Asymmetric catalysis with N-heterocyclic carbenes

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Received 2 Dec 2013 | Accepted 12 Feb 2014 | Published 6 Mar 2014

N-heterocyclic carbenes are a class of persistent carbenes stabilized by adjacent heteroatoms that are part of a heterocycle. They play a central role in multiple enzymatic biosynthetic reactions that involve thiamine diphosphate. Inspired by this biocatalysis machinery, N-heterocyclic carbenes have emerged as one of the most versatile classes of organocatalysts for organic reactions. However, the asymmetric synthesis of carboncarbon bonds through a non-covalent interaction mechanism has not been previously established for chiral carbenes. Here, we report an N-heterocylic carbene-catalysed, highly enantioselective process that uses weak hydrogen bonds to relay asymmetric bias. We nd that catalytic amounts of hexauoroisopropanol are the critical proton shuttle that facilitates hydrogen transfer to provide high-reaction rates and high enantioselectivity. We demonstrate that a successful asymmetric reaction of this type can be accomplished through a rational design that balances the pKa values of the substrate, the carbene precursor and the product.

DOI: 10.1038/ncomms4437

Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

Jiean Chen1 & Yong Huang1

1 Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China. Correspondence and requests for materials should be addressed to Y.H. (email: mailto:[email protected]

Web End [email protected] ).

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The use of N-heterocyclic carbenes (NHCs) in organic synthesis has led to substantial advances in transition-metal catalysis1 and organocatalysis2 over the past decade.

Extensive research has shown that chiral NHCs are a class of privileged chiral ligands for transition-metal catalysis3,4 and that they are versatile chiral organocatalysts5,6 that can generate one enantiomer preferentially in numerous organic transformations7,8. NHCs can catalyse chemical bond synthesis because of several unique chemical characteristics: they are strong s-donors1 and good Brnsted bases, and they have moderate p-acidity9. For metal catalysis, the strong s-donor nature of NHCs makes them excellent ligands for late transition metals for asymmetric olen metathesis1012, hydrogenation1316 and conjugate additions17,18. Typically, an NHC-mediated organocatalytic reaction proceeds through a mechanism similar to the thiamine diphosphate mechanism, wherein a highly nucleophilic acyl-anion equivalent is the key reaction intermediate and is generated by the addition of the NHC catalyst to an aldehyde19,20. This umpolung species, also known as the Breslow intermediate, reacts with various electrophiles to form addition products. The hydrolysis of those adducts regenerates the NHC catalyst and generates the acyl addition/ substitution products, often with high enantiomeric excess (ee) when a chiral NHC is used (Fig. 1a, for example, Benzoin condensation21 and the Stetter reaction22,23). NHCs can also react with acyl halides/anhydrides/esters24,25, electron-decient olens26,27 and ketenes28,29, forming either highly reactive acylating agents or BaylisHillman-type intermediates through a nucleophilic addition reaction (Fig. 1b,c)30. These intermediates can undergo a series of stereoselective nucleophilic and electrophilic reactions to produce functionalized carbonyl compounds. Catalyst turnover is generally achieved by alcoholysis or elimination. All of the aforementioned enantioselective processes utilize strong bond interactions (coordinate or covalent bonds) to ensure the robust communication of chiral information between the NHC and the substrate. Despite the well-established concept of asymmetric hydrogen bond catalysis3134, NHCs have yet to identify themselves as good asymmetric Brnsted base catalysts for carboncarbon bond-forming reactions. Several transesterication reactions using NHCs have been reported, in which the carbene species were believed to exhibit Brnsted base characteristics3539. Although transesterication of unactivated esters has been reported through the use of achiral NHC catalysts3538, only highly reactive vinyl esters were successful in the asymmetric versions39. Alternative nucleophile catalysis by NHC may occur for these reactions, as supported by recent work by Chi and co-workers25,40,41. Presumably, an acyl imidazolium cation intermediate is formed by the substitution of the vinyl alcohol with NHC, which in turn undergoes alcoholysis. Nevertheless, highly selective carbon carbon bond synthesis utilizing weak H-bond interactions alone remains challenging (Fig. 1d).

