Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters Enabled

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Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters Enabled by Synergistic Pd and Cu Catalysis Qinglong Zhang, Huimin Yu, Lulu Shen, Tianhua Tang, Dongfang Dong, Weiwei Chai, and Weiwei Zi J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Sep 2019 Downloaded from pubs.acs.org on September 3, 2019

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Journal of the American Chemical Society

Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters Enabled by Synergistic Pd and Cu Catalysis Qinglong Zhang,‡ Huimin Yu,‡ Lulu Shen, Tianhua Tang, Dongfang Dong, Weiwei Chai and Weiwei Zi* State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Supporting Information Placeholder ABSTRACT: Herein we describe the use of synergistic Pd and Cu catalysis for stereodivergent coupling reactions between 1,3-dienes and aldimine esters. By using different enantiomers of the two metal catalysts, all four stereoisomers of the coupling products, which have two vicinal stereocenters, could be accessed with high diastereoselectivity and enantioselectivity. This atomeconomical cross-coupling reaction has a wide substrate scope and good functional group tolerance. Our work highlights the power of synergistic catalysis for asymmetric coupling reactions involving Pd-hydride catalysts.

As an atom-economical strategy for C–C bond formation, coupling reactions between enols/enolates and unsaturated hydrocarbons with catalysis by transition-metal hydrides (MH) have been attracting increasing attention.1 These reactions are initiated by addition of M-H to the unsaturated hydrocarbon to form an electrophilic π-allyl metal intermediate, which reacts with the enolizable carbonyl compound to form a C–C bond (Scheme 1A). Substantial progress on asymmetric versions of these reactions has been made.2–4 However, controlling the stereochemistry when two contiguous stereocenters are generated by these methods remains a formidable challenge; Dong and co-workers reported the only successful example to date.5 These investigators developed a cooperative system involving Rh-H and Jacobsen’s amine for stereodivergent coupling of aldehydes with alkynes. Inspired by this work, as well as recent advances in Ir-catalyzed stereodivergent allylic alkylation reactions,6-8 we herein report a protocol for asymmetric coupling reactions between 1,3-dienes and aldimine esters with synergistic catalysis9 by Pd and Cu; all four possible stereoisomers of the coupling products could be obtained regio-, enantio-, and diastereoselectively by various using combinations of different enantiomers of the two catalysts. Pioneering work by Malcolmson and co-workers demonstrated that Pd-phosphinooxazoline (Pd-PHOX) catalysts can be used to accomplish the addition of various activated C-pronucleophiles to 1,3-dienes with high

enantioselectivity.2d,2e However, these investigators did not evaluate less reactive pronucleophiles,10,11 such as amino acid derivatives. Zhou et al. reported a Ni(0)-catalyzed coupling of 1,3-dienes with simple ketones, but nearly 1:1 mixtures of diastereomers were obtained when two stereocenters were generating.4 We speculated that activation of the nucleophiles by a second transition metal not only would widen the scope of the reaction with respect to less reactive nucleophiles, such as aldimine esters, but also would provide additional control over the stereochemistry. Therefore, we set out to design a system for stereoselective C–C coupling reactions with two catalytic cycles, each involving a different transition metal.

Scheme 1. Proposed Strategy for Synergistic Catalysis by Pd and Cu A. M-H catalyzed coupling unsaturated hydrocarbons with carbon nucleophiles O

.

R

R3

M-H

R

R

M = Rh, Ni, Pd

Me

G

[M]

R1

O

R4

H(Me)

R2

G R3 R4

H

R

B. Synergistic Catalysis by Pd/Cu for stereodivergent coupling (this work)

electrophile

O

R1

OMe

nucleophile

[Cu*]

[Pd*]

N

R

2

R

R1

Ar

R2

1

[BH]

[Pd*H]

base

Ar [Pd*]

[BH]

