Dmitry M. Volochnyuk

Following Ramachandran: exit vector plots (EVP) as a tool to navigate chemical space covered by 3D bifunctional scaffolds. The case of cycloalkanes

An approach to the analysis and visualization of chemical space covered by disubstituted scaffolds, which is based on exit vector plots (EVPs), is used for analysis of the simplest disubstituted cyclic cores – cycloalkanes – deposited in the Cambridge Structural Database (CSD). It is shown that four clearly defined regions are found in EVPs of the cycloalkanes, similar to those observed in Ramachandran plots for peptides. These results can be used for directed design of more complex scaffolds, classification of conformational space for the disubstituted scaffolds, rational scaffold replacement, or SAR studies.

Following Ramachandran 2: exit vector plot (EVP) analysis of disubstituted saturated rings

Analysis of disubstituted heteroaliphatic, as well as all common saturated rings using the exit vector plots (EVPs) tool is described, which is based on the Cambridge Structural Database (CSD) data. It is shown that the combined EVPs for saturated rings are similar to those observed for cycloalkanes (i.e. α, β, γ, and δ regions are found). In addition to that, a new region (e) is found which is not accessible by simple cycloalkane derivatives. It is shown that while introducing saturated rings into the molecules is widely considered as an approach to increase their non-planarity, not many of them are truly three-dimensional; some recommendations are given to address this issue.

Reaction of hydrazones derived from active methylene compounds with Vilsmeier–Haack reagent

Reaction of hydrazones derived from active methylene compounds with the Vilsmeier–Haack reagent was studied. Compounds with sulfone, ester, nitrile, triphenylphosphonium, and phthalimide moieties were evaluated. It was found that electron-withdrawing and steric effects provided by the substituent at α position strongly influenced the regioselectivity of the reaction. Increasing mesomeric electron-withdrawing effect of this group favors the formation of functionalized 1,3,4-trisubstituted pyrazoles as compared to 1,3-disubstituted pyrazole-4-carbaldehydes. On the contrary, enhanced steric hindrance and lowered electron-withdrawing effect shift the balance toward 1,3-disubstituted pyrazole-4-carbaldehydes. Other factors such as substituent at the nitrogen atom of the hydrazone, as well as reagent ratio, can affect the outcome of the reaction dramatically, so that in certain cases acyclic products are obtained.Graphical abstract

Reaction of hydrazones derived from electron-deficient ketones with Vilsmeier-Haack reagent

Abstract Reaction of hydrazones derived from ketones bearing an acceptor substituent adjacent to the carbonyl group (α,α,α-trifluoroacetone and ethyl pyruvate) with Vilsmeier-Haack reagent was studied. In most cases, the method allows for regioselective preparation of 1,3-disubstituted pyrazole-4-carbaldehydes – the products of initial C-electrophilic attack, although in one case, the product resulting from concurrent N- and C-attacks of the electrophile at the hydrazone moiety is observed. Under analogous conditions, the reaction of N-arylhydrazone derived from butanedione leads to the formation of 3-chloro-3-(1-arylpyrazol-3-yl)acrylaldehyde – the product of double formylation at both ketone and hydrazone moieties of the starting material.

A stereolibrary of conformationally restricted amino acids based on pyrrolidinyl/piperidinyloxazole motifs

Abstract A stereolibrary of conformationally restricted oxazole-containing amino acids, namely all isomers of 5–pyrrolydinyl- and 5-piperidinyloxazole-4-carboxylic acids, were designed and synthesized in three steps by the reaction of the corresponding N-Boc-protected amino acids and ethyl isocyanoacetate. These natural products-inspired amino acids are valuable building blocks for the synthesis of peptidomimetics and potential lead compounds for drug discovery.

Novel Synthetic Approaches to (Trifluoromethyl)triazoles

New synthetic procedures for the trifluoromethyl-substi- tuted triazoles, 3-(trifluoromethyl)-4H-1,2,4-triazole and 4-(trifluo- romethyl)-1H-1,2,3-triazole, have been elaborated. The target compounds were prepared from commercially available trifluoro- acethydrazide (one step) and methyl propiolate (three steps), re- spectively.