1,3,5-Tri- and 1,3,4,5-tetra-substituted 1,4-diazepin-2-one solid-phase synthesis

Solid-phase syntheses of 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones 15-18 have been accomplished by employing inexpensive commercially available alpha- and beta-amino acids on Wang resin. Reductive amination of the imine formed by condensation of Wang aldehyde resin respectively with beta-alaninate 2 and beta-homophenylalaninate 3, followed by aminoacylation with a set of alpha-N-Boc amino acids (Phe epsilon-( Z)-Lys, and Leu) gave tertiary amide resins 7 and 8. Exposure of resins 7 and 8 to an excess of vinyl magnesium bromide in the presence of copper cyanide gave the corresponding gamma,delta-unsaturated ketone resins 9 and 10 by way of a cascade addition. Diazepinones were made by Boc deprotection and intramolecular reductive amination. To diversify the heterocycle, N-alkylation was performed using a series of alkyl halides. Alternatively, diazepinones 15e-g were obtained from treatment of methyl beta-alaninate resins 4 and 20 under similar copper-catalyzed cascade conditions to afford the gamma,delta-unsaturated ketone 21, which was acylated using alpha-N-Fmoc-amino acids (Phe, Trp, gamma-(t-Bu)-Glu). Formation of diazepinones 15 followed a similar protocol, after Fmoc removal with piperidine. Cleavage of the heterocycles with TFA/TES 95:5 gave the N1-p-hydroxybenzyl diazepinones 15-18 in overall isolated yields from 6 to 24% after purification in purities ranging from 81 to 100% according to LCMS analysis.     

Enantiospecific synthesis of the phospholipase A2 inhibitors (-)-cinatrin C1 and (+)-cinatrin C3

The enantiospecific synthesis of (-)cinatrin C1 (3) and (+)-cinatrin C3 (5) from the D-arabinose derivative 9 is described. The stereochemistry at C2 was introduced via a chelation-controlled addition of a carbanion to alpha-hydroxy ketone 8. The best selectivity was achieved by use of the Grignard reagent derived from trimethylsilylacetylene. Transformation of the terminal alkyne into methyl ester 17 followed by acetal hydrolysis and selective lactol oxidation gave cinatrin C1 dimethyl ester (7). Base hydrolysis and acid induced relactonization then gave a 1:1 mixture of cinatrins C1 (3) and C3 (5).     

Cyclization of aryllithiums tethered to methylenecycloalkanes: stereoselective synthesis of 4a-substituted cis-hexahydrofluorenes

The cyclization of an aryllithium tethered to a methylenecycloalkane, generated from 2-(o-bromobenzyl)-1-methylenecycloalkanes 1, 2, and 3 by low-temperature lithium-bromine exchange, has been found to be a kinetically slow but thermodynamically favorable process that proceeds at a convenient rate in an exclusively 5-exo fashion when solutions of the aryllithium in n-heptane-di-n-butyl ether (9:1 v/v) are warmed to 45 degrees C. The cyclization affords stereoisomerically pure cis-fused products (7 and 8) when the methylenecycloalkane is five- or six-membered but it is less stereoselective when the methylenecycloalkane is seven-membered. The ring-closure of the aryllithium derived from 2-(o-bromobenzyl)-1-methylenecyclohexane (2) provides an experimentally convenient route to stereoisomerically pure 4a-substituted cis-hexahydrofluorenes in 60-90% isolated yield.     

A formal total synthesis of (-)-cephalotaxine.

A formal total synthesis of (-)-cephalotaxine (1) has been achieved. The key step is an intramolecular aldol condensation of the diketone 9, which in turn was obtained in three steps from the azabicyclic compound 6 derived from D-proline according to Seebach's procedure. Treatment of 9 with a catalytic amount of sodium 2-methyl-2-butanolate in benzene at room temperature gave the alpha, beta-unsaturated ketone 8 in 43% yield. Catalytic hydrogenation of 8 followed by reduction of the ketone 22 with sodium borohydride and acetylation of the resulting alcohol 23 gave the acetoxy derivative 24, which, after deprotection, was acylated with (methylthio)acetic acid to give the amide 26. Compound 26 was converted into optically active ketolactam 4 following the synthetic operations developed for the synthesis of the racemic compound.     

