Visible-light-promoted
organic reactions can offer increased reactivity
and selectivity via unique reaction pathways to address a multitude
of practical synthetic problems, yet few practical solutions exist
to employ these reactions for multikilogram production. We have developed
a simple and versatile continuous stirred tank reactor (CSTR) equipped
with a high-intensity laser to drive photochemical reactions at unprecedented
rates in continuous flow, achieving kg/day throughput using a 100
mL reactor. Our approach to flow reactor design uses the Beer–Lambert
law as a guideline to optimize catalyst concentration and reactor
depth for maximum throughput. This laser CSTR platform coupled with
the rationale for design can be applied to a breadth of photochemical
reactions.
The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield on scales ranging to 13 mol. The effects of ligand structure, metal salt, and solvent on the reaction are described. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must be then removed to maximize stereoselectivity and reactivity. The reaction has been extended to other dicarbonyl substrates, and a variety of substitution patterns are tolerated on the nitroolefin partner. The reaction has also been employed in the synthesis of the antidepressant rolipram. Investigations relating to the mechanism of the reaction are also described.
[reaction: see text] Treatment of a variety of alcohols, amines, and N-hydroxylamines with 2,2,2-trifluoroethyl formate gave the corresponding formylated adducts in high yields.
Thioaldehydes containing virtually any -substitutent can be generated by photofragmentation of phenacyl sulfides. Donor-substituted derivatives are reactive toward electron-rich dienes and give 2 + 4 cycloadducts with regiochemistry corresponding to advanced C-C bonding in the transition state. Acceptor-substituted thioaldehydes react in the opposite regiochemical sense with C-S bonding advanced. A number of unusual thioaldehydes have been trapped, including the parent HCH=S, Me3SiCHS, Ph2P(0)CH=S, PhS02CH=S, and CNCH=S, as well as more conventional alkylor acyl-substituted derivatives.
Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A
convergent strategy required methodologies for preparation of
an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and
a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner.
A [3+2] cycloaddition of an enantiopure azomethine ylide
followed by a diastereoselective crystallization was employed
to prepare the benzopyranopyrrolidine in high diastereomeric
and enantiomeric purity. Conditions for reduction of an O-aryl
lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished
in high yield. The thienopyrazine was prepared by condensation
of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen
substitutive deamination to prepare regiospecific trisubstituted
pyrazines will be described.
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