Asymmetric Barton-Zard Reaction To Access 3-Pyrrole-Containing

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Asymmetric Barton-Zard Reaction To Access 3Pyrrole-Containing Axially Chiral Skeletons Xiao-Long He, zhao Huiru, Xue Song, Bo Jiang, Wei Du, and Ying-Chun Chen ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00767 • Publication Date (Web): 04 Apr 2019 Downloaded from http://pubs.acs.org on April 4, 2019

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ACS Catalysis

Asymmetric BartonZard Reaction To Access 3Pyrrole-Containing Axially Chiral Skeletons Xiao-Long He,†,§ Hui-Ru Zhao,†,§ Xue Song,† Bo Jiang,† Wei Du,*† and Ying-Chun Chen*†,‡

†

Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China ‡

College of Pharmacy, Third Military Medical University, Chongqing 400038, China

Abstract –Developing an efficient and reliable catalytic protocol to access atropisomeric compounds, especially those bearing five-membered heteroaryl structures with lower rotation barriers, is a challenging task. Here, we disclose an unprecedented atropenantioselective BartonZard reaction via a central-to-axial chirality transfer strategy, by employing substituted nitroolefins with a -ortho-substituted (hetero)aryl group and -isocyano substrates with various electron-withdrawing groups, under the catalysis of Ag2O and a cinchona-derived phosphine ligand, providing a robust approach to construct axially chiral 3-(hetero)aryl pyrroles with substantial skeleton and functionality versatility. An alternative asymmetric phase transfer ACS Paragon Plus Environment

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catalysis protocol also demonstrates to be practical for the direct construction of axially chiral bisphosphine dioxides. In addition, good conformational stability is generally observed for the obtained atropisomers, and their potential application as valuable organocatalysts has been well demonstrated in a highly stereoselective formal [4 + 2] cycloaddition reaction.

KEYWORDS. BartonZard reaction, pyrrole, atropisomer, central-to-axial chirality transfer, silver

INTRODUCTION The axially chiral skeleton constitutes the important structural motif in a number of natural products and biologically active substances.1 It also serves as the core scaffold for abundant privileged ligands and organocatalysts.2 Not surprisingly, the development of efficient protocols to enantioselectively construct atropisomeric compounds is of great significance to the synthetic community.3 A variety of enantioenriched six-membered biaryl atropisomers have been conveniently furnished through diverse strategies, such as asymmetric aryl–aryl coupling,4 de novo construction of aromatic ring,5 functionalization of racemic or prochiral biaryls,6 or central-to-axial chirality transfer approach.7 In contrast, the enantioselective construction of atropisomeric five-membered heteroaryl structures is more challenging and less explored,7c,8 probably due to the reduced barriers to rotation impeding the conformational

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ACS Catalysis

stability.9 Shi8e and Tan8g independently demonstrated that chiral Brønsted acid-mediated asymmetric arylation of indoles is a powerful tool to access axially chiral indole skeletons. Besides, the Rodriguez group7c produced fused furan-containing atropisomers via a central-toaxial chirality transfer cyclization strategy. On the other hand, only one example involved the atropenantioselective construction of simple pyrrole-based atropisomers with a stereogenic CN axis, through a Fe(OTf)3/chiral phosphoric acid (CPA)-promoted asymmetric PaalKnorr reaction of 1,4-diketones and ortho-substituted anilines (Scheme 1a).8f,i Nevertheless, these methods mainly rely on the specialized substrates with relatively limited functional group tolerance, which might dramatically restrict the latent application of the obtained axially chiral products. Therefore, the development of a robust atropenantioselective protocol, which can deliver axially chiral five-membered heteroaryl-containing substances with broad functionality availability, would be highly desirable. Pyrroles belong to a class of electron-rich heteroaromatic rings, ubiquitous in natural products as well as material sciences.10 Among the numerous meaningful tools, the BartonZard reaction represents one of the most straightforward strategies to access highly functionalized pyrroles, through the reaction of α-isocyanoacetates and nitroolefins under basic conditions (Scheme 1b).11 Although first disclosed in 1985, this elegant reaction has not been utilized in asymmetric transformations due to the absence of stereocenters at the pyrrole ACS Paragon Plus Environment

