A novel family of BINAP ligands were prepared with alkoxy-and acetoxy-derived substituents in the 3,3′-positions. They were prepared through a convergent synthesis starting from readily available 4-bromo-2-naphthol. These ligands afforded excellent enantioselectivities in the asymmetric hydrogenation of substituted olefins. The presence of the 3,3′-substituents was shown to be beneficial by a direct comparison with the parent unsubstituted BINAP.
The Ullmann coupling of 1 (R = H) gives a 2:1 mixture of diastereomers 2 (R = H) in 81% yield that are easily separated by silica gel chromatography. This procedure avoids the generally cumbersome and sometimes difficult resolution step with DBTA. Similar Ullmann couplings and separation of the corresponding diastereomers are employed with other derivatives of 1 (R = O/Bu, /Pr, Ph, and mesityl) ultimately affording a new series of 3,3'-disubsituted-MeO-BIPHEP derivatives. The use of these new derivatives in palladium-catalyzed asymmetric Heck reaction, Pd-catalyzed polyene cyelizations and rhodium-catalyzed hydrogenations is also reported.
I n t e r -a n d I n t r a m o l e c u l a r H e c k / M i z o r o k i R e a c t i o n sAbstract: A series of 3,3¢-disubstituted BINAP ligands are used in asymmetric inter-and intramolecular Heck/Mizoroki reactions and their enantioselectivity compared to BINAP.It was not until the early to mid 1990's that the Heck/ Mizoroki reaction really caught the attention of synthetic chemists. 1,2 This is evidenced by the large number of reviews written on the Heck/Mizoroki reaction since 1990. 3 While the majority of work on the Heck/Mizoroki reaction has been focused on non-asymmetric conditions, asymmetric reactions have gained popularity 4 since the first reports in this area by Shibasaki 5 and Overman. 6 Since our synthesis of (+)-halenaquinone in 1996 7 via an asymmetric intramolecular double Heck/Mizoroki reaction, we have been interested in applying new chiral phosphine containing ligands for effecting asymmetric Heck/ Mizoroki reactions. 8 Recently, we have developed synthetic routes to 3,3¢-disubstituted MeO-BIPHEP 9 derivatives 2, used them in various asymmetric intra-and intermolecular Heck/Mizoroki reactions and shown that some of them outperform MeO-BIPHEP (1). 10 As an extension of this work, we herein report on the use of 3,3¢-disubstituted BINAP 11 systems 4-7 in asymmetric Heck/ Mizoroki reactions and compare their enantioselectivity to BINAP (3, Figure 1).We first compared the efficacy of ligands 4-7 in the asymmetric Heck/Mizoroki arylation of 2,3-dihydrofuran 8 with phenyl triflate 9 12 and compared the results to those obtained with (S)-BINAP (3, Table 1). (S)-3,3¢-Di-Oi-Pr-BINAP (5) provided an excellent conversion to products (100%) and a product ratio of 99:1 for isomers 10:12. Compound 10 was formed with a 73% ee, which was clearly higher than that obtained with (S)-BINAP (entries 1 and 2, Table 1). The best result in terms of ee (%) was with the 3,3¢-di-OPiv-BINAP (6, entry 3). Although the conversion to products was only 68%, compound 10 was formed with an ee of 80%. Finally, 3,3¢-di-OBn-BINAP gave 10 with a disappointing 40% ee although the conversion to products was excellent. In all cases none of the conjugated isomer 11 was detected by 1 H NMR or GC. With these results in hand, we turned our attention to using ligands 4-7 in intramolecular Heck/Mizoroki reactions.Intramolecular Heck/Mizoroki reaction of 13 with 6 13 gave a disappointing 2% ee when compared to that obtained with (S)-BINAP (3, 84%, Table 2). Unfortunately, the ee (%) was not increased noticeably when (S)-7 and (S)-5 were used. Mixtures of cyclized products 14 (and 15) were obtained with 13% and 19% ee, respectively. Upon closer examination of the HPLC trace; however, we Figure 1PPh 2 PPh 2 MeO MeO R R R R PPh 2 PPh 2 1 R = H (MeO-BIPHEP) 2a R = OMe 2b R = Oi-Pr 2c R = Ot-Bu 2d R = OPh 2e R = OTolyl 2f R = OPiv 2g R = Ph 2h R = i-Pr 3 R = H (BINAP) 4 R = OMe 5 R = Oi-Pr 6 R = OPiv 7 R = OBnTable 1 Asymmetric Heck/Mizoroki Results with BINAP 3 and Ligands 5-7 Entry Ligand Conversion (%) Ratio of products (ee, %)
A novel class of 3,3¢-disubstituted xylBINAP ligands have been synthesized and tested in the hydrogenations of substituted olefins. This new substitution pattern has demonstrated that the 3,5-dialkyl meta effect and 3,3¢-disubstitution can operate in a synergistic fashion in Rh-catalyzed hydrogenation of dehydroamino acids. Notably, (S ax )-8 outperforms BINAP, xylBINAP and previously reported 3,3¢-disubstituted BINAP derivatives in the hydrogenation of methyl N-acetamido cinnamate.Asymmetric catalysis is one of the most powerful methods for forming an array of enantioenriched chiral structures. Transition-metal-based processes, which make up a large component of this field, rely on an organic ligand to impart chirality on the forming product during the catalytic cycle. Although a large pool of chiral ligands is available, there is still a need for new ligands, as not all of the existing ligands are suitable for all substrates. One method of developing new chiral ligands is to optimize the electronic and steric properties of an existing ligand through systematic modification of its framework.Within the realm of transition-metal-mediated asymmetric processes, the utility of chiral biaryl diphosphine ligands has been widely demonstrated. 1 2,2¢-Bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP; 1) is one of the most commonly utilized chiral biaryl phosphines available, and its modification has been well documented. 2 In 2005, our group reported the first modification of the 3-and 3¢-positions of BINAP. 3 It was postulated that modifications made at the 3 and 3¢ positions of BINAP would most drastically affect the steric and electronic properties of the ligand due to the proximity of these positions to the phosphorus atoms. To this end, we demonstrated that ligands 2-5 outperformed BINAP in the Rh-catalyzed hydrogenation of N-acetamido acrylic acid and its methyl ester, providing enantioselectivities of up to >99% ee for the resulting alanines ( Figure 1). Also included in our initial report was the hydrogenation of methyl N-acetamido cinnamate using 1-5. Performing this hydrogenation with BINAP led to poor enantioselectivity of the corresponding phenyl alanine but ee values as high as 74.7% were achieved by using ligand 4 with OC(O)tBu groups in the 3 and 3¢ positions of the binaphthalene framework. Although 3,3¢-disubstitution provided an increase in enantioselectivity for the hydrogenation of methyl N-acetamido cinnamate, we saw the opportunity for further improvement. Figure 1 3,3¢-Disubstituted BINAP and 3,3¢-disubstituted xylBINAP derivativesWe envisioned that exchanging the phenyl rings in our 3,3¢-disubstituted BINAP derivatives 2-5 for 3,5-dimethylphenyl (m-xylyl) rings would allow us to take advantage of the 3,5-dialkyl meta effect. 4 It has been demonstrated that using 3,5-dialkylphenyl substituents on phosphorus in place of simple phenyl rings, causes the chiral pocket to become more rigid and well-defined due to hindered rotation about the P-C ipso bonds, which translates into higher catalyst selectivity...
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