Asymmetric Synthesis of Tropanes by Rhodium-Catalyzed [4+3] Cycloaddition.

Transcription

1 Asymmetric Synthesis of Tropanes by Rhodium-Catalyzed [4+3] Cycloaddition. Ravisekhara P. Reddy and Huw M. L. Davies* Department of Chemistry, University at Buffalo, The State University of ew York, Buffalo, Y Supporting Information Experimental Procedures S-2 to S-10 Spectral Data S-11 to S-17 S-1

2 General Information: Commercial reagents from Aldrich Chemical Company and Acros Organics were purchased at the highest commercial purity and used without further purification unless otherwise stated. All reactions were performed using glassware that was oven dried overnight (60 C) and then flame dried under vacuum prior to use. Tetrahydrofuran (THF), hexanes, dichloromethane (DCM), acetonitrile and toluene were used either directly from a solvent purification system (solvent was passed through two columns of activated alumina) purchased from MBRAU. 2,2-dimethylbutane (2,2-DMB) was purchased from Lancaster Synthesis, passed through activated silica gel (heated to 120 C overnight) and distilled from sodium under argon. All other solvents were of reagent grade. - pyrrole was purified by bulb-to-bulb kugelrohr distillation immediately before use. Hydrogenations were carried out using a Parr hydrogenator at the specified H 2 pressure. Reaction solvents used in rhodium carbenoid transformations were degassed by bubbling argon gas through for 15 to 20 minutes prior to use. Organic reaction mixtures were concentrated using a Buchi rotary evaporator. Optical rotations were measured using a Jasco DIP-370 digital polarimeter. Analytical TLC was performed on 250µm Whatman silica gel (Aluminum backing, UV 254 nm) plates using UV light and phosphomolybdic acid (10% in ethanol) as visualizing agents. Column chromatography was carried out using E. Merck silica 60 ( mesh). 1 H MR spectra were recorded on a Varian uclear Magnetic Resonance spectrometer at 300, 400, or 500 MHz and 13 C spectra were recorded at 75 or 125 MHz, with the sample solvent being CDCl 3, unless otherwise noted. The following abbreviations are used to explain the multiplicities: b, broad; s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet S-2

3 of doublets; dt, doublet of triplets; dq, doublet of quartets; ddd, doublet of doublet of doublets. Infrared spectra were obtained on a icolet Impact 420 FT-IR spectrometer. High-resolution mass spectra were obtained from the Mass Spectroscopy Facility at the University at Buffalo, The State University of ew York. Diastereomeric ratios were determined by values derived from the 500 MHz 1H MR spectra of the crude reaction. Enantiomeric excess was determined by high performance liquid chromatography (HPLC) using chiral analytical columns (specified for each compound) with i-propanol (ipa) in hexane as the eluent (% ipa specified for each compound). The compounds tert-butyl 1H-pyrrole-1-carboxylate (7), 1-phenyl-1H-pyrrole (14), 1-ptolyl-1H-pyrrole (15) were purchased from Aldrich and the compounds tert-butyl 2- methyl-1h-pyrrole-1-carboxylate (1) 1, methyl-2-diazobut-3-enoate (2) 2, 3-(tert-butyldimethyl-silanyloxy)-2-diazo-but-3-enoic acid methyl ester (10) 3, tert-butyl -2,5- dimethyl-1h-pyrrole-1-carboxylate (12) 1, 1-tert-butyl 2-methyl 1H-pyrrole-1,2- dicarboxylate (13) 4, tert-butyl 4,5,6,7-tetrahydroindole-1-carboxylate (16) 1 were prepared by literature procedures and the spectral data showed good agreement with the literature data. General Procedure: To a solution of pyrrole (0.19 mmol) and the catalyst Rh 2 (S- PTAD) 4 (3.0 mg, 1 mol %) in freshly distilled 2,2-dimethylbutane (10 ml) at 50 o C was added a solution of 10 (100 mg, 0.39 mmol, 2 equiv) in 2,2-dimethylbutane (5 ml) over 60 min via syringe pump. The reaction mixture was stirred for a further 60 min at 50 o C 1 Davies, H. M. L.; Matasi, J. J.; Hodges, M. L.; Huby,. J. S.; Thornley, C.; Kong,.; Houser, J. H. J. Org. Chem. 1997, 62, Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc. 1996, 118, Bernard, H.; Buelow, G.; Lange, U. E. W.; Mack, H.; Pfeiffer, T.; Schaefer, B.; Seitz, W.; Zierke, T. Synthesis, 2004, 14, S-3

