Ring-closing metathesis (RCM) reaction: application in the synthesis of cyclopropyl-lactone segment of solandelactones

An efficient synthesis of cyclopropyl-lactone containing fragment of solandelactones has been achieved via ring-closing olefinic metathesis reaction. Grubbs’


Introduction
The formation of rings represents a central theme in natural product synthesis. 1A number of natural products contain medium-sized saturated as well as unsaturated lactone rings. 2 This class of compounds continues to generate intense interest from synthetic organic chemists due to their interesting structural features associated with important biological activities.Usually, medium sized lactone rings are achieved by Yamaguchi lactonisation 3 under high dilution condition or Bayer-Villiger 4 ring expansion reaction.In order to facilitate the formation of medium-sized rings, several features should be installed in the substrate so that it can provide some sort of conformational constraint or restraint.For example, under Yamaguchi condition, the eight-and nine-membered lactone rings corresponding to solandelactones 3a and halicholactone 3b respectively were facilitated by the presence of cis-alkene conformational restraint.6][7][8] Because of the enthalpic as well as entropic influences, eightmembered lactone rings are the most difficult to prepare.Herein, we describe the application of RCM reaction as flexible approach towards the synthesis of saturated and unsaturated eightmembered lactone rings present in solandelactones.
Solandelactones (1) belonging to the growing class of oxylipins containing a transbifunctional cyclopropane ring and fatty acid lactones of marine origin were isolated from the hydroid Solanderia secunda of Korean waters and their structures were elucidated by exhaustive spectroscopic and chemical method. 9Their structural uniqueness as well as intriguing biological activities led us to synthesize them in a suitable manner.These compounds were found to be structurally similar to some other marine oxylipins viz constanolactones (3), 10 halicholactone (2a) and neohalicholactone (2b) (Fig. 1). 11It is interesting to note that all of the above metabolites possess linear C 20 carbon skeletons derived from eicosanoid origin.In contrast, solandelactones with saturated and unsaturated eight-membered lactone rings and C 22 carbon skeleton are thought to be of docosanoid precursor.We previously developed a highly convergent approach for the formal synthesis of solandelactones, 3a which is crucial to the work described herein.

Results and Discussion
Our previous synthesis provided a method for the preparation of compound 7. 3a As outlined in the retrosynthetic analysis (Scheme 1), the chiral pool D-glyceraldehyde (8) was obtained from D-mannitol following the literature precedent. 12Accordingly, D-mannitol was converted to corresponding 1,2,5,6-diacetonide followed by NaIO 4 assisted cleavage to provide Dglyceraldehyde (8), which was purified by vacuum distillation (b.p. 75-80 o C at 30 mm/Hg).D-Glyceraldehyde was then added to the refluxing solution of ethoxycarbonylmethylene triphenylphosphorane in benzene to give a mixture (E: Z = 9:1) of geometrical isomers 9 and 10 which were separated by flash chromatography.The predominant (E)-olefinic ester obtained after chromatographic separation from minor (Z)-isomer, was characterized by 1 H NMR spectroscopy.The allyl alcohol 11 was secured in excellent yield through the reduction of ester 9 with DIBAL-H at -78 o C in CH 2 Cl 2. In the 1 H NMR of compound 11, the olefinic proton resonated at 5.90 and 5.65 ppm as multiplets integrating for two protons and disappearance of signal due to methyl and methylene protons of ester functionality confirmed the structure.The optical rotation of compound 11 was found to be in agreement with the reported value [α] D +32.5 (c 3.5, CHCl 3 ); lit. 13[α] D +33.9 (c 3.6, CHCl 3 ).The allylic alcohol was converted to its silyl ether 12 using TBDPSCl and imidazole in dry CH 2 Cl 2 at 0 o C. The next stage in our synthesis was the stereoselective cyclopropanation of compound 12.This was accomplished by the standard modified Simmons-Smith cyclopropanation following Taguchi's protocol 14 using Et 2 Zn and CH 2 I 2 in 95% yield and with >98% de (Scheme 2).Compound 13 obtained showed identical spectral and physical characteristic to that in the literature. 14The silyl ether was then deprotected by using TBAF in THF at 0 o C to obtain the cyclopropyl methanol 14.Compound 14 was then subjected to mild oxidation condition using IBX 15 to afford the aldehyde 15.Subsequent addition of aldehyde 15 to allylmagnesium bromide in ether provided the homoallyl alcohol 7 and 7a as 1:1 diastereomeric mixture in 89% yield, separable with difficulty by repeated column chromatography.This problem is however circumvented by subjecting the homoallyl alcohol mixture to Candida cylindracea lipase (CCL) catalyzed enzymatic resolution 16 and the resolution was remarkably high and did not acylate the (S)-alcohol 7a even after prolonged exposure under same reaction condition.After enzymatic resolution, the stereochemical assignment of the secondary hydroxyl bearing centre was achieved following modified Mosher's method. 17Accordingly, compound 7 was converted to its (R)-and (S)-(MTPA) ester with α-methoxy-α-(trifluoromethyl)phenyl acetic acid which showed negative chemical shift differences (∆δ = δ S -δ R ) for protons on C 1 through C 5 while protons on C 7 through C 9 showed positive differences, which is consistent with C 6 bearing an R-configuration (Fig. 2).Although this manipulation gave the desired product 7 along with 7a, the undesired intermediate was easily converted into 7 in 74% yield via standard Mitsunobu protocol.The next phase of our endeavor was the formation of eight-membered lactone ring with Zdouble bond.Esterification of homoallyl alcohol 7 was achieved by the treatment with 4pentenoyl chloride and Et 3 N in CH 2 Cl 2 .The ring-closing metathesis of compound 6 under different reaction condition using Grubbs' RuCl 2 (=CHPh)-(PCy 3 ) 2 catalyst (I) ended up with complete recovery of the starting material.When, we tried the RCM reaction with Grubbs' RuCl 2 (=CHPh)(PCy 3 )(IEMS) catalyst (II) in the presence of catalytic amount of Ti(Oi-Pr) 4 under high dilution condition (0.001M in CH 2 Cl 2 at reflux), the desired Z-isomer 5 was obtained in 71% yield along with the corresponding dimer (10%).It is worth mentioning that under low dilution, the dimer compound was the major product obtained.The exclusive formation of the (Z)-isomer was confirmed by comparing the 1 H and 13 C NMR, IR, mass, and [α] D value with the reported data.3a Had it been a mixture of (Z)-and (E)-isomer, we would have a complicated 13 C NMR spectrum.The chemical shifts of olefinic carbons appeared at 127.6 and 129.0 ppm indicating the presence of cis-double bond.The total synthesis of solandelactones (1) can be achieved by introducing the side chains using the synthetic protocol published for the synthesis of constanolactones (3). 18

