Desymmetrization of cyclohexa-2,5-dienes through a diastereoselective protonation-hydroamination cascade

Article abstract of DOI:10.1021/ol0618353

(Chemical Equation Presented) Intramolecular hydroamination of cyclohexa-2,5-dienes led with high selectivity to the corresponding bicyclic allylic amines. This study demonstrates that the reaction does not proceed through a direct hydroamination of one of the diastereotopic olefins but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene, and is concluded by a highly regioselective protonation of the final allylic anion.

Full text of DOI:10.1021/ol0618353

S1
Desymmetrization of Cyclohexa-2,5-dienes through a
Diastereoselective Protonation–Hydroamination Cascade
Raphaël Lebeuf,† Frédéric Robert,† Kurt Schenk,‡ Yannick Landais†*
†
University Bordeaux-I, Laboratoire de Chimie Organique et Organométallique
351, Cours de la Libération, 33405 Talence cedex, France.
University of Lausanne, Institut de cristallographie, BPS-Dorigny
‡
CH-1015 Lausanne, Switzerland.
Supporting information
Table of contents:
Pages
● General Procedures
● Synthesis
S2
Precursor of 1b
S3
1b
S3
2a
S4
4
S4
5
S5
6
S5
7
S6
8
S6
9
S7
Precursor of 11
S8
11
S8
13
S9
14
S9
15
S10
S10
S11
S11
S12
S12
S13
S13
S14
S14
S15
16
17
18
19
20a
20b
21
22
Precursor of 23
23
● Copy of 1H and 13C spectra
S16-90

S2
General:
1H NMR and 13C NMR were recorded on a Brüker Avance 300 (1H: 300 MHz, 13C: 75.5
MHz), Brüker AC-250 FT (1H: 250 MHz, 13C: 62.9 MHz), using solvent peak as internal
reference. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and hertz
respectively.
InfraRed (IR) spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR
spectrophotometer. Melting points were uncorrected and determined by using a Büchi-Totolli
apparatus.
Rotational optical activities were determined using a Perkin-Elmer polarimeter, model 341,
using a sodium lamp (589 nm) in a chloroform solution (iso reagent, stabilized with 0.6% of
EtOH).
Merck silica gel (0.043-0.063 mm) was used for flash chromatography. In some cases, silica
gel was preliminary deactivated by mixing with 5% (v/v) of triethylamine. CH2Cl2 was
distilled under CaH2. THF, toluene and Et2O were distilled from sodium and benzophenone.
Acetone was distilled over calcium sulfate. Ethanol was dried over magnesium turnings.
All reactions were carried out under nitrogen. All reagents and starting materials, unless noted,
were directly used as obtained commercially.
3-Hydroxy-5-methoxybiphenyl1 and 2-(1-phenyl-2,5-cyclohexadien-1-yl)acetate2 were
synthesized according to previously reported procedures. The chiral amines, (R)-2-methoxy-1-
phenyl-ethylamine, (-)-R-2-methoxymethoxy-1-phenyl-ethylamine, 2-(R)-triethylsilanyloxy-1-
phenyl-ethylamine, (1S,2R)-2-methoxy-indan-1-ylamine, were prepared by adaptation of a
published procedure3.
For Birch reductions, lithium wire (3.2mm diameter, 0.01% sodium content) was cut into small
pieces and hammered before use. NH3 gas was dried by passing through potassium hydroxide
pellets.
1
2
Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett., 2005, 7, 4557-4560.
Müller, P. M.; Pfister, R. Helv. Chim. Acta 1973, 66, 771-779.
3 Bream, R. N.; Ley, S. V.; McDermott, B.; Procopiou, P. A. J. Chem. Soc., Perkin Trans. 1 2002, 2237-2242.

S3
Synthesis:
[1-(3-Hydroxy-5-methoxy-phenyl)-cyclohexa-2,5-dienyl]-acetic acid methyl ester (precursor of 1b):
In a dry three-necked flask equipped with a dry-ice condenser was introduced 3-
HO
CO2Me
hydroxy-5-methoxybiphenyl1 (2.25 g, 11.25 mmol, 1 eq.) in THF (50 mL). A
solution of n-BuLi (2.5 M in hexane, 5.0 mL, 12.5 mmol, 1.1 eq.) was added
dropwise at -78°C. After 15 minutes, ammonia (approx. 100 mL) was condensed
with the dry-ice condenser filled with an acetone/liquid nitrogen mixture placed at -
MeO
78°C. Lithium wire (0.173 g, 24.71 mmol, 2.2 eq.) was added. The cold bath was replaced by a room-
tempered one to reflux ammonia for one hour. The red-brown mixture was then cooled to -78°C and
methyl chloroacetate (3.1 mL, 34 mmol, 3 eq.) in THF (10 mL) was added in one portion. The mixture
turned immediately brown. After 10 minutes, ammonia was evaporated and a half-saturated ammonium
chloride solution was added. Extraction with ether, washing with brine, drying with sodium sulfate and
evaporation of the solvents gave a brown paste, which was purified by flash chromatography (petroleum
ether/EtOAc, 75:25) to give the product (1.51 g, 5.52 mmol, 49%) as a yellow oil.
1H NMR (CDCl3, 300 MHz): δ = 6.45-6.44 (m, 1H, aromatic H), 6.42-6.41 (m, 1H, aromatic H), 6.27-
6.25 (m, 1H, aromatic H), 5.87-5.76 (m, 4H, olefinic H), 3.73(s, 3H, ArOCH3), 3.59 (s, 3H, CO2CH3),
2.81 (s, 2H, CH2CO2Me), 2.63 (broad s, 2H, bis-allylic CH2).
13C NMR (CDCl3, 75.5 MHz): δ = 172.0 (C=O), 160.9 (aromatic C), 157.1 (aromatic C), 149.4
(aromatic C), 131.1 (2 olefinic CH), 124.2 (olefinic CH), 106.2 (aromatic CH), 105.1 (aromatic CH),
99.2 (aromatic CH), 55.4 (ArOCH3), 51.7 (CO2CH3), 45.6 (CH2CO2Me), 42.7 (aliphatic C), 25.9 (bis-
allylic CH2).
IR (film, NaCl): νmax = 3404, 2952, 1715, 158, 1434, 1195, 1159, 1059, 967, 841, 715 cm-1.
HRMS (EI): [M]+˙ C16H18O4: calcd. 274.1205; found 274.1212 (2 ppm).
[1-(3,5-Dimethoxy-phenyl)-cyclohexa-2,5-dienyl]-acetic acid methyl ester (1b):
In a dry two-necked flask equipped with a condenser, [1-(3-hydroxy-5-methoxy-
MeO
CO2Me
phenyl)-cyclohexa-2,5-dienyl]-acetic acid methyl ester (1.40 g, 5.11 mmol) was
dissolved in acetone (50 mL). Potassium carbonate (4.23 g, 30.66 mmol, 6 eq.) and
dimethylsulfate (1.94 mL, 20.44 mmol, 4 eq.) were added and the mixture was
warmed to 60°C for 16 hours. Acetone was evaporated and the residue was diluted
MeO
in water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate
and solvent was evaporated. After purification by flash chromatography (petroleum ether/EtOAc 93/7)
the product 1b (1.18 g, 4.09 mmol, 80%) was obtained as a pale yellow oil.
1H NMR (CDCl3, 300 MHz): δ = 6.49 (d, J = 2.2 Hz, 2H, 2 aromatic H), 6.31 (t, J = 2.2 Hz, 1H,
aromatic H), 5.91-5.79 (m, 4H, olefinic H), 3.77 (s, 6H, 2 OCH3), 3.59 (s, 3H, CO2CH3), 2.84 (s, 2H,
CH2CO2Me), 2.68-2.65 (m, 2H, bis-allylic CH2).
13C NMR (CDCl3, 75.5 MHz): δ = 171.4 (C=O), 160.9 (2 aromatic C), 149.2 (aromatic C), 131.3 (2
olefinic CH), 124.1 (2 olefinic CH), 104.9 (2 aromatic CH), 97.8 (aromatic CH), 55.3 (2 OCH3), 51.4
(CO2CH3), 45.5 (CH2CO2Me), 42.8 (aliphatic C), 25.9 (bis-allylic CH2).
IR (film, NaCl): νmax = 2951, 2837, 1738, 1595, 1456, 1425, 1311, 1205, 1157, 1065, 835 cm-1.
MS (EI, 70 eV) m/z (%): 288 [M]+ (5), 215 [M-CH2OMe]+ (100).
HRMS (EI): [M]+ C17H20O4: calcd. 288.1362; found 288.1360 (0 ppm).

