Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid

Article abstract of DOI:10.3762/bjoc.10.110

Several strategies aimed to "freeze" natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson's and Alzheimer's and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3-C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction.

Full text of DOI:10.3762/bjoc.10.110

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane
derivatives as conformationally “frozen” analogues
of L-glutamic acid
Beatrice Bechi1,2, David Amantini3,4, Cristina Tintori1, Maurizio Botta*1
and Romano di Fabio*3,5
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1114–1120.
1Università degli Studi di Siena, Dipartimento Farmaco Chimico
Tecnologico, Via A. Moro 2, 53100, Siena, Italy, 2Present address:
Manchester Institute of Biotechnology, School of Chemistry,
University of Manchester, Oxford Road, Manchester, M13 9PL, UK,
3Neurosciences Centre of Excellence for Drug Discovery,
GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4,
37135, Verona, Italy, 4Present address: Galapagos SASU, 102
avenue Gaston Roussel, 93230 Romainville, France and 5Present
address: Drug Design and Discovery, Aptuit S.r.l., Via A. Fleming 4,
37135 Verona, Italy
doi:10.3762/bjoc.10.110
Received: 07 January 2014
Accepted: 04 April 2014
Published: 14 May 2014
Associate Editor: S. You
© 2014 Bechi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Maurizio Botta* - botta.maurizio@gmail.com; Romano di Fabio* -
romano.difabio@aptuit.com
* Corresponding author
Keywords:
Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds
Abstract
Several strategies aimed to “freeze” natural amino acids into more constrained analogues have been developed with the aim of
enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of par-
ticular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a
critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson’s and
Alzheimer’s and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors
(GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu.
This frozen amino acid derivative was designed to further limit the rotation around the C3–C4 bond present in the azetidine deriva-
tive Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium
catalyzed cyclopropanation reaction.
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Introduction
L-Glutamic acid (L-Glu) is the primary excitatory neurotrans- latter approach, Ib, shown in Figure 1, was designed as a novel
mitter in the mammalian central nervous system (CNS) playing potential ligand of the L-Glu receptors and building block for
a critical role in the learning and memory process [1-3]. L-Glu peptidomimetics. To the best of our knowledge, few struc-
receptors can be subdivided in ionotropic receptors (NMDA, turally related azetidine derivatives 10a,b,11a,b and Ia [20-22],
AMPA and kainite receptors) [4,5] and G-protein coupled or have been reported to date. The preparation of compound Ib
metabotropic glutamate receptors (mGluRs) [6,7]. To date, appears challenging due to both the need to control the stereo-
eight different metabotropic receptor subtypes (mGluR1–8) chemistry of three contiguous chiral centers and the presence of
have been identified. Compounds that modulate the function of a [2.3]-spiro junction connecting the cyclopropane moiety with
the mGluRs might be useful for treating a wide range of CNS a highly functionalized azetidine ring. Here, we describe the
disorders including schizophrenia, depression, anxiety, addic- original synthetic approach of compound Ib along with the
tion, pain, epilepsy and neurodegenerative diseases such as stereochemical elucidation of the diastereoisomers obtained.
Parkinson’s and Alzheimer’s. Therefore, the identification of
potent and selective mGluRs agonists and/or antagonists is crit- Results and Discussion
ical to elucidate the role of the individual GluRs in the patho- It was envisioned that the synthesis of compound Ib could be
physiology of these CNS diseases. In the last decade several accomplished as highlighted in Scheme 1 starting from the
potent in vitro and in vivo mGluR agonists have been reported known ketone derivative IV [23,24], pursuing two different
(Figure 1).
synthetic strategies: a) cyclopropanation of an α,β-unsaturated
ester (compound III, Z = COOR); b) metal-catalyzed cyclopro-
Eglumegad (LY354740, 2a) [8-10] was identified by Eli Lilly panation of the corresponding terminal olefin derivative (com-
and investigated as a potential treatment for anxiety and drug pound III, Z = H) with a diazoacetate derivative.
