Chiral Counteranions in Asymmetric Catalysis

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					Chiral Counteranions in
Asymmetric Catalysis
Katrien Brak

University of California-Berkeley, Department of Chemistry, Berkeley, CA 94720



                                                         ∗ 1                   ∗ 2                                              O
                                                          R                     R
                                                                  N        N                                                  O P O
                                                                  H        H                                                   O
                                                                      Cl       O                                             LAu     H

                                                             R3        N

                                                                      R4                         X      Y∗

                                                  ∗ R1                 R2                                                               O   O
                                                         N        N                                                                       P
                                                                                                                                        O   O
                                                         H        H                                      O
                                                                                           O                                            Pd       H        R2
                                                             Cl                                P                                                      N
                                                                                                 O       N

                                                                                               O                                            Me
                                                                                                      Me       R

Asymmetric ion pairing of chiral anions with cationic intermediates and catalysts has recently emerged as a method
to prepare enantioenriched compounds. Numerous reports prove the rich potential of this new approach for
asymmetric catalysis. Recent developments in the applications of chiral counteranions in both organo- and
transition-metal catalysis will be reviewed.

   The synthesis of natural products and therapeutic                                                 time only cationic counterions had been effectively
agents requires methods for the preparation of                                                       applied to control the stereochemical outcome of
enantiomerically pure compounds. As a result, much of                                                reactions.3-4 This changed recently in both organo- and
chemistry over the last 30 years has focused on                                                      transition-metal catalysis with several successful reports
developing strategies for asymmetric transformations. In                                             of chiral anionic counterion controlled stereoselectivity.
organocatalysis, several powerful methods for
differentially activating prochiral starting materials have
been developed. Notable in the context of this review are
                                                                                                             asymmetric organocatalysis:
hydrogen bonding1 and Brønsted acid2 catalysis, which
are strategies that rely on chiral information being                                                                     X    H    Y∗                      X   H   Y∗              X       Y∗

transferred through a hydrogen bond (Figure 1). In                                                                         chiral
                                                                                                                        H-bond donor
                                                                                                                                                          Brønsted acid
asymmetric transition-metal catalysis, stereoselectivity
has traditionally been achieved via coordinating chiral                                                      asymmetric transition-metal catalysis:

ligands.                                                                                                                                ∗
                                                                                                                                      Ln M                         Ln     M   Y∗
   In both organo- and transition-metal catalysis, another                                                                         chiral ligand               chiral counteranion

approach towards asymmetric induction has capitalized
on ion-pairing charged intermediates or catalysts with                                               Figure 1. A comparison of strategies for asymmetric organo-
                                                                                                     and transition-metal catalysis.
chiral counterions. Somewhat surprisingly, for a long

  1                                                                                                      3
      Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.                                              Hashimoto, T.; Keiji, M. Chem. Rev. 2007, 107, 5656.
  2                                                                                                      4
      Akiyama, T. Chem. Rev. 2007, 107, 5744.                                                                Lacour, J.; Hebbe-Viton, V. Chem. Soc. Rev. 2003, 32, 373.
   The first reported organocatalytic reaction utilizing
chiral anions to induce asymmetry in reactions involving
prochiral cationic intermediates appeared in 2003. Nelson                                    Scheme 2. Chiral phosphate anion directed transfer
                                                                                             hydrogenation reactions of aldehydes and ketones.
et al. investigated the possibility of inducing asymmetry
in both a Mannich and an aziridinium opening reaction                                                                   O
with a D2-symmetric chiral borate anion 1 (Scheme 1).5                                                     O        O                                O
                                                                                        O                                                    O                                      O
                                                                                                      ∗         P                    O
                                                                                                                    O        ∗           P
Unfortunately, all of the observed enantioselectivities                            H                       O
                                                                                                                    H2               O       O       N            Hantzsch

were low (< 15% ee). 1H-NMR spectroscopy showed that                                Me         R           (20 mol%)
                                                                                                                                                                  ester 3a       Me          R
the borate anion 1 did interact with the aziridinium                              R = aryl, alkyl
                                                                                                                                                  Me        R
                                                                                                                                                                                63-90% yield
                                                                                                                                                                                 90-98% ee
cation. Additionally, the chiral counterion was shown to                                                O
have an effect on the sense and level of induction of                                                O P
                                                                                                          O CO2tBu                                                                       O
                                                                                        O                             O O      CO 2t Bu
asymmetry, thereby setting the stage for further studies in                                        ∗
                                                                                                         H3N     iPr
                                                                                                                       P   H            Hantzsch                                 R   1
                                                                                   R1                                        N   iPr
this area.                                                                                              (5 mol%)         O
                                                                                                                                        ester 3b
                                                                                                                                                                                   R     2
                                                                                    R    2
                                                                                                                                             R1                                          R3
                                                                                           R3                                                                                   68-99% yield
                                                                                  R = aryl, alkyl                                                                                70-98% ee
                                                                                                                                                 R2      R3

