Brief, efficient and highly diastereoselective synthesis of (±)-pumiliotoxin C based on the generation of an octahydroquinoline precursor via a four-component reaction

Article abstract of DOI:10.1039/c1cc11246e

A short and highly diastereoselective synthesis of the amphibian alkaloid pumiliotoxin C is described, based on the preparation of an octahydroquinoline derivative through a four-component reaction. The route proceeds in 66% overall yield from 1,3-cyclohe

Full text of DOI:10.1039/c1cc11246e

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J. Carlos Menéndez from Universidad Complutense,
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Brief, efficient and highly diastereoselective synthesis
of ( )-pumiliotoxin C based on the generation of an
octahydroquinoline precursor via a four-component reaction
Pumiliotoxin C is one of the bioactive metabolites isolated
from Central and South American poison dart frogs. A concise
and diastereoselective synthesis of this alkaloid was developed,
exploiting the high synthetic efficiency associated to a new
multicomponent synthesis of octahydroquinolines. Image credit:
Dong Lin © California Academy of Sciences.
See S. Maiti and J. C. Menéndez,
Chem. Commun., 2011, 47, 10554.
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COMMUNICATION
Brief, efficient and highly diastereoselective synthesis of (Æ)-pumiliotoxin
C based on the generation of an octahydroquinoline precursor via a
four-component reactionw
´
Swarupananda Maiti and J. Carlos Menendez*
Received 2nd March 2011, Accepted 18th April 2011
DOI: 10.1039/c1cc11246e
A short and highly diastereoselective synthesis of the amphibian
alkaloid pumiliotoxin C is described, based on the preparation of
an octahydroquinoline derivative through a four-component
reaction. The route proceeds in 66% overall yield from 1,3-
cyclohexanedione and includes two hydrogenation steps, whose
stereochemical outcome was controlled via nitrogen acylation.
The decahydroquinoline ring system is the key structural
fragment of many biologically active alkaloids1 isolated from
skin extracts of dendrobatid or mantelline frogs (Fig. 1). It has
also been obtained from bufonids and other organisms such as
tunicates, marine flatworms, and myrmicine ants. In many
cases, these natural products have potent pharmacological
activities, particularly as nicotinic receptor antagonists.2 Their
ecological and pharmacological importance, coupled with
their challenging structures, has spurred a large amount of
work aimed at the synthesis of these alkaloids. One of the most
representative members of the group is cis-decahydroquinoline
195A, also known as pumiliotoxin C. This compound is
isolated from frogs of the Dendrobatidae family,3 which
probably obtain the alkaloid from ants in their diet and
accumulate it in their skins to serve as a passive chemical
defense.4 In spite of its small size, the concise construction of
pumiliotoxin C poses an interesting synthetic challenge
because it contains four stereocenters, three of which are
contiguous, and it has received much attention from the
synthetic community in recent years.5 However, most of these
syntheses require lengthy routes and only one of them6 is
focused on achieving synthetic efficiency by application of the
contemporary methods involving the generation of several
bonds in a single operation,7 such as multicomponent
reactions. Indeed, while this type of methodology is finding
widespread application in library synthesis,8 its systematic use
in target-oriented synthesis, and specially in the construction
of natural products, is still at its early stages.9 In this context,
the purpose of our work was to design and translate into
Fig. 1 Structure of (À)-pumiliotoxin C and some related natural
products.
Scheme 1 Synthetic plan for the construction of pumiliotoxin C.
practice a short synthesis of pumiliotoxin C having a multi-
component reaction as the pivotal transformation. Thus, our
synthetic strategy was based on the bond-creating reactions
summarized in Scheme 1, featuring as the key step the one-pot
conversion of 1,3-cyclohexanedione into a octahydroquinoline
derivative through the generation of one C–C, two C–N and
one C–O bonds in a single synthetic operation. This planned
reaction can be viewed as an extension of our recently
described synthesis of 6-alkoxy-1,4,5,6-tetrahydropyridines
based on
a
CAN-catalyzed four-component reaction
Departamento de Quı´mica Orga´nica y Farmace´utica,
Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
E-mail: josecm@farm.ucm.es; Fax: +34 913941822;
Tel: + 34 913941840
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of representative spectra.
