Stereoselective Step Research Articles

Stereoselective Synthesis of Tetrazole CB92834, a Potent Retinoid Compound.

Abstract An improved, convergent synthesis of CB92834 is relying on a Suzuki cross-coupling reaction and easily allows multigram-scale preparation of the compound. The approach features three highly stereoselective steps.

Utility of the Ammonia‐Free Birch Reduction of Electron‐Deficient Pyrroles: Total Synthesis of the 20S Proteasome Inhibitor, clasto‐Lactacystin β‐Lactone

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.

Stereoselective synthesis of tetrazole CB92834, a potent retinoid compound

An improved, convergent synthesis of CB92834 is relying on a Suzuki cross-coupling reaction and easily allows multigram-scale preparation of the compound. The approach features three highly stereoselective steps.

Catalytic asymmetric addition of β-keto phosphonates to an activated imine—formation of optically active functionalized phosphonate α-amino acid derivatives

The direct stereoselective addition of an activated imine to beta-keto phosphonates in the presence of chiral Lewis acid complexes is developed. The evaluation of different activated imines shows that an N-tosyl-alpha-imino ester adds in a diastereo- and enantioselective fashion to beta-keto phosphonates activated by especially chiral copper(II)-bisoxazoline complexes. An evaluation of Lewis acids, chiral ligands and reaction conditions, such as solvent, bases and other additives, shows that high yields, moderate diastereoselectivity and good enantioselectivity are obtained. The scope of the reaction is demonstrated for the reaction of beta-keto phosphonates and finally, the mechanism for the catalytic stereoselective step is presented.

Postulation of the mechanism of the selective synthesis of isotactic poly(methyl methacrylate) catalysed by [Zr[(Cp)(Ind)CMe2](Me)(thf)](BPh4): a Hartree-Fock, MP2 and density functional study.

The bridged. C1-symmetric, single-component zirconocene [Zr((Cp)(Ind)CMe2](Me)(thf)](BPh4) (Ind = indenyl, Cp = cyclopentadienyl) polymerises methyl methacrylate (MMA) selectively to isotactic poly(methyl methacrylate) (PMMA) without further cocatalysts or activators. To elucidate the stereoselective steps of the polymerisation of MMA by using this catalyst we studied the propagation steps occurring with the derivative [Zr[(Cp)(Ind)CH2][-O-C(OMe)=C(Me)(Et)](MMA)]+ by ab initio calculations at the Hartree-Fock(HF) level of theory. After the initiation step, which consumes the first two MMA molecules, each new catalytic cycle begins with the stereoselective addition of a new MMA molecule at the indenyl side of the zirconocene fragment. At the same time the enolate ring undergoes a stereoselective in-plane ring shift to the side opposite to the indenyl ring. These findings are used to postulate a mechanism for the polymerisation that explains the stereoselective synthesis of isotactic PMMA.

Unusual nonchelation controlled allylation of a N-monoprotected α-amino aldehyde: stereoselective entry to nonracemic trifluoromethyl dipeptide isosteres

An efficient synthesis of the non-racemic (66–68% e.e.) homoallylic β-trifluoromethyl β-amino alcohol (2S,3R)-9, a key intermediate in the synthesis of trifluoromethylated dipeptide isosteres and oligopeptides, was developed starting from N-Cbz-trifluoropyruvaldehyde-N,S-ketal (R)-1a. The correct syn-stereochemistry was achieved by combining two moderately stereoselective steps: (1) addition of allylmagnesium chloride to (R)-1a, occurring with unusual nonchelation control; (2) reductive desulfenylation of the phenylacetate 6 with NaBH4/pyridine.

Preparation of an A-ring building block for the total synthesis of 1α,25-dihydroxy vitamin D3 and structurally related congeners: lipase-catalyzed stereoselective esterification of a suitable epoxyalcohol

An useful A-ring building block for the total synthesis of vitamin D3 congeners, compound 7, has been prepared starting from vitamin D2 by a chemo-enzymatic approach that relies on lipase-catalyzed acylation in an organic solvent for the stereoselective step.