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motif. Nevertheless, since stereogenic centers would be generated in the early Michael addition step of the BartonZard reaction process, we envisaged that axially chiral 3arylpyrrole skeletons might be constructed after the sequential cyclization and elimination of HNO2 by introducing suitable ortho-substitutions into -aryl -substituted nitroethylene substrates, via a central-to-axial chirality transfer strategy, as proposed in Scheme 1c.12

Scheme 1. Strategies to Construct Axially Chiral Pyrrole-Based Compounds a) Asymmetric PaalKnorr reaction to access 1-arylpyrroles CO2R O

NH2

CO2R +

Ar

CPA Fe2(OTf)3 Ar

N

O b) Classical BartonZard reaction to access pyrroles Ar

RO2C NC base Ar NO2 O 2N

CN

CO2R +

Ar

HNO2 N H

CO2R

c) Asymmetric BartonZard reaction to access 3-arylpyrroles CN

EWG +

O 2N chiral catalyst R

NO2

CN *

*

EWG central-to-axial cyclization

R

O 2N R

N ***

NH HNO2 EWG aromatization

rotation hindered

R

EWG

axially chiral pyrroles

RESULTS AND DISCUSSION Screening Conditions. Based on the above considerations, we initially conducted the BartonZard reaction of nitroolefin 1a bearing -methyl and -1-(2-tosyloxy)naphthyl groups with ethyl -isocyanoacetate 2a in toluene at room temperature, in the presence of excess K2CO3 and a chiral phase transfer catalyst (PTC) C1. The corresponding 3-(1-naphthyl)-1HACS Paragon Plus Environment

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ACS Catalysis

pyrrole product 3a could be obtained in a high yield, albeit with poor enantioselectivity, indicating that the central-to-axial chirality transfer seemed to be feasible (Table 1, entry 1). As no promising improvements could be achieved by tuning the PTC conditions,13 we turned our attention to the catalytic system developed by Dixon, which has been successfully applied in the asymmetric reactions of -isocyanoacetates.14 Pleasingly, the combination of Ag2O and quinine-derived aminophosphine L1 gave the axially chiral 3a with a significantly improved ee value (entry 2). Moreover, high enantioselectivity with retained reactivity was observed by employing tert-butyl -isocyanoacetate 2b as the substrate (entry 3, product 3b). Other silver salts produced comparable yields and ee values (entries 46), but no enantioselectivity could be induced with CuOAc (entry 7). Interestingly, the sole substance L1 could promote the BartonZard reaction albeit with reduced yield and enantioselectivity (entry 8), whereas no reaction occurred in the absence of both K2CO3 and silver salt (entry 9). More chiral ligands L2L5 derived from cinchona alkaloids were further tested, but generally with inferior results (entries 1013). Subsequently, a few solvents were screened (entries 14−17), and excellent yield and ee value were obtained in PhCF3 (entry 17). The base survey revealed K2CO3 as the preferred choice in terms of enantiocontrol (entries 1820). The asymmetric reaction proceeded equally well at a larger scale (entry 21), and slightly improved yield and enantioselectivity were gained at lower catalyst loadings (entry 22), even at a 1.0 mmol scale (entry 23). A high conversion still could be obtained with 1.0 mol % Ag2O and 2.0 mol % L1, but with slightly reduced enantioselectivity (entry 24). Table 1. Screening Conditions for Asymmetric BartonZard Reaction of Nitroolefin 1a and Isocyanoacetates 2a


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NO2

NH

metal (5 mol %) L (10 mol %) CO2R base (2.0 equiv) OTs + CN 2a R = Et solvent, rt, 24 h 2b R = tBu

1a

R3 Br N Ar OBn

N C1 Ar = 3,5-tBu2C6H3

CO2R OTs 3

N

R1

OMe

H N O

PPh2

N N

R2 N L1 R1 = OMe, R2 = H, R3 = vinyl L2 R1 = OMe, R2 = tBu, R3 = vinyl L3 R1 = OMe, R2 = H, R3 = ethyl L4 R1 = H, R2 = H, R3 = vinyl

