An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines

Article abstract of DOI:10.1016/j.tetlet.2011.07.047

Herein we describe the efficient stereoselective preparation of C8 substituted indolizidines bearing a 6-methylene group, from the chiral pool starting material l-proline. This synthesis, employing a Tsuji-Trost reaction as the key step, represents a potentially, efficient route to pumiliotoxin natural product epimers. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2011.07.047

Tetrahedron Letters 52 (2011) 4878–4881
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An intramolecular Tsuji-Trost reaction based approach to the synthesis
of 6-methylene indolizidines
⇑
Romy E. Martin, Marta E. Polomska, Lindsay T. Byrne, Scott G. Stewart
School of Biomedical, Biomolecular and Chemical Science, University of Western Australia, 35 Stirling Hwy, Crawley, 6009 WA, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe the efficient stereoselective preparation of C8 substituted indolizidines bearing a 6-
Received 17 May 2011
Revised 23 June 2011
Accepted 11 July 2011
Available online 21 July 2011
methylene group, from the chiral pool starting material L-proline. This synthesis, employing a Tsuji-Trost
reaction as the key step, represents a potentially, efficient route to pumiliotoxin natural product epimers.
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Indolizidines
Intramolecular Tsuji-Trost reaction
Allylation
Pumiliotoxins
A wide range of biologically active alkaloids have been isolated
from skin excretions of amphibians.1,2 The pumiliotoxins are one
class of these alkaloids, comprisingof approximately 24 members.3,4
Alkaloids which are designated as pumiliotoxins are characterised
structurally by a (Z)-6-alkylidene-8-hydroxy-8-methylindolizidine
ring system, with the general structure 1 (Fig. 1) and differ only in
their alkylidene side chain. The pumiliotoxins were first isolated
from the Panamanian poison frog Dendrobates pumilio in 1963.5
Since this time the physiological effects of the pumiliotoxins, mainly
cardiotonic effects have been widely studied.6–8 It is the potential of
pumiliotoxinsascardiotonicagentscoupledwith alimitedavailabil-
ity of natural sources that drives efforts to obtain larger amounts of
these compounds. Synthetic chemistry, through the efficient
construction of indolizidines, will play a major role in the pharmaceu-
tical development of these compounds. The preparation of pumiliotox-
ins has attracted many synthetic groups,9 with much of the pioneering
work being carried out by Overman.1 Approaches to the indolizidine
core within this group have focused on an intramolecular ene cyclisa-
tion,10 an iminium ion-vinylsilane cyclisation,11–13 as well as an
iminium ion-alkyne variation to generate the N-heterocycle bearing
an exocyclic double bond.13 Later studies by the group of Gallagher
led to the preparation of 5-indolizidinone 2 which was used as an
intermediate in the synthesis of pumiliotoxin 215D (3).14 As a result
of the preparation of this indolizidinone 2, a number of procedures
have emerged for the syntheses of several related pumiliotoxin alka-
loids.15–20 More recently the group of Kibayashi prepared a common
precursor to a pumiliotoxin bearing an alkyl halide side chain in
HO CH3
HO
H C
H3
OH
H
H
N
N
N
O
H3C
pumiliotoxin215D
R
2
1
RO CH3
H
(3)
HO CH3
N
H
5
RO
CH3
N
H
OH
CH3
H3C
pumiliotoxin B
N
CH3 OH
(4)
6
Figure 1. Indolizidine alkaloids and some synthetic precursors.
order to access a range of these alkaloids.21 In this process, the key
ring formation step was an intramolecular cyclodehydration from
adiol precursor. Conveniently, thiscommonhalogenated intermedi-
ate was applied in the further synthesis of pumiliotoxins A and B (4)
through a Negishi type cross-coupling reaction.
In this study we describe the preparation of a protected 6-meth-
ylene indolizidine 5 as a potentially common intermediate for the
synthesis of epimeric natural indolizidines. This synthetic pathway
also offers an approach to the natural pumiliotoxins through sim-
ilar transformations and preparation of indolizidine 6. The overall
synthetic plan centres around the intramolecular Tsuji-Trost
allylation reaction22–24 as the key ring-forming step, a reaction
⇑
Corresponding author.
E-mail address: sgs@cyllene.uwa.edu.au (S.G. Stewart).
