An allylation-metathesis sequence as a convergent strategy towards enantiopure equivalents of highly functionalized cyclic dienes

Article abstract of DOI:10.1016/S0040-4039(03)01791-X

Highly enantioenriched equivalents of cyclic dienes have been readily prepared by asymmetric allylation of unsaturated aldehydes using a chiral allyltitanium reagent, followed by a ring-closing metathesis. The resulting β-hydroxy allylsilanes react stereo

Full text of DOI:10.1016/S0040-4039(03)01791-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7197–7199
An allylation-metathesis sequence as a convergent strategy
towards enantiopure equivalents of highly functionalized
cyclic dienes
Laurence de Fays,a Jean-Michel Adamb and Le´on Ghoseza,*
aInstitut Europe´en de Chimie et Biologie, c/o ENSCPB, 16 avenue Pey Berland, 33607 Pessac Cedex, France
bDepartement de Chimie, Universite´ Catholique de Louvain, place L. Pasteur, B-1348 Louvain-la-Neuve, Belgium
Received 20 June 2003; revised 11 July 2003; accepted 22 July 2003
Dedicated to Professor Georges Hoornaert on the occasion of his retirement from the KUL.
Abstract—Highly enantioenriched equivalents of cyclic dienes have been readily prepared by asymmetric allylation of unsaturated
aldehydes using a chiral allyltitanium reagent, followed by a ring-closing metathesis. The resulting b-hydroxy allylsilanes react
stereoselectively with a wide variety of electrophilic reagents.
© 2003 Elsevier Ltd. All rights reserved.
We have previously reported a two-step reaction
sequence consisting of an asymmetric allylation of an
prompts us to quickly describe our own studies on the
enantioselective synthesis of b-hydroxy allylsilanes 1
and their transformation into a wide variety of enantio-
enriched synthetic intermediates.
aldehyde followed by
a diastereoselective silicon-
directed [2+2] cycloaddition (Scheme 1).1 This illus-
trated a convergent strategy for the enantioselective
synthesis of polycyclic compounds.
More recently we became interested in a variation of
this strategy which combines an asymmetric metallation
(step 1) with a ring-closing metathesis (RCM) as a
general route to enantiomerically pure b-hydroxy-allyl-
silanes 1 which can be looked upon as chiral equivalents
of cyclic conjugated dienes (Scheme 2). The dense func-
tionality of these products make them prone to undergo
useful transformations into a wide range of enantiomeri-
cally enriched mono- and polycyclic molecules.
Scheme 1.
Examples of sequential asymmetric allylation-RCM
have been reported, but in these cases the olefinic
partners for the RCM were linked by a heteroatom
which became part of the newly formed ring.2 The
sequence of Scheme 2 has been very recently investi-
gated by Roush et al. who showed that it could be
elegantly applied to the synthesis of conduritols and
inositols of high enantiomeric purity.3 This report
* Corresponding author. Tel.: +33 5 4000 2217 or 2216; fax: +33 5 40
00 22 15; e-mail: l.ghosez@iecb-polytechnique.u-bordeaux.fr
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01791-X

