Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• and 12b afforded ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 13a and 13b, respectively [39] (Scheme 3). 1.2. Alkylations of fluorinated aryl halides with a chiral auxiliary Alternatively, the coupling of the bis(dimethoxybenzyl)-protected sulfonamide 14, instead of the esters 10a and 10b

• synthesized by alkylation of 26a,b with the chiral auxiliary 31, which was obtained by reaction of the cyclic dipeptide 30 with triethyloxonium tetrafluoroborate. The alkylation reaction of 26a,b was carried out with n-BuLi in THF at −78 °C to give 32a,b. Acid hydrolysis of the alkylated product 32a,b

• useful Boc-(R)-amino acids 38a,b [44] (Scheme 8). A one-pot double alkylation of the chiral auxiliary 39 with benzyl iodides 40a,b gave cis-dialkyl derivatives 41a,b in 70–72% yield. The subsequent removal of the auxiliary followed by treatment with Fmoc-OSu gave the N-protected 2-fluoro- and 2,6

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• stereoselective organic electrochemical reactions along with the synthetic accomplishments achieved with these methods. Keywords: chiral auxiliary; chiral catalyst; chiral electrode; chiral electrolyte; chiral mediator; electroorganic chemistry; Introduction Electric current-assisted exchange of electrons

• 1995, Murakami and his group published two sequential reports on the controlled potential electrolysis of racemic 147 catalyzed by a number of hydrophobic vitamin B12 enzymes 148 to afford hydrogen-substituted product 149 with good enantioselectivity (Scheme 48) [87][88]. Chiral auxiliary approach In

• chiral auxiliary ([92]. The authors established that the Mannich addition occurred exclusively on the Si-face of the N-acyliminium ions, resulting in the threo-isomer as the major isomer (with moderate yields and good diastereomeric ratios). Upon catalytic hydrogenation followed by methanolysis, threo

α-Photooxygenation of chiral aldehydes with singlet oxygen

• Dominika J. Walaszek,
• Magdalena Jawiczuk,
• Jakub Durka,
• Olga Drapała and
• Dorota Gryko

Beilstein J. Org. Chem. 2019, 15, 2076–2084, doi:10.3762/bjoc.15.205

• ) or a chiral auxiliary (i.e., oxazolidinone) into the substrate structure is required for highly stereoselective reactions [20][21][22]. ‘One-pot’ photochemical α,β-functionalization of cinnamaldehyde Over the last few years, photochemical methods for asymmetric functionalisation of carbonyl compounds

• observed for reactions of singlet oxygen with substrates that do not possess chiral auxiliary or do not impose significant steric hindrance. Experimental General information 1H and 13C NMR spectra were recorded at rt on Bruker 400 and Varian 600 MHz instruments with TMS as an internal standard. The

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

• 12 steps with 15% yield. Interestingly, in this synthesis only four intermediates needed to be purified. In 1999, Yang and co-workers reported an elegant chiral auxiliary-assisted, lanthanide triflate-catalyzed oxidative radical polycyclization of olefin-cation-based enantioselective synthesis of

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• efficiency of a 2-substituted N-(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary. Keywords: alkaloids; amino acids; asymmetric synthesis; ceramides; chiral catalysis; chiral pool; N-(1-phenylethyl)aziridine chiron; sphingoids; Introduction The synthesis of enantiomerically pure

• which is finally easily removed [11]. Among three-carbon chirons related to Garner’s aldehyde derivatives of N-(1-phenylethyl)aziridine-2-carboxylic acid 5–8 (Figure 2) play an important role in asymmetric synthesis as they function as a chiral synthon combined with a chiral auxiliary [(R)- or (S)-1

• are possible employing ester and aldehyde groups and the stereochemical outcome of these reactions is controlled by configurations at C2 and at the chiral auxiliary (Scheme 3). The opening of the aziridine ring is expected to occur at the less substituted carbon atom and can be executed with

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

• Sven Götz,
• Andreas Schneider and
• Arne Lützen

Beilstein J. Org. Chem. 2019, 15, 1339–1346, doi:10.3762/bjoc.15.133

• that the energy barrier for the racemization in each case is around 110 kJ mol−1 [62][68][69]. Thus, the necessary synthetic steps to introduce the chiral auxiliary and cleave it after successful isolation of the pure diastereomers can only be performed under rather mild conditions in order to avoid

