Ring contraction reactions of 2-O-methanesulfonates of α-hydroxy-γ-lactones in aqueous medium to oxetane-2-carboxylic acids: A convenient synthesis of 3'-O-methyloxyetanocin and a formal synthesis of oxetanocin

Article abstract of DOI:10.1016/0040-4039(93)88027-G

Barton decarboxylative rearrangement of thiohydroxamic ester 17 directly provided the key oxetanosylthiopyridyl glycosides 18 which were successfully coupled to N-benzoyladenine. A two-step ring contraction of the tosylate 7 to the oxetane-2-carboxamide 2

Full text of DOI:10.1016/0040-4039(93)88027-G

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RING CONTRACTION REACTIONS OF
AQUEOUS MEDIUM TO
OF
IN
ACIDS: A CONVENIENT SYNTHESIS OF
AND A FORMAL SYNTHESIS OF
K. Saksena,’
K. Ganguly. Viyyoor M. Girijavallabhan. Russell E. Pike, Yao-Tsung Chen and Mohindar S. Puar
Scherfng-Plough Research Institute, 60 Orange Street, Bloomfieid, N.J. 07003, U.S.A.
Barton decarboxylative
of thiohydroxamic ester 17 directly provided the key
glycosides
which were successfully coupled to N-benzoyladenine. A two-step ring contraction of the
tosylate 7 to the oxetane-2carboxamide 23 is described. Attempted ring contraction of the triflate 24 gave the
unexpected products 25 and 26. A ring expansion reaction (e.g.
21a) was also observed.
Oxetanocin 1 the first natural oxetanosyl-N-glycosie and its analogs show promising antiviral activities against HSV,
humancytomegalovirus and
versatile approach, the
anhydrous
A number of elegant syntheses of 1 and other analogs have been
In a
3 were ring contracted to oxetane-2-carboxylic esters 4 in the presence of
After hydrolysis the resulting acids 4a were then subjected to Barton decaboxylative
Thus, in a “low yield” synthesis of 1 (Ad adenine), the
to provide unstable chlorooxetanes 5.
chlorooxetane 5a was converted to protected 1 and its a-anomer. For the success of the transformations 3
anhydrous conditions were found to be essential. It was also shown that under these conditions, the corresponding
4,
0-mesylates provided virtually no oxetanes.
We now show that especially under aqueous hydrolytic conditions, ring
contraction of such
is an efficient process culminating in an opportune synthesis of 2 and its anomer
OR
3
mostly
Y = Subs.
heteroatoms etc.]
X
H, Y
The
substrates 6 11 and 24 were readily prepared from diacetone glucose according to published
In initial experiments, when the mesylate 6 and the tosylate 7 were treated with anhydrous in
methanol over 24-36 hours, the oxetane-2-methylesters 12b were isolated in -30% and 10% yields respectively
(anomer the unchanged lactones being the major components in these This suggested that
the poor leaving group ability of 0-mesylate and tosylate imposed an element of reversibility causing the intermediate
oxy-anion to relactonize. In contrast, we found that treatment of the mesylates 6 and 8 11 in methanol with aqueous
sodium hydroxide readily provided the
acids
(72%). 148 (56%) 158 (48%)
for
These oxetane-2-carboxylic acids were fully characterized as their methyl
and (35%). The predominant isomers in these reactions were derived from inversion of configuration at C-2
-14a and
esters 12b 16b.
for
and 16a).
Y
MS
Ts
MS
Y
Y
OR
H
H
= Me
MS
M
[M
S
Ts =
S
H
7721

7722
3’
B n
dil. HCI
R.T.
(X H)
(X = Me)
Me-p
H
banzylamine
(major isomer)
R.T.

