Synthesis and reactions of derivatives of 1,7-dioxaspiro[5.5]undec-2-en-4-one

Barrett, Anthony G. M.; Carr, Robin A. E.; Finch, Mark A. W.; Florent, Jean‐Claude; Richardson, Geoffrey; Walshe, Nigel

doi:10.1021/jo00372a028

Cited by 23 publications

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“…These results are in total agreement with literature precedents for the reduction of analogous simpler spiroketals. 25,27 The situation is far less favorable for 26 when the C-18 methyl group is present. Not only is there no clear selectivity in the case of NaBH 4 reduction, but a non-negligible amount of adduct 28, where the ester function is reduced, was obtained, probably due to the overall steric hindrance around the carbonyl keto group.…”

Section: Methodsmentioning

confidence: 99%

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Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Lopez¹,

Poupon²,

Prunet³

et al. 2004

Synthesis

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Studies dealing with the diastereoselective installation of nine stereogenic centers of the C-12-C-25 subunit of bafilomycin A 1 1 are described. A spiroketal precursor has been chosen as a rigid scaffold owing to the central spiro center, the configuration of which is dictated by predictable anomeric effects. A strategy using a previously described anti-Danishefsky condensation of chiral anti-aldehyde 6(OTES) with pentan-2,4-dione bis(trimethylsilyl)ether 7 (M = TMS), followed by an oxalate condensation to the other end of the pentanedione unit, afforded the required spiroketalic enone precursor 24. After generating the C-18 and C-17 centers through an enolate methylation reaction-Luche reduction sequence followed by a Mitsunobu inversion to give 27, the remaining C-16 methyl group was achieved via a hydroxy-directed cyclopropanation-reductive opening sequence to give the fully functionalized C-15-C-25 spiroketal 35. Further elongation at the C-14 center involved a Felkin-Ahn stereocontrolled addition of trimethylsilylacetylene followed by a one-pot O-methylation-desilylation, affording the acetylenic subunit 44, ready to be transformed into the vinylstannne required for the subsequent Stille coupling reaction with a C-1-C-11 subunit of bafilomycin A 1 . A 15-epi spiroketal intermediate has also been synthesized, as well as various 18-desmethyl analogues for comparative studies.Bafilomycin A 1 (1) belongs to a group of antibiotics called 'plecomacrolides' that all have 16 or 18 carbons. 2 This 16-membered unsaturated macrolide, as well as its 18-membered congener concanamycin A, 3 are potent selective inhibitors of vacuolar-type H + -ATPases (V-ATPases) 4 and are therefore endowed with broad potential biological activity, though they are too toxic for therapeutic use. However, recent structure-activity studies on bafilomycins, as well as recent advances in the characterization of particular V-ATPase enzyme isoforms, may provide new avenues for the development of less toxic and more specific analogues to fight specific diseases where V-ATPases dysfunction may be involved, such as osteoporosis. 5 The unique biological activity of bafilomycin A 1 as well as its challenging complex structure, which includes the unique folded tetrahydropyran hemiketalic side chain, are continuously stimulating the interest of the chemistry community. 6Our current program toward the total synthesis of 1 involves the late coupling of two major fragments of similar complexity using a Pd-catalyzed reaction to form the C-11-C-12 bond, followed by a macrolactonization as the final steps. We have recently published a synthesis of the C-1-C-11 subunit of bafilomycin A 1 using both non-Wittig and desymmetrization methodologies. 7 For the C-12-C-25 subunit, as summarized in Scheme 1, we envision two synthons: linear 2a, on which hemiketalization would be performed after the macrocyclization, and spiroketal 2b, which would undergo concomitant spiroketal 'semi-opening' to liberate the hydroxy at C-15 and lactonization.These two compounds would b...

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Section: Methodsmentioning

confidence: 99%

“…The stereochemistry observed here for the condensation product is also in agreement with a similar case described by Barrett et al for an aldol condensation reaction on an analogous oxospiroketal. 25…”

Section: Synthesis Of Intermediatementioning

confidence: 99%

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Lopez¹,

Poupon²,

Prunet³

et al. 2004

Synthesis

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“…b-Keto esters can easily be prepared by reactions of acylhalogenides and ketones in the presence of metalorganic bases (LDA, LiHMDS, etc.). This transformation poses not a challenge and the reaction proceeds without any problems (Scheme 40) [21].…”

Section: 2-difunctional Compoundsmentioning

confidence: 99%

Logic of organic chemistry

2016

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A system of logic disconnection or construction of organic molecules is given to overcome serious problems in the study of organic chemistry. Based on the logic system of polar reactions of donors and acceptors several different reactions can be created to access a required target molecule. By a following careful analysis of these proposals several transformations can be detected as the preferred ones. Moreover, by the introduction of the ''umpolung'' principle additional options are given to synthesize a required molecule. These considerations were discussed in the 1,2-, 1,3-, 1,4-, 1,5-and 1,6-difunctional series.

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“…[2] 1,3,5,7-Tetracarbonyl compounds and their higher homologues are unstable because they easily form phenols by intramolecular aldol condensations. Polyketides are available by reaction of 1,3-dicarbonyl dianions with carboxylic acid derivatives.…”

Section: Introductionmentioning

confidence: 99%

Experimental and Theoretical Study of the Keto–Enol Tautomerization of 3,5‐Dioxopimelates

et al. 2011

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Synthesis and reactions of derivatives of 1,7-dioxaspiro[5.5]undec-2-en-4-one

Cited by 23 publications

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Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Logic of organic chemistry

Experimental and Theoretical Study of the Keto–Enol Tautomerization of 3,5‐Dioxopimelates

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Synthesis and reactions of derivatives of 1,7-dioxaspiro[5.5]undec-2-en-4-one

Cited by 23 publications

References 0 publications

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A1

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A1

Logic of organic chemistry

Experimental and Theoretical Study of the Keto–Enol Tautomerization of 3,5‐Dioxopimelates

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Product

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Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