RESUMO
We report full details of a method for 1,3-reductive transposition of α-alkoxy-α,ß-unsaturated hydrazones to provide E-alkenes with high 1,4-stereocontrol between the two respective allylic stereocenters. The process couples a chelation-controlled reduction of the hydrazone with an in situ allylic strain controlled retro-ene reaction of an allyl diazene, i.e., an allylic diazene rearrangement. Such stereotriads are frequently observed motifs in natural products. We observed a fortuitous kinetic preference for the E-hydrazone geometry during the hydrazonation reaction, as only the E-isomers could undergo chelation-controlled reduction.
Assuntos
Compostos Alílicos/química , Hidrazonas/síntese química , Imidas/química , Compostos de Tosil/síntese química , Hidrazonas/química , Cinética , Estrutura Molecular , Estereoisomerismo , Compostos de Tosil/químicaRESUMO
Breslow intermediates that bear radical-stabilizing Nâ substituents, such as benzyl, cinnamyl, and diarylmethyl, undergo facile homolytic C-N bond scission under mild conditions to give products of formal [1,3]â rearrangement rather than benzoin condensation. EPR experiments and computational analysis support a radical-based mechanism. Implications for thiamine-based enzymes are discussed.
Assuntos
Álcoois/síntese química , Tiamina/síntese química , Álcoois/química , Carboxiliases/química , Carboxiliases/metabolismo , Radicais Livres/síntese química , Radicais Livres/química , Estrutura Molecular , Teoria Quântica , Tiamina/químicaRESUMO
A novel Claisen rearrangement in which the Breslow intermediate is engaged as a hydroxy-substituted N,S-ketene acetal to provide complex 3° alcohols without the use of organometallic reagents is reported. The reaction constitutes an unprecedented reactivity mode for the Breslow intermediate.
Assuntos
Álcoois/síntese química , Benzotiazóis/síntese química , Álcoois/química , Benzotiazóis/química , Etilenos/química , Indicadores e Reagentes , Cetonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Over the course of developing a multigram scale preparation of epoxy quinol 1 via asymmetric transfer hydrogenation (ATH) using the Noyori Ru(arene)(S,S-TsDPEN) catalysts, we observed several unexpected phenomena, including (i) chemoselective alkene vs ketone reduction of an enedione, (ii) a significant arene ligand effect (p-cymene vs. mesitylene) on the reaction pathway, and (iii) solvent-based reversal of the sense of enantioinduction.
RESUMO
The C21-C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 ß-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product.
RESUMO
Epoxy quinol 1a was prepared on a multi-gram scale by Noyori transfer hydrogenative desymmetrization of the readily available meso epoxy diketone 4. Although the intrinsic enantioselectivity for the desymmetrization was modest (82:18 er at 4% conversion), a highly enantiopure product (99.6:0.4 er) could be obtained in one operation in 44% yield via kinetic resolution of the minor enantiomer with long reaction times (48 h), or in 73% yield by combination with an enzymatic resolution of a 93:7 er mixture.
RESUMO
The fully substituted hydroisobenzofuran core of the massileunicellins containing 8 contiguous stereocenters was prepared in 12 steps from (S)-(+)-carvone. Noteworthy elements of the synthesis include a one-step oxidative rearrangement/epoxidation, a novel stereoselective directed reduction of a keto diol, and a directed hydrogenation of a congested tetrasubstituted alkene.
RESUMO
Three structurally related sets of hydroisobenzofuran analogs of sclerophytin A were prepared in three or four steps from (S)-(+)-carvone via an aldol-cycloaldol sequence. The most potent members of each set of analogs exhibited IC(50)'s of 1-3 microM in growth inhibitory assays against KB3 cells. The NCI 60-cell line 5-dose assay for analog 6h revealed a GI(50)=0.148 microM and LC(50)=9.36 microM for the RPMI-8226 leukemia cell line, and a GI(50)=0.552 microM and LC(50)=26.8 microM for the HOP-92 non-small cell lung cancer cell line.
Assuntos
Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Furanos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Furanos/síntese química , Furanos/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
The C22-C34 fragment of antascomicin B lacking the C31 and C32 hydroxyl groups has been prepared in 11 steps from commercially available 2-OH-cyclohexanone. An Ireland-Claisen rearrangement was employed to install the C26 and C27 stereocenters. Our recently reported diastereoselective acyclic 1,3-reductive transposition was used to establish the remote C23 stereocenter. Directed hydrogenation was employed to set the C29 stereocenter. The model compound contains 5 of the stereocenters and all of the carbons of the corresponding fragment of antascomicin B.
RESUMO
One-pot reduction/allylic diazene rearrangement of lactic acid- and mandelic acid-derived alpha,beta-unsaturated tosyl hydrazones leads to 1,4-syn- or 1,4-anti-E-2-alkenyl arrays in high yield and diastereoselectivity. Either the syn or the anti diastereomer can be prepared by choosing the appropriate alkene stereoisomer of the hydrazone. The E-alkenes led to the 1,4-syn isomers, while the Z-alkenes led to the 1,4-anti isomers, both with > or =20:1 diastereoselectivity.
