Synthesis of a conformationally rigid analogue of 2-aminoadipic acid containing an 8-azabicyclo[3.2.1]octane skeleton

Article abstract of DOI:10.1055/s-0029-1216963

A new, conformationally rigid analogue of 2-aminoadipic acid, 8-[(benzyloxy)carbonyl]-3-methylene-8-azabicyclo[3.2.1]octane-1,5-dicarboxylic acid, is synthesized from dimethyl rac-2,5-dibromohexanedioate. The key steps involve alkylation-cyclization of 1-

Full text of DOI:10.1055/s-0029-1216963

PAPER
3327
Synthesis of a Conformationally Rigid Analogue of 2-Aminoadipic Acid
Containing an 8-Azabicyclo[3.2.1]octane Skeleton
A
C
onformationall
l
y Rigid
a
A
nalogue
d
of 2-Aminoa
i
dipic
A
m
cid ir S. Kubyshkin,a,c Pavel K. Mykhailiuk,*a,c Anne S. Ulrich,b,c Igor Komarova
a
Department of Chemistry, Kyiv National Taras Shevchenko University, Vul. Volodymyrska 64, 01033 Kyiv, Ukraine
Institut für Biologische Grenzflächen, Karlsruhe Institute of Technology, Forschungszentrum Karlsruhe, POB 3640, 76021 Karlsruhe,
Germany
Institut für Organische Chemie, Karlsruhe Institute of Technology, Universität Karlsruhe, Fritz-Haber-Weg 6, 76133 Karlsruhe, Germany
Fax +380(44)2251273; E-mail: pashamk@gmx.de
b
c
Received 11 May 2009; revised 19 May 2009
possibility of further asymmetric derivatization of 3. The
starting pyrrolidine 4 was obtained from dimethyl rac-
2,5-dibromohexanedioate 5a5 and (S)-1-phenylethyl-
amine according to the literature procedure (Scheme 1).6
Abstract: A new, conformationally rigid analogue of 2-amino-
adipic acid, 8-[(benzyloxy)carbonyl]-3-methylene-8-azabicyc-
lo[3.2.1]octane-1,5-dicarboxylic acid, is synthesized from dimethyl
rac-2,5-dibromohexanedioate. The key steps involve alkylation–
cyclization of 1-benzyl 2,5-dimethyl pyrrolidine-1,2,5-tricarboxy- Next, treatment of pyrrolidine 4 with lithium diisopropyl-
late with 3-chloro-2-(chloromethyl)prop-1-ene to yield the 8-azabi-
amide (1.15 equiv) at –78 °C for two hours, followed by
cyclo[3.2.1]octane skeleton.
subsequent addition of 1-bromo-3-chloropropane (1.5
Key words: conformational restriction, bicyclic compounds, pyr-
rolidines, alkylations, cyclization
equiv), afforded compound 6 in 40% yield as a single dia-
stereomer.7 The addition of hexamethylphosphoramide
(HMPA) (4–6 equiv) as a cosolvent8 was found to be cru-
cial for the success of this step.9 Despite the fact that prep-
The concept of conformational restriction has been widely aration of the 8-azabicyclo[3.2.1]octane skeleton via
utilized to modify the physical, chemical and biological intramolecular alkylation of substituted pyrrolidines has
characteristics of organic compounds.1 In particular, ap- already been described in the literature,10 all our attempts
plication of this concept to a-amino acids is of significant to cyclize 6 were unsuccessful. Reacting substituted pyr-
practical interest since conformationally restricted amino rolidine 6 with various bases (lithium diisopropylamide,
acids, upon replacing their natural analogues, have been sodium hydride, lithium hexamethyldisilazide or potassi-
used to improve the pharmacological properties of pep- um hexamethyldisilazide) in the presence of hexameth-
tides and peptidomimetics.2 (2R)-Aminoadipic acid (1) is ylphosphoramide did not produce 7 even at room
a
selective competitive N-methyl D-aspartic acid temperature. Upon increasing the temperature, a complex
(NMDA) glutamate receptor antagonist.3 We recently mixture was formed from which the target compound 7
prepared its non-chiral, conformationally rigid analogue 2 was isolated, albeit in a very poor yield (less than 1%).
which contains a 7-azabicyclo[2.2.1]heptane skeleton.4
Herein we report our studies on the synthesis of bicyclic
compounds of type 3, analogues of (2R)-aminoadipic
acid, possessing a conformationally rigid 8-azabicyc-
To reduce steric hindrance at the reaction center in 6,
which may be preventing the alkylation, we replaced the
chiral phenylethylamine auxiliary with the less bulky ben-
zylamine moiety.11 The corresponding analogue 9 was ob-
lo[3.2.1]octane skeleton (Figure 1).
tained in 44% yield from pyrrolidine 84 using the same
strategy as that applied for the synthesis of 6. However,
cyclization of 9 into bicyclic compound 10 did not occur.
