Academic literature on the topic '[2 + 2] and [4 + 2] cycloadditions reactions. Diels-Alder reactions'

It has generally been observed that prospective intramolecular Diels-Alder cycloadditions that would form a γ-lactone are reluctant to proceed. In the course of a synthesis of (±)-neovibsanin B 4, Hiroshi Imagawa and Mugio Nishizawa of Tokushima Bunri University reversed (Organic Lett. 2009, 11, 1253) the usual connectivity and found that the dienyl ester 1 could be induced to cyclize to 3. The solvent 2 improved both the yield and the diastereoselectivity of the cycloaddition. It was not surprising that Johann Mulzer of the University of Vienna could see (Organic Lett. 2009, 11, 1151) no evidence of cyclization on heating the acrylate 5. In contrast, following the lead of Barriault, they found that MgBr2 -tethered cycloaddition of methyl acrylate 7 with the alcohol 6 proceeded smoothly, to give 8, which they carried on to valerenic acid 9. Intramolecular Diels-Alder reactions to form 6,6-systems are often facile. Mohammad Movassaghi of MIT, en route to (-)-himandrine 12, showed (J. Am. Chem. Soc. 2009, 131, 9648) that the tetraene 10 cyclized to 11 at 95°C with 5:1 dr. In this case the solvent was the more typical acetonitrile with 10% diethyl aniline. The intramolecular Diels-Alder reaction is concerted but nonsynchronous (Tetrahedron Lett. 1981, 22, 5141), with β-bond formation preceding α-bond formation. This contributes to the reluctance of 8 to cyclize. In contrast, Henry N. C. Wong of the Chinese University of Hong Kong observed (Angewandte Chem. Int. Ed. 2009, 48, 2351) that the tetraene 13, which is polarity matched, cyclized to 14 spontaneously as soon as it was formed. Functional group conversion completed the synthesis of (±)-pallavicinolide A 15. The transannular Diels-Alder (TADA) reaction can proceed with high diastereocontrol, but the factors directing these cyclizations are not completely understood. In the course of a synthesis of (+)-phomopsidin 18, Masahisa Nakada of Waseda University found (Tetrahedron 2009, 65, 888) that 16 led to 17 with 16:1 dr. In contrast, the triene epimeric to 16 at the silyloxy group cyclized with only 2:1 dr.

En route to sarcandralactone A 3, Scott A. Snyder of Scripps Florida effected (Angew. Chem. Int. Ed. 2015, 54, 7842) Diels–Alder cycloaddition of the activated enone 1 to the Danishefsky diene. On exposure to trifluoroacetic acid, the adduct was unraveled to the ene dione 2. Michael N. Paddon-Row of the University of New South Wales and Michael S. Sherburn of the Australian National University prepared (Nature Chem. 2015, 7, 82) the allene 4 in enantiomerically-pure form. Sequential cycloaddition with 5 followed by 6 gave an adduct that was decarbonylated to 7. Further cycloaddition with nitro­ethylene 8 led to the pseudopterosin (−)-G-J aglycone 9. The protein–protein interaction inhibitor JBIR-22 12 contains a quaternary α-amino acid pendant to a bicyclic core. Nicholas J. Westwood of the University of St. Andrews set (Angew. Chem. Int. Ed. 2015, 54, 4046) the absolute configuration of the core 11 by using an organocatalyst to activate the cyclization of 10. Metal catalysts can also be used to set the absolute configuration of a Diels–Alder cycloaddition. In the course of establishing the structure of the marine natural prod­uct muironolide A 15, Armen Zakarian of the University of California, Santa Barbara cyclized (J. Am. Chem. Soc. 2015, 137, 5907) the enol form of 13 preferentially to the diastereomer 14. Unactivated intramolecular Diels–Alder cycloadditions have been carried out with more and more challenging substrates. A key step in the synthesis (Chem. Asian. J. 2015, 10, 427) of (−)-platencin 18 by Martin G. Banwell, also of the Australian National University, was the cyclization of 16 to 17. In another illustration of the power of the unactivated intramolecular Diels–Alder reaction, Thomas J. Maimone of the University of California, Berkeley cyclized (Angew. Chem. Int. Ed. 2015, 54, 1223) the tetraene 19 to the tricycle 20. Allylic chlo­rination followed by reductive cyclization converted 20 to chatancin 21.

