Spirodiepoxides in Total Synthesis:  Epoxomicin

Katukojvala, Sreenivas; Barlett, Kristin N.; Lotesta, Stephen D.; Williams, Lawrence J.

doi:10.1021/ja044563c

Cited by 50 publications

(29 citation statements)

References 13 publications

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“…18,19 This methodology has been applied in the context of several total syntheses of natural products (i.e. epothilone A and B, 20 epoxomicin, 21 gigantecin, 22 leucascandrolide A, 23 indolizidine, 24 and strongylodiol A and B). 25 1.3 Conjugate Addition of Preformed Metal Alkynylides.…”

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confidence: 99%

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Fujimori¹,

Knöpfel²,

Zarotti³

et al. 2007

Bulletin of the Chemical Society of Japan

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In this account, new methods for the catalytic and stereoselective conjugate addition of terminal alkynes are described. Our laboratories have disclosed asymmetric addition reactions to aldehydes and imines using a combination of a zinc or copper salt and a terminal alkyne. Under these conditions, terminal alkyne is transformed in situ into an alkynyl metal species. Recently, it was found that these in situ generated alkynyl metal species can undergo conjugate additions to alkylidene malonate-type acceptors. In the zinc(II) triflate-catalyzed system, a highly diastereoselective conjugate addition has been realized using a chiral oxazepene acceptor. Subsequently, alternative conjugate addition protocols have been developed which employ a terminal alkyne, substoichiometric amounts of copper and a highly eletrophilic Meldrum's acid derived acceptor. This reaction can be made enantioselective using a novel atropisomeric P,Nligand (PINAP). With this ligand, excellent enantioselectivities can be achieved for the conjugate addition of aromatic alkynes to various Meldrum's acid derived acceptors.

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confidence: 99%

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Fujimori¹,

Knöpfel²,

Zarotti³

et al. 2007

Bulletin of the Chemical Society of Japan

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“…[1][2][3][4][5][6][7][8][9][10] Sequential allene oxidation gives SDEs. Nucleophilic SDE opening effectively translates the three-carbon axis of chirality of the allene into a densely functionalized motif: two differentially functionalized stereogenic centers separated by a ketone.…”

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confidence: 99%

“…To test this hypothesis, we examined a series of related nucleophiles, a key subset of which is shown in Table 1. Anionic and neutral nucleophiles have been shown to add to SDEs efficiently under non-acidic conditions, including deprotonated benzenesulfonamide, lithium benzimidate, azide, [1] certain aliphatic alkoxides, phenyl thiolate, chloride, fluoride, [5] organocuprates, [2] along with ammonia and a limited number of secondary amines. [5] Cyanide, an anionic carbon nucleophile, as well as the anionic oxygen nucleophiles acetate [12] and phenoxide, added to give the corresponding products in good yield (Table 1, entries 1-3).…”

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confidence: 99%

“…SDE stereochemistry was assigned based on analogy to earlier models: The first oxidation is highly selective, the second oxidation is less selective, and the product ratios matched the SDE ratios. [1][2][3][4][5] Although spontaneous formation of imidazoles from the imidazolines complicated imidazoline isolation, thiazolines and oxazolines were readily obtained in pure form. NOE analysis allowed trans assignment of the carbinol and the alkyl substutuents of the azolines (2 a and 2 b), as expected based on thermodynamic considerations.…”

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confidence: 99%

“…As with other nucleophilic openings, SDE opening takes place with inversion at the least-substituted site. [1,2,5] Second, weakly acidic reagents, for example, water, methanol, and phenol, open SDEs very slowly under neutral conditions. Consequently, a large excess of reagent is required for reasonable reaction times.…”

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Spirodiepoxides: Heterocycle Synthesis and Mechanistic Insight

et al. 2007

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The spirodiepoxide (SDE) functional group has emerged as an electrophile with potential applications in synthesis. [1][2][3][4][5][6][7][8][9][10] Sequential allene oxidation gives SDEs. Nucleophilic SDE opening effectively translates the three-carbon axis of chirality of the allene into a densely functionalized motif: two differentially functionalized stereogenic centers separated by a ketone. To be applied generally, nucleophiles that effect SDE opening must continue to be identified, a general method for the stereoselective formation of SDEs must be developed, and a mechanistic understanding of nucleophilic opening must be established. This report is focused on new mechanistic insight gained through investigations on the formation of heterocycles from SDEs. We relate herein the formation of azoles from SDEs, the first crystal structure of an SDE, and a new mechanistic model for nucleophilic SDE opening supported by computational analysis.Despite the mechanistic rationales suggested by others, [5][6][7][8][9]

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