Synthesis of 2,5-diazabicyclo[2.2.2]octanes by dieckmann analogous cyclization

Article abstract of DOI:10.1071/CH08350

Starting with (S)-aspartate, methyl (S)-2-[1-allyl-4-(4-methoxybenzyl)-3,6- dioxopiperazin-2-yl]acetate 10 was synthesized in a four-step synthesis. Deprotonation of 10 and subsequent trapping of the first cyclization product led to the bicyclic mixed acetal 13 in 15% yield. The low yield of 13, compared with the yield of the corresponding glutamate derivatives, is explained by the higher energy (strain) of the bicyclo[2.2.2]octane system and the lower conformational flexibility of the shorter acetate side chain. The formation of a six-membered Na⁺-chelate 12 as intermediate is responsible for the high diastereoselectivity of the cyclization step.

Full text of DOI:10.1071/CH08350

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 914–919
www.publish.csiro.au/journals/ajc
Synthesis of 2,5-Diazabicyclo[2.2.2]octanes by Dieckmann
Analogous Cyclization
Ralph Holl,A Mareike Dykstra,A Martin Schneiders,B Roland Fröhlich,B
Masato Kitamura,C Ernst-Ulrich Würthwein,B and Bernhard WünschA,D
AInstitut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität
Münster, Hittorfstraße 58-62, 48149 Münster, Germany.
BOrganisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40,
48149 Münster, Germany.
CDepartment of Chemistry, Graduate School of Science, Nagoya University, Furo, Chikusa,
Nagoya 464-8602, Japan.
DCorresponding author. Email: wuensch@uni-muenster.de
Starting with (S)-aspartate, methyl (S)-2-[1-allyl-4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]acetate 10 was synthe-
sized in a four-step synthesis. Deprotonation of 10 and subsequent trapping of the first cyclization product led to the
bicyclic mixed acetal 13 in 15% yield. The low yield of 13, compared with the yield of the corresponding glutamate
derivatives, is explained by the higher energy (strain) of the bicyclo[2.2.2]octane system and the lower conformational
flexibility of the shorter acetate side chain.The formation of a six-membered Na+-chelate 12 as intermediate is responsible
for the high diastereoselectivity of the cyclization step.
Manuscript received: 14 August 2008.
Final version: 29 September 2008.
Introduction
epoxide opening.[11] However, enantiomerically pure products
are not accessible according to these methods. Furthermore, with
exception of the third method, which results in two regioisomeric
alcohols in the ratio of 2.7:1, the produced bicycles do not bear
further substituents in the two-carbon bridge.
Therefore, we planned to synthesize enantiomerically pure
2,5-diazabicyclo[2.2.2]octanetriones 6 starting with the smaller
homologue (S)-aspartate as outlined in Scheme 1. At first piper-
azinediones 4 with an acetate side chain should be synthesized.
The establishment of the bicyclic structure will be realized as
described for the glutamate derivatives 1. However, the two-
carbon acetate side chain of 4 comprises lower conformational
flexibility than the propionate side chain of 1, which could
prevent cyclization.
Recently we have described a new variation of the Dieckmann-
type cyclization. This variation is based on a quantitative
deprotonation of the starting compound with a strong base and
trapping of the first cyclization product with trimethylsilyl chlo-
ride (TMSCl).[1,2] Whereas the driving force of the standard
Dieckmann cyclization is the deprotonation of the finally formed
β-dicarbonyl compound, the new variation allows the synthesis
of cyclization products, which cannot form stabilized anions.
This method has been applied to the synthesis of bridged
piperazines 3 which, because of the additional carbonyl moi-
ety in position 2, serve as valuable starting compounds for the
preparation of novel δ[3,4] and κ receptor agonists[5,6] as well
as σ receptor ligands.[6–8] Generally, compounds with reduced
conformational flexibility should lead to more potent receptor
ligands as a result of favourable entropic factors.
