Atropisomerism in Styrene: Synthesis, Stability, and Applications

SYNOPEN2509-9396 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2021, 5, 68–85 review 68 en

SynOpen J. Feng, Z. Gu Review

Jia 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 China [email protected] b Ocean College, Minjiang University, Fuzhou, Fujian 350108, P. R. of China

ZhenhuaDepartmentofeMail ChinaCorresponding [email protected] Gu of Chemistry Author 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.

Received: 25.01.2021 tive molecules, medicines, and materials science.1 Atropiso- Accepted after revision: 02.02.2021 meric biaryls are also a prominent scaffold and have been Published online: 10.03.2021 DOI: 10.1055/s-0040-1706028; Art ID: so-2021-d0005-r widely studied because of their stable chiral axis and diver- License terms: gent applications in asymmetric synthesis. In contrast, at- © 2021. The Author(s). This is an open access article published by Thieme under the ropisomeric styrenes have been overlooked for a half centu- terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, ry as a result of the perceived ‘poor stability’ of the chiral

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, axis located in the Csp2–Csp2 bond between the vinyl and transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) aryl groups. This review summarizes the early studies of atropisomeric styrenes, including their discovery, resolution, Abstract Atropisomeric styrenes are a class of optically active com- and synthesis, as well as the recent developments in cata- pounds, the chirality of which results from restricted rotation of the C(vinyl)–C(aryl) single bond. In comparison with biaryl atropisomers, lytic asymmetric synthesis. Compounds showing signifi- the less rigid skeleton of styrenes usually leads them to have lower rota- cant aromaticity, such as atropisomeric 4-aryl isoquinolin- tional barriers. Although it has been overlooked for a long time, scien- 1(2H)-ones, are not discussed here because they are more tists have paid attention to this class of unique molecules in recent akin to biaryl atropisomers.2 years and have developed many methods for the preparation of optically active atropisomeric styrenes. In this article, we review the development of the concept of atropisomeric styrenes, along with their isola- tion, asymmetric synthesis, and synthetic applications. 2 The Concept of Styrene Atropisomerism 1 Introduction 2 The Concept of Styrene Atropisomerism It is generally accepted that the stability of biaryl axial 3 Early Research: Separation of Optically Active Styrenes 4 Synthesis of Optically Active Styrenes chirality originates from the characteristics of the axis and 5 Stability of the Chirality of Atropisomeric Styrenes the steric hindrance of groups adjacent to the axis. For sty- 6 Outlook rene derivatives, prevention of free rotation around the axis connecting the vinyl and aryl groups is much harder and Key words atropisomers, styrene, axial chirality, asymmetric synthe- needs more sterically hindered substituents. It is clear that sis, asymmetric C–H functionalization styrenes are generally less rigid than biaryls, resulting in the rotational barriers of styrenes being lower than the cor- 1Introduction responding barriers of biaryls. As early as 1928, Hyde and Adams3 stated that ‘The molecules (1) would undoubtedly be Atropisomerism arises from restricted rotation around less rigid, but if the free rotation around the bond joining the a single bond as a result of the steric hindrance of adjacent unsaturated linkage to the substituted ring is prevented, any moieties, ring strain, or other structural factors. It is an im- position of the olefin or carbonyl group and the unsubstituted portant way for chiral molecules bearing no stereogenic ring in space should give an asymmetric molecule.’ This was centers to demonstrate three-dimensional character. As the first time that chemists predicted the possibility of axial representative atropisomers, biaryls occur widely in bioac- chirality existing in styrene compounds.

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3 Early Research: Separation of Optically CO2H Me CO2H R5 Me H H H Active Styrenes R4 Me Me Me iPr R3 Me O2N Me Me Me Br Br R1 R2 NMe 4 3 In 1930, the attempt of Maxwell and Adams to separate I Me NO2 NH2 NH2 the enantiomers of styrenes 2, 3, and 4 by resolution ended Me Me Br with failure (Scheme 1), with the low steric bulk of the - 1 234 5 hydrogen atom of the styrene accounting for the unaccom- 5 Me Me Me plished separation. In 1938, Mills and Dazeley succeeded Me Cl Cl Cl Et β CO2H CO2H CO2H H in synthesizing racemic o-(,-dimethyl--isopropylvinyl)- Me Me Me Me Me Me phenyltrimethyl ammonium iodide (5) and resolving its NMe3 isomers, which verified the original postulate about the I Br Br Br ClO2S Br Me Me Me possibility of stable atropisomerim in styrenes. On replac- 6 7 8 9 ing the methyl group (with Z-geometry to the aryl ring) with a hydrogen atom to form 6, no enantiomers could be Scheme 1 Atropisomeric styrenes in early studies separated. In 1940, Miller and Adams6 completed the synthesis of a more sterically hindered styrene, -chloro--(2,4,6- Notable retention of partial chirality was observed by trimethyl-3-bromophenyl)--methylacrylic acid (7), and its Fuji and co-workers in the alkylation reaction of 10 with a enantiomers were successfully resolved. With a chlorine carbon stereogenic center at the -position of a carbonyl atom at the -position of the styrene and a methyl group group in 1991.8 It seemed that the size of the electrophile adjacent to the axis, compound 7 demonstrated excellent did not affect the enantioselectivity (Scheme 2, table). The stability, displaying no decrease in enantiopurity on heat- authors carried out rapid HPLC analysis of byproduct 12, ing to reflux in ethanol for 15 h or in glacial acetic acid for which gave a 65% enantiomeric excess (ee) value. The con- 12 h. Bromination of 7 afforded the optically inactive sym- trol experiment indicated that alkylation would form atro- metric compound 8. In contrast, the installation of a sulfo- pisomeric enolate INT-1, which could be attacked by the nyl group on 7 gave the optically active compound 9. Later, electrophile to afford the C-alkylation product 11 and O-al- Adams and co-workers carried out further research into the kylation product 12 with moderate ee values (Scheme 2, relevance between structure and atropisomeric stability in bottom). styrenes.6,7

Biographical Sketches

Jia Feng received his Bachelor’s of China) under the supervision the construction of atropiso- degree from Shandong Univer- of Professor Zhenhua Gu in meric molecules via novel meth- sity (P. R. of China) and his PhD 2018. He is now a postdoctoral odology and the asymmetric from the University of Science researcher in the same group. synthesis of bioactive mole- and Technology of China (P. R. His research interests include cules.

