Diversity-oriented synthesis of novel polycyclic scaffolds using polymer-bound reagents

Article abstract of DOI:10.1039/b807869f

A concise sequence utilizing a Petasis three component reaction followed by a tandem aza-Cope-Mannich cyclization afforded novel polycyclic heterocycles in good yield; alternative iminium cyclization based on a Pictet-Spengler reaction or aminal formation

Full text of DOI:10.1039/b807869f

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Diversity-oriented synthesis of novel polycyclic scaffolds using
polymer-bound reagentsw
Domingo Garcıa-Cuadrado, Sofia Barluenga and Nicolas Winssinger*
´
Received (in Cambridge, UK) 9th May 2008, Accepted 16th June 2008
First published as an Advance Article on the web 28th July 2008
DOI: 10.1039/b807869f
A concise sequence utilizing a Petasis three component reaction
followed by a tandem aza-Cope–Mannich cyclization afforded
novel polycyclic heterocycles in good yield; alternative iminium
cyclization based on a Pictet–Spengler reaction or aminal
formation led to divergent pathways affording skeletal diversity.
The search for new small molecules to perturb biological
systems as chemical-genetic probes or drug leads has created
a demand for efficient synthetic sequences leading to diverse
‘‘drug-like’’ structures.1 Our attention was drawn to iminium
cyclizations which offer a wide array of complexity-building
cascade reactions2 that have been the cornerstones of elegant
natural product syntheses.3,4 Herein we report short divergent
pathways exploiting the reactivity of iminium intermediates to
access heterocyclic frameworks 5, 7 and 9 by cyclization
Scheme 1 Aza-Cope–Mannich reaction sequence with unsubstituted
compound 10.
through an aza-Cope–Mannich tandem reaction, aminal
formation or Pictet–Spengler reaction to yield diverse bicyclic
systems (Fig. 1). The key amino alcohol 2 was derived
from a three component Petasis reaction.5–7 To the best of
our knowledge, heterocyclic systems 5 and 7 have not been
reported previously whereas heterocycles such as 9 have been
reported with an acyl or urea at the bridgehead nitrogen.8
To evaluate the efficiency of the planned aza-Cope–
Mannich cyclization, we subjected the unsubstituted
compound 10w to TsOH in toluene (Scheme 1). To our
gratification, the bicyclic product 11 was obtained in good
yield after three hours as a 4 : 1 mixture of diastereoisomers
which could be separated upon reduction of the aldehyde to
the corresponding alcohol. As neither diastereoisomer was
Laboratoire de Chimie Organique et Bioorganique, Institut de Science
´
et d’Ingenierie Supramoleculaires, Universite Louis Pasteur – CNRS,
8 allee Gaspard Monge, 67000 Strasbourg, France.
´
´
´
E-mail: winssinger@isis.u-strasbg.fr; Fax: (þ33) 3 90 24 51 12
w Electronic supplementary information (ESI) available: Experimental
procedure and additional kinetic measurements of templated reac-
tions. See DOI: 10.1039/b807869f
Fig. 1 Divergent pathways leading to heterocycles 5, 7 and 9 based on alternative iminium cyclizations of intermediates 4, 6 and 8.
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Scheme 2 Synthesis of bicyclic heterocycles 19 and 20.
crystalline, the alcohols were acylated with 3,5-dinitrobenzoyl
chloride thus yielding 12. The major diastereoisomer afforded
diffracting crystals which confirmed the postulated structure
and defined the preferred relative stereochemistry among the
two newly formed stereogenic centers as anti. Evaluation of
tolerance of substitutions on the backbone of compound 10
suggested that this reaction sequence should be broadly
applicable. The only substitution which was found to inhibit
the desired cyclization pathway was at the terminal position of
the alkene.
16 examples).16 A limitation on the part of the boronic acid is
that alkyl boronic acids were not productive in our hands.
Alternatively, the new carbon–nitrogen bond could also be
made by reductive amination (vide infra). The crude product
18 was then treated with the sulfonic acid resin to obtain 19 by
aza-Cope–Mannich reaction (36–77% yield, 15 examples) or
20 by aminal formation (65% yield, 1 example) depending on
the nature of the substituent X in fragment 17. As the product
of either cyclization bears a tertiary amine, the product
remained on the resin as a salt and was recovered by washing
with a solution of ammonia in methanol. Any residual amine
15 from an incomplete Petasis reaction did not remain asso-
