Asymmetric synthesis of enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines

Tetrahedron: Asymmetry 22 (2011) 1411–1422

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Asymmetric synthesis of enantiomerically pure 1,4-diand 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines Soumya Sarkar, Dirk Schepmann, Bernhard Wünsch ⇑ Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany

a r t i c l e

i n f o

Article history: Received 20 June 2011 Accepted 25 July 2011 Available online 1 September 2011

a b s t r a c t A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of different alkyl groups (methyl, ethyl, allyl) with high diastereoselectivity (dr >99:1). The relative configuration of the new stereogenic center was determined by NOE experiments. Tricyclic lactams trans-9 and cis-10 were also used for the introduction of two substituents and, moreover, the establishment of spirocyclic rings. Reduction of the substitution products 11 and 12 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and the final hydrogenolytic removal of the N-(2-hydroxy-1-phenylethyl) residue provided enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-3-benzazepines 17 and ent-17. In receptor binding studies with radioligands, the 3-benzazepines 17a–g and ent-17a–g did not show any interactions with r1, r2 or NMDA receptors. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction The tetrahydro-3-benzazepine ring system is of interest from a medicinal chemistry point of view, because it contains the phenylethylamine structural element, which is found in many natural products and pharmacologically active compounds.1–3 Derivatives with the 3-benzazepine scaffold are well known as agonists or antagonists at dopamine D14,5 and dopamine D3 receptors.6 The 1phenyl derivative 1 (SCH-23390) represents a typical D1 receptor antagonist7,8 (Fig. 1). Furthermore, 1-methyl-2,3,4,5-tetrahydro1H-3-benzazepine 2 has been described as a selective 5-HT2C receptor agonist, which can be used for the treatment of obesity.9,10 It has also been shown that compounds with the 3-benzazepine scaffold are active in the animal models of various neurological disorders including Parkinson’s disease11 and Alzheimer’s disease.12 Recently, syntheses of racemic13 and enantiomerically pure 1-substituted 3-benzazepines 314,15 and enantiomerically pure 4substituted 1-benzyltetrahydro-3-benzazepines 416–18 were reported (Fig. 1), which showed moderate to high affinity to the phencyclidine (PCP) binding site of the NMDA receptor. The NMDA receptor is one of the excitatory ionotropic glutamate receptors, which is activated by N-methyl-D-aspartate (NMDA). It controls the penetration of Na+- and Ca2+-ions into the neuron by highly balanced systems and plays a crucial role in important physiological processes such as learning and memory. However, over-stimulation of NMDA receptors results in an uncontrolled influx of Ca2+ ions ⇑ Corresponding author. Tel.: +49 251 8333311; fax: +49 251 8332144. E-mail address: [email protected] (B. Wünsch). 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.07.027

leading to neuronal cell death. Acute and chronic neurodegenerative disorders including epilepsy, Alzheimer’s or Parkinson’s disease are associated with increased activation of the NMDA receptor.19–21 The synthesis of 1-benzyltetrahydro-3-benzazepines 4 with various substituents at the 4-position was accomplished by benzylation of various tricyclic lactams of type 9 and 10.16,17 Herein we report on the asymmetric synthesis of 4-methyltetrahydro-3-benzazepines 5 bearing various substituents at the 1-position. (Fig. 1) In particular, the stereocontrol of the small CH3 residue at the 11aposition is investigated. An additional feature of this manuscript is the stereoselective introduction of two substituents at the 1position. 2. Results and discussion The asymmetric synthesis of differently substituted 3-benzazepines 5 started from commercially available o-phenylenediacetic acid 6, which was transformed into methyl keto acid 7 upon treatment with an excess of MeLi22 (Scheme 1). Condensation of methyl keto acid 7 with (R)-2-amino-2-phenylethanol 8 led to the diastereomeric tricyclic lactams trans-9 and cis-10. The ratio of the diastereomeric methyl derivatives trans-9 to cis-10 was almost 50:50.16–18 The trans- and cis-configured tricyclic lactams trans-9 and cis-10 were separated and exploited for the synthesis of enantiomerically pure 3-benzazepines 17 with various substituents at the 1-position. For the introduction of one substituent at the 6-position, the tricyclic lactams trans-9 and cis-10 were deprotonated with 1.2 equiv of LHMDS at 78 °C and the formed enolates were trapped with

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5 4 3 NH 1 2

NH H 3C

R

2

3

CH3

Cl

5

N CH3

1

HO

1

R2

4 3 NH 2

5 4 3 NH 1 2

R2

1

R

Ph

5 4

1

Figure 1. Development of differently substituted tetrahydro-3-benzazepines 5 from biologically active lead compounds.

alkyl halides at 78 °C to afford the monosubstituted tricyclic lactams 11a–c and 12a–c, respectively. (Scheme 1, Table 1) All transformations took place with high diastereoselectivity and produced only one diastereomer according to GC–MS analysis (dr >99:1). The high diastereoselectivity is in good agreement with the previously observed high diastereoselectivity for the benzylation16,17 of trans9 and cis-10. The high diastereoselectivity was not limited to large electrophiles such as benzyl bromide, since even very small electrophiles such as methyl iodide or ethyl iodide led to high diastereoselectivity. The relative configuration of the alkylated products 11a–c and 12a–c and thus the absolute configuration of the newly formed stereogenic center at the 6-position of the tricyclic system was confirmed by NOE experiments. The NOE difference spectrum of the methylated compound 12a showed an increase of the signal at 3.79 ppm (6-H) after irradiation at 1.65 ppm (CH3) thus indicating a cis-arrangement of these groups and a (S)-configuration at C6. In the control experiment, irradiation at 3.79 ppm (6-H) led to an increased signal at 1.65 ppm (CH3). Similarly, the configuration of the newly formed stereogenic center of compounds 11a–c [(R)configuration] and 12b–c [(S)-configuration] was confirmed by corresponding NOE experiments. The stereochemistry of the alkylated products 11a–c and 12a–c reveals that the CH3 moiety at C11a of trans-9 and cis-10 controls the attack to the electrophile, which takes place exclusively from the opposite face to the C-11a methyl moiety.

Next, two substituents were introduced at the 6-position of the tricyclic systems. At first, the alkylation of trans-9 and cis-10 was tried using 3 equiv of base LHMDS and methyl iodide at 0 °C. The dimethyl derivatives 11d and 12d were isolated in 71% and 64% yield, respectively. (Scheme 1, Table 1) Similar yields were obtained with 5 equiv of the larger electrophile ethyl iodide, which gave diethyl derivatives 11e and 12e. Five- and six-membered spirocyclic ring systems were also synthesized following the described strategy. Deprotonation of trans-9 and cis-10 with an excess of LHMDS and reaction of the formed enolates with one equivalent of 1,4-diiodobutane or 1,5-diiodopentane gave the spirocyclic 3-benzazepines 11f,g and 12f,g in good yields (Scheme 1, Table 1). For the introduction of two different substituents23,24 at the 6position, the monomethylated tricyclic lactam 11a was deprotonated with LHMDS and the enolate was reacted with different alkyl halides. (Scheme 2) Initially, the reaction conditions (78 °C, 3 equiv of LHMDS, 2 h, EtI) employed successfully for monoalkylation of trans-9 and cis-10 were unsuccessful in yielding the dialkylated product 13a. Increasing the reaction temperature to 0 °C did not lead to the desired product 13a. However, performing the deprotonation of 11a with 3 equiv of LHMDS at +25 °C and the subsequent addition of an excess of ethyl iodide at 78 °C provided the expected 6-ethyl-6-methyl derivative 13a together with the hydroxylated product 14a (ratio 13a:14a = 80:20). A similar result was obtained after alkylation of 11a with benzyl bromide using the

H3C

O N

10

(c)

CH3

(a)

CO2H

O

7

N 6

7

2

R1 11a-f

R

trans-9

2

Ph

O

(b) +

CO2H 6

1

O 4

Ph

O CO2H

H3C

11

H3C

H3C

O N O

cis-10

(c)

O N

Ph R1

R2

Ph

O

12a-f

Scheme 1. Reagents and conditions: (a) CH3Li (8 equiv), THF, 0 °C?20 °C, 24 h, 50%; (b) (R)-2-amino-2-phenylethanol 8, 120 °C toluene, reflux, 45% (trans-9), 42% (cis-10); (c) LHMDS, RX; for further details of the reaction conditions see Table 1.

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S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422 Table 1 Introduction of alkyl substituents at the 6-position of trans-9 and cis-10 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Educt

Temp (°C)

RX

trans-9 trans-9 trans-9 cis-10 cis-10 cis-10 trans-9 trans-9 cis-10 cis-10 trans-9 trans-9 cis-10 cis-10

78 78 78 78 78 78 0 0 0 0 0 0 0 0

CH3I C2H5I Allyl-Br CH3I C2H5I Allyl-Br CH3I C2H5I CH3I C2H5I I(CH2)4I I(CH2)5I I(CH2)4I I(CH2)5I

H3C

Equiv of RX 1.2 1.2 2.0 1.2 1.2 2.0 3.0 5.0 3.0 5.0 1.0 1.0 1.0 1.0

H3C

O N

R1

1. LHMDS, 25 °C

R1

R2

11a 11b 11c 12a 12b 12c 11d 11e 12d 12e 11f 11g 12f 12g

CH3 C2H5 H2C@CHCH2 CH3 C2H5 H2C@CHCH2 CH3 C2H5 CH3 C2H5 (CH2)4 (CH2)5 (CH2)4 (CH2)5

H H H H H H CH3 C2H5 CH3 C2H5

O

H3C

N

2. R2X, -78 °C

Ph

Product

R

O

1

Ph

N

R2

R

OH

Ph

O

14a-c

13a-d

11a,b,h

1

45 48 66 47 53 64 71 63 64 71 48 51 54 47

O

+

O

Yield (%)

Scheme 2.

