Formal total synthesis of RK-397 via an asymmetric hydration and iterative allylation strategy

A formal total synthesis of the oxopentaene macrolide antibiotic RK-397 has been achieved. Nine stereocenters were established by a combination of allylation and our asymmetric hydration reactions and a 1,5 anti-selective aldol reaction. The synthesis proceeded in 19 steps from simple achiral conjugated dienoates.     

过渡金属催化的不对称氢化反应的国内研究进展

手性过渡金属催化剂催化的不对称氢化反应是制备光学纯手性氨基酸、 手性醇、 手性胺和手性酸等手性化合物的重要手段和途径. 本文主要概括了近20年内中国科学家在手性膦配体及其过渡金属催化剂的设计合成及不对称催化氢化新反应两方面的研究进展, 并展望了该领域的发展前景.     

Enantioselective total synthesis of (-)-erinacine B

The first enantioselective total synthesis of (-)-erinacine B has been achieved. Our approach features convergent construction of the 5-6-7 tricyclic cyathane core system via chiral building blocks prepared using asymmetric catalysis developed by us and highly stereoselective construction of all stereogenic centers in the aglycon. [reaction: see text].     

Chiral N-heterocyclic biscarbenes based on 1,2,4-triazole as ligands for metal-catalyzed asymmetric synthesis

A facile and straightforward synthetic procedure for the preparation of new chiral bis-1,2,4-triazolium salts and their corresponding rhodium(I) biscarbene complexes are reported. It is widely applicable for the synthesis of 1,2,4-triazolium salts. The new chiral biscarbenes represent promising ligands for transition metal-catalyzed asymmetric syntheses. Their first successful application is demonstrated by the rhodium-catalyzed hydrogenation of dimethylitaconate and methyl-2-acetamidoacrylate which yielded enantioselectivities of up to 61% ee.     

Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric Mannich reaction of N-protected aminoacetaldehydes: formal synthesis of (-)-agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.     

Recent advances in transition metal-catalyzed enantioselective hydrogenation of unprotected enamines

Transition metal-catalyzed enantioselective hydrogenation of enamines is undoubtedly a useful and environment-friendly method for the preparation of optically pure chiral amines and amine derivatives. Over the last few decades, the use of transition metal catalysts containing chiral phosphorus or phosphine-oxazoline ligands attracted much attention for the hydrogenation of unprotected enamines. A number of efficient chiral catalysts have been developed, and some of them have shown high potential for the application in the synthesis of optical chiral amines in both laboratory and industry. This tutorial review focuses on the contributions concerning the transition metal-catalyzed enantioselective hydrogenation of unprotected enamines for the synthesis of chiral amines and amine derivatives.     

手性磷酸催化剂在不对称合成中的应用

手性磷酸是2004年报道的一类具有新型结构的强酸性Bronsted酸催化剂,近几年来的研究取得了很大的进展,已经成为有机小分子催化剂的一个重要分支。手性磷酸在催化一系列亚胺的加成和还原反应比如Mannich、亚胺的氢转移、亚胺的膦酰化、Pictet-Spengler、 Strecker、aza-Diels-Alder、 Friedel-Craft和α-重氮酯的烷基化等反应时都表现出了非常好的催化活性和立体选择性。本文主要综述了手性磷酸催化剂应用于亚胺相关反应的研究进展。     

金属催化的不对称氢化反应研究进展与展望

手性过渡金属络合物催化的不对称氢化反应是合成光学活性化合物的重要方法. 本文从手性配体及手性催化剂、不对称催化新反应、新方法和新策略三个方面简要评述新世纪以来过渡金属催化的不对称氢化反应研究领域的新进展. 从新世纪初至今, 手性单磷配体得到了复兴, 出现了如MonoPhos、SiPhos、DpenPhos等高效单齿亚磷酰胺酯配体; 磷原子手性(P-手性)配体也得到了快速发展, 如BenzP*、ZhanPhos、TriFer等已成为新的高效手性双膦配体; 螺环骨架手性配体成为新世纪手性配体设计合成的亮点, 除了SiPhos、SIPHOX、SpinPHOX等高效手性螺环配体外, 手性螺环吡啶胺基磷配体SpiroPAP的铱催化剂成为目前最高效的分子催化剂. 不对称催化氢化新反应研究也取得了突破, 如非保护烯胺、杂芳环化合物及N-H亚胺的氢化等反应都实现了高对映选择性. 自组装手性催化剂、树枝状手性催化剂、铁磁性纳米负载的可回收手性催化剂, 以及“混合”配体手性催化剂等新方法和新策略也在不对称催化氢化反应中得到了应用. 然而, 手性过渡金属络合物催化的不对称氢化研究仍然充满挑战, 也期待新的突破.     

Catalytic asymmetric assembly of stereodefined propionate units: an enantioselective total synthesis of (-)-pironetin

Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantioenriched aldehydes afford cis-disubstituted beta-lactones as surrogates for syn aldols; the mismatched AAC reactions provide anti-selective aldols in the form of trans-disubstituted 2-oxetanones. The utility of this reaction technology in synthesis activities is exemplified in a catalytic asymmetric total synthesis of (-)-pironetin.     

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.     

Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.     

Asymmetric catalysis as a method for the synthesis of chiral organophosphorus compounds

This review discusses methods for the metallo-, organo- and biocatalytic asymmetric synthesis of chiral organophosphorus compounds with many applications in stereoselective synthesis with references to updated literature reports as well as the author’s original research. Asymmetric catalytic hydrogenation and reduction with chiral organometallic complexes, together with actively used asymmetric organocatalytic versions of various reactions enable us to synthesize chiral organophosphonates and phosphinates with high enantioselectivity and purity. Asymmetric catalysis is also an effective tool to realize some classic reactions of phosphorus chemistry in a stereospecific manner.     

Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: toward the synthesis of an anthrax lethal factor inhibitor

A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]     

First total synthesis of the anti-inflammatory lipid mediator Resolvin D6

The first total synthesis of Resolvin D6, an endogenous lipid mediator of resolution of inflammation derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C4 and C17 were generated via an asymmetric Noyori transfer hydrogenation and a Sharpless catalytic asymmetric epoxidation, respectively. A mild copper catalyzed coupling of cis-1,4-dibromo-2-butene with TMS-acetylene generated the C7–C14 fragment. Pd⁰/Cu^I Sonogashira couplings and Zn(Cu/Ag) reduction completed the synthesis of Resolvin D6.     

Enantioselective synthesis of martinelline chiral core and its diastereomer using asymmetric tandem Michael-aldol reaction

The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem Michael-aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the α,β-unsaturated aldehyde.     

Asymmetric synthesis and absolute configuration of streptophenazine G

The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1'S,2'R,6'S. The asymmetric total synthesis of 6'-epi-streptophenazine G is also described.     

Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade

An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric 2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide monomers and provide insight into the stereocontrol elements for these reactions.     

Total synthesis of the anti-inflammatory lipid mediator Resolvin E2

The total synthesis of Resolvin E2, an endogenous lipid mediator of the resolution of inflammation derived from eicosapentaenoic acid, has been achieved. The chiral hydroxy-groups at C5 and C18 were generated in a simple, efficient, and environmentally friendly manner via an asymmetric Noyori transfer hydrogenation in water using sodium formate as a reducing agent. Pd⁰/Cu^I Sonogashira couplings of the three key fragments and Zn(Cu/Ag) reduction completed the synthesis of Resolvin E2.     

Enantioselective total synthesis of (+)-tricycloclavulone

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.     

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.