S4
(1-Phenyl-cyclohexa-2,5-dienyl)-acetaldehyde (2a):
In a dry three-necked flask equipped with a thermometer was introduced 2-(1-phenyl-
2,5-cyclohexadien-1-yl)acetate2 (3.013 g, 13.21 mmol) in toluene (40 mL). The solution
was cooled to –78°C and a solution of DIBAL-H (1 M in hexane, 13.9 mL, 1.05 eq.)
was added dropwise over 20 minutes in such a manner that the temperature was
O
H
maintained between –80°C to –75°C. After 30 minutes, the mixture was allowed to warm slightly to –
20°C in 3 hours. Methanol (1 mL) was added followed by a concentrated solution of potassium tartrate
(20 mL). After stirring 1 hour at room temperature, the organic layer was separated. The aqueous layer
was extracted twice with ether and the organic phases were combined, washed with brine, and dried over
sodium sulfate. Evaporation of the solvent, and purification by flash chromatography (petroleum
ether/EtOAc 95:5) gave 2a (2.055 g, 10.4 mmol, 78%) as a colorless liquid.
1H NMR (CDCl3, 300 MHz): δ = 9.73 (t, J = 3.0 Hz, 1H, CHO), 7.38-7.35 (m, 4H, aromatic H), 7.27-
7.22 (m, 1H, aromatic H), 5.99-5.93 (m, 2H, 2 olefinic CH), 5.82-5.76 (m, 2H, 2 olefinic CH), 2.83 (d, J
= 3.0 Hz, 2H, CH2CHO), 2.76-2.72 (m, 2H, CHaHb).
13C NMR (CDCl3, 75.5 MHz): δ = 203.1 (CHO), 146.2 (aromatic C), 131.2 (2 olefinic CH), 128.6
(aromatic CH), 126.5 (aromatic CH), 126.2 (2 aromatic CH), 124.5 (2 olefinic CH), 52.2 (CH2CHO),
25.9 (CH2).
IR (film, NaCl): νmax = 3025, 2816, 1715, 1492, 1420, 1044, 1032, 946, 746, 697 cm-1.
MS (SIMS) m/z (%): 221 [M+Na]+ (03), 155 [M-CH2CHO]+ (100).
HRMS (SIMS): [M+Na]+ C14H14ONa: calcd. 221.0942; found 221.0941 (0.7 ppm).
[2-(1-Phenyl-cyclohexa-2,5-dienyl)-ethyl]-(1-phenyl-ethyl)-amine (4):
To a solution of 2a (0.237 g, 1.20 mmol) in CH2Cl2 (12 mL) and sodium sulfate (1.70
H
g, 12.0 mmol, 10 eq.) was added (L)-(-)-α-phenylethylamine (0.160 g, 1.32 mmol, 1.1
eq.). After stirring 4 hours at room temperature, the solution was filtered and salt
washed with CH2Cl2. Evaporation of the solvent gave an oily product. This oil was
diluted in methanol (12 mL) and NaBH4 was added in one portion at 0°C. After stirring
2h at room temperature, water (0.5 mL) was added at 0°C and methanol was
HN
Ph
evaporated. The residue was partitioned between a 10% NaOH solution and ether. The organic layer was
separated and the aqueous layer extracted twice with ether. The organic layers were combined, dried over
sodium sulfate, filtered and evaporated. After purification by flash chromatography (deactivated silica
gel, petroleum ether/EtOAc 85:15) the product 4 (0.307 g, 1.01 mmol, 85%) was obtained as a colorless
oil.
1H NMR (CDCl3, 300 MHz): δ = 7.36-7.15 (m, 10H, aromatic H), 5.83-5.77 (m, 2H, olefinic H), 5.61-
5.57 (m, 2H, olefinic H), 5.76 (q, J = 6.4 Hz, 1H, CH), 2.72-2.48 (m, 4H, bis-allylic CH2 and CH2N),
2.12-1.95 (m, 2H, CH2CH2N), 1.35 (d, J = 6.4 Hz, CH3), 1.36 (broad s, 1H, NH).
13C NMR (CDCl3, 75.5 MHz): δ = 148.1 (aromatic C), 146.0 (aromatic C), 132.6 (2 olefinic CH), 128.5
(2 aromatic CH), 128.4 (2 aromatic CH), 126.9 (aromatic CH), 126.6 (2x2 aromatic CH), 126.0
(aromatic CH), 123.7 (olefinic CH), 123.6 (olefinic CH), 58.5 (CH), 44.6 (CH2N), 43.3 (aliphatic C),
40.2 (CH2CH2N), 26.1 (bis-allylic CH2), 24.4 (CH3).
IR (film, NaCl): νmax = 3023, 2815, 1492, 1446, 1128, 947, 762, 698 cm-1.
MS (SIMS) m/z (%): 304 [M+H]+ (100), 288 [M-CH3]+ (08), 155 [M-CH2CH2NH(CH(CH3)Ph)]+ (25).
HRMS (SIMS): [M+H]+ C22H26N: calcd. 304.2065; found 304.2071 (-1.8 ppm).
20
= -47° (C = 0.9, CHCl3).
[ ]
α
D

S5
(2-Methoxy-indan-1-yl)-[2-(1-phenyl-cyclohexa-2,5-dienyl)-ethyl]-amine (5):
MeO
To a solution of 2a (0.125 g, 0.632 mmol) in CH2Cl2 (6 mL) and 4Å molecular
sieves (0.52 g) was added (1S,2R)-2-methoxy-indan-1-ylamine (0.103 g, 0.632
mmol, 1 eq.). After stirring at room temperature overnight, the solution was filtered.
Evaporation of the solvent gave an oil which was diluted in methanol (6 mL).
NaBH4 (53 mg, 1.40 mmol, 2.2 eq.) was then added in one portion at 0°C. After
HN
stirring 2 hours at room temperature, water (0.5 mL) was added at 0°C and methanol was evaporated.
The residue was partitioned between a 10% NaOH solution and ether. The organic layer was separated
and the aqueous layer extracted ether. The organic layers were combined, dried over sodium sulfate,
filtered and evaporated. After purification by flash chromatography (deactivated silica gel, petroleum
ether/EtOAc 95:5), the product 5 (164 mg, 0.475 mmol, 75%) was obtained as an oil.
1H NMR (CDCl3, 300 MHz): δ = 7.44-7.31 (m, 5H, aromatic CH), 7.24-7.18 (m, 4H, aromatic H), 5.92-
5.85 (m, 2H, 2 olefinic CH), 5.74-5.67 (m, 2H, 2 olefinic CH), 4.12 (broad s, 2H, CHN and CHOCH3),
3.41 (s, 3H, OCH3), 3.12-2.90 (m, 2H, benzylic CH2), 2.85-2.78 (m, 2H, CH2NH), 2.75-2.71 (m, 2H, bis-
allylic CH2), 2.26-2.03 (m, 2H, CH2CH2N), 1.94 (broad s, 1H, NH).
13C NMR (CDCl3, 75.5 MHz): δ = 148.1 (aromatic C), 143.8 (aromatic C), 140.1 (aromatic C), 132.7 (2
olefinic CH), 128.4 (aromatic CH), 127.6 (aromatic CH), 126.7 (aromatic CH), 126.6 (aromatic CH),
126.0 (aromatic CH), 125.2 (aromatic CH), 124.7 (aromatic CH), 123.6 (olefinic CH), 123.5 (olefinic
CH), 82.0 (CHOMe), 65.3 (CHNH), 57.2 (OCH3), 44.7 (CH2NH), 43.3 (aliphatic C), 40.4 (CH2CH2N),
35.5 (benzylic CH2), 26.2 (bis allylic CH2).
IR (film, NaCl): νmax = 3022, 2927, 2819, 1462, 1095, 752, 722, 697 cm-1.
MS (SIMS) m/z (%) : 368 [M+Na]+ (10), 346 [M+H]+ (100), 314 [M-OCH3]+ (05).
HRMS (SIMS): [M+H]+ C24H28NO: calcd. 346.2171; found 346.2167 (1.0 ppm)
20
[ ]
α
= -41° (C = 1.04, CHCl3).
D
(2-Methoxy-1-phenyl-ethyl)-[2-(1-phenyl-cyclohexa-2,5-dienyl)-ethyl]-amine (6):
MeO
HN
To a solution of 2a (0.163 g, 0.823 mmol) in CH2Cl2 (8 mL) with sodium sulfate (1.170
g, 8.23 mmol, 10 eq.) was added (R)-2-methoxy-1-phenyl-ethylamine (0.213 g, 0.861
mmol, 1.05 eq.). After stirring 3 hours at room temperature, the solution was filtered
and the salts washed with CH2Cl2. Evaporation of the solvent gave an oil which was
diluted in methanol (8mL). NaBH4 was added in one portion at 0°C.After stirring 2h at
room temperature, water (0.5 mL) was added at 0°C and the methanol was evaporated.
H
Ph
The residue was partitioned between a 10% NaOH solution and ether. The organic layer was separated
and the aqueous layer extracted twice with ether. The organic layers were combined, dried over sodium
sulfate, filtered and evaporated to give a oily product which was purified by flash chromatography
(deactivated silica gel, petroleum ether/EtOAc 95:5) to give 6 (0.234 g, 0.703 mmol, 85%) as an oil.
1H NMR (CDCl3, 300 MHz): δ = 7.38-7.26 (m, 9H, aromatic H), 7.21-7.15 (m, 1H, aromatic H), 5.83-
5.77 (m, 2H, 2 olefinic H), 5.64-5.56 (m, 2H, 2 olefinic H), 3.94-3.89 (m, 1H, CHN), 3.51-3.38 (m, 2H,
CH2O), 3.39 (s, 3H, OCH3), 2.65-2.63 (m, 2H, bis-allylic CH2), 2.59-2.52 (m, 2H, CH2N), 2.07 (t, J =
8.5Hz, 2H, CH2CH2N).
13C NMR (CDCl3, 75.5 MHz): δ = 148.1 (aromatic C),141.0 (aromatic C), 132.7 (olefinic CH), 132.4
(olefinic CH), 128.4 (2 aromatic CH), 128.3 (2 aromatic CH), 127.6 (2 aromatic CH), 127.4 (aromatic
CH), 126.6 (2 aromatic CH), 126.0 (aromatic CH), 123.6 (olefinic CH), 123.5 (olefinic CH), 78.0
(CH2O), 63.0 (CHN), 58.9 (OCH3), 44.3 (CH2N), 43.2 (aliphatic C), 40.2 (CH2CH2N), 26.0 (bis allylic
CH2).
IR (film, NaCl): νmax = 3336, 3024, 2883, 2817, 1599, 1492, 1454, 1194, 1105, 948, 761, 699 cm-1.

