DOI:
10.1039/C0MD00017E
(Concise Article)
Med. Chem. Commun., 2010,
1, 87-102
Received
22nd February 2010
, Accepted 25th March 2010
First published on
28th April 2010
Introduction
COMPOUND LINKS
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Download mol file of compound(S)-Glutamate, which is the main excitatory neurotransmitter in the central nervous system (CNS), and other excitatory amino acids (EAAs) operate through two different classes of COMPOUND LINKS
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Download mol file of compoundglutamate receptors. The first class are ionotropic receptors, which consists of COMPOUND LINKS
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Download mol file of compoundNMDA (COMPOUND LINKS
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Download mol file of compoundN-methyl-D-aspartate), AMPA (COMPOUND LINKS
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Download mol file of compound2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate) and kainate receptors, and the second class are metabotropic receptors with the mGluR1–mGluR8 subtypes.1 The NMDA receptor subtype, which is selectively activated by COMPOUND LINKS
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Download mol file of compoundN-methyl-D-aspartate, represents the target system of the following report.
The physiological activation of the NMDA receptor is important for the development of neurons and for processes like memory and learning. However, an overactivation of the NMDA receptor leads to an increased influx of Ca2+-ions into neurons resulting in damage of the neuronal cells (excitotoxicity). Therefore, compounds blocking the excessive influx of Ca2+-ions through the NMDA receptor associated ion channel into neurons are of major interest as neuroprotective agents, which may be used for the therapy of cerebral ischemia, stroke, epilepsy and trauma (brain injury). Moreover, permanent increased activation of NMDA receptors has been discussed to be involved in the development of chronic neurodegenerative disorders like Parkinson`s disease, Alzheimer`s disease and alcohol dependency. Altogether the NMDA receptor represents an interesting target for the development of novel drugs for the therapy of neurological disorders.2
The opening of the NMDA receptor-associated cation channel is controlled by various ligands interacting with different binding sites at the receptor protein. The receptor comprises binding sites for COMPOUND LINKS
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Download mol file of compound(S)-glutamate, COMPOUND LINKS
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Download mol file of compoundglycine, polyamines, Zn2+, Mg2+, H+ and phencyclidine (PCP, 1, Fig. 1).3
Our interest has been focused on the PCP binding site, which is located within the cation channel. Compounds interacting with the PCP binding site work as non-competitive NMDA receptor antagonists by blocking the cation channel and inhibiting the passage of cations, in particular the influx of Ca2+-ions. Up to now, memantine (2b, Fig. 1) is the only NMDA receptor antagonist with moderate NMDA receptor affinity (Ki = 1.2 μM),4 which is used for the treatment of severe Alzheimer's Disease.4 The particular advantage of memantine is the fast off rate kinetic preventing the drug from accumulating in the ion channel. Therefore, memantine leaves rapidly inactivated ion channels and is not present when the next normal impulse arrives. The physiological neurotransmission is not disturbed by memantine resulting in minimal adverse effects. In contrast, pathologically tonically activated NMDA receptors are blocked by memantine.4 Parkinson's Disease can be treated with the desmethyl derivative COMPOUND LINKS
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Download mol file of compoundamantadine (2a).
In contrast to memantine (2b), the piperidine derivative COMPOUND LINKS
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Download mol file of compounddexoxadrol (3) binds with high affinity (Ki = 11.4 nM) at the phencyclidine binding site within the NMDA receptor associated cation channel. COMPOUND LINKS
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Download mol file of compoundDexoxadrol was synthesized by Hardie et al. in the 1960s and revealed local anesthetic, spasmolytic, and central nervous system activity.5 Later, phencyclidine-like dissociative anesthetic activities were found.6 Unfortunately, clinical trials of COMPOUND LINKS
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Download mol file of compounddexoxadrol had to be stopped because of the psychotomimetic side effects. Since the severe side effects of COMPOUND LINKS
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Download mol file of compounddexoxadrol are attributed to its high NMDA receptor affinity and unfavorable kinetic properties, novel analogues with moderate affinities between those of COMPOUND LINKS
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Download mol file of compounddexoxadrol and memantine should display the desired pharmacological activity with an improved side effect profile.
Several derivatives of COMPOUND LINKS
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Download mol file of compounddexoxadrol have been synthesized in order to get more insight into the structure–affinity relationships within this compound class. In particular, the substituents and the size and the heteroatoms of the oxygen heterocycle have been modified.7 In addition to various N-substituents, the piperidine ring has been exchanged for simple primary, secondary and tertiary amines.8,9
In order to broaden the structure–affinity relationships of this class of COMPOUND LINKS
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Download mol file of compoundNMDA antagonist, we became interested in the influence of substituents in the piperidine moiety on the NMDA receptor affinity. For this purpose, a novel strategy for the synthesis of oxo-COMPOUND LINKS
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Download mol file of compounddexoxadrol analogues and homologues has been elaborated involving a hetero-Diels–Alder reaction.10,11 The resulting racemic oxo-COMPOUND LINKS
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Download mol file of compounddexoxadrol 4 with the same relative configuration as COMPOUND LINKS
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Download mol file of compounddexoxadrol had a NMDA receptor affinity of 470 nM.10 This promising affinity stimulated the synthesis of further COMPOUND LINKS
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Download mol file of compounddexoxadrol derivatives modified in position 4 of the piperidine moiety.
Herein we report on the synthesis and NMDA receptor affinity of all the possible diastereomeric COMPOUND LINKS
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Download mol file of compounddexoxadrol analogues bearing OH, OCH3, NH2 and NHCH3 groups at position 4 of the piperidine ring. Since the first experiments with alcohols were very promising, primary amines representing bioisosteres12 of the alcohols, methyl ethers, which cannot act as COMPOUND LINKS
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Download mol file of compoundH-bond donors and methylamines with the same size as methyl ethers but having COMPOUND LINKS
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Download mol file of compoundH-bond donor and COMPOUND LINKS
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Download mol file of compoundH-bond acceptor properties were included into the study.
Chemistry
The synthesis was started with the acetalization of COMPOUND LINKS
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Download mol file of compoundbenzophenone (COMPOUND LINKS
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Download mol file of compound6) with COMPOUND LINKS
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Download mol file of compoundglycerol (COMPOUND LINKS
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Download mol file of compound5) to yield the dioxolane 7.10,11 Swern oxidation13 of the primary alcohol 7 afforded the aldehyde 8,10 which was condensed with COMPOUND LINKS
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Download mol file of compoundp-methoxybenzylamine (PMB-NH2, 9) to give the imine 10. In contrast to the reported synthesis with COMPOUND LINKS
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Download mol file of compoundbenzylamine,10,11 in this project the p-methoxybenzyl protective group was selected, because the chromatographic purification and separation of the products were easier. Without isolation the imine 10 was reacted with COMPOUND LINKS
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Download mol file of compoundDanishefsky's diene 1114,15 in an Yb(OTf)3-catalyzed hetero-Diels–Alder reaction16 to afford the 1,2-disubstituted dihydropyridones 12a and 12c as a mixture of unlike- and like-configured diastereomers (unlike-12a
:
like12c = 43
:
57). Selective reduction of the double bond of 12a/12c with LiBEt3H in the presence of BF3·OEt2 yielded the piperidin-4-ones COMPOUND LINKS
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Download mol file of compound13a (unlike configuration) and 13c (like configuration) in the ratio 41
:
59, which were separated by flash chromatography (Scheme 1).
![Synthesis of PMB-protected 4-oxo-dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) TosOH·H2O, toluene, reflux, 6 h, 73%. (b) oxalyl chloride, DMSO, CH2Cl2, −78 °C, 30 min, then NEt3, rt, 72%. (c) 9, trimethyl orthoformate, rt, 16 h. (d) Yb(OTf)3, 11, THF, 0 °C, 4 h, then 25 °C, 16 h, 75% from 8. (e) BF3.OEt2, THF, −78 °C, 30 min, then LiBEt3H, −78 °C, 2 h, 37% (13a), 54% (13c).](/image/article/2010/MD/c0md00017e/c0md00017e-s1.gif) |
| Scheme 1 Synthesis of PMB-protected 4-oxo-COMPOUND LINKS
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Download mol file of compounddexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) TosOH·H2O, COMPOUND LINKS
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Download mol file of compoundtoluene, reflux, 6 h, 73%. (b) COMPOUND LINKS
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Download mol file of compoundoxalyl chloride, COMPOUND LINKS
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Download mol file of compoundDMSO, CH2Cl2, −78 °C, 30 min, then NEt3, rt, 72%. (c) 9, COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate, rt, 16 h. (d) Yb(OTf)3, 11, COMPOUND LINKS
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Download mol file of compoundTHF, 0 °C, 4 h, then 25 °C, 16 h, 75% from 8. (e) BF3.OEt2, COMPOUND LINKS
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Download mol file of compoundTHF, −78 °C, 30 min, then LiBEt3H, −78 °C, 2 h, 37% (COMPOUND LINKS
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Download mol file of compound13a), 54% (13c). | |
Reduction of COMPOUND LINKS
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Download mol file of compound13a with NaBH4 resulted in the formation of a mixture (87
:
13) of diastereomeric alcohols, which could not be separated. The same problem was faced after NaBH4 reduction of the like-configured diastereomer 13c (diastereomeric ratio = 83
:
17). In order to improve the diastereoselectivity during the ketone reduction various reducing agents including L-Selectride (LiB(sec-Bu)3H), K-Selectride (KB(sec-Bu)3H), and LiBH4 were investigated, but the diastereoselectivity did not exceed 88
:
12 (Table 1).
Since the separation of the diastereomeric alcohols failed due to considerable tailing of the basic amines, the p-methoxybenzyl (PMB) protective group of COMPOUND LINKS
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Download mol file of compound13a and 13c was replaced by the benzyloxycarbonyl (Cbz) protective group. After hydrogenolytic removal (H2, Pd/C) of the PMB group, the deprotected piperidines 14a and 14c were acylated with COMPOUND LINKS
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Download mol file of compoundbenzyl chloroformate (Cbz-Cl) in the presence of COMPOUND LINKS
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Download mol file of compoundtriethylamine to yield the Cbz-protected piperidines 15a and 15c, respectively. The ketones 15a and 15c were reduced unselectively with NaBH4 to afford 1
:
1 mixtures of diastereomeric alcohols 16a/16b and 16c/16d, respectively, which were separated by fc. Finally, the Cbz group of 16a–d was removed upon hydrogenolysis with H2, Pd/C to yield the piperidines 17a–d (Scheme 2).
![Synthesis of 4-hydroxy dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) H2, Pd/C 10%, MeOH, 16 h, rt. (b) PhCH2OCOCl, NEt3, THF, 1 h, rt, 83% (15a from 13a), 86% (15c from 13c). (c) NaBH4, MeOH, 1 h, 0 °C, 43% (16a), 45% (16b), 43% (16c), 47% (16d). (d) H2, Pd/C 10%, MeOH, 4 h, rt, 80% (17a), 75% (17b), 88% (17c), 89% (17d).](/image/article/2010/MD/c0md00017e/c0md00017e-s2.gif) |
| Scheme 2 Synthesis of 4-hydroxy dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) H2, Pd/C 10%, MeOH, 16 h, rt. (b) PhCH2OCOCl, NEt3, COMPOUND LINKS
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Download mol file of compoundTHF, 1 h, rt, 83% (15a from COMPOUND LINKS
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Download mol file of compound13a), 86% (15c from 13c). (c) NaBH4, MeOH, 1 h, 0 °C, 43% (16a), 45% (16b), 43% (16c), 47% (16d). (d) H2, Pd/C 10%, MeOH, 4 h, rt, 80% (COMPOUND LINKS
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Download mol file of compound17a), 75% (COMPOUND LINKS
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Download mol file of compound17b), 88% (17c), 89% (17d). | |
The relative configuration of the three centers of chirality was assigned by an X-ray crystal structure analysis. For this purpose, a sample of 17d was recrystallized from an COMPOUND LINKS
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Download mol file of compoundn-hexane–CH2Cl2 mixture to get crystals, which were suitable for an X-ray structure analysis (Fig. 2). The structure of the racemic compound 17d proved the like-configuration (RS/RS) of the two centers of chirality at position 4 of the COMPOUND LINKS
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Download mol file of compound1,3-dioxolane ring and position 2 of the piperidine ring (ring junction). The configuration of the third center of chirality at position 4 of the piperidine ring is correlating with the configuration of the other two centers of chirality. However, the piperidine 17d consists of the two enantiomers (R,R,R)-17d and (S,S,S)-17d. The relative configurations of the diastereomers of 17d as well as all precursors 12–16 were deduced from this X-ray crystal structure analysis and comparison of the corresponding NMR data.
![X-Ray crystal structure of 17d (racemic).](/image/article/2010/MD/c0md00017e/c0md00017e-f2.gif) |
| Fig. 2 X-Ray crystal structure of 17d (racemic). | |
In order to obtain the corresponding methoxy derivatives 19a–d the alcohols 16a–d were deprotonated with NaH and subsequently methylated with COMPOUND LINKS
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Download mol file of compoundmethyl iodide in COMPOUND LINKS
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Download mol file of compoundDMF. Treatment of the methyl ethers 18a–d with H2 and Pd/C led to cleavage of the Cbz-protective group and the four diastereomeric methoxy derivatives 19a–d were isolated in 77–90% yields (Scheme 3).
