Vinylogous Mukaiyania-Michael Reactions between 2-SiLyIoxyfurans and cyclic enones or unsaturated oxo esters

Article abstract of DOI:10.1002/ejoc.201000504

Lewis acid catalyzed vinylogous Mukaiyama-Michael (VMM) reactions between 2-(trialkylsilyloxy)furans 1 and α, β-unsaturated cyclic enones 2 or oxo esters 4 have been investigated. Both substrates proved to be useful Michael acceptors in the title reaction, giving the butenolides 3 and 5 in good yields. A comparative study between the α,β-unsaturated cyclic enones 2 and the oxo esters 4 as Michael acceptors showed better diasterecontrol with the latter class of compounds. In both series, crystal structures of the major isomers revealed anti relationships of newly formed stereogenic centers. From these data, two types of transition states could be proposed: an open TS with antiperiplanar orientation or a Diels-Alder-like TS with exo approach.

Full text of DOI:10.1002/ejoc.201000504

FULL PAPER
DOI: 10.1002/ejoc.201000504
Vinylogous Mukaiyama–Michael Reactions between 2-Silyloxyfurans and
Cyclic Enones or Unsaturated Oxo Esters
Laurent Chabaud,*[a] Thierry Jousseaume,[a] Pascal Retailleau,[a] and Catherine Guillou*[a]
Keywords: Homogeneous catalysis / Michael addition / Mukaiyama reaction / Diastereoselectivity / Cyclic enones
Lewis acid catalyzed vinylogous Mukaiyama–Michael
(VMM) reactions between 2-(trialkylsilyloxy)furans 1 and
α,β-unsaturated cyclic enones 2 or oxo esters 4 have been
investigated. Both substrates proved to be useful Michael ac-
ceptors in the title reaction, giving the butenolides 3 and 5
in good yields. A comparative study between the α,β-unsatu-
rated cyclic enones 2 and the oxo esters 4 as Michael ac-
ceptors showed better diasterecontrol with the latter class of
compounds. In both series, crystal structures of the major iso-
mers revealed anti relationships of newly formed stereogenic
centers. From these data, two types of transition states could
be proposed: an open TS with antiperiplanar orientation or a
Diels–Alder-like TS with exo approach.
and cyclohex-2-en-1-one.[12] However, no detailed studies
on the reactivity and the diastereoselectivity arising from
reactions between silyloxyfurans and other cyclic enones 2
have been undertaken. Furthermore, to the best of our
knowledge, no examples of VMM reactions between the sil-
yloxyfurans 1 and the cyclic α,β-unsaturated oxo esters 4
have been reported. In view of the potential synthetic appli-
cations of the γ-butenolides 3 and 5 (Scheme 1),[3d,3e] here
we report a study on the VMM reactions between the 2-
(trialkylsilyloxy)furans 1 and the cyclic Michael acceptors 2
and 4.
Introduction
Since the development of the Mukaiyama aldol reac-
tion[1] and its vinylogous version (the addition of O-silyl
dienolates),[2] the 2-(trialkylsilyloxy)furans 1 (Scheme 1)
have emerged as attractive reagents for the introduction of
γ-butenolides and γ-lactones, frameworks found in many
natural products.[3] Lewis acid catalyzed vinylogous Mukai-
yama aldol reactions with aldehydes have been extensively
studied and have led to various strategies for diastereo- and
enantioselective reactions.[2a] Because ketones are less reac-
tive than aldehydes, vinylogous Mukaiyama aldol reactions
between O-silylated dienolates and ketones have been
limited to highly electrophilic ketones[4] and, more recently,
cycloalkanones.[5]
Alternatively, vinylogous Mukaiyama–Michael (VMM)
reactions between the 2-(trialkylsilyloxy)furans 1 and α,β-
unsaturated carbonyl compounds have proven to be a valu-
able and complementary method for introducing γ-butenol-
ides.[6] Since then, acyclic Michael acceptors, such as α,β-
unsaturated imides,[6a–6f] aldehydes,[6g–6i] and ketones,[6j–6n]
have been investigated for the development of stereocon-
trolled access to γ-butenolides.
In contrast, the use of cyclic Michael acceptors in VMM
reactions with compounds 1 have attracted much less atten-
tion. p-Quinones[7] and p-quinols were found to be particu-
larly useful Michael acceptors for the synthesis of benzo-
furans[8] and heterocyclic cage compounds,[9] respectively.
Surprisingly, the use of α,β-unsaturated cyclic enones has
been limited to 4-substituted cyclopent-2-en-1-ones[10,11]
Scheme 1. VMM reactions between the 2-(trialkylsilyloxy)furans 1
and the cyclic α,β-unsaturated enones 2 or oxo esters 4.
Results and Discussion
Studies on the Substituted Cycloalkenones 2 (R4 = H)
[a] Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS
1, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax: +33-1-69077247
Our investigation began with the identification of the op-
timal catalytic system in terms of efficiency and diastereo-
selectivity. For this purpose we chose the commercially
View this journal online at
E-mail: chabaud@icsn.cnrs-gif.fr
guillou@icsn.cnrs-gif.fr
wileyonlinelibrary.com
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available cyclohex-2-en-1-one derivate 2a as a Michael
In addition, Otera et al. have shown that Mukaiyama–
acceptor and 2-(trimethylsilyloxy)furan (TMSOF 1a) as a Michael reactions of ketene silyl acetals incorporating bulky
γ-butenolide precursor (Scheme 2).
silyloxy groups produce high selectivities.[15] The nature of
the silyl group was thus modified through the use of a 2-
(tert-butyldimethylsilyl) group [i.e., TBSOF 1b] (Table 2,
Entry 2), which gave a higher diastereoselectivity than
TMSOF 1a. Use of 2-(triisopropylsilyloxy)furan (1c), how-
ever, led to a significant decrease in selectivity (Table 2, En-
try 3).
Table 2. Vinylogous Mukaiyama–Michael reactions with the cyclic
enones 2.
Scheme 2. VMM reactions between the 2-(trialkylsilyloxy)furans
1a–e and the cyclic α,β-unsaturated enones 2a–g.
We were delighted to find that the VMM reaction with
the cyclohex-2-en-1-one 2a afforded the γ-butenolide 3a in
good to excellent yields in the presence of a variety of Lewis
acids (Table 1).[13] It is noteworthy that only the expected
1,4-addition product was observed in the crude mixture by
1H NMR spectroscopy. Furthermore, the addition occurs
exclusively at the 5-position in the furan ring.
Table 1. Screening of Lewis acid catalysts in the reaction between
1a and 2a.
Entry
Conditions
Yield [%][a]
dr[b]
1
2
3
4
5
6
SnCl4, –78 °C
Sn(OTf)2, –78 °C
TiCl4, –78 °C
96
95
77:23
73:27
75:25
–
57:43
70:30
91
Ti(OiPr)4, –78 °C to r.t.
BF3.OEt2, –78 °C
Cu(OTf)2, –45 °C
n.r.[c]
51
77
[a] Isolated yields. [b] Determined by HPLC on the crude mixtures.
[c] No reaction.
Of the catalysts tested, SnCl4 (10 mol-%) proved the most
efficient, giving the butenolide 3a in 96% yield and 77:23
diastereomeric ratio (Table 1, Entry 1). Other Lewis acids
such as Sn(OTf)2 and TiCl4 also efficiently catalyzed the
formation of the γ-butenolide 3a (Entries 2–3) but with
slightly lower stereocontrol. In contrast, the less reactive
Ti(OiPr)4 did not give any of the desired products, even at
room temperature (Entry 4). Boron trifluoride–diethyl ether
gave only poor diastereoselectivity and a moderate yield
(Entry 5). Finally, copper(II) triflate was examined (En-
try 6), but the reaction had to be carried out at –45 °C for
completion to be reached. The γ-butenolide 3a was isolated
in good yield but with a lower selectivity than in the case
of SnCl4.
It has been reported that a single-electron transfer (SET)
mechanism may operate in Mukaiyama–Michael reactions
under SnCl4 catalysis conditions, leading to a less stereo-
selective pathway.[14] To prevent such a mechanism, a test
reaction between 1a and 2a was carried out in the presence
of 1,4-dinitrobenzene (1 equiv.) and SnCl4 (10 mol-%). No
[a] Isolated yields. [b] Determined by HPLC on the crude mixtures.
[c] Major isomer, relative configuration determined by X-ray struc-
ture analysis (see Figure 1). [d] SnCl4 (0.2 equiv.) was used. [e] The
relative configurations of the major isomers were not determined.
[f] Determined by 1H NMR spectroscopy on the crude mixtures.
[g] An 18% yield of the 1,2-addition product was isolated (dr =
53:47).
With the optimized conditions to hand, we studied the
improvement in selectivity was observed even in the pres- influence of a substituent on the silyloxyfuran component.
ence of this strong electron acceptor, indicating that a SET The TBSOF 1d, bearing a methyl group at C-3 (R1 = Me),
mechanism should not be operative.
was thus investigated and found to furnish the γ-butenolide
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Mukaiyama–Michael Reactions between Furans and Enones or Oxo Esters
3aЈ in excellent isolated yield, but with slightly lower dia- Studies on the Cyclic α,β-Unsaturated Oxo Esters 4 (R4 =
stereoselectivity (Table 2, Entry 4). As before, increasing the CO2R5)
size of the silyl group, in the shape of the (triisopropylsilyl-
oxy)furan 1e, did not improve the diastereoselectivity
Several examples of Lewis acid catalyzed Michael ad-
dition reactions with cyclic α,β-unsaturated oxo esters have
(Table 2, Entry 5).
been reported.[14a,19] To the best of our knowledge, however,
A series of cyclic enones was then examined in these
no examples of VMM reaction between the silyloxyfurans
1 and the cyclic α,β-unsaturated oxo esters 4 have been re-
ported. We thus turned our attention to a study of the
VMM reactions between the silyloxyfurans 1 and the cyclic
α,β-unsaturated oxo esters 4 (Scheme 3). Before we began
our investigation, we realized that VMM reactions with the
Michael acceptors 4 would form the β-oxo esters 5, each
VMM reactions. The influence of the enone ring size on
stereoselectivity was examined with cyclopent-2-en-1-one
(2b). The corresponding 1,4-adduct 3b was obtained in
good yield, but with only modest selectivity (Table 2, En-
try 6).[16] Cyclohept-2-en-1-one (2c) also reacted efficiently
with 1b with good diastereocontrol (Table 2, Entry 7). It is
worth mentioning that no 1,2-addition products were ob-
served with these two cyclic enones 2b and 2c.
