An axial-to-axial chirality transfer strategy for atroposelective construction of C–N axial chirality

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Article

An axial-to-axial chirality transfer strategy for

atroposelective construction of C–N axial

chirality

Ze-Shui Liu, Pei-Pei Xie, Yu

Hua, ..., Hong-Gang Cheng, Xin

Hong, Qianghui Zhou

hxchem@zju.edu.cn (X.H.)

qhzhou@whu.edu.cn (Q.Z.)

Highlights

Unique axial-to-axial chirality

transfer for C–N axial chirality

construction

Ability to assemble two vicinal and

remote stereogenic axes

Step-economic and scalable

synthesis of enantioenriched

phenanthridinones

Broad scope, good yields, and

excellent enantioselectivities

C–N axially chiral skeletons are prevalent in bioactive natural products and

pharmaceuticals. However, their atroposelective synthesis remains a formidable

challenge. Herein, an efﬁcient method for the synthesis of C–N axially chiral

phenanthridinones through palladium/chiral norbornene cooperative catalysis is

reported. The strategy involves a unique axial-to-axial chirality transfer process,

which has been scarcely reported. DFT calculations are performed to elucidate the

reaction mechanism and the chirality transfer process, providing broader

implications for future studies in asymmetric synthesis.

Liu et al., Chem 7, 1–16

July 8, 2021 ª 2021 Elsevier Inc.

https://doi.org/10.1016/j.chempr.2021.04.005

Please cite this article in press as: Liu et al., An axial-to-axial chirality transfer strategy for atroposelective construction of C–N axial chirality, Chem

(2021), https://doi.org/10.1016/j.chempr.2021.04.005

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Article

An axial-to-axial chirality

transfer strategy for atroposelective

construction of C–N axial chirality

Ze-Shui Liu,^1,4Pei-Pei Xie,^2,4Yu Hua,¹Chenggui Wu,¹Yuanyuan Ma,¹Jiangwei Chen,¹

1,5,

Hong-Gang Cheng,¹Xin Hong,^2,3,and Qianghui Zhou

*

SUMMARY

The bigger picture

Axial chirality widely exists in

bioactive natural products,

pharmaceuticals, chiral materials,

and chiral ligands and catalysts in

asymmetric catalysis. As such, the

efﬁcient, modular, and

C–N axially chiral skeletons are ubiquitous in bioactive natural

products, pharmaceuticals, and chiral ligands. However, their atro-

poselective synthesis remains a formidable challenge because of

their innate low conﬁgurational stability compared with that of

well-developed C–C atropisomers. Herein, we report a general

and efﬁcient method for accessing C–N atropisomers through an

axial-to-axial chirality transfer strategy based on palladium/chiral

norbornene cooperative catalysis. The obtained C–N axial chirality

originates from the preformed transient C–C axial chirality with

high ﬁdelity. A variety of C–N axially chiral phenanthridinones

are obtained in excellent enantioselectivities (44 examples, up

to >99% ee). This method can be applied for the construction of

two stereogenic axes via double atroposelective C–H arylation

or further transformation of the products via axial-to-axial

diastereoinduction. Additionally, the reaction mechanism and the

chirality transfer process are elucidated by density functional

theory calculations.

enantioselective assembly of

these scaffolds from readily

available starting materials

represents one of the most

challenging yet fascinating

directions in synthetic organic

chemistry. In sharp contrast to the

well-developed C–C axial

chirality, atroposelective

construction of C–N axial chirality

has been less investigated

because of the innate higher

degree of rotational freedom of

the latter. Herein, we report an

efﬁcient atroposelective

INTRODUCTION

As we know, C–C atropisomers, e.g., axially chiral biaryls, are prevalent and privi-

leged frameworks, and their construction has been well developed in the past de-

cades.^1–4C–N atropisomers, the siblings of C–C atropisomers, are also commonly

found in bioactive natural products,⁵medicinal chemistry,⁶and recently in asym-

metric catalysis as chiral ligands⁷(Figure 1A). However, compared with that of

well-developed C–C atropisomers, the construction of C–N atropisomers has

been less explored, which is probably due to the innate higher degree of rotational

freedom and lower rotation barrier around a C–N bond.^3,8–10In 2002, the Taguchi¹¹

and Curran¹²groups independently reported the ﬁrst asymmetric syntheses of atro-

pisomeric anilides through a palladium (Pd)-catalyzed N-allylation reaction, albeit

with unsatisﬁed enantioselectivities. Since then, a number of catalytic asymmetric

approaches have been developed for accessing these synthetically challenging skel-

etons (Figure 1B). Excellent stereoselectivities were obtained by means of N–H func-

tionalization of anilides, including Pd-catalyzed N-arylation (Buchwald-Hartwig

amination),^13,14intramolecular Ullmann-type amination,¹⁵phase-transfer-catalyzed

