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

Abstract

DMDO epoxidation of bromoallenes gives directly α,β-unsaturated carboxylic acids under the reaction conditions. Calculated (ωB97XD/6-311G(d,p)/SCRF = acetone) potential energy surfaces and ²H- and ¹³C-labeling experiments are consistent with bromoallene oxide intermediates which spontaneously rearrange via a bromocyclopropanone in an intersecting bromoallene oxide – Favorskii manifold.

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The remarkably wide structural diversity and complexity of halogenated C₁₅ acetogenin metabolites isolated from marine red algae of Laurencia species¹ continue to stimulate innovative efforts in their target synthesis,² in the discovery of new synthetic transformations³ and in advancing biosynthetic hypotheses.⁴ A recent re-isolation⁵ of obtusallene IV (1)⁶ from Laurencia marilzae provided also 12-epoxyobtusallene IV (2) and unnamed α,β-unsaturated 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 α,β-unsaturated carboxylate 3 may also be connected biogenetically by epoxidation.

Fig. 1 Metabolites 1–3 from Laurencia marilzae and proposed biogenesis via epoxidation events.

While the epoxidation of allenes^8,9 and vinyl bromides¹⁰ has been studied, the epoxidation of bromoallenes has not been reported.¹¹ Herein, we report the hitherto unknown direct conversion of bromoallenes to α,β-unsaturated carboxylic acids via an initial epoxidation event and the presumed intermediacy of a bromoallene oxide. We also show by computational modeling and ²H- and ¹³C-labeling studies that the latter's spontaneous reorganization to an α,β-unsaturated carboxylic acid under the reaction conditions is consistent with a bromocyclopropanone intermediate in an intersecting allene oxide – Favorskii manifold.

Bromoallene 4¹² 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 situ¹⁴ or as a solution (ESI†)¹⁵ (Scheme 1), gave a mixture of Z and E-α,β-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†).

Scheme 1 Epoxidation of bromoallene 4 using DMDO solution.

Mechanistically, we invoke the following pathway for the formation of α,β-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 ¥, ESI†). Spontaneous epoxide opening^8cvia 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 α,α- and α,α′-dibromoketones where the resulting bromocyclopropanones E are known to collapse after attack by water giving hydrate F to α,β-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 α,β-unsaturated carboxylic acid products 5.

Fig. 2 Mechanistic rationale for conversion of bromoallenes into α,β-unsaturated carboxylic acids, with the carbon atoms of the functional groups numbered 1–3 showing an interchange of carbon atoms 1 and 2 (see also interactive Fig. 2 in HTML version of this article).

This mechanism can be subjected to scrutiny via density functional level (ωB97XD/6-311G(d,p)/SCRF = acetone)¹⁹ exploration of the potential energy surface (R = H, Me, presented as an interactive version of Fig. 2 (ref. 20) via a digital data repository²¹). Oxygen transfer from dimethyldioxirane to form both A and B (TS1) have thermally accessible free energy activation barriers (R = H, 26.8 for A, 27.3 for B; R = Me, 26.8 for A, 24.6 kcal mol⁻¹ for B), followed by a second, lower energy dyotropic rearrangement (TS2) to give E. An intrinsic reaction coordinate (IRC) reveals that TS2 (R = H,Me) represents the concerted transformation of A or B to E, with C/D acting as “hidden intermediates” in the process.²² Such hidden intermediates can be potentially transformed to real ones by tuning the substituents, and in this instance changing R from H or Me to OMe is predicted to accomplish this by stabilization of C/D (see interactive Fig. 2). TS2 itself (R = Me) has some early character of C/D; the C–Br bond is calculated to initially contract in length due to a significant stabilising resonance contribution of Br lone pairs, from 1.924/1.896 Å (A and B respectively) via 1.840/1.885 (TS2), 1.856/1.868 (C/D acting as hidden intermediates) to 1.921/1.922 Å (E).²³ Calculations having demonstrated the thermal accessibility of the epoxidation-bromocyclopropanone sequence, ²H- and ¹³C-labeling experiments were necessary to verify the overall reorganization (4 to A/B to E to F to 5, Fig. 2) of the carbon framework.²⁴

Deuterated bromoallene (1-²H)-4 was prepared by addition of ethynylmagnesium bromide to heptanal, in situ deprotonation of the propargylic alkoxide with n-butyllithium and quenching with MeOH-d₄ to give labeled propargylic alcohol (1-²H)-6 (Scheme 2). Subsequent alcohol trisylation²⁵ gave (1-²H)-7, and S_N2′ displacement of the trisylate with bromide under the action of LiCuBr₂ (ref. 26) provided bromoallene (1-²H)-4 with 70% deuterium incorporation at the 1-position.†

Scheme 2 Synthesis of deuterated bromoallene (1-²H)-4.