In this paper, we describe an enantioselective Michael addition reaction in which NHCs are successfully used as a chiral Brnsted base for the rst time. The enantioselectivity for this reaction is accomplished by combining a chiral triazolium salt, a lithium base and an acidic additive that serves as the pivotal proton shuttle to produce a high-reaction rate and high enantioselectivity.

ResultsAnalysis of NHC-catalysed Michael addition reactions. Relative to amines, NHCs are signicantly stronger Brnsted bases, and their conjugate acids have pKa values in the range of 1725, similar to alkoxides4244. In the case of a Brnsted base-catalysed

conjugate addition reaction, the regeneration of the free NHC catalyst in the nal step of the catalytic cycle would require a very basic product enolate. The competing retro-Michael could racemize the newly generated stereogenic centre if the nal protonation step is not fast enough (Fig. 2a). In addition, a single-point binding mode creates a rather oppy H-bond complex, which further discourages facial discrimination. As a result, a good level of enantioselectivity has not been achieved when using a chiral NHC as an organic base catalyst. A recent study on NHC-catalysed oxy-Michael addition showed that facial discrimination was poor with popular chiral-NHC scaffolds; only 11% enantioselectivity was achieved for an intramolecular addition reaction, possibly as a result of a loosely stacked catalyst/substrate ion pair (Fig. 2b)45. In a separate report on carbo-Michael addition, strongly basic NHCs showed excellent catalytic activity. However, an attempt to inuence this reaction asymmetrically was unsuccessful, likely due to the two aforementioned reasons (Fig. 2c)46. In our opinion, these fundamental obstacles have prevented the development of successful asymmetric Brnsted base catalysis using NHCs.

Proton-shuttling strategy for Brnsted base catalysis using NHCs. To address the general problem of the lack of asymmetric control for NHCs used as chiral Brnsted base catalysts, we developed a proton-shuttling strategy (Fig. 3)47. This design takes advantage of a stable cyclic enol form that predominates in solution with 1,3-dicarbonyl compounds. The NHC catalyst might form a well-organized cyclic intermediate through a hydrogen-bonding interaction, instead of fully deprotonating the substrate. In addition, the acidic nature of the 1,3-dicarbonyl compounds might allow direct proton transfer from the substrate to the product anion without forming a stable NHC acid salt. The NHC would in fact become a proton-shuttle promoter, as opposed to a hard base. Furthermore, this proton-shuttling strategy might favour the use of NHCs derived from less basic triazolium salts, which are the class of scaffold that has been most successful in delivering high enantiomeric control for other types of catalytic mechanisms48.

Preliminary evaluation of NHCs as Brnsted base catalysts. We used the Michael addition reaction between 1,3-diketones and nitroolens as a template for testing our design (Fig. 4)4952. Conrming our initial hypothesis, we found that strong Brnsted base NHCs, such as N,N-dialkylimidazolium-generated NHCs, neither catalysed nor generated appreciable conversion for this reaction. This result is in sharp contrast to previous reports that used NHCs as Brnsted bases for both oxy- and carbo-Micheal addition reactions45,46. Those reports primarily used N-alkyl imidazolium-derived NHCs because they are strongly basic. We suggest that such NHCs can fully deprotonate a diketone substrate, which triggers the rst nucleophilic addition cycle, and that the reaction stalls at the imidazolium stage because the conjugate imidazolium salt has a high pKa and cannot be redeprotonated4244. When a C2-symmetric imidazolium salt with two identical chiral alkyl chains on both nitrogen atoms was used stoichiometrically, no ee was observed for the product, suggesting that the diketone enolate and imidazolium cation ion pair is rather loose and exible or that the reaction is reversible due to slow protonation of the product anion. In sharp contrast, less basic N,N-diarylimidazolium- and triazolium-derived NHCs catalysed the reaction smoothly, despite the attenuated deprotonation potential resulting from the reduced basicity of their corresponding NHCs (Supplementary Table 1). It is suggested that this reaction likely operates through a hydrogen-bonded complex, and not a fully charged ion pair. The result