Zhenhua Gu studied chemis- University of California Berkeley nology of China (P. R. of China). try at Nanjing University in (USA) with Professor K. P. C. Research in his group mainly fo- 2002, and then he pursued his Vollhardt and the University of cuses on the development of PhD studies with Professor California at Santa Barbara new methods for asymmetric Shengming Ma at the Shanghai (USA) with Professor A. Zakarian. synthesis, particularly for atrop- Institute of Organic Chemistry In 2012, he began his indepen- isomers and related natural (P. R. of China). He conducted dent academic career at the products. postdoctoral research at the University of Science and Tech-

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Ph Ph Ph addition of vinylidene ortho-quinone methide type inter- O OM MeO O MeO MeO mediates is also an attractive approach. Base Electrophile E OEt OEt OEt

OEt OEt OEt 4.1 Chirality Transfer Strategy

10 (93% ee) INT-1 11 In 2001, Miyano, Hattori, and co-workers10 reported the Entry Electrophile Yield/% ee/% synthesis of tertiary alcohol (R,R)-16, which was derived

1 MeI 48 66 from the 1,2-addition of (R)-14 and 15. Compound 16 was 2 EtI 27 65 3 PhCH2Br 31 67 stereospecifically transformed into atropisomeric (R)-17 4 CH2=CHCH2Br 36 48 with up to 95% ee on treatment with (CF3CO)2O in dichloro- Control experiment: Ph methane at room temperature (Scheme 3). Interestingly, OMe MeO the authors found that there was an equilibrium between Standard conditions 10 (93% ee) 11 (48%, 66% ee) + OEt conformational isomers 16a and 16b observable from the 1 OEt H 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 12 (15%, 65% ee) transfer from point to axial chirality can be assumed to oc- Scheme 2 Enantioselective alkylation via an intermediate atropisoeno- cur because of the much lower conversion rate from 16a late into (R)-17 than the rate from 16b into (S)-17.

In 2016, Clayden and co-workers9 synthesized a series O MgBr Me OMe Yb(OTf)3, THF, r.t. OMe of 1-aryl-3,4-dihydroisoquinolines 13, which are structural + OH analogs of styrene featuring a potentially atropoisomerical- Me ly stable axis. They studied the stabilities by calculation of (R)-14 15 (R,R)-16 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, (CF3CO)2O, CH2Cl2, r.t. OMe the half-life of iodide 13d was too short to separate the en- (R,R)-16 Me 94%, 95% ee antiomers at ambient temperature. (R)-17

Compound X ΔG (kJ mol–1) t1/2 MeO N 13a H 54.7 10–4 s 13b Cl <90 <5 min X H H 13c Br 92.9 15 min OH 13d I 81.9 <1 min Me OH OMe 1:5.7 (in CDCl ) 13e OTf 103.1 36 d 3 Me 16a 16b 13 13f P(O)Ph2 >>100 >25 d Scheme 3 Synthesis of atroposelective styrenes via chirality transfer Figure 1 Substituent effect on the stability of 1-aryl-3,4-dihydroisoquinolines 4.2 Chiral Auxiliary Strategy

4 Synthesis of Optically Active Styrenes With the assistance of chiral auxiliaries, chiral atropisomeric styrenes can be synthesized in a diastereoselective Given the unique scaffolds of atropisomeric styrenes manner. Subsequent removal of the auxiliary affords the at- and their important applications in bioactive molecules and ropisomeric styrenes. In 1996, Baker et al.11 disclosed a medicines, many approaches to access enantioselective sty- point to axial chirality transfer via a formal 1,3-hydrogen renes have been developed during recent decades. In early shift (Scheme 4). Reaction of (1R)-menthyl (R)-(1-p-tolyl- studies, atropisomeric chirality was constructed from point sulfinyl)-naphthalene-2-carboxylate (18) with indenyllithi- chirality via chirality transfer. The optically active styrenes um delivered major product 19 in 88% yield and with 59% could be separated as single distereomers with the aid of diastereoselectivity, together with minor products 20 and chiral auxiliaries. Of all approaches, catalytic asymmetric 21 in a combined yield of 9% with a ratio of 1:1. Esters 20 synthesis comes to the fore because of its high efficiency and 21, with relatively stable axial chirality, were separated and divergent functional-group tolerance. Recently, transi- by preparative HPLC. The half-life of interconversion be- tion-metal-catalyzed cross-couplings, including C–H func- tween 20 and 21 was about 25 h in solution at 25 °C. Treat- tionalization in a step- and atom-economic manner, have ment of isomer 19a (99% de) with an excess of LiAlH4 af- become a powerful method for the preparation of atropoac- forded carbinol ent-22 in quantitative yield with 98% ee. A tive styrenes. Furthermore, organo-catalyzed electrophilic control experiment was performed by quenching the reac-

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

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O Indenyllithium S THF, 0 °C ++ CO R* H 2 CO2R* R R

R* = (1R)-menthyl R* = (1R)-menthyl ratio of 20:21 = 1:1

18 19 20 R = CO2R* LiAlH4 21 R = CO2R* Et2O 22 R = CH2OH 0 °C ent-22 R = CH2OH

_ D H AlL2 LiAlH , Et O, 0 °C –1 4 2 2 mol L DCl in D2O H O CO R* 2 CH2OH

19a INT-2 ent-22-d

Scheme 4 Point to axial chirality transfer strategy

89% deuterium incorporation. The authors proposed that Stereochemical relay stragety: A HO .. .. the reduction of 19a with the S-conformation at C-1′ gave O OH O O S I Step A S Step B R ent-22-d via INT-2, on the basis of this labeling experiment. R B Diastereoselective synthesis of axial styrenes with the OH X X aid of a chiral sulfoxide auxiliary was applied successfully OH O O central axial (+ central) to the stereospecific synthesis of the antibiotic TAN-1085 O A A Y 12 Y (23). Suzuki and co-workers reported an asymmetric syn- OH Step C B thesis of 23 through a stereochemical relay strategy featur- TAN-1085 (23) CHO OH ing a three-step conversion of chirality: central to axial OH (step A), axial to axial (step B), and axial to central (step C) axial central (Scheme 5). Suzuki–Miyaura coupling of boronic acid 24 and vinyl iodide 25 containing the chiral sulfoxide auxiliary OMOM and subsequent silylation and mono-deprotection of the OMOM phenol afforded atropisomeric styrenes 27a and 27b with a MOMO B O [Pd(PPh3)]4 diastereoselective ratio of 25:75. Conformation 27b was fa- OTBDPS HO K3PO4, DME/H2O MOMO SnBr2, toluene vored over 27a by the formation of an intramolecular hy- 24 then tBuPh2SiCl O 27a/27b S OTBS

I imidazole, DMF = 25:75 drogen bond. Product 27b was separated by flash chroma- p-Tol .. O OTBS

tography on silica gel, and subsequent benzylation gave 28 S 26 (d.r. 38:62) p-Tol .. inseperable in more than 99% ee, which could be enantioselectively 25 converted into TAN-1085 in a few steps. OMOM OMOM 13 Meanwhile, the same group realized an asymmetric NaH, BnBr synthesis of atropisomeric styrenes bearing two axial axes DMF OTBDPS + OTBDPS H O HO via a similar strategy (Scheme 6). Treatment of vinyl iodide O p-Tol

S OTBS S OTBS

.. 30, featuring a chiral sulfoxide auxiliary, with aryl boric p-Tol .. O acid 29 furnished atropisomeric styrene 31 as one diaste- 27b 27a reomer. After a two-step transformation, 32, bearing two OMOM terminal alkenes, was prepared from 31 and could be selec- OTBDPS steps tively converted into planar chiral cyclophane 33. In a simi- BnO TAN-1085 (23) O

lar procedure, planar chiral cyclophanes 34 and 35, also S OTBS with the ansa-chain, were readily accessed. The atropiso- p-Tol .. meric vinyl arene structure also possibly exists in ring- 28 90%, >99% ee, d.r. >99:1 strained macrobiaryl alkenes.14 Scheme 5 Asymmetric synthesis of TAN-1085 (23) 4.3 Catalytic Asymmetric Synthesis of Atropiso- meric Styrenes been developed. These strategies include the cross-coupling of aryl halides and hydrazones, Suzuki–Miyaura cross-cou- Benefiting from the rapid development of transition- plings, and cross--coupling reactions via C–H activation. metal-catalyzed cross-coupling reactions, many novel and efficient approaches to access atropisomeric styrenes have

