The asymmetric bioreduction of activated CC-bonds catalyzed by a single flavoprotein was achieved via direct hydrogen transfer from a sacrificial 2-enone or 1,4-dione as hydrogen donor without requirement of a nicotinamide cofactor. Due to its simplicity, this system has clear advantages over conventional FAD-recycling systems.
The BINOL ligand (R)-2 that contains bulky 3,3'-tertiaryalkyl groups shows improved catalytic properties than the previously reported 3,3'-substituted BINOL ligands in the asymmetric alkyne addition to aromatic aldehydes. It can catalyze the phenylacetylene addition to aromatic aldehydes with high enantioselectivity (86 - 94% ee) and good yields without using Ti(O(i)Pr)(4) and a Lewis base additive. The catalytic properties of several analogs of (R)-2 in the asymmetric alkyne addition to aldehydes have also been studied. .
The four possible isomers of C-1,2 ketols in the 17β-hydroxy-A-nor-5β-androstane series have been prepared and their rearrangements under various conditions examined. The stabilities are found to be in the order of the 2α-hydroxy-1-ketone (IIIa) > the 2β-hydroxy-1-ketone (IIa) > the 1β-hydroxy-2-ketone (Ia) > the 1α-hydroxy-2-ketone (XIIIa), and the results are discussed. Furthermore, the four A-nor-5β-androstane-1,2,17β-triols, epimeric at C-1,2 have been prepared in connection with the structural elucidation of the ketols.
We report a novel approach to the synthesis of GlcNAcstatins-members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-α-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S(N)2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.
Efficient syntheses and a preliminary evaluation of 1,2,11,11a-tetrahydrocyclopropa[c]-naphtho[2,3-e]indole (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives containing an anthracene and phenanthrene variant of the CC-1065 or duocarmycin alkylation subunit are detailed.
The stereospecific intramolecular alkylation of a hydroperoxyacetal provides the basis for the first asymmetric synthesis of the dioxane propionate core of the peroxyplakorates. Chemoselective hydrometallation of an alkyne in the presence of a peroxide is used to introduce a synthon for the polyunsaturated side chains of the peroxyplakorates. The route suggests a general solution for the 1,2-dioxane unit in many peroxide natural products.
Pd(OAc)(2)-catalyzed domino reactions of 1,2-dihalobenzenes and 2-haloaryl arenesulfonates with hindered Grignard reagents to form substituted fluorenes, which are believed to occur through palladium associated aryne intermediates, is described. Such palladium associated aryne reaction pathway was found to be favored by omitting the use of phosphine and N-heterocyclic carbene ligands for palladium catalysts and with better leaving groups. Our study suggested that Pd(leaving group)X associated arynes should be formed first and the sp(3) C-H activation preferentially occurred at benzylic C-(1°)H bonds. The work described here provides a high yield, one-step access to substituted fluorenes from readily available 1,2-dihalobenzenes and 2-haloaryl arenesulfonates and hindered Grignard reagents, and this substituted fluorene-making method may find applications in the preparation of substituted fluorene-containing molecules including polymers.
Substituted α-alkoxysilanes can be deprotonated by alkyllithium bases and made to undergo Wittig rearrangements to afford the #x0005B;1,4]- and [1,2]-rearranged products in varying ratios. Substitution at the benzylic migrating carbon and/or at the allylic carbon of the allyl moiety impacts the rearrangement reaction, influencing the reactivity as well as the [1,4]-/[1,2]-selectivity. Diastereomeric α-alkoxysilanes show different reactivities with the syn diastereomer being the more reactive isomer.
The chemistry of 1,2,3,4-tetrahydro-1,5-naphthyridines and 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines has been explored with the goal of discovering reactions at N1 suitable for library development. Epoxide openings, palladium-catalyzed N-arylations, DEPBT-promoted acylations, and urea formation through the reaction with isocyanates were all successful. The epoxide opening chemistry using homochiral epichlorohydrin, with epoxide reclosure and a second nucleophilic opening led to the preparation of a small 24-membered library.
Theophylline was converted to 7-(2-phenyl-2-methanesulfonyloxy)ethyl congener and the product was treated with ammonia or
primary amines in a mixture solution of water and organic solvents. Two products were proven to be the styrene analogue and
7-(2-amino-2-phenylethyl)theophylline. The structure of the third product was elucidated as the 1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine derivatives by spectroscopic analysis including HMBC correlation and X-ray crystallography.
1,2,9-Trimethoxy-10-hydroxyaporphine (VII) is the structure recently proposed1 for rogersine, a natural aporphine alkaloid. An unambiguous synthesis of the compound with this structure proves the structure of rogersine to be in error.The origin, of 2-methoxy-N-acetylnornuciferine (VIII) which was recently2 used in an NMR study of aporphine alkaloids, is also now reported.
