Studies on Pumiliotoxin A Alkaloids: An Approach to Preparing the Indolizidinic Core by Intramolecular Diastereoselective N-Heterocyclic Carbene Catalyzed Benzoin Reaction

Article abstract of DOI:10.1002/ejoc.201600172

In this article, we describe the development of a convergent organocatalytic strategy to prepare the indolizidinic core of the pumiliotoxin A alkaloid family. The key step of the proposed strategy is based on a diastereoselective N-heterocyclic carbene ca

Full text of DOI:10.1002/ejoc.201600172

DOI: 10.1002/ejoc.201600172
Communication
Alkaloids
Studies on Pumiliotoxin A Alkaloids: An Approach to Preparing
the Indolizidinic Core by Intramolecular Diastereoselective
N-Heterocyclic Carbene Catalyzed Benzoin Reaction
[a]
[a]
[a]
José Tiago M. Correia, Laís V. Acconcia, and Fernando Coelho*
1
Abstract: In this article, we describe the development of a con- intermediate generated from an enal moiety (umpolung a to
1
vergent organocatalytic strategy to prepare the indolizidinic d – acyl anion equivalent) attacks a ketone moiety intramolec-
core of the pumiliotoxin A alkaloid family. The key step of the ularly to provide the indolizidinone core in good yield with
proposed strategy is based on a diastereoselective N-hetero- good selectivity.
cyclic carbene catalyzed benzoin reaction, in which the Breslow
Introduction
in collaboration with Daly, to assign certain structural aspects
and to obtain sufficient synthetic material for biological as-
The indolizidine ring stands out among all the heterocyclic scaf-
folds present in nature, because it is present in the primary
[
4,5]
says.
Since those preliminary contributions, many other
groups have attempted to develop new strategies to synthesize
these compounds. However, to date, only noncatalyzed and or-
ganometallic-catalyzed transformations have been used as key
[
1]
structures of several biologically active natural products. One
of the largest classes of indolizidinic alkaloids is the pumilio-
toxin A class, which is subdivided into pumiliotoxins 1 and allo-
pumilioxins 2; this class contains chemical-defense compounds
that are isolated from the skin of Central American dart poison
[
6]
methodologies to prepare these indolizidinic cores. Because
organocatalysis has become a well-established field in homoge-
[
7]
neous catalysis during the past 15 years, an organocatalyzed
strategy represents a promising alternative for further applica-
tions.
[
2]
frogs (dendrobatidae) (Figure 1). Despite their toxicity, these
compounds are known for their cardiotonic and insecticide
[
3]
activities as well as for their unique structures, which have
attracted the attention of synthetic, medicinal, and pharmaceu-
tical chemistry groups. The first synthetic studies were devel-
oped independently by the groups of Overman and Kibayashi,
N-Heterocyclic carbene (NHC) organocatalysis has reached
its most sophisticated level over the past 10 years. Many reactiv-
ities have been improved or disclosed by combining these
highly reactive catalysts with structurally different aldehydes,
[
8]
activated esters, or anhydrides. The application of NHC cataly-
sis in total synthesis was recently reviewed by Scheidt and co-
[
9]
workers, who identified the robustness of this catalytic strat-
egy.
Inspired by the unconventional disconnection approach al-
lowed by umpolung transformations mediated by NHCs, we
performed our retrosynthesis, recognizing that acyloin 3, a sim-
plified analogue of a well-known intermediate to access allo-
[
6a,6c]
pumiliotoxin's dihydroxylated indolizidinic core 2,
could be
prepared from keto enal 4 by diastereoselective intramolecular
benzoin condensation promoted by an NHC precatalyst
(Scheme 1). This reactivity goes against the natural behavior of
enals, which usually react as homoenolate equivalents (umpol-
1
3
[10]
ung a to d ) under NHC-catalyzed reactions.
To the best
Figure 1. Pumiliotoxin A alkaloids.
of our knowledge, although inter- and intramolecular benzoin
reactions involving aliphatic and aromatic aldehydes attacking
[
a] Institute of Chemistry, University of Campinas
P. O. Box 6154, 13083-970 Campinas, São Paulo, Brazil
E-mail: coelho@iqm.unicamp.br
[
11]
ketones have been widely reported, only few intermolecular
versions of benzoin reactions involving Breslow intermediates
www.iqm.unicamp.br
www.unicamp.br
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600172.
1
1
(
umpolung a to d ) generated from enals have been described
[
12]
by using imines and non-enolizable ketones as electrophiles.
Additionally, some examples of intramolecular and intermolec-
1972
Eur. J. Org. Chem. 2016, 1972–1976
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
ular Stetter reactions involving Breslow intermediates from en- treated with adduct 6a[17] in MeOH by a vinylogous allylic sub-
[
18]
als can be found in the literature, which reinforces the feasibility stitution to provide 5a (Scheme 2).
of our strategy.
