CHIRALITY 3:151- 155 (1991)

Synthesis of the [S] Gingerol Enantiomers MICHEL MARTIN AND PHILIPPE GUIBET

Les Laboratoires Beecham, Unit4 de Recherche, 4, Rue du Chesmy Beauregard, 35760 Saint Grkgoire, France

ABSTRACT ( + )-~S~-5-Hydroxy-l-~4-hydroxy-3-methoxyphenyl~-3-dodecanone l a commonly named ( + )-(S)-[81 gingerol is a natural product known to have car- diotonic activity.'-5 A total synthesis of both enantiomers is described with details for the first time using a general synthetic scheme which was recently outlined in the literature.6 This synthesis relies both on the separation of the diastereoisomers 4a and 4b by simple column chromatography on silica gel and on an HPLC analysis on a chiral phase to determine the optical purity of the enantiomers 8a and 8b of protected [81 gingerol. The gingerol isomers were thus obtained in good chemical yields in greater than 96% enantiomeric excess.

KEY WORDS: ( - )-(R) and ( + 14s) [81 gingerol, enantiomers synthesis, chiral sta- tionary phase, HPLC

INTRODUCTION

Three different gingerols, namely ( + )-(S) [61, ( + )-(S) [81, and ( + )-(S)[lO] gingerols, have been isolated from the rhizome of ginger.2 These three compounds differ only by the length of the aliphatic chain.

Cardiotonic tests have shown l a to be the most active.' We wished to obtain ( + )-(S) and ( - )-(R)-[81 gingerol, respectively, in order to check the inotropic activity described with the pure ( + )-(S)-enantiomer2 and to compare i t with that of the corresponding (-)-(R) one. It was also of interest to find a general process which would allow the preparation of similar compounds once the activity of ( + )-(S)-[81 gingerol had been confirmed.

We did not find in the literature any description of the resolution of racemic [8] gingerol or synthesis of either enantiomer, although some authors have pub- lished an enantioselective synthesis of ( + )-(S) and/or ( - )-(R)-[61 gingerol. Diverse enantiomeric excesses were obtained using different sequences. Giovani et al.7 obtained (+ )-(S)-[g]-gingerol with 30 to 40% enan- tiomeric excess in nine steps and with an overall yield of 20%. Both enantiomers were obtained by Enders et a1.* who claimed a 33-39% enantiomeric excess for a nine step scheme in an overall yield of 26.4%. Cinquini et a1.6 obtained a 96% enantiomeric excess in a five step sequence (good overall yield) for (+ )-(S)-[61 gin- gerol. These authors simply outlined their synthetic scheme without giving experimental details. Finally, Le Gall et al.' very recently published the enantiose- lective synthesis of (+)-(S)-[6] gingerol with a 96% en- antiomeric excess in nine steps and 10.1% overall yield.

We report here the synthesis of (+)-(S)-la and ( - )-(R)-[8] gingerol l b using a synthetic scheme simi- lar to that outlined by Cinquini for the preparation of ( + )-(S)-[6] gingeroL6 This method relies on the easy separation of the intermediate diastereoisomers 4a and

0 1991 Wiley-Liss, Inc.

4b obtained by the stereospecific addition of a second asymmetric center to the dihydroisoxazole 2 (Scheme 1) and also on an HPLC analytical method using chiral phase to show separation of l a and lb . This allowed us to obtain for the first time ( + )-(S)- and ( - )-(R)-[81 gin- gerol l a and l b with very good optical purity. The ab- solute configuration of compounds 4a and 4b were rea- soned back from the known absolute configuration of the naturally occurring isomer 1a.l'

MATERIALS AND METHODS

Melting points were determined with a Gallenkamp capillary apparatus and are uncorrected. Optical rota- tions were measured on a Perkin Elmer 141 Polarim- eter. IR spectra were recorded on a Shimadzu IR-408 spectrophotometer. 'H NMR spectra were recorded with a Bruker AC-200 spectrometer. The residual sol- vent peak was used as an internal standard and spectra were recorded in CDC13. Multiplicities are reported as (s) singlet, (d) doublet, (t) triplet, (9) quartet, (m) mul- tiplet, etc. Thin-layer chromatography was carried out on plastic sheets (Merck 5735) while flash chromatog- raphy was performed using Merck 7734 silica gel (63- 200 pm) and preparative HPLC was carried out on a Jobin-Yvon (now called Axxial) column (i.d. 80 mm) using Merck 7736 silica gel (10-40 pm). Elemental analyses were performed by Eraly Micro-Analyse in Noisy Le Roy (France). Chiral HPLC was performed using a Waters M 6000 A pump, U6K injector, 481 Lambda-Max spectrophotometer detector set at 230 nm and an analytical column (250 x 4.6 mm i.d.1 packed with N-(3,5-dinitrobenzoyl)-(R)-phenylglycine co- valently bound to an amino silicon polymer. A flow rate of 1 ml/min was used. Reactions involving carbanions

Received for publication May 29, 1990; accepted November 19, 1990. Address reprint requests to Michel Martin at the address given above.

