Enolate Alkylation Research Articles

Stereoselective Palladium-Catalyzed Allylic Alkylation of Peptide Enolates

Stereoselective Palladium-Catalyzed Allylic Alkylation of Peptide Enolates

Angucyclinone Antibiotics: Total Syntheses of YM-181741, (+)-Ochromycinone, (+)-Rubiginone B2, (−)-Tetrangomycin, and MM-47755

A concise and highly enantioselective route has been developed for the synthesis of angucyclinone-type natural products. Utilizing this strategy, total syntheses of five natural products YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755 have been accomplished in 22%, 23%, 19%, 18%, and 12% overall yields, respectively. Our approach for the synthesis of these natural products having the benz[a]anthraquinone skeleton is based on a sequential intramolecular enyne metathesis, intermolecular Diels-Alder reaction (DAR), and aromatization. The intramolecular enyne metathesis reaction was employed for the synthesis of enantiopure 1,3-dienes in excellent yields. Furthermore, the synthesis of YM-181741 as well as structurally similar angucyclinones such as (+)-ochromycinone and (+)-rubiginone B2 was achieved via asymmetric enolate alkylation of an oxazolidinone in excellent de. The related angucyclinones (-)-tetrangomycin and MM-47755, bearing a labile tertiary alcohol, were synthesized via Sharpless asymmetric epoxidation of a known allylic alcohol followed by opening the epoxide with Red-Al. The introduction of oxygen functionality at C-1 in all these natural products was accomplished by photooxygenation under a positive pressure of oxygen.

Role of the Countercation in Diastereoselective Alkylations of Pyramidalized Bicyclic Serine Enolates. An Easy Approach to α-Benzylserine

The use of a chiral serine equivalent as an excellent chiral building block has been demonstrated in the synthesis of alpha-benzylserine through a diastereoselective lithium enolate alkylation reaction and subsequent acid hydrolysis. The role of a coordinating countercation (lithium) in the alkylation reaction has been investigated. Theoretical studies have been performed in order to elucidate the stereochemical outcome of the alkylation process, which occurs with total retention of configuration.

Enantioselective Synthesis of α‐Tertiary Hydroxyaldehydes by Palladium‐Catalyzed Asymmetric Allylic Alkylation of Enolates.

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.

An Approach to Cyclic α‐Amino Acids by a Novel Hetero Diels—Alder/Intramolecular Hydantoin Enolate Alkylation Strategy: An Approach to Halichlorine.

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.

Ring Reversal of a Spirocyclic Patchouli Odorant: Molecular Modeling, Synthesis, and Odor of 6‐Hydroxy‐1,1,6‐trimethylspiro[4.5]decan‐7‐one