Starting with (S)-glutamate, piperazinediones 1 with a pro-
pionate side chain were prepared first. In the key step of
the synthesis, 1 was treated with lithium hexamethyldisilazane
(LiHMDS) and subsequently with TMSCl to diastereoselec-
tively provide the mixed methyl silyl acetal 2.[1,2] The reaction
sequence proceeded without racemization, as could be shown by
various analytical methods (Scheme 1).[4]
Results and Discussion
In order to synthesize the piperazinedione 10 with an acetate side
chain in position 2, (S)-aspartic acid was used as a starting com-
pound (Scheme 2). After transformation of (S)-aspartate with
TMSCl and methanol into the diester hydrochloride 7·HCl the
chloroacetamide 8 was prepared by acylation with chloroacetyl
chloride. During the reaction of the chloroacetamide 8 with
4-methoxybenzylamine, an SN2 reaction and intramolecular
aminolysis took place consecutively, which directly provided the
piperazinedione 9 in 85% yield. The orthogonal allyl protective
group was attached by allylation with allyl bromide after depro-
tonation of the secondary amide 9 with NaHMDS to obtain the
piperazinedione 10 in 52% yield.
In order to broaden the structure affinity relationships, piper-
azines with a substituted two-carbon bridge came into focus.
Compounds with the 2,5-diazabicyclo[2.2.2]octane frame-
work have been synthesized by a double cyclization of 2,5-
dibromohexanediamide derivatives,[9] by a [4 + 2]cycloaddition
of pyrazin-2(1H)-ones with ethene,[10] and by an intramolecular
© CSIRO 2008
10.1071/CH08350
0004-9425/08/110914

Synthesis of 2,5-Diazabicyclo[2.2.2]octanes
915
O
O
O
H
R2
R2
R2
R1
N
R1
R1
ϩ
N
N
N
(1) LiHMDS
(2) TMSCl
H3O
N
N
(S)-glutamate
H3CO
O
O
O
H3CO
O
OSi(CH3)3
O
2
3
1
O
O
O
H
R2
R2
R2
R1
R1
N
R1
ϩ
H3O
N
N
N
N
(1) Base
N
(S)-aspartate
(2) TMSCl
O
O
O
H3CO
H3CO
O
O
OSi(CH3)3
4
5
6
Scheme 1. Comparison of the cyclization strategy of piperazinediones with propionate and acetate side chains.
CO2H
CO2CH3
CO2CH3
O
O
(a)
(b)
H
H
(a)
CO2H
PMB
PMB
H2N
Cl H3N
N
N
N
N
H
H
(S)-aspartate
7·HCl
O
ONa
H3CO
H3CO
O
O
10
PMB
11
Cl
N
O
CO2CH3
CO2CH3
(d)
(c)
CO2CH3
O
N
H
O
N
H
O
O
H
H
3
5
N
(b)
2
N
4
8
PMB
PMB
N
9
N
8
6
1
7
O
O
H3CO
H3CO
PMB
N
Na
O
OSi(CH3)3
O
13
12
CO2CH3
O
N
H
O
(c)
PMB
N
N
10
O
Scheme 2. (a) TMSCl, CH3OH, room temp., 16 h, 99%; (b) ClCH2COCl,
CH2Cl2, NaHCO3, room temp., 16 h, 67%; (c) 4-methoxybenzylamine,
(PMB-NH2), NEt3, CH3CN, Bu4NI, reflux, 48 h, 85%; (d) NaHMDS, THF,
−78◦C, allyl bromide, Bu4NI, −78◦C, 1 h, room temp., 2 h, 52%.
O
14
Scheme 3. (a) NaHMDS, THF, −78◦C, 40 min; (b) TMSCl, THF, −78◦C,
1 h, then room temp., 2 h, 15%; (c) 0.5 M HCl, THF, room temp., 16 h, 95%.
The piperazinedione 10 was treated with LiHMDS and sub-
sequently with TMSCl in analogy to the propionate derivatives
1.[1,2] However, in contrast to the analogous propionate deriva-
tives 1, which formed the bicyclic products 2 in more than
80% yield, the yield of the cyclization product 13 was only
5.3% (Scheme 3). In order to improve the reaction, the type
of base (NaHMDS, LiHMDS, KHMDS), the amount of base
(1.1–3.0 equiv.), the reaction temperature (−78 to 0◦C), and
the time between addition of the base and TMSCl (cyclization
time: 40 min to 12 h) were systematically varied. In this series of
experiments the best yield of 13 (15%) was achieved using 3.0
equivalents of NaHMDS instead of LiHMDS at −78◦C and a
cyclization time of 60 min. However, even under these optimized
reaction conditions most of the starting material was recovered
unchanged.
gave the bicyclic ketone 14 in 95% yield. Under these very
mild reaction conditions opening of the bicyclic system was not
observed.
