Asymmetric Diels-Alder reaction of aminodienes with a nonracemic acrylate bound to rink resin: A comparison of these reactions with their solution-state analogues

Article abstract of DOI:10.1002/ejoc.200700677

The asymmetric Diels-Alder reactions between (3R)-4,4-dimethyl-2- oxopyrrolidin-3-yl acrylate derivatives and three N-Z-protected 1-aminodienes have been investigated both in solution and on a solid support. Comparable results for each reaction were obser

Full text of DOI:10.1002/ejoc.200700677

FULL PAPER
DOI: 10.1002/ejoc.200700677
Asymmetric Diels–Alder Reaction of Aminodienes with a Nonracemic Acrylate
Bound to Rink Resin: A Comparison of These Reactions with Their Solution-
State Analogues
Olivier Songis,[a] Pierre Yves Géant,[a] Guillaume Sautrey,[a] Jean Martinez,[a] and
Monique Calmès*[a]
Keywords: Asymmetric synthesis / Diels–Alder reactions / Supported synthesis / Cyclic β-amino acids / Microwave
activation / Chiral auxiliaries
The asymmetric Diels–Alder reactions between (3R)-4,4-di-
methyl-2-oxopyrrolidin-3-yl acrylate derivatives and three
N-Z-protected 1-aminodienes have been investigated both in
solution and on a solid support. Comparable results for each
thesis by conventional heating and microwave activation re-
vealed that the microwave technique is often advantageous.
We have also demonstrated that reaction on a solid support
offered an excellent resolution of the problem of low reactiv-
reaction were observed with the formation of the correspond- ity and instability of the reagents.
ing constrained cyclic β-amino acids in high yield and mod-
erate-to-good selectivity when using optimized conditions. A
detailed comparison of both solution and solid-support syn-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
reactions that involve supported chiral amino acid trienes
have also been developed by Sun and Murray and co-
workers.[11]
The development of organic chemistry on solid supports
has progressed rapidly during recent years and numerous
synthetic methods involving solid supports have been used
in combinatorial chemistry.[1] Among them, various asym-
metric organic reactions have been carried out with poly-
mer-supported chiral ligands or catalysts.[2] On the other
hand, stereoselective syntheses of complex molecules using
a polymer-supported chiral auxiliary are not well devel-
oped.[3] This is particularly the case for asymmetric solid-
phase Diels–Alder reactions whose supported syntheses
mainly concern racemic preparations.[4,5] The asymmetric
Diels–Alder reaction, which is among the most important
carbon–carbon bond-forming reactions, is widely used in
solution to prepare six-membered rings with several ste-
reogenic centres in a regio- and stereocontrolled way.[6]
Therefore, it is surprising that only a few asymmetric solid-
phase reactions involving the use of a chiral auxiliary have
been reported so far. These few examples involve (1) a sup-
ported chiral diene, such as a chiral siloxyaminofuran[7] or a
chiral cyclohexadiene-1,2-diol[8] and (2) a supported chiral
acrylate as dienophile derived from a chiral butane-1,3-
diol[9] or a chiral oxazolidinone.[10] Some intramolecular
A few years ago we developed a new chiral auxiliary that
can be used both in solution and on solid supports. This
chiral alcohol, (3S)- or (3R)-4-(3-hydroxy-4,4-dimethyl-2-
oxopyrrolidin-1-yl)benzoic acid [(S)- or (R)-1], has a car-
boxylic acid function that can be protected in solution or be
used for attachment to an amine-functionalized insoluble
polymer to afford (S)- or (R)-2a and -2b, respectively. Sev-
eral successful applications of this chiral auxiliary have been
described.[12,13] We have also shown that the acrylate deriva-
tive was an efficient dienophile under Diels–Alder reaction
conditions both in solution and on a solid support.[13]
In our first study, we reported Diels–Alder cycloaddition
reactions that involve the chiral acrylate (R)-3a or (R)-3b
and a non-functionalized diene such as isoprene, cyclopen-
tadiene or cyclohexadiene which react to form the corre-
sponding chiral cyclic carboxylic acids.[12a,12b] More re-
cently we focused our attention on the asymmetric synthesis
of constrained cyclic β-amino acids which are an important
class of compound; they are subunits of natural products
and often play an important role in structural or mechan-
istic investigations. Their incorporation into peptides or
peptidomimetics induced conformational restrictions that
have important structural consequences. With this aim we
first investigated the asymmetric Diels–Alder cycloaddition
of the chiral acrylate (R)-3a with 1-[(benzyloxycarbonyl)-
amino]butadiene (4)[14] and 1-[(benzyloxycarbonyl)amino]-
[a] Institut des Biomolécules Max Mousseron (IBMM) UMR 5247
CNRS-Université Montpellier 1 et 2, Bâtiment Chimie (17),
Université Montpellier,
2, place E. Bataillon, 34095 Montpellier cedex 5, France
E-mail: Monique.Calmes@univ-montp2.fr
308
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318

Diels–Alder Reaction of Nonracemic Acrylates and Aminodienes
Application of the solid-phase approach to these cyclo-
addition reactions was investigated to evaluate the advan-
tages and disadvantages of the solid-phase strategy. Com-
pared with the reactions in solution, the solid-phase tech-
nology allows the use of a large excess of reagents to drive
the reaction to completion and also allows, “by filtration”,
a rapid isolation of the desired compounds, an easy elimi-
nation of byproducts and excess reagents, and a facile sepa-
ration and recovery of the chiral material attached to the
solid support for recycling. However, because longer reac-
cyclohexadiene (5)[15] in solution which yielded, respec- tion times are usually required in solid-phase synthesis
tively, the corresponding cyclic and bicyclic β-amino ac- compared with reactions in solution we investigated cyclo-
ids.[13c,13d]
addition reactions that involve the above relatively unstable
Scheme 1. Diels–Alder reaction in solution and in solid-phase conditions using the acrylates (R)-3a and (R)-3b and the dienes 4, 5 and 6.
309
Eur. J. Org. Chem. 2008, 308–318
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

O. Songis, P. Y. Géant, G. Sautrey, J. Martinez, M. Calmès
FULL PAPER
dienes. We also extended our investigation by using a third
diene, benzyl 1,2-dihydropyridine-1-carboxylate (6)[16] as
the Diels–Alder reaction of this compound with an acrylate
is a well established route to the azabicyclo[2.2.2]octane
ring (isoquinuclidine) which is found in several biologically
active natural products, particularly in the iboga-type in-
dole alkaloids.[17]
We report in this study a detailed comparison of the
asymmetric Diels–Alder reactions carried out both in solu-
tion and on a solid support using the N-Z-protected 1-ami-
nodienes 4, 5 and 6 and the acrylate derivatives of the chiral
alcohol 1, compounds (R)-3a and (R)-3b (Scheme 1).
Results and Discussion
Scheme 2. Acidic cleavage of the benzhydrylamide bond of sup-
ported adducts 7b–16b.
For solid-phase synthesis the chiral auxiliary was linked
to a Rink resin[18] because the bond created between the
chiral auxiliary and the polymer was stable under the reac- isfactory yields and high levels of stereoselectivity.[6,20]
tion conditions and during the basic final hydrolysis of the However, such conditions will not be used in our experi-
ester bond. Furthermore, the benzhydrylamide bond could ments since we have previously shown that the use of some
be selectively cleaved in an acidic medium (5% TFA in Lewis acid catalysts resulted in diene decomposition.[13c,13d]
CH2Cl2) allowing both an easier control of the different
solid-phase synthetic steps and a possible quantitative re- Z-protected 1-aminodienes 4, 5 and 6 and the chiral acryl-
covery of the intermediate amide compounds (Scheme 2). ates (R)-3a and (R)-3b (Scheme 1) are summarized in
The stability of the benzyloxycarbonyl (Z) group during Tables 1 and 2.
The results of the Diels–Alder reactions between the N-
both the basic hydrolysis of the ester bond of the adduct
Compared with our previous results obtained in solu-
and the acidic cleavage of the benzhydrylamine bond as well tion, in toluene at 60 °C, the microwave-assisted cycload-
as the possibility of its removal by catalytic hydrogenolysis dition reaction between the chiral acrylate (R)-3a and the
increased the interest in its use for aminodiene protection. aminodiene 4 resulted in a significant decreased reaction
The possible limitation of the Z moiety resided in its reac- time. These results are in agreement with a lot of reports
tivity under some Lewis acid catalyzed conditions,[19] gen- that have been published in recent years supporting the ad-
erally used to promote the Diels–Alder reaction to give sat- vantages of using microwave irradiation in organic synthe-
Table 1. Diels–Alder reactions in solution-phase conditions using the acrylate (R)-3a.
Entry
T [°C]
Diene (equiv.)[a]
Solvent
Time
% Conversion[b] Adducts (ratio)[c]
1
2
3
4
5
6
7
8
r.t.
60
80
MW 60
MW 80
MW 150
r.t.
80
80
4 (2)
4 (2)
4 (2)
4 (2)
4 (2)
4 (2)
5 (4)
5 (4)
5 (4)
5 (4)
5 (4)
5 (4)
5 (4)
5 (4)
6 (4)
6 (4)
6 (4)
6 (4)
6 (4)
6 (4)
6 (4)
6 (4)
toluene[d]
96 h
24 h
30 min
3 h and 5 h
30 min
20 min
96 h
15 h
6 h
15 h
1.5 h
1.5 h
2 h and 4 h
1.5 h
72 h
15 h
1 h
1 h
10 h
10 h
1 h
Ͼ99
Ͼ99
95
7a/8a (85:15)
toluene[d]
7a/8a (85:15)
–
7a/8a (85:15)
toluene or CH3CN[d]
85 and Ͼ99
Ͼ99
7a/8a (85:15)
–
7a/8a (85:15)
CH3CN[d]
Ͼ99
7a/8a (73:27)
toluene[d]
80[e,f]
35[e,f]
58[e,f]
50[e,f]
15[e,f]
Ͼ99
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (30:60:3:7)
9a/10a/11a/12a (24:50:8:18)
–
toluene[d]
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
110
toluene[d]
MW 80
MW 80
MW 110
MW 160
r.t.
