Formal Total Synthesis of Fostriecin

Article abstract of DOI:10.1021/ol020193q

(Matrix Presented) Addition of magnesium anion 4 (M = MgBr, R¹ = TES) to ketone 6 (R² = PMB) at -78°C in THF proceeded under chelation control to provide alcohol 7, which possesses the full set of the chiral centers of fostriecin. Su

Full text of DOI:10.1021/ol020193q

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4615-4618
Formal Total Synthesis of Fostriecin
Yong-Gang Wang and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received September 23, 2002
ABSTRACT
1
2
Addition of magnesium anion 4 (M ) MgBr, R ) TES) to ketone 6 (R ) PMB) at −78 °C in THF proceeded under chelation control to provide
alcohol 7, which possesses the full set of the chiral centers of fostriecin. Subsequently, 7 was transformed successfully to the known key
intermediate 2.
After its isolation in 1983,1 the antitumor activity of fostriecin
against a broad range of cancerous cell lines and its inhibi-
tory activity against protein serin/threonine phosphatases
have attracted much interest among both biological and
pharmaceutical researchers.2 In 1997, the relative and ab-
solute stereochemistry of fostriecin was established by the
Boger group,3 which made investigation at the molecular
level possible. However, a few years passed before the
first total synthesis of fostriecin (1) was reported by Boger
in 2001.4 Since then, three total syntheses have been
reported.5 The conjugated triene unit has been synthesized
by joining two parts at the C(12) and C(13) carbons with a
palladium catalyst. The vinyl halides such as 2 are those
which belong to a partner containing the highly congested
diene. This strategy for the construction of the triene unit is
C(5)-C(11) functionality and another partner is the orga-
nometallic corresponding to the remaining C(13)-C(18)
efficient and straightforward, and thence synthesis of the
central moiety is of much interest at present.6 Although
elegant syntheses of this complex moiety have been pub-
lished, we examined another approach to this moiety in order
not only to establish a route to 1 but also to provide a
potentially versatile route to the analogues.
Illustrated in Scheme 1 is our approach to 2, in which the
key reaction is chelation-controlled addition of anion 4 to
R-alkoxy ketone 6 furnishing the adduct 7 with the full set
of the chiral centers. The metal for the chelation is MgX,7
(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. (c) Leopold, W. R.; Shillis, J. L.; Mertus,
A. E.; Nelson, J. M.; Roberts, B. J.; Jackson, R. C. Cancer Res. 1984, 44,
1928-1932.
(2) (a) Jackson, R. C.; Fry, D. W.; Boritzki, T. J.; Roberts, B. J.; Hook,
K. E.; Leopold, W. R. AdV. Enzyme Regul. 1985, 23, 193-215. (b) de Jong,
R. S.; de Vires, E. G. E.; 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.
(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.
(6) (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.
10.1021/ol020193q CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/27/2002

