Total synthesis of (-)-γ-lycorane using diastereoselective 5-endo-trig radical cyclization of N-vinylic α-halo amides

Article abstract of DOI:10.1055/s-1998-2212

Bu₃SnH-mediated radical cyclization of α-iodo-N-(6-oxocylohex-1- enyl)-N-[(S)-1-phenylethyl]acetamide (6) proceeded in a 5-endo-trig manner with moderate diastereoselectivity to give (3aS, 7aR)-octahydroindole-2,7- dione 8a as the major product

Full text of DOI:10.1055/s-1998-2212

SYNTHESIS
December 1998
1803
Total Synthesis of (Ð)-γ-Lycorane Using Diastereoselective 5-Endo-Trig Radical
Cyclization of N-Vinylic α-Halo Amides
Masazumi Ikeda,*a Shinji Ohtani,a Tatsunori Sato,a Hiroyuki Ishibashi*b
a Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Fax +81(75)5954763; E-mail: ikeda@mb.kyoto-phu.ac.jp
b Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Fax +81(76)2344476; E-mail: isibasi@dbs.p.kanazawa-u.ac.jp
Received 13 April 1998; revised 11 June 1998
Abstract: Bu3SnH-mediated radical cyclization of α-iodo-N-(6-
oxocyclohex-1-enyl)-N-[(S)-1-phenylethyl]acetamide (6) pro-
ceeded in a 5-endo-trig manner with moderate diastereoselectivity
to give (3aS,7aR)-octahydroindole-2,7-dione 8a as the major
product, which was converted into (–)-γ-lycorane (15).
Key words: asymmetric induction, 5-endo-trig cyclization, (–)-γ-
lycorane, radical cyclization, tributyltin hydride
Great interest has recently been directed towards asym-
metric induction in radical cyclizations induced by chiral
auxiliary control.1 In continuation of our studies on the
asymmetric synthesis of natural products using radical cy-
clization of α-halo amides as the key step,2 we reported
that α-bromo-N-(cyclohex-1-enyl)acetamide 1 bearing an
(S)-1-phenylethyl group on the nitrogen atom, upon treat-
Scheme 2
ment with Bu3SnH in the presence of 2,2'-azobisisobuty-
ronitrile (AIBN) in boiling toluene, underwent 5-endo-
trig radical cyclization to give (3aR,7aR)-octahydroindol-
2-one 2a as the major product.3,4 However, the diastereo-
selectivity for the products 2a and 2b was disappointingly
low (ca. 3:2). Therefore, we turned our attention to the 6-
oxo congener 6, and found that the cyclization of 6 pro-
ceeded with a moderate degree of diastereoselectivity to
give (3aS,7aR)-octahydroindole-2,7-dione 8a as the major
product. The present paper describes the application of
this method to the total synthesis of (–)-γ-lycorane (15).
diastereoselectivity than did 1. The stereochemistry of
8a,b was established by transforming 8a to (–)-γ-lycorane
(15) (vide infra). It is interesting to note that the absolute
configuration of the cis-juncture of the major product 8a
[(3aS,7aR)] is opposite to that of 2a [(3aR,7aR), note,
there is a change of CIP priorities] in spite of using the
same chiral auxiliary. The high combined yield (84%) of
8a,b as compared to 2a,b (58%) may be explained in
terms of the capto-dative stabilizing effect5 of the cyclized
radical intermediates [-N–C•–C=O].
In an attempt to improve the diastereoselectivity in the cy-
clization, we also examined the reaction of 7 bearing a
sterically more demanding 1-(1-naphthyl)ethyl group on
the nitrogen atom. As expected, much higher diastereo-
selectivity was observed for the products 9a and 9b
(3.2:1), but the combined yield was reduced to 42%.
Scheme 1
Some of lycorine-class of Amaryllidaceae alkaloids dis-
play potentially useful biological properties including an-
tiviral activity.6 It is known that (–)-lycorine can be con-
verted into (–)-γ-lycorane (15) through several chemical
transformations.7 Although γ-lycorane does not appear to
possess any useful pharmacological properties, many at-
tempts have been made to synthesize this compound8 be-
cause its pentacyclic structure provides a means to dem-
onstrate the utility of new synthetic methods. However,
only a limited example has so far been reported for the
synthesis of optically active γ-lycorane.9 We envisioned
that the major product 8a obtained from 6 would be con-
verted to optically active γ-lycorane through radical cy-
clization of 13 (Scheme 3).
