4 research outputs found
Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines
Synthetic
approaches toward multigram preparation of spirocyclic
α,α-disubstituted pyrrolidines from readily available
starting materials are discussed. It was shown that although a number
of synthetic methodologies have been known to date, many of the title
compounds remain hardly accessible. The most appropriate literature
method (which relied on reaction of imines and allyl magnesium halide,
followed by bromocyclization) was identified and optimized. It was
found that the method is most fruitful for simple non-functionalized
substrates. Two novel approaches based on the Sakurai or Petasis reactions
of cyclic ketones, followed by hydroboration–oxidation at the
allyl moiety thus introduced, were elaborated. The latter method had
the largest scope and was beneficial for the substrates containing
organosulfur or protected amino functions. For the synthesis of 4-azaspiro[2.4]Âheptane,
an alternative synthetic scheme commencing from tert-butyl cyclopropanecarboxylate (instead of the corresponding ketone)
was developed. It was shown that the whole set of the methodologies
developed can be used for the synthesis of various spirocyclic α,α-disubstituted
pyrrolidinesî—¸advanced building blocks of potential importance
to medicinal and agrochemistryî—¸at up to a 100 g scale
Toward Lead-Oriented Synthesis: One-Pot Version of Castagnoli Condensation with Nonactivated Alicyclic Anhydrides
One-pot variation of Castagnoli condensation,
that is, reaction
of cyclic anhydrides, amines, and aldehydes, has been developed as
a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and
6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues.
Utility of the method to multigram preparation of building blocks
and synthetic intermediates was also demonstrated. The final products
are obtained in high yields and diastereoselectivity. The method fits
well in the concept of lead-oriented synthesis; in particular, it
can be used for the design of lead-like compound libraries, even if
the strictest cut-offs are applied to the physicochemical properties
of their members
Screening of Palladium/Charcoal Catalysts for Hydrogenation of Diene Carboxylates with Isolated-Rings (Hetero)aliphatic Scaffold
A series of seven palladium-containing composites, i.e., four Pd/C and three Pd(OH)2/C (Pearlman’s catalysts), was prepared using modified common approaches to deposition of Pd or hydrated PdO on charcoal. All the composites were tested in the catalytic hydrogenation of diene carboxylates with the isolated-ring scaffold, e.g., 5,6-dihydropyridine-1(2H)-carboxylates with 2-(alkoxycarbonyl)cyclopent-1-en-1-yl and hex-1-en-1-yl substituents at the C(4)-position. The performance of the composites was also studied via the hydrogenation of quinoline as a model reaction. The composites were characterized by transmission and scanning electron microscopy (TEM and SEM), powder X-ray diffraction, and low-temperature N2 adsorption. It was found that the composites containing Pd nanoparticles (NPs) of 5–40 nm size were the most efficient catalysts for the hydrogenation of dienes, providing the reduced products with up to 90% yields at p(H2) = 100 atm, T = 30 °C for 24 h. The method of Pd NPs formation had more effect on the catalyst performance than the size of the NPs. The catalytic performance of Pearlman’s catalysts (Pd(OH)2/C) in the hydrogenation of dienes was comparable to or lower than the performance of the Pd/C systems, though the Pearlman’s catalysts were more efficient in the hydrogenation of quinoline
One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones
A simple
and cost-effective one-pot parallel synthesis approach
to sulfides, sulfoxides, and sulfones from thiourea was elaborated.
The method combines two procedures optimized to the parallel synthesis
conditions: alkylation of thiourea with alkyl chlorides and mono or
full oxidation of in situ generated sulfides with H<sub>2</sub>O<sub>2</sub> or H<sub>2</sub>O<sub>2</sub>–(NH<sub>4</sub>)<sub>2</sub>MoO<sub>4</sub>. The experimental set up required commonly
used lab equipment: conventional oven and ultrasonic bath; the work
up includes filtration or extraction with chloroform. The method was
evaluated on an 81 member library of drug-like sulfides, sulfoxides,
and sulfones yielding the compounds on a 30–300 mg scale. A
small-scale synthesis of 2-(benzhydrylsulfinyl)Âacetamide (modafinil)
utilizing our approach resulted in similar efficiency to the published
procedures