An organocatalytic one-pot cascade incorporating the Achmatowicz reaction affording 3-pyrone derivatives

Article abstract of DOI:10.1039/c4cc03815k

The development of an organocatalytic one-pot cascade for the annulation of simple starting materials: α,β-unsaturated aldehydes, hydrogen peroxide, β-carbonyl compounds and NBS to furnish optically active 3-pyrones in good yield and with excellent enanti

Full text of DOI:10.1039/c4cc03815k

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An organocatalytic one-pot cascade incorporating
the Achmatowicz reaction affording 3-pyrone
derivatives†
Cite this: Chem. Commun., 2014,
50, 7604
Received 9th April 2014,
Accepted 29th May 2014
Lars Krogager Ransborg, Lennart Lykke, Niels Hammer, Line Næsborg and
Karl Anker Jørgensen*
DOI: 10.1039/c4cc03815k
www.rsc.org/chemcomm
The development of an organocatalytic one-pot cascade for the
annulation of simple starting materials: a,b-unsaturated aldehydes,
hydrogen peroxide, b-carbonyl compounds and NBS to furnish
optically active 3-pyrones in good yield and with excellent enan-
tioselectivity is presented. Further diversification of the obtained
products is demonstrated by selective reductive transformations.
Fig. 1 Naturally occurring 3-pyrone derivatives.
Owing to their potential as orthogonally functionalised building
blocks, 3-pyrones are widespread intermediates in the synthesis
of complex natural products.1–4 The application of 3-pyrones in
diversity-oriented synthesis and in organometallic enantiomeric
scaffolding has also been demonstrated.5,6 In addition to their
usefulness as reactive intermediates, derivatives of 3-pyrone can
also be found in naturally occurring compounds. These include
the sugar L-aculose, which is a common constituent of the
carbohydrate side chain in saquamycins and moromycins,7 the
cellulose pyrolysis product (À)-levoglucosenone,8 and the recently
isolated apotirucallane (+)-trichostemonate (Fig. 1).9
Numerous routes for the formation of 3-pyrones have been
demonstrated, among which the Achmatowicz reaction stands out
as one of the most successful (Fig. 2a).10 This reaction, which
allows for the formation of multi-substituted products from
hydroxyalkyl substituted furans, has been widely studied, and
various modifications of the original conditions have been demon-
strated, including stereoselective methodologies for the formation
of optically active products. The stereocontrol has been achieved in
various ways; e.g. by formation of the starting material via enantio-
selective hydrogenation or alkylation of the parent carbonyl sub-
stituted furan, by chiral resolution of the starting material or by
application of enantioselective oxidation conditions such as the
Sharpless epoxidation or dihydroxylation.4,11–13 While these stra-
tegies allow for the formation of the target 3-pyrones in high yield
and enantioselectivity, they are limited by the availability of
appropriate furan starting materials. An enantioselective proce-
dure for the direct formation of 3-pyrones from acyclic starting
materials would therefore be of major interest (Fig. 2b).
The application of asymmetric organocatalytic reactions in one-
pot strategies has recently been demonstrated as a powerful tool
for the direct formation of chiral heteroaromatic compounds and
their derivatives.14 One-pot methodologies allow newly formed
reactive intermediates to be incorporated in a reaction cascade,
thereby avoiding their purification and the time and material costs
associated therewith. Additionally, complicated structures can be
assembled from simple starting materials without the use of
protecting group strategies and other means necessary for success-
ful stepwise synthesis. As a result, the development of new one-pot
Center for Catalysis, Department of Chemistry, Aarhus University, Langelandsgade
140, DK-8000 Aarhus C, Denmark. E-mail: kaj@chem.au.dk; Tel: +45 8715 5956
† Electronic supplementary information (ESI) available: Experimental details,
analytical data for full characterisation and NMR spectra. See DOI: 10.1039/
c4cc03815k
Fig. 2 (a) The Achmatowicz reaction. (b) Envisioned one-pot formation of
3-pyrones from acyclic starting materials.
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methodologies is a rapidly expanding field in organic synthesis.15
It was therefore envisioned that multi-substituted 3-pyrones could
be obtained via an organocatalytic one-pot cascade reaction,
forming the hydroxy substituted furans needed for the final
Achmatowicz step in situ.16
Initial investigations revealed that furans 6, formed via an
asymmetric organocatalytic epoxidation of nonenal 1 followed by
cyclisation with 2,4-pentanedione 4 and subsequent CSA catalysed
aromatisation, could serve as substrates for the Achmatowicz reac-
tion when m-CPBA was used as oxidant. When the reaction sequence
was performed in toluene, the entire cascade could, as envisioned,
be completed under one-pot conditions, without isolation of any
intermediates. Through a screening of oxidants (see ESI†), NBS with
addition of water was found to be a superior alternative to m-CPBA.
Furthermore, the chiral CSA was found to be replaceable with TFA.
Notably, the observed diastereomeric ratio is under thermodynamic
control, underlined by the observation of minor amounts of the
open chain triketone as well as inseparability of the diastereomeric
hemi-ketals. As such the diastereomeric ratio was not significantly
affected by either change of reaction conditions or choice of solvent.
With the optimised one-pot cascade established, investigations
were directed towards the scope of the reaction (Scheme 1). Incor-
poration of various alkyl substituents in the 2-position of the
3-pyrone products (originating from 1) was carried out, successfully