The radical precursor 6 was prepared by condensation of
cyclohexane-1,2-dione (3) with (–)-(S)-1-phenylethyl-
amine followed by treatment of the resulting enamine 4
with chloroacetyl chloride and then with sodium iodide.
When a boiling solution of 6 in toluene was treated slowly
with a toluene solution of 1.3 equivalents of Bu3SnH con-
taining a catalytic quantity of AIBN, an inseparable mix-
ture of (3aS,7aR)- and (3aR,7aS)-octahydroindole-2,7-di-
ones 8a and 8b was obtained in 84% combined yield.
The 1H NMR spectrum showed the ratio of 8a/8b to be ca.
2:1, indicating that the compound 6 proceeded with higher

SYNTHESIS
Papers
1804
Mps were determined using a Yanaco micromelting point apparatus
and are uncorrected. IR spectra were recorded with a JASCO IR-A-
100 spectrophotometer. 1H (60 and 300 MHz) and 13C NMR
(75.4 MHz) spectra were measured on a JEOL JNM-PMX 60 or a
Varian XL-300 spectrometer for solutions in CDCl3. δ Values quoted
In order to synthesize 13, the regioselective formation of
olefin 11 from 8a was required. Reduction of 8a,b with
NaBH4 gave a mixture of alcohols 10a and 10b in 76%
combined yield, which could be separated by careful
chromatography on silica gel to give pure 10a in 46%
yield. Compound 10a was then treated with Martin
sulfurane dehydrating agent10 {[PhC(CF3)2O]2SPh2}
{bis[α,α-bis(trifluoromethyl)benzenemethanolato]diphe-
nylsulfur} to give 11 in 74% yield.
are relative to TMS (0 ppm) and CDCl3 (77.02 ppm) for 1H and 13
C
NMR, respectively. Optical rotations were measured with a JASCO
DIP-360 polarimeter. Exact mass determinations were obtained with
a JEOL-SX 102A instrument. Column chromatography was per-
formed on silica gel 60 PF254 (Nacalai Tesque) under pressure.
2-Iodo-N-(6-oxocyclohex-1-enyl)-N-[(S)-1-phenylethyl]acet-
amide (6):
2-Chloro-N-(6-oxocyclohex-1-enyl)-N-[(S)-1-phenylethyl]acet-
amide
To a solution of cyclohexane-1,2-dione (1.22 g, 10.9 mmol) in ben-
zene (50 mL) was added (–)-(S)-1-phenylethylamine (1.32 g,
10.88 mmol) and the mixture was heated under reflux for 2 h with
azeotropic removal of the water thus formed. After the solvent had
been evaporated off, the resulting enamine 4 was dissolved in CH2Cl2
(30 mL). Chloroacetyl chloride (1.60 g, 14.1 mmol) was added drop-
wise to the solution at 0°C and the mixture was stirred at r.t. for 15 h.
To the mixture was added sat. NaHCO3 (30 mL) at 0°C and it was
then stirred for 10 min. The organic layer was separated, dried
(MgSO4) and concentrated. The residue was chromatographed (silica
gel, hexane/EtOAc 2:1) to afford 2-chloro-N-(6-oxocyclohex-1-
enyl)-N-[(S)-1-phenylethyl]acetamide (1.69 g, 53%); mp 136–137°C
(hexane/EtOAc).
IR (CCl4): ν = 1740, 1695, 1660 cm–1.
1H NMR (60 MHz): δ = 1.38, 1.58 (both d, total 3H, J = 7.0 Hz,
CHMe), 1.75–2.75 (m, 6H), 3.81 (s, 2H, COCH2Cl), 5.52–6.32 (m,
2H), 7.30 (br s, 5H, ArH).
Anal. Calcd for C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80. Found: C,
65.95; H, 6.22; N, 4.93.