R2 R1

R2

(R,R)-3 CO2Me R3 NH2

[Cu]*

R2

(S,R)-3 CO2Me

R1 H2N

R3

base + N

2 R2

(R,S)-3 CO2Me

R1

R3 NH2

CO2Me R

(S,S)-3 CO2Me

R1 H2N

R3

all stereoisomers accessible  regioselective enantioselective diastereoselective stereodivergent

Aldimine esters were chosen as the nucleophiles for our research because of their well-established stereocontrol in asymmetric transformations, such as cycloaddition reaction12,

ACS Paragon Plus Environment

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allylic alkylation13. Recently, Zhang13a and Wang13b independently disclosed that π-allyl Pd species was able to react with copper complexed azomethine ylide under strong base conditions, stereoselectively giving allylation product. In our designed system (Scheme 1B), we envisioned that under the influence of a suitable base and a transition metal such as Cu, the metalated azomethine ylides would serve as nucleophiles in reactions with electrophilic π-allyl Pd intermediates generated by Pd-H-mediated migratory insertion reactions of 1,3-dienes. Pd-H would be generated by reaction of a Pd(0) species with a protonated Brønsted base, which would simultaneously regenerate the Brønsted base to participate in the Cu catalytic cycle. We rationalized that the Cu and Pd catalysts would dictate the configurations of the nucleophile and electrophile, respectively, thus allowing us to control the configurations of the two stereogenic centers of products 3 during the coupling process. That is, we envisioned that all four possible stereoisomers might be accessed by using various combinations of two chiral catalysts: PdR + CuR, PdS + CuR, PdS + CuS, and PdR + CuS. Initial trials were carried out at 30 °C with 1,3-diene 1a and alanine-derived aldimine ester 2a as model substrates, Et3N as the base, and Pd-PHOX complex Pd-1 as the catalyst (Table 1). To our delight, when a Cu(I) complex with the phosphinoferrocenyloxazoline ligand (S,SP)-L1 was used to activate the aldimine ester, desired coupling product 3aa was obtained in 53% yield (entry 1). Although the diastereoselectivity was poor (dr = 1.6:1), the ee value for the major stereoisomer was 95%. The choice of base Et3N was crucial to the reaction (entry 2). Strong bases Cs2CO3 and DBU failed to give any desired coupling product. Sterically bulky base, such as iPr2NEt, DABCO could catalyze this reaction, yet with extremely low conversion (< 5% after 4 days). It appeared that bulky weak base was not able to deprotonate aldimine ester 2a even though the latter was activated by cationic Cu(I). On the other hand, for strong base Cs2CO3 or DBU, the deprotonation step was achievable; however, the resulting [B · H]+ was not able to oxidatively add to Pd(0) and therefore no Pd-H species could be generated to promote the catalytic cycle.14 Further optimization was focusing on the chiral ligands for the two metals. Switching the Cu(I) ligand to (S,SP)-L2 gave a better yield and a slightly higher dr (entry 3). Therefore, we used L2 as the Cu(I) ligand for the remaining optimization experiments. Evaluation of a series of bisphosphine-derived Pd complexes revealed that Josiphos-derived Pd-6 gave the best results (entries 4–8). When the combination of Cu(I)/(S,Sp)-L2 and Pd-6 was used, (2S,3R)-3aa was isolated as a single stereoisomer in 88% yield with excellent enantioselectivity and diastereoselectivity (>99% ee, >20:1 dr, entry 8). In contrast, when the reaction was conducted with (R,RP)-L2 as the Cu(I) ligand instead of (S,SP)-L2, the diastereoselectivity was completely reversed: (2R,3R)-3aa was obtained instead of (2S,3R)-3aa in 83% yield with 14:1 dr and >99% ee (entry 9). Control experiments revealed that both the Pd and the Cu catalysts were indispensable (entries 10 and 11).15,16

Table 1. Optimization of Reaction Conditions for Coupling of 1a with 2aa

Page 2 of 7

i) Pd cat. (4 mol%) Ar Ph

N

+

1a

CO2Me Me

2a (Ar = p-F-C6H4)