S6
MS (SIMS) m/z (%): 356 [M+Na]+ (07), 334 [M+H]+ (100), 288 [M-CH2OCH3]+ (66).
HRMS (SIMS): [M+H]+ C23H28NO: calcd. 334.2171; found 334.2167 (1.2 ppm).
20
[ ]
α
= -48° (C = 0.94, CHCl3).
D
(2-Methoxymethoxy-1-phenyl-ethyl)-[2-(1-phenyl-cyclohexa-2,5-dienyl)-ethyl]-amine (7):
Compound 2a (363 mg, 1.83 mmol) and (-)-R-2-methoxymethoxy-1-phenyl-
ethylamine (332 mg, 1.83 mmol, 1 eq.) were condensed in CH2Cl2 (18 mL) with
sodium sulfate (2.60 g, 18.3 mmol, 10 eq.) for 4 hours. After filtration and
evaporation of the solvent, the oil was diluted with MeOH (18 mL) and NaBH4
(139 mg, 3.66 mmol, 2 eq.) was added in portions at 0°C. After stirring for 2
hours at room temperature, ether was added followed by a 10% NaOH solution.
OMOM
HN
H
Ph
After stirring for 30 minutes, the aqueous layer was extracted with ether, the combined organic layers
were washed with a saturated Na2CO3 solution and dried over sodium sulfate. Solvents were evaporated
and after purification by flash chromatography (deactivated silica gel, petroleum ether/EtOAc 90:10), 7
(523 mg, 1.46 mmol, 80% yield), was obtained as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ = 7.38-7.23 (m, 9H, aromatic H), 7.19-7.14 (m, 1H, aromatic H), 5.83-
5.74 (m, 2H, 2 olefinic H), 5.63-5.53 (m, 2H, 2 olefinic H), 4.66-4.61 (AB system, J = 15.0Hz, 2H,
OCHaHbO), 3.88 (dd, J = 4.1 and 8.7Hz, 1H, CHN), 3.67-3.50 (ABX system, J = 9.8 and 53.5Hz, 2H,
CHCHaHbO), 3.33 (s, 3H, OCH3), 2.72-2.79 (m, 2H, bis-allylic CH2), 2.59-2.50 (m, 2H, CH2N), 2.08-
2.00 (m, 2H, CH2CH2N), 1.93 (broad s, 1H, NH).
13C NMR (CDCl3, 75.5 MHz): δ = 148.1 (aromatic C), 141.1 (aromatic C), 132.6 (olefinic CH), 132.5
(olefinic CH), 128.5 (2 aromatic CH), 128.4 (2 aromatic CH), 127.7 (2 aromatic CH), 127.5 (aromatic
CH), 126.7 (2 aromatic CH), 126.0 (aromatic CH), 123.6 (2 olefinic CH), 96.8 (OCH2O), 73.0
(CHCH2O), 63.2 (NCHPh), 55.5 (OCH3), 44.4 (CH2N), 43.3 (aliphatic C), 40.3 (CH2CH2N), 26.1 (bis-
allylic CH2).
IR (film, KBr): νmax = 3023, 2927, 2818, 1492, 1453, 1152, 1107, 1039, 948, 761, 733, 699 cm-1.
MS (ESI) m/z (%): 364 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C24H30NO2: calcd 364.2277; found 364.2279.
20
= -42° (C = 1.55, CHCl3).
[ ]
α
D
[2-(1-Phenyl-cyclohexa-2,5-dienyl)-ethyl]-(1-phenyl-2-triethylsilanyloxy-ethyl)-amine (8):
OTES
To a solution of 2a (1.02 g, 4.07 mmol) in CH2Cl2 (20 mL) and sodium sulfate
HN
H
(5.78 g, 40.7 mmol, 10 eq.), was added 2-(R)-triethylsilanyloxy-1-phenyl-
ethylamine (0.81 g, 4.07 mmol). After stirring at room temperature overnight, the
solution was filtered and salts were washed with CH2Cl2. After evaporation of the
solvent, the oily residue was diluted in methanol (20 mL) and NaBH4 (0.31 g,
Ph
8.14 mmol, 2 eq.) was added in portions at 0°C. After stirring 3 hours at room temperature, a half-
saturated Na2CO3 solution was added at 0°C. After stirring 30 minutes, the solution was extracted twice
with ether. A 10% NaOH solution was added to the aqueous layer which was again extracted twice with
ether. The combined organic layers were dried over sodium sulfate. After filtration and evaporation of
the solvent, the product was purified by flash chromatography (deactivated silica gel, petroleum
ether/EtOAc 98:2) to give 8 (1.08 g, 2.49 mmol, 61%) as a colorless liquid.
1H NMR (CDCl3, 300 MHz): δ = 7.36-7.21 (m, 9H, aromatic H), 7.19-7.13 (m, 1H, aromatic H), 5.83-
5.73 (m, 2H, 2 olefinic H), 5.63-5.53 (m, 2H, 2 olefinic H), 3.76 (dd, J = 4.2 and 9.1Hz, 1H, PhCHN),
3.66 (dd, J = 4.2 and 9.8Hz, 1H, CHaHxO), 3.53 (dd, J = 9.1 and 9.8Hz, 1H, CHaHxO), 2.71-2.54 (m,