ciated with the resin as it forms the cyclic imine which is less
basic and can be washed off. The final products were thus
To facilitate the isolation of the products and make this
chemistry amenable to high throughput synthesis, we explored
the possibility of using supported reagents9,10 for the sequence,
mindful that the final cyclization could be carried out using
sulfonic acid resin which would capture the final product. The
‘‘catch-and-release’’ strategy has been elegantly applied by Ley
and coworkers in the final step of syntheses using solid
supported reagents.11–14 Starting from readily available amine
13 (Scheme 2), the peptide coupling with Fmoc-protected
amino acid 14 was achieved with polymer bound carbodiimide
(490% yield, 11 examples) followed by an Fmoc deprotection
using catalytic DBU and a thiol resin to sequester the fulvene
byproduct.15 Conveniently, the DBU remains associated with
the resin and product 15 was obtained in excellent yield and
purity (94–99% yield, 20 examples). Amine 15 was then
converted to the amino alcohol 18 using the Petasis procedure
with boronic acid 16 and hydroxyaldehyde 17 (83–96% yield,
Scheme 3 Synthesis of bicyclic heterocycles 21 and 22.
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In conclusion, we report efficient synthetic pathways leading
to diverse heterocycles in four steps containing up to five
points of diversity. The starting materials are derived from
amino acids, boronic acids and readily available hydroxyl
aldehydes. The use of supported reagents greatly facilitates
the isolation of the products and renders this chemistry
amenable to high throughput synthesis. The utility of the
novel heterocyclic frameworks as biological probes is currently
being explored.
A fellowship from the French Ministry of Research and
Education is gratefully acknowledged (DG-C).
Notes and references
Scheme 4 Synthesis of key intermediate 18 and 23 by reductive
amination and formation of heterocycle 24 by Pictet–Spengler.
1 R. L. Strausberg and S. L. Schreiber, Science, 2003, 300, 294–295.
2 J. Royer, M. Bonin and L. Micouin, Chem. Rev., 2004, 104,
2311–2352.
generally obtained in 485% purity without a single tradi-
tional purification.
3 For selected example, see: L. E. Overman, Acc. Chem. Res., 1992,
25, 352–359.
4 For selected example, see: A. G. Myers and B. A. Lanman, J. Am.
Chem. Soc., 2002, 124, 12969–12971.
5 G. K. S. Prakash, M. Mandal, S. Schweizer, N. A. Petasis and
G. A. Olah, J. Org. Chem., 2002, 67, 3718–3723.
6 N. A. Petasis and I. A. Zavialov, J. Am. Chem. Soc., 1998, 120,
11798–11799.
7 N. A. Petasis and I. A. Zavialov, J. Am. Chem. Soc., 1997, 119,
445–446.
As shown in Scheme 3, compound 19 bearing a ketone
could be further diversified by reduction using a polymer
supported borohydride (21, 490%, 15 examples) or by oxime
formation (22, 490%, 4 examples). The excess hydroxylamine
used in the latter reaction was conveniently sequestered using
an aldehyde resin.
8 S.-C. Lee and S. B. Park, J. Comb. Chem., 2006, 8, 50–57.
9 S. V. Ley and I. R. Baxendale, Nat. Rev. Drug Discovery, 2002, 1,
573–586.
10 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, L. G.
Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and
S. J. Taylor, J. Chem. Soc. Perkin Trans. 1, 2000, 23, 3815–4195.
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Compound 18 could also be conveniently accessed from
amine 15 and aldehyde 17 using a reductive amination with
supported cyanoborohydride (Scheme 4, 53–80%, 7 examples)
and subsequently cyclized to 19 or 20 using the aforemen-
tioned sulfonic acid procedure. If compound 15 was substi-
tuted with a nucleophilic aromatic system at R3 such as an
indole, the formation of the iminium would engender the
Pictet–Spengler reaction. To this end, compound 15 was
engaged in a reductive amination to obtain 23 (53–80%, 3
examples) which was subjected to sulfonic acid resin. As for
the cyclization of 18, the product of the reaction (24, 70–81%,
3 examples) remained associated with the resin and could be
recovered cleanly following a wash with a solution of ammo-
nia in methanol. Prolonged exposure at 60 1C afforded the
product without Boc.
16 For an elegant application of the Petasis reaction in diversity-
oriented synthesis, see: N. Kumagai, G. Muncipinto and S. L.
Schreiber, Angew. Chem., Int. Ed., 2006, 45, 3635–3638.
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