RESUMEN
A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Piranos/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Compuestos Heterocíclicos con 2 Anillos/química , Estructura Molecular , Piranos/químicaRESUMEN
Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields.
RESUMEN
A study of the ring-closing metathesis reactions of two bis(enynes) is presented. These substrates, which contain two alkenes and two alkynes, as well as a resident stereocenter, can potentially generate metathesis products resulting from many reaction pathways. In this contribution we present our results on these reactions, show how small changes in reaction conditions can lead to different product ratios, and attempt to provide a rationale for the outcomes.
Asunto(s)
Alquinos/química , Rutenio/química , Catálisis , Ciclización , Espectroscopía de Resonancia Magnética , Estructura Molecular , EstereoisomerismoRESUMEN
A highly efficient TMSI-mediated deprotection and direct isolation method to obtain zwitterionic compounds from the corresponding N-Boc derivatives has been developed. This method has been demonstrated in the final deprotection/isolation of the ß-lactamase inhibitor MK-7655 as a part of its manufacturing process. Further application of this process toward other zwitterionic compounds, such as dipeptides and tripeptides, has been successfully developed. Furthermore, a catalytic version of this transformation has been demonstrated in the presence of BSA or BSTFA.
Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/aislamiento & purificación , Dipéptidos/química , Compuestos de Trimetilsililo/química , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/aislamiento & purificación , Estructura Molecular , Solubilidad , AguaRESUMEN
We report the discovery of novel N,N'-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catalysts afford substantial improvements in enantioselectivity and reaction rate for intramolecular spirocyclization reactions with catalyst loadings as low as 0.3â mol% under mild conditions.
Asunto(s)
Alcaloides de Cinchona/química , Alcaloides de Cinchona/síntesis química , Catálisis , Estructura Molecular , Compuestos de Espiro , EstereoisomerismoRESUMEN
A general method for the preparation of α-hydroxyacetophenones is presented. Functionalized arylmagnesium species are transmetalated to the corresponding arylzinc intermediates, which undergo Cu(I)-catalyzed reaction with acetoxyacetyl chloride. Acidic hydrolysis of the acetate group releases the target α-hydroxyacetophenones with minimal production of undesired polymeric degradates that are often observed under alternative conditions.
Asunto(s)
Acetofenonas/química , Acetofenonas/síntesis química , Acetatos/química , Catálisis , Hidrólisis , Estructura Molecular , Compuestos Organometálicos/química , EstereoisomerismoRESUMEN
An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.
Asunto(s)
Alcoholes/química , Antifúngicos/síntesis química , Antifúngicos/farmacología , Crisenos/química , Crisenos/síntesis química , Equinocandinas/química , Glucosiltransferasas/antagonistas & inhibidores , Glicósidos/química , Paladio/química , Triterpenos/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.
Asunto(s)
Azepinas/síntesis química , Rutenio/química , Triazoles/síntesis química , Aminación , Catálisis , Hidrogenación , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Cinética , Neuropéptidos/antagonistas & inhibidores , Orexinas , EstereoisomerismoRESUMEN
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Asunto(s)
Técnicas de Química Sintética/métodos , Indoles/química , Indoles/síntesis química , Lactamas/química , Compuestos Macrocíclicos/química , Catálisis , Ciclización , Ciclopropanos , Hidrogenación , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Paladio/química , Prolina/análogos & derivados , SulfonamidasRESUMEN
A general approach for the synthesis of 1,5-disubstituted-1,2,4-triazole compounds is described. A series of new oxamide-derived amidine reagents can be accessed in excellent yield with minimal purification necessary. Typically, these amidine reagents are stable crystalline solids and in certain cases were found to exist in a cyclic form as determined by NMR spectroscopy. Under optimized conditions, the direct reaction of these prepared reagents with various hydrazine hydrochloride salts efficiently generates the target triazoles. Both aromatic and aliphatic hydrazines react readily with the amidine reagents under very mild reaction conditions, delivering desired 1,5-disubstituted-1,2,4-triazole derivatives in good yields.
