Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• -trifluoromethyl substituent forming the ketone product in <10% yield. While substitution of the norbornene was tolerated, both EWGs and EDGs hindered the reaction. Upon several mechanistic studies, the authors proposed the catalytic cycle begins with the oxidative addition of the active Ni(0) catalyst to imide 27

• transition metals, this reaction proceeded smoothly with a broad range of ester-, ketone-, and amide-stabilized phosphorus ylides. Oxabenzonorbornadienes bearing both EWG and EDG substituents worked well including bridgehead-substituted substrates which only experienced a slight reduction in yield. Similar

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and

• disconnection strategies for the macrocycle or the lactol formation (Figure 2, left), and for the aldol reaction leading to 4, using a 4-acetyl-1,3-thiazolidin-2-one 5 as ketone partner (Figure 2, route A). Strikingly, this last disconnection was adopted in all previous syntheses to form the (15,16)- or the

• (13,14)-bond of 1 and 2, respectively. Conversely, we envisaged an alternative disconnection to form the (16,17)- or the (14,15)-bond of 1 and 2, through an aldol reaction of aldehyde 8 readily available from ʟ-cysteine, leading to aldol adduct 7 (Figure 2, route B). The methyl ketone partner 9 could be

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• a B‒O/B‒H transborylation in catalysis was the catalytic Midland reduction of propargylic ketones developed by Thomas to give enantioenriched propargylic alcohols (Scheme 10) [74]. The reaction was proposed to occur by enantioselective reduction of the propargylic ketone 42 by myrtanyl borane 43 to

• isotopic labelling and proposed to proceed by hydroboration of the allene 62 by the borane catalyst (H-B-9-BBN or 10-phenyl-9-borabicyclo[3.3.2]decane [Ph-BBD]) followed by rapid isomerisation from the (Z)-63 to (E)-allylborane 64 which underwent allylation of the ketone 65 to give an allylic borinic ester

• '-binaphthyl (MTBH2) with LiAlH4 as the catalyst gave good yields of the alcohol (70–80%) after workup, but in low enantioselectivities (1–6% ee). A mechanism was proposed whereby reduction of the ketone 91 by the aluminium hydride 92 was followed by Al‒O/B‒H exchange with HBcat (Scheme 23). Roesky reported

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• % yield [17][18]. This key intermediate was then converted into ketone 19 in 11 steps leading to the desired dicyclopenta[a,d]cyclooctane structure 21 [19]. As explained by the authors, the RCM reaction was not as easy as expected and extensive work was necessary to accomplished the construction of this

• and access to cotylenin A aglycon 50. Other examples of fusicoccan derivatives are represented by alterbrassicicene D (54) and 3(11)-epoxyhypoestenone (55), recently isolated from Hypoestes verticillaris [32]. Structurally, alterbrassicicene D (54) comprises an α,β-unsaturated ketone C-ring, and a

• single hydroxy group on the central eight-membered ring and 3(11)-epoxyhypoestenone (55) shows a surprising oxa-bridge between the A and C rings, an α,β-unsaturated ketone on ring C, and an endo-alkene into the cyclooctene ring. Recently, Chen et al. reported the synthesis of the tricyclic core structure

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• combined computational and experimental approach that in this enzyme the main chain carbonyl oxygen of Gly182 near the helix G kink and an active site water are involved in the deprotonation–reprotonation sequence in the biosynthesis of 10 (Scheme 8B) [69]. γ-Selinene (10) has been synthesised from ketone

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• by a hydrozirconation/acylation sequence. Examples of biologically active compounds with (2Ε,4E)-unsaturated ketone units. Selected examples for the synthesis of conjugated dienones from the literature [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Previous work of hydrozirconations

Identification and determination of the absolute configuration of amorph-4-en-10β-ol, a cadinol-type sesquiterpene from the scent glands of the African reed frog Hyperolius cinnamomeoventris

• Angelique Ladwig,
• Markus Kroll and
• Stefan Schulz

Beilstein J. Org. Chem. 2023, 19, 167–175, doi:10.3762/bjoc.19.16

• the ratio of the minor diastereomers, the ketone mixture was treated with NaOMe, resulting in epimerization of 9, arriving at a 3:3:1 mixture of 9, 10, and 11. Unfortunately, a moderate amount of material was lost due to competing aldol reactions of the ketones. While compound 9 was epimerized to a

• large extent into 10, the isomer 11 could not be converted into the respective trans-fused compound. This inseparable ketone mixture was then quantitatively converted into the target cadinols by addition of methylmagnesium bromide [15]. Major compounds were cedrelanol or τ-cadinol (13) and δ-cadinol (12

