Taming chlorine azide: access to 1,2-azidochlorides from alkenes.

The in situ preparation and trapping of chlorine azide provided a versatile one-pot method for the azidochlorination of alkenes. Gaseous ClN3 generated from sodium azide, hypochlorite, and acetic acid can be explosive if isolation is attempted. Instead, we generated the reagent in biphasic media in the presence of olefinic compounds dissolved in the organic layer or evenly emulsified throughout the solution in the absence of organic solvent. Under these conditions, ClN3 is created slowly and trapped immediately at the aqueous-organic interface. The resulting safe and reliable procedure provided 1,2-azidochloride derivatives of a variety of substrates, with evidence for both polar and radical mechanisms. Minor impurities characterized in the product mixtures indicated the presence of alternative reaction pathways deriving primarily from radical intermediates.

Photoinduced intramolecular cyclopentanation vs photoprotolytic oxametathesis in polycyclic alkenes outfitted with conformationally constrained aroylmethyl chromophores.

Intramolecular photoinduced cyclizations are investigated in photoprecursors assembled in a modular fashion via a Diels-Alder reaction of acetylenic dienophiles with subsequent Michael additions of aromatic ketones to install a chromophore capable of initiating Paternò-Büchi cycloadditions or radical cyclization cascades. The protolytic oxametathesis in these systems allows for rapid access to novel polycyclic scaffolds decorated by formyl groups and carboxylates suitable for subsequent modifications. In conformationally constrained photoprecursors, a radical rearrangement takes place resulting in intramolecular 1,3-diradical cyclopentanation of the double bond.

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs).

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC50=292.17±27.71 µM and 331.94±21.21 µM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC50=275.24±13.15 µM). These values are significantly lower than those of ascorbic acid (EC50=1129.32±88.79 µM) and α-tocopherol (EC50=944.62±148.00 µM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68±0.27; synthetic (S,S)-SDG-1: 2.09±0.16; synthetic (R,R)-SDG-2: 1.96±0.27], peroxyl [natural (S,S)-SDG-1: 2.55±0.11; synthetic (S,S)-SDG-1: 2.20±0.10; synthetic (R,R)-SDG-2: 3.03±0.04] and DPPH [natural (S,S)-SDG-1: EC50=83.94±2.80 µM; synthetic (S,S)-SDG-1: EC50=157.54±21.30 µM; synthetic (R,R)-SDG-2: EC50=123.63±8.67 µM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.

Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents.

Reaction of 10-deacetylbaccatin III (III) and its 7-TES derivative (IV) with DAST under various conditions resulted in the formation of an array of new fluorinated and non-fluorinated 13-keto taxoid compounds (2a­4a) through a vinylogous pinacol­pinacolone rearrangement. Further fluorination of some of these products (2a, 3a) with NFSi or Selectfluor gave additional derivatives. Sodium borohydride reduction of the 13-keto group of these products (2a, 2b, 3a, 3b, 4a, 8, 9, 11­14) led to a series of 9α-hydroxy taxoid derivatives, which were esterified using the docetaxel side chain employing the corresponding protected ß-lactam, followed by deprotection to furnish a library of docetaxel analogs and related compounds. A selected number of synthesized compounds (7, 10, 19a, 19b, 21a, 21b, 23, 27, 29, 34­36) were submitted to the National Cancer Institute (NCI) 60 cell line screening program and tested for cytotoxic properties. Taxoids 19a, 19b, 21a, 21b, 23, 27, 29, 34 and 35 were found to exhibit significant anticancer activity against various cancerous cell lines with 23, 27, and 29 being the most potent compounds, demonstrating GI50 values of ≤5 nM in several assays.

Bio-inspired synthesis and biological evaluation of a colchicine-related compound library.

A bio-inspired investigation of the reactions of substrates of type 1 with VOF(3) and PIFA [phenyliodine(III) bis(trifluoroacetate)] led to a collection of colchicine-like compounds 2-5 and related systems. Biological evaluation revealed that some of the synthesized products had significant cytotoxic properties against the colon cancer cell line HT-29.