      Scheme 1. Chiral boron anion directed Mannich and
                                                                                                                O  O
                aziridinium opening reactions.                                          iPr
                                                                                                          iPr    P   iPr
                                                                                                                                                                       H H
                                                                                                                O O                                      MeO2C                  CO 2Me

                                                                                                   iPr                      iPr
                              Me2 N                                                                                                                                     N    R
                    N                     Ph                                                                                                                            H
                                                                                                                                                                  Hantzsch ester
      N              Me                                           O   O                                                                                            3a: R = iPr
                                                                    B                                                                                              3b: R = Me
                [M+][1-]                                          O   O                                             2
 Ph       H                         N
               (10 mol%)
               ee < 12%              Me                            1

 Ph       Cl        BnNH2
                                                                    Ph    NHBn
                                                                                    In 2008, List et al. reported the epoxidation of enals
 Ph       N
                   [M+][1-]     Ph                     ee < 15%
                                                                    Ph    N
                                                                                 using once again phosphate anion 2 as the source of
                  (50 mol%)
                                                                                 chirality (Scheme 3).9 The excellent enantioselectivity
                                  O            O
                                ∗         B        ∗
                                    O          O
                                                                                 observed with symmetric β,β-disubstituted enals gave
                                                                                 insight into the mechanism. In contrast to the
   Several years later, List et al. described the first highly                   differentially substituted substrates, conjugate addition
successful example of asymmetric counteranion-directed                           intermediate 4 is achiral. This suggests that the chiral
catalysis. An achiral ammonium cation and a chiral                               phosphate is involved in the epoxide forming event. The
                                                                                 authors propose the enantioselectivity results from a
phosphate counteranion catalyzed the transfer
                                                                                 phosphoric acid-assisted cyclization to form epoxide 5.
hydrogenation of aromatic and aliphatic α,β-unsaturated
                                                                                 Since intermediate 4 is not charged, it is unlikely that the
aldehydes with a Hantzsch ester in excellent                                     stereochemical communication occurs via an ion pair.
enantioselectivities (Scheme 2). 6 This was an extension                         Thus despite the authors’ claims, this transformation
of asymmetric Brønsted acid catalysis where primary                              would be better classified as Brønsted acid catalysis. In a
amines and chiral phosphoric acid 2 were previously used                         subsequent report, this chemistry was extended to cyclic
succesfully for this transformation.7 The use of an achiral                      enones; a substrate class for which high enantioselectivity
secondary amine ensured that ion-pairing and not                                 had not previously been achieved.10
Brønsted acid catalysis was responsible for asymmetric
induction. However, hydrogen bonding of the phosphate
counteranion to the Hantzsch ester cannot be ruled out.
                                                                                        Scheme 3. Chiral phosphate anion directed epoxidation.
   The transfer hydrogenation reaction was then extended
to ketones (Scheme 2).8 For these more challenging                                                        O                                                                     O
substrates, both the cation and anion had to be chiral to                                                       H
                                                                                                                              H N
                                                                                                                             O 3                                                     H
achieve high selectivity. For salts with achiral                                                                          O P
                                                                                                                              O                                                 O
                                                                                                 R1       R2                                                            R   1
counteranions, enantioselectivity was at best 54%. The                                                                  ∗   O
                                                                                                                                       CF 3
                                                                                              R 1 = aryl; R 2 =H                 (20 mol%)                               60-95% yield
less sterically demanding primary amines were found to                                               and                                                                   > 94:6 dr
be optimal catalysts. Mechanistically, the reaction most                                      R1 = R 2 = alkyl                                                            90-96% ee

