Ynones, synthesis

Scheme 29 Ynones synthesis from aldehydes via C-C bond cleavage...

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

Cyclocondensation processes of p-dicarbonyl derivatives or their analogues are still widely employed for the synthesis of new isoxazoles. Non-proteinogenic heterocyclic substituted ct-amino acids have been synthesised using the alkynyl ketone functionality as a versatile building block ynone 2, derived from protected L-aspartic acid 1, reacted with hydroxylamine hydrochloride affording the isoxazole 3 with enantiomeric purity greater than 98% ee <00 JCS(P 1 )2311 >. 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

The most unique feature of furan synthesis using palladium chemistry is heteroannulation. Enones, ynones and ynols all have been annulated into furans and benzofurans. More importantly, trapping the reactive Pd(II) intermediates at different stages with electrophiles offers unique opportunities to synthesize substituted furans and benzofurans. 

Another illustration of the utility of this chemistry is provided by its use as the key step in a synthesis of prostaglandin PGF2Q [24]. In this case, the radical formed from bromoacetal (35) undergoes an intramolecular S-exo-trig cyclization onto the olefin of the cyclopentene ring, thereby generating a new radical capable of undergoing another reaction. When it was intercepted intermolecularly by ynone (36), enone (37) was produced in a 55% yield (Scheme 10). 

Besides, iodoarenes aryliodonium salts were used as electrophilic coupling partners in the synthesis of ynones. The carbonylative cross-coupling can be run in aqueous DME in the presence of Pd(OAc)2 and Gul as co-catalyst and NaHG03 as a base at 30 °G. ... 

Diastereoselective reduction of the chiral silyloxy ynone A with (RJt)-43 and 2-propanol predominantly gives (7R,9R)-B (Scheme 1.88) [328]. The chirality of the C9 position is controlled by the BINAP-Ru catalyzed asymmetric hydrogenation. The chiral product is a key intermediate in the synthesis of taurospongin A, a potent inhibitor of DNA polymerase 3 and HIV reverse transcriptase. 

The acid promoted 6-endo-dig ring closure of the ynone 744 features in the total synthesis of (JJ-espicufolin (Equation 297) <1999CC1005>. 

This methodology was utilized effectively by Inanaga and coworkers in the total synthesis of methynolide.96 Using the silver acetylide in this case allowed for the mild introduction of the acetylenic moiety, avoiding the use of strong base in the presence of the base sensitive ynone product (Scheme 1.36). 

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

A new approach for the synthesis of functionalized 4-alkylquinolines was developed utilizing electrogenerated carbanions <07SL1031>. The desired 4-alkylquinolines 83 were synthesized through a sequential alkylation/heterocyclization of p-(2-aminophenyl)-a,p-ynones 84 and the electrogenerated carbanions of nitroalkanes 85. This novel approach avoided metal and base catalysts and is performed under solvent free conditions. 

Pd-catalysed oxidative heterocyclisation features in a synthesis of substituted dihydropyran-4-ones from P-hydroxy-ynones. The process involves domino Wacker - Heck coupling of the ynones with ethyl acrylate and, although yields are only moderate, the stereochemistry of the ynone is retained in the product (Scheme 24) <06JOC8390>. 

CL128>. Based on a Diels-Alder reaction between a 2-bromobenzoquinone and a 2-methylbutadiene and a subsequent base-promoted ynone cyclisation, the anthra[l,2-b]pyran-4,7,12-trione system 33 has been synthesised <06AG(E)6990> and the methodology used in an enantioselective total synthesis of the pluramycin antibiotic, y-indomycinone <06OL5873>. 

A high yielding one-pot synthesis of 2,4-disubslilulcd-3//-benzo / l,4 diazcpines 135 was described involving in situ generation of ynones 133 by palladium(II) catalysed... 

Chelation control has also been implicated in conjugate addition reactions. For example, during a synthesis of the macrolide antibiotic 6-ep/-erythromycin, Mul-zer and co-workers86 found that the stereochemistry at the anomeric centre (l position) of the tetrahydropyranyl protecting group had a profound effect on the stereochemistry of conjugate addition of lithium dimethylcuprate to the ynone 49.1 [Scheme 1.49]. 

Utimoto et al. [145] reported a procedure for the synthesis of macrocyclic ynones by intramolecular acylation of )-(trimethylsilyl)ethynylalkanoyl chlorides in the presence of Lewis acid. For example, in the synthesis of f — )-muscone 216), cyclization of alkyne acid chloride 238 gave the macrocycle 239 in 52% yield, which was hydrogenated to f — )-muscone (Scheme 80). 

Scheme 1 Ynones and enones as three-carbon building blocks in heterocycle synthesis...

With this versatile alkynone synthesis in hand, the application to the pyrimidine synthesis was tested as well. As previously shown, 4-(indol-3-yl)- and4-(7-aza-indol-3-yl)-2-amino pyrimidines 36, which are structurally related to the marine natural products class of meridianins, have displayed a considerable potential as kinase inhibitors [143]. Therefore, upon reacting indolyl (37, X = CH) and 7-aza-indolyl (45, X = N) substituted alkynones or the pyirolyl ynones 46 with an excess of guanidinium hydrochloride and potassium carbonate in 2-methoxy ethanol at 120°C for 12-24 h the heteroaryl substituted 2-amino pyrimidines 47, 48, and 49 were obtained in good to excellent yields (Scheme 29). 

