A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

• Daniel P. Pienaar,
• Kamogelo R. Butsi,
• Amanda L. Rousseau and
• Dean Brady

Beilstein J. Org. Chem. 2019, 15, 2930–2935, doi:10.3762/bjoc.15.287

• diols 1 and 8, thereby indicating that the hemiketals are still fully reducible under standard ketone reduction conditions. Purification of 6 afforded only a 10% overall yield of the diol 8, but the direct conversion of crude intermediate product 6 resulted in a doubling of the overall yield of the diol

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• catalytic hydrogenation to 4 followed by protection with TBDMS to give 5 in 63% yield for three steps. The synthesis of the other half of the photochrome started with bromination of difluorinated aniline to give 6 followed by copper-catalyzed cyanation to 7 in 62% overall yield. Diazonization of 7 with

• % overall yield. Installation of the cationic head was performed in two steps: first bromination of 11 via Appel reaction, followed by treatment with trimethylamine to give 2 in 35% overall yield. Photoswitch 2 is the first example of a bifunctional, asymmetrically substituted 4FAB chromophore that actually

• maleimide using hydroxymethylation with formaldehyde, followed by treatment with thionyl chloride to give a chloromethyl intermediate, which was reacted in situ with maleimide to give 1 in 6% overall yield. Crucially, photochrome 1 also maintained the near-ideal photochemical properties of Hecht’s 4FABs [12

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• to just 7 steps from 16 and improves the overall yield to 40–50 %. Mouse pharmacokinetics for 1 Assessment of 1 in mouse liver microsomes (MLM) showed excellent metabolic stability (Cli 1.0 μL/min/mg protein) which predicts for low clearance in vivo. Binding to mouse plasma proteins (mPPB) was very

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• ][10][11]. However, routes involving azide chemistry proved to be more superior in most instances than azide free alternatives [2][12]. Hayashi’s group developed highly efficient two ‘one-pot’ sequences towards Tamiflu at gram-scale, which proceeded in 10 steps with an outstanding 60% overall yield [1

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• after preparative HPLC purification and lyophilization. The overall yield for this 11-step synthesis ranged from 7% to 15% for almost all solonamide analogues 9, based on the initial resin’s molarity. The exception relays on those containing ᴅ-Ala and ʟ-Leu amino acid residues sequentially attached to

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

• Shital K. Chattopadhyay,
• Subhankar Ghosh,
• Sarita Sarkar and
• Kakali Bhadra

Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245

• has occasionally led to a mixture of isomers or even the Z-isomer as the predominant one [22]. Hydrogenation of 10a led to saturation of the double bond as well as concomitant removal of the O-benzyl group leading to SAHA (1) in an acceptable overall yield of 61% over three steps. On the other hand

• approach, cross metathesis of 8 was first done with methyl heptenoate to prepare compound 12 in good yield. This was then hydrolyzed to get the corresponding acid 13. An amide bond formation between this acid and aniline under usual conditions provided DDSAHA derivative 10a in an overall yield of 56% over

Chiral terpene auxiliaries V: Synthesis of new chiral γ-hydroxyphosphine oxides derived from α-pinene

• Anna Kmieciak and
• Marek P. Krzemiński

Beilstein J. Org. Chem. 2019, 15, 2493–2499, doi:10.3762/bjoc.15.242

• borane–dimethyl sulfide adduct in THF at 50 ºC. Oxidation of the alkylborane with mCPBA gave the desired alcohol 27 in 51% overall yield. Finally, diastereomeric endocyclic allylic alcohols 16 and 18 were treated with chlorodiphenylphosphine in the presence of DMAP to produce diphenylphosphinites 28 and

Indium-mediated C-allylation of melibiose

• Christian Denner,
• Manuel Gintner,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2019, 15, 2458–2464, doi:10.3762/bjoc.15.238

• optimization procedures (Scheme 2). The overall yield of the isolated epimers was 92%. According to Binder et al. [17] and our own experience [18], we expected the syn-product (2-syn) to be the main diastereomer. However, the determination of the configuration is not possible by NMR analysis. Consequently, the

• -acetylation was conducted leading to a mixture of all four species, indicated by NMR analysis (Scheme 3). In the case of 2-syn the β-pyranose species 5-syn-β was obtained as the main product, besides α-pyranose (5-syn-α) as well as both anomers of the furanoid form (Scheme 4). The overall yield obtained over

• three steps was 72% (4 species), from this mixture the main product 5-syn-β was isolated in 58% yield and could be fully characterized by NMR (Supporting Information File 1). In the case of 2-anti the same reaction sequence gave an overall yield of 65%, which is a slightly lower conversion compared to 2

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• ), isocyanide (1.1 equiv) and TMSN3 (1.1 equiv) in EtOH at 100 °C (MW radiation, two cycles of 15 min each). Influence of substituents R and R2 on the reaction outcome. For compounds 4k–m the overall yield in parentheses refers to the mixture of regioisomers. Influence of the alkyne and R1 substituent on the

