RESUMO
Experimental and computational studies illuminating the factors that guide metal-centered stereogenicity and, therefrom, selectivity in transfer hydrogenative carbonyl additions of alcohol proelectrophiles catalyzed by chiral-at-metal-and-ligand octahedral d6 metal ions, iridium(III) and ruthenium(II), are described. To augment or invert regio-, diastereo-, and enantioselectivity, predominantly one from among as many as 15 diastereomeric-at-metal complexes is required. For iridium(III) catalysts, cyclometalation assists in defining the metal stereocenter, and for ruthenium(II) catalysts, iodide counterions play a key role. Whereas classical strategies to promote selectivity in metal catalysis aim for high-symmetry transition states, well-defined low-symmetry transition states can unlock selectivities that are otherwise difficult to achieve or inaccessible.
RESUMO
The first total synthesis and structure validation of an arenimycin/SF2446 type II polyketide is described, as represented by de novo construction of SF2446 B3, the aglycone shared by this family of type II polyketides. Ruthenium-catalyzed α-ketol-benzocyclobutenone [4 + 2] cycloaddition, which occurs via successive stereoablation-stereoregeneration, affects a double dynamic kinetic asymmetric transformation wherein two racemic starting materials combine to form the congested angucycline bay region with control of regio-, diastereo-, and enantioselectivity. This work represents the first application of transfer hydrogenative cycloaddition and enantioselective intermolecular metal-catalyzed C-C bond activation in target-oriented synthesis.
Assuntos
Antibacterianos , Policetídeos , Reação de Cicloadição , Policetídeos/química , Estereoisomerismo , CatáliseRESUMO
The first deoxygenative Heck reactions are described, as illustrated by formate-mediated cine-substitutions of vinyl triflates with aryl iodides. The collective data corroborate a mechanism in which Pd(OAc)2 and Bu4NI form the dianionic iodide-bridged dimer [Pd2I6][NBu4]2, which, under reducing conditions, serves as a precursor to the palladium(I) complex [Pd2I4][NBu4]2. Dinculear oxidative addition of aryl iodide forms [Pd2I5(Ar)][NBu4]2, which dissociates to the monometallic complex [PdI2(Ar)][NBu4]. Vinyl triflate migratory insertion-sulfonate elimination delivers a palladium(IV) carbene, which upon ß-hydride elimination/C-H reductive elimination gives the product of cine-substitution. These processes are the first efficient formate-mediated cross-electrophile reductive couplings beyond carbonyl addition.
RESUMO
The first use of 1,4-pentadiene and 1,5-hexadiene as allylmetal pronucleophiles in regio-, anti-diastereo-, and enantioselective carbonyl addition from alcohol proelectrophiles is described. As corroborated by deuterium labeling experiments, primary alcohol dehydrogenation delivers a ruthenium hydride that affects alkene isomerization to furnish a conjugated diene, followed by transfer hydrogenative carbonyl addition. Hydrometalation appears to be assisted by the formation of a fluxional olefin-chelated homoallylic alkylruthenium complex II, which exists in equilibrium with its pentacoordinate η1 form to enable ß-hydride elimination. This effect confers remarkable chemoselectivity: while 1,4-pentadiene and 1,5-hexadiene are competent pronucleophiles, higher 1,n-dienes are not, and the olefinic functional groups of the products remain intact under conditions in which the 1,4- and 1,5-dienes isomerize. A survey of halide counterions reveals iodide-bound ruthenium-JOSIPHOS catalysts are uniquely effective in these processes. This method was used to prepare a previously reported C1-C7 substructure of (-)-pironetin in 4 vs 12 steps.
RESUMO
The first correlation between metal-centered stereogenicity and regioselectivity in a catalytic process is described. Alternate pseudo-diastereomeric chiral-at-ruthenium complexes of the type RuX(CO)[η3-prenyl][(S)-SEGPHOS] form in a halide-dependent manner and display divergent regioselectivity in catalytic C-C couplings of isoprene to alcohol proelectrophiles via hydrogen autotransfer. Whereas the chloride-bound ruthenium-SEGPHOS complex prefers a trans-relationship between the halide and carbonyl ligands and delivers products of carbonyl sec-prenylation, the iodide-bound ruthenium-SEGPHOS complex prefers a cis-relationship between the halide and carbonyl ligands and delivers products of carbonyl tert-prenylation. The chloride- and iodide-bound ruthenium-SEGPHOS complexes were characterized in solution and solid phase by 31P NMR and X-ray diffraction. Density functional theory calculations of the iodide-bound catalyst implicate a Curtin-Hammett-type scenario in which the transition states for aldehyde coordination from an equilibrating mixture of sec- and tert-prenylruthenium complexes are rate- and product-determining. Thus, control of metal-centered diastereoselectivity has unlocked the first catalytically enantioselective isoprene-mediated carbonyl tert-prenylations.
