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Letter
Enantioselective Synthesis of Atropisomers Featuring Pentatomic Heteroaromatics by Pd-Catalyzed C–H Alkynylation Shuo Zhang, Qi-Jun Yao, Gang Liao, Xin Li, Han Li, Hao-Ming Chen, Xin Hong, and Bing-Feng Shi ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04870 • Publication Date (Web): 01 Feb 2019 Downloaded from http://pubs.acs.org on February 3, 2019
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ACS Catalysis
Enantioselective Synthesis of Atropisomers Featuring Pentatomic Heteroaromatics by Pd-Catalyzed C–H Alkynylation Shuo Zhang,† Qi-Jun Yao,† Gang Liao,† Xin Li,† Han Li,† Hao-Ming Chen,‡ Xin Hong,*,† and BingFeng Shi*,† † Department ‡ School
of Chemistry, Zhejiang University Hangzhou 310027 (China) of Chemical & Environmental Engineering, Wuyi University, Jiangmen 529020 (China)
ABSTRACT: Due to the lower rotational barriers, the catalytic asymmetric construction of atropisomeric species featuring a fivemembered ring remains a formidable challenge. Herein, we describe a Pd-catalyzed atroposelective C–H alkynylation to synthesize such atropisomers. A wide range of atropisomers displaying either a stereogenic C–N or C–C bond featuring one or even two fivemembered rings were obtained (up to 98% yield and up to >99% ee). Various five-membered heteroarenes, including pyrroles, thiophenes, benzothiophenes, and benzofurans were compatible with this protocol. Notably, this strategy offers the catalytic asymmetric synthesis of axially chiral 3,3‘-bisbenzothiophene with good ee (96% ee). Computational studies revealed the key structural elements that differentiate the rotational barriers of benzothiophene and benzofuran moieties. KEYWORDS: five-membered heteroatropisomers • palladium • atroposelective • C‒H alkynylation • rotational barrier
Axially chiral biaryl backbones are one of the most prominent structural motifs that are widely represented in natural products and pharmaceuticals, and used as privileged chiral ligands.1 Therefore, strategies to construct these biaryl scaffolds have been well investigated and great achievements have been accomplished.2 However, these established methods are mainly restricted to the construction of hexatomic aromatic carbocyclic compounds (6,6-ring system), such as biphenyls, binaphthyls, and phenylnaphthyls,2 the access to atropisomers containing one or even two five-membered rings (5,6- or 5,5-ring systems) connected through C-C or C-N bond have seldom been reported.3 Nevertheless, atropisomeric species containing fivemembered rings are widely exist in natural products (Figure 1a).4 The design of chiral diphosphines containing pentatomic heteroaryls has also gained intensive attentions, considering that the steric and electronic properties of the phosphine groups, crucial parameters for catalytic activity, could be easily tuned by the introduction of different heteroarenes/or simply changing the positions of connection (Figure 1a).5 For example, optically pure tetraMe-bitianp was successfully employed as a superb ligand in Ru(II)-catalyzed asymmetric hydrogenation of α- and β-oxo esters with outstanding enantiocontrol.5a-c BINAPFu surpassed BINAP in an asymmetric Heck reaction.5d Therefore, the development of a catalytic asymmetric synthesis of atropisomers featuring one or two five-membered heteroarenes is highyl appealing. However, the lower conformational stability resulted from the increased distance of substituents ortho to the axis within these heteroatropisomeric species renders the asymmetric synthesis more challenging (Figure 1b).3,6 There were only sporadic examples dealing with this intractable issue (Figure 1c).7-12 In 2012, Itami and Yamguchi reported a Pd-catalyzed CH/C-B coupling to form thiophene-naphthyl atropisomers using a chiral 2,2’-bis(2-oxazoline) ligand with moderate ee (up to 72% ee).7 In 2017, Rodriguez and co-workers reported the enantioselective synthesis of furan-aryl atropisomers by an oxidative central-to-axial chirality conversion strategy.8 The
