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

• to the compound’s natural antipode. Our lab’s novel approach to (−)-quinic acid (21) allowed access to either enantiomer of this important substance. We have also intercepted a key intermediate in Danishefsky’s synthesis of (±)-dysidiolide (29), rendering the former racemic route enantioselective

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• synthetic track for the [15N3]-preQ1 base (1) was designed with the concept in mind to access the complementary 15N patterns of [15N9]-preQ1 base (2) and [H215N(C7')]-preQ1 base (3) by employing the same key steps. In this sense, the key intermediate [H215N(C6)]-2,6-diaminopyrimidin-4-one (13) for target 2

• convenient. First, we prepared the 15N-labeled aldehyde 18 as the key intermediate (Scheme 4). This was achieved by reaction of 3-chloropropanol (15) with [15N]-phthalimide 16 to give [15N]-3-phthalimidopropan-1-ol (17). All further steps were in direct analogy as described for targets 1 and 2, namely

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

• tetrahydropyran 92 as key intermediate of the synthesis. Oxidation of 92 and heating to 220 ºC resulted in a concurrent selenoxide elimination and Claisen rearrangement to give 93 via intermediate 81. Face-selective Simmons–Smith cyclopropanation, reduction of both carbonyl groups, and chemoselective oxidation of

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• imine plane reinforces the CN− to attack the imine group below the plane. The enforcement hinders the scrambling. In the second stage, the aminonitrile transforms to alanine, where an amide Me-CH(NH2)-C(=O)-NH2 is the key intermediate. The rate-determining step is the hydrolysis of the cyano group of N

• alanine in the acidic solution. The traditional Strecker reaction gave racemic α-aminonitriles (mixtures of equal amounts of R and S forms), where an imine RCH=NH was considered to be the key intermediate [2]. Three typical reactions are presented in Scheme 1(b) [3]. In 1963, Harada reported the first

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• bicyclic 1,2-oxazine derivative 3 was used as key building block for the Suzuki cross-coupling reaction to synthesize p-terphenyl-linked derivatives 1. The key intermediate 3 was prepared by a Lewis acid-induced rearrangement of 3,6-dihydro-2H-oxazine 4, that origins from a stereoselective [3 + 3

Concise total synthesis of two marine natural nucleosides: trachycladines A and B

• Haixin Ding,
• Wei Li,
• Zhizhong Ruan,
• Ruchun Yang,
• Zhijie Mao,
• Qiang Xiao and
• Jun Wu

Beilstein J. Org. Chem. 2014, 10, 1681–1685, doi:10.3762/bjoc.10.176

• ), nucleoside 3 could be synthesized by using 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose (5) as a carbohydrate acceptor by a Vorbrüggen glycosylation with the corresponding silylated nucleobases and a Lewis acid as a catalyst. As the key intermediate for the preparation of the anti-HCV nucleoside

• synthetic stage, carbohydrate 4 is a versatile intermediate for the diversity-oriented synthesis of the related 2′-C-β-methyl-5′-deoxyribonucleosides. As the key intermediate for the preparation of the antitumor drug capecitabine [24][25], 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (6) is commercially

• environment of 2-OH the benzoylation with benzoyl chloride required an extended reaction time (48 h) and 2 equiv DMAP as base and catalyst. At last, the 1-O-methyl group was transformed to 1-O-acetate glycosylation acceptor 4 as an anomeric mixture (α:β = 2:3) in 84% yield. Therefore, the key intermediate 4

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• conditions (LiOH, THF/H2O, 1:1, 68% yield for the two steps), and the alcohol moieties were protected as formyl esters (formic acid, 50 °C, 85% yield) to give key intermediate 10. Employing the formyl protecting groups [32], diazoketone 3 (for its structure see Scheme 1) was readily obtained from acid 10 via

• analog that still exhibits similar inhibitory activity on hedgehog-signaling. For the sake of brevity of the overall synthetic sequence we defined carbacyclopamine analog 2 (see Figure 1) as our primary target. Results and Discussion A retrosynthetic analysis identified diazo compound 3 as a key

• intermediate in the synthesis of 2 (see Scheme 1). We envisioned a rhodium-catalyzed C–H-insertion into the C17–H bond to occur with a high degree of selectivity (both regio- and stereoselectivity) to form the all-carbon E-ring (for its structure see 11, Scheme 2). Furthermore, a Wagner–Meerwein rearrangement

