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Biomedical subjects

Barry M Trost

Publications and source records attributed to Barry M Trost.

At least 109 records · Page 6Linked to original sources
PubMed2002

Enantioselective synthesis of (-)-codeine and (-)-morphine.

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.

Analgesics, Opioid↗
PubMed2002

Utilization of molybdenum- and palladium-catayzed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers: a concise synthesis of tipranavir.

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the quaternary and tertiary stereogenic centers, respectively.

Catalysis↗
PubMed2002

The unusual role of CO transfer in molybdenum-catalyzed asymmetric alkylations.

Spectroscopic and crystallographic studies were undertaken to gain insight into the mechanism of the highly regio- and enantioselective allylic aklylation reaction catalyzed by molybdenum. The chiral ligand (L*) consisting of the mixed benzamide/picolinamide of (S,S,)-trans-1,2-diaminocyclohexane reacts with a typical Mo precatalyst, (norbornadiene)Mo(CO)4, to give a neutral complex L*Mo(CO)4 in which the ligand binds to the metal in a bidentate fashion through the pyridine and adjacent amide group. Reaction of this complex with the methyl carbonate of cinnamyl alcohol gives the corresponding pi-allyl complex L*(CO)2Mo(eta3-CH2=CH-CHPh). NMR and X-ray crystallographic characterization of this complex reveal the ligand binds in a facially capping tridentate fashion via the pyridine nitrogen, the nitrogen of the adjacent amide group, which has now been deprotonated, and the carbonyl oxygen of the remote amide. Surprisingly, the face of the allyl group open to attack with nucleophiles is that which would lead to the sense of stereochemistry opposite to that which is observed in catalytic reactions. Furthermore, the allyl complex in its isolated form is unreactive toward sodium dimethyl malonate. However, in the presence of a source of carbon monoxide (either Mo(CO)6 or gaseous CO), the allyl complex reacts with malonate to give the typically observed branched alkylated product in high yield and enantiomeric excess. The metal-containing product of this reaction is the molybdate complex [L*Mo(CO)4]-Na+. Reaction of the molybdate complex with linear or branched allylic carbonates regenerates the allyl complex, thus closing the catalytic cycle. Both the allyl complex and the molybdate complex are the only metal-containing species observed by NMR in typical catalytic reactions and thus appear to be catalyst resting states. Turnover of the catalytic cycle therefore involves shuttling of carbon monoxide between the two catalyst resting states. Coordination of CO appears to be necessary to activate the allyl complex toward nucleophilic attack, in effect stabilizing the molybdenum fragment as a leaving group.

Journal Article↗
PubMed2002

Ruthenium-catalyzed alkene-alkyne coupling: synthesis of the proposed structure of amphidinolide A.

The ruthenium-catalyzed alkene-alkyne coupling provides a powerful method for the synthesis of 1,4 dienes and a way to simplify synthetic strategy. The latter potential is explored in the context of a synthesis of the assigned structure of amphidinolide A, which also raises the question of the applicability of this reaction for macrocyclizations. Employing this reaction allows simplification of the target to three subunits corresponding to C-1 to C-6, C-7 to C-15, and C-16 to C-25. The C-7 to C-15 subunit involves introduction of chirality by an asymmetric dihydroxylation. The route to the C-16 to C-25 subunit introduces chirality by a Pd-catalyzed asymmetric allylic alkylation and an asymmetric epoxidation. Assembly of the three subunits employs the Ru-catalyzed addition inter- and intramolecularly. The synthesis culminated in the formation of the assigned structure and is identical to the synthetic samples prepared independently by two completely different routes. As noted by the other two groups, this structure appears to be a diastereomer of the natural product. Because this synthesis introduces all of the stereochemistry of the subunits by catalytic asymmetric processes, either enantiomer as well as diastereomers can be readily accessed to define the correct structure. Notably, the Ru-catalyzed macrocyclization to this macrolide proceeded in better yields than either a Pd-catalyzed cross-coupling or a Ru-catalyzed metathesis, macrocylization methods for the other two total synthesis.

Alkenes↗
PubMed2002

An acid-catalyzed macrolactonization protocol.

[reaction: see text] An efficient macrolactonization protocol devoid of any base was developed derived from the use of vinyl esters in transesterification. Subjecting a hydroxy acid and ethoxyacetylene to 2 mol % [RuCl(2)(p-cymene)](2) in toluene followed by addition of camphorsulfonic acid or inverse addition provided macrolactones in good yields.

Acids↗
PubMed2002

Stereocontrolled synthesis of (+)-boronolide.

Boronolide was synthesized stereoselectively from hydroxyacetylfuran 5 and valeraldehyde 6 using a novel dizinc aldol catalyst. Ring closing metathesis provides the lactone ring. The synthesis requires 12 steps and proceeds in 26% overall yield. [reaction: see text]

Lactones↗
PubMed2002

DYKAT of Baylis-Hillman adducts: concise total synthesis of furaquinocin E.

Baylis-Hillman adducts are easily accessible building blocks; the lack of asymmetric versions of the Baylis-Hillman reaction has however precluded their widespread use in asymmetric synthesis. A Pd-catalyzed DYKAT on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck reaction, allows the enantio- and diastereoselective construction of dihydrobenzofurans in a very efficient manner. These synthons represent the core structure of the furaquinocins. Introduction of different side chains and use of different squaric acid derivatives for the construction of the naphthoquinone allow the flexible synthesis of this class of natural products. This new approach is successfully applied to the synthesis of furaquinocin E and an analogue.

