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Title:
Catalytic enantioselective synthesis of 2-aryl-chromenes\xe2\x80\xa0

Paper sections:
Introduction
<p>Chromenes constitute a privileged class of structural motifs present in a myriad of natural products and medicinally important agents.1 Given the prevalence of this structural unit, there has been considerable interest in developing methods for the generation of the chromene skeleton. While procedures to access racemic 2-aryl-2H-chromenes are readily available,2 the difficulty in generating enantioselective variants is underscored by the scarcity of documented strategies to produce these bioactive structures. The construction of enantioen-riched 2-aryl-2H-chromenes has been recently reported by You through a Ru-catalyzed ring-closing metathesis reaction of chiral allyl ethers3 and also by Schaus via the chiral Brønsted acid (CBA)/Lewis acid-catalyzed addition of aryl boronates to in situ formed pyrylium ions.4 In addition, Rueping has recently reported a CBA-catalyzed closure of allylic cations, but this innovative approach requires substitution at C4.5 Based on our platform developing new approaches to construct pyran and related motifs,6 we began investigating substrate/catalyst activation combinations to access chromenes via an asymmetric catalytic process. After extensive exploration with substrates such as 1 (not shown), easily accessed from chalcone precursors, the use of either organocatalysis or transition metal catalysis led to an invariable observation: compounds with unprotected ortho-substituted phenols were typically unstable and often underwent uncatalyzed cyclizations to racemic chromenes rapidly (eqn (1)).</p><p>With this crucial data in hand and the background reaction a major hurdle, our reaction design criteria became clear: (a) promote phenol formation during the course of the reaction, (b) avoid any background reactions by activating an allylic system through a chiral metal complex or organocatalytic mechanism, and (c) promote a 6-endo-trig type closure of the phenol/phen-oxide with control of the absolute stereochemistry. Based on this logic, we envisaged that 2-aryl-2H-chromenes could be constructed through a 6-endo-trig Pd-catalyzed asymmetric allylic substitution (Fig. 1).7 While Pd-catalyzed allylic alkylation is a prominent strategy for C–C and C–heteroatom bond formation,8 to the best of our knowledge there are no reports of a general asymmetric 6-endo-trig variant.9</p>

Results and discussion
<p>We began our investigation by combining bis-acetate 1a with potassium carbonate, Pd2(dba)3 and a variety of phosphor-amidite ligands. Initial survey of bidentate ligands, such as PHOX or Trost ligand, afforded low reaction conversion and enantio-selection. Although monodentate phosphoramidites are efficient chiral ligands in promoting various Pd-catalyzed reactions,10 their application in asymmetric allylic substitutions remains underdeveloped. Motivated by a recent report from van Leeuwen and coworkers involving the use of BINOL- and TADDOL-derived phosphoramidites for Pd-catalyzed intermolecular allylic alkyl-ations,11 our initial ligand screen included BINOL-, SIPHOS-, and TADDOL-derived phosphoramidites.12 Our preliminary experiments with BINOL-derived ligand L1a provided chromene 2a in quantitative yield with an encouraging 69 : 31 enantiomeric ratio (Table 1, entry 1). Unfortunately, modification of the amine constituent to piperidine, dimethylamine, 1-phenylethylamine (results not shown) or bis[(S)-l-phenethyl]amine (entry 2), was detrimental to both the conversion and enantioselectivity. The modification of the ligand backbone to SIPHOS-derived ligand (Ra,R,R)-L2 and TADDOL-derived ligand L3a resulted in significantly improved levels of enantioselectivity (entries 3 and 5, respectively). Interestingly, the diastereomer (Sa,R,R)-L2 (entry 4) afforded racemic chromene product, suggesting a mismatch of stereogenic elements.