Various substituted cyclohex-2-en-1-ones – in particular,
the cyclic enones 2d–f bearing C-3 substituents (R2 = Me,
Et) – were then investigated. Interestingly, the use of 3-
methylcyclohex-2-en-1-one (2d) allowed the formation of
3d, containing a quaternary stereogenic center, with excel-
lent selectivity (Table 2, Entry 8). In a similar way, the
VMM reactions between the silyloxyfuran 1b and isopho-
rone (2e) (Table 2, Entry 9) or 3-ethylcyclohex-2-en-1-one
(2f)[17] (Table 2, Entry 10) led to the corresponding γ-buten-
olides 3e or 3f, respectively, with good stereocontrol. Fi-
nally, the 4,4Ј-dimethylcyclohex-2-en-1-one (2g)[18] reacted
with 1a to give the Michael addition product 3g in a 77:23
ratio, but with a small amount of aldol adduct as well
(Table 2, Entry 11). In this case, the use of a bulkier silyl
group on the furan derivative (i.e., 1b) suppressed the aldol
side reaction, but dramatically decreased the diastereoselec-
tivity (Table 2, Entry 12).
Scheme 3. Vinylogous Mukaiyama–Michael reactions between the
2-(trialkylsilyloxy)furans 1 and the cyclic α,β-unsaturated oxo es-
ters 4.
Table 3. Vinylogous Mukaiyama–Michael reactions with the cyclic α,β-unsaturated oxo esters 4.
[a] Isolated yields. [b] Determined by NMR spectroscopy on the corresponding phosphates 6 (see Experimental Section). [c] Major isomer,
relative configuration determined by X-ray structure analysis (see Figure 1).
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containing three stereogenic centers and potentially existing
as a mixture of four diastereomers. Furthermore, in solu-
tion, the β-oxo esters 5 might exist in equilibrium with their
enol forms, leading to two more diastereomers. Faced with
the expected complexity of 1H NMR spectra of compounds
5, we thus decided to convert them into stable vinyl phos-
phates 6, which should be more amenable to diastereomeric
1
ratio estimation by H NMR spectroscopy.
A series of α,β-unsaturated oxo esters (i.e., 4a–d and 4aЈ–
dЈ) were synthesized to allow comparison of the results with
those obtained with the analogous cyclic enones 2.[20] Two
sets of cyclic α,β-unsaturated oxo esters (methyl and ethyl
esters) were tested as well, for comparison of the influence
of the R5 group on the diastereoselectivity. Copper(II) tri-
fluoromethanesulfonate was chose in this study, because the
doubly activated Michael acceptor was expected to be reac-
tive enough without use of a strong Lewis acid such as
SnCl4. Moreover, the use of a copper(II) salt might allow
the development of an asymmetric version of the reac-
tion.[14a,19a,19b,21]
Figure 1. ORTEP representations of the major isomers of 3a, 3aЈ,
3d, and 5aЈЈ.
The results of the reactions between the silyloxyfurans
1a and 1d and the α,β-unsaturated ester 4a–d and 4aЈ–dЈ,
catalyzed by Cu(OTf)2 (10 mol-%) at –78 °C in dichloro-
methane, are given in Table 2. Most substrate combinations
afforded the VMM products 5 with higher diastereoselectiv-
ities than had been obtained with the cycloalkenones 2a–g
(Table 2). The butenolides 5a and 5aЈ, for instance, were
both obtained with excellent stereocontrol, whatever the na-
ture of the R5 group (Table 3, Entries 1, 2). In turn, the
silyloxyfuran 1d, which had given poor selectivity with the
enone 2a (Table 2, Entry 4), only gave one stereoisomer
(i.e., 5aЈЈ) with the oxo ester 4a (Table 3, Entry 3). Introduc-
tion of an ester function on cyclopentyl (4b and 4bЈ,
Table 3, Entries 4–5) and 4,4-dimethylcyclohexyl rings (4c
and 4cЈ, Table 3, Entries 6, 7) also improved the diastereo-
selectivities. Interestingly, in these examples, ethyl esters
gave better results than their methyl counterparts. In con-
trast, no changes were observed in the cases of the seven-
membered ring 4d and 4dЈ, whatever the nature of R5
(Table 3, Entries 8,9).
troduction of a second chelating group is beneficial in terms
of increasing the diastereoselectivity and leads to the same
major isomer.
Proposed Transition States
Lewis acid coordination with cyclic ketones is usually a
nonselective process, because the participating lone pairs
are positioned in similar steric and electronic environments
(Figure 2). The lack of differentiation between A1 and A2
could be a possible explanation for the modest diastereo-
selectivity observed with cyclohex-2-en-1-one (2a). In con-
trast, two-point binding of the unsaturated β-oxo ester to
the Lewis acid (i.e., B) is presumed, because this affords the
most reactive of the possible catalyst–substrate complexes.
In this chelate B, a high level of lone-pair differentiation is
achieved. The metal center is then positioned close to the
intracyclic double bond, which is probably a key feature for
producing high diastereoselectivity as observed with sub-
strates 4a and 4aЈ.
Relative Stereochemistries of the Major Isomers
The relative configurations of the major diastereomers of
four of our γ-butenolides (i.e., 3a, 3aЈ, 3d, and 5aЈЈ) have
been established by X-ray crystallographic analysis (Fig-
ure 1).[22]
In each case, the major isomer has the anti relative con-
figuration. These data revealed that the introduction of a
methyl group at the 3-position of the silyloxyfuran (com-
pare 3a and 3aЈ) only affects the level of diastereocontrol
Figure 2. Coordination modes.
From the X-ray data, the anti relative configurations of
(Table 2, Entries 2, 4), without changing the sense of the the major isomers in the oxo ester series can thus be ex-
diastereoselectivity. The same conclusion can be drawn with plained by transition states as depicted in Figure 3. At this
3a and 3d, the latter bearing a methyl group at the C-3 stage of the study, we cannot conclude with certainty
atom of the enone (Table 2, Entries 2, 8). Compounds 3aЈ whether these additions proceed through an open geometry
(Table 2, Entry 4) and 5aЈЈ (Table 3, Entry 3) also have the (TS1 vs. TS2) or a Diels–Alder-type transition state (TS3
same relative configuration. These results show that the in- vs. TS4).
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Mukaiyama–Michael Reactions between Furans and Enones or Oxo Esters
whether the major isomers arise from open or Diels–Alder-
like transition states, and further studies to address this
point are currently in progress.
Experimental Section
General: All reactions were carried out under argon in dry solvents
unless noted otherwise. Reactions were monitored by thin-layer
chromatography on Merck silica gel plates (60 F254) with a fluores-
cent indicator. Yields refer to chromatographically pure or crystal-
line compounds. All commercially available reagents were used
without further purification. All solvents were dried and distilled
before use: CH2Cl2 was distilled from P2O5, THF was distilled from
sodium/benzophenone, methanol and ethanol were distilled from
Mg/I2, and NEt3 was distilled from KOH. All separations were
carried out under flash-chromatographic conditions on silica gel
(Redi Sep prepacked column, 230–400 mesh) at medium pressure
(20 psi) with use of a CombiFlash Companion. All new com-
pounds gave satisfactory spectroscopic analyses (IR, 1H NMR, 13
C
NMR, HRMS). NMR spectra were determined with Bruker Av-
1
ance 300 or Bruker Avance 500 instruments. H NMR spectra are
reported in parts per million (δ) relative to residual solvent peak.
Data for 1H are reported as follows: chemical shift (δ, ppm), multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, sext =
sextet, dd = double doublet, m = multiplet), coupling constant in
Hz, and integration. 13C NMR spectra were obtained with a
Bruker Avance 300 (75.5 MHz) spectrometer and are reported in
parts per million (δ) relative to the residual solvent peak. HRMS
spectra were obtained with an ESI TOF Thermoquest AQA Navi-
Figure 3. Proposed transition states.
Open transition states (TS1 vs. TS2) have been proposed
in order to account for the diastereocontrol in vinylogous
Mukaiyama aldol reactions[23] and VMM reactions with cy-
clic acceptors.[8] In our case, an antiperiplanar (TS1) ap-
proach of the silyloxyfuran to the cyclic enone might ex-
plain the formation of the major anti isomers. TS3 and
TS4, reminiscent of a Diels–Alder-type transition state,
gator spectrometer. Infrared (IR) (ν, cm–1) spectra were recorded
˜
with a Fourier Perkin–Elmer Spectrum BX FT-IR instrument.
Melting points were measured in capillary tubes and are uncor-
rected. Compounds 2a–e and 2g are commercially available. Com-
pounds 2f, 4a–d, and 4Јa–d were prepared according to a reported
cannot be excluded. The major anti isomers would then procedure.[18]
arise from an exo approach (TS3) of the silyloxyfuran to
General Procedure A. Lewis-Acid-Catalyzed Mukaiyama–Michael
the cyclic enone. Such exo selectivity has previously been
observed in studies of high-pressure-promoted Diels–Alder
reactions involving cycloalkenones and silyloxyfurans[11] or
3-(methylsulfanyl)furan.[24] In our case, no Diels–Alder
product was observed prior to hydrolysis of the crude mix-
ture with HCl (1 ). Furthermore, no evidence of any
Diels–Alder product was observed by 1H NMR spec-
troscopy.[25] Further studies directed towards understanding
of the origin and the sense of the stereocontrol are continu-
ing.[26]
Additions to Cyclic Enones: The silyloxyfuran (1.3 equiv.) was
added at –78 °C to a solution of the enone (1 equiv.) in dichloro-
methane (5 mLmmol–1). A solution of the Lewis acid (0.1 equiv. or
0.2 equiv., 1  in DCM) was then added at –78 °C, and the reaction
mixture was stirred at this temperature until no more enone re-
mained (TLC). The reaction was quenched with HCl solution (1 )
at –78 °C and the mixture allowed to warm to room temperature.
It was diluted with water, and the aqueous layer was extracted with
EtOAc (ϫ3). The organic layer was dried with Na2SO4, filtered,
and then concentrated under reduced pressure. The resulting resi-
due was treated with THF/HCl (1 ) (1:1, v/v, 10 mLmmol–1) at
room temperature for 30 min. The reaction mixture was diluted
with H2O, extracted with EtOAc (ϫ3), and dried with Na2SO4,
and the solvent was evaporated. The crude mixture was purified
through silica gel to afford the title compound.
