PMR detection of carbocation intermediates in the pinacol rearrangement in a superacid

Conclusions The formation of carbocation intermediates in the pinacol rearrangement, namely, - and -hydroxy-substituted carbonium ions, was established by PMR spectroscopy in the case of the transformation of 3,6,9,10-tetramethyl-9,10-dihydrophenanthrene-9,10-diol to 3,6,9,9-tetramethyl-9,10-dihydro-10-phenanthrenone in the HSO₃F-SO₂ClF acid system. The rate of the isomerization of the -hydroxy-substituted cation to the -hydroxy-substituted cation was estimated.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 12, pp. 2804–2807, December, 1984.     

Synthesis of aza analogues of the anticancer agent batracylin

Three series of pyrido-fused pyrimido[2,1-a]isoindol-7-ones were prepared from readily available (aminopyridinyl)(aryl)methanones by reduction followed by a Mitsunobu reaction with phthalimide and acid-catalysed cyclodehydration. This approach provides a wide variety of aza analogues of the antitumour agent batracylin.     

Mechanism of abietadiene synthase catalysis: stereochemistry and stabilization of the cryptic pimarenyl carbocation intermediates

Abietadiene synthase (AS) catalyzes the complex cyclization-rearrangement of (E,E,E)-geranylgeranyl diphosphate (8, GGPP) to a mixture of abietadiene (1a), double bond isomers 2a-4a and pimaradienes 5a-7a as a key step in the biosynthesis of the abietane resin acid constituents (1b-4b) of conifer oleoresin. The reaction proceeds at two active sites by way of the intermediate, copalyl diphosphate (9). In the second site, a putative tricyclic pimaradiene or pimarenyl(+) carbocation intermediate of undefined C13 stereochemistry and annular double bond position is formed. Three 8-oxy-17-nor analogues of 9 (17 and 19a,b) and three isomeric 15,16-bisnorpimarenyl-N-methylamines (26a-c) were synthesized and evaluated as alternative substrates and/or inhibitors for recombinant AS from grand fir. The stereospecific cyclization of 8 alpha-hydroxy-17-nor CPP (19a) to 17-normanoyl oxide (20a) and the higher inhibitory potency of the norpimarenylamine 26a (K(i) = 0.1 nM) both suggest pimarenyl intermediates having the 13 beta methyl configuration and 8,14-double bond corresponding to sandaracopimaradiene (5a). The 2000-fold stimulation of inhibition by 26a in the presence of inorganic pyrophosphate indicates an important role for carbocation/OPP anion stabilization of the secondary sandaracopimaren-15-yl(+) ion. The failure of 8 beta-hydroxy-17-nor CPP (19b) to undergo enzymatic cyclization was taken as evidence that 9 is bound with a "coplanar" side chain conformation and that the S(N)' cyclization occurs on the 17 alpha face. The routing of the sandarcopimara-15-en-8-yl carbocation toward various diterpenes in biogenetic schemes is attributed to differing conformations of ring C and/or orientations of the C13 vinyl group in the active sites of the corresponding diterpene cyclases.     

Unexpected cycloisomerizations of nonclassical carbocation intermediates in gold(I)-catalyzed homo-Rautenstrauch cyclizations

An unexpected gold(I)-catalyzed homo-Rautenstrauch rearrangement of 1-cyclopropyl propargylic esters to cyclohexenones is disclosed. This rearrangement represents new evidence for the recently discussed gold-stabilized nonclassical carbocation character of intermediates in gold catalysis. A mechanistic study proved partial chirality transfer from optically active propargyl acetates.     

Synthesis of a new enantiopure chiral aza crown ether and its application in enantiomeric separation

A new enantiopure chiral aza crown ether (S,S)‐1,7‐bis(4‐phenyl‐5‐hydroxy‐2‐oxo‐3‐ zapentyl)‐1,7‐diaza‐12‐crown‐4 ligand (1) has been synthesized and used as a chiral selector in the enantiomeric separation of D/L‐carnitine by capillary electrophoresis.     

Quantifying intermediates in template-directed natural product biosynthesis

High-performance mass spectrometry is providing new experimental windows into the enzymology of natural product biosynthesis. The first quantitative assessments of covalently attached biosynthetic intermediates promise to shine new light on template-directed biosynthesis.     

Assembly intermediates in polyketide biosynthesis: enantioselective syntheses of beta-hydroxycarbonyl compounds

A versatile approach for the enantioselective synthesis of functionalised beta-hydroxy N-acetylcysteamine thiol esters has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted delta-lactones.     

