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

• cleanly obtained in 75% yield from triethyl phosphite and 3-chloro-2-methylpropene by addition of NaI [14]. Subsequent reduction of the ester with LiAlH4 and oxidation with IBX gave aldehyde 7 in 95% yield. Grignard addition of vinylmagnesium bromide afforded the alcohol 8, which comprised the desired

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

• of enol-ether formation/Grignard addition lead to intermediate 43, from which simple acidic treatment led to rhodomollein XXII, while α-oxidation in the presence of rhenium oxide followed by acidic work-up afforded rhodomollein XX. Interestingly, Ding’s synthesis constitutes an efficient approach (22

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

• precursor for an intramolecular Friedel–Crafts cyclization (Scheme 9) [24]. Therefore, phenylacetaldehyde 52 was converted to the alcohol 53, which was esterified with the α-ketoacid 54 to give ketoester 55. Grignard addition to the keto carbonyl and subsequent TBS deprotection delivered the tertiary

• 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

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• . Importantly, the choice of the solvent was crucial for obtaining high diastereoselectivities in the Grignard addition step, in which dichloromethane was performing better than THF. On the other hand, diastereoselectivities for addition products 75 were higher working with (RS)-74 than its (SS) diastereoisomer

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• formation of 1,1-dichloro-1-alkenones 6 from 1,1,1-trifluoroalkanones 5, which in turn are accessed by the Grignard addition of 1,1,1-trifluoroalkylmagnesium halides to nitriles (Figure 2b). It is worth noting that the 1,1,1-trifluoroalkyl halides (n = 1, 2, 3) are commercially available, whereas the

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• Stille coupling between oxazole vinylstannane 24 and dienyl iodide (rac)-20 as the final step. The synthesis began with alcohol (Z)-15a, which was readily prepared in 65% yield from propargyl alcohol (14) by using a copper(I)-catalyzed methyl Grignard addition followed by in situ iodinolysis. The Swern

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• metathesis using Grubbs’ 2nd generation catalyst (G-II, Scheme 3) [13]. Replacing the N-Boc protecting group with an N-tosyl group and allylic oxidation gave 30. The introduction of the allyl group at C-11 made use of the Kishi protocol [22] of the allyl-Grignard addition, followed by an ionic reduction. The

• considerably more efficient than the Ghosh synthesis of 102. Syntheses of the C-1–C-6 segment of spliceostatin E (10) The Ghosh group’s synthesis of the C-1–C-6 segment of spliceostatin E (10) relied on a Cu-catalyzed Grignard addition to tert-butyldiphenylsilyl-protected (R)-glycidol, followed by the

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• metathesis (RCM) [67][68]. Starting from 3-cyanocyclohex-2-enone, the authors obtained a versatile intermediate able to provide the appropriate dienyne precursors (A–C, Scheme 4) by multicomponent Grignard addition-alkylations. Through divergent cyclizations involving a chemoselective enyne metathesis

Regioselective addition of Grignard reagents to N-acylpyrazinium salts: synthesis of substituted 1,2-dihydropyrazines and Δ⁵-2-oxopiperazines

• Valentine R. St. Hilaire,
• William E. Hopkins,
• Yenteeo S. Miller,
• Srinivasa R. Dandepally and
• Alfred L. Williams

Beilstein J. Org. Chem. 2019, 15, 72–78, doi:10.3762/bjoc.15.8

• the Grignard addition to various mono- and disubstituted N-acylpyrazinium salts (Figure 1). Phenyl chloroformate was the acylating reagent of choice for this study due to benzyl or methyl chloroformates producing products in very poor yields. A variety of alkyl Grignard reagents were shown to add

• examination of the Grignard addition to benzyloxy- or p-methoxybenzyloxy (PMB)-substituted pyrazinium salts, resulted in obtaining dihydropyrazines in yields that were comparable to the methoxy salts (Figure 1, compounds 4a,b and 5). We next subjected disubstituted N-acylpyrazinium salts to this reaction

• salts (yields refer to isolated yields). Phenyl Grignard addition to methoxy-substituted N-acylpyrazinium salts. Conversion of dihydropyrazine to Δ5-2-oxopiperazines under acidic conditions. One-pot synthesis of substituted Δ5-2-oxopiperazines. Supporting Information Supporting Information File 14

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

• Raja Ben Othman,
• Mickaël J. Fer,
• Laurent Le Corre,
• Sandrine Calvet-Vitale and
• Christine Gravier-Pelletier

Beilstein J. Org. Chem. 2017, 13, 1533–1541, doi:10.3762/bjoc.13.153

• 5a [51], R1 = TIPS). Some compounds were also N3-allylated (1b, 4b and 5b) to evaluate the possible influence of R2 on the diastereoselectivity of the nucleophilic addition (Scheme 1). Primary alcohols 1–5 were submitted to an oxidation/Grignard addition sequence leading to the corresponding

