Synthesis of an optically active, bicyclic 2-pyridone dipeptide mimetic

The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycarbonylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid] in optically active form (60% ee) is described. Key steps in the synthesis of 1 include the osmium-catalyzed asymmetric dihydroxylation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the intramolecular cyclization of protected diol 19 [(3'R)-[6-[4'-(tert-butyldimethylsilanyloxy)-3'-hydroxybutyl]-2-methoxypyridin-3-yl]carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H-indolizin-6-yl]carbamic acid benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are also discussed.     

Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors

Microbial enantioselective ester hydrolysis for the preparation of optically active (3R,5S)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (-)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (-)-enantiomer was an active inhibitor. Bulkiness of the ester moiety did not affect the enantioselectivity but did affect reactivity. The racemic ethyl ester of the 5-(2-methoxyphenyl) analogue, 5-(2,3-dimethoxyphenyl) analogue and 5-(2,4-dimethoxyphenyl) analogue were also hydrolyzed with Pseudomonas taetrolens to afford enantiomerically pure (-)-carboxylic acids in large scale. As another route to (3R,5S)-(-)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid [(-)-1c], the earlier intermediate (-)-2-amino-5-chloro-alpha-(2,3-dimethoxyphenyl)benzyl alcohol [(-)-12] was successfully obtained by asymmetric hydrolysis of (+/-)-5-chloro-alpha-(2,3-dimethoxyphenyl)-2-pivaloylaminobenzyl acetate with Pseudomonas sp. S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product (-)-12 was converted to (-)-1c without racemization.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Synthesis of novel lysophosphatidylcholine analogues using serine as chiral template

Four novel lysophosphatidylcholine (lysoPC) analogues, (S)-N-stearoyl-O-phosphocholineserine methyl ester [(S)-1a], (R)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3-phosphatidylcholine [(R)-2a], (R)-N-stearoyl-O-phosphocholineserine methyl ester [(R)-1b], and (S)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3-phosphatidylcholine [(S)-2b], were synthesized starting from serine as a chiral template. These synthetic compounds exhibited greatly enhanced hyphal transition inhibitory activity in Candida as compared to the natural lysoPC.     

Phenolic glycosides from Pyrola japonica

Five new phenolic glycosides, 2-beta-D-glucopyranosyloxy-5-hydroxyphenylacetic acid methyl ester (4), 4-hydroxy-2-[3-hydroxy-3-methylbutyl]-5-methylphenyl beta-D-glucopyranoside (5), 4-hydroxy-2-[(E)-4-hydroxy-3-methyl-2-butenyl]-5-methylphenyl beta-D-glucopyranoside (7), 4-hydroxy-2-[(2E,6Z)-8-beta-D-glucopyranosyloxy-3,7-dimethylocta-2,6-dien-1-yl]-5-methylphenyl beta-D-glucopyranoside (8), and 2,7-dimethyl-1,4-dihydronaphthalene-5,8-diol 5-O-beta-D-xylopyranosyl(1-->6)-beta-D-glucopyranoside (10), were isolated from the whole plants of Pyrola japonica (Pyrolaceae), together with androsin, (-)-syringaresinol glucoside, homoarbutin, pirolatin, hyperin, monotropein and chimaphilin.     

Beta-hydroxy-gamma-lactones as chiral building blocks for the enantioselective synthesis of marine natural products

The enantioselective synthesis of trans-(+)-laurediol, (2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol, and (2S,3S,5S)-5-[(1S)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol are described. In addition, a formal synthesis of trans-(-)-kumausyne is also developed. All the synthetic procedures have in common the use of enantiomerically enriched beta-hydroxy-gamma-lactones, easily available by Sharpless asymmetric dihydroxylation (AD) from the suitable beta,gamma-unsaturated ester. The use of Katsuki-Sharpless asymmetric epoxidation (AE) as an additional enantioselective reaction provides cyclic compounds of high enantiomeric purity.     