80
160
toluene or CH3CN[d]
–
toluene or CH3CN[d]
42 and 95
Ͼ99
CH3CN[d]
toluene[d]
0[e]
toluene[d]
0[e]
–
toluene[d]
20[e,f]
≈5[e]
13a/14a/15a/16a (10:60:6:24)
[f]
160
–
–
MW 110
MW 110
MW 160
MW 160
toluene[d]
30[e,f]
60[e,f]
50[e,f]
Ͼ99
13a/14a/15a/16a (10:60:6:24)
[g]
–
–
toluene or CH3CN[d]
–
13a/14a/15a/16a (10:52:6:32)
13a/14a/15a/16a (10:52:6:32)
1 h
[a] Amount selected according to the instability of the diene. [b] Determined by HPLC analysis and based on the disappearance of the
acrylate. [c] Ratio determined by chiral HPLC analysis. [d] Acrylate concentration 0.2 m. [e] No residual diene. [f] Side-product formation.
[g] Difficult to determine accurately.
310
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318

Diels–Alder Reaction of Nonracemic Acrylates and Aminodienes
Table 2. Diels–Alder reactions in solid-phase conditions using the acrylate (R)-3b.
Entry
T [°C]
Diene (equiv.)
Solvent
Time [h]
% Conversion[a]
Adducts (ratio)[b]
1
2
3
4
5
6
7
8
r.t.
60
MW 60
r.t.
60
MW 60
r.t.
80
MW 80
r.t.
160
4 (2)
4 (2)
toluene[c]
toluene[c]
toluene[c]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
toluene[d]
96
24
5
20
1
1
96
2
Ͼ99
Ͼ99
Ͼ99
Ͼ99
95
Ͼ99
67
50
Ͼ99
0
7c/8c (85:15)
7c/8c (85:15)
4 (2)
7c/8c (85:15)
4 (22)
4 (22)
4 (22)
5 (22)
5 (22)
5 (22)
6 (22)
6 (22)
6 (22)
7c/8c (85:15)
7c/8c (85:15)
7c/8c (85:15)
9c/10c/11c/12c (30:60:3:7)
9c/10c/11c/12c (30:60:3:7)
9c/10c/11c/12c (30:60:3:7)
–
9
2
144
1
10
11
12
Ͼ99
Ͼ99
13c/14c/15c/16c (10:52:6:32)
13c/14c/15c/16c (10:52:6:32)
MW 160
1
[a] Determined by HPLC analysis after TFA cleavage and based on the disappearance of the acrylate. [b] Determined by chiral HPLC
analysis. [c] 6.4 mL/g of resin. [d] A minimum of toluene was used (3.2 mL/g of resin); the Rink amide resin was swollen overnight in
toluene and the solvent above the resin was removed before use.
sis.[21] We observed total consumption of the acrylate and chromatography. These results underline the advantage of
the formation of the cycloadducts within 5 h, whereas un- the solid-phase technology for slow or thermal reactions
der thermal reaction conditions the same results were ob- involving relatively unstable reagents.
tained, but only after 24 h (Table 1, entries 2 and 4). Al-
As in the solution conditions, the supported reaction was
though solvent effects are generally of particular signifi- completely regioselective yielding only the ortho re-
cance in microwave-mediated reactions,[21] when the reac- gioisomer. We could not detect any trace of the meta re-
1
tion was carried out in a polar solvent such as acetonitrile, gioisomer by H NMR spectroscopy of the crude mixture.
identical results were obtained (Table 1, entry 4). This en- Two Diels–Alder cycloadducts, 7c and 8c (amide deriva-
hancement of the reaction rate was even more pronounced tives), were isolated in an 85:15 ratio after TFA treatment
under microwave irradiation at 80 °C[22] in solvent-free con- of the supported 7b/8b mixture (Scheme 2). LiOH hydroly-
ditions (Table 1, entry 5), but no beneficial effect was de- sis of the 7c/8c mixture at room temperature (Scheme 3)
tectable compared with the reaction carried out under the yielded the β-amino acid mixture (1R,2S)-17/(1S,2R)-17 af-
same conditions but in the absence of microwave acti- ter elimination of the amide chiral auxiliary by precipi-
vation[22] (Table 1, entry 3). In all cases the same stereose- tation. These compounds possessed HPLC profiles as well
1
lectivity[23] was observed; an endo-selective cycloaddition as H and 13C NMR spectra identical to those obtained
facially controlled process in a 85:15 ratio in favour of the in solution[13c] from the 7a/8a mixture as the cycloaddition
(1R,2S) compound 7a when starting from the (R) chiral reaction proceeds with the same stereoselectivity in both
acrylate 3a. When the reaction was carried out in acetoni- solution and on the solid support.
trile at 150 °C instead of 60 °C, the reaction time was de-
creased (20 min), but lower selectivity was obtained
(Table 1, entries 4 and 6).
The same reaction was investigated on a solid support by
using the polymer bound acrylate (R)-3b. The reactions on
the solid support were monitored by HPLC after acid treat-
ment of the resin (Scheme 2). By using the same reaction
conditions as those used in experiments carried out in solu-
tion, comparable results, that is, the same yield and stereo-
selectivity, were observed with the temperature and micro-
wave activation only affecting the reaction rate (Table 2, en-
tries 1–3). By using a large excess of the aminodiene 4 and
Scheme 3. LiOH hydrolysis of the adduct mixture 7c/8c.
Previous optimization studies of the Diels–Alder reac-
a minimum of toluene as solvent, a significant increase in tion in solution between the chiral acrylate (R)-3a and the
the reaction rate was observed (Table 2, entries 1 and 2 vs. aminodiene 5 have shown that microwave irradiation in sol-
4 and 5). It should be underlined that under these reaction vent-free conditions at 80 °C were the best experimental
conditions comparable results were observed with or with- conditions (Table 1, entry 12). Under these conditions we
out microwave irradiation (Table 2, entries 5 and 6).
observed total consumption of the acrylate within 1.5 h, af-
The use of a large excess of diene did not cause complica- fording cleanly and in good yield the corresponding cy-
tions since the supported adducts could easily be purified cloadducts. Without microwave activation but at the same
from both the excess and the possible polymerized diene by temperature, only moderate yields were obtained along with
simply washing. This was not possible for adducts obtained decomposition of the residual aminodiene, making purifica-
in solution conditions; these adducts could not be isolated tion and separation of the obtained diastereomers difficult
easily or in a totally pure form even after column (Table 1, entry 9). In most cases we observed the same re-
Eur. J. Org. Chem. 2008, 308–318
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
311

O. Songis, P. Y. Géant, G. Sautrey, J. Martinez, M. Calmès
FULL PAPER
gioselectivity; mixtures of the four expected cycloadducts 6. In solution conditions, the Diels–Alder reaction did not
(Scheme 1) were obtained with the two diastereoisomers 9a occur even after 72 h at room temperature, or at 80 °C, and
(30%) and 10a (60%) predominant. The reaction proceeded significant decomposition of the diene was observed
with a moderate endo selectivity (2:1) and good facial selec- (Table 1, entries 15 and 16). When the reaction was carried
tivity (9:1) which mainly resulted from an endo approach out in toluene or without solvent at 160 °C only poor yields
on the Cα Si face of the dienophile (R)-3a.[13d]
were obtained with the formation of side-products and sig-
By using microwave activation (80 °C) in solid-phase nificant decomposition of the residual diene (Table 1, en-
conditions with a minimum of toluene as solvent and a tries 17 and 18). As observed previously with diene 4 and
large excess of diene 5 we obtained similar results to those particularly diene 5, the best results were obtained by using
obtained with the best experimental conditions in solution microwave activation in solvent-free conditions but at a
(Table 2, entry 9 and Table 1, entry 12). A significant in- high temperature (160 °C) (Table 1, entries 21 and 22). Un-
crease in the reaction rate was observed even without mi- der the same reaction conditions but at a lower temperature
crowave activation when a high concentration of diene 5 (110 °C) only a moderate conversion level was observed de-
was used in comparison with solution conditions (Table 1, spite a longer reaction time and the formation of side-prod-
entries 8 and 9 and Table 2, entry 8) and as described pre- ucts (Table 1, entries 19 and 20).
viously in the case of diene 4. However, in the case of diene
The reaction at 160 °C using microwave activation in sol-
5, the effect of the diene concentration was not as signifi- vent-free conditions yielded a mixture of the four expected
cant as it was in the case of diene 4. An increased yield was cycloadducts in a 10:52:6:32 ratio[24] (Scheme 1), the two
obtained when using microwave activation (Table 2, entries diastereoisomers 14a (52%) and 16a (32%) being predomi-
5, 6 and 8, 9). It should also be underlined that despite the nant. A better facial selectivity was observed at 160 °C un-
large excess of diene 5 the reaction remained slower than in der thermal conditions or at 110 °C by using microwave
solution at room temperature which might be due to the activation. Unfortunately under these conditions the purifi-
steric hindrance induced by the backbone of the insoluble cation step was difficult due to the presence of the residual
polymer (Table 1, entry 7 and Table 2, entry 7). This was diene and/or side-products.
less obvious at 80 °C probably because of faster diffusion
of the reagent towards the reactive sites of the polymer.