S7
2H, bis-allylic CH2), 2.56-2.49 (m, 2H, CH2N), 2.09-1.96 (m, 2H, CH2CH2N), 1.88 (broad s, 1H, NH),
0.95 (t, J = 7.9Hz, 9H, Si(CH2CH3)3), 0.59 (q, J = 7.9Hz, 6H, Si(CH2CH3)3).
13C NMR (CDCl3, 75.5 MHz): δ = 148.2 (aromatic C), 141.4 (aromatic C), 132.7 (olefinic CH), 132.6
(olefinic CH), 128.4 (2 aromatic CH), 128.3 (2 aromatic CH), 127.8 (2 aromatic CH), 127.3 (aromatic
CH), 126.7 (2 aromatic CH), 126.0 (aromatic CH), 123.6 (olefinic CH), 123.5 (olefinic CH), 68.4
(CH2O), 65.5 (PhCHN), 44.4 (CH2N), 43.4 (aliphatic C), 40.4 (CH2CH2N), 26.1 (bis-allylic CH2), 6.9 (3
SiCH2CH3), 4.5 (3 SiCH2CH3).
IR (film, KBr): νmax = 3024, 2954, 2875, 1492, 1454, 1239, 1078, 1008, 730, 699 cm-1.
MS (ESI) m/z (%): 434 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C28H40NOSi: calcd 434.2879; found 434.2867 (2.8 ppm).
Element. Anal. Calcd. for C28H39NOSi (433): C 77.54, H 9.06, N 3.23; found: C 77.66, H 9.06, N 3.10.
{2-[1-(3,5-Dimethoxy-phenyl)-cyclohexa-2,5-dienyl]-ethyl}-(2-methoxy-1-phenyl-ethyl)-amine (9):
OMe
In a dry three necked flask equipped with a thermometer, 1b (1.108 g, 3.85 mmol)
H
was dissolved in toluene (11 mL). DIBAL-H (1 M in hexane, 4 mL, 4 mmol, 1.05
eq.) was added dropwise in such a manner that temperature never exceeded –
70°C. After addition, the temperature was allowed to rise slowly to –40°C during
2 hours. Then, methanol (1 mL) was added followed by a concentrated solution of
potassium tartrate. After 2 hours stirring, the two phases were separated and the
aqueous layer extracted with ethyl acetate. The combined organic layers were
H
N
MeO
Ph
MeO
washed with brine, dried over sodium sulfate and evaporated. The intermediate aldehyde was used as a
crude mixture without further purification.
[1-(3,5-Dimethoxy-phenyl)-cyclohexa-2,5-dienyl]-acetaldehyde (564 mg, maximum 2.19 mmol),
was diluted in CH2Cl2 (20 mL), and sodium sulfate (3.10 g, 21.9 mmol) was added followed by (R)-(-)-
(2-methoxy-1-phenyl-ethyl)-amine (330 mg, 2.19 mmol). After stirring for 4 hours at room temperature,
salts were filtered and solvent evaporated. The oil was diluted in methanol (20 mL) and NaBH4 (165 mg,
4.36 mmol) was added at 0°C. After 2 hours at room temperature, water (1 mL) was added and methanol
was evaporated. The residue was partitioned between a 10% sodium hydroxide solution and ether. The 2
phases were separated and the aqueous layer extracted with ether. The combined extracts were washed
with saturated Na2CO3 solution, dried over sodium sulfate and filtered. Solvent was evaporated, and after
purification by flash chromatography (deactivated silica gel, petroleum ether/EtOAc 85:15), 9 was
obtained as a colorless oil (473 mg, 0.120 mmol, 45% over two steps, 54% corrected yield, some ester
1b, 177 mg, 0.615 mmol, being also recovered).
1H NMR (CDCl3, 300 MHz): δ = 7.36-7.24 (m, 5H, aromatic H), 6.49 (d, J = 3.3Hz, 2H, 2 aromatic H),
6.28 (t, J = 3.3Hz, 1H, aromatic H), 5.80-5.72 (m, 2H, 2 olefinic H), 5.60-5.50 (m, 2H, 2 olefinic H),
3.86 (dd, J = 4.1 and 9.0Hz, 1H, PhCHN), 3.76 (s, 6H, 2 OCH3), 3.48-3.34 (m, 2H, CH2O), 3.36 (s, 3H,
OCH3), 2.62-2.57 (m, 2H, bis-allylic CH2), 2.52-2.46 (m, 2H CH2N), 2.01-1.96 (m, 2H, CH2CH2N), 1.81
(broad s, 1H, NH).
13C NMR (CDCl3, 75.5 MHz): δ = 160.8 (2 aromatic C), 150.8 (aromatic C), 141.0 (aromatic C), 132.4
(olefinic CH), 132.1 (olefinic CH), 128.5 (2 aromatic CH), 127.7 (2 aromatic CH), 127.5 (aromatic CH),
123.9 (olefinic CH), 123.8 (olefinic CH), 105.2 (2 aromatic CH), 97.8 (aromatic CH), 80.0 (CH2O), 63.1
(PhCHN), 59.0 (OCH3), 55.4 (2 OCH3), 44.4 (CH2N), 43.5 (aliphatic C), 40.3 (CH2CH2N), 26.0 (bis-
allylic CH2).
IR (film, KBr): νmax = 3023, 2932, 1592, 1454, 1424, 1308, 1203, 1152, 1063, 926, 834, 760, 702 cm-1.
MS (ESI) m/z (%): 394 [M+H]+ (100).
HRMS (EI): [M]+. C25H31NO3: calcd. 393.2304; found: 393.2306 (0 ppm)
23
= -36° (C = 1.04, CHCl3).
[ ]
α
D

S8
(1-Hydroxymethyl-cyclohexa-2,5-dienyl)-acetonitrile (precursor of 11):
HO
CN
In a three-necked flask equipped with a dry-ice condenser, was introduced lithium
benzoate (1.92 g, 15 mmol) and THF (50 mL). Ammonia (around 100 mL) was condensed
at -78°C and lithium wire (0.23 g, 33 mmol, 2.2 eq.) was added. The cold bath was
removed and ammonia allowed to reflux for 1 hour (-33°C). Chloroacetonitrile (2.9 mL,
45 mmol, 3 eq.) diluted in THF (7 mL) was added at –78°C in one portion. The media turned brown
immediately. Ammonia was evaporated after 5 minutes and the mixture was acidified by a 1 M HCl
solution. The aqueous layer was extracted with ether. The combined extracts were washed with brine,
dried over sodium sulfate and solvents were evaporated. The dark brown paste was filtered through celite
and eluted with CH2Cl2. After evaporation of the solvent, the paste was filtered through a short plug of
silica gel and eluted with ethyl acetate. The compound 10 (2.31 g) was used without further purification
(NMR analysis shows a mixture of 12% of benzoic acid and 88% of product).
To the crude mixture of 10 (684 mg, around 4.2 mmol) diluted in THF (12 mL) was added triethylamine
(590 µL, 4.2 mmol, 1 eq.) and ethyl chloroformate (400 µL, 4.2 mmol, 1 eq.) at –10°C. After 30 minutes,
the mixture was filtered and salts were washed with THF. NaBH4 (476 mg, 3 eq.) was added at 0°C
followed by methanol (2.6 mL) dropwise. After 2 hours at room temperature, the media was acidified
with a 1 M HCl solution and extracted with ether. The combined organic layers were washed with brine,
dried over sodium sulfate and solvents were evaporated. The crude was purified by flash chromatography
(petroleum ether/EtOAc 70/30) to give the product (348 mg, 2.33 mmol, 56% over 2 steps) as a white
solid (m.p. = 41.3-42.8°C).
1H NMR (CDCl3, 300 MHz): δ = 6.05 (dt, J = 10.2 and 3.4Hz, 2H, 2 olefinic H), 5.57 (dt, J = 10.2 and
1.9Hz, 2H, 2 olefinic H), 3.51 (s, 2H, CH2O), 2.84-2.61 (m, 2H, bis-allylic CH2), 2.45 (s, 2H, CH2CN),
1.79 (broad s, 1H, OH).
13C NMR (CDCl3, 75.5 MHz): δ = 129.1 (2 olefinic CH), 126.5 (2 olefinic CH), 117.7 (CN), 68.9
(CH2O), 40.7 (aliphatic C), 26.8 (bis-allylic CH2), 26.7 (CH2CN).
IR (solid, KBr): νmax = 3477, 3022, 2865, 2258 (CN), 1298, 1081, 1038, 947, 733, 707 cm-1.
Element. Anal. Calcd for C9H11NO (149.2): C 72.46, H : 7.43, N 9.39.; found: C 72.80, H 7.75, N 9.11.
(1-Benzyloxymethyl-cyclohexa-2,5-dienyl)-acetonitrile (11):
In a two-necked flask, sodium hydride (60% in mineral oil, 162 mg, 4.05 mmol, 1.2 eq.)
CN
BnO
was washed three times with pentane and dissolved in THF (15 mL). (1-hydroxymethyl-
cyclohexa-2,5-dienyl)-acetonitrile (502 mg, 3.37 mmol) diluted in THF (15 mL) was
added dropwise at 0°C. The mixture was stirred at this temperature for 30 minutes.
Tetrabutylammonium iodide (62 mg, 0.17 mmol, 0.05 eq.) was added and then benzyl bromide (806 mg,
4.72 mmol, 1.4 eq.). The solution was stirred 1 hour at 0°C then 4 hours at room temperature. Excess of
sodium hydride was then destroyed with a small amount of water at 0°C. After filtration over celite,
eluting with ether, evaporation of solvent and purification by flash chromatography (petroleum
ether/EtOAc 95/5) the product 11 (697 mg, 2.92 mmol, 86%) was obtained as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ = 7.40-7.27 (m, 5H, aromatic H), 6.00-5.93 (m, 2H, 2 olefinic H), 5.69-
5.64 (m, 2H, 2 olefinic H), 4.54 (s, 2H, OCH2Ph), 3.38 (s, 2H, CqCH2O), 2.83-2.61 (m, 2H, bis-allylic
CH2), 2.54 (s, 2H, CH2CN).
13C NMR (CDCl3, 75.5 MHz): δ = 138.0 (aromatic C), 128.5 (2 aromatic CH), 127.8 (aromatic CH),
127.7 (2 olefinic CH), 127.6 (2 aromatic CH), 127.0 (2 olefinic CH), 118.0 (CN), 76.1 (CqCH2O), 73.6
(OCH2Ph), 39.5 (aliphatic C), 27.1 (CH2CN), 26.8 (bis-allylic CH2).
IR (film, KBr): νmax = 3030, 2860, 2244 (CN), 1454, 1418, 1361, 1106, 1075, 738, 716, 699 cm-1.
HRMS (EI): [M-BzOCH2]+. C8H8N: calcd. 118.0657; found 118.0664 (5 ppm).