Anti-Bacterial Agents↗
PubMed2002

Callipeltoside a: total synthesis, assignment of the absolute and relative configuration, and evaluation of synthetic analogues.

The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established. A convergent strategy is employed wherein the target is dissected into three units-the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The stereochemistry of the latter derives from the chiral pool and two asymmetric reactions-a ketone reduction using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chain-one based upon olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction. It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20 and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance of the chloro substituent and the necessity of the sugar.

Anti-Bacterial Agents↗
PubMed2002

4-Aryloxybutenolides as "chiral aldehyde" equivalents: an efficient enantioselective synthesis of (+)-brefeldin a.

4-(2'-Naphthoxy)-2-butenolide, readily available with high enantiopurity by a dynamic kinetic asymmetric transformation (DYKAT) of racemic 4-acyloxybutenolides (available in two steps from furfural), serves as an excellent chiral building block where the naphthoxy group strongly directs the stereochemistry of cycloadditions to the double bond. Notably, the cycloadditions of trimethylenemethanepalladium intermediates which do not exhibit good diastereoselectivity in additions to acceptors that possess many common and important chiral auxiliaries undergo cycloadditions with excellent regio- and stereocontrol. The utility of this process set the stage for an efficient new synthesis of (+)-brefeldin A, a compound of growing pharmacological significance. This synthesis also highlights the Pd-catalyzed DYKAT of crotyl carbonate to create the remote stereocenter. A new two-step method to convert aldehydes to delta-hydroxy-E-alpha,beta-enoates is also outlined.

Aldehydes↗
PubMed2002

A chemoselective reduction of alkynes to (E)-alkenes.

The trans reduction of all types of alkynes to give (E)-olefins is achieved through a two-stage trans hydrosilylation and protodesilylation. Reaction of an alkyne and a silane with the ruthenium catalyst [Cp*Ru(MeCN)3]PF6 results in clean hydrosilylation to give only the (Z)-trans addition product at ambient temperature with catalyst loadings of 1-5 mol %. The crude vinylsilane products are then protodesilylated by the action of cuprous iodide and TBAF at rt-35 degrees C. The reaction is compatible with many sensitive functional groups and provides a general trans-alkyne reduction not possible by other means.

Alkenes↗
PubMed2002

Formation of vinyl halides via a ruthenium-catalyzed three-component coupling.

The ruthenium-catalyzed three-component coupling of an alkyne, an enone, and halide ion to form E- or Z-vinyl halides has been investigated. Through systematic optimization experiments, the conditions effecting the olefin selectivity were examined. In general, more polar solvents such as DMF favored the formation of the E-isomer, and less polar solvents such as acetone favored formation of the Z-isomer. The optimized conditions for the formation of E-vinyl chlorides were found to be the use of cyclopentadienyl ruthenium (II) cyclooctadiene chloride, stannic chloride pentahydrate as a cocatalyst, and for a chloride source, either ammonium chloride in DMF/water mixtures or tetramethylammonium chloride in DMF. A range of several other ruthenium (II) catalysts was also shown to be effective. A wide variety of vinyl chlorides could be formed under these conditions. Substrates with tethered alcohols or ketones either five or six carbons from the alkyne portion gave instead diketone or cyclohexenone products. For formation of vinyl bromides, a catalyst system involving the use of cyclopentadienylruthenium (II) tris(acetonitrile) hexafluorophosphate with stannic bromide as a cocatalyst was found to be most effective. The use of ammonium bromide in DMF/acetone mixtures was optimal for the synthesis of E-vinyl bromides, and the use of lithium bromide in acetone was optimal for formation of the corresponding Z-isomer. Under either set of conditions, a wide range of vinyl bromides could be formed. When alkynes with propargylic substituents are used, enhanced selectivity for formation of the Z-isomer is observed. When aryl acetylenes are used as the coupling partners, complete selectivity for the Z-isomer is obtained. A mechanism involving a cis or trans halometalation is invoked to explain formation of the observed products. The vinyl halides have been shown to be precursors to alpha-hydroxy ketones and cyclopentenones, and as coupling partners in Suzuki-type reactions.

Catalysis↗
PubMed2002

Synthesis of novel quaternary amino acids using molybdenum-catalyzed asymmetric allylic alkylation.

The Mo-catalyzed asymmetric allylic alkylation using azlactones provides extraordinary levels of selectivity. Thus, a wide range of cinnamyl-type substrates react with 2-methyl and 2-benzyl azlactones to give only the product resulting from attack at the more substituted carbon. Using other alkyl substituents such as 2-methylthioethyl, isobutyl, allyl, and isopropyl provides products that still retain excellent regioselectivity but small quantities of the linear product are also observed. In all cases, excellent diastereo- and enantioselectivity of the branched alkylated product are observed. This new asymmetric reaction provides ready access to unusual quarternary amino acids, important building blocks for biological applications. The reactions complements the Pd AAA wherein the cinnamyl substrate leads to only the product of attack at the primary terminus of the allyl moiety.

Alkylation↗
PubMed2002

Chemo-, regio-, and enantioselective Pd-catalyzed allylic alkylation of indolocarbazole pro-aglycons.

[reaction: see text] Monosubstituted isomerically pure indolopyrrolocarbazole precursors have been prepared via palladium-catalyzed asymmetric allylic alkylation methodology, employing both achiral cyclopentenyl electrophiles and chiral glycal derivatives. Chemoselective allylation of (bis)indole lactam pro-aglycon 3 allows access to N-distally substituted indolopyrrolocarbazole derivatives; glyoxamide precursor 14 provides entry into N-proximally substituted derivatives.

Alkylation↗