Asymmetric diels-alder cycloaddition of 1-aminocyclohexadiene to chiral acrylate: Synthesis of enantiopure bridgehead-aminobicyclo[2.2.2]octane-2- carboxylic acid derivatives

Article abstract of DOI:10.1002/ejoc.200700236

The acrylate derivative of the (R)-4-(3-hydroxy-4,4-dimethyl-2- oxopyrrolidin-1-yl)benzoic acid benzyl ester (R)-2 reacted with 1-(benzyloxycarbonylamino)cyclohexadiene 3 under microwave irradation in solvent-free conditions to yield [4+2] cycloadducts in

Full text of DOI:10.1002/ejoc.200700236

FULL PAPER
DOI: 10.1002/ejoc.200700236
Asymmetric Diels–Alder Cycloaddition of 1-Aminocyclohexadiene to Chiral
Acrylate: Synthesis of Enantiopure Bridgehead-Aminobicyclo[2.2.2]octane-2-
carboxylic Acid Derivatives
Olivier Songis,[a] Claude Didierjean,[b] Camille Laurent,[a] Jean Martinez,[a] and
Monique Calmès*[a]
Keywords: Asymmetric synthesis / Diels–Alder reactions / Chiral auxiliaries / Bicyclic β-amino acids / Microwave activation
The acrylate derivative of the (R)-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl)benzoic acid benzyl ester (R)-2 reacted
5-ene-2-carboxylic acid [(1S,2R,4R)-4], (1R,2R,4S)-1-(benzyl-
oxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid
[(1R,2R,4S)-5] and (R)-1-aminobicyclo[2.2.2]octane-2-carbox-
ylic acid [(R)-6]. This work has led to the preparation of these
enantiopure bicyclic β-amino acids and provides a rare ex-
ample of an asymmetric Diels–Alder reaction by microwave
activation.
with 1-(benzyloxycarbonylamino)cyclohexadiene
3 under
microwave irradation in solvent-free conditions to yield [4+2]
cycloadducts in good yields (91%). The reaction proceeded
with moderate endo selectivity (67%) and good facial selec-
tivity (90%). The major cycloadducts were isolated and
transformed to afford three enantiopure bicyclic β-amino ac- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ids: (1S,2R,4R)-1-(benzyloxycarbonylamino)bicyclo[2.2.2]oct-
Germany, 2007)
found that the acrylate derivative (S)- or (R)-2 is an efficient
Introduction
chiral dienophile.[8]
Conformationally constrained amino acids[1] are of great
interest owing to their dominant role in both synthetic and
medicinal chemistry. Incorporation of constrained cyclic
amino acids into peptides or peptidomimetics induces con-
formational restriction and produces significant structural
effects that can be used for structural and biomechanistic
investigations.[2,3]
In this context, the synthesis of new sterically con-
strained cyclic amino acids in an enantiomerically pure
form is particularly attractive. We have focused our atten-
tion on bicyclic amino acids possessing a bicyclo[2.2.2]-
octane structure; the interest in these compounds is high-
lighted by the publication of several investigations in recent
years.[4–7] Some of these synthetic derivatives exhibit notice-
able biological activities; for example, 2-aminobicyclo-
[2.2.2]octane-2-carboxylic acids selectively disturb levels of
neutral amino acids in the cerebral cortex,[5] while dihydrox-
ylated 1-aminobicyclo[2.2.2]octane-4-carboxylic acids have
been used as scaffolds for antiviral agents.[6]
In the study herein reported, the asymmetric Diels–Alder
cycloaddition of 1-(benzyloxycarbonylamino)cyclohexa-
diene 3 to the acrylate derivative (R)-2 was examined with
a view to preparing enantiopure bicyclic β-amino acids
bearing an amino group at the bridgehead: 1-(benzyloxy-
carbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acids (4
and 5) and 1-aminobicyclo[2.2.2]octane-2-carboxylic acid
(6). These compounds combine the particular structural
properties of constrained cyclic amino acids[1c,1d] and those
of β-amino acids that are more resistant than α-amino acids
to enzymatic degradation.[9]
We have previously reported the preparation of a new
chiral auxiliary, the (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl)benzoic acid [(S)- or (R)-1], and have
[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
[b] Laboratoire de Cristallographie et de Modélisation des Ma-
tériaux Minéraux et Biologiques, UMR UHP-CNRS 8036,
B. P. 239, 54506 Vandoeuvre lès Nancy, France
3166
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3166–3172

Diels–Alder Cycloaddition of Aminocyclohexadiene to Acrylate
FULL PAPER
When the acrylate derivative 2 reacted with the 1-(benzyl-
oxycarbonylamino)cyclohexadiene 3 (4 equiv.) in toluene at
room temperature, 80% of the starting material was con-
sumed after 96 h and no residual diene was observed.
Analysis of the crude reaction (HPLC and LC/MS) showed
the formation of a mixture of the four expected cyclo-
adducts, with the two diastereoisomers 7 (30%) and 8
(60%) predominating (Table 1, entry 1).
The following experiments (Table 1, entries 2–4) under-
lined both the low reactivity of the reacting partners and
the instability of the aminodiene 3 under thermal condi-
tions.
Racemic endo and exo 1-aminobicyclo[2.2.2]oct-5-ene-2-
carboxylic acid derivatives have previously been obtained
by Diels–Alder reaction between protected 1-aminocy-
clohexadiene and dimethylacrylamide.[7] These compounds
have been used as precursors to generate antibodies capable
of catalysing Diels–Alder cycloaddition reactions and to
control the stereochemistry of the reaction.[7]
Although Lewis acid catalysts generally allow the Diels–
Alder reactions to proceed with satisfactory yields and a
high level of stereoselectivity,[11] the use of a variety of such
catalysts (TiCl4, AlEtCl2, [Sc(OTf)3]) was accompanied by
diene decomposition (Table 1, entry 8).[12] To suppress this
decomposition, we tested the simultaneous use of hindered
bases to buffer the reaction medium. We examined the reac-
tion of the acrylate (R)-2 with the protected aminodiene 3
using ethylaluminium dichloride (AlEtCl2) as catalyst and
various quantities of di-tert-butylpyridine, present in the re-
action mixture prior addition of the Lewis acid. The reac-
tion with AlEtCl2 and 0.5 equiv. of di-tert-butylpyridine re-
sulted in decomposition of the diene with no formation of
cycloadducts (Table 1, entry 9). On the other hand, adding
a large excess of this base suppressed the decomposition of
the aminodiene and led to the total consumption of the
acrylate within 2 h with the formation of only the two dia-
stereoisomers 8 and 10 (Table 1, entry 10). The dramatically
increased rate of reaction and the different diastereoiso-
To the best of our knowledge there is no example of the
asymmetric version of this cycloaddition reaction.