Double-tandem [4π+2π]·[2π+2π]·[4π+2π]·[2π+2π] synthetic sequence with photoprotolytic oxametathesis and photoepoxidation in the chromone series.

Chromones are introduced into a double-tandem [4(π)+2(π)]·[2(π)+2(π)]·[4(π)+2(π)]·[2(π)+2(π)] synthetic sequence, culminating in photoprotolytic oxametathesis, which leads to an expeditious growth of molecular complexity over a few experimentally simple steps. The overall reaction can potentially be utilized in diversity-oriented synthesis, as it allows for three or more diversity inputs furnishing novel unique polycyclic scaffolds decorated with a variety of functionalities and aromatic/heterocyclic pendants. The polycyclic alkenes, resulting from the oxametathesis step, were found to undergo efficient and clean photoinduced epoxidation when irradiated in the presence of molecular oxygen.

First Example of Intramolecular [2pi+2pi] Alkene-Arene Photocyclization in the Chromone Series and its Synthetic Utility.

Diels-Alder adducts of chromones are shown to undergo an intramolecular [2(pi)+2(pi)] alkene-arene photocyclization, leading to a versatile polycyclic diene, which is capable of dimerization or can be introduced into a high yielding photoprotolytic oxametathetic sequence. This allows for an expeditious growth of molecular complexity over a few experimentally simple steps with stereochemistry being defined and locked at the very first Diels-Alder step. The overall reaction can potentially be utilized in Diversity-Oriented Synthesis as it allows for three or more diversity inputs furnishing novel unique polycyclic scaffolds, which can readily be decorated with a variety of functionalities and aromatic/heterocyclic pendants.

Positional Analogue Scanning: An Effective Strategy for Multiparameter Optimization in Drug Design.

Minimizing the number and duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes or drug candidates is an ongoing challenge in biomedical research. Small structure modifications to hit or lead compounds can have meaningful impacts on pharmacological profiles due to significant effects on molecular and physicochemical properties and intra- and intermolecular interactions. Rapid pharmacological profiling of an efficiently prepared series of positional analogues stemming from the systematic exchange of methine groups with heteroatoms or other substituents in aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing design cycles (e.g., exchange of aromatic or heteroaromatic CH groups with N atoms or CF, CMe, or COH groups). In this Perspective, positional analogue scanning is shown to be an effective strategy for multiparameter optimization in drug design, whereby substantial improvements in a variety of pharmacological parameters can be achieved.

Effect of intramolecular Paternò-Büchi reaction on the thermodynamics and kinetics of nearly degenerate [3,3]-sigmatropic shift in fluxional polycycles.

In reactions with weak dienophiles, cyclooctatetraene (COT) often yields 2:1 adducts possessing the fluxional bicyclo[5.1.0]octadiene moiety. They undergo fast, nearly degenerate Cope rearrangement with an activation barrier similar to that of the parent dihydrobullvalene. Irradiation to excite the carbonyl moiety induces an intramolecular Paterno-Buchi cyclization yielding endo-oxetanes and significantly changing the Cope-averaged NMR spectra. In this paper we examine the effect of skeletal distortion caused by intramolecular [2 + 2]-photoaddition on thermodynamics and the activation barrier of the [3,3]-sigmatropic tautomerism. Our finding is that such a distortion lifts the energetic degeneracy of the two valence tautomers, while not affecting the activation barrier.

Interrupted oligomerization revisited: simple and efficient one-pot multicomponent approach to versatile synthetic intermediates.

A novel multicomponent reaction allowing for a one-pot formation of three carbon-carbon bonds has been developed. It is based on in situ generation and anionic dimerization of methylenedithiane and produces a versatile synthetic equivalent of 4-hydroxy-1,3-alkanediones which, among other things, offers expeditious one-pot access to 3(2H)-furanones.

Photoactive barbiturate receptors: an ultimate lock-and-key system in which the key unlocks the lock.