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NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4437 ARTICLE

a R

O N X

Electrophiles

R H

N X

Breslow intermediate

Oxidation

N X

Nucleophiles

R X

N X

Electrophiles

BaylisHillman type

X N X

N X

Electrophiles

Then nucleophiles

N X

R R

N X

Electrophiles

R H

R R

N X

Ion pair or hydrogen bond interaction

Transesterification only

Figure 1 | NHCs as organocatalysts for asymmetric synthesis. (a) NHCs nucleophilically add to an aldehyde, generating an umpolung acyl-anion equivalent (Breslow intermediate). (b) NHCs react with acyl halides/anhydrides/esters or electron-decient olens to generate chiral carbonyl compounds. (c) NHCs react with ketenes to form a [1, 2]-dipolar species that undergoes [n 2] annulation reactions. (d) NHCs as asymmetric Brnsted bases remain elusive, except for

the transesterication of highly reactive vinyl esters. The shaded area highlights the reactive sites that possess a partial charge.

strongly supports our initial notion of maintaining complementary pKas for the substrate, catalyst and product.

Condition screening and reaction optimization. With these preliminary data in hand, we explored the feasibility of controlling the enantioselectivity of the Michael addition reaction of 1,3-diketone compounds and nitroalkenes catalysed by a chiral triazolium salt-derived NHC (Table 1). The product ee was highly sensitive to the structures of chiral NHCs. Aminoindanol-derived catalysts promoted a moderately selective reaction. The base used to generate the free NHC catalyst also had a strong effect on the selectivity of the reaction. Lithium inorganic bases were rapidly identied as the best co-catalysts (Supplementary Table 2). The facial selectivity was strongly inuenced by the aryl substituent on the triazolium nitrogen. In contrast to the popular NHC-catalysed acyl-anion reactions, the pentauorinated phenyl catalyst did not promote the reaction due to its low pKa. A mesityl group showed the highest enantioselectivity. Organic base co-catalysts (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, DBU) produced moderate yields and ees, likely as a result of interference from their conjugate acid forms, which may disrupt the organization of the transition state. Because the nal proton transfer is

likely to be the most problematic step, we tested a number of additives bearing an acidic proton that could act as a proton shuttle (Supplementary Table 3). Surprisingly, we found that a highly acidic alcohol, hexauoroisopropanol (HFIP), afforded both higher yields and improved enantioselectivity. The reaction was also sensitive to solvent, with only ethers affording both high yields and high ees (Supplementary Table 4). Our investigation resulted in the following optimized reaction parameters: 20 mol% NHC precursor, 16 mol% lithium bis(trimethylsilyl)amide (LHMDS), 20 mol% HFIP and 4 molecular sieves in methyl t-butylether (MTBE) at 40 C for 48 h. The reaction occurred

smoothly when using 5 mol and 10 mol% catalyst loading, but the reaction time was longer. For the sake of easy operation at small scales, 20 mol% catalyst loading was chosen for the substrate scope survey.

Substrate scope. Under the optimized conditions, both aryl and aliphatic nitroalkenes were suitable substrates for this reaction (Table 2). The use of aryl, including heteroaryl substituted nitroalkenes resulted in particularly high reactivity and selectivity, regardless of the substitution pattern and the electronic characteristics of the substituents. Yields greater than 80% and ees of

