C O M M U N I C A T I O N S
levels of biologically and medicinally relevant functionality. Ortho-
substituted salicylate esters are a common structural motif found
in a growing number of benzolactone natural products with desirable
biological properties (e.g., the antitumor compound radicicol).10
Acylation-based macrolactonizations of ortho-substituted salicylic
acid substrates are challenging due to increased electron density
and steric hindrance at the acyl carbon center.11 Under the allylic
oxidation conditions, we found that both MOM- and benzyl-
protected, ortho-substituted salicylic acids readily cyclize to afford
the corresponding 14-membered ring macrolides 12 and 13 in 57%
yields (eq 2).
by 13C NMR spectroscopy showed a Pd-bound carboxylate sug-
gestive of intermediate 17 (13CdO: 16, δ 170.7; 17, δ 178.6;14 3,
δ 166.6). Evidence for the monomeric nature of 17 was obtained
via ESI-HRMS (C18H23O4Pd [M + H]+, predicted 409.0639, found
409.0598). Addition of BQ to 17 results in formation of macrolide
3 in 52% yield (62% catalytic reaction, Table 1, entry 1). Signif-
icantly, in the absence of BQ, reductive elimination is not observed.
These studies confirm that macrolactonization proceeds via a serial
ligand catalysis mechanism and provide evidence in support of BQ-
promoted inner-sphere C-O bond formation from a templated
π-allylPd carboxylate intermediate.5b,6 According to this mechanism,
high dilutions are unnecessary because the catalyst dictates that
the maximum concentrations of reactive π-allyl and carboxylate
moieties are 5-10-fold lower than the substrate concentration.7
In summary, this report describes the first examples of Pd-
catalyzed macrolactonizations of ω-alkenoic acids via C-H oxida-
tion. These reactions proceed without the use of high-dilution or
Schlenk line techniques and display remarkable levels of selectivity
and scope. Mechanistic studies support that macrolactonization
proceeds via a Pd-templated π-allyl carboxylate intermediate such
as 17. Future studies will explore chemoselectivity issues with
respect to internal olefins5b and the effects of substrate and reagent
chirality on diastereoselectivity in the context of complex molecule
synthesis.
Acknowledgment. M.C.W. thanks the Henry Dreyfus Founda-
tion, the University of Illinois (UIUC), and Merck Research
Laboratories for financial support. K.J.F. is a Harvard University
graduate student completing doctoral work with M.C.W at UIUC.
L.E.S. thanks Harvard College for a summer undergraduate research
fellowship. We thank Dustin Covell for checking our experimental
procedure and Daniel Bachovchin for starting materials.
Supporting Information Available: Detailed experimental pro-
cedures, full characterization, and a complete list of authors for ref
12b. This material is available free of charge via the Internet at http://
pubs.acs.org.
The indole nucleus is of particular value to the medicinal chemist.
For example, a large number of indolocarbazoles of biological
interest are known like the PKC inhibitor rebeccamycin12a and the
related macrocyclic compound LY 333531 developed by Lilly.12b,c
Using the allylic C-H oxidative macrolactonization, a novel 17-
membered bis(indolyl)maleimide macrolide 14 was readily formed
in 58% isolated yield (eq 3). Macrolactonization of this nitrogen-
rich substrate serves to further highlight the broad functional group
compatibility of this C-H oxidation method.
Macrocyclic depsipeptides have been shown to exhibit potent
cytotoxic, antimicrobial, and anti-inflammatory properties.13 A linear
tripeptide containing an R-olefin tether was successfully cyclized
under these conditions to provide 19-membered depsipeptide 15
in 61% yield and 3:1 dr (eq 4). This preliminary result suggests
that remote chirality can direct the diastereoselectivity of macro-
lactone formation.
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chiometric mixtures of 13C-labeled alkenoic acid 16 and bis-
sulfoxide/Pd(OAc)2 complex 2 were heated and monitored by H
NMR spectroscopy, peaks consistent with a π-allylPd complex 17
were observed. Simultaneous monitoring of the C-H cleavage step
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