An efficient stereoselective total synthesis of 11 β -methoxycurvularin

A very short and efficient stereoselective total synthesis of a macrocyclic ketone, 11 β -methoxy- curvularin was achieved by employing the Sharpless asymmetric epoxidation, formation of propargyl alcohols from an epoxy-chloride, and intramolecular Friedel-Crafts acylation as the


Introduction
11β-Methoxycurvularin (5) was first isolated from the mycelium of hybrid strain ME-005 which is a polyketide metabolite of various Curvularia, Pencillium, Alternaria, and Cochiobolous species.It was found to exhibit cytotoxicity 1 and antimicrobial activities 2.3 against four types of human cancer cell lines such as [NCI-H460, MCF-7, SF-268, 41A Pa Ca-2]. 4 It also shows some effect in the spindle formation of embryos of sea urchin cells to give barrel like spindles and terminate the first step of cell division, which is a promising tool for anticancer drug discovery.Furthermore, it also shows binding affinity with tubulins. 5 Structurally, 11β-methoxycurvularin shows different configuration at C-11 in the 12membered lactone ring.The first total synthesis of these natural products has been reported by Liang et al. 6 which led to a revision of the spectroscopic data of the originally proposed structures (4 and 5).We herein report a new synthetic route tor the stereoselective total synthesis of 11(β)methoxycurvularin.Our approach utilizes mainly the Sharpless asymmetric epoxidation to introduce absolute stereocentre at C-11 for the construction of the key fragment 8, which in turn comes from a commercially available homopropargyl alcohol 12.
Accordingly, the aromatic portion was expected to arise from the readily available 3,5dimethoxyphenylacetic acid 7. 7,8 Retrosynthesis of the 12-membered lactone ring 5 led to a known compound 6 along with the key fragment 8, which in turn could be prepared from 9 and 10 in 65% yield.The fragment 9 was synthesized from homopropargyl alcohol 12 in seven steps.Thus treatment of homopropargyl alcohol 12 with BnBr in the presence of NaH 9,10 gave the benzyl ether 13 (Scheme 2) which upon reaction with paraformaldehyde in the presence of magnesium turnings and ethyl bromide gave the alcohol 14 in 72% yield.Reduction of 14 with LAH furnished an allyl alcohol 15, which was then subjected to the Sharpless asymmetric epoxidation 11,12 by using titanium isopropoxide, L(+)-DIPT, 4.5 M TBHP to afford the epoxide with 95% ee.This chiral epoxide was then converted into propargyl alcohol 17 which was subsequently protected as its methyl ether 9 by using NaH and MeI in 85% yield.Regioselective ring opening of (S)-methyloxirane 10 with 9 using n-BuLi, BF 3 OEt 2 gave the secondary homopropargyl alcohol 8 in 65% overall yield. 13  Reagents and conditions: i) BnBr, NaH, dry THF, 0 o -rt, 93%; ii) EtMgBr, Mg turnings, (HCHO) n , dry THF 72%; iii) LAH, dry THF, reflux, 90%; iv As shown in the Scheme 3, the esterification 7 of 8 with 3,5-dimethoxyphenylacetic acid 7 using DCC and DMAP at room temperature afforded compound 18 in 80% yield.Subsequent deprotection of the benzyl group and reduction of the triple bond were achieved by hydrogenation using 10% Pd/C 14 in ethyl acetate to afford the alcohol 19 in 70% yield.Oxidation of 19 using Jones reagent 15,16 (CrO 3 , H 2 O, H 2 SO 4 ; acetone, 0 o -rt) gave the desired carboxylic acid 6 in 80% yield.
Intramolecular Friedel-Crafts acylation of 6 was achieved using a mixture of trifluoroacetic acid and trifluoroacetic anhydride 17-20 to give a macrolide 20 in 50% yield.Finally, the deprotection of 20 with freshly prepared AlI 3 in benzene gave the target molecule, 11βmethoxycurvularin 5 in 65% yield as colorless oil.

