Atropisomerism in Styrene: Synthesis, Stability, and

68

J. Feng, Z. Gu ReviewSynOpen

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Atropisomerism in Styrene: Synthesis, Stability, and ApplicationsJia Fenga

Zhenhua Gu*a,b 0000-0001-8168-2012

a Department of Chemistry and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. of [email protected]

b Ocean College, Minjiang University, Fuzhou, Fujian 350108, P. R. of China

Corresponding AuthorZhenhua GuDepartment of Chemistry and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. of ChinaeMail [email protected]

Received: 25.01.2021Accepted after revision: 02.02.2021Published online: 10.03.2021DOI: 10.1055/s-0040-1706028; Art ID: so-2021-d0005-r

License terms:

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Abstract Atropisomeric styrenes are a class of optically active com-pounds, the chirality of which results from restricted rotation of theC(vinyl)–C(aryl) single bond. In comparison with biaryl atropisomers,the less rigid skeleton of styrenes usually leads them to have lower rota-tional barriers. Although it has been overlooked for a long time, scien-tists have paid attention to this class of unique molecules in recentyears and have developed many methods for the preparation of optical-ly active atropisomeric styrenes. In this article, we review the develop-ment of the concept of atropisomeric styrenes, along with their isola-tion, asymmetric synthesis, and synthetic applications.1 Introduction2 The Concept of Styrene Atropisomerism3 Early Research: Separation of Optically Active Styrenes4 Synthesis of Optically Active Styrenes5 Stability of the Chirality of Atropisomeric Styrenes6 Outlook

Key words atropisomers, styrene, axial chirality, asymmetric synthe-sis, asymmetric C–H functionalization

1 Introduction

Atropisomerism arises from restricted rotation around

a single bond as a result of the steric hindrance of adjacent

moieties, ring strain, or other structural factors. It is an im-

portant way for chiral molecules bearing no stereogenic

centers to demonstrate three-dimensional character. As

representative atropisomers, biaryls occur widely in bioac-

tive molecules, medicines, and materials science.1 Atropiso-

meric biaryls are also a prominent scaffold and have been

widely studied because of their stable chiral axis and diver-

gent applications in asymmetric synthesis. In contrast, at-

ropisomeric styrenes have been overlooked for a half centu-

ry as a result of the perceived ‘poor stability’ of the chiral

axis located in the Csp2–Csp2 bond between the vinyl and

aryl groups. This review summarizes the early studies of at-

ropisomeric styrenes, including their discovery, resolution,

and synthesis, as well as the recent developments in cata-

lytic asymmetric synthesis. Compounds showing signifi-

cant aromaticity, such as atropisomeric 4-aryl isoquinolin-

1(2H)-ones, are not discussed here because they are more

akin to biaryl atropisomers.2

2 The Concept of Styrene Atropisomerism

It is generally accepted that the stability of biaryl axial

chirality originates from the characteristics of the axis and

the steric hindrance of groups adjacent to the axis. For sty-

rene derivatives, prevention of free rotation around the axis

connecting the vinyl and aryl groups is much harder and

needs more sterically hindered substituents. It is clear that

styrenes are generally less rigid than biaryls, resulting in

the rotational barriers of styrenes being lower than the cor-

responding barriers of biaryls. As early as 1928, Hyde and

Adams3 stated that ‘The molecules (1) would undoubtedly be

less rigid, but if the free rotation around the bond joining the

unsaturated linkage to the substituted ring is prevented, any

position of the olefin or carbonyl group and the unsubstituted

ring in space should give an asymmetric molecule.’ This was

the first time that chemists predicted the possibility of axial

chirality existing in styrene compounds.

© 2021. The Author(s). SynOpen 2021, 5, 68–85Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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3 Early Research: Separation of Optically Active Styrenes

In 1930, the attempt of Maxwell and Adams4 to separate

the enantiomers of styrenes 2, 3, and 4 by resolution ended

with failure (Scheme 1), with the low steric bulk of the -

hydrogen atom of the styrene accounting for the unaccom-

plished separation. In 1938, Mills and Dazeley5 succeeded

in synthesizing racemic o-(,-dimethyl--isopropylvinyl)-

phenyltrimethyl ammonium iodide (5) and resolving its

isomers, which verified the original postulate about the

possibility of stable atropisomerim in styrenes. On replac-

ing the methyl group (with Z-geometry to the aryl ring)

with a hydrogen atom to form 6, no enantiomers could be

separated.

In 1940, Miller and Adams6 completed the synthesis of a

more sterically hindered styrene, -chloro--(2,4,6-

trimethyl-3-bromophenyl)--methylacrylic acid (7), and its

enantiomers were successfully resolved. With a chlorine

atom at the -position of the styrene and a methyl group

adjacent to the axis, compound 7 demonstrated excellent

stability, displaying no decrease in enantiopurity on heat-

ing to reflux in ethanol for 15 h or in glacial acetic acid for

12 h. Bromination of 7 afforded the optically inactive sym-

metric compound 8. In contrast, the installation of a sulfo-

nyl group on 7 gave the optically active compound 9. Later,

Adams and co-workers carried out further research into the

relevance between structure and atropisomeric stability in

styrenes.6,7

Notable retention of partial chirality was observed by

Fuji and co-workers in the alkylation reaction of 10 with a

carbon stereogenic center at the -position of a carbonyl

group in 1991.8 It seemed that the size of the electrophile

did not affect the enantioselectivity (Scheme 2, table). The

authors carried out rapid HPLC analysis of byproduct 12,

which gave a 65% enantiomeric excess (ee) value. The con-

trol experiment indicated that alkylation would form atro-

pisomeric enolate INT-1, which could be attacked by the

electrophile to afford the C-alkylation product 11 and O-al-

kylation product 12 with moderate ee values (Scheme 2,

bottom).

Scheme 1 Atropisomeric styrenes in early studies

R4

R3

R5

R2R1

1

HMe

CO2H

O2N Me

NO2MeMe

HMe

Me

Me Me

NH2

Me

HMe

CO2H

Br Br

NH2

Br

2 3 4

iPrMe

Me

NMe3

I

5

EtH

Me

NMe3

I

6

ClCO2H

Me

Me Me

BrMe

7

ClCO2H

Me

Me Me

Br

Me

8

Br

ClCO2H

Me

Me Me

Br

Me

9

ClO2S

β

Biographical Sketches

Jia Feng received his Bachelor’sdegree from Shandong Univer-sity (P. R. of China) and his PhDfrom the University of Scienceand Technology of China (P. R.

of China) under the supervisionof Professor Zhenhua Gu in2018. He is now a postdoctoralresearcher in the same group.His research interests include

the construction of atropiso-meric molecules via novel meth-odology and the asymmetricsynthesis of bioactive mole-cules.

Zhenhua Gu studied chemis-try at Nanjing University in2002, and then he pursued hisPhD studies with ProfessorShengming Ma at the ShanghaiInstitute of Organic Chemistry(P. R. of China). He conductedpostdoctoral research at the

University of California Berkeley(USA) with Professor K. P. C.Vollhardt and the University ofCalifornia at Santa Barbara(USA) with Professor A. Zakarian.In 2012, he began his indepen-dent academic career at theUniversity of Science and Tech-

nology of China (P. R. of China).Research in his group mainly fo-cuses on the development ofnew methods for asymmetricsynthesis, particularly for atrop-isomers and related naturalproducts.