S9
[2-(1-Benzyloxymethyl-cyclohexa-2,5-dienyl)-ethyl]-(2-methoxy-1-phenyl-ethyl)-amine (13):
MeO
In a dry three-necked flask equipped with a thermometer, (1-benzyloxymethyl-
cyclohexa-2,5-dienyl)-acetonitrile (445 mg, 1.86 mmol, 1 eq.) was introduced in
toluene (9 mL). DIBAL-H (1 M solution in hexane, 1.95 mL, 1.05 eq.) was added
dropwise, and the temperature kept below –70°C. After addition, the temperature
was allowed to rise slowly to –0°C during 4 hours. Methanol was added (1 mL)
BnO
H
N
H
Ph
followed by a 1 M solution of HCl. After 15 minutes, the 2 phases were separated and the aqueous layer
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium
sulfate and evaporated. After purification by flash chromatography (petroleum ether/EtOAc 95/5) an
inseparable mixture of starting material and 13 (326 mg) was obtained which was used in the next step.
The mixture was diluted in CH2Cl2 (6 mL), and sodium sulfate (950 mg, 6.70 mmol) was added followed
by (R)-(-)-(2-methoxy-1-phenyl-ethyl)-amine (121 mg, 0.80 mmol). After stirring for 4 hours, the salts
were filtered and solvents evaporated. The oil was diluted in methanol (6 mL) and NaBH4 (51 mg, 1.24
mmol) was added at 0°C. After 2 hours at room temperature, a 10% sodium hydroxide solution was
added. The media was stirred with ether 30 minutes. The 2 phases were separated and the aqueous layer
extracted with ether. The combined organic layer were washed with a saturated Na2CO3 solution and
dried over sodium sulfate. Solvents were evaporated to give an oil which was purified by flash
chromatography (deactivated silica gel, petroleum ether/EtOAc 9:1). Starting material (147 mg, 0.615
mmol, 33%) was eluted first then 13 (262 mg, 0.695 mmol, 37%, 56% corrected yield) as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ = 7.36-7.23 (m, 10H, aromatic H), 5.82-5.73 (m, 2H, 2 olefinic H), 5.54-
5.43 (m, 2H, 2 olefinic H), 4.50 (s, 2H, PhCH2O), 3.83 (dd, J = 9.1 and 4.1Hz, 1H, PhCHN), 3.45-3.33
(m, 2H, CH2OCH3), 3.35 (s, 3H, OCH3), 3.22 (s, 2H, CqCH2O), 2.68-2.47 (m, 2H, bis-allylic CH2), 2.44-
2.38 (m, 2H, CH2N), 1.66-1.61 (m, 2H, CH2CH2N).
13C NMR (CDCl3, 75.5 MHz): δ = 141.0 (aromatic C), 138.8 (aromatic C), 130.6 (olefinic CH), 130.3
(olefinic CH), 128.4 (aromatic CH), 128.3 (aromatic CH), 127.6 (aromatic CH), 127.5 (aromatic CH),
127.4 (aromatic CH), 125.6 (olefinic CH), 125.5 (olefinic CH), 78.7 (CqCH2O), 77.9 (CH2OMe), 73.4
(PhCH2O), 63.1 (PhCHN), 58.9 (OCH3), 44.0 (CH2N), 40.8 (aliphatic C), 37.8 (CH2CH2N), 26.6 (bis-
allylic CH2).
IR (film, KBr): νmax = 3026, 2852, 1454, 1360, 1195, 1102, 1028, 757, 735, 700 cm-1.
MS (ESI) m/z (%): 378 [M+H]+ (100).
HRMS (EI): [M-CH2OMe]+ C23H26NO: calcd 332.2014; found: 332.2026 (3 ppm).
20
= -53° (C = 0.89, CHCl3).
[ ]
α
D
3a-Phenyl-1-(1-phenyl-ethyl)-2,3,3a,4,5,7a-hexahydro-1H-indole (14):
The compound 4 (110 mg, 0.363 mmol) dissolved in THF (0.7 mL) and n-BuLi (2.5
M in hexane, 30 µL, 0.2 eq.) was added at room temperature. The reaction was stirred
for 4 hours during which the solution turned from orange to yellow. One drop of
water was added and the organic layer was diluted with ether, washed with a saturated
Na2CO3 solution and dried over sodium sulfate. Solvents were evaporated to give a
Ph
N
pale yellow oil of 14 (102 mg, 0.336 mmol, 93%) as a mixture of diastereoisomer in a 63:37 ratio.
13C NMR (CDCl3, aliphatic signals, 75.5 MHz):
Major product: 61.9 (NCHPh), 47.7 (NCH-CH=), 42.5 (CH2), 40.3 (CH2), 38.0 (aliphatic C), 34.2 (CH2),
23.9 (CH2), 22.4 (CH3).
Minor product: 61.0 (NCHPh), 48.9 (NCH-CH=), 42.5 (CH2), 40.0 (CH2), 37.9 (aliphatic C), 34.8 (CH2),
23.8 (CH2), 22.9 (CH3).

S10
1-(2-Methoxy-indan-1-yl)-3a-phenyl-2,3,3a,6,7,7a-hexahydro-1H-indole (15):
The compound 5 (137 mg, 0.397 mmol) was dissolved in THF (2 mL) and n-BuLi
(2.5 M in hexane, 60 µL, 0.4 eq.) was added at room temperature. After 3 hours, one
drop of water was added and the organic layer was diluted with ether, washed with a
saturated Na2CO3 solution and dried over sodium sulfate. Solvents were evaporated to
give an oil which was purified by flash chromatography (deactivated silica gel,
petroleum ether/EtOAc 98:2 to 95:5). The compound 15 (35 mg, 0.101 mol, 26%),
MeO
N
Ph
was eluted first as a 9:1 mixture of 2 isomers, then starting material (57 mg, 0.165 mmol, 42%).
1H NMR (Major isomer, CDCl3, 300 MHz): δ = 7.36-7.14 (m, 9H, aromatic H), 6.42-6.30 (m, 1H,
olefinic H), 6.06-6.01 (m, 1H, olefinic H), 4.67 (d, J = 7.2Hz, 1H, NCHPh), 4.24-4.16 (m, 1H, CHOMe),
3.55 (s, 3H, OCH3), 3.48 (s, 1H, allylic CH), 3.19-2.95 (m, 4H, CH2N and CH2Ph), 2.28 (td, J = 12.4 and
4.9Hz, 1H), 2.16-1.81 (m, 5H), 1.73-1.63 (m, 1H), 1.61-1.46 (m, 1H).
13C NMR (Major isomer, CDCl3, 62.9 MHz): δ = 147.9 (aromatic C), 141.1 (aromatic C), 138.7
(aromatic C), 132.8 (olefinic CH), 128.1 (aromatic CH), 127.8 (2 aromatic CH), 126.7 (2 aromatic CH),
126.6 (2 aromatic CH), 125.6 (aromatic CH), 125.0 (2 aromatic CH and 1 olefinic CH), 81.3 (CHOMe),
60.4 (allylic CH), 60.1 (NCHPh), 57.8 (OCH3), 45.7 (aliphatic C), 44.6 (CH2), 39.4 (CH2), 38.1 (CH2),
34.7 (CH2), 24.4 (CH2).
MS (ESI) m/z (%): 346 [M+H]+ (100).
1-(2-Methoxy-1-phenyl-ethyl)-3a-phenyl-2,3,3a,4,5,7a-hexahydro-1H-indole (16):
The compound 6 (490 mg, 1.47 mmol) was dissolved in THF (1.5 mL) and n-BuLi (2.5 M
in hexane, 120 µL, 0.2 eq.) was added at room temperature. The reaction was stirred for 4
hours during which the solution turned from orange to yellow. A drop of water was added
and the organic layer was diluted with ether, washed with a saturated Na2CO3 solution and
OMe
H
Ph
N
dried over sodium sulfate. Solvents were evaporated and 16 was obtained as a colorless oil
in a nearly quantitative yield.
1H NMR (CDCl3, 300 MHz): δ = 7.42-7.25 (m, 9H, aromatic H), 7.21-7.15 (m, 1H,
aromatic H), 6.22-6.16 (m, 1H, olefinic H), 6.05-5.99 (m, 1H, olefinic H), 4.23 (t, J =
6.6Hz, 1H, PhCHN), 3.90-3.78 (m, 2H, CH2O), 3.38 (s, 3H, OCH3), 3.23-3.21 (m, 1H, allylic CH), 3.06-
2.98 (m, 1H, CHaHxN), 2.65-2.98 (m, 1H, CHaHxN), 2.17-1.96 (m, 4H), 1.75-1.56 (m, 2H).
13C NMR (CDCl3, 75.5 MHz): δ = 148.3 (aromatic C), 138.0 (aromatic C), 131.4 (olefinic CH), 128.9 (2
aromatic CH), 128.1 (2 aromatic CH), 127.9 (2 aromatic CH), 127.3 (olefinic CH), 126.6 (2 aromatic
CH), 126.2 (aromatic CH), 125.6 (aromatic CH), 75.3 (CH2O), 62.3 (PhCHN), 60.8 (allylic CH), 58.9
(OCH3), 46.5 (aliphatic C), 45.8 (CH2N), 37.9 (CH2), 34.7 (CH2), 23.6 (CH2).
IR (film, NaCl): νmax = 3025, 2924, 2826, 1495, 1452, 1192, 1112, 764, 700 cm-1.
MS (EI, 70 eV) m/z (%): 288 [M-CH2OCH3]+. (80), 91 [tropylium]+. (100).
HRMS (EI): [M-CH2OMe]+ C21H22N: calcd. 288.1752; found 288.1756 (1 ppm).
20
= -102° (C = 1.20, CHCl3).
[ ]
α
D