152 MARTIN AND GUIBET

4a

1 iii

! I V

iv

I 4b

I I V 1

cH30d 7b ro I

l v

i vi i "I

i b

i 2 PhNCO. c&. Et3N, 1-Nonene , reflux, 1 h. ii 1) nBuLi. 0 , - 8 5 0 ~ 2) dCHP H CH,< 0-s':

III 1) LDA, THF. -9O'C 2) R:$JcH,,, iv A , toluene. CH3 Q 3

CH3 5 vi HZ, Pdic. MeOH v H,. NI Raney, MeOH. H20, B(OH),.

Scheme 1.

L81 GINGEROL ENANTIOMERS 153

were carried out under argon. THF was distilled from sodiumhenzophenone, benzene and toluene were dried over sodium, diisopropylamine and 2,2,6,6-tetrameth- ylpiperidine were distilled from calcium hydride and stored over 4 A molecular sieves. n-BuLi (2.5 M in hex- anes) was purchased from Janssen and titrated using the method of Suffert." Most of the compounds men- tioned hereafter are named using their code number used in Scheme 1.

5-Heptyl-4,5-dihydro-3-methyl isoxazole (2)

To 1-nonene (25 g, 0.198 moll and phenylisocyanate (43.8 g, 0.36 mol) in dry benzene (50 ml) under argon was added a solution of nitroethane (15.5 g, 0.198 mol) and triethylamine (20 drops, catalyst) in dry benzene (30 ml) over 15 min. The mixture was stirred for 1 h then refluxed for 1 h. After cooling, ether (100 ml) was added and the resulting precipitate filtered. The fil- trate was concentrated and the residue purified by flash chromatography on silica gel (hexane:ethyl ace- tate 6: l ) then distilled (bp 82"C, 0.3 mm) to give 2 (33 g, 86%). 'H NMR 6 0.88 (t, 3H, J = 6.2 Hz), 1.27 (m, 12H), 1.98 ( s , 3H), 2.54 (dd, lH, J = 8.3, 16.8 Hz), 2.97 (dd, lH, J = 10.1, 16.8 Hz), 4.53 (m, 1H). Anal. Calcd for C,,H,,NO: C, 72.08; H, 11.55; N, 7.64. Found: C, 71.85; H, 11.50; N, 7.45.

5-Heptyl-4,5-dihydro-3-[(4-methylphenyl)sul~nylmethyl] isoxazole (4a and 6 )

To 2,2,6,6-tetramethylpiperidine (9.2 ml, 54.6 mmol) a t - 10" to - 5°C in THF (250 ml) under argon was slowly added BuLi (2.5 M , 22 ml, 54.6 mmol) in hex- anes. The solution was stirred a t 0°C for 15 min, cooled to - 85°C and a solution of 2 (10 g, 54.6 mmol) in THF (100 ml) was slowly added keeping the temperature under -85°C. Stirring was maintained for 1.75 h at - 85°C and a solution of 3 (8.03 g, 27.3 mmol) in THF (100 ml) was added over 15 min. The reaction was al- lowed to stir a t -85°C for 1.75 h and was then quenched with a saturated aqueous solution of ammo- nium chloride (120 ml). The mixture was stirred until the temperature reached 20°C and the aqueous phase was extracted with CH,Cl, (2 x 100 ml). The organic phases were mixed, dried over MgSO, and concen- trated. The residue was purified by chromatography on silica gel (1 kg) using a Jobin-Yvon preparative column and 1/1 hexane:ethyl acetate mixture as eluent to af- ford pure 4a and 4b.