Conclusions
General Procedure B. Cu-Catalyzed Mukaiyama–Michael Additions
to Activated Cyclic Unsaturated Oxo Esters: Cu(OTf)2 (0.1 equiv.)
was suspended in CH2Cl2 (38 mLmmol–1) under argon. A solution
of enone (1 equiv.) in CH2Cl2 (0.8 mLmmol–1) was added at room
temp., and the mixture became homogeneous. The solution was
cooled to –78 °C, and the silyloxyfuran (1.2 equiv.) was added. The
reaction was monitored by TLC (usually 2–3 h). The reaction was
quenched with aqueous saturated NH4Cl at –78 °C and the mixture
allowed to warm to room temperature. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (ϫ3). The com-
We have shown that vinylogous Mukaiyama–Michael re-
actions between the silyloxyfurans 1 and the cyclic enones
2 or the α,β-unsaturated cyclic oxo esters 4 constitute a
valuable method for introducing γ-butenolides onto cyclo-
alkene systems. In general, only 1,4-adducts were obtained,
with the major diastereomers having anti relative configura-
tions. X-ray data from this preliminary study revealed that
both the six-membered cyclic enones 2 and the oxo esters 4
lead to the same major diastereomers, with better dia-
stereocontrol in the latter case. At this stage it is still unclear bined organic layers were dried with Na2SO4, filtered, and concen-
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L. Chabaud, T. Jousseaume, P. Retailleau, C. Guillou
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trated under reduced pressure. The resulting residue was treated by
THF/HCl (1 ) (1:1, v/v, 10 mLmmol–1) at room temperature for
30 min. The reaction mixture was diluted with H2O, extracted with
EtOAc (ϫ3), dried with Na2SO4, and filtered, and the solvent was
evaporated. The crude mixture was purified through silica gel to
afford the title compound.
24.3 (CH ), 10.5 (CH ) ppm. IR (film): ν = 3081, 2927, 1746,
˜
2 3
1705 cm–1. MS (ESI+): m/z (%) = 217 (100) [M + Na]. HRMS:
calcd. for C11H14NaO3 217.0841; found 217.0831.
5-(3-Oxocyclopentyl)furan-2(5H)-one (3b): This compound was pre-
pared according to the General Procedure A from cyclopent-2-en-
1-one (2b, 70 µL, 0.819 mmol) and 2-(tert-butyldimethylsilyloxy)-
furan (1b, 227.3 mg, 1.15 mmol) in the presence of tin(IV) chloride
solution (1  in DCM, 0.16 mL, 0.16 mmol) in DCM (4 mL). The
crude mixture was purified through silica gel (heptane to heptane/
EtOAc, 5:5) to afford a colorless oil (120.9 mg, 89%). 1H NMR
(500 MHz, CDCl3, ratio 69:31): major: δ = 7.47 (dd, J = 1.4,
5.7 Hz, 1 H, CH=CH–CO), 6.20 (dd, J = 1.9, 5.7 Hz, 1 H,
CH=CH–CO), 5.08 (m, 1 H, CHO), 2.55 (m, 1 H), 2.45–2.32 (m,
2 H), 2.26–2.16 (m, 2 H), 2.04–1.89 (m, 2 H) ppm; minor: δ = 7.44
(dd, J = 1.4, 5.7 Hz, 1 H, CH=CH–CO), 6.21 (dd, J = 1.9, 5.8 Hz,
1 H, CH=CH–CO), 5.08 (m, 1 H, CHO), 2.52 (m, 1 H), 2.46–2.35
(m, 2 H), 2.25–2.15 (m, 3 H), 1.76 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): major: δ = 216.1 (Cq, C=O), 172.3 (Cq, O–
C=O), 154.3 (CH, CH=CH–CO), 122.5 (CH, CH=CH–CO), 84.8
(CH, CHO), 39.3 (CH, CHCHO), 39.1 (CH2), 37.7 (CH2), 25.3
(CH2) ppm; minor: 216.0 (Cq, C=O), 172.3 (Cq, O–C=O), 154.3
(CH, CH=CH–CO), 122.6 (CH, CH=CH–CO), 84.5 (CH, CHO),
40.3 (CH2), 39.4 (CH, CHCHO), 37.6 (CH2), 24.1 (CH2) ppm. IR
General Procedure C. Phosphate Formation: A solution of the β-
oxo ester (1 equiv.) in THF (4.5 mLmmol–1) was added at 0 °C to
a suspension of NaH (95%, 1.1 equiv.) in THF (4.5 mLmmol–1).
After the mixture had been kept at this temperature for 30 min,
diethyl chlorophosphate (1.1 equiv.) was added, and the mixture
was further stirred at 0 °C for 30 min. The reaction mixture was
quenched with saturated aqueous NH4Cl solution and extracted
with EtOAc (ϫ3). The organic layer was dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude residue
was purified by silica gel chromatography to afford the title com-
pound.
5-(3-Oxocyclohexyl)furan-2(5H)-one (3a): This compound was pre-
pared according to the General Procedure A from cyclohex-2-en-
1-one (2a, 0.1 mL, 1.03 mmol) and 2-(tert-butyldimethylsilyloxy)-
furan (1b, 285.9 mg, 1.44 mmol) in the presence of tin(IV) chloride
solution (1  in DCM, 0.21 mL, 0.21 mmol) in DCM (5 mL). The
crude mixture was purified through silica gel (heptane to heptane/
EtOAc, 6:4) to afford a white solid (80.4 mg, 90%); m.p. 53–54 °C
(major diastereomer). 1H NMR (300 MHz, CDCl3, ratio 84:16):
major: δ = 7.41 (dd, J = 1.5, 5.7 Hz, 1 H, CH=CH–CO), 6.18 (dd,
J = 2.0, 5.8 Hz, 1 H, CH=CH–CO), 5.03 (m, 1 H, CHO), 2.44–
2.36 (m, 1 H), 2.33–2.24 (m, 2 H), 2.24–2.18 (m, 1 H), 2.18–2.10
(m, 2 H), 1.97 (m, 1 H), 1.79–1.61 (m, 2 H) ppm; minor: δ = 7.44
(dd, J = 1.5, 5.8 Hz, 1 H, CH=CH–CO), 6.19 (dd, J = 2.0, 5.9 Hz,
1 H, CH=CH–CO), 4.29 (m, 1 H, CHO), 2.48 (m, 1 H), 1.89 (m,
1 H), 1.51 (m, 1 H) ppm, other signals masked by the major isomer.
13C NMR (75 MHz, CDCl3): major: δ = 209.2 (Cq, C=O), 172.3
(Cq, O–C=O), 154.1 (CH, CH=CH–CO), 122.3 (CH, CH=CH–
CO), 83.4 (CH, CHO), 41.4 (CH2), 41.0 (CH, CHCHO), 40.8
(CH2), 27.5 (CH2), 24.5 (CH2) ppm; minor: δ = 209.1 (Cq, C=O),
172.3 (Cq, O–C=O), 154.0 (CH, CH=CH–CO), 122.4 (CH,
CH=CH–CO), 85.2 (CH, CHO), 43.7 (CH2), 41.3 (CH, CHCHO),
(film): ν = 3090, 2905, 1730 cm–1. MS (ESI+): m/z (%) = 189 (100)
˜
[M + Na]. HRMS: calcd. for C9H10NaO3 189.0528; found
189.0523.
5-(3-Oxocycloheptyl)furan-2(5H)-one (3c): This compound was pre-
pared by the General Procedure A from cyclohept-2-en-1-one (2c,
0.1 mL, 0.717 mmol) and 2-(tert-butyldimethylsilyloxy)furan (1b,
198.3 mg, 1 mmol) in the presence of tin(IV) chloride solution (1 
in DCM, 0.14 mL, 0.14 mmol) in DCM (4.4 mL). The crude mix-
ture was purified through silica gel (heptane to heptane/EtOAc,
1
6:4) to afford a colorless oil (119 mg, 85%). H NMR (500 MHz,
CDCl3, ratio 84:16): δ = 7.45 (dd, J = 1.3, 5.7 Hz, 1 H min,
CH=CH–CO), 7.41 (dd, J = 1.2, 5.7 Hz, 1 H maj, CH=CH–CO),
6.19 (m, 1 H maj + 1 H min, CH=CH–CO), 4.98 (m, 1 H maj,
CHO), 4.95 (m, 1 H min, CHO), 2.59–2.34 (m, 4 H maj + 4 H
min), 2.13 (m, 1 H maj + 1 H min), 2.03 (m, 1 H maj + 1 H min),
1.93 (m, 2 H maj + 2 H min), 1.60 (m, 1 H maj + 1 H min), 1.40
(m, 2 H maj + 2 H min) ppm. 13C NMR (75 MHz, CDCl3): major:
δ = 211.8 (Cq, C=O), 172.3 (Cq, O–C=O), 154.0 (CH, CH=CH–
CO), 122.6 (CH, CH=CH–CO), 85.9 (CH, CHO), 43.4 (2ϫ CH2),
38.4 (CH, CHCHO), 31.0 (CH2), 27.9 (CH2), 23.8 (CH2) ppm;
minor: δ = 211.9 (Cq, C=O), 172.3 (Cq, O–C=O), 154.0 (CH,
CH=CH–CO), 122.7 (CH, CH=CH–CO), 86.2 (CH, CHO), 45.0
(CH2), 43.8 (CH2), 38.3 (CH, CHCHO), 32.3 (CH2), 28.1 (CH2),
40.8 (CH ), 25.3 (CH ), 24.1 (CH ) ppm. IR (film): ν = 3100, 2958,
˜
2
2
2
2935, 1746, 1729, 1705 cm–1. MS (ESI+): m/z (%) = 203 (100) [M
+ Na]. HRMS: calcd. for C10H12NaO3 203.0694; found 203.0676.
3-Methyl-5-(3-oxocyclohexyl)furan-2(5H)-one (3aЈ): This com-
pound was prepared according to the General Procedure A from
cyclohex-2-en-1-one (2a, 0.1 mL, 0.986 mmol) and 2-(tert-butyldi-
methylsilyloxy)-3-methylfuran (1c, 293 mg, 1.38 mmol) in the pres-
ence of tin(IV) chloride solution (0.2 mL) in DCM (5 mL). The
crude mixture was purified through silica gel (heptane to heptane/
EtOAc, 5:5) to afford a white solid (181.9 mg, 95%); m.p. 73–74 °C
(major diastereomer). 1H NMR (300 MHz, CDCl3, ratio 76:24):
major: δ = 6.98 (m, 1 H, CH=CH–CO), 4.88 (m, 1 H, CHO), 2.40
23.7 (CH ) ppm. IR (film): ν = 3091, 2927, 2858, 1745, 1693 cm–1.
˜
2
MS (ESI+): m/z (%) = 217 (100) [M + Na]. HRMS: calcd. for
C11H14NaO3 217.0841; found 217.0847.
