A novel synthesis of (+)-biotin from L-cysteine

(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis base-catalyzed cyanosilylation of alpha-amino aldehyde 3 to provide anti-O-TMS-cyanohydrin 4 with high stereoselectivity and in high yield (anti/syn = 92:8, 96%). Treatment of 4 with a di-Grignard reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the 4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic carbonate 6b that was elaborated from 5.     

A practical synthesis of (+)-biotin from L-cysteine

Alpha-amino aldehyde 4, which is readily derived from L-cysteine through cyclization and elaboration of the carboxy group, was subjected to the Strecker reaction, which, via sodium bisulfite adduct 16, afforded alpha-amino nitrile 5 with high diastereoselectivity (syn/anti=11:1) and in high yield. Amide 6, derived from 5, was converted to thiolactone 8, a key intermediate in the synthesis of (+)-biotin (1), by a novel S,N-carbonyl migration and cyclization reaction. The Fukuyama coupling reaction of 8 with the zinc reagent 21, which has an ester group, in the presence of a heterogeneous Pd/C catalyst allowed the efficient installation of the 4-carboxybutyl chain to provide 9. Compound 9 was hydrogenated and the protecting groups removed to furnish 1 in 10 steps and in 34 % overall yield from L-cysteine.     

An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.     

An unusual stereochemical outcome of radical cyclization: synthesis of (+)-biotin

An enantioselective synthesis of (+)-biotin 1 starting from naturally available cysteine is described. The key steps are the unusual stereochemical outcome of radical cyclization of compound 10 to prepare 5,5-fused system 11, and the introduction of C4-sidechain at C₆ in 13 via a Grignard reaction.     

2-Thiazolidinone: a novel thiol protective surrogate of complete atom efficiency, a practical synthesis of (+)-biotin

2-Thiazolidinone derivatives were shown to be novel protective surrogates of a thiol group in l-cysteine derivatives. After elaboration at the C-4 substituent, the thiol group was completely liberated by simple heating in DMF whose atom efficiency is 100%. A practical synthesis of (+)-biotin was accomplished by the use of the strategy employing 4-functionalized 2-thiazolidinone derivatives as the intermediates, allowing a synthesis of (+)-biotin in 10 steps and in 31% overall yield. Short steps, high yield, and ease of operation of the present approach would permit the hitherto most efficient access to (+)-biotin.     

Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl]thymine

Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is (1)C(4). The key to the synthesis of 4 involves the stereoselective introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via hydroboration/oxidation of a C-4'-exocyclic vinylic intermediate selectively yielded the undesired alpha-directed hydroxymethyl group. Therefore, we envisaged another approach in which the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-alpha-l-lyxopyranose with beta-tributylstannyl styrene. This allowed stereoselective beta-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) into the desired 4-hydroxymethyl group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl(2) as Lewis acid (22). After suitable protection, Barton deoxygenation of the 2'-hydroxyl function of the obtained ribo-nucleoside yielded the desired 2'-deoxynucleoside 4, indeed showing the expected equatorial orientation of the thymine ring ((4)C(1)).     

Total synthesis of (+)-brefeldin A

(+)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol via tandem Li-I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with SmI2, and (4) a 2-methyl-6-nitrobenzoic anhydride-mediated (Shiina) lactonization.     

Total Synthesis of (+)-Sinefungin

Sinefungin (1) a nucleoside antibiotic isolated from Streptomyces has been synthesized from D-ribose. Both the C-6 and C-9 stereogenic centers were constructed by efficient asymmetric syntheses. The C-6 amine stereochemistry was set by a highly diastereoselective allylation (>99% de) of a (1S,2R)-1-amino-2-indanol-derived oxazolidinone 9 followed by a Curtius rearrangement of 11 to 12. The C-9 amino acid stereochemistry of sinefungin (1) was established by a rhodium chiral bisphosphine-catalyzed asymmetric hydrogenation of an alpha-(acylamino)acrylate derivative. The anomeric adenosylation of the mixture of anomeric acetates 20 in the presence of C-6 urethane NH was found to be extremely difficult. Conversion of the C-6 urethane NH as its N-benzyl derivative 21 was necessary prior to the adenosylation reaction. Successful adenosylation was effectively carried out by Vorbrüggen's protocol utilizing persilylated N(6)-benzoyladenine and trimethylsilyl triflate.     

