Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis

24 mins ago - Soc. , Just Accepted Manuscript ... mechanism investigation indicates that the chiral aldehyde 3f acts both as an organocatalyst to acti...
2 downloads 0 Views 360KB Size
Subscriber access provided by TULANE UNIVERSITY

Communication

Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective #-Allylic Alkylation of Amino Acid Esters Lei Chen, Ming-Jing Luo, Fang Zhu, Wei Wen, and Qi-Xiang Guo J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01910 • Publication Date (Web): 21 Mar 2019 Downloaded from http://pubs.acs.org on March 21, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 6

Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective α-Allylic Alkylation of Amino Acid Esters Lei Chen,† Ming-Jing Luo,† Fang Zhu, Wei Wen, Qi-Xiang Guo* Key Laboratory of Applied Chemistry of Chongqing Municipality, and Chongqing Key Laboratory of Soft-Matter Material Chemistry and Function Manufacturing, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.

Supporting Information Placeholder ABSTRACT: A chiral aldehyde is rationally combined with a Lewis acid and a transition metal for the first time to form a triple catalytic system. This co-catalytic system exhibits good catalytic activation and stereoselective-control abilities in the asymmetric α-allylation reaction of N-unprotected amino acid esters and allyl acetates. Optically active α, α-disubstituted α-amino acids (α-AAs) are generated in good yields (up to 87%) and enantioselectivities (up to 96% ee). Preliminary mechanism investigation indicates that the chiral aldehyde 3f acts both as an organocatalyst to activate the amino acid ester via the formation of a Schiff base, and as a ligand to facilitate the nucleophilic attack process by coordinating with π-allyl Pd(II) species.

systems. Thus, we envisioned that the combination of a transition metal catalyst with a chiral aldehyde could overcome the limitations currently associated with chiral aldehyde catalysis. As exemplified in Figure 1, with a primary amine substrate, the chiral aldehyde can generate a nucleophilic α-imine carbanion intermediate (II), while the transition metal can promote the formation of an active electrophilic species (E+) simultaneously. The subsequent asymmetric nucleophilic reaction between II and E+ affords a chiral imine (III), whereupon, either by hydrolysis or amine exchange, the chiral amine product (P*) is released and the catalyst or imine I is regenerated. However, although this concept provides a good blueprint for chiral aldehyde catalysis, the combination of chiral aldehyde catalysts with transition metals has not been explored. H N I

H

2N

H

2

R

2O

RC

R*

Chiral Aldehyde Catalytic Cycle

R*CHO (catalyst)

E 

R

- H+

NH2 P*

R

N

R*

E+

Transition-Metal Catalytic Cycle

II

RCH2NH2

Chiral aldehyde catalysis has gradually become a powerful asymmetric synthesis strategy in amine chemistry.1 Using this approach, various asymmetric organic reactions including transamination,2 hydroamination3 and the α-functionalization of amino acids,4-7 can be realized. Among these, the direct catalytic asymmetric α-functionalization of amino acids is undoubtedly the most important, because of the exceptional importance of amino acids in biological processes. To date, four types of transformations have been successful disclosed in this field. The earliest report concerned the aldol-based addition of amino acids to aldehydes by employing chiral pyridoxal-based enzymatic catalysis.4 More recently, our group firstly reported a chiral aldehyde catalytic strategy involving the reversible formation of an imine in asymmetric alkylation of 2-aminomalonate.5 Subsequently, the catalytic asymmetric activations of glycine derivatives by aldehydes were disclosed by Zhao and Yuan6 and our group7 independently. These works suggest that chiral aldehyde catalysis could be a powerful means to achieve the asymmetric transformations of amino acids and even amines, because the catalytically-generated nucleophilic carbanion in such syntheses can be trapped by a variety of electrophiles. However, in its present form, chiral aldehyde catalysis will only proceed in the presence of highly active electrophiles, and thus the potential range of applications is very limited. Combinations of organic and transition metal catalysts have been shown to provide a level of reactivity not achievable with a single catalyst,8 and transition metals combined with chiral organic catalysts such as quaternary ammonium salts,9 amines10 and acids11 have already become important chiral catalytic

