Leighton allylation and Grubbs ring-closing metathesis reaction. The highly reactive Z,Z,E-triene moiety was installed via a late-stage Suzuki-Miyaura cross-coupling of a remarkably stable Z-vinyl boronate. The relative and absolute stereocenters of the C-8,9,11 triol were generated with a regio-and stereoselective asymmetric hydration/oxidation sequence.

Full text of DOI:10.1021/ol101340n

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3752-3755
Total Synthesis of Fostriecin: Via a Regio-
and Stereoselective Polyene Hydration,
Oxidation, and Hydroboration Sequence
Dong Gao and George A. O’Doherty*
Department of Chemistry and Chemical Biology, Northeastern UniVersity,
Boston, Massachusetts 02115 and Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506
g.o’doherty@neu.edu
Received June 10, 2010
ABSTRACT
A total synthesis of the fostriecin has been achieved in 24 steps from enyne 11. The lactone moiety was installed by a Leighton allylation and
Grubbs ring-closing metathesis reaction. The highly reactive Z,Z,E-triene moiety was installed via a late-stage Suzuki-Miyaura cross-coupling
of a remarkably stable Z-vinyl boronate. The relative and absolute stereocenters of the C-8,9,11 triol were generated with a regio- and
stereoselective asymmetric hydration/oxidation sequence.
Fostriecin (1, CI-920) is a structurally novel phosphorylated
polyene-, polyol-, and pyranone-containing natural product,
which was isolated from Steptomyces pulVeraceus in 1983
(Figure 1).1 In addition to its compelling structural features,
cell activity has been linked to the phosphate portion of the
molecule and its ability to inhibit the protein phosphatases
1, 2A, and 4 (PP1, PP2A, and PP4). Of particular interest is
fostriecin’s ability to selectively inhibit phosphatases 2A and
4 over phosphatases 1 (e.g., IC50 ) 45 nM for PP1, 1.5 nM
for PP2A, and 3.0 nM for PP4).4 Because of its unique
structure and compelling biological activity, fostriecin has
been extensively studied by both chemists and biologists.
In addition to the mechanism-of-action studies, fostriecin
was the subject of several clinical trials at the National
Cancer Institute. Although its gross structure was known,
the complete stereochemical assignment of fostriecin was
determined in 1997 by Boger.5 These efforts from Boger
also led to its first total synthesis.6a Fostriecin’s potential
use as a chemotherapeutic agent has inspired many more
total syntheses.6,7 Similarly, the isolation and structural
elucidation of related natural products with similar antitumor,
Figure 1. Fostriecin (1, CI-920).
fostriecin has been shown to possess significant cytotoxic
activity against a broad range of cell lines,2 such as leukemia,
lung cancer, breast cancer, and ovarian cancer in vitro and
also antitumor activity against leukemia in vivo.3 This cancer
(3) Reviews: (a) Jackson, R. C.; Fry, D. W.; Boritzki, T. J.; Roberts,
B. J.; Hook, K. E.; Leopold, W. R. AdV. Enzyme Regul. 1985, 23, 193. (b)
Scheithauer, W.; Hoff, D. D. V.; Clark, G. M.; Shillis, J. L.; Elslager, E. F.
Eur. J. Clin. Oncol. 1986, 22, 921.
(1) (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983,
36, 1595. (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Wilmer, 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.
(4) Reviews: (a) Walsh, A. H.; Cheng, A.; Honkanen, R. E. FEBS Lett.
1997, 416, 230. (b) Hastie, C. J.; Cohen, P. T. W. FEBS Lett. 1998, 431,
357.
(2) (a) Lewy, D. S.; Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr.
Med. Chem. 2002, 9, 2005. (b) De Jong, R. S.; De Vries, E. G. E.; Mulder,
N. H. Anti-Cancer Drugs. 1997, 8, 413.
(5) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62,
1748.
