Synthesis of novel polyhydroxylated tetrahydropyranopyrroles

Article abstract of DOI:10.1055/s-2007-968030

The stereoselective access to original polyhydroxylated tetrahydropyranopyrroles is described. The key steps involve an inverse-demand Diels-Alder reaction and a ring contraction of a pyridazine heterocycle. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-968030

LETTER
403
Synthesis of Novel Polyhydroxylated Tetrahydropyranopyrroles
Synthesis of
N
é
ovel Polyh
b
a
hydro-Pyra
s
no-Pyrrol
t
es ien Naud,a Muriel Pipelier,a Christophe Chaumette,a Guillaume Viault,a François Huet,b Stéphanie Legoupy,b
Didier Dubreuil*a
a
Université de Nantes, CNRS, Laboratoire de Synthèse Organique, UMR 6513, Faculté des Sciences et des Techniques, 2 Rue de la
Houssinière, BP 92208 44322 Nantes Cedex 3, France
Fax +33(2)51125402; E-mail: didier.dubreuil@univ-nantes.fr
b
Université du Maine, CNRS, Laboratoire de Synthèse Organique, UCO2M, UMR 6011, Faculté des Sciences et des Techniques,
Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
Received 21 September 2006
O
Abstract: The stereoselective access to original polyhydroxylated
OH
O
O
O
tetrahydropyranopyrroles is described. The key steps involve an
inverse-demand Diels–Alder reaction and a ring contraction of a
pyridazine heterocycle.
O
O
OH
HO
Key words: pyrroles, pyridazines, a-pyrones, ring contractions,
cycloadditions
MeN
(3R)-7-butyl-6,8-dihydroxy-3-
pentylisochroman-1-one (5)
hippeastrine (6)
O
H
OH
O
N
O
a-Pyrone derivatives (5,6-dihydro-2H-pyran-2-one) iso-
lated from natural sources have attracted much attention
during the last decade due to their medicinal potential1 as
antiviral, antitumor, antimalarial or antifungal agents.
O
I
MeO
TsHN
O
O
OH
The biological activities of a,b-unsaturated d-lactones are
mainly attributed to their Michael acceptor character.2
However, the broad range of biological targets aimed at
by the a-pyrone skeleton can also be ascribed to the
presence of various cyclic and acyclic functionalized sub-
stituents. For example, a-pyrones bearing free or acetylat-
ed polyhydroxylated side chains, such as boronolide (1),3
goniotriol (2)4 and analogues 3 and 4,5 have shown potent
antimalarial and antitumor activities (Figure 1).
O
dehydroaltenusin (7)
indololactone (8)
Figure 2
that particular case, a hydrogen-bonding donor–acceptor-
pairing effect between the indolo ring and the keto ester
group has been suggested.
With these considerations in mind, we have developed a
stereoselective access to original 5-polyhydroxylated a-
pyrones bearing a pyrrole heterocycle at the 3a,7a-posi-
tion (Figure 3).
O
O
O
OR
O
OR
OH OH
R
OH OH
OR OR
3a
4
HO
R = H, (+)-goniotriol (2)
R = Ac, 4 antitumoral
R = Ac, (+)-boronolide (1)
R = H, 3 antimalarial
CO2Me
R = Ph
OH
O
N
7a
H
R = n-Bu
O
Figure 1
Figure 3
On the other hand, a-pyrones fused to hydroxylated aro-
matic or non-aromatic rings are found in antimalarial di-
hydroisocoumarin derivative 5,6 cytotoxic hippeastrine
(6)7 and in dehydroaltenusin (7), which is a potent inhibi-
tor of mammalian DNA polymerase a (Figure 2).8
Recently, an original indololactone (8),9 obtained in the
course of the production of quinoleinone analogues of
pancratistatin, has been shown to act by a different mech-
anism against pancreas and breast adenocarcinoma. In
The access to the tetrahydropyranopyrrole analogues
was envisaged from acetylenic sugar precursors following
a cycloaddition–ring-contraction–lactonization sequence
(Scheme 1). Thus, the formation of the a-pyrrolopyrone
skeleton A was thought to be the result of intramolecular
transesterification between the selected free hydroxyl of
the sugar moiety and one ester group of the pyrrolo moiety
B. The intermediate B should derive from a ring-contrac-
tion process of a suitable functionalized pyridazine het-
erocycle C produced by an inverse-demand Diels–Alder
cycloaddition between acetylenic sugar dienophiles and
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (9).
