Methylene-P-Toluenesulfonamide (−)-Carvone Is Spearmint Oil, Whereas the (S)-(+)- a B Enantiomer Is a Constituent of Dill and Caraway Oils

Methylene-P-Toluenesulfonamide (−)-Carvone Is Spearmint Oil, Whereas the (S)-(+)- a B Enantiomer Is a Constituent of Dill and Caraway Oils

Note 351 Synthesis and Analgesic-like Effect diterpene skeletons. Among the monoterpene starting − of (6R,4S)-p-Mentha-1,8-dien-6-yl- materials, probably the (+)- and ( )-forms of car- vone are the most versatile. The best source of (R)- methylene-p-toluenesulfonamide (−)-carvone is spearmint oil, whereas the (S)-(+)- a b enantiomer is a constituent of dill and caraway oils. Dami˜ao P. de Sousa , Franklin F. F. Nobrega ´ , The cost of (R)-(−)-carvone is usually much lower Reinaldo N. de Almeidab,andTimothyJ.Brocksomc than that of the (+)-isomer, but both enantiomers of a Laborat´orio de Qu´ımica de Produtos Naturais e Sint´eticos carvone have been used as chirons in the synthesis of Bioativos (LAPROBIO), Departamento de Fisiologia, Universidade Federal de Sergipe, diverse intermediates and natural compounds, princi- CEP 49100-000 S˜ao Crist´ov˜ao, Sergipe, Brazil pally terpenoids [1 – 4]. b Laborat´orio de Tecnologia Farmacˆeutica, Universidade The range of pharmacological activity that has been Federal da Para´ıba; Caixa Postal 5009, CEP 58051 – 970, recorded for terpenes is remarkably wide. They are Jo˜ao Pessoa, Para´ıba, Brazil c Laborat´orio de Qu´ımica Bio-Orgˆanica, Departamento de found to function as anticonvulsant, antinociceptive, Qu´ımica, Universidade Federal de S˜ao Carlos, sedative, and anxiolytic agents [5 – 11]. The range Caixa Postal 676, 13565-905 S˜ao Carlos, SP, Brazil of pharmacological effects of this family of natu- Reprint requests to Dr. Dami˜ao P. de Sousa. ral products is apparently due to a variety of ac- E-mail: damiao [email protected] tion mechanisms. Terpene derivatives also have been shown to have several effects on the central ner- Z. Naturforsch. 2009, 64b, 351 – 355; vous system (CNS), including antinociceptive [12, 13] received October 19, 2008 and sedative [14] activity. These facts led us to The synthesis of a monoterpene-based para-toluenesulf- verify in mice the psychopharmacological profile onamide is reported starting from naturally occurring (R)- of (6R,4S)-p-mentha-1,8-dien-6-yl-methylene-p-tolu- − ( )-carvone (1), by 1,2-addition of HCN followed by reduc- enesulfonamide (4), an intermediate prepared from tion with lithium aluminum hydride to afford the amino alco- − hols 3a and 3b. Tosylation of this mixture with p-toluenesulf- (R)-( )-carvone (1) in our terpene total synthesis onyl chloride furnished sulfonamide 4 in 55 % overall yield. studies. Compound 4 was evaluated in behavior animal models to in- vestigate its effects on the central nervous system. It showed Results and Discussion low toxicity and sedative action in mice, indicating it to be psychoactive. It also caused a decrease in the spontaneous (R)-(−)-Carvone (1) is an excellent, cheap and com- motor activity of mice. This depressant effect was confirmed in the acetic acid-induced writhing test, which demonstrated mercially available, chiral enantiopure starting mate- a significant antinociceptive response more potent than 1. rial for the synthesis of natural occurring compounds. The present results provide evidence that sulfonamide 4 has We have already reported the synthesis of a chiral analgesic-like psychopharmacological activity. synthetic intermediate for perhydroazulene terpenoids, − Key