A stereoselective synthesis of ( S )-dapoxetine starting from trans-cinnamyl alcohol

A novel stereoselective synthesis of (S)-dapoxetine starting from commercially available transcinnamyl alcohol is described. Sharpless Asymmetric Epoxidation (SAE) is utilized as the key step in this synthetic strategy.


Introduction
Recently, it has been suggested that premature ejaculation (PE) might be associated with perturbations in serotonergic 5-hydroxytryptamine (5-HT) neurotransmission. 1,2It has been proposed that PE may be caused by decreased central serotonergic signaling, hyposensitivity of the 5-HT 2C receptor, or hypersensitivity of the 5-HT 1A receptor, all of which have been shown to decrease ejaculatory latency time in animal model systems. 3,4PE is a common problem, which may be associated with considerable anxiety, frustration, and negative impact on affected men and their sexual partners.No pharmaceutical agents have been approved for this indication.However, therapies that target 5-HT neurotransmission, such as selective serotonin reuptake inhibitor (SSRI) anti-depressants, have been used in this setting with varying efficacy and tolerability.
Dapoxetine is the first agent to be developed specifically to treat PE.This agent significantly prolongs IELT and increases the sense of control and sexual satisfaction for men with PE and their partners.Dapoxetine is well tolerated, with a favorable pharmacokinetic profile that allows for on-demand use.Dapoxetine hydrochloride is an SSRI with a short half-life developed specifically for the treatment of men with PE, [5][6][7][8] but is slightly different from the SSRIs (such as zoloft, paxil, and prozac) (Figure 1) widely prescribed for depression and other psychiatric disorders such as bulimia or anxiety.The American Urological Association as well as the International Consultation on Sexual Dysfunctions now recommends the off-label use of SSRIs, which increase 5-HT neurotransmission, for the management of PE. 1,9,10 Although the off-label use of antidepressant SSRIs such as fluoxetine, sertraline, and paroxetine may increase ejaculatory latency time [11][12][13] these SSRIs do not reach peak plasma concentrations for several hours after administration; many require a long lead-in dosing period for efficacy 1 and the typically long half-lives of these drugs can result in significant drug accumulation in the body, increased exposure to medication and, consequently, an increased likelihood of adverse events. 6,14In addition, men taking antidepressant SSRIs daily have reported sexual side effects such as decreased libido and erectile dysfunction after prolonged treatment with these drugs. 6If approved by the Food and Drug Administration (FDA), this would make dapoxetine join the ranks of erectile dysfunction drugs such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra) and some dopamine agonists such as cabergoline (Dostinex) and pramipexole, as drugs which can be used to improve male sexual health.Very few methods are currently available for the synthesis of pharmaceutically important and potent (S)-dapoxetine.Toru Koizumi et al. reported only synthesis of intermediate 8 (Scheme 1) by employing asymmetric induction in the 1,3-dipolar cyclo-addition of (R)-(+)-p-tolylvinyl sulfoxide with acyclic nitrones in high enantiomeric excess.16a Another method described in the literature to synthesize (S)-dapoxetine is a radiochemical synthesis from (S)-(+)-N-methyl-α-[2-(1-naph-thalenyloxy)ethyl]benzene methanamine hydrochloride using 11 CH 3 I. 16b Recently, two asymmetric synthetic approaches have been reported for the synthesis of (S)-dapoxetine starting from achiral starting materials. 17As a part of our ongoing project for the asymmetric synthesis of biologically active compounds, 18 herein we wish to report a novel synthetic route for the synthesis of (S)-dapoxetine (I), starting from the commercially available and inexpensive achiral starting material trans-cinnamyl alcohol 1. Scheme 1. Retrosynthetic approach to (S)-dapoxetine (I).

