1,3-Dipolar cycloadditions of diazomethane to chiral electron-deficient olefins: the origin of the pi-facial diastereoselection

The stereochemical outcome of diazomethane cycloadditions to several chiral electron-deficient olefins has been investigated in order to establish the origin of the pi-facial diastereoselection. Nitro olefins, vinyl sulfones, enoates, and 2-amino enoates have been used for such a purpose. These substrates have been prepared from D-glyceraldehyde acetonide through Wittig-type condensations and present an alkoxy substituent, provided by the bulky dioxolane ring, attached to the stereogenic allylic carbon. Syn-adducts have been obtained in all cases as the major isomers, independently of the Z/E stereochemistry of the double bond and the number and the nature of the substituents, the chirality of the asymmetric allylic carbon being the only thing responsible for the diastereoselection. Theoretical calculations show that steric hindrance due to the bulky dioxolane group is the main factor governing the preference for the syn-attack of diazomethane to the olefinic double bond.     

Stereoselective synthesis of cyclobutyl α-aminocyclopropyl carboxylic acid derivatives

The highly stereoselective cyclopropanation of chiral cyclobutyl dehydro amino acids, synthesized from (−)-α-pinene or (−)-verbenone, has been achieved by means of a 1,3-dipolar cycloaddition with diazomethane. The proximity of the double bond to the neighbouring stereogenic center of the cyclobutyl moiety is crucial to obtain cyclopropanes as single diastereomers whose configuration has been determined by X-ray structural analysis. DFT theoretical calculations of the more stable conformations allow us to understand the π-facial diastereoselection as the result of steric hindrance by the gem-dimethyl substitutuents and the side chain of the cyclobutane-ring. Chiroptical properties of these products have been studied by ORD and CD techniques and their behavior in CSA-NMR experiments has been ascertained.     

Unsymmetrical hybrid ferrocene-based phosphine-phosphoramidites: a new class of practical ligands for Rh-catalyzed asymmetric hydrogenation

[reaction: see text] The synthesis and application of a new family of air-stable, highly unsymmetrical ferrocene-based phosphine-phosphoramidites is described. The new ligands exhibit excellent enantioselectivities (over 99% ee) in the Rh-catalyzed asymmetric hydrogenation of enamides, dimethyl itaconate, and methyl (Z)-acetamidocinnamate even with high catalyst turnovers (S/C=10,000). The binaphthyl moiety is crucial for reactivity and enantioselectivity, and its absolute configuration plays a dominant role in determining the chirality of the hydrogenation products.     

Synthesis and diastereoselective catalytic hydrogenation of optically active cyclobutyl α,β-dehydro-α-dipeptides

Optically active cyclobutyl (Z)-α,β-dehydro-α-dipeptides have been efficiently synthesized through the coupling of conveniently protected glycine or (S)-phenylalanine residues with a (Z)-dehydro-α-amino acid derivative prepared, in turn, from (−)-verbenone as a chiral precursor. The alternative use of (R,R)- and (S,S)-Et–duphos–Rh as the hydrogenation catalyst led to the stereoselective production of both diastereomeric saturated dipeptides in each case. Thus, the chirality of the catalyst employed has been shown to be the factor governing the configuration of the newly created stereogenic centre. Regarding structural features, both NMR and CD data establish a marked conformational bias for both the unsaturated and the saturated peptides synthesized herein.     

Cobalt-Catalyzed Enantioselective Hydrogenation of Trisubstituted Carbocyclic Olefins: An Access to Chiral Cyclic Amides

The enantioselective hydrogenation of cyclic enamides has been achieved using an earth-abundant cobalt-bisphosphine catalyst. Using CoCl₂/(S,S)-Ph-BPE, several trisubstituted carbocyclic enamides were reduced with high activity and excellent enantioselectivity (up to 99 %) to the corresponding saturated amides. The methodology can be extended to the synthesis of chiral amines by base hydrolysis of the hydrogenation products. Preliminary mechanistic investigations reveal the presence of a high spin cobalt (II) species in the catalytic cycle. We propose that the hydrogenation of the carbon-carbon double bond proceeds via a sigma-bond-metathesis pathway.     