Results and Discussion
The 1-(benzyloxycarbonylamino)cyclohexadiene 3 was
obtained from the cyclohexa-1,3-dienecarboxylic acid[10] via
formation of the acyl azide followed by Curtius rearrange-
ment at 110 °C and subsequent trapping with benzyl
alcohol.[7] The enantiopure (R)-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl)benzoic acid [(R)-1] and the corre-
sponding acrylate benzyl ester (R)-2 were prepared as de-
scribed previously.[8b]
The results of the Diels–Alder reactions between (R)-2 meric ratios observed with respect to our first experiment,
and 3 (Scheme 1) are summarized in Table 1 (entries 1–16). pointed to both the beneficial effect of AlEtCl2 and the ef-
Scheme 1. Diels–Alder reaction between the acrylate (R)-2 and the (Z-amino)diene 3.
Eur. J. Org. Chem. 2007, 3166–3172
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O. Songis, C. Didierjean, C. Laurent, J. Martinez, M. Calmès
FULL PAPER
Table 1. Diels–Alder reaction of the aminodiene 3 with the acrylate (R)-2.[a]
Ratio[c] of
7/8/9/10
Entry
T [°C]
Additive (equiv.)
3 (equiv.)
Solvent[a]
Time [h]
Conversion [%][b]
1
2
3
4
5
6
7
8
room temp.
80
80
110
160
80
room temp.
room temp.
–
–
–
–
–
–
4
4
4
4
4
2
4
4
toluene
toluene
CH3CN
toluene
toluene
–
96
15
15
15
15
15
96
1
80[d,e]
35[e,f]
30:60:3:7
30:60:3:7
30:60:3:7
30:60:3:7
30:60:3:7
30:60:3:7
17:65:3:15
–
50[e,f]
50[d,e]
Ͼ99[d,e]
55[e,f]
4  LiNTf2 (18)
TiCl4 (0.1 or 1), AlEtCl2 (1 or 2),
acetone
CH2Cl2
40[d,e]
[d]
–
Sc(OTf)3 (0.1 or 1)
AlEtCl2 (2), base (1)
AlEtCl2 (2), base (4)
[Eu(fod)3] or [Yb(fod)3] (1)
–
–
–
–
–
[d]
9
room temp.
room temp.
room temp.
MW 80
MW 110
MW 160
MW 80
4
4
4
4
4
4
2
4
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
–
2
2
–
10
11
12
13
14
15
16
Ͼ99[e,g]
75[d,e]
15
0:78:0:22
30:60:3:7
30:60:3:7
30:60:3:7
24:50:8:18
30:60:3:7
30:60:3:7
96
1.5
1.5
1.5
2
33
Ͼ99
Ͼ99
Ͼ99
MW 80
–
1.5
[a] Acrylate concentration = 0.2 . [b] Determined by HPLC analysis and based on acrylate disappearance. [c] See ref.[16] [d] No residual
diene was observed. [e] Side-products were formed. [f] A little residual diene was detected. [g] The results were irreproducible.
fective role of a large excess of di-tert-butylpyridine which at the same temperature no difference in the selectivity was
acted without interfering with the Lewis acid, as described observed (Table 1, entries 5 and 14). This underlines the
previously.[13]
dramatic effect of microwave activation in solvent-free con-
In an attempt to increase the stereoselectivity of the reac- ditions. Another important feature was the cleanness of the
tion, we investigated the use of mild Lewis acid catalysts crude reaction medium which allowed easier purification
such as the lanthanide complexes [Eu(fod)3] or [Yb(fod)3], and separation of the diastereomers obtained than is the
which may be appropriate when the cycloaddition reaction case when the reaction is carried out at room temperature
involves acid-sensitive reagents.[11c,14] Under these condi- or under thermal or catalytic conditions.
tions decomposition of the diene was avoided, but both the
Finally, even if we did not observe an enhancement of
reaction rate and the diastereoisomeric ratio were compar- the Diels–Alder reaction in a concentrated lithium salt solu-
able to those in the absence of Lewis acid catalyst (Table 1, tion, which is the classic effect of this polar medium,[11c]
entries 1 and 11).
we achieved a modification of the diastereoisomeric ratios,
Among various other conditions that have been reported probably as a result of the Lewis acid character of the lith-
to favour the Diels–Alder reaction,[11] we also tested the use ium ion which should favour the more polar transition state
of microwave activation (MW) and the use of a polar me- (Table 1, entry 7).
dium such as concentrated solutions of lithium trifluorome-
thanesulfonimide (LiNTf2).