Novel method for synthesis of aryl hydrazones from α-diazo esters: scope and limitations of nucleophiles

Aryl hydrazones, the precursor of Fischer indole synthesis, were easily obtained by nucleophilic addition of aryllithium reagents to diazo esters. The aryl hydrazones were converted into indoles in good yields by heating with thionyl chloride in alcohol. Grignard reagent was also a good nucleophile, whereas organozinc reagent did not react with diazo esters. Aryllithium reagents were prepared by reacting aryl bromides having various substitutions at 2-, 3-, 4-, or multi positions with n-BuLi. The addition of nucleophiles derived from bromopyridines to diazo esters also gave hydrazones.     

Enantiospecific synthesis of the phospholipase A2 inhibitor (-)-cinatrin B

The first enantiospecific synthesis of phospholipase A2 (PLA2) inhibitor (-)-cinatrin B (2) from the D-arabinose derivative 9 is described. The spirolactone system was formed by an Ireland-Claisen rearrangement of the allyl ester 8 followed by hydrolysis and stereoselective iodolactonization. The stereoselectivity of the rearrangement was controlled by the asymmetry in the allylic alcohol fragment. Ester (S)-8 gave the desired rearrangement product 7 and the epimer 13 in high yield as a 73:27 ratio, respectively. The final stereocenter at C2 was introduced via a chelation-controlled addition of the Grignard reagent derived from trimethylsilylacetylene to alpha-hydroxy ketone 6. Transformation of the terminal alkyne into the methyl ester 21 followed by acetal hydrolysis and selective lactol oxidation afforded cinatrin B methyl ester (22). Base hydrolysis and acid-induced relactonization then gave (-)-cinatrin B (2).     

1,4-Addition of an aryllithium reagent to diethyl ketomalonate. Scalable synthesis of ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate

While optimizing the synthesis of pharmaceutical building block 3 [ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate], we encountered an unusual addition of an aryllithium reagent to the ketone oxygen atom of diethyl ketomalonate. Compound 3 was ultimately prepared on a large scale by a two-step sequence involving (1) annulation of a functionalized Grignard reagent with diethyl ketomalonate and (2) selective mono-reduction of a geminal diester using lithium tri-tert-butoxyaluminum hydride.     

Squaric acid ester-based total synthesis of echinochrome A

The total synthesis of echinochrome A is described. Both key intermediates 5 and 8 were efficiently prepared from diisopropyl squarate 7. Nucleophilic addition of aryllithium 8 to 5, followed by thermal ring-expansion/cyclization of the 1,2-adduct 4, furnished hydroquinone 3. Oxidation and full deprotection of 3 gave the title compound.     

Synthesis of optically active (+)-19-nortestosterone by asymmetric bis-annulation reaction

Michael reaction of 1,7-pctadien-3-one with 2-methylcyclopentane-1,3-dione, followed by intramolecular aldol condensation promoted by L-amino acids produced the optically active (+)-4-(3-butenyl)-7a-methyl-5,6,7,7a-tetrahydroindane-1,5-dione in high chemical and optical yields. The PdCl₂-catalyzed oxidation of the terminal double bond gave the methyl ketone, which had 76% optical purity and was made 100% optically pure by recrystallization. Then aldol condensation afforded the tricyclic ketone, which was alkylated with 3-butenyl iodide to afford (?)-3β-t-butoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-(3-butenyl)-3aβ-methyl-1H-benz[e]inden-7-one. The synthesis of this compound means the total synthesis of (+)-19-nortestosterone.     