Scott A. Snyder at Columbia University demonstrated (J. Am. Chem. Soc. 2012, 134, 17714) that tetrahydrofuran 1 could be readily converted to oxocane 2 by treatment with the BDSB reagent developed in his laboratory. Reduction of 2 with DIBAL-H initiated a second ring closure by mesylate displacement to form the bicycle 3, which represented a formal total synthesis of laurefucin 4. Andrew L. Lawrence at the Australian National University found (Org. Lett. 2012, 14, 4537) that upon treatment with catalytic base, rengyolone 6, which was prepared in one pot from phenol 5, could be converted to the natural products incarviditone 7 and incarvilleatone 8. This demonstration provides strong support for the postulated biomimetic formation of these natural products. Shuanhu Gao at East China Normal University reported (Angew. Chem. Int. Ed. 2012, 51, 7786) the total synthesis of (+)-fusarisetin A 12 via biomimetic oxidation of equisetin 10 to produce the peroxy compound 11, followed by reduction. The bicyclic carbon skeleton of equisetin 10 was synthesized by intramolecular Diels-Alder reaction of trienyl aldehyde 9. The ellagitannin natural product (+)-davidiin 15 possesses a glucopyranose core with the unusual 1C4 (tetraaxial) conformation due to the presence of a biaryl bridge between two of the galloyl groups. Hidetoshi Yamada at Kwansei Gakuin University constructed (Angew. Chem. Int. Ed. 2012, 51, 8026) this bridge by oxidation with CuCl2 of 13, in which the three sterically demanding triisopropylsiloxy groups enforce the requisite tetraaxial conformation. John A. Porco, Jr. at Boston University applied (J. Am. Chem. Soc. 2012, 134, 13108) his asymmetric [3+2] photocycloaddition chemistry to the total synthesis of the aglain natural product (+)-ponapensin 20. Irradiation of hydroxyflavone 16 with methyl cinnamate 17 in the presence of diol 18 afforded the entire core framework 19 of ponapensin 20, which was accessed in just a few further synthetic transformations. Finally, Silas P. Cook at Indiana University reported (J. Am. Chem. Soc. 2012, 134,13577) a five-pot total synthesis of the antimalarial (+)-artemisinin 25. Cyclohexenone 21 was converted by simple operations to aldehyde 22. This aldehyde was then engaged in a [4+2] cycloaddition with the silyl ketene acetal 23 to produce, after an impressive Wacker oxidation of the disubstituted olefin, bicycle 24.

The diterpene vinigrol 3, isolated from Virgaria nigra F-5408, is a tumor necrosis factor (TNF) inhibitor. Jon T. Njardarson of the University of Arizona envisioned (Angew. Chem. Int. Ed. 2013, 52, 8648) that Wharton fragmentation of 1 could deliver 2, suit­ably functionalized for elaboration to 3. The tetracyclic 1 was prepared by the triply-convergent assembly of the phenol 11. Addition of allyl magnesium bromide to 4 proceeded with high regio- and geomet­ric selectivity, to give an alcohol that was methylated, then iodinated with inversion to give 5. Condensation of the phosphonate 7 with the derived aldehyde 6 led to the alcohol 8, that was coupled under Mitsunobu conditions with the phenol 9 to give 10. Oxidation of 11 gave an intermediate that underwent intramolecular Diels–Alder cycloaddition to deliver 12. On exposure to the Pd catalyst, 12 cyclized to the diene 13. On exposure to tBuOK/ tBuOH, the mesylate 1 smoothly fragmented to the hoped-for ketone 2. Although this has been referred to as a Grob fragmentation, in fact this reaction was developed (J. Org. Chem. 1961, 26, 4781) by Peter S. Wharton, then at the University of Wisconsin, and would more properly bear his name. Subsequent transformations took advantage of the hindered nature of the trisubsti­tuted alkene of 2. Hydrogenation of the disubstituted alkene proceeded selectively, to give an intermediate that was condensed with 14, leading to the enone 15. Two more selective hydrogenations, with the Wittig methylenation in between, completed the construction of the pendant isopropyl group. Once the isopropyl group was installed, what remained was the oxidation of 16 to 19. The epoxidation of 17 proceeded with high facial selectivity, to give an intermedi­ate that was carried on by iodination and reduction to the alcohol 18. Allylic oxidation converted 18 into 19, that was deprotected to give Vinigrol 3. It is instructive to compare and contrast this approach to vinigrol 3 with the two that we have previously highlighted (OHL September 6, 2010; December 24, 2012). Each strategy offers its own advantages.

