Total synthesis of olivomycin A [19]

Full text of DOI:10.1021/ja984229e

1990
J. Am. Chem. Soc. 1999, 121, 1990-1991
trisaccharides (e.g., 5) was poor (typically less than 15% yield
Total Synthesis of Olivomycin A
of the desired â-glycoside),15 we have developed an alternative
approach in which the C residue 6 is first coupled to the aglycon,
followed by sequential addition of the D-E disaccharide 7 and
the A-B disaccharide 4. The protected aglycon, 3, was synthesized
via modifications of our second generation olivin synthesis,12
specifically involving the use of crotyl ether protecting groups
for the C(6) and C(9) phenols and a cyclopentylidene ketal for
the side chain diol unit.16 The reducing A-B disaccharide 4 was
synthesized in two steps from the protected precursor 813 ((i) HF-
Et3N, CH3CN, 65 °C, 81%; (ii) NH2NH2, MeOH, 0 to 25 °C,
82%), while both 6 and 7 originated from glycal 9.17 The selection
of 9 as the precursor to the C and D monosaccharide units was
dictated by our observation that a polar substituent at C(6) is
required to maximize stereoselectivity of the electrophilic addition
of PhSCl to glucal derivatives,17 as well as the fact that 6-bromo-
glycosyl-1R-trichloroacetimidates18 have consistently given higher
â-selectivity in glycosylation reactions19,20 than the corresponding
6-tosyl-1R-trichloroacetimidates used in most of our earlier
studies.14,15 The use of C(2)-heteroatom substitutents (e.g., -Br,
-SAr, -SePh) to direct â-glycosidation reactions is a well-
established strategy for synthesis of 2-deoxy-â-glycosides.21-23
William R. Roush,*,1 Richard A. Hartz, and Darin J. Gustin
Department of Chemistry, UniVersity of Michigan
Ann Arbor, Michigan 48109
Department of Chemistry, Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed December 8, 1998
Olivomycin A (1) is a prominent member of the aureolic acid
family of antitumor antibiotics, a group of clinically active agents
that also includes mithramycin and chromomycin A3 (2).2-4 The
aureolic acids are known to bind in the minor groove of double
stranded DNA as 2:1 antibiotic:Mg2+ complexes, with selectivity
for GC rich sequences.5-8 Recently, the GC rich promoter regions
of the c-myc protooncogene and the dihydrofolate-reductase gene
have been identified as possible biological targets of mithramy-
cin.9,10 We report herein a highly stereoselective total synthesis
of olivomycin A, constituting the first chemical synthesis of any
member of the aureolic acid group.11
Our original plan called for olivomycin A to be assembled by
the late stage coupling of a protected version of the aglycon,
olivin,12 and activated forms of the A-B disaccharide13 and the
C-D-E trisaccharide units.14,15 However, because earlier studies
indicated that the efficiency of the glycosidation of protected
aureolic acid aglycons with several fully elaborated C-D-E
(1) Correspondence to this author should be sent to the University of
Michigan address. E-mail: roush@umich.edu.
(2) Remers, W. A. In The Chemistry of Antitumor Antibiotics; Wiley-
Interscience: New York, 1979; pp 133-175.
(3) Remers, W. A.; Iyengar, B. S. In Cancer Chemotherapeutic Agents;
Foye, W. O., Ed.; American Chemical Society: Washington, DC, 1995; p
578.
(4) For the isolation of the newest member of the aureolic antibiotic family,
see: Ogawa, H.; Yamashita, Y.; Katahira, R.; Chiba, S.; Iwasaki, T.; Ashizawa,
T.; Nakano, H. J. Antibiot. 1998, 51, 261.
(5) Gao, X.; Mirau, P.; Patel, D. J. J. Mol. Biol. 1992, 223, 259.
(6) Sastry, M.; Patel, D. J. Biochemistry 1993, 32, 6588.
(7) Van Dyke, M. W.; Dervan, P. B. Biochemistry 1983, 22, 2373.
(8) Liu, C.; Chen, F.-M. Biochemistry 1994, 33, 1419.
(9) Snyder, R. C.; Ray, R.; Blume, S.; Miller, D. M. Biochemistry 1991,
30, 4290.
Treatment of 917 with PhSCl in CH2Cl2 (0 to 23 °C) followed
by hydrolysis of the intermediate glycosyl chloride (Ag2CO3, THF,
H2O) provided the 2-thiophenyl pyranose in 81-96% yield, which
was converted to the trichloroacetimidate derivative 6 by exposure
to excess NaH in Cl3CCN (as solvent) at -40 to -20 °C (57-
66% yield following chromatographic purification).17,18 Desilyl-
ation of 9 with HF-pyridine in THF gave monosaccharide 10,18
which was coupled with the olivomycose derivative 11 (TMSOTf,
4 Å molecular sieves, CH2Cl2, -78 °C, 74% yield).24 The resulting
(10) Blume, S. W.; Snyder, R. C.; Ray, R.; Thomas, S.; Koller, C. A.;
Miller, D. M. J. Clin. InVest. 1991, 88, 1613.
(11) Franck, R. W.; Weinreb, S. M. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 173-
207. This article reviews synthetic efforts in this area through 1987, including
the work of Weinreb and Franck on the synthesis of trimethyl olivin, as well
as the substantial contributions of the Thiem group on the synthesis of the di-
and trisaccharide units of olivomycin A, chromomycin A3, and mithramycin.
References to the more recent syntheses of aureolic acid di- and trisaccharides
of Binkley, Franck, Thiem, Crich, and Toshima are provided in refs 12 and
14.
(16) A summary of our synthesis of 3 is provided in the Supporting
Information.