challenge of catalytic asymmetric construction of indole-based axially chiral biaryl skeletons was tackled until recently.9-10 In 2017, Shi and co-workers reported the asymmetric addition to construct axially chiral indole-naphthyl skeletons with a chiral phosphoric acid (CPA) as the organocatalyst.9a Tan and coworkers reported the organocatalytic arylation and rearrangement reactions to access indole-aryl backbones using CPA as the organocatalyst.10a They also demonstrated the access of arylpyrroles by asymmetric Paal-Knorr reaction with CPA as the organocatalyst.10b Gu reported a Pd(0)/phosphoramidite-catalyzed atroposelective synthesis of indole-based atropsiomers via an intramolecular C–H arylation.12 Although these elegant achievements showcase the feasibility of catalytic asymmetric synthesis of atropisomers containing one five-membered heteroarene (5,6-ring system), asymmetric synthesis of atropisomeric systems displaying two five-membered heteroaryls (5,5-ring system) remains undeveloped.9b Recently, atroposelective C–H functionalization has emerged as a powerful strategy to construct axially chiral biaryl backbones,2e,13 as demonstrated by the seminal works from the groups of Murai,14 Miller,15 Wencel-Delord and Colobert,16 You,17 Antonchick and Waldmann,18 Cramer,19 us,20 and others.7,12,21 However, in sharp contrast to the above-mentioned, widespread applications of organocatalytic strategy to construct atropisomers featuring five-membered rings,8-11 C–H activation strategy has been seldom used, largely due to the conformational unstability of these skeletons under relatively high temperature emplyed in C–H activation reactions.7,12 Inspired by the pioneering work by Yu on the creation of piont chirality via transient chiral auxiliary enabled C–H activation22 and our continuous interests in asymmetric C–H activation,20,23 we decided to address this formidble challenge. We rationalized that the introduction of a bulky group, such as TIPS-protected alkynyl to replace the smaller C2‘–H via C–H activation, could increase the rotational barriers of the newly formed axial chirality (Figure 1d). Herein, we report the synthesis of axially
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chiral heteroaryls through a Pd-catalyzed atroposelective C–H alkynylation using tert-leucine as an efficient, catalytic, and transient chiral auxiliary. Compared to previous reports (Figure 1c),7-12 this protocol features the compatibility with a wide range of five-membered heteroarenes (including pyrroles, thiophenes, benzothiophenes, and benzofurans), and high enantiocontrol (up to >99% ee). Notably, this is the first example of asymmetric synthesis of axially chiral bisbenzothiphene (Figure 1d). a) Atropisomerism in Natural Products and Ligands Featuring a Five-Membered Ring Me Cl Me HN N
OMe Me
OH O Cl
Cl O
OH
N
Br Cl R1=H, (-)-marinopyrrole A R1=Br, (-)-marinopyrrole B
N H
OMe (M)-(+)-murrastifoline F 5,6-ring system
entry
L-tert-leucine
O
5
L-tert-leucine
tetraMe-bitianp BINAPFu 5,5-ring system
6
PPh2
PPh2
PPh2
7 l2
l3
l 3'
8
X = heteroatom
X 5,5-ring system
5,6-ring system
S
9 10 H N
O H
Ph
NO2
11
Ph OH
12 [7]
thiophene-naphthyl Pd(OAc)2/chiral bisox oxidative coupling R N
Ar
indole-naphthyl organocatalyst/CPA asymmetric addition
13
R'
N
L-tert-leucine
MOMO R
R'
indole-naphthyl[12] PdCl2/phosphoramidites intramolecular CH cyclization
[10b]
pyrrole-aryl organocatalyst/CPA Paal-Knorr reaction
L-tert-leucine L-tert-leucine L-valine L-phenylglycine Lcyclohexylglycine L-phenylalanine
Pd(OAc)2 (10 mol%) ligand (30 mol%)
N
CHO TIPS
2 equiv AgTFA solvent, temp, 72 h 3a
solvent toluene HOAc
temp (oC) 55 55
DCM toluene:DCE = 1:1 HOAc:DCE = 1:1 HOAc:toluene = 1:1
55 55
HOAc:toluen e = 2:1 HOAc:toluene = 2:1 HOAc:toluene = 2:1 HOAc:toluene = 2:1 HOAc:toluene = 2:1
55
HOAc:toluene = 2:1
55
HOAc:toluene = 2:1
55
55 55
60 65 55 55
Yield (%)b
eed
0
--
44
99
28
98
10
94
60
99
81c
98
85c 85 85 46 16 5 50
98 97 95 9 2 13 0
aReaction
N
NHR'
indole-aniline/naphthyl organocatalyst/CPA organocatalytic arylation
L-tert-leucine
[9]
[8]
benzo(furan)-aryl organocatalyst/squaramide central-to-axial chirality conversion CO2R
[10a]