</p><p>Due to the shortened reaction time with ligand L3a compared to L2 and the opportunity to rapidly evaluate a wide range of TADDOL-derived ligands, we focused our efforts on the optimization of this ligand backbone. We began by evaluating a variety of N-substituents, including achiral and sterically less demanding amine moieties (entry 6–8). In comparison to ligand L3a, other acyclic amines such as dimethylamine (entry 6) and diisopropyl amine (entry 7) resulted in decreased enantioselectivity, while replacement with the more rigid piperidinyl substituent afforded chromene 2a with improved selectivity (82 : 18 er, entry 8).12d To understand the effects of ligand rigidity on engendering enantioselection, the isopropylidene acetal of L3 was substituted with an acyclic dimethyl ether motif. With the less rigid L4 as the ligand, chromene 2a was furnished with low enantioselectivity (entry 9).</p><p>The last point of variation of the TADDOL-derived ligands lies in the substitution about the arene rings. The examination of various aryl-substituted TADDOL ligands (entry 10–12) revealed that enantioselectivity can be enhanced through the placement and positioning of methyl groups on the aryl ring, culminating in a 93 : 7 er attained for ligand L3g (entry 12). A full investigation of this distal effect and the balance between electronic and steric parameters on this ligand is currently ongoing. We then revisited the effects of the nitrogen substituent. Interestingly, the replacement of the piperidine with a pyrrolidine resulted in a significant decrease in enantioselectivity (entry 13), while incorporation of a 7-membered aze-pane maintained the previously observed 93 : 7 er (entry 14). Efforts to increase enantioselectivity by utilizing acyclic amines were ineffective (entry 15). Finally, the incorporation of ethyl groups at the 3- and 5-position of the aryl ring was explored. We were pleased to find that with this ligand (L3k), chromene 2a was obtained in 71% isolated yield with 95 : 5 er (entry 16).</p><p>With selective conditions developed, several bis-acetate substrates were evaluated (Table 2). The high levels of enantio selectivity observed for 2a were maintained with extended aromatic substrates (2b and 2c). Electron-donating groups on the styrenyl component were also well tolerated, with methyl substitution in the ortho- or para-positions (2d and 2e, respectively) affording the chromene products in good yield and excellent enantioselectivity. The electron-rich 3-methoxy substituted cyclization precursor also performed well in this reaction, generating chromene 2f (78%, 94 : 6 er).</p><p>The incorporation of electron-withdrawing (2g–2l) substituents around the aromatic ring was also accommodated. Furthermore, we found that the electronegative fluorine substituent can occupy various positions while maintaining high er. The erosion of enantioselectivity was observed with substrates possessing a trifluoromethyl, dichloro, or the strongly electronegative nitro group (2j–2l), but a fluorine substituent was tolerated at various positions (2m and 2n). The electron-donating methoxy group was also accommodated, albeit with a slight decrease in enantioselectivity (2o). Additionally, the preparation of chromene 2p indicates that this system tolerates moderate substitution adjacent to the phenoxide.</p><p>The complete conversion of racemic substrates 1 to the enantioenriched chromenes indicates that a dynamic kinetic asymmetric transformation (DYKAT) might be operative.13 Since both enantiomers of the starting material must go through a common intermediate, and the unsymmetrical 1,3-disubstituted allyl substrate precludes racemization through a palladium π–σ–π allyl rearrangement, the generation of an achiral ortho-quinone methide intermediate (4) is proposed to account for the high levels of enantioselectivity observed for the chromene products (Scheme 1).</p><p>Our current understanding of the reaction starts with the subjection of either enantiomer of 1a to potassium carbonate and methanol, which rapidly produces the nucleophilic phenoxide in situ (±3, Path A). This deacylation promotes ejection of the secondary acetate to form the achiral trans-o-quinone methide (o-QM, 4a).14 A subsequent coordination and addition of the chiral palladium complex generates the π allyl intermediate (5) which undergoes intramolecular attack of the proximal phenoxide after bond rotation to achieve the proper conformation (6). For this pathway, the rate of o-QM formation is faster than addition of the palladium-ligand complex to ±3 (or ±1). If this is not the case, then an alternative potential pathway could be operative (Path B). This process involves the generation of