Utilization of CO2 as a C1 Building Block in a Tandem Asymmetric A3

We report a tandem asymmetric aldehyde–alkyne–amine (A3) coupling-carboxylative cyclization sequence for the highly enantioselective synthesis of ...
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Letter

Utilization of CO2 as a C1 Building Block in a Tandem Asymmetric A3 Coupling-Carboxylative Cyclization Sequence to 2-Oxazolidinones Xiao-Tong Gao, Chen-Chen Gan, Si-Yue Liu, Feng Zhou, Hai-Hong Wu, and Jian Zhou ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03370 • Publication Date (Web): 14 Nov 2017 Downloaded from http://pubs.acs.org on November 14, 2017

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Utilization of CO2 as a C1 Building Block in a Tandem Asymmetric A3 Coupling-Carboxylative Cyclization Sequence to 2-Oxazolidinones Xiao-Tong Gao,† Chen-Chen Gan,† Si-Yue Liu,‡ Feng Zhou*,† Hai-Hong Wu*,† and Jian Zhou*,†,§,║ †

Shanghai Key Laboratory of Green Chemistry and Chemical Process and §Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, P. R. China. ‡ College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, P. R. China ║

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P R China.

ABSTRACT: We report a tandem asymmetric aldehyde–alkyne–amine (A3) coupling-carboxylative cyclization sequence for the highly enantioselective synthesis of chiral N-aryl 2-oxazolidinones. This is a rare example of a multicatalyst-promoted asymmetric tandem reaction using CO2 as a C1 synthon. Notably, the copper species and ligand from the upstream A3 reaction are internally reused to facilitate the downstream silver-catalyzed carboxylative cyclization.

KEYWORDS

CO2 transformation, Asymmetric tandem reaction, Carboxylative cyclization, A3 coupling, 2-Oxazolidinone

Utilization of carbon dioxide (CO2) as an inexpensive, nontoxic and renewable C1 feedstock has attracted everincreasing attention worldwide in the past decade. This not only provides a promising complement to carbon capture and storage but offers the promise to develop cost-effective protocols to value-added chemicals.1 However, although a variety of elegant reactions using CO2 as C1 synthon have been developed, the merger of CO2 chemical fixation into catalytic asymmetric tandem reactions for the synthesis of chiral compounds of important applications is largely undeveloped.2,3 As an important class of heterocycles, 2-oxazolidinones have wide applications in organic synthesis, pharmaceutical chemistry and agrochemistry.4 Among their known synthetic methods,5 those based on CO2 are very attractive,6 and in particular, the carboxylative cyclization of propargylamines and CO2 has developed quickly since the seminal work of Mitsudo and Watanabe (Scheme 1A).7,8 Besides the elegant catalystfree protocols disclosed by the groups of Ikariya9 and Han10 using supercritical CO2 and an ionic liquid system at elevated temperature, respectively, the use of metal catalysts to realize this reaction at mild conditions is of current interest. For example, Yamada reported that silver salts could catalyze this reaction under mild conditions.11 Meanwhile, copper12a–c, palladium12d–g and gold12h–j catalysis also showed their value. Despite significant achievements, the synthesis of chiral 2oxazolidinones via cyclization of propargylamines and CO2 remains unexplored.7–12 Most known catalytic protocols are limited to N-alkyl propargylamines, and only a highly active N-aryl propargylamine with a terminal alkyne worked (Scheme 1A).12g Possibly, N-aryl propargylamines undergo alkyne hydroarylation more easily than CO2 incorporation as a result of the lower nucleophilicity of the nitrogen atom. This is further supported by the fact that under Ag(I), Cu(I) and Au(I) catalysis, N-aryl propargylamines readily undergo cycloisomerization.13

Scheme 1. Carboxylative Cyclization of Propargylamine

On the other hand, chiral N-aryl propargylanilines can be readily obtained via catalytic asymmetric A3 coupling reaction.14 The development of carboxylative cyclization of N-aryl propargylamine and CO2, in combination with an asymmetric A3 coupling reaction, would provide a highly efficient strategy for the one-pot synthesis of chiral N-aryl 2-oxazolidinones from simple starting materials (Scheme 1B). Here, we wish to report our efforts in developing such an unprecedented tandem asymmetric A3 coupling-carboxylative cyclization sequence. We began by investigating the carboxylative cyclization of N-phenyl propargylamine 4a under a CO2 pressure of 1.0 MPa. Known metal catalysts for the corresponding reaction of Nalkyl propargylamines were first examined.11,12 Not surprisingly, (IPr)AuCl12h and Pd(OAc)212e as the catalyst afforded only the undesired hydroarylation adduct 6 (entries 1, 2, Table 1).