SYNLETT 2007, No. 3, pp 0403–0406
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-968030; Art ID: G25806ST
© Georg Thieme Verlag Stuttgart · New York

404
S. Naud et al.
LETTER
OR'
R
OR'
O
R
ring
contraction
R
R'O
C-sugar
R
CO2Me
D
9
Diels–Alder
lactonization
CO2Me
+
CO2Me
N
OH
MeO2C
O
NH
N
N
N
N
H
N
MeO2C
MeO2C
CO2Me
N
A
B
C
Scheme 1
Starting from commercially available D-ribose, the 2,3,5- tramolecular SN2 substitution at the C5-center with inver-
tri-O-benzyl ribofuranose (10) was synthesized in three sion of configuration. So, as predicted, pure diols (5R)-11
steps following a well-established procedure.10 As pre- and (5S)-11 afforded the acetylenic C-ribosyl 13b and
dicted, the addition of phenylacetylene and hexyne anions 13a, respectively. The structures of C-ribosyls 13a and
to ribofuranose 10 gave the acetylenic diols 11 and 12, re- 13b were unambiguously confirmed by comparison with
spectively, as a mixture of two stereoisomers at the C5-po- NMR data described by Williams12 in the case of the 13b-
sition (Scheme 2). Reaction with a lithium acetylenic anomer and according to the X-ray structure that we
anion afforded a 1:1 mixture of diol isomers (5R)-11 and obtained for the 13a-anomer. In the same way, the C5-
(5S)-11 in 87% yield, whereas using Grignard’s reagent11 configuration of diols 12 was attributed consecutively to
led to an 8:2 ratio in favor of (5R)-11 (80%, Table 1).
the cyclization of the isomer 5R leading exclusively to the
ribosyl 14b, which fully corroborates with NMR data de-
scribed by Seitz.13 Therefore, the (5S)-12 configuration
was then attributed to the other isomer, which cannot be
purified at this step.
Ph
MgBr
OBn OH
THF, 50–60 °C
O
OH
2 h
or
BnO
BnO
5
R
Li
OH OBn
R
The diols (5R)-11, (5S)-11 and (5R,S)-12 have to be pro-
tected prior to being engaged in the [4+2] cycloaddition,
otherwise side reactions occurred and no pyridazine was
isolated. Thus, benzyl ether groups were introduced, un-
der the usual conditions, to give the acetylenic dienophiles
(3R)-15, (3S)-15 and (7R,S)-16, respectively (Scheme 3).
