α,β-unsaturated δ-lactones from copper-catalyzed asymmetric vinylogous mukaiyama reactions of aldehydes: Scope and mechanistic insights

Article abstract of DOI:10.1002/chem.200600335

A direct regio-, diastereo-, and enantiocontrolled access to α,β-unsaturated δ-lactones is described, based on the reaction of a silyl dienolate and an aldehyde in the presence of 10% of Carreira's catalyst. The scope and limitations of this reaction, as well as mechanistic insights concerning the reactivity of an allyl copper species, are discussed.

Full text of DOI:10.1002/chem.200600335

DOI: 10.1002/chem.200600335
a,b-Unsaturated d-Lactones from Copper-Catalyzed Asymmetric Vinylogous
Mukaiyama Reactions of Aldehydes: Scope and Mechanistic Insights
BelØn Bazµn-Tejeda,[a] Guillaume Bluet,[a] Garance Broustal,[a] and
Jean-Marc Campagne*[a, b]
Abstract: A direct regio-, diastereo-, and enantiocontrolled access to a,b-unsatu-
rated d-lactones is described, based on the reaction of a silyl dienolate and an al-
dehyde in the presence of 10% of Carreiraꢀs catalyst. The scope and limitations of
this reaction, as well as mechanistic insights concerning the reactivity of an allyl
copper species, are discussed.
Keywords: aldol reaction · copper ·
lactones mechanistic studies
vinylogous Mukaiyama reactions
·
·
Introduction
The synthetic potential of this reaction was rapidly recog-
nized and the so-called vinylogous Mukaiyama reaction has
found numerous synthetic applications, as illustrated, for ex-
ample, in the total syntheses of lepicidin A, swhinolide A,
ratjadone, and aurilide, as well as several synthetic ap-
proaches to natural products.[1d,5–8] Despite this great syn-
thetic potential (an aldol product with an extra conjugated
double bond, which can easily undergo further manipula-
tion), catalytic and asymmetric vinylogous Mukaiyama reac-
tions of a,b-unsaturated esters (ketones) have long re-
mained an unexplored area.[1a,c] The development of regio-
(a/g), diastereo- (E/Z, syn/anti), and enantiocontrolled reac-
tions is, notably in the context of the total synthesis of poly-
propionates of natural products, of great interest. In 1998, in
the course of a project aimed at the total synthesis of octa-
lactin A, we became interested in the development of cata-
lytic and asymmetric vinylogous Mukaiyama reactions.
More recently, impressive results have been obtained in
Denmarkꢀs and Evansꢀ groups using phosphoramidite-based
Lewis bases and Cu–PyBox (PyBox=2,6-bis[(4S)-isopropyl-
2-oxazolin-2-yl]pyridine) Lewis acids, respectively.[9–12] In
this paper, we wish to report our own efforts to develop cat-
alytic and asymmetric vinylogous Mukaiyama (CAVM) re-
actions, which have opened a catalytic and asymmetric
access to a,b-unsaturated d-lactones.
The vinylogous aldol reaction of an a,b-unsaturated ester
(or ketone) (vinylogy is the transmission of electronic effects
through a conjugated system) is an aldol reaction leading to
a d-hydroxy a,b-unsaturated carbonyl compound.[1] Howev-
er, this reaction generally suffers from regioselectivity prob-
lems, affording an a,g-mixture of aldol products
(Scheme 1).[2] Due to this lack of regioselectivity, this meth-
Scheme 1. The vinylogous aldol reaction affording an a,g-mixture of
aldol products.
odology did not find synthetic success until the early 1970s.
At that time, first Mukaiyama,[3] and then Paterson and
Fleming,[4] described the use of silyl dienolates in the pres-
ence of Lewis acids at low temperatures, which led to the
exclusive formation of the g-aldol product.
[a]Dr. B. Bazµn-Tejeda, Dr. G. Bluet, G. Broustal, Dr. J.-M. Campagne
Institut de Chimie des Substances Naturelles, CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax : (+33)467144322
Results and Discussion
By analogy with the structure of the octalactin side chain,
we initiated our studies by carrying out the reaction of the
a-substituted silyl dienolate 1 with aldehydes in the pres-
ence of various catalysts (Ti-binol (binol=1,1’-binaphtha-
E-mail: jean-marc.campagne@enscm.fr
[b]Dr. J.-M. Campagne
Current address: Ecole Nationale SupØrieure de Chimie
8, rue de lꢀEcole Normale, 34296 Montpellier (France)
8358
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FULL PAPER
lene-2,2’-diol), Carreiraꢀs catalyst[13] [CuF(tol-binap)]
(binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), and
various chiral ammonium fluorides derived from cinchona
alkaloids). Interesting results were obtained by using Carrei-
raꢀs catalyst, albeit with modest enantioselectivities (up to
77% ee) (Scheme 2).[14]
Scheme 2. CAVM reaction using Carreiraꢀs catalyst.
Scheme 4. Postulated reaction mechanism showing the activated a-
copper enolate A species and a related six-membered transition state.L*
= tol-binap.
According to Carreiraꢀs mechanistic studies,[13] a catalytic
cycle could be postulated involving the formation of a
copper dienolate (Scheme 3). However, this catalytic cycle
to the formation of the expected “linear” vinylogous aldol
product 5a and the a,b-unsaturated lactone 4a (Scheme 5).
Interestingly, the linear product was obtained without any
Scheme 5. Reaction of 2 with Carreiraꢀs catalyst and benzaldehyde to
give 5a and 4a.
Scheme 3. A catalytic cycle involving the formation of a copper dienolate
for a CAVM reaction using Carreiraꢀs catalyst. L* = tol-binap.
selectivity (syn/anti 1:1; 8% ee), whereas the lactone was ob-
tained as a single anti diastereoisomer with 87% ee.[16]
a,b-Unsaturated lactones are highly valuable intermedi-
ates present in a large number of natural products[17] pos-
sessing potent (mainly cytotoxic) biological activities. Exam-
ples include ratjadone,[6b] spicigerolide,[18] callystatin,[19] go-
niothalamin,[20] and fostriecin.[21] Furthermore, the unsaturat-
ed lactone moiety has been found to play a fundamental
role in the biological activity of fostriecin.[21b] Accordingly,
this methodology was applied to several other aliphatic, a,b-
unsaturated, and aromatic aldehydes, as illustrated in
Table 1. Diastereomerically pure anti lactones 4a–g were ob-
tained in moderate to good yields, with enantioselectivities
ranging from 85% to 91%.