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Scheme 2 Enantioselective alkylation via an intermediate atropisoeno-late

In 2016, Clayden and co-workers9 synthesized a series

of 1-aryl-3,4-dihydroisoquinolines 13, which are structural

analogs of styrene featuring a potentially atropoisomerical-

ly stable axis. They studied the stabilities by calculation of

the rotational barrier energies. The data given in Figure 1

show that the stability increased as the size of the adjacent

substituted moiety X increased (13a–13f). Nevertheless,

the half-life of iodide 13d was too short to separate the en-

antiomers at ambient temperature.

Figure 1 Substituent effect on the stability of 1-aryl-3,4-dihydroiso-quinolines

4 Synthesis of Optically Active Styrenes

Given the unique scaffolds of atropisomeric styrenes

and their important applications in bioactive molecules and

medicines, many approaches to access enantioselective sty-

renes have been developed during recent decades. In early

studies, atropisomeric chirality was constructed from point

chirality via chirality transfer. The optically active styrenes

could be separated as single distereomers with the aid of

chiral auxiliaries. Of all approaches, catalytic asymmetric

synthesis comes to the fore because of its high efficiency

and divergent functional-group tolerance. Recently, transi-

tion-metal-catalyzed cross-couplings, including C–H func-

tionalization in a step- and atom-economic manner, have

become a powerful method for the preparation of atropoac-

tive styrenes. Furthermore, organo-catalyzed electrophilic

addition of vinylidene ortho-quinone methide type inter-

mediates is also an attractive approach.

4.1 Chirality Transfer Strategy

In 2001, Miyano, Hattori, and co-workers10 reported the

synthesis of tertiary alcohol (R,R)-16, which was derived

from the 1,2-addition of (R)-14 and 15. Compound 16 was

stereospecifically transformed into atropisomeric (R)-17

with up to 95% ee on treatment with (CF3CO)2O in dichloro-

methane at room temperature (Scheme 3). Interestingly,

the authors found that there was an equilibrium between

conformational isomers 16a and 16b observable from the1H NMR spectrum. The ratio was 1:5.7 in CDCl3 but ranged

from 1:1 to 1:6.3 depending on the solvent. The chirality

transfer from point to axial chirality can be assumed to oc-

cur because of the much lower conversion rate from 16a

into (R)-17 than the rate from 16b into (S)-17.

Scheme 3 Synthesis of atroposelective styrenes via chirality transfer

4.2 Chiral Auxiliary Strategy

With the assistance of chiral auxiliaries, chiral atropiso-

meric styrenes can be synthesized in a diastereoselective

manner. Subsequent removal of the auxiliary affords the at-

ropisomeric styrenes. In 1996, Baker et al.11 disclosed a

point to axial chirality transfer via a formal 1,3-hydrogen

shift (Scheme 4). Reaction of (1R)-menthyl (R)-(1-p-tolyl-

sulfinyl)-naphthalene-2-carboxylate (18) with indenyllithi-

um delivered major product 19 in 88% yield and with 59%

diastereoselectivity, together with minor products 20 and

21 in a combined yield of 9% with a ratio of 1:1. Esters 20

and 21, with relatively stable axial chirality, were separated

by preparative HPLC. The half-life of interconversion be-

tween 20 and 21 was about 25 h in solution at 25 °C. Treat-

ment of isomer 19a (99% de) with an excess of LiAlH4 af-

forded carbinol ent-22 in quantitative yield with 98% ee. A

control experiment was performed by quenching the reac-

tion with DCl in D2O within 5 mins and gave ent-22 with

OMeO

Ph

OEt

OEt

BaseOM

MeO

Ph

OEt

OEt

Electrophile

OE

Ph

OEt

OEt

MeO

10 (93% ee) 11

Entry

1234

Electrophile

MeIEtI

PhCH2BrCH2=CHCH2Br

Yield/%

48273136

ee/%

66656748

Control experiment:

10 (93% ee)Standard conditions

11 (48%, 66% ee) + OEt

OEt

Ph

MeOOMe

12 (15%, 65% ee)

INT-1

N

X

Compound X ΔG (kJ mol–1) t1/2

13a13b13c13d13e13f

HClBrI

OTfP(O)Ph2

54.7<9092.981.9

103.1>>100

<5 min15 min<1 min36 d

>25 d13

10–4 s

OMe +

MgBrOMe Yb(OTf)3, THF, r.t.

Me

(CF3CO)2O, CH2Cl2, r.t.

OH

MeO

OH OMe

(R)-14 15 (R,R)-16

(R,R)-16

(R)-17

16a 16b1:5.7 (in CDCl3)

94%, 95% ee

H

Me

H

Me

OMe

OHMe

OMe

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89% deuterium incorporation. The authors proposed that

the reduction of 19a with the S-conformation at C-1′ gave

ent-22-d via INT-2, on the basis of this labeling experiment.

Diastereoselective synthesis of axial styrenes with the

aid of a chiral sulfoxide auxiliary was applied successfully

to the stereospecific synthesis of the antibiotic TAN-1085

(23). Suzuki and co-workers12 reported an asymmetric syn-

thesis of 23 through a stereochemical relay strategy featur-

ing a three-step conversion of chirality: central to axial

(step A), axial to axial (step B), and axial to central (step C)

(Scheme 5). Suzuki–Miyaura coupling of boronic acid 24

and vinyl iodide 25 containing the chiral sulfoxide auxiliary

and subsequent silylation and mono-deprotection of the

phenol afforded atropisomeric styrenes 27a and 27b with a

diastereoselective ratio of 25:75. Conformation 27b was fa-

vored over 27a by the formation of an intramolecular hy-

drogen bond. Product 27b was separated by flash chroma-

tography on silica gel, and subsequent benzylation gave 28

in more than 99% ee, which could be enantioselectively

converted into TAN-1085 in a few steps.

Meanwhile, the same group13 realized an asymmetric

synthesis of atropisomeric styrenes bearing two axial axes

via a similar strategy (Scheme 6). Treatment of vinyl iodide

30, featuring a chiral sulfoxide auxiliary, with aryl boric

acid 29 furnished atropisomeric styrene 31 as one diaste-

reomer. After a two-step transformation, 32, bearing two

terminal alkenes, was prepared from 31 and could be selec-

tively converted into planar chiral cyclophane 33. In a simi-

lar procedure, planar chiral cyclophanes 34 and 35, also

with the ansa-chain, were readily accessed. The atropiso-

meric vinyl arene structure also possibly exists in ring-

strained macrobiaryl alkenes.14

4.3 Catalytic Asymmetric Synthesis of Atropiso-meric Styrenes

Benefiting from the rapid development of transition-

metal-catalyzed cross-coupling reactions, many novel and

efficient approaches to access atropisomeric styrenes have

been developed. These strategies include the cross-coupling

of aryl halides and hydrazones, Suzuki–Miyaura cross-cou-

plings, and cross--coupling reactions via C–H activation.