The two major Diels–Alder adducts 7 and 8 formed under
microwave activation in solvent-free conditions were isolated
Several Diels–Alder cycloaddition reactions have been in pure form after two consecutive column chromatographic
studied under the action of microwave irradiation, often af- runs on silica gel. When starting from the crude obtained
fording reduced reaction times, increased yields and the at room temperature or under thermal conditions a smaller
suppression of side-product formation.[15] The microwave- quantity of each diastereoisomer 7 and 8 was obtained, even
assisted cycloaddition reaction between the chiral acrylate after an additional chromatographic run. Attempts to isolate
(R)-2 and the aminodiene 3 at 160 °C in acetonitrile or at the pure minor adducts 9 and 10 by column chromatography
80 °C in solvent-free conditions was significant (Table 1, en- failed, even for compound 10 when starting from the 78:22
tries 14–16). We observed total consumption of the acrylate mixture of 8 and 10 obtained when using AlEtCl2/di-tert-
with formation of the cycloadducts within 1.5 h (or 2 h butylpyridine (Table 1, entry 10).
when using 2 equiv. of the diene), whereas under classical
Notably, microwave irradiation in solvent-free conditions
thermal reaction conditions (Table 1, entries 2, 3 and 5) or at 80 °C are the best experimental conditions for this Diels–
in solvent-free conditions without microwave irradiation Alder reaction, affording cleanly and in reproducible good
(Table 1, entry 6), moderate-to-good conversions were ob- yield, two separable optically pure cycloadducts.
tained after 15 h with considerable decomposition of the
Concerning the endo/exo or facial selectivity of the reac-
residual aminodiene making the final purification step diffi- tion, we first determined the relative stereochemistry of
1
cult. When the reaction was carried out in acetonitrile at 80 these two compounds on the basis of H NMR analysis
or 110 °C instead of 160 °C (Table 1, entries 12 and 13), after assignment of the signals by H,H and C,H COSY
only a low yield was obtained within 1.5 h. On the other spectroscopy.
hand, lower selectivity was observed at 160 °C with micro-
wave activation, whereas under classical thermal conditions NMR spectra of compounds 7 and 8 indicating that there
There were some significant differences in the 1H and 13
C
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Eur. J. Org. Chem. 2007, 3166–3172

Diels–Alder Cycloaddition of Aminocyclohexadiene to Acrylate
FULL PAPER
are different spatial interactions in these two compounds.
This is particularly the case for the protons that interact
with the CO2R group. The 6-H signal of compound 8 is at
6.0 ppm, whereas it is at 6.5 ppm for compound 7. The 7a-
H signals are at 2.35 and 1.9 ppm, respectively. On the other
hand, the 5-H signals of compounds 7 and 8 have similar
chemical shifts.
We observed the presence of a NOE effect between the
2-H and 7a-H protons in compound 8 (Figure 1), indicating
that these two atoms are in close proximity as a result of
an endo cycloaddition reaction. Conversely, as no NOE ef-
fect was observed between the 2-H and 7a-H protons of
compound 7, it can be assumed that this compound results
from exo selectivity.
Figure 2. ORTEP drawing of adduct 8.
compared with that obtained from the chiral experiment.
The HPLC trace of the mixture of bicyclic β-amino acids 4
and 5 showed that all four stereoisomers were separable on
the chiracel OD column.
Palladium-catalysed hydrogenation of the double bond
concomitant with hydrogenolysis of the carbamate moiety
of the acid (1S,2R,4R)-4 yielded the bicyclic β-amino acid
(R)-6 with only one asymmetric carbon atom (Scheme 2).
To establish the absolute configuration of the pure com-
pound 7 and to obtain the corresponding bicyclic β-amino
acids, we followed the transformation route developed for
Figure 1. NOE relationships for compounds 7 and 8.
The stereochemistry of the endo adduct 8 that crys- the endo (3ЈR,1S,2R,4R)-8 adduct. LiOH hydrolysis of com-
tallized from diethyl ether/petroleum ether was confirmed pound 7 at room temperature (Scheme 2) yielded bicyclic β-
unambiguously by X-ray diffraction analysis (Figure 2).[17] amino acid 5 possessing different HPLC profile and NMR
Furthermore, from the known (R) configuration of the chi- spectra to those of compound 4. Palladium-catalysed hy-
ral auxiliary, the absolute configuration of the newly gener- drogenation of the acid 5 yielded the corresponding bicyclic
ated stereocentres was also determined and indicated that β-amino acid which has the same specific rotation sign and
the major adduct 8 has the (3ЈR,1S,2R,4R) configuration value as that of compound (R)-6 obtained from 8, showing
resulting from endo selectivity at the Cα Si face. Unfortu- that the (R) enantiomer was also obtained. The stereochem-
nately, compound 7, could not be crystallized and was ob- istry of this bicyclic β-amino acid allowed us to establish
tained as a colourless oil.
the (1R,2R,4S) configuration for compound 5 and the
LiOH hydrolysis of compound (3ЈR,1S,2R,4R)-8 at room (3ЈR,1R,2R,4S) configuration for compound 7 resulting
temperature yielded the enantiopure (1S,2R,4R)-1-(benzyl- from an exo selectivity, the reaction always occurring on the
oxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid Cα Si face of the chiral dienophile.
[(1S,2R,4R)-4] (Scheme 2). To control the optical purity of
These results show that despite the moderate endo/exo
4 and to ensure that no epimerization had occurred during selectivity and due to a good facial selectivity induced by
removal of the chiral auxiliary, we performed the Diels– the chiral auxiliary (R)-2, when the only required com-
Alder reaction with racemic acrylate (SR)-2. This afforded pound was the bicyclic β-amino acid (R)-6, it could be ob-
a racemic mixture; the HPLC profile of this mixture was tained directly in good yield from a mixture of adducts 7
Scheme 2. Synthesis of β-amino acid (R)-6. Reagents: (a) LiOH, H2O, THF; (b) H2, 10% Pd/C, CH3OH.