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CuI mixed with DBU12c was inactive (entry 3), and the most efficient known catalyst, AgOAc/DBU,11b failed as well (entry 4). Considering that organic bases played an important role in the Ag-catalyzed versions, to facilitate the incorporation of the CO2 to form the carbamate and to serve as a ligand to tune the catalytic property of Ag(I),11d,e we optimized different organic bases. To our delight, the use of 1,3-diphenylguanidine (DPG) significantly accelerated the desired cyclization, affording 2oxazolidinone 5a in 54% yield within 24 h, without the detection of byproduct 6 by NMR analysis of the reaction mixture (entry 6). Further studies revealed that both DMF and 1,2dichloroethane (DCE) were suitable solvents (entries 6 –8). While reaction in DMF resulted in a slightly higher yield, DCE was chosen as the optimal solvent, as it was also suitable for A3 coupling. After evaluating different silver salts, AgOBz proved to be the most promising, affording 5a in 70% yield (entries 8–12). Table 1. Carboxylative Cyclization Reaction

Solvent

Time (h)

---

CH3OH

---

Toluene

Entry

Cat.

Base

1b

(IPr)AuCl

2b

Pd(OAc)2

Yield (%)a 5a

6

24

---

80

24

---

25

CuI

DBU

DMSO

24

---

---

4

AgOAc

DBU

DMF

24

---

---

5

AgOAc

TMG

DMF

24

---

---

6

AgOAc

DPG

DMF

24

54

---

7

AgOAc

DPG

Toluene

24

10

---

8

AgOAc

DPG

DCE

36

45

---

9

AgClO4·H2O

DPG

DCE

36

60

---

10

AgOTf

DPG

DCE

36

25

---

11

AgTFA

DPG

DCE

36

35

---

12

AgOBz

DPG

DCE

36

70c

---

3

b

Determined by 1H NMR using mesitylene as internal standard. 50 oC. c Isolated yield. Note: 4a was not fully consumed in entries 6–12. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. TMG = 1,1,3,3-Tetramethylguanidine. DPG = 1,3-Diphenylguanidine.

Having established the conditions for the two distinct catalytic reactions, we next tried combining both into a one-pot tandem synthesis, to save time, labor and resources and to avoid yield losses associated with the purification of chiral amines 4. It is worth mentioning that the merger of both steps into one pot was not as trivial as it first appeared because the catalyst and the excess reagents from the first step might deactivate the catalyst of the next step, a well-known challenge in developing a multicatalyst promoted asymmetric tandem reaction (MPATR)17. Although DCE was identified as a suitable solvent for both steps based on our experience on MPATR,18 it was apparent that the alkyne, usually used in excess for A3 reactions,14–16 would interfere with AgOBz for the cyclization due to a strong soft–soft interaction. Accordingly, control experiments were conducted to evaluate the influence of each reaction component of the A3 reaction on the AgOBzcatalyzed cyclization. Table 2. Control Experiments

Entry

a b

Meanwhile, we investigated the catalytic enantioselective A3 reaction to synthesize chiral N-aryl propargylamine 4a. The criterion for our screening was that the A3 reaction must be run in DCE, to coordinate with carboxylative cyclization to form our designed tandem sequence shown in Scheme 1B. It should be noted that although remarkable progress has been made in the catalytic asymmetric A3 reaction since the pioneering work of Li et al.,15 most protocols relied on the use of air-sensitive and costly Cu(I) salts such as CuOTf and CuPF6, with very limited examples based on air-stable Cu(II) salts.16 We successfully found our new PYBOX ligand L in combination with Cu(OTf)2 worked well in the A3 reaction of aldehyde 1a, phenylacetylene 2a and aniline 3a in DCE at 25 °C, giving propargylamine 4a in 98% yield and 94% ee. For details, see supporting information.

