Stereoselective synthesis of photoreactive peptidomimetic gamma-secretase inhibitors

The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO(2)-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.     

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens

We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.     

Synthetic studies on (+)-manzamine A: stereoselective synthesis of the tetracyclic core framework

The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered ring is efficiently constructed utilizing our Ns-strategy.     

Rapid synthesis of CDP840 with 2-pyrimidyl vinyl sulfide as a platform

A rapid synthesis of CDP840 (a potential therapeutic agent for asthma), using 2-pyrimidyl vinyl sulfide as a platform, has been established. This method includes a stereoselective double Mizoroki-Heck-type arylation, a Liebeskind-Srogl-type cross-coupling reaction, and a Pd/C-catalyzed hydrogenation.     

Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis

This account examines double asymmetric induction from theoretical and practical viewpoints. In the context of four major organic reactions-the aldol, Diels-Alder, catalytic hydrogenation, and epoxidation-it is shown that a double asymmetric induction can be analyzed in terms of the single asymmetric reactions of each of the two chiral reactants. A rule which qualitatively relates the results of these single asymmetric reactions with the outcome of the double asymmetric reaction is proposed. A powerful new strategy based on this rule for the predictable creation of new chiral centers is discussed and the use of this strategy for the synthesis of sugars and macrolides is presented.     

Asymmetric hydrogenation of aromatic compounds

The asymmetric hydrogenation of aromatic and heteroaromatic compounds arguably presents one of the most attractive methods for the synthesis of six-membered cyclic compounds. In recent years, a number of promising stereoselective methods for the asymmetric hydrogenation of pyridines and related heterocycles have been reported.     

Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins

The development of new general methods for the synthesis of chiral fluorine‐containing molecules is important for several scientific disciplines. We herein disclose a straightforward method for the preparation of chiral organofluorine molecules that is based on the iridium‐catalyzed asymmetric hydrogenation of trisubstituted alkenyl fluorides. This catalytic asymmetric process enables the synthesis of chiral fluorine molecules with or without carbonyl substitution. Owing to the tunable steric and electronic properties of the azabicyclo thiazole‐phosphine iridium catalyst, this stereoselective reaction could be optimized and was found to be compatible with various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups, providing the highly desirable products in excellent yields and enantioselectivities.     

Asymmetric synthesis of fluorinated cyclic beta-amino acid derivatives through cross metathesis

The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fluorinated imidoyl chlorides. Subsequent chemoselective hydrogenation of the olefin moiety, Dieckmann condensation, and stereoselective reduction of the iminic double bond afforded the corresponding beta-amino esters with several ring sizes. The asymmetric version of the process was achieved by using (-)-8-phenylmenthol as a chiral auxiliary.     

First example of an atropselective dehydro-Diels-Alder (ADDA) reaction

A new concept of a stereoselective synthesis of axially chiral biaryls, formed in the course of the dehydro-Diels-Alder (DDA) reaction, has been disclosed. It is based on asymmetric induction of the newly formed chirality axis by a chirality center, which is present in the two synthesized DDA reactants. Depending on the different length of the linkers joining the alkyne moieties the DDA reaction may be triggered photochemically or thermally, where only the thermal variant was stereoselective.     

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.     

Synthesis of an advanced intermediate enroute to (−)-clavosolide A

A stereoselective route to an advanced intermediate toward the synthesis of clavosolide A is disclosed. The key steps include Wadsworth-Emmons cyclopropanation, utilization of a sulfinyl moiety as an internal nucleophile to open a cyclopropane ring activated by Hg(II)- to create the C3-C5 stereogenic centers, CC bond formation employing an α-chloro sulfide, asymmetric transfer hydrogenation, regioselective hydrosilylation and Tamao-Fleming oxidation.     

2-Phospha[3]ferrocenophanes with planar chirality: synthesis and use in enantioselective organocatalytic [3 + 2] cyclizations

Planar chiral phosphines displaying a new ferrocenophane scaffold have been prepared via a stereoselective approach. The P-cyclohexyl substituted phosphine affords high levels of asymmetric induction in the organocatalytic [3 + 2] annulation reaction between allenes and electron-poor olefins.     

不对称Kabachnik-Fields反应合成研究进展

不对称三组分Kabachnik-Fields反应合成光学活性的α-氨基膦酸酯,由于其多组分反应自身所具有的独特优势,近年来已成为一个非常有吸引力的研究领域.从手性催化剂催化和光学活性底物诱导两方面综述了不对称Kabachnik-Fields反应合成手性α-氨基膦酸酯及其衍生物的最新研究进展,重点介绍了手性催化剂与手性底物构型对反应立体选择性的影响及其有关反应机理.最后提出了不对称多组分Kabachnik-Fields反应研究中存在的一些问题,并对其今后的发展方向进行了展望.     

