Azabicycloalkenes as synthetic intermediates - Synthesis of conformationally constrained glutamate analogues

Article abstract of DOI:10.1002/ejoc.200700104

As a part of our study of the cancer-specific protease PSMA (prostate-specific membrane antigen) we present a stereoselective synthesis of conformationally constrained glutamate mimetics. Key intermediates are azabicycloalkenes which are synthesized via d

Full text of DOI:10.1002/ejoc.200700104

FULL PAPER
DOI: 10.1002/ejoc.200700104
Azabicycloalkenes as Synthetic Intermediates – Synthesis of Conformationally
Constrained Glutamate Analogues
Wolfgang Maison*[a]
Keywords: Glutamate mimetics / Amino acids / Tumour marker / Peptidomimetics / Neurotransmitter
As a part of our study of the cancer-specific protease PSMA
(prostate-specific membrane antigen) we present a stereose-
lective synthesis of conformationally constrained glutamate
mimetics. Key intermediates are azabicycloalkenes which
are synthesized via diastereoselective or enantioselective
imino-Diels–Alder protocols. The versatility of the route is
demonstrated with the preparation of Asp, Glu and HGlu-
mimetics based on proline or pipecolic acid scaffolds. These
scaffolds are assembled by an oxidative cleavage of azabicy-
cloalkenes and subsequent conversions of the resulting dial-
dehydes via chlorite oxidation or Wittig olefination. The re-
sulting cyclic amino acids are obtained as Cbz-protected de-
rivatives or free amines ready for further manipulation at
their N-terminus and are useful as building blocks for the
assembly of conformationally rigid PSMA ligands.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
cesses involving 2-azabicycloalkenes have been reported by
our group to give diazabicycloalkanes 6.[10] Other known
domino reactions with scaffolds 1 include metathesis se-
quences, which are excellent methods for the synthesis of
indolizidine scaffolds 7.[11] In addition, bicyclic amino
alcohol derivatives like 8 have been prepared from 1 and
are used as ligands for asymmetric catalyses.[12]
Introduction
Strained and unsaturated heterocycles of the azabicy-
cloalkene type are extremely versatile synthetic intermedi-
ates for a number of different target structures. As ideal
synthetic intermediates, they are easy to synthesize in large
quantities by Diels–Alder chemistry from low-cost starting
materials[1] and have functional groups that can be ad-
dressed by a number of different chemical reactions. In this
respect, 2-azabicycloalkenes are particularly valuable, be-
cause of their rich follow-up chemistry resulting from their
unique strained bicyclic structure.[2] In addition, diastereo-
selective and enantioselective imino-Diels–Alder protocols
to azabicycloalkenes are well established[3] and a practical
catalytic enantioselective approach to carbamate-protected
2-azabicycloalkenes has recently been communicated by our
group.[4]
A selection of accessible target structures starting from
2- and 3-substituted azabicycloalkenes 1 is shown in Fig-
ure 1 and a lot more transformations are known for higher
substituted analogs of 1. The azabicycloalkene scaffold has
a unique reactivity with respect to the strained double
bond. This feature has been explored by several groups with
rearrangement reactions to give hydroisoquinolines 2[5] or
bicyclic urea derivatives 3.[6] Oxidative conversions of the
double bond are also valuable methods for the preparation
of cyclic amino acids 4 in peptide[7] and non-peptide con-
text.[8] In addition, bicyclic amines 1 are useful for the prep-
aration of diazabicycloalkanes 5.[9] Oxidative domino pro-
[a] Justus-Liebig-Universität Gießen, Institut für Organische
Chemie,
Heinrich-Buff-Ring 58, 35392 Giessen
Fax: +49-641-9919864
E-mail: wolfgang.maison@org.chemie.uni-giessen.de
Figure 1. Scaffolds accessible from 2-azabicycloalkenes.
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Synthesis of Conformationally Constrained Glutamate Analogues
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Special reactivity is also observed with respect to the eral neurological disorders.[21] In this context, Hodgson has
strained nitrogen heterocycle, a fact that has been explored reported an elegant racemic synthesis of kainoids starting
in different ring opening reactions. Bicyclic hydrazines like from 7-azabicycloalkenes recently.[22]
9[13] and amino alcohols 10[14] are thus accessible from N-
The most successful inhibitors of PSMA are analogs of
amino or N-hydroxy-azabicycloalkenes. Acidic and re- the transition state for peptide bond hydrolysis of NAAG
ductive cleavage of azabicycloalkenes gives cyclopentene de- (Figure 2) and are thus based on phosphonates, phosphan-
rivatives or chiral amines like 11,[15] which are valuable ates and phosphoramidates.[23] However, conformational
building blocks for carbocyclic nucleosides[16] and lactones constraint of the native substrate NAAG is also a valuable
12.[17] In this context it should also be noted that the 2- strategy for the design of new PSMA inhibitors. With con-
azabicycloalkene scaffold can be used as a general protec- formationally constrained glutamate analogs like 13–15 we
tion group for primary amines that is cleaved off via acid would like to synthesize building blocks for a combined
catalysed retro-Diels–Alder reaction.[18]
strategy of PSMA binding by conformationally constrained
In this paper we report the application of the above men- transition state analogues which would be accessible by N-
tioned oxidative cleavage strategy of 2-azabicycloalkenes to terminal phosphorylation of cyclic amino acids of type 13–
the synthesis of conformationally constrained aspartate, 15.
glutamate and homoglutamate derivatives. These com-
pounds are interesting building blocks for the synthesis of
Asp-Glu dipeptide mimetics. In this context we have been
investigating conformationally constrained mimetics of N-
Results and Discussion
acetylaspartyl glutamate (NAAG) for a while.[19] NAAG is
an important neurotransmitter and the natural substrate of
a cancer-specific protease called prostate-specific membrane
antigen (PSMA) which we have used successfully for im-
aging of prostate cancer cells with low molecular weight
ligands.[20]
In addition, aspartate and glutamate are the major excit-
atory neurotransmitters and our targeted mimetics might
thus be of general interest as new ligands for glutamate re-
ceptors which are known to play an important role in sev-
Figure 3 shows two stereoselective strategies to 19. Key
steps are either enantioselective (route A) or diastereoselec-
tive (route B) imino-Diels–Alder reactions to bicyclic inter-
mediates 16 and 17, respectively. Both routes are short (4–
6 steps) and should give amino acids 18 or 19 with two
additional side chains attached to a proline or pipecolic
acid scaffold. This adds an additional negative charge to
our glutamate mimetics, which is known to enhance the
binding properties of PSMA ligands. For later phosphory-
lation at the N-terminus, the desired amino acids 19 would
have to be synthesized with a free amine and base labile
protection at the carboxylic acids.[24]
Figure 3. Retrosynthesis of cyclic amino acids 18–19.
The synthesis of intermediate amino diols 17 was ac-
complished by a diastereoselective imino-Diels–Alder reac-
tion followed by a twofold hydroxylation and deprotection
as described previously.[25] Diastereoselective Diels–Alder
conversions of imino-dienophiles are known to proceed with
a high degree of stereoselectivity if the chiral information is
present at the N-terminus of the starting imine. We chose
phenylethylamine as a cheap source of chirality, following
known procedures for the cycloaddition to azabicyclohep-
tene 20 and azabicyclooctene 21.[26] An advantage of this
diastereoselective approach is its easy scale up especially for
tert-butyl esters like 23 because all intermediates are easy
Figure 2. Conformationally constrained amino acids and the di-
peptide NAAG, the natural substrate of PSMA.
