Jian-Ping Qu

Switchable Reactions of Cyclopropanes with Enol Silyl Ethers. Controllable Synthesis of Cyclopentanes and 1,6-Dicarbonyl Compounds

Cu(SbF(6))(2)-catalyzed reaction of 2-substituted cyclopropane-1,1-dicarboxylates 1 with enol silyl ethers 2 can be readily controlled: the reaction undergoes a cycloaddition to provide substituted cyclopentane derivatives 3 in excellent yields with high diastereoselectivities in the presence of complex 8/Cu(II); however, the same substrates afford acyclic 1,6-dicarbonyl products 4 via a cycloaddition-ring-opening reaction in up to 92% yield in the absence of ligand 8. The mechanism for the ligand-switchable reactions was investigated by both control experiments and (1)H NMR studies. The substrate scope and limitation of the tunable transformation were also examined.

Highly diastereoselective construction of fused carbocycles from cyclopropane-1,1-dicarboxylates and cyclic enol silyl ethers: scope, mechanism, and origin of diastereoselectivity.

Cyclopropane rings true: By selecting the appropriate substituents on the ester and silyl groups, fused cyclopentane derivatives with multiple contiguous stereocenters can be synthesized with excellent diastereoselectivity through Cu(II)/bisoxazoline-catalyzed intermolecular [3+2] cycloaddition reactions of cyclopropane-1,1-dicarboxylates and cyclic enol silyl ethers (see scheme).

Enantio- and regioselective iridium-catalyzed allylic esterification.

A highly enantioselective and regioselective Ir-catalyzed allylic esterification is described, in which branched allylic esters are synthesized directly. Carboxylates were used as nucleophiles and linear allylic phosphates as electrophiles. In some cases the allylic substitution reaction was found to be accompanied by a kinetic resolution process, which causes a change of the enantiomeric excess.

Enantioselective syntheses of the alkaloids cis-195A (pumiliotoxin C) and trans-195A based on multiple applications of asymmetric catalysis.

Short enantio- and diastereoselective syntheses of the decahydroquinoline alkaloids cis- (pumiliotoxin C) and trans-195A are presented. Key steps are an enantioselective iridium-catalyzed allylic amination, a Suzuki-Miyaura coupling, a catalyst-controlled copper-catalyzed 1,4-addition, and a reductive amination.

Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis

Metal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, and copper. The palladium- and the iridium-catalyzed versions have turned out to be particularly versatile in organic synthesis because of the very broad scope of the nucleophile and great functional group compatibility. Assets of the iridium-catalyzed reaction are the formation of branched, chiral products from simple monosubstituted allylic substrates, high degrees of regio- and enantioselectivity, and use of modular, readily available chiral ligands. The possibility to use carbon, nitrogen, oxygen, and sulfur compounds as well as fluoride as nucleophiles allows a wide range of chiral building blocks to be prepared. Our Account begins with the presentation of fundamental reaction schemes and chiral ligands. We will focus our discussion on reactions promoted by phosphoramidite ligands, though numerous chiral ligands have been employed. The subsequent section presents a brief overview of reaction mechanism and experimental conditions. Two versions of the iridium-catalyzed allylic substitution have emerged. In type 1 reactions (introduced in 1997), linear allylic esters are commonly used as substrates under basic reaction conditions. In type 2 reactions (introduced in 2007), environmentally friendly branched allylic alcohols can be reacted under acidic conditions; occasionally, derivatives of allylic alcohols have also been applied. A unique feature of the type 2 reactions is that highly electrophilic allylic intermediates can be brought to reaction with weakly activated alkenes. The subsequent text is ordered according to the strategies followed to transform allylic substitution products to desired targets, most of which are natural products or drugs. Syntheses starting with an intermolecular allylic substitution are discussed first. Some fairly complex targets, for example, the potent nitric oxide inhibitor (-)-nyasol and the drug (-)-protrifenbute, have been synthesized via less than five steps from simple starting materials. Most targets discussed are cyclic compounds. Intermolecular allylic substitution with subsequent ring closing metathesis is a powerful strategy for their synthesis. Highlights are stereodivergent syntheses of Δ9-tetrahydrocannabinols (THC), wherein iridium- and organocatalysis are combined (dual catalysis). The combination of allylic alkylation with a Diels-Alder reaction was utilized to synthesize the ketide apiosporic acid and the drug fesoterodine (Toviaz). Sequential allylic amination, hydroboration and Suzuki-Miyaura coupling generates enones suitable for conjugate addition reactions; this strategy was employed in syntheses of a variety of alkaloids, for example, the poison frog alkaloid (+)-cis-195A (pumiliotoxin C). Intramolecular substitutions offer interesting possibilities to build up stereochemical complexity via short synthetic routes. For example, in diastereoselective cyclizations of chiral compounds, substrate control can be overruled by catalyst control in order to generate cis- and trans-isomers selectively from a given precursor. This approach was used to prepare a variety of piperidine and pyrrolidine alkaloids. Finally, complex polycyclic structures, including the structurally unusual indolosesquiterpenoid mycoleptodiscin A, have been generated diastereo- and enantioselectively from olefins by polyene cyclizations and from electron-rich arenes, such as indoles, in dearomatization reactions.