Rational design of cyclopropane-based chiral PHOX ligands for intermolecular asymmetric Heck reaction

• Marina Rubina,
• William M. Sherrill,
• Alexey Yu. Barkov and
• Michael Rubin

Beilstein J. Org. Chem. 2014, 10, 1536–1548, doi:10.3762/bjoc.10.158

• -Bu substituent in the dihydrooxazole ring of the ligand resulted in a reversal of enantioselectivity. Such an unexpected change in the catalyst selectivity motivated us to perform structural analysis of the key intermediate complexes invoked in the catalytic cycle of the Heck arylation. First, we

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• and dipeptide 13, building block 14 was obtained in 70% yield. Isolation and purification of key intermediate 14 was substantially facilitated by the finding that the compound could be efficiently precipitated from a MeOH/DCM/diethyl ether solvent mixture. The synthesis of building block 16 started

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA 10.3762/bjoc.10.139 Abstract 2-Hydroxy-4-pentynoic acid (1) is a key intermediate towards ‘clickable’ polylactide which allows for efficient introduction of a broad range of pendant functional groups

• great power to tune physicochemical properties of PLA by ‘click’ modification of acetylene functionalized PLA. Precursor 1 is the key intermediate in the preparation of these ‘clickable’ PLAs. It was synthesized in 40% overall yield via hydrolysis of ester 2 which was generated by Reformatsky-type

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

• [32], we have employed their 7-step synthesis of a stereoisomerically pure amino alcohol as the key intermediate. According to the previously reported protocol, D-serine (2) was transformed into protected derivative 3 (4 steps, 59% overall yield, Scheme 1). Alcohol 3 was then oxidized to a D-serinal

• sequence. Finally, the previously reported hydrogenolytic debenzylation of 4 [32] provided amino alcohol key intermediate 5 in quantitative yield for the deprotection step and in 29% overall yield over 7 steps from D-serine (2, Scheme 1). It should be noted that Garner's aldehyde is often used instead of

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• byproduct 19 was isolated from the reaction mixture. To overcome this synthetic hurdle and to obtain amounts of the key intermediate 18 which are large enough to investigate its reactivity in the following cyclopropanation reaction, we decided to attempt the Petasis olefination reaction [38][39]. The

• from D-serine, their synthesis was accomplished in 10 steps in good overall yield. After an extensive investigation on the best synthetic approach, key intermediate 20 was successfully prepared by an efficient rhodium-catalyzed cyclopropanation of a terminal double bond of compound 18 with ethyl

Direct C–H trifluoromethylation of di- and trisubstituted alkenes by photoredox catalysis

• Ren Tomita,
• Yusuke Yasu,
• Takashi Koike and
• Munetaka Akita

Beilstein J. Org. Chem. 2014, 10, 1099–1106, doi:10.3762/bjoc.10.108

• . Triphenylethenes 2l and 2m (only E-isomer) are also applicable to this photocatalytic C–H trifluoromethylation. Remarkably, the E-isomer of 3m is a key intermediate for the synthesis of panomifene, which is known as an antiestrogen drug [71][72]. These results show that the present protocol enables the efficient

One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines

• Christian Muschelknautz,
• Robin Visse,
• Jan Nordmann and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 599–612, doi:10.3762/bjoc.10.51

• minute electronic distributions in the zwitterionic key intermediate, which is controlled in the allenyl enolate moiety by the indolyl nitrogen substituent R1 and by the fragment X on the iminium part, which participates in the stabilization on that side of the zwitterion. The former hypothesis is

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

• p-toluenesulfonylisocyanate (18) is essential for the formation of the key intermediate. Moreover, the formation of the five-membered product 17 is thermodynamically favored by the use of small ligands in the Au complex. Only aryl substituents were well tolerated on imine and alkyne reaction

An oxidative amidation and heterocyclization approach for the synthesis of β-carbolines and dihydroeudistomin Y

• Suresh Babu Meruva,
• Akula Raghunadh,
• Raghavendra Rao Kamaraju,
• U. K. Syam Kumar and
• P. K. Dubey

Beilstein J. Org. Chem. 2014, 10, 471–480, doi:10.3762/bjoc.10.45

• . Accordingly eudistomin Y (6) could be obtained by the aromatization of dihydro-β-carboline 12. The dihydro-β-carboline 12 in turn could be synthesized from ketoamide 9 under Lewis acid mediated Bischler–Napieralski reaction. The key intermediate, ketoamide 9 required for the synthesis could easily be accessed