Total syntheses of (+)-tedanolide and (+)-13-deoxytedanolide

Convergent total syntheses of the potent cytotoxins (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) are described. The carbon framework of these compounds was assembled via a stereoselective aldol reaction that unifies the C(1)-C(12) ketone fragment 5 with a C(13)-C(23) aldehyde fragment 6 (for 13-deoxytedanolide) or 52 (for tedanolide). Multiple obstacles were encountered en route to (+)-1 and (+)-2 that required very careful selection and orchestration of the stereochemistry and functionality of key intermediates. Chief among these issues was the remarkable stability and lack of reactivity of hemiketals 33b and 34 that prevented the tedanolide synthesis from being completed from aldol 4. Key to the successful completion of the tedanolide synthesis was the observation that the 13-deoxy hemiketal 36 could be oxidized to C(11,15)-diketone 38 en route to 13-deoxytedanolide. This led to the decision to pursue the tedanolide synthesis via C(15)-(S)-epimers, since this stereochemical change would destabilize the hemiketal that plagued the attempted synthesis of tedanolide via C(15)-(R) intermediates. However, use of C(15)-(S)-configured intermediates required that the side-chain epoxide be introduced very late in the synthesis, owing to the ease with which the C(15)-(S)-OH cyclized onto the epoxide of intermediate 50.     

A convergent and stereocontrolled cycloaddition strategy toward eudesmane sesquiterpenoid: total synthesis of (±)-6β,14-epoxyeudesm-4(15)-en-1β-ol

We present in this report the development of a convergent and highly stereocontrolled cycloaddition strategy toward the synthesis of C-1, C-6, and C-14 tris-oxygenated eudesmane sesquiterpenoids. This approach was demonstrated in the first total synthesis of (±)-6β,14-epoxyeudesm-4(15)-en-1β-ol (1), a structurally unique ethereal eudesmane sesquiterpenoid, via an effective Diels-Alder construction of a compact functionalized tricycle intermediate from readily available N-benzylfurfurylamine (2) and homoprenyl maleic anhydride (3) as the C(5) and C(10) building blocks, respectively.     

Catalytic asymmetric total synthesis of (+)-lactacystin

Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a stable masked alpha-hydroxy ketoimine analogue. Excellent enantioselectivity (98% ee) and practical catalyst activity were produced under the optimized catalyst preparation method using 2.5 mol % Gd{N(SiMe3)2}3 as a metal source and 3.8 mol % D-glucose-derived ligand 8. This reaction was conducted on a 5 g scale. The chiral tetrasubstituted C-5 carbon efficiently controlled the stereochemistry of the other three chiral centers of lactacystin. Chelation-controlled Meerwein-type reduction of ketone 5 using i-PrMgBr (originally reported by Kang in a related substrate) selectively produced the desired secondary alcohol at the C-9 position. The C-6 hydroxy and C-7 methyl groups were introduced via a silyl conjugate addition followed by the Tamao oxidation and Donohoe methylation, respectively, in a highly stereoselective manner. A practical amount of enantiomerically pure clasto-lactacystin beta-lactone (2), the biologically active form of (+)-lactacystin, can be synthesized using this route. clasto-Lactacystin beta-lactone (2) was converted to (+)-lactacystin following the reported procedure.     

Diastereoselective amidoalkylation of (3S,7aR)-6-benzyl-7-hydroxy-3-phenyltetra- hydro-5H-imidazo[1,5-c][1,3]thiazol-5-one: a short and highly efficient synthesis of (+)-biotin

A short and highly efficient synthesis of (+)-biotin in 10 steps with 20% overall yield has been achieved from L-cysteine involving amidoalkylation of hydroxy imidazothiazolone 4 via an acyliminium ion intermediate to furnish C-7-substituted imidazothiazolones 5b as the key step.     

Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4, 3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4, 3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.     

Amphidinolides T2, T3, and T4, new 19-membered macrolides from the dinoflagellate Amphidinium sp. and the biosynthesis of amphidinolide T1.

Three new 19-membered macrolides, amphidinolides T2 (2), T3 (3), and T4 (4), structurally related to amphidinolide T1 (1) have been isolated from two strains of marine dinoflagellates of the genus Amphidinium. The structures of 2-4 were elucidated on the basis of spectroscopic data. The absolute configurations at C-7, C-8, and C-10 of 1-4 were determined by comparison of NMR data of their C-1-C-12 segments with those of synthetic model compounds for the tetrahydrofuran portion. The biosynthetic origins of amphidinolide T1 (1) were investigated on the basis of 13C NMR data of a 13C enriched sample obtained by feeding experiments with [1-(13)C], [2-(13)C], and [1,2-(13)C2] sodium acetates and 13C-labeled sodium bicarbonate in the cultures of the dinoflagellate. These incorporation patterns suggested that amphidinolide T1 (1) was generated from four successive polyketide chains, an isolated C1 unit formed from C-2 of acetates, and three unusual C2 units derived only from C-2 of acetates. Furthermore, it is noted that five oxygenated carbons of C-1, C-7, C-12, C-13, and C-18 were not derived from the C-1 carbonyl, but from the C-2 methyl of acetates.     

