3-vinyl-2,5-dihydrofuran derivatives via enyne metathesis

Article abstract of DOI:10.1055/s-2007-984503

Acyclic enynes having the alkyne moiety directly connected to the asymmetric carbon atom of an acetal were obtained in two steps. These reactive substrates were then subjected to ruthenium-catalyzed enyne metathesis to produce (5-ethoxy-4-vinyl-2,5-dihydr

Full text of DOI:10.1055/s-2007-984503

LETTER
1703
3-Vinyl-2,5-dihydrofuran Derivatives via Enyne Metathesis
3
-Vinyl-2,5-dihydrof
u
.
n
D
erivativ
M
e
s
via Enyne Metathes
eis rcedes Rodriguez-Fernandez, Sophie Vuong, Brigitte Renoux, Christophe Len*
Synthèse et Réactivité des Substances Naturelles, UMR 6514, FR 2703, Université de Poitiers, 40 Avenue du Recteur Pineau,
86022 Poitiers Cedex, France
Fax +33(5)49453501; E-mail: christophe.len@univ-poitiers.fr
Received 14 March 2007
present on the glycone precursor immediately prior to
condensation by a base to effect nucleoside formation.
Abstract: Acyclic enynes having the alkyne moiety directly
connected to the asymmetric carbon atom of an acetal were ob-
tained in two steps. These reactive substrates were then subjected to
ruthenium-catalyzed enyne metathesis to produce (5-ethoxy-4-
vinyl-2,5-dihydrofuran-2-yl)methanol derivatives in racemic and
enantiomerically pure form. These products are useful glycosyl
donors for the preparation of d4T analogues.
Metathesis5 is an extremely useful method in organic
chemistry due to the development of selective catalysts
such as the ruthenium carbenes 4–6, which offer a good
compromise between efficiency and tolerance to func-
tional groups (Figure 2).5b The intramolecular enyne
metathesis known as ring-closing enyne metathesis
(RCEYM), is a particularly powerful method for the con-
struction of various cyclic 1,3-diene systems6 and has
been in use for several years. This work includes several
examples which start from a stereochemically pure
acyclic enyne as exemplified in carbohydrate chemistry.7
Key words: enyne, metathesis, carbohydrate, cyclization, furan
Several nucleoside analogues have been shown to be
highly effective as antiviral and antitumour agents. The
2¢,3¢-didehydro-2¢,3¢-dideoxynucleosides (d4Ns)1 are
effective nucleoside reverse transcriptase inhibitors
(NRTIs), and form the most important class of com-
pounds active against the human immunodeficiency virus
(HIV), which causes AIDS. Among the NRTIs approved
by the US Food and Drug Administration (US FDA) for
the treatment of AIDS, the 2¢,3¢-didehydro-2¢,3¢-dideoxy-
thymidine (d4T, stavudine)2 is a very potent and selective
inhibitor of HIV reverse transcriptase. In an attempt to in-
vestigate a wider structure–activity relationship for this
type of NRTI, a number of d4N analogues have been syn-
thesized with the 2¢- and 3¢-protons replaced by a vinyl
group (1, 2) or the benzene ring of a benzo[c]furan core,
3. Two strategies were employed3,4 for the preparation of
compounds 1–3 (Figure 1). The first one invoked the
direct substitution of the 2¢,3¢-didehydro-2¢,3¢-dideoxy-
nucleosides with organotin reagent3a–c or the formation of
the tributyltinvinyl nucleoside followed by palladium-
catalysed cross-coupling.3a–c The second one required
convergent syntheses3d–f,4 in which the final target func-
tionalities in the 2¢- and/or 3¢-positions and p-character are
N
N
Mes
Mes
N
N
Cl
PCy3
Ru
Mes
Mes
Cl
Cl
Ru
O
Cl
Cl
Ru
Ph
Ph
PCy3
Cl
PCy3
4
5
6
first-generation
Grubbs catalyst
second-generation
Grubbs catalyst
second-generation
Hoveyda–Grubbs catalyst
Figure 2 Ruthenium catalysts for metathesis
In order to prepare new nucleoside analogues of d4T an
efficient synthesis of the enantiomerically pure glycosyl
donors cis-12 and trans-12 has been sought (Scheme 2).
Compounds cis-12 and trans-12 have potential as versa-
tile intermediates that can undergo further selective trans-
formations such as cycloaddition.
O
NH2
NH2
N
N
N
NH
N
N
O
N
N
O
O
N
O
N
TBDPSO
TBDPSO
HO
1
2
3
Figure 1 Nucleoside analogues 1–3 having 2¢-vinyl or 3¢-vinyl group or a benzo[c]furan core
SYNLETT 2007, No. 11, pp 1703–1706
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984503; Art ID: G06807ST
© Georg Thieme Verlag Stuttgart · New York