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OMOM

(HO)2B B(OH)2 CH(OMe)2 CH(OMe)2 MOMO [Pd(PPh3)4] (30 mol%) 29 OR O K3PO4 DME/H O H .. 2 .. .. I MeO OMe S RO S .. S O S O p-Tol O p-Tol O p-Tol O p-Tol H O

S H p-Tol .. 30 31 32

OH O O

.. H .. S S .. S .. O .. S O S .. S O p-Tol HO O p-Tol p-Tol O H p-Tol O H O p-Tol p-Tol O

33 34, E/Z 11:1 35

Scheme 6 Synthesis of atropisomeric styrenes with a chiral sulfide auxiliary

It is anticipated that, when styrene structures have the alytic asymmetric synthesis of styrene-type atropisomers vinyl unit as part of a five- or six-membered ring fused to (Scheme 7). The protocol with aryl halides 36 and hydra- another aromatic ring, the atropisomerism of these com- zones 37 as standard substrates delivered dihydro-binaph- pounds may be more stable than that of acyclic styrenes. thalenes 38 in up to 99% yield with up to 97% ee. The reac- For example, dihydro-binaphthalenes and 1-(1H-inden-3- tion exhibited a broad functional-group tolerance. In the yl)naphthalene are supposed to have higher rotational bar- proposed mechanism, the oxidative insertion of Pd(0) into riers than vinyl naphthalenes. 36 gives INT-3, which coordinates with the in situ generat- ed carbene species derived from hydrazone 37 with the aid 4.3.1 Palladium-Catalyzed Cross-Coupling of Aryl of tBuOLi. The newly formed palladium carbene species Halides And Hydrazones INT-4 undergoes migration/insertion reactions to produce INT-5, which affords the final product via reductive elimi- In view of the importance of the axial chirality in sty- nation and liberation of the Pd(0) catalyst. The chiral renes, in 2016, Gu and co-workers15 developed the first cat- styrene was readily oxidized to the atropisomeric biaryl

R3 R3 NNHTs Pd(OAc)2 (10 mol%) 39: Br O 2 Ar' R Ar' P 39 (20 mol%) Ar tBuOLi (2.5 equiv) O O O 1 + R2 R Ar P N P Ar 1,4-dioxane, 50 °C 1 O O R3 R3 R Ar Ar' Ar'

36 37 38 Ar' = 4-FC6H4 up to 99% yield up to 97% ee

0 Pd L2 36a 38a (COCl)2, CH2Cl2, r.t. O then LiAlH , THF, 0 °C 4 P P Ph Ph Ph Ph 37a PdBrL O 38a, 99% ee 40, 95%, 99% ee 2 tBuOLi P Ph Ph N2 PdBrL2 O P INT-3 Ph Ph Application as a chiral ligand: INT-5

migration/ CO2Et insertion N [{Pd(allyl)Cl} ], 40 H 2 Br Cs2CO3, CH2Cl2, 40 °C L CO2Et Pd O + N 88%, 83% ee P OAc N2 Ph Ph Ph Ph Ph Ph

INT-4

Scheme 7 Carbene strategy for the synthesis of atropisomeric styrenes

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SynOpen J. Feng, Z. Gu Review compound without erosion of enantiopurity. Moreover, the enones 46 and aryl boronic acids (Scheme 9). BoPhoz 49 ex- P(V) compound 38a was uneventfully reduced to phosphine hibited superior stereocontrol over other types of ligand. 40, which was successfully applied in an asymmetric allyla- The advantage of this strategy is that the ,-unsaturated tion reaction as an (alkene, phosphine) bidentate ligand. ketone displays diverse reactivity in its downstream trans- In further related studies, Wu et al.16 employed P-ste- formations. Thus, the final products bearing axial chirality, reogenic bidentate phosphine ligand 44 in the asymmetric known as ‘platform molecules,’ could be diversely convert- synthesis of atropisomeric vinyl arenes with excellent ste- ed into atropisomeric biaryls. For example, 48a was oxi- reocontrol (Scheme 8). In this report, dialkyl phosphonates dized into quinone 50 with TBHP in presence of [Co(acac)2]. 41 were compatible substrates, delivering atropisomeric vi- Furthermore, 48a underwent aromatization with NBS and a nyl arenes 43 with good yields and enantioselectivities. The catalytic amount of BPO to deliver phenol 51, without loss protocol was successfully applied to the synthesis of atrop- of axial integrity. After a three-step transformation, involv- isomeric compound 43b containing an indene skeleton ing oxime formation, reduction, and aromatization, -ami- (86% ee). For product 43c, with a seven-membered ring, the no atropisomeric biaryl 52 was prepared efficiently. A ben- racemic product was observed. Diphenyl phosphine oxide zyl group could be installed at the -position in 53 by an al- 38a was synthesized in 75% yield with 87% ee, which is dol reaction followed by oxidation. Notably, aryl iodide 54 slightly lower than the results of Gu and co-workers. The could also be accessed in 75% yield over three steps via con- utility was demonstrated by a gram-scale synthesis of 43e densation with hydrazide followed by iodization and aro- without loss of enantioselectivity. The merit of this work is matization. that dimethyl phosphonate 43a could be further converted into dimethyl phosphine oxide 45 with methyl magnesium 4.3.4 C–H Activation for the Synthesis of Atroposelec- bromide. tive Vinyl Arenes

R1 The last twenty years have witnessed important devel- Pd(OAc) (10 mol%) Br O 2 ( )n NNHTs 44 (10 mol%) opments in C–H activation strategies in organic synthe- P OR tBuOLi (3.0 equiv) O + 1 1c,18 OR R P sis. Several approaches based on C–H activation have

( ) 1,4-dioxane, 50 °C OR n OR been developed for the construction of atropisomeric sty- n = 1,2 41 42 43 renes. In 2018, Gu and co-workers19 developed a visible-light- accelerated stereospecific C–H arylation for the preparation Br O NNHTs Standard conditions of tetrasubstituted atropisomeric vinyl arenes. The reaction P OEt + O OEt 2.50 g scale P OEt was based on their previously synthesized atropisomeric OEt vinyl arene 38, which reacted with diaryliodonium salts to 41a 42a 43e, 77%, 86% ee give 56 without loss of enantiopurity (Scheme 10). A radical pathway was proposed on the basis of control experiments and DFT calculations. A diaryl iodine cation can be O O O MeMgBr O formed from diaryliodonium salts under standard condi- P OMe P Me P P OMe Me tions, which can lead to iodobenzene cationic radical INT-6 OMe tBu tBu OMe and phenyl radical INT-7 under irradiation. Radical addition 43a 45 44 88% ee 73%, 89% ee to 38, followed by association with the palladium catalyst and -H elimination give the final product. Kinetic studies selected examples: showed that the kinetic isotope effect value changed from 3.6 in the absence of light to 1.1 on irradiation with visible O O O O P P P P OMe OEt OEt Ph light, which indicated that the C–H functionalization step OMe OEt OEt Ph was the rate-determining step in the absence of irradiation 43a 43b 43c 43d with visible light. 65%, 88% ee 62%, 86% ee 66%, racemic 75%, 87% ee Based on the -aryl-,-cyclohexenone skeleton, Cui, Scheme 8 Palladium-catalyzed atropisomeric styrene synthesis with Xu, and co-workers20 reported an asymmetric oxime- aryl halides and carbene precursors directed C–H olefination reaction in 2018 (Scheme 11). Un-

