Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.
Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.
Activation of sp(3) C-H bonds adjacent to nitrogen in heterocycles is an attractive transformation that is emerging as a practical method in organic synthesis. This tutorial review aims to summarize the key examples of direct functionalization of nitrogen-containing heterocycles via metal-mediated and metal-catalyzed processes, which is meant to serve as a foundation for future investigations into this rapidly developing area of research. The review covers functionalization of N-heterocycles via alpha-lithiation with alkyllithium/diamine complexes, alpha-amino radical formation, metal-catalyzed direct C-H activation, C-H oxidations and oxidative couplings, and metal-catalyzed carbene insertions.
C
2-Symmetric bis(oxazolinyl)pyridine (pybox)−Cu(II) complexes have been shown to catalyze
enantioselective Mukaiyama aldol reactions between (benzyloxy)acetaldehyde and a variety of silylketene acetals.
The aldol products are generated in high yields and in 92−99% enantiomeric excess using as little as 0.5 mol
% of chiral catalyst [Cu((S,S)-Ph-pybox)](SbF6)2. With substituted silylketene acetals, syn reaction diastereoselection ranging from 95:5 to 97:3 and enantioselectivities ≥95% are observed. Investigation into the reaction
mechanism utilizing doubly labeled silylketene acetals indicates that the silyl-transfer step is intermolecular.
Further mechanistic studies revealed a significant positive nonlinear effect, proposed to arise from the selective
formation of the [Cu((S,S)-Ph-pybox)((R,R)-Ph-pybox)](SbF6)2 2:1 ligand:metal complex. A stereochemical
model is presented in which chelation of (benzyloxy)acetaldehyde to the metal center to form a square pyramidal
copper intermediate accounts for the observed sense of induction. Support for this proposal has been obtained
from double stereodifferentiating reactions, EPR spectroscopy, ESI spectrometry, and, ultimately, the X-ray
crystal structure of the aldehyde bound to the catalyst. The C
2-symmetric bis(oxazolinyl)−Cu(II) complex
[Cu((S,S)-tert-Bu-box)](OTf)2 is also an efficient catalyst for the aldol reaction, but the scope with this system
is not as broad.
Chiral diphosphines1 are the ligands of choice for a wide range of enantioselective transition-metal-catalyzed processes.2 While chirality may be independently incorporated on either
The scope of the Diels−Alder reaction catalyzed by bis(oxazoline) copper complexes has been
investigated. In particular, [Cu((S,S)-t-Bu-box)](SbF6)2 (1b) has been shown to catalyze the Diels−Alder reaction
between 3-propenoyl-2-oxazolidinone (2) and a range of substituted dienes with high enantioselectivity. This
cationic complex has also been employed in the catalysis of analogous intramolecular processes with good
success. The total syntheses of ent-Δ1-tetrahydrocannabinol, ent-shikimic acid, and isopulo’upone, featuring
the use of this chiral catalyst in more complex Diels−Alder processes, are described. Similarly, the cationic
copper complex 9a, [Cu((S,S)-t-Bu-pybox)](SbF6)2, is effective in the Diels−Alder reactions of monodentate
acrolein dienophiles while the closely related complex, 9d [Cu((S,S)-Bn-pybox)](SbF6)2, is the preferred Lewis
acid catalyst for acrylate dienophiles in reactions with cyclopentadiene.
A modular approach to the synthesis of a class of mixed phosphorus/sulfur ligands was designed to
identify important ligand structural features for enantioselective palladium-catalyzed allylic subsitutions of
acyclic and cyclic ayllic esters. After a systematic variation of the ligand substituents at sulfur, phosphorus,
and the ligand backbone, ligand 11k was found to be optimal in the palladium-catalyzed allylic substitution
of 1,3-diphenylpropenyl acetate with dimethyl malonate or benzylamine in high yield and excellent
enantioselectivity (95−98% ee). A similar optimization of the mixed phosphorus/sulfur ligand for the palladium-catalyzed allylic substitution of cycloalkenyl acetates showed that 49g afforded the highest enantioselectivities
(91−97% ee). Application of this methodology to heterocyclic substrates was developed as an efficient approach
to the enantioselective synthesis of 3-substituted piperidines and dihydrothiopyrans. Models for asymmetric
induction are discussed based on the absolute stereochemistry of the products, X-ray crystallographic data,
and NMR spectroscopic data for relevant π-allyl complexes.
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.
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