Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• . Intermediate 25 was prepared through TBDMS protection and desulfonylation of 24, itself derived from the condensation of epoxide 23b and sulfone 27. The precursor 27 was synthesized from Roche ester 29 via a sequence of steps, including reduction, three-carbon homologation, and enzymatic desymmetrization. An

• constructing Omura’s C1–C11 fragment Yadav and Yadav, in 2013, reported their work on preparing the C1–C11 fragment 61 of borrelidin. Their approach employed an iterative sequence of oxidation, Wittig olefination, hydrogenation, and asymmetric methylation for carbon homologation, alongside Sharpless

• stereochemistry (Scheme 11). A further two-carbon homologation of compound 76 through an oxidation and Wittig olefination sequence yielded unsaturated ester 77 in 92% yield. The ester group in 77 was reduced using DIBAL-H, achieving a 95% yield. Sharpless epoxidation of alcohol 78 was then performed using (−)-DET

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• fluoride and BF3·OEt2 as activator. A range of unsaturated amines 5 were cyclised to racemic β-fluorinated piperidines 6. Good yields were reported for all compounds except those with substituents present on the alkene. Homologation of the carbon chain from 5 to 6 carbons gave both 6- and 7-membered rings

• unsaturated dicarbonyls 74 (Scheme 39) [57]. Using PhI(OAc)2 as an oxidant and TMSBr as a source of bromine and reaction promoter, a range of bromomethyldihydrofurans 75 were cyclised in good yields. Both 5- and 6-membered rings were formed, with homologation of the unsaturated chain. The authors initially

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• , obtained by a 3,3’-diiodo-BINOL 39-catalysed asymmetric CH(CF3)-homologation of dehydrated vinylboronic acids 40 with trifluoromethyl diazomethane at 40 °C. The resulting enantioenriched transient (α-trifluoromethyl)allylboronic acid diethyl esters 41 were converted into the chromatographically stable 1,8

• excellent enantioselectivities (89–98% ee) and low to moderate yields (48–72%). The homologation step proceeds via the stereoretentive 1,2-migration of the vinyl group from the tetracoordinated boron to the highly electrophilic carbon of the diazomethane, concerted with the elimination of the nitrogen

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• is a promising synthetic reagent not only as a one-carbon homologation reagent but also as a nitrogen source for nitrogen-containing molecules. Because of their isoelectronic structure with carbon monoxide, isocyanides also react with nucleophiles, electrophiles, carbon radicals, and transition metal

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• originally synthesized by Palazzo et al. [76] and several other derivatives were developed based on ethylamine-chain homologation [77]. Triazoles: Hall and co-workers [78] developed 1,2,3-triazolyl analogues 111 of ʟ-histidine for ʟ-type amino acid transporter 1 (LAT1) activity, a sodium-independent membrane

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• homologation and hydrolysis led to aldehyde (±)-46 which could then be oxidised to acid (±)-47 using a Pinnick oxidation. BCH 42b also led to ester (±)-48 via a Horner–Wadsworth–Emmons reaction followed by hydrogenation of the formed alkene. 1,2-BCH 44 could be turned into amine (±)-49 by oxime formation and

• 1,4-BCHs (Scheme 11B) [55]. From carboxylic acid 100e, Curtius rearrangement led to amine 101 and a photoredox decarboxylative conjugate addition to diester 102. From boronate ester 100f, oxidative deborylation led to alcohol 103, arylation led to furan 104 and Matteson homologation to boronate ester

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

• synthesis started from 3-hydroxy-2-methoxybenzaldehyde (34), which was converted into Grignard reagent 35 and added onto 3-methylbut-2-enal (Scheme 6). A sequence involving Claisen rearrangement, Roskamp homologation, diazo transfer and intramolecular cyclopropanation led to intermediate 37. The hydroxy

• [3.2.1]octane 67 was achieved by a radical cyclization using n-Bu3SnH in refluxing toluene. A sequence involving an ester reduction, Ley–Griffith oxidation and Seyferth–Gilbert homologation with Bestmann–Ohira reagent allowed to obtain the alkynyl bicylo[3.2.1]octane 69. On the other hand, the five

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• transformation. Introduction of an α-methyl substitution in propargylamine (compound 16) was tolerated and the respective reaction gave product 17 in a yield comparable to (and somewhat better than) that of unsubstituted compound 5a. Homologation of propargylamine made a significant impact on the course of the

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

• reactivity in their synthesis of (+)-awajanomycin (92), a marine natural product with a γ-lactone-δ-lactam core structure (Scheme 15) [30][31]. Key step was an asymmetric allylboration of diethyl mesoxalate (90a) with boronate 89, which was easily accessible through a Matteson homologation of dichloromethyl