![Synthesis of 4-methoxy dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) NaH, MeI, DMF, 4 h, rt, 85% (18a), 80% (18b), 93% (18c), 91% (18d). (b) H2, Pd/C 10%, MeOH, 4 h, rt, 78% (19a), 90% (19b), 81% (19c), 77% (19d).](/image/article/2010/MD/c0md00017e/c0md00017e-s3.gif) |
| Scheme 3 Synthesis of 4-methoxy dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) NaH, MeI, COMPOUND LINKS
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Download mol file of compoundDMF, 4 h, rt, 85% (18a), 80% (18b), 93% (18c), 91% (18d). (b) H2, Pd/C 10%, MeOH, 4 h, rt, 78% (COMPOUND LINKS
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Download mol file of compound19a), 90% (19b), 81% (COMPOUND LINKS
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Download mol file of compound19c), 77% (COMPOUND LINKS
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During the analysis of the 1H NMR spectra an interesting flip of the piperidine ring was observed. Whereas the piperidine ring of derivatives with a proton (e.g.14, 17, COMPOUND LINKS
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Download mol file of compound19) or a PMB group (e.g.13) attached to the N-atom adopts the 1C4 conformation, the corresponding Cbz derivatives (e.g.15, 16, 18) exist in the 1C4-conformation. Due to allylic strain17,18 the N-acyl-residue of 15, 16 and 18 forces the substituent in position 2 to adopt an axial orientation, which is only possible after changing the piperidine ring conformation. This piperidine ring flip is of particular importance for the interpretation of the 1H NMR data and the correct assignment of the relative configuration of all products. For example, the tt (J = 11.2/4.5 Hz) at 3.52 ppm in the 1H NMR spectrum of the Cbz-derivative 18d clearly indicates an axial orientation of 4-H, and the quintet (J = 2.9 Hz) at 3.60 ppm in the 1H NMR spectrum of the secondary amine COMPOUND LINKS
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Download mol file of compound19d proves the equatorial position of 4-H.
For the synthesis of amino substituted COMPOUND LINKS
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Download mol file of compounddexoxadrol derivatives reductive aminations19 of the PMB-protected ketones COMPOUND LINKS
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Download mol file of compound13a and 13c were performed. Although the transformations were successful, the separation of the formed diastereomeric amines was not possible. Therefore, again the Cbz protected ketones 15a and 15c were used for the introduction of amino moieties.
The reductive amination of unlike-configured ketone 15a with COMPOUND LINKS
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Download mol file of compoundbenzylamine or COMPOUND LINKS
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Download mol file of compoundmethylamine in the presence of NaBH(OAc)319 led to the diastereomeric benzylamines 20a/20b and methylamines 22a/22b in the ratio ≈7
:
3, respectively, which were separated by flash chromatography (Scheme 4). Subsequent hydrogenolytic removal of the Cbz-protective group resulted in the primary amines COMPOUND LINKS
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Download mol file of compound21a and COMPOUND LINKS
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Download mol file of compound21b, since the benzyl moiety of the 4-benzylamino group was also cleaved, and the methylamines COMPOUND LINKS
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Download mol file of compound23a and COMPOUND LINKS
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Download mol file of compound23b.
![Synthesis of 4-amino dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) PhCH2NH2 or MeNH2, NaBH(OAc)3, CH2Cl2, 2 h, rt, 58% (20a), 29% (20b), 92% (20c), 64% (22a), 26% (22b), 90% (22c). (b) PhCH2NH2 or MeNH2, trimethyl orthoformate, 14 h, rt; then NaBH4, MeOH, 1.5 h, 0 °C, 59% (20c), 37% (20d), 47% (22c), 36% (22d). (c) H2, Pd/C 10%, MeOH, 4 h, rt, 89% (21a), 87% (21b), 91% (21c), 83% (21d), 89% (23a), 78% (23b), 87% (23c), 82% (23d).](/image/article/2010/MD/c0md00017e/c0md00017e-s4.gif) |
| Scheme 4 Synthesis of 4-amino dexoxadrol derivatives (only one enantiomer is shown, all compounds are racemic). Reagents and conditions: (a) PhCH2NH2 or MeNH2, NaBH(OAc)3, CH2Cl2, 2 h, rt, 58% (20a), 29% (20b), 92% (20c), 64% (22a), 26% (22b), 90% (22c). (b) PhCH2NH2 or MeNH2, COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate, 14 h, rt; then NaBH4, MeOH, 1.5 h, 0 °C, 59% (20c), 37% (20d), 47% (22c), 36% (22d). (c) H2, Pd/C 10%, MeOH, 4 h, rt, 89% (COMPOUND LINKS
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Download mol file of compound21a), 87% (COMPOUND LINKS
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Download mol file of compound21b), 91% (COMPOUND LINKS
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Download mol file of compound21c), 83% (COMPOUND LINKS
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Download mol file of compound21d), 89% (COMPOUND LINKS
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Download mol file of compound23a), 78% (COMPOUND LINKS
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Download mol file of compound23b), 87% (COMPOUND LINKS
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Download mol file of compound23c), 82% (23d). | |
In contrast to ketone 15a, a high diastereoselectivity was observed during the reductive amination of like-configured ketone 15c with COMPOUND LINKS
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Download mol file of compoundbenzylamine or methylamine and NaBH(OAc)3, which yielded the diastereomeric amines 20c/20d and 22c/22d in the ratio of about 9
:
1. The main diastereomers 20c and 22c were isolated by flash chromatography, and subsequently treated with H2 and Pd/C to obtain the primary amine COMPOUND LINKS
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Download mol file of compound21c and the methylamine COMPOUND LINKS
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Download mol file of compound23c, respectively.
In order to get the fourth diastereomers COMPOUND LINKS
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Download mol file of compound21d and COMPOUND LINKS
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Download mol file of compound23d, ketone 15c was first converted into imines upon stirring with COMPOUND LINKS
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Download mol file of compoundbenzylamine or methylamine in COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate overnight. After removal of the volatile components, COMPOUND LINKS
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Download mol file of compoundmethanol was added to the residue and the imines were reduced with NaBH4 at 0 °C. This procedure yielded the diastereomeric benzylamines 20c and 20d in the ratio 61
:
39 and the methylamines 22c and 22d in the ratio 57
:
43 after fc. After separation of the diastereomers hydrogenolytic cleavage led to the final amines COMPOUND LINKS
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Download mol file of compound21d and COMPOUND LINKS
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Download mol file of compound23d.
During this reaction sequence the above described flip of the piperidine ring was also observed, when the N-substituent was changed from the Cbz-group (20/22) to a proton (21/23).
The affinities of the novel COMPOUND LINKS
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Download mol file of compounddexoxadrol analogues to the PCP binding site of the NMDA receptor were determined in competition experiments using the potent and selective radioligand [3H]-(+)-MK-801. A membrane preparation from pig brain cortex was employed as receptor material.20,21 In addition to the affinity towards the PCP binding site the affinity of selected compounds towards the ifenprodil binding site of NR2B containing NMDA receptors was investigated. For this purpose the competitive receptor binding assay recently developed in our group was used. Briefly, in this assay tritium-labelled ifenprodil was employed as a radioligand. Membrane homogenates prepared from L(tk−) cells stably expressing recombinant human NR1a/NR2B receptors served as receptor material. The high density of NMDA receptors renders this system selective.22
Since some potent NMDA receptor antagonists also interact with σ receptors and vice versa,23,24 the σ1 and σ2 receptor affinity of the piperidines was also determined. In the σ assays, the radioligands [3H]-(+)-pentazocine (σ1) and [3H]-(+)-ditolylguanidine (σ2), and membrane preparations from guinea pig brains (σ1) and rat livers (σ2) were used. In the σ2 assay, the σ1 binding sites were selectively masked with an excess of non-tritiated COMPOUND LINKS
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Download mol file of compound(+)-pentazocine.25,26,27
The Cbz-protected compounds 20 and 22 were also included into his study, because they contain a basic functional group. It should be noted that the basic amino group is at another position of the piperidine ring and the O-heterocycle in position 2 adopts an axial orientation in these compounds.
The receptor binding data are summarized in Table 2. For compounds with high COMPOUND LINKS
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Download mol file of compoundNMDA affinity the competition curves with six compound concentrations were recorded three times and the resulting Ki-values with SEM are given. For compounds showing only low NMDA receptor interaction in the first screening, only the inhibition (%) at a compound concentration of 1 μM is given in Table 2. Some compounds indicated promising σ1 and/or σ2 affinities in the first screening. However, recording of the complete competition curves revealed only low affinity, and therefore the experiments were performed only once (n = 1).
Compound |
X |
R |
Stereochemistryb |
K
i ± SEM/nMa |
COMPOUND LINKS
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Download mol file of compoundNMDA (PCP) ([3H]-(+)-MK-801) |
σ1 ([3H]-(+)-pentazocine) |
σ2([3H]-di-o-tolylguanidine) |
The Ki-values were determined in three independent experiments (n = 3) unless otherwise noted.
All compounds were tested as racemic mixtures. In the column stereochemistry the relative configuration of the three centers of chirality is given.
Percent inhibition at a concentration of 1μM of the test compound.
|
14a
10
|
O |
COMPOUND LINKS
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Download mol file of compoundH |
2S-4′R |
84% |
1390 ± 90 |
54% |
14c
10
|
2S-4′S |
470 ± 173 |
0% |
36% |
COMPOUND LINKS
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Download mol file of compound17a
|
OH |
2S,4R-4′R |
0%c |
318 (n = 1) |
0%c |
COMPOUND LINKS
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Download mol file of compound17b
|
2S,4S-4′R |
3%c |
259 (n = 1) |
30%c |
17c
|
2S,4R-4′S |
527 ± 106 |
1250 (n = 1) |
2%c |
17d (WMS-2508) |
2S,4S-4′S |
44 ± 13 |
971 (n = 1) |
13%c |
COMPOUND LINKS
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Download mol file of compound19a
|
OCH3 |
2S,4R-4′R |
37%c |
17 ± 4.5 |
18%c |
19b
|
2S,4S-4′R |
21%c |
15 ± 1.8 |
23%c |
COMPOUND LINKS
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Download mol file of compound19c
|
2S,4R-4′S |
49%c |
0%c |
5%c |
COMPOUND LINKS
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Download mol file of compound19d
|
2S,4S-4′S |
981 ± 96 |
831 (n = 1) |
9%c |
20a
|
NHCH2Ph |
Cbz |
2S,4R-4′R |
8%c |
12%c |
23%c |
20b
|
2S,4S-4′R |
30%c |
20%c |
442 (n = 1) |
20c
|
2S,4R-4′S |
20%c |
0%c |
14%c |
20d
|
2S,4S-4′S |
15%c |
179 (n = 1) |
8%c |
COMPOUND LINKS
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Download mol file of compound21a
|
NH2 |
COMPOUND LINKS
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Download mol file of compoundH |
2S,4R-4′R |
26%c |
45%c |
15%c |
COMPOUND LINKS
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Download mol file of compound21b
|
2S,4S-4′R |
25%c |
0%c |
13%c |
COMPOUND LINKS
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Download mol file of compound21c
|
2S,4R-4′S |
44%c |
20%c |
26%c |
COMPOUND LINKS
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Download mol file of compound21d
|
2S,4S-4′S |
17%c |
33%c |
17%c |
22a
|
NHCH3 |
Cbz |
2S,4R-4′R |
7%c |
22%c |
28%c |
22b
|
2S,4S-4′R |
7%c |
17%c |
18%c |
22c
|
2S,4R-4′S |
10%c |
353 (n = 1) |
42%c |
22d
|
2S,4S-4′S |
6%c |
8%c |
35%c |
COMPOUND LINKS
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Download mol file of compound23a
|
NHCH3 |
COMPOUND LINKS
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Download mol file of compoundH |
2S,4R-4′R |
16%c |
40%c |
44%c |
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Download mol file of compound23b
|
2S,4S-4′R |
16%c |
972 (n = 1) |
3670 (n = 1) |
COMPOUND LINKS
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Download mol file of compound23c
|
2S,4R-4′S |
40%c |
21%c |
12%c |
COMPOUND LINKS
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Download mol file of compound23d
|
2S,4S-4′S |
30%c |
32%c |
37%c |
COMPOUND LINKS
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Download mol file of compounddexoxadrol |
— |
|
11 ± 0.3 |
— |
— |
(+)-MK-801 |
— |
|
2.8 ± 1.8 |
— |
— |
COMPOUND LINKS
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Download mol file of compound(+)-pentazocine |
— |
|
— |
4.2 ± 1.1 |
— |
COMPOUND LINKS
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Download mol file of compounddi-o-tolyl guanidine |
— |
|
— |
89 ± 29 |
58 ± 18 |
The receptor binding data in Table 2 clearly show that the compounds 20–23 with a basic amino moiety at position 4 do not interact significantly with the PCP binding site of the NMDA receptor. Moreover, the σ1 and σ2 receptor affinity of the amines 20–23 was also very low. The Ki-value of the most potent basic σ1 ligand (20d) is considerably higher than 100 nM, indicating very low σ1 affinity.
In the alcohol (17) and COMPOUND LINKS
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Download mol file of compoundmethyl ether series (COMPOUND LINKS
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Download mol file of compound19) the stereochemistry plays a crucial role for the NMDA receptor affinity. In particular, the two centers of chirality at position 2 of the piperidine ring and in position 4 of the 1,3-dioxolane ring (ring junction) should be like-configured. This observation is in good accordance with literature results showing that COMPOUND LINKS
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Download mol file of compounddexoxadrol with (S,S)-configuration represents the most potent stereoisomer.6 Additionally, the stereocenter at position 4 of the piperidine ring should have the same configuration as the other two stereocenters. This results in an axial orientation of the functional group at position 4 of the piperidine ring. The effect of the stereochemistry on the NMDA receptor affinity becomes particularly evident for the alcohol series 17. Whereas COMPOUND LINKS
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Download mol file of compound17a and COMPOUND LINKS
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Download mol file of compound17b with unlike-configuration of the ring junction didn't interact considerably with the NMDA receptor, the like-configured derivatives 17c and 17d were considerably more active. The racemic piperidine 17d (WMS-2508) with an axially oriented OH-moiety provided a Ki-value of 44 nM, which is slightly increased compared with the Ki-value of the enantiomerically pure lead compound COMPOUND LINKS
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Download mol file of compounddexoxadrol (11.4 nM). Despite its 15-fold lower affinity, the potency of the diastereomer 17c (Ki = 527 nM) is still in a promising range considering the affinity of memantine (compare Introduction).
