Origin of regioselectivity in the intramolecular [2+2] photoreaction of α, β-unsaturated furanones to a terminal alkene

The tetracyclic Lycopodium alkaloid fawcettimine 3 and its derivatives are of interest as inhibitors of acetylcholine esterase. F. Dean Toste of the University of California, Berkeley recently reported (Angew. Chem. Int. Ed. 2007, 46, 7671) the first enantioselective synthesis of 3. The key to the synthesis was the rapid assembly of the enantiomerically-enriched hydrindane 2. The preparation of 2 began with the enantioselective Robinson annulation of the β-keto ester 4 with crotonaldehyde 5, mediated by the organocatalyst 6. In this protocol, originally developed by Karl Anker Jørgensen, the single stereogenic center was established by conjugate addition, presumably to the chiral iminium salt generated by the condensation of 5 with 6. Subsequent aldol (or more likely Mannich) cyclization followed by elimination gave 7. Hydrolysis and decarboxylation by heating with p-TsOH converted 7 to 1. This procedure was robust enough to allow preparation of a ten gram batch of 1. This Jørgensen annulation is the current method of choice for the enantioselective preparation of 2,5-dialkyl cyclohexenones. Conjugate addition of the propargyl anion equivalent 8 to 1 proceeded with the expected > 95:5 axial diastereoselectivity, to give the silyl enol ether 9. Exposure of the derived iodide 10 to catalytic [Ph3 PAu]Cl and AgBF4 induced smooth cyclization to the cis hydrindane 2. Before constructing the nine-membered ring amine of fawcettimine 3, it was first necessary to protect the ketone as the ketal. Pd-mediated coupling of the alkenyl iodide with the organoborane derived from 11 then proceeded smoothly, as did the subsequent hydroboration of the terminal alkene. Neither the mesylate nor the tosylate derived from 12 could be induced to cyclize. In contrast, intramolecular displacement of the iodide proceeded well, to give 13. Hydroboration followed by oxidation then gave 15, which on deprotection cyclized to (+)-fawcettimine 3. Several aspects of this synthesis are attractive. While the stereochemical outcome of the hydroboration of 14 could not necessarily be predicted with confidence, in fact it did not matter, as the stereogenic center adjacent to the ketone could be epimerized under the trifluoroacetic acid deprotection conditions, and only the desired diastereomer would be able to add in an intramolecular fashion to the cyclohexanone.

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The Garg Synthesis of (±)-Aspidophylline A

Organic Synthesis ◽

10.1093/oso/9780199965724.003.0106 ◽

2013 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Drug Resistance ◽

Trifluoroacetic Acid ◽

Keto Ester ◽

Heck Cyclization ◽

Final Assembly ◽

Fischer Indolization ◽

Perceived Difficulty ◽

Bicyclic Ketones ◽

Terminal Alkene ◽

Allyl Iodide

The pentacyclic Apocynaceae alkaloid aspidophylline A 3 reverses drug resistance in resistant KB cells. In developing a strategy for the assembly of 3, Neil K. Garg of UCLA envisioned (J. Am. Chem. Soc. 2011, 133, 8877) the intramolecular Pd-catalyzed cyclization of 1 to 2. The starting material for the cyclohexenone derivative 1 was the known tricyclic anhydride 7. This was readily available in gram quantities by oxidation of the commercial pyridone 4. The double decarboxylation to 8 was delicate but could be effected by iterative small-batch microwave heating. Protection of 8 followed by fragmentation and alkylation than delivered 1. The intramolecular Heck cyclization of 1 indeed proceeded smoothly, giving the bicyclic diene 2. Deprotection of the ketone revealed a doubly activated enone, which could be selectively reduced under modifi ed dissolving metal conditions to give the keto ester 12. Alkylation of the lithium enolate with allyl iodide then gave 13, predominantly as the diastereomer illustrated. Reduction followed by selective Johnson-Lemieux oxidative cleavage of the terminal alkene then completed the construction of the diol 14. The vision for the final assembly of the alkaloid was to effect interrupted Fischer indolization of an alkylated cyclohexanone such as 15. To this end, several bicyclic ketones were explored, but none was successful. Finally, attention was turned to the more rigid tricyclic lactone 15. Happily, exposure of 15 to phenylhydrazine in the presence of trifluoroacetic acid led to an intermediate that was not isolated, but directly combined with methanolic K2CO3 to open the lactone, allowing closure of the tetrahydrofuran ring, to give 16. Simple arene sulfonamides can be advantageous in synthesis, as they do not appear as rotameric mixtures in NMR, and are often crystalline. Nevertheless, they have not commonly been used because of the perceived difficulty of deprotection. Sonication of 16 with Mg powder in methanol containing solid NH4Cl led to smooth desulfonylation. Formylation then completed the synthesis of aspidophylline A 3.