likely proceeds via an imminium-phosphate hydrogen                                Proposed mechanism for R1 = R 2 = alkyl:
bond. Therefore while the new catalyst system expanded                                    O
                                                                                              NR 2                  O                                    NR2
                                                                                       O P
                                                                                            O       t BuOOH ∗          P O H                                                         O NR 2
                                                                                                                                                                                O P
the substrate scope, is not an unambiguous example of                                ∗   O      H
                                                                                                                     O t BuO
                                                                                                                                                              H                    O     H
asymmetric counterion-directed catalysis.                                                R    R
                                                                                                                            R                            R            tBuOH
                                                                                                                                                                                  R    R
                                                                                                                                                    4                                5
   5                                                                                                                                              achiral
     Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron: Asymmetry 2003,
14, 1995.
     Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193.
   7                                                                               9
     Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005,              Wang, X.; List, B. Angew. Chem. Int. Ed. 2008, 47, 1119.
44, 7424.                                                                            Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130,
     Nolwenn, J. A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.             6070.
  Jacobsen et al. have elegantly demonstrated                                                                                    asymmetric catalysis via anion-binding expands the arena
counteranion asymmetric catalysis in an enantioselective                                                                         of hydrogen bonding catalysis to reactions involving
Pictet-Spengler-type cyclization of hydroxylactams in the                                                                        cationic intermediates lacking Lewis basic sites for
presence of TMSCl or AcCl as a dehydrating agent                                                                                 productive catalyst binding.
(Scheme 4).11,12 The enhanced reactivity when R2 = alkyl                                                                           In addition to these insightful reports in
versus R2 = H, pointed to an SN1-type mechanism. The                                                                             organocatalysis, several examples of chiral counteranion
enantiodetermining step was therefore likely the addition                                                                        control in transition-metal mediated reactions have
of the indole to the N-acyliminium ion. As catalyst                                                                              recently emerged. The basic principle of stereochemical
binding to the weakly Lewis basic N-acyl iminium ion                                                                             communication via ion-pairing in transition-metal
had been ruled out by DFT analyses, the authors                                                                                  catalysis was established by Arndtsen et al.14,15 Chiral
proposed enantioinduction arises from binding of the                                                                             boron anions ion-paired with achiral cationic copper
thiourea catalyst to the chloride counterion of the charged                                                                      catalysts were used in the aziridination and
electrophile. Consistent with this model was the                                                                                 cyclopropanation of olefins (Scheme 5). The initial
observation that replacement of chloride with bromide or                                                                         studies with binaphthol based borate 1 resulted in less
iodide counterions resulted in pronounced effects on the                                                                         than 10% ee. Subsequent studies with various borate
enantioselectivity.                                                                                                              counteranions prepared from tartaric acid and α-amino
                                                                                                                                 acid derivatives resulted in at most 34% ee. In examples
                                                                                                                                 using both chiral ligands and chiral counterions, the
                                                                                                                                 existence of matched (28% ee) and mismatched (6% ee)
  Scheme 4. Hydrogen bond donor catalysis by anion binding.                                                                      diastereomeric ion pairs upon changing the anion
                                                                                                                                 chirality from (R) to (S) demonstrated that the chiral
                                                               S                                                                 counterion did influence the enantioselectivity. The
  n=1,2              N
                                             6            N         N                                                N           studies by Arndtsen et al. showed that ion pairing with a
      R      2
                                         (10 mol%)        H         H                 R    1