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

• removal of the chiral auxiliary with simultaneous formation of a N-Boc derivative 30. The hydroxymethyl to carboxylate transformation to form the protected diester (2S,3R)-31 required prior basic deacetylation followed by standard oxidation and esterification. Diastereoisomer (2S,3S)-31 was also prepared

• of a chiral auxiliary with lithium dibutylcuprate. Next, titanium tetrachloride-catalyzed cyanation secured another carboxy group and after a few transformations an oxazolidinone (4S,5R)-39 was obtained as a major (7:1) product readily purified chromatographically. To complete the synthesis of (2S,3R

• )-2 N-Boc protection preceded the cleavage of the oxazolidine ring while silylation of the hydroxy group was necessary before oxidation of the C=C bond (Scheme 9) [58]. Further applications of the ketopinic acid framework as a chiral auxiliary relied on fine tuning of the steric environment around the

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step

• Pierre-Antoine Nocquet,
• Aurélie Macé,
• Frédéric Legros,
• Jacques Lebreton,
• Gilles Dujardin,
• Sylvain Collet,
• Arnaud Martel,
• Bertrand Carboni and
• François Carreaux

Beilstein J. Org. Chem. 2018, 14, 2949–2955, doi:10.3762/bjoc.14.274

• depending on the absolute configuration of the chiral auxiliary used. The aldehyde 5 was first prepared according to a described procedure in two steps from methyl L-lactate (Scheme 1) [31]. The reaction with (R)- or (S)-oxazolidinones 6 led to the formation of 2,3-syn aldol products 7 in good yields with a

Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

• Romain Sallio,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to

• reactions implying the use of a chiral auxiliary resulted effectively in various optically pure compounds [10][18][19][20]. Second, enantioselective syntheses of these bicylic lactams were performed by using chiral transition metal- or organocatalysts which control the configuration of the trisubstituted

• reached only for specific substitution patterns on the amide nitrogen atom and to a lesser extent on the Michael acceptor. In order to overcome these limitations, we decided to incorporate a chiral auxiliary in our substrates combined with a proper chiral phase-transfer organocatalyst to operate an

Addition of dithi(ol)anylium tetrafluoroborates to α,β-unsaturated ketones

• Yu-Chieh Huang,
• An Nguyen,
• Simone Gräßle,
• Sylvia Vanderheiden,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2018, 14, 515–522, doi:10.3762/bjoc.14.37

• dithioacetal. The scope of the presented procedure is shown with four additional transformations including the use of additional electrophiles and nucleophiles, the use of a chiral auxiliary and subsequent reduction of selected products. Additionally, we extended the reaction to the synthesis of diene

• chiral auxiliary and subsequent reduction of selected products. Furthermore, we extended the reaction to the addition of ynones to α-alkyl or aryl-substitued dithiolanylium TFBs showing their successful transformation to diene dithiolanes in two examples. One limitation of the procedure concerning the

• demonstrated by examples including the use of additional electrophiles (13a, 13b) or nucleophiles (9i, 9j), the use of a chiral auxiliary (15) or reductions of the obtained products 4 (16a, 16b). aCH2Cl2, 1 equiv Me2AlCl, rt; 13a: 1 h, 13b: 18 h. bdr was calculated from the 1H NMR results. Synthesis of diene

The selective electrochemical fluorination of S-alkyl benzothioate and its derivatives

• Shunsuke Kuribayashi,
• Tomoyuki Kurioka,
• Shinsuke Inagi,
• Ho-Jung Lu,
• Biing-Jiun Uang and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2018, 14, 389–396, doi:10.3762/bjoc.14.27

• anodic fluorination was performed with the benzothioate derivative 1k having a camphor group as a chiral auxiliary. The anodic fluorination proceeded to afford the corresponding α-fluoro products as a diastereoisomeric mixture (43% de) in a reasonable yield 42% along with benzoyl fluoride as byproduct

Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ⁶-sulfanyl)acetic acid esters with aldehydes

