RESUMEN
The desymmetrization of meso-hydrobenzoin is described using chiral phosphine catalysts 8b-d and 9-11. The best enantioselectivity at room temperature was obtained with the newly synthesized phospholane 8c and benzoic anhydride, but the reaction is very slow. Much faster reactions, but somewhat lower enantioselectivities were observed using the bicyclic phosphine catalyst 9. To obtain product 5a with >90% ee required conditions where the ee is upgraded due to the formation of the dibenzoate 6a. Among the new phospholane catalysts, 8b has the best selectivity in the kinetic resolution of benzylic alcohols, but not at the level observed previously with catalyst 11.
RESUMEN
The synthesis and evaluation of chiral phosphines 11, 15a, 19a, 24a, and 28a as nucleophilic catalysts for anhydride activation and kinetic resolution of alcohols is described. The relative reactivity follows the order 11a > 11b > 15a > 1 in the monocyclic series, and 24a > 19a > 28ain the bicyclic series, with an overall rate advantage of ca. 2 orders of magnitude for the bicyclic phospholanes over the monocyclic analogues. The increased reactivity of the bicyclic phospholanes for the acylation of alcohols is attributed to conformational effects and ground-state destabilization in a highly associative mechanism. Kinetic resolution data demonstrate promising enantioselectivities for 24a.
RESUMEN
A total synthesis of (-)-hemiasterlin has been accomplished in nine steps from 25(8) (>35% yield overall). An improved enantiocontrolled route to the tetramethyltryptophan subunit 32 was developed using an asymmetric Strecker synthesis (five steps, 50% yield from 25), and the dipeptide 22 was prepared in seven steps, 37% yield from valinol. The synthesis exploits the high reactivity of a Bts-protected amino acid chloride in the difficult peptide coupling of sterically hindered amino acid residues 18 and 20 to form 21 (70%, recrystallized) and also uses N-Bts intermediates for the high-yielding N-methylations of 14 and 31. In addition, the Bts-protected di-tert-butyl N-acylimidodicarbonate 33 is shown to undergo efficient coupling with 22 to form 34 (97% in the coupling step; 79% over the activation; coupling sequence from 32).
Asunto(s)
Antineoplásicos/síntesis química , Oligopéptidos/síntesis química , Animales , Cristalización , Poríferos/química , EstereoisomerismoRESUMEN
[reaction: see text] Suzuki coupling of 18 and 30 affords 9 as an interconverting mixture of two atropisomers. Treatment with LDA at -23 degrees C affords the macrocyclic ketone 8 in 57% yield.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Toxinas Marinas/síntesis química , Oxazoles/síntesis química , Antineoplásicos/química , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Toxinas Marinas/química , Oxazoles/químicaRESUMEN
[reaction: see text] The kinetic resolution of racemic allylic alcohols 3, 6, and 12--17 has been explored using the PBO catalyst 7 for activation of isobutyric anhydride. Trisubstituted allylic alcohols (12--15; 17) are the best substrates and react with an enantioselectivity of s = 32--82 at -40 degrees C.
RESUMEN
Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO(2)CH(2)CH(2)OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe(3)(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.
Asunto(s)
Aziridinas/síntesis química , Oxazoles/química , Aziridinas/química , Espectroscopía de Resonancia Magnética , Espectrofotometría InfrarrojaRESUMEN
Triene 5 has been prepared by the E-selective olefination of aldehyde 12 with the ylide 11. Several alternative syntheses of 12 were evaluated, and the successful route involved conversion of 22 into the vinyl ether 23 by Petasis olefination, followed by Claisen rearrangement. Diels-Alder cycloaddition of 5 with 4 gave the adduct 6 in 77% yield, and Reformatsky cyclization under dilution conditions afforded 10 (67%). After conversion to enol silane 32, oxidation with dimethyldioxirane produced 34. Conversion to a key intermediate 38 using electrophilic selenenylation and selenoxide rearrangement, followed by enolate alkylation and deprotection, gave 43. The X-ray crystal structure of 43 was determined to prove the stereochemistry.
