Ji-Woong Lee, Thomas Mayer-Gall, Klaus Opwis, Choong Eui Song, Jochen Stefan Gutmann, and Benjamin List
Science
DOI: 10.1126/science.1242196
I’ve written a research highlight for Nature Chemistry talking about Opwis’ and List’s recent paper on organotextile catalysis in Science. Take a look.
Image credit: © 2013 American Association for the Advancement of Science
Sergey Pronin, Christopher Reiher, and Ryan Shenvi
Nature
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.
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.
References:
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
Fraser Stoddart’s group have reported a catenane molecule that can be oxidised to a stable paramagnetic radical state. The oxidation states of the molecule are easily configurable, so this structure has significant potential for use in data storage on the molecular level.
From the Chemistry World article:
The key to the stability of the new radical compound is the mechanical bond that links the two macrocycles, forcing the charged species to remain close. And that proximity means that the molecule never oxidises to a fully charged species but stops at the paramagnetic species •7+. That, says Barnes, is because the molecule is trying to minimise the charge in the centre where the two catenanes link. ‘The charged units have no choice but to interact with one another,’ explains Barnes, so it holds on to that remaining electron to reduce the charge repulsion.
But while the •7+ species is paramagnetic, all the other charged species are diamagnetic, as the electrons spins pair. Using cyclic voltammetry it is possible to quickly switch between the paramagnetic and diamagnetic states by adding and removing electrons. And it is this simple switching that could be the key to a potential application of the material: memory storage.
Robert W. Huigens III, Karen C. Morrison, Robert W. Hicklin, Timothy A. Flood Jr, Michelle F. Richter and Paul J. Hergenrother
Nature Chem.
DOI: 10.1038/nchem.1549
To synthetic chemists, natural products are generally viewed as end-points in synthetic projects (or occasionally as tools, such as ligands or catalysts). Rarely, are complex natural products considered as launching-off points in the synthesis of other interesting molecules. A recent report takes this rather unusual approach by applying the principles of diversity oriented synthesis (DOS) in preparing a series of molecules with drug-like molecular properties.
The authors take three widely available natural products and carry out numerous derivatisations and transformations to give 49 dissimilar molecular scaffolds, a process they dub ‘compexity-to-diversity’ (CtD). A few examples are shown below.
These molecules are presented as exemplifying a new approach to preparing drug-like molecules. They are analysed in characteristics typical of drug molecules and compared with a common screening library of 150,000 molecules.
In terms of diversity, these molecules display considerable structural dissimilarity (established by calculating Tanimoto coefficients for each pair of molecules), even within derivatives of the same natural product.
The CtD molecules display superior lipophilicity (average ClogP = 2.90) compared with the screening collection (average ClogP = 3.99), with over 60% of CtD molecules in the optimal logP range of 0 to 4. Similarly, the CtD library also displays a far higher fraction of sp3 character than the screening compounds, a property indicating a high degree of 3D structure and correlated with enhanced aqueous solubility.
The authors argue that molecular complexity is advantageous in drug-like molecules as more complex molecules might bind their targets more specifically. They point to the number of stereogenic centres the molecule contains as a surrogate for molecular complexity and show that their CtD molecules contain far more stereocentres than the compounds in the screening collection.
Despite demonstrating clear drug-like properties (particularly ClogP), the molecules have not been analysed in another significant property indicative of the likelihood of observing drug-like behaviour: molecular weight. While molecular complexity offers the possibility of tighter target binding, it also decreases the chances of observing binding in any given target site. This is correlated with molecular weight, where it is estimated that each heavy atom added to the molecule increases the number of potential structures by a factor of 10.1 The chances of finding hit molecules is increased when screening molecules with lower molecular weight (due to better sampling of chemical space), albeit with potentially weaker binding (cf. fragment-based design).
The six CtD molecules displayed above lie in the molecular weight range of 353 to 505, outside of the optimal range of 200 to 350 for lead compounds, though within the boundaries of the Lipinski rule of 5 for drug-like molecules.
This approach is, of course, not limited to the derivatisation of the natural products or classes presented within this paper, but that similar structural modifications may be carried out on any readily available complex molecules to prepare diverse structures with drug-like properties.
1. A. Nadin, C. Hattotuwagama, I. Churcher Angew. Chem. Int. Ed. 2012, 51, 1114 and references 27-29 therein.
Naoki Ishida, Yasuhiro Shimamoto, and Masahiro Murakami
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206166
Preparation of cyclic carbonates by incorporation of CO2 into strained cyclic systems is well known and widely exploited. A standard synthesis of these compounds is through addition of epoxide into CO2 followed by ring expansion. Murakami and co-workers take a similar approach in cyclic carbonate synthesis in order to demonstrate a process involving 2 goals in green chemistry: CO2 incorporation, and sunlight activation.