R
HO2C
CO2H
CO2H
Next, the suitability of the benzyloxycarbonyl (Cbz) N-
protecting group was investigated. Mono-alkylation of 11
(itself prepared via removal of the benzyl group in 8 and
N-protection of the resulting product using benzyl chloro-
formate) on reaction with 1-bromo-3-chloropropane gave
a mixture of diastereomers 12a,b (3:1) in an improved
79% yield. However, all attempts to prepare the desired 8-
azabicyclo[3.2.1]octane skeleton 13 failed. Exchanging
the chloride leaving group for the more labile iodide
(compound 14) did not improve the situation (Scheme 2).
HO2C
HO2C
CO2H
N
H
H2N
N
H
1
2
3
Figure 1 The structures of (2R)-Aminoadipic acid and conforma-
tionally rigid analogues
Initially, a strategy involving consecutive bis-alkylation
of the corresponding protected 2,5-dicarbomethoxypyrro-
lidine was investigated to prepare the unsubstituted rigid
amino acid 3a (R = H). The chiral phenylethyl residue
was chosen as an N-protecting group in order to enable the
Recently, Stevens et al. reported that 3-chloro-2-(chlo-
romethyl)prop-1-ene was an efficient reagent for the alky-
lation of pyroglutamic acid derivatives in their synthesis
of a 6-azabicyclo[3.2.1]octane cage system.12 In fact,
mono-alkylation of 11 with 3-chloro-2-(chlorometh-
SYNTHESIS 2009, No. 19, pp 3327–3331
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216963; Art ID: Z09309SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3328
V. S. Kubyshkin et al.
PAPER
Cl
Br
c
a
b
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
MeO2C
N
N
N
CO2Me
31%
40%
trace
Ph
Ph
Ph
Br
Br
5a
4
6
7
Cl
b
d
CO2Me
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
N
N
N
71%
44%
Ph
Ph
Ph
Br
5b
10
8
9
Scheme 1 Reagents and conditions: (a) (i) (S)-1-phenylethylamine (1 equiv), K2CO3 (3 equiv), toluene–H2O, reflux, 30 h, (ii) NaOMe–
MeOH, H2O, r.t., 36 h; (b) (i) LDA (1.15 equiv), HMPA (5 equiv), THF, –78 °C, 2 h, (ii) 1-bromo-3-chloropropane (1.5 equiv), –78 °C to r.t.,
12 h; (c) LDA (1.5 equiv), HMPA (5 equiv), THF, (i) –78 °C to r.t., 12 h, or (ii) reflux, 10 h; (d) 1-phenylmethanamine (1 equiv), K2CO3
(3 equiv), toluene–H2O, reflux, 30 h.
Cl
a
b
MeO2C
CO2Me
MeO2C
CO2Me
N
N
MeO2C
CO2Me
79%
96%
N
Cbz
Ph
Cbz
CO2Me
MeO2C
N
8
12a,b
11
Cbz
I
c
13
d
80%
MeO2C
CO2Me
48%
N
Cl
Cbz
e
14
MeO2C
CO2Me
MeO2C
CO2Me
N
N
33%
Cbz
Cbz
16
15a,b
Scheme 2 Reagents and conditions: (a) (i) H2, 5% Pd/C, 40 °C, 48 h, (ii) CbzCl (1.1 equiv), K2CO3, H2O, r.t., 12 h; (b) (i) LDA (1.05 equiv),
HMPA (5 equiv), THF, –78 °C, 2 h, (ii) 1-bromo-3-chloropropane (1.5 equiv), –78 °C to r.t., 12 h; (c) (i) LDA (1.15 equiv), HMPA (5 equiv),
THF, –78 °C, 2 h, (ii) 1,3-diiodopropane (1.5 equiv), –78 °C to r.t., 12 h; (d) (i) LDA (1.15 equiv), HMPA (5 equiv), THF, –78 °C, 2 h,
(ii) 3-chloro-2-(chloromethyl)prop-1-ene (1.5 equiv), –78 °C to r.t., 12 h; (e) LDA (1.5 equiv), HMPA (5 equiv), THF, (i) –78 °C, 2 h,
(ii) –78 °C to r.t., 12 h.