Carbenoid-mediated nucleophilic “hydrolysis” of 2-(dichloromethylidene)-1,1,3,3-tetramethylindane with DMSO participation, affording access to one-sidedly overcrowded ketone and bromoalkene descendants^§

• Rudolf Knorr,
• Thomas Menke,
• Johannes Freudenreich and
• Claudio Pires

Beilstein J. Org. Chem. 2014, 10, 307–315, doi:10.3762/bjoc.10.28

• reagent 41 furnished the known [44][45] bromoalkene 42b as the only product [30][46]. Conclusion The observed features of the “hydrolysis” reaction of the unactivated α,α-dichloroalkene 6 with solid KOH in DMSO are incompatible with the key intermediate 9 of the ARE [12] mechanism. Instead, a Cl,K

Triphenylene discotic liquid crystal trimers synthesized by Co₂(CO)₈-catalyzed terminal alkyne [2 + 2 + 2] cycloaddition

• Bin Han,
• Ping Hu,
• Bi-Qin Wang,
• Carl Redshaw and
• Ke-Qing Zhao

Beilstein J. Org. Chem. 2013, 9, 2852–2861, doi:10.3762/bjoc.9.321

• (Colro) and hexagonal columnar mesophases (Colho). Furthermore, the structure-mesomorphic property relationship is discussed. The synthetic route is shown in Scheme 1 and Scheme 2. Results and Discussion Synthesis and characterization We synthesized the key intermediate 1, 2-hydroxy-3,6,7,10,11-pentakis

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• concept flow synthesis of the key intermediate used to produce the bromo derivative of the CAPIC precursor, 2-bromo-4-methylnicotinonitrile (6b). The synthesis telescopes three steps using substantially less expensive starting materials. Flow or continuous chemistry is alternative to batch chemistry where

Oxidative 3,3,3-trifluoropropylation of arylaldehydes

• Akari Ikeda,
• Masaaki Omote,
• Shiho Nomura,
• Miyuu Tanaka,
• Atsushi Tarui,
• Kazuyuki Sato and
• Akira Ando

Beilstein J. Org. Chem. 2013, 9, 2417–2421, doi:10.3762/bjoc.9.279

• reaction mechanism shown in Scheme 2, which includes the isomerization of 5 to 6 in the formation of 3. To support our proposed mechanism, a computational calculation was performed with Gaussian 03W at the B3LYP/6-31+G* level of theory to confirm that key intermediate 7 was involved in the isomerization

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• PTX 237A (3) [6]. Thus, it is logic to envision that an efficient synthesis of this key intermediate would allow access to other member of pumiliotoxins and their analogues. To date more than ten synthetic approaches to (8S,8aS)-5 have been published [12][13][14][15][18][19][20][21][22][27][28][29][30

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• in xylenes undergoes ring-closure yielding the desired pyrimidine 3.22 but unfortunately only in modest yield. However, this key intermediate could be readily N-methylated, and in a simple extension to the sequence subjected to direct amide formation, debenzylation and finally coupled with the

Gold(I)-catalyzed enantioselective cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2013, 9, 2250–2264, doi:10.3762/bjoc.9.264

• . This key intermediate is then trapped by the nitrone to afford XIV, which eventually evolves to the product by an intramolecular cyclization (Scheme 17). Finally, the same group recently reported a related reaction of 1-(1-alkynyl)cyclopropyl ketones such as 28, by means of a gold(I)-catalyzed

Gold(I)-catalyzed hydroarylation reaction of aryl (3-iodoprop-2-yn-1-yl) ethers: synthesis of 3-iodo-2H-chromene derivatives

• Pablo Morán-Poladura,
• Eduardo Rubio and
• José M. González

Beilstein J. Org. Chem. 2013, 9, 2120–2128, doi:10.3762/bjoc.9.249

• preparative aspects for the title compounds, a preliminary mechanistic proposal to justify the obtained results could reasonably involve the generation of gold–vinylidene B as key intermediate behind the formation of the corresponding 3-iodo-2H-chromenes 2 (X = O, Scheme 4A). Gold–vinylidenes have been

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• is derived from L-tryptophan (36) [25], indicate a close biosynthetic relationship between these alkaloids. After additional experiments, the authors concluded that lycogalic acid A (38) is the biosynthetic key intermediate for the biogenesis of indolocarbazoles. This hypothesis was verified through