Diastereoselective Conjugate Addition Research Articles

ChemInform Abstract: Regio‐ and Diastereoselective Conjugate Addition of Grignard Reagents to Aryl Substituted α,β‐Unsaturated Carbonyl Compounds Derived from Oppolzer′s Sultam.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective Synthesis of a Mealybug Pheromone with an Irregular Monoterpenoid Skeleton

The first enantioselective synthesis of a mealybug sex pheromone with an unprecedented monoterpenoid skeleton has been accomplished by using a highly diastereoselective conjugate addition of an organocopper reagent to a gamma-alkyl-alpha,beta-unsaturated ester intermediate as the key step.

Antileukemic activity of aminoparthenolide analogs

A series of aminoparthenolide analogs have been synthesized through a diastereoselective conjugate addition of several primary and secondary amines to the α-methylene-γ-butyrolactone function of the very lipophilic sesquiterpene lactone, parthenolide. Seventeen of the above amines derivatives were evaluated in a full panel of 60 cancer cell lines for anticancer activity. Compound 12, derived from tyramine, was found to be cytostatic as well as cytotoxic toward acute lymphoblastic leukemia cells (ALL, CCRF-CEM) at nanomolar concentrations, while the ( R)-(1,2,3,4-tetrahydro-1-naphthyl)amino derivative 9 was found to be cytostatic toward human anaplastic large T-cell lymphoma (SR) cells at concentrations below 10 nM.

Regio- and diastereoselective conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds derived from Oppolzer's sultam

Asymmetric conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds ( 1) has been achieved with great regioselectivity (>20:1) and good to excellent diastereoselectivity (de up to 98%). The nucleophilicity and stereospecific blockade of the Grignard reagents play a key role in controlling the regioselectivities and diastereoselectivities of the conjugate addition reaction.

Application of rhodium-catalyzed cyclohydrocarbonylation to the syntheses of enantiopure homokainoids

Kainic acid, rigidified (S)-glutamic acid, is a well-known kainite receptor agonist for the excitatory transmission in the central nerve system. Our interest in highly selective kainite ligands, prompted us to design a series of new kainic homologues, "homokainoids", i.e., conformationally rigidified (S)-glutamic acids. For the syntheses of enantiopure novel homokainoids (pipecolinoglutamic acids), we successfully applied cyclohydrocarbonylation (CHC) reaction that has been developed in these laboratories. Efficient total syntheses of enantiopure novel homokainoids from (R)-serine feature the highly diastereoselective conjugate addition and the regioselective CHC process in the key steps.

Enantioselective Synthesis of the Hydroazulene Core of 3α‐Hydroxy‐15‐rippertene

AbstractAs part of a project directed toward the total synthesis of the tetracyclic diterpene 3α‐hydroxy‐15‐rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved by starting from (–)‐isopulegol. A regio‐ and diastereoselective formal hydromethallylation and a regioselective ring expansion served as the key steps in the formation of the seven‐membered ring. Completion of the bicyclic title compounds was then achieved by cyclopentene annulation through diastereoselective conjugate addition of organocuprates and subsequent intramolecular aldol condensations.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Diastereoselective Conjugate Addition of Organoboron Nucleophiles

The stereoselectivity of the addition of boronic acids to conjugated systems bearing an oxygen at the γ-position was shown to be completely selective for the anti product (3, 5 and 7). The conformation of the alkene did not influence the stereochemical outcome, as both E- and Z-enoates gave the anti product. Furthermore, protection of the hydroxyl group was shown to be unnecessary.

Asymmetric synthesis of N, O, O, O-tetra-acetyl d- lyxo-phytosphingosine, jaspine B (pachastrissamine) and its C(2)-epimer

The highly diastereoselective conjugate addition of lithium ( S)- N-benzyl- N-(α-methylbenzyl)amide to a γ-silyloxy-α,β-unsaturated ester and in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine has been used as the key step in the asymmetric synthesis of N, O, O, O-tetra-acetyl d- lyxo-phytosphingosine, jaspine B (pachastrissamine) and its C(2)-epimer.

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Abstract In this account, new methods for the catalytic and stereoselective conjugate addition of terminal alkynes are described. Our laboratories have disclosed asymmetric addition reactions to aldehydes and imines using a combination of a zinc or copper salt and a terminal alkyne. Under these conditions, terminal alkyne is transformed in situ into an alkynyl metal species. Recently, it was found that these in situ generated alkynyl metal species can undergo conjugate additions to alkylidene malonate-type acceptors. In the zinc(II) triflate-catalyzed system, a highly diastereoselective conjugate addition has been realized using a chiral oxazepene acceptor. Subsequently, alternative conjugate addition protocols have been developed which employ a terminal alkyne, substoichiometric amounts of copper and a highly eletrophilic Meldrum’s acid derived acceptor. This reaction can be made enantioselective using a novel atropisomeric P,N-ligand (PINAP). With this ligand, excellent enantioselectivities can be achieved for the conjugate addition of aromatic alkynes to various Meldrum’s acid derived acceptors.