N-alkylation,¹⁶and cinchona alkaloid-catalyzed N-allylation.^17–19Efﬁcient ap-

proaches to directly constructing the atropisomeric C–N bond were also devel-

oped.^20–23Other effective means included assembling the C–N atropisomers via

de novo construction of the aromatic ring^24–27and desymmetrization of prochiral

anilides.^28–31Recently, enantioselective C–H bond functionalization has emerged

construction of C–N atropisomers

via palladium/chiral norbornene

cooperative catalysis. The key to

success is the unique axial-to-axial

chirality transfer process, which

has been scarcely reported. This

strategy is expected to inspire

future studies in asymmetric

synthesis and ﬁnd applications in

broad research ﬁelds.

Chem 7, 1–16, July 8, 2021 ª 2021 Elsevier Inc.

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¹Sauvage Center for Molecular Sciences,

Engineering Research Center of Organosilicon

Compounds & Materials (Ministry of Education),

College of Chemistry and Molecular Sciences,

and Institute for Advanced Studies, Wuhan

University, Wuhan 430072, China

²Department of Chemistry, Zhejiang University,

Hangzhou 310058, China

³State Key Laboratory of Clean Energy Utilization,

Zhejiang University, Hangzhou 310027, China

⁴These authors contributed equally

⁵Lead contact

Figure 1. Representative C–N atropisomers and their synthetic strategies

as a powerful approach to constructing C–N axial chirality.^32–37Despite these signif-

icant achievements, there is still room for improvement with regard to reaction efﬁ-

ciency, substrate generality, and product diversity. Therefore, developing more

*Correspondence: hxchem@zju.edu.cn (X.H.),

qhzhou@whu.edu.cn (Q.Z.)

https://doi.org/10.1016/j.chempr.2021.04.005

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versatile and straightforward methods by using readily available starting materials to

construct enantiopure C–N axial chirality is a highly desirable yet challenging task.

Palladium/norbornene (Pd/NBE) cooperative catalysis, namely the Catellani reac-

tion,³⁸enables simultaneous functionalization at both ortho- and ipso-positions of

aryl halides, offering an efﬁcient approach for polysubstituted arenes.^39–44Recently,

our group developed a general method to access C–C atropisomers via Pd/chiral

NBE* cooperative catalysis.⁴⁵On the basis of this chemistry, we envisioned a unique

axial-to-axial chirality transfer strategy for C–N axial chirality construction via a pre-

formed transient C–C axial chirality. As shown in Figure 1C, simple aryl iodide (1) is

used as the substrate, and readily available 2,6-disubstituted aryl bromide with a

tethered amide group (2) is utilized as both the arylating and terminating reagents.

The process of oxidative addition, chiral NBE* insertion, and C–H activation leads to

chiral aryl-NBE* palladacycle (ANP) complex A, which is then oxidized by aryl bro-

mide 2. The resulting Pd^IVcomplex subsequently undergoes reductive elimination

and b-carbon elimination to form the key intermediate: axially chiral Pd complex

B. Complex B eventually leads to the ﬁnal product phenanthridinone 3 via interme-

diate C, which involves the intramolecular amidation to afford the desired C–N

axially chiral phenanthridinone 3 alongside the chirality transfer from the C–C axis

