Use of Allylic Strain To Enforce Stereochemistry. Direct Syntheses of 7,8-Dihydroxycalamenene and Mansonone C

Abstract

Direct syntheses of 7,8-dihydroxycalamenene and mansonone C were achieved. The cis-stereochemistry required for the synthesis of 7,8-dihydroxycalamenene was introduced by an intramolecular cyclization directed by allylic strain.

Allylic 1,3-strain has been used in acyclic systems to direct the introduction of new stereogenic centers.¹ Notable examples include the work of Kishi,² Adam,³ and Giese.⁴ We are not aware of any application of allylic strain to control the relative stereochemistry in disubstituted tetralins. Tetralins such as 1, 3, and 4 have attracted considerable synthetic attention (Figure 1).⁵ 7,8-Dihydroxycalamenene (1a) exhibits useful anti-infective activity.⁶ Hydroxycalamenene (1b) was isolated from Hypericum elodeoides.⁷ Mansonone C (2), extracted from the heartwood of Mansonia altissima,⁸ was found to possess promising antifungal, larvicidal, and anti-oxidant properties.⁹ Schmalz recorded a synthesis of 1a using arenechromium complexes to introduce the relative stereo-chemistry.¹⁰

Figure 1.

Tetralin-derived products and mansonone C.

Many synthetic approaches to these compounds begin with natural products such as menthone wherein the relative stereochemistry has already been established.¹¹

Several researchers have noted that attempts to install stereochemistry by epimerization or by cyclization onto the aromatic ring have led to mixtures.^12,13 We report herein that a system such as 5, wherein allylic strain between G and the methyl group forces the methyl group to be axial as the six-membered ring is being formed, affords exclusively the cis-stereoisomer 7 (Scheme 1).

Scheme 1.

In order to evaluate the directing effect, we first synthesized allylic acetate 8 (Scheme 2). Allylic acetate 8 was synthesized starting from 6-methyl-5-hepten-2-one and the anion of 1,4-dimethoxybenzene. Dehydroxylation of the resulting benzylic alcohol using Li/NH₃ followed by allylic oxidation by the method of Sharpless¹⁴ yielded an allylic alcohol which, upon acetylation, afforded 8. Surprisingly, cyclization of allylic acetate 8 using the conditions of Ma and Zheng¹⁵ afforded tetralin 10 and naphthalene 11 in 51% and 37% yields, respectively. Compound 9, the expected product, was not isolated.

Scheme 2.

We believe that compounds 10 and 11 result from a novel cation-mediated disproportionation reaction. Comparison of the NMR spectrum of 10 with that of the literature compound¹³ showed that the cis-stereoisomer was exclusively formed.

In support of this allylic strain assisted stereoselective cyclization, we have found that cyclization of allylic acetate 12, which does not contain the directing group G, affords tetralin 13 as a 1.3:1 mixture of diastereomers (Scheme 3).

Scheme 3.

With the stereochemistry of 10 established, we began the synthesis of 1a by the reaction of 5-methyl-4-hexen-1-al¹⁶ with the anion of 1,2-bis(methoxymethoxy)-3-methylbenzene (Scheme 4). The resulting alkoxide was in situ acetylated by the addition of acetic anhydride. The displacement of the acetate to the corresponding methyl group was achieved using Me₃Al to afford 15. In order to enhance the stability for the acid-mediated cyclization, MOM protecting groups were converted to the more stable methyl ether 16. It was then oxidized and acetylated by the same methods used to generate 8. Cyclization of 17 using trifluoroacetic acid in acetic acid at 70 °C for 12 h followed by deprotection by the use of BBr₃ generated 7,8-dihydroxycalamenene (1a) in two steps (30% yield). Interestingly enough, mansonone C (2) was also obtained from the same reaction in two steps (46% yield). The direct synthesis of 7,8-dihydroxycalamenene (1a) demonstrates the advantage of employing the concept of allylic strain in organic synthesis.

Scheme 4.