Construction of a 3D Molecular Library: Development of 910k Novel Drug Molecules Based on 16 Types of Spirocyclic Frameworks
Abstract and Background Introduction
Diversity-Oriented Synthesis (DOS) is one of the most groundbreaking strategies in modern medicinal chemistry, with its core value lying in systematically constructing structurally diverse molecular libraries to provide a rich material basis for innovative drug development. In the current paradigm of drug discovery, structural novelty often correlates positively with biological activity, which showcases the unique advantages of DOS strategies in overcoming existing bottlenecks in drug structures. Due to their unique spatial configurations and rigid structural characteristics, spiro compounds hold irreplaceable value in modulating physicochemical properties, metabolic stability, and target binding specificity.
This study innovatively integrates Petasis reaction with Grubbs Ring-Closing Metathesis (RCM) to develop a modular and scalable DOS-like synthetic strategy. This approach successfully overcomes technical bottlenecks where efficiency and diversity are difficult to balance in traditional spiro compound synthesis, achieving the construction of an ultra-large-scale chemical space containing 910,000 novel molecular structures starting from 16 types of Bemis-Murcko scaffolds. This achievement not only provides unprecedented resources for structural diversity for medicinal chemists but also offers innovative solutions through computer-aided virtual high-throughput screening technology to accelerate future drug discovery processes.
Optimization and Development of Spiro Molecular Building Block Synthesis Strategy
Optimization System for Petasis Reaction Conditions
The Petasis three-component reaction was selected as the core building block due to its unique advantage in efficiently introducing two olefin fragments simultaneously. During the optimization process for reaction conditions, our research team utilized ^19F NMR as the primary monitoring method because model substrate 4,4-difluorocyclohexanone (1a), along with its intermediate imine (5a) and final product (4a), exhibited characteristic signal differences on fluorine spectra. After systematic solvent screening, temperature gradient experiments, and material ratio optimization were conducted; it was ultimately determined that under optimal conditions—using toluene as solvent at 40°C for 72 hours—with a substrate feed ratio set at (1a : ext{Alkenylboronic acid ester} : ext{Allylamine} =1:1.25:1.1), while maintaining an initial ketone concentration at (1M)—the conversion rate could reach up to (99%).
It is noteworthy that this optimization process focused not only on conversion rates but also delved into multidimensional parameters such as byproduct generation, operational simplicity, and compatibility with subsequent reactions. Specifically addressing air sensitivity issues led our research team to develop standardized operating procedures under inert gas protection ensuring reproducibility meets gram-scale preparation needs. This rigorous optimization methodology laid a solid foundation for subsequently constructing structurally diverse spiro frameworks.
Development and Application of Modular Protecting Group Strategies In constructing spiro building blocks,u200bu200bu200bu200b selecting amino protecting strategies directly impacts Grubbs RCM success rates since traditional protecting groups like Boc or Cbz often lead to catalyst deactivation under metal-catalyzed conditions.u200b Our study innovatively employed trifluoroacetic anhydride (TFAA) as an amino-protecting reagent; TFAA-derived trifluoroacetamides effectively prevent poisoning Grubbs catalysts while being easy-to-introduce yet selectively removable during subsequent steps.u200b The systematic optimization surrounding protecting group strategies enabled successful construction yielding excellent results even when scaling up multi-gram quantities involving six/seven-membered rings ((10a/11a)). For different stages within reactions,u200b our research team developed stepwise deprotection schemes:u200b first completing double bond reduction alongside TFA-deprotection via catalytic hydrogenation ((Pd/C,H_2)); producing target amine-based spiro building blocks ((14a/15a)); whereas substrates containing acid-sensitive groups underwent selective deprotection using basic hydrolysis conditions.u200b Such flexible protective group methodologies provided crucial technical support towards complex spiroskeleton constructions.