4 and then cooled. The solvent was removed under reduced pressure and the crude mixture was purified by flash column chromatography to give the pure product. 1698, 1605, 1366, 1200 cm -1 ; 1 H MR (500 MHz, CDCl 3 ) δ 6.46 (bs, 0.3H, minor rotamer), 6.43 (bs, 0.7H, major rotamer), 5.89 (bs, 1H), 5.18 (bs, 0.3H, minor rotamer), 5.09 (bs, 0.7H, major rotamer), 4.64 (bs, 0.7H, major rotamer), 4.59 (bs, 0.3H, minor rotamer), 3.69 (s, 3H), 2.85 (bd, J = 18Hz, 0.7H, major rotamer), 2.69 (bd, J = 18Hz, 0.3H, minor rotamer), 1.82(d, J = 18 Hz, 0.3H, minor rotamer), 1.78 (d, J = 18Hz, 0.7H, major rotamer), 1.40 (s, 9H), 0.91(s, 9H), 0.15(s, 2H, minor rotamer), 0.14(s, 4H, major rotamer); 13 C MR (75 MHz, CDCl 3 ) δ 165.5, 157.8, 153.2, 137.9, 127.6, 114.9, 79.8, 56.4, 55.9, 50.8, 32.5, 28.2, 25.5, 18.2, -3.9; HPLC analysis: (92% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 17.7 min (minor), 18.9 min (major); HRMS (ESI) m/z Calcd for [M+a] + (C 20 H 33 O 5 Si+a) + : found: (tert-Butyl-dimethyl-silanyloxy)-8-aza-bicyclo[3.2.1]octa-2,6-diene-2,8- dicarboxylic acid 8-tert-butyl ester 2-methyl ester (11): colorless oil (86% yield); R f = 0.42 (8:1 hexanes:ethyl acetate); [α] 25 D (c = 0.63, CHCl 3 ); FTIR (neat) 2946, 2852, 3-(tert-Butyl-dimethyl-silanyloxy)-5-methyl-8-aza-bicyclo[3.2.1]octa-2,6-diene-2,8- dicarboxylic acid 8-tert-butyl ester 2-methyl ester (17): colorless oil (69% yield); R f = 0.55 (6:1 pentane:ether); [α] 25 D (c = 0.55, CHCl 3 ); FTIR (neat) 2950, 2929, 2856, 1716, 1694, 1365, 1167, 842 cm -1 ; 1 H MR (500 MHz, CDCl 3 ) δ 6.24 (s, 1H), 5.78 (s, S-4

