Stereocontrolled synthesis and cycloaddition of 1,2,4-trioxygenated 1,3-dienes

Article abstract of DOI:10.1021/jo0521854

A new stereocontrolled synthetic pathway to 1,2,4-trioxygenated 1,3-dienes from pyruvic aldehyde dimethyl acetal (14a) is described. Reacting the cyclohexylamine-derived imine of this starting material with chloroalkyl ethers under basic conditions afford

Full text of DOI:10.1021/jo0521854

Stereocontrolled Synthesis and Cycloaddition of 1,2,4-Trioxygenated
1,3-Dienes
Nicolas Pichon,† Anne Harrison-Marchand,† Loic Toupet,‡ and Jacques Maddaluno*,†
Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF, UMR 6014 CNRS,
UniVersite´ de Rouen, 76821 Mont St Aignan Cedex, France, and Groupe de Matie`re Condense´e et
Mate´riaux, UMR 6626 CNRS, UniVersite´ de Rennes I, 35042 Rennes Cedex, France
jmaddalu@crihan.fr
ReceiVed October 20, 2005
A new stereocontrolled synthetic pathway to 1,2,4-trioxygenated 1,3-dienes from pyruvic aldehyde dimethyl
acetal (14a) is described. Reacting the cyclohexylamine-derived imine of this starting material with
chloroalkyl ethers under basic conditions affords ketoacetals 18-20, which were then transformed into
eight different enoxysilanes 12. A δ-elimination triggered by tert-butyllithium yields 1,2,4-trioxygenated
dienes 13. Increasing the bulkiness of the silyloxy group or that of the acetal moiety leads stereoselectively
to the (1E,3E) or (1Z,3E) isomers of 13, respectively. Hyperbaric [4 + 2] cycloadditions between 13
(13c, 13d, 13g) and N-methylmaleimide or methyl- and phenylacrylates give access to the expected
cycloadducts with fine stereo- and regiocontrol.
Introduction
known as the Danishefsky diene,1j,2 Scheme 1), which is
routinely used in Diels-Alder and hetero-Diels-Alder cycload-
ditions. In contrast, trioxygenated 1,3-dienic systems, which are
expected to be more convergent reagents to access carbohydrates
via a [4 + 2] cycloaddition, still show limited applications,
probably because of the middle yields and low Z/E stereose-
lectivities associated with their synthesis. Three synthetic
approaches are known to date to attain such structures. An early
paper by Scheeren7 describes the preparation of both 1,2,4- and
1,2,3-trioxygenated 1,3-dienes through a preliminary acid-
Oxygenated dienes exhibit a high reactivity and selectivity
in various types of transformations.1 They are also useful
building blocks in the synthesis of natural products such as sugar
derivatives.1a,2-6 The most popular representative of this family
of compounds is certainly the 1,3-dioxygenated 1,3-diene 4 (best
† Universite´ de Rouen.
‡ Universite´ de Rennes I.
(1) For articles about mono-oxygenated dienes: (a) Heras, M.; Gulea,
M.; Masson, S.; Philouze, C. Eur. J. Org. Chem. 2004, 160-172. (b)
Domagalska, B. W.; Syper, L.; Wilk, K. A. Tetrahedron 2004, 60, 1931-
1939. (c) White, J. D.; Choi, Y. HelV. Chim. Acta 2002, 85, 4306-4327.
For articles about dioxygenated dienes: (d) Anada, M.; Washio, T.;
Shimada, N.; Kitagaki, S.; Nakajima, M.; Shiro, M.; Hashimoto, S. Angew.
Chem., Int. Ed. 2004, 43, 2665-2668. (e) Bull, S. D.; Davidson, M. G.;
Johnson, A. L.; Robinson, D. E. J. E.; Mahon, M. F. Chem. Commun. 2003,
1750-1751. (f) Coquerel, Y.; Greene, A. E.; Depre´s, J.-P. Org. Lett. 2003,
5, 4453-4455. (g) Wang, B.; Feng, X.; Huang, Y.; Liu, H.; Cui, X.; Jiang,
Y. J. Org. Chem. 2002, 67, 2175-2182. (h) Alves, M. J.; Azoia, N. G.;
Bickley, J. F.; Fortes, A. G.; Gilchrist, T. L.; Mendonc¸a, R. J. Chem. Soc.,
Perkin Trans. 1 2001, 2969-2976. (i) Virgili, M.; Moyano, A.; Perica`s,
M. A.; Riera, A. Tetrahedron 1999, 55, 3959-3986. (j) Danishefsky, S.;
Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807-7808. (k) Johnson, J. R.;
Jobling, W. H.; Bodamer, G. W. J. Am. Chem. Soc. 1941, 63, 131-135.
For articles about tri/tetraoxygenated dienes: (l) Albrecht, U.; Nguyen, T.
H. V.; Langer, P. J. Org. Chem. 2004, 69, 3417-3424. (m) Nguyen, V. T.
H.; Langer, P. Tetrahedron Lett. 2005, 46, 1013-1015. (n) Yamashita, Y.;
Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793-
3798.
(2) (a) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.
Soc. 1992, 114, 4518-4529. (b) Danishefsky, S. J.; DeNinno S. L.; Chen,
S.; Boisvert, L.; Barbachyn, M. J. Am. Chem. Soc. 1989, 111, 5810-5818.
(c) Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1989, 111, 2193-
2204. (d) Danishefsky, S. J. Acc. Chem. Res. 1981, 14, 400-406.
(3) Golebiowski, A.; Kozak, J.; Jurczak, J. J. Org. Chem. 1991, 56,
7344-7347.
(4) (a) Bataille, C.; Be´gin, G.; Guillam, A.; Lemie`gre, L.; Lys, C.;
Maddaluno, J.; Toupet, L. J. Org. Chem. 2002, 67, 8054-8062. (b) Guillam,
A.; Toupet, L.; Maddaluno, J. J. Org. Chem. 1999, 64, 9348-9357.
(5) Heras, M.; Gulea, M.; Masson, S. Chem. Commun. 2001, 611-612.
(6) (a) Cousins, R. P. C.; Pritchard, R. G.; Raynor, C. M.; Smith, M.;
Stoodley, R. J. Tetrahedron Lett. 2002, 43, 489-492. (b) Helliwell, M.;
Phillips, I. M.; Pritchard, R. G.; Stoodley, R. J. Tetrahedron Lett. 1999,
40, 8651-8655. (c) Larsen, D. S.; Stoodley, R. J. J. Chem. Soc., Perkin
Trans. 1 1989, 1841-1852.
(7) (a) Aben, R. W.; Scheeren, H. W. J. Chem. Soc., Perkin Trans. 1
1979, 3132-3138. (b) Aben, R. W.; Scheeren, H. W. Synthesis 1982, 779-
780.
10.1021/jo0521854 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/01/2006
1892
J. Org. Chem. 2006, 71, 1892-1901

Synthesis and ReactiVity of 1,2,4-Trioxygenated Dienes
SCHEME 1. Known Routes to 1,2,3- and
1,2,4-Trioxygenated 1,3-Dienes
Extending the above methodology to R,â-unsaturated acetals
bearing a silyloxy group at C2 (12, Scheme 3) not only provides
a relatively straightforward access to trioxygenated 1,3-dienes
but also demonstrates that an enol ether double bond is an
appropriate vector for a conjugate elimination reaction. No ex-
ample of such a reaction seems to be described to date.
SCHEME 3. 1,2,4-Trioxygenated 1,3-Dienes via a
δ-Elimination through an Enol Ether Double Bond?
We present here the synthesis of 12 and its transformation
into diene 13. We conclude with a preliminary study concerning
the reactivity of 13 in model Diels-Alder cycloadditions.
Results and Discussion
Preparation of Enoxysilanes 12. The required precursors,
viz. 2-trialkylsilyloxy R,â-unsaturated acetals 12, were prepared
from pyruvic aldehyde dimethyl acetal 14a, which revealed a
convenient precursor (Scheme 4). To diversify the acetal group,
and thus the OR1 alkoxy substituent, on the final diene, a trans-
acetalization of 14a was considered. A bulky secondary alcohol
was retained to evaluate a possible influence of the size of the
leaving group on the chemical and stereochemical outcomes of
the δ-elimination. Reacting 14a with 2 equiv of pentan-3-ol in
the presence of a catalytic amount of p-toluenesulfonic acid in
cyclohexane led, after refluxing for 24 h in a Dean-Stark
apparatus, to acetal 14b in a modest 27% yield, comparable
with results given in the literature.12 The use of a larger amount
catalyzed [2 + 2] cycloaddition between a ketene and a vinyl
ether (Scheme 1). The resulting alkoxycyclobutanone is trans-
formed, by trimethylsilylation, into a mixture of silyloxycy-
clobutenes 1. Cyclobutene 1a undergoes an electrocyclic ring
conrotatory opening at 25 °C to provide the single (1Z,3E)-
1,4-dialkoxy-3-trimethylsilyloxybuta-1,3-diene 2. The 1,2,3-
isomer 3 is isolated after warming 1b at 80 °C. Another strategy
is proposed by Danishefsky8 to attain 1,2,4-trioxygenated 1,3-
dienes such as 6 (Scheme 1). It relies on the transformation of
ketone 5 into its silyl enol ether. Ketone 5 results from a Rubot-
tom9 oxidation of the “classic” dioxygenated diene 4. This route
provides a mixture of three isomers. An additional way to 1,2,3-
trioxygenated 1,3-dienes, for instance 9, is described by Olsen.10
It is based on the transformation of ketone 7 into keto aldehyde
8 that a double silylation turns into diene 9 (Scheme 1).
We present in this paper a new synthetic pathway affording
1,2,4-trioxygenated 1,3-dienes. This work takes advantage of
our experience with the δ-elimination on R,â-unsaturated acetals
such as 10 (Scheme 2),4,11 triggered by n-butyllithium at low
temperature. This procedure offers a relatively efficient one-
step stereoselective access to (1Z,3E)-1,4-dialkoxy 1,3-dienes
11.
SCHEME 4. Syntheses of Butan-2-ones 18-20 from
Pyruvic Aldehyde Dimethyl Acetal 14a
SCHEME 2. Synthesis of 1,4-Dioxygenated 1,3-Diene via a
δ-Elimination
(8) (a) Danishefsky, S. J.; Kerwin, J. F.; Kobayashi, S. J. Am. Chem.