Scheme 4 Point to axial chirality transfer strategy

SO

CO2R*

R* = (1R)-menthyl

IndenyllithiumTHF, 0 °C

CO2R*H + +

RR

18 19 20 R = CO2R* 21 R = CO2R*

22 R = CH2OH

LiAlH4Et2O0 °C ent-22 R = CH2OH

CO2R*H

R* = (1R)-menthyl

LiAlH4, Et2O, 0 °CO

AlL2

_

2 mol L–1 DCl in D2O

CH2OH

DH

ent-22-dINT-219a

ratio of 20:21 = 1:1

Scheme 5 Asymmetric synthesis of TAN-1085 (23)

HOOHO

O OOH

OH

O

OH

TAN-1085 (23)

OS

R

X

..O

SR

X

Step A

B

A

B

AY

CHO

A

OHOH

Y

Step B

Step C

central axial (+ central)

axial central

Stereochemical relay stragety:

B O

OMOM

MOMO

HO

O Sp-Tol ..

I

OTBS

O Sp-Tol ..

OTBS

MOMOOTBDPS

OMOM

O Sp-Tol ..

OTBS

OOTBDPS

OMOM

H

p-Tol S

.. O

OTBS

HOOTBDPS

OMOM

24

25

26 (d.r. 38:62)inseperable

27a27b

27a/27b= 25:75

[Pd(PPh3)]4K3PO4, DME/H2O

+

then tBuPh2SiClimidazole, DMF

SnBr2, toluene

NaH, BnBr

DMF

O Sp-Tol ..

OTBS

BnOOTBDPS

OMOM

28

TAN-1085 (23)steps

90%, >99% ee, d.r. >99:1

..

I

SynOpen 2021, 5, 68–85

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It is anticipated that, when styrene structures have the

vinyl unit as part of a five- or six-membered ring fused to

another aromatic ring, the atropisomerism of these com-

pounds may be more stable than that of acyclic styrenes.

For example, dihydro-binaphthalenes and 1-(1H-inden-3-

yl)naphthalene are supposed to have higher rotational bar-

riers than vinyl naphthalenes.

4.3.1 Palladium-Catalyzed Cross-Coupling of Aryl Halides And Hydrazones

In view of the importance of the axial chirality in sty-

renes, in 2016, Gu and co-workers15 developed the first cat-

alytic asymmetric synthesis of styrene-type atropisomers

(Scheme 7). The protocol with aryl halides 36 and hydra-

zones 37 as standard substrates delivered dihydro-binaph-

thalenes 38 in up to 99% yield with up to 97% ee. The reac-

tion exhibited a broad functional-group tolerance. In the

proposed mechanism, the oxidative insertion of Pd(0) into

36 gives INT-3, which coordinates with the in situ generat-

ed carbene species derived from hydrazone 37 with the aid

of tBuOLi. The newly formed palladium carbene species

INT-4 undergoes migration/insertion reactions to produce

INT-5, which affords the final product via reductive elimi-

nation and liberation of the Pd(0) catalyst. The chiral

styrene was readily oxidized to the atropisomeric biaryl

Scheme 6 Synthesis of atropisomeric styrenes with a chiral sulfide auxiliary

B(OH)2(HO)2B

OMOM

MOMO

O Sp-Tol ..

I

H

MeO OMe

[Pd(PPh3)4] (30 mol%)

CH(OMe)2

S

CH(OMe)2

Sp-Tol OO p-Tol

OR

RO.. .. SSp-Tol OO p-Tol

O

O.. ..

H

H

SSp-Tol OO p-Tol

O

O.. ..

H

HSS

p-Tol OO p-Tol

O

O.. ..

H

H

OH

HOSp-Tol O

.. SO p-Tol

..

29

30 31 32

33 34, E/Z 11:1 35

K3PO4DME/H2O

Scheme 7 Carbene strategy for the synthesis of atropisomeric styrenes

PBr O

ArAr

NNHTs

+P

O

ArAr

Pd(OAc)2 (10 mol%)39 (20 mol%)

tBuOLi (2.5 equiv)R1 R2

R3 R3

R3 R3

R2

R11,4-dioxane, 50 °C

O

O OP

OAr' Ar'

Ar' Ar'

N

Ar' = 4-FC6H4

39:

up to 99% yieldup to 97% ee

Application as a chiral ligand:

Ph Ph

OAc

NH

CO2Et

[{Pd(allyl)Cl}2], 40Cs2CO3, CH2Cl2, 40 °C

Ph Ph

N CO2Et

PO

PhPh

P PhPh

38a, 99% ee 40, 95%, 99% ee

(COCl)2, CH2Cl2, r.t.then LiAlH4, THF, 0 °C

36 37 38

Pd0L2

PdBrL2

PO

PhPh

37a

tBuOLi

N2 PdBrL2

PO

Ph Ph

PdPO

PhPh

BrL

N2

migration/insertion

INT-3

INT-4

INT-5

36a 38a

+88%, 83% ee

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compound without erosion of enantiopurity. Moreover, the

P(V) compound 38a was uneventfully reduced to phosphine

40, which was successfully applied in an asymmetric allyla-

tion reaction as an (alkene, phosphine) bidentate ligand.

In further related studies, Wu et al.16 employed P-ste-

reogenic bidentate phosphine ligand 44 in the asymmetric

synthesis of atropisomeric vinyl arenes with excellent ste-

reocontrol (Scheme 8). In this report, dialkyl phosphonates

41 were compatible substrates, delivering atropisomeric vi-

nyl arenes 43 with good yields and enantioselectivities. The

protocol was successfully applied to the synthesis of atrop-

isomeric compound 43b containing an indene skeleton

(86% ee). For product 43c, with a seven-membered ring, the

racemic product was observed. Diphenyl phosphine oxide

38a was synthesized in 75% yield with 87% ee, which is

slightly lower than the results of Gu and co-workers. The

utility was demonstrated by a gram-scale synthesis of 43e

without loss of enantioselectivity. The merit of this work is

that dimethyl phosphonate 43a could be further converted

into dimethyl phosphine oxide 45 with methyl magnesium

bromide.

4.3.2 Suzuki–Miyaura Cross-Coupling for Synthesis of 2-Aryl Cyclohex-2-Enone Atropisomers

In 2017, Gu and co-workers17 disclosed an asymmetric

synthesis of 2-aryl cyclohex-2-enone atropisomers 48 via

Suzuki–Miyaura coupling of 2-iodo-3-methylcyclohex-2-

enones 46 and aryl boronic acids (Scheme 9). BoPhoz 49 ex-

hibited superior stereocontrol over other types of ligand.

The advantage of this strategy is that the ,-unsaturated

ketone displays diverse reactivity in its downstream trans-

formations. Thus, the final products bearing axial chirality,

known as ‘platform molecules,’ could be diversely convert-

ed into atropisomeric biaryls. For example, 48a was oxi-

dized into quinone 50 with TBHP in presence of [Co(acac)2].

Furthermore, 48a underwent aromatization with NBS and a

catalytic amount of BPO to deliver phenol 51, without loss

of axial integrity. After a three-step transformation, involv-

ing oxime formation, reduction, and aromatization, -ami-

no atropisomeric biaryl 52 was prepared efficiently. A ben-

zyl group could be installed at the -position in 53 by an al-

dol reaction followed by oxidation. Notably, aryl iodide 54

could also be accessed in 75% yield over three steps via con-

densation with hydrazide followed by iodization and aro-

matization.

