Scheme 1
Figure 1. The minimum-energy conformations of thymidine (A),
B, and C.
considerable interest. The torsion angles for the homo dimers
of A-C are compiled in Table 1. Herein, we report the first
dride and pyridine. Failure to execute this protocol leads
instead to tight complexation of the aluminum ion to the
triad of hydroxyl groups. For formation of the spirocyclic
nucleoside analogues, we chose to involve the Lewis acid-
induced coupling of 3 to persilylated thymine7 as in the syn
series.5 The three chromatographically separated products
generated in this reaction were produced in relative yields
that varied widely as a function of the quality of the
trimethylsilyl triflate. The greater the level of adventitious
triflic acid that develops upon prolonged storage of this
reagent (through hydrolysis and degradation), the more
elevated are the proportions of 5 and especially 6. The finding
that the structurally unusual 6 could be made predominant
provided support for the conclusion that oxonium ion D can
indeed be generated transitorily. Irreversible capture of the
activated nucleoside base subsequently materializes.
Table 1. Relevant Torsional Angles for [Thymidine]2, B2, and
C2 (Values in Degrees)
angle
A2
B2
C2
R
â
γ
δ
ꢀ
-63.1
178.4
58.2
126.2
175.3
-85.9
-57.4
116.6
45.6
144.4
-171.3
-37.4
124.7
-89.7
152.7
76.3
-97.0
-88.0
ú
successful access to nucleosides of type B and thereby extend
the range of candidates amenable to further scrutiny. Unlike
the syn series where the MOM protecting group was well
tolerated,5 this substituent proved to be more problematic
when dealing with the somewhat more elevated steric
congestion resident in the anti diastereomers.
Our primary interest was the possible inhibitory steric
effect induced by the protected 5′-hydroxyl on proper
formation of the nucleosidic bond. Initially, attention was
paid to 1, a spirobutenolide building block available in
racemic and enantiopure forms.6 Although the efficiency of
the dihydroxylation of 1 proved to be somewhat variable,
this transformation provided a reliable means for establishing
the C2′-C3′ configurational pattern defined in 2 (Scheme
1). The success of the ensuing reductive acetylation with
generation of 3 rests significantly on a direct quench of the
reaction of the Dibal-H reaction mixture with acetic anhy-
The mode of reaction observed for 3 is not limited to this
specific spirocyclic pseudosugar but appears to be general
for the â-oriented MOM series. Another representative
example, displayed in Scheme 2, consists of the reaction of
lactone 7 with bis(trimethylsilyl)adenine (8)8 in the presence
of trimethylsilyl triflate under otherwise comparable condi-
tions. In this manner, ready access was gained to 9. To our
(5) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L. Org.
Lett. 2001, 3, 4039.
(6) Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K.; Kahane,
A. L.; Lanter, J. C.; Corral, M. A. J. Org. Chem. 2001, 66, 2828.
(7) Vorbru¨ggen, H.; Bennua, B. Chem. Ber. 1981, 114, 1279.
(8) Nishimura, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 352.
4044
Org. Lett., Vol. 3, No. 25, 2001