Synthesis of cyclobutane fused γ -butyro lactones through intramolecular [2+2] photocycloaddition. Application in a formal synthesis of grandisol

An approach to the synthesis of cyclobutane fused γ -butyrolactones is described. The key step involves a Cu(I) catalysed intramolecular [2+2] photocycloaddition of 1,6-dienes in which the two alkene units are tethered through acetal oxygen. The resulting bicyclic lactols were then oxidised to provide the title compounds. The synthetic potential of these lactones is illustrated by a formal synthesis of grandisol.


Introduction
The cyclobutane ring is present in many naturally occurring molecules.Grandisol 1, 1 the pheromone 2, 2 hebellophyllene 3 3 and kelsoene 4 4 are a few representative examples.Cyclobutane derivatives are also extensively used as synthetic intermediates 5 taking advantage of their inherent ring strain that renders them to undergo facile ring enlargement and ring cleavage.Thus development of methodologies for the synthesis of highly functionalised four membered rings is of continued interest. 6We envisaged that cyclobutane fused γ-butyro lactones represented by the general structure 5 may lead to access to the natural products 1-4.We herein, report 7 a general protocol for the synthesis of the cyclobutane fused γ-butyro lactones and its application in a formal synthesis of grandisol 1.
failed to induce stylization even in the presence of sanitizers or metal catalysts, probably because the diene 6 exists in the most stable S-trans conformation 8 rather than the less stable S-cis conformation required for cycloaddition.Salomon et. al 9 has demonstrated that diallyl ether derivatives undergo smooth photobicyclisation to produce 3-oxabicyclo[3.2.0]heptanes in the presence of Cu(I) catalyst which brings the diene in the required S-cis conformation through formation of Cu(I) complex.Based on this observation we anticipated that photobicyclisation of the diene 9 (Scheme 1) in which the two π-units are tethered through an acetal oxygen, would produce the bicyclic lactol 10.Oxidation of the lactol 10 will then provide the desired lactone 11.
To begin, the diene 9a was prepared (Scheme 1) in 68% yield through transacetalisation of acrolein diethyl acetal 7 (R=Et) with the allyl alcohol 8a in benzene under reflux with azeotropic removal of ethanol in the presence of PPTS as catalyst.Cycloaddition of the diene 9a was carried out in diethyl ether solution in the presence of cuprous trifluoromethane sulfonate (CuOTf) as catalyst by irradiating with quartz filtered light.The photoadduct 10a was isolated in 50% yield.The gross structure of the photoadduct 10a was established through its 1 H and 13 C NMR spectra.
The exo-stereochemical assignment to the photoadduct 10a was based on comparison of the coupling constant of the C 2 -H with those reported 10 for analogous exo and endo-2-substituted-3oxabicyclo[3.2.0]heptanes.
It has been reported that in exo-2-substituted-3oxabicyclo[3.2.0]heptanes, the C 2 -H which is trans to C1-H exhibits a coupling constant of 1.5 Hz, while the C 2 -H which is cis to C 1 -H in the corresponding endo structure exhibits a higher coupling constant of 5.5 Hz.The C 2 -H in the photoadduct 10a was found to appear at δ 4.82 as a singlet i.e. with J =0.Thus C 2 -and C 1 -hydrogens bear a trans relationship in the photo adduct 10a.
The formation of the adduct 10a with OEt group occupying an exo position is in contrast to the formation of the endo-adduct 15a from Cu(I) catalyzed photo cycloaddition of 3-hydroxy-1,6-heptadiene.The latter reaction is believed 11 to proceed through a tricordinated Cu(I) complex 13a.However, an analogous Cu(I) complex 13b with the bulkier OEt group occupying an endo position, necessary for formation of the endo-adduct 15b, would be highly sterically crowded.Thus cycloaddition of the diene 3a takes place through the less crowded Cu(I) complex 14 resulting in exo adduct 10a.
The photoadduct 10a was then treated with hot 80% aqueous acetic acid to afford the lactol 11a in 71% yield.Retention of configuration at C2-centre during deprotection was indicated by the appearance of the C 2 -H at δ5.19 as a singlet and is attributed to be the result of addition of H2O to the intermediate oxonium ion 16 from the least hindered exo face.Oxidation of the lactol 11a finally afforded the lactone 12a in 68% yield.The generality of this four-step protocol was established by the synthesis of the lactones 10bd in very good yields.The diene 9b, prepared from transacetalisation of acrolein diethyl acetal with crotyl alcohol, afforded the photoadduct 10b as a mixture of two diastereoisomers in 1:2.5 ratio as determined from the integration of the C2-H singlets at δ 4.79 (minor isomer) and 4.90 (major isomer).The adduct 10b was converted to the lactone mixture 12b through oxidation of the corresponding lactols 11b.

Scheme -2
The dienes 9c and 9d were prepared from transacetalisation of acrolein dimethyl acetal 7 (R = OMe) with allyl alcohol and methyallyl alcohol respectively.UV irradiation of these dienes in the presence of CuOTf afforded cycloadducts which underwent partial in situ demethylation, possibly through catalysis by TfOH generated from CuOTf during irradiation, to produce a mixture of the adducts 10c, 11c and 10d, 18 respectively.These lactols without characterisation, were directly treated with acid and the resulting products were oxidised with Jones reagent to provide the known lactones 12c and 12d.It is worth mentioning that in the lactol 18 the stereochemistry at C 2 is opposite to those of the lactols 11a,b as indicated by the coupling constant of the C 2 -H which appeared as a doublet at δ 4.89 (J = 9.9 Hz).The reversal of stereochemistry at C 2 may be attributed to the addition of H 2 O to the oxonium ion 17 from the endo face as addition from the exo face is blocked by the C 5 -Me.
The synthetic potential of the cyclobutane fused γ-butyro lactone is demonstrated by a formal synthesis of grandisol 1 (Scheme 2).The lactone 12d, on reaction with excess of MeLi, afforded the diol 19 in 71% yield.Swern oxidation of the diol 19 afforded the known diastereomeric mixture of the lactols 20.The mixture of lactols 20 has already been transformed 12 to grandisol, thus accomplishing its formal synthesis. 13n conclusion transacetalisation of an acrolein acetal with allyl alcohol in conjunction with photocycloaddition and oxidation offers an excellent route to cyclobutane fused γ-butyro lactones.An application of this synthetic protocol has been demonstrated by a formal synthesis of grandisol.

Experimental Section
General Procedures.Compounds described here are all racemates.All reactions were carried out under an atmosphere of N 2 .Column chromatography was performed on silica gel (60-120 mesh).Petroleum refers to the fraction of petroleum ether bp 60-80 o C. Ether refers to diethyl ether.Organic extracts were dried over anhydrous Na 2 SO 4 .IR spectra were recorded in thin film.Unless otherwise stated, 1 H and 13 C NMR spectra were recorded in CDCl 3 solution at 300 MHz and 75 MHz respectively.Elemental analyses were carried out at the microanalytical laboratory of this laboratory.