Pallescensin synthesis

The phosphonate 1 does not react with the aldehyde 2 under usual conditions (NaOCHj, DMF, 20-110°).2 Addition of a catalytic amount of 15-crown-6 permits the desired condensation in 45% yield. The product (3) was used for synthesis of pallescensin-E (4). 

Wittig-Homer reactions.3 The reaction of the phosphonate 2 with the aldehyde 1 under literature conditions gives the fraras-stilbene 3 in only about 10% yield. Addition of 15-crown-5 raises the yield to 45%. This step was used in a synthesis of pallescensin E (4), a furanosesquiterpene in a marine sponge. 

An intramolecular 2-alkylation was also observed in a sulfonyl free radical induced addition-cyclization <95SL763>. A key intermediate in a new synthesis of pallescensin A (a biologically active labdane diterpene) was prepared by a cationic cyclization reaction with a furan <95SYN1141>. The sonochemical Barbier reaction was extended to carboxylate salts. 2-Furanylketones 10 can be obtained by sonication of a mixture of furan, lithium carboxylate, an alkylchloride, and lithium in THF <95JOC8>. 

We shall describe two examples of this reaction being used as part of the synthesis of natural products. The first is pallescensin A, a metabolite of a sponge. 

This reaction worked well, as did the rest of the synthesis of pallescensin A which was first made by this route. The key step, the acylation of the lithium enolate, is interesting because it could have alkylated instead. The acid chloride is more electrophilic than the alkyl chloride in this reaction, though alkylation does occur in the next step, Notice how the lithium atom holds the molecules together during the reaction. 

A furoannulation protocol via dichlorocarbene adducts of alkyl enol ethers has been applied to the synthesis of the furanosesquiterpene pallescensin A (Equation 39) <2006TL6817>. 

This compound must arise from bromonium ion cyclization of the 6,7-bromohydrin of farnesol acetate. Hydrolysis of the acetate group in (47) and sequential treatment with phosphorus tribromide and water gave obtusenol (46). Other syntheses of marine sesquiterpenoids include those of pallescensin-E (48),30 furoventalene (49),81 and dactyloxene-B (50) and -C (51).32 The last mentioned established the absolute configurations of the two dactyloxenes. A second synthesis of ancistrofuran (53) and its C-2 epimer has been recorded starting from the lactone (52) which is derived from homogeranic acid (Scheme 3).33... 

An electrocyclization of the 1,3,5-triene 12 was employed in the stereoselective synthesis of ( )-pallescensin (ll)95. Thermolysis of furan 12 in xylene (200°C) presumably forms the intermediate 13 via 1.6-ECRC, how ever 13 is not observed, rather it undergoes a suprafacial [1,5] hydrogen shift to afford the cts-fused tricyclic 14. The synthesis of ( )-pallescensin (11) required the trans-fused tricycle 15 rather than the cis, and it was found that this desired stereoisomer could be obtained w hen the 1,6-ECRC was carried out in the presence of silica gel. It was reasoned that the mildly acidic silicon dioxide could reasonably effect the acid-catalyzed epimerization of 14 to 15. Reduction and protodesilylation of 15 completed the synthesis of 11. 

Further additions to the long list of tobacco constituents include 5(13),7 -megastigmadiene-6,9-diol (44), (3S,6i ,9i )-4,7 -megastigmadiene-3,9-diol (45) and its 95-epimer, and a seco-nor-carotenoid , 3,3-dimethyl-7-hydroxy-octan-2-one (46), all from Greek tobacco. The structures (47), (48), and (49) of pallescensin-1, -2, and -A have been proved by synthesis from a-cyclocitral (50)." ... 

Nature has found it possible to assemble a wide range of furanosesqui- and diterpenes. Although it is quite clear that these substances are not biosynthesized via any sigmatropic scheme, the atom economy of such isomerization reactions appeared to us to warrant application to this field. A thrust in this direction would require, however, that a furan ring be willing to utilize its n electrons in a manner suitable to rebonding. Precedent for an adaptation of this type was scarce [41]. Nonetheless, we have succeeded in developing a relatively concise enantioselective synthesis of natural (+)-pallescensin A (81), a marine metabolite first isolated in 1975 [42] and prepared earlier on several occasions [43-48]. 

A biomimetic synthesis of ( )-pallescensin A (107 R = H) has been achieved through the concerted Bp3 Et20-induced cyclization of epoxide (106) to yield crystalline (107 R = OH) (25%), followed by subsequent deoxygenation. The cyclization of the parent diene with BF3-Et20 gave (107 R == H) directly (84%) as an almost pure oil. 

Functionalized homoallyl alcohols can be cyclized with Pd(0) catalysts to give chiral 3-methylene-tetrahydrofurans <93TL4655>. The cyclization of p.y-dihydroxyketones in the presence of acids yields fiirans. Starting with (+)-Wieland-Miescher ketone this method was used for a total synthesis of (+) pallescensin A <93JCR(S)58>. y-Substituted y-butyrolactones of high enantiomeric purity can be obtained from aldehydes by the following sequence of reactions <94JOC365>. 

A second synthesis of the marine sesquiterpenoid pallescensin A (49) has been achieved by acid-catalysed cyclization of the furanodiene (48). Continued... 

We shall describe two examples of this reaction being used as part of the synthesis of natural products. The first is pallescensin A, a metabolite of a sponge. It is quite a simple compound and some chemists in Milan conceived that it might be made from the chloro-diketone shown below, which might in turn be made by acylation of the enolate of a symmetrical ketone. 

The enone formation has been applied to a number of natural product syntheses. The enone 524 was prepared from the complex molecule 523 and successfully applied to the total synthesis of pallescensin [212], Even the phenolic OH in 525 was converted to the conjugated ketone. The reaction was utilized as a key step in hypoxyxylerone synthesis [213]. In the total synthesis of galbulimima alkaloid GB 13, Mander converted a cyclohexanone in the complicated molecule 526 to the corresponding cyclohexenone via silyl enol ether in 82% yield [214]. 

Baker and Sims have shown that addition of a catalytic quantity of 15-crown-5 to a Wadsworth-Emmons reaction greatly facilitates olefin formation. For example, reaction between the aldehyde (31), phosphonate (32), and sodium hydride in the presence of 15-crown-5 gave the heterocyclic stilbene analogue (33) (45% the key step in a synthesis of the furanosesquiterpene pallescensin-E). ... 

Baker, R. and Sims, R.J. (1981) Synthesis of pallescensin-E use of crown ether in the Wadsworth procedure for olefin formation. Tetrahedron Lett., 22,161-162. 

Kurth, M.J. and Soares, C.J. (1987) Asymmetric aza-Claisen rearrangement synthesis of (- -)-dihydropallescensin-2 [( )-penlan-pallescensin]. Tetrahedron Lett., 2, 1031-1034. 

Liotta, D. and Ott, W. (1987) Triene cyclizations. The total synthesis of pallescensin A. Synth. Commun., 17,1655-1665. 

Shishido, K., Umimoto, K., and Shibuya, M. (1990) An alternative total synthesis of (-F)-pallescensin A based on the intramolecular [3-F2] cycloaddition reaction. Heterocycles, 31, 597-598. 

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