A new and simple method for the synthesis of highly functionalised pyrrolizidines, indolizidines and pyrroloazepines

Article abstract of DOI:10.1016/j.tetlet.2008.08.061

The reaction of 5-, 6- and 7-membered cyclic thioimidates with cyclopropenones gives access to highly functionalised pyrrolizidines, indolizidines and pyrroloazepines via a formal [3+2] cycloaddition process.

Full text of DOI:10.1016/j.tetlet.2008.08.061

Tetrahedron Letters 49 (2008) 6316–6319
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new and simple method for the synthesis of highly functionalised
pyrrolizidines, indolizidines and pyrroloazepines
Paul A. O’Gorman, Ting Chen, Hannah E. Cross, Saleena Naeem, Arnaud Pitard,
*
M. Ilyas Qamar, Karl Hemming
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 5-, 6- and 7-membered cyclic thioimidates with cyclopropenones gives access to highly
functionalised pyrrolizidines, indolizidines and pyrroloazepines via a formal [3+2] cycloaddition process.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 July 2008
Revised 13 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Keywords:
Indolizidine
Pyrrolizidine
Cyclopropenone
Alkaloid
Current interest in the pyrrolizidine nucleus 1 is typified by the
role of polyhydroxylated pyrrolizidines, such as hyacinthacine A1
2, as glycosidase inhibitors important in the possible treatment
of various cancers, diabetes and viral infections such as AIDS.1
Many non-polyhydroxylated pyrrolizidines have also attracted
interest, examples being the jenamidines 3 and 4, which inhibit
leukaemia cell lines at clinically useful levels and show a range
of other antitumour and antibiotic properties.2 The pyrrolizidine
nucleus is also seen embedded in more complex natural products
such as UCS1025A, an antiproliferative telomerase inhibitor,3 and
mitomycins A and C 5 and 6, potent and clinically prescribed anti-
tumour agents.4 The indolizidine nucleus 7 is present in several
classes of important alkaloid natural products,5 such as indoliz-
idines 209D 8,6 167B 96 and 223AB 107 which are secreted by
the skin of the frog species dendrobatidae, and are noted for their
ability to block nicotinic receptor channels and to function as
potent analgesics or as potential leads in the search for treatments
for Alzheimer’s disease and other neurological disorders.5–7 Poly-
hydroxylated indolizidines,5,8 such as castanospermine9 and
swainsonine10 11, are of interest as antiviral, antitumour, and
immunoregulatory agents and, like their pyrrolizidine counter-
parts, have attracted interest as glycosidase inhibitors and as
potential antidiabetic agents.5,8–11 The pyrroloazepine nucleus 12
is present in the stemona alkaloids, a group of bioactive molecules
of which stenoamide 13 is typical,12 and which have attracted
interest, for example, as possible treatments for a range of respira-
tory diseases.
O
OH
H
N
X
N
H
O
OH
OH
R1
R2
N
HN
1
2
3 X = H
4 X = OH
O
NH2
O
O
OMe
H
X
N
N
NH
N
Me
R1
O
R
7
5 X = OMe
6 X = NH2
8 R = n-hex, R1 = H
9 R = n-Pr, R1 = H
10 R = n-Pr, R1 = n-Bu
HO
OH
O
H
N
Me
OH
O
H
N
13
H
H
N
11
12
* Corresponding author. Tel.: +44 (0)1484472188; fax: +44 (0)1484472182.
E-mail address: k.hemming@hud.ac.uk (K. Hemming).
O
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.061

P. A. O’Gorman et al. / Tetrahedron Letters 49 (2008) 6316–6319
6317
O
O
O
EtS
Ph
SEt
Ph
N
Ph
Ph
Ph
N
N
R1
MeCN
3 - 7 days
R1
R1
51 - 62%
R2
R2
EtS
Ph
R2
14
15
16
R
1 = R2 = H; R1 = R2 = Me; R1 = H, R2 = Me
Scheme 1.
