Synthesis of morphan derivatives with additional substituents in 8-position

Janine Stefaowitz 1 , Dirk Schepmann 1 , Constantin Daniliuc 2 , Susumu Saito 3  and Bernhard Wünsch 1 , 4
  • 1 Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany
  • 2 Organisch-Chemisches Institut, Corrensstraße 40, D-48149 Münster, Germany
  • 3 Research Center for Materials Science, Nagoya University Chikusa, Nagoya 464-8602, Japan
  • 4 Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-Universität Münster, Germany, Tel.: +49-251-8333311, Fax: +49-251-8332144
Janine Stefaowitz, Dirk Schepmann, Constantin Daniliuc, Susumu Saito and Bernhard Wünsch

Abstract

The morphan system (2-azabicyclo[3.3.1]nonane) as a substructure of morphine is of major interest in medicinal chemistry. Herein, the synthesis of morphan derivatives with additional substituents at the propano bridge is reported. In order to avoid the isolation of the smelly and volatile nitrile 6 and the very polar primary amine 9, an efficient one-pot, three-step sequential transformation of the mesylate 5 into amides 10 was developed. The key step of the synthesis was the stereoselective intramolecular opening of the epoxides 11ad leading to the exo-configured 8-hydroxymorphans 12ad. The configuration of the exo-configured hydroxymorphan 12d bearing the κ- and σ-pharmacophoric 3,4-dichlorophenylacetyl moiety was inverted by oxidation and stereoselective reduction. An X-ray crystal structure analysis of the benzamide 12c confirmed the relative configuration of the hydroxymorphans 12ad and 14d.

1 Introduction

The bicyclic morphan system (2-azabicyclo[3.3.1]nonane) represents a substructure of the natural product morphine (Fig. 1), which is isolated from the dried condensed juice of a poppy, Papaver somniferum. The strong analgesic effect of morphine is based on the activation of μ-, κ- and δ-opioid receptors in the central nervous system [1]. In order to find novel analgesics, compounds based on substructures of morphine were developed including morphinanes (without furan ring), benzomorphans (without cyclohexene ring), morphans (without phenyl ring) and piperidines (only piperidine ring is left) [2]. In Fig. 1 morphan 1 exhibiting strong analgesic activity is shown exemplarily [3].

Fig. 1:
Fig. 1:

Morphine and morphan derivatives 1 and 2.

Citation: Zeitschrift für Naturforschung B 71, 10; 10.1515/znb-2016-0129

In addition to strong analgesic activity, morphans are reported to interact with σ receptors as well. Originally, the σ receptor was regarded as an opioid receptor subtype [4], but nowadays the class of σ receptors is accepted to be an own class of receptors with a characteristic ligand binding profile and a distinct distribution pattern in the central nervous system and peripheral tissues [5, 6]. The σ receptor is subdivided into two subtypes, which are termed the σ1 and σ2 receptor. The morphan derivative 2 with a benzylidene moiety in 8-position adjacent to the carbonyl group in 7-position represents one of the most potent and selective σ2 receptor ligands (Ki2)=16.5 nm) known so far [7, 8].

Due to the promising σ2 affinity of 2 we are interested in morphan derivatives with additional substituents at the propano bridge (positions 6–8). Various methods for the synthesis of the morphan framework have been reported [9]. However, only few methods led to morphans with additional substituents at the propano bridge. The intramolecular aminoselenylation of a cyclohexene derivative [10], the gold-catalyzed intramolecular hydroamination of a cyclohexadiene derivative [11], the iodolactamization [12] and the intramolecular epoxide opening [13] represent the most promising approaches for the synthesis of morphan derivatives, which allow the further modification of the substitution pattern of the propano bridge.

In this project we decided to use cyclohexene derivatives (e.g. compounds 710) as starting materials. Reaction of the nitrogen atom in various functional groups of the side chain with the cyclohexene double bond should give the morphan system with an additional substituent in 8-position of the propano bridge.

2 Synthesis

According to the literature the nitrile 6 [14] was prepared by LiAlH4 reduction of the aldehyde 3, subsequent conversion of the resulting alcohol 4 into mesylate 5 and SN2 reaction of 5 with NaCN (Scheme 1). Working with nitrile 6 was very problematic due to the unpleasant smell of the compound, which is increased by its high volatility. Moreover, the high volatility of nitrile 6 has to be taken into account during concentration of solutions under reduced pressure.

Scheme 1:
Scheme 1:

Synthesis of 2-(cyclohexen-4-yl)acetamide derivatives.

Reagents and reaction conditions: (a) LiAlH4, THF, 0°C, 90 min, 93%. (b) MesCl, pyridine, 0°C, 2 h, 90%. (c) NaCN, DMSO, 110–120°C, 90 min, 90%. (d) Ru/chitin, H2O, 120°C, 24 h, 62%. (e) NaH, THF, r. t., 45 min, then (Boc)2O, THF, r. t., 2.5 d, 85%.

Citation: Zeitschrift für Naturforschung B 71, 10; 10.1515/znb-2016-0129

Iodolactamization of primary amide 7 was the first plan to construct the desired morphan skeleton. For the transformation of nitriles into primary amides, acid and base catalyzed hydration reactions have been reported [14, 15]. However, the yield after NaOH or H2SO4 catalyzed addition of H2O to the nitrile 6 did not exceed 40% despite several optimization experiments. Recently, Ru bound at the surface of chitin had been developed as a heterogenous nitrile hydration catalyst [16]. Reaction of nitrile 6 with the Ru-chitin catalyst in an aqueous medium at 120°C provided the primary amide 7 in 62% yield.

The iodolactamization has been reported for the cyclization of unsaturated aliphatic primary amides. For this purpose, the primary amide is reacted with trimethylsilyl triflate to yield an N,O-bis(trimethylsilyl) derivative, which is treated with I2 to form iodolactams [12, 17, 18]. Although several experiments were performed, starting with the primary amide 7 the desired iodolactam could not be detected.

Therefore a bromolactamization reaction of the N-Boc-amide 8 was envisaged. The N-Boc-amide 8 was prepared in 85% yield by deprotonation of the primary amide 7 with NaH and subsequent reaction of the anion with (Boc)2O. According to the method of Yeung and Corey [19], the N-Boc-amide was deprotonated with KOtBu and the anion was reacted with N-bromosuccinimide (NBS). However, all attempts failed to produce the brominated morphan derivative by bromolactamization of the N-Boc-amide 8.

Therefore it was planned to reverse the amide moiety, i.e. to attach the carbonyl moiety at the other side of the N atom as shown for the amides 10 (Scheme 2). Thus the nitrile 6 was reduced with LiAlH4 [20] to yield the primary amine 9, which was isolated as HCl salt in 76% yield. Acylation of the primary amine 9 yielded the amide 10. The benzamide 10c has already been described in the literature [13], the Boc- and Cbz derivatives 10a and 10b were selected due to the facile removal of these protecting groups, and the dichlorophenylacetyl moiety of 10d was introduced since κ-opioid receptor agonists [21, 22] and σ ligands [22, 23] often contain this substituent. The yield of the amide 10d was increased to 98% by DCC coupling of the free amine 9 with 2-(3,4-dichlorophenyl)acetic acid.

Scheme 2:
Scheme 2:

Synthesis of diastereomeric hydroxymorphans. Reagents and reaction conditions: (a) LiAlH4, THF, r. t., 12 and 14 h, 76% (9·HCl). (b) 9·HCl, RC(=O)Cl or (Boc)2O, NEt3, CH2Cl2, r. t., 2–4 h, 57–75% (10ad), (c) 1. 9·HCl, NaOH, CH2Cl2; then (3,4-dichlorophenyl)acetic acid, DCC, r. t., 3 h, 98%. (d) 1. KCN, 18-crown-6, THF, 85°C, 24 h; 2. LiAlH4, THF, 85°C, 24 h; 3. RC(=O)Cl. NaOH, 85°C, 3 h, 13% (10b), 30% (10d). (e) mCPBA, CHCl3, r. t., 18 h, 48–80%. (f) strong base, THF, 8–38%. (g) Dess-Martin periodinane, CH2Cl2, r. t., 18 h, 37%. (h) NaBH4, THF, EtOH, r. t., 12 h, 31%. The compounds 1214 were prepared as racemic mixtures. In the Scheme only one enantiomer is shown.

Citation: Zeitschrift für Naturforschung B 71, 10; 10.1515/znb-2016-0129

In order to avoid the purification and isolation of the volatile and smelly nitrile 6 and the polar primary amine 9, a one-pot three-step reaction sequence for the synthesis of carbamate 10b and (dichlorophenyl)acetamide 10d starting from mesylate 5 was developed. Mesylate 5 was reacted with KCN and 18-crown-6 in boiling THF to yield the nitrile 6. After cooling down, LiAlH4 was added to the reaction mixture to prepare the primary amine 9. The excess of LiAlH4 was destroyed by addition of H2O and NaOH. Without any separation benzyl chloroformate or (dichlorophenyl)acetyl chloride were added to produce the carbamate 10b and (dichlorophenyl)acetamide 10d in 13% and 30% yield over three steps, respectively.

As described for the iodolactamization of primary amide 7, the benzamide 10c was reacted with trimthylsilyl trilflate and then with I2. However, as described for 7 the formation of a morphan derivative could not be detected.

Therefore, instead of a halolactamization reaction the opening of epoxides was planned to obtain morphan derivatives with an additional OH moiety in the propano bridge. The epoxides 11 were obtained in 48–80% yields after reaction of the cyclohexene derivatives 10 with m-chloroperbenzoic acid (mCPBA) [24]. The benzamide 11c has already been reported [13]. According to an HPLC analysis the ratio of diastereomers of epoxides 11 was 55:45 to 60:40. The diastereomers cis-11d and trans-11d were separated by preparative HPLC (Agilent® Prep C18 column).

The intramolecular opening of the epoxide 11c (mixture of diastereomers) with KOtBu in boiling THF has already been reported by Dolby and Nelson [13]. However, instead of the reported yield of 40%, only 28% of the bicyclic alcohol 12c could be isolated using the same reaction conditions. After careful optimization of each cyclization, the hydroxymorphans 12a, 12c and 12d were isolated in 25–38% yields, the yield of the Cbz-protected morphan 12b was only 8%.

The diastereomeric alcohol 14d was prepared by oxidation of the alcohol 12d with Dess–Martin periodinane (DMP) [25, 26] to obtain the ketone 13d, which was reduced diastereoselectively to afford the exo-configured alcohol 14d (Scheme 2).