To define the endo/exo isomeric ratio, an aliquot of the
10:52:6:32 mixture of the cycloadducts 13a–16a was hy-
In all cases four Diels–Alder cycloadducts 9c/10c/11c/12c drolyzed to remove the chiral auxiliary and then treated
(amide derivatives) in a 30:60:3:7 ratio were obtained after with iodine. It resulted in conversion of the two major endo
cleavage from the resin under acidic conditions.[24] LiOH isomers into the corresponding iodolactone mixture 20
hydrolysis of this mixture at room temperature (Scheme 4) (84% yield), the two minor exo isomers remaining uncy-
yielded the corresponding β-amino acid mixture clized (16%) (Scheme 5).
(1R,2R,4S)-18/(1S,2R,4R)-19/(1S,2S,4R)-18/(1R,2S,4S)-19
Although the reaction proceeded with moderate endo
in a 30:60:3:7 ratio after elimination of the amide chiral selectivity (84%) and poor facial selectivity (62%), three of
auxiliary by precipitation. All these compounds were iden- the four cycloadducts, compounds 14a, 15a and 16a, were
tified by chiral HPLC analysis. The ratio is similar to that isolated in pure form but in low yield after column
obtained previously in solution when starting from the cor- chromatography. Removal of the chiral auxiliary from the
responding 9a/10a/11a/12a mixture. The stereoselectivity of major endo adduct 14a afforded the pure enantiomer
this cycloaddition reaction in both solution and on solid (1R,4R,7R)-21 (Scheme 6). Its absolute configuration
support was similar.
(1R,4R,7R) was assigned by comparison of its optical rota-
The significance of both temperature and microwave ac- tion with that of the known corresponding ester deriva-
tivation was even more pronounced when using the diene tive.[25] Compound (1R,4R,7R)-21 corresponded to the ex-
Scheme 4. LiOH hydrolysis of the adduct mixture 9c/10c/11c/12c.
Scheme 5. Reagents and conditions: (a) LiOH, THF/H2O, room temp.; (b) I2/KI/NaHCO3, DCM/H2O, room temp.
312
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318

Diels–Alder Reaction of Nonracemic Acrylates and Aminodienes
pected enantiomer since with both the diene 4 and 5 and proved to be difficult. On the other hand, it could be as-
the acrylate 3 possessing the R configuration, the main sumed that the separation of the corresponding hydroge-
Diels–Alder cycloadduct obtained resulted from an endo nated derivatives, a 90:10 mixture of only the two diastereo-
selective approach on the Cα Si face of the dienophile. Ac- isomeric compounds (3ЈR,2R)-22c and (3ЈR,2S)-22c,[26]
cording to the results described above, it can be assumed should be easier (Scheme 7). We investigated this hydrogen-
that the configuration of the major exo adduct 13a was ation reaction on a solid support in the presence of the solu-
(1S,4S,7R) which corresponds to an exo approach always ble Wilkinson’s catalyst.[27] This catalyst usually allows ole-
on the Cα Si face of the dienophile.
fins to be hydrogenated under mild temperature and pres-
sure conditions in which the benzylcarbamate amino pro-
tecting group remains unaffected. The effect of the amount
of catalyst and the nature of the solvent[28] on the course of
the reaction was investigated. The results are summarized
in Table 3.
Table 3. Hydrogenation reaction of the supported cycloadduct
using the Wilkinson’s catalyst.
Scheme 6. LiOH hydrolysis of the adduct 14a.
Entry Catalyst
Solvent[a]
Time [h] % Conversion[b]
The same reaction was investigated on a solid support by
using the polymer-bound acrylate (R)-3b. As in solution
this Diels–Alder reaction did not occur at room tempera-
ture (Table 2, entry 10). Under thermal or microwave acti-
vation with a minimum of toluene as solvent and a large
excess of diene 6 we observed the total consumption of the
acrylate within 1 h at 160 °C (Table 2, entries 11 and 12). In
the case of dienes 4 and 5, as described above, a significant
increase in the reaction rate was observed even without mi-
crowave activation when using an excess of diene 6, afford-
1
1 %
CH2Cl2 or CH3OH or
toluene
CH3OH
toluene
toluene/CH3OH (95:5)
24
0
2
3
4
5
20 %
20 %
20 %
24
24
24
24
0
50
Ͼ99[b]
Ͼ99
10–20 % CH2Cl2
[a] 3.2 mL/g of resin. [b] A dark resin was obtained. After cleavage
from the resin no identified products were obtained. We assumed
that only phosphane-derived side-products were recovered.
No reaction of the supported cycloadduct was observed
ing the corresponding cycloadducts in good yield (Table 1, within 24 h in the presence of 1% of Wilkinson’s catalyst
entry 18 and Table 2, entry 11). These results proved the whatever the solvent used (Table 3, entry 1). When using
efficiency of the solid-phase technology for reactions that 20% of the catalyst with toluene as the solvent the reaction
involved the diene 6 although it should be underlined that partially occurred. Addition of a protic co-solvent such as
a few polymer side-products were ineluctably formed.
methanol accelerated the reaction (Table 3, entries 3 and 4).
Among the constrained β-amino acids mentioned above, The use of methanol alone led only to the recovery of only
the asymmetric preparation of bicyclo[2.2.2]octane deriva- the starting material after stirring for 24 h (Table 3, entry 2).
tives bearing an amino group at the bridgehead was par- With 10, 15 or 20% catalyst, dichloromethane was shown
ticularly interesting since, except for our recent work,[13d] to be the solvent of choice, cleanly yielding total hydrogena-
no other such syntheses have been described to date. Conse- tion of the double bond within 24 h (Table 3, entry 5). By
quently, we decided to explore in more detail the supported using these optimized conditions, the two hydrogenated
synthesis of these compounds.
Diels–Alder cycloadducts (3ЈR,2R)-22c and (3ЈR,2S)-22c
Separation by crystallization or by column chromatog- (amide derivatives) were obtained in a 90:10 ratio after acid
raphy of the endo/exo mixture of the cycloadducts obtained treatment of the resin. The dominant compound (3ЈR,2R)-
in solid-phase conditions after acid cleavage, that is, the 22c was isolated in pure form after column chromatography
four amide derivatives 9c/10c/11c/12c in a 30:60:3:7 ratio, on silica gel (Scheme 7). LiOH hydrolysis of compound
Scheme 7. Reagents and conditions: (a) H2/RhCl(PPh3)3; (b) TFA, CH2Cl2; (c) chromatographic separation; (d) LiOH, THF/H2O, room
temp.
Eur. J. Org. Chem. 2008, 308–318
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
313

O. Songis, P. Y. Géant, G. Sautrey, J. Martinez, M. Calmès
FULL PAPER
5 μ, (250ϫ10 mm), flow: 1 mL/min, eluent I: H2O (0.1% TFA)/
CH3CN (0.1% TFA) 30:70, eluent II: H2O (0.1% TFA)/CH3CN
(0.1% TFA) 60:40. Column C: Chiracel OD, 5 μ, (250ϫ10 mm),
flow: 1 mL/min, hexane/2-propanol: 40:60. Column D: Chiracel
OJ-R, 5 μ, (250ϫ10 mm), flow: 1 mL/min, H2O (0.1% TFA)/
CH3CN (0.1% TFA) 75/25.
(3ЈR,2R)-22c at room temperature yielded the correspond-
ing (R)-β-amino acid 23 after elimination of the amide chi-
ral auxiliary by precipitation.[29]
Conclusion
The enantiopure chiral auxiliary 4-[(3R)-3-hydroxy-4,4-dimethyl-2-
oxopyrrolidin-1-yl]benzoic acid [(R)-1], benzyl 4-[(3R)-3-hydroxy-
4,4-dimethyl-2-oxopyrrolidin-1-yl]benzoate [(R)-2a], benzyl 4-
We have demonstrated that (3R)-1-(4-carboxyphenyl)-
4,4-dimethyl-2-oxopyrrolidin-3-yl acrylate derivatives can
be used as chiral dienophiles in asymmetric Diels–Alder re- [(3R)-3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl]benzoate
[(R)-3a], and the Rink-amide-supported acrylic ester (R)-3b were
actions with three 1-N-Z-aminodienes to prepare con-
strained cyclic β-amino acids both in solution and on a so-
lid support.
prepared as described previously.[12,13]
General Procedure for Diels–Alder Reactions of the Acrylate Esters
Our studies have revealed that the microwave technique (R)-3a with Dienes 4, 5 and 6: A mixture of diene 4, 5 or 6 (2 or
4 equiv.) and benzyl (R)-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrro-
lidin-1-yl)benzoate [(R)-3a] (2.55 g, 6.5 mmol, 1 equiv.) in dry ace-
tonitrile or toluene (30 mL) or in solvent-free conditions was stirred
at the selected temperature or heated by microwave irradiation at
the selected temperature (initial power 300 W) for the specified
time. The reaction was monitored by HPLC using column A and
eluent I. After cooling and solvent concentration in vacuo the
crude product was submitted to column chromatography on silica
gel.
is often advantageous not only by increasing the reaction
rate but also by enabling transformations that did not al-
ways occur under conventional heating. Microwave acti-
vation produces less complex crude mixtures compared
with those often obtained when using room temperature or
thermal conditions which allowed easy purification and
separation of the obtained cycloadducts. We have also dem-
onstrated that reaction on a solid support rapidly leads to
completion of the reaction when a large excess of diene is
used while avoiding the problem of degradation or contami-
nation of the final products with residual or polymerized
diene.
