Diastereoselective Alkylation Research Articles

ChemInform Abstract: Stereoselective Synthesis of Functionalized Pyroglutamates.

AbstractA highly diastereoselective alkylation of threonine‐based oxazoline (I) becomes possible with Baylis—Hillman‐derived allyl bromides or Baylis—Hillman acetates.

Diastereoselective alkylation reactions of 1-methylcyclohexa-2,5-diene-1-carboxylic acid

The deprotonation and alkylation of 1-methylcyclohexa-2,5-diene-1-carboxylic acid has been investigated under a range of conditions. In all cases, the formation of compounds 14 was found to be completely stereoselective, although compound 14c was formed as an impurity when alkyl iodides were used as electrophiles, and doubly-alkylated compounds 17 were formed in some cases when alkyl bromides were used.

Synthesis of (L)-4-Fluorotryptophan

A new synthesis of stereochemically pure (L)-4-fluorotryptophan [i.e., (2S)-4-fluorotryptophan] in seven steps from 4-fluoroindole is described. A key reaction in the synthetic strategy is a diastereoselective alkylation of the Schollkopf chiral auxiliary with a fluorinated electrophile. All reaction steps are efficient and proceed in at least 80% yield.

The Diastereoselective Alkylation of Arenesulfenate Anions Using Homochiral Electrophiles

A series of Boc-protected β-amino sulfoxides were prepared by the reaction of arenesulfenate anions with chiral Boc-protected β-amino iodides. The stereoselective substitution reaction is believed to arise through precoordination of the sulfenate counterion with the nitrogen lone pair of the electrophile.

Stereoselective synthesis of (3 S,5 S,6 S)-tetrahydro-6-isopropyl-3,5-dimethylpyran-2-one; a C5-epimer of a component of a natural sex pheromone of the wasp Macrocentrus grandii, the larval parasitoid of the European corn borer Ostrinia nubilalis

(3 S,5 S,6 S)-Tetrahydro-6-isopropyl-3,5-dimethylpyran-2-one, a C5-epimer of a component of the natural sex pheromone of the wasp Macrocentrus grandii, the larval parasitoid of the European corn borer Ostrinia nubilalis, was synthesized starting from methyl l-valinate. The transformation includes a Kulinkovich cyclopropanation reaction, a cationic cyclopropyl-allyl rearrangement of cyclopropyl methanesulfonate, a diastereoselective alkylation of Oppolzer’s ( N-propionyl)-(2 R)-bornane-10,2-sultam and a diastereoselective hydrogenation using Wilkinson’s catalyst as the key steps.

ChemInform Abstract: Asymmetric Synthesis of α‐Methyl‐α‐amino Acids via Diastereoselective Alkylation of (1S)‐(+)‐3‐Carene Derived Tricyclic Iminolactone (V).

ChemInform Abstract: Asymmetric Synthesis of α‐Methyl‐α‐amino Acids via Diastereoselective Alkylation of (1S)‐(+)‐3‐Carene Derived Tricyclic Iminolactone (V).

An Access to Chiral β-Benzyl-γ-butyrolactones and Its Application to the Synthesis of Enantiopure (+)-Secoisolariciresinol, (-)-Secoisolariciresinol, and (-)-Enterolactone

Both enantiomers of secoisolariciresinol and enantiopure (-)-enterolactone were synthesized through a highly stereoselective convergent synthesis. An Evans diastereoselective alkylation followed by a substrate-induced diastereoselective α-alkylation of the newly formed optically active β-benzyl-γ-butyrolactone gave the β-β′ linkage of the target skeleton. The (S,S)- and (R,R)-enantiomers of secoisolariciresinol and (-)-enterolactone were obtained in 12-14% (11 steps) and 20% (7 steps) overall yield, respectively.

