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

• quaternary centers, two of which are stereogenic. Being a hydrocarbon, (−)-thujopsene (10) has few natural handles for retrosynthetic analysis. Inspired by the complexity of this relatively small natural product, several total syntheses of racemic 10 have been reported [25][26][27][28][29] along with at

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

• the corresponding seco-acid and the subsequent construction of the 8-membered lactone moiety. The retrosynthetic analysis of 1 is depicted in Scheme 1 [31]. First, the 8-membered ring in 1 could be efficiently constructed via lactonization using MNBA with DMAP. The chain precursor 2 would be

• chemical shifts in 1’. Δδ corresponds to the difference in chemical shift for natural and synthetic products (Δδ = δ(synthetic) – δ(natural)). Retrosynthetic analysis. Synthesis of 2,3-cis-astakolactin. MNBA-mediated lactonization. Synthesis of 2,3-trans-astakolactin. Yields of astakolactin (1) using

Scalable synthesis of 5,11-diethynylated indeno[1,2-b]fluorene-6,12-diones and exploration of their solid state packing

• Bradley D. Rose,
• Peter J. Santa Maria,
• Aaron G. Fix,
• Chris L. Vonnegut,
• Lev N. Zakharov,
• Sean R. Parkin and
• Michael M. Haley

Beilstein J. Org. Chem. 2014, 10, 2122–2130, doi:10.3762/bjoc.10.219

• overcome the synthetic roadblock that Scheme 1 represented. The improved synthetic route to 8 arises from a retrosynthetic analysis of the current method to prepare IF derivatives [9][10][11][13]. The needed modification must include halogens at the 5 and 11 positions for subsequent functionalization, such

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

• Information File 1). Retrosynthetic analysis of the bifunctional cytidine derivative 1 for functionalization of a periodate-oxidized RNA library. Introduction of the triazolyl moiety into the uridine derivative 7 generating synthon 3. I: 4 equiv POCl3, 16 equiv triazole, 20 equiv NEt3, MeCN, 60 min at 0 °C

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

• . From a synthetic point of view, the target nucleosides could be synthesized from either 1,2,3,5-tetra-O-benzoyl-2-C-β-methyl-D-ribofuranose (5) (route A) or 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (6) (route B). The corresponding retrosynthetic analysis is shown in Figure 2. In synthetic route (A

• synthesis of versatile 5′-deoxy-2′-C-branched nucleosides. Structures of trachycladine A and B. Retrosynthetic analysis of trachycladines A and B. The X-ray crystal structural of 1-O-methyl-3-O-(2,4-dichlorobenzyl)-5-deoxy-α-D-ribofuranose (9). Synthesis of 5-deoxy-1-O-acetyl-2,3-di-O-benzoyl-2-C-β-methyl-D

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

• 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

• application in the rational design of new hedgehog inhibitors based on lead structure 2. Future work will focus on the synthesis of carbacyclopamine analogs with a piperidine F-ring and their biological investigation. Structures of cyclopamine (1) and carbacyclopamine analog 2. Retrosynthetic analysis of

Efficient routes toward the synthesis of the D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa

• Aritra Chaudhury,
• Sajal K. Maity and
• Rina Ghosh

Beilstein J. Org. Chem. 2014, 10, 1488–1494, doi:10.3762/bjoc.10.153

• pivotal intermediates 1a and 1b which were obtained using previously reported methods [40][41] and then proceeding forward to the monomeric building blocks required according to the retrosynthetic analysis (Figure 2). The procedures used and the results obtained to reach the intermediate targets have been

• -manno-trisaccharide derivative (bearing 4,6-O-benzylidene protection on each mannose unit) offer great potential in future oligosaccharide syntheses based on 6-deoxy hexoses. Repeating unit of the A-band polysaccharide of P. aeruginosa. Retrosynthetic analysis. Preparation of the monomeric building

