Proof-of-principle direct double cyclisation of a linear C₁₅-precursor to a dibrominated bicyclic medium-ring ether relevant to Laurencia species

Abstract

Bicyclic dibrominated C₁₅ medium-ring ether hexahydrolaureoxanyne was produced directly from an acyclic model C₁₅-epoxide when treated with NBS with water as the solvent.

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Since the original isolation of Laurencin (1a) in 1965,¹ marine red algae of Laurencia species have provided a wide variety of C₁₅-acetogenic halogenated diastereo- and constitutional isomeric monocyclic (C₁₅H₂₁BrO₂) and bicyclic (C₁₅H₂₀Br₂O₂) medium-ring ethers that are oxygenated at both C-6 and C-7 (Fig. 1).² Both the monocyclic and bicyclic metabolites have received considerable synthetic attention, with numerous necessarily different strategies used to forge the 7-, 8-, or 9-membered medium-ring, control the cis or trans α,α′-ether stereochemistry, install the requisite halogen(s), and – in the case of the bicyclic ethers – to fashion the second ring.^3–5 Various recent studies have also been directed at the further understanding of their biogenesis,⁶ where the early pioneering work of Murai⁷ demonstrated enzymatic bromoetherifications of straight-chain co-isolated unsaturated C₁₅-diols – laurediols (3E,6R,7R)-7a and (3Z,6S,7S)-7b⁸ – to monocyclic medium-ring ethers deacetyl laurencin 1b and prelaureatin 2 respectively, albeit in very low yields (Scheme 1, top).⁹ We have recently advanced an alternative biogenesis for the monocyclic (C₁₅H₂₁BrO₂) medium-ring ethers from Laurencia species from (6S,7R)-epoxide 8via an intramolecular bromonium ion assisted epoxide ring-opening (IBIAERO) reaction with water functioning as the external nucleophile (Scheme 1, bottom, 8→B→O/O′→1b/2), and experimentally corroborated this with a model epoxide for the concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.^10,11 The bicyclic metabolites are generally considered to originate by further bromoetherification of the residual unsaturation of the monocyclic compounds – the Z-configured medium-ring alkene or the pendant enyne – using the free alcohol of the original monocyclic compound located either at C-6 or C-7 as the nucleophile (Scheme 1, top).⁷ Several laboratory demonstrations of these later transformations have been successful, either as enzymatic-mediated bromoetherifications of naturally occurring monocycles,¹² or as part of the synthetic strategy in a total synthesis of the bicyclic natural products.¹³ Interestingly, although bromocyclisation events had been postulated for both monocycle and bicycle formation, prior to our 2012 report¹⁰ and Snyder's recent elegant work,^6b,c a non-enzymatic bromonium-ion induced cyclisation process to directly form medium-ring ether cores relevant to Laurencia species had not been reported. Moreover, to the best of our knowledge, there has been no report of a C₁₅-dibrominated bicyclic medium-ring ether relevant to Laurencia species being formed directly from a linear unsaturated C₁₅-precursor by two successive bromination events in the same pot. Herein we report on a successful strategy to effect such a transformation.

Fig. 1 Representative monocyclic and bicyclic halogenated medium-ring ethers of formulae C₁₅H₂₁BrO₂ (1b, 2) and C₁₅H₂₀Br₂O₂ (3–6) from Laurencia species that are oxygenated at C-6 and C-7. Laurencin 1a is related as the acetate of 1b.

Scheme 1 Irie–Murai biogenesis of monocyclic medium-ring ethers from laurediols 7a and 7b (top); alternative biogenesis of deacetyllaurencin 1b and prelaureatin 2via IBIAERO reaction with water functioning as the external nucleophile (bottom). The other six possible monocyclic ethers of formulae C₁₅H₂₁BrO₂ are not shown.

