Synthesis of the diacetate of 4-chloro-2-hydroxymethyl-2-buten-1-ol. A useful synthon in the chemistry of the isoprene unit

a versatile procedure for the synthesis of the diacetate of 4-chloro-2-hydroxymethyl-2-buten-1-ol, a precursor of the dihydroxyprenyl synthon, is described. Its application to the synthesis of an unusual metabolite of a prenyl-containing drug is illustrated.     

Asymmetric total synthesis of halicholactone.

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.     

Simple and efficient production of (Z)-4-hydroxytamoxifen, a potent estrogen receptor modulator

A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.     

Synthesis of Aristotelia-Type Alkaloids. Part VIBiomimetic Synthesis of (+)-Aristofruticosine

(S)-Perilla alcohol ( 5 ) was transformed into (S)-7-(phenylthio)-p-menth-1-en-8-amine ( 11 ) in five steps. Condensation of this building block with 1-(4-methoxyphenylsulfonyl)-1H-indole-3-acetaldehyde ( 12 ) led to the expected imine 15 which cyclized in 54% yield to protected 20-(phenylthio)hobartine 16 upon exposure to anh. HCOOH. Treatment of this intermediate with an alkylating reagent led to (+)-aristofruticosine protected in the indole moiety via an intramolecular, allylic nucleophilic displacement reaction. Subsequent reductive removal of the protecting group completed the first synthesis of the Aristotelia alkaloid (+)-aristofruticosine ((+)- 4 ). This straightforward synthesis confirmed the tentative structure (+)- 4 , proposed by Bick and Hai, and established the hitherto unknown absolute configuration of this metabolite.     

Near-UV activation of yeast growth.

Near-UV radiation (337 nm) at fluences of 2-10 kJ m-2 activates, during the lag-phase, subsequent growth of the yeast Candida guilliermondii. Photostimulation occurs only after a temperature-dependent time interval (1-2 h) between short-period irradiation and the onset of cell growth on a nutrient medium. A photoactivated enzymatic synthesis of an intermediate metabolite regulating cell growth is proposed as the cause of the biochemical changes responsible for the photostimulatory effect. On the basis of the observed disappearance of photostimulation after adding para-chlorphenylalanine (a specific inhibitor of serotonin synthesis), serotonin is suggested to act as the active metabolite. The regulatory function of serotonin is confirmed by the stimulatory effect of exogenous serotonin and its dependence on concentration, which resembles the dependence on near-UV fluence.     

Synthesis of an electrophilic keto-tetraene 15-oxo-Lipoxin A4 methyl ester via a MIDA boronate

15-oxo-Lipoxin A₄ (15-oxo-LXA₄) has been identified as a natural metabolite of the fatty acid signaling mediator Lipoxin A₄. Herein, we report a total synthesis of the methyl ester of 15-oxo-LXA₄ to be used in investigations of potential electrophilic bioactivity of this metabolite. The methyl ester of 15-oxo-LXA₄ was synthesized in a convergent 15 step (9 steps longest linear) sequence starting from 1-octyn-3-ol and 2-deoxy-d-ribose with Sonogashira and Suzuki cross-couplings of a MIDA boronate as key steps.     

The first total synthesis and absolute stereochemistry of plakortone G from the Jamaican sponge Plakortis sp.

Total synthesis of plakortone G (1), a secondary metabolite of the Jamaican sponge Plakortis sp., was successfully achieved. The absolute configuration of this molecule was determined by comparison of the synthetic diastereomers with reported data to possess the (4R,8R)-configuration 14.     

Synthetic studies directed toward the pseurotins. Part II. Synthesis of related highly functionalized furan-3(2H)-ones

The synthesis of 2,2-bis(hydroxymethyl)-4-methyl-5-phenylfuran-3(2H)-one ( 9 ), 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2,2-bis(hydroxymethyl)-4-methylfuran-3(2H)-one ( 24 ), and 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2-(hydroxymethyl)-4-methylfuran-3(2H)-one ( 28 ), which represent more advanced, suitably functionalized intermediates for the synthesis of pseurotin A ( 1 ), a secondary metabolite of Pseudeurotium ovalis STOLK , is described.     

Synthesis of Two Metabolites of the Antiarrythmicum Amiodarone

The metabolism of the potent antiarrythmic drug amiodarone (AMI; 1 ) has yet not been fully investigated. Recently, in vitro experiments revealed that in rabbit‐liver microsomes, AMI ( 1 ) and its main metabolite MDEA ( 2 ) were biotransformed to the hydroxylated derivatives 3′‐OH‐AMI ( 3 ) and 3′‐OH‐MDEA ( 4 ), respectively. To establish the chemical structure of 3 and 4 , we developed a total synthesis of these two metabolites of AMI ( 1 ). ¹H‐ and ¹³C‐NMR Signal assignment from HSQC and HMBC 2D NMR data of synthesized 4 showed that the proposed structure of metabolite 4 is correct. Even the structure of 3 was found to be correct by comparing its HPLC/MS‐MS/MS with the data described earlier.     

Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor

The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.     