Due to diastereoselective opening of the epoxides 11 by the amide anion from the backside (SN2) and diastereoselective attack of the carbonyl moiety of 13d by the reducing agent also from the less hindered backside, the exo- and endo-configured alcohols 12 and 14d were expected to be formed, respectively. However, the assignment of the relative configuration of these alcohols by interpretation of the 1H NMR spectra was difficult due to the existence of rotational isomers and overlapping signals. The signals for characteristic protons in 1-, 3- and 8-position of the diastereomeric alcohols 12d and 14d and the ketone 13d are summarized in Table 1. The broad singlet at 3.72 ppm and the broad doublet at 4.02 ppm (J=2.0 Hz) for 8-H of the rotational isomers of 12d are in good accordance with an equatorial orientation of this proton with respect to the cyclohexane ring of the bicyclic system. Unfortunately, the signals for 8-H of the diastereomeric alcohol 14d merge in a multiplet at 3.81–3.95 ppm together with some signals of the PhCH2C=O moiety.

Table 1:

1H NMR signals (δ in ppm) for characteristic protons in 1-, 3- and 8-position of the diastereomeric alcohols 12d and 14d and the ketone 13d.a

Compd.1-CH3-CH28-CHRatio of rotamers
12d (exo)3.89, 0.4H3.30+4.13, 2×0.4H3.72, sb, 0.4H60:40
4.37, 0.6H3.45–3.53, 2×0.6H4.02, db, 0.6H
13d4.22, 0.5H3.99, 0.5H50:50
4.68, 0.5H3.41–3.56, 3×0.5H
14d (endo)4.09, 0.2H3.20+4.26, 2×0.2H3.81–3.95, m, 0.8+0.2H80:20
4.76, 0.8H3.47+3.54, 2×0.8H

asb, Singlet broad; db, doublet broad.

In order to assign the relative configuration of the alcohols 12 unequivocally, the benzamide 12c was crystallized from EtOAc to yield crystals which were suitable for an X-ray crystal structure analysis, (Fig. 2). In this structure the OH moiety is exo-oriented. It adopts an axial orientation with respect to the cyclohexane ring. The OH moiety and the N atom of the amide group show an anti-periplanar orientation with a torsion angle O2–C13–C12–N1 of –173.3(2)°. The 8-CH2 moiety and the carbonyl O atom also adopt an anti-periplanar orientation (torsion angle C8–N1–C1–O1 175.4(3)°).

Fig. 2:
Fig. 2:

Molecular structure of hydroxymorphan 12c in the crystal. Displacement ellipsoid are drawn at the 15% probability level, H atoms as spheres with arbitrary radii.

Citation: Zeitschrift für Naturforschung B 71, 10; 10.1515/znb-2016-0129

3 Conclusion

For the synthesis of morphan derivatives with additional substituents at the propano bridge, various methods have been investigated. Bromo- and iodolactamization of cyclohexene derivatives 7, 8 and 10 failed to yield 8-halo substituted morphans. However, the intramolecular opening of the epoxides 11 provided 8-hydoxy substituted morphans 12. The yields of the 8-hydroxymorphans 12 did not exceed 40%, since the precursor epoxides 11 were formed as approximately 1:1-mixtures of diastereomers. As the (3,4-dichlorophenyl)acetyl moiety represents an important pharmacophoric element of κ and σ receptor ligands, the morphan derivative 12d bearing this substituent was prepared. Moreover, the exo-configured alcohol 12d was converted into its endo-configured diastereomer 14d by oxidation and stereoselective reduction. The crystal structure determination of the benzamide 12c confirms unequivocally the relative configuration of the morphan derivatives 12ad and 14d.

4 Experimental

4.1 Chemistry, general methods

Unless otherwise noted, moisture sensitive reactions were conducted under dry nitrogen. THF was dried with sodium-benzophenone and was freshly distilled before use. Water residues in compounds were removed by lyophilization with a Christ Alpha 1-2 LD Plus apparatus. Thin layer chromatography (TLC): Silica gel 60 F254 plates (Merck). Flash chromatography (fc): Silica gel 60, 40–64 μm (Merck); parentheses include: diameter of the column, eluent, fraction size, Rf value. Melting point: Melting point apparatus SMP 3 (Stuart Scientific), uncorrected. MS: MAT GCQ (Thermo-Finnigan); IR: IR spectrophotometer 480Plus FT-ATR-IR (Jasco). NMR spectra: Agilent 600-MR (600 MHz for 1H, 151 MHz for 13C), Agilent 400-MR spectrometer (400 MHz for 1H, 101 MHz for 13C) (Agilent); δ in ppm referred to tetramethylsilane; coupling constants are given with 0.5 Hz resolution.

4.2 HPLC methods

HPLC method 1 for the determination of the purity: Merck Hitachi Equipment; UV detector: L-7400; autosampler: L-7200; pump: L-7100; degasser: L-7614; column: LiChrospher® 60 RP-select B (5 μm), 250–4 mm; flow rate: 1.00 mL.min−1; injection volume: 5.0 μL; detection at λ=210 nm; room temperature; solvents: A: water with 0.05% (v/v) CF3CO2H; B: CH3CN with 0.05% (v/v) CF3CO2H: gradient elution: (A%): 0–4 min: 90%, 4–29 min: gradient from 90% to 0%, 29–31 min: 0%, 31–31.5 min: gradient from 0% to 90%, 31.5–40 min: 90%.

HPLC method 2 for the determination of the purity of acid labile compounds. Method 2 corresponds to method 1, but the solvents A and B did not contain CF3CO2H.

HPLC method 3 for the separation of diastereomeric epoxides 11: Merck Hitachi Equipment; UV detector: Dionex UItiMate 3000 RS variable wavelength; autosampler Dionex UltiMate 3000 autosampler; Dionex UltiMate 3000 pump; degasser; data transfer: D-line; data acquisition: Chromeleon7; column: Phenomenex Gemini 5 μm, C18, 110 A, 250–4 mm; flow rate 1.00 mL.min−1; injection volume 5.0 μL, detection at λ=254 nm; room temperature; elution solvents: method 3a: water-CH3CN 50:50; method 3b: water-CH3CN 60:40; method 3c: water-CH3CN 70:30.

HPLC method 4 for the preparative separation of diastereomeric epoxides cis-11d and trans-11d: Merck Hitachi Equipment; UV detector L-7400; autosampler L-7200; pump L-7150; interface D7000; degasser; data transfer: D-line; data acquisition: HSM-software LACHrom; column: Agilent Prep C18, 10 μm, 21.2×250 mm; flow rate 20.0 mL min−1; injection volume 400 μL, detection at λ=210 nm; room temperature; elution solvent: water-CH3CN 70:30.

4.3 Synthetic procedures

4.3.1 (Cyclohex-3-en-1-yl)methanol (4)

Under N2, at 0°C a solution of cyclohex-3-ene-1-carbaldehyde (3, 6.58 g, 7.0 mL, 59.7 mmol) in THF (5 mL) was added to a mixture of LiAlH4 (2.49 g, 65.7 mmol) in THF (20 mL). During the addition the temperature was kept below 20°C. After 90 min stirring at 0°C, the mixture was carefully treated with THF-H2O 4:1 until gas production was ceased. Under cooling, H2SO4 (15% aqueous solution) was added until the precipitate was dissolved. The solution was extracted with Et2O (3×50 mL). The combined organic layers were washed with aq. NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo. The crude product was purified by Kugelrohr distillation. Colorless oil, b. p. 110°C at 5.8 mbar, yield 6.23 g (93%). Rf=0.45 (EtOAc:C6H12 50:50). C7H12O (112.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.28–1.32 (m, 1H, 6-CH2), 1.68–1.84 (m, 3H, 1-CH, 2-CH2, 6-CH2), 2.04–2.14 (m, 3H, 2-CH2, 5-CH2,), 3.51 (dd, J=10.5/6.1 Hz, 1H, CH2OH), 3.55 (dd, J=10.5/6.1 Hz, 1H, CH2OH), 5.65–5.71 (m, 2H, CH=CH). A signal for the proton of the OH moiety is not seen in the spectrum. – 13C NMR (100 MHz, CDCl3): δ (ppm)=24.8 (1C, C-5), 25.3 (1C, C-6), 28.2 (1C, C-2), 36.5 (1C, C-1), 68.0 (1C, CH2OH), 126.0 (1C, C-3), 127.3 (1C, C-4). – FT-IR: ν (cm−1)=3318 (s, v(OH)), 2913 (m, v(CH), alkyl), 1022 (s, δ(HC=CH)). – Exact mass (APCI): m/z=113.0966 (calcd. 113.0961 for C7H13O+, [M+H]+) [12].

4.3.2 [(Cyclohex-3-en-1-yl)methyl] methanesulfonate (5)

Under N2, at 0°C the alcohol 4 (2.50 g, 22.3 mmol) was added dropwise to a solution of methanesulfonyl chloride (2.59 mL, 33.4 mmol) in pyridine (15 mL). After stirring for 2 h at 0°C, conc. HCl was added (pH 1–2) and the mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with aq. NaHCO3 solution and H2O, dried (Na2SO4) and concentrated in vacuo. The residue was purified by Kugelrohr distillation. Colorless oil, b. p. 150°C at 2.4 mbar, yield 3.82 g (90%). Rf=0.49 (EtOAc:C6H12 50:50). C8H14O3S (190.1). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.33–1.39 (m, 1H, 6-CH2), 1.77–1.84 (m, 2H, 1-CH, 6-CH2), 2.02–2.18 (m, 4H, 2-CH2, 5-CH2,), 3.00 (s, 3H, SO3CH3), 4.11 (d, J=6.6 Hz, 2H, CH2O), 5.62–5.71 (m, 2H, CH=CH). – 13C NMR (100 MHz, CDCl3): δ (ppm)=24.4 (1C, C-5), 25.1 (1C, C-6), 27.9 (1C, C-2), 33.7(1C, C-1), 37.6 (1C, SO3CH3), 74.2 (1C, CH2O), 125.25 (1C, C-3), 127.4 (1C, C-4). – FT-IR: ν (cm−1)=2916 (m, v, C–H, alkyl), 1350 (s, ν, -SO2-), 1145 (s, ν, -SO2O-), 937 (s, δ, HC=CH). – Exact mass (APCI): m/z=191.0746 (calcd. 191.0736 for C8H15O3S+, [M+H]+) [12].