HN

O PPh2 L5

yield

entry

metal

L

base

solvent

1d,e

/

/

K2CO3

toluene

92

23

2e

Ag2O

L1

K2CO3

toluene

90

67

3

Ag2O

L1

K2CO3

toluene

92

87

4f

AgOAc

L1

K2CO3

toluene

90

88

5

Ag2CO3

L1

K2CO3

toluene

94

84

6f

AgNO3

L1

K2CO3

toluene

95

82

7f

CuOAc

L1

K2CO3

toluene

64

0

8g

/

L1

K2CO3

toluene

75

80

9

/

L1

/

toluene

trace

/

10

Ag2O

L2

K2CO3

toluene

98

84

11

Ag2O

L3

K2CO3

toluene

92

85

12

Ag2O

L4

K2CO3

toluene

67

79

13

Ag2O

L5

K2CO3

toluene

84

75

14

Ag2O

L1

K2CO3

DCM

84

85

15

Ag2O

L1

K2CO3

EtOAc

92

86

16

Ag2O

L1

K2CO3

Et2O

95

92

17

Ag2O

L1

K2CO3

PhCF3

92

94

18g

Ag2O

L1

Na2CO3

PhCF3

84

77

19

Ag2O

L1

Cs2CO3

PhCF3

88

17

20

Ag2O

L1

K3PO4

PhCF3

95

90

(%)b

ee (%)c


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ACS Catalysis

21h

Ag2O

L1

K2CO3

PhCF3

92

93

22h,i

Ag2O

L1

K2CO3

PhCF3

98

95

23i,j

Ag2O

L1

K2CO3

PhCF3

95

96

24h,k

Ag2O

L1

K2CO3

PhCF3

95

87

a Unless

noted otherwise, the reactions were carried out with 1a (0.025 mmol), 2b (0.05 mmol), metal (5 mol %) and L (10 mol %) in solvent (0.5 mL) at rt for 24 h. b Isolated yield of 3b (R = tBu). c Determined by HPLC analysis on a chiral stationary phase. d C1 was used. e 2a was used and 3a was obtained (R = Et). f With 10 mol % metal. g For 5 d. h At a 0.1 mmol scale. i With Ag2O (2.5 mol %), L1 (5 mol %). j At a 1.0 mmol scale. k With Ag2O (1.0 mol %), L1 (2.0 mol %), for 36 h.

Substrate Scope Survey of Asymmetric BartonZard Reaction. With the optimized catalytic conditions in hand, we next explored the substrate scope and limitations of the asymmetric BartonZard reaction. The results are summarized in Scheme 2. A few 2-naphthol derived nitroolefins 1 with various O-protecting groups were first tested in the reactions with -isocyanoacetate 2b, and high yields with good to excellent enantioselectivity were generally obtained (products 3cf), including the preparation of ent-3f with ligand L5 (data in parenthesis). In addition, the one with a free OH group smoothly gave the corresponding product 3g with moderate enantiocontol. Notably, nitroolefins 1 with other orthofunctional groups on the naphthyl ring were compatible, delivering products 3h and 3i in outstanding yields with excellent enantioselectivity. Furthermore, ortho-alkyl-substituted ones were also tolerated, giving the axially chiral products 3j and 3k with good enantioselectivity after the DBU-assisted elimination and aromatization. Moreover, nitroolefins 1 with different substituents on the naphthyl ring, including electron-donating and -withdrawing groups, were further explored, generally delivering the products 3l−p with excellent results. On the other hand, it was found that the -substitutions of nitroolefins 1 had apparent effect on the enantioselectivity, whereas similar good reactivity was observed (products 3q and 3r). Scheme 2. Substrate Scope for Construction of 3-Arylpyrrole 3a,b,c


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NH

NO2 R1 R R2

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Ag2O (2.5 mol %) L1 (5 mol %) K2CO3 (2.0 equiv)

EWG

+ CN

3b R = OTs, 98%, 95% ee 3c R = OMs, 97%, 80% ee CO2tBu 3d R = OTf, 92%, 89% eed R 3e R = OMOM, 97%, 88% ee 3f R = OTBS, 82%, 93% ee (80%, 86% ee)e 3g R = OH, 95%, 78% eef NH 3l R2 = 3-OMe, 87%, 92% eeg CO2tBu 3m R2 = 6-Br, 92%, 87% ee OTs 3n R2 = 6-CN, 99%, 90% ee 3o R2 = 6-OMe, 81%, 96% ee 3p R2 = 7-Br, 98%, 86% ee NH

