CHIRALITY 26:793–800 (2014)

Bromolactamization: Key Step in the Stereoselective Synthesis of Enantiomerically Pure, cis-Configured Perhydropyrroloquinoxalines 1

ADRIAN SCHULTE,1 XINGCI SITU,1 SUSUMU SAITO,2 AND BERNHARD WÜNSCH1* Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Münster, Germany 2 Graduate School of Science and Institute for Advanced Research, Nagoya University Chikusa, Nagoya, Japan

ABSTRACT Compounds based on the pyrroloquinoxaline system can interact with serotonin 5-HT3, cannabinoid CB1, and μ-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB with LiOtBu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations. Chirality 26:793 – 800, 2014. © 2014 Wiley Periodicals, Inc. KEY WORDS: bromolactamization; cis-configured perhydroquinoxaline; proline; pyroglutamate; stereoselectivity; kinetic resolution INTRODUCTION

The pyrroloquinoxaline motif is found in several pharmacologically active compounds,1 including serotonin 5-HT3 receptor agonists (e.g., 1),1,2 cannabinoid CB1 receptor antagonists (e.g., 2),3 μ-receptor agonists (e.g., 3),4 and chemotherapeutics.5,6 Some drugs containing this scaffold are shown in Figure 1. The first synthesis of compounds with an aromatic pyrroloquinoxaline scaffold was performed by Boyer and coworkers.7 Very recently, stereoselective syntheses of partially and fully hydrogenated pyrroloquinoxalines were presented by Cho et al.8 and Rees,9 respectively, the latter using proline derivatives from the chiral pool for aziridine ring opening. We herein investigated different approaches for the stereoselective synthesis of perhydropyrroloquinoxalines using (S)-proline and (S)-pyroglutamate derivatives as starting materials from the chiral pool. The amino acids contain a carboxyl group, which is envisaged to transfer the chiral information from the pyrrolidine ring to the double bond of the cyclohexene ring attached to the pyrrolidine N-atom (Fig. 2). For this purpose, the [3 + 2] cycloaddition10 of azide 4a to triazole 5, the

Fig. 1. Examples of pharmacologically active pyrroloquinoxaline derivatives. © 2014 Wiley Periodicals, Inc.

Fig. 2. Concept for the transfer of chirality from the pyrrolidine to the cyclohexene ring using [3 + 2] cycloaddition, electrophilic aziridination, or halolactamization, giving pyrroloquinoxalines.

N-electrophilic aziridination11 of N-tosyloxy derivative 4b to aziridine 6, as well as the halolactamization of the amides 4c and 4d to the halolactams 7a and 7b, respectively, were investigated. The triazole and aziridine rings as well as the additional halide substituent should allow further transformations. Examples of related asymmetric halolactamizations are rare12: A bromolactamization employing a chiral auxiliary derived from (S)-proline13 and a iodolactamization with a

*Correspondence to: B. Wünsch, Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany. E-mail: [email protected] Received for publication 20 March 2014; Accepted 06 May 2014 DOI: 10.1002/chir.22350 Published online 5 July 2014 in Wiley Online Library (wileyonlinelibrary.com).

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chiral oxazolidinone auxiliary14 are the only examples reported so far. EXPERIMENTAL SECTION General Methods CH2Cl2 and THF were dried by distillation over CaH2 and sodium, respectively. DMSO was dried over molecular sieves (4 Å). All reactions were carried out under N2 atmosphere. The reactions were monitored by thin layer chromatography (TLC) using silica gel 60 F254 plates on aluminum sheets (Merck, Darmstadt, Germany). Silver ion thin layer Ag flash chromatography TLC was conducted on silica gel-coated plates (F254, Merck) which had been dipped into an aqueous solution of AgNO3 (1.0 M) and dried using a commercially available hot air dryer. Flash chromatography (FC): Silica gel 60, 40–63 μm (Macherey-Nagel); parentheses include: diameter of the column, length of the column, Ag eluent, fraction size, Rf-value. Silver ion flash chromatography FC was conducted following a method developed by Cert and Moreda.15 The argentated silica gel was obtained as follows: AgNO3 (3.0 g) was dissolved in H2O (7 mL). The resulting solution was added to silica gel (30 g, silica gel 60, 40 μm, Merck) under shaking in a round-bottom flask covered in aluminum foil. The flask was vigorously shaken for 20 s. It was then subjected to rotation under room pressure using a rotary evaporator, affording the desired argentated silica gel. Melting point: melting point apparatus SMP 3 (Stuart Scientific, Stone, UK), uncorrected. Optical rotation: Polarimeter 341 (Perkin–Elmer, Boston, MA), wavelength:
1
1 589 nm, path length 1 dm, temp. +20°C; units [deg mL dm g ] are omitted; concentration [mg/mL] and solvent are given in brackets. Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI): MicroTOF QII mass spectrometer (Bruker Daltronics, Billerica, MA), software: Data Analysis. Deviations of the found exact masses from the calculated exact masses: 5 mDa or less. Electrospray ionization (ESI): LCQ Finnigan MAT mass spectrometer (Thermo Finnigan, Pittsburgh, PA), software: Xcalibur 1.3 (Thermo Scientific), mass-to-charge ratios [m/z] and relative intensity of the signals (%) are 1 13 given. H NMR (400.3 MHz), C NMR (100.7 MHz): Unity Mercury Plus 400 NMR spectrometer (Varian, Palo Alto, CA) or AV400 NMR spectrometer (Bruker); δ in ppm related to tetramethylsilane. IR: FT/IR Prestige 21 IR spectrometer (Shimadzu, Kyoto, Japan), ATR technique. (2S)-1-[(1S)- and (1R)-Cyclohex-2-en-1-yl]pyrrolidine-2-carboxamide (4cA/B). (S)-Prolinamide (8a, 488 mg, 4.28 mmol, 1.2 equiv.)

was dissolved in dry DMSO (3 mL) and overlaid with cyclohexane (5 mL). DBU (0.635 mL, 4.28 mmol, 1.2 equiv.) and 3-chlorocyclohex-1-ene (9a, 0.352 mL, 3.56 mmol, 1.0 equiv.) were added dropwise. The mixture was stirred at ambient temperature for 2 d. The solvents were removed under reduced pressure and the residue was dissolved in CH2Cl2. FC (d = 3 cm, l = 10 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 7 : 1 ➔ 1 : 1 ➔ 1 : 3 ➔ 0 : 1, Rf = 0.63 (TLC, ethyl acetate : methanol = 1 : 1)) gave a 1 : 1 mixture of diastereomers 4cA and 4cB. Colorless solid, mp 111–112°C, yield 565 mg (82%), C11H18N2O (194.3 g/mol). = -70.6 (c = 0.31, CHCl3). Two sets of signals (1H NMR ½α28:0 D intensity ratio = 1:1) are seen in the nuclear magnetic resonance (NMR) spectra originating from two diastereomers. 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.34–1.58 (m, 2H, 5-CH2,cycl, 6-CH2,cycl), 1.58–1.84 (m, 4H, 4-CH2,py, 5-CH2,cycl, 6-CH2,cycl), 1.84–1.97 (m, 3H, 4-CH2,cycl, 3-CH2,py), 1.97–2.12 (m, 1H, 3-CH2,py), 2.59 (dt, 2J = 9.4 Hz, 3J = 4.7 Hz, 0.5x1H, 5-CH2,py), 2.63 (dt, 2J = 9.2 Hz, 3J = 4.4 Hz, 0.5x1H, 5-CH2,py), 2.97 (td, 2 J = 9.2 Hz, 3J = 9.2 / 3.9 Hz, 0.5x1H, 5-CH2,py), 3.03 (td, 2 J = 9.4 Hz, 3J = 9.4 / 4.4 Hz, 0.5x1H, 5-CH2,py), 3.24 (ddd, J = 7.4 / 5.1 / 2.1 Hz, 1H, 1-CHcycl), 3.31 (dd, J = 8.4 / 3.5 Hz, 0.5x1H, 2-CHpy), 3.32 (dd, J = 8.9 / 3.9 Hz, 0.5x1H, 2-CHpy), 5.53 (dtd, 3 J = 10.3 Hz, 4J = 2.6 Hz, 3J = 2.1 Hz, 0.5x1H, 2-CHcycl), 5.57 (dtd, 3 J = 10.3 Hz, 4J = 2.7 Hz, 3J = 2.1 Hz, 0.5x1H, 2-CHcycl), 5.77 (dtdd, Chirality DOI 10.1002/chir