Table 2 Introduction of two different substituents at the 6-position

a

Entry

Educt

R1

R2 X

Products

R1

R2

Ratio 13:14a

1 2 3 4

11a 11a 11b 11h16

CH3 CH3 C2H5 CH2Ph

C2H5I PhCH2Br CH3I CH3I

13a,14a 13b,14a (13c),14b (13d),14c

CH3 CH3 C2H5 CH2Ph

C2H5 CH2Ph CH3 CH3

80:20 60:40 0:100 0:100

Yield (%) 32 60 30 35

The ratio of 13:14 was calculated by integration of the characteristic signals in the 1H NMR spectra of the unpurified products.

same reaction conditions. Again, the 6-benzyl-6-methyl substituted compound 13b was formed together with the hydroxylated product 14a. In this case, the ratio of 13b:14a was 60:40 reflecting the increased size of the electrophile benzyl bromide (Table 2). Due to the same Rf values of 13a,b and 14a, it was not possible to purify the products 13a,b by flash chromatography. All attempts to alkylate the ethyl and benzyl substituted tricyclic lactams 11b and 11h16,17 with methyl iodide led exclusively to the hydroxylated products 14b and 14c, that is, the corresponding dialkylated products were not formed (Scheme 2). It has been shown that the additional oxygen atom of 14a–c does not originate from O2 or moisture, since all reactions were conducted strictly under N2 excluding air and water and were repeated at least twice. Therefore it was assumed that the oxygen atom of the new OH group originates from the tricyclic lactam itself. Moreover, a similar oxidation was observed during the oxazolidine ring opening of trans-9 with phenylmagnesium bromide.25 It can be concluded that the introduction of a second different alkyl group at the 6-position of tricyclic lactams 11 and 12 is problematic due to low yields, the formation of hydroxylated side products 14a–c and isolation problems. The conversion of mono- and dialkylated tricyclic lactams 11 and 12 into the corresponding 3-benzazepines required two successive reduction steps (Scheme 3). At first, the oxazolidine moiety and the lactam group were reduced by AlH3, which was generated in situ upon mixing 1 equiv of AlCl3 and three equivalents of LiAlH426 (Table 3). With the exception of the sterically demanding diethyl derivatives 11e and 12e, which required a reaction temper-

11a-g

(a)

CH3 H N

(b)

NH

Ph

1 R2 R

R2 R1

15a-g

17a-g H

12a-g

CH3 H

OH

(a)

CH3

N

OH Ph

(b)

H CH3 NH

2 R1 R

2 R1 R

16a-g

ent-17a-g

Scheme 3. Reagents and conditions: (a) AlCl3/LiAlH4 (1:3), THF; 0 °C or 70 °C, for yields see Table 3; (b) H2 (1 atm), Pd/C, CH3OH, HCl, 4–6 h, for yields see Table 3.

ature of 70 °C, all reductions were performed at 0 °C. The AlH3 reductions took place with retention of configuration16–18 leading to products 15a–g with an (R)-configuration and 16a–g with an (S)-configuration at the 4-position of the 3-benzazepine ring system, respectively. The retention of configuration can be explained by coordination of the Lewis acidic reducing agent AlH3 to the oxygen atom, opening of the oxazolidine ring and delivering

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Table 3 Reduction of 11 and 12 with AlCl3/LiAlH4 (1:3) and hydrogenolytic removal of the (R)-configured 2-hydroxy-1-phenylethyl residue Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a b c

Educt

R1

R2

Producta

11a 11b 11c 12a 12b 12c 11d 11e 12d 12e 11f 11g 12f 12g

CH3 C2H5 H2C@CHCH2 CH3 C2H5 H2C@CHCH2 CH3 C2H5 CH3 C2H5 (CH2)4 (CH2)5 (CH2)4 (CH2)5

H H H H H H CH3 C2H5 CH3 C2H5

15a 15b 15c 16a 16b 16c 15d 15e 16d 16e 15f 15g 16f 16g

Yield (%)

Productb

Yield (%)

55 82 75 60 80 72 71 85 69 73 75 60 70 69

17a 17b 17cc ent-17a ent-17b ent-17cc 17d 17e ent-17d ent-17e 17f 17g ent-17f ent-17g

70 82 88 60 77 90 77 75 66 85 78 69 89 80

Product after reduction with AlCl3/LiAlH4 (1:3). Product after hydrogenolysis. For 17c and ent-17c, R1 = propyl.

one hydride from the same face as the departing oxygen atom. A retention of configuration has been shown for other similar systems.16–18 The diastereomerically pure products 15 and 16 were obtained in good yields (Table 3). Finally the 2-hydroxy-1-phenylethyl residue (original chiral auxiliary) at the 3-benzazepine N-atom of 15 and 16 had to be removed. The hydrogenolytic removal (H2, Pd/C) of this group gave high yields only, when 1 M HCl (1.5 mL) was added to the reaction mixture (Scheme 3, Table 3). The diastereomeric 3-benzazepines 15 and 16 were transformed into enantiomeric 3-benzazepines 17 and ent-17 by removal of the (R)-configured N-residue. For the allyl derivatives 15c and 16c, an additional hydrogenation of the double bond took place leading to the corresponding propyl derivatives 17c and ent-17c. In conclusion this strategy allows the synthesis of enantiomerically pure 1,4-disubstituted and 1,1,4-trisubstituted 3-benzazepines in only four reaction steps starting from methyl keto acid 7. 3. Receptor binding studies The affinities of the enantiomerically pure tetrahydro-3-benzazepines 17a–g and ent-17a–g toward NMDA receptors (PCP site), r1 and r2 receptors were investigated in competitive receptor binding studies. The affinity toward the PCP binding site of the NMDA receptor was determined with the radioligand [3H]-(+)MK-801 and fresh pig brain cortex membrane preparations.15 In the r assays, the radioligands [3H]-(+)-pentazocine (r1) and [3H]-ditolylguanidine (r2) and membrane preparations from guinea pig brains (r1) and rat livers (r2) were used.27–30 The 3-benzazepines 17a–g and ent-17a–g showed very low affinities toward the PCP binding site of the NMDA receptor and the r1 and r2 receptors. At a test compound concentration of 1 lM, the inhibition of radioligand binding was lower than 50% indicating IC50 values greater than 1 lM. 4. Conclusion In conclusion, enantiomerically pure 3-benzazepines 17a–g and ent-17a–g were synthesized from tricyclic lactams trans-9 and cis10. After deprotonation with LHMDS both 6-mono- and 6,6-dialkyl derivatives were obtained diastereoselectively. The configuration of the newly formed stereogenic center at the 6-position of the tricyclic lactams was confirmed by NOE experiments. The stepwise introduction of two different alkyl substituents at the 6-position was limited due to unexpected hydroxylation. Treatment with

AlCl3/LiAlH4 1:3 led to the reductive opening of the oxazolidine moiety and reduction of the lactam group. The final secondary amines 17 and ent-17 were prepared by hydrogenolytic cleavage of the N-(2-hydroxy-1-phenylethyl) moiety. The di- and trisubstitued 3-benzazepines 17 and ent-17 did not show any significant affinities to NMDA receptors (PCP site), or r1 and r2 receptors. 5. Experimental section 5.1. General 5.1.1. General methods and equipment Unless otherwise mentioned, THF was dried with sodium/benzophenone and was freshly distilled before use. Thin layer chromatography (TLC): Silica Gel 60 F254 plates (Merck). Flash chromatography (FC): Silica gel 60, 40–64 lm (Merck); parentheses include: diameter of the column, length of column, fraction size, eluent, Rf value. IR: IR spectrophotometer 480Plus FT-ATR-IR (Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz): Mercury plus 400 spectrometer (Varian); d in ppm related to tetramethylsilane; coupling constants are given with 0.5 Hz resolution. Where necessary, the assignment of the signals in the 1H NMR and 13C NMR spectra was performed using 1H–1H and 1H–13C COSY NMR spectra as well as NOE (nuclear Overhauser effect) difference spectroscopy. Optical rotations were determined with a Polarimeter 341 (Perkin Elmer); length 1 dm, wavelength 589 nm (sodium D line); the unit of the specific rotation [deg. mL dm1 g1] is omitted; concentration of the sample c [g/100 mL] and the solvents used are given in brackets. MS: EI = electron impact, ESI = electro spray ionization: MicroTof (Bruker Daltronics, Bremen), Calibration with sodium formate clusters before measurement. Gas liquid chromatography (GLC) was performed on a Shimadzu GC-17A gas chromatograph equipped with an SE-54 capillary column (30 m  0.32 mm, 0.25 lm film thickness) by CS-Chromatography Service using the following program: N2 carrier gas, injection temperature 250 °C, detector temperature 300 °C; temperature program: start temperature 40 °C, heating rate 10 °C/min, end temperature 280 °C for 5 min. 5.1.2. General procedure A for the monoalkylation of tricyclic lactams trans-9 and cis-10 Under N2 atmosphere, LHMDS (1 M in THF, 1.2 equiv) was added to a cooled solution (78 °C) of tricyclic lactam (1.0 equiv) dissolved in THF (6 mL). After stirring for 1 h at 78 °C, alkyl halide (1.2 equiv for methyl iodide and ethyl iodide and 2.0 equiv for ally bromide) was added and the solution was further stirred for 3 h at