4.3.4 C–H Activation for the Synthesis of Atroposelec-tive Vinyl Arenes

The last twenty years have witnessed important devel-

opments in C–H activation strategies in organic synthe-

sis.1c,18 Several approaches based on C–H activation have

been developed for the construction of atropisomeric sty-

renes.

In 2018, Gu and co-workers19 developed a visible-light-

accelerated stereospecific C–H arylation for the preparation

of tetrasubstituted atropisomeric vinyl arenes. The reaction

was based on their previously synthesized atropisomeric

vinyl arene 38, which reacted with diaryliodonium salts to

give 56 without loss of enantiopurity (Scheme 10). A radi-

cal pathway was proposed on the basis of control experi-

ments and DFT calculations. A diaryl iodine cation can be

formed from diaryliodonium salts under standard condi-

tions, which can lead to iodobenzene cationic radical INT-6

and phenyl radical INT-7 under irradiation. Radical addition

to 38, followed by association with the palladium catalyst

and -H elimination give the final product. Kinetic studies

showed that the kinetic isotope effect value changed from

3.6 in the absence of light to 1.1 on irradiation with visible

light, which indicated that the C–H functionalization step

was the rate-determining step in the absence of irradiation

with visible light.

Based on the -aryl-,-cyclohexenone skeleton, Cui,

Xu, and co-workers20 reported an asymmetric oxime-

directed C–H olefination reaction in 2018 (Scheme 11). Un-

der Pd(OAc)2 catalysis, Ac-L-Ala-OH and 2-aryl cyclohex-2-

enone oxime ethers 57 were smoothly converted into atro-

pisomeric vinyl arenes 58 with excellent enantioselectivity.

One of the two C–C double bonds in 58a could be selectively

reduced to give 59 via Pd/C catalysis under an atmosphere

of hydrogen. After acting as a temporary directing group,

the oxime ether group could be removed to release the

Scheme 8 Palladium-catalyzed atropisomeric styrene synthesis with aryl halides and carbene precursors

PBr O

OROR

NNHTs

+PO

OROR

Pd(OAc)2 (10 mol%)44 (10 mol%)

tBuOLi (3.0 equiv)R1

R1

1,4-dioxane, 50 °C

44

41 42 43

P

O

P

O

OMeOMe tBu tBu

PO

OMeOMe

43a65%, 88% ee

PO

OEtOEt

43b62%, 86% ee

PO

OEtOEt

PO

PhPh

43d75%, 87% ee

43c66%, racemic

selected examples:

PBr O

OEtOEt

+

NNHTsStandard conditions

PO

OEtOEt

2.50 g scale

43e, 77%, 86% ee

PO

OMeOMe

43a88% ee

P

O

MeMe

4573%, 89% ee

n = 1,2

( )n

( )n

MeMgBr

41a 42a

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ketone group with HCl. Diaryl phosphine 61 was achieved

by treating 58b with diphenyl phosphorus chloride; the

product was subjected to asymmetric allylation to provide

62 in moderate yield with 37% ee.

In 2019, Liu, Mao, and co-workers21 developed a car-

bopalladation and C–H olefination for the asymmetric syn-

thesis of atropisomeric styrenes (Scheme 12). Treatment of

alkyne 63 with naphthyl iodide 64 afforded atropoactive

styrene 65 featuring an oxindole scaffold with moderate

enantioselectivity. In this reaction, the TADDOL-derived

phosphoramidite ligand 66 displayed the best stereoinduc-

tion. A mechanism involving intramolecular C–H activation

was proposed. The atroposelective insertion of the C≡C tri-

ple bond of 63 into INT-12 gave INT-13, which was regard-

ed as the key intermediate for stereoinduction. An intramo-

lecular C–H palladation of INT-13 formed palladacycle INT-

14, which delivered final product 65 and liberated Pd(0) af-

ter reductive elimination.

By using the concept of transient chiral auxiliaries, Shi

and co-workers22 realized a palladium-catalyzed asymmet-

ric olefination of styrene 67 in 2020 (Scheme 13). Chiral

amino amide 70 was chosen as the optical transient chiral

auxiliary, and atropisomeric styrenes 69 were synthesized

with good yields and high stereoselectivity (up to 99% ee).

Palladacycle complex 72 was prepared by treating 71, fea-

turing an imine moiety, with stoichiometric Pd(OAc)2 in

35% yield. The structure of palladium complex 72 was con-

firmed by single-crystal X-ray diffraction analysis. The ap-

plication of 72 instead of Pd(OAc)2/70 to the asymmetric C–H

olefination reaction under the standard conditions gave op-

tically active 69a with 80% ee, which indicated the possibil-

ity of an in situ formed amino amide transient directing

group. The utility of the products was demonstrated by em-

ploying the corresponding ,-unsaturated chiral carboxyl-

ic acids (CCAs) as chiral ligands for the enantioselective

Scheme 9 Divergent syntheses from atropisomeric styrenes

Me O

R1

I

+R2

BO

R

R3

[Pd(acac)2] (5 mol%)49 (7.5 mol%)

KOH, DCE/H2O (1:1)65 °C

OMeR2 O

R

R1

R3

B = B(OH)2 or B(pin)

FePPh2

NP Ph

Ph

Et

46 4748 49

OMeOMe

48a, 99% eeplatform molecule

[Co(acac)2]TBHP, acetone

58%, 98% ee

OMeOMe

50

O

BPO (10 mol%)NBS, CCl4,

94%, 99% ee

OHMeOMe

51

NHCO2MeMeOMe

52

1) NH2O

H HCl, NaOAc

2) Fe, C

lCO2Me, T

HF

3) DDQ, T

HF, r.t.

59%, 99% ee

NaH, PhCHO84%, 94% ee

OHMeOMe

53

Ph

1) N2H

4 H2O, MeOH

2) I2 , TEA, 0 °C to r.t.

3) DDQ, dioxane

75%, 99% ee

IMeOMe

54

divergent synthesis from 48:

Scheme 10 Visible-light-mediated C–H arylation

Ar+

Pd(OAc)2 (5 mol%)PPh3 (5 mol%), NaHCO3

DCE, visible lightHP(O)Ar'2 P(O)Ar'2

INT-10

PhPdIV PdX X

L

L'

INT-9

PhPdIII

[Ph2IOTf]*

PhI+

Ph

visible light

INT-6

INT-7

INT-8

Ph-I

Ar Ar

Ar

38

INT-11

Ph

Ar

base

56

Ph

H/DP(O)Ph2

PhP(O)Ph2

standardconditions

1.05–1.14

Off 3.6

substrate light kH/kD

On38a or 38a-d

38a or 38a-d

38 56

38a/38a-d 56a

Ar2IOTf

R R

55

PhI

PhOTf

+PdII

SynOpen 2021, 5, 68–85

75


Csp3–H amidation of thioamides. In comparison with biaryl

acid 75, the styrene-based acid 74 derived from 69 gave an

improved enantioselectivity (from 42% ee to 64% ee).

Later, the same group23 disclosed the asymmetric syn-

thesis of atropisomeric styrenes via C–H alkenylation by us-

ing a 2-pyridyl moiety as a directing group (Scheme 14).

The starting material 76 could ‘freely’ rotate around the vi-

nyl–arene axis under the reaction conditions. The pyridine

nitrogen atom could coordinate with palladium and the

readily available L-pyroglutamic acid to form INT-15.