3

J = 10.3 / 2.7 Hz, 4J = 2.2 Hz, 4J = 0.5 Hz, 0.5x1H, 3-CHcycl), 5.81 (dtdd, 3J = 10.3 / 3.9 Hz, 4J = 1.9 Hz, 4J = 0.7 Hz, 0.5x1H, 3CHcycl), 6.12 (bs, 0.5x1H, NH2), 6.19 (bs, 0.5x1H, NH2), 7.36 (bs, 1H, NH2). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 21.3 (C-4py), 21.7 (C-4py), 24.8 (C-6cycl), 25.0 (C-6cycl), 25.4 (C-3py), 25.5 (C-3py), 26.9 (C-5cycl), 28.7 (C-5cycl), 31.4 (C-4cycl), 31.7 (C-4cycl), 49.1 (C-5py), 51.0 (C-5py), 57.5 (C-1cyclx2), 62.6 (C2py), 64.5 (C-2py), 127.4 (C-2cycl), 128.2 (C-2cycl), 130.8 (C-3cycl), 131.2 (C-3cycl), 179.7 (C = O), 180.1 (C = O). FT-IR: υ (cm1 ) = 3395 (s, NH2), 3202 (m, NH2), 2930 (s, C-H), 2861 (m, CH), 2809 (w, C-H), 1626 (s, C = O). Exact mass (ESI+): m/ z = 195.1492 (calcd. 195.1497 for C11H19N2O [MH]+), 217.1316 (calcd. 217.1317 for C11H18N2ONa [MNa]+). tert-Butyl N-{(2S)-1-[(1R)- and (1S)-cyclohex-2-en-1-yl]pyrrolidin2-ylcarbonyl}carbamate (4dA/B). NaH (57%-w/w suspension

in mineral oil, 554 mg, 13.6 mmol, 10 equiv.) was washed with n-hexane (3 x 40 mL) and dried (nitrogen flushing) before it was suspended in CH2Cl2 (15 mL). The mixture was cooled to 0°C and a solution of the amide 4c (362 mg, 1.32 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) was added dropwise. After 15 min, the mixture was warmed to ambient temperature and stirred for 45 min. The mixture was cooled to 0°C and Boc2O (0.50 mL, 2.4 mmol, 1.8 equiv.) was added dropwise. The mixture was allowed to warm to ambient temperature and stirred for 2.5 d. Water (20 mL) was carefully added. The resulting layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by FC (d = 3 cm, l = 10 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 24 : 1 ➔ 7 : 1, Rf = 0.56 (TLC, ethyl acetate : cyclohexane = 1:1)) to afford a 1:1 mixture of the diastereomers 4dA and 4 dB. Colorless oil, yield 338 mg (87%), C16H26N2O3 (294.4 g/mol). = -50.2 (c = 0.15, CHCl3). 1H NMR (400 MHz, CDCl3): ½α24:3 D δ (ppm) = 1.45 (s, 0.5x9H, C(CH3)3), 1.47 (s, 0.5x9H, C(CH3) 3), 1.47–1.57 (m, 2H, 5-CH2,cycl, 6-CH2,cycl), 1.58–1.85 (m, 0.5x1H + 3H, 5-CH2,cycl, 6-CH2,cycl, 4-CH2,py), 1.89–2.00 (m, 0.5x1H + 2H, 4-CH2,cycl, 6-CH2,cycl), 2.00–2.13 (m, 2H, 3-CH2, 2 3 py), 2.61 (td, J = 10.2 Hz, J = 10.2 / 7.3 Hz, 0.5x1H, 5-CH2,py), 2 3 2.65 (td, J = 10.2 Hz, J = 10.2 / 5.5 Hz, 0.5x1H, 5-CH2,py), 3.03 (ddd, 2J = 9.1 Hz, 3J = 6.7 / 2.7 Hz, 0.5x1H, 5-CH2,py), 3.12 (ddd, 2J = 9.1 Hz, 3J = 6.7 / 1.8 Hz, 0.5x1H, 5-CH2,py), 3.17–3.27 (m, 1H, 1-CHcycl), 3.38 (dd, J = 12.7 / 9.2 Hz, 0.5x1H, 2-CHpy), 3.38 (dd, J = 13.0 / 9.2 Hz, 0.5x1H, 2-CHpy), 5.54 (ddt, 3J = 11.0 / 4.4 Hz, 4J = 2.6 Hz, 1H, 2-CHcycl), 5.83 (ddd, J = 11.0 / 7.4 / 2.0 Hz, 1H, 3-CHcycl), 9.58 (s, 0.5x1H, NH), 9.63 (s, 0.5x1H, NH). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 20.6 (C-5cycl), 21.4 (C-5cycl), 24.7 (C-4py), 25.0 (C4py), 25.3 (C-4cycl), 25.4 (C-4cycl), 27.2 (C-6cycl), 28.2 (C(CH3) 3x2), 28.4 (C-6cycl), 31.5 (C-3py), 31.7 (C-3py), 49.1 (C-5py), 51.5 (C-5py), 57.3 (C-1cycl), 57.5 (C-1cycl), 63.5 (C-2py), 65.4 (C-2py), 82.1 (C(CH3)3), 82.3 (C(CH3)3), 126.9 (C-2cycl), 127.1 (C-2cycl), 131.8 (C-3cyclx2), 149.6 (N(C = O)O), 149.7 (N(C = O) O), 174.8 (CHC = O), 175.1 (CHC = O). FT-IR: υ (cm-1) = 3294 (bm, N-H), 2932 (s, C-H), 2867 (s, C-H), 1781 (s, N(C = O)O), 1717 (s, CHC = O). Exact mass (ESI+): m/z = 195.1492 (calcd. 195.1497 for C11H19N2O [MH - CH2 = C(CH3)2CO2]+), 239.1385 (calcd. 239.1396 for C12H19N2O3 [MH - CH2 = C(CH3)2]+), 295.2014 (calcd. 295.2022 for C16H27N2O3 [MH]+), 317.1835 (calcd. 317.1841 for C16H26N2O3Na [MNa]+), 611.3772 (calcd. 611.3785 for C32H12N4O6Na [M2Na]+).