5-(1-Methyl-3-oxocyclohexyl)furan-2(5H)-one (3d): This compound
was prepared according to the General Procedure A from 3-methyl-
(m, 1 H), 2.32–2.23 (m, 2 H), 2.21–2.08 (m, 3 H), 1.96 (m, 1 H), cyclohex-2-en-1-one (2d, 0.07 mL, 0.60 mmol) and 2-(tert-butyldi-
1.93 (s, 3 H, CH3), 1.77–1.62 (m, 2 H) ppm; minor: δ = 7.02 (m, 1 methylsilyloxy)furan (1b, 168 mg, 0.85 mmol) in the presence of
H, CH=CH–CO), 4.76 (m, 1 H, CHO), 2.48–2.35 (m, 3 H), 2.31 tin(IV) chloride solution (1  in DCM, 0.12 mL, 0.12 mmol) in
(m, 1 H), 2.19–2.09 (m, 2 H), 1.89 (m, 1 H), 1.93 (s, 3 H, CH3), DCM (3 mL). The crude mixture was purified through silica gel
1.65 (m, 1 H), 1.49 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): (heptane to heptane/EtOAc, 5:5) to afford a white solid (110 mg,
major: δ = 209.6 (Cq, C=O), 173.6 (Cq, O–C=O), 146.3 (CH,
94%). 1H NMR (500 MHz, CDCl3, ratio 92:8): major: δ = 7.46
CH=CH–CO), 131.2 (Cq, CH=CCH3–CO), 83.2 (CH, CHO), 41.6 (dd, J = 1.5, 5.8 Hz, 1 H, CH=CH–CO), 6.21 (dd, J = 2.0, 5.8 Hz,
(CH2), 41.5 (CH, CHCHO), 41.0 (CH2), 27.7 (CH2), 24.7 (CH2), 1 H, CH=CH–CO), 4.82 (dd, J = 1.8, 1.8 Hz, 1 H, CHO), 2.40–
10.6 (CH3) ppm; minor: δ = 209.3 (Cq, C=O), 173.5 (Cq, O–C=O),
146.2 (CH, CH=CH–CO), 131.1 (Cq, CH=CCH3–CO), 83.1 (CH, 0.95 (s, 3 H, CH3) ppm; minor: δ = 4.78 (m, 1 H, CHO), 0.93 (s, 3
CHO), 43.9 (CH2), 41.8 (CH, CHCHO), 41.1 (CH2), 25.6 (CH2),
H, CH3) ppm; other signals masked by major isomer. 13C NMR
2.24 (m, 3 H), 2.10–1.96 (m, 3 H), 1.88 (m, 1 H), 1.64 (m, 1 H),
5476
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5471–5481

Mukaiyama–Michael Reactions between Furans and Enones or Oxo Esters
(75 MHz, CDCl3): major: δ = 209.6 (Cq, C=O), 172.2 (Cq, O– 5-(2,2-Dimethyl-5-oxocyclohexyl)furan-2(5H)-one (3g): This com-
C=O), 152.9 (CH, CH=CH–CO), 123.2 (CH, CH=CH–CO), 89.3 pound was prepared according to the General Procedure A from
(CH, CHO), 47.8 (CH2), 42.3 (Cq, CCH3), 40.5 (CH2), 32.7 (CH2),
21.2 (CH2), 20.1 (CH3) ppm; minor: δ = 209.7 (Cq, C=O), 172.3
(Cq, O–C=O), 152.8 (CH, CH=CH–CO), 123.1 (CH, CH=CH–
4,4-dimethylcyclohex-2-en-1-one (2g, 0.1 mL, 0.737 mmol) and 2-
(trimethylsilyloxy)furan (1a, 0.16 mL, 0.96 mmol) in the presence
of tin(IV) chloride solution (1  in DCM, 0.076 mL, 0.076 mmol)
CO), 88.7 (CH, CHO), 49.9 (CH2), 42.2 (Cq, CCH3), 31.0 (CH2), in DCM (3.8 mL). The crude mixture was purified through silica
21.1 (CH2) ppm; other signals masked by major isomer. IR (film):
˜
[M + Na]. HRMS: calcd. for C11H14NaO3 217.0840; found (21.1 mg, 18%). H NMR (300 MHz, CDCl3, ratio 77:23): major:
gel (heptane to heptane/EtOAc, 5:5) to afford 3g as a white solid
ν = 3100, 2950, 1742, 1697 cm–1. MS (ESI+): m/z (%) = 217 (100)
(95.2 mg, 62%) and the 1,2-addition product as a colorless oil
1
217.0841. M.p. 89–92 °C (major diastereomer).
δ = 7.47 (dd, J = 1.5, 5.8 Hz, 1 H, CH=CH–CO), 6.12 (dd, J =
2.1, 5.8 Hz, 1 H, CH=CH–CO), 5.12 (m, 1 H, CHO), 2.46–2.36
(m, 1 H), 2.35–2.29 (m, 1 H), 2.28–2.21 (m, 1 H), 2.20–2.11 (m, 2
H), 1.73 (m, 2 H), 1.20 (s, 6 H, 2ϫCH3) ppm; minor: δ = 7.30 (dd,
J = 1.6, 5.7 Hz, 1 H, CH=CH–CO), 6.10 (dd, J = 2.1, 5.7 Hz, 1
H, CH=CH–CO), 5.32 (m, 1 H, CHO), 2.00–1.86 (m, 2 H), 1.77
(m, 1 H), 1.58 (m, 1 H), 1.17 (s, 3 H, CH3), 1.16 (s, 3 H, CH3)
ppm, other signals masked by the major isomer. 13C NMR
(75 MHz, CDCl3): major: δ = 209.0 (Cq, C=O), 171.9 (Cq, O–
C=O), 154.4 (CH, CH=CH–CO), 122.8 (CH, CH=CH–CO), 83.4
(CH, CHO), 48.9 (CH, CHCHO), 40.4 (CH2), 38.8 (CH2), 37.5
(CH2), 32.4 [Cq, C(CH3)2], 29.5 (CH3), 20.9 (CH3) ppm; minor: δ
= 209.8 (Cq, C=O), 172.7 (Cq, O–C=O), 156.0 (CH, CH=CH–
CO), 122.1 (CH, CH=CH–CO), 81.7 (CH, CHO), 48.0 (CH,
CHCHO), 39.8 (CH2), 37.7 (CH2), 35.6 (CH2), 32.8 [Cq,
5-(1,3,3-Trimethyl-5-oxocyclohexyl)furan-2(5H)-one (3e): This com-
pound was prepared according to the General Procedure A from
isophorone (2e, 70 mg, 0.506 mmol) and 2-(tert-butyldimethylsilyl-
oxy)furan (1b, 130 mg, 0.66 mmol) in the presence of tin(IV) chlo-
ride solution (1  in DCM, 0.1 mL, 0.1 mmol) in DCM (2.5 mL).
The crude mixture was purified through silica gel (heptane to hep-
tane/EtOAc, 6:4) to afford a colorless oil (46.3 mg, 42%). 1H NMR
(300 MHz, CDCl3, ratio 88:12): major: δ = 7.45 (dd, J = 1.6,
6.0 Hz, 1 H, CH=CH–CO), 6.20 (dd, J = 2.1, 5.9 Hz, 1 H,
CH=CH–CO), 4.78 (dd, J = 1.7, 2.0 Hz, 1 H, CHO), 2.30 (d, J =
12.9 Hz, 1 H), 2.25 (d, J = 12.3 Hz, 1 H), 2.14 (dt, J = 13.7, 1.7 Hz,
1 H), 2.02 (dt, J = 13.7, 1.7 Hz, 1 H), 1.95 (d, J = 14.2 Hz, 1 H),
1.51 (dt, J = 14.2, 1.7 Hz, 1 H), 1.09 (s, 3 H, CH3), 1.05 (s, 3 H,
CH3), 1.04 (s, 3 H, CH3) ppm; minor: δ = 7.43 (dd, J = 1.5, 5.8 Hz,
1 H, CH=CH–CO), 6.20 (dd, J = 2.0, 5.9 Hz, 1 H, CH=CH–CO),
4.70 (dd, J = 1.7, 2.0 Hz, 1 H, CHO), 2.62 (d, J = 13.5 Hz, 1 H),
1.66 (d, J = 14.2 Hz, 1 H), 1.31 (dt, J = 12.3, 1.5 Hz, 1 H), 1.07 (s,
3 H, CH3), 1.01 (s, 3 H, CH3) ppm; other signals masked by the
major isomer. 13C NMR (75 MHz, CDCl3): major: δ = 210.0 (Cq,
C=O), 172.3 (Cq, O–C=O), 152.8 (CH, CH=CH–CO), 123.5 (CH,
CH=CH–CO), 89.8 (CH, CHO), 53.5 (CH2), 47.1 (CH2), 47.8
(CH2), 42.2 (Cq, CCH3), 35.5 [Cq, C(CH3)2], 33.7 (CH3), 29.1
(CH3), 22.5 (CH3) ppm; minor: δ = 172.4 (Cq, O–C=O), 152.9
(CH, CH=CH–CO), 123.5 (CH, CH=CH–CO), 53.7 (CH2), 48.9
(CH2), 43.4 (CH2), 41.9 (Cq, CCH3), 35.4 [Cq, C(CH3)2], 33.3
(CH3), 29.2 (CH3), 23.3 (CH3) ppm; other signals masked by the
C(CH ) ], 28.7 (CH ), 21.7 (CH ) ppm. IR (film): ν = 3117, 2950,
˜
3 2
3
3
1748, 1733, 1702 cm–1. MS (ESI+): m/z (%) = 231 (100) [M + Na].
