Total Synthesis of Aigialomycin D:  Surprising Chemoselectivity Dependence on Alkyne Structure in Nickel-Catalyzed Cyclizations

Chrovian, Christa C.; Knapp-Reed, Beth; Montgomery, John

doi:10.1021/ol702961v

Cited by 58 publications

(22 citation statements)

References 27 publications

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“…4a,9 This limitation was confirmed in a recent attempt to access exo-selective reductive macrocyclizations 10 using existing protocols including those originating from our laboratory. 11 However, a recent disclosure from our laboratory described studies with an expanded set of ligands, wherein a broad range of alkynes participated in intermolecular reductive couplings to provide either regioisomer in a ligand-controlled process.…”

Section: Resultsmentioning

confidence: 65%

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Nickel-catalyzed regiodivergent approach to macrolide motifs

2012

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A strategy for regiochemical reversal of reductive macrocyclizations of aldehydes and terminal alkynes has been developed. Using an advanced synthetic intermediate directed towards the methymycin/neomethymycin class of macrolides, selective endocyclization provides the natural twelve-membered ring series, whereas ligand alteration enables selective exocyclization to provide access to the unnatural eleven-membered ring series. The twelve-membered ring adduct was converted to 10-deoxymethynolide, completing an efficient total synthesis of this natural product.

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Section: Resultsmentioning

confidence: 65%

“…4a,9 Utilizing triethylsilane as a reducing agent and 30 mol% Ni(COD) 2 , 30 mol % IMes-HCl, and 40 mol % KO- t -Bu in THF allowed clean production of reductive endocyclization product 14 and its C7 epimer in 58% yield (Scheme 2). Notably a 4:1 dr, favoring diastereomer 14 , was obtained under these conditions.…”

Section: Resultsmentioning

confidence: 99%

Nickel-catalyzed regiodivergent approach to macrolide motifs

2012

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“…We therefore examined the reaction more extensively, and in analogy to an observation made in our recent synthesis of aigialomycin D,xiii we ultimately found that employing 2.0 equiv of Garner aldehyde 1 in couplings of 2d with trace water in THF allowed reasonably efficient couplings,xiv providing the desired vinyl silane 3d in 65 % isolated yield with complete stereocontrol (>98:2 dr, >98:2 Z : E , Scheme 4). n -Bu 4 NF-mediated deprotection of 3d to 11 proceeded in 91 % isolated yield, which was followed by the 2N HCl deprotection described above (73 % yield) to complete a more direct synthesis of D- erythro -sphingosine.…”

Section: Resultsmentioning

confidence: 93%

Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and alkynylsilanes: application to the synthesis of d-erythro-sphingosine

Sa-ei

Montgomery

2009

Tetrahedron

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A strategy for the nickel-catalyzed reductive coupling of α-aminoaldehydes with silyl alkynes has been developed. The process proceeds with exceptional regiocontrol and diastereoselectivity. A variety of protected serinal derivatives were examined, and Garner aldehyde afforded the highest chemical yields of an easily deprotected coupling product. Use of a C-15 alkyne allowed a direct and efficient synthesis of D-erythro-sphingosine. With this silyl alkyne of interest, coupling reactions were most efficient when trace water was employed with THF as solvent. Using this procedure, D-erythro-sphingosine was prepared by a short sequence, wherein the alkene stereochemistry, C-3 stereocenter, and the C-3-C-4 carbon-carbon bond were all efficiently installed by the key nickel-catalyzed coupling process.

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“…The NHC catalyst is more reactive than analogous phosphinebased catalysts and a broad range of alkynes and aldehydes undergo reductive coupling under these conditions. Macrocyclization via nickel -catalyzed reductive coupling has been shown to be a powerful tool in the synthesis of several natural products, including amphidinolide T1 [41] , amphidinolide T4 [41] , ( − ) -terpestacin [42] , and aigialomycin D [43] . A general protocol for nickel -catalyzed macrocyclizations was published using ligand -based control of regioselectivity (Scheme 8.22 ) [44] .…”

Section: Simple Aldehyde and Alkyne Reductive Couplingsmentioning

confidence: 99%

“…Resorcinylic macrolides are a family of natural products that possess a 14 -membered macrolide core with a fused benzenoid subunit. A member of this family that has drawn signifi cant scientifi c attention due to its antimalarial and cytotoxic activity is aigialomycin D. In one total synthesis of aigialomycin D, late -stage nickel -catalyzed macrocyclization was employed to afford the macrocyclic core [43] . Macrolide precursor 45 was cyclized in 61% yield in a 1 : 1 diastereoselectivity.…”

Section: Use In Natural Product Synthesismentioning

confidence: 99%

Nickel‐Catalyzed Reductive Couplings and Cyclizations

Malik

Baxter

Montgomery

2010

Catalysis Without Precious Metals

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Many classes of standard organic transformations involve the coupling or cycloaddition of two different π -components to assemble a more functionalized product. Many such processes are amenable to the union of two complex fragments, thus allowing convergent approaches to complex organic molecules. Diels -Alder cycloadditions, Prins addition reactions, and ene reactions are examples of broadly useful processes that involve the union of two π -components in a selective manner. As a complement to these classical transformations, the reductive coupling of two π -components provides an alternative strategy for assembly of complex fragments from the same types of starting materials [1 -8] . Whereas the starting components resemble those required for the types of standard organic transformations noted above, the products obtained differ structurally and are obtained in a reduced oxidation state based on the action of the reducing agent employed.A number of transition metal catalyst/reducing agent combinations are known to promote various reductive coupling processes. In addition to the nickelcatalyzed variants that are the subject of this chapter, important advances have been made with titanium -[9 -13] , iridium - [14] , and rhodium -catalyzed variants [15] . Many reducing agents have been employed, and the most widely used classes include silanes, organozincs, organoboranes, molecular hydrogen, and alcohols. The specifi c focus of this chapter will be the development of nickel -catalyzed reductive couplings and cyclizations between a polar π -component and a non -polar π -component. This strategy allows the two π -components to be differentiated in catalytic reactions, and thus avoids homocoupling processes that are often problematic in transformations of this type. The use of either aldehydes or α , β -unsaturated carbonyls as the polar component, and alkynes as the non -polar component has been a primary focus of our laboratories and will be the subject of this chapter. Extensive related developments involving dienes as the non -polar component reported by the laboratories of Mori [16] , Sato [17] , and Tamaru [18] have been reviewed elsewhere [3] and will not be extensively discussed in this 8 Catalysis Without Precious Metals. Edited by R. Morris Bullock

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Total Synthesis of Aigialomycin D: Surprising Chemoselectivity Dependence on Alkyne Structure in Nickel-Catalyzed Cyclizations

Cited by 58 publications

References 27 publications

Nickel-catalyzed regiodivergent approach to macrolide motifs

Nickel-catalyzed regiodivergent approach to macrolide motifs

Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and alkynylsilanes: application to the synthesis of d-erythro-sphingosine

Nickel‐Catalyzed Reductive Couplings and Cyclizations

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