KEY STEP FOR PERHYDROPYRROLOQUINOXALINES

Methyl (S)-1-[(1R)- or (1S)-cyclohex-2-en-1-yl]pyrrolidine-2-carboxylate (4eA) and Methyl (S)-1-[(1S)- or (1R)-cyclohex-2-en-1-yl]pyrrolidine2-carboxylate (4eB). Preparation by nucleophilic substitution:

(S)-Proline methyl ester hydrochloride (8b.HCl, 500 mg, 3.02 mmol, 1.25 equiv.) was dissolved in dry DMSO (1.5 mL) and overlaid with cyclohexane (1.5 mL). DBU (0.50 mL, 3.8 mmol, 2.0 equiv.) and 3-bromocyclohex-1-ene (9b, 0.180 mL, 1.90 mmol, 1.0 equiv.) were added dropwise to the vigorously stirred mixture. The stirring frequency was then reduced until the mixture formed two layers. Stirring was continued for 6 d. The mixture was applied to a silica gel column and purified by FC (d = 3 cm, h = 10 cm, V = 60 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 39 : 1 ➔ 19 : 1 ➔ 9 : 1, Rf = 0.55 (TLC, cyclohexane : ethyl acetate = 1:1, detection: KMnO4)) to give a 1:1 mixture of the diastereomers 4eA and 4eB. Pale yellow oil, yield 331 mg (82%), C12H19NO2 (209.3 g/mol). Preparation by Tsuji-Trost reaction:(S)-Proline methyl ester hydrochloride (8b.HCl, 50 mg, 0.30 mmol, 1.5 equiv.) was dissolved in dry DMSO (1.5 mL). NEt3 (84 μL, 0.60 mmol, 3.0 equiv.), carbonate 9c (39 mg, 0.20 mmol, 1.0 equiv.) and tetrakis(triphenylphosphine)palladium (4.6 mg, 4.0 μmol, 0.020 equiv.) were added to the stirred solution and stirring was continued for 24 h. The mixture was applied to a silica gel column and purified by FC (d = 1 cm, h = 8 cm, cyclohexane : ethyl acetate = 1 : 0 ➔ 39 : 1 ➔ 19 : 1 ➔ 9 : 1, Rf = 0.55 [TLC, cyclohexane : ethyl acetate = 1 : 1, detection: KMnO4]) to afford a 1:1 mixture of the diastereomers 4eA and 4eB. Pale yellow oil, yield 30 mg (70%), C 12 H 19 NO 2 (209.3 g/mol). Exact mass (ESI + ): m/z = 210.1475 (calcd. 210.1489 for C 12 H 20 NO 2 [MH] + ).Separation of the diastereomers by silver ion flash chromatography:A mixture of the diastereomers 4eA and 4eB (165 mg) was subjected to FC Ag (d = 2 cm, h = 15 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 19 : 3 ➔ 7 : 3 ➔ 13 : 7 ➔ 1 : 1). Coeluted silver ions were removed by dissolving the fractions in CH2Cl2 (10 mL) and subsequently washing with brine (5 mL). The resulting organic layers were dried (Na2SO4) and concentrated under reduced pressure. 4eA (Rf = 0.50 [TLCAg, cyclohexane : ethyl acetate = 1:1, detection: KMnO4]): Colorless oil, yield 72 mg (44%), 30:0 C12H19NO2 (209.3 g/mol). ½αD = –10.1 (30°C, c = 1.70 1 mmol/L, CH2Cl2). H NMR (400 MHz, CDCl3): δ (ppm) = 1.30–1.40 (m, 1H, 5-CH2,cycl), 1.40–1.52 (m, 1H, 5-CH2,cycl), 1.67–1.76 (m, 2H, 6-CH2,cycl, 4-CH2,py), 1.76–1.82 (m, 1H, 6CH2,cycl), 1.82–1.88 (m, 2H, 3-CH2,py, 4-CH2,py), 1.89–1.95 (m, 2H, 4-CH2,cycl), 1.95–2.08 (m, 1H, 3-CH2,py), 2.68 (dt, 2 J = 8.9 Hz, 3J =7.2 Hz, 1H, 5-CH2,py), 3.04 (td, 2J = 8.9 Hz, 3 J = 8.9 / 3.2 Hz, 1H, 5-CH2,py), 3.35 (ddd, J = 6.2 / 2.8 / 2.4 Hz, 1H, 1-CHcycl), 3.48 (dd, J = 9.1 / 4.3 Hz, 1H, 2-CHpy), 3.64 (s, 3H, OCH3), 5.61 (ddd, 3J = 10.1 / 2.8 Hz, 4J = 1.9 Hz, 1H, 2-CHcycl), 5.76 (dtd, 3J = 10.1 / 5.0 Hz, 4J = 0.9 Hz, 1H, 3-CHcycl). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 21.5 (C-6cycl), 24.0 (C-5cycl), 25.4 (C-4cycl), 26.2 (C-4py), 30.6 (C-3py), 50.0 (C-5py), 52.0 (OCH3), 56.6 (C-1cycl), 61.0 (C-2py), 128.3 (C-2cycl), 130.6 (C-3cycl), 176.1 (C = O). FT-IR: υ (cm
1) = 2930 (s, C-H), 1730 (s, C = O). 4eB (Rf = 0.38 [TLCAg, cyclohexane : ethyl acetate = 1:1, detection: KMnO4]): Colorless oil, yield 85 mg (51%), = –60.2 (c = 1.70 mmol/L, C12H19NO2 (209.3 g/mol). ½α30:0 D CH2Cl2). 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.40–1.55 (m, 2H, 5-CH2,cycl), 1.68–1.80 (m, 2H, 6-CH2,cycl, 4-CH2,py), 1.81–1.84 (m, 1H, 6-CH2,cycl), 1.85–1.90 (m, 2H, 3-CH2,py,

795

4-CH2,py), 1.91–1.96 (m, 2H, 4-CH2,cycl), 1.96–2.13 (m, 1H, 3-CH2,py), 2.64 (dt, 2J = 8.9 Hz, 3J = 7.7 Hz, 1H, 5-CH2,py), 3.06 (td, 2J = 8.9 Hz, 3J = 3.6 Hz, 1H, 5-CH2,py), 3.30 (ddd, J = 5.6 / 2.8 / 2.2 Hz, 1H, 1-CHcycl), 3.51 (dd, J = 8.8 / 4.9 Hz, 1H, 2-CHpy), 3.66 (s, 3H, OCH3), 5.62 (d, J = 10.0 Hz, 1H, 2-CHcycl), 5.78 (dtd, 3J = 10.0 / 4.6 Hz, 4J = 0.8 Hz, 1H, 3-CHcycl). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 21.4 (C-6cycl), 24.0 (C-5cycl), 25.5 (C-6cycl), 27.6 (C-4py), 30.2 (C-3py), 49.1 (C-5py), 52.0 (OCH3), 56.9 (C-1cycl), 62.4 (C-2py), 127.4 (C-2cycl), 130.9 (C-3cycl), 175.8 (C = O). FT-IR: υ (cm
1) = 2926 (s, C-H), 2855 (m, C-H), 1732 (s, C = O). The absolute configuration of 4eA and 4eB could not be assigned. (2S)-1-[(1R)- or (1S)-Cyclohex-2-en-1-yl]pyrrolidine-2-carbohydrazide (4fA). The methyl ester 4eA (69 mg, 0.33 mmol, 1.0 equiv.) was