2-Iodo-N-(6-oxocyclohex-1-enyl)-N-[(S)-1-phenylethyl]aceta-
mide (6):
Scheme 3
The chloroacetamide (998 mg, 3.42 mmol) obtained above was dis-
solved in CH3CN (20 mL), and NaI (5.43 g, 36.2 mmol) was added to
the solution which then stirred at r.t. for 5 h. The insoluble material
was filtered off and the filtrate concentrated. The residue was chro-
matographed (silica gel, hexane/EtOAc 2:1) to give 6 (1.20 g, 91%);
mp 150–151°C (hexane/EtOAc).
Deprotection of the N-(1-phenylethyl) group of 11 was
accomplished by treatment with sodium in liquid ammo-
nia to give 12 in 83% yield. Subsequent N-alkylation of
12 with 2-bromo-4,5-(methylenedioxy)benzyl chloride
provided quantitatively the requisite radical precursor
13, which was treated with Bu3SnH and AIBN in boiling
benzene to give lycorane derivative 14 in 52% yield. Fi-
nally, reduction of lactam 14 with LiAlH4 in boiling
THF gave (–)-γ-lycorane (15) in 64% yield, whose spec-
tral properties were virtually identical with those report-
ed for (+)-γ-lycorane.9 Thus, we established the absolute
stereochemistry of the radical cyclization products 8a,b
and accomplished the first total synthesis of (–)-γ-lyc-
orane (15).
IR (CCl4): ν = 1740, 1695 cm–1.
1H NMR (60 MHz): δ = 1.30, 1.53 (both d, total 3H, J = 7.0 Hz,
CHMe), 1.6–2.7 (m, 6H), 3.22 and 3.60 (ABq, 1H each, J = 15.0 Hz,
COCH2I), 5.45–6.25 (m, 2H), 7.1–7.3 (m, 5H, ArH).
Anal. Calcd for C16H18INO2: C, 50.15; H, 4.73; N, 3.65. Found: C,
50.28; H, 4.80; N, 3.42.
2-Iodo-N-[(S)-1-(1-naphthyl)ethyl]-N-(6-oxocyclohex-1-enyl)acet-
amide (7):
2-Chloro-N-[(S)-1-(1-naphthyl)ethyl]-N-(6-oxocyclohex-1-enyl)-
acetamide
According to the procedure described above for the preparation of 6,
the enamine 5 prepared from cyclohexane-1,2-dione (1.42 g,
12.6 mmol) and (–)-(S)-1-(1-naphthyl)ethylamine (2.16 g, 12.6 mmol)
was treated with chloroacetyl chloride (1.85 g, 16.4 mmol) to give 2-
chloro-N-[(S)-1-(1-naphthyl)ethyl]-N-(6-oxocyclohex-1-enyl)aceta-
mide (2.77 g, 64%) as an oil.
In summary, we revealed that the Bu3SnH-mediated 5-
endo-trig radical cyclization of α-iodo-N-(6-oxocyclo-
hex-1-enyl)-N-[(S)-1-phenylethyl]acetamide (6) proceed-
ed with moderate diastereoselectivity and the major prod-
uct 8a served as a useful intermediate for the synthesis of
optically active lycorane alkaloids. Further work on the
refinement of the chiral auxiliaries and an application of
the method to the synthesis of more complex lycorine al-
kaloids is now in progress.
IR (CCl4): ν = 1690, 1665 cm–1.
1H NMR (60 MHz): δ = 1.6–2.6 (m, 6H), 1.50 (d, 3H, J = 7.0 Hz,
CHMe), 3.76 (s, 2H, COCH2Cl), 5.25–5.55 (m, 1H, C=CH), 6.64 (q,
1H, J = 7.0 Hz, CHMe), 7.1–8.3 (m, 7H, ArH).
HRMS: Calcd for C20H20ClNO2, 341.1182; found m/z 341.1186.