Scheme 1. A Strategy for Synthesis of the Key Intermediate 2
Scheme 2. Preliminary Study
and this anion is expected to be generated from iodide 3
through lithiation followed by transmetalation with MgX2.
On the other hand, a transformation of 5 illustrated in Scheme
1 was envisioned for synthesis of ketone 6. Herein, we
disclose the successful result of this approach, where the
asymmetric chiral centers of 3 and 5 were created by using
the Sharpless asymmetric epoxidation.8
of TES ether 13, derived from 11d, with DDQ furnished
alcohol 14 in 82% yield.
With these preliminary results in mind, synthesis of
fostriecin was performed as depicted in Schemes 3-5.
First, we studied a protective group at the C(9) hydroxyl
group which should be removed at a later stage after the
chelation-controlled addition. Ketones 10 with different
protective groups (R ) MOM, EE, MEM, PMB) were
chosen as model compounds of 6 and submitted to the
reaction with magnesium anion 9 derived from 8 [(1) n-BuLi;
(2) MgBr2] to afford the addition products 11a-d in good
yields (Scheme 2). As expected,7 the protective groups we
Scheme 3. Synthesis of C(8)-C(12) Intermediate 6a
1
examined furnished high stereoselectivity of >20:1 by H
NMR spectroscopy (300 MHz), and thence deprotection was
studied with these products under the following conditions:
PPTS/MeOH, PPTS/n-PrOH,9a MgBr2/Et2O,9b CBr4/i-PrOH9c
for MOM ether 11a; PPTS/MeOH for EE ether 11b; ZnBr2/
CH2Cl2,9d TiCl49d in CH2Cl2 or hexane for MEM ether 11c;
9e
DDQ in wet CH2Cl2 for PMB ether 11d. However, these
conditions resulted in recovery of the ethers, production of
Me ether (from 11b/MeOH), formation of acetal 12 (from
11d), or production of mixtures. On the contrary, reaction
(7) Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031-
1034.
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976. (b) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240. (c) Gao,
Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(9) (a) Monti, H.; Leandri, G.; Klos-Ringuet, M.; Corriol, C. Synth.
Commun. 1983, 13, 1021-1026. (b) Kim, S.; Kee, I. S.; Park, Y. H.; Park,
J. H. Synlett 1991, 183-184. (c) Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F.
Tetrahedron 2001, 57, 2121-2126. (d) Corey, E. J.; Gras, J.-L.; Ulrich, P.
Tetrahedron Lett. 1976, 809-812. (e) Horita, K.; Yoshioka, T.; Tanaka,
T.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986, 42, 3021-3028.
a Reagents and conditions: (a) t-BuOOH (1.0 equiv), L-(+)-DIPT
(0.35 equiv), Ti(O-i-Pr)4 (0.30 equiv), 4A MS, 49%; (b) PMBOC-
(CCl3)dNH, CSA, CH2Cl2, 93%; (c) LiAlH4, 93%; (d) (COCl)2,
DMSO then Et3N; (e) LiCl, DBU, (EtO)2P(dO)CH2CO2Et, 99%
(two steps); (f) DIBAL (2.5 equiv), 92%; (g) t-BuOOH (1.5 equiv),
D-(-)-DIPT (0.24 equiv), Ti(O-i-Pr)4 (0.20 equiv), 4A MS, 92%;
(h) CCl4, PPh3, NaHCO3 (cat.), 83%; (i) n-BuLi, THF, 91%; (j)
TBSCl, 94%; (k) O3, n-PrOH, 85%.
4616
Org. Lett., Vol. 4, No. 26, 2002

Scheme 4. Synthesis of C(3)-C(7) Intermediate 7a
Scheme 5. Final Stage Leading to the Key Intermediate 2a
a Reagents and conditions: (a) n-BuLi, THF, -78 °C then
MgBr2; (b) -78 to -50 °C, 91%; (c) HF, 98%; (d) CH2dCHCOCl,
DIPEA, 85%; (e) TESOTf, 89%; (f) (PCy3)2RuCl2(dCHPh) (0.1
equiv), Ti(O-i-Pr)4 (0.3 equiv), CH2Cl2, 83%; (g) NIS (1.2 equiv),
AgNO3 (2 equiv), acetone, 83%; (h) DDQ, rt, 2 h, CH2Cl2/H2O
(18:1), 82% from 34; (i) o-(NO2)C6H4SO2NdNH (1.2 equiv), Et3N
(2 equiv), 88%.
a Reagents and conditions: (a) CH2dCHCH2MgCl, THF, 100%;
(b) t-BuOOH (1.5 equiv), D-(-)-DIPT (0.35 equiv), Ti(O-i-Pr)4
(0.30 equiv), 4A MS, 46% and >99% ee of 27, 45% and >99%
ee of (S)-26; (c) LDA, Bu3SnH; (d) I2, Et2O, 98% from 27, 84%
from 30; (e) TESCl, 93-100%; (f) t-BuOOH (2.0 equiv), L-(+)-
DIPT (0.35 equiv), Ti(O-i-Pr)4 (0.30 equiv), 4A MS, 95%; (g) 3,5-
(NO2)2C6H3CO2H, DIAD, PPh3, 93%; (h) NaOH, 94%.
afforded ketone 6 (R2 ) PMB), the C(8)-C(13) intermediate,
in good yield.
Racemic alcohol rac-16, prepared by aldol reaction of
methacrolein and the anion derived from ethyl acetate (LDA,
THF, -78 °C) in 91% yield, was submitted to kinetic
resolution through the Sharpless asymmetric epoxidation8b,c
to furnish (R)-16 with 98% ee by 1H NMR spectroscopy of
the corresponding MTPA ester (Scheme 3). The isolated
yield after chromatography on silica gel was 49% based on
rac-16. The corresponding epoxide 23 produced by the
epoxidation (checked by TLC) was quite unstable during
workup (10% tartaric acid and NaF), and thus isolation of
(R)-16 by chromatography on silica gel was performed easily.
Protection of the hydroxyl group of (R)-16 furnished PMB
(PMB ) CH2C6H4(OMe)-p) ether 17 in 93% yield, which
was converted into allylic alcohol 19 by the standard
sequence of reactions through aldehyde 18 in good overall
yield. A catalytic version of the Sharpless asymmetric
epoxidation8c of 19 proceeded efficiently to produce epoxide
20 in 92% yield with a 23:1 ratio of 20 (1H NMR two peaks
at 4.42 and 4.46 ppm: doublet, J ) 12 Hz) and 24 (two
peaks at 4.44 and 4.48 ppm: doublet, J ) 12 Hz). Although
the mixture (20 and 24) was not separated at this stage,
transformation of the mixture by the Yadav protocol10
furnished acetylenic alcohol 22 in 76% yield after chroma-
tography on silica gel without contamination of the diaste-
reomer. Finally, TBS protection of 22 followed by ozonolysis
Synthesis of another key intermediate 3 (R1 ) TES) was
accomplished by a sequence delineated in Scheme 4. Kinetic
resolution11 of racemic alcohol rac-26, derived from aldehyde
25, by using the Sharpless asymmetric epoxidation8b,c with
D-(-)-DIPT as a chiral source afforded epoxide 27 and (S)-
26 in 46% yield with >99% ee (by the MTPA method) and
in 45% yield with >99% ee, respectively. Both products were
converted into the target compound 3 (R1 ) TES) by using
the literature procedure.12 Thus, epoxide 27 after separation
by chromatography was transformed into iodide 29 through
vinyl stannane 28 in 98% yield. On the other hand, four-
step conversion of (S)-26 [(1) asymmetric epoxidation with
L-(+)-DIPT, (2) Mitsunobu inversion,13 (3) Bu3SnLi, (4)
(10) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990,
46, 7033-7046.
(11) Kinetic resolution of γ-silylallylic alcohols: Kitano, Y.; Matsumoto,
T.; Sato, F. Tetrahedron 1988, 44, 4073-4086.
(12) Okamoto, S.; Shimazaki, T.; Kobayashi, Y.; Sato, F. Tetrahedron
Lett. 1987, 28, 2033-2036.
(13) Mitsunobu, O. Synthesis 1981, 1-28.
Org. Lett., Vol. 4, No. 26, 2002
4617

