Pentacyclic Compounds by Samarium Diiodide‐Induced Cascade Cyclizations of Naphthyl‐Substituted 1,3‐Diones

Abstract

Treatment of naphthyl-substituted cyclopentane-1,3-diones with the samarium diiodidehexamethylphosphoramide (HMPA) complex in the presence of tert-butyl alcohol provided the expected tetracyclic diols with steroid-like structures. Surprisingly, reactions without the proton source led to the efficient formation of a new pentacyclic diol. In this case the toxic additive HMPA could be substituted by a combination of lithium bromide (in situ generation of samarium dibromide) and N,N-dimethylimidazolidone. The styrene-like alkene moiety of this product was used to prepare an ensemble of highly substituted pentacyclic steroid-like compounds.Keywords: electron transfer; ketyl-aryl coupling; polycycles; radical reactions; samarium diiodide; steroids In earlier communications we have reported that garyl ketones undergo novel samarium diiodide-induced cyclizations leading to synthetically useful hexahydronaphthalene derivatives.[1] The closely related reaction of simple cyclic g-naphthyl-substituted ketones furnished tetracyclic compounds with steroidlike constitution, but "unnatural" cis/cis annulation of rings B/C/D.[2] Here we describe our experiments with cyclic 1,3-diones as precursors for the crucial samarium ketyls, [3] which were performed to generate steroid analogous products with additional functionality in ring D.The required naphthyl-substituted 1,3-diketones were prepared by a straightforward four-step synthesis following the Torgov approach to steroids as exemplified for compound 5 (Scheme 1).[4] Dione 3 was obtained by addition of vinylmagnesium bromide to tetralone 1 followed by a Pd-catalyzed allylic alkylation.[4d] Oxidation of 3 with DDQ [4e] and subsequent reduction [5] of the alkene moiety furnished dione 5 in 35 % overall yield. Analogously, 6 and 13 were prepared from the corresponding precursors. Cyclopentane-1,3-dione derivative 5 was treated with an excess of samarium diiodide in the presence of HMPA [6] and tert-butyl alcohol and provided the expected diols 7a/7b in yields varying between 67-74 %. The ratio of diastereomers 7a/7b strongly depends on the amount of the proton source (Table 1, entries 1-4). Standard conditions (8 equivs.) led to an unselective reaction (entry 1), whilst use of only 1 equiv. of tert-butyl alcohol (entry 4) induced a highly diastereoselective formation of tetracyclic diol 7a.[7] The relative configurations of 7a and 7b were unequivocally proven by X-ray analyses.[8] The conversion of cyclohexane-1,3-dione derivative 6 into tetracyclic diol 8 is rather slow and even after a reaction time of two days 25 % of 6 was recovered (entry 5). We assume a mechanism for these cyclizations as proposed before, [2] but here a subsequent stereoselective reduction of the remaining cycloalkanone carbonyl group by the excess of samarium diiodide generates the second hydroxy group. This step affords products 7 and 8 with trans-arranged hydroxy groups. However, the protonation at the carbon adjacent to the benzene ring proceeds with varying stereoselectivity, being strongly d...

Nitrogen‐Containing Tricyclic and Tetracyclic Compounds by Stereoselective Samarium Diiodide Promoted Cyclizations of Quinolyl‐Substituted Ketones – A New Access to Azasteroids

“…The polycyclic compounds obtained under the reductive conditions reported above contain a styrene‐type double bond, which provides a suitable handle for subsequent synthetic transformations 3f,3i,3j. A few typical examples leading to highly functionalized compounds are presented in Scheme .…”

Samarium Diiodide Induced Cyclizations of γ‐, δ‐ and ε‐Indolyl Ketones: Reductive Coupling, Intermolecular Trapping, and Subsequent Transformations of Indolines

“…[12] However, it cannot be excluded that the reductive radical cyclization mechanism proceeds through an "arene-first" [4g] mechanism as suggested by Kise et al [19] It is believed that in a first step samarium ketyl B is formed in equilibrium from SmI 2 and indolyl ketone A. The ketyl radical B subsequently adds to the activated aromatic system through a six-membered transition state C. For steric and electronic reasons, the bulky samarium alkoxide, presumably bearing three or four ligands, is assumed to favor an equatorial position leaving the methyl group in an axial position.…”

“…[10,11] In further consequence, we systematically investigated appropriately substituted ketones with aryl and naphthyl groups as acceptors for the electronrich ketyl radicals. [12] An obvious extension of the described SmI 2 -induced cyclization-dearomatization reaction involved the employment of N-heteroaromatic ring systems, such as quinoline, [13] pyrrole, and indole derivatives. [14] The general importance of N-heterocycles, of indole derivatives in particular, [15] originates from their ubiquitous presence in natural products and pharmaceutically relevant compounds.…”

Transition‐Metal‐Mediated or ‐Catalyzed Syntheses of Steroids and Steroid‐Like Compounds

“…Reissig et al showed that treatment of the naphthyl-substituted cyclopentane-1,3-diones 79 (Scheme 32) with SmI 2 /HMPA in the presence of a proton donor could bring about the formation of the alcohols 80 with the steroid skeleton. [71] With the unsubstituted naphthalene moiety the reaction proceeded with good yield (70 %) and selectivity (α/β = 91:9).…”