HRMS: calcd. for C12H16NaO3 231.0997; found 231.0986. 1,2-Ad-
dition product 5-(1-hydroxy-4,4-dimethylcyclohex-2-enyl)furan-
1
2(5H)-one: H NMR (300 MHz, CDCl3, ratio 53:47): δ = 7.49 (m,
1 H maj + 1 H min, CH=CH–CO), 6.19 (m, 1 H maj + 1 H min,
CH=CH–CO), 5.74 (m, 1 H min, CH=CH), 5.70 (m, 1 H maj,
CH=CH), 5.50 (dd, J = 10.1, 1.4 Hz, 1 H maj, CH=CH), 5.41 (d,
J = 10 Hz, 1 H min, CH=CH), 4.96 (dd, J = 1.8, 1.7 Hz, 1 H min,
CHO), 4.92 (dd, J = 1.8, 1.7 Hz, 1 H maj, CHO), 2.09 (br. s, 1 H
maj + 1 H min, OH), 1.91–1.77 (m, 2 H), 1.74–1.60 (m, 4 H), 1.55–
1.44 (m, 2 H), 1.03 (s, 3 H maj + 3 H min, CH3), 0.97 (s, 3H min,
CH3), 0.95 (s, 3 H maj, CH3) ppm. 13C NMR (75 MHz, CDCl3):
major: δ = 172.9 (Cq, O–C=O), 153.2 (CH, CH=CH–CO), 144.3
(CH, CH=CH), 123.9 (CH, CH=CH), 123.1 (CH, CH=CH–CO),
88.6 (CH, CHO), 70.4 (Cq, COH), 32.4 (CH2), 32.0 [Cq,
C(CH3)2], 29.8 (CH3), 29.3 (CH2), 26.9 (CH3) ppm; minor: δ =
172.9 (Cq, O–C=O), 153.6 (CH, CH=CH–CO), 144.0 (CH,
CH=CH), 124.6 (CH, CH=CH), 122.9 (CH, CH=CH–CO), 87.5
(CH, CHO), 70.7 (Cq, COH), 32.7 (CH2), 32.0 [Cq, C(CH3)2], 29.4
major isomer. IR (film): ν = 3092, 2956, 1748, 1707 cm–1. MS
˜
(ESI+): m/z (%) = 245 (100) [M + Na]. HRMS: calcd. for
C13H18NaO3 245.1154; found 245.1155.
5-(1-Ethyl-3-oxocyclohexyl)furan-2(5H)-one (3f): This compound
was prepared according to the General Procedure A from 3-ethyl-
cyclohex-2-en-1-one (2f, 70 mg, 0.564 mmol) and 2-(tert-butyldi-
methylsilyloxy)furan (1b, 145 mg, 0.733 mmol) in the presence of
tin(IV) chloride solution (1  in DCM, 0.11 mL, 0.11 mmol) in
DCM (2.8 mL). The crude mixture was purified through silica gel
(heptane to heptane/EtOAc, 6:4) to afford a colorless oil (62.4 mg,
53%). 1H NMR (300 MHz, CDCl3, ratio 88:12): major: δ = 7.46
(dd, J = 1.4, 5.8 Hz, 1 H, CH=CH–CO), 6.16 (dd, J = 2.1, 5.9 Hz,
1 H, CH=CH–CO), 4.95 (dd, J = 1.6, 2.0 Hz, 1 H, CHO), 2.28 (m,
2 H), 2.20 (m, 1 H), 2.02 (m, 5 H), 1.50 (m, 1 H), 1.36 (m, 1 H),
0.91 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm; minor: δ = 7.50 (dd, J =
1.5, 5.8 Hz, 1 H, CH=CH–CO), 6.18 (m, 1 H, CH=CH–CO), 4.91
(dd, J = 1.8, 1.9 Hz, 1 H, CHO), 0.89 (t, J = 7.6 Hz, 3 H, CH2CH3)
ppm; other signals masked by the major isomer. 13C NMR
(75 MHz, CDCl3): major: δ = 210.2 (Cq, C=O), 172.5 (Cq, O–
C=O), 153.2 (CH, CH=CH–CO), 123.2 (CH, CH=CH–CO), 87.2
(CH, CHO), 46.3 (CH2), 44.8 (Cq, CCH2CH3), 40.6 (CH2), 29.1
(CH2), 26.9 (CH2), 20.9 (CH2), 7.65 (CH3, CH2CH3) ppm; minor:
(CH ), 29.3 (CH ), 27.8 (CH ) ppm. IR (film): ν = 3439, 2954,
˜
3
2
3
1738 cm–1. MS (ESI+): m/z (%) = 231 (100) [M + Na]. HRMS:
calcd. for C12H16NaO3 231.0997; found 231.1002.
Methyl 2-Oxo-6-(5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxyl-
ate (5a): This compound was prepared as described in General Pro-
cedure B from methyl 6-oxocyclohex-1-enecarboxylate (4a, 60 mg,
0.384 mmol) in DCM (0.8 mL) and 2-(trimethylsilyloxy)furan (1a,
76 µL, 0.461 mmol) in the presence of copper(II) triflate (13.7 mg,
0.038 mmol) in DCM (1.4 mL). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a col-
orless oil (76.4 mg, 83%). IR (film): ν = 2950, 1743, 1711 cm–1. MS
˜
(ESI+): m/z (%) = 261 (100) [M + Na]. HRMS: calcd. for
C12H14NaO5 261.0739; found 261.0742.
δ = 153.3 (CH, CH=CH–CO), 86.6 (CH, CHO), 47.0 (CH2), 44.6 Methyl 2-(Diethoxyphosphoryloxy)-6-(5-oxo-2,5-dihydrofuran-2-yl)-
(Cq, CCH2CH3), 28.5 (CH2), 26.7 (CH2) ppm; other signals
cyclohex-1-enecarboxylate (6a): This compound was prepared as
described in General Procedure C from the oxo ester 5a (32.6 mg,
0.136 mmol) in solution in THF (0.7 mL), NaH (60% in oil, 6 mg,
0.15 mmol) in suspension in THF (0.7 mL), and diethyl chloro-
masked by the major isomer. IR (film): ν = 3090, 2941, 2881, 1746,
˜
1702 cm–1. MS (ESI+): m/z (%) = 231 (100) [M + Na]. HRMS:
calcd. for C12H16NaO3 231.0997; found 231.0995.
Eur. J. Org. Chem. 2010, 5471–5481
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5477

L. Chabaud, T. Jousseaume, P. Retailleau, C. Guillou
FULL PAPER
phosphate (23 µL, 0.15 mmol). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a white
through silica gel (heptane to heptane/EtOAc, 3:7) to afford a col-
solid (56.7 mg, 70%). IR (film): ν = 3083–2860, 1736, 1703, 1649,
˜
orless oil (34.2 mg, 67%). 1H NMR (300 MHz, CDCl3, ratio 95:5): 1610, 1222 cm–1. MS (ESI+): m/z (%) = 275 (100) [M + Na].
major: δ = 7.45 (dd, J = 1.6, 5.7 Hz, 1 H, CH=CH–CO), 6.07 (dd, HRMS: calcd. for C13H16NaO5 275.0895; found 275.0904.
J = 2.1, 5.7 Hz, 1 H, CH=CH–CO), 5.14 (m, 1 H, CHO), 4.17 (m,
4 H, 2ϫPOCH2), 3.74 (s, 3 H, CO2CH3), 3.36 (m, 1 H, CHCHO),
2.45 (m, 2 H), 1.84–1.52 (m, 4 H), 1.35 (m, 6 H, 2ϫPOCH2CH3)
ppm; minor: δ = 7.37 (dd, J = 1.6, 5.9 Hz, 1 H, CH=CH–CO), 6.13
(dd, J = 2.2, 5.8 Hz, 1 H, CH=CH–CO), 3.07 (m, 1 H, CHCHO)
ppm; other signals masked by the major isomer. 13C NMR
(75 MHz, CDCl3): major: δ = 172.6 (Cq, O–C=O), 166.5 (Cq,
CO2Me), 155.3 [d, JP,C = 7.1 Hz, Cq, COP(OEt)2], 154.8 (CH,
CH=CH–CO), 121.8 (CH, CH=CH–CO), 114.0 (d, JP,C = 8.0 Hz,
Cq, CCO2Me), 84.9 (CH, CHO), 64.6 (d, JP,C = 6.2 Hz, CH2,
POCH2CH3), 51.8 (CH3, CO2CH3), 37.7 (CH, CHCHO), 28.4
(CH2), 22.8 (CH2), 19.4 (CH2), 16.0 (d, JP,C = 7.8 Hz, CH3,
Methyl
2-(Diethoxyphosphoryloxy)-6-(4-methyl-5-oxo-2,5-dihy-
drofuran-2-yl)cyclohex-1-enecarboxylate (6aЈЈ): This compound was
prepared as described in General Procedure C from the oxo ester
5aЈЈ (27.3 mg, 0.108 mmol) in solution in THF (1 mL), NaH (60%
in oil, 4.8 mg, 0.12 mmol) in suspension in THF (0.55 mL), and
diethyl chlorophosphate (18 µL, 0.1112 mmol). The crude mixture
was purified through silica gel (heptane to heptane/EtOAc, 3:7) to
1
afford a colorless oil (23 mg, 55%). H NMR (300 MHz, CDCl3,
ratio Ͼ95:Ͻ5): major: δ = 7.00 (m, 1 H, CH=CH–CO), 4.97 (m, 1
H, CHO), 4.16 (m, 4 H, 2ϫPOCH2), 3.73 (s, 3 H, CO2CH3), 3.28
(m, 1 H, CHCHO), 2.44 (m, 2 H), 1.87 (t, J = 1.8 Hz, 3 H, CH3),
1.84–1.54 (m, 4 H), 1.35 (m, 6 H, 2ϫPOCH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): major: δ = 173.7 (Cq, O–C=O), 166.7 (Cq,
CO2Me), 154.8 [d, JP,C = 7.3 Hz, Cq, COP(OEt)2], 147.0 (CH,
POCH CH ) ppm. IR (film): ν = 2984, 1752, 1722, 1663 cm–1. MS
˜
2
3
(ESI+): m/z (%) = 397 (100) [M + Na]. HRMS: calcd. for
C16H23NaO8P 397.1028; found 397.1024.
CH=CH–CO), 130.5 (Cq, CH=CCH3–CO), 114.3 (d, JP,C
=
8.2 Hz, Cq, CCO2Me), 82.7 (CH, CHO), 64.6 (d, JP, C = 6.5 Hz,
CH2, POCH2CH3), 51.8 (CH3, CO2CH3), 37.9 (CH, CHCHO),
28.3 (CH2), 23.0 (CH2), 19.4 (CH2), 16.0 (d, JP,C = 7.3 Hz, CH3,
Ethyl 2-Oxo-6-(5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate
(5aЈ): This compound was prepared as described in General Pro-
cedure B from ethyl 6-oxocyclohex-1-enecarboxylate (4aЈ, 500 mg,
2.97 mmol) in DCM (7.4 mL) and 2-(trimethylsilyloxy)furan (1a,
0.58 mL, 3.56 mmol) in the presence of copper(II) triflate (107 mg,
0.297 mmol) in DCM (7 mL). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a col-
POCH CH ), 10.6 (CH ) ppm. IR (film): ν = 2948, 1757, 1727,
˜
2
3
3
1660, 1030 cm–1. MS (ESI+): m/z (%) = 411 (100) [M + Na].
HRMS: calcd. for C17H25NaO8P 411.1185; found 411.1182.