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a

Additive

X

Yield (%)a

1

None

---

45

2

Phenylacetylene (2a)

50

20

3

Aniline (3a)

20

53

4

Cu(OTf)2

10

97

5

CuOTf

10

98

6

L

12

90

7

CuOTf/L

10/12

97

8

Cu(OTf)2/L

10/12

90

Isolated yield.

For a rapid comparison, all reactions were quenched after 24 h. Without any additive, AgOBz-catalyzed cyclization afforded 5a in 45% yield (entry 1, Table 2). As expected, the presence of 50 mol% of phenylacetylene 2a severely retarded the reaction, giving 5a in only 20% yield (entry 2), possibly due to the competitive binding of 2a and 4a to Ag(I). The addition of 20 mol% aniline 3a improved the yield to 53% (entry 3). This was in accordance with literature reports that primary amines could react with CO2 to form carbamic acid to enhance the effective concentration of CO2 in solution, helpful for carboxylative cyclization.12a,b Very surprisingly, the addition of Cu(OTf)2 strongly accelerated the Ag-catalyzed cyclization to complete within 24 h to afford 5a in 97% yield (entry 4). We further tested the effect of CuOTf as the additive because it might be generated in situ in the A3 reaction,19 and a similar hastening effect was observed (entry 5). An obvious ligandacceleration effect20 took place when L was added to the Agcatalyzed cyclization (entry 6). In contrast, without any addi-

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tive, the cyclization did not complete even after 36 h (entry 12, Table 1). Furthermore, no matter adding CuOTf/L or Cu(OTf)2/L, the yield of 5a was substantially enhanced to 97% and 90%, respectively (entries 7, 8). Based on the above control experiments, we speculated that the key to develop the desired tandem sequence was to avoid the use of excess alkyne in the A3 coupling step. With this in mind, we then optimized the condition to integrate both steps into a one-pot operation. The initial Cu-catalyzed A3 coupling was run in air at 25 °C in DCE for 15 h till the full conversion of aldehyde, and then AgOBz and DPG were added for the next cyclization with a CO2 pressure of 1.0 MPa at 25 °C. As expected, when decreasing the use of alkyne 2a from 1.5 to 1.2 and 1.0 equiv for the A3 reaction, the yield of the desired 2-oxazolidinone 5a was improved from 40% to 68% and 92%, respectively, without erosion of ee value (entries 1–3, Table 3). Interestingly, when decreasing the usage of 2a from 1.5 to 1.0 equiv for A3 reaction, our new ligand L afforded similar yield whilst the use of A and B resulted in obviously diminished yield.22 Under this condition, reducing the loading of AgOBz to 10 mol% resulted in the diminished 40% yield of 5a (entry 4). However, if lowering the loading of DPG to 50 mol%, the sequence could still afford 5a in 97% yield if running the cyclization step for 36 h (entry 5), but further lowering its use to 20 mol% led to greatly diminished yield (entry 6). It should be noted that no cyclization occurred if either AgOBz or DPG was absent (entries 7, 8), so the absence of both, suggests copper species from the A3 step were unable to mediate the subsequent cyclization. We also conducted the tandem reaction under 0.1 MPa of CO2, and found the reaction proceeded in a much slower rate. Even the cyclization step was run for 72 h, product 5a was still obtained in only 25% and 58% yield, respectively, in the presence of 50 mol% or 100 mol% of DPG (entries 9-10). Table 3. Condition Optimization for Tandem Reaction Ph

O

2a (X equiv) Ph CHO 1a (0.20 mmol)

Ph NH2

+

Cu

3a (0.24 mmol) One-pot sequential!