Through good cooperation of the directing group and chiral

ligand, modulation of the reactivity and induction of the

stereoselectivity were achieved to give atropisomeric prod-

ucts 77 with good yields and enantioselectivity. The gener-

ality of substrate scope was investigated with different sub-

stituted styrenes. The reaction with alkynyl bromide was

also successful, giving the coupling products with very high

enantiopurity.

Scheme 11 Palladium-catalyzed C–H olefination with oxime ether as a directing group

NOMe

R1

R2 H+ R3

Pd(OAc)2 (10 mol%)Ac-L-Ala-OH (20 mol%)

AgOAc, MeOH NOMe

R1

R2 R3

O

AcHN OH

Ac-L-Ala-OH

24 examplesup to 88% yieldup to 99% ee

NOMe

Me

CO2Et

Pd/C (5 mol%)H2 (balloon)

MeOHN

OMeMe

CO2Et

NOMe

MeHO CO2Et

Ph2PClEt3N, THF N

OMeMe

Ph2PO CO2Et Ph

OAc

Ph

CO2MeMeO2C

+

[Pd(allyl)Cl]2 (2 mol%)61 (5 mol%), BSACsOAc, toluene

Ph Ph

MeO2C CO2Me

60%, 37% ee

55%, 97% ee

52%, 97% ee

99% ee

96% ee

NOMe

MeCO2Et HCl, dioxane

OMeCO2Et

56%, 99% ee99% ee

57 58

58a 59 58a 60

58b 61 62

Scheme 12 Double functionalization of an alkyne

NR

O

H

Ar2

Ar1

+

IOMe

Pd(OAc)2 (10 mol%)66 (20 mol%)

Cs2CO3, toluene

NO

R

Ar2

Ar1

OMe

O

O OP

OPh Ph

Ph Ph

N O

66

[Pd0]

[PdII]OMe

O

OMe[PdII]

NR

O

OMe[PdII]

NR

INT-12

63 64 65

63

64

INT-13

INT-14

65

up to 67% ee

I

SynOpen 2021, 5, 68–85

76


Scheme 14 Pyridine-group-directed asymmetric C–H functionalization

Very recently, Wang and co-workers24 reported a C–H

olefination and arylation for the asymmetric synthesis of

atropisomeric styrenes by utilizing a carboxylic acid direc-

tion strategy (Scheme 15). The protocol demonstrated a

broad substrate scope, high yields, and excellent stereose-

lectivity (up to 99% ee). Notably, the absolute configuration

of the products was the opposite configuration to the prod-

ucts of Shi and co-workers, despite Boc-L-leucine and 70

being derived from the same amino acid, L-leucine. The au-

thors explained these observations by proposing two differ-

ent models for the stereoinduction. In TS-1, the bulky alkyl

chain of the amino acid points upward and pushes the alke-

nyl group away from the palladium. However, in TS-2, the

upward tBu group forces the alkenyl group downward,

which leads to the opposite configuration. The utility of

these CCAs was further demonstrated by two

Cp*Co(CH3CN)3[SbF6]2/CCA-catalyzed asymmetric C–H

functionalization reactions.

4.4 Atropisomeric Synthesis of Styrenes Prompted by Nucleophilic Addition

In 2017, Tan and co-workers25 reported an organocata-

lyzed atroposelective synthesis of atropisomeric styrenes

by means of nucleophilic addition to propanal derivatives

(Scheme 16). In the presence of chiral pyrrole 83, alkynal 81

was activated by forming INT-16, which underwent nucleo-

philic attack to generate INT-17 stereoselectively. Isomeri-

zation of INT-17 gave iminium ion INT-18, which could be

converted into final product 82 by hydrolysis. With regard

to substrate scope, styrenes bearing an iodine and sul-

fophenyl group (82a, 82b) could be tolerated, but installa-

tion of a methyl group at the -position of the axis greatly

decreased the stereoselectivity to 54% ee (82c). A nucleo-

phile containing an allyl moiety was also compatible (82d).

Scheme 13 C–H olefination strategy

CHO

H + R

CHO

R


H2N

O

NtBu2

Pd(OAc)2 (10 mol%), 70 (30 mol%)(BnO)2PO2H (50 mol%) Co(OAc)2.4H2O, BQ, O2

70:

rac-67 68

N

S

MePh

+NO

O

Ph

O

[Cp*Co(MeCN)3][SbF6]2 (5 mol%)CCA (10 mol%), o-DCB

N

S

Me

Ph

NHCOPh

H

CO2HPhiPr Ph iPr Ph

CO2H

74, 73%, 64% ee 75, 78%, 42% ee

Ph NNEt2

O

Me

HPd(OAc)2 (1 equiv)AcOD-d1 (0.2 M)

Ph NNEt2

O

Me

PdOAc

71 72, 35% yield

Ph

Me

CHO Ph

Me

CHO

CO2nBu

69a, 88%, 80% ee

72 instead of Pd(OAc)2/70standard conditions

69

67a

73

HOAc /DMSO (10:1)

40 °C, 1 h

MS 13X, 40 °C, 24 h

Biaryl-type CCA

VS

Styrene-type CCA

DGR3

R2

R1H

Pd(OAc)2 (10 mol%)L-pGlu-OH (20 mol%)

Ag3PO4, MeCN/tBuOH (4:1) N R2

R3

R1

PdN

OO

OH

DGR3

R2

R1FGFG

DG = 2-pyridylFG = alkenyl, alkynyl

NHO

CO2H

L-pGlu-OH

nPr

nPr

MeN

BuO2C

77a, 95%, 93% ee

MeN

BuO2C

77b, 87%, 95% ee

Me

Me

MeNTIPS

77c, 86%, 99% ee

MeNTIPS

77d, 54%, 97% ee

76 77INT-15

SynOpen 2021, 5, 68–85

77


In 2018, Yan and co-workers26 described an enantio-

selective synthesis of sulfone-containing atropisomeric sty-

renes with the cooperation of quinine-derived thiourea 86

and L-proline (Scheme 17). A series of enantioenriched sty-

renes 85 was prepared with good enantioselectivity and ex-

cellent E/Z selectivity by treating 1-alkynyl-naphthalen-2-

ols 84 with sodium sulfinates. Based on control experi-

ments and DFT calculations, a vinylidene o-quinone

methide (VQM) was proposed as the key intermediate,

which significantly influenced the subsequent series of

studies in this area. VQM intermediate INT-19 bears an at-

ropisomeric allenyl moiety, which is critical for the high en-

antioselectivity in subsequent reactions. The activated sul-

finate anion derived from the combination of L-proline and

sodium sulfinate would act as a nucleophile to attack INT-

19, forming final product 85a. The role of boric acid was

probably to release L-proline from the complex for the next

catalytic cycle.