1704
M. M. Rodriguez-Fernandez et al.
LETTER
O
O
O
O
OH
TBDPSO
TBDPSO
RO
(ii)
+
( )
( )
( )
rac-7 (R = H)
rac-8 (R = TBDPS)
rac-10
rac-11
(i)
Scheme 1 Reagents and conditions: (i) TBDPSCl, imidazole, DMF, 20 °C, 24 h (80%); (ii) 9, P2O5, CHCl3, 45 °C, 2 d (65%).
O
O
O
O
O
O
TBDPSO
TBDPSO
TBDPSO
(i)
+
( )
rac-10 + rac-11
( )
rac-cis-12
( )
rac-trans-12
Scheme 2 Reagents and conditions: (i) 5, CH2Cl2, 20 °C, 5 d.
Retrosynthetic analysis suggested that but-3-en-1,2-diol tion Grubbs catalyst 5 and variant conditions (Scheme 2,
(rac-7) and 3,3-diethoxypropyne (9) were the most prom- and Table 1).
ising starting point. Compounds rac-7 and 9 had the ad-
The RCEYM reaction, in the absence of an ethylene atmo-
vantage of being stable, inexpensive, and easily available.
sphere, did afford the five-membered ring system but the
This strategy used an enyne having the alkyne moiety
yield was poor (Table 1, entry 1) and a large quantity of
directly connected to the asymmetric carbon atom C-1 of
starting material was recovered. The presence of an ethyl-
an acetal that, to the best of our knowledge, was not re-
ene atmosphere (Table 1, entries 2–4), under Mori’s con-
ported as substrate for RCEYM.
ditions,8 favoured the RCEYM by ensuring a better
At first, the synthesis of racemic acyclic enynes and the turnover of the active catalyst with yne-then-ene
optimization of the RCEYM were explored. The selective mechanism9 or ene-then-yne mechanism.10 The use of a
silylation of the primary hydroxyl group of the diol rac-7 higher concentration of catalyst (10% vs. 3%) resulted in
with tert-butyldiphenylsilyl chloride in DMF in the pres- polymerisation and rather than enhancing the yield of the
ence of imidazole afforded the corresponding ether rac-8 cyclic enynes rac-cis-12 and rac-trans-12 (Table 1, en-
in 80% yield. Then, compound rac-8 was treated with the tries 2 and 3). Due to the presence of three oxygen atoms,
alkyne 9 and P2O5 in chloroform to afford the tert-butyl- addition of Ti(Oi-Pr)4 as Lewis acid using the protocol de-
diphenylsilyl (TBDPS)-protected 2-(1-ethoxyprop-2- scribed by Fürstner,11 gave a moderate 26% yield (39%
ynyloxy)-but-3-en-1-ol derivatives, rac-10 and rac-11 based on recovered rac-10 and rac-11, Table 1, entry 4).
(1:1) in 65% yield (Scheme 1). It was notable that protec- In our hands, the use of toluene or CH2Cl2 in 80 °C and
tion of the diol rac-7, either by selective benzoylation or 40 °C, respectively, did not afford the target rac-cis-12
silylation with tert-butyldimethylsilyl chloride, gave a and rac-trans-12 but gave a polymerisation mixture.
species which was prone to partial migration of the
protecting group during the subsequent acetalisation.
To study the influence of the protecting group on the cy-
clization, substrates rac-13–rac-20 were prepared. Under
Starting from the mixture of acyclic enynes rac-10 and the conditions optimised for the acyclic enyne mixture
rac-11, RCEYM was investigated for the formation of the rac-10 and rac-11 (Table 1, entry 2: 0.03 M, 3 mol% 5,
conjugated oxacyclic 1,3-dienes, rac-cis-12 and rac- CH2Cl2, ethylene, 20 °C, 5 d), the dienes rac-21–rac-24
trans-12, using commercially available second-genera- were obtained in 27–50% yield (Scheme 3, Table 2).12
Table 1 RCEYM of Enynes rac-10 and rac-11 Using Ruthenium Carbenes 5 as Catalyst
Entry
Cat. (%)
Recovered yield (%) of
Yield (%) of
Yield (%) of
rac-10 and rac-11
rac-cis-12
rac-trans-12
1a,b
2a,c
3
3
67
–
7
25
13
13
7
25
9
3a,c
10
3
–
4a,c,d
32
13
a Reagents and conditions: 0.03 M of rac-10 and rac-11, 5, CH2Cl2, 20 °C, 5 d.
b Under nitrogen pressure.
c Under ethylene pressure.
d Ti(Oi-Pr)4 (0.3 equiv).
Synlett 2007, No. 11, 1703–1706 © Thieme Stuttgart · New York