Expansion Of Structural Diversity And Scalable Preparation
Innovative Synthetic Pathways For Bifunctional Spiro Building Blocks nAddressing challenges associated with obtaining unstable unsaturated amines possessing additional functionalities led our research team designing alternative synthetic routes: u3000 initially synthesizing intermediates (16) via participation from benzylamine through Petasis reactions followed by alkylation using acrylate (17; u3000 thus generating RCM precursors(18). This route cleverly avoids complications arising from separating/purifying unstable intermediates whilst employing C2v symmetric ketones((1B-ih) o resolve separation difficulties caused by non-enantiomeric mixtures preserving scaffold diversity enhancing applicability across various reactions respectively! nExperimental findings revealed crude products((18A) can undergo efficient cyclization forming(19A) without purification significantly simplifying operations whereby all eighteen categories yield direct utilization within RCM yielding bicyclic products((19A-H); achieving yields ranging between(64%-82%! nSuch “one-pot” continuous response approaches enhanced synthesis efficiencies reducing material losses attributed purifications hence providing feasible solutions suitable gram scale preparations! n Special Processing Techniques For Multifunctional Building Blocks nConcerning compounds featuring acid-sensitive moieties(Oxazolidinones/Boc-Nitrogen-containing cyclic systems)(21f&21h);our researchers devised specialized processing techniques wherein compound22f underwent NaOH-mediated hydrolysis amidst dry methanol resulting sodium salt formation;(21h’s synthesis necessitated multiple sequential transformations including prior alkaline hydrolysis converting esters into respective acids followed hydrogenations targeting desired outputs!(21H)! These meticulous control measures exemplify profound understanding regarding structure sensitivities involved! ! Upon modifications phases;research teams executed classic conversions(Curtis rearrangements etc.) successfully transforming carboxylic groups into amines producing orthogonally protected diamines[24&26];these transitions enriched available functional group varieties thereby substantially boosting derivative capabilities concerning resultant library compositions! Ultimately constructed composite libraries comprise two single-functionalized units,eighteen bifunctionals,and one tri-functional module culminating comprehensive structural diversity systems established herewith! ### Computer-Aided Virtual Chemical Space Construction **High Throughput Simulation Strategies For Real Chemical Spaces Developed Within Study Utilizing Enamine REAL Database Engine As Computational Platform Employing Classic Amide Coupling Reactions Models Conducted Systematic Virtual Derivations On Synthesized Structures Conclusively Yielded Unique Compounds Via Cross-Couplings Achieving Unprecedented Efficiencies Not Attainable Using Traditional Experimental Approaches![...] Final outcomes resulted distinctive sets comprising free-carboxylic(acids)+free-amino(bases)-bearing species enabling expansive chemical spaces exceeding approximately[360 billion] molecules validated originality through UMAP dimensionality reductions confirming minimal overlaps relative known databases reinforcing significant contributions made toward diversifying chemistries explored herein further analyses reveal compliance against 'Drug-Like Five Principles' showcasing promising leads present amongst identified fragments supporting ongoing investigations geared around developing drugs targeting intricate protein interactions requiring sophisticated architectures!!! ### Future Prospects & Directions Ahead Constructed ultra-large scale libraries offer invaluable resource across numerous pharmaceutical sectors driving advancements AI-driven discoveries amplifying predictive modeling capacities whilst PROTAC technologies may leverage rigidity optimizing linker designs combating escalating antimicrobial resistance issues faced globally!! Additionally central nervous system therapeutics benefit metabolically stable constructs improving brain penetrability aspects finally facilitating selective covalent inhibitors paving pathways vast selections warheads fostering exploration avenues ahead!! Subsequent inquiries should pursue expanding block types integrating heteroatoms/special functionalities alongside refining algorithms unlocking potentials embedded within aforementioned chemical realms establishing automated platforms bridging virtual evaluations tangible syntheses lastly conducting extensive bioactivity assessments leading toward structured activity relationship databases guiding future optimizations accordingly propelling these developments advancing foundational studies transitioning practical applications ultimately contributing significantly innovation landscapes emerging fields tackling critical healthcare challenges!