Asymmetric total synthesis of eicosanoid

An asymmetric total synthesis of eicosanoid 4 starting from 2,2-dimethyl-( R )-1,3-dioxolane-4-carbaldehyde is described. The key steps involved for the synthesis include modified Simmons-Smith cyclopropanation, stereoselective reduction


Introduction
As a part of defense mechanism, marine organisms produce a fascinating range of secondary metabolites endowed with unusual and unexpected biological profiles.The arachidonic acid pathway in marine organisms provided a number of oxylipins such as 1-3 containing the cyclopropyl-lactone groups. 1 Eicosanoid 4 was isolated by the incubation of arachidonic acid with an acetone powder of the Caribbean soft coral Plexaura homomalla. 2In conjunction with other marine fatty acid metabolites (Figure 1), 3 eicosanoid 4 also incorporate a cyclopropanelactone motif and lipoxygenase inhibiting activity and therefore provoked a considerable synthetic interest.4a,g It is likely that the origin of eicosanoid 4 might have occurred from transformation analogous to that as constanolactones 3. 2 To expedite current pharmaceutical evaluations of this family, we describe herein an asymmetric total synthesis of eicosanoid 4. Our synthetic protocol involved modified Simmons-Smith cyclopropanation, stereoselective reduction of ketone, ring-closing metathesis (RCM) and Nozaki-Hiyama-Kishi coupling reaction (Scheme 1).Our interest for the synthesis of natural products in a concise manner following our general synthetic protocol, described herein is an efficient chiral pool approach taking 2,2-dimethyl-(R)-1,3-dioxolane-4-carbaldehyde 8 as the starting material as depicted in the retro-synthetic analysis (Scheme 1).

Results and Discussion
Following our earlier related work, 5b D-glyceraldehyde was converted to cyclopropyl aldehyde 13 with good overall yield.Allyl Grignard reaction on the resulting aldehyde 13 afforded compound 14 in a 1:1 diastereomeric mixture separable with difficulty by repeated column chromatography in 87% yield.This problem was however circumvented by subjecting the homoallyl alcohol mixture to oxidation under 2-iodoxybenzoic acid (IBX) condition and selective reduction of the ketocompound with K-selectride 6 provided the diastereomers in the ratio of 9:1.The diastereomers were separated by column chromatography.The selectivity in reduction was rationalized on the basis of chelation controlled Cram's model.

S-(cis)
H - Interaction between cyclopropyl C-C bonds and carbonyl π orbitals is maximized when the cyclopropyl and carbonyl groups are oriented orthogonally.Both the bisect (S)-(cis) and (S)-(trans) conformation are able to provide maximum stabilization.Mark Lautens et al. reported that treatment of tributylsilyl cyclopropyl ketone with LiBH 4 resulted in a diastereomeric mixture of 2.5:1 and explained the stereoselectivity by proposing the following (S)-(cis) model. 7But S. Shuto and co-workers reported the reverse stereoselectivity with diisobutylaluminium hydride (DIBAL-H) (Figure 2) and it was explained by (S)-(trans) model. 6When 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. 8According to the method, the minor isomer 14b was converted to its (R)-and (S)-2-methoxy-2-(trifluoromethyl)-2-phenylacetic acid (MTPA) ester with corresponding 2-methoxy-2-(trifluoromethyl)-2-phenylacetic 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 Reface in the (S)-(trans) conformation.Although this manipulation gave the desired product 14a along with 14b, the undesired intermediate was easily converted into 14a in 76% yields over two steps via standard Mitsunobu protocol.The next job was to construct the six-membered lactone ring.The required isomer 14a was then treated with acryloyl chloride in CH 2 Cl 2 to afford the ester 16 in 92% yield.
Ring-closing metathesis (RCM) 10 was then attempted on 16.So, treatment of 16 with Grubbs' first generation catalyst in refluxing CH 2 Cl 2 provided after 36h the desired sixmembered lactone 17 in 90% yield (Scheme 3).In 1 H NMR of compound 17, the frequency corresponding to olefinic protons appeared at 6.72 ppm as a multiplet and at 6.04 ppm as a doublet and other protons at their respective regions. 13C NMR was in consistent with the assigned structure and elemental analysis substantiated the proposed structure.Reduction of double bond, hydrolysis of acetonide ring followed by oxidation with NaIO The final job of our endeavor was the introduction of the side chain on the cyclopropyllactone main core which was achieved smoothly by subjecting compound 6 and 19 with chromium(II) chloride and catalytic amount of nickel(II) chloride to afford the corresponding allyl alcohol 20 in a 1:1 ratio (Scheme 4). 12The total synthesis of eicosanoid 4 was completed by oxidation of the derived hydroxyl group with Dess-Martin periodinane 13 in 89% yield and the obtained product was identical in all respect to the reported data of the eicosanoid 4. 4g

