Abstracts

ARTICLE

A new route to keto and alkyl derivatives of (R)-carvone via diastereoselective conjugate addition of nitronate ions

Jeronimo S. Costa^II; Bruno S. Freire^I; André L. S. Moura^I; Vera L. Patrocinio Pereira^* * e-mail: patrocinio@nppn.ufrj.br ^{, I}

^INúcleo de Pesquisas de Produtos Naturais, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco H, Cidade Universitária, 21941-590 Rio de Janeiro-RJ, Brazil

^IICentro Federal de Educação Tecnológica de Química, CEFETEQ, Rua Lúcio Tavares, 1045, 26530-060 Nilópolis-RJ, Brazil

ABSTRACT

The reactivity and diastereoselectivity of conjugate addition of different nitronates ions to (R)-carvone was systematically studied. The Michael adducts 2a-e were obtained in good yield and 3,2-cis-3,5-trans selectivity. The nitroadducts 2b,c were transformed via Nef reaction into (R)-carvone ketone derivatives 9,10 and nitroadducts 2b,d led to (R)-carvone alkylated derivatives 11,12, via a denitration reaction.

Keywords: nitroalkyl anions, Michael addition, Nef reaction, tetrabutylammonium fluoride

RESUMO

A reatividade e diastereosseletividade da adição conjugada de íons nitronatos representativos à (R)-carvona foi estudada. Os adutos de Michael 2a-e foram obtidos em bom rendimento e boa 3,2-cis-3,5-trans-seletividade. Os nitroadutos 2b e 2c foram transformados via uma reação de Nef nos ceto-derivados 9 e 10 ao passo que uma reação de desnitração transformou 2b e 2d nos derivados alquilados da carvona 11 e 12.

Introduction

Both enantiomers of carvone are commercially available at low cost and have been extensively used as chiral starting material in enantioselective syntheses of natural products with diverse biological activities.^1-6 The functional richness of 1 allows different synthetic transformations such as conjugate additions, electrophilic additions to electron-rich double bond, frame rearrangement, a-alkylation, carbonyl 1,2-addition, etc. In the case of conjugate addition, different nucleophiles have been added onto electron deficient double bond of 1, for example alkyl Grignard reagents,⁷ organocopper reagents,⁸ cyanide anion,⁸ allyl organoindium reagent,⁹ thiophenolate,¹⁰ silyl enol ethers¹¹ and alcoholate.¹² The stereochemistry of the addition of these nucleophiles is preferentially trans to the isopropenyl group.^7,8,10,13 Giving pursuit to our strategy to study the reactivity and diastereoselectivity of nitronate anions in nucleophilic additions to chiral nonracemic eletrophiles,^14-17 we imagine to develop a new route for the stereocontrolled introduction of acyl and alkyl groups into the structure of naturally occuring (R)-carvone and in this manner provides an entry into various potentially important synthetic intermediates. Thus the keto and alkyl derivatives of (R)-Carvone (1) 9-12 could be synthesized via conjugate addition of representative nitroalkanes 3-8 to 1 followed by Nef and denitration reaction, respectively.

Results and Discussion

The Table 1 shows the results obtained in the conjugate addition of nitroalkanes 3-8 to 1 using mostly TBAF.3H₂O as base.

Our results show that TBAF is an efficient promoter of the conjugate addition of 3-7 to 1 (entries 1-7). Others bases such as triethylamine, amberlyst-A21 or KF supported on alumine were not effective. Secundary nitroalkane 8 was essentially not reactive, even under severe reaction conditions (entries 8,9). The addition of the primary nitroalkanes 4 and 5 required excess of reagent (5 equiv.) or longer reaction time for efficient transformation to the desired adducts (entries 2-4). The diastereoselectivity was substantially increased by use of higher concentration of base and longer reaction time (entries 5-7), possibly due to epimerization of the stereocenter at a-carbonyl position¹⁸ (compare entries 2-4 with 5-7). No stereocontrol in the nitromethine stereocenter could be obtained due to easy epimerization of this sterereocenter in basic reaction media.^15,16 The transformation of the nitroadducts obtained in synthetic useful alkylated and keto-derivatives of 1 was also accomplished. Thus, the nitroadducts 2b,c could be transformed into corresponding ketone derivatives 9, 10 via a Nef reaction^19-21 mediated by Oxone^TM in good yield and good 3,2-cis-3,5-trans-selectivity, (d.e. 80%), Scheme 1.

