VAPOL catalyst

Wulff and coworkers have applied their aluminum catalyst 2 containing a vaulted biphenanthrol ligand (VAPOL, Section 2.1) to the Diels-Alder reaction between methyl acrylate and cyclopentadiene [25] (Scheme 1.32). In this Diels-Alder reaction auto-induction is observed, because of a cooperative interaction between the product... 

Catalysts prepared either from VAPOL (109) or from VANOL (110) ligands and triphenylborate were found to catalyze the asymmetric aziridination efficiently. Good to high yields, excellent enantioselectivities, and cis diastereoselectivities were observed with all the reported substrates, which included aromatic, heteroaromatic and aliphatic imines (Table 1.14). 

In 2007, AntiUa and coworkers disclosed the first asymmetric organocatalytic reduction of acyclic a-imino esters (Scheme 23) [39], Chiral VAPOL phosphate (5)-16 (5 mol%) served as a catalyst for the transfer hydrogenation of the latter (62) employing commercially available dihydropyridine 44a to give both aromatic and aliphatic a-amino esters 63 in very high yields (85-98%) and enantioselectivities (94-99% ee). 

In 2007, AntiUa and coworkers described the Brpnsted add-catalyzed desymmetrization of me yo-aziridines giving vicinal diamines [75]. hi recent years, chiral phosphoric acids have been widely recognized as powerful catalysts for the activation of imines. However, prior to this work, electrophiles other than imines or related substrates like enecarbamates or enamides have been omitted. In the presence of VAPOL-derived phosphoric acid catalyst (5)-16 (10 mol%) and azidotrimethylsilane as the nucleophile, aziridines 129 were converted into the corresponding ring-opened prodncts 130 in good yields and enantioselectivities (49-97%, 70-95% ee) (Scheme 53). 

The Rawal group next applied diol catalysis to the enantioselective vinylogous Mukaiyama aldol (VMA) reaction of electron-deficient aldehydes [105]. Screening of various known chiral diol derivatives, including VANOL, VAPOL, BINOL, BAMOL, and TADDOL, revealed that 38a was the only catalyst capable of providing products in acceptable levels ofenantioselection (Scheme 5.55). Subsequent to this work, Scettri reported a similar study of TADDOL-promoted VMA reactions with Chan s diene [106]. 

Obtaining optimum asymmetric induction in the cycloaddition of methacrolein with the catalyst prepared from the VAPOL ligand involved the slow addition of the dienophile. Initially 10 % of the dienophile was added, the remainder being added over 3 h with a syringe pump (Table 15). If the dienophile was added in one portion asymmetric induction in the cycloadduct 3 at the end of the reaction was only 87.7 % ee (Table 15, entry 3). The amount of asymmetric induction was also found to be a function of concentration, and increased from 91.4 to 97.8 % ee when the concentration of dienophile was reduced from 1.0 to 0.05 m (Table 15, entries 1 and 2). The amount of induction was also found to be function of the substrate-to-catalyst ratio— selectivity was lower at higher ratios (Table 15, entries 1 and 3). Finally, it was observed that as5nmnetric induction was less at the early stages of the reaction that at the end. When the reaction was stopped after 30 % completion the induction was 81.1 % ee whereas at 100 % completion it was 87.7 % ee (Table 15, entries 3 and 5). 

Table 15. Diels-Alder reactions with catalyst 244 from VAPOL to give cycloadduct 3.

The observations made for the VAPOL-aluminum catalyst in Table 15 are suggestive of asymmetric auto-induction similar to that for catalysis of the same reaction by a chiral aluminum catalyst prepared from the diol 225 (Sch. 24 Fig. 1) [48]. Because the Diels-Alder reaction between methacrolein and cyclopentadiene was too fast, monitoring of the time course of asymmetric induction, thus this was done for the reaction between methyl acrylate and cyclopentadiene [53]. The VAPOL-aluminum catalyst catalyzes the reaction of methyl acrylate and cyclopentadiene with asymmetric auto-induction as indicated in Fig. 2. The first data point that was collected was after 20 % conversion, at which point the cycloadduct 141 was 47 % ee when the last data point was collected at the end of the reaction it was found that 141 was 82 % ee. 

In a similar [4+2] reaction of a, -unsaturated esters, the aluminum catalyst complexed with the ligand S-VAPOL resulted in autoinduction , because of cooperative interaction of the product with the catalyst to generate a more selective catalytic species (Scheme 6.48) [68]. The ee% gradually increased as the reaction time lengthened. In the proposed intermediate, penta-coordinated aluminum complex 77, the cycloadduct is recognized as a complementary ligand, leading to substantial asymmetric induction. The acrylate is activated effectively within this hybridized complex which adopts pentacoordination [87]. 

A screen of chiral Lewis acids was carried out by Jorgensen, but this effort failed to reveal any effective enantioselective catalysts [31]. However, very recently Wulff disclosed an extremely exciting result in the VAPOL-BH3 catalyzed reaction between ethyl diazoacetate and imines (Scheme 14) [32]. Although the details had not been published at the time this chapter was written, it seems likely that this method will constitute an important breakthrough and establish a new direction for future research in the field of asymmetric aziridination catalysis. 