Soc. 1982, 104, 358-360. (b) Danishefsky, S. J.; Maring, C. J. J. Am. Chem.
Soc. 1985, 107, 1269-1274.
(9) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319-4322.
(10) Olsen, R. K.; Feng, X. Tetrahedron Lett. 1991, 32, 5721-5724.
(11) (a) Guillam, A.; Maddaluno, J.; Duhamel, L. J. Chem. Soc., Chem.
Commun. 1996, 1295-1296. (b) Guillam, A.; Toupet, L.; Maddaluno, J. J.
Org. Chem. 1998, 63, 5110-5122.
(12) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem.
Soc., Perkin Trans. 1 2002, 965-981.
J. Org. Chem, Vol. 71, No. 5, 2006 1893

Pichon et al.
SCHEME 5. Syntheses of Enoxysilanes 12 from
butan-2-ones 18-20
of alcohol was not retained even if it led to better conversions.
Indeed, the difficulties encountered to eliminate the excess of
pentan-3-ol when purifying 14b prompted us to engage only 2
equiv of this alcohol, privileging the quality of 14b to its
quantity. Note that the precursor 14a is cheap and commercially
available.
The functionalization of the pyruvic methyl group was
undertaken next. Deprotonating 14 by LDA in THF at low
temperature and then trapping the resulting lithium enolate by
various chloromethyl ethers was first examined.13 This route
was a dead-end, a product of self-condensation being most
probably obtained,14 together with starting material and uni-
dentified byproducts (Figure 1). A possible chelation of the
lithium of LDA by two oxygens of 14 could be at the origin of
this result. This chelation would keep apart the nitrogen of the
amide and the methyl group to be deprotonated. The Li+ Lewis
acid character would complementarily activate the carbonyl,
facilitating the self-condensation by this method.
TABLE 1. Yields of Syntheses of 12
yield
R4 R2R2′R2′′SiCl R2 R2′ R2′′ 12 (%)
entry ketone
R1
Me
1
2
3
4
5
6
7
8
18
18
18
19
19
19
19
20
Me
Me
Me
Et
21
22
23
21
24
25
23
21
Et Et Et 12a 99
iBu iBu iBu 12b 37
Ph Ph tBu 12c 34
Et Et Et 12d 99
Me Me tBu 12e 43
Me
Me
Me
Me
Me
Me
Et
Et
Et
iPr iPr iPr 12f
65
Ph Ph tBu 12g 52
Et Et Et 12h 96
CHEt2 Et
Worthy of note is the selective recovery of the Z-isomers
of 12 that could be proved thanks to bidimensional NMR stu-
dies such as NOESY experiments on 12a. The main infor-
mation given by this analytical technique is the correlation
between H3 and both H1 and H4 (Figure 2). Such a Z-stereo-
selectivity, previously observed in the literature from a
â-alkoxy ketone,16 may be rationalized considering a chelated
transition state organizing the LiHMDS and the ketoacetal
(Figure 2).
FIGURE 1. Proposed mechanism for the self-condensation of 14 in
the presence of LDA.
The disappointing result above led us to first react ketoacetals
14 with cyclohexylamine, then to deprotonate the resulting
iminoacetal and conduct the expected C-alkylation with chlo-
romethyl ethers (Scheme 4). Such an alternative has been
proposed to efficiently afford C-alkylation products from
dialkylpyruvates in the presence of LDA.15 Iminoacetals 15a
and 15b (Scheme 4) were isolated in 92% and 56% crude yields,
respectively. Immediate alkylation of the lithium enamide of
15, generated by reacting LDA on 15, with chloromethyl methyl
ether 16 and chloromethyl ethyl ether 17 led to the expected
butan-2-ones 18 and 19 from 15a but failed with 15b, probably
because of the bulky acetal residue. We dodged this problem
by preparing 20 from 19 in a late trans-acetalization step. The
butan-2-one 20 was thus recovered in 20% yield after refluxing
19 in the presence of 2 equiv of pentan-3-ol in cyclohexane in
a Dean-Stark apparatus.
The enoxysilanes 12 were then isolated reacting 18-20 with
lithium hexamethyldisilazane for 20 min at -78 °C and
quenching the resulting enolates with a set of chlorotrialkylsi-
lanes 21-25 (Scheme 5, Table 1). Eight acetalic enoxysilanes
12 (12a-h) were thus prepared in medium to good yields and
used to evaluate the influence of the bulkiness of the R4 group
(entry 1 vs 4, entry 3 vs 7), of the silyloxy substituent (entries
1-3, entries 4-7), and of the acetal appendage (entry 4 vs entry
8) on the consecutive δ-elimination.
FIGURE 2. Possible origin for the Z-configuration of 12.
Preparation of Dienes 13 by δ-Elimination from 12. The
optimization of this key-step reaction has been conducted on
the silyloxy acetal 12a, which showed to be the easiest to prepare
and was recovered with the best overall yield (72% from
commercial 14a). Resorting to our previous experimental con-
ditions,11 we tried to deprotonate the C4 position of 12a (Scheme
6) using 1-3 equiv of n-butyllithium at -40 °C in THF.
However, only the starting material was recovered after workup.
Increasing the quantity of this base and/or the temperature as
well as the time of the reaction did not yield a trace of diene
12a. The use of lithium and potassium amides (LDA, KDA) or
potassium tert-butylate led to either 12a or unidentified byprod-
ucts, respectively. We then decided to employ a stronger
alkyllithium, viz. tert-butyllithium, and varied the solvent, the
time, and the temperature of the reaction (Scheme 6). The results
are gathered in Table 2.
No reaction was observed in the presence of 1 equiv of tert-
butyllithium after 1 h at -78 °C in THF (entry 1). Increasing
the amount of base (entries 2 and 3) in the same solvent allowed
(13) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233-2238.
(14) This compound was identified in the crude mixture but not fully
characterized: 1H NMR (200 MHz, CDCl3) δ 1.12 (3H, s), 2.46 (1H, d, J
) 16.1 Hz), 2.85 (1H, d, J ) 16.1 Hz), 3.29 (3H, s), 3.30 (3H, s), 3.40
(3H, s), 3.41 (3H, s), 4.00 (1H, s), 4.46 (1H, s).
(15) (a) Stark, C. B. W.; Pierau, S.; Wartchow, R.; Hoffmann, H. M. R.
Chem. Eur. J. 2000, 6, 684-691. (b) Tian, S.-K.; Hong, R.; Deng, L. J.
Am. Chem. Soc. 2003, 125, 9900-9901.
(16) (a) Matsumoto, K.; Ohta, H. Chem. Lett. 1989, 1589-1592. (b)
Craig, D.; Pennington, M. W. Tetrahedron Lett. 1993, 34, 8539-8542. (c)
Craig, D.; Pennington, M. W.; Warner, P. Tetrahedron 1999, 55, 13495-
13512.
1894 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis and ReactiVity of 1,2,4-Trioxygenated Dienes
SCHEME 6. Synthesis of Diene 13a from 12a, via a
tBuLi-Induced δ-Elimination
SCHEME 7. Synthesis of 13a-h, via a δ-Elimination, from
12a-h
TABLE 3. Yields of the Synthesis of 13a-h, via a δ-Elimination,
from 12a-h
TABLE 2. Yields of the Synthesis of Dienes 13a from 12a via a
tBuLi-Induced δ-Elimination
conversion (1E,3E)/
R1
12a Me
12b Me
R4 R2 R2′ R2′′ 13
(%)
(1Z,3E)
T
(°C)
t
conversion
(%)
(1E,3E)/
(1Z,3E)
entry 12
entry
solvent
X equiv
(h)
1
2
3
4
5
6
7
8
Me Et Et Et 13a
Me iBu iBu iBu 13b
Me Ph Ph tBu 13c
Et Et Et Et 13d
Et Me Me tBu 13e
Et iPr iPr iPr 13f
Et Ph Ph tBu 13g
98
99
91
98
91
91
98
95
50:50
60:40
87:13a
50:50
60:40
75:25
87:13
13:87
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
Et2O
DME
Toluene
Pentane
1
1.5
3
3
3
3
3
3
3
-78
-78
-78
-78
-40
-40
-40
-40
-40
1
1
1
2
1
1
1
1
1
0
25
70
90
98
a
5
0
0
50:50
50:50
50:50
50:50
12c Me
12d Me
12e Me
12f Me
12g Me
50:50
12h CHEt2 Et Et Et Et 13h
a Ratio determined after [4 + 2] cycloaddition with N-methylmaleimide
26.
a Degradation of the starting material.
butyllithium in THF at -40 °C for 1 h was the best compromise
in terms of yields and stereocontrol. These latter conditions were
thus retained to extend the δ-elimination to the enoxysilanes
12b-h (Scheme 7, Table 3). The experimental conditions
optimized on 12a and applied on 12b-h were shown to be
relatively general as all the enoxysilanes were almost quanti-
tatively transformed into the corresponding dienes 13. Compar-
ing entries 1-3 to 4-8 suggests that R4 has little if any influ-
ence on the reactivity and stereoselectivity of the δ-elimina-
tion. In contrast, increasing the bulkiness of the silyloxy group
results in favoring one isomer, and excesses up to 74% were
attained with the tert-butyldiphenylsilyloxy group (entries 3 and
7). The other isomer could be also formed with excess up to
74%, from a hindered acetal (entry 8). It is thus possible to
synthesize at will one or the other of the two possible
stereoisomers of 13, simply swapping a bulky group for another
on the precursor 12.
the formation of the expected diene. Actually, 25% of 13a was
formed using 1.5 equiv of tBuLi at -78 °C after 1 h (entry 2)
and 70% with 3 equiv of the same base in similar conditions
(entry 3). Increasing the time of the reaction (entry 4) or the
temperature (entry 5) was efficient: 90% of 13a was recovered
by reacting 12a with 3 equiv of the same base for 2 h at
-78 °C in THF (entry 4), and an almost complete conversion
(98%) of the enoxysilane into 13a was observed after 1 h at
-40 °C, still in THF and with 3 equiv of tBuLi (entry 5). Only
two isomers of the expected dienes were formed in all cases
and in an equivalent ratio. The configuration of these two species
is discussed later. The influence of the solvent on the stereo-
control and the reactivity was examined next. Dimethoxymethyl
ether (DME) was shown to be the only other solvent in which
the formation of 13a could proceed, but in a much lower yield
and without any modification of the selectivity (entry 7). A
complete degradation was observed in diethyl ether (entry 6),
while no reaction occurred at all in toluene (entry 8) or pentane
(entry 9). The influence of TMEDA, LiBr, or HMPA was also
evaluated, but the results mentioned above were unchanged. This
preliminary study suggested that the use of 3 equiv of tert-
To determine the stereochemistry of the two isomers, we
measured the chemical shifts and the H3-H4 coupling constant
(JH3-H4) and compared these values to those reported in the
literature.7,8 The three isomers of the 1,2,4-trioxygenated diene
FIGURE 3. Coupling constants and chemical shifts of dienes 6, 2, and 13.