Synthesis of acremines A, B and F and studies on the bisacremines

• Nils Winter and
• Dirk Trauner

Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

• both secondary allylic alcohols and afforded 2 in good overall yield (Scheme 3). Bisacremine E (7) was proposed to be formed in nature via [4 + 2] cycloaddition involving two acremine F (5) units [4]. Although dimerization of 5 through a Diels–Alder cycloaddition is not electronically favorable, we

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

• isomerization of olefin 43, the benzylic oxidation of 8, the use of m-CPBA to introduce the C-9,11 epoxide and the non-stereoselective reduction of the C-14 carbonyl group using sodium borohydride, caused an unacceptable overall yield (1.6%). This pioneering work undoubtedly established the basis for the future

• 18.5% overall yield. Importantly, by late-stage installation of the C-13 isopropyl group, this synthesis also provided a useful approach for the synthesis of other structurally relevant derivatives of triptolide such as C-15 and C-16 modified derivatives of triptolide. In 1980, van Tamelen and co

• 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

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• (Scheme 2), starting with the monoprotection of 1,5-pentanediol (6), followed by Swern oxidation, which afforded 7 in an overall yield of 57% [26]. The so obtained aldehyde 7 was treated with vinylmagnesium bromide in the presence of cerium chloride to afford 8 in 89% yield. An overall translocation of

• the TBDMS group from the primary to the secondary alcohol was achieved by a protection/deprotection sequence, which smoothly provided alcohol 10 in 71% yield over two steps. A final Swern oxidation gave the building block 3 in 91% yield (33% overall yield from 1,5-pentanediol 6). The other key

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• are highly suitable for electronic data processing (EDP). This algorithm is also suitable as a basis for fair cost assessment of complex chemical syntheses. Keywords: efficiency; efficiency algorithm; multicomponent; overall yield; synthesis algorithm; synthesis efficiency; synthesis evaluation

• ]. Concrete and reliable criteria must be available for this purpose, criteria that can be easily determined and measured, and which can also form the basis for an algorithm. The standard evaluation of a chemical synthesis is traditionally based on the overall yield yoa. This is the product of all sequential

• synthesis steps yn (Equation 1). An extreme example for the impact of the overall yield is the tropinone synthesis by Willstätter (yoa = 0.75%) [7][8] compared to the Robinson–Schöpf synthesis (yoa = 90%) [9][10]) using a double Mannich reaction, a multicomponent reaction (MCR) [11][12][13]. The Mannich-3CR

Borylation and rearrangement of alkynyloxiranes: a stereospecific route to substituted α-enynes

• Ruben Pomar Fuentespina,
• José Angel Garcia de la Cruz,
• Gabriel Durin,
• Victor Mamane,
• Jean-Marc Weibel and
• Patrick Pale

Beilstein J. Org. Chem. 2019, 15, 1416–1424, doi:10.3762/bjoc.15.141

• afforded a mixture of the 2 possible isomers, although in similar overall yield (Table 2, entry 2 vs 1). Decreasing the temperature from −78 to −92 °C for the deprotonation–borylation steps rewardingly allowed the exclusive formation of the E-enyne 4 as a single isomer (Table 2, entry 3). After these

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• % ee) compared to the batch process with the same catalyst. Nonetheless, the enantioselectivity remains constant during the whole time of experiment, as shown in Figure 1. Finally, the overall yield of isolated Michael adduct 5 was 42% after column chromatography, which is in agreement with the

Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• product amine was not isolated. Instead, it was immediately reacted with the N-hydroxysuccinimidyl ester of Boc-leucine to give 12a in yields of 56–80% overall for two steps. We also obtained the corresponding Z-protected analogue 12b in 43% overall yield for two steps. Both 10 and 12a could be oxidized

• Na2S2O4 or H2/Pd). What finally proved effective was the two step sequence of oxidation of 12a with CAN followed by treatment of the resulting quinone 13 with sodium borohydride in dry methanol – a sequence that gave 14 (which upon standing readily re-oxidizes back to 13) in 34% overall yield from 12a. A

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• acid 144, Cbz removal of the macrocycle 145 formed led to another diamine intermediate that was involved in a second double Ugi reaction with paraformaldehyde, tert-butyl isocyanide and diacid 146, to yield cryptand 147 in 31% overall yield from 130. Other macroheterocycles were synthesized in this

An efficient synthesis of the guaiane sesquiterpene (−)-isoguaiene by domino metathesis

• Yuzhou Wang,
• Ahmed F. Darweesh,
• Patrick Zimdars and
• Peter Metz

Beilstein J. Org. Chem. 2019, 15, 858–862, doi:10.3762/bjoc.15.83

• required to effect the relay metathesis of 3 to (−)-isoguaiene (1) in refluxing benzene in a good yield of 51%. Thus, by application of a domino metathesis strategy featuring trienyne 3, only 9 steps were needed to secure the guaiane sesquiterpene 1 in 19.7% overall yield starting from (S)-citronellal (5