Asymmetric Total Synthesis of (‐)‐Octahydro‐1H‐benzofuro[3,2‐e]isoquinoline,A Partial Structure of Morphine

Octahydro‐1 H‐benzofuro[3,2‐e]isoquinolines, which possess the ACNO partial structure of morphine, displayed potent oral analgesic and narcotic‐antagonism activity. However, due to inefficiency in their synthesis the ACNO derivatives have not been developed for clinical use. Here, we report in detail the first asymmetric total synthesis of (‐)‐octahydro‐1 H‐benzofuro[3,2‐e]isoquinoline as exemplified by the preparation of (‐)‐ 1 and (‐)‐ 2 . The key intermediate (+)‐5‐hydroxy‐3,4,5,6,7,8‐hexahydro‐1 H‐isoquinoline‐2‐carboxylic acid ethyl ester ((+)‐ 5 ) was prepared in 81% yield and with 100% ee by asymmetric reduction of 5‐oxo‐3,4,5,6,7,8‐hexahydro‐1 H‐isoquinoline‐2‐carboxylic acid ethyl ester ( 6 ) using RuCl[(R,R)‐Tsdpen](p‐cymene) as catalyst with a S/C of 200. The three chiral centers of ACNO skeleton were constructed via a reaction sequence of asymmetric transfer hydrogenation, Heck reaction, and catalytical hydrogenation, and all of these stereoselective reactions were metal‐catalyzed (i.e. Ru, Pd, and Pt, respectively).     

Enantioselective synthesis and absolute configurations of aculeatins A and B

The two naturally occuring, bioactive spiroacetals aculeatins A and B have been synthesized for the first time in enantiopure form using an asymmetric allylation as the only chirality source. A further key step was a stereoselective aldol reaction with remote induction. The absolute configurations of the natural products have been established and the previously assigned relative configurations have been corrected.     

Chiral α-branched mono phosphine auxiliaries,reversal of sense of asymmetric induction upon substitution

A group of 10 (mono- or bis-) α-chiral mono phosphine ligands was synthesized from enantiopure phosphepine sulfide 3 by one or two subsequential highly diastereoselective α-deprotonation/alkylation steps, followed by desulfuration with Raney nickel. Their relative configuration was determined by X-ray crystal structure analysis. The new monophosphine ligands were tested in asymmetric hydrogenation, hydroboration, and Suzuki–Miyaura coupling showing asymmetric inductions up to 91% ee. In the case of hydrogenation, clear evidence was found that enantioselectivity is substantially controlled through α-C chirality rather than through biaryl chirality, which was demonstrated by a change of the sense of asymmetric induction upon change of substituents.     

A new entry to asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones, using a carbohydrate derived amide as both a chiral auxiliary and a proton source

A new entry for the asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones was developed by using a carbohydrate-derived amide as both a chiral auxiliary and a proton source. Unlike the previously reported examples, the chiral auxiliary employed in this reaction also successfully functioned as a protonating agent. Excellent asymmetric induction could be achieved by this dual stereoselective control in the reaction process.     

Enantioselective hydrogenation of alpha-aryloxy alpha,beta-unsaturated acids. Asymmetric synthesis of alpha-aryloxycarboxylic acids

[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.     

Stereoselective assembly of a 1,3-diene via coupling between an allenic acetate and a (B)-alkylborane: synthetic studies on amphidinolide B1

The preparation of three fragments for the total synthesis of amphidinolide B1 has been described. The C16 stereochemistry was set by asymmetric allylic alkylation. C21 and C25 stereogenic centers were set by an enantioselective/diastereoselective double allylation reaction. The C9 configuration was set by an asymmetric heteroene reaction. A differentially substituted stereodefined 1,3-diene iodide was synthesized by iodide-mediated S(N)2' reaction. A novel stereoselective method to assemble a 1,3-diene by coupling an allenic acetate and (B)-alkylborane is also reported. [structure: see text]     

Dual-function cinchona alkaloid catalysis: catalytic asymmetric tandem conjugate addition-protonation for the direct creation of nonadjacent stereocenters

Catalytic tandem asymmetric reactions constitute a powerful strategy for the asymmetric construction of nonadjacent stereocenters in acyclic molecules directly from achiral precursors. In this Communication, we report a highly enantioselective and diastereoselective addition of trisubstituted carbon donors to 2-chloroacrylonitrile catalyzed by bifunctional cinchona alkaloid catalysts. This represents the first asymmetric tandem conjugate addition-protonation with efficient catalytic control of two nonadjacent stereocenters. As demonstrated in a concise and highly stereoselective formal total synthesis of (-)-manzacidin A, this asymmetric tandem reaction establishes a new and versatile catalytic approach for the enantioselective and diastereoselective creation of 1,3-tertiary-quaternary stereocenters.