Total synthesis: an enabling science
This thematic issue focuses on total synthesis as an enabling science. Total synthesis is the science of constructing molecules from simple starting materials and often deals with complex architectures that require a retrosynthetic problem-solving analysis. Total synthesis and the discovery of original synthetic methodologies have always been intimately linked. Old and recent achievements show that connections to other disciplines are important to the success of total synthesis and can be a source of new discoveries. Indeed, as a science allowing the preparation of useful functional compounds, it is strongly connected to biological and medicinal studies, while the development of natural-product-based tools for chemical biology often requires the construction of complex molecules (biology-driven total synthesis). Incidentally, the term "total synthesis" is not limited to natural products but also, sometimes, involves complex drugs. Furthermore, it is possible to test biosynthetic hypotheses concerning natural products through synthetic approaches (biomimetic synthesis). In addition, total syntheses have also been achieved with enzymes, strengthening the links to biology.
Total synthesis is not limited to academic laboratories but rather also pursued in industry, where a particular efficiency and economy of tasks is paramount. This requires permanent technological progress. Thus, the recent boom of machine learning and computational chemistry for retrosynthetic analyses and beyond foreshadows a renew interests to harvest increasingly complex synthetic strategies for industrial processes. In terms of discoveries in organic chemistry, total synthesis is a fruitful feed, and serendipity has well been exploited. Even dead ends, yet always heartbreaking for synthetic chemists, still provide a wealth of useful information for the chemical community. Finally, this is not to forget that organic chemistry, which is above all an experimental science, is performed daily by researchers in the laboratory, and some of these life stories can be truly inspiring to current and future generations. This thematic issue anticipates articles covering any of these remarks in the form of original research papers and reviews. In addition, submissions that highlight key topics and provide accounts and insights, or even biographical articles based on scientific data and/or evidence, are welcome.
- Letter
- Published 07 Sep 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Scheme 1: Structures of hangtaimycin (1) and its co-metabolites.
-
![]()
Scheme 2: First synthetic route towards TDD (4).
-
![]()
Figure 1: HPLC analyses of (Z)-4 on a chiral stationary phase. A) Nearly racemic 4 from the first synthetic r...
-
![]()
Scheme 3: Second synthetic route towards TDD ((Z)-4).
-
![]()
Figure 2: X-ray structure of (rac)-4.
-
![]()
Figure 3: Bioactivity testing with hangtaimycin (1). A) Growth retardation of model species B. subtilis 168 a...
-
-
Supp. Info
- Review
- Published 15 Sep 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Scheme 1: Structures of vicinal ketoesters and examples for their typical reactivity.
-
![]()
Scheme 2: Doyle’s diastereoselective intramolecular aldol addition of α,β-diketoester.
-
![]()
Scheme 3: Synthesis of euphorikanin A (16) by intramolecular, nucleophilic addition [6].
-
![]()
Scheme 4: Ketoester cycloisomerization for the synthesis of preussochromone A (24) [10].
-
![]()
Scheme 5: Diastereoselective, intramolecular aldol reaction of an α-ketoester 28 in the synthesis of (−)-preu...
-
![]()
Scheme 6: Synthesis of an α-ketoester through Riley oxidation and its use in an α-ketol rearrangement in the ...
-
![]()
Scheme 7: Azomethine imine cycloaddition towards the synthesis of the proposed structure of palau’amine (44) [19]....
-
![]()
Scheme 8: Intramolecular diastereoselective carbonyl-ene reaction of an α-ketoester in the synthesis of jatro...
-
![]()
Scheme 9: Grignard addition to an α-ketoester and subsequent Friedel–Crafts cyclization in the synthesis of (...
-
![]()
Scheme 10: Diastereoselective addition to an auxiliary modified α-ketoester in the formal synthesis of (+)-cam...
-
![]()
Scheme 11: Intramolecular photoreduction of an α-ketoester in the synthesis of (rac)-isoretronecanol (69) [26].