Our work began as part of an ongoing series of projects con-
cerned with the reactions of cyclopropenones13 and other small
ring systems.14,15 Working with small ring cyclic thioimidates, as
shown in Scheme 1, we were able to show that 4-vinyl-1-azetines
1413 underwent an expected reaction with diphenylcycloprope-
none (DPP), whereby the 1-azetine took part in a formal [2+3]
cycloaddition16 with the cyclopropenone to furnish the adduct 15
which underwent an unexpected aza-Cope rearrangement to fur-
nish the 7-azabicyclo[4.2.1]nonenes 16 which are interesting ana-
logues13b of the 9-azabicyclo[4.2.1]nonene nucleus that is present
in the homotropane alkaloid natural product class, of which the
potent neurotoxin anatoxin-a is the most well-known member.
We have now investigated the reactions of a variety of 5-, 6-
and 7-membered cyclic thioimidates 18 (X = S) with a range of
cyclopropenones (Scheme 2) and report the results herein. The ma-
jor impetus for this work was its potential to provide a rapid access
to the highly sought after pyrrolizidine, indolizidine and pyr-
roloazepine nuclei 19, which would be replete with easily mani-
pulated functional groups for future applications, including
natural product target synthesis. Cyclic thioimidates 18 (X = S)
were readily available by alkylation of the appropriate thiolactam
17 (X = S) with triethyloxonium tetrafluoroborate (Meerwein’s
reagent) in dichloromethane (ꢀ50–80% yield)17 or with neat
dimethyl sulfate (90–95% yield), whereby the thiolactams were
accessed by thiation of the corresponding lactam 17 (X = O) with
Lawesson’s reagent (>90%). We were pleased to observe that
O
O
Me2SO4 o-r
R3O+BF4
X
XR
RX
R2
R1
R1
R2
NH
N
N
n
65 - 85%
50 - 95%
n
n
17
18
19
n = 1, 2, 3
X = O or S
R2
XR
XR
O
R = Et or Me
O
R1, R2 = Ph
N
N
n
R1
R1
R2
Scheme 2.
1. NaNH2, NH3
2. R1Br
O
NH3
OH OH
O
O
O
O
O
O
Cl Cl
Cl Cl
R1
22
20
21
H+, THF, rt, 3 - 4 h
O
23 R1 = Et
24 R1 = H
R1
O
S
XR
-
Et3O+BF4
50 - 80%
23 or 24
EtS
R2
R1
MeCN, 24 - 72 h
NH
n
N
N
45 - 74%
n
n
18, XR = SEt
n = 1, 2, 3
R1 = H, R2 = Et
R1 = R2 = H
25a-f
O
1. LR
EtS
-
2. Et3O+BF4
O
SEt
Ph
Ph
DPP, MeCN
54%
N
NH
N
45%
26
27
Scheme 3.
28

6318
P. A. O’Gorman et al. / Tetrahedron Letters 49 (2008) 6316–6319
reactions of compounds 18 with commercially available diphenyl-
cyclopropenone proceeded well to furnish the requisite highly
functionalised pyrrolizidines, indolizidines and pyrroloazepines
19a–f (R1 = R2 = Ph; XR = SEt or SMe, n = 1, 2 or 3; 6 examples) in
good to excellent yields, as shown in Scheme 2, which also shows
a suggested mechanism for the reaction based upon earlier
precedents.13,16,18
O
O
O
O
reflux
MeS
MeS
toluene
m-CPBA
Ph
Ph
Ph
Ph
Ph
- MeSOH
73%
quant.