-H

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

E

H

2O



R

N

R*

III

Figure 1. A new catalytic strategy based on combining a chiral aldehyde and a transition metal. Due to its exceptional ability to activate inert chemical bonds and its suitable level of compatibility with other catalysts, palladium has become an important transition metal for use with various organic catalysts to realize challenging organic transformations.12 Among these achievements, the wellestablished π-allyl Pd(II) complexes13 inspired us to evaluate our above proposal by combing chiral aldehyde and palladium in direct α-allylation reaction of N-unprotected amino acid esters and allyl acetates, which could provide one of the most straightforward methods for the preparation of optically active nonproteinogenic α, α-disubstituted α-amino acids (α-AAs) containing chiral quaternary carbon centers. However, it is a very challenging work because the undesired N-allylation always exists in reaction. In fact, all of the reported examples except one

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

utilized N-protected amino acid esters as reactants to avoid this side reaction.14,15 Initially, the direct α-allylation of methyl phenylalaninate (1a) with cinnamyl acetate (2a) was assessed in the promotion of a chiral aldehyde (3a) and palladium. Besides, the Lewis acid ZnCl2 was added to stabilize the Schiff base and improve the α-carbon acidity of amino ester via the formation of a Zn-Schiff base complex.16 The base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), was added to accelerate the deprotonation process. As expected, the desired product 4a could be obtained in 13% yield and 58% enantioselective excess (ee) (Table 1, entry 1), while the Nallylation product became the major. The results obtained using other chiral aldehydes (3b-3c) indicated that this type of catalyst was not a suitable promoter for this transformation. Employing 3d, a chiral BINOL-analogue bearing two hydroxyl groups, increased both the yield and enantioselectivity of 4a, to 30% and 73% ee, respectively (Table 1, entry 4). Based on this outcome, the catalysts 3e-3m were also screened, and the results demonstrated that 3f gave the best enantioselectivity (Table 1, entry 6) while 3i produced the highest yield (Table 1, entry 9). Using 3f as the catalyst, other reaction conditions were also optimized. For example, the alkoxy screening showed that ethyl phenylalaninate (1b) gave better yield and enantioselectivity (Table 1, entry 14); while lowering the reaction temperature could inhibit the N-allylation side reaction and improve the yield as well as enantioselectivity of 4a greatly (Table 1, entry 18-19). Bases, Lewis acids and phosphine ligands were then screened, but no better results were obtained (See Supporting Information). The chiral aldehyde 3i, which gave the best yield, was then used to promote this reaction under the above optimized reaction conditions, giving product 4a in 85% yield and 87% ee (Table 1, entry 20). In terms of the enantioselectivities, the reaction conditions depicted in entry 19 was utilized in the following substrate scope investigation.

12

3l

4a

0.5

60

64

13

3m

4a

5

29

59

14

3f

4b

2

40

82

15

3f

4c

1

35

80

16

3f

4d

3.5

37

79

17

3f

4e

1

38

77

18

3f

4b

4

60

89e

19

3f

4b

48

74

94fg

20

3i

4b

48

85

87fg

a

Reaction conditions: D,L-1 (0.3 mmol), 2a (0.2 mmol), 3 (0.02 mmol), dppp (0.02 mmol), [Pd(C3H5)Cl]2 (0.01 mmol), ZnCl2 (0.04 mmol), DBU (0.2 mmol), in PhCH3 (1.5 mL) at 80 oC. b Isolated yield. c Determined by chiral HPLC. d ND = Not Determined. e At 50 oC. f At 0 oC. g 40 mol % ZnCl2.

Table 2. The scope of allyl acetates.a COOEt

Ph

AcO

NH2

COOR AcO

NH2 1a: R = Me; 1b: R = Et 1c: R = iPr; 1d: R = tBu 1e: R = Bn

Ph 2a

ZnCl2 (20 mol %), DBU PhCH3, 80 oC

Cl

Bn

NH2

X

Bn

4f 51h, 53% yield, 94% ee

NH2 COOR

3a: R = H, X = Br CHO 3b: R = C H , X = Br 6 5 R 3c: R = C6H5, X = H

entry

3

4

time (h)

