C-aryl glycosides via tandem intramolecular benzyne-furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester

Article abstract of DOI:10.1021/ja0652619

A triply convergent total synthesis of vineomycinone B₂ methyl ester has been achieved by an approach with a longest linear sequence of 16 steps. The synthesis features the use of silicon tethers as disposable linkers to control the regiochemis

Full text of DOI:10.1021/ja0652619

Published on Web 09/28/2006
C-Aryl Glycosides via Tandem Intramolecular Benzyne-Furan Cycloadditions.
Total Synthesis of Vineomycinone B2 Methyl Ester
Chi-Li Chen, Steven M. Sparks,† and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas 78712
Received July 22, 2006; E-mail: sfmartin@mail.utexas.edu
The vineomycins are a group of glycosidic antibiotics that were
isolated from a culture of Streptomyces matensis Vineus and found
to be active against Gram-positive bacteria and sarcoma-180 solid
tumors in mice.1 Acid-catalyzed methanolysis of vineomycin B2
furnished the aglycone vineomycinone B2 methyl ester (1). Bearing
an olivose residue appended to one ring of the anthrarufin core, 1
is a representative member of the C-aryl glycoside family of natural
products.2 A (3R)-hydroxyisovaleryl side chain adorns the opposite
side of the core, making vineomycinone B2 methyl ester an
intriguing target of modest complexity. Indeed, the structure of 1
coupled with its potential anticancer activity has rendered vine-
omycinone B2 methyl ester the object of a number of investigations,
four of which have culminated in total syntheses.3 Despite these
successes, there remains ample opportunity for the development
of new chemistries.
In the context of an interest in C-aryl glycoside antibiotics, we
recently developed a general entry to the four major classes of this
Figure 1. Retrosynthesis of vineomycinone B2 methyl ester (1).
family of natural products.4 The strategy features the ring opening
Scheme 1 a
of cycloadducts that are obtained from Diels-Alder cycloadditions
of substituted benzynes with glycosyl furans. Having established
the basic elements of the approach, we turned to the task of applying
it to the syntheses of naturally occurring C-aryl glycosides as an
obligatory test of its true utility. We now report the application of
this methodology to a facile synthesis of vineomycinone B2 methyl
ester (1).
a Reaction conditions: (a) 3-lithiofuran, THF, -78 °C; HCl, EtOH then
NaCNBH3, HCl, 50 °C, 80%; (b) LDA, THF, -78 °C; Me2Si(Cl)CHdCH2,
70%; (c) 9-BBN, THF; H2O2, NaOH, 94%.
The two substituents on 1 are unsymmetrically positioned on
the anthrarufin nucleus. Hence, the major challenge is controlling
the regioselectivity in the Diels-Alder reactions that would
simultaneously assemble the aromatic framework and introduce the
carbohydrate and aliphatic residues. We had previously developed
a practical solution to this problem by using disposable silicon
tethers to link the reacting benzyne and furan moieties.4d On the
basis of that advance, a novel and highly convergent strategy
eventuated for preparing 1 (Figure 1). The synthesis features tandem
intramolecular benzyne-furan cycloadditions originating from the
key intermediate 3 to generate the bisoxabenzonorbornadiene 2 in
a single operation.5 The conversion of 2 into 1 requires cleavage
of the silicon tethers, ring opening of the bisoxabenzonorbornene
core, global removal of the oxygen protecting groups, and adjust-
ment of the oxidation level in the alkyl side chain. The cycloaddition
precursor 3 would be prepared by iterative Mitsunobu coupling of
tetrabromohydroquinone (5) with the silicon-substituted furans 4
and 6, both of which would be derived from readily available
starting materials.
heating with NaCNBH3 in ethanolic HCl to form glycosylfuran 8
in 80% overall yield.6 Regioselective metalation4d,7 of 8 followed
by trapping with chlorodimethylvinylsilane furnished the vinyl
silane 9, which was subjected to hydroboration/oxidation8 to deliver
furan 4 in 66% yield over two steps.
