Studies towards the synthesis of hyperireflexolide A

The first approach to hyperireflexolide A, based on the synthesis of γ-lactone-fused cyclopentane 5, a functionalized key intermediate, is presented. Compound 5 is involved in hydrolysis, α-allylation at C-8 and α-methylation at C-10 stereoselectively from the convex face. Then it is subjected to cross metathesis to give α,β-unsaturated ketone 11 as precursor in the total synthesis of hyperireflexolide A.

In the literature, numerous synthetic methods are reported to attain γ-lactone-fused cyclopentanes [25][26][27][28][29][30][31].Earlier from our lab, we reported a short and efficient methodology for the synthesis of γ-lactone-fused cyclopentane 5 [32].The cis-ring junction of this carbocylic ring system offers a high degree of selectivity for the assemblage of various substituents on the convex surface.The lactone part can serve as a useful tool to append various side chains.

Results and Discussion
The presence of a γ-lactone-fused cyclopentane moiety in hyperireflexolide A (1) attracted our attention.In fact, the ketal moiety in 5 could not only act as a surrogate for C-9 carbonyl but also facilitate installation of an angular methyl group.
The retrosynthetic analysis for hyperireflexolide A is depicted in Scheme 1.We envisioned that hyperireflexolide A (1) could be synthesized by metal-catalyzed opening of the epoxide 2  with 2-bromopropene followed by lactonization.Enone 3 could be synthesized from 4 by installation of the methyl group at C-10 followed by cross metathesis reaction.Compound 4 could be obtained from the γ-lactone-fused cyclopentane 5 by deprotection of C-9 followed by allylation at C-8.
In order to check the feasibility of the alkylation reaction of γ-lactone-fused β-ketoester 6, initially a mixture of 6 and 7 was subjected to methylation using 1.1 equiv of K 2 CO 3 in the presence of methyl iodide (MeI).The α-methylated β-ketoester 8 was obtained in good yield.In the 1 H NMR, 8 showed a signal at 3.70 ppm as doublet for C-10 (ring junction) proton confirming the selective methylation at C-8.Further, installation of the methyl group at C-10 was achieved by treatment of 8 with 1.1 equiv of K 2 CO 3 in the presence of MeI to give bismethylated γ-lactone-fused β-ketoester 9 in 72% yield (Scheme 3).These results demonstrated that regioselective alkylation at the two sites were possible.Notably, one diastereomeric product was isolated from these bis-alkylation reactions due to favorable attack from the less hindered convex face of 6 [10] to give α,α'-cis stereochemistry.Now the stage has been set for allylation of γ-lactone fused cyclopentanone 6. Treatment of 6 with K 2 CO 3 in the presence of allyl bromide at 0 °C afforded α-allylated γ-lactone-fused β-ketoester 4 in 88% yield.In the 1 H NMR a signal appeared at 3.64 ppm as doublet for ring junction (C-10) proton confirmed that selective allylation occurred at C-8. Compound 4 was then subjected to methylation at C-10 using K 2 CO 3 and MeI to obtain the requisite γ-lactone fused cyclopentanone 10 in excellent yield (Scheme 4).Allylation and methylation both were occurred stereoselectively from the convex face to give α,α'-cis stereochemistry.The allyl derivative 10 was then subjected to cross metathesis reaction with ethyl vinyl ketone.Initially, the reaction performed using Grubbs' 1st generation catalyst (3-20 mol %) was unsuccessful.Treatment of 10 with ethyl vinyl ketone using Grubbs' 2nd generation catalyst (3 mol %) in the presence of CH 2 Cl 2 furnished (E)-enone 11 in 77% yield as shown in Scheme 4. In the 1 H NMR spectrum, 11 showed a signal at 6.13 ppm as doublet with coupling constant 15.8 Hz (trans-configuration) for the α-proton of enone [34][35][36][37].
After successfully synthesizing the side chain via cross-metathesis, our next task was the steresoselective epoxidation of (E)-enone 11.Unfortunately, the stereoselective epoxidation of 11 under basic conditions were unsuccessful [38], which prevented completion of the proposed synthetic sequence.

Conclusion
In conclusion, synthetic studies towards hyperireflexolide A, the synthetic precursor α,β-unsaturated ketone 11 was synthesized.Failure of the stereoselective epoxidation of 11 prevented completion of the proposed synthetic sequence.Future studies will include the stereoselective epoxidation of 11 followed by opening of the epoxide and lactonization or 1,4-nucleophilic addition to the α,β-unsaturated ketone 11 followed by epoxidation of the resulted enolate with subsequent lactonization to achieve hyperireflexolide A (1).

Experimental General methods
All the reactions were performed in oven dried apparatus and the reaction mixtures were magnetically stirred.Thin-layer chromatography was performed on Acme and Spectrochem Silica gel (Mumbai, India) coated on microscopic slides.Visualization of spots was effected by exposure to iodine or spraying with 4% ethanolic H 2 SO 4 and charring.Column chromatography was performed using Acme's silica gel (100-200 mesh), and ethyl acetate/hexane was used as eluent.Evaporation of solvents was performed at reduced pressure using a Büchi rotary evaporator.
Melting points were recorded on JSGW melting point apparatus and are uncorrected.Infrared spectra were recorded on Perkin-Elmer 1320 and Shimadzu 420 spectrophotometers as KBr pellets (solids), or as thin films on NaCl flats (liquids). 1H NMR spectra were recorded at 400 MHz on a JEOL spectrometer unless otherwise mentioned (500 MHz).Data are reported as follows: (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet; integration; coupling constant(s) in Hz; assignment).Chemical shifts are reported in ppm, and coupling constants are reported in Hz.Proton decoupled 13 C NMR spectra were recorded at 100 MHz (125 MHz) on a JEOL spectrometer.Samples for NMR were made in CDCl 3 .Tetramethylsilane was used as the internal standard.
Commercial grade solvents were distilled before use.Ethyl acetate was distilled over anhydrous sodium carbonate.Dichloromethane and dichloroethane (1,2-DCE) were distilled over phosphorous pentoxide and stored over 4 Å molecular sieves.Acetone was distilled over anhydrous K 2 CO 3 .Methanol was refluxed and distilled over magnesium turnings and stored over 4 Å molecular sieves.Distilled water was used for aqueous reactions and aqueous work-up.