Ph2 P

O

Ar = 4-CF3C6H5 Pd-1

Pd

t

Bu

BF4

O

P Cy2

Fe

Pd-4

P Pd

Ph

Ph

t

Bu2 P Pd P Cy2

Pd BF4

Ph

O

iPr

Fe

Ph

(S,Sp)-L1

O N

PPh2

Fe

BF4

Pd-6

N

PPh2

BF4

Pd-3

Pd-5

N Fe

BF4

Ph

P

Cy2 P

P H P Bu

(2S,3R)-3aa

Pd-2

H t

H2N Me

Ph

P Ph2

t Bu BF4

Pd

CO2Me

Ph

Pd

N

Ar2P

Me

Cu(MeCN)4PF6 (5 mol%) ligand L (5.5 mol%) Et3N ( 2.0 equiv) THF (0.2 M), 30 oC ii) citric acid

(S,Sp)-L2

Ph2P

Fe

(R,Rp)-L2

Cu ligand yield drb ee (%)c L (%)b 1 Pd-1 (S,Sp)-L1 53 1.6:1 95/67 2d Pd-1 (S,Sp)-L1 20:1 >99/— 9 Pd-6 (R,Rp)-L2 90 (83) 1:14 —/>99 10 — (S,Sp)-L2 NR — — 11 Pd-6 — NR — — aThe absolute configuration of (2S,3R)-3aa was assigned by analogy with (2S,3R)-3aa. Reaction conditions: i) 1a (0.2 mmol), 2a (0.1 mmol), Pd cat. (4 mol%), Cu(MeCN)4PF6 (5 mol %), (S,Sp)-L or (R,Rp)-L (5.5 mol%), Et3N (200 mol%), THF (0.5 mL), 30 °C, 36 h; ii) citric acid (10%, 4 mL). In all cases, the regioselectivity was >20:1. bDetermined by 1H NMR analysis of the crude product. NR, no reaction. Isolated yields are provided in parentheses. cDetermined by HPLC. d Cs2CO3, DBU, iPr2NEt or DABCO was used instead of Et3N. entry

Pd cat.

Scheme 2. Stereodivergent Access to All Four Stereoisomers of 3aa Me

Me

Pd-6

CO2Me

Ph Me

NH2

(R,Rp)-L2/Cu

Pd-6 Ph

(S,Sp)-L2/Cu

1a

(2R,3R)-3aa, 83% yield >99% ee, 14:1 dr N

ent-Pd-6

CO2Me Me

NH2

(R,Rp)-L2/Cu

(2R,3S)-3aa, 84% yield >99% ee, >20:1 dr

aSee

Me

CO2Me

Me Ph

H2N

(2S,3R)-3aa, 88% yield >99% ee, >20:1 dr

+ Ar

CO2Me

Ph

Me

2a

Ar = p-F-C6H4

Me

ent-Pd-6 (S,Sp)-L2/Cu

CO2Me

Ph H2N

Me

(2S,3S)-3aa, 82% yield >99% ee, 13.6:1 dr

the SI for experimental details.

To test the stereodivergence of our coupling method, we carried out reactions of 1a and 2a in the presence of four different pairs of enantiomers of the Pd and Cu catalysts. As


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shown in Scheme 2, all four stereoisomers of 3aa could be obtained in good yields with excellent enantio- and diastereoselectivities. This result indicated that during the coupling process, each metal catalyst independently controlled a different stereogenic center; that is, one catalyst controlled the stereochemistry of the electrophilic allyl moiety, and the other controlled the stereochemistry of the nucleophilic enolate moiety during the coupling process. Next, we explored the scope of the reaction with respect to the 1,3-diene (Table 2). The R group could be a phenyl ring with an electron-deficient, electron-neutral, or electron-rich substituent, and the position of the substituent had little effect on the reaction outcome (entries 1–8). In all cases, the corresponding products (3ba–3ia) were obtained in moderate to good yields with excellent enantioselectivity and exclusive diastereoselectivity. Substrates with other aromatic rings (naphthalene [3ja], furan [3ka], thiophene [3la], and indole [3ma]) performed well under the standard conditions (entries 9–12). An alkyl-substituted 1,3-diene was also tested (entry 13) and found to give a low yield of the corresponding product (3na), although the dr was >20:1 and the ee was 93%.17 The absolute configuration of 3ga was determined to be (2S,3R) by means of single-crystal X-ray analysis (CCDC 1934998).18

