Astruc D. - Modern arene chemistry (2002)(en)

14.6 Control of Atropisomerism 523

Scheme 46. Possible involvement of a benzylic cation (or equivalent) in the DDQ-mediated oxidative cyclization of a trans-butyrolactone stegane precursor.

Scheme 47. Iron(III)- and ruthenium(IV)-mediated oxidative cyclization of an unsaturated stegane precursor en route to the natural product schizandrin.

iron(III) reagent had never previously been reported to promote oxidative coupling. Luckily, in this example, the atropisomer generated upon AraAr bond formation matches that required for the natural compound, thus allowing the synthesis to proceed without an equilibration step.

These examples illustrate one important point: whereas oxidative arylic coupling is the natural (biosynthetic) pathway for linking two aryl units, it cannot be assumed that reproducing the reaction in vitro will furnish the same stereochemical outcome. This same issue of atrop-selectivity upon biaryl coupling was addressed by Evans and co-workers in an attempted biomimetic synthesis of 197, the M(5-7) unit of vancomycin [134, 135]. The more stable, natural isomer 197b is obtained only as a minor component in this kinetically controlled AraAr coupling reaction (Scheme 48). However, subsequent thermal equilibration leads to a preponderance of the desired compound.

Some natural compounds o er a chiral structural backbone that biases the outcome of the oxidative coupling of appended aryls (e.g., the ellagitannins). It was plausible to suppose, therefore, that two aryl units could be linked by a non-natural chiral tether to induce atropselective coupling upon exposure to an appropriate oxidant. In one of their attempts to realize the total synthesis of calphostin D (200) [136], Merlic and co-workers showed that, in the presence of dioxygen in trifluoroacetic acid (TFA), the precursor 198 a ords the coupled compound 199 as a single diastereoisomer. Unfortunately, the relative configuration was incorrect for the calphostin target (Scheme 49).

524 14 Oxidative Aryl-Coupling Reactions in Synthesis

Scheme 48. Vanadium(V)-mediated biomimetic oxidative cyclization of the precursor to a vancomycin fragment.

Scheme 49. Oxygen-mediated oxidative cyclization of a putative calphostin D precursor.

14.6.2

Oxidative Coupling of Two Chiral Molecules

A serendipitous use of a chiral auxiliary in atrop-selective biaryl bond formation has recently been published by Kita and co-workers [39, 137]. With diaryl substrate 201, which is related to precursors of the ellagitannins (see Section 14.6.1), PIFA-mediated oxidative coupling did not lead to the expected ellagitannin structure 202 (Scheme 50). Rather surprisingly, this reaction proceeds with intermolecular AraAr bond formation. The chiral glucose framework e ciently transfers stereochemical information, but not in a intramolecular closure.

Bringmann and co-workers have shown that modest control of atrop-selectivity can be achieved upon oxidative intermolecular coupling (dimerization) of the chiral phenol 205 [77]. In the synthesis of magistophorenes A and B (206a/b), the chiral precursor 205 afforded both isomers with a slight preference for the ‘‘B’’ series when exposed to di-tert-butyl peroxide (DTBP) (Scheme 51).

14.6.3

Stoichiometric Chiral Oxidation Reagents

The use of a chiral reagent for the oxidative coupling of naphthols has received much attention as the product chiral binaphthols are widely used in asymmetric synthesis [138]. The well-known oxidative coupling of 2-naphthol by dioxygen in the presence of a copper com-

14.6 Control of Atropisomerism 525

Scheme 50. Unexpected intermolecular coupling of a digalloylated glucose precursor promoted by PIFA.

Scheme 51. Di-tert-butyl peroxide-mediated oxidative dimerization of a chiral phenol precursor to the magistophorenes.

plex and an amine has been extended to an asymmetric version by prospecting among the wide range of commercially available chiral amines. Following work initiated by Brussee [79, 80], Smrcina and co-workers have demonstrated that in the case of 207 and the chiral amine mediator sparteine, the reaction is an actual enantioselective oxidative coupling, whereas in other cases the enantiomeric excesses result from second-order asymmetric transformations or diastereoselective crystallizations (Scheme 52) [88].

The observed atrop-selection can be rationalized in terms of the intermediacy of a complex containing square-planar copper. A transition state superimposed on this rigid framework

Scheme 52. Enantioselective cross-coupling of naphthols in the presence of the chiral amine sparteine and copper(II).

14.6 Control of Atropisomerism 527

the system and the heterogeneous nature of the components make mechanistic inquiry into the origins of asymmetric induction a daunting challenge.

14.6.4

Catalytic Enantioselective Oxidative Coupling

The most intriguing work in the field of asymmetric oxidative aryl coupling has been directed towards finding catalytic enantioselective reactions. The main goal in these studies has been the synthesis of chiral binaphthyl units as an improvement over stoichiometric chiral reagent enantioselective syntheses.

Horseradish peroxidase (HRP) as a biocatalyst has been separately studied by Sridhar and Schreier [140, 141]. Unfortunately, contrasting results were reported. Sridhar claimed to have coupled naphthol derivatives with noticeable enantioselection, whereas Schreier et al. did not observe any significant asymmetric induction upon AraAr bond formation (Scheme 53). A problem of ee measurement technique was cited by the latter author to explain the ee observed by Sridhar et al. ([a]D versus chiral HPLC).

