Enantioselective synthesis of the carbocyclic moiety of (-)-carbovir

Article abstract of DOI:10.1016/S0040-4039(03)00749-4

Enantioselective construction of the protected carbocycle moiety of the anti-HIV drug carbovir was achieved in 11 steps from (S)-(-)-ethyl lactate. The two key steps are a Claisen [3+3] sigmatropic rearrangement of (3S,4E)-3-(4-methoxy-phenoxymethyl)-hex-

Full text of DOI:10.1016/S0040-4039(03)00749-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4125–4128
Enantioselective synthesis of the carbocyclic moiety of
(−)-carbovir
Emmanuel Roulland, Claude Monneret and Jean-Claude Florent*
UMR 176 CNRS-Institut Curie, Section Recherche, 26 rue d’Ulm, 75248 Paris Cedex 05, France
Received 12 December 2002; revised 21 March 2003; accepted 24 March 2003
Abstract—Enantioselective construction of the protected carbocycle moiety of the anti-HIV drug carbovir was achieved in 11 steps
from (S)-(−)-ethyl lactate. The two key steps are a Claisen [3+3] sigmatropic rearrangement of (3S,4E)-3-(4-methoxy-phen-
oxymethyl)-hex-4-enoic acid dimethylamide and next, a ruthenium-catalysed ring closure metathesis leading to (1S,4S)-4-(4-
methoxy-phenoxymethyl)-cyclopent-2-enol. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
ethyl lactate 4 (Scheme 2). First, the hydroxyl function
was protected with a tert-butyldiphenylsilyl group to
give compound 5 quantitatively, then the ester moiety
was reduced using di-iso-butylaluminium hydride,
affording the corresponding aldehyde which was
directly used in the next step without further
purification.
Optically pure 4-(tert-butyl-dimethyl-silanyloxymethyl)-
cyclopent-2-enol 11 is of great interest as a building
block used for the introduction of the pseudo-ribose
moiety present in the structure of the anti-HIV drug
(−)-carbovir 3a and abacavir 3b (Fig. 1).2 This carbo-
cycle, with its correct chirality, will mimic the ribose
moiety of natural nucleosides.
The primary hydroxyl moiety is indeed phosphorylated
by the cellular nucleoside kinases before the viral
reverse transcriptase incorporates the resulting pseudo-
nucleoside into the growing nucleic acid chain, thus
leading to the termination of the DNA elongation. In
continuation of previous studies on the synthesis of
asymmetric polysubstituted cyclopentenes, we wish to
report an enantioselective preparation of the building
block 2 closely related to 1.3 In order to obtain
cyclopentenol A (Scheme 1), we chose an extension of
our strategy4 based on a ruthenium-catalysed ring clo-
sure metathesis (RCM) and [3+3] sigmatropic rear-
rangement. Thanks to this strategy, cyclopentenol A
could be obtained by RCM of the 1,5-diene B, itself
resulting from amide C. This could be prepared from
the asymmetric alcohol D through a Claisen [3+3]
sigmatropic rearrangement, (S)-ethyl lactate being used
as the source of chirality.
Figure 1.
2. Results and discussion
Our synthesis started from the readily available (S)-(−)-
* Corresponding author. Tel.: +33-(0)1-42-34-66-58; fax: +33-(0)1-42-
34-66-31; e-mail: jean-claude.florent@curie.fr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00749-4

