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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 October 2.
Published in final edited form as:
PMCID: PMC2752905
NIHMSID: NIHMS143870

Synthesis of (+)-CP-99,994 via Pd(0)-Catalyzed Asymmetric Allylic and Homoallylic C-H Diamination of Terminal Olefin

Abstract

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This paper describes an asymmetric synthesis of the potent substance P receptor antagonist (+)-CP-99,994 from 4-phenyl-1-butene via Pd(0)-catalyzed asymmetric allylic and homoallylic C-H diamination.

(+)-CP-99,994 (1) is a potent and selective non-peptide substance P receptor antagonist (Figure 1).1 Its biological activity has led to the development of various syntheses of this molecule and related analogues.2-5 Recently, we reported that terminal olefins can be enantioselectively diaminated at allylic and homoallylic carbons via C-H activation using di-tert-butyldiaziridinone (3) as nitrogen source with a catalyst derived from Pd2(dba)3 and the tetramethylpiperidine-based phosphorus amidite ligand 5 (Scheme 1).6,7 Herein, we wish to report the extension of this diamination process to the synthesis of (+)-CP-99,994.

Figure 1
The Structure of (+)-CP-99,994

The retrosynthetic plan for (+)-CP-99,994 is outlined in Scheme 2. Compound 1 can be obtained from diamino acid 7 via lactam 6. Compound 7 can be derived from diamination of 4-phenyl-1-butene (10).

The synthesis of (+)-CP-99,994 is described in Scheme 3. Allylic and homoallylic C-H diamination of 4-phenyl-1-butene (10) with di-tert-butyldiaziridinone (3), Pd2(dba)3, and ligand ent-5 gave imidazolidinone 9 in 78% yield and 90% ee. Compound 9 was oxidized to aldehyde 11 in 90% yield via dihydroxylation with OsO4-NMO, followed by oxidative cleavage with NaIO4.8 The olefination3b of aldehyde 11, followed by hydrogenation3b gave ester 13 in high yields.

One of the tert-butyl groups on the imidazolidinone of 13 was selectively removed with CF3CO2H in CH2Cl2 to give compound 14 along with very small amounts of 15 in 98% yield.9 At this point, compounds 14 and 15 could not be separated by flash column chromatography. Treating compounds 14 and 15 with sodium bis(trimethylsilylamide) and subsequently with nosyl chloride10 gave compound 16 in 72% yield after recrystallization from hexanes and ethyl acetate. The remaining tert-butyl group of compound 16 was removed with methanesulfonic acid to give compound 17 in 95% yield and >99% ee. Cleavage of the imidazolidinone ring of 17 with potassium hydroxide solution,11 followed by cyclization in refluxing AcOH12 led to lactam 18 in 72% yield in two steps. It was found that the nosyl group of 18 could not be removed with thiophenol under basic conditions. Compound 18 was then transformed to compound 19 in 94% yield by alkylation with 2-methoxybenzyl chloride. The removal of the nosyl group was realized by treating 19 with thiophenol and K2CO3 to give compound 6 in 79% yield.13 Based on a known procedure,1b,2a,b reduction of compound 6 with borane dimethylsulfide (THF, reflux, 15 h) and subsequent treatment with saturated HCl-Et2O gave (+)-CP-99,994 (1) as its dihydrochloride salt in 80% yield and >99% ee. The spectroscopic data and optical rotation were consistent with literature data.1a,3c,3e,4b,4f X-ray structure of (+)-CP-99,994 (1) dihydrochloride salt is shown in Supporting Information.1a

In conclusion, (+)-CP-99,994 (2HCl) was synthesized from 4-phenyl-1-butene in overall 20% yield and >99% ee. The vicinal diamine moiety was introduced onto a readily available terminal olefin with our recently developed asymmetric allylic and homoallylic C-H diamination process. The selective removal of one of the tert-butyl groups allows ready differentiation of the two nitrogens. Further application of the diamination strategy to other biologically significant molecules is in progress.

