Stereoselective Convergent Synthesis of Tetrahydro-5H-benzo[c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition

Abstract

The diene methyl ethers or acetates, constructed from the Li–Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)­bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda–Grubbs II as a catalyst to provide the corresponding benzannulated (Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5H-benzo­[c]­fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5–C6) and trans at the site of nucleophilic attack (C6–C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5H-benzo­[c]­fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

4b-Aryltetrahydroindeno[1,2-a]indenes by Acid-Catalyzed Trans­annular Cyclization of Benzannulated Cyclooctene Alcohols

“…A plausible mechanism to account for the formation of the 5/5 bis-indane framework is outlined in Scheme 4. Similar to the proposed mechanism of our previous report on the 6/5 tetrahydronaphthalene-fused indane, 20 the initial carbocation was likely to form following protonation/ionization of the alcohol/acetate. Interestingly, the ring size (8-vs 9-), the…”

“…This was prepared in a straightforward manner from 1-allyl-2-bromobenzene ( 6 ) via the intermediates 7 and 8 in 74% yield over three steps (Scheme 2 ). Unfortunately, despite many attempts using a range of Lewis or Brønsted acids and nucleophiles under various conditions that had previously been shown to be successful for the transannular cyclization of 1 , 20 we were unable to convert 5 into an indane-fused indane 9a or 9b . In most cases, the corresponding products 10a and 10b arising from nucleophilic substitution reactions on the acetate were obtained in virtually quantitative yields (see Supporting Information, Table S1).…”

“…On the basis of our previous report on the synthesis of 1 entailing the use of secondary benzannulated cyclononene acetates as the substrate, we first embarked on the preparation of the benzannulated cyclooctene acetate 5 which could be prepared straightforwardly from 1-allyl-2-bromobenzene 6 via the intermediates 7 and 8 in 74% yield over three steps (Scheme 2). Unfortunately, despite many attempts using different Lewis/Brønsted acids and nucleophiles under various conditions previously shown to be successful for the transannular cyclization for 1, 20 we could not convert 5 to the indane-fused indane 9a and 9b. In most cases, only the corresponding products 10a and 10b arising from the nucleophilic substitution reactions on the acetate could be obtained virtually quantitatively (Table S1, SI).…”

“…[15][16][17][18][19] Recently, our group has reported the synthesis of the tetrahydro-5H-benzo[c]fluorene 1, a framework comprising the tetrahydronaphthalene-fused indane, via the acid-mediated transannular cyclization of the corresponding benzannulated cyclononene 2 (Scheme 1). 20 We now envisioned that such chemistry could be applicable to efficiently prepare the bisindane, the tetrahydroindano[1,2a]indene 3, from the benzannulated cyclooctene 4 by using simple building blocks and requiring relatively mild conditions.…”

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

“…Alkene and alkyne metathesis [1][2][3][4], constituting highly versatile and powerful catalytic processes for constructing complex organic molecules [5][6][7][8][9][10][11][12], have found broad application in the fields of pharmaceutical synthesis [13][14][15], materials science [16][17][18][19][20], or in advanced techniques and technologies [21][22][23][24][25][26][27][28][29][30]. Thus, numerous multistep total syntheses of organic compounds, including bioactive molecules [31][32][33][34][35] and natural products [36,37], have been performed in a highly chemo-and stereoselective manner through metathesis routes [38][39][40][41][42][43]. In ingeniously elaborated procedures, olefin metathesis has been frequently employed as such or associated with name reactions like Grignard, Wittig, Diels-Alder, Suzuki-Miyaura, Heck, etc., resulting in the assembly of diverse intricate building blocks of the targeted structures [...…”