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R H +

pKa=B

Floppy ion pairor H-bond complex

Poor selectivity

N X

Strong base

Retro-Michael

N X

pKa=A

R1 E

pKa=C

Slow protonation if A>C

N X

BF4

Ph Ph

Mes Mes

BF4

N N

CO2Bn

COMe

10 mol%

n-BuLi, 4 MS, 30 C, THF

O Ph

90% yield, 11% ee

OBn

+ COMe 20 mol%

KHMDS,RT, DCM/toluene

88% yield, 0% ee

Figure 2 | NHC as a chiral Brnsted base is strategically problematic. (a) NHC-catalysed Michael addition reactions lack asymmetric control: (1). typically, pKa A4BBC, so the nal protonation step is slow, and the retro-Michael reaction becomes competitive. (2). Single-point H-bonding or ion pairing generally lacks enantio-control. (b) A chiral triazolium salt-catalysed oxy-Michael reaction provides low enantioselectivity, even for an intramolecular reaction. (c) The lack of enantioselective control was also observed for a carbo-Michael addition reaction. DCM, dichloromethane; KHMDS, potassium bis(trimethylsilyl)amide; RT, room temperature; THF, tetrahydrofuran.

R1 R2

NX N

O R3

NHC O H O

NO2

pKa=A pKa=B

R R

R3 O

pKa=C

Organized transition state proton shuttling

Figure 3 | Proton-shuttling strategy for brnsted base catalysis using NHCs. The use of a 1,3-dicarbonyl substrate has two benets: it generates an organized catalyst/substrate pair, and it promotes efcient proton transfer from the starting material to the product. Here, pKa A044C044B0.

95% were uniformly observed. Aliphatic nitroalkenes showed a somewhat attenuated reactivity with moderate enantioselectivity. For example, a nitroalkene with a b-iPr substituent generated the desired product 3k with 47% yield and 75% ee. 1,3-Diketones were the best nucleophiles for this NHC-catalysed asymmetric Michael addition. Moderate diastereoselectivity was observed for asymmetric 1,3-diketones (Fig. 5). Both diastereomers were formed to have good to excellent ees. 1,3-ketoesters were also tolerated. We examined various 1,3-dicarbonyl substrates and found that both the reactivity and selectivity were highly sensitive to the pKa of the substrate; those with signicantly higher or lower acidities than 1,3-diketones were poor substrates. This observation supports our original hypothesis that the pKa values

of the substrate, product and NHC precursor should be well balanced to obtain sufcient catalytic turnover and facial discrimination.

Enantioselective Michael reaction on a 5 mmol scale. A large-scale reaction using 5 mmol (E)-(2-nitrovinyl)benzene was carried out with 20 mol% 5a. The desired product, 3b, was isolated with 90% yield and 99% ee under the standard conditions described in Table 2.

DiscussionThe transition state conguration for this reaction and the role of HFIP are complicated. Several experiments were performed to

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Catalyst (20 mol%) Base (16 mmol%) HFIP (20 mol%)

4 MS, solvent 40 C, 48 h

R R

O O

Ph NO2

+ Ph NO2

1a: R = Ph 1b: R = Me

2 3a: R = Ph 3b: R = Me

BF4 4a: Ar = Ph 4b: Ar = Naph

BF4

N N

5a: Ar = 2,4,6-Trimethylphenyl 5b: Ar = C6F55c: Ar = 2,6-Diethylphenyl5d: Ar = 4-MeOC6H45e: Ar = Bn

Figure 4 | Survey of NHC catalysts for the Michael addition reaction. (a) Reactions were performed using 0.3 mmol of 1,3-dicarbonyl compounds and0.1 mol nitroalkene in 1.2 ml solvent at 40 C for 48 h. (b) Catalysts evaluated.

Table 1 | Condition screening and reaction optimization*.

