Fourth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), www.mdpi.org/ecsoc-4.htm, September 1-30, 2000

[C0022]

Hisahiro Hagiwara

Graduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Tel / Fax +81-25-262-7368, E-mail: [email protected]

Abstracts: Nor- and bisnorsesquiterpenoids 1 and 2 have been synthesized starting from (S)-(+)-Wieland-Miescher ketone analogue 4 via solid state Baeyer-Villiger reaction as a key step.

Cryptoporic acid 3, isolated from basidiomycetes fungi (Cryptoporus volvatus) by Hashimoto and Asakawa,¹ has strong inhibitory activity on the release of superoxide anion radical from guinea pig peritonel macrophages (Figure 1). From the dry powders of the mushroom ingested by the beetle Tibolium castaneum, several novel metabolites were isolated whose relative stereostructures were determined by combination with extensive 2D NMR studies. Among them, a norsesquiterpene hydroxy-acid 1 and a bisnorsesquiterpene keto-acid 2 are unique monocyclofarnesane derivatives and anticipated to be metabolites of cryptoporic acid 3 via bio-Baeyer-Villiger transformation by the insects.¹ Their absolute stereostructures at C-2 were determined to be R as depicted in Figure 1, structures 1 and 2, by employing Kusumi's PGME (phenylglycine methyl ester) method.² This paper deals with the first total syntheses of 1 and 2 demonstrating efficiency of solid state Baeyer-Villiger reaction.

Total synthesis of norsesquiterpenoid 1 ³

According to the plausible biogenetic pathway¹ of 1 and 2 via bio-Baeyer-Villiger reaction of bio-degradation products of 3, decalone 12 (Scheme 1) was chosen as a key intermediate for the total synthesis of 1. Though optically active decalone 8 is known in literature,⁴ we took an alternative route from alcohol 5 derived from optically active (S)-(+)-Wieland-Miescher ketone analogue 4⁵ (>95% e.e.). By employing Barton's radical protocol,⁶ the hydroxyl group at C-6 of the alcohol 5 was removed to give ketal 7 in 88% overall yield followed by deprotection of the ketal to give the decalone 8 {[a ]_D²¹ - 42.2 (c 2.2, CHCl₃)} in 95% yield. In order to ensure mono-methylation at C-2 of the decalone 8, methoxycarbonyl group was introduced at first to give 10, which was followed by methylation to afford 11 and finally demethoxycarbonylation to give decalone 9 as an diastereomeric mixture. However, overall yield of the reactions from decalones 8 to 9 was unsatisfactory. Fortunately, mono-methylation of 8 with excess LDA and methyl iodide furnished 9 as a 1 : 1 diastereomeric mixture in 97% yield. No dimethylation occurred under the reaction conditions employed. The methyl group at C-2 of the decalone 9 was isomerized in 95% yield by treatment with base into the thermodynamically more stable a-isomer 12 in which the orientation of methyl group was apparent from coupling patterns of the proton at C-2 (d 2.68, ddq, J=12.8, 6.4, 6.4 Hz). Under normal circumstances, the sterically congested and less strained carbonyl groups resist to Baeyer-Villiger reaction. In fact, attempted Baeyer-Villiger reactions of the decalone 12 with various peracids^7,8 in solvent were not successful resulting in recovery of 12. Hence, we turned our attention to solid state Baeyer-Villiger reaction⁹ whose advantages have been underestimated in natural product synthesis. Solid state reaction of the decalone 8 provided lactone 26 in 90% yield at room temperature overnight (Figure 2). Encouraged by this success, the solid state Baeyer-Villiger reaction of 12 was then investigated. While monitoring the progress of the solid state reaction by tlc, we observed the formation of a new reaction product which was supposed to be an adduct of the decalone 12 with MCPBA, since it disappeared gradually with increasing amount of lactone 13. In order to enhance rearrangement, the reaction mixture was heated to 60°C to give the lactone 13 in 72% yield. Finally, alkaline hydrolysis of the lactone 13 furnished hydroxy acid 1 in 79% yield as a crystalline compound (m.p. 102 ~ 104°C, natural 103 ~ 104°C). The spectral data including optical rotation {[a ]_D²¹ - 7.9 (c 0.5, CHCl₃), lit.,¹ [a ]_D²¹ - 6.8 (c 0.6, CHCl₃)} completely agreed with those of the natural product 1 which indicates no epimerisation at C-2 during alkaline hydrolysis of the lactone 13.