5 1H), 4.64 (s, 1H), 3.69 (s, 3H), 2.90 (bs, 1H), 1.80 (d, J = 18.0 Hz, 1H),1.67 (bs, 3H), 1.44 (s, 9H), 0.86 (s, 9H), 0.12 (s, 6H); 13 C MR (75 MHz, CDCl 3 ) δ 167.3, 164.2, 150.0, 144.2, 124.2, 121.4, 80.1, 62.9, 58.7, 51.0, 31.2, 28.3, 25.5, 20.4, 17.9, -3.6; HPLC analysis: (96% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 9.5 min (minor), 10.7 min (major); HRMS (ESI) m/z Calcd for [M+a] + (C 21 H 35 O 5 Si+a) + : found: (tert-Butyl-dimethyl-silanyloxy)-1,5-dimethyl-8-aza-bicyclo[3.2.1]octa-2,6-diene- 2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (18): colorless oil (72% yield); R f = 0.58 (9:1 pentane:ether); [α] 25 D (c = 1.87, CHCl 3 ); FTIR (neat) 2962, 2925, 2856, 1700, 1354, 1332, 1254, 1168, 1054, 843, 772 cm -1 ; 1 H MR (400 MHz, CDCl 3 ) δ 6.08 (d, J = 6.0Hz, 1H), 5.46 (d, J = 6.0, 1H), 3.70 (s, 3H), 2.86 (d, J = 17.2 Hz, 1H), 1.75 (d, J = 17.2Hz, 1H), 1.67 (s, 6H), 1.44 (s, 9H), 0.87 (s, 9H), 0.13 (s, 6H); 13 C MR (75 MHz, CDCl 3 ) δ 167.8, 165.0, 151.7, 140.9, 131.1, 121.3, 80.2, 66.0, 65.8, 51.1, 37.6, 28.3, 25.5, 23.7, 21.8, 17.9, -3.5; HPLC analysis: (92% ee), Chiralcel OD-H, 0.50 ml/min, 0.2% i-propanol in hexane, 21.5 min (major), 25.6 min (minor); HRMS (ESI) m/z Calcd for [M+a] + (C 22 H 37 O 5 Si+a) + : found: (tert-Butyl-dimethyl-silanyloxy)-8-aza-bicyclo[3.2.1]octa-3,6-diene-1,4,8- tricarboxylic acid 8-tert-butyl ester 1,4-dimethyl ester (19): colorless oil (71% yield); S-5

6 R f = 0.3 (5:1 pentane:ether); [α] 25 D (c = 0.73, CHCl 3 ); FTIR (neat) 2947, 2931, 2856, 1746, 1712, 1603, 1434, 1368, 1307, 1203, 1082, cm -1 ; 1 H MR (500 MHz, CDCl 3 ) δ 6.57 (bs, 0.4 H, minor rotamer), 6.53 (bs, 0.6 H, major rotamer), 5.77 (bs, 1H), 5.27 (s, 0.4H, minor rotamer), 5.18 (s, 0.6 H, major rotamer), 3.82 (s, 3H), 3.72 (s, 3H), 3.26 (d, J = 18.0 Hz, 0.6 H, major rotamer), 3.07 (d, J = 18.0 Hz, 0.4 H, major rotamer), 2.14 (d, J = 18.0 Hz, 1H), 1.38 (s, 9H), 0.93 (s, 9H), 0.19 (s, 6H); 13 C MR (75 MHz, CDCl 3 ) δ 170.5, 165.3, 158.8, 138.2, 128.2, 123.4, 114.1, 81.1, 67.3, 58.4, 52.7, 51.0, 33.4, 28.1, 25.3, 18.2, -3.9; HPLC analysis: (92% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 14.6 min (major), 42.5 min (minor); HRMS (ESI) m/z Calcd for [M] + (C 22 H 35 O 7 Si+a) + : found: Ph 3-(tert-Butyl-dimethyl-silanyloxy)-8-phenyl-8-aza-bicyclo[3.2.1]octa-2,6-diene-2- carboxylic acid methyl ester (20): orange oil (64% yield); R f = 0.3 (4:1 pentane:ether); [α] 25 D (c = 0.45, CHCl 3 ); FTIR (neat) 2952, 2919, 2853, 1719, 1684, 1594, 1502, 1368, 1252, 1200, 1051, 839 cm -1 ; 1 H MR (500 MHz, CDCl 3 ) δ 7.20 (m, 2H), 6.79 (m, 3H), 6.58 (dd, J = 6.0, 2.5 Hz, 1H), 6.08 (dd, J = 6.0, 2.5 Hz, 1H), 5.12 (d, J = 2.5 Hz, 1H), 4.67 (m, 1H), 3.75 (s, 3H), 2.58 (dd, J = 18.0, 5.5 Hz, 1H), 1.77 (d, J = 18Hz, 1H), 0.79 (s, 9H), (s, 3H), (s, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 166.4, 157.3, 145.9, 138.3, 129.1, 128.4, 118.8, 115.9, 113.7, 57.7, 57.1, 51.1, 30.1, 25.5, 18.2, -4.4; HPLC analysis: (92% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 31.1 min (minor), 39.9 min (major); HRMS (ESI) m/z Calcd for [M+a] + (C 21 H 29 O 3 Si+a) + : found: S-6