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422

78 °C. Completion of the transformation was confirmed by TLC. Saturated NaCl solution was added (10 mL) to hydrolyze the excess of LHMDS and the mixture was extracted with EtOAc (3  10 mL). The organic layer was washed with NaCl solution (10 mL) and water (10 mL). The aqueous layer was reextracted with EtOAc (2  10 mL). The combined organic layers were dried (Na2SO4), filtered, the solvent was evaporated in vacuo and the residue was purified by FC. 5.1.3. General procedure B for dialkylation of tricyclic lactams trans-9 and cis-10 Under N2 atmosphere, LHMDS (1 M in THF, 3.0 equiv) was added to a cooled solution (0 °C) of tricyclic lactam (1.0 equiv) dissolved in THF (6 mL). After stirring for 1 h at 0 °C, an excess of alkyl halide (3.0 equiv for methyl iodide and 5.0 equiv for ethyl iodide) was added. For the introduction of five and six membered spirocyclic rings 1,4-diiodobutane or 1,5-diiodopentane (1.0 equiv) was added at 0 °C. The solution was stirred for a further 3 h at 0 °C. Completion of the conversion was confirmed by TLC. Saturated NaCl solution (10 mL) was then added and the mixture was extracted with EtOAc (3  10 mL). The organic layer was washed with NaCl solution (10 mL) and water (10 mL) and the aqueous layer was reextracted with EtOAc (2  10 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo and the residue was purified by FC. 5.1.4. General procedure C for the reduction of tricyclic lactams 11 and 12 with AlCl3/LiAlH4 Under N2 at 0 °C, dry THF (8 mL) was added to anhydrous AlCl3 (1.02 mmol, 1.0 equiv). The resulting clear colorless solution was stirred at 0 °C for 5 min. Then a solution of LiAlH4 (1 M in THF, 3.05 mL, 3.05 mmol, 3.0 equiv) was added via syringe. The resulting clear, colorless solution was allowed to warm to rt and was stirred for 20 min to give a solution of alane (AlH3). A solution of tricyclic lactam (1.02 mmol, 1.0 equiv) in dry THF (8 mL) was added to the stirred, cooled (0 °C) solution of alane in THF under N2. The resulting solution was stirred at 0 °C for 3 h and then warmed to rt over 30 min. For 6,6-disubstituted tricyclic lactams, the reaction was carried out at a higher temperature and for a longer time (for 6,6-dimethyl derivatives: 0 °C, overnight, and for 6,6-diethyl derivatives: 70 °C, overnight). The resulting clear solution was cooled to 0 °C before 1 M HCl (only few drops) was added carefully. The resulting slurry was diluted with water (10 mL) and extracted with CH2Cl2 (3  15 mL). The combined organic layers were washed with 1 M NaOH and brine (15 mL), dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by FC. 5.1.5. General procedure D for the hydrogenolysis of 15 and 16 A mixture of phenylethanol derivative 15 or 16, Pd/C (10% by wt), methanol and 1 M HCl (1.5 mL) was stirred at rt under a H2 atmosphere (balloon) for 4–6 h. The reaction mixture was filtered using a silica gel bed and the solvent was removed under reduced pressure to obtain a residue, which was dissolved in CH2Cl2 (10 mL). The CH2Cl2 layer was washed with 1 M NaOH (3  4 mL), which was extracted with CH2Cl2 (2), dried (Na2SO4), filtered, concentrated in vacuo, and the residue was purified by FC. 5.2. Synthetic procedures 5.2.1. Starting compounds The keto acid 7 was prepared as described in the literature.22 The synthesis of the diastereomeric tricyclic lactams trans-9 and cis-10 was performed according to the literature.16,17

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5.2.2. (3R,6R,11aS)-6,11a-Dimethyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11a Following general procedure A, trans-9 (110 mg, 0.38 mmol) was alkylated with methyl iodide (29 lL, 0.46 mmol). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc 8:2, Rf = 0.42 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 52 mg (45%). C20H21NO2 (307.4 g/mol). FT-IR (ATR, film): m (cm1) = 2976 (aliphatic C–H), 1649 (C@O). 1H NMR (CDCl3): d (ppm) = 1.48–154 (m, 6H, CH3/CH3), 3.35 (d, J = 15.3 Hz, 1H, 11-H), 3.40 (d, J = 15.3 Hz, 1H, 11-H), 3.73 (dd, J = 8.8/8.2 Hz, 1H, 2-H), 3.93 (q, J = 6.9 Hz, 1H, 6-H), 4.21 (t, J = 8.8 Hz, 1H, 2-H), 5.03 (t, J = 8.4 Hz, 1H, 3-H), 7.08–7.26 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 14.1 (1C, CH3), 27.1 (1C, CH3), 41.7 (1C, C-11), 44.6 (1C, C-6), 61.4 (1C, C-3), 69.0 (1C, C-2), 94.5 (1C, C-11a), 124.9,125.6, 127.2, 127.3, 128.1, 128.7, 130.3 (9C, Ph-CH), 133.9, 139.8, 140.7 (3C, Ph-C), 169.9 (1C, C@O). ½a23 589 ¼ 154:4 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C20H21NO2Na 330.1465, found 330.1467. Purity (HPLC): 91.2% (tR = 20.07 min). GLC: tR = 16.9 min.

5.2.3. (3R,6R,11aS)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11b Following general procedure A, trans-9 (100 mg, 0.34 mmol) was alkylated with ethyl iodide (0.68 mmol, 54 lL). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc 85:15, Rf = 0.54 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 52 mg (48%). C21H23NO2 (321.4 g/mol). FT-IR (ATR, film): m (cm1) = 2963 (aliphatic C–H), 1653 (C@O). 1H NMR (CDCl3): d (ppm) = 0.95 (t, J = 7.3 Hz, 3H, CH2CH3), 1.52 (s, 3H, CH3), 1.85–1.89 (m,1H, CH2CH3), 2.28–2.32 (m,1H, CH2CH3), 3.33 (d, J = 15.4 Hz, 1H, 11-H), 3.39 (d, J = 15.4 Hz, 1H, 11-H), 3.63 (t, J = 7.1 Hz, 1H, 6-H), 3.72 (dd, J = 8.8/8.2 Hz, 1H, 2-H), 4.23 (t, J = 8.8 Hz, 1H, 2-H), 5.06 (t, J = 8.4 Hz, 1H, 3-H), 7.01– 7.28 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 12.9 (1C, CH2CH3), 21.6 (1C, CH3), 26.9 (1C, CH2CH3), 44.8 (1C, C-6), 49.9 (1C, C-11), 61.2 (1C, C-3), 69.0 (1C, C-2), 94.6 (1C, C-11a), 125.4, 125.7, 127.2, 127.3, 128.0, 128.7, 130.3 (9C, Ph-CH), 134.1, 138.9, 140.7 (3C, Ph-C), 169.3 (1C, C@O). ½a23 589 ¼ 169:9 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na 344.1621, found 344.1614. Purity (HPLC): 99.2% (tR = 18.36 min). GLC: tR = 17.2 min.

5.2.4. (3R,6R,11aS)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11c Following general procedure A, trans-9 (91 mg, 0.31 mmol) was alkylated with allyl bromide (0.62 mmol, 54 lL). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc 85:15, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 68 mg (66%). C22H23NO2 (333.4 g/mol). FT-IR (ATR, film): m (cm1) = 2985 (aliphatic C–H), 1653 (C@O). 1H NMR (CDCl3): d (ppm) = 1.54 (s, 3H, CH3). 2.55–2.69 (m, 1H, CH2– CH@CH2), 2.96–3.08 (m, 1H, CH2–CH@CH2), 3.30 (d, J = 15.4 Hz, 1H, 11-H), 3.45 (d, J = 15.4 Hz, 1H, 11-H), 3.72 (dd, J = 8.8/ 8.2 Hz, 1H, 2-H), 3.80–3.87 (m, 1H, 6-H), 4.22 (t, J = 8.8 Hz, 1H, 2-H), 4.95–5.11 (m, 3H, 3-H/CH2–CH@CH2), 5.76–5.91 (m, 1H, CH2–CH@CH2), 7.01–7.32 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 26.9 (1C, CH3), 31.9 (1C, CH2–CH@CH2), 44.5 (1C, C-6), 47.2 (1C, C-11), 60.9 (1C, C-3), 68.8 (1C, C-2), 94.3 (1C, C-11a), 116.6 (1C, CH2–CH@CH2), 125.2, 125.3, 127.0, 127.2, 127.9, 128.5, 130.2 (9C, Ph-CH), 133.8, 136.2, 138.0, 140.4 (4C, Ph-C/ CH2–CH@CH2), 168.5 (1C, C@O). ½a23 589 ¼ 210:0 (c 0.20, CH2Cl2). Exact mass (ESI): m/z = calcd for C22H23NO2Na 356.1621, found 356.1626. Purity (HPLC): 93.3% (tR = 21.73 min). GLC: tR = 17.5 min.

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5.2.5. (3R,11aS)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11d Following general procedure B, trans-9 (41 mg, 0.14 mmol) was dimethylated with an excess of methyl iodide (26 lL, 0.42 mmol). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.62 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 31 mg (71%). C21H23NO2 (321.4 g/mol). FT-IR (ATR, film): m (cm1) = 2972 (aliphatic C–H), 1631 (C@O). 1H NMR (CDCl3): d (ppm) = 1.12 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.66 (s, 3H, CH3), 3.02 (d, J = 14.4 Hz, 1H, 11-H), 3.40 (d, J = 14.4 Hz, 1H, 11H), 3.73 (dd, J = 9.6/9.1 Hz, 1H, 2-H), 4.37 (dd, J = 8.8/8.4 Hz, 1H, 3H), 5.51 (dd, J = 9.6/8.4 Hz, 1H, 2-H), 7.05–7.42 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 23.6 (1C, CH3), 31.1 (1C, CH3), 31.7 (1C, CH3), 47.1 (1C, C-11), 50.0 (1C, C-6), 62.6 (1C, C-3), 69.7 (1C, C-2), 95.6 (1C, C-11a), 125.9, 127.1, 127.5, 127.8, 128.0, 128.9, 131.3 (9C, Ph-CH) 133.5 139.7, 143.6 (3C, Ph-C), 176.7 (1C, C@O). ½a23 589 ¼ þ107:2 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na 344.1621, found 344.1627. Purity (HPLC): 92.4% (tR = 22.09 min). 5.2.6. (3R,11aS)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo-[2,3-b][3]benzazepin-5(6H)-one 11e Following general procedure B, trans-9 (100 mg, 0.34 mmol) was diethylated with an excess of ethyl iodide (105 lL, 1.70 mmol). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.63 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 75 mg (63%). C23H27NO2 (349.5 g/mol). FT-IR (ATR, film): m (cm1) = 2959 (aliphatic C–H), 1625 (C@O). 1H NMR (CDCl3): d (ppm) = 0.57 (t, J = 7.4 Hz, 3H, CH2CH3), 0.62 (t, J = 7.4 Hz, 3H, CH2CH3), 1.31 (s, 3H, CH3), 1.34– 1.48 (m, 1H, CH2CH3), 1.94–2.04 (m, 1H, CH2CH3), 2.14–2.24 (m, 1H, CH2CH3), 2.35–2.45 (m, 1H, CH2CH3), 3.06 (d, J = 14.4 Hz, 1H, 11-H), 3.41 (d, J = 14.4 Hz, 1H, 11-H), 3.86 (t, J = 9.7 Hz, 1H, 2-H), 4.35–4.41 (m, 1H, 2-H), 5.48 (dd, J = 10.2/7.9, 1H, 3-H), 7.13–7.39 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 9.7 (1C, CH2CH3), 9.8 (1C, CH2CH3), 24.5 (1C, CH3), 36.2 (1C, CH2CH3), 38.4 (1C, CH2CH3), 48.1 (1C, C-11), 59.9 (1C, C-6), 64.0 (1C, C-3), 69.9 (1C, C-2), 95.5 (1C, C-11a), 126.8, 127.3, 127.7, 127.8, 128.5, 128.7, 131.2 (9C, Ph-CH), 135.7, 139.4, 139.9 (3C, Ph-C), 175.3 (1C, C@O). ½a23 589 ¼ þ120:5 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H27NO2Na 372.1934, found 372.1933. Purity (HPLC): 96.9% (tR = 22.48 min). 5.2.7. (3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10 -cyclopentan]-5one 11f Following general procedure B, trans-9 (56 mg, 0.19 mmol) was alkylated with 1,4-diodobutane (25 lL, 0.19 mmol). The crude product was purified by FC (d = 3 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.59 (cyclohexane/ EtOAc 6:4)). Colorless liquid, yield 32 mg (48%). C23H25NO2 (347.5 g/mol). FT-IR (ATR, film): m (cm1) = 2954 (aliphatic C– H), 1632 (C@O). 1H NMR (CDCl3): d (ppm) = 1.20 (s, 3H, CH3), 1.53–1.62 (m, 1H, CH2), 1.67–1.82 (m, 4H, CH2), 2.17–2.28 (m, 1H, CH2), 2.57–2.71 (m, 2H, CH2), 3.24 (d, J = 14.7 Hz, 1H, 11H), 3.43 (d, J = 14.7 Hz, 1H, 11-H), 3.73 (t, J = 8.9 Hz, 1H, 2-H), 4.34 (t, J = 8.7 Hz, 1H, 2-H), 5.45 (t, J = 8.8 Hz, 1H, 3-H), 7.01– 7.33 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 24.6 (1C, CH3), 26.1, 26.5 (2C, CH2–CH2CH2CH2), 40.1, 42.3 (2C, CH2–CH2CH2CH2), 46.1 (1C, C-11), 59.9 (1C, C-6), 62.3 (1C, C-3), 69.2 (1C, C-2), 95.2 (1C, C-11a), 125.6, 127.0, 127.3, 127.7, 127.9, 128.8, 131.5 (9C, Ph-CH), 134.2, 140.5, 143.4 (3C, Ph-C), 175.1 (1C, C@O). ½a23 589 ¼ þ24:8 (c 0.12, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H25NO2Na 370.1778, found 370.1780. Purity (HPLC): 96.4% (tR = 22.34 min).

