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Search for "formal synthesis" in Full Text gives 41 result(s) in Beilstein Journal of Organic Chemistry.
Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs
- Amina Moutayakine and
- Anthony J. Burke
Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19
- dibenzodiazepinones in good yields (up to 45%; 2 steps) and much milder conditions using copper as the catalyst. The synthetic utility of this novel strategy was showcased by demonstrating a formal synthesis for the antipsychotic drug clozapine and to an anticancer triazole–DBDAP hybrid. Keywords: Buchwald–Hartwig
- good yield (this represented a formal synthesis to clozapine [26], if the procedure of Rao [27] is used, which entails heating 4e with 1-methylpiperidine and Ti(IV)Cl4, Scheme 4). Also compound 4a can be transformed to Hügel's 1,2,3-triazole-DBDAP using the methodology described in their report (Scheme
Graphical Abstract
Figure 1: Biologically active dibenzodiazepinones.
Scheme 1: Different synthetic routes to DBDAPs (a–c), including our novel approach (d).
Scheme 2: One-pot synthesis of 5H-dibenzo[b,e][1,4]diazepin-11-ol (5).
Scheme 3: Scope of the Chan–Lam coupling between o-phenylenediamines and 2-bromophenylboronic acids (please n...
Scheme 4: Scope of the synthesis of DBDAPs. Please note that product 4g contained some unidentified impuritie...
Scheme 5: Proposed mechanism.
Synthesis of ether lipids: natural compounds and analogues
- Marco Antônio G. B. Gomes,
- Alicia Bauduin,
- Chloé Le Roux,
- Romain Fouinneteau,
- Wilfried Berthe,
- Mathieu Berchel,
- Hélène Couthon and
- Paul-Alain Jaffrès
Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96
- [61]. A first hemi-synthesis was reported by Demopoulos et al. [56] and by Blank et al. [62] and two formal syntheses were reported by Benveniste et al. [63][64]. The second formal synthesis starts from the glycerol ether lipid 2.1 that reacted with trityl chloride to yield 2.2. Then, the benzylation
- work includes, in addition to the oxidation of such type of polyunsaturated EL incorporated in liposomes [99], the formal synthesis of some oxidized derivatives. As an illustration, lyso-PAF 15.1 (extracted from egg albumin) was acylated using Steglich conditions with ω-unsaturated carboxylic acid to
Graphical Abstract
Figure 1: Chemical structure of some natural ether lipids (ELs).
Figure 2: Synthesis of lyso-PAF and PAF from 1-O-alkylglycerol [64].
Figure 3: Synthesis of lyso-PAF from 1,3-benzylideneglycerol 3.1 [69].
Figure 4: A) Synthesis of the two enantiomers of octadecylglycerol (4.6 and 4.10) from ᴅ-mannitol (4.1); B) s...
Figure 5: Four-step synthesis of PAF 5.6 from (S)-glycidol [73].
Figure 6: Synthesis of 1-O-alkylglycerol A) from solketal, B) from ᴅ- or ʟ-tartaric acid and the intermediate ...
Figure 7: Synthesis of EL building blocks starting from substituted glycidol 7.1a–c [82].
Figure 8: Synthesis of PAF 8.5 by using phosphoramidite 8.2 [86].
Figure 9: Synthesis of oleyl-PAF 9.7 from ʟ-serine [88].
Figure 10: Synthesis of racemic analogues of lyso-PAF 10.8 and PAF 10.9 featuring a phenyl group between the g...
Figure 11: Synthesis of racemic deoxy-lyso-PAF 11.7 and deoxy-PAF 11.8 [91].
Figure 12: Synthesis of racemic thio-PAF 12.8 [93].
Figure 13: Racemic synthesis of 13.6 to illustrate the modification of the glycerol backbone by adding a methy...
Figure 14: Racemic synthesis of 14.5 as an illustration of the introduction of methyl substituents on the glyc...
Figure 15: Synthesis of functionalized sn-2-acyl chains of PC-EL; A) Steglich esterification or acylation reac...
Figure 16: Synthesis of racemic mc-PAF (16.3), a carbamate analogue of PAF [102].
Figure 17: A) Synthesis of (R)-17.2 and (S)-17.6 starting from (S)-solketal (17.1); B) synthesis of N3-PAF (17...
Figure 18: Modification of the phosphocholine polar head to produce PAF analogues [81].
Figure 19: Racemic PAF analogues 19.3 and 19.5 characterized by the absence of the phosphate group [107].
Figure 20: Synthesis of PIP3-PAF (20.7) [108].
Figure 21: Large-scale synthesis of C18-edelfosine (21.8) [116].
Figure 22: Synthesis of C16-edelfosine (22.10) starting from isopropylidene-ʟ-glyceric acid methyl ester (22.1...
Figure 23: Phosphocholine moiety installation by the use of chlorophosphite 23.2 as key reagent [119].
Figure 24: Synthesis of rac-1-alkyl-2-O-methylglycerol (AMG) [120].
Figure 25: Synthesis of stereocontrolled 1-alkyl-2-O-methyl glycerol 25.9 (AMG) from dimethyl ᴅ-tartrate [81].
Figure 26: A) Racemic synthesis of thioether 26.4 [129,130], B) structure of sulfone analogue 26.5 [129].
Figure 27: Stereocontrolled synthesis of C18-edelfosine thioether analogue 27.8 [118].
Figure 28: Synthesis of thioether 28.4 that include a thiophosphate function [134].
Figure 29: Synthesis of ammonium thioether 29.4 and 29.6 [135].
Figure 30: Synthesis of the N-methylamino analogue of edelfosine 30.6 (BN52211) [138].
Figure 31: Synthesis of 1-desoxy analogues of edelfosine; A) with a saturated alkyl chain; B) synthesis of the...
Figure 32: Stereocontrolled synthesis of edelfosine analogue (S)-32.8 featuring a C18:1 lipid chain [142].
Figure 33: Synthesis of edelfosine analogues with modulation of the lipid chain; A) illustration with the synt...
Figure 34: Synthesis of phospholipid featuring a carbamate function to link the lipid chain to the glycerol un...
Figure 35: Synthesis of sesquiterpene conjugates of phospho glycero ether lipids [148].
Figure 36: Racemic synthesis of methyl-substituted glycerol analogues 36.7 and 36.10: A) synthesis of diether ...
Figure 37: Racemic synthesis of ilmofosine (37.6) [155,156].
Figure 38: A) Stereoselective synthesis of 38.5 via a stereoselective hydroboration reaction; B) synthesis of ...
Figure 39: Racemic synthesis of SRI62-834 (39.6) featuring a spiro-tetrahydrofurane heterocycle in position 2 ...
Figure 40: Racemic synthesis of edelfosine analogue 40.5 featuring an imidazole moiety in sn-2 position [160].
Figure 41: Racemic synthesis of fluorine-functionalized EL: A) Synthesis of 41.6 and B) synthesis of 41.8 [161-163].
Figure 42: A) Synthesis of the β-keto-ester 42.6 that also features a decyl linker between the phosphate and t...
Figure 43: Synthesis of phosphonate-based ether lipids; A) edelfosine phosphonate analogue 43.7 and B) thioeth...
Figure 44: Enantioselective synthesis of phosphonates 44.3 and 44.4 [171].
Figure 45: Racemic synthesis of phosphinate-based ether lipid 45.10 [172].
Figure 46: Racemic synthesis of edelfosine arsonium analogue 46.5 [173].
Figure 47: Synthesis of edelfosine dimethylammonium analogue 47.2 [118].
Figure 48: Synthesis of rac-C18-edelfosine methylammonium analogue 48.4 [176].
Figure 49: A) Synthesis of edelfosine N-methylpyrrolidinium analogue 49.2 or N-methylmorpholinium analogue 49.3...
Figure 50: A) Synthesis of edelfosine’s analogue 50.4 with a PE polar group; B) illustration of a pyridinium d...
Figure 51: A) Synthesis of 51.4 featuring a thiazolium cationic moiety; B) synthesis of thiazolium-based EL 51...
Figure 52: Synthesis of cationic ether lipids 52.3, 52.4 and 52.6 [135,183].
Figure 53: Synthesis of cationic carbamate ether lipid 53.5 [184].
Figure 54: Synthesis of cationic sulfonamide 54.5 [185].
Figure 55: Chemical structure of ONO-6240 (55.1) and SRI-63-119 (55.2).
Figure 56: Synthesis of non-ionic ether lipids 56.2–56.9 [188].
Figure 57: Synthesis of ether lipid conjugated to foscarnet 57.6 [189].
Figure 58: A) Synthesis of ether lipid conjugated to arabinofuranosylcytosine; B) synthesis of AZT conjugated ...
Figure 59: Synthesis of quercetin conjugate to edelfosine [191].
Figure 60: Synthesis of 60.8 (Glc-PAF) [194].
Figure 61: A) Synthesis of amino ether lipid 61.7 functionalized with a rhamnose unit and its amide analogue 6...
Figure 62: A) Synthesis of glucose ether lipid 62.4; B) structure of ether lipid 62.5 possessing a maltose uni...
Figure 63: A) Synthesis of glucuronic methyl ester 63.8; B) structure of cellobiose 63.9 and maltose 63.10 ana...
Figure 64: A) Synthesis of maltosyl glycerolipid 64.7; B) structure of lactose analogue 64.8 prepared followin...
Figure 65: A) Asymmetric synthesis of the aglycone moiety starting from allyl 4-methoxyphenyl ether; B) glycos...
Figure 66: A) Synthesis of ohmline possessing a lactose moiety. B) Structure of other glyco glycero lipids pre...
Figure 67: A) Synthesis of lactose-glycerol ether lipid 67.5; B) analogues possessing a maltose (67.6) or meli...
Figure 68: Synthesis of digalactosyl EL 68.6, A) by using trityl, benzyl and acetyl protecting groups, B) by u...
Figure 69: A) Synthesis of α-ohmline; B) structure of disaccharide ether lipids prepared by using similar meth...
Figure 70: Synthesis of lactose ether lipid 70.3 and its analogue 70.6 featuring a carbamate function as linke...
Figure 71: Synthesis of rhamnopyranoside diether 71.4 [196].
Figure 72: Synthesis of 1-O-hexadecyl-2-O-methyl-3-S-(α-ᴅ-1'-thioglucopyranosyl)-sn-glycerol (72.5) [225].
Figure 73: A) Preparation of lipid intermediate 73.4; B) synthesis of 2-desoxy-C-glycoside 73.10 [226].
Figure 74: Synthesis of galactose-pyridinium salt 74.3 [228].
Figure 75: Synthesis of myo-inositol derivative Ino-C2-PAF (75.10) [230].
Figure 76: A) Synthesis of myo-inositol phosphate building block 76.7; B) synthesis of myo-inositolphosphate d...
Figure 77: A) Synthesis of phosphatidyl-3-desoxy-inositol 77.4; B) synthesis of phosphono-3-desoxyinositol 77.9...
Figure 78: A) Structure of diether phosphatidyl-myo-inositol-3,4-diphosphate 78.1; B) synthesis of phosphatidy...
Figure 79: A) Synthesis of diether-phosphatidyl derivative 79.4 featuring a hydroxymethyl group in place of a ...