Conditional photofragmentation is achieved with binary systems incorporating the isophthaloyl bis-aminopyridine barbiturate recognition motif and dithiane- or trithiane-based photolabile modules, which cleave only in the presence of an external sensitizer. The components of the host-guest molecular recognition pair were each outfitted with either the sensitizer or the photocleavable module. In these pairs, photoinduced fragmentation is contingent on a molecular recognition event, which brings the sensitizer into the immediate proximity of the photolabile latch. [structure: see text]

Conformational analysis of spiro-bis-dithiepins: a peculiar case of axial chirality.

Spiro-bis-dithiepins are synthesized via dehydrative ring expansion in alpha-hydroxyalkyl spiro-bis-dithianes. Atypical of spiranes possessing axial chirality, the two most stable conformers of substituted spiro-bis-dithiepin have virtually colinear double bonds; i.e., each enantiomer exists in a form of two energy degenerate syn and anti conformations. Because of the high polarizability of the vinyl sulfide moiety, spiro-bis-dithiepins bearing electron-withdrawing substituents offer access to two-state systems possessing large dipole moments, which can be modulated by conformational events. [structure: see text]

Strained to the limit: when a cyclobutyl moiety becomes a thermodynamic sink in a protolytic ring-opening of photogenerated oxetanes.

Strained polycyclic oxetanes generated photochemically from the Diels-Alder adducts of cyclic dienes and enones undergo deep skeletal rearrangements under protolytic ring-opening conditions offering expeditious access to chlorohydrins and other products of unique skeletal topology.

Harvesting the strain installed by a Paternò-Büchi step in a synthetically useful way: high-yielding photoprotolytic oxametathesis in polycyclic systems.

High-yielding one-pot photoinduced transformation of readily available endoaroyl and heteroaroyl Diels-Alder adducts into novel polycyclic aldehydes or their hemiacetals, decorated by carbo- and heterocyclic pendants, is described.

2,6,7-trithiabicyclo[2.2.2]octanes as promising photolabile tags for combinatorial encoding.

The adducts of trithiabicyclo[2.2.2]octane (TTBO) and carbonyl compounds undergo efficient photoinduced fragmentation with quantum yields comparable to that of dithiane adducts. The effect of the third sulfur on the stability of the respective radical cations and radicals is examined computationally and experimentally in a laser flash photolysis study. A straightforward synthetic approach to a variety of 4-substituted trithiabicyclo[2.2.2]octanes from 3-bromo-2,2-bis(bromomethyl)propanol is developed, making a diverse set of mass-differentiated photolabile tags readily available for combinatorial encoding.

Direct screening of solution phase combinatorial libraries encoded with externally sensitized photolabile tags.

Solution phase combinatorial chemistry holds an enormous promise for modern drug discovery. Much needed are direct methods to assay such libraries for binding of biological targets. An approach to encoding and screening of solution phase libraries has been developed based on the conditional photorelease of externally sensitized photolabile tags. The encoding tags are released into solution only when a sought-for binding event occurs between the ligand and the receptor, outfitted with an electron-transfer sensitizer. The released tags are analyzed in solution revealing the identity of the lead ligand or narrowing the range of potential leads.

When ethyl is infinitely different from methyl: double addition of lithiated dithianes to aromatic carboxylates revisited.

Addition of lithiated alkyl dithianes to benzoyl chloride or methyl benzoate does not produce the expected product of double addition, alpha,alpha-bis(alkyldithianyl) benzyl alcohol, for alkyls larger than methyl. Instead, the first step intermediate, i.e. 2-benzoylated dithiane, undergoes an electron-transfer reduction by the second molecule of the dithianyl anion. This reduction is followed by the ring-opening mesolytic fragmentation of the dithiane ring in the ketyl anion radical and subsequent radical recombination yielding acetophenone-tethered thioortho esters 4, alpha-[3-(2-alkyl-1,3-dithiane-2-ylthio)propylthio]-alpha-alkyl-acetophenones. It appears that the Corey-Seebach bisaddition of lithiated dithianes to methyl benzoate is an exception rather than the rule in the alkyl dithiane series.