We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.
To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C–C and C–N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late-stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.
Driven by the ever-increasing pace
of drug discovery and the need
to push the boundaries of unexplored chemical space, medicinal chemists
are routinely turning to unusual strained bioisosteres such
as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their
lead compounds. Too often, however, the difficulty of installing these
fragments surpasses the challenges posed even by the construction
of the parent drug scaffold. This full account describes the development
and application of a general strategy where spring-loaded, strained
C–C and C–N bonds react with amines to allow for the
“any-stage” installation of small, strained ring systems.
In addition to the functionalization of small building blocks and
late-stage intermediates, the methodology has been applied to bioconjugation
and peptide labeling. For the first time, the stereospecific strain-release
“cyclopentylation” of amines, alcohols, thiols,
carboxylic acids, and other heteroatoms is introduced. This report
describes the development, synthesis, scope of reaction, bioconjugation,
and synthetic comparisons of four new chiral “cyclopentylation”
reagents.
A unified approach to ent-atisane diterpenes and
related atisine and hetidine alkaloids has been developed from ent-kaurane (−)-steviol (1). The conversion
of the ent-kaurane skeleton to the ent-atisane skeleton features a Mukaiyama peroxygenation with concomitant
cleavage of the C13–C16 bond. Conversion to the atisine skeleton
(9) features a C20-selective C–H activation using
a Suárez modification of the Hofmann–Löffler–Freytag
(HLF) reaction. A cascade sequence involving azomethine ylide isomerization
followed by Mannich cyclization forms the C14–C20 bond in the
hetidine skeleton (8). Finally, attempts to form the
N–C6 bond of the hetisine skeleton (7) with a
late-stage HLF reaction are discussed. The synthesis of these skeletons
has enabled the completion of (−)-methyl atisenoate (3) and (−)-isoatisine (4).
The distinct experimentally observed regiochemistries of the reactions between mesoionic münchnones and β-nitrostyrenes or phenylacetylene are shown by DFT/BDA/ETS-NOCV analyses of the transition states to be dominated by steric and reactant reorganization factors, rather than the orbital overlap considerations predicted by Frontier Molecular Orbital (FMO) Theory.
The ubiquity of nitrogen-containing
small molecules in medicine
necessitates the continued search for improved methods for C–N
bond formation. Electrophilic amination often requires a disparate
toolkit of reagents whose selection depends on the specific structure
and functionality of the substrate to be aminated. Further, many of
these reagents are challenging to handle, engage in undesired side
reactions, and function only within a narrow scope. Here we report
the use of diazirines as practical reagents for the decarboxylative
amination of simple and complex redox-active esters. The diaziridines
thus produced are readily diversifiable to amines, hydrazines, and
nitrogen-containing heterocycles in one step. The reaction has also
been applied in fluorous phase synthesis with a perfluorinated diazirine.
A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with baker's yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.
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