A radical approach towards indolizidine 167B

Article abstract of DOI:10.1016/S0040-4039(01)02189-X

The alkaloids (+)- and (-)-indolizidine 167B were synthesized via radical addition of a carbon radical to a chiral acrylamide. Further cyclization in the presence of BBr₃, treatment with 'nickel boride' and stereospecific hydrogenation over palladium/carbon in acetic acid were other key steps in this synthesis.

Full text of DOI:10.1016/S0040-4039(01)02189-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 455–458
A radical approach towards indolizidine 167B
Marta C. Corvo and M. Manuela A. Pereira*
Departamento de Qu´ımica, Centro de Qu´ımica Fina e Biotecnologia, Faculdade de Cieˆncias e Tecnologia,
Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal
Received 24 September 2001; revised 14 November 2001; accepted 16 November 2001
Abstract—The alkaloids (+)- and (−)-indolizidine 167B were synthesized via radical addition of a carbon radical to a chiral
acrylamide. Further cyclization in the presence of BBr3, treatment with ‘nickel boride’ and stereospecific hydrogenation over
palladium/carbon in acetic acid were other key steps in this synthesis. © 2002 Elsevier Science Ltd. All rights reserved.
Indolizidine alkaloids isolated as trace amounts from
the skin of neotropical frogs display a wide range of
biological activity.1 Several asymmetric syntheses
towards these alkaloids have been developed in the last
decade, some of them to obtain the (−)-indolizidine
167B (1) (Fig. 1).2 Despite the studies involving chiral
auxiliaries to control the stereochemistry in radical
reactions,3 there are only a few examples of radical
stereocontrol involved in indolizidine alkaloid
synthesis.2h,4
Low temperature irradiation† of 4 in dichloromethane
yielded the corresponding carbon radical which, in the
presence of an excess of chiral acrylates or acrylamides
(5), prepared by the reaction of an optically pure
alcohol or amine6 with acryloyl chloride, gave rise to
the addition products 6.7 The stereocontrol on the C-4
center was only achieved when an acrylamide was used
(5d–e). Experiments performed with chiral acrylic esters
derived from (1R,2S,5R)-(−)-menthol (5a), [(1S)-endo]-
(−)-borneol (5b) and [(1R)-endo]-(+)-fenchol (5c) pro-
vided a good chiral induction at the C-2 center (32, 24
and 29% d.e., respectively) but lack induction at the
C-4 stereogenic center on the addition product (6a–c).
These addition products (6a–c) yielded 38–58% from 2.
When using (S)-N-(1-phenylethyl)acrylamide (5d), we
obtained the N-(1-phenylethyl)-2-(2-pyridinylsulfanyl)-
4-(1H-pyrrol-1-yl) heptanamide (6d) in 53% yield, with
low chiral induction in the new stereogenic center C-4
close to pyrrole ring (53:47 of S/R ratio) and 32% of
chiral induction at C-2. The herein C-4 configuration
was established by the 13C NMR data and the specific
optical rotation on the latter compound (+)-1,2m since
this stereocenter does not change along the synthetic
pathway. When acetonitrile was used as solvent the
(4R)-6d was the major stereoisomer formed in 16% d.e.
If we use the hindered acrylamide, (S)-N-isopropyl-N-
(1-phenylethyl) acrylamide (5e), a lower yield of addi-
tion product 6e (12%) was achieved and with the bulky
(S)-N-neopentyl-N-(1-phenylethyl)acrylamide (5f) no
addition product was formed (Table 1).
We report herein a new synthesis towards indolizidine
167B where the stereocontrol is achieved by a stereose-
lective addition of a carbon radical onto an optically
pure acrylamide. After the conversion of the a-amino
acid DL-norvaline onto a pyrrole derivative by conden-
sation with tetrahydro-2,5-dimethoxyfuran in acidic
medium, the resulting carboxylic acid (2) was converted
into the corresponding Barton ester (4) by DCC and
N-hydroxy-2-thiopyridone (3) (Scheme 1).5
H
1
N
3
5
1
Figure 1. (−)-Indolizidine 167B (1).
The low yields obtained by the addition of carbon
radicals to acrylamides have previously been reported
Keywords: alkaloids; indolizidines; radicals and radical reactions;
stereocontrol.