Figure 80: Synthesis of Glc-amine-PAF [78].
Figure 81: Synthesis of glucosamine ether lipid 81.4 and its analogues functionalized in position 3 of the ami...
Figure 82: Synthesis of fully deprotected aminoglucoside ether lipid 82.5 [246].
Figure 83: Synthesis of C-aminoglycoside 83.12 using Ramberg–Bäcklund rearrangement as a key step [250].
Figure 84: A) List of the most important glyco lipids and amino glyco lipids included in the study of Arthur a...
Figure 85: Synthesis of mannosamine ether lipid 85.6 [254].
Figure 86: A) Synthesis of glucosamine ether lipids with a non-natural ʟ-glucosamine moiety; B) synthesis of e...
Figure 87: A) Structure of the most efficient anticancer agents 87.1–87.4 featuring a diamino glyco ether lipi...
Figure 88: A) Synthesis of diamino glyco ether lipid 87.4; B) synthesis of bis-glycosylated ether lipid 88.10 [256]....
Figure 89: Synthesis of triamino ether lipid 89.4 [260].
Figure 90: Synthesis of chlorambucil conjugate 90.7 [261].
Figure 91: Three main methods for the preparation of glycerol ether lipid 91.3; A) from solketal and via a tri...
Figure 92: Four different methods for the installation of the phosphocholine polar head group; A) method using...
Figure 93: Illustration of two methods for the installation of saccharides or aminosaccharides; A) O-glycosyla...
Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine
- Alessio Regni,
- Francesca Bartoccini and
- Giovanni Piersanti
Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70
- functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a
Graphical Abstract
Figure 1: (a) Transformations of DMAT to different classes of ergot alkaloids. (b) and (c) Strategies for the...
Scheme 1: Synthesis of compound 5.
Scheme 2: Photoredox-catalyzed radical decarboxylative cyclization of 5.
Figure 2: Proposed reaction mechanism for photoredox-catalyzed radical decarboxylative cyclization.
Scheme 3: Synthesis of tryptophan derivatives 8 and 10.
Figure 3: Proposed reaction mechanism for photoredox-catalyzed radical decarboxylative cyclization.
Scheme 4: Methylation of 11 and the formal total synthesis of (±)-6,7-secoagroclavine.
Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities
- Jorge de Lima Neto and
- Paulo Henrique Menezes
Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31
- /formal synthesis of these compounds will be summarized and, finally, the biological activity and potential for therapeutic applications will be addressed. Thus, this review demonstrates not only the challenge in isolating these compounds, but also the synthetic complexity of preparing them in sufficient
- equiv) in PhMe led to the corresponding macrolide 28 in 20% yield. Since the demethylation step of 28 was known [27], the authors described a formal synthesis of combretastatin D-2 (2, Scheme 6). Despite the low yield, the authors managed to bypass the dimerization reaction previously reported by Boger
- , and the formal synthesis of 2 was achieved after 8 steps with an overall yield of 4.5%. Rychnovsky and Hwang hypothesized that the low yields from the Mitsunobu reaction in the previous synthesis of compound 2 were linked to the instability of the allylic oxyphosphonium ion formed with intermediates
Graphical Abstract
Figure 1: Structures of some members of the combretastatin D series, corniculatolides, and isocorniculatolide...
Scheme 1: Biosynthetic pathway proposed by Pettit and co-workers.
Scheme 2: Biosynthetic pathway towards corniculatolides or isocorniculatolides proposed by Ponnapalli and co-...
Scheme 3: Retrosynthetic approaches.
Scheme 4: Attempt of total synthesis of 2 by Boger and co-workers employing the Mitsunobu approach [27].
Scheme 5: Total synthesis of combretastatin D-2 (2) reported by Boger and co-workers employing an intramolecu...
Scheme 6: Formal synthesis of combretastatin D-2 (2) by Deshpande and co-workers using the Mitsunobu conditio...
Scheme 7: Total synthesis of combretastatin D-2 (2) by Rychnovsky and Hwang [36].
Scheme 8: Divergent synthesis of (±)-1 form combretastatin D-2 (2) by Rychnovsky and Hwang [36].
Scheme 9: Enantioselective synthesis of 1 by Rychnovsky and Hwang employing Jacobsen catalyst [41].
Scheme 10: Synthesis of fragment 57 by Couladouros and co-workers [43,45].
Scheme 11: Formal synthesis of compound 2 by Couladouros and co-workers [43,45].
Scheme 12: Synthesis of fragment 66 by Couladouros and co-workers [44,45].
Scheme 13: Synthesis of fragment 70 by Couladouros and co-workers [44,45].
Scheme 14: Synthesis of fragment 77 by Couladouros and co-workers [44,45].
Scheme 15: Synthesis of combretastatins 1 and 2 by Couladouros and co-workers [44,45].
Scheme 16: Formal synthesis of compound 2 by Gangakhedkar and co-workers [48].
Scheme 17: Synthesis of fragment 14 by Cousin and co-workers [50].
Scheme 18: Synthesis of fragment 91 by Cousin and co-workers [50].
Scheme 19: Formal synthesis of compound 2 by Cousin and co-workers [50].
Scheme 20: Synthesis of 2 diolide by Cousin and co-workers [50].
Scheme 21: Synthesis of combretastatin D-4 (4) by Nishiyama and co-workers [54].
Scheme 22: Synthesis of fragment 112 by Pettit and co-workers [55].
Scheme 23: Synthesis of fragment 114 by Pettit and co-workers [55].
Scheme 24: Attempt to the synthesis of compound 2 by Pettit and co-workers [55].
Scheme 25: Synthesis of combretastatin-D2 (2) starting from isovanilin (80) by Pettit and co-workers [55].
Scheme 26: Attempted synthesis of combretastatin-D2 (2) derivatives through an SNAr approach [55].
Scheme 27: Synthesis of combretastatin D-4 (4) by Pettit and co-workers [55].
Scheme 28: Synthesis of combretastatin D-2 (2) by Harras and co-workers [57].
Scheme 29: Synthesis of combretastatin D-4 (4) by Harras and co-workers [57].
Scheme 30: Formal synthesis of combretastatin D-1 (1) by Harras and co-workers [57].
Scheme 31: Synthesis of 11-O-methylcorniculatolide A (5) by Raut and co-workers [69].
Scheme 32: Synthesis of isocorniculatolide A (7) and O-methylated isocorniculatolide A 8 by Raut and co-worker...
Scheme 33: Synthesis of isocorniculatolide B (10) and hydroxyisocorniculatolide B 175 by Kim and co-workers [71].
Scheme 34: Synthesis of compound 9, 178, and 11 by Kim and co-workers [71].
Scheme 35: Synthesis of combretastatin D-2 prodrug salts [55].
Figure 2: ED50 values of the combretastatin D family against murine P388 lymphocytic leukemia cell line (appr...
Figure 3: IC50 of compounds against α-glucosidase [19].
Combining the best of both worlds: radical-based divergent total synthesis
- Kyriaki Gennaiou,
- Antonios Kelesidis,
- Maria Kourgiantaki and
- Alexandros L. Zografos
Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1
- cyclization of aldehyde 135, obtained also from 131, provided the pentacyclic core of (−)-strempeliopine (136) as a single diastereoisomer in 65% yield. Then, Barton’s radical deoxygenation resulted in the total synthesis of 136. Further, FGI of both diastereoisomers of 130 allowed the formal synthesis of
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).
Total synthesis of grayanane natural products
- Nicolas Fay,
- Rémi Blieck,
- Cyrille Kouklovsky and
- Aurélien de la Torre
Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181
- fit with the requisites of modern organic synthesis, as it requires over 40 steps to synthesize grayanotoxin II and was performed in racemic form (in the case of the formal synthesis), it represents an impressive piece of synthetic work. Achieving the synthesis of such a complex structure represented
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.
Vicinal ketoesters – key intermediates in the total synthesis of natural products
- Marc Paul Beller and
- Ulrich Koert
Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129
- alcohol 56, which was dehydroxylated to the diastereomeric cations VIII and IX. Friedel–Crafts reaction gave diastereomeric lactones 57 and 58. The major diastereomer 58 could be converted to the complex polyphenol (−)-hopeanol (59) in seven further steps. (+)-Camptothecin In the formal synthesis of the
- α-ketoester in the synthesis of jatrophane diterpenoids [22]. Grignard addition to an α-ketoester and subsequent Friedel–Crafts cyclization in the synthesis of (−)-hopeanol (59) [24]. Diastereoselective addition to an auxiliary modified α-ketoester in the formal synthesis of (+)-campthotecin (65
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...
Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds
- Sumana Mandal,
- Raju D. Chaudhari and
- Goutam Biswas
Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153
- )-salt-mediated cyclized ring formation in the syntheses of (±)-fastigilin C and (−)-fastigilin C. Formal synthesis of (±)-thallusin. Total synthesis of hippuristanol and its analog. Total synthesis of solanoeclepin A. a) Synthesis of Hg(OTf)2-catalyzed azaspiro structure for the formation of natural
Graphical Abstract
Scheme 1: Schematic representation of Hg(II)-mediated addition to an unsaturated bond.
Scheme 2: First report of Hg(II)-mediated synthesis of 2,5-dioxane derivatives from allyl alcohol.
Scheme 3: Stepwise synthesis of 2,6-distubstituted dioxane derivatives.
Scheme 4: Cyclization of carbohydrate alkene precursor.
Scheme 5: Hg(II)-mediated synthesis of C-glucopyranosyl derivatives.
Scheme 6: Synthesis of C-glycosyl amino acid derivative using Hg(TFA)2.
Scheme 7: Hg(OAc)2-mediated synthesis of α-ᴅ-ribose derivative.
Scheme 8: Synthesis of β-ᴅ-arabinose derivative 18.
Scheme 9: Hg(OAc)2-mediated synthesis of tetrahydrofuran derivatives.
Scheme 10: Synthesis of Hg(TFA)2-mediated bicyclic nucleoside derivative.
Scheme 11: Synthesis of pyrrolidine and piperidine derivatives.
Scheme 12: HgCl2-mediated synthesis of diastereomeric pyrrolidine derivatives.
Scheme 13: HgCl2-mediated cyclization of alkenyl α-aminophosphonates.
Scheme 14: Cyclization of 4-cycloocten-1-ol with Hg(OAc)2 forming fused bicyclic products.
Scheme 15: trans-Amino alcohol formation through Hg(II)-salt-mediated cyclization.
Scheme 16: Hg(OAc)2-mediated 2-aza- or 2-oxa-bicyclic ring formations.
Scheme 17: Hg(II)-salt-induced cyclic peroxide formation.
Scheme 18: Hg(OAc)2-mediated formation of 1,2,4-trioxanes.
Scheme 19: Endocyclic enol ether derivative formation through Hg(II) salts.
Scheme 20: Synthesis of optically active cyclic alanine derivatives.
Scheme 21: Hg(II)-salt-mediated formation of tetrahydropyrimidin-4(1H)-one derivatives.
Scheme 22: Cyclization of ether derivatives to form stereoselective oxazolidine derivatives.
Scheme 23: Cyclization of amide derivatives induced by Hg(OAc)2.
