Rearranging The Bicyclo[3.1.0]Hexane Template Of Carbocyclic Nucleosides To Improve Binding Recognition By Kinases

Abstract

A novel bicyclo[3.1.0]hexane carbocyclic nucleoside (4) with a south-like conformation amenable to interact with the herpes thymidine kinase (HSV-tk) was synthesized with an endo-hydroxyl group positioned at the tip of the bicyclo[3.1.0]hexane ring system opposite to the tip of the fused cyclopropane ring. The introduction of the hydroxymethyl chain through a Baylis-Hillman type reaction and the regioselective opening of a cyclic sulfite intermediate to introduce the nitrogen functionality at the correct position are highlighted.

Recent Contributions from the Baylis−Hillman Reaction to Organic Chemistry

“…Lei and Porco 984 have developed a facile methodology for total synthesis of the diazobenzofluorene antibiotic (-)kinamycin C, starting from the Baylis-Hillman adduct derived from the substituted quinine monoketal and formaldehyde, according to the reaction sequence shown in Marquez and Comin, 986 during their studies to understand the binding recognition by herpes thymidine kinase (HSVtk), have synthesized a novel bicyclic nucleoside using the Coelho and co-workers 989 have developed total synthesis of (()-bupropion, following the reaction sequence shown in Scheme 483, starting from the Baylis-Hillman adduct Webber and Krische 991 recently reported an interesting stereocontrolled formal synthesis of (()-quinine and (()-7-hydroxyquinine involving the intramolecular Baylis-Hillman reaction of the substrate 489 as the key step (Scheme 485).…”

“…Marquez and Comin, during their studies to understand the binding recognition by herpes thymidine kinase (HSV-tk), have synthesized a novel bicyclic nucleoside using the Baylis−Hillman reaction as the key step, following the reaction sequence shown in Scheme .…”

The Properties of Locked Methanocarba Nucleosides in Biochemistry, Biotechnology, and Medicinal Chemistry

“…As an example of this strategy, the target compound 125 was designed by a two-step reshuffling depicted in Figure 12.4 [41,42]. The reason for using this approach in drug discovery will be discussed in Section 4.1.…”

“…In seeking to alleviate this problem, it was decided to reposition the fused cyclopropane ring in 75 to the other end of the molecule, thereby generating a new compound (124) that still maintained an S-like conformation but allowed the thymine ring to sample the anti range, as shown earlier in Figure 12.4 [41,42]. Because compound 124 was prone to undergo ring opening at room temperature via a retroaldol reaction, the critical 3 0 -OH (nucleoside numbering) was relocated to the opposite end of the pseudoboat ring, where it could engage in H-bonding with the receptor in a manner akin to that of 75.…”