yield (%)b

ee (%)c

1

3a

4a

3.5

13

58

2

3b

4a

18

trace

NDd

3

3c

4a

18

trace

NDd

4

3d

4a

18

30

73

5

3e

4a

2

44

50

6

3f

4a

1.5

35

75

7

3g

4a

1.0

55

59

8

3h

4a

4

30

60

9

3i

4a

1.5

74

62

10

3j

4a

4

41

44

11

3k

4a

3.5

40

25

Bn

Bn

NH2

OH OH

COOEt 4

NH2 COOEt

4g 69h, 75% yield, 94% ee OMe

Bn

Bn

Me

TMS

Bn

Bn

Me

Bn

Bn

NH2 COOEt

4r 96h, 61%yield, 85% ee

N Ts

NH2

Bn

COOEt

Bn

NH2

NH2 COOEt

4s 96h, 71% yield, 93% ee

NH2

4n 69h, 66% yield, 95% ee

NH2 COOEt

COOEt

Bn

NH2

O

4q 106h, 62% yield, 88% ee

4p 85h, 74% yield, 91% ee

Ph

Bn

COOEt 4k 70h, 61% yield, 91% ee

4m 72h, 66% yield, 95% ee

COOEt

4o 50h, 50% yield, 94% ee

F

COOEt

NH2

S

COOEt

4j 72h, 61% yield, 96% ee

COOEt

NH2

4h 41h, 58% yield, 93% ee

COOEt

NH2

4l 72h, 72% yield, 88% ee

Bn Cl

NH2

COOEt

Me

CHO 3d: R = Me; 3e: R = SiPh3 OH 3f: R = SiMe3; 3g: R = 4-FC6H4 OH 3h: R = 4-MeOC6H4; 3i: R = 4-CF3C6H4 3j: R = 1-naphthyl; 3k: R = 9-anthryl 3l: R = 3,5-2FC6H3; 3m: R = 3,5-2MeC6H3 R

OH

MeO

NH2

4i 48h, 54% yield, 94% ee

4a: R = Me; 4b: R = Et 4c: R = iPr; 4d: R = tBu 4e: R = Bn

R

ZnCl2 (40 mol %), DBU PhCH3, 0 oC

COOEt

Bn

Ph

CHO

3f (10 mol %) dppp (10 mol %) [Pd(C3H5)Cl]2 (5 mol %)

3f

MeO

Ph

R 2

1b

Table 1. Reaction condition optimization.a 3 (10 mol %) dppp (10 mol %) [Pd(C3H5)Cl]2 (5 mol %)

Page 2 of 6

Ph

Bn

NH2 COOEt

4t 76h, 41% yield, 91% ee

a

Reaction conditions: D,L-1b (0.3 mmol), 2 (0.2 mmol), 3f (0.02 mmol), dppp (0.02 mmol), [Pd(C3H5)Cl]2 (0.01 mmol), ZnCl2 (0.08 mmol), DBU (0.2 mmol), in PhCH3 (1.5 mL), at 0 oC. Various substituted allyl acetates were subsequently used as acceptors. The allyl acetates bearing substituted phenyls gave the corresponding products 4f-4l in good yields and excellent enantioselectivities, and the electronic properties and position of substituents on the phenyl rings were found not to significantly affect the experimental outcomes. Non-phenyl aryls, including naphthyl, furyl, thienyl and indolyl-substituted allyl acetates, also produced products 4m-4p in good yields and enantioselectivities. Alkyl, alkenyl and alkynyl-substituted allyl acetates were then examined. The yield was found to decrease when phenyl acetenyl-

ACS Paragon Plus Environment

Page 3 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society substituted allyl acetate was used as the acceptor (Table 2, 4t), while all the other allyl acetates gave the corresponding products 4q-4s in good yields and excellent enantioselectivities. The allylsubstituted chiral amino acid ester 4q represents one of the most useful building blocks for the preparation of PLG peptidomimetics.14c

Table 3. The scope of amino acid esters.a R

COOEt AcO

NH2

Ph 2a

1

3f (10 mol %) dppp (10 mol %) [Pd(C3H5)Cl]2 (5 mol %) ZnCl2 (40 mol %), DBU PhCH3, 0 oC