Scheme 24: Hg(OAc)2/Hg(TFA)2-promoted cyclization of salicylamide-derived amidal auxiliary derivatives.
Scheme 25: Hg(II)-salt-mediated cyclization to form dihydrobenzopyrans.
Scheme 26: HgCl2-induced cyclization of acetylenic silyl enol ether derivatives.
Scheme 27: Synthesis of exocyclic and endocyclic enol ether derivatives.
Scheme 28: Cyclization of trans-acetylenic alcohol by treatment with HgCl2.
Scheme 29: Synthesis of benzofuran derivatives in presence of HgCl2.
Scheme 30: a) Hg(II)-salt-mediated cyclization of 4-hydroxy-2-alkyn-1-ones to furan derivatives and b) its mec...
Scheme 31: Cyclization of arylacetylenes to synthesize carbocyclic and heterocyclic derivatives.
Scheme 32: Hg(II)-salt-promoted cyclization–rearrangement to form heterocyclic compounds.
Scheme 33: a) HgCl2-mediated cyclization reaction of tethered alkyne dithioacetals; and b) proposed mechanism.
Scheme 34: Cyclization of aryl allenic ethers on treatment with Hg(OTf)2.
Scheme 35: Hg(TFA)2-mediated cyclization of allene.
Scheme 36: Hg(II)-catalyzed intramolecular trans-etherification reaction of 2-hydroxy-1-(γ-methoxyallyl)tetrah...
Scheme 37: a) Cyclization of alkene derivatives by catalytic Hg(OTf)2 salts and b) mechanism of cyclization.
Scheme 38: a) Synthesis of 1,4-dihydroquinoline derivatives by Hg(OTf)2 and b) plausible mechanism of formatio...
Scheme 39: Synthesis of Hg(II)-salt-catalyzed heteroaromatic derivatives.
Scheme 40: Hg(II)-salt-catalyzed synthesis of dihydropyranone derivatives.
Scheme 41: Hg(II)-salt-catalyzed cyclization of alkynoic acids.
Scheme 42: Hg(II)-salt-mediated cyclization of alkyne carboxylic acids and alcohol to furan, pyran, and spiroc...
Scheme 43: Hg(II)-salt-mediated cyclization of 1,4-dihydroxy-5-alkyne derivatives.
Scheme 44: Six-membered morpholine derivative formation by catalytic Hg(II)-salt-induced cyclization.
Scheme 45: Hg(OTf)2-catalyzed hydroxylative carbocyclization of 1,6-enyne.
Scheme 46: a) Hg(OTf)2-catalyzed hydroxylative carbocyclization of 1,6-enyne. b) Proposed mechanism.
Scheme 47: a) Synthesis of carbocyclic derivatives using a catalytic amount of Hg(II) salt. b) Proposed mechan...
Scheme 48: Cyclization of 1-alkyn-5-ones to 2-methylfuran derivatives.
Scheme 49: Hg(NO3)2-catalyzed synthesis of 2-methylenepiperidine.
Scheme 50: a) Preparation of indole derivatives through cycloisomerization of 2-ethynylaniline and b) its mech...
Scheme 51: a) Hg(OTf)2-catalyzed synthesis of 3-indolinones and 3-coumaranones and b) simplified mechanism.
Scheme 52: a) Hg(OTf)2-catalyzed one pot cyclization of nitroalkyne and b) its plausible mechanism.
Scheme 53: Synthesis of tricyclic heterocyclic scaffolds.
Scheme 54: HgCl2-mediated cyclization of 2-alkynylphenyl alkyl sulfoxide.
Scheme 55: a) Hg(OTf)2-catalyzed cyclization of allenes and alkynes. b) Proposed mechanism of cyclization.
Scheme 56: Stereoselective synthesis of tetrahydropyran derivatives.
Scheme 57: a) Hg(ClO4)2-catalyzed cyclization of α-allenol derivatives. b) Simplified mechanism.
Scheme 58: Hg(TFA)2-promoted cyclization of a γ-hydroxy alkene derivative.
Scheme 59: Synthesis Hg(II)-salt-mediated cyclization of allyl alcohol for the construction of ventiloquinone ...
Scheme 60: Hg(OAc)2-mediated cyclization as a key step for the synthesis of hongconin.
Scheme 61: Examples of Hg(II)-salt-mediated cyclized ring formation in the syntheses of (±)-fastigilin C and (...
Scheme 62: Formal synthesis of (±)-thallusin.
Scheme 63: Total synthesis of hippuristanol and its analog.
Scheme 64: Total synthesis of solanoeclepin A.
Scheme 65: a) Synthesis of Hg(OTf)2-catalyzed azaspiro structure for the formation of natural products. b) Pro...
Progress in the total synthesis of inthomycins
- Bidyut Kumar Senapati
Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7
- ,E,E)-triene (rac)-11 in 50% yield [59]. Since triene (rac)-11 has been previously transformed into inthomycin C, this study demonstrated the formal synthesis of racemic inthomycin C ((rac)-3) [21][22][43][50]. An interesting application of the O-directed free radical hydrostannation reaction was
- followed by immediate TBS ether formation produced (+)-110a in 82% yield over 2 steps. Wittig olefination of (+)-110a with phosphonate 111 furnished the desired (E)-(+)-112a, which was then converted into Hatakeyama’s enynol (−)-82b using a four-step sequence to complete the formal synthesis of inthomycin
- formal synthesis of inthomycin C ((−)-3). In 2018, Donohoe et al. demonstrated a tin-free, short and efficient total synthesis of inthomycin C ((−)-3) by comprising the three key steps of C−C bond-forming reactions: i) a vinylogous Mukaiyama aldol reaction, ii) an olefin cross-metathesis reaction, and
Graphical Abstract
Figure 1: The inthomycins A–C (1–3) and structurally closely related compounds.
Figure 2: Syntheses of inthomycins A–C (1–3).
Scheme 1: The first total synthesis of racemic inthomycin A (rac)-1 by Whiting.
Scheme 2: Moloney’s synthesis of the phenyl analogue of inthomycin C ((rac)-3).
Scheme 3: Moloney’s synthesis of phenyl analogues of inthomycins A (rac-1) and B (rac-2).
Scheme 4: The first total synthesis of inthomycin B (+)-2 by R. J. K. Taylor.
Scheme 5: R. J. K. Taylor’s total synthesis of racemic inthomycin A (rac)-1.
Scheme 6: The first total synthesis of inthomycin C ((+)-3) by R. J. K. Taylor.
Scheme 7: The first total synthesis of naturally occurring inthomycin C ((–)-3) by Ryu et al.
Scheme 8: Preparation of E,E-iododiene (+)-84 and Z,E- iododiene 85a.
Scheme 9: Hatakeyama’s total synthesis of inthomycin A (+)-1 and inthomycin B (+)-2.
Scheme 10: Hatakeyama’s total synthesis of inthomycin C ((–)-3).
Scheme 11: Maulide’s formal synthesis of racemic inthomycin C ((rac)-3).
Scheme 12: Hale’s synthesis of dienylstannane (+)-69 and enyne (+)-82b intermediates.
Scheme 13: Hale’s total synthesis of inthomycin C ((+)-3).
Scheme 14: Hale and Hatakeyama’s resynthesis of (3R)-inthomycin C (−)-3 Mosher esters.
Scheme 15: Reddy’s formal syntheses of inthomycin C (+)-3 and inthomycin C ((−)-3).
Scheme 16: Synthesis of the cross-metathesis precursors (rac)-118 and 121.
Scheme 17: Donohoe’s total synthesis of inthomycin C ((−)-3).
Scheme 18: Synthesis of dienylboronic ester (E,E)-128.
Scheme 19: Synthesis of the alkenyl iodides (Z)- and (E)-130.
Scheme 20: Burton’s total synthesis of inthomycin B ((+)-2).
Scheme 21: Burton’s total synthesis of inthomycin C ((−)-3).
Scheme 22: Burton’s total synthesis of inthomycin A ((+)-1).
Scheme 23: Synthesis of common intermediate (Z)-(+)-143a.
Scheme 24: Synthesis of (Z)-and (E)-selective fragments (+)-145a–c.
Scheme 25: Kim’s total synthesis of inthomycins A (+)-1 and B (+)-2.
Scheme 26: Completion of total synthesis of inthomycin C ((–)-3) by Kim.
All-carbon [3 + 2] cycloaddition in natural product synthesis
- Zhuo Wang and
- Junyang Liu
Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251
- -workers applied the enantioselective [3 + 2] annulation to complete the formal synthesis of (−)-ditryptophenaline (12) [46] (Scheme 7C). The synthesis began with the catalytic asymmetric [3 + 2] annulation of symmetric isoindigo 104 and allene 101 with chiral phosphine catalyst 102 to give spirocyclic
- cycle. (C) Application of phosphine-catalyzed asymmetric [3 + 2] annulation to prepare the chiral adduct 105 with symmetric isoindigo 104 in the formal synthesis of (−)-ditryptophenaline (12). (A) Rhodium-catalyzed intracmolecular [3 + 2] cycloaddition [49]. (B) The proposed catalytic cycle of the
Graphical Abstract
Figure 1: Highly-substituted five-membered carbocycle in biologically significant natural products.
Figure 2: Natural product synthesis featuring the all-carbon [3 + 2] cycloaddition. (Quaternary carbon center...
Scheme 1: Representative natural product syntheses that feature the all-carbon [3 + 2] cyclization as the key...
Scheme 2: (A) An intramolecular trimethylenemethane diyl [3 + 2] cycloaddition with allenyl diazo compound 38...
Scheme 3: (A) Palladium-catalyzed intermolecular carboxylative TMM cycloaddition [36]. (B) The proposed mechanism....
Scheme 4: Natural product syntheses that make use of palladium-catalyzed intermolecular [3 + 2] cycloaddition...
Scheme 5: (A) Phosphine-catalyzed [3 + 2] cycloaddition [17]. (B) The proposed mechanism.
Scheme 6: Lu’s [3 + 2] cycloaddition in natural product synthesis. (A) Synthesis of longeracinphyllin A (10) [41]...
Scheme 7: (A) Phosphine-catalyzed [3 + 2] annulation of unsymmetric isoindigo 100 with allene in the preparat...
Scheme 8: (A) Rhodium-catalyzed intracmolecular [3 + 2] cycloaddition [49]. (B) The proposed catalytic cycle of t...
Scheme 9: Total synthesis of natural products reported by Yang and co-workers applying rhodium-catalyzed intr...
Scheme 10: (A) Platinum(II)-catalyzed intermolecular [3 + 2] cycloaddition of propargyl ether 139 and n-butyl ...
Scheme 11: (A) Platinum-catalyzed intramolecular [3 + 2] cycloaddition of propargylic ketal derivative 142 to ...
Scheme 12: (A) Synthesis of phyllocladanol (21) features a Lewis acid-catalyzed formal intramolecular [3 + 2] ...
Scheme 13: The recent advances of [3 + 2] annulation in natural product synthesis. (A) The preparation of melo...
A review of the total syntheses of triptolide
- Xiang Zhang,
- Zaozao Xiao and
- Hongtao Xu
Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194
- the reported procedure finalized the synthesis of triptolide. Overall, the first asymmetric total synthesis of (−)-triptonide (19 steps, 0.06% yield) and formal synthesis of triptolide were realized from ʟ-dehydroabietic acid (26). Although the overall yield of the synthesis is very low, the authors
- -elimination and acid hydrolysis to give the key triptophenolide methyl ether (8) in racemic form (16.5%). In 2008, Sherburn and co-workers developed an approach to the formal synthesis of triptolide (Figure 2, route G, Scheme 5) [71]. Key features of the synthesis include two intermolecular Diels–Alder
- oxidation of the tertiary radical and reduction of the [Au-Au]3+ ion could give the cyclization product and regenerate the dimeric gold photocatalyst. Later, the utility of this photoredox methodology was demonstrated in a concise formal synthesis of triptolide (1) via the reaction of bromobutenolide 19
Graphical Abstract
Figure 1: Structures of triptolide (1), triptonide (2), tripdiolide (3), 16-hydroxytriptolide (4), triptrioli...
Figure 2: Syntheses of triptolide.
Scheme 1: Berchtold’s synthesis of triptolide.
Scheme 2: Li’s formal synthesis of triptolide.
Scheme 3: van Tamelen’s asymmetric synthesis of triptonide and triptolide.
Scheme 4: Van Tamelen’s (method II) formal synthesis of triptolide.
Scheme 5: Sherburn’s formal synthesis of triptolide.
Scheme 6: van Tamelen’s biogenetic type total synthesis of triptolide.
Scheme 7: Yang’s total synthesis of triptolide.
Scheme 8: Key intermediates or transformations of routes J–N.
N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds
- Iwona E. Głowacka,
- Aleksandra Trocha,
- Andrzej E. Wróblewski and
- Dorota G. Piotrowska
Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168
- ring opening at the less substituted carbon and effective deoxygenation performed at the C2 substituent [39]. This strategy was applied in the formal synthesis of (R,R)-formoterol (14) and (R)-tamsulosin (15) (Scheme 5) which have been used as therapeutic drugs for many years [40][41]. They are
Graphical Abstract
Figure 1: Examples of three-carbon chirons.
Figure 2: Structures of derivatives of N-(1-phenylethyl)aziridine-2-carboxylic acid 5–8.
Figure 3: Synthetic equivalency of aziridine aldehydes 6.
Scheme 1: Synthesis of N-(1-phenylethyl)aziridine-2-carboxylates 5. Reagents and conditions: a) TEA, toluene,...
Scheme 2: Absolute configuration at C2 in (2S,1'S)-5a. Reagents and conditions: a) 20% HClO4, 80 °C, 30 h the...
Scheme 3: Major synthetic strategies for a 2-ketoaziridine scaffold [R* = (R)- or (S)-1-phenylethyl; R′ = Alk...
Scheme 4: Synthesis of cyanide (2S,1'S)-13. Reagents and conditions: a) NH3, EtOH/H2O, rt, 72 h; b) Ph3P, CCl4...
Scheme 5: Synthesis of key intermediates (R)-16 and (R)-17 for (R,R)-formoterol (14) and (R)-tamsulosin (15)....
Scheme 6: Synthesis of mitotic kinesin inhibitors (2R/S,1'R)-23. Reagents and conditions: a) H2, Pd(OH)2, EtO...
Scheme 7: Synthesis of (R)-mexiletine ((R)-24). Reagents and conditions: a) TsCl, TEA, DMAP, CH2Cl2, rt, 1 h;...
Scheme 8: Synthesis of (−)-cathinone ((S)-27). Reagents and conditions: a) PhMgBr, ether, 0 °C; b) H2, 10% Pd...
Scheme 9: Synthesis of N-Boc-norpseudoephedrine ((1S,2S)-(+)-29) and N-Boc-norephedrine ((1R,2S)-29). Reagent...
Scheme 10: Synthesis of (−)-ephedrine ((1R,2S)-31). Reagents and conditions: a) TfOMe, MeCN then NaBH3CN, rt; ...
Scheme 11: Synthesis of xestoaminol C ((2S,3R)-35), 3-epi-xestoaminol C ((2S,3S)-35) and N-Boc-spisulosine ((2S...
Scheme 12: Synthesis of ʟ-tryptophanol ((S)-41). Reagents and conditions: a) CDI, MeCN, rt, 1 h then TMSI, MeC...
Scheme 13: Synthesis of ʟ-homophenylalaninol ((S)-42). Reagents and conditions: a) NaH, THF, 0 °C to −78 °C, 1...
Scheme 14: Synthesis of ᴅ-homo(4-octylphenyl)alaninol ((R)-47) and a sphingolipid analogue (R)-48. Reagents an...
Scheme 15: Synthesis of florfenicol ((1R,2S)-49). Reagents and conditions: a) (S)-1-phenylethylamine, TEA, MeO...
Scheme 16: Synthesis of natural tyroscherin ((2S,3R,6E,8R,10R)-55). Reagents and conditions: a) I(CH2)3OTIPS, t...
Scheme 17: Syntheses of (−)-hygrine (S)-61, (−)-hygroline (2S,2'S)-62 and (−)-pseudohygroline (2S,2'R)-62. Rea...
Scheme 18: Synthesis of pyrrolidine (3S,3'R)-68, a fragment of the fluoroquinolone antibiotic PF-00951966. Rea...
Scheme 19: Synthesis of sphingolipid analogues (R)-76. Reagents and conditions: a) BnBr, Mg, THF, reflux, 6 h;...
Scheme 20: Synthesis of ᴅ-threo-PDMP (1R,2R)-81. Reagents and conditions: a) TMSCl, NaI, MeCN, rt, 1 h 50 min,...
Scheme 21: Synthesis of the sphingolipid analogue SG-14 (2S,3S)-84. Reagents and conditions: a) LiAlH4, THF, 0...
Scheme 22: Synthesis of the sphingolipid analogue SG-12 (2S,3R)-88. Reagents and conditions: a) 1-(bromomethyl...
Scheme 23: Synthesis of sphingosine-1-phosphate analogues DS-SG-44 and DS-SG-45 (2S,3R)-89a and (2S,3R)-89a. R...
Scheme 24: Synthesis of N-Boc-safingol ((2S,3S)-95) and N-Boc-ᴅ-erythro-sphinganine ((2S,3R)-95). Reagents and...
Scheme 25: Synthesis of ceramide analogues (2S,3R)-96. Reagents and conditions: a) NaBH4, ZnCl2, MeOH, −78 °C,...
Scheme 26: Synthesis of orthogonally protected serinols, (S)-101 and (R)-102. Reagents and conditions: a) BnBr...
Scheme 27: Synthesis of N-acetyl-3-phenylserinol ((1R,2R)-105). Reagents and conditions: a) AcOH, CH2Cl2, refl...
Scheme 28: Synthesis of (S)-linezolid (S)-107. Reagents and conditions: a) LiAlH4, THF, 0 °C to reflux; b) Boc2...
Scheme 29: Synthesis of (2S,3S,4R)-2-aminooctadecane-1,3,4-triol (ᴅ-ribo-phytosphingosine) (2S,3S,4R)-110. Rea...
Scheme 30: Syntheses of ᴅ-phenylalanine (R)-116. Reagents and conditions: a) AcOH, CH2Cl2, reflux, 4 h; b) MsC...
Scheme 31: Synthesis of N-Boc-ᴅ-3,3-diphenylalanine ((R)-122). Reagents and conditions: a) PhMgBr, THF, −78 °C...
Scheme 32: Synthesis of ethyl N,N’-di-Boc-ʟ-2,3-diaminopropanoate ((S)-125). Reagents and conditions: a) NaN3,...
Scheme 33: Synthesis of the bicyclic amino acid (S)-(+)-127. Reagents and conditions: a) BF3·OEt2, THF, 60 °C,...
Scheme 34: Synthesis of lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypropanamide (R)-130. Reagents and condit...
Scheme 35: Synthesis of N-Boc-norfuranomycin ((2S,2'R)-133). Reagents and conditions: a) H2C=CHCH2I, NaH, THF,...
Scheme 36: Synthesis of MeBmt (2S,3R,4R,6E)-139. Reagents and conditions: a) diisopropyl (S,S)-tartrate (E)-cr...
Scheme 37: Synthesis of (+)-polyoxamic acid (2S,3S,4S)-144. Reagents and conditions: a) AD-mix-α, MeSO2NH2, t-...
Scheme 38: Synthesis of the protected 3-hydroxy-ʟ-glutamic acid (2S,3R)-148. Reagents and conditions: a) LiHMD...
Scheme 39: Synthesis of (+)-isoserine (R)-152. Reagents and conditions: a) AcCl, MeCN, rt, 0.5 h then Na2CO3, ...
Scheme 40: Synthesis of (3R,4S)-N3-Boc-3,4-diaminopentanoic acid (3R,4S)-155. Reagents and conditions: a) Ph3P...
Scheme 41: Synthesis of methyl (2S,3S,4S)-4-(dimethylamino)-2,3-dihydroxy-5-methoxypentanoate (2S,3S,4S)-159. ...
Scheme 42: Syntheses of methyl (3S,4S) 4,5-di-N-Boc-amino-3-hydroxypentanoate ((3S,4S)-164), methyl (3S,4S)-4-N...
Scheme 43: Syntheses of (3R,5S)-5-(aminomethyl)-3-(4-methoxyphenyl)dihydrofuran-2(3H)-one ((3R,5S)-168). Reage...
Scheme 44: Syntheses of a series of imidazolin-2-one dipeptides 175–177 (for R' and R'' see text). Reagents an...
Scheme 45: Syntheses of (2S,3S)-N-Boc-3-hydroxy-2-hydroxymethylpyrrolidine ((2S,3S)-179). Reagents and conditi...
Scheme 46: Syntheses of enantiomers of 1,4-dideoxy-1,4-imino-ʟ- and -ᴅ-lyxitols (2S,3R,4S)-182 and (2R,3S,4R)-...
Scheme 47: Synthesis of 1,4-dideoxy-1,4-imino-ʟ-ribitol (2S,3S,4R)-182. Reagents and conditions: a) AcOH, CH2Cl...
Scheme 48: Syntheses of 1,4-dideoxy-1,4-imino-ᴅ-arabinitol (2R,3R,4R)-182 and 1,4-dideoxy-1,4-imino-ᴅ-xylitol ...
Scheme 49: Syntheses of natural 2,5-imino-2,5,6-trideoxy-ʟ-gulo-heptitol ((2S,3R,4R,5R)-184) and its C4 epimer...
Scheme 50: Syntheses of (−)-dihydropinidine ((2S,6R)-187a) (R = C3H7) and (2S,6R)-isosolenopsins (2S,6R)-187b ...
Scheme 51: Syntheses of (+)-deoxocassine ((2S,3S,6R)-190a, R = C12H25) and (+)-spectaline ((2S,3S,6R)-190b, R ...
Scheme 52: Synthesis of (−)-microgrewiapine A ((2S,3R,6S)-194a) and (+)-microcosamine A ((2S,3R,6S)-194b). Rea...
Scheme 53: Syntheses of ʟ-1-deoxynojirimycin ((2S,3S,4S,5R)-200), ʟ-1-deoxymannojirimycin ((2S,3S,4S,5S)-200) ...
Scheme 54: Syntheses of 1-deoxy-ᴅ-galacto-homonojirimycin (2R,3S,4R,5S)-211. Reagents and conditions: a) MeONH...
Scheme 55: Syntheses of 7a-epi-hyacinthacine A1 (1S,2R,3R,7aS)-220. Reagents and conditions: a) TfOTBDMS, 2,6-...
Scheme 56: Syntheses of 8-deoxyhyacinthacine A1 ((1S,2R,3R,7aR)-221). Reagents and conditions: a) H2, Pd/C, PT...
Scheme 57: Syntheses of (+)-lentiginosine ((1S,2S,8aS)-227). Reagents and conditions: a) (EtO)2P(O)CH2COOEt, L...
Scheme 58: Syntheses of 8-epi-swainsonine (1S,2R,8S,8aR)-231. Reagents and conditions: a) Ph3P=CHCOOMe, MeOH, ...
Scheme 59: Synthesis of a protected vinylpiperidine (2S,3R)-237, a key intermediate in the synthesis of (−)-sw...
Scheme 60: Synthesis of a modified carbapenem 245. Reagents and conditions: a) AcOEt, LiHMDS, THF, −78 °C, 1.5...
Metal-free formal synthesis of phenoxazine
- Gabriella Kervefors,
- Antonia Becker,
- Chandan Dey and
- Berit Olofsson
Beilstein J. Org. Chem. 2018, 14, 1491–1497, doi:10.3762/bjoc.14.126
- Gabriella Kervefors Antonia Becker Chandan Dey Berit Olofsson Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106-91 Stockholm, Sweden 10.3762/bjoc.14.126 Abstract A transition metal-free formal synthesis of phenoxazine is presented. The key step of the sequence is
- cyclization step. Attempts to perform the cyclization with t-BuOK and DMEDA only resulted in byproduct formation. The deprotection of 2 is reported to proceed in high yield [18], and the synthesis of 2 hence constitutes a metal-free formal synthesis of phenoxazine (1). The complete route is depicted in Scheme
- expect the methodology to be applicable also for phenoxazine derivatives. Conclusion A transition metal-free formal synthesis of phenoxazine is presented, relying on the O-arylation of phenol 4 with unsymmetrical diaryliodonium salt 5a to provide substituted diaryl ether 3 as the key step. This species
Graphical Abstract
Figure 1: Compounds containing a phenoxazine moiety.
Scheme 1: Reported syntheses of phenoxazine derivatives.
Scheme 2: Retrosynthesis of phenoxazine.
Scheme 3: Synthesis of iodonium salt 5a.
Scheme 4: Synthesis of iodonium salt 7.
Scheme 5: O-Arylation via route B.
Scheme 6: a) Cyclization of diaryl ether 3. b) Attempted one pot-synthesis of 2. aBased on recovered 3.
Scheme 7: Formal synthesis of phenoxazine (1). aBased on recovered 3.
Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines
- Hélène Pellissier
Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114
- -donating and electron-withdrawing groups. The lowest yield (51%) was obtained in the reaction of a fluorinated isatin imine (R1 = Me, R2 = 7-F). The utility of this methodology was demonstrated by its application in the formal synthesis of the anticancer agent AG-041R. Furthermore, several of the formed
Graphical Abstract
Scheme 1: Mannich reaction of N-Boc-isatin imines with ethyl nitroacetate (2) catalyzed by a cinchona alkaloi...
Scheme 2: Mannich reaction of N-Boc-isatin imines with 1,3-dicarbonyl compounds catalyzed by a cinchona alkal...
Scheme 3: Mannich reaction of N-alkoxycarbonylisatin imines with acetylacetone catalyzed by a cinchona alkalo...
Scheme 4: Mannich reaction of isatin-derived benzhydrylketimines with trimethylsiloxyfuran catalyzed by a pho...
Scheme 5: Mannich reaction of N-Boc-isatin imines with acetaldehyde catalyzed by a primary amine.
Scheme 6: Mannich reaction of N-Cbz-isatin imines with aldehydes catalyzed by L-diphenylprolinol trimethylsil...
Scheme 7: Addition of dimedone-derived enaminones to N-Boc-isatin imines catalyzed by a phosphoric acid.
Scheme 8: Addition of hydroxyfuran-2-one-derived enaminones to N-Boc-isatin imines catalyzed by a phosphoric ...
Scheme 9: Zinc-catalyzed Mannich reaction of N-Boc-isatin imines with silyl ketene imines.
Scheme 10: Tin-catalyzed Mannich reaction of N-arylisatin imines with an alkenyl trichloroacetate.
Scheme 11: Aza-Morita–Baylis–Hillman reaction of N-Boc-isatin imines with acrolein catalyzed by β-isocupreidin...
Scheme 12: Aza-Morita–Baylis–Hillman reaction of N-Boc-isatin imines with acrolein (35) catalyzed by α-isocupr...
Scheme 13: Aza-Morita–Baylis–Hillman reaction of N-Boc-isatin imines with maleimides catalyzed by β-isocupreid...
Scheme 14: Aza-Morita–Baylis–Hillman reaction of N-Boc-isatin imines with nitroolefins catalyzed by a cinchona...
Scheme 15: Friedel–Crafts reactions of N-Boc-isatin imines with 1 and 2-naphthols catalyzed by a cinchona alka...
Scheme 16: Friedel–Crafts reactions of N-alkoxycarbonyl-isatin imines with 1 and 2-naphthols catalyzed by a ci...
Scheme 17: Friedel–Crafts reaction of N-Boc-isatin imines with 6-hydroxyquinolines catalyzed by a cinchona alk...
Scheme 18: Aza-Henry reaction of N-Boc-isatin imines with nitromethane catalyzed by a bifunctional guanidine.
Scheme 19: Domino addition/cyclization reaction of N-Boc-isatin imines with 1,4-dithiane-2,5-diol (53) catalyz...
Scheme 20: Nickel-catalyzed additions of methanol and cumene hydroperoxide to N-Boc-isatin imines.
Scheme 21: Palladium-catalyzed addition of arylboronic acids to N-tert-butylsulfonylisatin imines.
Useful access to enantiomerically pure protected inositols from carbohydrates: the aldohexos-5-uloses route
- Felicia D’Andrea,
- Giorgio Catelani,
- Lorenzo Guazzelli and
- Venerando Pistarà
Beilstein J. Org. Chem. 2016, 12, 2343–2350, doi:10.3762/bjoc.12.227
- stereocentres, represents a general access to inositol derivatives. In particular, in a complete stereoselective fashion, inositols of six different configurations characterised by the 2,3,6-cis arrangement of three substituents were obtained from aldohexos-5-uloses. Furthermore, the formal synthesis of L-chiro
Graphical Abstract
Figure 1: Stereoisomeric inositols.
Scheme 1: Retrosynthetic approach to inositols from aldohexos-5-uloses.
Figure 2: Hypothesis of the preferred transition state.
Figure 3: Stereoselective reduction of inosose intermediate.
Scheme 2: Intramolecular cyclization of an orthogonally protected L-lyxo-aldohexos-5-ulose derivative.
The direct oxidative diene cyclization and related reactions in natural product synthesis
- Juliane Adrian,
- Leona J. Gross and
- Christian B. W. Stark
Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200
- for divalent cations. It is commonly used to both modify intracellular Ca2+ concentrations and to investigate Ca2+ transport across biological membranes [58]. In 2011, Kocienski and co-workers reported on a formal synthesis of ionomycin using an auxiliary-directed, diastereoselective permanganate
- 17 could successfully be converted into alcohol 18, an intermediate in the previously reported total synthesis of ionomycin (19) by Kocienski and co-workers [60] and also in the preceding syntheses developed by the group of Evans [61] and the Hanessian group [62], thus completing a formal synthesis
- successfully applied to the total syntheses of two more mono-THF acetogenins, cis-uvariamicin I and cis-reticulatacin, by the Brown group [85]. A formal synthesis of cis-solamin A (29) was published in 2005 by the Donohoe group, employing their Os(VI)-catalyzed oxidative cyclization of 5,6-dihydroxyalkenes as
Graphical Abstract
Scheme 1: Putative structures of geraniol 1a (R = H) or 1b (R = H) (in 1924), their expected dihydroxylation ...
Scheme 2: Correlation between the substrate double bond geometry and relative stereochemistry of the correspo...
Scheme 3: Mechanisms and classification for the metal-mediated oxidative cyclizations to form 2,5-disubstitut...
Scheme 4: Synthesis of (+)-anhydro-D-glucitol and (+)-D-chitaric acid using an OsO4-mediated oxidative cycliz...
Scheme 5: Total synthesis of neodysiherbaine A via a Ru(VIII)- and an Os(VI)-catalyzed oxidative cyclization,...
Scheme 6: Formal synthesis of ionomycin by Kocienski and co-workers.
Scheme 7: Total synthesis of amphidinolide F by Fürstner and co-workers.
Scheme 8: Brown`s and Donohoe`s oxidative cyclization approach to cis-solamin A.
Scheme 9: Total synthesis of cis-solamin A using a Ru(VIII)-catalyzed oxidative cyclization and enzymatic des...
Scheme 10: Donohoe´s double oxidative cyclization approach to cis-sylvaticin.
Scheme 11: Permanganate-mediated approach to cis-sylvaticin by Brown and co-workers.
Scheme 12: Total synthesis of membranacin using a KMnO4-mediated oxidative cyclization.
Scheme 13: Total synthesis of membrarollin and its analogue 21,22-diepi-membrarollin.
Scheme 14: Total synthesis of rollidecin C and D using a late stage Re(VII)-catalyzed oxidative polycyclizatio...
Scheme 15: Co(II)-catalyzed oxidative cyclization in the total synthesis of asimilobin and gigantetrocin A.
Scheme 16: Mn(VII)-catalyzed oxidative cyclization of a 1,5-diene in the synthesis of trans-(+)-linalool oxide....
Scheme 17: Re(VII)-catalyzed oxidative cyclization in the total synthesis of teurilene.
Scheme 18: Total synthesis of (+)-eurylene via Re(VII)- and Cr(VI)-mediated oxidative cyclizations.
Scheme 19: Synthesis of cis- and trans-THF Rings of eurylene via Mn(VII)-mediated oxidative cyclizations.
Scheme 20: Cr(VI)-catalyzed oxidative cyclization in the total synthesis of venustatriol by Corey et al.
Scheme 21: Ru(VIII)-catalyzed oxidative cyclization of a 1,5-diene in the synthesis and evaluation of its ster...
Scheme 22: Ru(VII)-catalyzed oxidative cyclization of a 5,6-dihydroxy alkene in the synthesis of the core stru...
The synthesis of functionalized bridged polycycles via C–H bond insertion
- Jiun-Le Shih,
- Po-An Chen and
- Jeremy A. May
Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97
- limitations. Bridged rings from N–H bond insertions. The synthesis of deoxystemodin. A model system for ingenol. Formal synthesis of platensimycin. The formal synthesis of gerryine. Copper-catalyzed bridged-ring synthesis. Factors influencing insertion selectivity. Bridged-lactam formation. The total
Graphical Abstract
Figure 1: Bridged polycyclic natural products.