(3ЈR,1R,2S)/(3ЈR,1S,2R)-1-[4-(Benzyloxycarbonyl)phenyl]-4,4-di-
methyl-2-oxopyrrolidin-3-yl 2-(Benzyloxycarbonylamino)cyclohex-3-
ene-1-carboxylate [(3ЈR,1R,2S)-7a/(3ЈR,1S,2R)-8a]: Synthesized ac-
cording to the general procedure from 1-(benzyloxycarbonyl-
amino)butadiene (4) (2.63 g, 13.0 mmol, 2 equiv.) using microwave
Finally, we have shown that the Diels–Alder reaction be-
tween the supported acrylate and the diene 5 followed by irradiation in solvent-free conditions at a temperature of 80 °C for
0.5 h. The expected pure mixture of the two endo cycloadducts 7a/
8a (2.90 g, 5.0 mmol, 77% yield) was obtained in an 85:15 ratio as
a colourless oil after rapid column chromatography on silica gel
with hexane/ethyl acetate (7:3).
hydrogenation on a solid support provides in good yield the
corresponding β-amino acids possessing a bicyclo[2.2.2]-
octane structure. Compared with the reaction in solution,
the solid-phase method is suitable for the preparation of
such compounds. The only possible limitation could be the
relatively low loading of the polymer making this approach
more expensive when a large quantity of compound is re-
quired.
The physical properties and chemical characteristics of the 1-(4-
benzyloxycarbonylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl 2-
(benzyloxycarbonylamino)cyclohex-3-ene-1-carboxylates
[(3ЈR,1R,2S)-7a/(3ЈR,1S,2R)-8a] are identical to those described
previously.[13c]
(3ЈR,1R,2R,4S)/(3ЈR,1S,2R,4R)/(3ЈR,1S,2S,4R)/(3ЈR,1R,2S,4S)-1-
[4-(Benzyloxycarbonyl)phenyl]-4,4-dimethyl-2-oxopyrrolidin-3-yl 1-
(Benzyloxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylate
[(3ЈR,1R,2R,4S)-9a/(3ЈR,1S,2R,4R)-10a/(3ЈR,1S,2S,4R)-11a/
(3ЈR,1R,2S,4S)-12a]: Synthesized according to the general pro-
cedure from 1-(benzyloxycarbonylamino)cyclohexa-1,3-diene (5)
(5.96 g, 26.0 mmol, 4 equiv.) by using microwave irradiation in sol-
vent-free conditions at a temperature of 80 °C for 1.5 h. The ex-
pected pure mixture of the four cycloadducts 9a/10a/11a/12a was
obtained (3.60 g, 5.90 mmol, 91% yield) in a 30:60:3:7 ratio as a
colourless oil after rapid column chromatography on silica gel with
cyclohexane/ethyl acetate (7:3).
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. Solvents were dried
and purified by conventional methods prior to use. Melting points
were determined with a Kofler Heizbank apparatus and are uncor-
rected. Microwave activation was performed with a Biotage initia-
tor 2.0 instrument. Optical rotations were measured with a Perkin–
1
1
Elmer 341 polarimeter. H and 13C NMR spectra (DEPT, H/13C
2D correlations) were recorded with a Bruker A DRX 400 spec-
trometer using the solvent as internal reference. Data are reported
as follows: chemical shifts (δ) in parts per million, coupling con-
stants (J) in Hertz (Hz). The ESI mass spectra were recorded with
a platform II quadrupole mass spectrometer (Micromass, Man-
chester, UK) fitted with an electrospray source. HPLC analyses
were performed with a Waters model 510 instrument or a Beckman
System Gold 126 instrument with a variable detector and the fol-
lowing conditions. Column A: SymmetrySchieldTM RP18, 3.5 μ,
(50ϫ4.6 mm), flow: 1 mL/min, eluent I: H2O (0.1% TFA)/CH3CN
(0.1% TFA), gradient 0Ǟ100% (15 min) and 100% (4 min), eluent
II: H2O (0.1% TFA)/CH3CN (0.1% TFA) 55:45, eluent III: H2O
(0.1% TFA)/CH3CN (0.1% TFA) 60:40, eluent IV: H2O (0.1%
The physical properties and chemical characteristics of the 1-(4-
benzyloxycarbonylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl 1-
(benzyloxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylates
[(3ЈR,1R,2R,4S)-9a/(3ЈR,1S,2R,4R)-10a/(3ЈR,1S,2S,4R)-11a/
(3ЈR,1R,2S,4S)-12a] are identical to those previously described.[13d]
(3ЈR,1S,4S,7R)/(3ЈR,1R,4R,7R)/(3ЈR,1R,4R,7S)/(3ЈR,1S,2S,4S)-1-
[4-(Benzyloxycarbonyl)phenyl]-4,4-dimethyl-2-oxopyrrolidin-3-yl 2-
(Benzyloxycarbonyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate
[(3ЈR,1S,4S,7R)-13a/(3ЈR,1R,4R,7R)-14a/(3ЈR,1R,4R,7S)-15a/
(3ЈR,1S,2S,4S)-16a]: Synthesized according to the general pro-
TFA)/CH3CN (0.1% TFA) 70:30. Column B: Chiracel OD-RH, cedure from 1-(benzyloxycarbonyl)-1,2-dihydropyridine (6) (5.56 g,
314
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318

Diels–Alder Reaction of Nonracemic Acrylates and Aminodienes
26.0 mmol, 4 equiv.) in the presence of a few crystals of hydroqui-
none by using microwave irradiation in solvent-free conditions at a
temperature of 160 °C for 1 h. The expected pure mixture of the
four cycloadducts 13a/14a/15a/16a was obtained (3.50 g,
5.80 mmol, 90% yield) in a 10:52:6:32 ratio as a colourless oil after
rapid column chromatography on silica gel with cyclohexane/ace-
(3ЈR,1S,4S,7S)-16a: Colourless oil. [α]2D0 = +46 (c = 0.8, CH2Cl2);
tR (HPLC, column A, eluent I) = 15.2 min; tR (HPLC, column B,
1
eluent I) = 18.3 min. MS (ESI): m/z = 609.3 [M + H]+. H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.04 and 1.11 [2s (40:60)*, 3 H,
CH3], 1.20 (s, 3 H, CH3), 1.90 (m, 2 H, 8-H), 2.79 and 2.83 [2 br.
m (60:40)*, 1 H, 4-H], 2.95 (m, 1 H, 3-H), 3.25 (m, 2 H, 7-H and
tone (7:3). Pure diastereoisomers (3ЈR,1R,4R,7R)-14a (0.30 g, 3-H), 3.49 (d, J = 9.6 Hz, 1 H, 5Ј-H), 3.55 (d, J = 9.6 Hz, 1 H, 5Ј-
0.49 mmol, Rf = 0.36, 99 % de), (3ЈR,1R,4R,7S)-15a (50 mg,
0.08 mmol, Rf = 0.43, 99 % de) and (3ЈR,1S,4S,7S)-16a (20 mg,
0.03 mmol, Rf = 0.34, 99% de) were isolated after several consecu-
tive flash column chromatography on silica gel with petroleum
ether/diethyl ether/acetone (5:3:1).
H), 5.05 and 5.09 [2s (60:40)*, 2 H, OCH2], 5.07 and 5.17 [2m
(40:60)*, 1 H, 1-H], 5.28 (s, 2 H, OCH2), 5.30 (s, 1 H, 3Ј-H), 6.24
and 6.35 [2m (40:60)*, 1 H, CH=], 6.39–6.49 (m, 1 H, CH=), 7.20–
7.39 (m, 10 H, H arom.), 7.64 (d, J = 8.8 Hz, 2 H, H arom.), 8.01
(d, J = 8.8 Hz, 2 H, H arom.) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 21.25 and 21.37 (CH3)*, 24.73 and 24.79 (CH3)*, 26.11
(C-8), 30.43 and 30.46 (C-4)*, 37.15 (C-4Ј), 43.83 and 44.08 (C-
7)*, 46.78 (C-1), 47.08 (C-3), 57.31 and 57.43 (C-5Ј)*, 66.69
(OCH2), 66.96 and 67.04 (OCH2), 78.17 (C-3Ј), 118.35 and 118.41
(CH arom.)*, 126.05 and 126.11 (C arom.)*, 127.76, 127.83,
127.99, 128.09, 128.62, 129.71 (CH arom.)*, 128.62 (C arom.)*,
129.71 and 130.30 (CH=)*, 130.79 (CH arom.), 135.52 and 136.04
(CH=)*, 136.71, 136.78, 142.97 and 143.02 (C arom.)*, 154.68,
155.22, 165.83, 169.13, 171.83 and 171.92 (CO)* ppm. HRMS
(FAB): calcd. for C36H37N2O7 [MH]+ 609.2601; found 609.2607.
(* The NMR spectra of this compound are complicated due to the
presence of carbamate rotamers.)
(3ЈR,1R,4R,7R)-14a: Colourless oil. [α]2D0 = –34 (c = 2, CH2Cl2); tR
(HPLC, column A, eluent I) = 15.4 min; tR (HPLC, column B,
1
eluent I) = 18.4 min. MS (ESI): m/z = 609.3 [M + H]+. H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.01 and 1.07 (2s (60:40)*, 3 H,
CH3), 1.17 (s, 3 H, CH3), 1.85 (m, 2 H, 8-H), 2.78 (2 br. m*, 1 H,
4-H), 2.93 (dd, J = 10.1 and 2.1 Hz, 1 H, 3-H), 3.19 (m, 1 H, 7-
H), 3.25 (d, J = 10.1 Hz, 1 H, 3-H), 3.49 (d, J = 9.6 Hz, 1 H, 5Ј-
H), 3.55 (d, J = 9.6 Hz, 1 H, 5Ј-H), 5.05 (s, 2 H, OCH2), 5.10–5.25
(2m (60:40)*, 1 H, 1-H), 5.27 (s, 2 H, OCH2), 5.29 (s, 1 H, 3Ј-H),
6.36–6.50 (2m (60:40)*, 2 H, CH=), 7.18–7.38 (m, 10 H, H arom.),
7.62 (d, J = 9.0 Hz, 2 H, H arom.), 7.99 (d, J = 9.0 Hz, 2 H, H
arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 21.14 and
21.27 (CH3)*, 24.62 and 24.68 (CH3)*, 25.97 and 26.03 (C-8)*,
30.41 and 30.58 (C-4)*, 37.03 and 37.08 (C-4Ј)*, 43.89 and 44.15
(C-7)*, 46.95 (C-1), 47.31 and 47.46 (C-3), 57.28 and 57.39 (C-5Ј),
66.67 (OCH2), 66.92 (OCH2), 78.15 and 78.28 (C-3Ј)*, 118.31 and
118.37 (CH arom.), 125.97 and 126.06 (C arom.)*, 127.70, 127.82,
127.92, 127.97, 128.18, 128.26, 128.46 and 128.62 (CH arom.)*,
128.85 and 128.93 (C arom.)*, 130.54 (CH=), 130.78 (CH-Arom),
131.15, 134.82 and 135.34 (CH=)*, 136.09, 136.77, 136.82, 143.01
and 143.08 (C arom.)*, 154.73, 155.25, 165.84, 169.07, 169.16,
171.17 and 171.90 (CO)* ppm. HRMS (FAB): calcd. for
C36H37N2O7 [MH]+ 609.2601; found 609.2571. (* The NMR spec-
tra of this compound are complicated due to the presence of carba-
mate rotamers.)