See DOI: 10.1039/c1cc11246e
between primary amines, acyclic 1,3-dicarbonyl compounds,
a,b-unsaturated aldehydes and alcohols.10
The translation of our four-component tetrahydropyridine
synthesis to a cyclic 1,3-diketone substrate, leading to a new
entry into 1,2,3,4,5,6,7,8-octahydroquinolines, turned out to
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Scheme 3 (a) Stereochemical study of compound 8 and proposed
explanation for its formation. (b) Explanation found in ref. 6 for the
stereochemical outcome of the reduction of the C4a–C8a internal
double bond of the N-acetyl derivative of compound 7, which was
opposite to the one observed by us.
Scheme 2 Diastereoselective construction of intermediate 8. Reagents
and conditions: (i) 1 + 2 + 4, In(OTf)3 (5 mol%), DCM, rt, 1 h, then 3,
rt., 5 h. (ii) Allyltrimethylsilane, BF3ÁEt2O, DCM, rt, 4 h. (iii) H2
(60 psi), Pd–C (10%), AcOH, 50 1C, 15 h. (iv) H2 (90 atm), Pt–C (5%),
50 1C, 24 h.
be non-trivial, since the application of our standard conditions
led only to extensive decomposition of the starting materials.
After some experimentation, we discovered that indium triflate
(5 mol%) was an excellent catalyst for the desired transformation,
and allowed to effect the reaction between 1,3-cyclohexane-
dione 1, benzylamine 2, acrolein 3 and ethanol 4, affording a
95% yield of octahydroquinoline derivative 5. Incorporation
of the three-carbon chain at C-2 was achieved in 93%
yield by allylation of 5 with allyltrimethylsilane in the
presence of boron trifluoride, a transformation that has some
interest because of the absence of literature precedent for
nucleophilic additions mediated by vinylogous acylation
intermediates onto polyhydroquinoline systems. Compound 6
obtained from this reaction was N-debenzylated to 7 by
hydrogenolysis, and this intermediate was transformed into 8
in a second hydrogenation step, with complete diastereo-
selectivity (Scheme 2).
The stereochemistry of the crucial reduction of the C4a–C8a
internal double bond was deduced from NOE experiments
and can be explained by assuming that the major conformer
for the ring system is the one with an equatorial arrangement
for the propyl substituent, in which the top face is more
accessible to the hydrogenation catalyst (Scheme 3a).
Interestingly, the stereochemical outcome observed by
us for the reduction of the internal double bond is the
opposite to the one previously described for an N-acyl
derivative of the same compound 7. This difference can be
explained through a conformational change caused by the
strain between the N-acyl and C2-propyl groups in N-acetyl-7,
leading to the acyl substituent preferring an axial arrangement
Scheme 4 Final stages of the synthesis of (Æ)-pumiliotoxin C.
Reagents and conditions: (i) BOC2O, K2CO3, CH3CN, reflux, 24 h.
(ii) Dess–Martin periodindane, DCM, rt, 4 h. (iii) Cp2TiMe2, toluene,
reflux, 20 h. (iv) H2 (1 atm), PtO2, MeOH, rt, 1 h. (v) CF3CO2H,
DCM, rt, 4 h.
(Scheme 3b).6 This effect was exploited at a later stage of our
synthesis.
The completion our synthesis is summarized in Scheme 4.
The N-BOC derivative of compound 8 was transformed into 9
by oxidation with the Dess–Martin reagent. A Petasis
methylenation reaction11 of 9 afforded 10,12 which was
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transformed into the natural product by diastereoselective
hydrogenation of the exocyclic double bond and a final
N-deprotection. An attempt was made to transform 8 directly
into pumiliotoxin C via a methylenation–reduction sequence,
avoiding the N-protection step, but in this case the final
hydrogenation lacked diastereoselectivity. Presumably, the
presence of the N-BOC substituent led to a diastereoselective
hydrogenation by forcing the system to exist predominantly in
a conformation where, in agreement with the previously
mentioned literature precedent,6 the carbamate substituent
blocked the top face of the molecule.
