Skeletal Editing Strategies Driven by Total Synthesis DOI
Sojung F. Kim, Charis Amber, G. Logan Bartholomew

и другие.

Accounts of Chemical Research, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast broader remodeling rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex such as natural products or pharmaceuticals. For past several years, our laboratory has developed methodologies, including ring contractions, expansions, transpositions both saturated unsaturated heterocycles, well other carbon scaffolds. This Account details evolution "skeletal logic" context extensive work on product total synthesis.Early in Sarpong group leveraged metal-mediated C-C bond cleavage situ-generated strained intermediates accomplish syntheses products, icetexane diterpenoids cyathane diterpenes. Continuing focus leveraging through "break-it-to-make-it" we then carvone access a variety terpenoids (including longiborneol sesquiterpenoids, phomactins, xishacorenes) from hydroxylated pinene derivatives. applying this framework alkaloid preparaherquimides lycodine-type alkaloids, recognized nitrogen-containing rings would enable direct conversion between distinct structurally related families. Thus, began developing methods selectively N-heterocycles; led deconstructive fluorination diversification piperidines ultimately recent body direct, modifications (single-atom editing). photomediated enantioselective contractions α-acylated motifs reductive cyclic hydroxylamines. azines (e.g., pyrimidine pyrazole), 15N isotopic labeling azines, phototranspositions indazoles benzimidazoles. To reaction development, cheminformatic analysis heteroaromatic edits served quantitatively inform which transformations most significantly expand accessible chemical space. Apart also reported single-nitrogen insertion amination carbonyl bonds. Ultimately, goal research is develop mild selective can be applied generally. While targeted simplified retrosyntheses logic daphenylline harringtonolide), multiple steps were still required achieve formal desired "edit". As such, continued development truly single-step, mild, reactions edit cores highly remains desirable.

Язык: Английский

Two-Step Constitutional Isomerization of Saturated Cyclic Amines Using Borane Catalysis DOI Creative Commons
Charis Amber,

Timothée M. Petitjean,

Giedre Sirvinskaite

и другие.

JACS Au, Год журнала: 2025, Номер 5(2), С. 851 - 857

Опубликована: Янв. 21, 2025

The prevalence of saturated azacycles within pharmaceuticals, natural products, and agrochemicals has prompted the development many methods that modify their periphery. In contrast, technologies interconvert distinct azacyclic frameworks, which would uniquely facilitate access to underexplored chemical space, are highly limited. Existing approaches for modifying core usually require either installation reactive functionality, must later be removed in subsequent steps, or use tailored substrates, limiting applicability drug discovery. Herein, we report a borane-catalyzed contraction N-hydroxy azacycles. This transformation is enabling, allowing reorganization connectivity substrate without altering molecular formula generating products vestigial functionality derived from auxiliary groups. outcome reductive Stieglitz-type can attributed key stereoelectronic interaction enforced by geometric constraints, mechanism investigate using density functional theory. method developed here enables rapid late-stage bioactive molecules featuring cyclic linear amines. Overall, general platform amine constitutional isomerization been achieved.

Язык: Английский

Процитировано

1
Ylide-Induced Ring Contraction of Coumarins to Benzofurans: Applications to the Synthesis of Bis-Heterocycles DOI
Sandeep Kumar,

Dinesh Kumar Gopalakrishnan,

Shashank Shrotriya

и другие.

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

We report an unusual ring contraction of 4-chlorocoumarin to benzofuranoyl sulfoxonium ylides using a Corey-ylide. These stabilized were subsequently utilized for the synthesis various valuable bis-heterocycles under both metal and metal-free conditions. The synthetic utility this method is illustrated through known bioactive compounds. Detailed mechanistic investigations quantum chemical calculations have provided insights into mechanism reaction.

Язык: Английский

Процитировано

0
ANROFRC Enables Skeletal Editing of 4-Arylpyrimidines into Diverse Nitrogen Heteroaromatics DOI Creative Commons
Haiyan Fu, Shun Li,

Yonglin Shi

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Abstract Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold strategies are thriving and evolving, one-to-multiple remain challenging to design. We present here novel for the skeletal editing of pyrimidines into wide range heteroarenes through addition nucleophiles, ring-opening, fragmentation, ring-closing (ANROFRC) processes. This method features in situ generation vinamidinium salt intermediate, which serves as unique N-C-C-C four-atom (A4) synthon that reacts with A1 A2 synthons. Mechanistic studies reveal C4-aryl substituents play crucial role stabilizing intermediate. work provides powerful tool systematic construction modification nitrogen heterocycles, thereby expanding conventional molecular techniques.

Язык: Английский

Процитировано

0
Skeletal Editing Strategies Driven by Total Synthesis DOI
Sojung F. Kim, Charis Amber, G. Logan Bartholomew

и другие.

Accounts of Chemical Research, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast broader remodeling rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex such as natural products or pharmaceuticals. For past several years, our laboratory has developed methodologies, including ring contractions, expansions, transpositions both saturated unsaturated heterocycles, well other carbon scaffolds. This Account details evolution "skeletal logic" context extensive work on product total synthesis.Early in Sarpong group leveraged metal-mediated C-C bond cleavage situ-generated strained intermediates accomplish syntheses products, icetexane diterpenoids cyathane diterpenes. Continuing focus leveraging through "break-it-to-make-it" we then carvone access a variety terpenoids (including longiborneol sesquiterpenoids, phomactins, xishacorenes) from hydroxylated pinene derivatives. applying this framework alkaloid preparaherquimides lycodine-type alkaloids, recognized nitrogen-containing rings would enable direct conversion between distinct structurally related families. Thus, began developing methods selectively N-heterocycles; led deconstructive fluorination diversification piperidines ultimately recent body direct, modifications (single-atom editing). photomediated enantioselective contractions α-acylated motifs reductive cyclic hydroxylamines. azines (e.g., pyrimidine pyrazole), 15N isotopic labeling azines, phototranspositions indazoles benzimidazoles. To reaction development, cheminformatic analysis heteroaromatic edits served quantitatively inform which transformations most significantly expand accessible chemical space. Apart also reported single-nitrogen insertion amination carbonyl bonds. Ultimately, goal research is develop mild selective can be applied generally. While targeted simplified retrosyntheses logic daphenylline harringtonolide), multiple steps were still required achieve formal desired "edit". As such, continued development truly single-step, mild, reactions edit cores highly remains desirable.

Язык: Английский

Процитировано

0