Synthesis of disparlure and monachalure enantiomers from 2,3-butanediacetals

• Adam Drop,
• Hubert Wojtasek and
• Bożena Frąckowiak-Wojtasek

Beilstein J. Org. Chem. 2020, 16, 616–620, doi:10.3762/bjoc.16.57

• –8 are obtained. We therefore decided to apply this compound for the synthesis of both enantiomers of disparlure and both enantiomers of monachalure. Results and Discussion Compound 14 was prepared and converted to 15 by Fukuyama reduction as described previously [37]. The overall yield for the

Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

• Anna R. Bockman and
• Jeffrey M. Pruet

Beilstein J. Org. Chem. 2020, 16, 509–514, doi:10.3762/bjoc.16.46

• modifications to the pteridine core which disrupt the hydrogen-bond assembly, such as benzylation of the lactam oxygen or conversion of the exocyclic amine to the pivalic amide [12][13]. The installation and subsequent removal of these groups naturally affects the overall yield and time necessary to generate

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• addition of chlorophosphine resulted in the desired ligand 58. However, the overall yield was lower than the yield obtained through the other method. Imidazole can be regioselectively deprotonated at the more acidic C2 position. The mono- and diphosphine imidazole ligands 62 and 63 were conveniently

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• CuBr∙SMe2/(R,S)-Josiphos (L9). However, the catalytic system was poorly selective toward sterically hindered organomagnesium nucleophiles (15–25% ee). The synthetic versatility of the thioester function was illustrated in the synthesis of (−)-lardolure (26% overall yield over 12 steps) via a relevant

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• one-pot, resulting in the generation of the stereochemically dense epoxyalcohol 37 in 68% overall yield. The treatment of compound 5 with EtMgBr as a Grignard reagent in the presence of CeCl3 gave the corresponding tertiary alcohol 38 with similar stereochemical features as of 36 in the formation of

Convenient synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-antigen of Escherichia albertii O4

• Tapasi Manna,
• Arin Gucchait and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2020, 16, 106–110, doi:10.3762/bjoc.16.12

• ) hydrogenolysis of benzyl ethers and benzylidene acetals over Pearlman’s catalyst [36] to furnish the desired pentasaccharide 1 in 49% overall yield (Scheme 4). The structure of compound 1 was unambiguously characterized by its NMR spectral analysis [signals at δ 5.37 (d, J = 2.0 Hz, H-1A), 5.29 (d, J = 3.5 Hz, H

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