Confertin

Intramolecular allylzinc aldehyde additions lead, in one synthetic step, to bicyelic a-methylene-y-lactones41. Interestingly, the (Z)-isomer gave only the r/5-fused bicyclic products, which arises from a. vyw-selectivc addition, while the ( >isomeric bromide furnished a cisjtrans mixture (yield 56%, cisjtrans 72 28)41 indicating that the double-bond torsion and the intramolecular carbonyl addition have similar rates. A similar sequence was the key step in a confertin synthesis28. 

This methodology has been applied to the synthesis of the bicyclic system (157),133 an advanced intermediate previously used in the synthesis of confertin.138 Reaction of the diazo compound (158) with rho-dium(II) mandelate gave an equilibrating mixture of the norcaradiene (159) and the fused cycloheptatriene (160) in essentially quantitative yield (Scheme 35). The mixture of (159) and (160) was converted to (157) in six steps in 20% overall yield. 

From six-membered rings Rearrangement as part of the pseudo-guaianolide to confertin synthesis [14]. 

Cycloheptane derivatives (7, 192-193). Wender et a/. have applied their cycloheptane annelation procedure to total syntheses of the pseudoguaianolides damsinic acid (1) and confertin (2). The paper describes the synthesis of 1-lithio-l-methyl-2-vinylcyclopropane, which is the annelation reagent utilized in the pseudo-guaianolide syntheses. 

Wender and coworkers could ingeniously solve this problem in their approach to damsinic acid and confertin by simultaneous irradiation and thermolysis giving the desired cycloheptadiene derivative contaminated by traces of H-shift products only (equation 170). 

Further studies on the synthesis of psuedoguaianolides cf. Vol. 6, p. 90) have resulted in the total synthesis of the cytotoxic compounds ( )-damsin (447) (Scheme 43) and ( )-confertin (449) (Scheme 44). The realization that many sesqui-terpenoids containing a-methylene-y-lactone rings display important biological activity (cf. pp. 88 and 96) has prompted the development of several procedures... 

The synthesis of cyclic ketones via acyl radical cyclizations represent by far the most frequently investigated approaches in the past two decades and such cyclizations are well discussed in a recent review [la]. Two recent examples of the application to natural product synthesis are given here. A seven-membered ring, a key compound in the overall synthesis of (-i-)-confertin, was prepared by Shishido and co-workers, utilizing 1-endo-trig acyl radical cyclization which occurred in a highly efficient manner (Scheme 4-39) [66]. 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

This methodology was featured in the synthesis of perhydroazulene sesquiterpenes such as damsinic aid (66) and confertin (67). The rearrangement of divinylcyclopropanes 63 is more effective under combined thermal and photochemical conditions, which also minimizes the competing production of 65. 

This reaction was employed in a stereospecific synthesis of the hydrazulene lactone 17, which was subsequently converted to the sesquiterpene confertin. ... 

Addition of sulfur nucleophiles such as phenylthiolate to diethyl l-(ethoxycarbonyl)vinylphos-phonate has been used in the synthesis of P-acetoxy- and p-hydroxy-a-methylene-y-butyrolac-tones Similarly, addition of isopropylthiolate to diethyl l-(ethoxycarbonyl)vinylphosphonate represents a key step in the synthesis of a-methylidenebutyrolactones such as confertin (Scheme arteannuin B, - - rhopaloic acid and hippospongic acid A Addition... 

Semmelhack, M.E, Yamashita, A., Tomesch, J.C., and Hirotsu, K., Total synthesis of confertin via metal-promoted cyclization-lactonization, J. Am. Chem. Soc., 100, 5565, 1978. 

Application of the prolinol-derived lithium amide 11 (Scheme 9)in the asymmetric synthesis of (-F)-confertin was successful with the addition of isoprope-nyllithium to 2-methylcyclopentenone being a key step [37]. 

Similar results are obtained in the synthesis of precursors (8 and 10) of naturally occurring confertin. Thus, hydrogenation of dienone 7 results in the formation of the thermodynamically more stable traw.r-fused hydroazulene 8 with a high degree of diastereoselectivity52. 

Shishido and coworkers [42] have employed a highly stereoselective 1-endo trig radical cyclization reaction for the construction of a key intermediate 174 in their synthesis of a pseudoguanolide (-l-)-confertin starting from the selenoester 173. 

---