Living polymers Ab initio molecular dynamics study of the initiation step in the polymerization of isoprene induced by ethyl lithium

The polymn. of isoprene induced by alkyl lithium compds. in hydrocarbon solvents is known to proceed with a high stereoselectivity to (Z)-1,4-polyisoprene. We have studied the initiation step of this reaction with the help of ab initio mol. dynamics simulations based on d. functional theory. Specifically, we have investigated the reaction of isoprene with Et lithium and, by applying simulated annealing techniques, we have characterized the products of the initiation step and found a cis-isomer to be energetically most favorable. Several alternative reaction pathways have been characterized in detail in terms of their corresponding transition states and reaction products. For our model system, the cis-trans isomerization turns out to be rate detg. and, although the addn. reaction has a low barrier, it constitutes the stereoselective step. Our calcns. allow us to discriminate between different possible reaction mechanisms and give a rationalization for the high stereoselectivity. In this regard, lithium plays a crucial role by preferentially stabilizing specific structures through the formation of 'chelated' complexes and agnostic interactions. [on SciFinder (R)]

Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Coenzyme A thioester formation is reported to be the first step of chiral inversion of R-ibuprofen. In order to investigate the mechanism of this reaction adenylate derivatives of the ibuprofen enantionmers were synthesized chemically. R- and S-ibuprofenyl-adenylates as well as free acids were incubated with rat liver mitochondria in the presence of coenzyme A, MgCl 2 with or without ATP. The optical antipodes formed by inversion and the coenzyme A thioester derivatives of both enantiomers were found after incubation of both R- or S-ibuprofenyl-adenlyate and R-ibuprofen. By contrast, after incubation with S-ibuprofen neither R-enantiomer nor coenzyme A thioesters were detected. These experiments suggest that the formation of R-ibuprofenyl-adenylate may be the first stereoselective step of chiral inversion.

A short synthesis of apoyohimbines via a sulfolene based intramolecular Diels-Alder reaction

Allo-apoyohimbine and apoyohimbine have been synthesized in a short sequence of high yielding, stereoselective steps. The key step is an intramolecular Diels-Alder reaction, which under kinetically controlled conditions provides the required hexahydroisoquinoline D/E-ring intermediate, but under thermodynamic control gives a hydroisoindole system, via a conjugated diene.

Synthesis of a new branched chain hexopyranosyl nucleoside: 1-[2′,3′-dideoxy-3′-C-(hydroxymethyl)-α-D-erythro-pentopyranosyl]-thymine

A straightforward synthesis of the branched chain nucleoside 7 is described. This synthesis involves two stereoselective steps : introduction of the hydroxymethyl group on the sugar is achieved by radical cydization of the (bromomethyl)dimethylsilyl ether of the allylic alcohol 8; the condensation reaction with thymine as base moiety resulted exclusively in the formation of the α-anomer.

The gold(I)-catalyzed aldol reaction utilizing chiral ferrocenylamine ligands: Synthesis of N-benzyl-substituted ligands

The synthesis and characterization of (R)-N-{2-[(R)-N-2-hydroxy-1-propyl-N-benzyl]aminoethyl}-N-benzyl-1-[(S)-1′,2-bis(diphenylphosphino)ferrocenyl]ethyl amine (9) and selected carbamate esters is described. The stereoselectivity of the gold(I)-catalyzed reaction of benzaldehyde with methyl iso-cyanoacetate was compared using the N-benzyl-substituted versus the corresponding N-methyl-substituted ferrocenylamine ligands. The lower diastereo- and enantioselectivity obtained using the N-benzyl-substituted ferrocenylamine ligands is consistent with the transition-state model proposed for the stereoselective step of the gold(I)-catalyzed aldol reaction utilizing ferrocenylamine ligands possessing both central and planar chirality.