Scheme 53. Horseradish peroxidase-mediated asymmetric oxidative dimerization of 2-naphthol (68a).

Photocatalytic enantioselective oxidative arylic coupling reactions have been investigated by two di erent groups. Both studies involved the use of ruthenium-based photocatalysts [142, 143]. In 1993, Hamada and co-workers introduced a photostable chiral ruthenium tris(bipyridine)-type complex (D-[Ru(menbpy)3]2þ) 210 possessing high redox ability [143]. The catalytic cycle also employed Co(acac)3 211 to assist in the generation of the active (D- [Ru(menbpy)3]3þ) species 212. The authors suggested that the enantioselection observed upon binaphthol formation was the result of a faster formation of the (R)-enantiomer from the intermediate 213 (second oxidation and/or proton loss), albeit only to a rather low extent (ee: 16 %) (Scheme 54).

The results of a recent study published by Katsuki and co-workers include improvements in the enantiomeric excess of binaphthol formation using chiral (NO)Ru(II)-(salicylidene) ethylenediamino (salen) complex 214 (Figure 7) [142]. The reaction was conducted under aerobic conditions so that dioxygen generated the active ruthenium reagent (Scheme 55). Yields of binaphthol as high as 95 % were realized.

Coupling attempts conducted with (R,S)-214 led to lower enantioselection upon CaC bond formation, an observation that points to the significant role played by the relative configuration (R,R) of the binaphthyl and ethylenediamine units in promoting asymmetric induction. This complex was found to be the most e cient among several di erent structural variations. Solvent e ects on this transformation were also studied (Table 35), with toluene and chlorobenzene giving the best results. Low solubility of the catalyst (diethyl ether and diiso-

14.6 Control of Atropisomerism 529

Tab. 35. Solvent e ects in the enantioselective oxidative dimerization of 2-naphthol (68a) by (R,R)-214.

a Measured by chiral HPLC.

propyl ether) or poisoning (acetonitrile and THF) are the suspected reasons for the poor performance in some other solvents.

This transformation has also been applied to other binaphthyl derivatives, and, curiously, it was observed that substitution at the C6 position of the naphthol precursors 68 influences the observed enantioselectivity (Table 36). Electron-withdrawing groups enhance the enantioselectivity but give lower yields, whereas electron-donating groups increase the yields but reduce the enantioselectivity.

Studies have also focused on vanadium-based asymmetric catalysts in addition to these photocatalytic systems. A catalytic achiral version of an oxidative coupling reaction was published in 1999 by Uang and co-workers (see Section 14.4.2) [70]. They developed an air-stable complex (VO(acac)2) that can be used in catalytic quantities in the presence of dioxygen as a re-oxidant. The promising results obtained led to an investigation of chiral versions of this reagent, and the initial reports document that such a reaction was possible with complexes

Tab. 36. Scope of the asymmetric oxidative dimerization of 2-naphthol derivatives by 214.

a Measured by chiral HPLC.

14.6 Control of Atropisomerism 531

Tab. 38. Enantioselective dimerization of 2-naphthol (and 2-naphthylamine) derivatives promoted by vanadium complexes 219 and 220.

a Measured by chiral HPLC.

ities were obtained (Table 38). X-ray structural analysis of complex 219, and examination of the ee dependence of the product (R)-binaphthol on the ee of complex 219, suggested that a monomeric V(IV) species mediates the reaction. The couplings with aminonaphthalene (71a and 112a) led to lower yields and lower enantioselectivities than with the phenolic analogues.

A catalytic version of the copper(II)-mediated stoichiometric chiral amine naphthol oxidative couplings has been developed as an extension of the successful achiral version. Smrcina and co-workers first carried out such a reaction in order to obtain information on the mechanism of their stoichiometric amine reactions. They obtained the biphenyl product (S)-207 in 41 % yield with a modest enantiomeric excess (32 % ee) (Scheme 56) [88].

Nakajima and co-workers have carried out extensive investigations into the influence of di erent chiral diamine-copper complexes on the oxidative dimerization of naphthols [146– 148]. As emerged from Smrcina’s work, the inclusion of an ester moiety on the naphthol precursor is an important factor for optimizing the enantioselectivity. After establishing a catalytic cycle with TMDA as the base and showing that sparteine gave promising results (Scheme 57), they focused their work on other chiral diamines (Table 39) [147].

The results from this chiral amine survey indicated that the secondary nitrogen in the pyrrolidine ring and the tertiary nitrogen in the side chain of the catalyst 221 are necessary

532 14 Oxidative Aryl-Coupling Reactions in Synthesis

Scheme 56. Enantioselective cross-coupling of 2-naphthol catalyzed by copper(II)/sparteine.

Scheme 57. Enantioselective oxidative dimerization of naphthol derivative 68f in the presence of a copper(I) pre-catalyst and sparteine.

Tab. 39. Survey of pyrrolidine substituent e ects on the enantioselective oxidative dimerization of 68f mediated by a copper(I) pre-catalyst.

a Measured by chiral HPLC.