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

• products in good yields and with excellent enantioselectivities (Scheme 16). In 2013, Ishimaru and co-workers developed a N-aryl-L-valinamide (cat. 5)-catalyzed asymmetric aldol reaction of isatins with ketones, affording the products in excellent yields and with up to >99% ee (Scheme 17) [33]. The

• reaction was performed under mild conditions using PTSA·H2O as the additive. Subsequently, the asymmetric aldol reaction of aliphatic aldehydes with isatins was achieved by the same group by using a structurally slightly modified organocatalyst (cat. 5, Scheme 18) [34]. Malonic acid as the additive and

• hydrogen bonds with organocatalyst (cat. 5) and isatin substrate. A novel N-prolinylanthranilamide-based pseudopeptide organocatalyst (cat. 6) was designed by Bunge et al. for the enantioselective aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one with isatins, affording the products in good yield and with

Scope and mechanism of the highly stereoselective metal-mediated domino aldol reactions of enolates with aldehydes

• M. Emin Cinar,
• Bernward Engelen,
• Martin Panthöfer,
• Hans-Jörg Deiseroth,
• Jens Schlirf and
• Michael Schmittel

Beilstein J. Org. Chem. 2016, 12, 813–824, doi:10.3762/bjoc.12.80

• ; domino aldol; metal enolate; tetrahydropyran; Introduction Since its discovery in the late nineteenth century the aldol reaction has become one of the most powerful tools in the field of carbon–carbon bond formation [1][2][3][4][5]. It is widely used in the formation of many natural products [6][7][8][9

• ][10][11], stereoselective syntheses [12][13][14][15][16], and tandem reactions [17][18][19]. While the latter processes usually comprise only one aldol reaction, tandem reaction sequences containing two consecutive aldol steps are mostly limited to the trimerization of enolates [20][21][22]. Metal

• , Ga, In, Ti, Zr, Sn), and various aldehydes and ketones is studied experimentally and computationally. Results Metal effect The experiments were performed to screen suitable metal fragments for their ability to promote the domino aldol reaction by studying the reaction between propiophenone (1a) and

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• steps (Scheme 1) [87][88]. This was followed by an aldol reaction of aldehyde 2 with N,N-dibenzylglycine tert-butyl ester (3) [89] and LDA as a key step of the synthesis (Scheme 1). The resultant products were the two 5'-epimers 4 (5'R,6'S) in 31% yield and 5 (5'S,6'S) in 14% yield, which could be

• glycine (100). Hence, LipK was revealed to be a transaldolase mediating a retro-aldol reaction of L-threonine (119) towards the enol(ate) and acetaldehyde (120), followed by a stereoselective aldol addition of the former to uridine-5'-aldehyde 99 (Scheme 12). Using synthetic reference compounds, it could

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

• Sara Meninno Chiara Volpe Giorgio Della Sala Amedeo Capobianco Alessandra Lattanzi Dipartimento di Chimica e Biologia “A. Zambelli”, Via Giovanni Paolo II, 84084, Fisciano, Italy 10.3762/bjoc.12.63 Abstract An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of

(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

• , Enders and co-workers described the three-component domino Michael–Michael aldol reaction between β-ketoesters 153, nitroalkenes 77 and α,β-unsaturated aldehydes 154, producing heavily substituted cyclohexanes 155 containing six contiguous stereocenters with excellent stereocontrol (Scheme 49) [70]. In

• -mercaptobenzaldehyde 163 to the exo-α,β-unsaturated ketone 177 and subsequent aldol reaction between the newly-formed enolate and the aldehyde moiety. The desired products were obtained utilizing low catalytic loading (5 mol %) in excellent yields (up to 98%) and enantioselectivities (up to 99% ee), but low to

• enolate of cyclohexanone. Two subsequent aldol reactions furnished the desired product. Miscellaneous thiourea-catalysts and catalytic systems promoting asymmetric transformations that lead to a six-membered ring The discovery of L-proline as an organocatalyst for the aldol reaction was of major

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

• -2-amino3-hydroxyindanones is catalysed by NHC 31. The imine electrophile is generated in situ from α-sulfonyl-N-Boc amine 33 (Scheme 19). Initial cross-aza-benzoin reaction of one of the aldehyde functionalities with the imine is followed by an intramolecular aldol reaction to furnish the indanone