L-tert-leucine
4
O
c) Previous Work: Atropisomers of 5,6-ring system
Me
L-tert-leucine
X
l 2'
Me
ligand
L-tert-leucine
X
6,6-ring system
Br 2a
rac-1a
b) Challenges
l1
+
H
1
TIPS
CHO
N
2
PPh2 S
5,5-ring system
Table 1. Optimization of Reaction Conditionsa
3
S Me Me
Me
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conditions: rac-1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol%), ligand (30 mol%), AgTFA (0.2 mmol) in 2 mL solvent at t oC under N2 for 72 h. b1HNMR yield using 1,3,5trimethoxybenzene as the internal standard. cIsolated yield. dThe ee value was determined by chiral HPLC. TIPS = triisopropylsilyl, AgTFA = silver trifluoroacetate.
d) This Work: Atropisomers of 5,6- and 5,5-ring systems Y
( )n
X
2
cat. Pd(OAc)2 CHO L-tert-leucine H Br SiR
2'
Y ( )n X
R CHO SiR 2'
( )m ( )m Z Z X = C or N; Y, Z = C or S or O; m, n = 0 or 1
Compatible with pyrrole, (benzo)thiophene, (benzo)furan Atropisomers featuring two pentatomic heteroaryls High enantioselectivity (up to >99% ee) transient-chiral-auxialiry enabled CH alkynylation
R
CHO
N
2
CHO
R'
X S
X CHO
X = S, O
CHO
X
Figure 1. The Importance of Axially Chiral Five-Membered Atropisomers and the Synthetic Challenges.
To verify the feasibility of our design, we commenced our study by investigations the reaction of rac-1a and TIPSprotected alkynyl bromide 2a. Gratifyingly, the alkynylated product 3a was obtained in 44% yield and 99% ee, when L-tertleucine was used as ligand in HOAc (Table 1, entry 2). 3a was proved to be conformationally stable as expected, and no erosion of the ee value was observed after heating at 120 oC overnight. Encouraged by these results, we investigated the solvent effect and found that a mixture of HOAc and toluene (2:1) gave the best results (entry 7, 85% yield, 98% ee). We then screened various other chiral α-amino acids and L-tert-leucine was proved to be optimal (entries 7-13).
With the optimized conditions in hand, we next explored the generality of the asymmetric C–H alkynylation. We first tested the scope of N-arylpyrroles, atropisomers featuring a C–N axis (Table 2a). Substituents either on the pyrrole ring or the aromatic ring were all compatible with this protocol, giving the corresponding products in moderate to excellent enantiocontrol (3a-3e, 64% to >99% ee). Arylpyrrole 1b bearing a phenyl group ortho to the axis, affording the desired product 3b only in 64% ee, presumably due to the reduced steric resistance. Next, we explored a class of axially chiral C-C bond atropisomers containing one five-membered heteroarenes. 2(Benzothiophen-3-yl) arylaldehyde derivatives with several different substituents on the aromatic ring all gave high enantioselectivity (Table 2b, 3f, 92%; 3h, 99%; 3j, 99%). Surprisingly, when benzothiophene was replaced with benzofuran, dramatic erosion of enantioselectivity occurred. For example, 3g was only obtained in moderate ee (71%). Other 2-(benzofuran-3-yl) arylaldehyde derivatives led to racemic products (3i, 3k). These results were in sharp contrast to those of the 2-(benzothiophen-3-yl) analogues. When benzothiophene and benzofuran were positioned at the upper side of the biaryls, the desired products were all afforded in high ee values (Table 2c, 3l-3r, 90-99% ee; 3m, 90% ee vs 3i, 0% ee). Benzothiophene-aryl type biaryls generally gave moderate yields (3l, 47%; 3n, 42%; 3o, 38%) with good
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ACS Catalysis enantioselectivities. Attempts to obtain good yields with maintained enantioselectivities by tuning other silver salts in HOAc, led to reduced yields.24 Sterically bulky substituents positioned ortho to the axis were needed to maintain the conformational stability and ensure good enantioselectivities (3s, 21% ee vs 3t, 76% ee). Other sterically bulky alkynyl
partners also gave high ee values (Table 2d, 3w, 97% ee; 3x, 84% ee; 3y, 98% ee). Unfortunately, alkynyl partners bearing smaller substituents, such as phenylacetylene bromide and TMS-protected alkynyl bromide, didn't give any desired product. N-arylindoles were also incompatible with this reaction (Table 2f).
