Elongation of β-hydroxyenones by cross-metathesis

Article abstract of DOI:10.1016/j.tetlet.2005.10.037

Enantioenriched aldol products derived from enones are notoriously difficult to prepare due to their sensitivity to retro-aldolisation, elimination and the requirement of a large excess of the enone donor for their preparation. However, some success has b

Full text of DOI:10.1016/j.tetlet.2005.10.037

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 8705–8709
Elongation of b-hydroxyenones by cross-metathesis
*
´
Franck A. Silva and Veronique Gouverneur
Chemistry Research Laboratory, 12 Mansfied Road, University of Oxford, OX1 3TA, UK
Received 7 September 2005; revised 30 September 2005; accepted 12 October 2005
Abstract—Enantioenriched aldol products derived from enones are notoriously difficult to prepare due to their sensitivity to retro-
aldolisation, elimination and the requirement of a large excess of the enone donor for their preparation. However, some success has
been obtained for the preparation of aldol products derived from methylvinylketone and pentenone using zinc-dinuclear catalysts or
catalytic antibodies. Herein, we describe how simple first-generation hydroxyenones can be easily elongated by alkene exchange
with structurally diverse olefinic partners in the presence of Ru-based metathesis catalysts allowing for the preparation of aldol
products difficult to access by direct aldolisation. The data suggest that even though unprotected aldols are suitable for these
cross-metathesis reactions, silyl-protected b-hydroxyenonesgenerally afforded the desired elongated productsin much higher chemi-
cal yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Direct catalytic asymmetric aldol reactions typically
involve relatively simple ketones as donors.1 Only
limited progress has been made in catalytic enantioselec-
tive aldol reactionsof enonesand ynonesdepsite the
enormousysnthetic potential of the correpsonding
multifunctional aldol products, which could be regarded
as versatile building blocks. The major problems to
overcome when using enones and ynones as donors,
are their ability to act aspowerful Michael acceptors
and the tendency of the aldol productsto undergo
retro-aldolisations or eliminations. Thus, their use in
aldol reactionsisvirtually unknown with the exception
of two recent reportsthat decsribed very elegant cata-
lytic asymmetric aldol reactions using methyl vinyl
ketone (MVK) and silyl-protected ynones in the pres-
ence of a dinuclear zinc catalyst.2 These studies are
limited to one representative enone (MVK) and two
ynonesused in combination with a large variety of alde-
hyde acceptors. Recently, we have demonstrated that
the very mild nature of aldolase antibodies allows for
the kinetic resolution of various racemic hydroxyenones
providing the recovered aldolshighly enantiomerically
enriched.3 Aldol productsderived from long-chain
enonescould not be resolved and therefore, thisbiocata-
lytic strategy is also restricted to a limited number of
substrates. Enantioenriched aldol products derived from
simple enones such as MVK or pent-3-en-2-one are
interesting as the existing stereogenic centre can be prop-
agated further in a sequence of diastereoselective trans-
formationsand the double bond can be elongated upon
cross-metathesis in the presence of olefinic partners.4 In
the literature, the cross-metathesis of a,b-unsaturated
5
carbonyl derivativeshasbeen extenisvely tsudied.
In
contrast, to date, only two isolated examples of cross-
metathesis reactions involving b-hydroxyenoneshave
been reported in the literature (Scheme 1, Eqs. 1 and
2). These preliminary results also demonstrated that
upon cross-metathesis, no epimerisation took place,
allowing therefore for the formation of second-genera-
tion enantioenriched hydroxyenones.2a,3 Herein, we
report on the scope and limitation of this elongation
process and on how general this transformation is to
access b-hydroxyenonesderived from firts-generation
aldol productsand variousreadily available olefinic
partners.
We prepared and studied the reactivity of four aldol
products 1–4 formally derived from MVK or pent-3-
en-2-one in combination with two conjugated aldehydes,
namely, p-nitrobenzaldehyde and anisaldehyde. These
aldol products 1–4, being particularly sensitive to elimi-
nation, were selected to test the mildness of the proposed
elongation procedure. Aldol products 1 and 2 derived
from pent-3-en-2-one were prepared by direct aldolisa-
tion in the presence of LDA at low temperature. This
strategy could not be applied for the preparation of
aldol 3 asonly productsof decomposition were formed
Keywords: Cross-metathesis; Hydroxyenones; Aldol reaction.
*
Corresponding author. Tel./fax: +44 1865 275 644; e-mail:
veronique.gouverneur@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.037