Conclusions
In summary, we have successfully demonstrated an efficient total synthesis of 11βmethoxycurvularin in a highly stereoselective manner.The synthesis utilizes the Sharpless asymmetric epoxidation, and an intramolecular Friedel-crafts acylation to construct 12membered macrocyclic lactone ring system.

Experimental Section
General.The reactions were conducted under N 2 atmosphere using anhydrous solvents such as DCM, THF.All reactions were monitored by thin layer chromatography (TLC) using silicacoated plates and visualizing under UV light.Yields refer to chromatographically pure products by 1 H and 13 C NMR. Air sensitive reagents were transferred by a syringe or with a double-ended needle.Evaporation of the solvent was performed at reduced pressure using a Buchi rotary evaporator. 1 H NMR spectra were recorded on Varian FT-200MHz (Gemini) and Bruker UXNMR FT-300MHz (Avance) in CDCl 3 .Chemical shift values were reported in ppm relative to tetramethylsilane (δ 0.0) as an internal standard.Mass spectra were recorded under electron impact at 70eV on LC-MS (Agilent Technologies).Column chromatography was performed on silica gel (60-120 mesh) supplied by Acme Chemical Co., India.Thin-layer chromatography was performed on Merck 60 F-254 silica gel plates.Optical rotations were measured with JASCO DIP-370 polarimeter.

[(2S,3S)-3-[2-(Benzyloxy)ethyl]oxiran-2-yl]methanol
[α] D 27 + 7.7 (c, 0.  (17).To freshly distilled ammonia (25 mL) in a 100 mL two neck round bottom flask fitted with a cold finger condenser, was added catalytic amount of ferric nitrite, followed by the piecewise addition of lithium metal (166 mg, 18.5 mmol) at -33 o C. The resulting grey color suspension was stirred for 30 min.To this was added the chloride 16 (600 mg, 2.64 mmol) in dry THF (3 mL) over a period of 5 min.After stirring the reaction mixture for 30 min, solid NH 4 Cl (2 g) was added and ammonia was allowed to evaporate.The residue was partitioned between water and ether and the aqueous layer was extracted with ether (2 × 50 mL).The combined organic layers were dried over anhydrous Na 2 SO 4 and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/hexanes, 2.5:7.5) to afford compound 17 as a colourless liquid (346 mg, 70%).
[α] D 27 -0.9(c, 0.  (6): Compound 19 (15 mg, 0.38 mmol) was taken in 5 mL of distilled acetone at 0 °C.Then a freshly prepared Jones reagent was added slowly at the same temperature until the orange brown color persists.The mixture was allowed to attain room temperature and the stirring was continued for further 30 min.The mixture was then quenched with water and extracted with EtOAc.Purification by silica gel column chromatography gave the acid 6 (100 mg, 80%  (20).The compound 6 (100 mg, 0.27 mmol) was dissolved in CF 3 COOH (7.5 mL) and (CF 3 CO) 2 O (1.2 mL).The solution was stirred overnight at room temperature and poured into an excess of NaHCO 3 solution.The mixture was extracted with Et 2 O (3.5 mL) and the extract was dried over anhydrous Na 2 SO 4 and concentrated in vacuo and the residue was purified by column chromatography (EtOAc/hexanes, 1: 5) to afford compound 20 as a colorless oil (52 mg, 50%).
[α] D 27 -16 (c, 0.  (5).To a stirred solution of iodine (1.1 g, 4.33 mmol) in dry benzene (10 mL) was added Al powder (167 mg, 4.70 mmol).The mixture was refluxed for 0.5 h and cooled to 10 o C. To this mixture Bu 4 NI (253 mg) and a solution of compound 20 (50 mg, 0.14 mmol) in dry benzene (4 mL) were added.The mixture was stirred for 15 min at 10 ºC and quenched with 2 M HCl at 0 o C. The mixture was then extracted with ethyl acetate (3 × 20 mL), the organic phase was washed with NaHCO 3 solution followed by brine solution and dried over Na 2 SO 4 and concentrated in vacuo.The residue was purified by coloumn chromatography (EtOAc/hexanes, 2 : 1) gave the compound 5 as a colorless oil (30 mg, 65%