Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid, perophoramidine

Abstract

The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ethercontaining precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred.

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

“…A related highly conjugated fused cyclohexanone underwent highly stereoselective additions with all organometallic reagents, including allylmagnesium halides (Scheme ). This stereoselectivity can be attributed to the steric congestion at the carbonyl group so that additions of allylmagnesium reagents are unlikely to occur at rates approaching the diffusion rate limit. Attack from the more accessible face of the ketone, as illustrated in transition state 629 , would lead to the observed product.…”

Synthesis of Indoloquinolines: An Intramolecular Cyclization Leading to Advanced Perophoramidine-Relevant Intermediates

“…Opening of the cyclic ether in 41 proceeded smoothly with 35 being obtained in 79% yield after reaction with TiCl 4 and allyltrimethylsilane in DCM at −78 °C for 4.5 h. The presence of the halogen substituents in 35 had little effect on this robust reaction which has previously been reported to proceed in a similar manner with the non-halogenated analogue 42 to give 43 (87% yield [ 44 ]). Previous attempts to differentiate between the two allyl groups present in 43 using an iodoetherification reaction resulted in the formation of 44 , the structural assignment of which (especially the relative stereochemistry) relied heavily on X-ray crystallographic analysis [ 44 ].…”

“…Opening of the cyclic ether in 41 proceeded smoothly with 35 being obtained in 79% yield after reaction with TiCl 4 and allyltrimethylsilane in DCM at −78 °C for 4.5 h. The presence of the halogen substituents in 35 had little effect on this robust reaction which has previously been reported to proceed in a similar manner with the non-halogenated analogue 42 to give 43 (87% yield [ 44 ]). Previous attempts to differentiate between the two allyl groups present in 43 using an iodoetherification reaction resulted in the formation of 44 , the structural assignment of which (especially the relative stereochemistry) relied heavily on X-ray crystallographic analysis [ 44 ]. It was proposed that the presence of the chlorine substitutents in 35 may steer the outcome of this reaction away from that observed with 43 as a reduction in the electron density in the aryl ring due to the presence of the net deactivating chlorines would be expected to slow the proposed reaction of this ring with an intermediate iodonium ion central to the formation of 44 from 43 ( Scheme 9 and Scheme S7 ).…”

“…As conversion of 32 to 34 clearly involved loss of the crotyl group (for one possible mechanism see Scheme S6 ), it was next decided to develop the crotyl chain in 29 (or in fact the allyl chain in 27 , Scheme 8 ) by reacting the double bond. Building on an approach previously reported by us in the dehalo series [ 44 ], 35 became the new target molecule. Subsequent conversion of 35 to 36 could provide an approach to perophoramidine 1 by differentiating between the two allyl groups as seen in a related system [ 21 ].…”

Synthesis of the ABCDG ring skeleton of communesin F based on carboborylation of 1,3-diene and Bi(OTf)3-catalyzed cyclizations

“…Because of their unique structure and biological activity, many research groups have conducted synthetic studies of communesins in which various synthetic methods were developed. [9][10][11][12][13][14] The first racemic total synthesis of communesin F was achieved by Qin and co-workers based on an intramolecular cyclopropanation strategy. 15 Weinreb and Funk also reported total synthesis of communesin F, independently.…”