                                                                                                           N R2          n=1,2
                                                                                                                                 cationic metal catalyst could be used as a strategy
     R   1
                                     indoles: TMSCl       O
                                                               Cl                                          H                     towards enantioinduction.
                                     pyrroles: AcCl
                             N                                                         indoles: 51-94%               yield
                             H                                                                   81-99%              ee
                                                          R2                           pyrroles: 51-86%              yield
                                                                                                 52-93%              ee
                                                                                                                                      Scheme 5. Aziridination and cyclopropanation of olefins.
                                          OTBS                      S                                           R2
                  Cl                                                                                       R2        CO 2Me
                             R2                                N         N
                                              OMe                                                                                                            O      O
                                                                                                                                                         ∗       B       ∗
                         O           R2                        H         H                                           O                    [Cu(NCMe) 4]                          PhINTs       Ts
R1                                                                                             R   1                                                         O 1 O                           N         41-90% yield
                                 7 (10 mol%)                        Cl                                                                               (1-3 mol%)                                         1-10% ee
                                                                                                                                               achiral diimine ligands                            Ph
                                                     R1                                                70-96% yield              Ph
                                                                                                        74-97% ee                                                                            CO 2Et
                                                                                                                                                                             N2 C(H)CO 2Et             12-34% yield
                                                                                                                                                                                                        6-28% ee
                                                                                                            CF3                                                                                   Ph
                         t Bu        S                                               tBu       S
                 N                                                           N
 nC 5 H11                        N        N                                                N           N             CF3
                                 H        H
                                                     Ph                          O
                                                                                           H           H                            In 2007, independent reports with silver, palladium,
                                 6                                                             7                                 and gold claimed to have successfully applied a chiral
                                                                                                                                 counteranion strategy to transition-metal catalysis.
                                                                                                                                 However, certain examples demonstrate the concept more
                                                                                                                                 clearly than others. Whether chiral ion pairing is the
                                                                                                                                 mode of enantioinduction is challenging to determine
   The thiourea anion-binding mode of asymmetric                                                                                 unambiguously.
catalysis was recently extended to reactions involving                                                                              Rueping et al. combined a Brønsted acid and a metal-
oxocarbenium intermediates.13 Chiral thiourea catalyst 7                                                                         catalyzed reaction for the formation of α-alkynylated
was shown to catalyze the enantioselective substitution of                                                                       amino acids.16      The proposed reaction mechanism
silyl ketene acetals onto 1-chloroisochromans with high                                                                          involves addition of achiral silver alkyne complex 9 to
enantioselectivity (Scheme 4). Addition of 10 mol% n-                                                                            chiral iminium ion pair 8 to give amino ester 10 (Scheme
Bu4NCl, resulted in complete inhibition of the reaction.                                                                         6). While exchange of the silver acetate counterion with
This provides evidence for a chloride-binding mode of                                                                            the chiral Brønsted acid cannot be excluded, the neutral
action for thiourea catalyst 7. As there is no potential for                                                                     silver complex 9 involved in the enantiodetermining step
hydrogen bonding to either the substrate or nucleophile,                                                                         remains achiral. Therefore, enantioselectivity is not
the enantioselective thiourea-catalyzed addition to                                                                              established through the complexation of a cationic metal
oxocarbenium ions is a clear-cut application of                                                                                  with a chiral counteranion.
asymmetric counteranion catalysis. The discovery of

  11                                                                                                                                14
     Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am.                                                             Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett. 2000,
Chem. Soc. 2007, 129, 13404.                                                                                                     2, 4165.
  12                                                                                                                                15
     Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett. 2008, 10,                                                                Llewellyn, D. B.; Arndtsen, B. A. Tetrahedron: Asymmetry 2005,
1577.                                                                                                                            16, 1789.
  13                                                                                                                                16
     Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.                                                                   Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem. Int.
2008, 130, 7198.                                                                                                                 Ed. 2007, 46, 6903.
                                                                                                        substrate are arranged 180º apart; therefore the counterion
                                                                                                        probably ends up closer to the substrate than the ligands
    Scheme 6. Proposed mechanism for the combined Brønsted                                              on gold. Additionally, the role of the chiral phosphate
      acid and Ag-catalyzed alkynylation of α-imino esters.                                             anion as a chiral counteranion is clearly defined since
                                                                                                        gold binds to the reaction substrate and to the phosphine
                     ∗   O
                                                                      Ph                                ligand during catalysis, leaving no open coordination
                                                   PMP                                                  sites for phosphate binding.
                                EtO 2C             H                  Ag                                   Toste et al. also demonstrated that for particularly
                 PMP                           8                         9                      Ph      difficult transformations, a chiral counteranion could be
                                                                                                        used in addition to a chiral ligand. This led to the
    EtO2 C       H
                                                                                                        observation of pronounced matched (82% ee) and
                                                                AcO          Ag                         mismatched (3% ee) cases. In analogy to the Pd ion pair
                                                                                                        in the work by List et al., hydrogen bonding to the
                                                                 O   O
                                                                                                        nucleophile can not be excluded as an additional mode of
                                           ∗                ∗
                           EtO2C                                 O
                                                                     O            Ag                    enantioinduction. However, the high enantioselectivity
                                          10           Ph                                               observed for electronically and sterically diverse
                                                                                                        nucleophiles (alcohols, amines, and carboxylic acids)
   List et al. reasoned that the concept of asymmetric                                                  suggests that this is not the case. Nevertheless, an
counteranion-directed catalysis could be applied to                                                     important extension of the chiral counterion strategy in
organometallic systems as well.17 They reported that                                                    transition-metal catalysis is the application to a system
combining a Pd(0) catalyst with the chiral phosphoric                                                   with no potential for hydrogen bonding.
acid 2 results in highly enantioselective Tsuji-Trost-type
α-allylations (Scheme 7).        The allylation reaction
proceeds via a well-established cationic π–allyl Pd(II)                                                 Scheme 8. Enantioselective Au-catalyzed hydro -alkoxylation,
complex in which the phosphate cocatalyst must be the                                                            -amination, and -carboxylation of allenes.
basis of asymmetric induction as it is the only source of
chirality. However, whether the chiral phosphate anion