14C-labeling of bromobutide, 2-bromo-3,3-dimethyl-N-(alpha, alpha-dimethylbenzyl)butyramide

Bromobutide, a novel herbicide, was labeled with carbon-14 independently at the carbonyl group and the phenyl ring for use in metabolic studies. 14C-Carbonation of neopentylmagnesium chloride (3) gave 3,3-dimethyl[1-14C]butyric acid (4a) quantitatively. Chlorination of 4a with thionyl chloride followed by alpha-bromination with bromine yielded 2-bromo-3,3-dimethyl[1-14C]-butyryl halide (5a), which was subsequently condensed with alpha, alpha-dimethylbenzylamine (6a) to afford [carbonyl-14C]bromobutide (1a). The overall yield of 1a was 76% from barium [14C]-carbonate (2). Similarly, condensation of alpha, alpha-dimethyl[phenyl-14C]benzylamine (6b), which was prepared from alpha-methyl[phenyl-U-14C]styrene (7) in three steps, with 2-bromo-3,3-dimethylbutyryl halide (5b) gave [phenyl-14C]bromobutide (1b) in 67% yield after purification. The specific activities of 1a and 1b were 1.38 and 0.781 GBq/mmol (37.2 and 21.1 mCi/mmol), respectively.     

Synthesis of 5S-(1-Oxoalkyl and Aryl)-2-pyrrolidinone Derivatives1

N-Benzyl pyroglutamate esters react with aryllithium reagents and methyllithium to give moderate to good yields of 5-(1-oxoaryl) or 5-(1-oxoalkyl)-2-pyrrolidinone derivatives. The reaction proceeds without racemization, but is accompanied by formation of 5-(1-hydroxy-1-alkyl)-2-pyrrolidinone derivatives. This reaction gives very poor yields of ketone products with most other alkyl organolithium reagents such as n-butyllithium. Grignard reagents react to give primarily the alcohol.     

Methylenecyclohexane annulation. Total synthesis of (±)-axamide-1, (±)-axisonitrile-1, and the corresponding C-10 epimers

Conjugate addition of 2-(5-chloro-1-pentenyl)magnesium bromide (12) to 2-methyl-2-cyclopenten-1-one (6), followed by intramolecular alkylation of the resultant product, afforded (85%) the bicyclic ketone 7, which was transformed (77%) into the enone 16. Titanium tetrachloride-catalyzed conjugate addition of 3-methyl-1,1-bis(trimethylsiloxy)-1-butene to 16 gave (93%) a 3:2 mixture of the keto acids 20 and 21, which were separated. Compound 20, the stereochemistry of which was confirmed by a single-crystal X-ray analysis, was converted into (±)-axamide-1 (1) and (±)-axisonitrile-1 (2), while 21 was transformed into the corresponding C-10 epimers 8 and 9, respectively.     

Total synthesis of milbemycins: a synthesis of (6R)-6-hydroxy-3,4-dihydromilbemycin E

