Diastereoselective Additions of Allylmetal Reagents to Free and Protected <i>syn</i>-<b>α,β</b>-Dihydroxyketones Enable Efficient Synthetic Routes to Methyl Trioxacarcinoside A

Smaltz, Daniel J.; Švenda, Jakub; Myers, Andrew G.

doi:10.1021/ol300377a

Cited by 13 publications

(13 citation statements)

References 40 publications

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“…High regioselectivity and diastereoselectivity, however, were observed in the addition to 23e through the γ-addition pathway. This addition could proceed either through ketone 23e or the corresponding magnesium alkoxide, considering that the rate of addition of allylic Grignard reagents to carbonyl compounds is comparable to the rate of proton transfer. , A control experiment indicated that addition to the magnesium alkoxide is consistent with the selectivity shown in Table . One equivalent of methylmagnesium chloride was first added to 23e at −78 °C to deprotonate the hydroxyl group, then prenylmagnesium chloride was added to the mixture.…”

Section: Resultsmentioning

confidence: 89%

Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds

Bartolo

Woerpel

2018

J. Org. Chem.

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Allylic Grignard reagents exhibit high reactivity and low selectivity in additions to carbonyl compounds. Additions of allylic Grignard reagents to carbonyl compounds were investigated using prenylmagnesium chloride as a mechanistic probe. When the carbonyl group is relatively unhindered, the addition proceeds through a six-membered transition state with allylic transposition. This process generally occurs with no diastereoselectivity because the reaction rates approach the diffusion limit. With hindered ketones, however, this pathway is disfavored, and the addition proceeds through a transition state resembling that of other Grignard reagents.

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Section: Resultsmentioning

confidence: 89%

Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds

Bartolo

Woerpel

2018

J. Org. Chem.

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“…The low selectivity exhibited in reactions of allylmagnesium halides with chiral, α-alkoxy ketones is evident when direct comparisons to other organomagnesium reagents are made . For example, we found that whereas addition of n -propylmagnesium chloride to ketone 2 was highly selective for the chelation-control product (eq ), addition of allylmagnesium chloride proceeded with low stereoselectivity, favoring the opposite stereoisomer (eq 2).…”

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confidence: 82%

Additions of Organomagnesium Halides to α-Alkoxy Ketones: Revision of the Chelation-Control Model

2017

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The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to α-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CHCl as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed.

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“… 12 We elected to explore initial couplings with 1- O -acetyl trioxacarcinose A ( 3 , Figure 2 ), which is available in multi-gram amounts by a short and practical sequence. 13 We found that when a mixture of diol 2 (1 equiv), glycosyl donor 3 (2 equiv, a 1:12 mixture of α- and β-anomers, respectively), and powdered 4-Å molecular sieves in dichloromethane at −40 °C was treated with boron trifluoride etherate (1.0 equiv) as promoter the α-monoglycoside 4 was formed in 79% yield (23 mg). The β-configured glycosylation product was not observed.…”

Section: Resultsmentioning

confidence: 95%

Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

2013

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The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogs that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogs arising from modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.The trioxacarcins are bacterial metabolites of remarkable structural complexity that broadly inhibit the growth of cultured bacterial and eukaryotic cells. [1][2][3][4][5] A number of unusual chemical features characterize the family, including a rigid, highly oxygenated polycyclic skeleton with a fused spiro epoxide function, as many as five ketal or hemiketal groups (three of them within a span of four contiguous carbon atoms) and one or more unusual glycosidic residues, eponymously identified as "trioxacarcinoses". The most potent family member yet identified, trioxacarcin A (Figure 1), displays subnanomolar IC 70 values in a number of different human cancer cell lines. Its extraordinary antiproliferative effects are believed to derive from the fact that trioxacarcin A efficiently and irreversibly alkylates G residues of duplex DNA, forming a covalent bond between the exocyclic carbon atom of the spiro epoxide function and N7 of the G residue that is alkylated. Both the DNA lesion and the product of depurination that is formed from it upon heating, a 1:1 adduct of guanine and Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsCorrespondence and requests for materials should be addressed to A.G.M. * myers@chemistry.harvard.edu Reprints and permission information is available online at http://npg.nature.com/reprintsandpermissions/. Additional information:The authors declare no competing financial interests.Supplementary information and chemical compound information accompany this paper at www.nature.com/naturechemistry. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript trioxacarcin A ("gutingimycin"), 6 have been crystallographically characterized in seminal work from researchers at the University of Göttingen. 7Although so far as we are aware trioxacarcins have...

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Diastereoselective Additions of Allylmetal Reagents to Free and Protected syn-α,β-Dihydroxyketones Enable Efficient Synthetic Routes to Methyl Trioxacarcinoside A

Cited by 13 publications

References 40 publications

Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds

Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds

Additions of Organomagnesium Halides to α-Alkoxy Ketones: Revision of the Chelation-Control Model

Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

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