The first transannular [4+3] cycloaddition reaction: synthesis of the ABCD ring structure of cortistatins

Abstract

A 14-membered macrocycle with an allene and a furan strategically located at across the ring from each other is synthesized using an allene ring closing metathesis reaction. Upon treatment of the macrocycle with a catalytic amount of Pd(OAc) 2 and other additives, the first transannular [4+3] cycloaddition occurred to yield 37% of a tetracyclic compound containing the ABC ring structure of the natural products cortistatins.Carbocyclic seven-membered rings appear in a variety of natural products and have provided a strong impetus for the development of new synthetic methodology. The potent cytostatic natural product cortistatin A, which contains a center oxabicyclo[3.2.1] octene ring system (Scheme 1), further underscores the significance of the development of synthetic methodologies in this area. The intermolecular version of the [4+3] cycloaddition reaction has been widely investigated for over three decades. [1][2][3] The intramolecular versions of [4+3] cycloadditions have also been investigated although not as widely as its intermolecular counterpart. [4][5][6] To the best of our knowledge, unlike the Diels-Alder reaction, 7-9 the transannular [4+3] cycloaddition variant has not been reported. In this communication, we report our successful implementation of the first transannular [4+3] cycloaddition reaction to the synthesis of the ABCD ring carbon frame of the cortistatins.The cortistatins contain a central oxabicyclo[3.2.1]-octene ring system. The first synthesis of cortistatin A was recently reported starting from a steroid precursor, prednisone. 10 Our retrosynthetic analysis in Scheme 1 indicates that a transannular [4+3] cycloaddition should provide an efficient synthetic route to the polycyclic structure frame of cortistatins by forming four rings in one transformation.In order to verify the feasibility of the transannular approach, our plan is to first synthesize a simple macrocycle containing both a furan moiety and an oxy-allyl cation precursor function. Common functional groups for generating oxyallyl cations are α-halogenated ketones. 1,2,4 However, at least one example was reported in which an allene oxide functional group was implicated in a [4+3] cycloaddition reaction. 11 In addition, nitrogen-stabilized oxyallyl cations can be generated in situ via epoxidations of allenamides, which can undergo inter-and intramolecular [4+3] cycloadditions with dienes. [12][13][14] Considering the advances in the chemistry of ring closing metathesis (RCM), 15,16 and a report from Janssen and Krause on © 2008 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: +0-513-529-2825; fax: +0-513-529-5715; e-mail: gungbw@muohio.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the produc...

Gold-catalyzed intermolecular [4C+3C] cycloaddition reactions

“…Our initial attempt to construct the tetracyclic ring system using a transannular [4C+3C] cycloaddition strategy was met with mixed results 3,4. In the same time, Mascarenas and co-workers reported an intramolecular [4C+3C] cycloaddition reaction, in which an allene functional group was selectively activated by Pt or Au catalyst 5.…”

Gold‐Catalyzed Transannular [4+3] Cycloaddition Reactions

“…The known mono-substituted furans 11a,b [9] were converted to the disubstituted furans 12a,b by alkylation of 1,4-dibromobutane with the lithiated furan followed by alkynylation of the resulting bromide. Removal of the tetrahydropyranyl ether protecting group from 12 followed by PCC oxidation provided the aldehyde 13 .…”

“…[9] It should be noted that the quality of the reagent CrCl 2 is very important to obtain a high yield of the macrocyclization products because an old bottle of CrCl 2 gave consistently lower yields of the macrocycle.…”

“…[9] The experiments were partially successful, DMDO oxidized the furan ring and afforded the diketone 4 in 83% yield, but a 37% yield of a tetracyclic product ( 5 ) was isolated when compound 3 was treated with a mixture of Pd(OAc) 2 , LiBr, and Cu(OAc) 2 , a catalytic system developed by Backvall. [10] The low yield of 5 prompted us to continue searching for a more efficient initiator for the transannular [4+3] cycloaddition reaction.…”

A Hypervalent Iodine-Induced Double Annulation Enables a Concise Synthesis of the Pentacyclic Core Structure of the Cortistatins

“…The rigid core framework of the cortistatins, with its seven-membered B ring and challenging tetrahydrofuran heterocycle, has inspired a growing number of creative undertakings in the area of chemical synthesis. The laboratories of Baran, 5 Nicolaou and Chen, 6 and Shair 7 have achieved impressive syntheses of the full structure of cortistatin A ( 1 ), while the groups of Sarpong, 8 Hirama, 9 Danishefsky, 10 Gung, 11 Yang, 12 Kobayashi, 13 and Magnus 14 have described conceptually interesting approaches to key elements of the cortistatin structure. Our laboratory was also drawn to the problem of synthesizing the polycyclic ring system that distinguishes the cortistatin class.…”