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Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids and analogous
Tetrahedron 68 (2012) 2001e2006
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Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids and analogous Kumaraswamy Sorra a, b, *, K. Mukkanti b, Srinivas Pusuluri a a b
Chemistry Services, GVK Biosciences Private Limited, Plot No.5C, IDA Uppal, Hyderabad 500 039, AP, India Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 September 2011 Received in revised form 24 November 2011 Accepted 13 December 2011 Available online 19 December 2011
A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladiumcatalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine alkaloids such as circumdatin H, J and other analogues. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Quinazolinobenzodiazepine Circumdatin BuchwaldeHartwig amination Palladium Lawesson’s reagent
1. Introduction Benzodiazepines are an important class of compounds’ representing as a member of the family of privileged scaffold.1 A large number of structurally interesting and biologically important natural and synthetic benzodiazepines are known in the literature.2 Benzodiazepine with fused quinazoline system appears in a number of naturally occurring alkaloids, such as circumdatins, benzomalvins, asperlicin, sclerotigenin (Fig. 1).3e7
Fig. 1. Structures of known quinazolinobenzodiazepine alkaloids.
* Corresponding author. Tel.: þ91 40 67126600; fax: þ91 40 27208866; e-mail address: [email protected] (K. Sorra). 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.12.032
Circumdatins, a sub-group of fused quinazolinobenzodiazepine alkaloids (Fig. 1), were first isolated by Rahbæk et al. from a marine fungus Aspergillus ochraceus (subgenus Circumdati).3e7 They possess antitumour, antifungal, insecticide, antibiotic activities,4e6,8 cholescystokinin antagonism,9 inhibition of substance P33d and mitochondrial NADH oxidase.10 The quinazolinobenzodiazepine moiety has received much attention in the synthetic community due to it’s structural and biological attributed features. In the total synthesis of quinazolinobenzodiazepine alkaloids, various methods have been developed for the synthesis of quinazolino [1,4] benzodiazepine moiety in their skeleton. Primarily, the cyclization has been done via the aza-Wittig reaction, known as the Eguchi protocol.11,12 Though, it provided a direct route to heterocyclic natural products; this approach has a down side of using explosive 2-azidobenzoic acids. Witt and Bergman synthesized circumdatin F via iminobenzoxazine intermediate by the MazurkiewiczeGanesan protocol, but it requires longer synthetic sequences.13 Bock’s group afforded the asperlicins C and E by regioselective annulation of benzodiazepinedione with anthranilic acid.14 Liu and co-workers synthesized racemic quinazolinobenzodiazepine by means of a one-pot synthesis.15 And also, lately progress has been made using metal triflate catalyzed dehydrocyclization of tripeptide-anthranilate16 and reductive cyclization of the 2-nitrobenzamides affords the quinazolinone.17 Most recently, copper-catalyzed N-arylation of a quinazolinone led to the benzodiazepine ring system.18
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In this communication, we report a concise and preferably convergent route for the synthesis of highly enantiopure pyrrolo quinazolino [1,4] benzodiazepine-2,5-diones via amination/cyclization domino reaction of amidines with o-bromobenzoates under BuchwaldeHartwig conditions.19 The present work represents a considerably improved synthesis and we envisioned that this reaction would make possible a short synthesis of enantiopure pentacyclic circumdatin H, J and their analogues.
Table 1 Optimization chart of palladium catalyzed conditions for quinazolino [1,4] benzodiazepine
2. Results and discussion Palladium catalyzed amination and followed by intramolecular cyclization involving in the tandem carbonenitrogen bond formation were preformed on the amidine 4a,b, which can be synthesized in three steps from the commercially available L-Proline and isatoic anhydrides (Scheme 1). The cyclocondensation of equimolar of naturally occurring L-proline with isatoic anhydride (1a) and methoxy isatoic anhydride (1b) in DMF at 150 C for 5 h provided corresponding products 2a20 and 2b17 in 85e90% yields. The dilactam compound 2a,b subsequently converted to mono thiolactams 3a,b using 0.5 equiv Lawesson’s reagent in toluene at 70 C for 6 h.20 The thiolactam 3a,b was reacted with anhydrous NH3 and HgCl2 afforded the amidine 4a,b21 in 90% yield, which were chosen as key precursors for the quinazolinone ring formation.
Entry Pd source 1 2 3 4 5 6 7 8 9 10 11 12 13
Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd (dppf) Cl2 Pd (dppf) Cl2 Pd (PPh3)4 Pd (PPh3)4 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2
Ligand Xantphos Xantphos BINAP Aphos Xantphos BINAP Xantphos BINAP Xantphos BINAP Xantphos Xantphos Xantphos
Base Cs2CO3 NaO-t-Bu Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 NaO-t-Bu NaO-t-Bu NaO-t-Bu NaO-t-Bu Cs2CO3 Cs2CO3 Cs2CO3
Temperature ( C) Time e
100 130e 100e 100e 100e 130e 100e 100e 100e 100e 100e 100f 100g
16 h 16 h 16 h 16 h 16 h 16 h 16 h 16 h 12 h 12 h 12 h 24 h 15 min
Yield of 6a (%) (NR)b (NR)b (NR)b (NR)b 10 8 30 32 65c 53c 75d 55d 78d
a All reactions were run with 4a (0.23 mmol), 5a (0.23 mmol), base (0.46 mmol, 2 equiv), Pd catalyst (5 mol %) and ligand (10 mol %) in 1,4-dioxane (2 mL) under Ar. Isolated yields. b No reaction. c 70% ee. d >99% ee. e The reaction was performed in sealed tube under oil-bath heating. f The reaction was performed under conventional oil-bath heating. g The reaction was performed under microwave irradiation.
Scheme 1. Palladium catalyzed N-arylation and followed by intramolecular cyclization: synthesis of circumdatin H, J and analogues. Reagents and conditions: (a) L-proline, DMF, 140 C, 5 h, 85% yield (b) Lawesson’s reagent, toluene, 70 C, 5 h, 85% yield (c) NH3, HgCl2, THF, 60 C, 1 h, 90e95% yield (d) Pd (OAc)2, Xantphos, Cs2CO3, 1,4dioxane, 100 C, sealed tube, 12 h or MW, 15 min. 70e85% yield.
Palladium catalyzed annulation of model substrate 4a with 5a has been extensively investigated resulting in a substantial optimization. The formation of the quinazolinone ring, while preserving the chiral integrity has been studied by changing the reaction parameters (Table 1). Our studies began with Pd2 (dba)3 with various phosphine ligands (Xantphos/()-BINAP/Aphos) in the presence of
different bases (NaO-t-Bu/Cs2CO3/K3PO4) at elevated temperatures, which prove to be incapable of amination (entries 1e4). As an alternate palladium source, the use of Pd (dppf) Cl2 under the same reaction conditions gave compound 6 in 8e10% yield. The results encouraged us to examine various catalysts, in the due course Pd(PPh3)4eXantphos/()-BINAP gave a moderate yield (entries 7, 8) and Pd(OAc)2eXantphos has demonstrated more effective to get the cyclized compound. Finally, cyclization of compound 6 has been achieved in 75% yield (>99% ee) with 5 mol % of Pd(OAc)2 and 10 mol % Xantphos in the presence of 2 equiv of Cs2CO3 in 1,4dioxane at 100 C (entry 11). The analytical and spectral data for compound 6 were in complete agreement with the reported data.22 While Buchwald’s amination using Pd(OAc)2eXantphos in the presence of NaO-t-Bu gave us a disappointing enantiomeric purity (70% ee) (entries 9, 10). For further optimization of the reaction conditions using Pd(OAc)2/Xantphos/Cs2CO3 in 1,4-dioxane, we continued to examine reactions at various temperatures and reaction duration. The reaction has taken 24 h for completion under conventional heating at 100 C resulted in moderate yield (55%) (entry 12), but in sealed tube it was completed in 12 h with good yield (entry 11). The time duration tremendously reduced under microwave heating, microwave exposure to 5 min at 100 C resulted low yield (35%) due to the incompletion of the reaction, the best yield was obtained when the reaction was run at 100 C for 15 min provided the desired compound 6 in 78% yield (entry 13). Delightfully, the chiral integrity was preserved in all the cases. The enantiomeric purity was determined by the chiral HPLC area method with a comparison of racemic compound 6, which was synthesized similarly from the DL-proline. Subsequently, functionalized cyclic amidine and o-bromobenzoates were investigated under the above optimized conditions
K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
to achieve the total syntheses of natural pyrrolo quinazolino [1,4] benzodiazepine-2,5-dione alkaloids (Scheme 1). Circumdatin H (7), which contains an additional methoxy substituent, the synthesis was preceded uneventfully from compound 4a and 5-methoxy-2bromo benzoate 5b. Circumdatin J (8), which contains methoxy substituent on both benzodiazepine and quinazolino rings was afforded from compound 4b and compound 5b. Both the circumdatin H and J were synthesized in 75% yield with >99% ee. The analytical and spectral data for the ()-circumdatins H (7) and J (8) were in complete agreement with the reported data.10,17,22 The natural products circumdatin E and circumdatin D contains hydroxy functionality on quinazolinone ring along with the methoxy substituents, here we have synthesized the methoxy derivative of the circumdatin D (9) and E (10) in 72e75% yield with >99% ee and for our convenience we named them as methoxy circumdatin D and E, respectively. Most of the natural circumdatins have electron rich substituents, such as hydroxy and methoxy groups; herein we employed the optimized conditions on various substituted systems including both activating and deactivating groups to examine the competence of the ring substituents on the reaction conditions (Scheme 2). Compound 4a was reacted with the substituted 2bromo benzoates 5dei under the above described conditions to afford compound 11e16, respectively, significantly the reaction was completed much faster (8 h) and obtained >80% yield with the electron-withdrawing substitutes rather than donating substituents. These results envisaged that the reaction conditions are well tolerated by both electron-withdrawing and electrondonating substituents in the Csp2 donors.
Scheme 2. Synthesis of quinazolino [1,4] benzodiazepines from deactivated and activated aromatic rings.
