Steroidal N-Sulfonylimidates: Synthesis and biological evaluation in breast cancer cells.

Unique derivatives of androstene and estrane series containing N-sulfonylimidate pendants were prepared from 17α-ethynyl steroids via Cu-catalyzed azide-alkyne cycloaddition to tosyl azide in the presence of alcohols. The synthesized compounds were screened for cytotoxicity against human breast cancer cell lines and ERα agonist activity. The hit compound 3,17ß-dimethoxy-17α-[iso-propyl-2'-N-tosylacetimidate]estra-1,3,5(10)-triene (4n) had no ERα-mediated hormonal activity and was found to exhibit potent cytotoxic effect in an ERα-positive breast cancer cell line. N-Sulfonylimidate 4n displayed high antiproliferative potency against triple-negative MDA-MB-231 breast cancer cells, while it was non-toxic towards normal mammary epithelial cells. Compound 4n was found to alter activity of various signaling pathways (NF-κB, Slug, cyclin D1, ERK) supporting the growth and invasiveness of tumor cells.

OFox imidates as versatile glycosyl donors for chemical glycosylation.

Previously we communicated 3,3-difluoroxindole (HOFox) - mediated glycosylations wherein 3,3-difluoro-3H-indol-2-yl (OFox) imidates were found to be key intermediates. Both the in situ synthesis from the corresponding glycosyl bromides and activation of the OFox imidates could be conducted in a regenerative fashion. Herein, we extend this study with the main focus on the synthesis of various OFox imidates and their investigation as glycosyl donors for chemical 1,2-cis and 1,2-trans glycosylation.

Synthesis of 2-(14)C-iminothiolane and 2-(13)C,(15)N-iminothiolane (Traut's reagent).

2-Iminothiolane has found utility in the growing area of antibody-drug conjugates by serving as a lysine-thiolating agent and the junction between the antibody and the cytotoxic payload during random conjugation of a monoclonal antibody. 2-(14)C-Iminothiolane was prepared from commercially available [(14)C]KCN using a four-step sequence in an overall 10% radiochemical yield. Stable-labeled 2-(13)C,(15)N-iminothiolane was also prepared from [(13)C(15)N]KCN in a similar manner. The ˙ labeled Traut's reagent produced by this sequence showed comparable reactivity as the commercially available unlabeled reagent with a representative monoclonal antibody and could serve as highly informative analytical tools to investigate antibody-drug conjugate formation via the random conjugation process.

2-Vinyl Threoninol Derivatives via Acid-Catalyzed Allylic Substitution of Bisimidates.

A diastereoselective synthesis of 4-vinyl oxazolines syn-2 was developed based on an acid-catalyzed cyclization of bistrichloroacetimidates (E)-1. The reaction likely involves an allyl carbenium ion intermediate in which the adjacent stereocenter directs the stereoselectivity for C-N bond formation. Oxazolines syn-2 were transformed to C-quaternary threoninol, threoninal, and threonine derivatives which can be further incorporated into complex natural compounds.

O-Benzoxazolyl imidates as versatile glycosyl donors for chemical glycosylation.

Herein, we report a new class of glycosyl donors, benzoxazolyl imidates, for chemical glycosylation. The O-benzoxazolyl (OBox) leaving group was designed with an aim to compare the relative reactivity and stability of similarly structured S-benzoxazolyl (SBox) glycosides (thioimidates) developed in our lab and glycosyl trichloroacetimidates (TCAI, O-imidates) developed by Schmidt. Novel OBox donors can be activated under catalytic conditions and provided excellent yields in glycosylation. The OBox imidates were found to be more reactive than either SBox or TCAI donors. The high reactivity profile was confirmed in direct competitive experiments and was found beneficial for HPLC-assisted solid-phase synthesis.

Solution-phase parallel synthesis of a multisubstituted cyclic imidate library.

The solution-phase parallel synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki-Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks.

In vitro and in vivo chemical labeling of ribosomal proteins: a quantitative comparison.

Thioimidates have emerged as reagents for probing the protein structure, folding, and interactions under physiological conditions. The same properties that give thioimidates biological relevance make these molecules ideal candidates for use in vivo. Through labeling of ribosomal proteins, we have quantified the in vivo and in vitro reactivity of two thioimidates: S-methylthioacetimidate (SMTA) and a novel, charge-carrying analogue, S-sulfethylthioacetimidate (SSETA). In vitro experiments demonstrate that both amidinating reagents can probe the protein structure. Under comparable in vivo conditions, SMTA is found to be membrane-permeable while SSETA is not. The use of mass spectrometry with permeant and impermeant thioimidates promises insights into the membrane topology and protein structure in the native environment.

Chiral imidate-ferrocenylphosphanes: synthesis and application as P,N-ligands in iridium(I)-catalyzed hydrogenation of unfunctionalized and poorly functionalized olefins.

A small library of chiral imidate-ferrocenylphosphane ligands was efficiently synthesized (8 examples) and evaluated in the iridium(I)-catalyzed hydrogenation of unfunctionalized and poorly functionalized olefins. These catalysts perform very well in a range of examples (yields and ee's up to 100%).