4.3.3 2-(Cyclohex-3-en-1-yl)acetonitrile (6)

Mesylate 5 (8.20 g, 43.1 mmol) dissolved in DMSO (5 mL) was added to a solution of NaCN (3.17 g, 64.8 mmol) in DMSO (30 mL) at 85°C and the mixture was heated to 110–120°C for 90 min. The mixture was extracted with Et2O (3×50mL). The combined extracts were washed with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by Kugelrohr distillation. Colorless oil, b. p. 140°C at 5.6 mbar, yield 4.70 g (90%). Rf=0.61 (EtOAc:C6H12 50:50). C8H11N (121.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.39–1.49 (m, 1H, 6-CH2), 1.78–1.88 (m, 2H, 1-CH, 6-CH2), 1.95–2.05 (m, 2H, 2-CH2), 2.18–2.26 (m, 2H, 5-CH2), 2.33 (dd, J=1.2/0.4 Hz, 2H, CH2CN), 5.60–5.71 (m, 2H, CH=CH). – 13C NMR (100 MHz, CDCl3): δ (ppm)=23.8 (1C, CH2CN), 24.4 (1C, C-5), 27.9 (1C, C-1), 30.8 (1C, C-2), 30.9 (1C, C-6), 118.9 (1C, CH2CN), 124.9 (1C, C-3), 127.0 (1C, C-4). – FT-IR: ν (cm−1)=2916 (m, v, C–H, alkyl), 2245 (m, ν, -C≡N), 1045 (s, δ, HC=CH), 655 (m, δ, HC=CH). – Exact mass (APCI): m/z=122.0987 (calcd. 122.0964 for C8H12N+, [M+H]+) [12].

4.3.4 2-(Cyclohex-3-en-1-yl)acetamide (7)

A mixture of RuCl3·3H2O (11.2 mg) and chitin (495 mg, 0.79 mmol) in H2O (30 mL) was heated to 50°C for 30 min. The mixture was concentrated under reduced pressure. The dark gray solid was dried in vacuo overnight. Under Ar, a Schlenk tube was charged with RuCl3/chitin (505.5 mg, 0.05 mmol Ru) and degassed H2O (15 mL). A 1 m NaOAc solution (3.50 mL) and later 0.16 m NaBH4 aq. (3.00 mL) were added dropwise. The mixture was stirred for 3.5 h at r. t. The solution was removed with a needle and Ar pressure. The activated catalyst was washed twice for 3 h with degassed H2O (7 mL) and dried in vacuo for 2 h. Degassed H2O (7 mL) and the nitrile 6 (182 mg, 1.5 mmol) were added. The mixture was shaken at 120°C for 84 h. The catalyst was filtered off and washed with methanol (5×10 mL). The solvent was removed in vacuo and the residue was purified by flash column chromatography (CH2Cl2-CH3OH 80:10, Ø=3 cm, V=10 mL). Colorless solid, m. p. 140°C, yield 130 mg (62%). Rf=0.32 (CH2Cl2-acetone 50:50). C8H13NO (139.2). – 1H NMR (600 MHz, CDCl3): δ (ppm)=1.27–1.35 (m, 1H, 6-CH2), 1.70–1.76 (m, 1H, 6-CH2), 1.77–1.82 (m, 1H, 2-CH2), 2.01–2.12 (m, 3H, 1-CH, 5-CH2) 2.14–2.21 (m, 3H, 2-CH2, CH2CO), 5.60–5.69 (m, 2H, CH=CH). – 13C NMR (150 MHz, CDCl3): δ (ppm)=24.9 (1C, C-5), 28.6 (1C, C-1), 31.1 (1C, C-6), 31.5 (1C, C-2), 42.9 (1C, CH2CO), 125.9 (1C, C-3), 127.0 (1C, C-4), 175.0 (1C, C=O). – FT-IR: ν (cm−1)=3344 (s, ν, CONH), 3170 (s, ν, CONH), 1624 (s, v, C=O), 648 (s, δ, HC=CH). – Exact mass (APCI): m/z=140.1075 (calcd. 140.1070 for C8H14NO+, [M+H]+) [17].

4.3.5 tert-Butyl N-[(cyclohex-3-en-1-yl)acetyl] carbamate (8)

NaH (0.40 g, 60% dispersion in mineral oil, 10 mmol) was washed in a strong nitrogen stream three times with THF (10 mL) to remove the mineral oil. The remaining NaH was suspended in THF (8 mL) and at 0°C acetamide 7 (0.10 g, 0.72 mmol) dissolved in THF (2 mL) was added over 30 min. The mixture was warmed to r. t. and stirred for 45 min. At 0°C di-tert-butyl dicarbonate (0.31 g, 1.44 mmol) was added dropwise. After complete addition, the mixture was stirred for 2.5 d at r. t. The mixture was treated with THF-H2O (3:1) and later with 1% NH4Cl solution. The organic layer was separated and the water layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash column chromatography (EtOAc-C6H12 5:95, Ø=2.5 cm, V=10 mL). Colorless solid, m. p. 47°C, yield 0.14 g (85%). Rf=0.84 (EtOAc:C6H12 10:90). C13H21NO3 (239.3). – 1H NMR (600 MHz, CDCl3): δ (ppm)=1.29–1.37 (m, 1H, 6-CH2), 1.53 (s, 9H, C(CH3)3), 1.71–1.85 (m, 2H, 5-CH2, 6-CH2), 2.04–2.10 (m, 2H, 2-CH2), 2.13–2.23 (m, 2H, 1-CH, 5-CH2), 2.78 (d, J=6.6 Hz, 2H, CH2CO), 5.60–5.69 (m, 2H, CH=CH). – 13C NMR (150 MHz, CDCl3): δ (ppm)=24.9 (1C, C-2), 27.8 (3C, C(CH3)3), 28.7 (1C, C-6), 30.0 (1C, C-1), 31.5 (1C, C-5), 43.3 (1C, CH2CO), 84.7 (1C, C(CH3)3), 126.1 (1C, C-3), 127.0 (1C, C-4), 149.8 (1C, O=C–OtBu), 173.6 (1C, CH2C=O). – FT-IR: ν (cm−1)=2982 (m, v, C–H, alkyl), 2920 (m, v, C–H, alkyl), 1744 (s, v, C=O), 1115 (s, v, C–O). – LC/MS ((+)-ESI): tR=7.3 min, m/z=249.1592 (calcd. 240.1594 for C13H22NO3, [M+H+])

4.3.6 2-(Cyclohex-3-en-1-yl)ethan-1-amine hydrochloride (9·HCl)

Under N2 at 0°C, a solution of the nitrile 6 (1.00 g, 8.25 mmol) in THF (2 mL) was added to a mixture of LiAlH4 (0.63 g, 16.50 mmol) in THF (10 mL). During the addition the temperature was kept below 20°C. After 12 h stirring at r. t., the mixture was treated with H2O under ice cooling until gas production was ceased. NaOH solution (50%) was added until the precipitate was dissolved and two phases were formed. The organic layer was separated and the water layer was extracted with Et2O (3×30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was dissolved in Et2O (2 mL) and HCl in Et2O (1 m) was added. The resulting colorless solid (9·HCl) was washed with Et2O and dried in vacuo. Colorless solid, m. p. 160–166°C (decomposition), yield 1.02 g (76%). Rf=0.47 (CH3OH-CH2Cl2 10:90+10% N,N-dimethylethylamine). C8H16ClN (161.7). – 1H NMR (400 MHz, DMSO): δ (ppm)=1.17 (ddt, J=15.7/10.2/7.8 Hz, 1H, 6-CH2), 1.49–1.72 (m, 5H, 1-CH, 2-CH2, 6-CH2, CHCH2CH2NH2), 1.98–2.10 (m, 3H, 5-CH2, 2-CH2), 2.81 (dd, J=8.3/7.1 Hz, 2H, CHCH2CH2NH2), 5.60–5.67 (m, 2H, CH=CH), 7.80 (bs, 2H, NH3+). – 13C NMR (100 MHz, DMSO): δ (ppm)=24.3 (1C, C-5), 27.9 (1C, C-6), 30.2 (1C, C-1), 30.9 (1C, C-2), 33.6 (1C, CHCH2CH2NH2), 36.8 (1C, CHCH2CH2NH2), 126.0 (1C, C-3), 126.8 (1C, C-4). – FT-IR: ν (cm−1)=2916 (s, v, NH3+), 1462 (s, δ, C–H), 652 (s, δ, HC=CH). – Exact mass (APCI): m/z=126.1282 (calcd. 126.1277 for C8H16N+, [M+H]+).

4.3.7 tert-Butyl N-[2-(cyclohex-3-en-1-yl)ethyl]carbamate (10a)

Under N2, a mixture of the amine hydrochloride 9·HCl (0.15 g, 1.20 mmol) and NEt3 (0.3 mL, 2.40 mmol) in dry CH2Cl2 (2 mL) was added dropwise to a solution of di-tert-butyl dicarbonate (0.39 mL, 1.80 mmol) in dry CH2Cl2 (5 mL). After stirring for 4 h at r. t., the mixture was treated with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with aq. NaHCO3 solution and with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash column chromatography (EtOAc-C6H12=10:90, Ø=3 cm, V=10 mL). Colorless oil, yield 0.18 g (67%). Rf=0.57 (EtOAc:C6H12 20:80). C13H23NO2 (225.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.18–1.28 (m, 1H, 6-CH2), 1.29–1.48 (m, 11H, CHCH2CH2NH, C(CH3)3), 1.55–1.76 (m, 3H, 1-CH, 2-CH2, 6-CH2), 1.99–2.13 (m, 3H, 2-CH2, 5-CH2), 3.17 (q, J=6.2 Hz, 2H, CHCH2CH2NH), 4.50 (bs, 1H, NH), 5.60–5.68 (m, 2H, CH=CH). – 13C NMR (100 MHz, CDCl3): δ (ppm)=25.2 (1C, C-5), 28.6 (3C, C(CH3)3), 28.8 (1C, C-6), 31.2 (1C, C-1), 31.7 (1C, C-2), 36.8 (1C, CHCH2CH2NH), 38.5 (1C, CHCH2CH2N), 79.2 (1C, C(CH3)3), 126.3 (1C, C-3), 127.2 (1C, C-4), 156.1 (1C, C=O). – FT-IR: ν (cm−1)=2974 (m, v, C–H, alkyl), 2913 (m, v, C–H, alkyl), 1690 (s, v, C=O), 1512 (s, δ, N–H), 1169 (s, v, C–O). – LC/MS ((+)-ESI): tR=6.5–6.6 min, m/z=226.1793 (calcd. 226.1802 for C13H24NO2+, [M+H+]).

4.3.8 Benzyl N-[2-(cyclohex-3-en-1-yl)ethyl]carbamate (10b)

Method A – Acylation of primary amine hydrochloride 9·HCl: Under N2, a solution of the amine hydrochloride 9·HCl (0.23 g, 1.42 mmol) and NEt3 (0.29 g, 0.40 mL, 2.85 mmol) in CH2Cl2 (2 mL) was added dropwise to a mixture of benzyl chloroformate (0.36 g, 0.27 mL, 2.13 mmol) in CH2Cl2 (5 mL). After stirring for 2 h at r. t., a saturated NaHCO3 solution was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined extracts were washed with aq. NaHCO3 solution and with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by flash column chromatography (EtOAc-C6H12=5:95, Ø=3 cm, V=7 mL). Yellow oil, yield: 0.23 g (62%).