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L. de Fays et al. / Tetrahedron Letters 44 (2003) 7197–7199
sis (Table 2). The configurations of the two new stereo-
genic centers (3S, 4R) of 4a were assigned by X-ray
diffraction analysis.1 The absolute configurations of
5a–c were assigned by analogy. t-Butyldimethylsilyl
ethers 5a,b underwent an extremely fast RCM reaction
in the presence of the first generation Grubbs’catalyst 8
(entries 1 and 2). Thus, with 5b, the RCM was com-
pleted in one hour in refluxing dichloromethane with as
little as 0.05 mol% catalyst (entry 3). The reaction was
much slower with the free alcohol 4b which is a better
coordinating group than the corresponding TBS ether
and could therefore deactivate the catalyst (entry 4).2a
The RCM of the homologous diene 5c was much
slower, requiring higher temperatures and more catalyst
(entry 5). However the use of 2 mol% of the new
generation Grubbs’ catalyst 9 enabled the reaction to
take place at room temperature in 2 hours (entry 6).
In our studies, the allylmetallation (step 1 of Scheme 2)
of the unsaturated aldehydes 3a–c4 was effected with
the (E)-g-dimethylphenylsilyl substituted titanium
reagent 2 generated from allyldimethylphenylsilane, n-
BuLi and (R,R)-Cl-TiCpTADDOL (Table 1).5
The reaction gave only the anti-b-hydroxyallylsilanes
4a–c in good yields and high enantiomeric purities.
Silylation of 4a–c yielded the corresponding silyl ethers
5a–c which were submitted to the ring-closing metathe-
Table 1. Asymmetric allylmetallation of 3-butenal, 4-pen-
tenal and 5-hexenal with 2
Compounds 6a–c contain a unique combination of an
allyl- and a b-silyloxysilane which should be prone to
undergo interesting transformations leading to a wide
variety of enantioenriched, highly functionnalized syn-
thetic building blocks. Scheme 3 shows a selection of
diastereoselective transformations illustrating the syn-
thetic utility of 6a–c. In these transformations, the silyl
group acts as stereodirecting group favouring the attack
on the opposite face. The enantiomeric purity of all
compounds described in Scheme 3 were identical to
those of anti-b-hydroxyallylsilanes 4a–c.
Entry
Product
n
Yield
de (%)
ee (%)
1
2
3
4a
4b
4c
1
2
3
68
68
75
>98
>98
>98
96
92
90
Clearly the synthetic utility of this asymmetric allyl-
metallation-RCM sequence would be greatly enhanced
if it could be successfully applied to substituted alde-
hydes (Scheme 4). We have examined the silyl allyltita-
nation of the acetonide-protected aldehyde 14 which
Reagents and conditions: (a) n-BuLi (1.1 equiv.) in THF, 20 min, rt
then (R,R)-Cl-TiCpTADDOL (1.15 equiv.), 30 min, −78°C to give a
solution of 2; (b) aldehyde 3 (1 equiv.), 3 h, −78°C, 40% aqueous
NH4F, 15 h, rt, flash chromatography (100% CH2Cl2), ee determined
by HPLC on a Chiralcel AS or OD column.
Table 2. Ring-closing metathesis of 4b and 5a,c
Entry
Diene
n
Cat. (mol%)
Conditions for (b)
Prod.
Yield (%)
1
2
3
4
5
6
5a
5b
5b
4b
5c
5c
1
2
2
2
3
3
8 (2)
DCM, rt, 5 min
DCM, rt, 2 min
DCM, reflux, 1 h
DCM, rt, 3 h
Toluene, 60°C, 2 h
DCM, rt, 2 h
6a
6b
6b
7
6c
6c
98
99
99
86
93
82
8 (1.6)
8 (0.05)
8 (5)
8 (7.5)
9 (2)
Reagents: (a) TBSCl (1.5 equiv.), imidazole (3 equiv.), 36 h, 50°C, DMF; (b) Mes=2,4,6-trimethylphenyl and Cy=cyclohexyl.

L. de Fays et al. / Tetrahedron Letters 44 (2003) 7197–7199
7199
Figure 1. Lowest energy conformation of 17.
the one occupied by the silyl substituent. However, the
dichlorocyclopropanation reaction under the classical
conditions (PTC or t-BuOK+CHCl3) did not take
place, probably as a result of the steric hindrance on
both faces of the double bond. It is interesting to note
that the dihydroxylation of the double bond was possi-
ble when the two oxygen atoms were not part of a
ring.3b
Scheme 3. Reagents and conditions: (a) N-methyl-1,2-oxido-
1,2,3,4-tetrahydroiso-quinoleine tetrafluoroborate (1 equiv.),
CH2Cl2, rt, 30 min; (b) Ethyl diazoacetate (1.2 equiv.), Cu-
(acac)2 (2 mol%), toluene, 90°C, 3 h; (c) K2OsO4·2H2O (2
mol%), NMO.H2O (1.7 equiv.), H2O/THF, rt, 48 h; (d)
Et3BnNCl (0.1 equiv.), NaOH 50%, CHCl3, rt, 15 h.
Acknowledgements
This work was supported by a MENRT fellowship
(LdF) and the Fonds National de la Recherche Scien-
tifique (J.-M.A.). We thank the ‘Conseil Re´gional
d’Aquitaine’ and the University of Bordeaux I for
support of our Institute.
References
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Scheme 4. Reagents and conditions: (a) n-BuLi (1.1 equiv.) in
THF, 20 min, rt then (R,R)-Cl-TiCpTADDOL (1.15 equiv.),
30 min, −78°C then 14 (1 equiv.), 3 h, −78°C, 40% aqueous
NH4F, 15 h, rt; (b) pyridine (3.5 equiv.), CH3COCl (2.5
equiv.), DCM, 4 h, rt; (c) Grubbs’catalyst 9 (8 mol%), boiling
DCM, 2 h.
proceeded indeed with high diastereoselectivity to give
the corresponding anti-b-hydroxyallylsilane 15. The
corresponding acetate 16 was subjected to RCM in the
presence of the second generation Grubbs’catalyst to
give 80% yield of the polysubstituted cylohexene 17 in
high enantiomeric purity (ee>95%).
1H NMR analysis and molecular modeling (Monte
Carlo exploration of conformational space with MM3
force field)6 of 17 suggested a half-chair conformation
with a pseudoaxial silyl substituent (Fig. 1). This should
allow an interaction (b-effect) with the olefinic bond
and favor electrophilic attack on the face opposite to
6. We thank Dr M. Laguerre for his help.