A new strategy for the preparation of heterocyclic β-amino esters: orthogonally protected β-amino esters with a piperidine skeleton

A simple strategy is presented for the introduction of a nitrogen atom into the carbocycle of an aminocyclopentenecarboxylic ester via dihydroxylation of the olefinic bond, followed by NaIO₄-mediated cleavage of the diol intermediate and ring expansion, resulting in new regioisomeric 3-amino-4-piperidinecarboxylic acid derivatives. This method permits the preparation of amino esters with a piperidine skeleton in enantiomerically pure form.     

A new route for the construction of the AB-ring core of Taxol

A new method for the construction of the AB-ring core of Taxol was developed utilizing a new skeletal transformation protocol as a pivotal step. The acid-catalyzed rearrangement of the cyclopentenone-allene photoadduct gave a bridged seven-membered ketone, which was easily transformed, using the intramolecular Suzuki reaction and the oxidative cleavage of the vicinal diol, to the bicyclic diketone.     

Direct lactonization of alkenols via osmium tetroxide-mediated oxidative cleavage

[reaction: see text] A highly efficient, mild, and simple protocol is presented for the tandem OsO(4)-mediated oxidative cleavage/oxidative lactonization of alkenols to lactones. The protocol couples the OsO(4)-catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of aldehydes in alcoholic solvents to their corresponding esters.     

Synthesis of orthogonally protected azepane β-amino ester enantiomers

A simple and convenient route is presented for the preparation of regio- and stereoisomers of novel azepane β-amino esters, starting from bicyclic β-lactam isomers. The synthetic procedure consists of dihydroxylation of the olefinic bond of the alicyclic amino esters, followed by NaIO₄-mediated cleavage of the diol intermediate and reductive ring closure, which furnishes novel regioisomeric 5-aminoazepane-4-carboxylate and 3-aminoazepane-4-carboxylates. This method also allows the preparation of amino esters with an azepane skeleton in enantiomerically pure form.     

An electrophilic cleavage procedure for the asymmetric dihydroxylation: direct enantioselective synthesis of cyclic boronic esters from olefins

A variation within the osmium-catalysed asymmetric dihydroxylation (AD) of olefins is described that yields cyclic boronic esters from olefins in a straight-forward manner. This process represents the first real product alteration in asymmetric dihydroxylation, since all previous protocols lead to free diols exclusively. A protocol based on the Sharpless AD conditions (for enantioselective oxidation of prochiral olefins) was developed that gives cyclic boronic esters with excellent enantiomeric excesses (ee's). Some of the ee's are higher than those reported for conventional AD. The unprecedented role of phenyl boronic acid on the course of the AD reaction was investigated in detail. PhB(OH)2 does not interfere with the chiral ligand, leaving the enantioselective step of olefin oxidation intact. The main role of the boronic acids-apart from protecting the diol products against potential overoxidation-relies on removing the diol entity in an electrophilic cleavage, which is in contrast to the conventional hydrolytic cleavage of the AD protocols. Thus, a mechanistically new cleavage for enantioselective dihydroxylation reactions is introduced within the present work.     

Synthesis of natural fragrant molecules cis-3-methyl-4-decanolide and aerangis lactone. General enantioselective routes to beta,gamma-cis-disubstituted gamma-lactones and gamma,delta-cis-disubstituted delta-lactones

General enantioselective routes to 3,4-cis-dialkyl substituted gamma-lactones and 4,5-cis-dialkyl substituted delta-lactones using TiCl(4)-mediated Evans asymmetric aldolization as the key step are reported. The syntheses are exemplified with two natural fragrant molecules, cis-3-methyl-4-decanolide (1) and aerangis lactone (2). The (R,R) steroegenic centers were established using (S)-phenylalanine-derived 2-oxazolidinone or thiazolidinethione as chiral auxiliary, whereas the (S,S) ones were constructed with auxiliary prepared from (R)-phenylglycine. NaBH(4)/CaCl(2)/THF in the presence of a small amount of EtOH was introduced as a new effective method for reductive cleavage of chiral oxazolidinone auxiliaries. Previously unknown, tricky concentration effects were observed during the monotosylation of diol 7 and BOM protection of Evans aldol 23.     

A formal synthesis of ezetimibe via cycloaddition/rearrangement cascade reaction

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.     