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.047

R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
4879
frequently utilised in the preparation of natural products25 and
new heterocyclic systems.26,27 This approach using a secondary
amine is unique in the synthesis of indolizidine systems and gen-
erally quite rare in the literature. The commercially available chiral
similar conditions using S-BINOL were investigated (entries 8–10,
Table 1). The yield of the allylated products for these transforma-
tions was excellent, however the diastereoselectivity was not re-
versed and full conversion into both compounds 11 and 12 was
sluggish. Interestingly, when the amount of S-BINOL and Ti(OiPr)4
was increased dramatically, the conversion was improved, but
without a drastic effect on the diastereoselectivity.
Since the diastereoisomer 12 was more accessible via the allyla-
tion method, with R-BINOL (entries 6 and 7, Table 1), the rest of the
synthesis of the indolizidine core was carried out with this stereo-
isomer. In order to prevent any unwanted retro-aldol type pro-
cesses later in the synthesis, the tertiary alcohol within compou
nd 12 was protected (TBDMSOTf, 2,6-lutidine) to generate the cor-
responding TBDMS ether 13 (83%) (Scheme 2). The dihydroxylation
of the olefin moiety within compound 13 was completed through
pool material
quired for the target indolizidines 5 or 6, was chosen as the starting
material. Protection of the amine moiety afforded the Boc- -proline
8 (82%) (Scheme 1).28 Additionally, it should be noted at this stage
that compound 8 is also available commercially. Boc- -proline
L-proline (7), containing one of the stereocentres re-
L
L
8 was converted into its corresponding Weinreb amide 9 upon
treatment with N-methoxy-N-methylamine, DCC and triethyl-
amine in excellent yield (82%),29 where more elaborate procedures
resulted in only small amounts of the desired product being iso-
lated. Treatment of this aforementioned compound with methyl-
lithium at ꢀ78 °C generated the methyl ketone 10 in good yield
(80%).30,31 The methyl ketone 10 was subsequently subjected to
reaction with allylmagnesium bromide to deliver a mixture of
the epimeric tertiary alcohols 11 and 12 (46:54 dr) which could
be separated via standard chromatography. The new stereogenic
centre formed at C2 within each of the epimers was initially inves-
tigated and later assigned by NOESY spectroscopy of both epimers
11 and 12. However, it was not until the rigid indolizidine core
from one of these epimers was prepared that the configuration of
this new stereogenic centre was confirmed.
Following this initial trial, attempts to improve the diastereose-
lectivity and generate reasonable synthetically viable quantities of
either diastereoisomer were sought (Table 1). The conditions
developed by the Ley group32 (entry 2) were applied to this system,
but unfortunately failed to improve the diastereoselectivity. Like-
wise, increasing the reaction temperature to access a potentially
more thermodynamically favoured product failed to influence the
diastereoselectivity. Reaction conditions based around the re-
agents BINOL and tetraallylstannane were then trialed, as devised
by Walsh for asymmetric allylations.33 In this enantioselective
reaction, R-BINOL was reported to generate the allyl addition prod-
uct bearing an S-stereogenic centre in high ee. Even though we
required a diastereoselective allylation, we were confident that
this was a good foundation for producing the stereoselectivity of
this reaction. Initially, we observed a dramatic improvement of
diastereoselectivity [12:88 in favour of epimer 12 (entry 4, Table
1)] at ambient temperature using 20 mol % of the in situ [(BINO-
Late)Ti(OiPr)2]3 complex.34,35 Increasing the amount of catalyst in
this system led to a decrease in the yield and diastereoselectivity
for compound 12 (entry 5). Increasing the time failed to have any
significant effect on the reaction, however, as expected, lowering
the temperature increased the diastereoselectivity for epimer 12
(entry 6). In order to attempt to reverse the diastereoselectivity,
treatment with AD-mix-
a avoiding the use of hazardous OsO4
(Scheme 2).36 In this process, large quantities of the diol 14 as a dia-
stereomeric mixture about C40, could be obtained in excellent
yields. Interestingly, this method required long reaction times.
Reactions carried out at room temperature overnight (AD-mix-
a
1.4 g/mmol) resulted in only 36% yield in comparison to 55% yield
following stirring for 48 h. The optimum yield of 82% was achieved
using a higher loading, AD-mix-a 1.8 g/mmol. This phenomenon is
possibly due to the steric effects of the TBDMS protecting group
within 13 and approach of the phthalazine-dihydroquinine osmium
complex. Treatment of the diol 14 with acetic anhydride in the
presence of triethylamine furnished the acetate 15 in excellent
yield (86%), whereas other reactions incorporating DMAP in the
reaction system only increased the likelihood of the corresponding
diacetylated product forming. Treatment of 15 with Dess-Martin
periodinane afforded the ketone 16 in 72% yield, while the precusor
2-iodoxybenzoic acid (IBX) gave an improved 96% yield. Subse-
quent treatment of this ketone with methyltriphenylphosphine
ylide, gave alkene 17 in 64% yield, however upon scale-up, this yield
was slightly lower.
