Chiral Auxiliary-Mediated Enantioenrichment of ( ± )-Ibuprofen , under Steglich conditions , with Secondary Alcohols derived from ( R )-Carvone

A síntese de uma série de álcoois secundários derivados da (R)-carvona, assim como o curso estereoquímico da esterificação destes derivados com (±)-ibuprofeno é apresentada. O composto comercial racêmico foi transformado nos respectivos ésteres diastereoisoméricos através do acoplamento mediado por DCC/DMAP, fornecendo o par de diastereoisômeros derivados de (S)ou (R)-ibuprofeno em relação até 5.7:1, dependendo do tipo de auxiliar quiral empregado.


Introduction
During the past two decades, the preparation of optically active drugs has received considerable attention both, from academics and industry.The reasons behind this interest are threefold, including the medical benefit from using a single chemical entity, the changing pharmaceutical regulations, which now require the development of optically active drugs as single stereoisomers, and also advances in strategies for the synthesis of optically pure compounds, which facilitated the task. 1 Ibuprofen (1, Figure 1) is a non-steroidal antiinflammatory agent of the class of the a-arylpropionic acids, which also includes flurbiprofen (2, Figure 1), fenoprofen (3, Figure 1), ketoprofen (4, Figure 1) and naproxen (5, Figure 1), amongst its most prominent members.The drug is marketed mostly as the racemate despite that it has been shown that the (S)-enantiomer is the main responsible for the therapeutic effect.The pure enantiomer is also available, being prescribed only for certain specific conditions. 2t has been demonstrated that (R)-ibuprofen as well as its congeners can be stereoselectively interconverted in vivo into their active enantiomers through a thioester-mediated epimerization process which involves the Co-enzyme A (CoA). 3 However, these acyl-CoA thioester derivatives are chemically reactive and may become involved in a transacylation reactions with endogenous nucleophiles, leading to covalent binding of the drug to proteins, the clinical consequences of which relate to the toxicity of this pharmaceutically active ingredient. 4It is also suspected that the acyl-CoA intermediate derived from (R)-ibuprofen may be responsible for the formation of mixed glyceryl esters, which once deposited in fatty tissue could cause unknown long-term effects, transforming (R)-ibuprofen into a pharmacological uncertainty. 5herefore, the selective preparation of (S)-ibuprofen has been the subject of intense research and numerous stereoselective chemical approaches have been explored for that purpose. 6In addition, resolutions of the racemate by means of crystallization of diastereomeric salts, 7 as well as chemoenzimatic transformations including esterificacion, trans-esterification, 8 enantioselective hydrolysis of esters, 9 amides 10 and nitriles 11 and other enzyme-mediated strategies, 12 and a yeast-mediated selective degradation of the unwanted enantiomer, 13 have also been reported.
Carvone is a naturally-occurring cyclohexylic terpenoid which is isolated from Carum carvi, Anethum graveolans and Mentha spicata, being available in both of its enantiomeric forms.It has been extensively employed as building block in organic synthesis. 14Interestingly, however, the use of carvone derivatives as chiral auxiliaries has only few and scattered precedents. 15he chiral auxiliary-mediated dynamic kinetic resolution of a-substituted carboxylic acids has been recently recognized as an approach towards the preparation of enantioenriched a-aminoacids, as well as their a-mercapto-, a-haloand a-hydroxycongeners.This is an effective alternative, provided configurational lability can be induced at the stereogenic a-carbonyl center. 16ecently, Amoroso and coworkers 17,18 reported the preparation of different a-arylpropionic acids in their enantioenriched forms, by using lactamide-type chiral auxiliaries.The diastereomeric mixtures of the corresponding lactamic esters were obtained in good yields and reasonable diastereoselectivities depending upon the solvent and chiral auxiliary used.Therefore, here we wish to report the synthesis of chiral secondary alcohols derived from (R)-carvone (6, Figure 1) and their reaction with racemic ibuprofen under Steglich conditions, 19 as a stereodivergent entry to enantioenriched mixtures of esters derived from either (S)-or (R)-ibuprofen, depending on the type of chiral auxiliary employed.