Eur. J. Org. Chem. 2007, 3166–3172
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O. Songis, C. Didierjean, C. Laurent, J. Martinez, M. Calmès
FULL PAPER
toluene extracts were dried with anhydrous magnesium sulfate and
concentrated to a volume of 25 mL. Caution: Acyl azides are po-
tentially explosive. The solution should not be evaporated to dry-
ness and the rotary evaporator should be placed in a fume hood
with the water bath at 40–50 °C. This acyl azide solution was then
added over 20 min to a stirred solution of benzyl alcohol (4.7 mL;
0.046 mol, 1.0 equiv.) in refluxing dry toluene (20 mL). After re-
fluxing for an additional 30 min, the toluene was removed in vacuo
to afford a yellow oily residue. This was purified by chromatog-
raphy on silica gel by using cyclohexane/acetone (9:1) as eluent (Rf
= 0.4) to yield the pale yellow semi-solid diene 3 (6.3 g, 60% yield).
tR (HPLC column A) = 8.3 min. 1H NMR (400 MHz, CD3CN,
25 °C): δ = 2.15–2.35 (m, 4 H, CH2), 5.12 (s, 2 H, OCH2), 5.53–
5.58 (dt, J = 9.3 Hz, 2.9 Hz, 1 H, 4-H), 5.92–5.97 (ddt, J = 9.3 Hz,
5.9 Hz, 1.7 Hz, 1 H, 3-H), 6.20 (d, J = 5.9 Hz, 1 H, 2–2), 7.10 (s,
1 H, NH), 7.30–7.50 (m, 5 H, H arom.) ppm. 13C NMR (100 MHz,
CD3CN, 25 °C): δ = 22.6 (C-5), 25.7 (C-6), 65.7 (OCH2), 104.2 (C-
2), 120.1 (C-4), 124.5 (C-3), 127.8, 128.0, 128.5 (CH arom.), 134.0
(C-1), 136.6 (C arom.), 152.7 (CO) ppm.
and 8. The enantiomer (S)-6 was easily obtained by the
same cycloaddition reaction by using the chiral auxiliary
(S)-2.
Conclusions
In this study we have established strategies for the synthe-
sis of some enantiopure bicyclic β-amino acids bearing an
amino group at the bridgehead. We have demonstrated that
benzyl (R)-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-
1-yl)benzoate [(R)-2] can be used as a chiral dienophile for
the asymmetric synthesis of 1-aminobicyclo[2.2.2]octane-2-
carboxylic acid derivatives. These syntheses constitute both
the first preparation of these enantiopure bicyclic β-amino
acids and a rare example of an asymmetric Diels–Alder re-
action under microwave activation. Further studies con-
cerning the transformation of these aminobicyclo[2.2.2]oct-
5-ene and -octane derivatives are now in progress.
(3ЈR,1R,2R,4S)- and (3ЈR,1S,2R,4R)-[N-(4-Benzyloxycarbonyl-
phenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl]
1-(Benzyloxycarbonyl-
amino)bicyclo[2.2.2]oct-5-ene-2-carboxylate [(3ЈR,1R,2R,4S)-7 and
(3ЈR,1S,2R,4R)-8]: A mixture of 1-(benzyloxycarbonylamino)cy-
clohexa-1,3-diene (3) (3.89 g, 17.0 mmol, 2 equiv.) and benzyl (R)-
4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate [(R)-
2] (3.32 g, 8.5 mmol, 1 equiv) was heated by microwave irradiation
at 80 °C (initial power 300 W) for 2 h. After cooling, the crude
product, which contained a 30:60:3:7 mixture of the four cycload-
ducts 7/8/9/10, was obtained. This was purified by rapid column
chromatography on silica gel using cyclohexane/ethyl acetate (7:3)
as eluent to yield a pure mixture of the cycloadducts in 90.6% yield
(4.81 g, 7.7 mmol). Diastereoisomers (3ЈR,1R,2R,4S)-7 (0.94 g,
1.5 mmol, 19.5% yield, Rf = 0.32, 99% de) and (3ЈR,1S,2R,4R)-8
(1.60 g, 2.6 mmol, 33.5% yield, Rf = 0.22, 99% de) were isolated
after being subjected to flash column chromatography on silica gel
twice using diethyl ether/petroleum ether (4:6) as eluent.
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. Optical rotations were measured with a Perkin-Elmer 341
polarimeter. 1H and 13C NMR spectra (DEPT, 1H/13C 2D corre-
lations) were recorded with a Bruker A DRX 400 spectrometer
using the solvent as internal reference. Data are reported as follows:
chemical shifts (δ) in parts per million, coupling constants (J) in
hertz (Hz). The ESI mass spectra were recorded with a platform II
quadrupole mass spectrometer (Micromass, Manchester, UK) fit-
ted with an electrospray source. HPLC analyses were performed
with a Waters model 510 instrument or a Beckman System Gold
126 instrument with variable detector using one of two columns;
column A: Nucleosil C18, 3.5 µ, (50ϫ4.6 mm), flow: 1 mL/min,
H2O (0.1% TFA)/CH3CN (0.1% TFA), gradient 0Ǟ100% (15 min)
and 100% (4 min); column B: Chiracel OD, flow: 1 mL/min, eluent
I: hexane/2-propanol: 85:15; eluent II: hexane (0.1% TFA)/2-pro-
panol (0.1% TFA) 90:10. Microwave activation was performed with
a Biotage Initiator 2.0 instrument.
Crystallisation of an aliquot of compound (3ЈR,1S,2R,4R)-8 from
diethyl ether/petroleum ether yielded colourless crystals suitable for
X-ray analysis.
(3ЈR,1R,2R,4S)-7: Colourless oil. [α]2D0 = –68 (c = 1.1, CH2Cl2); tR
(HPLC, column A) = 16.3 min; tR (HPLC, column B, eluent I) =
24.9 min. IR (KBr): ν = 3334 (m), 1727 (s), 1710 (s), 1689 (s) cm–1.
