Formal Asymmetric Synthesis Research Articles

Practical Racemic and Asymmetric Formal Total Syntheses of the Homocamptothecin Derivative and Anticancer Agent Diflomotecan via Tertiary Homoallylic Alcohols as Masked Aldol Equivalents

An efficient and scalable racemic as well as an asymmetric to the key building block for the synthesis of homocamptothecin and derivatives thereof such as the potent anticancer agent diflomotecan (4) are described. In the asymmetric route, the pyridone ring was assembled applying straightforward carbonyl chemistry. The selective generation of the quaternary stereocenter was accomplished by self reproduction of chiral information starting from (S)-2-hydroxybutyric acid (22) utilizing an allyl moiety to act as a masked carbonyl group. The optically pure DE building block (7) (er > 99.95: 0.05) was obtained in 9.0% overall yield over 10 steps (two chromatographic purifications). The asymmetric de novo pyridone approach has the potential to serve as the basis for a technical synthesis of diflomotecan.

Intramolecular biaryl coupling reaction of benzyl benzoate and phenyl benzoate derivatives, and its application to the formal synthesis of (−)-steganone

Construction of the biaryl moiety of stegane and related compounds through an intramolecular biaryl coupling reaction is described. Undesired products were obtained by the intramolecular coupling reaction of benzyl benzoates ( 8, 13, and 14) because of their steric and electrostatic properties, and only that of phenyl benzoates ( 26b and 26c) afforded the desired biaryl lactones in good yields. An asymmetric formal synthesis of the title compound has been achieved using an enantioselective lactone-opening reaction followed by a four-step conversion to the known compound.

Organocatalytic Conjugate Addition of Malonates to α,β‐Unsaturated Aldehydes: Asymmetric Formal Synthesis of (‐)‐Paroxetine, Chiral Lactams, and Lactones.

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.

Organocatalytic Conjugate Addition of Malonates to α,β‐Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−)‐Paroxetine, Chiral Lactams, and Lactones

Einfach und effektiv: Die Anwendungsbreite der Titelreaktion wird mit der Synthese chiraler Lactone und Lactame aufgezeigt, von denen letztere eine Verbindungsklasse bilden, die für die Synthese von Pharmaka wie (−)-Paroxetin und (+)-Femoxetin sehr wichtig ist.

Organocatalytic Conjugate Addition of Malonates to α,β‐Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−)‐Paroxetine, Chiral Lactams, and Lactones

Organocatalytic conjugate addition of malonates to alpha,beta-unsaturated aldehydes : Asymmetric formal synthesis of (-)-paroxetine, chiral lactams, and lactones

A Stereocontrolled Formal Asymmetric Synthesis of Pseudodistomin C.

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 Asymmetric Formal Synthesis of Fasicularin.

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.

A Versatile Approach for the Asymmetric Syntheses of (1R,9aR)-Epiquinamide and (1R,9aR)-Homopumiliotoxin 223G

[reaction: see text] Using 5b as a common intermediate, the first asymmetric synthesis of (-)-epiquinamide (4) and a formal asymmetric synthesis of (-)-homopumiliotoxin 223G (2) is described. A key feature of our approach is the flexible introduction of a functionalized C(4) side chain to (S)-3-benzyloxyglutarimide 7 in a regio- and diastereoselective manner. Utilization of a tandem Swern oxidation-Grignard addition strategy efficiently prevented racemization. An unexpected NaN(3)-promoted methanesulfonic acid elimination yielded 17, a reaction which could be useful for the syntheses of 8-dehydrodesmethylpumiliotoxins such as alkaloid 235C (3).

A Stereocontrolled Formal Asymmetric Synthesis of Pseudodistomin C

An efficient and stereocontrolled formal asymmetric synthesis of pseudodistomin C has been achieved by employing intramolecular transamidation reaction, exo-methylenation, and highly stereoselective hydroboration. The resulting 2-hydroxymethylpiperidine derivative (15) was further converted into the key intermediate (2) for the synthesis of pseudodistomin C.

Catalytic and Asymmetric Vinylogous Mukaiyama Reactions on Aliphatic Ketones: Formal Asymmetric Synthesis of Taurospongin A.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dinuclear Asymmetric Zn Aldol Additions: Formal Asymmetric Synthesis of Fostriecin.

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.

