Simone
Lucarini
,
Annalida
Bedini
,
Gilberto
Spadoni
and
Giovanni
Piersanti
*
Institute of Medicinal Chemistry, University of Urbino “Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino (PU), Italy. E-mail: giovanni.piersanti@uniurb.it; Fax: +39 0722 303313; Tel: +39 0722 303323
First published on 13th November 2007
A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT2melatonin receptor antagonist. The synthetic strategy involved the conversion of 4-phenyl-2-tetralone to enamide followed by diastereoselective reduction affording cis-4-P-PDOT in good yield. The mechanism of the reduction step was explored by employing deuterated reagents.
Melatonin (N-acetyl-5-methoxytryptamine, MLT), a neurohormone mainly secreted by the pineal gland during dark periods, is an indole derivative with a flexible ethylamido chain attached at the C3 position. In mammals, melatonin modulates a variety of cellular, neuroendocrine and physiological processes through activation of at least two high-affinity G-protein coupled receptors, named MT1 and MT2.4
Converging evidence from pharmacophore analysis, 3D-QSAR and GPCR comparative modelling in the field of melatonin receptor ligands has allowed the definition of the structural requirements for MT2 selective antagonism.5–7 In particular, we evidenced that the presence of a bulky substituent in an area corresponding to positions 1 and 2 of the indole nucleus of MLT, and “out-of-plane” from the indole ring, confers selectivity for the MT2receptor and leads to a reduction of intrinsic activity.8 The melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-PDOT, Fig. 1) fulfilled this requirement9 and is one of the most interesting melatonin MT2 selective antagonists.
Fig. 1 |
Recently, we examined the influence of different stereochemistries of 4-phenyl-2-propionamidotetralin on the binding affinity and intrinsic activity at human MT1 and MT2 receptors.10 The (±)-cis diastereoisomer of compound1 (Fig. 1) has higher MT2 binding affinity (pKi = 10.8), as compared to its corresponding trans-isomer (pKi = 8.45) and good selectivity for the MT2receptor (MT2/MT1 = 225) rendering cis-4-P-PDOT one of the most used pharmacological tools to identify functional MT2 receptors.
Although this compound has been used in small amounts in in vitro tests to provide some understanding of the roles of MT1 and MT2melatonin receptors,11–13 more precise and specific in vivo animal experiments, where large amounts of compound are required, are necessary to clarify the physiological role of both receptors.
The need for multi-gram amounts of this very expensive substance14 for in vivo studies prompted us to design a more efficient, diastereoselective route to the more active cis-4-P-PDOT.
The method used in the first patent route,15 involved a base-catalyzed condensation between phenylacetone and benzaldehyde, followed by ring closure via an intramolecular Friedel–Crafts alkylation with AlCl3 in CS2 to give 4-phenyl-2-tetralone. The 4-phenyl-2-propionamidotetralin 1 was obtained by reductive amination with benzylamine, deprotection and finally acylation with propionic anhydride according to the Schotten–Baumann procedure. The overall yield for 4-P-PDOT prepared according to this synthetic route was very low (ca. 1%) and moreover there is no mention of the stereochemistry of the product synthesized.
Our initial approach to the synthesis of the cis-diastereoisomer of compound 1 (Scheme 1)10 was based on the protocol reported by Wyrick et al.16 and involved the synthesis of 4-phenyl-2-tetralone 4 by cyclization of trans-1,4-diphenyl-3-buten-2-one 3 in polyphosphoric acid followed by reduction with NaBH4 to give a 85 : 15 cis–trans mixture of tetralols 5. The predominantly cis-tetralol was epimerized via the ester intermediate 6 to the trans-alcohol 7. The latter was converted to the cis-primary amine 9 by tosylation, followed by reaction with sodium azide in aqueous DMF then catalytical (10% Pd/C) hydrogenation. Finally, the primary amine was converted to (±)-cis-4-phenyl-2-propionamidotetralin 1 by acylation with propionic anhydride.
Scheme 1 Precedented synthetic approach. Reagents: (a) PhCHO, NaOH, water, 60 °C, 18 h; (b) PPA, xylene, reflux, 2 h; (c) NaBH4, MeOH, reflux, 16 h; (d) DEAD, (C6H5)3P, PhCOOH, THF, 55 °C, 4 h; (e) NaOH, MeOH, reflux, 2 h; (f) TsCl, Py, 5 °C, 5 days; (g) NaN3, DMF–H2O, 50 °C, 4 h; (h) H2 (4 atm.) 10% Pd/C, 2-propanol, rt, 24 h; (i) (C2H5CO)2O, Et3N, toluene, rt, 24 h. |
The described synthetic procedure (Scheme 1) involved overall nine tedious steps, several flash chromatography purifications, the use of some hazardous reagents and the overall transformations are not very efficient.
