A mathematical model of realistic constitutional chemistry. A synthon approach. II: The model and organic synthesis

The notion of a Synthetic Precursor/Successor (SPS) is introduced, and an algorithm for the generation of all SPSs is given. The recursive algorithm is based on the so-called stabilization of a reaction center with respect to the whole synthon. The notion of the immersion of a subsynthon into a synthon and the notion of the order of SPSs are introduced. A mathematical theory of SPSs is given.     

Crystal structure prediction of aminols: advantages of a supramolecular synthon approach with experimental structures

The supramolecular synthon approach to crystal structure prediction (CSP) takes into account the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked. The working assumption is that while the experimental structure need not be at the global minimum, it will appear somewhere in a list of computationally generated structures so that it can be suitably identified and ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols. In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in the training database. Small and large synthons in these 13 crystal structures were then identified. Small synthons are of high topological but low geometrical value and are used in negative screens to eliminate computationally derived structures that are chemically unreasonable. Large synthons are more restrictive geometrically and are used in positive screens ranking upward predicted structures that contain these more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed with respect to their synthon content. The results are encouraging, and the predictions were classified as good, unclear, or bad. Two predictions were verified with actual crystal structure determinations.     

Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.

X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.     

Stereoselective synthesis of a new chiral synthon: a cyclic pseudodipeptide containing an aspartic acid derivative and l-valine

A simple stereoselective synthesis of cyclic synthons 4a,b and 10a,b, derived from an l-valine unit and an unnatural derivative of the aspartic acid, has been accomplished starting from the chiral synthon 1 and following the procedure already reported by us for the synthesis of similar compounds. These cyclic synthons are interesting substrates because they can behave as both electrophiles and nucleophiles and could be useful starting materials for the preparation of higher peptides such as, for instance, the unnatural tetrapeptides 15 and 18, through the condensation of 4a with 6a or 13 with 17, respectively.     

A facile two synthon approach to the camptothecin skeleton

A synthesis of deethyldesoxycamptothecin via the reaction of two readily accessible synthons is described. One of the synthons constitutes the ABC ring system of camptothecin, while the second provides all the C atoms of the rings D and E. The synthetic approach is suited for the total synthesis of camptothecin analogues.     

Novel synthon for incorporating 1,3-dimethyl imidazolium group into molecular architecture

The synthesized 1,3-dimethylated imidazolium-carbaldehydes serves as synthons for incorporating a permanently cationic imidazolium group into molecular framework. The utility of new synthon was demonstrated in a variety of reactions: Knoevenagel, Wittig, Schiff base formation, based-mediated electrophilic substitution, and oxidation, including synthesis of the natural product norzooanemonin.     

A New 2H‐Azirin‐3‐amine as a Synthon for 2‐Methylaspartate

The synthesis of a novel 2,2‐disubstituted 2H‐azirin‐3‐amine 3a as a building block for racemic Asp(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 3a with thiobenzoic acid and the amino acid Z‐Val‐OH yielded the racemic monothiodiamide 10a and the dipeptide 11 as a mixture of diastereoisomers, respectively (Scheme 2). In 11 , each of the protecting groups was removed selectively (Scheme 3). First attempts toward the preparation of enantiomerically pure synthons for Asp(2Me) with a chiral auxiliary group in the side chain are described. Synthons 3b with a 1‐(naphthalen‐1‐yl)ethyl ester group and 3c with a menthyl ester group were prepared and reacted with thiobenzoic acid to form monothiodiamides 10b and 10c (Scheme 2). However, the diastereoisomers of the synthons 3b and 3c could not be separated by chromatography.     

A new synthon for the synthesis of aminoinositol derivatives

The regio- and stereoselective synthesis of a new synthon, trans-3,8-dioxatricyclo[3.2.1.0^2,4]octane-6,7-diamine, from 7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate is reported. Transformation of the acid functionalities to acyl azides followed by Curtius rearrangement gave the corresponding trans-diisocyanate, which was reacted with HCl to produce a trans-diamino compound that is a potentially important synthon for the versatile synthesis of aminocyclitols.     

Enantioselective synthesis of methyl (5Z,8S)-8,9-epoxynon-5-enoate, an eicosanoid synthon

A six-step synthesis of methyl (5Z,8S)-8,9-epoxynon-5-enoate, a known synthon of constanolactones and hepoxilins, from 5-hexynoic ester was developed. The enantiomeric purity of the synthon was attained by S-enantiodirected dihydroxylation of a double bond in the intermediate methyl non-8-en-5-ynoate with subsequent enantioselective hydrolysis of the epoxide group in the admixture of the minor R-enantiomer. Dedicated to Academician V. A. Tartakovsky on his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1586–1592, August, 2007.     