The authors show that azetidine derivatives can be prepared from α-methylaminoketones through irradiation with sunlight alone. These high energy intermediates are relatively stable and their stored solar energy can be released in reaction with CO2 under mild conditions. The reaction can tolerate various aryl groups, but chain length is fixed as a hydroxypyrrolidine derivative is too stable to undergo ring opening.
Kohei Fuchibe, Masaki Takahashi, and Junji Ichikawa
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206946
We don’t often consider the trifluoromethyl group as a reactive centre. But it is, of course, a highly polarised moiety and, under the right conditions, fluoride can act as a competent leaving group. Ichikawa and coworkers employ hydrazines as nucleophiles in two successive displacements of fluoride from vinyl trifluoromethyl adducts to give 3-fluoropyrazole scaffolds.
After testing other possible reaction pathways, they postulate that the reactive intermediate in the cyclisation step, after loss of the tosyl anion, is an azomethine ylide.
Bharat Kumar, Ruth Viboh, Margel Bonifacio, William Thompson, Jonathan Buttrick, Babe Westlake, Min-Soo Kim, Robert Zoellner, Sergey Varganov, Philipp Mçrschel, Jaroslav Teteruk, Martin Schmidt, and Benjamin T. King
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201203266
Both Kekulé and Clar representations of aromatic systems are commonplace in organic chemistry notation. The use of one or the other is usually dependent upon convention or preference. In most cases, neither one is wrong. Very rarely do the differing conventions predict differing physical properties of a molecule.
Kekulene is a well known cyclic polyaromatic hydrocarbon (PAH) consisting of 12 fused benzene rings. It’s structure can be described consistently by both Kekulé and Clar representations. However, not all PAHs exhibit the same consistency.
King and coworkers report a new PAH, dubbed septulene, which they synthesise, characterise and compare to the properties of the related kekulene molecule.
Unlike kekulene, septulene has an odd number of carbon atoms in both the inner and outer carbon rings. Because of this, the only way to resolve the Kekulé structure of septulene is to include a radial π-bond. This π-bond is fundamentally different from all the other bonds in the molecule and breaks the symmetry present in the structure described by the Clar representation. As such, if the Kekulé representation is consistent with reality, septulene will present very different physical properties to kekulene.
The authors studies do, in fact, show that septulene has very similar properties to those of kekulene. The NMR chemical shifts of the inner protons are particularly characteristic. The crystal structure also reveals that there are only 6 unique bonds in the molecule, matching kekulene, highlighting the symmetry of the system. The authors conclude that the similarity in properties between septulene and kekulene cannot follow from the Kekulé representation of the molecule and that only the Clar representation is correct in describing septulene’s, and, indeed, all PAHs’, structure.
Of course, the use of Clar representation for all molecules is not prescribed, the authors suggest that chemists understand the subtle differences between the two representations and use the most appropriate to describe each molecule.
[For anyone up for a challenge, can you ChemDraw the structure of septulene less haphazardly than me?]
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.
Zhi Ren, Fanyang Mo, and Guangbin Dong
J. Am. Chem. Soc.
DOI: 10.1021/ja3082186
Selective C-H oxidation of unactivated alkyl groups is a remarkably powerful way of installing new functionality in simple substrates. We’ve featured some developments in this area previously.
C-H oxidation at the β-carbon of an unactivated alcohol has, so far, been inaccessible due to the deactivating inductive effect of the proximal oxygen. Dong and co-workers have overcome this problem in a method that allows the selective preparation of orthogonally protected 1,2-diols from simple alcohol precursors.
Their method employs a neat oxime derivative of the alcohol to direct palladium C-H insertion β to oxygen. Oximes are known to direct palladation of C-H bonds on the ‘other side’ of the oxime moiety; by removing appropriate C-H bonds from the oxime directing group, palladation in this case occurs on the desired oxygen ‘side’.
The authors note that reaction concentration is critical to the success of the oxidation process. The optimised process uses a concentration of 0.2 M. At lower concentration (0.1 M) the reaction does not go to completion; at higher concentration (0.4 M) decomposition products are observed. Whether or not this narrow range of optimal conditions is variable by substrate is not discussed, but the scope of the reaction is exemplified in a number of substrates with consistently good conversion.
Selective preparation of 1,2 diol derivatives is critical to any application of this methodology in synthesis. The oxime directing group can be removed as a protecting group in the presence of the adjacent acetate. Similarly, the oxime is stable under conditions for acetate cleavage, allowing selective differentiation between the two masked hydroxyl groups.
Interestingly, the reaction gives better yields on larger scale. A test example showed an improvement from 61% yield on 0.1 mmol scale to 80% yield from a 5 mmol reaction.
In one example, a substrate derived from menthol was subjected to the reaction conditions. Instead of observing the expected 1,2 oxidation product, a postulated intermediate undergoes an interesting skeletal rearrangement to give an unusual substituted cyclopentane scaffold.
The Chemistry Cascade 