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Monday, January 14, 2013
Tristan H. Lambert
Columbia University

C-O Ring Construction: The Reisman Synthesis of (-)-Acetylaranotin

The Prins cyclization is a powerful approach for the construction of oxygen-containing heterocycles. B. V. Subba Reddy at the Indian Institute of Technology has reported (Tetrahedron Lett. 2012, 53, 3100. DOI: 10.1016/j.tetlet.2012.04.029) an approach to 2,6-dioxabicyclo[3.2.1]octanes 2 by way of a tandem Prins reaction / intramolecular acetalization of the diol 1 and a variety of aldehydes. Christine L. Willis of the University of Bristol utilized (Angew. Chem. Int. Ed. 2012, 51, 3901. DOI: 10.1002/anie.201108315) non-traditional γ,δ-unsaturated alcohols 3 for a Prins-type strategy to access bicyclic heterocycles 5, while Zhenlei Song of Sichuan University employed (Angew. Chem. Int. Ed. 2012, 51, 5367. DOI: 10.1002/anie.201201323) a bis(silyl) homoallylic alcohol 7 in the synthesis of structures such as 8, corresponding to the B ring of the bryostatins. In a mechanistically related process, the conversion of unsaturated ketones 9 to tetrahydropyranyl products 11 by treatment with a boronic acid 10 and triflic anhydride was described (Org. Lett. 2012, 14, 1187. DOI: 10.1021/ol300272j) by Aurelio G. Csáky at the Universidad Complutense in Spain.

A powerful approach to heterocycles is via the ring-expansion of smaller, and especially strained, ring systems. Jon T. Njardarson of the University of Arizona has been exploring such strategies, and has reported (Angew. Chem. Int. Ed. 2012, 51, 5675. DOI: 10.1002/anie.201201367) the conversion of vinyl oxetanes to dihydropyrans via catalysis by transition metals or Brĝnsted acids. The use of a chiral catalyst such as 13 allowed for the enantioselective conversion of divinyl oxetane 12 to enantioenriched dihydropyran 14. Meanwhile, Amir H. Hoveyda at Boston College and Richard R. Schrock at MIT have developed (J. Am. Chem. Soc. 2012, 134, 2788. DOI: 10.1021/ja210946z) a highly reactive and stereoselective catalyst for the ring-opening / cross-metathesis of several ring systems such as 15 with enol ethers. Notably, reactions occur rapidly (e.g. 10 min) using as little as 0.15 mol% catalyst.

An alkynyl cyclopropyl ketone such as 17 can be converted (Angew. Chem. Int. Ed. 2012, 51, 4112. DOI: 10.1002/anie.201200450) to products 18 by treatment with a gold/silver catalyst mixture, as shown by Zhongwen Wang at Nankai University. Notably, the oxabicyclic ring structure contained within 18 is present in a diversity of natural product structures. Endoperoxides represent another intriguing naturally occurring motif often associated with useful biological activity. Tehshik P. Yoon at the University of Wisconsin at Madison has found (Org. Lett. 2012, 14, 1640. DOI: 10.1021/ol300428q) that six-membered endoperoxides such as 20 can be efficiently prepared by a ruthenium photocatalyst under visible light irradiation. This catalyst is significantly more effective than the organic photosensitizers traditionally used for such processes.

John Montgomery at the University of Michigan has reported (Chem. Sci. 2012, 3, 892. DOI: 10.1039/C2SC00866A) that the nickel-catalyzed reductive cyclization of alkynyl ketone 23 can be regiochemically controlled by the choice of carbene ligand. Use of the IMes ligand 22 results in production of the 12-membered macrolide 21, which corresponds to the naturally occurring 10-deoxymethynolide. Alternatively, use of the ligand 24 results in a complete regiochemical reversal, leading to the 11-membered ring 25 as a single diastereomer.

The first enantioselective total synthesis of the epidithiodiketopiperazine natural product (-)-acetylaranotin has been achieved (J. Am. Chem. Soc. 2012, 134, 1930. DOI: 10.1021/ja209354e) by Sarah E. Reisman at the California Institute of Technology. Two notable challenges presented by acetylaranotin include how to prepare the complex dihydrooxepine rings and how to construct the dithiodiketopiperazine core under conditions that leave the dihydrooxepines intact. To set the absolute configuration, an enantioselective azomethine ylide cycloaddition between acrylate 26 and imine 27 delivered the pyrrolidine 28. After conversion to intermediate 29, the key dihydrooxepine ring was constructed by a metal-catalyzed heterocycloisomerization to produce 30, followed by chloride elimination. Orthogonal deprotection provided access to amine 31 and acid 32, which were successfully coupled and converted to the natural product. The use of basic conditions (not shown) to install the dithio functionality was key to maintaining the integrity of the dihydrooxepine rings.

T. H. Lambert, Org. Chem. Highlights 2013, January 14.