Authentic 1-hydroxy-2,9,10-trimethoxyaporphine (II) has been synthesized, and its N-methyl salt shown to correspond to the quaternary alkaloid from Fagara tinguassoiba. Natural glaucentrine corresponds to corydine (XIX) rather than to structures II or XI.
Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4 + 3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 4H-1,3-oxazines in 47-96% yield.
This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas alpha-tetralones can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.
Calixarenes constrained to 1,3-alternate conformation and functionalized at the upper rim with four and two nitronyl nitroxides have been synthesized, and characterized by X-ray crystallography, magnetic resonance (EPR and (1)H NMR) spectroscopy, and magnetic studies. Such calixarene tetraradicals and diradicals provide scaffolds for through-bond and through-space intramolecular exchange couplings.
In investigations aimed at exploring the potential of disubstituted allenes in stereoselective synthesis, we report studies that explore the reductive cross-coupling reaction of vinylsilanes with a range of substituted allenes. Regiochemical control is attained by employing allenic alkoxides, where the proximal heteroatom dictates the site-selectivity in a process that proceeds by net formal metallo-[3,3] rearrangement (directed carbometalation/elimination). Stereoselectivity in these reactions is complex, with both the nature of allene substitution and relative stereochemistry of the substrate impacting the stereoselective generation of each alkene of a substituted 1,3-diene. 2009 Elsevier Ltd. All rights reserved.
Photooxygenation of 1,1,3-trimethyl-1,2-dihydropentalene gives an unstable endoperoxide which upon decomposition delivers a bicyclic cyclopropanone intermediate; this species either extrudes CO to give a cycloheptadienone or undergoes a 1,3-acyl shift, both processes occurring most likely in a stepwise manner via diradical intermediates. Alternatively, C3a-C4 cleavage in the dioxygen diradical derived from the endoperoxide yields a 2-cyclopropyl substituted cyclopentadienone epoxide.
A highly enantio- and diastereoselective pentenylation of aldehydes is described. The homoallylic alcohol derived from 1,3-dimethylallylation of (-)-menthone undergoes an efficient allyl-transfer reaction with a wide range of aliphatic aldehydes in the presence of an acid catalyst to give rise to the corresponding 4-methyl-2(E)-penten-4-yl-5-ol products in good yields with high enantio- and 4,5-syn-selectivities.
This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas nitrate esters can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.
(±)-6α- and β-Methylestra-1,3,5(10)-trien-17β-ol (VII a and b; R = Me) and (-)-13β- ethyl-6β-methylgona-1,3,5(10)-trien-17β-ol (VIIb; R = Et) have been totally synthesized from 3-m-methoxyphenylbutyl bromide. The second compound has been converted to various (±)-13β- ethylgon-4-en-3-ones, the biological activities of which are reported.
Several 2H-1,4-benzoxazin-3-thiones have been newly prepared. UV, IR and NMR studies establish that the predominant tautomer in these potentially tautomeric compounds is the thiolactam form. Methylation gives the S-Me and not the N-Me derivative. NMR spectroscopy is useful in distinguishing between isomeric benoxazine structures and between exocyclic and endocyclic double bonds in the hetero ring. Nucleophilic displacement reactions have been carried out on 2H-1,4-benzoxazin-3-thione and its S-Me and N-Me derivatives using hydrazine hydrate, morpholine, cyclohexylamine and aniline. In each case NMR has been used to ascertain the structure of the reaction product.
Reaction of thiomaleic anhydride with triphenylphosphine gives the title compound which undergoes reaction with a variety of aldehydes to give a range of alkylidene thiomaleic anhydrides (substituted monothio itaconic anhydrides). Subsequent treatment with tert-butoxycarbonylamino-substituted thiols, or under radical conditions with tert-butoxycarbonylamino-substituted alkyl halides results in a series of substituted monothiomaleic anhydrides, that on exposure to trifluoroacetic acid and then base lead to thiocarboxyl substituted 1,4-thiazepin-5-ones and piperidinones, respectively, that are ultimately trapped by reaction with 2,4-dinitrobenzenesulfonamides to give the corresponding amides.
The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore rearrangement as a key transformation has been developed. The approach features an acetylide stitching step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone. Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized xanthones. The utility of the approach was demonstrated by its application to a concise and efficient synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named dulcisxanthone C was also corrected to that of the xanthone 1.
Synthesis of a potential Src family SH2 domain inhibitor incorporating a 1,4-cis-enediol scaffold is reported. The synthetic route offers straightforward and highly selective access to the enediol and its associated chiral centers. Key steps include stereocontrolled syn-aldol coupling, amide alkynylation, and asymmetric ketone reduction.