† Phillips high pressure mercury vapour lamp with internal reflector,
125 HPR.
* Corresponding author. Fax: 351 21 2948550; e-mail: mmm@
dq.fct.unl.pt
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02189-X

456
M. C. Cor6o, M. M. A. Pereira / Tetrahedron Letters 43 (2002) 455–458
S
1) SOCl2, MeOH
2) DMTHF, NaOAc, AcOH
3) KOH, MeOH
NH2
CO2H
HO
N
N
N
3
C3H7
O
N
S
η = 79%
C3H7
C3H7
CO2H
DCC, CH2Cl2,
0 ºC to r.t.
DL-norvaline
O
4
2
hν
CH2Cl2
-40 ºC
O
R
R =
CH3
η = 0-58 %
(from 2)
a)
5a-f
d)
H
N
O
H3C CH3
5'
2'
b)
c)
CH3
CH3
H3C
e)
f)
NiCl2-NaBH4
EtOH/H2O or
Zn/AcOH
N
N
N
O
C3H7
4
C3H7
R
η = 30-88%
S
2
R
CH3
CH3
O
N
O
H3C
N
O
7b-e
6a-e
Scheme 1.
Table 1. Chemical yields of compounds 6 from 2 and 7
nickel(II) chloride and sodium borohydride (‘nickel
boride’8) in aqueous ethanol solution or by zinc in
acetic acid,5 led to compounds 7b–e. Treatment of 7d
by boron tribromide for 1 week led to the cyclic ketone
97 in poor yield (18%). When the same reaction was
performed in a pure diastereomer of 6d, epimerization
of the carbon center holding the thiopyridyl group was
observed. It seems that the thiopyridyl group favours
the amine elimination during ring closure, which
yielded the desired cyclic ketone 87 in 72%.
(%)
a
b
c
d
e
6a
7
(4R)
(4R)
(4S)
(4S)
21
–
21
–
29
15
25
5
21b
29
15b
15
38c
28
31c
7
6a
7
21b
15b
42c
40c
a Both epimers at C-2 (2S,2R).
b Zn/acetic acid method.
c NiCl2–NaBH4 method.
Removal of the thiopyridyl group by treatment with
‘nickel boride’ and catalytic stereospecific hydrogena-
tion of the resulting ketone 9, over palladium/carbon
(10%) in acetic acid9 yielded 74% of the desired
indolizidine 167B (1) (Scheme 2, Table 2).
by Barton and Liu.8 All of the diastereomeric amide
pairs (6d–e), R and S at C-2 and C-4 were resolved by
TLC. This observation was important because it means
that the addition products 6d–e could be purified by
column chromatography and the diastereomeric pure
samples obtained (Scheme 1). Removal of the thiopy-
ridyl group from 6 yielded 7.7 When the transformation
is performed on the diastereomers (4S)-6d or (4R)-6d,
the N-[(1S)-1-phenylethyl]-4-(1H-pyrrol-1-yl)heptana-
mides, (4S)-7d and (4R)-7d, are obtained, respectively
(Table 2).
The enantiomer of 1 (+)-(5S,8aS)-indolizidine 167B,
[h]D25=+101 (c 0.44, CH2Cl2)10 was achieved from the
pure diastereomer (4S)-6d in 32% yield. A mixture of
6d diastereomers (4S and 4R) yielded the (−)-(5R,8aR)-
indolizidine 167B (1) mixed with the (+) enantiomer.
The specific optical rotation value, [h]2D5=−27.5 (c 0.30,
CH2Cl2),11 agrees with the 4S/4R ratio calculated from
1
the H NMR spectrum.
In summary, we have developed a method for obtaining
indolizidine 167B from racemic norvaline using a
stereoselective addition of a carbon radical onto an
optically pure acrylamide. This strategy involves the use
of a Barton ester as the carbon radical precursor. The
further application of this method to the synthesis of
other indolizidine alkaloids is being pursued (Scheme
2).
