Studies towards the total synthesis of halicholactone and neohalicholactone : a stereoselctive synthesis of C 1-C 13 fragment

A stereoselective synthesis of C1-C13 fragment of halicholactone (1a) and neohalicholactone (1b) starting from (R)-isopropylidene glyceraldehyde is described. Key transformations include Simmons-Smith cyclopropanation, stereoselective reduction, ring-closing metathesis (RCM).


Introduction
Discovery in early 1960 that the marine coral Plexaura homomalla produces enormous quantities of prostaglandins 1 initiated a fascinating era in the field of natural products chemistry.After this discovery, a number of secondary and non-primary metabolites produced from marine organisms have been studied extensively which often possess unusual and sometime unexpected biological activities.Interest on the part of chemists have been two fold, natural product chemists have investigated marine organisms as source of the new and unusual molecules, while synthetic organic chemists have followed by targeting these novel structures for development of new analogues and new synthetic methodologies and strategies.In 1989, secondary metabolites halicholactone (1a) and neohalicholactone (1b) showing lipoxygenase inhibitor activity were isolated from the marine sponge Halichondria okadai by the Yamada group. 2 The structure of halicholactone (1a) and neohalicholactone (1b) were originally formulated on the basis of spectroscopic data and partial degradation and the relative stereochemistry by X-ray diffraction analysis of neohalicholactone (1b). 3It is likely that the halicholactone originates from transformation analogous to those represented for the constanolactones except initiated through a 15-lipoxygenase introduced hydroperoxide.
The elegant structural and stereochemical features of halicholactone (1a) and neohalicholactone (1b) (Figure 1) decorated with dense functionalities that include an unsaturated nine-membered lactone, a trans-disubstituted cyclopropane ring and five stereocenters present a considerable challenge as synthetic targets, particularly with respect to stereochemistry and functional group sensitivity, attracted our attention to undertake its synthesis.Although, a few number of partial and total synthesis have been reported, 4 the stereoselctive construction of the stereogenic centers of C-9 to C-12 is still remained to be solved.Our interest for the synthesis of natural products in a concise manner and to fix the stereogenic centers from C-9 to C-12 of halicholactone (1a) and neohalicholactone (1b), described herein is an efficient chiral pool approach taking (R)-2,3-O-isopropylidene glyceraldehyde (8) as the starting material as depicted in the retrosynthetic analysis (Scheme 1).

Results and Discussion
From the retrosynthetic analysis of halicholactone (1a) and neohalicholactone (1b) (Scheme 1), the (R)-2, 3-O-isopropylidene glyceraldehyde (8) was chosen as suitable starting material which was converted to cyclopropyl carboxaldehyde 7 following the method reported by us. 5 Subsequent addition of aldehyde 7 to allylmagnesium bromide in ether provided the homoallyl alcohol 6 and 6a 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 oxidation under IBX 6 condition and selective reduction of the ketocompound 10 with K-selectride 6 provided the diastereomers 6 and 6a in the ratio of 9:1.The diastereomers were separated by column chromatography (Scheme 2

S-(trans)
O When DIBAL-H is coordinated to the carbonyl group, due to steric repulsion between the two bulky isobutyl group and the substituent in the cyclopropyl group, S-(trans) conformation is preferred.The same argument holds true in the case of K-selectride, which demands a lot of steric repulsion due to its three sec-butyl groups.The newly created secondary hydroxyl group bearing center was assigned following modified Mosher's method. 9Accordingly, minor isomer 6a 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 (Figure 3).The major S-isomer was the result of the hydride attack from the less hindered Re-face in the S-(trans) conformation.Although this manipulation gave Having obtained the required homoallyl alcohols starting from (R)-2, 3-O-isopropylidene glyceraldehyde (8) in high yield and good selectivity, the next job was to construct the ninemembered lactone ring with Z-double bond.The required isomer 6 was then treated with 5hexenoic acid and EDCI in CH 2 Cl 2 to afford the ester 11 in 92% yield.The spectral information from 1 H and 13 C NMR, IR, mass spectra and elemental analysis proved the structure 11 beyond doubt.In the IR spectrum, an intense peak at 1725 cm -1 indicated the presence of ester functionality.In 1 H NMR, two terminal olefinic protons were resonated at 5.68 and 4.98 ppm respectively.The rest of the protons resonated at their expected chemical shift regions.The carbonyl peak of the ester functionality appeared at 172.6 ppm and two terminal olefins at 137.7, 133.5, 117.7 and 115.3 ppm respectively in 13 C NMR, confirmed the assigned structure 11.

S-(cis)
Our final task ring-closing metathesis (RCM) 11 was then attempted on 11.So, treatment of 11 with Grubbs' first generation catalyst in refluxing CH 2 Cl 2 provided after 24h the desired ninemembered lactone 5 in 64% yield along with the corresponding dimer 12 (10%) (Scheme 3).In 1 H NMR, the frequencies corresponding to olefinic protons appeared at 5.46 ppm as a multiplet, four allylic and two methylene protons adjacent to the carbonyl group resonated between 2.46 ppm to 2.07 ppm and other protons at their respective regions. 13C NMR was in consistent with the assigned structure.Cis-geometry was ascertained by comparing the 13 C NMR value of olefin carbons with our earlier report.4a IR absorption at 1739 cm -1 confirmed the lactone ring and in EIMS a signal at [M-CH 3 ] + substantiated the proposed structure.It is noteworthy to mention here that the Grubbs' second generation catalyst provided the same product with high yield (76%) and dimer 12 (11%) under high dilution condition in 16h.The total synthesis of halicholactone (1a) and neohalicholactone (1b) can be achieved by introducing the side chains using the synthetic protocol published for the synthesis of constanolactones (3).

Conclusions
In conclusion, the present synthesis compares well with the earlier reported synthesis of the halicholactone 1a and neohalicholactone 1b and offers an efficient alternative route to this important class of compounds and their analogs.The strategy and the approach described is of general applicability for the formation of a library of other related compounds of structural and biological importance by simply changing the side chain as well as lactone ring size.In addition, presence of a stereodefined hydroxyl group at C-12 and a primary hydroxyl group at C-13 of compound 5 enable us to fix the stereogenic centers from C-9 to C-12 and provides the necessary functionalities required for the total synthesis of target molecules.

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).Infrared spectra were recorded with Shimadzu IR 470 and Perkin-Elmer 683 spectrometers.Proton NMR spectra were recorded on Bruker AC-200 machine in CDCl 3 with TMS as internal standard.Mass spectra were obtained with Finningan MAT 1210 mass spectrometer.Optical rotations were measured with digital polarimeter.Elemental analysis was done on elemental analyzer model 1108 EA.All

Grignard Reaction
To an ice cooled solution of aldehyde 7 (2.9g, 17.0 mmol) in anhydrous ether (20 mL) was added dropwise 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 9.

Figure 2 .
Figure 2. Conceivable transition states of the hydride reduction of cyclopropyl ketones.
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 °C.