Methyl
2-Oxo-5-(5-oxo-2,5-dihydrofuran-2-yl)cyclopentanecarb-
oxylate (5b): This compound was prepared as described in General
Procedure B from methyl 7-oxocyclopent-1-enecarboxylate (4b,
60 mg, 0.428 mmol) in DCM (1.1 mL), 2-(trimethylsilyloxy)furan
(1a, 84 µL, 0.513 mmol), and copper(II) triflate (15.2 mg,
0.042 mmol) in DCM (1.1 mL). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a yel-
orless oil (53 mg, 86%). IR (film): ν = 2940, 1745, 1711, 1641, 1613,
˜
1220, 818 cm–1. MS (ESI+): m/z (%) = 275 (100) [M + Na]. HRMS:
calcd. for C13H16NaO5 275.0895; found 275.0899.
Ethyl 2-(Diethoxyphosphoryloxy)-6-(5-oxo-2,5-dihydrofuran-2-yl)-
cyclohex-1-enecarboxylate (6aЈ): This compound was prepared as
described in General Procedure C from the oxo ester 5aЈ (53.9 mg,
0.214 mmol) in solution in THF (1 mL), NaH (60% in oil, 9.4 mg,
0.235 mmol) in suspension in THF (1 mL), and diethyl chlorophos-
phate (36 µL, 0.235 mmol). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a col-
low oil (45.3 mg, 47%). IR (film): ν = 2955, 1748, 1726, 1103 cm–1.
˜
MS (ESI+): m/z (%) = 247 (100) [M + Na]. HRMS: calcd. for
C11H12NaO5 247.0582; found 247.0586.
Methyl 2-(Diethoxyphosphoryloxy)-5-(5-oxo-2,5-dihydrofuran-2-yl)-
cyclopent-1-enecarboxylate (6b): This compound was prepared as
described in General Procedure C from the keto ester 5b (20.6 mg,
0.092 mmol) in solution in THF (0.85 mL), NaH (60% in oil, 4 mg,
0.1 mmol) in suspension in THF (0.45 mL), and diethyl chloro-
phosphate (15.3 µL, 0.1 mmol). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 3:7) to afford a col-
orless oil (18.5 mg, 56%). 1H NMR (300 MHz, CDCl3, ratio
81:19): major: δ = 7.45 (dd, J = 5.7, 1.6 Hz, 1 H, CH=CH–CO),
6.18 (dd, J = 5.8, 2.1 Hz, 1 H, CH=CH–CO), 5.46 (m, 1 H, CHO),
4.31–4.17 (m, 4 H, 2ϫPOCH2), 3.74 (s, 3 H, CO2CH3), 3.59 (m, 1
H, CHCHO), 2.69 (m, 2 H), 2.04 (m, 1 H), 1.64 (m, 2 H), 1.38 (m,
6 H, 2ϫPOCH2CH3) ppm; minor: 7.39 (dd, J = 5.7, 1.5 Hz, 1 H,
CH=CH–CO), 6.14 (dd, J = 5.9, 2.1 Hz, 1 H, CH=CH–CO), 5.56
(m, 1 H, CHO), 4.31–4.17 (m, 4 H, 2ϫPOCH2), 3.76 (s, 3 H,
CO2CH3), 3.29 (m, 1 H, CHCHO), 2.78 (m, 2 H), 1.85 (m, 2 H),
1.38 (m, 6 H, 2ϫPOCH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
major: δ = 172.8 (Cq, O–C=O), 163.5 (Cq, CO2Me), 161.7 [d, JP,C
= 6.1 Hz, Cq, COP(OEt)2], 154.1 (CH, CH=CH–CO), 122.7 (CH,
CH=CH–CO), 111.7 (d, JP,C = 8.8 Hz, Cq, CCO2Me), 84.4 (CH,
1
orless oil (55 mg, 66%). H NMR (300 MHz, CDCl3, ratio 95:5):
major: δ = 7.46 (dd, J = 1.5, 5.6 Hz, 1 H, CH=CH–CO), 6.06 (dd,
J = 2.1, 5.2 Hz, 1 H, CH=CH–CO), 5.14 (m, 1 H, CHO), 4.28–
4.09 (m, 6 H, CO2CH2 + 2ϫPOCH2), 3.35 (m, 1 H, CHCHO),
2.44 (m, 2 H), 1.84–1.51 (m, 4 H), 1.39–1.21 (m, 9 H, CO2CH2CH3,
2ϫPOCH2CH3) ppm; minor: δ = 7.37 (dd, J = 1.5, 5.7 Hz, 1 H,
CH=CH–CO), 6.11 (dd, J = 2.1, 5.7 Hz, 1 H, CH=CH–CO), 5.10
(m, 1 H, CHO), 3.05 (m, 1 H, CHCHO) ppm; other signals masked
by the major isomer. 13C NMR (75 MHz, CDCl3): major: δ = 172.5
(Cq, O–C=O), 166.0 (Cq, CO2Et), 154.9 [d, JP,C = 8.1 Hz, Cq, CO-
P(OEt)2], 154.8 (CH, CH=CH–CO), 121.9 (CH, CH=CH–CO),
114.3 (d, JP,C = 9.2 Hz, Cq, CCO2Et), 84.9 (CH, CHO), 64.6 (d,
JP,C = 5.3 Hz, CH2, POCH2CH3), 60.9 (CH2, CO2CH2), 37.7 (CH,
CHCHO), 28.3 (CH2), 22.7 (CH2), 19.5 (CH2), 16.0 (d, JP,C
=
6.9 Hz, CH3, POCH2CH3), 14.1 (CH3, CO2CH2CH3) ppm. IR
(film): ν = 2983, 1753, 1720, 1024 cm–1. MS (ESI+): m/z (%) = 411
˜
(100) [M + Na]. HRMS: calcd. for C17H25NaO8P 411.1185; found
411.1182.
CHO), 65.2 (d, JP,C = 7.6 Hz, CH2, POCH2CH3), 65.1 (d, JP,C
=
7.6 Hz, CH2, POCH2CH3), 51.4 (CH3, CO2CH3), 43.7 (CH,
CHCHO), 32.5 (CH2), 20.7 (CH2), 16.0 (d, JP,C = 6.4 Hz, CH3,
Methyl 2-(4-Methyl-5-oxo-2,5-dihydrofuran-2-yl)-6-oxocyclohexane-
carboxylate (5aЈЈ): This compound was prepared as described in
General Procedure B from methyl 6-oxocyclohex-1-enecarboxylate
(4a, 50 mg, 0.32 mmol) in solution in DCM (0.4 mL), triisopro-
pyl(3-methylfuran-2-yloxy)silane (1d, 97.7 mg, 0.384 mmol) in
solution in DCM (0.4 mL), and copper(II) triflate (11.6 mg,
0.032 mmol) in DCM (0.8 mL). The crude mixture was purified
POCH CH ) ppm IR (film): ν = 2952, 1751, 1714, 1697, 1649,
˜
2
3
1018 cm–1. MS (ESI+): m/z (%) = 383 (100) [M + Na]. HRMS:
calcd. for C15H21NaO8P 383.0872; found 383.0880.
Ethyl 2-Oxo-5-(5-oxo-2,5-dihydrofuran-2-yl)cyclopentanecarboxyl-
ate (5bЈ): This compound was prepared as described in General
5478
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5471–5481

Mukaiyama–Michael Reactions between Furans and Enones or Oxo Esters
Procedure B from ethyl 7-oxocyclopent-1-enecarboxylate (4bЈ,
60 mg, 0.389 mmol) in DCM (1 mL), 2-(trimethylsilyloxy)furan
(1a, 77 µL, 0.467 mmol), and copper(II) triflate (14.1 mg,
0.039 mmol) in DCM (1 mL). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a
(dd, J = 5.8, 2.1 Hz, 1 H, CH=CH–CO), 5.03 (m, 1 H, CHO),
4.22–4.04 (m, 4 H, 2ϫPOCH2), 3.67 (s, 3 H, CO2CH3), 2.88 (m, 1
H, CHCHO), 1.17 (s, 3 H, CH3), 1.02 (s, 3 H, CH3) ppm; other
signals masked by the major isomer. 13C NMR (75 MHz, CDCl3):
major: δ = 172.8 (Cq, O–C=O), 167.3 (Cq, CO2Me), 156.7 [d, JP,C
slightly yellow oil (60 mg, 65%). IR (film): ν = 2980, 1746, 1716, = 8.5 Hz, Cq, COP(OEt)2], 156.2 (CH, CH=CH–CO), 120.8 (CH,
˜
1098 cm–1. MS (ESI+): m/z (%) = 261 (100) [M + Na]. HRMS:
calcd. for C12H14NaO5 261.0739; found 261.00732.
CH=CH–CO), 110.8 (d, JP,C = 8.2 Hz, Cq, CCO2Me), 82.2 (CH,
CHO), 64.6 (d, JP,C = 6.7 Hz, CH2, POCH2CH3), 51.7 (CH3,
CO2CH3), 48.1 (CH, CHCHO), 31.9 [Cq, C(CH3)2], 31.2 (CH2),
27.8 (CH3), 27.2 (CH3), 26.5 (CH2), 16.0 (d, JP,C = 6.6 Hz, CH3,
Ethyl 2-(Diethoxyphosphoryloxy)-5-(5-oxo-2,5-dihydrofuran-2-yl)-
cyclopent-1-enecarboxylate (6bЈ): This compound was prepared as
described in General Procedure C from the oxo ester 5bЈ (25.8 mg,
0.108 mmol) in solution in THF (1 mL), NaH (60% in oil, 4.8 mg,
0.119 mmol) in suspension in THF (0.55 mL), and diethyl chloro-
phosphate (18.2 µL, 0.119 mmol). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 3:7) to afford a col-
POCH2CH3) ppm. IR (film): ν = 2954, 1757, 1704, 1276,
˜
1022 cm–1. MS (ESI+): m/z (%) = 425 (100) [M + Na]. HRMS:
calcd. for C17H25NaO8P 425.1341; found 425.1345.