Experimental Section

Synthesis of compound 9

A 50-mL flask containing Pd2(dba)3 (0.345 g, 0.38 mmol) and ligand ent-5 (0.769 g, 1.66 mmol) was evacuated and then filled with argon three times. Upon addition of benzene (2.0 mL, distilled from sodium), the resulting mixture was immersed in an oil bath (65 °C), stirred for 45 min, and then concentrated under vacuum at room temperature. 4-Phenyl-1-butene (1.0 g, 7.6 mmol) was then added. The resulting mixture was immersed in an oil bath (65 °C) with stirring. Then di-tert-butyldiaziridinone (3.21 g, 18.9 mmol) was added by syringe pump at a rate of 1.89 mmol/h. Upon completion of addition (10 h), the reaction mixture was stirred for additional 5 h and purified by flash chromatography (silica gel, hexane : ethyl acetate = 30:1, v/v) to give the diamination product along with a small amount of dba, which was further purified by flash chromatography (silica gel, toluene then hexane:ethyl acetate = 30:1, v/v) to give diamination product 9 as a colorless oil (1.75 g, 78% yield, 90% ee). The enantioselectivity was determined by HPLC (Chiralpak AD Column, NO. AD00CE-EA001, hexanes:i-propanol = 90:10, v/v). [α]20D = −29.2° (c 1.0, CHCl3) (90% ee); IR (KBr) 1689 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 6.04 (ddd, J = 17.7, 10.2, 8.4 Hz, 1H), 5.20 (d, J = 17.7 Hz, 1H), 4.16 (s, 1H), 3.65 (d, J = 8.4 Hz, 1H), 1.34 (s, 9H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.1, 144.0, 140.9, 128.9, 127.8, 125.8, 115.7, 64.9, 63.3, 53.6, 53.4, 29.0, 28.8; HRMS Calcd for C19H29N2O (M + 1): 301.2274; Found: 301.2279.

Synthesis of compound 11

To a solution of compound 9 (2.33 g, 7.8 mmol) in 1,4-dioxane (140 mL) - H2O (45 mL) was added Me3NO•2H2O (1.73 g, 15.6 mmol) and aqueous OsO4 (2.75 mL, 0.45 mmol, 4% w/w). Then the resulting mixture was stirred at rt for 14 h. Upon addition of NaIO4 (5.81 g, 27.2 mmol), the reaction mixture was stirred at rt for 4 h, quenched with saturated aqueous Na2S2O3, and extracted with ethyl acetate (50 mL × 3), washed with brine, dried (MgSO4), filtered, concentrated, and recrystallized form hexane to give aldehyde 11 as a yellow crystal (2.12 g, 90% yield). mp. 120-122 °C; [α]20D = −10.0° (c 1.0, CHCl3); IR (KBr) 1728, 1674 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.77 (d, J = 3.3 Hz, 1H), 7.40-7.26 (m, 5H), 4.56 (d, J = 1.8 Hz, 1H), 3.66 (dd, J = 3.3, 1.8 Hz, 1H), 1.37 (s, 9H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 201.0, 159.0, 142.7, 129.1, 128.4, 125.8, 68.9, 57.6, 54.3, 53.8, 29.0, 28.8; Anal. Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26; Found: C, 71.29; H, 8.54; N, 9.12.

Synthesis of compound 12

To a solution of aldehyde 11 (2.10 g, 6.9 mmol) in CH2Cl2 (40 mL) was added methyl (triphenylphosphoranylidene)acetate (2.55 g, 7.6 mmol). Upon stirring at rt for 4 h, the reaction mixture was concentrated and purified by flash chromatography (silica gel, hexane:ethyl acetate = 8:1, v/v) to give compound 12 as a colorless oil (2.44 g, 99% yield). [α]20D = −66.9° (c 1.0, CHCl3); IR (KBr) 1728, 1690 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 7.04 (dd, J = 15.6, 7.8 Hz, 1H), 5.97 (d, J = 15.6 Hz, 1H), 4.18 (d, J = 1.5 Hz, 1H), 3.81 (dd, J = 7.8, 1.5 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.7, 158.9, 149.1, 143.4, 129.1, 128.2, 125.8, 121.5, 62.7, 62.3, 53.9, 53.7, 52.0, 28.7; HRMS Calcd for C21H31N2O3 (M + 1): 359.2329; Found: 359.2332.

Synthesis of compound 13

A suspension of compound 12 (2.40 g, 6.7 mmol) and palladium on activated carbon (10 wt. %) (0.24 g) in MeOH (100 mL) was stirred under H2 atmosphere (ballon) at rt for 2 h. The reaction mixture was filtered through Celite and concentrated to give compound 13 as a colorless oil (2.41 g, 99% yield). [α]20D = +6.0° (c 1.0, CHCl3); IR (KBr) 1739, 1686 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 4.18 (s, 1H), 3.69 (s, 3H), 3.21 (dd, J = 7.5, 2.4 Hz, 1H), 2.58-2.36 (m, 2H), 2.06-1.84 (m, 2H), 1.36 (s, 9H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.6, 158.7, 144.2, 128.9, 127.8, 125.6, 61.1, 60.9, 53.5, 52.9, 52.0, 30.7, 29.0; HRMS Calcd for C21H33N2O3 (M + 1): 361.2486; Found: 361.2490.