10.1021/ol101340n  2010 American Chemical Society
Published on Web 08/05/2010

antibacterial, and antifungal activities have occurred (e.g.,
phoslactomycins A-F (2),8 cytostatin (3),9 and leustroduc-
sins A-C and H (4a-c) in Figure 2).10
routes will provide access to analogues with similar biologi-
cal activities, yet more desirable physical properties. Fur-
thermore, the unique structural features of fostriecin, which
includes an unsaturated lactone, the C-8-C-11 triol mono-
phosphate component, and the conjugated Z,Z,E-trienol,
make it an interesting target for synthetic organic chemists.
We became interested in the synthesis of fostriecin out of
the same desire to develop a new route to the molecule for
SAR-type studies, as well as from our ongoing interest in the
synthesis of polyol pyranone-containing natural products.12 In
particular, we wanted to explore the use of our trienoate
asymmetric hydration/oxidation reaction sequence for the
C-8,9,11 triol portion of the molecule.13 From a strategic point
of view, the pentaene portion of the target molecule made this
approach more challenging. Herein we report our successful
efforts at regioselectively applying this polyene asymmetric
hydration/oxidation reaction sequence in an efficient synthesis
of fostriecin. In this regard, our route uniquely uses a late stage
trans-hydroboration reaction.14 In addition, it takes advantage
of the stereoselective stability of a Z-vinyl boronate interme-
diate,15,16 which offers a significant alternative for the construction
of the Z,Z,E-triene portion of this molecule (vide infra).
Figure 2. Natural products related to fostriecin.
Unfortunately, because of concerns over the stability of
fostriecin, its clinical trials were halted in early phase I.11
However, interest still exists in new synthetic routes to
fostriecin and related molecules. It is hoped that these new
Our synthetic efforts started with an investigation of the
chemo- and regioselectivity of the asymmetric oxidation and
subsequent reduction of yne-trienoate 10 to install the C-11
propargyl alcohol. Although we expected the Sharpless
dihydroxylation to occur at the double bond furthest away
from the electron-withdrawing group, we have previously
found that this reaction can give regioisomers. In practice,
our synthesis began with the preparation of the trienoate 10
from commercially available enyne 11 (Scheme 1).
(6) (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. 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) Wang,
Y. G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615. (e) Miyashita, K.; Ikejiri,
M.; Kawasaki, H.; Maemura, S.; Imanishi, T. Chem. Commun. 2002, 7,
742. (f) Esumi, T.; Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002,
24, 3042. (g) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi,
T. J. Am. Chem. Soc. 2003, 125, 8238. (h) Fujii, K.; Maki, K.; Kanai, M.;
Shibasaki, M. Org. Lett. 2003, 5, 733. (i) Trost, B. M.; Frederiksen, M. U.;
Papillon, J. P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem.
Soc. 2005, 127, 3666. (j) Maki, K.; Motoki, R.; Fujii, K.; Kanai, M.;
Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
17111. (k) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Okado, K.; Toyo,
T.; Shoji, M. Org. Lett. 2008, 10, 1405. (l) Robles, O.; McDonald, F. Org.
Lett. 2009, 11, 5498. (m) Shibahara, S.; Fujino, M.; Tashiro, Y.; Okamoto,
N.; Esumi, T.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Synthesis 2009,
17, 2953. (n) Sarkar, S.; Wanzala, E.; Shibahara, S.; Takahashi, K.; Ishihara,
J.; Hatakeyama, S. Chem. Commun. 2009, 39, 5907.
Scheme 1. Fostriecin (1) Retrosynthesis
(7) For the synthesis of related molecules, see: (a) Cossy, J.; Pradaux,
F.; BouzBouz, S. Org. Lett. 2001, 3, 2233. (b) Kiyotsuka, Y.; Igarashi, J.;
Kobayashi, Y. Tetrahedron Lett. 2002, 43, 2725. (c) Ramachandran, V.;
Liu, H.; Reddy, V.-R.; Brown, H. C. Org. Lett. 2003, 5, 3755. (d) Shimada,
K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048. (e)
Bialy, L.; Waldmann, H. Chem.sEur. J. 2004, 10, 2759. (f) Wang, Y.-G.;
Takeyama, R.; Kobayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 3320. (g)
Lawhorn, B. G.; Boga, S. B.; Wolkenberg, S. E.; Colby, D. A.; Gauss,
C.-M.; Swingle, M. R.; Amable, L.; Honkanen, R. E.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 16720. (h) Shibahara, S.; Fujino, M.; Tashiro, Y.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2008, 10, 2139. (i)
Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi, T. J. Org.
