Threonine derivative 610 and benzyl imidate 711 (Scheme
1) were coupled following the procedure described by
Matsuda et al.9a for the total synthesis of pederin. Crude 8
was then reduced with NaBH4 in EtOH, affording benzyl
carbinolamide 9 in 36% overall yield from 6 + 7.12
Hydrogenation over palladium hydroxide in EtOH afforded
carbinolamide 10 as a syrup in quantitative yield. It was not
possible to carry out both reductive processes in a single
step under any condition tested.
The bromosugar (15) required for glycosylation of carbino-
lamide 10 was prepared starting from L-rhamnose, which
was converted to oxime 12 in four steps.13 Treatment of 12
with LiA1H4 in dry ether effected reduction to the amine
with excellent control of stereochemistry; this intermediate
was converted directly to trichloroethylcarbamate 13 (color-
less crystals, mp 87-89 °C, 84% overall yield from 12).
Removal of the acetonide was realized by treatment with
Dowex 50W-X8 resin; following acetylation, methyl taloside
14 was isolated in 99% overall yield (colorless crystals from
hexane, mp 85-87 °C). Methyl taloside 14 was converted
to the respective acetoxy sugar by treatment with AcOH and
Ac2O in the presence of catalytic amounts of H2SO4;16
bromination was then effected in 51% yield by treatment
(7) Although the structures of tallysomycins A (1) and B (2) have been
established,1b,d only limited data is available concerning the absolute
stereochemistry at the 25 asymmetric centers common to all tallysomycins.
Given the published work on the talose moiety1d and the probability that
the 18 asymmetric centers that bleomycin A2 (4) and tallysomycin S2B (3)
share in common have the same absolute configurations, only the two (non-
carbohydrate) asymmetric centers unique to tallysomycin lack tentative
assignments. Aside from possible stereochemical differences, tallysomycin
S2B differs from bleomycin A2 in two ways, namely, the absence of a methyl
group in the valerate moiety and the presence of two hydroxyl groups of
undefined stereochemistry within the aminoethylbithiazole moiety, one of
which is conjugated to a talose sugar as part of a glycosylcarbinolamide.
(8) Katritzky, A. R.; Fan, W. Q.; Black, M.; Pernak, J. J. Org. Chem.
1992, 57, 547.
Figure 1. Structures of tallysomycins (1-3), bleomycin A2 (4),
and key synthetic tallysomycin intermediate 5.
(9) (a) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T.
Tetrahedron 1988, 44, 7063. (b) Hong, C. Y.; Kishi, Y. J. Org. Chem.
1990, 55, 4242. (c) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113,
9693. (d) Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J. Org. Chem. 1997,
62, 474 and references therein.
(10) (S)-Threonine was N-protected by treatment with a basic, aqueous
solution of methyl chloroformate (Seebach, D.; Charczuk, R.; Gerber, C.;
Renaud, P.; Berner, H.; Schneider, H. HelV. Chim. Acta 1989, 72, 401),
followed by silylation in an overall yield of 41%.
(11) (R)-2,2-Dimethyl-1,3-dioxolane-4-carboxamide (Iwadare, K. Bull.
Chem. Soc. Jpn. 1939, 14, 131) was converted to benzyl imidate 7 essentially
quantitatively by treatment with benzyl iodide-silver oxide (Pougny, J.-
R.; Sinay¨, P. Tetrahedron Lett. 1976, 4073). The product contained ∼15%
of the N-benzylamide and was used in the next step without further
purification.
(12) Carbinolamide 9 was isolated as colorless crystals after SiO2 column
chromatography and crystallization from hexane. 1H NMR indicated that a
single isomer, presently of unknown absolute configuration at the newly
formed stereocenter, had been separated from the mixture of isomers formed
during the reduction.
(13) Following conversion to methyl rhamnoside (Binkley, R. W.;
Goewey, G. S.; Johnston, J. C. J. Org. Chem. 1984, 49, 992) and
introduction of the isopropylidene group (Bebault, G. M.; Dutton, G. S.
Can. J. Chem. 1972, 50, 3373), the 4-OH group was oxidized with RuO2
and KIO4.14,15 Treatment with hydroxylamine hydrochloride then afforded
12 as colorless crystals in 50% overall yield from rhamnose.
(14) (a) Lawton, B. T.; Szarek, W. A.; Jones, J. K. N. Carbohydr. Res.
1969, 10, 456. (b) Aspinall, G. O.; Takeo, K. Carbohydr. Res. 1983, 121,
61.
bleomycins in DNA interaction,4 toxicities,5,6 and antitumor
activities,5 we have embarked on a program to effect the
total synthesis of tallysomycin S2B (3), as well as structural
congeners useful for mechanistic analysis.
Structurally, the tallysomycins are quite similar to the
bleomycins. They differ primarily in that tallysomycin
contains a talose sugar as part of a glycosylcarbinolamide.7
While there are published examples of the synthesis of alkyl
carbinolamides,8 including the natural products pederin,
onnamide A, and mycalamides A and B,9 no glycosyl-
carbinolamide has been reported as a synthetic product to
date. Presently, we describe the synthesis of one isomer of
the threonylbithiazole moiety of tallysomycin (5), which
includes the structurally unique glycosylcarbinolamide moi-
ety.
(4) (a) Strong, J. E.; Crooke, S. T. In Bleomycin: Chemical, Biochemical
and Biological Aspects; Hecht, S. M., Ed.; Springer-Verlag: New York,
1979; pp 244-254. (b) Mirabelli, C. K.; Huang, C.-H.; Crooke, S. T.
Biochemistry 1983, 22, 300.
(5) Miyaki, T.; Numata, K.-I.; Nishiyama, Y.; Tempo, O.; Hatori, M.;
Imanishi, H.; Konishi, M.; Kawaguchi, H. J. Antibiot. 1981, 34, 665.
(6) Ginsburg, E.; Gram, T. E.; Trush, M. A. Cancer Chemother.
Pharmacol. 1984, 12, 111.
(15) Gunner, S. W.; Overend, W. G.; Williams, N. R. Carbohydr. Res.
1967, 4, 498.
(16) Baker, B. R.; Joseph, J. P.; Schaub, R. E. J. Am. Chem. Soc. 1955,
77, 5905.
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Org. Lett., Vol. 3, No. 18, 2001