J. Org. Chem, Vol. 71, No. 5, 2006 1895

Pichon et al.
SCHEME 8. Proposed Model To Explain the (1E,3E) and (1Z,3E) Configurations of Dienes 13
6 isolated by Danishefsky were shown to be (1Z,3Z), (1Z,3E),
and (1E,3E) (Figure 3). The difference between the 3E and the
3Z configuration translates into JH3-H4, which is worth ∼5 Hz
and ∼12 Hz, respectively. Similarly, the 3E configuration
determined in Scheeren’s diene 2 corresponds to a similar JH3-H4
value (12 Hz). As all dienes 13 isolated above exhibit a JH3-H4
) 12 Hz, we assumed that the δ-elimination conducted from
the enoxysilanes 12 led to the two isomers (1Z,3E) and (1E,3E)
(Figure 3). Each isomer was then identified by comparing the
chemical shifts to those given by Danishefsky (Figure 3), and
all of the above attributions were further supported by a series
of bidimensional NOESY NMR experiments.
hydes in the presence of mild Lewis acids.7,8 Nevertheless, a
few applications of these reagents in homo-Diels-Alder reac-
tions have been reported, with a total regio- and endoselectiv-
ity.6a,c,17 The relative reactivity of the dienes 13 has thus been
evaluated in a set of [4 + 2] cycloadditions involving N-methyl-
maleimide and methyl- and phenylacrylates as dienophiles. The
favorable effect of high pressure on the reactions described with
1,4-dialkoxy 1,3-dienes 11 with respect to classical thermal or
Lewis acid activations11 prompted us to conduct these cycload-
ditions under 8 to 16 kbar, at room temperature and for 24 h.
The preliminary thermal experiments run with these dienes were
not pursued because of their tendency to polymerize in these
conditions.
The 3E stereoselectivity can be rationalized considering an
intramolecular coordination between the lithium atom and the
oxygen of the silyloxy group (Scheme 8). This preference for
the E configuration is in sharp contrast to the Z selectivity
observed with allylic ethers in previous cases.11 In the present
case, the consecutive elimination of the methoxy group would
involve an allylic R-silyloxy-lithiated intermediate, which could
evolve through two transition states (proE-TS, proZ-TS). These
later would be more or less isoenergetic for 13a, 13b, and 13d
since both isomers were isolated in 50:50 ratios. When increas-
ing the bulkiness of the trialkylsilyloxy part, the isomer (1E,3E)
became predominant. This suggests that the proE-TS would be
favored by the steric constraint, provided the â-elimination takes
place in a pure “anti” fashion. Indeed, as shown on the Newman
projections placing one methoxy group anti to the lithium
(Scheme 8), only one steric strain shows around the silyloxy
group in the proE-TS against two in the proZ-TS. In contrast,
the use of a bulky acetal enhances the proportion of the (1Z,3E)
isomer. This preference is more difficult to justify on the basis
of the simple unsolvated model below.
The hyperbaric cycloaddition of the equimolar ratio of both
isomers of 13d with N-methylmaleimide 26 and phenyl acrylate
27 led to the expected cycloadducts 28 (55% overall yield) and
29 (32% overall yields), respectively (Scheme 9).
Each cycloaddition mainly led to two cycloadducts (trans,
cis) that were separated by flash chromatography and isolated
in an almost 50:50 ratio. The exact configurations and confor-
mations of each adduct have been determined on account of
mono- and bidimensional NMR studies. All cycloadducts were
thus shown to derive from an endo approach since the main
isomers presented a syn configuration between their C3 and C4
substituents (Scheme 9). This stereoselectivity is in fine agree-
ment with comparable situations.11,12 Adducts 29 correspond
to half-chair conformations, while adducts 28 preferably adopt
a convex boat-type folding. The preference of such flexible
systems for convex conformation has been discussed in the
literature for comparable systems.18 The access to 29 pointed
out the regiodirectivity related to dienes 13. Both isomers 29
trans and 29 cis indeed place the silyloxy group and the
phenyloxycarbonyl group in a 1-4 position on the cyclohexenyl
moiety. Note that the presence of about 15% of the exo isomer
was also noticed in this case. Close results were obtained with
Cycloaddition of 13 with N-Methylmaleimide and Acry-
lates. The 1,2,4-trioxygenated-1,3-dienes 2 and 6 have been
essentially used in heterocycloaddition toward activated alde
SCHEME 9. [4 + 2] Cycloadditions of 13d with N-Methylmaleimide 26 and Phenyl Acrylate 27
methyl acrylate but in much lower overall yields (20%,
1896 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis and ReactiVity of 1,2,4-Trioxygenated Dienes
SCHEME 10. [4 + 2] Cycloadditions of 13c and 13g with N-Methylmaleimide 26 and Phenyl Acrylate 27
trans/cis ) 60:40), probably because of the polymerization of
this dienophile, which occurs very easily under hyperbaric
conditions.19
Conclusion
These results show that 1,2,4-trioxygenated 1,3-dienes can
be prepared from commercially available pyruvic aldehyde
dimethyl acetal 14a in four synthetic steps and with overall
yields in the 4-72% range. Reacting 14a with cyclohexylamine
and then chloroalkyl ethers under basic conditions led to
ketoacetals 18 to 20, which were treated by LiHMDS and then
chlorotrialkylsilanes to afford eight enoxysilanes 12. δ-Elimina-
tions prompted on 12 by tert-butyllithium gave the expected
1,2,4-trioxygenated 1,3-dienes 13. These latter transformations
were performed in quantitative yields and led to two isomers
((1Z,3E) and (1E,3E)) on the four possible ones. Stereoselective
approaches favoring either 13 (1Z,3E) or 13 (1E,3E) were finally
worked out. While bulky trialkylsilyloxy substituent increase
the proportion of dienes (1E,3E), bulky acetals rather provide
dienes (1Z,3E). Three dienes (13c, 13d, and 13g) were reacted
with N-methylmaleimide and acrylates (phenyl, methyl) at room
temperature, for 24 h in THF and under hyperbaric conditions.
They all gave the corresponding endo cycloadducts, the (1E,3E)
and (1Z,3E) isomers reacting in comparable rates. The regiose-
lectivity of the reaction could be evidenced using the acrylates
as dienophiles.
Reacting N-methylmaleimide with 13g and phenyl acrylate
with 13c transformed the mixtures of isomers of these two
dienes into the corresponding endo cycloadducts 30 (43% overall
yield) and 31 (47% overall yield), respectively. Interestingly,
the trans and cis cycloadducts were formed in a 84:16 ratio for
30 and 81:19 ratio for 31 (Scheme 10). The resemblance of
this latter values with the 87:13 ratio between the (1E,3E) and
(1Z,3E) isomers of 13g and 13c suggests that these two
compounds react at comparable rates. We can even generalize
saying that isomers 13 (1E,3E) are the precursors of the adducts
trans while 13 (1Z,3E) provides the cis cycloadducts.
Here again, all compounds could be perfectly characterized
by NMR. The endo selectivity and convex boat-type folding
were evidenced for adducts 30. The trans relationship between
the methoxy and ethoxy groups, imposed by the (1E,3E)
configuration of the 13g isomer, put the methoxy in an equatorial
position and the ethoxy in an axial one, and could be confirmed
in the case of 30 trans by a single-crystal X-ray analysis (Figure
4). Complementarily, the regioselectivity of 13 was proven
thanks to a second single-crystal X-ray analysis conducted on
31 trans (Figure 4).
Experimental Section
1,1-Bis(1-ethylpropyloxy)propan-2-one 14b. Pentan-3-ol (10.1
mL, 93.4 mmol, 2.2 equiv) was added, in a Dean-Stark apparatus,
to a mixture of pyruvic aldehyde dimethyl acetal 14a (5 g, 42.3
mmol, 1 equiv) and p-toluenesulfonic acid monohydrate (0.08 g,
0.42 mmol, 0.01 equiv) in cyclohexane (50 mL). The resulting
reaction mixture was stirred at 81 °C for 24 h and then cooled to
room temperature. After evaporation of the solvent and then dilution
with diethyl ether (20 mL), the organic layer was washed with a
0.1 M solution of NaOH (20 mL). The aqueous layer was twice
extracted with diethyl ether (2 × 20 mL), and the combined organics
were dried (MgSO4), filtered, and concentrated. Purification of the
residue by flash chromatography on silica (heptane/AcOEt 90:10)
gave 14b as a yellow oil (2.68 g, 27%): IR (neat) ν 1729, 1462,
1351, 1103, 1010 cm-1; EIMS (70 eV) m/z 230 (M+, <1), 217
(100), 187 (M+ - MeCdO, 10), 143 (M+ - OCH(Et)2, 17), 87
1
([OCH(Et)2]+, 64), 71 ([CH(Et)2]+, 81); H NMR (300 MHz) δ
0.73 (6H, t, J ) 7.2), 0.83 (6H, t, J ) 7.2), 1.33-1.51 (8H, m),
2.07 (3H, s), 3.31 (1H, t, J ) 5.8), 3.34 (1H, t, J ) 5.8), 4.39 (1H,
s); 13C NMR (75 MHz) δ 9.2, 9.7, 23.2, 26.1, 26.5, 80.3, 102.2,
204.9. Anal. Calcd for C13H26O3: C, 67.79; H, 11.38. Found: C,
67.53; H, 11.67.
