Asymmetric Synthesis of Highly Substituted ?-Lactones by Nucleophile-Catalyzed [2+2] Cycloadditions of Disubstituted Ketenes with Aldehydes (original) (raw)
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In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer β-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer β-lactones were obtained in good to excellent yields (up to 90%), with excellent levels of enantioselectivity (≥90% ee for 33 Z and E isomer examples), good to excellent (Z)-olefin isomer selectivity (≥90:10 for 20 examples), and excellent regioselectivity (only one regioisomer formed). Full details of catalyst development studies, catalyst loading investigations, substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1-2 equiv) as an additive to the alkaloid catalyst system was found to favor formation of the E isomer of the ketene heterodimer...
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
Beilstein Journal of Organic Chemistry
The acylation of the acetonitrile anion with lactones and esters in ethereal solvents was successfully exploited using inexpensive KOt-Bu to obtain a variety of β-ketonitriles and trifunctionalized building blocks, including useful O-unprotected diols. It was discovered that lactones react to produce the corresponding derivatized cyclic hemiketals. Furthermore, the addition of a catalytic amount of isopropanol, or 18-crown-6, was necessary to facilitate the reaction and to reduce side-product formation under ambient conditions.
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.
Journal of the American Chemical Society, 2002
General. Unless otherwise stated, all reactions were carried out under strictly anhydrous, air-free conditions. All solvents were dried and distilled by standard methods. Unless otherwise mentioned, all acid chlorides were purchased directly or made from their corresponding acid and purified before use. Catalysts 4c, 1 4d, 2 4e, 1 4h, 3 4i, 4 4j, 5 imine 5a, 6 N,O-acetal 7 7 and phenyldiazoketone 10 8 were prepared according to literature procedure. Products 6a-d, 6g-i 9 , and 6e 10 were previously characterized. All additional reagents used were commercially available from Aldrich and Acros Chemicals. For photochemical reactions, a Southern New England Ultra Violet Company Rayonet Photo Mini-Reactor (8 x 4W bulbs) was employed. For React IR experiments an ASI Applied Systems ReactIR™ 1000 was used. 1 H and 13 C NMR spectra were acquired on a Varian Unity Plus 400 MHz instrument in CDCl 3. The 1 H (400 MHz) and 13 C (101 MHz) chemical shifts are given in parts per million (δ) with respect to internal TMS standard or residual solvent peaks. FTIR spectra were recorded on a Bruker Vector 22 spectrometer and optical rotations were recorded on a Perkin Elmer 120 polarimeter at room temperature.