At this stage, all carbon
[
13]
Intermediate 4 could be prepared from a atoms that would constitute the indolizinic core were incorpo-
diastereoisomeric mixture of esters 5 through a reduction–oxid- rated. However, the maximum overall yield achieved in this se-
ation sequence. Finally, 5 could be prepared through nucleo- quence after chromatographic purification was 45 % for these
philic substitution between Morita–Baylis–Hillman carbonate 6 two steps.
and a diastereoisomeric mixture of 2-(1-hydroxyethyl)pyrrol-
idine (7). In this step, the (E) double-bond configuration, which
is an important structural aspect in the structure of the target,
would be highly favored. Another important aspect of the pro-
posed strategy of this study is that the stereocenter present
at C2 of 7 serves as a stereochemistry-controlling element for
[
9]
cyclization. Considering the versatility of this convergent
strategy, we assumed that starting from an appropriated en-
antiopure α-methylated aldehyde,[4–6,14] access to any of the
allopumiliotoxins would be allowed.
Scheme 2. Reagents and conditions: (a) 1,4-diazabicyclo[2.2.2]octane (DABCO,
equiv.), THF/H O (1:1), 48 h, 70 %; (b) Boc O (1.1 equiv.), 4-(dimethyl-
amino)pyridine (DMAP, 0.2 equiv.), CH Cl , 90 min, 83 %; (c) 1. MeMgCl (3 ),
THF, 10 °C to r.t., 18 h, 93 %; 2. LiAlH (0.3 equiv.), CH Cl , –78 °C, 50 min;
d) TFA (14 equiv.), CH Cl , 1 h; (e) 1. Et N (5 equiv.), 6a (1 equiv.), MeOH, 3 h;
. NH OH (70 % from 10); (f) DIBAL-H (4.5 equiv.), CH Cl , –78 °C, 3 h, 60 %;
g) 1. (COCl) , DMSO, –78 °C, 30 min; 2. N,N-diisopropylethylamine (DIPEA),
1
2
2
2
2
M
4
2
2
(
2
2
3
2
4
2
2
(
2
–
78 °C to r.t., 40 %. Major byproduct 12 was detected in the oxidation step.
To circumvent this issue and by assuming that a loss of 7
Scheme 1. Retrosynthetic analysis of the proposed strategy.
might have occurred during its isolation, we changed the se-
quence. Thus, in a one-pot sequence, the TFA salt of 7 was
dissolved in MeOH and treated with an excess amount of trieth-
ylamine (5 equiv.) prior to its reaction with 6a. Under this proto-
col, 5a was produced in a higher yield (95 %) after filtration
Results and Discussion
Carbonate 6a, the first building block in the proposed strategy, through a pad of silica gel; however, unfortunately, analysis by
was easily prepared in two steps in an overall yield of 58 % NMR spectroscopy detected contamination with unreacted 10.
by a Morita–Baylis Hillman reaction/tert-butoxycarbonyl (Boc) To our surprise, we were not able to eliminate 10 by standard
activation sequence,[ as shown in Scheme 2 (part A). The chromatographic separation. Unfortunately, 5a and 10 pre-
second building block, a diastereoisomeric mixture of (2S)-N- sented the same chromatographic profile in several different
Boc-2-(1-hydroxyethyl)pyrrolidine (10), was prepared from com- eluent mixtures. This purification issue was overcome by remov-
mercially available (2S)-N-Boc-(N-ethoxy-N-methyl)prolinamide ing residual 10 from the crude reaction product mixture by
15]
(
8, Weinreb amide) also in two steps (86 % overall yield), which using the same experimental protocol as that used to isolate
[
17]
started with the addition of methylmagnesium bromide to 8 at
7
before proceeding to column purification (Scheme 2b).
10 °C to afford (2S)-N-Boc-2-acetylpyrrolidine in 93 % yield. This This one-pot sequence and “scavenging” of remaining unpro-
intermediate was reduced in the presence of LiAlH to provide tected starting material 10 afforded the pure mixture of dia-
4
1
0 as a diastereoisomeric mixture (1:1) in 92 % yield [Scheme 2 stereoisomers in 70 % yield from 10. During these studies, we
[
16]
(
part B)]. With these building blocks (i.e., compounds 6a and were able to isolate a small amount of one of the diastereoiso-
0), the next step was removal of the protecting group in 10 mers of product 5a, which proved to be very useful during NMR
1
to obtain 2-(1-hydroxyethyl)-substituted pyrrolidine 7. Thus, spectroscopic characterization of the mixture (see pages S14–
pyrrolidine 10 was treated with trifluoroacetic acid (TFA) in di- S17 in the Supporting Information). Intermediate 5a was easily
chloromethane to afford 7 as its TFA salt. The crude salt was reduced with diisobutylaluminum hydride (DIBAL-H) in toluene
neutralized with a saturated solution of NH OH and was then to produce diol 11 in 60 % yield; the other DIBAL-H solutions
4
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1973
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
investigated in this study did not produce complete accompanied by a complex mixture of byproducts was ob-
reduction, even if used in excess amount (Scheme 2b). Again, tained. Therefore, despite this challenging oxidation step, we
isolation and characterization of a small enriched sample of decided to continue the study and start the screening of the
one of the diastereoisomers of 11 was possible (see pages S20– key step of intramolecular benzoin condensation. The screening
S21).