The reaction of homophthalic acid and some aza analogues with vilsmeier reagent: a reinvestigation

Homophthalic acid and its pyrido and 8‐methylquinolino analogues with dimethylformamide/phosphoryl chloride at 0 ° give the appropriate 4‐(dimethylaminomethylene)isochroman‐1,3‐dione ( 2a, 2b, 2c , respectively). Under the literature conditions for conversion of 2a to 2‐methyl‐1‐oxo‐1,2‐dihydroisoquinoline‐4‐carboxylic acid ( 3a ), the aza analogues give instead 7‐hydroxy‐5‐oxo‐5H‐pyrano[4,3‐b]pyridine‐8‐carbox‐aldehyde ( 5b ) and 3‐hydroxy‐6‐methyl‐1‐oxo‐1H‐pyrano[4,3‐b]quinoline‐4‐carboxaldehyde ( 5c ), respectively. Modified conditions were required to isolate analogues 3b and 3c . Further, while reaction of 2a with hydrogen chloride in methanol gave the known change to methyl 1‐oxo‐1H‐isochromene‐4‐carboxylate ( 4 ), 2b and 2c gave only products of oxa‐ring cleavage. Methyl 2‐(cis‐2‐hydroxyvinyl)‐8‐methylquinoline‐3‐carboxylate ( 8 ) was the main product from 2c , while a novel quinolizinium species ( 11 ) was formed in good yield from 2b.     

Asymmetric biosynthesis of intermediates of anti-HIV drugs

Human immunodeficiency virus (HIV) infection is the fifth most common cause of death and many new HIV infections occur every year. The prevalence of HIV also seriously affects the quality of a patient’s life. More than forty anti-HIV drugs have been put into clinical uses, many of which are chiral molecules with multiple stereogenic centers, for example abacavir, lamivudine, zidovudine, stavudine, tenofovir, atazanavir. However, the chemical synthesis of these chiral intermediates have the disadvantages of low enantiomeric purity and complex synthetic steps. The benefits of asymmetric biosynthesis of chiral drugs include high enantiomeric excess (e.e.), good product selectivity, mild reaction conditions, and less side effects. The biosynthesis of the chiral intermediates of these anti-HIV drugs is thus particularly important. Herein, we review the different sources of enzymes and microbial cells for the asymmetric biosynthesis of the above chiral anti-HIV drug intermediates. We also review recent biotechnology progress in engineering these enzymes and microbial cells with improved biocatalytic activities, including enzyme and cell immobilization, surface display of enzymes, and directed evolution of enzymes. These biotechnology processes enable the efficient biosynthesis of these chiral intermediates, facilitating the industrial production of anti-HIV drugs with reduced costs.     

Deoxynucleoside H-Phosphonate diester intermediates in the synthesis of internucleotide phosphate analogues

Polymer bound deoxynucleoside H-phosphonate diesters are used as precursors to phosphoramidate, thiophosphate and phosphate triester analogues of DNA.     

Efficient two-step synthesis of methylphytylbenzoquinones: precursor intermediates in the biosynthesis of vitamin E

Methylphytylbenzoquinone was synthesized from δ-tocopherol by a simple two-step sequence. Oxidative cleavage of the benzopyran ring with cerium sulfate followed by dehydration using Burgess reagent afforded the methylphytylbenzoquinone as a mixture of positional and geometric isomers which were separated by HPLC. The biological activity of the product corresponds to the natural biosynthetic precursor of vitamin E. The above method is a general procedure applicable to the preparation of any of the tocopherol derivatives.     

Gamma-radiolysis of chiral terpenes: α-(−)pinene and α-(+)pinene

The terpenes α-(+)-pinene, and α-(−)pinene have been radiolyzed at radiation doses of 150, 300 and 600 kGy. The radiolyzed samples have been analyzed by FT-IR spectroscopy and polarimetry. Both α-(+)-, α-(−)-pinenes show a linear trend to radioracemization as a function of the radiation dose administered ≈2.5·10⁻³ [α]_D/kGy. The solvent fractionation and the liquid chromatographic analysis (HPLC) of the radiolyzed samples shows that both α-pinene enantiomers produce ocimene and dipentene together with minor quantities of other products and a resin. The kinetics of α-pinene decomposition under radiolytic conditions can be described by a pseudofirst order rate constant k∼5.3·10⁻⁷s⁻¹ while the radiation chemical yield for the same reaction has a G = 5.0 molecules/100 eV, so that about 30% of the original α-pinene is converted into other products at 600 kGy.     