Chem. 2008, 73, 5360. (j) Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn,
S. V.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11, 935. (k) Knig, C. M.;
Gebhardt, B.; Schleth, C.; Dauber, M.; Koert, U. Org. Lett. 2009, 11, 2728.
For a synthesis/structural correction of sultriecin, see: (l) Burke, C. P.; Haq,
N.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 2157.
(8) (a) Fushimi, S.; Shimazu, A.; Seto, H. J. Antibiot. 1989, 42, 1019.
(b) Fushimi, S.; Furihata, K.; Seto, H. J. Antibiot. 1989, 42, 1026. (c) Ozasa,
T.; Suzuki, K.; Sasamata, M.; Tanaka, K.; Kobori, M.; Kadota, S.; Nagai,
K.; Saito, T.; Watanabe, S.; Iwanami, M. J. Antibiot. 1989, 42, 1331–1338.
(d) Ozasa, T.; Tanaka, K.; Sasamata, M.; Kaniwai, H.; Shimizu, M.;
Matsumoto, H.; Iwanami, M. J. Antibiot. 1989, 42, 1339. (e) Shibata, T.;
Kurihara, S.; Yoda, K.; Haruyama, H. Tetrahedron 1995, 51, 1999.
(9) (a) Amemiya, M.; Someno, R.; Sawa, R.; Naganawa, H.; Ishizuka,
M.; Takeuchi, T. J. Antibiot. 1994, 47, 541. (b) Amemiya, M.; Ueno, M.;
Masuda, T.; Nishida, C.; Hamada, M.; Ishizuka, M.; Takeuchi, T. J. Antibiot.
1994, 47, 536.
In order to protect the terminal acetylene, the primary
alcohol of 11 was first protected as a silyl ether (TBSCl/
(11) 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.; de Vries, E. G. E. Br. J. Cancer 1999, 79, 882.
(12) (a) Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 1069. (b) Gao, D.;
O’Doherty, G. A. J. Org. Chem. 2005, 70, 9932.
(13) (a) Guo, G.; Mortensen, M. S.; O’Doherty, G. A. Org. Lett. 2008,
10, 3149. (b) Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 6087. (c) Li,
M.; O’Doherty, G. A. Org. Lett. 2006, 8, 3987. (d) Ahmed, Md. M.;
Mortensen, M. S.; O’Doherty, G. J. Org. Chem. 2006, 71, 7741. For other
oxidation/reduction asymmetric hydration approaches, see: (e) Gansauer,
A.; Fan, C.-A.; Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129, 3484.
(10) (a) 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. (b) Kohama, T.; Nakamura, T.; Kinoshita,
T.; Kaneto, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512.
Org. Lett., Vol. 12, No. 17, 2010
3753

Et3N), and then a TMS group was added to the terminal
acetylenic position (n-BuLi/trimethylchlorosilane) to give
fully protected enynol 12 in 85% yield for two steps (Scheme
2). Selective deprotection of the silyl-ether with aqueous
Scheme 3. Asymmetric Hydration and Oxidation of Triene 10
Scheme 2. Synthesis of Trieneoate 10
reagent system of dienoate 17 cleanly gave a diol product, which
was then protected as a bis-triethylsilyl ether 18 (TESOTf/2,6-
lutidine) in good overall yield (62% for 2 steps) and diastere-
omeric and enantiomeric purity (>96% ee and dr). The terminal
trimethyl silyl group was then selectively removed (K2CO3 in
EtOH) to give 19 (92%).
With the desired triol stereochemistry of fostriecin in-
stalled, we next turned to the key rhodium catalyzed trans-
hydroboration reaction (Scheme 4).14 Because of the per-
acetic acid in THF afforded an allylic alcohol, which was
directly oxidized with MnO2 to provide aldehyde 13 (78%).