BnO
OBn
THF, –5 °C to 10 °C
2 h
(5R)-11
10
R = Ph
(5S)-11
(5R)-12
(5S)-12
R = n-Bu
R
O
TsCl
BnO
pyridine, 60 °C
3 h
OBn OBn
BnO
OBn
(5R)-11
(5S)-11
R = Ph
NaH, BnBr
3
R = Ph
13b
13a
14b
39%
52%
63%
BnO
THF–DMF
overnight
(5R,S)-12
R = n-Bu
OBn OBn
R
R = n-Bu
(3R)-15
R = Ph
76%
77%
(3S)-15
Scheme 2
(7R,S)-16
R = n-Bu
62%
Table 1 Reaction of Phenylacetylene and Hexyne Anions to
Ribofuranose 10 to Afford 11 and 12
BnO
BnO
OBn
OBn
tetrazine 9
R
1'
Conditions
Acetylenic Yield (%) Ratio 5R:5S
BnO
toluene, reflux,
5 d
diols
MeO2C
CO2Me
N
N
(1'R)-17
(1'S)-17
R = Ph
55%
66%
Ph–C≡C–MgBr, THF,
11
11
80
87
85
8:2
1:1
1:1
50–60 °C
(1'R,S)-18
R = n-Bu
46%
Ph–C≡C–Li, THF, –5 °C to
10 °C
Scheme 3
Bu–C≡C–Li, THF, –5 °C to 12
10 °C
The cycloaddition reactions between acetylenic dieno-
philes and tetrazine 914 were then achieved following
Boger’s procedure.15 Diels–Alder cycloaddition of acetyl-
enic dienophiles (3R)-15, (3S)-15 and (7R,S)-16 afforded
the corresponding pyridazines (1¢R)-17, (1¢S)-17 and
(1¢R,S)-18 in 55%, 66% and 46% yields, respectively. The
yields of the reaction are in accordance with those report-
ed during [4+2] cycloaddition of acetylenic C-ribofurano-
syl with tetrazine 9.16 These relatively moderate yields
could be due to a steric hindrance between the two part-
ners slowing down the reaction, during which a partial
degradation of tetrazine occurred. The pyridazines (1¢R)-
Both acetylenic diol isomers are of interest to provide a-
pyrone analogues, so they were then isolated by flash
chromatography on silica gel to yield (5S)-11, (5R)-11
and (5R)-12 as pure diastereoisomers.
The absolute configurations of diols 11 and 12 were
unambiguously assigned after their conversion into their
corresponding known C-ribofuranosyl analogues.
The cyclization process, initiated by treatment with tosyl
chloride in pyridine,11 proceeded via a regioselective in-
Synlett 2007, No. 3, 403–406 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Polyhydroxylated Tetrahydropyranopyrroles
405
HO
OH
18 and (1¢S)-18 were purified by semipreparative HPLC
OH
on a silica gel column.
(1'R)-19
(1'S)-19
R = Ph
HO
R
1'
The ring-contraction process of pyridazines 17 and 18 into
pyrroles 19 and 20, respectively, was initiated with 20
equivalents of zinc dust in refluxing acetic acid, according
to Boger’s procedure (Scheme 4).15 When the reactions
were carried out in the 1¢R series, over 15 hours, the yields
of pyrroles (1¢R)-19 and (1¢R)-20 did not exceed 18%. In
the latter reaction conditions, a concomitant surprising
deprotection of the benzyl ether groups at C1¢ and C4¢ oc-
curred to give the diols (1¢R)-21 and (1¢R)-22 as by-prod-
ucts in 44% and 17% yields, respectively. The position of
the free hydroxyl groups was assigned with the help of an
HMBC NMR experiment.
H2, Pd/C
HO
MeO2C
MeOH, 1 h
(1'R)-20
(1'S)-20
R = n-Bu
CO2Me
N
H
89%
98%
(1'R)-23
(1'S)-23
R = Ph
85%
95%
(1'R)-24
(1'S)-24
R = n-Bu
OH OH
R
Na2CO3
MeOH, 1 h
HO
4'
O
CO2Me
OH
O
N
H
(4R)-25 49%
R = Ph
BnO
BnO
OBn
48%
(4S)-25
OBn
38%
72%
(4R)-26
(4S)-26
R = n-Bu
R
1'
BnO
MeO2C
Scheme 5
CO2Me
N
H
(1'R)-19
(1'S)-19
R = Ph
46%
60%
In conclusion, we have performed the synthesis of four
novel tetrahydropyranopyrroles (4R)-25, (4S)-25, (4R)-26
and (4S)-26 in a nine-step reaction sequence from D-
ribose. The key step of the synthesis is a ring contraction
of pyridazines, which were accessible via a Diels–Alder
cycloaddition from acetylenic C-sugars. The biological
properties of these compounds are currently being evalu-
ated. In an extension of this work, the synthesis of new
tetrahydropyranopyrrole derivatives from various fura-
nose and pyranose sugars is underway. These analogues
would enable the influence of the length and the stereo-
chemistry of side chains on biological potential to be
assessed. The introduction of aryl or alkyl substituents on
the sugar skeleton, by analogy with boronolide (1) or
goniotriol (2), is also under investigation.
