Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes: Novel Building Blocks for Asymmetric Catalysis

Abstract

We report the synthesis of three novel and chiral salicylic aldehyde building blocks 6−8, each in both enantiomerically pure forms. Two of these salicylic aldehydes were prepared from (+)-camphene and each bear a [2.2.1]bicycloheptyl substituent ortho to the salicylic hydroxy group. In the third case, the chiral element at the 6-position is a (1-phenylethyl) group. The synthetic sequences consisted of ortho-alkylation of para-cresol with either camphene or styrene and subsequent ortho-formylation of the product phenols. The chromatographic separation of enantiomers was accomplished through the diastereomeric imines obtained from condensation of the racemic salicylic aldehydes with (R)-phenylglyci-

Separation of racemic salycylaldehydes containing isobornyl substituent using (R)-1-phenylethylamine

“…The absolute configuration of the chiral centers in the enantiomerically-enriched salicylaldehydes (+)-and (-)-(IIa, IIb) was established from the configuration of imines prior to hydrolysis. The data on the absolute configuration and signs of the angles of the optical rotation of (+)-and (-)-(IIb) enantiomers are consistent with those published in [6].…”

“…The reaction products were separated by column chromatography (graduent elution with petroleum ether-Et 2 O with growing content of the latter). The spectral characteristics of aldehydes obtained were in agreement with those described in [6,12]. Schiff bases III, IV.…”

“…The separation of phenols containing a chiral fragment is carried out using preparative HPLC that requires the application of expensive columns packed with chiral stationary phases [6,7]. The other approach employs a preliminary preparation of therpenophenol derivatives with expensive chiral reagents, for instance, (R)-phenylglycinol [6].…”

Separation of racemic salycylaldehydes containing isobornyl substituent using (R)-1-phenylethylamine

“…The absolute configuration of the chiral centers in the enantiomerically-enriched salicylaldehydes (+)-and (-)-(IIa, IIb) was established from the configuration of imines prior to hydrolysis. The data on the absolute configuration and signs of the angles of the optical rotation of (+)-and (-)-(IIb) enantiomers are consistent with those published in [6].…”

“…The reaction products were separated by column chromatography (graduent elution with petroleum ether-Et 2 O with growing content of the latter). The spectral characteristics of aldehydes obtained were in agreement with those described in [6,12]. Schiff bases III, IV.…”

“…The separation of phenols containing a chiral fragment is carried out using preparative HPLC that requires the application of expensive columns packed with chiral stationary phases [6,7]. The other approach employs a preliminary preparation of therpenophenol derivatives with expensive chiral reagents, for instance, (R)-phenylglycinol [6].…”

Evaluation of antiviral activity of terpenophenols and some of their N- and O-derivatives

“…Terpenophenols 1-6, 13-19 and their derivatives 29, 30 were synthesized according to known methods. 8, [16][17][18][19] Hydrochlorides 21-28 were prepared to increase the solubility of previously prepared Mannich bases 6,7, 20 in DMSO. Compounds 13-30 are racemates.…”

“…Compounds 13-30 are racemates. R = 6-Me (13), 5-Me (14), 2,4-Me 2 (15), 2-ОН ( 16), 2-ОН, 4-Me (17), 3-ОН (18), 4-ОН (19) By condensation of substituted isobornylbenzaldehydes with 1-adamantylamine followed by reduction (in situ) of intermediate imines, aminomethyl derivatives containing the 1-adamantyl group at the nitrogen atom were synthesized for the fi rst time; they were also converted into the corresponding hydrochlorides 27 and 28. The synthesis of compound 27 is shown in Scheme 2 as an example.…”

Separation of racemic salycylaldehydes containing isobornyl substituent using (R)-1-phenylethylamine

“…The absolute configuration of the chiral centers in the enantiomerically-enriched salicylaldehydes (+)-and (-)-(IIa, IIb) was established from the configuration of imines prior to hydrolysis. The data on the absolute configuration and signs of the angles of the optical rotation of (+)-and (-)-(IIb) enantiomers are consistent with those published in [6].…”

“…The reaction products were separated by column chromatography (graduent elution with petroleum ether-Et 2 O with growing content of the latter). The spectral characteristics of aldehydes obtained were in agreement with those described in [6,12]. Schiff bases III, IV.…”

“…The separation of phenols containing a chiral fragment is carried out using preparative HPLC that requires the application of expensive columns packed with chiral stationary phases [6,7]. The other approach employs a preliminary preparation of therpenophenol derivatives with expensive chiral reagents, for instance, (R)-phenylglycinol [6].…”

Evaluation of antiviral activity of terpenophenols and some of their N- and O-derivatives

“…Terpenophenols 1-6, 13-19 and their derivatives 29, 30 were synthesized according to known methods. 8, [16][17][18][19] Hydrochlorides 21-28 were prepared to increase the solubility of previously prepared Mannich bases 6,7, 20 in DMSO. Compounds 13-30 are racemates.…”

“…Compounds 13-30 are racemates. R = 6-Me (13), 5-Me (14), 2,4-Me 2 (15), 2-ОН ( 16), 2-ОН, 4-Me (17), 3-ОН (18), 4-ОН (19) By condensation of substituted isobornylbenzaldehydes with 1-adamantylamine followed by reduction (in situ) of intermediate imines, aminomethyl derivatives containing the 1-adamantyl group at the nitrogen atom were synthesized for the fi rst time; they were also converted into the corresponding hydrochlorides 27 and 28. The synthesis of compound 27 is shown in Scheme 2 as an example.…”

Separation of racemic salycylaldehydes containing isobornyl substituent using (R)-1-phenylethylamine

“…The absolute configuration of the chiral centers in the enantiomerically-enriched salicylaldehydes (+)-and (-)-(IIa, IIb) was established from the configuration of imines prior to hydrolysis. The data on the absolute configuration and signs of the angles of the optical rotation of (+)-and (-)-(IIb) enantiomers are consistent with those published in [6].…”

“…The reaction products were separated by column chromatography (graduent elution with petroleum ether-Et 2 O with growing content of the latter). The spectral characteristics of aldehydes obtained were in agreement with those described in [6,12]. Schiff bases III, IV.…”

“…The separation of phenols containing a chiral fragment is carried out using preparative HPLC that requires the application of expensive columns packed with chiral stationary phases [6,7]. The other approach employs a preliminary preparation of therpenophenol derivatives with expensive chiral reagents, for instance, (R)-phenylglycinol [6].…”

Evaluation of antiviral activity of terpenophenols and some of their N- and O-derivatives

“…Terpenophenols 1-6, 13-19 and their derivatives 29, 30 were synthesized according to known methods. 8, [16][17][18][19] Hydrochlorides 21-28 were prepared to increase the solubility of previously prepared Mannich bases 6,7, 20 in DMSO. Compounds 13-30 are racemates.…”

“…Compounds 13-30 are racemates. R = 6-Me (13), 5-Me (14), 2,4-Me 2 (15), 2-ОН ( 16), 2-ОН, 4-Me (17), 3-ОН (18), 4-ОН (19) By condensation of substituted isobornylbenzaldehydes with 1-adamantylamine followed by reduction (in situ) of intermediate imines, aminomethyl derivatives containing the 1-adamantyl group at the nitrogen atom were synthesized for the fi rst time; they were also converted into the corresponding hydrochlorides 27 and 28. The synthesis of compound 27 is shown in Scheme 2 as an example.…”