Guaianolides synthesis

Substituted furan formation by an indirect cyclization of 1,4-dicarbonyl derivatives has also been adopted as a key step in the synthesis of 3-oxa-guaianolides. Although 1,4-dicarbonyl compounds have been traditionally considered as the direct precursors for furans, treatment of 1,4-dicarbonyl compounds having a tertiary acetoxy group with p-toluenesulfonic acid leads to only 11% yield of an alkenylfurans as derived from a cyclization/acetoxy-elimination route. The following scheme shows an alternative multi-step conversion of the 1,4-dicarbonyl that leads to a more acceptable yield of the acetoxyfuran . 

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

The reaction conditions of the classical Paal-Knorr furan synthesis can be too harsh, when labile functionality has to be preserved. In the synthesis of the 3-oxa guaianolide 4, a five-step detour proved to be more efficient than direct cyclization (Scheme 4) <2000T6331>. Cyclic carbinol amides yield a-trifluoromethyl-sulfonamido furans upon treatment with triflic anhydride (Equation 7) <20030L189>. 

Methylenation. In a synthesis of the two guaianolide sesquiterpenes dehydrocostus lactone (4) and estafiatin (6), usual methods for methylenation of the ketone group of 2 resulted only in p-elimination. However, use of the anion of 1 effected the desired reaction, albeit in modest (15%) yield. 

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. 

In addition to the sulfoximines, Johnson has studied phosphinothioic amides as alkene precursors. This reagent has not achieved the popularity of the sulfoximines. It can be utilized for ketone methylen-ation with resolution, as well as for Ae synthesis of more highly substituted alkenes. Rigby has found that in the synthesis of guaianolides this reagent was effective where Peterson and Wittig reactions gave only p-elimination. ... 

Synthesis of 6,12-sesquiterpenolides This section describes the synthesis of sesquiterpenes bearing a lactone moiety between C(6) and C(12). The transformation of the A-ring in santonin to give eudesmanolides, guaianolides, and elemanolides, as well as the modification of the lactone ring is described. Some microbiological transformations of santonin and its derivatives are also described. 

A review has recently appeared describing the synthesis of hydroazulene sesquiterpenes through rearrangement of substituted hydronaphthalene precursors, including some syntheses of guaianolides from santonin (1)... 

The overall yield of this synthesis was poor and so the same authors devised a new sequence starting from compound 206, obtained from santonin in 10 steps in 23% overall yield (Scheme 27). Solvolysis of 206 gave, in 75% yield, a 2 1 3 mixture of guaianolides 207, 208 and 209, which possess tetra-, tri-, and di-substituted double bonds, respectively. It is likely that the solvolytic rearrangement of206 proceeded via 210, since... 

Different procedures for the synthesis of guaianolides have been reviewed [16]. Some of these will be discussed in the following paragraph. 

A early partial synthesis of the guaianolide nucleus was based on photochemical rearrangement of a-santonin (44) to give isophotosantonic lactone (45) [17] (Scheme 98.5). The stereochemistry of this reaction is remarkable. Irradiation of the santonin isomer, in which the C6-06 bond is 3 disposed gives the C6-06, C7-C11 cis isomer of 45 [18]. 

Scheme 98.7 Synthesis of the starting material 46 for preparation of guaianolides...

Yuuya S, Hagiwara H, Suzuki T, Ando M, Yamada A, Suda K, Kataoka T, Nagai K (1998) Guaianolides as immunomodulators. synthesis and biological activities of dehydiocostus lactone, mokko lactone, eremanthin, and their derivatives. J Nat Prod 62(l) 22-30... 

Schall A, Reiser O (2008) Synthesis of biologically active guaianolides with a trans-annulated lactone moiety. Eur J Organ Chem 14 2353-2364... 

Andrews SP, Ball M, Wierschem F, Cleator E, Oliver S, Hogenauer K, Simic O, Antonello A, Hunger U, Smith MD, Ley SV (2007) Total synthesis of five thapsigargins guaianolide natural products exhibiting sub-nanomolar SERCA inhibition. Chem Eur J 13(20) 5688-5712... 

The continued search for novel synthetic routes to the sesquiterpene pseudo-guaianolides has resulted in several new approaches to the hydroazulene ring system. Lansbury and Serelis have shown that the hydroxycyclopentanone (191) undergoes facile cationic cyclization on treatment with formic acid, leading directly to the hydroazulenedione (192). Further manipulation of (192) led to the total synthesis of damsinic acid (193). In an impressive synthesis of the closely... 

Greene, A.E. and Edgar, M.T., Synthesis of oxoisodehydroleucodin a novel guaianolide from Montanoa imbricata, J. Org. Chem., 54,1468,1989. 

---