der Pd(OAc)2 catalysis, Ac-L-Ala-OH and 2-aryl cyclohex-2- 4.3.2 Suzuki–Miyaura Cross-Coupling for Synthesis of enone oxime ethers 57 were smoothly converted into atro- 2-Aryl Cyclohex-2-Enone Atropisomers pisomeric vinyl arenes 58 with excellent enantioselectivity. One of the two C–C double bonds in 58a could be selectively In 2017, Gu and co-workers17 disclosed an asymmetric reduced to give 59 via Pd/C catalysis under an atmosphere synthesis of 2-aryl cyclohex-2-enone atropisomers 48 via of hydrogen. After acting as a temporary directing group, Suzuki–Miyaura coupling of 2-iodo-3-methylcyclohex-2- the oxime ether group could be removed to release the

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R1 Ph 1 R B [Pd(acac)2] (5 mol%) P Ph 2 49 (7.5 mol%) N R O Me O + R Et 2 Me O KOH, DCE/H2O (1:1) R O PPh2 65 °C R Fe I R3 46 47 R3 48 49

B = B(OH)2 or B(pin) divergent synthesis from 48:

[Co(acac)2] BPO (10 mol%) Me O Me OH Me O TBHP, acetone NBS, CCl4, OMe OMe OMe 58%, 98% ee 94%, 99% ee

1) N 2) I 2 H 48a, 99% ee 3) DDQ,2 , TEA, dioxane4 H 0 °C to r.t. 51 50 Me, THF 2 O, MeOH OH HCl,2 NaOAc platform molecule 2 75%, 1) NH 99% 2) Fe, ClCO NaH, PhCHO 3) DDQ, THF, r.t. 84%, 94% ee ee 59%, 99% ee

Me NHCO2Me Me OH Me I OMe OMe OMe

52 53 54

Scheme 9 Divergent syntheses from atropisomeric styrenes

In 2019, Liu, Mao, and co-workers21 developed a car- Pd(OAc) (5 mol%) R 2 R PPh3 (5 mol%), NaHCO3 bopalladation and C–H olefination for the asymmetric syn- H Ar DCE, visible light + Ar2IOTf P(O)Ar'2 P(O)Ar'2 thesis of atropisomeric styrenes (Scheme 12). Treatment of 55 alkyne 63 with naphthyl iodide 64 afforded atropoactive

38 56 styrene 65 featuring an oxindole scaffold with moderate 56 enantioselectivity. In this reaction, the TADDOL-derived

base phosphoramidite ligand 66 displayed the best stereoinduction. A mechanism involving intramolecular C–H activation Ph L I OTf was proposed. The atroposelective insertion of the C≡C tri- Ph Ph Ph IV X Pd X ple bond of 63 into INT-12 gave INT-13, which was regard- Pd II +Pd L' visible light ed as the key intermediate for stereoinduction. An intramo- Ar Ar [Ph2IOTf]* lecular C–H palladation of INT-13 formed palladacycle INT- INT-10 INT-11 14, which delivered final product 65 and liberated Pd(0) af- PhI+ Ph-I ter reductive elimination. INT-6 By using the concept of transient chiral auxiliaries, Shi Ph 22 III Ph and co-workers realized a palladium-catalyzed asymmet- Pd Ph INT-7 ric olefination of styrene 67 in 2020 (Scheme 13). Chiral Ar Ar 38 amino amide 70 was chosen as the optical transient chiral INT-9 INT-8 auxiliary, and atropisomeric styrenes 69 were synthesized with good yields and high stereoselectivity (up to 99% ee). standard H/D Ph substrate light k /k conditions H D Palladacycle complex 72 was prepared by treating 71, fea- P(O)Ph2 P(O)Ph2 38a or 38a-d On 1.05–1.14 turing an imine moiety, with stoichiometric Pd(OAc)2 in 38a or 38a-d Off 3.6 35% yield. The structure of palladium complex 72 was con- 38a/38a-d 56a firmed by single-crystal X-ray diffraction analysis. The ap-

Scheme 10 Visible-light-mediated C–H arylation plication of 72 instead of Pd(OAc)2/70 to the asymmetric C–H olefination reaction under the standard conditions gave optically active 69a with 80% ee, which indicated the possibil- ketone group with HCl. Diaryl phosphine 61 was achieved ity of an in situ formed amino amide transient directing by treating 58b with diphenyl phosphorus chloride; the group. The utility of the products was demonstrated by em- product was subjected to asymmetric allylation to provide ploying the corresponding ,-unsaturated chiral carboxyl- 62 in moderate yield with 37% ee. ic acids (CCAs) as chiral ligands for the enantioselective

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Pd(OAc)2 (10 mol%) Ac-L-Ala-OH (20 mol%) O OMe OMe R1 N AgOAc, MeOH 1 + R3 R N 2 AcHN OH R H 24 examples R2 R3 up to 88% yield Ac-L-Ala-OH up to 99% ee 57 58

OMe Pd/C (5 mol%) OMe Me N OMe Me N H2 (balloon) Me N Me O CO2Et MeOH CO2Et HCl, dioxane CO2Et CO2Et

58a 59 58a 60 99% ee 55%, 97% ee 99% ee 56%, 99% ee

Ph PCl 2 [Pd(allyl)Cl] (2 mol%) OMe Et N, THF OMe OAc 2 Me N 3 Me N 61 (5 mol%), BSA MeO C CO Me HO CO2Et Ph2PO CO2Et Ph Ph CsOAc, toluene 2 2 + Ph Ph 58b 61 MeO2C CO2Me 62 96% ee 52%, 97% ee 60%, 37% ee

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

R O O R Ar1 Pd(OAc) (10 mol%) N Ph Ph N I 2 Ar1 66 (20 mol%) O O H OMe 2 Cs2CO3, toluene Ar P N O 2 + Ar OMe O O Ph Ph 66 63 64 65 up to 67% ee

64 65 [Pd0]

R N O I [PdII] OMe [PdII] OMe INT-12

R INT-14 N O

II 63 [Pd ] OMe

INT-13

Scheme 12 Double functionalization of an alkyne

Csp3–H amidation of thioamides. In comparison with biaryl readily available L-pyroglutamic acid to form INT-15. acid 75, the styrene-based acid 74 derived from 69 gave an Through good cooperation of the directing group and chiral improved enantioselectivity (from 42% ee to 64% ee). ligand, modulation of the reactivity and induction of the Later, the same group23 disclosed the asymmetric syn- stereoselectivity were achieved to give atropisomeric prod- thesis of atropisomeric styrenes via C–H alkenylation by us- ucts 77 with good yields and enantioselectivity. The gener- ing a 2-pyridyl moiety as a directing group (Scheme 14). ality of substrate scope was investigated with different sub- The starting material 76 could ‘freely’ rotate around the vi- stituted styrenes. The reaction with alkynyl bromide was nyl–arene axis under the reaction conditions. The pyridine also successful, giving the coupling products with very high nitrogen atom could coordinate with palladium and the enantiopurity.