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to purify by crystallisation. N-terminal protection was
achieved with Cbz-Cl following a standard procedure to
give both diols 24 and 25 (Scheme 1) in good yields.
Scheme 2. Enantioselective synthesis of carbamate-protected aza-
bicycloalkene 26.
Intermediate diols 24, 25 and the olefine 26 are all suit-
able for conversion to dialdehydes 27 or 28 as shown in
Scheme 3. Either ozonolysis of azabicycloalkene 26 or per-
iodate cleavage of diols 24 or 25 gave dialdehydes 27 or 28
in very clean conversions as determined by 1H-NMR of the
crude product which is more than 90% pure. Crude dialde-
hydes 27 and 28 can be stored at –18 °C for a month. How-
ever, they are configurationally labile on silica gel and were
therefore used for further transformations without purifica-
tion.
Scheme 1. Diastereoselective synthesis of Cbz-protected aminodiols
24 and 25.
Scheme 3. Oxidative cleavage to dialdehydes 27 and 28.
A much shorter alternative is the enantioselective synthe-
sis of Cbz-protected azabicycloalkene 26 via the copper-cat-
Dialdehydes 27 and 28 are versatile intermediates for the
alyzed Diels–Alder reaction depicted in Scheme 2. Copper- synthesis of different amino acid mimetics, because the al-
catalyzed enantioselective imino-Diels–Alder reactions have dehyde may be converted into almost any functionality
been developed by Jørgensen[27] and a useful protocol for present in amino acid side chains.
the application of this approach to the synthesis of carba-
Our first target structures were aspartate mimetics 30
mate-protected azabicycloalkenes has recently been com- and 32 which were synthesized as depicted in Scheme 4.
municated by our group.[4] However, this approach is lim- Chlorite oxidation of dialdehydes 27 and 28 gave carboxylic
ited to azabicycloheptenes, which are obtained in good yield acids 29 and 31 in excellent yields and without epimer-
and enantioselectivity. For the corresponding Diels–Alder isation of the relatively labile α-amino aldehyde moiety. In
conversions with cyclohexadiene to azabicyclooctenes, the proline series the carboxylic acid 29 was converted into
yields and enantioselectivities were generally found to be the methyl ester using thionyl chloride in methanol. Under
low. In consequence, we use the diastereoselective approach these conditions a transesterification of the ethyl ester in 29
outlined in Scheme 1 for the synthesis of azabicyclooctenes occurred to give an all-methyl ester intermediate which was
like 21 and if large quantities of enantiomerically pure in- deprotected with hydrogen and Pd/C to give 30 as the free
termediates 20 or 21 are needed.
amine.
Scheme 4. Synthesis of aspartate mimetics 30 and 32.
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Scheme 5. Synthesis of glutamate mimetics 34 and 36.
The tert-butyl ester in 28 caused an additional deprotec- not isolated, but treated subsequently with silver trifluo-
tion step in the pipecolic acid series, because we needed roacetate in methanol to give methyl esters 33 and 35 in
base labile protection for the carboxylic acids in our final Scheme 5. In the proline series, 33 was deprotected at the
products. This is due to the planed derivatisation of the N-terminus with Pd/C and hydrogen to give the free amine
amino termini to transition state analogs like phosphor- 34 in quantitative yield.
amidates. However, derivative 28 is useful due to the easy
In the pipecolic acid series, 35 was treated with TFA to
purification of tert-butyl ester derivatives in this series. Oxi- deprotect the tert-butyl ester, followed by reprotection of
dation of dialdehyde 28 gave the diacid 31 which was depro- the resulting carboxylic acid as the methyl ester and Cbz-
tected with TFA to give a tricarboxy piperidine in quantita- deprotection under standard hydrogenolytic conditions to
tive yield. Esterification to the methyl ester was again per- give the free amine 36.
formed with thionyl chloride in methanol followed by Cbz-
Further homologation to homoglutamate mimetics is de-
deprotection using Pd/C and hydrogen to give the free picted in Scheme 6 and was achieved by a Wittig olefination
amine 32 ready for further manipulation at the N-terminus. of aldehydes 27 and 28 to give both diolefines 37 and 39 in
The stereochemistry of pyrrolidine and piperidine deriva- excellent yields. Treatment of 37 with hydrogen and Pd/C in
tives 30 and 32 was at this point determined unambiguously methanol gave directly the homoglutamate mimetic 38.
by 2D-NOESY experiments.
Again two steps more were needed in the pipecolic acid
Dicarboxylic acids 29 and 31 are ideal intermediates for series. Carboxylic acid 39 was obtained in a two step se-
Arndt–Eistert homologation to give Cbz-protected gluta- quence by treatment of an intermediate Wittig adduct syn-
mate mimetics 33 and 35. We have used a standard method thesized from dialdehyde 28 with TFA. Subsequent treat-
for homologation of carboxylic acids with isobutyl chloro- ment of carboxylic acid 39 with MeOH and SOCl2 then
formiate giving a mixed anhydride intermediate that was gave the trimethyl ester 40 in acceptable 63% yield. In this
treated with diazomethane. The resulting diazo ketone was case we learned that, unlike the conversion of 37 to 38 in
Scheme 6. Synthesis of homoglutamate mimetics 38 and 42.
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the proline series, hydrogenolysis of the Cbz-protected tri- the coupling constant (6.3 Hz) change to the expected val-
1
methyl ester 40 under standard conditions in MeOH leads ues for non-acylated piperidines if the H NMR spectrum
to almost complete cyclization to the undesired lactam 41. of 36 is measured in [D4]MeOH instead of CDCl3.
However, the target homoglutamate mimetic 42 is obtained
quantitatively as a hydrochloride salt upon hydrogenolysis
of 40 in acidic methanol. It should be noted that intra-
molecular lactam formation occurs spontaneously in the
pipecolic acid series if the Cbz-group in 40 is cleaved under
alkaline or neutral conditions. It is, however, no problem in
the proline series and deprotection of Cbz-protected 37 un-
der neutral conditions to pyrrolidine 38 proceeds quantita-
tively without any observable pyrrolizidine side product.