5.2.8. (3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10 -cyclohexan]-5one 11g Following general procedure B, trans-9 (60 mg, 0.21 mmol) was alkylated with 1,5-diiodopentane (31 lL, 0.21 mmol). The crude product was purified by FC (d = 3 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.60 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 38 mg (51%). C24H27NO2 (361.5 g/mol). FT-IR (ATR, film): m (cm1) = 2926 (aliphatic C–H), 1637 (C@O). 1H NMR (CDCl3): d (ppm) = 1.16–1.20 (m, 2H, CH2), 1.28 (s, 3H, CH3), 1.40–1.54 (m, 3H, CH2), 1.71–1.80 (m, 1H, CH2), 1.84–1.95 (m, 1H, CH2), 1.97–2.03 (m, 1H, CH2), 2.14–2.22 (m, 1H, CH2), 2.48– 2.59 (m, 1H, CH2), 3.28 (d, J = 15.4 Hz, 1H, 11-H), 3.42 (d, J = 15.4 Hz, 1H, 11-H), 3.72 (t, J = 9.2 Hz, 1H, 2-H), 4.29 (t, J = 8.6 Hz, 1H, 2-H), 5.40 (t, J = 8.9 Hz, 1H, 3-H), 6.97–7.51 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 23.2 (1C, CH3), 23.6, 24.7, 25.9 (3C, CH2CH2CH2CH2CH2), 36.2, 37.3 (2C, CH2-(CH2)3CH2), 47.1 (1C, C-11), 53.2 (1C, C-6), 62.5 (1C, C-3), 69.4 (1C, C-2), 95.6 (1C, C-11a), 126.2, 127.1, 127.4, 127.6, 127.7, 128.7, 129.4, 131.9 (9C, Ph-CH), 134.4, 140.3, 142.2 (3C, Ph-C), 175.9 (1C, C@O). ½a23 589 ¼ þ32:3 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C24H27NO2Na 384.1934, found 384.1936. Purity (HPLC): 99.7% (tR = 22.92 min). 5.2.9. (3R,6S,11aR)-6,11a-Dimethyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12a Following general procedure A, cis-10 (83 mg, 0.28 mmol) was alkylated with methyl iodide (21 lL, 0.34 mmol). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc 85:15, Rf = 0.31 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 40 mg (47%). C20H21NO2 (307.4 g/mol). FT-IR (ATR, film): m (cm1) = 2927 (aliphatic C–H), 1655 (C@O). 1H NMR (CDCl3): d (ppm) = 1.40 (d, J = 6.9 Hz, 3H, CH3), 1.65 (s, 3H, CH3), 3.35 (d, J = 15.5 Hz, 1H, 11-H), 3.49 (d, J = 15.5 Hz, 1H, 11-H), 3.64 (dd, J = 9.1/1.9 Hz, 1H, 2-H), 3.79 (q, J = 6.8 Hz, 1H, 6-H), 4.28 (dd, J = 9.1/7.6 Hz, 1H, 2-H), 4.82 (dd, J = 7.6/1.8, 1H, 3-H), 6.37–6.41 (m, 2H, arom), 6.79–7.31 (m, 7H, arom). 13C NMR (CDCl3): d (ppm) = 12.1 (1C, CH3), 27.1 (1C, CH3), 41.1 (1C, C-6), 45.2 (1C, C11), 60.1 (1C, C-3), 70.7 (1C, C-2), 94.2 (1C, C-11a), 124.6, 125.3, 127.1, 127.2, 127.4, 127.7, 128.3, 128.9, 130.2 (9C, Ph-CH), 135.0, 141.0, 142.1 (3C, Ph-C), 169.5 (1C, C@O). ½a23 589 ¼ þ124:8 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C20H21NO2Na 330.1465, found 330.1462. Purity (HPLC): 92.7% (tR = 19.53 min). GLC: tR = 16.5 min. 5.2.10. (3R,6S,11aR)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12b Following general procedure A, cis-10 (71 mg, 0.25 mmol) was ethylated with EtI (0.50 mmol, 40 lL). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc 85:15, Rf = 0.40 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 41 mg (53%). C21H23NO2 (321.4 g/mol). FT-IR (ATR, film): m (cm1) = 2946 (aliphatic C–H), 1654 (C@O). 1H NMR (CDCl3): d (ppm) = 1.00 (t, J = 7.3 Hz, 3H, CH2CH3), 1.71 (s, 3H, CH3), 1.75– 1.86 (m, 1H, CH2CH3), 2.15–2.27 (m, 1H, CH2CH3), 3.43 (d, J = 15.4 Hz, 1H, 11-H), 3.52–3.60 (m, 2H, 11-H/6-H), 3.73 (dd, J = 9.2/1.9 Hz, 1H, 2-H), 4.35 (dd, J = 9.1/7.6 Hz, 1H, 2-H), 4.90 (dd, J = 7.5/1.8 Hz, 1H, 3-H), 6.46–6.51 (m, 2H, arom), 6.91–7.37 (m, 7H, arom). 13C NMR (CDCl3): d (ppm) = 12.8 (1C, CH2CH3), 20.1 (1C, CH3), 26.3 (1C, CH2CH3), 45.3 (1C, C-6), 49.4 (1C, C11), 60.2 (1C, C-3), 70.7 (1C, C-2), 94.2 (1C, C-11a), 125.4, 125.5, 127.1, 127.7, 128.3, 130.3 (9C, Ph-CH), 135.2, 140.2, 142.1 (3C, Ph-C), 168.9 (1C, C@O). ½a23 589 ¼ þ120:6 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na 344.1621, found 344.1622. Purity (HPLC): 96.5% (tR = 18.27 min). GLC: tR = 16.7 min.