RESUMO
The first systematic study of catalytic enantioselective 1,2-additions to acrolein is described. Specifically, using allyl alcohol as a tractable, inexpensive acrolein proelectrophile, iridium-catalyzed acrolein allylation is achieved with high levels of regio-, anti-diastereo-, and enantioselectivity. This process delivers 3-hydroxy-1,5-hexadienes, a useful compound class that is otherwise challenging to access via enantioselective catalysis. Two-fold use of this method unlocks concise total syntheses of amphidinolide R (9 vs 23 steps, LLS) and amphidinolide J (9 vs 23 or 26 steps, LLS), which are prepared in fewer than half the steps previously possible, and the first total synthesis of amphidinolide S (10 steps, LLS).
Assuntos
Álcoois , Compostos Alílicos , Acroleína , EstereoisomerismoRESUMO
Cyclometalated π-allyliridium-C,O-benzoate complexes discovered in the Krische laboratory display unique amphiphilic properties, catalyzing both nucleophilic carbonyl allylation and electrophilic allylation of diverse amines as well as nitronates. Given the importance of chiral amines in FDA-approved small-molecule drugs, a collaboration with medicinal chemists at Genentech that included on-site graduate student internships was undertaken to explore and expand the scope of π-allyliridium-C,O-benzoate-catalyzed allylic amination and related processes. As described in this Account, our collective experimental studies have unlocked asymmetric allylic aminations of exceptionally broad utility and scope. Specifically, using racemic branched alkyl-substituted allylic acetate proelectrophiles, primary and secondary aliphatic or aromatic amines, including indoles, engage in highly regio- and enantioselective allylic amination. Additionally, unactivated nitronates were found to be competent nucleophilic partners for regio- and enantioselective allylic alkylation, enabling entry to ß-stereogenic α-quaternary primary amines. Notably, these π-allyliridium-C,O-benzoate-catalyzed allylic substitutions, which display complete branched regioselectivity in reactions of alkyl-substituted allyl electrophiles, complement the scope of corresponding iridium phosphoramidite-catalyzed allylic aminations, which require aryl-substituted allyl electrophiles to promote high levels of branched regioselectivity. Computational, kinetic, ESI-CID-MS, and isotopic labeling studies were undertaken to understand the mechanism of these processes, including the origins of regio- and enantioselectivity. Isotopic labeling studies suggest that C-N bond formation occurs through outer-sphere addition to the π-allyl. DFT calculations corroborate C-N bond formation via outer-sphere addition and suggest that early transition states and distinct trans effects of diastereomeric chiral-at-iridium π-allyl complexes render the reaction less sensitive to steric effects, accounting for complete levels of branched regioselectivity in reactions of hindered amine and nitronate nucleophiles. Reaction progress kinetic analysis (RPKA) reveals a zero-order dependence on allyl acetate, a first-order dependence on the catalyst, and a fractional-order dependence on the amine. As corroborated by ESI-CID-MS analysis, the 0.4 kinetic order dependence on the amine may reflect the intervention of cesium-bridged amine dimers, which dissociate to form monomeric cesium amide nucleophiles. Hence, the requirement of cesium carbonate (vs lower alkali metal carbonates) in these processes may reside in cesium's capacity for Lewis acid-enhanced Brønsted acidification of the amine pronucleophile. Beyond the development of catalytic processes for the synthesis of novel chiral amines, the present research was conducted by graduate students who benefited from career development experiences associated with training in both academic and industrial laboratories.
Assuntos
Aminas , Irídio , Alquilação , Aminas/química , Benzoatos , Catálise , Césio , Humanos , Irídio/química , Cinética , Estereoisomerismo , EstudantesRESUMO
In this Perspective, the use of methanol and ethanol as C1 and C2 feedstocks in metal-catalyzed C-C couplings to π-unsaturated pronucleophiles via hydrogen auto-transfer is surveyed. In these processes, alcohol oxidation to form an aldehyde electrophile is balanced by reduction of an π-unsaturated hydrocarbon to form a transient organometallic nucleophile. Mechanistically related reductive couplings of paraformaldehyde mediated by alcohol reductants or formic acid also are described. These processes encompass the first catalytic enantioselective C-C couplings of methanol and ethanol and, more broadly, illustrate how the native reducing ability of alcohols enable the departure from premetalated reagents in carbonyl addition.