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• -bed reactors were developed by the groups of de Souza and Yadav [33][34]. Very recently, Kirschning and co-workers presented a general method for the Matteson reaction in flow, allowing iterative homologation of various terpene boronate esters 17, which are subsequently oxidized to the corresponding

• homologation reactor module (and then, if desired, even to a third) to reiterate homologation. The resulting reaction mixture is either collected directly to provide the homologated pinacol boronates 19, e.g., menthol-derived compound 21, which was found to have a “rather sweet, slightly apple-like, fruity

• acyltransferase in a packed-bed reactor and the corresponding odor profiles of selected examples [9][32]. Synthesis of homologated alcohols 20 by iterative homologation of terpenyl boronate esters 17 followed by oxidation in flow. Sequential three-step synthesis of (S)-α-phellandrene (30) from (R)-carvone (25

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• . Eventually, trans-crotonaldehyde (62) is selected as the precursor for this study. The study began with the enantioselective epoxidation of trans-crotonaldehyde (62) under Jørgensen conditions using organocatalyst 63, followed by a two-carbon homologation to obtain α,β-unsaturated epoxy ester 64 in 78% yield

• cyclization to form the furan ring is then expected to occur concurrently. (−)-Diethyl tartrate (98) was eventually selected as the precursor to construct the unsaturated ester 96 after a double two-carbon homologation. In the reverse order, the synthesis of 13 began with the conversion of diethyl tartrate 98

• primary alcohol 99 (90%). Oxidation of this moiety with IBX to its corresponding aldehyde served as a substrate for the two-carbon homologation via Wittig reaction giving ester 96 in 80% yield over the two steps. After reduction of the ester group to its primary alcohol counterpart, the Sharpless

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines

• Matthew J. Fleming and
• David M. Hodgson

Beilstein J. Org. Chem. 2021, 17, 2385–2389, doi:10.3762/bjoc.17.155

• -carbon homologation of an epoxide to an allylic alcohol (cf Scheme 3) can also be achieved using excess dimethylsulfonium methylide [12][13], although non-terminal alkenes have not been shown to be directly accessible by higher homologation. To examine the latter in the context of the current chemistry

• -lithio epoxides or aziridines [3][4][5]. Proposed eliminative cross-coupling of carbenoids to allylic alcohols (X = O) or allylic amines (X = NSO2t-Bu). Allylic alcohol 6 by one-carbon homologation from epoxide 5. Internal allylic alcohols from epoxides and stannane 7. Cyclopropylidene synthesis from

Fritsch–Buttenberg–Wiechell rearrangement of magnesium alkylidene carbenoids leading to the formation of alkynes

• Tsutomu Kimura,
• Koto Sekiguchi,
• Akane Ando and
• Aki Imafuji

Beilstein J. Org. Chem. 2021, 17, 1352–1359, doi:10.3762/bjoc.17.94

• homologation [3]. Much effort has been devoted to developing a procedure for the synthesis of alkynes from carbonyl compounds, and the Corey–Fuchs method, the Seyferth–Gilbert method, and the Ohira–Bestmann modification have been developed (Scheme 1) [4][5][6][7]. These methods consist of the Wittig or Horner

• alkynes 4 when magnesium alkylidene carbenoids 3 were left without reactants (Scheme 2d). Herein, we report the synthesis of alkynes 4 from carbonyl compounds 1 with one-carbon homologation via the FBW rearrangement of magnesium alkylidene carbenoids 3 as a key step. A mechanistic study on the FBW

• provides a convenient route to the synthesis of alkynes from carbonyl compounds through one-carbon homologation. The trans relationship between the substituent with a high migratory aptitude and the chloro group was of importance for the successful 1,2-rearrangement. Experimental All reactions involving

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• and a subsequent homologation step involving a putative copper difluorocarbene will allow the formation of the CuCF2CF3 species. With this tool in hand, a panel of aryl iodides was functionalized (Scheme 24). Conclusion This review aims at providing an overview of the recent advances made since 2014

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• -closing metathesis [9][21][22]. The C3–C4 bond has been assembled by 1,2-cuprate rearrangement [23]. Iterative construction of the polyketide from smaller building blocks has been achieved by Matteson homologation [24], that was also applied to the synthesis of the related polyketide section of lagunamide

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• chiral template for the synthesis of (2S,3R)-2 since configurations at C3 and C4 in the hexose are retained in the target compound. The disclosed strategy relied on prior transformation of D-glucose into azidofuranoside 57 [66] and next to acid 58. Homologation of acid 58 was accomplished by the Arndt

• , dioxane/water; d) NaIO4, then NaOCl2, H2NSO3H; e) MeI, K2CO3, acetone; f) AcOH, H2O; g) NaOH, MeOH; h) PDC, DMF; i) CF3COOH, CH2Cl2; j) H2, 5% Pd/C, MeOH, H2O. Two-carbon homologation of the protected L-serine. Reagents and conditions: a) Fmoc-succinimide, Na2CO3, dioxane, H2O; b) (3-hydroxymethyl)-3