˜
1
MS (ESI): m/z = 623.2 [M + H]+. H NMR (400 MHz, CD3CN,
25 °C): δ = 0.91 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.30 (m, 2 H, 7-
H, 8-H), 1.55 (m, 1 H, 3-H), 1.72 (m, 1 H, 8-H), 1.86 (m, 1 H, 7-
H), 2.06 (m, 1 H, 3-H), 2.54 (m, 1 H, 4-H), 3.23 (br. d, J = 10.9 Hz,
1 H, CHCO), 3.35 (d, J = 9.6 Hz, 1 H, 5Ј-H), 3.56 (d, J = 9.6 Hz,
1 H, 5Ј-H), 4.85 (d, J = 12.5 Hz, 1 H, OHCHC6H5), 5.04 (d, J =
12.5 Hz, 1 H, OHCHC6H5), 5.30 (s, 2 H, OCH2C6H5), 5.49 (s, 1
H, 3Ј-H), 5.99 (s, 1 H, NH), 6.21 (t, J1 = J2 = 6.5 Hz, 1 H, CH=),
6.52 (d, J = 6.5 Hz, 1 H, CNCH=), 6.95–7.40 (m, 10 H, H arom.),
7.59 (d, J = 8.9 Hz, 2 H, H arom.), 7.99 (d, J = 8.9 Hz, 2 H, H
arom.) ppm. 13C NMR (100 MHz, CD3CN, 25 °C): δ = 20.83
(CH3), 23.97 (C-7), 24.31 (CH3), 28.04 (C-8), 29.02 (C-4), 30.74 (C-
3), 37.03 (C-4Ј), 43.58 (C-2), 55.71 (C-1), 57.62 (C-5Ј), 65.97
(OCH2), 66.74 (OCH2), 78.44 (C-3Ј), 118.59 (CH arom.), 126.20
(C arom.), 127.46, 127.68, 128.18, 128.26, 128.31, 128.65, 130.80
(CH arom.), 132.55 (C-5), 136.05 (C arom.), 136.33 (C-6), 136.48,
142.86 (C arom.), 155.71 (NH-CO-O), 165.83 (CO-OBn), 169.94
(CO-NC6H4-), 173.99 (O-CO-C) ppm. HRMS (FAB): calcd. for
C37H39N2O7 [MH+]: 623.2757; found 623.2773.
The racemic and enantiopure chiral auxiliaries (RS)- and (R)-4-(3-
hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid [(RS)-1
and (R)-1] and the corresponding benzyl acrylates, benzyl (RS)-
and (R)-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzo-
ates [(RS)-2 and (R)-2], were prepared as described previously.[8]
1-(Benzyloxycarbonylamino)cyclohexa-1,3-diene (3): N,N-Diisopro-
pylethylamine (9.7 mL, 0.056 mol, 1.2 equiv.) was added dropwise
to a stirred solution of cyclohexa-1,3-diene-1-carboxylic acid[10]
(5.76 g, 0.046 mol, 1.0 equiv.) in anhydrous acetone (30 mL) at
room temperature under argon. After stirring for 10 min at 0 °C, a
solution of ethyl chloroformate (5.6 mL, 0.059 mol; 1.3 equiv.) in
anhydrous acetone (15.4 mL) was added over 30 min whilst main-
taining the temperature below 0 °C. Stirring was continued for an
additional 30 min at 0 °C and a solution of sodium azide (7.18 g,
0.110 mol, 2.4 equiv.) in water (17.5 mL) was added in several por-
tions over 20 min whilst maintaining the temperature below 0 °C.
Stirring was continued for an additional 20 min at 0 °C and the
reaction mixture was diluted with ice/water (50 mL). The acyl azide
was isolated by extraction with toluene (6ϫ40 mL). The combined
(3ЈR,1S,2R,4R)-8: M.p. 98 °C. [α]2D0 = –7.5 (c = 1.9, CH2Cl2); tR
(HPLC, column A) = 15.9 min; tR (HPLC, column B, eluent I) =
3170
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Eur. J. Org. Chem. 2007, 3166–3172

Diels–Alder Cycloaddition of Aminocyclohexadiene to Acrylate
FULL PAPER
29.6 min. IR (KBr): ν = 3340 (m), 1745 (s), 1705 (s), 1699 (s) cm–1.
dried with anhydrous Na2SO4, concentrated in vacuo affording the
expected acid (88–92% yield) along with about 5% of compound
(R)-1 (NMR analysis) as the saponification was not totally regiose-
˜
1
MS (ESI): m/z = 623.2 [M + H]+. H NMR (400 MHz, CD3CN,
25 °C): δ = 0.97 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.38 (m, 1 H, 8-
H), 1.62 (m, 2 H, 7-H, 8-H), 1.79 (m, 2 H, 3-H), 2.34 (m, 1 H, 7- lective. This mixture was purified by column chromatography on
H), 2.60 (m, 1 H, 4-H), 3.35 (t, J1 = J2 = 6.9 Hz, 1 H, CHCO), silica gel using CH2Cl2/ethyl acetate (5:5) as eluent to yield the pure
3.39 (d, J = 9.6 Hz, 1 H, 5Ј-H), 3.53 (d, J = 9.6 Hz, 1 H, 5Ј-H), expected acid.
4.91 (d, J = 12.5 Hz, 1 H, OHCHC6H5), 5.03 (d, J = 12.5 Hz, 1 H,
(1S,2R,4R)-4: Synthesized from compound (3ЈR,1S,2R,4R)-8
OHCHC6H5), 5.30 (s, 2 H, OCH2C6H5), 5.37 (s, 1 H, 3Ј-H), 5.99
(d, J = 8.5 Hz, 1 H, CNCH=), 6.07 (s, 1 H, NH), 6.30 (dd, J =
6.7 Hz, 8.5 Hz, 1 H, CH=), 7.20 (m, 10 H, H arom.), 7.59 (d, J =
8.9 Hz, 2 H, H arom.), 7.99 (d, J = 8.9 Hz, 2 H, H arom.) ppm.
13C NMR (100 MHz, CD3CN, 25 °C): δ = 21.05, 24.48 (CH3),
25.99 (C-8), 29.36 (C-4), 29.72 (C-3), 29.95 (C-7), 37.12 (C-4Ј),
45.18 (C-2), 56.68 (C-1), 57.49 (C-5Ј), 66.12 (OCH2), 66.71
(OCH2), 78.40 (C-3Ј), 118.42 (CH arom.), 126.07 (C arom.),
127.61, 127.73, 128.01, 128.15, 128.17, 128.24, 128.29, 128.32,
128.46, 128.57, 128.63, 130.78 (CH arom.), 132.39 (C-6), 134.07
(C-5), 136.07, 136.56, 142.95 (C arom.), 155.52 (NH-CO-O), 165.82
(CO-OBn), 169.69 (CO-NC6H4-), 173.39 (O-CO-C) ppm. HRMS
(FAB): calcd. for C37H39N2O7 [MH+]: 623.2757; found 623.2777.