NH CO2tBu OTs

N 3s 88%, 92% ee

NH

a

EWG R

3h R = NO2, 95%, 90% ee 3i R = POPh2, 96%, 86% eeg,h 3j R = Et, 65%, 86% eei 3k R = iPr, 70%, 86% eei

NH R1

CO2tBu 1 OTs 3q R = Et, 93%, 66% ee 1 3r R = Bn, 85%, 92% ee NH CO2tBu

NH CO2tBu Boc N

CO2tBu Me

3t 73%, 88% ee

MeO

OTs

OMe

3u 96%, 86% eei,j

NH

NH

R 3

NH

R2

EWG

R2

PhCF3, rt, 2472 h

2

1

R

1

OMe 3v 82%, 86% eei,j NH

NH

Ts

PO(OEt)2

POPh2

POPh2

OTs

OMs

OMe

NO2

3w 55%, 57% ee

3x 85%, 86% eei

3y 82%, 82% eek

3z 79%, 81% eei

Unless noted otherwise, the reactions were carried out with 1 (0.1 mmol), 2b (0.15 mmol),

K2CO3 (0.2 mmol), Ag2O (2.5 mol %) and L1 (5 mol %) in PhCF3 (2.0 mL) at rt for 2472 h.

b

Yield of the isolated product. c Determined by HPLC analysis on a chiral stationary phase. d The absolute configuration of 3d was determined by X-ray analysis. The other products were assigned by analogy. e The data in parenthesis were obtained with L5. f In ethyl acetate (2.0 mL) at 0 ºC for 24 h, and at rt for another 12 h.

g

Ee was determined after conversion to an N-Boc

derivative. h 2a was used in toluene (2.0 mL) at 0 ºC for 24 h, and at rt for another 12 h. i After the completion of cyclization, DBU (0.2 mmol) was added for another 6 h. j At 0 ºC for 24 h. k After the completion of cyclization, CsOH (0.2 mmol) was used for another 6 h.

To further demonstrate the scope of the atropenantioselective BartonZard reaction, we employed nitroolefins 1 bearing other types of aromatic ring systems in the reactions with 2b. As shown in Scheme 2, both quinoline and 7-indole-based nitroolefins 1 were well adapted, affording the atropisomers 3s and 3t in good results. It was noteworthy that axially chiral pyrrole-phenyl skeletons 3u and 3v were efficiently attained with good enantioselectivity. ACS Paragon Plus Environment

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ACS Catalysis

Besides -isocyanoacetates, other isocyano substrates were utilized in the catalytic atropenantioselective transformation. While 4-toluenesulfonylmethyl isocyanide 2c displayed lower reactivity and afforded the desired product 3w in moderate yield and enantioselectivity, the

assembly

of

diethyl

-isocyanomethylphosphonate

2d

or

-

isocyanomethyldiphenylphosphine oxide 2e with suitable nitrololefins 1 provided the corresponding axially chiral products 3xz with high enantioselectivity. DBU or CsOH was required to promote the final aromatization process in some cases. In the exploration of the generality of the asymmetric BartonZard reaction, we anticipated to construct the atropisomeric 3-pyrroles bearing other type of five-membered heteroaromatic scaffolds. As shown in Scheme 3, the nitroolefin 4a with a -3-(2-phenyl)indolyl substituent exhibited good reactivity with -isocyanoacetate 2b under the standard catalytic conditions, and DBU was indispensable for the complete aromatization to afford the final atropisomer 5a in excellent yield and enantioselectivity. Similar results were obtained with an N-Boc-protected substrate (product 5b). Replacing 2-phenyl group with a t-butyl one or introducing substitutions into the indole ring delivered the expected products 5ce in comparable yields with good to excellent enantioselectivity. Importantly, some functionalities could be directly introduced. The substrate with a 2-diphenylphosphine oxide group showed sluggish reactivity, whereas the desired product 5f could be furnished in a moderate yield by extending the time, but with excellent enantioselectivity. Using the N-methyl analogue greatly improved the reactivity (product 5g). The product 5h with a 3-(2-methoxycarbonyl)indolyl group was yielded in a quantitative yield with high enantioselectivity, and slightly reduced enantiocontrol was observed by introducing a substituent into the 4-site of indole ring (products 5i and 5j). Furthermore, 3benzofuran and 3-benzothiophene-based substrates were also applicable, giving the corresponding products 5km in excellent yields with high enantiocontrol. Remarkably, the axially chiral pyrroleACS Paragon Plus Environment