The cyclization of 10 to the mixed methyl silyl acetal 13 led
stereoselectively to only one diastereomer. It was not possible to
unequivocally determine the configuration of the newly formed
stereocentre at position 7 of the bicyclic system. Therefore, an
X-ray crystal structure analysis of 13 was envisaged. Recrys-
tallization of 13 from diisopropyl ether gave colourless crystals
that were suitable for X-ray crystal structure analysis. Since the
configuration of the chiral centre in position 4 is given by the
starting compound (S)-aspartate, the configuration of the mixed
methyl silyl acetal 13 is proven by the X-ray structure to be
(1S,4S,7R) (Fig. 1).
Careful hydrolysis of the mixed methyl silyl acetal 13 with
0.5 M HCl in tetrahydrofuran (THF) at ambient temperature
The (7R)-configuration supports the postulated reaction
course of the Dieckmann-type cyclization. The enolate 11

916
R. Holl et al.
generated upon NaHMDS deprotonation of the acetate 10 stereo-
selectively attacks the Si-face of the ester moiety to form the
hemiacetal anion 12, which is trapped by TMSCl. In contrast
to the diastereomeric hemiacetal anion with (7S)-configuration
the (7R)-configured anion 12 is stabilized by a six-membered
Na-chelate.
In order to evaluate possible reasons for the very different
yields obtained for 2 and 13 in the cyclization reactions, we
performed density functional theory (DFT) calculations of a
series of model compounds. Besides the experimentally known
6,8-diazabicyclo[3.2.2]nonanes 2 and the 2,5-diazabicyclo
[2.2.2]octane 13 we have also included the corresponding 7,9-
diazabicyclo[4.2.2]decane system into this study, which would
result from the next higher homologue of 1 (2-aminoadipic
acid as starting compound). We used the B3LYP/6-31G(d)
method for the geometry optimizations and the SCS-MP2/6-
31G(d)//B3LYP/6-31G(d) method[12] for the energy determina-
tions (including zero point correction) as implemented in the
GAUSSIAN03 package of programs.[13] In order to allow a direct
comparison of the bicyclo-octane 13, -nonane 2, and -decane
systems we have chosen a series of three model compounds
with the same molecular formula (C12H20N2O4). These three
isomeric model compounds differ in ring size and in the nature
of the alkoxy groups being two propoxy groups for the bicy-
clooctane ring system, an ethoxy and a propoxy group for the
bicyclononane system, and two ethoxy groups for the bicy-
clodecane system (Fig. 2). We assumed that ring strain energy
contributions of the bicyclic systems were not severely falsified
by the energy contribution of such varying alkoxy groups. The
bicyclooctane system including the eight-membered ring came
out best in energy (Erel 0.00 kcal mol−1), the bicyclononane sys-
tem with the seven-membered ring, calculated in two isomeric
forms, showed a relative energy of 1.09 and 1.16 kcal mol−1
,
O31
C21
respectively, whereasthebicyclooctanesystemincludingthesix-
membered ring came out highest in energy (3.21 kcal mol−1).
Although the energy sequenceobtained fits to chemical intuition,
the relative differences between the isomeric model compounds
are not very large. However, assuming a Hammond-postulate
like reaction course with product-like transition states, kinetic
barriers in the same sequence may well be reason for the dif-
ferent experimental yields obtained. Of course, such transition
states are very strongly influenced by the nature of the counter
ion and the chemical environment, which do not allow a serious
attempt to model such a reaction computationally.
C3
N2
C23
N5
C22
C27
C51
C24
C25
O28
C6
O61
C53
C1
C7
C4
C8
C52
C26
C29
C76
O71
O75
Si1
C74
C72
C73
Conclusions
We have shown that the piperazinedione 10 bearing an acetate
side chain can be cyclized according to our recently described
Fig. 1. X-Ray crystal structure analysis of the mixed methyl silyl
acetal 13.