Asymmetric synthesis of α-chloro-ß-amino-N-sulfinyl imidates as chiral building blocks.

New chiral α-chloro-ß-amino-N-sulfinyl imidates were synthesized in high yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of (R(S))-methyl N-tert-butanesulfinyl-2-chloroethanimidate with aromatic aldimines. The α-chloro-ß-amino-N-sulfinylimidates proved to be excellent building blocks for the asymmetric synthesis of ß-amino-α-chloro amides and esters, aziridine-2-carboxylic amides and esters, trans-2-aryl-3-chloroazetidines, and methyl 4-phenyloxazolidin-2-one-5-carboxylate. The obtained absolute anti-diastereoselectivity is the opposite of the stereochemical outcome observed for α-methyl-substituted imidates.

Combinatorial synthesis of 3,5-dimethylene substituted 1,2,4-triazoles.

Combinatorial cyclizations of imidates and hydrazides with methylene linked R groups, generated from the corresponding nitriles and carboxylic acids, respectively, provided a large library of 3,5-dimethylene substituted 1,2,4-trizoles. [formula: see text].

Novel amidinating cross-linker for facilitating analyses of protein structures and interactions.

A novel bifunctional thioimidate cross-linking reagent (diethyl suberthioimidate) that modifies amines without sacrificing their native basicity is developed. Intermolecular cross-linking of neurotensin and intramolecular cross-linking of cytochrome c under physiological conditions is investigated with this reagent. Because it does not perturb the electrostatic properties of a protein, it is unlikely to lead to artifactual conclusions about native protein structure. The interpeptide cross-links formed with this reagent are easily separated from other tryptic fragments using strong cation exchange chromatography, and they have a readily identified mass spectrometric signature. The use of this novel amidinating protein cross-linking reagent holds great promise for efficient, large-scale structural analysis of complex systems.

A facile route to gamma-nitro imidates via four-component reaction of alkynes with sulfonyl azides, alcohols, and nitroolefins.

Gamma-nitro imidates were synthesized via a copper-catalyzed four-component cascade reaction of sulfonyl azides, alkynes, alcohols, and nitroolefins. This one-step procedure is general and efficient, and the reaction condition is mild.

Preparation and utility of trihaloethyl imidates: useful reagents for the synthesis of amidines.

2,2,2-Trifluoro- and trichloroethyl imidates, which are easily prepared by reaction of a nitrile and a trihaloethanol in the presence of HCl, have proven to be excellent reagents for the preparation of amidines under mild reaction conditions. Depending on the nature of the amine nucleophile, the imidates can react either as the free-base or the hydrochloride salt in a telescoped process. In several cases, the p-bromobenzoate salt of the desired product was directly isolated from the reaction mixture.

Asymmetric synthesis of alpha-alkylated N-sulfinyl imidates as new chiral building blocks.

Alpha-alkylation of N-sulfinyl imidates, prepared via condensation of tert-butanesulfinamide with ortho esters, led to alpha-substituted N-sulfinyl imidates in good-to-excellent diastereomeric ratios (dr up to >99:1) and yields. Deprotection of the alkylated N-sulfinyl imidates gave access to the corresponding imidate hydrochlorides in outstanding yields. These imidate hydrochlorides proved to be excellent intermediates for an easy transformation to chiral amides in good yields and enantiomeric excess upon simple heating in chloroform. Hydrolysis of the alpha-benzylated imidate hydrochlorides afforded the corresponding chiral esters with >95% ee.

A new entry of copper-catalyzed four-component reaction: facile access to alpha-aryl beta-hydroxy imidates.

Alpha-aryl beta-hydroxy imidates are efficiently obtained by the four-component reaction of ethyl glyoxylates, aryl acetylenes, sulfonyl azides, and alcohols using a copper catalyst. The developed procedure is characterized by high selectivity, mild reaction conditions, a wide substrate scope, and an excellent functional group tolerance. Facile transformations of the obtained sulfonylimidate moiety to other carbonyl groups such as sulfonamides or esters were also demonstrated.

Exploration of the "traceless" reductive ligation of S-nitrosothiols.

The first "traceless" reductive ligation of S-nitrosothiols using phosphine ester/thioester conjugates is reported. Experiments also show that stable thioimidate compounds could be formed in the reaction between S-nitrosothiols and some phosphine-thioester substrates.

Room-temperature palladium-catalyzed C-H activation: ortho-carbonylation of aniline derivatives.

Pd and CO--ureally got me! The title reaction proceeds efficiently at 18 degrees C under CO (1 atm) with 5 % [Pd(OTs)(2)(MeCN)(2)] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ = benzoquinone, Ts = 4-toluenesulfonyl).

The synthesis of cyclic imidates from amides of glucuronic acid and investigation of glycosidation reactions.

The synthesis of novel cyclic glycosyl imidates and an investigation of their potential as donors in glycosidation reactions is described. The results show that 1,2-cis glycosides obtained from the reactions of glycosyl acetates or cyclic imidates, each derived from amides of glucuronic acid, result from the anomerisation of initially formed 1,2-trans glycosides.