As the two dienolates 1 and 2 differ only in the position
of the methyl group, it was intriguing to study the behavior
of dienolate 6 (which bears no methyl group) under the
same reaction conditions. Hence, dienolate 6a was synthe-
sized, starting from ethyl crotonate, in one step and 50–70%
yield as a 9:1 Z/E mixture (Scheme 6).[22] However, both the
does not account for the origin of the enantioselectivity be-
cause the chiral copper center seems to be far away from
the prochiral aldehyde.
To explain the origin of the enantioselectivity, we first
postulated that the activated species might be an a-copper
enolate A (Scheme 4).[15] Thus, a six-membered transition
state (Scheme 4, equation (a)), accounting for the origin of
the enantioselectivity, was postulated.
According to this hypothesis and starting from a g-substi-
tuted dienolate 2, we thus anticipated to control, through a
related six-membered transition state, both enantio- and dia-
stereoselectivities (Scheme 4, equation (b)). Accordingly, g-
substituted dienolate 2 was synthesized from the commer-
cially available ester 3 in 60% yield as an inseparable
(3E,1Z/E) mixture. Its reactivity was first studied in the
presence of Carreiraꢀs catalyst and benzaldehyde, which led
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J.-M. Campagne et al.
Table 1. Catalytic asymmetric vinylogous Mukaiyama reactions of silyl
dienolate 2 with various aldehydes in the presence of [CuF{(S)-tol-
binap}](10%).
Table 2. Catalytic asymmetric vinylogous Mukaiyama reactions of silyl
dienolate 6a with various aldehydes in the presence of [CuF{(S)-tol-
binap}](10%).
Entry Aldehyde
Yield Ratio[a]
[%] 4/5
Lactones 4
anti/
Entry Aldehyde
6a
equiv
[conc
Lactone 7:8[a] Lactone ee[b]
ee
[%]
(isolated [%]
yield
G
syn[a]
[m]]
[%])
1
benzaldehyde
85
86:14 4a >98:2 87[b]
(98)[c]
1
2
benzaldehyde
1.5
7aa
60:40
80:20
90:10
90:10
60:40
90:10
70:30
75:25
60:40
75:25
50
68
72
80
64
85
60
65
40
65
85
2
3
4
5
6
7
1-naphthaldehyde
2,3-dimethoxybenzaldehyde
furaldehyde
cinnamaldehyde
iPrCHO
95
87
60
60
65
60
80:20 4b >98:2 85[d]
81:19 4c >98:2 91[e]
50:50 4d >98:2 86[f]
70:30 4e >98:2 82[g]
64:36 4 f >98:2 91[h]
36:64 4g >98:2 90[h]
A
2
85
A
3
2
85
AHCTREUNG
butyraldehyde
4
7ab
7ac
75 (97)[c]
AHCTREUNG
[a]Determined by 1H NMR of the crude product. [b]HPLC DAICEL-
OD, hexane-2-propanol, 95:5. [c] ee after recrystallization (heptane).
[d]HPLC DAICEL-OJ, hexane/2-propanol, 82:18. [e]HPLC DAICEL-
OJ, hexane/2-propanol, 95:5. [f]HPLC DAICEL-OJ, hexane/2-propanol,
95:5. [g]HPLC DAICEL-OJ, hexane/2-propanol, 90:10. [h]HPLC Chir-
alPAK AD, hexane/ethanol, 99:1.
5
2,3-dimethoxy-
benzaldehyde
82
82
60
60
85
85
AHCTREUNG
6
2
AHCTREUNG
7
7ad
7ae
AHCTREUNG
8
2
AHCTREUNG
9
AHCTREUNG
10
2
A
Scheme 6. Synthesis of dienolate 6a from ethyl crotonate. LDA = lithi-
um diisopropylamide.
[a]Determined by 1H NMR of the crude product. [b]Determined by
chiral HPLC. [c] ee after recrystallization from diethyl ether.
synthesis and purification (by kugelrohr distillation) of dien-
olate 6a proved troublesome, particularly the removal of all
of the residual 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyri-
midinone (DMPU).[22b] Incidentally, all efforts to improve
this protocol by using 2,2,6,6-tetramethylpiperidine (TMP),
hexamethylphosphoramide (HMPA), phosphoric acid tripyr-
rolidine, or lithium bis(trimethylsilyl)amide (LiHMDS)
proved unsuccessful in our hands.
The reaction of dienolate 6a (R = Et, R’ = Me) with
benzaldehyde in the presence of 10% of Carreiraꢀs catalyst,
[CuF{(S)-tol-binap}], led to the formation of a 60:40 mixture
of the a,b-unsaturated d-lactone 7aa and the linear vinylo-
gous aldol product 8aa (Scheme 7).
and 5), a,b-unsaturated (entry 7), and aliphatic aldehydes
(entry 9), leading to the predominant formation of the lac-
tones 7ab–ae in good yields and with good enantioselectivi-
ties.
The first attempts to optimize the reaction (with benzal-
dehyde) showed the crucial importance of the amount of
silyl dienolate 6a on the lactone/linear product ratio
(Table 2, entries 2 and 3). By simply conducting the reaction
with two equivalents of silyl dienolate at a concentration of
0.1m, the ratio could be increased to 90:10 without a de-
crease in the enantioselectivity (85% ee). These modified
conditions also proved to be beneficial in the reactions with
2,3-dimethoxybenzaldehyde (Table 2, entry 6) and isobutyr-
aldehyde (entry 10). The reaction with cinnamaldehyde
(entry 8) provides a direct and one-step access (65% yield
and 60% ee) to goniothala-
min,[20] a known natural product
that possesses interesting bio-
logical activities[20a,b] and for
Scheme 7. Reaction of 6a (R = Et, R’ = Me) with benzaldehyde in the
presence of Carreiraꢀs catalyst to give 7aa and 8aa.
which a multistep synthesis has
previously been described.[20c,d]
However,
all
experiments
aimed at increasing the enantioselectivity by changing the
reaction conditions (ligand, dienolate structure) or by re-
crystallization proved unsuccessful (vide infra).