7723
The
photolytic decarboxylatlve rearrangement
(4 in DMF, in the presence of bromine (4 equiv.) and 4A molecular
protected nucleoslde (anomeric) mixture 19 in -60% yield. Removal of the group
was converted in a one-pot sequence to the
ester 17 which was subjected to
to provide thiipyrldyl glycosides
in 30% Coupling of
led to
provided
6.96 H
yield) to provide
This also constitutes a formal
has been previously converted to
prolonged storage or in contact added acids undergo
Such furanosyl-C-glycosides could also be detected
easily
anomers
m.p.
5.9 Hz) and
m.p.
d,
Z)
in over 90% yield
Both isomers were debenzylated (Pd black,
methyl oxetanosin 2,
synthesis of oxetanocin 1 since the
We found that
[ a
and
methyicarboxylate
l’-epimer 2a.
13b
acids 12a
on
-30%
contraction reactions described
a
expansion reaction (e.g.
Immediately after some of the
oxetanocin diesters have been observed during transglycosidation
Ring expansion reactions of N-benzoyl
Formation of 218 appears to be a
above.
unusual example of a ring expansion reaction accompanying debenzylation. We have not studied these
reactions in the presence of other protecting groups.
contraction
In a two-step variant of the above
contraction reactions, the tosylate 7 upon treatment
benzylamine in THF at
room tempsrature cleanly gave the acyclic benzylamide 22. Treatment of 22 with
in THF at room temperature
(-2.5 hrs.) led to
23 in overall 90% yield from 7 (anomer ratio
minor isomer).
5.04, d,
6.6 Hz,
major isomer; 4.64,
6.0 Hz,
Reaction of the more reactive triflate 24 with benzylamine as above gave exclusively the a-aminobenzyl-y-lactone 25
Also, attempted ring contraction of 24 with in anhydrous
dii not provide 12b but only the orthoesters (-60% yield). In view of ample precedents for ring
rather than 23 the ring contraction
product.
contraction of closely related triflates, these anamolous results are inexplicable at this time.
Perhaps an ‘aziridine-aminal’ species such as [I] might be involved in the formation of 25 although direct nucleophilic
displacement of the triflate group by benzylamine is a more plausible explaination. We propose an ‘epoxy-acetal’
species [III] as a possible intermediate in the formation of
The tetrahedral intermediate [I I) may act as a
common species for the well documented ring contraction reactions,”
as well as
via I I). To the best of our
knowledge, formation of
We are currently evaluating the scope and limitations of the above ring contraction reactions as well as the unusual
transformations, 218 and 24
from 24 is a novel orlhoester forming reaction under basic
Acknowledgements: We thank Sir Derek Barton. FRS, for stimulating discussions. We would also like to thank Dr. B.
Pramanik and Mr. P. Banner for hllh resolution mass spectral data.
References and Notes:
I.
2.
3.
H. Nakamura. S. Hasegawa, N.
H. Hoshino. N. N.
T. Takita and Y. litaka,
T. Takita and T. Takeuchi, Ant&t..
1966,
1077.
4713; S. Nishiyama, S. Yamamura. K. Kato and T.
S.
Y. Ichlkawa, K. Kato and T. Takita,
Takita,
4739 and 4743.
4. D. W.
and J. B. Kramer, J. Am. Chem.
7217.
5. R. Humbalek and G. Just, Tetrahedron
1990.
Peach, K.
Y. Wang, D. R. Wiiy, S. Choi, R. Storer, P. L. Meyers and C. J.
5 were so unstable that it was found necessary to first convert them to thiophenyl glywsides
N- benzoyladenine just before
used here were stable to chromatography and to storage at under argon for several months.
5445.
6. (a) G. N. Austin, G. W. J. Fleet, J.
and Jon C. Son, Tetrahedron
4741; (b) F. X. Wilson,
ibid., 6931.
G. W. J. Fleet, K.
These
for
The
7.
purification; they were then regenerated back to chlorooxetanes for coupling
thiopyridylglycosides

