TY - JOUR

T1 - NMR-Verified Dearomatization of 5,7-Substituted Pyrazolo[1,5-a]pyrimidines

AU - Novikova, Daria

AU - Al Mustafa, Ammar

AU - Grigoreva, Tatyana

AU - Vorona, Svetlana

AU - Selivanov, Stanislav

AU - Tribulovich, Vyacheslav

N1 - Number: 18 Publisher: Multidisciplinary Digital Publishing Institute

PY - 2023/9/12

Y1 - 2023/9/12

N2 - Tetrahydropyrazolo[1,5-a]pyrimidine (THPP) is an attractive scaffold for designing biologically active compounds. The most obvious way to obtain such compounds is to reduce pyrazolopyrimidines with complex hydrides, because the pyrimidine ring is reduced in the preference over the pyrazole ring. The presence of substituents at positions five and seven of pyrazolo[1,5-a]pyrimidines complicates the set of reaction products but makes it more attractive for medicinal chemistry because four possible stereoisomers can be formed during reduction. However, the formation of only syn-isomers has been described in the literature. This article is the first report on the formation of anti-configured isomers along with syn-isomers in the reduction of model 5,7-dimethylpyrazolo[1,5-a]pyrimidine, which was confirmed by NMR. The bicyclic core in the syn-configuration was shown to be conformationally stable, which was used to estimate the long-range interproton distances using NOESY data. At the same time, long-range dipole–dipole interactions corresponding to a distance between protons of more than 6 Å were first registered and quantified. In turn, the bicyclic core in the trans-configuration represents a conformationally labile system. For these structures, an analysis of conformations observed in solutions was carried out. Our results indicate the significant potential of trans-configured tetrahydropyrazolo[1,5-a]pyrimidines for the development of active small molecules. While possessing structural lability due to the low energy of the conformational transition, they have the ability to adjust to the active site of the desired target.

AB - Tetrahydropyrazolo[1,5-a]pyrimidine (THPP) is an attractive scaffold for designing biologically active compounds. The most obvious way to obtain such compounds is to reduce pyrazolopyrimidines with complex hydrides, because the pyrimidine ring is reduced in the preference over the pyrazole ring. The presence of substituents at positions five and seven of pyrazolo[1,5-a]pyrimidines complicates the set of reaction products but makes it more attractive for medicinal chemistry because four possible stereoisomers can be formed during reduction. However, the formation of only syn-isomers has been described in the literature. This article is the first report on the formation of anti-configured isomers along with syn-isomers in the reduction of model 5,7-dimethylpyrazolo[1,5-a]pyrimidine, which was confirmed by NMR. The bicyclic core in the syn-configuration was shown to be conformationally stable, which was used to estimate the long-range interproton distances using NOESY data. At the same time, long-range dipole–dipole interactions corresponding to a distance between protons of more than 6 Å were first registered and quantified. In turn, the bicyclic core in the trans-configuration represents a conformationally labile system. For these structures, an analysis of conformations observed in solutions was carried out. Our results indicate the significant potential of trans-configured tetrahydropyrazolo[1,5-a]pyrimidines for the development of active small molecules. While possessing structural lability due to the low energy of the conformational transition, they have the ability to adjust to the active site of the desired target.

KW - 5-a]pyrimidine

KW - conformational analysis

KW - dearomatization

KW - long-range interproton distance

KW - NOESY

KW - proton–proton vicinal constants

KW - pyrazolo[1

KW - t$_1$ noise

KW - t$_2$ noise

UR - https://www.mendeley.com/catalogue/7d16aeda-229e-3e95-93a7-3e36dd51d022/

U2 - 10.3390/molecules28186584

DO - 10.3390/molecules28186584

M3 - Article

C2 - 37764360

VL - 28

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 18

M1 - 6584

ER -