N
N
N
Ph
19d
29
OH
31
Having successfully accessed the diphenyl adducts from the
commercially available diphenylcyclopropenone, we next ex-
tended the process to more useful cyclopropenone substitution
patterns. Cyclopropenone chemistry is of some interest in the liter-
ature,18 including some natural products,19 and the extraterrestrial
occurrence of the parent system.20 We accessed monoalkyl and
unsubstituted cyclopropenones using the chemistry shown in
Scheme 3.19 Thus, acetal 20 was cyclised in liquid ammonia to gen-
erate the cyclopropenone acetal 21. Deprotonation and alkylation
gave the alkylated cyclopropenone acetal 22. A wide selection of
cyclopropenones is available via this route.19 In this study we only
investigated the reactions of the mono-ethyl and unsubstituted
variants as we felt it would be of most interest to establish the reg-
iochemical outcome of reactions involving the mono-substituted
system, and that the unsubstituted system offered a substrate
which would be most suited to future manipulations. Deprotection
of the cyclopropenone acetals 21 and 22 gave the ethyl and unsub-
stituted cyclopropenones 23 and 24 which were reacted with the
three cyclic thioimidates 18 (XR = SEt; n = 1–3) to furnish a series
of six pyrrolizidines, indolizidines and pyrroloazepines 25, in good
yields,21 as shown in Scheme 3. The non-symmetric ethylcyclo-
propenone 23 (R1 = H, R2 = Et) gave only single regioisomers as
shown in Scheme 3 (structures confirmed by HMBC), presumably
due to the imidate nitrogen attacking the cyclopropenone at the
least hindered carbon in the initial stages of the reaction (see
Scheme 2 for mechanism). It is also possible to further vary the
nature of the imidate partner in the reaction. As an example, the
dihydropyridine 27, available from treatment of the readily acces-
sible22 lactam 26 with Lawesson’s reagent (LR) and Meerwein’s
reagent, gave access to the indolizidine 28 on reaction with DPP
in a yield of 54%.
O
OH
prototropic
shift
Ph
Ph
Ph
Ph
Ph
tautomerise
N
N
N
Ph
30
Scheme 4.
mechanistic rationale, whereby a tautomerism-prototropic shift-
tautomerism sequence starting from the unstable initial product
30 leads to product 31 as shown in Scheme 4. The incoming proton
in the final tautomerism enters from the least sterically hindered
face, that is, trans to the existing phenyl group, resulting in the
two phenyl groups being cis to each other.
We are currently exploring other desulfurisation reactions of
compounds 19, 25 and 28 and analogues, together with other
transformations such as conjugate additions, reductions, dihydr-
oxylations, epoxidations, aziridations, Wittig homologations and
bridgehead thioether/ether manipulations together with possible
asymmetric versions of the cyclopropenone addition reaction.
Studies towards the total syntheses of the jenamidines 3 and 4
and other natural products 8–11 are also underway.
Acknowledgements
We thank the University of Huddersfield for funding, facilities,
and for PhD studentships (to P.A.O’G, A.P. and M.I.Q.); Dr. Neil
McLay of the University of Huddersfield for NMR spectroscopy;
and the EPSRC National Mass Spectrometry Service Centre at the
University of Wales Swansea, for mass spectrometry.
The reactions detailed in Schemes 2 and 3 show that one of the
strengths of this route to pyrrolizidines, indolizidines and pyr-
roloazepines is the versatility of the reaction due to the high level
of diversity available in the two reaction partners.
References and notes
A second potential strength lies with the easily manipulated
functionality that is available within the adducts 19, 25 and 28
which will enable future applications to be developed in the syn-
thesis of natural products and interesting non-natural analogues
of the pyrrolizidines, indolizidines and pyrroloazepines. The result
of one such process, the desulfurisation of compound 19d, is
shown in Scheme 4. Oxidation of the sulfide moiety in compound
19d gave the sulfoxide 29 as a 3:2 mixture of diastereoisomers,
which on treatment in toluene at reflux underwent b-elimination
of methyl sulfenic acid to furnish the final isolated product 31.
The structure of product 3123 was assigned on the basis of exten-
sive NMR studies (COSY, HSQC, HMBC and NOESY) which showed,
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for example: the presence of the two sp3 CHs
a and b to the car-
6. (a) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093; (b) Patil, N. T.; Pahadi,
N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101; (c) Kamimura, A.; Nagata,
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bonyl; a clear CO–CHPh–CHPh chain; three extra CH groups in
the aromatic region (due to the new pyrrole ring); a strong nOe be-
tween the two phenyl rings indicative of a cis relationship between
these two groups; a lack of any nOe between either of the two sp3
CHs and the ortho protons of the phenyl ring on the neighbouring
carbon indicating that each of these Hs is trans rather than cis to
the phenyl group on the neighbouring carbon. That these two
protons are cis to each other is also consistent with literature
precedent and with the observed coupling constant of 4.4 Hz (with
8–11 Hz being typical of a trans relationship).3b,10c,24 Further
evidence for the formation of compound 31 lies with a plausible
7. Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547.