Table 2. Scope of atropisomers featuring pentatomic heteroaromaticsa Y ( )n R1 R2
X
R3
Pd(OAc)2 (10 mol%) L-tert-leucine (30 mol%) 2 equiv AgTFA
Br
HOAc:toluene = 2:1 55 °C, 72 h, N2
CHO + H
( )m Z rac-1
Y ( )n R1 R2
X
Z
2
CHO R3 ( )m
3
a) Pyrrole-Aryl CHO TIPS
N
c) (Benzo)thiophene-Aryl, Benzofuran-Aryl
CHO TIPS
N Ph
3a, 87%, 98% ee
CHO TIPS
N
S
X
3b, 67%, 64% ee
CHO TIPS
3d, 63% , >99% ee
CHO TIPS
3e, 43%, 87% ee
b) Aryl-Benzothiophene, Aryl-Benzofuran
3l, X = S, 47%, 99% ee (X-ray) 3m, X = O, 77%, 90% ee O CHO TIPS R
3p, R = iPr, 42%, 92% ee 3q, R = Me, 55%, 97% ee 3r, R = Et, 40%, 96% ee
CHO
CHO
TIPS
X
TIPS
X
3f, X = S, 84%, 92% ee 3g, X = O, 82%, 71% ee (X-ray) e) 5,5-ring system
Me 3n, 42%, 98% ee
OMe 3o, 38%, 98% ee
S S
CHO TIPS
CHO TIPS i
Pr
3t, 30%, 76% ee 3s, 64%, 21% ee
OMe
d) Alkyne
MeO Me
TIPS Me
3c, 66%, 98% ee
N
CHO
TIPS
TIPS
Ph
S
CHO
CHO
Me
CO2Et N
X = C or N Y, Z = C, S or O m, n = 0 or 1
MeO
CHO
N
CHO
R
N
OTBS CHO
TIPS
X
3h, X = S, 47%, 99% ee 3i, X = O, 70%, 0% ee
3j, X = S, 97%, 99% ee 3k, X = O, 86%, 0% ee
3w, R = TBS, 50%, 97% ee 3x, R = tBu, 66%, 84% ee
3y, 61%, 98% ee
f) Unsuccessful: Aryl-Indole
S CHO TIPS
CHO
CHO
N
N
1za
1zb
X 3u, X = S, 98%, 93% ee 3v, X = O, 98%, 5% ee
3g
3l
a
Reaction conditions: rac-1 (0.1 mmol), alkynyl bromide 2 (0.3 mmol), Pd(OAc)2 (0.01 mmol), L-tert-leucine (0.03 mmol), AgTFA (0.2 mmol), HOAc:toluene = 2:1 (2 mL), 55 oC, N2, 72 h. TBS = tert-butyldimethylsilyl.