Starting with these initial experiments, we set out to opti-
mize this methodology and to gain insight into the reaction
mechanism by modifying the various reaction parameters
(precatalysts, dienolate structure, ligand, etc.) in a model re-
action of silyl dienolates 6 with benzaldehyde.
Purification by using flash chromatography led to the iso-
lation of the lactone 7aa in 50% yield and 85% ee, whereas
the linear product 8aa was isolated in 8% ee. The S configu-
ration was assigned to the newly created stereogenic center
by comparison with the previously described enantiomeri-
cally pure lactone.[23] As summarized in Table 2, the same
reaction was carried out with various aromatic (entries 4
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Mukaiyama Reactions
FULL PAPER
Influence of the precatalyst: In the original procedure,[13] the
Table 4. Influence of the structure of the silyl dienolate 6 on the CAVM
reaction with benzaldehyde.
precatalyst was made in situ by mixing Cu(OTf)2 (10%;
G
Entry
R
Silyl
group
Dienolate Lactone/
Yield
(lactone+linear)
[%]
ee
Tf=triflate), a nonhygroscopic source of fluoride, tetrabutyl-
ammonium triphenyldifluorosilicate (TBAT) (20%), and the
ligand (11%) (Table 3, entry 1). The amount of precatalyst
can be reduced to 5% with no deleterious effect on yield,
ee, or lactone/linear product ratio (Table 3, entry 2). Howev-
er, no reaction was observed with just 1% of precatalyst
(Table 3, entry 3). In order to substitute the fluoride source,
Z/E ratio
linear
ratio
ACHTREUNG
1
2
3
4
Et TMS
Et TBDMS 6b 90:10
Me TMS
tBu TMS
6a 90:10
90:10
30:70
85:15
15:85
85
43
80
78
85
81
80
99
6c 90:10
6d 80:20
Influence of the ligand: In
order to optimize the enantio-
selectivity, a screening of sever-
al ligands was carried out
(binap, binap*,[27] binap-Fu,[28]
Cl-MeO-biphep, MeO-biphep,
Trostꢀs ligand, difluorphos,[29]
Table 3. Influence of the copper precatalyst on the CAVM reaction of silyl dienolate 6a with benzaldehyde.
Entry
Copper
source
Base
[%]
Tol-binap
[%]
Lactone/linear
ratio
Lactone+linear
(combined yield) [%]
ee [%]
1
2
Cu
10%
Cu(OTf)2
5%
Cu(OTf)2
1%
Cu(OTf)2
10%
CuCl
10%
CuCl
10%
CuCl
10%
CuCl
1%
N
TBAT
(20)
TBAT
(10)
TBAT
(2)
TBAT
(10)
TBAT
(20)
NaOtBu
(10)
NaOtBu
(10)
NaOtBu
(1)
11
90:10
85
82
–
87
87
–
5
85:15
C1-tunaphos,[30] segphos.[31]
)
3
1
no reaction
no reaction
0:100
As previously observed by
other groups,[29–31] there is a cor-
relation between the dihedral
angle and the enantioselectivity,
but again to the detriment of
the lactone/linear ratio (com-
pare entries 3, 5, and 10 in
Table 5). However, the best
ligand in terms of enantioselec-
tivity and lactone/linear ratio
appears to be MeO-biphep,
with which the lactone 7aa was
4
11
11
11
5
–
–
5
42
70
60
–
–
6
60:40
87
87
–
7
50:50
8
1
no reaction
–
9
Cu
A
NaOtBu
(10)
–
10
10
<10
(a-product)
–
10%
CuF2
10%
10
no reaction
–
–
[CutBuO(tol-binap)](from
CuCl, NaOtBu, and tol-binap)
was successfully used, leading
to the lactone/linear product
mixture in a 60:40 ratio, with
87% ee
for
the
lactone
(Table 3, entry 6). Finally, under
Riantꢀs conditions in the pres-
ence of CuF2 and tol-binap, no
reaction was observed.[24]
Dienolate structure: Modifica-
tion of the silyl group was next
investigated by using a tert-bu-
tyldimethylsilyl
(TBDMS)
group.[25] However, although a
dramatic decrease in the lactone/linear ratio could be ob-
served, the enantioselectivity remained unchanged (Table 4,
entry 2). The ester group was found to have a greater influ-
ence on the enantioselectivity, as illustrated with dienolate
6d, for which the enantioselectivity could be raised up to
99% ee, although to the detriment of the lactone/linear ratio
(Table4, entry 4).[26]
obtained in 62% isolated yield and 92% ee (Table 5,
entry 5).
Mechanistic insights: As regards the reaction mechanism,
several hypotheses may be envisaged at first glance
(Scheme 8): a) a hetero-Diels–Alder (HDA)-type mecha-
nism;[32–34] b) copper playing the role of Lewis acid in a clas-
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J.-M. Campagne et al.
Table 5. Ligand effects on the CAVM reaction of silyl dienolate 6a with
benzaldehyde.
A similar situation was observed with the unsubstituted
dienolate 6a (Scheme 10). Starting from a 90:10 mixture of
the Z/E dienolate 6a (from ethyl crotonate) or from a 40:60
Entry Ligand
Dihedral Lactone/linear Isolated yield ee
angle
7aa/8aa
of 7aa
7aa
[8]
ratio
[%]
[%]
1
2
3
4
5
6
7
8
tol-binap
binap*
binap
Cl-MeO-biphep
MeO-biphep
binap-Fu
Trostꢀs ligand
difluorphos
segphos
90:10
80:20
75:25
60:40
78:22
65:35
0:100
50:50
60:40
50:50
75
68
49
54
62
49
–
40
51
35
85
75
70
83
92
60
–
94
96
96
86.2
72.3
67.6
67.2
60.0
9
10
Scheme 10. Synthesis of 6a and 6a’.
C1-tunaphos
Z/E dienolate 6a’ (obtained from the b,g-unconjugated
ester), the same lactone 4a was obtained in similar yield
and with similar enantioselectivity.
