Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• regio- and enantioselectivity. Disclosed herein, this discovery has enabled the first total synthesis of (−)-anverene (1) (Scheme 1, bottom), a secondary metabolite from the algae Plocamium cartilagineum with selective antibiotic activity against vancomycin-resistant Enterococcus faecium (VREF) [10

• . Unlike Table 1, entry 1, which was taken to completion, bromochlorinations quenched at low conversion exhibited high enantioselectivity for 6, but also constitutional isomer ratios (cr) as low as 2:1 for 6:7 (not shown). These observations are consistent with a highly selective catalytic reaction

• , and can adopt both monomeric and oligomeric structures, several of which can be catalytically active [12]. When Cl2Ti(OiPr)2 is used in place of ClTi(OiPr)3, bromochloride 7 forms very quickly with no enantioselectivity and with inherent substrate regioselectivity. The additional Ti(OiPr)4 may limit

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• , entry 8). It was found that the reaction took place to afford the desired cyclopentane 3a. Encouraged by this result, we carried out further investigations of the co-catalysts promoted process (Table 2). First, we determined the diastereo- and enantioselectivity of the reaction. The 1H NMR of the

• performed in THF was interesting: No reaction occurred at rt (Table 2, entry 8), but at 50 °C, 54% yield with high enantioselectivity for both isomers while 3a’’ as the major product (dr: 3a’’:3a’ = 5:1, Table 2, entry 9) was obtained. We decided to further optimize the reaction in CHCl3 accordingly (Table

• high yields and excellent enantioselectivities for major isomer 3’ and minor 3’’’ products, while the electronic effect on enantioselectivity is more pronounced for minor 3’’ (Table 3, entries 1–5). A similar trend is observed with the aromatic α,β-unsaturated aldehydes with electron-withdrawing at

Artificial Diels–Alderase based on the transmembrane protein FhuA

• Hassan Osseili,
• Daniel F. Sauer,
• Klaus Beckerle,
• Marcus Arlt,
• Tomoki Himiyama,
• Tino Polen,
• Akira Onoda,
• Ulrich Schwaneberg,
• Takashi Hayashi and
• Jun Okuda

Beilstein J. Org. Chem. 2016, 12, 1314–1321, doi:10.3762/bjoc.12.124

• influence the endo/exo ratio as well as the enantioselectivity [30]. Artificial Diels–Alderases have also been reported to show good endo/exo selectivities as well as high enantioselectivities in a benchmark reaction of azachalcone with cyclopentadiene [22][23][24][25][26][27]. The artificial Diels

• absence of any enantioselectivity suggests that no preferential orientation of the substrate at the active site within the barrel structure is possible. Notably, no protein precipitated during catalysis, showing the advantageous feature of membrane proteins in terms of robustness as compared to soluble

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• , catalytically generated from 1, to α-substituted acrylates 2 followed by enantioselective protonation of the resulting lithium enolate (Scheme 1) [14]. The ortho-trimethylsilyl substituent on the phenyl ring was necessary for achieving high levels of enantioselectivity. All of the reactions proceeded in high

• stoichiometric chiral Mg-(bis)oxazoline complex was required to achieve high enantioselectivity. Higher enantioselectivity was generally observed for reactions using secondary or tertiary alkyl halides. When performing radical conjugate additons to give 2-hydroxymethyl esters 7c, the authors observed a complete

• nucleophiles for the conjugate addition–enantioselective protonation of α-aminoacrylates (vide infra). In 2010, Mikami and co-workers reported a hydrogen atom transfer strategy for the synthesis of β-perfluorobutyl-α-amino ester 13 in low yield and modest enantioselectivity, and the absolute configuration of

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

• efficiency and excellent enantioselectivity. Among the many oxazoline-derived ligands that have been reported in the literature, SimplePHOX [17] and ThrePHOX [18] have emerged as some of the most versatile and most easily accessible ligand classes. However, although iridium complexes derived from these

• various test substrates were much lower than those induced by the tert-butyloxazoline analog with the exception of the result obtained with the allylic alcohol S2 (Table 1). Surprisingly, the presence of two geminal phenyl substituents at C(5) had a negative impact on the enantioselectivity, as shown by