Treatment of 6d with boron tribromide yielded the
cyclic ketone 8 with concomitant removal of the chiral
auxiliary (Scheme 2). Albeit this is a known reaction in
ester derivatives9 this is the first example involving the
less reactive amide analogues. The thiopyridyl group
bound to the C-2 center in 6d plays an important role
during ring closure. Its removal by the combination of

M. C. Cor6o, M. M. A. Pereira / Tetrahedron Letters 43 (2002) 455–458
457
1
Table 2. Specific optical rotation and H and 13C NMR spectroscopic data of compounds (4S)-7d, (4R)-7d and (5S)-9
[h]2D5
1H NMR l (400 MHz, CDCl3)
13C NMR l (100 MHz, CDCl3)
7d (4S)
−41.4°a
7.30 (m, 5H, Harom), 6.50 (d, 2H, J=1.6 Hz, H(2%),
H(5%)), 6.10 (d, 2H, J=1.6 Hz, H(3%), H(4%)), 5.55 (brd,
1H, J=7.2 Hz, N-H), 5.09 (quint, 1H, J=7.2 Hz,
171.0, 143.7, 128.5, 127.3, 126.0, 118.8, 107.5, 59.1, 48.5,
38.8, 32.6, 31.9, 21.4, 19.2, 13.5
CH
(m, 1H, H(3)), 1.84 (m, 2H, H(3), H(2)), 1.67 (m, 2H),
1.42 (d, 3H, J=6.8 Hz, CHCH3), 1.12 (m, 2H), 0.82 (t,
3H, J=7.2 Hz, CH2CH3
7.32 (m, 5H, Harom), 6.62 (s, 2H, H
2H, H(3%), H(4%)), 5.54 (d, 1H, J=6.0 Hz, N-H), 5.09
(quint, 1H, J=6.8 Hz, CHCH3), 3.84 (m, 1H, H(4)),
2.18 (m, 1H, H(2)), 1.90 (m, 3H, H(3), H(2)), 1.71 (m,
2H), 1.46 (d, 3H, J=6.8 Hz, CHCH3), 1.16 (m, 2H),
0.85 (t, 3H, J=7.2 Hz, CH2CH3
6 CH3), 3.74 (m, 1H, H(4)), 2.10 (m, 1H, H(2)), 1.98
6
6
)
7d (4R)
9 (5S)
−65.3°b
+13.2°c
6
(2%), H(5%)), 6.13 (s,
171.0, 143.0, 128.5, 127.2, 126.0, 118.8, 107.6, 59.2, 48.6,
38.8, 32.6, 31.8, 21.6, 19.3, 13.6
6
6
6
)
7.02 (dd, 1H, J=4.0, 1.2 Hz, H(3)), 6.92 (m, 1H, H(1)), 187.4, 130.3, 125.1, 114.3, 110.1, 54.4, 38.8, 33.1, 27.5,
6.24 (dd, 1H, J=4.0, 2.4 Hz, H(2)), 4.18 (m, 1H, H(5)), 19.1, 13.7
2.67 (m, 1H, H(7)), 2.52 (m, 1H, H(7)), 2.37 (m, 1H,
H(6)), 2.12 (m, 1H, H(6)), 1.90 (m, 1H, CH
1.76 (m, 1H, CH2CH2CH3), 1.44 (m, 2H, CH2CH2
0.99 (t, 3H, J=7.4 Hz, CH2CH3
6
2CH2CH3),
6
6
CH3),
6
)
a c 8.20, CHCl3.
b c 1.05, CHCl3.
c c 0.63, CHCl3.
7d
BBr3
CH2Cl2
η = 18 %
O
O
NiCl2-NaBH4
EtOH/H2O
BBr3
CH2Cl2
H2(65 psi),
Pd/C 10%, AcOH
1
3
2'
S
8
1
6d
N
N
N
η = 60 %
η = 72 %
η = 74 %
5
5'
8
9
Scheme 2.