• Anna-Lena Dreier,
• Andrej V. Matsnev,
• Joseph S. Thrasher and
• Günter Haufe

Beilstein J. Org. Chem. 2018, 14, 373–380, doi:10.3762/bjoc.14.25

• conditions and application of enantiopure Lewis acids or SF5-substituted acetamides bearing a chiral auxiliary will result in asymmetric aldol addition reactions in the future. Conclusion From octyl SF5-acetate and TMSOTf/Et3N, a (Z)-enolate (ketene silylacetal) was preferentially formed as has already been

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• have proposed the six-membered transition state E affording (R,R)-32 as major product. Indeed, transition state F is unfavored due to repulsive steric interactions between the chiral auxiliary and the ketamine R2 group. In 2016, Xu and Su reported a novel practical and rapid access to chiral {3[(N-tert

Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides

• Masanori Inaba,
• Tatsuya Sakai,
• Shun Shinada,
• Tsuyuka Sugiishi,
• Yuta Nishina,
• Norio Shibata and
• Hideki Amii

Beilstein J. Org. Chem. 2018, 14, 182–186, doi:10.3762/bjoc.14.12

• asymmetric synthesis of 3-(trifluoromethyl)phthalide (1a) using a chiral auxiliary was published to date. In 2006, Pedrosa and co-workers discribed the diastereoselective nucleophilic trifluoromethylation of aldehyde 5, which was prepared by condensation of ortho-phthalaldehyde with (−)-8-benzylaminomenthol

• . Asymmetric synthesis of 1a using a chiral auxiliary. Catalytic asymmetric synthesis of 1a. Trifluoromethylation/cyclization of 2-cyanobenzaldehyde. Trifluoromethylation/cyclization of 2-cyanobenzaldehyde (2) in the presence of chiral catalysts. Supporting Information Supporting Information File 2: General

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• followed a general procedure to access to (2S,3S)-CF3-threonine through an aldol reaction of CF3CHO with the Ni(II) complex of the chiral Schiff base of glycine which was introduced by Belokon et al. [23][24]. The chiral auxiliary (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide (11) was obtained

• conditions gave the nickel Schiff base complex 12 in 71% yield as red crystals. The nucleophilic glycine equivalent 12 went through the aldol reaction with trifluoroacetaldehyde to give complex 13 in moderate yield (66%). Further hydrolysis of complex 13 led to the recovery of the chiral auxiliary 11 and

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• be achieved using an olefination reaction, a metathesis reaction or a copper-mediated reduction of 3,3-difluoropropenes. Pannecoucke’s group employed a chiral auxiliary, the Evans oxazolidinone, to prepare the non-racemic dipeptide isostere 35 (Scheme 7) [34]. Stereoselective alkoxymethylation on the

• oxazolidinone derivative 31 was first achieved with an excellent yield (88%) and diastereoselectivity (de > 95%). The chiral auxiliary was then removed and the free alcohol was oxidized to the corresponding aldehyde 32. Alkene 33 was then obtained after olefination of 32 with low selectivity ((Z):(E) = 64:36

• by Fujii, Otaka and co-workers, which showed that the sultam moiety is a useful chiral auxiliary to control the stereochemistry during the incorporation of the lateral chain (see Scheme 15) [37]. The copper-mediated reduction of 3,3-difluoropropene 40 bearing a sultam (Xs) as a chiral auxiliary

Diastereoselective Mannich reactions of pseudo-C₂-symmetric glutarimide with activated imines

• Tatsuya Ishikawa,
• Tomoko Kawasaki-Takasuka,
• Toshio Kubota and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2017, 13, 2473–2477, doi:10.3762/bjoc.13.244

• , entry 7). Because the employment of the phenylalanine-based oxazolidinone as the chiral auxiliary under the same conditions gave similar results as the one obtained from valine (Table 1, entries 8 vs 7), we decided the conditions in entry 7 (Table 1) as the best of all tested and investigated the

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

• trifluoromethyl nucleophiles, such as TMS–CF3 [84][85] has been described to be inefficient. Still, the asymmetric synthesis of CF3-substituted propargylamines has been described, using (R)-2-methoxy-1-phenylethan-1-amine as chiral auxiliary [86][87][88]. However, cleavage of the protective group requires

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• chiral auxiliary to control the chirality of the carbon atom in α-position of the phosphorus atom as exemplified by the alkylation of the phosphonodiamide 88 (Figure 27). Furthermore, phosphonodiamide can be purified by different methods including chromatography and their transformation to phosphonic

