Samarium Diiodide-Promoted Cyclization of N-(ω-Iodoalkyl)imides to Polyhydroxylated Indolizidinones and Pyrrolizidinones: Synthesis of (+)-Lentiginosine

Full text of DOI:10.1021/jo9913762

J . Org. Chem. 2000, 65, 621-623
621
Sch em e 1
Sa m a r iu m Diiod id e-P r om oted Cycliza tion
of N-(ω-Iod oa lk yl)im id es to
P olyh yd r oxyla ted In d olizid in on es a n d
P yr r olizid in on es: Syn th esis of
(+)-Len tigin osin e
Deok-Chan Ha,* Chang-Soo Yun, and Yeonbae Lee
Department of Chemistry, Korea University,
5-1-2 Anam-dong, Seoul 136-701, Korea
Received August 31, 1999
Nitrogen-fused bicyclic alkaloids, having pyrrolizidine
(1), indolizidine (2), and quinolizidine (3) ring systems,
have been the targets of many synthetic efforts due to
their interesting and potent biological activities including
antiviral, antitumor, and glucosidase inhibitions.1 Many
synthetic methodologies have been developed for the
efficient construction of these bicyclic structures, includ-
ing acyliminium ion and R-acylamino radical cyclizations
from 2-pyrrolidinone intermediates.2,3 Recently, Heck-
type cyclization of iodovinyl-substituted cyclic enamides
and titanium-mediated cyclization of ω-vinyl imides were
also reported.4 In this paper, we would like to add a new
cyclization method, SmI2-mediated cyclization of N-ω-
iodoalkyl cyclic imides, to the synthetic arsenal for these
alkaloids.
Sch em e 2
proved the efficacy of these SmI2-promoted reactions.7 In
our previous study, we reported our preliminary results
on SmI2-promoted cyclization of N-(iodoalkyl)-substituted
cyclic imides of the type 4 to construct pyrrolizidinone,
indolizidinone, and quinolizidinone ring systems of type
5 and 6 (Scheme 1).8
The N-ω-iodoalkyl cyclic imides 9a -d for the reductive
cyclization were prepared from the imide 7a derived from
L-tartaric acid and the imide 7b from L-malic acid
(Scheme 2).9,10 Oxidative removal of the 4-methoxybenzyl
group from 7a followed by the introduction of the io-
doalkyl groups provided 9a and 9b. Also, imide 7b was
converted to 9c and 9d after the silylation and N-
iodoalkylation.
Thus, N-(3-iodopropyl) and N-(4-iodobutyl)imide de-
rivatives 9a -d were subjected under the SmI2-promoted
reductive cyclization conditions in the presence of cata-
lytic amounts of tris(dibenzoylmethido)iron(III)[Fe(DBM)3]
in THF (Table 1). Imide 9a provided pyrrolizidinone 10a
as a single isomer in 77% yield. The stereochemistry of
Samarium diiodide has been extensively used in the
reduction of aldehydes and ketones designed to undergo
elimination, cyclization, and coupling reactions.5,6 More
recent studies about intramolecular acyl substitution
reactions of halo-substituted esters and lactones further
* To whom correspondence should be addressed. Phone: 82-2-3290-
3131. Fax: 82-2-3290-3121 E-mail: dechha@kuccnx.korea.ac.kr.
(1) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988, 27, 1465-
1487. Robins, D. J . Nat. Prod. Rep. 1995, 12, 413-418. Liddell, J . R.
Nat. Prod. Rep. 1996, 13, 187-194. Michael, J . P. Nat. Prod. Rep. 1997,
14, 619-636.
(2) Himstra, H.; Speckamp. W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: London, 1991; Vol. 2, pp 1047-
1082.
(3) Hart, D. J .; Choi, J .-K.; Burnett. D. A.; Tsai, Y.-M. J . Am. Chem.
Soc. 1984, 106, 8201-8209.
(4) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Org. Chem.
1995, 60, 398-404. Lee, J .; Ha, J . D.; Cha, J . K. J . Am. Chem. Soc.
1997, 119, 8127-8128.
(5) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693-2698. Molander, G. A. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon: London, 1991; Vol. 1, pp 251-282.
Molander, G. A. Chem. Rev. 1992, 92, 29-68. Imamoto, T. In Lan-
thanides in Organic Synthsis; Academic Press: London, 1994; Chapter
4, pp 21-65. Curran, D. P.; Fevig, T. L.; J asperse, C. P.; Totleben, M.