Synthesis of compound 14 and compound 15

To a solution of compound 13 (2.30 g, 6.4 mmol) in CH2Cl2 (25 mL) at 0 °C was added CF3CO2H (25 mL) dropwise over 30 min. The reaction mixture was then warmed to room temperature slowly, stirred at room temperature for 10 h, and concentrated. The resulting residue was dissolved in CH2Cl2 (100 mL), washed with saturated aqueous Na2CO3 and brine, dried (MgSO4), filtered, and concentrated to give a mixture of compounds 14 and 15 as a colorless oil (1.91 g, 98% yield) (the ratio of compound 14 to 15 is 15 to 1 based on 1H NMR). [α]20D = −13.4° (c 1.0, CHCl3); IR (KBr) 1737, 1688 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.64 (brs, 1H), 4.37 (d, J = 3.3 Hz, 1H), 3.67 (s, 3H), 3.23-3.16 (m, 1H), 2.45-2.36 (m, 2H), 1.99-1.81 (m, 2H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.5, 161.7, 144.2, 128.9, 127.8, 125.9, 65.4, 58.2, 54.0, 51.8, 31.5, 29.7, 28.8; HRMS Calcd for C17H25N2O3 (M + 1): 305.1860; Found: 305.1861.

Synthesis of compound 16

To a stirred solution of compounds 14 and 15 (1.76 g, 5.8 mmol) in THF (12 mL) at −78 °C was added dropwise sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.1 mL, 6.1 mmol) over 10 min. After stirring at −78 °C for 15 min, a solution of 4-nitrobenzenesulfonyl chloride (1.54 g, 6.9 mmol) in THF (8 mL) was added dropwise at −78 °C over 10 min. The reaction mixture was stirred at −78 °C for another 2 h and allowed to warm to 0 °C slowly. Upon addition of water (30 mL), the mixture was extracted with ethyl acetate (50 mL × 3), washed with brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography (silica gel, hexane:ethyl acetate = 6:1, v/v) to give a white solid (2.45 g, 86% yield) which was recrystallized from hexanes (15 mL) and ethyl acetate (10 mL) to give compound 16 as a white crystal (2.05 g, 72%). mp. 131-132 °C; [α]20D = +37.6° (c 1.0, CHCl3); IR (KBr) 1727, 1532, 1397, 1350, 1174 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 9.0 Hz, 2H), 8.19 (d, J = 9.0 Hz, 2H), 7.34-7.22 (m, 3H), 6.92 (d, J = 6.9 Hz, 2H), 4.42 (s, 1H), 3.98-3.93 (m, 1H), 3.71 (s, 3H), 2.49 (t, J = 7.5 Hz, 2H), 2.25-2.12 (m, 2H), 1.24 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.9, 152.1, 150.6, 144.6, 141.3, 129.8, 129.4, 128.8, 125.1, 124.1, 62.6, 62.2, 55.6, 52.1, 30.6, 29.0, 28.2; Anal. Calcd for C23H27N3O7S: C, 56.43; H, 5.56; N, 8.58; Found: C, 56.66; H, 5.68; N, 8.72.

Synthesis of compound 17

To MeSO3H (5 mL) was added compound 16 (1.69 g, 3.5 mmol) at rt. After stirring for 1 h, the reaction mixture was added dropwise to saturated aqueous Na2CO3 (30 mL) with vigorous stirring. The white precipitate was collected by suction filtration, dried under vacuum, and recrystallized from hexane and EtOAc to give compound 17 as a white solid (1.46 g, 95% yield, >99% ee) (the enantioselectivity was determined by HPLC, Chiralpak AD-H Column, NO. ADH0CE-FD069, hexanes:i-propanol = 85:15, v/v). mp. 123-125 °C; [α]20D = +47.9° (c 1.0, CHCl3); IR (KBr) 3314, 1730, 1532, 1351, 1175 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.7 Hz, 2H), 7.36-7.22 (m, 3H), 6.94 (d, J = 7.5 Hz, 2H), 5.59 (s, 1H), 4.39 (s, 1H), 4.23-4.21 (m, 1H), 3.72 (s, 3H), 2.60-2.52 (m, 2H), 2.37-2.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 172.8, 155.1, 150.6, 143.6, 140.5, 129.4, 129.0, 125.0, 124.1, 65.7, 58.3, 52.1, 30.6, 29.0; Anal. Calcd for C19H19N3O7S: C, 52.65; H, 4.42; N, 9.69; Found: C, 52.42; H, 4.65; N, 9.68.