Divergent routes to chiral cyclobutane synthons from (-)-alpha-pinene and their use in the stereoselective synthesis of dehydro amino acids

Several polyfunctionalized cyclobutane derivatives have been synthesized using commercial (-)-alpha-pinene and (-)-verbenone as chiral precursors. Thus, oxidative cleavage of these compounds by using ruthenium trichloride afforded quantitatively (-)-cis-pinonic and (-)-cis-pinononic acids, respectively, without epimerization. These products were converted into several types of aldehydes, which are the key intermediates in the synthesis of cyclobutane dehydro amino acids via Wittig-Horner condensations with suitable phosphonates. These reactions are highly stereoselective, affording exclusively (Z) isomers, stereochemistry being assessed by NMR experiments. The obtained dehydro amino acids are polyfunctionalized molecules useful for the synthesis of other alpha-amino acids, with additional chiral centers, whose configuration must be induced by the chirality of the terpene employed as a precursor.     

Synthesis of 1,2-amino alcohols by sigmatropic rearrangements of 3-(N-tosylamino)allylic alcohol derivatives

Sigmatropic rearrangements of 3-(N-tosylamino)allylic alcohol derivatives, a particular subclass of functionalized enamides, have been investigated. Whereas the presence of the nitrogen atom alters the stereochemical outcome of Ireland-Claisen rearrangements of glycolates derived from such substrates, [2,3]-Wittig rearrangements of α-allyloxy acetamides or propargylic ethers derivatives provide access to a wide variety of functionalized 1,2-amino alcohols usually with high levels of stereocontrol, as well as to heterocyclic compounds. The stereoselectivity issues of these rearrangements (1,2-diastereoselectivity, auxiliary-induced diastereoselection, chirality transfer, and double stereodifferentiation) were thoroughly investigated.     

有机立体化学中若干术语和命名的讨论

本文对有机立体化学中若干基本术语作了介绍,指出了当前文献和教科书中某些使用不当的词汇。对“顺序规则”中用Ｒ／Ｓ系统指明构型使用过程中的敏感性能作了说明。     

Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl-2-hydroxymethylperhydro-1,3-benzoxazine derivatives

Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.     

Stereoselective alkene isomerization over one position

Although controlling both the position of the double bond and E:Z selectivity in alkene isomerization is difficult, 1 is a very efficient catalyst for selective mono-isomerization of a variety of multifunctional alkenes to afford >99.5% E-products. Many reactions are complete within 10 min at room temperature. Even sensitive enols and enamides susceptible to further reaction can be generated. Catalyst loadings in the 0.01-0.1 mol% range can be employed. E-to-Z isomerization of the product from diallyl ether was only <10(-6) times as fast as its formation, showing the extremely high kinetic selectivity of 1.     

Lewis base catalyzed aldol additions of chiral trichlorosilyl enolates and silyl enol ethers

[structures: see text] The consequences of double diastereodifferentiation in chiral Lewis base catalyzed aldol additions using chiral enoxysilanes derived from lactate, 3-hydroxyisobutyrate, and 3-hydroxybutyrate have been investigated. Trichlorosilyl enolates derived from the chiral methyl and ethyl ketones were subjected to aldolization in the presence of phosphoramides, and the intrinsic selectivity of these enolates and the external stereoinduction from chiral catalyst were studied. In the reactions with the lactate derived enolate, the strong internal stereoinduction dominated the stereochemical outcome of the aldol addition. For the 3-hydroxyisobutyrate- and 3-hydroxybutyrate derived enolates, the catalyst-controlled diastereoselectivities were observed, and the resident stereogenic centers exerted marginal influence. The corresponding trimethylsilyl enol ethers were employed in SiCl4/bisphosphoramide catalyzed aldol additions, and the effect of double diastereodifferentiation was also investigated. The overall diastereoselection of the process was again controlled by the strong external influence of the catalyst.     

Synthese stereoselective de dienes conjugues a partir d'alcools α-alleniques

The reaction of a Grignard reagent with an α-allenic phosphate leads exclusively in every studied case to 1,3-dienes. An high stereoselectivity is observed for the formation of both double bonds ; particularly, the organometallic species attacks preferentially in a trans direction from a groupe located on the terminal allenic carbon. In the case of the esters of secondary alcohols, it is more difficult to determine the factors which govern the stereochemistry of the other double bond. The Z configuration is then favored in the reaction phosphate + RMgX but the E configuration is predominant in the reaction acetate + R₂CuLi.     

