Synthetic Feasibility Research Articles

Predicting synthetic accessibility: application in drug discovery and development.

The estimation and use of synthetic accessibility in the drug discovery process is discussed. A distinction is drawn between synthetic feasibility and accessibility and the practical uses of an accessibility score are examined. Various techniques used in the estimation of accessibility are described and their utility and potential accuracy compared.

The aza-xylylene Diels–Alder approach for the synthesis of naturally occurring 2-alkyl tetrahydroquinolines

The recently discovered intramolecular aza-xylylene Diels–Alder reaction, based on a 1,4-dehydrohalogenation reaction, was extended in terms of substrates and leaving groups allowing the assembly of tetrahydroquinolines in two synthetic steps. Intramolecular cleavage of a thiocarbamate using triphenylphosphine and tetrachloromethane (Appel conditions) to give chloromethyl phenylisocyanate has been presented for the first time. The synthetic feasibility of this process was demonstrated in the first total syntheses of the alkaloids rac-Angustureine and 1-methyl-2-propyltetrahydroquinoline.

2,7,12,17‐Tetra(p‐butylphenyl)‐3,6,13,16‐tetraazaporphycene: The First Example of a Straightforward Synthetic Approach to a New Class of Photosensitizing Macrocycles

AbstractSelected on the basis of computational studies and synthetic feasibility, the title compound 9c has been obtained by cross‐coupling of 4,4′‐bis(p‐butylphenyl)‐2,2′‐biimidazole‐5,5′‐dicarbaldehyde (28c) followed by oxidative aromatization. The introduction of a Suzuki coupling protocol opens the way to 2,7,12,17‐tetraryl‐substituted 3,6,13,16‐tetraazaporphycenes avoiding the development of a de novo synthesis whenever a new peripheral substituent is desired. As predicted by computational studies, oxidation of the non‐aromatic precursor 33c to yield the azaporphycene macrocycle 9c is more favourable than in the case of porphycene itself. The absorption spectrum of 9c shows a substantial bathochromic shift relative to porphycene 1a, revealing a synergism between aza substitution in the macrocycle and phenyl substitution at its periphery. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Heterobuckybowls: a theoretical study on the structure, bowl-to-bowl inversion barrier, bond length alternation, structure-inversion barrier relationship, stability, and synthetic feasibility.

Hybrid density functional theory (DFT) calculations at the B3LYP/cc-pVDZ level have been performed on a series of heterobuckybowls, 3X, C(18)X(3)H(6) (X = O, NH, CH(2), BH, S, PH, PH(3), Si, SiH(2), and AlH). The minimum energy conformations and the transition states for bowl-to-bowl inversion, where the geometry is bowl shaped, are computed and characterized by frequency calculations. The geometries of heterotrindenes, 2X, C(12)X(3)H(6) (X = O, NH, CH(2), BH, S, PH, PH(3), Si, SiH(2), and AlH), were obtained, and the bond length alternation (Delta) in the central benzenoid ring shows remarkable sensitivity as a function of substituent with a wide range of fluctuations (-0.014 to +0.092 A). The Delta computed in 2BH was found to be comparable with the highest bond alternation reported to date in benzenoid frameworks. The inversion dynamics of these heterobowls and their bowl depths were fit to a mixed quartic/quadratic function. The size of the heteroatom seems to exclusively control the bowl depth and rigidity as well as the synthetic feasibility. In contrast, the bond length alternation seems to be controlled by electronic factors and not by the size of the substituted atom either in trindenes or in heterosumanenes. The thermodynamic stability of this class of compounds is very much comparable with trithiasumanene (3S), which has been synthesized recently. The chemical hardness (eta) was measured to assess the stability of the heterosumanenes. The strain energy buildup in a sequential ring closure strategy along two synthetic routes, namely a triphenylene route and a trindene route, were explored, and the trindene route was found to be highly favorable for making such compounds compared to the triphenylene route. However, in both routes the ease of the synthetic feasibility increases as the size of the heteroatom increases.

Aspartic Protease Inhibitors Designed from Computer-Generated Templates Bind As Predicted

[reaction: see text] Novel tripeptide-derived peptidomimetics 1, 7ab, and 8ab, inspired by templates generated by the structure-generating program GrowMol, were synthesized, shown to inhibit Rhizopus chinensis pepsin, and found by X-ray crystallography to bind to the enzyme in the GrowMol-predicted mode. Repetitive evaluation of the computer-generated templates for synthetic feasibility and optimal enzyme interactions led to the designed compounds.

