Alkylation of enolate ions generated regiospecifically via organocopper reactions. Synthesis of decalin sesquiterpene valerane and of prostaglandin model systems

Abstract

Results are reported on alkylation reactions of four different structural types of cycloalkanone enolate ions (1-4) each of which is generated regiospecifically via an organocopper reaction with an , '-dibromo ketone or with a 2-cycloalkenone. These results provide information on the relative rates of enolate alkylation vs. equilibration in these systems, and they have led to a new total synthesis of the decalin sesquiterpene valerane and to an efficient method for construction of model systems for the E series of 11-deoxyprostaglandins.Regiospecific generation and alkylation of one enolate structural isomer of an unsymmetrical ketone under nonequilibrating conditions are often difficult and yet highly desirable.3 Copper-catalyzed conjugate addition of Grignard reagents to cyclohexenones and subsequent alkylation by reactive (e.g., benzylic) halides have been used in synthesis of lycopodine alkaloids4 and of substituted hydroazulenes.5 Stoichiometric organocopper conjugate addition reactions followed by alkylation6 or followed by Michael addition7 have recently been studied and have been applied to synthesis of steroids.8 We have been examining alkylation reactions of four different structural types of cycloalkanone enolate ions (1-4) which are generated regiospecifically via an organocopper reaction with an , '-dibromo ketone9 or with a 2-cycloalkenone.10 The results presented here provide information on the relative rates of enolate alkylation ví. enolate equilibration in these systems; these reactions have led to a new total synthesis of the decalin sesquiterpene valerane (itself not a natural product) and to a highly efficient method for direct conversion of 2cyclopentenone to trans-2,3-dialkylcyclopentanones, which are models for the E series of 11-deoxyprostaglandins.

Alkylations of Enols and Enolates

“…Scheme 9) show that alkylations of conformationally mobile l-enolates of 3-alkyl-and 2,3-dialkyl-cyclohexanones give products having the new groups at C-2 trans to the groups at C-3 with stereoselectivities in the 75 to 95% range. 41 ,44,45,79 Enolates of this type may exist as an equilibrium mixture of conformations (41) and (42). Conformation (42), having the 3-alkyl quasiaxial, is likely to be quite important, particularly when an alkyl group is present at C-2, because A 1,2-strain would destabilize conformation (41), which has a 3-alkyl group quasiequatoriaL Steric interactions involving the 3-alkyl group and the approaching electrophilic reagent appear to be minimized in either of the two possible transition states which lead to the introduction of the new group trans to the C-3 substitutent.…”

“…41 ,44,45,79 Enolates of this type may exist as an equilibrium mixture of conformations (41) and (42). Conformation (42), having the 3-alkyl quasiaxial, is likely to be quite important, particularly when an alkyl group is present at C-2, because A 1,2-strain would destabilize conformation (41), which has a 3-alkyl group quasiequatoriaL Steric interactions involving the 3-alkyl group and the approaching electrophilic reagent appear to be minimized in either of the two possible transition states which lead to the introduction of the new group trans to the C-3 substitutent. However, it is somewhat surprising that the stereoselectivity in favor of the trans'product is apparently somewhat greater for the allylation of the C-2-unsubstituted enolate (41a) H(42a) than for the 2-methyl enolate (41b) H (42b).45,79 (41) a: R 1 =Me, R 2 = H b: Rl =R2 =Me (42) The results of methylations of lithium 1(2)-enolates of (43a)75 and (43b)76 of trans-2-decalones are shown in Scheme 19.…”

“…104 Also, as shown in Scheme 28, conjugate addition-cycloalkylation was employed to synthesize a cis-fused decalone related to the sesquiterpene, (±)-valerane. 41 Apparently, in these cases, the enolate intermediate adopts a conformation having the 4-bromobutyl side chain quasiaxial, and C-C bond formation occurs via equatorial attack to give initially a twist-boat conformation of the product. In addition to (±)-valerane, a wide variety of other sesquiterpenes, including (±)-ishwarane,105 (±)-ishwarone,106 copaene,107 ylangene,107 (±)-seychellene l08 ,109 (±)-sativene,110 (±)-longifoline,111 (±)-copacamphene,112 (±)-damsin,113 (±)-a 902L capnellene,114 (±)-pentalenene,115 (-)-f3-vetivone I16 and (±)-f3-eudesmoI I17 have been synthesized by pathways involving cycloalkylation of saturated ketone enolates.…”

Chemistry of carbanions. XXVIII. Carbon-13 nuclear magnetic resonance spectra of metal enolates

“…This observation is consistent with the practice of adding HMP to an Et20 solution of a lithium enolate in order to increase its rate of reaction with an alkyl halide. 14 Interestingly, the most effective additive for increasing the value at the a carbon of the enolate 5 (to 25.9)…”

Methoxy(phenylthio)(trimethylsilyl)methane as a one-carbon homologation reagent: efficient 1,4-addition of a formyl or a carboxy anion equivalent to cyclic .alpha.-enones concomitant with in situ .alpha.-alkylation

“…2-(Phenylthio)butane (5a): liquid; 1H NMR (100 MHz, CDClg) 1.02 (t, J = 6 Hz, 3 ), 1.29 (d, J = 6 Hz, 3 ), 1.34-1.82 (m, 2 ), 3.20 (m, J = 6 Hz, 1 ), 7.20-7.50 (m, 5 H). and cis-8c were separated by column chromatography; 1H NMR (100 MHz, CDClg) 1.65-2.20 (m, 2 ), 2.70-3.10 (m, 2 H), 3.60-3.80 (m, 1 H), 3.66 (s, 3 H), 3.86 (s, 3 ), 4.14 (d, J = 4 Hz, 1 H), 6.26 (s, 1 ), 6.60 (s, 1 H), 6.94-7.42 (m, 10 H); IR 1260, 1500 cm "1. cis-6,7-Dimethoxy-l-phenyl-2-(phenylthio)-1,2,3,4-tetrahydronaphthalene (cis-Bc): yellow liquid; XH NMR (100 MHz, CDClg) 1.84-2.10 (m, 2 ), 2.80-3.00 (m, 2 ), 3.60-3.80 (m, 1 H), 3.66 (s, 3 H), 3.86 (s, 3 ), 4.40 (d, J = 3 Hz, 1 H), 6.36 (s, 1 ), 6.60 (s, 1 ), 7.00-7.36 (m, 10 H); IR 1260,1500 cm"1; MS, m/z (M+) caled for C24H24G2S 376.1497, found 376.1513. 6.7-Dimethoxy-l-(3'-oxobutyl)-2-(phenylthio)-l,2,3,4tetrahydronaphthalene (8d): yellow liquid; 1H NMR (100 MHz, CDClg) 2.08 (s, 3 ), 2.36-3.05 (m, 10 H), 3.82 (s), 3.90 (s), 3.96 (s), 6.84 (s, 1 ), 7.00 (s, 1 ), 7.05-7.44 (m, 5 H); IR 1260, 1510, 1710 cm"1; MS, m/z (M+) caled for C22H2603S 370.1603, found 370.1601.…”