RESUMO
Ruthenium-catalyzed cycloadditions to form five-, six-, and seven-membered rings are summarized, including applications in natural product total synthesis. Content is organized by ring size and reaction type. Coverage is limited to processes that involve formation of at least one C-C bond. Processes that are stoichiometric in ruthenium or exploit ruthenium as a Lewis acid (without intervention of organometallic intermediates), ring formations that occur through dehydrogenative condensation-reduction, σ-bond activation-initiated annulations that do not result in net reduction of bond multiplicity, and photochemically promoted ruthenium-catalyzed cycloadditions are not covered.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Organometálicos/química , Compostos Policíclicos/síntese química , Rutênio/química , Catálise , Ciclização , Oxirredução , Processos Fotoquímicos , EstereoisomerismoRESUMO
The first metal-catalyzed oxidative alkynylations of primary alcohols or aldehydes to form α,ß-acetylenic ketones (ynones) are described. Deuterium labelling studies corroborate a novel reaction mechanism in which alkyne hydroruthenation forms a transient vinylruthenium complex that deprotonates the terminal alkyne to form the active alkynylruthenium nucleophile.
RESUMO
The total synthesis of soraphen A, a myxobacterial metabolite and inhibitor of acetyl CoA carboxylase, was completed in 11 steps (longest linear sequence), less than half the steps previously required. Seven metal-catalyzed processes were deployed to unlock step-economy (comprising five asymmetric processes and four C-C bond formations). The present route does not utilize chiral auxiliaries, and four of five C-C bond formations exploit non-premetalated partners. To maximize convergency, an asymmetric Tsuji reduction was developed using a Pd-AntPhos catalyst that allows a metathesis-inactive allylic carbonate to serve as a masked terminal olefin, thereby enabling successive olefin metathesis events.
Assuntos
Alcenos/química , Inibidores Enzimáticos/síntese química , Macrolídeos/síntese química , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Carbono/química , Catálise , Cristalografia por Raios X , Inibidores Enzimáticos/química , Macrolídeos/química , Conformação Molecular , Oxirredução , Paládio/química , EstereoisomerismoRESUMO
The first enantioselective ruthenium-catalyzed carbonyl vinylations via hydrogen autotransfer are described. Using a ruthenium-JOSIPHOS catalyst, primary alcohols 2a-2m and 2-butyne 1a are converted to chiral allylic alcohols 3a-3m with excellent levels of absolute stereocontrol. Notably, 1°,2°-1,3-diols participate in site-selective C-C coupling, enabling asymmetric carbonyl vinylation beyond premetalated reagents, exogenous reductants, or hydroxyl protecting groups. Using 2-propanol as a reductant, aldehydes dehydro-2a, 2l participate in highly enantioselective 2-butyne-mediated vinylation under otherwise identical reaction conditions. Regio-, stereo-, and site-selective vinylations mediated by 2-pentyne 1b to form adducts 3n, 3o, and epi-3o also are described. The tiglyl alcohol motif obtained upon butyne-mediated vinylation, which is itself found in diverse secondary metabolites, may be converted to commonly encountered polyketide stereodiads, -triads, and -tetrads, as demonstrated by the formation of adducts 4a-4d. The collective mechanistic studies, including deuterium labeling experiments, corroborate a catalytic cycle involving alcohol dehydrogenation to form a transient aldehyde and a ruthenium hydride, which engages in alkyne hydrometalation to form a nucleophilic vinylruthenium species that enacts carbonyl addition. A stereochemical model for carbonyl addition invoking formyl CH···I[Ru] and CH···O≡C[Ru] hydrogen bonds is proposed based on prior calculations and crystallographic data.
Assuntos
Rutênio , Álcoois/química , Aldeídos/química , Catálise , Hidrogênio/química , Rutênio/química , EstereoisomerismoRESUMO
Catalytic reductive coupling of enone, acrylate, or vinyl heteroaromatic pronucleophiles with carbonyl or imine partners offers an alternative to base-mediated enolization in aldol- and Mannich-type reactions. In this review, direct catalytic reductive aldol and Mannich reactions are exhaustively catalogued on the basis of metal or organocatalyst. Stepwise processes involving enone conjugate reduction to form discrete enol or (metallo)enolate derivatives followed by introduction of carbonyl or imine electrophiles and aldol reactions initiated via enone conjugate addition are not covered.
