A stereoselective synthesis of (+)-boronolide

Abstract

A stereoselective synthesis of (+)-boronolide is described. The key steps involve a stereoselective reduction of an α-hydroxy ketone, allylation of an α-hydroxy aldehyde and a ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester utilizing Grubbs’ catalyst.

The bark and branches of Tetradenia fruticosa and the leaves of Tetradenia barberae are traditional folk medicines in Madagascar and Southern Africa.¹ The active principle, boronolide (1), an α-pyrone derivative containing a polyacetoxylated side chain, has been isolated from these species since 1971.^1a,b The deacetylated boronolide (2) and 1^’,2^’-dideacetylated boronolide (3) have also been isolated from Iboza riparia, a central-African species ubiquitously used in tribal medicine.² The root extract of these plants is traditionally used by the Zulu as an emetic agent and is known to be effective against malaria.^1c The absolute configuration of (+)-boronolide was determined through X-ray crystallographic analysis and chemical degradation.^1b,3b

The biological properties of boronolide and its deacetylated derivatives have fostered significant interest in their synthesis. Three total syntheses of boronolide have now been reported in the literature.^4–6 The first synthesis was carried out in racemic form utilizing acrolein dimer as the starting material.⁴ The synthesis by Nagano and co-workers utilized the chiral centers of D-glucose.⁵ The recent synthesis by Honda et al. utilized Sharpless dihydroxylation as the key steps, however, the synthesis lacks stereochemical control.⁶ Herein we report an asymmetric synthesis of (+)-boronolide from diethyl D-tartrate. The key steps involve a stereoselective allylation of an α-hydroxy aldehyde, asymmetric reduction of an α-hydroxy ketone and ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester utilizing Grubbs’ catalyst.⁷

A key structural feature of (+)-boronolide is the presence of a substituted α,β-unsaturated δ-lactone moiety. As shown in Fig. 1, we planned to construct this unsaturated lactone unit by a ring-closing olefin metathesis of the acrylate ester 4. The syntheses of such α,β-unsaturated γ- and δ-lactones have been recently developed by both Nicolaou and us.⁸ Stereoselective synthesis of the acrylate ester 4 would be achieved from the key starting material, 1-O-benzyl-2,3-O-isopropylidene-D-threitol derivative 5. Preparation of 5 in multigram quantities was carried out from diethyl-D-tartrate utilizing the protocol described by Seebach et al.⁹

Fig. 1.

Isopropylidene derivative 5 was first converted to Weinreb amide 6 (Scheme 1). Thus, oxidation of alcohol 5 by Jones’ reagent in aqueous acetone at 0°C afforded the corresponding carboxylic acid in 68% yield.¹⁰ The resulting carboxylic acid was then converted into the Weinreb amide 6 by treatment with isobutyl chloroformate and N-methylpiperidine in a mixture (10:1) of CH₂Cl₂ and THF followed by subsequent treatment of the reaction mixture with N-methoxy-N-methylamine and N-methylpiperidine in CH₂Cl₂.¹¹ Weinreb amide 6 was isolated in 83% yield after silica gel chromatography. To install the butyl side chain of (+)-boronolide, Weinreb amide 6 was treated with butylmagnesium bromide in THF at −20°C to afford the ketone 7 in 96% yield. Reduction of the ketone 7 by L-selectride in THF at −78°C provided the (S)-alcohol 8 stereoselectively (12:1 by 500 MHz ¹H NMR and ¹³C NMR analysis) in near quantitative yield.¹² Alternatively, Swern oxidation of 5 followed by the treatment of the resulting aldehyde with nBuLi in THF at −78°C, afforded the (S)-alcohol 8 and its epimer as a 1:1 mixture in 80% yield. Of particular interest, the reaction of the above aldehyde with nBuLi in the presence of ZnBr₂ has been shown to provide the corresponding (R)-carbinol selectively.¹³ The (S)-alcohol 8 so obtained from the L-selectride reduction, was reacted with acetic anhydride in the presence of triethylamine and a catalytic amount of DMAP in CH₂Cl₂ to furnish the acetate derivative 9 in 98% yield.

Scheme 1.

