Author Archives: georgek86

Regio- and Enantioselective Aminofluorination of Alkenes

Wangqing Kong, Pascal Feige, Teresa de Haro, and Cristina Nevado
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208471

nevado

Multisubstituded, saturated 5-, 6- and 7- membered heterocycles are part of many bio-active molecules. Fluorinated derivatives of such structures have also been shown to display better pharmacological properties such as solubility and metabolic stability. Hence their enantioselective preparation in a facile and efficient manner is of great interest for synthetic chemists.

nevado1

Classical approaches involve cycloadditions such as inverse-electron demand Diels-Alder or [2,3] azomethine ylide reactions1, whereas more modern approaches focus on transition metal catalysed aminoalkylations2. Cristina Nevado’s group in Zurich, have recently reported a metal-free regio- and enantioselective aminofluorination for the preparation of 6- and 7-membered fluorinated heterocyclic compounds.

nevado2

The reaction is highly regioselective yielding the 6-endo-cyclisation product only. Using their newly discovered conditions they investigated the scope of the intramolecular aminofluorination.

nevado3

From the data presented in the supporting information, aromatic substituents seem to have a positive influence on enantioselective induction. The preparation of 7-membered rings was also performed. However it required the addition of a catalytic amount of [(Ph3P)AuNTf2].

fig4

The authors also investigated the scope of intermolecular aminofluorinations in a non-asymmetric manner, using p-xyleneIF2 as the fluorine source.

nevado5

This method provides a facile route to fluorinated surrogates of saturated heterocyclic compounds. It would be interesting to see it applied for the preparation of morpholine or piperazine containing compounds in the future.

References:

1. a) Geraldine Masson et al. Org. Bio. Chem. 2012 ; b) Marco Potowski et al. Angew. Chem. Int. Ed. 2012.

2. a) Josephine S. Nakhla et al. Org. Let. 2007 ; b) Matthew L. Leathen et al. J. Org. Chem. 2009.

Catalytic Asymmetric C–N Bond Formation: Phosphine-Catalyzed Intra- and Intermolecular γ-Addition of Nitrogen Nucleophiles to Allenoates and Alkynoates

Rylan J. Lundgren, Ashraf Wilsily, Nicolas Marion, Cong Ma, Ying Kit Chung, and Gregory C. Fu
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208957

fig2

A carbonyl group provides a pivot point for the functionalisation of its proximal positions – α and β. This can be demonstrated by the reactivity of classical enolates as α-functionalisation nucleophiles and Michael acceptors as β-functionalisation electrophiles, as well as their corresponding reactivities in enamine and imminium organocatalysis.

fig1

In a recent report Lundgren et al. have successfully demonstrated that γ-functionalisation of carbonyl compounds is also achievable, both intra- and inter- molecularly. Using a spirophospine ligand to induce stereoselectivity, the group has demonstrated the feasibility of asymmetric C-N bond formation with nitrogen nucleophiles and alkynoates or allenoates as electrophiles.

fig2

Investigating the scope of the reaction revealed that a good range of functional groups can be accommodated in either intramolecular reactions with alkynoates or intermolecular reactions with allenoates.

fig3

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The process provides access to novel reactivity and it may even prove complementary to the classical α- and β- asymmetric functionalisation of carbonyl compounds. It would be interesting to see if a γ-, β-, α-cascade addition would be possible.

Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via Enantioselective Acylation: Synthetic and Mechanistic Studies

Sarah Yunmi Lee, Jaclyn M. Murphy, Atsushi Ukai, and Gregory C. Fu
J. Am. Chem. Soc
DOI:10.1021/ja307425g

Fu1

Dynamic Kinetic Resolution is a well established methodology for the stereoselective preparation of chemicals, which overcomes the low yield issue inherent in classic kinetic resolution. There are two strategies; the first one relies on the fast interconvertion of the two enantiomers of the starting material between them and the difference in relative conversion rates to the desired product (A). The second relies on the conversion of only one of the enantiomers of the product back to the starting material (B).

Fu2

Although the first strategy can be implemented without the need of an enzyme, the second required atleast one enzyme – usually a deacetylase enzyme – to be successfully applied. Only recently, a non-enzymatic dynamic kinetic resolution methodology for the acylation of secondary amines, relying on the second approach has been reported. A ferrocene is used for the acylation of the substrate, whilst a ruthenium complex deacetylates only one enantiomers of the acylated product. The authors demonstrated the applicability of their method on a variety of substrates.

Fu3

This non-enzymatic method is not fascinating only because the lack of an enzyme which can prove to be scare or even not compatible with the reaction conditions. It overcomes the “other enantiomer” issue. Enzymes are fantastic catalysts however they are evolved specifically to do one job and one job only, making them inherently useless for the preparation of the other enantiomer of the desired product. For non-enzymatic processes such as the one above this is not an issue. If the enantiomer of the ruthenium catalyst was used then the product obtained would have the opposite stereochemistry.

This is the first non-enzymatic dynamic kinetic resolution method for secondary alcohols reported and hopefully it will provide incentive for future development as well as inspiration for more such approaches.

Enantioselective Synthesis of Protected Nitrocyclohexitols with Five Stereocenters. Total Synthesis of (+)-Pancratistatin.

Fernando Cagide-Fagín, Olaia Nieto-García, Hugo Lago-Santomé, and Ricardo Alonso
J. Org. Chem.
DOI: 10.1021/jo3022567

alonso1

Six-membered all-carbon rings are common substructures in a range of natural products, making their synthesis a challenging target for organic chemists. The concise stereoselective synthesis of such molecules is an even greater challenge.

alonso2

Organocatalysis and more specifically enamine catalysis is one of the most elegant process for stereoselective synthesis alongside stereoselective cycloadditions. The combination of the two has been shown to provide a facile and concise stereoselective synthesis of six-membered all-carbon rings in a recent publication by Cagide-Fagín F. et al.
The authors treat a dioxanone with (R)-2-methoxymethyl pyrrolidine and the readily formed enamine reacts with a β-(hetero)aryl-α-nitro-α,β-enal to give the product of a formal [3+3] cycloaddition. The stereochemistry is controlled by the preference for the formation of the (E)-enamine intermediate over the (Z) and the facial selectivity provided by the substituents at the 2-postition of the pyrrolidine.

alonso3

It is a one-pot procedure and all reaction components are readily commercially available or can be synthesised in two steps. The authors demonstrated the applicability of their new method by stereoselectively synthesising Pancrastatin in nine simple steps starting from the achiral dioxanone.

alonso4

The stereoselective synthesis of Pancrastatin has been previously reported in twelve steps starting from pinitol[1] or 21 steps starting from a non-cyclic building block.[2]

Despite the low relatively low yields of the [3+3] annulation process, this methodology provides a facile and concise way of constructing six-membered all-carbon rings. Hopefully, this report will provide incentive for future studies to further optimising the process.

1. Zhou, P. et al. Tetrahedron Lett. 2006, 47, 3707–3710
2. Kim, D. et al. Org Lett. 2002, 4, 1343-1345