Method B – one-pot three-step procedure starting with mesylate 5: Under N2, mesylate 5 (3.00 g, 15.77 mmol) was added to a mixture of KCN (2.05 g, 31.54 mmol) and 18-crown-6 (4.18 g, 15.77 mmol) in THF (75 mL). The mixture was heated to 85°C for 24 h. After cooling to 0°C, LiAlH4 (0.66 g, 17.35 mmol) was added. The mixture was heated to 85°C for 24 h. At 0°C the mixture was carefully treated with H2O until gas production had ceased. Then NaOH solution (50%) was added until the precipitate was dissolved and two layers were formed. Benzyl chloroformate (4.48 mL, 5.38 g, 31.54 mmol) was added and the mixture was heated to 85°C for 3 h. After cooling to r. t., the organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with aq. NaHCO3 solution and with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by flash column chromatography (EtOAc-C6H12=5:95, Ø=3 cm, V=7 mL). Yellow oil, yield: 0.52 g (13%). Rf=0.35 (EtOAc:C6H12 40:60). C16H21NO2 (259.3). – 1H NMR (400 MHZ, CDCl3): δ (ppm)=1.19–1.31 (m, 1H, 6-CH2), 1.43–1.53 (m, 2H, CHCH2CH2NH), 1.56–1.77 (m,3H, 1-CH, 2-CH2, 6-CH2), 2.00–2.14 (m, 3H, 2-CH2, 5-CH2), 3.25 (t, J=7.2 Hz, 2H, CHCH2CH2NH), 4.71 (bs, 1H, NH), 5.09 (s, 2H, CH2O), 5.61–5.69 (m, 2H CH=CH), 7.31–7.39 (m, 5H, CHarom.). – 13C NMR (100 MHz, CDCl3): δ (ppm)=25.1 (1C, C-5), 28.8 (1C, C-6), 31.1 (1C, C-1), 31.7 (1C, C-2), 36.8 (1C, CHCH2CH2NH), 39.1 (1C, CHCH2CH2NH), 66.7 (1C, CH2O), 126.3 (1C, C-3), 127.2 (1C, C-4), 128.2 (2 C, C-2arom., C-6arom.), 128.5 (3C, C-3arom., C-4arom., C-5arom.), 136.7 (1C, C-1arom.), 156.5 (1C, C=O). – FT-IR: ν (cm−1)=3329 (m, v, NH), 2978 (m, v, C–H, alkyl), 2909 (m, v, C–H, alkyl), 1694 (s, v, C=O), 1524 (s, δ, N–H), 1246 (s, v, C–O), 732 (m, γ, C–H, mono-substituted arom.), 694 (m, γ, C–H, mono-substituted arom.). – Exact mass (APCI): m/z=260.1655 (calcd. 260.1645 for C16H22NO2+, [M+H+]). – Purity (HPLC, method 1): 78.7%, tR=22.9 min.

4.3.9 N-[2-(Cyclohex-3-en-1-yl)ethyl]benzamide (10c)

Under N2, a mixture of the amine hydrochloride 9·HCl (0.50 g, 3.99 mmol) and NEt3 (1.10 mL, 7.98 mmol) in CH2Cl2 (2 mL) was added dropwise to a solution of benzoyl chloride (0.92 mL, 7.98 mmol) in CH2Cl2 (5 mL) [13]. After stirring for 3 h at room temperature, the mixture was treated with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with aq. NaHCO3 solution and with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by flash column chromatography (EtOAc-C6H12 20:80→30:70, Ø=3 cm, V=10 mL). Colorless solid, m. p. 81–83°C, yield 0.68 g (75%). Rf=0.51 (EtOAc:C6H12 50:50). C15H19NO (229.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.26–1.32 (m, 1H, 6-CH2), 1.55–1.80 (m, 5H, 1-CH, 2-CH2, 6-CH2, CHCH2CH2NH), 2.04–2.07 (m, 2H, 5-CH2), 2.13–2.18 (m, 1H, 2-CH2), 3.51 (td, J=7.3/5.2 Hz, 2H, CHCH2CH2NH), 5.53–5.68 (m, 2H, CH=CH), 6.19 (bs, 1H, NH), 7.39–7.43 (m, 2H, 3-CHarom., 5-CHarom.), 7.47–7.50 (m, 1H, 4-CHarom.), 7.75 (dd, J=7.1/1.4 Hz, 2H, 2-CHarom., 6-CHarom.). – 13C NMR (100 MHz, CDCl3): δ (ppm)=25.1 (1C, C-5), 28.8 (1C, C-6), 31.4 (1C, C-1), 31.8 (1C, C-2), 36.4 (1C, CHCH2CH2NH), 38.1 (1C, CHCH2CH2N), 126.2 (1C, C-3), 127.0 (2C, C-2arom., C-6arom.), 127.2 (1C, C-4), 128.7 (2C, C-3arom., C-5arom.), 131.5 (1C, C-4arom.), 134.9 (1C, C-1arom.), 167.7 (1C, C=O). – FT-IR: ν (cm−1)=2913 (m, v, C–H, alkyl), 1636 (s, v, C=O), 1539 (s, δ, N–H), 700 (m, γ, C–H, mono-substituted arom.), 652 (m, γ, C–H, mono-substituted arom.). – Exact mass (APCI): m/z=230.1550 (calcd. 230.1539 for C15H20NO+, [M+H+]). – Purity (HPLC, method 1): 93.4%, tR=20.73 min.

4.3.10 N-[2-(Cyclohex-3-en-1-yl)ethyl]-2-(3,4-dichlorophenyl)acetamide (10d)

Method A – Acylation of primary amine hydrochloride 9·HCl: Under N2, a mixture of amine hydrochloride 9·HCl (0.30 g, 2.39 mmol) and NEt3 (0.66 mL, 0.48 g, 4.79 mmol) in dry CH2Cl2 (5 mL) was added dropwise to a solution of 2-(3,4-dichlorophenyl)acetyl chloride (0.64 g, 2.88 mmol) in dry CH2Cl2 (5 mL). After stirring at r. t. for 2 h, the mixture was treated with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with aq. NaHCO3 solution and with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo. The crude oil was purified via flash column chromatography (EtOAc-C6H12=30:70, Ø=3 cm, V=10 mL). Colorless solid, yield: 0.41 g (57%).

Method B – Acylation of primary amine 9 using a coupling reagent; Amine hydrochloride 9·HCl was dissolved in NaOH and the amine 9 was extracted with Et2O. The solvent was removed in vacuo to afford the amine 9. A mixture of amine 9 (2.00 g, 15.9 mmol), (3,4-dichlorophenyl)acetic acid (6.48 g, 31.9 mmol) and DCC (6.58 g, 31.9 mmol) in dry CH2Cl2 (40 mL) was stirred at r. t. for 3 h. A saturated solution of NaHCO3 was added and the precipitate was filtered off. The resulting layers were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified via flash column chromatography (EtOAc-C6H12=30:70, Ø=5 cm, V=10 mL). Colorless solid, yield 4.88 g (98%).

Method C – one-pot three-step procedure starting with mesylate 5: Under N2, mesylate 5 (3.00 g, 15.8 mmol) was added to a mixture of KCN (2.05 g, 31.5 mmol) and 18-crown-6 (4.17 g, 15.8 mmol) in THF (45 mL). The mixture was heated to 85°C for 24 h. After cooling to 0°C, LiAlH4 (0.66 g, 19.0 mmol) was added. The mixture was heated to 85°C for 24 h. At 0°C the mixture was carefully treated with H2O until gas production was ceased. NaOH solution (50%) was added until the precipitate was dissolved and two layers were formed. 2-(3,4-Dichlorophenyl)acetyl chloride (5.30 g, 17.4 mmol) was added and the mixture was heated to 85°C for 3 h. After cooling to r. t., the organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified via flash column chromatography (EtOAc-C6H12=30:70, Ø=5 cm, V=10 mL). Colorless solid, yield 1.50 g (30%).

M. p. 75°C. Rf=0.49 (EtOAc:C6H12 50:50). C16H19Cl2NO (312.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.17–1.28 (m, 1H, 6-CH2), 1.39–1.58 (m, 3H, 1-CH, CHCH2CH2NH), 1.61–1.73 (m, 2H, 6-CH2, 2-CH2), 1.99–2.11 (m, 3H, 2-CH2, 5-CH2), 3.28 (td, J=7.4/5.7 Hz, 2H, CHCH2CH2NH), 3.48 (s, 2H, CH2CO), 5.45 (bs, 1H, NH), 5.59–5.67 (m, 2H, CH=CH), 7.11 (dd, J=8.2/2.1 Hz, 1H, 6-CHarom.), 7.36 (d, J=2.1 Hz, 1H, 2-CHarom.), 7.40 (d, J=8.2 Hz, 1H, 5-CHarom.). – 13C NMR (100 MHz, CDCl3): δ (ppm)=25.1 (1C, C-5), 28.8 (1C, C-6), 31.4 (1C, C-1), 31.7 (1C, C-2), 36.2 (1C, CHCH2CH2NH), 37.9 (1C, CHCH2CH2NH), 42.8 (1C, CH2C=O), 126.1 (1C, C-4), 127.2 (1C, C-3), 128.8 (1C, C-6arom.), 130.9 (1C, C-5arom.), 131.4 (1C, C-2arom.), 131.7 (1C, C-3arom.), 133.0 (1C, C-4arom.), 135.2 (1C, C-1arom.), 169.8 (1C, C=O). – FT-IR: ν (cm−1)=3283 (w, v, N–H), 2978 (m, v, C–H, alkyl), 2912 (m, v, C–H, alkyl), 1639 (s, v, C=O), 1551 (s, δ, N–H). – Exact mass (APCI): m/z=312.0929 (calcd. 312.0916 for C16H2035Cl2NO+, [M+H+]). – Purity (HPLC, method 1): 97.5%, tR=23.3 min.