Turning to the synthesis of furan 6, 3-methyl-3-butenol was first
protected as its PMP ether and subjected to Sharpless asymmetric
dihydroxylation conditions to afford diol 11 in 93% yield over two
steps (96% ee) (Scheme 2).9 The primary tosylate derived from 11
was cyclized by deprotonation with n-BuLi to give an intermediate
epoxide that underwent facile opening in situ with 3-lithiofuran in
the presence of BF3•OEt2 to provide the tertiary alcohol 12 in 76%
overall yield. O-Benzylation of the hydroxyl group in 12 gave 13,
regioselective bromination of which with NBS furnished bromide
14 in 86% yield over two steps.10 The furyl bromide was subjected
to metal-halogen exchange, and the resulting anion was trapped
with chlorodimethylvinylsilane to afford the vinylsilane 15 in 87%
yield. Subsequent hydroboration and oxidation of the vinyl moiety
as before delivered the furan 6.
Preparation of 4 commenced by adding 3-lithiofuran to the
known lactone 74c to afford a mixture of lactols, which were in
equilibrium with the open chain keto-alcohol (Scheme 1). This
mixture was treated directly with ethanolic HCl to furnish an
intermediate ethyl acetal that was stereoselectively reduced upon
The assembly of 3 then proceeded uneventfully (Scheme 3).
Alcohol 6 and the monoprotected phenol 1611 underwent Mitsunobu
coupling employing DIAD and PPh3 to furnish the aryl ether 17 in
75% yield. Removal of the silyl protecting group utilizing
HF•pyridine in THF released the phenol 18 that was then coupled
† Present address: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park,
NC 27709.
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J. AM. CHEM. SOC. 2006, 128, 13696-13697
10.1021/ja0652619 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
20 with IBX generated an aldehyde intermediate, which was
transformed into acid 21 in 70% yield by reaction with NaClO2.
Global deprotection of the benzyl groups with BBr3 followed by
workup with methanolic hydrogen chloride provided synthetic
vineomycinone B2 methyl ester (1) in 71% yield. The synthetic
1
material thus obtained gave H and 13C NMR spectra identical to
those of an authentic sample.
In summary, a novel and highly convergent synthesis of
vineomycinone B2 methyl ester (1) has been completed by a process
that required 16 steps, the same length as the shortest previous
synthesis of 1,3b in the longest linear sequence. The synthesis
features the first application of our strategy for using silicon tethers
as disposable linkers to control the regiochemistry in Diels-Alder
reactions of substituted benzynes and furans. Such constructions
enable the rapid assembly of the glycosyl-substituted aromatic cores
of complex C-aryl glycoside antibiotics from simple starting
materials. Other applications of this strategy are in progress and
will be reported in due course.
a Reaction conditions: (a) p-MeO-C6H4OH, DIAD, PPh3, THF, 98%;
(b) AD-Mix R, H2O, t-BuOH, 95%, 96% ee; (c) TsCl, Et3N, DMAP,
CH2Cl2; (d) n-BuLi, -78 °C; 3-lithiofuran, BF3‚OEt2, THF, -78 °C, 76%
(2 steps); (e) KH, DMF, 0 °C; BnBr, 100%; (f) NBS, DMF, 0°C, 86%; (g)
n-BuLi, THF, -78 °C; Me2Si(Cl)CHdCH2, 87%; (h) 9-BBN, THF; H2O2,
NaOH, 96%.
Scheme 3 a
Acknowledgment. We thank the National Institutes of Health
(GM 31077), the Robert A. Welch Foundation, Pfizer, Inc., and
Merck Research Laboratories for their generous support of this
research. We are also grateful to Prof. Marcus A. Tius (University
of Hawaii) for providing an authentic sample of vineomycinone
B2 methyl ester (1).
a Reaction conditions: (a) 6, DIAD, PPh3, THF, 75%; (b) HF‚py, THF,
0°C, 85%; (c) 4, DIAD, PPh3, THF, 85%.
Scheme 4 a
Supporting Information Available: Experimental procedures for
2-4, 9, 17, and 19, spectral data and copies of 1H NMR spectra for all
new compounds together with copies of 1H NMR spectra of synthetic
and authentic 1 and a tabular comparison of 13C NMR data for synthetic
and authentic 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Ohmura, S.; Tanaka, H.; Ohiwa, R.; Awaya, J.; Masuma, R.; Tanaka, K.
J. Antibiot. 1977, 30, 908. (b) Imamura, N.; Kakinuma, K.; Ikekawa, N.;
Tanaka, H.; Ohmura, S. J. Antibiot. 1981, 34, 1517.