Synthesis of compound 18

A suspension of compound 17 (1.38 g, 3.2 mmol) in 60% (w/w) aqueous KOH (50 mL) was stirred at room temperature for 36 h. The resulting clear solution was diluted with water (20 mL) and adjusted to pH 5-6 with 12 N HC1. The yellow precipitate was collected by suction filtration, washed with water, and dried under vacuum to give a yellow solid (0.985 g, 79% yield). A suspension of the above yellow solid (0.860 g, 2.2 mmol) in AcOH (50 mL) was heated at reflux for 3 h. The resulting clear solution was concentrated under vacuum to give the crude product, which was recrystallized from EtOAc and MeOH to give compound 18 as a yellow solid (0.751 g, 91% yield) (72% yield for two steps). mp. 149-151 °C; [α]20D = −7.75° (c 0.40, CH3OH); IR (KBr) 3103, 1653, 1527, 1350, 1162 cm−1; 1H NMR (300 MHz, CD3OD) δ 8.18 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 9.0 Hz, 2H), 7.26-7.14 (m, 5H), 4.78 (d, J = 4.2 Hz, 1H), 3.93-3.87 (m, 1H), 2.64-2.37 (m, 2H), 2.04-1.78 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 174.5, 151.0, 148.2, 139.0, 129.3, 128.9, 128.8, 125.3, 60.6, 52.8, 28.5, 26.6; HRMS Calcd for C17H18N3O5S (M + 1): 376.0962; Found: 376.0964.

Synthesis of compound 19

A suspension of compound 18 (0.60 g, 1.6 mmol), 2-methoxybenzyl chloride (0.376 g, 2.4 mmol), sodium iodide (0.024 g, 0.16 mmol), and cesium carbonate (0.78 g, 2.4 mmol) in DMF (4 mL) was heated at 80 °C for 5 h. The resulting reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 3), washed with brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography (silica gel, CH2Cl2:MeOH = 100:1, v/v) to give compound 19 as a yellow solid (0.751 g, 94% yield). mp. 135-137 °C; [α]2D = −100.2° (c 1.0, CHCl3); IR (KBr) 3206, 1666 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.50-7.36 (m, 5H), 7.05 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 6.21 (s, 1H), 5.09-5.07 (m, 1H), 4.77-4.72 (m, 1H), 3.66 (d, J = 15.6 Hz, 1H), 3.46 (s, 3H), 3.26 (d, J = 15.6 Hz, 1H), 2.67-2.63 (m, 2H), 2.26-2.15 (m, 1H), 2.00-1.85 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 170.5, 156.8, 149.4, 147.2, 137.8, 131.3, 129.4, 128.9, 128.8, 127.9, 123.7, 123. 0, 120.0, 109.6, 59.6, 58.6, 54.7, 44.4, 31.4, 20.4; HRMS Calcd for C25H26N3O6S (M + 1): 496.1537; Found: 496.1541.

Synthesis of compound 6

A mixture of compound 19 (0.731 g, 1.5 mmol), PhSH (0.25 g, 2.3 mmol), K2CO3 (0.21 g, 1.5 mmol), and DMSO (4 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (30 mL × 3), washed with brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography (silica gel, CH2Cl2:MeOH = 25:1, v/v) to give compound 6 as a yellow oil (0.368 g, 79% yield). [α]20D = +40.5° (c 1.0, CHCl3); IR (KBr) 3201, 3063, 1660 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 5H), 7.19 (td, J = 8.1, 1.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 5.90 (brs, 1H), 4.74 (d, J = 3.3 Hz, 1H), 3.77 (d, J = 13.8 Hz, 1H), 3.56 (d, J = 13.8 Hz, 1H), 3.50 (s, 3H), 3.08-3.00 (m, 1H), 2.79-2.66 (m, 1H), 2.43-2.33 (m, 1H), 2.10-2.00 (m, 1H), 1.91-1.80 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.8, 157.5, 138.6, 129.5, 128.7, 128.3, 128.1, 127.6, 127.0, 120.3, 110.0, 60.7, 54.9, 52.9, 46.4, 27.5, 23.5; Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03; Found: C, 73.80; H, 6.97; N, 9.19.