SYNTHESIS
December 1998
1805
2-Iodo-N-[(S)-1-(1-naphthyl)ethyl]-N-(6-oxocyclohex-1-enyl)acet-
amide (7):
J = 7.1, 3.8 Hz, 7a-H), 4.00 (br s, 1H, 7-H), 5.49 (q, 1H, J = 7.3 Hz,
CHMe), 7.25–7.46 (m, 5H, ArH).
The chloride (1.06 g, 3.09 mmol) obtained above was treated with NaI
(2.32 g, 15.45 mmol) in a manner similar to that described above for
the preparation of 6. After workup, the crude material was chromato-
graphed (silica gel, hexane/EtOAc 2:1) to give compound 7 (684 mg,
51%); mp 176–177°C (hexane/EtOAc).
Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C,
74.08; H, 8.18; N, 5.55.
10b:
IR (CCl4): ν = 3600, 1690 cm–1.
IR (CCl4): ν = 1690, 1650 cm–1.
1H NMR (300 MHz): δ = 1.11–1.30 (m, 2H), 1.46–1.79 (m, 5H), 1.60
(d, 3H, J = 7.3 Hz, CHMe), 2.14 (dd, 1H, J = 15.0, 8.0 Hz, one of 3-
H2), 2.27–2.48 (m, 1H, 3a-H), 2.59 (dd, 1H, J = 14.9, 13.0 Hz, one of
3-H2), 3.05–3.12 (m, 1H, 7-H), 3.47 (dd, 1H, J = 7.3, 3.7 Hz, 7a-H),
5.71 (q, 1H, J = 7.3 Hz, CHMe), 7.27–7.56 (m, 5H, ArH).
HRMS: Calcd for C16H21NO2, 259.1572; found m/z 259.1570.
1H NMR (60 MHz): δ = 1.6–2.7 (m, 6H), 1.56 (d, 3H, J = 7.0 Hz,
CHMe), 3.28 and 3.70 (ABq, 1H each, J = 10.0 Hz, COCH2I), 5.4–
5.6 (m, 1H, C=CH), 6.76 (q, 1H, J = 7.0 Hz, CHMe), 7.3–8.3 (m, 7H,
ArH).
Anal. Calcd for C20H20INO2: C, 55.44; H, 4.65; N, 3.23. Found: C,
55.56; H, 4.73; N, 3.04.
(3aS,7aR)-1-[(S)-1-Phenylethyl]-2,3,3a,4,5,7a-hexahydroindol-2-
one (11):
(3aS,7aR)- and (3aR,7aS)-1-[(S)-1-Phenylethyl]octahydroindole-
2,7-diones (8a and 8b):
Martin sulfurane (3.2 g, 4.75 mmol) was added to a solution of 10a
(308 mg, 1.19 mmol) in benzene (10 mL) and the mixture was heated
to 50°C for 2 h. Sat. NaHCO3 (10 mL) was added to the mixture and
it was extracted with Et2O. The extract was dried (MgSO4) and con-
centrated, and the residue was chromatographed (silica gel, hexane/
EtOAc 3:1) to give 11 (211 mg, 74%) as an oil.
To a boiling solution of 6 (748 mg, 1.95 mmol) in toluene (200 mL)
was added a solution of Bu3SnH (737 mg, 2.54 mmol) and AIBN
(64 mg, 0.39 mmol) in toluene (40 mL) via a syringe over 4 h, and the
mixture was further heated under reflux for 3 h. After evaporation of
the solvent, Et2O (20 mL) and 8% aq KF (20 mL) were added to the
residue, and the mixture was vigorously stirred at r.t. for 30 min. The
organic layer was separated, dried (MgSO4) and concentrated. The
residue was chromatographed (silica gel, hexane/EtOAc 2:1) to give
a mixture of 8a and 8b (421 mg, 84%) in a ratio of ca. 2:1 as an oil.
IR (CCl4): ν = 1700 cm–1.
IR (CCl4): ν = 1685 cm–1.