To investigate the proof-of-principle demonstration of a direct double cyclisation of a C₁₅ unsaturated linear precursor to a bicyclic medium-ring ether relevant to Laurencia species we targeted hexahydroepoxide (6S*,7R*)-[H₆]-8, with the aim that this would undergo an initial IBIAERO reaction via [H₆]-B where water functions as both the solvent and the nucleophile (Scheme 2). The use of water in this manner thus guarantees a free hydroxyl group for any subsequent bromoetherification reaction (e.g., [H₆]-1b→[H₆]-3, Scheme 2) with a second equivalent of an electrophilic bromine source. While we had previously demonstrated successful IBIAERO reactions in water with NBS as the electrophilic bromine source,¹¹ the attempted IBIAERO reaction of a model epoxide as a truncated C₁₂ alcohol (inset, Scheme 2) under the same conditions had failed.¹⁰‡ We considered that hexahydroepoxide [H₆]-8 offered distinct benefits compared to this earlier model and also to epoxide 8 for the proposed experiment: (i) the hydrophilic hexahydro chain may encourage folding of the substrate in water thus inherently facilitating the IBIAREO reaction; (ii) post-IBIAERO reaction, the only region of unsaturation will be located in the medium ring and – compared with the hypothetical use of the putative biosynthetic precursor itself, epoxide 8 – there can be no complicating bromoetherifications to form bromoallene adducts by cyclisation onto any C₁–C₄ enyne moiety; (iii) hexahydrobicyclic compounds of formulae C₁₅H₂₆O₂Br₂ are known in the literature as a consequence of the structural elucidation of the naturally occurring compounds via hydrogenation,¹⁴ providing data for identification of bicyclic products.

Scheme 2 Proposed proof-of-principle direct cyclisation of (6S*,7R*)-[H₆]-8 to bicyclic medium ring ethers via IBIAERO reaction and subsequent bromoetherification of the remaining unsaturation.

Accordingly, epoxide (6S*,7R*)-[H₆]-8 was synthesised from bromide 12, itself prepared from (E)-2-penten-1-ol (9) via a known sequence^10,15 with minor modifications. Subsequent copper-mediated coupling¹⁶ with hept-1-yne gave novel enediyne 13 (Scheme 3).† Chemoselective and stereoselective hydrogenation¹⁷ afforded (E,Z,Z)-doubly skipped triene 14. Epoxidation of triene 14 with DMDO¹⁸ was found to be entirely selective for the Z-olefins,¹⁹ giving a mixture of mono epoxides (6S*,7R*)-[H₆]-8 and 15 which could be separated by chromatography.§¶||

Scheme 3 Synthesis of (6S*,7R*)-[H₆]-8.

With epoxide (6S*,7R*)-[H₆]-8 in hand, it was treated with two equivalents of NBS – a water stable reagent – under high dilution conditions in water (Scheme 4).** Here, various dibromination adducts, bromohydrin regioisomers, and dibromotetrahydrofurans are expected to be formed by competing processes.¹⁰ In the event, as expected, a complex mixture was obtained that was subjected to extensive chromatography, where ‘non-polar’ components could be separated away from ‘polar’ components.†† Much to our delight, by further chromatography of the non-polar components, hexahydrolaureoxanyne [(±)-[H₆]-3]^12a was isolated as a bicyclic medium-ring ether with ¹H NMR data identical to that previously reported,†‡‡ along with dibromoepoxides 16. Thus the desired proof-of-principle has been achieved. This also constitutes the first synthetic route to the laureoxanyne bicyclic medium-ring ether scaffold, and the isolated yield of (±)-[H₆]-3 (2.5%) from (6S*,7R*)-[H₆]-8 compares well with the reported enzymatic conversion of deacetyl laurencin 1b (obtained from natural laurencin 1a) into 3 (3%).^12a

Scheme 4 Proof-of-principle direct double cyclisation of (6S*,7R*)-[H₆]-8 into (±)-[H₆]-3via IBIAERO reaction and subsequent bromoetherification of the remaining unsaturation (cf., Scheme 2).