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• stereoselective elimination and decarboxylation in situ. The corresponding aldehyde 22 was then homologated by an Abiko–Masamune anti-aldol addition [74] with ephedrine-derived ester 23, which proceeded with excellent yield and stereoselectivity. However, the subsequent removal of the sterically hindered chiral

• auxiliary proved demanding. The Menche group realized that a transformation to a Weinreb amide may be realized in an effective manner by an in situ activation of 24 with iPrMgCl [75], followed by a methylation of the free hydroxy group and introduction of the methyl ketone. This procedure proved superior to

Diastereoselective anodic hetero- and homo-coupling of menthol-, 8-methylmenthol- and 8-phenylmenthol-2-alkylmalonates

• Matthias C. Letzel,
• Hans J. Schäfer and
• Roland Fröhlich

Beilstein J. Org. Chem. 2017, 13, 33–42, doi:10.3762/bjoc.13.5

• -methylmenthol- (2)-, 8-phenylmenthol- (3)-, and 8-p-anisylmenthol- (4)-2-alkylmalonates (Figure 1). Results and Discussion Anodic hetero- and homo-coupling of carboxylates The carboxylic acids 13a/b–18a/b for the Kolbe electrolyses were synthesized according to Scheme 1. The chiral auxiliary 1–4 is acylated

• interaction between the carbonyl and the phenyl group [24]. In order to enhance this interaction, the phenyl group was replaced for the more electron-rich anisyl group by applying 8-anisylmenthol (4) as chiral auxiliary. However, with acetic acid or 3,3-dimethylbutyric acid (20) as coacid no radical hetero

• as a chiral auxiliary [27] to control the stereochemistry in Diels–Alder reactions [28], [2 + 2]- and [3 + 2]-cycloadditions and asymmetric ene reactions [29]; furthermore, it has been applied in 1,4-cuprate additions [30], Grignard additions [31], in supramolecular chemistry [32] and in alkylation

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• an oxidative cyclization using stoichiometric amounts of sodium permanganate to furnish trans-THF diol 78 in 73% yield with an excellent diastereomeric ratio of 97:3 induced by a cyclohexanol derived chiral auxiliary. This key intermediate was subsequently converted to natural trans-(+)-linalool

• be solved in future investigations. To date there is only a single report on an enantioselective oxidative cyclization of a 1,5-diene using permanganate together with a chiral counter ion. Other strategies use either a chiral auxiliary, a subsequent desymmetrization or start from a chiral 5,6

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• nitroso dienophiles with masked o-benzoquinones [128]. For instance, they synthesized synthon 152 from 2-methoxyphenol (150) and the chiral auxiliary 151 with 99% de, which was further utilized for the synthesis of (+)-conduramine E-1 (153, Scheme 30). The hetero-Diels–Alder reaction of chloronitroso

• enantioselectivity encouraged the Inomata group to further investigate the reaction [152]. Their investigation of enantioselective hetero-Diels–Alder reactions resulted in an enantioselectivity of up to 92% ee, when nitrosobenzene and a dienol were reacted in the presence of tartaric acid ester as a chiral auxiliary

Experimental and theoretical insights in the alkene–arene intramolecular π-stacking interaction

• Valeria Corne,
• Ariel M. Sarotti,
• Carmen Ramirez de Arellano,
• Rolando A. Spanevello and
• Alejandra G. Suárez

Beilstein J. Org. Chem. 2016, 12, 1616–1623, doi:10.3762/bjoc.12.158

• reported the synthesis of a novel chiral auxiliary that demonstrated to be very efficient in an asymmetric Diels–Alder reaction between the acrylic ester derivative and cyclopentadiene [16]. The facial selectivity of this reaction proved to be due to an aryl–vinyl π-stacking intramolecular interaction that

• fixed the conformation of the dienophile (Figure 1) [16]. Given this precedent, we aimed to gain further insight into this type of interaction, by exploring the effect caused by the introduction of electronically different substituents at the aromatic ring of the chiral auxiliary. For this reason, we

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

• length via stereospecific nucleophilic displacement of the chiral auxiliary with complete inversion of configuration at the sulfur center [46][47]. Sulfoxide 3 is incorporated into the catalyst via a [3 + 2] oxidative cycloaddition with allylruthenium complex 4. Desilylation of cationic complex 5, ion