Titanium-mediated cross-coupling of allenic alcohols with alkynes has been investigated. Divergent reaction pathways were discovered that provide either stereodefined 1,4-dienes or substituted cross-conjugated trienes. In short, allene substitution plays a critical role in the determination of reaction pathway.
On irradiation, 1,4-dihydropyridines have been shown to undergo three types of reaction: disproportionation, isomerization and dimerization. The presence of 2,6-substituents inhibits these reactions except in the case of 3a which undergoes disproportionation. The diester 10 and diketone 11 yield mixtures of the corresponding 1,2-isomers and photodimers. The structure and stereochemistry of the dimers derived from 10 have been established by X-ray and NMR methods to be head-to-tail anti, 17, and head-to-tail syn, 16. The latter compound cyclizes to the cage isomer 15 upon further irradiation.
Interest in the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin prompted us to develop a new method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of allenes 6, 33, ent-39, 42 and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium allenyltrifluoroborate 45 gave superior results and was utilized in a double allylboration sequence with two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72-98%), and with high enantioselectivity (>95% e.e.), diastereoselectivity (d.r. >20:1), and (E)/(Z) selectivity (>20:1). This new method was applied to the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin.
For the development of novel endocannabinoid templates with potential resistance to hydrolytic and oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this end, we recently disclosed the synthesis and preliminary biological data for the (13S)-methyl-anandamide. We report now the total synthesis of the (10S)- and (10R)-methyl-counterparts. Our synthetic approach is stereospecific, efficient, and provides the analogs without the need for resolution. Peptide coupling, P-2 nickel partial hydrogenation, and cis-selective Wittig olefination are the key steps.
The preparation of 17β-hydroxy-5α,10α-androstan-2-one IIa is described. Several aspects of the chemistry of the new compound are discussed. The conversion of IIa to the corresponding 3-keto derivative, 17β-hydroxy-5α,10α-androstan-3-one is also described.
Ozonolysis of methyl fusidate diacetate or methyl 24,25-dihydrofusidate diacetate followed by reaction with zinc-acetic acid leads to 3α-acetoxy-4α,8,14-trimethyl-18-nor-5α,8α,9β,14β-androst-12-en-17-one (V), 3α-acetoxy-4α,8,14-trimethyl-18-nor-5α,8α,9β,14β-androst-12,15-dien-17-one (VI) and 3α,11-ga-diacetoxy-4α,8,14-trimethyl-18-nor-5α,8α,9β,14β-androst-15-en-17-one (VII). The mechanism of formation of these compounds is discussed. Alkaline equilibration of the 13-epimeric 3α-hydroxy-17-ketones XII and XIII gives a 60:40 mixture of the trans and cis isomers respectively.
The enzymatic transformation of desoxycholic acid by Mycobacterium mucosum 1210 has been studied. 3,12-diketo-Δ4-bisnorcholenic and 9α-hydroxy-3,12-diketo-Δ4-bisnorcholenic acid have been isolated in the form of methyl esters.
The microbiological transformation of cholic acid by the culture Mycobacterium N 1210 has been studied. The following products have been isolated in the form of methyl esters: 7α-hydroxy-3,12-diketo-Δ4-cholenic (IIIa), 7α-hydroxy-3,12-diketo-Δ4-bisnorcholenic (IVa), 7α-hydroxy-3,12-diketo-Δ4,8(9)-bisnorcholadienic (Va), 7-hydroxy-3,12-diketo-Δ4,6-bisnorcholadienic (VIa), 12α-hydroxy-3-keto-Δ4,6-choladienic (VIIa), 12α-hydroxy-3-keto-Δ4,6-bisnorcholadienic (VIIIa) and 3,12-diketo-Δ4,6-bisnorcholadienic (IXa) acids.
In teh enzymatic transformation of cholic acid by the culture Mycobacterium mucosum 1210, 7α,12α-dihydroxy-3-oxo-Δ4-bisnorcholenic acids have been isolated and identified (in the form of methyl esters). Thus a microbiological α-oxidation of the side chain of cholic acid has been demonstrated.
Many different 3alpha-hydroxysteroids in the androstane and pregnane steroid series enhance the actions of gamma-aminobutyric acid (GABA) at GABA type-A (GABA(A)) receptors in the mammalian central nervous system. Recent studies have shown that (3alpha,5alpha)-3-hydroxyandrostan-17-one (androsterone) is less active at these receptors than its enantiomer ent-androsterone. Further structure-activity relationship (SAR) studies are needed to explore the structural features of ent-androsterone that are important for its enhanced action at these receptors. Molecular modeling shows that 2beta-hydroxysteroids are similar in three-dimensional shape to the enantiomers of 3alpha-hydroxysteroids. The development of synthtetic methods to gain access to C(17)-substituted analogues of 2beta-hydroxygonanes for SAR studies is demonstrated with the synthesis of (2beta,5alpha,13beta,14beta)-2-hydroxygonan-17-one.