(0.80 mg, 1.28 mmol) in THF (8 mL), the acid (1S,2R,4R)-4 was
obtained as a colourless oil (0.23 g, 0.76 mmol, 59% yield, Ͼ99%
ee). [α]2D0 = –7 (c = 1, CH Cl ). IR (KBr): ν = 3360 (m), 3300–2900
˜
2
2
(br), 1728 (s), 1658 (s) cm–1. MS (ESI): m/z = 302.2 [M + H]+. tR
(HPLC column A) = 8.9 min; tR (HPLC, column B, eluent II) =
1
11.2 min. H NMR (400 MHz, CD3CN, 25 °C): δ = 1.32–1.41 (m,
1 H, 8-H), 1.52–1.70 (m, 3 H, 8-H, 7-H, 3-H), 1.92–1.99 (m, 1 H,
3-H), 2.10–2.19 (m, 1 H, 7-H), 2.62 (m, 1 H, 4-H), 3.23 (dd, J =
10.1 Hz, 5.2 Hz, 1 H, CHCOO), 5.07 (d, J = 12.7 Hz, 1 H, HCHO),
5.11 (d, J = 12.7 Hz, 1 H, HCHO), 5.98 (s, 1 H, NH), 6.15 (d, J =
8.6 Hz, 1 H, CNCH=), 6.30 (dd, J = 6.7 Hz, 8.6 Hz, 1 H, CH=),
7.31–7.42 (m, 5 H, H arom.) ppm. 13C NMR (100 MHz, CD3CN,
25 °C): δ = 24.93 (C-8), 29.36 (C-4), 30.46 (C-7), 31.07 (C-3), 45.10
(C-2), 55.81 (C-1), 65.54 (CH2O), 127.55, 127.75, 128.41 (CH
arom.), 132.76 (C-5), 133.13 (C-6), 137.51 (C arom.), 155.17 (NH-
CO-O), 174.32 (COOH) ppm. HRMS (FAB): calcd. for
C17H20NO4 [MH]+: 302.1392; found 302.1397.
(3ЈR,1S,2S,4R)-9:[18] tR (HPLC, column A) = 15.8 min, tR (HPLC,
column B, eluent I) = 40.7 min.
(3ЈR,1R,2S,4S)-10:[18] tR (HPLC, column A) = 15.8 min, tR (HPLC,
column B, eluent I) = 49.1 min.
(1R,2R,4S)-5: Synthesized from compound (3ЈR,1R,2R,4S)-7
(0.50 g, 0.80 mmol) in THF (5 mL), the acid (1R,2R,4S)-5 was ob-
tained as a colourless oil (0.15 g, 0.49 mmol, 62% yield, Ͼ99% ee).
rac-(3ЈRS,1RS,2RS,4SR)- and rac-(3ЈRS,1SR,2RS,4RS)-[N-(4-Ben-
zyloxycarbonylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl] 1-(Benzyl-
oxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylate
[rac-
[α]2D0 = –40 (c = 2, CH Cl ). IR (KBr): ν = 3408 (m), 3200–2500
˜
2
2
(3ЈRS,1RS,2RS,4SR)-7 and rac-(3ЈRS,1SR,2RS,4RS)-8]: A crude
racemic mixture of the four cycloadducts was obtained as a colour-
less oil following the procedure described above by reaction of race-
mic acrylate (RS)-2 with the diene 3. Crystallisation of the residue
from diethyl ether afforded directly a pure mixture of the exo rac-
(3ЈRS,1RS,2RS,4SR)-7 and endo rac-(3ЈRS,1SR,2RS,4RS)-8 dia-
stereoisomers which were easily isolated after flash column
chromatography on silica gel using diethyl ether/petroleum ether
(4:6) as eluent.
(br), 1710 (s), 1697 (s) cm–1. MS (ESI): m/z = 302.2 [M + H]+. tR
(HPLC column A) = 9.1 min; tR (HPLC, column B, eluent II) =
1
13.4 min. H NMR (400 MHz, CD3CN, 25 °C): δ = 1.25–1.40 (m,
2 H, 8-H, 7-H), 1.58–1.75 (m, 2 H, 7-H, 3-H), 1.88 (ddd, J =
12.6 Hz, 5.0 Hz, 2.3 Hz, 1 H, 3-H), 1.95–2.10 (m, 1 H, 8-H), 2.57
(m, 1 H, 4-H), 3.06 (dd, J = 11.3 Hz, 4.6 Hz, 1 H, CHCOO), 5.06
(d, J = 12.8 Hz, 1 H, HCHO), 5.13 (d, J = 12.8 Hz, 1 H, HCHO),
5.95 (s, 1 H, NH), 6.26 (dd, J = 6.6 Hz, 8.5 Hz, 1 H, CH=), 6.40
(d, J = 8.5 Hz, 1 H, CNCH=), 7.30–7.40 (m, 5 H, H arom.) ppm.
13C NMR (100 MHz, CD3CN, 25 °C): δ = 24.68 (C-7), 26.49 (C-
8), 29.07 (C-4), 30.33 (C-3), 43.57 (C-2), 55.06 (C-1), 65.45 (CH2O),
127.48, 127.77, 128.45 (CH arom.), 132.44 (C-5), 137.24 (C-6),
137.47 (C arom.), 155.19 (NH-CO-O), 175.30 (COOH) ppm.
