Organic Letters
Letter
reaction and the Pummerer-type thioglycosylation and
describe the properties of 4′-thioLNA/BNA.
A diol group of 16 was protected by bis(tert-butyl)silylene to
give 17, oxidation of which by mCPBA gave a sulfoxide 18 in
good yield. As the synthesis of the sugar portion was finished,
the sulfoxide 18 was subjected to the Pummerer-type
To synthesize 4′-thioLNA/BNA monomer 11, synthesis of
4
′-hydroxymethyl-4′-thionucleoside or the corresponding 4-
17−20
thioribose derivative was necessary, followed by the strategy of
LNA/BNA synthesis, in which the aldol reaction of 5-aldehyde
derivative with formaldehyde is typically used.
thioglycosylation developed by us,
giving a mixture of
anomers, 19a,b (β/α = 1.8:1), in 70% yield. The decreased
formation of β-anomer 19a, compared with our previous
11−13
In the case
1
5,16
of 4′-thionucleoside, Haraguchi and his co-workers reported
results on 4′-thioribonucleosides,
strongly suggested that
the synthesis of various 4′-substituted 2′-deoxy-4′-thionucleo-
the shielding of the α-side by the 2,3-isopropilidene group was
insufficient. In the case of 4′-thioribonucleosides, switching
2,3-isopropylidene to a 3-pentylidene group improved the β-
14
sides using the aldol reaction. On the other hand, we
reported the synthesis of 4′-thioribonucleoside by using a
tandem ring-contraction-reduction reaction of 5-thiopyrano-
2
1
selectivity of the Pummerer-type thioglycosylation as
15,16
side 12, which gave a 4-thioribose.
In this reaction, a 5-
following the Ichikawa’s report regarding glycosylation of
22
aldehyde derivative 13 should be formed after the first ring
ribosyl fluoride derivatives.
contraction step, as shown in Scheme 1. Considering these
Thus, we repeated the synthesis of the thioglycosylation
substrate from a 3-pentylidene derivative 20, as shown in
Scheme 2. All the steps including the tandem ring-contraction-
Using the Tandem Ring-Contraction-Aldol Reaction
Scheme 2. Pummerer-Type Thioglycosylation of 18 and 23
results, we intended to synthesize 4-hydroxymethyl-4-thio-
ribose by developing a tandem ring-contraction-aldol reaction
based on the above-described reaction. If we used an
appropriate base catalyst, instead of NaBH , in the presence
4
of formaldehyde, the ring contraction of 5-thiopyranoside 12
would give the 5-aldehyde 13, which would react with
formaldehyde to give an aldol product 15 in a one pot
reaction. After reducing the aldehyde, the desired 4-
hydroxymethyl-4-thioribose 16 was formed. Thus, we first
studied the tandem reaction of 12 converting to 16 (Scheme
1
).
As we expected, mesylation of 12 followed by treatment with
formaldehyde in the presence of K CO gave a mixture of the
aldol reaction resulted in the formation of products with good
chemical yields and gave a sulfoxide derivative 23 bearing a 3-
pentylidene group at the 2,3-positions. The Pummerer-type
thioglycosylation of 23 afforded the desired 4′-thiouridine
derivatives 24a and 24b in 78% yield with improved β-
selectivity (β/α = 4.2:1) as expected. Also, the same reaction of
23 with silylated thymine gave a similar result (66% yield, β/α
= 6.2:1).
2
3
products including 15, which were reduced by NaBH to give
1
4
6. However, the reaction lacked reproducibility, prompting us
Information). The reaction using less than 1 equiv of K CO
hydride reduction (entry 1, Table S1 in the Supporting
Information). Under the semioptimized conditions (1.5 equiv
2
3
The resulting 4′-thionucleoside derivatives 24a and 25a,
after separation from their α-anomers by column chromatog-
raphy, were desilylated by treating with NH F·HF in DMF to
2
3
4
improved the chemical yield of 16 (entries 6−9, Table S1 in
the Supporting Information). Finally, 1.5 equiv of MsCl and 8
equiv of formaldehyde in the presence of 3 equiv of K CO in
give 26 and 27. Finally, the synthesis of 4′-hydroxymethyl-4′-
thionucleosides was achieved by treatment of 26 and 27 with
aqueous TFA, giving the desired uridine and ribosylthymine
derivatives 28 and 29 in good yields, respectively (Scheme 3).
Next, we intended to synthesize the 4′-thioLNA/BNA
monomer starting from 26, which we had in hand. By
following the method for synthesizing LNA/BNA nucleo-
2
3
THF over 72 h were determined to be the optimized
conditions for the tandem ring-contraction-aldol reaction.
Under these conditions, the reaction of 12 gave 16 in 75%
yield in three steps. It is noteworthy that the reaction could be
handled even in multigram-scale synthesis, giving the desired
for this reaction is also shown in Scheme S1 (see the
Supporting Information).
11−13
sides,
we attempted to synthesize a selectively protected
compound at the 5″-hydroxyl group of 26. However, the
introduction of the tosyl and benzyl groups failed (data not
shown). Only the benzoyl group could be selectively installed
4
063
Org. Lett. 2021, 23, 4062−4066
Maeda, Rion