Consequently, a mechanism involving an eight-membered
transition state (hypothesis (b), Scheme 8) can probably be
ruled out. Among the other possibilities, we serendipitously
obtained some mechanistic insights using the Segphos
ligand. We observed that the CAVM reactions were faster in
the presence of segphos[31] compared to those performed
with tol-binap. Indeed, the CAVM reaction could be carried
out at À788C with segphos (no reaction occurs with tol-
binap), leading to a 1:1 mixture of the two diastereoisomeric
a-aldol products (Scheme 11). After purification on silica
Scheme 8. Possible CAVM reaction mechanisms. L* = tol-binap.
sical Mukaiyama reaction involving an eight-membered
transition state;[35] c) reaction involving, as previously postu-
lated (vide supra), the formation of an allyl–copper inter-
mediate.
According to hypothesis (b), the anti diastereoselectivity
may stem from the E stereochemistry of the terminal dieno-
late double bond. Consequently, starting from a Z-terminal
double-bond dienolate, a syn diastereoselectivity outcome
could be expected. In order to test this hypothesis, the 3Z
dienolate 2’ was synthesized starting from the corresponding
a,b-unsaturated ester (Scheme 9).[6a] However, when this di-
enolate 2’ was submitted to the vinylogous Mukaiyama reac-
tion with benzaldehyde in the presence of Carreiraꢀs catalyst
(10%), lactone 4a was obtained with the same anti diaster-
eoselectivity (anti/syn 98:2, 82–84% ee) as previously ob-
served with dienolate 2.
Scheme 11. The CAVM reaction with segphos as the catalyst ligand at
À788C.
gel, the two diastereoisomers 9 and 10 were isolated in a 1:1
ratio and with low enantiomeric excesses of 13% and
12% ee, respectively.
In order to monitor the evolution of these two a-aldol
products under the reaction conditions at room temperature,
these compounds were next independently synthesized[36]
from silyl dienolate and benzaldehyde in the presence of
TBAT at À788C. This reaction
yielded a 4:4:2 mixture of anti-
a 9, syn-a 10, and racemic g-
aldol 8aa (Scheme 12).
The three products were sep-
arated by using flash chroma-
tography and, independently,
were treated with a catalytic
amount of the chiral copper
catalyst. The two racemic a-
Scheme 9. Synthesis of 3Z dienolate 2’ from the corresponding a,b-unsaturated ester.
compounds led to the same
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Mukaiyama Reactions
FULL PAPER
(Scheme 16). The a-copper enolate may evolve into the O-
enolate B, but such a process is known to be particularly
slow and thus the HDA pathway may not be the predomi-
Scheme 12. Synthesis of anti-a 9, syn-a 10, and racemic g-aldol 8aa.
mixture of lactone and linear product, whereas linear 8aa
remained unchanged. Interestingly, the same lactone was
isolated with the same enantiomeric excess (85% ee) from
both the racemic syn and anti diastereoisomers (Scheme 13).
Scheme 16. Proposed CAVM retro-aldol reaction mechanism leading to
an allyl–copper species A. L* = tol-binap.
nant one.[15,37] We thus believe the allyl–copper to be the
active species in the asymmetric transformation. Such spe-
cies have also recently been invoked in some catalytic and
asymmetric allylation reactions that take place in the pres-
ence of TBAT and a copper catalyst.[38] In conclusion, the
CAVM might be viewed as a racemic “regular” a-aldol reac-
tion, followed by an asymmetric allylation (Scheme 16).
Scheme 13. Synthesis of 7aa and 8aa from both the racemic syn and anti
diastereoisomers.
From these observations, the CAVM appears to proceed
by two successive steps: first by a nonselective “regular” a-
aldol reaction, followed by a rearrangement to give the
enantio-enriched lactone 4a (Scheme 14).
Synthetic applications: The synthetic potential of the
CAVM reaction has been illustrated in the short accesses
that it provides to the Prelog–Djerassi lactone,[16a] and the
three main fragments of discodermolide[16b] starting from
a,b-unsaturated lactone 11. This lactone 11 was obtained as
a single diastereoisomer in 60% isolated yield starting from
chiral aldehyde 12 (obtained in two steps from the corre-
sponding Roche ester). From this lactone intermediate, the
Prelog–Djerassi lactone was then obtained in three steps
and the three main fragments of discodermolide, C1–C5,
C7–C15, and C17–C24, in two, five, and two steps, respec-
tively (Scheme 17).
Scheme 14. The two steps of the CAVM reaction.
We have shown that this rearrangement is not an intramo-
lecular reaction. Indeed, when the racemic a-aldol product 9
was treated with the copper catalyst in the presence of an
another aldehyde (2,3-dimethoxybenzaldehyde), a 1.5:1 mix-
ture of the two lactones 7aa and 7ac was obtained
(Scheme 15).
To explain this rearrangement, we hypothesize a retro-
aldol reaction leading to an allyl–copper species
A
Scheme 15. Reaction of rac-9 with 2,3-dimethoxybenzaldehyde in the
presence of a copper catalyst to give lactones 7aa and 7ac.
Scheme 17. Synthesis of the Prelog–Djerassi lactone and the three main
fragments of discodermolide.
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J.-M. Campagne et al.
(300 MHz, CDCl3, 258C): d = 0.23 (s, 9H), 1.72 (dd, J = 1.4, 6.9 Hz,
3H), 3.56 (s, 3H), 4.41 (d, J = 10.3 Hz, 1H), 5.33 (dq, J = 14.9, 6.9 Hz,
1H), 6.10 ppm (m, 1H). Data are in accordance with those reported pre-
viously.[38]
Conclusion
We have developed an efficient catalytic and asymmetric
access to a,b-unsaturated lactones based on a one-step
regio- (g/a), diastereo- (anti/syn; Z/E), and enantioselective
protocol. From a mechanistic point of view, the results are
indicative of a mechanism involving a nonselective a-aldol
reaction followed by an asymmetric allylation. Further de-
velopments and synthetic applications of this methodology
are currently under investigation in our group.