Identification of amphilectosins as key intermediates in pseudopterosin biosynthesis

Amphilectosins A and B have been identified from the organic extract of Pseudopterogorgia elisabethae collected in the Florida Keys, along with seco-pseudopterosins and pseudopterosins. The structures of the amphilectosins, "C-12-C-13 dehydro seco-pseudopterosins", suggested that these metabolites provide the biosynthetic link between the seco-pseudopterosins (serrulatane diterpenes) and pseudopterosins (amphilectane diterpenes). This biosynthetic relationship was confirmed through various radiolabeling experiments. Incubation studies with the amphilectosins revealed the selective transformation of amphilectosin A to pseudopterosin Y and the transformation of amphilectosin B to pseudopterosin F, which suggests that the alpha/beta stereochemistry for the isobutenyl group in the pseudopterosins arises from the selective ring closure of the cis- and trans-amphilectosins.     

Engineered biosynthesis of aklanonic acid analogues

Aklanonic acid, an anthraquinone natural product, is a common advanced intermediate in the biosynthesis of several antitumor polyketide antibiotics, including doxorubicin and aclacinomycin A. Intensive semisynthetic and biosynthetic efforts have been directed toward developing improved analogues of these clinically important compounds. The primer unit of such polyfunctional aromatic polyketides is an attractive site for introducing novel chemical functionality, and attempts have been made to modify the primer unit by precursor-directed biosynthesis or protein engineering of the polyketide synthase (PKS). We have previously demonstrated the feasibility of engineering bimodular aromatic PKSs capable of synthesizing unnatural hexaketides and octaketides. In this report, we extend this ability by preparing analogues of aklanonic acid, a decaketide, and its methyl ester. For example, by recombining the R1128 initiation module with the dodecaketide-specific pradimicin PKS, the isobutyryl-primed analogue of aklanonic acid (YT296b, 10) and its methyl ester (YT299b, 12) were prepared. In contrast, elongation modules from dodecaketide-specific spore pigment PKSs were unable to interact with the R1128 initiation module. Thus, in addition to revealing a practical route to new anthracycline antibiotics, we also observed a fundamental incompatibility between antibiotic and spore pigment biosynthesis in the actinomycetes bacteria.     

Chemical and microbiological syntheses of intermediates in gibberellin biosynthesis

A partial synthesis of kaurenoic acid 1 from the hydroxy acid 3 is described. The hydroxylation of the 2′-carboxyethyl ester of 1 by Gibberella fujikuroi has been utilized for the synthesis of 7β-hydroxykaurenoic acid 2. An alternative synthesis of 2 is provided by the microbiological conversion of 3 to the 7β-hydroxy derivative by Calonectria decora.     

Synthesis of novel aza analogues of 2-substituted-2,3-dihydro-1,4-benzodioxins as potential new scaffolds for drug discovery

New synthesis approaches that have led to a series of novel aza analogues of the 2-substituted-2,3-dihydro-1,4-benzodioxin core, bearing versatile bromomethyl group on the non aromatic oxygenated ring, are described. According to their structures these novel scaffolds can be useful intermediates for the preparation of potential new therapeutic agents.     

Biosynthesis of the angiogenesis inhibitor borrelidin: directed biosynthesis of novel analogues

We report the directed biosynthesis of borrelidin analogues and their selective anti-proliferative activity against human cancer cell lines.     

Synthesis of aza analogs of 2-aminocheomone

Aza analogs of 2-aminochromone 3- 2-amino-4-oxo-4H-pyrano [2,3-b]pyridine and 2-amino-4-oxo-4H-pyrano [3,2-c]pyridine 3- were synthesized. It was established from the PMR and IR spectra that these compounds exist in the amino ketone form.     

Efficient oxidative radical cyclizations of ester enolates with carbocation desilylation as termination: synthesis of cyclopentanoid monoterpenes and analogues

[reaction: see text] An efficient oxidative radical cyclization approach for the synthesis of 2-alkenyl cyclopentane or cyclohexane carboxylates from omega-silylallyl ester enolates induced by recyclable SET oxidant ferrocenium hexafluorophosphate has been developed. A new tandem alkoxycarbonylation/oxidative radical cyclization/cationic termination process forms the basis for a five-step synthesis of the cyclopentanoid monoterpene dihydronepetalactone and analogues.