Similarly, the nitroadducts 2b, 2d were easily denitrated²² to corresponding alkylated derivatives 11 and 12 (Scheme 2).

The unambiguous stereochemical assignment to the two new stereocenters formed in the conjugate addition (excluding the nitromethine stereocenter) could be done by chemical correlation with diastereomers of 12¹⁸ and by analysis of the spin coupling constant between H-2 and H-3 proton (J_{H1e H2a} 4.8Hz) in the ¹H NMR spectrum obtained, see Scheme 2. This valor is in agreement with a cis relationship among these hydrogens.¹⁸ The synthesis of 12 confirm the trans kinetical controled addition of nitronate ions to (R)-carvone (1)^7,8,10,13 and the epimerization of a carbonyl stereocenter in the conditions employed.¹⁸

Conclusions

The transformation of the obtained nitroadducts into alkylated derivatives of carvone complements methodologies of alkylation with the advantage of employing less demanding reaction conditions and low cost reagents. Additionally, the successful Nef reaction allowed the polarity inversion at the nitromethine center, enabling the direct introduction of different acyl groups in the in carvone which might be less practical via other methodologies. The highly functionalised chiral cyclohexanones 10-12 can be view as excellent starting compounds for the total synthesis of enantiomerically pure natural products.^1-6

Experimental

TBAF.3H₂O solid, nitromethane (3), nitroethane (4), 1-nitropropane (5), 2-nitropropane (8), THF, benzene, AIBN, n-Bu₃SnH and amberlyst-A21 were commercially available (Aldrich, Across or Merck) and were used as purchased. Methyl nitroacetate (6),²³ 1,1-dimetoxi-3-nitropropane (7)²⁴ were prepared according to literature procedures. ¹H NMR and ¹³C NMR spectra were recorded on Gemini-200 (200 MHz) Varian Instruments or on Brucker avance DRX (400 MHz) with TMS as internal reference. The coupling constant (J) is in Hertz (Hz). The IR spectra were recorded on a Nicolet Magna-IR-760 spectrometer and only the principal bands are reported. The analyses by GC-mass was realized on Shimadzu GC/MS-QP 500.

General procedure-preparation of the nitroadducts 2a-e

(2R,3R,5R)-5-isopropenyl-2-methyl-3-nitromethyl-cyclohexanone 2a. To a solution of 1 (1.0 g, 6.6 mmol) in 20 mL THF, under stirring, was added 3 (0.5 mL, 7.3 mmol) followed a solution of TBAF.3H₂O (0.6 g, 2 mmol) in 5 mL THF. The mixture was stirred at room temperature for 12 hours, then washed with H₂O (50.0 mL), extracted with CH₂Cl₂ (3 ´ 50.0 mL), the organic phase was dried over Na₂SO₄ and the solvent was removed in vacuum. The residue was purified by column chromatography on silica gel (Hexane/EtOAc 80:20) yielding 1.2 g (88%) of a mixture of diastereoisomers 2a (6.2 : 17.9 : 8. 4 : 1.0) as yellow oil. IR (neat) n_max/cm^-1: 2974; 2939; 2882; 1713; 1645; 1552; 1452; 1435; 1382; 1220; 898. ¹³C NMR (50 MHz, CDCl₃), major isomer: d 209.9; 145.5; 112.7; 78.7; 46.7; 43.6; 39.7; 38.7; 30.1; 21.6; 12.7. MS (70eV): m/z (%): M^+. 211 (3); 150 (6); 107 (20); 67 (52); 41 (100).

Nitroadduct 2d, mixture of diastereoisomers (10.0 : 7.5 : 4.5 : 1.0). IR (neat) n_max/cm^-1: 2972; 2920; 2884; 1756; 1713; 1645; 1561; 1439; 1370; 1217. ¹³C NMR (50 MHz, CDCl₃), spectroscopy data for the major isomer: d 209.5; 163.8; 145.4; 112.9; 88.6; 53.5; 46.2; 43.9; 43.7; 40.6; 27.7; 21.5; 12.3. MS (70eV): m/z (%): M^+. 269 (9); 222 (2); 163 (10); 150 (20); 121 (33); 107 (36); 95 (49); 67 (100); 55 (63).