Results and Discussion
The Sharpless asymmetric epoxidation (SAE) can be envisioned as a powerful tool offering considerable opportunities for synthetic manipulations, 19 which has been employed as a key step in our synthetic strategy as shown in Scheme 1.We envisioned that the amino alcohol 8 could be prepared from the xanthate ester 6, which in turn could be prepared from the azido diol 3. The azido diol 3 itself could be prepared from the epoxide 2 which in turn could be synthesized by Sharpless asymmetric epoxidation of the commercially available trans-cinnamyl alcohol 1. trans-cinnamyl alcohol 1 was subjected to SAE conditions 20 to give the epoxide 2 in 88% yield with 98% ee. 21Regioselective opening of the epoxide 2 with NaN 3 gave the azido diol 3 as the single product in 97% yield.The azido diol 3 was converted into the mono-TBS protected azido alcohol 4 in 96% yield, which on reduction with 5%Pd(C) in EtOAc followed by treatment of the amine with (Boc) 2 O afforded the N-Boc protected alcohol 5 in 88% yield (Scheme 2).The secondary alcohol 5 was converted into its xanthate ester 6 under standard reaction conditions in 84% yield, followed by a deoxygenation under the Barton-McCombie 22 protocol using n-Bu 3 SnH and a catalytic amount of AIBN in toluene under reflux conditions affording the protected amino alcohol 7, which was further treated with TFA in DCM to give the amino alcohol 8 in 81% isolated yield in two steps.The amino alcohol 8 was converted in to (S)dapoxetine (I) by employing the literature procedure 17a (85% yield from 8, Scheme 3).

Conclusions
In conclusion, a novel total synthesis (S)-dapoxetine with high enantio-selectivity starting from a commercially available achiral starting material has been developed in which the chiral center was established by Sharpless asymmetric epoxidation to afford (S)-dapoxetine (I).

Experimental Section
General Procedures.Solvents were purified and dried by standard procedures prior to use.All the fine chemicals used were reagent grade procured commercially and used without further purification.Optical rotation was measured using sodium D line (589 nm) on a JASCO-P-1020polarimeter under standard conditions.Infrared spectra were recorded on Perkin Elmer FT-IR spectrometer.Enantiomeric excess was measured using either the chiral HPLC (Lichrocart 250-4 [4 mmID × 25 cm] HPLC-Cartridge (R.R.-Whelk-01)) or by comparison with optical rotation.Elemental analyses were carried out with a Carlo Erba CHNS-O EA 1108 Elemental analyzer. 1H-NMR and 13 C-NMR spectra were recorded on a Bruker Avance DPX 200/400 spectrometer by using TMS as internal standard.MS analyses were performed on a Peseiex API QSTAR Pulsar with an electrospray ionization mass spectrometer (LC-MS), using MeOH as a solvent (m/z, fragentor 70 V).

tert-Butyl
(1R,2R)-3-(tert-butyldimethylsilyloxy)-2-(methylthio-carbonothioyloxy) -1phenylpropylcarbamate (6).To a of 5 (0.404 g, 1.06 mmol) in THF (10 mL) at 0 o C was added sodium hydride (50% assay, 0.056 g, 1.17 mmol).Vigorous gas evolution was observed.After the reaction mixture was stirred for 20 min, carbon disulfide (0.100 mL, 1.64 mmol) was added in one portion.Stirring was continued for the next 30 min after which methyl iodide (0.20 mL, 3.18 mmol) was added in a single portion.The reaction mixture was stirred for another 2 h (progress of reaction mixture was monitored by TLC) and the reaction was quenched by the addition of ice-cold water (2 mL).The solution was filtered, concentrated in vacuo and the residue was extracted with ethyl acetate (3 X 5 mL).The combined organic extracts were washed with saturated sodium bicarbonate (5 mL) solution.The organic layer was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.The crude product was purified by silica-gel column chromatography using 12% ethyl acetate in petroleum ether as eluent, to give 6 as a pale yellow solid (0.418 g, 84% ) were added at room temperature under inert atmosphere.The reaction mixture was heated at reflux till completion of reaction (progress of reaction was monitored by TLC).After the completion of the reaction (as shown by TLC), toluene was removed under reduced pressure to give a thick viscous residue.This residue was dissolved in 15 mL of THF and 1.0 mL of TFA was added to the solution at 10 o C under a nitrogen atmosphere.The reaction mixture was stirred at RT for 5 h.Then, 20 mL of 1.0 M NaOH solution was slowly added at 0 o C and the mixture was extracted with EtOAc/MeOH (95:5) (2x15mL).The organic extracts were combined dried over MgSO 4 and the solvent was evaporated under reduced pressure.The separated crude product was purified by silica-gel column chromatography with CHCl 3 /MeOH (9:1) to afford 8 as a colorless solid 0.065 g (81% for two steps).