was guided by the limited number of reports concerning NHC-
In the next step, intermediate 11 was converted into keto catalyzed reactions involving acyl anion Breslow intermediates
enal 4a by Swern oxidation {[α]2 = +41.5 (c = 0.5, CH Cl )}.
5
[19]
[12,13]
from enals.
Two of the most popular nonchiral precatalysts
D
2
2
Following the assumed rationalization and on the basis of litera- were tested: benzimidazolium salt 13, which was used by Yadav
ture precedent, this methodology proved to be the best choice in the nucleophilic substitution of α-brominated ketones with
to oxidize both the primary allylic and secondary hydroxy benzaldehydes and cinnamaldehyde;[20] and triazolium tetra-
groups simultaneously. Sequential oxidation would not be a fluoroborate 14, a precatalyst that has been widely used in sev-
[
6]
good strategy owing to the high risk of hemiketal formation eral NHC-catalyzed transformations. Precatalyst 14 has the ad-
and consecutive oxidation, which would produce a lactone. Di- vantage of being activated by weak bases, which would avoid
carbonyl compound 4a proved to be highly unstable primarily racemization of pH-sensitive substrates, such as 4, as well as a
under acidic conditions; therefore, its isolation required caution. possible aldol side reaction, which would produce byproduct
Although analysis of the crude product by NMR spectroscopy 16 (see the scheme of Table 1). Initially, we were interested in
demonstrated that dicarbonyl compound 4a presented an ac- seeing how far the transfer of chirality to a neighbor stereocen-
ceptable degree of purity, certain additional spots were seen ter could go. Depending on this result, chiral precatalysts would
by TLC analysis. To mitigate the acid instability of 4a, the silica be applied in future studies. These results are summarized in
gel used for purification was doped with Et N. However, after Table 1. Unfortunately, catalyst 13 failed in all attempts (Table 1,
3
chromatography, we isolated only 40 % of 4a and a major by- Entries 1–3); only messy reaction mixtures were observed after
product that was characterized as mercaptan 12 (Scheme 2b).
96 h by analysis of the crude product mixture by TLC and
H NMR spectroscopy, which indicated that side reactions and
1
A rapid comparison between the spectra showed that the
1
H NMR signals of 12 were completely superimposed with the degradation of the starting material had occurred. The strong
signals of 4a in the crude product with the exception of the basicity of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) likely con-
characteristic signal of the aldehyde group, which was margin- tributed to that result. The desired product could only be de-
ally higher in field. To improve this yield, we tested Dess–Martin tected when we changed the catalyst to 14 and used potassium
periodinane (DMP) as an oxidant. Unfortunately, a lower yield carbonate (30 mol-%) as a base. At that point, we also discov-
Table 1. Diastereoselective NHC-catalyzed intramolecular benzoin reaction.[a]
Entry
Catalyst
mol-%)
Base
(equiv.)
Solvent
THF
t
[h]
Yield
[%]
dr[b]
(3a/3b)
(
n.d.[
n.d.[
c]
–
–
–
1
2
3
4
5
6
7
8
9
13 (30)
13 (30)
13 (30)
14 (20)
14 (30)
14 (30)
14 (15)
14 (30)
14 (30)
DBU (0.3)
DBU (0.3)
DBU (0.3)
96
96
96
120
120
120
120
120
48
c]
CH
CH
THF
THF
2
Cl
CN
2
[
c]
d]
d]
3
n.d.
K
2
CO
3
(0.3)
(55)[
50:50
40:60
75:25
75:25
75:25
75:25
[
AcONa (1.0)
AcONa (1.0)
AcONa (1.0)
AcONa (1.0)
AcONa (1.0)
(58)
[
e,f]
CH
CH
2
Cl
Cl
2
69
56[
49[
59[
f]
2
2
f]
f]
toluene
CH Cl
2
2
1
[
a] All reactions were performed at room temperature. [b] The diastereomeric ratio (dr) was determined by H NMR spectroscopy. [c] n.d.: not determined, as
1
decomposition of the starting material was observed. [d] The yield was determined by H NMR spectroscopy by using 1,2,4,5-tetramethylbenzene as an
internal standard. [e] A CH Cl solution (0.5 mL) of catalyst 14 (30 mol-%) and AcONa (1.0 equiv.) was stirred at room temperature for 1 h. After that time, a
CH Cl solution (0.5 mL) of 4a was added, and the mixture was stirred for 120 h. The organic solution was diluted, washed with distilled water, and purified
by silica-gel column chromatography. [f] Yield of isolated product.
