Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate

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Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate Jian Lv, Qichao Zhang, Xingren Zhong, and Sanzhong Luo J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11085 • Publication Date (Web): 23 Nov 2015 Downloaded from http://pubs.acs.org on November 23, 2015

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Journal of the American Chemical Society

Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate Jian Lv1,2,‡, Qichao Zhang1,‡, Xingren Zhong1and Sanzhong Luo1,2,*

1

Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of

Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

2

Collaborative Innovation Center of Chemical Science and

Engineering (Tianjin), Tianjin 300071, China.

Abstract: Stable carbocations such as tritylium ions have been widely explored as organic Lewis acid catalysts and reagents in organic synthesis. However, to achieve asymmetric carbocation catalysis remains elusive ever since their first identification over one century ago. The challenges mainly come from their limited compatibility, scarcity of chiral carbocation as well as the extremely low barrier to racemization of chiral carbenium ions. We reported here in a latent concept for asymmetric carbocation catalysis. In this strategy, chiral trityl phosphate is employed as the carbocation precursor, which undergoes facile ionic dissociation upon mild external stimulation (e.g. acid, H-bonding, polar substrates) to form a catalytically active chiral ion-pair for substrate activation and chiral induction. The latent strategy provides an enabling solution to the long sought-after asymmetric carbocation catalysis as illustrated in three different enantioselective transformations.

1

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The development of new catalytic motif remains a frontline in the evolution of asymmetric catalysis.1 Ever since the discovery of the first trityl cation in 1901,2 stable carbocations have been actively pursued as conceptually attractive organic Lewis acid catalysts.3-5 However, progresses along this line have been rather slow and to achieve asymmetric carbocation catalysis remains elusive despite of the prevalence of organocatalytic concepts and strategies.6 The primary reason is the limited compatibility of carbocations with many nucleophilic reactants.7 Though as bench stable and easily accessible salts, carbocations such as tritylium ions can still react with most nucleophiles, resulting in the interception of the active centers. Consequently, there have been always concerns regarding the precise nature of carbocation catalysis. For examples, hidden proton/silyl catalysis has been noted due to the reaction of carbocations with nucleophilic reactants or even moisture.8 Last but not the least, regulation of chiral inductions by a sp2-hybridized carbocation is a notoriously challenging task, due to the scarcity of chiral carbocations9 as well as the extremely low barrier to racemization of chiral carbenium ions.10 The install of remote chiral centers to trityl cations has been attempted with unfortunately poor enantioselectivity.6d Clearly, new concept and strategy is required in order to achieve asymmetric carbocation catalysis. Capitalizing on the known chiral counteranion effect and chiral ion pair catalysis,11 we proposed here a latent carbocation concept for asymmetric carbocation catalysis. Accordingly, chiral trityl phosphates were employed as latent carbocationic species by either in-situ mixing chiral phosphate salt and trityl derivatives or separately prepared. The chiral phosphate anion plays a key role in stabilizing tritylcation as a neutral species to suppress uncontrolled catalyst interception. Provided with the labile nature of phosphate C-O bonds as known in 2


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many chemical12 and enzymatic13 processes, the resulted trityl phosphate may undergo facile ionic dissociation upon mild external stimulation (e.g. acid, H-bonding, polar substrates) to form a chiral ion-pair,14-16 which simultaneously participates in catalysis to activate substrate and to induce stereoselectivity via the known counter anion effect (Figure 1).

Challenges with asymmetric carbocation catalysis

LA O

Tr O

LUMO activation Challenges: - scarce of chiral carbocations - hidden proton catalysis - Interception of carbocations

Trityl cation (1901)

This work: Asymmetric Latent Carbocation Catalysis Simultaneous Trityl cation generation and activation:

O *

P

S

*

O S P

O Tr

O Tr

Trityl Phosphate Latent carbocation

Substrate stimulation

O

*

P

S

Tr+ Chiral ion pair

O

Activation & chiral induction

Figure 1.Asymmetric carbocation catalysis.

Results and Discussion Characterizations of chiral trityl phosphate. We started by first examining the properties of chiral trityl phosphate (TP-1). Upon in situ mixing sodium phosphate 1a and Ph3CBF4 (eq. 1), typical orange color of tritylium ion solution became colorless. The methine carbon

13

C

signal was completely shifted from 210.8 ppm, characteristic of a deshielded carbenium ion, to 81.9 ppm corresponding to the formation of phosphate C-O bond (Figure 2A). Identical methine carbon signal was also observed when Ph3C-Br with a C-Br covalent bond (δ = 79.2 cm-1) was treated with 1a. In UV-vis spectra, free tritylium ion such as Ph3CBF4 showed a 3



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characteristic twin absorption band at λmax = 432 and 411 nm. When a solution of free tritylium ion Ph3CBF4was titrated with sodium phosphate 1a, the twin absorption was gradually decayed and completely disappeared with one equivalent of 1a (Figure2B, Figure S1 for UV titration spectra). The in situ formed species can be fully characterized as trityl phosphate (e.g. TP-1) by 1H NMR, 13C NMR, 31P NMR and DOSY spectrums (Figure 2, and SI). Latent trityl carbocation TP-1 could also be obtained when Ph3C-OH was treated with free acid 1b or Ph3C-Br treated with silver phosphate1c. In addition, trityl phosphates with variations on phosphate moiety such as TP-2 and TP-3 can be prepared in-situ following the same procedure, and the obtained latent carbocations demonstrated similar spectroscopic properties (Figure 2B). [Ph 3C]+[BF4] - + 1