Conclusions
Within this paper we describe an efficient general ap-
proach to conformationally rigid amino acid mimetics. The
approach is stereoselective and principally suitable for the
preparation of various amino acid analogues based on pro-
line or pipecolic acid scaffolds. We have focussed on aspart-
ate (30 and 32), glutamate (34 and 36) and homoglutamate
(38 and 42) mimetics in this study which were obtained as
free amines with base labile protection of the carboxyl
A closer look at the NMR-data of our target products
reveals interesting conformational preferences of the pipec-
olic acid derivatives. The chemical shift and multiplicity of
groups. As a part of our study of the cancer-specific prote-
2-H is a good indicator of the ring conformation in piperi-
ase PSMA, we are going to use these amino acids as build-
ing blocks for the assembly of dipeptide mimetics for
NAAG, the natural substrate of PSMA. In addition, our
amino acids might be of general interest as new analogues
dines like 32, 36, 41 and 42.[28] As depicted in Figure 4, the
chemical shift of 2-H in our targeted aspartate and homo-
glutamate mimetics 32 and 42 is generally around 4.0–
3
4.1 ppm and the J2,3 coupling constant is 6–7 Hz. This in-
of aspartate, glutamate and natural products like the kain-
dicates a trans-coupling and is in accordance with a chair
ates.[30] They are thus interesting ligands for neurologically
conformation of the six-membered ring and the substitu-
important glutamatergic receptors. In this context, it should
ents at C2 and C3 in equatorial position. In contrast, acyl-
be noted that the targeted proline and pipecolic acid deriva-
ated piperidines like 41 show a significant downfield shift
tives have an additional side chain (besides the one mimick-
for 2-H and prefer a conformation with substituents at C2
ing the native amino acid side chain) suitable for further
in the axial position to avoid pseudo allylic 1,3-strain.[29]
structural modification.
3
This results in a small J2,3 coupling constant, which is for
41 (broad singlet for 2-H) not resolved. Surprisingly, gluta-
mate mimetic 36 shows the same small coupling constant
Experimental Section
(1.9 Hz) indicating an axial position of the carboxymethyl
group at C2. We attribute this, for a non-acylated piperidine
untypical, conformation to an intramolecular hydrogen
bond of either the ester at C3 (shown in Figure 4) or the
ester at C5 (not shown) to the piperidine NH in CDCl3.
Support for an intramolecular hydrogen bond comes from
an additional finding: the chemical shift (δ =3.93 ppm) and
General: Melting points were determined in open capillaries in a
Dr. Lindström instrument and are uncorrected. 1H NMR and 13C-
NMR spectra were recorded with a Bruker-Karlsruhe AMX 400
spectrometer (400 MHz/100.6 MHz) or on a Bruker-Karlsruhe
DRX 5001 spectrometer (500 MHz/125.8 MHz). Chemical shifts,
δ, are presented in part per million (ppm) and coupling constants,
J, in Hertz (Hz) from tetramethylsilane (TMS, 0 ppm) as the in-
ternal standard for CDCl3 and residual solvent peaks for other
deuterated solvents. – Mass spectra were obtained with a Varian
MS MAT 311A in EI mode or a VG/70–250 F (VG Analytical)
instrument in FAB mode in a p-nitrobenzylalkohol matrix. – Ele-
mental analyses were performed with a C,H,N Analyser EA 1108
from Carlo–Erba. The following starting materials were synthe-
sized according to literature procedures: methyl (triphenyl-
phosphoranylidene)acetate,[31] ethyl (1S,3S,4R)-2-[(1R)-phenyl-
ethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
20,[32]
ethyl
(1S,3S,4S,5S,6R)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carb-
oxylate 22,[25] 2-benzyl 3-ethyl (1S,3S,4R)-2-azabicyclo[2.2.1]hept-
5-ene-2,3-dicarboxylate 26.[4]
Azabicyclooctene 21: The title compound was prepared according
to a recently published protocol[25] in 71% (51.3 g) yield as a
colourless solid. Rf = 0.34 (hexane/EtOAc, 10:1). 1H NMR
(500 MHz, CDCl3): δ = 0.90–0.98 (m, 1 H), 1.17–1.24 (m, 13 H),
1.49–1.55 (m, 1 H), 1.95 (br., 1 H), 2.64 (s, 1 H), 2.71 (s, 1 H), 3.34
3
(br., 1 H), 3.54 (br., 1 H), 6.18 (dd, J = 6.9 Hz, 1.9 Hz, 1 H), 6.33
(dd, 3J = 6.9 Hz, 6.9 Hz, 1 H), 7.09–7.36 (m, 5 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 18.9, 19.4, 26.6, 28.2, 34.1, 47.9, 63.1, 65.6,
128.8, 128.1, 128.6, 132.6, 133.0 ppm. HRMS (FAB) calcd. for
C20H28NO2 [MH+] 314.2120, found 314.2143. C20H27NO2 (313.4):
calcd. C 76.64, H 8.68, N 4.47; found C 76.37, H 8.91, N 4.38.
Figure 4. Representative 1H NMR-data (500 MHz in CDCl3) of
pipecolic acids.
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Aminodiol 23: The title compound was prepared according to a
recently published protocol[25] from azabicyclooctene 21 in 26.8 g
(74%) yield as a colourless solid. Rf = 0.50 (dichloromethane/
Dialdehyde 27: Cbz-protected diol 24 (1.66 g, 4.9 mmol) was dis-
solved in acetone/water (2.5:1, 25 mL), cooled to 0 °C and treated
with NaIO4 (2.1 g, 9.8 mmol). The resulting suspension was stirred
MeOH, 9:1). 1H NMR (400 MHz, CDCl3): δ = 1.22–1.31 (m, 2 H), for 2 h at 0 °C and 2 h at room temp. Water (50 mL) was added
1.38 (s, 9 H), 1.50–1.59 (m, 1 H), 1.78–1.95 (m, 2 H), 2.11–2.14 (m,
and the resulting solution was extracted with ethyl acetate four
3
1 H), 2.95–2.99 (m, 1 H), 3.53 (t, J = 2.0 Hz, 1 H), 4.06–4.09 (m, times with each 50 mL. The combined organic phases were washed
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.5, 20.1, 28.4, 35.1,
with brine, dried with NaSO4, filtered and the solvent was removed
49.3, 57.4, 66.0, 67.0, 82.8, 173.5 ppm. HRMS (FAB) calcd. for
in vacuo to give the title compound 27 (1.65 g) as a colourless oil,
C12H22NO4 [MH+] 244.1549, found 244.1552. C12H21NO4 (243.3): which was used without further purification in the next step.
calcd. C 59.24, H 8.70, N 5.76; found C 59.14, H 8.93, N 5.69.
Dialdehyde 28: Cbz-protected diol 25 (2.20 g, 5.8 mmol) was dis-
solved in acetone/water (2.5:1, 30 mL), cooled to 0 °C and treated
Cbz-Protected Diol 24: Aminodiol 22 (2.00 g, 9.9 mmol) was dis-
with NaIO4 (2.1 g, 9.8 mmol). The resulting suspension was stirred
solved in dioxane/water, 1:1 (50 mL) and cooled to 0 °C. NaHCO3
for 3 h at room temp. Water (50 mL) was added and the resulting
(0.92 g, 11.0 mmol) was added and the solution was stirred for
solution was extracted with ethyl acetate four times with each
5 min at 0 °C before Cbz-Cl (1.88 g, 11.0 mmol) were slowly added
50 mL. The combined organic phases were washed with brine,
via an addition funnel. The resulting mixture was stirred for two
dried with NaSO4, filtered and the solvent was removed in vacuo
hours at 0 °C and additional two hours at room temp. Dioxane
to give the title compound 28 (2.40 g) as a colourless oil, which
was removed in vacuo and the residue was treated with water
was used without further purification in the next step.
(50 mL) and extracted four times with dichloromethane (each
50 mL). The combined organic phases were washed with 0.5  HCl
(50 mL) and water (50 mL). The organic phase was dried with
NaSO4, filtered and the solvent removed in vacuo to give 3.2 g
of a yellow oil that was purified by chromatography on silica gel
(dichloromethane/MeOH, 96:4) to give 2.83 g (85% yield) of the
title compound 24 as a colourless oil. Rf = 0.47 (dichloromethane/
MeOH, 95:5). 1H NMR (500 MHz, CDCl3, 2:1 mixture of rota-
mers): δ = 1.09 (t, 3J = 7.1 Hz, 2 H), 1.19 (t, 3J = 7.1 Hz, 1 H),
Dicarboxylic Acid 29: Dialdehyde 27 (1.20 g, 3.6 mmol) and 2-
methyl-2-butene (1.01 g, 14.4 mmol) were dissolved in tBuOH
(250 mL) and treated with a solution of NaClO2 (0.85 g, 9.4 mmol)
and NaH2PO4 (1.09 g, 8.6 mmol) in water. The resulting yellow
solution was stirred at room temp. for 12 h. tBuOH was removed in
vacuo and the resulting solution treated with 0.1  aqueous NaOH
solution (50 mL) and washed three times with dichloromethane.
The remaining aqueous phase was adjusted to pH ca. 1 with HCl
1.72–1.81 (m, 2 H), 2.51 (br. s, 1 H), 3.42 (br. s, 2 H), 3.65–3.70 and extracted four times with EtOAc (each 50 mL). The combined
(m, 1 H), 3.76–3.87 (m, 2 H), 3.97–4.15 (m, 3 H), 4.89–4.93 (m, organic phases were washed with brine (50 mL), dried with NaSO4,
0.7 H), 5.05–5.10 (m, 1.3 H), 7.16–7.29 (m, 5 H) ppm. 13C NMR filtered and the solvent was removed in vacuo to give 1.20 g (91%)
(125 MHz, CDCl3, 2:1 mixture of rotamers): δ = 14.1, 14.2, 28.2,
28.9, 47.6, 48.2, 60.0, 60.1, 60.2, 60.3, 61.6, 61.7, 67.4, 67.5, 71.1,
72.2, 72.5, 72.9, 127.7, 128.1, 128.2, 128.3, 128.6, 128.7, 136.0,
136.4, 154.3, 154.6, 170.2, 170.7 ppm. HRMS (FAB) calcd. for
of the title compound 29 as a colourless solid. 1H NMR (400 MHz,
3
CDCl3, 3:3 mixture of rotamers): δ = 1.03 (t, J = 7.3 Hz, 1.8 H),
1.18 (t, 3J = 7.3 Hz, 1.2 H), 2.38–2.68 (m, 2 H), 3.03–3.10 (m, 1
H), 3.91–4.19 (m, 2 H), 4.41–4.56 (m, 1 H), 4.91–5.21 (m, 3 H),
C17H22NO6 [MH+] 336.1447, found 336.1449. C17H21NO6 (335.4): 7.14–7.30 (m, 5 H), 8.23 (br. s, 2 H) ppm. 13C NMR (101 MHz,
calcd. C 60.89, H 6.31, N 4.18; found C 60.96, H 6.41, N 4.09.
CDCl3, mixture of rotamers): δ = 14.1, 14.3, 20.7, 21.2, 30.2, 31.2,
46.0, 47.0, 58.5, 59.0, 61.6, 62.1, 67.9, 68.2, 127.8, 127.9, 128.0,
128.2, 128.3, 128.6, 135.8, 136.0, 154.7, 154.8, 171.0, 171.1, 175.3,
175.4, 175.6, 175.7 ppm. HRMS (FAB) calcd. for C17H20NO8
[MH+] 366.1189, found 366.1183. C17H19NO8 (365.3): calcd. C
55.89, H 5.24, N 3.83; found C 55.93, H 5.35, N 3.71.
Cbz-Protected Diol 25: Aminodiol 23 (2.00 g, 8.2 mmol) was dis-
solved in dioxane/water, 1:1 (50 mL) and cooled to 0 °C. NaHCO3
(0.76 g, 9.0 mmol) was added and the solution was stirred for 5 min
at 0 °C before Cbz-Cl (1.54 g, 9.0 mmol) were slowly added via an
addition funnel. The resulting mixture was stirred for two hours at
0 °C and additional two hours at room temp. Dioxane was removed
in vacuo and the residue was treated with water (50 mL) and ex-
tracted four times with dichloromethane (each 50 mL). The com-
bined organic phases were washed with 0.5  HCl (50 mL) and
water (50 mL). The organic phase was dried with NaSO4, filtered
and the solvent removed in vacuo to give 3.9 g of a yellow oil that
was purified by chromatography on silica gel (dichloromethane/
MeOH, 96:4) to give 2.78 g (84% yield) of the title compound 25
as a colourless foam. Rf = 0.21 (dichloromethane/MeOH, 96:4). 1H
NMR (500 MHz, CDCl3, 7:3 mixture of rotamers): δ = 1.26–1.38
Trimethyl Ester 30: Dicarboxylic acid 29 (0.35 g, 0.96 mmol) was
dissolved in a mixture of SOCl2 (0.40 g, 3.4 mmol) and abs. MeOH
(10 mL) at 0 °C. The resulting solution was allowed to reach room
temp. and was stirred for 24 h. The solvent was removed in vacuo
and the resulting crude product 0.34 g (93%) was used without
1
further purification in the next step. H NMR (400 MHz, CDCl3,
1:1 mixture of rotamers): δ = 2.39–2.59 (m, 2 H), 3.01–3.07 (m, 1
H), 3.46 (s, 3 H), 3.65 (s, 1.5 H), 3.66 (s, 4.5 H), 4.46 (dd, 3J =
3
1.8 Hz, 9.1 Hz, 0.5 H), 4.52 (dd, J = 2.3 Hz, 9.1 Hz, 0.5 H), 4.89–
4.99 (m, 2 H), 5.12–5.20 (m, 1 H), 7.18–7.31 (m, 5 H) ppm.
(m, 1 H), 1.36 (s, 7 H), 1.47 (s, 2 H), 1.78–1.91 (m, 2 H), 1.95–2.09 The crude Cbz-protected triester (0.30 g, 0.79 mmol) was dissolved
(m, 1 H), 2.23–2.25 (m, 0.7 H), 2.28–2.31 (m, 0.3 H), 2.59 (br. s, 2 in MeOH (10 mL) and treated with 5% Pd/C (10 mg). The resulting
H), 3.89–4.01 (m, 2 H), 4.07–4.10 (m, 0.7 H), 4.10–4.12 (m, 0.3 H), mixture was stirred for 24 h under hydrogen (balloon technique) at
4.16–4.20 (m, 0.3 H), 4.22–4.25 (m, 0.7 H), 5.02–5.06 (m, 0.6 H),
room temp. The mixture was filtered, the solvent was removed in
5.10–5.17 (m, 1.4 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR vacuo and the resulting residue purified by chromatography on sil-
(125 MHz, CDCl3, 2:1 mixture of rotamers): δ = 13.0, 13.1, 18.8,
18.9, 28.3, 28.4, 36.6, 36.8, 48.6, 49.0, 59.1, 59.2, 65.0, 65.7, 67.1,
67.3, 67.7, 67.9, 82.1, 82.2, 128.2, 128.3, 128.4, 128.5, 128.8, 128.9,
136.4, 136.5, 155.3, 155.4, 169.9, 170.3 ppm. HRMS (FAB) calcd.