Direct C?H Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct C? H functionalization of various enamides and enecarbamates was realized through visible‐light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)₂(dtbbpy)PF₆] as photocatalyst in combination with Na₂HPO₄, enamides such as N‐vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2‐bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C?C double bond in the E configuration could not be alkylated. Alkylation of N‐vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N‐vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron‐deficient bromides such as 3‐bromoacetyl acetate with N‐vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C?C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.     

Synthesis of Novel Pyrimidine Derivatives Containing the Vinylsulfanyl Group by Regio‐ and Stereoselective Addition of Thiouracils to Ethynyl Ketones

A regio‐ and stereoselective method for preparation of novel functionalized pyrimidine derivatives containing the vinylsulfanyl group has been developed based on addition reactions of 2‐thiouracils with phenylethynyl ketones. Reactions with ketones containing the disubstituted triple bond afford adducts of Z‐stereochemistry, whereas addition to ketone with the terminal triple bond gives preferentially products of E‐configuration.     

Asymmetric silaboration of terminal allenes bearing alpha-stereogenic centers: stereoselection based on "reagent control"

A highly enantioface-selective silaboration of allenes having stereogenic centers at the alpha-positions of the double bonds has been achieved using a combination of a chiral silylborane (-)-2 and a chiral Pd/(R)-3 catalyst. The chiral reagent system efficiently controlled the stereochemistry of the new stereogenic centers even in the reactions of mismatched combinations. [reaction: see text]     

Julia-Kocienski reaction-based 1,3-diene synthesis: aldehyde-dependent (E,E/E,Z)-selectivity

A new modification of Julia-Kocienski olefination reaction based on the use of cation-specific chelating agents that yields 1,3-dienes with predictable (E/Z)-selectivity on newly created double bond was developed. The influence of the aldehyde structure on reaction (E/Z) selectivity is discussed and rationalized.     

Stereoselective Synthesis of 8,12-Furanoeudesmanes from Santonin. Absolute Stereochemistry of Natural Furanoeudesma-1,3-diene and Tubipofurane

Ketobutenolide 3, easily obtained from santonin (1), has been transformed into two natural furanoeudesmanes 4 and 5, isolated from Commiphora molmol and Tubipora musica, respectively. trans- And cis-decalin systems were obtained by stereoselective reduction of the C(4)-C(5) double bond in 3 in the following way: hydrogenation of 3 over Pd/C followed by acidic treatment gave the cis isomer 10 as the major product; selective hydrogenation of the C(1)-C(2) double bond with the Wilkinson's catalyst followed by reduction with NaTeH yielded mainly the trans isomer 9. Compounds 9 and 10 were transformed into 4 and 5 in parallel sequences. Optical rotation and CD measurements of the synthetic products revealed that the stereochemistry of both natural products should be revised to their enantiomeric form.     

On the stereoselective hydrogenation of chiral cyclobutyl dehydro-amino acid derivatives: influence of the catalyst in the π-facial diastereoselection

Several optically active cyclobutyl dehydro-amino acid derivatives have been hydrogenated employing Wilkinson, (S,S)-chiraphos-Rh and Et-duphos-Rh (both enantiomers) as catalysts. The use of a chiral catalyst has been revealed to be crucial for the production of saturated amino acids with high stereoselectivity from substrates in which the chiral cyclobutyl unit is separated from the double bond by a methylene group.     

Total synthesis of (+)- and (-)-duryne: a potent anticancer agent from the marine sponge Cribrochalina dura. Establishment of the central double bond geometry and the absolute configuration of the chiral centers

Duryne is a C30 polyacetylenic alcohol with C2 symmetry. Despite its potent cytotoxicity, its central double bond geometry and the absolute configuration of the chiral centers were not determined. We report the total syntheses of both enantiomers of the anticancer natural product (+)-duryne and the establishment of its stereochemistry by synthesizing both geometric isomers. The natural (+)-duryne is identified as (15Z) and (3S,28S) as shown in structure 1. The autoxidation/Wittig coupling reaction was employed to synthesize the central (Z)-olefin. The stereochemistry of the (E)-alkene isomer was constructed stereoselectively by using LiAlH4 reduction of the corresponding alkyne. The absolute configurations of the chiral centers are established by using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase.