6124
J. Am. Chem. Soc. 2000, 122, 6124-6125
interested in developing a synthesis of landomycin A to probe
the structure-function relationships of the structurally novel hexa-
saccharide. Sulikowski has reported a pioneering synthesis of the
landomycin A hexasaccharide by a route featuring his glycosyl
tetrazole and glycosyl phosphite glycosidation methodology.14
More recently, Kirschning outlined a synthesis of the landomycin
A-B-C repeat trisaccharide that features use of a 2-deoxy-2-
iodo-glucosyl acetate donor for construction of the A-B glyco-
sidic linkage.15,16 We report herein a highly stereoselective synthe-
sis of hexasaccharide glycal 1 using our recently introduced 2-
deoxy-2-iodo-glucopyranosyl trichloroacetimidate glycosidation
technology.17,18 Each of the three 2-deoxy-â-glycosidic linkages
in 1 was established with g95% selectivity using this technology.
This is the most highly stereoselective synthesis of a structurally
complex deoxyoligosaccharide containing 2,6-dideoxy-â-glyco-
sidic linkages reported to date.
A Highly Stereoselective Synthesis of the
Landomycin A Hexasaccharide Unit
William R. Roush* and Chad E. Bennett
Department of Chemistry, UniVersity of Michigan
Ann Arbor, Michigan 48109
ReceiVed March 1, 2000
Landomycin A1 is a member of the angucycline antibiotic fam-
ily that exhibits a range of biological activities.2,3 Landomycin A
in particular has been studied as a potential antitumor agent.1,4,5
Although the mode of action of landomycin A has not been estab-
lished unequivocally, it is known that the natural product interacts
with DNA,5 and inhibits DNA synthesis and G1/S cell cycle
progression.6 It is also known that the cytostatic activities of other
members of the landomycin family (e.g., landomycins A-E)
depend on the length of the oligosaccharide chain.4
In planning the synthesis of 1, we focused on the coupling of
two advanced trisaccharide intermediates (ultimately, 8 and 9)
that could be derived from a common precursor such as 2. An-
ticipating that our Mitsunobu glycosidation protocol will be useful
for connecting the hexasaccharide to the phenolic aglycon,19 we
targeted 12 as a key intermediate. On the basis of our previous
studies of the stereochemistry of PhSeCl additions to glycals (a
step required to activate 12 for Mitsunobu coupling with the ag-
lycon),20 it was necessary to retain C(6)-heteroatom substituents
on the A residue of 12, and hence also the repeat trisaccharide
precursor 2. In turn, intermediate 2 would be assembled from
the conformationally inverted 2-iodo-1,6-anhydroglucose deriva-
tive 318 (precursor to the A and A′ residues), 2-iodoglycosyl tri-
chloroacetimidate 418 (precursor to the B and B′ residues), and
the L-rhodinosyl acetate 521 (precursor to the C and C′ residues).
Intermediates 3 and 4 also derive from a common precursor, and
the C(6)-acetoxy substituents of 2 are an artifact of this lineage.
Concerns about the acid lability of the B-C and B′-C′ R-glyco-
sidic linkages involving the L-rhodinose residue dictated that we
use our 2-deoxy-2-iodo-glycosyl trichloroacetimidate glycosida-
tion protocol for the late stage coupling of 8 and 9.22 Fur-
thermore, we considered it prudent to defer the deoxygenation
of the C(6) positions of 2 (and hence also of 8 and 9) until after
the hexasaccharide was fully assembled, since past experience
(10) Gao, X.; Mirau, P.; Patel, D. J. J. Mol. Biol. 1992, 223, 259.
(11) Sastry, M.; Patel, D. J. Biochemistry 1993, 32, 6588.
(12) Kahne, D.; Silva, D.; Walker, S. DNA-Binding Glycoconjugates;
Kahne, D., Silva, D., Walker, S., Eds.; Oxford University Press: New York,
1999, p 174.
The landomycin A hexasaccharide is a structurally complex
deoxyoligosaccharide7 containing four 2,6-dideoxy-â-glycosidic
linkages and two 2,3,6-trideoxy-R-glycosidic linkages. This hexa-
saccharide exists as a head-to-tail dimer of a repeating A-B-C
trisaccharide subunit. In view of the role played in DNA binding
by the oligosaccharide units of several families of natural products,
including the aureolic acids and the calicheamicins,8-13 we became
(13) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30,
1387.
(14) Guo, Y.; Sulikowski, G. A. J. Am. Chem. Soc. 1998, 120, 1392.
(15) Kirschning, A. Eur. J. Org. Chem. 1998, 2267.
(16) The Kirschning trisaccharide synthesis appeared while our work was
in progress. We have also explored the use of 2-deoxy-2-iodo-glycosyl acetate
donors in a first generation synthesis of the A-B-C trisaccharide, but have
found it advantageous to use the 2-deoxy-2-iodo-glycosyl imidate technology
described herein, in view of the much greater reactivity of these donors. A
discussion of our first generation synthesis of the A-B-C trisaccharide will
be deferred to a full paper on the synthesis of 1.
(1) Weber, S.; Zolke, C.; Rohr, J.; Beale, J. M. J. Org. Chem. 1994, 59,
4211.
(2) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103.
(3) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127.
(4) Rohr, J.; Wohlert, S.-E.; Oelkers, C.; Kirschning, A.; Ries, M. Chem.
Commun. 1997, 973.
(5) Depenbrock, H.; Bornschlegl, S.; Peter, R.; Rohr, J.; Schmid, P.;
Schweighart, P.; Block, T.; Rastetter, J.; Hanauske, A.-R. Ann. Hematol. 1996,
73, A80.
(6) Crow, R. T.; Rosenbaum, B.; Smith, R., III; Guo, Y.; Ramos, K. S.;
Sulikowski, G. A. Bioorg. Med. Chem. Lett. 1999, 9, 1663.
(7) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr. Chem. 1997,
188, 1.
(8) Remers, W. A.; Iyengar, B. S. Mithramycin and Other Aureolic Acids;
Remers, W. A., Iyengar, B. S., Ed.; American Chemical Society: Washington,
DC, 1995; p 578.
(9) Skarbek, J. D.; Speedie, M. K. Antitumor Antibiotics of the Aureolic
Acid Group: Chromomycin A3, Mithramycin A and OliVomycin A; Skarbek,
J. D., Speedie, M. K., Eds.; CRC Press: Boca Raton, FL, 1981; Vol. 1, pp
191-235.
(17) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(18) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891.
(19) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236.
(20) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997, 53,
8825.
(21) Our synthesis of L-rhodinose derivative 7 and studies of its glycosi-
dation reactions will be reported elsewhere.
(22) The 6-acetyl-2-deoxy-2-iodo-glycosyl trichloroacetimidates undergo
glycosidation reactions at -78 °C under silyl triflate catalysis, while the
corresponding 6-acetyl-2-deoxy-2-iodo-glycosyl acetates require reaction
temperatures around 0 °C. For example, glycosyl imidate 8 reacted with
p-methoxybenzyl alcohol at -78 °C to provide the corresponding â-p-
methoxybenzyl trisaccharide in 79% yield. However, when attempts were made
to couple 2-deoxy-2-iodo-glycosyl acetate 2 with p-methoxybenzyl alcohol
and TBSOTf at 0 °C, the B-C R-glycosidic linkage to the L-rhodinose unit
was cleaved cleanly to afford glycosyl acetate 7 in 99% yield along with
p-methoxybenzyl R-rhodinoside in near quantitative yield.
10.1021/ja000743k CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000