Planar chiral DMAP

Tao B, Ruble JC, Hole DA, Fu GC (1999) Nonenzymatic kinetic resolution of propargylic alcohols by a planar-chiral DMAP Derivative crystallographic characterization of the acylated catalyst. J Am Chem Soc 121 5091-5092... 

Fu and co-workers have detailed the use of planar chiral DMAP and PPY analogs as catalysts for the resolution of secondary unsaturated alcohols (Fig. 1) [15]. Both ferrocene and ruthenocene-based catalysts have been examined, with the iron-based catalysts generally proving less reactive but more selective [16]. Catalysts are prepared in racemic form and are subsequently resolved by preparative chiral HPLC. 

Scheme 4. Planar chiral DMAP analog 10 as a catalyst for kinetic resolution of secondary alcohols...

The preparation of optically active /Mactams by asymmetric synthesis is also a topic of major interest, because of the pharmaceutical and biochemical importance of those molecules [44]. A typical and economical route consists of a [2+2]-cycloaddition of a ketene to an imine. Many diastereoselective versions of this reaction type are known [45] as well as catalytic processes involving chiral (metal) catalysts [46, 47] or biocatalysts [48]. A [2+2]-cycloaddition of a ketene to an imine, however, can also be performed very efficiently when applying nucleophilic amines as chiral catalysts [49-60]. Planar-chiral DMAP derivatives have also been found to be suitable catalysts [61]. 

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and use of acetic anhydride as an inexpensive and readily available acyl donor [19]. Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7). As a consequence, enantiomerically highly enriched alcohols (> 95% ee) could be obtained at conversions only slightly above 50%. 

Fu et al. used the planar chiral DMAP derivative 46 (Scheme 13.24) [39]. Although this catalyst has been employed successfully for kinetic resolution of a large variety of racemic secondary alcohols (Section 12.1), substrate 47 seems to be the only meso-diol that has been desymmetrized by use of the acylation catalyst... 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

Construction of quaternary stereocenters by enantiocontrolled oxygen to carbon acyl shift is not limited to the azlactone structure. Using the pentaphenylated planar chiral DMAP derivative 79c (Scheme 13.42) Fu and Hills achieved rearrangement of O-acylated oxindoles 84 (Scheme 13.45) and benzofuranones 85 (Scheme 13.46) with very good yields and enantiomeric excesses up to 99% [88]. 

The MacMillan group has also shown that cycloaddition reactions (see also Chapter 8) can be performed highly diastereo- and enantioselectively. The [3+2]-cycloaddition of nitrones and a,/i-un saturated carbonyl compounds in the presence of 20 mol% of a phenylalanine-derived imidazolidinone acid salt led to products with 99% ee [32]. An example of an enantioselective rearrangement reaction (see also Section 13.6) with 99% ee has been reported by the Fu group [33], who used 2 mol% of a planar chiral DMAP derivative as catalyst. 

Scheme 8.11 Preparation of a (—)-baclofen intermediate using Fu s planar chiral DMAP 4b [54].

Table 8.5 Fu s planar chiral DMAP-catalyzed KR of sec-propargylic alcohols [53].

In 1993, Vedejs et al. [5,6] showed that tributylphosphine is a potent catalyst for the acylation of alcohols by acetic and benzoic anhydrides as efficient as 4-(di-methylamino)pyridine DMAP [7,8]. However, the DMAP catalyst is more versatile since it presents catalytic activity in the reaction of alcohols with a larger variety of electrophiles. Due to these properties, Fu [9] realized the design and synthesis of a new family of chiral nucleophilic catalysts illustrated by the planar-chiral DMAP derivative I which is a very efficient catalyst in different enantioselective reactions such as addition of alcohols to ketenes [10], rearrangement of O-acylated azalactones [11], and kinetic resolution of secondary alcohols [12-14]. 

The enantioselective discrimination of one of the hydroxyl groups of meso-diols can give chiral monoprotected diols, which serve as versatile intermediates for asymmetric organic synthesis. In addition to the enzymatic methods, a number of chemical approaches have been reported using chiral 1,2-diamine catalysts, chiral phospholane-based catalysts, planar chiral DMAP derivatives, and oligopeptide-based catalysts [2,28], Surprisingly, however, relatively a few publications are devoted to this reaction with cinchona-based organocatalysts. 

Kinetic resolutions. Baylis-Hillman adducts are deracemized by exploiting their reactivity toward Pd(0)-catalyzed substitution, using chiral ligand 2. Both the planar chiral DMAP derivative 3 and the axially chiral analogue (4) ° and 5" have been developed as catalysts for enantioselective acylation. Benzylic alcohols undergo enantioselective acylation with the aid of 6. Methanolysis of meio-anhydrides in the presence of a cinchona alkaloids is a good way to desymmetrize such compounds. ... 