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5.2.11. (3R,6S,11aR)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12c Following general procedure A, cis-10 (49 mg, 0.17 mmol) was allylated with allyl bromide (0.34 mmol, 29 lL). The crude product was purified by FC (d = 3 cm, l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.43 (cyclohexane/EtOAc 6:4)). Colorless oil, yield 36 mg (64%). C22H23NO2 (333.4 g/mol). FT-IR (ATR, film): m (cm1) = 2971 (aliphatic C–H), 1654 (C@O). 1H NMR (CDCl3): d (ppm) = 1.65 (s, 3H, CH3), 2.47–2.51 (m, 1H, CH2– CH@CH2), 2.87–2.91 (m, 1H, CH2–CH@CH2), 3.37 (d, J = 15.5 Hz, 1H, 11-H), 3.50 (d, J = 15.5 Hz, 1H, 11-H), 3.63–3.71 (m, 2H, 2H/6-H), 4.28 (dd, J = 9.1/7.6 Hz, 1H, 2-H), 4.82 (dd, J = 7.5/ 1.7 Hz, 1H, 3-H), 4.96 (dd, J = 10.2/1.7 Hz, 1H, CH2–CH@CH2), 5.04 (dd, J = 17.2/1.7 Hz, 1H, CH2–CH@CH2), 5.76–5.91 (m, 1H, CH2–CH@CH2), 6.39–7.32 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 25.2 (1C, CH3), 29.5 (1C, CH2–CH@CH2), 44.0 (1C, C-6), 45.8 (1C, C-11), 58.9 (1C, C-3), 69.4 (1C, C-2), 93.0 (1C, C-11a), 115.5 (1C, CH2–CH@CH2), 124.0, 124.1, 125.8, 126.0, 126.4, 127.0, 129.1 (9C, Ph-CH), 133.8, 135.3, 138.4, 140.7 (4C, Ph-C/CH2–CH@CH2), 167.0 (1C, C@O). ½a23 589 ¼ þ125:6 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C22H23NO2Na 356.1621, found 356.1613. Purity (HPLC): 97.1% (tR = 19.08 min). GLC: tR = 17.1 min. 5.2.12. (3R,11aR)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12d Following general procedure B, cis-10 (102 mg, 0.35 mmol) was dimethylated with an excess of methyl iodide (65 lL, 1.05 mmol). The crude product was purified by FC (d = 1 cm, l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.53 (cyclohexane/EtOAc 6:4)). Colorless oil, yield 38 mg (64%). C21H23NO2 (321.4 g/mol). FTIR (ATR, film): m (cm1) = 2946 (aliphatic C–H), 1613 (C@O). 1H NMR (CDCl3): d (ppm) = 0.90 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.57 (s, 3H, CH3), 3.11 (d, J = 14.6 Hz, 1H, 11-H), 3.76 (dd, J = 9.1/ 2.1 Hz, 1H, 2-H), 3.88 (d, J = 14.6 Hz, 1H, 11-H), 4.26 (dd, J = 9.1/ 7.5 Hz, 1H, 2-H), 4.95 (dd, J = 7.4/2.1 Hz, 1H, 3-H), 7.01–7.39 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 23.9 (1C, CH3), 27.4 (1C, CH3), 31.6 (1C, CH3), 46.7 (1C, C-11), 49.3 (1C, C-6), 62.9 (1C, C3), 70.3 (1C, C-2), 93.8 (1C, C-11a), 126.1, 127.3, 127.4, 127.7, 127.8, 128.7, 132.3 (9C, Ph-CH), 134.9, 143.1, 143.7 (3C, Ph-C), 171.7 (1C, C@O). ½a23 589 ¼ 64:5 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na 344.1621, found 344.1621. Purity (HPLC): 94.3% (tR = 20.67 min). 5.2.13. (3R,11aR)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11atetrahydro[1,3]oxazolo-[2,3-b][3]benazepin-5(6H)-one 12e Following general procedure B, cis-10 (64 mg, 0.22 mmol) was diethylated with an excess of ethyl iodide (88 lL, 1.1 mmol). The crude product was purified by FC (d = 1 cm, l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.59 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 54 mg (71%). C23H27NO2 (349.5 g/mol). FT-IR (ATR, film): m (cm1) = 2909 (aliphatic C-H), 1615 (C@O). 1H NMR (CDCl3): d (ppm) = 0.28 (t, J = 7.4 Hz, 3H, CH2CH3), 0.74 (t, J = 7.4 Hz, 3H, CH2CH3), 1.19 (s, 3H, CH3), 1.22–1.32 (m, 1H, CH2CH3), 2.05–2.20 (m, 2H, CH2CH3), 2.34–2.43 (m, 1H, CH2CH3), 3.20 (d, J = 14.6 Hz, 1H, 11-H), 3.75 (d, J = 14.6 Hz, 1H, 11-H), 3.90 (dd, J = 9.2/1.2 Hz, 1H, 2-H), 4.34 (dd, J = 9.1/6.6 Hz, 1H, 2-H), 5.09 (d, J = 6.1 Hz, 1H, 3-H), 7.06–7.30 (m, 6H, arom), 7.41–7.46 (m, 3H, arom). 13C NMR (CDCl3): d (ppm) = 9.4 (1C, CH2CH3), 10.9 (1C, CH2CH3), 24.8 (1C, CH3), 34.6 (1C, CH2CH3), 41.6 (1C, CH2CH3), 48.4 (1C, C-11), 60.6 (1C, C-6), 64.3 (1C, C-3), 70.0 (1C, C-2), 93.0 (1C, C-11a), 126.6, 126.7, 127.3, 127.7, 128.6, 129.1, 131.9 (9C, Ph-CH), 135.8, 140.9, 143.6 (3C, Ph-C), 171.1 (1C, C@O). ½a23 589 ¼ 79:7 (c 0.19, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H27NO2Na 372.1934, found 372.1932. Purity (HPLC): 96.7% (tR = 22.43 min).

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5.2.14. (3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10 -cyclopentan]-5one 12f Following general procedure B, cis-10 (69 mg, 0.24 mmol) was reacted with 1,4-diiodobutane (32 lL, 0.24 mmol). The crude product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/ EtOAc 85:15, Rf = 0.59 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 44 mg (54%). C23H25NO2 (347.5 g/mol). FT-IR (ATR, film): m (cm1) = 2921 (aliphatic C–H), 1617 (C@O). 1H NMR (CDCl3): d (ppm) = 1.24 (s, 3H, CH3), 1.40–1.49 (m, 2H, CH2), 1.58–1.74 (m, 2H, CH2), 1.84–1.91 (m, 1H, CH2), 2.07–2.14 (m, 1H, CH2), 2.44– 2.47 (m, 1H, CH2), 2.74–2.81 (m, 1H, CH2), 3.43 (d, J = 14.9 Hz, 1H, 11-H), 3.84 (dd, J = 9.1/2.6 Hz, 1H, 2-H), 3.89 (d, J = 14.9 Hz, 1H, 11-H), 4.41 (dd, J = 9.1/7.9 Hz, 1H, 2-H), 4.99 (dd, J = 7.8/ 2.6 Hz, 1H, 3-H), 7.08–7.33 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 24.3 (1C, CH3), 24.7, 34.7 (2C, CH2CH2CH2CH2), 40.3, 45.3 (2C, CH2CH2CH2CH2), 59.6 (1C, C-6), 62.1 (1C, C-3), 70.5 (1C, C-2), 94.4 (1C, C-11a), 126.1, 127.2, 127.3, 127.4, 127.7, 128.5, 132.1 (9C, Ph-CH), 135.6, 142.9, 143.0 (3C, Ph-C), 171.5 (1C, C@O). ½a23 589 ¼ 9:6 (c 0.24, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H25NO2Na 370.1778, found 370.1774. Purity (HPLC): 94.8% (tR = 22.01 min). 5.2.15. (3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10 -cyclohexan]-5one 12g Following general procedure B, cis-10 (45 mg, 0.15 mmol) was reacted with 1,5-diiodopentane (21 lL, 0.15 mmol). The crude product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.61 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield 25 mg (47%). C24H27NO2 (361.5 g/mol). FT-IR (ATR, film): m (cm1) = 2954 (aliphatic C–H), 1640 (C@O). 1H NMR (CDCl3): d (ppm) = 1.10 (s, 3H, CH3), 1.17–1.37 (m, 3H, CH2), 1.45–1.63 (m, 3H, CH2), 1.77–1.87 (m, 1H, CH2), 2.03–2.17 (m, 2H, CH2), 2.40–2.50 (m, 1H, CH2), 3.35 (d, J = 15.4 Hz, 1H, 11H), 3.74 (dd, J = 9.1/2.8 Hz, 1H, 2-H), 3.95 (d, J = 15.4 Hz, 1H, 11-H), 4.32 (dd, J = 9.1/7.9 Hz, 1H, 2-H), 4.96 (dd, J = 7.9/2.7 Hz, 1H, 3-H), 6.99–7.38 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 23.0, 23.3, 24.3, 26.0 (4C, CH3/CH2CH2CH2CH2CH2), 31.6, 36.4 (2C, CH2CH2CH2CH2CH2), 46.1 (1C, C-11), 51.8 (1C, C-6), 61.9 (1C, C-3), 70.1 (1C, C-2), 94.5 (1C, C-11a), 126.0, 127.0, 127.1, 128.3, 129.6, 132.8 (9C, Ph-CH), 135.7, 140.6, 142.9 (3C, Ph-C), 172.4 (1C, C@O). ½a23 589 ¼ 6:1 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C24H27NO2Na 384.1934, found 384.1928. Purity (HPLC): 93.7% (tR = 22.85 min). 5.2.16. (R)-2-[(1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 15a Following general procedure C, 11a (47 mg, 0.15 mmol) was reduced with AlH3 and the product was purified by FC (d = 2 cm, l = 20 cm, V = 15 mL, cyclohexane/EtOAc 90:10, Rf = 0.53 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 24 mg (55%). C20H25NO (295.4 g/mol). FT-IR (ATR, film): m (cm1) = 3404 (w, OH), 2926 (w, aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.94 (d, J = 4.1 Hz, 3H, CH3), 1.19 (d, J = 6.9 Hz, 3H, CH3), 2.28 (dd, J = 12.6/9.0 Hz, 1H, 2H), 2.43 (dd, J = 15.8/5.6 Hz, 1H, 5-H), 3.00–3.22 (m, 4H, 1-H/2-H/ 4-H/5-H), 3.54 (dd, J = 9.3/3.6 Hz, 1H, CH2OH), 3.77–3.93 (m, 2H, CH2OH/NCHPh), 6.93–7.30 (m, 9H, arom). A signal for the OH proton is not detected. 13C NMR (CDCl3): d (ppm) = 17.6 (1C, CH3), 19.5 (1C, CH3), 29.7 (1C, C-1), 40.7 (1C, C-5), 41.6 (1C, C-2), 51.5 (1C, C4), 60.6 (1C, CH2OH), 64.4 (1C, NCHPh), 125.9, 126.8, 127.7, 128.3, 128.4, 130.1 (9C, Ph-CH), 136.4, 137.9, 143.7 (3C, Ph-C). ½a23 589 ¼ þ24:4 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C20H25NOH 296.2009, found 296.2009. Purity (HPLC): 96.7% (tR = 16.80 min).