Replacement of the OH-moiety at position 4 of the piperidine derivative 17d by a methoxy group (COMPOUND LINKS
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Download mol file of compound19d) led to a drastic reduction of the NMDA receptor affinity (COMPOUND LINKS
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Download mol file of compound19d: Ki = 981 nM). We assume that the reduced affinity of the methyl ether COMPOUND LINKS
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Download mol file of compound19d is due to the increased size of the methoxy group compared with the smaller hydroxy group.
Only negligible inhibition of radioligand binding at the ifenprodil binding site of the NMDA receptor was detected at a concentration of 1 μM for the test compounds 17c (30% inhibition), 17d (0% inhibition) and COMPOUND LINKS
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Download mol file of compound19d (29% inhibition). The low inhibition indicates IC50 values higher than 1 μM for these test compounds. Obviously, at least the most potent ligand 17c, 17d and COMPOUND LINKS
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Download mol file of compound19d reveal high selectivity for the PCP binding site over the ifenprodil binding site of the NMDA receptor.
Concerning σ1 receptor affinity, the stereochemistry at the ring junction is also very important. In contrast to the NMDA receptor, the σ1 receptor prefers piperidines with unlike-configuration of the ring junction. The unlike-configured alcohols COMPOUND LINKS
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Download mol file of compound17a and COMPOUND LINKS
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Download mol file of compound17b show moderate σ1 affinities and the corresponding methyl ethers COMPOUND LINKS
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Download mol file of compound19a and 19b are very potent σ1 ligands (Ki = 17 and 15 nM). Comparison of the σ1 affinities of the diastereomers COMPOUND LINKS
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Download mol file of compound19a/19b clearly indicates that the configuration at position 4 of the piperidine moiety is of minor importance for the σ1 affinity.
Conclusion
The influence of substituents in position 4 of the piperidine moiety of COMPOUND LINKS
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Download mol file of compounddexoxadrol analogues on the NMDA and σ receptor affinity has been investigated. Potent COMPOUND LINKS
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Download mol file of compoundNMDA antagonists were obtained, when a hydroxy moiety was introduced into position 4. like-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the 1,3-dioxolane ring) as well as axial orientation of the OH moiety are crucial for high NMDA receptor affinity. The most potent COMPOUND LINKS
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Download mol file of compoundNMDA antagonist 17d was very selective against σ1 receptors, σ2 receptors and the ifenprodil binding site of the NMDA receptor. However, changing of the configuration of the ring junction led to potent and selective σ1 ligands (COMPOUND LINKS
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Download mol file of compound19a, 19b). Since the prepared compounds are still racemic mixtures, the NMDA and σ1 receptor affinities will be further increased by enantiomerically pure ligands. Having the low NMDA receptor affinity of memantine with its ideal binding kinetic at the NMDA receptor in mind the alcohol 17c and the methyl ether COMPOUND LINKS
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Download mol file of compound19d with moderate NMDA receptor affinity could also be of interest with respect to the side effect profile.
Experimental
Chemistry general
Unless otherwise noted, moisture and oxygen sensitive reactions were conducted in dry glassware (Schlenk flask sealed with a rubber septum) under N2 (dried with phosphorous pentoxide (Granusic® A, Baker)). Yb(OTf)3 (Aldrich) was stored in a desiccator over P4O10 in vacuo at rt. COMPOUND LINKS
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Download mol file of compoundDanishefsky's diene 11 was stored under N2 at −25 °C. COMPOUND LINKS
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Download mol file of compoundTHF was dried with COMPOUND LINKS
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Download mol file of compoundsodium/benzophenone and was freshly distilled before use. COMPOUND LINKS
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Download mol file of compoundMethanol was dried with COMPOUND LINKS
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Download mol file of compoundmagnesium and iodine, distilled, and stored over molecular sieves 4 Å. CH2Cl2 was dried with CaH2 and freshly distilled before use. Thin layer chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash chromatography (fc): Silica gel 60, 40–64 μm (Merck); parentheses include: Diameter of the column (cm), length of the stationary phase (cm), eluent, fraction size (mL) and retention factor Rf. Melting point: melting point apparatus SMP 3 (Stuart Scientific), uncorrected. IR: IR spectrophotometer 480Plus FT-ATR-IR (Jasco). 1H NMR (400 MHz, 300 MHz, 600 MHz), 13C NMR (100 MHz) and 19F NMR (300 MHz, 600 MHz) spectra were recorded on a Unity COMPOUND LINKS
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Download mol file of compoundMercury Plus 400 (400 MHz) NMR spectrometer (Varian), Brucker AV 300 (300 MHz), and Varian Unity Plus 600 (600 MHz) operating at 23 °C. High temperature NMR was recorded in Unity COMPOUND LINKS
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Download mol file of compoundMercury Plus 400 (400 MHz) NMR spectrometer (Varian) at 100 °C. Chemical shifts δ are reported in parts per million (ppm) against the reference compound COMPOUND LINKS
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Download mol file of compoundtetramethylsilane and calculated using the chemical shift of the signal of the residual non-deuterated solvent, for 19F NMR chemical shifts δ are reported in parts per million (ppm) against the reference compound CFCl3 and calculated using the chemical shift of the signal of the solvent. High temperature 1H NMR spectra were recorded using C6D5NO2 as solvent. MS: HRMS (ESI): Finnigan MAT 4200s, Brucker Daltonics Micro Tof and Waters Micromass Quatro LCZ, peaks are given in m/z (% of basis peak). EI, electron impact, MAT GCQ (Thermo-Finnigan). HPLC: Merck Hitachi Equipment; UV detector: L-7400; autosampler: L-7200; pump: L-7100; degasser: L-7614; column: LiChrospher® 60 RP-select B (5 μm); LiChroCART® 250–4 mm cartridge; flow rate: 1.000 mL min−1; injection volume: 5.0 μL; detection at λ = 210 nm; Method A: solvents: A: water with 0.05% (v/v) COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid; B: COMPOUND LINKS
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Download mol file of compoundacetonitrile with 0.05% (v/v) COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid: gradient elution: (A%): 0–4 min: 90%, 4–29 min: gradient from 90%, to 0%, 29–31 min: 0%, 31–31.5 min: 0% to 90%, 31.5–40 min: 90%; Method B: solvents: A: water with 0.05% (v/v) COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid; B: COMPOUND LINKS
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Download mol file of compoundmethanol with 0.05% (v/v) COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid: gradient elution: (A%): 0–1 min: 80%, 1–22 min: gradient from 80%, to 0%, 22–30 min: 0%, 30–31.5 min: 0% to 80%, 31.5–40 min: 80%. The purity of all test compounds was greater than 95%, which was determined by one of the given HPLC methods.
General procedures
General procedure A: exchange of the PMB group for the Cbz group.
The PMB-piperidone 13 was dissolved in MeOH (6 mL), Pd/C 10% was added and the suspension was stirred under H2 atmosphere (balloon) at rt overnight. The reaction mixture was filtered through Celite®, which was rinsed with MeOH and the filtrate was evaporated to dryness. Under N2 the crude product was dissolved in COMPOUND LINKS
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Download mol file of compoundTHF and Cbz-Cl (1.5 equivalents) was added followed by NEt3 (1.5 equivalents). The reaction mixture was stirred at rt for 1 h. Then a saturated solution of NaHCO3 and EtOAc were added. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried (K2CO3) filtered and concentrated in vacuo. The residue was purified by fc (3 cm, 12 cm, petroleum ether–EtOAc = 7
:
3, 10 mL).
General procedure C: conversion of alcohols 16 into methyl ethers.
Under N2 the alcohol 16 was dissolved in COMPOUND LINKS
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Download mol file of compoundDMF (2 mL). Then NaH (2 equivalents) was added followed by CH3I (1 equivalent). The reaction mixture was stirred at rt for 4 h. Then ice cold water and EtOAc were added. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (K2CO3,) filtered and concentrated in vacuo. The residue was purified by fc (2 cm, 12 cm, petroleum ether–EtOAc = 7
:
3, 20 mL).
General procedure F: removal of the Cbz protective group.
The Cbz-protected piperidine was dissolved in MeOH (6 mL), Pd/C (10%) was added and the suspension was stirred under H2 atmosphere (balloon) at rt for 4 h. The reaction mixture was filtered through Celite®, which was rinsed with MeOH and the filtrate was evaporated to dryness. The product was purified by fc (2 cm, 12 cm, EtOAc–MeOH–NEtMe2 = 94
:
5
:
1, 10 mL) for the hydroxyl and methoxy derivatives and (2 cm, 12 cm, MeOH–NEtMe2 = 99
:
1, 5 mL) for the amine derivatives.
(±)-(2RS)-1-(4-Methoxybenzyl)-2-[(4SR) and (4RS)-2,2-diphenyl-1,3-dioxolan-4-yl)]-2,3-dihydropyridin-4(1H)-one (12a and 12c).
The aldehyde 8 (787.4 mg, 3.1 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate (5 mL), COMPOUND LINKS
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Download mol file of compound4-methoxybenzylamine (PMB-NH29, 0.4 mL, 3.1 mmol) was added and the solution was stirred overnight at rt. The mixture was evaporated to dryness, the obtained yellow oil was dissolved in COMPOUND LINKS
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Download mol file of compoundTHF (10 mL) and the resulting solution was cooled down to 0 °C. Then a solution of Yb(OTf)3 (384 mg, 0.62 mmol) in COMPOUND LINKS
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Download mol file of compoundTHF (2 mL) was added and the mixture was stirred at 0 °C for 15 min. Then, COMPOUND LINKS
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Download mol file of compoundDanishefsky's diene 11 (1.08 mL, 5.67 mmol) was added and it was stirred for another 4 h at 0 °C before the reaction mixture was allowed to warm to rt overnight. A saturated solution of NaHCO3 and EtOAc were added, the organic layer was separated, the aqueous layer was extracted twice with EtOAc, the organic layer was dried (K2CO3), filtered and concentrated in vacuo. The residue was purified by fc (2 cm, 12 cm, COMPOUND LINKS
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Download mol file of compoundcyclohexane–EtOAc = 1
:
1, 20 mL, Rf 0.20). Yellow oil, yield 1.0133 g (75%). IR (neat): ν/cm−1 = 1637 (m, C
O), 1579 (s, C
C), 1071 (m, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.97 (d, J = 16.9 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, 3x-H), 2.48 (dd, J = 16.9/2.8 Hz, 0.57 COMPOUND LINKS
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Download mol file of compoundH, 3°-H), 2.68 (dd, J = 16.9/7.9 Hz, 0.57 COMPOUND LINKS
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Download mol file of compoundH, 3°-H), 2.73 (dd, J = 16.9/7.3 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, 3x-H), 3.45–3.49 (m, 0.43 COMPOUND LINKS
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Download mol file of compoundH, 2x-H), 3.71 (dd, J = 8.6/5.9 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, OCH2x), 3.77–3.79 (m, 0.57 COMPOUND LINKS
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Download mol file of compoundH, OCH2°), 3.80 (s, 3 × 0.57 COMPOUND LINKS
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Download mol file of compoundH, OCH3°), 3.81 (s, 3 × 0.43 COMPOUND LINKS
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Download mol file of compoundH, OCH3x), 3.99 (dd, J = 8.3/6.9 Hz, 0.57 COMPOUND LINKS
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Download mol file of compoundH, OCH2°), 4.04 (dd, J = 8.6/6.7 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, OCH2x),4.05–4.09 (m, 0.57 COMPOUND LINKS
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Download mol file of compoundH, OCH°), 4.29 (d, J = 14.9 Hz, 0.57 COMPOUND LINKS
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Download mol file of compoundH, PhCH2°), 4.30–4.34 (m, 0.57 COMPOUND LINKS
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Download mol file of compoundH, 2°-H), 4.41 (d, J = 14.9 Hz, 0.57 COMPOUND LINKS
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Download mol file of compoundH, PhCH2°), 4.44 (d, J = 14.7 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, PhCH2x), 4.65 (d, J = 14.9 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, PhCH2x), 4.82 (dt, J = 9.8/6.3 Hz, 0.43 COMPOUND LINKS
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Download mol file of compoundH, OCHx), 4.94 (d, J = 7.5 Hz, 1H, 5x-H + 5°-H), 6.85–6.89 (m, 3H, 2 × Ph + 6x-H + 6°-H), 7.02–7.15 (m, 3H, Ph), 7.26–7.34 (m, 5H, Ph), 7.47–7.52 (m, 4H, Ph). The ratio of 12a
:
12c = 43
:
57; ° = index for the major diastereomer 12c; x = index for the minor diastereomer 12a. 13C NMR (CDCl3): δ (ppm) = 36.7 (C-3°), 37.3 (C-3x), 55.2 (C-2°), 56.1 (C-2x), 58.2 (OC°H3, OCxH3), 58.7 (PhC°H2), 59.4 (PhCxH2), 66.7 (OC°H2), 66.8 (OCxH2), 74.1 (OC°H, OCxH), 96.8 (C5x), 98.5 (C5°), 109.4 (OC°O), 110.5 (OCxO), 114.2/ 114.3/ 125.6/ 125.8/ 125.9/ 126.0/ 128.0/ 128.1/ 128.2/ 128.3/ 128.5/ 128.7/ 128.9/ 141.6/ 141.8/ 141.9 (COMPOUND LINKS
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Download mol file of compoundPhC), 152.6 (C-6x), 153.2 (C-6°), 159.4/159.5 (COMPOUND LINKS
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Download mol file of compoundPhC), 188.7 (C-4x), 189.5 (C-4°). HRMS: calcd. for C28H27NO4H 442.2018, found 442.2013. HPLC (Method A): Purity 42% (12a), tR = 22.6 min, 53% (12c), tR = 22.0 min, together 95%.