CHO

Ph

R

NH2

OH OH

COOEt 4

TMS

3f

F

Cl NH2

Ph

COOEt

4u 70h, 60% yield, 89% ee

NH2

Ph

COOEt 4vb

48h, 25% yield, 82% ee

NH2 Ph

COOEt 4w 70h, 47% yield, 89% ee

O 2N NH2

Me Ph

COOEt

4xc 70h, 57% yield, 92% ee

NH2 Ph

COOEt

4yc 58h, 60% yield, 88% ee

H N

Ph NH2

Ph

COOEt

COOEt 4abf

72h, 71% yield, 62% ee

70h, 54% yield, 89% ee

NH2 COOEt

4adc 48h, 56% yield, 92% ee

Ph

4aec 120h, 21% yield, 95% ee

COOEt

4ag 61h, 47%yield, 80% ee

Ph

COOEt

4ac 120h, 53% yield, 90% ee (4ac': 13% yield)d NH2 Ph

Ph

COOEt

4afc 110h, 39% yield, 82% ee (48h, 64% yield, 81% ee)e

a) without palladium COOEt

Ph

NH2 1b

COOEt

4ahc 65h, 52% yield, 87% ee

3

AcO

Ph 2a

b) without ZnCl2 COOEt

Ph

AcO

NH2 1b

Ph 2a

c) with modified chiral aldehyde catalyst Ph

COOEt NH2 1b

AcO

Ph 2a

CHO

3f (10 mol %) ZnCl2 (40 mol %), DBU PhCH3, 50 oC, 48 h

Bn

Ph

NH2 COOEt

4b 0% yield

3f (10 mol %) dppp (10 mol %) [Pd(C3H5)Cl]2 (5 mol %)

Ph

Bn

NH2

COOEt 4b 14% yield, 55% ee

DBU PhCH3, 50 oC, 36 h 3 (10 mol %) dppp (10 mol %) [Pd(C3H5)Cl]2 (5 mol %) ZnCl2 (40 mol %), DBU PhCH3, 0 oC, 48 h CHO

OH OH

CbzHN NH2

NH2 Ph

COOEt

Scheme 1. Control experiments.

NH2

NH2

MeOOC

MeS

COOEt

4zc 72h, 44% yield, 87% ee (4z': 43% yield)d (48h, 87% yield, 89% ee)e

NH2 Ph

4aac

Ph

NH2 Ph

enantioselectivities. However, only a 21% yield resulted from the reaction of ethyl valinate and 2a (Table 3, 4ae), possibly due to the steric effect of the isopropyl group. Amino acids containing thioether, ester and amino groups were also applicable to this reaction, giving products 4ag-4ai in moderate yields and high enantioselectivities. Two amino acid substrates that did not give satisfactory yields in association with 3f were re-examined using the chiral aldehyde 3i as the catalyst. The yield of 4z was increased from 44% to 87%, while that of 4af was increased from 39% to 64%, and the enantioselectivities of these two products were maintained at a high level. Generally, the N-allylation side reaction is one of the main factors affecting the yields of products 4. For example, the N-allylation by-products 4z’ and 4ac’ were isolated in 43% and 13% yields, respectively. The absolute configuration of products 4ab was established on the basis of the comparison of the literature data with the experimental values (see Supporting Information). The stereochemistries of compounds 4 were assigned by analogy with that of 4ab.

Ph

OH

Bn

NH2 COOEt

4b CHO OH OCH3

NH2

Ph

COOEt 4aic 48h, 60% yield, 88% ee

3n 4b: 18% yield, 84% ee

3o 0 % yield

3p 0% yield

a Reaction conditions: D,L-1 (0.2 mmol), 2a (0.2 mmol), 3f (0.02 mmol), dppp (0.02 mmol), [Pd(C3H5)Cl]2 (0.01 mmol), ZnCl2 (0.08 mmol), DBU (0.2 mmol), in PhCH3 (1.5 mL), at 0 oC. b At 30 oC. c Using L-amino ester 1 as reactant. d Yield of the Nallylation by-product. e Using 3i as catalyst. f Using D-amino ester 1 as reactant.

The amino acid substrate scope was then investigated (Table 3). Phenylglycines were found to be good substrates in this reaction, while steric effects were determined to modify the yields. As an example, product 4u was generated in good yield, but 4v was only obtained in a 25% yield, although both were generated in high enantioselectivities. Ethyl phenylalaninates bearing otho-, metaor para-substituted phenyls gave excellent enantioselectivities. A moderate yield was obtained with ethyl 2-F phenylalaninate (Table 3, 4w) and the yields increased when the substituent was moved to the meta- or para-position of the phenyl ring (Table 3, 4x and 4y). Other aryl-substituted amino acid derivatives, including ethyl 2-naphthylalaninate, tryptophanate and homophenylalaninate, were also introduced as donors, and the corresponding products 4z-4ab were obtained in 44%–71% yields and with 62%–89% ees. Alkyl-substituted amino acids were also observed to react with phenyl allyl acetate (2a) smoothly, giving products 4ac-4af in moderate yields and high-to-excellent