Scheme 17 Synthesis of atropisomeric styrenes via VQMs

Scheme 15 Asymmetric C–H olefination and arylation with a carboxyl-ic acid directing group

PhCO2Me

Ph OH

O ArBpinPd(OAC)2

Boc-L-leucine

Ag2CO3, BQ, KHCO3H2O, tAmylOH, air

R1 R2R1

Pd(OAc)2Boc-L-leucine

KOH, H2O, iPrOH1 atm O2

R3

PhCO2Me

R1

R3

PhCO2Me

Me

CO2Me

7879 80

80a57%, 94% ee

PhCO2Me

79a97%, 97% ee

CO2MePh

CO2Me

79b68%, 90% ee

Me CO2Me

then methylationthen methylation

N

O

O Pd O OKH

PhtBu

R'O

H

TS-1 TS-2

N

Et2NO Pd

O

O

H

tBu

Ph

PhCOOH

R FGPh

CHO

R FG

opposite absolute configurations

Wang's product(s) Shi's product(s)

Scheme 16 Chiral pyrrole-catalyzed synthesis of chiral styrenes

R1

H

O

+

Ac Ac

R2

83 (5 mol%)LiOAc, CH2Cl2

Nu

NuCHO

R1

NH

Ar

OTIPS

Ar

83, Ar = 3,5-Me2C6H3

NH

R3

R1

H

N R3

R1

H

N

NuNu

R3

R1

Nu N

R3H

CHO

I

AcAcBr

82a: 96%, 94% ee

CHO

SO2Ph

AcAcBr

82b: 40%, 82% ee (Z/E = 96:4)

CHO

Br

AcAcBr

82c: 89%, 54% ee

Me

CHO

I

AcAc

82d: 87%, 94% ee

81 82

INT-16 INT-17 INT-18

OH

R1

R2ArSO2Na

86 (10 mol%)L-proline (10 mol%)

H3BO3, CH3Cl

SO2ArR1

OH

R2

NNH

H N

OMe

NHSNHAr'

86, Ar' = 3,5-(CF3)2C6H3

up to 99% ee, E/Z >99:1

H

N HNQ

N HAr'

S O

H

N HNQ

N HAr'

S O

NH H

COONaPhSO2–

activated sulfinate anionPhSO2

–

H3BO3

86

NH H

COONa

L-proline + ArSO2Na

VQM intermediate (INT-19)nucleophilic addition

OH

Ph

SO2PhPh

OH

84 85

85a 84a

SynOpen 2021, 5, 68–85

78


Based on the key optically active intermediate, VQM,

Yan and co-workers27 completed the asymmetric synthesis

of atropisomeric sulfone-containing styrenes bearing up to

three axes with high enantio- and diastereoselectivities

(Scheme 18a). Alkynes 87 reacted with arylsulfinic acid to

deliver enantioenriched multi-axis styrenes 88 smoothly

with the assistance of the chiral quinine-derived squara-

mide catalysts 89 via tetrasubstituted VQM INT-20. This al-

lowed kinetic resolution with an excellent selectivity factor

(S). Later, the same group28 disclosed the asymmetric syn-

thesis of atropisomeric 1,4-distyrene 2,3-naphthalene diols

by means of organocatalysis (Scheme 18b). Nucleophilic ad-

dition of an amidosulfone to a VQM with the aid of cincho-

na squaramide 93 under mild reaction conditions afforded

92 featuring two chiral axes. Catalytic asymmetric synthe-

sis of a sulfone-containing atropisomeric styrene via the

Michael addition reaction of -amido sulfones to ynones

was achieved by the same group (Scheme 18c).29 The meth-

odology employed N-squaramide 96 as the catalyst, giving

the atropisomeric styrenes 95 with excellent enantioselec-

tivity.

Benefiting from the versatile reactivity of VQM and its

analogs, in 2019, Tan and co-workers30 achieved the con-

struction of a series of disubstituted atropisomeric 1,1′-

(ethene-1,1-diyl)binaphthol (EBINOL) derivatives by utiliz-

ing 2-naphthol as the nucleophile (Scheme 19). Under ca-

talysis with compound 100, atropisomeric styrenes 99

were synthesized in high yields and enantioselectivity,

along with complete E/Z selectivity, under mild reaction

conditions. The utility of this transformation was exhibited

by the preparation of atropisomeric EBINOL-based chiral

phosphonic acid (ECPA) 101 and phosphoramidites 105a

and 105b. Under catalysis with 101, alkylation of indole

(102) with N-(1-phenylvinyl)acetamide (103) afforded ter-

tiary amine 104 smoothly with moderate enantioselectivi-

ty. By contrast, a BINOL-derived CPA gave a lower stereose-

Scheme 18 Synthesis of atropisomeric styrenes via tetrasubstituted VQMs

OH

R3

R1

R2

NNH

H N

OMe

O NHAr'

OAr' = 3,5-(CF3)2C6H3

89

ArSO2H89 (10 mol%)

NIS, DCM

O

R3

R1

R2

I

OH

R3

R1

R2

ISO2Ar

INT-2087 88up to 98% ee, E/Z >20:1

>20:1 d.r.

OH

Ph

ISO2Ph

(1Sa,2Ra)-88a93%, 95% ee

E/Z >20, >20:1 d.r.

OHI

SO2Ph

(1Sa,2Ra)-88b90%, 92% ee

E/Z >20, >20:1 d.r.

S

OH

Me

ISO2Ph

Cl

(1Sa,2Ra,3Sa)-88c43% (45% conv.), 96% ee

E/Z >20, >20:1 d.r.S = 117

R1

R2

SO2R3

NHBoc

OH

OH

SO2R3

R3O2S

R1

R2

OH

OH

90

(91)

92

93 (10 mol%)CHCl3

N

NH

H N

OMe

O

O

N

NH

H

N

OMe

93

(a)

(b)

N

NH

H N

OMe

O

HN

NHAr

O

O

96, Ar = 3,5-(CF3)2C6H3

OR1

R2

94

96 (20 mol%)PhCF3

R1

O

SO2R3

R2

95

(c)

(91)

SynOpen 2021, 5, 68–85

79


lectivity and a SPINOL-based CPA failed in the induction of

enantioselectivity. The phosphoramidite was obtained as

the pair of diastereoisomers 105a and 105b exhibiting

P-stereocenters because of the lack of C2-symmetry of

EBINOL. EBINOL-Phos 105a efficiently prompted the asym-

metric hydrogenation of enamides 106 with 97% yield and

90% ee, whereas 105b afforded the product in low yield. The

alternative phosphoramidites Phos-bs and Phos-sr did not

give satisfactory results.

In 2020, Li, Yan, Liu, and co-workers31 applied asymmet-

ric nucleophilic addition for the synthesis of atropisomeric

styrenes bearing a stereocenter and a chiral axis (Scheme

20). Racemic 5H-oxazol-4-ones 109 worked as nucleophiles

to attack the in situ formed VQM intermediate derived from

108 to afford 110 with high enantioselectivity, high diaste-

reoselectivity, and a good E/Z ratio. This method offers an

efficient approach to these stereoisomers, which have po-

tential applications in asymmetric synthesis.