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Download mol file of compound(±)-(2RS)-1-(4-Methoxybenzyl)-2-[(4SR)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidin-4-one (COMPOUND LINKS
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Download mol file of compound13a) and COMPOUND LINKS
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Download mol file of compound(±)-(2RS)-1-(4-Methoxybenzyl)-2-[(4RS)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidin-4-one (13c).
Under N212a/c (43
:
57, 1.0133 g, 2.3 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundTHF (10 mL) and the solution was cooled down to −78 °C, BF3·OEt2 (0.58 mL, 4.6 mmol) was added slowly and the solution was stirred for 30 min at −78 °C. Then a 1M solution of LiEt3BH in COMPOUND LINKS
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Download mol file of compoundTHF (4.61 mL, 4.6 mmol) was added slowly and the reaction mixture was stirred for 2 h at −78 °C. Afterwards a saturated solution of NaHCO3 and EtOAc were added and the reaction mixture was warmed to rt. Then EtOAc was added, the organic layer was separated, the aqueous layer was extracted twice with EtOAc, the organic layer was dried (K2CO3), filtered and concentrated in vacuo. The residue was purified by fc (4 cm, 20 cm, petroleum ether–EtOAc = 85
:
15, 20 mL).
Compound COMPOUND LINKS
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Download mol file of compound13a (Rf 0.16): Pale yellow oil, yield 0.3752 g (37%). IR (neat): ν/cm−1 = 1714 (s, C
O), 1205(s) / 1070 (s, –C–O–C–). 1H NMR (CDCl3): δ (ppm) = 2.21 (ddd, J = 14.7/ 5.0/1.3 Hz, 1H, 5-H), 2.26–2.33 (m, 1H, 5-H), 2.40–2.47 (m, 1H, 3-H), 2.66 (ddd, J = 14.8/5.9/0.9 Hz, 1H, 3-H), 2.78–2.84 (m, 1H, 6-H), 3.17 (ddd, J = 12.9/8.3/4.7 Hz, 1H, 6-H), 3.31 (q, J = 5.6 Hz, 1H, 2-H), 3.82 (s, 3H, OCH3), 3.85 (d, J = 13.4 Hz, 1H, PhCH2), 3.94 (t, J = 7.6 Hz, 1H, OCH2), 4.05 (d, J = 13.4 Hz, 1H, CH2Ph), 4.07 (dd, J = 7.8/7.0 Hz, 1H, OCH2), 4.37 (q, J = 7.2 Hz, 1H, OCH), 6.87–6.89 (m, 2H, Ph), 7.25–7.37 (m, 8H, Ph), 7.48–7.55 (m, 4H, Ph). HRMS: calculated for C28H29NO4H 444.2169, found 444.2164. EI (70 eV): m/z (rel. int.) = 443 (M+, 2), 366 (M-Ph, 2), 218 (M- diphenyldioxolanyl, 10), 121 (CH2C6H4OCH3, 100), 77 (Ph, 18). HPLC (Method A): Purity 95%, tR = 18.6 min.
Compound 13c (Rf 0.11): Pale yellow oil, yield 0.5477 g (54%). IR (neat): ν/cm−1 = 1709 (s, C
O), 1450 (m, C–H), 1205 (s) / 1069 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 2.30 (dt, J = 15.1/3.8 Hz, 1H, 5-H), 2.51(ddd, J = 15.4/9.5/6.1 Hz, 1H, 5-H), 2.64 (dd, J = 14.9/5.9 Hz, 1H, 3-H), 2.71 (ddd, J = 14.8/4.0/1.2 Hz, 1H, 3-H), 2.96 (dt, J = 10.8/5.1 Hz, 1H, 6-H), 3.11–3.20 (m, 2H, 2-H + 6-H), 3.81 (s, 5H, OCH3, CH2Ph), 3.88 (dd, J = 8.0/7.0 Hz, 1H, OCH2) 4.08 (dd, J = 8.1/7.1, 1H, OCH2), 4.30 (q, J = 6.8 Hz, 1H, OCH), 6.87–6.89 (m, 2H, Ph), 7.23–7.37 (m, 8H, Ph), 7.43–7.45 (m, 2H, Ph), 7.52–7.54 (m, 2H, Ph). HRMS: calcd. for C28H29NO4H 444.2169, found 444.2173. EI (70 eV): m/z (rel. int.) = 443.2 (M+, 2), 218 (M-diphenyldioxolanyl, 12), 121(CH2C6H4OCH3, 100), 77 (Ph, 18). HPLC (Method A): Purity 96%, tR = 19.2 min.
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Download mol file of compound(±)-Benzyl (2RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-oxopiperidine-1-carboxylate (15a).
According to General Procedure A the COMPOUND LINKS
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Download mol file of compoundpiperidone COMPOUND LINKS
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Download mol file of compound13a (0.3752 g, 0.84 mmol) was transformed into the secondary amine 14a, (crude yield 0.241 g, 88%). The crude product 14a (0.241 mg, 0.75 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundTHF (3 mL) and PhCH2OCOCl (0.16 mL, 1.12 mmol) was added followed by NEt3 (0.16 mL, 1.12 mmol). The residue was purified by fc (Rf 0.36). Colorless oil, yield 323.4 mg (83%). IR (neat): ν/cm−1 = 1695 (s, C = O/Cbz C
O), 1206 (s) /1080 (s, C–O–C). 1H NMR (C6D5NO2, 100 °C): δ (ppm) = 1.92 (dd, J = 15.7/3.4 Hz, 1H, 3-H), 2.02–2.11 (m, 1H, 5-H), 2.15 (d broad, J = 15.7 Hz, 1H, 3-H), 2.34 (ddd, J = 15.2/7.5/2.6 Hz, 1H, 5-H), 3.13 (COMPOUND LINKS
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Download mol file of compoundddt, J = 15.1/11.4/3.9 Hz, 1H, 6-H), 3.56 (ddd, J = 15.0/ 7.5/3.5 Hz, 1H, 6-H), 3.60–3.64 (m, 1H, 2-H), 3.87–3.96 (m, 2H, OCH2Ph), 4.47–4.53 (m,1H, OCH), 4.75 (dd, J = 12.6/3.1 Hz, 1H, OCH2), 4.82 (dd, J = 12.6/3.2 Hz, 1H, OCH2), 6.76–7.17 (m, 15 COMPOUND LINKS
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Download mol file of compoundH, Ph). HRMS: calcd. for C28H27NO5Na 480.1787, found 480.1781. HPLC (Method A): Purity 98%, tR = 22.9 min.
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Download mol file of compound(±)-Benzyl (2RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-oxopiperidine-1-carboxylate (15c).
According to General Procedure A the COMPOUND LINKS
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Download mol file of compoundpiperidone 13c (0.5477 g, 1.23 mmol) was transformed into the secondary amine 14c (crude yield 0.3587 g, 90%). Compound 14c (0.3587 mg, 1.11 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundTHF (3 mL) and PhCH2OCOCl (0.28 mL, 1.66 mmol) was added followed by NEt3 (0.17 ml, 1.66 mmol). The residue was purified by fc (Rf 0.21). Colorless oil, yield 0.4881 g (86%). IR (neat): ν/cm−1 = 1697 (s, C = O/Cbz C
O), 1206(s)/ 1082 (s, C–O–C). 1H NMR (C6D5NO2, 100 °C): δ (ppm) = 2.03–2.17 (m, 1H, 3-H), 2.12 (ddd, J = 16.3/6.6/3.0 Hz, 1H, 5-H), 2.23 (ddd, J = 15.7/7.2/2.8 Hz, 1H, 5-H), 2.45 (dt, J = 15.8/2.8 Hz, 1H, 6-H), 3.18–3.26 (m, 1H, 3-H), 3.61 (ddd, J = 15.0/ 8.5/3.5 Hz, 1H, 6-H), 3.64–3.67 (m, 1H, 2-H), 3.93–4.04 (m, 2H, OCH2Ph), 4.31–4.36 (m,1H, OCH), 4.77 (dd, J = 12.6/2.8 Hz, 1H, OCH2), 4.82 (dd, J = 12.6/3.0 Hz, 1H, OCH2), 6.81–7.63 (m, 15 COMPOUND LINKS
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Download mol file of compoundH, Ph). HRMS: calcd. for C28H27NO5Na 480.1787, found 480.1781. HPLC (Method A): Purity 98%, tR = 23.0 min.
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Download mol file of compound(±)-Benzyl (2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-hydroxypiperidine-1-carboxylate (16a) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(2SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-hydroxypiperidine-1-carboxylate (16b).
According to General Procedure B compound 15a (0.2754 g, 0.6 mmol) was dissolved in MeOH (2 mL) and NaBH4 (22 mg, 0.6 mmol) was added. The diastereomeric alcohols 16a and 16b were separated by fc.
Compound 16a (Rf 0.13): Colorless oil, yield 0.118 g (43%). IR (neat): ν/cm−1 = 1670 (s, Cbz C
O), 1204 (s)/1069 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.54–1.57 (m broad, 3H, 3-H + 5-H), 1.63–1.68 (m broad, 1H, 3-H), 1.91–1.95 (m broad, 1H, 6-H), 3.23 (ddd, J = 14.1/11.9/4.4 Hz, 1H, 6-H), 3.75–3.80 (m broad, 1H, 2-H), 3.92 (s broad, 1H, OH), 3.98–4.02 (m, 2H, OCH2), 4.34–4.38 (m broad, 1H, 4-H), 4.46 (s broad, 1H, OCH), 4.98 (d, J = 12.1 Hz, 1H, OCH2Ph), 5.09 (d, J = 12.4 Hz, 1H, OCH2Ph), 7.17–7.27 (m, 10H, Ph), 7.36–7.42 (m, 5H, Ph). HRMS: calculated for C28H29NO5Na 482.1938, found 482.1938. HPLC (Method A): Purity 98%, tR = 22.19 min.
Compound 16b (Rf 0.08): Colorless oil, yield 0.125 g (45%). IR (neat): ν/cm−1 = 1675 (s, Cbz C
O), 1205 (s)/1070 (s, C–O–C). 1H NMR (C6D5NO2, 100 °C): δ (ppm) = 1.04 (qd, J = 12.6/4.8 Hz, 1H, 5-H), 1.29 (td, J = 12.5/6.3 Hz, 1H, 3-H), 1.53–1.59 (m broad, 2H, 3-H + 5-H), 1.81 (d, J = 4.7 Hz, 1H, OH), 2.83 (td, J = 13.5/2.6 Hz, 1H, 6-H), 3.49 (td, J = 7.7/2.2 Hz, 1H, 2-H), 3.71 (t broad, J = 7.3 Hz, 1H, OCH2), 3.76–3.83 (m, 1H, 4-H), 3.88 (d broad, J = 13.7 Hz, 1H, 6-H), 4.05 (q, J = 7.0 Hz, 1H, OCH), 4.31 (t broad, J = 6.5 Hz, 1H, OCH2), 4.69 (d, J = 12.7 Hz, 1H, OCH2Ph), 4.82 (d, J = 12.7 Hz, 1H, OCH2Ph), 6.78–7.63 (m, 15H, Ph). HRMS: calculated for C28H29NO5Na 482.1938, found 482.1934. HPLC (Method A): Purity 95%, tR = 21.6 min.
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Download mol file of compound(±)-Benzyl (2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-hydroxypiperidine-1-carboxylate (16c) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-hydroxypiperidine-1-carboxylate (16d).
According to General Procedure B compound 15c (0.1816 g, 0.4 mmol) was dissolved in MeOH (2 mL) and NaBH4 (15 mg, 0.4 mmol) was added. The diastereomeric alcohols 16c and 16d were separated by fc.
Compound 16c (Rf 0.26): Colorless oil, yield 78.9 mg (43%). IR (neat): ν/cm−1 = 1671 (s, Cbz C
O), 1201(s) / 1049 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.19 (s broad, 2H, 3-H), 1.65–1.56 (m, 3H, 5-H + OH), 2.12 (d broad, J = 15.0 Hz, 1H, 6-H), 3.06–3.37 (m, 1H, 6-H), 3.87–3.91 (m broad, 3H, 2-H + 2OCH2), 4.07 (s, 1H, 4-H), 4.13–4.77 (m, 1H, OCH), 5.00–5.07 (m, 2H, OCH2Ph), 6.90–7.69 (m, 15H, Ph). HRMS: calculated for C28H29NO5Na 482.1938, found 482.1935. HPLC (Method A): Purity 98%, tR = 22.2 min.
Compound 16d (Rf 0.16): Colorless oil, yield 87.5 mg (47%). IR (neat): ν/cm−1 = 1671 (s, Cbz C
O), 1201 (s) / 1049 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.15–1.23 (m, 3H, 3-H + 5-H), 1.83 (s broad, 1H, OH), 2.33 (d broad, J = 10.8 Hz, 1H, 5-H), 2.69–3.07 (m, 1H, 6-H), 3.89 (s broad, 2H, 6-H + 2-H), 3.95–4.05 (m, 1H, 4-H), 4.05–4.19 (m, 1H, OCH2), 4.19–4.27 (m, 1H, OCH2), 4.28–4.52 (m, 1H, OCH), 5.03 (s broad, 2H, OCH2Ph), 6.94–7.79 (m, 15H, Ph). HRMS: calculated for C28H29NO5Na 482.1938, found 482.1930. HPLC (Method A): Purity 96%, tR = 21.6 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-ol (COMPOUND LINKS
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Download mol file of compound17a).
