Development of a Concise and Diversity-Oriented Approach for the Synthesis of Plecomacrolides via the Diene−Ene RCM

Lu, Kui; Huang, Mengwei; Xiang, Zheng; Liu, Yongxiang; Chen, Jiahua; Yang, Zhen

doi:10.1021/ol060221v

Cited by 35 publications

(25 citation statements)

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“…Due to the increasing importance of the ring‐closing metathesis (RCM) reaction for the formation of cyclic compounds ― and especially macrocycles ― in the last decade,19 it appeared to us that an alternative and more direct strategy involving RCM would give a more efficient alternative for the construction of the macrocyclic core of the bafilomycins at the C‐12–C‐13 junction. We were initially dissuaded from undertaking such an approach when we became aware of the negative preliminary results obtained by the Yang group in 2006 20. These authors failed in their attempt to construct the 16‐membered macrolactone core of the bafilomycins by RCM using an analogous C‐12–C‐13 disconnection when the C‐2–C‐4 diene was already present in the polyenic ester precursor.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insight into the Electronic Influences Imposed by Substituent Variation in Polyazine‐Bridged Ruthenium(II)/Rhodium(III) Supramolecules

White

Mallalieu

Wang

et al. 2014

Chemistry A European J

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Unusual and unprecedented multipathway electrochemical mechanisms for a new class of supramolecular Ru/Rh bimetallic photocatalysts have been uncovered. The near isoenergetic Rh(dσ*) and bridging ligand(π*) molecular orbitals and a rate of halide loss that occurs on the cyclic voltammetry timescale provide a series of closely related complexes which display four different electrochemical mechanisms. A single complex displays two concurrent electrochemical pathways in marked contrast to all previously studied cis-[Rh(NN)(2)X(2)] motifs.

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Section: Introductionmentioning

confidence: 99%

Mechanistic Insight into the Electronic Influences Imposed by Substituent Variation in Polyazine‐Bridged Ruthenium(II)/Rhodium(III) Supramolecules

White

Mallalieu

Wang

et al. 2014

Chemistry A European J

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“…Structures of bafilomycin A 1 (1), 24-demethylbafilomycin A 2 (2), and 24-demethylbafilomycin C 1 (3) and the strategic bond disconnections between C11-C12 and C12-C13 According to the early findings by Yang and co-workers, 25 the non-functionalized 16-membered tetraene macrolactone could not be constructed directly via the 1,3-diene-ene RCM, presumably due to high ring-strain caused by the two sets of 1,3-diene moieties. We confirmed this result with the RCM reaction of a fully functionalized seco substrate, which decomposed in the presence of the RCM initiator.…”

Section: Figurementioning

confidence: 99%

“…An aldol reaction of the a,b-unsaturated aldehyde 12 25 with the lithium enolate derived from the methoxyacetate 13 26 and LiHMDS was carried out. Two major syn-diastereomers (2S*,3R*)-14 are expected to form preferentially from the (Z)-enolate of 13.…”

Section: Figurementioning

confidence: 99%

“…[22][23][24] Here, we report on the construction of the 16-membered macrolactone core and on the finding that the appended groups influence the geometry of the forming C12-C13 double bond. According to the early findings by Yang and co-workers, 25 the non-functionalized 16-membered tetraene macrolactone could not be constructed directly via the 1,3diene-ene RCM, presumably due to high ring-strain caused by the two sets of 1,3-diene moieties. We confirmed this result with the RCM reaction of a fully functionalized seco substrate, which decomposed in the presence of the RCM initiator.…”

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Influence of Appended Groups on the Formation of 16-Membered Macrolactone Core Related to the Plecomacrolides via Diene-Ene Ring-Closing Metathesis