Conclusions
In summary, we have demonstrated the feasibility of achieving saturated and unsaturated lactone rings present in solandelactones employing ring-closing metathesis.The synthesis of right hand hemisphere of solandelactones disclosed herein is noteworthy for the simplicity of the C-C bond formation, which we believe will prove advantageous in the synthesis of related cyclopropyl and lactone containing oxylipins.Synthesis of other related biologically active compounds via RCM is the subject of current interest and will be reported in due course.

Experimental Section
General Procedures.Solvents were purified and dried by standard procedures before use.
Column chromatography was carried out with silica gel (60-120 mesh The solution was stirred for 1h at same temperature and allowed to warm to 0 o C slowly.After completion of the reaction (monitored by TLC), MeOH (20 mL) was added slowly followed by the addition of cold aqueous saturated sodium potassium tartrate (50 mL).The biphasic mixture was stirred for further 2h and then partitioned.Aqueous layer was extracted with CH 2 Cl 2 (2x70 mL).Combined organic extracts were dried over Na 2 SO 4 (anhydrous) and purified by silica gel column chromatography using ethyl acetate/light petroleum ether (1:4) to obtain 5.43g (86%) of pure allyl alcohol 11.Colorless viscous liquid; [α] D = +32.5 (c 3.5, CHCl 3 ), lit. 13[α] D = +33.9(c 3.6, CHCl 3 );

Grignard reaction
To an ice cooled solution of aldehyde 15 (2.9g, 17.0 mmol) in anhydrous ether (20 mL) was added dropwise to an ether solution of allyl magnesium bromide [prepared from allyl bromide (2.94 mL, 34.0 mmol) and Mg (1.22g, 51.0 mmol) in ether (50 mL)] and stirring was continued for 3h at room temperature.The reaction mixture was then quenched with 5% HCl (20 mL) and extracted with ethyl acetate (3x50 mL).The combined organic layers were washed successively with aqueous NaHCO 3 , H 2 O, brine and dried over Na 2 SO 4 (anhydrous).The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using ethyl acetate/light petroleum ether (1:4) to afford 3.14g (87%) of pure homoallyl alcohol diastereomers 16.
Mass spectrawere obtained with Finningen MAT 1210 mass spectrometer.Optical rotations were measured with digital polarimeter.Elemental analysis was done on elemental analyzer model 1108 EA.All reactions were monitored on 0.25 mm E-Merck pre-coated silica gel (TLC) plates (60F-254) with UV or I 2 , anisaldehyde reagent in ethanol.Light petroleum refers to mixture of hexanes with bp 60-80 o C. The reaction mixture was refluxed for 6h and cooled to room temperature.Benzene was evaporated under reduced pressure.The residue was triturated with diisopropyl ether (3x100mL) to discard the insoluble triphenylphosphine oxide.All diisopropyl ether portions were combined and concentrated.The crude compound was then purified by silica gel column chromatography using ethyl acetate/light petroleum ether (1:9) to afford 8.