2
2
2
2
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
ered that the chromatographic profiles of the starting material
and the product were similar upon using Et N-doped TLC.
3
Therefore, TLC could not be used to monitor the evolution of
the reaction to its completion. The yield and diastereoselectivity
of the reaction with catalyst 14 and potassium carbonate were
determined by analysis of the crude product by NMR spectro-
scopy (Table 1, Entry 4). Although, the yield seemed promising,
no diastereoselectivity was observed; therefore, we decided to
test sodium acetate as a base. This salt is hygroscopic and is a
weaker base than those commonly used; thus, we decided to
increase its stoichiometry to 1 equiv. to drive the equilibrium
toward the direction of the carbene. Under these conditions,
we observed no modification to the reaction yield, but marginal
diastereoselectivity favoring undesired diastereoisomer 3b was
observed (Table 1, Entry 5). The effect of the solvent was also
considered in this study of this reaction. To our surprise, we
Scheme 3. Possible transition states for the intramolecular benzoin condensa-
tion key step.
observed an increase in the yield and diastereoselectivity in Conclusions
favor of desired diastereoisomer 3a upon using dichloro-
We developed a new strategy to prepare the indolizidinic core
methane in the reaction with catalyst 14 (Table 1, Entry 6). The
use of a smaller amount of catalyst (15 mol-%) in the reaction
in CH Cl significantly decreased the yield, although the dia-
of pumiliotoxin A alkaloids. This strategy begins with a Morita–
Baylis–Hillman adduct and employs a diastereoselective NHC-
catalyzed intramolecular benzoin condensation as its key step.
The indolizidinic core was produced in an overall yield of 12 %
over eight steps from Weinreb amide 8. To the best of our
knowledge, this is the first application of Morita–Baylis–Hillman
and NHC catalysis toward the preparation of this class of
alkaloids. With this strategy in hand, further work envisioning
the total synthesis of pumiliotoxin A alkaloids are ongoing in
our laboratory.
2
2
stereoselectivity remained the same (Table 1, Entry 7). In tolu-
ene, a heterogeneous reaction took place, and after 5 d of reac-
tion, the product was recovered in a lower yield with the same
diastereoselectivity (Table 1, Entry 8). To optimize the experi-
mental conditions, we interrupted the reaction in CH Cl after
2
2
48 h. In this case, full conversion was observed, as determined
by NMR spectroscopy, but only 59 % of the product was recov-
ered. A plausible explanation for this moderate yield can be
attributed to decomposition of the products during the purifi-
cation steps. Neither compound 15 nor aldol product 16 was
detected under any of the described conditions.
Acknowledgments
The authors thank the Fundação de Apoio à Pesquisa do Estado
de São Paulo (Fapesp) (processes 2013/10449-5 and 2013/
The relative configurations of both diastereoisomers were
determined by a sequence of two-dimensional NMR spectro-
scopy analyses. Compounds 3a and 3b were easily separated
by using preparative thin-layer chromatography (see the Sup-
porting Information for details). Diastereoisomer 3a has the
same relative configuration as that exhibited by most natural
pumiliotoxins. The transition state can be simply rationalized by
considering two possible chairlike transition states and seems
to suffer some influence of the solvent used, although further
studies must be performed to confirm this proposal (Scheme 3).
Felkin-type approach T1, which produces 3a, seems to be more
stable in less polar media given that the dipole moments of the
carbonyl groups subtract from each other. On the other hand,
in anti-Felkin-type approach T2, the dipole moments of the
carbonyl groups add to each other, which makes it more polar;
therefore, T2 is less stabilized than T1 in solvents with lower
polarities (Scheme 3). The fact that products 15a/15b are not
formed can be explained by the high steric hindrance between
the catalyst and the pyrrolidine moiety, which prevents the re-
quired alignment of the orbitals; therefore, electronic conjuga-
0
7600-3) and the Conselho Nacional de Desenvolvimento Cien-
tífico e Tecnológico (CNPq) for financial support. J. T. M. C.
thanks Fapesp for a fellowship (process 2012/21809-0), and
L. V. A. thanks Fapesp for a fellowship (Pprocess 2013/24386-5).
Keywords: Alkaloids · Carbenes · Diastereoselectivity ·
Organocatalysis · Umpolung
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Received: February 16, 2016
Published Online: March 31, 2016
Eur. J. Org. Chem. 2016, 1972–1976
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