for C20H28NO6 [MH+] 378.1917, found 378.1923. C20H27NO6
(377.4): calcd. C 63.64, H 7.21, N 3.71; found C 63.96, H 7.31, N
3.79.
ica gel (Et2O) to give 0.19 g (100%) of the title compound 30 as a
1
colourless oil. Rf = 0.57 (Et2O). H NMR (500 MHz, CDCl3): δ =
2.25–2.32 (m, 1 H), 2.41–2.52 (m, 2 H), 3.20 (ddd, 3J = 6.3 Hz,
6.9 Hz, 2.5 Hz, 1 H), 3.71 (s, 3 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 3.98
3
3
(dd, J = 7.3 Hz, 1 H), 4.28 (d, J = 6.3 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 33.3, 47.1, 52.5, 52.6, 52.7, 59.7, 62.7,
173.0, 173.3, 173.9 ppm. HRMS (FAB) calcd. for C10H16NO6
Eur. J. Org. Chem. 2007, 2276–2284
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2281

W. Maison
FULL PAPER
[MH+] 246.0978, found 246.0979. C10H15NO6 (245.2): calcd. C
48.98, H 6.17, N 5.71; found C 48.69, H 6.31, N 5.70.
raphy on silica gel (Et2O) to give 0.20 g (100%) of the title com-
pound 32 as a colourless oil. Rf = 0.68 (Et2O). 1H NMR (500 MHz,
CDCl3): δ = 1.75–1.84 (m, 3 H), 1.85–1.95 (m, 1 H), 2.49 (br., 1
Dicarboxylic Acid 31: Dialdehyde 28 (1.60 g, 4.3 mmol) and 2-
methyl-2-butene (1.63 g, 23.2 mmol) were dissolved in tBuOH
3
H), 2.78–2.83 (m, 1 H), 3.64 (dd, J = 6.9 Hz, 4.1 Hz, 1 H), 3.67
(s, 3 H), 3.70 (s, 3 H), 3.71 (s, 3 H), 4.06 (d, 3J = 6.9 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 23.9, 25.2, 42.3, 52.1, 52.2, 52.4,
54.7, 56.4, 172.4, 173.4, 173.6 ppm. HRMS (FAB) calcd. for
C11H18NO6 [MH+] 260.1134, found 260.1136. C11H17NO6 (259.3):
calcd. C 50.96, H 6.61, N 5.40; found C 50.79, H 6.34, N 5.54.
(150 mL) and treated with
a solution of NaClO2 (1.37 g,
15.1 mmol) and NaH2PO4 (1.91 g, 13.9 mmol) in water. The re-
sulting yellow solution was stirred at room temp. for 12 h. tBuOH
was removed in vacuo and the resulting solution treated with 0.1 
aqueous NaOH solution (50 mL) and washed three times with
dichloromethane. The remaining aqueous phase was adjusted to
pH ca. 1 with HCl and extracted four times with EtOAc (each
50 mL). The combined organic phases were washed with brine
(50 mL), dried with NaSO4, filtered and the solvent was removed
in vacuo to give 1.75 g (100%) of the title compound 31 as a
Cbz-Protected Triester 33: The title compound was prepared fol-
lowing a known procedure for Arndt–Eistert homologation from
diacid 29 (0.70 g, 1.9 mmol).[33] The resulting residue was purified
by chromatography on silica gel (PE/EtOAc, 8:2) to give 0.71 g
(89%) of the title compound 33 as a colourless oil. Rf = 0.29 (PE/
EtOAc, 7:3). 1H NMR (500 MHz, CDCl3, 2:1 mixture of rota-
mers): δ = 1.03 (t, 3J = 7.2 Hz, 2 H), 1.80 (t, 3J = 7.2 Hz, 1 H),
2.15–2.49 (m, 3 H), 2.82–3.16 (m, 4 H), 3.60 (s, 3 H), 3.69 (s, 3 H),
1
colourless solid. H NMR (400 MHz, CDCl3, 3:1 mixture of rota-
mers): δ = 1.27 (s, 6 H), 1.37 (s, 3 H), 1.58–1.69 (m, 0.7 H), 1.74–
2.00 (m, 2.6 H), 2.03–2.12 (m, 0.7 H), 3.10–3.18 (m, 0.3 H), 3.20–
3
3.25 (m, 0.7 H), 4.20 (dd, J = 6.5 Hz, 0.7 H), 4.43 (br. s, 0.3 H), 3.88–3.99 (m, 1.4 H), 4.09–4.17 (m, 0.6 H), 4.33–4.40 (m, 1 H),
4.94–5.25 (m, 3 H), 7.16–7.28 (m, 5 H), 8.44 (br. s, 2 H) ppm. 13C
4.74 (d, 3J = 19.3 Hz, 0.7 H), 4.78 (d, 2J = 19.3 Hz, 0.3 H), 4.92
3
3
3
NMR (101 MHz, CDCl3, mixture of rotamers): δ = 17.2, 17.6, (d, J = 12.3 Hz, 1 H), 5.09 (d, J = 19.3 Hz, 0.7 H), 5.12 (d, J =
25.9, 38.8, 39.7, 53.1, 53.3, 53.9, 66.2, 80.7, 81.0, 126.1, 126.2,
126.6, 133.9, 134.0, 154.9, 155.4, 168.4, 168.6, 175.6, 175.9, 176.1
ppm. HRMS (FAB) calcd. for C20H26NO8 [MH+] 408.1658, found
408.1651. C20H25NO8 (407.4): calcd. C 58.96, H 6.18, N 3.44;
found C 58.93, H 6.25, N 3.37.
19.3 Hz, 0.3 H), 7.19–7.31 (m, 5 H) ppm. 13C NMR (101 MHz,
CDCl3, mixture of rotamers): δ = 14.1, 14.2, 31.9, 32.6, 38.1, 39.1,
45.5, 46.4, 51.7, 52.9, 54.3, 55.1, 61.6, 61.7, 62.2, 62.6, 67.3, 67.5,
127.9, 128.1, 128.2, 128.5, 128.6, 136.2, 136.3, 154.2, 154.6, 171.2,
171.5, 171.6, 171.8, 172.7 ppm. HRMS (FAB) calcd. for
C21H28NO8 [MH+] 422.1815, found 422.1809. C21H27NO8 (421.4):
calcd. C 59.85, H 6.46, N 3.32; found C 59.97, H 6.35, N 3.40.
Trimethyl Ester 32: tert-Butyl ester 31 (0.58 g, 1.4 mmol) was dis-
solved in dichloromethane (5 mL) and treated with TFA (5 mL).