4a (2.16 g, 49.2%), m.p. 75"C, 'H NMR 6 0.89 (t, 3H, J = 6.1 Hz), 1.28 (m, 12H), 2.43 (s, 3H), 2.61 (dd, lH , J = 17.4, 8.4 Hz), 3.08 (dd, lH, J = 17.4, 10.5 Hz), 3.75 (d, lH , J = 13.5 Hz), 3.86 (d, lH, J = 13.5 Hz), 4.56 (m, lH), 7.35 (d, 2H, J = 8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz). Anal. Calcd for C,,H,,NO,S: C, 67.25; H, 8.46; N, 4.36; S, 9.97. Found: C, 67.24; H, 8.38; N, 4.36; S, 9.85.

la],, + 125.2" (c = 0.5 in CHCI, at 25°C).

4b (2.03 g, 46.2%), m.p. 79"C, 'H NMR 6 0.88 (t, 3H, J = 6.2 Hz), 1.27 (m, 12H), 2.43 (s, 3H), 2.66 (dd, lH, J = 17.3, 8.2 Hz), 3.02 (dd, lH, J = 17.3, 10.2 Hz), 3.73 (d, lH, J = 13.4 Hz), 3.85 (d, lH, J = 13.4 Hz), 4.51 (m,

lH), 7.35 (d, 2H, J = 8.3 Hz), 7.52 (d, 2H, J = 8.3 Hz). Anal. Calcd for C,,H,,NO,S: C, 67.25; H, 8.46; N, 4.36; S, 9.97. Found: C, 67.24; H, 8.25; N, 4.41; S, 9.87.

(all , + 288.4" ( c = 0.5 in CHC1, at 25°C)

(E)S-Heptyl4,5-dihydro-3-[[3-methoxy-4-(phenylmeth~y)- phenyllethenyll isoxazole (7a and 6 )

To diisopropylamide (1.93 ml, 14.1 mmol) in THF (60 ml) a t -5°C was slowly added BuLi (2.5 M , 5.65 ml, 14.1 mmol) under stirring and keeping the tempera- ture below 0°C. After 15 min a t OT, the lithium diiso- propylamide (LDA) solution was cooled to -40°C and added to a solution of 4a (4.13 g, 12.85 mmol) in THF (260 ml) a t -90°C taking care that the temperature did not rise above - 90°C. The mixture was stirred for 1.5 h a t - 85°C then hexamethylphosphoric triamide (HMPA) (7.07 ml) and a solution of 5 (4.34 g, 14.1 mmol) in THF (60 ml) were successively added. The reaction mixture was allowed to warm to room temper- ature and stirred for a further 2 h. The reaction was quenched with saturated aqueous ammonium chloride (120 ml). The aqueous phase was extracted with di- ethyl ether (2 x 130 ml) and the combined organic layers were dried over MgSO, and concentrated. The residue obtained was taken up in a mixture of pyridine (6 ml) and dry toluene (100 ml) and refluxed for 45 min. The solvents were evaporated and the crude compound purified by flash chromatography on silica gel (hex- ane:methylene ch1oride:ethyl acetate 6:35:0.5) to afford 7a (4.31 g, 83%), m.p. 101°C. 'H NMR 6 0.88 (t, 3H, J = 6.9 Hz), 1.28 (m, 12H), 2.80 (dd, lH , J = 8.3, 16.2 Hz), 3.22 (dd, lH, J = 10.3, 16.2 Hz), 3.92 (s, 3H), 4.66 (m, lH), 5.18 (s, 2H), 6.63 (d, lH , J = 16.4 Hz), 6.83 to 7.04 (m, 3H), 6.96 (d, lH , J = 16.4 Hz), 7.30 to 7.47 (m, 5H). Anal. Calcd for Cz6H3,NO,: C, 76.62; H, 8.16; N, 3.44. Found: C, 76.71; H, 8.12; N, 3.43.

The enantiomer 7b was prepared following the same procedure starting from 4b. It was obtained in 58% yield, m.p. 111.5"C. 'H NMR data were identical to those of 7a. Anal. Calcd for C,,H,,NO,: C, 76.62; H, 8.16; N, 3.44. Found: C, 76.44; H, 8.34; N, 3.46.

5-Hydroxy-I-1(3-methoxy-4-phenylmethoxy)- phenyl]9-dodecanone (8a and b)

A mixture of 7a (4.25 g, 10.4 mmol) and boric acid (1.29 g, 20.8 mmol) in methanol (300 ml) and water (60 ml) was hydrogenated under atmospheric pressure in presence of freshly prepared W-2 Raney Nickel (4 g) a t 25°C for 13 h under vigorous stirring. The catalyst was filtered off through celite and washed with methanol. Most of the methanol was evaporated taking care that the temperature did not rise above 30°C. The oily res- idue in suspension in water was taken up in diethyl ether. The water was discarded and the remaining so- lution was dried over MgSO, then concentrated. The crude compound was purified by flash chromatography on silica gel (hexane:methylene chloride 2:l) to afford 8a (0.80 g, 18.6%), m.p. 52.5"C.

IR (KBr) 3400, 1700, 1520, 1250, 1140 cm-'; 'H NMR 6 0.88 (t, 3H, J = 6.7 Hz), 1.27 (m, 12H), 2.47 (dd,

154 MARTIN AND GUIBET

Fig. 1. HPLC chromatogram of the mixture 8a:8b (1:l) obtained on (R)-phenyl glycine covalently substituted aminopropyl silica gel col- umn (5 pm, 250 x 4.6 mm). Mobile phase: hexane:CH,Cl,:EtOH (89:lO:l). Detection: UV, 230 nm. Flow rate: 1.0 mlimin. Injected amount 3 pg in 10 p1.

lH, J = 8.3, 17.4 Hz), 2.59 (dd, lH, J = 3.5, 17.4 Hz), 2.69 to 2.77 (m, 2H), 2.81 to 2.89 (m, 2H), 2.95 (d, lH, J = 3.4Hz), 3.87 (s, 3H), 4.02 (m, lH), 5.12 (s, 2H), 6.61 to 6.81 (m, 3H), 7.29 to 7.46 (m, 5H). Anal. Calcd for C26H3604: C, 75.69; H, 8.79. Found: C, 75.68; H, 8.61.

A second fraction corresponding to a mixture of 8a

Fig. 2. HPLC chromatogram of 8a charged with x% of 8b. Condi- tions as in Figure 1. Injected amount 3.5 pg in 10 ~ 1 .

and l a was also isolated (0.85 g) and it was used mixed with pure 8a in the next step.

A mixture of 7b (4.16 g, 10.2 mmol) and boric acid (1.24 g, 20.1 mmol) in methanol (450 ml) and water (60 ml) was hydrogenated under atmospheric pressure in the presence of W-2 Raney Nickel (5 g) at 25°C for 25 h with vigorous stirring. The catalyst was filtered off through celite and washed with methanol. The solvent was evaporated taking care that the temperature did not rise above 30°C. The crude product obtained was purified by flash chromatography on silica gel (hexane: ethyl acetate 2:l) to afford 8b (2.36 g, 56%), m.p. 55.5"C. IR (KBr) and 'H NMR data were identical to those of 8a. Anal. Calcd for C26H3604: C, 75.69; H, 8.79. Found: C, 75.81; H, 8.80.

5-Hydmxy-l-(4-hydroxy3-methoxyphenyl)-3-dodecanone (1 a and b)

8a (1.5 g, 3.6 mmol) in methanol (50 ml) was hydro- genated at 25°C and at atmospheric pressure in pres- ence of 5% Pd on charcoal (0.15 g). The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure taking care that the temperature did not rise above 30°C. The res- idue was purified by flash chromatography on silica gel (hexane:ethyl acetate 2:l) to give la (0.95 g, 81%), m.p. 30.5-31°C. IR (KBr) 3500, 1730, 1510, 1460, 1275 cm-l; 'H NMR 6 0.88 (t, 3H, J = 6.7 Hz), 1.27 (m, 12H), 2.47 (dd, lH, J = 8.3,17.5 Hz), 2.59 (dd, lH, J = 3.6, 17.5 Hz), 2.68 to 2.76 (m, 2H), 2.80 to 2.89 (m, 2H), 2.97 (d, lH, J = 2.4 Hz), 3.87 (s, 3H), 4.02 (m, lH), 5.52

Fig. 3. HPLC chromatogram of 8b charged with x% of 8a. Condi- tions as in Figure 1. Injected amount 3.5 pg in 10 ~ 1 .

155 [81 GINGEROL ENANTIOMERS

TABLE 1. Comparison of the optical rotation of synthetic and natural [81 gingerol

Compound [cyItD t ("C) Solvent

Natural [81

l a + 25.4" 25 Chloroform l b - 25.9" 25 Chloroform

a Chloroform gingerol' + 26.2"

T h e temperature was not given.

(s, lH), 6.63 to 7.26 (m, 3H). Anal. Calcd for C1gH3004: C, 70.77; H, 9.38. Found: C, 70.83; H, 9.26.

[aID + 25.4" (c = 0.5 in CHC1, at 25°C).

