Tag Archives: Asymmetric synthesis

Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Sergey Pronin, Christopher Reiher, and Ryan Shenvi
DOI: 10.1038/nature12472


The bimolecular nucleophilic substitution (SN2) reaction is a well understood and widely used chemical transformation that allows a chemist to affect useful functional group interconversions or combine two molecules. A significant advantage of the SN2 reaction over the related (and often competitive) unimolecular nucleophilic substitution (SN1) reaction is that it provides predictable stereoinversion at the electrophilic carbon centre. SN2 processes do, however, suffer from a significant limitation: intolerance of tertiary electrophilic carbon atoms, where steric crowding inhibits the approach of the nucleophilic reacting partner. This drawback limits the stereochemical complexity of possible reaction substrates and the utility of nucleophilic substitution in the synthesis of challenging chiral molecules.

Now, a team of researchers from California led by Ryan Shenvi have developed a process that allows the stereochemical inversion of tertiary alcohols with nitrogen-based nucleophiles. The key reaction in their discover y involves Lewis-acid-catalyzed solvolysisof a tertiary alcohol derivative – trifluoroacetate or perfluoroalkanoate esters — in the presence of excess trimethylsilyl cyanide. Addition of the cyanide nucleophile to the carbocation of a postulated contact ion pair, generated by solvolysis, occurs with high enantioselectivity, giving tertiary isonitrile products in a remarkably simple transformation. The researchers compare this process to proposed biosynthetic pathways of nitrogen-based marine terpenoids, which are known to derive from the addition of inorganic cyanide to highly substituted carbon centres.


As well as extending the scope of traditional SN2 processes, Lewis-acid-catalyzed solvolysis also provides complementary reactivity. Because the reaction is conceptually related to the SN1 reaction in the generation of a reactive carbocation in the contact ion pair, activated primary and secondary alcohols do not undergo solvolysis even over extended reaction times. The utility of the process was further demonstrated by converting the isonitrile products into various useful nitrogen-based compounds, such as amines, formamides and isothiocyanates.

The influence of steric crowding on this SN2-like reaction has not, however, been eliminated; branched tertiary alcohols react with lower stereoselectivity than minimally substituted analogues. Despite this, the reported transformation fills a gap in modern synthetic methodology and may lead to further developments in the synthesis of other stereo-defined tertiary-substituted compounds.

Uncovering alkenes: complex products from all-carbon substrates


Molecules containing simple alkene functionality are attractive substrates in synthesis. Carbon-carbon double bonds are relatively stable groups, lacking polarisation, they can be carried through synthetic processes involving acid, base, mildly oxidative and reductive conditions. But, the availability of the π-electrons for reaction embodies remarkable potential for constructing substituted contiguous stereocentres and the possibility of introducing complex functionality to an all-carbon system.

In recent years, functionalisation of unactivated alkenes has blossomed with developments in robust metal-catalysed processes and new oxidating agents. In the last few weeks several reports of new alkene functionalisations have been published that cover many aspects of this broad area, and show the diverse utility of alkenes in synthesis.

Hayashi and co-workers have published an elegant cyclising difunctionalisation of dienes.[1] The process is an iridium-catalysed C-H activation of cyclic aryl N-sulfonyl ketimines and gives spirocyclic aminoindane scaffolds with high diastereoselectivity.


We’ve already discussed an asymmetric cyclising aminofluorination reaction carried out by a chiral hypervalent iodine fluoride oxidant.[2] The reaction is endo-selective and prepares fluoropiperidine-based systems. Extension of the reaction to a racemic intermolecular process with styrene substrates was also demonstrated.


In a similar example of intermolecular alkene difunctionalisation, Zhang reports aminocyanation and diamination of (predominantly) styrene substrates.[3] The principle reagent for functionalisation is NFSI (N-fluorobenzenesulfonimide), which aminates the terminal end of the double bond. Subsequent reaction with TMSCN gives the aminonitrile product. Alternatively, an alkylnitrile may be used to give the Ritter product of the second addition.


The authors suggest a copper(I)-catalysed radical mechanism, generating a carbon-centered radical intermediate after amination by •N(SO2Ph)2. This reaction gives some idea of the kind of complex functionality that can be introduced to all-carbon alkene substrates by oxidative processes.