yl)prop-1-ene smoothly afforded a mixture of the two dia- In summary, we have shown that intramolecular alkyla-
stereomeric alkenes 15a,b (3:4) in a good yield of 80%. tion of pyrrolidine derivatives to form the corresponding
Subsequent cyclization of the mixture of 15a,b with lithi- 8-azabicyclo[3.2.1]octane skeleton is highly dependent
um diisopropylamide in the presence of hexamethylphos- on both the alkylating agent and the N-protecting group.
phoramide produced the target 8-azabicyclo[3.2.1]octane The benzyloxycarbonyl group was found to be superior
16 in 33% yield. Attempts to transform 11 into 16 via a than benzyl and phenylethyl groups in the above-
one-step bis-alkylation were only partially successful re- mentioned reactions. 3-Chloro-2-(chloromethyl)prop-1-
sulting in a mixture of the target compound 16, starting ene was shown to be an efficient electrophilic agent for
material 11, and the mono-alkylated diastereomeric prod- constructing this cage system. The conformationally rigid
ucts 15a,b. Finally, basic hydrolysis of 16 afforded the analogue of 2-aminoadipic acid, Cbz-3b was obtained in
target compound, Cbz-3b (Scheme 3).
good yield and the preparation of other representative ex-
amples is ongoing.
Starting materials and reagents were purchased from Acros, Merck,
Fluka and Enamine. Solvents were purified according to standard
procedures. Melting points were recorded using a Büchi 510 melt-
ing point apparatus and are uncorrected. Analytical TLC was con-
ducted using Polychrom SIF254 plates. Column chromatography
was performed using Kieselgel Merck 60 silica gel (230–400 mesh)
as the stationary phase. 1H and 13C NMR spectra were recorded ei-
ther on a Varian Unity Plus 400 spectrometer (at 400.4 and 100.7
MHz, respectively) or on a Bruker Avance 500 spectrometer (at
a
MeO2C
CO2Me
HOOC
COOH
N
N
97%
Cbz
Cbz
16
Cbz-3b
Scheme 3 Reagents and conditions: (a) NaOH (10 equiv), MeOH–
H2O–THF (5:8:5), r.t., 96 h.
Synthesis 2009, No. 19, 3327–3331 © Thieme Stuttgart · New York

PAPER
A Conformationally Rigid Analogue of 2-Aminoadipic Acid
3329
499.9 or 124.9 MHz) using CDCl3 or CD3OD as solvent. Chemical
shifts are reported in ppm downfield from TMS as the internal stan-
dard. Mass spectra were recorded on an Agilent 1100 LCMSD SL
instrument by chemical ionization (CI). Elemental analyses were
obtained using a Elementar Vario MICRO cube instrument.
1H NMR (CDCl3, 400 MHz): d = 7.30–7.21 (m, 5 H, Ph), 3.91 (d,
2JH–H = 13.6 Hz, 1 H, CH2Ph), 3.74 (s, 3 H, OCH3), 3.66 (d, 2JH–H
13.6 Hz, 1 H, CH2Ph), 3.61 (dd, J = 12.8, 3.2 Hz, 1 H, CHCO2Me),
3.49 (t, J = 6.0 Hz, 2 H, CH2Cl), 3.45 (s, 3 H, OCH3), 2.30 (m, 1 H),
2.20–1.91 (m, 4 H), 1.89–1.77 (m, 3 H).
=
13C NMR (CDCl3, 100 MHz): d = 174.11 (s, CO2Me), 173.87 (s,
CO2Me), 139.06 (s, C, Ph), 128.99 (s, CH, Ph), 128.63 (s, CH, Ph),
128.01 (s, CH, Ph), 71.87 (s, NCCO), 65.11 (s, NCHCO), 52.93 (s,
NCH2), 51.34 (s, OCH3), 51.02 (s, OCH3), 45.82 (s, CH2Cl), 33.51
(s, CH2), 32.24 (s, CH2), 28.12 (s, CH2), 27.68 (s, CH2).
Mono-alkylated Pyrrolidines 6, 9, 12a,b, 14 and 15a,b; General
Procedure
To a soln of the N-protected 2,5-dicarbomethoxypyrrolidine (1
equiv) and HMPA (4–6 equiv) in THF at –78 °C was added drop-
wise a soln of LDA (1.15 equiv) in THF. The resulting black mix-
ture was stirred for 2 h at –78 °C followed by slow addition of the
alkylating agent (1.5 equiv). The reaction mixture was left to stir
overnight (12 h) whilst gradually warming to r.t. The reaction mix-
ture was quenched with saturated NH4Cl (50 mL), THF was re-
moved under vacuum. Extraction with EtOAc (3 × 100 mL), drying
over MgSO4, filtration, and evaporation followed by flash column
chromatography (silica gel, hexane–EtOAc mixtures) afforded the
products as colorless oils. Typical reaction scale was 1–3 g of start-
ing material.
