Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template

Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a "one-bead, one-stock solution" technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.     

Extensively stereodiversified scaffolds for use in diversity-oriented library synthesis

The syntheses of stereodiverse libraries of 12 and 19 are reported, where each asterisk represents an independently varied stereocenter. These scaffolds provide additional templates for investigations of geometric diversity in library syntheses. Libraries of these N-Fmoc-amino acids were further functionalized by incorporation into a peptide sequence, demonstrating the utility of 12 and 19 as building blocks for diversity oriented synthesis.     

Accelerating fluorescent sensor discovery: unbiased screening of a diversity-oriented BODIPY library

Herein, we report the first systematic and unbiased evaluation of the BODIPY fluorophore library against a wide panel of biologically relevant molecules, and discoveries of 2 novel fluorescent probes for BSA and dopamine.     

Expanding the chemical space in practice: diversity-oriented synthesis

Diversity-Oriented Synthesis (DOS) aims to broaden the frontier of accessible collections of complex and diverse small molecules. This review endeavours to dissect the DOS concept through three elements of diversity: building block, stereochemistry, and skeleton. Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported.     

Studies towards the synthesis of neopeltolide: synthesis of a ring-closing metathesis macrocyclization precursor

An advanced ring-closing metathesis precursor for the synthesis of the marine macrolide neopeltolide is prepared in a stereocontrolled manner by the coupling of the C2-C10 and C11-C16 subunits. The metathesis reaction of 4 with Grubbs’ II or Nolan’s indenylidene catalyst led to the unexpected formation of cycloheptene 18.     

Total synthesis of haterumalides NA and NC via a chromium-mediated macrocyclization

The syntheses of haterumalides NA and NC were accomplished via the macrocyclization of a chlorovinylidene chromium carbenoid onto a pendant aldehyde to generate the C8-C9 bond with the desired stereoisomer as the major product. Utilizing the latter chemistry enables access to both C9 hydroxylated (haterumalides NC and ND) and C9 deoxygenated forms (haterumalides NA, NB, and NE; via deoxygenation of the C9-hydroxyl).     

Homolytic macrocyclization in the synthesis of thiacrown ethers

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, PP. 2663–2664, November, 1990.     

Concise and diversity-oriented synthesis of ligand arm-functionalized azoamides

Azoamides, previously established as bioactive intracellular GSH-depleting agents, were decorated with a terminal alkyne moiety to 4 and then were transformed, by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), into different ligand-arm functionalized azoamides 6. Azides 5 having ligand-arms amenable for binding to platinum(II) were selected for this study. Because, for the fragile azoamides 4, the typically employed reaction conditions for CuAAC failed, several alternative solvents and copper catalysts were tested. Excellent results were obtained with copper(II) sulfate pentahydrate/metallic copper and especially with heterogeneous catalysts, such as copper-in-charcoal, cupric oxide, and cuprous oxide. The heterogeneous catalysts were employed to obtain the desired products in almost quantitative yields by a simple three-step "stir-filter-evaporate" protocol with no or negligible contamination with copper impurities. This is of particular importance because compounds 6 have been designed for coordination.     

Development of a bio-inspired acyl-anion equivalent macrocyclization and synthesis of a trans-resorcylide precursor

Studies on the macrocyclization of alpha,omega-dialdehydes have revealed a strong dependence on ring size with respect to the ultimate efficiency of the reaction. Strong catalyst dependence was observed, as thiazolium salts led to no detectable product formation, whereas electron-deficient triazolium salts served as precatalysts for the cyclization. Surprisingly, the N-pentafluorophenyl triazolium variant led to cyclization at room temperature within a short 90-min reaction time. These findings were applied to a range of substrates, including the synthesis of a key intermediate in a rapid synthesis of trans-resorcylide.     

Total synthesis of (+)-phomactin a using a B-alkyl Suzuki macrocyclization

A total synthesis of (+)-phomactin A is described using a B-alkyl Suzuki macrocyclization to incorporate the isolated trisubstituted olefin. This macrocyclization was accomplished with the sensitive hydrated furan ring in place. (R)-(+)-pulegone was used to establish the highly substituted cyclohexene core of the molecule.     

Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis

The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.     

Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis

[reaction: see text] Two pairs of complexity-generating reactions with an essential product-substrate relationship along a synthetic pathway are demonstrated. This pathway illustrates a key element in a planning algorithm for diversity-oriented synthesis. This element facilitates the efficient synthesis of structurally complex compounds, and it can be integrated with ones that provide structurally diverse compounds.     

Iodocyclization and Prins-type macrocyclization: an efficient formal synthesis of leucascandrolide A

The formal total synthesis of leucascandrolide A has been achieved in 20 steps from a known epoxide with an overall yield of 11.5% following a recently developed strategy for the construction of trans-2,6-disubstituted-3,4-dihydropyrans and a Lewis acid catalyzed intramolecular Prins-cyclization of an aldehydic homoallylic alcohol to generate the tetrahydropyran ring with three stereogenic centers and macrocycle concomitantly.     

Stereoselective and diversity-oriented synthesis of trisubstituted allylic alcohols and amines

Stereoselective and diversity-oriented synthesis of trisubstituted olefins was achieved by using ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing group for allylic substitution. The starting point of this methodology was a set of α-methylene aldehydes derived from Baylis-Hillman adducts. Subsequent addition of different organometallic reagents led to a variety of allylic alcohol substrates. After introduction of the reagent-directing o-DPPB group, copper-mediated allylic substitution with a wide range of Grignard reagents enabled the stereoselective construction of a large number of E-configured trisubstituted allylic alcohols and amines in excellent yields and stereoselectivities. Remarkable is the synthetic flexibility, which allows a wide range of permutations starting from an aldehyde followed by successive introduction of the substituents R(2) and R(3) from organometallic Grignard based reagents. Thus, starting from only a few precursors, a diversity-oriented synthesis of stereodefined trisubstituted allylic alcohols and amines becomes possible.     

Microwave enhanced palladium catalysed coupling reactions: a diversity-oriented synthesis approach to functionalised flavones

Microwave enhanced diversity-oriented synthesis (MEDOS) using palladium catalysed protocols is introduced as a powerful new strategy for the synthesis of systematically modified small molecules and is highlighted by application to functionalised flavones.     

Intramolecular aminolysis of trichloroethyl esters: a mild macrocyclization protocol for the preparation of cryptophycin derivatives

The bifunctional catalyst 2-hydroxypyridine (2-pyridone) is shown to promote the intramolecular aminolysis of the polyfunctionalized long-chain amino trichloroethyl ester 8 to afford cryptophycin-51 (4). This process for the construction of the macrocyclic core of cryptophycin derivatives is noteworthy for its convenience, avoidance of expensive coupling reagents, and use of mild reaction conditions.     

The site-selective functionalization of halogen-bearing phenols: an exercise in diversity-oriented organometallic synthesis

The organometallic approach to diversity-oriented organic synthesis was subjected to a further test, this time in the phenol series. The model compounds selected were 2,3,6-trifluorophenol, the three isomers of (trifluoromethoxy)phenol and the three isomers of chlorophenol. A combination of optionally site selective metalations and protective group-controlled metalations enabled the selective generation of several isomeric intermediates in each case and their subsequent conversion into functionalized derivatives, in particular hydroxybenzoic acids.     

Stereoselective diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based polycyclic derivatives

A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.