The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.
The total synthesis of (±)-streptonigrin,
a potent tetracyclic
aminoquinoline-5,8-dione antitumor antibiotic that reached phase II
clinical trials in the 1970s, is described. Two routes to construct
a key pentasubstituted pyridine fragment are depicted, both relying
on ring-closing metathesis but differing in the substitution and complexity
of the precursor to cyclization. Both routes are short and high yielding,
with the second-generation approach ultimately furnishing (±)-streptonigrin
in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate.
This synthesis will allow for the design and creation of druglike
late-stage natural product analogues to address pharmacological limitations.
Furthermore, assessment of a number of chiral ligands in a challenging
asymmetric Suzuki–Miyaura cross-coupling reaction has enabled
enantioenriched (up to 42% ee) synthetic streptonigrin intermediates
to be prepared for the first time.
In
one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclinical
studies, we needed a strategy to enable supply of two candidates in
a cost-effective and productive manner. The active pharmaceutical
ingredients (APIs) were structurally complex and were initially obtained
via long linear sequences resulting in time-consuming manufactures.
In addition, both two candidates comprised a biaryl fragment with
hindered rotation along the chiral axis. As a result, a pair of stable
atropisomers was generated for each candidate. With special attention
to the chromatographic challenges for the atropisomer separation and
for the API purification, this article describes our initial efforts
to develop synthetic routes that were amenable for multigram synthesis
of our two drug candidates. In particular, the consequences of implementing
a key Suzuki reaction late or early in the sequence are discussed.
Route
design and proof of concept synthesis was conducted on a
synthetically challenging atropisomeric KRASG12C inhibitor
to support clinical API manufacture. Improvements to the synthesis
of a chiral piperazine fragment gave reduced step count and streamlined
protecting group strategy via the formation and methanol ring opening
of an N-carboxy-anhydride (NCA). The complex atropisomeric
nitroquinoline was accessed via an early stage salt-resolution followed
by a formal two-part nitromethane-carbonylation, avoiding a high temperature
Gould–Jacobs cyclization that previously led to atropisomer
racemization. The substrate scope of the formal nitromethane-carbonylation
strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.
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