-
![]()
Scheme 12: α-Ketoester as nucleophile in a Tsuji–Trost reaction in the synthesis of (rac)-corynoxine (76) [27].
-
![]()
Scheme 13: Mannich reaction of an α-ketoester in the synthesis of (+)-gracilamine (83) [28].
-
![]()
Scheme 14: Enantioselective aldol reaction using an α-ketoester in the synthesis of (−)-irofulven (87) [29].
-
![]()
Scheme 15: Allylboration of a mesoxalic acid ester in the synthesis of (+)-awajanomycin (92) [30,31].
-
![]()
Scheme 16: Condensation of a diamine with mesoxolate in the synthesis of (−)-aplaminal (96) [32].
-
![]()
Scheme 17: Synthesis of mesoxalic ester amide 102 and its use in the synthesis of (rac)-cladoniamide G (103) [33].
-
![]()
Scheme 18: The thermodynamically controlled, intramolecular aldol addition of a vic-tricarbonyl compound in th...
-
- Full Research Paper
- Published 19 Sep 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Scheme 1: Retrosynthetic scheme of the target molecule 1.
-
![]()
Scheme 2: Synthesis of dihydrofuran-monoterpenoid 1. a) i. O3, −78 °C; ii. PPh3, rt, 76%; b) 1-bromobut-2-yne...
-
![]()
Scheme 3: Racemic resolution of allenol 3 and synthesis of derivatives. a) Lipase AK, vinyl acetate, t-BuOMe,...
-
-
Supp. Info
- Full Research Paper
- Published 04 Oct 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Structures of leustroducsins and phoslactomycins.
-
![]()
Figure 2: Synthetic strategy for the leustroducins and phoslactomycins.
-
![]()
Figure 3: strategy for the synthesis of central fragment 4: nitroso Diels–Alder reaction.
-
![]()
Scheme 1: A highly regio-and stereoselective nitroso Diels–Alder cycloaddition between Wightman’s reagent 6 a...
-
![]()
Scheme 2: Hydrolysis of enol phosphate in the unprotected cycloadduct.
-
![]()
Scheme 3: Attempts for hydrolysis of the enol phosphate under basic conditions.
-
![]()
Scheme 4: Cleavage of enol phosphate with Red-Al.
-
![]()
Scheme 5: Synthesis of the protected central fragment 11b.
-
![]()
Scheme 6: Synthesis and derivatization of the lactone fragment.
-
![]()
Scheme 7: Coupling reaction between alkyne 19 and ketone 11b.
-
![]()
Scheme 8: Coupling reaction between vinyl iodide 20 and ketone 11b.
-
![]()
Scheme 9: Oxidation of the acetal to the lactone.
-
- Full Research Paper
- Published 18 Nov 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Structures of longicatenamides A–D (1–4).
-
![]()
Scheme 1: Retrosynthesis of longicatenamycin A (1).
-
![]()
Scheme 2: Synthesis of building block 10.
-
![]()
Scheme 3: Synthesis of building block 7.
-
![]()
Scheme 4: Total synthesis of longicatenamycin A (1).
-
![]()
Figure 2: LC–MS extracted ion chromatograms (EICs) of synthesized and natural 1. Column: Imtakt Cadenza CD-C1...
-
-
Supp. Info
- Letter
- Published 23 Nov 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Scheme 1: Classification of benzo[c]phenanthridine alkaloids.
-
![]()
Scheme 2: Representative synthetic strategies for macarpine (1).
-
![]()
Scheme 3: Retrosynthetic analysis of marcarpine precursor 12 for a partial synthesis.
-
![]()
Scheme 4: Syntheses of precursors 5 and 8.
-
![]()
Scheme 5: Synthesis of enol silyl ether 10.
-
![]()
Scheme 6: Formal total synthesis of macarpine (1).
