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

• quaternary stereocenters [35][36][37], we envisioned that the Henry reaction of nitroalkanes with 1H-pyrrole-2,3-diones should take place with a chiral bifunctional amine-thiourea catalyst, leading to 3-hydroxy-3-nitromethyl-1H-pyrrol-2(3H)-ones bearing quaternary stereocenters (Scheme 1) [14]. Notably, this

• -pyrrole-2,3-diones with a chiral bifunctional amine-thiourea possessing multiple hydrogen-bond donors as the catalyst. With the developed protocol, a range of 3-hydroxy-3-nitromethyl-1H-pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in good yield (up to 75%) and with moderate to good

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

• important synthetic route to optically active α-amino acid derivatives with chiral quaternary stereocenters [1][2]. Since an α-amino acid moiety is frequently found in biologically active compounds, considerable efforts have been made to achieve a stereoselective synthesis of this structure [3][4]. In

Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

• Jochen Kraft,
• Martin Golkowski and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 166–171, doi:10.3762/bjoc.12.18

• of tertiary carbon stereocenters, remains an ongoing challenge. Over the last decades though, transition metal-catalyzed reactions like the asymmetric allylic alkylation (Tsuji–Trost reaction) have evolved into one of the more powerful tools for synthesizing such tertiary stereocenters [7][8]. As a

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• with pyridines. In 2011, Maruoka and co-workers investigated the use of isoquinolinium ions protected as azomethine imines [30]. The use of a CuOAc/Ph-Pybox catalyst enables the addition of a wide variety of alkynes to form isoquinolines with tertiary stereocenters in high yields and ee’s (Scheme 8A

• ). Although lower ee’s were observed with o-tolylacetylene (43% ee) and 1-heptyne (75% ee), all other alkynes resulted in ≥85% ee. Even more impressive, the authors discovered conditions for a highly enantioselective alkynylation to form tetrasubstituted stereocenters. With 1-alkylisoquinolinium ions, high

• substrates, suggesting that more stable oxocarbenium ions result in more selective reactions, potentially because they lead to later enantiodetermining transition states. We have also discovered a CuSPh/Ph-Pybox catalyst that enables the formation of diaryl, tetrasubstituted stereocenters via an

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of

• clinical application of 1, as well as the development of more active derivatives. Due to the unique tricyclic core of 1, which bears four contiguous stereocenters, various approaches for the synthesis of key intermediate 2 (Scheme 1) have been reported [14][15][16][17][18][19][20][21][22][23], including a

• , the proposed strategy offers an efficient construction of all stereocenters of tricyclic core 2, based on the initially established chiral stereocenter, as the configuration at the C1 and C2 positions of 2 would presumably be controlled by face-selective reduction of ketone 3. The Michael precursor 7

Recent advances in copper-catalyzed asymmetric coupling reactions

• Fengtao Zhou and
• Qian Cai

Beilstein J. Org. Chem. 2015, 11, 2600–2615, doi:10.3762/bjoc.11.280

• (Scheme 16). In 2014, Cai et al. [46] applied the desymmetrization strategy to construct chiral cyano-bearing all-carbon quaternary stereocenters, affording 1,2,3,4-tetrahydroquinoline analogues in good yields and excellent enantioselectivities (Scheme 17). The same group also observed that achiral

• -substituted quaternary stereocenters (Scheme 22). Asymmetric C–O coupling Numerous methods have been developed during the last two decades for the formation of aryl C–O bonds but asymmetric aryl C–O coupling is still a challenge [6][7][8][9][10]. In 2013, Beaudry and Quamar Salih reported the first copper

• -halophenoxyl)-1,3-diols by the same group [54]. However, the palladium catalytic systems suffered from limited substrate scope and poor efficiency and enantioselectivity for the formation of quaternary stereocenters. Recently, Cai et al. carried out such couplings using a CuI/cyclized diamine catalytic system

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

• blumiolide C was accomplished in an overall yield of 0.63%. In 2005, Hiersemann and co-workers reported an approach towards the synthesis of xeniolide F [13] employing a catalytic asymmetric Claisen rearrangement to set the crucial stereocenters at the C2 and C3 positions (Scheme 10) [54]. The synthesis

• butenolide 140 from (R)-citronellol (139) in an 11-step sequence. Next, the two stereocenters at C2 and C3 position were installed by stereoselective conjugate addition of enantiopure α-allylphosphonamide 141 to butenolide 140. After cleavage of the chiral auxiliary by ozonolysis, aldehyde 142 was protected

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

• rearrangements and cyclizations experimentally. The structure elucidation of terpenoids can be challenging because of the multicyclic carbon skeletons with several contiguous stereocenters. The assistance of 13C labels can in such cases be especially helpful, and if completely 13C-labeled carbon backbones can be

• stereocenters deduced from labeling experiments. Structure of thiomarinol A (27). Bold bonds indicate carbon atoms derived from 4-hydroxybutyrate. Structures of artemisinin (28), ingenol (29) and paclitaxel (30). The revised (31) and the previously suggested (32) structure of hypodoratoxide and the structure of