General Procedure for Diels–Alder Reactions of the Supported Acryl-
ate Esters (R)-3b with Dienes 4, 5 and 6: The diene 4, 5 or 6
(22 equiv.) was added to the Rink amide supported acrylic ester
(R)-3b (1.40 g, 1.0 mmol, 0.715 mmol/g) swollen in dry toluene
(4.5 mL). The reaction was stirred at the selected temperature or
heated by microwave irradiation at the selected temperature for the
specified time. The reaction was monitored by HPLC (column A,
eluents I and II) after removal of the reaction product from an
aliquot of the resin by acidic cleavage (5% TFA in dry CH2Cl2,
40 min at room temperature). At the end of the reaction the solu-
tion was removed from the resin by filtration, the resin was washed
with CH2Cl2 (3 ϫ 20 mL), CH2Cl2/CH3OH (8:2) (3 ϫ 20 mL),
CH2Cl2 (3ϫ20 mL) and diethyl ether (3ϫ15 mL) and dried under
reduced pressure. A solution of 5% TFA in dry CH2Cl2 (40 mL)
was added to this resin swollen in dry CH2Cl2 and the reaction
mixture was stirred for 40 min at room temperature. The solution
was removed from the resin by filtration and the resin was washed
with CH2Cl2 (3ϫ20 mL), CH2Cl2/CH3OH (8:2) (3ϫ20 mL) and
CH2Cl2 (3 ϫ 20 mL). Evaporation of the combined solvents in
vacuo afforded the expected compound.
(3ЈR,1R,4R,7S)-15a: Colourless oil. [α]2D0 = –20 (c = 1, CH2Cl2); tR
(HPLC, column A, eluent I) = 15.4 min; tR (HPLC, column B,
1
eluent I) = 15.7 min. MS (ESI): m/z = 609.3 [M + H]+. H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.87, 1.05 and 1.17 (3s (10:10:80)*,
6 H, 2CH3), 1.58 (m, 1 H, 8-H), 2.12 (m, 1 H, 8-H), 2.75 (2m, 1
H, 4-H), 2.78 (m, 1 H, 7-H), 2.99 and 3.50 (2m (80:20)*, 1 H, 3-
H), 3.25–3.45 [2m (20:80)*, 1 H, 3-H], 3.46 (d, J = 9.6 Hz, 1 H, 5Ј-
(3ЈR,1R,2S)/(3ЈR,1S,2R)-1-(4-Carbamoylphenyl)-4,4-dimethyl-2-
H), 3.51 (d, J = 9.6 Hz, 1 H, 5Ј-H), 4.97 (d, J = 12.7 Hz, 1 H, oxopyrrolidin-3-yl 2-(Benzyloxycarbonylamino)cyclohex-3-ene-1-
OCHH), 5.02 (d, J = 12.7 Hz, 1 H, OCHH), 5.07 (m, 1 H, 1-H),
5.28 (s, 2 H, OCH2), 5.29 and 5.34 [2s (20:80)*, 1 H, 3Ј-H], 6.42
(m, 2 H, CH=), 7.30 (m, 10 H, H arom.), 7.65 (d, J = 8.9 Hz, 2 H,
H arom.), 8.01 (d, J = 8.9 Hz, 2 H, H arom.) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 20.73 and 20.95 (CH3)*, 24.16 and
carboxylate [(3ЈR,1R,2S)-7c/(3ЈR,1S,2R)-8c]: Synthesized accord-
ing to the general procedure from 1-(benzyloxycarbonylamino)-
buta-1,3-diene (4) (4.61 g, 22.0 mmol, 22 equiv.) by using micro-
wave irradiation at a temperature of 60 °C for 1 h. The expected
pure mixture of two endo amide cycloadducts 7c/8c (0.31 g,
24.43 (CH3)*, 25.35 and 25.49 (C-8)*, 30.11 and 30.20 (C-4)*, 0.61 mmol, 61% yield) was obtained in a 85:15 ratio as a white
37.20 and 37.57 (C-4Ј)*, 44.00 and 44.29 (C-7)*, 47.35 and 47.67
(C-1)*, 48.09 and 48.53 (C-3)*, 57.37 and 57.63 (C-5Ј)*, 66.68
solid after rapid column chromatography on silica gel with ethyl
acetate. tR (HPLC, column A, eluent I) = 11.51 (85%) and 11.65
(OCH2), 78.41 and 78.47 (C-3Ј)*, 118.40 (CH arom.), 125.97 and (15%) min; tR (HPLC, column D) = 69.8 (85%) and 76.6 (15%)
126.03 (C arom.)*, 127.43, 127.76, 127.88, 128.00, 128.18, 128.27,
128.41, 128.47 and 128.62 (CH arom.)*, 128.85 and 128.93 (C
arom.)*, 130.77 (CH arom.), 131.85 and 132.10 (CH=)*, 135.26,
135.33 and 136.07 (C arom.)*, 136.59 and 136.98 (CH=)*, 143.03
and 143.15 (C arom.)*, 155.51, 165.84, 169.43, 169.78, 172.40 and
172.66 (CO)* ppm. HRMS (FAB): calcd. for C36H37N2O7 [MH]+
609.2601; found 609.2583. (* The NMR spectra of this compound
are complicated due to the presence of carbamate rotamers.)
min. MS (ESI): m/z = 505.9 [M + H]+. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.02 and 1.05 [2s (≈85:15), 3 H, CH3], 1.18 (s,
3 H, CH3), 1.92–2.12 (m, 4 H, 5-H and 6-H), 3.02 (br. m, 1 H, 1-
H), 3.42 (d, J = 9.5 Hz, 1 H, 5Ј-H), 3.51 (d, J = 9.6 Hz, 1 H, 5Ј-
H), 4.62 (br. m, 1 H, 2-H), 4.93–5.05 (m, 2 H, OHCHC6H5), 5.30
and 5.33 [2s (≈85:15), 1 H, 3ЈH], 5.58 (br. m, 2 H, CH= and NH),
5.74 (br. m, 1 H, CH=), 6.09–6.40 (br. d, 2 H, NH2), 7.18–7.27 (m,
5 H, H arom.), 7.56 and 7.59 [2d (≈85:15), J = 8.6 Hz, 2 H, H
Eur. J. Org. Chem. 2008, 308–318
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
315

O. Songis, P. Y. Géant, G. Sautrey, J. Martinez, M. Calmès
FULL PAPER
arom.], 7.73 and 7.76 [2d (≈85:15), J = 8.6 Hz, 2 H, H arom.] ppm.
21.23 and 21.34 (CH3)*, 24.57, 24.65 and 24.71 (CH3)*, 25.91,
25.98 and 26.03 (C-8)*, 30.18, 30.38, 30.56 and 30.60 (C-4)*, 37.10
13C NMR (100 MHz, CDCl3, 25 °C): δ = 21.06 and 21.14 (CH3),
22.35 and 22.97 (C-5 and C-6), 24.65 (CH3), 37.25 and 37.28 (C- and 37.22 (C-4Ј)*, 4.85, 44.05 and 44.14 (C-7)*, 46.79, 46.99, 47.06,
4Ј), 43.03 and 43.53 (C-1), 46.81 and 47.29 (C-2), 57.50 (C-5Ј),
66.76 (OCH2C6H5), 78.16 and 78.20 (C-3Ј), 118.62 and 118.78 (CH
47.26 and 47.45 (C-1 and C-3)*, 57.33 and 57.44 (C-5Ј)*, 66.97 and
67.02 (OCH2), 78.20, 78.27 and 78.36 (C-3Ј)*, 118.71 and 118.71
arom.), 126.91 and 127.10 (CH=), 127.94, 127.97 (CH arom.), (CH arom.), 127.42, 127.64, 127.69, 127.74, 127.81, 127.98, 128.26,
128.06 (C arom.), 128.40, 128.49, 128.52, 128.18 (CH arom.),
129.36 and 129.56 (CH=), 136.48, 141.92, 142.06 (C arom.), 155.90,
156.03, 168.79, 169.44, 169.60, 171.19, 172.24, 172.44 (CO) ppm.
128.36, 128.41, 128.49, 128.56, 129.03 and 128.93 (CH arom. and C
arom.)*, 130.20, 130.46, 131.00 and 131.84 (CH=)*, 134.93, 135.40,
136.08 and 136.73 (CH=)*, 136.73 and 136.78 (C arom.)*, 142.07
and 142.12 (C arom.)*, 154.73, 155.29, 168.92, 168.99, 169.20,
169.26, 171.80 and 171.95 (CO)* ppm. HRMS (FAB): calcd. for
C29H32N3O6 [MH]+ 518.2291; found 518.2289. (* The 13C NMR
spectroscopic data concern only the two major diastereoisomers
14c and 16c and are complicated due to the presence of carbamate
rotamers.)