• the enantioselectivity and catalytic activity of the corresponding iridium complexes. Initial attempts to introduce a silyl or acetyl group by deprotonation with potassium hydride and subsequent reaction with silyl triflates or acetyl chloride failed. The NeoPHOX ligand 14 showed no reaction under

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

• and enantioselectivity of this reaction, as there was a severe matched/mismatched effect observed with another diastereomer. In contrast to the ruthenium-catalyzed [5 + 2] cycloaddition of enynes, which is thought to proceed through a ruthenacyclopentene intermediate [26], it has been proposed that

• that, upon coordination to ruthenium, create diastereomeric, chiral-at-ruthenium complexes (Figure 1c). It was unclear a priori whether this transfer of stereochemical information would have an adventitious, negligible, or detrimental impact on the enantioselectivity of the reaction. With this

• that the sulfoxide must be bound to the metal in order for the reaction to proceed. Raising the temperature to 60 °C had a negligible impact on enantioselectivity (Table 1, entry 2). Our proposed mechanism of the racemic redox bicycloisomerization reaction necessitates the decomplexation of one

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• reported cinchonine-derived bifunctional thiourea catalyst 12 afforded the addition product 13 in high yield with good levels of diastereo- and enantioselectivity (95:5 dr, 90:10 er for the major diastereomer 13). The relative stereochemical configuration of the minor diastereomeric product 14 was

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• situ, giving the corresponding products with 93–99% ee. This modified protocol was also extended to electron-rich heteroarene substrates. Interestingly, hexafluoroisopropanol (HFIP) was found to be able to improve the enantioselectivity significantly. The authors also proposed a possible transition

• were used for the reaction. The phenolic hydroxy group of the catalyst was thought to be crucial in controlling the enantioselectivity by forming hydrogen bonds with reactants. Besides, enantioselective additions of allenes to isatins were also achieved under these conditions, giving the desired

• effects on the enantioselectivity. Compared to acetone and cycloheptanone, good enantioselectivities were obtained for cyclohexanone. Based on the previously observed catalytic performance of amino acid metal salts in asymmetric catalysis, Luo and co-workers reported that phenylalanine lithium salt (cat

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• catalyst control for these reactions should be pursued. Ideally, the catalyst would dictate the diastereoselectivity, the enantioselectivity, and the location of C–H bond insertion to provide any of the possible product isomers selectively on demand. Bridged polycyclic natural products. Strategic

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• (Scheme 2, compounds 13–15) proceeded with poor diastereocontrol but the results were improved by changing to catalyst C2 [62]. Nonetheless, in both cases the enantioselectivity for the major diastereomer was excellent. Finally, and starting from the corresponding bicyclic imidazolones, quaternary proline

• demonstrated to be either less reactive and/or less stereoselective in their addition reaction to nitrostyrene thus affording the corresponding Michael adducts with no diastereoselectivity and/or poor enantioselectivity (Scheme 3). Useful applications of the Michael adducts coming from the Michael addition of

• tetrasubstituted Michael adducts in high diastereo- and enantioselectivity. The efficiency of the previous 2-thio-imidazol-4(5H)-ones as pronucleophiles in Michael reactions has also been corroborated in the addition to these α-silyloxyenones as Michael acceptors [55]. First attempts to carry out the Michael

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• is an important tool for the synthesis of complex molecules due to the high control of enantioselectivity in the formation of stereogenic centers. This paper presents a brief review of the early issues, related mechanistic studies and recent applications on this chemistry area. Keywords: C–H

• coworkers (Scheme 4) [38]. In addition to the novelty of the use of the chiral copper complex 11 for controlling the enantioselectivity, the authors proposed the participation of the copper carbenoid 13, formed from the reaction between the copper complex 11 and methyl diazoacetate 9 as active intermediate

• reaction. The catalyst 17c showed opposite enantioselectivity when compared to the catalysts 17a and 17b, with the S-enantiomer formed as the major product. In 1991, Doyle and coworkers published asymmetric synthesis of lactones from alkyl diazoacetates in high enantioselectivity by intramolecular rhodium