1H NMR (300 MHz): δ = 1.52–1.71 (m, 2H), 1.60 (d, 3H, J = 7.2 Hz,
CHMe), 1.82–2.15 (m, 2H), 2.24–2.36 (m, 1H), 2.31 (dd, 1H, J =
17.8, 6.5 Hz, one of 3-H2), 2.45 (dd, 1H, J = 17.8, 10.0 Hz, one of 3-
H2), 3.62–3.68 (m, 1H, 7a-H), 5.53–5.60 (m, 1H), 5.54 (q, 1H, J =
7.2 Hz, CHMe), 5.83–5.90 (m, 1H), 7.27–7.40 (m, 5H, ArH).
HRMS: Calcd for C16H19NO, 241.1467; found m/z 241.1464.
1H NMR (300 MHz): δ = 1.44–2.86 (m, 9H), 1.59 (d, 3H × 2/3, J =
7.2 Hz, CHMe for 8a), 1.70 (d, 3H × 1/3, J = 7.3 Hz, CHMe for 8b),
3.69 (d, 2/3H, J = 8.3 Hz, 7a-H for 8a), 4.02 (d, 1/3H, J = 7.1 Hz, 7a-
H for 8b), 5.22 (q, 1/3H, J = 7.3 Hz, CHMe for 8b), 5.45 (q, 2/3H, J
= 7.2 Hz, CHMe for 8a), 7.15–7.40 (m, 5H, ArH).
(3aS,7aR)-2,3,3a,4,5,7a-Hexahydroindol-2-one (12):
Na (134 mg, 5.83 mmol) and a solution of 11 (281 mg, 1.16 mmol) in
anhyd THF (3 mL) were added successively to liquid NH3 (ca. 3 mL)
at –78°C, and the mixture was stirred at the same temperature for
1.5 h. The reaction was quenched by addition of NH4Cl, and then al-
lowed to warm to r.t. to remove any excess NH3. The salts were fil-
tered off and washed with Et2O. The combined organic layer was con-
centrated and the residue was chromatographed (silica gel, hexane/
EtOAc 1:2) to give 12 (132 mg, 83%); mp 103.5–105°C (hexane/
EtOAc); [α]D22 +173.4 (c = 1.05, EtOH).
HRMS: Calcd for C16H19NO2, 257.1416; found m/z 257.1424.
(3aS,7aR)- and (3aR,7aS)-1-[(S)-1-(1-Naphthyl)ethyl]octahydro-
indole-2,7-diones (9a and 9b):
Following the procedure described above for the preparation of 8a,b,
compound 7 (684 mg, 1.58 mmol) was treated with Bu3SnH (597 mg,
2.05 mmol) and AIBN (52 mg, 0.32 mmol) in toluene, and the crude
material was purified by column chromatography (silica gel, hexane/
EtOAc 2:1) to give a mixture of 9a and 9b (204 mg, 42%) in a ratio
of ca. 3.2:1 as an oil.
IR (CHCl3): ν = 3480, 1690 cm–1.
1H NMR (300 MHz): δ = 1.51–1.76 (m, 2H, 4-H2), 1.92–2.20 (m, 2H,
5-H2), 2.13 (dd, 1H, J = 16.1, 4.6 Hz, one of 3-H2), 2.48 (dd, 1H, J =
15.9, 8.1 Hz, one of 3-H2), 2.50–2.62 (m, 1H, 3a-H), 4.00–4.06 (br,
1H, 7a-H), 5.65–5.72 (m, 1H), 5.91–5.99 (m, 1H), 6.78–7.02 (br, 1H,
NH).
IR (CCl4): ν = 1695 cm–1.
1H NMR (300 MHz): δ = 1.13–1.94 (m, 6H), 1.75 (d, J = 6.9 Hz,
CHMe for 9b), 1.86 (d, J = 7.1 Hz, CHMe for 9a), 2.06–2.38 (m, 2H),
2.50–2.65 (m, 1H), 3.15 (d, J = 8.3 Hz, 7a-H for 9a), 4.04 (d, J =
7.1 Hz, 7a-H for 9b), 6.06 (q, J = 7.3 Hz, CHMe for 9a), 6.19 (q, J =
7.1 Hz, CHMe for 9b), 7.35–7.94 (m, 7H, ArH).
13C NMR (75.4 MHz): δ = 22.3 (CH2), 24.1 (CH2), 33.0 (CH), 36.1
(CH2), 51.5 (CH), 125.2, 130.7, 177.7 (CO).