Figure 2. Proposed catalytic cycles. To the best of our knowledge, the triple catalytic system consisting of a chiral aldehyde, a Lewis acid and a transition metal has not been explored previously. To gain insight into this multi-cooperative catalytic process, control experiments were carried out. As shown in Scheme 1, the model reaction does not work without palladium catalyst (Scheme 1, a), so, a classic TsujiTrost allylation mechanism is possible.12,13 Besides, in the absence of ZnCl2, this reaction can proceed successfully, but much lower yield and enantioselectivity was obtained (Scheme 1,

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

b vs Table 1, entry 18). This result indicates that it is possible to form a zinc-Schiff base complex (I) in this reaction, because the formation of this complex can stabilize the Schiff base and further improve the α-carbon acidity of the amino acid ester.16 Thus facilitate the Schiff base formation and subsequent deprotonation processes. With these information in hand, a possible reaction mechanism is summarized in Figure 2. Firstly, a Schiff base is generated from chiral aldehyde 3f and amino acid ester 2b, and then combines with ZnCl2 to form the Zn-Schiff base complex (I). This Zn-Schiff base intermediate is deprotonated by DBU and transformed into the active enolate intermediate (II). At the same time, an electrophilic π-allyl Pd(II) complexes (E) is generated from allyl acetate and palladium by oxidative addition. Subsequently, the enolate intermediate II attacks the π-allyl Pd(II) complex E via an inter- or intramolecular manner. As results, the Zn-Schiff base complex (III) is produced and the active palladium catalyst is regenerated. Finally, the product 4b is released from Zn-Schiff base (III) by amine exchange or hydrolysis. In order to clarify what’s manner is favored in the nucleophilic attack step, three modified chiral aldehydes were used as catalysts in the model reaction (Scheme 1, c). We found compound 4b was obtained in 18% yield and 84% ee when using chiral aldehyde 3n, but none of the desired product was generated with chiral aldehydes 3o and 3p. These results indicate that the presence of a hydroxyl group at the 2' position of the BINOL aldehyde (3) is crucial to this reaction. One of the most reasonable interpretations is that a temporary intramolecular transition state I (Figure 2, TS I) can be formed from the enolate intermediate (II) and the π-allyl Pd(II) species E via an anion exchange between 2' hydroxyl and acetate anion. Thus, the intramolecular nucleophilic attack becomes a dominant pathway. In conclusion, this work demonstrated the first catalytic strategy based on a combination of a chiral aldehyde, a Lewis acid and a transition metal. Using this triple catalytic system, the allylation reactions of N-unprotected amino esters and allyl acetates proceeded smoothly, giving chiral nonproteinogenic α, αdisubstituted α-amino acids (-AAs) in good yields and excellent enantioselectivities. The proposed mechanism demonstrates that the presence of a 2' hydroxyl group is vital to the success of this reaction, possibly because this hydroxyl group coordinates with the π-allyl Pd(II) species, thus facilitating the reaction process.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H, 13C NMR and HPLC spectra (PDF) Representative experimental procedures and analytical data for all new compounds (PDF)

AUTHOR INFORMATION Corresponding Author [email protected]

Author Contributions † L.

C. and M. J. L. contributed equally.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We are grateful for financial support from NSFC (21472150, 21871223, 21272002), the Chongqing Science Technology Commission (cstccxljrc201701, cstc2018jcyjAX0548).

