The synthesis of hydroxy-pyrrolizidines and indolizidines from cyclopropenones: Towards hyacinthacines, australines and jenamidines

Article abstract of DOI:10.1016/j.tetlet.2012.05.117

The reaction of cyclic imines (1-pyrrolines and piperideines) with a cyclopropenone leads to pyrrolizidines and indolizidines, respectively, each with a hydroxy group on the carbon atom at the bridgehead. The cyclopropenone functions as an all-carbon 1,3-dipole equivalent towards the cyclic imine in this reaction, and the cyclic imines used include polyhydroxylated systems, thus allowing access to australine, alexine and hyacinthacine type compounds. The pyrrolizidine products contain the core of the jenamidine and bohemamine natural products, which are of interest as cell-proliferation inhibitors and cell-cell adhesion inhibitors.

Full text of DOI:10.1016/j.tetlet.2012.05.117

Tetrahedron Letters 53 (2012) 4100–4103
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of hydroxy-pyrrolizidines and indolizidines
from cyclopropenones: towards hyacinthacines, australines and jenamidines
⇑
Vishnu V. R. Kondakal, M. Ilyas Qamar, Karl Hemming
Institute for Materials, Medicines and Molecular Sciences, Division of Chemistry, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield,
West Yorkshire 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 cyclic imines (1-pyrrolines and piperideines) with a cyclopropenone leads to pyrrolizi-
dines and indolizidines, respectively, each with a hydroxy group on the carbon atom at the bridgehead.
The cyclopropenone functions as an all-carbon 1,3-dipole equivalent towards the cyclic imine in this
reaction, and the cyclic imines used include polyhydroxylated systems, thus allowing access to australine,
alexine and hyacinthacine type compounds. The pyrrolizidine products contain the core of the jenami-
dine and bohemamine natural products, which are of interest as cell-proliferation inhibitors and cell–cell
adhesion inhibitors.
Received 10 April 2012
Revised 10 May 2012
Accepted 24 May 2012
Available online 30 May 2012
Keywords:
Hyacinthacine
Alexine
Ó 2012 Elsevier Ltd. All rights reserved.
Jenamidine
Pyrrolizidine and indolizidine
Cyclopropenone
The pyrrolizidine1 and indolizidine1b,2 heterocycles attract sig-
nificant attention due to their biological activity, and the synthetic
challenges that they present.1,2 Typical compounds, shown in
Figure 1, are natural iminosugars such as hyacinthacines A1/A2
(1),3 hyacinthacines B1/B2 (2),4 australine (3) (and its bridgehead
epimer alexine)5 and castanospermine (4),6 which have attracted
interest as glycosidase inhibitors. Glycosidases play important
roles in a number of diseases including many cancers, lysomal stor-
age disorders such as Gaucher’s disease, and type II diabetes.7 Imi-
nosugars have also gained interest as antiviral compounds and
antibiotics.7 Also of importance are indolizidine alkaloids with
alkyl substituents, such as the amphibian derived indolizidine
195B (5),8 and related systems.1b,9 These continue to attract inter-
est as, for example, inhibitors of nicotinic receptor-channels and
neuromuscular transmission. Of particular interest to our work
are pyrrolizidines such as bohemamine (6)10 and the related de-
epoxidised NP25302,11 a rare pyrrolizidin-1-one sub-class isolated
from Actinosporangium sp. and from marine Streptomyces sp., mem-
bers of which have shown significant cell–cell adhesion inhibitory
activity. The structurally related fungal derived pyrrolizin-1-ols,
epohelmins A and B (7)12 are lanosterol synthase inhibitors. Of
great relevance to the work reported in this Letter are systems that
have a hydroxy group on the carbon atom at the bridgehead such
as the antitumour, antibiotic and antiviral clazamycins A and B
(8),13 jenamidines B1/B2 (9b) and C (10),11a,14 and the synthetic
8a-hydroxy-indolizidines.15 Jenamidine A1/A2 (9a) inhibits prolif-
eration of leukaemia cell line K-562 with a reported GI50 of
1.9
l
g/mL.11a,14
HO
HO
X
HO
HO
HO
HO
HO
Y
N
H
N
H
N
X
Y
H
HO
OH
1 A2: Y = OH, X = H 2 B2: X = CH2OH, Y = H
A1: Y = H, X = OH B1: X = H, Y = CH2OH
3
O
H
O
HN
N
H
N
H
N
HO
OH
HO
H
O
O
6
5
4
O
N
Cl
N
H
C5H11
HO
O
NH
7
8
OH
HN
O
HN
OH
N
N
OH
10
HO
X
9a A1/A2: X = H
O
O
9b B1/B2: X = OH
⇑
Corresponding author. Tel.: +44 1484 472188; fax: +44 1484 472182.
E-mail address: k.hemming@hud.ac.uk (K. Hemming).
Figure 1. Indolizidine and pyrrolizidine natural products.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.117

V. V. R. Kondakal et al. / Tetrahedron Letters 53 (2012) 4100–4103
4101
R1
O
R3/4/5
N
R3/4/5
N
O
13 X = H
R2
+
N
N
N
OTBDMS
BnO
[ O ]
( )n
( )n
R1
R2
14 X = OH
X
17
18
19
11
12
OBn
Scheme 1. Synthesis of hydroxy-pyrrolizidines and indolizidines.
BnO
Me
N
N
In this Letter, we describe a new synthesis of bridgehead (7a-
and 8a-) hydroxy-substituted pyrrolizidines and indolizidines
(14) (see Scheme 1) from the reaction of cyclic imines 11 (n = 1
or 2) with cyclopropenones 12, a process that we believe proceeds
through the rapid aerial oxidation of a transient intermediate 13.
The reaction of cyclic imines with cyclopropenones is a process
that we have studied previously using cyclic imines 15 that are 2-
substituted (X = O, S; R = Me, Et),16 and we have shown that a range
of alkoxy- and alkylthio-substituted cyclic imines react to give
bicyclic systems 16 in the azetidinopyrrole (n = 0), pyrrolizidine
(n = 1), indolizidine (n = 2) and pyrroloazepine (n = 3) classes, as
summarised in Scheme 2.
In order to produce compounds with a bridgehead hydrogen, a
feature common to natural products 1–5, 7 and 9a, we sought to
explore the reactions of 2-unsubstituted cyclic imines with cyclop-
ropenones, and report the results of this study herein. We began
our study with the synthesis of the imines 17–21 shown in Figure
2, with the ultimate goal of natural product syntheses.
20
21
Figure 2. Cyclic imines selected for study.
3/4/5 R1
R
3/4/5 R1
R
R3/4/5
N
O
N
R2
N
( )n
R2
+
( )n
( )n
R1
R2
H
13
O
OH
17-21
12
3/4/5 R1
22
3/4/5 R1
R
R
O2
For R3/4/5, R1,
R2 and n, see
Table 1
N
R2
N
R2
( )n
( )n
O
O
HO
14
HO
O
23
Scheme 3. Synthesis of 7a-/8a-hydroxy-indolizidines and pyrrolizidines.
Imine 17 was selected to allow, after reaction with an appropri-
ate cyclopropenone, direct access to analogues 13 (see Scheme 1)
of the jenamidines (9a) and, after manipulation of the enone
functionality and/or side-chains, access to jenamidines A1/A2
themselves. Imine 17 was accessed by cyclisation of 4-aminobutyr-
aldehyde diethyl acetal which was stabilised as its zinc iodide
complex.17 Imine 18 was chosen ultimately to explore access to
hyacinthacines B1/B2 (2), but also to a range of potentially interest-
ing hydroxymethyl pyrrolizidines, and we synthesised it as a single
reactions occurred extremely smoothly, but we were surprised to
discover an extra 16 mass units in the mass spectra of the products.
This, together with the absence of a C–H signal (the expected
bridgehead C–H) in each of the 13C and 1H NMR spectra, the pres-
ence of an additional quaternary carbon (13C) and a clear OH in the
infra-red and 1H NMR spectra, led us to believe that the products
that had formed were the alcohols 14a and 14b, rather than the
expected compounds 13a and 13b.27 Alcohols 14a and 14b were
isolated in 61% and 84% yields, respectively. Compound 14a was
crystalline and found to be suitable for study by X-ray crystallogra-
phy (Fig. 3),28 which confirmed that the structure was that de-
duced. We assume that the expected adducts 13, via their enol
tautomers 22, are unusually susceptible to aerial oxidation, and
enantiomer using an aza-Wittig based route starting from L-glu-
tamic acid, exactly as described by Banfi et al.18 Imines 1919 and
2020 were chosen as they offer a potential route into indolizidines
such as 5 and analogues, and these imines were made by an
adaptation of reported N-chlorination-dehydrochlorination
sequences.19,20 Imine 21 was chosen due to its ready availablity21
and its potential to allow access to polyhydroxylated pyrrolizi-
dines, including hyacinthacine A2 (1) and australine (3) and/or
their epimers, after pyrrolidinone reduction and benzyl
deprotection.
