Enantioselective Total Synthesis of the Potent Antitumor Agent (-)-Mucocin Using a Temporary Silicon-Tethered Ring-Closing Metathesis Cross-Coupling Reaction

Article abstract of DOI:10.1021/ja0384734

The enantioselective total synthesis of the annonaceous acetogenin (?)-mucocin (1) was accomplished using a triply convergent 12-step sequence (longest linear sequence) in 13.6% overall yield. This represents the first application of the temporary silicon-tethered (TST) ring-closing metathesis (RCM) cross-coupling reaction and the enantioselective alkyne/aldehyde addition to the synthesis of a complex annonaceous acetogenin. Moreover, all three fragments required for the coupling reactions are conveniently prepared in 5?6 steps from two readily available enantiomerically enriched epoxides. Finally, this synthesis stimulated the development of a new approach for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans, using the bismuth tribromide-mediated reductive etherification reaction, which represents a motif that is prevalent in a wide range of pharmacologically significant natural products. Copyright

Full text of DOI:10.1021/ja0384734

Published on Web 11/05/2003
Enantioselective Total Synthesis of the Potent Antitumor Agent (-)-Mucocin
Using a Temporary Silicon-Tethered Ring-Closing Metathesis
Cross-Coupling Reaction
P. Andrew Evans,* Jian Cui, Santosh J. Gharpure, Alexei Polosukhin, and Hai-Ren Zhang
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received September 11, 2003; E-mail: paevans@indiana.edu
Scheme 1
The potent antitumor agent mucocin (1) was isolated from the
leaves of Rollinia mucosa (jacq.) Baill. (Annonaceae) by McLaugh-
lin and co-workers in 1995.1-3 This agent has exquisite selectivity
for the inhibition of A-549 (lung cancer) and PACA-2 (pancreatic
cancer) solid tumor cell lines with potency 10,000 times that of
adriamycin (doxorubicin). Annonaceous acetogenins selectively
inhibit cancerous cells through the blockage of the mitochondrial
complex I (NADH-ubiquinone oxidoreductase), and the inhibition
of the plasma membrane NADH oxidase, which depletes ATP and
induces apoptosis (programmed cell death) in malignant cells.4
In a program directed toward the construction of nonadjacent
tetrahydrofuran containing acetogenins, we have developed a new
approach to the construction of C2-symmetrical 1,4-diols, using a
temporary silicon-tethered (TST) ring-closing metathesis (RCM)
homo-coupling reaction.5 Herein, we now describe a novel and
expeditious synthesis of mucocin (1), which utilizes the TST-RCM
cross-coupling reaction (Scheme 1).6,7 This approach capitalizes
on the localized C2-symmetry and thereby permits the construction
of 2 and 3 from a common synthetic intermediate, the known
homoallylic epoxide 5.8 We further envisioned that the C4-C5 bond
could be formed by enantioselective addition of the alkyne 3 to
the aldehyde 4, thereby providing a new strategic disconnection
for this class of biologically important molecules.9 The key feature
of this approach is the utilization of a triply convergent strategy,
that can be adapted to facilitate the synthesis of related annonaceous
acetogenins, resulting in one of the most expeditious syntheses of
a complex acetogenin developed to date.
The synthesis of the 3-hydroxy-2,6-disubstituted tetrahydropyran
2 was accomplished using the novel six-step strategy outlined in
Scheme 2. Mitsunobu inversion of the allylic alcohol 5 using
p-methoxyphenol afforded the requisite aryl ether.10 Regiospecific
ring opening of the epoxide with the homoenolate equivalent11
derived from tert-butyldimethylsilyl protected divinyl carbinol,
followed by an in situ protection of the resultant secondary alcohol,
afforded the differentially protected triene 7 in 96% overall yield.
Chemoselective Sharpless asymmetric dihydroxylation of the triene
7 using AD-mix-â furnished the hydroxy ketone 8 in 70% yield
(ds g99:1 by HPLC), after recycling the recovered triene 7 (2×).12
The alkyl side chain was then introduced Via the conjugate addition
of the cuprate derived from octylmagnesium bromide and copper
cyanide to furnish the ketone 9 and thereby set the stage for the
reductive etherification. Treatment of 9 with bismuth tribromide
and tert-butyldimethylsilane in acetonitrile, followed by in situ
protection of the secondary alcohol, furnished the tert-butyldi-
methylsilyl ether 10 in 93% yield (ds g19:1 by NMR).13 Finally,
the p-methoxyphenyl ether was oxidatively cleaved with ceric
ammonium nitrate (CAN) to complete the construction of 2.10
The construction of the tetrahydrofuran 3 was also initiated from
the homoallylic epoxide 5, as outlined in Scheme 3. Mitsunobu
inversion of 5 followed by regiospecific ring opening of the epoxide
Scheme 2 a
a (a)p-MeOC6H4OH,DIAD,PPh3,THF,0°C,80%;(b)(CH2dCH)2CHOTBS,
sBuLi, THF, -78 °C, then TBSOTf, 2,6-lutidine, -78 to 0 °C, 96%; (c)
t
AD-mix-â, BuOH/H2O, MeSO2NH2, 0 °C (3×), 70%; (d) noctylMgBr,
CuCN, THF, -78 °C, 65%; (e) BiBr3, tBuMe2SiH, MeCN, 0 °C, then 2,6-
lutidine, TBSOTf, 0 °C, 93%; (f) (NH4)2Ce(NO3)6, MeCN/H2O, -5 °C, 91%.