Powerful methods for catalytic, enantioselective intermolecular Diels-Alder reactions have been developed. Ben L. Feringa and Gerard Roelfes of the University of Groningen have shown (Organic Lett. 2007, 9, 3647) that a catalyst prepared by combining salmon testes DNA with a Cu complex directed the absolute sense of the addition of 1 to cyclopentadiene 2 . Mukund P. Sibi of North Dakota State University has reported (J. Am. Chem. Soc . 2007, 129 , 395) related work with achiral pyrazolidinone dienophiles and chiral Cu catalysts. Tohru Fukuyama of the University of Tokyo found (Angew. Chem. Int. Ed . 2007, 46, 5734) that the MacMillan catalyst 5 was effective at mediating the addition of acrolein 4 to the pyridine-derived diene 3, enabling an enantioselective synthesis of the prominent antiviral (-)-oseltamivir (tamiflu) 7. Hisashi Yamamoto of the University of Chicago has demonstrated (J. Am. Chem. Soc . 2007, 129, 9534 and 9536) that the novel catalyst 10 effected addition of methyl acrylate 9 to the diene 8, leading to an elegant enantioselective synthesis of the tetracycle 12, the key intermediate in the Nicolaou synthesis of platensimycin. New illustrations of the power of the intramolecular Diels-Alder reaction have been put forward. Demonstrating the influence of a single subsituent on the tether, William R. Roush of Scripps/Florida found (Organic Lett . 2007, 9, 2243) that cyclization of 13 led to the diastereomer 14, complementary to the result observed with an acyclic triene. Ryo Shintani and Tamio Hayashi of Kyoto University have extended (Angew. Chem. Int. Ed . 2007, 46, 7277) their studies of chiral diene-based Rh catalysts to the enantioselective cyclization of alkynyl dienes such as 16. Jonathan W. Burton of the University of Oxford and Andrew B. Holmes of the University of Melbourne employed (Chem. Commun . 2007, 3954) the MacMillan catalyst 5 for the cyclization of 18 to 19. It is impressive that ent- 5 catalyzed the cyclization of 18 cleanly into the diastereomer of 19 in which both of the newly-created stereogenic centers were inverted.

The Streptomyces metabolite (-)-FR182877 3 binds to and stabilizes microtubules, showing the same potency of anticancer activity as Taxol (paclitaxel). Masahisa Nakada of Waseda University assembled (Angew. Chem. Int. Ed. 2009, 48, 2580) the hexacyclic ring system of 3 by the tandem intramolecular Diels-Alder–intramolecular hetero Diels-Alder cyclization of 1, generating seven new stereogenic centers in a single step. The construction of the pentaene substrate 1 started with the known aldehyde 4, prepared by homologation of commercial ethyl 3-methyl-4-oxocrotonate. Addition of the propionyl oxazolidine anion 5 proceeded with high diastereocontrol, to give 6. The acyl oxazolidinone was not an efficient acylating agent, so it was converted to the Weinreb amide. Protection and deprotection then delivered the allylic acetate 7. The key step in the pentaene assembly was the carefully optimized Negishi-Wipf methylation of 8, followed by Pd-mediated coupling of the alkenyl organometallic so generated with the allylic acetate, to give 9. Condensation of the derived keto phosphonate 11 with the known aldehyde 12 then delivered the enone 13. The Nakada group has worked extensively on the intramolecular Diels-Alder reaction of substrates such as 1. They have shown that protected anti diols such as 1 cyclize with substantial diastereocontrol and in the desired sense. In contrast, cyclizations of protected syn diols proceed with poor diastereocontrol. The enone 13 was therefore reduced to the anti diol and protected, leading to 14 . Oxidation of 14 at room temperature led to a complex mixture, but slow oxidation at elevated temperature delivered 2 . Although the yield of 2 was not much better than if the reactions were carried out sequentially, first the intramolecular Diels-Alder cyclization, then the intramolecular hetero Diels-Alder cyclization, with the cascade protocol pure 2 was more readily separated from the reaction matrix. With 2 in hand, there was still the challenge of assembling the seven-membered ring. Cyclization was effected with an intramolecular Heck protocol. The two diastereomers of the allylic alcohol 15 cyclized with comparable efficiency. Ir-catalyzed alkene migration then converted the allylic alcohols to a mixture of ketones, which was equilibrated to give the more stable diasteromer.

A vast majority of novices in universities predominantly utilize algorithmic mental processes to resolve assigned tasks and tests. Although algorithmic thinking is an essential part of human cognitive functions, experts on didactics call for methods, which develop also conceptual thinking in beginners. Currently, heuristic molecular modeling gains an important position in chemistry education since it inherently integrates several conceptual thinking principles. Herein, it is focused on computational analysis of eight potential immunomodulators prepared by Diels-Alder reactions to exemplify con