addiction. Modifications to this molecule resulted in the identi-
fication of the analogues MGS0008 (3) [11] and MGS0028 (4) After having accomplished this key step, intermediate II would
[12,13]. In addition, the conformationally constrained analogues be transformed into the target compound Ib by sequential
of L-Glu 6a,b, 7, 8 and 9a,b were reported [14-18] as either deprotection and oxidation of the primary alcohol to access the
ionotropic or metabotropic glutamate receptors ligands, targeted bridged amino acid derivative. Scheme 2 shows that
obtained by “freezing” the glutamate skeleton in search for the synthesis started from the known azetidinone derivative 16
subtype selective bioactive conformations [19]. Following the [23,24], whose preparation was further optimized by replacing
Figure 1: Glutamate receptor ligands.
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step c) CH2N2 (diazomethane) with TMSCHN2 (trimethylsilyl
diazomethane).
This intermediate was transformed into intermediate 17 by a
Horner–Wadsworth–Emmons reaction [23,24], thereby
obtaining 17 as the single E-isomer in 68% yield after purifica-
tion by flash chromatography (Scheme 3).
Then, a systematic study of the reactivity of compound 17 was
undertaken to identify the most efficient method to introduce
the cyclopropane ring on the sterically hindered, α,β-unsatu-
rated trisubstituted olefin group. With this goal in mind, both
the Corey–Chaykovsky [25-27] and the Simmons–Smith [28-
33] cyclopropanation reaction were attempted (highlighted in
Scheme 1: Proposed synthetic plan for the preparation of compound
of type Ib.
Scheme 2: Synthesis of 3-azetidinone derivative 16.
Scheme 3: Synthetic routes to prepare target cyclopropyl derivatives 20. Reagents and conditions: a) (EtO)2POCH2COOEt, NaH, THF, 0 °C, −78 °C,
rt, 2 h 30 min, 68%; b) i. methyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to rt, 2 h 30 min, 23%; ii. Tebbe reagent 0.5 M in toluene, Pyr,
THF, −40 °C to rt, 36%; iii. Petasis reagent, toluene, 70–90 °C in the dark, 2 h, 58%; iv. trimethylsilylsulfoxonium iodide, DBU, MeCN, 60 °C, 6 h;
v. Et2Zn, CH2I2, DCM, 0 °C to rt, 5 days; vi. ethyl diazoacetate, Rh2(OAc)4 10 mol %, DCM, 40 °C, 48 h, 60%. vii. TEA.3HF, TEA, THF, 50 °C, 24 h,
92%; viii. TEA.3HF, TEA, THF, 50 °C, 24 h, 92% then DIBAL, DCM, −78 °C to rt, 12 h, 27%.
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Beilstein J. Org. Chem. 2014, 10, 1114–1120.