(3ЈR,1R,2R,4S)/(3ЈR,1S,2R,4R)/(3ЈR,1S,2S,4R)/(3ЈR,1R,2S,4S)-1-
(4-Carbamoylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl 1-(Benzyl-
oxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylate
[(3ЈR,1R,2R,4S)-9c/(3ЈR,1S,2R,4R)-10c/(3ЈR,1S,2S,4R)-11c/
(3ЈR,1R,2S,4S)-12c]: Synthesized according to the general pro-
cedure from 1-(benzyloxycarbonylamino)cyclohexa-1,3-diene (5)
(5.04 g, 22.0 mmol, 22 equiv.) by using microwave irradiation at a
temperature of 80 °C for 2 h. The expected pure mixture of the four
cycloadducts 9c/10c/11c/12c was obtained (0.31 g, 0.58 mmol, 58%
yield) in a 30:60:3:7 ratio as a white solid after rapid column
chromatography on silica gel with cyclohexane/AcOEt/acetone
(4:4:2). tR (HPLC, column A, eluent III) = 5.8 (11c and 12c), 6.4
(10c) and 7.9 min (9c). MS (ESI): m/z = 532.2 [M + H]+. 1H NMR
(400 MHz, CDCl3, 25 °C): δ* = 0.91 and 0.97 (35:65) (s, 3 H, CH3),
1.13 and 1.18 (35:65) (s, 3 H, CH3), 1.30–2.16 (m, 4 H, 3-H, 7-H
and 8-H), 2.42 (br. m, 1 H, 7-H), 2.68 (br. m, 1 H, 4-H), 3.30–3.63
(m, 3 H, 2-H and 5Ј-H), 4.90–5.12 (m, 2 H, CH2C6H5), 5.42 and
5.55 (35:65) (s, 1 H, 3Ј-H), 6.08 and 6.10 (35:65) (s, 1 H, NH),
6.26–6.60 (m, 4 H, CH=CH and NH2), 7.06–7.46 (m, 5 H, H
arom.), 7.59 (d, J = 7.9 Hz, 2 H, H arom.), 7.99 (d, J = 7.9 Hz, 2
H, H arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ* = 20.83
and 21.04 (CH3), 23.97 (C-7), 24.23 and 24.41 (CH3), 25.85 and
28.03 (C-8), 28.99 and 29.34 (C-4), 30.14 (C-7), 30.71 (C-3), 37.02
and 37.13 (C-4Ј), 43.57 and 45.12 (C-2), 55.69 and 56.68 (C-1),
57.46 and 57.59 (C-5Ј), 65.99 and 66.13 (OCH2), 78.40 and 78.49
(C-3Ј), 118.70 and 118.83 (CH arom.), 127.45, 127.59, 127.75,
127.98, 128.22, 128.32, 128.56 and 129.24 (CH arom.), 132.41 and
132.57 (C-5), 134.01 (C arom.), 136.44 and 136.51 (C-6), 141.89
(C arom.), 155.52 and 155.59 (NH-CO-O), 168.78, 169.71, 169.92,
173.44 and 173.98 (CO) ppm. HRMS (FAB): calcd. for
C30H34N3O6 [MH]+ 532.2448; found 532.2466. (* The NMR spec-
troscopic data concern only the two major diastereoisomers 9c and
10c.)
General Procedure for the Saponification of Compounds 7c/8c, 9c/
10c/11c/12c or (2R,3ЈR)-22c: A solution of LiOH·H2O (1.2 equiv.)
in water was added dropwise to a solution of compound 7c/8c, 9c/
10c/11c/12c or (2R,3ЈR)-22c in THF and the mixture was stirred at
room temperature until completion of the hydrolysis (4–8 h) (moni-
tored by HPLC, column A, eluent I). The organic solvent was re-
moved in vacuo, saturated aqueous NaHCO3 was added and the
mixture was extracted with ethyl acetate. The aqueous phase was
acidified (pH = 2) and extracted with CH2Cl2. The combined or-
ganic phases were dried with anhydrous Na2SO4 and the solvent
was concentrated in vacuo to afford the crude mixture of the ex-
pected acid and the chiral auxiliary amide. The latter was precipi-
tated by using diethyl ether and removed by filtration.
(1R,2S)/(1S,2R)-2-(Benzyloxycarbonylamino)cyclohex-3-ene-1-
carboxylic Acid [(1R,2S)-17/(1S,2R)-17]: Synthesized according to
the general procedure from the mixture (3ЈR,1R,2S)-7c/
(3ЈR,1S,2R)-8c (85:15) (0.1 g, 0.2 mmol). The expected pure mix-
ture of two endo acids (33 mg, 0.12 mmol, 60% yield) was obtained
in an 85:15 ratio as a colourless oil after column chromatography
on silica gel with CH2Cl2/AcOEt (5:5). The physical properties and
chemical characteristics of the (1R,2S)/(1S,2R)-2-(benzyloxycar-
bonylamino)cyclohex-3-ene-1-carboxylic acids [(1R,2S)-17 and
(1S,2R)-17] are identical to those previously described.[13c]
(1R,2R,4S)/(1S,2R,4R)/(1S,2S,4R)/(1R,2S,4S)-1-(Benzyloxycarbon-
ylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic Acid [(1R,2R,4S)-18/
(1S,2R,4R)-19/(1S,2S,4R)-18/(1R,2S,4S)-19]: Synthesized accord-
ing to the general procedure from the mixture (3ЈR,1R,2R,4S)-9c/
(3ЈR,1S,2R,4R)-10c/(3ЈR,1S,2S,4R)-11c/(3ЈR,1R,2S,4S)-12c
(30:60:3:7) (80 mg, 0.15 mmol). The expected mixture of four acids
(1R,2R,4S)-18/(1S,2R,4R)-19/(1S,2S,4R)-18/(1R,2S,4S)-19 was ob-
tained as a colourless oil in a 30:60:3:7 ratio (28 mg, 0.09 mmol,
61% yield) after column chromatography on silica gel with CH2Cl2/
AcOEt (5:5). The physical properties and chemical characteristics
of the four 1-(benzyloxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-
carboxylic acids [(1R,2R,4S)-18/(1S,2R,4R)-19/(1S,2S,4R)-18/
(1R,2S,4S)-19] are identical to those previously described.[13c]
(3ЈR,1S,4S,7R)/(3ЈR,1R,4R,7R)/(3ЈR,1R,4R,7S)/(3ЈR,1S,2S,4S)-1-
(4-Carbamoylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl 2-(Benzyl-
oxycarbonyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate
[(3ЈR,1S,4S,7R)-13c/(3ЈR,1R,4R,7R)-14c/(3ЈR,1R,4R,7S)-15c/
(3ЈR,1S,2S,4S)-16c]: Synthesized according to the general pro-
cedure from 1-(benzyloxycarbonyl)-1,2-dihydropyridine (6) (4.70 g,
22.0 mmol, 22 equiv.) in the presence of a few crystals of hydroqui-
none by using microwave irradiation at a temperature of 160 °C for
1 h. The expected pure mixture of the four cycloadducts 13c/14c/
15c/16c was obtained (0.26 g, 0.50 mmol, 50% yield) in a 10:52:6:32
ratio as a white solid after rapid column chromatography on silica
gel with CH2Cl2/acetone (7:3). tR (HPLC, column A, eluent IV) =
19.5 (13c), 20.9 (16c) and 22.3 min (14c and 15c). MS (ESI): m/z =
(1R,4R,7R)-2-(Benzyloxycarbonyl)-2-azabicyclo[2.2.2]oct-5-ene-7-
carboxylic Acid [(1R,4R,7R)-21]: A solution of LiOH·H2O
(1.2 equiv.) was added dropwise in water to a solution of compound
518.2 [M + H]+. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.94– (3ЈR,1R,4R,7R)-14a (104 mg, 0.17 mmol) in THF and the mixture
1.19 (7s, 6 H, CH3), 1.60, 1.83 and 2.05 [3m (≈8:84:8), 2 H, 8-H],
was stirred at room temperature until completion (5 h) (monitored
2.66 (br. m, 0.1 H, 7-H), 2.79 (m, 1 H, 4-H), 2.92–3.02 (m, 1 H, 3- by HPLC, column A, eluent I). The organic solvent was removed
H), 3.22 (m, 1.9 H, 3-H and 7-H), 3.34–3.52 (m, 2 H, 5Ј-H), 4.92–
5.17 (s and m, 3 H, OCH2 and 1-H), 5.22, 5.28 and 5.33 [3s
(≈6:84:10), 1 H, 3Ј-H], 6.12–6.45 (m, 4 H, CH=CH and NH2), 7.22
(m, 5 H, H arom.), 7.62 (br. s, 2 H, H arom.), 7.18 (br. s, 2 H, H
arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):* δ = 21.12,
in vacuo, saturated aqueous NaHCO3 was added and the mixture
was extracted with ethyl acetate. The aqueous phase was acidified
(pH = 2) and extracted with CH2Cl2. The combined organic phases
were dried with anhydrous Na2SO4 and the solvent was concen-
trated in vacuo to afford a crude mixture of the expected acid (88%
316
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318

Diels–Alder Reaction of Nonracemic Acrylates and Aminodienes
yield) and about 5% of the compound (R)-1 (NMR analysis) as the
saponification was not totally regioselective. This was submitted to
column chromatography on silica gel with CH2Cl2/ethyl acetate
(5:5) to yield the pure expected acid (1R,4R,7R)-21 (31 mg,
0.11 mmol, 64% yield) as a white solid; m.p. 136 °C. [α]2D0 = –95 (c
= 1.5, CHCl3); tR (HPLC, column A, eluent I) = 8.30 min; tR
11b/12b (1.61 g, 1.0 mmol, 0.615 mmol/g) swollen in dry CH2Cl2
(5 mL). This mixture was stirred under 1 atm of H2 for 24 h at
room temperature. The solution was then removed from the resin
by filtration, the resin was washed with CH2Cl2 (3 ϫ 20 mL),
CH2Cl2/CH3OH (8:2) (3ϫ20 mL), CH2Cl2 (3ϫ20 mL) and diethyl
ether (3ϫ15 mL) and dried under reduced pressure. A 5% TFA
solution in dry CH2Cl2 (40 mL) was added to this resin swollen in
(HPLC, column B, eluent II) = 7.2 min. MS (ESI): m/z = 288.0 [M
1
+ H])+. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.76 (m, 2 H, 8- dry CH2Cl2 and the reaction mixture was stirred for 40 min at
H), 2.78 [2 br. m (70:30)*, 1 H, 4-H], 2.91 (d, J = 10.1 Hz, 1 H, 3-
room temperature. The resin was filtered and washed with CH2Cl2
H), 3.05 (m, 1 H, 7-H), 3.23 (d, J = 10.1 Hz, 1 H, 3-H), 5.08 and (3 ϫ 20 mL), CH2Cl2/CH3OH (8:2) (3 ϫ 20 mL) and CH2Cl2
5.13 [2s (70:30)*, 2 H, OCH2], 5.05 and 5.22 [2m (70:30)*, 1 H,
1-H], 6.25–6.40 [2m (70:30)*, 2 H, CH=], 7.24–7.31 (m, 5 H, H
arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.96 (C-8),
30.37 and 30.58 (C-4)*, 43.72 and 43.97 (C-7)*, 46.59 and 46.99
(C-1)*, 47.09 and 47.36 (C-3)*, 67.03 (OCH2), 127.87, 128.01,
128.50 and 128.62 (CH arom.), 130.30 and 130.82 (CH=)*, 135.13
and 135.57 (CH=)*, 136.65 (C arom.), 154.85 and 155.30 (CO)*,
177.70 and 177.90 (CO)* ppm. HRMS (FAB): calcd. for
C16H18NO4 [MH]+ 288.1236; found 288.1236. (*The NMR spectra
of this compound are complicated due to the presence of carba-
mate rotamers.)