Cu(OTf )2 (10 mol%)

Ph

L (12 mol%) DCE, 25 o C, 15 h

Ph

5a (94% ee) AgOBz (Y mol%)

NH

DPG (Z mol%)

Ph 4a

CO 2, DCE, 25 oC

Ph

2a (X)

AgOBz (Y)

DPG (Z)

CO2 (MPa)

Time (h)

Yield (%)a

1

1.5

20

100

1.0

24

40

2

1.2

20

100

1.0

24

68

3

1.0

20

100

1.0

24

92

4

1.0

10

100

1.0

24

40

5

1.0

20

50

1.0

36

97

6

1.0

20

20

1.0

24

21

7

1.0

---

20

1.0

24

---

8

1.0

20

---

1.0

24

---

9

1.0

20

50

0.1

72

25

10

1.0

20

100

0.1

72

58

Entry

Isolated yield.

Table 4. Substrate Scope of the Tandem Reaction

Entry

Yield Ee (%)a (%)b

1 (R1)

2 (R2)

3 (Ar)

1

Ph

Ph

Ph

5a

97

94

2

4-MeC6H4

Ph

Ph

5b

91

96

3

4-EtC6H4

Ph

Ph

5c

91

96

4

4-ClC6H4

Ph

Ph

5d

97

96

5

4-BrC6H4

Ph

Ph

5e

90

96

6

4-FC6H4

Ph

Ph

5f

96

96

7

3-MeC6H4

Ph

Ph

5g

90

95

5

8

3-BrC6H4

Ph

Ph

5h

85

94

9

2-MeC6H4

Ph

PMP

5i

82

96

Ph

Ph

5j

87

90

10 3,4-(Me)2C6H3

O

Ph

CO2

a

Ph N

Ag

The results shown in Tables 2 and 3 are very interesting, suggesting that the copper species, ligand and remaining aniline from the upstream A3 reaction, but not alkyne, could be internally reused to facilitate the downstream silver-catalyzed cyclization. Although a detailed explanation of the acceleration effect in the Ag-catalyzed carboxylative cyclization awaits further studies, it is worth mentioning that this protocol constitutes a rare example of asymmetric tandem reactions capable of internally recycling residue from the upstream step to facilitate the downstream reaction.21 Despite some elegant tandem sequences can internally reuse byproduct and/or excess reagent, this newly developed sequence first demonstrates that the remaining catalyst from the upstream step could serve as a cocatalyst or additive to improve greatly the efficiency of the downstream step.

11

2-naphthyl

Ph

Ph

5k

90

91

12

Ph

PMP

Ph

5l

84

94

13

Ph

4-MeC6H4

Ph

5m

90

92

14

Ph

4-FC6H4

Ph

5n

90

94

15

Ph

4-ClC6H4

Ph

5o

84

92

16

Ph

4-BrC6H4

Ph

5p

95

93

17

Ph

3-ClC6H4

Ph

5q

99

93

18

Ph

2-ClC6H4

Ph

5r

99

96

19

Ph

CH3(CH2)4

PMP

5s

44

91

20

Ph

Ph

PMP

5t

85

92

21

Ph

Ph

4-MeC6H4

5u

82

94

22

Ph

Ph

4-EtC6H4

5v

94

95

23

Ph

Ph

3-MeC6H4

5w

86

92

24c

Ph

Ph

3-FC6H4

5x

92

94

25

c

Ph

Ph

3-BrC6H4

5y

Ph

Ph

Ph

5a

97 84 (1.1g)

94

d

26

94

Isolated yield. b Determined by chiral HPLC analysis. c 50 oC for the cyclization step. d On a 4.0 mmol scale, 5 mol% of Cu(OTf)2 for the A3 reaction.