Entry Catalystw Base Solvent Product Yield (%)z ee (%)y 1 4a t-BuONa DCM 3a o5 02 4b t-BuONa DCM 3a 25 03 5a t-BuONa DCM 3a 86 764 5a DBU DCM 3a 61 695 5a LHMDS DCM 3a 74 796 5b LHMDS DCM 3a o5 407 5c LHMDS DCM 3a 73 698 5d LHMDS DCM 3a 80 509 5e LHMDS DCM 3a 81 1710 5a LHMDS Toluene 3a 70 7211 5a LHMDS Et2O 3a 63 9112 5a LHMDS MTBE 3a 56 96 13 5a LHMDS MTBE 3b 92 99 14|| 5a LHMDS MTBE 3b 50 (67) 91 15z 5a LHMDS MTBE 3b 20 91

*Reactions were performed using 0.3 mmol of 1,3-dicarbonyl compounds and 0.1 mol nitroalkene in 1.2 ml solvent at 40 C for 48 h (Fig. 4).

wFor the catalyst structures, see Supplementary Table 1. zDetermined by 1H NMR integration of the crude mixture.

yDetermined by chiral HPLC.

||10 mol% catalyst loading and base, 50% yield for 2 days and 67% yield for 4 days. z5 mol% catalyst loading and base, 2 days.

better understand the mechanism underlying this unprecedented NHC-catalysed process. We observed a positive lithium effect. Under otherwise identical reaction conditions, NaHMDS generated a lower yield with signicantly decreased enantioselectivity (84% yield, 60% ee) relative to LHMDS (92% yield, 99% ee). When 12-crown-4 was used together with the lithium cation, a poor yield and low ee were obtained (36% and 36%, respectively). These results strongly suggest that lithium is involved in the transition state, possibly as a Lewis acid activator for the electrophile. However, when commercially available lithium acetylacetonate was employed without the NHC catalyst, only trace amounts of product were observed at room temperature (Fig. 6a). Pentane-2,4-dione reacted with (E)-(2-nitrovinyl) benzene in a non-selective manner without a catalyst at room temperature, and several products were formed. With the addition of HFIP (20 mol%), the reaction was cleaner, and the major reaction pathway was the Michael addition reaction (Fig. 6b). When catalytic levels of lithium acetylacetonate were introduced with HFIP, the reaction was rapid, and the desired product was isolated quantitatively (Fig. 6c). These data suggest that the nal deprotonation step is critical. In the absence of a proton source, the Michael addition reaction is inhibited. The

reaction showed a negative non-linear effect (Fig. 7), which suggests that more than one NHC is involved in the carbon carbon bond formation step, and the NHC pair with opposite absolute stereochemistry resulted in a faster reaction. Such results suggest that there is a delicate, enzyme-like transition state with multiple non-covalent bond interactions.

Additional proton additives were also tested, but only HFIP showed better results than the additive-free reaction. Triuoroethanol and (CF3)3COH inhibited the Michael addition reaction.

Stoichiometric HFIP resulted in a fast racemic reaction. Only catalytic levels (0.10.3 eq.) of HFIP enhanced both the yield (92% versus 57% without HFIP) and ee (99% versus 50% without HFIP). This strong HFIP effect is intriguing. Rovis and co-workers53,54 showed that less basic triazolium salt-derived NHC catalysts can co-exist with weak Brnsted acids (for example, carboxylic acids). A control experiment was carried out to test the benzoin condensation reaction using benzaldehyde under our standard conditions. The desired benzoin product was isolated with 52% yield and 49% ee (Fig. 8), conrming the existence of a free NHC species under these conditions. HFIP is believed to act as a hydrogen bond linker that helps stabilize the transition state of the carboncarbon bond-forming step. In

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Table 2 | Enantioselective Michael addition reactions of 2,4-pentadione*.

Entry R Yieldw (%) eez (%) 1 Ph, 3b 92 992 1-Naphthyl, 3c 95 973 4-Me-Ph, 3d 99 984 2-MeO-Ph, 3e 89 965 2-Br-Ph, 3f 85 956 3-Cl-4-F-Ph, 3g 80 977 2-CF3-Ph, 3h 94 958 3-CF3-Ph, 3i 98 999 2-thiophenyl, 3j 80 98 10 iPr, 3k 47 7511 C2H4Ph, 3l 87 80

*Reactions were performed under the optimized condition described in Table 2, entry 13. wIsolated yield.

zDetermined by chiral HPLC.