(3ϫ20 mL). Evaporation of the combined solvents in vacuo af-
forded the expected mixture of compounds (3ЈR,2R)-22c and
(3ЈR,2S)-22c in a 90:10 ratio (0.30 g, 0.56 mmol, 56 %). Dia-
stereoisomer (3ЈR,2R)-22c (0.11 g, 0.2 mmol, 20% yield, 99% de)
was isolated as a white solid after flash column chromatography
on silica gel with cyclohexane/ethyl acetate/acetone (5:3:3); m.p.
109 °C; [α]2D0 = –81 (c = 1.7, CH2Cl2); tR (HPLC, column A, eluent
I) = 10.7 min; tR (HPLC, column C) = 7.9 min. MS (ESI): m/z =
1
534.0 [M + H]+. H NMR (400 MHz, CDCl3, 25 °C): δ = 0.94 (s,
3 H, CH3), 1.21 (s, 3 H, CH3), 1.62 and 1.76 (2m, 6H and 3 H, 3-
H, 4-H, 5-H, 6-H, 7-H and 8-H), 2.10 (br. d, J = 13.0 Hz, 1 H, 3-
H), 2.62 (br. s, 1 H, 7-H), 3.36 (d, J = 9.6 Hz, 1 H, 5Ј-H), 3.48 (dd,
J = 10.6 and 3.2 Hz, 1 H, 2-H), 3.54 (d, J = 9.6 Hz, 1 H, 5Ј-H),
4.81 (d, J = 12.5 Hz, 1 H, OHCHC6H5), 4.97 (d, J = 12.5 Hz, 1
H, OHCHC6H5), 5.45 (s, 1 H, 3Ј-H), 5.50 (s, 1 H, NH), 5.50–5.70
(br. d, 2 H, NH2), 6.95–7.28 (m, 5 H, H arom.), 7.57 (d, J = 8.8 Hz,
2 H, H arom.), 7.73 (d, J = 8.8 Hz, 2 H, H arom.) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 20.93 (CH3), 23.63 (C-4), 24.39
(CH3), 25.36, 25.98, 28.38, 29.09, 30.44 (C-3, C-5, C-6, C-7, C-8),
37.01 (C-4Ј), 43.06 (C-2), 52.17 (C-1), 57.58 (C-5Ј), 65.79 (OCH2),
78.33 (C-3Ј), 118.80, 127.46, 127.64, 128.26, 128.41 (CH arom.),
129.20, 136.60, 142.03 (C arom.), 155.20, 160.51, 169.77, 174.59
(CO) ppm. HRMS (FAB): calcd. for C30H36N6O3 [MH]+ 534.2604;
found 564.2625.
Iodocyclization of the endo Isomers of the Four Diels–Alder Cycload-
ducts 13a/14a/15a/16a to Form 8-(Benzyloxycarbonyl)-2-iodo-4-oxa-
8-azatricyclo[4.3.1.03,7]decan-5-one (20): A solution of LiOH·H2O
(35 mg, 1.1 equiv.) in water (1.2 mL) was added dropwise to a mix-
ture of the four Diels–Alder cycloadducts 13a/14a/15a/16a (0.45 g,
0.74 mmol) in THF (5 mL) and the resulting solution was stirred
at room temperature for 5 h (monitored by HPLC, column A, elu-
ent I). The organic solvent was removed in vacuo, saturated aque-
ous NaHCO3 was added (10 mL) and the mixture was extracted
with ethyl acetate (2ϫ20 mL). The aqueous phase was acidified
(pH = 2) and extracted with ethyl acetate (4ϫ20 mL). The com-
bined organic phases were dried with anhydrous Na2SO4 and con-
centrated in vacuo to afford the expected endo/exo acid mixture
(0.20 g, 94% yield) in a 84:16 ratio.[24] A NaHCO3 aqueous solu-
tion (0.185 g, 2.1 mmol, 3 equiv., 3.6 mL), KI (0.67 g, 4.0 mmol)
and I2 (0.31 g, 1.2 mmol) were added to a solution of this mixture
in CH2Cl2 (5.5 mL) at 0 °C. The reaction mixture was stirred at
room temperature for 24 h, poured into aqueous Na2S2O3 (10 mL)
to decompose the excess I2 and extracted with CH2Cl2 (4ϫ5 mL).
The extract was washed (H2O, saturated NaCl), dried (Na2SO4)
and concentrated in vacuo to afford the corresponding iodolactone
mixture 20 as a white solid (0.18 g, 81% yield); tR (HPLC, column
A, eluent I) = 10.1 min. MS (ESI): m/z = 413.9 [M + H]+. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.00 and 2.05 [2m (67:33)*, 1 H, 10-
H], 2.21 and 2.14 [2m (67:33)*, 1 H, 10-H], 2.28 and 2.34 [br. m
(67:33)*, 1 H, 1-H], 2.75 and 2.80 [2dd (67:33)*, J = 10.2 and
5.2 Hz, 1 H, 6-H], 3.33 (m, 1 H, 9-H), 3.95 (d, 1 H, 9-H), 4.31 (br.
s, 1 H, 2-H) 4.70 and 4.85 [2t (67:33)*, J1 = J2 = 5.2 Hz, 1 H, 7-
H], 4.96 and 5.00 [2d (67:33)*, J = 5.5 Hz, 2 H, 3-H], 5.14 (s, 2 H,
OCH2), 7.27 (m, 5 H, H arom.) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 25.14 and 25.56 (C-2)*, 26.87 (C-10), 33.32 and 33.43
(C-1)*, 36.32 and 36.50 (C-6)*, 47.76 and 47.89 (C-9)*, 48.53 and
49.12 (C-7)*, 67.72 and 67.91 (OCH2)*, 127.93, 128.30, 128.52,
128.63 and 128.70 (CH arom.)*, 135.82 and 136.10 (C arom.)*,
154.72 and 155.50 (CO)*, 175.43 and 175.56 (CO)* ppm. HRMS
(FAB): calcd for C16H17NO4 [MH]+ 414.0202; found 414.0196.
(* The NMR spectra of this compound are complicated due to the
presence of carbamate rotamers.)
(R)-1-(Benzyloxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylic
Acid [(R)-23]: Synthesized according to the general saponification
procedure from compound (3ЈR,2R)-22c (82 mg, 0.15 mmol). The
expected pure compound (R)-23 (24 mg, 52% yield) was obtained
as a colourless oil after column chromatography on silica gel with
CH2Cl2/AcOEt (5:5). [α]2D0 = –78 (c = 2.4, CH2Cl2); tR (HPLC,
column A, eluent I) = 9.3 min. MS (ESI): m/z = 304.0 [M + H]+.
1H NMR (400 MHz, CD3CN, 25 °C): δ = 1.66 and 1.93 (2m, 6 H
and 4 H, 3-H, 4-H, 5-H, 6-H, 7-H and 8-H), 2.35 (m, 1 H, 7-H),
3.36 (ddd, J = 10.5, 6.2 and 2.0 Hz, 1 H, 2-H), 4.99 (d, J = 12.8 Hz,
1 H, OHCHC6H5), 5.07 (d, J = 12.8 Hz, 1 H, OHCHC6H5), 5.50
(s, 1 H, NH), 7.37 (m, 5 H, H arom.) ppm. 13C NMR (100 MHz,
CD3CN, 25 °C): δ = 23.76 (C-4), 25.40, 25.48, 27.08, 29.73, 30.30
(C-3, C-5, C-6, C-7, C-8), 42.81 (C-2), 51.51 (C-1), 65.28 (OCH2),
127.47, 127.71, 128.40 (CH arom.), 137.57 (C arom.), 154.87,
175.52 (CO) ppm. HRMS (FAB): calcd. for C17H22N4O [MH]+
304.1549; found 304.1550.
