Angewandte
Chemie
DOI: 10.1002/anie.200905949
Homogeneous Catalysis
Remote Control of Regio- and Diastereoselectivity in the
Hydroformylation of Bishomoallylic Alcohols with Catalytic Amounts
of a Reversibly Bound Directing Group**
Christian U. Grꢀnanger and Bernhard Breit*
The hydroformylation of olefins is the largest volume
application of homogeneous catalysis in industry with about
9 million tons of oxo products produced worldwide each
year.[1,2] In this transformation alkenes are reacted with
synthesis gas in the presence of a metal catalyst to furnish the
homologated aldehydes—a conversion in complete accord
with the criteria of atom economy.[3] The aldehydes formed
are useful functional groups suitable for further skeleton-
expanding transformations, which may be performed even as
tandem processes.[4] Despite these obvious advantages, the
hydroformylation of olefins is still not commonly employed in
the course of a complex synthesis, because of the difficulty in
controlling regio- and stereoselectivity simultaneously. A
number of catalysts exist today that allow the hydroformy-
lation of terminal aliphatic alkenes to give linear products
selectively (linear-selective).[5] Conversely, no catalyst is
known for a general hydroformylation of terminal and
internal alkenes to give branched products selectively
(branched-selective).[6] One solution to this problem has
been the use of removable catalyst-directing groups cova-
lently bound to the substrate that facilitate both regiocontrol
and acyclic stereocontrol in reactions of allylic and homo-
allylic alcohols.[7] However, an obvious drawback of this
approach is the requirement of additional steps for introduc-
tion and removal of the directing group as well as the need for
stoichiometric amounts. More preferable would be the use of
catalytic amounts of the directing group, as we have recently
shown in a supramolecular approach based on complemen-
tary hydrogen bonding between the substrate and the catalyst
system.[8] Alternatively, we and others have reported on the
use of catalyst-directing groups which bind covalently but
reversibly to the substrate.[9,10,11] Thus, we identified diphe-
nylphosphinites as ideal systems for the reversible transes-
terification of alcohols under hydroformylation conditions.
Hence, a highly regioselective hydroformlyation of homo-
allylic alcohols could be realized using this catalyst system to
furnish g-lactols in excellent yields (Scheme 1a).[9] The basis
for the observed high regioselectivity is the preference for the
transition state of an intramolecular 6-exo-trig hydrometalla-
tion over that of the 7-endo-trig alternative. Here, the
Scheme 1. Remote control of regioselectivity in the hydroformylation of
homoallylic and bishomoallylic alcohols.
functional hydroxy group to which the directing group is
bound has a 1,3-relation to the reacting functional group; this
is the maximum distance ever reported in directed hydro-
formylation to achieve efficient substrate control.[2]
We herein report that it is possible to shift the hydroxy
function to which the directing group becomes bound yet one
more atom further away from the reacting functional alkene
group into a remote 1,4-relation (Scheme 1b) and still get
excellent levels of both regioselectivity and diastereoselec-
tivity in the course of the hydroformylation. This can serve in
the atom-economical preparation of a wide range of d-lactols
and lactones and even structural units of polypropionate
natural products, all of which are important building blocks in
organic synthesis.
We began our studies on hydroformylation of pent-4-en-1-
ol (1) employing the reaction conditions we developed
previously for the position-selective hydroformylation of
homoallylic alcohols (Table 1). To our surprise, a smooth
hydroformylation reaction was observed with excellent levels
of regioselectivity in favor of the branched product, the d-
lactol 2 (Table 1, entry 1). However, the reaction was slower
than in the case of homoallylic alcohols, and thus conversion
[*] Dipl.-Chem. C. U. Grꢀnanger, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie und Biochemie
Freiburg Institute for Advanced Studies (FRIAS)
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg i. Brsg. (Germany)
Fax: (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the Fonds der Chemischen Industrie,
the DFG (“Catalysts and Catalytic Reactions for Organic Synthesis”,
GRK 1038), and the Krupp Foundation (Alfried Krupp Award for
young university teachers to B.B.). We thank Umicore and Wacker
for generous gifts of chemicals, Dr. M. Keller and Dr. J. Geier for
analytical help, and K. Rießle for laboratory assistance.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 967 –970
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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