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

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.

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.

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.

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].

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

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

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.

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.

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.

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.

Palladium-Catalyzed Aerobic Dehydrogenative Aromatization of Cyclohexanone Imines to Arylamines

Alakananda Hajra, Ye Wei, and Naohiko Yoshikai
Org. Lett.
DOI:10.1021/ol302568b

Substituted anilines are common core structures for a wide range of molecules. They are usually synthesised by S_NAr chemistry, transition metal-catalysed C-N bond forming couplings or the reduction of nitroarene precursors. The common feature of these methodologies is that the aryl ring is already present in the starting material.

A recent report outlines a more indirect way of preparing such molecules employing a Pd-catalysed dehydrogenative aromatisation of cycloheximines. Rather than sourcing the aryl ring from the starting material, this methodology forms the substituted arene by a dual dehydrogenative catalytic cycle that leads to aromatisation of the cycloheximine substrate.

The use of expensive or wasteful stoichiometric by-products is avoided by using an oxygen atmosphere to achieve successive oxidations. The authors demonstrate the applicability of their method by preparing a variety of substituted anilines.

This method provides an expedient preparation of anilines that complements traditional methods by bypassing possible problems embodied in aromatic substitutions.

Highly Enantioselective Catalytic [6+3] Cycloadditions of Azomethine Ylides

Marco Potowski, Jonathan Bauer, Carsten Strohmann, Andrey Antonchick, Herbert Waldmann
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201204394

Cycloaddition reactions are very useful for generating multiple stereocentres in one step. The fact that they also provide enantiocontrol with the use of chiral Lewis acids or auxiliaries makes these reactions very attractive in most aspects of organic synthesis.

Waldmann and co-workers have reported an enantioselective [6+3] cycloaddition of azomethine ylides with fulvenes using a metal salt with a chiral ferrocene-derived ligand to provide stereocontrol.

Azomethine ylides are readily formed by β-carbonyl imines, which can be prepared simply by condensation between an amino acid ester and an aldehyde.

Waldmann’s group took things a step further; they used the product of the enantioselective [6+3] cycloaddition in a subsequent [4+2] cycloaddition. The second cycloaddition proceeds diastereoselectively allowing the construction of eight stereocentres – up to 98:2 er – in one pot.

A remarkable degree of complexity can be achieved in a single process from three simple starting materials.

“Black Swan Events” in Organic Synthesis

William Nugent
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201202348

The moral of this article can be summarised in three words of folk wisdom: never say never. This article provides a refreshing insight into the misplaced preconceptions of chemists working in previous decades, and how these preconceptions were overturned.

The author lays out a series of dogmatic statements which over the past two decades have been proven incorrect. These statements are classed into two categories depending whether they were brought down by a single publication – “Change through revolution”, or a series of reports – “Change through evolution”.

A selected few are:

“Gold compounds are simply to unreactive to be useful as homogeneous catalysts”

A report by Teles et al. in 1998 demonstrated that a cationic Au(I) complex catalyses the addition of oxygen nucleophiles to acetylenes:

“Olefin metathesis is an ill-defined reaction of olefinic hydrocarbons and unlikely to find any use in organic synthesis”

For students studying organic synthesis today, it’s hard to imagine a time before ubiquitous olefin metathesis, more so that it was considered so far out of reach. R.H. Grubbs ultimately shared the Nobel Prize in Chemistry in 2005 for his research on ruthenium catalysed olefin metathesis.

“Efficient enantioselective catalysis requires the use of a metal complex”

And then came one of the most elegant and sophisticated aspects of catalysis in organic synthesis: organocatalysis, with the work of MacMillan, List, Barbas and others.

As the author points out, a common characteristic of the above overruled statements is that often, the scientific literature contained hints that the “common belief” was incorrect. However, these hints were not picked up on until a report was published proving that the original discounted phenomenon was in fact achievable.

The discovery of something completely new and revolutionary is often preceded by flashes of insights or moments of wisdom that will most probably be ignored until three or four decades later when someone has the curiosity to move it forwards.

So what assumptions about the behavior of molecules do we make today that will populate a surrogate of this article in 50 years?

Highly Diastereo- and Enantioselective Cu-Catalyzed [3 + 3] Cycloaddition of Propargyl Esters with Cyclic Enamines toward Chiral Bicyclo[n.3.1] Frameworks

Cheng Zhang, Xin-Hu Hu, Ya-Hui Wang, Zhuo Zheng, Jie Xu, and Xiang-Ping Hu
J. Am. Chem. Soc.
DOI: 10.1021/ja303129s

Bridged bicyclic structures are common motifs in many naturally occurring and bioactive compounds. As such, these systems are attractive targets for synthetic chemists. However, their highly shape-defined structure poses an interesting synthetic challenge. Common approaches in preparation of bridged systems include regiospecific Heck couplings and carbenoid addition-Claisen rearrangement cascades.

These approaches, although reliable, are characterized by long syntheses of the cyclization substrates.

A group from the Chinese Academy of Sciences in Beijing has recently reported a diastereo- and enantio-selective Cu(II)-catalysed formal [3+3] cycloaddition for the preparation of bicyclo(n.3.1) structures from simple propargyl esters and cyclic enamines. Treatment of the propargyl ester with Cu(OAc)₂ in the presence of a chiral tridentate ligand yield a very reactive allenylidene intermediate, which undergoes cycloaddition in the presence of an enamine nucleophile.

