[Song, Zhen-Lei] Sichuan Univ, Key Lab Drug Targeting, Educ Minist, Dept Med Chem,W China Sch Pharm, Chengdu 610041, Peoples R China

Semipinacol rearrangement in natural product synthesis.

Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio-organic chemistry. Indeed, many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well-described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic C-F bond which functions as a chemically inert steering group for conformational control.

Fluorine Conformational Effects in Organocatalysis: An Emerging Strategy for Molecular Design

The ten year old Houk–List model for rationalising the origin of stereoselectivity in the organocatalysed intermolecular aldol addition is revisited, using a variety of computational techniques that have been introduced or improved since the original study. Even for such a relatively small system, the role of dispersion interactions is shown to be crucial, along with the use of basis sets where the superposition errors are low. An NCI (non-covalent interactions) analysis of the transition states is able to identify the noncovalent interactions that influence the selectivity of the reaction, confirming the role of the electrostatic NCHδ+⋯Oδ− interactions. Simple visual inspection of the NCI surfaces is shown to be a useful tool for the design of alternative reactants. Alternative mechanisms, such as proton-relays involving a water molecule or the Hajos–Parrish alternative, are shown to be higher in energy and for which computed kinetic isotope effects are incompatible with experiment. The Amsterdam manifesto, which espouses the principle that scientific data should be citable, is followed here by using interactive data tables assembled via calls to the data DOI (digital-object-identifiers) for calculations held on a digital data repository and themselves assigned a DOI.

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The Houk–List transition states for organocatalytic mechanisms revisited

Strategien zum molekularen Design, die von den intrinsischen stereoelektronischen und elektrostatischen Effekten fluorierter organischer Molekule profitieren, sind bisher hauptsachlich auf die bioorganische Chemie beschrankt. Bei vielen konformativen Fluoreffekten handelt es sich zwar um akademische Kuriositaten ohne unmittelbare Anwendung, die Renaissance der Organokatalyse bietet allerdings die Moglichkeit zur Erforschung vieler dieser ausfuhrlich beschriebenen Phanomene zur molekularen Praorganisation. In diesem Kurzaufsatz werden Beispiele zur Verbesserung von Katalysatoren durch die Einfuhrung einer aliphatischen C-F-Bindung erlautert, die als eine chemisch inerte dirigierende Gruppe zur Steuerung der Konformation dient.

Konformative Fluoreffekte in der Organokatalyse: eine neuartige Strategie zum molekularen Design

Decarboxylative halogenation, or halodecarboxylation, represents one of the fundamental key methods for the synthesis of ubiquitous organic halides. The method is based on conversion of carboxylic acids to the corresponding organic halides via selective cleavage of a carbon-carbon bond between the skeleton of the molecule and the carboxylic group and the liberation of carbon dioxide. In this review, we discuss and analyze major approaches for the conversion of alkanoic, alkenoic, acetylenic, and (hetero)aromatic acids to the corresponding alkyl, alkenyl, alkynyl, and (hetero)aryl halides. These methods include the preparation of families of valuable organic iodides, bromides, chlorides, and fluorides. The historic and modern methods for halodecarboxylation reactions are broadly discussed, including analysis of their advantages and drawbacks. We critically address the features, reaction selectivity, substrate scopes, and limitations of the approaches. In the available cases, mechanistic details of the reactions are presented, and the generality and uniqueness of the different mechanistic pathways are highlighted. The challenges, opportunities, and future directions in the field of decarboxylative halogenation are provided.

Decarboxylative Halogenation of Organic Compounds.

The syntheses of (±)-epibatidine and (±)-epiboxidine have been accomplished from commercial 2-methoxy-3,4-dihydro-2H-pyran. A recently developed aza-Prins-pinacol rearrangement was employed for the construction of the key 7-azabicyclo[2.2.1]heptane skeleton of these targets.

Aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes: syntheses of (+/-)-epibatidine and (+/-)-epiboxidine.

7-Azabicyclo[2.2.1]heptane-2-carboxylic acid 11 was prepared in enantiopure form, and its catalytic potential in the direct aldol reaction between acetone and 4-nitrobenzaldehyde was assessed. The bicyclic system was found to be more selective than its monocyclic analogue β-proline 5b. A comparative density functional theory study of proline 1, β-proline 5b, and 11 in the latter reaction revealed the origin of the improved enantioselectivity of 11 over 5b. The geometry of the carboxylic acid group in the transition states, which depended critically on pyrrolidine ring conformation, was found to play a key role.

https://spiral.imperial.ac.uk/bitstream/10044/1/15240/2/Journal%20of%20Organic%20Chemistry_74_14_2009.pdf

Yunas Bhonoah

Papers

Aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes: syntheses of (+/-)-epibatidine and (+/-)-epiboxidine.

Constrained β-Proline Analogues in Organocatalytic Aldol Reactions: The Influence of Acid Geometry

Syntheses of ()-Epibatidine and ()-Epiboxidine