Graphical Abstract
Scheme 1: The power of radical retrosynthesis and the tactic of divergent total synthesis.
Figure 1: Evolution of radical chemistry for organic synthesis.
Scheme 2: Divergent total synthesis of α-pyrone-diterpenoids (Baran).
Scheme 3: Divergent synthesis of pyrone diterpenoids by merged chemoenzymatic and radical synthesis (part I, ...
Scheme 4: Divergent synthesis of pyrone diterpenoids by merged chemoenzymatic and radical synthesis (part II,...
Scheme 5: Divergent synthesis of drimane-type hydroquinone meroterpenoids (Li).
Scheme 6: Divergent synthesis of natural products isolated from Dysidea avara (Lu).
Scheme 7: Divergent synthesis of kaurene-type terpenoids (Lei).
Scheme 8: Divergent synthesis of 6-oxabicyclo[3.2.1]octane meroterpenoids (Lou).
Scheme 9: Divergent synthesis of crinipellins by radical-mediated Dowd–Backwith rearrangement (Xie and Ding).
Scheme 10: Divergent total synthesis of Galbulimima alkaloids (Shenvi).
Scheme 11: Divergent synthesis of eburnane alkaloids (Qin).
Scheme 12: Divergent synthesis of Aspidosperma alkaloids (Boger).
Scheme 13: Photoredox based synthesis of (−)-FR901483 (160) and (+)-TAN1251C (162, Gaunt).
Scheme 14: Divergent synthesis of bipolamines (Maimone).
Scheme 15: Flow chemistry divergency between aporphine and morphinandione alkaloids (Felpin).
Scheme 16: Divergent synthesis of pyrroloazocine natural products (Echavarren).
Scheme 17: Using TEMPO to stabilize radicals for the divergent synthesis of pyrroloindoline natural products (...
Scheme 18: Radical pathway for preparation of lignans (Zhu).
Scheme 19: Divergent synthesis of DBCOD lignans (Lumb).
Graphical Abstract
Scheme 1: Examples of aza-Nazarov reactions.
Scheme 2: Aza-Nazarov cyclization on gram scale.
Scheme 3: Scope of the aza-Nazarov cyclization with acyclic imines. aThe syntheses of aza-Nazarov products 19b...
Figure 1: X-ray crystal structure of compound 19l.
Scheme 4: Proposed mechanism for the formation of diastereomers 19 and 22.
Scheme 5: Preparation of acyl chloride 23.
Scheme 6: Aza-Nazarov reaction tested using β-TMS-substituted acyl chloride 23.
Scheme 7: Hydrolysis of N-acyliminium intermediates.
Scheme 8: (a) Two possible pathways for the formation of 7 and (b) investigation of the reaction between imin...
Scheme 9: (a) Preparation of acyl chlorides 6ba and 6bb in diastereomerically pure forms, (b) aza-Nazarov cyc...
Graphical Abstract
Scheme 1: Synthesis of acyclic (DIS) and cyclic (CDIS) diaryliodonium salts.
Figure 1: Substrate scope using the optimized conditions of Table 3. Yield is based on collecting for 3 h 20 min (2....
Graphical Abstract
Figure 1: Training set of tri- and tetracoordinate phosphorus compounds; chemical shifts are in ppm, referenc...
Figure 2: (a) Plot of experimental vs calculated chemical shifts of tri- and tetracoordinate phosphorus compo...
Figure 3: Plot of experimental vs calculated chemical shifts of training set compounds reported by Latypov et...
Figure 4: “Large” compounds selected for 31P NMR calculation by Latypov [37].
Figure 5: Stereoisomers and unusual phosphorus compounds used for chemical shift calculations.
Figure 6: Phosphorus-catalyzed oxygen transfer reaction intermediates.
Figure 7: Phosphirane reactions.
Figure 8: (a) Plot of experimental vs scaled chemical shifts derived from the tri- and tetracoordinate phosph...
Graphical Abstract
Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
Scheme 3: Synthesis of 3-picoline and nicotinic acid.
Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
Scheme 8: Synthesis of rosiglitazone.
Scheme 9: Syntheses of 2-pyridones.
Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
Scheme 11: Polymer-assisted synthesis of rosiglitazone.
Scheme 12: Synthesis of pioglitazone.
Scheme 13: Meerwein arylation reaction towards pioglitazone.
Scheme 14: Route towards pioglitazone utilising tyrosine.
Scheme 15: Route towards pioglitazone via Darzens ester formation.
Scheme 16: Syntheses of the thiazolidinedione moiety.
Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
Scheme 19: Synthesis of moxifloxacin.
Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
Scheme 21: Synthesis of levofloxacin.
Scheme 22: Alternative approach to the levofloxacin core 1.125.