dissolved in ethanol (2 mL). Hydrazine hydrate (280 μL, 5 mmol, 15 equiv.) was added. The mixture was stirred at room temperature (r.t.) for 48 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 and purified by FC (d = 3 cm, h = 5 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 1 : 1 ➔ 0 : 1 ➔ ethyl acetate : methanol = 3 : 1, Rf = 0.70 (TLC, ethyl acetate : methanol = 1:1, detection: KMnO4)) to afford the hydrazide 4fA. Pale yellow oil, yield 64 mg (94%), C11H19N3O (209.2 g/mol). ½α22:6 D = 23.4 (c = 1.0, CHCl3). Two sets of signals (1H NMR intensity ratio = 7:3) are seen in the NMR spectra due to rotational isomerism. 1H NMR (400 MHz, CD3OD): δ (ppm) = 1.36–1.47 (m, 1H, 6-CH2,cycl), 1.48–1.65 (m, 1H, 5-CH2,cycl), 1.65–1.81 (m, 3H, 5-CH2,cycl, 4-CH2,py), 1.81–1.93 (m, 2H, 6CH2,cycl, 3-CH2,py), 2.53 (ddd, 2J = 9.3 Hz, 3J = 8.8 / 6.1 Hz, 0.3x1H, 5-CH2,py), 1.93–2.09 (m, 3H, 4-CH2,cycl, 3-CH2,py), 2.70 (ddd, 2J = 8.9 Hz, 3J = 6.9 / 2.9 Hz, 0.7x1H, 5-CH2,py), 3.09 (ddd, 2 J = 8.9 Hz, 3J = 6.5 / 2.1 Hz, 0.7x1H, 5-CH2,py), 3.13 (ddd, 2 J = 9.3 Hz, 3J = 6.0 / 2.0 Hz, 0.3x1H, 5-CH2,py), 3.28 (td, J = 5.3 / 2.7 Hz, 0.3x1H, 1-CHcycl), 3.31 (td, J = 3.3 / 1.7 Hz, 0.7x1H, 1CHcycl), 3.33 (dd, J = 10.2 / 3.0 Hz, 0.3x1H, 2-CHpy), 3.41 (dd, J = 10.0 / 3.2 Hz, 0.7x1H, 2-CHpy), 5.64 (ddd, 3J = 10.4 / 4.0 Hz, 4 J = 2.4 Hz, 1H, 2-CHcycl), 5.84 (ddd, J = 10.2 / 6.0 / 3.9 Hz, 1H, 3-CHcycl). Signals for the NH and NH2 protons are not seen in the spectrum. 13C{1H} NMR (100 MHz, CD3OD): δ (ppm) = 22.4 (C-4py, both), 25.2 (C-4cycl, minor), 25.3 (C-4cycl, major), 26.3 (C-6cycl, major), 26.4 (C-6cycl, minor), 27.1 (C5cycl, minor), 28.0 (C-5cycl, major), 32.3 (C-3py, major), 32.9 (C-3py, minor), 51.7 (C-5py, major), 51.8 (C-5py, minor), 58.5 (C-1cycl, major), 58.6 (C-1cycl, minor), 62.7 (C-2py, major), 64.4 (C-2py, minor), 128.4 (C-2cycl, minor), 128.9 (C-2cycl, major), 131.8 (C-3cycl, major), 132.1 (C-3cycl, minor), 172.4 (C = O, minor), 177.0 (C = O, major). FT-IR: υ (cm
1) = 3316 (b, N-H), 2934 (s, C-H), 2866 (s, C-H), 1636 (s, C = O). Exact mass (ESI+): m/z = 210.16004 (calcd. 210.15281 for C11H20N3O [MH]+). The absolute configuration of 4fA could not be assigned. (2S)-N-Hydroxy-1-[(1R)- and (1S)-cyclohex-2-en-1-yl]pyrrolidine2-carboxamide (4gA/B). The methyl ester 4e (266 mg,

1.27 mmol, 1.0 equiv.) was dissolved in abs. methanol (4 mL). Hydroxylamine hydrochloride (884 mg, 12.7 mmol, 10 equiv.) and sodium methoxide (756 mg, 14 mmol, 11 equiv.) were added to the stirred solution. The mixture was heated to reflux for 45 min, then immobilized on silica gel (1 g) and purified by FC (cyclohexane : ethyl acetate = 1 : 0 ➔ 1 : 1 ➔ 3 : 1, Rf = 0.40 (TLC, cyclohexane : ethyl acetate (1:1), detection: KMnO4)) to afford a 1:1 mixture of the diastereomers 4gA and 4gB. Pale yellow oil, yield 254 mg (95%), C11H18N2O2 (210.3 g/mol). ½α22:7 = –25.6 (c = 1.0, MeOH). D Chirality DOI 10.1002/chir

796

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Two sets of signals (1H NMR intensity ratio = 1:1) are seen in the NMR spectra originating from two diastereomers. 1H NMR (400 MHz, CD3OD): δ (ppm) = 1.33–1.46 (m, 1H, CH2CH-CH = CH), 1.46–1.61 (m, 1H, CH2-CH2-CH = CH), 1.61– 1.88 (m, 4H, CH2-CH-CH = CH, CH2-CH2-N, CH2-CH2-CH = CH), 1.88–2.09 (m, 4H, CH2-CH-CO, CH = CH-CH2), 2.56–2.65 (m, 1H, CH2-N), 2.96 (ddd, J = 9.0 / 6.5 / 2.4 Hz, 0.5H, CH2N), 2.99–3.05 (m, 0.5H, CH2-N), 3.20–3.29 (m, 1H, CH-CH = CH), 3.48 (dd, J = 9.4 / 3.3 Hz, 0.5H, CH-CO), 3.51 (dd, J = 11.1 / 3.3 Hz, 0.5H, CH-CO), 5.55 (d, J = 10.3 Hz, 0.5H, CH = CH-CH2), 5.57 (d, J = 10.6 Hz, 0.5H, CH = CH-CH2), 5.84 (ddd, J = 10.0 / 6.3 / 2.2 Hz, 1H, CH = CH-CH2). Signals for the NH and OH protons are not seen in the spectrum. 13C{1H} NMR (100 MHz, CD3OD): δ (ppm) = 21.3 (CH2-CH2-CH = CH), 21.7 (CH2-CH2-CH = CH), 24.7 (CH2-CH2-N), 24.9 (CH2-CH2-N), 25.4 (CH = CH-CH2), 25.5 (CH = CH-CH2), 27.3 (CH2-CH-CH = CH), 28.6 (CH2-CH-CH = CH), 31.2 (CH2-CH-CO), 31.4 (CH2CH-CO), 48.9 (CH2-N), 51.0 (CH2-N), 57.7 (CH-CH = CH), 61.6 (CH-CO), 63.6 (CH-CO), 127.2 (CH = CH-CH2), 127.7 (CH = CH-CH2), 131.3 (CH = CH-CH2), 131.6 (CH = CH-CH2), 172.4 (CONHOH), 172.8 (CONHOH). FT-IR: υ (cm
1) = 3174 (bs, O-H, N-H), 2927 (s, C-H), 2859 (s, C-H), 1650 (s, C = O). Exact mass (ESI+): m/z = 211.1441 (calcd. 211.1447 for C11H19N2O2 [MH]+). tert-Butyl cyclohex-2-en-1-yl carbonate (9c).16

