Organic chemists have always been fascinated by the cyclopropane subunit.1 The smallest cycloalkane is found as a basic structural element in a wide range of naturally occurring compounds.2 Moreover, many cyclopropane-containing unnatural products have been prepared to test the bonding features of this class of highly strained cycloalkanes3 and to study enzyme mechanism or inhibition.4 Cyclopropanes have also been used as versatile synthetic intermediates in the synthesis of more functionalized cycloalkanes5,6 and acyclic compounds.7 In recent years, most of the synthetic efforts have focused on the enantioselective synthesis of cyclopropanes.8 This has remained a challenge ever since it was found that the members of the pyrethroid class of compounds were effective insecticides.9 New and more efficient methods for the preparation of these entities in enantiomerically pure form are still evolving, and this review will focus mainly on the new methods that have appeared in the literature since 1989. It will elaborate on only three types of stereoselective cyclopropanation reactions from olefins: the halomethylmetal-mediated cyclopropanation reactions (eq 1), the transition metal-catalyzed decomposition of diazo compounds (eq 2), and the nucleophilic addition-ring closure sequence (eqs 3 and 4). These three processes will be examined in the context of diastereoand enantiocontrol. In the last section of the review, other methods commonly used to make chiral, nonracemic cyclopropanes will be briefly outlined.

Stereoselective Cyclopropanation Reactions

1,2-Amino Alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric Synthesis

Metal-mediated reductive hydrodehalogenation of organic halides.

Stereochemical Control in Organic-Synthesis Using Silicon-Containing Compounds

TADDOLs, which contain two adjacent diarylhydroxymethyl groups in a trans relationship on a 1,3-dioxolane ring, can be prepared from acetals or ketals of tartrate esters by reaction of the latter with aromatic Grignard reagents. They are extraordinarily versatile chiral auxiliaries. Here, a historical review of the subject is followed by discussion of the preparation of TADDOLs and analogous systems, including TADDOLs with N-, P-, O-, and S-heteroatom ligands appropriate for metals. Crystal structure analysis reveals that the heteroatoms on the diarylmethyl groups are almost always in close proximity to each other, joined together by H-bonds, and predisposed to form chelate complexes in which the metallic centers reside in propeller-like chiral environments. Applications of TADDOL derivatives in enantioselective synthesis extend from utilization as stoichiometric chiral reagents or in Lewis acid mediated reactions, to roles in catalytic hydrogenation and stereoregular metathesis polymerization. Derivatives and complexes based on the following metals have so far been investigated: Li, B, Mg, Al, Si, Cu, Zn, Ce, Ti, Zr, Mo, Rh, Ir, Pd, Pt. The number of stereoselective reactions already accomplished with TADDOLs is correspondingly large. It is also easy to prepare TADDOL derivatives that are readily polymerizable and graftable, and to transform them into immobilized solid-phase catalysts. The result is catalysts, simply or dendritically immobilized in polystyrene or on silica gel and characterized by unexpected stability even after multiple use in titanium TADDOLate mediated reactions. TADDOLs show further unusual characteristics that make them useful for applications in material science and supramolecular chemistry: they are the most effective doping agents known for phase transformations of achiral (nematic) into chiral (cholesteric) liquid crystals. The TADDOL OH group that is not involved in intramolecular H-bonding shows a strong tendency to associate intermolecularly with H-bond acceptors. In the process of crystallization this leads, enantioselectively, to the formation of inclusion compounds that lend themselves to the separation of racemic mixtures not otherwise suited to the classical method of crystallization through diastereomeric salts. The high melting points of TADDOLs even make possible the resolution of racemates by distillation! Host-guest compounds formed between TADDOLs and achiral partners can serve as platforms for enantioselective photoreactions. It seems safe to predict that many more applications will be discovered for the TADDOLs and their derivatives. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.

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TADDOLs, Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries

Norephedrine-derived 2-alkenyloxazolidines: stereochemistry of cyclization and allylic stereocenter directed asymmetric conjugate addition

Asymmetric synthesis of functionalized α -amino-β-hydroxy acids via chiral norephedrine-derived oxazolidines

Neuroinflammation and cholinergic dysfunction, leading to cognitive impairment, are hallmarks of aging and neurodegenerative disorders, including Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AChEI), the symptomatic therapy in AD, attenuate and delay the cognitive deficit by enhancing cholinergic synapses. The α7 nicotinic acetylcholine (ACh) receptor has shown a double-edged sword feature, as it binds with high affinity Aβ1–42, promoting intracellular accumulation and Aβ-induced tau phosphorylation, but also exerts neuroprotection by stimulating anti-apoptotic pathways. Moreover, it mediates peripheral and central anti-inflammatory response, being the effector player of the activation of the cholinergic anti-inflammatory pathway (CAIP), that, by decreasing the release of TNF-α, IL-1β, and IL-6, it may have a role in improving cognition. The finding in preclinical models that, in addition to their major function (choline esterase inhibition) AChEIs have neuroprotective properties mediated via α7nAChR and modulate innate immunity, possibly as a result of the increased availability of acetylcholine activating the CAIP, pave the way for new pharmacological intervention in AD and other neurological disorders that are characterized by neuroinflammation. CHRFAM7A is a human-specific gene acting as a dominant negative inhibitor of α7nAChR function, also suggesting a role in affecting human cognition and memory by altering α7nAChR activities in the central nervous system (CNS). This review will summarize the current knowledge on the cholinergic anti-inflammatory pathway in aging-related disorders, and will argue that the presence of the human-restricted CHRFAM7A gene might play a fundamental role in the regulation of CAIP and in the response to AChEI.

Silvia Cardani

Papers

Norephedrine-derived 2-alkenyloxazolidines: stereochemistry of cyclization and allylic stereocenter directed asymmetric conjugate addition

Asymmetric synthesis of functionalized α -amino-β-hydroxy acids via chiral norephedrine-derived oxazolidines

Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders.

Norephedrine derived 2-methoxy oxazolidines as chiral formyl cation equivalents

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes: synthetic applications using thioesters