Assuntos
Acrilatos/química , Alcenos/química , Cetonas/química , Compostos de Vinila/química , Catálise , Complexos de Coordenação/química , Iminas/química , Metais Pesados/química , OxirreduçãoRESUMO
Neaumycin B is a femtomolar inhibitor of U87 human glioblastoma. Using a newly developed anti-diastereoselective ruthenium-catalyzed butadiene-mediated crotylation of primary alcohol proelectrophiles via hydrogen auto-transfer, as well as a novel variant of the catalytic asymmetric vinylogous Mukaiyama aldol (VMA) reaction applicable to linear aliphatic aldehydes and terminally methylated dienyl ketene acetals, preparation of the key C1-C19 and C23-C35 substructures of neaumycin B is achieved in 12 and 7 steps (LLS), respectively.
Assuntos
Rutênio , Humanos , Estereoisomerismo , Butadienos , Aldeídos/química , CatáliseRESUMO
Iodide-bound ruthenium-JOSIPHOS complexes catalyze the redox-neutral C-C coupling of primary alcohols with methylallene (1,2-butadiene) or 1,3-butadiene to form products of anti-crotylation with good to excellent levels of diastereo- and enantioselectivity. Distinct from other methods, direct crotylation of primary alcohols in the presence of unprotected secondary alcohols is possible, enabling generation of spirastrellolideâ B (C9-C15) and leucascandrolideâ A (C9-C15) substructures in significantly fewer steps than previously possible.
Assuntos
Rutênio , Rutênio/química , Butadienos/química , Hidrogênio/química , Estereoisomerismo , Álcoois/química , Catálise , Etanol , Estrutura MolecularRESUMO
Cyclometallated iridium-PhanePhos complexes generated in situ from [Ir(cod)Cl]2 and (R)-PhanePhos catalyze 2-propanol-mediated reductive couplings of 2-substituted dienes with oxetanone and N-acyl-azetidinones to form branched homoallylic oxetanols and azetidinols with excellent control of regio- and enantioselectivity without C-C cleavage of the strained ring via enantiotopic π-facial selection of transient allyliridium nucleophiles. This work represents the first systematic study of enantioselective additions to symmetric ketones.
Assuntos
Compostos Alílicos , Irídio , 2-Propanol , Catálise , Polienos , EstereoisomerismoRESUMO
The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together in one total synthesis.
Assuntos
Compostos Alílicos/química , Compostos Organometálicos/química , Policetídeos/química , Hidrogenação , Conformação Molecular , EstereoisomerismoRESUMO
Highly tractable 1-aryl-1-propynes, which are readily accessible via Sonogashira coupling, serve as chiral allylmetal pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereo- and enantioselective aldehyde (α-aryl)allylations with primary aliphatic or benzylic alcohol proelectrophiles. This method enables convergent construction of homoallylic sec-phenethyl alcohols bearing tertiary benzylic stereocenters. Both steric and electronic features of aryl sulfonic acid additives were shown to contribute to the efficiency with which a more selective and productive iodide-bound ruthenium catalyst is formed. As corroborated by isotopic labeling studies, a dual catalytic process is operative in which alkyne-to-allene isomerization is followed by allene-carbonyl reductive coupling via hydrogen auto-transfer. Crossover of ruthenium hydrides emanating from these two discrete catalytic events is observed. The utility of this method is illustrated by conversion of selected reaction products to the corresponding phenethylamines and the first total syntheses of the neolignan natural products (-)-crataegusanoids A-D.
Assuntos
Álcoois/química , Alcinos/química , Rutênio/química , Alquilação , Produtos Biológicos/síntese química , Produtos Biológicos/química , Carbono/química , Catálise , EstereoisomerismoRESUMO
The first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles is described. Using an iodide-modified ruthenium-BINAP-catalyst and O-benzhydryl alkoxyallene 1a, carbonyl (α-alkoxy)allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically enriched syn-sec,tert-diols. Internal chelation directs intervention of (Z)-σ-alkoxyallylruthenium isomers, which engage in stereospecific carbonyl addition.
Assuntos
Alcadienos/química , Compostos Alílicos/química , Complexos de Coordenação/química , Naftalenos/química , Rutênio/química , Catálise , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
The first examples of rhodium-catalyzed carbonyl addition via hydrogen autotransfer are described, as illustrated in tandem butadiene-mediated carbonyl addition-redox isomerizations that directly convert primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-labeling crossover experiment reveals that the rhodium alkoxide obtained upon carbonyl addition enacts redox isomerization without dissociation of rhodium at any intervening stage.