2,2-Diphenyl-[3,3-biphenanthrene]-4,4-diol, 3,3-Diphenyl-[2,2-binaphthrene]-1,1-diol

[147702-16-7] [147702-14-5]  · C40H26O2, C32H22O2  · (MW 538.19, 438.52)

(reagent used as a chiral catalyst for asymmetric Diels-Alder, aziridination reaction and for imino-aldol reaction)

Alternate Name VAPOL (VAulted PhenanthrOLs), VANOL (VAulted NapthOLs).

Physical Data: VAPOL: mp >250 °C; VANOL: mp 231-233 °C.

Solubility: soluble in toluene, hexane, benzene, ethyl acetate, dichloromethane, and chloroform.

Form Supplied in: R and S isomers as white solid.

Handling, Storage, and Precautions: solid is air stable while its organic solutions turn yellow upon standing after 1 day. To help prevent oxidation and decomposition, store in a tight-lidded container, preferably under nitrogen at <5 °C.

Synthesis and Resolution of 2,2-Diphenyl-[3,3-biphenanthrene]-4,4-diol (VAPOL).1c

2,2-Diphenyl-[3,3-biphenanthrene]-4,4-diol is prepared in four steps (1) starting from 1-bromonaphthlene (1) and chromium hexacarbonyl via the corresponding Fischer carbene complex (2).

Complex 2 is reacted with phenyl acetylene to yield the benzannulated product 3 after acetylation. Demethylation and reductive cleavage of the acetoxy group is carried out in a single step by employing aluminum trichloride and propane thiol to give the phenanthrene monomer unit 4. Racemic VAPOL 5 is obtained in 40% overall yield from 1 by oxidative coupling of 4 in air at 185 °C. The racemic VAPOL is then converted to its phosphoric acid derivative 6 with phosphorus oxychloride. The R and S enantiomers are then resolved with (-)-cinchonidine (2). VANOL is prepared in a similar fashion, but is resolved with (-)-brucine (3).

Catalytic Asymmetric Diels-Alder Reaction

One of the most significant reactions in terms of synthetic utility is the Diels-Alder reaction. Since the first example of a chiral Lewis acid-catalyzed enantioselective Diels-Alder reaction,2 great progress has been made in the development of catalytic enantioselective versions of the homo3 and the heteroatom Diels-Alder reactions.4 The asymmetric induction in chiral cycloadducts from reaction via catalytic methods is strongly influenced by the type of chiral ligands employed. Bis(oxazoline)3b and 1,1-binaphth-2-ol (BINOL) have been two of the most popular chiral ligands to be employed for these reactions. In 1993, VAPOL and VANOL were introduced by Wulff and co-workers1 as new ligands for Lewis acid catalyzed reactions (4). They have reported both aluminum1a and boron1b complexes of these ligands as chiral Lewis acids for Diels-Alder reactions. The catalyst is generated in situ by reacting VAPOL or VANOL with diethyl aluminum chloride in anhydrous dichloromethane at 25 °C for 30 min. It was observed that 10 mol % of the VAPOL-Al catalyst gave optimal results with 98:2 exo/endo ratio and with high enantioselectivity (97.8% ee) (1, entry 3).1a

The same enantioselectivity was maintained in the reaction even when the catalyst loading was decreased from 10 to 0.5 mol % (1, entry 4). It should be noted, however, that higher induction values are obtained upon slow addition of the dienophile (acrolein) to the reaction pot. While the VANOL-derived catalyst under the same conditions gave comparable exo/endo ratios, it gave poorer enantioselectivity than the VAPOL ligand. When BINOL (1, entries 7 and 8) was used as a ligand, poor yields and poor enantioselectivities (41% ee) were observed.1a

Autoinduction Phenomenon

An autoinduction is observed5 with the VAPOL-Al catalyst in the Diels-Alder reactions for both aldehydes and ester dienophiles, but is more pronounced for those of esters (5). The induction at earlier stages of the reaction are much lower than the induction at the end of the reaction. The basic principle of the proposed mechanism for this asymmetric induction is that more than one carbonyl compound coordinates to the aluminum catalyst. The mechanism (6) shows that the product can be incorporated into the catalyst and can account for the autoinduction if this catalyst gives a higher induction. This suggested that other carbonyl compounds could be added to increase the asymmetric induction for the reaction. Indeed, a remarkable increase in induction is observed when both simple carbonyl and 1,3-dicarbonyl compounds are used as additives in the reaction mixture. (The reaction was performed at 0 °C, while the reactions in absence of the 1,3-diacarbonyl compounds were performed at -80 °C.) This suggests that both five- and six-coordinated aluminum species may be involved in this auto-induction process. Greater than 99% ee was observed for cycloadduct 12 if 0.5 equiv of di-tert-butyl-2,2-dimethylmalonate is added at the beginning of the reaction.