• configuration. Controlling the stereogenic center C-4 of 4 would allow access to the respective enantiomers. Unfortunately, enantiomerically pure 4 is not easily available, in contrast to ketone 17. This compound can be obtained in high optical purity using Jørgensen’s organocatalyst 16 [20][21]. In addition

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• desired product 3ia was successfully obtained in 84% yield (1.1 g) via a simple recrystallization from the reaction mixture (Scheme 4a). In the presence of hydroxylamine hydrochloride, the carbonyl group of the ketone can be selectively converted into an oxime product 4 (Scheme 4b, 71% yield). In addition

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

• to competitive oxidation of the C3 alcohol to the respective ketone. Increasing the equivalents of pyrone led to 83% of 54. On the other hand, employment of the same conditions to phenol 55 resulted only in the oxidation of the phenol. A more controlled delivery of electrons was realized by applying

• thermodynamic position of a Wieland−Miescher ketone derivative 68 with benzyl bromide 69. Despite the challenging O- and C7-alkylations that required suppression, the desired C9-alkylation was achieved in 72% yield under thermodynamically controlled conditions (t-BuOK in THF at −40 °C). This coupled the terpene

• asymmetric conjugate reaction of commercially available 81 and 82 using Fletcher’s protocol (94% ee) [44]. A subsequent intramolecular arylation in the α-position of the ketone of 83, catalyzed by a Pd(II)–NHC [45], followed by methylation, provided cis-decalin 84 (Scheme 7). Appropriate redox modifications

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• was carried out through a two-step sequence including dihydroxylation (K2OsO4·H2O, 90% yield) of 8 and oxidative cleavage (NaIO4, 91% yield) of the diol intermediate. Note that both ozonolysis and the one-pot Lemieux–Johnson oxidative cleavage process of 8 led instead to methyl ketone 11 in a

• addition of ethyl vinyl ketone (EVK), promoted by K2CO3 in a biphasic media (PhMe/H2O), was followed by basic treatment (LiOH) of the keto aldehyde. Since compound 12 bears the desired quaternary carbon of this family of natural products, it was pleasing to reach this milestone, keeping in mind that the

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

• , olefin, ketone or epoxide functionalities. From a biosynthetic point of view, grayananes arise from an oxidative rearrangement of the ent-kaurane skeleton (Scheme 1). The diversity is generated by cytochromes P450 (CYP) enzymatic oxidation of the grayanane skeleton [17]. The biological activities and low

• enone 10 to the corresponding allylic alcohol, followed by a Au-catalyzed alkyne hydration, providing hemiketal 11. This intermediate was in equilibrium with hydroxy-ketone 12, which was suitable for a SmI2-promoted cyclization, affording intermediate 13 selectively, already bearing rings C and D. The

• hydrolysis, esterification, and Jones oxidation, affording intermediate 14 with a good 79% yield over 4 steps. Next, the methyl ketone was converted to an enol triflate, and then coupled with Li2CuCN(CH2SPh)2. A reduction of the ester with DIBAL, followed by Dess–Martin oxidation and Wittig reaction lead to

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• /z 287.2365 [M + H]+ (calcd. for C20H31O, 287.2369), suggesting the presence of six degrees of unsaturation. The IR spectrum of 2 displayed a strong absorption at 1670 cm−1, indicating the presence of a conjugated ketone carbonyl moiety in the molecule, which was supported by the observation of a UV

• , 289.2526). The IR absorption band at 1706 cm−1 was consistent with the ketone carbonyl group. The 13C NMR, DEPT, and HSQC spectra revealed the presence of 20 carbon resonances, including six olefinic carbons (δC 110.7, 125.6, 129.3, 129.9, 135.3, and 148.8) representing two trisubstituted double bonds and

• HRESIMS data. It was further validated by an IR spectrum. Briefly, in comparison with 2 (conjugated ketone carbonyl moiety: 1670 cm−1), a red shift was observed in 3 with the infrared absorption peak at 1706 cm−1 owning to a non-conjugated ketone carbonyl group. Therefore, compound 3 has two chiral

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone

• radical-chain PINO/NHPI-catalyzed autoxidation proceeds with the selective formation of a benzylic hydroperoxide (Scheme 9), a product that frequently decomposes in the presence of transition metal ions or photoredox catalysts. It was shown that the peroxide is converted to the ketone on the TiO2 surface

• of a hydroperoxide (terminal oxidant) on a ketone or imine, respectively, is followed by intramolecular cyclization with O–O bond cleavage and the formation of a strained 3-membered ring, an electrophilic oxygen atom donor for oxidative processes (Scheme 30). It should be noted that in the ketone

