Asymmetric Synthesis of Bicyclic β-Lactones via the Intramolecular, Nucleophile-Catalyzed Aldol Lactonization: Improved Efficiency and Expanded Scope (original) (raw)
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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.
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
Lactone Synthesis by Enantioselective Orthogonal Tandem Catalysis
Angewandte Chemie, 2019
In this work, we report enantioselective orthogonal tandem catalysis for the one pot conversion of Meldrums acid derivatives and alkynes into d-lactones. This new transformation, which resembles a formal [4+2] cycloaddition with concomitant decarboxylation and loss of acetone, proceeds in high yields and excellent enantioselectivity (up to 99 % ee) over a broad substrate scope. The products are densely functionalized and ripe for further transformations, as demonstrated here by both ring-opening reactions and reduction to saturated lactones. It was discovered that a new and serendipitously formed Ag I-Me-StackPhos complex efficiently catalyzes the highly selective 6-endo-dig cyclization, completely reversing the regiochemistry that has been previously reported in related systems. More generally, in this study we identify a pair of compatible catalysts for alkyne difunctionalization that operate concurrently, which enable the alkyne to act as both a nucleophile and an electrophile in sequential one-pot transformations. Scheme 1. Enantio-and regioselective orthogonal tandem catalysis.
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.
?-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.
Angewandte Chemie International Edition, 2010
Ongoing efforts have been dedicated to the development of reaction processes controlled by chiral hypervalent iodine reagents with high enantioselectivity. [1-12] The oxidation of sulfides into sulfoxides, [2] the a-oxygenation of ketones, [3, 4] the dioxygenation of alkenes, [4, 5, 12] and the dearomatization of phenols [6-8, 9b] have been reported, and most of these reactions resulted in an encouraging level of enantioselectivity. Kita and co-workers reported dearomatizing spirolactonization of naphthols (78-86 % ee) using a spirocyclic iodine(III) reagent. [6] Ishihara and co-workers recently reported that higher enantioselectivities were obtained for the spirolactonization by using a chiral iodine compound derived from lactic acid. [8] Our studies with optically active hypervalent iodine compounds have been focused on mechanisms of the reaction concerned [11] as well as synthetic applications. [12] Asymmetric oxidation of 4-acyloxybut-1-ene into 3-acyloxytetrahydrofuran (up to 64 % ee) was achieved by using chiral hypervalent iodine(III) reagents, 1 and 2, which have a lactate moiety as a chiral source. [12] During the course of these studies for the asymmetric oxidative cyclization of alkenes, we found that oxidation of ortho-alk-1-enylbenzoate with the hypervalent iodine reagent regio-and diastereoselectively gave 3-alkyl-4oxyisochroman-1-one in a practically useful degree of enantiomeric purity (90-98 % ee); the isochromanone framework is a biologically relevant building block of natural products. [13, 14] Herein, we report the synthetic utility of such enantiodifferentiating endo-selective oxylactonizations. The series of optically active hypervalent iodine (III) reagents 1-6 employed in this report is shown in Scheme 1. On the basis of reagents 1 and 2 reported previously, [12] the structures of the iodine reagents were tuned for improved enantioselectivity. The X-ray crystallographic structures of 1-4 showed a typical T-shape orientation around the iodine center, where the two acetoxy ligands occupied apical positions (see the Supporting Information). 2-Ethenylbenzoic acid (7 a) was subjected to the reaction conditions with the optically active hypervalent iodine(III) reagent. The reaction was carried out in the presence of paratoluenesulfonic acid (TsOH) to activate the iodine reagent, and the tosylate also worked as a nucleophile to give lactones 8 a and 9 a (Table 1). The reaction proceeded regioselectively to give the d-lactone product 8 a as the major product. The reaction with 6 gave a higher ee value of 8 a with high regioselectitvity (Table 1, entry 5).