S11
3a-(3,5-Dimethoxy-phenyl)-1-(2-methoxy-1-phenyl-ethyl)-2,3,3a,6,7,7a-hexahydro-1H-indole (17):
The compound 9 (362 mg, 0.92 mmol) was dissolved in THF (1.8 mL) and n-BuLi
(2.5 M in hexane, 110 µL, 0.3 eq.) was added at room temperature. The reaction was
stirred for 4 hours during which the solution turned from orange to yellow. A drop of
water was added and the organic layer was diluted with ether, washed with a saturated
Na2CO3 solution and dried over sodium sulfate. Solvents were evaporated and the
crude product was purified by flash chromatography (deactivated silica gel petroleum
ether/EtOAc 95/5 to 90/10). Compound 17 (180 mg, 0.458 mmol, 46%) was obtained
as a white solid (m.p. = 112.2-113.2°C) which was crystallized with ethyl acetate and
H
MeO
Ph
N
MeO
OMe
hexane, to give crystals suitable for X-Ray analysis.
1H NMR (CDCl3, 300 MHz): δ = 7.35-7.21 (m, 5H, aromatic H), 6.39 (d, J = 2.3Hz, 2H ,2 aromatic H),
6.26 (t, J = 2.3Hz, 1H, aromatic H), 6.13-6.05 (m, 1H, olefinic H), 6.00-5.92 (m, 1H, olefinic H), 4.16 (t,
J = 6.6Hz, 1H, NCHPh), 3.82-3.71 (m, 2H, CH2OMe), 3.75 (s, 6H, 2 OCH3), 3.32 (s, 3H, OCH3), 3.32
(d, J = 3.4Hz, 1H, allylic CH), 2.97-2.90 (m, 1H, CHaHxN), 2.59-2.51 (m, 1H, CHaHxN), 2.08-1.9 (m,
4H), 1.70-1.58 (m, 2H).
13C NMR (CDCl3, 62.9 MHz): δ = 160.3 (2 aromatic C), 151.0 (aromatic C), 137.9 (aromatic C), 131.5
(olefinic CH), 128.9 (2 aromatic CH), 128.2 (2 aromatic CH), 127.4 (aromatic CH), 126.1 (olefinic CH),
105.4 (2 aromatic CH), 96.9 (aromatic CH), 75.3 (CH2O), 62.3 (PhCHN), 60.9 (CqCHN), 59.0 (OCH3),
55.3 (2 OCH3), 46.9 (aliphatic C), 45.8 (CH2), 37.8 (CH2), 34.6 (CH2), 23.7 (allylic CH2).
IR (solid, KBr): νmax = 2925, 1618, 1583, 1452, 1337, 1197, 1157, 1113, 1047, 841, 702 cm-1.
MS (ESI) m/z (%): 394 [M+H]+ (100).
20
= -122° (C = 1.54, CHCl3).
[ ]
α
D
3a-Benzyloxymethyl-1-(2-methoxy-1-phenyl-ethyl)-2,3,3a,4,5,7a-hexahydro-1H-indole (18):
OMe
The compound 13 (82 mg, 0.218 mmol) was dissolved in THF (0.4 mL) and n-
BnO
BuLi (2.5 M in hexane, 40 µL, 0.4 eq.) was added at room temperature. The
reaction was stirred for 2 hours during which the solution turned from orange to
yellow. A drop of water was added and the organic layer was diluted with ether,
N
H
Ph
washed with a saturated Na2CO3 solution and dried over sodium sulfate. Solvents were evaporated and
after purification by flash chromatography (deactivated silica gel, petroleum ether/EtOAc 97:3), the
product 18 (67 mg, 0.178 mmol, 82%) was obtained as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ = 7.40-7.28 (m, 10H, aromatic H), 5.97-5.88 (m, 1H, olefinic H), 5.81-
5.75 (m, 1H, olefinic H), 4.56-4.47 (AB system, JAB = 27.2Hz, 2H, PhCH2O), 3.93 (t, J = 6.0Hz, 1H,
PhCHN), 3.79-3.74 (m, 1H, CHaHbOMe), 3.66-3.60 (m, 1H, CHaHbOMe), 3.40-3.18 (AB system, JAB
=
85.1Hz, 2H, CH2OBn), 3.32 (s, 3H, OCH3), 2.96 (s, 1H, allylic H), 2.82-2.68 (m, 2H, CH2N), 2.18-1.89
(m, 2H, allylic H), 1.83-1.60 (m, 2H), 1.68 (t, J = 7.1Hz, 2H).
13C NMR (CDCl3, 75.5 MHz): δ = 140.0 (aromatic C), 139.0 (aromatic C), 130.1 (olefinic CH), 128.6 (2
aromatic CH), 128.3 (2 aromatic CH), 128.2 (2 aromatic CH), 127.5 (2 aromatic CH), 127.4 (aromatic
CH), 127.3 (aromatic CH), 125.4 (olefinic CH), 76.8 (CH2OMe), 76.8 (CqCH2O), 73.3 (CH2OPh), 64.0
(NCHPh), 59.3 (allylic CH), 59.0 (OCH3), 47.3 (CH2N), 43.2 (aliphatic C), 31.1 (CH2), 28.4 (CH2), 22.0
(CH2).
IR (film, KBr): νmax = 3026, 2854, 1495, 1453, 1361, 1192, 1109, 1028, 735, 696 cm-1.
MS (ESI) m/z (%): 378 [M+H]+ (100).
HRMS (EI): [M-CH2OMe]+ C23H26NO: calcd 332.2014; found: 332.2026 (3 ppm).
20
= -100° (C = 1.56, CHCl3).
[ ]
α
D