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5.2.17. (R)-2-[(1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H3-benzazepin-3-yl]-2-phenylethanol 15b Following general procedure C, 11b (35 mg; 0.11 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.54 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 27 mg (82%). C21H27NO (309.4 g/mol). FT-IR (ATR, film): m (cm1) = 3445 (OH), 2927 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.83–0.98 (m, 6H, CH2CH3/CH3), 1.52–1.68 (m, 2H, CH2CH3), 2.33–2.61 (m, 3H, 2-H/ 5-H/CH2OH), 2.82–2.98 (m, 1H, 1-H), 3.06–3.27 (m, 3H, 2-H/4-H/ 5-H), 3.62–3.66 (m, 1H, CH2OH), 3.79–3.90 (m, 2H, CH2OH/NCHPh), 6.89–7.31 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 12.3 (1C, CH2CH3), 12.6 (1C, CH3), 21.3 (1C, CH2CH3), 26.7 (1C, C-1), 41.5 (1C, C-5), 44.6 (1C, C-2), 49.7 (1C, C-4), 60.7 (1C, CH2OH), 68.8 (1C, NCHPh), 125.2, 125.8, 126.4, 127.6, 128.2, 128.5, 130.4 (9C, Ph-CH), 138.1, 142.4 (3C, Ph-C). ½a23 589 ¼ þ28:3 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H27NOH 310.2165, found 310.2167. Purity (HPLC): 93.1% (tR = 17.32 min). 5.2.18. (R)-2-[(1R,4R)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 15c Following general procedure C, 11c (30 mg; 0.09 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.58 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 22 mg (75%). C22H27NO (321.5 g/mol). FT-IR (ATR, film): m (cm1) = 3441 (OH), 2924 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.90 (d, J = 4.1 Hz, 3H, CH3), 1.24 (s, 1H, CH2OH), 2.32–2.56 (m, 4H, CH2–CH@CH2/2-H/5H), 3.00–3.14 (m, 1H, 1-H), 3.15–3.33 (m, 3H, 2-H/4-H/5-H), 3.56–3.68 (m, 1H, CH2OH), 3.87–4.00 (m, 2H, CH2OH/NCHPh), 4.96–5.19 (m, 2H, CH2–CH@CH2), 5.69–5.99 (m, 1H, CH2–CH@CH2), 6.89–7.34 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 17.5 (1C, CH3), 38.6 (1C, CH2–CH@CH2), 42.0 (1C, C-1), 46.8 (1C, C-5), 49.8 (1C, C-2), 51.8 (1C, C-4), 61.0 (1C, CH2OH), 64.7 (1C, NCHPh), 116.7 (1C, CH2–CH@CH2), 126.2, 126.8, 127.9, 128.5, 128.6, 130.6 (9C, Ph-CH), 136.8, 138.2, 142.3 (4C, Ph-C/CH2–CH@CH2). ½a23 589 ¼ þ38:8 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C22H27NOH 322.2165, found 322.2162. Purity (HPLC): 96.9% (tR = 17.59 min). 5.2.19. (R)-2-[(R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanol 15d Following general procedure C, 11d (22 mg; 0.07 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.64 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 15 mg (71%). C21H27NO (309.4 g/mol). FT-IR (ATR, film): m (cm-1) = 3441 (OH), 2962 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.98 (d, J = 4.1 Hz, 3H, CH3), 1.12 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.36 (d, J = 13.1 Hz, 1H, 5-H), 2.59–2.70 (m, 2H, 2-H/5-H), 3.19–3.31 (m, 2H, 2-H/4-H), 3.51–3.61 (m, 1H, CH2OH), 3.78–3.91 (m, 2H, CH2OH/NCHPh), 7.13 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 19.1 (1C, CH3), 25.8 (1C, CH3), 30.9 (1C, CH3), 41.6 (1C, C-1), 53.6 (1C,C-5), 58.0 (1C, C-2), 61.0 (1C, C-4), 64.6 (1C, CH2OH), 68.2 (1C, NCHPh), 125.9, 127.1, 127.2, 127.9, 128.5, 128.8, 131.7 (9C, Ph-CH), 135.2, 137.6, 146.8 (3C, Ph-C). [a]23589 = +2.2 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H27NOH 310.2165, found 310.2161. Purity (HPLC): 94.9% (tR = 15.15 min). 5.2.20. (R)-2-[(R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 15e Following general procedure C, 11e (25 mg; 0.07 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.60 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 20 mg (85%). C23H31NO (337.4 g/mol). FT-IR (ATR, film): m (cm1) = 3454 (OH), 2962

(aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.52 (t, J = 7.4 Hz, 3H, CH2CH3), 0.90 (t, J = 7.4 Hz, 3H, CH2CH3), 0.95 (d, J = 4.1 Hz, 3H, CH3), 1.40–1.50 (m, 3H, CH2CH3/CH2OH), 1.62–1.66 (m, 1H, CH2CH3), 1.98–2.02 (m, 1H, CH2CH3), 2.34–2.38 (m, 2H, 2-H/5-H), 2.86–2.90 (m, 1H, 4-H), 3.20–3.24 (m, 2H, 2-H/5-H), 3.55–3.58 (m, 1H, CH2OH), 3.75–3.79 (m, 1H, CH2OH), 3.86–3.90 (m, 1H, NCHPh), 6.88–7.34 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 8.8 (1C, CH3), 8.9 (2C, 2  CH2CH3), 28.9 (1C, CH2CH3), 29.9 (1C, CH2CH3), 41.9 (1C, C-1), 47.2 (1C, C-5), 52.6 (1C, C-2), 54.2 (1C, C4), 61.0 (1C, CH2OH), 64.7 (1C, NCHPh), 125.8, 126.4, 127.9, 128.1, 128.5, 128.8 (9C, Ph-CH), 131.9, 144.3 (3C, Ph-C). ½a23 589 ¼ þ18:6 (c 0.20, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H31NOH 338.2478, found 338.2474. Purity (HPLC): 95.8% (tR = 19.14 min). 5.2.21. (R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,10 -cyclopentan]-3-yl]-2-phenylethanol 15f Following general procedure C, 11f (40 mg; 0.12 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (75%). C23H29NO (335.5 g/mol). FT-IR (ATR, film): m (cm1) = 3423 (OH), 2952 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.66 (d, J = 6.3 Hz, 3H, CH3), 1.40–2.16 (m, 8H, CH2), 2.41–2.75 (m, 4H, 2-H/4-H/5-H/ CH2OH), 3.24–3.39 (m, 2H, 2-H/5-H), 3.59–3.62 (m, 1H, CH2OH), 3.68–3.80 (m, 2H, CH2OH/NCHPh), 6.84–7.26 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 13.9 (1C, CH3), 24.1, 24.6 (2C, CH2CH2CH2CH2), 36.4, 38.8 (2C, CH2CH2CH2CH2), 43.7 (1C, C-1), 52.8 (1C, C-5), 53.2 (1C, C-2), 55.2 (1C, C-4), 62.7 (1C, CH2OH), 70.3 (1C, NCHPh), 125.7, 126.2, 126.5, 127.8, 128.6, 129.0 (9C, Ph-CH), 131.5, 138.2, 147.4 (3C, Ph-C). ½a23 589 ¼ þ17:4 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C23H29NOH 336.2322, found 336.2324. Purity (HPLC): 93.7% (tR = 18.19 min). 5.2.22. (R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,10 -cyclohexan]-3-yl]-2-phenylethanol 15g Following general procedure C, 11g (53 mg; 0.15 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.58 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 30 mg (60%). C24H31NO (349.5 g/mol) FT-IR (ATR, film): m (cm1) = 3428 (OH), 2924 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.96 (d, J = 3.5 Hz, 3H, CH3), 1.10–1.32 (m, 4H, CH2), 1.39 (s, 1H, CH2OH), 1.51–1.85 (m, 5H, CH2), 1.89–2.08 (m,1H, CH2), 2.28–2.45 (m, 2H, 2-H/5-H), 3.04–3.20 (m, 2H, 2-H/4-H), 3.26 (dd, J = 14.8/6.4 Hz, 1H, 5-H), 3.51 (dd, J = 10.4/4.6 Hz, 1H, CH2OH), 3.70–3.76 (m, 1H, NCHPh), 3.89 (dd, J = 10.6/4.5 Hz, 1H, CH2OH), 6.86–7.40 (m, 9H, arom). 13 C NMR (CDCl3): d (ppm) = 18.4 (1C, CH3), 22.6, 22.9, 23.4, 24.5, 25.8 (5C, CH2), 41.1 (1C, C-1), 43.5 (1C, C-5), 50.9 (1C, C-2), 53.7 (1C, C-4), 60.7 (1C, CH2OH), 62.3 (1C, NCHPh), 125.6, 125.7, 126.0, 127.8, 128.4, 128.6 (9C, Ph-CH), 131.4, 137.4, 147.6 (3C, Ph-C). ½a23 589 ¼ þ2:2 (c 0.30, CH2Cl2). Exact mass (ESI): m/z = calcd for C24H31NOH 350.2478, found 350.2498. Purity (HPLC): 93.2% (tR = 18.56 min). 5.2.23. (R)-2-[(1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 16a Following general procedure C, 12a (37 mg; 0.12 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.52 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 21 mg (60%). C20H25NO (295.4 g/mol). FT-IR (ATR, film): m (cm1) = 3427 (OH), 2926 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.86 (d, J = 4.1 Hz, 3H, CH3), 1.39 (d, J = 7.0 Hz, 3H, CH3), 2.49 (s, 1H, CH2OH), 2.66 (dd, J = 14.4/7.4 Hz, 1H, 2-H), 2.88 (dd, J = 12.3/5.2 Hz, 1H, 5-H), 2.89– 3.09 (m, 1H, 1-H), 3.12–3.44 (m, 3H, 2-H/4-H/5-H), 3.65–3.77 (m,