Sun¹,

Feng²,

Guan³

et al. 2009

Synlett

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A 1,3-diene-ene ring-closing metathesis (RCM) strategy was investigated for assembling the 16-membered macrolactone core of the plecomacrolides. It was found that the desired (10E,12E)-diene unit could be constructed from the fully functionalized C13-C17 homoallyl alcohol fragment and the C1-C12 acid fragment possessing one E double bond at C2-C3 or C3-C4. The functional groups at C2 and C3 resulted in preferential formation of the undesired (12Z)-macrolactone, while additional appended groups at C6-C8 furnished the (12Z)-macrolactone as the sole RCM product.Bafilomycin A 1 (1, Figure 1) 1 is a representative member of the 16-membered plecomacrolide family, 2,3 which are best known for possessing a folding hemiacetal subunit on the side chain. The macrolactone core is connected to the hemiacetal via a three-carbon linker (C16-C18 for 1). Formation of an intramolecular hydrogen bonding network among the lactone/linker/hemiacetal motif was suggested to play an important role in the biological functions, 4 although non-supportive findings were obtained from a study on synthetic analogues. 5 Most of the plecomacrolides deliver antifungal and antibacterial activity. Moreover, bafilomycin A 1 is known to be a specific inhibitor of vacuolar H + -ATPase (V-ATPase) and it holds some promise for treating osteoporosis. 5-8 24-Demethylbafilomycin A 2 (2) 9a is produced together with 24-demethylbafilomycin C 1 (3) by a commensal microbe Streptomyces sp. CS associated with Maytenus hookeri. 9 It was reported that the macrolide 2 exerts strong cytotoxicity, with IC 50 values of 1.13 and 0.01 mM against P388 and A549 tumor cell lines, respectively. The complex structure of 1 has attracted much synthetic effort. After the first total synthesis of bafilomycin A 1 was accomplished by Evans and Calter in 1993, 10 several total syntheses of 1 were developed by Toshima, 11 Roush, 12 Hanessian, 13 and Carreira, 14 along with studies on the fragment syntheses by many other research groups. [15][16][17][18][19][20][21] In general, the 1,3-diene functionality between C10-C13 was constructed by formation of the C11-C12 bond via palladium-catalyzed cross-coupling reactions of vinyl tin 10,11,13,15,16,18 or boron 12 derivatives with vinyl iodides. Alternatively, a Sonogashira reaction has been used to form the enyne intermediate, which was subsequently reduced to the 1,3-diene. 14 We envisaged a different approach to the assembly of the 16-membered tetraene macrolactone core by employing 1,3-diene-ene ring-closing metathesis (RCM). [22][23][24] Here, we report on the construction of the 16-membered macrolactone core and on the finding that the appended groups influence the geometry of the forming C12-C13 double bond. Figure 1Structures of bafilomycin A 1 (1), 24-demethylbafilomycin A 2 (2), and 24-demethylbafilomycin C 1 (3) and the strategic bond disconnections between C11-C12 and C12-C13 According to the early findings by Yang and co-workers, 25 the non-functionalized 16-membered tetraene macrolactone could not be constructed directly vi...

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“…Conversion of the remaining hydroxyl group to α,β-unsaturated ester 5 was accomplished by an oxidation-Wittig reaction sequence 8. Successive reductions of the double bond and ester by catalytic hydrogenation and treatment with DIBAL-H, followed by a second two-carbon Wittig olefination afforded α,β-unsaturated ester 6 .…”

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Motualevic acids and analogs: Synthesis and antimicrobial structure–activity relationships

Cheruku

Keffer

Dogo‐Isonagie

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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Synthesis of the marine natural products motualevic acids A, E, and analogs in which modifications have been made to the ω-brominated lipid (E)-14,14-dibromotetra-deca-2,13-dienoic acid or amino acid unit are reported, together with antimicrobial activities against Staphylococcus aureus, methicillin-resistant S. aureus, Enterococcus faecium, and vancomycinresistant Enterococcus.Starting with Fleming's discovery of penicillin in the 1920's, the discovery and development of new antibiotics was marked by unmatched success in the area of drug discovery and remained at the fore for decades.1 Numerous classes of antibacterial agents were discovered from Nature, and many of those are in clinical use today. The expansion of antibiotic research reached its peak by the middle of the last century, then paused for four decades before approval of oxazolidinone linezolid in 20002 and the lipopeptide daptomycin in 2003.3 Nonetheless, a variety of infectious diseases persist as true global health burdens,4 and infections associated with drug resistant organisms5 such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. (VRE) continue to rise. To help alleviate this problem, development of new antibiotics that function with unique mechanisms of action and can escape the resistance mechanisms used by drug resistant bacteria are needed. Combined studies involving discovery and synthesis of new antimicrobial natural products can be valuable in this area.7Recently we reported the isolation, structure elucidation and antibacterial properties of motualevic acids A-E (1a-c and 8, for example) from the marine sponge Siliquariaspongia sp.7 These compounds contain an unusual ω-brominated lipid (E)-14,14-dibromotetradeca-2,13-dienoic acid, where motualevic acids A-D are its glycyl conjugates and motualevic acid E the free acid (Figure 1). Antimicrobial assays revealed that motualevic acid A (1a) inhibited the growth of S. aureus (SA) and MRSA at low micromolar concentrations, while motualevic acid E (8) showed greatly diminished activity, effective against SA only at much higher concentrations (50 µg/disk). Interestingly, the naturally occurring amides 1b and 1c and the Z isomer of 1a also exhibited greatly diminished antimicrobial activity providing some insight into the structure-activity relationships for this series. To obtain a more general picture of the chemical features necessary for antimicrobial activity, we have synthesized motualevic acids A and E together ©2010 caroleb@mail.nih.gov, tel (301)594-5187. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the jou...

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Development of a Concise and Diversity-Oriented Approach for the Synthesis of Plecomacrolides via the Diene−Ene RCM

Cited by 35 publications

References 43 publications

Mechanistic Insight into the Electronic Influences Imposed by Substituent Variation in Polyazine‐Bridged Ruthenium(II)/Rhodium(III) Supramolecules

Mechanistic Insight into the Electronic Influences Imposed by Substituent Variation in Polyazine‐Bridged Ruthenium(II)/Rhodium(III) Supramolecules

Influence of Appended Groups on the Formation of 16-Membered Macrolactone Core Related to the Plecomacrolides via Diene-Ene Ring-Closing Metathesis

Motualevic acids and analogs: Synthesis and antimicrobial structure–activity relationships

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