(B and C) to the C–N axis (3). Although it is strategically promising, several chal-

lenges need to be addressed. First, the identiﬁcation of a suitable chiral NBE* medi-

ator to ensure both good reactivity and enantioselectivity is crucial. However, to

date, Pd/chiral NBE* cooperative catalysis has been rarely studied.^45–49Second,

the envisaged axial-to-axial chirality transfer should occur with high ﬁdelity to pre-

serve enantiopurity of the products. As we know, chirality transfer strategies, such

as central-to-central, central-to-axial, and axial-to-central transfer, have already

become excellent tools for the control of stereochemistry in asymmetric synthe-

sis.^50–53Surprisingly, axial-to-axial chirality transfer has been scarcely reported,

and the factors that control this unique process remain largely unexplored, which

we believe is owing to the innate dynamic nature of axial chirality.^54,55Therefore,

it is highly challenging yet encouraging to demonstrate the axial-to-axial chirality

transfer strategy in a general way. Lastly, the reaction has to be performed under

mild reaction conditions to avoid the potential racemization of C–N atropisomers

because of their conﬁgurational vulnerability.

RESULTS AND DISCUSSION

To test our hypothesis, we initiated our studies with a model reaction by using simple

2-iodotoluene (1a) and 2,6-disubstituted aryl bromide (2a) as the reactants (Figure 2).

To our delight, under the reported reaction conditions⁴⁵—Pd(OAc)₂as the catalyst,

(1S,4R)-2-ethyl-ester-substituted chiral NBE* (N^1*[99% ee]) as the chiral mediator,

and heating at 105^ꢀC—the desired C–N axially chiral phenanthridinone 3a was

indeed obtained with excellent yield (95%), albeit in only 24% ee. This preliminary

result indicates that our previous design is feasible. The low enantioselectivity of

3a was probably due to its low conﬁgurational stability at a high reaction tempera-

ture (105^ꢀC). After extensive optimization of the reaction parameters, including

lowering the reaction temperature to 70^ꢀC (see Table S1 for details), the desired

C–N axially chiral phenanthridinone 3a was afforded with excellent yield and enan-

tioselectivity (91% yield, 92% ee) under the optimal reaction conditions (Figure 2, en-

try 1). Control experiments were subsequently conducted to elucidate the role of

each component of the reaction conditions. Not surprisingly, the Pd catalyst, chiral

NBE* mediator, phosphine ligand, and base were all essential for this transformation

(entries 2–5). The use of PdCl₂instead of Pd(OAc)₂resulted in a dramatically

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Figure 2. Selected optimization of reaction conditions

^aAll reactions were performed on a 0.1 mmol scale.

^bGC yield with biphenyl as an internal standard.

^cDetermined by chiral HPLC analysis.

^dIsolated yield in parentheses.

^eMeCN (0.2 M), 48 h.

decreased yield and enantioselectivity (entry 6). Tri(2-furyl)phosphine (TFP) is a bet-

ter ligand than PPh₃in terms of both reaction efﬁciency and enantioselectivity (entry

7). When the methyl ester-substituted chiral NBE* (N^2*) was used instead of N^1*, the

yield of 3a dropped to 76% (entry 8). The C2-amide substituted NBE* (N^3*) proved to

be an inferior mediator in terms of both yield and stereoselectivity (entry 9). When

the stronger base Cs₂CO₃was used instead of K₂CO₃, the yield decreased dramat-

ically (entry 10). Besides MeCN, DMF was also a suitable solvent (entry 11). Notably,

the loading of N^1*could be reduced to 25 mol % without obvious erosion of the re-

action yield and enantioselectivity, although higher reaction concentration and

longer reaction time were required (entry 12).

With the optimal reaction conditions in hand, we ﬁrst set out to explore the reaction

scope of aryl iodides (1) (Figure 3). In principle, aryl iodides with different electronic

properties were all well tolerated, providing the desired axially chiral phenanthridi-

nones in moderate to high yields (42%–96%) and good enantioselectivities (87%–

98% ee) (Figure 3). A variety of ortho-substituents in aryl iodides were compatible,

such as ethyl (3b), tert-butyldimethylsilyl (TBS)-protected hydroxymethyl (3c), ester

(3d), phenyl (3e), ﬂuoro (3f), benzyloxy (3g), and methoxy (3h). Moreover, aryl iodides

bearing additional substituents at other positions were also examined, and it was

found that alkyl (3i and 3k), ﬂuoro (3l), chloro (3j), bromo (3m), ester (3n), and amide

(3o) groups at 3- or 4-positions were all amenable. In addition, bicyclic (3s–3u) and

polycyclic (3v) aryl iodides were also investigated, and they afforded the desired

products with excellent enantioselectivities (91%–96% ee). The use of densely func-

tionalized aryl iodide substrates led to penta-substituted aromatics (3w and 3x) with

moderate yields. Moreover, heteroaryl iodide 1y was also a suitable substrate to

deliver 3y in 50% yield and 96% ee. Remarkably, meta-substituted aryl iodides,

which used to be problematic substrates in Catellani-type arylation reactions,⁴⁴

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Figure 3. Substrate scope with respect to aryl iodides

All reactions were performed on a 0.1 mmol scale. Isolated yields are reported.