According to General Procedure F 16a (102.5 mg, 0.22 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 12.5 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound17a (Rf 0.32): Colorless crystals, mp 126 °C, yield 58.2 mg (80%). IR (neat): ν/cm−1 = 1067 (s, C–O–C), 697 (s, O–H). 1H NMR (CDCl3): δ (ppm) = 1.17 (q, J = 11.4 Hz, 1H, 3-Hax), 1.36 (qd, J = 12.3/4.5 Hz, 1H, 5-Hax), 1.68 (ddd, J = 9.8/4.4/2.2 Hz, 1H, 3-H), 1.87 (COMPOUND LINKS
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Download mol file of compoundddt, J = 12.1/4.4/2.1 Hz, 1H, 5-H), 2.31 (bs, 2H, NH, OH), 2.50–2.60 (m, 2H, 6-H), 3.07 (ddd, J = 12.0/4.1/2.7 Hz, 1H, 2-H), 3.54 (tt, J = 11.0/4.5 Hz, 1H, 4-H), 3.80–3.85 (m, 1H, OCH2), 3.96–4.01 (m, 2H, OCH2 + OCH), 7.22–7.30 (m, 6H, Ph), 7.42–7.49 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 35.9 (C-5), 38.0 (C-3), 44.2 (C-6), 58.3 (C-2), 67.4 (OCH2), 69.2 (C-4), 80.1 (OCH), 110.1 (OCO), 126.3 (Ph-C), 126.5 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.1 (Ph-C), 142.4 (Ph-C). HRMS: calculated for C20H23NO3H 326.1751, found 326.1749. HPLC (Method A): Purity 99%, tR = 15.8 min.
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Download mol file of compound(±)-(2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-ol (COMPOUND LINKS
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Download mol file of compound17b).
According to General Procedure F 16b (91.9 mg, 0.20 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 9.5 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound17b (Rf 0.21): Colorless oil, 48.9 mg (75%). IR (neat): ν/cm−1 = 1067 (s, C–O–C), 696 (s, O–H bending). 1H NMR (CDCl3): δ (ppm) = 1.37 (ddd, J = 13.3/11.1/2.9 Hz, 1H, 3-Hax), 1.46 (ddd, J = 13.2/5.0/3.2 Hz, 1H, 3-H), 1.62 (dq, J = 13.0/2.8 Hz, 1H, 5-H), 1.70 (tdd, J = 12.2/4.4/2.8 Hz, 1H, 5-H), 2.19 (s broad, 2H, NH + OH), 2.83 (ddd, J = 11.4/4.6/2.8 Hz, 1H, 6-H), 2.95–3.05 (m, 2H, 2-H + 6-H), 3.79–3.85 (m, 1H, OCH2), 3.91–3.95 (m, 1H, OCH2), 3.97 (q, J = 5.5 Hz, 1H, OCH), 4.10 (quint, J = 3.1 Hz, 1H, 4-H), 7.24–7.34 (m, 6H, Ph), 7.42–7.49 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 32.9 (C-5), 35.1 (C-3), 39.8 (C-6), 53.5 (C-2), 64.0 (C-4), 67.0 (OCH2), 79.9(OCH), 109.6 (OCO), 126.1 (Ph-C), 126.2 (Ph-C), 127.9 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 141.8 (Ph-C), 142.0 (Ph-C). HRMS: calculated for C20H23NO3H 326.1751, found 326.1742. HPLC (Method A): Purity 99%, tR = 16.2 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-ol (17c).
According to General Procedure F 16c (112.4 mg, 0.24 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 13.0 mg) was added. The product was purified by fc. Compound 17c (Rf 0.11): Colorless oil, yield 70.0 mg (88%). IR (neat): ν/cm−1 = 1067 (s, C–O–C), 697 (s, O–H). 1H NMR (CDCl3): δ (ppm) = 1.01 (q, J = 11.4 Hz, 1H, 3-Hax), 1.31 (qd, J = 12.4/4.5 Hz, 1H, 5-H), 1.86 (ddd, J = 12.1/4.2/2.0 Hz, 1H, 5-H), 1.99 (dt, J = 12.0/2.0 Hz, 1H, 3-H), 2.07 (s broad, 2H, NH + OH), 2.54 (td, J = 12.4/2.0, 1H, 6-H), 2.80 (ddd, J = 11.6/4.3/2.3 Hz, 1H, 2-H), 3.05 (ddd, J = 12.3/4.0/2.5 Hz, 1H, 6-H), 3.57 (tt, J = 10.8/4.4 Hz, 1H, 4-H), 3.92 (t, J = 7.2 Hz, 1H, OCH2), 4.03 (td, J = 6.7/4.5 Hz, 1H, OCH), 4.11 (t, J = 7.2 Hz, 1H, OCH2), 7.22–7.30 (m, 6H, Ph), 7.44–7.51 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 35.7 (C-5), 37.7 (C-3), 44.1 (C-6), 56.4 (C-2), 65.8 (OCH2), 68.8 (C-4), 78.9 (OCH), 109.5 (OCO), 125.9 (Ph-C), 126.1 (Ph-C), 127.9 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 128.2 (Ph-C), 141.7 (Ph-C), 141.9 (Ph-C). HRMS: calculated for C20H23NO3H 326.1751, found 326.1745. HPLC (Method A): Purity 97%, tR = 15.6 min.
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Download mol file of compound(±)-(2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-ol (17d, WMS-2508).
According to General Procedure F 16d (119.9 mg, 0.26 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 12.00 mg) was added. The product was purified by fc. Compound 17d (Rf 0.09): Colorless crystals, mp 126 °C, yield 75.3 mg (89%). IR (neat): ν/cm−1 = 1066 (s, C–O–C), 698 (s, O–H). 1H NMR (CDCl3): δ (ppm) = 1.40 (ddd, J = 11.9/9.0/2.5 Hz, 1H, 3-H), 1.56 (bs, 2H, NH + OH), 1.60–1.71 (m, 2H, 3-H, 5-H), 1.74 (ddd, J = 8.1/5.4/3.2 Hz, 1H, 2-H), 2.84 (ddd, J = 12.2/4.4/3.0 Hz, 1H, 5-H), 3.02 (td, J = 12.0/3.6 Hz, 1H, 6-H), 3.26 (ddd, J = 11.7/4.1/2.8 Hz, 1H, 6-H), 3.93 (t, J = 7.1 Hz, 1H, OCH2), 4.05 (td, J = 6.5/4.6 Hz, 1H, OCH), 4.12 (t, J = 7.0 Hz, 1H, OCH2), 4.20 (quint, J = 3.1 Hz, 1H, 4-H), 7.26–7.36 (m, 7H, Ph), 7.46–7.54 (m, 3H, Ph). HRMS: calculated for C20H23NO3H 326.1751, found 326.1747. HPLC (Method A): Purity 96%, tR = 16.1 min.
A sample of compound 17d was recrystallized with COMPOUND LINKS
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Download mol file of compoundn-hexane–CH2Cl2 mixture and the resulting crystals were used for the X-ray crystal structure analysis.
X-Ray crystal structure analysis of 17d.
Formula C20H23NO3, M = 325.39, colorless crystal 0.20 × 0.15 × 0.05 mm, a = 6.2254(4), b = 33.9225(23), c = 8.1729(6) Å, β = 97.459(2)°, COMPOUND LINKS
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Download mol file of compoundV = 1711.4(2) Å3, ρc = 1.263 g cm−3, μ = 6.77 cm−1, empirical absorption correction (0.8764 ≤ T ≤ 0.9669), Z = 4, monoclinic, space group P21/n (No. 14), λ = 1.54178 Å, T = 223(2) K, ω and φ scans, 5702 reflections collected (±h, ±k, ±l), [(sinθ)/λ] = 0.58 Å−1, 2001 independent (Rint = 0.055) and 1472 observed reflections [I ≥ 2 σ(I)], 222 refined parameters, R = 0.064, wR2 = 0.171, max. (min.) residual electron density 0.23(−0.23) e Å−3, hydrogen atoms calculated and refined as riding atoms.
Data set was collected with a Nonius KappaCCD diffractometer. Programs used: data collection COLLECT (Nonius B.V., 1998), data reduction Denzo-SMN (Z. Otwinowski and W. Minor, Methods in Enzymology, 1997, 276, 307–326), absorption correction Denzo (Z. Otwinowski, D. Borek, W. Majewski and W. Minor, Acta Crystallogr., 2003, A59, 228–234), structure solution SHELXS-97 (G. M. Sheldrick, Acta Crystallogr., 1990, A46, 467–473), structure refinement SHELXL-97 (G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112–122), graphics SCHAKAL (E. Keller, Universität Freiburg, 1997).
CCDC 750839 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (internet.) +44(1223)336-033, E-mail: mailto:deposit@ccdc.cam.ac.uk]
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Download mol file of compound(±)-Benzyl (2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine-1-carboxylate (18a).
According to General Procedure C compound 16a (76.5 mg, 0.16 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundDMF (2 mL) and NaH (7.00 mg, 0.32 mmol) was added followed by MeI (0.01 mL, 0.16 mmol). The product was purified by fc. Compound 18a (Rf 0.40): Colorless oil, yield 64.8 mg (85%). IR (neat): ν/cm−1 = 1694 (s, Cbz C
O), 1080 (s, O–CH3), 1205 (s) / 1027 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.44–1.49 (m, 1H, 3-H), 1.51–1.53 (m, 1H, 5-H), 1.68 (ddd, J = 14.7/6.3/3.1 Hz, 1H, 3-H), 1.77 (d broad, J = 14.0 Hz, 1H, 5-H), 3.14 (s, 3H, OCH3), 3.20 (d broad, J = 13.2 Hz, 1H, 6-H), 3.39–3.41 (m, 1H, 2-H), 3.64 (t, J = 7.6 Hz, 1H, OCH2), 3.97 (d broad, J = 13.8 Hz, 1H, 6-H), 4.04 (t, J = 7.2 Hz, 1H, OCH2), 4.30–4.34 (m 1H, 4-H), 4.74 (dt, J = 9.5/6.9 Hz, 1H, OCH), 4.86 (s broad, 1H, OCH2Ph), 5.13 (d, J = 12.5 Hz, 1H, OCH2Ph), 7.12–7.42 (m, 15H, Ph). HRMS: calculated for C29H31NO5Na 496.2094, found 496.2099. HPLC (Method B): Purity 98%, tR = 21.5 min.
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine-1-carboxylate (18b).
According to General Procedure C compound 16b (69.9 mg, 0.15 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundDMF (2 mL) and NaH (7.00 mg, 0.32 mmol) was added followed by MeI (0.01 mL, 0.16 mmol). The product was purified by fc. Compound 18b (Rf 0.33): Colorless oil, yield 57.1 mg (80%). IR (neat): ν/cm−1 = 1693 (s, Cbz C
O), 1092 (s, O–CH3), 1205(s) / 1026 (s, C–O–C). 1H NMR (C6D5NO2, 100 °C): δ (ppm) = 0.84–0.96 (m, 1H, 5-H), 1.18 (ddd, J = 13.4/4.7/2.5 Hz, 1H, 5-H), 1.55 (d broad, J = 13.2 Hz, 2H, 3-H), 2.70–2.81 (m,1H, 6-H), 2.84 (s, 3H, OCH3), 3.22–3.34 (m, 1H, 2-H), 3.49 (t, J = 7.8 Hz, 1H, OCH2), 3.69–3.73 (m,1H, OCH), 3.85 (d broad, J = 13.5 Hz, 1H, 6-H), 4.01–4.07 (m, 1H, OCH2), 4.26–4.30 (m, 1H, 4-H), 4.69 (d, J = 12.7 Hz, 1H, OCH2Ph), 4.82 (d, J = 12.7 Hz, 1H, OCH2Ph), 6.79–7.18 (m, 15H, -Ph). HRMS: calculated for C29H31NO5Na 496.2094, found 496.2090. HPLC (Method B): Purity 99%, tR = 21.2 min.
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Download mol file of compound(±)-Benzyl (2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine-1-carboxylate (18c).
According to General Procedure C compound 16c (77.8 mg, 0.17 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundDMF (2 mL) and NaH (8 mg, 0.34 mmol) was added followed by MeI (0.01 mL, 0.17 mmol). The product was purified by fc. Compound 18c (Rf 0.58): Colorless oil, yield 74.8 mg (93%). IR (neat): ν/cm−1 = 1695 (s, Cbz C
O), 1085 (s, O–CH3), 1205 (s) / 1027 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.56 (ddd, J = 13.3/4.6/2.9 Hz, 1H, 3-H), 1.66–1.80 (m, 2H, 3-H + 5-H), 2.41 (d broad, J = 13.9 Hz, 1H, 5-H), 2.89–3.11 (m, 1H, 6-H), 3.37 (s, 3H, OCH3), 3.51–3.54 (m, 1H, 6-H), 3.84–3.85 (m broad, 3H, OCH2 + 2-H), 4.08–4.29 (m, 1H, 4-H), 4.62–4.84 (m, 1H, OCH), 5.04 (s, 2H, OCH2Ph), 6.80–7.63 (m, 15H, Ph). HRMS: calculated for C29H31NO5Na 496.2094, found 496.2093. HPLC (Method A): Purity 98%, tR = 25.16 min.
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine-1-carboxylate (18d).
According to General Procedure C compound 16d (102.6 mg, 0.22 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundDMF (2 mL) and NaH (10 mg, 0.44 mmol) was added followed by MeI (0.013 mL, 0.22 mmol). The product was purified by fc. Compound 18d (Rf 0.55): Colorless oil, yield 94.1 mg (91%). IR (neat): ν/cm−1 = 1696 (s, Cbz C
O), 1092 (s, O–CH3), 1205 (s) / 1027 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.22–1.27 (m, 1H, 3-H), 1.31 (s broad, 1H, 5-H), 1.82–2.01 (m, 1H, 3-H), 1.87–1.97 (m broad, 1H, 5-H), 2.72–3.06 (m, 1H, 6-H), 3.17 (s, 3H, OCH3), 3.52 (tt, J = 11.2/4.5 Hz, 1H, 4-H), 3.82–3.90 (m broad, 2H, 6-H + 2-H), 4.11–4.18 (m, 1H, OCH2), 4.25 (q, J = 6.7 Hz, 1H, OCH), 4.28–4.49 (m, 1H, OCH2), 5.04 (s, 2H, OCH2Ph), 6.84–7.67 (m, 15H, Ph). HRMS: calculated for C29H31NO5Na 496.2094, found 496.2093. HPLC (Method A): Purity 98%, tR = 24.48 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine (COMPOUND LINKS
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Download mol file of compound19a).
