A concise synthetic pathway towards 5-substituted indolizidines

Article abstract of DOI:10.1016/j.tetlet.2006.12.074

The total synthesis of 5-(2′-hydroxyethyl)indolizidine via 5-thioindolizidinone is described. The key step is the transformation of 5-thioindolizidinone via Eschenmoser's sulfide contraction. The racemic mixture of 5R,9R- and 5S,9S-5-(2′-hydroxyethyl)indolizidine was obtained in seven steps in 17% overall yield from 2-allyl cyclopentanone.

Full text of DOI:10.1016/j.tetlet.2006.12.074

Tetrahedron Letters 48 (2007) 1159–1161
A concise synthetic pathway towards 5-substituted indolizidines
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´
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Tamas R. Varga, Peter Nemes, Zoltan Mucsi and Pal Scheiber
Department of Chemistry, Faculty of Veterinary Science, Szent Istva´n University, H-1400 Budapest, PO Box 2, Hungary
Received 20 October 2006; revised 5 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—The total synthesis of 5-(20-hydroxyethyl)indolizidine via 5-thioindolizidinone is described. The key step is the transfor-
mation of 5-thioindolizidinone via Eschenmoser’s sulfide contraction. The racemic mixture of 5R,9R- and 5S,9S-5-(20-hydroxy-
ethyl)indolizidine was obtained in seven steps in 17% overall yield from 2-allyl cyclopentanone.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1-Azabicyclo[4.3.0]nonane (indolizidine) represents the
core of a number of natural products, isolated from
both plant and animal sources.1 A recent review reports
more than eight hundred compounds of this type that
have been detected in the skin of neotropical poison
frogs (family Dendrobatidae).2 Due to their extremely
low abundance and strong biological activity, including
neuromodulation, enzyme inhibition and antitumor,
immunoregulatory and antiviral activity, the simple frog
alkylindolizidines are especially attractive targets.3,4
ever, the resulting enamino ketone 6 proved unstable.
Therefore, it was treated with perchloric acid (Caution!)
to yield the stable iminium salt 7, which was subjected to
Clemmensen reduction.12 After chromatographic sepa-
ration, the products were identified from their mass
spectra. The major components were the deoxygenated
iminium hydroxide base and the saturated aminoketone,
while ( ) 5-n-propylindolizidine (8) was formed in a low
yield (10%). The attempted reduction of tosylhydrazone
of 6 or 7 with Na[BH3CN] proved unsuccessful.13
We have developed a novel, efficient and concise syn-
thetic strategy to prepare 5-substituted indolizidines of
a natural origin (e.g., 167B toxin) or new synthetic prod-
ucts with diverse functionalities on the C-5 side chain
(7–11).
The more stable enamino ester 9 was prepared from 5
with ethyl bromoacetate in a moderate yield. The E
and Z isomers of 9 were characterized by NMR, and
isomer E:Z ratio was found to be 1:3.14 The catalytic
hydrogenation of 9 resulted in b-amino acid ester 10,
quantitatively,15 which was further reduced smoothly
with LiAlH4 to the desired b-amino alcohol 11.16
The synthesis of the key intermediate 5 started from
cyclopentanone (1) (Scheme 1). Stork’s enamine proto-
col5 was employed to prepare 2-allylcyclopentanone
(2), which was then converted to 2-(30-bromopro-
pyl)cyclopentanone (3a) via radical, anti-Markovnikov
addition of gaseous HBr.6,7 After bromide–azide
exchange, 2-(30-azidopropyl)cyclopentanone (3b) gave
5-indolizidinone 4 via a Schmidt-reaction.8 Using
Lawesson’s reagent,9 lactam 4 was transformed into
novel 5-thioindolizidinone 5 in an excellent yield.10 To
attach C-5 side chain 5 was reacted with bromoacetone
via Eschenmoser’s sulfide contraction sequence.11 How-
The 1H and 13C NMR spectra revealed that hydrogena-
tion of 9 took place with a high diastereoselectivity. The
strong Bohlmann bands at 2790 and 2710 cmꢀ1 in the
infrared spectrum and the absence of an interaction be-
tween 5-H/9-H in the selective 1D- and 2D-NOSEY of
10 indicated the axial position of the 20-hydroxyethyl
group on C-5 and consequently 5R,9R- and 5S,9S-con-
1
figurations. A second series of signals in the H NMR
spectrum of 10 was assigned to the minor diastereomer,
whose yield was 2.3%, as determined by GC–MS.
The overall yield for 11 starting from 2 (seven steps) is
17%. Amino alcohol 11 can also be transformed to 8
from the tosylate of 11 with (CH3)2LiCu, according to
the published procedure.17
Keywords: Eschenmoser’s sulfide contraction; 5-Thioindolizidinone;
5-Substituted indolizidines; 2-Allyl cyclopentanone.
*
Corresponding author. Tel.: +36 1 478 4176; fax: +36 1 478 4268;
e-mail: varga.tamas.robert@aotk.szie.hu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.074