Synthesis of Carbocycles via Intramolecular Conjugate Additions: Total Syntheses of Axane Sesquiterpenoids

Syntheses of (+/-)-axamide-1 (2) and (+/-)-axisonitrile-1 (1) are described. The syntheses require 12 steps and 13 steps, respectively, from vinylogous ester 8 and feature the diastereoselective cyclization of unsaturated ester 7 to perhydroindan 5. Some interesting reactions of the organometallic derived from [(trimethylsilyl)methyl]magnesium chloride and cerium trichloride are also described.     

Pyrrolo[2,3-d] pyrimidines. I. 5-hydroxypyrrolo[2,3-d] pyrimidines

5-Hydroxy-7-alkyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriles (VIIb-d) and 5-hydroxy-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, ethyl ester (VIIa) were prepared from 5-carbethoxy-4-chloro-2-phenylpyrimidine (IV) via 4-[(cyanomethyl)alkylamino[-2-phenyl-5-pyrimidinecarboxylic acid, ethyl esters (Vb-d) and 4-[(carboxymethyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid, diethyl ester (Va), respectively. The hydroxy group of the pyrrolo-[2,3-d]pyrimidines could be methylated, acetylated and tosylated. Hydrolysis of 5-methoxy-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (IX) afforded the corresponding amide (X).     

Syntheses of (-)-funebrine and (-)-funebral, using sequential transesterification and intramolecular cycloaddition of a chiral nitrone

The first syntheses of (-)-funebrine [(-)-1] and (-)-funebral [(-)-2] are described. The syntheses feature sequential formation of nitrone VI from methyl glyoxylate (5) with oxime 6, transesterification of nitrone VI with (E)-crotyl alcohol (4), and intramolecular cycloaddition of the resulting nitrone VII bearing crotyl ester to afford cycloadduct 7 as a major product. The adduct 7 was readily elaborated to amino lactone (-)-3, the key synthetic intermediate of (-)-1 and (-)-2.     

C-linked disaccharide analogue of the Thomsen-Friedenreich (T)-epitope alpha-O-conjugated to L-serine

Condensation of a silylated beta-D-galactopyranosylaldehyde (3) with isolevoglucosenone (4) in the presence of Et(2)AlI provided bicyclic enone 5. Subsequent addition of BnNHOMe gave adduct 6, which was converted into 4-O-acetyl-1,6-anhydro-3-C-[(1 R)-1,3,4,5,7-penta-O-acetyl-2,6-anhydro-D-glycero-L-manno-heptitol-1-C-yl]-2-azido-2,3-dideoxy-beta-D-galacto-hexopyranose after liberation of the 2-amino group, its transformation into a 2-azido moiety, desilylation, and peracetylation. Ring-opening of the 1,6-anhydro galactopyranosyl unit and O-glycosidation with Fmoc-Ser-O-tBu afforded a 5:1 mixture of alpha- and beta-galactosides. Treatment with CH(3)COSH gave pure N-[(9H-fluoren-9-ylmethoxy)carbonyl]-{4,6-di-O-acetyl-3-C-[(1 R)-2,6-anhydro 1,3,4,5,7-penta-O-acetyl-D-glycero-L-manno-heptitol-1-C-yl]-2-[(N-acetyl)amino]-2,3-dideoxy-alpha-D-galactopyranosyl}-l-serine tert-butyl ester (2), a protected form of a C-disaccharide analogue of the Thomsen-Friedenreich (or T) epitope (beta-D-Galp-(1-->3)-alpha-D-GalNAcp) alpha-O-conjugated to L-serine.     

Reactions of 2-isocyanatobenzoyl chloride and 2-carbomethoxyphenyl isocyanate with 5-aminotetrazole

Treatment of 2-isocyanatobenzoyl chloride ( 4 ) with 5-aminotetrazole (5-AT) gave 3-(5-tetrazolyl)quinazoline-2,4(1H,3H)-dione ( 1 ) directly. Treatment of 2-carbomethoxyphenyl isocyanate ( 5 ) with 5-AT gave 2-[((5-amino-1H-tetrazol-1-yl)carbonyl)amino]benzoic acid methyl ester ( 6 ) as a kinetic product, which was thermally isomerized to 2-[((1H-tetrazol-5-ylamino)carbonyl)amino]benzoic acid methyl ester ( 7 ), the thermodynamically more stable urea. Cyclization of 7 with polyphosphoric acid gave 2-(1H-tetrazol-5-ylamino)-4H-3,1-benzoxazin-4-one ( 2 ). Urea 6 was quite labile in solution, as shown by nmr, and readily reacted with methanol to give 2-[(methoxycarbonyl)amino]benzoic acid methyl ester ( 10 ).     

