Total synthesis of (+)-milbemycin .beta.3

Barrett, Anthony G. M.; Carr, Robin A. E.; Attwood, Stephen V.; Richardson, Geoffrey; Walshe, Nigel

doi:10.1021/jo00375a017

Cited by 105 publications

(35 citation statements)

References 10 publications

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“…[34,35] The subsequent bromination of the remaining olefin had to be performed with 4-dimethylaminopyridinium bromide perbromide in the presence of 4-dimethylaminopyridine (DMAP) as the reagent, [36] because attempted addition of Br 2 led to partial decomposition of the material. The outcome of the elimination of the resulting vicinal dibromide 21 strongly depended on the chosen base.…”

Section: Resultsmentioning

confidence: 99%

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Fürstner

Souza

Turet

et al. 2006

Chemistry A European J

126

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The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne–yne metathesis of suitable diyne or enyne–yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me₂C₆H₃)N]₃Mo (37) as precatalyst activated in situ with CH₂Cl₂, as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)₃WCΞCMe₃] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine, and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner–Wadsworth–Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C[BOND]C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography

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Section: Resultsmentioning

confidence: 99%

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Fürstner

Souza

Turet

et al. 2006

Chemistry A European J

126

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“…However, we knew 2 that heating 1, which exists in its cyclic hemiacetal forms (1'/1'', 60:40), with the stabilised Wittig reagent Ph 3 P=CHCOOEt would give the (E)-unsaturated ester impurified by 7% of its Z isomer (which could not be separated by flash chromatography). 2 We needed to avoid stereoisomeric mixtures, as we required stereopure C20-C25 fragments. We synthesised 1/1'/1'' in four steps, in 50% overall yield, from O-protected (S)-2-hydroxypropanal 3 and treated the equilibrium mixture (Scheme 2)…”

mentioning

confidence: 99%

Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

Carrillo

Costa

Sidera

et al. 2011

Tetrahedron Letters

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“…10 Compound 3 can be prepared inexpensively from dimethyl oxalate in 50 g scale. 11 Employing nonpolar hexane solvent in both the lithiation reaction and the subsequent carbonyl attack reaction is crucial for a good yield. Yield is poor (~30%) when THF is used instead of hexane.…”

mentioning

confidence: 99%

Short and Efficient Synthesis of Cyclopentadithiophene and Its Dialkylated Product

Park¹,

Lee

2010

Bulletin of the Korean Chemical Society

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Total synthesis of (+)-milbemycin .beta.3

Cited by 105 publications

References 10 publications

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

Short and Efficient Synthesis of Cyclopentadithiophene and Its Dialkylated Product

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