Horner-Emmons reaction of triethyl-2-phosphonopropionate
with aldehyde 13 provided dienynes 14a/b in 91% yield as
a 4:1 mixture of E/Z-isomers. Although the E/Z-double bond
isomers could be separated by SiO2 chromatography on a
preparative scale, it was easier to carry the mixture forward.
Exposure of a CH2Cl2 solution of the two isomers 14a/b
with 2.5 equiv of DIBAL-H at -78 °C provided a mixture
of allylic alcohols, which without purification were oxidized
with MnO2 to afford aldehydes 15a/b (87% yield for 2 steps).
At this stage, the undesired double bond isomer 15b was
readily converted into the desired isomer 15a by treating the
mixture with 10 mol % TFA in CH2Cl2 (86% of >20:1 ratio).
Finally, a stabilized Wittig olefination between aldehyde 15a
with EtO2CCHdPh3 in toluene at reflux gave trienoate 10
in 94% yield (E/Z ratio >20/1).
Scheme 4. Substrate Optimization for the trans-Hydroboration
With a practical approach to the trienoate 10 in hand, we
turned our attention to the asymmetric hydration/oxidation
sequence of 10 to provide a suitably protected triol 19 (Scheme
3).17 This began with an asymmetric dihydroxylation and
subsequent palladium-catalyzed reduction of the most electron-
deficient double bond of 10. Exposure of 10 to Sharpless AD-
mix-R reagent system regioselectively provided the correspond-
ing diol,18 which was subsequently converted (triphosgene/Py)
to a carbonate 16 (80% for 2 steps). Treatment of 16 with 2.0
mol % Pd2(dba)3· CHCl3, 4.0 mol % PPh3,and a mild hydride
source (3 equiv, Et3N/HCO2H) provided a propargylic alcohol,
which was then protected to a silyl ether 17 (64% yield for 2
steps). A second Sharpless dihydroxylation with the AD mix-ꢀ
ceived instability of the organoborane intermediates, we first
investigated the trans-hydroboration of late stage intermedi-
ates like 20 with the pyranone ring installed. Unfortunately,
when terminal alkyne 20 was exposed to Miyaura’s typical
procedure, no desired products were detected. A similar lack
of reactivity was observed for the propargyl alcohol 21.
Success was finally achieved when both the hydroxyl group
and pyranone ring were removed. Thus when the TBS-
protected propargyl alcohol 22 was exposed to the Miyaura
conditions (1.5 mol % Rh[(cod)Cl]2, 6 mol % of Pi-Pr3,
triethylamine, catechol borane then pinacol)14 the desired
trans-hydroboration proceeded smoothly to give Z-vinylbo-
rane 23 (70%, >10:1). To our surprise the vinyl borane 23
was stable to silica gel chromatography and all attempts to
stereoselectively convert the Z-vinyl boronate into a vinyl
halide like 24 (e.g., NBS and I2).
(14) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000,
122, 4990. For its use in synthesis, see: ref.6c
(15) For an example of a stable vinyl boronate in natural product
synthesis, see: Penner, M.; Rauniyar, V.; Kaspar, L. T.; Hall, D. G. J. Am.
Chem. Soc. 2009, 131, 14216.
(16) We found that these vinyl-boronates rival the vinyl-trifluoroborates
in terms of reaction compatibility, see: Molander, G. A.; Cooper, D. J. J.
Org. Chem. 2008, 73, 3885.
(17) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447.
(18) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005,
61, 6337.