S12
1-(2-Methoxymethoxy-1-phenyl-ethyl)-3a-phenyl-2,3,3a,4,5,7a-hexahydro-1H-indole (19):
The compound 7 (652 mg, 1.82 mmol) was dissolved in THF (1.8 mL) and n-BuLi
(2.5 M in hexane, 145 µL, 0.2 eq.) was added at room temperature. The reaction
was stirred for 3 hours during which the solution turned from orange to yellow.
Water (0.5 mL) was added and the organic layer was diluted with ether, washed
with a saturated Na2CO3 solution and dried over sodium sulfate. Evaporation of
solvents gave 19 (625 mg, 96%) which was used without purification.
OMOM
H
N
Ph
1H NMR (CDCl3, 250 MHz): δ = 7.37-7.10 (m, 10H, aromatic H), 6.21-6.13 (m, 1H olefinic H), 6.03-
5.94 (m, 1H, olefinic H), 4.65-4.56 (AB system, JAB = 22.4Hz, 2H, OCH2O), 4.22 (t, J = 7.3Hz, 1H,
PhCHN), 3.97 (d, J = 7.3Hz, 2H, CHCH2O), 3.25 (s, 3H, OCH3), 3.14-3.08 (m, 1H, allylic H), 3.02-2.93
(m, 1H, CHaHxN), 2.58-2.48 (m, 1H, CHaHxN), 2.14-1.89 (m, 4H), 1.71-1.46 (m, 2H).
13C NMR (CDCl3, 62.9 MHz): δ = 148.3 (aromatic C), 137.4 (aromatic C), 131.8 (olefinic CH), 129.0 (2
aromatic CH), 128.2 (2 aromatic CH), 127.8 (2 aromatic CH), 127.4 (aromatic CH), 12.6 (2 aromatic
CH), 125.9 (olefinic CH), 125.7 (aromatic CH), 96.6 (OCH2O), 69.8 (CHCH2O), 62.1 (PhCHN), 60.7
(allylic CH), 55.4 (OCH3), 46.4 (aliphatic C), 45.5 (CH2), 38.0 (CH2), 34.8 (CH2), 23.7 (CH2).
IR (film, KBr): νmax = 3024, 2926, 2822, 1601, 1495, 1452, 1150, 1111, 1042, 917, 764, 700 cm-1.
MS (ESI) m/z (%): 364 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C24H30NO2: calcd 364.2277; found 364.2279 (-0.6 ppm).
20
= -100° (C = 1.26 CHCl3).
[ ]
α
D
Preparation of 20a and 20b:
The compound 19 (625 mg, 1.746 mmol), used as a crude, was dissolved in isopropanol (10 mL, HPLC
grade). A concentrated solution of hydrochloric acid (0.4 mL) was then added and the media was
warmed to 55°C for 16 hours. The solution was extracted with EtOAc. The organic layer was washed
with a saturated Na2CO3 solution and dried over sodium sulfate. After purification by flash
chromatography (deactivated silica gel, petroleum ether/EtOAc 90/10), the compound 20b (17 mg, 0.054
mmol, 3%) was eluted first then 20a (406 mg, 1.27 mmol, 70% over two steps).
2-Phenyl-2-(3a-phenyl-2,3,3a,4,5,7a-hexahydro-indol-1-yl)-ethanol (20a):
1H NMR (CDCl3, 300 MHz): δ = 7.40-7.12 (m, 10H, aromatic H), 6.33-6.25 (m, 1H,
OH
olefinic H), 6.11-6.03 (m, 1H, olefinic H), 4.25 (dd, J = 4.9 and 10.5Hz, 1H,
NCHPh), 4.03 (t, J = 10.5Hz, 1H, CHaHxOH), 3.70 (dd, J = 4.9 and 10.5Hz, 1H,
CHaHxOH), 3.30 (broad s, 1H, OH), 3.17 (d, J = 4.1Hz, 1H, allylic H), 3.05 (td, J =
8.7 and 3.4Hz, 1H, CHaHxN), 2.33 (td, J = 9.03 and 8.7Hz, 1H, CHaHxN), 2.17-1.92
(m, 4H), 1.78-1.69 (m, 1H), 1.60-1.45 (m, 1H).
H
N
Ph
13C NMR (CDCl3, 62.9 MHz): δ = 147.5 (aromatic C), 134.9 (aromatic C), 133.2 (olefinic CH), 129.2 (2
aromatic CH), 128.3 (2 aromatic CH), 128.0 (aromatic CH), 127.9 (2 aromatic CH), 126.6 (2 aromatic
CH), 125.8 (aromatic CH), 124.6 (olefinic), 61.4 (NCHPh), 60.9 (CH2OH), 59.7 (allylic CH), 46.2
(aliphatic C), 42.6 (CH2N), 38.6 (CH2), 35.5 (allylic CH2), 24.0 (CH2).
IR (film, NaCl): νmax = 3432, 3025, 2930, 1494, 1058, 1031, 910, 765, 700 cm-1.
MS (ESI) m/z (%): 320 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C22H26NO: calcd 320.2014; found 320.2030 (-4.9 ppm).
20
= -178° (C = 0.83, CHCl3).
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S13
2-Phenyl-2-(3a-phenyl-2,3,3a,4,7,7a-hexahydro-indol-1-yl)-ethanol (20b):
1H NMR (CDCl3, 300 MHz): δ = 7.41-7.13 (m, 10H, aromatic H), 5.91-5.82 (m,
1H, olefinic H), 5.74-5.65 (m, 1H, olefinic H), 4.11 (dd, J = 4.5 and 10.5Hz, 1H,
CHaHxO), 3.98 (dd, J = 9.8 and 10.5Hz, 1H, CHaHxO), 3.68 (dd, J = 4.5 and
9.8Hz, 1H, PhCHN), 3.14-3.04 (m, 2H, Cq-CHN and CHaHxN), 2.98 (broad s, 1H,
OH), 2.72 (ddd, J = 10.2, 9.4 and 4.2Hz, 1H, CHaHxN), 2.54-2.40 (m, 3H, allylic
H), 2.10-1.98 (m, 1H, allylic H), 1.97-1.79 (m, 2H, CH2CH2N).
OH
Ph
N
13C NMR (CDCl3, 62.9 MHz): δ = 146.1 (aromatic C), 135.6 (aromatic C), 129.1 (2
aromatic CH), 128.4 (2 aromatic CH), 128.3 (2 aromatic CH), 127.9 (aromatic CH), 126.4 (2 aromatic
CH), 126.2 (aromatic CH), 126.2 (olefinic CH), 123.8 (olefinic CH), 62.6 (CqCHN), 61.0 (PhCHN), 60.6
(CH2O), 45.9 (aliphatic C), 41.3 (CH2N), 37.2 (CH2CH2N), 33.8 (allylic CH2), 24.0 (allylic CH2).
IR (film, KBr): νmax = 3427, 3026, 2883, 1600, 1495, 1445, 1223, 1138, 1060, 1028, 761, 700, 660 cm-1.
MS (SIMS) m/z (%): 320 [M+H]+ (100), 288 [M-CH2OH]+ (45), 265 (65), 234 (32).
HRMS (SIMS): [M+H]+ C22H26NO: calcd 320.2014; found 320.2025 (-3.2 ppm).
23
= -120° (C = 0.81, CHCl3).
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3a-Phenyl-1-(1-phenyl-2-phenylselanyl-ethyl)-2,3,3a,4,5,7a-hexahydro-1H-indole (21):
To a solution of 20a (618 mg, 1.94 mmol) in CH2Cl2 (20 mL) was added
SePh
triethylamine (235 mg, 2.33 mmol, 1.2 eq.) and mesyl chloride (244 mg, 2.13
mmol, 1.1 eq.) at 0°C. After stirring for 4 hours at room temperature, the mixture
was diluted with CH2Cl2, washed with a saturated Na2CO3 solution, dried over
sodium sulfate and filtered. Evaporation of the solvents gave an oil. This product
was diluted in ethanol (10 mL) and added, at 0°C, to a PhSeNa solution formed by
H
N
Ph
heating sodium borohydride (155 mg, 4.07 mmol, 2.1 eq.) and diphenyldiselenide (604 mg, 1.94 mmol, 1
eq.) in ethanol (10 mL) at 80°C for 30 minutes. The resulting solution was then heated to 80°C for 2
hours. After concentration of the solution, a saturated Na2CO3 solution was added. Extraction with ethyl
acetate, drying over sodium sulfate and evaporation of solvents gave a paste which was purified by flash
chromatography (deactivated silica gel, petroleum ether/EtOAc 100/0 to 99/1) to give 21 (716 mg, 1.56
mmol, 80%) as a colorless oil
1H NMR (CDCl3, 300 MHz): δ = 7.49-7.46 (m, 2H, aromatic H), 7.30-7.15 (m, 13H, aromatic H), 5.97-
5.86 (m, 2H, olefinic H), 4.55 (dd, J = 5.5 and 10.1Hz, 1H, PhCHN), 3.63 (dd, J = 10.1 and 12.7Hz, 1H,
CHaHxSe), 3.10-3.02 (m, 2H, allylic CH and CHaHxN), 2.97 (dd, J = 5.5 and 12.7Hz, 1H, CHaHxSe),
2.30 (dt, J = 8.7 and 8.7Hz, 1H, CHaHxN), 2.02-1.97 (m, 2H, CH2CH2N), 1.93-1.81 (m, 2H), 1.59-1.40
(m, 2H).
13C NMR (CDCl3, 75.5 MHz): δ = 148.0 (aromatic C), 141.1 (aromatic C), 135.4 (2 aromatic CH), 131.8
(olefinic CH), 129.8 (aromatic C), 128.9 (2 aromatic CH), 128.3 (2 aromatic CH), 128.1 (2 aromatic
CH), 127.9 (2 aromatic CH), 127.8 (aromatic CH), 126.8 (aromatic CH), 126.6 (2 aromatic CH), 125.7
(aromatic CH), 125.2 (olefinic CH), 64.5 (allylic CH), 58.2 (CH2Se), 51.2 (CH2N), 47.0 (aliphatic C),
46.9 (PhCHN), 38.9 (CH2), 34.6 (CH2), 23.6 (CH2).
IR (film, NaCl): νmax = 3058, 3023, 2929, 2790, 1600, 1579, 1495, 1476, 1437, 910, 739, 693 cm-1.
MS (SIMS) m/z (%): 460 [M+H (80Se)]+ (30), 302 [M -PhSeH]+ (23), 212 (100).
HRMS (SIMS): [M+H (80Se)]+ C28H30N80Se: calcd 460.1543; found 460.1539 (1.0 ppm).