Asymmetric Synthesis of α-Methyl-α-Amino Acids via Diastereoselective Alkylation of (1S)-(+)-3-Carene Derived Tricyclic Iminolactone

A novel carene-based alanine-equivalent tricyclic iminolactone 16 has been synthesized via stereoselective dihydroxylation of the double bond, IBX oxidation of the secondary alcohol, esterification of the tertiary alcohol, deprotection of the resulting ester, and subsequent cyclization from commercially available (1S)-(+)-3-carene in 79% overall yield. The iminolactone 16 demonstrated high reactivity toward alkylation with a wide range of electrophiles at room temperature under phase-transfer catalysis conditions. The alkylated products were produced with excellent diastereoselectivities (>98% de) in good isolated yields (86-94%). High yields (83-91%) of optically pure (S)-α-methyl-α-substituted-α-amino acids were obtained by basic hydrolysis of the dialkylated iminolactones with the recovery of the chiral auxiliary 15 (78-87%).

Diastereoselective alkylation of chiral glycinate derivatives containing the a-phenylethyl group.

Novel chiral glycinate derivatives (S)-6 and (S)-7 contain- ing the a-phenylethyl group, were prepared and studied as potential precursors of enantiopure a-substituted-a-amino acids. In particu- lar, the alkylation of enolate (S)-7-Li showed substantial (78:22 dr) stereoinduction by the N-(1-phenylethyl)benzamide chiral auxiliary. Addition of DMPU showed no appreciable effect upon the diastere- oselectivity.

ChemInform Abstract: Catalytic Asymmetric 6π‐Electrocyclization: Accessing Highly Substituted Optically Active 2‐Pyrazolines via Diastereoselective Alkylations.

AbstractThe chiral phosphinic acid BPN catalyzes the 6π‐electrocyclization of hydrazones to give 2‐pyrazolines in high yield and generally good to excellent e.e.

A novel strategy toward the synthesis of N-(β-glycosyl)asparagines based on the alkylation of ethyl nitroacetate using N-(β-glycosyl)iodoacetamides

A conceptually novel strategy has been developed for the synthesis of N-(β-glycosyl)asparagine precursors in good yield by the alkylation of ethyl nitroacetate using six per-O-acetylated N-(β-glycosyl)iodoacetamides derived from mono- and disaccharides. The use of a chiral organocatalyst, N-(9-anthracenylmethyl)cinchoninium chloride (10 mol %), resulted in diastereoselective alkylation up to 64% de. Single crystal structure analysis of the purified major diastereomer of the Glc derivative revealed an absolute configuration of S at the α-carbon of the monosubstituted ethyl nitroacetate which is a precursor of the l-asparagine conjugate.

ChemInform Abstract: Highly Regio- and Diastereoselective Friedel-Crafts Alkylation of Phenols. Synthesis of 2-Hydroxymandelic Esters.

Abstract Ortho-hydroxyalkylation of phenol substrates was performed via coordinative complexes of metal phenolates with chiral glyoxylates: optically active 2-hydroxymandelic esters have been obtained with good yields and very high diastereoselectivity (up to 94% d.e.).

ChemInform Abstract: Diastereoselective Alkylation of Chiral Tin(II) Enolates onto Cyclic Acyl Iminium Ions. Asymmetric Total Synthesis of (-)-Supinidine.

Abstract The scope and mechanism of the asymmetric alkylation of chiral tin (II) enolate 10 with cyclic acyl iminium ion 5 were investigated. An application of the reaction to the asymmetric synthesis of (-)-supinidine was also achieved.

ChemInform Abstract: Diastereoselective Alkylation of Carbanions Derived from 1,3- Oxathianes.

Abstract Carbanions derived from 4-substituted-1,3-oxathiolane and oxathiane were studied. The magnesium anion of 2-phenyl-4-t-butyldiphenylsilyloxy-1,3- oxathiane reacts with benzaldehyde to give the benzhydrol adduct in a seven to one ratio of diastereoisomers. It was also found that solvent had an effect on site of metalation and in ether 2-phenyl-4-dimethylamino-1,3-oxathiane reacts with s-butylithium to give ortho metalation. The resulting anion reacts with benzaldehyde to give a 4:1 ratio of diastereoisomers.