Results and Discussion
Three series of secondary alcohols were prepared.In the first one, (R)-carvone was submitted to a conjugate addition reaction with thiophenol under thermodynamic conditions, 20 furnishing thioethers (7a-c, Scheme 1) in 4, 34 and 16% yield, respectively.On the other hand, reaction with PhSH and 2-naphthalenethiol under kinetic 21 conditions afforded sulfides (7a and 8, Scheme 1) in 60 and 92% yield, respectively.
The stereochemistry of these products was deduced by comparison with literature data, 22 analysis of the enhancement of signals in nuclear Overhauser effect (nOe) experiments and examination of their 1 H NMR spectra, which revealed that H-3 was considerably more deshielded in 7a (d 3.89 ppm) than in 7b (d 2.91 ppm) and 7c (d 3.29 ppm), pointing out to a pseudo-axial orientation of the heteroatomic substituent.The preferential generation of 7a and 8 under kinetic conditions is consistent with an axial Michael addition of the thiols from the a-face of carvone, driven by stereoelectronic effects, and subsequent protonation of the resulting enolate from the opposite and less hindered b-face.Compounds 7b and 7c may result from the base-mediated equilibration of 7a under the reaction conditions. 23iastereoselective reduction of ketones 7a, 7b and 8 with K-Selectride in anhydrous THF, 24 from the less encumbered b-face of their corresponding carbonyl moiety, 25 provided alcohols 9a, 9b and 10 (Scheme 1) in 58, 66 and 56%, respectively.
For the second series, where the aromatic substituent is directly attached to a cyclohexenic six-membered ring, (R)-carvone was subjected to the direct addition of three different Grignard reagents.The procedure stereoselectively furnished alcohols 15a-c (Scheme 2), as result of an antiperiplanar attack of the Grignard reagent with respect to the isopropenyl group. 27In turn, these tertiary allylic alcohols were treated with PCC/Al 2 O 3 , producing an oxidative allylic transposition 28 to the corresponding 3-phenyl-(S)-carvone derivatives 16a-c (Scheme 2) in yields ranging from 71 to 86%. 29  Figure 1.Chemical structures of (±)-ibuprofen (1), other relevant a-arylpropionic acid type non-steroidal anti-inflammatory agents (2-5) and R-carvone (6).Vol.21, No. 6, 2010   These ketones were stereoselectively reduced with sodium borohydride in a MeOH-THF mixture, furnishing the secondary allylic alcohols 17a-c (Scheme 2) in 83-94% yield.Their configuration was determined as 1S,5S based on literature precedents 30 and the results of a nOe experiment, where signal enhancement of H-5 was observed upon irradiation of H-1.

Me
The third group of chiral alcohols was obtained after subjecting (R)-carvone to conjugate addition reactions with aryl and 1-naphthyl Grignard reagents in the presence of copper(I) iodide 31 to which TMSCl was added in order to ensure efficient transformations. 32ese gave the corresponding silyl enol ether intermediates 18a and 18b (Scheme 3) in high yields, as single diastereomers to which the (3S,5R)-configuration was assigned on the basis of literature precedents, 33 an exhaustive NMR analysis of 18b and knowledge of the role of the isopropenyl group in determining the stereochemistry of the conjugate addition product.The stereochemical result of this reaction is consistent with the outcome of the reductions of ketones 16a-c, resulting from a nucleophilic attack anti-periplanar to the bulky isopropenyl group.
In turn, these were desilylated by careful treatment with TBAF in Et 2 O in order to avoid the production of diastereomeric mixtures at the stereocenter adjacent to the carbonyl, due to the base-catalyzed epimerization of the initial product. 34In this process, protonation of the trapped intermediate enolate from the less hindered face anti-periplanar to the C-5 substituent, furnished ketones 19a and 19b (Scheme 3) in 96 and 90% yields, respectively.Finally, ketones 19a,b were stereoselectively reduced with K-selectride to the corresponding secondary alcohols 20a and 20b (Scheme 3) in 80% yield.Interestingly, the stereochemical outcome of the reduction was different from that previously observed with the sulfur-containing alcohols and could be attributed to a different preferred conformation of the starting ketones, where the bulky aryl substituents are located equatorially, flipping the isopropenyl moiety to a pseudo-axial position, thus hindering the approach of the reducing agent from the side of the isopropenyl group.
This speculation was confirmed by nOe experiments on 19a and 19b, which revealed that irradiation of the methylene carbon of the isopropenyl moiety excerted signal enhancement of H-3 (Figure 2).On the other hand, detection of H-3 signal enhancement in 20a upon irradiation of the C-2 methyl group and also of H-9b confirmed that they were located on the same side of the molecule.Furthermore, the axial nature of the hydroxyl group was established from the values of the coupling constants between H-1 and its neighbours in its 1 H NMR spectrum (4.5 and 5.9 Hz) and its lack of nOe signal enhancement of H-1 upon irradiation of H-9b.
The performance of the chiral auxiliaries was evaluated through their submission to esterification reactions with (±)-ibuprofen, under the conditions described by Steglich, 19 which employ the DCC-DMAP reagent system as condensing agent.
As shown in Table 1, alcohol 9a provided up to a 28:72 mixture of diastereomeric esters in 89% combined yield, when the reaction was carried out in CHCl 3 at -50 ºC (entry 1).Furthermore, when the bulkier 2-naphthyl thioether 10 was used as chiral auxiliary, a slight improvement in the diastereomeric ratio (26:74)  was observed, at the expense of a slight decrease in yield of product (entry 10).On the other hand alcohol 9b, a diastereomer of 9a, furnished essentially equimolecular mixtures of diastereomeric esters (entries 4-9), according to NMR and HPLC peak area integration, regardless the solvent and temperature conditions employed.
In an attempt to improve the product diastereomeric ratio, the reactions with the related sulfoxide 13 and sulfone 14 were explored.However, essentially no chiral induction was observed among the resulting esters (entries 11-14).
Chiral auxiliaries 17a-c gave diastereomeric ratios nearing 2:1 (Table 2), always favouring the same ester which as discussed below, was demonstrated to be that derived from (S)-ibuprofen.The best results in terms of chemical and optical yields were obtained with alcohol 17a, when subjected to esterification in toluene at -20 ºC (entry 3).
When chiral alcohols 20a and 20b were subjected to esterification with (±)-ibuprofen under Steglich conditions (Table 3), it was observed that the best results were obtained when chloroform was employed as solvent (entries 1, 2 and 13) and that the product was enantioenriched in the ester derived from (R)-ibuprofen.Comparison with esters prepared with pure (S)-ibuprofen indicated that the major diastereomer is that derived from (R)-ibuprofen.Interestingly, slightly improved diastereomeric ratios were obtained when a five-fold excess of ibuprofen was employed, while changing the order of addition of the reagents, preincubation of a mixture of the acid and the alcohol with activated 4Å molecular sieves and the addition of triethylamine (entries 3-5) did not improve the diastereomeric ratios of ester products.
In addition, a trend was observed, indicating that the bulkier 1-naphthyl derivative 20b slightly outperformed its congener 20a, probably by leading to a chiral auxiliary with a conformationally more rigid cyclohexyl ring.Under the typical conditions, a ratio of products up to 82:18 was observed (entry 13).These levels of enantioenrichment are similar to those previously informed by the group of Amoroso. 17or the sake of comparison, the effect of placing a bulkier group near the secondary alcohol was examined with (-)menthol (31, Scheme 4), the esterification of which with (±)-ibuprofen in CHCl 3 at 0ºC gave 55% of a nearly 1:1 mixture of diasteromeric esters 32 (Scheme 4).
The group of Amoroso has demonstrated that ibuprofen and other a-substituted carboxylic acids undergo a dynamic kinetic resolution process when subjected to the Steglich esterification. 19As shown in Scheme 5, when an a-substituted carboxylic acid (I) reacts with DCC and DMAP, enantiomeric acyl-DMAP derivatives II and III are formed as intermediates.Under these conditions, it has been proposed that the stereogenic center becomes labile and the enantiomeric acyl-DMAP derivatives are thus capable of being interconverted.When a chiral alcohol (R*OH) is added to the reaction medium, both acyl-DMAP intermediates can react to furnish diastereomeric ester products (IV and V).Two main conditions are required for a successful dynamic kinetic resolution.One of them is that interconversion between the acyl-DMAP derivatives II and III should proceed at a faster rate than formation of the ester products and the other is that the acyl-DMAP intermediates should react at very different rates with the chiral auxiliary.
In order to gain further understanding on the studied esterification, a series of esterifications were carried out with pure (S)-ibuprofen.After examination of the products, it was observed that when the reaction was carried out with alcohol 20a the resulting major diastereomers where those carrying the (R)-configuration on the ibuprofen a-carbonyl stereocenter.On the contrary, when the esterifications where carried out with alcohols 17a-c, the prevailing diastereomers were those derived from (S)-ibuprofen (Tables 1-3).However, composition of the mixtures was different from those arising from the racemic acid, pointing out to poor compliance of the studied transformations with the requirements for a successful dynamic kinetic resolution.Particularly, the experiments revealed that interconversion of the enantiomeric acyl-DMAP intermediates is not fast enough, compared with their reaction with the chiral auxiliary, to grant a more optically efficient transformation.
In conclusion, it was demonstrated that secondary alcohols derived from naturally-occurring (R)-carvone are able to provide good yields of enantioenriched mixtures of ibuprofen esters, that their performance is similar to that of other chiral alcohols and that depending on the chosen chiral auxiliary, production of (R)-or (S)-ibuprofen derived esters may be favoured.

Experimental
Melting points were taken on an Ernst Leitz Wetzlar model 350 hot-stage microscope and are reported uncorrected.Specific rotation data were obtained with a Jasco DIP 1000 photopolarimeter, fitted with 1 dm cells.FT-IR spectra were determined employing a Shimadzu Prestige 21 spectrophotometer as solid dispersions in KBr disks, or as thin films held between NaCl cells.The 1 H and 13 C NMR spectra were acquired in CDCl 3 in a Bruker Avance spectrometer (300.13 and 75.48 MHz for 1 H and 13 C, respectively), with tetramethylsilane (TMS) as internal standard.The chemical shifts are reported in ppm downfield from TMS and coupling constants (J) are given in Hertz.DEPT 135 and DEPT 90 experiments aided the interpretation and assignment of the fully decoupled 13 C NMR spectra.In special cases, 2D-NMR (COSY, HMBC, HMQC and J-resolved spectra) and selective nOe experiments were also employed.Pairs of signals marked with "#", " ‡" or with an asterisk, "*", as superscripts indicate that their assignments may be exchanged.
In the conventional work-up procedure, the reaction was diluted with brine (5-10 mL) and the products were extracted with EtOAc (4-5 × 20 mL).The combined organic extracts were then washed once with brine (5 mL), dried over Na 2 SO 4 and concentrated under reduced pressure.The residue was submitted to flash column chromatography with silica gel 60 H. Elution was carried out with hexane-EtOAc mixtures, under positive pressure and employing gradient of solvent polarity techniques.
All new compounds gave single spots on TLC plates run in different hexane-EtOAc and CH 2 Cl 2 -toluene solvent systems.Chromatographic spots were detected by exposure to UV light (254 nm), followed by spraying with ethanolic ninhydrin (amines) or with ethanolic p-anisaldehyde/ sulfuric acid reagent and careful heating of the plates for improving selectivity.
The diastereomeric esters of ibuprofen were best separated on a Varian ProStar liquid chromatograph fitted with a 250 × 4.6 mm C-18 Luna column (Phenomenex, 5 mm particle size), using a 80:20 mixture of MeOH:50 mmol L -1 phosphate buffer, pH 5.5 as mobile phase, pumped at 1 mL min -1 .Detection wavelength was 254 nm.

S , 3 R , 5 R ) -5 -I s o p r o p e n y l --m e t h y l -3phenylcyclohexanone 19a:
CuI (500 mg, 2.64 mmol) was added to a stirred 1.18M THF solution of PhMgBr (8 mL, 5.28 mmol), cooled to 0 ºC.After stirring 15 min, a solution of (R)-carvone (209 mg, 1.39 mmol) and TMSCl (772 mg, 7.1 mmol) in THF (2 mL) was introduced dropwise and the reaction was further stirred 45 min at 0 ºC.Then, the mixture was treated with saturated NH 4 Cl and the reaction products were extracted with EtOAc (4 × 50 mL).The combined organic extracts were washed with brine (10 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure.The resulting residue was filtered through a short plug of silica gel, furnishing 18a (380 mg, 96%), as a yellowish oil.Without further purification, a stirred solution of the silyl ether 18a (100 mg, 0.35 mmol) in Et 2 O (10 mL) was cooled to 0 ºC and treated with 1M TBAF in THF (0.42 mL, 0.42 mmol).After 2 h at this temperature, the volatiles were removed under reduced pressure and the residue was chromatographed affording ketone 19a (72 mg, 95%), as a pale yellow oil.[a] D 25 -55.

Scheme 5 .
Scheme 5. Proposed mechanism of the DCC-DMAP mediated dynamic kinetic resolution of a-substituted carboxylic acids.

Table 2 .
Esterification a Deduced by comparison with esters prepared with pure (S)-ibuprofen.
1 H enone 16c: 18% PCC on Al 2 O 3 (1.09g, 0.91 mmol) was added portionwise to a solution of alcohol 15c (98 mg, 0.38 mmol) in anhydrous CH 2 Cl 2 (15 mL), and the resulting suspension was stirred 1 day at room temperature.The solids were separated by filtration through Celite and the filter was washed with CH 2 Cl 2 (3 × 10 mL).