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• . It was decided to keep at least one benzyl group in the structure of the peptoids and vary the isopropyl and isobutyl groups, thus maintaining a greater similarity with the structure of the San A depsipeptide. The retrosynthetic analysis of the depsipeptoids (Scheme 1) shows that the proposed

• biological activities. Sansalvamide A (1) and its depsipeptoid analogues (2). Generic structures of (a) peptide, (b) peptoid, (c) depsipeptide and (d) depsipeptoid. Structures of six pentadepsipeptoid analogues of San A. Retrosynthetic analysis of the cyclic depsipeptoids. Synthesis of acyclic depsipeptoids

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• -hydroxy-β-amino acid) in 2a is present in several biologically active compounds such as taxol, balanol and bestatin. Therefore, this methodology could be potentially exploited for the synthesis of the chiral segment of these compounds. Microginin (1) and (2S,3R)-AHDA (2a). Retrosynthetic analysis of AHDA

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

• Discussion Retrosynthetic analysis of target molecules One common feature of activated biosynthesis intermediate analogues such as 5a is their relative low stability. In the natural context, PKS intermediates are quickly processed by downstream domains or tailoring enzymes. However, if analogues are

• configuration of the double bond in the dehydration product is presently unknown. In a previous study, we have shown that BorDH3 only accepts surrogates with the shown 2D,3D-configuration if incubated with simple 3-hydroxy-2-methyl-SNAc pentanoates [7][12]. Retrosynthetic analysis of surrogate substrates for

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

• ); HRMS (EI) m/z: [M]+ calcd for C18H14N2OF, 293.1090; found, 293.1070. Natural products containing the β-carboline skeletal. COSY and HSQC of 8a and 7a. Retrosynthetic analysis of 6. Plausible mechanism of the oxidative amidation for 9. Synthesis of α-ketoamide 9. Synthesis of dihydroeudistomin Y

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• from methionine and studies towards the preparation of glutamic and aspartic acid derived heterocycles are presented. Following the retrosynthetic analysis in Figure 2 the relative configuration of B (cis/trans) should be controlled through targeted protecting group (PG) manipulation: Reduction of the

• other pharmacologically relevant targets on a gram scale. Natural products and other bioactive piperidine derivatives of type B. Retrosynthetic analysis of piperidines B (X = OH or leaving group, PG = protecting group). Synthesis of the protected amino acids 2. (a) KOH for 1b. b) PG–X = Cbz–Cl (1a–c

Synthesis of the B-seco limonoid core scaffold

• Hanna Bruss,
• Hannah Schuster,
• Rémi Martinez,
• Markus Kaiser,
• Andrey P. Antonchick and
• Herbert Waldmann

Beilstein J. Org. Chem. 2014, 10, 194–208, doi:10.3762/bjoc.10.15

• of the crucial C9–C10 bond (Scheme 1) [35]. In this paper we present a full report on this synthesis [36] as well as further synthetic studies towards the application of the developed strategy to the total synthesis of B-seco limonoid natural products. Results and Discussion Retrosynthetic analysis

• precursor 30 and possible transition state involved in the Ireland–Claisen rearrangement. Conformations of rearrangement precursors 66 and 77 and possible transition states involved in the Ireland–Claisen rearrangements. R = MOM. Retrosynthetic analysis of the B-seco limonoid framework employing a [3,3

• ]-sigmatropic rearrangement for formation of the C9–C10 bond. R = Me or CO2H, LG = leaving group. Retrosynthetic analysis of the B-seco limonoid scaffold employing a Claisen rearrangement as key step for formation of the C9–C10 bond. PG = protecting group, LG = leaving group. Synthesis of alcohols 19, 20 and 22

Total synthesis of (+)-grandiamide D, dasyclamide and gigantamide A from a Baylis–Hillman adduct: A unified biomimetic approach