REFERENCES (1) (a) List, B.; Kennemur, J. L. Chiral-Aldehyde-Catalyzed αFunctionalization of Glycine Esters. Synfacts 2018, 14, 1094. (b) Gong, L.-Z. Chiral aldehyde catalysis: a highly promising concept in asymmetric catalysis. Sci. China Chem. 2019, 62, 3-4. (c) Sun, L.; Chen, X. Y.; Enders, D. Aldehyde Catalysis: New Options for Asymmetric Organocatalytic Reactions. Chem. 2018, 4, 2026-2028. (d) Wang, Q.; Gu, Q.; You, S.-L. Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes. Angew. Chem. Int. Ed. 2019, 58, 2-10. (e) Chen, J. F.; Liu, Y. E.; Gong, X.; Shi, L. M.; Zhao, B. G. Biomimetic Chiral Pyridoxal and Pyridoxamine Catalysts. Chin. J. Chem. 2019, 37, 103-112. (2) Shi, L.; Tao, C.; Yang, Q.; Liu, Y. E.; Chen, J.; Chen, J.; Tian, J.; Liu, F.; Li, B.; Du, Y.; Zhao, B. Chiral Pyridoxal-Catalyzed Asymmetric Biomimetic Transamination of α-Keto Acids. Org. Lett. 2015, 17, 57845787. (3) (a) MacDonald, M. J.; Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. A Catalytic Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene Hydroaminations. J. Am. Chem. Soc. 2011, 133, 20100-20103. (b) MacDonald, M. J.; Hesp, C. R.; Schipper, D. J.; Pesant, M.; Beauchemin, A. M. Highly Enantioselective Intermolecular Hydroamination of Allylic Amines with Chiral Aldehydes as Tethering Catalysts. Chem.-Eur. J. 2013, 19, 2597-2601. (c) Li, B.-J.; El-Nachef, C.; Beauchemin, A. M. Organocatalysis using aldehydes: the development and improvement of catalytic hydroaminations, hydrations and hydrolyses. Chem. Commun. 2017, 53, 13192-13204. (d) Guimond, N.; MacDonald, M. J.; Lemieux, V.; Beauchemin, A. M. Catalysis through Temporary Intramolecularity: Mechanistic Investigations on Aldehyde-Catalyzed Cope-type Hydroamination Lead to the Discovery of a More Efficient Tethering Catalyst. J. Am. Chem. Soc. 2012, 134, 16571-16577. (4) Selected examples: (a) Duckers, N.; Baer, K.; Simon, S.; Groger, H.; Hummel, W. Threonine aldolases-screening, properties and applications in the synthesis of non-proteinogenic β-hydroxy-α-amino acids. Appl. Microbiol. Biotechnol. 2010, 88, 409-424. (b) Clapes, P.; Garrabou, X. Current Trends in Asymmetric Synthesis with Aldolases. Adv. Synth. Catal. 2011, 353, 2263-2283. (c) Franz, S. E.; Stewart, J. D. Chapter Three-Threonine Aldolases. Adv. Appl. Microbiol. 2014, 88, 57-101. (d) Hernandez, K.; Zelen, I.; Petrillo, G.; Usón, I.; Wandtke, C. M.; Bujons, J.; Joglar, J.; Parella, T.; Clapés, P. Engineered L-Serine Hydroxymethyltransferase from Streptococcus thermophilus for the Synthesis of α, α-Dialkyl-α-Amino Acids. Angew. Chem., Int. Ed. 2015, 54, 3013-3017. (e) Fesko, K.; Uhl, M.; Steinreiber, J.; Gruber, K.; Griengl, H. Biocatalytic Access to α,α-Dialkyl-α-amino Acids by a MechanismBased Approach. Angew. Chem., Int. Ed. 2010, 49, 121-124. (f) Kimura, T.; Vassilev, V. P.; Shen, G.-J.; Wong, C.-H. Enzymatic Synthesis of βHydroxy-α-amino Acids Based on Recombinant d- and l-Threonine Aldolases. J. Am. Chem. Soc. 1997, 119, 11734-11742. (5) Xu, B.; Shi, L.-L.; Zhang, Y.-Z.; Wu, Z.-J.; Fu, L.-N.; Luo, C.-Q.; Zhang, L.-X.; Peng, Y.-G.; Guo, Q.-X. Catalytic asymmetric direct αalkylation of amino esters by aldehydes via imine activation. Chem. Sci. 2014, 5, 1988-1991. (6) Chen, J.; Gong, X.; Li, J.; Li, Y.; Ma, J.; Hou, C.; Zhao, G.; Yuan, W.; Zhao, B. Carbonyl catalysis enables a biomimetic asymmetric Mannich reaction. Science 2018, 360, 1438-1442. (7) Wen, W.; Chen, L.; Luo, M.-J.; Zhang, Y.; Chen, Y.-C.; Ouyang, Q.; Guo, Q.-X. Chiral Aldehyde Catalysis for the Catalytic Asymmetric Activation of Glycine Esters. J. Am. Chem. Soc. 2018, 140, 9774-9780. (8) (a) Shao, Z.; Zhang, H. Combining transition metal catalysis and organocatalysis: a broad new concept for catalysis. Chem. Soc. Rev. 2009, 38, 2745-2755. (b) Du, Z.; Shao, Z. Combining transition metal catalysis and organocatalysis-an update. Chem. Soc. Rev. 2013, 42, 1337-1378. (c) Zhong, C.; Shi, X. When Organocatalysis Meets Transition-Metal Catalysis. Eur. J. Org. Chem. 2010, 2999-3025. (d) Chen, D. F.; Han, Z. Y.; Zhou, X. L.; Gong, L. Z. Asymmetric Organocatalysis Combined with Metal Catalysis: Concept, Proof of Concept, and Beyond. Acc. Chem. Res. 2014, 47, 2365-2377. (9) (a) Nakoji, M.; Kanayama, T.; Okino T.; Takemoto, Y. Chiral Phosphine-Free Pd-Mediated Asymmetric Allylation of Prochiral Enolate with a Chiral Phase-Transfer Catalyst. Org. Lett. 2001, 3, 3329-3331. (b) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Pd-Catalyzed Asymmetric Allylic Alkylation of Glycine Imino Ester Using a Chiral Phase-Transfer Catalyst. J. Org. Chem. 2002, 67, 7418-7423. (c) Chen, G.-S.; Deng, Y.-J.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Palladium-catalyzed allylic alkylation of tert-