Figure 3: Structures of nifedipine, amlodipine and clevidipine.
Scheme 23: Mg3N2-mediated synthesis of nifedipine.
Scheme 24: Synthesis of rac-amlodipine as besylate salt.
Scheme 25: Aza Diels–Alder approach towards amlodipine.
Scheme 26: Routes towards clevidipine.
Figure 4: Examples of piperidine containing drugs.
Figure 5: Discovery of tiagabine based on early leads.
Scheme 27: Synthetic sequences to tiagabine.
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
Scheme 28: Enantioselective synthesis of solifenacin.
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
Scheme 30: Improved route to carmegliptin.
Figure 9: Structures of lamivudine and zidovudine.
Scheme 31: Typical routes accessing uracil, thymine and cytosine.
Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
Scheme 33: Synthesis of lamivudine.
Scheme 34: Synthesis of raltegravir.
Scheme 35: Mechanistic studies on the formation of 3.22.
Figure 10: Structures of selected pyrimidine containing drugs.
Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
Scheme 37: Synthesis of imatinib.
Scheme 38: Flow synthesis of imatinib.
Scheme 39: Syntheses of erlotinib.
Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
Scheme 41: Synthesis of lapatinib.
Scheme 42: Synthesis of rosuvastatin.
Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
Scheme 44: Syntheses of varenicline and its key building block 4.5.
Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
Scheme 46: Asymmetric synthesis of bortezomib.
Figure 13: Structures of some prominent piperazine containing drugs.
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
Scheme 48: Syntheses of azelastine (5.1).
Figure 15: Structures of captopril, enalapril and cilazapril.
Scheme 49: Synthesis of cilazapril.
Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
Scheme 50: Synthesis of lamotrigine.
Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
Scheme 52: Conventional synthesis of imiquimod (no yields reported).
Scheme 53: Synthesis of imiquimod.
Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
Figure 18: Structures of various anti HIV-medications.
Scheme 55: Synthesis of abacavir.
Figure 19: Structures of diazepam compared to modern replacements.
Scheme 56: Synthesis of ocinaplon.
Scheme 57: Access to zaleplon and indiplon.
Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
Scheme 60: Early synthetic route to sildenafil.
Scheme 61: Convergent preparations of sildenafil.
Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
Scheme 62: Short route to imidazotriazinones.
Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
Scheme 64: Bayer’s approach to the vardenafil core.
Scheme 65: Large scale synthesis of vardenafil.
Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
Scheme 67: Different routes to temozolomide.
Scheme 68: Safer route towards temozolomide.
Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
Graphical Abstract
Figure 1: Examples of prominent natural products: N-butyrylhomoserine lactone (1), pyoverdin (2), malleicypro...
Figure 2: Biosynthetic principles of (A) assembly line-like pathways and (B) discrete multi-enzymatic assembl...
Figure 3: Universal (A, B, F) NP class and NP family-specific (C, D, F) signature sequences in NP BGCs and se...
Figure 4: Concepts of algorithms in order of complexity and examples of genome mining tools that employ the r...
Figure 5: Examples of peptide NPs, the corresponding BGCs of which were determined through retrobiosynthetic ...
Figure 6: gcBGC prioritization process. The bar represents all identified gene clusters in one organism and i...
Figure 7: Genome alignments of related organisms revealing the presence of syntenic (purple) as well as non-s...
Graphical Abstract
Figure 1: Structures of RBV, betulinic acid (1), and ursolic acid (2).
Scheme 1: Synthesis of 1-azido-3-nitrobenzene (c).
Scheme 2: Synthesis of the triazole-substituted triterpene derivatives 7 and 8.
Figure 2: (A) Activity of compound 8 in A549 cells infected with RSV. MTT assay 96 h after treatment. DMSO (0...
Figure 3: Superposition of the top-ranked docking solution of compound 8 (carbon atoms in yellow, in stick re...
Graphical Abstract
Figure 1: Representative natural products and biologically active molecules containing an oxindole moiety [7-13].
Scheme 1: Selected photocatalytic decarboxylative radical cascade reactions of N-arylamides.
Scheme 2: Arylamide substrate scope with isolated yields of products.
Scheme 3: Alkyl radical precursor scope with isolated yields of products.
Scheme 4: Selected mechanistic experiments.
Graphical Abstract
Figure 1: Primary structure of digyalipopeptide A (1).
Figure 2: Key COSY and HMBC correlations for compound 1.
Figure 3: Key TOCSY and NOESY correlations for compound 1.
Figure 4: Liquid chromatography high resolution electrospray ionization mass spectrometry (LC–HRESIMS) sequen...
Figure 5: The absolute stereochemistry of compound 1.
Figure 6: Global natural products social molecular networking (GNPS).