J . Synlett 1992, 943-961. Skrydstrup, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 345-347. Molander, G. A. Acc. Chem. Res. 1998, 31, 603-
609.
(6) Inanaga, J .; Ujikawa, O.; Yamaguchi, M. Tetrahedron Lett. 1991,
32, 1737-1740. Molander, G. A.; McKie, J . A. J . Org. Chem. 1992, 57,
3132-3139. Curran, D. P.; Totleben, M. J . J . Am. Chem. Soc. 1992,
114, 6050-6058. Enholm, E. J .; Trivellas, A. Tetrahedron Lett. 1994,
35, 1627-1628. Enholm, E. J .; Schreier, J . A. J . Org. Chem. 1995, 60,
1110-1111. Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-
338.
(7) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216-
7227. Molander, G. A.; Shakya, S. R. J . Org. Chem. 1994, 59, 3445-
3452.
(8) Ha, D.-C.; Yun, C.-S.; Yu, E. Tetrahedron Lett. 1996, 37, 2577-
2580. Ha, D.-C.; Yun, C.-S. Bull. Kor. Chem. Soc. 1997, 18, 1039-
1041.
(9) Yoda, H.; Shirakawa, K.; Takabe, K. Chem. Lett. 1991, 489-
490. Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett. 1991, 32,
3401-3404. Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetra-
hedron: Asymmetry 1993, 4, 1455-1456.
(10) Chamberlin, A. R.; Chung, J . Y. L. J . Am. Chem. Soc. 1983,
105, 3653-3656.
10.1021/jo9913762 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/31/1999

622 J . Org. Chem., Vol. 65, No. 2, 2000
Notes
Ta ble 1. Sm I2-P r om oted Cycliza tion s of
Sch em e 3
N-(ω-Iod oa lk yl)su ccin im id es
Sch em e 4
nosine (16). The spectroscopic data of 16 were compared
and found to be identical with those reported.12 Dihy-
droxylation of enamide 10b with cat. OsO4-NMO pro-
vided 17 as an inseparable epimeric mixture (Scheme 4),
and the other two possible stereoisomers were not
observed. Attempt to reduce 17 with CF3CO2H/Et3SiH
resulted in an unidentifiable complex mixture. But
reduction of the crude 17 with LAH in THF heated at
reflux directly provided the desilylated 1,2,8-trihydroxy-
indolizidinones 18 and 19 with 30% and 9% overall
yields, respectively, from 10b. The stereochemistry of
C(8) and C(8a) 18 and 19 were assigned based on the
results of the NOE experiments.
In summary, we have shown that SmI2-promoted
reductive cyclization of N-(ω-iodoalkyl) cyclic imide pro-
vides an expedient approach to pyrrolizidine and indolizi-
dine ring systems. The synthesis of polyhydroxylated
indolizidines and pyrrolizidines, including (+)-lentigi-
nosine, from readily available imides demonstrate the
synthetic utility of this approach for diverse nitrogen-
fused bicyclic alkaloids and their analogues.
the hydroxy group at the ring junction of 10a was
tentatively assigned, and the assignment was based on
the results of the NOE study of the reduction product
from 10a (vide infra). The 4-iodobutyl derivative 9b was
cyclized to the corresponding hydroxy indolizidinone
which was slowly dehydrated to enamide 10b during the
purification by SiO2 chromatography.8 Thus, for the best
result, the crude cyclization product from 9b was directly
subjected to the dehydration conditions (4 Å powdered
molecular sieves, cat. p-TsOH, CH2Cl2), and the enamide
10b was isolated in 82% yield. Imide 9c gave a 1:4
mixture of 10c and 10d in 54% yield, while cyclization
and dehydration of the 4-iodobutyl derivative 9d gave
75% of 10e and 10% of 10f. The stereochemistry of 10c
and 10d was not confirmed and tentatively assigned. The
regioselectivities in the cyclizations of 9c and 9d were
quite contrasting. The selectivity of 10e over 10f can be
easily understood in terms of the well-known antiperi-
planar electronic effect of an R-substituent of the imide
carbonyl group.11 The reason for the reversed selectivity
in the cyclization of 9c is not clear at this stage, but the
increased angle strain during the second five-membered
ring formation together with the probable steric effect
by Sm(III) Lewis acid chelated to the imide carbonyl may
play a significant role in the reversed regioselectivity.