Ethyl 3,3-Dimethyl-6-oxo-2-(5-oxo-2,5-dihydrofuran-2-yl)cyclohex-
anecarboxylate (5cЈ): This compound was prepared as described
in General Procedure B from ethyl 3,3-dimethyl-6-oxocyclohex-1-
1
orless oil (25 mg, 62%). H NMR (300 MHz, CDCl3, ratio 85:15):
major: δ = 7.45 (dd, J = 5.8, 1.5 Hz, 1 H, CH=CH–CO), 6.13 (dd, enecarboxylate (4cЈ, 60 mg, 0.305 mmol) in solution in DCM
J = 5.8, 2.0 Hz, 1 H, CH=CH–CO), 5.46 (m, 1 H, CHO), 4.31– (1 mL), 2-(trimethylsilyloxy)furan (1a, 60 µL, 0.367 mmol), and
4.13 (m, 6 H, CO2CH2, 2ϫPOCH2), 3.59 (m, 1 H, CHCHO), 2.69
copper(II) triflate (11 mg, 0.0305 mmol) in DCM (0.7 mL). The
(m, 2 H), 2.02 (m, 1 H), 1.62 (m, 1 H), 1.37 (m, 6 H, crude mixture was purified through silica gel (heptane to heptane/
2ϫPOCH2CH3), 1.29 (t, J = 7.2 Hz, 3 H, CO2CH2CH3) ppm; EtOAc, 6:4) to afford a colorless oil (58.9 mg, 69%). IR (film): ν =
˜
minor: δ = 7.38 (d, J = 5.7, 1.5 Hz, 1 H, CH=CH–CO), 6.17 (dd, 2962, 1752, 1639, 1607, 1216 cm–1. MS (ESI+): m/z (%) = 303 (100)
J = 5.8, 2.1 Hz, 1 H, CH=CH–CO), 5.56 (m, 1 H, CHO), 4.31– [M + Na]. HRMS: calcd. for C15H20NaO5 303.1208; found
4.13 (m, 6 H, CO2CH2, 2ϫPOCH2), 3.28 (m, 1 H, CHCHO), 2.79 303.1194.
(m, 2 H), 1.82 (m, 2 H) 1.37 (m, 6 H, 2ϫPOCH2CH3), 1.30 (t, J
= 7.2 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
major: δ = 172.8 (Cq, O–C=O), 163.0 (Cq, CO2Et), 161.4 [d, JP,C
= 6.7 Hz, Cq, COP(OEt)2], 154.1 (CH, CH=CH–CO), 122.7 (CH,
CH=CH–CO), 111.9 (d, JP,C = 8.5 Hz, Cq, CCO2Et), 84.4 (CH,
Ethyl 2-(Diethoxyphosphoryloxy)-5,5-dimethyl-6-(5-oxo-2,5-dihy-
drofuran-2-yl)cyclohex-1-enecarboxylate (6cЈ): This compound was
prepared as described in General Procedure C from the oxo ester
5cЈ (24 mg, 0.085 mmol) in solution in THF (0.77 mL), NaH (60%
in oil, 3.8 mg, 0.095 mmol) in suspension in THF (0.43 mL), and
diethyl chlorophosphate (15 µL, 0.095 mmol). The crude mixture
was purified through silica gel (heptane to heptane/EtOAc, 3:7) to
afford a colorless oil (16.9 mg, 47%, 53% based on starting mate-
rial). 1H NMR (300 MHz, CDCl3, ratio 89:11): major: δ = 7.36
(dd, J = 5.6, 1.8 Hz, 1 H, CH=CH–CO), 5.93 (dd, J = 5.7, 2.1 Hz,
1 H, CH=CH–CO), 5.31 (m, 1 H, CHO), 4.22–4.06 (m, 6 H,
CO2CH2, 2ϫPOCH2), 2.95 (m, 1 H, CHCHO), 2.51 (m, 2 H), 2.15
(m, 1 H), 1.41–1.22 (m, 10 H, CO2CH2CH3, 2ϫPOCH2CH3), 1.19
(s, 3 H, CH3), 1.02 (s, 3 H, CH3) ppm; minor: δ = 7.44 (dd, J =
CHO), 65.1 (d, JP,C = 7.1 Hz, CH2, POCH2CH3), 65.0 (d, JP,C
=
7.1 Hz, CH2, POCH2CH3), 60.4 (CH2, CO2CH2), 43.7 (CH,
CHCHO), 32.5 (CH2), 20.7 (CH2), 16.0 (d, JP,C = 7.0 Hz, CH3,
POCH CH ), 14.2 (CH , CO CH CH ) ppm. IR (film): ν = 2983,
˜
2
3
3
2
2
3
1753, 1714, 1693, 1649, 1020 cm–1. MS (ESI+): m/z (%) = 397 (100)
[M + Na]. HRMS: calcd. for C16H23NaO8P 397.1028; found
397.1012.
Methyl
3,3-Dimethyl-6-oxo-2-(5-oxo-2,5-dihydrofuran-2-yl)cyclo-
hexanecarboxylate (5c): This compound was prepared as described
in General Procedure B from methyl 3,3-dimethyl-6-oxocyclohex- 5.6, 1.8 Hz, 1 H, CH=CH–CO), 6.08 (dd, J = 5.6, 2.1 Hz, 1 H,
1-enecarboxylate (4c, 60 mg, 0.329 mmol) in solution in DCM
(1 mL), 2-(trimethylsilyloxy)furan (1a, 65 µL, 0.395 mmol), and
copper(II) triflate (11.9 mg, 0.033 mmol) in DCM (0.7 mL). The
crude mixture was purified through silica gel (heptane to heptane/
CH=CH–CO), 5.03 (m, 1 H, CHO), 2.87 (m, 1 H, CHCHO) ppm;
other signals masked by the major isomer. 13C NMR (75 MHz,
CDCl3): major: δ = 172.8 (Cq, O–C=O), 167.0 (Cq, CO2Et), 156.3
[Cq, COP(OEt)2], 156.3 (CH, CH=CH–CO), 120.9 (CH, CH=CH–
EtOAc, 6:4) to afford a white solid (57.8 mg, 66%). IR (film): ν = CO), 111.1 (d, JP,C = 8.1 Hz, Cq, CCO2Et), 82.2 (CH, CHO), 64.6
˜
3091–2949, 1738, 1642, 1606, 1217 cm–1. MS (ESI+): m/z (%) = 289
(100) [M + Na]. HRMS: calcd. for C14H18NaO5 289.1052; found
289.1064.
(d, JP,C = 6.2 Hz, CH2, POCH2CH3), 64.5 (d, JP,C = 5.6 Hz, CH2,
POCH2CH3), 60.8 (CH2, CO2CH2), 48.1 (CH, CHCHO), 31.9 [Cq,
C(CH3)2], 31.2 (CH2), 27.8 (CH3), 27.2 (CH3), 26.4 (CH2), 16.1 (d,
JP,C = 7.0 Hz, CH3, POCH2CH3), 14.0 (CH3, CO2CH2CH3) ppm.
IR (film): ν = 2975–2876, 1757, 1702, 1278, 1026 cm–1. MS (ESI+):
Methyl 2-(Diethoxyphosphoryloxy)-5,5-dimethyl-6-(5-oxo-2,5-dihy-
drofuran-2-yl)cyclohex-1-enecarboxylate (6c): This compound was
prepared as described in General Procedure C from the oxo ester
5c (30 mg, 0.112 mmol) in solution in THF (1 mL), NaH (60% in
oil, 4.9 mg, 0.123 mmol) in suspension in THF (0.6 mL), and di-
ethyl chlorophosphate (19 µL, 0.123 mmol). The crude mixture was
purified through silica gel (heptane to heptane/EtOAc, 3:7) to af-
˜
m/z (%) = 439 (100) [M + Na]. HRMS: calcd. for C19H29NaO8P
439.1498; found 439.1500.
Methyl
2-Oxo-7-(5-oxo-2,5-dihydrofuran-2-yl)cycloheptanecarb-
oxylate (5d): This compound was prepared as described in General
Procedure B from methyl 7-oxocyclohept-1-enecarboxylate (4d,
67.3 mg, 0.4 mmol), 2-(trimethylsilyloxy)furan (1a, 79 µL,
0.48 mmol), and copper(II) triflate (14.4 mg, 0.04 mmol) in DCM
1
ford a colorless oil (32.1 mg, 71%). H NMR (300 MHz, CDCl3,
ratio 85:15): major: δ = 7.35 (dd, J = 5.6, 1.6 Hz, 1 H, CH=CH–
CO), 5.93 (dd, J = 5.7, 2.2 Hz, 1 H, CH=CH–CO), 5.30 (m, 1 H, (2 mL). The crude mixture was purified through silica gel (heptane
CHO), 4.22–4.04 (m, 4 H, 2ϫPOCH2), 3.66 (s, 3 H, CO2CH3), to heptane/EtOAc, 5:5) to afford a colorless oil (84.3 mg, 83%). IR
2.94 (m, 1 H, CHCHO), 2.49 (m, 2 H), 2.13 (m, 1 H), 1.40–1.27 (film): ν = 2934–2863, 1745, 1698, 1436, 1158 cm–1. MS (ESI+):
˜
(m, 7 H, 2ϫPOCH2CH3), 1.19 (s, 3 H, CH3), 1.02 (s, 3 H, CH3)
m/z (%) = 275 (100) [M + Na]. HRMS: calcd. for C13H16NaO5
ppm; minor: 7.41 (dd, J = 5.7, 1.4 Hz, 1 H, CH=CH–CO), 6.08 275.0895; found 275.0894.
Eur. J. Org. Chem. 2010, 5471–5481
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5479

L. Chabaud, T. Jousseaume, P. Retailleau, C. Guillou
FULL PAPER
Methyl 2-(Diethoxyphosphoryloxy)-7-(5-oxo-2,5-dihydrofuran-2-yl)-
cyclohept-1-enecarboxylate (6d): This compound was prepared as
described in General Procedure C from the oxo ester 5d (49 mg,
0.194 mmol) in solution in THF (0.87 mL), NaH (60% in oil,
8.5 mg, 0.213 mmol) in suspension in THF (0.96 mL), and diethyl
chlorophosphate (32 µL, 0.213 mmol). The crude mixture was puri-
fied through silica gel (heptane to heptane/EtOAc, 3:7) to afford a
colorless oil (49.1 mg, 65%). 1H NMR (300 MHz, CDCl3, ratio
84:16): major: δ = 7.46 (dd, J = 1.6, 5.7 Hz, 1 H, CH=CH–CO),
6.08 (dd, J = 2.0, 5.8 Hz, 1 H, CH=CH–CO), 5.19 (m, 1 H, CHO),
4.07 (m, 4 H, 2ϫPOCH2), 3.71 (s, 3 H, CO2CH3), 3.21 (m, 1 H,
CHCHO), 2.84 (m, 1 H), 2.51 (m, 1 H), 1.90–1.62 (m, 6 H), 1.31
(m, 6 H, 2ϫPOCH2CH3) ppm; minor: δ = 7.60 (d, J = 5.5 Hz, 1
H, CH=CH–CO), 5.29 (d, J = 9.7 Hz, 1 H, CHO), 3.73 (s, 3 H,
CO2CH3), 2.75 (m, 2 H), 2.61 (m, 1 H), 2.07 (m, 2 H) ppm; other
signals masked by the major isomer. 13C NMR (75 MHz, CDCl3):
major: δ = 172.4 (Cq, O–C=O), 167.9 (Cq, CO2Me), 156.9 [d, JP,C
= 9 Hz, Cq, COP(OEt)2], 154.8 (CH, CH=CH–CO), 122.0 (CH,
CH=CH–CO), 118.3 (d, JP,C = 7.6 Hz, Cq, CCO2Me), 85.1 (CH,
Acknowledgments
The authors thank the Centre National de la Recherche Sci-
entifique and the Institut de Chimie des Substances Naturelles for
financial support and Prof. J. Y. Lallemand for his interest in this
work. We also thank Prof. Y. Landais (Institut des Sciences Molé-
culaires, University of Bordeaux) and Dr. J. Molgó (Laboratoire de
Neurobiologie Cellulaire et Moléculaire, Gif-sur-Yvette) for fruitful
discussions.