Following studies using benzyloxymethyl isopropenyl ketone 5 and ethyl 3-(3-furyl)-3-oxopropanoate 6, Robinson reactions between aryloxymethyl isopropenyl ketones 19 and 5 and ethyl 3-(2-trimethylsilyl-3-furyl)-3-oxopropanoate 20 were found to be stereoselective giving cyclohexanones 21 and 41, in which the 3-(arylmethoxy) substituents were cis to the 2-hydroxyl groups, as the major products. After reduction and protection of ketone 21, selective PMB-deprotection, oxidation and stereoselective reduction inverted the configuration at C3 to give the diol 30. Protection of the secondary 3-hydroxyl group followed by modification of the protected 4-alcohol then gave the hydroxybutenolides 36 and 37 after oxidation of the silylated furan using singlet oxygen. The 3-benzyloxycyclohexanone 41 was also converted into the hydroxybutenolide 37 via the (2-trimethylsilylethoxy)methyl (SEM) ether 35. The Wittig reaction between the ylid generated from 2-methylpropyl(triphenyl)phosphonium salt and hydroxybutenolide 36 gave predominantly the (2Z,4Z)-dienyl acid 38 which was taken through to the butenolide 40. Similarly, the racemic hydroxybutenolide 37 was condensed with the racemic ylid derived from phosphonium salt 53 to give, after SEM-deprotection and 5-membered lactone formation, a mixture of the (9Z,2'Z)-dienyl lactones 58 and 59 containing ca. 10% of the corresponding (9Z,2'E)-isomers 60 and 61. (2'Z)/(2'E)-Isomerisation of the dienes 58 and 59 using iodine followed by deprotection gave a mixture of the seco-acids 62 and 63. Selective macrocyclisation of the seco-acid 62 in which the relative configuration of the C1-C7 and C17-C19 fragments (milbemycin numbering) corresponded to that present in the natural milbemycins, gave the beta-milbemycin analogue 65 after butenolide reduction. The hydroxybutenolide 37 was also condensed with the ylid derived from the phosphonium salt 1 and the product taken through to (6R)-6-hydroxy-3,4-dihydromilbemycin E 77. Preliminary attempts to convert the beta-milbemycin analogues 65 and 77 into tetrahydrofurans corresponding to analogues of alpha-milbemycins by treatment with toluene p-sulfonyl chloride under basic conditions gave the primary allylic chlorides 78 and 79.     

Desoxy-nitrozucker. 3. Mitteilung. Synthese von Ketosen durch Kettenverlängerung von 1-Desoxy-1-nitro-aldosen. Nucleophile Additionen und Solvolyse von Nitroaethern

Synthesis of Ketoses by Chain Elongation of 1-Deoxy-1-nitroaldoses. Nucleophilic Additions and Solvolysis of Nitro Ethers A method for the preparation of chain elongated uloses based upon the base-catalyzed addition of 1-deoxy-1-nitroaldoses to aldehydes and Michael acceptors and subsequent solvolytic replacement of the nitro group by a hydroxy group is described. Thus, addition of 1 , 3 and 9 to formaldehyde, followed by solvolysis gave the chain elongated ulose derivatives 2 , 8 and 10 (63–76%), respectively. The configuration at the anomeric center of the addition products was deduced from ¹³ C – NMR . spectra and mutarotation. In the case of 3 , the primary addition products 4 and 6 were isolated and acetylated to 5 and 7 . The nitro derivatives 4 – 7 do not follow Hudson's rule of isorotation. Addition of 1 to benzaldehyde (44%) and to nonanal (74%) preceded with a small degree of diastereoselectivity to give 15a / 15b , and 11 / 12 , respectively. The configuration of the secondary hydroxyl group of 12 was determined by correlation with methyl 2-hydroxydecanoate ( 14 ). Addition of 1 to the galacroaldehyde 16 gave a single compound 17 (78%). The structure of this dodecosulose was determined by X-ray crystallography. Solvolysis of the acetylation product 18 in formamide gave the hemiacetal 19 (69%). Michael addition of 1 to acrylonitrile, methyl vinyl ketone and cyclohexenone under solvolytic conditions gave the hemiacetals 27 , 30 and 31a , b (49%, 71% and 76%, respectively). Under non-solvolytic conditions (Bu₄NF), 1 reacted with acrylonitrile, and crotononitrile to give the anomeric nitro ethers 23 and 24 (67%) and 25 and 26 (84%). respectively. Similarly. 3 added to acrylonitrile to give 28 and 29 (55%, 4:1). This reaction appears to proceed under kinetic control. Addition of 1 to ethyl propiolate and solvolysis yielded the unsaturated spirolactone 32 (50%) and the hemiacetal 33 (17%). Hydrogenation of 32 gave the saturated spirolactone 34 (100%) which was also obtained from 1 and methyl acrylate (63%). Addition of 1 to dimethylmaleate gave the unsaturated ester 35 (48%).     

