Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

Wang, Jingjing; Ting, Samuel Z.Y.; Harvey, Joanne E.

doi:10.3762/bjoc.11.197

Cited by 5 publications

(25 citation statements)

References 47 publications

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“…This synthesis is significant to get the N-acyl aminal derivatives of zampanolide. In 2015, Wang et al [135] studied that a linchpin approach is the 18-membered macrocyclic lactones ( Fig. 11), were first isolated from an Indonesian sponge Hyattella sp.…”

Section: Fig 10 Total Synthesis Strategies Of Zampanolide and Dactylmentioning

confidence: 99%

Recent advances in microtubule-stabilizing agents

Cao

Zheng

Wang

et al. 2018

European Journal of Medicinal Chemistry

143

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Highly dynamic mitotic spindle microtubules are superb therapeutic targets for a group of chemically diverse and clinically successful anticancer drugs. Microtubule-targeted drugs disrupt microtubule dynamics in distinct ways, and they are primarily classified into two groups: microtubule destabilizing agents (MDAs), such as vinblastine, colchicine, and combretastatin-A4, and microtubule stabilizing agents (MSAs), such as paclitaxel and epothilones. Systematic discovery and development of new MSAs have been aided by extensive research on paclitaxel, yielding a large number of promising anticancer compounds. This review focuses on the natural sources, structural features, mechanisms of action, structure-activity relationship (SAR) and chemical synthesis of MSAs. These MSAs mainly include paclitaxel, taccalonolides, epothilones, FR182877 (cyclostreptin), dictyostatin, discodermolide, eleutherobin and sarcodictyins, zampanolide, dactylolide, laulimalides, peloruside and ceratamines from natural sources, as well as small molecular microtubule stabilizers obtained via chemical synthesis. Then we discuss the application prospect and development of these anticancer compounds.

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Section: Fig 10 Total Synthesis Strategies Of Zampanolide and Dactylmentioning

confidence: 99%

Recent advances in microtubule-stabilizing agents

Cao

Zheng

Wang

et al. 2018

European Journal of Medicinal Chemistry

143

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“…The results are summarized in her paper. 46 The reaction of the zampanolide fragments 112, 113 and 116 with aldehyde 117, the C3-C8 fragment for the synthesis of zampanolide, gave yields between 66% and 69% when they were conducted in refluxing toluene (Scheme 2.35).…”

Section: Gray's Work On Fragments For the Synthesis Of Sidechain Analogsmentioning

confidence: 99%

“…The formation of the macrocycle using an RCM at C8/C9 has been shown in the zampanolide system before and is well established. 26,29,35,36,44 The two other major disconnections are a Bestmann ylid linchpin to form the dienoate motif of 127 as described by Wang, 45,46 and a stereoselective alkynylation to connect fragment 127 and 128 and install the correct configuration at C15. In a first outline the protecting group strategy only involves silyl protecting groups, however it could easily be modified and adjusted as needed while the synthesis was progressing.…”

Section: Thesismentioning

confidence: 99%

“…Wang et al published a paper on the preparation of conjugated dienoates with Bestmann ylid in 2015. 46 They found that when there was a high conversion rate but low yield in a reaction, conducting the reaction at lower temperatures or a change of solvent to THF was beneficial. This is also described in Chapter 2.2.4.…”

Section: Analog 1: Non-thp Alkyne Analogmentioning

confidence: 99%

“…These data were consistent with those reported previously. 45,46 tert-Butyl(hex-1-en-5-yn-3-yloxy)dimethylsilane -109…”

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

confidence: 99%

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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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ChemInform Abstract: Preparation of Conjugated Dienoates with Bestmann Ylide: Towards the Synthesis of Zampanolide and Dactylolide Using a Facile Linchpin Approach.

2015

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Approach. -The Bestmann ylide (III) is used as a linking entity between C3-C8 aldehyde and C16-C20 alcohol fragments to synthesize unsaturated esters. This highly efficient single-step protocol contrasts with other routes that require multi-step sequences. -(WANG, J.; TING, S. Z. Y.; HARVEY*, J. E.; Beilstein J. Org. Chem. 11 (2015Chem. 11 ( ) 1815Chem. 11 ( -1822 Sch. Chem. Phys. Sci., Victoria Univ.,

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Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

Cited by 5 publications

References 47 publications

Recent advances in microtubule-stabilizing agents

Recent advances in microtubule-stabilizing agents

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

ChemInform Abstract: Preparation of Conjugated Dienoates with Bestmann Ylide: Towards the Synthesis of Zampanolide and Dactylolide Using a Facile Linchpin Approach.

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