Conclusions
In conclusion, we have achieved the total synthesis of eicosanoid 4 starting from 2,2-dimethyl-(R)-1,3-dioxolane-4-carbaldehyde.Modified Simmons-Smith cyclopropanation, stereoselective reduction, ring-closing metathesis (RCM) and Nozaki-Hiyama-Kishi reactions have been used successfully to construct the core cyclopropyl and lactone moiety.The strategy reported herein could be applied for getting different lactone as well as side chain motifs for a diversity oriented synthesis of the above natural products for pharmacological studies and work towards this end are underway in our laboratory 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).NMR spectra were recorded on Bruker AC-200 and Bruker DRX-500 machine in CDCl 3 with TMS as internal standard.Mass spectra were 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.Petroleum ether refers to mixture of hexanes with bp 60-80 o C.

3-[2,2-Dimethyl-(4S)-1,3-dioxolan-4-yl]-(E)-2-propen-1-ol (10).
To a solution of 9 (8.0g, 40.0 mmol) in CH 2 Cl 2 was added DIBAL-H (40.84 ml, 1M solution in toluene) at -78 o C. 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 and purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:4) to obtain 5.43g (86%) of pure allyl alcohol 10 as colorless viscous liquid.[α] D = +32.5 (c 3.5, CHCl 3 ); 1   (11).To a solution of allyl alcohol 10 (5.0g, 31.6 mmol) in CH-2 Cl 2 (40 ml) was added imidazole (6.45g, 94.9 mmol) at 0 o C. The reaction mixture was then stirred for 15 min at the same temperature and tert-butyldiphenylchlorosilane (TBDPSCl) (9.65 ml, 38.0 mmol) was added.The reaction mixture was allowed to warm to room temperature and stirred overnight.After completion of the reaction (monitored by TLC), water (20 ml) was added to it.Organic layer was separated and aqueous layer was extracted with CH 2 Cl 2 (2x50 ml).Combined organic extracts were washed successively with water and brine, dried over Na 2 SO 4 and purified by silica gel column chromatography using 5% ethyl acetate/petroleum ether to afford 10.0g (80%) of pure silyl ether 11 as colorless liquid.(12).Et 2 Zn (142.5 ml, 115.9 mmol, 1M solution in hexane) was added dropwise to a clear solution of 11 (9.5g, 23.2 mmol) in CH 2 Cl 2 (200 ml) at -78 o C.After 10 min, CH 2 I 2 (9.3 ml, 115.9 mmol) was added through syringe.The reaction mixture was stirred at the same temperature for 4h and then at -10 o C for 20h.The reaction mixture was poured into a saturated solution of NH 4 Cl.Organic layer was separated and aqueous layer was extracted with CH 2 Cl 2 (2x100 ml).Combined organic extracts were washed successively with water, brine, dried over Na 2 SO 4 and purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:19-1:9) to give 9.34g (95%) of pure compound 12 as colorless liquid.

2-(6-Oxotetrahydro-2H-pyran-2-yl)cyclopropanecarbaldehyde (19).
To a vigorously stirred solution of 18 (0.1g, 0.5 mmol) in CH 2 Cl 2 (10 ml), added in one lot suspension of NaIO 4 supported on silica gel (1.5g) in CH 2 Cl 2 (10 ml) at 0 o C.After stirring at the same temperature for 0.5h, the solid was removed by filtration, washed with CH 2 Cl 2 (10 ml), combined filtrates were concentrated under vacuum and the residue filtered through a pad of silica gel column using ethyl acetate/petroleum ether (1:3) to afford the aldehyde 19 (0.08g, 94%) as a colorless liquid.* This aldehyde was found to decompose on storage and was used immediately for the next reaction.

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