Novel Concepts in Directed Biaryl Synthesis, IX. Synthesis and Structure of Benzonaphthopyranones, Useful Bridged Model Precursors for Stereoselective Biaryl Syntheses

Abstract

A practicable two-step procedure for the preparation of a series of lactone-type bridged biaryls 7 as favorable substrates for subsequent atropisomer-selective ring-opening reactions is described. Due to the efficiency of the coupling step, which tolerates even a telt·butyl group next to the biaryl axis and avoids problems of regioselectivity, a variety of differentlyThe regio-and stereoselective construction of natural and unnatural hindered biaryl systems is a synthetic challenge that has successfully been approached only very recentlyP-4 1 . Exemplarily for the substitution pattern as in 1, which is found in many naturally occurring biaryls l 5 1 , we have developed a useful procedure in which the two formal partial goals of stereoselective biaryl synthesis are attained consecutively l 6-11 1 : The CC bond formation is performed by intramolecular aryl coupling of the ester-type prefixed aromatics as in 3, and the asymmetric induction at this biaryl axis is achieved by an atropdiastereo-or enantioselective ring opening of the resulting lactones 2. Hence, such bridged biaryls 2 play a crucial role in this concept: Although they already possess the biaryl axis, most of them are axially prostereogenicl6.7.12.IJJ, i.e. they do not occur as stable atropisomers (helimers) at the synthetically relevant temperatures. Apparently, the rotational barrier of 2 is drastically lower than that of the open-chain final target biaryls 1 and thus allows rapid helimerization (e.g. at room temperature).For a thorough investigation of the structures of such bridged biaryls, of their isomerization mechanism, and eso 2 00 n ~o V 3 substituted representatives is prepared. These cover a broad range of steric hindrance and thus molecular distortion. The structures are investigated mainly by NMR spectroscopy and X-ray diffraction, showing the lactones 7 to be helically distorted, depending on the size of the residues R. pecially of the unprecedented stereocontrolled ring opening process, there is a great need of appropriately substituted representatives of this stereochemically interesting class of bridged biaryls. In this paper, we describe a practicable synthetic pathway to a series of benzonaphthopyranones of the general type 7, with a broad variety of substituents of most different sizes next to the biaryl axis. Part of this work has recently been reported in preliminary form 1 9 • 10 1.The structural type 7 was chosen for different reasons: On the one hand, its substitution pattern (alkyl groups and oxygen functions in ortho-positions with respect to the axis) is similar to that of many naturally occurring biaryls. Also, the symmetrical structure of the variable phenolic component helps to avoid additional problems of regioselectivity in the intramolecular aryl coupling step. A further advantage of the lactones 7 was their supposed tendency to afford crystals suitable for X-ray structure analysis (see below). By contrast, the long-chain O-substituted derivative 7c was prepared because of its expected favorable solubility properties,...

Atropo-Diastereoselective Cleavage of Configurationally Unstable Biaryl Lactones with Alkali Metal Activated Primary 1-Arylethylamines

“…Further transformation reactions on the amide function: For even more diversified applications of the ring-opening reactions with metalated phenylethylamine (8) to the enantioselective synthesis of various axially chiral biaryl target molecules, efficient routes for the removal of the centrochiral amine substituent are required, either with conservation or cleavage of the (aryl-C*HMe) À N bond and thus retention or loss of the nitrogen introduced. The saponification of these amides to give the corresponding carboxylic acids has already been shown in Scheme 7.…”

“…All reactions were carried out under an atmosphere of dry inert gas with the Schlencktube technique. [18] and the lactones 4 a and 4 b [8] were prepared according to literature procedures.…”

“…[8,9] Depending on the size of the residue R next to the biaryl axis, the lactones 4 (Scheme 2) are not flat, but rather helically distorted and thus exist in their two enantiomeric forms, (P)-4 and (M)-4, [10] which, because of the bridging lactone function, rapidly interconvert at room temperature. [8] From this enantiomeric equilibrium, 4 can be ring-opened highly atropo-diastereoselectively or -enantioselectively with chiral O- [11,12] or H-nucleophiles. [13] In preliminary investigations, several chiral N-nucleophiles were tested which led to the corresponding biaryl amides 5 in good diastereomeric ratios.…”

Atropselektive Synthese axial‐chiraler Biaryle

“…[59] Die Gegenwart eines sechsgliedrigen Rings erleichtert noch immer merklich die Rotation, wenn auch in einem geringeren Ausmaß. Eine Vergleichsstudie an den Benzonaphthopyranonen 32 und 33 (Abbildung 7), die als racemische Gemische ihrer helical verdrillten Atrop-Enantiomere (M)-und (P)-32 und -33 (Torsionswinkel von 268 für 33 a bis 368 für 33 f) vorliegen, [45,60,61] zeigte, dass DG°2 98 K mit der Größe des ortho-Substituenten R steigt. [62] Somit atropisomerisieren 32 a-d (R = H, OMe, Me, Et) schnell bei Raumtemperatur mit Halbwertszeiten t 298 K < 1 min, während sich das Lacton 32 e (R = iPr) knapp über der Schwelle zur Atropisomerie (t 298 K = 28 min) befindet.…”

1,4-Dibromonaphthalene-2,3-diylbis(1′-bromo-2′-naphthoate)·CHCl3, a Potential Precursor to Lactone-Bridged Teraryls

“…Recently, a conceptionally novel and highly ef ficient approach to stereochemically homogen eous, even highly hindered biaryl systems was elaborated, by atropisomer-selective ring cleavage of axially prostereogenic, i.e. configuratively labile lactone-bridged biaryls of type 1 [3][4][5][6]. In an at tempt to extend this efficient method to the prepa ration of target molecules with even two or more stereogenic axes, e.g.…”