Hydroxylactam 10a was easily converted to 1,2-dihy-
droxypyrrolizidine 13 through the stereoselective reduc-
tion to 11 with Et3SiH/CF3COOH and desilylation in
methanolic hydrochloride followed by LAH reduction
(Scheme 3).
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents obtained from commercial
sources were used as received, and solvents were dried prior to
use. All reactions, unless otherwise noted, were performed in
flame-dried glassware under an atmosphere of dry argon.
Column chromatography was performed on silica gel. Melting
points are uncorrected. 1H NMR spectra were recorded at 300
MHz and 13C NMR at 75 MHz. Infrared spectra were recorded
in the FT mode. Data for high-resolution mass spectra and
elemental analyses were obtained from Organic Chemistry
Research Center, Sogang University at Seoul, Korea.
(3R,4R)-3,4-Bis[(ter t-bu tyld im eth ylsilyl)oxy]-2,5-p yr r o-
lid in d ion e (8a ). To a solution of 7a (6.30 g, 13.2 mmol) in 126
mL of acetonitrile cooled at 0 °C was added ceric ammonium
nitrate (28.9 g, 52.8 mmol) in 63 mL of water in several portions
over 20 min. The mixture was stirred at 0 °C for 5 h, diluted
with 200 mL of water, and extracted three times with 200-mL
portions of EtOAc. The organic extracts were washed with
The same approach was also applied to 10b to provide
the least hydroxylated indolizidine alkaloid, (+)-lentigi-
(11) Kayser, M. M.; Wipff, G. Can. J . Chem. 1982, 60, 1192-1198.
Kayser, M. M.; Salvador, J .; Morand, P.; Krishnamurty, H. G. Can. J .
Chem. 1982, 60, 1199-1206. Kayser, M. M.; Salvador, J . Morand, P.
Can. J . Chem. 1983, 61, 439-441. Vijin, R. J .; Hiemstra, H.; Kok, J .
J .; Knotter, M.; Speckamp, W. N. Tetrahedron 1987, 43, 5019-5030.
(12) Pastuszak, I.; Molyneux, R. J .; J ames, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886-1891. Cordero, F. M.; Cicchi, S.; Goti,
A.; Brandi, A. Tetrahedron Lett. 1994, 35, 949-952.

Notes
J . Org. Chem., Vol. 65, No. 2, 2000 623
saturated aqueous NaHCO3, dried (MgSO4), and concentrated
under reduced pressure. Purification of the residue by chroma-
tography on silica gel (1:8, EtOAc/hexanes) gave 8a (2.79 g, 59%)
as a colorless oil. Rf ) 0.31 (1:6, EtOAc/hexanes); [R]21D +134.7°
(c 1.14, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1 H), 4.52
(s, 2H), 0.84 (s, 18H), 0.22 (s, 6H), 0.17 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 173.5, 77.4, 25.6, 18.2, -4.5, -5.1; IR (CH2Cl2,
cm-1) 1750, 1468, 1323, 1252; MS (EI) m/z (relative intensity)
302 (M+ - 57, 26.3). Anal. Calcd for C16H33NO4Si2: C, 53.44; H,
9.25; N, 3.89. Found: C, 53.44; H, 9.47; N, 3.75.
EtOAc/hexanes) gave 14 (395 mg, 93%) as a colorless oil. Rf )
0.41 (1:6, EtOAc/hexanes); [R]20D +47.7° (c 1.75, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.15 (d, J ) 6 Hz, 1H), 4.07 (s, 1H), 3.81 (t,
J ) 6 Hz, 1H), 3.0-3.07 (m, 1H), 2.59 (m, 1H), 2.02-2.06 (m,
1H), 1.88 (m, 1H), 1.71 (m, 1H), 1.37 (m, 2H), 1.16 (m, 1H), 0.94
(s, 9H), 0.90 (s, 9H), 0.09-0.22 (m, 12H); 13C NMR (75 MHz,
CDCl3) δ 169.9, 80.7, 78.0, 59.4, 39.3, 30.4, 25.8, 25.6, 23.9, 23.2,
18.1, 17.7; IR (CH2Cl2, cm-1) 2909, 1714, 1419, 1253, 1137; MS
(EI) m/z (relative intensity) 342 (M+-57, 100). Anal. Calcd for
C20H41NO3Si2: C, 60.09; H, 10.34; N, 3.50. Found: C, 60.04; H,
10.46; N, 3.61.