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T. R. Varga et al. / Tetrahedron Letters 48 (2007) 1159–1161
O
O
(v)
(iii)-(iv)
O
(i)-(ii)
(vi)
N
Y
4 Y = O
5 Y = S
X
2
CH2
1
3a X = Br
3b X = N3
(vii)
N+
(ix)
(viii)
N
N
-
ClO4
H3C
H3C
H3C
6
7
8
O
O
H
N
H
8
1
3
7
6
9
2
(xii)
(xi)
N
(x)
N
5
4
5
O
O
1'
HO
10
9
11
2'
O
O
CH3
CH3
Scheme 1. Reagents, conditions and yields: (i) morpholine, cat. HCO2H, toluene, reflux, 4 h, 50%; (ii) H2C@CHCH2Br, CH3CN, reflux, 18 h, H2O,
reflux, 1 h, 29%; (iii) HBr gas, cat. (PhCO)2O2, n-pentane, rt, 1 h; (iv) NaN3, DMF, 35 ꢁC, 48 h; (v) TFA, rt, 1 h, 36% for (iii)–(v); (vi) Lawesson’s
reagent, THF, rt, 0.5 h, 95%; (vii) BrCH2COCH3, CH3CN, rt, 18 h, Ph3P, i-Pr2NEt, rt, 18 h, 43%; (viii) HClO4 aq, i-PrOH/CH2Cl2, rt, 5 h, 46%; (ix)
Zn(Hg), HCl aq, reflux, 18 h, 10%; (x) BrCH2CO2C2H5, CH3CN, rt, 18 h, Ph3P, i-Pr2NEt, CH3CN, rt, 18 h, 55%; (xi) H2, 1 MPa, cat. PtO2, EtOH,
rt, 3 h, quant.; (xii) LiAlH4, Et2O, rt, 0.5 h, 90%.
8. Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113,
8965–8966.
In conclusion, we have achieved a simple diastereoselec-
tive synthesis of 5-substituted indolizidines. The trans-
formations of esters 9 and 10 provide an opportunity
to prepare further new derivatives.
9. Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.;
Lawesson, S. O. Tetrahedron 1984, 40, 2047–2052.
10. Data for 5: white crystals; mp 55–56 ꢁC; mmax/cmꢀ1 2938
(C–H), 1520 (C–N), 1109 (C@S); dH (250 MHz, CDCl3;
Me4Si) 3.85 (2H, m, 3-H2), 3.34 (1H, m, 9-H), 2.85 (2H, m,
6-H2), 1.20–2.25 (8H, br, 1-H2, 2-H2, 7-H2, 8-H2); dC
(63 MHz, CDCl3; Me4Si) 196.12 (C-5), 62.43 (C-9), 53.23
(C-3), 40.38 (C-8), 33.66 (C-6), 29.59 (C-1), 21.92 (C-7),
21.06 (C-2).
Acknowledgements
´
The research Grant NKB/2006 from Szent Istvan
University is greatly acknowledged. The authors are
´
indebted to Ms. Sarolta Gaal for her technical help in
11. Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. Helv.
Chim. Acta 1971, 54, 710–734.
the synthesis.
12. The preparation of solid 6ÆHCl and 6ÆHBr failed due to the
low basicity of 6. Organic perchlorates are explosives,
therefore one should handle them with great care! Data for
7: pale yellow crystals; dH (400 MHz, CD3NO2; Me4Si)
1.95 (2H, s, CH2CO), 1.91 (1H, m, 3a-H), 1.70–1.78 (2H,
m, 3b-H, 1-H), 0.77 (1H, m, 6a-H), 0.66 (1H, m, 6b-H),
0.22–0.33 (2H, m, 7a-H, 2a-H), 0.16 (3H, s, CH3), ꢀ0.38 to
0.05 (5H, m, 2-H2, 8-H2, 2b-H), ꢀ0.62 (1H, m, 7b-H); dC
(100 MHz, CD3NO2; Me4Si) 201.58 (CO), 183.75 (C-5),
66.90 (C-9), 54.87 (C-3), 51.08 (CH2CO), 34.16 (C-6), 32.08
(C-2), 30.63 (CH3), 26.69 (C-7), 22.31 (C-1), 18.45 (C-8).
13. Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am.
Chem. Soc. 1973, 95, 3662–3668.
References and notes
1. Gilchrist, T. L. Heterocyclic Chemistry; Addison Wesley
Longman: UK, 1997; pp 193–207.
2. Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod.
2005, 68, 1556–1575.
3. Robinson, R. S.; Dovey, M. C.; Gravestock, D. Eur. J.
Org. Chem. 2005, 505–511.
4. Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 398–404.
5. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovic,
J.; Terrel, R. J. Am. Chem. Soc. 1963, 207–222.
6. House, O. H.; Chu, C.; Phillips, W. V.; Sayer, T. S. B.;
Yau, C. J. Org. Chem. 1977, 42, 1709–1717.
7. Crandall, J. K.; Magaha, H. S.; Henderson, M. A.;
Widener, R. K.; Tharp, G. A. J. Org. Chem. 1982, 47,
5372–5380.
14. Data for 9: pale yellow oil; m/z (ESI, HPLC–MS) 210.2
(8.9 · 105, M+H+).
dH (400 MHz, CDCl3; Me4Si) for the Z-isomer (minor)
4.37 (1H, br, C@CHCO2Et), 4.17 (2H, q, J1 = 7.5 Hz,
CO2CH2), 3.20 (3H, m, 3-H2, 9-H), 2.87 (2H, tt,
J1 = 3.2 Hz, J2 = 14.8 Hz, 6-H2), 1.22 (3H, t, J1 =