Research on arylhydrazones of substituted glyoxylic acids

3-Aryl-4-(arylhydrazonochloroformyl)-2-[(carbethoxy or carbarnoyl)cyanomethylene]-4-thiazolines were obtained by condensation of arylhydrazones of chloromethylglyoxylic chloride with arylamides of cyanomonothiomalonic acid ethyl ester or amide. The chlorine atom in these compounds is readily exchanged by a hydrazino group to give 3-aryl-4-(arylhydrazonohydrazinoformyl)-2-[(carbethoxy or carbamoyl)cyanomethylene]-4-thiazolines. 2-(Arylhydrazonocarbethoxyformyl)-4-(arylhydrazonochloroformyl)thiazoles were obtained by reaction of arylhydrazones of chloromethylglyoxylic chlorides with arylhydrazones of monothiomesoxalic acid ethyl ester amide. Arylhydrazones of ethyl 1H-tetrazolyl-5-glyoxylate were synthesized by condensation of arylhydrazones of ethyl cyanoglyoxylate with ammonium azide in dimethylformamide.     

Studies on penem and carbapenem. I. Syntheses and oral absorption of ester-type prodrugs of sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-c arboxylat e

Acyloxyalkyl esters (2a-d), alkyloxycarbonyloxyalkyl esters (2e-g) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (2h) of (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3- carboxylic acid (1) were synthesized. Enhanced oral absorption was observed in mice reflecting increased lipophilicity, compared with the parent 1 itself. Among them, the ester 2h showed a prolonged plasma level and a large area under the blood concentration-time curve (AUC) in rats. These ester-type prodrugs of penem 1 in phosphate buffer (pH 6.86) were much more stable than those of cephalosporins which easily degraded via isomerization to delta 2 cephalosporins.     

A novel oxamide rearrangement

An efficient, base-induced rearrangement of 2-[(1,2-dioxo-2-(methylamino)ethyl)phenylamino]benzoic acid methyl ester ( 7a ) to the isomeric 2-[(1,2-dioxo-2-(phenylamino)ethyl)methylamino]benzoic acid methyl ester ( 27a ) is described. This novel rearrangement must proceed through a spiro intermediate wherein benzoate is acting as a Michael receptor. When 2-[(1,2-dioxo-2-(methylamino)ethyl)methylamino]benzoic acid methyl ester ( 28 )-an oxamide which would produce a degenerate spiro intermediate — was subjected to rearrangement conditions, the product obtained was 1,3-dimethyl-2,4-(1H,3H)quinazolinedione ( 29 ). This latter transformation may have proceeded via a benzodiazepinetrione intermediate.     

Synthesis of 3-arylsulfonylmethyl-1,2,4-oxadiazole-5-carboxylic acid derivatives

Several new 3-arylsulfonylmethyl-1,2,4-oxadiazole-5-carboxylic acid derivatives have been synthesized. A typical example, 3-[(4-chlorophenylsulfonyl)methyl]-1,2,4-oxadiazole-5-carboxylic acid ethyl ester ( 2c ), was prepared from the reaction of 2-(4-chlorophenylsulfonyl)acetamide oxime ( 1c ) with ethyl oxalyl chloride. The hydrazide derivative ( 3f ) showed antihypertensive activity in rats. Various structural modifications to improve activity are discussed.     

The synthesis of μ-(η5-η5-4,5-dihydro-as-indecenyl)bis(η5-cyclopentadienyliron)

μ-(η⁵,η⁵-4,5-Dihydro-as-indecenyl)bis(η⁵-cyclopentadienyliron) (I) was synthesized from 2-[(dimethylamino)methyl]biferrocene via 2-[(dimethylamino)methyl]biferrocene methiodide. The latter was converted to 2-(cyanomethyl)biferrocene, which was subjected to base hydrolysis to give (2-biferrocenyl)acetic acid. The acid was cyclized with trifluoroacetic anhydride to [4-μ-(η⁵,η⁵-as-indecenyl)bis(η⁵-cyclopentadienyliron)]trifluoroacetate ester. Hydrolysis of the latter followed by reduction gave compound I.     