Under standard deprotection conditions, removal of the Boc moi-
ety within compound 17 was achieved with TFA (added dropwise at
0 °C) to afford a mixture of the Tsuji-Trost precursor amine 18 and
the related amine alcohol 19 (see Supplementary data). In the key
ring-forming process the secondary amine 18 was treated with
Pd(PPh3)4 (10 mol %) in the presence of triethylamine, to afford
the desired indolizidine-based product 20 in a good yield (66%).
An immediate reaction of the amine precursor was observed sug-
gesting formation of the palladium
p-allyl system is rapid. This
clean transformation suggests that the pyrrolidine is an appropriate
nucleophile for the intramolecular Tsuji-Trost reaction as observed
for other N-heterocycles.23 The use of a secondary amine in an inter-
molecular Tsuji-Trost reaction has been reported in the literature,
but has been more common in the synthesis of azaspirocyclic ring
systems.27,37,38
To our knowledge, this is the first report of a secondary amine
being used in this manner. Formation of the desired product was
confirmed by the presence of two signals at 4.84 and 4.70 ppm in
the 1H NMR spectrum assigned to the olefinic methylene protons,
as well as the molecular ion of m/z 282 in the FAB high-resolution
mass spectrum.39
O
O
O
H
H
H
a
OH
b
OH
N OMe
CH3
N
N
N
Boc
H
Boc
7
8
9
c
The stereochemistry at C8 of the indolizidine 20 was confirmed
with the aid of a series of 1D-NOESY experiments. The key NOE
interactions are displayed in Figure 2. There was no interaction
between the C8 methyl group and the proton at C8a which would
be expected for the alternative stereochemistry at C8. Secondly,
positive correlations between several other key protons on the ind-
olizidine N-heterocyclic core were also observed. It should be
noted here that the Overman group has produced a related free
alcohol variant of compounds 20 and 6 previously, however in
slightly lower yields.10 In order to carry this compound further to
O
H3C
H
HO
OH
CH3
H
H
d
2'
CH3
2'
+
N
N
Boc
N
Boc
Boc
10
dr 46: 12
11
54:
Scheme 1. Reagents and conditions: (a) (Boc)2O, Et3N, CH2Cl2, reflux, 24 h, 82%; (b)
MeONHMeꢁHCl, DCC, Et3N, CH2Cl2, reflux, 16 h, 82%; (c) MeLi, THF, ꢀ78 °C ? rt, 2 h,
80%; (d) allylmagnesium bromide, THF, 0 °C, 3 h, 75%, dr = 46:54 (11:12).

4880
R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
Table 1
Diastereoselective allylation of ketone 10
Entry
Conditionsa
Yieldb (%)
drc S,S 11:S,R 12
1
2
3
4
5
6
7
8
9
10
Allylmagnesium bromide, THF, 3 h, 0 °C
75
82
80
81
77
83
78
81e
80e
92
46:54
46:54
46:54
12:88
21:79
14:86
12:88
36:64
34:66
31:69
d
Allylmagnesium bromide, Ti(OiPr)4 THF, 0.5 h, ꢀ78 °C
Allylmagnesium bromide, THF, 0.5 h, 35 °C
Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 24 h, rt
Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt
Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 68 h, rt
Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, 0 °C
Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt
Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 60 h, rt
Tetraallyltin, Ti(OiPr)4, S-BINOL (60 mol %), 2-propanol, CH2Cl2, 60 h, rt
a
Reactions were carried out on 150 mg of ketone 10 and each reaction was repeated twice where the yield and diastereomeric ratio (dr) are averaged over two
experiments.
b
Isolated yields are reported, the two diastereoisomers were separated using standard column chromatography.
c
d
e
The configuration of the new stereogenic centre at C20 was determined later by NOESY spectroscopy for each indolizidine epimer.
2 equiv.
The yield indicated was based on recovery of starting material 10.
H C
H3
CH
3OH
TBSO
H
OH
TBOS CH3
H
were the allylation which may be used to also generate a diastereo-
merically pure indolizidine, and a pyrrolidine-tethered intramolec-
ular Tsuji-Trost reaction. Work is in progress in order to expand
this synthetic protocol to the total synthesis of the pumiliotoxin
alkaloids and derivatives.
a
b
4'
N
Boc
N
Boc
13
N
OH
Boc
14
12
c
Acknowledgements
CH3
TBSO CH
H
TBSO
3O
TBSO CH3
H
OH
The authors would like to thank Dr. Tony Reeder for mass spec-
tra acquisition. Romy Martin is the recipient of an Australian Post-
graduate Award (APA).
