Recent developments in chemical diversity
Diversity-oriented synthesis (DOS) is an important field involving the synthesis of libraries of diverse small molecules for applications including biological screening. The last decade has witnessed major progress in the field, with continued emphasis on structural and functional diversity for DOS library construction, leading to recent successes of biologically active molecules obtained from DOS compound collections. In the original paradigm for DOS, compound and library design were often based on the incorporation of functional, skeletal, and stereochemical diversity elements. An emerging theme in the area involves the development of novel reaction methodologies as a means to access or discover new “chemotypes”, advancing alongside the technology that enables progress in this area. In this way, organic chemists are empowered by the paradigm of “chemical diversity as a function of novel chemical reactions”, exploring a diverse repertoire of approaches to achieve their goals.
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Figure 1: Natural products with α-carboline subunits.
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Scheme 1: Retrosynthetic inverse electron Diels–Alder approach to α-carbolines.
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Scheme 2: Condensation of isatins with ethyl oxaloamidrazonate to form triazines.
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Scheme 3: Amidation of triazine ester 8a.
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Scheme 4: Microwave-promoted IEDDA reaction of isatin derived triazines.
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Scheme 5: One-pot amidation/cycloaddition of triazine ester 8a.
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Scheme 6: Amidation/cycloaddition forming α-carbolines 14.
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Scheme 7: Intramolecular hydrogen bonding prevents IEDDA cycloaddition of 14b.
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Scheme 8: Preparation of unprotected triazine 15, and its lack of reactivity in cycloadditions.
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Scheme 9: Transesterification and subsequent cycloaddition of 17a.
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Figure 1: Structures of Smo antagonists and agonists.
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Scheme 1: General synthetic route for Sant-75. Reagents and conditions: (a) Pd(PPh3)4, PhMe, Na2CO3, H2O, 85 ...
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Scheme 2: Substituent-modifications on the motif A. Reagents and conditions: (a) CH2Cl2, Et3N; (b) CH2Cl2, TF...
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Scheme 3: Substituent-modifications on the motif A. Reagents and conditions: (a) (i) FeCl3, Zn, H2O, DMF, 100...
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Scheme 4: Core modification on the motif A. Reagents and conditions: (a) BOP, DIEA, DMF; (b) CH2Cl2, TFA.
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Figure 2: Core modification on the motif B.
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Scheme 5: Synthesis of key intermediate biaryl aldehydes. Reagents and conditions: (a) Pd(OAc)2, PPh3, 1,4-di...
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Scheme 6: Chemical modifications on the motif C. Reagents and conditions: (a) Pd(OAc)2, PPh3, 1,4-dioxane, Na2...
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Scheme 7: Chemical modifications on the motif D. Reagents and conditions: (a) R2COCl, CH2Cl2.
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Figure 1: Overview of the DOS strategy.
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Scheme 1: Synthesis of linear cyclisation precursors 1–4.
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Scheme 2: AlCl3 catalysed tandem Boc-removal/bicyclisation processes; the yields quoted refer to the isolated...
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Scheme 3: (a) AlCl3 catalysed formation of tricyclic alkaloid 10 along with an X-ray crystal structure of 10;...
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Scheme 4: (a) Optimal conditions to obtain trans-8 and 10 and the control experiments carried out to probe th...
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Scheme 5: DOS of 5-5-6 and 5-6-6 tricyclic alkaloids 13 and 14.
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Scheme 6: Total synthesis of myrrhine, epi-myrrhine and myrrhine-N-oxide.
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Scheme 7: Use of nitromethane in DOS: Synthesis of meso-diphenylpyrrolidizine 17.
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Scheme 8: Use of Tris as a substrate for DOS: Synthesis of decorated morpholines 22 and 23.
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- Published 22 Jun 2012
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Figure 1: (a) Biosynthetic outline of aromatic polyketides; (b) structure of indole alkaloids composed of ind...
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Figure 2: (a) Synthetic plans based on modular assembly and divergent cyclizations leading to fused skeletons...
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Scheme 1: Four-step synthesis of hexacyclic skeleton 25.
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Scheme 2: Four-step synthesis of hexacyclic skeleton 30.
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Scheme 3: Parallel and four-step synthesis of tetracyclic skeletons 39–42 and 47–48.
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Scheme 4: Synthesis of branched precursors, 51 and 52, using amines 49 and 50, with different methylene lengt...
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Scheme 5: Four-step synthesis of hexacyclic scaffold 63 employing manifold 15. For details of the synthesis o...
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- Published 02 Jul 2012
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Scheme 1: Unexpected alkylative pyridine dearomatization during our previous work on the synthesis of spiroox...
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Figure 1: X-ray crystal structure of compound 6b.
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Figure 2: X-ray crystal structure of compound 3d.
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Scheme 2: Application of spiro [1,3]oxazino compound 3a in D–A reactions.
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Figure 3: X-ray crystal structure of compound 8a.
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Scheme 1: Terphenyl scaffold 1 [13,14]; oxazole-pyridazine-piperazine 2 [14,15] and aryl-triazoles 3 and 4 [15,16] as α-helix mime...
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Scheme 2: Synthesis of azido-functionalized resins 7 and 9.
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- Published 10 Jul 2012
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Figure 1: Tetrahydro-β-carboline containing scaffolds 1–3.
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Figure 2: Library of tetrahydro-β-carboline containing compounds 1–7 and calculated properties (amolecular we...
