Baomin Fan

Asymmetric Hydrogenation of Quinoxalines with Diphosphinite Ligands: A Practical Synthesis of Enantioenriched, Substituted Tetrahydroquinoxalines†

The 1,2,3,4-tetrahydroquinoxaline ring system is an important structural unit in many bioactive compounds. Optically pure tetrahydroquinoxaline derivatives have shown great potential for pharmaceutical applications. For example, chiral compound A has been pursued as a potent vasopressin V2 receptor antagonists, and optically pure compound B is a promising inhibitor of cholesteryl ester transfer protein. In both cases, the chirality of the compounds was found to play a very important role in the relevant bioactivity of these compounds. The most convenient and straightforward route to chiral tetrahydroquinoxalines is the asymmetric hydrogenation of quinoxalines. Although several kinds of heteroaromatic compounds, such as quinolines, indoles, furans, pyridines, and pyrazines have been successfully hydrogenated with good to excellent enantioselectivities and yields in the presence of chiral transition-metal catalysts, the enantioselective hydrogenation of substituted quinoxaline derivatives has been less extensively studied. In 1987, Murata et al. first reported the rhodium-catalyzed asymmetric hydrogenation of 2-methylquinoxaline with only 3% ee. Later Bianchini et al. enantioselectively hydrogenated 2-methylquinoxaline with an orthomelated dihydride iridium complex to produce the product with up to 90% ee, but the reduction suffered from lower conversions. The performance of [RuCl2(diphosphine)(diamine)] complexes [3d,e] and Ir/PQphos (PQ-phos = (R)-[6,6-(2S,3S-butadioxy)]-(2,2’)-bis(diphenylphosphino)-(1,1’)-biphenyl) was also investigated, but only gave medium to low ee values. Given the importance of chiral tetrahydroquinoxalines and in view of the lack of efficient methods for the preparation of these compounds, the development of a practical and highly efficient catalytic asymmetric synthetic method appeared to be of great importance. Herein we describe the asymmetric hydrogenation of quinoxalines with an easily accessible Ir/diphosphinite catalyst. Good to excellent enantioselectivity (up to 98 % ee), unprecedented high catalytic activity (TOF up to 5620 h ), and productivity (TON up to 18 140) were observed for a wide range of substrates. Recently, the combination of transition metals and chiral phosphinite ligands has led to efficient catalysts for the asymmetric hydrogenation of prochiral olefins. In comparison with diphosphines, diphosphinites offer the advantages of easy preparation and derivatization. Recently, we have demonstrated that the easily accessible chiral diphosphinite ligands derived from (R)-H8-binol (binol = (1,1’-bi-2-naphthyl)) and (R)-1,1-spirobiindane-7,7-diol provided excellent catalytic activity and/or enantioselectivity in the Ir-catalyzed asymmetric hydrogenation of quinolines. Based on our previously optimized reaction conditions, we first investigated the performance of the [{IrCl(cod)}2] (cod = 1,5-cyclooctadiene)/(R)-H8-binapo or the (R)-sdpo/I2 catalyst system in THF for the asymmetric hydrogenation of 2-methylquinoxaline (1 a). To our delight, both catalysts worked efficiently with full conversions and good enantioselectivities (Table 1, entries 1 and 2), and (R)-H8-binapo gave the desired product in somewhat better enantiomeric excess. In sharp contrast to [*] Dr. W. Tang, J. Wang, Dr. B. Fan, Prof. Z. Zhou, Dr. K.-h. Lam, Prof. A. S. C. Chan Department of Applied Biology and Chemical Technology and Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis The Hong Kong Polytechnic University, Hong Kong (China) E-mail: bcachan@polyu.edu.hk

Ligand-Controlled Enantioselective [2 + 2] Cycloaddition of Oxabicyclic Alkenes with Terminal Alkynes Using Chiral Iridium Catalysts

The first catalytic asymmetric [2 + 2] cycloaddition of oxabicyclic alkenes and terminal alkynes has been developed. This iridium-catalyzed enantioselective [2 + 2] cycloaddition allows the formation of four stereocenters in a single step with excellent enantioselectivity (94-->99% ee).

Organocatalytic Enantioselective Michael Addition of 2,4-Pentandione to Nitroalkenes Promoted by Bifunctional Thioureas with Central and Axial Chiral Elements

Two novel bifunctional amine-thiourea organocatalysts 1 and 2, which both bear central and axial chiral elements, have been developed to promote enantioselective Michael reaction between 1,3-dicarbonyl compounds and nitro olefins. The catalyst 2 afforded the desired products with good levels of enantioselectivity (up to 96% ee), showing clearly that two chiral elements of 2 are matched, and enhance the stereochemical control.

