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循环二核酸MK-1454的立体选择合成的多种催化反应

  • 0Department of Process Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States.

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Diels–Alder Reaction Forming Cyclic Products: Stereochemistry 01:28

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The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.

For the electrons to flow seamlessly between the two π systems, specific stereochemical and conformational requirements must be met.
Stereochemical Orbital Symmetry
The frontier molecular orbitals that satisfy the symmetry...

Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction 01:26

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α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.

However, enamines are neutral and less reactive than enolates, which bear a net negative charge. Consequently, enamines are effective Michael donors...

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation 01:27

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Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).

The ring-forming reaction occurs in two stages: Michael addition and the subsequent...

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry 01:29

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Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.

Dienophiles with one or more electron-withdrawing substituents form stereochemically different products in which the substituents are oriented in an endo (towards) or exo (away) configuration relative to the double bond.

The endo isomer is formed faster and is the kinetic product. The exo isomer is more stable and is the thermodynamic...

Conjugate Addition of Enolates: Michael Addition 01:08

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The attack of a nucleophile at the β carbon of an α,β-unsaturated carbonyl compound is called conjugate addition. Conjugate addition reactions of active methylene compounds, such as β-diketones, β-keto esters, β-keto nitriles, and α-nitro ketones, are called Michael addition reactions.

The reaction is catalyzed by a base that abstracts the acidic methylene hydrogen, generating a doubly-stabilized enolate ion that serves as the nucleophile or the Michael...

Cycloaddition Reactions: Overview 01:16

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Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.

The feasibility of cycloaddition reactions under thermal and photochemical conditions can be...