CH 2Cl2, RT

TP

(1)

Ar 1

1a: Ar 1 = Ar 2 = 4-PhC 6H 4, X = Na 1b: Ar1 = Ar2 = 4-PhC 6H 4, X = H O O 1c: Ar 1 = Ar 2 = 4-PhC 6H 4, X = Ag P O OX TP-1: Ar 1 = Ar 2 = 4-PhC 6H 4, X =C TP-2: Ar 1 = Ar 2 = 2,4,6-(CH 3) 3C 6H 2 , TP-3: Ar 1 = 2,4,6-(CH 3) 3C 6H 2, Ar2 = H, Ar 2

3

Figure 2. Characterizations of chiral trityl phosphate. (A) 13C NMR (CD2Cl2) spectra of compounds Ph3CBF4, 1a and TP-1, the label of red, blue and green dots represents the responding carbon signal in the structure of TP-1. (B) UV-Vis absorption spectra of Ph3CBF4 (0.1 mM) and TP-1, 2 and 3 (0.05 mM), respectively, in CH2Cl2 at room temperature.

4


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+

LA

CD 2 Cl2 RT

OPPh3 31 P

OPPh3 TP-1•OPPh 3 Ph3 CBF4•OPPh 3 (C 6F5)3B•OPPh3

LA•OPPh3 (2)

NMR (ppm) ∆δ vs. OPPh 3 0 27.8 5.0 32.8 17.5 45.3 18.3 46.1

Figure 3.Analytical Lewis acidity of latent carbocation

The Lewis acidity of latent carbocation was examined by using the Gutmann-Beckett method.17 The binding of triphenylphosphine oxide (1.0 equiv) to TP-1 (1.0 equiv) was evaluated on the basis of the change in the

31

P NMR chemical shift of OPPh3 upon

complexation in CD2Cl2 at room temperature (eq. 2). A change of +5.0 ppm in the 31P NMR chemical shift of OPPh3 was observed. This chemical shift is much smaller than the change observed upon binding to B(C6F5)3 (∆δ = +18.3 ppm) and Ph3CBF4 (∆δ = +17.5 ppm) (Figure 3, S2), suggesting that TP-1, as a neutral species, still behaves like a Lewis acid though in a much lower apparent acidity.

(C) O F3C Tr OP* Trityl Phosphate

2

Tr

CO 2Et Tr

2n

OP*

UV active @ 405 and 424 nm

O

OP*

F3C CO2 Et Activated chiral ion pair

Figure 4.UV-Vis titrations of carbocarion with ethyl trifluoropyruvate 2. (A) The UV-vis absorption spectra of TP-1 (2.5mM in 2.0 mL CH2Cl2) upon the addition of 2 (0-84.7 mM) at room temperature, respectively. The insets show a plot of ∆A @ 405 nm against [2]/[TP-1]. (B) The UV-Vis absorption spectra of Ph3CBF4 (0.25 mM in 1.0 mL CH2Cl2) upon the addition of 2 (0, 0.25, 0.50, 1.00, 1.50, 2.50, 5



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3.50, 5.0 mM) at room temperature, respectively. (C) Illustration of simultaneous trityl cation generation and substrate activation.

The interaction of TP with a typical carbonyl compound in Lewis acid catalysis such as ethyl trifluoropyruvate 2 was next examined. Upon in situ mixing TP-1 and ethyl trifluoropyruvate 2, the colorless solution became yellow (Figure 4A, inside) and the characteristic twin absorption of trityl cation at λmax= 425 and 405 nm was clearly observed by UV-visible spectra (Figure 4A). The twin absorption signal was gradually enhanced with the addition of trifluoropyruvate, an indication of the increasing formation of trityl cation (Figure 4A). There seems also a threshold concentration of trifluoropyruvate required for effective generation of trityl cation (Figure 4A, inside figure). These results suggested that trifluoropyruvate could stimulate the dissociation of trityl phosphate to generate the trityl cation, likely via the known polarization effect as frequently encountered in SN-1 type reactions. The in-situ generated trityl cation may simultaneously engage in substrate activation if the stimulator itself is a reaction partner, thus setting the stage for effective catalysis (Figure 4C). UV titration of TrBF4 by trifluoropyruvate 2 confirmed the interception of free tritylium ion with pyruvate and this interaction (Figure 4B) could be further verified by19F-NMR (SI, Figure S3). Asymmetric catalysis bytrityl phosphate Friedel-Crafts reactions of α-ketoesters and indoles.18-20 We next investigated whether the latent carbocation could facilitate asymmetric catalytic reaction via in situ formed chiral carbocationic ion pair (Figure 1). To implement this strategy, different trityl cations, chiral phosphoric acids or salts 1,21,22 and their combinations were then examined in the model reactions of indole 3a and α-ketoester 4a. In experiments, trityl derivatives were first treated 6


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Table 1. Optimization studies for asymmetric catalyzed Friedel-Crafts reaction by carbocationsa NH

O O

+ Ph N H

O

TrX (10 mol%) 1 (10 mol%) CH2 Cl2, -70 °C 4h

CPh 3 O O

Ph

N H

O

3a

4a

Entry

TrX

1

Yield (%)b/5a

ee (%)c

1

TrBF4

‒

Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate

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