HRMS: Calcd for C20H21NO2, 307.1572; found m/z 307.1570.
Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N, 10.21. Found: C,
70.01; H, 8.11; N, 10.49.
(3aS,7S,7aR)-7-Hydroxy-1-[(S)-1-phenylethyl]octahydroindol-2-
one (10a) and (3aR,7R,7aS)-7-Hydroxy-1-[(S)-1-phenylethyl]-oc-
tahydroindol-2-one (10b):
(3aS,7aR)-1-[2-Bromo-4,5-(methylenedioxy)benzyl]-
NaBH4 (148 mg, 3.9 mmol) was added slowly to a solution of the
mixture of 8a and 8b (333 mg, 1.3 mmol) and the mixture was stirred
at r.t. overnight. After evaporation of the solvent, brine (10 mL) was
added to the residue and it was extracted with EtOAc. The organic
layer was dried (MgSO4) and concentrated, and the residue was chro-
matographed (silica gel, EtOAc). The first fraction gave 10b (88 mg,
26%) as an oil. The second fraction gave 10a (155 mg, 46%); mp
141–142°C (hexane/EtOAc).
2,3,3a,4,5,7a-hexahydroindol-2-one (13):
To a suspension of NaH (60% mineral oil dispersion) (58 mg,
1.44 mmol) [washed with anhyd pentane (3 × 3 mL) before use] in
anhyd DMF (3 mL) was added dropwise a solution of 12 (132 mg,
0.96 mmol) in anhyd DMF (3 mL) at r.t., and the mixture was stirred
at the same temperature for 30 min. A solution of 2-bromo-4,5-(me-
thylenedioxy)benzyl chloride (240 mg, 0.96 mmol) was added and
the mixture was stirred at r.t. for 30 min. The mixture was poured into
water (10 mL) and extracted with EtOAc. The organic layer was
washed with brine, dried (MgSO4), and concentrated. The residue
was chromatographed (silica gel, hexane/EtOAc 3:2) to give 13 (337
mg, quant.), whose spectral data were identical with those reported
for the corresponding (3aR,7aS) enantiomer.8
10a:
IR (CCl4): ν = 3400, 1670 cm–1.
1H NMR (300 MHz): δ = 1.20–1.96 (m, 7H), 1.68 (d, 3H, J = 7.3 Hz,
CHMe), 2.15 (dd, 1H, J = 14.9, 8.3 Hz, one of 3-H2), 2.21–2.34 (m,
1H, 3a-H), 2.66 (dd, 1H, J = 14.9, 12.7 Hz, one of 3-H2), 3.02 (dd, 1H,
IR (CHCl3): ν = 1675 cm–1.

SYNTHESIS
Zahouily, M.; Journet, M.; Malacria, M. Synlett 1994, 366.
Curran, D. P.; Shen, W.; Zhang, J.; Geib, S. V.; Lin, C.-H.
Heterocycles 1994, 37, 2315.
Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.; Rossetti, M.
Heterocycles 1994, 38, 2663.
Curran, D. P.; Geib, S. J.; Lin, C.-H. Tetrahedron: Asymmetry
1994, 5, 199.
Papers
1806
1H NMR (300 MHz): δ = 1.52–1.78 (m, 2H), 1.93–2.18 (m, 2H), 2.30
(dd, 1H, J = 15.1, 4.6 Hz, one of 3-H2), 2.43–2.54 (m, 1H), 2.56 (dd,
1H, J = 15.1, 8.1 Hz, one of 3-H2), 3.83–3.89 (m, 1H, 7a-H), 4.27 and
4.78 (ABq, 1H each, J = 15.5 Hz, NCH2Ar), 5.70–5.78 (m, 1H), 5.93–
6.01 (m, 1H), 5.97 (s, 2H, OCH2O), 6.76 (s, 1H, ArH), 6.98 (s, 1H,
ArH).