Highly Diastereoselective Conjugate Addition of Aryllithium to Chiral β‐Nitrostyrene Derivative: An Application to the Asymmetric Synthesis of 4‐Aryl‐1,2,3,4‐tetrahydroisoquinoline.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Asymmetric synthesis of β-substituted Baylis–Hillman products via lithium amide conjugate addition

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis–Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium ( R)- N-methyl- N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe) 3 and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis–Hillman products in good yield and high de and ee.

Diastereoselective Conjugate Addition of Organocuprates to 3,4‐Dimethyl‐5,6‐dihydro‐2(1H)‐pyridinones. A Concise Synthesis of trans‐3,4‐Dimethyl‐4‐phenylpiperidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Asymmetric synthesis of 3,4-anti- and 3,4-syn-substituted aminopyrrolidines via lithium amide conjugate addition

The diastereoselective conjugate addition of homochiral lithium amides to methyl 4-(N-allyl-N-benzylamino)but-2-enoate has been used as the key step in a simple and efficient protocol for the preparation of 3,4-substituted aminopyrrolidines. This protocol provides a complementary and stereoselective route to both anti- and syn-3-amino-4-alkylpyrrolidines as well as anti- and syn-3-hydroxy-4-aminopyrrolidines, in high de and ee viabeta-amino enolate functionalisation. This methodology has been applied to the synthesis of anti-(3S,4S)- and syn-(3R,4S)-3-methoxy-4-(N-methylamino)pyrrolidine.

Asymmetric synthesis of β-amino-γ-substituted-γ-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.

Highly Diastereoselective Conjugate Addition of Aryllithium to Chiral β-Nitrostyrene Derivative: An Application to the Asymmetric Synthesis of 4-Aryl-1,2,3,4-tetrahydroisoquinoline

Abstract Highly diastereoselective conjugate addition of aryllithium to β-nitrostyrene derivative, having chiral acetal moiety derived from (S,S)-1,2-bis(1-hydroxypropyl)benzene, was achieved. The adduct was transformed to 4-aryl-1,2,3,4-tetrahydroisoquinoline in high enantiomeric excess (ee).

Diastereoselective Conjugate Addition of Organocuprates to 3,4-Dimethyl-5,6-dihydro-2(1H)-pyridinones. A Concise Synthesis of trans-3,4-Dimethyl-4-phenylpiperidines

[reaction: see text] Conjugate addition of aryl or alkyl cuprates to 3,4-dimethyl-5,6-dihydro-2(1H)-pyridinones led to diastereoisomerically pure 3,4,4-trisubstituted 2-piperidinones in 39-78% yields. The yields and the diastereochemistry of piperidinones depended on both the N-protecting group and the organocuprate. Reduction then deprotection of the trans-3,4-dimethyl-4-phenyl product provided the corresponding piperidine, analogue of a key precursor of opioid receptor antagonists.

A new route to keto and alkyl derivatives of (R)-carvone via diastereoselective conjugate addition of nitronate ions

The reactivity and diastereoselectivity of conjugate addition of different nitronates ions to (R)-carvone was systematically studied. The Michael adducts 2a-e were obtained in good yield and 3,2-cis-3,5-trans selectivity. The nitroadducts 2b,c were transformed via Nef reaction into (R)-carvone ketone derivatives 9,10 and nitroadducts 2b,d led to (R)-carvone alkylated derivatives 11,12, via a denitration reaction.

Diastereoselective Conjugate Addition of Cyanide to α,β‐Unsaturated Oxazolidinones: Enantioselective Synthesis of ent‐Pregabalin and Baclofen.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing ( R)-β-amino butyric acid, ( R)-β-amino pentanoic acid, ( S)-β-leucine, ( R)-β-amino octanoic acid, ( S)-β-phenylalanine, ( S)-β-tyrosine methyl ether, ( S)-β-tyrosine hydrochloride and ( S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products ( R)-β-DOPA and ( R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.

A new asymmetric synthesis of (+)-12 b-epidevinylantirhine

We report a new asymmetric synthesis of the indole alkaloid derivative (+)-12 b-epidevinylantirhine through stereoselective cyclization of a tethered indole nucleus onto an N-acyliminium ion intermediate, generated from a readily available non-racemic bicyclic lactam building block, and subsequent template modification through a highly diastereoselective conjugate addition protocol. In addition, we present the first X-ray crystal structure of this indole target.