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CHO Pd(OAc)2 (10 mol%), 70 (30 mol%) CHO 70: (BnO)2PO2H (50 mol%) H + R R Co(OAc)2.4H2O, BQ, O2 t N Bu2 HOAc /DMSO (10:1) H2N O rac-67 68 69 28 examples up to 95% yield up to 99% ee

CHO CHO NEt2 NEt2 Ph Ph Ph N Pd(OAc)2 (1 equiv) Ph N n 72 instead of Pd(OAc)2/70 CO2 Bu H O AcOD-d1 (0.2 M) Pd O standard conditions OAc 40 °C, 1 h Me Me Me Me 71 72, 35% yield 67a 69a, 88%, 80% ee

Styrene-type CCA Biaryl-type CCA Ph S H [Cp*Co(MeCN)3][SbF6]2 (5 mol%) S N CCA (10 mol%), o-DCB CO2H O + N N NHCOPh Ph O VS CO2H Me MS 13X, 40 °C, 24 h Me iPr Ph Ph iPr Ph O Ph

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

Scheme 13 C–H olefination strategy

2 R2 Pd(OAc)2 (10 mol%) R O L-pGlu-OH (20 mol%) O DG DG 3 N 2 3 R Ag3PO4, MeCN/tBuOH (4:1) R FG R 1 Pd FG R1 H R N R3 CO2H N H R1 O H O L-pGlu-OH 76 INT-15 77 DG = 2-pyridyl FG = alkenyl, alkynyl

nPr Me

N nPr N TIPS N Me TIPS N BuO2C Me BuO2C Me Me Me

77a, 95%, 93% ee 77b, 87%, 95% ee 77c, 86%, 99% ee 77d, 54%, 97% ee Scheme 14 Pyridine-group-directed asymmetric C–H functionalization

Very recently, Wang and co-workers24 reported a C–H 4.4 Atropisomeric Synthesis of Styrenes Prompted olefination and arylation for the asymmetric synthesis of by Nucleophilic Addition atropisomeric styrenes by utilizing a carboxylic acid direc- tion strategy (Scheme 15). The protocol demonstrated a In 2017, Tan and co-workers25 reported an organocata- broad substrate scope, high yields, and excellent stereose- lyzed atroposelective synthesis of atropisomeric styrenes lectivity (up to 99% ee). Notably, the absolute configuration by means of nucleophilic addition to propanal derivatives of the products was the opposite configuration to the prod- (Scheme 16). In the presence of chiral pyrrole 83, alkynal 81 ucts of Shi and co-workers, despite Boc-L-leucine and 70 was activated by forming INT-16, which underwent nucleo- being derived from the same amino acid, L-leucine. The au- philic attack to generate INT-17 stereoselectively. Isomeri- thors explained these observations by proposing two differ- zation of INT-17 gave iminium ion INT-18, which could be ent models for the stereoinduction. In TS-1, the bulky alkyl converted into final product 82 by hydrolysis. With regard chain of the amino acid points upward and pushes the alke- to substrate scope, styrenes bearing an iodine and sul- nyl group away from the palladium. However, in TS-2, the fophenyl group (82a, 82b) could be tolerated, but installa- upward tBu group forces the alkenyl group downward, tion of a methyl group at the -position of the axis greatly which leads to the opposite configuration. The utility of decreased the stereoselectivity to 54% ee (82c). A nucleo- these CCAs was further demonstrated by two phile containing an allyl moiety was also compatible (82d).

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

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R3 O ArBpin studies in this area. VQM intermediate INT-19 bears an at- CO Me CO2Me Pd(OAC) 2 Ph Pd(OAc)2 Ph OH 2 Ph ropisomeric allenyl moiety, which is critical for the high en- Boc-L-leucine Boc-L-leucine R3 2 1 1 R antioselectivity in subsequent reactions. The activated sul- R KOH, H2O, iPrOH R1 Ag2CO3, BQ, KHCO3 R H O, tAmylOH, air 1 atm O2 2 finate anion derived from the combination of L-proline and then methylation then methylation 79 78 80 sodium sulfinate would act as a nucleophile to attack INT- 19, forming final product 85a. The role of boric acid was CO2Me CO2Me CO Me Ph Ph 2 CO2Me Ph probably to release L-proline from the complex for the next CO2Me Me CO2Me Me catalytic cycle.

79a 79b 80a 97%, 97% ee 68%, 90% ee 57%, 94% ee R1 OMe 86 (10 mol%) SO2Ar R1 H Ph O L-proline (10 mol%) N O tBu OH tBu H3BO3, CH3Cl OH 2 Et2N R NH OK O O 2 O Pd O Pd R ArSO2Na H N N N H H S NH O 84 85 NHAr' R' Ph up to 99% ee, E/Z >99:1 86, Ar' = 3,5-(CF ) C H TS-1 TS-2 3 2 6 3

COOH CHO Ph opposite absolute Ph configurations R FG R FG

PhSO – COONa N COONa 2 N Wang's product(s) Shi's product(s) H H H H H H activated sulfinate anion – Scheme 15 Asymmetric C–H olefination and arylation with a carboxyl- PhSO2 NQ NQ ic acid directing group NH NH O S O S N H N H Ar' 26 Ar' In 2018, Yan and co-workers described an enantio- L-proline + ArSO2Na selective synthesis of sulfone-containing atropisomeric sty- nucleophilic addition VQM intermediate (INT-19) Ph renes with the cooperation of quinine-derived thiourea 86 H3BO3 SO Ph and L-proline (Scheme 17). A series of enantioenriched sty- Ph 2 renes 85 was prepared with good enantioselectivity and ex- OH OH cellent E/Z selectivity by treating 1-alkynyl-naphthalen-2- ols 84 with sodium sulfinates. Based on control experi- 85a 84a ments and DFT calculations, a vinylidene o-quinone methide (VQM) was proposed as the key intermediate, 86 which significantly influenced the subsequent series of Scheme 17 Synthesis of atropisomeric styrenes via VQMs

O Ac Ac 83 (5 mol%) Nu R1 LiOAc, CH2Cl2 CHO H R1 + Ar Ar 2 N R H 81 OTIPS 82 Nu 83, Ar = 3,5-Me2C6H3

3 N R H 3 N R 3 N R Nu H Nu N R1 H Nu R1 R1 H R3

INT-16 INT-17 INT-18

Br Br Br Ac Ac Ac Ac Ac Ac Ac Ac CHO CHO CHO CHO I I SO2Ph Me Br

82a: 96%, 94% ee 82b: 40%, 82% ee 82c: 89%, 54% ee 82d: 87%, 94% ee (Z/E = 96:4)