(a) CrO₃, H₂SO₄, Me₂CO–H₂O, 0°C (68%); (b) Me₂CHCH₂OCOCl, N-methylpiperidine, CH₂Cl₂–THF (10:1); (MeO)NHMe·HCl, N-methylpiperidine, CH₂Cl₂ (83%); (c) CH₃(CH₂)₃MgBr, THF, −20°C (96%); (d) L-selectride, THF, −78°C (99%); (e) Ac₂O, Et₃N, DMAP (cat), CH₂Cl₂ (98%); (f) H₂, Pd(OH)₂ (cat), EtOAc–MeOH (4:1), (quant.); (g) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, −78°C; (h) allylmagnesium bromide, ZnCl₂, THF, −78°C (53% from 8)

For conversion of 9 to aldehyde 10, the benzyl protecting group was removed by a catalytic hydrogenation of 9 with Pearlman’s catalyst (Pd(OH)₂) in a mixture of ethyl acetate and methanol (4:1) under a hydrogen filled balloon at 23°C for 12 h. Swern oxidation of the resulting alcohol provided the aldehyde 10. The elaboration of the α-pyrone unit with appropriate stereochemistry of (+)-boronolide then required the stereoselective allylation of 10. Thus, attempted allylation of 10 with allyltrimethylsilane in CH₂Cl₂ in the presence of TiCl₄ at −78°C provided the homoallylic alcohol 11 selectively (selectivity ratio 4:1 by 500 MHz ¹H NMR) however, the reaction was sluggish and the conversion was poor (30–35%). The reaction with allyltributyltin in the presence of SnCl₄ at −78°C has also resulted (4:1 mixture of alcohol 11 and 12) in comparable diastereoselectivities and conversion. The best result was obtained when the allylation of 10 was carried out with diallyl zinc at −78°C utilizing Kishi’s protocol.¹⁴ Thus, ZnCl₂ (7.2 equiv., 1 M solution in Et₂O, Aldrich) was added to allylmagnesium bromide (5 equiv., 1 M solution in Et₂O, Aldrich) in THF at 0°C and the mixture was stirred for 30 min, warmed to 23°C and stirred for an additional 1 h. The resulting diallyl zinc was cooled to −78°C and the aldehyde 10 in THF was added dropwise over a period of 3 min. The mixture was stirred at −78°C for 12 h and quenched with water followed by standard work up to furnish the homoallylic alcohol 11 stereoselectively (isomer ratio 5:1) in 53% yield (from 8). The isomers were separated by silica gel chromatography to provide diastereomerically pure 11.

The alcohol 11 was converted to its acrylate ester 13, the RCM precursor. Acryloyl chloride followed by triethylamine were added dropwise to alcohol 11 in CH₂Cl₂ at 0°C. The mixture was warmed to 23°C for 30 min to furnish the ester 13 in 80% isolated yield. Olefin metathesis of 13 with commercially available Grubbs’ catalyst (10 mol%) in the presence of Ti(OⁱPr)₄ (30 mol%) in refluxing CH₂Cl₂ (0.007 M solution) for 12 h, afforded the α,β-unsaturated-δ-lactone 14 in 84% yield after silica gel chromatography (Scheme 2).¹⁵ In the absence of Ti(OⁱPr)_4, the reaction was substantially slower (50% conversion after 12 h).^8b To complete the synthesis, the removal of the isopropylidene group was effected by exposure to Dowex 50 W-X8 (H⁺) resin in H₂O at 70°C for 3 h. The resulting crude mixture was treated with acetic anhydride and triethylamine in CH₂Cl₂ in the presence of a catalytic amount of DMAP at 0°C for 30 min to furnish the synthetic (+)-boronolide 1, [α]_D²³ +25 c 0.2, EtOH; lit.^1b [α]_D²³ +28 c 0.08, EtOH. Spectral data (IR and 500 MHz ¹H NMR) for the synthetic boronolide is identical to that reported for the natural product.¹

Scheme 2.

(a) CH₂=CHCOCl, Et₃N, 0°C to 23°C, CH₂Cl₂ (80%); (b) Cl₂(PCy₃)₂Ru_CHPh (10 mol%), Ti(OⁱPr)₄ (30 mol%), CH₂Cl₂, 40°C (84%); (c) Dowex 50 W-X8 (H⁺), H₂O, 70°C; (d) Ac₂O, Et₃N, DMAP (cat), CH₂Cl₂, 0°C (quant.)

In conclusion, (+)-boronolide has been synthesized in a diastereoselective manner in 19% overall yield from the known isopropylidene derivative 5.⁹ The present synthetic route can easily be amenable to generate the other stereoisomers and structural variants of boronolide. Stereoselective reduction of an α-hydroxy ketone, allylation as well as the efficient construction of unsaturated lactones by olefin metathesis are particularly noteworthy.