MS (CI): m/z (%) = 356.4 [(M+ + H), 37Cl], 354.4 [(M+ + H), 35Cl].
1-Benzyl 2,5-Dimethyl 2-(3-Chloropropyl)pyrrolidine-1,2,5-tri-
carboxylate (12a, 12b)
LDA (1.05 equiv) was used in this experiment; the use of LDA
(1.15 equiv) led to formation of a substantial amount (ca. 10%
yield) of bis-alkylated product 12c.
Data for 12a: Colorless oil; yield: 59%; Rf = 0.35 (hexane–EtOAc,
5:1).
1H NMR (CDCl3, 400 MHz): d (mixture of rotamers) = 7.39–7.18
(m, 5 H, Ph), 5.11–4.91 (m, 2 H, OCH2), 4.50 (2 × dd, J = 9.2, 3.2
Hz, 1 H, NCH), 3.64, 3.59, 3.51, 3.35 (4 × s, 6 H, OCH3), 3.42 (m,
2 H, CH2Cl), 2.36–2.27 (m, 1 H), 2.26–1.92 (m, 4 H), 1.92–1.70 (m,
3 H).
13C NMR (CDCl3, 100 MHz): d (mixture of rotamers) = 174.18,
173.95, 173.04, 172.86 (4 × s, CO2Me), 154.82, 154.14 (2 × s,
NCO), 136.43, 136.14 (2 × s, C, Ph), 128.62, 128.55, 128.50,
128.41, 128.04, 127.57 (6 × s, CH, Ph), 70.05, 69.15 (2 × s, NCCO),
67.75, 67.25 (2 × s, OCH2), 61.92, 61.03 (2 × s, NCHCO), 52.73,
52.49, 52.42, 52.24 (4 × s, OCH3), 45.54, 45.43 (2 × s, CH2Cl),
35.79, 34.43, 32.57, 31.73 (4 × s, CH2CH2), 27.45, 27.33, 27.11,
26.81 (4 × s, CH2CH2).
8-Azabicyclo[3.2.1]octanes 7 and 16; General Procedure
To a soln of the mono-alkylated N-protected 2,5-dicarbomethoxy-
pyrrolidine (1 equiv) and HMPA (4–6 equiv) in THF at –78 °C was
slowly added LDA (1.5 equiv) in THF. The reaction mixture was
left to stir overnight (12 h) whilst gradually warming to r.t.; in the
case of 6, the reaction mixture was additionally heated under reflux
for 10 h. The reaction mixture was quenched with saturated NH4Cl
(50 mL), THF was removed under vacuum. Extraction with EtOAc
(3 × 100 mL), drying over MgSO4, filtration, and evaporation and
purification by flash column chromatography (silica gel, hexane–
EtOAc mixtures) gave the cyclized products 7 and 16 as colorless
oils. Typical reaction scale was 1–3 g of starting material.
Dimethyl (5R)-2-(3-Chloropropyl)-1-[(1S)-1-phenylethyl]pyr-
rolidine-2,5-dicarboxylate (6)
Colorless oil; yield: 40%; Rf = 0.70 (hexane–EtOAc, 2:1).
MS (CI): m/z (%) = 400.0 [(M+ + H), 37Cl], 398.0 [(M+ + H), 35Cl].
Data for 12b: Colorless oil; yield: 20%; Rf = 0.20 (hexane–EtOAc,
5:1).
1H NMR (CDCl3, 400 MHz): d = 7.24–7.14 (m, 5 H, Ph), 4.24 (q,
J = 7.2 Hz, 1 H, NCHCH3), 3.81 (d, J = 8.8 Hz, 1 H, CHCO2Me),
3.60 (m, 2 H, CH2Cl), 3.51 (s, 3 H, OCH3), 3.36 (s, 3 H, OCH3),
2.35 (m, 1 H), 2.21–1.96 (m, 5 H), 1.90 (m, 1 H), 1.67 (dd, J = 6.8,
3.2 Hz, 1 H), 1.30 (d, J = 7.2 Hz, 3 H, NCHCH3).
13C NMR (CDCl3, 100 MHz): d = 175.39 (s, CO2Me), 174.14 (s,
CO2Me), 143.93 (s, C, Ph), 128.64 (s, CH, Ph), 128.16 (s, CH, Ph),
127.63 (s, CH, Ph), 70.65 (s, NCCO), 63.73 (s, NCHCO), 60.71 (s,
NCHCH3), 51.55 (s, OCH3), 51.26 (s, OCH3), 45.77 (s, CH2Cl),
33.45 (s, CH2), 32.31 (s, CH2), 29.38 (s, CH2), 28.68 (s, CH2), 22.45
(s, NCHCH3).