Cyclohex-2-en-1ol (551 mg, 5.62 mmol, 1.0 equiv.) was dissolved in absolute (abs.) THF (19 mL) and cooled to –78°C using a dry ice / acetone bath. A solution of n-butyllithium in n-hexane (1.6 M, 3.5 mL, 5.62 mmol, 1.0 equiv.) was added dropwise. The mixture was subsequently warmed to 0°C and stirred for 5 min. A solution of di-tert-butyl dicarbonate (1.16 g, 5.34 mmol, 0.95 equiv.) in abs. THF (8 mL) was slowly added. The mixture was warmed to ambient temperature and stirred for 4 h. It was then diluted with ethyl acetate (25 mL) and washed with H2O (2 x 25 mL) and brine (20 mL). The organic layer was separated, dried (NaSO4), and concentrated under reduced pressure. The residue was purified by FC (d = 4 cm, l = 15 cm, V = 60 mL, 0 : 1 ➔ 999 : 1 ➔ 99 : 1 petroleum ether : ethyl acetate, Rf = 0.68 (TLC, cyclohexane : ethyl acetate = 4 : 1, detection: KMnO4)) to afford the desired carbonate 5c. Pale yellow oil, yield 1.04 g (100%), C11H18O3 (198.3 g/mol). Spectroscopic data are identical to the reported data. (S)-1-Phenylpyrrolidine-2-carboxamide (11). The

amide 4c (200 mg, 1.03 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (3 mL). n-Pentane (5 mL) and NEt3 (0.32 mL, 2.3 mmol, 2.2 equiv.) were added and the resulting mixture was cooled to 0°C. Chlorotrimethylsilane (0.29 mL, 2.3 mmol, 2.2 equiv.) was added dropwise. The mixture was warmed to ambient temperature and stirred for 30 min. The mixture was filtered (glass frit, no. 4) and the residue was dried by flushing with nitrogen. The residue was dissolved in abs. THF (15 mL). A solution of iodine (575 mg, 2.27 mmol, 2.2 equiv.) in abs. THF (10 mL) was added and the resulting mixture was heated to reflux for 25 h. The mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous NaHCO3 solution (20 mL) and a saturated aqueous Na2S2O5 solution (2 x 20 mL). The combined aqueous layers were extracted with ethyl acetate (25 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to afford the crude product (192 mg), which was purified by precipitation from solution Chirality DOI 10.1002/chir

in ethyl acetate (10 mL) with Et2O (40 mL). Washing with Et2O (20 mL) afforded the aniline 11. Yellow solid, mp 138– 139°C, yield 150 mg (77%), C11H14N2O (190.2 g/mol). 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.95–2.01 (m, 2H, 4-CH2, 2 3 py), 2.15–2.25 (m, 2H, 3-CH2,py), 3.16 (ddd, J = 9.8 Hz, J = 8.4 2 3 / 5.1 Hz, 1H, 5-CH2,py), 3.58 (ddd, J = 9.8 Hz, J = 6.8 / 2.4 Hz, 1H, 5-CH2,py), 3.93 (t, J = 6.0 Hz, 1H, 2-CHpy), 6.05 (bs, 1H, NH2), 6.43 (bs, 1H, NH2), 6.58 (d, J = 8.4 Hz, 2H, 2-CHar), 6.74 (t, J = 7.3 Hz, 1H, 4-CHar), 7.19 (dd, J = 8.4 / 7.3 Hz, 2H, 3-CHar). 13 C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 24.4 (C-4py), 31.6 (C-3py), 49.8 (C-5py), 64.1 (C-2py), 113.2 (C-2ar), 118.3 (C-4ar), 129.6 (C-3ar), 147.4 (C-1ar), 177.9 (C = O). FT-IR: υ (cm1 ) = 3296 (bs, N-H), 2944 (s, C-H), 2870 (s, C-H), 1669 (s, C = O). Exact mass (ESI+): m/z = 213.0994 (calcd. 213.1004 for C11H14N2ONa [MNa]+). Spectroscopic data are identical to the reported data.20 Methyl (S)-1-[(1R)- and (1S)-cyclohex-2-en-1-yl]-5-oxopyrrolidine2-carboxylate (13aA/B). NaH (60%-w/w suspension in min-

eral oil, 399 mg, 9.97 mmol, 1.5 equiv.) was suspended in CH2Cl2 (15 mL) and the resulting mixture was cooled to 0° C. (S)-Methyl pyroglutamate (12, 0.78 mL, 6.6 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred at 0°C for 15 min. The bromide 9b (1.95 mL, 16.6 mmol, 2.5 equiv.) was added and the resulting mixture was heated to reflux for 24 h. After cooling to ambient temperature, a small amount of water was carefully added until complete solution of salts. The resulting mixture was diluted with brine (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by FC (d = 8 cm, l = 12 cm, V = 100 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 7 : 1 ➔ 3 : 1 ➔ 1 : 1, Rf = 0.31 (TLC, cyclohexane : ethyl acetate = 1 : 1)) to afford a 1:1 mixture of the diastereomers 13aA and 13aB. Pale yellow oil, yield 1.03 g (70%), C12H17NO3 (223.3 g/mol). ½α27:7 = -28.4 (c = 0.13, D CHCl3). 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.28–1.40 (m, 0.5x1H, 6-CH2,cycl), 1.52–1.63 (m, 0.5x1H, 5-CH2,cycl), 1.63–1.73 (m, 2H, 6-CH2,cycl, 5-CH2,cycl), 1.73–1.80 (m, 0.5x1H, 6-CH2,cycl), 1.80–1.90 (m, 0.5x1H, 6-CH2,cycl), 1.92–1.97 (m, 2H, 4-CH2,cycl), 1.97–2.02 (m, 1H, 3-CH2,py), 2.17–2.28 (m, 1H, 3-CH2,py), 2.26–2.31 (m, 0.5x1H, 4-CH2,py), 2.31–2.36 (m, 0.5x1H, 4-CH2,py), 2.58 (dd, 2J = 10.2 Hz, 3J = 9.0 Hz, 0.5x1H, 4CH2,py), 2.62 (dd, 2J = 10.3 Hz, 3J = 9.5 Hz, 0.5x1H, 4-CH2,py), 3.70 (s, 0.5x3H, CH3), 3.73 (s, 0.5x3H, CH3), 4.17 (dd, J = 9.1 / 1.4 Hz, 0.5x1H, 2-CHpy), 4.21 (dd, J = 9.1 / 1.8 Hz, 0.5x1H, 2-CHpy), 4.73 (ddd, J = 8.6 / 6.0 / 2.8 Hz, 1H, 1-CHcycl), 5.33 (dd, J = 10.0 / 8.6 Hz, 0.5x1H, 2-CHcycl), 5.39 (ddd, 3J = 10.0 / 4.7 Hz, 4J = 2.5 Hz, 0.5x1H, 2-CHcycl), 5.83 (ddd, J = 10.0 / 6.4 / 3.7 Hz, 0.5x1H, 3CHcycl), 5.90 (ddd, J = 10.0 / 6.5 / 3.3 Hz, 0.5x1H, 3-CHcycl). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) = 20.9 (C-5cycl), 21.3 (C5cycl), 24.1 (C-4cycl), 24.6 (C-3py, C-4cycl), 24.9 (C-3py), 27.0 (C6cyclx2), 30.1 (C-4pyx2), 48.1 (C-1cycl), 48.8 (C-1cycl), 52.4 (CH3), 52.5 (CH3), 57.6 (C-2py), 58.0 (C-2py), 126.0 (C-2cycl), 127.1 (C-2cycl), 131.9 (C-3cycl), 132.3 (C-3cycl), 173.8 (O-C = O), 174.0 (O-C = O), 175.4 (N-C = O), 175.6 (N-C = O). FT-IR: υ (cm-1) = 2935 (m, C-H), 2866 (m, C-H), 1741 (s, OC = O), 1686 (s, NC = O). Exact mass (APCI): m/z = 224.1322 (calcd. 224.1287 for C12H18NO3 [MH]+). tert-Butyl N-{(S)-1-[(1R)- and (1S)-cyclohex-2-en-1-yl]-5-oxopyrrolidine2-carbonyl}carbamate (13bA/B). The methyl ester 13a (100 mg,

