Studies on the synthesis of aureolic acid antibiotics: Acyloin glycosidation studies

Full text of DOI:10.1021/jo960932e

6098
J . Org. Chem. 1996, 61, 6098-6099
diastereomeric â-anomers 5 was obtained in good (5c) to
excellent (5a , 5b ) yield, with R-anomers not being
detected. One of the diastereomers of 5b (R ) Br) was
smoothly elaborated to the 2,6-dideoxyglycoside 6 upon
treatment with RaNi in EtOH (75% yield).
Stu d ies on th e Syn th esis of Au r eolic Acid
An tibiotics: Acyloin Glycosid a tion Stu d ies
William R. Roush,* Karin Briner, Brenda S. Kesler,
Megan Murphy, and Darin J . Gustin
Department of Chemistry, Indiana University,
Bloomington, Indiana 47405
Received May 21, 1996
Several recent reports have detailed our progress
toward the total synthesis of olivomycin A, a representa-
tive member of the aureolic acid family of antitumor
antibiotics.1,2 We have developed highly stereoselective
syntheses of the aglycon, olivin,3 the A-B disaccharide,4
and the C-D-E trisaccharide.5 We have also demon-
strated that the Mitsunobu glycosidation protocol is
suitable for coupling of the A-B disaccharide to the C(6)-
phenol of advanced synthetic intermediates.4 We report
herein studies on the remaining problem, namely the
glycosidation of the aglycone C(2)-acyloin unit.
We next examined the glycosidation reactions of chro-
momycinone derivatives 712 and 8.13 In the event,
treatment of 7 with 1.8 equiv of imidate 3b in the
presence of TMSOTf at -10 to 0 °C provided a ca. 15:1
mixture of â- and R-glycosides in 44% yield, with the
desired â-anomer 9 predominating. The reaction of
chromomycinone diacetate derivative 8 with 3a in the
presence of BF3‚Et2O was similarly selective for the
â-anomer 10; however, the yield in this case was only
20%. The efficiency of these glycosidations is hampered
by steric hindrance of the 2-hydroxy group and by the
fact that especially 8 exists as a mixture with the
hemiketal isomer 11 (8:11 ) 50:50 in CD3CN; 75:25 in
CDCl3; 90:10 in toluene-d8 at 20 °C). We anticipate that
the efficiency of these glycosidations will be improved by
using aglycon derivatives with the side chain C(2′) ketone
masked as an alcohol derivative.
Several studies on the synthesis of 2-deoxyglycosides
of acyloins have been reported.6-9 Franck has demon-
strated that the electrophilic addition reactions of glycals
with the naphthylsulfenate ester of 2-hydroxytetralone,
or with 2-hydroxytetralone in the presence of arylbis-
(arylthio)sulfonium salts, provide the desired â-glycosides
with excellent selectivity.7,8 More recently, Ikegami has
shown that the reaction of 2-hydroxytetralone with
2-(arylthio)-R-D-glucosyl tetramethylphosphoramidates is
highly selective for the â-glycosidic product.9 Franck also
cites unpublished work from Thiem’s laboratory in which
a modified Koenigs-Knorr glycosidation of a 2-bromo-
2-deoxyglucose unit with the C(2) acyloin of an olivin
derivative provides the â-glycoside in 21% yield.10
We began by exploring the reactions of racemic 2-hy-
droxytetralone 4 with 2-(phenylthio)glucosyl imidates
3a -3c.5,11 In all three cases, a ca. 1:1 mixture of
(1) Remers, W. A.; Iyengar, B. S. In Cancer Chemotherapeutic
Agents; Foye, W. O., Ed.; American Chemical Society: Washington,
DC, 1995; p 578.
(2) Leading references to the work of Weinreb, Franck, Thiem,
Binkley, Crich, and Toshima, who have made important contributions
to the synthesis of the aureolic acid antibiotics, are provided in ref 4.
(3) Roush, W. R.; Murphy, M. J . Org. Chem. 1992, 57, 6622.
(4) Roush, W. R.; Lin, X.-F. J . Am. Chem. Soc. 1995, 117, 2236 and
references cited therein.
(5) Sebesta, D. P.; Roush, W. R. J . Org. Chem. 1992, 57, 4799.
(6) Thiem, J .; Gerken, M.; Snatzke, G. Liebigs Ann. Chem. 1983,
448.