a

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Next, we evaluated the scope of this tandem asymmetric A3 coupling-carboxylative cyclization sequence with respect to different aldehydes, alkynes and anilines under the optimized conditions (Table 4). First, aryl aldehydes with either electronwithdrawing or -donating substituents worked well to afford chiral 2-oxazolidinones 5a–j in 82–97% yield and 90–96% ee (entries 1–10). 2-Naphthaldehyde also furnished the desired product 5k in 90% yield and 91% ee (entry 11). Second, both aryl and alkyl alkynes were all viable substrates. Aryl alkynes with different substituted phenyl groups provided the desired adducts 5l–r in 84–99% yield with 92–96% ee (entries 12–18). Aliphatic 1-heptyne also gave the corresponding product 5s in 91% ee, albeit with diminished 44% yield (entry 19). Finally, primary arylamines with electron-rich, -neutral and -deficient groups on the phenyl ring were also examined. The desired 2oxazolidinones 5t–y were readily obtained in high to excellent yields and ee values (entries 20–25). The scalability of the tandem reaction was further shown by a 4.0 mmol scale reaction using 5 mol% of copper catalyst, affording chiral 2oxazolidinone 5a in 84% yield and 94% ee (entry 26).22 However, aliphatic primary amines and aliphatic aldehydes are not compatible under this condition. This is not surprising, since both still presented as challenging substrates in the A3 coupling reaction.14–16 The absolute configuration of the chiral 2oxazolidinone 5e was determined to be R by X-ray analysis.23 In summary, we have developed a novel tandem asymmetric A3 coupling-carboxylative cyclization sequence for the facile synthesis of chiral N-aryl 2-oxazolidinones with excellent ee values under mild conditions. This process constitutes a rare example of MPATR using CO2 as a C1 synthon, as well as catalytic carboxylative cyclization of N-aryl propargylamines and CO2. The key to the efficiency of the sequence is that the copper species and ligand from the upstream A3 reaction are internally reused to facilitate the downstream Agcatalyzed carboxylative cyclization. The development of novel CO2-participated MPATR are now in progress in our laboratory.

ASSOCIATED CONTENT Supporting Information. Experimental details, optimization of reaction conditions, characterization of products, X-ray data of 5e, copies of NMR and HPLC spectra of all products. This material is available free of charge via the internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail for F. Zhou: [email protected] * E-mail for H. H. Wu: [email protected] * E-mail for J. Zhou: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Financial support from 973 Program (2015CB856600) and NSFC (21502053, 21573073, 21472049, 21725203) is appreciated.

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(8) Arshadi, S.; Vessally, E.; Sobati, M.; Hosseinian, A.; Bekhradnia, A. J. CO2 Util. 2017, 19, 120–129, also see ref. 2a-d and 6a-c. (9) Kayaki, Y.; Yamamoto, M.; Suzuki, T.; Ikariya, T. Green Chem. 2006, 8, 1019–1021. (10) (a) Hu, J.; Ma, J.; Zhu, Q.; Zhang, Z.; Wu, C.; Han, B. Angew. Chem., Int. Ed. 2015, 54, 5399–5403. (b) Hu, J.; Ma, J.; Zhang, Z.; Zhu, Q.; Zhou, H.; Lu, W.; Han, B. Green Chem. 2015, 17, 1219– 1225. (11) For a review: (a) Sekine, K.; Yamada, T. Chem. Soc. Rev. 2016, 45, 4524–4532. (b) Yoshida, S.; Fukui, K.; Kikuchi, S.; Yamada, T. Chem. Lett. 2009, 38, 786–787. (c) Sekine, K.; Kobayashi, R.; Yamada, T. Chem. Lett. 2015, 44, 1407–1409. (d) Yoshida, M.; Mizuguchi, T.; Shishido, K. Chem. Eur. J. 2012, 18, 15578–15581. (e) Yuan, R.; Wei, B.; Fu, G. J. Org. Chem. 2017, 82, 3639–3647. (12) (a) Yoo, W.-J.; Li, C.-J. Adv. Synth. Catal. 2008, 350, 1503– 1506. (b) Yu, B.; Cheng, B.-B.; Liu, W.-Q.; Li, W.; Wang, S.-S.; Cao, J.; Hu, C.-W. Adv. Synth. Catal. 2016, 358, 90–97. (c) Zhao, Y.; Qiu, J.; Tian, L.; Li, Z.; Fan, M.; Wang, J. ACS Sustainable Chem. Eng. 2016, 4, 5553–5560. (d) Bacchi, A.; Chiusoli, G. P.; Costa, M.; Gabriele, B.; Righi, C.; Salerno, G. Chem. Commun. 1997, 13, 1209– 1210. (e) Shi, M.; Shen, Y.-M. J. Org. Chem. 2002, 67, 16–21. (f) García-Dominguez, P.; Fehr, L.; Rusconi, G.; Nevado, C. Chem. Sci. 2016, 7, 3914–3918. (g) Brunel, P.; Monot, J.; Kefalidis, C. E.; Maron, L.; Martin-Vaca, B.; Bourissou, D. ACS Catal. 2017, 7, 2652–2660. (h) Hase, S.; Kayaki, Y.; Ikariya, T. Organometallics 2013, 32, 5285– 5288. (i) Hase, S.; Kayaki, Y.; Ikariya, T. ACS Catal. 2015, 5, 5135– 5140. (j) Yuan, R.; Lin, Z. ACS Catal. 2015, 5, 2866–2872. (k) Liu, X.; Wang, M.-Y.; Wang, S.-Y.; Wang, Q.; He, L.-N. ChemSusChem 2017, 10, 1210–1216. (13) Arcadi, A.; Blesi, F.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Marinelli, F. Org. Biomol. Chem. 2012, 10, 9700–9708, and ref. 12i. (14) (a) Yoo, W.-J.; Zhao, L.; Li, C.-J. Aldrichimica Acta 2011, 44, 43–51. (b) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790–3807. (15) (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638–5639. (b) Wei, C.; Mague, J. T.; Li. C.-J. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5749–5754. (16) (a) Bisai, A.; Singh, V. K. Org. Lett. 2006, 8, 2405–2408. (b) Nakamura, S.; Ohara, M.; Nakamura, Y.; Shibata N.; Toru T. Chem. Eur. J. 2010, 16, 2360–2362. (c) Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 3480. (d) Li, Z.; Jiang, Z.; Su, W. Green Chem. 2015, 17, 2330–2334. (17) (a) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem. Eur. J. 2010, 16, 9350. (b) Zhou J. Chem. Asian J. 2010, 5, 422–434. (c) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012, 10, 211– 224. (d) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337–1378. (e) Chen, D.-F.; Han, Z. Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365–2377.