Metabolites of felbamate; synthesis of 2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate, 2-phenyl-2-hydroxy-1,3-propanediol dicarbamate,and 2-phenyl-1,3-propanediol monocarbamate

Three major metabolites of felbamate, namely 2-(4-hydroxyphyenyl)-1, 3-propanediol dicarbamate. [4], 2-hydroxy-2-phenyl-1,3-propanediol dicarbamat [12], and 2-phenyl-1,3-propanediol monocarbamate [17] were prepared. The first metabolite, 4, was synthesised from p-methoxy-phenylacetic acid [1] via five steps involving carboxylation, reduction, phosgenation, demethylation, and carbonation. The second one, 12, was prepared from 2-phenyl-1,3-propanediol [7] by the following five steps; phosgenation, halogenation, carbonation, dehalogenation, and ammonolysis. The synthesis of the third metabolite, 17, started with 7, via the following five steps: methylation, phosgenation, carbonation, and demethylation.     

Formal total synthesis of (-)-apicularen A via transannular conjugate addition

The formal total synthesis of the myxobacteria metabolite (-)-apicularen A (1) is described. The key step involved a novel acid-mediated transannular conjugate addition of the C13 hydroxyl into the alpha,beta-unsaturated ketone in either of the macrolactones 5a or 5b to provide the same trans-pyranone 4. Conversion of 4 into the known apicularen intermediate diol 3 completed the formal synthesis. [reaction: see text]     

Enantioselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol,a bioactive metabolite of the marine sponge Cribrochalina vasculum

The first stereoselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol, an immunosuppressive and antitumoral metabolite isolated from the Caribbean sponge Cribrochalina vasculum, has been achieved and its stereostructure has been confirmed. The key step of the synthesis involves a borane-mediated reduction of the parent (E)-19-methyl-1-trimethylsilylicos-4-en-1-yn-3-one in the presence of a chiral oxazaborolidine.     

Total synthesis of (-)-aplaminal

The total synthesis and assignment of absolute configuration of (-)-aplaminal ( 1), a cytotoxic metabolite from a sea hare possessing a triazobicyclo[3.2.1]octane skeleton, has been achieved. The synthesis entailed condensation of a monoprotected diamine ( 3) with dimethyl 2-oxomalonate ( 4) to generate the imidazolidine core ( 2). Introduction of the third nitrogen via Mitsunobu activation and azide displacement, followed by reduction and lactam formation (AlMe 3), furnished (-)-aplaminal ( 1). Overall, the synthesis entailed 9 steps and proceeded in 19% overall yield.     

Synthesis of Terfenadine Carboxylate

A synthesis of terfenadine carboxylate, 1, a metabolite of terfenadine 2, is described. In the key step, the sodium salt of 2-(4-bromophenyl)-2-methylpropionic acid, 7, was lithiated via a metal-halogen exchange using t-BuLi and subsequently condensed with 4-[4-(hydroxydiphenylmethylpiperidin-1-yl]butyraldehyde, 5, to afford terfenadine carboxylate, 1.     

Synthesis of Aristotelia-type alkaloids. Part VIII. Synthesis of (±)-aristolasicone

The revised structure of the indole alkaloid aristolasicone ( 2 ) was confirmed through a convergent total synthesis of the racemic form of this metabolite. The key step involves a one-pot condensation/cyclization reaction between 1-(4-methoxyphenylsulfonyl)-1H-indole-2-acetaldehyde ( 9 ) and (±)-trans-5-(2,6-difluorobenzyloxy)-p-menth-l-en-8-amine ((±)-7). The resulting allohobartine derivative (±)- 13 , obtained in 84% yield, was deprotected and oxidized to (±)-alloscrratenone ((±)- 15 ) which cyclized smoothly to the target molecule (±)-2 upon exposure to BF₃ · Et₂O.     

Enantiospecific Synthesis of Trisubstituted Butyrolactone Natural Products and Their Analogs

A general methodology for the synthesis of highly substituted butyrolactones in enantiomerically pure form has been developed. The application of this process in a highly efficient synthesis of lactone natural products blastmycinone (1), NFX-2 (2), antimycinone (3), and NFX-4 (4) and two lipid metabolites (5, 6) are described. Additionally, the total synthesis of 5-epi-blastmycinone (22), 5-epi-NFX-2 (21b), 5-epi-NFX-4 (21c), and lipid metabolite analogs (19, 20) are also described. The overall yields for the target molecules are the highest reported so far in the literature.     

Synthesis of racemic cis-5-hydroxy-3-phthalimidoglutarimide. A metabolite of thalidomide isolated from human plasma

[reaction: see text] A synthesis of the glutarimide-derived metabolite of thalidomide, 5'-hydroxythalidomide (2), is described. The synthesis employed the lactone derivative of N-benzyloxycarbonyl (CBZ)-protected 4-hydroxyglutamic acid 12, which is prepared by a de novo route from diethyl acetamidomalonate. The reaction of 12 with 4-methoxybenzylamine gave the corresponding isoglutamine, which then provided the key CBZ-protected N-PMB-glutarimide 14 after dehydration. Deprotection of both the CBZ and PMB groups followed by phthalimidation and deacetylation of the 3-amino-5-acetoxyglutarimide 16 afforded 2.     

Determination of the metabolites of bezitramide in urine. II. The basic metabolite.

A high-performance liquid chromatographic method for the determination of low levels (less than 1 microgram/ml) of the basic metabolite of bezitramide, 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one, in human urine is described. Special attention is given to the separation from the basic metabolite of droperidol, a drug frequently co-administered with bezitramide.     

Stereoselective anti aldol reactions of erythrulose derivatives. Functionalized chiral d3 and d4 synthons

An improved procedure for the synthesis of anti aldols from protected erythrulose derivatives is reported. The preparation of functionalized d3 and d4 synthons with various stereochemical arrays by means of this methodology is described and subsequently applied to a stereoselective formal synthesis of the natural metabolite goniothalesdiol.