A catalytic multicomponent coupling reaction for the enantioselective synthesis of spiroacetals

Article abstract of DOI:10.1039/c3cc00118k

The first multicomponent catalytic asymmetric synthesis of spiroacetals has been described. Hybrid molecules comprising a spiroacetal scaffold (a natural-product inspired scaffold) and an α-amino acid motif (a privileged fragment) are easily available through a gold phosphate-catalysed one-pot three component coupling reaction of alkynols, anilines and glyoxylic acid. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc00118k

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A catalytic multicomponent coupling reaction for the
enantioselective synthesis of spiroacetals†
Cite this: Chem. Commun., 2013,
49, 2715
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Lara Cala, Abraham Mendoza, Francisco J. Fan˜anas* and Felix Rodrıguez*
Received 6th January 2013,
Accepted 12th February 2013
DOI: 10.1039/c3cc00118k
www.rsc.org/chemcomm
The first multicomponent catalytic asymmetric synthesis of spiro- of enantioenriched chroman [6,6]-spiroacetals.8b The third
acetals has been described. Hybrid molecules comprising a spiro- example has also been reported very recently by B. List and
acetal scaffold (a natural-product inspired scaffold) and an a-amino colleagues.8c They used a confined Brønsted acid based on a
acid motif (a privileged fragment) are easily available through a C2-symmetric imidophosphoric acid motif to achieve catalytic
gold phosphate-catalysed one-pot three component coupling reac- enantioselective spiroacetalization of 2-hydroxyalkyl-substituted
tion of alkynols, anilines and glyoxylic acid.
cyclic enol ethers. It should be noted that only the first example
implies an intermolecular coupling process and the other two
Natural products are an exceptional source of drug leads and are intramolecular reactions.
a continuous inspiration for the design of small-molecule
Thus, the scarcity of catalytic asymmetric methods for the
libraries for drug discovery.1 In this context, spiroacetals have enantioselective synthesis of spiroacetals, and in particular the
been found as a key structural unit in many biologically active absence of asymmetric approaches to the [5,5]-spiroacetal scaf-
and structurally diverse natural products.2 Interestingly, it has fold motivated us to investigate this issue. We envisaged that
been shown that simplified spiroacetals derived from natural the three-component coupling reaction of alkynol derivatives 1,
products frequently retain biological activity similar to the arylamines 2 and glyoxylic acid 3 in the presence of an appro-
parent natural product.3 Therefore, the spiroacetal framework priate chiral catalyst should lead to enantioenriched [5,5]-
makes an ideal candidate for the development of potentially spiroacetal derivatives 4 (Scheme 1).9
useful natural-product-like compounds.4 In this context, we
We thought that the cycloisomerization reaction of alkynol
have recently reported a new strategy for the synthesis of derivatives 1 should deliver the exocyclic enol ethers 5. More-
functionalized chroman spiroacetals,5 which was further over the condensation reaction between glyoxylic acid and
exploited in the total synthesis of the bioactive natural product amines 2 should give imines 6. Further reaction between these
(–)-berkelic acid.6
in situ formed intermediates 5 and 6 would lead to our desired
Following our interest in this field, we became particularly
interested in the development of a ‘‘reagent-controlled’’ asym-
metric synthesis of spiroacetals.7 In this context, it should be
stressed that despite the unquestionable interest in optically
active spiroacetals, to the best of our knowledge, only three
strategies for the enantioselective synthesis of these com-
pounds from achiral substrates have been reported.8 Thus,
K. A. Jørgensen and colleagues reported a copper-catalyzed
asymmetric hetero-Diels–Alder reaction where just two examples
of chiral [6,5]-spiroacetals were synthesized with moderate
enantioselectivity.8a Z. Wang, K. Ding and colleagues applied
an iridium-catalyzed hydrogenation reaction for the synthesis
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Instituto Universitario de Quımica Organometalica ‘‘Enrique Moles’’,
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Universidad de Oviedo, Julian Claverıa 8, 33006-Oviedo, Spain. E-mail: fjfv@uniovi.es,
frodriguez@uniovi.es; Fax: +34 985103446; Tel: +34 985106224
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization data. CCDC 888585. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc00118k
Scheme 1 Our approach for the enantioselective synthesis of spiroacetals.