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E. Roulland et al. / Tetrahedron Letters 44 (2003) 4125–4128
Scheme 2. Reagents and conditions: (a) tert-BuPh2SiCl, imidazole, CH2Cl2, rt; (b) iso-Bu2AlH, CH2Cl2, −78°C; (c)
Ph3PꢀCHCO2Et, PhMe, 80°C. (d) iso-Bu2AlH, THF, −78°C to 0°C; (e) DEAD, PPh3, 4-MeOPhOH, THF, rt; (f) TBAF, THF,
rt.
The salt-free Horner–Emmons reaction with (carbo-
ethoxymethylene)triphenylphosphorane exclusively led
to an a,b-unsaturated ethyl ester of E configuration.
This ester was then reduced to an alcohol 6 using 2
equiv. of di-iso-butylaluminium hydride (71% from 5).
A protection of the primary hydroxyl function was
achieved via a Mitsunobu reaction5 with 4-methoxyphe-
nol, affording 4-methoxyphenyl ether (PMP) ether 7.
Deprotection of the secondary alcohol function of com-
pound 7, carried out using tetrabutylammonium
fluoride, gave optically pure compound 8 in 58% yield
from ethyl lactate. A Claisen [3+3] sigmatropic rear-
rangement reaction was then undertaken using
dimethylacetamide dimethylacetal in refluxing decahy-
dronaphthalene,6 which readily rearranged, exclusively
leading to the dimethylamide 10 via the vinyl ether
intermediate 9 (Scheme 3). As depicted in Figure 2, the
[3+3] sigmatropic rearrangement of intermediate 9 took
place via the transition state A of lower energy. For this
reason, the reaction led to exclusive formation of the S
isomer 10 featuring an E double bond. The (R,Z isomer
1
11 was not detected by H NMR). The actual optical
purity of the rearranged product 10 was easily verified
at the last step of our synthesis. The N,N-dimethyl-
amide compound 10 was then converted into the alde-
hyde 13 in two steps: (i) treatment of 10 with 3 equiv.
of lithium triethylborohydride6 led to alcohol 12, (ii)
subsequent Swern oxidation7 gave the aldehyde 13 in
89% overall yield. The second ethylenic function was
then introduced via a reaction with vinyllithium,
affording the 1,6-diene as an equimolar mixture of the
two possible diastereoisomers 14a and 14b. The RCM
reaction of 1,6-dienes 14a,b was then achieved using
Grubbs’ catalyst,8 leading to a mixture of two cyclopen-
tenols: the expected compound 2 and his diastereoiso-
mer 15.
Scheme 3. Reagents and conditions: (a) Me2N(MeO)2CCH3, decalin, reflux; (b) LiEt3BH, THF, −78°C to rt; (c) (COCl)2, DMSO,
CH2Cl2, −78°C, then NEt3; (d) BrHCꢀCH2, tert-BuLi, −78°C, THF; (e) Cl2(Cy3P)2RuꢀBn, CH2Cl2, rt.
Figure 2. Transition state in the Claisen [3+3] sigmatropic rearrangement reaction.

E. Roulland et al. / Tetrahedron Letters 44 (2003) 4125–4128
Table 1. Chemical shifts of trans cyclopentenols 1 and 2 (ppm)
4127
Entry
H5b
H5a
H1
H2
H3
H4
1
2
2 l=
1 l=
1.95
1.77
2.07
1.91
4.96
4.78–4.92
6.05
5.94
5.96
5.85
3.35
2.85–3.10
Table 2. Observed and computed coupling constants for cyclopentenols 2 and 1
Entry
H1–H5a
H4–H5b
H4–H5a
H1–H5b
1
2
3
4
Coupling constants for 2
7.1 Hz
−28°
7 Hz
7.8 Hz
+155°
7.5 Hz
7.8 Hz
4.9 Hz
+35°
5.5 Hz
4.6 Hz
3.2 Hz
+91°
0 Hz
Calculated torsion angles for 2
Estimated coupling constants for 2
Coupling constants for 1
7.3 Hz
3.3 Hz
since it can be easily removed with cerium ammonium
nitrate or with smooth anodic oxidation.5b,c,d Our strat-
egy, based on a Claisen rearrangement followed by a
metathesis-based ring closure, provides an original
entry in the RCM-based preparation of five-membered
carbocycles and thus completes other preparations of
polysubstituted cycles previously reported.11 It is also
noteworthy that other carbocyclic nucleosides have
recently been constructed using metathesis strategy.2g
A very fast RCM reaction (less than 1 h) was observed,
consistent with the reported9 reaction speed for 1,6-
dien-3-ol. Separation of 2 and 15 was easily performed
by flash chromatography.
Acknowledgements
The 1H NMR study of the compounds 2 and 15
allowed us to assign their absolute stereochemistries.
The homoallylic protons H5a and H5b provided most of
the information. In Table 1, summarised are the 1H
NMR signals of compound 2. These values can be
compared with the reported signals of the related com-
pound 1.1b It is a general observation that chemical
shifts of the geminal H5-protons of cis-1,4-disubsti-
tuted-cyclopentenes present large differences, often in
the range of 1 ppm.10 On the other hand, this difference
does not usually exceed 0.3 ppm for the trans isomers.
As seen in Table 1, the differences between H5a and H5b
signals for products 2 and 1 are smaller than 0.3 ppm.
A further computer-based modelisation, using the ran-
dom search function (SYBYL 6.5/Tripos force field),
gave the conformer of lowest energy for compound 2.
From this, a calculation of the coupling constants could
be done and gave values similar to the observed one
(Table 2).
This work was financially supported by the Centre
National de la Recherche Scientifique, the Institut
Curie and the Servier laboratories.
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