AbstractMolecular modeling calculations on the recently discovered high‐impact patchouli odorant (+)‐(1S,4R,5R,9S)‐1‐hydroxy‐1,4,7,7,9‐pentamethylspiro[4.5]decan‐2‐one (1) indicated that ring reversal of the spirocyclic system should lead to molecules in which two of the five methyl substituents could be spared without significantly affecting the overall shape or conformational equilibrium. Intramolecular ene reactions promised simple access to the desired target compound,(5R*,6R*)‐6‐hydroxy‐1,1,6‐trimethylspiro[4.5]decan‐7‐one(2), but all attempts failed utterly. The elaborated alternative six‐step synthesis of target structure 2 commenced with the addition of HCl gas to 5‐bromo‐2‐methyl‐2‐pentene (16), giving 1‐bromo‐4‐chloro‐4‐methylpentane (15). Spiroannulation of cyclohexanone with this building block by TiCl4‐mediated alkylation of the TMS enolate 14 and subsequent cyclization by means of tBuOK afforded 1,1‐dimethylspiro[4.5]decan‐6‐one (12). The reaction of this spirocyclic ketone with MeLi furnished the corresponding tertiary alcohol 17, which was dehydrated by Appel–Lee bromination with concomitant dehydrohalogenation. The resulting alkene mixture containing 1,1,6‐trimethylspiro[4.5]dec‐6‐ene (4) as the major component was subjected to the ketohydroxylation method developed by Plietker to provide, after repeated chromatography, target compound 2 in 33 % yield. To study the influence of the gem‐dimethyl position on the olfactory properties, the analogous spirocyclic 2,2,6‐trimethylketone 22 was also synthesized. Spiroannulation of cyclohexanone with 1,4‐dibromo‐2,2‐dimethylbutane (18), with the use of 2.2 equiv. tBuOK as base, furnished 2,2‐dimethylspiro[4.5]decan‐6‐one (19). The reaction of 19 with MeLi and subsequent Appel–Lee bromination/dehydrohalogenation led to an isomeric mixture containing 2,2,6‐trimethylspiro[4.5]dec‐6‐ene (21) as the main component. The ketohydroxylation method according to the protocol of Plietker concluded the synthesis of the second target structure 22. In contrast to methyl carbinol 17, which has a typical woody‐earthy patchouli odor, the odor of target molecule 2 was displaced towards the camphoraceous and minty side. The 2,2,6‐trimethylalcohol 20 emanated a camphoraceous and vetiver‐type note, while the second target molecule, 22, was only weakly woody, cedar‐like, and powdery in smell.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates

Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates

Theoretical Evidence for Pyramidalized Bicyclic Serine Enolates in Highly Diastereoselective Alkylations

A new chiral serine equivalent and its enantiomer have been synthesized from (S)- and (R)-N-Boc-serine methyl esters (Boc: tert-butyloxycarbonyl). The use of these compounds as chiral building blocks has been demonstrated in the synthesis of alpha-alkyl alpha-amino acids by diastereoselective potassium enolate alkylation reactions and subsequent acid hydrolyses. Theoretical studies were performed to elucidate the stereochemical outcome of both the formation of five-membered cyclic N,O-acetals and the subsequent alkylation process, which occurs with total retention of configuration. This feature could be explained in terms of the high degree of pyramidalization of enolate intermediates.

Asymmetric Total Synthesis and Formal Total Synthesis of the Antitumor Sesquiterpenoid (+)-Eremantholide A

[structure: see text]. A new asymmetric total synthesis of (+)-eremantholide A is reported in which a Hoveyda-Grubbs ring-closing metathesis (RCM) reaction is used to assemble the nine-membered oxonin ring, and an enolate alkylation between the 3(2H)-furanone 2 and O-triflate 3 is exploited for C(9)-C(10) bond construction. An Evans asymmetric aldol reaction and a Sharpless asymmetric epoxidation served to stereoselectively install the C(6), C(7), and C(8) stereocenters of the target structure.

Conjugate Addition of 2- and 4-Pyridylcuprates: An Expeditious Asymmetric Synthesis of Natural (−)-Evoninic Acid

[reaction: see text] The scope and limitations of the conjugate addition of 2- and the first 4-pyridyl Gilman homocuprates to various alpha,beta-unsaturated Michael acceptors are delineated. The conjugate addition of the cuprate of 2-bromo-3-methylpyridine to (E)-methyl crotonate then diastereoselective enolate alkylation and lipase-mediated enantioselective ester hydrolysis have enabled an efficient four-step first asymmetric synthesis of the Celastraceae sesquiterpenoid esterifying ligand (-)-(1'S,2'S)-evoninic acid.

Asymmetric Total Syntheses of (+)-3-(Z)-Laureatin and (+)-3-(Z)-Isolaureatin by “Lone Pair−Lone Pair Interaction-Controlled” Isomerization

The first asymmetric total syntheses of the dihalogenated medium-sized dioxabicyclic marine natural products (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2) have been accomplished. Notable features of the highly stereo-, regio-, and chemoselective syntheses of these alpha,alpha'-trans-oxocene natural products include an intramolecular amide enolate alkylation to construct the alpha,alpha'-cis-oxocene, novel "lone pair-lone pair interaction-controlled" epimerizations to the alpha,alpha'-trans-oxocenes, various strategies for stereoselective introduction of halogen atoms, and novel olefin cross-metatheses for construction of the (Z)-enyne systems.