Encouraged by these results, we initiated glycosidation
studies using the fully elaborated C-D-E-trisaccharide
imidate 13. Treatment of C-D-E glycal 1214 with PhSCl
(7) Ramesh, S.; Franck, R. W. J . Chem. Soc., Chem. Commun. 1989,
960.
(8) Grewal, G.; Kaila, N.; Franck, R. W. J . Org. Chem. 1992, 57,
2084.
(9) Hashimoto, S.; Yanagiya, Y.; Honda, T.; Ikegami, S. Chem. Lett.
1992, 1511.
(10) See footnote 4b in ref 7 and ref 7 in: Ramish, S.; Kaila, N.;
Grewal, G.; Franck, R. W. J . Org. Chem. 1990, 55, 5.
(11) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694.
(12) Miyamoto, M.; Morita, K.; Kawamatsu, Y.; Noguchi, S.; Maru-
moto, R.; Sasai, M.; Nohara, A.; Nakadaira, Y.; Lin, Y. Y.; Nakanishi,
K. Tetrahedron 1966, 22, 2761.
(13) Chromomycinone derivative 8 was synthesized by treatment
of chromomycinone acetonide12 with 2 equiv of AcCl and 2.2 equiv of
DBU in CH2Cl2.
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Communications
J . Org. Chem., Vol. 61, No. 18, 1996 6099
followed by hydrolysis of the anomeric chlorides (AgOTf,
tetramethylurea, THF, H2O) and activation of the result-
ing pyranose by treatment with excess NaH and Cl3CCN
(as solvent) provided imidate 13 in 63% overall yield.11
Treatment of racemic acyloin 1415 (2 equiv) with 13 (1
equiv) in CH2Cl2 at -78 to -60 °C in the presence of
TMS-OTf (0.2 equiv) and 4 Å molecular sieves then
provided â-glycoside 15 in 55-61% yield as a ca. 1.4:1
mixture of epimers at C(2) of the aglycon; R-glycosides
were not detected. The C(2) epimers were separated
chromatographically, and each was individually elabo-
rated to the respective epimers of 16 by sequential
chloroacetyl groups, NaI in DMF to displace the two
tosylate groups, and finally Ra-Ni in THF to reductively
remove the three iodo and the two phenylthio substitu-
ents. There was no evidence of epimerization of C(2)
during this sequence. The overall yield of 16 was 30-
35% from 15.
We have also demonstrated that glycosidation of
synthetic aglycon 17 with trisaccharide imidate 13 (1.8
equiv) at -5 °C provides 18 in 17% yield as a ca. 1:1
mixture of â and R anomers. Efforts to improve the
stereoselectivity and efficiency of this coupling are un-
derway.16
In summary, we have established that the reactions
of acyloins 4, 7, 8, and 14 and 2-(arylthio)-R-D-glucosyl
trichloroacetimidates 3 and 13 give â-glycosides with
excellent diastereoselectivity. The first glycosidation of
an aureolic acid aglycon with an intact C-D-E trisac-
charide has also been accomplished. Further progress
toward the completion of an olivomycin total synthesis
will be reported in due course.
Ack n ow led gm en t. This research was supported by
a grant from the NIH (GM 38907) and postdoctoral
fellowships from Merck Research Laboratories (B.S.K.)
and the Swiss National Science Foundation (K.B.). We
also thank Prof. K. Nakanishi for providing the natural
chromomycinone used in these studies.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds (58
pages).
treatment with 2 M NH3 in MeOH to remove the two
J O960932E
(14) Trisaccharide 12 with chloroacetate groups in the C and D
residues was synthesized by using appropriate modifications of our
published procedure (ref 5); details of the synthesis of 12 are provided
in the Supporting Information. Acetate protecting groups in the C and
D residues could not be removed selectively in the presence of the
isobutyrate in the E residue.
(16) Glycosidation (13, TMSOTf, -40 to -10 °C) of an analog of
aglycon 17 with the C(2′) carbonyl replaced by a 2′-(R)-OAc unit
provided a 1:1 mixture of R and â trisaccharide derivatives in 35%
yield. However, at -78 °C the â isomer was obtained with good
selectivity (ca. 10-15% yield). Glycosidation of 7 with 13 (BF3‚Et2O,
CH2Cl2, -5 to 23 °C, 4 Å sieves) gave the â-trisaccharide conjugate in
ca. 10% yield, while attempted glycosidations of 8 with 13 were
unsuccessful.
(15) Details of the synthesis of acyloin 14 are provided in the
supporting information.