Synthesis of (+)-CP-99,994

To a solution of compound 6 (0.328 g, 1.06 mmol) in THF (3 mL) was added borane dimethylsulfide in THF (2.0 M, 2.8 mL, 5.6 mmol) under argon. The reaction mixture was heated at reflux for 18 h. After the reaction mixture was cooled to room temperature, MeOH (5 mL) was added dropwise (cautiously) to decompose the excess borane dimethylsulfide. The resulting mixture was then concentrated. EtOH (9 mL) and powdered K2CO3 (0.311 g, 2.25 mmole) were added. The resulting mixture was heated at reflux for 18 h, cooled, and concentrated. Water (20 mL) was added to the resulting residue. The mixture was extracted with CH2Cl2 (20 mL × 4), dried (MgSO4), filtered, and concentrated. Then the residue was dissolved in a minimum amount of CH2Cl2 (2 mL), followed by addition of saturated HCl-ether (50 mL). After stirring for 2 h, white solids were collected by filtration, and recrystallized from a hot MeOH-EtOH (1:1, v/v) to give the 2HCl salt of (+)-CP-99,994 (1) as a white crystalline solid (0.31 g, 80% yield). mp. 253-255 °C; [α]20D = +77.3° (c 11.0, MeOH); IR (KBr) 3461, 3386, 1603, 1491, 1440 cm−1; 1H NMR (300 MHz, CD3OD) δ 7.76-7.68 (m, 2H), 7.62-7.52 (m, 3H), 7.40 (td, J = 7.8, 1.5 Hz, 1H), 7.21 (dd, J = 7.8, 1.5 Hz, 1H), 6.98-6.92 (m, 2H), 5.03 (d, J = 3.6 Hz, 1H), 4.14 (d, J = 13.2 Hz, 1H), 4.06-3.98 (m, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.70 (s, 3H), 3.72-3.62 (m, 1H), 3.38-3.28 (m, 1H), 2.55-2.40 (m, 2H), 2.34-2.22 (m, 1H), 2.06-1.94 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 159.0, 133.0, 132.84, 132.80, 131.2, 130.9, 128.4, 122.0, 119.0, 111.9, 60.4, 58.4, 56.1, 49.1, 45.6, 25.3, 17.8; Anal. Calcd for C19H26Cl2N2O: C, 61.79; H, 7.10; N, 7.58; Found: C, 61.53; H, 6.96; N, 7.74.

A suspension of the 2HCl salt of (+)-CP-99,994 (1) (0.105 g, 0.28 mmol) in CH2Cl2 (5 mL) and 1N NaOH (10 mL) was stirred at room temperature for 15 min. Then the mixture was extracted with CH2Cl2 (10 mL × 3). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give (+)-CP-99,994 as yellow oil (0.075 g, 89% yield, >99% ee) (the enantioselectivity was determined by HPLC (Chiralcel OD-H Column, NO. ODHOCE-ME069, hexanes:i-propanol = 90:10). [α]20D = +69.8° (c 1.0, CHCl3); IR (KBr) 3329, 1492, 1461, 1241 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.34-7.18 (m, 5H), 7.15 (td, J = 8.1, 1.5 Hz, 1H), 6.97 (dd, J = 7.2, 1.2 Hz, 1H), 6.80 (t, J = 7.8 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 3.87 (d, J = 2.1 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 3,43 (s, 3H), 3.41 (d, J = 13.8 Hz, 1H), 3.31-3.24 (m, 1H), 2.85-2.73 (m, 2H), 2.19-2.10 (m, 1H), 2.01-1.82 (m, 3H), 1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 157.6, 142.3, 129.7, 128.2, 127.9, 126.6, 126.3, 120.0, 109.8, 64.0, 54.8, 54.6, 47.8, 46.8, 28.1, 20.3; HRMS Calcd for C19H25N2O (M + 1): 297.1961; Found: 297.1965.

Supplementary Material

1_si_001

2_si_002

Acknowledgment

We are grateful to the generous financial support from the General Medical Sciences of the National Institutes of Health (GM083944-02).

Footnotes

Supporting Information Available: The synthetic procedure for ligand ent-5, the X-ray structure of (+)-CP-99,994 (1) (2HCl), and the data for the determination of the enantiomeric excess of compounds 9, 17, and 1 along with the NMR spectra for ligand ent-5 and compounds 1, 6, 9, 11-19 (38 pages). This material is available free of charge via the Internet at http://pubs.acs.org.

Reference

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