CO2Me

Ph NO2

3u3v

H H

3m3s

O O

Me Me

OMe

Me Ph

NO2

3w 3x 3a

Figure 5 | Substrate scope of the nucleophile. Deviation from 2,4-pentadione is indicated in red. R1 Ph, 3m, (yield: 95%, dr 1:1, ee: 93%, 97%);

R1 2-Me-Ph, 3n (yield: 77%, dr 1.4:1, ee: 98%, 98%); R1 4-Cl-Ph, 3o (yield: 99%, dr 1.7:1, ee: 91%, 95%); R1 3-F-Ph, 3p (yield: 88%, dr 1.2:1,

ee: 86%, 91%); R1 4-MeO-Ph, 3q (yield: 75%, dr 1.3:1, ee: 90%, 90%); R1 4-Me-Ph, 3r (yield: 92%, dr 1.3:1, ee: 94%, 95%); R1 3-CF3-Ph,

3s (yield: 76%, dr 1:1, ee: 90%, 88%); 3t (yield: 86%, dr 1.4:1, ee: 96%, 94%); R2 H, 3u, (yield: 97%, dr 3:1, ee: 92%, 75%); R2 F, 3v, (yield: 95%,

dr 1.7:1, ee: 84%, 77%); 3w (yield: 90%, dr 1.2:1, ee: 84%, 82%); 3x (yield: 79%, dr 1.4:1, ee: 80%; 80%); 3a (yield:56%, ee: 96%).

+ 4 MS, MTBE, RT

OLi

Ph NO2 Me Me

O O

Me NO2

<10%

+ HFIP (20 mol %)

4 MS, MTBE, RT

Ph NO2 Me Me

O O

Me NO2

55%

+ HFIP (20 mol%)

4 MS, MTBE, RT

Ph NO2 Me Me

O O

Me NO2

>95%

O 0.2 eq.

OLi

Figure 6 | Control experiments. (a) Fully deprotonated 2,4-pentadione failed to react with (E)-(2-nitrovinyl)benzene. (b) A catalytic amount of HFIP promoted the Michael addition of pentane-2,4-dione to (E)-(2-nitrovinyl)benzene. (c) A stoichiometric amount of proton source is required to achieve efcient nucleophilic addition.

addition, the strong acidity of HFIP may also further facilitate the nal proton-transfer step and disfavour the retro-Michael reaction.

In summary, we have rationally designed a reaction in which chiral NHCs catalyse a highly enantioselective carboncarbon bond-forming reaction through a non-covalent bonding inter-

action. The intellectual considerations were focused on the nal catalytic step, the proton transfer, which was critical and potentially problematic. Through careful balancing of the pKas of the substrate, catalyst and product, a highly enantioselective process for Michael addition to nitroolens was developed. The acidic co-catalyst HFIP was found to signicantly enhance this

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100

eevalue of the product (%)

50ee value of the catalyst (%)

Figure 7 | Non-linear effects. The ee of the product was lower than predicted for an ideal linear situation when the optical purity of the catalyst was compromised.

17.1 min,

5a (20 mol%) LHMDS(16 mmol%) HFIP (20 mol%)

4 MS, solvent

40 C, 48 h

BF4

96% ee; 25[a]D 7.4 (c 0.40 in CHCl3)55.

5 mmol-scale synthesis of (S) 3-(2-nitro-1-phenylethyl)-pentane-2,4-dione 3b. NHC Catalyst 5a (418 mg, 0.2 equiv.) and 4- oven-dried molecular sieves (5 g) were dissolved in dry MTBE (30 ml) in a 100 ml round bottom ask. The mixture was degassed and back-lled with argon (5 ) before LHMDS (1 M in

tetrahydrofuran/ethylbenzene, 0.8 ml, 0.16 equiv.) was slowly added. The reaction vessel was degassed/back-lled with argon (5 ) and stirred at room temperature

(25 C) for 10 min before HFIP (105 ml, 0.2 equiv.) was added from a syringe. The ask was sealed with a rubber septum and stirred at 40 C for 1 h. Then, 1b