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pyrrole skeleton 5n, which might have a lower rotation barrier, was first synthesized in acceptable yield and ee value. Scheme 3. Construction of Axially Chiral Five-Membered 3-Heteroarylpyrrolesa,b,c NO2

R1

R

X 4

+

CO2tBu

CN

2b

EWG R1

R 5

X NH CO2tBu

CO2tBu MeO

Ph

Ph

Ph N H 5a 90%, 95% ee

N Boc NH

Ph N H 5e 85%, 84% eed

POPh2 N

R 5f R = H, 55%, 91% eee 5g R = Me, 83%, 80% eef

NH

NH

CO2tBu

CO2tBu

CO2Me

5j 89%, 83% ee

5d 80%, 90% ee

NH CO2tBu

CO2tBu

Ph

N H

N H 5c 99%, 90% ee

5b 91%, 93% ee NH

a

NH

NH

CO2tBu

CO2tBu

N H

2) DBU (2.0 equiv) 6h

NH

NH

Me

1) Ag2O (2.5 mol %) L1 (5 mol %) K2CO3 (2.0 equiv) PhCF3, rt, 24 h

Ph O 5k 97%, 86% eed

CO2tBu

NH Br

CO2tBu

CO2Me N H 5h 99%, 90% eeg

CO2Et N H 5i 90%, 70% eed

NH

NH CO2tBu

CO2tBu R S 5l R = Bn, 90%, 80% ee 5m R = Ph, 95%, 96% ee

Me

N Boc

Me 5n 70%, 75% eeh

Unless noted otherwise, the reactions were carried out with nitroolefin 4 (0.1 mmol), -

isocyanoacetate 2b (0.15 mmol), K2CO3 (0.2 mmol), Ag2O (2.5 mol %) and L1 (5 mol %) in PhCF3 (2.0 mL) at rt for 24 h. Then DBU (0.2 mmol) was added for another 6 h. yield;

c

Ee value was determined by HPLC analysis on a chiral column.

d

At 0 ºC.

b

Isolated

e

For 7 d,

and CsOH (0.2 mmol) was added for another 6 h. f In toluene for 48 h, and CsOH (0.2 mmol) was added for another 6 h. g In toluene, at 0 ºC. h At 10 ºC.

Axially chiral bisphosphines and corresponding dioxides have been extensively applied as metal ligands or organocatalysts in asymmetric catalysis; nevertheless, multiple synthetic transformations are usually required starting from chiral precursors.15 As the asymmetric BartonZard reaction of -isocyanomethyldiarylphosphine oxides and -arylnitroolefins with an

ortho-phosphine oxide substitution could straightforwardly provide the desired chiral ACS Paragon Plus Environment

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bisphosphine

ACS Catalysis

dioxides,

we

devoted

our

effort

to

the

reaction

of

-

isocyanomethyldiphenylphosphine oxide 2e and nitroolefin 1i. Unfortunately, although clean reaction was accomplished based on Ag2O/ligand L1 catalysis, only poor enantioselectivity could be obtained (Scheme 4, 75% yield, 21% ee). After some screening studies, we were pleased to find that the PTC system of ammonium salt C216 and CsOH was highly efficient for this specialized combination even at 20 C, and the desired axially chiral product 3aa was obtained in a quantitative yield with high enantioselectivity, providing a convenient and effective protocol to directly access valuable chiral bisphosphine dioxides. Scheme 4. Construction of an Axially Chiral Bisphosphine Dioxide under PTC NO2 POPh2 +

1i

NH POPh2 C2 (10 mol %) CsOH (2.0 equiv) NC 2e

toluene, 20 C 24 h

with Ag2O/L1: 75%, 21% ee

POPh2

Cl N

HO

POPh2

3aa 99%, 89% ee

N

N N C2

N

Racemization Study. In order to investigate the stereochemical stability of these axially chiral 3-arylpyrrole substances, we carried out the racemization experiments.17 As summarized in Scheme 5, the pyrroles 3b and 3y with a 2-substituted 1-naphthyl group showed a relatively high rotation barrier, and the enantiopurity almost remained unchanged after heating in iPrOH at 80 C for about 20 h, whereas lower stability was observed for chiral 3v with a 2,6disubstituted phenyl group (G‡ = 29.4 kcal/mol, half-time t1/2 = 19.9 h). Nevertheless, ACS Paragon Plus Environment

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compound 5a with an indolyl group exhibited poorer stability even at 60 C; as expected, introducing a substituent at 4-position of indole ring dramatically improved the rotation barrier, and no ee reduction was detected by heating 5j even in toluene at 100 C for over 4 h. In addition, the rotation barrier of chiral compound 5n possessing two five-membered heterocyclic rings was determined to be 27.5 kcal/mol at 60 C, corresponding to a half-life of 16.1 h.