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422

3H, CH2OH/NCHPh), 7.10–7.34 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 17.4 (2C, CH3), 29.9 (1C, C-1), 43.6 (1C, C-5), 47.3 (1C, C2), 57.0 (1C, C-4), 61.3 (1C, CH2OH), 71.0 (1C, NCHPh), 126.6, 126.9, 127.8, 128.5, 128.8 (9C, Ph-CH), 138.0, 139.7 (3C, Ph-C). ½a23 589 ¼ 12:3 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C20H25NOH 296.2009, found 296.2005. Purity (HPLC): 97.9% (tR = 16.23 min). 5.2.24. (R)-2-[(1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 16b Following general procedure C, 12b (57 mg; 0.18 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 44 mg (80%). C21H27NO (309.4 g/mol). FT-IR (ATR, film): m (cm1) = 3447 (OH), 2960 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.78–0.92 (m, 6H, CH3/ CH2CH3). 1.67–1.80 (m, 1H, CH2CH3), 1.89–2.01 (m, 2H, CH2CH3/ CH2OH), 2.39–2.79 (m, 3H, 1-H/2-H/5-H), 2.80–2.90 (m, 1H, 4-H), 3.11–3.52 (m, 3H, CH2OH/2-H/5-H), 3.55–3.86 (m, 2H, CH2OH/ NCHPh), 6.96–7.40 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 13.1 (2C, CH3/CH2CH3), 24.4 (1C, CH2CH3), 43.9 (1C, C-1), 45.9 (2C, C-2/C-5), 57.0 (1C, C-4), 61.6 (1C, CH2OH), 71.3 (1C, NCHPh), 126.4, 127.8, 128.5, 128.9 (9C, Ph-CH), 139.7 (3C, Ph-C). ½a23 589 ¼ 18:7 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H27NOH 310.2165, found 310.2168. Purity (HPLC): 94.7% (tR = 16.93 min). 5.2.25. (R)-2-[(1S,4S)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 16c Following general procedure C, 12c (31 mg; 0.09 mmol) was reduced with AlH3, and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.53 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 20 mg (72%). C22H27NO (321.5 g/mol). FT-IR (ATR, film): m (cm1) = 3441 (OH), 2925 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.73 (d, J = 4.1 Hz, 3H, CH3), 2.33–2.48 (m, 2H, CH2–CH@CH2), 2.51–2.71 (m, 3H, 2-H/5H/CH2OH), 2.75–2.93 (m, 2H, 2-H/5-H), 3.02–3.46 (m, 3H, 1-H/4H/CH2OH), 3.48–3.77 (m, 2H, NCHPh/CH2OH), 4.90 (d, J = 10.1 Hz, 1H, CH2–CH@CH2), 4.99 (d, J = 17.3 Hz, 1H, CH2–CH@CH2), 5.68 (m, 1H, CH2–CH@CH2), 6.79–7.50 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 29.9 (1C, CH3), 36.0 (1C, CH2–CH@CH2), 43.7 (1C, C-5), 45.9 (1C, C-1/C-2), 56.8 (1C, C-4), 61.6 (1C, CH2OH), 71.2 (1C, NCHPh), 116.2 (1C, CH2–CH@CH2), 126.6, 127.8, 128.5, 128.6, 128.9 (9C, Ph-CH), 137.3, 139.7 (4C, Ph-C/CH2–CH@CH2). ½a23 589 ¼ 3:6 (c 0.15, CH2Cl2). Exact mass (ESI): m/z = calcd for C22H27NOH 322.2165, found 322.2159. Purity (HPLC): 93.9% (tR = 17.28 min). 5.2.26. (R)-2-[(S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanol 16d Following general procedure C, 12d (48 mg; 0.15 mmol) was reduced with AlH3, which was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.60 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 31 mg (69%). C21H27NO (309.4 g/ mol). FT-IR (ATR, film): m (cm1) = 3441 (OH), 2960 (aliphatic C– H). 1H NMR (CDCl3): d (ppm) = 0.71 (d, J = 6.4 Hz, 3H, CH3), 1.22 (s, 3H, CH3), 1.28 (s, 3H, CH3), 2.59–2.98 (m, 4H, 2-H/4-H/5-H/ CH2OH), 3.28–3.45 (m, 2H, 2-H/5-H), 3.53–3.64 (m, 1H, CH2OH), 3.77–3.97 (m, 2H, CH2OH/NCHPh), 6.85–7.32 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 15.1 (1C, CH3), 30.4, 30.9 (2C, 2  CH3), 41.2 (1C, C-1), 55.9 (1C, C-5), 58.0 (1C, C-2), 61.0 (1C, C-4), 62.4 (1C, CH2OH), 70.1 (1C, NCHPh), 126.3, 126.9, 127.8, 128.5, 128.9 (9C, Ph-CH), 131.7, 137.4, 147.1 (3C, Ph-C). ½a23 589 ¼ 10:2 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H27NOH 310.2165, found 310.2161. Purity (HPLC): 96.6% (tR = 16.35 min).

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5.2.27. (R)-2-[(S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepin-3-yl]-2-phenylethanol 16e Following general procedure C, 12e (42 mg; 0.12 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (73%). C23H31NO (337.4 g/mol). FT-IR (ATR, film): m (cm1) = 3441 (OH), 2963 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.52 (t, J = 7.4 Hz, 3H, CH2CH3), 0.71 (t, J = 7.4 Hz, 3H, CH2CH3), 0.77 (d, J = 6.1 Hz, 3H, CH3), 1.38 (m, 1H, CH2CH3), 1.50–1.61 (m, 1H, CH2CH3), 1.70– 1.84 (m, 1H, CH2CH3), 1.92–2.17 (m, 1H, CH2CH3), 1.95–2.05 (m, 1H, CH2OH), 2.46–2.51 (m, 1H, 5-H), 2.60 (d, J = 14.2 Hz, 1H, 2H), 3.00–3.35 (m, 3H, 2-H/4-H/5-H), 3.55–3.65 (m, 1H, CH2OH), 3.69–3.86 (m, 2H, CH2OH/NCHPh), 6.86–7.30 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 8.6 (1C, CH2CH3), 8.8 (2C, CH2CH3/CH3), 29.9 (1C, CH2CH3), 30.5 (1C, CH2CH3), 47.0 (1C, C-1), 51.9 (1C, C5), 55.4 (1C, C-2), 62.4 (2C, C-4/CH2OH), 70.4 (1C, NCHPh), 126.0, 126.3, 127.8, 128.2, 128.5, 128.9 (9C, Ph-CH), 132.05, 138.0, 144.3 (3C, Ph-C). ½a23 589 ¼ 14:6 (c 0.24, CH2Cl2). Exact mass (ESI): m/ z = calcd for C23H31NOH 338.2478, found 338.2466. Purity (HPLC): 97.7% (tR = 18.21 min). 5.2.28. (R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,10 -cyclopentan]-3-yl]-2-phenylethanol 16f Following general procedure C, 12f (24 mg; 0.07 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 16 mg (70%). C23H29NO (335.5 g/mol). FT-IR (ATR, film): m (cm1) = 3423 (OH), 2925 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.88 (d, J = 6.1 Hz, 3H, CH3), 1.18 (s, 1H, CH2OH), 1.55–1.95 (m, 7H, CH2), 2.04–2.16 (m, 1H, CH2), 2.41–2.55 (m, 2H, 2-H/5-H), 2.76 (d, J = 14.3 Hz, 1H, 2H), 3.08–3.29 (m, 2H, 4-H/5-H), 3.52–3.64 (m, 1H, CH2OH), 3.75– 3.94 (m, 2H, CH2OH/NCHPh), 6.84–7.33 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 17.8 (1C, CH3), 24.4, 24.5 (2C, CH2CH2CH2CH2), 38.9, 39.8 (2C, CH2CH2CH2CH2), 42.2 (1C, C-1), 53.2 (1C, C-5), 53.6 (1C, C-2), 55.6 (1C, C-4), 61.0 (1C, CH2OH), 64.9 (1C, NCHPh), 125.7, 126.2, 126.6, 127.7, 128.4 (9C, Ph-CH), 131.3, 136.6, 146.9 (3C, Ph-C). ½a23 589 ¼ 24:7 (c 0.20, CH2Cl2). Exact mass (ESI): m/ z = calcd for C23H29NOH 336.2322, found 336.2327. Purity (HPLC): 90.4% (tR = 18.23 min). 5.2.29. (R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,10 -cyclohexan]-3-yl]-2-phenylethanol 16g Following general procedure C, 12g (44 mg; 0.12 mmol) was reduced with AlH3 and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.57 (cyclohexane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (69%). C24H31NO (349.5 g/mol). FT-IR (ATR, film): m (cm1) = 3441 (OH), 2923 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.85 (d, J = 5.9 Hz, 3H, CH3), 1.09–1.90 (m, 11H, CH2/CH2OH), 2.31–3.24 (m, 5H, 2-H/4H/5-H), 3.48–3.82 (m, 3H, CH2OH/NCHPh), 6.88–7.39 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 16.3 (1C, CH3), 22.7, 22.9, 26.2 (3C, CH2CH2CH2CH2CH2), 27.2, 30.4 (2C, CH2(CH2)3CH2), 35.8 (2C, C-1/C-5), 43.8 (1C, C-2), 53.7 (1C, C-4), 62.9 (1C, CH2OH), 69.1 (1C, NCHPh), 126.3, 127.1, 127.7, 128.5, 128.9, 131.1 (9C, Ph-CH), 138.0, 140.4, 147.7 (3C, Ph-C). ½a23 589 ¼ 10:6 (c 0.25, CH2Cl2). Exact mass (ESI): m/z = calcd for C24H31NOH 350.2478, found 350.2482. Purity (HPLC): 90.5% (tR = 19.02 min). 5.2.30. (1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine 17a According to general procedure D, 15a (40 mg, 0.14 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,Ndimethylethanamine 50:49.5:0.5, Rf = 0.19 (EtOAc/petroleum

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ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 16 mg (70%). C12H17N (175.3 g/mol). FT-IR (ATR, film): m (cm-1) = 3264 (w, N–H), 2930 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 1.18 (d, J = 6.3 Hz, 3H, CH3), 1.33 (d, J = 7.2 Hz, 3H, CH3), 1.98 (s, 1H, NH), 2.58 (dd, J = 13.0/9.0 Hz, 1H, 2-H), 2.73 (d, J = 14.1 Hz, 1H, 5-H), 2.76–2.84 (m, 1H, 4-H), 2.93 (dd, J = 14.0/9.1 Hz, 1H, 5-H), 3.06 (dd, J = 13.0/1.8 Hz, 1H, 2-H), 3.08–3.19 (m, 1H, 1-H), 7.05–7.15 (m, 2H, arom), 7.19 (d, J = 3.7 Hz, 2H, arom). 13C NMR (CDCl3): d (ppm) = 18.4 (1C, CH3), 24.0 (1C, CH3), 29.9 (1C, C-1), 40.0 (1C, C-5), 46.4 (1C, C2), 52.8 (1C, C-4), 124.8, 126.1, 126.5, 129.7 (4C, Ph-CH), 140.7, 145.6 (2C, Ph-C). [a]23589 = +8.6 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C12H17NH 176.1434, found 176.1430. Purity (HPLC): 99.2% (tR = 11.96 min). 5.2.31. (1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine ent-17a According to general procedure D, 16a (18 mg, 0.06 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.19 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 6 mg (60%). ½a23 589 ¼ 8:8 (c 0.11, CH2Cl2). Exact mass (ESI): m/z = calcd for C12H17NH 176.1434, found 176.1433. Purity (HPLC): 95.6% (tR = 12.15 min). 5.2.32. (1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepine 17b According to general procedure D, 15b (18 mg, 0.06 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.21 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 9 mg (82%). C13H19N (189.3 g/mol). FT-IR (ATR, film): m (cm1) = 3302 (N–H), 2923 (w, aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.97 (t, J = 7.3 Hz, 3H, CH2CH3), 1.08 (d, J = 6.1 Hz, 3H, CH3), 1.50–1.61 (m, 1H, CH2CH3), 1.75–1.98 (m, 2H, CH2CH3/NH), 2.50 (dd, J = 12.8/ 8.5 Hz, 1H, 5-H), 2.77–2.96 (m, 4H, 1-H/2-H/4-H/5-H), 3.12 (dd, J = 13.2/2.5 Hz, 1H, 2-H), 7.00–7.24 (m, 4H, arom). 13C NMR (CDCl3): d (ppm) = 12.8 (1C, CH2CH3), 22.9 (1C, CH3), 24.9 (1C, CH2CH3), 29.9 (1C, C-1), 45.1 (1C, C-5), 47.9 (1C, C-2), 52.4 (1C, C4), 126.0, 126.5, 130.0 (4C, Ph-CH), 144.7 (2C, Ph-C). ½a23 589 ¼ þ8:8 (c 0.17, CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH 190.1601, found 190.1589. Purity (HPLC): 95.7% (tR = 13.45 min). 5.2.33. (1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepine ent-17b According to general procedure D, 16b (42 mg, 0.14 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.21 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 20 mg (77%). ½a23 589 ¼ 8:9 (c 0.15, CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH 190.1601, found 190.1590. Purity (HPLC): 97.7% (tR = 13.11 min). 5.2.34. (1R,4R)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3benzazepine 17c According to the general procedure D, 15c (26 mg, 0.08 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.18 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 15 mg (88%). C14H21N (203.3 g/mol). FT-IR (ATR, film): m (cm1) = 3289 (N–H), 2923 (w, aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.90 (t, J = 7.3 Hz, 3H, CH2CH2CH3), 1.07 (d, J = 6.3 Hz, 3H, CH3), 1.28–1.57