Chem. Commun., 2013, 49, 2715--2717 2715
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[5,5]-spiroacetal derivatives 4. Regarding the catalyst, we
thought that the combination of (JohnPhos)AuMe and a
(R)-BINOL-derived phosphoric acid XH would be ideal because
the cationic gold phosphate formed should be able to catalyse
both the cycloisomerization of 1 to form the cyclic enol ethers 5
and the formal asymmetric [3 + 2]-cycloaddition between these
enol ethers 5 and imines 6.10 The particular structural features
of compounds 4 should be remarked. These products may be
considered as hybrid molecules comprising a spiroacetal
unit (a natural-product inspired scaffold) and an a-amino acid
motif (a privileged fragment). The concept of combining a
biologically active motif within a natural product-inspired
scaffold system is very attractive because it provides compounds
with enhanced structural complexity along with potential
bioactivity.11
After a few experiments to check the feasibility of the
proposed reaction (see ESI†), we found that the use of the
phosphoric acid XAH containing the bulky 9-anthracenyl sub-
stituents led to the best results (Scheme 1). Thus, as shown in
Scheme 2, several alkynol derivatives 1, anilines 2 and glyoxylic
acid 3 were reacted in toluene as the solvent at room tempera-
ture in the presence of the phosphate gold catalyst (5 mol%
(JohnPhos)AuMe/XAH). Under these conditions, a series of
compounds 4 with diverse functionality around the central
spiroacetal framework were obtained in high yield and
enantioselectivity. The reaction was general in terms of the
alkynol 1 used and substitution at all carbons of the chain
connecting the hydroxy group and the alkyne was tolerated
without erosion of efficiency and enantioselectivity. Unsubsti-
tuted 4-pentyn-1-ol could also be used in this reaction (4o).
Anilines 2 containing an electron-withdrawing group or a
halogen were appropriate coupling partners for this multicom-
ponent reaction.12 Furthermore, the reaction is not limited to
the construction of [5,5]-spiroacetal frameworks and [6,5]-
spiroacetal derivatives may be obtained when the reaction is
performed with 5-hexyn-1-ol derivatives 1 (n = 2). Accordingly,
compound 4p was synthesized and isolated in very high yield
(94%), with good diastereoselectivity (dr = 4 : 1) and an 80 : 20
enantiomeric ratio. Interestingly, in this case the best result
was obtained by using the phosphoric acid derivative XBH. It
should be noted that for the purpose of testing biological
activity both diastereoisomers 4 and diast-4 are of high interest
and so we tried to isolate both. However, if required, the
diastereoselectivity of the reaction may be improved by heating
the reaction mixture for several hours.13 It is also important to
remark that the enantiomeric excesses of the minor diastereo-
isomers were very high and comparable to those observed for Scheme 2 Asymmetric synthesis of spiroacetals 4. aPhosphoric acid derivative
XBH was used.
the major diastereoisomers (see ESI†). The absolute configu-
ration of 4n was determined by single-crystal X-ray analysis and
the configuration of the remaining products was assigned by
analogy.14
carbon–carbon triple bond of alkynol 1 produces complex 7.
A plausible mechanism for the present reaction is illustrated This coordination favours the intramolecular exo-addition of
in Scheme 3. In the first place, we propose the in situ generation the hydroxy group to the alkyne, giving rise to alkenyl–gold
of the active catalytic species by reaction of (JohnPhos)AuMe complex 8. A conventional protodemetallation reaction delivers
with the Brønsted acid XH. This reaction leads to the formation the exocyclic enol ether 5 regenerating the gold-derived catalyst.
of the corresponding gold phosphate complex after releasing a On the other hand, the condensation reaction between glyoxylic
molecule of methane. Coordination of the gold cation to the acid 3 and anilines 2 gives rise to imine 6. We feel likely that
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2716 Chem. Commun., 2013, 49, 2715--2717
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in a process where the only by-product is water. This reaction
represents one of the very few examples of reagent-controlled
asymmetric synthesis of spiroacetals and the first based on a
multicomponent coupling process. The products obtained
could be considered as hybrid molecules comprising a spiro-
acetal unit (a natural-product inspired scaffold) and an a-amino
acid motif (a privileged fragment).