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

• -diones is mainly focused on three-component spiro-heterocyclization reactions [30][31][32]. However, for the catalytic asymmetric transformation, only one example of an aldol reaction of 1H-pyrrole-2,3-diones with ketones has been reported so far (Scheme 1) [33]. Recently, our group developed a chiral

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

• Hong-Bo Zhang,
• Yong-Chun Luo,
• Xiu-Qin Hu,
• Yong-Min Liang and
• Peng-Fei Xu

Beilstein J. Org. Chem. 2016, 12, 253–259, doi:10.3762/bjoc.12.27

• trifluoroacetic anhydride in DCM (Scheme 2). Finally, we propose a mechanism for the reaction. Initially, substrate 1 is activated by catalyst (I), which reacts with substrate 2 via two Michael addition reactions to sequentially produce II and III. Then, IV is generated from III by an aldol reaction. Finally, the

A novel and practical asymmetric synthesis of dapoxetine hydrochloride

• Yijun Zhu,
• Zhenren Liu,
• Hongyan Li,
• Deyong Ye and
• Weicheng Zhou

Beilstein J. Org. Chem. 2015, 11, 2641–2645, doi:10.3762/bjoc.11.283

• acetate aldol reaction [10]. However, these methods are undermined by poor yield, low enantioselectivity, and complex synthetic procedure. Chiral tert-butanesulfinamide, developed by García Ruano and Ellman, has been proven to be a broadly useful reagent for the preparation of chiral amines via the chiral

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• [7.2.0]undecane ring system 31 as found in xeniaphyllanes [3]. Finally, double C–H oxidation furnishes the β-hydroxy aldehyde 32 which can undergo a retro-aldol reaction with concomitant opening of the cyclobutane ring to form dialdehyde 33 as the common biogenetic precursor of xenicins, xeniolides and

• construction of the cyclononene unit [49]. The synthesis started with a diastereoselective Evans syn-aldol reaction between substituted propanal 86 and E-crotonyl-oxazolidinone 85 (Scheme 9). The resulting secondary alcohol was silylated and the chiral auxiliary was cleaved with lithium borohydride. Acylation

• function in bicycle 93. The side chain of blumiolide C was introduced by an aldol reaction between lactone 93 and aldehyde 94. In the final sequence, blumiolide C (11) was obtained via stereospecific dehydration, removal of the para-methoxybenzyl ether and oxidation. In summary, the total synthesis of

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• incorporation of labeled Gly into the methyl group was rationalized by glycine degradation, directing the labeling via tetrahydrofolate and SAM into aspirochlorine biosynthesis. The conversion of the Phe residue to Gly may proceed through either oxidative C–C bond cleavage or a retro-aldol reaction in 18, in

Total synthesis of panicein A₂

• Lili Yeung,
• Lisa I. Pilkington,
• Melissa M. Cadelis,
• Brent R. Copp and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 1991–1996, doi:10.3762/bjoc.11.215

• of panicein A2 Firstly, aldehyde 10 was required; it was prepared through methylation followed by Vilsmeier–Haack reaction of 2,3,5-trimethylphenol (11), giving 10 in 51% yield over two steps (Scheme 1) [7]. Aldehyde 10 then underwent an aldol reaction according to the procedures of Samokhvalov et al

Thiazole formation through a modified Gewald reaction

• Carl J. Mallia,
• Lukas Englert,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 875–883, doi:10.3762/bjoc.11.98

• the more stable (electron withdrawing group) anion enable a retro-aldol reaction following. Substituted malonitriles are also tolerated forming the corresponding cyanothiazole in good yield, with no indication of the dithiazole product observed (entry 8, Table 4). Benzyl groups are also tolerated

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• , enantioselective tandem conjugate addition–aldol reaction of cyclic enones [19]. While tandem conjugate addition–α-functionalization reactions were well known prior to Feringa’s publication [20] (Scheme 1), this work was unique because of the high enantioselectivity that was observed through the use of a chiral