Enantioselective synthesis of (+)-cryptophycin 52 (LY355703), a potent antimitotic antitumor agent

A highly enantioselective and convergent synthesis of cryptophycin 52 (2), an exceedingly potent cytotoxic agent, is described. Cryptophycin 52, a synthetic variant of the cryptophycin family, is currently undergoing clinical trials. The synthesis is convergent and involves assembly of three fragments, phenyl hexenal 3, d-tyrosine phosphonate 4, and protected beta-amino acid derivative 5. The synthesis of fragment 3 involves an efficient and stereocontrolled construction of both stereogenic centers at C-3 and C-4 by cleavage of a substituted tetrahydrofuran ring via an acyloxycarbenium ion intermediate. Both of these stereogenic centers were derived from optically active 4-phenylbutyrolactone, synthesized enantioselectively by Corey-Bakshi-Shibata reduction.     

Biotransformation of (+)-isofraxinellone by Aspergillus niger and insect antifeedant activity

The biotransformation of (+)-isofraxinellone (1) by Aspergillus niger was investigated. Compound 1 was transformed to only one new compound 2. The structure of 2 was identified as (-)-(4S)-4-hydroxyisofraxinellone which was regio- and stereo-selective hydroxylated at the C-4 position by IR, EI-MS 1D and 2D NMR. Absolute configuration of hydroxyl group at the C-4 position was detected by modified Mosher’s method. Antifeedant activity of compounds 1 and 2 against larvae of Spodoptera litura was assayed. These compounds showed potent antifeedant activity and ED₅₀ (50% of effective dose) values were 3.91 and 4.43 μg/cm², respectively.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

A novel procedure for the preparation of zinc reagents: a practical synthesis of (+)-biotin

The use of bromine for activation of zinc dust allowed smooth and reproducible reduction of iodide 1 to the corresponding zinc reagent 2. The zinc reagent 2 obtained by the present protocol was allowed to the Fukuyama coupling reaction with thiolactone 3 to provide a key intermediate 4 for (+)-biotin in high yield using a reasonably fair amount of 1 (1.4 equiv).     

Synthesis of [3,4-(13)c(2)]-enriched bile salts as NMR probes of protein-ligand interactions

Synthetic methodology that allows for incorporation of isotopic carbon at the C-3 and C-4 positions of bile salts is reported. Three [3,4-(13)C(2)]-enriched bile salts were synthesized from either deoxycholic or lithocholic acid. The steroid 3alpha-OH group was oxidized and the A-ring was converted into the Delta(4)-3-ketone. The C-24 carboxylic acid was next converted into the carbonate group and selectively reduced to the alcohol in the presence of the A-ring enone. Following protection of the 24-OH group, the Delta(4)-3-ketone was converted into the A-ring enol lactone. Condensation of the enol lactone with [1,2-(13)C(2)]-enriched acetyl chloride and subsequent Robinson annulation afforded a [3,4-(13)C(2)]-enriched Delta(4)-3-ketone that was subsequently converted back into a 3alpha-hydroxy-5beta-reduced bile steroid. C-7 hydroxylation, when necessary, was achieved via conversion of the Delta(4)-3-ketone into the corresponding Delta(4,6)-dien-3-one, epoxidation of the Delta(6)-double bond, and hydrogenolysis/hydrogenation of the 5,6-epoxy enone system. The [3,4-(13)C(2)]-enriched bile salts were subsequently complexed to human ileal bile acid binding protein (I-BABP), and (1)H-(13)C HSQC spectra were recorded to show the utility of the compounds for investigating the interactions of bile acids with I-BABP.     

Synthetic studies toward marine toxic polyethers (2) synthesis of the B-segment of okadaic acid and coupling with the C-segment

Part of okadaic acid 1a was synthesized stereoselectively in the form of 4a (involving C-16 through C-38 with 10 asymmetric carbons), by coupling the equivalents of 2 and 3 as the synthetic segments B and C (Scheme 1), the former being prepared via 12 and 6 from a D-glucopyranose derivative (Scheme 2).