The same strategy was employed to the synthesis of 2 starting from optically active (S)-(+)-Wieland-Miescher ketone analogue 4⁵ (>95% e.e.) to target decalone 20 as a key intermediate with all requisite stereocenters for 2 (Scheme 2). Reduction of a ,b -unsaturated moiety of enone 14 with lithium in liquid ammonia provided in 84% yield ketone 15 which was reduced with lithium aluminum hydride to give a mixture of two inseparable isomeric alcohols 16. Deprotection of the acetal provided b - and a -alcohol 17 in 83 and 12% yields respectively in two steps. Coupling constants of the proton at C-5 of the major isomer 17 (d 2.64, ddq, J 14.0, 13.8 and 7.0 Hz) revealed equatorial orientation of the methyl group at C-5 and trans ring junction of the decalin framework. In order to introduce methyl group at C-2, the b -alcohol 17 was protected with TMSCl to give TMS ether 18 in 94% yield. Treatment of the ketone 18 with LDA at -20°C followed by addition of MeI provided an inseparable 1 : 1 diastereomeric mixture of monomethylated products 19 in 73% yield. When hydroxy group at C-6 of 17 was protected as TBDMS ether, all similar attempts have failed. By treatment with sodium methoxide, the decalones 19 equilibrated into 98% yield with concomitant deprotection of TMS group to thermodynamically stable a -isomer 20 in which the orientation of methyl group was apparent from coupling patterns of the proton at C-2 (d 2.68, ddq, J 12.8, 6.4 and 6.4 Hz). All the requisite stereocenters for the target compound 2 were furnished at this stage.

Solid state Baeyer-Villiger reaction of 20 with MCPBA gave a small amount of lactonic compounds. Then, the hydroxy group of 20 was quantitatively acetylated as an acetate to provide 21. Though conventional Baeyer-Villiger reaction of 21 in solvent with MCPBA or trifluoroperacetic acid⁸ with or without Yb(OTf)₃⁷ was very sluggish and resulted again in recovery of 21, solid state reaction⁹ of the acetate 21 with MCPBA furnished desired lactonic compound 22 and its regio-isomer 23 in 58 and 27% yields respectively.

Hydrolysis of the lactone 22 with aqueous potassium hydroxide followed by Jones oxidation provided very unstable acid 2 which was soon esterified with diazomethane to give methyl ester 25 in 52% overall yield in three steps. Spectral data of the synthetic 25 were completely identical with the data of the natural 25 including optical rotation [a ]_D²³ - 13.1 (c 0.26, CHCl₃) {lit.,¹ [a ]_D²³ - 14.3 (c 0.28, CHCl₃)}.

Some of our results on the solid state Baeyer-Villiger reactions are compiled in Table 1.

Smooth reactions and perfect regioselectivities of the decalones 8 and 12 in entries 5 and 6 rather than the decalone 21 in entry 4 might be result of 1,3-steric repulsions between two axial methyl groups at C-5 and C-8a in 8 and 12 (Figure 2). The rate determining step of Baeyer-Villiger reaction is migration from Crieege's intermediate via early transition state.^10,11 To this end, semiempirical molecular orbital calculations (PM3)¹² on Crieege's intermediates 28a and b derived from the decalone 12 were performed by using Gaussian 98.¹³ Though the difference of heat of formation of both intermediates 28a and b were subtle (0.07 Kcal), C-1-C-8a bond in the more stable intermediate 28a was longer (1.61 Å)¹⁴ than C-1- C-2 bond (1.56 Å) and anti periplaner (dihedral angle 173°) to O-O bond. These results explain regioselectivity of the present Baeyer-Villiger reactions. Substrates 19 ~ 21, 8 and 12 in the Table 1 were all unreactive in Baeye-Villiger reactions in solvent. However, exact reasoning of great enhancement in the present solid state Baeye-Villiger reaction is yet to be clarified.

In conclusion, we have completed the total synthesis of norsesquiterpenoid 1 and bisnorsesquiterpenoid 2, demonstrating effectiveness of solid state Baeyer-Villiger reaction in natural product synthesis.

We thank Profs. T. Hashimoto and Y. Asakawa, Tokushima Bunri University, for providing an authentic sample of the natural product 1 and spectral data of 25.

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