Synthesis of 4-mercapto-l-lysine derivatives: Potential building blocks for sequential native chemical ligation

A general and diastereoselective synthesis of (2S, 4S)-4-mercapto-l-lysine derivative was described. The key features of this synthesis include Zn-mediated diastereoselective Reformatsky reaction and selective reduction of methyl ester with sodium borohydride. Introduction of thiol functional group on lysine side chain proved to be appropriate for dual native chemical ligation. This methodology allows to develop various 4-substituted l-lysine derivatives.     

Deoxyribonolactone lesion in DNA: synthesis of fluorinated analogues

Mono- and difluorinated derivatives of 2-deoxyribonolactone were synthesized using diastereoselective Reformatski reaction as a key step.     

Enantioselective Preparation,Conformational Analysis and Absolute Configuration of Highly Substituted Aziridines

The first example of organocatalytic aziridination reaction of α‐substituted‐α,β‐unsaturated ketones is presented. The reaction was found to be highly enantio‐ and diastereoselective, yielding N‐tosylated aziridines. Low‐temperature nuclear magnetic resonance (NMR) spectra allowed for the determination of the N‐inversion barrier, that was found to be quite lower with respect to unsubstituted aziridines. A thorough conformational analysis supported by low‐temperature NMR data allowed for the determination of the absolute configuration of the main stereoisomer by means of time‐dependent Density Functional Theory simulation of the electronic circular dichroism spectra. Chirality 27:875–887, 2015. © 2015 Wiley Periodicals, Inc.     

Synthesis of enantiopure trans-N-Boc-3-aminobicyclo[2.2.2]octane-2-carboxylic acids and their bicyclic 1,3-amino alcohol derivatives via the [4+2] cycloaddition of 1,3-cyclohexadiene to a chiral β-nitroacrylate

The chiral β-nitroacrylate 2 derived from the (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) benzoic acid 1 acts as a reactive dienophile in a diastereoselective Diels-Alder reaction with 1,3-cyclohexadiene. The major cycloadducts have been isolated and transformed into enantiopure trans(2S,3S)- or (2R,3R)-N-Boc-3-aminobicyclic[2,2,2]octane-2-carboxylic acids 5. The trans-(2S,3S)- or (2R,3R)-N-Boc 3-(hydoxymethyl)-2-aminobicyclic[2,2,2]octane 6 derivatives were also obtained.     

Deoxyribonolactone Lesion in DNA: Synthesis of Fluorinated Analogues

Abstract

Mono- and difluorinated derivatives of 2-deoxyribonolactone were synthesized using diastereoselective Reformatski reaction as a key step.     

Structure,aromaticity, stability,and energetic performance of the analogues and derivatives of s-heptazine

The reaction mechanism of diastereoselective oxidative dearomatization by iodoxybenzoic acid of key compounds involved in the total synthesis of epicocconone analogs, which are efficient fluorophores with a wide range of applications in protein staining and separation, was studied using density functional theory. In particular, the conformational space was investigated, as was the role of the so-called hypervalent twist move, which is thought to be the rate-determining step. Both kinetic and thermodynamical aspects of the mechanism were considered from static and dynamic viewpoints, including solvent effects. The results were then rationalized using conceptual density functional theory and Bader’s atoms-in-molecules framework, which demonstrated how complementary these two approaches are when studying organic chemistry reactions theoretically.     

Stereoselective synthesis of a protected form of (6R,7E,9S,10R,12Z)-6,9,10-trihydroxy-7,12-hexadecadienoic acid

The protected stereoisomer of a trihydroxy unsaturated fatty acid, which could be employed as a potential nigricanoside α-chain building block, was synthesized by using Evans asymmetric alkylation, Sharpless kinetic resolution, and diastereoselective reduction as the key steps.     

Highly diastereoselective synthesis of enantiopure naphthylaminoalcohols with analgesic properties

The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalcohols has been performed. The chiral racemic key intermediate 3-dimethylamino-2-methyl-1-(naphthalen-2-yl)propan-1-one and enantiomers were prepared and transformed into the desired compounds by addition of the organometallic reagent. The chemical characterization of all diastereoisomers was accomplished by 1H NMR and HPLC analyses and the absolute configuration assigned by CD spectroscopy. The in vitro and in vivo profile has also been evaluated.     

Matrix compare analysis discriminates subtle structural differences in a family of novel antiproliferative agents, diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones

A diastereoselective synthesis of diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones is described employing a tandem Michael-aldol addition as key step. The novel compounds exhibit antiproliferative activity in a panel of in vitro cultivated cancer cell lines. The bioinformatic tool COMPARE was able to discriminate between two closely related subgroups of the title compounds, namely 1,3- and 2,3-disubstituted derivatives.     

Total synthesis of 12,13-desoxyepothilone B (Epothilone D)

A highly convergent total synthesis of 12,13-desoxyepothilone B (4, Epothilone D) is described involving the coupling of vinyl iodide (5) and olefin (6). Key steps in the synthesis are the introduction of chirality at C15 via highly enantioselective lipase-mediated enzymatic resolution, diastereoselective alkylation at C8, highly diastereoselective Evans aldol reaction to establish C6-C7, and Mukaiyama aldol reaction to introduce chiral center C3. Palladium catalyzed Suzuki coupling of (5) and (6) provided the methyl ester (27), which was converted to 12,13-desoxyepothilone B (4).     

Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through thermal and MW‐promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six‐membered carbo‐ and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero‐Diels‐Alder cycloaddition.     

Synthesis of tunicaminyluracil derivatives

A tunicaminyluracil derivative, which is a key component of the tunicamycin nucleoside antibiotics, was synthesized using a samarium diiodide (SmI2) mediated aldol reaction and intramolecular Pummerer reaction as the key steps. The alpha-phenylthio ketone 11, the precursor of the samarium enolate, was prepared from D-galactose. Treatment of 11 with SmI2 at -40 degrees C resulted in complete conversion to the corresponding samarium enolate, and subsequent addition of uridine 5'-aldehyde 12 afforded the desired aldol products 13a,b. Compound 13a was converted to the sulfoxide 15 by a sequential diastereoselective reduction of the ketone and an oxidation with mCPBA. Activation of 15 with Tf2O provided the desired cyclized compound 17. In this reaction, the aldol product 13a was also obtained as a consequence of a competitive intramolecular version of DMSO-oxidation via a 7-membered ring intermediate. Compound 18 or 19 are ready for use as a glycosyl donor in glycosylations to provide a range of analogues as potential glycosyltransferase inhibitors as well as related natural products.     

Diastereoselective [2+2] photocycloaddition of chiral cyclohexenonecarboxylates to ethylene

The diastereoselective [2+2] photocycloaddition of cyclohexenonecarboxylates containing various chiral auxiliaries to ethylene is described. The effect of the auxiliary, reaction temperature, and solvent on diastereoselectivity was examined. The (?)‐8‐(p‐methoxyphenyl)menthyl group was found to be the most effective chiral auxiliary. The photoreaction of (?)‐8‐(p‐methoxyphenyl)menthyl cyclohexenonecarboxylate in methylcyclohexane at ?78°C gave the corresponding bicyclo[4.2.0]octanone derivative in 81% diastereomeric excess (d.e.). The extent of diastereoselectivity was found to be closely related to the most stable π‐stack conformation of the starting cyclohexenones. Chirality 15:504–509, 2003. © 2003 Wiley‐Liss, Inc.     

Stereoselective synthesis of a new muscarinic M3 receptor antagonist, J-104129.

A diastereoselective synthesis of J-104129 (1) was developed. A key step of this synthesis was Michael addition of enolate generated from cis-chiral dioxolane 2 to cyclopentenone, followed by hydrogenolysis of the resultant enol triflate 4. A mixture of cyclopentyldioxolane (5, 6) was hydrolyzed with sodium hydroxide to yield carboxylic acid 7 in 86% ee.     

17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure-activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors

A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic structure of the mammalian CYP2C5 enzyme. With the aid of molecular modeling, optimization of the biphenyl moiety was performed to give an acetamide derivative, which was resolved by HPLC to give the active (-)-enantiomer. The obtained active enantiomer showed not only potent inhibition of both rat and human 17,20-lyase,with IC(50) values of 14 and 26 nM, respectively, but also excellent selectivity (>300-fold) for inhibition of 17,20-lyase over CYP3A4. Moreover, the active enantiomer significantly reduced both serum testosterone and DHEA concentrations in a monkey model after single oral administration. Asymmetric synthesis of the active enantiomer was also developed via a chiral intermediate using a diastereoselective Grignard reaction.     

Synthesis and biological evaluation of new jasplakinolide (jaspamide) analogs

Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide.     

Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018)

A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The isomers were obtained with 70-76% yields in 99-100% ee.     

Substrate specificity and diastereoselectivity of strictosidine glucosidase, a key enzyme in monoterpene indole alkaloid biosynthesis

Strictosidine glucosidase (SGD) from Catharanthus roseus catalyzes the deglycosylation of strictosidine, an intermediate from which thousands of monoterpene indole alkaloids are derived. The steady-state kinetics of SGD with a variety of strictosidine analogs revealed the substrate preferences of this enzyme at two key positions of the strictosidine substrate. Additionally, SGD from C. roseus turns over both strictosidine and its stereoisomer vincoside, indicating that although this enzyme prefers the naturally occurring diastereomer, the enzyme is not completely diastereoselective. The implications of the substrate specificity of SGD in metabolic engineering efforts of C. roseus are highlighted.     

Study of the green tea polyphenols catechin-3-gallate (CG) and epicatechin-3-gallate (ECG) as proteasome inhibitors

The green tea polyphenol catechin-3-gallate (CG) and epicatechin-3-gallate (ECG) were synthesized enantioselectively via a Sharpless hydroxylation reaction followed by a diastereoselective cyclization. Their potencies to inhibit the proteasome activity were measured. The unnatural enantiomers were found to be equally potent to the natural compounds.     

Stereoselective total synthesis of a potent natural antifungal compound (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one

A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one (1), a potent natural antifungal compound, is described. The sequence involves diastereoselective iodine-induced electrophilic cyclization, epoxide ring opening with a vinyl Grignard reagent and ring closing metathesis (RCM) as the key steps.