The resulting solution was stirred at room temp. for 2 h. The sol-
vent was removed in vacuo to give 0.50 g (100%) of the Cbz-pro-
tected tricarboxylic acid as a colourless solid. Rf = 0.26 (dichloro-
methane/MeOH, 95:5). 1HNMR (400 MHz, D2O, 1:1 mixture of
Triester 34: Cbz-protected triester 33 (0.15 g, 0.36 mmol) was dis-
solved in MeOH (10 mL) and treated with 5% Pd/C (10 mg). The
resulting mixture was stirred for 24 h under hydrogen (balloon
technique) at room temp. The mixture was filtered and the solvent
rotamers): δ = 1.61–2.00 (m, 4 H), 2.68–2.75 (m, 0.5 H), 2.82–2.88 was removed in vacuo to give 0.10 g (100%) of the title compound
1
(m, 0.5 H), 4.09 (dd, 3J = 5.3 Hz, 8.2 Hz, 0.5 H), 4.35 (dd, 3J =
5.5 Hz, 5.5 Hz, 0.5 H), 4.54 (d, J = 6.8 Hz, 0.5 H), 4.85 (d, J =
as a colourless oil. H NMR (400 MHz, [D4]MeOH): δ = 1.19 (t,
3J = 7.2 Hz, 3 H), 1.62–2.00 (m, 3 H), 2.31–2.64 (m, 4 H), 3.60 (s,
3
3
4.3 Hz, 0.5 H), 5.10–5.22 (m, 2 H), 7.40–7.52 (m, 5 H) ppm. 3 H), 3.62–3.75 (m, 1 H), 3.65 (s, 3 H), 4.10–4.14 (m, 1 H), 4.24
13CNMR (101 MHz, D2O, mixture of rotamers): δ = 22.3, 22.7,
25.8, 45.9, 47.7, 58.6, 59.1, 60.6, 60.7, 67.8, 127.8, 128.5, 129.0,
136.7, 159.7, 160.0, 180.5, 180.6, 181.0, 181.3, 182.0, 182.2 ppm.
HRMS (FAB) calcd. for C16H18NO8 [MH+] 352.1032, found
352.1027. C16H17NO8 (351.31): calcd. C 54.70, H 4.88, N 3.99;
found C 54.93, H 4.92, N 3.87.
(q, 3J = 7.2 Hz, 2 H) ppm. HRMS (FAB) calcd. for C13H22NO6
[MH+] 288.1447, found 288.1451. C13H21NO6 (287.3): calcd. C
54.35, H 7.37, N 4.88; found C 54.15, H 7.48, N 4.66.
Cbz-Protected Triester 35: The title compound was prepared fol-
lowing a known procedure for Arndt–Eistert homologation from
diacid 31 (1.40 g, 3.4 mmol).[33] The resulting residue was purified
by chromatography on silica gel (PE/EtOAc, 8:2) to give 0.91 g
(57%) of the title compound 35 as a colourless oil. Rf = 0.23 (PE/
The resulting triacid (0.60 g, 1.7 mmol) was dissolved in a mixture
of SOCl2 (1.19 g, 10 mmol) and abs. MeOH at 0 °C. The solution
was allowed to reach room temp. and was stirred for 24 h at room
temp. The solvent was removed in vacuo and the resulting residue
purified by chromatography on silica gel (PE/EtOAc, 7:3) to give
0.46 g (69%) of the Cbz-protected trimethyl ester as a colourless
oil. Rf = 0.16 (PE/EtOAc, 7:3). 1H NMR (400 MHz, CDCl3, 1:1
mixture of rotamers): δ = 1.61–2.07 (m, 4 H), 2.88–3.09 (m, 1 H),
3.44 (br. s, 3 H), 3.66 (br. s, 6 H), 4.28–4.35 (m, 0.5 H), 4.53–4.59
(m, 0.5 H), 4.70–4.75 (m, 0.5 H), 4.94–5.20 (m, 2.5 H), 7.20–7.30
1
EtOAc, 8:2). H NMR (400 MHz, CDCl3, due to rotational isom-
erism most signals are extremely broadened): δ = 1.38 (s, 4.5 H),
1.41 (s, 4.5 H), 1.63–1.90 (m, 4 H), 2.0 (br., 1 H), 2.4 (br., 1 H),
2.49–2.61 (m, 2 H), 2.8 (br., 1 H), 3.2 (br., 1 H), 3.63 (s, 3 H), 3.65
(s, 1.5 H), 3.70 (s, 1.5 H), 4.4 (br., 1 H), 5.03–5.21 (m, 2 H), 7.24–
7.38 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 22.2, 24.8,
27.8, 27.9, 37.2, 38.3, 49.9, 51.7, 51.8, 52.4, 56.2, 56.7, 67.5, 81.9,
82.3, 127.9, 128.0, 128.1, 128.2, 128.5, 136.4, 136.5, 156.2, 156.9,
(m, 5 H) ppm. 13C NMR (101 MHz, D2O, mixture of rotamers): δ 170.7, 171.8, 172.3, 174.0 ppm. HRMS (FAB) calcd. for
= 20.5, 21.1, 24.5, 24.7, 42.1, 43.5, 52.7, 52.9, 55.7, 55.9, 56.4, 56.8,
68.4, 128.6, 128.9, 157.1, 172.3, 172.6 ppm. HRMS (FAB) calcd.
for C19H24NO8 [MH+] 394.1502, found 394.1503. C19H23NO8
(393.39): calcd. C 58.01, H 5.89, N 3.56; found C 58.15, H 5.96, N
3.46.
C24H34NO8 [MH+] 464.2284, found 464.2290. C24H33NO8 (463.5):
calcd. C 62.19, H 7.18, N 3.02; found C 61.99, H 7.12, N 3.06.
Trimethyl Ester 36: Cbz-protected triester 35 (0.50 g, 1.1 mmol) was
dissolved in dichloromethane (5 mL) and treated with TFA (5 mL).
The resulting solution was stirred for 2 h at room temp. and the
solvent was removed in vacuo to give crude acid which was used
without further purification in the next step. This acid was dis-
solved in a mixture of SOCl2 (0.50 g, 4.0 mmol) and abs. MeOH
(10 mL) at 0 °C. The resulting solution was allowed to reach room
temp. and was stirred for 24 h at room temp. The solvent was re-
The resulting Cbz-protected triester (0.30 g, 0.8 mmol) was dis-
solved in MeOH (15 mL) and treated with 5% Pd/C (10 mg). The
resulting mixture was stirred for 24 h under hydrogen (balloon
technique) at room temp. The mixture was filtered, the solvent was
removed in vacuo and the resulting residue purified by chromatog-
2282
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2276–2284

Synthesis of Conformationally Constrained Glutamate Analogues
FULL PAPER
moved in vacuo and the resulting crude product was purified by
column chromatography on silica gel (PE/EtOAc, 7:3) to give the
Cbz-protected trimethyl ester as a colourless oil (0.38 g, 82% yield).
3.61 (s, 3 H), 3.67 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3,
mixture of rotamers): δ = 30.0, 31.2, 31.7, 32.7, 38.7, 43.9, 51.7,
51.8, 52.4, 58.1, 64.6, 173.7, 174.0, 175.5 ppm. HRMS (FAB) calcd.