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Figure 3: Results of high-throughput docking analysis. Top: A docking-score matrix arranged by compound IDs a...
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- Published 13 Jul 2012
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Figure 1: Representative isoindolinone natural products and pharmaceuticals.
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Scheme 1: Formation of isomerized azepinoisoindoline 3 and oxirane 5.
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Figure 2: X-Ray structure of epoxide 5.
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Figure 3: Relative energies of alkene isomers based on RB3LYP/6-311G* calculations with MacSpartan ’06.
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Scheme 2: Ring-closing metathesis of diene 2 in the absence of Ti(OiPr)4 and isolation of hydroxy epoxide 6 a...
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Figure 4: X-Ray structure of epoxyalcohol 6.
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Scheme 3: Preparation and RCM reaction of bis-terminal diene analogue 7.
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Scheme 4: Conversion of epoxide 5 to 1,2-amino alcohols.
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Figure 5: Amine building blocks for library synthesis.
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Figure 6: X-ray structure of amino alcohol 10{7}.
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- Published 26 Jul 2012
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Scheme 1: Diverse synthesis of indoles using Bartoli reactions. aSee [24].
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Figure 1: Nitroarenes on solid supports. In red: Nitroarenes failed to give indoles. aResin has been reported...
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Figure 2: Temperature optimization with Grignard reagent 2{b}.
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Figure 3: Temperature optimization with Grignard reagent 2{a}. Isolated yield.
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Figure 4: Optimization studies of ester 1{h} with a Grignard reagent 2{d} to give indole 3{h,d} and methyl 3-...
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Scheme 2: Stille reaction on solid supports.
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Scheme 3: Suzuki reaction on solid supports.
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Scheme 4: Sonogashira–Hagihara reaction on solid supports.
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- Published 27 Jul 2012
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Figure 1: Representative biologically active aminomethylcoumarins.
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Scheme 1: Approach to diversely substituted coumarins.
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Scheme 2: Scope of the decarboxylative coupling.
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Scheme 3: Scope of Suzuki-coupling of coumarinyl acetates.
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Scheme 4: Coupling of (coumarinyl)methyl acetates with N- and S-nucleophiles.
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Scheme 5: Scope of the coumarinyl acetate and aryl sulfinate coupling reaction.
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Scheme 6: Scope of the coumarinyl acetate and amine coupling reaction.
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Figure 2: Library planning for amine (A) and coumarin (C) coupling partners.
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Figure 3: Results for the synthesis of a 128-member library of aminated coumarins by using the Chemspeed SLT1...
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- Published 31 Jul 2012
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Figure 1: Four-fold PEEK-reactors with increasing chamber depths from left to right and different techniques ...
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Scheme 1: Synthesis of carbazole (2) by photolysis.
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Scheme 2: Synthesis of arylazides 2 by solid-phase synthesis.
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Figure 2: Photolysis results in batch setup (flask) with a xenon lamp (400 W, λ > 345 nm).
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Figure 3: Carbazole synthesis in miniaturized photoreactors Type II (PEEK and Teflon), flow control, P = 0.92...
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Figure 4: Carbazole synthesis in miniaturized photoreactors Type II (PEEK and Teflon), power control, flow 26...
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Figure 5: Test setup with continuously operating, miniaturized photoreactor.
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Figure 6: The miniaturized photoreactor (PEEK) during photolysis.
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- Published 15 Aug 2012
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Figure 1: Biologically active benzofused sultams.
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Scheme 1: Proposed library generation by microwave-assisted intermolecular SNAr diversification reaction.
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Scheme 2: Utilization of a reaction pairing strategy for the synthesis of benzoxathiazocine 1,1-dioxides core...
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Figure 2: Benzoxathiazocine 1,1-dioxides 1–8 and amine library building blocks {1–10}.
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Figure 3: (i) Simple cartoon of the library compounds, with a core of MW ~ 80, based on Lipinski’s rules (MW ...
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Figure 4: Distribution of 80 compounds (colored spheres) relative to the set of 771 known orally available dr...
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Figure 5: Comparison of a small set of our representative compounds versus two sultams synthesized by our gro...
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Figure 6: Three representative compounds with high QED values.
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Figure 7: Representation of Z-scores for the 80 compounds.
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- Published 20 Aug 2012
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Scheme 1: Cycloisomerization/nucleophilic addition of alkynyl benzaldehyde 1 to isochromene 2.
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Figure 1: Reaction screen with diynyl benzaldehyde 3.
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Scheme 2: Sequential cycloisomerizations of substrate 3. Condition A: PtCl2 (10 mol %), Cu(MeCN)4PF6 (10 mol ...
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Figure 2: X-ray crystal structure of cyclopropane 6.
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Scheme 3: Proposed reaction pathway for diastereoselective, sequential cycloisomerization.
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Scheme 4: Proposed alternative reaction pathway affording 23.
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- Published 19 Oct 2012
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Scheme 1: Three-step sequence for the preparation of γ-lactams from maleimides, aldehydes and amines. Potenti...
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Scheme 2: The transfer of the diastereoselective ratio of 3 to the enantioselectivity of the overall process ...
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Scheme 3: Combination of the Michael addition step with the reductive amination/lactamization step and of the...
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Scheme 4: Combination of the Michael addition, the reductive amination/lactamization, and the epimerization s...
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Scheme 5: Chemspeed 4 × 8 × 8 library of γ-lactams 6.
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