An investigation into the role of 2,6-lutidine as an additive for the RuCl3-NaIO4 mediated oxidative cleavage of olefins to ketones

2,6-Lutidine has been identified as a beneficial additive for the oxidative cleavage of olefins to ketones by NaIO₄ in the presence of catalytic RuCl₃, improving the yield and shortening the reaction times. In the absence of 2,6-lutidine reactions stalled at the diol intermediate with incomplete conversion to the desired ketones. The reaction protocol described herein also avoids the use of harmful solvents such as CCl₄ and DCE and is tolerant of a range of functional groups.     

催化氧化法合成缩丙酮－（R）－和（S）－甘油酸

以Ｄ－和Ｌ－酒石酸为原料，合成出高光学纯度的缩丙酮－（Ｒ）－和（Ｓ）－甘油酸（１ａ，１ｂ），总收率分别为３２．８和３４．１％，制备的关键步骤为三氯化钌与次氯酸钠对邻二醇结构中Ｃ－Ｃ键的选择性氧化断裂     

Regioselective cleavage of myoglobin with copper(II) compounds at neutral pH

Selective hydrolytic cleavage of myoglobin was studied with CuCl2, Cu(ClO4)2, Cu(AC)2, and binuclear Cu(II) complexes of 3,6,9,16,19,22-hexaaza-6,19-bis (2-hydroxyethyl)-tricyclo- [22,2,2,2(11,14)]-triaconta-1,11,13,24,27,29-hexaene (1) and 3,6,9,16,19,22-hexaaza-tricyclo-[22,2,2,2(11,14)]-triaconta- 1,11,13,24,27,29-hexaene (2). The sites of cleavage were precisely determined by LC-ESIMS and further confirmed by an MS/MS method through fragmentation from both the N-terminal and C-terminal. The peptide bonds of Gln91-Ser92 and Ala94-Thr95 were remarkably cleaved by Cu(II) anchored to the side chain of the His93 residue. The data presented in this study show that Cu(II)-mediated cleavage of myoglobin is able to proceed at neutral pH, more selectively than Pd(II)-mediated cleavage, and buffer solution of phosphate and NH4HCO3 accelerates the cleavage reaction.     

Asymmetric Synthesis and Application of Chiral Spirosilabiindanes

Reported here is the development of a class of chiral spirosilabiindane scaffolds by Rh‐catalyzed asymmetric double hydrosilation, for the first time. Enantiopure SPSiOL (spirosilabiindane diol), a new type of chiral building block for the preparation of various chiral ligands and catalysts, was readily prepared on greater than 10 gram scale using this protocol. The potential of this new spirosilabiindane scaffold in asymmetric catalysis was preliminarily demonstrated by development of the corresponding monodentate phosphoramidite ligands (SPSiPhos), which were used in both a Rh‐catalyzed hydrogenation and a Pd‐catalyzed intramolecular carboamination.     

由D-(-)-核糖合成Aigialomycin D C2'—C7'片段的简捷方法

报道以D-(-)-核糖为起始原料合成Aigialomycin D的关键手性中间体C的一种简便方法. 化合物C是未见报道的新手性化合物.     

Asymmetric total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J using acetate migration and RCM reaction

A concise, unified and stereoselective total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J from a common polyhydroxylated cyclohexenol intermediate which was synthesized from readily available D-ribose has been described. The synthetic avenue includes stereoselective Grignard reaction, silyl ether deprotection followed by acetate migration, RCM reaction, oxidative diol cleavage, hydroxymethylation and oxidative rearrangement as key steps.     

A NEW EFFICIENT PROTOCOL FOR THE PREPARATION OF CHIRAL BISPHOSPHINES OF THE BICP FAMILY

A new procedure for the synthesis of chiral BICP ligands is described. The protocol involves the reaction of sodium diarylphosphide–borane complex with chiral 2,2′-bisbenzenesulfonyl-1,1′-dicyclopentane in toluene, followed by HBF₄·OMe₂-mediated BH₃ decomplexation.     

Anionic cyclization approach toward perhydrobenzofuranone: stereocontrolled synthesis of the hexahydrobenzofuran subunit of avermectin