2003
The proposed mechanistic way for quinazolinone cyclization is depicted in Scheme 3. In the first stage, the amination of AreBr (5a) with 4a via BuchwaldeHartwig approach of the palladium complex containing the chelating phosphine ligand produce the uncyclized aminated compound (17).19,23 In the next stage, the base catalyzed medium could trigger the intramolecular cyclization with the proximate nitrogen to lead the quinazolinobenzodiazepine ring system. 3. Conclusion We have developed a highly efficient and concise synthetic strategy for the total synthesis of enantiopure circumdatin alkaloids under palladium-catalyzed conditions. It features a quinazolino ring cyclization process as a key synthetic step with preserving the chiral integrity. This efficient strategy should allow easy access to a variety of quinazolino [1,4] benzodiazepine alkaloids and their analogues. 4. Experimental 4.1. General All reactions dealing with Palladium catalyst were conducted under an atmosphere of argon. The solvents were purified according to standard procedures prior to use, Pd catalysts, ligands and Cs2CO3 were purchased from Aldrich and all commercial chemicals were used as received. For thin-layer chromatography (TLC) analysis, Merck precoated Plates (silica gel 60 F254) were used and eluting solvents are indicated in the procedures. Merck silica gel 60 (230e400 mesh) was used for flash column chromatography. Melting point (mp) determinations were performed by using Meltemp apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Unity instrument at rt at 400 MHz. Chemical shifts are reported in d parts per million (ppm) downfield from tetramethylsilane (TMS) with reference to internal solvent and coupling constants in hertz. Mass spectra were obtained on Micromass QuattroMicroÔAPI-autospectrometer using APCI technique. HRMS TOF ES mass spectra were recorded on a WatersAlliance 2695 Separation Module/Q-TOF Micromass. Infrared (IR) spectra were recorded on a PerkineElmer FT-IR spectrometer. Optical rotations ([a]D) were measured on a JASCO P-1030 polarimeter and data are reported as follows: [a]D temp, concentration (c g/
Scheme 3. Mechanistic proposal for the Pd catalyzed amination and intramolecular cyclization.
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100 mL) and solvent. Liquid chromatography-mass spectrometry (LCMS) on a Waters Acquity UPLC photodiode array detector system using ESI technique under the following conditions: column used: Acquity-UPLC BEH-C18 (2.150 mm) 1.7 m, Mobile Phase: A: 0.025% aqueous CF3COOH, B:0.025% CF3COOH in acetonitrile, T/%B: 0/15, 3/95, 4/95, 4.1/15; flow rate: 0.4 mL/min, diluent: acetonitrile; UV: max-plot. Enantiomeric excess (ee) was determined by HPLC analysis using Chiralpak IA column (2504.6 mm), 5 m, hexane/ ethanol (1:1) with 0.1% isopropyl amine at 1.0 mL/min. All isolated compounds had purity greater than 99% (area percent) as judged by HPLC analysis area method. 4.1.1. (11aS)-11-Thioxo-1,2,3,10,11,11a-hexahydro-5H pyrrolo [2,1-c] [1,4]benzodiazepin-5-one (3a). To a suspension of dilactam compound 2a (1.0 g, 4.62 mmol) in 100 mL toluene was added Lawesson’s reagent (0.94 g, 2.31 mmol). The yellow suspension was heated to 70 C for 5 h. After this time a yellow solid has precipitated, which was recrystallized from ethanol to yield pure 3a (923 mg, 86% yield) as yellow crystals. Rf (50% EtOAc/pet ether) 0.50; mp 291e292 C; ½a27 D þ729.1 (c 1.08, DMSO); nmax (KBr) 3446, 3171, 2943, 1616, 1605, 1521. 1417, 1374, 1270, 1141, 1030, 886, 832, 813, 753, 695 cm1; dH (400 MHz, CDCl3) 9.73 (1H, br, NH), 8.04 (1H, d, J¼8.0 Hz, ArH), 7.53e7.49 (1H, m, ArH), 7.37e7.33 (1H, m, ArH), 7.05 (1H, d, J¼8.4 Hz, ArH), 4.22 (1H, d, J¼7.6 Hz, NCH), 3.80e3.77 (1H, m, CH2), 3.64e3.57 (1H, m, CH2), 3.13e3.08 (1H, m, CH2), 2.31e2.22 (1H, m, CH2), 2.18e2.08 (1H, m, CH2), 2.03e1.97 (1H, m, CH2); dC (100 MHz, DMSO-d6) 201.9, 164.1, 136.4, 132.1, 130.2, 127.7, 125.6, 121.8, 59.7, 46.8, 28.9, 22.6; MS (APCI) m/z 233 (MHþ); HRMS (TOF ESþ): MHþ, found 233.0738. C12H13N2OS requires 233.0749. 4.1.2. (11aS)-7-Methoxy-11-thioxo-1,2,3,10,11,11a-hexahydro-5Hpyrrolo[2,1-c][1,4]benzodiazepin-5-one (3b). Dilactam compound 2b (3 g, 12.19 mmol) was converted to 3b using the procedure for the preparation of 3a. This gave yellow solid; 85% yield; Rf (50% EtOAc/ pet ether) 0.50; mp 196e197 C; ½a26 D þ 632 (c 1.02, MeOH); nmax (KBr) 3467, 3247, 2958, 1627, 1606, 1497, 1434, 1385, 1301, 1245, 1164, 1095, 1026, 872, 820, 788, 630 cm1; dH (400 MHz, CDCl3) 9.65 (1H, br, NH), 7.50 (1H, d, J¼2.8 Hz, ArH), 7.06 (1H, dd, J¼8.8, 3.2 Hz, ArH), 7.0 (1H, d, J¼8.8 Hz, ArH), 4.19 (1H, d, J¼7.2 Hz, NCH), 3.93 (3H, s, OCH3), 3.84e3.76 (1H, m, CH2), 3.63e3.56 (1H, m, CH2), 3.12e3.08 (1H, m, CH2), 2.32e2.23 (1H, m, CH2), 2.16e1.96 (2H, m, CH2); dC (100 MHz, CDCl3) 200.8, 164.9, 157.6, 129.6, 129.2, 122.5, 120.1, 113.5, 60.1, 55.8, 47.3, 29.5, 22.9; MS (APCI) m/z 263 (MHþ); HRMS (TOF ESþ): MHþ, found 263.0875. C13H15N2O2S requires 263.0854. 4.1.3. (S)-11-Aminio-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a] [1,4] diazepine-5 (11aH)-one (4a). A suspension of 3a (2.5 g, 10.77 mmol) and mercuric chloride (3.5 g, 12.93 mmol, 1.2 equiv) in dry THF (125 mL) was warmed to 60 C and an ammonia stream was bubbled into the solution. After 1 h, the solution became black (formation of mercuric sulfide), the stream of ammonia was stopped and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through Celite, washed with a mixture of methanol/THF, the combined filtrate was concentrated, the solid residue was washed with acetone and Et2O and dried to give the amidine 4a as pale yellow solid. 95% yield; Rf (15% MeOH/CHCl3) 0.40; mp 314e315 C; ½a26 D þ582.3 (c 1.04, DMSO); nmax (KBr) 3541, 3365, 3128. 1673, 1616, 1580, 1453, 1403, 1257, 1239, 1149, 762, 702 cm1; dH (400 MHz, DMSO-d6) 7.75 (1H, d, J¼8.0 Hz, ArH), 7.44 (1H, t, J¼7.6 Hz, ArH), 7.40e7.20 (2H, m, NH2), 7.12 (1H, t, J¼8.4 Hz, ArH), 7.06 (1H, d, J¼7.6 Hz, ArH), 4.06 (1H, d, J¼6.8 Hz, NCH), 3.66e3.61 (1H, m, CH2), 3.41e3.34 (2H, m, CH2), 2.13e2.05 (1H, m, CH2), 1.98e1.91 (2H, m, CH2); dC (100 MHz, DMSO-d6) 164.8, 161.9, 143.6, 129.9, 126.7, 126.5, 124.9, 122.5, 54.1, 46.4, 26.0,
23.3; MS (APCI) m/z 216 (MHþ); HRMS (TOF ESþ): MHþ, found 216.1129. C12H14N3O requires 216.1137. 4.1.4. (S)-11-Aminio-7-methoxy-2,3-dihydro-1H-benzo[e] pyrrolo [1,2-a][1,4]diazepine-5 (11aH)-one (4b). Thiolactam 3b (2.5 g, 9.54 mmol) was converted to 4b using the procedure for the preparation of 4a. This gave off white solid, 90% yield; Rf (15% MeOH/CHCl3) 0.40; mp 189e190 C; ½a26 D þ615.9 (c 1.05, DMSO); nmax (KBr) 3389, 3325, 3206, 1609, 1488, 1437, 1405, 1267, 1228, 1034, 834, 762 cm1; dH (400 MHz, DMSO-d6) 7.40e7.20 (3H, br, NH2 and ArH), 71.2e7.06 (2H, m, ArH), 4.13 (1H, d, J¼7.2 Hz, NCH), 3.77 (3H, s, OCH3), 3.67e3.62 (1H, m, CH2), 3.40e3.36 (2H, m, CH2), 2.12e2.08 (1H, m, CH2), 2.05e1.96 (2H, m, CH2); dC (100 MHz, DMSO-d6) 164.5, 161.3, 154.7, 127.6, 126.4, 123.0, 119.2, 112.4, 55.3, 54.0, 46.4, 26.0, 23.3; MS (APCI) m/z 246 (MHþ).
4.2. General procedure for the Pd catalyzed synthesis of quinazolinone [1,4] benzodiazepine Method A: A sealed tube was charged with compound 4a,b (0.93 mmol), 5aee (0.93 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv of Cs2CO3 (1.86 mmol) and 10 mL of 1,4-dioxane. The mixture was degassed and backfilled with argon, the reaction vessel was sealed with a Teflon tap and heated at 100 C for 12 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in chloroform, washed with 10% citric acid solution, brine solution, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by flash column chromatography using 3e5% of MeOH/CHCl3 as an eluent to give the title cyclized compound. Method B: To a thick-well borosilicate glass vial (5 mL) was added compound 4a,b (0.23 mmol), compound 5aee (0.23 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv Cs2CO3 (0.46 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and the reaction vial was sealed and placed in the CEM-DISCOVER microwave reactor and irradiated at 100 C for 15 min. After cooled to rt, the product was isolated as above described in method A. 4.2.1. (S)-()-Desmethoxy circumdatin H (6). Pale yellow solid; method A: 75% yield, method B: 78% yield; Rf (10% MeOH/CHCl3) 0.60; mp 251e252 C; ½a27 D 123.5 (c 0.54, MeOH); nmax (KBr) 3435, 3067, 2972, 2879, 1690. 1643, 1615, 1473, 1450, 1417, 1362, 1295, 1251, 1215, 1115, 1021, 973, 897, 782, 778, 764, 704 cm1; dH (400 MHz, DMSO-d6) 8.18 (1H, d, J¼8.0 Hz, ArH), 7.89 (1H, t, J¼7.2 Hz, ArH), 7.83 (1H, d, J¼7.6 Hz, ArH), 7.74 (1H, d, J¼8.4 Hz, ArH), 7.67e7.56 (4H, m, ArH), 4.64 (1H, d, J¼6.4 Hz, NCH), 3.63e3.59 (1H, m, CH2), 3.49e3.42 (1H, m, CH2), 2.94e2.93 (1H, m, CH2), 2.16e2.08 (2H, m, CH2), 1.99e1.98 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.7, 153.6, 146.1, 134.1, 133.2, 132.3, 130.7, 129.9, 128.6, 128.3, 127.6, 127.5, 127.4, 121.4, 58.8, 46.4, 26.9, 23.6; MS (APCI) m/z 318 (MHþ); HRMS (TOF ESþ): MHþ, found 318.1205. C19H16N3O2 requires 318.1243. 4.2.2. (S)-()-Circumdatin H (7). Pale yellow solid; method A: 75% yield, method B: 79% yield; Rf (10%MeOH/CHCl3) 0.55; mp 216e217 C; ½a29 D 106 (c 0.82, MeOH); nmax (KBr) 3435, 3065, 2972, 1692, 1646, 1619, 1491, 1456, 1423, 1361, 1278, 1235, 1022, 875, 832, 789, 761, 707 cm1; dH (400 MHz, CDCl3) 7.99 (1H, d, J¼7.2 Hz, ArH), 7.67 (1H, d, J¼2.8 Hz, ArH), 7.64 (1H, d, J¼8.8 Hz, ArH), 7.58e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼8.8, 2.8 Hz, ArH), 4.54 (1H, d, J¼8.0 Hz, NCH), 3.93 (3H, s, OCH3), 3.82e3.77 (1H, m, NCH2), 3.64e3.57 (1H, m, CH2), 3.18e3.14 (1H, m, CH2), 2.32e2.30 (1H, m, CH2), 2.17e2.12 (1H, m, CH2), 2.10e2.05 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.6, 158.9, 151.5, 140.5, 133.4, 132.4, 130.7, 129.9, 129.1, 128.6, 128.3, 124.8, 122.3, 106.9, 58.7, 55.8, 46.5, 26.9, 23.7; MS
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(APCI) m/z 348 (MHþ); HRMS (TOF ESþ): MHþ, found 348.1338. C20H18N3O3 requires 348.1348. 4.2.3. (S)-()-Circumdatin J (8). Pale yellow solid; method A: 75% yield; Rf (10% MeOH/CHCl3) 0.50; mp 189e191 C; ½a29 D 63.2 (c 1.19, 1:1 MeOH/CH2Cl2); nmax (KBr) 3436, 2936, 2875, 1687, 1633, 1617, 1491, 1465, 1439, 1368, 1282, 1238, 1029, 869, 835, 771 cm1; dH (400 MHz, CDCl3) 7.67 (1H, d, J¼2.8 Hz, ArH), 7.63 (1H, d, J¼8.8 Hz, ArH), 7.47 (1H, d, J¼8.8 Hz, ArH), 7.46 (1H, d, J¼2.0 Hz, ArH), 7.37 (1H, dd, J¼8.8, 2.8 Hz, ArH), 7.11 (1H, dd, J¼9.2, 3.2 Hz, ArH), 4.56 (1H, d, J¼4.2 Hz, ArH), 3.92 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.80e3.75 (1H, m, NCH), 3.64e3.58 (1H, m, CH2), 3.18e3.13 (1H, m, CH2), 2.32e2.29 (1H, m, CH2), 2.17e2.12 (1H, m, CH2), 2.11e2.05 (1H, m, CH2); dC (100 MHz, CDCl3) 164.3, 161.7, 159.1, 158.9, 151.6, 140.6, 133.5, 129.7, 129.1, 126.2, 124.7, 122.3, 117.9, 112.9, 106.8, 58.8, 55.8, 55.7, 46.5, 26.9, 23.6; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1469. C21H20N3O4 requires 378.1454. 4.2.4. (S)-()-Methoxy circumdatin E (9). Off white solid; method A and B: 75% yield; Rf (10%MeOH/CHCl3) 0.50; mp 263e264 C; ½a28 D 145 (c 0.38, 1:1 MeOH/CHCl3); nmax (KBr) 3432, 2924, 2851, 1647, 1457, 1375, 1260, 1214, 1099, 1048, 1020, 836, 789, 669 cm1; dH (400 MHz, DMSO-d6) 7.83 (1H, d, J¼6.4 Hz, ArH), 7.64e7.57 (3H, m, ArH), 7.13 (1H, d, J¼2.4 Hz, ArH), 7.01 (1H, d, J¼2.8 Hz, ArH), 4.60 (1H, d, J¼6.0 Hz, NCH), 3.94 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.57e3.55 (1H, m, CH2), 3.48e3.46 (1H, m, CH2), 3.0e2.95 (1H, m, CH2), 2.18e2.11 (2H, m, CH2), 2.01e1.95 (1H, m, CH2); dC (100 MHz, CDCl3) 164.5, 161.5, 159.5, 156.0, 150.6, 133.4, 132.3, 131.7, 130.7, 129.8, 128.6, 128.3, 123.2, 106.0, 98.1, 58.9, 56.5, 55.8, 46.5, 27.0, 23.8; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1469. C21H20N3O4 requires 378.1454. 4.2.5. (S)-()-Methoxy circumdatin D (10). Pale yellow solid; method B: 72% yield; Rf (10% MeOH/CHCl3) 0.50; mp 171e173 C; ½a28 D 98.6 (c 0.53, CHCl3); nmax (KBr) 3435, 2925, 2857, 1636, 1615, 1457, 1377, 1282, 1236, 1214, 1160, 1057, 1040, 842, 772, 669 cm1; dH (400 MHz, DMSO-d6) 7.50 (1H, d, J¼9.2 Hz, ArH), 7.27 (1H, d, J¼2.4 Hz, ArH), 7.20 (1H, dd, J¼8.8, 3.2 Hz, ArH), 7.12e7.10 (1H, m, ArH), 7.01 (1H, d, J¼2.4 Hz, ArH), 4.62 (1H, d, J¼5.6 Hz, NCH), 3.94 (3H, s, OCH3), 3.78 (6H, s, OCH3, OCH3), 3.55e3.46 (2H, m, CH2), 3.0e2.95 (1H, m, CH2), 2.15e2.10 (2H, m, CH2), 2.01e1.95 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.7, 159.4, 159.1, 155.9, 150.7, 133.4, 131.7, 129.6, 126.2, 123.2, 117.9, 112.8, 105.9, 98.0, 58.9, 56.5, 55.8, 55.7, 46.5, 27.0, 23.8; MS (APCI) m/z 408 (MHþ); HRMS (TOF ESþ): MHþ, found 408.1543. C22H22N3O5 requires 408.1559. 4.2.6. Compound (11). Yellow solid; method A: 82% yield, method B: 70% yield; Rf (10% MeOH/CHCl3) 0.60; mp 239e240 C; ½a27 D 18.3 (c 0.76, CHCl3); nmax (KBr) 3447, 3082, 2957, 2883, 1699, 1683, 1654, 1611, 1577, 1523, 1454, 1412, 1344, 1278, 1242, 1183, 1122, 1090, 849, 824, 787, 750, 717, 694 cm1; dH (400 MHz, CDCl3) 9.17 (1H, d, J¼2.8 Hz, ArH), 8.59 (1H, dd, J¼8.8, 2.8 Hz, ArH), 8.03 (1H, d, J¼8.0 Hz, ArH), 7.86 (1H, d, J¼8.8 Hz, ArH), 7.64e7.55 (3H, m, ArH), 4.59 (1H, d, J¼7.6 Hz, NCH), 3.83e3.80 (1H, m, CH2), 3.63e3.61 (1H, m, CH2), 3.18e3.14 (1H, m, CH2), 2.32e2.30 (1H, m, CH2), 2.20e2.10 (2H, m, CH2); dC (100 MHz, CDCl3) 164.1, 160.5, 156.9, 150.2, 146.2, 132.3, 132.2, 131.0, 131.2, 129.3, 129.2, 128.9, 127.9, 123.9, 121.1, 58.9, 46.6, 27.0, 23.6; MS (APCI) m/z 363 (MHþ); HRMS (TOF ESþ): MHþ, found 363.1091. C19H15N4O4 requires 363.1093. 4.2.7. Compound (12). Pale yellow solid; method A: 76% yield, method B: 85% yield; Rf (10% MeOH/CHCl3) 0.50; mp 264e265 C; ½a26 D 75.1 (c 0.69, MeOH); nmax (KBr) 3436, 3088, 2954, 1703, 1646, 1610, 1476, 1457, 1365, 1273, 1159, 1102, 978, 869, 781, 706 cm1; dH (400 MHz, CDCl3) 8.34e8.30 (1H, m, ArH), 8.0 (1H, d, J¼7.2 Hz,
2005
ArH), 7.59e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼10.0, 2.4 Hz, ArH), 7.23 (1H, dd, J¼8.4, 2.4 Hz, ArH), 4.54 (1H, d, J¼7.2 Hz, NCH), 3.82e3.77 (1H, m, CH2), 3.64e3.59 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.31e2.29 (1H, m, CH2), 2.18e2.06 (2H, m, CH2); dC (100 MHz, CDCl3) 168.0, 165.4, 164.3, 160.9, 154.9, 148.4, 148.2, 132.6, 138.8, 130.5, 130.1, 128.5, 118.2, 116.3, 113.2, 58.9, 46.5, 26.9, 23.6; MS (APCI) m/z 336 (MHþ); HRMS (TOF ESþ): MHþ, found 336.1110. C19H15N3O2F requires 336.1148. 4.2.8. Compound (13). White solid; method A: 80% yield; Rf (10% MeOH/CHCl3) 0.60; mp 197e200 C; ½a28 D 77.56 (c 0.52, CHCl3); nmax (KBr) 3434, 3053, 2925, 1697, 1648, 1615, 1466, 1418, 1363, 1276, 1074, 829, 721 cm1; dH (400 MHz, CDCl3) 8.27 (1H, m, ArH), 8.0 (1H, d, J¼8.0 Hz, ArH), 7.74e7.73 (1H, m, ArH), 7.72 (1H, m, ArH), 7.67e7.26 (3H, m, ArH), 4.54 (1H, d, J¼7.6 Hz, NCH), 3.83e3.77 (1H, m, CH2), 3.64e3.57 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.31e2.05 (3H, m, CH2); dC (100 MHz, CDCl3) 164.5, 160.9, 154.1, 144.8, 135.3, 133.6, 133.1, 132.5, 131.0, 130.2, 129.4, 129.0, 128.4, 126.9, 122.8, 59.0, 46.7, 27.2, 23.8; MS (APCI) m/z 352 (MHþ); HRMS (TOF ESþ): MHþ, found 352.0878. C19H15N3O2Cl requires 352.0853. 4.2.9. Compound (14). Yellow solid; method A: 82% yield; Rf (10% MeOH/CHCl3) 0.60; mp 267e269 C; ½a28 D 79.85 (c 0.51, 1:1 MeOH/CHCl3); nmax (KBr) 3435, 3047, 2926, 2229, 1700, 1686, 1644, 1609, 1594, 1484, 1417, 1364, 1248, 1217, 839 cm1; dH (400 MHz, CDCl3) 8.63 (1H, s, ArH), 8.03e8.97 (2H, m, ArH), 7.81 (1H, d, J¼8.4 Hz, ArH), 7.64e7.54 (3H, m, ArH), 4.57 (1H, d, J¼6.8 Hz, NCH), 3.83e3.79 (1H m, CH2), 3.64e3.57 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.32e2.09 (3H, m, CH2); dC (100 MHz, CDCl3) 164.1, 160.2, 156.5, 148.7, 136.6, 132.7, 132.4, 132.2, 130.9, 130.1, 129.2, 128.9, 127.9, 122.1, 117.7, 111.1, 58.9, 46.6, 27.0, 23.6; MS (APCI) m/z 343 (MHþ); HRMS (TOF ESþ): MHþ, found 343.1181. C20H15N4O2 requires 343.1195. 4.2.10. Compound (15). Off white solid; method A: 72% yield; Rf (10%MeOH/CHCl3) 0.30; mp 297e299 C; ½a26 D 111.99 (c 0.52, DMSO); nmax (KBr) 3435, 3305, 3070, 2926, 1690, 1616, 1543, 1492, 1457, 1420, 1361, 1312, 1251, 1163, 1011, 897, 845, 710 cm1; dH (400 MHz, DMSO-d6) 10.35 (1H, s, AceNH), 8.47 (1H, s, ArH), 8.02 (1H, d, J¼8.8 Hz, ArH), 7.82 (1H, d, J¼7.6 Hz, ArH), 7.71e7.55 (4H, m, ArH), 4.62 (1H, d, J¼6.8 Hz, NCH), 3.60e3.58 (1H, m, CH2), 3.48e3.41 (1H, m, CH2), 2.90 (1H, m, CH2), 2.15e2.01 (5H, m, CH2, COCH3), 1.97 (1H, m, CH2); dC (100 MHz, DMSO-d6) 168.6, 163.4, 161.1, 152.9, 141.3, 138.5, 133.1, 132.1, 130.5, 129.0, 128.4, 127.9, 126.2, 121.3, 114.8, 58.4, 46.0, 26.36, 23.98, 23.18; MS (APCI) m/z 375 (MHþ); HRMS (TOF ESþ): MHþ, found 375.1445. C21H19N4O3 requires 375.1457. 4.2.11. Compound (16). Off white solid; method A: 78% yield; Rf (10%MeOH/CHCl3) 0.50; mp 276e278 C; ½a26 D 123.83 (c 0.51, 1:1 MeOH/CHCl3); nmax (KBr) 3447, 2957, 2929, 1682, 1651, 1609, 1500, 1458, 1394, 1359, 1302, 1242, 1202, 1155, 1001, 870 cm1; dH (400 MHz, CDCl3) 7.99 (1H, d, J¼7.6 Hz, ArH), 7.63 (1H, s, ArH), 7.58e7.49 (3H, m, ArH), 7.11 (1H, s, ArH), 4.53 (1H, d, J¼8.0 Hz, NCH), 4.05 (3H, s, OCH3), 4.0 (3H, s, OCH3), 3.82e3.77 (1H, m, CH2), 3.65e3.58 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.35e2.28 (1H, m, CH2), 2.20e2.04 (2H, m, CH2); dC (100 MHz, CDCl3) 164.5, 161.0, 155.2, 152.5, 149.5, 142.3, 133.4, 132.3, 130.5, 129.8, 128.5, 128.4, 114.8, 108.1, 106.4, 58.7, 56.4, 56.3, 46.4, 26.9, 23.7; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1412. C21H20N3O4 requires 378.1412. Acknowledgements The authors are grateful to the GVK Biosciences management for the financial support and encouragement. We are thankful to
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K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
Dr. Srinivasa Rao Alapati and Dr. Balaram Patro for their valuable suggestions and support. Supplementary data The 1H NMR and 13C NMR copies of all compounds were attached. Supplementary data associated with this article can be found in the online version, at doi:10.1016/j.tet.2011.12.032. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513e521. 2. (a) Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini, C. Curr. Med. Chem. 2007, 14, 2680e2701; (b) Lueddens, H.; Korpi, E. R. Handbook of Contemporary Neuropharmacology; JohnWiley and Sons: NewYork, NY, 2007; Vol. 2; p 93; (c) Bacon, E. R.; Chatterjee, S.; Williams, M. Comprehensive Medicinal Chemistry II; Elsevier: Amsterdam, 2006; Vol. 6; p 139. 3. (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R. S. L.; Lotti, V. J.; Chen, T. B. J. Antibiot. 1985, 38, 1633e1637; (b) Chang, R. S. L.; Lotti, V. J.; Monaghan, R. L.; Birnbaum, J.; Stapley, E. O.; Goetz, M. A.; Albers-Schonberg, G.; Patchett, A. A.; Liesch, J. M.; Hensens, O. D.; Springer, J. P. Science 1985, 230, 177e179; (c) Goetz, M. A.; Monaghan, R. L.; Chang, R. S. L.; Ondeyka, J.; Chen, T. B.; Lotti, V. J. J. Antibiot. 1988, 41, 875e877; (d) Sun, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A. M.; Cooper, R. J. Antibiot. 1994, 47, 515e522; (e) Joshi, B. K.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 1999, 62, 650e652. 4. Dai, J.-R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L. S.; Ng, S. W.; Huang, Y.; Butler, M. S. J. Nat. Prod 2001, 64, 125e126. 5. Raebaek, L.; Breinholt, J. J. Nat. Prod 1999, 62, 904e905. 6. Raebaek, L.; Breinholt, J.; Frisvald, J. C.; Christopherson, C. J. Org. Chem 1999, 64, 1689e1692. 7. The structure of circumdatins A and B was recently revised, see: Ookura, R.; Kito, K.; Ooi, T.; Namikoshi, M.; Kusumi, T. J. Org. Chem. 2008, 73, 4245e4247. 8. Zhang, D.; Yang, X.; Kang, J. S.; Choi, H. D.; Son, B. W. J. Antibiot. 2008, 61, 40e42. 9. Bock, M. G.; DiPardo, R. M.; Rittle, K. E.; Evans, B. E.; Freidinger, R. M.; Veber, D. F.; Chang, R. S. L.; Chen, T. B.; Keegan, M. E.; Lotti, V. J. J. Med. Chem.1986, 29,1941e1945.
10. Lopez-Gresa, M. P.; Gonzalez, M. C.; Primo, J.; Moya, P.; Romero, V.; Estornell, E. J. Antibiot. 2005, 58, 416e419. 11. (a) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep. Proced. Int. 1992, 24, 211; (b) Eguchi, S.; Okano, T. J. Synth. Org. Chem. Jpn. 1993, 51, 203; (c) Wamhoff, H.; Richard, G.; Stoelben, S. Adv. Heterocycl. Chem. 1995, 64, 159e249; (d) Molina, P.; Viliplana, M. J. Synthesis 1994, 1197e1218; (e) Gusar, N. I. Russ. Chem. Rev. 1991, 60, 146; (f) Ming-Wu, D.; Zhao-Jie, L. Chin. J. Org. Chem. 2001, 21, 1; (g) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301e3307; (h) Tseng, M. C.; Lai, C.-Y.; Chu, Y.-W.; Chu, Y. H. Chem. Commun. 2009, 445e447. 12. (a) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417e6418; (b) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehu, A.; Yashima, E.; Okamoto, Y. Tetrahedron 1998, 54, 7997e8008. 13. Witt, A.; Bergman, J. J. Org. Chem. 2001, 66, 2784e2788. 14. Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.; Springer, S. M.; Freidinger, R. M. J. Org. Chem. 1987, 52, 1646e1647. 15. Liu, J. F.; Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.; Yohannes, D.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 70, 10488e10493. 16. Tseng, M. C.; Yang, H. Y.; Chu, Y. H. Org. Biomol. Chem. 2010, 8, 419e427. 17. (a) Zhichkin, P. E.; Jin, X.; Zhang, H.; Peterson, L. H.; Ramirez, C.; Snyder, T. M.; Burton, H. S. Org. Biomol. Chem. 2010, 8, 1287; (b) Al-Said, N. H.; KhaledShawakfeh, Q.; MohammadIbrahim, I.; Sami, H. Tayyem Arkivoc 2010, (ix), 282e292. 18. Kshirsagar, U. A.; Argade, N. P. Org. Lett. 2010, 12 (16), 3716e3719. 19. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Rational Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond Formation; Acc. Chem. Res 1998, 31, 805e818; (b) Kirsch, G.; Hesse, S.; Comel, A. Curr. Org. Synth. 2004, 1, 47e63; (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Parisi, L. M. Tetrahedron Lett 2004, 45, 2431e2434; (d) Bacchi, A.; Costa, M.; Della Ca`, N.; Fabbricatore, M.; Fazio, A.; Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 574e585; (e) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101e4111; (f) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2115e2134; (g) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920e928. 20. Kamal, A.; Howard, P. W.; Reddy, N.; Reddy, P.; Thurston, D. E. Tetrahedron 1997, 53, 3223e3230. 21. Schmidt, Andreas; Shilabin, Abbas Gholipour; Nieger, M. Heterocycles 2005, 65 (3), 625e632. 22. Bose, D. S.; Chary, M. V. Synthesis 2010, 643e650. 23. Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemiere, G. L. H. Chem. Commun. 2004, 2466e2467.
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Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids and analogous Kumaraswamy Sorra a, b, *, K. Mukkanti b, Srinivas Pusuluri a a b
Chemistry Services, GVK Biosciences Private Limited, Plot No.5C, IDA Uppal, Hyderabad 500 039, AP, India Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 September 2011 Received in revised form 24 November 2011 Accepted 13 December 2011 Available online 19 December 2011
A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladiumcatalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine alkaloids such as circumdatin H, J and other analogues. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Quinazolinobenzodiazepine Circumdatin BuchwaldeHartwig amination Palladium Lawesson’s reagent
1. Introduction Benzodiazepines are an important class of compounds’ representing as a member of the family of privileged scaffold.1 A large number of structurally interesting and biologically important natural and synthetic benzodiazepines are known in the literature.2 Benzodiazepine with fused quinazoline system appears in a number of naturally occurring alkaloids, such as circumdatins, benzomalvins, asperlicin, sclerotigenin (Fig. 1).3e7
Fig. 1. Structures of known quinazolinobenzodiazepine alkaloids.
* Corresponding author. Tel.: þ91 40 67126600; fax: þ91 40 27208866; e-mail address: [email protected] (K. Sorra). 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.12.032
Circumdatins, a sub-group of fused quinazolinobenzodiazepine alkaloids (Fig. 1), were first isolated by Rahbæk et al. from a marine fungus Aspergillus ochraceus (subgenus Circumdati).3e7 They possess antitumour, antifungal, insecticide, antibiotic activities,4e6,8 cholescystokinin antagonism,9 inhibition of substance P33d and mitochondrial NADH oxidase.10 The quinazolinobenzodiazepine moiety has received much attention in the synthetic community due to it’s structural and biological attributed features. In the total synthesis of quinazolinobenzodiazepine alkaloids, various methods have been developed for the synthesis of quinazolino [1,4] benzodiazepine moiety in their skeleton. Primarily, the cyclization has been done via the aza-Wittig reaction, known as the Eguchi protocol.11,12 Though, it provided a direct route to heterocyclic natural products; this approach has a down side of using explosive 2-azidobenzoic acids. Witt and Bergman synthesized circumdatin F via iminobenzoxazine intermediate by the MazurkiewiczeGanesan protocol, but it requires longer synthetic sequences.13 Bock’s group afforded the asperlicins C and E by regioselective annulation of benzodiazepinedione with anthranilic acid.14 Liu and co-workers synthesized racemic quinazolinobenzodiazepine by means of a one-pot synthesis.15 And also, lately progress has been made using metal triflate catalyzed dehydrocyclization of tripeptide-anthranilate16 and reductive cyclization of the 2-nitrobenzamides affords the quinazolinone.17 Most recently, copper-catalyzed N-arylation of a quinazolinone led to the benzodiazepine ring system.18
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In this communication, we report a concise and preferably convergent route for the synthesis of highly enantiopure pyrrolo quinazolino [1,4] benzodiazepine-2,5-diones via amination/cyclization domino reaction of amidines with o-bromobenzoates under BuchwaldeHartwig conditions.19 The present work represents a considerably improved synthesis and we envisioned that this reaction would make possible a short synthesis of enantiopure pentacyclic circumdatin H, J and their analogues.
Table 1 Optimization chart of palladium catalyzed conditions for quinazolino [1,4] benzodiazepine
2. Results and discussion Palladium catalyzed amination and followed by intramolecular cyclization involving in the tandem carbonenitrogen bond formation were preformed on the amidine 4a,b, which can be synthesized in three steps from the commercially available L-Proline and isatoic anhydrides (Scheme 1). The cyclocondensation of equimolar of naturally occurring L-proline with isatoic anhydride (1a) and methoxy isatoic anhydride (1b) in DMF at 150 C for 5 h provided corresponding products 2a20 and 2b17 in 85e90% yields. The dilactam compound 2a,b subsequently converted to mono thiolactams 3a,b using 0.5 equiv Lawesson’s reagent in toluene at 70 C for 6 h.20 The thiolactam 3a,b was reacted with anhydrous NH3 and HgCl2 afforded the amidine 4a,b21 in 90% yield, which were chosen as key precursors for the quinazolinone ring formation.
Entry Pd source 1 2 3 4 5 6 7 8 9 10 11 12 13
Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd (dppf) Cl2 Pd (dppf) Cl2 Pd (PPh3)4 Pd (PPh3)4 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2 Pd (OAc)2
Ligand Xantphos Xantphos BINAP Aphos Xantphos BINAP Xantphos BINAP Xantphos BINAP Xantphos Xantphos Xantphos
Base Cs2CO3 NaO-t-Bu Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 NaO-t-Bu NaO-t-Bu NaO-t-Bu NaO-t-Bu Cs2CO3 Cs2CO3 Cs2CO3
Temperature ( C) Time e
100 130e 100e 100e 100e 130e 100e 100e 100e 100e 100e 100f 100g
16 h 16 h 16 h 16 h 16 h 16 h 16 h 16 h 12 h 12 h 12 h 24 h 15 min
Yield of 6a (%) (NR)b (NR)b (NR)b (NR)b 10 8 30 32 65c 53c 75d 55d 78d
a All reactions were run with 4a (0.23 mmol), 5a (0.23 mmol), base (0.46 mmol, 2 equiv), Pd catalyst (5 mol %) and ligand (10 mol %) in 1,4-dioxane (2 mL) under Ar. Isolated yields. b No reaction. c 70% ee. d >99% ee. e The reaction was performed in sealed tube under oil-bath heating. f The reaction was performed under conventional oil-bath heating. g The reaction was performed under microwave irradiation.
Scheme 1. Palladium catalyzed N-arylation and followed by intramolecular cyclization: synthesis of circumdatin H, J and analogues. Reagents and conditions: (a) L-proline, DMF, 140 C, 5 h, 85% yield (b) Lawesson’s reagent, toluene, 70 C, 5 h, 85% yield (c) NH3, HgCl2, THF, 60 C, 1 h, 90e95% yield (d) Pd (OAc)2, Xantphos, Cs2CO3, 1,4dioxane, 100 C, sealed tube, 12 h or MW, 15 min. 70e85% yield.
Palladium catalyzed annulation of model substrate 4a with 5a has been extensively investigated resulting in a substantial optimization. The formation of the quinazolinone ring, while preserving the chiral integrity has been studied by changing the reaction parameters (Table 1). Our studies began with Pd2 (dba)3 with various phosphine ligands (Xantphos/()-BINAP/Aphos) in the presence of
different bases (NaO-t-Bu/Cs2CO3/K3PO4) at elevated temperatures, which prove to be incapable of amination (entries 1e4). As an alternate palladium source, the use of Pd (dppf) Cl2 under the same reaction conditions gave compound 6 in 8e10% yield. The results encouraged us to examine various catalysts, in the due course Pd(PPh3)4eXantphos/()-BINAP gave a moderate yield (entries 7, 8) and Pd(OAc)2eXantphos has demonstrated more effective to get the cyclized compound. Finally, cyclization of compound 6 has been achieved in 75% yield (>99% ee) with 5 mol % of Pd(OAc)2 and 10 mol % Xantphos in the presence of 2 equiv of Cs2CO3 in 1,4dioxane at 100 C (entry 11). The analytical and spectral data for compound 6 were in complete agreement with the reported data.22 While Buchwald’s amination using Pd(OAc)2eXantphos in the presence of NaO-t-Bu gave us a disappointing enantiomeric purity (70% ee) (entries 9, 10). For further optimization of the reaction conditions using Pd(OAc)2/Xantphos/Cs2CO3 in 1,4-dioxane, we continued to examine reactions at various temperatures and reaction duration. The reaction has taken 24 h for completion under conventional heating at 100 C resulted in moderate yield (55%) (entry 12), but in sealed tube it was completed in 12 h with good yield (entry 11). The time duration tremendously reduced under microwave heating, microwave exposure to 5 min at 100 C resulted low yield (35%) due to the incompletion of the reaction, the best yield was obtained when the reaction was run at 100 C for 15 min provided the desired compound 6 in 78% yield (entry 13). Delightfully, the chiral integrity was preserved in all the cases. The enantiomeric purity was determined by the chiral HPLC area method with a comparison of racemic compound 6, which was synthesized similarly from the DL-proline. Subsequently, functionalized cyclic amidine and o-bromobenzoates were investigated under the above optimized conditions
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to achieve the total syntheses of natural pyrrolo quinazolino [1,4] benzodiazepine-2,5-dione alkaloids (Scheme 1). Circumdatin H (7), which contains an additional methoxy substituent, the synthesis was preceded uneventfully from compound 4a and 5-methoxy-2bromo benzoate 5b. Circumdatin J (8), which contains methoxy substituent on both benzodiazepine and quinazolino rings was afforded from compound 4b and compound 5b. Both the circumdatin H and J were synthesized in 75% yield with >99% ee. The analytical and spectral data for the ()-circumdatins H (7) and J (8) were in complete agreement with the reported data.10,17,22 The natural products circumdatin E and circumdatin D contains hydroxy functionality on quinazolinone ring along with the methoxy substituents, here we have synthesized the methoxy derivative of the circumdatin D (9) and E (10) in 72e75% yield with >99% ee and for our convenience we named them as methoxy circumdatin D and E, respectively. Most of the natural circumdatins have electron rich substituents, such as hydroxy and methoxy groups; herein we employed the optimized conditions on various substituted systems including both activating and deactivating groups to examine the competence of the ring substituents on the reaction conditions (Scheme 2). Compound 4a was reacted with the substituted 2bromo benzoates 5dei under the above described conditions to afford compound 11e16, respectively, significantly the reaction was completed much faster (8 h) and obtained >80% yield with the electron-withdrawing substitutes rather than donating substituents. These results envisaged that the reaction conditions are well tolerated by both electron-withdrawing and electrondonating substituents in the Csp2 donors.
Scheme 2. Synthesis of quinazolino [1,4] benzodiazepines from deactivated and activated aromatic rings.
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The proposed mechanistic way for quinazolinone cyclization is depicted in Scheme 3. In the first stage, the amination of AreBr (5a) with 4a via BuchwaldeHartwig approach of the palladium complex containing the chelating phosphine ligand produce the uncyclized aminated compound (17).19,23 In the next stage, the base catalyzed medium could trigger the intramolecular cyclization with the proximate nitrogen to lead the quinazolinobenzodiazepine ring system. 3. Conclusion We have developed a highly efficient and concise synthetic strategy for the total synthesis of enantiopure circumdatin alkaloids under palladium-catalyzed conditions. It features a quinazolino ring cyclization process as a key synthetic step with preserving the chiral integrity. This efficient strategy should allow easy access to a variety of quinazolino [1,4] benzodiazepine alkaloids and their analogues. 4. Experimental 4.1. General All reactions dealing with Palladium catalyst were conducted under an atmosphere of argon. The solvents were purified according to standard procedures prior to use, Pd catalysts, ligands and Cs2CO3 were purchased from Aldrich and all commercial chemicals were used as received. For thin-layer chromatography (TLC) analysis, Merck precoated Plates (silica gel 60 F254) were used and eluting solvents are indicated in the procedures. Merck silica gel 60 (230e400 mesh) was used for flash column chromatography. Melting point (mp) determinations were performed by using Meltemp apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Unity instrument at rt at 400 MHz. Chemical shifts are reported in d parts per million (ppm) downfield from tetramethylsilane (TMS) with reference to internal solvent and coupling constants in hertz. Mass spectra were obtained on Micromass QuattroMicroÔAPI-autospectrometer using APCI technique. HRMS TOF ES mass spectra were recorded on a WatersAlliance 2695 Separation Module/Q-TOF Micromass. Infrared (IR) spectra were recorded on a PerkineElmer FT-IR spectrometer. Optical rotations ([a]D) were measured on a JASCO P-1030 polarimeter and data are reported as follows: [a]D temp, concentration (c g/
Scheme 3. Mechanistic proposal for the Pd catalyzed amination and intramolecular cyclization.
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100 mL) and solvent. Liquid chromatography-mass spectrometry (LCMS) on a Waters Acquity UPLC photodiode array detector system using ESI technique under the following conditions: column used: Acquity-UPLC BEH-C18 (2.150 mm) 1.7 m, Mobile Phase: A: 0.025% aqueous CF3COOH, B:0.025% CF3COOH in acetonitrile, T/%B: 0/15, 3/95, 4/95, 4.1/15; flow rate: 0.4 mL/min, diluent: acetonitrile; UV: max-plot. Enantiomeric excess (ee) was determined by HPLC analysis using Chiralpak IA column (2504.6 mm), 5 m, hexane/ ethanol (1:1) with 0.1% isopropyl amine at 1.0 mL/min. All isolated compounds had purity greater than 99% (area percent) as judged by HPLC analysis area method. 4.1.1. (11aS)-11-Thioxo-1,2,3,10,11,11a-hexahydro-5H pyrrolo [2,1-c] [1,4]benzodiazepin-5-one (3a). To a suspension of dilactam compound 2a (1.0 g, 4.62 mmol) in 100 mL toluene was added Lawesson’s reagent (0.94 g, 2.31 mmol). The yellow suspension was heated to 70 C for 5 h. After this time a yellow solid has precipitated, which was recrystallized from ethanol to yield pure 3a (923 mg, 86% yield) as yellow crystals. Rf (50% EtOAc/pet ether) 0.50; mp 291e292 C; ½a27 D þ729.1 (c 1.08, DMSO); nmax (KBr) 3446, 3171, 2943, 1616, 1605, 1521. 1417, 1374, 1270, 1141, 1030, 886, 832, 813, 753, 695 cm1; dH (400 MHz, CDCl3) 9.73 (1H, br, NH), 8.04 (1H, d, J¼8.0 Hz, ArH), 7.53e7.49 (1H, m, ArH), 7.37e7.33 (1H, m, ArH), 7.05 (1H, d, J¼8.4 Hz, ArH), 4.22 (1H, d, J¼7.6 Hz, NCH), 3.80e3.77 (1H, m, CH2), 3.64e3.57 (1H, m, CH2), 3.13e3.08 (1H, m, CH2), 2.31e2.22 (1H, m, CH2), 2.18e2.08 (1H, m, CH2), 2.03e1.97 (1H, m, CH2); dC (100 MHz, DMSO-d6) 201.9, 164.1, 136.4, 132.1, 130.2, 127.7, 125.6, 121.8, 59.7, 46.8, 28.9, 22.6; MS (APCI) m/z 233 (MHþ); HRMS (TOF ESþ): MHþ, found 233.0738. C12H13N2OS requires 233.0749. 4.1.2. (11aS)-7-Methoxy-11-thioxo-1,2,3,10,11,11a-hexahydro-5Hpyrrolo[2,1-c][1,4]benzodiazepin-5-one (3b). Dilactam compound 2b (3 g, 12.19 mmol) was converted to 3b using the procedure for the preparation of 3a. This gave yellow solid; 85% yield; Rf (50% EtOAc/ pet ether) 0.50; mp 196e197 C; ½a26 D þ 632 (c 1.02, MeOH); nmax (KBr) 3467, 3247, 2958, 1627, 1606, 1497, 1434, 1385, 1301, 1245, 1164, 1095, 1026, 872, 820, 788, 630 cm1; dH (400 MHz, CDCl3) 9.65 (1H, br, NH), 7.50 (1H, d, J¼2.8 Hz, ArH), 7.06 (1H, dd, J¼8.8, 3.2 Hz, ArH), 7.0 (1H, d, J¼8.8 Hz, ArH), 4.19 (1H, d, J¼7.2 Hz, NCH), 3.93 (3H, s, OCH3), 3.84e3.76 (1H, m, CH2), 3.63e3.56 (1H, m, CH2), 3.12e3.08 (1H, m, CH2), 2.32e2.23 (1H, m, CH2), 2.16e1.96 (2H, m, CH2); dC (100 MHz, CDCl3) 200.8, 164.9, 157.6, 129.6, 129.2, 122.5, 120.1, 113.5, 60.1, 55.8, 47.3, 29.5, 22.9; MS (APCI) m/z 263 (MHþ); HRMS (TOF ESþ): MHþ, found 263.0875. C13H15N2O2S requires 263.0854. 4.1.3. (S)-11-Aminio-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a] [1,4] diazepine-5 (11aH)-one (4a). A suspension of 3a (2.5 g, 10.77 mmol) and mercuric chloride (3.5 g, 12.93 mmol, 1.2 equiv) in dry THF (125 mL) was warmed to 60 C and an ammonia stream was bubbled into the solution. After 1 h, the solution became black (formation of mercuric sulfide), the stream of ammonia was stopped and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through Celite, washed with a mixture of methanol/THF, the combined filtrate was concentrated, the solid residue was washed with acetone and Et2O and dried to give the amidine 4a as pale yellow solid. 95% yield; Rf (15% MeOH/CHCl3) 0.40; mp 314e315 C; ½a26 D þ582.3 (c 1.04, DMSO); nmax (KBr) 3541, 3365, 3128. 1673, 1616, 1580, 1453, 1403, 1257, 1239, 1149, 762, 702 cm1; dH (400 MHz, DMSO-d6) 7.75 (1H, d, J¼8.0 Hz, ArH), 7.44 (1H, t, J¼7.6 Hz, ArH), 7.40e7.20 (2H, m, NH2), 7.12 (1H, t, J¼8.4 Hz, ArH), 7.06 (1H, d, J¼7.6 Hz, ArH), 4.06 (1H, d, J¼6.8 Hz, NCH), 3.66e3.61 (1H, m, CH2), 3.41e3.34 (2H, m, CH2), 2.13e2.05 (1H, m, CH2), 1.98e1.91 (2H, m, CH2); dC (100 MHz, DMSO-d6) 164.8, 161.9, 143.6, 129.9, 126.7, 126.5, 124.9, 122.5, 54.1, 46.4, 26.0,
23.3; MS (APCI) m/z 216 (MHþ); HRMS (TOF ESþ): MHþ, found 216.1129. C12H14N3O requires 216.1137. 4.1.4. (S)-11-Aminio-7-methoxy-2,3-dihydro-1H-benzo[e] pyrrolo [1,2-a][1,4]diazepine-5 (11aH)-one (4b). Thiolactam 3b (2.5 g, 9.54 mmol) was converted to 4b using the procedure for the preparation of 4a. This gave off white solid, 90% yield; Rf (15% MeOH/CHCl3) 0.40; mp 189e190 C; ½a26 D þ615.9 (c 1.05, DMSO); nmax (KBr) 3389, 3325, 3206, 1609, 1488, 1437, 1405, 1267, 1228, 1034, 834, 762 cm1; dH (400 MHz, DMSO-d6) 7.40e7.20 (3H, br, NH2 and ArH), 71.2e7.06 (2H, m, ArH), 4.13 (1H, d, J¼7.2 Hz, NCH), 3.77 (3H, s, OCH3), 3.67e3.62 (1H, m, CH2), 3.40e3.36 (2H, m, CH2), 2.12e2.08 (1H, m, CH2), 2.05e1.96 (2H, m, CH2); dC (100 MHz, DMSO-d6) 164.5, 161.3, 154.7, 127.6, 126.4, 123.0, 119.2, 112.4, 55.3, 54.0, 46.4, 26.0, 23.3; MS (APCI) m/z 246 (MHþ).
4.2. General procedure for the Pd catalyzed synthesis of quinazolinone [1,4] benzodiazepine Method A: A sealed tube was charged with compound 4a,b (0.93 mmol), 5aee (0.93 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv of Cs2CO3 (1.86 mmol) and 10 mL of 1,4-dioxane. The mixture was degassed and backfilled with argon, the reaction vessel was sealed with a Teflon tap and heated at 100 C for 12 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in chloroform, washed with 10% citric acid solution, brine solution, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by flash column chromatography using 3e5% of MeOH/CHCl3 as an eluent to give the title cyclized compound. Method B: To a thick-well borosilicate glass vial (5 mL) was added compound 4a,b (0.23 mmol), compound 5aee (0.23 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv Cs2CO3 (0.46 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and the reaction vial was sealed and placed in the CEM-DISCOVER microwave reactor and irradiated at 100 C for 15 min. After cooled to rt, the product was isolated as above described in method A. 4.2.1. (S)-()-Desmethoxy circumdatin H (6). Pale yellow solid; method A: 75% yield, method B: 78% yield; Rf (10% MeOH/CHCl3) 0.60; mp 251e252 C; ½a27 D 123.5 (c 0.54, MeOH); nmax (KBr) 3435, 3067, 2972, 2879, 1690. 1643, 1615, 1473, 1450, 1417, 1362, 1295, 1251, 1215, 1115, 1021, 973, 897, 782, 778, 764, 704 cm1; dH (400 MHz, DMSO-d6) 8.18 (1H, d, J¼8.0 Hz, ArH), 7.89 (1H, t, J¼7.2 Hz, ArH), 7.83 (1H, d, J¼7.6 Hz, ArH), 7.74 (1H, d, J¼8.4 Hz, ArH), 7.67e7.56 (4H, m, ArH), 4.64 (1H, d, J¼6.4 Hz, NCH), 3.63e3.59 (1H, m, CH2), 3.49e3.42 (1H, m, CH2), 2.94e2.93 (1H, m, CH2), 2.16e2.08 (2H, m, CH2), 1.99e1.98 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.7, 153.6, 146.1, 134.1, 133.2, 132.3, 130.7, 129.9, 128.6, 128.3, 127.6, 127.5, 127.4, 121.4, 58.8, 46.4, 26.9, 23.6; MS (APCI) m/z 318 (MHþ); HRMS (TOF ESþ): MHþ, found 318.1205. C19H16N3O2 requires 318.1243. 4.2.2. (S)-()-Circumdatin H (7). Pale yellow solid; method A: 75% yield, method B: 79% yield; Rf (10%MeOH/CHCl3) 0.55; mp 216e217 C; ½a29 D 106 (c 0.82, MeOH); nmax (KBr) 3435, 3065, 2972, 1692, 1646, 1619, 1491, 1456, 1423, 1361, 1278, 1235, 1022, 875, 832, 789, 761, 707 cm1; dH (400 MHz, CDCl3) 7.99 (1H, d, J¼7.2 Hz, ArH), 7.67 (1H, d, J¼2.8 Hz, ArH), 7.64 (1H, d, J¼8.8 Hz, ArH), 7.58e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼8.8, 2.8 Hz, ArH), 4.54 (1H, d, J¼8.0 Hz, NCH), 3.93 (3H, s, OCH3), 3.82e3.77 (1H, m, NCH2), 3.64e3.57 (1H, m, CH2), 3.18e3.14 (1H, m, CH2), 2.32e2.30 (1H, m, CH2), 2.17e2.12 (1H, m, CH2), 2.10e2.05 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.6, 158.9, 151.5, 140.5, 133.4, 132.4, 130.7, 129.9, 129.1, 128.6, 128.3, 124.8, 122.3, 106.9, 58.7, 55.8, 46.5, 26.9, 23.7; MS
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(APCI) m/z 348 (MHþ); HRMS (TOF ESþ): MHþ, found 348.1338. C20H18N3O3 requires 348.1348. 4.2.3. (S)-()-Circumdatin J (8). Pale yellow solid; method A: 75% yield; Rf (10% MeOH/CHCl3) 0.50; mp 189e191 C; ½a29 D 63.2 (c 1.19, 1:1 MeOH/CH2Cl2); nmax (KBr) 3436, 2936, 2875, 1687, 1633, 1617, 1491, 1465, 1439, 1368, 1282, 1238, 1029, 869, 835, 771 cm1; dH (400 MHz, CDCl3) 7.67 (1H, d, J¼2.8 Hz, ArH), 7.63 (1H, d, J¼8.8 Hz, ArH), 7.47 (1H, d, J¼8.8 Hz, ArH), 7.46 (1H, d, J¼2.0 Hz, ArH), 7.37 (1H, dd, J¼8.8, 2.8 Hz, ArH), 7.11 (1H, dd, J¼9.2, 3.2 Hz, ArH), 4.56 (1H, d, J¼4.2 Hz, ArH), 3.92 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.80e3.75 (1H, m, NCH), 3.64e3.58 (1H, m, CH2), 3.18e3.13 (1H, m, CH2), 2.32e2.29 (1H, m, CH2), 2.17e2.12 (1H, m, CH2), 2.11e2.05 (1H, m, CH2); dC (100 MHz, CDCl3) 164.3, 161.7, 159.1, 158.9, 151.6, 140.6, 133.5, 129.7, 129.1, 126.2, 124.7, 122.3, 117.9, 112.9, 106.8, 58.8, 55.8, 55.7, 46.5, 26.9, 23.6; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1469. C21H20N3O4 requires 378.1454. 4.2.4. (S)-()-Methoxy circumdatin E (9). Off white solid; method A and B: 75% yield; Rf (10%MeOH/CHCl3) 0.50; mp 263e264 C; ½a28 D 145 (c 0.38, 1:1 MeOH/CHCl3); nmax (KBr) 3432, 2924, 2851, 1647, 1457, 1375, 1260, 1214, 1099, 1048, 1020, 836, 789, 669 cm1; dH (400 MHz, DMSO-d6) 7.83 (1H, d, J¼6.4 Hz, ArH), 7.64e7.57 (3H, m, ArH), 7.13 (1H, d, J¼2.4 Hz, ArH), 7.01 (1H, d, J¼2.8 Hz, ArH), 4.60 (1H, d, J¼6.0 Hz, NCH), 3.94 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.57e3.55 (1H, m, CH2), 3.48e3.46 (1H, m, CH2), 3.0e2.95 (1H, m, CH2), 2.18e2.11 (2H, m, CH2), 2.01e1.95 (1H, m, CH2); dC (100 MHz, CDCl3) 164.5, 161.5, 159.5, 156.0, 150.6, 133.4, 132.3, 131.7, 130.7, 129.8, 128.6, 128.3, 123.2, 106.0, 98.1, 58.9, 56.5, 55.8, 46.5, 27.0, 23.8; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1469. C21H20N3O4 requires 378.1454. 4.2.5. (S)-()-Methoxy circumdatin D (10). Pale yellow solid; method B: 72% yield; Rf (10% MeOH/CHCl3) 0.50; mp 171e173 C; ½a28 D 98.6 (c 0.53, CHCl3); nmax (KBr) 3435, 2925, 2857, 1636, 1615, 1457, 1377, 1282, 1236, 1214, 1160, 1057, 1040, 842, 772, 669 cm1; dH (400 MHz, DMSO-d6) 7.50 (1H, d, J¼9.2 Hz, ArH), 7.27 (1H, d, J¼2.4 Hz, ArH), 7.20 (1H, dd, J¼8.8, 3.2 Hz, ArH), 7.12e7.10 (1H, m, ArH), 7.01 (1H, d, J¼2.4 Hz, ArH), 4.62 (1H, d, J¼5.6 Hz, NCH), 3.94 (3H, s, OCH3), 3.78 (6H, s, OCH3, OCH3), 3.55e3.46 (2H, m, CH2), 3.0e2.95 (1H, m, CH2), 2.15e2.10 (2H, m, CH2), 2.01e1.95 (1H, m, CH2); dC (100 MHz, CDCl3) 164.4, 161.7, 159.4, 159.1, 155.9, 150.7, 133.4, 131.7, 129.6, 126.2, 123.2, 117.9, 112.8, 105.9, 98.0, 58.9, 56.5, 55.8, 55.7, 46.5, 27.0, 23.8; MS (APCI) m/z 408 (MHþ); HRMS (TOF ESþ): MHþ, found 408.1543. C22H22N3O5 requires 408.1559. 4.2.6. Compound (11). Yellow solid; method A: 82% yield, method B: 70% yield; Rf (10% MeOH/CHCl3) 0.60; mp 239e240 C; ½a27 D 18.3 (c 0.76, CHCl3); nmax (KBr) 3447, 3082, 2957, 2883, 1699, 1683, 1654, 1611, 1577, 1523, 1454, 1412, 1344, 1278, 1242, 1183, 1122, 1090, 849, 824, 787, 750, 717, 694 cm1; dH (400 MHz, CDCl3) 9.17 (1H, d, J¼2.8 Hz, ArH), 8.59 (1H, dd, J¼8.8, 2.8 Hz, ArH), 8.03 (1H, d, J¼8.0 Hz, ArH), 7.86 (1H, d, J¼8.8 Hz, ArH), 7.64e7.55 (3H, m, ArH), 4.59 (1H, d, J¼7.6 Hz, NCH), 3.83e3.80 (1H, m, CH2), 3.63e3.61 (1H, m, CH2), 3.18e3.14 (1H, m, CH2), 2.32e2.30 (1H, m, CH2), 2.20e2.10 (2H, m, CH2); dC (100 MHz, CDCl3) 164.1, 160.5, 156.9, 150.2, 146.2, 132.3, 132.2, 131.0, 131.2, 129.3, 129.2, 128.9, 127.9, 123.9, 121.1, 58.9, 46.6, 27.0, 23.6; MS (APCI) m/z 363 (MHþ); HRMS (TOF ESþ): MHþ, found 363.1091. C19H15N4O4 requires 363.1093. 4.2.7. Compound (12). Pale yellow solid; method A: 76% yield, method B: 85% yield; Rf (10% MeOH/CHCl3) 0.50; mp 264e265 C; ½a26 D 75.1 (c 0.69, MeOH); nmax (KBr) 3436, 3088, 2954, 1703, 1646, 1610, 1476, 1457, 1365, 1273, 1159, 1102, 978, 869, 781, 706 cm1; dH (400 MHz, CDCl3) 8.34e8.30 (1H, m, ArH), 8.0 (1H, d, J¼7.2 Hz,
2005
ArH), 7.59e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼10.0, 2.4 Hz, ArH), 7.23 (1H, dd, J¼8.4, 2.4 Hz, ArH), 4.54 (1H, d, J¼7.2 Hz, NCH), 3.82e3.77 (1H, m, CH2), 3.64e3.59 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.31e2.29 (1H, m, CH2), 2.18e2.06 (2H, m, CH2); dC (100 MHz, CDCl3) 168.0, 165.4, 164.3, 160.9, 154.9, 148.4, 148.2, 132.6, 138.8, 130.5, 130.1, 128.5, 118.2, 116.3, 113.2, 58.9, 46.5, 26.9, 23.6; MS (APCI) m/z 336 (MHþ); HRMS (TOF ESþ): MHþ, found 336.1110. C19H15N3O2F requires 336.1148. 4.2.8. Compound (13). White solid; method A: 80% yield; Rf (10% MeOH/CHCl3) 0.60; mp 197e200 C; ½a28 D 77.56 (c 0.52, CHCl3); nmax (KBr) 3434, 3053, 2925, 1697, 1648, 1615, 1466, 1418, 1363, 1276, 1074, 829, 721 cm1; dH (400 MHz, CDCl3) 8.27 (1H, m, ArH), 8.0 (1H, d, J¼8.0 Hz, ArH), 7.74e7.73 (1H, m, ArH), 7.72 (1H, m, ArH), 7.67e7.26 (3H, m, ArH), 4.54 (1H, d, J¼7.6 Hz, NCH), 3.83e3.77 (1H, m, CH2), 3.64e3.57 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.31e2.05 (3H, m, CH2); dC (100 MHz, CDCl3) 164.5, 160.9, 154.1, 144.8, 135.3, 133.6, 133.1, 132.5, 131.0, 130.2, 129.4, 129.0, 128.4, 126.9, 122.8, 59.0, 46.7, 27.2, 23.8; MS (APCI) m/z 352 (MHþ); HRMS (TOF ESþ): MHþ, found 352.0878. C19H15N3O2Cl requires 352.0853. 4.2.9. Compound (14). Yellow solid; method A: 82% yield; Rf (10% MeOH/CHCl3) 0.60; mp 267e269 C; ½a28 D 79.85 (c 0.51, 1:1 MeOH/CHCl3); nmax (KBr) 3435, 3047, 2926, 2229, 1700, 1686, 1644, 1609, 1594, 1484, 1417, 1364, 1248, 1217, 839 cm1; dH (400 MHz, CDCl3) 8.63 (1H, s, ArH), 8.03e8.97 (2H, m, ArH), 7.81 (1H, d, J¼8.4 Hz, ArH), 7.64e7.54 (3H, m, ArH), 4.57 (1H, d, J¼6.8 Hz, NCH), 3.83e3.79 (1H m, CH2), 3.64e3.57 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.32e2.09 (3H, m, CH2); dC (100 MHz, CDCl3) 164.1, 160.2, 156.5, 148.7, 136.6, 132.7, 132.4, 132.2, 130.9, 130.1, 129.2, 128.9, 127.9, 122.1, 117.7, 111.1, 58.9, 46.6, 27.0, 23.6; MS (APCI) m/z 343 (MHþ); HRMS (TOF ESþ): MHþ, found 343.1181. C20H15N4O2 requires 343.1195. 4.2.10. Compound (15). Off white solid; method A: 72% yield; Rf (10%MeOH/CHCl3) 0.30; mp 297e299 C; ½a26 D 111.99 (c 0.52, DMSO); nmax (KBr) 3435, 3305, 3070, 2926, 1690, 1616, 1543, 1492, 1457, 1420, 1361, 1312, 1251, 1163, 1011, 897, 845, 710 cm1; dH (400 MHz, DMSO-d6) 10.35 (1H, s, AceNH), 8.47 (1H, s, ArH), 8.02 (1H, d, J¼8.8 Hz, ArH), 7.82 (1H, d, J¼7.6 Hz, ArH), 7.71e7.55 (4H, m, ArH), 4.62 (1H, d, J¼6.8 Hz, NCH), 3.60e3.58 (1H, m, CH2), 3.48e3.41 (1H, m, CH2), 2.90 (1H, m, CH2), 2.15e2.01 (5H, m, CH2, COCH3), 1.97 (1H, m, CH2); dC (100 MHz, DMSO-d6) 168.6, 163.4, 161.1, 152.9, 141.3, 138.5, 133.1, 132.1, 130.5, 129.0, 128.4, 127.9, 126.2, 121.3, 114.8, 58.4, 46.0, 26.36, 23.98, 23.18; MS (APCI) m/z 375 (MHþ); HRMS (TOF ESþ): MHþ, found 375.1445. C21H19N4O3 requires 375.1457. 4.2.11. Compound (16). Off white solid; method A: 78% yield; Rf (10%MeOH/CHCl3) 0.50; mp 276e278 C; ½a26 D 123.83 (c 0.51, 1:1 MeOH/CHCl3); nmax (KBr) 3447, 2957, 2929, 1682, 1651, 1609, 1500, 1458, 1394, 1359, 1302, 1242, 1202, 1155, 1001, 870 cm1; dH (400 MHz, CDCl3) 7.99 (1H, d, J¼7.6 Hz, ArH), 7.63 (1H, s, ArH), 7.58e7.49 (3H, m, ArH), 7.11 (1H, s, ArH), 4.53 (1H, d, J¼8.0 Hz, NCH), 4.05 (3H, s, OCH3), 4.0 (3H, s, OCH3), 3.82e3.77 (1H, m, CH2), 3.65e3.58 (1H, m, CH2), 3.17e3.12 (1H, m, CH2), 2.35e2.28 (1H, m, CH2), 2.20e2.04 (2H, m, CH2); dC (100 MHz, CDCl3) 164.5, 161.0, 155.2, 152.5, 149.5, 142.3, 133.4, 132.3, 130.5, 129.8, 128.5, 128.4, 114.8, 108.1, 106.4, 58.7, 56.4, 56.3, 46.4, 26.9, 23.7; MS (APCI) m/z 378 (MHþ); HRMS (TOF ESþ): MHþ, found 378.1412. C21H20N3O4 requires 378.1412. Acknowledgements The authors are grateful to the GVK Biosciences management for the financial support and encouragement. We are thankful to
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Dr. Srinivasa Rao Alapati and Dr. Balaram Patro for their valuable suggestions and support. Supplementary data The 1H NMR and 13C NMR copies of all compounds were attached. Supplementary data associated with this article can be found in the online version, at doi:10.1016/j.tet.2011.12.032. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513e521. 2. (a) Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini, C. Curr. Med. Chem. 2007, 14, 2680e2701; (b) Lueddens, H.; Korpi, E. R. Handbook of Contemporary Neuropharmacology; JohnWiley and Sons: NewYork, NY, 2007; Vol. 2; p 93; (c) Bacon, E. R.; Chatterjee, S.; Williams, M. Comprehensive Medicinal Chemistry II; Elsevier: Amsterdam, 2006; Vol. 6; p 139. 3. (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R. S. L.; Lotti, V. J.; Chen, T. B. J. Antibiot. 1985, 38, 1633e1637; (b) Chang, R. S. L.; Lotti, V. J.; Monaghan, R. L.; Birnbaum, J.; Stapley, E. O.; Goetz, M. A.; Albers-Schonberg, G.; Patchett, A. A.; Liesch, J. M.; Hensens, O. D.; Springer, J. P. Science 1985, 230, 177e179; (c) Goetz, M. A.; Monaghan, R. L.; Chang, R. S. L.; Ondeyka, J.; Chen, T. B.; Lotti, V. J. J. Antibiot. 1988, 41, 875e877; (d) Sun, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A. M.; Cooper, R. J. Antibiot. 1994, 47, 515e522; (e) Joshi, B. K.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 1999, 62, 650e652. 4. Dai, J.-R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L. S.; Ng, S. W.; Huang, Y.; Butler, M. S. J. Nat. Prod 2001, 64, 125e126. 5. Raebaek, L.; Breinholt, J. J. Nat. Prod 1999, 62, 904e905. 6. Raebaek, L.; Breinholt, J.; Frisvald, J. C.; Christopherson, C. J. Org. Chem 1999, 64, 1689e1692. 7. The structure of circumdatins A and B was recently revised, see: Ookura, R.; Kito, K.; Ooi, T.; Namikoshi, M.; Kusumi, T. J. Org. Chem. 2008, 73, 4245e4247. 8. Zhang, D.; Yang, X.; Kang, J. S.; Choi, H. D.; Son, B. W. J. Antibiot. 2008, 61, 40e42. 9. Bock, M. G.; DiPardo, R. M.; Rittle, K. E.; Evans, B. E.; Freidinger, R. M.; Veber, D. F.; Chang, R. S. L.; Chen, T. B.; Keegan, M. E.; Lotti, V. J. J. Med. Chem.1986, 29,1941e1945.
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