Site isolated base and acid catalyzed azaspirocyclization cascades

Article abstract of DOI:10.1039/b716568d

A one-pot, site isolated base (PS-BEMP) and acid (Si-TsOH) catalyzed cyclization cascade to azaspirocyclic molecules is reported; the reaction is simple to perform, atom efficient (water is the only byproduct) and broad in its scope to a diverse range of azaspirocyclic products. The Royal Society of Chemistry.

Full text of DOI:10.1039/b716568d

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Site isolated base and acid catalyzed azaspirocyclization cascadesw
a
b
a
¨
Adam W. Pilling, Jutta Bohmer and Darren J. Dixon*
Received (in Cambridge, UK) 29th October 2007, Accepted 14th December 2007
First published as an Advance Article on the web 3rd January 2008
DOI: 10.1039/b716568d
A one-pot, site isolated base (PS-BEMP) and acid (Si-TsOH)
catalyzed cyclization cascade to azaspirocyclic molecules is
reported; the reaction is simple to perform, atom efficient (water
is the only byproduct) and broad in its scope to a diverse range of
azaspirocyclic products.
The desire for practically simple and synthetically efficient
organic transformations has led to the development of many
new innovative strategies and concepts. Cascade reaction
strategies allow rapid and efficient synthesis of complex mole-
cules from relatively simple starting materials by enabling
several bond-forming events to occur in the same reaction
vessel. This also negates the necessary drain of resources
associated with one-reaction, one-pot approaches. A myriad
of elegant cascade sequences catalyzed by single chemical
entities has been reported1 but those involving more than
one mutually compatible catalyst are much less common.2
Furthermore, the concept of anchoring mutually destructive
reagents onto solid supports (known commonly as site isola-
tion) to allow their simultaneous use in one-pot cascade
sequences has still to be fully exploited.3 Despite some recent
advances concerning the types of materials that provide the
solid support required to permit such reaction cascades,4 the
organic transformations achieved by the cascades themselves
have been largely limited to deprotections and condensations.
Realizing the potential of site-isolated reagents for facilitat-
ing multistep reaction sequences, we recently reported a new
cyclization cascade mediated by strongly basic and strongly
acidic reagents for the one-pot construction of complex poly-
heterocyclic molecules.5 In an advancement of this work, here
we present the use of two site isolated catalysts for the efficient
one-pot formation of complex azaspirocyclic compounds. The
concept of the cascade is shown in Scheme 1. In a base
catalyzed process, a carboxamide pro-nucleophile 1 should
undergo a Michael addition reaction with an enone Michael
acceptor 2 bearing a tethered p-nucleophilic trapping group.
The Michael adduct 3 is then poised to undergo an acid
catalyzed N-acyl iminium ion formation/trap sequence.6 Com-
bining these two powerful reactions through the site isolation
concept should allow direct access to the azaspirocycle motif 4,
Scheme 1 Site isolation catalysis: combining a base catalyzed Mi-
chael addition with an acid catalyzed N-acyl iminium ion cyclization.
the core structure of numerous natural product targets,7 in
one pot.
In our previous studies, super-stoichiometric amounts of
Amberlysts 15 resin (2 equiv.) were required for satisfactory
reaction rates in the acid mediated cyclization step. Therefore
our primary objective was to find conditions that would allow
the proposed azaspirocyclization cascade to proceed using
catalytic quantities of both solid-supported base and solid-
supported acid. Commercially available PS-BEMP8,9 had
Table 1 Proof of principle and acid screen of Michael addition/
N-acyl iminium ion cyclization cascade
Acid
Loading
Product(s) (yield)
a School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Darren.Dixon@man.ac.uk;
Fax: þ44 (0)161 2754939; Tel: þ44 (0)161 2751426
b Syngenta, Jealott’s Hill International Research Centre, Bracknell,
Berkshire, UK RG42 6EY
w Electronic supplementary information (ESI) available: Experimental
procedures, and spectral data for compounds 7–21, 24 and 25. See
DOI: 10.1039/b716568d
Amberlysts 15
MP-TsOH II
K10 montmorillonite
KSF montmorillonite
Si-TsOH
10 mol%
7 (74%)
7 (71%)
7 (6%), 8 (61%)
7 (9%), 8 (70%)
8 (85%)
10 mol%
100 mass%a
100 mass%a
10 mol%
a
100 mass% refers to 1 mg of montmorillonite per 1 mg of 5.
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Scheme 3 Formal total synthesis of (ꢁ)-perhydrohistrionicotoxin.
tory yields. Pleasingly, the use of Si-TsOH10 (10 mol%) gave
smooth conversion to the desired azaspirocycle 8 in 85% yield.
With proof of concept established and the desired product
isolated in good yield, the scope of the reaction cascade was
probed. Four points of diversity (the electron withdrawing
group, C-2 substituent and N-substitution of the Michael
donor, and the N-acyl iminium ion trap) were identified and
systematically varied to establish the breadth of the sequence.
The results are presented in Scheme 2.z The Michael donor
can be a malonamate, b-keto amide or cyanoacetamide; the C-
2 substituent can be methyl, benzyl, p-methoxy phenyl or ester;
N-methyl and primary amides can be used and dimethoxy
phenyl, indole, pyrrole and thiophene traps can be employed
to generate 6,6 or 6,5 azaspirocyclic frameworks.
The utility of this reaction was further demonstrated in the
formal total synthesis of (ꢁ)-perhydrohistrionicotoxin 26
(Scheme 3). When diester 22 was treated with enone 23 in
the presence of PS-BEMP then Si-TsOH in the same reaction
vessel, smooth conversion to adduct 24 was observed.z Sub-
sequent double ester hydrolysis and decarboxylation furnished
known spirocyclic lactam 25,11 the formation of which consti-
tutes a formal total synthesis of (ꢁ)-perhydrohistrionicotoxin.
In conclusion, the concept of site isolation has been
exploited in one-pot base catalyzed Michael addition–acid
catalyzed N-acyl iminium ion spirocyclization cascades to
generate a series of complex azaspirocycles. The reaction has
broad scope, is atom efficient (water is the only byproduct)
and its utility has been demonstrated in a formal total synth-
esis of (ꢁ)-perhydrohistrionicotoxin.
Scheme 2 Library of azaspirocyclic compounds generated via the
catalytic cascade.
already proven to be a very efficient basic catalyst for Michael
additions and thus was employed here.
Further developments of these reaction sequences requiring
both acid and base catalysts are ongoing and will be reported
in due course.
Accordingly, proof of principle studies were combined with
an acid screen in the reaction of malonamate 5 with enone 6 in
the presence of PS-BEMP (10%) and acid catalyst in dichloro-
methane at room temperature for 24 h. The results are
summarized in Table 1.z Amberlysts 15 and MP-TsOH II
proved to be ineffective, giving only the enamide intermediate
7, whilst K10 and KSF montmorillonite clays gave unsatisfac-
We thank EPSRC and Syngenta for support (to AWP).
Notes and references
z Michael donors represented by 1 were synthesised by alkylation of
commercially available malonamates and cyanoacetamides following
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the relevant procedure in ref. 12. Michael acceptors represented by 2
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carboxylic acids via transformation to the Weinreb amide (ref. 13)
and subsequent addition of vinyl magnesium bromide (ref. 14). 22 was
synthesised from ethyl malonamate and ethyl chloroformate following
the relevant procedure in ref. 15 and 23 was synthesised in three steps
from 2-ethylfuran (ref. 16).
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8 PS-BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhy-
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834 | Chem. Commun., 2008, 832–834