-
-
Supp. Info
- Letter
- Published 30 Nov 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Selected representative natural products with 6-5-5 tricyclic skeleton.
-
![]()
Scheme 1: Retrosynthetic analysis of aberrarone (1).
-
![]()
Scheme 2: Synthetic study toward aberrarone (1).
-
-
Supp. Info
- Full Research Paper
- Published 01 Dec 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Structures of halichonic acid ((+)-1) and halichonic acid B ((+)-2).
-
![]()
Scheme 1: Synthesis of (−)-7-amino-7,8-dihydrobisabolene (4) and its conversion to cyclization precursor 7.
-
![]()
Scheme 2: Synthesis of the halichonic acids via a key intramolecular aza-Prins cyclization.
-
![]()
Scheme 3: Proposed intermediates for the intramolecular aza-Prins reaction leading to the formation of ethyl ...
-
-
Supp. Info
- Review
- Published 12 Dec 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: General structure of grayanane natural products.
-
![]()
Scheme 1: Grayanane biosynthesis.
-
![]()
Scheme 2: Matsumoto’s relay approach.
-
![]()
Scheme 3: Shirahama’s total synthesis of (–)-grayanotoxin III.
-
![]()
Scheme 4: Newhouse’s syntheses of fragments 25 and 29.
-
![]()
Scheme 5: Newhouse’s total synthesis of principinol D.
-
![]()
Scheme 6: Ding’s total synthesis of rhodomolleins XX and XXII.
-
![]()
Scheme 7: First key step of Luo’s strategy.
-
![]()
Scheme 8: Luo’s total synthesis of grayanotoxin III.
-
![]()
Scheme 9: Synthesis of principinol E and rhodomollein XX.
-
![]()
Scheme 10: William’s synthetic effort towards pierisformaside C.
-
![]()
Scheme 11: Hong’s synthetic effort towards rhodojaponin III.
-
![]()
Scheme 12: Recent strategies for grayanane synthesis.
-
- Full Research Paper
- Published 19 Dec 2022
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Scheme 1: Routes to crispatene, photodeoxytridachione, aureothin, and tridachiapyrone B.
-
![]()
Scheme 2: Desymmetrization of 2.
-
![]()
Scheme 3: Addition of lithiocyclopentadiene to pyrone 2.
-
![]()
Scheme 4: Plan to reach 2,5-cyclohexadienone 5.
-
![]()
Scheme 5: Preparation of 2,5-cyclohexadienone 5.
-
![]()
Scheme 6: Attempts to perform the conjugate addition.
-
![]()
Scheme 7: Updated route to tridachiapyrone B.
-
-
Supp. Info
- Review
- Published 02 Jan 2023
-
PDF -
Album-
![]()
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).
-
- Perspective
- Published 14 Feb 2023
-
PDF -
Album-
![]()
Scheme 1: Structure of the (8E,10Z)-tetradecadienal (1, sex pheromone of the horse-chestnut leaf miner) and r...
-
![]()
Scheme 2: a) Alkyl–vinyl seminal cross-coupling reaction by Kochi; b) improved procedure described by Cahiez.
-
![]()
Scheme 3: Iron-catalyzed cross-coupling of n-OctMgCl with a 1-butadienyl phosphate.
-
![]()
Scheme 4: Synthesis of several insect sex pheromones (a) red bollworm moth, b) European grapevine moth, c) ho...
-
![]()
Scheme 5: Cross-coupling of alkyl Grignard reagents with a) alkenyl or b) aryl halides involving EtOMgCl as a...
-
![]()
Scheme 6: Total synthesis of codling moth sex pheromone 4 using an iron-mediated cross-coupling between an α,...
-
- Full Research Paper
- Published 16 Feb 2023
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Calling male Hyperolius cinnamomeoventris with exposed vocal sac carrying the yellow gular gland. Figure 1 ...
-
![]()
Figure 2: Macrolides identified in gular glands of male Hyperolius cinnamomeoventris.