Syntheses of (5E)-PGE2 and New 6-Functionalized Derivatives by the Use of Palladium-Catalyzed Decarboxylative Allylic Alkylation

(5 )-Prostaglandin E₂ (7) was synthesized fron ( )-4- -butyldimethylsilyloxy-2-cyclopentenone (1) by 2-alkenyloxycarbonylatlon of the organocopper conjugate-addition adduct (3) followed by intramolecular palladium-catalyzed decarboxylative allylic alkylation. The (5 )-prostaglandin E₂ skeleton was also obtained from the β-keto allylic ester (11) by a similar decarboxylative allylic alkylation. The decarboxylative allylic alkylation of another type of the three-component coupling product (12) gave new 6-methyleneprostaglandin E1 skeleton (15a), which was converted into new 6-methylprosta-glandin I methyl ester (20) 6-methyleneprostaglandin F₁ derivative (16) by two different ways. The stereochemistry of this intramolecular decarboxylative allylic alkylation was discussed in the reaction of 2-[( )- or ( )-2-butenyloxy-carbonyl] cyclopentanone systems.     

Asymmetric Synthesis of (S)-5,5,5,5′,5′,5′,5′-Hexafluoroleucine

(S)-5,5,5,5′,5′,5′-Hexafluoroleucine ((S)- 13 ) of 81 % ee is prepared from hexafluoroacetone ( l ) and ethyl bromopyruvate (= ethyl 2-oxopropanoate) in 7 steps with an overall yield of 18% (Schemes 1 and 2). Key step in this sequence is the highly enantioselective reduction of the carbonyl group in α-keto ester 4 either by bakers' yeast (91 % ee) or by ‘catecholborane’ 6 utilizing an oxazaborolidine catalyst, yielding hydroxy ester (R)- 5 with 99% ee. The absolute configuration was determined by X-ray analysis of the HCl adduct (S,R)- 9b of (2S)-N-[(R)- l-phenylethyl]-5,5,5,5′,5′,5′-hexafluoroleucine ethyl ester.     

Additional minor diterpene glycosides from Stevia rebaudiana

From the commercial extract of the leaves of Stevia rebaudiana, two additional new diterpenoid glycosides were isolated and their structures were characterized as 13-[(2-O-beta-glucopyranosyl-3-O-beta-D-xylopyranosyl-beta-D-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid beta-D-glucopyranosyl ester (1) and 13-[(2-O-beta-D-xylopyranosyl-beta-D-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid beta-D-glucopyranosyl ester (2) on the basis of extensive spectral data (NMR and MS) and chemical studies.     

Seven membered ring chelates derived from γ-hydroxyamides and triphenyltin or diphenylboron

N-Benzyl-4-hydroxy-butyramide (1), 4-hydroxy-N-[(R)-1-phenyl-ethyl]-butyramide (2), and (R)-4-hydroxy-2-methyl-N-[(R)-1-phenyl-ethyl]-butyramide (3a) were used to prepare new diphenylboron and triphenyltinoxy compounds: diphenylborinic acid 3-benzylcarbamoyl-propyl ester (4), diphenylborinic acid 3-[(R)-1-phenyl-ethylcarbamoyl]-propyl ester (5) and diphenylborinic acid (R)-3-[(R)-1-phenyl-ethylcarbamoyl]-butyl ester (6), N-benzyl-4-triphenyltinoxy-butyramide (7), 4-triphenyltinoxy-N-[(R)-1-phenyl-ethyl]-butyramide (8), and (R)-4-triphenyltinoxy-2-methyl-N-[(R)-1-phenyl-ethyl]-butyramide (9). The X-ray diffraction analysis of a crystalline structure of the new γ-hydroxyamide 3a is reported, as well as that of the first example of a crystalline structure where a diphenylborinic ester forms a seven membered chelate, by a carbonyl coordination to boron (4). Structural studies of tin and boron esters were performed by NMR. The CO internal coordination to tin atoms, affording seven membered rings, was observed by ¹¹⁹Sn NMR experiments at low temperature.