• propargyl alcohols 11–15 (Scheme 2). The aldehydes 6–10 resulting from oxidation with IBX were isolated and directly submitted to Grignard addition without further purification. Grignard reagents were prepared from trimethylsilyl-, triethylsilyl- or triisopropylsilylacetylene and ethylmagnesium bromide in

• organometallic reagent on nucleoside aldehydes. Influence of the protecting groups and conditions on the diastereoselectivity of the alkynyl Grignard addition on uridine derived aldehydes. Supporting Information Supporting Information File 107: Description of the materials and methods, and the preparation and

NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

• Jaroslav Padevět,
• Marcus G. Schrems,
• Robin Scheil and
• Andreas Pfaltz

Beilstein J. Org. Chem. 2016, 12, 1185–1195, doi:10.3762/bjoc.12.114

• configuration at the hydroxy-substituted carbon atom. Double addition of methylmagnesium chloride and subsequent introduction of the diphenylphosphine unit proceeded well in 68% yield following the procedures worked out for the 1st generation NeoPHOX ligands. Alternative strategies involving Grignard addition

• to the threonine methyl ester or N-protected derivatives were also briefly investigated, but failed. Grignard addition to the chloro amide 11 was not attempted because earlier studies with chloro amide 15 had shown that an undesired β-lactam 16 was formed upon treatment with Grignard reagents (Scheme

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• synthetic sequence of p-anisyl catalyst 1. In situ reduction of 4-methoxysulfonyl chloride by triphenylphosphine and trapping with (−)-menthol affords diastereomerically pure sulfinate ester 2 after enrichment by recrystallization [45]. Grignard addition attaches a TMS-protected alkyne of appropriate tether

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• allyl-Grignard addition to enantiopure tert-butanesulfinyl ketimines and an efficient cross-metathesis of an unreactive urea substrate in the presence of an organic phosphoric acid. It is expected that these strategies and tactics will find applications in functional target synthesis and stimulate

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

• assemble the erythrina skeleton. To this end, they have identified cyclobutene derivative 48 as a useful synthone for RRM. The cyclobutene derivative 46 has been extended via Grignard addition followed by cyclization reaction. Later, cyclobutene derivative 48 was treated with catalyst 1 in the presence of

• from 199 via Grignard addition followed by O-allylation. The double DA adduct 199 has been derived from cyclopentadiene and 1,4-benzoquinone. Next, compound 202 was exposed to catalyst 2 in the presence of ethylene (24) to generate the expected hexacyclic system 203 (70%) containing 10 stereogenic

• the RRM protocol for the synthesis of condensed polycyclic systems. To this end, bicyclo[2.2.2]octene derivative 321 has been identified as a key starting material. The required key building block 323 has been prepared from the known bis-DA adduct 321 [67] via allyl Grignard addition followed by O

Design and synthesis of hybrid cyclophanes containing thiophene and indole units via Grignard reaction, Fischer indolization and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Ajay Kumar Chinnam and
• Mukesh E. Shirbhate

Beilstein J. Org. Chem. 2015, 11, 1514–1519, doi:10.3762/bjoc.11.165

• via Grignard addition, Fischer indolization and ring-closing metathesis as key steps. Keywords: cyclophane; Grignard reaction; Fischer indolization; ring-closing metathesis; Introduction Modern olefin metathesis catalysts enable a late stage ring-closing step starting with bisolefinic substrates

• cyclophanes the development of powerful and general synthetic methods is highly desirable. Herein, we report a new approach to thiophene- and indole-containing hybrid cyclophane derivatives via Grignard addition, Fischer indolization and RCM as key steps. Strategy The retrosynthetic strategy to the target

• of 3 followed by an RCM of diindole 5 can deliver target molecule 1 (Route B). The advantages of these approaches are: one can vary the length of the alkene chain during the Grignard addition, and generate diverse cyclophanes of different ring size. Diverse aromatic rings can be incorporated by

Spiro annulation of cage polycycles via Grignard reaction and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Mohammad Saifuddin,
• Rashid Ali and
• Gaddamedi Sreevani

Beilstein J. Org. Chem. 2015, 11, 1367–1372, doi:10.3762/bjoc.11.147

• provides a hemiketal with various nucleophiles [34][35][36][37][38][39]. In view of various applications of cage molecules and the documented difficulties in their synthesis, we conceived a short synthetic route to C2-symmetric bis-spiro-pyrano cage compound 7. To this end, the Grignard addition and ring

• -closing metathesis (RCM) are considered as viable options. The retrosynthetic analysis to the target bis-spiro-cage compound 7 is shown in Figure 2. The target compound 7 could be obtained from O-allylation of the Grignard addition product 11 followed by the two-fold RCM sequence. The required cage dione

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• and an RCM as key steps. In this regard, the α,α'-dibromo-m-xylene (136) was treated with arylboronic acid 180, to give the dialdehyde 181 which on reaction with indium-mediated Grignard addition reaction gave diolefin 182. Later RCM of diolefin 182 delivered cyclophane 183. Subsequent oxidation of