Catalytic Asymmetric Aziridination Reaction

Aziridines are very important synthetic targets due to their utility in providing access to unnatural optically pure amino acids6 and amines for preparation of biologically active molecules in the pharmaceutical industry. This strained three-membered ring functionality is structurally analogous to epoxides and cyclopropanes.7 In recent years mastery over enantioselective catalytic synthesis of epoxides8a-e and cyclopropanes8f-h has been made possible by the development of several effective catalysts. Success in the asymmetric catalyst preparation of chiral aziridines lags far behind that of epoxides despite the recent activity.9

Catalysts derived from boron Lewis acids and both the VAPOL and VANOL ligands have been recently reported to provide the first general asymmetric catalytic synthesis of aziridines.10 This methodology involves the addition of ethyl diazoacetate to imines catalyzed by a VAPOL-boron or VANOL-boron catalyst. Initially BH3·THF complex10a was used as the boron source for the preparation of the catalyst. This VAPOL-BH3 catalyst exhibit high asymmetric inductions (>50:1 de; 94-97% ee) for imines prepared from aryl aldehydes as well as from aliphatic aldehydes. It should be mentioned that only benzhydryl imines formed from the corresponding aldehydes gave the best results. (Benzyl and trityl amine were previously used to prepare imines, but gave poor asymmetric inductions.) Later, it was found that the success of the reaction was dependent on the batch of BH3·THF complex employed. Older bottles of the boron reagent gave higher induction values. Upon careful analysis it was found that the impurity present was B(OBu)3. The use of tributylborate as the boron source gave identical induction values observed for older BH3·THF bottles. Eventually, after screening several borate esters, a catalyst prepared from triphenyl borate [B(OPh)3] and VAPOL was found to give exceptionally good asymmetric inductions (90-98% ee) for aryl as well as for aliphatic substrates. (Typically the catalyst is prepared by treating three equiv of the boron reagent with VAPOL/VANOL in orgainic solvents (for example, CH2Cl2, PhCH3, C6H5) followed by heating at 55 °C. The solvent is then removed under vacuum and the solid mass heated at 55 °C for an additional 30 min. The catalyst is dissolved in solvent, the imine, and then the diazo compound are added.) A catalyst prepared from the VANOL ligand was also effective and, in fact, a remarkably small variation was found between the two catalysts for all of the substrates (2, 7). When the BINOL ligand was compared with VANOL and VAPOL, the BINOL-derived catalyst gave poor induction (20% ee), low cis/trans ratio and an increased proportion of the noncyclized side products 18 and 19. This newly developed methodology has been applied to the enantioselective synthesis of L-DOPA10b and chloroamphenicol10c and for the latter with the shortest route ever reported (eqs 8 and 9).

Catalytic Asymmetric Imino-Aldol Reaction

The synthetic utility of this reaction lies in its ability to directly access b-amino acids. Kobayashi et al.11 recently developed the first catalytic asymmetric imino-aldol reaction using 3,3-dibromoBINOL11a and 6,6-dibromoBINOL11b as chiral ligands and zirconium (IV) tert-butoxide as the Lewis acid.11 Their method involves the catalytic reaction of imines derived from o-aminophenols and ketene acetals to generate the imino-aldol product. The use of VAPOL as a chiral ligand was investigated and was compared with 6,6-dibromoBINOL and BINOL based catalysts on the imino-aldol reaction mediated by zirconium (10).12 The catalyst is prepared by reaction of the ligand with 0.5 equiv of zirconium tetralkoxide in the presence of 0.6 equiv of N-methyl imidazole at room temperature for 1 h.

It was found that VAPOL and 6,6-diboromoBINOL catalysts are superior to BINOL at -45 °C.15 When the reaction was performed at room temperature, the asymmetric induction for VAPOL remained unchanged, while that for dibromoBINOL and BINOL decreased. Additionally, a series of imines 19 were prepared where the position of the methyl group on the arene ring was changed. It was observed that, there was a profound change in asymmetric inductions (>98% ee), when the ortho-position was methylated.12 The VAPOL-zirconium catalyst is remarkably temperature independent giving an induction of >98% ee at 25 °C and at 100 °C. Moreover, the inductions could be maintained when 2 mol % of the catalyst was employed at 100 °C (3, entries 6-10) and this is true for a variety of imines. Chiral b-amino esters can be then obtained from the corresponding imino-aldol products by treatment with five equiv of cerric ammonium nitrate in 1 M nitric acid (eqs 11 and 12).


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Aniruddha P. Patwardhan & William D. Wulff

Michigan State University, East Lansing, Michigan, USA



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