With imines 17–21 synthesised as described,17–21 we started to
explore their reactivity towards diphenylcyclopropenone (12a;
R1 = R2 = Ph), phenylcyclopropenone (12b; R1 = H, R2 = Ph) and
cyclopropenone (12c; R1 = R2 = H). Diphenylcyclopropenone is
commercially available, whilst phenylcyclopropenone16c,22 and
cyclopropenone23 were synthesised as described in the literature.
Cyclopropenones have attracted recent interest as all-carbon 1,3-
dipole equivalents,16,24 as alkyne precursors in click processes,25
and as novel catalytic platforms.26 The first cyclopropenone reac-
tions performed in our current study, as shown in Scheme 3, were
those of imines 17 and 20 (the most readily available) with
commercially available diphenylcyclopropenone (12a). These two
R1
O
16
N
N
n = 0, 1, 2, 3
X = O or S
+
( )n
R2
( )n
R1
R2
XR
R = Me or Et
RX
15
12
O
Scheme 2. The use of 2-substituted cyclic imines.
Figure 3. X-ray crystallographic structure (ORTEP) of compound 14a.

4102
V. V. R. Kondakal et al. / Tetrahedron Letters 53 (2012) 4100–4103
Table 1
their epimers), and their 7a-/8a-hydroxy analogues. A programme
of study focused on the synthesis of 8a-hydroxy analogues of the
alkylated indolizidines (such as compound 5) is also underway
alongside our continuing studies on the jenamidines.
7a-/8a-Hydroxy-indolizidines and pyrrolizidines from cyclopropenones 12 and
imines 17–2127
Product
n
Imine
12, R1 and R2
Yield (%)
14a
14b
14c
14d
14e
14f
14g
14h
14i
1
2
1
2
1
1
1
2
1
17
19
17
19
18
18
18
20
21
R1 = R2 = Ph
R1 = R2 = Ph
R1 = H, R2 = Ph
61
84
26
57
36
30
37
33
34
Acknowledgments
R
1 = H, R2 = Ph
This work was supported by the University of Huddersfield
Studentships (to V.V.R.K. and M.I.Q.). We thank Dr Neil McLay,
University of Huddersfield, for NMR and mass spectroscopic
support, Dr Craig Rice, University of Huddersfield, for X-ray crystal-
lographic studies, and the EPSRC national mass spectrometry
service, University of Wales, Swansea for HRMS.
R1 = H, R2 = Ph
R1 = R2 = H
R1 = R2 = Ph
R1 = R2 = H
R1 = R2 = H
that the initial product of oxidation, the hydroperoxide 23 (Scheme
3), undergoes O–O cleavage to form the isolated alcohols 14. It is
known that enols and their derivatives can undergo easy oxidation
References and notes
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Other imines and cyclopropenones behaved in the same manner
and the results are summarised in Table 1.27 Imines 17, 18 and 19
reacted with phenylcyclopropenone to give compounds 14c, 14d
and 14e as single regioisomers (R1 = H, R2 = Ph; easily identified
by HMBC), presumably due to the attack of the cyclopropenone
12 by the imine at the least hindered carbon, as we previously ob-
served when working with this and other mono-substituted cyclop-
ropenones.16 With imines 18, 20 and 21, the products 14e–i were
isolated as single diastereoisomers. Each of the pyrrolizidines
14e-g showed the CH2OTBDMS and OH groups to be cis to each
other (NOESY). We were unable to determine the relative stereo-
chemistry in indolizidine 14h, but by analogy to that observed in
compounds 14e–g, we have tentatively assigned the OH and Me
groups as cis to each other. Pyrrolizidine 14i was formed from the
chiral pool derived enantiopure21 imine 21. The stereochemistry
of the new stereocentre–the bridgehead OH–was established by
NOESY which showed OH to be cis to the adjacent OBn and cis to
the CH2OBn group, and also confirmed the relative stereochemistry
of the other chiral centres. In the case of compound 14i, the enol 22
was the initial isolated product but underwent quantitative conver-
sion (CDCl3, NMR tube) into the 7a-hydroxypyrrolizidine 14i over
24 h. Whilst this is significant in terms of the proposed mechanism
in Scheme 3, this was the only system where we were able to ob-
serve enol formation. The use of imine 21 has allowed us to produce
systems that are closely related to the hyacinthacine, australine and
alexine natural products (1–3). The 7a-hydroxypyrrolizidines 14
(n = 1) produced from the pyrrolines 17, 18 and 21 have a core
structure that is closely related to the 7a-hydroxypyrrolizidine nat-
ural products 8, 9b and 10. It is of note that natural product 9a has
hydrogen at the bridgehead position and this presents the intrigu-
ing possibility that the jenamidine B1/B2 (9b) may arise from
jenamidine A1/A2 (9a) through the type of mechanism presented
in Scheme 3. Natural products 8 and 10 may have similar origins,32
and we are actively pursuing this possibility.