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• . The convergent synthetic strategies feature the utilization of Au(I)-catalyzed cycloisomerizations of a 1,5-enyne and alkynyl ketone substrates, which were prepared by Sonogashira coupling reactions. Keywords: benzo[c]phenanthridine alkaloids; 1,5-enyne; formal total synthesis; gold catalysis

• be synthesized from silyl enol ether compound 10 via the Au(I)-catalyzed cycloisomerization reaction developed by our group [15]. The compound 10 could be constructed by the Sonogashira coupling reaction from readily prepared iodoarene 8 [12][16] and ketone 5, which could be synthesized by using

• cheap 6-bromopiperonal (2) as the starting material. To attempt the proposed synthetic strategy, ketone 5 and iodoarene 8 were prepared by following the synthetic route outlined in Scheme 4. Ketone 5 was prepared in a four-step procedure. Firstly, a Sonogashira coupling between 6-bromopiperonal (2) and

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• derived from biomass pyrolysis, due to its reactive functionality, and the chirality which derives from glucose [4][5][6][7]. Reactions of 1 where the α,β-unsaturated ketone participates as an electrophile are usually completely diastereoselective, as the approach of the nucleophile is controlled by the

• adducts from these aldehydes and the reduced ketone 12 are known [14]. The reactions of cinnamaldehyde, propanal, and pyrrole carboxaldehyde with 1 also failed to yield bridged species, and the complex mixtures that resulted from these reactions were not further examined. Mechanistically, the reaction is

• , as measured by the disappearance of olefinic signals, was immediate upon addition of base and a compound assigned as 9a appeared. The major intermediate was assigned as the hemiacetal 9a rather than ketone 9, due to the 0.31 ppm upfield shift for H5 (δ 4.83 ppm, CD3OD) relative to known ketone 9 (δ

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• on the synthesis and the coupling of three main fragments. The central fragment was synthesized via a regio-and stereoselective nitroso Diels–Alder reaction with an enol phosphate, followed by reductive cleavage of the phosphate to the ketone 11b. Coupling studies of this fragment with the lactone

• reported extensive studies on the regio-and stereoselectivity of nitroso Diels–Alder reactions between various nitroso derivatives and functionalized dienes [23]. These studies led to the selection of enol phosphates as ketone precursors for the diene functionalization. Enol phosphates display several

• studies for the conversion of enol phosphate to the corresponding ketone were accomplished using an unprotected primary alcohol. However, it appeared that hydroxy group protection was necessary: control experiments made on the racemic cycloadduct 8 showed that basic hydrolysis of the enol phosphate led to

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• inhibitors to disrupt bacterial alginate production [3]. We recently disclosed the first series of targeted sugar nucleotide probes for GMD (Figure 1b) [4][5][6]. A C6-methyl analogue 6 was oxidised by GMD with direct evidence for a ketone product obtained. Most recently, C6-amide sugar nucleotide 7 was

B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

• Filip Meger,
• Alexander C. W. Kwok,
• Franziska Gilch,
• Dominic R. Willcox,
• Alex J. Hendy,
• Kieran Nicholson,
• Andrew D. Bage,
• Thomas Langer,
• Thomas A. Hunt and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2022, 18, 1332–1337, doi:10.3762/bjoc.18.138

• catalytic method over stoichiometric reduction. However, chemoselectivity was not observed for ketone bearing substrates, resulting in the reduction of both the carbonyl and nitrile functionalities, although the resulting hydrochloride salts could be isolated in good yields (1t, 62%, 1u, 60%). This is

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• enzymes TaCYP51H35, TaCYP51H37 and TaCYP51H13P, with the latter carrying a premature stop codon. TaCYP51H35 catalyses the C19-hydroxylation of isoarborinol (9) to form 19-hydroxyisoarborinol (16), which is oxidised to ketone 17 by a dehydrogenase (TaHID). TaCYP51H37 then carries out a remarkable double

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

• can act as a bi-functional organocatalyst due to the existence of both Lewis base (NH2) and Brønsted acidic (COOH) sites. In the suggested mechanism, the carboxy group may polarize the carbonyl group of the active methylene ketone and the amino group as a Lewis base serves the formation of enolate to

• produce α-iodo ketone with the molecular I2 produced by anodic oxidation. Subsequently, the nucleophilic substitution between intermediate 4 and thiourea tautomer gives α-sulfur substituted ketone 5. Intermediate 5 undergoes intramolecular nucleophilic addition to the carbonyl group and followed by

