The Trost Synthesis of (−)-Lasonolide A

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Grignard Reagent ◽  
Kinetic Resolution ◽  
Phosphonium Salt ◽  
Ethane Oxidation ◽  
Total Syntheses ◽  
Lasonolide A ◽  
Terminal Alkene ◽  
The Caribbean ◽  
Aldol Addition ◽  
Diastereoselective Reduction

(−)-Lasonolide A 4, isolated from the Caribbean sponge Forcepia sp., showed remarkable anticancer activity in the NIH 60-cell screen. The central step in the syn­thesis of 4 reported (J. Am. Chem. Soc. 2014, 136, 88) by Barry M. Trost of Stanford University was the remarkably selective, convergent Ru-mediated coupling of 1 with 2 to give 3. To prepare 1, the authors took advantage of the underutilized Cu-mediated addi­tion of a Grignard reagent 6 to propargyl alcohol 5, to give 7. Coupling with the ace­tonide 8 followed by deprotection led to the phosphonium salt 9. The other half of 1 was prepared from the acetonide 10 of the commodity chemical 1,1,1-tris(hydroxymethyl)ethane. Oxidation followed by Zn-catalyzed aldol addition of the ketone 11 led to the alcohol 12. Diastereoselective reduction followed by protection gave 13. Condensation with benzaldehyde proceeded with remarkable diastereoselection, setting the quaternary center of 14. Spontaneous intramolecular Michael addition proceeded under the conditions of the subse­quent Horner-Emmons reaction, leading to the aldehyde 15. Wittig reaction with the phosphonium salt 9 followed by deprotection completed the preparation of the alkyne 1. The β-ketoester 18 prepared by the addition of 17 to 16 was prone to unwanted conjugation, and the terminal alkene was easily reduced under hydrogenation con­ditions. Enzymatic conditions were found to effect dynamic kinetic resolution and reduction, to give 19. The derived ketone 21, from coupling with 20 was reduced using the Corey organocatalyst, then hydrosilated, leading to 22. Under metathesis with 23, the product unsaturated aldehyde cyclized to 24. Homologation followed by allylation then completed the construction of 2. Acetone was the solvent of choice for the coupling of 1 with 2. This led to the acetonide 3, that was hydrolyzed and protected to give 25. Yamaguchi macrolac­tonization followed by deprotection then delivered (−)-lasonolide A 4. It is instruc­tive to compare this work to the four previous total syntheses of 4, one of which (Org. Highlights November 26, 2007) we have previously highlighted.

scholarly journals Developing a Methodology for Catalytic Asymmetric Crotylation of Aldehydes

Synlett ◽  
2021 ◽  
Author(s):  
Andrei V. Malkov ◽  
Aleksandr E. Rubtsov
Keyword(s):  
Kinetic Resolution ◽  
Lewis Base ◽  
Chiral Auxiliaries ◽  
Organometallic Reagents ◽  
Total Syntheses ◽  
Base Catalysts ◽  
Homoallylic Alcohols ◽  
Stereogenic Centers ◽  
Long Time ◽  
Lewis Base Catalysts

AbstractAsymmetric crotylation has firmly earned a place among the set of valuable synthetic tools for stereoselective construction of carbon skeletons. For a long time the field was heavily dominated by reagents bearing stoichiometric chiral auxiliaries, but now catalytic methods are gradually taking center stage, and the area continues to develop rapidly. This account focuses primarily on preformed organometallic reagents based on silicon and, to some extent, boron. It narrates our endeavors to design new and efficient chiral Lewis base catalysts for the asymmetric addition of crotyl(trichloro)silanes to aldehydes. It also covers the development of a novel protocol for kinetic resolution of racemic secondary allylboronates to give enantio- and diastereomerically enriched linear homoallylic alcohols. As a separate topic, cross-crotylation of aldehydes by using enantiopure branched homoallylic alcohols as a source of crotyl groups is discussed. Finally, the synthetic credentials of the developed methodology are illustrated by total syntheses of marine natural products, in which crotylation plays a key role in setting up stereogenic centers.1 Introduction2 Pyridine N-Oxides as Lewis Base Catalysts3 Bipyridine N,N′-Dioxides as Lewis Base Catalysts4 Chiral Allylating Reagents5 Synthetic Applications6 Concluding Remarks

Kinetic resolution of racemic .alpha.-methylbenzyl methacrylate: asymmetric selective polymerization catalyzed by Grignard reagent-(-)-sparteine derivative complexes

1982 ◽  
Vol 104 (17) ◽  
pp. 4618-4624 ◽  
Author(s):  
Yoshio Okamoto ◽  
Koichi Suzuki ◽  
Tatsuki Kitayama ◽  
Heimei Yuki ◽  
Hiroyuki Kageyama ◽  
...  
Keyword(s):  
Grignard Reagent ◽  
Kinetic Resolution

Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

Synthesis ◽  
2021 ◽  
Author(s):  
Udo Nubbemeyer ◽  
Jonas Donges ◽  
Sandra Hofmann ◽  
Johannes C. Walter ◽  
Julia Reichertz ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Structure Elucidation ◽  
High Selectivity ◽  
Streptomyces Coelicolor ◽  
Building Blocks ◽  
Optically Active ◽  
Hplc Separation ◽  
Total Syntheses ◽  
Diastereoselective Reduction ◽  
Allyl Alcohols

AbstractStarting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

scholarly journals Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

2021 ◽  
Vol 14 (9) ◽  
pp. 938
Author(s):  
Mizuki Moriyama ◽  
Xiaoxi Liu ◽  
Yuki Enoki ◽  
Kazuaki Matsumoto ◽  
Yoo Tanabe
Keyword(s):  
Enantiomeric Excess ◽  
Chiral Discrimination ◽  
Synthetic Analogue ◽  
Synthetic Analogues ◽  
Total Syntheses ◽  
Chiral Compounds ◽  
Mukaiyama Aldol ◽  
Aldol Addition ◽  
Chemical Class

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.

Bifunctional reagents in organic synthesis. Total syntheses of the sesquiterpenoids (±)-pentalenene and (±)-9-epi-pentalenene

1989 ◽  
Vol 67 (1) ◽  
pp. 160-164 ◽  
Author(s):  
Edward Piers ◽  
Veranja Karunaratne
Keyword(s):  
Organic Synthesis ◽  
Grignard Reagent ◽  
Dimethyl Sulfide ◽  
Total Syntheses ◽  
Intramolecular Alkylation

Transformation of the readily available keto acetal 14 into the enone 23 was accomplished via a seven-step sequence of reactions. Reaction of 23 with the bifunctional Grignard reagent 5 in the presence of copper(I) bromide – dimethyl sulfide, followed by intramolecular alkylation of the resultant chloro ketone 24, gave the tetracyclic ketone 25. Treatment of 25 with hydrogen in the presence of platinum afforded a mixture of the ketones 27 and 28 (42:58, respectively), which was transformed into a separable mixture of (±)-pentalenene (1) (32%) and (±)-9-epi-pentalenene (30) (33%). Keywords: ±-pentalenene synthesis, ±-9-epi-pentalenene synthesis, sesquiterpenoid synthesis, methylenecyclopentane annulation, bifunctional reagents, triquinane synthesis.

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