Scheme 16 Chiral pyrrole-catalyzed synthesis of chiral styrenes

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Based on the key optically active intermediate, VQM, odology employed N-squaramide 96 as the catalyst, giving Yan and co-workers27 completed the asymmetric synthesis the atropisomeric styrenes 95 with excellent enantioselec- of atropisomeric sulfone-containing styrenes bearing up to tivity. three axes with high enantio- and diastereoselectivities Benefiting from the versatile reactivity of VQM and its (Scheme 18a). Alkynes 87 reacted with arylsulfinic acid to analogs, in 2019, Tan and co-workers30 achieved the con- deliver enantioenriched multi-axis styrenes 88 smoothly struction of a series of disubstituted atropisomeric 1,1′- with the assistance of the chiral quinine-derived squara- (ethene-1,1-diyl)binaphthol (EBINOL) derivatives by utiliz- mide catalysts 89 via tetrasubstituted VQM INT-20. This al- ing 2-naphthol as the nucleophile (Scheme 19). Under ca- lowed kinetic resolution with an excellent selectivity factor talysis with compound 100, atropisomeric styrenes 99 (S). Later, the same group28 disclosed the asymmetric syn- were synthesized in high yields and enantioselectivity, thesis of atropisomeric 1,4-distyrene 2,3-naphthalene diols along with complete E/Z selectivity, under mild reaction by means of organocatalysis (Scheme 18b). Nucleophilic ad- conditions. The utility of this transformation was exhibited dition of an amidosulfone to a VQM with the aid of cincho- by the preparation of atropisomeric EBINOL-based chiral na squaramide 93 under mild reaction conditions afforded phosphonic acid (ECPA) 101 and phosphoramidites 105a 92 featuring two chiral axes. Catalytic asymmetric synthe- and 105b. Under catalysis with 101, alkylation of indole sis of a sulfone-containing atropisomeric styrene via the (102) with N-(1-phenylvinyl)acetamide (103) afforded ter- Michael addition reaction of -amido sulfones to ynones tiary amine 104 smoothly with moderate enantioselectivi- was achieved by the same group (Scheme 18c).29 The meth- ty. By contrast, a BINOL-derived CPA gave a lower stereose-

(a) 1 1 R R R1

2 ArSO2H R 89 (10 mol%) R3 R2 3 R NIS, DCM I 3 R SO2Ar R2 I OH OH O

87 INT-20 88 up to 98% ee, E/Z >20:1 >20:1 d.r.

Me Cl OMe Ph H N SO Ph S SO Ph SO Ph I 2 I 2 I 2 OH OH OH NH N O NHAr'

(1Sa,2Ra)-88a (1Sa,2Ra)-88b (1Sa,2Ra,3Sa)-88c O 93%, 95% ee 90%, 92% ee 43% (45% conv.), 96% ee Ar' = 3,5-(CF3)2C6H3 E/Z >20, >20:1 d.r. E/Z >20, >20:1 d.r. E/Z >20, >20:1 d.r. 89 S = 117

(b) R1

3 SO2R OMe R1 93 (10 mol%) H OH OH N N CHCl3 Boc NH OH NH OH OMe N R2 H 3 R3O S O N SO2R 2 H N 2 R (91) O 90 92 93

Scheme 18 Synthesis of atropisomeric styrenes via tetrasubstituted VQMs

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2 R1 R

9-anthryl 100 (5 mol%) OH O OH XH PhCF3 O 1 XH P + R O NHTf

R2 R2 9-anthryl R2 100 97 98 99 67 examples XH = NHAr, NHBn, OH up to 99% yield, 99% ee

AcHN Ph NHAc Me Ar CPA (5 mol%) O O + PhCF3 P N OH N tBu O H H Ar 102 103 (R)-104 ECPA 101: 95%, 73% ee ECPA 101 (Ra)-BINOL-CPA: 50% ee (Ra)-SPINOL-CPA: 1% ee

Ph Me Ph Me Me O N O Me Ph Ph P P O O Me P N P N O tBu O N O O tBu Ph Ph Ph Me Ph Me Me

EBINOL-Phos 105a EBINOL-Phos 105b Phos-bs Phos-sr

O O H2 (30 bar) 105a: 97%, 90% ee Rh(cod)2BF4 (0.5 mol%) OMe iPrOH OMe Phos (1.1 mol%) 105b: trace NHAc NHAc Phos-bs: NR Phos-sr: 24%, –8% ee 106 (R)-107

Scheme 19 Atroposelective synthesis of atropisomeric EBINOL lectivity and a SPINOL-based CPA failed in the induction of In 2020, Li, Yan, Liu, and co-workers31 applied asymmet- enantioselectivity. The phosphoramidite was obtained as ric nucleophilic addition for the synthesis of atropisomeric the pair of diastereoisomers 105a and 105b exhibiting styrenes bearing a stereocenter and a chiral axis (Scheme

P-stereocenters because of the lack of C2-symmetry of 20). Racemic 5H-oxazol-4-ones 109 worked as nucleophiles EBINOL. EBINOL-Phos 105a efficiently prompted the asym- to attack the in situ formed VQM intermediate derived from metric hydrogenation of enamides 106 with 97% yield and 108 to afford 110 with high enantioselectivity, high diaste- 90% ee, whereas 105b afforded the product in low yield. The reoselectivity, and a good E/Z ratio. This method offers an alternative phosphoramidites Phos-bs and Phos-sr did not efficient approach to these stereoisomers, which have po- give satisfactory results. tential applications in asymmetric synthesis.

Ar O N OMe O 111 R2 2 Ar' H N N R (10 mol%) OH O Ar + 1 N HO R O CHCl3 NH OMe R1 Ar' N H O N H 108 rac-109 110 N O up to 96% ee 111 E/Z >99:1; d.r. >20:1

O O O O N N N Me N Ph Et p-Tol Et Ph Et Ph Et O Ph O Ph O O S HO HO HO HO

(Ra,R)-110a, 83%, 92% ee (Ra,R)-110b, 85%, 94% ee (Ra,R)-110c, 84%, 88% ee (Ra,R)-110d, 82%, 92% ee E/Z >99:1; d.r. >20:1 E/Z >99:1; d.r. >20:1 E/Z >99:1; d.r. >20:1 E/Z >99:1; d.r. >20:1

Scheme 20 Construction of atropisomeric styrenes with multiple stereoelements

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5 CF3 1 R 1 CO2R CO R H 2 F N 114 (10 mol%) N 2 1 1 N R CO2R Cs2CO3, toluene R2 CO2R O F C R4 R4 3 H F R5 R3 R3 Br Br F tBu N 112 113 114 tBu

CO2Et CO2Et PMB CO2Et Bn CO2Et N N N N Bn CO2Et Bn CO2Et Bn CO2Et Bn CO2Et R I I I

R = I, 113a, 84%, 92% ee 113c, 91%, 94% ee 113d, 76%, 84% ee 113e, 65%, 91% ee R = CF3, 113b, 87%, 94% ee

Ph OH R5 CO2Et NHnPr a) DIBAL-H, Et2O N LDA N N Bn CO2Et b) nPrNH2, TfOH, Et2O THF Bn CO2Et Bn CO2Et I I I R5 = Ph R5 = vinyl

115, 57%, 91% ee 113a, 92% ee 116, 84%, 90% ee 113e, 91% ee 78:22 d.r.