• Andivelu Ilangovan and
• Shanmugasundar Saravanakumar

Beilstein J. Org. Chem. 2014, 10, 127–133, doi:10.3762/bjoc.10.9

• ). The spectral data is in accordance with the published data for natural dasyclamide [7] which further confirms the structure of the natural product. Synthesis of gigantamide A As given in the retrosynthetic analysis and based on the preference in literature for the preparation of jatropham by

• . Retrosynthetic analysis: A unified synthetic approach for the synthesis of grandiamide D, dasyclamide and gigantamide A. Preparation of N-(4-aminobutyl)cinnamamide. Synthesis of (±)-grandiamide D. Asymmetric synthesis of natural (+)-grandiamide D. Various approaches for the synthesis of (E)-N-(4-cinnamamidobutyl

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• remains important. A similar target is the closely related natural product ophiocordin (2). Herein, we describe a general approach to some of these targets. Results and Discussion The key feature of our retrosynthetic analysis (Figure 2) is the identification of the dehydro derivative of balanol 4 as the

Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

• John Li,
• May May Leong,
• Alastair Stewart and
• Mark A. Rizzacasa

Beilstein J. Org. Chem. 2013, 9, 2762–2766, doi:10.3762/bjoc.9.310

• can produce useful amounts of this important compound as well as novel isomers. Results and Discussion Retrosynthetic analysis A retrosynthetic analysis of RvD2 (1) is shown in Scheme 1. It was envisaged that the target compound 1 could be secured via a Sonogashira coupling to form the C11–C12 bond

• RvD2 (1) has been completed using a common linchpin Wittig reaction. Using this approach, we were able to prepare sufficient quantities of this important inflammation resolving compound for further biological evaluation. Structures of resolvins D1 (1) and D2 (2). Retrosynthetic analysis of RvD2 (1

The total synthesis of D-chalcose and its C-3 epimer

• Jun Sun,
• Song Fan,
• Zhan Wang,
• Guoning Zhang,
• Kai Bao and
• Weige Zhang

Beilstein J. Org. Chem. 2013, 9, 2620–2624, doi:10.3762/bjoc.9.296

• retrosynthetic analysis of I and I′ is presented in Scheme 1. Diol II and II′ arose from a Sharpless asymmetric dihydroxylation that form the C2 stereogenic center. The installation of the C3 stereocenter on vinyl ether III was proposed to utilize a Grignard reaction followed by chromatographic separation

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C₃-building block

• Volker M. Schmiedel,
• Stefano Stefani and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2013, 9, 2564–2569, doi:10.3762/bjoc.9.291

• ][49][50]. Employing other aldehydes instead of pentadecanal our straightforward route should also allow the synthesis of analogues of jaspine B. Structure of jaspine B 1 and its stereoisomers 2–4. Retrosynthetic analysis of jaspine B leading to pentadecanal and an alkoxyallene. Synthesis of racemic

Synthesis of the spiroketal core of integramycin

• Evgeny. V. Prusov

Beilstein J. Org. Chem. 2013, 9, 2446–2450, doi:10.3762/bjoc.9.282

• products with tetramic acid fragments we embarked on the development of a concise and modular approach towards integramycin and related natural products. According to the retrosynthetic analysis, which is outlined in Figure 2, the target molecule may be assembled from an appropriate spiroketal advanced

• , Microbial drugs). Retrosynthetic analysis of integramycin. Synthesis of the aromatic subunit. Sharpless epoxidation/Myers alkylation approach to the C16–C22 carboxylic acid fragment. Coupling of the fragments and spiroketalization. Supporting Information Supporting Information File 527: Experimental

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

• product. On the basis of the abovementioned analysis, a retrosynthetic analysis of (8S,8aS)-5 is displayed in Scheme 5, which features the formation of the fused pyrrolidine ring from the but-3-ene-1-yl group, the expected trans-diastereoselective methylation as the key step, and protected (R)-3