1H NMR (CDCl3, 400 MHz): d (mixture of rotamers) = 7.41–7.17
(m, 5 H, Ph), 5.25–4.93 (m, 2 H, OCH2), 4.48 (dd, J = 12.0, 8.8 Hz,
0.3 H, NCH), 4.37 (dd, J = 8.0, 4.4 Hz, 0.7 H, NCH), 3.75, 3.54,
3.53, 3.47 (4 × s, 6 H, OCH3), 3.50 (m, 2 H, CH2Cl), 2.43–1.51 (m,
8 H).
13C NMR (CDCl3, 100 MHz): d (mixture of rotamers) = 172.84,
172.77, 171.84, 171.18 (4 × s, CO2Me), 153.26, 152.76 (2 × s,
NCO), 136.86, 136.69 (2 × s, C, Ph), 128.73, 128.56, 128.40,
128.26, 127.95, 127.88 (6 × s, CH, Ph), 69.26, 68.31 (2 × s, NCCO),
67.30, 67.10 (2 × s, OCH2), 61.35, 60.60 (2 × s, NCHCO), 52.25,
52.13, 52.08, 51.88 (4 × s, OCH3), 44.54, 44.50 (2 × s, CH2Cl),
35.82, 34.66, 33.54, 32.67 (4 × s, CH2CH2), 29.97, 29.25, 28.29,
28.18 (4 × s, CH2CH2).
MS (CI): m/z (%) = 370.4 [(M+ + H), 37Cl], 368.4 [(M+ + H), 35Cl].
Dimethyl 8-[(1S)-1-Phenylethyl]-8-azabicyclo[3.2.1]octane-1,5-
dicarboxylate (7)
MS (CI): m/z (%) = 400.0 [(M+ + H), 37Cl], 398.0 [(M+ + H), 35Cl].
Colorless oil; yield: <1%; Rf = 0.45 (hexane–EtOAc, 4:1).
1-Benzyl 2,5-Dimethyl 2,5-Bis(3-chloropropyl)pyrrolidine-
1,2,5-tricarboxylate (12c)
LDA (1.15 equiv) was used in this experiment.
1H NMR (CDCl3, 400 MHz): d = 7.42 (d, J = 7.6 Hz, 2 H, Ph), 7.25
(t, J = 7.6 Hz, 2 H, Ph), 7.15 (t, J = 7.6 Hz, 1 H, Ph), 4.18 (q, J = 6.8
Hz, 1 H, NCHCH3), 3.78 (s, 3 H, OCH3), 2.79 (s, 3 H, OCH3), 2.46
(ddd, J = 13.2, 4.4, 1.6 Hz, 1 H), 2.42 (ddd, J = 11.6, 4.4, 1.6 Hz, 1
H), 2.30 (tdd, J = 12.0, 4.0, 1.6 Hz, 1 H), 2.01 (dd, J = 12.8, 5.6 Hz,
1 H), 1.93–1.72 (m, 6 H), 1.21 (d, J = 6.8 Hz, 3 H, NCHCH3).
Colourless oil; yield: 10%; Rf = 0.50 (hexane–EtOAc, 5:1).
1H NMR (CDCl3, 400 MHz): d = 7.42–7.25 (m, 5 H, Ph), 5.12 (d,
2JH-H = 12.0 Hz, 1 H, OCH2), 4.98 (d, 2JH-H = 12.0 Hz, 1 H, OCH2),
3.72 (s, 3 H, OCH3), 3.51 (m, 2 H, CH2Cl), 3.45 (s, 3 H, OCH3),
3.40 (t, J = 6.8 Hz, 2 H, CH2Cl), 2.25 (t, J = 6.4 Hz, 2 H), 2.16 (m,
4 H), 2.10–1.80 (m, 6 H).
13C NMR (CDCl3, 100 MHz): d = 173.98 (s, CO2Me), 173.78 (s,
CO2Me), 153.63 (s, NCO), 136.05 (s, C, Ph), 128.68 (s, CH, Ph),
128.64 (s, CH, Ph), 128.50 (s, CH, Ph), 71.08 (s, NCCO), 70.02 (s,
MS (CI): m/z (%) = 332.4 [(M+ + H)].
