DOI: 10.1002/chem.201402684
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Asymmetric Catalysis
Stereodivergent Organocatalytic Intramolecular Michael Addition/
Lactonization for the Asymmetric Synthesis of Substituted
Dihydrobenzofurans and Tetrahydrofurans
Dorine Belmessieri, Alix de la Houpliere, Ewen D. D. Calder, James E. Taylor, and
Andrew D. Smith*[a]
Abstract: A stereodivergent asymmetric Lewis base cata-
lyzed Michael addition/lactonization of enone acids into sub-
stituted dihydrobenzofuran and tetrahydrofuran derivatives
is reported. Commercially available (S)-(À)-tetramisole hydro-
chloride gives products with high syn diastereoselectivity in
excellent enantioselectivity (up to 99:1 d.r.syn/anti, 99% eesyn),
whereas using a cinchona alkaloid derived catalyst gives the
corresponding anti-diastereoisomers as the major product
(up to 10:90 d.r.syn/anti, 99% eeanti).
Introduction
molecular organic photocatalytic polar-radical cyclisation reac-
tions between alcohols and alkenes to form a range of substi-
tuted THFs with modest levels of diastereoselectivity.[5]
Substituted tetrahydrofurans (THFs) and dihydrobenzofurans
are important structural motifs found within many natural
products and biologically active molecules.[1] For example, THF
and dihydrobenzofuran cores are found within natural-product
classes including macrolides,[1a,e] pterocarpans,[1b] acetoge-
nins,[1f] polyether ionophores,[1h] and plant lignans.[1d,i] As a con-
sequence, a large number of asymmetric synthetic methodolo-
gies towards both substituted THFs and dihydrobenzofurans
has been developed.[2,3] However, there are relatively few orga-
nocatalytic methodologies for the synthesis of either THFs or
dihydrobenzofurans.
Substituted dihydrobenzofurans have also been synthesized
by using organocatalysis,[6] with both imine- and enamine-
based strategies used to construct the dihydrobenzofuran ring
stereoselectively. For example, Jørgensen and co-workers re-
ported that mandelic acid salts of primary amino-cinchona al-
kaloid 2 catalyze the intramolecular cyclisation of aryloxyaceto-
phenones containing a pendant enone 1 to form syn-2,3-sub-
stituted dihydrobenzofuran derivatives 3 (up to 83:17 d.r.syn/anti
)
in good yield with high enantioselectivity (up to 99% eesyn
;
Scheme 1a).[6a] Zhou and co-workers have reported that a pri-
mary amine/thiourea bifunctional catalyst promotes a related
intramolecular cyclisation onto nitro-alkenes, forming anti-2,3-
dihydrobenzofurans with reasonable levels of diastereoselectiv-
ity and high enantioselectivity.[6b] However, considering their
synthetic importance, the development of catalytic asymmetric
routes towards substituted THF and dihydrobenzofuran deriva-
tives is still a worthwhile goal.
One strategy that has been utilized for the organocatalytic
synthesis of THFs is intramolecular oxy-Michael addition to
construct the THF ring.[4] For example, Asano and Matsubara
showed that a thiourea–cinchona alkaloid-based bifunctional
organocatalyst effectively promotes the asymmetric intramo-
lecular oxy-Michael addition of e-hydroxy-a,b-unsaturated ke-
tones to form a range of 2-substituted THF derivatives in excel-
lent yield with high levels of enantioselectivity.[4c] More recent-
ly, Corbett and Johnson have synthesized highly functionalized
bicyclic dialkyl ethers through a diaryl prolinol-catalyzed inter-
molecular oxy-Michael addition/Michael desymmetrization re-
action between p-quinols and a,b-unsaturated aldehydes,
giving a range of products in high levels of diastereo- and
enantioselectivity.[4b] Nicewicz and co-workers have reported
an alternative approach to THFs through both intra- and inter-
We have previously developed a number of organocatalytic
methodologies based on Michael addition/cyclization cascades
of Michael acceptors with ammonium enolates generated from
isothiourea-based catalysts[7,8] and carboxylic acids.[9–11] For ex-
ample, this strategy has been successfully applied to the asym-
metric synthesis of dihydropyranones,[9g,j] dihydropyridones,[9i]
a-hydrazino esters,[9h] b-lactams,[9b] and more recently, for the
synthesis of pyridines[9e] and pyrones.[9c] Of particular relevance
is the application of this strategy to the highly diastereo- and
enantioselective synthesis of syn-2,3-substituted dihydrobenzo-
furans through (S)-(À)-tetramisole hydrochloride 5 catalyzed in-
tramolecular Michael addition/lactonization of in situ activated
enone acids 4, followed by nucleophilic ring-opening (Sche-
me 1b).[9j] This methodology was subsequently utilized for the
stereoselective synthesis of substituted pyrrolidine derivatives
[a] D. Belmessieri, A. de la Houpliere, E. D. D. Calder, Dr. J. E. Taylor,
Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St. Andrews
North Haugh, St. Andrews, KY16 9ST (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402684.
Chem. Eur. J. 2014, 20, 1 – 9
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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