Asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-ene carboxylate

An expeditious asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-enecarboxylate has been achieved in four steps in 42% overall yield employing as the key step a domino reaction initiated by a highly diastereoselective lithium amide 1,4-conjugate addition to a nona-2,7-diendioic diester followed by a 6-exo-trig cyclisation of the thus formed enolate. Cope elimination protocol of the cyclic adduct affords, depending on the lithium amide used, the corresponding nitro-compound or the expected cyclohexene derivative. The methyl group attached to the cyclohexane ring is achieved by selective ester hydrolysis and subsequent Barton decarboxylation.

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Pent-3-yl (1S,2S,6S,αS)-2-(N-methyl-N-α-methylbenzylamino)-6-(pent-3-yloxycarbonylmethyl)-cyclohexanecarboxylateC28H45O4NEe, de: >95% (NMR)[α]D20=-2.5 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 1S,2S,6S,αS

(1S,2S,3S,αS)-2-[(2-Pent-3-yloxycarbonyl-3-N-methyl-N-α-methylbenzylamino) cyclohexylacetic acidC23H35O4NEe, de: >95% (NMR)[α]D20=-2.8 (c 2.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 1S,2S,3S,αS

Methyl (1R,2R,6R)-6-methoxycarbonylmethyl-2-nitrocyclohexanecarboxylateC11H17O6NEe, de: >95% (NMR)[α]D20=+2.9 (c 0.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 1R,2R,6R

Pent-3-yl (1S,2S,6S,αS)-6-methyl-2-(N-methyl-N-α-methylbenzylamino) cyclohexanecarboxylateC22H35O2NEe, de: >95% (NMR)[α]D20=-6.2 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 1S,2S,6S,αS

Pent-3-yl (S)-6-pent-3-yloxycarbonylmethyl cyclohex-1-enecarboxylateC19H32O4Ee: >95% (NMR)[α]D20=+18.1 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-2-(2-Pent-3-yloxycarbonyl cyclohex-2-enyl)acetic acidC14H22O4Ee:>95% (NMR)[α]D20=+23.9 (c 1.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: S

Pent-3-yl (R)-6-methyl-cyclohex-1-ene carboxylateC13H22O2Ee: >95% (NMR)[α]D20=+46.0 (c 0.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: R