4.3.11 tert-Butyl N-[2-(7-oxabicyclo[4.1.0]heptan-3-yl)ethyl]carbamate (11a)

Cyclohexene 10a (0.18 g, 0.79 mmol) was dissolved in CHCl3 (4 mL) and the solution was added to a suspension of m-chloroperbenzoic acid (0.36 g, 1.59 mmol) in CHCl3 (6 mL). The mixture was stirred at r. t. for 18 h. A K2CO3 solution (1 g K2CO3 in 100 mL of H2O) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were washed with aq. NaHCO3 solution and saturated NaCl solution. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified by column chromatography (EtOAc-C6H12=10:90→30:70, Ø=2.5 cm, V=10 mL). Colorless oil, yield 0.11 g (57%). Rf=0.57 (EtOAc-C6H12 50:50). C13H23NO3 (241.3). – 1H NMR (600 MHz, CDCl3): δ (ppm)=0.92 (2× td, J=11.5/6.4 Hz, 0.5H, 4-CH2), 1.13–1.18 (m, 0.5H, 4-CH2), 1.30–1.55 (m, 14H, 2-CH2, 3-CH, 4-CH2, C(CH3)3, CHCH2), 1.70 (m, 0.5H, 5-CH2), 1.83 (2× dd, J=11.5/6.4 Hz, 0.5H, 5-CH2), 1.97–2.01 (m, 0.5H, 5-CH2), 2.03–2.08 (m, 0.5H, 2-CH2), 2.11–2.18 (m, 1H, 2-CH2, 5-CH2), 3.03 (m, 4H, 1-CH, 6-CH, CH2NH), 4.46 (bs, 1H, NH). – 13C NMR (150 MHz, CDCl3): δ (ppm)=23.7 (1C, C-5), 24.5 (1C, C-4), 26.3 (1C, C-5), 27.1 (1C, C-3), 27.2 (1C, C-4), 28.7 (3C, C(CH3)3), 30.4 (1C, C-3), 30.7 (1C, C-2), 31.8 (1C, C-2), 36.5 (1C, CHCH2), 37.2 (1C, CHCH2), 38.2 (1C, CH2NH), 38.3 (1C, CH2NH), 51.8 (1C, C-6), 52.0 (1C, C-6), 52.6 (1C, C-1), 53.1 (1C, C-1), 79.3 (2× 1C, C(CH3)3), 166.0 (2× 1C, NHC=O). – FT-IR: ν (cm−1)=2978 (m, v, C–H, alkyl), 1694 (s, v, C=O), 1169 (s, ν, C–O). – LC/MS ((+)-ESI):tR=5.3–5.4 min, m/z=242.1747 (calcd. 242.1751 for C13H24NO3+, [M+H+]).

4.3.12 Benzyl N-[2-(7-oxabicyclo[4.1.0]heptan-3-yl)ethyl]carbamate (11b)

Cyclohexene 10b (0.37 g, 1.43 mmol) was dissolved in CHCl3 (4 mL) and the solution was added to a suspension of m-chloroperbenzoic acid (0.64 g, 2.86 mmol) in CHCl3 (6 mL). The mixture was stirred at r. t. for 18 h. A K2CO3 solution (1 g K2CO3 in 100 mL of H2O) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were washed with aq. NaHCO3 solution and saturated NaCl solution. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified by flash column chromatography (EtOAc-C6H12=20:80, Ø=3 cm, V=10 mL). Yellow oil, yield 0.19 g (48%). Rf=0.55 (EtOAc:C6H12 50:50). C16H21NO3 (275.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)=0.92 (2× td, J=11.5/6.4 Hz, 0.5H, 4-CH2), 1.08–1.52 (m, 5.5H, 3-CH, 2-CH2, 4-CH2, CHCH2CH2NH), 1.70 (2× dt, J=13.4/4.1Hz, 0.5H, 5-CH2), 1.83 (2× dd, J=11.5/6.4 Hz, 0.5H, 5-CH2), 1.95–2.18 (m, 2H, 2-CH2, 5-CH2), 3.10–3.22 (m, 4H, CHCH2CH2NH,1-CH, 6-CH), 4.73 (bs, 1H, NH), 5.08 (s, 2H, OCH2), 7.30–7.35 (m, 5H, CHarom.). Ratio of diastereomers 45: 55 (HPLC method 3c). – 13C NMR (100 MHz, CDCl3): δ (ppm)=23.5 (1C, C-5), 24.4 (1C, C-4), 25.2 (1C, C-5), 27.0 (1C, C-3), 27.1 (1C, C-4), 30.2 (1C, C-3), 30.6 (1C, C-2), 31.7 (1C, C-2), 36.4 (1C, CHCH2CH2NH), 37.1 (1C, CHCH2CH2NH), 38.7 (2× 1C, CHCH2CH2N), 51.7 (1C, C-1), 51.9 (1C, C-1), 52.6 (1C, C-6), 53.0 (1C, C-6), 66.8 (2× 1C, OCH2), 128.2 (2C, C-2arom., C-6arom.), 128.6 (3C, C-3arom., C-4arom., C-5arom.), 136.7 (1C, C-1arom.), 156.5 (1C, C=O). – FT-IR: ν (cm−1)=3340 (w, v, N–H), 2924 (m, v, C–H, alkyl), 1701(s, v, C=O), 1528 (s, δ, N–H), 1242 (s, v, C–O), 737 (s, γ, C–H, mono-substituted arom.), 698 (s, γ, C–H, mono-substituted arom.). – LC/MS ((+)-ESI): tR=5.5–5.6 min, m/z=276.1602 (calcd. 276.1594 for C16H22NO3+, [M+H+]). – Purity (HPLC, method 2): 66%, tR=19.70 min.

4.3.13 N-[2-(7-Oxabicyclo[4.1.0]heptan-3-yl)ethyl]benzamide (11c)

Cyclohexene 10c (0.25 g, 1.10 mmol) was dissolved in CHCl3 (4 mL) and the solution was added to a suspension of m-chloroperbenzoic acid (50%, 0.56 g, 2.20 mmol) in CHCl3 (6 mL) [13]. The mixture was stirred at r. t. for 18 h. A K2CO3 solution (1 g K2CO3 in 100 mL of H2O) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were washed with aq. NaHCO3 solution and saturated NaCl solution. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified by flash column chromatography (EtOAc-C6H12=85:15, Ø=2.5 cm, V=10 mL). Colorless solid, m. p. 56°C, yield 0.27 g (80%). Rf=0.21 (EtOAc-C6H12 50:50). C15H19NO2 (245.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)=0.92–1.02 (m, 0.5H, 4-CH2), 1.13–1.75 (m, 6H, 2-CH2, 3-CH, 4-CH2, 5-CH2, CHCH2CH2NH), 1.81–1.90 (m, 0.5H, 5-CH2), 1.98–2.05 (m, 0.5H, 5-CH2), 2.09–2.23 (m, 1.5H, 2-CH2, 5-CH2), 3.12–3.18 (m, 2H, 1-CH, 6-CH), 3.39–3.53 (m, 2H, CHCH2CH2NH), 6.11 (bs, 1H, NH), 7.40–7.51 (m, 3H, 3-CHarom., 4-CHarom., 5-CHarom.), 7.73–7.75 (m, 2H, 2-CHarom., 6-CHarom.). Ratio of diastereomers 40:60 (HPLC method 3a). – 13C NMR (100 MHz, CDCl3): δ (ppm)=23.5 (1C, C-5), 24.5 (1C, C-4), 25.2 (1C, C-5), 27.1 (1C, C-4), 27.5 (1C, C-3), 30.6 (1C, C-3), 30.7 (1C, C-2), 31.8 (1C, C-2), 36.1 (1C, CHCH2CH2NH), 37.8 (1C, CHCH2CH2NH), 51.8 (1C, C-6), 52.0 (1C, C-6), 52.6 (1C, C-1), 53.1 (1C, C-1), 126.9 (2C, C-2arom., C-6arom.), 128.7 (2C, C-3arom., C-5arom.), 131.5 (1C, C-4arom.), 134.8 (1C, C-1arom.), 167.7 (1C, C=O). – FT-IR: ν (cm−1)=2978 (m, v, C–H, alkyl), 1639 (m, v, C=O), 1543 (s, δ, N–H), 710 (m, γ, C–H, mono-substituted arom.), 695 (m, γ, C–H, mono-substituted arom.). – Exact mass (APCI): m/z=246.1490 (calcd. 246.1489 for C15H20NO2+, [M+H+]). – Purity (HPLC, method 2): 96%, tR=16.93 min.

4.3.14 N-[2-((1RS,3SR,6SR)-7-Oxabicyclo[4.1.0]heptan-3-yl)ethyl]-2-(3,4-dichloro-phenyl)acetamide (cis-11d) and N-[2-((1RS,3RS,6SR)-7-Oxabicyclo[4.1.0]-heptan-3-yl)ethyl]-2-(3,4-dichlorophenyl)-acetamide (trans-11d)

Cyclohexene 10d (1.5 g, 4.80 mmol) dissolved in CHCl3 (5 mL), was added to a mixture of m-chloroperbenzoic acid (50%, 2.15 g, 9.61 mmol) in CHCl3 (10 mL). The mixture was stirred at r. t. for 18 h. A K2CO3 solution (1 g K2CO3 in 100 mL of H2O) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with NaHCO3 solution and saturated NaCl solution. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified by flash column chromatography (EtOAc-C6H12=40:60, Ø=6 cm, V=10 mL) to give a 40:60 mixture of diastereomers (HPLC method 3b) as a colorless solid, m. p. 80°C, yield 0.90 g (57%). The diastereomers were separated by preparative HPLC, method 4. After separation, the solvents were removed in vacuo and the products were lyophilized.

cis-11d (fraction 1: tR=59.37 min): Colorless oil. Rf=0.33 (EtOAc-C6H12 70:30). C16H19Cl2NO2 (328.2). – 1H NMR (600 MHz, CDCl3): δ (ppm)=1.09 (ddd, J=12.3/4.3/2.3 Hz, 0.5H, 4-CH2), 1.13 (ddd, J=12.3/4.3/2.3 Hz, 0.5H, 4-CH2), 1.18–1.35 (m, 4H, 3-CH2, 4-CH2, CHCH2CH2NH), 1.40 (dd, J=11.1/2.4 Hz, 0.5H, 2-CH2), 1.43 (dd, J=11.1/2.4 Hz, 0.5H, 2-CH2), 1.64–1.73 (m, 1H, 5-CH2), 2.00 (ddd, J=7.7/3.9/1.9 Hz, 0.5H, 2-CH2), 2.03 (ddd, J=7.7/3.9/1.9 Hz, 0.5H, 2-CH2), 2.10 (dq, J=4.3/2.3 Hz, 0.5H, 5-CH2), 2.12 (dt, J=4.5/2.3 Hz, 0.5H, 5-CH2), 3.09 (td, J=4.5/1.9 Hz, 1H, 1-CH), 3.12 (dq, J=3.9/1.9 Hz, 1H, 6-CH), 3.19–3.26 (m, 2H, CHCH2CH2NH), 3.46 (s, 2H, CH2CO), 5.46 (bs, 1H, NH), 7.10 (dd, J=8.2/1.5 Hz, 0.5H, 6-CHarom.), 7.11 (dd, J=8.2/1.5 Hz, 0.5H, 6-CHarom.), 7.36 (d, J=1.5 Hz, 0.5H, 2-CHarom.), 7.37 (d, J=1.5 Hz, 0.5H, 2-CHarom.), 7.40 (d, J=8.2 Hz, 0.5H, 5-CHarom.), 7.41 (d, J=8.2 Hz, 0.5H, 5-CHarom.). – 13C NMR (150 MHz, CDCl3): δ (ppm)=24.4 (1C, C-4), 25.2 (1C, C-5), 30.5 (1C, C-3), 30.6 (1C, C-2), 36.6 (1C, CHCH2CH2NH), 37.6 (1C, CHCH2CH2NH), 42.9 (1C, CH2C=O), 51.7 (1C, C-1), 52.5 (1C, C-6), 128.8 (1C, C-6arom.), 130.9 (1C, C-5arom.), 131.2 (1C, C-2arom.), 131.6 (1C, C-4arom.), 133.0 (1C, C-3arom.), 135.3 (1C, C-1arom.), 169.7 (1C, C=O). – FT-IR: ν (cm−1)=3291(w, v, N–H), 2924 (m, v, C–H, alkyl), 1643 (s, v, C=O). – LC/MS ((+)-ESI): tR=5.8 min, m/z=328.0879 (calcd. 328.0866 for C16H2035Cl2NO2+, [M+H+]). – Purity (HPLC, method 2): 86%, tR=20.01 min.