Recent advances in C(sp³)–H bond functionalization via metal–carbene insertions

• Bo Wang,
• Di Qiu,
• Yan Zhang and
• Jianbo Wang

Beilstein J. Org. Chem. 2016, 12, 796–804, doi:10.3762/bjoc.12.78

• (I) complexes. In some cases, high regioselectivity and enantioselectivity have been achieved in the C–H bond insertion of small alkanes. This review highlights the most recent accomplishments in this field. Keywords: alkane; diazo compounds; C–H bond functionalization; C–H bond insertion; metal

• methyl ethers [21]. The use of 2,2,2-trichloroethyl aryldiazoacetates, in combination with sterically crowded chiral Rh(II) catalysts Rh2(R-BPCP)4, enhances the site-selectivity and the enantioselectivity of the reaction. Interestingly, the C–H bonds of a methyl group show high reactivity over the

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• transformation (Table 1, entry 4). Different from N-Boc-oxindole, using N-unprotected oxindole and N-benzyl-substituted oxindole as the substrates, accomplished the reaction with every low enantioselectivity (Table 1, entries 7 and 8), incidated the N-Boc protecting group is crucial for this system. Next, the

• -trichloroethane or the less polar solvent toluene gave no improvement in enantioselectivity in comparison to the originally used DCM (Table 2, entries 1–9). To our delight, lowering the reaction temperature increased the reaction yield significantly (Table 2, entries 10–16), while the highest ee value (90%) with

• DEAD was obtained at −30 °C (Table 2, entry 13). Interestingly, the use of other azodicarboxylates with larger R group as amination reagent revealed different optimum reaction temperatures for the best enantioselectivity, and −78 °C was identified as optimal for di-tert-butyl azodicarboxylate (2d, DBAD

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• McDermott et al. in 2008 (Figure 6) [41]. In two steps (asymmetric deprotonation followed by a carbon dioxide quench and coupling with N-benzylpiperazine, 22) product 23 was produced in 48% yield with 89:11 enantioselectivity favoring the R-configuration of the newly generated carbon center. In contrast to

• enantioselectivity were obtained for N-Boc-pyrrolidines when (−)-sparteine or (+)-sparteine surrogate 28 was used. The reactions could be conducted at −30 or −20 °C with a slight drop of the enantiomeric ratio in comparison to the results at −78 °C. They also reported one example of asymmetric lithiation trapping of

• was found to be problematic. Similar to the Coldham discovery, they also noted that the distal N-alkyl substituents have a profound effect on the overall reaction yield and enantioselectivity, with the bulkier alkyl substituents giving better results. The rationale is that the bulky alkyl substituent

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

• Sara Meninno,
• Chiara Volpe,
• Giorgio Della Sala,
• Amedeo Capobianco and
• Alessandra Lattanzi

Beilstein J. Org. Chem. 2016, 12, 643–647, doi:10.3762/bjoc.12.63

• -Michael/aldol reactions [16][17][18][19][20] enabled the synthesis of differently functionalized tetrahydrothiophenes bearing up to three contiguous chiral centers, including quaternary ones, with good to high control of the diastereo- and enantioselectivity. Surprisingly, to date there has been one

• - and enantioselectivity (Table 1, entries 1–5). Thiourea catalyst VII afforded the best result, leading to products 5/6 in a ratio of 72/28 although with low ee values (Table 1, entry 6). Reacting trisubstituted olefin 2a with compound 4, led to three isomers with modest diastereocontrol when using

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• (compare entries 5 versus 6 and 12 versus 13 in Table 1). An increase in both the yield and the enantioselectivity for the reaction of 1a with 2a (Table 1, entries 6 and 7), but no differences in the reaction of 1a with 3a (Table 1, entries 13 and 14) were observed when the unsupported thiourea VI

• change in the stereoselectivity, when the reaction was carried out in less polar solvents such as DCM, toluene, or THF (Table 1, entries 19–21), although both the yield and diastereo- and enantioselectivity were maintained when acetonitrile, a more polar solvent, was used (Table 1, entries 22–24). We