(1'R)-20
(1'S)-20
R = n-Bu
68%
60%
R = Ph
(1'R)-17
(1'S)-17
Zn, AcOH
+
reflux, 30 min
R = n-Bu
(1'R)-18
(1'S)-18
BnO
OBn
OH
HO
R
1'
BnO
MeO2C
CO2Me
N
H
(1'R)-21 traces
(1'R)-22 traces
R = Ph
R = n-Bu
Scheme 4
A decrease in the reaction time to 30 minutes limited the
debenzylation side reaction to trace level and the targeted
pyrroles (1¢R)-19 and (1¢R)-20 were isolated in 46% and
68% yields, respectively, with only traces of (1¢R)-21 and
(1¢R)-22.
Acknowledgment
This work was supported by the ‘Ministère de l’Education Nationa-
le, de l’Enseignement Supérieur et de la Recherche’ with a doctoral
fellowship to S.N.
Ring contraction of pyridazines (1¢S)-17 and (1¢S)-18 was
also achieved over 30 minutes to lead to the pyrroles (1¢S)-
19 and (1¢S)-20 in 60% yield, respectively. No hydroxyl
deprotection side reaction was encountered in this series,
even after 15 hours.
References and Notes
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The access to pyrrolo-pyrones was achieved in two steps.
Debenzylation of pyrroles 19 and 20 (1¢R and 1¢S) under
the usual hydrogenation conditions (H2, Pd/C) afforded
the corresponding pyrroles 23 and 24 (1¢R and 1¢S) in
good yields (85–98%, Scheme 5).17 Then, lactonization
was performed in basic medium (Na2CO3, MeOH) to af-
ford the pyrones (4R)-25, (4S)-25, (4R)-2618 and (4S)-26
in moderate to good yields (38–72%).
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Synlett 2007, No. 3, 403–406 © Thieme Stuttgart · New York

406
S. Naud et al.
LETTER
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(18) NMR Data of (4R,5S,1¢R,2¢R)-3-Butyl-4-hydroxy-2-
methoxycarbonyl-7-oxo-5-(1¢,2¢,3¢-trihydroxyprop-1¢-
yl)-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole [(4R)-26].
1H NMR (400 MHz, CD3OD): d = 0.94 [t, 3 H, Hd(Bu),
3J = 7.3 Hz], 1.40 [m, 2 H, Hg(Bu)], 1.50–1.67 [m, 2 H,
Hb(Bu)], 2.85 [m, 2 H, Ha(Bu)], 3.74 (dd, 1 H, H3¢a,
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J3¢a–3¢b = 11.5 Hz, J3¢a–2¢ = 6.6 Hz), 3.83 (dd, 1 H, H3¢b,
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J3¢b–3¢a = 11.5 Hz, J3¢b–2¢ = 4.0 Hz), 3.87 (s, 3 H, OMe), 4.00
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Hz), 4.56 (dd, 1 H, H5, J5–1¢ = 7.9 Hz, J5–4 = 2.1 Hz), 5.00 (d,
1 H, H4, J4–5 = 2.1 Hz). 13C NMR (100 MHz, CD3OD): d =
4.2 [Cd(Bu)], 23.7 [Cg(Bu)], 25.3 [Ca(Bu)], 34.3 [Cb(Bu)],
52.1 (OMe), 60.7 (C4), 63.9 (C3¢), 72.1 (C1¢), 73.8 (C2¢), 84.1
(C5), 121.5, 126.2 (C2, C5), 130.8, 131.8 (C3, C4), 160.7,
162.5 (2 CO). HRMS: m/z calcd for C16H24NO8 [M + H]+:
358.1502; found: 358.1490. [a]D20 +21.2 (c 1.65, MeOH).
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Synlett 2007, No. 3, 403–406 © Thieme Stuttgart · New York