Dichlorocarbene Adducts of Alkyl Enol Ethers as Precursors to Furans: Application to a Total Synthesis of the Furanosesquiterpene (.+‐.)‐Pallescensin A.

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 β2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives

Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium beta-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2'-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of beta-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of beta-amino-beta'-hydroxy N-acyl oxazolidinones.

On the origins of diastereoselectivity in the alkylation of diketopiperazine enolates

High levels of diastereoselectivity are observed for benzylation of the lithium enolates of (S)-N,N′-bis-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-dione, (S)-N(1)-para-methoxybenzyl-N(4)-methyl-3-iso-propyl-piperazine-2,5-dione and (S)-N(1)-methyl-N(4)-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-dione. These data suggest that the high diastereofacial selectivity observed for alkylation of these diketopiperazine templates is mainly a consequence of the relay of stereochemical information from C(3) to C(6) via the influence of 1,2-torsional strain introduced by the N-alkyl substituents, rather than through minimisation of steric interactions alone.

Substrate-Controlled Formal Synthesis of (+)-Laurenyne by a Chemoselective Chelation-Controlled Alkylation Strategy

A substrate-controlled formal synthesis of (+)-laurenyne has been accomplished featuring a highly stereoselective chemoselective chelation-controlled amide enolate alkylation for synthesis of the α,α'-syn-bis-alkene without resorting to use of a chiral auxiliary.

Diastereoselective synthesis of quaternary α-amino acids from diketopiperazine templates

Sequential enolate alkylations of (S)-N(1)-methyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one and (S)-N(1)-p-methoxybenzyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one proceed with excellent levels of diastereoselectivity (>90% de) affording quaternary alpha-amino acids in high enantiomeric excess (>98% ee) after deprotection and hydrolysis.

Enantioselective Synthesis of α-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates

Chiral α-tertiary hydroxyaldehydes are very versatile building blocks in synthetic chemistry. Herein, we report the first examples of a catalytic asymmetric protocol for the synthesis of such compounds from readily available α-halo or α-hydroxy ketones or enol silyl ethers with excellent yields and enantioselectivity. Its synthetic utility is demonstrated in the short, efficient formal synthesis of (S)-oxybutynin. In this process, the chiral ligand controls the regioselectivity as well as the enantioselectivity.

Enantioselective Synthesis of α‐Terpineol and Nephthenol by Intramolecular Acyloxazolidinone Enolate Alkylations.

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.

Stereospecific and Stereodivergent Construction of Tertiary and Quaternary Carbon Centers through Switchable Directed/Nondirected Allylic Substitution

This study introduces the ortho-diphenylphosphanylbenzoate (o-DPPB)/o-DPPB oxide system as a switchable directing/nondirecting leaving group in a copper-mediated allylic substitution with Grignard and organozinc reagents. With this system, the regioselective, stereospecific, and stereodivergent construction of quaternary as well as tertiary carbon centers is possible in a reliable and predictable fashion. Starting from one substrate enantiomer, both optical antipodes of the substitution products are readily available. Hence, this methodology features reversed polarity in comparison to established enolate alkylation chemistry and may be an interesting alternative, particularly for the construction of quaternary stereogenic carbon centers.

An alkylation route to carbo- and heteroaromatic amino acids

Amino acids carrying aromatic carbo- and heterocycles in the side chain, such as naphthyl-, biphenyl- and pyridylalanines, have been prepared by alkylation of a glycine enolate with a haloalkyl carbocycle or heterocycle, with enantiomeric excess up to 87% using the ephedrine amide protocol.