According to General Procedure F 18a (73.1 mg, 0.16 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 7.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound19a (Rf 0.46): Colorless oil, yield 40.8 mg (78%). IR (neat): ν/cm−1 = 1067 (s, C–O–C), 1085 (s, O–CH3). 1H NMR (CDCl3): δ (ppm) = 1.02 (q, J = 11.5 Hz, 1H, 3-Hax), 1.26 (qd, J = 12.4/4.4 Hz, 1H, 5-H), 1.72 (COMPOUND LINKS
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Download mol file of compoundddt, J = 11.8/4.2/2.1 Hz, 1H, 5-H), 1.94 (ddd, J = 12.3/4.3/2.2 Hz, 1H, 3-H), 2.03 (s broad, 1H, NH), 2.47–2.57 (m, 2H, 6-H, 2-H), 3.05–3.13 (m, 2H, 6-H, 4-H), 3.25 (s, 3H, OCH3), 3.78–3.84 (m, 1H, OCH2), 3.93–3.99 (m, 2H, COMPOUND LINKS
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Download mol file of compoundOCH, OCH2), 7.18–7.27 (m, 6H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 32.1 (C-5), 34.6 (C-3), 44.2 (C-6), 55.7 (OCH3), 58.4 (C-2), 67.3 (OCH2), 77.7 (C-4), 80.2 (OCH), 110.1 (OCO), 126.3 (Ph-C), 126.5 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.2 (Ph-C), 142.4 (Ph-C). HRMS: calculated for C21H25NO3H 340.1907, found 340.1908. HPLC (Method A): Purity 95%, tR = 16.9 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine (19b).
According to General Procedure F 18b (57.1 mg, 0.12 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 5.0 mg) was added. The product was purified by fc. Compound 19b (Rf 0.23): Colorless oil, yield 36.8 mg (90%). IR (neat): ν/cm−1 = 1069 (s, C–O–C), 1085 (s, O–CH3). 1H NMR (CDCl3): δ (ppm) = 1.32 (ddd, J = 13.3/10.9/2.8 Hz, 1H, 3-Hax), 1.55 (dddd, J = 13.3/12.4/4.7/2.3 Hz, 1H, 5-H), 1.62 (ddd, J = 13.9/5.7/2.8 Hz, 1H, 3-H), 1.85 (COMPOUND LINKS
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Download mol file of compoundddt, J = 13.9/5.2/2.6 Hz, 1H, 5-H), 2.24 (bs, 1H, NH), 2.85 (ddd, J = 11.6/4.7/2.5 Hz, 1H, 6-H), 2.92–3.02 (m, 2H, 6-H + 2-H), 3.29 (s, 3H, OCH3), 3.57 (quint, J = 3.0 Hz, 1H, 4-H), 3.87 (t, J = 6.8 Hz, 1H, OCH2), 3.95 (q, J = 6.8 Hz, 1H, OCH), 4.01 (t, J = 6.8 Hz, 1H, OCH2) 7.18–7.27 (m, 6H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 29.2 (C-5), 32.3 (C-3), 40.2 (C-6), 53.7 (C-2), 55.6 (OCH3), 67.1 (OCH2), 73.1 (C-4), 80.1 (OCH), 109.8 (OCO), 126.2 (Ph-C), 126.3 (Ph-C), 127.9 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 141.9 (Ph-C), 142.0 (Ph-C). HRMS: calculated for C21H25NO3H 340.1907, found 340.1901. HPLC (Method A): Purity 97%, tR = 17.4 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine (COMPOUND LINKS
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Download mol file of compound19c).
According to General Procedure F 18c (58.7 mg, 0.12 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 6.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound19c (Rf 0.41): Colorless oil, yield 34.2 mg (81%). IR (neat): ν/cm−1 = 1068 (s, C–O–C), 1087 (s, O–CH3). 1H NMR (CDCl3): δ (ppm) = 0.91 (q, J = 11.6 Hz, 1H, 3-Hax), 1.21 (qd, J = 12.3/4.4 Hz, 1H, 5-H), 1.55 (s broad, 1H, -NH), 1.93 (ddd, J = 12.2/4.2/2.1 Hz, 1H, 5-H), 2.04 (dt, J = 11.9/2.2 Hz, 1H, 3-H), 2.49 (td, J = 12.4/2.5 Hz, 1H, 6-H), 2.77 (ddd, J = 11.7/4.3/2.3 Hz,1H, 6-H), 3.04 (ddd, J = 12.3/4.1/3.0, 1H, 2-H), 3.11 (tt, J = 10.9/4.3 Hz, 1H, 4-H), 3.27 (s, 3H, OCH3), 3.87 (t, J = 7.2 Hz, 1H, OCH2), 3.98 (td, J = 6.8/4.6 Hz, 1H, OCH), 4.08 (t, J = 6.7 Hz, 1H, OCH2) 7.18–7.27 (m, 6H, Ph), 7.39–7.47 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 32.7 (C-5), 34.8 (C-3), 44.5 (C-6), 55.7 (OCH3), 56.8 (C-2), 66.2 (OCH2), 77.9 (C-4), 79.5 (OCH), 109.8 (OCO), 126.3 (Ph-C), 126.5 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 128.5 (Ph-C), 142.2 (Ph-C), 142.3 (Ph-C). HRMS: calculated for C21H25NO3H 340.1907, found 340.1907. HPLC (Method A): Purity 94%, tR = 16.2 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methoxypiperidine (COMPOUND LINKS
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Download mol file of compound19d).
According to General Procedure F 18d (94.1 mg, 0.19 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 9.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound19d (Rf 0.23): Colorless oil, yield 52.3 mg (77%). IR (neat): ν/cm−1 = 1205/1068 (s, C–O–C), 1087 (s, O–CH3). 1H NMR (CDCl3): δ (ppm) = 1.28 (ddd, J = 13.1/11.4/2.7 Hz, 1H, 3-H), 1.55 (dddd, J = 13.7/12.4/4.8/2.7 Hz, 1H, 5-H), 1.75 (s broad, 1H, NH), 1.82 (dtd, J = 13.9/5.1/2.4 Hz, 1H, 5-H), 1.94 (ddd, J = 13.4/5.2/2.4 Hz, 1H, 3-H), 2.82 (ddd, J = 12.0/4.7/2.4 Hz, 1H, 6-H), 2.95 (td, J = 12.3/2.7 Hz, 1H, 6-H), 3.19 (ddd, J = 11.7/4.2/2.6 Hz, 1H, 2-H), 3.30 (s, 3H, OCH3), 3.60 (quint, J = 2.9 Hz, 1H, 4-H), 3.95 (t, J = 7.0 Hz, 1H, OCH2), 4.05 (td, J = 6.5/4.5 Hz, 1H, OCH), 4.11 (t, J = 6.5 Hz, 1H, OCH2), 7.24–7.36 (m, 6H, Ph), 7.47–7.55 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 30.2 (C-5), 31.9 (C-3), 41.0 (C-6), 52.3 (OCH3), 55.9 (C-2), 66.2 (OCH2), 73.6 (C-4), 79.7 (OCH), 109.8 (OCO), 126.4(Ph-C), 126.5 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 128.5 (Ph-C), 142.3 (Ph-C), 142.5 (Ph-C). HRMS: calculated for C21H25NO3H 340.1907, found 340.1905. HPLC (Method A): Purity 98%, tR = 17.7 min.
(±)-Benzyl (2RS,4SR)-4-Benzylamino-2-[(4SR)-2,2-diphenyl-1,3-dioxolan-4-yl] piperidine-1-carboxylate (20a) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-4-Benzylamino-2-[(4SR)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidine-1-carboxylate (20b).
According to General Procedure D compound 15a (0.103 g, 0.22 mmol) dissolved in CH2Cl2 (2 mL) was reacted with COMPOUND LINKS
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Download mol file of compoundbenzylamine (0.04 mL, 0.33 mmol) and NaBH(OAc)3 (70 mg, 0.33 mmol). The diastereomeric amines 20a and 20b were separated by fc.
Compound 20a (Rf 0.62): Colourless oil, yield 66.7 mg (58%). IR (neat): ν/cm−1 = 1690 (s, Cbz C
O), 1205 (s)/1086 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.27–1.32 (m, 1H, 3-H), 1.55–1.61 (m broad, 3H, 3-H + 5-H), 1.78–1.87 (m, 1H, 6-H), 1.93 (ddd, J = 14.0/6.0/3.9 Hz, 1H, 2-H), 2.97 (quint, J = 4.3 Hz, 1H, 4-H), 3.42 (td, J = 11.9/3.3 Hz, 1H, 6-H), 3.68 (d, J = 13.0 Hz, 1H, CH2Ph), 3.73 (d, J = 13.0 Hz, 1H, CH2Ph), 3.89 (t, J = 7.4 Hz, 1H, OCH2), 3.95 (s, 1H, NH), 4.05 (t, J = 7.4 Hz, 1H, OCH2), 4.36 (q, J = 6.8 Hz, 1H, OCH), 5.05 (d, J = 12.4 Hz, 1H, OCH2Ph), 5.22 (d, J = 12.5 Hz, 1H, OCH2Ph), 7.15–7.57 (m, 20H, Ph). HRMS: calculated for C35H36N2O4H 549.2748, found 549.2743. HPLC (Method A): Purity 98%, tR = 21.6 min.
Compound 20b (Rf 0.25): Colourless oil, yield 33.5 mg (29%). IR (neat): ν/cm−1 = 1688 (s, Cbz C
O), 1205 (s)/1070 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.20–1.29 (m broad, 1H, 3-H), 1.51 (s broad, 3H, 3-H + 5-H + NH), 1.73–1.76 (m broad, 1H, 5-H), 1.91–1.96 (m broad, 1H, 6-H), 2.97–3.17 (m, 2H, 6-H + 4-H), 3.77–3.83 (m broad, 3H, 2-H + CH2Ph), 4.00 (s broad, 1H, OCH2), 4.27–4.30 (m broad, 2H, OCH + OCH2), 4.89(d broad, J = 10.5 Hz, 1H, OCH2Ph), 5.15 (d, J = 11.8 Hz, 1H, OCH2Ph), 7.22–7.45 (m, 20H, Ph). HRMS: calculated for C35H36N2O4H 549.2748, found 549.2743. HPLC (Method A): Purity 97%, tR = 20.4 min.
(±)-Benzyl (2RS,4SR)-4-Benzylamino-2-[(4RS)-2,2-diphenyl-1,3-dioxolan-4-yl] piperidine-1-carboxylate (20c) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-4-Benzylamino-2-[(4RS)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidine-1-carboxylate (20d).
According to General Procedure E compound 15c (0.129 g, 0.28 mmol) dissolved in COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate (2 mL) was reacted with COMPOUND LINKS
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Download mol file of compoundbenzylamine (0.05 mL, 0.42 mmol) added. Then NaBH4 (16 mg, 0.42 mmol) was added. The diastereomeric amines 20c and 20d were separated by fc.
Compound 20c (Rf 0.52): Colourless oil, yield 90.6 mg (59%). IR (neat): ν/cm−1 = 1693 (s, Cbz C
O), 1203 (s)/1087 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.17–1.20 (m, 1H, 3-H), 1.31–1.36 (m, 1H, 3-H), 1.46–1.62 (m broad, 2H, 5-H), 1.69 (d broad, J = 13.0 Hz, 1H, 6-H), 2.07 (d broad, J = 14.3 Hz, 1H, 6-H), 2.97 (quint, J = 3.7 Hz, 1H, 4-H), 3.20–3.29 (m broad, 1H, 2-H), 3.69 (d, J = 13.0 Hz, 1H, CH2Ph), 3.81 (d, J = 13.0 Hz, 1H, CH2Ph), 3.83–3.92 (m, 2H, NH + OCH2), 4.04–4.10 (m, 1H, OCH), 4.91–4.95 (m, 1H, OCH2), 4.98–5.07 (m, 2H, OCH2Ph), 7.08–7.26 (m, 15H, Ph), 7.32–7.38 (m, 5H, Ph). HRMS: calculated for C35H36N2O4H 549.2748, found 549.2743. HPLC (Method A): Purity 97%, tR = 22.6 min.
Compound 20d (Rf 0.10): Colourless oil, yield 56.3 mg (37%). IR (neat): ν/cm−1 = 1697 (s, Cbz C
O), 1204 (s)/1070 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.21–1.28 (m broad, 2H, 3-H + NH), 1.31–1.39 (m broad, 2H, 3-H + 5-H), 1.84–1.91 (m broad, 1H, 5-H), 2.44 (d broad, J = 12.9 Hz, 1H, 6-H), 2.77–3.02 (m broad, 2H, 6-H + 4-H), 3.79 (d broad, J = 14.9 Hz, 2H, CH2Ph), 3.87–3.99 (m broad, 2H, 2-H + OCH2), 4.22–4.37 (m broad, 2H, OCH + OCH2), 5.11 (s broad, 2H, OCH2Ph), 7.27–7.47 (m, 20H, Ph). HRMS: calculated for C35H36N2O4H 549.2748, found 549.2741. HPLC (Method A): Purity 92%, tR = 22.0 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-amine (COMPOUND LINKS
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Download mol file of compound21a).
