An approach towards chiral 5-hydroxyalkyl butan-4-olides: total synthesis of (-)-muricatacin and related natural products

A general approach towards synthesis of 5-hydroxyalkylbutan-4-olides from D-mannitol has been described. The approach has been used successfully for total synthesis of (-)-muricatacin, an anti-tumour natural product. Other related natural and unnatural compounds were also synthesized


Introduction
Chiral hydroxylactones occupy an important position as bio-active molecules and useful synthetic intermediates in total synthesis.One such group of hydroxylactones is 5hydroxyalkylbutan-4-olides 1.These are found widely in nature and show diverse biological properties.Some of these compounds are known to have insect antifeedant activity 1 and are cytotoxic to human tumor cells. 2 The short chain homologues are important flavor constituents in wine, sherry, and tobacco smoke. 3These are also found in microbial metabolite cultures of Erwinia quernica 4 and Streptomyces griseus. 5Many of these butanolides are often used as synthons in the synthesis of complex and biologically important natural products. 6These have been used as precursors to HIV-1 protease inhibitors. 7One such molecule that has attracted much attention since its isolation was (-)-muricatacin 1d.It was isolated from the seeds of Anona muricata L. (annonaceae), 8 commonly known as sour group or guanabana, and is grown commercially as a fruit crop throughout the tropical regions of the world.This plant, as well as others in the family of annonaceae, are a source of many annonaceous acetogenins that are known to have anti-tumor properties. 2 Both the enantiomers of 1d are found in nature.The isolated material is a mixture of the two, the (-)-(R,R)-1d being predominant (ee of ca. 25 % based on optical rotation).It is shown to be cytotoxic towards human tumor cells.Biological studies revealed that the length of the side chain is very crucial.Decreasing the length of the alkyl side chain led to decreased activity and increasing the chain length did not show any increase in the activity.Both (+)-and (-)-muricatacin (threo) have the same activity.0][11] Most of the known syntheses are target oriented.In this paper we describe a general approach towards hydroxy lactones from D-mannitol. 12 We have also synthesized (-)muricatacin and related natural products.

Results and Discussion
While working on total synthesis of (-)-boronolide 13 and hexadecanolide, a pheromone 14 we realized that 5-hydroxyalkylbutan-4-olides 1 type natural products can also easily be synthesized from D-mannitol.The retrosynthetic analysis for our approach is shown in Scheme 1.The γlactone unit can be constructed from the corresponding hydroxy acid, which can come from the acetonide 2. The appropriate alkyl group can be added on the aldehyde of 3 (Scheme 1).The synthesis commences with diacetonide benzyl ether 5, which was subjected to selective hydrolysis using acetyl chloride in MeOH at 0 °C to give a diol 6 in 88 % yield. 15The diol 6 was subjected to oxidative cleavage using LTA in CH 2 Cl 2 and the crude aldehyde was reduced with NaBH 4 to provide the alcohol 7. The alcohol was then tosylated, and the crude tosylate was reduced with NaBH 4 in DMSO to give 8, whose acetonide group was cleaved using trifluoroacetic acid in THF-water mixture (4:1).The diol 9, thus obtained, was cleaved to aldehyde by using LTA.The aldehyde, without any purification, was subjected to Wittig olefination reaction with (benzyloxycarbonylmethylene)triphenylphosphorane to obtain α,βunsaturated ester 10, which was converted into the target compound 1a by hydrogenation over Pd/C followed by treatment of the resulting crude hydroxy acid with p-TsOH (Scheme 2).We extended the above approach to compounds with different alkyl groups in the side chain.For alkyl groups other than methyl, the scheme was modified.The aldehyde, obtained from the diol 6, was treated with ylides, prepared from phosphonium salts with different alkyl groups to provide olefins 11.The acetonide group of 11 was cleaved, as described earlier.The diol 12, thus obtained, was converted into the olefinic compound 13 using the aforementioned Wittig chemistry.Conversion of 13 into target compounds such as 1b, 1c, 1d, and 1e was carried out as described for 1a.In this way, we were able to synthesize several hydroxyalkyl γlactones in ~45 % overall yield (Scheme 3).
In order to show some more versatility in our approach, we set out to synthesise some analogues having extra hydroxy groups.This was accomplished from the known diol 14, 13 which was subjected to oxidative cleavage with LTA, and the aldehyde obtained was then allowed to react with the ylide prepared from (ethoxycarbonylmethylene)triphenylphosphorane to provide α,β-unsaturated ester 15 as a mixture of cis and trans isomers (ratio 70:30).The mixture, on treatment with CuCl 2 .2H 2 O 16 gave the lactone after cleaving the acetonide group.Only the cis isomer lactonized, and the trans isomer remained unreacted.The unsaturated lactone 16 was hydrogenated to provide a saturated lactone 17 which could be an important precursor in synthesis (Scheme 4).

