Alkynic synthesis from lactones

The application of this methodology to suitably functionalized alkynes has allowed a direct and easy synthesis of important heterocyclic compounds starting from readily available substrates. New /1-lactone [100,101] and /3-lactam [102] derivatives were synthesized in good yields from a,a-disubstituted propynyl alcohols and amines, respectively (Eq. 38), through the mechanistic route shown in Scheme 18, path a. The substitution a to the triple bond was a necessary requisite for cychzation to occur, owing to the reactive rotamer effect [301]. 

Dehydrobromination of bromotrifluoropropene affords the more expensive trifluoropropyne [237], which was metallated in situ and trapped with an aldehyde in the TIT group s [238]synthesis of 2,6-dideoxy-6,6,6-trifluorosugars (Eq. 77). Allylic alcohols derived from adducts of this type have been transformed into trifluoromethyl lactones via [3,3] -Claisen rearrangements and subsequent iodolactonisation [239]. Relatively weak bases such as hydroxide anion can be used to perform the dehydrobromination and when the alkyne is generated in the presence of nucleophilic species, addition usually follows. Trifluoromethyl enol ethers were prepared (stereoselectively) in this way (Eq. 78) the key intermediate is presumably a transient vinyl carbanion which protonates before defluorination can occur [240]. Palladium(II)-catalysed alkenylation or aryla-tion then proceeds [241]. 

In certain other systems, there is compelling evidence for the insertion into a metal-caiboxylate complex (equation 37). For example, in the synthesis of a-methylene-y-lactones from alkynic alcohols,70,71 no double bond rearrangement to a butenolide occurs, a reaction shown to take place in the presence of transition metal hydrides. The source of the vinyl proton (deuterium) on the a-methylene group is indeed the alcohol function. Finally, palladium carboxylate complexes containing alkynic (equation 40) or vinyl tails (equation 41) can be isolated and the corresponding insertion reaction can be observed. 

Carbocyclization of a radical derived from butyrolactone 91 onto an alkyne under reductive conditions gave the bicyclic lactone 92 in moderate yield [95JOC8179]. This intermediate was used m the total synthesis of (+)-eremantholide A 93. 

An original diastereoselective approach to the synthesis of steganone analogues was reported by Motherwell and co-workers, Fig. (29) [144], The diyne 135 was obtained from bromide 133 and lactone 134 via diastereoselective alkylation and deprotection of the alkyne groups. A cobalt-mediated [2+2+2] cycloaddition of 135 with... 

A similar convergent synthetic strategy was applied in our synthesis of annona-cin, using sequential assembly of the three key fragments, aldehyde 29, phospho-nium 30, and alkyne 14 (Scheme 10-9). In this synthesis, the a,p-unsaturated-y-lactone unit was constructed after completion of the linear skeleton. A modified method was applied into the synthesis of segment 3 (Scheme 10-5), in which the six carbons, as well as two chiral centers from D-glucono-8-lactone, were all incorporated into the final target. Therefore, the efficiency of the whole... 

The synthesis of furanones (y-lactones) from alkynes and carbon monoxide consititutes a unique variation of the [2 + 2 + 2] pattern. The ring incorporates both carbons from the C=carbon from one CO, and both carbon and oxygen from the other CO. The process is therefcMe a 2 + 2 -i-1 cycloaddition of the form [2TTfw + Zno-o 2ncol- The formal result of such a cycloaddition is a carbene at position 4, the carbon atom of the irco participant (equation 12). 

The Chiron (-)-(lOa) was obtained with very high diastereoselectivity from a-pyrone sulfone and optically active vinyl ether (Scheme 69). This lactone was later used in the asymmetric synthesis of (-)-methyltriacetyl-4-epishikimate (10b). 3-Sulfonylnitroalkenes were also shown to be reactive alkyne equivalents in Diels-Alder reactions. ... 

Brefeldin (20) is a 13-membered lactone isolated from a number of sources and has a wide spectrum of biological activity. Many of the syntheses of this lactone use alkynes as intermediates. Thus, Living-house and Stevens used an elegant ring opening of a bicyclo[3.1.0]hexane to give the desired trans stereochemistry (Scheme 38), whereas in the synthesis of Kitahara and coworkers, a more conventional alkynide alkylation was involved (Scheme 39). 

The brief report of Jacobsen s total synthesis starts with a detailed retrosynthetic analysis. The compound was broken into four pieces 21a after removal of the phosphate. The unsaturated lactone 24 (M is a metal) could be made by an asymmetric oxo-Diels-Alder reaction from diene 22 and ynal 23. The epoxide 25 provides a second source of asymmetry. One cis alkene comes from an alkyne 26 and the rest from a dienyl tin derivative 27. 

No doubt joining the alkyne to the alkene could also have been done by a coupling reaction in the coordination sphere of a metal but an alternative is to imagine the alkene as coming from the dehydration of an alcohol 251. This allows disconnection to the known lactone 250. The synthesis of the alkyne uses DIBAL for partial reduction and the differential protection of the two OH groups by more or less hindered silyl groups. 

There are several attractive methods for the constmction of macrolides (Scheme 22). An intramolecular alkenylzinc/aldehyde addition from w-alkynal ester 144 in the presence of (-)-DAIB furnished 18-membered lactone 145, which led to (-(-)-aspicilin (146) [102]. In the total synthesis of 10-deoxymethynolide... 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

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