Approaches to the synthesis of cytochalasans. Part 6. Synthesis of the C(14)–C(23) subunit of cytochalasins A,B. F and desoxaphomin

The synthesis of methyl (4R, 8R,)-10-bromo-8-methyl-4-(1,3,6-trioxaheptane)-2-deceneoate ( 5 ), a synthon for the construction of the macrocyclic moieties of the cytochalasins A ( 1), B. (2) F (3) and desoxaphomin ( 4 ) is described. (S)-Glutamic acid ( 6 ) was transformed to the C₅-epoxide 10 and 3-methylglutaric acid ( 11 ) to the C₅-bromide 15 . Coupling of both 10 and 15 by a CuI-catalyzed Grignard reaction gave the decanol 16 in very high yield. The latter was transformed by several steps to synthon 5 .     

New approach to carbamoyl-polyoxamic acid derivatives through an oxazolidinone synthon

A key oxazolidinone synthon was obtained through condensation of vinyl magnesium with an epoxyimine, followed by a carbonation/cyclisation reaction in the presence of ammonium carbonate. Oxidative ozonolysis after protection and carbamolylation (optional) afforded the (5-O-carbamoyl-)polyoxamic derivatives in 9% (or 14%) total yield in six (or four) steps.     

Modular synthesis of pyrrolo[2,1‐b]thiazoles and related monocyclic pyrrolo structures

A modular synthesis of selectively‐substituted pyrrolo[2,1‐b]thiazoles (Δ⁶ isomeric form) has been implemented, involving a distinctive bicyclization reaction of a mucobromic acid derivative followed by a Suzuki‐Miyaura coupling. A novel process of Δ⁶ to Δ⁷ isomerization of the pyrrolothiazole structure was uncovered that appears to involve a 1,4‐addition‐1,2‐elimination mechanism. Preparation of 1,5‐dihydropyrrol‐2‐one structures, selectively substituted at the 3‐ and 4‐positions, was also achieved using the mucobromic acid synthon in a reductive amination process. J. Heterocyclic Chem., (2011).     

A practical and enantiospecific conversion of d-galactose to a substituted α,β-unsaturated δ-lactone synthon

A multi-gram synthesis of a substituted α,β-unsaturated δ-lactone synthon, 1, was developed from commercially available d-galactose. The use of a Horner–Wadsworth–Emmons reaction was able to furnish, with Z selectivity, the enone ester that spontaneously lactonised to provide enantiomerically pure 1.     

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.     

Enantioselective synthesis of (1E,3S)-1-iodoundec-1-en-5-yn-3-ol,the eicosanoid synthon

A synthesis of the title compound, the synthon for the constanolactones and other eicosanoids, has been developed from achiral starting compounds. The synthesis is based on the S-enantiodirected dihydroxylation of the double bond to introduce a chirality and on the use of conformational restriction of the triple bond (the latent Z-double bond) surroundings.     

Studies for a Diastereoselective Synthesis of the Tetracyclic Diterpenic Diol Stemarin: A Model Study for a New Preparation of the Key Intermediate and the Synthesis of (+)-18-Deoxystemarin

Methods for a stereoselective preparation of compounds of type 2b , a key intermediate of a previous synthesis of the tetracyclic diterpene stemarin ( la ), have been tested on model compounds 5a, 5c , and 8a . Thus, (±)-(1RS,6SR,8SR,11SR)-hydroxytricyclo[6.2.2.0^l,6]dodecan-9-one ( 5a ) was transformed by the Mitsunobu reaction into (±)-(1RS,6SR,8SR,11RS)-11-(benzoyloxy)tricyclot[6.2.2.0^1,6]dodecan-9-one ( 6b ; Scheme 2). The latter was also obtained from (±)-(1RS,6SR,8SR,11RS)-11-[(4)-toluenesulfonyloxy]tricyclo[6.2.2.0^1,6]dodecan-9-one ( 5c ) by the action of Et₄N (PhCOO) in acetone. Compound 6b was then converted into (±)-(1RS,6RS,8RS,9RS)-tricyclo[6.2.2.0^1,6]dodecan-9-ol ( 8b ), a model for 2b . Compound 8b was also prepared from its epimer 8a by the Mitsunobu reaction via ester 7b . The inversion of configuration of bicyclo[2.2.2]octan-2-ols or derivates was not previously described. The model studies paved the way to the diastereoselective synthesis of (+)-18-deoxystemarin ( 1b ) via 12β-hydroxy-13-methyl-9β,13β-ethano-9β-podocarpan-15-one ( 10a ) and 13-methyl-9β,13β-ethano-9β-podpcarpan-12α-ol ( 11b ).     

New Applications of Computers in Chemistry

The mathematical model of constitutional chemistry described here is based on a concept of isomerism which has been extended from molecules to ensembles of molecules. A chemical reaction is the conversion of an ensemble of molecules into an isomeric ensemble. An ensemble of molecules is representable by an atomic vector and an associated bond and electron (BE)- matrix, and a reaction by a reaction (R)-matrix. These BE-and R-matrices serve as a basis for computer programs for the deductive solution of chemical problems. We present here algorithms and computer programs based on the theory of BE- and R-matrices. They enable the classification and documentation of structrues, substructures and reactions, the prognosis of reaction products,the design of syntheses, the construction of networks of mechanistic and synthetic pathways and the prediction of chemical reactions.     