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Current studies in our laboratory are focusing upon the synthe-
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V. V. R. Kondakal et al. / Tetrahedron Letters 53 (2012) 4100–4103
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was obtained from mixing imine 2121 (0.3710 g, 0.92 mmol) and
cyclopropenone 12c23 (R1 = R2 = H; 0.050 g, 0.92 mmol) in MeCN (10 mL) at
0 °C for 1 h and then warming to room temperature over 4 h. Compound 14i:
IR: tmax (neat, cmÀ1): 3359 (b, m), 3062 (w), 3031 (m), 2926 (m), 2867 (m),
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1688 (s), 1538 (s), 1454 (m), 1362 (m), 1206 (m), 1111 (s), 738 (m), 699 (m); 1
H
NMR (500 MHz, CDCl3), dH: 3.44–3.47 (1H, ddd, J 7.2, 5.9, 4.7, CHN), 3.53 (1H,
dd, J 7.2, 9.4, CHCH2OBn), 3.58 (1H, dd, J 4.7, 9.4, CHCH2OBn), 3.82 (1H, d, J 6.8,
C(OH)CHOBn), 3.89 (1H, br s, OH), 4.17 (1H, dd, J 5.9, 6.8, CH(CHOBn)2), 4.49
(1H, d, J 11.7, OCH2Ph), 4.51 (1H, d, J 11.9, OCH2Ph), 4.55 (1H, d, J 11.9, OCH2Ph),
4.61 (1H, d, J 11.7, OCH2Ph), 4.66 (1H, d, J 11.7, OCH2Ph), 4.97 (1H, d, J 11.7,
OCH2Ph), 5.23 (1H, d, J 3.7, C@CH), 7.17–7.19 (2H, m, ArH), 7.28–7.37 (13H, m,
ArH), 7.76 (1H, d, J 3.7, HC@C); 13C NMR: dc (125 MHz, CDCl3): 62.90 (CH),
71.58 (CH2), 72.50 (CH2), 73.06 (CH2), 73.28 (CH2), 82.00 (CH), 87.07 (CH),
92.02 (C), 102.24 (CH), 127.36 (CH), 127.47 (CH), 127.51 (CH), 127.57 (CH),
127.75 (CH), 128.05 (CH), 128.07 (CH), 128.13 (CH), 128.14 (CH), 136.68 (C),
137.18 (C), 137.30 (C), 168.75 (CH), 201.73 (C@O); m/z (electrospray) HRMS:
calcd for C29H29NO5 + Na+ = 494.1938, found: 494.1947 [2 ppm error].
28. Crystallographic data have been deposited at the Cambridge Crystallographic
Data Centre as a CIF deposition with file number CCDC 873002. Copies of these
data can be obtained free of charge on application to CCDC, 12, Union Road,
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27. Products 14a–i reported in Table 1 all gave satisfactory spectroscopic data (1H and
13C NMR, IR, mass spectra and HRMS). Typical procedure: A solution of the
cyclopropenone 12 in dry MeCN was added dropwise over 1 min. to an
equimolar amount of the imine 17–21 in the same solvent at room temperature
(commercial diphenylcyclopropenone and phenylcyclopropenone16c,22) or at
0 °C (cyclopropenone23). The mixture was stirred at room temperature for 4 h
or overnight until IR showed the absence of the distinctive cyclopropenone
absorbance at ꢀ1840 cmÀ1. The solvent was removed by rotary evaporation
and the residual oil was purified by silica gel column chromatography
(typically using hexane: EtOAc 4:6). As an example, compound 14i (0.1480 g)
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32. We would like to thank the reviewer for useful comments on these aspects of
the manuscript.