Figure 2: Strategic limitations.
Scheme 1: Bridged rings from N–H bond insertions.
Scheme 2: The synthesis of deoxystemodin.
Scheme 3: A model system for ingenol.
Scheme 4: Formal synthesis of platensimycin.
Scheme 5: The formal synthesis of gerryine.
Scheme 6: Copper-catalyzed bridged-ring synthesis.
Scheme 7: Factors influencing insertion selectivity.
Scheme 8: Bridged-lactam formation.
Scheme 9: The total synthesis of (+)-codeine.
Scheme 10: A model system for irroratin.
Scheme 11: The utility of 1,6-insertion.
Scheme 12: Piperidine functionalization.
Scheme 13: Wilkinson’s catalyst for C–H bond insertion.
Scheme 14: Bridgehead insertion and the total synthesis of albene and santalene.
Scheme 15: The total synthesis of neopupukean-10-one.
Scheme 16: An approach to phomoidride B.
Scheme 17: Carbene cascade for fused bicycles.
Scheme 18: Cascade formation of bridged rings.
Scheme 19: Conformational effects.
Scheme 20: Hydrazone cascade reaction.
Scheme 21: Mechanistic studies.
Scheme 22: Gold carbene formation from alkynes.
Scheme 23: Au-catalyzed bridged-bicycle formation.
Scheme 24: Gold carbene/alkyne cascade.
Scheme 25: Gold carbene/alkyne cascade with C–H bond insertion.
Scheme 26: Platinum cascades.
Scheme 27: Tungsten cascade.
Catalytic asymmetric formal synthesis of beraprost
- Yusuke Kobayashi,
- Ryuta Kuramoto and
- Yoshiji Takemoto
Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285
- (1). Retrosynthetic analysis of beraprost (1). Preparation of Michael precursors 7 and 8. First attempt at the synthesis of 2 from 6. Achievement of a formal synthesis of 2. Optimization of asymmetric intramolecular oxa-Michael reaction. Supporting Information Supporting Information File 476
Graphical Abstract
Figure 1: Structure of PGI2 and beraprost (1).
Scheme 1: Retrosynthetic analysis of beraprost (1).
Scheme 2: Preparation of Michael precursors 7 and 8.
Scheme 3: First attempt at the synthesis of 2 from 6.
Scheme 4: Achievement of a formal synthesis of 2.
Recent applications of ring-rearrangement metathesis in organic synthesis
- Sambasivarao Kotha,
- Milind Meshram,
- Priti Khedkar,
- Shaibal Banerjee and
- Deepak Deodhar
Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199
- system intact, this protocol opened an efficient strategy for the formal synthesis of porantheridine and a total synthesis of andrachcinidine (Scheme 63). They also reported the formal synthesis of (±)-porantheridine (301) and total synthesis of (±)-8-epihalosaline (300) via a sequential NDA reaction and
Graphical Abstract
Figure 1: Ruthenium alkylidene catalysts used in RRM processes.
Figure 2: General representation of various RRM processes.
Figure 3: A general mechanism for RRM process.
Scheme 1: RRM of cyclopropene systems.
Scheme 2: RRM of cyclopropene with catalyst 2. (i) catalyst 2 (2.5 mol %), ethylene (24, 1 atm), (ii) toluene...
Scheme 3: RRM of various cyclopropene derivatives with catalyst 2. (i) catalyst 2 (2.5 mol %), CH2Cl2 (c = 0....
Scheme 4: RRM of substituted cyclopropene system with catalyst 2.
Scheme 5: RRM of cyclobutene system with catalyst 2.
Scheme 6: RRM approach to various bicyclic compounds.
Scheme 7: RRM approach to erythrina alkaloid framework.
Scheme 8: ROM–RCM sequence to lactone derivatives.
Scheme 9: RRM protocol towards the synthesis of lactone derivative 58.
Scheme 10: RRM protocol towards the asymmetric synthesis of asteriscunolide D (61).
Scheme 11: RRM strategy towards the synthesis of various macrolide rings.
Scheme 12: RRM protocol to dipiperidine system.
Scheme 13: RRM of cyclopentene system to generate the cyclohexene systems.
Scheme 14: RRM of cyclopentene system 74.
Scheme 15: RRM approach to compound 79.
Scheme 16: RRM approach to spirocycles.
Scheme 17: RRM approach to bicyclic dihydropyrans.
Scheme 18: RCM–ROM–RCM cascade using non strained alkenyl heterocycles.
Scheme 19: First ROM–RCM–ROM–RCM cascade for the synthesis of trisaccharide 97.
Scheme 20: RRM of cyclohexene system.
Scheme 21: RRM approach to tricyclic spirosystem.
Scheme 22: RRM approach to bicyclic building block 108a.
Scheme 23: ROM–RCM protocol for the synthesis of the bicyclo[3.3.0]octene system.
Scheme 24: RRM protocol to bicyclic enone.
Scheme 25: RRM protocol toward the synthesis of the tricyclic system 118.
Scheme 26: RRM approach toward the synthesis of the tricyclic enones 122a and 122b.
Scheme 27: Synthesis of tricyclic and tetracyclic systems via RRM protocol.
Scheme 28: RRM protocol towards the synthesis of tetracyclic systems.
Scheme 29: RRM of the propargylamino[2.2.1] system.
Scheme 30: RRM of highly decorated bicyclo[2.2.1] systems.
Scheme 31: RRM protocol towards fused tricyclic compounds.
Scheme 32: RRM protocol to functionalized tricyclic systems.
Scheme 33: RRM approach to functionalized polycyclic systems.
Scheme 34: Sequential RRM approach to functionalized tricyclic ring system 166.
Scheme 35: RRM protocol to functionalized CDE tricyclic ring system of schintrilactones A and B.
Scheme 36: Sequential RRM approach to 7/5 fused bicyclic systems.
Scheme 37: Sequential ROM-RCM protocol for the synthesis of bicyclic sugar derivatives.
Scheme 38: ROM–RCM sequence of the norbornene derivatives 186 and 187.
Scheme 39: RRM approach toward highly functionalized bridge tricyclic system.
Scheme 40: RRM approach toward highly functionalized tricyclic systems.
Scheme 41: Synthesis of hexacyclic compound 203 by RRM approach.
Scheme 42: RRM approach toward C3-symmetric chiral trimethylsumanene 209.
Scheme 43: Triquinane synthesis via IMDA reaction and RRM protocol.
Scheme 44: RRM approach to polycyclic compounds.
Scheme 45: RRM strategy toward cis-fused bicyclo[3.3.0]carbocycles.
Scheme 46: RRM protocol towards the synthesis of bicyclic lactone 230.
Scheme 47: RRM approach to spiro heterocyclic compounds.
Scheme 48: RRM approach to spiro heterocyclic compounds.
Scheme 49: RRM approach to regioselective pyrrolizidine system 240.
Scheme 50: RRM approach to functionalized bicyclic derivatives.
Scheme 51: RRM approach to tricyclic derivatives 249 and 250.
Scheme 52: RRM approach to perhydroindoline derivative and spiro system.
Scheme 53: RRM approach to bicyclic pyran derivatives.
Scheme 54: RRM of various functionalized oxanorbornene systems.
Scheme 55: RRM to assemble the spiro fused-furanone core unit. (i) 129, benzene, 55 °C, 3 days; (ii) Ph3P=CH2B...
Scheme 56: RRM protocol to norbornenyl sultam systems.
Scheme 57: Ugi-RRM protocol for the synthesis of 2-aza-7-oxabicyclo system.
Scheme 58: Synthesis of spiroketal systems via RRM protocol.
Scheme 59: RRM approach to cis-fused heterotricyclic system.
Scheme 60: RRM protocol to functionalized bicyclic systems.
Scheme 61: ROM/RCM/CM cascade to generate bicyclic scaffolds.
Scheme 62: RCM of ROM/CM product.
Scheme 63: RRM protocol to bicyclic isoxazolidine ring system.
Scheme 64: RRM approach toward the total synthesis of (±)-8-epihalosaline (300).
Scheme 65: Sequential RRM approach to decalin 304 and 7/6 fused 305 systems.
Scheme 66: RRM protocol to various fused carbocyclic derivatives.
Scheme 67: RRM to cis-hydrindenol derivatives.
Scheme 68: RRM protocol towards the cis-hydrindenol derivatives.
Scheme 69: RRM approach toward the synthesis of diversed polycyclic lactams.
Scheme 70: RRM approach towards synthesis of hexacyclic compound 324.
Scheme 71: RRM protocol to generate luciduline precursor 327 with catalyst 2.
Scheme 72: RRM protocol to key building block 330.
Scheme 73: RRM approach towards the synthesis of key intermediate 335.
Scheme 74: RRM protocol to highly functionalized spiro-pyran system 339.
Scheme 75: RRM to various bicyclic polyether derivatives.
Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams
- Katherine M. Byrd
Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60
Graphical Abstract
Scheme 1: Generic mechanism for the conjugate addition reaction.
Figure 1: Methods to activate unsaturated amide/lactam systems.
Scheme 2: DCA of Grignard reagents to an L-ephedrine derived chiral α,β–unsaturated amide.
Figure 2: Chiral auxiliaries used in DCA reactions.
Scheme 3: Comparison between auxiliary 5 and the Oppolzer auxiliary in a DCA reaction.
Scheme 4: Use of Evans auxiliary in a DCA reaction.
Figure 3: Lewis acid complex of the Evans auxiliary [43].
Scheme 5: DCA reactions of α,β-unsaturated amides utilizing (S,S)-(+)-pseudoephedrine and the OTBS-derivative...
Figure 4: Proposed model accounting for the diastereoselectivity observed in the 1,4-addition of Bn2NLi to α,...
Scheme 6: An example of a tandem conjugate addition–α-alkylation reaction of an α,β-unsaturated amide utilizi...
Scheme 7: Conjugate addition to an α,β-unsaturated bicyclic lactam leading to (+)-paroxetine and (+)-femoxeti...
Scheme 8: Intramolecular conjugate addition reaction to α,β-unsaturated amide.
Scheme 9: Conjugate addition to an α,β-unsaturated pyroglutamate derivative.
Scheme 10: Cu(I)–NHC-catalyzed asymmetric silylation of α,β-unsaturated lactams and amides.
Scheme 11: Asymmetric copper-catalyzed 1,4-borylation of an α,β-unsaturated amide.
Scheme 12: Asymmetric cross-coupling 49 to phenyl chloride.
Scheme 13: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam.
Scheme 14: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide.
Scheme 15: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide using a chiral bicyclic dien...
Scheme 16: Synthesis of (R)-(−)-baclofen through a rhodium-catalyzed asymmetric 1,4-arylation of lactam 58.
Scheme 17: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide and lactam employing organo[...
Scheme 18: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam employing benzofuran-2-ylzi...
Figure 5: Further chiral ligands that have been used in rhodium-catalyzed 1,4-additions of α,β-unsaturated am...
Scheme 19: Palladium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to a α,β-unsaturated lactam.
Scheme 20: SmI2-mediated cyclization of α,β-unsaturated Weinreb amides.