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• . Subsequent hydrolysis of 18 with dilute aqueous hydrochloric acid afforded the desired ethyl ester 19 in 59% yield. Given the three steps required to convert the aldehyde 15 into the desired α-hydroxy acetic acid ethyl ester 19, we decided to pursue a more direct one-carbon homologation procedure. We

• the aldehyde 15 in hand, homologation involving the addition of the MAC reagent 20 afforded the TBS protected α-hydroxyacetic acid ethyl ester 21 in in 76% yield (Scheme 8). Based on the purported mechanistic reasoning of Nemoto, addition of the methine anion of 20 to 15 proceeds to the intermediate

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• of catalytic mercury iodide; it is a critical step for the formation of the compound 72. Hydrolysis of intermediate 68 led to ketone 69 in high yield containing an acetic acid residue β to the carbonyl group. A sequence of the one-carbon homologation of ketone 69 is followed by isomerization into the

Electrochemically modified Corey–Fuchs reaction for the synthesis of arylalkynes. The case of 2-(2,2-dibromovinyl)naphthalene

• Fabiana Pandolfi,
• Isabella Chiarotto and
• Marta Feroci

Beilstein J. Org. Chem. 2018, 14, 891–899, doi:10.3762/bjoc.14.76

• dihalides or vinyl bromides using sodium in ammonia or strong bases [8]. Alternatively, the compounds are accessible by homologation of aldehydes following the Bestmann modification of the Seyferth–Gilbert reaction, using in situ generated dimethyl (diazomethyl)phosphonate [9][10]. Moreover, the aldehyde

• homologation to terminal alkynes can also be obtained using the Corey–Fuchs reaction [11]. This is a two-step reaction in which an aldehyde is at first converted into a 1,1-dibromoalkene with chain extension by one carbon atom through the reaction with carbon tetrabromide and triphenylphosphine (Scheme 1

Quinone-catalyzed oxidative deformylation: synthesis of imines from amino alcohols

• Xinyun Liu,
• Johnny H. Phan,
• Benjamin J. Haugeberg,
• Shrikant S. Londhe and
• Michael D. Clift

Beilstein J. Org. Chem. 2017, 13, 2895–2901, doi:10.3762/bjoc.13.282

• decarboxylative homologation of α-amino acids [32], which demonstrated for the first time that quinone organocatalysts can be utilized to enable oxidative C–C bond cleavage to provide versatile imine intermediates. To further exploit the utility of this chemistry, we sought to develop a new method for the

• iminoquinone intermediate is likely required for productive reactivity. To demonstrate the synthetic utility of this methodology, we performed a sequential oxidative deformylation/Mukaiyama−Mannich addition under our previously reported conditions for decarboxylative amino acid homologation (Scheme 4) [32]. In

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• synthesis of amino acid analogous propargylamines, furnished with Cα-substituents imitating various amino acid side chains. The direct conversion of amino acids into propargylamines by the Corey–Fuchs or the Seyferth–Gilbert homologation has been successfully used for the preparation of several natural

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• not formed or was very unstable, which meant that the subsequent Wacker-type oxidation [24] to 9 could not be attempted. Concurrent with the homologation attempts described above (Scheme 1), some model studies were performed (Table 1) to ascertain the feasibility of performing α-fluorinations on other

• attempt to develop an iterative fluorination/homologation strategy (Scheme 1, boxed), we considered whether an ester could be employed as the repeating unit, instead of an aldehyde. Accordingly, the model ester 20 (see Supporting Information File 1) was treated with an electrophilic fluorine source under

• proposed iterative fluorination/homologation approach (Scheme 1, boxed), we were forced to conclude that this was not a viable route to α,β,γ-trifluoro-δ-amino acids 6. The next approach that was investigated is shown in Scheme 2. Having learned that homologation reactions involving fluorinated substrates

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• homologation methodology; the required fragments were also obtained by the sequential application of this methodology. Of note, Burkart’s 1st generation approach aiming to assemble the cyclized C1–C14 fragment with the C15–C20 extension was unsuccessful, since the keto group located at C14 failed to undergo

• –Gilbert homologation [128][129] under Bestmann–Ohira conditions [130][131], a Schwartz hydrozirconation/iodination sequence [132], and appropriate protecting group manipulations. Vinyl iodide 21, which comprises the C8–C13 segment was prepared from TBDPS-protected (R)-hydroxy-2-methylbut-3-ene 20 that was

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• -Haloalkyllithiums are a useful class of organometallic reagents widely employed in synthetic chemistry. In fact, they allow the direct homologation of carbonyl compounds and imines leading to β-halo-alcohols and amines that are useful building blocks [29][30][31]. This work represents a remarkable example of flash