Scheme 3). Regrettably, when these reactions were performed was carefully studied in different solvents (i.e., CH2Cl2, DCE,
under different reaction conditions by changing the base, the toluene) and with variable amounts of both ethyl diazoacetate
solvent, the temperature and the reaction time, only trace and Rh2(OAc)4. In particular, encouraging results were
amounts of final product 20 were obtained. Following these obtained when the reaction was performed in CH2Cl2 in the
initial negative results, compound 17 was de-silylated to presence of 1 equivalent of ethyl diazoacetate added to the reac-
remove the steric bulk of the protecting group and improve the tion mixture by a syringe pump over 10 h, heated under reflux,
reactivity towards the cyclopropanation reactions, affording and in the presence of a catalytic amount of Rh2(OAc)4. Under
compound 21. In addition, the ester moiety was reduced with these conditions target compound 20 was obtained in poor yield
DIBAL (diisobutylaluminium hydride) to yield compound 22. (12%) as a mixture of diastereoisomers inseparable by flash
Corey–Chaykovsky cyclopropanation and Simmons–Smith cy- chromatography. Then, the use of an excess of ethyl diazoace-
clopropanation protocols were then performed on both deriva- tate (8 equivalents) led to an increased reaction yield of up to
tives 21 and 22 obtaining only trace amounts of products 23 and 51%. Finally, an optimization study on both the reaction
24. Based on this initial set of results, we decided to abandon concentration (0.025 M) and the catalyst loading (10%
the synthetic strategy a) and to explore the synthetic feasibility Rh2(OAc)4), enabled us to improve the yield up to 60%. As
of approach b), namely the cyclopropanation of the corres- already anticipated, compound 20 was obtained as a mixture of
ponding terminal olefin derivative 18. To explore this alter- diasteroisomers. The HPLC analysis of the mixture revealed the
native approach, we managed to prepare the ethylidene deriva- presence of six diasteroisomers: two of them major (relative
tive 18 by using either the Wittig or the Tebbe olefination reac- ratio: 49%, 33%), the others minor (12%, 3%, 1.8% and 1.2%,
tion [34-37]. The former reaction, when accomplished in the respectively). The presence of two unexpected additional dia-
presence of methyltriphenylphosphonium bromide and BuLi stereoisomers can be explained based upon a partial racemisa-
(butyllithium), successfully afforded the olefin derivative 18, tion of the chiral center next to the nitrogen, most likely occur-
albeit in low yield (23%). The Tebbe reaction was found to be ring during the Petasis olefination reaction of intermediate 16.
more capricious, and it worked successfully only in small scale The two most abundant diastereoisomers were isolated in pure
(50 mg of compound 16) and in the presence of a large excess form by semi-preparative chiral HPLC and their stereochem-
of Tebbe reagent (from 4 to 8 equivalents), giving the target istry was elucidated by NOE studies [40]. In principle, as shown
compound 18, but only in limited yield (37%). However, when in Figure 2, the attack of the carbene intermediate to the olefin
this reaction was scaled-up (400 mg of compound 16), no moiety 18 can occur at both the re and si faces of the terminal
conversion to the desired olefin derivative 18 was observed, olefin group, therefore affording both the trans and the cis pair
and, regrettably, only the byproduct 19 was isolated from the of diasteroisomers.
reaction mixture. To overcome this synthetic hurdle and to
obtain amounts of the key intermediate 18 which are large
enough to investigate its reactivity in the following cyclopropa-
nation reaction, we decided to attempt the Petasis olefination
reaction [38,39]. The initial attempts afforded compound 18 in
50% average yield, but also resulted in significant amounts of
the undesired byproduct 19 (ratio 18:19 = 4:1 by 1H NMR), a
compound difficult to separate by flash chromatography from
product 18. Therefore, a thorough optimization of the reaction
conditions was undertaken to maximize the yield, avoiding the
formation of the byproduct 19. In particular, when the reaction
was performed with a large amount of compound 16 (1.5 g)
under dilute reaction conditions (0.034 M solution in toluene)
by adding 3 equivalents of the Petasis reagent and stirring the
reaction mixture at 70–90 °C for 2 h, the olefin derivative 18
was isolated in 58% yield after purification by flash chromatog-
raphy. Notably, under these reaction conditions no formation of
the byproduct 19 was observed. After successfully obtaining
terminal olefin 18, the efforts were then focused on the explo-
ration of the reactivity of the terminal olefin towards the key cy-
Figure 2: Mechanism for the attack of the carbene intermediate to the
olefin moiety 18.
clopropanation step performed in the presence of ethyl diazo-
acetate and Rh2(OAc)4 (rhodium acetate dimer). The reaction
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Beilstein J. Org. Chem. 2014, 10, 1114–1120.
