Synthetic Studies on Mycolactones: Synthesis of the Mycolactone Core ­Structure through Ring-Closing Olefin Metathesis

Abstract

The mycolactone core structure 2a has been prepared through ring-closing olefin metathesis from diene 3 with exquisite E selectivity. The preparation of diene 3 included a highly efficient stereoselective synthesis of carboxylic acid 5. The mycolactone core structure 2a may serve as a versatile intermediate for the ­synthesis of mycolactone and analogues thereof.

Key words

Buruli - mycolactone - ring-closing olefin metathesis - natural products - stereoselectivity - total synthesis

References and Notes

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  West African strains of M. ulcerans produce mycolactone C only as a minor metabolite.

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1

Current Address: CARBOGEN AMCIS AG, 5502 Hunzenschwil, Switzerland.

2

The term ‘mycolactone’ usually refers to the naturally occurring mixture of mycolactones A and B, which are geometric isomers at the C4′=C5′ double bond. Although both isomers can be isolated separately, each of them rapidly isomerizes to the mixture of mycolactones A and B.

23

The reaction of 14a with (+)-Ipc₂B(CH₂CH=CH₂) represents the mismatched reactant combination. The matched case [reaction of ent-14a with (+)-Ipc₂B(CH₂CH=CH₂)] has been reported by Fürstner and co-workers to produce the syn product in good yield and with excellent selectivity (see ref. 22).

25

Preparation of 16: To a solution of diene 3 (565 mg, 0.97 mmol) in CH₂Cl₂ (320 mL, 0.003 M) was added [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro(phenylmethylene)(tricyclohexylphosphine)Ru (Grubbs’ II catalyst; 42 mg, 0.075 mmol) and the mixture was heated to reflux for 4 h (with additional 21 mg of catalyst being added after 2 h). After cooling to r.t., H₂O (50 mL) was added to the reaction mixture and a part of the solvent was removed under reduced pressure. The layers were separated and the aqueous solution was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic extracts were dried over MgSO₄ and the solvent was evaporated in vacuo. Purification of the residue by flash chromatography in EtOAc-hexane (1:10) gave 16 (391 mg, 72%) as a faintly yellow, viscous oil; [α]²⁰ _D -44.0° (c = 0.61, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.3 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 4.85-4.97 (m, 2 H), 4.02-4.08 (m, 1 H), 3.80-3.86 (m, 1 H), 3.37-3.42 (m, 1 H), 2.46 (s, 3 H), 2.35-2.43 (m, 2 H), 2.00-2.11 (m, 2 H), 1.58-1.94 (m, 6 H), 1.65 (s, 3 H), 1.30-1.45 (m, 2 H), 0.90-0.99 (m, 15 H), 0.60 (q, J = 8.0 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.2, 144.8, 138.1, 132.9, 129.8, 128.0, 120.4, 77.6, 72.5, 71.6, 45.3, 37.6, 35.6, 33.5, 33.3, 31.4, 21.7, 21.6, 18.7, 15.7, 13.4, 7.0, 5.1. IR (film): 2954, 2912, 2876, 1731, 1366, 1244, 1176, 1022, 969, 815, 672 cm^{- 1}. HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₂₉H₄₈O₆SSi: 575.2833; found: 575.2827.
The assignment of the newly formed double bond as E was based on the absence of cross peaks between the C8-methyl group and C9-H in both NOESY and ROSY experiments. As expected for an E configured double bond between C8 and C9 a strong NOE cross peak was observed between C9-H and the 7-CH₂ moiety.

27

Encouraged by the efficiency and selectivity of ring closure observed with RCM substrate 3, we have also investigated triene 17 as a possible substrate for RCM-mediated formation of the 12-membered ring (Figure [3] ). However, treatment of this compound with Grubbs’ second-generation catalyst did not produce any of the desired 12-membered macrolactone. Instead, and perhaps not too surprisingly, the major product formed in the reaction appears to be cyclohexene 18 (based on MS analysis of the reaction mixture).