T. R. Varga et al. / Tetrahedron Letters 48 (2007) 1159–1161
1161
7.5 Hz, CH3), 1.20–1.90 (8H, br m, 1-H2, 2-H2, 7-H2, 8-
H2); dC (100 MHz, CDCl3; Me4Si) 169.70 (CO), 160.52 (C-
5), 81.15 (C@CHCO2Et), 61.60 (CO2CH2), 58.84 (C-9),
47.67 (C-3), 33.59 (C-8), 29.60 (C-1), 25.89 (C-6), 22.47 (C-
7), 19.96 (C-2), 14.06 (CH3); dH (400 MHz, CDCl3; Me4Si)
for the E-isomer (major) 4.37 (1H, br, C@CHCO2Et), 4.05
(2H, q, J1 = 7.5 Hz, CO2CH2), 3.21 (2H, m, 6-H2), 3.20
(3H, m, 3-H2, 9-H), 1.22 (3H, t, J1 = 7.5 Hz, CH3), 1.20–
1.90 (8H, br m, 1-H2, 2-H2, 7-H2, 8-H2); dC (100 MHz,
CDCl3; Me4Si) 168.82 (CO), 160.52 (C-5), 81.15
(C@CHCO2Et), 57.88 (CO2CH2), 58.84 (C-9), 47.67 (C-
3), 33.12 (C-8), 29.60 (C-1), 25.89 (C-6), 22.47 (C-7), 19.96
(C-2), 14.71 (CH3).
J1 = 8.5 Hz, 3b-H), 1.83 (1H, m, 9-H), 1.68 (4H, br m, 1a-
H, 2a-H, 6-H2), 1.47 (4H, br m, 1b-H, 2b-H, 7a-H, 8a-H),
1.26 (2H, br m, 7b-H, 8b-H); 1.23 (3H, t, J1 = 7.1 Hz,
CH3); dC (100 MHz, CDCl3; Me4Si) 169.51 (CO), 64.19
(C-9), 59.76 (CO2CH2), 59.53 (C-5), 51.10 (C-3), 40.60
(CH2CO2Et), 31.75 (C-6), 30.66 (C-8), 30.55 (C-1), 24.41
(C-7), 20.40 (C-2), 13.79 (CH3).
16. Data for 11: colourless oil; m/z (ESI, HPLC–MS) 170.4
(5.4 · 105, M+H+).
dH (400 MHz, CDCl3; Me4Si) 3.96 (1H, s, OH), 3.69 (2H,
dd, J1 = 6.8 Hz, J2 = 7.4 Hz, CH2OH), 3.49 (1H, dt,
J1 = 7.2 Hz, J2 = 5.4 Hz, 3a-H), 2.53 (1H, m, 5-H), 2.25
(1H, q, J1 = 5.6 Hz, 3b-H,), 2.12 (1H, m, 9-H), 1.20–2.20
(12H, br m, 1-H2, 2-H2, 6-H2, 7-H2, 8-H2, CH2CH2OH);
dC (100 MHz, CDCl3; Me4Si) 65.65 (C-9), 61.52 (C-5),
59.41 (CH2OH), 50.93 (C-3), 34.12 (CH2CH2OH), 29.86
(C-6), 29.45 (C-8), 28.51 (C-1), 23.96 (C-7), 19.86 (C-2).
17. Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37,
1445–1446.
15. Data for 10: pale yellow oil; m/z (ESI, HPLC–MS) 212.3
(9.7 · 106, M+H+). dH (400 MHz, C6D6; Me4Si) 4.08 (2H,
q, J1 = 7.1 Hz, CO2CH2), 3.19 (1H, dt, J1 = 1.6 Hz,
J2 = 8.4 Hz, 3a-H), 2.71 (1H, dd, J1 = 5.0 Hz,
J2 = 12.3 Hz, CH2CO2Et), 2.60 (1H, m, 5-H), 2.39 (1H,
dd, J1 = 7.4 Hz, J2 = 14.4 Hz, CH2CO2Et), 2.01 (1H, q,