8706
F. A. Silva, V. Gouverneur / Tetrahedron Letters 46 (2005) 8705–8709
OBn
OH
O
OH
O
BnO
TBSO
TBSO
5 mol % 8
OBn
DCM, reflux, 4 h
65%
eq.12(a)
OH
O
OH
O
dodecene
5 mol % 7
9
DCM, reflux, 4 h
90% ee
91% ee
MeO
MeO
Scheme 1. Elongation of b-hydroxyenones.2a,3
eq.23
80%
under these conditions. The b-hydroxyenone 3 waspre-
reactionswere best performed in dichloromethane at re-
flux or at room temperature using an excess of the ole-
finic partner. The use of toluene at 80 °C wasnot
advantageous as under these conditions, products of
elimination were formed in significant amounts. We
therefore studied the scope and limitations of these
cross-metathesis reactions using 5 mol % of the Hov-
eyda–Grubbscatalyts 7 in DCM using 3 equiv of the
olefinic partner (Scheme 3).
pared in good overall yield using a three-step sequence
starting with the synthesis of b-hydroxyester 5 followed
by the conversion of this ester into the corresponding
Weinreb amide 6. Treatment of the Weinreb amide 6
with an excess of vinylmagnesium bromide afforded
the unsubstituted aldol product 3, which waspurified
by fast filtration to avoid decomposition.
We also prepared the silyl-protected aldol product 4 to
investigate to what extent the presence of the free
hydroxy group wasbeneficial or detrimental for the
cross-metathesis coupling. The direct protection of 1
Under these conditions, we examined the coupling of
aldol products 1–4 with five representative olefinic
partners, namely ethyl acrylate, methylene cyclohexane,
hex-3-ene-1,6-diol, dodecene and styrene. Our results
are summarised in Table 1. The data showed that for
the unprotected aldol 1, the cross-metathesis with dode-
cene and styrene proceeded smoothly to give the desired
elongated products 9a and 9b in good yields(entries1
and 2). Both productswere formed and isolated aspure
E-isomers. Methylene cyclohexane also proved to be a
suitable substrate and allowed the formation of the
gem-substituted hydroxyenone 9c with an isolated
chemical yield of 42% (entry 3). With olefinsfeaturing
electron-withdrawing groupssuch asethyl acrylate, the
reaction waslow yielding with 24% of the deisred
aldol product 9d isolated (entry 4). Similarly, the
waslow yielding in the preesnce of
t-BuMeSiCl and
imidazole in DMF because the major compound formed
under these conditions is the product resulting from a
Michael addition of imidazole on the double bond.6
However, the desired protected aldol 4 wasobtained
in 97% yield replacing imidazole with diisopropylethyl-
amine (Scheme 2).7
In a preliminary study, we found that the most suitable
catalyst for the cross-metathesis reaction of hydroxy-
enoneswasthe Hoveyda–Grubbscatalyts
78 although
the second-generation Grubbs catalyst 89 gave, in most
cases, the desired products, albeit in lower yields. The
O
O
O
OH O
a
H
H
+
1 R = OMe 57%
2 R = NO2 66%
R
R
OH
a
COOEt
+ MeCOOEt
98%
MeO
5
MeO
b
76%
OH
O
OH
O
c
NMeOMe
55%
3
6
MeO
MeO
MeO
OH
O
t-BuMe2SiO
O
d
4
MeO
97%
Scheme 2. Reagentsand conditions: (a) LDA, THF, À78 °C, 0.5 h; (b) NH(OMe)Me, AlMe3, 0 °C to rt, 3 h then 2 N HCl; (c) vinylmagnesium
bromide, THF, 0 °C then NH4Cl; (d) t-BuMe2SiCl, i-PrNEt2, DMF, rt, 48 h.