(15 mmol, 3.0 equiv.) was slowly added, and the mixture was stirred for another 1 h at 40 C. A solution of (E)-(2-nitrovinyl)benzene (5 mmol, 1.0 equiv) in MTBE

(30 ml) was slowly added over the course of 40 min, and the resulting mixture was stirred at 40 C for 48 h. Upon the complete consumption of (E)-(2-nitrovi

nyl)benzene, the reaction was ltered through a short plug of silica gel and concentrated. The residue was puried by silica gel ash column chromatography (eluent: hexane/EtOAc 8:1) to yield the desired addition product 3b (1.120 g,

90%) as a white solid. 1H NMR (500 MHz, CDCl3): d 7.31 (dt, J 23.1, 8.1 Hz, 3H),

7.19 (d, J 7.1 Hz, 2H), 4.724.57 (m, 2H), 4.37 (d, J 10.7 Hz, 1H), 4.304.17

(m, 1H), 2.29 (s, 3H), 1.94 (s, 3H); 13C NMR (125 MHz, CDCl3): d 201.75, 200.99, 136.04, 129.33, 128.55, 127.95, 78.18, 70.72, 42.81, 30.42 and 29.56. HPLC (IA-H, 10% EtOH in hexanes, 1 ml min 1, 210 nm): tmajor 14.0 min, t

minor

CHO

52% yield, 49% ee

Mes

Figure 8 | Benzoin condensation under Brnsted base conditions. A facile benzoin condensation proceeded smoothly when benzaldehyde was used under otherwise identical conditions as those used for the Michael addition reaction. This result demonstrates the existence of free NHC in the reaction system.

21.4 min,

reaction in terms of both yield and enantioselectivity. We expect that this concept will be widely used to design new enantioselective organic transformations that use NHCs as a new class of Brnsted bases and ion pair organocatalysts.

Methods

Materials. All solvents were distilled according to general practice before use. All reagents were purchased and used without further purication unless otherwise specied. Solvents for ash column chromatography were technical grade and distilled before use. Analytical thin-layer chromatography was performed using silica gel plates with HSGF 254 (0.150.2 mm) manufactured by Shandong Huanghai Chemical Company (Qingdao, China). Visualization of the developed chromatogram was performed by measuring UV absorbance (254 nm) and using appropriate stains. Flash column chromatography was performed using Qingdao Haiyang Chemical HG/T2354-92 silica gel (4575 mm) with the indicated solvent system according to standard techniques.

General spectroscopic methods. 1H NMR and 13C NMR data were recorded on Bruker 400 MHz (100 MHz for 13C) nuclear resonance spectrometers unless otherwise specied. Chemical shifts (d) in ppm are reported relative to the residual signals of chloroform (1H 7.26 p.p.m. and 13C 77.16 p.p.m.). Multiplicities are described as follows: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Coupling constants (J) are reported in Hertz (Hz).

13C NMR spectra were recorded with total proton decoupling. Chiral high-performance liquid chromatography (HPLC) was recorded on a Shimadzu LC-20A spectrometer using Daicel Chiralcel columns. HRMS (ESI) analysis was performed

by the Analytical Instrumentation Center at Peking University, and HRMS data were reported as ion mass/charge (m/z) ratios in atomic mass units. 1H NMR,

13C NMR and HPLC spectra are provided for all compounds; see Supplementary Figures 196. See the Supplementary Methods for the characterization data for compounds not listed in this section.