• reactions of 4-chloro- (1b) and 4-fluoronitrostyrene (1c) were very similar than those obtained in the reaction with β-nitrostyrene (1a), maintaining the yield and the enantioselectivity, although 1c reacted slowly within 48 h (compare entries 1 and 2 in Table 2 versus entry 5 in Table 1), but the less

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding

• chiral thiourea organocatalyst and a Brønsted acid (AH) could provide better results in terms of reactivity and enantioselectivity. Thus, in 2011, they published an article where it was proved that the synergic system between the thiourea ent-4 and mandelic acid led to the final products 5 with a

• enantioselectivity, further modifications of the catalytic structure led to highly active catalysts. Indeed, the best results were obtained with the quinolinium thioamide 6, where the NH moiety adjacent to the pyridine ring of the analogous thiourea was “removed”. Likely, in this case, the intramolecular hydrogen

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• dienophile 32, using compound 34 as the catalyst (Scheme 12) [23]. This reaction provided products in 84–99% yield and with a diastereoselectivity of up to >20:1 and excellent enantioselectivity (88–99% ee). In 2015, Dixon, Paton and co-workers demonstrated an elegant route to morphan skeletons, utilizing

• proceeded in good to excellent yield and excellent enantioselectivity for almost all of the substrates that were tested. This methodology was further extended in the total synthesis of (−)-mesembrine. This natural product contains a sterically hindered and arylated quaternary carbon center, which was

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• yields (Scheme 14). Interestingly, preliminary experiments to develop an enantioselective version of this reaction using a chiral NHC returned promising levels of enantioselectivity (76% ee). Subsequently, Gravel and co-workers reported a high yielding chemoselective and enantioselective intermolecular

• -keto esters afforded fully substituted β-halo-α-glycolic acid derivatives in high diastereoselectivity and enantioselectivity [32]. The NHC generated from the amino indanol-derived chiral triazolium salt 29 provided the best results (Scheme 16). A variety of aromatic aldehydes and a series of β-halo α

• yields and enantioselectivity (Scheme 17). It is noteworthy that the catalytically generated Breslow intermediates undergo selective 1,2-addition with ynones and the competing Stetter-type reactivity was not observed [33]. Aza-benzoin reactions In aza-benzoin reactions, the acyl anions generated from

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• asymmetric organocatalysis. This fascinating class of bifunctional catalyst offers a genuine alternative to the more commonly used thiourea systems and because of the different spacing between the functional groups, can control enantioselectivity where other organocatalysts have failed. In the main, this

• this work, Shi, Li and co-workers partnered the isatin derived N-Boc ketimines 8 with MVK (6, Scheme 3a) to obtain the corresponding adducts 9 with very good selectivity [22]. Interestingly, replacing the Boc group with an ethyl carbamate decreased the yield and enantioselectivity dramatically, as did

• -additions that have been facilitated by CPD and CPN derived catalysts. For example, and amongst the earliest examples in the field, underivatized CPD or CPN were used in the addition of dimethyl malonate (40) to a range of nitrostyrenes 41, giving the resulting adducts with excellent enantioselectivity

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• , followed by an evaluation of their enthalpic penalties or rewards and the mechanical strengths of the relevant hydrogen bonds (relaxed force constants; compliance constants). The protocol was able to reproduce the experimentally known enantioselectivity favoring the S-enantiomer. In a second step, the

• enantioselectivity (it is well known that (S)-linezolid is the only active enantiomer) of the recognition process [16][42]. Again, the working-shell was used for this purpose as starting structure. The chirality of linezolid was inverted in place inside the receptor. (R)-Linezolid was rotated by 180° around an

• -lzd system. Our calculated enthalpy is 24.1 kJ/mol higher than lowest minimum of the ribo/S-lzd system. 2) Due to our simulation the experimentally known enantioselectivity can be rationalized on an atomistic level of resolution: while present in both ribosomal/linezolid complexes (R-lzd and S-lzd

Enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine

• Huanzhen Ni,
• Weijun Yao and
• Yixin Lu

Beilstein J. Org. Chem. 2016, 12, 343–348, doi:10.3762/bjoc.12.37

• good yields and with good E/Z ratios, and amide–phosphine 3b worked best (Table 1, entries 2–4). L-Alanine-based phosphine 3d and L-threonine-derived catalysts 3e and 3f did not provide better results (Table 1, entries 5–7). By employing L-threonine-derived catalyst 3g, the enantioselectivity of the

• enantioselectivity of the reaction and was chosen for further investigations. With the optimized conditions established, the substrate scope of this [3 + 2] annulation was explored by varying α-substituted allenoates 1 and imines 2 (Table 2). Firstly, different ester groups at the allenoates were examined (Table 2

• the employment of various α-benzyl allenoates led to the formation of the products in consistently high E/Z ratios and enantioselectivities (Table 2, entries 4–6). It seemed that the presence of the ortho substituent in allenoates led to better enantioselectivity and decreased chemical yield (Table 2

Application of 7-azaisatins in enantioselective Morita–Baylis–Hillman reaction

• Qing He,
• Gu Zhan,
• Wei Du and
• Ying-Chun Chen

Beilstein J. Org. Chem. 2016, 12, 309–313, doi:10.3762/bjoc.12.33

• stereocontrol [6][7][8][9][10][11][12]. Maleimides are also good nucleophilic precursors in the MBH reactions and in 2013, Chimni developed an asymmetric MBH reaction of isatins and maleimides with excellent enantioselectivity [13]. Later, the same group expanded this strategy to isatin-derived ketimines under

• have been synthesized in good to excellent yields and with moderate to high enantioselectivity in a shorter time (for most cases, the reaction time is 24 h). Results and Discussion The enantioselective MBH reaction was first investigated with N-methyl-7-azaisatin (1a) and N-phenylmaleimide (2a) in

• toluene catalyzed by β-ICD. To our delight, the desired product 3a was obtained in 45% yield and with excellent enantioselectivity at 50 °C after 72 h (Table 1, entry 1). The reaction could be accelerated significantly by increasing the amounts of 2a (Table 1, entries 2–5), and almost a quantitative yield

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

• Ming-Liang Zhang,
• Deng-Feng Yue,
• Zhen-Hua Wang,
• Yuan Luo,
• Xiao-Ying Xu,
• Xiao-Mei Zhang and
• Wei-Cheng Yuan

Beilstein J. Org. Chem. 2016, 12, 295–300, doi:10.3762/bjoc.12.31

• -pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in acceptable yield (up to 75%) and enantioselectivity (up to 73% ee). Keywords: asymmetric catalysis; bifunctional catalysts; Henry reaction; organocatalysis; 1H-pyrrole-2,3-diones; Introduction Asymmetric organocatalysis has been

• bifunctional, thiourea-tertiary amine catalyst 3b, derived from quinine and L-valine, furnished a similar result to catalyst 3a (Table 1, entry 2). Next, the reaction was attempted with catalyst 3c derived from L-phenylalanine and catalyst 3d derived from L-phenylglycine, and improvements in enantioselectivity

• were observed (Table 1, entries 3 and 4). Changing L-phenylalanine to D-phenylalanine furnished catalyst 3e, and the enantioselectivity was improved to 61% ee (Table 1, entry 5). Having identified 3e as the best catalyst, we undertook a solvent screening for this transformation with 20 mol % 3e at 30

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• 3 in high yield with high enantioselectivity. A computational study of the transition state of this reaction revealed that inter- and intramolecular hydrogen-bonding networks between catalyst and substrate are critical for obtaining high enantioselectivity [22]. Based upon these insights, we

• ) [23]. Initially, the R3 substituent on the chiral spacer of the catalyst 1 was optimized (Table 1, entries 1–4). The catalyst with a benzyl group at R3 (1a) afforded 5a in excellent yield with moderate enantioselectivity for R configuration (Table 1, entry 1) [24][25]. When R3 was changed to a phenyl

• group, the enantioselectivity was slightly increased to 59% ee (Table 1, entry 2). In the case of a methyl group, 5a was obtained in 98% yield with 50% ee (Table 1, entry 3). An isopropyl group as R3 group was most effective, affording 5a with 66% ee (Table 1, entry 4). Next, we optimized R1 and R2 on