(3R,4R)-3,4-Bis[(ter t-bu tyld im eth ylsilyl)oxy]-N-(4-iod o-
bu tyl)-2,5-p yr r olid in d ion e (9b). To a mixture of 8a (0.92 g,
2.56 mmol), potassium carbonate (3.54 g, 25.6 mmol), and tetra-
n-butylammonium bromide (0.25 g, 0.77 mmol) in 30 mL of
acetone was added 1,4-diiodobutane (0.68 mL, 5.12 mmol) at
room temperature. The reaction mixture was stirred at room
temperature for 18 h, diluted with 150 mL of distilled water,
and extracted twice with 150-mL portions of CH2Cl2. The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. Purification of the residue by chroma-
tography on silica gel (1:1, CH2Cl2/hexanes) gave 9b (1.18 g, 85%)
(1S,2R,8a S)-1,2-Dih yd r oxy-3-in d olizid in on e (15). A solu-
tion of 14 (220 mg, 0.55 mmol) in 5 mL of 10% methanolic HCl
was stirred for 3 h at room temperature. The reaction mixture
was quenched by NH3 solution, filtered over a Celite pad, and
concentrated under reduced pressure. Purification of the residue
by chromatography on silica gel (8:1, CH2Cl2/MeOH) to give 15
(81 mg, 86%) as a white solid: Rf ) 0.38 (8:1, CH2Cl2/MeOH);
mp 136-137 °C; [R]21 +52.3° (c 1.99, MeOH); 1H NMR (300
D
MHz, CD3OD) δ 3.79-3.93 (m, 2H), 3.48 (t, J ) 7 Hz, 1H), 2.90
(m, 1H), 2.47 (m, 1H), 1.92 (m, 1H), 1.67 (m, 1H), 1.52 (m, 1H),
1.11-1.13 (m, 2H), 0.94-1.08 (m, 1H); 13C NMR (75 MHz, CD3-
as a colorless oil. Rf ) 0.55 (1:6, EtOAc/hexanes); [R]21 +90.6°
D
(c 2.32, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.45 (s, 2H), 3.47
(m, 2H), 3.17 (t, J ) 7 Hz, 2H), 1.70-1.79 (m, 4H), 0.93 (s, 18H),
0.21 (s, 6H), 0.16 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 173.1,
76.7, 37.3, 30.4, 28.4, 25.6, 18.1, 5.2, -4.5, -5.1; IR (CH2Cl2,
cm-1) 1723, 1467, 1362, 1252, 1135; MS (EI) m/z (relative
intensity) 484 (M+ - 57, 100). Anal. Calcd for C20H40NO4Si2I: C,
44.35; H, 7.44; N, 2.59. Found: C, 44.34; H, 7.71; N, 2.62.
(1S,2R)-1,2-Bis[(ter t-bu tyldim eth ylsilyl)oxy]pyr r olizidin -
8-en e-3-on e (10b). To a solution of SmI2 (9.36 mmol) in 63 mL
of THF cooled at 0 °C was added 65 mg (0.09 mmol) of Fe(DBM)3
in 10 mL of THF via cannula followed by stirring for 2 h at 0
°C. A solution of imide 7b (1.69 g, 3.12 mmol) in 10 mL of THF
was added via cannula, and the resulting mixture was stirred
for 2 h at 0 °C. The mixture was quenched by Ruchelle’s salt
and extracted three times with 50-mL portions of EtOAc. The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The solid residue was dissolved in 20
mL of CH2Cl2, and 4 Å powered molecular sieves (1.2 g) and
p-TsOH (60 mg, 0.31 mmol) were added. The mixture was stirred
for 3 h at room temperature and filtered over Celite, and the
filtrate was concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (1:8, EtOAc/
hexanes) gave 10b (970 mg, 78%) as a colorless oil. Rf ) 0.50
OD) δ 172.8, 80.8, 77.4, 60.3, 40.6, 31.6, 25.2, 24.0; IR (KBr, cm-1
)
1683, 1451, 1370, 1280; MS (EI) m/z (relative intensity) 171 (M+,
13.4). Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18.
Found: C, 56.15; H, 7.64; N, 8.06; HRMS calcd for C8H13NO3
(M+) 171.0895, found 171.0897.