The asymmetric construction of atropisomers displaying two five-membered heteroarenes (5,5-ring system) is more challenging. We were delighted to find that this protocol was compatible with 3,3’-bisbenzothiophene and the desired product 3u was obtained in excellent yield and good enantioselectivity (Table 2e, 98% yield, 93% ee). The absolute configuration of products 3d, 3g and 3l was determined by the X-ray analysis, and those of the other chiral heteroaryls were assigned analogously. To further understand of the conformational stability of fivemembered heteroatropisomers, density functional theory (DFT) calculations were performed to obtain the rotational barrier and corresponding half-life of a series of biaryl compounds containing benzothiophene and benzofuran moieties (Figure 2a). There appeared a noteworthy trend that the benzothiophene-containing biaryls have significantly higher rotational barriers compared to the benzofuran equivalents. This is consistent with our experimental results that the replacement of benzothiophene with benzofuran led to remarkable decrease
of enantioselectivity (Table 2b). This effect is an interesting addition to the general consensus that the steric bulkiness of the ortho-substituents of biaryl compounds is the leading factor that controls the rotational barrier. The shape of heterocycle leads to the remarkable change of rotational barrier of benzothiophene- and benzofurancontaining biaryls. Due to the different atomic radii of sulfur and oxygen, the shape of thiophene and furan are different, and the C-C-C angle of thiophene is larger comparing with the corresponding angle of furan (Figure 2b). This change of bond angle makes the ortho hydrogens closer in 3-phenylthiophene than 3-phenylfuran. However, the highlighted H-H distances in TS1 is not short enough to create significant steric repulsions, and the rotational barriers are similar for the two biaryls (1.4 kcal/mol vs. 1.0 kcal/mol). With benzothiophene and benzofuran, the same effect is amplified, especially due to the hydrogen of the additional benzene ring. The closest H-H distance in TS2-S is 1.72 Å while the same distance in TS2-O is 1.90 Å, leading to 3.0 kcal/mol difference of the rotational
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barriers. When the phenyl group is replaced by naphthyl group, these biaryl compounds are similar to the computed ones in Figure 2a, and the barrier difference increases to 7.2 kcal/mol (TS3-S vs TS3-O). The introduction of naphthyl group further differentiates the two biaryl compounds in TS3 for the same reason. The H-H steric repulsions are translated to the geometric change of naphthyl moieties, as reflected by the highlighted dihedral angle in TS3-S and TS3-O. These computations reveal the important effects of heterocycle shape on the rotational barrier of biaryl compounds. The barriers to rotation of 3m and 3u were also measured experimentally and the results showed good agreement with the calculated ones (3m, ∆G‡ = 30.9 kcal/mol; 3u, ∆G‡ = 31.7 kcal/mol).24
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S
S standard CHO conditions
S CHO TIPS
H
NaClO2, NaH2PO4 2-methylbut-2-ene
COOH TIPS (1)
t-BuOH
S
S
S
3u, 92%, 93% ee 1.77g
rac-1u 1.2 g, 4.08 mmol)
4a, quant., 93% ee
To demonstrate the practicality of this strategy, a gram-scale reaction between 1u and 2a was conducted and the desired product 3u was isolated in 92% yield and 93% ee (eq 1). Subsequent oxidation of 3u with NaClO2 gave axially chiral carboxylic acid 4a in quantitative yield with the retention of chirality (eq 1).
a) Calculated rotational barriers and corresponding half-life OMe X
MeO Me
CHO
MeO
TIPS
CHO
X
3f, X=S,
G = 36.8 kcal/mol t1/2 = 5046 years
3g, X=O, G = 29.6 kcal/mol t1/2 = 30 days
S
X CHO
CHO
CHO TIPS
TIPS X
X 3j, X=S,
TIPS
Me
TIPS
G = 31.0 kcal/mol t1/2 = 254 days
3l, X=S,
G = 35.9 kcal/mol t1/2 = 1270 years
3k, X=O, G = 21.5 kcal/mol 3m, X=O, G = 30.8 kcal/mol t1/2 = 187 days t1/2 = 10 second
G = 39.5 kcal/mol t1/2 = 316396 years
3u, X=S, G = 31.6 kcal/mol t1/2 = 2 years
3q, X=O, G = 34.0 kcal/mol t1/2 = 69 years
3v, X=O, G = 24.6 kcal/mol t1/2 = 1204 seconds
3z, X=S,
b) DFT-optimized transition states and free energy barriers
TS1-S TS1-O G‡ = 1.4 kcal/mol G‡ = 1.0 kcal/mol
TS2-S G‡ = 5.6 kcal/mol
TS3-S G‡ = 16.6 kcal/mol
TS2-O G‡ = 2.6 kcal/mol
TS3-O G‡ = 9.4 kcal/mol
Figure 2. DFT calculations. Barriers (∆G‡) and half-lives were calculated at 55 oC.
