A New Route to Keto and Alkyl Derivatives of ( R )-Carvone via Diastereoselective Conjugate Addition of Nitronate Ions

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
][3][4][5][6] The functional richness of 1 allows different synthetic transformations such as conjugate additions, electrophilic additions to electron-rich double bond, frame rearrangement, α-alkylation, carbonyl 1,2addition, 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 ethers 11 and alcoholate. 12The stereochemistry of the addition of these nucleophiles is preferentially trans to the isopropenyl group. 7,8,10,13Giving pursuit to our strategy to study the reactivity and diastereoselectivity of nitronate anions in nucleophilic additions to chiral nonracemic eletrophiles, [14][15][16][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.3H 2 O 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 position 18 (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. 15,16The transformation of the nitroadducts obtained in synthetic useful alkylated and ketoderivatives of 1 was also accomplished.Thus, the nitroadducts 2b,c could be transformed into corresponding ketone derivatives 9, 10 via a Nef reaction [19][20][21] mediated by Oxone TM in good yield and good 3,2-cis-3,5-trans-selectivity, (d.e.80%), Scheme 1.
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 12 18 and by analysis of the spin coupling constant between H-2 and H-3 proton (J H1e H2a 4.8Hz) in the 1 H NMR spectrum obtained, see Scheme 2. This valor is in agreement with a cis relationship among these hydrogens. 18The 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

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New Route to Keto and Alkyl Derivatives of (R)-Carvone J. Braz.Chem.Soc.

Table 1 .
Synthesis of nitroderivatives 2a-f via Michael reaction of 3-8 to 1 a After purification by flash chromatography.b Measured by 13 C NMR and/or GC-mass.C All eight possible diastereoisomers were formed.Scheme 2. Synthesis of alkylated derivatives 11 and 12 from 2b and 2d, respectively.Scheme 1. Synthesis of ketone derivatives 9 and 10 from 2b and c, respectively.