A catalytic formal [5+2] cycloaddition approach to the diastereoselective synthesis of azepino[1,2-a]indoles is reported. The reaction presumably proceeds through a Lewis acid catalyzed formal [2+2] cycloaddition of an alkene with an N-indolyl alkylidene β-amide ester to form a donor-acceptor cyclobutane intermediate, which subsequently undergoes an intramolecular ring-opening cyclization. Azepine products are formed in up to 92% yield with high degrees of diastereoselectivity (up to 34:1 d.r.).
GSK3527497,
a preclinical candidate for the inhibition of TRPV4,
was identified starting from the previously reported pyrrolidine sulfonamide
TRPV4 inhibitors 1 and 2. Optimization of
projected human dose was accomplished by specifically focusing on
in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel
approach to modulate Vdssu and present results that suggest
that molecular-shape-dependent binding to tissue components governs
Vdssu in addition to bulk physicochemical properties. Optimization
of CLu within the series was guided by in vitro metabolite
identification, and the poor FaSSIF solubility imparted by the crystalline
properties of the pyrrolidine diol scaffold was improved by the introduction
of a charged moiety to enable excellent exposure from high crystalline
doses. GSK3527497 is a preclinical candidate suitable for oral and
iv administration that is projected to inhibit TRPV4 effectively in
patients from a low daily clinical dose.
The
calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl
alkylidene β-ketoesters with mono- and disubstituted aryl olefins
to form cyclohepta[b]indole derivatives has been
established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether
revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged
cyclohepta[b]indoles. Overall, the method’s
highlights include: (1) use of a green, calcium-based catalyst (2.5
mol % loading); (2) reaction times under 1 h; (3) mild reaction conditions;
(4) substrate-derived chemodivergence; (5) functional group tolerance;
and (6) examples of derivatization.
Continuous flow processing represents
an emerging technology in
the chemical and pharmaceutical industries. Herein, we describe a
tandem, bicatalytic continuous flow cyclopropanation-homo-Nazarov-type
ring-opening cyclization to form hydropyrido[1,2-a]indoles, which represents a naturally occurring chemical scaffold
present in many bioactive and therapeutically relevant molecules.
The tandem flow reactions provided high conversions (>97%) with
product
throughputs on the order of 3–5 g h–1. The
individual transformations (cyclopropanation and ring-opening cyclization)
were separately optimized in the batch then successfully transferred
to the flow. Significantly, this represents the first literature example
of continuous flow cyclopropane ring-opening cyclizations; hydropyrido[1,2-a]indoles are formed on a multigram scale (>4 g h–1 throughput) in near-quantitative yields from N-indolyl-1,1-cyclopropyl
β-amidoesters. Overall, the continuous flow technology exhibited
superior yields, relative to the batch reactions, for both the ring-opening
cyclizations and the tandem, bicatalytic reactions. These results
provide the basis for large-scale implementation of bicatalytic cyclopropanation-ring-opening
cyclization reactions for complex synthesis and represent initial
efforts toward the development of an industrially viable, four-step
continuous flow synthesis of hydropyrido[1,2-a]indoles.
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