words: p-Toluenesulfonamide, Carvone, starting from (R)-( )-carvone (1) with initial 1,2- Monoterpene, Analgesic Activity, addition of the nucleophile trimethylsilyl cyanide [3]. Antinociceptive Activity In the present paper we report the synthesis of a p-toluenesulfonamide beginning with 1,4-addition of cyanide to (R)-(−)-carvone (1), a reaction already known to furnish selectively the adduct 2 in 90 % yield, isolated by crystallization [15, 16]. Introduction Thus, the reaction of (R)-(−)-carvone (1) with The total synthesis of naturally occurring terpenes potassium cyanide and acetic acid in ethanol under has always been an important research area, with the the published conditions [16] produced the nitrile 2 use of simple, chiral, enantiopure monoterpenes as (Scheme 1). Reduction of compound 2 with LiAlH4 starting materials being a relevant option [1, 2]. These gave a 95 : 5 mixture of amino alcohols 3a and 3b in monoterpene starting materials are readily available, 89 % yield. The constitution of the 3a/3b mixture was frequently in both enantiomeric forms, and contain sig- confirmed by micro-analysis of the L-(+)-tartaric acid nificant scaffolds of the desired mono-, sesqui-, and salts. Sulfonylation of these amino alcohols using p- 0932–0776 / 09 / 0300–0351 $ 06.00 c 2009 Verlag der Zeitschrift f¨ur Naturforschung, T¨ubingen · http://znaturforsch.com 352 Note CN O O HO CH2NH2 KCN, EtOH, H O 2 LiAlH4, THF acetic acid, 0 oC, 90 % r. t., 89 % % 9 6 1 o 2 C, 20 3a: a-OH 1 y, P 3b: β -OH Cl, Ts O CH2NH S O Scheme 1. Synthesis of (6R,4S)-p- mentha-1,8-dien-6-yl-methylene-p-tolu- 4 enesulfonamide (4). Fig. 1. Effect of sulfonamide 4 on spon- taneous motoric activity in mice. n =8; * p < 0.05, ** p < 0.01 significantly dif- ferent from control. Fig. 2. Effect of sulfonamide 4,(R)- (−)-carvone, morphine on acetic acid- induced writhing in mice. n =8;*p < 0.01 significantly different from control. toluenesulfonyl chloride afforded the easily purified p- ioral screening were suggestive of a central depres- toluenesulfonamide 4, in 69 % yield. TLC analysis of sant effect. The animals were found to show de- the reaction product suggested that both aminoalco- creased locomotive activity and an increase in sedation hols, 3a and 3b, had reacted. Noteworthy in this re- at 0.5 h and 1 h (Fig. 1) after administration of com- action is the concomitant dehydration of the secondary pound 4 (60 mg kg−1) indicating that the sulfonamide alcohol under the reaction conditions, which was not is psychoactive. In the evaluation of the antinocicep- entirely unexpected with the temperature used. tive profile, 4 (30, 60, 90 mg kg−1) significantly de- The pharmacological effects of the sulfonamide 4 on creased the incidence of acetic acid-induced writhing the CNS were then evaluated. The toxicological evalu- (Fig. 2). Compound 4 at 90 mg kg−1 produced a near- ation of compound 4 did not induce mortality up to a maximal inhibition of the writhing response, similar − dose of 1000 mg/kg in mice, and no significant toxic to3mgkg 1 of morphine. In comparison with the re- effect was found during the observation period. sults found for unprotected terpenes, such as (R)-(−)- On the basis of animal observation, 4 (60 mg kg−1) carvone (1) [6, 9], compound 4 was more potent and did not affect the motoric coordination and mus- less toxic. The LD50 value reported for (R)-(−)-carv- − cle tone. However, the parameters of the behav- one is 426.6 (389.0 – 478.6) mg kg 1 [6]. Fig. 2 shows Note 353 that a sulfonamide group in