New synthetic technology for the stereocontrolled construction of 1,1'-disaccharides and 1,1':1'',2-Trisaccharides. Synthesis of the FG ring system of everninomicin 13,384-1

Full text of DOI:10.1021/ja971574f

J. Am. Chem. Soc. 1997, 119, 9057-9058
9057
Scheme 1. Stereoselective Construction of 1,1′-Disaccharides
5 and 7a
New Synthetic Technology for the Stereocontrolled
Construction of 1,1′-Disaccharides and
1,1′:1′′,2-Trisaccharides. Synthesis of the FG Ring
System of Everninomicin 13,384-1
K. C. Nicolaou,* F. L. van Delft, S. R. Conley,
H. J. Mitchell, Z. Jin, and R. M. Rodr´ıguez
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed May 15, 1997
a Bn ) PhCH2; TMSOTf ) Me3SiOSO2CF3.
With its imposing molecular structure, everninomicin
13,384-1 (1, Figure 1) poses considerable challenge to the
synthetic chemist. Isolated1 from Micromonospora carbonacea
var. africana (collected from the banks of the Nyiro river in
Kenya), this antibiotic shows promising antibacterial properties
against drug-resistant pathogens (e.g., methicillin-resistant Sta-
phylococci and vancomycin-resistant Streptococci and Entero-
cocci)2 and, therefore, constitutes a unique opportunity for
discovery and invention in the areas of chemical synthesis,
biology, and medicine. Among its challenging features3 are the
1,1′-disaccharide bridge, linking carbohydrate units F and G
(see shaded area in Figure 1), its two orthoester frameworks,
and its nitro sugar moiety. In this Communication we report
new synthetic technology for the stereoselective construction
of 1,1′-disaccharides4 and 1,1′:1′′,2-trisaccharides, and its ap-
plication to the synthesis of the FG ring system (compound 2,
Scheme 3) of everninomicin 13,384-1 (1).
Scheme 2. Stereocontrolled Construction of
1,1′;1′′,2-Trisaccharide 9
the FG ring system of everninomicin 13,384-1 (see shaded area
in Figure 1 and compound 2, Scheme 3). Compounding the
challenge, one of the sugars is linked in a â-mannoside fashion.
To circumvent this problem, the C-2 hydroxyl group in 3 (R )
H) was utilized to fix the anomeric oxygen in the desired
â-configuration via a five-membered ring stannane5 (e.g.,
compound 6, Scheme 1). Subsequent reaction with trichloro-
acetimidate 4 in the presence of TMSOTf resulted in the
stereoselective formation of the 1â,1′R-disaccharide 7 (66%
yield) with no trace of 1R,1′R-linked stereoisomer. More
impressively, reaction of the corresponding glycosyl fluoride 8
(see Scheme 2 and Table 1) in excess (2.2 equiv) with stannane
6 led to trisaccharide 9 (84% yield), in which all three glycosidic
bonds were formed stereoselectively.6
The generality of these glycosidation reactions was explored
and selected results are shown in Table 1.7 It was found that
(a) both disaccharides and trisaccharides can be formed in
stereocontrolled fashion, (b) trichloroacetimidate donors lead
to good yields of disaccharides under the proper stoichiometry
(entries 1, 5, 9, 13, and 15), and (c) glycosyl fluorides used in
excess favor trisaccharide formation (entries 4, 8, 12, and 18).8
The application of the present technology to the stereocon-
trolled synthesis of FG ring system 2 of everninomicin
As expected4i,j,l-p, the reaction of carbohydrate acceptor 3
(R ) Bn, Scheme 1) with trichloroacetimidate donor 4 in the
presence of TMSOTf led to the disaccharide 5 (87% yield) with
the 1R,1′R-stereochemistry. This result calls attention to the
problem of simultaneously controlling the stereochemistry at
two anomeric centers while forming the glycosidic linkage of
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M. G.; Horan, A. C. In 19 pp. Cont.-in-part of U.S. Ser. No. 405,822 (1986);
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Tetrahedron 1979, 35, 1207-1237. (c) Ganguly, A. K. In Topics in
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(7) Coupling of tin acetal 6 with a variety of other donors and conditions
(e.g., thioglycosides/DMTST,6c glycophosphates/TMSOTf) was also inves-
tigated but gave inferior yields. Moreover, fully acetylated imidates and
fluorides were found to be inert under the applied reaction conditions.
(8) As expected, TMSOTf-induced coupling of imidate 4 with the tin
acetal derived from 3,4,6-tri-O-benzyl-D-glucopyranose afforded a mixture
of products consisting primarily of the corresponding 1R,1′R-disaccharide
and the 2-O-substituted disaccharide in ca. 1:2 ratio.
S0002-7863(97)01574-6 CCC: $14.00 © 1997 American Chemical Society

9058 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Communications to the Editor
Figure 1. Structure of everninomicin 13,384-1. Rings F and G are shaded.
Table 1. Synthesis of â-Linked 1,1′-Disaccharides and 1,1′;1′′,2-Trisaccharidesa
Scheme 3. Stereocontrolled Synthesis of FG Ring System 2
of anomeric configuration of the remaining substrates was found
in the chemical shift of the mannose H-5 proton, typically
appearing at δ ∼3.4 ppm for the â-linked glycoside.
of Everninomicin 13,384-1a
The described chemistry is expected to find application in
synthetic carbohydrate chemistry and facilitate a projected total
synthesis of everninomicin 13,384-1 (1) and its congeners.11
Acknowledgment. We thank Dr. Dee H. Huang and Dr. Gary
Siuzdak for NMR and mass spectroscopic assistance, respectively. This
work was financially supported by the National Institutes of Health
USA, The Skaggs Institute for Chemical Biology, fellowships from
the Netherlands Organization for Scientific Research (NWO) (to
F.L.v.D.), the National Science Foundation (to S.R.C.), and the National
Institutes of Health USA (to Z.J.), and grants from Schering Plough,
Amgen, Hoffmann LaRoche, Merck, DuPont Merck, and Pfizer.
a PMB ) p-MeO-C6H4CH2. Rings F and G are shaded.
13,384-1 (1) is shown in Scheme 3. Thus, conversion of the
F-carbohydrate unit 259 to its di-n-butylstannyl derivative 26
under standard conditions, followed by reaction with 0.7 equiv
of ring G trichloroacetimidate donor 279 in the presence of
TMSOTf, furnished the desired 1â,1′R-disacccharide 2 in 67%
yield as a single stereoisomer. The stereochemistry of the
glycosidic linkages of compounds 5, 7, 9, and 2 was assigned
on the basis of the anomeric 13C-1H spin-coupling constants,4m,10
measuring 174.1, 156.9, 151.2, and 159.1 Hz, respectively. Proof
Supporting Information Available: Procedures for the preparation
of the disaccharides and trisaccharides, schemes for the synthesis of
compounds 25 and 27, and a listing of selected data for compounds 2,
5, 7, 9, 11, 12, 13R, 13â, 15, 16, 18R, 18â, 19, 20, 23-25, 27, and 28
(21 pages). See any current masthead page for ordering and Internet
access instructions.
JA971574F
(10) Podlasek, C. A.; Wu, J.; Stripe, W. A.; Bondo, P. B.; Serianni, A.
S. J. Am. Chem. Soc. 1995, 117, 8635-8644.
(11) All new compounds exhibited satisfactory spectral and exact mass
data.
(9) For the preparation of this intermediate, see Supporting Information.