O
O
O
O
N
N
O
O
N
N
O
O
Model for compound 13
Model for compound 2
2,5-Diazabicyclo[2.2.2]octane: Erel ϭ 3.21 kcal molϪ1
6,8-Diazabicyclo[3.2.2]nonane, diast. 1: Erel ϭ 1.16 kcal molϪ1
O
O
O
O
O
N
N
O
N
N
O
O
Model for the homolog of 2
Model for compound 2
7,9-Diazabicyclo[4.2.2]decane: Erel ϭ 0.0 kcal molϪ1
6,8-Diazabicyclo[3.2.2]nonane, diast. 2: Erel ϭ 1.09 kcal molϪ1
Fig. 2. Determination of the relative energy of the bicyclic compounds by DFT calculations: Model compounds with the same molecular formula
(C12H20N2O4) are chosen for the three bicyclic systems. SCS-MP2/6-31G(d)//B3 LYP/6-31G(d) including zero-point correction.

Synthesis of 2,5-Diazabicyclo[2.2.2]octanes
917
Dieckmann-type cyclization protocol to form piperazine deriva-
tives with a C-2 bridge. In contrast to the glutamate derivatives
3 the yield of 13 is rather low, which is explained by the higher
energy (ring strain) of the more constrained system 13 and the
reduced conformational flexibility of the shorter acetate side
chain of 10. The high diastereoselectivity of the cyclization sup-
ports the hypothesis that the six-membered metal-chelate 12 is
the driving force of the cyclization.
room temperature for 16 h. The organic layer was separated
and washed with 0.5 M NaOH (×2). The aqueous layer was
extracted with CH2Cl2 (×2) and the combined organic layers
were dried (Na2SO4), filtered, and concentrated under vac-
uum. The residue was purified by flash chromatography (8 cm,
cyclohexane/ethyl acetate = 1/1, 30 mL, Rf = 0.41) to give a
colourless oil, yield 8.24 g (67%). HPLC: tR 10.4 min, purity
99.8%. [α]2D0 +50.7 (c 0.43, CH2Cl2). C8H12ClNO5 (237.6). m/z
(EI) 240 (MH (Cl37), 41%), 238 (MH (Cl35), 100). δH (CDCl3)
2.85 (dd, J 17.2/4.7, 1H, CH2CO2CH3), 3.08 (dd, J 17.2/4.7, 1H,
CH2CO2CH3), 3.71 (s, 3H, CO2CH3), 3.78 (s, 3H, CO2CH3),
4.05 (d, J 14.9, 1H, ClCH2CO), 4.10 (d, J 14.9, 1H, ClCH2CO),
4.85 (dt, J 8.6/4.7, 1H, CHCH2CO2CH3), 7.57 (d, J 8.6, 1H,
NH). νmax/cm−1 3319 (m br, νN–H), 2956 (m, νC–H aliph.), 1735
(s, νC=O ester), 1670 (s, νC=O amide), 1523 (m, δN–H).
Experimental
General Methods
Unless otherwise noted, moisture sensitive reactions were con-
ducted under dry nitrogen. THF was dried with sodium/
benzophenone and was freshly distilled before use. TLC used
silica gel 60 F254 plates (Merck). Flash chromatography used
silica gel 60, 40–64 µm (Merck); parentheses include: dia-
meter of the column, eluent, fraction size, RF value. Melt-
ing points were determined on a SMP 3 (Stuart Scientific)
melting point apparatus, and were uncorrected. Mass spec-
trometry was performed on a MAT GCQ (Thermo-Finnigan).
A 480Plus FT-ATR-IR (Jasco) IR spectrophotometer was
employed. 1H NMR (400 MHz) spectra were acquired on a
Unity Mercury Plus 400 spectrometer (Varian). Signals are
reported in δ (ppm) relative to tetramethylsilane. Coupling
constants are given with 0.5 Hz resolution. HPLC was per-
formed with a Merck Hitachi Equipment equipped with a
UV detector (L-7400), an autosampler (L-7200), a pump
(L-7100), degasser (L-7614), using a LiChrospher 60 RP-select
B (5 µm) column, and a LiCroCART 250-4 mm cartridge. The
flow rate was 1.000 mL min−1 with an injection volume of
5.0 µL and detection at λ 210 nm. The solvents used were: A)
water with 0.05% (v/v) trifluoroacetic acid and B) acetonitrile
with 0.05% (v/v) trifluoroacetic acid. Experiments were per-
formed with a gradient elution: 0.0 min: 90.0% of A, 10.0%
of B; 4.0 min: 90.0% of A, 10.0% of B; 29.0 min: 0.0% of A,
100.0% of B; 31.0 min: 0.0% of A, 100.0% of B; 31.5 min:
90.0% of A, 10.0% of B; 40.0 min: 90.0% of A, 10.0% of B.