[1] a) K. Narasaka, K. Soai, T. Mukaiyama, Chem. Lett. 1974, 3,
1223–1224; b) K. Narasaka, K. Soai, Y. Aikawa, T. Mukai-
yama, Bull. Chem. Soc. Jpn. 1976, 49, 779–783.
[2] For reviews, see: a) G. Casiraghi, F. Zanardi, G. Appendino,
G. Rassu, Chem. Rev. 2000, 100, 1929–1972; b) S. F. Martin,
Acc. Chem. Res. 2002, 35, 895–904; c) S. E. Denmark, J. R.
Heemstra Jr., G. L. Beutner, Angew. Chem. Int. Ed. 2005, 44,
4682–4698; d) M. Kalesse, Top. Curr. Chem. 2005, 244, 43–76.
[3] For some recent examples of natural products containing γ-
butenolide units, see: a) S. Huang, L. Yang, W. Xiao, C. Lei, J.
Liu, Y. Lu, Z. Weng, L. Li, R. Li, J. Yu, Q. Zheng, H. Sun,
Chem. Eur. J. 2007, 13, 4816–4822; b) H. N. Kamel, D. Fer-
reira, L. F. Garcia-Fernandez, M. Slattery, J. Nat. Prod. 2007,
70, 1223–1227; c) Y. Wang, C. Tang, P. Dien, Y. Ye, J. Nat.
Prod. 2007, 70, 1356–1359; d) T. Hu, I. W. Burton, A. D. Cem-
bella, J. M. Curtis, M. A. Quilliam, J. A. Walter, J. L. Wright,
J. Nat. Prod. 2001, 64, 308–312; e) T. Seki, M. Satake, L. Mac-
Kenzie, H. Kaspar, T. Yasumoto, Tetrahedron Lett. 1995, 36,
7093–7096; f) J. S. Roach, P. LeBlanc, N. I. Lewis, R. Munday,
M. A. Quilliam, S. L. MacKinnon, J. Nat. Prod. 2009,
72,1237–1240.
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Am. Chem. Soc. 1999, 121, 686–699; b) S. Naito, M. Escobar,
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4208; c) J. C.-D. Le, B. L. Pagenkopf, Org. Lett. 2004, 6, 4097–
4099; d) M. Frings, I. Atodiresei, J. Runsink, G. Raabe, C.
Bolm, Chem. Eur. J. 2009, 15, 1566–1569; e) M. Frings, I. Ato-
diresei, Y. Wang, J. Runsink, G. Raabe, C. Bolm, Chem. Eur.
J. 2010, 16, 4577–4587, and references therein.
CHO), 64.5 (d, JP,C = 6.4 Hz, CH2, POCH2CH3), 63.5 (d, JP,C
=
5.9 Hz, CH2, POCH2CH3), 51.9 (CH3, CO2CH3), 41.4 (CH,
CHCHO), 32.0 (CH2), 29.6 (CH2), 27.8 (CH2), 24.5 (CH2), 23.5
(CH2), 16.0 (d, JP,C = 6.3 Hz, CH3, POCH2CH3), 15.9 (d, JP,C
=
6.3 Hz, CH , POCH CH ) ppm. IR (film): ν = 2929, 1755, 1714,
˜
3
2
3
1028 cm–1. MS (ESI+): m/z (%) = 411 (100) [M + Na]. HRMS:
calcd. for C17H25NaO8P 411.1185; found 411.1184.
Ethyl 2-Oxo-7-(5-oxo-2,5-dihydrofuran-2-yl)cycloheptanecarboxyl-
ate (5dЈ): This compound was prepared as described in General
Procedure B from ethyl 7-oxocyclohept-1-enecarboxylate (4dЈ,
60 mg, 0.329 mmol) in DCM (0.8 mL), 2-(trimethylsilyloxy)furan
(1a, 65 µL, 0.395 mmol), and copper(II) triflate (11.9 mg,
0.033 mmol) in DCM (0.9 mL). The crude mixture was purified
through silica gel (heptane to heptane/EtOAc, 6:4) to afford a col-
orless oil (68 mg, 78%). IR (film): ν = 2932, 1750, 1701, 1628, 1602,
˜
1157 cm–1. MS (ESI+): m/z (%) = 289 (100) [M + Na]. HRMS:
calcd. for C14H18NaO5 289.1052; found 289.1042.
[5] a) K. Kong, D. Romo, Org. Lett. 2006, 8, 2909–2912; b) T.
Ollevier, J.-E. Bouchard, J. Desyroy, J. Org. Chem. 2008, 73,
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Ethyl 2-(Diethoxyphosphoryloxy)-7-(5-oxo-2,5-dihydrofuran-2-yl)-
cyclohept-1-enecarboxylate (6dЈ): This compound was prepared as
described in General Procedure C from the oxo ester 5dЈ (21.7 mg,
0.081 mmol) in solution in THF (0.75 mL), NaH (60% in oil,
3.6 mg, 0.09 mmol) in suspension in THF (0.4 mL), and diethyl
chlorophosphate (14 µL, 0.09 mmol). The crude mixture was puri-
fied through silica gel (heptane to heptane/EtOAc, 3:7) to afford a
colorless oil (21.2 mg, 65%). 1H NMR (300 MHz, CDCl3, ratio
84:16): major: δ = 7.46 (dd, J = 5.7, 1.6 Hz, 1 H, CH=CH–CO),
6.09 (dd, J = 5.8, 2.0 Hz, 1 H, CH=CH–CO), 5.21 (m, 1 H, CHO),
4.19 (q, J = 7.2 Hz, 2 H, CO2CH2), 4.14 (m, 4 H, 2ϫPOCH2),
3.21 (m, 1 H, CHCHO), 2.84 (m, 1 H), 2.54 (m, 1 H), 1.96–1.60
(m, 6 H), 1.38–1.28 (m, 6 H, 2ϫPOCH2CH3), 1.30 (t, J = 7.2 Hz,
3 H, CO2CH2CH3) ppm; minor: δ = 7.62 (dd, J = 5.8, 1.4 Hz, 1
H, CH=CH–CO), 6.08 (m, 1 H, CH=CH–CO), 5.29 (m, 1 H,
CHO), 2.76–2.63 (m, 2 H) ppm; other signals masked by the major
isomer. 13C NMR (75 MHz, CDCl3): major: δ = 172.4 (Cq, O–
C=O), 167.5 (Cq, CO2Et), 156.9 [d, JP,C = 8.9 Hz, Cq, COP-
(OEt)2], 154.7 (CH, CH=CH–CO), 122.1 (CH, CH=CH–CO),
118.7 (d, JP,C = 7.9 Hz, Cq, CCO2Et), 85.1 (CH, CHO), 64.5 (d,
JP,C = 6.0 Hz, CH2, POCH2CH3), 61.1 (CH2, CO2CH2), 41.4 (CH,
CHCHO), 31.9 (CH2), 27.7 (CH2), 24.6 (CH2), 23.5 (CH2), 16.1
(d, JP,C = 6.9 Hz, CH3, POCH2CH3), 14.0 (CH3, CO2CH2CH3)
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ppm. IR (film): ν = 2930, 1753, 1704, 1273, 1018 cm–1. MS (ESI+):
˜
m/z (%) = 425 (100) [M + Na]. HRMS: calcd. for C18H27NaO8P
425.1341; found 425.1333.
5480
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5471–5481

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For the preparation of 4a, 4c, 4aЈ, and 4cЈ, see: M. Shizuka,
M. L. Snapper, Angew. Chem. Int. Ed. 2008, 47, 5049–5051; for
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CCDC-704234 (3a), -704233 (3aЈ), -704235 (3d), and
-771491 (5ЈЈa) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[21]
[22]
[13] Michael additions of the lithium dienolate of 2H-furan-5-one
to substituted cyclopentenones, giving high diastereoselectivi-
ties (dr: Ͼ95:Ͻ5), have already been described.[10] However, our
attempts to apply this method to cyclohex-2-enone led to ex-
tensive polymerization of the enone.
[14] For a discussion, see: a) A. Bernardi, K. Karamfilova, S. San-
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[15] For a discussion on the influence of the silyl group on stereose-
lectivity, see: a) J. Otera, Y. Fujita, T. Sato, H. Nozaki, J. Org.
Chem. 1992, 57, 5054–5055; b) J. Otera, Y. Fujita, S. Fukuzumi,
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[16] This result matches the previous example of VMM reactions
of TMSOF with 4-substituted cyclopentenones, which gave
very low stereoselectivities.[10]
[23]
[24] H. S. P. Rao, R. Murali, A. Taticchi, H. W. Scheeren, Eur. J.
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[25] 1H NMR monitoring of the reaction between the silyloxyfuran
1a and the oxo ester 4a in CDCl3, with a catalytic amount of
Eur(fod)3, known to catalyze Diels–Alder reactions, did not
allowed us to observe any Diels–Alder adduct. M. Bednarski,
S. Danishefsky, J. Am. Chem. Soc. 1983, 105, 3716–3717.
[26] At this stage, it cannot be excluded that different pathways
might be possible with each substrate 2 and 4.
[17] For the preparation of 2f, see: N. J. A. Martin, B. List, J. Am.
Chem. Soc. 2006, 128, 13368–13369.
[18] For preparation of 2g, see: H.-J. Liu, E. N. C. Browne, S. Y.
Chew, Can. J. Chem. 1988, 66, 2345–2347.
Received: April 13, 2010
Published Online: August 24, 2010
[19] a) A. Bernardi, G. Colombo, C. Scolastico, Tetrahedron Lett.
1996, 37, 8921–8924; b) M. Shizuka, M. L. Snapper, Angew.
Eur. J. Org. Chem. 2010, 5471–5481
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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