In conclusion, we have demonstrated the proof-of-principle direct cyclisation of a linear unsaturated C₁₅-precursor into a C₁₅-dibrominated bicyclic medium-ring ether relevant to Laurencia species – where hexahydrolaureoxanyne (±)-[H₆]-3 has an identical bicyclic medium ring ether framework to laureoxanyne 3 – by two successive bromination events in the same pot. These studies are also consistent with epoxide (6S,7R)-8 acting as the biogenetic precursor¹⁰ for bromocyclisation to bicyclic medium-ring ethers of Laurencia species via IBIAERO reactions followed by subsequent bromoetherification events.

We thank the Dinu Patriciu Foundation for funding (to D.-T. S.).

Notes and references

1. (a) T. Irie, M. Suzuki and T. Masamune, Tetrahedron Lett., 1965, 16, 1091–1099; (b) T. Irie, M. Suzuki and T. Masumune, Tetrahedron, 1968, 24, 4193–4205.
2. For comprehensive reviews see: (a) B.-G. Wang, J. B. Gloer, N.-Y. Ji and J.-C. Zhao, Chem. Rev., 2013, 113, 3632–3685; (b) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro and M. R. Prinsep, Nat. Prod. Rep., 2014, 31, 160–258 and earlier reviews in this series.
3. For a comprehensive review of the synthesis of medium-ring ethers from Laurencia sp., see: K. Fujiwara, Top. Heterocycl. Chem., 2006, 5, 97–148 . See also ref. 2a.
4. For recent leading syntheses of C₁₅Laurencia metabolites see: (a) G. Kim, T.-i. Sohn, D. Kim and R. S. Paton, Angew. Chem., 2014, 126, 276–280; (b) C. Recsei, B. Chan and C. S. P. McErlean, J. Org. Chem., 2014, 79, 880–887; (c) J. Rodríguez-López, N. Ortega, V. S. Martín and T. Martín, Chem. Commun., 2014, 50, 3685–3688; (d) M. T. Holmes and R. Britton, Chem. – Eur. J., 2013, 19, 12649–12652; (e) D. J. Shepherd, P. A. Broadwith, B. S. Dyson, R. S. Paton and J. W. Burton, Chem. – Eur. J., 2013, 19, 12644–12648; (f) B. S. Dyson, J. W. Burton, T.-i. Sohn, B. Kim, H. Bae and D. Kim, J. Am. Chem. Soc., 2012, 134, 11781–11790; (g) M. J. Kim, T.-i. Sohn, D. Kim and R. S. Paton, J. Am. Chem. Soc., 2012, 134, 20178–20188 and references cited therein.
5. For two recent accounts of research in the arena see: (a) T. Martín, J. I. Padrón and V. S. Martín, Synlett, 2014, 12–32; (b) D. Kim, Synlett, 2014, 33–57.
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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterising data and ¹H and ¹³C NMR spectra for all compounds; a comparison of ¹H NMR data for (±)-[H₆]-3 with the literature data. See DOI: 10.1039/c4cc06402j

‡ We speculate that the truncated C₁₂ epoxide suffers from an intramolecular hydrogen bond from the alcohol functional group reducing its nucleophilicity.

§ 25% of a bis-epoxide was also observed.

¶ Attempted epoxidation of 14 with mCPBA was unselective for the Z-olefins.

|| ¹H-¹³C and ¹H-¹H NMR correlation spectroscopy were used to distinguish between epoxides (6S*,7R*)-[H₆]-8 and 15.†

** In an experiment with 1 equivalent of NBS in water, (±)-[H₆]-3 was isolated in 1.8% yield after extensive chromatography.

†† The ‘polar’ components were expected to contain regioisomeric bromohydrins and dibromohydrins by reference to our earlier work (ref. 10) and were not further characterised.

‡‡ The medium-ring bicyclic structure of [H₆]-3 is also supported by a characteristic NOESY cross-peak between H₇ and H₉ as previously reported (as an nOe) for 3 (ref. 12a).†

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