8. (a) Jiang, X.-P.; Cheng, Y.; Shi, G.-F.; Kang, Z.-M. J. Org. Chem. 2007, 72, 2212; (b)
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Shind, V. S.; Dhavale, D. D. J. Org. Chem. 2006, 71, 4667; (d) Machan, T.; Davis, A.
S.; Liawruangrath, B.; Pyne, S. G. Tetrahedron 2008, 64, 2725.
10. (a) El Nemr, A. Tetrahedron 2000, 56, 8579; (b) Pyne, S. G. Curr. Org. Synth. 2005,
2, 39; (c) Heimgärtner, G.; Raatz, D.; Reiser, O. Tetrahedron 2005, 61, 643; (d)

P. A. O’Gorman et al. / Tetrahedron Letters 49 (2008) 6316–6319
6319
Déchamps, I.; Gomez Pardo, D.; Cossy, J. Tetrahedron 2007, 63, 9082; (e) Bi, J.;
Aggarwal, V. K. Chem. Commun. 2008, 120; (f) Abrams, J. N.; Satheesh Babu, R.;
Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem. 2008, 73,
1935.
removed by reduced pressure rotary evaporation, and the crude sample was
purified by column chromatography (eluent: petroleum ether: ethyl acetate,
4:1, silica gel [Aldrich] 70–230 mesh, 60 Å, 10 g) to yield the title compound
(0.24 g, 74%) as a clear yellow oil. Anal. Calcd for C11H17NOS: C, 62.52; H, 8.11;
11. Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2004, 69,
3139.
12. (a) Olivio, H. F.; Tovar-Miranda, R.; Barragán, E. J. Org. Chem. 2006, 71, 3287; (b)
Alibés, R.; Blanco, P.; Casas, E.; Closa, M.; de March, P.; Figueredo, M.; Font, J.;
Sanfeliu, E.; Álvarez-Larena, Á. J. Org. Chem. 2005, 70, 3157; (c) Hanessian, S.;
Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem. 2003, 68, 7219.
13. (a) Hemming, K.; Redhouse, A. D.; Smalley, R. K.; Thompson, J. R.; Kennewell, P.
D.; Westwood, R. Tetrahedron Lett. 1992, 33, 2231; (b) Hemming, K.; O’Gorman,
P. A.; Page, M. I. Tetrahedron Lett. 2006, 47, 425.
N, 6.63. Found: C, 62.47; H, 7.82; N, 6.39. IR: m
max (neat, cm-1): 2966 (m), 2930
(m), 1681 (s), 1591 (s), 1456 (w), 1375 (m). 1H NMR (500 MHz, CDCl3), dH: 7.41
(1H, s, C@CH), 3.38 (1H, ddd, J 11.1, 6.3, 3.9, CH2CHHN), 3.15 (1H, ddd, J 11.1,
7.0, 4.0, CH2CHHN), 2.38 (2H, q, J 7.5, S–CH2CH3), 2.09 (2H, q, J 7.6, C–CH2CH3),
1.99 (2H, m, CH2CSEt), 1.79 (2H, m, CH2CH2CH2), 1.09 (3H, t, J 7.6, C–CH2CH3),
1.00 (3H, t, J 7.5, S–CH2CH3); 13C: dc (125 MHz, CDCl3): 203.64 (C@O), 164.95
(CH), 121.36 (q), 80.01 (q), 48.83 (CH2), 33.78 (CH2), 26.57 (CH2), 23.12 (CH2),
15.73 (CH2), 14.05 (CH3), 12.99 (CH3). m/z (electrospray) HRMS: found,
212.1108, calcd for C11H17NOS + H+ = 212.1105.
14. (a) Hemming, K.; Morgan, D. T.; Smalley, R. K. J. Fluorine Chem. 2000, 106, 83;
(b) Hemming, K.; Luheshi, A. B.-N.; Redhouse, A. D.; Smalley, R. K.; Thompson, J.
R.; Kennewell, P. D.; Westwood, R. Tetrahedron 1993, 49, 4383.
15. (a) Tsang, W. Y.; Ahmed, N.; Harding, L. P.; Hemming, K.; Laws, A. P.; Page, M. I.