Moreover, in conjunction with readily available Mgl2 as a co-catalyst, Fu s planar chiral DMAP derivative 381 has been applied successfully to an MBH reaction involving the addition of cyclopentenone to aromatic and aliphatic aldehydes, affording the corresponding adduct in good to excellent yields with moderate to excellent enantiomeric excesses (Scheme 2.219). This work first suggests that the scope of reactions catalyzed by Fu s planar chiral DMAP catalysts can be increased by employing a simple co-catalyst. ... 

Scheme 22.1 Acylative kinetic resolution of racemic secondaiy alcohols with Fu s planar-chiral DMAP catalysts.

Seitzberg, ).G., Dissing, C., Sotofte, L, Norrby, P.-O., and Johannsen, M. (2005) Design and synthesis of a new type of ferrocene-based planar chiral DMAP analogues. A new catalyst system for asymmetric nudeophilic catalysis. J. Org. Chem., 70, 8332-8337. 

Recently, Connell and coworker screened a series of chiral amine nucleophiles (90-95) for the asymmetric MBH reaction of aromatic and aliphatic aldehydes with cyclopentenone in the presence of Mgl2 (Scheme 31.29) [43], They identified Fu s planar chiral DMAP catalyst 91 as the most efficient catalyst for this asymmetric MBH reaction, affording the products 97 in good to excellent yields and moderate to excellent enantioselectivities. Both aromatic aldehydes and aliphatic aldehydes were suitable for this reaction. They also pointed out that Mgl2 as a co-catalyst could accelerate the reaction rate. 

In 2010, Fossey et al. developed a new class of planar chiral ferrocene nucleophilic catalysts combining both central and planar chirality [59]. Inspired by Fu s planar chiral DMAP and by Birman s 2-phenyl-2,3-dihydroimidazo[l,2-a]pyridine, Rp-57 proved to be a remarkably effective catalyst for the KR of various racemic secondary aryl alkyl alcohols, particularly bulky aryl alkyl alcohols, which are usually difficult to resolve. Typically, by performing the reaction in the presence of Rp-57 (2mol%), propionic anhydride (0.75 equiv.) and i-Pr2NEt (0.75 equiv.) in toluene at 0°C, selectivity factors ranging from s = 31 for substrates such as a-methyl benzyl alcohol to s = 534 in the case of the more bulky a-tert-butyl benzyl alcohol could be obtained (Scheme 41.13). Remarkably, the selectivity could be further increased by running the reaction at lower temperatures (s = 801 at -20 °C and up to s = 1892 at -40 °C), albeit with a concomitant loss in activity. 

Fu et al. were the first to develop an efficient catalytic system for the KR of primary amines [120], Their method relied on the use of a stoichiometric amount of the O-acylated azlactone 111 as the achiral acyl donor in conjunction with a catalytic amount of a planar chiral DMAP derivative 112. Hence, after optimizing the reaction conditions, they were able to resolve various racemic primary aryl alkyl amines with moderate to good selectivities ranging from s = 11 to 27 independently of the substitution pattern on the aromatic ring or on the alkyl chain (Scheme 41.43). 

The Fu group has reported the first nonenzymatic DKR of secondary alcohols [41]. In this DKR, a planar-chiral DMAP derivative ((+)-Cg-Phg-DMAP) as the resolution catalyst was coupled with a Ru complex 6 as the racemization catalyst in the presence of an acyl carbonate (Scheme 5.25). The DKR of simple secondary alcohols provided good )delds but lower enantiopurities compared to the enzymatic DKRs. It is noteworthy that the DKR of sterically more demanding substrates carr3dng a branched side chain (isopropyl or cyclopentyl) also provided similarly good results (Chart 5.25). 

In 1996 Fu and Ruble [12] reported the first study of ferrocene derivatives fitted with a trigonal nitrogen atom acting as a Lewis base. Interestingly, in this seminal work, the two main families of planar chiral DMAP were introduced, namely, azaferrocenes and pyridinoferrocenes. These studies resulted in the development of an impressive number of innovative transformations and these advances have been reviewed in several contributions [13]. The underlying concept at the basis of the stereoselection, presented in Scheme 8.1, relies on the symmetry breaking ... 

Following this work, Fu et al. [21] reconsidered the catalytic addition of alcohols to ketenes by using planar-chiral DMAP derivatives in a Br0nsted acid/base catalysis process. In order to favor the protonation of the catalyst, a prerequisite for a Brpnsted acid/base pathway, the more acidic phenols were anployed. After having checked that phenol protonates DMAP 45c, different other phenols were reacted with ethylphenylketene 35b in the presence of chiral DMAP 45c (3 mol%) at room temperature in toluene. The best level of stereoselection was obtained with the more sterically hindered 2-ferf-butylphenol affording ester 50b in 91% ee. 

The mechanism proposed in Scheme 3.25 draws close parallels to the nucleophilic catalysis pathway already encountered with planar-chiral DMAP derivatives 45. The ketene 35 firstly reacts with the in situ generated nucleophilic NHC 54 giving rise to a chiral triazolium enolate 55. Subsequent diastereoselective protonation... 

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