Overarching
principles for salting-out extraction are long-established
but poorly disseminated. We highlight the opportunity for more widespread
application of this technique using the Hofmeister series as a foundational
basis for choosing the right salt. The power of this approach is exemplified
by the aqueous workup of a highly water-soluble nucleoside in which
the use of sodium sulfate allowed for high recoveries without relying
on back extraction.
This communication discloses the first instance of the enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)2 and PtBu3-HBF4. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 degrees C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine.
A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S(N)Ar coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of alpha-arylpyrrolidines during the course of the project. In this method, (-)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.
As
practitioners of organic chemistry strive to deliver efficient
syntheses of the most complex natural products and drug candidates,
further innovations in synthetic strategies are required to facilitate
their efficient construction. These aspirational breakthroughs often
go hand-in-hand with considerable reductions in cost and environmental
impact. Enzyme-catalyzed reactions have become an impressive and necessary
tool that offers benefits such as increased selectivity and waste
limitation. These benefits are amplified when enzymatic processes
are conducted in a cascade in combination with novel bond-forming
strategies. In this article, we report a highly diastereoselective
synthesis of MK-1454, a potent agonist of the stimulator of interferon
gene (STING) signaling pathway. The synthesis begins with the asymmetric
construction of two fluoride-bearing deoxynucleotides. The routes
were designed for maximum convergency and selectivity, relying on
the same benign electrophilic fluorinating reagent. From these complex
subunits, four enzymes are used to construct the two bridging thiophosphates
in a highly selective, high yielding cascade process. Critical to
the success of this reaction was a thorough understanding of the role
transition metals play in bond formation.
Here
we report the fluorination–dynamic kinetic resolution
(DKR) process for the commercial supply of belzutifan (MK-6482). Key
process safety and robustness issues in the Selectfluor fluorination
reaction were identified and addressed on the basis of increased mechanistic
understanding. Aggressive process optimization enabled a single-pot
direct isolation process that allowed delivery of the fluorodiol product
with low process mass intensity.
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