J. Am. Chem. Soc. 2005, 127, 8946; (b) Ahmed, N.; Tsang, W. Y.; Hemming, K.;
Page, M. I. Can. J. Chem. 2005, 1432; (c) Tsang, W.-Y.; Ahmed, N.; Hemming, K.;
Page, M. I. Org. Biomol. Chem. 2007, 5, 3993; (d) Tsang, W. Y.; Ahmed, N.;
Hemming, K.; Page, M. I. J. Org. Chem. 2008, 73, 4504.
22. Moriconi, E. J.; Meyer, W. C. Tetrahedron Lett. 1968, 9, 3823.
23. Procedure and data for compound 31: To a solution of 5-methylthio-2,3-diphenyl-
1-azabicyclo[3.3.0]oct-2-en-4-one (19d, n = 1, XR = SMe, R1 = R2 = Ph) (110 mg,
0.34 mmol) in dichloromethane (7 mL) was added m-CPBA (60 mg, 0.34 mmol)
in dichloromethane (3 mL) and the whole was stirred at 0 °C for 4.5 h at which
point TLC analysis showed no starting material.
A solution of saturated
aqueous sodium thiosulfate (10 mL) was added and the mixture was allowed
to warm to room temperature and added to a solution of saturated aqueous
sodium hydrogen carbonate (10 mL). The crude sulfoxide was extracted into
dichloromethane (3 Â 10 mL), the extracts were dried (MgSO4), and the solvent
was removed. The crude sulfoxide was dissolved in freshly distilled, anhydrous
toluene under an atmosphere of dry nitrogen and heated overnight at reflux to
give, after removal of the solvent and purification by flash silica column
chromatography (eluent: petroleum ether: ethyl acetate, 9:2), 2,3-diphenyl-1-
azabicyclo[3.3.0]oct-5,7-dien-4-one (31) as a pale yellow solid (68 mg, 73%), mp
132–134 °C. Anal. Calcd for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C,
83.38; H, 5.49; N, 5.37. IR: mmax (neat, cmÀ1): 2975 (w), 2925 (w), 1693 (s),
1575 (m), 1556 (m), 1521 (s), 1374 (s), 1274 (m), 1132 (s), 1018 (m), 996 (m),
669 (s); 1H NMR (500 MHz, CDCl3), dH: 7.44–7.30 (6H, m, Ar), 7.18 (2H, dd, J 7.6,
1.4 Ar), 7.10 (2H, m, Ar), 6.95 (2H, br s, Ar), 6.66 (1H, dd, J 3.8, 2.5 pyrroleNCH),
5.48 (1H, d, J 4.4 CHPh), 4.12 (1H, d, J 4.4 CHPh). 13C: dc (100 MHz, CDCl3):
188.31 (q), 139.53 (q), 137.24 (q), 132.91 (q), 129.29 (CH), 129.11 (CH), 128.72
(CH), 128.24 (CH), 127.77 (CH), 126.15 (CH), 122.85 (CH), 117.71 (CH), 108.70
(CH), 67.51 (CH), 67.44 (CH); m/z (electrospray) HRMS: calcd for
16. (a) Heimgartner, H.; Stierli, F.; Prewo, R.; Bieri, J. H. Helv. Chim. Acta 1983, 66,
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17. Fresh Meerwein’s reagent gave yields at the higher end of the range.
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21. All new compounds gave satisfactory 1H/13
C NMR spectra (including
DEPT, COSY, HSQC and HMBC spectra), mass spectra, HRMS/microanalysis
and IR spectra. Typical procedure: Synthesis of 3-ethyl-5-ethylthio-1-
azabicyclo[3.3.0]oct-2-en-4-one (25a, n = 1, R1 = H, R2 = Et). To 5-ethylthio-3,4-
dihydro-2H-pyrrole (18, n = 1, XR = SEt; 0.20 g, 1.55 mmol) dissolved in freshly
distilled anhydrous acetonitrile (5 mL) was added, in one portion, with stirring,
2-ethylcyclopropenone19 (23, 0.15 g, 1.83 mmol). The solution was stirred
under an atmosphere of dry nitrogen at room temperature for 24 h, after which
time TLC confirmed that the reaction had gone to completion. The solvent was
C
19H15NO + Na+ = 296.1046, found: 296.1055.
24. (a) Sarabèr, F. C. E.; Baranovsky, A.; Jansen, B. J. M.; Posthumus, M. A.; de Groot,
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2002, 9, 37.