(−)-Methyl (S)-2-[4-(4-Methoxybenzyl)-
3,6-dioxopiperazin-2-yl]acetate 9
Compound 8 (7.13 g, 30.0 mmol) was dissolved in aceto-
nitrile (230 mL) and 4-methoxybenzylamine (5.88 mL, 6.17 g,
45.0 mmol), triethylamine (6.38 mL, 4.64 g, 45.9 mmol), and
tetrabutylammonium iodide (1.11 g, 3.00 mmol) were added.
The mixture was heated to reflux for 48 h. The volume of
solvent was then reduced by two thirds under vacuum. The
residue was filtered and poured into 0.5 M HCl.The mixture was
extracted with CH2Cl2 (×3), the combined organic layers were
dried (Na2SO4), filtered, and concentrated under vacuum. The
residue was purified by flash chromatography (8 cm, petroleum
ether/acetone = 1/1, 30 mL, Rf = 0.42) to give a yellow oil,
yield 7.82 g (85%). [α]2D0 −12.6 (c 0.49, CH2Cl2). C15H18N2O5
(306.3). m/z (EI) 306 (M, 38%), 185 (M − CH2PhOCH3, 18),
121 (CH2PhOCH3, 100). δH (CDCl3) 2.82 (dd, J 17.2/8.6, 1H,
CH2CO2CH3), 3.10 (dd, J 17.2/3.1, 1H, CH2CO2CH3), 3.70
(s, 3H, CO2CH3), 3.80 (s, 3H, ArOCH3), 3.81 (d, J 18.0, 1H,
O=CCH2N), 3.88 (d, J 18.0, 1H, O=CCH2N), 4.37–4.42 (m,
1H, CHCH2CO2CH3), 4.53 (s, 2H, NCH2Ar), 6.67 (s, 1H, NH),
6.87 (d, J 8.6, 2H, 3ꢀ-H4-methoxybenzyl, 5ꢀ-H4-methoxybenzyl), 7.19
(d, J 8.6, 2H, 2ꢀ-H4-methoxybenzyl, 6ꢀ-H4-methoxybenzyl). νmax/cm−1
3241 (m br, νN–H), 2953 (w, νC–H aliph.), 1734 (m, νC=O ester),
1656 (s, νC=O amide), 1611 (m), 1512 (m, νC=C arom.).
(+)-Dimethyl (S)-Aspartate Hydrochloride 7·HCl
(S)-Aspartic acid (10.0 g, 75.1 mmol) was suspended in
methanol (150 mL). Under ice-cooling chlorotrimethylsilane
(33.5 mL, 262 mmol) was added dropwise. The mixture was
stirred for 16 h at room temperature. The volatiles were then
removed under vacuum. The residue was dissolved in methanol
and the mixture was concentrated under vacuum. Diethyl
ether was then added (×3) and the mixture was concen-
trated under vacuum. The product was obtained as a colourless
solid, mp 112◦C, yield 14.7 g (99%). [α]2D0 +10.2 (c 0.65,
H2O). C6H12ClNO4 (197.6). m/z (EI) 162 (M − Cl, 70%). δH
(CDCl3) 3.25 (dd, J 18.0/5.5, 1H, CH2CO2CH3), 3.35 (dd, J
18.0/5.5, 1H, CH2CO2CH3), 3.75 (s, 3H, CO2CH3), 3.84 (s,
3H, CO2CH3), 4.59–4.66 (m, 1H, CHCH2CO2CH3), 8.73 (s,
3H, NH+3 ). νmax/cm−1 2865 (m, νC–H aliph.), 1766 (m), 1732
(s, νC=O ester).
(+)-Methyl (S)-2-[1-Allyl-4-(4-methoxybenzyl)-
3,6-dioxopiperazin-2-yl]acetate 10
Under an N2 atmosphere a solution of 9 (6.24 g, 20.4 mmol)
and tetrabutylammonium iodide (1.50 g, 4.07 mmol) in THF
(150 mL) was cooled to −78◦C. A 2.0 M solution of sodium
hexamethyldisilazane (NaHMDS) inTHF (11.2 mL, 22.4 mmol)
was then added dropwise. After stirring the mixture at −78◦C
for 40 min allyl bromide (8.9 mL, 12.3 g, 102 mmol) was added.