Cyclohexyl(2,2-dimethoxy-1-methylethylidene)amine 15a. Pyru-
vic aldehyde dimethyl acetal 14a (10 g, 84.6 mmol, 1 equiv) was
added to a mixture of cyclohexylamine (11 mL, 96.1 mmol, 1.1
equiv) and calcium chloride (500 mg) in diethyl ether (50 mL).
The resulting reaction mixture was stirred at 45 °C for 16 h. After
FIGURE 4. Single-crystal X-ray analyses of 30 trans and 31 trans.
(17) Tietze, L. F.; Gu¨nter, C.; Gericke, K. M.; Schuberth, I.; Bukoczi,
G. Eur. J. Org. Chem. 2005, 2459-2467.
(18) Maddaluno, J.; Gaonac’h, O.; Marcual, A.; Toupet, L., Giessner-
Prettre, C. J. Org. Chem. 1996, 61, 5290-5306.
(19) The use of hydroquinone is usually required to avoid the polym-
erization of methyl acrylate when using hyperbaric activation. This radical
inhibitor has not been introduced in our experimental conditions since it
reacted with dienes 13.
J. Org. Chem, Vol. 71, No. 5, 2006 1897

Pichon et al.
the mixture was cooled to room temperature, the solvent was
evaporated to give 15a as a yellow oil (15.54 g, 92%): IR (neat)
ν 1667, 1447, 1358, 1070 cm-1; CI (NH3) m/z 200 (MH+, 100);
1H NMR (200 MHz) δ 1.19-1.78 (10H, m), 1.78 (3H, s), 3.34
(6H, s), 3.22-3.37 (1H, m), 4.38 (1H, s); 13C NMR (75 MHz) δ
11.7, 25.1, 25.9, 33.6, 55.2, 59.4, 109.2, 164.0.
0.1 M solution of NaOH (5 mL). The aqueous layer was twice
extracted with diethyl ether (2 × 5 mL), and the combined organics
were dried (MgSO4), filtered, and concentrated. Purification of the
residue by flash chromatography on silica (heptane/AcOEt 90:10)
gave 20 as a yellow oil (165 mg, 20%): IR (neat) ν 1728, 1463,
1379, 1104, 1021 cm-1; EIMS (70 eV) m/z 288 (M+, <1), 201
(M+ - OCH(Et)2, 25), 71 ([CH(Et)2]+, 100); 1H NMR (300 MHz)
δ 0.82 (6H, t, J ) 7.5), 0.92 (6H, t, J ) 7.5), 1.17 (3H, t, J ) 7.1),
1.42-1.59 (8H, m), 2.93 (2H, t, J ) 6.8), 3.41-3.52 (4H, m), 3.70
(2H, t, J ) 6.8), 4.54 (1H, s); 13C NMR (75 MHz) δ 9.4, 9.9, 15.4,
26.1, 26.5, 36.3, 65.3, 66.5, 80.4, 101.9, 205.2. Anal. Calcd for
C16H32O4: C, 66.63; H, 11.18. Found: C, 66.68; H, 11.52.
1,1,4-Trimethoxy-2-triethylsilyloxybut-2-ene 12a. nBuLi 2.1
M (3.23 mL, 6.78 mmol, 1.1 equiv) was added at -78 °C to a
solution of hexamethyldisilazane (1.55 mL, 7.34 mmol, 1.2 equiv)
in freshly distilled THF (5 mL). After 30 min of stirring at this
temperature, chlorotriethylsilane 21 (1.03 mL, 6.13 mmol, 0.99
equiv) was introduced, followed by a solution of 1,1,4-trimethoxy-
butan-2-one 18 (1 g, 6.16 mmol, 1 equiv) in dry THF (1 mL). The
resulting reaction mixture was stirred at -78 °C for 2 h and then
at room temperature for 2 h before the reaction was quenched by
the addition of a 0.1 M solution of NaOH (5 mL). The aqueous
layer was extracted with diethyl ether (2 × 10 mL), and the
combined organics were dried (MgSO4), filtered, and concentrated
to give 12a as a yellow oil (1.7 g, 99%), which could be purified
by flash chromatography on silica (cyclohexane/AcOEt 80:20): IR
(neat) ν 1675, 1458, 1198, 1114 cm-1; CI (NH3) m/z 294 (MH+ +
2,2-Bis(1-ethylpropyloxy)-1-methylethylidenecyclohexyl-
amine 15b. 1,1-Bis(1-ethylpropyloxy)propan-2-one 14b (1 g, 4.34
mmol, 1equiv) was added, in a Dean-Stark apparatus, to a mixture
of cyclohexylamine (496 µL, 4.34 mmol, 1 equiv) and calcium
chloride (50 mg) in toluene (5 mL). The resulting reaction mixture
was stirred at 110 °C for 24 h. After the mixture was cooled to
room temperature, the solvent was evaporated to give 15b as a
yellow oil (759 mg, 56%): IR (neat) ν 1668, 1461, 1328, 1105,
1
1008 cm-1; CI (NH3) m/z 312 (MH+, 100); H NMR (200 MHz)
δ 0.81 (6H, t, J ) 7.3), 0.91 (6H, t, J ) 7.3), 1.24-1.83 (18H, m),
1.87 (3H, s), 3.23-3.45 (3H, m), 4.64 (1H, s); 13C NMR (50 MHz)
δ 9.8, 10.0, 11.9, 25.3, 26.0, 26.3, 26.7, 33.5, 59.1, 79.3, 105.5,
166.0.
1,1,4-Trimethoxybutan-2-one 18. nBuLi 2.4 M (4.6 mL, 11.04
mmol, 1.1 equiv) was added at -78 °C to a solution of diisopro-
pylamine (1.70 mL, 12.1 mmol, 1.2 equiv) in freshly distilled THF
(10 mL). After 30 min of stirring at this temperature, a solution of
2,2-dimethoxy-1-methylethylidenecyclohexylamine 15a (2 g, 10.03
mmol, 1 equiv) in dry THF (5 mL) was introduced, followed, after
an additional 2 h of stirring at -78 °C, by a solution of chloromethyl
methyl ether 16 (1.14 mL, 15.0 mmol, 1.5 equiv) in dry THF (2
mL). The resulting reaction mixture was stirred at room temperature
for 24 h before the reaction was quenched by the addition of a
saturated solution of NaHCO3 (10 mL). The aqueous layer was
extracted with diethyl ether (2 × 10 mL), and the combined organics
were dried (MgSO4), filtered, and concentrated. Purification of the
residue by flash chromatography (heptane/AcOEt 70:30) gave 18
as a yellow oil (1.29 g, 79%): IR (neat) ν 1731, 1450, 1389, 1193,
1073 cm-1; EIMS (70 eV) m/z 162 (M+, <1), 131 (M+ - OMe,
NH3, 35), 277 (MH+, 5), 262 (MH+ - Me, 95), 245 (MH+
-
1
MeOH, 100); H NMR (300 MHz) δ 0.67 (6H, q, J ) 8.0), 0.96
(9H, t, J ) 8.0), 3.30 (3H, s), 3.31 (6H, s), 4.02 (2H, d, J ) 6.9),
4.50 (1H, s), 5.11 (1H, t, J ) 6.9); 13C NMR (75 MHz) δ 5.7, 7.0,
53.8, 58.1, 66.6, 102.8, 107.5, 148.4. Anal. Calcd for C13H28O4Si:
C, 56.48; H, 10.21. Found: C, 56.65; H, 10.46.
1,1,4-Trimethoxy-2-triisobutylsilyloxybut-2-ene 12b. nBuLi
2.2 M (925 µL, 2.03 mmol, 1.1 equiv) was added at -78 °C to a
solution of hexamethyldisilazane (465 µL, 2.2 mmol, 1.2 equiv) in
freshly distilled THF (5 mL). After 30 min of stirring at this
temperature, chlorotriisobutylsilane 22 (495 µL, 1.84 mmol, 0.99
equiv) was introduced, followed by a solution of 1,1,4-trimethoxy-
butan-2-one 18 (0.3 g, 1.85 mmol, 1 equiv) in dry THF (2 mL).
The resulting reaction mixture was stirred at -78 °C for 2 h and
then at room temperature for 2 h before the reaction was quenched
by the addition of a 0.1 M solution of NaOH (5 mL). The aqueous
layer was extracted with diethyl ether (2 × 10 mL), and the
combined organics were dried (MgSO4), filtered, and concentrated
to give 12b as a yellow oil (0.25 g, 37%), which may be purified
by flash chromatography on silica (cyclohexane/AcOEt 80:20): IR
(neat) ν 1674, 1464, 1363, 1218, 1088 cm-1; EIMS (70 eV) m/z
360 (MH+, <1), 161 (MH+ - Si(iBu)3, 41), 75 ([CH(OMe)2]+,
1
28), 75 ([CH(OMe)2]+, 100); H NMR (300 MHz) δ 2.81 (2H, t,
J ) 6.4), 3.33 (3H, s), 3.41 (6H, s), 3.66 (2H, t, J ) 6.4), 4.49
(1H, s); 13C NMR (75 MHz) δ 37.7, 54.7, 58.8, 67.0, 104.0, 203.9.
Anal. Calcd for C7H14O4: C, 51.84; H, 8.70. Found: C, 51.88; H,
8.92.
4-Ethoxy-1,1-dimethoxybutan-2-one 19. nBuLi 2.25 M (12.3
mL, 27.7 mmol, 1.1 equiv) was added at -78 °C to a solution of
diisopropylamine (4.26 mL, 30.4 mmol, 1.2 equiv) in freshly
distilled THF (20 mL). After 30 min of stirring at this temperature,
a solution of 2,2-dimethoxy-1-methylethylidenecyclohexylamine
15a (5 g, 25.1 mmol, 1 equiv) in dry THF (10 mL) was introduced,
followed, after an additional 2 h of stirring at -78 °C, by a solution
of chloromethyl ethyl ether 17 (3.49 mL, 37.6 mmol, 1.5 equiv) in
dry THF (5 mL). The resulting reaction mixture was stirred at room
temperature for 24 h before the reaction was quenched by the
addition of a saturated solution of NaHCO3 (20 mL). The aqueous
layer was extracted with diethyl ether (2 × 20 mL), and the
combined organics were dried (MgSO4), filtered, and concentrated.
