Ynones, cyclization

An example of an exo-dig process would be the base-catalyzed cyclization of an -hydroxy-a,/S-ynone ... 

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>. 

Pd-catalyzed isomerization of ynones to furans has been an active area of research over the last decade. Huang et al. described a Pd-catalyzed rearrangement of a,P-acetylenic ketones to furans in moderate yield [102], For example, Pd(dba)2 promoted the isomerization of alkyne 124 to a putative allenyl ketone intermediate 125, which subsequently cyclized to the corresponding furan 126. 

Other than the aforementioned ynones, P-iodo-p/y-enone 132 was also converted into a 2,5-disubstituted furan, 133, under Pd-catalyzed cyclization conditions using Herrmann s catalyst, palladacycle catalyst 101 [105]. 

The imine 217, formed from acetophenone and the 1-aminoimidazole, has been transformed into the enamine 218 which is then cyclized to 219 in trifluoroacetic acid (TFA) (Equation 40) <1995SC3271 >. The diaminoimidazole 220 reacts with ynone 221 to form 222 (Equation 41) <1998CHE1189>. Bromochalcones and chalcone dibromides can also be used in place of the ynone. Similar reactions have been used to prepare the dihydro analogues of 222 <1999CHE1207>. The reaction between 1-aminoimidazoles and 1,3-diketones has been extended to prepare bis-heterocyclic compounds, for example, 223 as ligands for transition metals (Equation 42) <2005EJI4382>. 

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). 

When subjected to mercury acetate the ynone 78 underwent a 5-endo-dig cyclization and after work-up with aqueous sodium chloride, furnished the pyrrolinones 79 and 80 in a ratio of 89/11. The mixture of pyrrolinones was reduced directly with sodium borohydride to the iST-Boc-pyrrolidinol 81 which was obtained as a single diastereoisomer. Reduction of the carbamate with lithium aluminum hydride gave (+)-preussin (2) in 37% overall yield. 

Cyclization ofsilyl enol ethers of -acetylenic ketones or aldehydes. Reaction of these derivatives of ynones or -als with HgCl2 (1.1 equiv) and hexamethyldisi-lazane (0.2 equiv.) as an acid scavenger in CH2C12 at 30° followed by acidification with aqueous HC1 and Nal (2 equiv. each) results in cyclic 0,y-enones. Thermal cyclization of these substrates requires high temperatures, which lead to decomposition and rearrangements.1... 

A tandem Michael-aldol reaction of ynone selenides with aldehydes provides a convenient route to 3-substituted selenochromen-4-ones 132 (Equation 49) <2002TL7039>. The reaction proceeds via an intermediate zwitterion formed via a 6-/ r/ -r//g-cyclization. 

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... 

Buchwald and his group have also synthesized y-butyrolactones successfully by a metallocene mediated cyclization of enones (and ynones) with carbon monoxide in a formal [2-r2-rl]-ad-dition, and have thus achieved the first hetero-Pauson-Khand reaction [31]. The reactions can be conducted in high yields with either stoichio-metrical or catalytical amounts of [Cp2Ti(PMe,)2] as the example in Scheme 9 shows. 

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). 

Furthermore, the concept of a sequential nucleophilic addition in acidic medium can be transposed to the conversion of the ynone intermediates with iodine monochloride [197] and subsequent cyclization [198] into chloro iodo furans in a one-pot fashion. Therefore, after coupling of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, NaCl, iodine monochloride, and PTSA were added to give after 4 h of stirring at room temperature the substituted 3-chloro-4-iodo furans 59 in moderate to decent yields (Scheme 34) [196]. 

Thermal cyclization of dienones enals, ynones, diones ketoesters, etc, to monocyclic spirocycfic bicyclB derivatives, (ene reaction of unsalurated enol)... 

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 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. 

Kuroda. C.. Kimura, Y, and Nogami, H., Intramolecular cyclization of 2-(alkoxycarbonyDallyIsilanes with ynones. Nucleophilic and electrophilic aspects of the 2-(alkoxycarbonyllallylsilane moiety. J. Chem. Res. (M), 822, 1998. 

Thermal cyclization of dienones, enals, ynones, diones, ketoesthers to monocyclic, spirocyclic bicyclic derivatives (ene reaction of unsaturated enol) (see 1st edition). 

Among the very few reported possibilities offered by transannular cycle contraction of cyclododecenyl radicals to construct 9,5-, 8,6- or 7,7-bicyclic systems, the radical tandem approach to the taxanes planned by Pattenden, from the substituted A-ring precursor 134, introduces a new conceptual strategy, described as E in Scheme 29. First, a 12-e Jo-dig macrocyclization involving alkyl radical 135 occurs easily on the triple bond of the ynone moiety. The produced vinyl radical (major conformer is presented) 136 cyclizes in a 6- n-endo)-exol - n-exo)-endo transannular manner to assemble the unusual tricyclo[9.3.1.0 ]pentadecane framework 137 as a 6 1 ratio of diastereomers (Scheme 38) [55]. 

Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-e rfo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp carbons and two conjugated enone moieties (Scheme 42),... 

Ynones 60 also can be cyclized by addition of nucleophiles HNu (e.g. HOR, HSR etc.) to give quinolines analogous to 61 with an additional Nu-substituent in the 4-position [97]. 

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