[1] a) J. S. Fruchtel, G. A. Jung, Angew. Chem. Int. Ed. Engl. 1996,
35, 17–42; b) S. J. Shuttleworth, S. M. Allin, P. K. Sharma,
Synthesis 1997, 1217–1239; c) R. C. Brown, J. Chem. Soc. Per-
kin Trans. 1 1998, 3293–3320; d) C. Blackburn, F. Albericio,
S. A. Kates, Drugs Future 1997, 22, 1007–1025; e) B. A.
Lorsbach, M. J. Kurth, Chem. Rev. 1999, 99, 1549–1581; f) S. J.
Shuttleworth, S. M. Allin, R. D. Wilson, D. Nasturica, Synthe-
sis 2000, 1035–11074; g) P. Cironi, M. Alvarez, F. Albericio,
Mini.-Rev. Med. Chem. 2006, 6, 11–25.
(3ЈR,2R)-1-(4-Carbamoylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl
1-(Benzyloxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylate
[(3ЈR,2R)-22c]: Wilkinson’s catalyst (0.14 mg, 0.15 equiv., 15%) was
added to the Rink amide supported cycloadduct mixture 9b/10b/
[2] For a general review of synthetic solid-supported chiral ligands
or catalysts, see: a) B. Clapham, T. S. Reger, K. D. Janda, Tetra-
hedron 2001, 57, 4637–4662; b) Q.-H. Fan, Y.-M. Li, A. S. C.
Eur. J. Org. Chem. 2008, 308–318
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
317

O. Songis, P. Y. Géant, G. Sautrey, J. Martinez, M. Calmès
FULL PAPER
Chan, Chem. Rev. 2002, 102, 3385–3466; c) M. Benglia, A. Pu-
glisi, F. Cozzi, Chem. Rev. 2003, 103, 3401–3429.
[3] For a general review of synthetic solid-supported chiral auxilia-
ries, see: C. W. Y. Chung, P. H. Toy, Tetrahedron: Asymmetry
2004, 15, 387–399.
[4] For general review of Diels–Alder reactions on solid supports,
see: J. Y. Kauhaluoma, Tetrahedron 2001, 57, 7053–7071.
[5] For examples, see: a) V. Yedidia, C. C. Leznoff, Can. J. Chem.
1980, 58, 1144–1150; b) M. Crawshaw, N. W. Hird, Tetrahedron
Lett. 1997, 38, 7115–7118; c) J. D. Winkler, Y.-S. Kwak, J. Org.
Chem. 1998, 63, 8634–8635; d) D. A. Heerding, D. T. Takata,
C. Kwon, W. F. Huffman, J. Samanen, Tetrahedron Lett. 1997,
38, 6815–6818; e) K. Paulvannan, Tetrahedron Lett. 1999, 40,
1851–1854; f) B. A. Burkett, C. L. L. Chai, Tetrahedron Lett.
1999, 40, 7035–7038; g) J. R. Morphy, Z. Rankovic, M. York,
Tetrahedron Lett. 2002, 43, 5973–5975.
[6] a) W. Carruthers in Tetrahedron Organic Chemistry Series. Cy-
cloaddition Reaction in Organic Synthesis, Pergamon Press, Ox-
ford, 1990, vol. 8; b) F. Fringuelli, A. Tatichi, The Diels–Alder
Reaction: Selected Practical Methods, Wiley-VCH, Weinheim,
2002; c) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassi-
likogiannakis, Angew. Chem. Int. Ed. 2002, 41, 1669–1698.
[7] R. H. Schlessinger, C. P. Bergstrom, Tetrahedron Lett. 1996, 37,
2133–2136.
[17]
a) M. E. Kuehne, I. Marko, Syntheses of Vinblastine-type Alka-
loids in The Alkaloids. Antitumor Bisindole Alkaloids from Ca-
tharanthus roseus (L.) (Eds.: A. Brossi, M. Suffness), Aca-
demic Press, San Diego, 1990, vol. 37, pp. 77–131; b) P. Popik,
P. Skolnick, Pharmacology of Ibogaine and Ibogaine-related Al-
kaloids in The Alkaloids. Chemistry and Biology (Ed.: G. A.
Cordell), Academic Press, San Diego, 1999, vol. 52, pp. 197–
231; c) S. D. Glick, I. M. Maisonneuve, K. K. Szumlinski,
Mechanisms of Action of Ibogaine: Relevance to Putative Thera-
peutic Effects and Development of a Safer Iboga Alkaloid Con-
gener in The Alkaloids (Eds.: K. R. Alper, S. D. Glick, G. A.
Cordell), Academic Press, San Diego, 2001, vol. 56, pp. 39–53.
a) H. Rink, Tetrahedron Lett. 1987, 28, 3787–3790; b) M. S.
Bernatowicz, S. B. Daniels, H. Köster, Tetrahedron Lett. 1989,
30, 4645–4648.
C. E. Cannizzaro, J. A. Ashley, K. D. Janda, K. N. Houk, J.
Am. Chem. Soc. 2003, 125, 2489–2506.
[18]
[19]
[20]
[21]
S. Kobayashi, K. A. Jorgensen, Cycloaddition reactions in or-
ganic synthesis, Wiley-VCH, Weinheim, 2002.
a) J. P. Tierney, P. Lidström (Eds.), Microwave-assisted organic
synthesis, Backwell Scientific, New York, 2004; b) C. O. Kappe,
A. Stadler, Microwaves in organic and medicinal chemistry,
Wiley-VCH, Weinheim, 2005, vol. 25; c) A. Loupy, Microwaves
in organic synthesis, Wiley-VCH, Weinheim, 2005, vols. 1 and
2, and references cited therein.
When this experiment was carried out at 60 °C, no reproducible
results were obtained due to the heterogeneous reaction me-
dium; the melting point of the diene is 72 °C.
[8] S. Wendeborn, A. De Mesmaeker, W. K.-D. Brill, Synlett 1998,
865–868.
[22]
[23]
[9] M. D. Corbridge, C. R. McArthur, C. C. Leznoff, Reactive
Polymers 1988, 8, 173–188.
[10] J. D. Winkler, W. Mc Coull, Tetrahedron Lett. 1998, 39, 4935–
4936.
[11] a) S. Sun, W. V. Murray, J. Org. Chem. 1999, 64, 5941–5945; b)
S. Sun, I. J. Turchi, D. Xu, W. V. Murray, J. Org. Chem. 2000,
65, 2555–2559.
Determined by HPLC analysis as described previously in
ref.[13c]
[24] Determined by chiral HPLC analysis as described in the Exp.
Section.
[12] a) R. Akkari, M. Calmès, N. Mai, M. Rolland, J. Martinez, J.
Org. Chem. 2001, 66, 5859–5965; b) R. Akkari, M. Calmès, D.
Di Malta, F. Escale, J. Martinez, Tetrahedron: Asymmetry
2003, 14, 1223–1228; c) R. Akkari, M. Calmès, N. Barthes, F.
Escale, J. Martinez, Tetrahedron: Asymmetry 2005, 16, 2179–
2185.
[13] a) R. Akkari, M. Calmès, J. Martinez, Eur. J. Org. Chem. 2004,
2441–2450; b) R. Akkari, M. Calmès, F. Escale, J. Iapichella,
M. Rolland, J. Martinez, Tetrahedron: Asymmetry 2004, 15,
2515–2525; c) M. Calmès, C. Didierjean, J. Martinez, O.
Songis, Tetrahedron: Asymmetry 2005, 16, 2173–2178; d) O.
Songis, C. Didierjean, J. Martinez, M. Calmès, Eur. J. Org.
Chem. 2007, 3166–3172.
[25] a) M. M. Campbell, M. Sainsbury, P. A. Searle, Tetrahedron
Lett. 1992, 33, 3181–3184; b) M. M. Campbell, H. S. Rabiasz,
M. Sainsbury, P. A. Searle, Tetrahedron 1992, 48, 9363–9372; c)
J.-F. Morelli, A. Pouilhès, Y. Langlois, Tetrahedron 1997, 53,
5195–5216.
[26] These bicyclic amino acids have only one asymmetric carbon
atom.
[27] a) L. A. Paquette (Ed.), Encyclopedia of reagents for organic
synthesis, Wiley, 1995, vol. 2, pp. 1253–1261, and references
cited therein; b) for one of the few examples of previous uses
of Wilkinson’s catalyst for hydrogenation on solid supports,
see: A. Speicher, T. Backes, S. Grosse, Tetrahedron 2005, 61,
11692–11696.
[14] P. J. Jessup, C. B. Petty, J. Roos, L. E. Overman, Org. Synth.
1980, 59, 1–9.
[15] a) H. Graden, J. Hallberg, N. Kann, J. Comb. Chem. 2004, 6,
783–788; b) V. E. Gouverneur, K. N. Houk, B. Pascal-Teresa,
B. Beno, K. D. Janda, R. A. Lerner, Science 1993, 262, 204–
208.
[28] It has been reported that the reaction rate of the hydrogenation
of olefins catalyzed by Wilkinson’s catalyst can be influenced
by solvents.
[29] The optical rotation of the free β-amino acid 23 obtained after
hydrogenolysis of compound (3ЈR,2R)-22c is in good accord
with the value previously measured, see ref.[13d]
Received: July 23, 2007
[16] R. J. Sundberg, J. D. Bloom, J. Org. Chem. 1981, 46, 4836–
4842.
Published Online: October 17, 2008
318
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 308–318