A One-pot Access to Diastereoselective Benzo[5,6]oxepino[2,3-c]pyrroles via Formal (5+2)-Annulation of Donor-/Acceptor-Type Aryl Vinyl diazosuccinimide with Ketones Under Silver Catalysis

A silver triflimide catalyzed one-pot protocol for the diastereoselective synthesis of dihydrobenzoxepines has been developed. Silver triflimide found to be an efficient catalyst for the formal (5+2)-cycloaddition to access dihydrobenzoxepines as a single diastereomer using vinyl diazo compounds as 5-C-synthons and ketones. An unmet challenge of utilizing the donor-/acceptor-type vinyl diazosuccinimides as 5-C-synthons under silver-catalysis is presented. This protocol found to be highly regio-, chemo- and diastereoselective, and works well with aliphatic as well as aromatic methyl ketones bearing electron deactivating as well as donating groups to afford dihydrobenzo[5,6]oxepino[2,3-c]pyrroles with a broad substrates scope. The control experiments and time dependent NMR studies revealed the plausible mechanism of this transformation. The protocol also proved to be scalable on the gram scale synthesis.

Chiral Phosphoric Acid-Catalyzed Enantioselective [4+3] Cyclization Reaction of 4-Indolylmethanols and Quinone Esters

An asymmetric [4+3] cyclization reaction of racemic 4-indolylmethanols and quinone esters catalyzed by chiral phosphoric acids has been developed. This method provides efficient access to biologically important benzoxepino[5,4,3-cd] indoles featuring both axial and central chirality in good yields with up to 98% ee and essentially single diastereomer in mild reaction conditions.

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

Application of the Intramolecular Diels–Alder Vinylarenе (IMDAV) Approach for the Synthesis of Thieno[2,3-f]isoindoles

3-(Thien-2-yl)- and 3-(thien-3-yl)allylamines, readily accessible from the corresponding thienyl aldehydes, can interact with a broad range of anhydrides and α,β-unsaturated acids chlorides (maleic, сitraconic­, and phenyl maleic anhydrides, сrotonyl and сinnamyl chlorides, etc.) leading to the formation of a thieno[2,3-f]isoindole core. Usually, the reaction sequence involves three successive steps: acylation of the nitrogen atom of the initial allylamine, the intramolecular Diels–Alder vinylarenе (IMDAV) reaction, and the final aromatization of the dihydrothiophene ring in the Diels–Alder adducts. The scope and limitations of the proposed method were thoroughly investigated. It was revealed with the aid of X-ray analysis that the key step, the IMDAV reaction, proceeds through an exo-transition state, giving rise to the exclusive formation of a single diastereomer of the target heterocycle. In the case of maleic anhydrides, the method allows to obtain functionally substituted thieno[2,3-f]isoindole carboxylic acids, which are potentially useful substrates for further transformations and subsequent bioscreening.

(2Sp,4R,6R,8Sp)-4,6-Dimethyl-1-phenyl-diferroceno-1-phosphines

Ferrocene-based compounds are powerful asymmetric ligands usable for chemical catalysis. We present the synthesis of six new homochiral diferroceno cycles potentially useful as P,O-, P,N- or P,S-ligands. Due to the stereoconservative nature of the SN1 reaction at carbons adjacent to ferrocene units, we obtained a single diastereomer of the 8-membered diferroceno[c,f]heterophosphocines in all cases.

General and stereoselective aminoxylation of biradical titanium(iv) enolates with TEMPO: a detailed study on the effect of the chiral auxiliary

Reactions of Ti(iv) enolates from N-acyl-4-tert-butyl-1,3-oxazolidine-2-thiones with TEMPO afford a single diastereomer of aminoxylated adducts in high yields.

Metal-Mediated C–C Ring Construction: The Ding Synthesis of (−)-Indoxamycin B

Shou-Fei Zhu of Nankai University developed (Angew. Chem. Int. Ed. 2014, 53, 13188) an iron catalyst that effected the enantioselective cyclization of 1 to 2. Bypassing diazo precursors, Junliang Zhang of East China Normal University used (Angew. Chem. Int. Ed. 2014, 53, 13751) a gold catalyst to cyclize 3 to 4. Taking advantage of energy transfer from a catalytic Ir complex, Chuo Chen of University of Texas Southwestern carried out (Science 2014, 346, 219) intramolec­ular 2+2 cycloaddition of 5, leading, after dithiane formation, to the cyclobutane 6. Intramolecular ketene cycloaddition has been limited in scope. Liming Zhang of the University of California Santa Barbara found (Angew. Chem. Int. Ed. 2014, 53, 9572) that intramolecular oxidation of an intermediate Ru vinylidene led to a species that cyclized to the cyclobutanone 8. James D. White of Oregon State University devised (J. Am. Chem. Soc. 2014, 136, 13578) an iron catalyst that mediated the enantioselective Conia-ene cyclization of 9 to 10. Xiaoming Feng of Sichuan University observed (Angew. Chem. Int. Ed. 2014, 53, 11579) that the Ni-catalyzed Claisen rearrangement of 11 proceeded with high diastereo- and enantiocontrol. The relative configuration of the product 12 was not reported. Robert H. Grubbs of Caltech showed (J. Am. Chem. Soc. 2014, 136, 13029) that ring opening cross metathesis of 13 with 14 delivered the Z product 15. Mn(III) cyclization has in the past required a stoichiometric amount of inorganic oxidant. Sangho Koo of Myong Ji University found (Adv. Synth. Catal. 2014, 356, 3059) that by adding a Co co- catalyst, air could serve as the stoichiometric oxidant. Indeed, 16 could be cyclized to 17 using inexpensive Mn(II). Matthias Beller of the Leibniz-Institüt für Katalyse prepared (Angew. Chem. Int. Ed. 2014, 53, 13049) the cyclohexene 20 by coupling the racemic alcohol 18 with the amine 19. Paultheo von Zezschwitz of Philipps-Universität Marburg added (Chem. Commun. 2014, 50, 15897) diethyl zinc in a conjugate sense to 21, then reduced the product to give 22. Depending on the reduction method, either diastereomer of the product could be made dominant. Nuno Maulide of the University of Vienna dis­placed (Angew. Chem. Int. Ed. 2014, 53, 7068) the racemic chloride 23 with diethyl zinc to give 24 as a single diastereomer.