(17) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997, 53,
8825.
(18) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837.
(19) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(20) Thiem, J.; Klaffke, W. Top. Curr. Chem. 1990, 154, 285.
(21) Thiem, J.; Gerken, M. J. Org. Chem. 1985, 50, 954 and references
therein.
(12) Roush, W. R.; Murphy, M. J. Org. Chem. 1992, 57, 6622.
(13) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236.
(14) Sebesta, D. P.; Roush, W. R. J. Org. Chem. 1992, 57, 4799.
(15) Roush, W. R.; Briner, K.; Kesler, B. S.; Murphy, M.; Gustin, D. J. J.
Org. Chem. 1996, 61, 6098.
(22) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A.
J. Am. Chem. Soc. 1986, 108, 2466.
(23) Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75.
10.1021/ja984229e CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 9, 1999 1991
Scheme 1
E-D glycal was then converted into the activated E-D-trichloro-
acetimidate 7 by the now familiar three-step sequence described
for the conversion of 9 to 6 ((i) PhSCl, CH2Cl2, 0 to 25 °C; then
AgOTf, tetramethylurea, THF, H2O (80% yield); (ii) NaH, Cl3-
CCN, -40 to -20 °C, 47% yield).
unstable at temperatures above 60 °C, and consequently standard28
Bu3SnH-AIBN reductive removal of the halogen and seleno-
phenyl substituents gave mixtures of products. However, use of
triethylborane as the radical initiator permitted the Bu3SnH
reduction of the iodo-, bromo-, and selenophenyl substituents of
16 to be performed in toluene at 25 to 45 °C (84% yield).29 The
two thiophenyl substituents and the BOM group were then excised
by using freshly prepared RaNi30 in a mixture of THF and EtOH
with external sonication (57% yield). Finally, the three TES ethers
were removed by treatment with HF-pyridine at 0 °C, thereby
providing totally synthetic (-)-olivomycin A in 76% yield. The
synthetic material was identified by comparison to an authentic
sample of (-)-olivomycin A, and the two were found to be
identical according to 1H and 13C NMR, HPLC, UV, mass
spectroscopy, and TLC analysis in four different solvent systems.
In summary, the first total synthesis of olivomycin A has been
completed by a route featuring three highly stereoselective
â-glycosidation reactions. Applications of this methodology to
the synthesis of aureolic acid analogues will be reported in due
course.
Treatment of the protected aglycon 3 with 7 equiv of 6 (added
in two portions) and 0.3 equiv of TBS-OTf in 2:1 hexane-CH2-
Cl2 at -60 °C provided an 8:1 mixture of 12 and the correspond-
ing R-glycoside anomer in 58% yield (51% isolated yield of 12,
R ) crotyl, contaminated with ca. 10% of 12, R ) H). Because
difficulties were subsequently encountered during attempts to
remove the crotyl protecting groups in the presence of the iodo
substituent of the C-D-E trisaccharide, the crotyl groups of 12
were removed (Pd(PPh3)4, Bu3SnH, HOAc, 90%)25 and the C(6)
phenol reprotected as a chloroacetate (84%). The TES ether was
then removed (95%) from the C monosaccharide unit, thereby
providing 13 in 72% overall yield. The glycosylation of 13 with
the E-D-imidate 7 (3 equiv of 7, 0.3 equiv of TBS-OTf, 1:1
hexane-CH2Cl2, -35 °C) provided the trisaccharide derivative
14 in 78% yield following removal of the phenolic chloroacetate
by brief treatment with methanolic NH3. Intermediate 14 was then
coupled with the reducing A-B disaccharide 4 (1.5 equiv) by using
our previously described Mitsunobu glycosidation protocol,13
which provided the targeted pentasaccharide 15 in 73-79% yield.
The final sequence of functional group manipulations required
to complete the olivomycin synthesis was initiated by the acid-
catalyzed cleavage of the cyclopentylidene ketal. This provided
the requisite triol in 54% yield after HPLC purification, along
with 14% of recovered 15 which could be recycled.26 The triol
was then per-triethylsilylated (in order to improve the solubility
properties of subsequent intermediates, 95% yield) and the two
chloroacetate units were removed by treatment with NH3 in
MeOH. In this way, the advanced intermediate 16 was obtained
in 78% yield along with 9% of recovered mono-chloroacetate.27
After recycling of recovered materials, the yield of 16 was 46-
52%. Related advanced intermediates proved to be somewhat
Acknowledgment. This research was supported by a grant from the
NIH (GM 38907) and a postdoctoral fellowship from Merck Research
Laboratories (R.A.H.). We thank Prof. R. Franck of Hunter College and
Dr. V. B. Zbarsky, Russian Academy of Medical Sciences, Moscow, for
providing authentic samples of olivomycin A.
Supporting Information Available: Schemes for the synthesis of
3, 4, 6, and 7; experimental details for the synthesis of 12-16 and
synthetic olivomycin A; and 1H and 13C NMR spectra for selected
compounds (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA984229E
(27) The isobutyrate ester is also sensitive to cleavage by NH3 in MeOH.
If this reaction was allowed to proceed until both chloroacetates were
completely removed, some cleavage of the isobutyrate ester on the E-sugar
was observed.
(28) Neumann, W. P. Synthesis 1987, 665.
(24) Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993, 264.
(25) Guibe, F. Tetrahedron 1998, 54, 2967.
(26) If the ketal hydrolysis was allowed to proceed to completion, product-
(s) resulting from glycoside hydrolysis were also produced.
(29) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. Jpn. 1989, 63, 143.
(30) Mozingo, R. Organic Syntheses; Wiley: New York, 1955; Collect.
Vol. III, p 181.