HRMS (FAB): calcd. for C17H20NO4 [MH]+: 302.1392; found
302.1408.
rac-(3ЈRS,1RS,2RS,4SR)-7: M.p. 111 °C; tR (HPLC, column A) =
16.3 min; tR (HPLC, column B, eluent I)
=
24.9 min
[(3ЈR,1R,2R,4S)-7 and (3ЈS,1S,2S,4R)-7]. The NMR spectroscopic
data are identical to those of (3ЈR,1S,2R,4R) enantiomer.
rac-(3ЈRS,1SR,2RS,4RS)-8: M.p. 127 °C; tR (HPLC, column A) =
15.9 min; tR (HPLC, column B, eluent I) = 29.6 [(3ЈR,1S,2R,4R)-
8] and 40.7 min [(3ЈS,1R,2S,4S)-8]. The NMR spectroscopic data
are identical to those of the (3ЈR,1S,2R,4R) enantiomer.
rac-(1SR,2RS,4RS)- and rac-(1RS,2RS,4SR)-1-(Benzyloxycar-
bonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic
Acid
[rac-
(1SR,2RS,4RS)-4 and rac-(1RS,2RS,4SR)-5]: A racemic mixture of
the two acids 4 and 5 was obtained as a colourless solid by saponifi-
cation of a mixture of rac-7 and rac-8, following the procedure
described above.
rac-(3ЈRS,1SR,2SR,4RS)-9:[19] tR (HPLC, column A) = 15.8 min;
tR (HPLC, column B, eluent I) = 40.7 min [(3ЈR,1S,2S,4R)-9 and
(3ЈS,1R,2R,4S)-9].
rac-(3ЈRS,1RS,2SR,4SR)-10:[19] tR (HPLC, column A) = 15.8 min;
tR (HPLC, column B, eluent I) = 49.1 [(3ЈR,1R,2S,4S)-10] and
78.4 min [(3ЈS,1S,2R,4R)-10].
rac-(1SR,2RS,4RS)-4: M.p. 151 °C; tR (HPLC, column A) =
8.9 min; tR (HPLC, column B, eluent II) = 11.2 [(1S,2R,4R)-4] and
13.4 min [(1R,2S,4S)-4]. The NMR spectroscopic data are identical
to those of the (1S,2R,4R) enantiomer.
(1S,2R,4R)- and (1R,2R,4S)-1-(Benzyloxycarbonylamino)bicyclo-
[2.2.2]oct-5-ene-2-carboxylic Acid [(1S,2R,4R)-4 and (1R,2R,4S)-5]:
A solution of LiOH·H2O (1.2 equiv.) in water was added dropwise
to a solution of compound (3ЈR,1R,2R,4S)-7 or (3ЈR,1S,2R,4R)-
8 in THF and the mixture was stirred at room temperature until
completion of the hydrolysis reaction (ca. 4 h) (monitored by
HPLC, column A). The organic solvent was removed in vacuo,
saturated aqueous NaHCO3 was added and the mixture was ex-
tracted with ethyl acetate. The aqueous phase was acidified (pH =
2) and extracted with CH2Cl2 The combined organic phases were
rac-(1RS,2RS,4SR)-5: M.p. 125 °C; tR (HPLC, column A) =
9.1 min; tR (HPLC, column B, eluent II) = 7.8 [(1S,2S,4R)-5] and
13.4 min [(1R,2R,4S)-5]. The NMR spectroscopic data are identical
to those of the (1R,2R,4S) enantiomer.
(R)-1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid [(R)-6]: 10% Pd/
C (70 mg, 0.066 mmol, 0.2 equiv.) was added to a solution of com-
pound (1S,2R,4R)-4 or compound (1R,2R,4S)-5 (100 mg,
0.33 mmol) in degassed methanol (9 mL). This mixture was stirred
Eur. J. Org. Chem. 2007, 3166–3172
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3171

O. Songis, C. Didierjean, C. Laurent, J. Martinez, M. Calmès
FULL PAPER
[7] V. E. Gouverneur, K. N. Houk, B. Pascal-Teresa, B. Beno,
K. D. Janda, R. A. Lerner, Science 1993, 262, 204–208.
[8] 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, 15, 2173–2178.
[9] K. Gademann, T. Hintermann, J. V. Scheiber, Curr. Med.
Chem. 1999, 6, 905–925, and references cited therein.
[10] H. Graden, J. Hallberg, N. Kann, J. Comb. Chem. 2004, 6, 783–
788.
[11] a) W. Carruthers in Tetrahedron Organic Chemistry Series. Cy-
cloaddition Reaction in Organic Synthesis, Pergamon Press, Ox-
ford, 1990, vol. 8; b) S. Kobayashi, K. A. Jorgensen, Cycload-
dition reactions in organic synthesis, Wiley-VCH, Weinheim,
2002; c) F. Fringuelli, A. Tatichi, The Diels–Alder Reaction:
Selected Practical Methods; John Wiley & Sons, New York,
2002, and references cited therein.
vigorously under 1 atm of H2 for 15 h at room temperature. The
suspension was filtered through Celite and concentrated in vacuo
to give the expected β-amino acid (R)-6 (55 mg, 0.32 mmol, 99%
yield, Ͼ99% ee). M.p. Ͼ220 °C (decomp.). [α]2D0 = –50 (c = 1.3,
CH OH). IR (KBr): ν = 3200–2500 (s), 2184 (s), 1653 (s), 1607 (s),
˜
3
1530 (s) cm–1. MS (ESI): m/z = 170.2 [M + H]+. 1H NMR
(400 MHz, D2O, 25 °C): δ = 1.44–1.70 (m, 8 H, 4-H, 5-H, 6-H, 7-
H, 8-H), 1.84–1.95 (m, 3 H, 3-H, 6-H), 2.44 (br. t, J1 = J2 = 8.1 Hz,
1 H, 2-H) ppm. 13C NMR (100 MHz, D2O, 25 °C): δ = 23.61 (C-
4), 24.87 (C-5), 24.90 (C-8), 25.86 (C-6), 30.19 (C-3), 30.72 (C-7),
44.48 (C-2), 52.38 (C-1), 181.67 (CO) ppm. HRMS (FAB): calcd.
for C9H16NO2 [MH]+: 170.1181; found 170.1185.
(RS)-1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid [(RS)-6]: A ra-
cemic mixture of the β-amino acid rac-6 was obtained as a colour-
less solid by hydrogenation of rac-4 or -5 following the procedure
described above. M.p. Ͼ220 °C (decomp.). The NMR spectroscopic
data are identical to those of the (R) enantiomer.