(m, 3H, CH2CH2CH3/NH), 1.68–1.87 (m, 2H, CH2CH2CH3), 2.50 (dd, J = 13.2/8.3 Hz, 1H, 5-H), 2.70–2.91 (m, 4H, 1-H/2-H/4-H/5H), 3.10 (dd, J = 13.2/2.8 Hz, 1H, 2-H), 6.95–7.14 (m, 4H, arom). 13 C NMR (CDCl3): d (ppm) = 14.7 (1C, CH2CH2CH3), 21.2 (1C, CH3), 29.9 (1C, CH2CH2CH3), 34.5 (1C, CH2CH2CH3), 45.1 (2C, C-2/C-5), 47.2 (1C, C-1), 52.3 (1C, C-4), 126.0, 126.4, 130.0 (4C, Ph-CH) 140.0, 144.8 (2C, Ph-C). ½a23 589 ¼ þ16:8 (c 0.19, CH2Cl2). Exact mass (ESI): m/z = calcd for C14H21NH 204.1747, found 204.1739. Purity (HPLC): 96.8% (tR = 15.23 min). 5.2.35. (1S,4S)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3benzazepine ent-17c According to general procedure D, 16c (36 mg, 0.17 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.18 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 10 mg (90%). ½a23 589 ¼ 16:4 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C14H21NH 204.1747, found 204.1763. Purity (HPLC): 97.3% (tR = 14.95 min). 5.2.36. (R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine 17d According to general procedure D, 15d (22 mg, 0.07 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 10 mg (77%). C13H19N (189.3 g/mol). FT-IR (ATR, film): m (cm1) = 3340 (N–H), 2925 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 1.18 (d, J = 6.4 Hz, 3H, CH3), 1.35 (s, 6H, CH3), 1.80 (s, 1H, NH), 2.79 (d, J = 14.8 Hz, 1H, 5-H), 2.87 (d, J = 13.8 Hz, 1H, 2-H), 2.91–2.99 (m, 2H, 2-H/4-H), 3.10 (dd, J = 14.8/9.5 Hz, 1H, 5-H), 7.04 (d, J = 7.4 Hz, 1H, arom), 7.06–7.12 (m, 1H, arom), 7.17 (t, J = 7.5 Hz, 1H, arom), 7.35 (d, J = 7.8 Hz, 1H, arom). 13C NMR (CDCl3): d (ppm) = 23.9 (1C, CH3), 26.5 (1C, CH3), 29.7 (1C, CH3), 41.4 (1C, C1), 47.4 (1C, C-5), 53.4 (1C, C-4), 59.5 (1C, C-2), 126.2, 126.5, 131.8 (4C, Ph-CH), 139.5, 148.1 (2C, Ph-C). ½a23 589 ¼ þ8:9 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH 190.1590, found 190.1594. Purity (HPLC): 98.0% (tR = 12.56 min). 5.2.37. (S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine ent-17d According to general procedure D, 16d (48 mg, 0.16 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 19 mg (66%). ½a23 589 ¼ 8:3 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH 190.1590, found 190.1582. Purity (HPLC): 98.2% (tR = 13.67 min). 5.2.38. (R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 17e According to general procedure D, 15e (12 mg, 0.04 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 6 mg (75%). C15H23N (217.4). FT-IR (ATR, film): m (cm1) = 3315 (N–H), 2925 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.73 (t, J = 7.5 Hz, 3H, CH2CH3), 0.86 (t, J = 7.4 Hz, 3H, CH2CH3), 1.11 (d, J = 6.4 Hz, 3H, CH3), 1.50–1.63 (m, 2H, CH2CH3/NH), 1.64–1.79 (m, 2H, CH2CH3), 1.84–1.95 (m, 1H, CH2CH3), 2.82–2.95 (m, 3H, 2-H/5-H), 3.00– 3.10 (m, 2H, 4-H/5-H), 7.04 (d, J = 7.2 Hz, 1H, arom), 7.10 (td, J = 7.3/1.4 Hz, 1H, arom), 7.15–7.27 (m, 2H, arom). 13C NMR

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422

(CDCl3): d (ppm) = 8.8 (1C, CH2CH3), 8.9 (1C, CH2CH3), 22.8 (1C, CH3), 31.2 (1C, CH2CH3), 32.2 (1C, CH2CH3), 44.9 (1C, C-1), 47.8 (1C, C-5), 52.8 (1C, C-4), 54.5 (1C, C-2), 126.0, 126.2, 129.0, 132.2 (4C, Ph-CH), 139.1, 143.7 (2C, Ph-C). ½a23 589 ¼ þ4:1 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C15H23NH 218.1903, found 218.1894. Purity (HPLC): 97.4% (tR = 15.56 min). 5.2.39. (S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3benzazepine ent-17e According to general procedure D, 16e (21 mg, 0.06 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.31 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 11 mg (85%). ½a23 589 ¼ 4:8 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C15H23NH 218.1903, found 218.1944. Purity (HPLC): 99.6% (tR = 15.50 min). 5.2.40. (R)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine1,10 -cyclopentane] 17f According to general procedure D, 15f (14 mg, 0.04 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.33 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 7 mg (78%). C15H21N (215.3 g/mol). FT-IR (ATR, film): m (cm1) = 3378 (N–H), 2934 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 1.17 (d, J = 6.4 Hz, 3H, CH3), 1.58–1.94 (m, 6H, CH2), 2.13–2.23 (m, 1H, CH2), 2.27–2.38 (m, 1H, CH2), 2.70 (d, J = 14.6 Hz, 1H, 5-H), 2.79– 2.93 (m, 3H, 2-H/4-H), 3.11 (dd, J = 14.6/9.6 Hz, 1H, 5-H), 7.01– 7.32 (m, 4H, arom). A signal for the NH proton is not detected. 13 C NMR (CDCl3): d (ppm) = 23.7 (1C, CH3), 23.9, 24.3 (2C, CH2CH2CH2CH2), 34.5, 37.2 (2C, CH2CH2CH2CH2), 47.3 (1C, C-5), 53.1 (1C, C-4), 53.4 (1C, C-2), 56.2 (1C, C-1), 125.6, 126.1, 126.2, 131.4 (4C, Ph-CH), 140.5, 148.3 (2C, Ph-C). ½a23 589 ¼ þ24:0 (c 0.15, CH2Cl2). Exact mass (ESI): m/z = calcd for C15H21NH 216.1747, found 216.1749. Purity (HPLC): 98.7% (tR = 15.06 min). 5.2.41. (S)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine1,10 -cyclopentane] ent-17f According to general procedure D, 16f (24 mg, 0.07 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.33 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 14 mg (89%). ½a23 589 ¼ 23:0 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C15H21NH 216.1747, found 216.1749. Purity (HPLC): 96.1% (tR = 15.15 min).

C-1), 53.6 (1C, C-2), 126.0, 126.2, 126.5, 132.1 (4C, Ph-CH), 139.6, 149.3 (2C, Ph-C). ½a23 589 ¼ þ12:0 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for C16H23NH 230.1903, found 230.1893. Purity (HPLC): 98.4% (tR = 15.92 min). 5.2.43. (S)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine1,10 -cyclohexane] ent-17g According to the general procedure D, 16g (22 mg, 0.06 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.36 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous oil, yield 11 mg (80%). ½a23 589 ¼ 14:7 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for C16H23NH 230.1903, found 230.1893. Purity (HPLC): 95.0% (tR = 16.08 min). 5.3. Receptor binding studies The NMDA receptor affinity was determined according to the literature.15 The r1 and r2 receptor affinities were recorded according to the literature.27–30 Acknowledgments We wish to thank the NRW Graduate School of Chemistry (2008–11) for a stipend, which was funded by the Government of the State Nordrhein-Westfalen and the Westfälische Wilhelms-Universität Münster.

References 1. 2. 3. 4. 5. 6.

7. 8. 9.

10.

11.

5.2.42. (R)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine1,10 -cyclohexane] 17g According to general procedure D, 15g (20 mg, 0.06 mmol) was hydrogenated and the product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethanamine 50:49.5:0.5, Rf = 0.36 (EtOAc/petroleum ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless oil, yield 8 mg (69%). C16H23N (229.4 g/mol). FT-IR (ATR, film): m (cm1) = 3302 (N–H), 2921 (aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 1.17 (d, J = 6.4 Hz, 3H, CH3), 1.46–1.79 (m, 8H, CH2), 1.90–1.99 (m, 1H, CH2), 2.15–2.24 (m, 1H, CH2), 2.71–2.83 (m, 2H, 2-H/5-H), 2.89–3.00 (m, 1H, 4H), 3.14 (dd, J = 14.8/9.3 Hz, 1H, 5-H), 3.32 (d, J = 14.1, 1H, 2-H), 7.03 (d, J = 7.4 Hz, 1H, arom), 7.08 (td, J = 7.3/1.3 Hz, 1H, arom), 7.18 (td, J = 7.6/1.7 Hz, 1H, arom), 7.39 (d, J = 7.9 Hz, 1H, arom). A signal for the NH proton is not detected. 13C NMR (CDCl3): d (ppm) = 22.6 (1C, CH3), 23.0, 26.4 (3C, CH2CH2CH2CH2CH2), 33.7, 35.6 (2C, CH2(CH2)3CH2), 43.4 (1C, C-5), 47.1 (1C, C-4), 52.8 (1C,

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