A novel prodrug approach for tertiary amines. 2. Physicochemical and in vitro enzymatic evaluation of selected N‐phosphonooxymethyl prodrugs

Quaternary amine prodrugs resulting from N‐phosphonooxymethyl derivatization of the tertiary amine functionality of drugs represents a novel approach for improving their water solubility. Separate reports have demonstrated the synthetic feasibility and rapid and quantitative prodrug to parent drug conversion in rats and dogs. This work is a preliminary evaluation of the physicochemical and in vitro enzymatic reversion properties of selected prodrugs. The loxapine prodrug had over a 15 000‐fold increase in aqueous solubility relative to loxapine free base at pH 7.4. The loxapine prodrug was also shown to be quite stable at neutral pH values. The time for degradation product (parent drug) precipitation from an aqueous prodrug formulation would be expected to dictate the shelf life. Using this assumption, together with solubility and elevated temperature chemical stability studies, the shelf life of a parenteral formulation of the loxapine prodrug was projected to be close to 2 years at pH 7.4 and 25 °C. In addition, the prodrugs of cinnarizine and loxapine have been shown to be substrates for alkaline phosphatase, an enzyme found throughout the human body, and revert to the parent compound in its presence. The results from these evaluations demonstrate that the derivatives examined have many of the ideal properties required for potential clinical application.

Trimethyl Orthoformate as a Highly Selective Mono-C-Methylating Agent for Arylacetonitriles

The mono-C-methylation of arylacetonitriles (ArCH2CN, 1) to produce 2-arylproprionitriles [ArCH(CH3)CN, 2] represents a valuable reaction especially from a pharmaceutical standpoint. In fact, a number of compounds 2 are key intermediates for the synthesis of nonsteroidal analgesics of the hydratropic acid (2-arylpropanoic acid) class.1 Common well-known examples are Ibuprofen, Ketoprofen, and Naproxen (Chart 1). However, synthetic procedures for the direct monomethylation of 1 fail with classical alkylating agents (methyl halides and dimethyl sulfate) because mixtures of monoand dimethylated products are always obtained (Scheme 1).2 For instance, the alkylation of phenylacetonitrile with CH3I is reported with a monoto dimethyl selectivity of 84%, at a conversion of 86%.3 Although a number of multistep alkylation methods have been developed for the preparation of 2-arylpropanoic acids,1 the achievement of an effective one-pot procedure still represents a challenging task and may deserve attention from both the economical standpoint and the synthetic feasibility. Concerning this, a very efficient procedure is the ruthenium-catalyzed reductive methylation of active methylene compounds carried out at 135-230 °C with paraformaldehyde.4 However, we extensively reported that direct highly selective mono-C-methylations of CH2acidic compounds (YCH2X) can also be performed by the use of dimethyl carbonate (DMC) as a methylating agent, without any metal catalyst.5-11 Thus, at 180-210 °C in the presence of weak bases (K2CO3), aryland aroxyacetonitriles, methyl aryland aroxyacetates (Y ) Ar, ArO; X ) CN, CO2CH3), and R-methylene sulfones (Y ) Ar, X ) SO2Ar, SO2R) yield the corresponding mono-Cmethyl derivatives with selectivities >99% at a complete substrate conversion. In addition, the procedure is a true environmentally benign one: DMC is a nontoxic reagent, the base can be used catalytically, and neither organic nor inorganic byproducts are formed and need to be disposed of.12,13

Novel angiotensin II receptor antagonists. Design, synthesis, and in vitro evaluation of dibenzo[a,d]cycloheptene and dibenzo[b,f]oxepin derivatives. Searching for bioisosteres of biphenylyltetrazole using a three-dimensional search technique.

Three-dimensional substructure searching (3D search), using the program MACCS-3D, was utilized for designing novel angiotensin II receptor antagonists which contain a bioisostere of the biphenylyltetrazole moiety of DuP 753. A 3D query was prepared from an overlay model of substructures of several potent AII antagonists. The search system retrieved 139 compounds from the database MDDR-3D, which consisted of 29,400 medicinal patent compounds. A tricyclic compound was selected from the retrieved compounds and then evolved by considering steric fitness to the overlay model and synthetic feasibility. Finally, various novel AII antagonists having dibenzo[a,d]cycloheptene or dibenzo[b,f]oxepin were designed and synthesized. The receptor binding activity (Ki) for several members of this series was in the 10(-10) M range, demonstrating the ability of 3D search technique to explore new lead structures.

Rational Selection of Test Series for QSAR‐Analysis

AbstractA method for the rational selection of test series with low collinearities of molecular descriptors and high data variance is presented (RVS method). This method selects analogs on the basis of a selection criterium which combines multiple correlation coefficients R, relative parameter variances V and the synthetic feasibility S of test series. Special flexibility of the method is provided by weighting factors which are adapted until a satisfactory series is obtained. Examples of the application of the RVS method are given, and the results are compared with results from other selection techniques.

On the rational selection of test series. 2. Two-dimensional mapping of intraclass correlation matrices.

A rational design of optimal test series can be performed by two-dimensional mapping of intraclass correlation matrices (TMIC method). The method results in a two-dimensional map from which substituents can be selected by simple inspection. Different test series can be obtained from the same map so that synthetic feasibility can easily be taken into account. The approach closely corresponds to the usual way of thinking of organic chemists, and the test series evaluated for an example show high data variance and low collinearities.