trans-11d (fraction 2, tR=66.31 min): Yellow solid, m. p. 101°C. Rf=0.33 (EtOAc-C6H12 70:30). C16H19Cl2NO2 (328.2). – 1H NMR (600 MHz, CDCl3): δ (ppm)=0.89–0.99 (m, 1H, 4-CH2), 1.31–1.36 (m, 3H, 5-CH2, CHCH2CH2NH), 1.43–1.48 (m, 2H, 3-CH, 4-CH2), 1.79 (dd, J=11.6/6.5 Hz, 0.5H, 2-CH2), 1.82 (dd, J=11.6/6.5 Hz, 0.5H, 2-CH2), 1.96 (ddd, J=6.6/5.0/2.4Hz, 0.5H, 2-CH2), 1.99 (ddd, J=6.6/5.0/2.4 Hz, 0.5H, 2-CH2), 2.11 (dt, J=3.8/1.9 Hz, 0.5H, 5-CH2), 2.13 (dt, J=3.8/1.9 Hz, 0.5H, 5-CH2), 3.11 (bt, J=4.5 Hz, 1H, 1-CH), 3.14 (dt, J=3.8/1.8 Hz, 1H, 6-CH), 3.22 (2× td, J=7.3/3.3 Hz, 2H, CHCH2CH2NH), 3.46 (s, 2H, CH2C=O), 5.49 (bs, 1H, NH), 7.10 (dd, J=8.2/2.2Hz, 1H, 6-CHarom.), 7.36 (d, J=2.2 Hz, 1H, 2-CHarom.), 7.40 (d, J=8.2Hz, 1H, 5-CHarom.). – 13C NMR (150 MHz, CDCl3): δ (ppm)=23.5 (1C, C-2), 27.0 (1C, C-4), 27.4 (1C, C-3), 31.8 (1C, C-5), 35.9 (1C, CHCH2CH2NH), 37.6 (1C, CHCH2CH2NH), 42.8 (1C, CH2CO), 51.9 (1C, C-1), 53.0 (1C, C-6), 128.8 (1C, C-6arom.), 130.9 (1C, C-2arom.), 131.4 (1C, C-5arom.), 131.6 (1C, C-4arom.), 132.9 (1C, C-3arom.), 135.2 (1C, C-1arom.), 169.7 (1C, C=O). – FT-IR: ν (cm−1)=3291(w, v, N–H), 2924 (m, v, C–H, alkyl), 1643 (s, v, C=O), 1523 (s, ν, C=O). – LC/MS ((+)-ESI): tR=5.8 min, m/z=328.0869 (calcd. 328.0866 for C16H2035Cl2NO2+, [M+H+]). – Purity (HPLC, method 2): 95%, tR=20.18 min.

4.3.15 tert-Butyl (1RS,5SR,8RS)-8-hydroxy-2-azabicyclo[3.3.1]nonane-2-carboxylate (12a)

Under N2, the epoxide 11a (0.10 g, 0.41 mmol) was dissolved in THF (6 mL) and a solution of LiHMDS in THF (1 m, 0.6 mL) was added dropwise at 0°C. After stirring for 24 h at r. t., H2O (10 mL) was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash column chromatography (EtOAc-C6H12=60:40, Ø=2.5 cm, V=10 mL). Colorless oil, yield 0.25 g (25%). Rf=0.27 (EtOAc:C6H12 50:50). C13H23NO3 (241.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=0.86–0.99 (m, 0.5H, 4-CH2), 1.08–1.55 (m, 14.5H, 4-CH2, 5-CH, 6-CH2, 7-CH2, 9-CH2, OC(CH3)3), 1.65–1.75 (m, 0.5H, 7-CH2), 1.78–1.88 (m, 0.5H, 9-CH2), 1.94–2.18 (m, 2H, 9-CH2, 7-CH2), 3.09–3.16 (m, 2H, 8-CH, 1-CH), 3.21–3.26 (m, 1H, 3-CH2), 3.62–3.68 (m, 1H, 3-CH2). – 13C NMR (100 MHz, CDCl3): δ (ppm)=23.5 (1C, C-9), 23.4 (1C, C-9), 24.4 (1C, C-6), 24.5 (1C, C-6), 25.2 (1C, C-7), 25.3 (1C, C-7), 26.9 (1C, C-4), 27.1 (1C, C-4), 27.4 (1C, C-5), 27.7 (1C, C-5), 28.3 (3C, C(CH3)3), 30.5 (1C, C-9), 30.6 (1C, C-9), 30.7 (1C, C-5), 30.8 (1C, C-5), 31.8 (1C, C-7), 35.6 (1C, C-6), 36.1 (1C, C-6), 36.2 (1C, C-4), 36.7 (1C, C-4), 38.2 (1C, C-3), 38.3 (1C, C-3), 42.0 (1C, C-3), 42.2 (C-3), 51.8 (1C, C-1), 51.9 (1C, C-1), 52.7 (1C, C-8), 53.0 (1C, C-8), 82.9 (1C, C(CH3)3), 83.0 (1C, C(CH3)3), 155.0 (1C, NCO2C(CH3)3), 155.3 (1C, NCO2C(CH3)3). – FT-IR: ν (cm−1)=3333 (s, v, O–H), 2925 (m, v, C–H, alkyl), 1709 (s, v, C=O), 1165 (s, v, C–O, alcohol). – Exact mass (APCI): m/z=242.1725 (calcd. 242.1751 for C13H24NO3+, [M+H+]).

4.3.16 Benzyl (1RS,5SR,8RS)-8-hydroxy-2-azabicyclo[3.3.1]nonane-2-carboxylate (12b)

Under N2, the epoxide 11b (0.10 g, 0.69 mmol) was dissolved in THF (6 mL) and a solution of NaHMDS in THF (1 m, 1.38 mL, 1.38 mmol) was added dropwise at 0°C. After stirring for 72 h at r. t., H2O (10 mL) was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The crude yellow oil was purified via flash column chromatography (EtOAc-C6H12=30:70, Ø=2.5 cm, V=10 mL). Colorless oil, yield 8.70 mg (9%). Rf=0.46 (EtOAc-C6H12 2:8). C16H21NO3 (275.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.33–1.95 (m, 9H, 4-CH2, 5-CH, 6-CH2, 7-CH2, 9-CH2), 3.12–3.24 (m, 2H, 8-CH, 3-CH2), 3.46–3.55 (m, 0.5H, 3-CH2), 3.64–3.70 (m, 0.5H, 3-CH2), 4.28 (bdd, J=23.8/2.7 Hz, 0.5H, 1-CH), 4.88 (bdd, J=27.0/2.5 Hz, 0.5H, 1-CH), 5.08–5.23 (m, 2H, CH2CO), 7.28–7.43 (m, 5H, CHarom.). – 13C NMR (100 MHz, CDCl3): δ (ppm)=24.0 (1C, C-5), 24.2 (1C, C-5), 24.7 (1C, C-6), 25.3 (1C, C-6), 26.4 (1C, C-7), 27.6 (1C, C-9), 28.2 (1C, C-9), 36.4 (1C, C-4), 37.2 (1C, C-4), 38.7 (1C, C-3), 40.1 (1C, C-3), 49.1 (1C, C-1), 52.0 (1C, C-8), 53.1 (1C, C-8), 67.2 (1C, CH2C=O), 67.4 (1C, CH2C=O), 70.0 (1C, C-1), 128.0 (2C, C-2arom., C-6arom.), 128.1 (2C, C-2arom., C-6arom.), 128.5 (3C, C-3arom., C-4arom., C-5arom.), 128.6 (3C, C-3arom., C-4arom., C-5arom.), 155.7 (1C, C-1arom.), 156.3 (1C, C-1arom.), 207.1 (1C, C=O). – FT-IR: ν (cm−1)=3345 (s, v, O–H), 2978 (m, v, C–H, alkyl), 2928 (m, v, C–H, alkyl), 1693 (s, v, C=O), 1242 (s, v, C–O, alcohol), 729 (m, δ, C–H, mono-substituted arom.), 693 (m, δ, C–H, mono-substituted arom.). – LC/MS ((+)-ESI): tR=XX min (supply XX), m/z=276.1602 (calcd. 276.1594 for C16H22NO3+, [M+H+]).