Analysis of triterpenoids in <Emphasis Type="Italic">Ganoderma lucidum</Emphasis> using liquid chromatography coupled with electrospray ionization mass spectrometry

Triterpenoids extracted from Ganoderma lucidum (Leyss. ex Fr.) Karst were separated and characterized using optimized reversed-phase liquid chromatography with diode array detection and electrospray ion trap tandem mass spectrometry (HPLC-DAD-ESI-MS(n)). They could be classified into five types depending on the fragmentation behavior. All triterpenoids gave [M - H](-) and [2M - H](-) ions by electrospray ionization monitored in the negative ion mode; in addition, compounds of types III and IV gave prominent [M - H - H(2)O](-) ions and the unsaturated bond at C-20, 22 would reduce the abundance of [M - H - H(2)O](-) ion. The key fragmentation information was cleavage at C- and D-rings despite the predominant losses of H(2)O and CO(2). Compounds with hydroxyls at C-7 and C-15 would produce a list of b, b - 1, b - 2, and b - 16 ions attributed to cleavage of D-ring; if the second alcohol at C-15 were oxidized to ketone, the prominent cleavage would occur at C-ring and produce a group of ions of a; if C-7 were oxidized to ketone, transference of two hydrogen atoms would occur during the cleavage of rings and a list of ions about a + 2 and/or b + 2 would appear instead. The above fragmentations and regularities in fragmentation pathways were reported for the first time, and were implemented for the analysis of triterpenoids in G. lucidum. The chloroform extract was separated on a Zorbax SB-C(18) column, eluting with an acetonitrile-0.2% acetic acid gradient. A total of 32 triterpenoids, including six new ones, were identified or tentatively characterized based on the tandem mass spectra of the HPLC peaks.     

Benzolactams. 4. Reaction of 3',4'- or 4',5'-dialkoxy-substituted 1-(2'-Bromobenzyl)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinolines with alkyllithium. 1,2 and 1,4 additions of alkyllithium to benzolactams

Treatment of 1-(2'-bromo-3',4'-dialkoxybenzyl)-1,2,3, 4-tetrahydroisoquinoline carbamates, 1a,c, with excess alkyllithium gave 8-oxoberbines, 2a,c, which were successively attacked in situ with another molecule of alkyllithium to give 1,2 and/or 1,4 addition products. A primary alkyllithium, such as MeLi or BuLi, gave a 1,2 addition product, 8-methyleneberbine 9a or 8-butylideneberbine 3a. t-BuLi preferred 1,4 addition, followed by elimination of the alkoxy group, to give 9-tert-butyl-8-oxoberbine 6a or 7c. s-BuLi gave a mixture of 1,2 and 1,4 addition products, 1-[2'-(2' '-methylbutyryl)benzyl]-1,2,3,4-tetrahydroisoquinoline 4a and 9-s-butyl-8-oxoberbine 5a. Similar treatments of carbamate 1b having no alkoxy group at its 3' position gave 1,2 addition products, 8-butylideneberbine 3b, 1-[2'-(2' '-methylbutyryl)benzyl]-1,2,3, 4-tetrahydroisoquinoline 4b, and 1-(2'-pivaloylbenzyl)-1,2,3, 4-tetrahydroisoquinoline 6b, in all cases. Reactions of 1a with s-BuMgCl and isoPrMgCl also gave the 1,4 adduct, 5a, and its 9-isoPr analogue, 12a. Treatment of 9a with excess NaBH(4) in AcOH gave (+/-)-coralydine (10b).     

Asymmetric synthesis of 2-(2-pyridyl)aziridines from 2-pyridineimines bearing stereogenic N-alkyl substituents and regioselective opening of the aziridine ring

The addition of chloromethyllithium to the imine derived from 2-pyridinecarboxaldehyde and (S)-valinol, protected as its O-trimethylsilyl ether, gave the 1,2-disubstituted aziridine with good yield and diastereoselectivity. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring and the alpha-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines which were not capable of bidentate chelation, e.g., 3- and 4-pyridineimine and benzaldimine. Preliminary studies showed the possibility to carry out regio- and stereospecific opening reactions of 2-(2-pyridyl)aziridines by attack of internally generated or external nucleophiles.     