Figure 6: Chiral Lewis acid complexes used in the Mukaiyama–Michael addition of α,β-unsaturated amides.
Scheme 21: Mukaiyama–Michael addition of thioester silylketene acetal to α,β-unsaturated N-alkenoyloxazolidino...
Scheme 22: Asymmetric 1,4-addition of aryl acetylides to α,β-unsaturated thioamides.
Scheme 23: Asymmetric 1,4-addition of alkyl acetylides to α,β-unsaturated thioamides.
Scheme 24: Asymmetric vinylogous conjugate additions of unsaturated butyrolactones to α,β-unsaturated thioamid...
Scheme 25: Gd-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrroles [205].
Scheme 26: Lewis acid-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrazole 107.
Scheme 27: Lewis acid mediated 1,4-addition of dibenzyl malonate to α,β-unsaturated N-acylpyrroles.
Scheme 28: Chiral Lewis acid mediated 1,4-radical addition to α,β-unsaturated N-acyloxazolidinone [224].
Scheme 29: Aza-Michael addition of O-benzylhydroxylamine to an α,β-unsaturated N-acylpyrazole.
Scheme 30: An example of the aza-Michael addition of secondary aryl amines to an α,β-unsaturated N-acyloxazoli...
Scheme 31: Aza-Michael additions of anilines to a α,β-unsaturated N-alkenoyloxazolidinone catalyzed by palladi...
Scheme 32: Aza-Michael additions of aniline to an α,β-unsaturated N-alkenoylbenzamide and N-alkenoylcarbamate ...
Scheme 33: Difference between aza-Michael addition ran using the standard protocol versus the slow addition pr...
Scheme 34: Aza-Michael additions of aryl amines salts to an α,β-unsaturated N-alkenoyloxazolidinone catalyzed ...
Scheme 35: Aza-Michael addition of N-alkenoyloxazolidiniones catalyzed by samarium diiodide [244].
Scheme 36: Asymmetric aza-Michael addition of p-anisidine to α,β-unsaturated N-alkenoyloxazolidinones catalyze...
Scheme 37: Asymmetric aza-Michael addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones catalyzed by i...
Scheme 38: Asymmetric 1,4-addition of purine to an α,β-unsaturated N-alkenoylbenzamide catalyzed by (S,S)-(sal...
Scheme 39: Asymmetric 1,4-addition of phosphites to α,β-unsaturated N-acylpyrroles.
Scheme 40: Asymmetric 1,4-addition of phosphine oxides to α,β-unsaturated N-acylpyrroles.
Scheme 41: Tandem Michael-aldol reaction catalyzed by a hydrogen-bonding organocatalyst.
Scheme 42: Examples of the sulfa-Michael–aldol reaction employing α,β-unsaturated N-acylpyrazoles.
Scheme 43: Example of the sulfa-Michael addition of α,β-unsaturated N-alkenoyloxazolidinones.
Figure 7: Structure of cinchona alkaloid-based squaramide catalyst.
Scheme 44: Asymmetric intramolecular oxa-Michael addition of an α,β-unsaturated amide.
Scheme 45: Formal synthesis atorvastatin.
Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation
- Yiyang Liu,
- Marc Liniger,
- Ryan M. McFadden,
- Jenny L. Roizen,
- Jacquie Malette,
- Corey M. Reeves,
- Douglas C. Behenna,
- Masaki Seto,
- Jimin Kim,
- Justin T. Mohr,
- Scott C. Virgil and
- Brian M. Stoltz
Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261
- [43], completing the formal synthesis of (−)-quinic acid (21). Additionally, one could in principle also access the less commercially abundant antipode (+)-quinic acid (21) using the catalyst (R)-t-Bu-PHOX. C) Dysidiolide Dysidiolide (29, Scheme 6) was isolated from the marine sponge Dysidea etheria
- synthesis. This formal synthesis shows the power of the enantioselective allylic alkylation to access formerly racemic constructs as single enantiomers; Danishefsky’s synthesis is now rendered enantioselective. D) Aspidospermine The aspidosperma alkaloids have garnered much attention as beautiful targets
- the natural product. Contrasting Meyers’ approach, which employed a chiral auxiliary as part of 39, we thought a catalytic enantioselective alkylation strategy would be ideal for a formal total synthesis of natural (−)-aspidospermine (36) via the antipode of 38. The formal synthesis began with 1,3
Graphical Abstract
Scheme 1: Three classes of Pd-catalyzed enantioselective allylic alkylations.
Figure 1: Selected natural products from Thujopsis dolabrata.
Scheme 2: Srikrishna and Anebouselvy’s approach to (+)-thujopsene.
Scheme 3: Formal total synthesis of (−)-thujopsene.
Scheme 4: Renaud’s formal total synthesis of (−)-quinic acid.
Scheme 5: Formal total synthesis of (−)-quinic acid.
Scheme 6: Danishefsky’s approach to (±)-dysidiolide.
Scheme 7: Formal total synthesis of (−)-dysidiolide.
Scheme 8: Meyers’ approach to unnatural (+)-aspidospermine.
Scheme 9: Formal total synthesis of (−)-aspidospermine.
Scheme 10: Magnus’ approach to (±)-rhazinilam.
Scheme 11: Formal total synthesis of (+)-rhazinilam.
Scheme 12: Amat’s approach to (−)-quebrachamine.
Scheme 13: Formal total synthesis of (+)-quebrachamine.
Scheme 14: Pandey’s approach to (+)-vincadifformine.
Scheme 15: Formal total synthesis of (−)-vincadifformine.
Scheme 16: Two generations of building blocks.
Chiral phosphines in nucleophilic organocatalysis
- Yumei Xiao,
- Zhanhu Sun,
- Hongchao Guo and
- Ohyun Kwon
Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218
- (Scheme 34). Chiral 2-alkyl-substituted 3-pyrrolines are highly valuable building blocks that can be further transformed into various biologically useful molecules. For example, with this reaction as a key step, a concise formal synthesis of (+)-trachelanthamidine was accomplished, highlighting the
Graphical Abstract
Figure 1: Cyclic chiral phosphines based on bridged-ring skeletons.
Figure 2: Cyclic chiral phosphines based on binaphthyl skeletons.
Figure 3: Cyclic chiral phosphines based on ferrocene skeletons.
Figure 4: Cyclic chiral phosphines based on spirocyclic skeletons.
Figure 5: Cyclic chiral phosphines based on phospholane ring skeletons.
Figure 6: Acyclic chiral phosphines.
Figure 7: Multifunctional chiral phosphines based on binaphthyl skeletons.
Figure 8: Multifunctional chiral phosphines based on amino acid skeletons.
Scheme 1: Asymmetric [3 + 2] annulations of allenoates with electron-deficient olefins, catalyzed by the chir...
Scheme 2: Asymmetric [3 + 2] annulations of allenoate and enones, catalyzed by the chiral binaphthyl-based ph...
Scheme 3: Asymmetric [3 + 2] annulations of N-substituted olefins and allenoates, catalyzed by the chiral bin...
Scheme 4: Asymmetric [3 + 2] annulations of 2-aryl-1,1-dicyanoethylenes with ethyl allenoate, catalyzed by th...
Scheme 5: Asymmetric [3 + 2] annulations of 3-alkylideneindolin-2-ones with ethyl allenoate, catalyzed by the...
Scheme 6: Asymmetric [3 + 2] annulations of 2,6-diarylidenecyclohexanones with allenoates, catalyzed by the c...
Scheme 7: Asymmetric [3 + 2] annulations of allenoate with alkylidene azlactones, catalyzed by the chiral bin...
Scheme 8: Asymmetric [3 + 2] annulations of C60 with allenoates, catalyzed by the chiral phosphine B6.
Scheme 9: Asymmetric [3 + 2] annulations of α,β-unsaturated esters and ketones with an allenoate, catalyzed b...
Scheme 10: Asymmetric [3 + 2] annulations of exocyclic enones with allenoates, catalyzed by the ferrocene-modi...
Scheme 11: Asymmetric [3 + 2] annulations of enones with an allenylphosphonate, catalyzed by the ferrocene-mod...
Scheme 12: Asymmetric [3 + 2] annulations of 3-alkylidene-oxindoles with ethyl allenoate, catalyzed by the fer...
Scheme 13: Asymmetric [3 + 2] annulations of dibenzylideneacetones with ethyl allenoate, catalyzed by the ferr...
Scheme 14: Asymmetric [3 + 2] annulations of trisubstituted alkenes with ethyl allenoate, catalyzed by the fer...
Scheme 15: Asymmetric [3 + 2] annulations of 2,6-diarylidenecyclohexanones with allenoates, catalyzed by the f...
Scheme 16: Asymmetric [3 + 2] annulations of α,β-unsaturated ketones with ethyl allenoates, catalyzed by the f...
Scheme 17: Asymmetric [3 + 2] annulations of α,β-unsaturated esters with allenoates, catalyzed by the ferrocen...
Scheme 18: Asymmetric [3 + 2] annulations of alkylidene azlactones with allenoates, catalyzed by the chiral sp...
Scheme 19: Asymmetric [3 + 2] annulations of α-trimethylsilyl allenones and electron-deficient olefins, cataly...
Scheme 20: Asymmetric [3 + 2] annulations of α,β-unsaturated ketones with an allenone, catalyzed by the chiral...
Scheme 21: Asymmetric [3 + 2] annulations of cyclic enones with allenoates, catalyzed by the chiral α-amino ac...
Scheme 22: Asymmetric [3 + 2] annulations of arylidenemalononitriles and analogues with an allenoate, catalyze...
Scheme 23: Asymmetric [3 + 2] annulations of α,β-unsaturated esters with an allenoate, catalyzed by the chiral...
Scheme 24: Asymmetric [3 + 2] annulations of 3,5-dimethyl-1H-pyrazole-derived acrylamides with an allenoate, c...
Scheme 25: Asymmetric [3 + 2] annulations of maleimides with allenoates, catalyzed by the chiral phosphine H10....
Scheme 26: Asymmetric [3 + 2] annulations of α-substituted acrylates with allenoate, catalyzed by the chiral p...
Scheme 27: Asymmetric [3 + 2] annulation of an N-tosylimine with an allenoate, catalyzed by the chiral phosphi...
Scheme 28: Asymmetric [3 + 2] annulations of N-tosylimines with an allenoate, catalyzed by the chiral phosphin...
Scheme 29: Asymmetric [3 + 2] annulations of N-tosylimines with an allenoate, catalyzed by the chiral phosphin...
Scheme 30: Asymmetric [3 + 2] annulations of N-diphenylphosphinoyl aromatic imines with butynoates, catalyzed ...
Scheme 31: Asymmetric [3 + 2] annulations of N-tosylimines with allenylphosphonates, catalyzed by the chiral p...
Scheme 32: Asymmetric [3 + 2] annulation of an N-tosylimine with an allenoate, catalyzed by the chiral phosphi...
Scheme 33: Asymmetric [3 + 2] annulations of N-diphenylphosphinoyl aromatic imines with allenoates (top), cata...
Scheme 34: Asymmetric [3 + 2] annulation of N-diphenylphosphinoylimines with allenoates, catalyzed by the chir...
