SYNOPEN2509-9396 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2021, 5, 68–85 review 68 en SynOpen J. Feng, Z. Gu Review Atropisomerism in Styrene: Synthesis, Stability, and Applications 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 at- ropisomeric 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 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. 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. © 2021. The Author(s). SynOpen 2021, 5, 68–85 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 69 SynOpen J. Feng, Z. Gu Review 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- SynOpen 2021, 5, 68–85 70 SynOpen J. Feng, Z. Gu Review 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.