Catalytic Asymmetric Aza Diels—Alder Reactions of Hydrazones Using a Chiral Zirconium Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis of 2,4,5-Trisubstituted Piperidines from Sulfinimine-Derived δ-Amino β-Ketoesters. Formal Synthesis of Pseudodistomin B Triacetate

[reaction: see text] N-Sulfinyl delta-amino beta-ketoester enaminones, a new sulfinimine-derived chiral building block, undergoes, on hydrolysis in one pot, an intramolecular Michael addition followed by a retro-Michael-type elimination to give enantiopure 2,4,5-trisubstituted piperidines, a structural motif found in numerous biologically active alkaloids. This new chiral building block is readily prepared by treating N-sulfinyl delta-amino beta-ketoesters with dimethylformamide dimethyl acetal. This new protocol was illustrated with a concise formal asymmetric synthesis of marine alkaloid pseudodistomin B triacetate.

Catalytic and Asymmetric Vinylogous Mukaiyama Reactions on Aliphatic Ketones: Formal Asymmetric Synthesis of Taurospongin A

Catalytic asymmetric vinylogous Mukaiyama reactions on ketones, leading to the formation of alpha,beta-unsaturated lactones with tertiary alcohols, have been described (11 examples, up to 93% ee). This methodology has been applied in a formal enantioselective synthesis of taurospongin A (12 steps, 6% overall yield).

Formal Synthesis of (+)-Anatoxin-a by Asymmetric [2+2] Cycloaddition

A formal asymmetric synthesis of (+)-anatoxin-a, a neurotoxic alkaloid from Anabaena flos aquae, has been achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether.

Dinuclear Asymmetric Zn Aldol Additions: Formal Asymmetric Synthesis of Fostriecin

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.

Catalytic asymmetric aza Diels–Alder reactions of hydrazones using a chiral zirconium catalyst

Catalytic asymmetric aza Diels–Alder reactions of acylhydrazones with Danishefsky’s dienes have been developed. A chiral zirconium complex derived from zirconium propoxide and 3,3′,6,6′-I 4BINOL was found to be effective in this reaction, and the desired optically active 2,3-dihydro-4-pyridone derivatives were obtained with high enantioselectivities. Asymmetric formal synthesis of a natural product, coniine, was conducted using this catalytic asymmetric reaction as a key step.

Asymmetric aza-[2,3]-Wittig sigmatropic rearrangements: chiral auxiliary control and formal asymmetric synthesis of (2S, 3R, 4R)-4-hydroxy-3-methylproline and (–)-kainic acid

A survey of 16 different chiral auxiliaries and a variety of strategies found that an (-)-8-phenylmenthol ester of a glycine derived migrating group can control the absolute stereochemistry of aza-[2,3]-Wittig sigmatropic rearrangements with diastereoselectivities of ca. 3 : 1 with respect to the auxiliary. In two specific examples, ca. 50% yields of enantiomerically pure products were obtained after chromatographic purification. These were synthetically manipulated with no erosion of stereochemistry into intermediates that completed formal asymmetric syntheses of (+)-HyMePro and (-)-kainic acid.

An Improved Asymmetric Synthesis of Unusual Amino Acid (2S,3S)‐3‐Hydroxyproline

An improved three‐steps method for the conversion of N‐benzyl (S)‐3‐hydroxypyrrolidin‐2‐one 6 to (2S,3S)‐3‐hydroxyproline 1 is reported. The key step is the reductive cyanation of 6. The synthesis of 1 constitutes a formal asymmetric synthesis of (2S,3S)‐3‐hydroxyproline betaines 2.

An Asymmetric Formal Synthesis of Fasicularin

An asymmetric formal synthesis of fasicularin (1) is described. This natural product, isolated from the extracts of the marine invertebrate Nephteis fasicularis, has shown modest cytotoxicity towards Vero cells. Fasicularin is among only two members of the cylindricine family of natural products, along with lepadiformine (2), to possess a trans A-B ring junction. Key steps of this approach to 1 involve a siloxy-epoxide semipinacol rearrangement of 5 to 6, a B-alkyl Suzuki-Miyaura coupling reaction by using enol trifluoromethanesulfonate 19 and a substrate-directed hydrogenation reaction of 24. This formal synthesis also highlights the difficulty in the incorporation of the thiocyanate functionality present in 1.