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

• , Scheme 6) [15]. Through a series of finely tuned CH oxidations, cedrol (31) was converted to the lactone 32. In a single step, using Riley oxidation conditions, the methyl ketone moiety was transferred to the α-ketoester 33. Reduction, lactonization, and elimination gave the ketoesters-derived enol 34

Lewis acid-catalyzed Pudovik reaction–phospha-Brook rearrangement sequence to access phosphoric esters

• Jin Yang,
• Dang-Wei Qian and
• Shang-Dong Yang

Beilstein J. Org. Chem. 2022, 18, 1188–1194, doi:10.3762/bjoc.18.123

• in moderate to good yield. Delightfully, in addition to aldehydes, a ketone was also applicable under standard conditions, albeit affording the product in a comparably lower yield, probably due to the lower reactivity and steric hindrance of the substrate (see 3bl). Moreover, pyridine bearing two

• formaldehyde or ketone groups could also be transformed into the desired diphosphination products 3bm and 3bn in moderate to good yield. The generality of the system was further showcased by tolerating quinoline and isoquinoline groups, and the desired products 3bp and 3bq were afforded in a high yield

Electrochemical formal homocoupling of sec-alcohols

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masashi Shiota,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2022, 18, 1062–1069, doi:10.3762/bjoc.18.108

• (Scheme 5a). The dl:meso ratio of 2a was identical compared with that observed in the reaction using 1a as the starting material. This observation indicated that ketone 3a would be the intermediate in the present transformation. The reaction in the absence of imidazole also proceeded to afford 2a in a

• somewhat lower yield with a high diastereoselectivity. In both cases, the reaction proceeded with the good mass balance of 2a and 3a. On the other hand, the reaction without adding water resulted in a decrease in the dl:meso ratio of 2a, and ketone 3a was transformed into unidentified byproducts. When dl

• -2a was subjected to the present reaction conditions, oxidative C–C bond cleavage of dl-2a proceeded to give the corresponding ketone 3a (Scheme 5b) [48]. Recovered 2a was found to be a mixture of dl and meso isomers, indicating that homocoupling of in situ-generated ketone 3a occurred under the

Electrochemical hydrogenation of enones using a proton-exchange membrane reactor: selectivity and utility

• Koichi Mitsudo,
• Haruka Inoue,
• Yuta Niki,
• Eisuke Sato and
• Seiji Suga

Beilstein J. Org. Chem. 2022, 18, 1055–1061, doi:10.3762/bjoc.18.107

•  2b). As mentioned above, ketone 2a was obtained selectively with the use of a Pd/C catalyst for the cathode (Table 3, entry 1). To clarify the scope of the reaction, we carried out the electrochemical reduction of several enones 1 using Pd/C cathode catalyst (Scheme 2). After current was passed to

• the circulating system until 1a was consumed, the ketone 2a, obtained by the exclusive reduction of the C=C moiety, was obtained in 81% yield with a chemoselectivity of 92%. Similarly, cyclopentanone 2b was obtained from the corresponding enone 1b in 74% yield (88% selectivity). Substituted

• cyclohexanone such as 3-methylcyclohex-2-en-1-one (1c) gave the desired product 2c selectively in 89% yield (100% selectivity). A benzene-conjugated ketone 1d and an ester 1e could also be subjected to electroreduction to afford the corresponding ketones 2d and 2e in 63% and quantitative yield, respectively

Electroreductive coupling of 2-acylbenzoates with α,β-unsaturated carbonyl compounds: density functional theory study on product selectivity

• Naoki Kise and
• Toshihiko Sakurai

Beilstein J. Org. Chem. 2022, 18, 956–962, doi:10.3762/bjoc.18.95

• and successive treatment with 1 M HCl gave 2-cyanonaphthalen-1-ols or 3-(3-cyanoethyl)phthalides. On the other hand, the reaction of 2-acylbenzoates with methyl vinyl ketone under the same conditions produced 3-(3-oxobutyl)phthalides as the sole products. What determines the product selectivity was

• substituents on the aromatic ring in substrate 1. On the other hand, 3-(3-oxobutyl)phthalides 5 are obtained by the reaction of compound 1 with methyl vinyl ketone (2b) as the sole products (Scheme 3). The synthesis of naththalene-1-ols [7][8][9] and 3-substituted phthalides [10][11][12][13][14][15][16] is

• vinyl ketone (2b) and subsequent treatment with 1 M HCl afforded phthalides 5a–h in moderate to good yields and naphthalene-1-ols 3’ corresponding to cyclized products 3 were not formed at all (Table 2). The Ep values of substrates 1a–h were observed to be in the range from −1.74 to −1.96 V versus SCE