In summary, we have developed a general and highly efficient method to access a new family of axially chiral heteroaryls by using the Pd-catalyzed atroposelective C-H alkynylation. A wide range of heteroarenes are compatible with strategy, affording the atropisomers in good enantioselectivity. We expect that this strategy would provide new opportunities to obtain various axially chiral frameworks, which might be promising for the development of new ligands based on the heteroaryl backbones.
* E-mail:
[email protected] (X. Hong) * E-mail:
[email protected] (B.-F. Shi)
ACKNOWLEDGMENT Financial support from the NSFC (21772170 and 21572201), the National Basic Research Program of China (2015CB856600), the Fundamental Research Funds for the Central Universities (2018XZZX001-02) and Zhejiang Provincial NSFC (LR17B020001) is gratefully acknowledged.
REFERENCES
ASSOCIATED CONTENT Supporting Information
(1)
For selected reviews, see: a) Smyth, J. E.; Butler, N. M.; Keller, P. A. A Twist of Nature- The Significance of Atropisomers in Biological Systems. Nat. Prod. Rep. 2015, 32,1562-1583; b) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Atroposelective Total Synthesis of Axially Chiral Biaryl Natural Products. Chem. Rev. 2011, 111, 563-639; c) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Total Synthesis of Chiral Biaryl Natural Products by Asymmetric Biaryl Coupling. Chem. Soc. Rev. 2009, 38, 3193-3207; d) Privileged Chiral Ligands and Catalysts; Zhou, Q.-L. Ed.; Wiley-VCH: Weinheim, Germany, 2011; e) Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994.
(2)
For recent reviews on the synthesis of axially chiral biaryls, see: a) Baudoin, O. The Asymmetric Suzuki Coupling Route to Axially Chiral Biaryls. Eur. J. Org. Chem. 2005, 4223-4229; b)
Experimental procedures, spectra data for all new compounds, DFT calculations. This material is available free of charge via the Internet at http://pubs.acs.org. X-ray crystal structure for 3d (CCDC 1872126) (CIF) X-ray crystal structure for 3g (CCDC 1872125) (CIF) X-ray crystal structure for 3l (CCDC 1872124) (CIF)
AUTHOR INFORMATION Corresponding Author
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a) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Design and Enantioselective Construction of Axially Chiral Naphthyl-Indole Skeletons. Angew. Chem. Int. Ed. 2017, 56,116121; b) During the preparation of our manuscript, Shi and coworkers reported the first example of construction of axially chiral 3,3’-bisindoles via asymmetric addition reactions using CPA as the organocatalyst: Ma, C.; Jiang, F.; Sheng, F.-T.; Jiao, Y.; Mei, G.-J.; Shi, F. Design and Catalytic Asymmetric Construction of Axially Chiral 3,3’-Bisindole Skeletons. Angew. Chem. Int. Ed. DOI: 10.1002/anie.201811177.