^a60^ꢀC for 45 h.

^b60^ꢀC for 60 h.

^c75^ꢀC for 30 h.

^d48 h.

^e24 h.

provided the mono C–H arylated products (3p–3r) with excellent regioselectivity and

stereocontrol.

Subsequently, the reaction scope of aryl bromides (2) was evaluated (Figure 4). Be-

sides the methyl group, the ortho-substitution of aryl bromides can be extended to

other functional groups, e.g., chloro (3A), nitro (3B), and naphthyl (3C), providing the

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Figure 4. Substrate scope with respect to aryl bromides

All reactions were performed on a 0.1 mmol scale. Isolated yields are reported.

^a24 h.

^b60^ꢀC.

^c60^ꢀC for 24 h.

^d48 h.

^e60 h.

^f75^ꢀC.

^g45^ꢀC for 72 h.

^h50^ꢀC for 72 h.

corresponding products with excellent yields and enantioselectivities (83%–97%

and 93%–98% ee). Modiﬁcations at the para-position of the aniline moiety of aryl

bromides (2) were well tolerated, including bromo (3D), phenyl (3E), aldehyde

(3F), alkenyl (3G), and alkynyl (3H). Notably, these functional groups can serve as

useful synthetic handles for further chemical manipulations. In addition, modiﬁca-

tions at the ortho-position of the aniline moiety were also investigated. In general,

sterically bulky aniline moieties were required for ensuring high ﬁdelity of the

axial-to-axial chirality transfer process. Switching one methyl of the tert-butyl group

to OTBS (3I), hydroxymethyl (3K–3M), or TBS-protected hydroxymethyl (3J)

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Figure 5. Observed ortho- and meta-substitution effects on the enantioselectivity and conﬁgurational stability of products and related DFT

calculation support

produced the corresponding axially chiral phenanthridinones with good to excellent

enantiocontrol. However, almost no enantioselectivities were observed when steri-

cally less hindered aniline moieties were introduced (3N–3P). Nevertheless, when

meta-substituted aryl iodides were used to react with these aryl bromides with a

less bulky aniline moiety, the mono C–H arylated products (3Q–3V) were obtained

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with excellent regioselectivities and enantioselectivities (90%–98% ee). Particularly

noteworthy is that the reaction also showed excellent chemoselectivity. When the ar-

ylation reagents contained two reactive C(sp²)–X sites, the reaction selectively

occurred at the C(sp²)–X bond adjacent to the electron-withdrawing amide group

(3D, 3U, and 3V). The absolute C–N axial conﬁguration of both 3h and 3C was unam-

biguously determined to be (R) by X-ray crystallographic analysis, and that of the

other products was assigned by analogy.

To understand the aforementioned interesting substituent effect on the rotation bar-

rier and conﬁgurational stability of C–N axial chirality, we performed density func-

tional theory (DFT) calculations (Figure 5A). Just as expected, reducing the size of

the ortho-substituent at aniline moiety led to a lower rotation barrier (3a versus

3aa). However, it was surprising to uncover that the meta-substitution at the aryl moi-

ety from aryl iodide (blue part) signiﬁcantly increased the rotation barrier of the cor-

responding C–N axis, as compared with that with the same substituent at the ortho-

position (3a⁰versus 3a, 3R versus 3R⁰, and 3Q versus 3Q⁰). We believe that this effect

is related to the ground-state distortion with an ortho-substituent. The DFT-opti-

mized structures of compounds 3Q and 3Q⁰are shown in Figure 5A. After the shift

of methyl substitution from the meta- to ortho-position, the steric repulsions be-

tween this ortho-methyl substituent and the aryl group of the aniline moiety obvi-

ously distorted the ground-state structure, which was reﬂected at the signiﬁcantly

