Total synthesis of confertin via metal-promoted cyclization-lactonization

Abstract

3) The preparation of 3a-methylpyrrolo [2,3-b]indole derivatives (i) has been well documented in connection with physostigmine. We have recently developed a simple synthesis of 3a-hydroperoxy-or 3a-hydroxypyrroloindoie derivatives (ii) by the dye-sensitlzed photooxygenatlon of trypt a m i n e~~ and tryptophans5 i) R4=CH3 & R~ii) R4sOH or OOH iii) R, i H R2, Rg= C02Me R4 = O H The excess acid should be quenched by way of pouring the mixture into a mixture of 10% sodium carbonate and methylene chlroide in an ice bath.The NMR spectrum showed the presence of two rotamers due to hindered rotation around the carbamate N-C bond. A similar spectrum was obtained in pyridine-ds at 25 "C, becoming a simple spectrum at 80 OC. The stereochemistry of the stable isomer 2a is not established unequivocally, but comparison of its spectral data and its rate of N.-acetylation with those of the cis-and trans3ahydroxypyrroloindole derivatives (iQ5 whose structures (see note 3) have been established by X-ray analysis, indicates trans with respect to the 3a hydrogen and the ester group configuration for the stable isomer 2a.The conversion of isomers may proceed via iv and v. The N,-protonated form (v) was found to be a major species from the uv spectrum of 2 in 85% phosphoric acid. Deuterium exchange was observed not only at the 3a and 8a hydrogens, but also at benzene ring hydrogens of 2a. Cf. S. Kang, T.H. Witherup, and S. Gross, J. Org. Chem., 42, 3769 (1977). 2&-Acetyltryptamine in 85% phosphoric acid, on the other hand, gave a dimeric product related to the skatole dimer as the main product. Tryptamine itself behaves similarly. These results indicate that the tautomerization to 2 competes with the dimerization. Furthermore, the nucleophilicity of the carbamate group seems to be greater than that of acetamido group in acidic media. The protection of the 2 position of indoles by sodium bisulfite adducts has been reported: J. Thesing, G. Semler, and M. Mohr, Chem. Ber., 95, 2205 (1962). Total Synthesis of Confertin via Metal-Promoted Cyclization-LactonizationSir: Confertin (1) is one of the simplest of the sesquiterpene a-methylene-y-lactones, a class of compounds which have attracted attention as synthesis targets because of general cytotoxicity. This member of the pseudoguaianolide family of sesquiterpenes has been the object of a successful total synthesis2 and the closely related structure, damsin, has been prepared by three research group^.^ In common with all previous syntheses of natural a-methylene-y-lactones, the strategy I 2 L\ 3 M 0002-7863/78/1500-5565$01 .OO/O Scheme I C 0 2 Me a. LiAIH4 b. CrO3 4 I d. BrCH2C02Me a. DCC (Moffatt) IO 2 Ni (COD12 2-1 b. C H 3 O S 0 2 F __* 0 132 14in these efforts involved addition of an a-methylene group to a carefully constructed y-butyrolactone derivatives4 We wish to report a new approach to sesquiterpene a-methylene-ylactones which we demonstrate with the total synthesis of confertin. Our strategy involves intramolecular coupling of an allylic metal species (e.g., 3) with an aldehyde ...

Bis(1,5-cyclooctadiene)nickel(0)

“…An allylic sulfonium ion (8) has shown a similar reactivity and has been utilized in the total synthesis of confertin. 25 Intramolecular coupling with an aldehyde followed by spontaneous lactonization yielded the tricyclic αmethylene-γ-lactone (9) (eq 6). Insertion of terminal alkynes into π-allylnickel complexes derived from allylic esters (10) has led to a catalytic synthesis of nonconjugated alkenynes (11 Ortho substituents on the aryl halide drastically reduce the rate of the reaction and an increase in temperature leads only to decomposition of the nickel catalyst.…”

Bis(1,5-cyclooctadiene)nickel(0)

“…An allylic sulfonium ion (8) has shown a similar reactivity and has been utilized in the total synthesis of confertin. 25 Intramolecular coupling with an aldehyde followed by spontaneous lactonization yielded the tricyclic α-methylene-γ-lactone (9) (eq 6). Insertion of terminal alkynes into π-allylnickel complexes derived from allylic esters (10) has led to a catalytic synthesis of nonconjugated alkenynes (11) Ortho substituents on the aryl halide drastically reduce the rate of the reaction and an increase in temperature leads only to decomposition of the nickel catalyst.…”

“…6a These intermediates can also be induced to react with carbonyl compounds, but they are much less nucleophilic than π-allylhalide-like complexes. 74 (25) [ Due to the lack of general methods for the production of medium-sized rings, the synthetic value of these reactions lies especially in their ability to generate cyclooctane ring systems. Control of the cyclodimerization of 1,3-dienes to give cyclooctadiene products preferentially is contingent upon the substitution of the diene as well as the composition of the catalyst system, with both of these factors being mutually dependent.…”

Pseudoguaianolides: Recent Advances in Synthesis and Applications

“…The previously mentioned Money's enantioselective approach for helenalin was applied also in the formal synthesis of mexicanin I from camphor derived dienone 14 as well as in that of confertin [37]. After the first stereoselective total synthesis of (±)confertin (3) reported in 1976 [39], several other procedures were reported [39][40][41][42][43][44][45][46][47][48][49][50], which often include the synthesis of the C10 epimer (±)-aromatin and of the 6,7-annullated lactone damsin and damsinic acid. Total syntheses of (+)-confertin date from 1987 [51][52][53][54].…”