The mixture was stirred at −78◦C for 1 h and was then allowed
to warm to room temperature. After stirring the mixture at
room temperature for 2 h, water was added and the mix-
ture was extracted with CH2Cl2 (×3). The combined organic
layers were dried (Na2SO4), filtered, and the solvent was
removed under vacuum. The residue was purified by flash
chromatography (8 cm, cyclohexane/ethyl acetate = 1/2, 30 mL,
Rf = 0.20) to give a colourless solid, mp 89◦C, yield 3.64 g
(52%). HPLC: tR = 17.3 min, purity 98.2%. [α]20 +57.1 (c 0.33,
CH2Cl2). C18H22N2O5 (346.4). m/z (EI) 346D(M, 39%), 225
(M − CH2PhOCH3, 10), 121 (CH2PhOCH3, 100). δH (CDCl3)
2.88 (dd, J 17.2/4.7, 1H, CH2CO2CH3), 3.13 (dd, J 17.2/3.1,
1H, CH2CO2CH3), 3.60 (s, 3H, CO2CH3), 3.63 (dd, J 15.7/7.0,
(+)-Dimethyl (S)-2-(2-Chloroacetylamino)succinate 8
Compound 7·HCl (10.2 g, 51.6 mmol) was dissolved in CH2Cl2
(300 mL). Under ice-cooling a solution of chloroacetyl chlo-
ride (12.7 mL, 18.1 g, 160 mmol) in CH2Cl2 (80 mL) was
added dropwise. After 40 min a saturated aqueous solution of
NaHCO3 (100 mL) was added and the mixture was stirred at

918
R. Holl et al.
1H, NCH2CH=CH2), 3.78 (d, J 17.2, 1H, O=CCH2N), 3.80
(s, 3H, ArOCH3), 4.03 (d, J 17.2, 1H, O=CCH2N), 4.23–
4.27 (m, 1H, CHCH2CO2CH3), 4.43 (ddt, J 15.7/5.5/1.6, 1H,
NCH2CH=CH2), 4.50 (d, J 14.9, 1H, NCH2Ar), 4.59 (d, J 14.9,
1H, NCH2Ar), 5.20–5.27 (m, 2H, NCH2CH=CH2), 5.67–5.78
5ꢀ-H4-methoxybenzyl), 7.21 (d, J 8.6, 2H, 2ꢀ-H4-methoxybenzyl, 6ꢀ-
H4-methoxybenzyl). νmax/cm−1 3080 (w, νC–H arom.), 2924 (m,
νC–H aliph.), 1735 (m, νC=O ester), 1660 (s, νC=O amide), 1611 (m),
1512 (m, νC=C arom.).
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (internat.) +44(1223)336-033,
Email: deposit@ccdc.cam.ac.uk].
(m, 1H, NCH2CH=CH2), 6.86 (d, J 8.6, 2H, 3ꢀ-H4-methoxybenzyl
,
(+)-(1S,4S)-5-Allyl-2-(4-methoxybenzyl)-2,5-
diazabicyclo[2.2.2]octane-3,6,7-trione 14
Under an N2 atmosphere the mixed methyl silyl acetal 13 (42 mg,
0.10 mmol) was dissolved in a degassed mixture of THF/0.5 M
HCl (9/1, 20 mL) and the mixture was stirred at room tempera-
ture for 16 h.Water was then added and the mixture was extracted
with CH2Cl2 (×3). The organic layer was dried (Na2SO4), fil-
tered, and the solvent was removed under vacuum. The residue
was purified by flash chromatography (1 cm, 1/2 cyclohexane/
ethyl acetate, 5 mL, Rf 0.25) to give a colourless solid, mp
149◦C, yield 30 g (95%). HPLC: tR 13.7 min, purity 97.1%.