Synthesis of (S) 2-(2-nitro-1-phenylethyl)-1, 3-diphenyl-propane-1, 3-dione 3a. NHC catalyst 5a (8.4 mg, 0.2 equiv.) and 4- oven-dried molecular sieves (100 mg) were dissolved in dry MTBE (0.3 ml) in a 15-ml test tube. The mixture was degassed and back-lled with argon (3 ) before LHMDS (1 M in tetra

hydrofuran/ethylbenzene, 16 ml, 0.16 equiv.) was slowly added. The reaction vessel was degassed and back-lled with argon, and HFIP (2.2 ml, 0.2 equiv.) was added from a micro-syringe. The test tube was sealed with a rubber septum and stirred at

40 C for 1 h. A solution of 1a (0.3 mmol, 3.0 equiv.) in MTBE (0.3 ml) was slowly added, and the mixture was stirred for 1 h at 40 C. A solution of 2a

(0.1 mmol, 1.0 equiv.) in MTBE (0.6 ml) was slowly added over the course of30 min, and the resulting mixture was stirred at 40 C for 48 h. When compound

2a was completely consumed, the reaction was ltered through a short plug of silica gel and concentrated. The residue was puried by silica gel ash column chromatography (eluent: hexane/EtOAc 8:1) to yield 3a (21 mg, 56%) as a white solid.

100 1H NMR (400 MHz, CD2Cl2): d 7.88 (d, J 7.6 Hz, 2H), 7.79 (d, J 7.6 Hz, 2H),

7.637.50 (m, 2H), 7.41 (dt, J 15.5, 7.7 Hz, 4H), 7.23 (m, 5H), 5.87 (d, J 8.2 Hz,

1H), 5.064.92 (m, 2H), 4.62 (dd, J 13.9, 8.3 Hz, 1H); 13C NMR (100 MHz,

CD2Cl2): d 194.07, 193.55, 136.81, 136.18, 135.81, 134.01, 133.73, 128.90, 128.81, 128.77, 128.62, 128.48, 128.29, 128.03, 77.40, 59.47 and 44.08. HPLC (IA-H, 10% EtOH in hexanes, 1 ml min 1, 254 nm): tmajor 14.8 min, t

minor

99% ee; 25[a]D 172.9 (c 0.95 in CHCl3)52.

References

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Acknowledgements

This work was nancially supported by grants from the National Basic Research Program of China (2010CB833201, 2012CB722602), the National Natural Science Foundation of China (21372013), the Shenzhen Peacock Program (KQTD201103) and the Shenzhen innovation funds (GJHZ20120614144733420). Y.H. thanks the MOE for the Program for New Century Excellent Talents in University. The Shenzhen municipal development and reform commission is acknowledged for their public service platform program.

Author contributions

Y.H. directed the research. Y.H. and J.C. designed the proton-shuttling strategy for NHC-catalysed Michael addition reactions. J.C. performed the experiments. Y.H. analysed the data. The paper was written by Y.H. with the assistance of J.C.

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How to cite this article: Chen, J. and Huang, Y. Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates. Nat. Commun. 5:3437 doi: 10.1038/ncomms4437 (2014).

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N-heterocyclic carbenes are a class of persistent carbenes stabilized by adjacent heteroatoms that are part of a heterocycle. They play a central role in multiple enzymatic biosynthetic reactions that involve thiamine diphosphate. Inspired by this biocatalysis machinery, N-heterocyclic carbenes have emerged as one of the most versatile classes of organocatalysts for organic reactions. However, the asymmetric synthesis of carbon-carbon bonds through a non-covalent interaction mechanism has not been previously established for chiral carbenes. Here, we report an N-heterocylic carbene-catalysed, highly enantioselective process that uses weak hydrogen bonds to relay asymmetric bias. We find that catalytic amounts of hexafluoroisopropanol are the critical proton shuttle that facilitates hydrogen transfer to provide high-reaction rates and high enantioselectivity. We demonstrate that a successful asymmetric reaction of this type can be accomplished through a rational design that balances the pKa values of the substrate, the carbene precursor and the product.

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Title

Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

Author

Chen, Jiean; Huang, Yong

Pages

3437

Publication year

2014

Publication date

Mar 2014

Publisher

Nature Publishing Group

e-ISSN

20411723

Source type

Scholarly Journal

Language of publication

English

DOI

https://doi.org/10.1038/ncomms4437

ProQuest document ID

1504534170

Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

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