Synthesis of a Conformationally Constrained Phenylalanine Derivative by a Strategic Combination of Ring-Closing Enyne Metathesis and Diels-Alder Reaction

PAPER 2925 Synthesis of a Conformationally Constrained Phenylalanine Derivative by a Strategic Combination of Ring-Closing Enyne Metathesis and Diels–Alder Reaction Synthesi ofaConformationalyConstrainedPhenyla ni eDerivative Sambasivarao Kotha,* Priti Khedkar Department of Chemistry, Indian Institute of Technology – Bombay, Mumbai 400076, India Fax +91(22)5723480; E-mail: srk@chem.iitb.ac.in Received 29 April 2008; revised 21 May 2008 CO2R Abstract: An efficient route towards the synthesis of a conformationally constrained phenylalanine derivative is demonstrated using the strategic combination of ring-closing enyne metathesis and Diels–Alder reaction as key steps. Key words: constrained amino acid, phenylalanine, ring closure, metathesis, Diels–Alder CO2R NR NR 1 2 CO2R CO2R In the view of increasing demand for peptide-based drugs,1 conformationally constrained amino acid derivatives have become useful tools in bioorganic chemistry. There are restrictions in employing peptides as drugs and these include several factors, such as instability towards proteolytic degradation, poor absorption after oral ingestion, rapid excretion through liver and kidneys, and undesired effects caused by interaction of the conformationally flexible peptides with various receptors. It has been well established that incorporation of a constrained amino acid unit in a peptide chain can modify the physiological as well as binding properties of the resulting peptide.2 Peptide modifications3 by incorporation of conformationally constrained amino acids in bioactive peptides and drugs can result in better substrates for structure–activity relationship studies.4 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic, 1) (Figure 1) is a constrained analogue of phenylalanine (Phe). In Tic 1, the six-membered heterocyclic ring is formed by incorporation of a methylene unit in between the amino group and the aromatic ring of the phenylalanine. This type of amino acid plays an important role in designing peptidomimetics.5 It was found that the incorporation of Tic 1 in the second position of an opioid receptor exerts conformational restrictions and results in distinct changes in its activity and selectivity.6 The tetrahydroisoquinoline unit is a key element in several peptide-based drugs and forms an integrated part of various biologically active molecular frameworks.7 Commonly, Tic 1 and its derivatives are assembled via Pictet– Spengler reaction and Bischler–Napieralsky reaction or by alkylation strategies.8 To expand the ‘building block approach’9 for the synthesis of highly functionalized Tic derivatives, our group has demonstrated that methodoloSYNTHESIS 2008, No. 18, pp 2925–2928xx. 208 Advanced online publication: 22.08.2008 DOI: 10.1055/s-2008-1067237; Art ID: Z09908SS © Georg Thieme Verlag Stuttgart · New York NR NR 3 Figure 1 (R = H) 4 Conformationally constrained phenylalanine analogues gies based on [2+2+2]-cyclotrimerization reactions10 and ring-closing enyne metathesis strategies are useful.11 Along similar lines, higher analogues of Tic 1 such as, 2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylic acid (2), 1,2,3,4,5,6-hexahydro-3-benzazocine-2-carboxylic acid (3), and 2,3,4,5,6,7-hexahydro-1H-3-benzazonine-2carboxylic acid (4) seem to be attractive