7 3-(tert-Butyl-dimethyl-silanyloxy)-8-p-tolyl-8-aza-bicyclo[3.2.1]octa-2,6-diene-2- carboxylic acid methyl ester (21): brown color oil (64% yield); R f = 0.3 (6:1 pentane:ether); [α] 25 D (c = 0.14, CHCl 3 ); FTIR (neat) 2948, 2926, 2857, 1720, 1682, 1609, 1515, 1436, 1367, 1252, 1198, 913, 840 cm -1 ; 1 H MR (400 MHz, CDCl 3 ) δ 7.02 (d, J = 7.60 Hz, 2H), 6.75 (bs, 2H), 6.58 (dd, J = 6.0, 2.8 Hz, 1H), 6.07 (dd, J = 6.0, 2.8 Hz, 1H), 5.12 (bs, 1H), 4.64 (bs, 1H), 3.75 (s, 3H), 2.60 (bs, 1H), 2.23 (s, 3H), 1.78 (d, J = 18.0 Hz, 1H), 0.81 (s, 9H), (s, 3H), (s, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 166.4, 157.3, 143.7, 138.2, 129.4, 128.2, 122.8, 116.3, 113.6, 58.1, 57.6, 51.1, 30.2, 25.5, 20.4, 18.2, -4.3; HPLC analysis: (92% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 31.3 min (major), 39.7 min (minor); HRMS (EI) m/z Calcd for [M] + (C 22 H 31 O 3 Si) + : found: (tert-Butyl-dimethyl-silanyloxy)-12-aza-tricyclo[ ,6]dodeca-6,9-diene-9,12- dicarboxylic acid 12-tert-butyl ester 9-methyl ester (22): colorless oil (76% yield); R f = 0.43 (5:1 pentane:ether); [α] 25 D (c = 0.78, CHCl 3 ); FTIR (neat) 2932, 2848, 1703, 1605, 1366,1252, 1200, 1117, 860, 738 cm -1 ; 1 H MR (500 MHz, CDCl 3 ) δ 5.97 S-7

8 (bs, 1H), 4.98 (bs, 1H), 3.69 (s, 3H), 2.66 (bs, 1H), 2.39 (m, 1H), 2.03 (m, 2H), (m, 4H), 1.39 (s, 9H), 1.27 (m, 2H), 0.93 (s, 9H), 0.17 (s, 6H); 13 C MR (75 MHz, CDCl 3 ) δ 165.7, 159.7, 154.2, 141.5, 128.1, 116.3, 114.3, 79.7, 63.9, 57.7, 50.8, 35.9, 28.3, 27.9, 25.7, 24.8, 22.3, 18.4, -3.9; HPLC analysis: (91% ee), R,R-Whelk, 0.65 ml/min, 0.3% i-propanol in hexane, 22.4 min (major), 35.8 min (minor); HRMS (ESI) m/z Calcd for [M+a] + (C 24 H 39 O 5 Si+a) + : found: TBAF, AcOH, THF, 0 o C H 2 2. a(sime 3 ) 2,THF, -78 o C Rh(PPh 3 ) 3 Cl PhTf 2 EtOH 3. PdCl 2, PPh 3, (-Bu) 3, HCOOH (42% over all from 11 ) 8-Aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (24): A Parr hydrogenator flask was charged with a solution of 11 (0.111 g, 0.25 mmol) and (PPh 3 ) 3 RhCl (6 mg, mmol, 2 mol %) in absolute ethanol (25 ml). The flask was pressurized to 45 psi with hydrogen and agitated for 12 h. The solvent was then removed under reduced pressure to give the crude product which was dissolved in ether (10 ml) and passed through celite to remove the catalyst. The solvent was removed and the product obtained then was dissolved in THF (10 ml) at 23 o C and to it was added TBAF (2M in THF, 0.14 ml, 0.28 mmol, 1.1 equiv) and the mixture was stirred for 15 min. The reaction was quenched by addition of water (10 ml) and the aqueous layer was extracted with ether (3X5 ml) and the combined organic layers were dried and concentrated to result the alcohol which was dissolved in THF (25 ml) and cooled down to -78 o C and to it was added ahmds (2M in THF, mmol, 1.05 equiv) and stirred for 30 min at -78 o C and then warmed up to 23 o C. To this solution at r.t was added PhTf 2 (0.25 mmol, 1.0 equiv) and the mixture was stirred for 12 h. The reaction was S-8