Scheme 21 Synthesis of atropisomeric styrenes via N-alkylation

N-Alkylation of enamide 112 also enabled preparation 113e with LDA. Atropisomer 116, featuring a seven-mem- of atropisomeric styrenes.32 Nucleophilic substitution of al- bered cyclic system, was also prepared by reduction of 113a kyl bromides with 112 in the presence of a catalytic with DIBAL-H followed by annulation with good enantiose- amount of 114 afforded enantioenriched styrenes 113 with lectivity and 78:22 diastereoselectivity. satisfactory stereoselectivity and good functional-group In 2020, Zhao and co-workers33 identified an aza-VQM tolerance (Scheme 21). Substrates including allyl bromide, as a key intermediate for the preparation of atropisomeric propargyl bromide, 4-methoxybenzyl bromide, and benzyl vinyl -anilines. A well-defined chiral sulfide was used as bromide were successfully applied in the protocol (113a– the catalyst, which promoted an asymmetric electrophilic 113e). A merit of this methodology was the rapid prepara- carbothiolation and intramolecular annulation reaction tion of atropisomeric 2-arylpyrrole scaffold 115 by treating (Scheme 22). INT-20 was formed by coordination of sulfur

Me 1 O NHR 120 (10 mol%) SR2 2 TMSOTf + N SR NHR1 S CH2Cl2/CHCl3 OiPr O (1:1) NHTs 117 118 119 120 2 R = Ar, CF3 up to 98% ee

O R2S NSR2 + TMSOTf Me H O O S N OiPr Ms N TMS NHTs TfO 120 O INT-22 –TfOH Me Me Ts N H O S O S F3C S 2 OiPr O OiPr SR H S 1 SR2 Ms N NHR N 117 Ts H OTf Ph 119 INT-20 INT-21

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

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H R Ar N Ar'' OH 124 (10 mol%) Ar' 124 (10 mol%) O Ar 4 Å MS, toluene H 4 Å MS, toluene Ar N H O H N N Ph

E = H E = OH 122 R 121 H 123 39 examples 12 examples Ar' Ar'' up to 95% yield NH up to 92% yield O O up to 95% ee up to 97% ee

Ar 121a 122a HO O P O O Ar 124 Ar Ar Ar = 2,4,6-iPr3C6H2 H O O Ph H O O N H P O P O PhH O H O π π N N π π INT-26 INT-23

H Ar N Ar Ph O O P O H H O N O O P π Ph O N H O π π (no reaction) N π

INT-25 INT-24 NH

Scheme 23 Chiral phosphoric acid catalyzed atroposelective synthesis of styrenes

reagent 118 and catalyst 120 with the aid of a Lewis acid. An atropisomeric styrene framework bearing a novel Subsequently, INT-20 reacted with alkyne 117 to generate seven-membered bridged ring was also synthesized by Shi sulfonium salt INT-21, which transformed into aza-VQM and co-workers in 2020 (Scheme 24).35 (3-Alkynyl-2-indo- INT-22 by elimination and liberated the catalyst. Intramo- lyl)methanols 125 can readily generate optically active al- lecular annulation of INT-22 afforded sulfur-containing at- lenes with the assistance of chiral phosphorous acid 127, ropisomeric styrenes 119. which was atroposelectively attacked by 2-naphthol to give Following this, Zhang and co-workers34 reported an acyclic chiral styrenes. Intramolecular dehydration afforded asymmetric nucleophilic addition of 1-(ethynyl)naphtha- the fused atropisomeric styrene 126. len-2-amines to achieve a divergent synthesis of atropiso- Later, the same group36 reported a kinetic resolution of meric styrenes (Scheme 23). The reaction employed indoles indole-based vinyl aniline 128 (Scheme 25). The resolution, or 4-hydroxycoumarins as substrates, and high yields and featuring a high selectivity factor (S), allowed efficient con- excellent enantioselectivity were obtained. Based on previ- trol of conversion and enantioselectivity and offered an ap- ous work and control experiments, a mechanism involving proach to a new class of atropisomeric styrenes. a – interaction and hydrogen-bond-mediated model was proposed. Combination of 121a with chiral phosphoric acid 4.5 Asymmetric Phase-Transfer Alkylation 124 would generate INT-23, which could isomerize to aza- VQM INT-24 in an enantioselective form. INT-24 could then Enolization of 3,4-dihydronaphthalen-2(1H)-one gives a be attacked by the indole to give INT-26. Subsequent disso- 3,4-dihydronaphthalen-2-ol intermediate. In 2017, Smith ciation of INT-26 would afford enantioenriched 122a and and co-workers37 realized an asymmetric O-alkylation regenerate 124. The hydrogen bond plays a vital role in the strategy for the atroposelective synthesis of atropisomeric reactivity and enantiocontrol. By contrast, N-methyl indole styrenes via chiral phase-transfer catalysis (Scheme 26). displayed no selectivity under identical conditions. The methodology employed ketone 132 as the enolate pre- cursor. O-Alkylation with the assistance of chiral ammoni-

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R2 tBu H OH 127 (10 mol%), toluene tBu OH + R2 R1 Ar G O N Ar R1 H N O O H Ar Ar 125 P O OH 126

1st nucleophilic G 2nd nucleophilic addition 127, G = 2-naphthyl addition

2 R R2 R2 tBu H H H tBu tBu OH – H O 1 O 2 Ar O R Ar Ar O 1 H H 1 H R N Ar R O O N Ar O H N P Ar O H * H O P H O P H O * *

MeO H H X tBu tBu tBu Br O O O N N N H Ph Ph H Ph Ph H Ph Ph 126a, 97%, 95% ee 126b, 87%, 91% ee X = Cl, 126c, 60%, 91% ee, E/Z >95:5 E/Z >95:5 E/Z >95:5 X = Br, 126d, 61%, 94% ee, E/Z >95:5

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

R R R O O O N N N HN O 131 (10 mol%) NH HN 2 R 3 Å MS, CH Cl 2 2 2 O + O + H H R N kinetic 1 NH H2N R 1 N 3 1 2 resolution R N R R 3 H R O

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

R G O R R N O O HN O NH N N HN O O 2 P fast reaction O R + OH H O N R1 H N H N 1 NH 3 2 R R1 2 R G H G = 2-naphthyl O O 131 P (Ra)-128 (Sa)-128 *

Bn Bn Bn Bn O O O O NH N N HN NH N N HN

O p-ClC H + H H Ph + H H 6 4 H N N H N N O 2 N Ph 2 H N Ph O O H 128a, 46%, 86% ee 130a, 48%, 90% ee 128b, 44%, 96% ee 130b, 51%, 87% ee S = 53 86:14 d.r. S = 56 90:10 d.r.