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of (13) C 4-BaP and the complete set of its (13) C 4-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl2-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of (13) C 4-BaP and (13) C 4-BaP-8-ol each require only four steps, and the (13) C-atoms are all introduced in a single step. (13) C 4-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of (13) C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic (13) C 4-BaP metabolites were estimated to be ≥99.9%.
The syntheses of 9-, 13-, and 9,13-desmethyl-vitamin A are described from the corresponding desmethyl homologues of vitamin A acid methyl esters. The latter were prepared by condensation of trans-β-ionylidene acetaldehyde and trans-5-(2′,6′,6′-trimethylcyclohexene-1′-yl-1′)-pentadiene 2,4-al-1 respectively, with the phosphonates of the appropriate crotonic acid esters. Biological investigations on growth promoting properties have shown that all-trans-13- and all-trans-9,13-desmethyl vitamin A acetate are completely inactive, while all-trans-9-desmethyl vitamin A acetate exhibits an activity of about 4%, when compared with all-trans-vitamin A acetate.
14β,18-Cycloprogesterone (VI) was prepared by deamination of Δ4,20(N)-3-oxo-18,20-iminopregnadiene (III). Deamination of 18-amino-5α-pregnane-3β,20-diol (VII) afforded 14β,18-cyclo-5α-pregnane-3β,20-diol (VIII).
The reaction of cyclic ketals derived from 14-hydroxydihydrocodeinone with a Vilsmeier reagent is described. The reactions of 14-hydroxydihydrocodeinone with dimethylsulphoxonium methylide, dimethylsulphonium methylide and amyl nitrite have been examined.Structures are proposed for the various products formed.
A study of the circular dichroism characteristics of various 16-substituted 20-keto pregnane and isopregnane derivatives has been made. The curves of the 16,17-trans compounds are simila to those of the 16-unsubstituted parent compounds. Modifications of functions in rings A and B have little effect, if any, on the circular dichroism maxima around 290 mμ. In the case of 16,17-cis compounds, both the configuration and the nature of the 16-substituent have an important bearing on the sign and intensity of the Cotton effect associated with the 17-acetyl side chain. The circular dichroism data for 16,17-epoxy-20-keto steroids are discussed.
3,3-Ethylenedioxy-5-androstene-17-one and estrone 3-methyl ether were subjected to Claisen condensations with ethyl acetate and trifluoroacetate. The enol acetates of 16-trifluoroacetyl derivatives underwent hydrogenolysis with the formation of trifluoroethyl compounds. UV and IR spectral data and other evidence are cited in support of the proposed structures.
Intramolecular cyclization by catalytic hydrogenation of 3β-acetoxy-16-picolinylidene-5-androsten-17-one (IV) (80° and 50–60 atm of hydrogen pressure over Pd/C as catalyst) gives rise to the formation of two cyclic products, namely, 5′,6′,7′,8′-tetrahydro-2′α-3′α-9′α-3β-acetoxy-androst-5-eno [16.17-b]indolizine (VII) and its 9′β-isomer (VIII), in a total yield of over 80%, the ratio of the two isomers being 3:1. The cyclized products have structures similar to naturally occuring alkaloid solanidine. A mechanism is proposed for the cyclization.
The mass spectra of the epimeric tertiary alcohols of a number of 17-alkylestradiols and 17- alkyl-19-nortestosterones have been studied. The dehydration under electron impact of the alcohols with 17α-OH-group was found to proceed more easily than their β-OH-epimers.
The configurations of dl-17a-methyl- and 17a-ethyl-3-methoxy-Δ1,3,5(10),8-d-homoestratetraen-17a-ols (1–11 and III–IV) and the corresponding dl-17a-methyl- and dl-17a-ethyl-19-nor-d-homotestosterones (VI–VII and VIII–XI) have been determined by three independent methods: chemical NMR and fragment mass spectroscopy. The configuration of the hydroxyl group in the ketols (VI–IX) has been correlated with their anabolic activity.
3β- and 3α-thiol 5β-pregnan-20-ones and 5β-androstan-17-ones have been prepared as examples of axial and equatorial thiol epimers in cis-fused fixed ring systems. The conformation of the epimers has been established by IR and NMR measurements.
The mass spectra of progesterone, 17-isoprogesterone and their 16 β-methyl derivatives were measured. The presence of 17α-acetyl group causes intensive rupture of the 15–16 and 13–17 bonds resulting in formation of the ions at m/e 244 and 71 (or 85).