Configurationally unstable biaryl lactones of type (M)-1 ⇌ (P)-1 and ring-opened 2-acyl-2‘-hydroxy
biaryl compounds of type (M)-4 ⇌ (P)-4 are versatile precursors for the atroposelective preparation
of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes
a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR
spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched
material for smaller interconversion rates. For the lactones, the free activation energies ΔG
⧧
298
increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe
(t
1/2 ≈ ms) < Me (t
1/2 ≈ s) < Et < i-Pr (t
1/2 ≈ min) < t-Bu (t
1/2 ≈ d). The formally ring-opened 2-acyl-2‘-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of
the high loss in activation entropy ΔS
⧧ as a consequence of the required intermediate ring closure
4 → 5.
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,...
The atropo-diastereoselective cleavage of lactone-bridged and thus configurationally unstable biaryls with chiral metal-activated 1-arylethylamines gives axially chiral biaryl amides in good yields and high atropo-diastereomeric ratios of up to 95:5. In this methodology, even the minor not desired rotational isomer can be recycled literally by recyclization back to the configurationally unstable lactone, and renewed stereoselective cleavage. Furthermore, by the use of the corresponding enantiomer of the N-nucleophile, the enantiomeric biaryl product is also attainable from the same lactone precursor (ªatropo-divergenceº). In addition, several methods have been developed to transform the amide function into a methyl or an aminomethylene group. All these options further enlarge the scope and the utility of the method elaborated.
A simple two‐step synthesis of a series of ether‐type bridged biaryls 3, as favorable models for studies of helimerization processes, is described. Starting from the known corresponding lactones 1, a variety of differently substituted representatives 3 is prepared, greatly varying by the degree of steric hindrance and thus molecular distortion. NMR spectroscopy and especially X‐ray diffraction reveal the ethers 3 to be helically distorted, depending on the size of the ortho substituents R.
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