Xiangbing Qi

Chiral Allene-Containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands.

Allenes in Asymmetric Catalysis. Asymmetric Ring-Opening of Meso-Epoxides Catalyzed by Allene-Containing Phosphine Oxides

Unsymmetrically substituted allenes (1,2-dienes) are inherently chiral and can be prepared in optically pure form. Nonetheless, to date the allene framework has not been incorporated into ligands for asymmetric catalysis. Since allenes project functionality differently than either tetrahedral carbon or chiral biaryls, they may create complementary chiral environments. This study demonstrates that optically active, C(2)-symmetric allene-containing bisphosphine oxides can catalyze the addition of SiCl(4) to meso-epoxides with high enantioselectivity. The epoxide opening likely involves generation of a Lewis acidic, cationic (bisphosphine oxide)SiCl(3) complex. The fact that high asymmetric induction is observed suggests that allenes may represent a new platform for the development of ligands and catalysts for asymmetric synthesis.

Synthesis of Cyclopentenones from Cyclopropanes and Silyl Ynol Ethers

Five-membered carbocyclic rings appear in all classes of organic materials including pharmaceutical agents, polymers, natural products and catalysts. Accordingly, their preparation has challenged synthetic chemistry since the inception of the field.[1] In this regard, [3+2] cycloadditions - both concerted and stepwise - represent convergent strategies for the construction of the cyclopentane nucleus.[2] Dipolar cycloadditions, in particular, have proven especially successful, and of the various all-carbon dipoles available, donor-acceptor cyclopropanes (1) have proven especially versatile.[3] In the presence of Lewis acids, these materials undergo ring-opening to yield 1,3-dipoles. Pursuing a general interest in the reactivity of electron-rich alkynes,[4] we envisioned a cycloaddition between such dipoles and ynol ethers (2, Scheme 1). In analogy to Diels-Alder reactions involving Danishefsky’s diene[ 5 ] we postulated that the intermediate vinylogous acetal 3 might decompose to the cyclopentenone 4 during the reaction. While donor-acceptor cyclopropanes have been shown to combine with indoles,[6] enol ethers[7] and aryl acetylenes,[8] a condensation with ynol derivatives has not been documented. Indeed, these alkynes have hardly been explored in the context of [3+2] cycloadditions.[9] Scheme 1 Cycloaddition of ynol ethers with 1,3-dipoles derived from opening of donor-acceptor cyclopropanes. EWG = electron-withdrawing group. Exploratory studies examined the reaction of cyclopropane 1a (R1, R2 = H) with ynol ether 2a (R3 = n-Bu) which is prepared in a single step from n-hexyne.[10] Several Bronsted and Lewis acids, including Me3SiOTf (Tf = SO2CF3), HN(Tf)2 and BBr3, promoted the formation of cyclopentadiene 5aa and cyclopentenone 4aa in moderate yield. Despite substantial efforts to optimize the reaction conditions, however, we were never able to develop a protocol that returned the cycloadducts in synthetically useful yield. Our early experiments suggested similarly mediocre performance with Me2AlCl; therefore, when we reinvestigated this Lewis acid several months after our initial experiments, we were surprised to find that it promoted the cycloaddition cleanly and rapidly.[11] Our hope that the increase in yield reflected improved technique was quickly dispelled when we discovered substantial differences in reactivity between aged and freshly opened bottles of reagents. Reactions involving Me2AlCl from a new bottle required >24h to go to completion (Table 1, entry 1). Under otherwise identical conditions, reagent drawn from bottles that had been used for several months displayed markedly superior reactivity (entry 2). Reasoning that this observation could be accounted for by evaporation (solutions of Me2AlCl in hexanes were used) or adventitious air or water, we performed a series of control experiments. Modest changes to the charge of Me2AlCl had little effect on the rate of the reaction (not shown), and neither did small amounts of water (entry 3). In contrast, when dry air was bubbled through solutions containing the Lewis acid, we could recapitulate the phenomenon observed with aged bottles of reagent, and isolate 4aa in good yield (entry 4).[12] Table 1 Effects of Additives on the Al(III)-Mediated Reaction of Silyl Under optimized reaction conditions, air was bubbled through a solution of the Al reagent (1 equiv) at room temperature. At -78 °C, cyclopropane (1.3 equiv) and ynol ether (1 equiv) were added, and the solution was stirred until the reaction was complete (2-24 h). HF·pyridine was added, and, after aqueous workup, cyclopentenone 4 was purified by flash chromatography. In this way, a series of substituted donor-acceptor cyclopropanes combined with a range of ynol ethers to yield enones in generally good yields (Table 2). Silyl ynol ethers bearing olefins, alkynes, ethers, halides and aromatic rings all functioned effectively in the transformation (entries 1-12). Unfortunately, the ynol derived from phenyl acetylene was a poor substrate (entry 13). Cis- and trans-disubstituted cyclopropanes appear to behave equivalently (entry 1-2). Likewise, substitution at C3 (entries 14-16), C1 (entry 17), or both (entries 18-19) is accommodated in the cycloaddition. Thus, tri-, tetra-, and even penta-substituted cyclopentenones can be formed in good yields and in a convergent manner. Furthermore, both partners in the cycloaddition can be accessed in a single operation from readily available materials. Table 2 Synthesis of Cyclopentenes from Ynolates and Cyclopropanes.[a] The NMR spectrum of anaerobic solutions of Me2AlCl revealed one singlet at -0.31 ppm (CDCl3). After oxygenation, the same solution displays two upfield singlets at -0.39 and -0.43 ppm and two downfield resonances suggestive of a methoxide (3.87 and 3.85 ppm). We interpret these signals as arising from (MeO)AlMeCl, the product of aerobic oxidation of one methyl-aluminum bond. The two sets of signals (ca. 1:2 ratio) likely correspond to diastereomeric cyclic trimers.[ 13 ] Indeed, addition of 1 equiv of methanol to Me2AlCl yields a substance with substantially the same spectrum, and the reagent thus produced is a better Lewis acid for the cycloaddition than Me2AlCl (Table 1, entry 5). Interestingly, while the major products formed upon addition of methanol or air to Me2AlCl are the same, the reaction of methanol is noticeably messier: an unidentified precipitant is formed, and the 1H NMR spectrum of the filtrate contains several minor products. Perhaps as a consequence, the cycloadditions using this reagent are lower yielding and generate more side products. Thus aerobic oxidation of dialkyl alanes constitutes a clean and efficient method to generate a strong but selective Lewis acid. Finally, it is important to note that we observe no difference between the (MeO)AlMeCl generated from new versus aged bottles of Me2AlCl (Table 1, entries 4 vs. 6). With respect to the utility of the methodology described here, comparisons to two standard syntheses of cyclopentenones are appropriate. This cycloaddition is more direct than the Nazarov cyclization, and, in contrast to that cyclization, yields a single olefin positional isomer.[14] Likewise, while the Pauson-Khand reaction is generally limited to intramolecular cyclizations, the reactivity described above functions efficiently in an intermolecular context.[15] While (MeO)AlMeCl has been characterized previously, it has found infrequent use as a Lewis acid.[ 16 ] In the present transformation, it appears strong enough to activate the cyclopropane towards ring-opening and to mediate the decomposition of the vinylogous acetal (3), but mild enough to coexist with the ynol ether and the cyclopentenone. Whether this favorable reactivity profile extends to other classes of dipolar cycloadditions and, more broadly, other Lewis-acid promoted reactions remains the subject of future investigations.

Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket

Background: Up-regulated pyruvate dehydrogenase kinase isoforms (PDKs) are associated with impaired glucose homeostasis in diabetes. Results: Novel PDK inhibitors were developed using structure-based design, which improves glucose tolerance with reduced hepatic steatosis in diet-induced obese mice. Conclusion: Obesity phenotypes are effectively treated by chemical intervention with PDK inhibitors. Significance: PDKs are potential drug targets for obesity and type 2 diabetes. Pyruvate dehydrogenase kinase isoforms (PDKs 1–4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure, and cancer and are potential therapeutic targets for these important human diseases. Here, we employed a structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 μm for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments pyruvate dehydrogenase complex activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.

Catalytic enantioselective [2,3]-rearrangements of amine N-oxides.

The first Pd-catalyzed enantioselective [2,3]-rearrangement of allylic amine N-oxides is described, which formally represents an asymmetric Meisenheimer rearrangement. The mild reaction conditions enable the synthesis of chiral nonracemic aliphatic allylic alcohol derivatives with reactive functional groups. On the basis of preliminary studies, a cyclization-mediated mechanism is proposed.

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.

Benzothiophene Carboxylate Derivatives as Novel Allosteric Inhibitors of Branched-chain α-Ketoacid Dehydrogenase Kinase

Background: Branched-chain amino acids (BCAA) are elevated in maple syrup urine disease, obesity, and type 2 diabetes. Results: We show that benzothiophene carboxylate derivatives are allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase (BDK). Conclusion: These BDK inhibitors robustly augment BCAA oxidation in mice, resulting in lower plasma BCAA. Significance: The BDK inhibitors are potentially useful for treatment of the above disorders. The mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC) is negatively regulated by reversible phosphorylation. BCKDC kinase (BDK) inhibitors that augment BCKDC flux have been shown to reduce branched-chain amino acid (BCAA) concentrations in vivo. In the present study, we employed high-throughput screens to identify compound 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) as a novel BDK inhibitor (IC50 = 3.19 μm). BT2 binds to the same site in BDK as other known allosteric BDK inhibitors, including (S)-α-cholorophenylproprionate ((S)-CPP). BT2 binding to BDK triggers helix movements in the N-terminal domain, resulting in the dissociation of BDK from the BCKDC accompanied by accelerated degradation of the released kinase in vivo. BT2 shows excellent pharmacokinetics (terminal T½ = 730 min) and metabolic stability (no degradation in 240 min), which are significantly better than those of (S)-CPP. BT2, its analog 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylic acid (BT2F), and a prodrug of BT2 (i.e. N-(4-acetamido-1,2,5-oxadiazol-3-yl)-3,6-dichlorobenzo[b]thiophene-2-carboxamide (BT3)) significantly increase residual BCKDC activity in cultured cells and primary hepatocytes from patients and a mouse model of maple syrup urine disease. Administration of BT2 at 20 mg/kg/day to wild-type mice for 1 week leads to nearly complete dephosphorylation and maximal activation of BCKDC in heart, muscle, kidneys, and liver with reduction in plasma BCAA concentrations. The availability of benzothiophene carboxylate derivatives as stable BDK inhibitors may prove useful for the treatment of metabolic disease caused by elevated BCAA concentrations.

Development of the Vinylogous Pictet–Spengler Cyclization and Total Synthesis of (±)‐Lundurine A

A novel vinylogous Pictet-Spengler cyclization has been developed for the generation of indole-annulated medium-sized rings. The method enables the synthesis of tetrahydroazocinoindoles with a fully substituted carbon center, a prevalent structural motif in many biologically active alkaloids. The strategy has been applied to the total synthesis of (±)-lundurine A.