LETTER
3-Vinyl-2,5-dihydrofuran Derivatives via Enyne Metathesis
1705
O
Thus, in compound trans-12, irradiation of H5 gave en-
hanced signals for protons of the methoxy group. The
same was true for H5 when protons of the methoxy group
were irradiated. Conversely, no NOE effect was observed
for the same protons of compound cis-12. The study of
the conformational analysis of the dienes cis-12 and
trans-12 has been performed on the basis of ab initio gas-
phase geometry optimisations using B3LYP 6-31G(d,p)
in the Gaussian 03 program package by means of molec-
ular modelling and confirmed this attribution (Figure 3).
Thus, for the lowest energy conformer found for com-
pound trans-12 the proximity of H5 and H of the
methyloxy group explained the NOE interaction observed
(d = 2.942 Å).
O
O
O
O
O
RO
RO
RO
(i)
+
( )
( )
( )
rac-13 + rac-14 (R = H)
rac-15 + rac-16 (R = Tr)
rac-17 + rac-18 (R = Bz)
rac-19 + rac-20 (R = Ac)
rac-cis-21 (R = H)
rac-cis-22 (R = Tr)
rac-cis-23 (R = Bz)
rac-cis-24 (R = Ac)
rac-trans-21 (R = H)
rac-trans-22 (R = Tr)
rac-trans-23 (R = Bz)
rac-trans-24 (R = Ac)
Scheme 3 Reagents and conditions: (i) 3 mol% 5, CH2Cl2 under
ethylene pressure, 20 °C, 5 d.
Table 2 RCEYM of Enynes rac-13 and rac-20 Using Ruthenium
Carbenes 5 as Catalysta
Entry
Starting
Yield (%)b
Yield (%)b
materials
of cis-enyne
of trans-enyne
1
2
3
4
13 and 14
15 and 16
17 and 18
19 and 20
cis-21 (7)
cis-22 (30)
cis-23 (16)
cis-24 (20)
trans-21 (20)
trans-22 (20)
trans-23 (32)
trans-24 (15)
a Reagents and conditions: 0.03 M, 3 mol% 5, CH2Cl2, 20 °C, 5 d
under ethylene pressure.
b Obtained after flash chromatography.
As reported,7a unprotected alcohol rac-13 and rac-14
afforded the corresponding cyclic enynes cis-21 and
trans-21 in rather poor yield (Table 2, entry 1). Among
the different protecting groups, both the trityl and benzoyl
derivatives rac-15–rac-18 were obtained in better yields
(Table 2, entries 2 and 3), similar to that for rac-10 and
rac-11 (Table 1, entry 2). In our hands, the acetates rac-
19 and rac-20 gave poor yields compared with those ob-
tained with the corresponding benzoate rac-17 and rac-18
(35% vs. 48%). The ratio cis:trans varied with the nature
of the protecting group and was dependant probably on
both stereoelectronic effects and potent p-p stacking.
Figure 3 Target dienes cis-12 and trans-12 and the corresponding
lowest energy conformers obtained on the basis of ab initio gas-phase
geometry optimisations using B3LYP 6-31G(d,p) in the Gaussion 03
package
It was notable that the stereochemistry for compounds cis-
12 and trans-12 was based on the magnitude of the cou-
pling between the dihydrofuran ring protons. The NMR
spectra on the 2,5-dihydrofuran system have been investi-
gated for several compounds with one or no substituent in
the dihydrofuran ring.4,16 In each case, the larger cross
ring coupling between H2 and H5 was assigned to the
trans-configuration and the smaller to the cis-configura-
tion. In agreement with the literature,4,16 the observed
coupling J2,5 was 0 Hz for compound cis-12 and 4.0 Hz for
compound trans-12.
It was notable that formation of a six-membered ring
(from endo-selectivity) was not detected, nor was there
any evidence of a dimer resulting from diene cross-met-
athesis (Tables 1 and 2). In our case, the formation of 1,3-
substituted 1,2-dienes showed absolute exo-selectivity for
the RCEYM.13
In summary, we have demonstrated a concise method
using RCEYM reaction for the synthesis of 2,3-didehy-
dro-2,3-dideoxyribo-D-ribofuranose derivatives as poten-
tial glycosyl donors for different glycosidation routes to
new nucleosides. The reported strategy permitted the syn-
thesis of enantiomerically pure carbohydrate analogues of
the series D or L starting from the chiral (S)- or (R)-but-3-
en-1,2-diols, respectively.
In order to prepare the 1,3-dienes in their enantiomerically
pure forms, application of the above strategy was repeated
starting from the commercial chiral (2S)-but-3-en-1,2-
diol (7). After selective silylation of 7, subsequent acetal-
isation and cyclisation afforded cis-1214 and trans-1215
with similar yields. Unfortunately, compounds cis-12 and
trans-12 gave poor quality crystals thus precluding the de-
termination of their configurations by X-ray crystallogra-
phy. With the 2-S carbon configuration determined by the
chiral diol 7, the absolute configurations for the dienes
cis-12 and trans-12 were assigned as 2S,5R and 2S,5S, re-
spectively, on the basis of proton NMR NOE experiments.
Acknowledgment
This work was supported by the regional programme for invited
researchers from the Région Poitou-Charentes, France.
Synlett 2007, No. 11, 1703–1706 © Thieme Stuttgart · New York