4.3.17 [(1RS,5SR,8RS)-8-Hydroxy-2-azabicyclo[3.3.1]nonan-2-yl]phenylmethan-1-one (12c)

Under N2, the epoxide 11c (180 mg, 0.73 mmol) was dissolved in THF (6 mL) and a solution of KOtBu in THF (1 m, 1.47 mL, 1.47 mmol) was added dropwise at 0°C. After stirring for 24 h under reflux conditions, H2O (10 mL) was added [13]. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The crude yellow oil was purified by flash column chromatography (EtOAc-C6H12=90:10, Ø=2.5 cm, V=20 mL). Colorless powder, m. p. 195–196°C, yield 40.8 mg (26%). Rf=0.25 (EtOAc-C6H12 80:20). C15H19NO2 (245.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.43 (bd, J=7.7 Hz, 0.6H, 7-CH2), 1.52–1.76 (m, 3.6H, 4-CH2, 6-CH2, 7-CH2, 9-CH2), 1.81–2.09 (m, 5.2H, 4-CH2, 5-CH, 6-CH2, 7-CH2, 9-CH2), 2.22 (bd, J =13.5 Hz, 0.6H, 9-CH2), 3.37–3.56 (m, 1.6H, 3-CH2), 3.80 (bs, 0.8H, 1-CH, 8-CH), 4.21 (bs, 0.6H, 8-CH), 4.35 (dd, 0.4H, J=14.7/8.1 Hz, 3-CH2), 4.55 (bs, 0.6H, 1-CH), 7.33–7.41 (m, 5H, CHbenzoyl). – 13C NMR (100 MHz, CDCl3): δ (ppm)=24.4 (1C, C-5), 24.7 (1C, C-9), 25.4 (1C, C-5), 25.6 (1C, C-9), 26.2 (1C, C-7), 26.5 (1C, C-6), 27.2 (1C,C-7), 28.7 (1C, C-4), 29.2 (1C, C-6), 29.3 (1C, C-3), 39.6 (1C, C-4), 44.0 (1C, C-3), 51.1 (1C, C-1), 54.2 (1C, C-1), 66.4 (1C, C-8), 69.0 (1C, C-8), 126.3 (2C, C-2benzoyl, C-6benzoyl), 126.7 (2C, C-2benzoyl, C-6benzoyl), 128.6 (2C, (2C, C-3benzoyl, C-5benzoyl), 128.7 (1C, C-4benzoyl), 129.5 (3C, C-3benzoyl, C-4benzoyl, C-5benzoyl), 136.9 (1C, C-1benzoyl), 137.2 (1C, C-1benzoyl), 171.9 (1C, C=O), 172.5 (1C, C=O). – FT-IR: ν (cm−1)=3337 (s, v, O–H), 2920 (m, v, C–H, alkyl), 1593 (s, v, C=O), 1427 (s, δ, O–H), 703 (m, δ, C–H, mono-substituted arom.), 633(m, δ, C–H, mono-substituted arom.). – Exact mass (APCI): m/z=246.1495 (calcd. 246.1489 for C15H20NO2+, [M+H+]). – Purity (HPLC, method 1): 97%, tR=15.83 min.

4.3.18 2-(3,4-Dichlorophenyl)-1-[(1RS,5SR,8RS)-8-hydroxy-2-azabicyclo[3.3.1]nonan-2-yl]-ethan-1-one (12d)

Under N2, the epoxide 11b (410 mg, 1.25 mmol) was dissolved in THF (6 mL) and a solution of NaHMDS in THF (1 m, 2.49 mL, 2.50 mmol) was added dropwise at 0°C. After stirring for 72 h at r. t., H2O (10 mL) was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The crude oil was purified via flash column chromatography (CH2Cl2-acetone=80:20, Ø=2.5 cm, V=10 mL). Colorless solid, m. p. 92°C, yield 154 mg (38%). Rf=0.46 (CH2Cl2-acetone 50:50). C16H19Cl2NO2 (328.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.36–1.42 (m, 1H, 7-CH2), 1.45–1.78 (m, 4H, 4-CH2, 6-CH2, 9-CH2), 1.85–2.04 (m, 3H, 4-CH2, 5-CH, 7-CH2), 2.11–2.19 (m, 1H, 6-CH2, 9-CH2), 3.30 (ddd, J=14.6/11.5/6.7 Hz, 0.4H, 3-CH2), 3.45–3.53 (m, 1.2H, 3-CH2), 3.62–3.73 (m, 2H, CH2CO), 3.72 (bs, 0.4H, 8-CH), 3.89 (bd, J=2.5 Hz, 0.4H, 1-CH), 4.02 (bd, J=2.0 Hz, 0.6H, 8-CH), 4.13 (2× dd, J=8.2/2.2 Hz, 0.4H, 3-CH2), 4.37 (bd, J=3.6 Hz, 0.6H, 1-CH), 7.07 (dd, J=8.4/2.2 Hz, 0.5H, 6-CHarom.), 7.11 (dd, J=8.4/2.2 Hz, 0.5H, 6-CHarom.), 7.35 (d, J=2.2 Hz, 1H, 2-CHarom.), 7.38 (d, J=8.4Hz, 0.5H, 5-CHarom.), 7.39 (d, J=8.4Hz, 0.5H, 5-CHarom.). A signal for the proton of the OH moiety is not seen in the spectrum. – 13C NMR (100 MHz, CDCl3): δ (ppm)=24.1, (1C, C-5), 24.8 (2C, C-5, C-9), 25.3 (1C, C-9), 26.0 (1C, C-7), 26.5 (1C, C-6), 26.8 (1C, C-6), 28.3 (1C, C-4), 28.6 (1C, C-7), 29.0 (1C, C-4), 39.3 (1C, C-3), 39.7 (1C, CH2C=O), 40.7 (1C, CH2C=O), 42.0 (1C, C-3), 50.9 (1C, C-1), 53.0 (1C, C-1), 66.3 (1C, C-8), 69.1 (1C, C-8), 128.5 (1C, C-6arom.), 128.6 (1C, C-6arom.), 128.9 (1C, C-4arom.), 130.6 (1C, C-5arom.), 130.7 (1C, C-5arom.), 130.9 (1C, C-2arom.), 131.0 (1C, C-2arom.), 131.1(1C, C-3arom.), 135.3 (1C, C-1arom.), 170.4 (1C, C=O). – FT-IR: ν (cm−1)=3325 (s, v, O–H), 2924 (m, v, C–H, alkyl), 1624 (s, v, C=O), 1412 (s, δ, O–H). – LC/MS ((+)-ESI): tR=5.7–5.8 min, m/z=328.0878 (calcd. 328.0866 for C16H2035Cl2NO2+, [M+H+]). – Purity (HPLC, method 1): 70.9%, tR=19.93 min.

4.3.19 (1RS,5SR)-2-[2-(3,4-Dichlorophenyl)acetyl]-2-azabicyclo[3.3.1]nonan-8-one (13d)

Dess-Martin periodinane (260 mg, 0.61 mmol) was added to a solution of bicyclic alcohol 12d (100 mg, 0.30 mmol) in CH2Cl2 (10 mL). After 18 h stirring at r. t., the mixture was treated with aq. NaHCO3 solution. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with saturated NaCl solution and dried (Na2SO4). The solvent was removed in vacuo. The crude product was purified by flash column chromatography (EtOAc-C6H12=60:40, Ø=2.5 cm, V=10 mL). Colorless oil, yield 40 mg (37%). Rf=0.41 (EtOAc:C6H12 80:20). C16H17Cl2NO2 (326.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)=1.61–1.66 (m, 0.5H, 6-CH2), 1.75–1.80 (m, 0.5H, 6-CH2), 1.82–1.87 (m, 0.5H, 4-CH2), 1.92–2.14 (m, 4.5H, 4-CH2, 6-CH2, 7-CH2), 2.23–2.28 (m, 1H, 5-CH), 2.36 (ddd, J=14.9/7.1/4.5 Hz, 0.5H, 9-CH2), 2.47–2.55 (m, 1H, 9-CH2), 2.65 (ddd, J=16.4/11.1/8.2 Hz, 0.5H, 9-CH2), 3.41–3.56 (m, 1.5H, 3-CH2), 3.63–3.71 (m, 2H, CH2CO), 3.99 (ddd, J=14.5/7.1/4.8 Hz, 0.5H, 3-CH2), 4.22 (bt, J=2.9 Hz, 0.5 H, 1-CH), 4.68 (bs, 0.5H, 1-CH), 7.08 (dd, J=8.2/2.1 Hz, 0.5H, 6-CHarom.), 7.12 (dd, J=8.2/2.1 Hz, 0.5H, 6-CHarom.), 7.34 (d, J=2.1 Hz, 1H, 2-CHarom.), 7.38 (d, J=8.2 Hz, 1H, 5-CHarom.). – 13C NMR (100 MHz, CDCl3): δ (ppm)=23.7 (2× 1C, C-5), 28.9 (1C, C-4), 30.1 (1C, C-4), 30.4 (1C, C-6), 30.8 (1C, C-6), 31.3 (1C, C-7), 32.4 (1C, C-7), 35.9 (1C, C-9), 37.2 (1C, C-9), 37.9 (1C, C-3), 39.8 (1C, CH2C=O), 40.3 (1C, CH2C=O), 40.7 (1C, C-3), 57.9 (1C, C-1), 59.7 (1C, C-1), 128.3 (1C, C-6arom.), 128.9 (1C, C-6arom.), 130.5 (1C, C-5arom.), 130.7 (1C, C-5arom.), 130.9 (1C, C-3arom.), 131.1 (1C, C-3arom.), 131.3 (1C, C-2arom.), 131.4 (1C, C-2arom.), 132.6 (1C, C-4arom.), 132.8 (1C, C-4arom.), 134.8 (1C, C-1arom.), 135.1 (1C, C-1arom.), 169.6 (1C, C=O), 171.1 (1C, C=O), 208.7 (1C, C-8), 210.0 (1C, C-8). – FT-IR: ν (cm−1)=2928 (m, v, C–H, alkyl), 1717 (m, v, C=O of ketone), 1639 (m, v, C=O of amide), 1030 (m, γ, C–H). – LC/MS ((+)-ESI): tR=5.8 min, m/z=326.0701 (calcd. 326.0709 for C16H1835Cl2NO2+, [M+H+]). – Purity (HPLC, method 1): 88.8%, tR=20.33 min.

4.3.20 2-(3,4-Dichlorophenyl)-1-[(1RS,5SR,8SR)-8-hydroxy-2-azabicyclo[3.3.1]nonan-2-yl]-ethan-1-one (14d)

The ketone 13d (37.0 mg, 0.11 mmol) was dissolved in THF (6 mL) and EtOH (2mL). NaBH4 (43.0 mg, 1.13 mmol) was added and the mixture was stirred at r. t. for 12 h. Then 2 m HCl and CH2Cl2 (10 mL) were added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (EtOAc-C6H12=9:1, Ø=2.5 cm, V=10 mL). Colorless solid, m. p. 179–181°C, yield 11.6 mg (31%). Rf=0.21 (EtOAc-C6H12 9:1). C16H19Cl2NO2 (314.2). – 1H NMR (600 MHz, CDCl3): δ (ppm)=1.55–189 (m, 7H, 4-CH2, 6-CH2, 7-CH2, 9-CH2), 1.94–2.02 (m, 2H, 4-CH2, 5-CH, 9-CH2), 3.20 (td, J=12.9/4.8 Hz, 0.2H, 3-CH2), 3.47 (dt, J=13.1/7.0 Hz, 0.8H, 3-CH2), 3.54 (dt, J=13.1/6.9Hz, 0.8H, 3-CH2), 3.72 (s, 1.6 H, CH2CO), 3.81–3.95 (m, 1.4 H, 8-CH, CH2CO), 4.09 (bs, 0.2H, 1-CH), 4.26 (dd, J=14.1/8.3 Hz, 0.2H, 3-CH2), 4.76 (s, 0.8H, 1-CH), 7.11 (dd, J=8.2/1.6 Hz, 1H, 6-CHarom.), 7.35 (d, J=1.6 Hz, 1H, 2-CHarom.), 7.40 (d, J=8.2 Hz, 1H, 5-CHarom.). A signal for the proton of the OH moiety is not seen in the spectrum. – 13C NMR (150 MHz, CDCl3): δ (ppm)=23.4 (1C, C-5), 24.5 (1C, C-5), 27.9 (1C, C-7), 28.2 (1C, C-4), 29.0 (1C, C-7), 29.1 (1C, C-4), 29.7 (1C, C-9), 29.8 (1C, C-6), 31.4 (1C, C-9), 32.2 (1C, C-6), 39.9 (1C, CH2C=O), 40.8 (1C, CH2C=O), 40.9 (1C, C-3), 42.4 (1C, C-3), 51.9 (1C, C-1), 53.4 (1C, C-1), 72.2 (1C, C-8), 74.0 (1C, C-8), 128.6 (1C, C-6arom.), 129.0 (1C, C-6arom.), 130.4 (1C, C-2arom.), 130.7 (1C, C-2arom.), 130.8 (1C, C-3arom.), 131.2 (2C, C-3arom., C-5arom.), 131.4 (1C, C-5arom.), 132.4 (1C, C-4arom.), 132.7 (1C, C-4arom.), 134.9 (1C, C-1arom.),136.7 (1C, C-1arom.), 172.1 (1C, C=O), 173.9 (1C, C=O). – FT-IR: ν (cm−1)=3379 (s, v, O–H), 2978 (m, v, C–H, alkyl), 2928 (m, v, C–H, alkyl), 1608 (s, v, C=O), 1443 (m, δ, O–H), 1069 (m, γ, C–H). – Purity (HPLC, method 1): 93.5%, tR=20.52 min.