0.448 mmol, 1.0 equiv.) and tert-butyl carbamate (78 mg, 0.672 mmol, 1.5 equiv.) were dissolved in abs. THF (4 mL).

797

KEY STEP FOR PERHYDROPYRROLOQUINOXALINES

At –18 to –20°C, a solution of lithium tert-butoxide in THF (1 M, 1.35 mL, 1.35 mmol, 3.0 equiv.) was added dropwise. The mixture was stirred for 3 d under slow warming to ambient temperature. A saturated aqueous NH4Cl solution (2 mL) was carefully added and the mixture was diluted with water (2 mL). The resulting layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by FC (d = 2 cm, l = 7 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 7 : 1 ➔ 7 : 3 ➔ 1 : 1, Rf = 0.15 (TLC, cyclohexane : ethyl acetate = 1 : 1)) to afford a 1:1 mixture of the diastereomers 13bA and 13bB. Colorless solid, mp 87– 88°C, yield 130 mg (94%), C16H24N2O4 (308.4 g/mol). ½α24:5 D = -30.2 (c = 0.13, CHCl3). 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.32–1.48 (m, 1H, 6-CH2,cycl, A/B), 1.49 (s, 0.5x9H, C(CH3)3, A), 1.50 (s, 0.5x9H, C(CH3)3, B), 1.52–1.64 (m, 0.5x1H, 5-CH2, cycl, A), 1.64–1.76 (m, 0.5x1H + 1H, 5-CH2,cycl, A/B), 1.76–1.85 (m, 0.5x1H, 6-CH2,cycl, A), 1.85–1.93 (m, 0.5x1H, 6-CH2,cycl, B), 1.93–2.07 (m, 3H, 4-CH2,cycl, A/B, 4-CH2,py, A), 2.25–2.40 (m, 2H, 3-CH2,py, A/B), 2.47–2.60 (m, 1H, 4-CH2,py, B), 4.78–4.67 (m, 1H, 1-CHcycl, A/B), 4.83–4.94 (m, 0.5x1H, 2-CHpy, B), 5.02–5.15 (m, 0.5x1H, 2-CHpy, A), 5.38 (d, J = 10.1 Hz, 0.5x1H, 2CHcycl, B), 5.49 (dd, J = 10.1 / 2.5 Hz, 0.5x1H, 2-CHcycl, A), 5.86 (ddd, J = 10.1 / 6.4 / 4.2 Hz, 0.5x1H, 3-CHcycl, A), 5.90 (ddd, J = 10.1 / 6.8 / 3.8 Hz, 0.5x1H, 3-CHcycl, B), 7.53 (s, 0.5x1H, NH, A), 7.59 (s, 0.5x1H, NH, B). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 20.6 (C-5cycl, A), 21.4 (C-5cycl, B), 24.7 (C-3py, A/B), 24.8 (C-4cycl, A), 25.3 (C-4cycl, B), 27.5 (C-6cycl, A/B), 28.1 (C(CH3)3, A/B), 29.8 (C-4py, B), 29.9 (C-4py, A), 48.1 (C1cycl, A), 49.1 (C-1cycl, B), 58.2 (C-2py, A/B), 83.4 (C(CH3)3, A), 83.5 (C(CH3)3, B), 126.1 (C-2cycl, A), 127.4 (C-2cycl, B), 132.1 (C-3cycl, B), 132.3 (C-3cycl, A), 150.1 (N-(C = O)-O, B), 162.7 (N(C = O)-O, A), 175.9 (CH2-C = O, A/B), 176.1 (CH-C = O, A/B). FT-IR: υ (cm
1) = 3267 (bw, N-H), 2978 (m, C-H), 2940 (m, CH), 1767 (s, (C = O)NH(C = O)symm.), 1690 (s, (C = O)NH (C = O)antisymm.), 1663 (s, CH2C = O). Exact mass (APCI): m/z = 309.1789 (calcd. 309.1814 for C16H25N2O4 [MH]+). tert-Butyl N-{(S)-1-[(1S)-cyclohex-2-en-1-yl]-5-oxopyrrolidine-2carbonyl}carbamate (13bB) and tert-Butyl (3aS,5aR,6R,9aR)-6-bromo1,4-dioxoperhydropyrrolo[1,2-a]quinoxali-ne-5-carboxylate (14A). A

1:1 mixture of the diastereomers 13bA and 13bB (250 mg, 0.811 mmol, 1.0 equiv.) was dissolved in abs. THF (15 mL). The mixture was cooled to –23°C using an NaCl/ice mixture. A solution of lithium tert-butoxide in THF (1 M, 0.89 mL, 0.89 mmol, 1.1 equiv.) was added dropwise to the stirred mixture. Stirring was continued for 1 h at 0°C. At –23°C and under protection from light, a solution of N-bromosuccinimide (289 mg, 1.62 mmol, 2.0 equiv.) in abs. THF (10 mL) was added dropwise. The resulting mixture was stirred at –23°C for 14 h. A saturated aqueous Na2SO3 solution (3 mL) and a saturated aqueous NH4Cl solution (3 mL) were carefully added and the mixture was diluted with water (5 mL). The resulting layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by FC (d = 3 cm, l = 10 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 ➔ 7 : 1 ➔ 7 : 3 ➔ 1 : 1) to obtain the bromolactam 14A and unreacted, diastereoenriched carbamate 13bB. 14A [Rf = 0.20 (TLC, cyclohexane : ethyl acetate = 1:1)]: colorless foam, mp 113–115°C, yield 149 mg (47%), C16H23BrN2O4 (387.3 g/mol). ½α24:8 = -18.2 (c = 0.10, CHCl3). 1H NMR D