Dimethyl 1-Benzyl-2-(3-chloropropyl)pyrrolidine-2,5-dicar-
boxylate (9)
Colorless oil; yield: 44%; Rf = 0.60 (hexane–EtOAc, 4:1).
Synthesis 2009, No. 19, 3327–3331 © Thieme Stuttgart · New York

3330
V. S. Kubyshkin et al.
PAPER
NCCO), 67.55 (s, OCH2), 52.79 (s, OCH3), 52.44 (s, OCH3), 45.69
(s, CH2Cl), 45.47 (s, CH2Cl), 34.93 (s, CH2), 33.87 (s, CH2), 33.36
(s, CH2), 32.49 (s, CH2), 28.14 (s, CH2), 27.93 (s, CH2).
Anal. Calcd for C20H24ClNO6: C, 58.61; H, 5.90; N, 3.42. Found: C,
58.63; H, 5.88; N, 3.19.
8-Benzyl 1,5-Dimethyl 3-Methylene-8-azabicyclo[3.2.1]octane-
1,5,8-tricarboxylate (16)
Colorless oil; yield: 33%; Rf = 0.55 (hexane–EtOAc, 2:1).
MS (CI): m/z (%) = 476.0 [(M+ + H), 37Cl/35Cl], 474.0 [(M+ + H),
35Cl/ 35Cl].
1-Benzyl 2,5-Dimethyl 2-(3-Iodopropyl)pyrrolidine-1,2,5-tri-
carboxylate (14)
Colorless oil; yield: 48%; Rf = 0.50 (hexane–EtOAc, 3:1).
1H NMR (CDCl3, 500 MHz): d = 7.38–7.25 (m, 5 H, Ph), 5.08–5.03
(2 × br s, 4 H, OCH2, =CH2), 3.91–3.25 (br s, 6 H, OCH3), 2.81–2.62
(br s, 2 H, CH2), 2.54–2.50 (2 × s, 2 H, CH2), 2.29 (d, J = 6.5 Hz, 2
H, CH2), 1.84 (d, J = 6.5 Hz, 2 H, CH2).
13C NMR (CDCl3, 125 MHz): d = 171.61 (s, CO2Me), 154.45 (s,
NCO), 139.91 (s, C=CH2), 135.33 (s, C, Ph), 128.52 (s, CH, Ph),
128.46 (s, CH, Ph), 128.40 (s, CH, Ph), 115.65 (s, C=CH2), 68.10
(s, OCH2), 67.88 (br s, NCCO), 52.30 (s, OCH3), 40.28 (br s,
CH2=CCH2), 33.75 (br s, CH2CH2).
1H NMR (CDCl3, 400 MHz): d (mixture of rotamers) = 7.35–7.15
(m, 5 H, Ph), 5.25–4.80 (m, 2 H, OCH2), 4.46 (dd, J = 9.2, 3.2 Hz,
1 H, NCH), 3.61, 3.56, 3.48, 3.31 (4 × s, 6 H, OCH3), 3.20–2.81 (m,
2 H, CH2I), 2.25–1.71 (m, 8 H).
13C NMR (CDCl3, 100 MHz): d = 174.08, 173.88, 172.97, 172.80
(4 × s, CO2Me), 154.76, 154.09 (2 × s, NCO), 136.42, 135.98 (2 ×
s, C, Ph), 128.62, 128.57, 128.50, 128.40, 128.03, 127.55 (6 × s,
CH, Ph), 69.80, 68.92 (2 × s, NCCO), 67.74, 67.23 (2 × s, OCH2),
61.91, 61.03 (2 × s, NCHCO), 52.73, 52.49, 52.45, 52.27 (4 × s,
OCH3), 35.98, 35.87, 35.14, 34.41 (4 × s, CH2CH2), 28.32, 27.96,
27.44, 26.81 (4 × s, CH2CH2), 7.34, 7.16 (2 × s, CH2I).
MS (CI): m/z (%) = 374 [(M+ + H)], 330 [(M+ – CO2)], 240 [(M+ –
Cbz)].
Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C,
64.29; H, 6.26; N, 3.59.
MS (CI): m/z (%) = 490.0 (M+ + H).