1706
M. M. Rodriguez-Fernandez et al.
LETTER
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9130.
(12) RCEYM Reaction of rac-15 and rac-16 – Typical
Procedure
The ruthenium catalyst 5 (3% mol) was dissolved in CH2Cl2
(26 mL) and ethylene gas was passed through the solution
for 20 min. The enyne mixture of rac-15 and rac-16 (400
mg, 0.98 mmol) in CH2Cl2 (12 mL) was then added and the
mixture was stirred under ethylene at 20 °C during 5 d. The
volatiles were eliminated under reduced pressure and the
residue was purified by flash chromatography (5% EtOAc in
hexane) to give rac-cis-22 (100 mg, 25%) and rac-trans-22
(100 mg, 25%) in order of fractions eluted.
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(14) Selected physico-chemical data for compound cis-12: Rf =
0.50 (5% EtOAc–hexane). 1H NMR (300 MHz, CDCl3): d =
7.71 (m, 4 H, Ph), 7.45 (m, 6 H, Ph), 6.48 (dd, 1 H, J = 12,
18 Hz, =CH), 6.18 (s, 1 H, H3), 5.87 (s, 1 H, H5), 5.46 (d, 1
H, J = 18 Hz, =CH), 5.23 (d, 1 H, J = 12 Hz, =CH), 4.80 (m,
1 H, J = 1 Hz, H2), 3.68 (m, 4 H, OCH2CH3, CH2OSi), 1.23
(t, 3 H, J = 8 Hz, CH3), 1.06 (s, 9 H, 3 CH3) ppm. 13C NMR
(75 MHz, CDCl3): d = 138.9 (C4), 136.0 (Ph), 135.9 (Ph),
133.9 (C3), 133.8 (Ph), 130.4 (=CH), 128.1 (Ph), 118.0
(=CH2), 107.6 (C5), 85.7 (C2), 67.6 (CH2OSi), 62.6 (OCH2),
27.2 (CH3 of t-Bu), 19.6 (Cq of t-Bu), 15.8 (CH3) ppm. ESI-
HRMS: m/z calcd [M + Na+]: 431.2018; found: 431.2034.
(15) Selected physico-chemical data for compound trans-12: Rf =
0.20 (5% MeOH–CH2Cl2). 1H NMR (300 MHz, CDCl3): d =
7.65 (m, 4 H, Ph), 7.38 (m, 6 H, Ph), 6.43 (m, 1 H, J = 12,
18Hz, =CH), 5.98 (s, 1 H, H3), 5.96 (d, 1 H, J = 4 Hz, H5),
5.43 (d, 1 H, J = 18, =CH), 5.24 (d, 1 H, J = 12 Hz, =CH),
4.90 (m, 1 H, H2), 3.72 (m, 4 H, OCH2CH3, CH2OSi), 1.26
(t, 3 H, J = 8 Hz, CH3), 1.04 (s, 9 H, 3 CH3) ppm. 13C NMR
(75 MHz, CDCl3): d = 138.8 (C4), 136.0 (Ph), 133.9 (Ph),
130.6 (C3), 130.0 (Ph), 129.0 (=CH), 128.1 (Ph), 118.0
(=CH2), 107.6 (C5), 85.6 (C2), 66.6 (CH2OSi), 62.1 (OCH2),
27.2 (CH3 of t-Bu), 19.6 (Cq of t-Bu), 15.8 (CH3). ESI-
HRMS: m/z calcd [M + Na+]: 431.2018; found: 431.2025.
(16) Barfield, M.; Spear, R. J.; Sternhell, S. J. Am. Chem. Soc.
1975, 97, 5160.
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