(3aS,11bR,11cR)-9,10-(Methylenedioxy)-1,2,3,3a,4,5,11b,11c-oc-
tahydropyrrolo[3,2,1-de]phenanthridin-5-one (14):
Nishida, M.; Ueyama, E.; Hayashi, H.; Ohtake, Y.; Yamaura,
Y.; Yanaginuma, E.; Yonemitsu, O.; Nishida, A.; Kawahara, N.
J. Am. Chem. Soc. 1994, 116, 6455.
Nishida, M.; Hayashi, H.; Yamaura, Y.; Yanaginuma, E.; Yo-
nemitsu, O.; Nishida, A.; Kawahara, N. Tetrahedron Lett. 1995,
36, 269.
Nishida, M.; Hayashi, H.; Yonemitsu, O.; Nishida, A.; Kawaha-
ra, N. Synlett 1995, 1045.
Nishida, M.; Nobuta, M.; Nakaoka, K.; Nishida, A.; Kawahara,
N. Tetrahedron: Asymmetry 1995, 6, 2657.
Nishida, M.; Hayashi, H.; Nishida, A.; Kawahara, N. J. Chem.
Soc., Chem. Commun. 1996, 579.
Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996, 52,
1069.
Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 3573.
Katsumata, A.; Iwaki, T.; Fukumoto, K.; Ihara, M. Heterocycles
1997, 46, 605.
A solution of Bu3SnH (125 mg, 0.43 mmol) and AIBN (9 mg,
0.05 mmol) in benzene (20 mL) was added to a boiling solution of 13
(100 mg, 0.29 mmol) in benzene (30 mL) over a period of 2 h via a
syringe, and the mixture was further heated under reflux for 1 h. After
workup as described above for the preparation of 8a,b, the crude ma-
terial was chromatographed (silica gel, hexane/EtOAc 3:2) to give 14
(40 mg, 52%), whose spectral data were identical to those reported for
the corresponding (3aR,11bS,11cS) enantiomer.9
IR (CHCl3): ν = 1670 cm–1.
1H NMR (300 MHz): δ = 1.08–1.44 (m, 3H), 1.67–1.82 (m, 3H), 2.09
(d, 1H, J = 16.1 Hz), 2.38–2.47 (m, 1H), 2.58 (dd, 1H, J = 16.1, 6.8
Hz), 2.75 (dt, 1H, J = 12.5, 4.2 Hz), 3.77 (t, 1H, J = 4.6 Hz), 4.32 and
4.54 (ABq, 1H each, J = 17.4 Hz, NCH2Ar), 5.92 (d, 1H, J = 1.4 Hz),
one of OCH2O), 5.94 (d, 1H, J = 1.4 Hz, one of OCH2O), 6.59 (s, 1H,
ArH), 6.62 (s, 1H, ArH).
13C NMR (75.4 MHz): δ = 23.6 (CH2), 27.8 (CH2), 30.3 (CH2), 33.0
(CH), 39.8 (CH2), 40.3 (CH), 42.7 (CH2), 55.7 (CH), 101.0 (CH2),
106.6 (CH), 108.5 (CH), 123.2, 131.6, 146.6, 147.7, 175.7 (CO).
Lee, E.; Jeong, J.-W.; Yu, Y. Tetrahedron Lett. 1997, 38, 7765.
(2) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato, T.;
Ikeda, M. J. Org. Chem. 1995, 60, 1276.
(–)-γ-Lycorane (15):
Ishibashi, H.; Kameoka, C.; Kodama, K.; Ikeda, M. Tetrahe-
dron 1996, 52, 489.
Ishibashi, H.; Kodama, K.; Kameoka, C.; Kawanami, H.; Ikeda,
M. Tetrahedron 1996, 52, 13867.
Ishibashi, H.; Kawanami, H.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 1997, 817.
To a suspension of LiAlH4 (28 mg, 0.74 mmol) in anhyd THF (3 mL)
was added dropwise a solution of 14 (100 mg, 0.23 mmol) in anhyd
THF (4 mL) at 0°C and the mixture was stirred at r.t. for 1.5 h. The
mixture was poured into Et2O and made alkaline with 5% aq NH4OH.