Hydrofunctionalisation of alkenes doesn’t provide the same high degree of complexity as oxidative difunctionalisation processes, but reactions in this category do offer a great deal of diversity in synthetic options while still providing regio- and stereocontrol of sp3 carbon centres. A report from Qing and co-workers describes a general and high yielding hydrotrifluoromethylation of unactivated alkenes.[4] Trifluoromethyl groups are useful moieties in pharmaceutical development of lead compounds. The group apply the method to a wide scope of unactivated alkene substrates showing tolerance to many other functionalities.


Hartwig’s group in Berkeley have developed an asymmetric hydroheteroarylation of bicycloalkenes.[5] The reaction is catalysed by an iridium DTBM-Segphos complex and tolerates various heteroaromatic coupling partners.


Alkenes offer chemists widely available, stable and highly tolerant substrates for synthesis. Careful application of modern reactions allows the uncovering of diverse and complex functionality from a carbon-carbon double bond, and new developments provide ever more effective methods for the preparation of desirable adducts.

1. DOI: 10.1021/ja311968d
2. DOI: 10.1002/anie.201208471
3. DOI: 10.1002/anie.201209142
4. DOI: 10.1002/anie.201208971
5. DOI: 10.1021/ja312360c

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.


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.

Amines Bearing Tertiary Substituents by Tandem Enantioselective Carbolithiation-Rearrangement of Vinylureas

Michael Tait, Morgan Donnard, Alberto Minassi, Julien Lefranc, Beatrice Bechi, Giorgio Carbone, Peter O’Brien, and Jonathan Clayden
Org. Lett.
DOI: 10.1021/ol3029324


Asymmetric construction of tertiary stereocentres next to nitrogen is a significant challenge in organic synthesis with only a few robust approaches available. Clayden and co-workers report a method of preparing α-tertiary amines asymmetrically that allows the introduction of a high degree of molecular complexity.

Their approach involves, initially, an asymmetric carbolithiation of a vinylurea under the influence of a chiral ligand for lithium. This step introduces an alkyl substituent and sets the configuration of the stereocentre next to nitrogen. The addition of DMPU to the reaction accelerates a subsequent aryl migration from the ‘other side’ of the urea to the lithiated carbon centre. Aryl migration occurs with retention of stereochemistry.

The real utility of this reaction is shown in the ability to select which enantiomer of the product is formed by using either naturally occuring (-)-sparteine (A) or a (+)-sparteine surrogate (B) as the chiral ligand.


The reaction has been applied to various substrates. Showing, in particular, variation in the introduced alkyl substituent and, remarkably, extension to the migration of a styrenyl group (the product of which is unstable and rearranges under mildly acidic conditions).


The desired complex amine adducts can be prepared by the deprotection of the urea products under basic conditions.

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


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).


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.


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


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.


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.


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.


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

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.

A Redox-Reconfigurable, Ambidextrous Asymmetric Catalyst

Shahab Mortezaei, Noelle R. Catarineu, and James W. Canary J. Am. Chem. Soc.
DOI: 10.1021/ja302283s

Various new catalysis paradigms are being developed in modern chemistry, such as cooperative catalysis, cascade catalysis or proximity catalysis. However, new work presented by Canary and co-workers features a new concept: templating of organocatalytic ligands by a metal centre, generating a rigid, chiral complex capable of carrying out asymmetric catalysis. The most remarkable feature of this catalytic complex is the ability to switch the enantioselectivity of the catalyst by altering the oxidation state of the metal.

Previous work from the group has revealed a copper ligand complex that switches ‘handedness’ of pseudo-helical ligand conformation upon one electron transfer to or from the metal centre; alternating between Cu(II) (right handed) and Cu(I) (left handed). The ligands are based on L-methioninol and the handedness of the structures is derived from the differing affinity of the copper for O– and S-ligands in different oxidation states.

In this piece of work, the ligands are further functionalised with organocatalytic urea moieties. The group show the ligand to be competent in catalysing the Michael addition of malonate to a nitroalkene in the absence of the copper. Without copper there is no selectivity, but complexes of the ligand with either Cu(I) or Cu(II) result in clear selectivity for R or S respectively.

When the Cu(II) catalyst is used in the reaction, isolated, reduced with ascorbate to Cu(I) and resubmitted to reaction conditions the yields and ee are consistent but the selectivity reversed. Whilst neither the yields nor selectivities are outstanding as yet, the concept opens new possibilities for developments in tuneable catalysis.