Synthesis of (+)-Peloruside A

Hoye, Thomas R.; Jeon, Jiye; Kopel, Lucas C.; Ryba, Troy D.; Tennakoon, Manomi A.; Wang, Y.

doi:10.1055/s-0030-1258876

Cited by 11 publications

(22 citation statements)

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“…112 In 2005, our laboratory completed the first total synthesis of natural (+)-peloruside A, 113 with an additional four total syntheses reported to date. 114 Although a number of analogues have been synthesized and evaluated for biological activity, the severe loss of activity demonstrated by peloruside congeners and analogues thus far has shed little light on the overall SAR picture. 115 …”

Section: Polyketide Candidates For Conformation-activity Relationsmentioning

confidence: 99%

Conformation–activity relationships of polyketide natural products

2015

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Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature’s assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide’s conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues.

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Section: Polyketide Candidates For Conformation-activity Relationsmentioning

confidence: 99%

Conformation–activity relationships of polyketide natural products

2015

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“…4a As highlighted in Figure 2, retrosynthetic simplification of peloruside A conformational analogues Z - 1 and E - 2 would allow consideration of a late stage ring-closing olefin metathesis to form the C12,C13-alkene from two previously reported fragments, B and C, and simple methyl ketone, fragment A. 10 …”

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confidence: 99%

“…11 The first of two key fragment coupling reactions proceeded efficiently utilizing an aldol reaction between the lithium enolate of methyl ketone 3 and aldehyde 4 previously prepared in our laboratory. 4b The resulting mixture of diasteromeric β-hydroxyketones were converted to the β-diketone 5 by oxidation with Dess-Martin periodinane. 12 The preparation of this intermediate set the stage for generation of the 4-pyranone and the subsequent fragment couplings necessary for completion of the peloruside skeleton.…”

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Rapid Access to Conformational Analogues of (+)-Peloruside A

Zhao

Taylor

2012

Org. Lett.

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“…Triene 12 produced the hindered Z -alkene 14 [2],[9]. [10] along with several by-products upon treatment with the first generation Grubbs precatalyst (Scheme 5). These additional, minor by-products were isolated and shown to be the macrocyclic dienes ( E )- 13 , ( Z )- 13 , and 15 .…”

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confidence: 99%

Allylmalonate as an Activator Subunit for the Initiation of Relay Ring‐Closing Metathesis Reactions

2011

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We have previously described a total synthesis of (+)-gigantecin (5, Scheme 1) in which the importance of sequencing competitive ring-closing vs. cross metathesis events was revealed.[1] The most significant results (Scheme 1) were that the direct RCM reaction of key substrate 2 [using the Hoveyda-Grubbs 2 nd generation initiator (HG2)] gave the 11-membered alkene 1 rather than the desired silacycloheptene derivative that would have arisen from closure of C15 with C16. By contrast, initial cross metathesis of 2 with 3 to form the C7/C8 bond was followed by RCM to give 4, which was carried on in straightforward fashion to 5.Relay metathesis, of both the ring-closing (RRCM) [2] and cross metathesis (Relay-CM) [3] flavors, is an alternative strategy for redirecting the outcome(s) of competitive metathesis pathways in complex polyfunctional substrates. We felt that polyene intermediates like 2 and 4 held further promise as vehicles for exploring new aspects of the RRCM process. Here we report observations that extend both the utility and our understanding of RRCM.We wondered if we could use RRCM to solve the regioselectivity problems outlined in Scheme 1, we considered arming the C15/C15' (or C16/C16') vinyl group in 2 with a relay activator unit as shown generically in 6 (or 7, Scheme 2). The goal was to have the process implied by arrows a then b in 6 (or a' then b' in 7) dominate, thereby closing the C15/C16 bond selectively over that of the C8/C16 (cf. numbering in 2). Also shown in Scheme 2 is a set of relay activated, terminal allyl-containing substrates 8a-e that we prepared (along with the malonate derivative 9b, Scheme 3) in order to test this idea. Each substrate was exposed to a variety of olefin metathesis conditions, differing principally in the choices of initiators, solvents, and temperature. Reaction progress and outcome were monitored by ESI-MS and 1 H NMR analyses. In most cases complete consumption of starting material 8 was observed and most, if not all, of the identified product(s) were macrocyclic alkenes in which ethylene, but not the relay unit, had been lost. The preponderance of evidence pointed to reaction pathways via c and d in 6 (and c' in 7), rather than the desired RRCM process via a/ b (or a'/b'). In turn, this suggested that at least in the setting of the family of complex polyenes 8, the rate constant of the critical relay event (a/a') within the relay subunits (cf. I-III, Scheme 2) was too slow to compete with the undesired macrocyclizations. This led us to then study the allylmalonate ester derivatives 9a and 9b. Although we had used malonate ester derivatives in our initial demonstrations of RRCM[2] (and dimethyl diallylmalonate itself has served as an important test substrate for many aspects of olefin metathesis, including incisive mechanistic studies [4]), this structural subunit had not been explored previously as the expendable relay activator moiety. The tetraene substrate 9a contains a capping terminal n-butyl group on C8'. Treatment of 9a with HG2 in hot methylene chlor...

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Synthesis of (+)-Peloruside A

Cited by 11 publications

References 0 publications

Conformation–activity relationships of polyketide natural products

Conformation–activity relationships of polyketide natural products

Rapid Access to Conformational Analogues of (+)-Peloruside A

Allylmalonate as an Activator Subunit for the Initiation of Relay Ring‐Closing Metathesis Reactions

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