Scheme 20 Construction of atropisomeric styrenes with multiple stereoelements

Scheme 19 Atroposelective synthesis of atropisomeric EBINOL

OH+

R1

XHR1

OH

XH

R2 R2

R2

R2

67 examplesup to 99% yield, 99% ee

XH = NHAr, NHBn, OH

100 (5 mol%)PhCF3 O

O PO

NHTf

9-anthryl

9-anthryl

97 98 99 100

tBu

O

O

Ar

Ar

PO

OH

ECPA 101

tBu

O

OP

N

Ph

PhMe

Me

EBINOL-Phos 105a

tBu

O

OP

EBINOL-Phos 105b

NPh

Me

PhMe

NH

+

NHAcCPA (5 mol%)

PhCF3

NH

AcHNMe

Ph

ECPA 101: 95%, 73% ee(Ra)-BINOL-CPA: 50% ee(Ra)-SPINOL-CPA: 1% ee

103 (R)-104

OMe

O

NHAc

H2 (30 bar)iPrOH OMe

O

NHAc

106 (R)-107

Rh(cod)2BF4 (0.5 mol%)Phos (1.1 mol%)

105a: 97%, 90% ee105b: tracePhos-bs: NRPhos-sr: 24%, –8% ee

OO

P N

MePh

MePh

OO P N

MePh

MePh

Phos-bs Phos-sr

102

R1

Ar

OH +O

N

OR2

Ar'

Ar

N

OR2

O

Ar'

R1

111(10 mol%)

N

NH

H N

OMe

O

O

N

NH

H

N

OMe

108 rac-109 110

111up to 96% eeE/Z >99:1; d.r. >20:1

Ph

N

OEt

O

Ph

(Ra,R)-110a, 83%, 92% eeE/Z >99:1; d.r. >20:1

Ph

N

OEt

O

p-Tol

(Ra,R)-110b, 85%, 94% eeE/Z >99:1; d.r. >20:1

N

OEt

O

Ph

(Ra,R)-110c, 84%, 88% eeE/Z >99:1; d.r. >20:1

HO

HO HO HO

Me N

OEt

O

Ph

HO

S

(Ra,R)-110d, 82%, 92% eeE/Z >99:1; d.r. >20:1

CHCl3

SynOpen 2021, 5, 68–85

80


N-Alkylation of enamide 112 also enabled preparation

of atropisomeric styrenes.32 Nucleophilic substitution of al-

kyl bromides with 112 in the presence of a catalytic

amount of 114 afforded enantioenriched styrenes 113 with

satisfactory stereoselectivity and good functional-group

tolerance (Scheme 21). Substrates including allyl bromide,

propargyl bromide, 4-methoxybenzyl bromide, and benzyl

bromide were successfully applied in the protocol (113a–

113e). A merit of this methodology was the rapid prepara-

tion of atropisomeric 2-arylpyrrole scaffold 115 by treating

113e with LDA. Atropisomer 116, featuring a seven-mem-

bered cyclic system, was also prepared by reduction of 113a

with DIBAL-H followed by annulation with good enantiose-

lectivity and 78:22 diastereoselectivity.

In 2020, Zhao and co-workers33 identified an aza-VQM

as a key intermediate for the preparation of atropisomeric

vinyl -anilines. A well-defined chiral sulfide was used as

the catalyst, which promoted an asymmetric electrophilic

carbothiolation and intramolecular annulation reaction

(Scheme 22). INT-20 was formed by coordination of sulfur

Scheme 21 Synthesis of atropisomeric styrenes via N-alkylation

HN

CO2R1

CO2R1

R2

R4

R3 R5

Br

114 (10 mol%)Cs2CO3, toluene

NCO2R1

CO2R1

R2

R4

R3

R5

N

O N

tBu

tBu

F

F

F

CF3

F3CH

Br

114

NCO2Et

CO2Et

R

112 113

R = I, 113a, 84%, 92% eeR = CF3, 113b, 87%, 94% ee

NCO2Et

CO2Et

I

113c, 91%, 94% ee

NCO2Et

CO2Et

I

PMB

113d, 76%, 84% ee

Bn Bn BnN

CO2Et

CO2Et

I

Bn

113e, 65%, 91% ee

Bn

NCO2Et

CO2Et

I

R5

113a, 92% ee113e, 91% ee

BnLDATHF

I

N CO2EtBn

Ph OH

115, 57%, 91% ee

a) DIBAL-H, Et2Ob) nPrNH2, TfOH, Et2O

I

N

NHnPr

CO2EtBn

116, 84%, 90% ee78:22 d.r.

R5 = vinylR5 = Ph

Scheme 22 Synthesis of atropisomeric styrenes via an aza-VQM intermediate

NHR1

+ N

O

SR2SR2

NHR1

R2 = Ar, CF3

S

NHTs

Me

OiPr

120 (10 mol%)TMSOTf

117 118 119 120up to 98% ee

S

NHTs

Me

OiPr

S

N

Me

OiPr

SR2

Ts H OTf

N SR2 + TMSOTf

N TMS

117

SNTs

H

S

Ph

NMsH

F3C S OO

O

Me

OiPr

R2S

NMs

H

TfO

SR2

NHR1

–TfOH

120

INT-20 INT-21

INT-22

119

O

O

OO

O

CH2Cl2/CHCl3(1:1)

SynOpen 2021, 5, 68–85

81


reagent 118 and catalyst 120 with the aid of a Lewis acid.

Subsequently, INT-20 reacted with alkyne 117 to generate

sulfonium salt INT-21, which transformed into aza-VQM

INT-22 by elimination and liberated the catalyst. Intramo-

lecular annulation of INT-22 afforded sulfur-containing at-

ropisomeric styrenes 119.

Following this, Zhang and co-workers34 reported an

asymmetric nucleophilic addition of 1-(ethynyl)naphtha-

len-2-amines to achieve a divergent synthesis of atropiso-

meric styrenes (Scheme 23). The reaction employed indoles

or 4-hydroxycoumarins as substrates, and high yields and

excellent enantioselectivity were obtained. Based on previ-

ous work and control experiments, a mechanism involving

a – interaction and hydrogen-bond-mediated model was

proposed. Combination of 121a with chiral phosphoric acid

124 would generate INT-23, which could isomerize to aza-

VQM INT-24 in an enantioselective form. INT-24 could then

be attacked by the indole to give INT-26. Subsequent disso-

ciation of INT-26 would afford enantioenriched 122a and

regenerate 124. The hydrogen bond plays a vital role in the

reactivity and enantiocontrol. By contrast, N-methyl indole

displayed no selectivity under identical conditions.

An atropisomeric styrene framework bearing a novel

seven-membered bridged ring was also synthesized by Shi

and co-workers in 2020 (Scheme 24).35 (3-Alkynyl-2-indo-

lyl)methanols 125 can readily generate optically active al-

lenes with the assistance of chiral phosphorous acid 127,

which was atroposelectively attacked by 2-naphthol to give

acyclic chiral styrenes. Intramolecular dehydration afforded

the fused atropisomeric styrene 126.

Later, the same group36 reported a kinetic resolution of

indole-based vinyl aniline 128 (Scheme 25). The resolution,

featuring a high selectivity factor (S), allowed efficient con-

trol of conversion and enantioselectivity and offered an ap-

proach to a new class of atropisomeric styrenes.

4.5 Asymmetric Phase-Transfer Alkylation

Enolization of 3,4-dihydronaphthalen-2(1H)-one gives a

3,4-dihydronaphthalen-2-ol intermediate. In 2017, Smith

and co-workers37 realized an asymmetric O-alkylation

strategy for the atroposelective synthesis of atropisomeric

styrenes via chiral phase-transfer catalysis (Scheme 26).