Purification of the residue by flash chromatography (heptane/AcOEt
70:30) gave 19 as a yellow oil (2.5 g, 56%): IR (neat) ν 1731,
1445, 1379, 1105, 1072 cm-1; CI (NH3) m/z 194 (MH+ + NH3,
100), 177 (MH+, 25); 1H NMR (300 MHz) δ 1.14 (3H, t, J ) 7.1),
2.80 (2H, t, J ) 6.4), 3.38 (6H, s), 3.45 (2H, q, J ) 7.1), 3.68 (2H,
t, J ) 6.4), 4.49 (1H, s); 13C NMR (75 MHz) δ 15.4, 38.3, 54.9,
65.1, 66.7, 104.1, 204.3. Anal. Calcd for C8H16O4: C, 54.53; H,
9.15. Found: C, 54.62; H, 9.41.
1
100); H NMR (300 MHz) δ 0.71 (6H, d, J ) 6.8), 0.95 (18H, d,
J ) 6.4), 1.79-1.93 (3H, m), 3.31 (3H, s), 3.32 (6H, s), 4.03 (2H,
d, J ) 6.6), 4.52 (1H, s), 5.11 (1H, t, J ) 6.6); 13C NMR (75
MHz) δ 24.4, 26.6, 26.8, 53.7, 58.1, 66.8, 102.6, 107.1, 148.1. Anal.
Calcd for C19H40O4Si: C, 63.28; H, 11.18. Found: C, 63.34; H,
11.29.
2-(tert-Butyldiphenylsilyloxy)-1,1,4-trimethoxybut-2-ene 12c.
nBuLi 2.25 M (1.5 mL, 3.37 mmol, 1.1 equiv) was added at -78
°C to a mixture of hexamethyldisilazane (775 µL, 3.67 mmol, 1.2
equiv) and HMPA (1 mL) in freshly distilled THF (5 mL). After
30 min of stirring at this temperature, tert-butylchlorodiphenylsilane
23 (800 µL, 3.08 mmol, 1 equiv) was introduced, followed by a
solution of 1,1,4-trimethoxybutan-2-one 18 (0.5 g, 3.08 mmol, 1
equiv) in dry THF (1 mL). The resulting reaction mixture was stirred
at -78 °C for 2 h and then at room temperature for 2 h before the
reaction was quenched by the addition of a 0.1 M solution of NaOH
(5 mL). The aqueous layer was extracted with diethyl ether (2 ×
10 mL), and the combined organics were dried (MgSO4), filtered,
and concentrated. The residue was purified by flash chromatography
on silica (heptane/AcOEt 90:10) to give 12c as a pale yellow oil
4-Ethoxy-1,1-bis(1-ethylpropyloxy)butan-2-one 20. 4-Ethoxy-
1,1-dimethoxybutan-2-one 19 (0.5 g, 2.84 mmol, 1 equiv) was
added, in a Dean-Stark apparatus, to a mixture of pentan-3-ol (645
µL, 5.96 mmol, 2.1 equiv) and p-toluenesulfonic acid monohydrate
(6 mg, 0.03 mmol, 0.01 equiv) in cyclohexane (20 mL). The
resulting reaction mixture was stirred at 81 °C for 24 h and then
cooled to room temperature. After evaporation of the solvent, the
residue was dissolved in diethyl ether (10 mL) and washed with a
1898 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis and ReactiVity of 1,2,4-Trioxygenated Dienes
(0.419 g, 34%): IR (neat) ν 1677, 1427, 1195, 1112 cm-1; EIMS
(70 eV) m/z 400 (MH+, <1), 199 (100), 183 (Ph2SiH+, 63), 167
(86), 145 ([MeOCH2CHdC(CH(OMe)2]+, 75), 75 ([CH(OMe)2]+,
36), 57 (tBu+, 67); 1H NMR (300 MHz) δ 1.08 (9H, s), 3.02 (6H,
s), 3.20 (3H, m), 3.96 (2H, d, J ) 6.8), 4.30 (1H, s), 5.17 (1H, t,
J ) 6.8), 7.36-7.44 (6H, m), 7.71-7.75 (4H, m); 13C NMR (75
MHz) δ 26.9, 53.8, 58.0, 66.8, 102.2, 106.9, 127.9, 130.1, 133.6,
135.1, 135.8, 148.2. Anal. Calcd for C23H32O4Si: C, 68.96; H, 8.05.
Found: C, 69.41; H, 8.13.
5.15 (1H, t, J ) 6.0); 13C NMR (75 MHz) δ 13.7, 15.6, 18.3, 53.3,
65.0, 65.7, 102.3, 107.4, 147.8.
2-(tert-Butyldiphenylsilyloxy)-4-ethoxy-1,1-dimethoxybut-2-
ene 12g. nBuLi 2.25 M (333 µL, 0.75 mmol, 1.1 equiv) was added
at -78 °C to a mixture of hexamethyldisilazane (171 µL, 0.81
mmol, 1.2 equiv) and HMPA (1 mL) in freshly distilled THF (5
mL). After 30 min of stirring at this temperature, tert-butylchlo-
rodiphenylsilane 23 (177 µL, 0.68 mmol, 1 equiv) was introduced,
followed by a solution of 4-ethoxy-1,1-dimethoxybutan-2-one 19
(120 mg, 0.68 mmol, 1 equiv) in dry THF (1 mL). The resulting
reaction mixture was stirred at -78 °C for 2 h then at room
temperature for 2 h before the reaction was quenched by the addition
of a 0.1M solution of NaOH (5 mL). The aqueous layer was
extracted with diethyl ether (2 × 10 mL), and the combined organics
were dried (MgSO4), filtered and concentrated. The residue was
purified by flash chromatography on silica (heptane/AcOEt 90:10)
to give 12g as a yellow oil (0.147 g, 52%): IR (neat) ν 1677, 1427,
4-Ethoxy-1,1-dimethoxy-2-triethylsilyloxybut-2-ene 12d. nBuLi
2.1 M (2.97 mL, 6.24 mmol, 1.1 equiv) was added at -78 °C to a
solution of hexamethyldisilazane (1.43 mL, 6.78 mmol, 1.2 equiv)
in freshly distilled THF (10 mL). After 30 min of stirring at this
temperature, chlorotriethylsilane 21 (1.03 mL, 6.14 mmol, 1.1
equiv) was introduced, followed by a solution of 4-ethoxy-1,1-
dimethoxybutan-2-one 19 (1 g, 5.67 mmol, 1 equiv) in dry THF (5
mL). The resulting reaction mixture was stirred at -78 °C for 2 h
and then at room temperature for 2 h before the reaction was
quenched by the addition of a 0.1 M solution of NaOH (5 mL).
The aqueous layer was extracted with diethyl ether (2 × 10 mL)
and the combined organics were dried (MgSO4), filtered, and
concentrated to give 12d as a yellow oil (1.63 g, 99%): IR (neat)
ν 1675, 1458, 1198, 1114 cm-1; CI (NH3) m/z 308 (MH+ + NH3,
1195, 1112 cm-1; EIMS (70 eV) m/z 414 (M+, <1), 357 (M+
-
tBu, 6), 183 (100), 75 ([CH(OMe)2]+, 43), 57 (tBu+, 87); 1H NMR
(300 MHz) δ 1.07 (9H, s), 1.12 (3H, t, J ) 7.2), 3.01 (6H, s), 3.32
(2H, q, J ) 7.2), 3.99 (2H, d, J ) 6.8), 4.29 (1H, s), 5.17 (1H, t,
J ) 6.8), 7.37-7.43 (6H, m), 7.70-7.72 (4H, m); 13C NMR (75
MHz) δ 15.6, 20.1, 27.0, 53.8, 65.1, 65.7, 102.3, 107.5, 127.8,
130.1, 133.7, 135.9, 147.7.
1
88), 276 (MH+ - Me, 100), 259 (MH+ - MeOH, 77); H NMR
4-Ethoxy-1-[bis(1-ethylpropyloxy)]-2-triethylsilyloxybut-2-
ene 12h. nBuLi 3.00 M (210 µL, 0.63 mmol, 1.8 equiv) was added
at -78 °C to a solution of hexamethyldisilazane (142 µL, 0.67
mmol, 1.9 equiv) in freshly distilled THF (5 mL). After 30 min of
stirring at this temperature, chlorotriethylsilane 21 (95 µL, 0.56
mmol, 1.6 equiv) was introduced, followed by a solution of
4-ethoxy-1,1-bis(1-ethylpropyloxy)butan-2-one 20 (100 mg, 0.35
mmol, 1 equiv) in dry THF (1 mL). The resulting reaction mixture
was stirred at -78 °C for 2 h then at room temperature for 2 h
before the reaction was quenched by the addition of a 0.1 M solution
of NaOH (5 mL). The aqueous layer was extracted with diethyl
ether (2 × 10 mL), and the combined organics were dried (MgSO4),
filtered, and concentrated to give 12h as a yellow oil, which did
not require any further purification (135 mg, 96%): EIMS (70 eV)
m/z 402 (M+, <1), 358 (M+ - EtOH, 8), 187 ([CH(OCHEt2)2]+,
21), 87 ([OCHEt2]+, 44), 71 ([CHEt2]+, 100); 1H NMR (200 MHz)
δ 0.80-1.00 (27H, m), 1.19 (3H, t, J ) 6.9), 1.45-1.56 (8H, m),
3.37-3.51 (4H, m), 4.06 (2H, d, J ) 6.6), 4.62 (1H, s), 4.95 (1H,
t, J ) 6.6); 13C NMR (50 MHz) δ 5.8, 6.1, 6.7, 7.1, 9.6, 9.9, 15.6,
26.0, 26.4, 65.0, 65.5, 78.9, 100.6, 107.7, 146.0.
(300 MHz) δ 0.68 (6H, q, J ) 7.5), 0.98 (9H, t, J ) 7.5), 1.19
(3H, t, J ) 7.2), 3.32 (6H, s), 3.46 (2H, q, J ) 7.2), 4.07 (2H, d,
J ) 6.8), 4.51 (1H, s), 5.13 (1H, t, J ) 6.8); 13C NMR (75 MHz)
δ 5.7, 7.0, 15.6, 53.8, 64.8, 65.7, 102.9, 108.0, 148.0.