The Lee Synthesis of (−)-Crinipellin A

The crinipellins are the only tetraquinane natural products. The enone crinipellins, including crinipellin A 3, have anticancer activity. Hee-Yoon Lee of the Korea Advanced Institute of Science and Technology (KAIST) envisioned (J. Am. Chem. Soc. 2014, 136, 10274) the assembly of 2 and thus 3 by the intramolecular dipolar cycloaddition of the diazoalkane derived from the tosylhydrazone 1. The initial cyclopentene was prepared from commercial 4 following the Williams procedure. Conjugate addition of the Grignard reagent 5 in the presence of TMS-Cl led to the silyl enol ether 6. Regeneration of the enolate followed by allylation gave 7. The preparation of the racemic ketone was completed by ozonolysis followed by selec­tive reduction and protection. Addition of hydride in an absolute sense led to separa­ble 1:1 mixture of diastereomers. Reoxidation of one of the diastereomers delivered enantiomerically enriched 8. A few steps later, after coupling with 10, the sidechain stereocenter was set by Sharpless asymmetric epoxidation. Oxidation of 11 gave the aldehyde, that was converted to the alkyne 12 by the Ohira protocol. Addition of the Grignard reagent 13 gave the allene 14 as an inconse­quential 1:1 mixture of diastereomers. Deprotection then led to the tosylhydrazone 1. The transformation of 1 to 2 proceeded by initial formation of the diazo alkane 15. Intramolecular dipolar cycloaddition gave 16, that lost N2 to give the trimethylene–methane diradical 17. The insertion into the distal alkene proceeded with remarkable stereocontrol, to give 2 as a single diastereomer—in 87% yield from 1. Direct α-hydroxylation of the ketone derived from 2 gave the wrong diastereo­mer, and hydride addition to 18 reduced the wrong ketone. As an alternative, the enantiomerically-pure sulfoximine anion was added to the more reactive ketone, and the product was reduced and protected to give 19. Allylic oxidation converted the alkene to the enone, and heating to reflux in toluene reversed the sulfoximine addi­tion, leading to 20. Epoxidation of 20 followed by α-methylenation delivered the enone 21, that proved to be particularly sensitive. Eventually, success was found with TASF. With a similarly sensitive substrate, Douglass F. Taber of the University of Delaware observed (J. Am. Chem. Soc. 1998, 120, 13285) that TBAF in THF buffered with solid NH4Cl worked well.

C–O Ring Construction: The Tong Synthesis of (−)-Aculeatin A

Oxetanes are both interesting structural elements and activated leaving groups. James A. Bull of Imperial College London cyclized (Chem. Commun. 2014, 50, 5203) the tosylate 1 to the oxetane with LiHMDS, then alkylated the product using the same base to give 2. J. S. Yadav of CSIR-Indian Institute of Chemical Technology estab­lished (Org. Lett. 2014, 16, 836) conditions for the cyclization of 3 to 4. Hiroaki Sasai of Osaka University used (Chem. Commun. 2013, 49, 11224) a Pd(II)–Pd(IV) cycle to convert 5 to 6. Lauri Vares of the University of Tartu dem­onstrated (Tetrahedron Lett. 2014, 55, 3569) that the racemic epoxide 7, a mixture of diastereomers, could be cyclized to 8 as a single diastereomer in high ee. Alistair Boyer of the University of Glasgow converted (Org. Lett. 2014, 16, 1660) the tria­zole 9, prepared from the corresponding alkyne, to the intermediate 10, that could be hydrolyzed to the ketone or reduced to the amine. Subhas Chandra Roy of the Indian Association for the Cultivation of Science devised (Eur. J. Org. Chem. 2014, 2980) a Ti(III)- mediated cascade conjugate addition–cyclization for the assembly of 12 from 11. Paul E. Floreancig of the University of Pittsburgh reported (Angew. Chem. Int. Ed. 2014, 53, 4926) the highly diastereoselective reductive cyclization of 13 to 14. Arun K. Ghosh of Purdue University prepared (J. Org. Chem. 2014, 79, 5697) the ketone 16 from the enantiomerically-pure alcohol 15. Professor Ghosh also described (Org. Lett. 2014, 16, 3154) a complementary approach to tetrahydropyrans based on the hetero Diels–Alder addition of the alkynyl aldehyde 18 to the diene 17 to give 19. Xin-Shan Ye of Peking University found (J. Org. Chem. 2014, 79, 4676) that the alcohol 20 could be cyclized to 21 with NBS, and to the diastereomer with PhSeCl. Jiyong Hong of Duke University showed (Org. Lett. 2014, 16, 2406) that an organo­catalyst could be used to mediate the cyclization of 22 to the oxepane 23. Mingji Dai, also of Purdue University, reported (Angew. Chem. Int. Ed. 2014, 53, 6519) the car­bonylative macrocyclization of the diol 24 to the lactone 25.