Copper-Catalyzed Oxidative C–H Amination of Tetrahydrofuran with Indole/Carbazole Derivatives

A simple α-C-H amination of cyclic ether with indole/carbazole derivatives has been accomplished by employing copper(II) chloride/bipy as the catalyst system. In the presence of the di-tert-butyl peroxide oxidant, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran successfully undergo C-H/N-H cross dehydrogenative coupling (CDC) with various carbazole or indole derivatives in good-to-excellent yields.

Asymmetric Hydroalkynylation of Norbornadienes Promoted by Chiral Iridium Catalysts

Across bonds: The first successful iridium-catalyzed asymmetric hydroalkynylation of nonpolar alkenes with good to excellent enantioselectivity is described (see scheme; cod = 1,5-cyclooctadiene, DCE = 1,2-dichloroethane). This catalytic system exhibits good functional group compatibility as NH(2), OH, Br, F, and SiMe(3) groups remain intact during the reaction.

A study on the substituent effects of norbornadiene derivatives in iridium-catalyzed asymmetric [2 + 2] cycloaddition reactions

Employing a series of norbornadiene derivatives as substrates, the effects of various substituents on the Ir-catalyzed asymmetric [2 + 2] cycloaddition reactions with arylacetylenes were studied. It was found that the atom forming the short bridge chain had a great effect on the enantioselectivity of the reaction. Heteroatoms, such as oxygen and nitrogen, always resulted in excellent enantioselectivity. However, carbon atoms could decrease the enantioselective control ability of the catalyst over the reaction. The groups on the unreacted carbon-carbon double bond were found to have but a little effect on the reaction. Based on the results of the experiments, a mechanism was also hypothesized for the reaction.

Oxidative coupling between C(sp2)–H and C(sp3)–H bonds of indoles and cyclic ethers/cycloalkanes

Cross-dehydrogenative-coupling (CDC) between C-H/C-H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.

Palladium/Zinc Co‐Catalyzed syn‐Stereoselectively Asymmetric Ring‐Opening Reaction of Oxabenzonorbornadienes with Phenols

A new palladium/zinc co-catalyst system associated with chiral (R)-Difluorphos for asymmetric ring-opening reaction of oxabenzonorbornadienes with phenols is reported. This catalyst system allows the formation of cis-2-aryloxy-1,2-dihydronaphthalen-1-ol products in good yields (up to 95 % yield) with excellent enantioselectivities (up to 99 % ee). The cis-configuration of the product has been confirmed by X-ray crystal structure analysis. To the best of our knowledge, it represents the first example in ring-opening reactions of bicycloalkenes with heteronucleophiles in a syn-stereoselective manner.

Rh-catalyzed highly enantioselective hydroalkynylation reaction of norbornadiene derivatives.

The complexes of various Rh precusors with ferrocenyl chiral ligand (R,S)-Cy2PF-PPh2 were found effective catalysts for the asymmetric hydroalkynylation reaction of norbornadiene derivatives. When RhCl3·3H2O was employed, good yields (up to 98%) and high enantioselectivities (up to >99.9% ee) could be obtained for the reactions of a broad scope of substrates.

Spexin Enhances Bowel Movement through Activating L-type Voltage-dependent Calcium Channel via Galanin Receptor 2 in Mice

A novel neuropeptide spexin was found to be broadly expressed in various endocrine and nervous tissues while little is known about its functions. This study investigated the role of spexin in bowel movement and the underlying mechanisms. In functional constipation (FC) patients, serum spexin levels were significantly decreased. Consistently, in starved mice, the mRNA of spexin was significantly decreased in intestine and colon. Spexin injection increased the velocity of carbon powder propulsion in small intestine and decreased the glass beads expulsion time in distal colon in mice. Further, spexin dose-dependently stimulated the intestinal/colonic smooth muscle contraction. Galanin receptor 2 (GALR2) antagonist M871, but not Galanin receptor 3 (GALR3) antagonist SNAP37899, effectively suppressed the stimulatory effects of spexin on intestinal/colonic smooth muscle contraction, which could be eliminated by extracellular [Ca2+] removal and L-type voltage-dependentCa2+ channel (VDCC) inhibitor nifedipine. Besides, spexin dramatically increased the [Ca2+]i in isolated colonic smooth muscle cells. These data indicate that spexin can act on GALR2 receptor to regulate bowel motility by activating L-type VDCC. Our findings provide evidence for important physiological roles of spexin in GI functions. Selective action on spexin pathway might have therapeutic effects on GI diseases with motility disorders.