8.
R.
H.
K. J. Ryan, D. W. Henry, C. E. Cass and G. A.
and
J.
Chem.,
When necessary
NMR
9. Ail new compounds were characterized by hiih resolution mass
2D
6:
and
COSY NMR
refer to isolated products and have not been
82.95 (m, 3.25 (s, 3.35
7.4 (m. 5H).
3 8.5
treated with aq. 1 N
with 1 N HCI (3.5 equiv.). Evaporation of the solvents
were obtained. Elemental analyses were obtained for crystalline
Selective spectral data given here.
NMR
3.55 (m,
3.75 (dd, J 10.8, 2.2 H Z.
ratio,
4.55
12.1 HZ,
broad,
84.9
NMR
3 6.0 HZ,
solution of
cooled (ii bath) and
extraction of the residue with
5.14 (d,
11.
procedure: A 10%
the reaction mixture
(3.5 equiv.) at R.T. After
hrs.
at
provided the crude
which was
isomers
on silica gel;
12 25% acetone in n-hexane followed by 25% methanol in
be separated in this manner
aitho h mixtures were used for Barton
12.
13.
H
83.3 (m,
4.87 m,
4.65
constants in oxetanes, see: A.
formation Of minor retention products, the available evidence
at latter stage. More detailed studies would be
3.38 (s,
4.9 (d.
J 12
3.5 (dd, J ll.5, 1.5
3.58 (m,
3.8 (dd, J 11.5, 2.6 H Z,
4.7
3.5
J 12 Hz.
3.7 (m,
6.6 Hz,
4.93
mlnor
7.4 (m, 5H); 3.3 (s,
3.4 (m,
5.1 (d, J2.3 9 Hz.
major
7.4 (m, 5H).
For
C.
P.
and F. Macchia, J. Org.
rules out interconversion of
473.
esters
nor
IO fully understand these results.
15.
16.
D. H. R. Barton, D. Crich and W.
D. Crich and T. J.
3901;
and
to warm I
J.
1988.1461; and cited references.
procedure by of
After 5 minutes activation period a solution of
ester 17 was prepared
mixed
in dry THF at -20
N-methyl morpholine to a 10% solution oi
in dry THF was added.
stirring for -30 minutes, the reaction was
O
Work-up by
isolation with
in n-hexane) to provide pure
temperature and irradiated
the crude product,
150 watts tungsten lamp for -60 minutes.
was
on silica gel (eluent: 25%
Some of the less polar fractions also contained the
ester of the acid
(-25%).
and
in 30% combined
NMR
63.2
3.4 (s,
7.66
3.6 (dd,
8.45 (m.
3.75 (d, broad, 2H). 4.65 (m. 3H). 4.85 (m, 6.86
6.6 HZ.
minor
3.38 (s,
3.6-3.8 (m. 4H). 4.65 (m,
4.85 (m,
6.88 (d.
S. Hanessbn, K.
2
7.4 Hr.
Isomer), 7.0-7.6 (m.
J. Liak, N. Oanh and
8.45 (m,
Chsm.
18.
1984,
6114; We cordially thank Professor
for
details of this procedure used originally for coupling of a
with
19.
Silica
chromatography (TLC grade), eluent: 1% methanol in ethylacetate
20.
63.4
8.2
3.66 fd, J
3.76
2a:
6.7 (d,
3.67
J 12.3 Hz,
3.9 (m,
4.68 (m.
(m,
6.5 (d,
6.07,
(m,
J
HZ,
3.89
J 12.5, 2.9 Hz,
4.98 (m.
6.88
anomer), 8.2
4.65 (dd,
6.8 Hz,
4.7 (m. 3H). 5.11
6.0 Hz, indicating the presence of
8.46 (s,
21.
22.
NMR
S3.5 (m,
major Isomer), 7.2-7.4 (m,
3.6 (dd,
3.69 (dd, 2H). 4.47
4.88 (m, H), 6.14
6.9 Hz,
8.8 HZ,
NMR
minor isomer: 4.92 (d,
1
(d.
3.4 (m,
3.64 (dd,
3.7
3.8
7.4
signals at 1.3
3H). 2.94 (m,
3H) and 4.65 (d,
-20% retention product (by integration).
1.22 1.22
J 7 Hz,
2.22 (m. broad,
2.29 (m,
3.76 (s,
3.92 (dd, J
1 HZ,
3607.
J
23.
24.
25.
These observations appear to be related I
see: H. Dahmlow. J.
O
some
C.
examples of
A. Ft.
cyclizations with concomitant
and A. Kohlmann, Tetrahedron
K. Kato. T. Minami.
Minami, T. Takita, S. Nishiyama, T. Ohgia, S. Yamamura, J.
Takita.
Nishiyama. S. Yamamura and H. Naganawa, Tetrahedron
1989,
1989, 1037.
2269; K.
NMR
73.7
176.8
139.8 (s), 137.8 (s), 126.5
53.1 (I) and 44.3 C3);
128.3 (d), 127.9 (d), 127.8 (d), 127.2 (d), 127.1 (d), 76.8
NMR 2.47 3.26 (s. 3.41 (dd, Hz,
70.6 (t), 70.1
4.55
J 11 H
Z
,
4.58 (d. J 11 H
Z
,
This data also ruled out the ring contracted oxetane-amide structure 23.
(anhydrous; 6 equiv.) in one The reaction
26.
27.
T
O a 10% solution of the triflate 24 in dry methanol was added
mixture was stirred at room temperature for 30 minutes and filtered to remove solids. Evaporation of the fittrate
preparative
and
on silica gel (eluent: 40% ethylacetate in n-hexane) provided
and 26b as colorless gums.
24:
8.8
NMR
62.95 (m,
3.35 (s,
3.54
3H). 3.75 (d,
4.55 (dd, 2H). 4.67 (s, broad,
5.78 (d,
7.4 (m, 5H).
C NMR
138.2
128.3
127.6
26b: 137.8
58.9 (q), 50.0 (q), 49.5 (q) and 48.4 (d,
end in 26b: 48.4 (OH function is
and no carbonyl absorption.
A. K. would like to dedicate this contribution to his mentor, Dr. R. H.
127.5 (d), 120.8
79.1 (d,
119.3 (s.
73.2
72.5 (d,
73.9 (d,
2.45, 44.0 (OH
69.7
50.9
72.4
49.3
71.8
and 44.0
128.4
127.7
77.8 (d,
73.5
Stereochemistry at
to
in
function is
[neat, isomers
Gall.
28.
(Received in USA 22 July 1992; accepted 23 September 1992)