A facile anionic cyclization approach toward stereocontrolled synthesis of the hexahydrobenzofuran subunit 3 of avermectin is described. As a model study, treatment of iodo compound 7 with n-BuLi at -100 degrees C effected metal-halogen exchange and subsequent anionic cyclization to afford perhydrobenzofuranone 8. For the total synthesis of subunit 3, compound 9 was dihydroxylated to give diol 10. Protection of the hydroxyl groups of diol 10 gave compound 11. Ketone 11 was then converted into the required enone 12 using Saegusa's protocol. On iodination followed by Luche reduction, enone 12 yielded alpha-iodo allylic alcohol 14, which on alkylation afforded ether 15. Conversion of the ester unit of 15 into a Weinreb amide group followed by anionic cyclization gave enone 17. 1,4-Addition of (MeOCH(2))(2)CuCNLi(2) to enone 17 followed by cleavage of the acetal unit afforded ketone 19. Preferential acetylation of the secondary alcoholic function of 19 afforded compound 20. The stereochemistry of 20 is confirmed by single-crystal X-ray analysis. Elimination of HOAc from 20 gave the crucial olefin 21. Hydrolysis of the acetate unit of 21 followed by protection of the resulting alcoholic function yielded tert-butyldimethylsilyl ether 23. Introduction of a hydroxyl group at the ring junction of 23, using Davis's procedure, finally afforded the hexahydrobenzofuran subunit 3.     

不对称羟内酯化合成白三烯A4中间体

为合成白三烯A4的关键中间体, 本文试验了若干7-手性中心-6,5-双键庚酸衍生物的不对称环氧化方法, 发现从D-甘油醛得的顺式烯化合物可选择性地羟内酯化, 游离羟基甲磺酰化后甲醇纳处理可得所需的5S, 6R氧桥, 水解, 过碘酸钠断键后即可顺利得到目标化合物.     

Alkyl C-O ring cleavage of bicyclic beta-lactones with Normant reagents: synthesis of a Merck IND intermediate

Highly diastereoselective Cu(I)-mediated, bicyclic beta-lactone ring cleavage reactions with either alkyl or aryl cuprates proceeded with inversion of stereochemistry to give optically active trans-substituted cyclopentanes and cyclohexanes. Optimization of typically problematic aryl cuprate additions was made possible by minimization of a competing bromide-induced ring cleavage process. The utility of this process was demonstrated by an efficient synthesis of a Merck investigational new drug (IND) intermediate for an anti-HIV CCR5 antagonist.     

PhI(OAc)2/I2-Mediated Decarboxylative C4-Amination of Coumarin-3-Carboxylic Acids via Csp2−H Dehydrogenative C−N Cross-Coupling under Ambient Conditions

An efficient and straightforward protocol for accessing a new series of functionalized 4-aminocoumarins from PIDA/I₂-mediated decarboxylative C₄-amination of coumarin-3-carboxylic acids via direct C_sp2−H dehydrogenative C−N cross-coupling with secondary amines under ambient conditions has been accomplished. The notable advantages of this protocol are the tolerance of diverse functional groups, mild reaction conditions at ambient temperature, moderate to good yields, short reaction times (in minutes), high regioselectivity, gram-scale applicability, and eco-friendliness. This is the first report of decarboxylative C_sp2−H cross-dehydrogenative C−N coupling of coumarin-3-carboxylic acids for synthesizing 4-aminocoumarins.     

Fe‐Catalyzed One‐Pot Oxidative Cleavage of Unsaturated Fatty Acids into Aldehydes with Hydrogen Peroxide and Sodium Periodate

A one‐pot method has been developed for the oxidative cleavage of internal alkenes into aldehydes by using 0.5 mol % of the nonheme iron complex [Fe(OTf)₂(mix‐bpbp)] (bpbp=N,N′‐bis(2‐picolyl)‐2,2′‐bipyrrolidine) as catalyst and 1.5 equivalents of hydrogen peroxide and 1 equivalent of sodium periodate as oxidants. A mixture of diastereomers of the chiral bpbp ligand can be used, thereby omitting the need for resolution of its optically active components. The cleavage reaction can be performed in one pot within 20 h and under ambient conditions. Addition of water after the epoxidation, acidification and subsequent pH neutralization are crucial to perform the epoxidation, hydrolysis, and subsequent diol cleavage in one pot. High aldehyde yields can be obtained for the cleavage of internal aliphatic double bonds with cis and trans configuration (86–98 %) and unsaturated fatty acids and esters (69–96 %). Good aldehyde yields are obtained in reactions of trisubstituted and terminal alkenes (62–63 %). The products can be easily isolated by a simple extraction step with an organic solvent. The presented protocol involves a lower catalyst loading than conventional methods based on Ru or Os. Also, hydrogen peroxide can be used as the oxidant in this case, which is often disproportionated by second‐ and third‐row metals. By using only mild oxidants, overoxidation of the aldehyde to the carboxylic acid is prevented.     

The OsO4-mediated oxidative cleavage of olefins catalyzed by alternative osmium sources

The OsO₄-mediated oxidative cleavage of olefins is compatible with alternative, easier-to-handle osmium sources. Four different osmium sources were employed with favorable results.