4.4 X-ray crystal structure analysis of 12c

Recrystallization of 12c from EtOAc gave colorless single crystals suitable for X-ray diffraction. T=223(2) K, Nonius Kappa CCD diffractometer, CuKα radiation, λ=1.54178 Å, ω and ϕ scans; an empirical absorption correction was applied (0.874≤T≤0.973). The hydrogen atom positions were calculated and refined as riding atoms. Flack (x) parameter refined to –0.45(44). Programs used: data collection, collect [27]; data reduction Denzo-SMN [28]; absorption correction, Denzo [29]; structure solution shelxs-97 [30]; structure refinement shelxs-97 [31] and graphics, xp [32].

Table 2 summarizes the crystal data and numbers pertinent to data collection and structure refinement.

Table 2:

Crystal structure data for 12c.

FormulaC15H19NO2
Mr245.31
Crystal size, mm30.20×0.12×0.04
Crystal systemMonoclinic
Space groupCc
a, Å5.9182(8)
b, Å18.9640(14)
c, Å11.2060(20)
β, deg97.460(15)
V, Å31247.0(3)
Z4
Dcalcd, g cm−31.307
F(000), e528
μ(CuKα), mm−10.7
((sinθ)/λ)max, Å−10.60
Refl. measured5158
Refl. unique/Rint1071/0.052
Param. refined164
R(F) / wR(F2)a (all refl.)0.1048
x(Flack)–0.45(44)
GoF (F2)b1.060
Δρfin (max/min), e Å−30.205/–0.169

aR1=||Fo|–|Fc||/Σ|Fo|, wR2=[Σw(Fo2Fc2)2w(Fo2)2]1/2, w=[σ2(Fo2)+(AP)2+BP]−1, where P=(Max(Fo2, 0)+2Fc2)/3; b GoF=[Σw(Fo2Fc2)2/(nobsnparam)]1/2.

CCDC 1480173 (12c) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgments

This work was performed within the framework of the International Research Training Group ‘Complex Functional Systems in Chemistry: Design, Synthesis and Applications’ in collaboration with the University of Nagoya. Financial support of this project by the IRTG Münster-Nagoya and the Deutsche Forschungsgemeinschaft is gratefully acknowledged. This work was partially supported by JSPS Core-to-Core Program, A. Advanced Research Network.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

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    A. E. Takemori, P. S. Portoghese, J. Pharmacol. Exp. Ther. 1987, 243, 91.

    • PubMed
    • Export Citation
  • [2]

    A. F. Casy, R. T. Parfitt, Opioid Analgesics – Chemistry and Receptors, Plenum Press, New York 1986.

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    E. L. May, J. M. Takeda, J. Med. Chem. 1970, 13, 805.

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    W. R. Martin, C. G. Eades, J. A. Thompson, R. E. Huppler, P. E. Gilbert, J. Pharmacol. Exp. Ther. 1976, 197, 517.

    • PubMed
    • Export Citation
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    T. Hayashi, S. Y. Tsai, T. Mori, M. Fujimoto, T. P. Su, Expert Opin. Ther. Targets 2011, 15, 557.

    • Crossref
    • PubMed
    • Export Citation
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    T. Maurice, T. P. Su, Pharmacol. Ther. 2009, 124, 195.

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    C. M. Bertha, M. V. Mattson, J. L. Flippen-Anderson, R. B. Rothman, H. Xu, X.-Y. Cha, K. Becketts, K. C. Rice, J. Med. Chem. 1994, 37, 3163.

    • Crossref
    • PubMed
    • Export Citation
  • [8]

    K. W. Crawford, W. D. Bowen, Cancer. Res. 2002, 62, 3133.

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    J. Bonjoch, F. Diaba, B. Bredshaw, Synthesis 2011, 7, 993.

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    M. E. Hediger, Bioorg. Med. Chem. 2004, 12, 4995.

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    M.-C. P. Yeh, H.-F. Pai, Z.-J. Lin, B.-R. Lee, Tetrahedron 2009, 65, 4789.

    • Crossref
    • Export Citation
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    G. Karig, A. Fuchs, A. Büsing, T. Brandstetter, S. Scherer, J. W. Bats, A. Eschenmoser, G. Quinkert, Helv. Chim. Acta 2000, 83, 1049.

    • Crossref
    • Export Citation
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    L. J. Dolby, S. J. Nelson, J. Org. Chem. 1973, 38, 2882.

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    W. Bauer, K.-H. Büchel, H. Döpp, T. Eicher, J. Falbe, C. J. Grundmann, H. Hagemann, M. Hanack, D. Klamann, H.-G. Korth, R. P. Kreher, C. Kropf, G. Krüger, K. Kühlein, R. Mayer, H. Pielartzik, M. Regitz, D. Schumann, G. Simchen, R. Sustmann, Houben-Weyl Methods in Organic Chemistry, Vol. E5, Georg Thieme Verlag Stuttgart, 1985, p. 262.

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    • Crossref
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    A. Matsuoka, T. Isogawa, Y. Morioka, B. R. Knappett, A. E. H. Wheatley, S. Saito, H. Naka, R. Soc. Chem. Adv. 2014, 5, 12152.

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    S. Knapp, K. E. Rodriques, A. T. Levorse, R. M. Ornaf, Tetrahedron Lett. 1985, 26, 1803.

    • Crossref
    • Export Citation
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    S. Knapp, A. T. Levorse, J. Org. Chem. 1988, 53, 4006.

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    Y.-Y. Yeung, E. J. Corey, Tetrahedron Lett. 2007, 48, 7567.

    • Crossref
    • Export Citation
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    B. Wünsch, C. Geiger in Houbel-Weyl, Science of Synthesis, Vol. 40a, (Eds.: D. Enders, E. Schaumann), Georg Thieme Verlag, Stuttgart, 2009, pp. 23–64.

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    C. Bourgeois, E. Werfel, F. Galla, K. Lehmkuhl, H. Torres-Gómez, D. Schepmann, B. Kögel, T. Christoph, W. Straßburger, W. Englberger, M. Soeberdt, S. Hüwel, H.-J. Galla, B. Wünsch J. Med. Chem. 2014, 57, 6845.

    • Crossref
    • PubMed
    • Export Citation
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    B. R. de Costa, W. D. Bowen, S. B. Hellewell, C. George, R. B. Rothman, A. A. Reid, J. M. Walker, A. E. Jacobson, K. C. Rice, J. Med. Chem. 1989, 32, 1996.

    • Crossref
    • PubMed
    • Export Citation
  • [23]

    L. Radesca, W. D. Bowen, L. Di Paolo, B. R. de Costa, J. Med. Chem. 1991, 34, 3058.

    • Crossref
    • PubMed
    • Export Citation
  • [24]

    R. N. McDonald, R. N. Steppel, J. E. Dorsey, Org. Synth., Coll. 1988, 6, 276B.

  • [25]

    D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.

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    D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.

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    R. W. W. Hooft, collect, Bruker Analytical X-ray Instruments Inc., Delft (The Netherlands) 2008.

  • [28]

    Z. Otwinowski, W. Minor in Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A (Eds.: C. W. Carter Jr, R. M. Sweet), Academic Press, New York, 1997, pp. 307.

  • [29]

    Z. Otwinowski, D. Borek, W. Majewski, W. Minor, Acta Crystallogr. 2003, A59, 228–234.

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    G. M. Sheldrick, Acta Crystallogr. 1990, A46, 467.

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    G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112.

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    XP – Interactive molecular graphics, (version 5.1), Bruker Analytical X-ray Instruments Inc., Madison, Wisconsin (USA) 1998.

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    Synthesis of 2-(cyclohexen-4-yl)acetamide derivatives.

    Reagents and reaction conditions: (a) LiAlH4, THF, 0°C, 90 min, 93%. (b) MesCl, pyridine, 0°C, 2 h, 90%. (c) NaCN, DMSO, 110–120°C, 90 min, 90%. (d) Ru/chitin, H2O, 120°C, 24 h, 62%. (e) NaH, THF, r. t., 45 min, then (Boc)2O, THF, r. t., 2.5 d, 85%.

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    Synthesis of diastereomeric hydroxymorphans. Reagents and reaction conditions: (a) LiAlH4, THF, r. t., 12 and 14 h, 76% (9·HCl). (b) 9·HCl, RC(=O)Cl or (Boc)2O, NEt3, CH2Cl2, r. t., 2–4 h, 57–75% (10ad), (c) 1. 9·HCl, NaOH, CH2Cl2; then (3,4-dichlorophenyl)acetic acid, DCC, r. t., 3 h, 98%. (d) 1. KCN, 18-crown-6, THF, 85°C, 24 h; 2. LiAlH4, THF, 85°C, 24 h; 3. RC(=O)Cl. NaOH, 85°C, 3 h, 13% (10b), 30% (10d). (e) mCPBA, CHCl3, r. t., 18 h, 48–80%. (f) strong base, THF, 8–38%. (g) Dess-Martin periodinane, CH2Cl2, r. t., 18 h, 37%. (h) NaBH4, THF, EtOH, r. t., 12 h, 31%. The compounds 1214 were prepared as racemic mixtures. In the Scheme only one enantiomer is shown.

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    Molecular structure of hydroxymorphan 12c in the crystal. Displacement ellipsoid are drawn at the 15% probability level, H atoms as spheres with arbitrary radii.