H
e
d
N
Boc
OAc
N
OAc
N
Boc
OAc
Boc
Supplementary data
16
15
17
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.047.
f
CH3
TBSO CH3
H
H3C
OTBS
8
H
References and notes
TBSO
8
g
N
a
N
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NH
OAc
H
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20
18
Scheme 2. Reagents and conditions: (a) TBS-triflate, 2,6-lutidine, CH2Cl2, 0 °C, 2 h,
83%; (b) AD-mix- , t-BuOH, H2O, Na2SO3, 0 °C ? rt, 48 h, 82%; (c) Ac2O, Et3N,
CH2Cl2, rt, 24 h, 86%; (d) Dess-Martin periodinane, CH2Cl2, rt, 2 h, 72%; (e)
BrCH3PPh3, NaHMDS, THF, rt, 2 h, 64%; (f) TFA, CH2Cl2, rt, 2 h; (g) Pd(PPh3)4
(10 mol %), Et3N, THF, 60 °C, 2 h, 66%.
a
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N
H
CH
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TBSO
TBSO
X
H
H
H
H
H
H
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Figure 2. Key NOE interactions for (8S,8aR)-methyleneindolizidine 20.
a series of pumiliotoxins, or their 8aR epimers, a Grubbs olefin
metathesis will be considered. Another option for further synthetic
studies towards these natural product alkaloids would be through
the 6-indolizidinone available through oxidative cleavage of com-
pound 20.
In conclusion, we have demonstrated a new and concise synthe-
sis of a compound bearing the indolizidine core with an exocyclic
methylene and two stereogenic centres at C8 and C8a. The key
transformations in the synthesis of this indolizidine derivative

R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
4881
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0.21 mmol) were added to
a
solution of secondary amine 18 (71 mg,
0.21 mmol) in THF. The reaction mixture was degassed using three freeze–
pump–thaw cycles and then warmed to 60 °C and stirred for 2 h. THF was
removed under reduced pressure and the resulting orange solid dissolved in
EtOAc (20 mL) and washed with H2O (2 mL). The aqueous layer was then back
extracted with EtOAc. The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure to give a pale-orange oil. Flash column
chromatography (5:95 MeOH:EtOAc) afforded the indolizidine 20 (39 mg, 66%)
as a pale-orange oil. 1H NMR (400 MHz, CDCl3): d 4.84 (s, 1H, C@CH2), 4.70 (s,
1H, C@CH2), 3.48 (dd, J = 11.6 and 1.2 Hz, 1H, H-5), 3.03–3.09 (m, 1H, H-4), 2.60
(d, J = 11.6 Hz, 1H, H-5), 2.36 (dd, 1H, J = 14.0 and 1.2 Hz, H-7), 2.01–2.11 (m,
2H, H-7 and H-4), 1.83–1.88 (m, 1H, H-1), 1.59–1.81 (m, 4H, H-2 and H-3), 1.18
(s, 3H, CH3), 0.86 (s, 9H, Si(CH3)2C(CH3)3), 0.09 (s, 3H, Si(CH3)2C(CH3)3), 0.08 (s,
3H, Si(CH3)2C(CH3)3) ppm; 13C NMR (400 MHz, CDCl3): d 142.8 (C@CH2), 110.8
(C@CH2), 72.9 (C-6), 72.2 (C-1), 58.7 (C-5), 54.5 (C-4), 46.9 (C-7), 28.2 (CH3),
26.2 (Si(CH3)2C(CH3)3), 23.6 (C-2), 21.4 (C-3), 18.7 (Si(CH3)2C(CH3)3), ꢀ1.6
(Si(CH3)2C(CH3)3) ppm; IR (neat): 3399 (N–H), 2957 (C–H), 2930 (C–H), 2856
(C–H), 1659, 1651 (C@C) cmꢀ1; MS (FAB) (m/z) = 282.3 [M+H]+ (92), 267.1
[MꢀCH3]+ (27), 251.1 (26), 207.1 (46), 193.1 (75), 191.1 (80.01), 133.1 (100);
HRMS (FAB) calculated for C16H32NOSi [M+H]: 282.2253, found: 282.2238.
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39. Preparation of (8S,8aR)-8-[(tert-butyldimethylsilyl)oxy]-8-methyl-6-methyleneo
ctahydroindolizine (20): Pd(PPh3)4 (24 mg, 0.02 mmol) and Et3N (0.03 mL,