-
![]()
Figure 3: Total ion chromatogram (TIC) of a gular gland extract of Hyperolius cinnamomeoventris on a polar DB...
-
![]()
Figure 4: Mass spectrum of sesquiterpene A (I = 1596) from the gular gland extract of male Hyperolius cinnamo...
-
![]()
Scheme 1: Racemic synthesis of cadinols modified from Taber and Gunn [13]. Conditions a) i) K2CO3 (0.35 equiv), 0...
-
![]()
Scheme 2: Enantioselective synthesis with (S)-Jørgensen’s organocatalyst S-16. Conditions: a) S-16 (5 mol %),...
-
![]()
Figure 5: TIC and gas chromatographic Kovats retention indices RI [24] values determined on a Hydrodex β-6TBDM ph...
-
![]()
Figure 6: Coinjection of R-14 and S-14 with a gular gland extract of Hyperolius cinnamomeoventris performed w...
-
![]()
Figure 7: Mass spectra of each cadinol-type diastereomer. The box colors refer to the peaks and compounds in Figure 5....
-
-
Supp. Info
- Review
- Published 03 Mar 2023
-
PDF -
Album-
![]()
Graphical Abstract
-
![]()
Figure 1: Examples of terpenes containing a bicyclo[3.6.0]undecane motif.
-
![]()
Figure 2: Commercially available first and second generation Grubbs and Hoveyda–Grubbs catalysts.
-
![]()
Figure 3: Examples of strategies to access the fusicoccan and ophiobolin tricyclic core structure by RCM.
-
![]()
Scheme 1: Synthesis of bicyclic core structure 12 of ophiobolin M (13) and cycloaraneosene (14).
-
![]()
Scheme 2: Synthesis of the core structure 21 of ophiobolins and fusicoccanes.
-
![]()
Scheme 3: Ring-closing metathesis attempts starting from thioester 22.
-
![]()
Scheme 4: Total synthesis of ent-fusicoauritone (28).
-
![]()
Figure 4: General structure of ophiobolins and congeners.
-
![]()
Scheme 5: Total synthesis of (+)-ophiobolin A (8).
-
![]()
Scheme 6: Investigation of RCM for the synthesis of ophiobolin A (8). Path A) RCM with TBDPS-protected alcoho...
-
![]()
Scheme 7: Synthesis of the core structure of cotylenin A aglycon, cotylenol (50).
-
![]()
Scheme 8: Synthesis of tricyclic core structure of fusicoccans.
-
![]()
Scheme 9: Total synthesis of (−)-teubrevin G (59).
-
![]()
Scheme 10: Synthesis of the core skeleton 63 of the basmane family.
-
![]()
Scheme 11: Total synthesis of (±)-schindilactone A (68).
-
![]()
Scheme 12: Total synthesis of dactylol (72).
-
![]()
Scheme 13: Ring-closing metathesis for the total synthesis of (±)-asteriscanolide (2).
-
![]()
Scheme 14: Synthesis of the simplified skeleton of pleuromutilin (1).
-
![]()
Scheme 15: Total synthesis of (−)-nitidasin (93) using a ring-closing metathesis to construct the eight-member...
-
![]()
Scheme 16: Total synthesis of (±)-naupliolide (97).
-
![]()
Scheme 17: Synthesis of the A-B ring structure of fusicoccane (101).
-
![]()
Scheme 18: First attempts of TRCM of dienyne substrates.
-
![]()
Scheme 19: TRCM on optimized substrates towards the synthesis of ophiobolin A (8).
-
![]()
Scheme 20: Tandem ring-closing metathesis for the synthesis of variecolin intermediates 114 and 115.
-
![]()
Scheme 21: Synthesis of poitediol (118) using the allylsilane ring-closing metathesis.
-
![]()
Scheme 22: Access to scaffold 122 by a NHK coupling reaction.
