Communications
DOI: 10.1002/anie.201003304
Domino Reactions
Concise Synthesis of Tetrahydropyrans by a Tandem Oxa-Michael/
Tsuji–Trost Reaction**
Liang Wang, Pengfei Li, and Dirk Menche*
Dedicated to Professor G. Helmchen on the occasion of his 70th birthday
Metal complexes have been successfully applied to a broad
range of organic transformations and occupy a central
position in preparative organic chemistry. In recent years,
the notion of combining several metal-mediated processes in
relay-type domino sequences has been attracting attention.[1,2]
Through the combination of several synthetic transformations
in a one-pot fashion, domino reactions efficiently transform
simple starting materials into products of structural complex-
ity. Surprisingly, oxa-Michael reactions have not been devel-
oped for such purposes, despite their obvious potential for
heterocycle synthesis, presumably because of the inherent
instability of the generated enolates towards eliminations or
retro processes.[3] Herein, we report the design and develop-
Scheme 1. Three-step tandem concept for the synthesis of tetrahydro-
pyrans.
ment of a conceptually novel cascade reaction based on an
oxa-Michael addition and an allylic substitution,[4] and
successfully implement this concept for the highly concise
synthesis of polysubstituted tetrahydropyrans.
then be generated (step 2), which would finally be trapped in
an intramolecular fashion through an allylic substitution
reaction, generating the desired THP motif in a highly direct
fashion (step 3). Notably, three new stereogenic centers are
assembled in this process, demonstrating a high increase in
structural complexity from very simple starting materials. It
should also be noted that the synthetic design is highly
convergent and flexible and may be readily adapted to various
other substrates enabling direct access to a broad range of
heterocycles.
Based on initial experiments with different Michael
acceptors,[19] nitroolefins were selected for further develop-
ment. The coupling of alcohol 6[20] and nitroolefin 7[21] was
studied in more detail (Table 1). Gratifyingly, after we had
evaluated reagents (bases, catalysts, ligands) and parameters
(temperature, solvent) our synthetic strategy could be suc-
cessfully implemented to generate the desired THP motif 8.
The best conditions included catalytic amounts of [{Pd-
(allyl)Cl}2] with PPh3 in combination with LiHMDS as th base
(Table 1, entry 10).[22] The absence of PPh3 resulted in lower
yields (Table 1, entries 8 and 10) and alternative ligands led to
lower selectivities [P(iOPr)3, P(OEt)3: Table 1, entries 11 and
12] or conversions (dppf, dppp, dppe, dppb: Table 1,
entries 13 and 14, footnote [h]). Methyl and tert-butyl car-
bonate proved to be the best leaving groups of those
evaluated (Table 1, entries 5–8). While in principle it might
be possible to run the reaction with the tert-butoxy-substi-
tuted substrate using only catalytic amounts of base, only low
degrees of conversion were observed in such cases (Table 1,
entries 8 and 9). Encouragingly, out of the eight possible
products only two major (8a, 8b) and one minor isomer (8c)
formed, suggesting a high degree of conformational bias in
this sequential process (see below). The major products differ
Substituted tetrahydropyrans (THPs) are prevalent con-
stitutional chemotypes and underlying structural motifs in
numerous natural products, registered drugs, and bioactive
synthons.[5] Various strategies for the construction of such
systems have been reported,[6] including cyclizations involving
oxocarbenium ions[7] and epoxides,[8] hetero-Diels–Alder
reactions,[9,10] Prins cyclizations,[11] intramolecular nucleo-
philic reactions,[12] Michael reactions,[13] reductions of cyclic
hemiacetals,[14] cyclizations involving nonactivated double
bonds,[15] and one-pot procedures based on alkene–alkyne
couplings followed by ether formation.[16] Inspired by present
targets in our group in combination with certain limitations of
these existing methods, we desired a more direct and concise
sequence for THP synthesis. As shown in Scheme 1, our
synthetic concept is based on a three-step sequential process
involving an oxa-Michael addition[3,17] and a Tsuji–Trost
coupling.[18] Accordingly, the readily available homoallylic
alcohol 1 should first add to the suitably acceptor-substituted
alkene 2 giving enolate 3 (step 1). A p-allyl complex 4 would
[*] L. Wang, Dr. P. Li, Prof. Dr. D. Menche
University of Heidelberg, Department of Organic Chemistry
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-54-4205
E-mail: dirk.menche@oci.uni-heidelberg.de
[**] Generous financial support from the Deutsche Forschungsge-
meinschaft (SFB 623 “Molekulare Katalysatoren: Struktur und
Funktionsdesign”) and the Wild-Stiftung is gratefully acknowledged.
We thank Prof. G. Helmchen for helpful discussions and sugges-
tions.
Supporting information for this article is available on the WWW
9270
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9270 –9273