The methodology employed ketone 132 as the enolate pre-

cursor. O-Alkylation with the assistance of chiral ammoni-

Scheme 23 Chiral phosphoric acid catalyzed atroposelective synthesis of styrenes

HN

Ph

HN

HN

R


HN

O

OH

O


124 (10 mol%)4 Å MS, toluene

124 (10 mol%)4 Å MS, toluene

121122 123

Ar

Ar

OO

PO

HO121a

Ar

OO

PO

OPh

N

H

H

π

π

Ar

OO

PO

O

N

H

π

π

PhH

Ar

OO

PO

O

N

H

π

π

Ph

NH

NH

Ar

OO

PO

O

NH

π

π

NH

PhH

Ar = 2,4,6-iPr3C6H2

124

INT-23

INT-24

INT-25

INT-26

122a

N

(no reaction)

E =

NH

H E =

O

OH

O

HR

Ar'

Ar'

Ar

ArAr

Ar''

Ar''

SynOpen 2021, 5, 68–85

82


um salt 134 afforded enol ether 133 with excellent enanti-

oselectivity. The procedure commenced with racemic ke-

tone 132, featuring central chirality, as the substrate; this

could generate the enolate with the aid of solid potassium

phosphate and coordinate with the chiral ammonium salt

to afford soluble diastereoselective ion pairs INT-27 and

INT-28. The diastereomers bearing atropisomeric informa-

tion could interconvert through protonation and deproton-

ation. Atropisomeric styrene 133a was exposed to m-chlo-

roperoxybenzoic acid to afford the corresponding epoxide,

Scheme 24 Atropisomeric styrene synthesis from 3-alkynyl-2-indolylmethanols

NH

OH

ArAr

tBu

+OH

NH

H

tBu

O

Ar Ar

R1

R1

R2

R2

N

OH

ArArR1

HtBu

H

R2

OH

POO

*

NH

H

tBu

O

Ar O

R1

R2

Ar

H

H

PO

O

*

H

N

H

tBu

OR1

R2

H

PO

O

*

Ar

ArH

– H2O

1st nucleophilicaddition

127 (10 mol%), toluene

OP

O OHO

G

G127, G = 2-naphthyl

125 126

NH

H

tBu

O

Ph Ph

126a, 97%, 95% eeE/Z >95:5

NH

H

tBu

O

Ph Ph

126b, 87%, 91% eeE/Z >95:5

Br

NH

tBu

O

Ph Ph

X = Cl, 126c, 60%, 91% ee, E/Z >95:5X = Br, 126d, 61%, 94% ee, E/Z >95:5

MeOX

2nd nucleophilicaddition

Scheme 25 Catalytic kinetic resolution

NR

OHN

NH2

+N

O

OR2

R3

kinetic resolutionR1

NR

OHN

HN

ONH

H R2

R3

O

R1H2N

NO

R

R1

NH

+

OP

O OHO

G

GG = 2-naphthyl

131

131 (10 mol%)3 Å MS, CH2Cl2

NR

OHN

HN

R1 H

ON

O

R3

R2

PO

O

*

H

NR

OHN

NH2R1H2N

NO

R

R1

NH

rac-128 129 (Ra)-128 (Sa,S)-130

NBn

OHN

HN

ONH

H Ph

Ph

O

H2N

NO

Bn

NH

+

128a, 46%, 86% ee 130a, 48%, 90% ee86:14 d.r.

NBn

OHN

HN

ONH

H p-ClC6H4

Ph

OH2N

NO

Bn

NH

+

128b, 44%, 96% ee 130b, 51%, 87% ee90:10 d.r.S = 53 S = 56

+

(Ra)-128 (Sa)-128

fast reaction

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83


which was subsequently rearranged with catalytic ytterbi-

um triflate to give 135 with central chirality. BINOL 136

was obtained readily by oxidation and dealkylation of 133a

without erosion of enantioselectivity.

5 Stability of the Chirality of Atropisomeric Styrenes

In comparison with biaryl atropisomers, atropisomeric

styrenes display less stability because of their less rigid

skeleton. The numbers and size of adjacent substituents can

dramatically affect the rotational barriers of styrenes. Al-

though no bridged atropisomeric styrenes have been dis-

cussed in the literature, fused molecules with appropriate

ring sizes showed excellent stability. Of course, the influ-

ence of the Z/E geometry of the C=C double on the stability

of the chiral axis cannot be ruled out. In early studies, com-

pound 2 was not resolvable because of the low steric hin-

derance of the hydrogen atom. Nevertheless, enantiomers

of compound 5, bearing an isopropyl moiety at the -posi-

tion, could be separated by resolution. In the research of

Adams and co-workers,6,7 (E)-137 with a carboxylic acid as

the adjacent group could be resolved, whereas the axis of

(Z)-138 could rotate freely at room temperature with hy-

drogen as the adjacent substituent (Figure 2).

Figure 2 Geometric effects on the stability of atropisomers

In accordance with racemization experiments and DFT

calculations, atropisomeric styrenes with suitable substitu-

ents have been synthesized and used as novel framework li-

gands or bioactive compounds. In Figure 3, the reported

data for the rotational barriers of some atropisomeric sty-

renes are depicted to demonstrate their structure–stability

relationships. It is foreseeable that the number and steric

size of the substituents next to the axis will significantly af-

fect the rotational barriers of these atropisomers. Currently,

it is hard to draw the conclusion that dihydro-binaphtha-

lene and 1-(1H-inden-3-yl)naphthalene structures have

higher chiral stabilities than the corresponding acyclic atro-

pisomeric styrenes.

Scheme 26 Asymmetric O-alkylation

OR1

R1

134 (10 mol%), K3PO4C6H6/CH2Cl2 (4:1)

132

BnI

OBnR1

R1

133

OR3OR3

N

OH

N

H

FF F

OMe

134

OOR3

OOMe

rac-132a

OOMe

standard conditions

standard conditions

OBnOMe

133a

fast

slow OBnOMe

ent-133a

major enantiomer

minor enantiomer

(central chirality)

INT-27

INT-28

axial chirality

OBn

OMe

133a, 92% ee

DDQ, CH2Cl2then BBr3 CH2Cl2

OHOH

13698%, 92% ee

mCPBA, CH2Cl2then Yb(OTf)2

O

OMe

13594%, 86% ee

OBn

R4N

R4N

ClCO2H

H

MeO Me

Cl

MeOH

CO2H

Me Me

Br

(E)-137[6,7] (Z)-138[6,7]

resolvable not resolvable

MeMe

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84


Figure 3 Rotational barriers

6 Outlook

Atropisomeric styrenes bearing a C(vinyl)sp2–C(aryl)sp2

bond as the rotation-restricted axis have been overlooked

for decades because of their relatively lower rotation barri-

ers in comparison with those of their biaryl counterparts.

Much effort has been devoted to exploiting approaches for

the synthesis of stable atropisomeric styrenes in the last

ten years. Many novel styrene frameworks have been con-

structed, demonstrating unique applications in asymmetric

synthesis. However, new methodologies for the efficient,

practical asymmetric synthesis of atropisomeric styrenes

with high enantioselectivity are still desirable.

Conflict of Interest

The authors declare no conflict of interest.

Funding Information

This work was supported by the National Natural Science Foundation

of China (21901236, 21871241).National Natural Science Foundation of China (21871241)National Natural Science Foundation of China (21901236)

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Documents

Atropisomerism in Styrene: Synthesis, Stability, and