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a) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E. (Diphenylphosphino)biheteroaryls: the first example of a new class of chiral atropisomeric chelating diphosphine ligands for transition metal catalysed stereoselective reactions. J. Chem. Soc., Chem. Commun. 1995, 685-686; b) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. New Class of Chiral Diphosphine Ligands for Highly Efficient Transition Metal-Catalyzed Stereoselective Reactions: The Bis(diphenylphosphino) Fivemembered Biheteroaryls. J. Org. Chem. 1996, 61, 6244-6251; c)
(11) During the preparation of this manuscript, Zhu and co-workers reported the catalytic enantioselective synthesis of axially chiral 3-arylpyrroles, see: Zheng, S.-C.; Wang, Q.; Zhu, J. Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3-Arylpyrroles. Angew. Chem. Int. Ed. 2019, 58, 1494-1498. (12) He, C.; Hou, M.; Zhu, Z.; Z. Gu. Enantioselective Synthesis of Indole-Based Biaryl Atropisomers via Palladium-Catalyzed Dynamic Kinetic Intramolecular C–H Cyclization. ACS Catal. 2017, 7, 5316-5320. (13) For reviews on asymmetric C-H functionalization, see: a) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Transition Metal-Catalyzed C-H Activation Reactions: Diastereoselectivity And Enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242-3272; b) Yang, L.; Huang, H. Catal. Sci. Technol. 2012, 2, 1099-1112; c) Engle, K. M.; J.-Q. Yu. Developing Ligands for Palladium(II)-
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Catalyzed C–H Functionalization: Intimate Dialogue between Ligand and Substrate. J. Org. Chem. 2013, 78, 8927-8955; d) Wencel-Delord, J.; Colobert, F. Asymmetric C(sp2)-H Activation. Chem. Eur. J. 2013, 19, 14010-14017; e) Zheng, C.; You, S.-L. Recent development of direct asymmetric functionalization of inert C–H bonds. RSC Adv. 2014, 4, 61736214; f) Pedroni, J.; Cramer, N. TADDOL-based Phosphorus(III)-ligands in Enantioselective Pd(0)-catalysed C– H Functionalisations. Chem. Commun. 2015, 51, 17647-17657; g) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N. Catalytic Enantioselective Transformations Involving C–H Bond Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117, 8908-8976; h) Gao, D.-W.; Gu, Q.; Zheng, C.; You, S.-L. Synthesis of Planar Chiral Ferrocenes via Transition-MetalCatalyzed Direct C–H Bond Functionalization. Acc. Chem. Res. 2017, 50, 351-365; i) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts. Science 2018, 359, 759. (14) Kakiuchi, F.; Gendre, P. L.; Yamada, A.; Ohtaki, H.; Murai, S. Atropselective alkylation of biaryl compounds by means of transition metal-catalyzed C–H/olefin coupling. Tetrahedron: Asymmetry 2000, 11, 2647-2651. (15) Gustafson, J. L.; Lim, D.; Miller, S. J. Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric Bromination. Science 2010, 328, 1251-1255. (16) a) Wesch, T.; Leroux, F. R.; Colobert, F. Atropodiastereoselective C-H Olefination of Biphenyl p-Tolyl Sulfoxides with Acrylates. Adv. Synth. Catal. 2013, 355, 21392144; b) Hazra, C. K.; Dherbassy, Q.; Wencel-Delord, J.; Colobert, F. Synthesis of Axially Chiral Biaryls through Sulfoxide-Directed Asymmetric Mild C-H Activation and Dynamic Kinetic Resolution. Angew. Chem. Int. Ed. 2014, 53, 13871-13875; c) Dherbassy, Q.; Schwertz, G.; Chessé, M.; Hazra, C. K.; Wencel-Delord, J.; Colobert, F. 1,1,1,3,3,3Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes. Chem. Eur. J. 2016, 22, 1735-1743; d) Dherbassy, Q.; Djukic, J.-P.; Wencel-Delord, J.; Colobert, F. Two Stereoinduction Events in One C−H Activation Step: A Route towards Terphenyl Ligands with Two Atropisomeric Axes. Angew. Chem. Int. Ed. 2018, 57, 4668-4672. (17) a) Zheng, J.; You, S.