iodination] afforded iodide 29 in good yield. Finally, TES
protection of iodo alcohol 29 furnished the key intermediate
3 with R1 ) TES.
afford lactone 34 in 83% yield. Without Ti(O-i-Pr)4, the
RCM was sluggish as stated by Ghosh,16 producing 34 only
in 62% yield with recovery of the starting 33 after 24 h.
Iodination of lactone 34 with NIS and AgNO3 proceeded
selectively at the terminal position of the acetylene moiety
and subsequent removal of PMB on 35 and reduction of 36
with o-(NO2)C6H4SO2NdNH17 furnished the target key
intermediate 2 in 60% yield from 34 (3 steps). The H and
13C NMR spectra of synthetic 2 were coincident with those
kindly provided by the authors of ref 5c.
To combine the above two pieces 3 (R1 ) TES) and 6
(R2 ) PMB) by the chelation-controlled addition, 2 equiv
of magnesium anion 4 (R1 ) TES, M ) MgBr), generated
from 3, was submitted to reaction with ketone 6 in THF at
-78 ∼ -50 °C (Scheme 5) for 1 h to produce 7 (R1 ) TES,
R2 ) PMB) in 91% yield with the ratio of 7 and the C(8)
1
1
epimer (structure not shown) being > 50:1 by H NMR
spectroscopy (δ 1.26 and 1.29 ppm, respectively). Addition-
ally, reaction of lithium anion 4 (M ) Li, R1 ) TES) and
ketone 6 was also examined under the same reaction
conditions to afford a mixture of 7 and the C(8) epimer in a
45:55 ratio.
The TES group of 7 was removed with HF and MeOH in
98% yield without concomitant loss of the TBS group at
the C(11) oxygen. Regioselective esterification of the result-
ing diol 31 with CH2dCHCOCl afforded ester alcohol 32
in 85% yield, and subsequent protection with TESOTf
produced the TES ether 33 in good yield. Ring-closing
metathesis (RCM)14 of 33 was accomplished with the
Grubbs’ 1st-generation catalyst15 (0.1 equiv) in the presence
of Ti(O-i-Pr)4 (0.3 equiv) in refluxing CH2Cl2 overnight to
Acknowledgment. We thank Professors T. Imanishi and
K. Miyashita of Osaka University for providing spectral data
of 2.
Supporting Information Available: Detailed description
of experimental procedures and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL020193Q
(15) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(16) Ghosh, A. K.; Bilcer, G. Tetrahedron Lett. 2000, 41, 1003-1006.
(17) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507-7507.
(14) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
4618
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