Substituted (2/J,3/J)-ethyl azmdine-2-carboxylates are synthesized from imines and ethyl diazoacetate. The catalyst system is composed from (PhOlsB and (Sl-VAPOL." Asymmetric cyclopropanation of electron-deficient aUcenes can be carried out with a Co(II) porphyrinate in which chiral substituents are set in two disjunct mero-positions. The presence of 129 or 130 renders the Corey-Chaykovsky method for cyclopiopana-tion of conjugated aldehydes asymmetric. Thus it is easy to access (15,2/J)-2-formylcyclo-propyl ketones from enals and acymethylsulfonium ylides. ... 

An alternative approach to aziridine synthesis involves transfer of a carbenoid species to imines. Jacobsen achieved the first asymmetric aziridination of imines by transfer of copper carbenoids derived from copper bis-oxazohne catalysts and ethyl diazoacetate onto imines, but this process only proceeds with moderate yield and selectivity. Better results have been achieved by addition of ethyl diazoacetate to imines in the presence of enantiopure Lewis acids such as the boron-based catalysts prepared from vaulted biaryls such as VAPOL (4.154) and B(OPh)3. A range of aryl and alkyl N-benzylaldimines, for example (4.155) and (4.156), undergo aziridination to give ds-aziridines with high ee using this procedure. 

At the same time, Antilla et al. developed a vaulted biphenanthrol (VAPOL)-based magnesium phosphate 20b mediated asymmetric aza-Darzens reaction for the synthesis of chiral aziridine derivatives. The catalyst was prepared in an identical procedure to the previously described process with VAPOL-derived phosphate and magnesium fert-butoxide, and applied in the enantioselective aza-Darzens reaction of N-benzoyl imines 23 and ot-chloro-1,3-diketone 24. The process formed a series of substituted aziridines 25 bearing various substituents at the aromatic ring, with good... 

In 2011, WulfTdescribed the first three-component catalytic asymmetric aziridi-nation reaction of an aldehyde 92, bis(dimethylanisyl)methylamine (163), and ethyl diazoacetate (164) to provide the corresponding chiral aziridine-2-carboxylic esters (165) [55]. When promoted by a chiral boroxinate catalyst in situ generated from B(OPh)3 and chiral Hgand (S)-VAPOL (2,2 -diphenyl-(4-biphenanthrol)), the reaction afforded products 165 with good yields and excellent diastereoselectivities and enantioselectivities (Scheme 11.36). This novel methodology furnished an effective solution to the problem of unstable imines derived from aliphatic aldehydes that cannot be purified. 

A multi-component catalytic asymmetric aziridination of aldehydes employs a protected amine and ethyl diazoacetate as reactants and an (5)-VAPOL boroxinate catalyst, giving aziridine-2-carboxylic esters in up to 99% ee. It works for some cases where preformed imines failed. ... 

Calcium VAPOL (2,2 -diphenyl-(4-biphenanthrol)) phosphate (150) has been reported as an efficient catalyst for the enantioselective Michael addition of 3-aryloxindoles to CH2=CHCOMe (<95% ee) and for chlorination of 3-substituted oxindoles with A-chlorosuccinimide (<99% ee). ... 

The Zr(OiPr)4 precursor with YANOL or VAPOL ligands forms highly active catalyst for asymmetric imine aldol reaction. Both ligands exhibit much higher optical induction than the corresponding BINOL-derived catalyst (140). 

The other recent examples of asymmetric syntheses involving Danishefsky s diene focused on hetero Diels-Alder reactions. Shibasaki and Feng separately reported asymmetric reactions with carbonyl dienophiles. Shibasaki demonstrated successful asymmetric reactions of ketones using a chiral Cu(I)-Walphos catalyst. Feng used a chiral A,iV -dioxide/In(OTf)3 catalyst in asymmetric cycloaddition reactions of aldehydes. Imine dienophiles are also amenable to asymmetric Diels-Alder reactions with Danishefsky s diene. Wulff reported enantioselective reactions using a VAPOL-B(OPh)3 catalyst system, while Snapper and Hoveyda disclosed silver-catalyzed enantioselective aza Diels-Alder reactions. ... 

The ligand (S)-VAPOL 36 was developed by the Wullf group and was successfully applied in the aluminium-catalysed asymmetric Diels-Alder reaction of methyl acrylate and methacrolein with cyclopentadiene (Scheme 19.45). It was also found that carbonyl additives displayed positive cooperativity with the (S)-VAPOL 36-diethylealuminium chloride catalyst on the autoinduction for the reaction with methyl aciylate. 

Spirocyclic phosphoric acid catalyst STRIP (6) turned out to be crucial in the development of the kinetic resolution of homoaldols. The SPINOL backbone outperformed a variety of other previously described phosphoric acids based on BINOL (3 and 2), H8-B1NOL (9), VAPOL (1), and TADDOL (10) backbones (Table 2). 

VAPOL-t3ipe ligands could also be used in a Zr-based system. The catalyst was formed from Zr(0/Pr)4//PrOH, (S)-VAPOL (2.2 equiv), and NMI (1.2 equiv) and produced the desired products in high yields and with excellent enantioselectivity at room tenqierature (eq 39). For less reactive substrates, tenqter-atures could be increased to 100 °C without decreasing enantioselectivity (93-98% ee). ... 

In 1999, WulfF and coworkers reported that catalyst (140), based on vaulted biaryls, catalyzes the asymmetric aziridination reaction of N-benzyl amines. The catalyst was prepared by treatment of S-VAPOL (141) with three equivalents of borane-THF complex followed by heating (Figure 5.9) [87]. The use of one equivalent of borane-THF also gives the same selectivity but requires longer time for the generation of the catalyst. 

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