A
to the above-described general procedure, and starting from commercial-
ly available (E)-methyl pent-2-enoate, the silyl dienolate 2’ was obtained
after kugelrohr distillation (508C, 1 mmHg) in 60% yield as an insepara-
ble mixture (1Z/E 70:30, 3E/Z 90:10). 1H NMR (300 MHz, CDCl3,
258C): d = 0.21 (s, 9H), 1.66 (dd, J = 1.6, 6.8 Hz, 3H), 3.59 (s, 3H), 4.54
(d, J = 10.8 Hz, 1H), 5.91 (m, 1H), 6.11 ppm (tq, J = 10.8, 1.7 Hz, 1H).
(1Z)-(1-Ethoxybuta-1,3-dienyloxy)trimethylsilane (6a):[36] According to
the above-described general procedure and starting from ethyl crotonate,
kugelrohr distillation of the crude mixture (458C, 1 mmHg) afforded 6a
(1.3 g, 70% yield) as an inseparable mixture, Z/E 90:10. 1H NMR
(300 MHz, CDCl3, 258C): d = 0.24 (s, 8.1H), 0.27 (s, 0.9H), 1.25 (t, J =
7.1 Hz, 0.3H), 1.31 (t, J = 7.0 Hz, 2.7H), 3.81 (q, J = 7.0 Hz, 1.8H), 3.92
(q, J = 7.1 Hz, 0.2H), 4.46 (d, J = 10.4 Hz, 0.9H), 4.54 (d, J = 10.4 Hz,
0.1H), 4.59 (dd, J = 1.8, 10.4 Hz, 1H), 4.83 (dd, J = 1.8, 17.2 Hz, 1H),
6.51 ppm (dt, J = 10.4, 17.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C):
d = 14.0, 62.4, 80.4, 106.9, 131.7, 157.2 ppm. Data are in accordance with
those reported previously.[36]
ExperimentalSection
General: Unless otherwise specified, the reactions were carried out in
oven-dried glassware under an argon atmosphere. H and 13C NMR spec-
1
tra were recorded at 300 and 75 MHz, respectively, in CDCl3 as solvent;
chemical shifts are given in ppm. Column chromatography was per-
formed on 230–-400 mesh silica gel. THF was distilled from sodium/ben-
zophenone. Dichloromethane, diisopropylamine, and chlorotrimethylsi-
lane were distilled over CaH2 prior to use. Elemental analyses were car-
ried out by the “laboratoire de micro-analyse ICSN, Gif-sur-Yvette”. IR
spectra were recorded on an FTIR spectrometer. Mass spectra were re-
corded with a Navigator LC/MS (source AQA) in electrospray ionization
mode. Optical rotations were determined operating at the sodium D line.
(5S)-Methyl-(6S)-phenyl-5,6-dihydropyran-2-one (4a): According to the
above-described general procedure for the MVCA reaction, lactone 4a
was obtained in 60% yield as a white powder. M.p. 66–688C; [a]D20
=
1
À39.8 (c = 0.67 in chloroform); H NMR (300 MHz, CDCl3, 258C): d =
1.02 (d, J = 7.2 Hz, 3H), 2.83 (m, 1H), 4.98 (d, J = 10.7 Hz, 1H), 6.10
(dd, J = 9.7, 2.5 Hz, 1H), 6.76 (dd, J = 9.7, 1.9 Hz, 1H), 7.39 ppm (m,
5H); 13C NMR (75 MHz, CDCl3, 258C): d = 15.8, 36.2, 86.0, 120.4, 127.4
(2C), 128.5 (2C), 128.9, 137.3, 151.1, 163.9 ppm; IR (KCl): n˜ = 3020,
1723, 1215 cmÀ1; MS (EI): m/z (%): 188 (20) [M+], 128 (20), 105 (15), 82
(100), 81 (42); elemental analysis calcd for C12H12O2 : C 76.57, H 6.43;
found: C 76.36, H 6.82; HPLC (DAICEL-OD, hexane/2-propanol, 95:5):
87% ee.
General procedure for the synthesis of silyl dienolates starting from a,b-
unsaturated esters: nBuLi (7 mL, 11 mmol) was added dropwise to a sol-
ution of N,N’-diisopropylethylamine (DIPA; 1.5 mL, 11 mmol) in anhy-
drous THF (20 mL) at À508C. The mixture was stirred for 30 min,
cooled to À788C, and then DMPU (1.4 mL, 11 mmol) was added drop-
wise. The resulting solution was stirred for 30 min and then the a,b-unsa-
turated ester (10 mmol) was added. This mixture was stirred for 30 min
and then a solution of trimethylsilane chloride (TMSCl; 2 mL) in anhy-
drous THF (2 mL) was added over a period of 15 min. The resulting solu-
tion was allowed to warm to room temperature and stirred for 2 h. The
solvent was removed under reduced pressure, the residue was taken up
in pentane (50 mL), and this solution was filtered. The solvent was re-
moved under reduced pressure and the crude material was distilled in a
kugelrohr apparatus (458C, 1 mmHg) to furnish the respective silyl dien-
olate as an inseparable Z/E mixture.
(5S)-Methyl-(6S)-naphthalen-2-yl-5,6-dihydropyran-2-one (4b): Accord-
ing to the above-described general procedure for the MVCA reaction,
lactone 4b was obtained in 68% yield as a pale yellow powder. M.p.
107–1108C; [a]2D0 = À37.3 (c = 0.3 in chloroform); 1H NMR (300 MHz,
CDCl3, 258C): d = 1.01 (d, J = 7.2 Hz, 3H), 2.92 (m, 1H), 5.12 (d, J =
10.8 Hz, 1H), 6.1 (dd, J = 9.7, 2.5 Hz, 1H), 6.76 (dd, J = 9.7, 2.1 Hz,
1H), 7.51 (m, 3H), 7.84 ppm (m, 4H); 13C NMR (75 MHz, CDCl3,
258C): d = 16.0, 35.3, 86.3, 120.6, 124.5, 125.6, 126.7, 127.2, 127.8, 128.2,
128.7, 133.6, 134.7, 135.9, 151.4, 164.0 ppm; IR (KCl): n˜ = 3020, 1720,
1602 cmÀ1; MS (EI): m/z (%): 238 (4) [M+], 127 (15), 82 (78), 82 (100);
HRMS (EI): m/z calcd for C16H14O2: 238.0994; found: 238.0996; HPLC
(DAICEL-OJ, hexane/2-propanol, 82:18): 85% ee.