Total synthesis of ent-cholesterol via a steroid C,D-ring side-chain synthon

For the first time, one of the two enantiomers of cholesterol (ent-cholesterol) has been synthesized by a synthetic route that starts from a precursor containing the D-ring and entire side chain of cholesterol. As part of the reported synthetic route, a method of general utility for the large scale (>10 g) preparation of each enantiomer of [1 alpha(R*),7a alpha]-1-(1,5-dimethylhexyl)-1,2,3,6,7,7a-hexahydro-7a-methyl-5H-inden-5-one, C,D ring-side chain synthons that can be used for the synthesis of enantiomers of vitamin D(3), cholesterol, and their analogues was also developed. Using the enantiomer of the C,D-ring side-chain synthon that leads to ent-cholesterol, the A- and B-rings were elaborated from a linear fragment that is sequentially cyclized to form the steroid B- and A-rings. Using this route, ent-cholesterol was prepared in 23 steps from the methyl ester of (1 alpha,5 alpha,6 alpha)-(+/-)-6-methyl-2-oxo-bicyclo[3.1.0]hexane-1-carboxylic acid in a total yield of 2.6%.     

Diphenyl cyanocarbonimidate. A versatile synthon for the construction of heterocyclic systems

A simple high yield synthesis of diphenyl cyanocarbonimidate is reported. This synthon may be used to prepare functionalized benzimidazoles, benzoxazoles and triazoles in good yield under mild conditions.     

The cyclic "silver-diphos" motif [Ag2(mu-diphosphine)2]2+ as a synthon for building up larger structures

The dinuclear, cyclic structural motif [Ag2(diphosphine)2](2+), here termed the "silver-diphos" motif, previously observed in many diphosphine-silver complexes, has been investigated as a synthon for building up larger structures such as coordination cages and polymers. A series of ligands containing one to four meta-substituted diphosphine groups, attached via a central core, has been synthesized from the corresponding fluoroarenes by reaction with KPPh2. Upon reaction with silver salts, the target synthon is adopted by meta-substituted diphosphines 1,3-bis(diphenylphosphino)benzene (L1), 2,6-bis(diphenylphosphino)benzonitrile (L2), and 3,5-bis(diphenylphosphino)benzamide (L3), each of which gives a single species in solution consistent with the expected dimeric complexes [Ag2L2(anion)2]. X-ray crystal structures of [Ag2(L1)2(OTf)2] and [Ag2(L2)2(SbF6)2] confirm the adoption of the silver-diphos motif in the solid state. Amide-functionalized diphosphine L3 forms a hydrogen-bonded chain structure in the solid state via the amide group. A discrete boxlike cage [Ag4(L4)2][SbF6]4 based on two silver-diphos synthons is formed when the tetraphosphine Ph2Sn{3,5-bis(diphenylphosphino)benzene}2 (L4) reacts with silver(I). Its single-crystal X-ray structure reveals a central cavity of minimum diameter, ca. 5.0 A, which contains a single SbF6(-) counterion disordered over two sites. In contrast to the highly selective behavior of the di- and tetra-phosphines L1-L4, the heptaphosphine P{3,5-bis(diphenylphosphino)benzene}3 L5 and the hexaphosphine PhSn{3,5-bis(diphenylphosphino)benzene}3 L6 give dynamic mixtures upon reaction with silver salts in solution. This nonspecific behavior is rationalized by the fact that their diphosphine groups are not appropriately disposed to form stable discrete structures based on the silver-diphos synthon. By contrast, the octaphosphine Sn{3,5-bis(diphenylphosphino)benzene}4 L7 does selectively form a single, discrete, highly symmetrical product in solution, [Ag4(L7)(OTf)4]. In this case, the ligand unexpectedly adopts an interarm tetra-chelating coordination mode, resulting in a continuous 24-membered ring around the periphery of the molecule. To understand the adoption of this unusual coordination mode, the alternative diphosphine Ph2Sn(3-diphenylphosphinobenzene)2 L8, which models a single interarm chelating site of L7, was also investigated. By contrast to L7, its coordination was nonspecific, giving mixtures of silver complexes upon reaction with AgOTf. The selective interarm chelation by L7 may therefore be stabilized by the continuous coordination ring in [Ag4(L7)(OTf)4]; that is, the four chelating sites can be thought of as acting in a cooperative manner. Alternatively, interarm steric repulsions between phenyl groups may favor interarm chelation. Overall, we conclude that, if the diphosphine groups are appropriately articulated to act independently (i. e., they are adequately separated and oriented), the silver-diphos synthon can be a useful tool for the coordination-based self-assembly of larger structures.