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Best Synthetic Methods: C-C Bond Construction

Organic Synthesis ◽

10.1093/oso/9780199965724.003.0022 ◽

2013 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Allylic Alcohol ◽

Synthetic Methods ◽

Grignard Reagents ◽

Ni Catalyst ◽

University Of Texas ◽

University Of British Columbia ◽

Terminal Alkene ◽

Major Producer ◽

The University ◽

Linear Product

Nobuaki Kambe of Osaka University found (Tetrahedron Lett. 2009, 50, 5644) that with a Ni catalyst, Grignard reagents coupled preferentially with primary alkyl iodides, even in the presence of the usually reactive ketone. Maurice Santelli of the Université d’Aix-Marseille devised (Tetrahedron Lett. 2009, 50, 5238) a protocol for the conversion of a ketal 4 to the doubly homologated product 6. Brian T. Gregg of AMRI established (Tetrahedron Lett. 2009, 50, 3978; Tetrahedron Lett. 2009, 50, 7070) a procedure for the homologation of a nitrile 7 to the amine 9. Replacement of the NaBH4 with a second Grignard reagent led to the α-quaternary amine (not shown). Toshiaki Murai of Gifu University independently developed (J. Org. Chem. 2009, 74, 5703) a protocol for coupling two Grignard reagents with the linchpin reagent 11 to give the amine 12. Laurel L. Schafer of the University of British Columbia demonstrated (Angew. Chem. Int. Ed. 2009, 48, 8361) Ta-catalyzed intramolecular addition of a methyl amine 14 to the terminal alkene 13 to give 15. Jason S. Kingsbury of Boston College extended (Organic Lett. 2009, 11, 3202) the Roskamp protocol to unstable diazo alkanes such as 17, to give 18. Katsukiyo Miura of Saitama University found (Organic Lett. 2009, 11, 5066) that Pt catalyzed the branched addition of a terminal alkenyl silane 19 to an aldehyde 16 to give the branched adduct 20. Silanes such as 19 are readily prepared directly from the corresponding terminal alkene. Kálmán J. Szabó of Stockholm University observed (J. Org. Chem. 2009, 74, 5695) that the allyl boronate derived from the allylic alcohol 21 could add to the aldehyde 23 to give, depending on the solvent, either the branched product 24 or the linear product 25. The Wittig reaction is a major producer of by-product waste in chemical synthesis. Yong Tang of the Shanghai Institute of Organic Chemistry found (J. Org. Chem. 2007, 72, 6628) that Ph3As could serve catalytically in the condensation of 26 with an aldehyde. Christopher J. O’Brien of the University of Texas at Arlington and Gregory A. Chass of the University of Wales described (Angew. Chem. Int. Ed. 2009, 48, 6836) a related procedure using a cyclic phosphine.

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Palladium catalyzed annulation of 2-iodobiphenyl with a non-terminal alkene enabled by neighboring group assistance

Chemical Communications ◽

10.1039/d0cc07133a ◽

2021 ◽

Vol 57 (1) ◽

pp. 121-124

Author(s):

Bo-Cheng Tang ◽

Cai He ◽

Xiang-Long Chen ◽

Jin-Tian Ma ◽

Miao Wang ◽

...

Keyword(s):

Neighboring Group ◽

Terminal Alkene ◽

Palladium Catalyzed

Neighboring group assisted annulation of non-terminal alkene with 2-iodobiphenyl.

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α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.15.245 ◽

2019 ◽

Vol 15 ◽

pp. 2524-2533 ◽

Cited By ~ 1

Author(s):

Shital K Chattopadhyay ◽

Subhankar Ghosh ◽

Sarita Sarkar ◽

Kakali Bhadra

Keyword(s):

Anticancer Drug ◽

Hela Cells ◽

Hydroxamic Acid ◽

Suberoylanilide Hydroxamic Acid ◽

Oxygen Species ◽

Synthetic Route ◽

Metathesis Reaction ◽

Cross Metathesis ◽

Terminal Alkene ◽

Derivatives Of

An alternate synthetic route to the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,ß-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were preliminarily evaluated for anticancer activity towards HeLa cells. The administration of the analogues caused a significant decrease in the proliferation of HeLa cells. Furthermore, one of the analogues showed a maximum cytotoxicity with a minimum GI50 value of 2.5 µg/mL and the generation of reactive oxygen species (ROS) as some apoptotic features.

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Palladium-catalyzed heck-type cascade cyclization of (Z)-1-iodo-1,6-dienes with N-tosyl hydrazones

Organic & Biomolecular Chemistry ◽

10.1039/c8ob01821a ◽

2018 ◽

Vol 16 (40) ◽

pp. 7356-7360 ◽

Cited By ~ 5

Author(s):

Jun Li ◽

Xiaochen Chi ◽

Long Meng ◽

Luyang Jiao ◽

Wenhui Shang ◽

...

Keyword(s):

Cascade Cyclization ◽

Terminal Alkene ◽

Palladium Catalyzed

A new way to synthesize tetrahydropyridine derivatives bearing a terminal alkene due to highly regioselective β-H elimination of alkylpalladium species.

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