Design and synthesis of fused polycycles via Diels–Alder reaction and ring-rearrangement metathesis as key steps

• Sambasivarao Kotha and
• Ongolu Ravikumar

Beilstein J. Org. Chem. 2015, 11, 1259–1264, doi:10.3762/bjoc.11.140

• used to design new polycycles. In this regard, ruthenium alkylidene catalysts are effective in realizing the RRM of bis-norbornene derivatives prepared by DA reaction and Grignard addition. Here, fused polycycles are assembled which are difficult to produce by conventional synthetic routes. Keywords

• : Diels–Alder reaction; Grignard addition; ring-rearrangement metathesis; polycycles; Introduction Design and synthesis of complex polycycles in a minimum number of steps will enhance the overall synthetic economy of the preparation of a target molecule. The ring-rearrangement metathesis (RRM) is a

• studied. Results and Discussion Our strategy to polycycles involves a Diels–Alder reaction (DA) [23][24][25], a Grignard addition [26] and a RRM as key steps. To begin with, a double DA reaction of cyclopentadiene (1) with 1,4-benzoquinone (2) gave the known bis-adduct 3 [27][28]. Later, it was reacted

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• reactions, ambient temperature Grignard addition and the high temperature elimination of water. In the process solutions of 2-bromobenzylbromide (128) and n-BuLi are delivered into a small tubular flow reactor maintained at −50 °C in order to perform a Wurtz-type coupling. The resultant aryllithium

• total residence time of 33 seconds (Scheme 22). Finally, the stream of 130 was combined with 3-(dimethylamino)propylmagnesium chloride (131) to affect a Grignard addition at ambient temperature followed by passage through an inductively heated reactor (210 °C, 810 kHz, 36 seconds residence time) which

Design and synthesis of novel bis-annulated caged polycycles via ring-closing metathesis: pushpakenediol

• Sambasivarao Kotha and
• Mirtunjay Kumar Dipak

Beilstein J. Org. Chem. 2014, 10, 2664–2670, doi:10.3762/bjoc.10.280

• rearrangement, a ring-closing metathesis (RCM) and an alkenyl Grignard addition. The introduction of olefinic moieties in the pentacycloundecane (PCUD) framework at appropriate positions followed by RCM led to the formation of novel heptacyclic cage systems. Keywords: Diels–Alder cycloaddition; Grignard

• the pentacyclic diallyldione 20, we ventured into the synthesis of PCUD based novel heptacyclic systems. The dione 20 was subjected to an allyl Grignard addition reaction, which resulted in the formation of tetra-allyldiol 21. The structure of diol 21 was established on the basis of high field 1H NMR

• (400 MHz) spectral data and further supported by 13C NMR spectral data (Scheme 3). The Grignard addition at a trigonal carbon may result in the formation of C–C bond in two possible ways (en face and zu face), but due to steric reasons only the exo–exo allyl addition product was isolated in the present

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

• Miroslav Palík,
• Jozef Kožíšek,
• Peter Koóš and
• Tibor Gracza

Beilstein J. Org. Chem. 2014, 10, 2077–2086, doi:10.3762/bjoc.10.216

• 2 steps starting from the aldehyde 31 using the Yamamoto’s [33] sequential O-nitrosoaldol and Grignard addition process using different reagents (Scheme 4). Thus, L-proline-catalysed oxidation of 31 with 2-nitrosotoluene gave the optically pure O-selective nitrosoaldol product 32, which underwent a

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• protecting group pattern. The most promising strategy to achieve these goals appeared to be a variation of the ex-chiral pool synthesis developed by Zhu and co-workers [32]. They have utilized the stereocenter of D-serine in a diastereoselective Grignard addition to protected D-serinal as the key step of

• derivative with limited stability, which was immediately converted into alcohol 4 by diastereoselective Felkin–Anh type Grignard addition with isopropyl magnesium chloride (50% yield over 2 steps from 3, dr > 95:5). However, we could not confirm that the use of diethyl ether as co-solvent in the Grignard

• and Grignard addition. The enantiomeric purity of reisolated 3 was determined by HPLC analysis as its racemization can readily occur via silyl migration under the basic reaction conditions (see Supporting Information File 2 for HPLC chromatograms and for the synthesis of the racemic reference). After

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• this work, they obtained 11 different compounds in yields up to 100% and diastereomeric excesses up to 86%. The starting phosphinates 52a–k were prepared using classical chemistry involving Grignard addition to EtOP(O)Cl2. Phenoxaphosphine Scheme 23 shows the synthesis of one phenoxaphosphine 56 in 55

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• be significantly slower than the desired reduction of the carbonyl function. Practically, the residual 3-chloropropanol remaining from the prior Grignard addition 5→7 step (vide supra) and sec-Bu3B/BEt3 from the reduction were easily separated through washing with Et2O of an (HCl) acidic, aqueous