-L. Construction of Axial Chirality by Rhodium-Catalyzed Asymmetric Dehydrogenative Heck Coupling of Biaryl Compounds with Alkenes. Angew. Chem. Int. Ed. 2014, 53, 13244-13247; b) Gao, D.-W.; Gu, Q.; You, S.-L. Pd(II)-Catalyzed Intermolecular Direct C–H Bond Iodination: An Efficient Approach toward the Synthesis of Axially Chiral Compounds via Kinetic Resolution. ACS Catal. 2014, 4, 27412745; c) Zheng, J.; Cui, W.-J.; Zheng, C.; You, S.-L. Synthesis and Application of Chiral Spiro Cp Ligands in RhodiumCatalyzed Asymmetric Oxidative Coupling of Biaryl
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(18) a) Jia, Z-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick, A. P.; Waldmann, H. General Enantioselective C−H Activation with Efficiently Tunable Cyclopentadienyl Ligands. Angew. Chem. Int. Ed. 2017, 56, 2429-2434; b) Shan, G.; Flegel, J.; Li, H.; Merten, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. C−H Bond Activation for the Synthesis of Heterocyclic Atropisomers Yields Hedgehog Pathway Inhibitors. Angew. Chem. Int. Ed. 2018, 57, 14250-14254. (19) Braconi, C. G. E.; Kuziola, J.; Wodrich, M. D.; Cramer, N. Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C−H Arylation. Angew. Chem. Int. Ed. 2018, 57, 11040-11044; b) Jang, Y.-S.; Woźniak, Ł.; Pedroni, J.; Cramer, N. Access to P- and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII-Catalyzed C−H Arylations. Angew. Chem. Int. Ed. 2018, 57, 12901-12905. (20) a) Yao, Q.-J.; Zhang, S.; Zhan, B.-B.; Shi, B.-F. Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary. Angew. Chem. Int. Ed. 2017, 56, 6617-6621; b) Liao, G.; Yao, Q.-J.; Zhang, Z.-Z.; Wu, Y.-J.; Huang, D.-Y.; Shi, B.F. Scalable, Stereocontrolled Formal Syntheses of (+)Isoschizandrin and (+)-Steganone: Development and Applications of Palladium(II)-Catalyzed Atroposelective C−H Alkynylation. Angew. Chem. Int. Ed. 2018, 57, 3661-3665; c) Liao, G.; Li, B.; Chen, H.-M.; Yao, Q.-J.; Xia, Y.-N.; Luo, J.; Shi, B.-F. Pd-Catalyzed Atroposelective C−H Allylation through β-O Elimination: Diverse Synthesis of Axially Chiral Biaryls. Angew. Chem. Int. Ed. 2018, 57, 17151-17155. (21) a) Li, S.-X.; Ma, Y.-N.; Yang, S.-D. P(O)R2‑Directed Enantioselective C−H Olefination toward Chiral Atropoisomeric Phosphine−Olefin Compounds. Org. Lett. 2017, 17, 1842; b) Sun, Q.-Y.; Ma, W.-Y.; Yang, K.-F.; Cao, J.; Zheng, Z.-J.; Xu, Z.; Cui, Y.-M.; Xu, L.-W. Enantioselective synthesis of axially chiral vinyl arenes through palladium-catalyzed C–H olefination. Chem. Commun. 2018, 54, 10706-10709. (22) a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Functionalization of C(sp3)–H bonds using a transient directing group. Science 2016, 351, 252-256; b) Park, H.; Verma, P.; Hong, K.; Yu, J.-Q. Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp3)−H fluorination. Nat. Chem. 2018, 10, 755-762. (23) Yan, S.-Y.; Han, Y.-Q.; Yao, Q.-J.; Nie, X.-L.; Liu, L.; Shi, B.F. Palladium(II)-Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids. Angew. Chem. Int. Ed. 2018, 57, 9093-9097. (24) See the Supporting Information for details.
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ACS Catalysis Y ( )n X
2
cat. Pd(OAc)2 CHO L-tert-leucine H Br SiR
2'
Y ( )n X
R CHO SiR 2'
( )m ( )m Z Z X = C or N; Y, Z = C or S or O; m, n = 0 or 1
Compatible with pyrrole, (benzo)thiophene, (benzo)furan Atropisomers featuring two pentatomic heteroaryls High enantioselectivity (up to >99% ee) transient-chiral-auxialiry enabled CH alkynylation
CHO
N
2
R'
R CHO X S
X CHO
X = S, O
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CHO
X
7
