Strategies for the Total Synthesis of C2−C11 Cyclized Cembranoids

Ellis, J. Michael; Crimmins, Michael T.

doi:10.1021/cr078117u

Cited by 52 publications

(28 citation statements)

References 243 publications

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“…208,209 Along with the biogenetically related briarellin, asbestinin, and sarcodictyin diterpenes, members of this large family have proven popular targets for total synthesis and many creative strategies have been described. 210 Of relevance to this review are 21 st century chiral pool syntheses of deacetoxyalcyonine acetate (by Molander) 167 and briarellins E and F (by Overman), 160 both of which were highlighted in Gaich and Mulzer’s review. 21 Paquette and co-workers first described a synthetic route to 168 during their studies toward the synthesis of related sclerophytin A.…”

Section: Syntheses From the 21st Centurymentioning

confidence: 99%

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

et al. 2017

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The pool of abundant chiral terpene building blocks (i.e. “chiral pool terpenes”) has long served as a starting point for the chemical synthesis of complex natural products, including many terpenes themselves. As inexpensive and versatile starting materials, such compounds continue to influence modern synthetic chemistry. This review highlights 21st century terpene total syntheses which themselves use small, terpene-derived materials as building blocks. An outlook to the future of research in this area is highlighted as well.

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Section: Syntheses From the 21st Centurymentioning

confidence: 99%

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

et al. 2017

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“…The natural role of these cembranoids was proposed, based on mollusk and fish lethality assays, to involve predation deterrence. 26 (þ)-Vigulariol 50, briarellin J 52, and 11-acetoxy-4deoxyasbestinin D 54 belong to the eunicellin, briarellin, and asbestinin family, respectively. 31 The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has gained significant attraction, and to date several total syntheses have been accomplished.…”

Section: Synthesis Of C2-c11 Cyclized Cembranoidsmentioning

confidence: 99%

Stereoselective Cycloaddition Reactions

Lee

Ahn

2013

Stereoselective Synthesis of Drugs and Natural Products

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Cycloaddition is a member of pericyclic reactions in which reactive components possessing conjugated π‐electrons (e.g., diene/dienophile, 1,3‐dipole/dipolarophile, and ketene/imine) transform into cyclic molecules. These reactions proceed in a concerted mechanism with a high degree of regio‐ and stereoselectivity. Thus, they have been widely used for the construction of cyclic skeletons of numerous natural products and pharmacologically active molecules. Based on the π‐electron systems of reactants, they can be further classified into [4 + 2], [3 + 2], and [2 + 2] cycloadditions that produce six‐, five‐, and four‐membered rings, respectively. On the other hand, whereas natural products and designed synthetic molecules may offer a starting point in drug development, improvement of their structures and properties is frequently needed to optimize their biological efficacy. To this end, solid‐phase synthesis is a powerful tool for generating a large number of compounds with synthetic convenience and many solid‐phase cycloaddition reactions have been reported to date. This review, in particular, summarizes stereoselective cycloaddition reactions and their solid‐phase versions carried out on polymer supports for the synthesis of natural products and their analogs, focusing on the reactions that were employed as key steps.

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“…[3b, 6] Due to the complex molecular architecture of cembranoids, as well as their potentiala sp harmacological agents, these natural products and their analogues have attracted much interest in the synthetic community. [5,7] These compounds are usually synthesized in ac hemical convergent approach,i nw hich multiple, separately generated fragments are combined in the desired product. Functional groups,i ncluding oxygen functions, are introduced already at an early stage of the synthesis which requiresl aboriousp rotecting group manipulations in the followings teps.…”

Section: Introductionmentioning

confidence: 99%

“…Functional groups,i ncluding oxygen functions, are introduced already at an early stage of the synthesis which requiresl aboriousp rotecting group manipulations in the followings teps. [7,8] Alternatively, am inimallyo xidized hydrocarbon skeleton, synthesized from simple building blocks, can be oxidized at a later-stage of synthesis, whicha llows am ore effective diversification. Inspired by terpeneb iosynthesis, Baran and co-workers introduced ab iomimetic "two-phase" approach for the total synthesis of naturalp roducts and their analogues.…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Route to Oxyfunctionalized Cembranoids Facilitated by Substrate and Protein Engineering

Le‐Huu

Rekow

Krüger

et al. 2018

Chemistry A European J

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Cembranoids constitute a large family of 14-membered oxygenated macrocyclic diterpenoids with potential as therapeutic agents. Selective late-stage oxidations of cembranoid scaffolds remain a challenge for chemical catalysts but can be accomplished by enzymes. Here, a new chemoenzymatic route to oxyfunctionalized 14-membered macrocycles including cembranoids is described. This route combines a metal-catalyzed ring-closing metathesis with a subsequent P450 BM3-catalyzed hydroxylation and delivers cembranoid-like analogues. Systematic substrate probing with a set of synthetic 14-membered macrocycles revealed that the regioselectivity of a P450 BM3-based biocatalyst increased with increasing ring rigidity as well as size and polarity of the exocyclic substituents. Enzyme regioselectivity could further be improved by first-sphere active site mutagenesis. The V78A/F87A variant catalyzed hydroxylation of cembranoid-ol (9S/R)-3 d with 90 % regioselectivity for C5 position. Extensive NMR analysis of Mosher esters and single crystal X-ray structure determination revealed a remarkable diastereoselectivity of this P450 BM3 mutant depending on substrate stereochemistry, which led exclusively to the syn-cembranoid-diols (5S,9S)-4 and (5R,9R)-4.

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Strategies for the Total Synthesis of C2−C11 Cyclized Cembranoids

Abstract: Scheme 2. Completion of (-)-7-Deacetoxyalcyonin Acetate Scheme 3. Overman's Completion of the Proposed Structure of Sclerophytin A

Cited by 52 publications

References 243 publications

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

Stereoselective Cycloaddition Reactions

Chemoenzymatic Route to Oxyfunctionalized Cembranoids Facilitated by Substrate and Protein Engineering

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