Asunto(s)
Citocalasina D/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Cristalografía por Rayos X , Ciclización , Citocalasina D/química , Espectroscopía de Resonancia Magnética , Inhibidores de la Síntesis del Ácido Nucleico/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
N-Benzothiazole-2-sulfonyl (Bts)-protected amino acid chlorides were used to prepare the hindered cyclosporin 8-11 tetrapeptide subunit 1. The synthesis was performed via 3a and the deprotected amines 5a, 13, and 19, including three repeated cycles involving N-methylation using iodomethane/potassium carbonate, deprotection of the Bts group, and N-acylation with a N-Bts-amino acid chloride such as 9b or 9c. Among three Bts cleavage methods compared (H3PO2/THF; NaBH4/EtOH; PhSH/K2CO3), the third gave somewhat higher overall yields. N-Acylation of 5a with the Bts-protected N-methylamino acid chloride 10b followed by deprotection was also highly efficient and could be used as an alternative route to 11. Each of the deprotected amines was isolated without chromatography using simple extraction methods to remove neutral byproducts. The tetrapeptide 1 was obtained in analytically pure form as the monohydrate.
Asunto(s)
Aminoácidos/química , Oligopéptidos/síntesis química , Sulfonas/química , Tiazoles/química , Acilación , Benzotiazoles , Cloruros , Ciclosporina/química , MetilaciónRESUMEN
An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio) undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process can also be carried out at room temperature by using iodine to catalyze the interconversion of 5 and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with retention of phosphorus configuration.
RESUMEN
[formula: see text] Cyclization of 8 with PPA followed by MCPBA oxidation affords the benzofuranone 10. Treatment with a chiral chloroformate in the presence of DMAP affords the target benzofuranone 13 via an enol ester 12.
Asunto(s)
Benzofuranos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Oxazoles/química , Tirosina/química , Animales , Benzofuranos/química , Cromatografía Líquida de Alta Presión , Cricetinae , Cristalografía por Rayos X , Estructura MolecularRESUMEN
[formula: see text] The synthesis of a 3-oxazol-5-yl-indole-4-triflate is described, featuring a Schölkopf reaction to prepare the oxazole. In addition, the participation of this intermediate in biaryl coupling reactions toward the total synthesis of the natural product diazonamide A is presented.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Mesilatos/síntesis química , Oxazoles/síntesis química , TermodinámicaRESUMEN
A striking red color appears upon heating the colorless title compound 1 due to rearrangement to the oxaphosphorane 3. The initiating event in this transformation may involve intramolecular O-to-P acyl transfer to give 2, followed by P-to-C acyl transfer, or an unprecedented concerted addition of acetyl and phosphanyl groups to the triple bond.
RESUMEN
The title reactions of beta,gamma-unsaturated N,N-diisopropylamides occur with useful diastereofacial selectivity. The major diol isomer from osmylation of alkenes 1, 10, 11, and 12 in the presence of TMEDA at -78 degrees C corresponds to the facial preference shown in transition state model 41 (R(Z) = H), while the opposite preference for 42 is observed with the Z-alkene 13. (Table 1). Hydroboration with 9-BBN does not show this inversion of diastereofacial selectivity for the Z-alkene. All of the results in Table 2 correspond to the usual preference for a transition state such as 45. Acid-catalyzed lactonization of the alcohols obtained in Tables 1 and 2 can be carried out with overall retention of configuration to afford delta-lactones. Butenolide 5 was prepared with 90% ee from alcohol 2a via osmylation followed by acid-catalyzed lactonization to 3 and elimination using SOCl(2)/pyridine.
RESUMEN
Transfer hydrogenation using the Noyori catalyst 5-Ts is effective for the enantioselective hydrogenation of imines containing fully substituted nitrogen groups (12 or 13). Analogues such as 11c could not be reduced in practical yield, apparently due to product inhibition of the catalyst. Asymmetric transfer hydrogenation of the aniline imine 8a was possible, but required impractical purity levels for the substrate, and the nitro analogue 7 could not be reduced efficiently. The best results were obtained with the bromophenyl imine 20. In the case of 20b, the product 21b was formed with 98.7% ee, and the material could be upgraded to >99% ee by crystallization of the hydrochloride salt. Reaction of 21b with NH(3) or MeNH(2) in the presence of Cu/CuCl gave the chiral anilines 10b or 23b. The latter substance is comparable to the commercially available 1 as a chiral proton donor for amide enolates and provides access to the hitherto unavailable enantiomeric series.