Rf = 0.19 (PE/EtOAc, 7:3). 1H NMR (400 MHz, CDCl3, due to for C14H24NO6 [MH+] 302.1604, found 302.1601. C14H23NO6
rotational isomerism most signals are extremely broadened): δ =
1.65–2.03 (m, 4 H), 2.26–2.39 (m, 1 H), 2.45–2.62 (m, 2 H), 2.26–
2.39 (m, 1 H), 2.8 (br., 1 H), 3.1 (br., 1 H), 3.42–3.55 (m, 1 H),
3.64 (s, 3 H), 3.65 (s, 3 H), 3.70 (s, 3 H), 4.5 (br., 1 H), 5.06–5.20
(m, 2 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (101 MHz, mixture
of rotamers CDCl3): δ = 22.7, 25.2, 26.0, 31.0, 36.8, 37.9, 50.1,
51.8, 51.9, 52.4, 52.5, 52.6, 55.4, 59.1, 67.8, 68.1, 128.1, 128.2,
128.3, 128.4, 128.6, 136.2, 136.3, 156.1, 171.5, 172.1, 172.2 ppm.
HRMS (FAB) calcd. for C21H28NO8 [MH+] 422.1815, found
422.1812. C21H27NO8 (421.45): calcd. C 59.85, H 6.46, N 3.32;
found C 59.65, H 6.71, N 3.23.
(301.3): calcd. C 55.80, H 7.69, N 4.65; found C 55.89, H 7.60, N
4.71.
Carboxylic Acid 39: Dialdehyde 28 (0.80 g, 2.1 mmol) was dissolved
in absol. THF (30 mL) and treated with methyl triphenylphosphan-
ylidene acetate (3.90 g, 11.6 mmol). The resulting solution was
stirred under nitrogen for 24 h at room temp. The solvent was re-
moved in vacuo and the resulting crude product was purified by
column chromatography on silica gel (PE/EtOAc, 8:2) to give the
diolefine as a colourless oil (0.93 g, 91% yield). Rf = 0.20 (PE/
1
EtOAc, 8:2). H NMR (400 MHz, CDCl3, due to rotational isom-
erism most signals are extremely broadened): δ = 1.41 (s, 9 H),
1.49–1.79 (m, 4 H), 2.8 (br., 1 H), 3.71 (s, 3 H), 3.74 (s, 3 H), 4.5
(br., 2 H), 5.03–5.20 (m, 2 H), 5.7 (br., 1 H), 5.91 (dd, 3J = 1.0 Hz,
15.8 Hz, 1 H), 6.84–6.99 (m, 2 H), 7.27–7.36 (m, 5 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 15.4, 23.4, 27.1, 28.0, 51.7, 51.8,
59.3, 66.0, 68.0, 82.5, 122.4, 128.3, 128.4, 128.6, 136.0, 148.2, 157.3,
166.6, 170.2, 170.5 ppm. HRMS (FAB) calcd. for C26H34NO8
[MH+] 488.2284, found 488.2286. C26H33NO8 (487.55): calcd. C
64.05, H 6.82, N 2.87; found C 64.23, H 6.80, N 2.94.
The resulting Cbz-protected trimethyl ester (0.35 g, 0.83 mmol) was
dissolved in MeOH (10 mL) and treated with 5% Pd/C (10 mg).
The resulting mixture was stirred for 24 h under hydrogen (balloon
technique) at room temp. The mixture was filtered, the solvent was
removed in vacuo and the resulting residue purified by chromatog-
raphy on silica gel (Et2O) to give 0.24 g (100%) of the title com-
pound 36 as a colourless oil. 1H NMR (500 MHz, CDCl3): δ =
1.29–1.55 (m, 3 H), 1.62–1.70 (m, 1 H), 2.34–2.43 (m, 2 H), 2.47
2
3
(dd, J = 15.3 Hz, J = 6.3 Hz, 1 H), 2.65–2.71 (m, 1 H), 2.76 (dd,
The resulting diolefine (0.90 g, 1.8 mmol) was dissolved in dichlo-
romethane (5 mL) and treated with TFA (5 mL). The solution was
stirred for 2 h at room temp. The solvent was removed in vacuo
and the resulting crude product was purified by column chromatog-
raphy on silica gel (PE/EtOAc, 1:1) to give the title compound 39
as a colourless oil (0.78 g, 100% yield). Rf = 0.13 (PE/EtOAc, 7:3).
1H NMR (400 MHz, CDCl3, due to rotational isomerism most sig-
nals are extremely broadened): δ = 1.50–1.62 (m, 1 H), 1.71–1.90
(m, 3 H), 2.2 (br., 1 H), 3.74 (s, 3 H), 3.76 (s, 3 H), 4.3 (br., 1 H),
2J = 15.3 Hz, J = 7.9 Hz, 1 H), 3.16–3.21 (m, 1 H), 3.54 (d, J =
1.9 Hz, 1 H), 3.67 (s, 3 H), 3.68 (s, 3 H), 3.74 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 25.6, 26.8, 30.8, 36.4, 40.9, 49.0,
51.7, 51.8, 52.2, 59.3, 172.5, 173.5, 174.0 ppm. HRMS (FAB) calcd.
for C13H22NO6 [MH+] 288.1447, found 288.1442. C13H21NO6
(287.3): calcd. C 54.35, H 7.37, N 4.88; found C 54.69, H 7.30, N
4.59.
3
3
Diolefine 37: Dialdehyde 27 (0.44 g, 1.2 mmol) was dissolved in ab-
sol. THF (30 mL) and treated with methyl triphenylphosphanylid-
ene acetate (1.77 g, 5.3 mmol). The resulting solution was stirred
under nitrogen for 24 h at room temp. The solvent was removed
in vacuo and the resulting crude product was purified by column
chromatography on silica gel (PE/EtOAc, 7:3) to give the title com-
pound 37 as a colourless oil (0.55 g, 100% yield). 1H NMR
(500 MHz, CDCl3, 1:1 mixture of rotamers): δ = 1.07 (t, 3J =
7.1 Hz, 1.5 H), 1.25 (t, 3J = 7.1 Hz, 1.5 H), 1.75–1.84 (m, 1 H),
2.43–2.54 (m, 1 H), 3.01–3.08 (m, 1 H), 3.71 (s, 1.5 H), 3.72 (s, 1.5
3
3
4.7 (br., 1 H), 5.08 (d, J = 12.1 Hz, 1 H), 5.18 (d, J = 12.1 Hz, 1
3
3
H), 5.74 (br. d, J = 14.5 Hz, 1 H), 5.94 (dd, J = 1.3 Hz, 15.7 Hz,
1 H), 6.91 (dd, J = 7.5 Hz, 15.7 Hz, 2 H), 7.24–7.35 (m, 5 H), 8.2
3
(br., 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 23.4, 26.9, 27.7,
52.2, 52.3, 58.6, 68.8, 122.8, 128.5, 128.6, 128.7, 135.2, 147.8, 157.6,
167.3, 176.0 ppm. HRMS (FAB) calcd. for C22H26NO8 [MH+]
432.1658, found 432.1652. C22H25NO8 (431.4): calcd. C 61.25, H
5.84, N 3.25; found C 61.23, H 5.76, N 3.17.
Cbz-Protected Trimethyl Ester 40: Carboxylic acid 39 (0.85 g,
2.0 mmol) was dissolved in a mixture of SOCl2 (0.47 g, 3.9 mmol)
and abs. MeOH (15 mL) at 0 °C. The resulting solution was al-
lowed to reach room temp. and was stirred for 24 h at room temp.