The resulting precipitate was filtered off and the filtrate was washed
with brine, dried (MgSO4) and concentrated. The residue was chro-
matographed (silica gel, CHCl3/MeOH 20:1) to give 15 (24 mg, 64%)
as an oil, whose spectral data were identical with those reported for
(+)-γ-lycorane;9 [α]D22 –14.8 (c = 0.99, EtOH) {Lit.7 [α]D20 –17.1 (c =
0.25, EtOH)}.
Ishibashi, H.; Kameoka, C.; Kodama, K.; Kawanami, H.; Ha-
mada, M.; Ikeda, M. Tetrahedron 1997, 53, 9611.
(3) Ishibashi, H.; Fuke, Y.; Yamashita, T.; Ikeda, M. Tetrahedron:
Asymmetry 1996, 7, 2531.
(4) Absolute configuration of 2a and 2b was deduced from the re-
sults with the N-[(S)-1-(1-naphthyl)ethyl] congener of 1, which
gave the corresponding (3aR,7aR)-octahydroindol-2-one as the
major product.
IR (CHCl3): ν = 2950, 1480 cm–1.
1H NMR (300 MHz): δ = 1.23–1.54 (m, 4H), 1.59–1.81 (m, 3H),
1.95–2.07 (m, 1H), 2.09–2.24 (m, 2H), 2.37 (t, 1H, J = 4.8 Hz, 11c-
H), 2.70–2.78 (m, 1H, 11b-H), 3.21 (d, 1H, J = 14.4 Hz, one of 7-H2),
3.38 (ddd, 1H, J = 9.3, 9.2, 3.8 Hz, one of 5-H2), 4.02 (d, 1H, J = 14.4
Hz, one of 7-H2), 5.88 and 5.89 (ABq, 1H each, J = 1.4 Hz, OCH2O),
6.49 (s, 1H, ArH), 6.61 (s, 1H, ArH).
(5) Viehe, H. G.; Merenyi, R.; Stella, L.; Janousek, Z. Angew.
Chem., Int. Ed. Engl. 1979, 18, 917.
(6) For a review, see: Martin, S. F. In The Alkaloids; Brossi, A. Ed.;
Academic: New York, 1987; Vol. 30, pp 251–376.
(7) Kotera, K. Tetrahedron 1961, 12, 248.
(8) For recent syntheses of racemic γ-lycorane, see:
Bäckvall, J.-E.; Andersson, P. G.; Stone, G. B.; Gogoll, A.
J. Org. Chem. 1991, 56, 2988.
13C NMR (75.4 MHz): δ = 25.2 (CH2), 29.3 (CH2), 30.4 (CH2), 31.7
(CH2), 37.4 (CH), 39.5 (CH), 53.7 (CH2), 57.1 (CH2), 62.9 (CH),
100.7 (CH2), 106.3 (CH), 108.3 (CH), 127.3, 133.2, 145.6, 146.0.
Pearson, W. H.; Schkeryantz, J. M. J. Org. Chem. 1992, 57,
6783.
Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
Banwell, M. G.; Wu, A. W. J. Chem. Soc., Perkin Trans. 1
1994, 2671.
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture of
Japan and Ciba-Geigy Foundation (Japan) for the Promotion of Sci-
ence (H.I.)
Angle, S. R.; Boyce, J. P. Tetrahedron Lett. 1995, 36, 6185.
(9) Synthesis of (+)-γ-lycorane has been reported by Mori and co-
workers. See:
Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.;
Mori, M. J. Org. Chem. 1995, 60, 2016.
(10) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2341.
For a recent example of the use of Martin sulfurane in total syn-
thesis, see:
(1) Porter, N. A.; Lacher, B.; Chang, V. H.-T.; Magnin, D. R. J. Am.
Chem. Soc. 1989, 111, 8309.
Curran, D. P.; Shen, W.; Zhang, J.; Heffner, T. A. J. Am. Chem.
Soc. 1990, 112, 6738.
Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Tetrahedron
Lett. 1990, 31, 2315.
Stack, J. G.; Curran, D. P.; Geib, S. J.; Rebek, J. Jr.; Ballester,
P. J. Am. Chem. Soc. 1992, 114, 7007.
Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. J. Am.
Chem. Soc. 1997, 119, 8438.