2-(tert-Butyldimethylsilyloxy)-4-ethoxy-1,1-dimethoxybut-2-
ene 12e. nBuLi 2.25 M (416 µL, 0.94 mmol, 1.1 equiv) was added
at -78 °C to a mixture of hexamethyldisilazane (214 µL, 1.01
mmol, 1.3 equiv) and HMPA (0.8 mL) in freshly distilled THF (3
mL). After 30 min of stirring at this temperature, tert-butylchlo-
rodimethylsilane 24 (128 mg, 0.85 mmol, 1 equiv) was introduced,
followed by a solution of 4-ethoxy-1,1-dimethoxybutan-2-one 19
(0.15 g, 0.85 mmol, 1 equiv) in dry THF (1 mL). The resulting
reaction mixture was stirred at -78 °C for 2 h and then at room
temperature for 2 h before the reaction was quenched by the addi-
tion of a 0.1 M solution of NaOH (5 mL). The aqueous layer
was extracted with diethyl ether (2 × 10 mL), and the combined
organics were dried (MgSO4), filtered, and concentrated. The
residue was purified by flash chromatography on silica (heptane/
AcOEt 90:10) to give 12e as a yellow oil (0.106 g, 43%): IR (neat)
ν 1677, 1471, 1252, 1112 cm-1; EIMS (70 eV) m/z 290 (M+, <1),
259 (M+ - OMe, 7), 245 (M+ - OEt, 15), 75 ([CH(OMe)2]+, 75),
1,4-Dimethoxy-2-triethylsilyloxy-1,3-butadiene 13a. tBuLi 1.5
M (362 µL, 0.54 mmol, 3.0 equiv) was added, at -40 °C and under
nitrogen atmosphere, to a solution of 1,1,4-trimethoxy-2-triethyl-
silyloxybut-2-ene 12a (50 mg, 0.18 mmol, 1 equiv) in freshly
distilled THF (1 mL). The resulting reaction mixture was stirred
for 1 h at -40 °C before the reaction was quenched by a 0.1 M
solution of NaOH (2 mL). The organic layer was dried (MgSO4),
filtered, and concentrated to give 13a as a yellow oil, which was
not purified due to its low stability on silica (43 mg, 98%): IR
1
59 ([CH2OEt]+, 100); H NMR (300 MHz) δ 0.14 (6H, s), 0.94
(9H, s), 1.19 (3H, t, J ) 7.2), 3.30 (6H, s), 3.46 (2H, q, J ) 7.2),
4.07 (2H, d, J ) 6.8), 4.52 (1H, s), 5.16 (1H, t, J ) 6.8); 13C NMR
(75 MHz) δ 15.6, 18.8, 26.1, 53.5, 64.8, 65.7, 102.4, 108.1, 147.9.
4-Ethoxy-1,1-dimethoxy-2-triisopropylsilyloxybut-2-ene 12f.
nBuLi 2.25 M (416 µL, 0.94 mmol, 1.1 equiv) was added at -78
°C to a mixture of hexamethyldisilazane (214 µL, 1.01 mmol, 1.2
equiv) and HMPA (0.8 mL) in freshly distilled THF (3 mL). After
30 min of stirring at this temperature, chlorotriisopropylsilane 25
(180 µL, 0.84 mmol, 0.99 equiv) was introduced, followed by a
solution of 4-ethoxy-1,1-dimethoxybutan-2-one 19 (0.15 g, 0.85
mmol, 1 equiv) in dry THF (1 mL). The resulting reaction mixture
was stirred at -78 °C for 2 h then at room temperature for 2 h
before the reaction was quenched by the addition of a 0.1 M solution
of NaOH (5 mL). The aqueous layer was extracted with diethyl
ether (2 × 10 mL), and the combined organics were dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
chromatography on silica (heptane/AcOEt 90:10) to give 12f as a
yellow oil (0.185 g, 65%): IR (neat) ν 1673, 1464, 1383, 1196,
1113 cm-1; EIMS (70 eV) m/z 332 (M+, 1), 301 (M+ - OMe,
5), 289 (MH+ - iPr, 35), 201 (100), 75 ([CH(OMe)2]+, 80), 59
([CH2OEt]+, 75); 1H NMR (300 MHz) δ 1.04-1.21 (24H, m), 3.30
(6H, s), 3.46 (2H, q, J ) 7.2), 4.12 (2H, d, J ) 6.0), 4.58 (1H, s),
1
(neat) ν 2956, 2877, 1670, 1463, 1114 cm-1; (isomer 1E,3E) H
NMR (300 MHz) δ 0.67-0.73 (6H, m), 0.89-1.01 (9H, m), 3.53
(3H, s), 3.60 (3H, s), 5.72 (1H, d, J ) 12.6), 5.76 (1H, s), 6.79
(1H, d, J ) 12.6); 13C NMR (75 MHz) d 5.2 or 5.6, 7.1 or 7.2,
56.5, 60.5, 97.9, 132.6, 137.3, 148.5; (isomer 1Z,3E) 1H NMR (300
MHz) δ 0.67-0.73 (6H, m), 0.89-1.01 (9H, m), 3.54 (3H, s), 3.55
(3H, s), 5.18 (1H, d, J ) 12.2), 5.48 (1H, s), 6.65 (1H, d, J )
12.2); 13C NMR (75 MHz) δ 5.2 or 5.6, 7.1 or 7.2, 56.8, 59.7,
101.2, 130.8, 133.2, 146.7.
1,4-Dimethoxy-2-triisobutylsilyloxy-1,3-butadiene 13b. tBuLi
1.5 M (277 µL, 0.41 mmol, 3.0 equiv) was added, at -40 °C and
under nitrogen atmosphere, to a solution of 1,1,4-trimethoxy-2-
triisobutylsilyloxybut-2-ene 12b (50 mg, 0.138 mmol, 1 equiv) in
freshly distilled THF (1 mL). The resulting reaction mixture was
stirred for 1 h at -40 °C before the reaction was quenched by a
0.1 M solution of NaOH (2 mL). The organic layer was dried
J. Org. Chem, Vol. 71, No. 5, 2006 1899

Pichon et al.
(MgSO4), filtered, and concentrated to give 13b as a yellow oil,
which was not purified due to its low stability on silica (45 mg,
99%): IR (neat) ν 1610, 1427, 1210, 1113 cm-1; (isomer 1E,3E)
1H NMR (200 MHz) δ 0.70 or 0.71 (6H, d, J ) 6.9), 0.94 or 0.96
(18H, d, J ) 6.6), 1.80-1.93 (3H, m), 3.52 (3H, s), 3.60 (3H, s),
5.71 (1H, d, J ) 12.8), 5.74 (1H, s), 6.79 (1H, d, J ) 12.8); 13C
NMR (50 MHz) δ 24.5, 26.1 or 26.6, 26.8, 56.5, 60.6, 98.0, 132.0,
was dried (MgSO4), filtered, and concentrated to give 13f as a
yellow oil, which was not purified due to its low stability on silica
(41 mg, 91%): IR (neat) ν 1610, 1427, 1210, 1113 cm-1; (isomer
1E,3E) 1H NMR (200 MHz) δ 1.05-1.16 (21H, m), 1.30 (3H, t, J
) 6.9), 3.50 (3H, s), 3.81 (2H, q, J ) 6.9), 5.74 (1H, d, J ) 12.8),
5.77 (1H, s), 6.83 (1H, d, J ) 12.8); 13C NMR (50 MHz) δ 13.2,
14.0, 18.5, 60.5, 65.3, 98.7, 131.8, 138.4, 147.8; (isomer 1Z,3E)
1H NMR (200 MHz) δ 1.05-1.16 (21H, m), 1.27 (3H, t, J ) 6.9),
3.51 (3H, s), 3.74 (2H, q, J ) 6.9), 5.19 (1H, d, J ) 12.1), 5.40
(1H, s), 6.68 (1H, d, J ) 12.1); 13C NMR (50 MHz) δ 12.5, 15.1,
18.1, 59.6, 65.7, 102.2, 130.0, 138.4, 145.7.
1
137.9, 148.7; (isomer 1Z,3E) H NMR (200 MHz) δ 0.70 or 0.71
(6H, d, J ) 6.9), 0.94 or 0.96 (18H, d, J ) 6.9), 1.80-1.93 (3H,
m), 3.53 (3H, s), 3.54 (3H, s), 5.15 (1H, d, J ) 12.2), 5.41 (1H, s),
6.66 (1H, d, J ) 12.2); 13C NMR (125 MHz) δ 24.5, 26.1 or 26.6,
26.8, 56.8, 59.6, 101.3, 129.6, 133.2, 146.8.
2-tert-Butyldiphenylsilyloxy-4-ethoxy-1-methoxy-1,3-butadi-
ene 13g. tBuLi 1.5 M (241 µL, 0.36 mmol, 3.0 equiv) was added,
at -40 °C and under nitrogen atmosphere, to a solution of 2-tert-
butyldiphenylsilyloxy-4-ethoxy-1,1-dimethoxybut-2-ene 12g (50
mg, 0.12 mmol, 1 equiv) in freshly distilled THF (1 mL). The
resulting reaction mixture was stirred for 1 h at -40 °C before the
reaction was quenched by a 0.1 M solution of NaOH (2 mL). The
organic layer was dried (MgSO4), filtered, and concentrated to give
13g as a yellow oil, which was not purified due to its low stability
2-tert-Butyldiphenylsilyloxy-1,4-dimethoxy-1,3-butadiene 13c.
tBuLi 1.5 M (277 µL, 0.41 mmol, 3.0 equiv) was added, at -40
°C and under nitrogen atmosphere, to a solution of 2-tert-
butyldiphenylsilyloxy-1,1,4-trimethoxybut-2-ene 12c (55 mg, 0.138
mmol, 1 equiv) in freshly distilled THF (1 mL). The resulting
reaction mixture was stirred for 1 h at -40 °C before the mixture
was quenched by a 0.1 M solution of NaOH (2 mL). The organic
layer was dried (MgSO4), filtered, and concentrated to give 13c as
a yellow oil, which was not purified due to its low stability on
silica (46 mg, 91%). 13c was not characterized furthermore since
it was directly reacted with N-methylmaleimide 26.