-
![]()
Scheme 23: Key step to construct the [5-8] bicyclooctanone core of aquatolide (4).
-
![]()
Scheme 24: Initial strategy to access aquatolide (4).
-
![]()
Scheme 25: Synthetic plan to cotylenin A (130).
-
![]()
Scheme 26: [5-8] Bicyclic structure of brachialactone (7) constructed by a Mizoroki–Heck reaction.
-
![]()
Scheme 27: Influence of the replacement of the allylic alcohol moiety.
-
![]()
Scheme 28: Formation of variecolin intermediate 140 through a SmI2-mediated Barbier-type reaction.
-
![]()
Scheme 29: SmI2-mediated ketyl addition. Pleuromutilin (1) eight-membered ring closure via C5–C14 bond formati...
-
![]()
Scheme 30: SmI2-mediated dialdehyde cyclization cascade of [5-8-6] pleuromutilin scaffold 149.
-
![]()
Scheme 31: A) Modular synthetic route to mutilin and pleuromutilin family members by Herzon’s group. B) Scaffo...
-
![]()
Scheme 32: Photocatalyzed oxidative ring expansion in pleuromutilin (1) total synthesis.
-
![]()
Scheme 33: Reductive radical cascade cyclization route towards (−)-6-epi-ophiobolin N (168).
-
![]()
Scheme 34: Reductive radical cascade cyclization route towards (+)-6-epi-ophiobolin A (173).
-
![]()
Scheme 35: Radical 8-endo-trig-cyclization of a xanthate precursor.
-
![]()
Figure 5: Structural representations of hypoestin A (177), albolic acid (178), and ceroplastol II (179) beari...
-
![]()
Scheme 36: Synthesis of the common [5-8-5] tricyclic intermediate of hypoestin A (177), albolic acid (178), an...
-
![]()
Scheme 37: Asymmetric synthesis of hypoestin A (177), albolic acid (178), and ceroplastol II (179).
-
![]()
Figure 6: Scope of the Pauson–Khand reaction.
-
![]()
Scheme 38: Nazarov cyclization revealing the fusicoauritone core structure 192.
-
![]()
Scheme 39: Synthesis of fusicoauritone (28) through Nazarov cyclization.
-
![]()
Scheme 40: (+)-Epoxydictymene (5) synthesis through a Nicholas cyclization followed by a Pauson–Khand reaction...
-
![]()
Scheme 41: Synthesis of aquatolide (4) by a Mukaiyama-type aldolisation.
-
![]()
Scheme 42: Tandem Wolff/Cope rearrangement furnishing the A-B bicyclic moiety 204 of variecolin.
-
![]()
Scheme 43: Asymmetric synthesis of the A-B bicyclic core 205 and 206 of variecolin.
-
![]()
Scheme 44: Formation of [5-8]-fused rings by cyclization under thermal activation.
-
![]()
Scheme 45: Construction of the [5-8-6] tricyclic core structure of variecolin (3) by Diels–Alder reaction.
-
![]()
Scheme 46: Synthesis of the [6-4-8-5]-tetracyclic skeleton by palladium-mediated cyclization.
-
![]()
Scheme 47: Access to the [5-8] bicyclic core structure of asteriscanolide (227) through rhodium-catalyzed cycl...
-
![]()
Scheme 48: Total syntheses of asterisca-3(15),6-diene (230) and asteriscanolide (2) with a Rh-catalyzed cycliz...
-
![]()
Scheme 49: Photocyclization of 2-pyridones to access the [5-8-5] backbone of fusicoccanes.
-
![]()
Scheme 50: Total synthesis of (+)-asteriscunolide D (245) and (+)-aquatolide (4) through photocyclization.
-
![]()
Scheme 51: Biocatalysis pathway to construct the [5-8-5] tricyclic scaffold of brassicicenes.
-
![]()
Scheme 52: Influence of the CotB2 mutant over the cyclization’s outcome of GGDP.
-
