Phosphoric BINOL

At the same time, however, the iridium-catalyzed hydrogenation of 80 was reported using chiral phosphoric acid diester 17be based on BINOL [47a]. Full conversion and a maximum e.e. of 50% was observed, again in a slow reaction. Interestingly, a catalyst based on palladium and 17be afforded 39% e.e. and full conversion in the hydrogenation of aryl imine 87. 

Keywords Asymmetric catalysis BINOL Dicarboxylic acids A-Triflyl phosphoramides Phosphoric acids Strong chiral Brpnsted acids... 

Axially chiral phosphoric acid 3 was chosen as a potential catalyst due to its unique characteristics (Fig. 2). (1) The phosphorus atom and its optically active ligand form a seven-membered ring which prevents free rotation around the P-0 bond and therefore fixes the conformation of Brpnsted acid 3. This structural feature cannot be found in analogous carboxylic or sulfonic acids. (2) Phosphate 3 with the appropriate acid ity should activate potential substrates via protonation and hence increase their electrophilicity. Subsequent attack of a nucleophile and related processes could result in the formation of enantioenriched products via steren-chemical communication between the cationic protonated substrate and the chiral phosphate anion. (3) Since the phosphoryl oxygen atom of Brpnsted acid 3 provides an additional Lewis basic site, chiral BINOL phosphate 3 might act as bifunctional catalyst. 

Phosphoric acids 3 bearing different aromatic substituents at the 3,3 -positions can be synthesized in a few steps starting from commercially available BINOL (6) (Scheme 3). The key step involves a palladium-catalyzed cross-coupling of boronic acid 7 and the respective aryl halide. Both the electronic and steric properties of potential catalyst 3 can be tuned by a proper choice of the substituents at the 3,3 -positions. Besides a simple phenyl group, Akiyama et al. introduced monosubsti-tuted phenyl derivatives as well as a mesityl group, whereas Terada and coworkers focused on substituents such as biphenyl or 4-(2-naphthyl)-phenyl. 

Fig. 3 Phosphoric acids derived from BINOL and Hj-BINOL...

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

In 2004, Terada and coworkers reported the first asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylation (Scheme 8). Aldimines 11 reacted with commercially available 2-methoxy furan (20) in the presence of BINOL phosphate (/ )-3q (2 mol%, R = S.S-MeSj-C Hj) to provide access to A-Boc-protected 2-furyl amines 21 in high yields (80-96%) and enantioselectivities (86-97% ee) [19]. 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

Prior to this work, Renaud and coworkers described an alternative phosphoric acid-catalyzed approach to DHPs 113 commencing with p-enaminoesters such as 114 and cinnamaldehydes 111. Besides developing a catalytic nonasymmetric protocol, the authors attempted a BINOL phosphate (5)-3k-catalyzed (R = 1-naphthyl) asymmetric version attaining moderate enantioselectivity (50% ee) (Scheme 45) [70]. 

In 2007, Terada et al. extended their previously described chiral phosphoric acid-catalyzed aza-ene-type reaction of M-acyl aldimines with disubstituted enecarbamates (Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry to enantioenriched piperidines 121 (Scheme 48). The sequential process was rendered possible by using monosubstituted 122 instead of a disubstituted enecarbamate 76 to produce a reactive aldimine intermediate 123, which is prone to undergo a further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent intramolecular cychzation of intermediate 124 terminates the sequence. The optimal chiral BINOL phosphate (R)-3h (2-5 mol%, R = 4-Ph-C H ) provided the 2,4,6-sub-stituted M-Boc-protected piperidines 121 in good to exceUent yields (68 to > 99%) and accomplished the formation of three stereogenic centers with high diastereo- and exceUent enantiocontrol (7.3 1 to 19 1 transicis, 97 to > 99% ee(trans)) [72]. 

In 2007, two groups independently described asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylations of indoles. While You et al. chose the conventional approach and employed imines as substrates (Scheme 11), Terada and coworkers came up with a different concept and used electron-rich alkenes as precursors (Scheme 49) [73]. Enecarbamates 125 reacted with indoles 29 in the presence of BINOL phosphate (R)-io (5 mol%, R = bearing 2,4,6-triisopropyl-... 

In 2008, Toste and coworkers reported the desymmetrization of me o-episulfonium ions 131 generated in situ from ring closure of sulfides 132 featuring a P-trichloro-acetimidate leaving group [76], Chiral BINOL-derived phosphoric acid (5)-3o (15 mol%, R = triggered the formation of the intermediate mera-epi-... 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Until 2006, a severe limitation in the field of chiral Brpnsted acid catalysis was the restriction to reactive substrates. The acidity of BINOL-derived chiral phosphoric acids is appropriate to activate various imine compounds through protonation and a broad range of efficient and highly enantioselective, phosphoric acid-catalyzed transformations involving imines have been developed. However, the activation of simple carbonyl compounds by means of Brpnsted acid catalysis proved to be rather challenging since the acid ity of the known BINOL-derived phosphoric acids is mostly insufficient. Carbonyl compounds and other less reactive substrates often require a stronger Brpnsted acid catalyst. 

In 2006, Yamamoto and Nakashima picked np on this and designed a chiral A -triflyl phosphoramide as a stronger Brpnsted acid catalyst than the phosphoric acids based on this concept. In their seminal report, they disclosed the preparation of new chiral BINOL-derived A -triflyl phosphoramides and their application to the asymmetric Diels-Alder (DA) reaction of a,p-unsaturated ketones with sily-loxydienes [83], As depicted in Scheme 59, chiral A-triflyl phosphoramides of the general type 4 are readily synthesized from the corresponding optically active 3,3 -substituted BINOL derivatives 142 through a phosphorylation/amidation route. 

Simon L, Goodman JM (2008) Theoretical study of the mechanism of Hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acids. J Am Chem Soc 130 8741-8747... 

The last few years have witnessed major advances in the use of small organic molecules as organic acid catalysts in asymmetric catalysis [1], Selected examples of such organic acid catalysts include urea and thiourea [2], TADDOL [3], BINOL [4], and phosphoric acid derived from BINOL [5] (Figure 2.1). 

Figure 5.2 Important structural and electronic properties of BINOL-derived chiral phosphoric acids.

While BINOL-derived chiral phosphoric acids have received great attention, a handful of reports implementing alternative chiral backbones have appeared [51]. 

For a related highly enantioselective reduction of a-imino esters with a BINOL-derived phosphoric add diester, see Kang, Q., Zhao, Z.-A. and You, S.-L. (2007) Adv. Synth. Catal., 349,1557-1660. 

An enantioselective Strecker reaction involving Brpnsted acid catalysis uses a BINOL-phosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at -40 °C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-l-amino-2-hydroxycyclohexane-l -carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl (g)... 

A BINOL-derived phosphoric acid derivative has been used as a catalyst in the enantioselective synthesis of a-amino phosphonates via hydrophosphonylation of imines with diisopropyl phosphite.82... 

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