Epoxidation of bromoallenes connects red algae metabolites by an intersecting bromoallene oxide – Favorskii manifold †

DMDO epoxidation of bromoallenes gives directly a , b -unsaturated carboxylic acids under the reaction conditions. Calculated ( x B97XD/ 6-311G(d,p)/SCRF = acetone) potential energy surfaces and 2 H- and 13 C-labeling experiments are consistent with bromoallene oxide intermediates which spontaneously rearrange via a bromocyclopropanone in an intersecting bromoallene oxide – Favorskii manifold.

The remarkably wide structural diversity and complexity of halogenated C 15 acetogenin metabolites isolated from marine red algae of Laurencia species 1 continue to stimulate innovative efforts in their target synthesis, 2 in the discovery of new synthetic transformations 3 and in advancing biosynthetic hypotheses. 4 A recent re-isolation 5 of obtusallene IV (1) 6 from Laurencia marilzae provided also 12-epoxyobtusallene IV (2) and unnamed a,bunsaturated carboxylate ester (3) with an identical macrocycle to epoxybromoallene 2 (Fig. 1). It seems reasonable to connect E-alkene 1 and trans-epoxide 2 biogenetically via enzymatic epoxidation, 7 and on the basis of their co-isolation, we propose that bromoallene 2 and a,b-unsaturated carboxylate 3 may also be connected biogenetically by epoxidation.
While the epoxidation of allenes 8,9 and vinyl bromides 10 has been studied, the epoxidation of bromoallenes has not been reported. 11 Herein, we report the hitherto unknown direct conversion of bromoallenes to a,b-unsaturated carboxylic acids via an initial epoxidation event and the presumed intermediacy of a bromoallene oxide. We also show by computational modeling and 2 H-and 13 C-labeling studies that the latter's spontaneous reorganization to an a,b-unsaturated carboxylic acid under the reaction conditions is consistent with a bromocyclopropanone intermediate in an intersecting allene oxide -Favorskii manifold.
Bromoallene 4 12 was selected as a suitable substrate for investigating epoxidation and was synthesized by a standard sequence from heptanal (ESI †). 13 Much to our delight, epoxidation of bromoallene 4 using dimethyl dioxirane (DMDO), generated either in situ 14 or as a solution (ESI †) 15 (Scheme 1), gave a mixture of Z and E-a,b-unsaturated carboxylic acids 5 directly in low but reproducible yields (note §, ESI †). The low yields can be attributed to decomposition of DMDO 16a under the reaction conditions to methyl radicals, 16b and subsequent radical attack on either of the products or starting materials (note ¶, ESI †).
Mechanistically, we invoke the following pathway for the formation of a,b-unsaturated carboxylic acids from DMDO mediated epoxidation of bromoallenes (Fig. 2). Initial epoxidation of the bromoallene would give bromoallene oxides of the type A and/or B (note f, ESI †). Spontaneous epoxide opening 8c via bromo oxyallyl cations C and D (note † †, ESI †) respectively converge on the same bromocyclopropanone E. This intermediate now intersects with the Favorskii rearrangement manifold of a,aand a,a 0 -dibromoketones where the resulting bromocyclopropanones E are known to collapse after attack by water giving hydrate F to a,b-unsaturated carboxylic acids 5 (note **, ESI †). 17,18 Evidently, there is sufficient water in the dioxirane solution to function as a nucleophile here (note ‡ ‡, ESI †).
Interestingly, regardless of the initial site of epoxidation, this mechanism predicts that carbon atoms 1 and 2 in bromoallene 4 interchange positions in the a,b-unsaturated carboxylic acid products 5.
In conclusion we have established that the hitherto unknown direct conversion of bromoallenes to a,b-unsaturated carboxylic acids using DMDO is consistent with an initial epoxidation event (note ***, ESI †) followed by a spontaneous reorganization via a bromocyclopropanone, a mechanism supported by calculations, in an intersecting bromoallene oxide -Favorskii manifold. These experiments support the proposed biogenesis of a,b-unsaturated carboxylate 3 from bromoallene 2 by epoxidation (note ‡ ‡ ‡, ESI †).
We thank the EPSRC for DTG funding (to J. C.).