8-[(Benzyloxy)carbonyl]-3-methylene-8-azabicyclo[3.2.1]oct-
ane-1,5-dicarboxylic Acid (Cbz-3b)
1-Benzyl 2,5-Dimethyl 2-[2-(Chloromethyl)prop-2-en-1-yl]pyr-
rolidine-1,2,5-tricarboxylate (15a, 15b)
Data for 15a: Colorless oil; yield: 34%; Rf = 0.45 (hexane–EtOAc,
2:1).
1H NMR (CDCl3, 400 MHz): d (mixture of rotamers) = 7.39–7.30
(m, 5 H, Ph), 5.41–4.86 (m, 4 H, OCH2, =CH2), 4.57 (2 × dd,
J = 8.8, 4.8 Hz, 1 H, NCH), 4.29–4.08 (m, 2 H, CH2Cl), 3.77, 3.73,
3.61, 3.43 (4 × s, 6 H, OCH3), 3.38, 3.27 (2 × d, 2JH-H = 14.4 Hz, 1
H, C-CH2-C=CH2), 3.88, 3.75 (2 × d, 2JH-H = 14.4 Hz, 1 H, C-CH2-
C=CH2), 2.25 (m, 2 H, CH2), 1.06 (m, 2 H, CH2).
13C NMR (CDCl3, 100 MHz): d (mixture of rotamers) = 174.11,
173.82, 172.61, 172.44 (4 × s, CO2Me), 155.16, 154.66 (2 × s,
NCO), 141.21, 141.17 (2 × s, C=CH2), 136.36, 135.77 (2 × s, C, Ph),
128.79, 128.52, 128.44, 128.40, 128.13, 127.87 (6 × s, CH, Ph),
120.73, 120.05 (2 × s, C=CH2), 70.17, 69.27 (2 × s, NCCO), 67.95,
67.46 (2 × s, OCH2), 62.38, 61.45 (2 × s, NCHCO), 52.76, 52.58,
52.43, 52.29 (4 × s, OCH3), 49.15, 48.88 (2 × s, CH2Cl), 37.39,
37.16 (2 × s, CH2=CCH2), 35.54, 34.26, 27.57, 26.98 (4 × s,
CH2CH2).
To a stirred soln of 16 (300 mg, 0.80 mmol) in MeOH–THF (10 mL,
1:1) was added dropwise a soln of NaOH (322 mg, 8.00 mmol, 10
equiv) in H2O (8 mL), and the resulting suspension was stirred for
96 h. The solvent was evaporated and the residue was dissolved in
H2O (ca. 10 mL). The aq phase was extracted with CH2Cl2 (3 × 2
mL), acidified to pH 2 with aq HCl and then extracted with EtOAc
(3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4
and evaporated to afford Cbz-3b as a white solid; yield: 269 mg
(97%); mp 199–201 °C.
1H NMR (CDCl3, 400 MHz): d = 7.38–7.24 (m, 5 H, Ph), 5.12–5.05
(2 × br s, 4 H, OCH2, =CH2), 2.80–2.60 (br s, 2 H, CH2), 2.56–2.52
(2 × s, 2 H, CH2), 2.34 (d, J = 7.2 Hz, 2 H, CH2), 1.91 (d, J = 7.2 Hz,
2 H, CH2).
13C NMR (CD3OD, 100 MHz): d = 174.92 (s, COOH), 156.44 (s,
NCO), 141.85 (s, C=CH2), 137.16 (s, C, Ph), 129.54 (s, CH, Ph),
129.24 (s, CH, Ph), 129.16 (s, CH, Ph), 116.17 (s, C=CH2), 69.68
(br s, NCCO), 69.06 (s, OCH2), 41.06 (br s, CH2=CCH2), 35.18 (br
s, CH2CH2).
MS (CI): m/z (%) = 345 (M+), 301 (M+ – CO2).
MS (CI): m/z (%) = 409 [(M+), 35Cl], 374 [(M+ – 35Cl)].
Anal. Calcd for C18H19NO6: C, 62.60; H, 5.55; N, 4.06. Found: C,
62.35; H, 5.78; N, 4.32.
Anal. Calcd for C20H24ClNO6: C, 58.61; H, 5.90; N, 3.42. Found: C,
58.61; H, 5.92; N, 3.09.
Data for 15b: Colorless oil; yield: 46%; Rf = 0.30 (hexane–EtOAc,
2:1).
References
(1) Hassian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241.
(2) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789. (b) Cativiela,
C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645. (c) Cativiela, C.; Díaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517. (d) Park, K.-H.;
Kurth, M. J. Tetrahedron 2002, 58, 8629. (e) Cativiela, C.;
Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18,
569.