Scheme 5. Stability Investigation of Diverse Axially Chiral Products NH

NH

NH CO2tBu

POPh2

OTs

OMe

3y

3b iPrOH, 80 C stable (20 h)

iPrOH, 80 C stable (20 h)

NH

CO2tBu MeO

3v OMe iPrOH, 80 C G‡ = 29.4 kcalmol t1/2 = 19.9 h NH

NH CO2tBu Ph

NH 5a iPrOH, 60 C G‡ = 26.7 kcal/mol t1/2 = 4.7 h

OTs

CO2tBu

CO2tBu CO2Me Me NH 5j toluene, 100 C stable (>4 h)

N Boc

5n Me iPrOH, 60 C G‡ = 27.5 kcal/mol t1/2 = 16.1 h

Rationalization of Atropenantioselectivity. In order to gain some insights into the catalytic mechanism, we performed the reaction between indole-derived nitroolefin 4a and tert-butyl isocyanoacetate 2b under the catalysis of Ag2O and ligand L1. The formal [3 + 2] intermediate18 5aa could be successfully isolated in a moderate yield with 95% ee and exclusive diastereoselectivity, whose structure has been unambiguously determined by X-ray analysis, as outlined in Scheme 6. Importantly, completely retained enantiomeric purity was obtained for the axially chiral product ACS Paragon Plus Environment

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ACS Catalysis

5a after aromatization by treatment with DBU. Therefore, based on the above observations, a plausible catalytic mechanism is proposed. The phosphino group of ligand L1 would bind with silver, which in turn coordinates with the enolate form of -isocyanoacetate 2b and nitro group of 4a, with an additional hydrogen bond between the protonated quinuclidine and the nitro oxygen atom to generate transition mode TS-I.14 The Michael addition occurs preferentially from the Re-face, followed by the intramolecular cyclization via transition mode TS-II to give the isolable chiral cycloadduct 5aa with a rotation-hindered architecture, which would be crucial for the central-toaxial chirality transfer.

Scheme 6. Isolation of the Key Intermediate and Proposed Catalytic Mechanism

O2N

NO2

Ag2O (2.5 mol %) L1 (5 mol %)

NC + N H 4a

Ph

Ph N H 5aa 95% ee, >19:1 dr

50% yield

2b

H CO2tBu

H

PhCF3, rt, 24 h

CO2tBu

N

NH DBU (2.0 equiv)

CO2tBu

PhCF3, 6 h

Ph

95% yield

N H 5a 95% ee

Ar = 3-(2-phenyl)indolyl Ar O N H O N Ag N

MeO N

O

central-to-axial chirality transfer Re-face attack O N H O N Ag

H OtBu

N O P Ph Ph

N

MeO O

N

TS-I

Ar

H

N

H CO2tBu

P Ph Ph

TS-II


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Synthetic Transformations and Application. The multiply functionalized and skeleton-diverse axially chiral products based on this new strategy would serve as useful building blocks for the synthesis of various valuable molecules, especially potential organocatalysts and ligands. To simply demonstrate their utility, a few transformations of the obtained products were performed. As illustrated in Scheme 7, product 3i (86% ee) could be easily increased to 99% ee by recrystallization. After methylation with methyl iodide, the intermediate 6 could be converted to the corresponding phosphine product 7 with almost retained enantiopurity, by heating with HSiCl3 and DIPEA in toluene at 80 C. Treating 7 with PhMgBr would afford a bifunctional phosphine 8 with a tertiary alcohol group. To our gratification, compound 8 could act as a highly efficient Lewis base organocatalyst in the formal [4 + 2] cycloaddition reaction of activated alkene 9 and 2,2-dienone 10 via a cascade crossRauhutCurrier/Michael addition/ elimination sequence, furnishing the spirooxindole product 11 in a moderate yield with exclusive diastereoselectivity and high enantioselectivity.19 Scheme 7. Synthetic Transformations and Application in Asymmetric Catalysis NH