Notes and references
1 For a review, see: T. F. Spanda, P. Jain, H. M. Garraffo, L. K. Pannell,
H. J. C. Yeh, J. W. Daly, S. Fukumoto, K. Imamura, T. Tokuyama,
J. A. Torres, R. R. Snelling and T. H. Jones, J. Nat. Prod., 1999, 62, 5.
2 N. Toyooka, S. Kobayashi, D. Zhou, H. Tsuneki, T. Wada,
H. Sakai, H. Nemoto, T. Sasaoka, H. M. Garraffo, T. F. Spande
and J. W. Daly, Bioorg. Med. Chem. Lett., 2007, 17, 5872.
3 For a review of alkaloids from amphibian skins, see: J. W. Daly,
T. F. Spande and H. M. Garraffo, J. Nat. Prod., 2005, 68, 1556.
4 R. A. Saporito, H. M. Garraffo, M. A. Donnelly, A. L. Edwards,
J. T. Longino and J. W. Daly, Proc. Natl. Acad. Sci. U. S. A., 2004,
101, 8045.
5 For a summary of work in this area, see: M. Amat, R. Fabregat,
R. Griera, P. Florindo, E. Molins and J. Bosch, J. Org. Chem.,
2010, 75, 3797.
6 H. M. Sklenicka, R. P. Hsung, M. J. McLaughlin, L.-L. Wei,
A. I. Gerasyuto and W. B. Brennessel, J. Am. Chem. Soc., 2002,
124, 10435.
In conclusion, we have developed a very short, diastereo-
selective synthesis of the amphibian alkaloid pumiliotoxin C.
The main features of the route were: (i) a novel synthesis
of 1,2,3,4,5,6,7,8-octahydroquinonines based on an indium
triflate-catalyzed four-component reaction that generated
one C–C, two C–N and one C–O bonds; (ii) the attachment
of a three-carbon chain to the octahydroquinoline C-2
position based on a nucleophilic attack of an allylsilane onto
a vinylogous acyliminium intermediate; (iii) two diastereo-
selective hydrogenation steps, whose outcome was tuned
through the presence or absence of an N-acyl substituent.
The overall yield of our route was 66% from 1,3-cyclo-
hexanedione, making it the most efficient synthesis of
pumiliotoxin C to date.
7 For
a review, see: Y. Coquerel, T. Boddaert, M. Presset,
D. Mailhol and J. Rodriguez, in Ideas in Chemistry and Molecular
Sciences, Advances in Synthetic Chemistry, ed. B. Pignataro, Wiley-
VCH, Weinheim, 2010, vol. 1, ch. 9, pp. 187–202.
8 For selected general reviews on multicomponent reactions, see:
(a) A. Domling, Chem. Rev., 2006, 106, 17; (b) B. B. Toure and
¨
D. G. Hall, Chem. Rev., 2009, 109, 4439.
9 For a review of the use of multicomponent reactions in natural
product synthesis, see: B. B. Toure
2009, 109, 4439.
10 V. Sridharan, S. Maiti and J. C. Mene
15, 4565.
11 For a review, see: R. C. Hartley and G. J. McKiernan, J. Chem.
Soc., Perkin Trans. 1, 2002, 2763.
12 Compound 10 was isolated as a mixture of two species that were
confirmed to be rotamers rather than diastereomers through its
N-deprotection, which led to a single compound (for its full
characterization, see the ESIw).
´
and D. G. Hall, Chem. Rev.,
´
ndez, Chem.–Eur. J., 2009,
We gratefully acknowledge financial support of this
work by MICINN (grant CTQ2009-12320-BQU) and UCM
´
(Grupos de Investigacion Consolidados, grant GR35/
10-A-920234).
c
10556 Chem. Commun., 2011, 47, 10554–10556
This journal is The Royal Society of Chemistry 2011