[12] A further problem with the use of Lewis acids is their possible
complexation with both the two starting materials and the Di-
els–Alder products when a large quantity of the Lewis acid is
required.
[1] a) C. Cativiela, M. D. Diaz-de-Villegas, Tetrahedron: Asym-
metry 1998, 9, 3517–3599; b) C. Cativiela, M. D. Diaz-de-Vil-
legas, Tetrahedron: Asymmetry 2000, 11, 645–732; c) F. Fülöp,
Chem. Rev. 2001, 101, 2181–2204; d) K.-H. Park, M. J. Kurth,
Tetrahedron 2002, 58, 8629–8659, and references cited therein.
[2] For examples of the application of constrained α-amino acids,
see: a) S. E. Gilson, N. Guillo, M. J. Tozer, Tetrahedron 1999,
55, 585–615; b) C. Gallopini, S. Meini, M. Tancredi, A.
Di Fenza, A. Triolo, L. Quartara, C. A. Maggi, F. Formaggio,
C. Toniolo, S. Mazzucco, A. Papini, P. Rovero, J. Med. Chem.
1999, 42, 409–414; c) P. Rovero, M. Pellegrini, A. Di Fenza, S.
Meini, L. Quartara, C. A. Maggi, F. Formaggio, C. Toniolo,
D. F. Mierke, J. Med. Chem. 2001, 44, 274–278.
[3] For examples of the application of constrained β-amino acids,
see: a) Y. Hayashi, J. Katade, T. Harada, K. Tachiki, Y. Takigu-
chi, M. Maramatsu, H. Miyazaki, T. Asari, T. Okazaki, Y.
Dato, E. Yasuda, M. Tano, I. Uno, I. Ojima, J. Med. Chem.
1998, 41, 2345–2360; b) S. H. Gellman, Acc. Chem. Res. 1998,
31, 173–180; c) P. Furet, C. Garcia-Echeverria, B. Gay, J.
Schoepfer, M. Zeller, J. Rahuel, J. Med. Chem. 1999, 42, 2358–
2363; d) P. G. Cheng, S. H. Gellman, W. F. DeGrado, Chem.
Rev. 2001, 101, 3219–3232; e) B. Bellier, C. Garbay, Eur. J. Med.
Chem. 2003, 38, 671–686; f) M. Sukopp, R. Schwab, L. Ma-
rinelli, E. Biron, M. Heller, E. Varkondi, A. Pap, E. Novellino,
G. Kéri, H. Kessler, J. Med. Chem. 2005, 48, 2916–2926; g) F.
Fülöp, T. A. Martinek, G. K. Toth, Chem. Soc. Rev. 2006, 35,
323–334.
[13] V. K. Aggarwal, A. Patin, S. Tisserand, Org. Lett. 2005, 7,
2555–2557.
[14] T. Imamoto, Lanthanides in organic synthesis, Academic Press,
London, 1994, and references cited therein.
[15] a) J. P. Tierney, P. Lidström (Eds.), Microwave-assisted organic
synthesis, Backwell Scientific, Oxford, 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.
[16] Three of the four cycloadducts were separable using an achiral
stationary phase and the ratio of the four cycloadducts was
accurately determined by HPLC analyses using a chiracel OD
column as a chiral stationary phase.
[17] Crystal data for ester (3ЈR,1S,2R,4R)-8: molecular formula
C37H38N2O7, M = 622.69, monoclinic, space group P21, a =
11.3555(3), b = 18.0458(5), c = 16.0537(4) Å, β = 100.922(1)°,
V = 3230.12(15) Å3, Z = 4, Dc = 1.28 Mgm–3. X-ray diffraction
data were collected at room temperature using a Bruker AXS
Kappa CCD system with Mo-Kα radiation. The structure was
solved by direct methods and the model was refined by full-
matrix least-squares procedures on F2 to give values of R1
=
0.0381 and of wR2 = 0.0803 for reflections with IϾ2σ(I).
CCDC-640598 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[4] a) J. D. Roberts, W. T. Moreland, W. Frazer, J. Am. Chem. Soc.
1953, 75, 637–640; b) C. M. Wynn, W. R. Vaughan, J. Org.
Chem. 1968, 33, 2371–2374; c) A. C. Braisted, P. G. Schultz, J.
Am. Chem. Soc. 1990, 112, 7430–7431; d) R. Chinchilla, L. R.
Falvello, N. Galindo, C. Najera, Tetrahedron: Asymmetry 1999,
10, 821–825; e) R. Chinchilla, L. R. Falvello, N. Galindo, C.
Najera, J. Org. Chem. 2000, 65, 3034–3041; f) R. C. Reynolds,
C. A. Johnson, J. R. Piper, F. M. Sirotnak, Eur. J. Med. Chem.
2001, 36, 237–242; g) D. Arad, A. S. Kende, J. Lan, Tetrahedron
Lett. 2002, 43, 5237–5239.
[18] HPLC data for the minor diastereoisomers 9 and 10 were de-
duced from a comparison of the HPLC profile of the crude
diastereoisomeric mixtures with those of enantiopure com-
pounds. It can be assumed that the endo approach at the Cα
Re face of the dienophile was also favoured, which allowed us
to assign the stereochemistry of compounds 9 and 10. This
was supported by the rac-4/rac-5 ratio of 67:33 obtained after
removal of the chiral auxiliary from a 30:60:3:7 mixture of
compounds 7/8/9/10.
[5] R. Zand, O. Z. Sellinger, R. Water, R. Harris, J. Neurochem.
1974, 23, 1201–1206.
[6] P. W. Smith, N. Trivedi, P. D. Howes, S. L. Sollis, G. Rahim,
R. C. Bethell, S. Lynn, Bioorg. Med. Chem. Lett. 1999, 9, 611–
614.
[19] HPLC data for the minor diastereoisomers rac-9 and rac-10
were deduced from a comparison of the HPLC profile of race-
mic mixtures with those of diastereoisomeric mixtures.
Received: March 15, 2007
Published Online: May 25, 2007
3172
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3166–3172