According to General Procedure F 20a (66.7 mg, 0.12 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 7.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound21a (Rf 0.30): Colourless oil, yield 35.0 mg (89%). IR (neat): ν/cm−1 = 1067 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 0.94 (q, J = 11.5 Hz, 1H, 3-Hax), 1.22 (qd, J = 12.3/4.2 Hz, 1H, 5-Hax), 1.57–1.62 (m, 1H, 3-H), 1.79 (s broad, 4H, 5-H + NH2 + NH), 2.56–2.64 (m, 2H, 6-H + 2-H), 2.65–2.70 (m, 1H, 4-H), 3.09 (ddd, J = 12.4/2.5/1.2 Hz, 1H, 6-H), 3.86 (t, J = 6.3 Hz, 1H, OCH2), 3.97 (t, J = 6.9 Hz, 1H, OCH2), 4.02 (q, J = 7.0 Hz, 1H, OCH), 7.24–7.33 (m, 6H, Ph), 7.45–7.52 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 36.8 (C-5), 38.9 (C-3), 45.1 (C-6), 49.2 (C-4), 58.9 (C-2), 67.4 (OCH2), 80.3 (OCH), 110.0 (OCO), 126.3 (Ph-C), 126.5 (Ph-C), 127.9 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.2 (Ph-C), 142.4 (Ph-C). HRMS: calculated for C20H24N2O2H 325.1911, found 325.1921. HPLC (Method A): Purity 96%, tR = 13.9 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-amine (COMPOUND LINKS
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Download mol file of compound21b).
According to General Procedure F 20b (33.5 mg, 0.06 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 4.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound21b (Rf 0.31): Colourless oil, 17.0 mg (87%). IR (neat): ν/cm−1 = 1069 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.24–1.29 (m, 1H, 3-H), 1.35–1.42 (m, 2H, 3-H + 5-H), 1.71 (tdd, J = 13.2/4.2/1.8 Hz, 1H, 5-H), 1.82 (s broad, 3H, NH + NH2), 2.80 (dt, J = 11.9/4.2 Hz, 1H, 6-H), 2.85–2.94 (m, 2H, 2-H + 6-H), 3.16 (quint, J = 3.9 Hz, 1H, 4-H), 3.72–3.78 (m, 1H, OCH2), 3.93–4.00 (m, 2H, OCH2 + OCH), 7.19–7.27 (m, 6H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 33.8 (C-5), 35.8 (C-3), 39.9 (C-6), 44.2 (C-4), 53.9 (C-2), 67.5 (OCH2), 79.6 (OCH), 110.1 (OCO), 126.4 (Ph-C), 126.5 (Ph-C), 126.6 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 128.5 (Ph-C), 142.2 (Ph-C), 142.4 (Ph-C). HRMS: calculated for C20H24N2O2H 325.1911, found 325.1919. HPLC (Method A): Purity 93%, tR = 13.6 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-amine (COMPOUND LINKS
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Download mol file of compound21c).
According to General Procedure F 20c (90.6 mg, 0.16 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 9.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound21c (Rf 0.30): Colourless oil, yield 49.2 mg (91%). IR (neat): ν/cm−1 = 1067 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 0.86 (q, J = 11.5 Hz, 1H, 3-Hax), 1.16 (qd, J = 12.1/4.0 Hz, 1H, 5-Hax), 1.76 (d broad, J = 10.9 Hz, 1H, 3-H), 1.87 (d broad, J = 12.1 Hz, 1H, 5-H), 2.50 (td, J = 11.1/2.3 Hz, 1H, 6-H), 2.68 (tt, J = 11.3/4.0 Hz, 1H, 4-H), 2.77 (ddd, J = 11.7/4.4/2.0 Hz, 1H, 6-H), 2.87 (s broad, 3H, NH2 + NH), 2.99 (ddd, J = 12.3/4.7/2.2 Hz, 1H, 2-H), 3.85 (t, J = 7.0 Hz, 1H, OCH2), 3.96 (td, J = 6.4/4.5 Hz, 1H, OCH), 4.06 (t, J = 6.6 Hz, 1H, OCH2), 7.18–7.29 (m, 6H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 35.7 (C-5), 37.8 (C-3), 44.9 (C-6), 49.1 (C-4), 56.9 (C-2), 65.9 (OCH2), 79.1 (OCH), 109.6 (OCO), 126.0 (Ph-C), 126.2 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 141.9 (Ph-C), 142.0 (Ph-C). HRMS: calculated for C20H24N2O2H 325.1911, found 325.1911. HPLC (Method B): Purity 98%, tR = 11.2 min.
COMPOUND LINKS
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Download mol file of compound(±)-(2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidin-4-amine (COMPOUND LINKS
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Download mol file of compound21d).
According to General Procedure F 20d (56.3 mg, 0.10 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 6.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound21d (Rf 0.21): Colourless oil, 27.0 mg (83%). IR (neat): ν/cm−1 = 1069 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.37–1.43 (m, 1H, 3-H), 1.49–1.52 (m, 2H, 3-H + 5-H), 1.60 (s broad, 3H, NH + NH2), 1.67–1.75 (m, 1H, 5-H),, 2.79 (dt, J = 12.4/4.2 Hz, 1H, 6-H), 2.94 (td, J = 12.0/3.0 Hz, 1H, 6-H), 3.15–3.19 (m, 1H, 2-H), 3.30 (quint, J = 3.7 Hz, 1H, 4-H), 3.94 (t, J = 6.5 Hz, 1H, OCH2), 4.03–4.11 (m, 2H, OCH2 + OCH), 7.25–7.34 (m, 6H, Ph), 7.44–7.52 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 34.2 (C-5), 36.1 (C-3), 40.5 (C-6), 44.3 (C-4), 52.2 (C-2), 66.6 (OCH2), 79.3 (OCH), 109.7 (OCO), 126.3 (Ph-C), 126.5 (Ph-C), 126.6 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.3 (Ph-C), 142.5 (Ph-C). HRMS: calculated for C20H24N2O2H 325.1911, found 325.1919. HPLC (Method A): Purity 94%, tR = 14.0 min.
(±)-Benzyl (2RS,4SR) -2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methylaminopiperidine-1-carboxylate (22a) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methylaminopiperidine-1-carboxylate (22b).
According to General Procedure D compound 15a (0.143 g, 0.31 mmol) was dissolved in CH2Cl2 (2 mL) and 2M solution of methylamine in COMPOUND LINKS
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Download mol file of compoundTHF (0.23 mL, 0.47 mmol) was added followed by NaBH(OAc)3 (99 mg, 0.47 mmol). The diastereomeric amines 22a and 22b were separated by fc.
Compound 22a (Rf 0.55): Colourless oil, yield 94.5 mg (64%). IR (neat): ν/cm−1 = 1688 (s, Cbz C
O), 1207 (s)/1090 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.25–1.31 (m, 1H, 3-H), 1.44–1.55 (m, 2H, 3-H + 5-H), 1.77–1.85 (m, 1H, 5-H), 1.89 (ddd, J = 13.6/6.1/3.8 Hz, 1H, 6-H), 2.34 (s, 3H, NCH3), 2.72 (quint, J = 5.0 Hz, 1H, 4-H), 3.37 (td, J = 12.8/3.8 Hz, 1H, 6-H), 3.85 (s broad, 1H, NH), 3.89 (t, J = 7.4 Hz, 1H, OCH2), 4.04 (t, J = 7.2 Hz, 1H, OCH2), 4.28 (q, J = 6.2 Hz, 1H, 2-H), 4.79 (q, J = 6.7 Hz, 1H, OCH), 5.01 (d, J = 12.5 Hz, 1H, OCH2Ph), 5.18 (d, J = 12.5 Hz, 1H, OCH2Ph), 7.23–7.35 (m, 10H, Ph), 7.47–7.53 (m, 5H, Ph). HRMS: calculated for C29H32N2O4H 473.2435, found 473.2437. HPLC (Method A): Purity 96%, tR = 19.2 min.
Compound 22b (Rf 0.23): Colourless oil, yield 37.6 mg (26%). IR (neat): ν/cm−1 = 1693 (s, Cbz C
O), 1208 (s)/1070 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.15–1.17 (m broad, 1H, 3-H), 1.42–1.46 (m broad, 1H, 5-H), 1.73 (d broad, J = 11.1 Hz, 1H, 3-H), 1.91 (s broad, 2H, 5-H + NH), 2.42 (s, 3H, NCH3), 2.78 (s broad, 1H, 6-H), 2.93–3.10 (m broad, 2H, 6-H + 4-H), 3.85 (s broad, 1H, 2-H), 4.06 (t broad, J = 6.3 Hz, 1H, OCH2), 4.28–4.36 (m broad, 2H, OCH + OCH2), 4.87 (d, J = 11.6 Hz, 1H, OCH2Ph), 5.16 (d, J = 10.6 Hz, 1H, OCH2Ph), 7.22–7.36 (m, 10H, Ph), 7.44–7.51 (m, 5H, Ph). HRMS: calculated for C29H32N2O4H 473.2435, found 473.2430. HPLC (Method A): Purity 98%, tR = 19.7 min.
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Download mol file of compound(±)-Benzyl (2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methylaminopiperidine-1-carboxylate (22c) and COMPOUND LINKS
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Download mol file of compound(±)-Benzyl (2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-4-methylaminopiperidine-1-carboxylate (22d).
According to General Procedure E compound 15c (0.143 g, 0.31 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundtrimethyl orthoformate (2 mL) and 2M solution of methylamine in COMPOUND LINKS
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Download mol file of compoundTHF (0.03 mL, 0.47 mmol) was added. Then NaBH4 (18 mg, 0.42 mmol) was added. The diastereomeric amines 22c and 22d were separated by fc.
Compound 22c (Rf 0.77): Colourless oil, yield 68.7 mg (47%). IR (neat): ν/cm−1 = 1692 (s, Cbz C
O), 1205 (s)/1090 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.18–1.21 (m, 1H, 3-H), 1.42 (d broad, J = 13.4 Hz, 1H, 5-H), 1.53–1.64 (m, 1H, 5-H), 1.68 (d broad, J = 13.7 Hz, 1H, 3-H), 1.95 (d broad, J = 14.2 Hz, 1H, 6-H), 2.34 (s, 3H, NCH3), 2.72 (quint, J = 4.0 Hz, 1H, 4-H), 3.20 (t broad, J = 12.7 Hz, 1H, 6-H), 3.70 (s broad, 1H, NH), 3.81–3.89 (m, 2H, OCH2), 3.96–4.02 (m, 1H, 2-H), 4.81 (dt, J = 9.5/5.9 Hz, 1H, OCH), 4.99 (d, J = 12.7 Hz, 1H, OCH2Ph), 5.04 (d, J = 12.7 Hz, 1H, OCH2Ph), 7.13–7.28 (m, 11H, Ph), 7.37–7.43 (m, 4H, Ph). HRMS: calculated for C29H32N2O4H 473.2435, found 473.2420. HPLC (Method A): Purity 96%, tR = 20.2 min.
Compound 22d (Rf 0.55): Colourless oil, yield 52.9 mg (36%). IR (neat): ν/cm−1 = 1693 (s, Cbz C
O), 1206 (s)/1070 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.28–1.38 (m broad, 1H, 3-H), 1.43–1.52 (m broad, 1H, 5-H), 1.94–2.02 (m broad, 1H, 3-H), 2.11–2.23 (m broad, 1H, 5-H), 2.35 (s, 3H, NCH3), 2.78–3.09 (m broad, 2H, 6-H + 4-H), 3.87–4.02 (m broad, 2H, 6-H + NH), 4.16–4.39 (m, 3H, 2-H + OCH + OCH2), 4.49 (t broad, J = 6.0 Hz, 1H, OCH2), 5.05–5.11 (m, 2H, OCH2Ph), 7.26–7.36 (m, 11H, Ph), 7.45–7.49 (m, 4H, Ph). HRMS: calculated for C29H32N2O4H 473.2435, found 473.2425. HPLC (Method A): Purity 94%, tR = 20.3 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-N-methylpiperidin-4-amine (COMPOUND LINKS
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Download mol file of compound23a).
According to General Procedure F 22a (94.5 mg, 0.20 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 9.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound23a (Rf 0.29): Colourless oil, yield 60.2 mg (89%). IR (neat): ν/cm−1 = 1068 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 0.85 (q, J = 11.5 Hz, 1H, 3-Hax), 1.12 (qd, J = 12.3/4.2 Hz, 1H, 5-Hax), 1.60 (dquint, J = 11.8/2.1 Hz, 1H, 5-H), 1.79–1.87 (m, 3H, 3-H + 2NH), 2.32 (tt, J = 11.7/4.1 Hz, 1H, 4-H), 2.33 (s, 3H, NCH3), 2.49–2.59 (m, 2H, 6-H), 3.06 (ddd, J = 11.9/4.1/2.4 Hz, 1H, 2-H), 3.76–3.84 (m, 1H, OCH2), 3.89–3.99 (m, 2H, OCH + OCH2), 7.16–7.27 (m, 6H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 32.9 (C-5), 33.2 (C-3), 35.2 (NCH3), 44.8 (C-6), 56.8 (C-2), 58.6 (C-4), 67.2 (OCH2), 80.2 (OCH), 109.8 (OCO), 126.1 (Ph-C), 126.3 (Ph-C), 126.5 (Ph-C), 128.0 (Ph-C), 128.1(Ph-C), 128.2 (Ph-C), 142.0 (Ph-C), 142.2 (Ph-C). HRMS: calculated for C21H26N2O2H 339.2067, found 339.2071. HPLC (Method A): Purity 97%, tR = 13.9 min.
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Download mol file of compound(±)-(2RS,4RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-yl]-N-methylpiperidin-4-amine (COMPOUND LINKS
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Download mol file of compound23b).