General procedure for the synthesis of silyl dienolates starting from b,g-
unsaturated esters: The above general procedure was followed, but with-
out the addition of DMPU.
(5S)-Methyl-(6S)-(2,3-dimethoxyphenyl)-5,6-dihydropyran-2-one
(4c):
Generalprocedure for the CAVM reactions: A solution of Cu(OTf)2
A
According to the above-described general procedure for the MVCA re-
(dried at 1008C over P2O5 prior to use) (18.4 mg, 0.05 mmol, 10%) and
(R or S)-tol-binap (38 mg, 0.055 mmol) in anhydrous THF (9 mL) was
stirred for 30 min at room temperature (a clear yellow solution was ob-
tained). A solution of TBAT (55.6 mg, 0.1 mmol) in anhydrous THF
(1 mL) was then added and, after an additional 15 min, a bright yellow
solution was obtained. Silyl dienolate (0.54 mmol) was added dropwise
(the solution turned red-brown in color), followed by the aldehyde
(0.27 mmol). The resulting mixture was stirred overnight at room temper-
ature and then the solvent was removed under reduced pressure. The
crude material was purified by using flash chromatography to provide the
desired lactone. Whenever required (when lactone and linear products
were obtained as an inseparable mixture), acetic anhydride (0.5 mL) and
pyrdine (0.5 mL) were added to the crude mixture. After 1.5 h at room
temperature, the mixture was diluted with toluene and the volatiles were
evaporated in vacuo (three times). Flash chromatography on silica gel
(heptane/EtOAc, 70:30) furnished the lactones.
action, lactone 4b was obtained in 61% yield as a pale yellow powder.
1
M.p. 92–948C; [a]2D0 = 8.5 (c = 0.27 in chloroform); H NMR (250 MHz,
CDCl3, 258C): d = 0.97 (d, J = 7.3 Hz, 3H), 2.91 (m, 1H), 3.85 (s, 3H),
3.87 (s, 3H), 5.40 (d, J = 10.9 Hz, 1H), 6.0 (dd, J = 9.7, 2.0 Hz, 1H),
6.70 (dd, J
=
9.7, 2.6 Hz, 1H), 6.85–7.15ppm (m, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d = 15.8, 34.8, 55.8, 61.3, 80.3, 112.7, 119.9,
120.3, 124.4, 131.2, 147.4, 151.8, 152.7, 164.4 ppm; IR (KCl): n˜ = 3022,
1724, 1521 cmÀ1; MS (EI): m/z (%): 248 (100) [M+], 166 (80), 82 (97), 77
(47); HRMS (EI): m/z calcd for C14H16O4: 248.1049; found: 248.1045;
HPLC (DAICEL-OJ, hexane/2-propanol, 95:5): 91% ee.
(5S)-Methyl-(6S)-furan-2-yl-5,6-dihydropyran-2-one (4d): According to
the above-described general procedure for the MVCA reaction, lactone
4d was obtained in 28% yield as a clear yellow oil. [a]2D0 = 7.3 (c = 0.74
in chloroform); 1H NMR (250 MHz, CDCl3, 258C): d = 1.01 (d, J =
7.2 Hz, 3H), 3.09 (m, 1H), 5.03 (d, J = 10.1 Hz, 1H), 6.0 (dd, J = 9.7,
2.4 Hz, 1H), 6.36 (dd, J = 3.2, 1.8 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H),
6.73 (dd, J = 9.8, 2.5 Hz, 1H), 7.36 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d = 16.2, 32.3, 78.3, 110.2, 110.5, 120.3, 143.3, 147.7, 150.9,
166.8 ppm; IR (KCl): n˜ = 3022, 2933, 1735, 1248 cmÀ1; MS (EI): m/z
(%): 178 (52) [M+], 95 (25), 82 (100), 54 (34); HRMS (EI): m/z calcd for
(3E,1Z)-(1-Methoxypenta-1,3-dienyloxy)trimethylsilane (2):[39] According
to the above-described general (DMPU-free) procedure, and starting
from commercially available (E)-methyl pent-3-enoate, the silyl dienolate
2 was obtained after kugelrohr distillation (508C, 1 mmHg) in 60% yield
as an inseparable mixture (1Z/E 70:30, 3E/Z
>
98:2). 1H NMR
8364
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8358 – 8366

Mukaiyama Reactions
FULL PAPER
C10H10O3: 179.0708; found: 179.0686; HPLC (DAICEL-OJ, hexane/2-
propanol, 95:5): 86% ee.
(S)-6-Styryl-5,6-dihydropyran-2-one (7ad):[40] According to the above-de-
scribed general procedure for the MVCA reaction, lactone 7ad was ob-
tained as a white solid (65% yield). M.p. 778C (lit. 808C); 1H NMR
(250 MHz, CDCl3, 258C): d = 2.54 (m, 2H), 5.1 (q, J = 5.3 Hz, 1H),
6.09 (d, J = 9.8 Hz, 1H), 6.28 (dd, J = 15.9, 6.3 Hz, 1H), 6.73 (d, J =
15.9 Hz, 1H), 6.90 (m, 1H), 7.28–7.43 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3, 258C): d = 30.0, 121.7, 125.0, 126.9, 128.5, 128.8, 133.3, 135.9,
144.7, 164.0 ppm; HPLC (ChiralPAK AD, hexane/ethanol, 95:5): 60% ee.
Data are in accordance with those reported previously.[40]
(5S)-Methyl-(6R)-styryl-5,6-dihydropyran-2-one (4e): According to the
above-described general procedure for the MVCA reaction, lactone 4e
was obtained in 30% yield as a clear yellow oil. [a]2D0 = 4.4 (c = 0.5 in
chloroform); 1H NMR (250 MHz, CDCl3, 258C): d
= 1.17 (d, J =
7.3 Hz, 3H), 2.63 (m, 1H), 4.66 (m, 1H), 6.01 (dd, J = 9.8, 2.3 Hz, 1H),
6.22 (dd, J = 15.9, 7.4 Hz, 1H), 6.73 (m, 2H), 7.27–7.51 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d
= 16.3, 34.1, 84.5, 120.5, 126.9 (2C),
(S)-6-Isopropyl-5,6-dihydropyran-2-one (7ae):[41] According to the above-
described general procedure for the MVCA reaction, lactone 7ae was
obtained as a yellow oil (65% yield). [a]2D0 = À49.6 (c = 1 in chloro-
128.5, 128.8 (2C), 135.0, 151.0, 167.0 ppm; IR (KCl): n˜ = 2925, 1720,
1217 cmÀ1; MS (ES+): m/z (%): 253 (100) [M+K+], 237 (65) [M+Na+],
215 (30) [M+H+]; HRMS (EI): m/z calcd for C14H14O2Na: 237.0891;
found: 237.0994; HPLC (DAICEL-OJ, hexane/2-propanol, 90:10):
82% ee.