¹³C-labeled bromoallene (1-¹³C)-4 was similarly targeted, commencing with silyl enol ether 8 formation²⁷ from octanal (Scheme 3). Oxidation using mCPBA gave interrupted Rubottom²⁸ adduct 9, which could be acetylated to give acetate 10. Desilylation using buffered TBAF²⁹ revealed protected α-hydroxyaldehyde 11, which we planned to use in a Wittig reaction with a suitably ¹³C-labeled phosphorous ylid. To the best of our knowledge, there is only a single report³⁰ using methyltriphenylphosphonium iodide to generate the Stork–Wittig reagent³¹ using an in situ deprotonation–iodination–deprotonation procedure which we adapted using ¹³C-labeled salt 12 – available from relatively inexpensive 99% atom ¹³C-labeled methyl iodide – to give vinyl iodides Z-(1-¹³C)-13, E-(1-¹³C)-13 and diiodide (1-¹³C)-14.³² Acetate deprotection as a mixture gave the corresponding alcohols Z-(1-¹³C)-15, E-(1-¹³C)-15 and (1-¹³C)-16 all with 99% ¹³C at the alkene terminus.†

Scheme 3 Synthesis of ¹³C-labeled bromoallene (1-¹³C)-4.

Dehydrohalogenation of Z- and E-iodides (1-¹³C)-15 in the presence of inseparable diiodide (1-¹³C)-16 with LDA gave propargylic alcohol (1-¹³C)-7 in good overall yield, with the unprecedented observation that LDA converts vinyl 1,1-diiodides into terminal alkynes also (note §§, ESI†). Interestingly, 4% of the alkyne product was found to be the 2-¹³C isotopomer (ESI†), implicating a 1,1-elimination reaction pathway for diiodide 16 and competitive alkyl group migration from a vinylidene intermediate (note ¶¶, ESI†). Alcohol (1-¹³C)-7 was then converted to the desired bromoallene (1-¹³C)-7 (as 4% of its 2-¹³C-isotopomer, ESI†) as previously described (cf., Scheme 2).

With (1-²H)-4 and (1-¹³C)-4 in hand, epoxidation with DMDO was conducted. For deuterated (1-²H)-4, after the reaction was conducted in the usual manner (cf., Scheme 1), E-(2-²H)-5 and Z-(2-²H)-5 were isolated each showing 65% deuteration at the α-position only (note ‡, ¥¥, ESI†). Evidently, this result is consistent with the proposed mechanism (cf., Fig. 2) (note †††, ESI†). More compellingly, epoxidation of bromoallene (1-¹³C)-4 gave (E-2-¹³C)-5³³ and (Z-2-¹³C)-5 (28% isolated yield) where carbon atoms 1 and 2 from the bromoallene have entirely interchanged positions, giving also 4% of each of the (E-1-¹³C)-5 and (Z-1-¹³C)-5 isotopomers (ESI†). The expected ¹J_CH coupling constants experienced by the α-vinyl protons of the major isotopomers are clearly apparent in their ¹H NMR spectra (Fig. 3).

Fig. 3 ¹H NMR spectra of (a) (E-2-¹³C)-5 and (b) (Z-2-¹³C)-5 displaying the expected ¹J_CH values for the α-vinyl protons.

In conclusion we have established that the hitherto unknown direct conversion of bromoallenes to α,β-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 α,β-unsaturated carboxylate 3 from bromoallene 2 by epoxidation (note ‡‡‡, ESI†).

We thank the EPSRC for DTG funding (to J. C.).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Notes §, ¶, ¥, ††, **, ‡‡, §§, ¶¶, ¥¥, †††, ***, ‡‡‡; general experimental; experimental details and characterising data for compounds leading to bromoallenes 4 (including ESI Scheme S1 for the synthesis of bromoallenes 4), (1-²H)-4 and (1-¹³C-4) and epoxidation thereof leading to E- and Z-5, (E-2-²H)- and (Z-2-²H)-5, and (E-2-¹³C)- and (Z-2-¹³C)-5; Copies of ¹H and ¹³C spectra for all compounds showing ²H and ¹³C isotopic shifts and coupling constants where appropriate; ESI references. See DOI: 10.1039/c3cc46720a

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