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• -workers [195]. This unusual heptacyclic marine natural product is a cytotoxic agent. Its synthesis is considered difficult due to the stereocenters present in the ring system of longithorone A and E. Moreover, hindered rotation around the quinone moiety adds even more complexity to its synthesis. Recently

Design and synthesis of fused polycycles via Diels–Alder reaction and ring-rearrangement metathesis as key steps

• Sambasivarao Kotha and
• Ongolu Ravikumar

Beilstein J. Org. Chem. 2015, 11, 1259–1264, doi:10.3762/bjoc.11.140

• conceptually novel, synthetically useful atom-economic method for the construction of complex molecules and by this process compounds containing several stereocenters are produced starting from simple starting materials. RRM involves a combination of two or more metathetic transformations, wherein multiple

• ]. Herein, we report two unique examples where the synthesis of hexacyclic systems containing 10 stereocenters have been generated by the application of RRM of readily available bis-norbornene derivatives using Grubbs’ catalysts (Figure 1). The higher analogue related to the bicyclo[2.2.2] system is also

• reaction and RRM as key steps. Here, we generated polycyclic compounds with 10 stereocenters involving six fused rings in four steps starting with readily available starting materials such as 1,3-cyclopentadiene, 1,3-cyclohexadiene and 1,4-benzoquinone. Further studies to expand the scope of this strategy

Cathodic hydrodimerization of nitroolefins

• Michael Weßling and
• Hans J. Schäfer

Beilstein J. Org. Chem. 2015, 11, 1163–1174, doi:10.3762/bjoc.11.131

• hydrodimers. The stereochemistry of the hydrodimer results from a β,ß-C–C bond formation and from a α,δ-diprotonation, which creates a dimer with four stereocenters with the exception of dimer 3, which has only two stereocenters. This means 23 diastereomers can be formed, which are decreased to six

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• . This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods

• install the initial stereocenters (Scheme 3). Treatment of 16 with LiHMDS in THF, followed by allyl chloroformate, furnished the known carbonate 17 in high yield [34]. This substrate smoothly undergoes palladium-catalyzed enantioselective decarboxylative allylation in the presence of (S)-t-Bu-PHOX (5

• bromolactonization of 22 to build in the requisite syn relationship between the carboxylate group and the 3-hydroxy group, ultimately leading to quinic acid. Unlike the allylic alkylations in Scheme 1, which form all-carbon stereocenters, we envisioned a unique modification of the silyl enol ether version to access

A modular phosphate tether-mediated divergent strategy to complex polyols

• Paul R. Hanson,
• Susanthi Jayasinghe,
• Soma Maitra,
• Cornelius N. Ndi and
• Rambabu Chegondi

Beilstein J. Org. Chem. 2014, 10, 2332–2337, doi:10.3762/bjoc.10.242

• stereocenters, while invoking step- [17], atom- [18][19][20][21], green- [22][23], and pot economy [24][25][26]. We have previously reported phosphate tether-mediated strategies to streamline the synthesis of 1,3-anti-diol containing natural products, including recent reports employing one-pot, sequential

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• synthesis of rare, 2-amino-functionalized heptoses and octoses. The indium-mediated allylation strategy again revealed to be a useful tool for the preparation of two-carbon chain elongated carbohydrates. Two new stereocenters were formed with high diastereoselectivity in the course of the synthesis owing to

De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

• Richard T. Desmond,
• Anniefer N. Magpusao,
• Chris Lorenc,
• Jeremy B. Alverson,
• Nigel Priestley and
• Mark W. Peczuh

Beilstein J. Org. Chem. 2014, 10, 2215–2221, doi:10.3762/bjoc.10.229

• ring, the presence of rigidifying planar units and stereocenters collectively govern the shape of a given macrocycle. In fact, we observed that the absolute configuration of C4 of the pyranose ring strongly influenced the shape and reactivity of macrocycle 3 [9]. In 3, the oxygens at C4 and C6 are both

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• spirocyclic compounds containing two neighboring quaternary and tertiary stereocenters in modest to excellent yields (up to 97%) and high enantioselectivities (up to 95% ee). Subsequently, the Fu group applied this approach to the [3 + 2] annulation of allenes with 1,1-disubstituted olefins to synthesize

• highly functionalized cyclopentenes that bear an array of heteroatom-substituted quaternary stereocenters [36]. From a screening of catalysts, they carefully examined the effect of substitution of the binaphthyl framework of chiral phosphines, identifying the 3,3´-diphenyl-substituted phosphepine B4 as

• conditions, the reactions worked efficiently to afford corresponding functionalized spirocyclic products with adjacent spiro-quaternary and tertiary stereocenters in good to excellent yields. These products were readily transformed into a variety of useful optically active amino acid analogues, including

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• stereocenters would originate from lactone 82, which in turn is the product of a conjugate addition of chiral allyl phosphonamide reagent 28c to butenolide 83 prepared from (R)-citronellol. The correct installation of the stereocenters of 82 was crucial to the success of the synthesis, as they would form a