The solvent was removed in vacuo and the resulting crude product
was purified by column chromatography on silica gel (PE/EtOAc,
7:3) to give the title compound 40 as a colourless oil (0.55 g, 63%
yield). Rf = 0.18 (PE/EtOAc, 7:3). 1H NMR (400 MHz, CDCl3,
due to rotational isomerism most signals are extremely broadened):
δ = 1.44–1.59 (m, 1 H), 1.64–1.86 (m, 3 H), 2.8 (br., 1 H), 3.6 (br.,
3 H), 3.71 (s, 3 H), 3.73 (s, 3 H), 4.2 (br., 1 H), 4.7 (br., 1 H), 5.04
3
H), 3.73 (s, 1.5 H), 3.74 (s, 1.5 H), 3.93–3.98 (m, 1 H), 4.21 (q, J
3
3
= 7.1 Hz, 1 H), 4.28 (d, J = 4.3 Hz, 0.5 H), 4.32 (d, J = 5.8 Hz,
3
0.5 H), 4.58–4.72 (m, 1 H), 4.98 (d, J = 12.2 Hz, 0.5 H), 5.02 (d,
3J = 12.2 Hz, 0.5 H), 5.15 (d, J = 12.2 Hz, 0.5 H), 5.16 (d, J =
3
3
12.2 Hz, 0.5 H), 5.78–5.98 (m, 2 H), 6.77 (dd, 3J = 7.4 Hz, 15.8 Hz,
3
0.5 H), 6.86 (dd, J = 7.6 Hz, 15.5 Hz, 1.5 H), 7.24–7.36 (m, 5 H)
ppm. 13C NMR (101 MHz, CDCl3, mixture of rotamers): δ = 14.1,
14.3, 21.2, 36.4, 37.5, 44.2, 45.2, 51.8, 51.9, 58.8, 59.4, 61.7, 61.8,
64.7, 65.0, 67.6, 67.8, 121.4, 121.6, 122.9, 123.0, 128.1, 128.2, 128.3,
128.5, 128.6, 135.9, 146.2, 146.4, 147.6, 148.2, 154.2, 166.2, 166.4,
166.5, 171.1, 171.3 ppm. HRMS (FAB) calcd. for C23H28NO8
[MH+] 446.1815, found 446.1817. C23H27NO8 (445.5): calcd. C
62.01, H 6.11, N 3.14; found C 62.13, H 6.04, N 3.10.
3
3
3
(d, J = 12.1 Hz, 1 H), 5.16 (d, J = 12.1 Hz, 1 H), 5.73 (br. d, J
3
3
= 15.1 Hz, 1 H), 5.88 (dd, J = 1.3 Hz, 15.8 Hz, 1 H), 6.83 (dd, J
= 8.0 Hz, 15.8 Hz, 2 H), 7.26–7.34 (m, 5 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 23.6, 27.1, 51.7, 51.8, 52.3, 53.8, 58.8, 68.2,
122.7, 128.4, 128.5, 128.6, 135.7, 147.3, 157.0, 166.5, 171.6 ppm.
HRMS (FAB) calcd. for C23H28NO8 [MH+] 446.1815, found
456.1819. C23H27NO8 (445.5): calcd. C 62.01, H 6.11, N 3.14;
found C 61.86, H 6.00, N 3.19.
Trimethyl Ester 38: Olefine 37 (0.35 g, 0.8 mmol) was dissolved in
absol. MeOH (30 mL) and treated with 5% Pd/C (10 mg). The re-
sulting mixture was stirred under hydrogen (balloon technique) for
24 h at room temp. The suspension was filtered and the solvent was
removed in vacuo to give the title compound 38 as a colourless oil
1
(0.28 g, 100% yield). H NMR (500 MHz, CDCl3): δ = 1.64–1.80 Lactam 41: Cbz-protected triester 40 (0.20 g, 0.5 mmol) was dis-
(m, 3 H), 1.95–2.13 (m, 3 H), 2.27–2.36 (m, 4 H), 2.44–2.58 (m, 2
H), 3.17–3.24 (m, 1 H), 3.44 (d, J = 6.9 Hz, 1 H), 3.60 (s, 3 H), resulting mixture was stirred for 24 h under hydrogen (balloon
solved in MeOH (15 mL) and treated with 5% Pd/C (10 mg). The
3
Eur. J. Org. Chem. 2007, 2276–2284
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2283

W. Maison
FULL PAPER
hedron Lett. 2003, 44, 2733–2736; 2-azabicycloalkenones have
been studied by Plumet: O. Arjona, A. G. Csáky, R. Medel,
J. Plumet, J. Org. Chem. 2002, 67, 1380–1383; for ROCM of
2-azabicycloalkenones see: M. Ishikura, M. Saijo, A. Hino,
Heterocycles 2003, 59, 573–585.
technique) at room temp. The mixture was filtered, the solvent was
removed in vacuo and the resulting residue purified by chromatog-
raphy on silica gel (Et2O/MeOH, 95:5) to give 0.10 g (75%) of the
1
title compound 41 as a colourless oil. Rf = 0.47 (Et2O). H NMR
(500 MHz, CDCl3): δ = 1.49–1.85 (m, 8 H), 2.20–2.45 (m, 6 H),
3.66 (s, 3 H), 3.69–3.78 (m, 1 H), 3.70 (s, 3 H), 4.59 (s, 1 H) ppm.
HRMS (FAB) calcd. for C14H22NO5 [MH+] 284.1498, found
284.1492. C14H21NO5 (283.3): calcd. C 59.35, H 7.47, N 4.94;
found C 59.51, H 7.57, N 4.88.
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was dissolved in a mixture of AcCl (0.8 mL) and MeOH (20 mL)
and treated with 10% Pd/C (10 mg). The resulting mixture was
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The mixture was filtered, the solvent was removed in vacuo to give
0.23 g (100%) of the title compound 42 as a colourless oil. 1H
NMR (500 MHz, [D4]MeOH): δ = 1.49–1.57 (m, 1 H), 1.60–1.71
(m, 3 H), 1.73–2.01 (m, 4 H), 2.03–2.09 (m, 1 H), 2.29–2.50 (m, 4
H), 3.44–3.51 (m, 1 H), 3.58 (s, 3 H), 3.60 (s, 3 H), 3.79 (s, 3 H),
4.03 (d, 3J = 6.3 Hz, 1 H) ppm. 13C NMR (101 MHz, [D4]MeOH):
δ = 24.0, 25.0, 27.2, 27.3, 31.0, 32.0, 36.4, 52.6, 52.8, 54.3, 54.9,
59.2, 170.3, 174.9, 175.4 ppm. C15H26ClNO6 (351.8): calcd. C
51.21, H 7.45, N 3.98; found C 51.71, H 7.72, N 4.06.
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Acknowledgments
We are grateful to BASF AG, Degussa AG and Merck KgaA for
material support. We thank the Alexander von Humboldt-Stiftung,
Fonds der Chemischen Industrie and the Deutsche Forschungs-
gemeinschaft (DFG) (MA 2529/1-2) for financial support.
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Received: February 7, 2007
Published Online: March 22, 2007
2284
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2276–2284