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Vaulted Biaryl Ligands and BINOL Derivatives

Aldrich ChemFiles 2006, 6.10, 5.

Aldrich ChemFiles 2006, 6.10, 5.

BINOL and its derivatives are some of the mostly widely used classes of ligands in asymmetric synthesis, and are utilized in a broad array of reaction classes including: Diels-Alder, ene, carbonyl addition and reductions, Michael additions, as well as many others. While tremendous success has been obtained with the BINOL platform, other C2-symmetric diol ligands have attracted considerable attention. Among these are the vaulted biaryl ligands developed by Wulff and co-workers (Michigan State University). Both vaulted 3,3’-biphenanthrol (VAPOL) and vaulted 2,2’-binaphthol (VANOL) have proven to be excellent ligands in catalytic asymmetric Diels-Alder, imine aldol, and aziridination reactions (Figure 2).1 Additionally, the phosphoric acid derivative of VAPOL was shown to be effective as a chiral Brønsted acid catalyst. In many of the examples illustrated herein, the vaulted biaryls give both higher yields and higher inductions than the same reactions using a BINOL ligand.

Figure 2

Very early on, a catalyst generated from Et2AlCl and VAPOL was shown to be an effective catalyst for the asymmetric Diels-Alder reactions.2 As shown in Scheme 6, the cycloaddition of acrolein with cyclopentadiene in the presence of the VAPOL-derived catalyst gave high conversions and excellent stereoselectivities for the exo isomer in very high optical purity. Analogous reactions with the BINOL-derived catalyst provided the cycloadduct in high yield, but in very low enantiomeric excess (13–41%).

Scheme 6

Aziridines are important building blocks in organic synthesis because they allow for convenient access to amines, amino alcohols, diamines, and other useful nitrogen-containing molecules. Most contemporary methods of chiral aziridine preparation have relied on the chiral pool. Recently, the Wulff group has developed a robust catalytic asymmetric aziridination reaction providing optically active aziridines in high yields and selectivities. The reaction relies on the addition of commercially available ethyl diazoacetate (EDA) to benzhydryl imines in the presence of arylborate catalysts prepared from vaulted aryl ligands and B(OPh)3.3 The aziridination reaction exhibits excellent selectivities for the cis isomer, and high enantiomeric excesses are obtained. The resultant benzyhydryl-protected aziridines undergo a variety of reactions, including: deprotection, reductive ring opening, and alkylation reactions (Scheme 7, Table 3). The asymmetric synthesis of leukointegrin LFA-1 antagonist BIRT-377 utilized an aziridination/alkylation methodology to provide the hydantoin target in excellent overall yield.

Scheme 7

Table 3

The highly expeditious synthesis of the antibacterial agent (–)-chloramphenicol utilized the asymmetric aziridination reaction, followed by a nucleophilic ring opening of the aziridine with dichloroacetic acid and subsequent acyl group migration (Scheme 8, Table 4). Both VANOL and VAPOL gave higher yields and stereoselectivities than the BINOL-derived catalyst.

Scheme 8

Table 4

Asymmetric imine aldol reactions are also catalyzed by vaulted biaryl-derived catalysts, providing an important method for the synthesis of chiral b-amino esters. The addition of silyl ketene acetals to aryl imines in the presence of either Zr-VANOL or Zr-VAPOL catalysts proceeds with high asymmetric induction and in excellent yield (Scheme 9, Table 5). Significantly, both catalysts exhibit substantially higher levels of induction over the analogous BINOL-derived catalyst.4

Scheme 9

Table 5

Antilla and co-workers demonstrated VAPOL hydrogenphosphate to be a useful chiral Brønsted acid catalyst in the addition of sulfonamides to Boc-activated aryl imines (Scheme 10).5 The resultant N,N-aminal products were prepared in high yields with impressive enantiopurities. The identical reaction with a BINOLderived Brønsted acid catalyst gave an excellent yield (95%), but a dismal level of asymmetric induction (<5% ee) was obtained. A variety of sulfonamides and aryl imines are active in the imine amidation reaction, and the resultant protected aminals are shelfstable compounds.

Scheme 10

Although a variety of protocols have been developed for the enantioselective reduction of ketimines to the corresponding chiral amines, these methods require the use of preformed, bench-stable imines. MacMillan and co-workers recently reported the first direct enantioselective organocatalytic reductive amination reaction, relying on the silylated BINOL phosphoric acid derivative depicted in Figure 3.6

Figure 3

In the presence of this phosphoric acid derivative and ethyl Hantzsch ester (HEH), both aryl and alkyl ketones underwent reductive amination, giving secondary amines in good yields (Scheme 11). The reaction conditions are tolerant of a variety ketone substitution motifs, as well as functionalized aryl amines (Figure 4). Additionally, the reaction is chemoselective towards methyl ketones, and the catalyst facial selectivity toward prochiral ketones bearing similar alkyl groups is pronounced.

Scheme 11

Figure 4

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  1. Syntheses of vaulted biaryls:
    (a) Bao, J. et al. J. Am. Chem. Soc. 1996, 118, 3392.
    (b) Zhang, Y. et al. Org. Lett. 2003, 5, 1813.
    (c) Yu. S. et al. Org. Lett. 2005, 7, 367.
  2. (a) Bao, J.; Wulff, W. D. J. Am. Chem. Soc. 1993, 115, 3814.
    (b) Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 3321.
    (c) Heller, D. P. et al. J. Am. Chem. Soc. 1997, 119, 10551.
  3. (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1991, 121, 5099.
    (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518.
    (c) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675.
    (d) Patwardhan, A. P. et al. Angew. Chem., Int. Ed. 2005, 44, 6169.
    (e) Patwardhan, A. P. et al. Org. Lett. 2005, 7, 2201.
  4. Xue, S. et al. Angew. Chem., Int. Ed. 2001, 40, 2271.
  5. Rowland, G. B. et al. J. Am. Chem. Soc. 2005, 127, 15696.
  6. Storer, R. I. et al. J. Am. Chem. Soc. 2006, 128, 84.

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