HSiCl3 CO2Et DIPEA POPh2 toluene 80 C, 3 h

CO2Et CH3I, NaH POPh2 THF, 3 h

3i 99% ee (recryst) PhMgBr THF 040 C 5h

NMe

NMe

7 90%, 98% ee

6 95%, 99% ee

NMe

Ph

NC

CN

CO2Et PPh2

Ph 8 (10 mol %)

HO Ph PPh2

O + N 9

O toluene, rt Ar, 12 h >19:1 dr 10

8 72%, 98% ee

Ph NC NC

N

O O

11 63%, 89% ee

CONCLUSION We report that the well-established BartonZard reaction can be utilized to construct axially chiral 3-aryl or 3-heteroarylpyrrole architectures. By employing a readily available Ag2O/cinchona-derived phosphine ligand catalytic system, a large number of nitroolefins ACS Paragon Plus Environment

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ACS Catalysis

bearing various -ortho-substituted (hetero)aromatic groups are efficiently assembled with isocyanoacetates,

and

4-toluenesulfonylmethyl

isocyanide,

diethyl

-

isocyanomethylphosphonate and even -isocyanomethyldiphenylphosphine oxide can be applied similarly, affording highly enantioenriched atropisomers with substantial skeleton and functionality versatility. In addition, simple chiral phase transfer catalysis also is identified as a highly enantioselective tool for some substrate combinations. The isolation of the key [3 + 2] cyclization intermediate indicates that the atropenantioselectivity relies on the central-to-axial chirality transfer in the cyclization process. These 3-(hetero)arylpyrrole-based atropisomers generally exhibit relatively good stability, and can be effectively converted to some valuable chiral substances, which have been successfully utilized as effective Lewis base organocatalysts in an asymmetric formal [4 + 2] cycloaddition reaction. We believe that these readily available axially chiral products bearing flexible structural and functional diversity would find broad application in asymmetric catalysis and other fields. More results will be reported in due course.

ASSOCIATED CONTENT Supporting Information


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More screening conditions, complete experimental procedures and characterization of new products, CIF files of enantiopure products 3d and 5aa, NMR spectra and HPLC chromatograms. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected] [email protected] Author Contributions §XLH

and HRZ contributed equally to this work.

Notes The authors declare no competing financial interests. ACKNOWLEDGMENT We are grateful for the financial support from NSFC (21602143), Sichuan University Spark Program (2018SCUH0058) and Sichuan Science and Technology Program (19YYJC2413).

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(12) During the final preparation of this manuscript, Zhu and co-workers reported the assemblies of -isocyanoacetates and alkynyl ketones to construct axially chiral 3-arylpyrroles, see: Zheng, S.-C.; Wang, Q.; Zhu, J. Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3-Arylpyrroles. Angew. Chem., Int. Ed. 2019, 58, 1494–1498.

(13) For more screenings with PTC conditions, see the Supporting Information.

(14) For selected examples, see: (a) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. A New Family of Cinchona-Derived Amino Phosphine Precatalysts: Application to the Highly Enantio- and Diastereoselective Silver-Catalyzed Isocyanoacetate Aldol Reaction. J. Am.

Chem. Soc. 2011, 133, 17101713. (b) de la Campa, R.; Ortín, I.; Dixon, D. J. Direct Catalytic Enantio- and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates. Angew. Chem.,

Int. Ed. 2015, 54, 4895–4898. (c) Ortín. I.; Dixon, D. J. Direct Catalytic Enantio- and Diastereoselective Mannich Reaction of Isocyanoacetates and Ketimines. Angew. Chem., Int.

Ed. 2014, 53, 34623465. (d) Shao, P.-L.; Liao, J.-Y.; Ho, Y. A.; Zhao, Y. Highly Diastereoand Enantioselective Silver-Catalyzed Double [3 + 2] Cyclization of α-Imino Esters with Isocyanoacetate. Angew. Chem., Int. Ed. 2014, 53, 54355439.