Herein we describe a more efficient synthesis of (±)-cis-4-P-PDOT in only three steps and high overall yield that is suitable for multigram-scale preparations.
Scheme 2 Retrosynthetic analysis. |
Scheme 3 Novel synthetic approach. Reagents: (a) AlCl3, CH2Cl2, 0 °C 30 min; (b) propylamide, PTSA cat., toluene, reflux, 4 h; (c) TES, TFA, −10 °C, 10 min. |
We envisioned, then, propionamide, as a less basic and nucleophilic enough alternative to the amine, to couple with the tetralone 4. In fact it is well-known that enamides can be easily prepared by the acid catalyzed condensation of primary amides with carbonyl compounds18 and we took advantage of this trivial fact in designing our synthetic route. Stereoselective reduction of the newly formed enamide 10 (Scheme 2) would complete the synthesis of the target compound.
The easy and direct route to the key enamide 10 was achieved by condensation of primary propylamide with the cyclic ketone 4 in the presence of p-toluenesulfonic acid as catalyst and continuous removal of water using Dean–Stark apparatus.
Given our project’s ongoing synthesis of novel analogs of 4-P-PDOT we required a general reduction procedure for enamides which would be tolerant to functional groups. In addition, we required the regiospecific delivery of a hydride equivalent to the vinyl group in anticipation of the preparation of several 3H-labeled analogs.
With all this in mind we thought to use ionic reduction conditions for a chemo-, regio- and stereoselective reduction of the enamide. We were delighted to find that treatment of the substrate 10 with Et3SiH (TES) in the presence of trifluoroacetic acid (TFA) furnished the desired product in excellent yield and good diastereoselectivity (91% yield; 81 : 19 cis–trans ratio). No reduction took place when acetic acid was used instead of TFA. Attempts to further improve the diastereoselectivity by lowering the temperature to −78 °C resulted in unacceptable low conversion rates.
It is noteworthy, that the present method offers a highly atom economic process to 4-P-PDOT.
The pure cis-isomer can be easily isolated by crystallization (acetone–n-hexane). The physical–chemical properties and NMR-spectra of compound cis-1 synthesized by the novel procedure (Scheme 3) were identical to those previously reported.11
The mechanism of the reduction was briefly explored by carrying out the reaction in the presence of deuterated and non-deuterated reagents. Reduction of 10 using Et3SiD in place of Et3SiH, resulted in high conversion to deuterium labeled 4-P-PDOT d1-cis-1a (Fig. 2) in about the same time (10 min). In contrast, by using CF3COOD only 4-P-PDOT d1-cis-1b was obtained. Comparison of the 1H NMR signals for the CH and -CH2groups of cis-1a and cis-1b with those of 1 showed simplified 1H NMR multiplet patterns due to substitution by 2H. This was confirmed by analysis of the MS spectrum which revealed almost complete mono-deuteriation (d1 95 atom%) and 13C NMR confirmed the location of the deuterium exclusively at the C2 (45.3) and C1 (36.5) for cis-1a and cis-1b respectively.
Fig. 2 |
Based on these results we hypothesized the mechanism shown in Scheme 4. The diastereoselectivity outcome of the reduction can be explained by both the Burgi–Dunitz trajectory for hydride approach to carbonyls and the Cieplak19 mode for the nucleophilic addition to a carbonyl group with non-chelating α-substituents. It is known that the stereochemistry of nucleophilic addition to cyclohexanones is determined by two factors: steric hindrance which favours the equatorial approach (b, Scheme 4), and electron donation from the cyclohexanone’s σC–C bonds into the σ* which favours the axial approach (a, Scheme 4) since the carbon–hydrogen bonds are better electron donors. Given the predominant cis product, we can confidently assume that the electronic factors prevail over the steric hindrance on substrate 10 in our reaction conditions.
Scheme 4 Proposed mechanism. |
There are certain advantages to our synthetic approach (Scheme 3) over the previous routes as presented and all of them can be included within the concepts of “atom economy”20 and “step economy”.21 Indeed precise control over the individual reactivity of functional groups (chemoselectivity) without the need to use protecting groups or useless interconversions of functional groups, has been achieved increasing the brevity and efficiency of the synthesis (only three steps and a high overall yield of 38%).
NMR δH (200 MHz, CDCl3) 2.90–3.01 (2 H, m, CH2), 3.65 (2 H, AB, JAB = 20.0 Hz, CH2), 4.48 (1 H, t, J = 6.6 Hz, CH), 7.01 (1 H, d, J = 7.0 Hz, ArH), 7.12–7.36 (8 H, m, ArH); IR (nujol) νmax/cm−1 1720 (CO); ESI-MS (m/z) 223 (M + 1).