demonstrating incorporation of primary alkyl groups (7a–c), a
secondary alkyl group (7d) and a cyclohexyl group (7e), all in good
yields and excellent enantioselectivities. The scope is limited by the
variety of reaction conditions which the aldehyde derived substi-
tuent has to sustain; unsatisfactory results were obtained for
a,b-unsaturated aldehydes carrying conjugated substituents such
as an ester or phenyl, as well as unsaturated alkyl chains.
Variation of the substituent at the 5- and 6- position of the
3-pyrone products was demonstrated through the application of a
selection of b-carbonyl compounds 4. An unsymmetric diketone was
successfully incorporated giving rise to the product in acceptable
yield and excellent enantiomeric excess, interestingly as a single
regioisomer (7f) despite the observation of a mixture of regioiso-
meric furan intermediates, supporting thermodynamic control of
the hemi-ketal ring closure. Ester substituted products were synthe-
sised in improved yields at the expense of slightly lowered diaster-
eoselectivities, but with maintained enantioselectivity (7g,h).
The substituent at the anomeric centre was successfully varied
through the incorporation of commercial b-keto esters, giving rise
to the products in good yields and excellent enantioselectivities
(7i–k). The improved diastereoselectivity observed for these sub-
strates can be attributed to the preference for pseudo equatorial
positioning of the larger substituents, adding to the generally
observed anomeric effect. Finally, replacement of one of the
carbonyl groups for an electron-poor aromatic ring was demon-
strated to be possible, affording the desired product with high
diastereoselectivity, however in slightly decreased yield and enan-
tiomeric excess (7l). An important limitation to the nucleophile
scope was found to be the inability of furans derived from cyclic
1,3-diketones to undergo the Achmatowicz reaction.
Scheme 1 Formation of chiral 3-pyrones. Major diastereomer depicted.
See ESI† for details. a ee of minor diastereomer could not be established.
evident that the anomeric effect allows the diastereomer with the
hydroxy group pseudo-axial to form as the major product.
The absolute stereochemistry of the products 7 follows from
the stereospecificity of the Achmatowicz reaction,10 as the abso-
lute stereochemistry of the intermediary furans is known.16 The
enantioselectivity originates from the well-studied organocataly-
tic epoxidation reaction.17
Having established the substituent scope of the reaction,
our attention turned towards selective reductive transforma-
tions of the obtained products. This constituted a major
challenge, as the products contain four possible candidates
for reduction, thus careful selection of reaction conditions would
be crucial for success. The Kishi reduction is a well-described
The relative stereochemistry of the two diastereomers of pro-
duct 7a was established by NOESY (Fig. 3), from which it was
Fig. 3 Determination of relative stereochemistry.
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Scheme 4 Selective hydrogenation/elimination.
Scheme 2 Selective Kishi reduction of hemi-ketal.
silane-mediated reduction of hemi-acetals to their corres-
ponding ethers, and we envisioned it would be sufficiently mild
to afford selective reduction in our system.13,18 Delightfully, the
unoptimised reaction proved successful, forming the desired
dehydroxy product 8 in moderate yield, with conserved enan-
tioenrichment and improved diastereomeric control (Scheme 2).
Next, investigations focused on the regioselective reduction
of the ketone functionality, and Luche conditions, which are
known to reduce unsaturated ketones in a 1,2-selective manner,
stood forward as the method of choice.19
Interestingly, the exocyclic ketone was selectively reduced
(Scheme 3a). To rationalise the formation of the product 9 as
exclusively one diastereoisomer, it is important to consider that
cerium catalyses the exchange of hydride with alcohols in the
reduction agent. We suggest that this allows the neighbouring axial
hydroxy group in 7a to direct the reducing agent in a tethered
fashion (Scheme 3b). Dictated by the Bu¨rgi–Dunitz trajectory, the
product 9 can then exclusively be formed from the major diaster-
eomer of 7a, thereby giving rise to the observed complete diastereos-
electivity. The relative stereochemistry of the product was confirmed
by NOESY (Scheme 3c).
To selectively modify the final main functionality of the 3-pyrone,
hydrogenation of the C–C-double bond was attempted. The reaction
was unsuccessful in methanol, but proceeded smoothly in ethyl
acetate. Interestingly, elimination immediately followed, affording
the product 10 in moderate yield under unoptimised conditions,
and with preserved enantiomeric excess (Scheme 4). Attempts to
avoid the elimination were unsuccessful, suggesting high thermo-
dynamic stability of the tetra-substituted olefin.
Results outlining the development of a new organocatalytic
one-pot reaction cascade for the annulation of chiral 3-pyrone
derivatives in good yields and excellent enantiomeric excesses
have been presented. A wide selection of functional groups has
successfully been incorporated in the products to demonstrate 12 A. Fu
ring systems have been conducted, in all cases affording the
desired products regio- and stereoselectively in good yield.
This work has been made possible by financial support from
Aarhus University, the Carlsberg Foundation and FNU.
Notes and references
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Scheme 3 Selective Luche reduction of the exocyclic ketone. (a) Reaction
conditions. (b) Tethered reaction intermediate. (c) Notable observed NOEs.
7606 | Chem. Commun., 2014, 50, 7604--7606
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