Letter
Macrolactam Synthesis via Ring-Closing Alkene−Alkene Cross-
Coupling Reactions
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ABSTRACT: Reported herein is a practical method for macro-
lactam synthesis via a Rh(III)-catalyzed ring closing alkene−alkene
cross-coupling reaction. The reaction proceeded via a Rh-catalyzed
alkenyl sp2 C−H activation process, which allows access to
macrocyclic molecules of different ring sizes. Macrolactams
containing a conjugated diene framework could be easily prepared
in high chemoselectivities and Z,E stereoselectivities.
acrolide1 is a ubiquitous motif present in many
Mpharmaceuticals and biologically active molecules;
therefore, they are also considered to be important compounds
for the development of new drugs.2 Accordingly, much interest
has been devoted to access this class of compounds. Among
the methods, macrolactamization,3 macroaldolization,4 and
macrolactonization5 are the common strategies employed
widely to construct such macrocyclic compounds. In recent
years, macrolides such as macrolactams containing a
conjugated diene moiety, such as geldanamycin,6 vicenistatin,7
and cyclomenal A,8 have attracted much attention, because of
their interesting biologically activities. Although macrolactam-
ization has been commonly used for the synthesis of
macrolactams, the construction of macrolactam rings contain-
ing fixed geometrical configurations of diene moieties can be
challenging. In recent years, there has been much work
directed toward the development of catalytic carbon−carbon
bond macrocyclization reactions, including the ring-closing
metathesis (RCM) strategy.9 However, all these reported
strategies have some disadvantages, such as the need to use
expensive catalysts, difficulty in accessing the substrates,
average E,Z selectivity, etc. Moreover, contradictory to the
principles of the atom economy, these reactions produce
hazardous byproducts stoichiometrically. Inspired by the
excellent work of Glorius on the use of acrylamide directing
group for alkenyl sp2 C−H activation,10a our group has
developed a modified version of this reaction to obtain high
Z,E selective dienes, using acetone as the solvent.10b Recently,
we reported the construction of macrolactams containing diene
moieties11 through ring-closing alkene−alkene coupling
reactions,12 using acrylamide-directed alkenyl sp2 C−H
activation strategy with acrylates. This new ring-closing
strategy has many advantages over existing methods, such as
high atom economy, no need to use organometallics/organo
halides, easily accessible starting materials, and the versatile
diene moiety obtained can be easily converted to other useful
functionalities. Compared to acrylate fragments, α,β-unsatu-
rated ketone fragments are difficult to use in coupling
reactions, because they readily polymerize themselves.
Hence, we thought of extending our intramolecular alkene
coupling strategy to the α,β-unsaturated ketone fragments (see
Scheme 1). Data obtained from previous work13 and this work.
Indeed, the desired 14-membered-ring product 2b contain-
ing the diene moiety could be obtained in 32% yield as a single
Z,E configuration when catalyst [RhCp*Cl2]2 (2.5 mol %) was
utilized in the presence of additive AgSbF6 and oxidant
Cu(OAc)2·H2O at 100 °C in acetone (Table 1, entry 1).
Replacing acetone with other solvents, such as 1,2-dichloro-
ethane (DCE), toluene, or 1,4-dioxane failed to further
improve the coupling reaction (Table 1, entries 2−4). Notably,
the coupling product was not observed when the additive was
omitted (Table 1, entry 5). The nature of the additive
appeared to be critical. Representative additives such as
NaOAc, KOAc, KPF6, and NABARF have been screened
(Table 1, entries 6−9) and the combination of Cu(OAc)2·
H2O with NaBARF turned out to be advantageous, yielding
Received: November 16, 2020
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A
Goh, Jeffrey