synthetic targets12 due to their projected utility in peptidomimetics and pharmacological studies.13 Most of the known methods available for the preparation of these compounds start with the preformed benzene derivatives, so they provide limited opportunity for the introduction of diverse functional groups in the benzene ring.12 Herein, we describe our efforts towards the synthesis of highly functionalized higher analogues of Tic 1 using ring-closing enyne metathesis14 and Diels–Alder reactions15 as key steps (Scheme 1). This strategy provides a unique advantage over the existing methods, as diverse substituents in the aromatic ring may be introduced by the judicious selection of the reacting partners. Ring-closing enyne metathesis is an attractive process, which enables the generation of a diene that can easily undergo Diels–Alder reaction with various dienophiles to deliver intricate polycyclic compounds. The preparation of the diene, in the presence of reactive functional groups (-NH2, -CO2Et) is not a trivial task. The commercial availability of Grubbs first generation catalyst, G-I and Grubbs second generation catalyst, G-II (Figure 2)16 has provided access to a wide range of dienes suitable for the construction of highly functionalized polycycles. 2926 PAPER S. Kotha, P. Khedkar R The first task in our strategy involves the alkylation of the amide nitrogen of ethyl 2-(tosylamino)pent-4-ynoate (5) with 4-bromobut-1-ene. The substrate 6 can be subjected to enyne metathesis to generate diene 7, which in turn may undergo a [4+2]-cycloaddition reaction with a suitable dienophile. Later on, oxidation of 8 may deliver the highly substituted seven-membered ring analogue of Tic. Thus, the enyne 6 can be used as a building block to construct various derivatives of 2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylic acid by ring-closing enyne metathesis and Diels–Alder reactions as key steps. R R R iv NTs EtO2C NTs EtO2C 9 8 iii NHTs ii i NTs CO2Et EtO2C CO2Et 5 Towards the realization of this strategy, the alkyne derivative 5 was treated with 4-bromobut-1-ene and potassium carbonate in dry acetonitrile at 65 °C to obtain ethyl 2[but-3-enyl(tosyl)amino]pent-4-ynoate (6) in 78% yield (Scheme 2). NTs 6 7 Scheme 1 A retrosynthetic approach to a conformationally constrained phenylalanine derivative. Reagents and conditions: (i) 4-bromobut-1-ene, base; (ii) Grubbs catalyst; (iii) dienophile; (iv) aromatization. Cl PCy3 Ph Ru Cl Mes N N Mes Ph Cl H PCy3 G-I The next task in hand was to realize the ring-closing enyne metathesis strategy as shown Scheme 1. When enyne 6 was subjected to ring-closing enyne metathesis in the presence of G-I for 24 hours in dry toluene, the complete conversion of starting material into diene 7 could not be achieved. However, Grubbs second generation catalyst G-II delivered the desired diene in 54% yield (Scheme 3). Although, the diene was characterized by 1H NMR, IR, and HRMS data, the 13C NMR spectrum of this material showed some minor additional peaks that may arise from decomposition of this sensitive diene. Therefore, the diene 7 was immediately subjected to Diels–Alder reaction with dimethyl acetylenedicarboxylate to furnish compound 8. Further, functionalized 2,3,4,5-tetrahydro-1H-3benzoazepine-2-carboxylic acid derivative 9 was obtained by the aromatization of 8 using 2,3-dichloro-5,6-dicyano1,4-benzoquinone (Scheme 4). Ru Cl H PCy3 G-II Figure 2 4-bromo-1-butene, K2CO3 TsHN CO2Et N Ts MeCN, 65 °C, 14 h, 78% CO2Et In conclusion, a building block approach towards the construction of a conformationally constrained phenylalanine analogue using ring-closing enyne metathesis and Diels– Alder reactions as key steps has been demonstrated. The 6 5 Scheme 2 G-I NTs EtO2C G-II NTs toluene, 100 °C, 24 h, mixture of 6 & 7 CO2Et 7 toluene, 100 °C, 24 h, 54% NTs EtO2C 7 6 Scheme 3 MeO2C MeO2C CO2Me CO2Me DDQ DMAD NTs EtO2C toluene, reflux, 39% NTs 8 Scheme 4 Synthesis 2008, No. 18, 2925–2928 © Thieme Stuttgart · New York NTs EtO2C EtO2C 7 toluene, reflux, 50% 9 PAPER Synthesis of a Conformationally Constrained Phenylalanine Derivative method has several advantages over the existing procedures, as it provides an opportunity to install the desired substituents in the benzene ring under construction. All reactions were monitored by TLC carried out on glass plates coated with Acme silica gel GF 254 (containing 13% CaSO4 as a binder). Visualization of the spots on TLC plates was achieved either by exposure to I2 vapor or UV light. Flash chromatography was performed using Acme silica gel (100–200 mesh). Hexane refers to fraction having boiling point 60–80 °C. All commercial grade reagents were used without further purification. IR spectra were recorded on a Nicolet Impact 400 FT-IR spectrometer in KBr– CH2Cl2. 1H NMR (400 MHz) and 13C NMR (75 and 100.6 MHz) spectra were determined at r.t. on a Varian VXR 300 in CDCl3 solns with TMS as internal reference. HRMS were determined on Micromass Q-Tof spectrometer. Starting material 5 was prepared using literature procedures.11,17 Ethyl 2-[But-3-enyl(tosyl)amino]pent-4-ynoate (6) To a stirred suspension of finely powdered K2CO3 (100 mg, 0.72 mmol) in anhyd MeCN (15 mL) was added 5 (43 mg, 0.145 mmol) and 4-bromobut-1-ene (24 mg, 0.17 mmol). The resulting heterogeneous mixture was heated at 65 °C for 14 h under N2. The mixture was cooled and filtered over a short Celite pad. The filtrate was concentrated under reduced pressure and diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with H2O (25 mL) and brine (25 mL) and dried (anhyd Na2SO4). Removal of the solvent gave the crude product that was purified by column chromatography (silica gel, 5% EtOAc–hexane) to give 6 (40 mg, 78%) as a colorless thick liquid; Rf = 0.5 (silica gel, 30% EtOAc–hexane). IR (neat): 1737, 1644, 1343, 1160 cm–1. 1 H NMR (400 MHz, CDCl3): d = 1.15 (t, J = 7.2 Hz, 3 H), 2.01 (t, J = 2.8 Hz, 1 H), 2.42–2.46 (m, 5 H), 2.67–2.88 (m, 2 H), 3.12–3.38 (m, 2 H), 4.05 (q, J = 7.2 Hz, 2 H), 4.66–4.70 (m, 1 H), 5.06–5.08 (m, 2 H), 5.65–5.77 (m, 1 H) 7.28 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.2 Hz, 2 H). 13 C NMR (100.6 MHz, CDCl3): d = 14.0, 21.5, 34.9, 46.0, 59.0, 61.7, 71.6, 79.4, 117.1, 127.7, 128.2, 129.4, 129.5, 130.0 134.7, 137.1, 143.5, 169.4. HRMS (Q-Tof): m/z [M + Na]+ calcd for C18H23NNaO4S: 372.1245; found: 372.1244. Ethyl 1-Tosyl-4-vinyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylate (7) To a soln of 6 (52.2 mg, 0.149 mmol) in dry degassed toluene (20 mL) was added Grubbs’ second generation catalyst G-II (13 mg, 0.015 mmol, 10 mol%). The mixture was heated at 100 °C for 24 h maintaining the inert atmosphere. The resulting brown soln was allowed to cool to r.t. and solvent was removed under reduced pressure to obtain a crude material that was purified by column chromatography (silica gel, 10% EtOAc–hexane) gave 7 (28 mg, 54%) as a colorless liquid; Rf = 0.5 (silica gel, 30% EtOAc–hexane). IR (neat): 1966, 1651, 1265 cm–1. 