Me

i) Pd-6 (4 mol%) Ar

R

1

entry 1 2 3 4 5

N

+

CO2Me Me

Cu(MeCN)4PF6 (5 mol%) (S,Sp)-L2 (5.5 mol%)

Et3N ( 2.0 equiv), THF (0.4 M), 30 oC, 2 d 2a ii) citric acid Ar = p-F-C6H4

3 (2S,3R)-3ba (2S,3R)-3ca (2S,3R)-3da (2S,3R)-3ea (2S,3R)-3fa

R p-Me-C6H4 m-Me-C6H4 o-F-C6H4 m-F-C6H4 p-F-C6H6

yield (%) 68 83 83 82 70

CO2Me

R H2N

(2S,3R)-3ga (2S,3R)-3ha (2S,3R)-3ia (2S,3R)-3ja (2S,3R)-3ka (2S,3R)-3la

12

(2S,3R)-3ma

13b

(2S,3R)-3na

>20:1 >20:1 >20:1 >20:1 >20:1

N Ts

(CH2)2OAc

72 70 78 73 69 67

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1

>99 >99 >99 >99 >99 >99

96

>20:1

>99

46

>20:1

93

the reaction conditions, see Table 1, entry 8. For more details see the SI.

Table 3. Substrate Scope with Respect to the Aldimine Estera Me

i) Pd-6 (6 mol%)

+

Ph

Ar

N

CO2Me R

1a

entry

3

Cu(MeCN)4PF6 (8 mol%) (S,Sp)-L2 (8.8 mol%)

1 2 3 4 5 6 7 8 9

(2S,3R)-3ab (2S,3R)-3ac (2S,3R)-3ad (2S,3R)-3ae (2S,3R)-3af (2S,3R)-3ag (2S,3R)-3ah (2S,3R)-3ai (2S,3R)-3aj

10

(2S,3R)-3ak

R for 3ab-3aj or 3ak-3ap R = Et R = nPr R = nBu R = CH2CH2Ph R = Bn R = CH2CO2Me R = (CH2)2NHCbz R = (CH2)2SMe R = allyl Me

CO2Me

Ph H2N

Et3N ( 2.0 equiv), THF (0.8 M), 30 oC, 4 d 2 ii) citric acid Ar = p-F-C6H4

R

(2S,3R)-3

yield (%)

dr

ee (%)

85 86 88 95 46 92 89 95 59

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

>99 >99 >99 >99 98 >99 >99 >99 >99

76

>20:1

>99

67

>20:1

>99

90

>20:1

>99

77

>20:1

>99

85

>20:1

>99

95

>20:1

>99

CO2Me

HN O

11 12

(2S,3R)-3al (2S,3R)-3am

Me O Ph

O H2N Me

CO2Me

Ph N Ph

Me

13 14 15

(2S,3R)-3an (2S,3R)-3ao (2S,3R)-3ap

CO2Et

Ph H2 N Me

Me

H2 N Me

Me

CO2iPr

Ph

CO2tBu

Ph H2 N

a

Me

See the SI for experimental details.