4-Ethoxy-1-methoxy-2-triethylsilyloxy-1,3-butadiene 13d.
tBuLi 1.5 M (344 µL, 0.52 mmol, 3.0 equiv) was added, at -40
°C and under nitrogen atmosphere, to a solution of 4-ethoxy-1,1-
dimethoxy-2-triethylsilyloxybut-2-ene 12d (50 mg, 0.17 mmol, 1
equiv) in freshly distilled THF (1 mL). The resulting reaction
mixture was stirred for 1 h at -40 °C before the reaction was
quenched by a 0.1 M solution of NaOH (2 mL). The organic layer
was dried (MgSO4), filtered, and concentrated to give 13d as a
yellow oil, which was not purified due to its low stability on silica
(43 mg, 98%): IR (neat) ν 1610, 1427, 1210, 1113 cm-1; (isomer
1E,3E) 1H NMR (200 MHz) δ 0.67 or 0.68 (6H, q, J ) 7.3), 0.98
or 0.99 (9H, t, J ) 7.3), 1.23-1.33 (3H, m), 3.51 (3H, s), 3.74 or
3.80 (2H, q, J ) 6.9), 5.73 (1H, d, J ) 12.8), 5.75 (1H, s), 6.73
(1H, d, J ) 12.8); 13C NMR (75 MHz) δ 5.2 or 5.6, 7.1 or 7.2,
56.5 or 56.9, 59.8, 66.0, 97.9, 132.5, 137.3, 148.5; (isomer 1Z,3E)
1H NMR (200 MHz) δ 0.67 or 0.68 (6H, q, J ) 7.3), 0.98 or 0.99
(9H, t, J ) 7.3), 1.23-1.33 (3H, m), 3.53 (3H, s), 3.74 or 3.80
(2H, q, J ) 6.9), 5.20 (1H, d, J ) 12.2), 5.45 (1H, s), 6.60 (1H, d,
J ) 12.2); 13C NMR (75 MHz) δ 5.2 or 5.6, 7.1 or 7.2, 56.5 or
56.9, 60.5, 63.4, 101.1, 130.8, 133.2, 146.7.
on silica (45 mg, 98%): IR (neat) ν 1610, 1427, 1210, 1113 cm-1
;
(isomer 1E,3E) 1H NMR (300 MHz) δ 1.08 (9H, s), 1.33 (3H, t, J
) 7.2), 3.16 (3H, s), 3.84 (2H, q, J ) 7.2), 5.33 (1H, s), 5.77 (1H,
d, J ) 12.8), 7.04 (1H, d, J ) 12.8), 7.37-7.40 (6H, m), 7.72-
7.78 (4H, m); 13C NMR (75 MHz) δ 15.1, 19.8, 27.0, 60.2, 65.3,
98.4, 128.0, 130.1, 133.2, 133.4, 135.8, 137.9, 147.5; (isomer 1Z,3E)
1H NMR (300 MHz) δ 1.06 (9H, s), 1.29 (3H, t, J ) 7.2), 3.32
(3H, s), 3.76 (2H, q, J ) 7.2), 5.25 (1H, s), 5.26 (1H, d, J ) 12.1),
6.86 (1H, d, J ) 12.1), 7.37-7.40 (6H, m), 7.72-7.78 (4H, m);
13C NMR (75 MHz) δ 15.2, 19.3, 26.9, 58.7, 65.8, 101.5, 127.5,
129.4, 130.0, 135.1, 135.5, 137.9, 146.0.
4-Ethoxy-1-(1-ethylpropyloxy)-2-triethylsilyloxy-1,3-butadi-
ene 13h. tBuLi 1.5 M (248 µL, 0.37 mmol, 3.0 equiv) was added,
at -40 °C and under nitrogen atmosphere, to a solution of 4-ethoxy-
1-[bis(1-ethylpropyloxy)]-2-triethylsilyloxybut-2-ene 12h (50 mg,
0.12 mmol, 1 equiv) in freshly distilled THF (1 mL). The resulting
reaction mixture was stirred for 1 h at -40 °C before the reaction
was quenched by a 0.1 M solution of NaOH (2 mL). The organic
layer was dried (MgSO4), filtered, and concentrated to give 13h
as a yellow oil, which was not purified due to its low stability
on silica (36 mg, 95%): IR (neat) ν 1622, 1462, 1108, 1006
cm-1; (isomer 1E,3E) 1H NMR (300 MHz) δ 0.66-0.75 (6H, m),
0.84-1.00 (15H, m), 1.26 (3H, t, J ) 7.2), 1.50-1.58 (4H, m),
3.34-3.42 (1H, m), 3.79 (2H, q, J ) 7.2), 5.79 (1H, s), 5.80 (1H,
d, J ) 12.8), 6.69 (1H, d, J ) 12.8); 13C NMR (75 MHz) δ 6.7,
7.1, 9.6, 15.6, 26.5, 65.0, 84.8, 99.5, 130.5, 133.8, 146.9; (isomer
1Z,3E) 1H NMR (300 MHz) δ 0.66-0.75 (6H, m), 0.84-1.00 (15H,
m), 1.26 (3H, t, J ) 7.2), 1.50-1.58 (4H, m), 3.34-3.42 (1H, m),
3.72 (2H, q, J ) 7.2), 5.23 (1H, d, J ) 12.4), 5.50 (1H, s), 6.55
(1H, d, J ) 12.4); 13C NMR (75 MHz) δ 5.7, 7.1, 10.1, 15.2, 27.1,
65.7, 85.6, 102.9, 129.9, 131.7, 144.6.
7-Ethoxy-4-methoxy-2-methyl-5-triethylsilyloxy-3a,4,7,7a-tet-
rahydroisoindole-1,3-dione 28. A solution of 4-ethoxy-1-methoxy-
2-triethylsilyloxy-1,3-butadiene 13d (0.2 g, 0.77 mmol, 1 equiv)
in freshly distilled THF (2.5 mL) was added to a solution of
N-methylmaleimide 26 (0.17 g, 1.16 mmol, 1.5 equiv) in dry THF
(2.5 mL) in a high-pressure cell. After 24 h at room temperature
and under 8 kbar, the solvent was evaporated and the residue was
purified by flash chromatography on silica (heptane/AcOEt 95:5).
Isomer 28 trans (yellow oil, 64 mg, 22%): IR (neat) ν 1705, 1434,
1291, 1202, 1098 cm-1; EIMS (70 eV) m/z 370 (M+, 1), 258
(NMM+, 100); 1H NMR (300 MHz) δ 0.72 (6H, q, J ) 7.9), 0.99
(9H, t, J ) 7.9), 1.10 (3H, t, J ) 7.1), 3.00 (3H, s), 3.07 (1H, dd,
J ) 6.2 and 10.4), 3.27 (1H, dd, J ) 6.2 and 10.4), 3.37 (3H, s),
3.40-3.54 (2H, m), 4.09 (1H, dd, J ) 1.5 and 6.7), 4.44 (1H, dd,
J ) 6.4 and 6.4), 5.28 (1H, dd, J ) 1.1 and 6.8); 13C NMR (75
MHz) δ 5.2, 6.9, 15.6, 25.3, 44.7, 45.7, 58.3, 64.2, 69.4, 75.2, 104.7,
157.3, 176.0, 176.3. Isomer 28 cis (yellow oil, 95 mg, 33%): IR
(neat) ν 1707, 1435, 1282, 1111 cm-1; EIMS (70 eV) m/z 370 (M+,
2-tert-Butyldimethylsilyloxy-4-ethoxy-1-methoxy-1,3-butadi-
ene 13e. tBuLi 1.5 M (344 µL, 0.52 mmol, 3.0 equiv) was added,
at -40 °C and under nitrogen atmosphere, to a solution of 2-tert-
butyldimethylsilyloxy-4-ethoxy-1,1-dimethoxybut-2-ene 12e (50
mg, 0.17 mmol, 1 equiv) in freshly distilled THF (1 mL). The
resulting reaction mixture was stirred for 1 h at -40 °C before the
reaction was quenched by a 0.1 M solution of NaOH (2 mL). The
organic layer was dried (MgSO4), filtered, and concentrated to give
13e as a yellow oil, which was not purified due to its low stability
on silica (40 mg, 91%): IR (neat) ν 1610, 1427, 1210, 1113 cm-1
;
1
(isomer 1E,3E) H NMR (300 MHz) δ 0.13 (6H, s), 0.95 (9H, s),
1.30 (3H, t, J ) 7.2), 3.52 (3H, s), 3.80 (2H, q, J ) 7.2), 5.73 (1H,
d, J ) 12.8), 5.74 (1H, s), 6.72 (1H, d, J ) 12.8); 13C NMR (75
MHz) δ -4.2, 15.0, 18.5, 26.2, 60.5, 65.3, 98.8, 133.0, 137.4, 147.6;
1
(isomer 1Z,3E) H NMR (300 MHz) δ 0.14 (6H, s), 0.96 (9H, s),
1.27 (3H, t, J ) 7.2), 3.53 (3H, s), 3.74 (2H, q, J ) 7.2), 5.20 (1H,
d, J ) 12.4), 5.45 (1H, s), 6.62 (1H, d, J ) 12.4); 13C NMR (75
MHz) δ -4.1, 15.2, 18.9, 26.4, 59.7, 65.8, 102.1, 130.7, 137.4,
145.8.
