Catalytic Asymmetric Synthesis of trans-Configured β-Lactones: Cooperation of Lewis Acid and Ion Pair Catalysis (original) (raw)
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Expedient Approach to α,β-Unsaturated δ-Lactones through a Catalytic Asymmetric [2+2] Cycloaddition
European Journal of Organic Chemistry, 2017
The stereoselective synthesis of cis-γ,δ-disubstituted α,βunsaturated δ-lactone fragment of leustroducsins or phoslactomycins was accomplished according to an original strategy involving a catalytic asymmetric ketene-aldehyde [2+2] cycloaddition leading to the formation of a cis-disubstituted β-lactone. Ring extension by enolate condensation and subsequent recyclization gave the target δ-lactone in a straightforward fashion. Coupling studies with cyclohexanone are also reported. Supporting information for this article is given via a link at the end of the document: copies of NMR spectra and XRay data
Angewandte Chemie International Edition, 2010
The ability to rapidly assemble complex carbocyclic frameworks in a catalytic, asymmetric manner has garnered great interest in recent years. This type of cascade process, which generates multiple C À C and C À X bonds and stereogenic centers, including quaternary carbon atoms, is highly useful in chemical biology, for example when attempting to synthesize a family of compounds around a natural product lead. We developed intramolecular nucleophile-catalyzed aldol lactonization (NCAL) processes that deliver bicyclic b-lactones from aldehyde acid substrates by using Cinchona alkaloid catalysts and modified Mukaiyama activating agents. [3] The NCAL methodology was more recently applied to keto acid substrates by using stoichiometric nucleophiles including 4-pyrrolidinopyridine (4-PPY), which led to a variety of racemic bi-and tricyclic b-lactones, and a nine-step enantioselective synthesis of salinosporamide A from d-serine. [5] Tricyclic-b-lactones (AE )-4 (Scheme 1) were also found to participate in a novel dyotropic process leading to spirocyclic g-lactones. In the latter report, we described a single example of an enantioselective NCAL process with keto acids leading to b-lactone (À)-4, by employing stoichiometric quantities of commercially available tetramisole (Scheme 1). Herein, we report a significant advance in the NCAL methodology with keto acids involving the use of catalytic homobenzotetramisole (S)-HBTM (6, Scheme 2) as chiral nucleophile (Lewis base), a tetramisole analogue, and p-toluenesulfonyl chloride rather than Mukaiyamas reagent, which led to bi-and tricyclic b-lactones in good yields and excellent enantioselectivities. In addition, we report transformations of these systems that lead to dramatically different topologies. Overall, the reported process provides an expedient route to useful templates for chemical biology through rapid synthesis of carbocyclic frameworks in optically active form. The resident b-lactone is also a versatile handle for further manipulations. Furthermore, the described methodology is the first example of catalytic desymmetrization reactions of cyclic diones by the NCAL process.
β-Lactones: Intermediates for Natural Product Total Synthesis and New Transformations
HETEROCYCLES, 2004
The exploration of β-lactone reactivity and transformations has continued since the first synthesis of these strained heterocycles by Einhorn in 1883. The principal reactivity modes of β-lactones include nucleophilic addition resulting in either acyl C2-O1 or alkyl C4-O1 cleavage, rearrangement leading to ring expansion, decarboxylation, and electrophilic reactions of β-lactone enolates.
?-Lactones: Intermediates from Natural Product Total Synthesis and New Transformations
ChemInform, 2005
The exploration of β-lactone reactivity and transformations has continued since the first synthesis of these strained heterocycles by Einhorn in 1883. The principal reactivity modes of β-lactones include nucleophilic addition resulting in either acyl C2-O1 or alkyl C4-O1 cleavage, rearrangement leading to ring expansion, decarboxylation, and electrophilic reactions of β-lactone enolates.
ChemInform, 2006
The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis--lactones. The well-documented upregulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl--lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted--lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent R-epimerization and R-alkylation or acylation led to trans--lactones and -lactones bearing R-quaternary carbons, respectively. Several of the ketene dimers and -lactones displayed antagonistic activity (apparent K i in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis--lactone 3d, displayed an apparent K i (2.5 ( 0.5 µM) of only ∼10-fold lower than that of orlistat (0.28 ( 0.06 µM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.
Angewandte Chemie International Edition, 2004
I. General THF was purified by passing it through a neutral alumina column. Zinc metal (Strem) was activated with hydrochloric acid. Benzaldehyde (Aldrich), ptrifluoromethylbenzaldehyde (Aldrich), p-tolualdehyde (Aldrich), and 2-bromo-2methylpropanoylbromide (Aldrich) were distilled prior to use. Quinidine (Avocado), LiClO 4 (Alfa Aesar), 2-napthaldehyde (Aldrich), 4-acetylbenzaldehyde (Aldrich), DIBAL-H (1.0 M in THF; Aldrich), sodium azide (Alfa Aesar), DMSO (Aldrich), and npropylamine (Aldrich) were used as received. Non-commercially available αbromoacid bromides were synthesized according to a literature procedure. 1 Catalysts 1, 2 2, 3 and O-TMS-quinidine 4 were prepared as previously reported. All reactions were carried out under an atmosphere of nitrogen or argon in ovendried glassware with magnetic stirring, unless otherwise indicated.
Diastereoselective Synthesis of Functionalized δ‐Lactones
Synthetic Communications, 2004
a b s t r a c t This paper describes a convenient synthesis of disubstituted functionalized d-lactams based on Michael addition of primary amines to dimethyl-E-2-alkylidene glutarates 2 followed by an intramolecular cyclisation.