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(15) As metal ligands, see: (a) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. Highly Effective Chiral Ortho-Substituted BINAPO Ligands (o-BINAPO): Applications in Ru-Catalyzed Asymmetric Hydrogenations of β-Aryl-Substituted β-(Acylamino) Acrylates and β-Keto Esters.

J. Am. Chem. Soc. 2002, 124, 49524953. (b) Lam, K. H.; Xu, L.; Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W. H.; Chan, A. S. Highly Enantioselective Iridium-Catalyzed Hydrogenation of Quinoline Derivatives Using Chiral Phosphinite H8-BINAPO. Adv. Synth. Catal. 2005, 347, 17551758. (c) Seki, T.; McEleney, K.; Crudden, C. M. Enantioselective Catalysis with a Chiral, Phosphane-Containing PMO Material. Chem. Commun. 2012, 48, 63696371. As organocatalysts, see: (d) Tokuoka, E.; Kotani, S.; Matsunaga, H.; Ishizuka, T.; Hashimoto, S.; Nakajima, M. Asymmetric Ring Opening of meso-Epoxides Catalyzed by the Chiral Phosphine Oxide BINAPO. Tetrahedron: Asymmetry 2005, 16, 23912392. (e) Shimoda, Y.; Kubo, T.; Sugiura, M.; Kotani, S.; Nakajima, M. Stereoselective Synthesis of Multiple Stereocenters by Using a Double Aldol Reaction. Angew. Chem., Int. Ed. 2013, 52, 3461–3464. (f) Kotani, S.; Yoshiwara, Y.; Ogasawara, M.; Sugiura, M.; Nakajima, M. Catalytic Enantioselective Aldol Reactions of Unprotected Carboxylic Acids under Phosphine Oxide Catalysis. Angew. Chem.,

Int. Ed. 2018, 57, 1587715881.


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(16) For selected examples with PTC C2, see: (a) Wei, Y.; He, W.; Liu, Y.; Liu, P.; Zhang, S. Highly Enantioselective Nitro-Mannich Reaction Catalyzed by Cinchona Alkaloids and NBenzotriazole Derived Ammonium Salts. Org. Lett. 2012, 14, 704707. (b) Li, M.; Ji, N.; Lan, T.; He, W.; Liu, R. Construction of Chiral Quaternary Carbon Center via Catalytic Asymmetric Aza-Henry Reaction with α-Substituted Nitroacetates. RSC Adv. 2014, 4, 2034620350. (c) Capobianco, A.; Di Mola, A.; Intintoli, V.; Massa, A.; Capaccio, V.; Roiser, L.; Palombi, L. Asymmetric

Tandem

Hemiaminal-Heterocyclization-Aza-Mannich

Reaction

of

2-

Formylbenzonitriles and Amines Using Chiral Phase Transfer Catalysis: An Experimental and Theoretical Study. RSC Adv. 2016, 6, 3186131870.

(17) For more details, see the Supporting Information. Also see: Li, S.-L.; Yang, C.; Wu, Q.; Zheng, H.-L.; Li, X.; Cheng, J.-P. Atroposelective Catalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita−Baylis−Hillman Carbonates. J. Am.

Chem. Soc. 2018, 140, 12836−12843.

(18) Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Organocatalytic Asymmetric Formal [3 + 2] Cycloaddition Reaction of Isocyanoesters to Nitroolefins Leading to Highly Optically Active Dihydropyrroles. Angew. Chem., Int. Ed. 2008, 47, 3414 –3417.


27

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 28

(19) The absolute configuration of chiral product 11 was assigned by analogy, see: Hu, F.-L.; Wei, Y.; Shi, M. Phosphine-Catalyzed Asymmetric Formal [4 + 2] Tandem Cyclization of Activated

Dienes

with

Isatylidenemalononitriles:

Enantioselective

Synthesis

of

Multistereogenic Spirocyclic Oxindoles. Adv. Synth. Catal. 2014, 356, 736742.

Graphic Abstract

NO2 Ag2O (2.5 mol %) NC L1 (5 mol %) + CO2tBu K2CO3, PhCF3 N H

Ph

DBU PhCF3 aromatization

NH CO2tBu

O 2N

N H

H CO2tBu

Ph N H 95% ee, >19:1 dr central-to-axial chirality transfer

Ph N H 95% ee asymmetric BartonZard reaction


28

Asymmetric Barton-Zard Reaction To Access 3-Pyrrole-Containing

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