Acknowledgements
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8(5H)-indolizinone (8): oil, H NMR (400 MHz, CDCl3)
l: 8.39 (d, 1H, J=4.4 Hz, H(5%)), 7.50 (t, 1H, J=7.6 Hz,
H(3%)), 7.27 (s, 1H, H(3)), 7.09 (m, 1H, H(4%)), 7.02 (d,
1H, J=4.4 Hz, H(2%)), 7.00 (d, 1H, J=5.6 Hz, H(2%)),
6.93 (s, 1H, H(1)), 6.31 (m, 1H, H(2)), 6.28 (m, 1H,
H(2)), 5.15 (dd, 1H, J=9.4, 5.3 Hz, H(5)), 5.06 (dd, 1H,
J=12.3, 4.7 Hz, H(5)), 4.34 (t, 1H, J=4.7 Hz, H(7)), 2.60
(m, 2H, H(6)), 2.65 (m, 2H, H(6)), 2.32 (q, 2H, J=11.6
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6. Guthrie, R. D.; Jaeger, D. A.; Meister, W.; Cram, D. J.
J. Am. Chem. Soc. 1971, 93, 5137–5153.
7. The new compounds gave satisfactory spectral and high
resolution mass data: (1S,2R,5R)-2-isopropyl-5-methylcy-
clohexyl-2-(2-pyridinylsulfanyl)-4-(1H-pyrrol-1-yl)hepta-
noate (6a): MALDI-FTMS HRMS (DHB): m/z:
465.2536 [M+Na+] calcd for C26H38N2O2S 465.2546;
(2R)-4,7,7-trimethylbicyclo[2.2.1]hep-2-yl-2-(2-pyridinyl-
sulfanyl)-4-(1H-pyrrol-1-yl)heptanoate (6b): MALDI-
FTMS HRMS (DHB): m/z: 441.2571 [M+H+] calcd for
Hz, CH
CH2CH2CH3), 1.51 (m, 2H, CH2CH2
J=7.3 Hz, CH2CH3
); 13C NMR (100 MHz, CDCl3) l:
6
2CH2CH3), 1.96 (q, 2H, J=7.6 Hz,
6
6
CH3), 1.02 (t, 3H,
6
183.4, 156.1, 149.3, 125.3, 123.6, 122.9, 122.8, 119.9,
119.7, 116.6, 115.5, 115.4, 110.8, 55.3, 54.1, 48.5, 45.4,
36.8, 36.5, 35.9, 35.1, 19.3, 18.0, 13.9; MALDI-FTMS
HRMS (DHB): m/z: 287.1212 [M+H+] calcd for
C26H36N2O2S
441.2570;
(2S)-1,3,3-trimethylbicyclo-
C16H18N2OS
287.1213;
5-propyl-6,7-dihydro-8(5H)-
[2.2.1]hept-2-yl-2-(2-pyridinylsulfanyl)-4-(1H-pyrrol-1-yl)-
heptanoate (6c): MALDI-FTMS HRMS (DHB): m/z:
441.2579 [M+H+] calcd for C26H36N2O2S 441.2570; N-
((1S)-1-phenylethyl)-2-(2-pyridinylsulfanyl)-4-(1H-pyrrol-
1-yl)heptanamide (6d): MALDI-FTMS HRMS (DHB):
m/z: 430.1942 [M+Na+] calcd for C24H29N3OS 430.1924;
N-isobutyl-N-[(1S)-phenylethyl]-2-(2-pyridinylsulfanyl)-4-
indolizinone (9): MALDI-FTMS HRMS (DHB): m/z:
178.1220 [M+H+] calcd for C11H15NO 178.1226.
8. Barton, D. H. R.; Liu, W. Tetrahedron 1997, 53, 12067–
12088.
9. Jefford, C. W.; Thornton, S. R.; Sienkiewicz, K. Tetra-
hedron Lett. 1994, 35, 3905–3908.
10. Takahata, H.; Bandoh, H.; Momose, T. Heterocycles
1995, 41, 1797–1804.
11. Previously described values for (−)-(5R,8aR)-indolizidine
167B (1): [h]2D0=−106.9 (c 1.10, CH2Cl2)2c and references
cited therein.
(1H-pyrrol-1-yl)heptanamide
(6e):
MALDI-FTMS
HRMS (DHB): m/z: 486.2570 [M+Na+] calcd for
C28H37N3OS 486.2550; N-[(1S)-1-phenylethyl]-4-(1H-
pyrrol-1-yl)heptanamide (7d): MALDI-FTMS HRMS
(DHB): m/z: 299.2104 [M+H+] calcd for C19H26N2O