The reaction is shown to work best with six membered cyclic enamines, which can also contain heteroatoms. However, decent yields were also obtained with five and seven membered nucleophiles.

The bicyclo(n.3.1) products can be functionalised stereoselectively either through C-C double bond chemistry or carbonyl chemistry and serve as building blocks for the synthesis of more complicated systems.

Enantioselective α-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis

Eduardas Skucas and David W. C. MacMillan
J. Am. Chem. Soc.
DOI: 10.1021/ja303116v

The stereoselective preparation of α-vinyl carbonyl compounds is a challenging task for synthetic chemists mainly due to their tendency to racemize under reaction conditions. MacMillan and Skucas report a multicatalysis protocol for the enantioselective α-vinylation of aldehydes under very mild conditions. Using vinyl iodonium triflate species as starting materials, an imidazolidinone organocatalyst to induce stereoselectivity, and a Cu(I) salt, they have devised an efficient and useful synthetic tool for the enantioselective preparation of β,γ-unsaturated aldehydes.

They propose that the Cu(I) catalyst undergoes an oxidative addition to the vinyl iodonium triflate substrate to form a highly electrophilic Cu(III) vinyl complex. At the same time, the imidazolidinone organocatalyst reacts with the aldehyde substrate to form the corresponding enamine. Complexation of the enamine with the Cu(III) species and subsequent reductive ellimination liberates the Cu(I) metal completing one of the catalytic cycles. Hydrolysis of the resulting imminium species yields the desired α-vinyl aldehyde and the imidazolidinone organocatalyst completing the second catalstic cycle.

The authors also investigated the scope of the reaction for both the aldehyde and vinyl coupling partners demonstrating that the protocol can tolerate sterically demanding β-branched aldehydes, protected heteroatoms, electron-poor styrenes as well as trisubstituted carbocycles. The stereochemical induction has been demonstrated to be completely under control of the organocatalyst as preexisting stereocentres do not influence the stereochemical outcome.

Utilising routine reactions, α-vinyl aldehydes can be transformed into a variety of compounds and used as versatile precursors for the synthesis of larger molecules.

Femtoreview: Carbonyl ylide cycloadditions in the synthesis of aspidosperma alkaloids

Aspidosperma alkaloids are challenging targets in natural product synthesis due to the complexity of their tightly fused polycyclic core scaffold. Intramolecular cycloadditions in carbonyl ylide intermediates have proven to be powerful transformations in accessing these structures.

Albert Padwa and co-workers have published two reports regarding the synthesis of the central core of the aspidosperma alkaloids.¹ Their approach utilises Rh(II)-catalysed carbenoid chemistry. In the presence of a Rh(II) catalyst, the substrate undergoes a cyclising intramolecular carbonyl ylide formation with the proximal amide carbonyl. This is subsequently trapped by an intramolecular dipolar cycloaddition forming the central apsidosperma alkaloid core. This intermediate compound was taken forward to the natural product vindoline.

More recently, Boger and co-workers have reported a divergent approach for the total synthesis of (-)-Aspidospermine and (+)-Spegazzinine.² Their approach also involves a carbonyl ylide intermediate, formed in this instance from an oxadiazole precursor by [4+2] cycloaddition and expulsion of N₂, which undergoes an intramolecular [3+2] cycloaddition to provide the central aspidosperma alkaloid core.

Both approaches demonstrate the complexity that can be generated with stereocontrol through the use of carbonyl ylides in intramolecular cycloadditions.

1. (a) Padwa et al., J. Org. Chem., 1995, 60, 6258, (b) Padwa et al., J. Org. Chem., 1998, 63, 556.
2. Boger et al., Org. Lett., 2012, 14, 2078.

Asymmetric Synthesis of Dihydropyranones from Ynones by Sequential Copper(I)-Catalysed Direct Aldol and Silver(I)-Catalysed Oxy-Michael Reactions

Shi-Liang Shi, Motomu Kanai and Masakatsu Shibasaki Angew. Chem. Int. Ed.

Dihydropyranones are useful intermediates for the synthesis of natural products and natural product-like scaffolds. They are accessible asymmetrically through hetero-Diels-Alder reactions using Danishefsky’s diene and aldehydes as starting materials. Shibasaki and co-workers report a stereoselective sequential aldol – oxy-Michael process for the synthesis of chiral dihydropyranones with ynones as substrates.

Ynones can be synthesised form silyl-alkynes and acyl chlorides or by PCC oxidation of the corresponding alcohol, available over one step by either method. However, taking the Danishefsky’s diene approach requires preparing starting materials by a longer route – usually four-steps – involving organolithium reagents.

In Shibasaki’s approach, the intermediate aldol is synthesised using a catalytic amount of copper(I) and (R)-DTBM-Segphos as the chiral ligand. After aqueous work-up, AgOTf is added to the crude mixture and the desired dihydropyranone is obtained after microwave irradiation. The applicability and success of this process was demonstrated by the synthesis of a range of chiral dihydropyranones using aliphatic aromatic aldehydes and ynones.

DOI: 10.1002/anie.201109209