• axial addition of methylmagnesium iodide to bicyclic keto-lactam 7. Holmes’ exclusive trans-diastereoselective methylation of N-Cbz-protected piperidin-3-one 8. Our plan for the trans-diastereoselective methylation of keto-lactam 10. Retrosynthetic analysis of (8S,8aS)-8-hydroxy-8-methylindolizidin-5

Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions

• Markus Leibeling and
• Daniel B. Werz

Beilstein J. Org. Chem. 2013, 9, 2194–2201, doi:10.3762/bjoc.9.258

• discovery research. Several natural occurring anthracycline antibiotics. Total synthesis of daunomycinone 6 according to Hansen. Synthesis of simplified anthracycline derivatives. Retrosynthetic analysis of anthracycline aglycone mimics. Si: any silyl group. Synthetic route for the synthesis of various

Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach

• Thi Thanh Huyen Trinh,
• Khanh Hung Nguyen,
• Patricia de Aguiar Amaral and
• Nicolas Gouault

Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242

• any racemization and obtaining N-protected compounds which may be useful for further transformations. In order to illustrate the efficiency of our method, we were interested in extending this methodology to quinolizidine privileged structures. Our retrosynthetic analysis is shown in Scheme 2. We

• , 168.1387. Previously reported approach from β-aminoynones for the synthesis of pyridones. Retrosynthetic analysis of (−)-epimyrtine. Synthesis of (−)-epimyrtine. Supporting Information Supporting Information File 542: Spectra of new compounds. Acknowledgements We thank the Program Ciências Sem Fronteiras

A concise enantioselective synthesis of the guaiane sesquiterpene (−)-oxyphyllol

• Martin Zahel and
• Peter Metz

Beilstein J. Org. Chem. 2013, 9, 2028–2032, doi:10.3762/bjoc.9.239

• ). Retrosynthetic analysis for (−)-oxyphyllol (1) and structures of the guaiane sesquiterpenes (+)-orientalol E (2) and (−)-englerin A (5). Attempted selective deoxygenation of diol 7. a) 1 mol % K2OsO4, NMO, acetone, water, THF, rt, 97%, diastereomeric ratio = 2:1 (ref. [6]); b) PhOC(S)Cl, pyridine, CH2Cl2, 0 °C

Stereoselective synthesis of the C79–C97 fragment of symbiodinolide

• Hiroyoshi Takamura,
• Takayuki Fujiwara,
• Isao Kadota and
• Daisuke Uemura

Beilstein J. Org. Chem. 2013, 9, 1931–1935, doi:10.3762/bjoc.9.228

• Julia–Kocienski olefination as the coupling reaction. The new retrosynthetic analysis of the C79–C97 fragment 8 is described in Scheme 2. We envisaged that the diol 8 could be synthesized by the Julia–Kocienski olefination [12][13][14] between aldehyde 9 and 1-phenyl-1H-tetrazol-5-yl (PT)-sulfone 10 and

• elucidation is currently underway and will be reported in due course. Structure of symbiodinolide (1). Our previous synthesis of the C79–C96 fragment 7. Retrosynthetic analysis of the C79–C97 fragment 8. Synthesis of aldehyde 20. Synthesis of PT-sulfones 23 and 24. Synthesis of the C79–C97 fragment 27. Julia

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

• James C. Anderson,
• Andreas S. Kalogirou,
• Michael J. Porter and
• Graham J. Tizzard

Beilstein J. Org. Chem. 2013, 9, 1737–1744, doi:10.3762/bjoc.9.200

• . Schematic nitro-Mannich reaction. Retrosynthetic analysis of piperazirum. (a) iBuMgCl, Et2O, −78 °C; (b) KOH, EtOH/H2O, 100 °C; (c) (COCl)2. (a) Li(Et3BH), THF, rt then 14, CF3CO2H, −78 °C, dr 70:30; (b) (CF3CO)2O, Py, CH2Cl2, 0 °C to rt; (c) Zn, 6 M HCl, EtOAc/EtOH, rt. (a) Li(Et3BH), CH2Cl2, rt then 19