the structure of 4 enhances (1S,2S,4R,6S)-6-Aminomethyl-8-p-menthen-2-ol (3a) and the pharmacological effect and reduces the toxicity. (1S,2R,4R,6S)-6-aminomethyl-8-p-menthen-2-ol (3b) A dry, nitrogen-purged, 100 mL three-necked flask with a Conclusions magnetic stirrer was charged with a suspension of lithium aluminum hydride (1.189 g, 31.3 mmol) in anhydrous The data reported in this paper demonstrate the psy- tetrahydrofuran (76 mL). A solution of 8.0 g (45.19 mmol) chopharmacological activity of compound 4 in mice. of nitrile 2 in tetrahydrofuran (12.5 mL) was added drop- The study shows that 4 has a CNS-depressant effect wise over 20 min to this suspension and the stirring con- similar to some commonly used drugs. This effect of tinued for a further 1 h. Destruction of the excess lithium the sulfonamide was not different from that observed aluminum hydride was effected by cautious dropwise ad- for other psychoactive terpenes [8, 9, 17]. However, 4 dition of water (10 mL), followed by dropwise addition showed low toxicity, fewer side effects, and an im- of 15 % NaOH (10 mL), and subsequent addition of water proved pharmacological profile. Our experimental re- (30 mL). Stirring was continued until a granular white pre- sults also suggest that by appropriate structural modifi- cipitate was formed. Filtration yielded a clear tetrahydrofu- cation of monoterpenes it should be possible to develop ran solution which was dried over anhydrous sodium sulfate. novel analgesic drugs. The aminoalcohols 3a and 3b, in a 95 : 5 ratio according to gas chromatographic analysis, were isolated as free amines by removal of the tetrahydrofuran under reduced pressure Experimental Section (7.341 g, 40.11 mmol, 89 % yield). The 3a/3b mixture (1.0 g) General was subjected to column chromatography over neutral alu- mina, eluting with hexane-EtOAc (1 : 1) to afford aminoal- GLC analyses were performed on a Shimadzu GC-17A cohol 3a (0.792 g, 79 % yield). Compound 3a: M. p. 72.8 – instrument equipped with a flame-ionization detector, us- ◦ α 30 + . ν 73.5 C. – [ ]D = 7 0(c =1.0;CHCl3). – IR (film): = ing a DB-1 (30 m × 0.25 mm) glass column. Column chro- 3489, 2933, 1647, 1037, 993, 887 cm−1.–1HNMR:δ = matography was performed on silica gel 60 (70 – 230 mesh 4.73 (2H, s), 3.75 (1H, q, J = 3.2 Hz), 2.92 (2H, s), 2.84 (2H, ASTM Merck). Radial thin-layer chromatography was car- d, J = 3.4 Hz), 2.35 (1H, tt, J = 3.6 Hz; 11.6 Hz), 2.00 – ried out on a Chromatotron model 8924 (silica gel 60PF274 1.93 (1H, m), 1.92 – 1.89 (1H, m), 1.87 – 1.84 (1H, m), 1.74 Merck). Melting points were determined on a Microqu´ımica (3H, s), 1.68 (1H, s), 1.65 – 1.59 (1H, m), 1.46 – 1.20 (2H, MQWAPF-301 apparatus and are uncorrected.

View Full Text

Details

  • File Type
    pdf
  • Upload Time
    -
  • Content Languages
    English
  • Upload User
    Anonymous/Not logged-in
  • File Pages
    5 Page
  • File Size
    -

Download

Channel Download Status
Express Download Enable

Copyright

We respect the copyrights and intellectual property rights of all users. All uploaded documents are either original works of the uploader or authorized works of the rightful owners.

  • Not to be reproduced or distributed without explicit permission.
  • Not used for commercial purposes outside of approved use cases.
  • Not used to infringe on the rights of the original creators.
  • If you believe any content infringes your copyright, please contact us immediately.

Support

For help with questions, suggestions, or problems, please contact us