Asunto(s)
Amidinas/química , Hidrazinas/química , Indicadores y Reactivos/química , Triazoles/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Triazoles/químicaRESUMEN
A general approach for the synthesis of 3,5-diarylcyclopentenones was developed. Key aspects of this approach are the intramolecular Friedel-Crafts-type cyclization of vinyl chlorides and subsequent Pd-catalyzed cross-coupling reactions. The requisite vinyl chloride-bearing arylacetic acid precursors are readily available by straightforward alkylation of arylacetic acid esters and undergo cyclization to yield 3-chloro-5-aryl-2-cyclopentenones when treated with AlCl(3). The vinylogous acid chloride functionality present in these immediate products allows for further elaboration via Pd-catalyzed cross-coupling chemistry, leading to a diverse array of products.
Asunto(s)
Pentanonas/química , Pentanonas/síntesis química , Cloruro de Vinilo/química , Acilación , Ciclización , Estructura MolecularRESUMEN
We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.
Asunto(s)
Péptidos/química , Fenol/química , Acetatos/química , Acetatos/metabolismo , Catálisis , Bases de Datos de Proteínas , Cinética , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Mucor/enzimología , Estereoisomerismo , TemperaturaRESUMEN
Under conventional heat (135-145 degrees C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a novel sp3 C-H activated cyclization to produce the corresponding isoindoles, and aliphatic oximes afford the corresponding dihydropyrroles. The cyclization occurs with various substrates in good yield (46-82%) leading to unique spiro-fused and cyclic imines. An initial mechanistic investigation suggests the reaction occurs via a nitrenium or vinyl nitrene intermediate. [reaction: see text]
Asunto(s)
Técnicas Químicas Combinatorias , Iminas/síntesis química , Oximas/química , Compuestos de Espiro/síntesis química , Anhídridos Acéticos/química , Ciclización , Calor , Iminas/química , Indoles/química , Microondas , Modelos Químicos , Pirroles/química , Compuestos de Vinilo/químicaRESUMEN
An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired ß-anomer from the glycosylation step.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Desoxiadenosinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Catálisis , Glicósidos/química , Glicosilación , Hidrogenación , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
[Reaction: see text] Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones 1a-j affords (E)-N-TMS-ketimines 2a-j that are reduced in situ to afford racemic perfluoromethylated amine hydrochloride salts 3a-j in 54-97% yields. Solvolysis of the N-Si bond in MeOH leads to formation of bench-stable, isolable N-H imine Z/E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures provides the first catalytic asymmetric synthesis of trifluoromethylated amines in 72-95% yields and 75-98% ee.
Asunto(s)
Aminas/química , Hidrógeno/química , Iminas/química , Nitrógeno/química , Catálisis , Hidrógeno/metabolismo , Enlace de Hidrógeno , Nitrógeno/metabolismo , Oxidación-Reducción , EstereoisomerismoRESUMEN
[reaction: see text]. A practical synthesis of sultams was developed via intramolecular sulfonamide dianion alkylation. This method has been applied toward the synthesis of chiral sultams, which are synthetically valuable as chiral auxiliaries.
RESUMEN
[reaction: see text] A new general method for the synthesis of medicinally important diversely functionalized imidazoles from N-acylated alpha-aminonitriles has been developed. N-Acylated alpha-aminonitriles were reacted with triphenylphosphine and carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H-imidazoles in good yield. This new methodology was applied for the synthesis of 2-butyl-4-chloro-5-hydroxymethylimidazole. These halo-imidazoles can be directly converted to 2,4,5-trisubstituted imidazoles through palladium-catalyzed coupling reactions.
RESUMEN
Asymmetric hydrogenation of ketone 1 using trans-RuCl(2)[(R)-xylbinap][(R)-daipen] (3) as a catalyst afforded secondary alcohol 2 quantitatively and in 99.4% ee. Further exploration of the effect of the thiazole ring substitution revealed that the catalyst was highly effective for the enantioselective hydrogenation of 5-benzoyl thiazoles, which afforded corresponding alcohols in 92-99% ee. The same protocol was applicable to a variety of aromatic-heteroaromatic ketones to generate secondary alcohols in excellent enantioselectivities. [reaction: see text]
RESUMEN
[reaction: see text] Experiments show that free radical hydrogen shift is significant in the Pschorr cyclization of diphenyl ethers (X = O) and thioethers (X = S) and does not take place with sufoxides (X = SO) and sulfones (X = SO(2)). DFT calculations of the product ratios, activation energies, rate constants for H-transfers, and ring-closings at the UB3PW91/6-31G(d,p) level are in excellent agreement with the experimental results reported here and elsewhere in the literature.
RESUMEN
Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]