Category Archives: Review

Uncovering alkenes: complex products from all-carbon substrates

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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.

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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.

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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.

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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.

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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.

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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

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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.