ACS Paragon Plus Environment

Page 4 of 6

Page 5 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society butyl(diphenylmethylene)-glycinate with simple allyl esters under chiral phase transfer conditions. Tetrahedron: Asymmetry 2001, 12, 1567-1571. (10) (a) Ibrahem, I.; Cordova, A. Direct Catalytic Intermolecular α-Allylic Alkylation of Aldehydes by Combination of Transition-Metal and Organocatalysis. Angew. Chem., Int. Ed. 2006, 45, 1952-1956. (b) Afewerki, S. Cordova, A. Combinations of Aminocatalysts and Metal Catalysts: A Powerful Cooperative Approach in Selective Organic Synthesis. Chem. Rev. 2016, 116, 13512-13570. (11) (a) Komanduri, V.; Krische, M. J. Enantioselective Reductive Coupling of 1,3-Enynes to Heterocyclic Aromatic Aldehydes and Ketones via Rhodium-Catalyzed Asymmetric Hydrogenation:  Mechanistic Insight into the Role of Brønsted Acid Additives. J. Am. Chem. Soc. 2006, 128, 16448-16449. (b) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Unifying Metal and Brønsted Acid Catalysis-Concepts, Mechanisms, and Classifications. Chem. Eur. J. 2010, 16, 9350-9365. (12) (a) Fernández-Ibañez, M. Á.; Maciá, B.; Alonso, D. A.; Pastor, I. M. Palladium and Organocatalysis: An Excellent Recipe for Asymmetric Synthesis. Molecules 2013, 18, 10108-10121. (b) Han, Z.-Y.; Gong, L.-Z. Asymmetric Organo/Palladium Combined Catalysis. Prog. Chem. 2018, 30, 505-512. (c) Jellerichs, B. G.; Kong, J. R.; Krische, M. J. Catalytic Enone Cycloallylation via Concomitant Activation of Latent Nucleophilic and Electrophilic Partners:  Merging Organic and Transition Metal Catalysis. J. Am. Chem. Soc. 2003, 125, 7758-7759. (13) Selected reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev. 1996, 96, 395-422. (b) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921-2934. (c) Cheng, Q.; Tu, H. F.; Zheng, C.; Qu, J. P.; Helmchen, G.; You, S. L. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions. Chem. Rev. 2019, 119, 18551969. Selected examples, see: (d) Tsuji, J.; Takahashi, H.; Morikawa, M. Organic syntheses by means of noble metal compounds XVII. Reaction of π-allylpalladium chloride with nucleophiles. Tetrahedron Lett. 1965, 6, 4387-4388. (e) Trost, B. M.; Fullerton, T. J.; New Synthetic Reactions. Allylic Alkylation. J. Am. Chem. Soc. 1973, 95, 292-294. (f) Jiang, G. X.; List, B. Direct Asymmetric α-Allylation of Aldehydes with Simple Allylic Alcohols Enabled by the Concerted Action of Three Different Catalysts. Angew. Chem. Int. Ed. 2011, 50, 9471-9474. (g) Wang, P. S.; Lin, H. C.; Zhai, Y. J.; Han, Z. Y.; Gong, L. Z. Chiral Counteranion Strategy for Asymmetric Oxidative C(sp3)-H/C(sp3)-H Coupling: Enantioselective αAllylation of Aldehydes with Terminal Alkenes. Angew. Chem. Int. Ed. 2014, 53, 12218-12221. (h) Su, Y. L.; Han, Z. Y.; Li, Y. H.; Gong, L. Z. Asymmetric Allylation of Furfural Derivatives: Synergistic Effect of Chiral Ligand and Organocatalyst on Stereochemical Control. ACS Catal. 2017, 7, 7917-7922. (i) Lin, H. C.; Wang, P. S.; Tao, Z. L.; Chen, Y. G.; Han, Z. Y.; Gong, L. Z. Highly Enantioselective Allylic C–H Alkylation of Terminal Olefins with Pyrazol-5-ones Enabled by Cooperative Catalysis of Palladium Complex and Brønsted Acid. J. Am. Chem. Soc. 2016, 138, 14354-14361. (14) Selected examples, see: (a) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,αDisubstituted α-Amino Acids Bearing Vicinal Stereocenters. J. Am. Chem. Soc. 2018, 140, 2080-2084. (b) Wei, L.; Zhu, Q.; Xu, S. M.; Chang, X.; Wang, C. J. Stereodivergent Synthesis of α,α-Disubstituted αAmino Acids via Synergistic Cu/Ir Catalysis. J. Am. Chem. Soc. 2018, 140, 1508-1513. (c) Wei, L.; Xu, S. M.; Zhu, Q.; Che, C.; Wang, C.-J. Synergistic Cu/Pd Catalysis for Enantioselective Allylic Alkylation of Aldimine Esters: Access to α,α-Disubstituted α-Amino Acids. Angew. Chem. Int. Ed. 2017, 56, 12312-12316. (d) You, S. L.; Hou, X. L.; Dai, L. X.; Cao, B. X.; Sun, J. Novel bis-N-[2(diphenylphosphino)ferrocenylcarbonyl]diamino-cyclohexane ligands: application in asymmetric allylic alkylation of imino esters with simple allyl carbonate. Chem. Commun. 2000, 1933-1934. (e) Kazmaier, U.; Zumpe, F. L.; Chelated Enolates of Amino Acid Esters-Efficient Nucleophiles in Palladium-Catalyzed Allylic Substitutions. Angew. Chem. Int. Ed. 1999, 38, 1468-1470. (f) Kanayama, T.; Yoshida, K.; Hiyabe, H.; Takemoto, Y. Enantio-and Diastereoselective Ir-Catalyzed Allylic Substitutions for Asymmetric Synthesis of Amino Acid Derivatives. Angew. Chem. Int. Ed. 2003, 42, 2054-2056. (g) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. Synthesis of β-Substituted αAmino Acids with Use of Iridium-Catalyzed Asymmetric Allylic Substitution. J. Org. Chem. 2003, 68, 6197-6201. (15) Fang, P.; Chaulagain, M. R.; Aron, Z. D. Catalytic α-Allylation of Unprotected Amino Acid Esters. Org. Lett. 2012, 14, 2130-2133.