(18) (a) Yin, X.-P.; Zeng, X.-P.; Liu, Y.-L.; Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 13740–13745. (b) Cao, Z.-Y.; Zhao, Y.-L.; Zhou, J. Chem. Commun. 2016, 52, 2537– 2540. (c) Zhao, Y.-L.; Cao, Z.-Y.; Zeng, X.-P.; Shi, J.-M.; Yu, Y.-H.; Zhou, J. Chem. Commun. 2016, 52, 3943–3946. (d) Ye, X.; Zeng, X.; Zhou, J. Acta Chim. Sinica 2016, 74, 984–989. (19) For the reduction of Cu(II) to Cu(I) by terminal alkynes: (a) Zhang, G.; Yi, H.; Zhang, G.; Deng, Y.; Bai, R.; Zhang, H.; Miller, J. T.; Kropf, A. J.; Bunel, E. E.; Lei, A. J. Am. Chem. Soc. 2014, 136, 924–926. The mechanism of Cu(II)-catalyzed A3 reaction is still unclear: (b) Meyet, C. E.; Pierce, C. J.; Larsen, C. H. Org. Lett. 2012, 14, 964–967 and ref. 16d. (20) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059–1070. (21) For review: (a) Zhou J. Multicatalyst System in Asymmetric Catalysis; John Wiley & Sons: New York, 2014; pp 633-670. For examples: (b) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42, 4680–4684. (c) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976–4980. (d) Portalier, F.; Bourdreux, F.; Marrot, J.; Moreau, X.; Coeffard, V.; Greck, C. Org. Lett. 2013, 15, 5642–5645. (e) Zeng, X.-P.; Cao, Z.-Y.; Wang, X.; Chen, L.; Zhou, F.; Zhu, F.; Wang, C.-H.; Zhou, J. J. Am. Chem. Soc. 2016, 138, 416–425. (22) As kindly suggested by one of the reviewers, we compared the potency of our ligand L with unmodified PYBOX A and B in the A3 reaction when using only 1.0 equiv of alkyne 2a. This result further suggested the superiority of our ligand L.

2a L (R = OBn, R1 = Ph) A (R = H, R1 = Ph) B (R = H, R1 = i-Pr) (X) Yield (%) Ee (%) Yield (%) Ee (%) Yield (%) Ee (%) 1.5 98 94 98 91 82 60 1.0 97 94 78 90 60 61

(23) The X-ray crystal structure information is available at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC-1571692 (5e). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

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