[α]2D0 +34.6 (c 0.10, CH2Cl2). C17H18N2O4 (314.3). m/z (EI)
314 (M, 9%), 121 (CH2PhOCH3, 100). δH (CDCl3) 2.47 (dd, J
18.8/3.1, 1H, 8-H), 2.61 (dd, J 18.8/1.6, 1H, 8-H), 3.78 (s, 3H,
ArOCH3), 4.00 (ddt, J 14.9/6.3/1.6, 1H, NCH2CH=CH2), 4.09
(ddt, J 14.9/6.3/1.6, 1H, NCH2CH=CH2), 4.16 (s, 1H, 1-H),
4.18 (dd, J 3.1/1.6, 1H, 4-H), 4.47 (d, J 14.9, 1H, NCH2Ar), 4.60
(d, J 14.9, 1H, NCH2Ar), 5.26–5.33 (m, 2H, NCH2CH=CH2),
5.69 (ddt, J 17.2/10.2/6.3, 1H, NCH2CH=CH2), 6.84 (d, J
8.6, 2H, 3ꢀ-H4-methoxybenzyl, 5ꢀ-H4-methoxybenzyl), 7.10 (d, J 8.6,
2H, 2ꢀ-H4-methoxybenzyl, 6ꢀ-H4-methoxybenzyl). νmax/cm−1 3005 (w,
νC–H arom.), 2959 (w, νC–H aliph.), 1752 (m, νC=O ketone), 1676 (s,
νC=O amide), 1613 (m), 1510 (m, νC=C arom.).
(+)-(1S,4S,7R)-5-Allyl-7-methoxy-2-(4-methoxybenzyl)-
7-(trimethylsiloxy)-2,5-diazabicyclo[2.2.2]octane-
3,6-dione 13
Under an N2 atmosphere 10 (485 mg, 1.40 mmol) was dissolved
inTHF (30 mL) and cooled to −78◦C. A 2 M solution of sodium
hexamethyldisilazane (NaHMDS) in THF (2.1 mL, 4.20 mmol)
was then added dropwise. After stirring at −78◦C for 40 min,
chlorotrimethylsilane (0.45 mL, 380 mg, 3.50 mmol) was slowly
added. The mixture was stirred at −78◦C for 1 h and at room
temperature for 2 h. A saturated solution of NaHCO3 was added
and the mixture was extracted with CH2Cl2 (×3). The com-
bined organic layers were dried (Na2SO4), filtered, and the
solvent was removed under vacuum.The residue was purified by
flash chromatography (3 cm, cyclohexane/ethyl acetate = 2/1,
20 mL, Rf = 0.18) to give a colourless solid, mp 103◦C, yield
84 mg (15%). HPLC: tR = 21.5 min, purity 96.1%. [α]2D0 +6.5
(c 0.13, CH2Cl2). C21H30N2O5Si (418.6). m/z (EI) 418 (M,
8%), 297 (M − CH2PhOCH3, 32), 121 (CH2PhOCH3, 100). δH
(CDCl3) 0.15 (s, 9H, OSi(CH3)3), 2.17 (dd, J 14.1/3.9, 1H, 8-
H), 2.22 (dd, J 14.1/2.3, 1H, 8-H), 3.02 (s, 3H, OCH3), 3.79 (s,
3H, ArOCH3), 3.86–3.95 (m, 3H, 1-H, 4-H, NCH2CH=CH2
(1H)), 4.06 (dd, J 14.9/5.5, 1H, NCH2CH=CH2), 4.21 (d, J
14.9, 1H, NCH2Ar), 4.76 (d, J 14.9, 1H, NCH2Ar), 5.22–
5.30 (m, 2H, NCH2CH=CH2), 5.71 (ddt, J 17.2/10.2/6.3,
Acknowledgements
This work was performed within the International Research Training Group
‘Complex Functional Systems in Chemistry: Design, Synthesis and Appli-
cations’ in collaboration with the University of Nagoya. Financial sup-
port of this IRTG by the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
1H, NCH2CH=CH2), 6.86 (d, J 8.6, 2H, 3ꢀ-H4-methoxybenzyl
,
5ꢀ-H4-methoxybenzyl), 7.14 (d, J 8.6, 2H, 2ꢀ-H4-methoxybenzyl, 6ꢀ-
H4-methoxybenzyl). νmax/cm−1 3016 (w, νC–H arom.), 2962 (m,
νC–H aliph.), 1685 (s, νC=O amide), 1612 (m), 1586 (m), 1508 (m,
νC=C arom.).
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