Homogeneous catalysis. Catalytic production of simple enols

Complexes of the type [Rh(diphosphine) (solvent) 2 ] + in dry acetone or tetrahydrofuran solutions are effective catalysts for generating synthetically useful quantities of simple enols from their corresponding allylic alcohols. A representative collection of simple enols has been produced, and the physical properties and stabilities are recorded. Although these catalysts also ketonize (tautomerize) the enols to their corresponding aldehydes and ketones, the simple enols are conveniently stable in solutions containing the milder catalysts. The mechanism of catalysis has been inferred from specific isotopic labeling experiments. The conclusions are as follows: the production of enols involves a hydrogen 1,3-shift mechanism involving hydrido-π-allylic intermediate. This process is also irreversible, and the stereoselective step is the α-hydrogen abstraction from the allylic substrate

ChemInform Abstract: Asymmetric Synthesis with Chiral Ferrocenylamine Ligands: The Importance of Central Chirality.

AbstractThe nature of the stereoselective step in the gold(I)‐catalyzed aldol reaction in the presence of the chiral ferrocenylamines (V) (a: (R),(S); b: (S),(R); c: (R),(R); d: (S),(S)) is investigated.

Total Synthesis Achieved Of N-Acetylneuraminic Acid

Two Yale University chemists have carried out the first total synthesis, from noncarbohydrate sources, of a complex, widely occurring sialic acid—N-acetylneuraminic acid, commonly known as NANA. Based on a series of highly stereoselective steps, the synthesis opens the way to systematic study of the role of structure and stereochemistry in the potent biological activity of sialic acids. Building on the synthesis, the Yale chemists also plan to attach appropriate sugar groups and other constituents to sialic acids, and thus obtain biologically important glycoproteins, oligosaccharides, and glycolipids. The synthesis was carried out by Michael P. DeNinno, a graduate student, and Samuel J. Danishefsky, Eugene Higgins Professor of Chemistry and chairman of Yale's department of chemistry. Their work is described briefly in the current issue of The Journal of Organic Chemistry [51, 2615 (1986)], and will be discussed in more detail in a forthcoming paper. Their research was supported by the National Institutes ...

Synthesis of anti‐9‐Bromo‐ and anti‐9‐Chlorobicyclo[4.2.1]nonatriene via Bicyclo[4.2.1]nonatriene→Bicyclo[4.2.1]nonatriene Rearrangement

AbstractThe first syntheses of 9‐bromo‐ and 9‐chlorobicyclo[4.2.1]nona‐2,4,6‐trienes were each achieved in three stereoselective steps from the 9,9‐bis(selenophenyl) derivative 9 in 79% overall yield for the bromide and 64% for the chloride. A deuterium‐labeling experiment reveals the first rearrangement of a bicyclo[4.2.1]nonatriene which leaves the ring system intact.

A Stereocontrolled Synthesis of the Pheromone 4‐Methyl‐3‐heptanol: Novel and Selective CC‐Linking Reactions

AbstractThe complete manuscript of this communication appears in: Angew. Chem. Suppl. 1982, 646. DOI:10.1002/anie.198206460

An improved preparation of some insect sex attractants: Synthesis and separation of geometrical isomers by formation of urea complexes

Wittig condensations of aldehydes or ketones with phosphonium salts are frequently used methods for the syntheses of straight-chain or branched alkenes. Suitable choice of reaction conditions may provide the desired geometrical isomer as reaction product. However, we have found that mixtures of geometrical isomers can be conveniently separated on a large scale by the relatively inexpensive method of urea inclusion complex formation. The recovery of both isomers from the separation procedure is almost quantitative. Urea inclusion complexes are formed preferentially withE isomers. Formation of the inclusion complex is affected by the skeletal structure and by the nature of the terminal functional group. By applying this method of separation at a convenient stage, several insect pheromones were prepared without the necessity of a stereoselective step. The technique was used for syntheses of (Z)-11-hexadecenal and (Z)-9-tetradecenal (components of theHeliothis virescens pheromone) and for the synthesis of candidate attractants possessing a trisubstituted double bond.