The enantiomer l b was prepared following the same procedure starting from 8b. It was obtained in 97% yield, m.p. 35°C. IR (KBr) and 'H NMR were identical to those of l a . Anal. Calcd for C1gH3004: C, 70.77; H, 9.38. Found: C, 70.88; H, 9.39.

[aID - 25.9" (c = 0.5 in CHC1, at 25°C).

RESULTS AND DISCUSSION

( + )-(S)- and ( - )-(R)-[8] gingerol were prepared ac- cording to the synthetic route outlined in Scheme 1. The dihydro isoxazole 2 was obtained (86%) by the re- action of the 1-nonene with the acetonitrile N-oxide generated in situ by using the Mukaiyama's process, i.e., by condensing nitroethane with phenyl isocyanate in the presence of triethylamine.12 The condensation of lithiated 2 with the sulfinate 313 proceeded with com- plete inversion of configuration at sulfur14 and gave a l i l mixture of the diastereoisomers 4a and 4b which were separated by column chromatography on silica gel leading to pure 4a (24.6% from 2) and 4b (23.1% from 2).

The synthesis was then carried on from each pure diastereoisomer. Metallation of 4 with LDA in the pres- ence of hexamethylphosphorotriamide (HMPA) and subsequent addition of 5' afforded 6. Attempts to iso- late 6 were unsuccessful because of its low stability. Indeed partial elimination of the tolylsulfinic acid was observed at a temperature as low as 30-40°C. Accord- ing to this result, we decided to completely transform 6 to 7 in boiling toluene, in the presence of pyridine.15 Only the E olefin was obtained as evidenced by the large 3JHH coupling constant (3JHH = 16.4 Hz). The double bond in 7 and the isoxazoline nucleus were si- multaneously reduced by a Raney-Nickel W-2 cata- lysed hydrogenation in acidic medium according to the process described for the 4,5-dihydroisoxazoles reduc- tion. l6 A partial hydrogenolysis of the benzyloxy func- tion occurred particularly when the catalyst was freshly prepared. The benzylated [81 gingerols 8a and 8b so obtained were analysed by HPLC on a Pirkle covalent phenylglycine chiral phase17 in order to check their optical purity (Fig. 1).

These two enantiomers were clearly separated under these conditions. However, similar trials carried out

with the [8] gingerol 1 were unsuccessful. It is likely that the presence of the very polar phenolic hydroxy group far from the chiral center hinders the separation of 1 into its isomers.

The optical purity of 8a and 8b was shown to be bet- ter than €US or S/R: 98/2. Our HPLC analytical tech- nique allowed us to observe the presence of 2% of 8a in 8b and vice versa. The corresponding chromatograms are shown in Figures 2 and 3.

The removal of the benzyl group by hydrogenolysis then afforded the compounds l a and lb . Their respec- tive optical rotations were measured and compared to that of natural [81 gingerol (Table 1).

These results were in good agreement with those ob- tained by HPLC for 8a and 8b.

In summary, we have described a short route to each enantiomer of [81 gingerol obtained in high enantio- meric purity.

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- . - - I

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Connell, D.W., Sutherland, M.D. Biosynthesis of [6]-Gingerol, pungent principle of zingiber oficinale. Aust. J . Chem. 22:1033- 1043, 1969. Suffert, J . Simple direct titration of organolithium reagents using N-pivaloyl-o-toluidine and/or N-pivaloyl-o-benzylaniline. J . Org. Chem. 54:509-510, 1989. Mukaiyama, T., Hoshino, T. The reactions of primary nitroparaf- fins with isocyanates. J. Am. Chem. Soc. 82:5339-5342, 1960. Aldrich Chimie, B.P. 234, 67006 Strasbourg CBdex. Solladie, G. Asymmetric synthesis using nucleophilic reagents containing a chiral sulfoxide group. Synthesis 185-196, 1981. Cinquini, M., Cozzi, F., Raimondi, L., Restelli, A. Enantiomeri- cally pure sulphinyl-4,5-dihydroisoxazoles. Gaz. Chim. Ital. 115: 347-350, 1985. Curran, D.P. Reduction of A'-isoxazolines. Raney-Nickel cata- lyzed formation of P-hydroxy ketones. J . Am. Chem. Soc. 105: 5826-5833, 1983. Pirkle, W.H., House, D.W., Finn, J.M. Broad spectrum resolution of optical isomers using chiral high performance liquid chromato- graphic banded phases. J. Chromatogr. 192:143-158, 1980.

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