ChemInform Abstract: Highly Diastereoselective Alkylation of 6-Methylperihydropyrimidin-4- ones Directed Towards the Synthesis of α-Substituted β- Amino Acids.

Abstract The highly diastereoselective alkylation of 6-methylperihydropyrimidin-4-ones 1 and 2 has been reported. The corresponding lithium enolates have been alkylated under a variety of conditions with good trans selectivity and all the reaction products have been easily separated and characterised.

ChemInform Abstract: Synthesis of (S)-α-Methylaspartic Acid by Diastereoselective Alkylation of a Chiral 2-Cyanopropanoate.

ChemInform Abstract: Synthesis of (S)-α-Methylaspartic Acid by Diastereoselective Alkylation of a Chiral 2-Cyanopropanoate.

Stereoselective synthesis of the C1–C13 fragment of bistramide A

The C1–C13 fragment of bistramide A was prepared from 5-hexenoic acid in 15 linear steps and in 16% overall yield. The core 2,6-trans-tetrahydropyran ring was obtained via a kinetically controlled oxa-Michael cyclization from the corresponding chiral α,β-unsaturated hydroxyester. This precursor was prepared by using a diastereoselective alkylation reaction using Davies Superquat auxiliary and a diastereoselective Roush’s allylboration as key steps.

ChemInform Abstract: Chiral N-Acyl-tert-butanesulfinamides: The “Safety-Catch” Principle Applied to Diastereoselective Enolate Alkylations.

Diastereoselective enolate alkylation reactions of N-acylsulfinamides and conversion of the alkylation products to a variety of enantiopure products are reported. Several sulfinamides were prepared in solution followed by acylation to provide N-acylsulfinamides. The N-acylsulfinamides were then evaluated in diastereoselective enolate alkylation reactions. Of the sulfinamides evaluated, tert-butanesulfinamide provided the highest diastereoselectivity. To establish the potential utility of sulfinamides as versatile auxiliaries, methods were developed for (1) the racemization-free acylation of tert-butanesulfinamide to prepare optically pure N-acyl-tert-butanesulfinamides, (2) the diastereoselective C-alkylation of N-acyl-tert-butanesulfinamides, (3) the conversion of the N-acyl-tert-butanesulfinamides to the active ester equivalent by N-alkylation and S-oxidation, and (4) the cleavage of the N-alkyl-N-acyl-tert-butanesulfonamides to give chiral alcohol, ester, amide, and carboxylic acid target compounds. These studies provide the groundwork for the development of sulfinamides as dual chiral auxiliaries and linkers for the multistep solid-phase synthesis of enantioenriched compounds.

ChemInform Abstract: The Formal Total Synthesis of Epothilone A.

The formal total synthesis of epothilone A is described. The key steps in the synthesis of the northern hemisphere are a Z-selective ten-membered ring-closing metathesis reaction (RCM) and the diastereoselective alkylation at C8. Aldehyde 3 is formed by introduction of the thiazole moiety by a Wittig reaction and subsequent functional group transformation. An efficient route to keto acid 5 is described.

ChemInform Abstract: Synthesis of Enantiomerically Pure cis-2,4-Disubstituted Piperidines: Extension of Chiral Homoenolate Alkylations Toward the Preparation of Nitrogen Heterocycles.

Abstract Enantiomerically pure cis -2,4-disubstituted piperidines were synthesized from chiral thiolactam 2 in six steps via a highly diastereoselective homoenolate alkylation which set the stereochemistry at the C4 carbon. In addition, two cleavage methods were used to cleave the lactam to the desired piperidines with a high level of diastereoselection at the newly created C2 stereocenter.