Scheme 25 Catalytic kinetic resolution um salt 134 afforded enol ether 133 with excellent enanti- to afford soluble diastereoselective ion pairs INT-27 and oselectivity. The procedure commenced with racemic ke- INT-28. The diastereomers bearing atropisomeric informa- tone 132, featuring central chirality, as the substrate; this tion could interconvert through protonation and deproton- could generate the enolate with the aid of solid potassium ation. Atropisomeric styrene 133a was exposed to m-chlo- phosphate and coordinate with the chiral ammonium salt roperoxybenzoic acid to afford the corresponding epoxide,

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OMe R1 R1 134 (10 mol%), K3PO4 OH O C6H6/CH2Cl2 (4:1) OBn OR3 OR3 N BnI R1 R1 N H F F 134 132 133 F

standard conditions R4N fast O OBn OMe OMe

O INT-27 133a OR3 major enantiomer axial chirality

rac-132a (central chirality) R4N O slow OBn OMe OMe standard conditions

INT-28 ent-133a minor enantiomer

mCPBA, CH2Cl2 DDQ, CH Cl O OBn 2 2 OH OBn then Yb(OTf)2 then BBr3 CH2Cl2 OMe OMe OH

135 136 133a, 92% ee 94%, 86% ee 98%, 92% ee

Scheme 26 Asymmetric O-alkylation

which was subsequently rearranged with catalytic ytterbi- Me Me Cl Br um triflate to give 135 with central chirality. BINOL 136 MeO Me Me Me was obtained readily by oxidation and dealkylation of 133a resolvable not resolvable CO2H H without erosion of enantioselectivity. Cl MeO H CO2H (E)-137[6,7] (Z)-138[6,7]

5 Stability of the Chirality of Atropisomeric Figure 2 Geometric effects on the stability of atropisomers Styrenes In accordance with racemization experiments and DFT In comparison with biaryl atropisomers, atropisomeric calculations, atropisomeric styrenes with suitable substitu- styrenes display less stability because of their less rigid ents have been synthesized and used as novel framework li- skeleton. The numbers and size of adjacent substituents can gands or bioactive compounds. In Figure 3, the reported dramatically affect the rotational barriers of styrenes. Al- data for the rotational barriers of some atropisomeric sty- though no bridged atropisomeric styrenes have been dis- renes are depicted to demonstrate their structure–stability cussed in the literature, fused molecules with appropriate relationships. It is foreseeable that the number and steric ring sizes showed excellent stability. Of course, the influ- size of the substituents next to the axis will significantly af- ence of the Z/E geometry of the C=C double on the stability fect the rotational barriers of these atropisomers. Currently, of the chiral axis cannot be ruled out. In early studies, com- it is hard to draw the conclusion that dihydro-binaphtha- pound 2 was not resolvable because of the low steric hin- lene and 1-(1H-inden-3-yl)naphthalene structures have derance of the hydrogen atom. Nevertheless, enantiomers higher chiral stabilities than the corresponding acyclic atro- of compound 5, bearing an isopropyl moiety at the -posi- pisomeric styrenes. 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 hydrogen as the adjacent substituent (Figure 2).

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COOH H Me Me O O2N Me CO2R* P(O)Ph2 OMe

Me NO2 Me [18] [16] 2[4] 20[11] R* = (1R)-menthyl 38a 48a unstable at r.t. 106.0 kJ mol–1 (54 °C) 120.1 kJ mol–1 (80 °C) 115.5 kJ mol–1 (100 °C)

Me Ac Ac Ac Ac S CHO Me N CHO Me CHO pBrC6H4 CHO F I

82a[24] 82e[24] 82f[24] 82g[24] 127.2 kJ mol–1 (25 °C) 67.8 kJ mol–1 (25 °C) 123.1 kJ mol–1 (25 °C) 106.3 kJ mol–1 (25 °C) [Calculated Results] [Calculated Results] [Calculated Results] [Calculated Results]

H H I tBu tBu OH Cl O O N N H Ph Ph H Ph Ph 139[24] 122.2 kJ mol–1 (25 °C) 126a[33] 126e[33] [Calculated Results] 117.2 kJ mol–1 (60 °C) 117.2 kJ mol–1 (60 °C)

Bn Bn Bn O O O NH N N HN Cl NH N

F H H H H2N N O N NHBz O BzHN

[34] [34] 128a 130c 140[34] –1 –1 114.0 kJ mol (80 °C) 124.4 kJ mol (100 °C) 119.6 kJ mol–1 (80 °C) Figure 3 Rotational barriers

6Outlook References

Atropisomeric styrenes bearing a C(vinyl) –C(aryl) (1) (a) Bao, X.; Rodriguez, J.; Bonne, D. Angew. Chem. Int. Ed. 2020, sp2 sp2 59, 12623. (b) Toenjes, S. T.; Gustafson, J. L. Future Med. Chem. bond as the rotation-restricted axis have been overlooked 2018, 10, 409. (c) Liao, G.; Zhou, T.; Yao, Q. J.; Shi, B. F. Chem. for decades because of their relatively lower rotation barri- Commun. 2019, 55, 8514. ers in comparison with those of their biaryl counterparts. (2) (a) Shan, G.; Flegel, J.; Li, H.; Merten, C.; Ziegler, S.; Antonchick, Much effort has been devoted to exploiting approaches for A. P.; Waldmann, H. Angew. Chem. Int. Ed. 2018, 57, 14250. the synthesis of stable atropisomeric styrenes in the last (b) Wang, F.; Qi, Z.; Zhao, Y.; Zhai, S.; Zheng, G.; Mi, R.; Huang, ten years. Many novel styrene frameworks have been con- Z.; Zhu, X.; He, X.; Li, X. Angew. Chem. Int. Ed. 2020, 59, 13288. (c) Zhu, S.; Chen, Y. H.; Wang, Y. B.; Yu, P.; Li, S. Y.; Xiang, S. H.; structed, demonstrating unique applications in asymmetric Wang, J. Q.; Xiao, J.; Tan, B. Nat. Commun. 2019, 10, 4268. synthesis. However, new methodologies for the efficient, (3) Hyde, J. F.; Adams, R. J. Am. Chem. Soc. 1928, 50, 2499. practical asymmetric synthesis of atropisomeric styrenes (4) Maxwell, R. W.; Adams, R. J. Am. Chem. Soc. 1930, 52, 2959. with high enantioselectivity are still desirable. (5) Mills, W. H.; Dazeley, G. H. J. Chem. Soc. 1939, 460. (6) Adams, R.; Miller, M. W. J. Am. Chem. Soc. 1940, 62, 53. (7) (a) Adams, R.; Anderson, A. W.; Miller, M. W. J. Am. Chem. Soc. Conflict of Interest 1941, 63, 1589. (b) Adams, R.; Binder, L. O. J. Am. Chem. Soc. 1941, 63, 2773. (c) Adams, R.; Gross, W. J. J. Am. Chem. Soc. 1942, The authors declare no conflict of interest. 64, 1786. (d) Adams, R.; Binder, L. O.; McGrew, F. C. J. Am. Chem. Soc. 1942, 64, 1791. (e) Adams, R.; Miller, M. W.; McGrew, F. C.; Anderson, A. W. J. Am. Chem. Soc. 1942, 64, 1795. (f) Adams, R.; Funding Information Theobold, C. W. J. Am. Chem. Soc. 1943, 65, 2383. (g) Adams, R.; Ludington, R. S. J. Am. Chem. Soc. 1945, 67, 794. (h) Adams, R.; This work was supported by the National Natural Science Foundation Mecorney, J. W. J. Am. Chem. Soc. 1945, 67, 798. of China (21901236, 21871241).National Natural Science Foundation of China 2(1871241)National Natural Science Foundation of China 2(1901236)

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