S14
3a-Phenyl-2,3,3a,4,5,7a-hexahydro-1H-indole (22):
To a solution of 21 (60 mg, 0.131 mmol) in methanol (2 mL) was added sodium
periodate (29 mg, 0.138 mmol, 1.05 eq.) and water (0.5 mL) at 0°C. After stirring at room
temperature for 18 hours, the mixture was acidified with a 1 M solution of HCl. After
stirring for additional 2 hours, the media was basified with a 10% sodium hydroxide
solution and extracted with ether. After washing the organic layer with saturated Na2CO3
solution and drying over sodium sulfate, the paste was purified by flash chromatography
H
N
(deactivated silica gel, CH2Cl2/MeOH 9/1) to give 22 as a oil (14 mg, 0.070 mmol, 51%).
1H NMR (CDCl3, 300 MHz): δ = 7.34-7.19 (m, 5H, aromatic H), 6.17-6.06 (m, 2H, 2 olefinic H), 5.93
(broad s, 1H, NH), 3.93 (s, 1H, CHN), 3.45 (ddd, J = 7.9, 8.3 and 11.7Hz, 1H, CHaHxN), 3.27-3.18 (m,
1H, CHaHxN), 2.37-2.19 (m, 2H), 2.06-1.91 (m, 2H), 1.79-1.72 (m, 1H, 1.62-1.50 (m, 1H).
13C NMR (CDCl3, 75.5 MHz): δ = 144.8 (aromatic C), 134.5 (CH), 128.4 (2 aromatic CH), 126.6 (CH),
126.3 (2 aromatic CH), 123.3 (CH), 59.2 (CHN), 47.3 (aliphatic C), 43.0 (CH2), 39.9 (CH2), 31.8 (CH2),
22.9 (CH2).
IR (solid, KBr): νmax = 3424, 2880, 2780, 2725, 2454, 1601, 1497, 1408, 767, 701 cm-1.
MS (SIMS) m/z (%): 200 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C14H18N: calcd 200.1439; found : 200.1436 (1.7 ppm).
1-(2-Methoxy-1-phenyl-ethyl)-3a-phenyl-octahydro-indole-6,7-diol (precursor of 23):
To a crude solution of 16 (345 mg, 1.04 mmol) in t-BuOH (5 mL) and water (5 mL)
was added K3Fe(CN)6 (1.022 g, 3.12 mmol, 3 eq.), potassium carbonate (429 mg, 3.12
MeO
H
Ph
mmol, 3 eq.), methanesulfonamide (98 mg, 1.04 mmol, 1 eq.), quinuclidine (4.6 mg,
N
OH
0.04 mmol, 0.04 eq.), and potassium osmate dihydrate (11.4 mg, 0.03 mmol, 0.03 eq.).
After stirring at room temperature for 24 hours, sodium sulfite (1.31 g, 10.4 mmol, 10
eq.) was added and the media was stirred for 30 minutes. The solution was basified
with a 10% NaOH solution and extracted with ethyl acetate (4 times). A paste was
OH
obtained after drying over sodium sulfate, filtration and evaporation of solvent, which was sufficiently
pure (by NMR) to be used directly in the next step (purification gave substantial lost of product).
Purification by flash chromatography (deactivated silica gel, petroleum ether/EtOAc 50/50) gave the title
compound as a colorless oil in moderate yield (around 50%).
1H NMR (CDCl3, 300 MHz): δ = 7.48-7.44 (m, 2H, aromatic H), 7.35-7.30 (m, 2H, aromatic H), 7.26-
7.15 (m, 4H, aromatic H), 7.08-7.04 (m, 2H, aromatic H), 4.96 (broad s, 1H, OH), 4.16-4.13 (m, 1H),
3.79 (d, J = 8.3 Hz, 1H), 3.70 (dd, J = 10.2 and 3.4 Hz, 1H), 3.60 (dd, J = 8.7 and 2.6 Hz, 1H), 3.29-3.24
(m, 1H), 3.26 (s, 3H, OCH3), 3.10 (t, J = 3.4 Hz, 1H), 2.92 (t, J = 8.7 Hz, 1H, CHaHxN), 2.58 (broad s,
1H, OH), 2.41-2.32 (m, 1H, CHaHxN), 2.56-2.09 (m, 3H), 1.95-1.85 (m, 1H), 1.72-1.62 (m, 2H).
13C NMR (CDCl3, 62.9 MHz): δ = 147.9 (aromatic C), 141.4 (aromatic C), 128.6 (2 aromatic CH), 128.4
(2 aromatic CH), 127.8 (2 aromatic CH), 127.0 (aromatic CH), 126.3 (2 aromatic CH), 126.2 (aromatic
CH), 75.7 (CH2O), 75.6 (CH), 69.0 (CH), 68.5 (CH), 68.0 (CH), 59.0 (OCH3), 50.4 (CH2), 50.2
(aliphatic C), 31.7 (CH2), 31.6 (CH2), 26.4 (CH2).
IR (film, NaCl): νmax = 3405, 2928, 2892, 1452, 1099, 1060, 910, 733, 702 cm-1.
MS (ESI) m/z (%): 368 [M+H]+ (100).
HRMS (EI): [M-CH2OMe]+ C21H24NO2: calcd 322.1807; found : 322.1836 (9 ppm).
20
= -39° (C = 0.8, CHCl3).
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S15
Acetic acid 7-acetoxy-1-acetyl-3a-phenyl-octahydro-indol-6-yl ester (23):
The solution of crude mixture of 1-(2-methoxy-1-phenyl-ethyl)-3a-phenyl-
octahydro-indole-6,7-diol with palladium (10% wt. on activated carbon, 220 mg, 0.2
eq.) and a small amount of perchloric acid in ethanol (3 mL) and water (2 mL) was
purged first with nitrogen then hydrogen through freeze-pump-thaw cycles. The
solution was stirred for 2 days at room temperature under an atmosphere of
hydrogen.
Ac
OAc
OAc
N
A 10% sodium hydroxide solution (1 mL) was added and the solution was filtered over celite and eluted
with ethyl acetate. After evaporation of the solvents, the resulting paste was diluted in CH2Cl2 (10 mL).
Triethylamine (2.2 mL, 15.5 mmol, 15 eq.), a small amount of DMAP then anhydride acetic acid (0.98
mL, 10.4 mmol, 10 eq.) were added at 0°C. After stirring overnight at room temperature, the organic
phase was washed with brine and dried over sodium sulfate. Purification by flash chromatography
(deactivated silica gel, petroleum ether/EtOAc 30/70) gave 23 as an oil (141 mg, 0.393 mmol, 38%, four
steps). NMR in CDCl3 shows a 1:1 mixture of two rotamers but deuterated benzene gives a 2:1 ratio and
spaces out signals.
Major rotamer:
1H NMR (C6H6, 300 MHz, only characteristic signals are noted): δ = 5.49-5.41 (m, 2H), 5.20 (dd, J = 9.2
and 2.8 Hz, 1H), 3.15 (t, J = 9.4 Hz, 1H, CHaHxN), 2.74 (ddd, J = 7.9, 9.8 and 10.2 Hz, 1H, CHaHxN),
2.08 (s, 3H), 1.74 (s, 3H), 1.66 (s, 3H).
13C NMR (C6H6, 75.5 MHz): δ = 171.0 (C=O), 169.9 (C=O), 169.2 (C=O), 146.6 (aromatic C), 129.1 (2
aromatic CH), 127.1 (aromatic CH), 125.6 (2 aromatic CH), 72.6 (CH), 70.4 (CH), 59.3 (CH), 49.4
(aliphatic C), 44.3 (CH2), 33.2 (CH2), 29.7 (CH2), 25.0 (CH2), 21.9 (CH3), 21.3 (CH3), 20.6 (CH3).
Minor rotamer:
1H NMR (C6H6, 300 MHz, only characteristic signals are noted): 5.68-5.64 (m, 1H), 5.00 (dd, J = 9.8
and 2.6 Hz, 1H), 4.55 (d, J = 9.8 Hz, 1H), 3.82-3.70 (m, 1H, CHaHxN), 3.49-3.39 (m, 1H, CHaHxN),
2.08 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H).
13C NMR (C6H6, 75.5 MHz): δ = 169.6 (C=O), 169.2 (C=O), 168.6 (C=O), 146.1 (aromatic C), 129.2 (2
aromatic CH), 127.3 (aromatic CH), 125.5 (2 aromatic CH), 74.0 (CH), 69.8 (CH), 63.5 (CH), 50.8
(aliphatic C), 43.2 (CH2), 30.5 (CH2), 29.6 (CH2), 24.8 (CH2), 21.9 (CH3), 21.3 (CH3), 20.6 (CH3).
IR (film, NaCl): νmax = 3460, 2952, 1732, 1651, 1454, 1225, 1047, 954, 764, 702 cm-1.
MS (SIMS) m/z (%): 382 [M+Na]+ (60), 360 [M+H]+ (100).
HRMS (SIMS): [M+H]+ C20H26NO5: calcd 360.1811; found : 360.1810 (0.3 ppm).
23
= +198° (C = 1.45, CHCl3).
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