Assuntos
Alcenos/química , Alcenos/síntese química , Imidas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland-Claisen rearrangement to install the C7 tertiary alcohol stereocenter, an SN2' reaction of an alkoxymethyl Cu reagent, and a diastereoselective Re-catalyzed allylic alcohol transposition.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Diterpenos/síntese química , Furanos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Catálise , Cobre/química , Ciclização , Diterpenos/química , Furanos/química , Estrutura MolecularRESUMO
The Ireland and ester enolate Claisen rearrangements of tertiary substituted bis-allylic esters derived from cyclohexenones afford pentenoic acids that possess tri- and tetrasubstituted alkylidenes with unprecedented levels of stereoselectivity. In some cases the higher energy exocyclic alkene is the major product. [reaction: see text]
Assuntos
Alcenos/química , Modelos Químicos , Alcenos/síntese química , Ciclização , Ésteres , Estrutura Molecular , EstereoisomerismoRESUMO
A convenient 3-step synthesis of (R)-7-hydroxycarvone (2) has been developed starting from (S)-alpha-pinene (7), using photooxygenation, oxidation, and fragmentation reactions. An improved synthesis of epoxy alcohol 6 and an unusual Ti(OiPr)(4) catalyzed hydroxy epoxide to keto alcohol rearrangement are also described.
Assuntos
Monoterpenos/química , Monoterpenos/síntese química , Monoterpenos Bicíclicos , Catálise , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
Investigating reactions of functionalized p-quinone methides continues to advance our design of a reagent being developed for controlled, in situ modification of DNA via phosphodiester alkylation. Previously reported investigations of p-quinone methides derived from catechols allowed for trapping of isolable trialkyl phosphates for characterization and mechanistic information. However, lactone formation with these derivatives required long reaction times, resulting in an unfavorable mixture of trialkyl phosphate and hydrolysis products. To enhance the rate and efficacy of trialkyl phosphate formation and trapping, a phenol derived p-quinone methide has been designed to enforce a conformation favoring lactonization of the dialkyl phosphate alkylated intermediate. The relative rates of phosphodiester alkylation and subsequent trapping of the phosphotriester adduct have been examined by UV and (1)H NMR analysis for p-quinone methide precursor 1 and the corresponding control, 1'. The incorporation of a methyl group at the meta-position of 1 (relative to 1') significantly improves the rate of lactionization to provide a much higher yield of the desired product, lactonized phosphotriester 5. The control reaction with 1' afforded only a minor amount of the corresponding lactonized trialkyl phosphate 5'.
Assuntos
Lactonas/química , Compostos Organofosforados/síntese química , Quinonas/química , Alquilação , DNA , Espectroscopia de Ressonância Magnética , Organofosfatos , Compostos Organofosforados/química , OxirreduçãoRESUMO
A novel Ireland-Claisen approach to the putative structure of eupomatilone-6 is described. The rearrangement established the C3 and C4 stereocenters and concomitantly generated a vinyl epoxide. The C5 oxygen was installed by cyclization of the pentenoic acid carboxyl group onto the vinyl epoxide in an S(N)2' fashion to afford the C5-epi stereochemistry. The natural C5 stereochemistry was accessed via a substrate directed dihydroxylation.
Assuntos
Benzofuranos/química , Fármacos Anti-HIV/química , Antifúngicos/química , Antineoplásicos/química , Benzofuranos/síntese química , Lignanas/síntese química , Lignanas/químicaRESUMO
[reaction: see text] A novel cycloaldol approach to the isobenzofuran core common to many of the eunicellin diterpenes is described. The cycloaldol precursor was prepared by aldol addition of (S)-(+)-carvone and methacrolein followed by etherification to a glycolate ester. Chemoselective enolization of the glycolate ester led to the cycloaldol adduct in high yield and diastereoselectivity. An oxidative rearrangement-allylic diazene rearrangement sequence established the requisite cis ring fusion.
Assuntos
Diterpenos/síntese química , Diterpenos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A variety of bis-allylic esters were prepared by vinylmetal addition to cycloalkenones followed by esterification either in situ or in a separate operation. For chiral cyclohexenones, the vinyl additions generally occurred with >10:1 diastereoselectivity. Although in some cases the bis-allylic esters proved to be sensitive to silica gel or other adsorbents, all of the esters examined could be isolated in acceptable purity. The Ireland-Claisen rearrangement of the bis-allylic esters occurred with complete regioselectivity via the exocyclic alkene. The alkene stereochemistry and the stereochemistry at C-2 and C-3 of the pentenoic acid products were consistent with a chairlike transition state in the rearrangement. Substituents at the carbons adjacent to the allylic carbinol carbon (i.e., C-2 or C-6 in cyclohexenone-derived substrates) directed the stereochemical course of the rearrangement. The rearrangements generally proceeded so as to place the larger of the C-2 or C-6 substituents in the pseudoequatorial position with respect to the chairlike transition state. For a bis-allylic ester bearing both a C-2-CH(3) and a C-6-OMEM substituent, the rearrangement product resulted from the nominally smaller OMEM substituent occupying a pseudoequatorial position with respect to the chairlike transition state.
Assuntos
Fatores Biológicos/síntese química , Ésteres/química , Ésteres/síntese química , Catálise , Química Orgânica/métodos , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
[structure: see text] A concise approach to the eupomatilone family of lignans is presented. The strategy employs an intramolecularly competitive Ireland-Claisen rearrangement of a densely functionalized bis-allylic ester. The rearrangement serves both to construct the A-ring and to establish the stereochemistry at C(3) and C(4).