(2) For general reviews of C-aryl glycosides, see: (a) Jaramillo, C.; Knapp,
S. Synthesis 1994, 1. (b) Levy, D. E.; Tang, C. In The Chemistry of
C-Glycosides; Elsevier Science: Tarrytown, NY, 1995. (c) Nicotra, F.
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R. Tetrahedron 1998, 54, 9913. (e) Liu, L.; McKee, M.; Postema, M. H.
D. Curr. Org. Chem. 2001, 5, 1133.
(3) For total syntheses of vineomycinone B2 methyl ester, see: (a) Danishef-
sky, S.; Uang, B. J.; Quallich, G. J. Am. Chem. Soc. 1985, 107, 1285. (b)
Tius, M. A.; Gomez-Galeno, J.; Gu, X. Q.; Zaidi, J. H. J. Am. Chem.
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1991, 113, 6982.
(4) For syntheses of C-aryl glycosides based on furan-benzyne cycloadditions,
see: (a) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc.
2001, 123, 6937. (b) Martin, S. F. Pure Appl. Chem. 2003, 75, 63. (c)
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a Reaction conditions: (a) 3.0 equiv of n-BuLi, ether, -20 °C, 85%; (b)
KOH, DMF/H2O (10:1); HCl, EtOH, 70 °C, 34%; (c) CAN, CH3CN, H2O,
-15 °C, 74%; (d) IBX, EtOAc, 80 °C; NaClO2, NaH2PO4, 2-methyl-2-
butene, t-BuOH, H2O, 70%; (e) BBr3, CH2Cl2, -78 °C; MeOH, HCl, rt,
71%.
with furan 4 via a second Mitsunobu reaction to deliver 3 in 72%
yield over two steps.
With the Diels-Alder precursor 3 in hand, the stage was set for
the pivotal domino benzyne-furan cycloaddition. Gratifyingly,
dropwise addition of n-BuLi (0.23 M, 3.0 equiv) to a solution of
tetrabromide 3 in Et2O at -20 °C afforded biscycloaddition product
2 in 85% yield as a mixture of diastereomers (Scheme 4). After
some experimentation, we discovered that the bonds between the
silicon atoms and the bridgehead carbon atoms in 2 were most
efficiently cleaved under modified Rickborn12 conditions using
KOH in DMF/H2O (10:1). Treatment of the crude mixture thus
obtained with hydrochloric acid resulted in the regioselective
opening4a-d of the two bicyclooxaheptene rings, and subsequent
air oxidation furnished the anthrarufin 19 in 34% overall yield
together with several unidentified products.
(5) See also: Hart, H.; Lai, C.-Y.; Nwokogu, G. C.; Shamouilian, S.
Tetrahedron 1987, 43, 5203.
(6) (a) Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610. (b) Boyd, V.
A.; Drake, B. E.; Sulikowski, G. A. J. Org. Chem. 1993, 58, 3191.
(7) Goldsmith, D.; Liotta, D.; Saindane, M.; Waykole, L.; Bowen, P.
Tetrahedron Lett. 1983, 24, 5835.
(8) Soderquist, J. A.; Brown, H. C. J. Org. Chem. 1980, 45, 3571.
(9) The enantiomer of 11 is known. See: Corey, E. J.; Guzman-Perez, A.;
Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805.
(10) For regioselective brominations, see: (a) Mitchell, R. H.; Lai, Y.-H.;
Williams, R. V. J. Org. Chem. 1979, 44, 4733. (b) Bock, I.; Bornowski,
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(11) Prepared in 35% yield by silylation of 1.25 equiv of 5 (Sigma-Aldrich)
with 1.0 equiv of TBSCl and imidazole in DMF.
Completion of the synthesis of vineomycinone B2 methyl ester
then required removal of the various protecting groups and
adjustment of the oxidation level of the aliphatic side chain. The
PMP group was thus cleaved under oxidative conditions with CAN
to give alcohol 20 in 74% yield. Subsequent oxidation of alcohol
(12) (a) The reaction using KOH in DMF/H2O (10:1) was more efficient than
in DMSO, but use of TBAF gave multiple unidentified products. (b) Netka,
J.; Crump, S. L.; Rickborn, B. J. Org. Chem. 1986, 51, 1189. (c)
Camenzind, R.; Rickborn, B. J. Org. Chem. 1986, 51, 1914.
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