Conclusions
We have developed a simple and flexible strategy for the synthesis of hydroxyalkylbutan-4olides from D-mannitol.Using the above strategy, a total synthesis of (-)-muricatacin and related compounds was accomplished.

Experimental Section
General procedure for oxidative cleavage of diols (6, 9, 12, or 14) using Pb(OAc) 4  To a solution of a diol in dry CH 2 Cl 2 (5 ml/mmol), LTA (1.1 eq.) was added at 0 °C and the reaction was allowed to proceed with gradual warming to rt.After all the diol was consumed (by tlc, usually 4 h), the reaction mixture was quenched by an addition of saturated aqueous NaHCO 3 solution.The solids were removed by filtration through celite pad.The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers were washed with water and brine.The organic layer was then dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give an aldehyde in quantitative yield, which was used as such in the next step.

General procedure for the synthesis of olefins (11)
To a suspension of a Wittig salt (1.3 eq with respect to aldehyde) in anhydrous THF (5 mL /mmol) at 0 °C, n-BuLi (1.3 eq., 1.43 M in hexanes) was added under N 2 atmosphere and was stirred for 30 min at the same temperature.To the resulting orange red solution, the crude aldehyde (obtained by an oxidative cleavage of the diol 6) in anhydrous THF (1 ml/mmol) was added slowly over a period of 10 min.The reaction mixture was stirred for 6 h with gradual warming to rt.All the solids were removed by filtration and the organic layer was concentrated and chromatographed over silica gel to give the olefins as a mixture of cis-trans isomers.

General procedure for cleavage of acetonide (8 or 11) with TFA
To a solution of acetonide (8 or 11) in THF and water (4:1) was treated with trifluoroacetic acid (1.5 equivalent) at 65 °C.After all the starting material was consumed (by tlc, usually 6 h), THF was removed in vacuo and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with saturated aqueous NaHCO 3 solution, water, and brine.The organic layer was finally dried over anhydrous Na 2 SO 4 , concentrated in vacuo and chromatographed over silica gel to give the diol 9 or 12.

General procedure for synthesis of α,β-unsaturated esters (10 or 13)
To a suspension of a Wittig salt (1.3 eq. with respect to a diol, obtained by treatment of benzyl bromoacetate with triphenylphosphine) in anhydrous THF (5 mL/mmol) at 0 °C was added n-BuLi (1.3 eq. with respect to diol) under N 2 atmosphere and stirred for 30 min.To this clear solution was added the crude aldehyde (obtained by oxidative cleavage of the corresponding diol) in anhydrous THF (1 ml/mmol) and stirred over night with gradual warming to rt.THF was removed in vacuo and the residue was chromatographed over silica gel to give the α,βunsaturated esters.The α,β-unsaturated ester was subjected to lactonization without purification and characterization.

General procedure for the synthesis of lactones (1)
The α,β-unsaturated ester (10 or 13) was dissolved in EtOH ( 3mL/mmol) and 50 -60 mg of 10 % Pd on activated charcoal was added to it.The flask was evacuated and purged with H 2 gas and the reaction was allowed to proceed for 12 h at rt under a balloon filled with H 2 gas.The reaction mixture was filtered through celite, washed with little EtOH, and concentrated in vacuo.
The residue was taken in benzene (5 ml/mmol) and 5 -10 mg of p-TSA was added and refluxed for 1 h.It was diluted with EtOAc and washed successively with water and brine.Finally the organic layer was dried over Na 2 SO 4 , concentrated and chromatographed over silica gel to give the lactone.

2,3-Bis-benzyloxy-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propan-1-ol (7).
The crude aldehyde obtained by oxidative cleavage of the diol 6 (1 g, 2.48 mmol) was taken in dry EtOH and cooled to 0 °C.To this cooled solution, NaBH 4 (142 mg, 3.74 mmol) was added and stirred for 1 h.The reaction mixture was quenched by an addition of saturated NH 4 Cl and EtOH was removed in vacuo.The aqueous layer was extracted with EtOAc, the combined organic layer was washed with water and brine.The organic layer was finally dried over Na 2 SO 4 , concentrated in vacuo and the residue was chromatographed over silica gel to give an alcohol 7 as a colorless oil; Yield 920 mg (99 %), R f 0.28 (20 % EtOAc in petroleum ether); 1