As expected based on data available in literature [41,42], the
reaction was highly diastereoselective toward the formation of
the two trans cyclopropane derivatives 20a and 20c. Further-
more, a partial facial selectivity was observed in favor of the Si
face attack (ratio 20a:20c = 1.5:1). To explain the results, the
relative stability of the four diastereoisomers 20a–d was
assessed by theoretical calculations. 10000 conformations were
generated for each molecule by using the mixed torsional/low-
mode conformational sampling method in MacroModel version
9.111. The resulting geometries were minimized with the
Polak–Ribiere Conjugate Gradient algorithm with OPLS-2005
Table 1: Relative energy values (kcal/mol) of the four diastereoisomer
20a–d calculated by the HF/631G* method.
Diasteroisomer
Relative energy value (kcal/mol)
20a (RRS)
20b (SRS)
20c (SSS)
20d (RSS)
0
1.49
0
4.48
as a force field until convergence to a gradient of 0.05 kJ/mol. Compounds 20a and 20c showed the same level of stability and
Redundant conformers were eliminated based on a rmsd cutoff were found to be more stable than 20b (+1.49 kcal/mol) and
of 0.5 Å, while an energy cutoff of 5 kcal/mol was applied to 20d (+4.48 kcal/mol). These results were in line with the level
discard unreasonable conformations. Default values were used of both diastereoselection and facial selectivity measured by
for all the remaining parameters. The lowest energy con- HPLC analysis, confirming that the reaction occurred with trans
formation of the four diastereoisomers 20a–d (Figure 3) was selectivity leading to the formation of the most stable diastereo-
saved to perform the following quantum-mechanical calcula- isomers. Finally, the most abundant compounds 20a and 20c
tions, which were obtained in vacuo at the Hartree–Fock SCF were deprotected by triethylamine trihydrofluoride and
level by using a 6-31G* basis set. Finally, a full geometry opti- triethylamine in THF at 60 °C, to give compounds 25a and 25c,
mization was carried out for each diastereoisomer by means of which were oxidized with Jones reagent, to afford acids 26a and
the Gaussian09 program [43].
26c. The final cleavage of the Boc protecting group was carried
out in the presence of formic acid at room temperature,
The relative energies of the four diastereoisomers depicted in affording the target amino acid derivatives 27a and 27c
Figure 3 are reported in Table 1. (Scheme 4).
Figure 3: Representation of the lowest energy conformation of each diastereoisomers.
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Beilstein J. Org. Chem. 2014, 10, 1114–1120.
Scheme 4: Synthesis of glutamate “frozen” analogues 4-carboxy-1-(ethoxycarbonyl)-5-azaspiro[2.3]hexane.
Conclusion
Supporting Information File 3
In conclusion, two complex bridged analogues 27a,c of
glutamic acid were synthesized. Starting from D-serine, their
synthesis was accomplished in 10 steps in good overall yield.
After an extensive investigation on the best synthetic approach,
key intermediate 20 was successfully prepared by an efficient
rhodium-catalyzed cyclopropanation of a terminal double bond
of compound 18 with ethyl acetate. The cyclopropanation reac-
tion occurred with trans selectivity preferentially affording the
two trans cyclopropane products. Theoretical calculations on
the stability of the four possible diastereoisomers were in agree-
ment with both literature and experimental data observed. The
final constrained amino acid derivatives 27a and 27c represent
Gaussian input files for QM calculations for compounds
20a, 20b, 20c and 20d.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-110-S3.pdf]
Supporting Information File 4
Copies of 1H and 13C NMR spectra for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-110-S4.pdf]
useful unnatural amino acid derivatives for both peptidomimetic Acknowledgements
synthesis and as ligands of the plethora of glutamate receptors.
We acknowledge GlaxoSmithKline for financial support. We
also thank Dr. Elena Dreassi and Dr. Claudio Zamperini for
their help with the HPLC analysis and Dr. Vincenzo Summa
and Dr. Federica Orvieto for their help with the HPLC purifica-
tions.
Supporting Information
Experimental section comprising the synthesis of all newly
synthesized compounds and intermediates, NOE studies
and HPLC analysis on compounds 20a and 20c, Gaussian
input files for QM calculations for compounds 20a, 20b,
20c and 20d, and copies of 1H and 13C NMR spectra for all
new compounds.
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