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1.
J Med Chem ; 66(23): 16388-16409, 2023 12 14.
Article in English | MEDLINE | ID: mdl-37991844

ABSTRACT

Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.


Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Proteolysis , Peptide Hydrolases/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
2.
J Am Chem Soc ; 143(1): 97-102, 2021 01 13.
Article in English | MEDLINE | ID: mdl-33369395

ABSTRACT

Intermolecular C-C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent 'ene'-reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, α-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.


Subject(s)
Alkenes/chemistry , Amides/chemical synthesis , Flavoproteins/chemistry , Oxidoreductases/chemistry , Alkylation/radiation effects , Biocatalysis/radiation effects , Catalytic Domain , Dinitrocresols/chemistry , Dinitrocresols/radiation effects , Flavoproteins/radiation effects , Light , Models, Chemical , Oxidoreductases/radiation effects
3.
ACS Cent Sci ; 2(5): 302-8, 2016 May 25.
Article in English | MEDLINE | ID: mdl-27280164

ABSTRACT

While preparative electrolysis of organic molecules has been an active area of research over the past century, modern synthetic chemists have generally been reluctant to adopt this technology. In fact, electrochemical methods possess many benefits over traditional reagent-based transformations, such as high functional group tolerance, mild conditions, and innate scalability and sustainability. In this Outlook we highlight illustrative examples of electrochemical reactions in the context of the synthesis of complex molecules, showcasing the intrinsic benefits of electrochemical reactions versus traditional reagent-based approaches. Our hope is that this field will soon see widespread adoption in the synthetic community.

4.
Nature ; 533(7601): 77-81, 2016 May 05.
Article in English | MEDLINE | ID: mdl-27096371

ABSTRACT

New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as "classics". Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.


Subject(s)
Carbon/chemistry , Chemistry Techniques, Synthetic , Hydrogen/chemistry , Oxidants/chemistry , Allyl Compounds/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Electrochemistry , Green Chemistry Technology , Oxidation-Reduction , Substrate Specificity
5.
J Org Chem ; 81(5): 1819-38, 2016 Mar 04.
Article in English | MEDLINE | ID: mdl-26863401

ABSTRACT

Significant efforts were made to complete a synthesis of the complex norcembranoid ineleganolide via a seemingly attractive strategy involving late-stage creation of the central seven-membered ring. While the two key enantioenriched building blocks were made via high-yielding sequences and their convergent union was efficient, the critical C4-C5 bond of this sterically congested natural product could never be forged. Several interesting examples of unexpected acid-base behavior and unanticipated proximity-induced reactivity accounted for most of the problems in the execution of the synthesis plan.

6.
J Org Chem ; 74(11): 4357-9, 2009 Jun 05.
Article in English | MEDLINE | ID: mdl-19413276

ABSTRACT

Peracetylated Neu5Ac2en methyl ester, an intermediate in the synthesis of the influenza neuraminidase inhibitor Relenza, has been synthesized in high yields from peracetylated Neu5Ac methyl ester by flash vacuum pyrolysis. Mechanistic evidence including deuterium labeled studies and DFT (B3LYP) calculations suggest this transformation proceeds via an intramolecular syn-elimination.


Subject(s)
N-Acetylneuraminic Acid/analogs & derivatives , Acetylation , Antiviral Agents , Enzyme Inhibitors/chemistry , Heating , Methods , N-Acetylneuraminic Acid/chemistry , Neuraminidase/antagonists & inhibitors , Organic Chemistry Phenomena , Vacuum , Zanamivir
7.
Carbohydr Res ; 343(5): 936-40, 2008 Apr 07.
Article in English | MEDLINE | ID: mdl-18282561

ABSTRACT

Sialic acid, an important carbohydrate found incorporated on the cell surface of many organisms, has been modified for use in a wide range of biological and pharmaceutical applications. We hypothesized that 4,7,8,9-tetra-O-acetyl-2-deoxy-2,3-dehydro-N-acetyl neuraminic acid methyl ester (4) could be efficiently synthesized in a one-pot reaction by heating peracetylated sialic acid (2) in pyridine and acetic anhydride to induce beta-elimination. When reduced to practice, this reaction produced only modest yields of 4. Six compounds, including three new decarboxylated sialic acid dimers, were also found to have been synthesized in the reaction. In an effort to better understand the chemistry and the mechanisms of this reaction, all of the side products were isolated and fully characterized.


Subject(s)
N-Acetylneuraminic Acid/chemical synthesis , Neuraminic Acids/chemical synthesis , Sialic Acids/chemical synthesis , Decarboxylation , Dimerization , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Chemical , Molecular Structure , N-Acetylneuraminic Acid/analogs & derivatives , N-Acetylneuraminic Acid/chemistry , Neuraminic Acids/chemistry , Sialic Acids/chemistry
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