4-Ethoxy-1-methoxy-2-triisopropylsilyloxy-1,3-butadiene 13f.
tBuLi 1.5 M (300 µL, 0.45 mmol, 3.0 equiv) was added, at -40
°C and under nitrogen atmosphere, to a solution of 4-ethoxy-1,1-
dimethoxy-2-triisopropylsilyloxybut-2-ene 12f (50 mg, 0.15 mmol,
1 equiv) in freshly distilled THF (1 mL). The resulting reaction
mixture was stirred for 1 h at -40 °C before the reaction was
quenched by a 0.1 M solution of NaOH (2 mL). The organic layer
1900 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis and ReactiVity of 1,2,4-Trioxygenated Dienes
1
1), 258 (NMM+, 100); H NMR (300 MHz) δ 0.68 (6H, q, J )
2.92 (3H, s), 3.10 (1H, dd, J ) 4.5 and 9.4), 3.66 (3H, s), 4.02
(1H, dd, J ) 5.3 and 5.3), 4.26 (1H, dd, J ) 1.5 and 4.5), 4.72
(1H, dd, J ) 1.1 and 5.3), 7.38-7.43 (6H, m), 7.68-7.74 (4H,
m); 13C NMR (75 MHz) δ 15.4, 19.7, 24.8, 26.6, 43.9, 46.8, 59.3,
63.6, 70.8, 74.1, 105.2, 128.1, 130.4, 132.2, 135.8, 154.5, 176.7,
178.6. Anal. Calcd for C28H35NO5Si: C, 68.12; H, 7.15. Found:
C, 68.19; H, 7.36. Isomer 30 cis (yellow oil, 13 mg, 7%): IR (neat)
ν 1705, 1428, 1289, 1203, 1113 cm-1; EIMS (70 eV) m/z 493 (M+,
<1), 436 (M+-tBu, 74), 213 (M+-tBuPh2SiOCdCH, 100), 57
8.3), 0.96 (9H, t, J ) 8.3), 1.08 (3H, t, J ) 7.1), 2.94 (3H, s),
3.14-3.15 (2H, m), 3.44-3.49 (2H, m), 3.51 (3H, s), 4.13-4.14
(1H, m), 4.34-4.38 (1H, m), 5.07 (1H, d, J ) 4.9); 13C NMR (75
MHz) δ 5.1, 6.8, 15.5, 24.9, 43.4, 46.5, 58.7, 64.3, 71.4, 75.0, 103.9,
154.5, 176.5, 178.5.
2-Ethoxy-5-methoxy-4-triethylsilyloxycyclohex-3-enecarboxy-
lic Acid Phenyl Ester 29. A solution of 4-ethoxy-1-methoxy-2-
triethylsilyloxy-1,3-butadiene 13d (0.15 g, 0.58 mmol, 1 equiv) in
freshly distilled THF (2.5 mL) was added to a solution of phenyl
acrylate 27 (0.143 mL, 0,87 mmol, 1.5 equiv) in dry THF (2.5
mL) in a high-pressure cell. After 24 h at room temperature and
under 8 kbar, the solvent was evaporated, and the residue was
purified by flash chromatography on silica (heptane/AcOEt 95:5).
Isomer 30 trans (yellow oil, 28 mg, 13%): IR (neat) ν 1762, 1653,
1193, 1159 cm-1; EIMS (70 eV) m/z 406 (M+, 21), 374
(M+-MeOH, 13), 258 (59, 13d), 59 (100); 1H NMR (300 MHz) δ
0,70 (6H, q, J ) 7.9), 1.00 (9H, t, J ) 8.0), 1.19 (3H, t, J ) 6.8),
2.18 (1H, ddd, J ) 3.8, 14.3 and 14.3), 2.31-2.23 (1H, m), 3.15
(1H, ddd, J ) 4.2, 4.2 and 15.4), 3.44 (3H, s), 3.44-3.54 (1H, m),
3.58 (1H, dd, J ) 2.3 and 3.4), 3.66 (1H, dq, J ) 6.8 and 9.0),
4.37 (1H, dd, J ) 4.9 and 4.9), 5.23 (1H, d, J ) 5.3), 7.07 (2H,
dd, J ) 1.1 and 8.7), 7.22 (1H, dddd, J ) 1.1, 1.1, 7.5 and 7.5),
7.38 (2H, dd, J ) 7.5 and 7.5); 13C NMR (75 MHz) δ 5.3, 7.0,
16.1, 25.1, 40.8, 58.5, 64.6, 72.2, 76.5, 104.6, 121.9, 125.9, 129.7,
151.4, 154.4, 172.0. Isomer 30 cis (yellow oil, 39 mg, 19%): IR
(neat) ν 1762, 1653, 1193, 1159 cm-1; EIMS (70 eV) m/z 406 (M+,
21), 374 (M+-MeOH, 13), 258 (59), 59 (100); 1H NMR (300 MHz)
δ 0,72 (6H, q, J ) 7.9), 1.00 (9H, t, J ) 7.9), 1.18 (3H, t, J )
7.2), 2.23 (1H, ddd, J ) 10.6, 13.2 and 13.2), 2.34 (1H, dddd, J )
1.1, 3.4, 6.4 and 13.2), 2.85 (1H, ddd, J ) 3.4, 3.4 and 13.2), 3.39-
3.47 (1H, m), 3.43 (3H, s), 3.66 (1H, dq, J ) 7.2 and 9.0), 3.79
(1H, dd, J ) 6.4 and 10.6), 4.36 (1H, dd, J ) 4.5 and 4.9), 5.22
(1H, dd, J ) 1.1 and 5.6), 7.07 (2H, dd, J ) 1.1 and 8.7), 7.22
(1H, dddd, J ) 1.1, 1.1, 7.5 and 7.5), 7.38 (2H, dd, J ) 7.5 and
7.5); 13C NMR (75 MHz) δ 5.4, 7.0, 16.0, 25.5, 44.4, 57.3, 64.0,
71.9, 76.3, 104.6, 121.8, 125.9, 129.7, 151.3, 156.1, 171.1.
5-tert-Butyldiphenylsilyloxy-7-ethoxy-4-methoxy-2-methyl-
3a,4,7,7a-tetrahydroisoindole-1,3-dione 30. A solution of 2-(tert-
butyldiphenylsilyloxy)-4-ethoxy-1-methoxy-1,3-butadiene 13g (0.15
g, 0.39 mmol, 1 equiv) in freshly distilled THF (0.5 mL) was added
to a solution of N-methylmaleimide 26 (60 mg, 0.54 mmol, 1.4
equiv) in dry THF (0.5 mL) in a high-pressure cell. After 24 h at
room temperature and under 16 kbar, the solvent was evaporated
and the residue was purified by flash chromatography on silica
(heptane/AcOEt 95:5). Isomer 30 trans (white solid, 71 mg,
36%): mp 120 °C (diethyl ether); IR (neat) ν 1705, 1429, 1114
cm-1; EIMS (70 eV) m/z 493 (M+, <1), 436 (M+ - tBu, 74), 213
1
([tBu]+, 75); H NMR (300 MHz) δ 0.90 (3H, t, J ) 6.8), 1.07
(9H, s), 2.84 (1H, dd, J ) 6.0 and 10.5), 2.97 (3H, s), 3.03-3.14
(2H+1H, m), 3.50 (3H, s), 4.17 (1H, dd, J ) 6.4 and 6.4), 4.24
(1H, dd, J ) 1.5 and 6.8), 5.01 (1H, dd, J ) 1.5 and 6.8), 7.37-
7.46 (6H, m), 7.64-7.76 (4H, m); 13C NMR (75 MHz) δ 15.3,
19.5, 25.2, 26.7, 44.6, 45.7, 58.8, 63.7, 68.8, 75.4, 108.0, 128.2,
130.5, 131.9, 135.8, 156.8, 176.0, 176.2.
4-tert-Butyldiphenylsilyloxy-2,5-dimethoxycyclohex-3-enecar-
boxylic Acid Phenyl Ester 31. A solution of 2-tert-butyldiphen-
ylsilyloxy-1,4-dimethoxy-1,3-butadiene 13c (0.15 g, 0.41 mmol, 1
equiv) in freshly distilled THF (2.5 mL) was added to a solution
of phenyl acrylate 27 (0.093 mL, 0,67 mmol, 1.6 equiv) in dry
THF (2.5 mL) in a high-pressure cell. After 24 h at room
temperature and under 16 kbar, the solvent was evaporated and
the residue was purified by flash chromatography on silica (heptane/
AcOEt 95:5). Isomer 31 trans (white solid, 80 mg, 38%): mp 136-
137 °C (diethyl ether); IR (neat) ν 1765, 1658, 1492, 1427, 1195,
1083 cm-1; EIMS (70 eV) m/z 516 (M+, <1), 459 (M+ - tBu,
57), 427 (M+ - tBu - MeOH, 33), 213 (79), 135 (100); 1H NMR
(300 MHz) δ 1.06 (9H, s), 2.12 (1H, ddd, J ) 4.1, 14.3 and 14.3),
2.19 (1H, ddd, J ) 2.3, 3.0 and 14.3), 2.92 (3H, s), 3.10 (1H, ddd,
J ) 3.8, 3.8 and 12.4), 3.50 (3H, s), 3.73 (1H, dd, J ) 2.3 and
3.4), 4.02 (1H, dd, J ) 4.5 and 4.9), 4.89 (1H, d, J ) 5.3), 7.01
(2H, dd, J ) 1.1 and 8.3), 7.19 (1H, ddd, J ) 1.1, 7.5 and 7.5),
7.33 (2H, d, J ) 7.5), 7.36-7.46 (6H, m), 7.73-7.79 (4H, m); 13
C
NMR (75 MHz) δ 19.6, 35.3, 36.7, 40.7, 56.1, 58.7, 73.3, 76.5,
105.1, 121.9, 125.9, 128.1, 129.7, 130.2, 130.3, 132.5, 132.7135.8,
151.3, 154.2, 172.0. Anal. Calcd for C31H36O5Si: C, 72.06; H, 7.02.
Found: C, 72.06; H, 7.18.
Acknowledgment. N.P. acknowledges the “Ministe`re de la
Recherche et de la Technologie” for a Ph.D. grant. We also
thank the Conseil Re´gional de Haute-Normandie for support
for the IRCOF high-pressure research program.
Supporting Information Available: Experimental procedures,
copies of the 1H NMR and 13C spectra for all compounds, and CIF
files. This material is available free of charge via the Internet at
http://pubs.acs.org.
(M+ - tBuPh2SiOCdCH, 100), 57 ([tBu]+, 75); H NMR (300
MHz) δ 0.85 (3H, t, J ) 7.1), 1.05 (9H, s), 2.86-2.99 (3H, m),
1
JO0521854
J. Org. Chem, Vol. 71, No. 5, 2006 1901