Nelson A (2005) Product class 7 ynones. In Cossy J (ed) Science of synthesis, vol 26. Georg Thieme, Stuttgart, pp 971-988... 

Alonso DA, Najera C, Pacheco MC (2004) Synthesis of ynones by palladium-catalyzed acylation of terminal alkynes with acid chlorides. J Org Chem 69 1615-1619 D Souza DM, Miiller TJJ (2008) Catalytic alkynone generation by Sonogashira reaction and its application in three-component pyrimidine synthesis. Nat Protoc 3 1660-1665 Karpov AS, Miiller TJJ (2003) A new entry to a three component pyrimidine synthesis by TMS-ynones via sonogashira-coupling. Org Lett 5 3451-3454... 

Merkul E, Oeser T, Muller TJJ (2009) Consecutive three-component synthesis of ynones by decarbonylative sonogashira coupling. Chem Eur J 15 5006-5011 Archer GA, Stembach LH (1968) Chemistry of benzodiazepines. Chem Rev 68 747-784 Popp FD, Noble AC (1967) Chemistry of diazepmes. Adv Heterocycl Chem 8 21-82 Stembach LH (1971) 1,4-benzodiazepines. Chemistry and some aspects of the stmcture-activity relationship. Angew Chem Int Ed Engl 10 34-43... 

Domino [3+2] cycloaddition/annulation reactions of aminophenyl-ynones 23 with nitrile oxides, generated in situ from chloro oximes 22, allowed the synthesis of isoxazolo[4,5-c]quinolines 24, in satisfactory yields <03EJO1423>. Bromine substituents on naphthoquinones activate and orient 1,3-DC with nitrile oxides. Compound 25 reacted with halo oximes 22 to give regioselectively only unsymmetrical naphthoquinones 26, as polyketide building blocks <03TL8901>. 

Figure 3.10 Synthesis of ynones through the coupling of terminal alkynes and acid chlorides in water.

A number of alkynic ketones have been reduced with the complex of LAH and (12) (1.1 2.5 equiv, ether, —78°C, 30-60 min) to give the corresponding (7 )-alcohols (Table 5). Johnson and co-workers have reported the reduction of ynone (17) to the (J )-alcohol in 84% ee and 95% yield with the LAH-Chirald complex. The resulting alcohol was an intermediate in an enantioselective synthesis of lla-hydroxyprogesterone. The thiophene ketone... 

Only a few examples of intramolecular ene reactions of 1,7-enynes are known. Pyrolysis of terminal alkyne (131) in toluene for 48 h at 255 C results in 17% conversion to ene adduct (133). Ester (132) is more reactive, giving ene adduct (134) in 85% yield on heating for 62 h at 225 C. Ficini and coworkers have found that similar reactions can be carried out conveniently by flash vacuum pyrolysis. Pyrolysis of (135) at 420 "C at 200 Torr gives 80% conversion to ene adduct (136), a model for the synthesis of the a ring of lS,25-dihydroxycalciferol. Dreiding found that flash vacuum pyrolysis of ynone (137) at 550 °C gives ene adduct (IM) in 15% yield along with other products. 

Another illustration of the power of this methodology to construct natural products is illustrated by Scheffold s synthesis of PGF2Q, in the manner portrayed in Eq. (38) [46]. Here the initially formed radical undergoes a 5-exo,trig cyclization with the simple alkene found in 199. The resulting radical, when intercepted by ynone 200, affords enone 201 the latter is an advanced stage intermediate en route to PGF2 . 

The highly reactive carbonyl of lactone (60), an intermediate in the synthesis of forskolin, was easily converted to propargyl ketone (61) by addition of the lithium alkynide as shown in equation (48). It is possible that the intermediate ketal alkoxide was not stable in solution because of ring strain however, no multiple addition products were reported, nor was there any Michael addition of the alkoxide to the resulting ynone. 

The total synthesis of pyrrolidinol alkaloid, (+)-preussin was achieved in five efficient transformations from commercially available fert-Boc-(S)-phenylalanine in the laboratory of S.M. Hecht. The key step involved the Hg "-mediated 5-endo-dig cyclization of ynone substrate affording the desired pyrrolidinone which, in two more steps, was converted into the natural product. 

The preparation of the C1-C21 subunit of the protein phosphatase inhibitor tautomycin was completed by J.A. Marshall et al., and it constituted a formal total synthesis of the natural product. The spiroketal carbon of the target was introduced by the Weinreb ketone synthesis between a lithioalkyne and A/-methoxy-A/-methylurea (a carbon monoxide equivalent). The triple bond of the resulting Weinreb s amide was first reduced under catalytic hydrogenation conditions to yield the corresponding saturated amide, which was reacted with another lithium acetylide to afford an ynone. 

In the laboratory of E.J. Corey, the first synthesis of nicandrenones (NIC), a structurally complex steroid-derived family of natural products, was accomplished. The side chain of NIC-1 was constructed from the known six-membered lactone which was converted to the Weinreb s amide by treating it with excess MeNH(OMe) HCI and trimethyl-aluminum. The resulting primary alcohol was protected as the TBS ether. The ethynylation of this amide was carried out by reaction with two equivalents of lithium trimethylsilylacetylide to afford an ynone, which was reduced enantioselectively to the corresponding propargylic alcohol using CBS reduction. 

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