We acknowledge financial support from MICINN of Spain
(grant CTQ2010-16790), MEC (FPU-predoctoral grant to L. C.).
Notes and references
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Scheme 3 Proposed mechanism for the formation of spiroacetals 4.
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5 J. Barluenga, A. Mendoza, F. Rodrıguez and F. J. Fananas, Angew.
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6 F. J. Fananas, A. Mendoza, T. Arto, B. Temelli and F. Rodrıguez,
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activation of the imine 6 by formation of an intramolecular
hydrogen bond and further interaction with the gold phosphate
would lead to an activated species I.15 Subsequent nucleophilic
addition of the enol ether 5 would give the oxonium inter-
mediates 9, which upon cyclization would provide the final
product 4 regenerating the catalyst. Interestingly, in the first
catalytic cycle the main role of the catalyst is played by its
cationic part, the gold(I) ion, being responsible for the activa-
tion of the alkynol 1. Meanwhile, in the second catalytic cycle,
the main role is played by the anionic part of the catalyst, the
phosphate, creating the appropriate chiral environment to
produce the final enantioenriched products 4.
To justify the formation of the enantiomer observed in
products 4 we consider the model proposed by M. Terada and
colleagues for the chiral phosphoric acid catalyzed reaction
between glyoxylates and enecarbamates.16 In this model, sup-
ported by computational studies, the key feature is the forma-
tion of a hydrogen bond between the formyl hydrogen atom
and one of the oxygen atoms of the phosphoric acid. We
propose a similar coordination mode that accounts for the
7 Substrate-controlled asymmetric synthesis of spiroacetals: B. R. Raju
and A. K. Saikia, Molecules, 2008, 13, 1942–2038.
8 (a) H. Audrain, J. Thorhauge, R. G. Hazell and K. A. Jørgensen, J. Org.
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K. Ding, Angew. Chem., Int. Ed., 2012, 51, 936–940; (c) I. Coric and
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(d) Z. Sun, G. A. Winschel, A. Borovika and P. Nagorny, J. Am. Chem.
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9 Some support for our proposed strategy was found in a reaction
´
reported by R. Lavilla and colleagues. See, O. Jimenez, G. de la Rosa
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11 M. Decker, Curr. Med. Chem., 2011, 18, 1464–1475.
12 The use of anilines with electron-donating groups led to mixtures of
unidentified products (see ESI†).
sense of asymmetric induction observed (I in Scheme 3). Thus, 13 For example, compound 4a, initially obtained as a 3 : 1 mixture of
diastereoisomers after one hour at room temperature, was trans-
formed into a 7 : 1 mixture of diastereoisomers (without erosion of
the enantioselectivity) when the crude reaction mixture was heated
in the double hydrogen-bonded complex formed, the enantio-
topic re face of the imine is effectively shielded by one of the
anthracenyl groups. In contrast, the si face is fully accessible
and hence the enol ether 5 attacks from the front side affording
intermediate 9 with S configuration. The final cyclization of 9
occurs preferentially by attack of the oxygen of the carbonyl
group from the re-face of the oxonium group to deliver
product 4.
In summary, we have developed a new and straightforward
synthetic protocol for the enantioselective synthesis of spiroacetals
using a gold-phosphate catalysed one-pot three-component
coupling reaction between alkynols, anilines and glyoxylic acid
at 110 1C for 2 hours in toluene.
14 CCDC 888585 (4n)†.
15 Similar activation by intramolecular hydrogen bond formation and
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the aldehyde functionality has been proposed for glyoxylic acid:
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1178–1187. Alternatively, activation of the imine by coordination
of the gold cation to the nitrogen could be proposed. However,
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acter: (b) S. Kobayashi, T. Busujima and S. Nagayama, Chem.–Eur. J.,
2000, 6, 3491–3494.
16 M. Terada, K. Soga and N. Momiyama, Angew. Chem., Int. Ed., 2008,
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