9 quenched by addition of water and extracted with dichloromethane. The solvent was removed under reduced pressure and the resulting crude product was subjected to the next step. The crude product was dissolved in DMF (15 ml) and to was added PPh 3 (0.3 mg, mmol, 0.5 mol %), (-Bu 3 ) (0.215 g, 0.9 mmol, 3.6 equiv) and PdCl 2 (1.3 mg, mmol, 3 mol %) and stirred for 2 h. The reaction was quenched by addition of water and extracted with ethyl acetate (3X10 ml) and concentrated. The resulting crude product was subjected to flash column chromatography (3:1 hexanes:etoac) to result the product 24 as a colorless oil; [α] 25 D (c = 0.35, CHCl 3 ), {lit 5. [α] 25 D (c = 1.00, CHCl 3 ), lit 6. [α] 25 D (c = 1.55, CHCl 3 ), lit 1. [α] 25 D (c = 2.45, CHCl 3 ) (66% ee}; 1 H MR (500 MHz, CDCl 3 ) δ 6.75 (s, 1H), 4.81 (bs, 1H), 4.33 (bs, 1H), 3.75 (s, 3H), 2.89 (bs, 1H), (m, 4H), 1.55 (m, 1H), 1.44 (s, 9H). 1 H MR data were consistent with published data 1,4,5. MeO 2 C TBSO C 4 H 9 OMOM 5-Butyl-3-(tert-butyl-dimethyl-silanyloxy)-6-methoxymethoxy-8-aza bicyclo[3.2.1]octa-2,6-diene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (26): To a solution of pyrrole 25 7 (55 mg, 0.19 mmol) and the catalyst Rh 2 (R-PTAD) 4 (3 mg, 1 mol %) in freshly distilled 2,2-dimethylbutane (10 ml) at 50 o C was added a solution of 8 (100 mg, 0.39 mmol, 2 equiv) in 2,2-dimethylbutane (5 ml) over 60 min via syringe pump. The reaction mixture was stirred for a further 60 min at 50 o C and cooled. The solvent was removed under reduced pressure and the crude mixture was purified by 5 Hernandez, A. S.; Thaler, A. T.; Castells, J.; Rapoport, H. J. Org. Chem. 1996, 61, Katoh, T.; Kakiya, K.; akai, T.; akamura, S.; ishide, K.; ode, M. Tetrahedron: Asymmetry 2002, 13, Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, S-9

10 flash column chromatography to give the product (68 mg, 79%) as a colorless oil. [α] 25 D (c = 0.62, CHCl 3 ); HPLC analysis: (84% ee), Chiralcel OD-H, 0.65 ml/min, 0.3% i-propanol in hexane, 9.5 min (minor), 12.5 min (major); 1 H MR (500 MHz, CDCl 3 ) δ 5.32 (bs, 1H), 5.08 (s, 1H), 4.92(d, J = 5.5 Hz, 1H), 4.85 (d, J = 5.5Hz, 1H) 3.70 (s, 3H), 3.41 (s, 3H), 2.60 (m, 1H), 2.30 (m, 1H), 2.0 (d, J = 18.0 Hz, 1H), 1.76 (m, 1H), 1.37 (m, 1H), 1.19 (m, 1H), 0.93 (s, 9H), 0.15 (s, 6H). The 1 H MR data were consistent with published data. 8 8 Smalley, T. L., Jr.; A synthetic approach to stemofoline: the total synthesis of (+/1)-isostemofoline. Avail. UMI, Order o. DA (1999), 207 pp. From: Diss. Abstr. Int., B 1999, 60(4), 1616 S-10

11 11 S-11

12 17 S-12

13 18 S-13

14 MeO 2 C 19 S-14

15 Ph 20 Ph S-15

16 21 S-16

17 22 S-17