(400 MHz, CDCl3): δ (ppm) = 1.51–1.60 (m, 10H, 7-CH2, C (CH3)3), 1.61–1.75 (m, 2H, 8-CH2), 1.83–1.91 (m, 2H, 2-CH2), 2.30–2.44 (m, 2H, 3-CH2, 9-CH2), 2.45–2.61 (m, 2H, 3-CH2, 9CH2), 2.64–2.73 (m, 1H, 7-CH2), 4.16 (td, J = 11.1 / 4.6 Hz, 1H, 6-CH), 4.20–4.24 (m, 1H, 9a-CH), 4.39 (dd, J = 8.5 / 5.4 Hz, 1H, 3a-CH), 4.82 (dd, J = 11.1 / 5.6 Hz, 1H, 5a-CH). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 20.8 (C-3), 21.4 (C-8), 27.9 (C-7), 28.1 (C(CH3)3), 30.2 (C-9), 36.5 (C-2), 52.1 (C-6), 52.3 (C-9a), 58.8 (C-3a), 59.7 (C-5a), 84.9 (C(CH3)3), 151.3 (N-(C = O)-O), 168.2 (C-4), 175.9 (C-1). FT-IR: υ (cm-1) = 2982 (m, C-H), 2932 (m, C-H), 1774 (s, (C = O)NH(C = O)symm.), 1713 (s, (C = O)NH (C = O)antisymm.), 1694 (s, 1-C = O). Exact mass (APCI): m/z = 287.0313 (calcd. 287.0395 for C11H79 16BrN2O2 [MH - CH2 = C(CH3)2CO2]+), 289.0293 (calcd. 289.0375 for C11H81 16BrN2O2 [MH - CH2 = C(CH3)2CO2]+), 331.0216 (calcd. 331.0293 for + C12H79 16BrN2O4 [MH - CH2 = C(CH3)2] ), 333.0196 (calcd. 81 333.0273 for C12H16BrN2O4 [MH - CH2 = C(CH3)2]+), 387.0831 (calcd. 387.0919 for C16H79 [MH]+), 389.0811 24BrN2O4 + (calcd. 389.0899 for C16H81 BrN O [MH] ). The differences 24 2 4 between observed and calculated values are greater than 5 mDa due to the formation of decomposition products under acidic conditions. 13bB [Rf = 0.13 (TLC, cyclohexane : ethyl acetate = 1:1)]: colorless solid, mp 87–88°C, yield 83 mg (33%), C16H24N2O4 (308.4 g/mol). ½α23:1 = -116.2 (c = 0.13, CHCl3). 1H NMR D (400 MHz, CDCl3): δ (ppm) = 1.33–1.46 (m, 1H, 6-CH2,cycl), 1.50 (s, 9H, C(CH3)3), 1.71–1.73 (m, 1H, 5-CH2,cycl), 1.84–1.94 (m, 2H, 5-CH2,cycl, 6-CH2,cycl), 1.95–2.02 (m, 2H, 4-CH2,cycl), 2.29–2.42 (m, 3H, 3-CH2,py, 4-CH2,py), 2.50–2.59 (m, 1H, 3-CH2,py), 4.69–4.77 (m, 1H, 1-CHcycl), 4.87–5.00 (m, 1H, 2-CHpy), 5.39 (ddt, 3J = 10.0 / 2.1 Hz, 4J = 1.2 Hz, 1H, 2-CHcycl), 5.83–6.00 (m, 1H, 3-CHcycl), 7.60 (s, 1H, NH). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 21.4 (C-5cycl), 24.7 (C-3py), 25.3 (C-4cycl), 27.0 (C-6cycl), 28.1 (C(CH3)3), 29.8 (C-4py), 49.2 (C-1cycl), 58.2 (C-2py), 83.6 (C(CH3)3), 127.3 (C-2cycl), 132.2 (C-3cycl), 150.1 (N-(C = O)-O), 175.8 (CH2-C = O), 176.6 (CH-C = O). FT-IR: υ (cm
1) = 3325 (bs, N-H), 3179 (s, N-H), 2936 (s, C-H), 2870 (m, C-H), 1775 (m, (C = O)NH(C = O)symm.), 1670 (bs, (C = O) NH(C = O)antisymm., CH2C = O). Exact mass (APCI): m/z = 209.1300 (calcd. 287.1290 for C11H17N2O2 [MH - CH2 = C (CH3)2CO2]+), 309.1788 (calcd. 309.1814 for C16H25N2O4 [MH]+).

RESULTS AND DISCUSSION

In order to obtain appropriate starting material for the cyclization, (S)-prolinamide (8a) and (S)-proline methyl ester (8b) were allylated with cyclohexenyl chloride (9a) and -bromide (9b), respectively, available from cyclohexene by Wohl-Ziegler reaction.17 (Scheme 1) In the presence of DBU the cyclohexenyl substituted proline derivatives 4c and 4e were obtained both in 82% yield. The methyl ester 4e was also prepared by Pd-catalyzed Tsuji-Trost reaction of the cyclohexenyl carbonate 9c with proline ester 8b in 70% yield. However, the amide 8a did not react with the carbonate 9c under the same Pd-catalyzed conditions. The allylation products 4c and 4e were obtained as approximate 1:1 mixtures of the diastereomers A and B (55:45 to 51:49 according to 1H NMR signal intensity). The diastereomeric esters 4eA and 4eB were separated by silver ion flash chromatography. However, despite careful analysis, NMR experiments did not allow the unequivocal assignment of the relative configuration. Chirality DOI 10.1002/chir

798

SCHULTE ET AL.

Scheme 1. Synthesis of various N-cyclohexenyl-substituted (S)-proline derivatives 4. Reagents and reaction conditions: (a) Y = Cl, DBU, DMSO:cyclohexane (3:5), r.t., 2.5 d, 82% (4c); (b) Y = OBoc, NEt3, Pd(PPh3)4, DMSO : CH2Cl2 (1 : 1), 1 d, 0% (4c); (c) Y = Br, DBU, DMSO:cyclohexane (1:1), r.t., 6 d, 82% (4e); (d) Y = OBoc, NEt3, Pd(PPh3)4, DMSO, r.t., 1 d, 70% (4e); (e) 1. NaH, CH2Cl2, 0°C ➔ r.t., 45 min; 2. Boc2O, CH2Cl2, r.t., 2.5 d, 87% (4d); (f) N2H4 ∙ H2O, EtOH, reflux, 48 h, 93% (4f); (g) H2NOH ∙ H2O, NaOMe, MeOH, reflux, 45 min, 95% (4 g).

The precursors for the planned [3 + 2] cycloaddition and electrophilic aziridination, i.e., the hydrazide 4f and the hydroxamic acid 4g, were produced by aminolysis of the methyl ester 4e with hydrazine and hydroxylamine monohydrate, respectively. The hydrazide 4f was treated with tert-butyl nitrite according to a known procedure,18 which however afforded a complex mixture of products. The reaction of the hydroxamic acid 4g with p-toluenesulfonyl chloride also led to decomposition. Therefore, the amide 4c should be used for the transfer of chirality from the N-atom to the double bond of the cyclohexene ring. The cyclization of δ,ε-unsaturated amides into δ-lactams by conversion into N,O-bis(trimethylsilyl) imidoesters and subsequent treatment with I2 at 0°C was reported by Knapp and Levorse.19 Therefore, the prolinamide 4c was treated with TMS-Cl to form the intermediate imidoester 10, which was reacted with I2. (Scheme 2). However, at a reaction temperature of 0°C a conversion into the iodolactam 7a could not be observed. Prolonged (24 h) heating under reflux of the reaction mixture led to oxidation of the cyclohexene moiety and the phenyl-substituted prolinamide 1120 was isolated in 77% yield. According to the bromolactamization protocol developed by Yeung and Corey,21 N-Boc-protected amides are deprotonated with LiOtBu at –20°C and subsequently treated with NBS to form bromolactams. Therefore, the prolinamide 4c was converted into the N-Boc amide 4d by deprotonation with NaH followed by reaction with di-tert-butyl dicarbonate. (Scheme 1) However, deprotonation of the N-Boc amide 4d with LiOtBu and subsequent addition of NBS at –23°C did not lead to any conversion of 4d. Increasing the temperature