Scheme 35: Asymmetric [3 + 2] annulation of an azomethine imine with an allenoate, catalyzed by the chiral pho...
Scheme 36: Asymmetric [3 + 2] annulations between α,β-unsaturated esters/ketones and 3-butynoates, catalyzed b...
Scheme 37: Asymmetric intramolecular [3 + 2] annulations of electron-deficient alkenes and MBH carbonates, cat...
Scheme 38: Asymmetric [3 + 2] annulations of methyleneindolinone and methylenebenzofuranone derivatives with M...
Scheme 39: Asymmetric [3 + 2] annulations of activated isatin-based alkenes with MBH carbonates, catalyzed by ...
Scheme 40: Asymmetric [3 + 2] annulations of maleimides with MBH carbonates, catalyzed by the chiral phosphine ...
Scheme 41: A series of [3 + 2] annulations of various activated alkenes with MBH carbonates, catalyzed by the ...
Scheme 42: Asymmetric [3 + 2] annulations of an alkyne with isatins, catalyzed by the chiral phosphine F1.
Scheme 43: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine B1.
Scheme 44: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine H5.
Scheme 45: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphines H13 and H12.
Scheme 46: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine H6.
Scheme 47: Kerrigan’s [2 + 2] annulations of ketenes with imines, catalyzed by the chiral phosphine B7.
Scheme 48: Asymmetric [4 + 1] annulations, catalyzed by the chiral phosphine G6.
Scheme 49: Asymmetric homodimerization of ketenes, catalyzed by the chiral phosphine F5 and F6.
Scheme 50: Aza-MBH/Michael reactions, catalyzed by the chiral phosphine G1.
Scheme 51: Tandem RC/Michael additions, catalyzed by the chiral phosphine H14.
Scheme 52: Intramolecular tandem RC/Michael addition, catalyzed by the chiral phosphine H15.
Scheme 53: Double-Michael addition, catalyzed by the chiral aminophosphine G9.
Scheme 54: Tandem Michael addition/Wittig olefinations, mediated by the chiral phosphine BIPHEP.
Scheme 55: Asymmetric Michael additions, catalyzed by the chiral phosphines H7, H8, and H9.
Scheme 56: Asymmetric γ-umpolung additions, catalyzed by the chiral phosphine A1.
Scheme 57: Asymmetric γ-umpolung additions, catalyzed by the chiral phosphines E2 and E3.
Scheme 58: Intramolecular γ-additions of hydroxy-2-alkynoates, catalyzed by the chiral phosphine D2.
Scheme 59: Intra-/intermolecular γ-additions, catalyzed by the chiral phosphine D2.
Scheme 60: Intermolecular γ-additions, catalyzed by the chiral phosphines B5 and B3.
Scheme 61: Intermolecular γ-additions, catalyzed by the chiral phosphines E6 and B4.
Scheme 62: Asymmetric allylic substitution of MBH acetates, catalyzed by the chiral phosphine G2.
Scheme 63: Allylic substitutions between MBH acetates or carbonates and an array of nucleophiles, catalyzed by...
Scheme 64: Asymmetric acylation of diols, catalyzed by the chiral phosphines E4 and E5.
Scheme 65: Kinetic resolution of secondary alcohols, catalyzed by the chiral phosphine E8 and E9.
Relay cross metathesis reactions of vinylphosphonates
- Raj K. Malla,
- Jeremy N. Ridenour and
- Christopher D. Spilling
Beilstein J. Org. Chem. 2014, 10, 1933–1941, doi:10.3762/bjoc.10.201
- combing organic fragments in natural product synthesis, the value of vinylphosphonates as synthetic intermediates would increase if their reactivity could be enhanced to a level where they would participate in cross metathesis reactions. As an example, we recently described a method for the formal
- synthesis of centrolobine (8) [9], an antileishmananial compound isolated from the heartwood of various Centrolobium species [12][13][14][15][16] (Scheme 2). The cis-THP substituted vinylphosphonate 5, formed by a stereospecific palladium-catalyzed cyclization of phosphono allylic carbonate 4, was cleaved
Graphical Abstract
Scheme 1: Palladium catalysed reaction of phosphono allylic carbonates.
Figure 1: Natural products prepared using vinyl phosphonate intermediates.
Scheme 2: Approaches to the synthesis of centrolobine.
Scheme 3: Relay ring closing metathesis and relay cross metathesis.
Scheme 4: Cross metathesis reactions of vinyl phosphonates.
Scheme 5: Transesterification of phosphonate esters.
Scheme 6: Relay cross metathesis of mono-allyl vinylphosphonates with methyl acrylate.
Scheme 7: Relay cross metathesis of mono-allyl vinylphosphonates with styrenes.
Scheme 8: Ring closing vs relay cross metathesis.
Scheme 9: Relay cross metathesis of diallyl vinylphosphonates with methyl acrylate.
Scheme 10: A cross metathesis reaction of both mono- and diallyl vinylphosphonates with methyl acrylate.
Scheme 11: A proposed mechanism for the relay cross metathesis reaction of allyl vinylphosphonates.
Scheme 12: A proposed mechanism for the TBAI catalysed transesterification.
Scheme 13: A selective synthesis of mono-allyl phosphonates.
Structure elucidation of female-specific volatiles released by the parasitoid wasp Trichogramma turkestanica (Hymenoptera: Trichogrammatidae)
- Armin Tröger,
- Teris A. van Beek,
- Martinus E. Huigens,
- Isabel M. M. S. Silva,
- Maarten A. Posthumus and
- Wittko Francke
Beilstein J. Org. Chem. 2014, 10, 767–773, doi:10.3762/bjoc.10.72
- approach includes a formal synthesis of optically active A and B. Until now, we did not find suitable conditions to separate the enantiomers of the tetramethyldiene 22 and the respective allyl alcohol 23 (or corresponding derivatives thereof) in order to assign the absolute configuration of the natural
Graphical Abstract
Figure 1: Published 70 eV EI mass spectra of the naturally occurring compounds A and B [12].
Figure 2: Synthesis of tetramethyltrideca-2,4-dienes 8, 14 and 15. Conditions: a: LiAlH4, Et2O, −30 °C to rt,...
Figure 3: 70 eV EIMS of synthetic tetramethyltrideca-2,4-dienes 8, 14 and 15. These spectra were run under th...
Figure 4: Synthesis of (2E,4EZ)-syn,syn-4,6,8,10-tetramethyltrideca-2,4-diene (22), as well as (2E,4E)- and (2...
Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis
- Sebastian Krüger and
- Tanja Gaich
Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14
- (51) could be accessed after 10 or 7 steps respectively. Piers and co-workers were the first to examine the DVCPR as a key step in the formal synthesis of (±)-quadrone (55, see Scheme 9) [49], and the total syntheses of sinularene (59) [50], prezizanol (63) and prezizaene (64) [51]. The synthesis of
- ). Davies and co-worker [91][92] investigated the formal synthesis of the sequiterpene-hydroquinone derivative frondosin B (99, see Scheme 12) [93] via an enantioselective cyclopropanation of trans-piperylene and subsequent divinylcyclopropane rearrangement, to further demonstrate the versatility of their
- over several steps (77% over three steps and 98% over two steps, respectively). Overman’s total synthesis of scopadulcic acid B. Davies’ total syntheses of tremulenolide A and tremulenediol A. Davies formal [4 + 3] cycloaddition approach towards the formal synthesis of frondosin B. Davies and Sarpongs
Graphical Abstract
Scheme 1: Vogel’s first approach towards the divinylcyclopropane rearrangement [4] and characterization of cis-d...
Scheme 2: Transition states for the Cope rearrangement and the related DVCPR. Ts = transition state.
Scheme 3: Two possible mechanisms of trans-cis isomerizations of divinylcyclopropanes.
Scheme 4: Proposed biosynthesic pathway to ectocarpene (21), an inactive degradation product of a sexual pher...
Scheme 5: Proposed biosynthesis of occidenol (25) and related natural compounds.
Scheme 6: Gaich’s bioinspired system using the DVCPR to mimick the dimethylallyltryptophan synthase. DMAPP = ...
Scheme 7: Iguchi’s total synthesis of clavubicyclone, part 1.
Scheme 8: Iguchi’s total synthesis of clavubicyclone, part 2.
Scheme 9: Wender’s syntheses of the two pseudoguainanes confertin (50) and damsinic acid (51) and Pier’s appr...
Scheme 10: Overman’s total synthesis of scopadulcic acid B.
Scheme 11: Davies’ total syntheses of tremulenolide A and tremulenediol A.
Scheme 12: Davies formal [4 + 3] cycloaddition approach towards the formal synthesis of frondosin B.
Scheme 13: Davies and Sarpongs formal [4 + 3]-cycloaddition approach towards barekoxide (106) and barekol (107...
Scheme 14: Davies formal [4 + 3]-cycloaddition approach to 5-epi-vibsanin E (115) containing an intermediate c...
Scheme 15: Echavarren’s total synthesis of schisanwilsonene A (126) featuring an impressive gold-catalzed casc...
Scheme 16: Davies early example of a formal [4 + 3]-cycloaddition in alkaloids synthesis.
Scheme 17: Fukuyama’s total synthesis of gelsemine, part 1.
Scheme 18: Fukuyama’s total synthesis of gelsemine, featuring a divinylcyclopropane rearrangement, part 2.
Scheme 19: Kende’s total synthesis of isostemofoline, using a formal [4 + 3]-cycloaddition, including an inter...
Scheme 20: Danishefsky’s total synthesis of gelsemine, part 1.
Scheme 21: Danishefsky’s total synthesis of gelsemine, part 2.
Scheme 22: Fukuyama’s total synthesis of gelsemoxonine.
Scheme 23: Wender’s synthetic access to the core skeleton of tiglianes, daphnanes and ingenanes.
Scheme 24: Davies’ approach towards the core skeleton of CP-263,114 (212).
Scheme 25: Wood’s approach towards actinophyllic acid.
Scheme 26: Takeda’s approach towards the skeleton of the cyanthins, utilitizing the divinylcyclopropane rearra...
Scheme 27: Donaldson’s organoiron route towards the guianolide skeleton.
Scheme 28: Stoltz’s tandem Wolff/DVCPR rearrangement.
Scheme 29: Stephenson’s tandem photocatalysis/arylvinylcyclopropane rearrangement.
Scheme 30: Padwa’s rhodium cascade involving a DVCPR.
Scheme 31: Matsubara’s version of a DVCPR.
Scheme 32: Toste’s tandem gold-catalyzed Claisen-rearrangement/DVCPR.
Scheme 33: Ruthenium- and gold-catalyzed versions of tandem reactions involving a DVCPR.
Scheme 34: Tungsten, platinum and gold catalysed cycloisomerizations leading to a DVCPR.
Scheme 35: Reisman’s total synthesis of salvileucalin B, featuring an (undesired) vinylcyclopropyl carbaldehyd...
Scheme 36: Studies on the divinylepoxide rearrangement.
Scheme 37: Studies on the vinylcyclopropanecarbonyl rearrangement.
Scheme 38: Nitrogen-substituted variants of the divinylcyclopropane rearrangement.
