This tutorial review presents some recent examples of intramolecular Diels-Alder (IMDA) reactions as key complexity-generating steps in the total synthesis of structurally intricate natural products. The opportunities afforded by transannular (TADA) versions of the IMDA reaction in complex molecule assembly are also highlighted. The review is aimed at a wide audience, ranging from advanced undergraduates to seasoned practitioners of total synthesis; since this is an educational overview, only selected highlights from the period 2000-2009 are presented, along with chosen references to other, more comprehensive, reviews.
The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the non-acyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.
A protocol for the hydrocarboxylation of disubstituted alkenes and terminal alkynes providing access to different secondary carboxylic acids and malonic acid derivatives has been developed. This methodology relies on an initial hydroboration using 9-BBN followed by carboxylation with carbon dioxide in the presence of a copper catalyst and the additive, cesium fluoride. Different cyclohexene, styrene, and stilbene derivatives could be utilized, and alkynes could be transformed into their corresponding dicarboxylic acids in good yields. Finally, six different terpenoids were carboxylated using the developed procedure.
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthdayWith a practical synthesis of the ABCD aldehyde in hand (2, Scheme 1), [1] herein we describe our progress that culminated in the synthesis of (+)-azaspiracid-1 (1) in 26 linear steps and 2.7 % overall yield.As outlined in Scheme 1, the addition of an anomeric sulfone anion derived from 3 to a C20-electrophile, as represented by aldehyde 2, could provide a highly convergent approach to the target. Since all nine rings of azaspiracid-1 (1) are formed prior to this final fragment coupling, the number of manipulations required after the coupling step would be minimal. Such anomeric sulfone anion additions have considerable precedent, both in the original investigations of anomeric sulfone anions derived from carbohydrates [2, 3] and subsequently in advanced fragment couplings in total synthesis, [4][5][6] although the crucial sulfone anion addition of 3 to electrophiles such as aldehyde 2 would represent the most complex anomeric sulfone anion addition to date.Conformational analysis of the HI spiroaminal portion of pentacyclic sulfone 3 (Figure 1) suggests, on the basis of anomeric stabilization and an analysis of steric effects, that this synthon exists in its favored configuration. Therefore, a number of ketalization events were incorporated into the assembly of 3, in which the molecule is anticipated to spontaneously form the desired tetracyclic FGHI system under equilibrating conditions. The fragment couplings to construct intermediate 4 (Scheme 1) would involve a boronmediated addition of the C27-methyl ketone of the FG ring fragment 6 to the E ring aldehyde 5, while a chelatecontrolled Mukaiyama aldol addition [7] of the enolsilane derived from the C35-methyl ketone of 7 to the aldehyde of 6 was anticipated to establish the stereocenter at C34. By inspection, two syn 1,3-dimethyl synthons of the same configuration are embedded in the azaspiracid structure in the E and the I rings. We were attracted to the possibility of constructing both of these subunits from the common
There
remains an insufficient number of P2X7 receptor antagonists
with adequate rodent potency, CNS permeability, and pharmacokinetic
properties from which to evaluate CNS disease hypotheses preclinically.
Herein, we describe the molecular pharmacology, safety, pharmacokinetics,
and functional CNS target engagement of Lu AF27139, a novel rodent-active
and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective
and potent against rat, mouse, and human forms of the receptors. The
rat pharmacokinetic profile is favorable with high oral bioavailability,
modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide
(LPS)-primed and 2′(3′)-O-(benzoylbenzoyl)adenosine-5′-triphosphate
(BzATP)-induced IL-1β release demonstrate functional CNS target
engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies.
Based on these properties, we believe Lu AF27139 will be a valuable
tool for probing the role of the P2X7 receptor in rodent models of
CNS diseases.
A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl2 and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of (13)C-labeled carbon monoxide generated from (13)COgen, the corresponding (13)C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific (13)C-isotope labeling.
Carbon dioxide is an intrinsically stable molecule. Therefore, its activation requires extra energy input in the form of reactive reagents and/or activated catalysts and, often, harsh reaction conditions. Reported here is a direct carboxylation reaction of aromatic aldehydes with carbon dioxide to afford α-keto acids as added-value products. In situ generation of a reactive cyanohydrin was the key to the successful carboxylation reaction under operationally mild reaction conditions (25-40 °C, 1 atm CO ). The resulting α-keto acids served as a platform for α-amino acid synthesis by reductive amination reactions, illustrating the chemical synthesis of essential bioactive molecules from carbon dioxide.
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