functions as a chiral counteranion or a chiral anionic                                                           HO
                                                                                                                      L(AuCl) 2 (2.5 mol%)
                                                                                                                                                   O P O
                                                                                                                                                    O                              H
ligand for palladium remains unclear. Furthermore, the                                                                 Ag-(R)-2 (5 mol%)
                                                                                                                                                 LAu   H
                                                                                                                                                           O                           O

influence of additional interactions on enantioselectivity,                                                                benzene

such as hydrogen bonding with the enamine nucleophile,
cannot be excluded.
                                                                                                                      L = (R)-binap, X = BF4 -                    52% yield, 6% ee
                                                                                                                      L = dppm, X = Ag-(R)-2                      90% yield, 97% ee

                                                                                                                 HO    O
Scheme 7. Palladium-mediated Tsuji-Trost-type α-allylation of                                                                   L(AuCl)2 (2.5 mol%)                        H
                       aldehydes.                                                                                                  AgX (5 mol%)

     Me                                                                                                               L = (R)-binap, X = Ag-(R)-2              91% yield, 3% ee

             H                                                                                                        L = (S)-binap, X = Ag-(R)-2              88% yield, 82% ee
R1               2 (1.5 mol%)                               O   O
         O        Pd(PPh3 )4      Me                          P                                                MesSO2HN
                                                            O   O                       Me                                     L(AuCl) 2 (2.5 mol%)                 H SO 2Mes
                   (3 mol%)                        N
     H                                1               R2                                                                        Ag-(R)-2 (5 mol%)                     N
                                  R                 H                                               H
R                                          O                Pd       H        R2        R
                                      O                                   N
                                           P                                                    O
                                             O                  Me                                                                 L = Ph(Me) 2P       88% yield, 98% ee

 R 1= aryl                                O                                            65-89% yield
 R 2 = CHPh 2                                                        R1                 70-97% ee

                                                                                                          In the last three years, there have been remarkable
  Despite limited examples of highly enantioselective                                                   results in the area of counteranion-directed asymmetric
gold-catalyzed transformations, Toste et al. recently                                                   catalysis. Currently, mechanistic ambiguity surrounds
described excellent chiral control in intramolecular                                                    many of the transformations utilizing this novel approach
heteroatom additions to allenes (Scheme 8).18 The                                                       and a more detailed understanding of the mechanisms at
reactions were catalyzed by cationic gold complexes with                                                play in chiral ion pairing situations will be important in
chiral phosphate counteranions. A strong solvent effect                                                 defining this new strategy for catalysis. Conceptually,
on enantioselectivity, with nonpolar solvents like benzene                                              however, the idea of chiral anion induced
being best, was consistent with an ion-pair model.                                                      enantioselectivity has opened the door to new
  Remarkably, Toste et al. observed that the influence of                                               enantioselective transformations: in organocatalysis, to
the counteranion (97% ee) can be stronger than the                                                      reactions proceeding via cationic intermediates where
influence of chiral ligands (6% ee) covalently bound to                                                 hydrogen bonding is unavailable and in transition-metal
gold. Gold differs from other metals in that it is known to                                             catalysis, to any reaction catalyzed by a cationic metal
bind to only two ligands at one time.19 The ligand and                                                  complex. Further efforts to exploit chiral counteranion
                                                                                                        controlled asymmetric catalysis will undoubtedly provide
     Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
                                                                                                        new and interesting chemical transformations.
     Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496.
     Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.

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