1 H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.2 Hz, 3 H), 2.38– 2.62 (m, 6 H), 3.00–3.16 (m, 1 H), 3.43–3.74 (m, 2 H), 3.94–4.08 (m, 2 H), 4.93–5.17 (m, 3 H), 5.75 (t, J = 6 Hz, 1 H), 6.25 (dd, J1 = 16 Hz, J2 = 10 Hz, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.71 (d, J = 8 Hz, 2 H). 13 C NMR (100.6 MHz, CDCl3): d = 14.1, 21.6, 28.7, 29.6, 42.7, 57.2, 61.3, 111.4, 117.1, 127.4, 128.3, 129.6, 130.0, 132.1, 137.1, 139.6, 143.3, 170.5. 2927 HRMS (Q-Tof): m/z [M + H]+ calcd for C18H24NO4S: 350.1426; found: 350.1412. 2-Ethyl 6,7-Dimethyl 3-Tosyl-2,3,4,5,5a,8-hexahydro-1H-3benzazepine-2,6,7-tricarboxylate (8) To a soln of 7 (27 mg, 0.077 mmol) in dry toluene (20 mL) was added DMAD (17 mg, 0.118 mmol). The mixture was heated to reflux for 17 h maintaining the inert atmosphere. At the completion of reaction (TLC) the mixture was allowed to cool to r.t. and solvent was removed under reduced pressure. The crude material obtained was purified by column chromatography (silica gel, 20% EtOAc–hexane) to give 8 (15 mg, 39%) as a colorless liquid; Rf = 0.26 (silica gel, 30% EtOAc–hexane). IR (neat): 1966, 1648, 1265, 1157 cm–1. 1 H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7.2 Hz, 3 H), 1.40– 1.51 (m, 2 H), 1.96 (td, J1 = 14 Hz, J2 = 4 Hz, 1 H), 2.11 (dd, J1 = 13.6 Hz, J2 = 11.6 Hz, 1 H), 2.40 (s, 3 H), 2.79–3.03 (m, 4 H), 3.36 (dd, J1 = 14 Hz, J2 = 12 Hz, 1 H), 3.76 (s, 6 H), 3.96–4.06 (m, 2 H), 4.50 (dd, J1 = 10 Hz, J2 = 7.2 Hz, 1 H), 5.55–5.59 (m, 1 H), 7.25 (d, J = 8 Hz, 2 H), 7.64 (d, J = 8 Hz, 2 H). 13 C NMR (100.6 MHz, CDCl3): d = 14.1, 21.6, 28.1, 34.9, 37.7, 42.5, 43.7, 52.4, 52.4, 58.8, 61.4, 121.7, 127.3, 127.5, 129.6, 129.6, 131.9, 132.8, 137.2, 137.6, 143.4, 168.0, 168.3, 171.6. HRMS (Q-Tof): m/z [M + Na]+ calcd for C24H29NNaO8S: 514.1512; found: 514.1524. 2-Ethyl 6,7-Dimethyl 3-Tosyl-2,3,4,5-tetrahydro-1H-3-benzazepine-2,6,7-tricarboxylate (9) To a soln of 8 (50 mg, 0.10 mmol) in dry toluene (25 mL) was added DDQ (80 mg, 0.35 mmol) and the mixture was refluxed for 48 h. The mixture was then allowed to cool to r.t. and solvent was removed under reduced pressure. The crude material obtained was purified by column chromatography (silica gel, 20% EtOAc–hexane) to give 9 (25 mg, 50%) as a colorless thick liquid; Rf = 0. 27 (silica–gel, 30% EtOAc–hexane). IR (neat): 1966, 1644, 1266 cm–1. 1 H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 7 Hz, 3 H), 2.38 (s, 3 H), 2.81–2.97 (m, 2 H), 3.27–3.44 (m, 4 H), 3.76–4.07 (m, 8 H), 5.16 (m, 1 H), 7.20–7.27 (m, 3 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.75 (d, J = 8 Hz, 1 H). 13 C NMR (100.6 MHz, CDCl3): d = 14.1, 21.5, 32.2, 38.9, 43.4, 52.5, 52.7, 56.0, 61.4, 126.8, 127.3, 128.4, 129.6, 131.5, 135.2, 137.1, 137.9, 142.3, 143.4, 165.9, 169.0, 169.6. HRMS (Q-Tof): m/z [M + H]+ calcd for C24H28NO4S: 490.1536; found: 490.1539. Acknowledgement We thank the DST, New Delhi for the financial support and SAIFMumbai for providing spectral facilities. P.K. thanks the CSIR, New Delhi for the award of research fellowship. References (1) (a) Pillai, O.; Panchagnula, R. Drug Discovery Today 2001, 6, 1056. (b) Fletcher, K. Pharm. Sci. Technol. Today 1998, 1, 49. (c) Cochran, A. G. Chem. Biol. 2000, 7, R85. (d) van Hest, J. C. M.; Tirrell, D. A. Chem. Commun. 2001, 1897. 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