An alternative and convenient synthesis of oct-7-enal, a naturally-occurring aldehyde isolated from the Japanese thistle Cirsium dipsacolepis

Bracca, Andrea B. J.; Kaufman, Teodoro S.

doi:10.1590/s0103-50532008000600011

Cited by 2 publications

(2 citation statements)

References 13 publications

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“…These data were consistent with those reported previously. 90 5-((tert-Butyldimethylsilyl)oxy)pentanal -147…”

Section: Chapter 3: Fragment Synthesis and Second Generation Retrosynthetic Approachmentioning

confidence: 99%

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

Geyrhofer¹

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<p>(-)-Zampanolide (1), a natural product isolated from a marine sponge, is a microtubule-stabilizing agent that exhibits activity in the nanomolar range against various cancer cells, including in P-gp pump overexpressing cells. This attribute makes (-)-zampanolide an interesting target for further investigation. In this work, a new method for a modular and convergent total synthesis of optically pure zampanolide was investigated, which would also allow the generation of “zampanalogs” following the same basic strategy. Their biological activity may then be assessed to allow the elucidation of structure-activity relationships of (-)-zampanolide and its analogs in tubulin binding. The synthetic plan consisted of the modular combination of four major fragments, which would be connected in the late stages of the synthesis and could therefore be easily exchanged to allow the generation of analogs. The C15-C16 bond would be connected via an alkynylation reaction, and a subsequent reductive methylation would install the trisubstituted alkene. The connections at C1 and C3 could be achieved through a Bestmann ylid linchpin reaction, while the macrolactonization would be completed using a ring-closing metathesis to form the C8-C9 alkene. The side chain could be attached at C20 using one of the established aza-aldol methods. The fragments necessary for the formation of the macrocycle were synthesized successfully. The purification strategy throughout the synthetic route was rationalized and provides an improvement with respect to yield and time compared to work previously done in this research group. Alongside these fragments, modified fragments that were originally intended to serve as model systems were synthesized, which could also be used as building blocks in the synthesis of “zampanalogs”. Several methods for a stereoselective alkynylation at C15 were tested. These led to only meager successes, so an approach using a non-stereoselective alkynylation, followed by oxidation and a stereoselective CBS-reduction, was chosen. For the installation of the trisubstituted alkene a reductive methylation with vitride was tested, but this only led to the reduction of the alkyne without methylation. This product may be employed for the synthesis of C17-desmethyl analogs. The reductive methylation at C16-C17 was ultimately achieved using the Gilman reagent in a similar manner to the installation of the C5 methyl group in the C3-C8 fragment. A linchpin strategy with the Bestmann ylid simultaneously formed the connectivity at C1 and C3. This process was successfully performed on multiple substrates arising from the model systems used in the alkynylation and reductive methylation reactions, yielding precursors to the ring-closing metathesis and potentially enabling the synthesis of various analogs. The ring-closing metathesis proved to be difficult in analogs lacking the C17 methyl group and cis-tetrahydropyran ring, and due to this tendency further investigations are necessary. Once the macrocycle has been closed, a global deprotection and oxidation of hydroxy groups is necessary to allow for the installation of the sidechain.</p>

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“…These data were consistent with those reported previously. 90 5-((tert-Butyldimethylsilyl)oxy)pentanal -147…”

Section: Chapter 3: Fragment Synthesis and Second Generation Retrosynthetic Approachmentioning

confidence: 99%

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

Geyrhofer¹

View full text Add to dashboard Cite

show abstract

“…These data were consistent with those reported previously. 90 5-((tert-Butyldimethylsilyl)oxy)pentanal -147…”

Section: Chapter 3: Fragment Synthesis and Second Generation Retrosynthetic Approachmentioning

confidence: 99%

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

Geyrhofer¹

View full text Add to dashboard Cite

show abstract

An alternative and convenient synthesis of oct-7-enal, a naturally-occurring aldehyde isolated from the Japanese thistle Cirsium dipsacolepis

Cited by 2 publications

References 13 publications

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

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