(3) (a) Biscoe, T. J.; Evans, R. H.; Francis, A. A.; Martin, M. R.;
Watkins, J. C.; Davies, J.; Dray, A. Nature 1977, 270, 743.
(b) McLennan, H.; Hall, J. G. Brain Res. 1978, 149, 541.
(c) Lodge, D.; Headley, P. M.; Curtis, D. R. Brain Res. 1978,
152, 603.
1H NMR (CDCl3, 400 MHz): d (mixture of rotamers) = 7.53–7.44
(m, 5 H, Ph), 5.45–5.11 (m, 4 H, OCH2, =CH2), 4.43 (2 × dd,
J = 8.8, 3.2 Hz, 1 H, NCH), 4.06–3.88 (4 × d, 2JH-H = 12.4 Hz, 2 H,
CH2Cl), 3.78, 3.76, 3.58, 3.54 (4 × s, 6 H, OCH3), 3.22, 3.07 (2 ×
d, 2JH-H = 14.4 Hz, 1 H, C-CH2-C=CH2), 3.73–3.69 (2 × d, 2JH-H
9.6 Hz, 1 H, C-CH2-C=CH2), 2.38–2.01 (m, 4 H, CH2CH2).
=
13C NMR (CDCl3, 100 MHz): d (mixture of rotamers) = 173.31,
173.03, 172.14, 171.84 (4 × s, CO2Me), 153.86, 153.47 (2 × s,
NCO), 141.47, 141.16 (2 × s, C=CH2), 136.24, 135.73 (2 × s, C, Ph),
128.52, 128.41, 128.43, 128.36, 128.17, 127.08 (6 × s, CH, Ph),
120.16, 119.68 (2 × s, C=CH2), 69.79, 68.80 (2 × s, NCCO), 67.81,
67.44 (2 × s, OCH2), 61.26, 60.57 (2 × s, NCHCO), 52.74, 52.56,
52.37, 52.18 (4 × s, OCH3), 48.64, 48.55 (2 × s, CH2Cl), 39.07, 37.4
(2 × s, CH2=CCH2), 36.06, 34.83, 28.25, 27.36 (4 × s, CH2CH2).
(4) Kubyshkin, V. S.; Mykhailiuk, P. K.; Komarov, I. V.
Tetrahedron Lett. 2007, 48, 4061.
(5) Dimethyl meso-2,5-dibromohexanedioate 5a was obtained
MS (CI): m/z (%) = 409 [(M+), 35Cl], 374 [(M+ – 35Cl)].
using an identical procedure to that described for diethyl
Synthesis 2009, No. 19, 3327–3331 © Thieme Stuttgart · New York

PAPER
A Conformationally Rigid Analogue of 2-Aminoadipic Acid
3331
meso-2,5-dibromohexanedioate, see: Guha, P. C.; Sankaran,
D. K. Org. Synth. 1955, 3, 623.
(8) (a) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994,
116, 9198. (b) Ferey, V.; Vedrenne, P.; Toupet, L.; Le Gall,
T.; Mioskowski, C. J. Org. Chem. 1996, 61, 7244.
(9) The conversion without addition of HMPA was only 15%
after 12 h at 20 °C. After 160 h, the transformation was
complete; however, in the 1H NMR spectrum of the crude
mixture, together with 6, a number of unidentified side
products were detected. All subsequent alkylations were
performed in the presence of HMPA.
(10) Xu, Y.-z.; Choi, J.; Calaza, M. I.; Turner, S.; Rapoport, H.
J. Org. Chem. 1999, 64, 4069.
(11) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. Synth.
Commun. 2000, 30, 1837.
(6) Three diastereomers of 4: meso-, (2R,5R)- and (2S,5S)- are
formed during the synthesis, each being suitable for
alkylation. We chose the crystalline (2R,5R)-isomer 4,
which was easily separated from the reaction mixture as it
crystallizes upon standing in a fridge; the product was
filtered off and was washed with hexane. For the original
procedure, see: Yamamoto, Y.; Hoshino, J.; Fujimoto, Y.;
Ohmoto, J.; Sawada, S. Synthesis 1993, 298.
(7) The configurations at C-2 and C-5 in compounds 6, 9, 12a,b,
14 and 15a,b were not determined since they are lost upon
subsequent transformation into the non-chiral 8-azabicy-
clo[3.2.1]octane skeleton.
(12) Masschelein, K. G. R.; Stevens, C. V.; Dieltiens, N.; Claeys,
D. D. Tetrahedron 2007, 63, 4712.
Synthesis 2009, No. 19, 3327–3331 © Thieme Stuttgart · New York