Transition-Metal-Free Hydrogenation of Aryl Halides: From Alcohol to Aldehyde

A transition-metal- and catalyst-free hydrogenation of aryl halides, promoted by bases with either aldehydes or alcohols, is described. One equivalent of benzaldehyde affords an equal yield as that of 0.5 equiv of benzyl alcohol. The kinetic study reveals that the initial rate of PhCHO is much faster than that of BnOH, in the ratio of nearly 4:1. The radical trapping experiments indicate the radical nature of this reaction. Based on the kinetic study, trapping and KIE experiments, and control experiments, a tentative mechanism is proposed. As a consequence, a wide range of (hetero)aryl iodides and bromides were efficiently reduced to their corresponding (hetero)arenes. Thus, for the first time, aldehydes are directly used as hydrogen source instead of other well-established alcohol-hydrogen sources.

Direct Wittig Olefination of Alcohols

A base-promoted transition metal-free approach to substituted alkenes using alcohols under aerobic conditions using air as the inexpensive and clean oxidant is described. Aldehydes are relatively difficult to handle compared to corresponding alcohols due to their volatility and penchant to polymerize and autoxidize. Wittig ylides are easily oxidized to aldehydes and consequently form homo-olefination products. By the strategy of simultaneously in situ generation of ylides and aldehydes, for the first time, alcohols are directly transferred to olefins with no need of prepreparation of either aldehydes or ylides. Thus, the di/monocontrollable olefination of diols is accomplished. This synthetically practical method has been applied in the gram-scale synthesis of pharmaceuticals, such as DMU-212 and resveratrol from alcohols.

Organopromoted Selectivity-Switchable Synthesis of Polyketones

In this work, an organopromoted metal-free pharmaceutical-oriented selectivity-switchable benzylic oxidation was developed, affording mono-, di-, and trioxygenation products, respectively, using oxygen as the oxidant under mild conditions. This process facilitates dioxygenation of 2,6-benzylic positions of heterocycles, which could be inhibited by heterocycle chelation to the metal cocatalysts. Enantiopure chiral ketones could also be prepared. The noninvolvement of transition metals and toxins avoids metal or hazardous residues, consequently ensuring a final-stage gram-scale synthesis of Lenperone.

n Bu4NOTf-promoted radical self-hydrogen transferring isomerization under transition metal-free conditions

We report the first allylic isomerization of alcohols catalyzed by nBu4NOTf generated in situ from tetrabutylammonium triflate and potassium tert-butoxide. Substituted ketones could be prepared under mild conditions in good to excellent yields. The relationship between catalysts and their reactivity has been investigated by systematic kinetic studies. The radical nature of this isomerization reaction has also been confirmed.

One-pot one-base conditions for two shots: organocatalyzed tandem isomerization–olefination of allylic alcohols

A one-pot isomerization–olefination of allylic alcohols using 1,10-phenanthroline as an organocatalyst in the presence of a base has been developed. Under one-pot one-base conditions, allylic isomerization and olefination were accomplished simultaneously. Either terminal or internal alkenes could be prepared in generally good to high yields from allylic alcohols without the involvement of transition metals or oxidants. This avoids the heavy metal and toxic residues in the resulting products and allows the applications of this method in pharmaceutical synthesis.