F. A. Silva, V. Gouverneur / Tetrahedron Letters 46 (2005) 8705–8709
8707
R5
OR2
O
OR2
O
R5
3 equiv.
R6
R4
R3
R4
5 mol % catalyst 7
R1
R1
DCM
Mes
N
Cl
Cl
N
Mes
Mes
N
Cl
Cl
N
Mes
Ph
Ru
Mes = 2,4,6,-Me3C6H2
Ru
PCy3
O
8
7
Scheme 3. Standard conditionsfor CM of b-hydroxyenones 1–4.
Table 1. CM of aldol products 1–4
Entry
1
Substrate, olefinic partner
Product
Yielda (%)
OH
OH
OH
O
O
1 or 3, dodecene
85 from 1b
76 from 3b
9
9a
MeO
MeO
MeO
2
3
1 or 3, styrene
66 from 1b
70 from 3b
Ph
9b
9c
O
O
O
1 or 3, methylene cyclohexane
42 from 1
50 from 3
OH
OH
OH
OH
4
5
6
7
1, ethyl acrylate
24
24
55
13
COOEt
9d
MeO
MeO
NO2
NO2
OH
1, hex-3-ene-1,6-diol
2, methylene cyclohexane
2, ethyl acrylate
9e
O
10a
O
COOEt
10b
t-BuMe2SiO
O
8
4, dodecene
91
80c
90
62
50
9
11a
MeO
t-BuMe2SiO
O
9
4, styrene
Ph
11b
MeO
t-BuMe2SiO
O
O
O
10
11
4, methylene cyclohexane
4, ethyl acrylate
4, hex-3-ene-1,6-diol
11c
MeO
t-BuMe2SiO
COOEt
11d
MeO
t-BuMe2SiO
12
OH
11e
MeO
a Isolated yields.
b Reaction carried out at room temperature.
c % Conversion.

8708
F. A. Silva, V. Gouverneur / Tetrahedron Letters 46 (2005) 8705–8709
HO
O
R'
t-BuMe2SiO
O
R'
nBu4N+F-, AcOH
THF, rt
R
R
MeO
MeO
11b R = Ph, R' = H
R'
9b yield = 77%
9c yield = 76%
9e yield = 70%
11c
=
R
11e R = CH2CH2OH, R' = H
Scheme 4. Deprotection of aldol products 11b–c and 11e.
cross-coupling of 1 with the unprotected hex-3-ene-1,
6-diol was not synthetically useful as only 24% of the
desired product 9e could be recovered after column
chromatography (entry 5). A similar trend of reactivity
wasobserved for the unprotected aldol 2 derived from
para-nitrobenzaldehyde instead of anisaldehyde, as re-
flected by the similar isolated yields for aldol products
10a–b (entries6 and 7). Aldol products 1 and 2 both
possess a terminal methyl group that can potentially
slow down the alkene exchange process. To test this
hypothesis, we studied next the reactivity of the unpro-
tected aldol product 3 derived from methyl vinyl ketone.
In the presence of dodecene, styrene or methylene cyclo-
hexane, all reactionsproceeded ms oothly to give the
desired products 9a–c with yields very similar to those
obtained with aldol 1 suggesting that the cross-meta-
thesis of terminal double bonds is not advantageous
(entries1–3). With the aim of improving the reaction
yields, we investigated the reactivity of the silyl-pro-
tected aldol 4 to determine to what extent the presence
of the free hydroxy group wasaffecting the efficiency
of the cross-coupling (entries 8–12).10
Indeed, in addition to the problemsoutlined in the intro-
duction such as the sensitivity of b-hydroxyenonesto
retro-aldolisation and elimination, direct aldol reaction
of enonesrequiresthe donor in excessand can therefore
be applied only to readily available a,b-unsaturated
ketones. The elongation process described herein cir-
cumventsthees problemseaisly by allowing for the
introduction of various substituents by a simple alkene
exchange reaction carried out in the presence of a Ru-
based metathesis catalyst.
Acknowledgements
The European Community isgratefully acknowledged
for generousfinancial uspport to F.S. (MRTN-CT-
2003-505020). We also thank Dr. Neil Hodnett who
wasfunded by the Leverhulme Truts (F/08 341/B) for
preliminary synthetic efforts on this project.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.037.
The results revealed that for all the olefinic partners, the
isolated yields of elongated products were significantly
improved reaching 91% for the reactionsinvolving
unfunctionalised olefins (entries 8–10) and 62% with
ethyl acrylate (entry 11). We were pleased to find that
hex-3-ene-1,6-diol wasa usitable olefinic partner for
compound 4 asthe deisred elongated aldol product
11e featuring both a silyl-protected secondary alcohol
and a primary unprotected alcohol wasioslated in
50% yield (entry 12). For all compounds 11a–e, the E/
Z-selectivity was excellent as no trace of the Z-isomer
could be detected in the crude mixtures. The presence
of the protected alcohol also presents the advantage of
allowing for easy purification of the products. The
deprotection of aldols 11a–e wascarried out uisng a
mixture of TBAF and acetic acid in THF allowing the
preparation of the free elongated aldol products 9b–c
and 9e with chemical yieldsranging from 70% to 77%
(Scheme 4).11 The purity is superior for these com-
pounds by comparison with those obtained by direct
cross-metathesis of the unprotected aldol products. This
deprotection procedure iscompatible with enantioen-
riched aldol productsasprevioulsy demontsrated in
our group for structurally related compounds.12
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