Copper-catalyzed cascade reactions of α,β-unsaturated esters with keto esters

• Zhengning Li,
• Chongnian Wang and
• Zengchang Li

Beilstein J. Org. Chem. 2015, 11, 213–218, doi:10.3762/bjoc.11.23

• conjugate reduction of the α,β-unsaturated diester with newly generated copper hydride, followed by aldol reaction to yield the key intermediate alkoxide A, which is subjected to further lactonization to form the lactone. Lam’s group has furnished a cobalt-catalyzed conjugate reductive aldolization

• of γ-carboxy-γ-lactones via a copper-catalyzed cascade reaction. Considering that the reported conjugate addition–aldolization–lactonization cascade reactions proceed via the key intermediate A in Figure 1, we envisioned that the conjugate reduction of a methacrylate and the following aldol reaction

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• by experimental tests [36]. The initially formed main product (R,R,R)-28 in the aldol reaction of acetaldehyde with 10 had the same configuration at C-2 as the proline unit in 10. The absolute configuration of this nickel(II) complex was determined by a single crystal X-ray structure analysis (see

• product 28 can coordinate the Ni atom liberating the carboxylate moiety and thus making the proton at C-2 accessible to base attack (Scheme 4). In order to obtain (R)-allo-threonine (4), it is necessary to carry out the aldol reaction of (R)-10 with an excess of acetaldehyde under strongly basic

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• sesterterpene metabolite isolated from the marine sponge Cacospongia scalaris, has been achieved, mainly featuring Johnson–Claisen rearrangement, asymmetric Mukaiyama aldol reaction and MNBA-mediated lactonization. Keywords: aldol reaction; astakolactin; lactonization; MNBA; terpenoids; Introduction

• constructed via an aldol reaction with ethyl acetate, followed by anti-selective methylation [32][33]. The trisubstituted alkene moiety of the prenyl chain of 3 could be stereoselectively constructed via a Johnson orthoester–Claisen rearrangement of 4 [34][35][36], which would be generated from compound 5

• . The construction of the α-methylene-β-hydroxy ester moiety in 5, which is commonly known as a Morita–Baylis–Hillman adduct, would be achieved via an aldol reaction between aldehyde 6 and ester 7, followed by oxidative deselenization [37]. The linear precursor 8 would be prepared from (E,E)-farnesol

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• charged proline catalyst has been tested in the direct asymmetric inverse aldol reaction between aldehydes and diethyl ketomalonate. Two intermediates in accordance with the List–Houk mechanism for enamine catalysis have been detected and characterized by gas-phase fragmentation. In addition, their

• of organic reactions, such as the direct asymmetric aldol reaction, one of the most important C–C bond-forming reactions in organic synthesis [51]. The currently accepted mechanism suggests a central enamine intermediate which forms a Zimmerman–Traxler-like transition state with the acceptor

• center by a rigid phenyl linker (Figure 1). We then tested the applicability of 1 for ESIMS mechanistic studies on the first “inverse” crossed aldol reaction (Scheme 1) published in 2002 by Jørgensen and coworkers [54] in which the aldehyde acts as the donor in contrast to the “normal” crossed aldol

Five-membered ring annelation in [2.2]paracyclophanes by aldol condensation

• Henning Hopf,
• Swaminathan Vijay Narayanan and
• Peter G. Jones

Beilstein J. Org. Chem. 2014, 10, 2021–2026, doi:10.3762/bjoc.10.210

• -tetraene (6), passing through the p-xylylene intermediate 8 en route [7]. We were, furthermore, interested in studying the aldol reaction of 9, since this process should pose several stereochemically interesting questions. As illustrated in Scheme 3, there are six different products that could be formed by

• dehydration experiment described below. The most plausible mechanism for the above aldol reaction also favors the discussed structural assignments. As shown above in Scheme 2, the starting material 9 favors a conformation in the solid state in which all carbonyl groups point towards the “inner” space of the

• the formation of 12 and 15 in the aldol reaction, both containing endo-configurated OH groups only (Scheme 4). The reaction is initiated by proton abstraction from one of the acetyl groups (9→16). The resulting enolate subsequently attacks the vicinal acetyl group, pushing the developing alcoholate

Synthesis of a bifunctional cytidine derivative and its conjugation to RNA for in vitro selection of a cytidine deaminase ribozyme

