A formal enantioselective synthesis of (+)-dodoneine via cyclic sulfate methodology

An enantioselective formal synthesis of (+)-dodoneine is described using the Sharpless asymmetric dihydroxylation and regioselective nucleophilic opening of cyclic sulfate as the key steps.

The compound (+)-Dodoneine 1 exhibited relaxing effect on preconstricted rat arotic rings.The unique as well as challenging structural feature of this class of compounds along with their potential biological activity has aroused great interest among synthetic organic and medicinal chemists. 2he synthesis approaches described till now in the literature for dodoneine 1 involve 1) enantioselective addition of allyl metal reagents to aldehydes, followed by Grubbs ring closing metathesis 3 2) Horner-Wadsworth-Emmons olefination and Crimmins aldol approach 4 and 3) Sharpless asymmetric epoxidation followed by 1,3-syn diasteroselective reduction and Grubbs ring closing metathesis. 5As part of our research work aimed at developing enantioselective syntheses of naturally occurring lactones, the Sharpless asymmetric dihydroxylation and subsequent transformation of the diols formed via cyclic sulfites/ sulfates were envisaged as powerful tools offering considerable opportunities for synthetic manipulations. 6Herein we report a new and highly enantioselective formal synthesis of (+)-dodoneine employing the Sharpless asymmetric dihydroxylation as the source of chirality.

Results and Discussion
Our approach for the synthesis of (+)-dodoneine was envisioned via the retrosynthetic route shown in Scheme 1.

Scheme 1. Retrosynthetic route to (+)-dodoneine.
The key intermediate aldehyde 2 was visualized as an ultimate precursor for the target molecule, which could be obtained from the hydride opening of cyclic sulfate 3 and subsequent hydrolysis.The cyclic sulfate 3 could be derived from commercially available p-hydroxy benzaldehyde 4 through series of reactions comprising double 2C Wittig olefinations and Sharpless asymmetric dihydroxylation.The salient feature of our synthetic strategy was on the presumption that regioselective nucleophilic opening of cyclic sulfate would occur at the αcarbon.The detailed route for the synthesis of aldehyde 2 with reagents and reaction conditions is outlined in Scheme 2.
The synthesis was initiated with TBS protection (TBS-Cl, imidazole, CH 2 Cl 2 , 0 ºC to room temperature, 1.5 h, 96% yield) of commercially available p-hydroxybenzaldehyde 4, followed by standard 2C Wittig olefination with Ph 3 PCHCOOEt in benzene under reflux conditions to give trans-olefin 5 in 92% yield.Reduction of trans-olefin ester 5 using LiAlH 4 at 25 ºC gave mixture of products along with low yield of desired alcohol 6.In order to obtain the best yield of alcohol 6, a two step procedure was devised involving catalytic hydrogenation of double bond using 10% Pd/C, H 2 (92% yield); followed by LiAlH 4 reduction of ester to alcohol 6 in dry THF at 0 ºC (91% yield).Swern oxidation of alcohol 6 and subsequent 2C Wittig reaction with (ethoxycarbonylmethylene)triphenylphosphorane in benzene under reflux conditions  nder the Sharpless asymmetric dihydroxylation reaction conditions gave diol 8 in 85% yield and 96% ee (from 1 H NMR analysis of its diacetate using Eu(III) chiral shift reagent).Sharpless and co-workers have also observed 6a,7 that vicinal diol cyclic sulfates are "like epoxides only more reactive".With this clue, the diol 8 was treated with thionyl chloride in the presence of triethyl amine in dichloromethane at 0 o C to give isomeric cyclic sulfite 9 in 94% yield.Ruthenium chloridesodium periodate oxidation of sulfite 9 gave cyclic sulfate 3 in 92% yield.The essential feature of our synthetic strategy shown in the Scheme 2 was observed on the presumption that the nucleophilic opening of the cyclic sulfate would occur in the regiospecific manner at the αposition.Reduction of cyclic sulfates to mono alcohols with sodium borohydride in dimethyl acetamide was originally recommended.7a The intermediate sulfate esters were then hydrolyzed in a 20% aqueous H 2 SO 4 -ether system.Alternatively, hydrolysis could be affected with a catalytic amount of concentrated sulfuric acid and 0.5-1.0equiv of water in THF. 8 We have observed that, hydrolysis (with catalytic amount of sulfuric acid and water) of intermediate sulfate ester, obtained from cyclic sulfate 3 after treatment with sodium borohydride in DMF at 25 ºC, was sluggish and gave the desired product alcohol 10 in low yields (<10%).Conducting both the stages of reaction at 0 ºC for longer hours (2-3 h each) improved the formation of alcohol 10 (52% yield), but α, β-unsaturated ester 7 was also obtained as side product in substantial amount (~35%).After series of experiments, we have established that treatment of cyclic sulfate 3 with sodium borohydride in DMF for 15 minutes at 0 ºC, followed by hydrolysis with catalytic amount of concentrated sulfuric acid and 0.35 equiv of water in THF at 0 ºC for 20 min afforded the desired alcohol 10 in quantitative yield (90%).The choice of reaction conditions (reaction temperature and time) is crucial for the successful yield of the desired product alcohol 10.
Next, the secondary hydroxyl group of compound 10 was protected (TBS-Cl, imidazole, CH 2 Cl 2 , overnight) to furnish TBS protected ester 11 in 95% yield.The ester 11 was then subjected to reduction with DIBAL-H in dichloromethane at -78 ºC to yield aldehyde 2 in 88% yield.Absolute stereo chemistry of the product aldehyde (S)-2 was ascertained by comparing all the analytical (specific rotation, Natural product (+)-Dodoneine 1 was finally obtained from aldehyde (S)-2 by following a well described 3,5 reaction sequence comprising asymmetric allylation with allyl magnesium bromide, acylation with acryloyl chloride and Grubbs ring closing metathesis.
In conclusion, a formal synthesis of (+) _ dodoneine 1 has been accomplished by Sharpless asymmetric dihydroxylation and regioselective nucleophilic opening of cyclic sulfate.The optimum conditions for the key steps, nucleophilic opening of cyclic sulfate 3 with sodium borohydride in regioselective manner at the α-position (0 o C / 15 min) and subsequent hydrolysis of sulfate ester (0 o C / 20 min) is ascertained after series of experimentations.Further application of this cyclic sulfate methodology to the synthesis of biologically active compounds for structureactivity studies is currently underway in our laboratory.

Experimental Section
General.All the reactions were monitored by TLC (recoated silica plates and visualizing under UV light).Air-sensitive reagents were transferred by syringe or double-ended needle.Evaporation of solvents was performed at reduced pressure on a Buchi rotary evaporator. 1 H and 13 C NMR spectra of samples in CDCl 3 were recorded on Bruker UXNMR FT-300 MHz (Avance) spectrometer and Varian FT-500MHz (Inova).Chemical shift reported are relative to an internal standard TMS (δ=0.0).Mass spectra were recorded in EI conditions at 70 eV on an LC-MSD (Agilent technologies) spectrometer.All high-resolution spectra were recorded on QSTAR XL hybrid MS/MS system (Applied Biosystems/ MDS sciex, Foster City, USA), equipped with an ESI source (IICT, Hyderabad).Column chromatography was performed on silica gel (60-120 mesh) supplied by Acme Chemical Co., India.TLC was performed on Merck 60 F-254 silica gel plates.Optical rotations were measured with JASCO DIP-370 Polarimeter at 25 0 C. Commercially available anhydrous solvents CH 2 Cl 2 , THF, and EtOAc were used as such without further purification.