Scheme 3 a
a (a)p-MeOC6H4OH,DIAD,PPh3,THF,0°C,80%;(b)CH2dCHCH2MgBr,
t
i
CuCN, Et2O, -78 °C, 90%; (c) Co(modp)2, O2, BuOOH, PrOH, 60 °C,
83%; (d) Tf2O, Et3N, CH2Cl2, -78 °C, 86%; (e) TMSCtC(CH2)4MgBr,
CuI, THF, -20 to -10 °C; then MeOH, TBAF, -20 °C to room
temperature, 73%.
(cf. Scheme 2) with the cuprate derived from allylmagnesium bro-
mide and catalytic copper cyanide afforded the secondary alcohol,
which was subjected to a cobalt(II) catalyzed oxidative cyclization
to afford the trans-2,5-tetrahydrofuran 11 in 75% overall yield (ds
g19:1).2d,14 Conversion of the primary alcohol 11 to triflate, fol-
lowed by cuprate displacement and in situ deprotection of tri-
methylsilyl group, furnished the B-ring fragment 3.
The synthesis of butenolide fragment 4 commenced with the
regioselective ring opening of commercially available (S)-propylene
oxide 6 (Scheme 4). Treatment of 6 with the carbanion derived
from the alkyne 12 afforded the secondary alcohol, which was
9
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J. AM. CHEM. SOC. 2003, 125, 14702-14703
10.1021/ja0384734 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
converted to the selenocarbonate 13 using phosgene and phenyl-
selenol.15 The selenocarbonate 13 was subjected to standard free
radical conditions, to afford the γ-butyrolactone in 80% yield.
Metal-catalyzed isomerization of the exo-cyclic olefin and subse-
quent hydrolysis of the diethyl acetal furnished the requisite
aldehyde 4 in good overall yield.
triply convergent 12-step sequence (longest linear sequence) in
13.6% overall yield. This approach represents the first application
of the temporary silicon-tethered (TST) ring-closing metathesis
(RCM) cross-coupling reaction and the enantioselective alkyne/
aldehyde addition in the synthesis of a complex annonaceous
acetogenin. Finally, the synthesis highlights the utility of the bismuth
tribromide-mediated reductive etherification for the construction
of 3-hydroxy-2,6-disubstituted tetrahydropyrans.
Scheme 4 a
Acknowledgment. This work is dedicated to Professor Philip
D. Magnus on the occasion of his 60th birthday. We sincerely thank
the National Institutes of Health (GM58877) for generous financial
support. We also thank Johnson and Johnson for a Focused GiVing
Award and Pfizer Pharmaceuticals for the CreatiVity in Organic
Chemistry Award. The Camille and Henry Dreyfus Foundation is
thanked for a Camille Dreyfus Teacher-Scholar Award (P.A.E.).
a (a) S-Propylene oxide 6, nBuLi, HMPA, THF, -30 °C; (b) COCl2,
Et3N, C6H6, 0 °C to room temperature, then PhSeH, pyridine, THF/C6H6,
0 °C to room temperature, 60% overall yield from 12; (c) nBu3SnH, AIBN,
C6H6, ∆, 80%; (d) RhH(CO)(PPh3)3, C6H6, 85 °C, 84%; (e) HCOOH,
pentane, 0 °C, 90%.
Note Added after ASAP. In the version posted 11/5/03, in
Scheme 2 the absolute configuration for the secondary tert-
butyldimethylsilyl ether in 7, 8, and 9 was incorrect. The version
posted 11/11/03 and the print version are correct.
Scheme 5 a
Supporting Information Available: Spectral data and detailed
experimental procedures for all of the synthetic intermediates (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao, G.-x.;
He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995,
117, 10409.
(2) For total syntheses of mucocin (1), see: (a) Neogi, P.; Doundoulakis, T.;
Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1998, 120, 11279. (b) Ba¨urle, S.; Hoppen, S.; Koert, U. Angew. Chem.,
Int. Ed. 1999, 38, 1263. (c) Takahashi, S.; Nakata, T. J. Org. Chem. 2002,
67, 5739. (d) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int.