3754
Org. Lett., Vol. 12, No. 17, 2010

For reasons associated with the end-game protecting group
strategy, we had to move forward with the bis-TES ether
protected vinyl boranes 25a/b for installation of the pyranone
ring and the E,E,Z-triene. When the more suitably protected
alkyne 19, with a bis-TES-ether protecting group, was exposed
to the same conditions, a slightly less selective trans-hydrobo-
ration reaction occurred to give 25a, along with the undesired
cis-hydroboration product 25b in a 6:1 ratio of inseparable
isomers. Once again vinyl boronate 25a/b was remarkably stable
to silica gel chromatography and several subsequent synthetic
transformations to install the pyranone ring (Scheme 5). To our
Scheme 6. Fostriecin End-Game
Scheme 5. trans-Hydroboration and Pyranone Installation
With all of the carbon atoms and stereocenters in place,
all that was needed to complete the synthesis was the
selective deprotection and phosphorylation of the C-9 TES-
group followed by global deprotection. Unfortunately, the
selective deprotection of silyl ether 33 required a three-step
sequence. First, exposure of 33 to HF·Py gave products of
C-9 TES and C-18 TBDPS deprotection 34 along with
monodeprotected products 35. A subsequent re-exposure of
35 to HF·Py gave improved yields of the bis-deprotected diol
34. Finally, the primary hydroxyl group of 34 was selectively
protected with TBDPSCl/imidazole to give silyl ether 5.
Product 5 was the intermediate reported by Imanishi and
others.6 Using the Imanishi protocol, 2 mg of protected
dephospho-fostriecin 5 was converted into fostriecin 1 (∼
0.5 mg), 1H NMR (600 MHz in D2O) and HRMS of which
matched those of the natural material.6a,g,21
In summary, an enantioselective synthesis of fostriecin has
been accomplished in 24 steps from commercially available
starting material (11). This highly enantio- and diastereo-
controlled route illustrates the utility of an iterative Sharpless
AD reaction, Noyori asymmetric reduction, asymmetric
Leighton allylation, Rh-catalyzed trans-hydroboration, and
Suzuki-Miyaura cross-coupling reaction sequence. It is also
worth noting that these new routes start from achiral sources.
Importantly, these key reactions are performed under catalyst
control. This strategy should facilitate the syntheses of
fostriecin analogues and similar structural natural products.
Efforts along these lines will be reported in due course.
delight, the Z-vinyl boronate displayed remarkable stability to
the reaction conditions. For instance, when the mixture of esters
25a/b was exposed to excess DIBALH, a good yield of allyl
alcohols 26a/b was isolated (92% yield, >6/1: Z/E ratio).
Moreover, when the mixture of allylic alcohols was oxidized
with MnO2, only aldehyde 27 was isolated as a single
vinylborane isomer in 78% yield. Diastereoselective allylation
of aldehyde 27 was achieved by simple exposure to a solution
of the Leighton allylsilane reagent (R,R)-28 (0.2 M in CH2Cl2)19
at -10 °C, providing allylic alcohol 29 in 85% yield with near
perfect stereocontrol (>99% ee and dr). A DCC-promoted
esterification with acrylic acid (3 equiv) and allylic alcohol 29
afforded a tetraene 30 in 76% yield. Exposure of a refluxing
CH2Cl2 solution of the tetraene 30 to the Grubbs catalyst 31
(10 mol %) resulted in a clean cyclization to pyranone 32 in
82% yield.
Acknowledgment. We are grateful to NIH (GM088839) and
With both the vinyl boronate 32 and vinyl iodide 8 in hand,
we then investigated the Suzuki-Miyaura cross-coupling.20
Our initial efforts using a Pd(PPh3)4/Ag2O system led to no
reaction. Further investigations led to an optimal condition,
which used a 20% Pd/PPh3 system (20% Pd2(dba)3·CHCl3/
80%PPh3). These conditions smoothly coupled vinyl boronate
32 and vinyl iodide 8 affording the Z,Z,E-triene 33 in
excellent alkene stereoselectivity (>20:1) and 80% yield.
NSF (CHE- 0749451) for the support of our research program.
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.
OL101340N
(21) The optical rotation data for our synthetic fostriecin did not match
that of the natural material. This could be a result of both the different
concentration and solvent. However, our optical rotation data for 5 did match
that reported by Imanishi; see Supporting Information.
(19) Kubota, K.; Leighton, J. Angew. Chem., Int. Ed. 2003, 42, 946.
(20) For a review, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
Org. Lett., Vol. 12, No. 17, 2010
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