(1S,2S,8a S)-1,2-Dih yd r oxyin d olizid in e [16, (+)-Len tigi-
n osin e]. To a solution of 15 (70 mg, 0.41 mmol) in 5 mL of THF
was added LiAlH4 (62 mg, 1.64 mmol), and the mixture was
heated at reflux for 4 h. Under ice cooling, the mixture was
quenched by careful addition of distilled water (0.5 mL) and 1
N NaOH (0.5 mL). The resulting mixture was filtered over Celite
pad and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (41:8:1, CH2Cl2/MeOH/
NH3) to give 16 (53 mg, 83%) as a white solid: Rf ) 0.33 (41:
8:1, CH2Cl2/MeOH/NH3); mp 106 °C; [R]20D +3.0° (c 0.70, MeOH);
1H NMR (300 MHz, CD3OD) δ 3.95 (m, 1H), 3.60 (dd, J ) 9, 3
Hz, 1H), 2.96 (d, J ) 11 Hz, 1H), 2.86 (d, J ) 11 Hz, 1H), 2.54
(dd, J ) 11, 7 Hz, 1H), 2.00 (m, 2H), 1.83 (m, 2H), 1.61 (m, 2H),
1.30 (m, 2H); 1H NMR (300 MHz, D2O) δ 4.01 (m, 1H), 3.59 (dd,
J ) 9, 3 Hz, 1H), 2.89 (d, J ) 11 Hz, 1H), 2.77 (d, J ) 11 Hz,
1H), 2.58 (dd, J ) 11, 7 Hz, 1H), 2.00 (m, 1H), 1.90 (m, 2H),
1.74 (m, 1H), 1.56 (m, 1H), 1.42 (m, 1H), 1.19 (m, 2H); 13C NMR
(75 MHz, CD3OD) δ 85.0, 77.5, 71.0, 62.8, 54.4, 29.3, 25.7, 24.9;
13C NMR (75 MHz, D2O) δ 86.0, 78.7, 71.6, 63.3, 55.7, 30.7, 27.1,
26.2; IR (KBr, cm-1) 3402, 2817; MS (CI, CH4) m/z (relative
intensity) 158 [(M + H)+, 100]. Anal. Calcd for C8H15NO2: C,
61.12; H, 9.62; N, 8.91. Found: C, 61.48; H, 9.43; N, 8.43; HRMS
calcd for C8H15NO2 (M+) 157.1103, found 157.1101.
(1:6, EtOAc/hexanes); [R]24 +111.1° (c 6.02, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 4.75 (m, 1H), 4.43 (m, 1H), 4.11 (d, J ) 6
Hz, 1H), 3.60 (m, 1H), 3.04 (m, 1H), 1.99 (m, 1H), 1.57-1.67 (m,
2H), 0.78 (s, 18H), 0.06 (s, 12H); 13C NMR (75 MHz, CDCl3) δ
169.5, 137.6, 98.8, 77.9, 75.9, 38.2, 25.8, 25.7, 21.3, 20.4, 18.2,
17.9, -4.2, -4.3, -4.6, -4.7; IR (CH2Cl2, cm-1) 2911, 1710, 1467,
1382, 1251; MS (EI) m/z (relative intensity) 397 (M+, 0.01), 340
(M+ - 57, 51.2). Anal. Calcd for C20H39NO3Si2: C, 60.40; H, 9.88;
N, 3.52. Found: C, 60.49; H, 10.07; N, 3.35.
Ack n ow led gm en t. This work was financially sup-
ported by the Korea Research Foundation through the
Basic Science Research Institute Program (BSRI-98-
3406).
(1S,2R,8a S)-1,2-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-3-in -
d olizid in on e (14). To a solution of 10b (420 mg, 1.06 mmol) in
5 mL of CH2Cl2 were added trifluoroacetic acid (0.15 mL, 1.94
mmol) and triethylsilane (0.50 mL, 3.13 mmol). The reaction
mixture was stirred for 3 h at room temperature, diluted with
100 mL of saturated aqueous NaHCO3, and extracted twice with
100-mL portions of CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. Puri-
fication of the residue by chromatography on silica gel (1:7,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data for 8b, 9a , 9c,
9d , 10a , 10c-f, 11-13, 18, 19, and NOE-difference of 11, 18,
and 19. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9913762