• template for the stereocontrolled incorporation of the remaining stereocenters. The construction of butenolide 83 started from (R)-citronellol (84), which could in principle, deliver the entire alkenyl side chain of acetoxycrenulide (10) (Scheme 11). However, the double bond needed to be transformed into a

• subunit (Figure 8) [116][117][118]. The first total synthesis of nudiflosides A and D was achieved by Hanessian and co-workers, which aimed at confirming their proposed structural and stereochemical assignment (Scheme 19) [49]. The correct installation of the stereocenters of the cyclopentane subunit 159

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• [30] and dynamic kinetic resolution [31]. However, in contrast to these routes, we desired to develop a synthesis of O-acylated (2S,3S)-3-hydroxyleucine derivatives which should be easily scalable and would enable O-acylation after construction of the stereocenters with only few changes in the

• confirmes the stereocenters to have the proposed (2R,3S)-configuration. In their synthesis of (2S,3S)-3-hydroxyleucine, Zhu and co-workers cyclized amino alcohol 5 towards an oxazolidinone, with the carbonyl group simultaneously providing O- and N-protection [32]. Removal of this protecting group required

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• derivatives were unreactive. Interestingly, two stereocenters are generated during the reactions. However, the observed diastereoselectivities were poor, ranging from 50:50 to 76:24. MCRs yielding isoquinoline cores are well documented in the literature and several examples involving alkynylbenzaldehydes and

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

• Hiroki Moriwaki,
• Daniel Resch,
• Hengguang Li,
• Iwao Ojima,
• Ryosuke Takeda,
• José Luis Aceña and
• Vadim A. Soloshonok

Beilstein J. Org. Chem. 2014, 10, 442–448, doi:10.3762/bjoc.10.41

• )benzyl groups results in low impact on the optical rotation of diastereomers 5e and 6e. Knowledge of one of the stereocenters in diastereomers 5 and 6 allowed us to use X-ray crystallography to determine the absolute configuration of the major product 5b [81]. The structure presented in Figure 2 shows

Efficient carbon-Ferrier rearrangement on glycals mediated by ceric ammonium nitrate: Application to the synthesis of 2-deoxy-2-amino-C-glycoside

• Alafia A. Ansari,
• Y. Suman Reddy and
• Yashwant D. Vankar

Beilstein J. Org. Chem. 2014, 10, 300–306, doi:10.3762/bjoc.10.27

• of the resulting diol by using 2,2-dimethoxypropane and a catalytic amount of para-toluenesulfonic acid (PTSA) to furnish the desired orthogonally protected 2-deoxy-2-amino-C-glycoside 12 as a single isomer in 82% yield (over 2 steps). The stereochemistry of the newly generated stereocenters in

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• the synthetic potential of these classes of organoboranes. These compounds, named boronated [3]-1-heterodendralenes by analogy with the corresponding carbotrienes [74], have been used to synthesize polycyclic heterocycles with control of multiple stereocenters [75]. Based on the intrinsic reactivity

New hydrogen-bonding organocatalysts: Chiral cyclophosphazanes and phosphorus amides as catalysts for asymmetric Michael additions

• Helge Klare,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2014, 10, 224–236, doi:10.3762/bjoc.10.18

• cyclodiphosphazane, respectively. This is similar to the mechanism proposed by Takemoto [9] for the addition of diethylmalonate to β-nitrostyrene. As 2-hydroxynaphthoquinone is not symmetric, two stereocenters are created in the addition step, which gives rise to four different isomers. As with the foregoing

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• 6 stereoselectively despite the presense of several stereocenters in the molecules (Figure 6). For assigning structures of byproducts we carried out the reaction of isatins 1, aroylacrylic acids 5 and proline in a boiling mixture of EtOH and water, which resulted in the formation and isolation of

Plakilactones G and H from a marine sponge. Stereochemical determination of highly flexible systems by quantitative NMR-derived interproton distances combined with quantum mechanical calculations of ¹³C chemical shifts

• Simone Di Micco,
• Angela Zampella,
• Maria Valeria D’Auria,
• Carmen Festa,
• Simona De Marino,
• Raffaele Riccio,
• Craig P. Butts and
• Giuseppe Bifulco

Beilstein J. Org. Chem. 2013, 9, 2940–2949, doi:10.3762/bjoc.9.331

• extend the application of NMR-derived interproton distances to a highly flexible molecular system with simultaneous assignment of four non-contiguous stereocenters. Chemical derivatization and quantum mechanical calculations of 13C on plakilactone G along with a plausible biogenetic interconversion

• -dehydroderivative (3) [23], that is likely the biosynthetic precursor of all side-chain-oxidized derivatives belonging to this family, this information was not considered for the validation of our protocol and all four stereocenters for plakilactones G and H have been investigated. Plakilactone G (1) was isolated

• stereocenters under investigation. For 2a, we observed an error of 25.3% for the distance between H-16–H-8 and 12.2% for the protons H-3–H-13a. The calculated interproton distance H-3–H-6 presents an error of 14.7%, whereas the distance H-15b–H-6 has an error of 11.8%. It is noteworthy that 2a has the key