Synthesis of D- and L-myo-Inositol 1,4,6-Trisphosphate, Regioisomers of a Ubiquitous Second Messenger

A regioisomer of the second messenger D-myo-inositol 1,4,5-trisphosphate [D-Ins(1,4,5)P(3), 1], DL-myo-inositol 1,4,6-trisphosphate [DL-Ins(1,4,6)P(3), 4ab], together with the chiral antipodes D-Ins(1,4,6)P(3)(4a) and L-Ins(1,4,6)P(3)(4b), was synthesized from myo-inositol. The racemic diol 6, after removal of the trans-ketal of fully protected 5 was p-methoxybenzylated to give the 6-O-alkylated derivative 9, as the major product in 52% yield. Gentle acidic hydrolysis of 9, followed by benzylation of the resulting triol, gave the fully protected compound 11ab. Isomerization of the two allyl groups followed by acidic hydrolysis of the resulting cis-prop-1-enyl moieties and the p-methoxybenzyl group gave the triol 13ab. Phosphorylation of 13ab followed by deprotection of the resulting compound, 14ab, with sodium in liquid ammonia and purification by ion exchange chromatography provided 4ab in 60% yield. The intermediate 9 was converted into the cis-diol 16ab in two steps. Selective acylation at the equatorial hydroxyl group using (S)-(+)-O-acetylmandelic acid in the presence of DCC and DMAP provided two diastereoisomers, 18 and 19, which were separated by flash chromatography. Further transformations provided the corresponding D- and L-1,4,6 triols, 13a and 13b, respectively, and phosphorylation, followed by deprotection of the fully blocked products as for the racemic 4ab, gave 4a and 4b, respectively. The absolute configuration of fully protected 11a was determined by transformation to the known compound L-1,2,4,5-tetra-O-benzyl-myo-inositol (22). Compound 4a was a full agonist at the platelet Ins(1,4,5)P(3) receptor for Ca(2+) release, but 4b was devoid of activity.     

The Diels-Alder Reaction of Dienes Derived from Substituted 3-(Phenyl-Thio)-3-Sulfolenes

Substituted 3-(phenylthio)-3-sulfolenes (3) and (4) are good precursors for 2-(phenylthio)-1,3-butadienes (5) and (6). The Diels-Alder reaction of the dienes derived from (3) and (4) with various dienophiles was studied. It was found that heating of sulfolenes (3) with methyl propiolate and N-phenylmaleimide afforded the Diels-Alder adducts of (5) directly and with complete regio- and stereospecificity. The same reaction with methyl vinyl ketone gave a mixture of endo and exo addition products. If sulfolenes (3) were first converted to the dienes (5) using lithium aluminum hydride and then reacted with methyl vinyl ketone in the presence of anhydrous zinc chloride, the stereoselectivity could be improved. Sulfolenes (4) also underwent cycloreversion/cycloaddition with methyl acrylate, methyl vinyl ketone, and N-phenylmaleimide, but gave mostly the double bond-isomerized cycloaddition products. The regiochemistry of cycloaddition was delicately dependent on the dienophiles used.     

Comparative study of anionic and radical cyclization for the preparation of 1,3-dimethylindans: highly stereoselective preparation of cis-1,3-disubstituted indans via intramolecular carbolithiation

[reaction: see text] The preparation of 1,3-dimethylindans from 4-(2-bromophenyl)-1-pentene (1) and 2-(2-iodo-1-methylethyl)styrene (2) substrates via radical-mediated cyclization and intramolecular carbolithiation has been investigated. Although cyclization of the radical derived from either substrate proceeds with modest selectivity for the cis-isomer, as does cycloisomerization of the aryllithium derived from substrate 1 (cis/trans approximately 2), intramolecular cyclization of the alkyllithium derived from substrate 2 is a highly cis-selective process (cis/trans = 12).