Conclusion
ARTICLES
additional products. The Swern reagent and AlEt2OEt/trifluoroace-
tone gave full, unselective conversion into multiple products that
bear olefins, as determined by 1H NMR spectroscopy. The reaction
of kirenol with DMP gave decomposition to a mixture of several
products, two of which contain aldehyde functionality, whereas
reaction with AlEt2OEt/trifluoroacetone gave full decomposition
to multiple products that bear new olefins.
The selective oxidation of one secondary alcohol among many can
be used strategically in a variety of synthetic contexts to alleviate the
need for protective groups to dictate site selectivity. The present cat-
alyst addresses this challenge and provides a foundation for further
advancements in hydrogen-transfer reactions involving X–H bonds.
Alcohols are the most common functional group in natural products
because of the selective hydroxylation of C–H bonds by P450
enzymes, whereas amino groups are less common because of the
lack of enzymes for a direct amination. Yet, nitrogen-based func-
tionality can impart favourable properties for biological activity.
The catalytic reactions that we have reported create new complex
architectures that could provide new leads for medicine, molecular
biology and agroscience. The ability to epimerize precisely the site of
an OH group, to convert an OH group into an NH group or to
incorporate nitrogen into the ring system or chain provides the
ability to combine nature’s spectacular synthetic prowess to create
complex architectures with modern catalytic synthetic chemistry
as a means to create unnatural products with enhanced physical
properties and function over those provided solely from
biosynthetic pathways.
The ability of modern oxidation and alternative transfer-dehydro-
genation catalysts to oxidize andrographolide, mupirocin methyl
ester and ouabain selectively was also assessed. The reaction of
andrographolide with benzoquinone and catalytic [Pd(neocu-
proine)(OAc)]2[OTf]2 (ref. 30), which was reported to oxidize sec-
ondary over primary alcohols in 1,2- and 1,3-diol units, gave
products that were similar to those of the reaction of DMP (65%
aldehyde, 30% keto-aldehyde and no 3-ketone). The attempted
oxidation of the same substrate with Ru-MACHO and KOH led to
a low conversion. Shvo’s dimer oxidized andrographolide under
optimized conditions to give a 43% yield of the 3-ketone, along
with three other products in 32, 19 and 4% yields derived from the
oxidation of the primary alcohol with a concomitant side reaction,
loss of the hydroxyenoate functionality and loss of the 1,1-disubsti-
tuted olefin, respectively. Ru-MACHO and KOH led to decompo-
sition of mupirocin methyl ester. Oxidation of mupirocin methyl
ester by Shvo’s dimer occurred concomitantly with multiple side
reactions, such that little product from the selective oxidation of
the alcohol to the ketone occurred. Waymouth’s catalyst gave a
low conversion of ouabain into multiple products, whereas the com-
bination of Ru-MACHO and KOH led to the decomposition of
ouabain without oxidation. Shvo’s dimer led to no conversion of
ouabain up to temperatures at which autodecomposition occurs.
Methods
General procedure for alcohol oxidation. Under N2, equimolar Ru-2 and
N-methylmorpholine (NMM) were combined in acetone or TFE to form a solution.
This solution was then added to a solution of the alcohol starting material in acetone
or a mixture of acetone and TFE in a vial, along with a magnetic stir bar if the
starting alcohol did not fully dissolve at room temperature. Next, the vial was sealed
and heated at 65 °C for several hours, with stirring if applicable. The reaction was
then cooled to room temperature and evaporated to dryness. Finally, the residue was
purified by recrystallization or column chromatography on silica gel.
Data availability. The data reported in this paper are available in the Supplementary
Materials. Crystallographic data for the structures reported in this paper are
Mechanistic analysis of kinetic versus thermodynamic origins of
the selectivity. The mechanism of ruthenium-catalysed transfer deposited at the Cambridge Crystallographic Data Centre (CCDC) under the
deposition numbers CCDC 1556838 (Ru-3-Cl), CCDC 1556837 (Ru-2-DABIII-
alkoxide), CCDC 1556836 (Ru-2), CCDC 1556835 (2e), CCDC 1556834 (2d),
CCDC 1556833 (2c) and CCDC 1556613 (1l). Copies of these data can be obtained
dehydrogenations is generally thought to begin by displacement
of one of the labile ligands with alcohol and the generation of a
ruthenium alkoxide7,31. When a tertiary amine is included in the
reactions, the generation of the alkoxide could occur by
deprotonation of the bound alcohol by an amine. In TFE solvent, no
base is needed for the alcohol oxidation to proceed (Fig. 1b), and
the generation of the alkoxide could occur by elimination of HOTf
stabilized by a substrate alcohol. β-hydrogen elimination from the
alkoxide would then generate the ketone and a ruthenium hydride. 1. Lewis, C. A. & Miller, S. J. Site-selective derivatization and remodeling of
The resulting hydride would insert acetone to form an isopropoxide
Received 20 March 2017; accepted 22 June 2017;
published online 14 August 2017
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