1
form); H NMR (250 MHz, CDCl3, 258C): d = 0.99 (d, J = 6.8 Hz, 3H),
1.03 (d, J = 6.8 Hz, 3H), 1.95 (m, 1H), 2.28–2.34 (m, 2H), 4.25 (m, 1H),
6.0 (d, J = 9.6 Hz, 1H), 6.87 ppm (m, 1H); 13C NMR (75 MHz, CDCl3,
258C): d = 18.2 (2C), 26.8, 32.4, 82.9, 121.7, 145.6, 165.1 ppm. Data are
in accordance with those reported previously.[41]
(5S)-Methyl-(6R)-isopropyl-5,6-dihydropyran-2-one (4 f): According to
the above-described general procedure for the MVCA reaction, lactone
4 f was obtained in 35% as a clear yellow oil. [a]2D0 = 24.2 (c = 0.72 in
chloroform); 1H NMR (250 MHz, CDCl3, 258C): d
= 0.94 (d, J =
6.8 Hz, 3H), 1.05 (d, J = 7.7 Hz, 3H), 1.08 (d, J = 7.5 Hz, 3H), 1.95 (m,
1H), 2.56 (m, 1H), 3.09 (dd, J = 9.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.7,
2.3 Hz, 1H), 6.62 ppm (dd, J = 9.7, 2.5 Hz, 1H); 13C NMR (75 MHz,
Acknowledgements
CDCl3, 258C):
d = 15.4, 16.3, 19.6, 29.0, 30.9, 87.8, 120.1, 151.9,
164.5 ppm; IR (KCl): n˜ = 2968, 1716, 1463, 1241 cmÀ1; MS (EI): m/z
(%): 154 (25) [M+], 111 (35), 82 (100), 54 (51); HRMS (EI): m/z calcd
for C9H14O2: 154.0994; found: 154.0996; HPLC (ChiralPAK AD, hexane/
ethanol, 99:1): 91% ee.
The authors thank the CNRS for financial support and CONACYT
(Mexico) for a Ph.D. grant (B.B.T.). Professors B. A. Keay, T. Hayashi,
and T. Saito are warmly acknowledged for their generous supply of li-
gands (binap-Fu, binap*, and segphos, respectively).
(5S)-Methyl-(6R)-butyl-5,6-dihydropyran-2-one (4g): According to the
above-described general procedure for the MVCA reaction, lactone 4g
was obtained in 19% yield as a clear yellow oil. [a]2D0 = 15.3 (c = 0.5 in
chloroform); 1H NMR (250 MHz, CDCl3, 258C): d
= 0.91 (~t, J =
[1]For general reviews, including vinylogous aldol reactions of hetero-
cyclic dienolates and masked acetoacetates, see: a) G. Casiraghi, F.
Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929; b) G.
Rassu, F. Zanardi, L. Battistini, G. Casiraghi, Chem. Soc. Rev. 2000,
29, 109; c) S. E. Denmark, J. R. Heemstra, G. L. Beutner, Angew.
Chem. 2005, 117, 4760; Angew. Chem. Int. Ed. 2005, 44, 4682; d) M.
Kalesse, Top. Curr. Chem. 2005, 244, 43; e) for an interesting ap-
6.89 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.3–1.7 (m, 4H), 2.50 (m, 1H),
4.05 (m, 1H), 5.92 (dd, J = 9.7, 2.2 Hz, 1H), 6.61 ppm (dd, J = 9.7,
2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d = 13.8, 16.5, 17.9,
29.7, 34.9, 83.4, 120.1, 151.5, 166.5 ppm; MS (EI): m/z (%): 177 (30)
[M+Na+]; HPLC (ChiralPAK AD, hexane/ethanol, 99:1): 90% ee.
(S)-6-Phenyl-5,6-dihydropyran-2-one (7aa):[23] According to the above-
described general procedure for the MVCA reaction, lactone 7aa was
obtained as a white solid in 72% yield. M.p. 848C; [a]2D0 = À188 (c =
1.5 in chloroform); 1H NMR (250 MHz, CDCl3, 258C): d = 2.36–2.78
(m, 2H), 5.43 (dd, J = 10.5, 5.5 Hz, 1H), 6.12 (d, J = 9.9 Hz, 1H), 6.95
(m, 1H), 7.27–7.50 ppm (m, 5H); 13C NMR (75 MHz, CDCl3, 258C): d =
31.7, 79.2, 121.7, 126.1 (3C), 128.6 (2C), 138.4, 144.8, 164.0 ppm; HPLC
(DAICEL OD, hexane/2-propanol, 95:5): 85% ee. Data are in accord-
ance with those reported previously.[23]
proach involving
a hydrogen-bond catalyzed reaction using a
masked acetoacetate, see also: V. B. Gondi, M. Gravel, V. H. Rawal,
Org. Lett. 2005, 7, 5657.
[2]This regioselectivity issue was recently solved using ATPH com-
plexes: S. Saito, T. Nagahara, M. Shiozawa, M. Nakadai, H. Yama-
moto, J. Am. Chem. Soc. 2003, 125, 6200.
[3]T. Mukaiyama, A. Ishida, Chem. Lett. 1975, 319.
[4]I. Fleming, J. Goldhill, I. Paterson, Tetrahedron Lett. 1979, 20, 3209.
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K. C. Nicolaou, J. Chem. Soc., Chem. Commun. 1994, 1147.