• ), which compares favorably with the previous synthesis of 1 from (+)-dihydrocarvone (10 steps, 6.9% overall yield) [6]. Scheme 3 depicts our first attempts to realize an alternative domino metathesis strategy using enediyne 7. Ozonolysis of the unsaturated acetal 10 gave aldehyde 23 [17][18] that was

• furnish 25 and subsequent acetal hydrolysis provided the known aldehyde 26 [25] in very good overall yield. In our hands, the "demethanation" of (S)-citronellol to produce the primary alcohol corresponding to aldehyde 26 according to the protocol of Abidi (NaNO2, aqueous AcOH) [26] as a potential shortcut

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• the major reaction pathway when the reaction was stirred for prolonged periods of time or heated to higher temperatures. Consequently, the overall yield of this process, at 14%, is lower than that of the process outlined in Scheme 1. Given the ease of alkylation of 3 with 1,2-dibromoethane, we

• stable for over one year. Gratifyingly, alkylation of adenine with iodide 14 proceeded smoothly under mild conditions to furnish phosphonate 6 in 70% yield. The overall yield of 6 from 18 was 58% which compared very favourably with that reported in Scheme 1. Interestingly, the unnatural N7-regioisomer 20

• affords 20 in a comparable overall yield of 13%. We conducted a temperature, solvent and base screen to determine what impact these parameters have on the regioselectivity of the alkylation (Table 2). The overall regioselectivity appeared insensitive to the reaction conditions with only a slight decrease

Efficient synthesis of 4-substituted-ortho-phthalaldehyde analogues: toward the emergence of new building blocks

• Clémence Moitessier,
• Ahmad Rifai,
• Pierre-Edouard Danjou,
• Isabelle Mallard and
• Francine Cazier-Dennin

Beilstein J. Org. Chem. 2019, 15, 721–726, doi:10.3762/bjoc.15.67

• complex molecular architectures. Nevertheless, literature generally describes their synthesis in very low yield (below 5%), mainly due to the inefficiency of the last oxidation step. In this paper, we report a reliable synthesis of 4-substituted-ortho-phthalaldehyde analogues in 51% overall yield owing to

• -dihydroisobenzofuran-5-ol intermediate has been tested and oxidation parameters of the dedicated structures were optimized. Finally, a rapid deprotection step was initiated to afford 4-MeO-OPA and 4-HO-OPA with 51% overall yield. Results and Discussion Firstly, 2-((prop-2-ynyloxy)methyl)furan (2) was synthesized

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• carried out, but a component such as Mosher acid with a tertiary carbon next to the carboxylic acid function was successfully used in the three-component reaction and the corresponding β-ketoenamide was converted into the corresponding pyridin-4-ol in good overall yield [36]. This demonstrates that

• nonaflate 8 – readily available from β-ketoenamide KE61 [33] – efficiently furnishing the disubstituted alkyne PM57. This intermediate was directly converted into pyrimidyl-substituted furopyridine derivative PM58 in very good overall yield. The example of compound PM58 nicely demonstrates the combination

• -based) pyridinyl nonaflate 8 gave OX25. The removal of the TMSE group by acid treatment and subsequent cyclization furnished the furopyridyl-substituted oxazole derivative OX26 in good overall yield [45]. The examples shown in Scheme 27 and Scheme 28 demonstrate the manifold options to synthesize

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• ). Similarly, fluorene was oxidized to a mixture of 9-fluorenyl acetate (5b, 31%) and fluorenone (5c, 20%). The same mixture of acetate and ketone is observed at a higher temperature (150 °C), but the overall yield was lower. It is proposed that the stabilizing presence of two benzene rings on the monooxidized

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

• , geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield

• -methylated product via oxazolidinone 24 was hampered by low yield on reaction with paraformaldehyde [47][48]. Although subsequent reduction of 24 with Et3SiH/TFA and reprotection of the free N-methyl amino acid with Boc2O proceeded smoothly and delivered iodotyrosine 25, the overall yield via 24 was not

• ), MeI (4-Me), and (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide (8, C1–C3, 2-Me). We obtained 8-hydroxyester 7 within nine steps and an overall yield of 21% starting from (R)-propylene oxide. The efficiency of our route to polyketide 7 compares well to earlier approaches. It proved to be possible

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

• Seema V. Kanojia,
• Sucheta Chatterjee,
• Subrata Chattopadhyay and
• Dibakar Goswami

Beilstein J. Org. Chem. 2019, 15, 490–496, doi:10.3762/bjoc.15.42

• reactions that use inexpensive reagents, are operationally simple and proceed with good to excellent yields and excellent stereoselectivities. The target compound was obtained in 23% overall yield starting from (S)-4. The protocol can also be used to access different HPA analogues and derivatives. Structure