Ed. 2002, 41, 4751.
(3) For alternative synthetic approaches to the 3-hydroxy 2,6-disubstituted
tetrahydropyran ring of mucocin (1), see: (a) Evans, P. A.; Roseman, J.
D. Tetrahedron Lett. 1997, 38, 5249. (b) Evans, P. A.; Murthy, V. S.
Tetrahedron Lett. 1999, 40, 1253. (c) Takahashi, S.; Fujisawa, K.; Sakairi,
N.; Nakata, T. Heterocycles 2000, 53, 1361.
(4) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovren, J. P.; Hui, Y.
H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113. (b) Morre, D. J.; de Cabo,
R.; Farley, C.; Oberlies, N. H.; McLaughlin, J. L. Life Sci. 1995, 56, 343.
(5) For examples of silicon-tethered ring-closing metathesis homo-coupling
reactions, see: (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992,
114, 7324. (b) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768.
(6) For examples of silicon-tethered ring-closing metathesis cross-coupling
reactions, see: (a) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999,
40, 1429. (b) Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J.
Org. Lett. 2002, 4, 4105 and pertinent references therein.
(7) For recent reviews on temporary silicon-tethered strategies, see: (a) White,
J. D.; Carter, R. G. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Fleming, I., Ed.; Georg Thieme Verlag: New
York, 2001; Vol. 4, pp 371-412. (b) Skrydstrup, M. In Science of
Synthesis: Houben-Weyl Methods of Molecular Transformations; Fleming,
I., Ed.; Georg Thieme Verlag: New York, 2001; Vol. 4, pp 439-530
and pertinent references therein.
a (a) 3, Et2Zn, PhMe, ∆, then (R)-BINOL, Ti(OiPr)4, THF, 4, 0 °C, 81%;
(b) TIPSOTf, pyridine, DMAP, THF, 0 °C, 96%; (c) (NH4)2Ce(NO3)6,
MeCN/H2O, -10 °C, 91%; (d) 2, Pr2SiCl2 (xs), CH2Cl2, imidazole, 0 °C
to room temperature, then 14, imidazole, 0 °C to room temperature, 74%;
(e) Grubbs’ catalyst (1.8 equiv), 1,2-DCE, ∆, 83%; (f) HF/MeCN, CH2Cl2,
room temperature, 91%; (g) TsNHNH2, NaOAc, 1,2-DME/H2O, ∆, 95%.
i
Scheme 5 outlines the manner in which the three fragments were
assembled to complete the synthesis of mucocin (1). The enanti-
oselective addition of the alkynyl zinc reagent derived from 3 to
the aldehyde 4 furnished the propargylic alcohol in 81% yield with
excellent selectivity (ds ) 20:1 by HPLC).9,16 Protection of the
alcohol as the triisopropylsilyl ether followed by deprotection of
the p-methoxyphenyl ether afforded the allylic alcohol 1410 and
thereby set the stage for the TST-RCM cross-coupling reaction. The
construction of the mixed bis-alkoxy silane was achieved from the
allylic alcohol 2 through the treatment with excess diisopropyldi-
chlorosilane to afford the mono-alkoxychlorosilane, followed by
the removal of the excess silylating agent and addition of the second
allylic alcohol 14. Ring-closing metathesis of the silicon-tethered
diene using stoichiometric Grubbs’ catalyst furnished 15 in 83%
yield and completed the construction of the carbon skeleton of
mucocin (1) (Scheme 5).17 The synthesis was concluded with the
fluoride-mediated deprotection of 15, followed by chemoselective
reduction with diimide.18 The spectroscopic data and optical rotation
of synthetic mucocin (1) were identical in all respects to the values
reported for the natural substance [1H/13C NMR, IR, [R]26D -16.0
(c ) 0.25, CH2Cl2)].
(8) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987,
109, 1525.
(9) (a) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002,
172. (b) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143.
(10) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985,
26, 6291.
(11) For the ring opening of dioxirane, which leads to a regioisomeric mixture,
see: Oppolzer, W.; Snowden, R. L. Tetrahedron Lett. 1976, 17, 4187.
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(13) (a) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem. Soc.
2003, 125, 11456. (b) Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett.
2003, 5, 3883.
(14) Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67.
(15) Evans, P. A.; Murthy, V. S. Tetrahedron Lett. 1998, 39, 9627 and pertinent
references therein.
(16) Extensive modification of the reported procedure was necessary to achieve
optimum selectivity.
(17) The construction of trans-1,4-silaketals using ring-closing metathesis is
known to be challenging, see: Evans, P. A.; Cui, J.; Buffone, G. P. Angew.
Chem., Int. Ed. 2003, 42, 1734.
In conclusion, we have accomplished an enantioselective total
(18) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996.
synthesis of the annonaceous acetogenin (-)-mucocin (1) using a
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