[6]a) J. Hassfeld, M. Christmann, M. Kalesse, Org. Lett. 2001, 3, 3561;
b) M. Kalesse, M. Christmann, U. Bhatt, M. Quitschalle, E. Claus,
A. Saeed, A. Burzlaff, C. Kasper, L. O. Hausted, E. Hofer, T. Schep-
er, W. Beil, ChemBioChem 2001, 2, 709; c) U. Bhatt, M. Christmann,
M. Quitschalle, E. Claus, M. Kalesse, J. Org. Chem. 2001, 66, 1885;
d) J. Hassfeld, M. Kalesse, Tetrahedron Lett. 2002, 43, 5093; e) J.
Hassfeld, M. Kalesse, Synlett 2002, 2007; f) J. Hassfeld, U. Eggert,
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2005, 863; h) F. P. Liesener, M. Kalesse, Synlett 2005, 2236.
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[8]K. Suenaga, T. Mutou, T. Shibata, T. Itoh, T. Fujita, N. Takada, K.
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[9]a) S. E. Denmark, G. L. Beutner, J. Am. Chem. Soc. 2003, 125, 7800;
b) S. E. Denmark, J. R. Heemstra, Synlett 2004, 2411; c) S. E. Den-
mark, G. L. Beutner, T. Wynn, M. D. Eastgate, J. Am. Chem. Soc.
2005, 127, 3774; d) S. E. Denmark, J. R. Heemstra, J. Am. Chem.
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[10]D. A. Evans, E. Hu, J. D. Burch, G. Jaeschke, J. Am. Chem. Soc.
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[11]For an impressive synthetic application of Denmarkꢀs methodology,
see: D. L. Aubele, S. Wan, P. E. Floreancig, Angew. Chem. 2005, 117,
3551; Angew. Chem. Int. Ed. 2005, 44, 3485.
(S)-6-(Naphthalen-2-yl)-5,6-dihydropyran-2-one (7ab): According to the
above-described general procedure for the MVCA reaction, lactone 7ab
was obtained as a white solid (80% yield). M.p. 1578C; [a]2D0 = À183
(c = 1 in chloroform); 1H NMR (250 MHz, CDCl3, 258C): d = 2.58–2.69
(m, 2H), 5.78 (dd, J = 5.7, 10.2 Hz, 1H), 6.2 (d, J = 10.2 Hz, 1H), 6.94–
7.04 (m, 1H), 7.47–7.61 (m, 3H), 7.85–7.91 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3, 258C): d = 31.7, 79.2, 121.7, 123.5, 125.1, 127.7, 128.0,
128.5, 133.0, 135.8, 144.8, 164.0 ppm; IR (KCl): n˜ = 3020, 1215, 756 cmÀ1
;
MS (EI): m/z (%): 154 (8) [M+], 156.0 (59), 128 (100), 87.0 (59); elemen-
tal analysis calcd for C15H12O2: C 80.34, H 5.39; found: C 79.79, H 5.43;
HPLC (ChiralPAK OD, hexane/2-propanol, 70:30): 76% ee (97% ee for
the lactone recrystallized from diethyl ether).
(S)-6-(2,3-Dimethoxyphenyl)-5,6-dihydropyran-2-one (7ac): According to
the above-described general procedure for the MVCA reaction, lactone
7ac was obtained as a white solid (80% yield). M.p. 1048C; [a]D20
=
À139.4 (c = 1 in chloroform); 1H NMR (250 MHz, CDCl3, 258C): d =
2.57–2.67 (m, 2H), 3.8 (s, 3H), 3.9 (s, 3H), 5.78 (dd, J = 9.9, 6.0 Hz,
1H), 6.14 (d, J = 9.8 Hz, 1H), 6.88–7.06 (m, 2H), 7.09–7.18 ppm (m,
2H); 13C NMR (75 MHz, CDCl3, 258C): d = 30.9, 55.9, 61.0, 74.9, 112.6,
118.8, 121.4, 124.4, 132.4, 145.6, 146.0, 152.4, 164.5 ppm; IR (KCl): n˜ =
2931, 1727, 1480 cmÀ1; MS (EI): m/z (%): 234.0 (77) [M+], 166.0 (100),
148.0 (44), 68.0 (61); elemental analysis calcd for C13H14O4: C 66.66, H
6.02; found: C 66.73, H 6.45; HPLC (ChiralPAK OD, hexane/ethanol,
95:5): 92% ee.
Chem. Eur. J. 2006, 12, 8358 – 8366
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8365

J.-M. Campagne et al.
[12]For an example of an asymmetric vinylogous Mukaiyama reaction
with a chiral silyl dienolate, see: S. Shirokawa, M. Kamiyama, T. Na-
kamura, M. Okada, A. Nakazaki, S. Hosokawa, S. Kobayashi, J.
Am. Chem. Soc. 2004, 126, 13604.
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3311.
[24]S. Sirol, J. Courmarcel, N. Mostefai, O. Riant, Org. Lett. 2001, 3,
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[13]a) J. Krueger, E. M. Carreira, J. Am. Chem. Soc. 1998, 120, 837;
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[14]G. Bluet, J.-M. Campagne, J. Org. Chem. 2001, 66, 4293.
[15]Late transition metals tend to favor the C-bound h3 form of the eno-
late.
[16]a) G. Bluet, B. Bazµn-Tejeda, J.-M. Campagne, Org. Lett. 2001, 3,
3807; b) B. Bazµn-Tejeda, M. Georgy, J.-M. Campagne, Synlett 2004,
720.
[25]We have not been able to isolate the TES dienolate derivative.
[26]All efforts to obtain the silyl dienolate with a phenyl ester group
(R’ = OPh) were unsuccessful in our hands.
[27]T. Senda, M. Ogasawara, T. Hayashi, J. Org. Chem. 2001, 66, 6852.
[28]a) N. G. Andersen, M. Parvez, B. A. Keay, Org. Lett. 2000, 2, 2817;
b) N. G. Andersen, B. A. Keay, Chem. Rev. 2001, 101, 997.
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N. Champion, P. Dellis, Angew. Chem. 2004, 116, 324; Angew.
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[17]For a review, see: L. A. Collett, M. T. Davies-Coleman, D. E. A.
Rivett, Prog. Chem. Org. Nat. Prod. 1998, 75, 181.
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Received: March 9, 2006
Published online: August 25, 2006
8366
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