(16) (a) Li, L.; Dang, Y. Q.; Li, H. W.; Wang, B.; Wu, Y. Fluorescent chemosensor based on Schiff base for selective detection of zinc(II) in aqueous solution. Tetrahedron Lett. 2010, 51, 618-621. (b) Casarotto, V.; Li, Z.; Boucau, J.; Lin, Y. M. Design and synthesis of a tridentate ligand for asymmetric bifunctional catalysis. Tetrahedron Lett. 2007, 48, 55615564. (c) Ray, D.; Nag, A.; Jana, A.; Goswami, D.; Bharadwaj, P. K. Coumarin derived chromophores in the donor–acceptor–donor format that gives fluorescence enhancement and large two-photon activity in presence of specific metal ions. Inorg. Chim. Acta 2010, 363, 2824-2832.

ACS Paragon Plus Environment

Journal of the American Chemical Society Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective α-Allylic Alkylation of Amino Acid Esters COOEt

AcO

Ar*CHO (10 mol %) palladium (5 mol %)

R2

ZnCl2, DBU, PhCH3

NH2

R1

O O

R2

R1 NH2

COOEt 30 examples up to 87% yield, 96% ee

OEt

N Zn O 2

R1

Re-face attack

Pd L

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 6

TMS

R2

proposed Transition State (TS)

ACS Paragon Plus Environment

6