(2R,3R,5R)-3-acetyl-5-isopropenyl-2-methyl-cyclohexanone 9a+9b

To a solution of 2b, (entry 3, table 1; 0.22g, 1 mmol) in MeOH (6 mL), was added 8 mL of a 0.5 mol L^-1 solution of Na₂HPO₄ whose solvent is a 1 mol L^-1 solution of NaOH. After 1 h, a solution of Oxone^TM (0.61 g, 1 mmol) in 3 mL of water was added to the stirred suspension. The resulting mixture was stirred at room temperature for 1 h, then acidified with a 10% solution of HCl and extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried with anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (Hexane/EtOAc 95:5) providing 0.14 g of 9a+9b (yield 70%, 9a:9b, 90:10, d.e. 80%) as a colorless oil. IR (neat) n_max/cm^-1: 2973, 2937, 2881, 1713,1646, 897. ¹H NMR (200 MHz, CDCl₃) for the major isomer: d 4.79 (d, 2H, J 8.1); 2.00-2.80 (m, 4H); 2.25 (s, 3H); 1.77 (s, 3H); 1.10-1.70 (m, 3H); 0.97 (d, 3H, J 6.2, 3H). ¹³C NMR (50 MHz, CDCl₃): d 210.9; 209.9; 146.4; 110.5; 57.2; 46.2; 45.3; 33.7; 30.0; 20.0; 16.6; 12.1. MS (70eV): m/z (%): M⁺ 194 (2); 151( M+. - COCH₃, 8 ); 109 (17); 55 (51); 43 ([CH₃CO]⁺, 100).

Denitration of 2b and 2d to 11 and 12, respectively-typical procedure

Methyl 2-((1S,2R,5R)-5-isopropenyl-2-methyl-3-oxo-cyclohexyl)acetate 12. A mixture of 2d (entry 6, Table 1) (0.72 g, 2.68 mmol), Bu₃SnH (3.9 g, 13.4 mmol) and AIBN (0.36 g, 2.2 mmol) in toluene (5 mL) was heated at 90 ºC for 90 min. The reaction mixture was subjected to column chromatography on silica gel (Hexane/EtOAc 96:4) to give 0.24 g (yield 68%) of 12 as colorless oil (d.e. 80%). IR (neat) n_max/cm^-1: 2971; 2952; 2938; 2880; 1737; 1712; 1645; 1437; 1378; 1249; 1220; 1163; 896. ¹H NMR (400 MHz, C₆D₆): d 1.02 (d, 3H, J 6.8); 1.34 (ddd, 1H, J 13.8, 9.5, 4.1); 1.63 (br s, 3H); 1.8-2.0 (m, 3H), 2.13 (dd, 1H, J 14.3, 5.9); 2.26 (dd, 1H, J 14.3, 3.4); 2.30-2.38 (m, 2H); 2.55 (1H, ddd, J 14.4, 4.8, 1.7); 3.4 (s, 3H); 4.85 (br s, 2H).¹³C NMR (100 MHz, C₆D₆): d 13.7; 23.6; 33.3; 37.6; 39.3; 41.4; 44.8; 51.8; 51.9; 113.1; 147.4; 173.1; 210.8. MS (70eV): m/z (%): M⁺ 224 (7); 193 (7); 150 (100); 151 (54); 109 (87); 67 (97).

(2R, 3R, 5R)-3-ethyl-5-isopropenyl-2-methyl-cyclohexanone 11. Data for the major isomer from mixture of diastereoisomers (1.1 : 1.0 : 2.4 : 13.6). IR (neat) n_max/cm^-1: 2966; 2935; 2875; 1712; 1645; 1445; 1377; 891. ¹H NMR (200MHz, CDCl₃): d 4.76 (m, 2H); 0.86-2.45 (m, 12H); 1.74 (brs, 3H); 1.04 (d, 3H, J 6.6). ¹³C NMR (50MHz, CDCl₃); spectroscopy data for the major isomer: d 212.9; 147.6; 109.4; 48.6; 46.5; 45.3; 45.0; 35.6; 26.1; 20.2; 11.2; 9.9. MS (70eV): m/z (%): M^+. 180 (9); 165 (6); 151 ( M^+. -Et, 3 ); 139 (3); 109 (44); 55 (78); 41 (100).

Acknowledgments

The authors thank FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro) for financial support and Professor Alessandro B. C. Simas for text revision.

Received: March 6, 2006

Published on the web: August 1, 2006

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