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A simple and general platform for generating stereochemically complex polyene frameworks by iterative cross-coupling.

Lee SJ, Anderson TM, Burke MD - Angew. Chem. Int. Ed. Engl. (2010)

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave, Urbana, IL 61801, USA.

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Aiming to maximally harness the inherent modularity of small molecules, we are pursuing the development of a synthesis strategy based on the iterative cross-coupling (ICC) of bifunctional building blocks representing the substructures that most commonly appear in natural products., In this vein, various combinations of trans- and cis-olefins are found in many small molecules derived from a wide range of biosynthetic pathways, including polyketides, hybrid peptide/polyketides, polyterpines, and fatty acids (Scheme 1)., Enabling stereospecific access to these stereochemically complex polyene frameworks, we herein describe the development of a novel ICC platform that yields bifunctional iodopolyenyl N-methyliminodiacetic acid (MIDA) boronates in all possible stereoisomeric forms... We recently reported three haloalkenyl MIDA boronates that enabled the preparation of a subset of polyene motifs by ICC... Accessing stereochemically complex polyene motifs is substantially more challenging because, in addition to the sensitivities observed with all polyenes to light, oxygen, and acid, frameworks containing cis double bonds can isomerize to the typically more thermodynamically stable all-trans structures... Moreover, poorly reactive polyenylchlorides proved to be minimally effective in complex applications... To overcome both of these limitations, we pursued a novel strategy for making iodopolyenyl MIDA boronates by ICC of iodide-masked bifunctional building blocks... To the best of our knowledge, iododegermylations of polyenylgermanium species were unreported... However, the facility of halodegermylation vs. halodesilylation of simple olefins suggested that the former process had superior potential to be efficient and stereoretentive in the context of structurally and stereochemically complex polyene systems... One-pot hydrostannylation of followed by iododestannylation of the resulting bis-metalated intermediate provided an excellent yield of (E)-... Alternatively subjecting to a series of silver-promoted alkyne iodination followed by PADC-mediated semireduction provided the complementary building block (Z)-... With these four core building blocks in hand, we sought general conditions for efficient cycles of stereospecific metal-selective couplings and iododegermylations (Scheme 2 A)... As shown in Scheme 5, we found that Liebeskind-type conditions are remarkably effective for the targeted metal-selective Stille couplings... As shown in Table 1, these new bifunctional building blocks collectively enable the preparation of a broad range of stereochemically complex polyene natural product frameworks... After surveying a variety of catalysts, bases, and solvents we found a very mild set of Buchwald-type cross-coupling conditions [Pd(OAc)2, SPhos or XPhos, Cs2CO3, THF, 23 °C] that proved to be highly effective... As a final test for this new platform, we targeted an ICC-based synthesis of the stereochemically complex polyene core of the exceptionally potent ion channel forming natural product vacidin A (Scheme 1)... These new building blocks represent important additions to a growing collection of MIDA boronates designed to support the development of a simple and flexible platform for the efficient synthesis of small molecules by ICC.

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Synthesis of the stereochemically complex heptaene core of vacidin A.
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sch07: Synthesis of the stereochemically complex heptaene core of vacidin A.


A simple and general platform for generating stereochemically complex polyene frameworks by iterative cross-coupling.

Lee SJ, Anderson TM, Burke MD - Angew. Chem. Int. Ed. Engl. (2010)

Synthesis of the stereochemically complex heptaene core of vacidin A.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037596&req=5

sch07: Synthesis of the stereochemically complex heptaene core of vacidin A.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave, Urbana, IL 61801, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Aiming to maximally harness the inherent modularity of small molecules, we are pursuing the development of a synthesis strategy based on the iterative cross-coupling (ICC) of bifunctional building blocks representing the substructures that most commonly appear in natural products., In this vein, various combinations of trans- and cis-olefins are found in many small molecules derived from a wide range of biosynthetic pathways, including polyketides, hybrid peptide/polyketides, polyterpines, and fatty acids (Scheme 1)., Enabling stereospecific access to these stereochemically complex polyene frameworks, we herein describe the development of a novel ICC platform that yields bifunctional iodopolyenyl N-methyliminodiacetic acid (MIDA) boronates in all possible stereoisomeric forms... We recently reported three haloalkenyl MIDA boronates that enabled the preparation of a subset of polyene motifs by ICC... Accessing stereochemically complex polyene motifs is substantially more challenging because, in addition to the sensitivities observed with all polyenes to light, oxygen, and acid, frameworks containing cis double bonds can isomerize to the typically more thermodynamically stable all-trans structures... Moreover, poorly reactive polyenylchlorides proved to be minimally effective in complex applications... To overcome both of these limitations, we pursued a novel strategy for making iodopolyenyl MIDA boronates by ICC of iodide-masked bifunctional building blocks... To the best of our knowledge, iododegermylations of polyenylgermanium species were unreported... However, the facility of halodegermylation vs. halodesilylation of simple olefins suggested that the former process had superior potential to be efficient and stereoretentive in the context of structurally and stereochemically complex polyene systems... One-pot hydrostannylation of followed by iododestannylation of the resulting bis-metalated intermediate provided an excellent yield of (E)-... Alternatively subjecting to a series of silver-promoted alkyne iodination followed by PADC-mediated semireduction provided the complementary building block (Z)-... With these four core building blocks in hand, we sought general conditions for efficient cycles of stereospecific metal-selective couplings and iododegermylations (Scheme 2 A)... As shown in Scheme 5, we found that Liebeskind-type conditions are remarkably effective for the targeted metal-selective Stille couplings... As shown in Table 1, these new bifunctional building blocks collectively enable the preparation of a broad range of stereochemically complex polyene natural product frameworks... After surveying a variety of catalysts, bases, and solvents we found a very mild set of Buchwald-type cross-coupling conditions [Pd(OAc)2, SPhos or XPhos, Cs2CO3, THF, 23 °C] that proved to be highly effective... As a final test for this new platform, we targeted an ICC-based synthesis of the stereochemically complex polyene core of the exceptionally potent ion channel forming natural product vacidin A (Scheme 1)... These new building blocks represent important additions to a growing collection of MIDA boronates designed to support the development of a simple and flexible platform for the efficient synthesis of small molecules by ICC.

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