• Nico Rublack and
• Sabine Müller

Beilstein J. Org. Chem. 2014, 10, 1906–1913, doi:10.3762/bjoc.10.198

• RNA catalysts that support an aldol reaction between an aldehyde and a ketone, relevant to the synthesis of sugars [6], or the linkage of ribose to nucleobases to generate nucleotides [7]. Such ribozymes are seen as important functional entities underscoring the RNA world theory, where ribonucleic

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

• Patrick Rabe,
• Tim A. Klapschinski,
• Nelson L. Brock,
• Christian A. Citron,
• Paul D’Alvise,
• Lone Gram and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2014, 10, 1796–1801, doi:10.3762/bjoc.10.188

• . Cyclohexenone 6 was first converted with NaHMDS and TMSCl into the corresponding silylenol ether that upon oxidation with m-CPBA under migration of the TMS group yielded the protected hydroxy ketone 7. Aldol reaction with tert-butyl acetate to 8a and deprotection with TBAF gave 9a in 24% yield over four steps

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• studied the enantioselective crossed aldol reaction of aldehydes with trichlorosilyl enol ethers. They obtained the aldol products in high yields with moderate to good enantioselectivities [101]. The chiral phosphoramidates used in this study and tested in many other enantioselective reactions (aldol

• reaction [102], Michael addition [103], Diels–Alder reaction [104], Friedel–Crafts alkylation [105]) illustrate the use of phosphoramidates as organocatalysts. These phosphoramidates were not synthesized by an AT reaction. Instead, the reaction of an amine with an electrophilic phosphorus species (P–Cl

A convenient enantioselective decarboxylative aldol reaction to access chiral α-hydroxy esters using β-keto acids

• Zhiqiang Duan,
• Jianlin Han,
• Ping Qian,
• Zirui Zhang,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2014, 10, 969–974, doi:10.3762/bjoc.10.95

• appears as a common procedure, affording chiral tertiary alcohols which are ubiquitous in the biological sciences and pharmaceutical industry [1][2][3][4][5][6]. The decarboxylative aldol reaction, broadly used for the generation of ester enolate equivalents by the promotion of releasing CO2, has become

• stereocontrolled nucleophilic alkylation [15][16][17][18][19], alkynylation [20][21], 1,2-addition [22][23][24][25][26] and aldol reaction [27][28][29][30][31][32] have been developed. Various nucleophiles such as organometallics, boronic acids and unsaturated ketones can be tolerated in this context (Figure 2

• investigating different Lewis acids with various chiral PyBox ligands 4–8 (Table 1), we discovered that Sc(OTf)3 and tridentate PyBox ligand 6a could promote the decarboxylative aldol reaction of β-keto acid 1a with α-keto ester 2a in excellent yield with high enantioselectivity in toluene (Table 1, entry 9

Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate–phosphate rearrangement and tandem intramolecular piperidine elimination

• Łukasz Górecki,
• Artur Mucha and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 883–889, doi:10.3762/bjoc.10.85

• we planned to envisage a nucleophilic addition of dialkyl phosphites to quinine-based carbonyl compounds and obtain 1-hydroxyalkylphosphonate derivatives (Abramov reaction, phospha-aldol reaction [22][23]). The scope, stereochemistry and side-reactions of the addition are described. Results and

• -aldol) reaction. These carbonyl compounds reacted with dialkyl and diphenyl phosphites producing quinotoxin enol phosphates that resulted from a tandem phosphonate–phosphate rearrangement and an intramolecular piperidine elimination. It can be hypothesized that the driving force of the structural

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• allylation as well as an anti-selective aldol reaction. Reference compounds representing the E- and Z-configured double bond isomers as potential products of the dehydratase reaction were obtained from a common precursor aldehyde by Wittig olefination and Still–Gennari olefination. The final deprotection of

• polyketide-derived thioesters suited for biosynthesis studies. Keywords: aldol reaction; coenzyme A; natural products; pig liver esterase; polyketide biosynthesis; protection groups; Introduction Borrelidin (1) is a macrolactone polyketide natural product with promising antibacterial, antimalarial

• thioester building blocks was planned for the synthesis of 6a and 6b. Starting from aldehyde 11, a common precursor for all molecules required in this study, aldol reaction and following transesterification should lead to thioester 8. The bismethyl esters 7a and 7b as well as the SNAc thioesters 6a and 6b