NMR δH (200 MHz, CDCl3) 1.18 (3 H, t, J = 7.6 Hz, NHCOCH2CH3), 2.29 (2 H, q, J = 7.6 Hz, NHCOCH2CH3), 2.70 (1 H, dd, J1 = 16.0 Hz, J2 = 9.4 Hz, C3Ha), 2.77 (1 H, dd, J1 = 16.0 Hz, J2 = 7.6 Hz, C3Hb), 4.21 (1 H, t, J = 8.2 Hz, CHPh2), 6.42 (1 H, br s, NH), 6.79 (1 H, d, J = 7.6 Hz, C1H), 7.01 (1 H, td, J1 = 7.4 Hz, J2 = 1.6 Hz, ArH), 7.11–7.32 (8 H m, ArH); δC (50 MHz, CDCl3) 9.5, 30.7, 36.0, 44.3, 111.2, 126.0, 126.4, 126.7, 127.1, 127.4, 128.3, 128.6, 133.4, 134.9, 135.2, 143.6, 172.4; IR (nujol) νmax/cm−1 3337 (NH), 1655 (CC); ESI-MS (m/z): 278 (M + 1); mp 123–124 °C.
NMR δH (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz, NHCOCH2CH3), 1.79 (1 H, apt q, J = 11.6 Hz, C3Ha), 2.22 (2 H, q, J = 7.6 Hz, NHCOCH2CH3), 2.37–2.46 (1 H, m, C3Hb), 2.79 (1 H, dd, J1 = 11.0 Hz, J2 = 15.8 Hz, C1Ha), 3.23 (1 H, ddd, J1 = 1.8 Hz, J2 = 5.3 Hz, J3 = 15.8 Hz, C1Hb), 4.25 (1 H, dd, J1 = 5.5 Hz, J2 = 11.5 Hz, C4H), 4.32–4.46 (1 H, m, C2H), 5.54 (1 H, brs d, J = 7.1 Hz, NH), 6.80 (1 H, d, J = 7.4 Hz, ArH), 7.01–7.37 (8 H, m, ArH); δC (50 MHz, CDCl3) 9.8, 29.8, 36.8, 40.4, 45.6, 46.1, 126.21, 126.24, 126.4, 128.56, 128.64, 129.0, 129.5, 134.9, 138.7, 146.0, 173.1; IR (nujol) νmax/cm−1 3289 (NH), 3024 (ArH), and 1670 (CO); ESI-MS (m/z): 280 (M + 1); mp 170–172 °C.
δ H (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz, NHCOCH2CH3), 1.79 (1 H, apt t, J = 12.0 Hz, C3Ha), 2.22 (2 H, q, J = 7.6 Hz, NHCOCH2CH3), 2.41 (1 H, ddd, J1 = 12.4 Hz, J2 = 5.8 Hz, J3 = 2.1 Hz, C3Hb), 2.80 (1 H, d, J = 15.6 Hz, C1Ha), 3.22 (1 H, d, J = 15.6 Hz, C1Hb), 4.24 (1 H, dd, J1 = 5.6 Hz, J2 = 11.2 Hz, C4H), 5.62 (1 H, br s, NH), 6.79 (1 H, d, J = 7.5 Hz, ArH), 7.00–7.36 (8 H, m, ArH); δC (50 MHz, CDCl3) 9.9, 29.8, 36.8, 40.3, 45.3 (1 C, t, J = 21.5 Hz), 46.1, 126.24, 126.26, 126.5, 128.6, 128.7, 129.1, 129.5, 135.0, 138.7, 146.0, 173.2; IR (nujol) νmax/cm−1 3291 (NH), 3026 (ArH), and 1670 (CO); ESI-MS (m/z): 281 (M + 1); mp 172–174 °C.
δ H (200 MHz, CDCl3) 1.15 (3 H, t, J = 7.6 Hz, NHCOCH2CH3), 1.78 (1 H, apt q, J = 11.7 Hz, C3Ha), 2.21 (2 H, q, J = 7.6 Hz, NHCOCH2CH3), 2.36–2.47 (1 H, m, C3Hb), 2.75–2.86 (0.5 H, m, C1Ha/Da), 3.19–3.27 (0.5 H, m, C1Hb/Db), 4.24 (1 H, dd, J1 = 5.6 Hz, J2 = 11.6 Hz, C4H), 4.31–4.44 (1 H, m, C2H), 5.54 (1 H, br d, J = 7.4 Hz, NH), 6.80 (1 H, d, J = 7.4 Hz, ArH), 7.01–7.34 (8 H, m, ArH); δC (50 MHz, CDCl3) 9.9, 29.9, 36.5 (1 C, t, J = 19.0 Hz), 40.4, 45.5, 46.1, 126.23, 126.27, 126.5, 128.6, 128.7, 129.1, 129.5, 134.9, 138.8, 146.0, 173.2; IR (nujol) νmax/cm−1 3291 (NH), 3023 (ArH), 1671 (CO); ESI-MS (m/z): 281 (M + 1); mp 171–173 °C.
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