diasteromeric π allyl palladium complexes (5a or 5b) from each enantiomer of 3. While one of these additions would be the "matched" case, a rapid interconversion between the diasteromeric intermediates is required so the "mismatched" complex undergoes smooth conversion to the observed enantiomer (2a) vs. the undesired isomer (ent-2a). Possible mechanisms for this involve generation of the achiral o-QM or direct addition of the palladium complex. For a related system, the possibility for racemization of the π-allylpalladium complex (such as 5b) by an intermolecular nucleophilic attack (or anti-addition) of a Pd(0) has been investigated.15 We currently favor Path A due to the lack of observed correlation between enantioselectivity and catalyst concentration, which disfavors Path B. Additionally, the use of bis-benzoylated substrates (vs. acetates) proceeds at the approximately the same rate with the similar levels of er and yield (see ESI† for details). More extensive investigations of this process are currently underway.</p><p>We wished to further elucidate the structure of the Pd(II)-L3k complex and its interaction with the bis-acetate substrate 1a, but to date have been unable to obtain suitable crystals. However, X-ray quality crystals of the related Pd(II) complex has been solved using ligand L3g in conjunction with 1,3-diphenylallyl acetate as a substrate surrogate incapable of closure (Scheme 2). The structure shows that the phosphoramidite ligand L3g is coordinated to the Pd(II) center through its phosphorus center and a single aryl ring.16 This η2-arene stabilization results in the observed 1 : 1 phosphoramidite-Pd(II) complex and supports mono-coordination of a bulky ligand to the palladium.17</p><p>To highlight the potential of this new approach, we pursued the synthesis of catechin 8, which has demonstrated anti-staphylococcal activity due to their ability to reverse methicillin resistance in strains of drug resistant S. aureus.18 Interestingly, this catechin analog has increased activity compared to the parent (—)-epicatechin gallate, which bears additional hydroxyl groups on the catechin core (7). The regioselective hydroboration of 2a delivered chromanol 7 with 9 : 1 dr favoring the desired anti relationship. The esterification of chromanol 7 with tri-OBn gallic acid chloride followed by hydrogenolysis afforded 8 in 65% yield over the two steps. In a second vignette, the synthesis of hydroxyflavanone 10 was accomplished. The race-mate of this compound exhibited promising levels of inhibition of M. tuberculosis H37Rv.19 The application of our methodology allows access to enantioenriched 10 and could facilitate improved structure-activity relationship (SAR) studies. A cis-dihydroxylation of chromene 2i (94 : 6 er) using 3 mol% OsO4 and NMO provided 2,3-trans-3,4-phenylchromandiol (5.6 : 1 dr).20 A recrystallization of the mixture provided a single dia-stereomer with >99 : 1 er. The exposure of diol 9 to MnO2 resulted in the desired benzylic oxidation, without epimerization at C-3, to furnish 10 in 59% yield (Scheme 3).</p>

Conclusions
<p>We have developed a catalytic enantioselective method for the synthesis of 2-aryl-2H-chromenes. A ligand structure–selectivity relationship study resulted in the development of a novel monodentate phosphoramidite system that enabled the synthesis of these privileged heterocycles with high yield and enantioselectivity. Crystallographic analysis provides mechanistic support that aryl ligand–metal interactions provide unanticipated additional rigidity in competing diasteroemeric transition states which promotes the high levels of enantioselectivity for the newly formed C–O bond. Investigations involving the use of these chiral phosphoramidite ligands for the formation of other heterocycles and detailed mechanistic studies are underway.</p>
An enantioselective Pd-catalyzed 6-endo-trig reaction for the synthesis of 2-aryl-chromenes has been developed. A systematic optimization of a TADDOL-derived ligand set resulted in the identification of a novel monodentate phosphoramidite\xe2\x80\x93palladium catalyst that accesses 2-aryl-2H-chromenes with high yield and enantioselectivity under mild conditions. The products obtained from this method can be transformed into biologically active compounds through functionalization of the chromene alkene.