RESUMEN
The monoterpene d-limonene inhibits the post-translational isoprenylation of p21ras and other small G proteins, a mechanism that may contribute to its efficacy in the chemoprevention and therapy of chemically induced rodent cancers. In the present study, the relative abilities of 26 limonene-like monoterpenes to inhibit protein isoprenylation and cell proliferation were determined. Many monoterpenes were found to be more potent than limonene as inhibitors of small G protein isoprenylation and cell proliferation. The relative potency of limonene-derived monoterpenes was found to be: monohydroxyl = ester = aldehyde > thiol > acid = diol = epoxide > triol = unsubstituted. All monoterpenes that inhibited protein isoprenylation did so in a selective manner, such that 21-26 kDa proteins were preferentially affected. Perillyl alcohol, one of the most potent terpenes, reduced 21-26 kDa protein isoprenylation to 50% of the control level at a concentration of 1 mM, but had no effect on the isoprenylation of 67, 47 or 17 kDa proteins. In particular, p21ras farnesylation was inhibited 40% by 1 mM perillyl alcohol. At the same concentration, perillyl alcohol completely inhibited the proliferation of human HT-29 colon carcinoma cells. The structure-activity relationships observed among the monoterpene isoprenylation inhibitors support a role for small G proteins in cell proliferation, and suggest that many limonene-derived monoterpenes warrant further investigation as antitumor agents.
Asunto(s)
Antineoplásicos/farmacología , Prenilación de Proteína/efectos de los fármacos , Terpenos/farmacología , Células 3T3 , Animales , División Celular/efectos de los fármacos , Línea Celular Transformada , Ciclohexenos , Humanos , Limoneno , Ratones , Relación Estructura-ActividadRESUMEN
The monoterpene d-limonene has been shown to an effective, non-toxic chemopreventive agent in mammary and other rodent tumor models. The studies reported here investigated structure-activity relationships among limonene and three hydroxylated derivatives in the prevention of dimethylbenz[a]anthracene (DMBA)-induced mammary cancer. Rats were fed control or 1% limonene, carveol, uroterpenol or sobrerol diets from 2 weeks before to one week after carcinogen administration. Carveol, uroterpenol and sobrerol significantly prolonged tumor latency and decreased tumor yield. Sobrerol was the most potent of the monoterpenes tested, decreasing tumor yield to half that of the control, a level previously achieved with 5% limonene diets. Excretion of radioactivity from [3H]DMBA was doubled in rats fed 5% limonene and nearly tripled in rats fed 1% sobrerol. Sobrerol is thus 5-fold more potent than limonene in both enhancing carcinogen excretion and in preventing tumor formation. These data demonstrate that hydroxylation of monoterpenes affects chemopreventive potential, with 2 hydroxyl groups greater than 1 greater than 0. Sobrerol, carveol and uroterpenol are novel cancer chemopreventive agents with little or no toxicity.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Mamarias Experimentales/prevención & control , Monoterpenos , Terpenos/uso terapéutico , 9,10-Dimetil-1,2-benzantraceno , Animales , Monoterpenos Ciclohexánicos , Ciclohexenos , Femenino , Hidroxilación , Limoneno , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Ratas , Ratas Endogámicas WF , Relación Estructura-ActividadRESUMEN
Limonene has been shown to be an effective, nontoxic chemopreventive and chemotherapeutic agent in chemically induced rat mammary-cancer models. The present study characterized circulating metabolites of limonene in female rats and determined their effects on cell growth. Metabolism of limonene was analyzed in plasma extracts by gas chromatography. Rapid conversion of limonene to two major metabolites was detected. These metabolites comprised more than 80% of the circulating limonene-derived material at 1 h after administration and thereafter, whereas limonene itself accounted for only 15%. The metabolites were characterized by mass spectroscopy and infrared spectroscopy. The probable structures were synthesized, and identities were confirmed by comparison of retention times and mass spectra. The two major circulating metabolites of limonene were found to be perillic acid and dihydroperillic acid. We have previously reported that limonene, perillic acid, and dihydroperillic acid inhibit the posttranslational isoprenylation of p21ras and other 21- to 26-kDa cell-growth-associated proteins in NIH3T3 cells and in mammary epithelial cells. In the present study, perillic acid was found to inhibit cell growth in a dose-dependent manner. Thus, perillic acid and dihydroperillic acid, the two major circulating metabolites of limonene in the rat, are more potent inhibitors of protein isoprenylation than is limonene, and perillic acid is also a more potent inhibitor of cell growth. These data raise the possibility that the antitumor effects of limonene in vivo may be mediated via perillic acid and, perhaps, other metabolites.