Scheme 2. Halolactamization vs. aromatization of N-cyclohexenylproline derivatives 4c and 4d. Reagents and reaction conditions: (a) (H3C)3SiCl, NEt3, n-pentane:CH2Cl2 (5:3), 0°C ➔ r.t., 30 min; (b) under N2: I2, THF, reflux, t 25 h, 77% (11). (c) under N2: LiO Bu, THF, –23°C, 1 h; 2. NBS, THF, reflux. Chirality DOI 10.1002/chir

stepwise from –23°C up to +66°C resulted finally in transformation. However, due to oxidation of the cyclohexene ring, only 1-phenyl (11) and 1-(bromophenyl) substituted prolinamides were detected by ESI-MS. In order to inhibit the oxidation of the cyclohexene ring, the electron-donating properties of the tertiary amino moiety of the proline derivatives 4c and 4d should be reduced by employing (S)-pyroglutamate derivatives 13. At first, methyl (S)-pyroglutamate (12) was deprotonated with NaH and subsequently treated with cyclohexenyl bromide (9b) to give the cyclohexenyl substituted pyroglutamate 13a in 70% yield. Deprotonation of tert-butyl carbamate with LiOtBu and reaction of this anion with the methyl ester 13a provided the N-Boc amide 13b as a 1:1 mixture of diastereomers in 94% yield (Scheme 3). Reaction of the 1:1 mixture of diastereomeric N-Boc amides (S,R)-13bA and (S,S)-13bB with LiOtBu and subsequently with NBS at –23°C according to the bromolactamization conditions developed by Yeung and Corey21 provided the tricyclic bromolactam (S,R,R,R)-14A and the N-Boc amide (S,S)-13bB in 47% and 33% yield, respectively. The relative configuration of the pyrroloquinoxaline (S,R,R, R)-14A was assigned by NMR spectroscopy and the results are consistent with those for cis,trans-configured iodolactones.22 The coupling constants of the methyne protons on the cyclohexane ring, J5a/6 = 11.1 Hz and J5a/9a = 5.6 Hz, indicate an axial orientation of 5a-H and 6-H and an equatorial orientation of 9a-H. This relative configuration of (S,R,R,R)14A is supported by a NOESY experiment showing a crosscorrelation between 5a-H and 9a-H. In contrast to the gCOSY spectrum, a cross-correlation between 5a-H and 6-H is not observed, indicating a 5a,9a-cis and a 5a,6-trans relative configuration. A further cross-correlation is observed between 3a-H and 9a-H, proving the cis-orientation of these protons. Since the absolute (S)-configuration of C-3a is given by the starting material methyl (S)-pyroglutamate (12), the absolute configuration of the complete molecule is defined as (3aS,5aR,6R,9aR). The diastereomeric N-Boc amide (S,S)-13bB did not react under these reaction conditions and was reisolated in 33% yield. The 1H NMR spectrum shows a ratio of (S, R)-13bA : (S,S)-13bB of 7:93, indicating a kinetically

Scheme 3. Synthesis and stereoselective bromolactamization of Ncyclohexenylpyroglutamate derivatives 13b. Reagents and reaction conditions: (a) 1. NaH, CH2Cl2, 0°C, 15 min; 2. 9b, CH2Cl2, reflux, 24 h, 70%. (b) t t BocNH2, LiO Bu, THF, –23°C ➔ r.t., 3 d, 94%. (c) under N2: 1. LiO Bu, THF, –23°C, 1 h; 2. NBS, THF, –23°C, 14 h, (S,R,R,R)-14A: 47%, (S,S)-13bB: 33%.

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that conformer 13bA-I of (S,R)-13bA with the N-Boc amide moiety directing towards the cyclohexene double bond is energetically favored. In the diastereomer (S,S)-13bB the conformer II has the lower energy with the N-Boc amide moiety oriented in the opposite direction. In total, three new stereogenic centers were established upon formation of the perhydropyrroloquinoxaline (S,R,R,R)-14A with high diastereoselectivity starting from (S)-pyroglutamate. ACKNOWLEDGMENT

Fig. 3. Conformational analysis of diastereomers (S,R)-13bA and (S,S)13bB. Top: Diagram of the heat of formation during rotation around the CN bond C2-C1-N-C(=O) of diastereomer (S,R)-13bA. Middle: Diagram of the heat of formation during rotation around the C-N bond C2-C1-N-C(=O) of diastereomer (S,S)-13bB. Bottom: Summary of the relative heat of formation and the energy barrier of the energetically most favored conformers of both diastereomers.

controlled differentiation of the diastereomers during the bromolactamization step. The preferred bromolactamization of the (S,R)-configured N-Boc amide (S,R)-13bA opposed to (S,S)-13bB might be explained by analyzing the conformational flexibility of the diastereomers. The structures were minimized at the PM3 level. Dihedral driver analysis of the allylic C–N bond [ϕ (C2-C1-N-C(=O))] led to at least two minima in which either the N-Boc amide (I) or the lactam carbonyl moiety (II) are approximately in syn-periplanar orientation with the olefinic double bond.23 It was found that conformer 13bA-I of (S, R)-13bA is more stable than conformer 13bA-II by 15.7 kJ/mol. The formation of the observed product (S,R,R, R)-14A might be explained by reaction of the imidate anion of conformer (S,R)-13bA-I with the double bond of the cyclohexene moiety. On the other hand, for diastereomer (S,S)-13bB conformer 13bB-II is energetically favored over the conformer 13bB-I by 11.8 kJ/mol. The preferred orientation of the N-Boc amide moiety away from the cyclohexene double bond in 13bB-II might explain the reduced reactivity of (S,S)-13bB during bromolactamization reaction. The rotational barrier lies at 63–70 kJ/mol for both diastereomers. (Fig. 3) CONCLUSION

The results show that the cyclization of N-cyclohexenylsubstituted proline derivatives strongly depends on the nature of the allylic N-atom. Thus, all attempts to cyclize the hydrazide 4f, the hydroxamic acid 4g, the amide 4c as well as the N-Boc made 4d with basic pyrrolidine N-atom led to decomposition or aromatization of the cyclohexene moiety. In contrast, the N-Boc amide (S,R)-13bA reacted with LiOtBu and NBS to give the tricyclic bromolactam (S,R,R,R)-14A. The bromolactamization is strongly dependent on the configuration of the N-Boc amide, since only the (S,R)-configured N-Boc amide (S,R)-13bA reacted to give the tricyclic product 14A. The diastereomer (S,S)-13bB remained unchanged and could be reisolated. Moreover, the bromolactamization took place with excellent diastereoselectivity, affording the cis-configured perhydroquinoxaline (S,R,R,R)-14A exclusively. A conformational analysis at the PM3 level revealed

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