increased dihedral angle (12.2^ꢀversus 20.8^ꢀ). This distortion destabilized the ground

state, leading to a decreased rotation barrier (33.0 versus 25.9 kcal/mol). These

interesting phenomena are consistent with the research by Kitagawa and co-

workers, who also observed a signiﬁcant decrease in the rotational barrier of C–N

chiral axis due to distortion.⁵⁶In addition, the rotation barrier of 3a was experimen-

tally measured (DG^s_exp), and a satisfying consistency was observed as compared

with the computational value (DG^s_calc) (DG^s

= 30.8 kcal/mol and DG^s

=

calc

exp

30.5 kcal/mol; see Figures S1 and S2 for details).

To further investigate the conﬁgurational stability of the products, we performed

racemization experiments (Figures 5B and 5C). First, we carefully monitored the

ee values during the experiments of heating a solution of 3a (92% ee) in MeCN at

different temperatures (Figure 5B). We found that the C–N axis of 3a with a

30.8 kcal/mol rotation barrier was stable only under 70^ꢀC, suggesting that these

C–N atropisomers should be prepared under mild reaction conditions to avoid race-

mization. In addition, removal of the TBS group of 3I (92% ee) with tetra-n-butylam-

monium ﬂuoride (TBAF) at room temperature provided the deprotected product 3N

with only 70% ee (Figure 5C; see Scheme S3 for details). Further heating 3N in

isopropyl alcohol at 70^ꢀC for 3 h led to a complete racemization. The calculated rota-

tion barrier of 3N was 26.7 kcal/mol, which was consistent with the experimental re-

sults. These experiments indicate that the sterically bulky substituent at the ortho-

position of aniline motif is essential to stabilizing the C–N axial conﬁguration.

Next, we focused on illustrating the synthetic utilities of this method. First, we per-

formed a scale-up experiment (3.0 mmol), which afforded 1.1 gram of the desired prod-

uct 3C without any erosion of the reaction efﬁciency and enantioselectivity, although a

longer reaction time was required (Figure 6A). It is worth mentioning that the loading of

N

^1*in this experiment was reduced to 25 mol % with 71% recovery after workup. Then,

aiming to assemble two stereogenic axes simultaneously, we performed an intriguing

double atroposelective process (Figure 6B). The reaction of diiodides 4,4⁰-diiodo-3,3⁰-

dimethyl-1,1⁰-biphenyl (1aa) and 1,5-diiodonaphthalene (1ab) with aryl bromide 2a

smoothly delivered the double C–H arylated products 3W and 3Y featuring two distal

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Figure 6. Synthetic applications

stereogenic C–N axes with excellent enantioselectivities.⁵⁷When 1aa was used as the

substrate, the single C–N coupling product 3X was also formed in 11% yield and 90%

ee. When 1ab was used, both 3Y and its meso-isomer 3Y’ were obtained in a 3:1 ratio.

Because the obtained C–N atropisomeric products are very useful intermediates, their

appealing synthetic applications were also demonstrated. For example, product 3V

could be readily coupled with arylboronic acids under very mild conditions⁵⁸without

any erosion of enantioselectivity (Figure 6C). The products (4a and 4b) uniquely pos-

sessing two vicinal C–N and C–C stereogenic axes were obtained with satisfactory

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Figure 7. DFT-computed free-energy changes of the catalytic cycle of Pd/chiral NBE*-catalyzed construction of C–N atropisomers via the

computational method of M06/6-311+G(d,p)-SDD-SMD(acetonitrile)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ

All free energies are in kcal/mol.

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diastereoselectivities (10–12:1 diastereomeric ratio [d.r.]). The absolute conﬁguration

of the newly formed C–C axis of 4a, dictated by the proximal chiral C–N axis through

an unconventional axial-to-axial diastereoinduction process, was assigned to be (S)

by nuclear Overhauser effect (NOE) spectroscopy experiments (see Figure S3 for de-

tails). The overall process constituted a serial axial-to-axial chirality transfer and axial-

to-axial stereoinduction event.⁵⁹Finally, a facile treatment of products 3L and 3M

with sodium tert-butoxide smoothly triggered an intramolecular esteriﬁcation to

deliver the 10- and 11-membered macrolactones embedded with a chiral C–N axis⁶⁰

(5 and 6) in 65% and 46% yields, respectively (Figure 6D).

To probe the reaction mechanism and the origins of enantioselectivity, we con-

ducted DFT calculations on the basis of the previous mechanistic studies on Cat-

ellani-type reactions.^61,62The free-energy changes of the operative catalytic cycle

are shown in Figure 7. From the bisligated Pd(0) species Cat, the oxidative addi-

tion of aryl iodide 1a occurred via TS8, generating the aryl Pd(II) intermediate 9.

Subsequent insertion of chiral NBE N^2*via TS11 produced the alkylated Pd(II) in-

termediate 12. Intermediate 12 underwent a base-assisted arene C–H bond activa-

tion via TS13, leading to ANP intermediate 14. From 14, the ligand exchange be-

tween aryl bromide 2a and phosphine ligand led to the intermediate 15, which

then underwent the secondary oxidative addition via TS16 to generate the

Pd(IV) intermediate 17. The subsequent reductive elimination produced the inter-

mediate 19 with C–C axial chirality between the two aryl fragments. From 19, the

b-carbon elimination through TS20 generated the intermediate 21 and released

the chiral NBE* N²*. 21 then underwent the base-assisted N–H deprotonation

via 22 to produce the amino Pd(II) intermediate 24, which eventually underwent

C–N reductive elimination via TS25 to produce the observed product 3a and re-

generated the active Pd(0) catalyst. The complete DFT-computed free-energy pro-

ﬁle is included in Figures S5 and S6. On the basis of our calculations, intermediate

12 was the on-cycle resting state. The rate-determining step was the C–C reductive

elimination via TS18, which compared with 12, required an overall barrier of

28.3 kcal/mol. The computations on alternative mechanistic considerations are

included in the supplemental information.

The overall enantioselectivity of a C–N atropisomer product is determined by a se-

ries of stereoselectivity-controlling steps, which are elaborated in Figure 8. Figure 8A

presents the DFT-computed free-energy changes of the catalytic cycle and the

chirality transfer process from chiral NBE* (N^2*) to the ﬁnal product 3a. From the

N

^2*-coordinated aryl Pd(II)iodide intermediate 10, the regioisomeric NBE* insertion

and subsequent C–H activation favor the formation of chiral ANP intermediate 14.

This selectivity is due to the intrinsic frontier orbital interaction between N^2*and

aryl Pd(II). In the alkene insertion, the ester-substituted oleﬁn acts as the electrophilic

component, and the aryl group of Pd(II) complex is the nucleophilic component. The

LUMO (lowest unoccupied molecular orbital) p* orbital of N^2*has a smaller distribu-

tion at the ester-substituted position, which leads to the intrinsic regioselectivity of

the alkene insertion at the other position (Figure S7). Through this regioselective

insertion step, the chirality transfers from N^2*to the ANP species 14 (the DFT-

computed free-energy changes of the competing formations of chiral cyclometal-

lated species [Figure S7] and a detailed discussion are included in the supplemental

information). From the chiral ANP 14, subsequent oxidative addition of aryl bromide

and reductive elimination generate a series of C–C atropisomeric intermediates.

This axial chirality control is dictated by the chirality induction of the chiral cyclome-

tallated fragment. As revealed in Figure 8B, TS18 is 8.5 kcal/mol more favorable than

TS34, which indicates a strong preference for the formation of (S)-axial chirality. In

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Figure 8. Origins of chirality transfer process

(A) DFT-computed free-energy changes of the catalytic cycle of Pd/chiral NBE*-catalyzed construction of C–N atropisomers and the chiral transfer

process. All free energies are in kcal/mol.

(B) DFT-optimized structures and the reason for formation of (S)-C–C axial chirality.

(C) DFT-optimized structures and the reason for formation of (R)-C–N axial chirality.

TS34, the aryl group from aryl bromide is proximal to the NBE* moiety, and the high-

lighted steric repulsions disfavor the subsequent C–C reductive elimination step of

this transition state. In contrast, such steric repulsions do not exist in TS18, and thus

the formation of intermediate 19 with (S)-axial chirality is favored (the DFT-computed

free-energy changes for the competing formation of C–C atropisomers [Figure S8]

and a detailed discussion are included in the supplemental information). Afterward,

the preformed C–C axial chirality controls the formation of C–N axial chirality of ﬁnal

product 3a through the irreversible C–N reductive elimination step. The competing

C–N reductive elimination transition states TS25 and TS39 are shown in Figure 8C.

