Synthesis of Optically Active 5-(tert-Butyldimethylsiloxy)-2-cyclohexenone and Its 6-Substituted Derivatives as Useful Chiral Building Blocks for the Synthesis of Cyclohexane Rings. Syntheses of Carvone, Penienone, and Penihydrone

Abstract

Optically active 5-(tert-butyldimethylsiloxy)-2-cyclohexenone (1) and its 6-substituted derivatives 2a,b were synthesized from the readily available optically active ethyl 3-(tert-butyldimethylsiloxy)-5-hexenoate (4), where the Ti(II)-mediated intramolecular nucleophilic acyl substitution reaction and the FeCl3-mediated ring expansion reaction of a 1-hydroxybicyclo[3.1.0]hexane are the key reactions. The enone 1 reacted with higher-order cyanocuprates with excellent diastereoselectivity to afford the trans-addition products, trans- 13, in excellent yields. The reaction of 1 with lower-order cyanocuprates proceeded with moderate to excellent syn-selectivity to afford cis- 13. Treatment of trans- and cis- 13 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or catalyst p-TSA (p-toluenesulfonic acid) resulted in a β-elimination reaction to furnish the corresponding optically active 5-substituted-2-cyclohexenones 14. The 1,4-addition reaction of 2a and 2b with organocyanocuprates followed by treatment of the resulting 20 with DBU provided the 2,5-disubstituted-2-cyclohexenones 19 with excellent ee. The conversion of 14 into the 3,5-disubstituted-2-cyclohexenone 22 has also been carried out via 1,2-addition of alkyllithium onto the carbonyl group and the following oxidation with PCC (pyridinium chlorochromate). Similarly, the conversion of 19 into 2,3,5-trisubstituted-2-cyclohexenones 24 has been carried out. A highly efficient, first total synthesis of penienone 25 and penihydrone 26 has been accomplished. Thus, the 1,4-addition reaction of 1 with the (E,E)-1,3-heptadienyl cyanocuprate and consecutive trap of the resulting copper enolate with formaldehyde gave 28, which upon treatment with DBU or Pyr·HF yielded 25 and 26, respectively. An efficient synthesis of both enantiomers of carvone starting from (S)- 20ab has been also accomplished.

Mechanisms of Copper‐mediated Addition and Substitution Reactions

“…In addition, the cyanide anion finds its way onto copper at the end of the reaction, forming RCu(CN)Li, while it is not known when the cyanide/copper coordination starts. The true role of the cyano group in the reactions of ''higher order cyanocuprates'' remains obscure [164,167]. 10.6.5…”

Straightforward and Efficient Synthesis of (4R,6S)-4-(tert-Butyldimethyl­siloxy)-6-(hydroxymethyl)tetrahydropyran-2-one

“…Subsequent TBS protection was achieved with TBSCl in DMF in the presence of imidazole to produce (S)-ethyl 3-(tert-butyldimethylsiloxy)-4-iodobutanoate (6) in 90% yield. We conveniently isolated products of the first two steps by vacuum distillation instead of chromatography 16 to facilitate a large-scale preparation. We modified the third reaction step of this sequence where we used vinylmagnesium chloride, which is an industrially produced and less hazardous chemical in comparison to vinylmagnesium bromide.…”

Enantioselective synthesis of (R)-isocarvone from (S)-perillaldehyde

“…Subsequently, a solution of PhSSPh (630 mg, 2.9 mmol) in 3 mL of dry THF was added to this mixture. The resultant mixture was stirred at rt for 1.5 h and poured into a saturated NH 4 Cl solution (10 mL) and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with 10% aq.…”

“…[1][2][3][4][5] Often, when such cyclohex-2-enones are needed, they are derived from naturally occurring sources, such as carvone, 6,7 pulegone, [8][9][10] sugars, 11 pinene, 12 quinic acid, 13,14 or quebrachitol. 15,16 A critical role in complex molecule construction relies on availability into specific optically pure targets along with reactions to elaborate and couple them.…”