According to General Procedure F 22a (37.6 mg, 0.08 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 4.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound23b (Rf 0.32): Colourless oil, yield 21.2 mg (78%). IR (neat): ν/cm−1 = 1067 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.29–1.36 (m, 1H, 3-H), 1.41 (d quint, J = 13.7/2.6 Hz, 1H, 5-H), 1.52–1.56 (m, 1H, 3-H), 1.61–1.69 (m, 1H, 5-H), 1.95 (s broad, 2H, 2NH), 2.31 (s, 3H, NCH3), 2.73–2.81 (m, 2H, 6-H + 4-H), 2.84–2.93 (m, 2H, 6-H + 2-H), 3.72–3.77 (m, 1H, OCH2), 3.93–3.97 (m, 2H, OCH + OCH2), 7.19–7.27 (m, 6H, Ph), 7.36–7.45 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 30.3 (C-5), 32.8 (C-3), 34.1 (NCH3), 40.4 (C-6), 52.6 (C-2), 54.2 (C-4), 67.6 (OCH2), 79.7 (OCH), 110.1 (OCO), 126.4 (Ph-C), 126.5 (Ph-C), 126.6 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.2 (Ph-C), 142.3 (Ph-C). HRMS: calculated for C21H26N2O2H 339.2067, found 339.2061. HPLC (Method A): Purity 92%, tR = 14.2 min.
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Download mol file of compound(±)-(2RS,4SR)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-N-methylpiperidin-4-amine (COMPOUND LINKS
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Download mol file of compound23c).
According to General Procedure F 22c (68.7 mg, 0.14 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 7.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound23c (Rf 0.21): Colourless oil, yield 41.2 mg (87%). IR (neat): ν/cm−1 = 1066 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 0.76 (q, J = 11.6 Hz, 1H, 3-Hax), 1.08 (qd, J = 12.3/4.2 Hz, 1H, 5-Hax), 1.54 (s broad, 2H, 2NH), 1.82 (ddd, J = 12.4/3.7/2.0 Hz, 1H, 3-H), 1.92 (dquint, J = 12.1/1.9 Hz, 1H, 5-H), 2.35 (tt, J = 11.1/3.9 Hz, 1H, 4-H), 2.34 (s, 3H, NCH3), 2.54 (td, J = 12.3/2.5 Hz, 1H, 6-H), 2.80 (ddd, J = 11.6/4.3/2.3 Hz, 1H, 2-H), 3.04 (ddd, J = 12.1/4.0/2.6 Hz, 1H, 6-H), 3.87 (t, J = 7.2 Hz, 1H, OCH2), 3.98 (td, J = 6.6/4.5 Hz, 1H, OCH), 4.08 (t, J = 7.2 Hz, 1H, OCH2), 7.19–7.28 (m, 6H, Ph), 7.39–7.47 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 24.0 (C-5), 31.7 (C-3), 31.8 (NCH3), 44.7 (C-6), 56.6 (C-2), 56.8 (C-4), 66.0 (OCH2), 79.1 (OCH), 109.6 (OCO), 126.1 (Ph-C), 126.2 (Ph-C), 128.0 (Ph-C), 128.1 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 141.9 (Ph-C), 142.0 (Ph-C). HRMS: calculated for C21H26N2O2H 339.2067, found 339.2074. HPLC (Method B): Purity 99%, tR = 11.3 min.
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Download mol file of compound(±)-(2RS,4RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-yl]-N-methylpiperidin-4-amine (COMPOUND LINKS
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Download mol file of compound23d).
According to General Procedure F 22d (52.9 mg, 0.11 mmol) was dissolved in COMPOUND LINKS
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Download mol file of compoundmethanol (5 mL) and Pd/C (10%, 5.0 mg) was added. The product was purified by fc. Compound COMPOUND LINKS
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Download mol file of compound23d (Rf 0.27): Colourless oil, yield 30.2 mg (82%). IR (neat): ν/cm−1 = 1086 (s, C–O–C). 1H NMR (CDCl3): δ (ppm) = 1.44 (ddd, J = 12.2/10.1/3.6 Hz, 1H, 3-H), 1.54–1.59 (m, 2H, 5-H + NH), 1.62–1.67 (m, 2H, 3-H + NH), 1.69–1.74 (m, 1H, 5-H), 2.41 (s, 3H, NCH3), 2.78 (dt, J = 12.4/4.1 Hz, 1H, 6-H), 2.88 (quint, J = 3.8 Hz, 1H, 4-H), 2.93 (td, J = 11.9/3.2 Hz, 1H, 6-H), 3.15 (ddd, J = 10.6/4.8/2.7 Hz, 1H, 2-H), 3.97 (t, J = 6.3 Hz, 1H, OCH2), 4.02–4.10 (m, 2H, OCH + OCH2), 7.27–7.36 (m, 6H, Ph), 7.46–7.54 (m, 4H, Ph). 13C NMR (CDCl3): δ (ppm) = 31.0 (C-5), 32.8 (C-3), 34.2 (NCH3), 41.0 (C-6), 52.5 (C-2), 52.8 (C-4), 66.7 (OCH2), 79.4 (OCH), 109.8 (OCO), 126.4 (Ph-C), 126.5 (Ph-C), 128.1 (Ph-C), 128.2 (Ph-C), 128.3 (Ph-C), 128.4 (Ph-C), 142.4 (Ph-C), 142.5 (Ph-C). HRMS: calculated for C21H26N2O2H 339.2067, found 339.2067. HPLC (Method A): Purity 95%, tR = 14.3 min.
Materials and general procedures
Pig brains were a donation of the local slaughterhouse (Coesfeld, Germany). The guinea pig brains and rat livers were commercially available (Harlan-Winkelmann, Borchen, Germany). Homogenizer: Elvehjem Potter (B. Braun Biotech International, Melsungen, Germany). Centrifuge: high-speed cooling centrifuge model Sorvall RC-5C plus (Thermo Fisher Scientific, Langenselbold, Germany). Filter: printed Filtermat Typ A and B (Perkin Elmer LAS, Rodgau-Jügesheim, Germany), presoaked in 0.5% aqueous polyethylenimine for 2 h at room temperature before use. The filtration was carried out with a MicroBeta FilterMate-96 Harvester (Perkin Elmer). The scintillation analysis was performed using Meltilex (Typ A or B) solid scintillator (Perkin Elmer) and a MicroBeta Trilux scintillation analyzer (Perkin Elmer). The overall counting efficiency was 20%. All experiments were carried out in triplicates using standard 96-well-multiplates (Diagonal, Muenster, Germany). The IC50-values were determined in competition experiments with at least six concentrations of the test compounds and were calculated with the program GraphPad Prism® 3.0 (GraphPad Software, San Diego, CA, USA) by non-linear regression analysis. The Ki-values were calculated according to the formula of Cheng and Prusoff.28 The Ki-values are given as mean value ± SEM from three independent experiments.
Affinity towards the phencyclidine binding site of the NMDA receptor, modified according to ref. 21
Preparation of the tissue.
Fresh pig brain cortex was homogenized with the potter (500–800 rpm, 10 up-and-down strokes) in 6 volumes of cold 0.32 M COMPOUND LINKS
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Download mol file of compoundsucrose. The suspension was centrifuged at 1200 × g for 10 min at 4 °C. The supernatant was separated and centrifuged at 23
500 × g for 20 min at 4 °C. The pellet was resuspended in 5–6 volumes of TRIS/COMPOUND LINKS
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Download mol file of compoundEDTA buffer (5 mM/1 mM, pH 7.5) and centrifuged again at 31
000 × g (20 min, 4 °C). This procedure was repeated twice. The final pellet was resuspended in 5–6 volumes of buffer, the protein concentration was determined according to the method of Bradford30 using bovine serum albumin as standard, and subsequently the preparation was frozen (−80 °C) in 1.5 mL portions containing about 0.8 mg protein mL−1.
Performance of the assay.
The test was performed with the radioligand [3H]-(+)-MK-801 (22.0 Ci/mmol; Perkin Elmer). The thawed membrane preparation (about 100 μg of the protein) was incubated with various concentrations of test compounds, 2 nM [3H]-(+)-MK-801, and TRIS/EDTA-buffer (5 mM/1 mM, pH 7.5) in a total volume of 200 μL for 150 min at rt. The incubation was terminated by rapid filtration through the presoaked filtermats using a cell harvester. After washing each well five times with 300 μL of water, the filtermats were dried at 95 °C. Subsequently, the solid scintillator was placed on the filtermat and melted at 95 °C. After 5 min, the solid scintillator was allowed to solidify at rt. The bound radioactivity trapped on the filters was counted in the scintillation analyzer. The non-specific binding was determined with 10 μM unlabeled (+)-MK-801. The Kd-value of (+)-MK-801 is 2.26 nM.29
Affinity toards the σ1 receptor, modified according to ref. 25–27
Preparation of the tissue.
Five guinea pig brains were homogenized with the potter (500–800 rpm, 10 up-and-down strokes) in 6 volumes of cold 0.32 M COMPOUND LINKS
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Download mol file of compoundsucrose. The suspension was centrifuged at 1200 g for 10 min at 4 °C. The supernatant was separated and centrifuged at 23
500 g for 20 min at 4 °C. The pellet was resuspended in 5–6 volumes of buffer (50 mM Tris, pH 7.4) and centrifuged again at 23
500 g (20 min, 4 °C). This procedure was repeated twice. The final pellet was resuspended in 5–6 volumes of buffer, the protein concentration was determined according to the method of Bradford30 using bovine serum albumin as standard, and subsequently the preparation was frozen (−80 °C) in 1.5 mL portions containing about 1.5 mg protein mL−1.
Performing of the σ1 assay.
The test was performed with the radioligand [3H]-(+)-pentazocine (42.5 Ci/mmol; Perkin Elmer). The thawed membrane preparation (about 75 μg of the protein) was incubated with various concentrations of test compounds, 2 nM [3H]-(+)-pentazocine, and buffer (50 mM TRIS, pH 7.4) in a total volume of 200 μL for 180 min at 37 °C. The incubation was terminated by rapid filtration through the presoaked filtermats by using the cell harvester. After washing each well five times with 300 μL of water, the filtermats were dried at 95 °C. Subsequently, the solid scintillator was placed on the filtermat and melted at 95 °C. After 5 min, the solid scintillator was allowed to solidify at rt. The bound radioactivity trapped on the filters was counted in the scintillation analyzer. The non-specific binding was determined with 10 μM unlabeled COMPOUND LINKS
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Download mol file of compound(+)-pentazocine. The Kd-value of the radioligand [3H]-(+)-pentazocine is 2.9 nM.
Affinity toards the σ2 receptor (modified according to ref. 25–27)
Preparation of the tissue.
Two rat livers were cut into small pieces and homogenized with a potter (500–800 rpm, 10 up-and-down strokes) in 6 volumes of cold 0.32 M COMPOUND LINKS
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Download mol file of compoundsucrose. The suspension was centrifuged at 1200 g for 10 min at 4 °C. The supernatant was separated and centrifuged at 31
000 g for 20 min at 4 °C. The pellet was resuspended in buffer (50 mM Tris, pH 8.0) and incubated at room temperature for 30 min. After the incubation, the suspension was centrifuged again at 31
000 g for 20 min at 4 °C. The final pellet was resuspended in buffer, the protein concentration was determined according to the method of Bradford30 using bovine serum albumin as standard, and subsequently the preparation was frozen (−80 °C) in 1.5 mL portions containing about 2 mg protein mL−1.
Performing of the σ2 assay.
The test was performed with the radioligand [3H]-di-o-tolylguanidine (50 Ci/mmol; ARC). The thawed membrane preparation (about 100 μg of the protein) was incubated with various concentrations of test compounds, 3 nM [3H]-di-o-tolylguanidine, 500 nM (+)–COMPOUND LINKS
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Download mol file of compoundpentazocine and buffer (50 mM TRIS, pH 8.0) in a total volume of 200 μL for 180 min at rt. The incubation was terminated by rapid filtration through the presoaked filtermats using a cell harvester. After washing each well five times with 300 μL of water, the filtermats were dried at 95 °C. Subsequently, the solid scintillator was placed on the filtermat and melted at 95 °C. After 5 min, the solid scintillator was allowed to solidify at rt. The bound radioactivity trapped on the filters was counted in the scintillation analyzer. The non-specific binding was determined with 10 μM unlabeled ditolylguanidine. The Kd-value of the radioligand [3H]-ditolylguanidine is 17.9 nM.
Affinity towards the ifenprodil binding site of the NMDA receptor (NR2B affinity), modified according to ref. 22
Preparation of the cell membranes.
For the binding assay, the cell pellet was resuspended in phosphate buffer saline (PBS) buffer and the number of cells was determined using an improved Neubauer's counting chamber (VWR, Darmstadt, Germany). Subsequently, the cells were lysed by sonication (4 °C, 6 × 10 s cycles with breaks of 10 s, device: Soniprep 150, MSE, London, UK). The resulting cell fragments were centrifuged with a high performance cool centrifuge (20
000 × g, 4 °C, Sorvall RC-5 plus, Thermo Scientific). The supernatant was discarded and the pellet resuspended in a defined volume of PBS yielding cell fragments of approximately 500
000 cells mL−1. The suspension of membrane homogenates was sonicated again (4 °C, 2 × 10 s cycles with a break of 10 min) and stored at −80 °C.
Performing of the NR2B binding assay.
The competitive binding assay was performed with the radioligand [3H]-ifenprodil (60 Ci/mmol; Perkin Elmer) using standard 96-well-multiplates (Diagonal, Muenster, Germany). The thawed cell membrane preparation (about 20 μg protein) was incubated with 6 different concentrations of test compounds, 5 nM [3H]–ifenprodil, and TRIS/EDTA-buffer (5 mM/1 mM, pH 7.5) in a total volume of 200 μL for 120 min at 37 °C. The incubation was terminated by rapid filtration through the presoaked filtermats by using the cell harvester. After washing each well five times with 300 μL of water, the filtermats were dried at 95 °C. Subsequently, the solid scintillator was placed on the filtermat and melted at 95 °C. After 5 min, the solid scintillator was allowed to solidify at rt. The bound radioactivity trapped on the filters was counted in the scintillation analyzer. The non-specific binding was determined with 10 μM unlabeled 1. The Kd-value of 1 is 7.6 nM.22
Acknowledgements
The NRW International Graduate School of Chemistry, Münster, which is funded by the Government of the State Nordrhein-Westfalen and the DAAD is deeply acknowledged for the financial support.
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