The highlighted steric repulsions between the methyl group of the biaryl fragment

t

with C–C axial chirality and the Bu group of the amidyl fragment disfavor TS39,

which results in a 2.7 kcal/mol preference for the formation of (R)-C–N axial chirality

via TS25 (the DFT-computed free-energy changes for the competing formation of

C–N atropisomers [Figure S9] and a detailed discussion are included in the supple-

mental information).

These DFT calculations are in good agreement with the observed high level of axial-

to-axial chirality transfer experimental results and the determined absolute C–N

axial conﬁgurations by X-ray crystallographic analysis.

CONCLUSION

We have developed a modular and convergent method for atroposelective construc-

tion of C–N axial chirality through Pd/chiral NBE* cooperative catalysis. The strategy

involves a unique axial-to-axial chirality transfer process. The obtained C–N axial

chirality originates from the preformed transient C–C axial chirality with high ﬁdelity.

A wide range of C–N axially chiral phenanthridinones were obtained in good yields

and excellent enantioselectivities. Other features include readily available starting

materials, the ability to assemble two vicinal and remote stereogenic axes, high

step economy, and scalability. DFT calculations revealed the reaction mechanism

and the origins of high ﬁdelity of the axial-to-axial chirality transfer process, providing

broader implications for future studies in asymmetric synthesis.

EXPERIMENTAL PROCEDURES

Resource availability

Lead contact

Further information and requests for resources should be directed to and will be ful-

ﬁlled by the lead contact, Qianghui Zhou (qhzhou@whu.edu.cn).

Materials availability

All materials generated in this study are available from the lead contact without

restriction.

Data and code availability

The data of the X-ray crystallographic structures of 3h and 3C have been deposited

in the Cambridge Crystallographic Data Center under accession numbers CCDC:

1946140 and 2008632.

Chem 7, 1–16, July 8, 2021

13

Please cite this article in press as: Liu et al., An axial-to-axial chirality transfer strategy for atroposelective construction of C–N axial chirality, Chem

(2021), https://doi.org/10.1016/j.chempr.2021.04.005

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Methods

Full experimental procedures are provided in the supplemental information.

SUPPLEMENTAL INFORMATION

Supplemental information can be found online at https://doi.org/10.1016/j.chempr.

2021.04.005.

ACKNOWLEDGMENTS

We are grateful to the National Natural Science Foundation of China (21871213

and 22071189 to Q.Z., 21801193 to H.-G.C., and 21702182 and 21873081

to X.H.), the China Postdoctoral Science Foundation (2016M602339 to H.-G.C.

and 2018M642894 to Z.-S.L.), Fundamental Research Funds for the Central Univer-

sities (2020XZZX002-02 to X.H.), the State Key Laboratory of Clean Energy Utiliza-

tion (ZJUCEU2020007 to X.H.), and start-up funding from Wuhan University for

ﬁnancial support. Calculations were performed on the high-performance

computing system at the Zhejiang University Department of Chemistry. We thank

Prof. Wen-Bo Liu for sharing the instruments, Prof. Hengjiang Cong and Dr. Wei

Yan for X-ray crystallographic analysis assistance, and Ms. Lisha Li and Mr. Hua

Tang for technical assistance.

AUTHOR CONTRIBUTIONS

Q.Z. conceived the concept. Q.Z. and X.H. directed the project. Z.-S.L. made the

initial discovery, performed the optimization, and explored the substrate scope

and synthetic applications. Y.H., C.W., Y.M., J.C., and H.-G.C. conducted prepara-

tion of the starting materials and data analysis. P.-P.X. conducted the DFT calcula-

tions. Q.Z., X.H., Z.-S.L., and P.-P.X. wrote the paper with feedback from all other au-

thors. Z.-S.L. and P.-P.X. contributed equally to this work.

DECLARATION OF INTERESTS

Q.Z. and Z.-S.L. have ﬁled a provisional patent application (202110327590.9). All

other authors declare no competing interests.

Received: February 3, 2021

Revised: March 11, 2021

Accepted: April 9, 2021

Published: May 13, 2021

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