Table 4. Demonstration of Stereodivergencea

Me

(2S,3R)-3

dr

p-Cl-C6H4 p-CF3-C6H4 p-MeO-C6H4 2-naphthyl 2-furyl 2-thiophenyl

aFor

Subsequently, we investigated the scope of the reaction with respect to the aldimine ester substrate (Table 3). Aldimines derived from both natural and unnatural α-amino acids were suitable coupling partners for 1,3-diene 1a (entries 1–10). Notably, substrates containing an extra coordination site (an ester [3ag], an amine [3ah], a methyl sulfide [3ai], and an olefin [3aj]) were well tolerated (entries 6–9). An aldimine ester derived from glutamic acid also reacted smoothly but gave lactam 3ak, as a result of lactamization during the acidic workup step (entry 10). A lactone (entry 11) and cyclic imine (entry 12) derived aldimine esters were also tested and found to afford corresponding cyclic products 3al and 3am, respectively, in good yields with excellent stereoselectivities. We also varied the ester group of the aldimine (entries 13–15). Reactions of substrates with ethyl, iPr, and tBu esters proceeded smoothly, furnishing the corresponding products with >20:1 dr and >99% ee. The presence of a bulky ester group slightly enhanced the yield (compare the yields of 3an, 3ao, and 3ap), perhaps because steric hindrance minimized hydrolysis of the starting aldimines during the reaction.

Table 2. Substrate Scope with Respect to the 1,3Dienea

6 7 8 9 10 11

ee (%) >99 >99 >99 >99 >99



Me R1

(S, Sp)-L2

1 Ar

N

H2N

Pd-6

+

CO2Me

R1

Cu (R, Rp)-L2 R1

2

Me

R

Me

CO2Me R2

2

CO2Me R2

NH2

Me CO2Me

Ph

Et

H2N

H2N

(2S,3R)-3ab, 85% yield dr >20:1, >99% ee

Me CO2Me

m-Me-C6H4

Me

(2S,3R)-3da, 83% yield dr >20:1, >99% ee

Me CO2Me NH2

Et

Me

(2R,3R)-3ab, 76% yield dr = 13:1, >99% ee

Me CO2Me

m-Me-C6H4

Me

H2N

(2S,3R)-3ca, 83% yield dr > 20:1, >99% ee

Me Ph

CO2Me

o-F-C6H4

NH2

(2R,3R)-3ca, 77% yield dr = 10:1, 99% ee

CO2Me

o-F-C6H4

enantioselectivities were excellent in all three cases. Moreover, the regioselectivity was completely controlled, with the addition occurring exclusively at the alkylsubstituted site. Finally, stereodivergent reactions were also achievable with these internal 1,3-dienes. Taken together, our results indicate that all four possible stereoisomers of synthetically useful amino acid esters with two vicinal stereogenic centers (at the α- and β-positions) could be readily obtained by means of our method.

Table 5. Stereodivergent Coupling of Internal 1,3Dienesa

NH2

Me

(2R,3R)-3da, 78% yield dr = 12:1, 97% ee

CH2R2 R

Ph Me

Me

Me CO2Me

p-F-C6H4

Me

H2N

(2S,3R)-3fa, 70% yield dr >20:1, >99% ee

CO2Me

2-Naphth H2N

Me p-F-C6H4

Me

2-Naphth

(2R,3R)-3ja, 70% yield dr = 14:1, >99% ee

CO2Me

m-F-C6H4 N

N

Me

Ph N

Ph Ph

(2S,3R)-3aq, 85% yield dr >20:1, >99% ee

aSee

CO2Me

Ph N

H2 N

Ph Ph

(2R,3R)-3aq, 85% yield dr >20:1, >99% ee


After examining the substrate scope of this coupling reaction, we explored its stereodivergence (Table 4). For this purpose, we used a single enantiomer of Pd-6 and two enantiomers of L2-Cu in reactions between various 1,3-dienes 1 and aldimine esters 2. Under these conditions, both diastereomers of 3ab, 3ca, 3da, 3fa, 3ja and 3am were isolated in high yields with high diastereo- and enantioselectivities. The reaction of an aldimine derived from a glycine ester could potentially afford a dual coupling product, so we used a bulky ketimine instead of an aldimine, to prevent the second coupling reaction. For example, 3aq and 3eq were generated without any modification of the standard reaction conditions, and both diastereoisomers were obtained in high yields with >20:1 dr and >99% ee. Notably, an additional acidic workup step was unnecessary for these ketimine products because they were stable during chromatographic purification. Enantioselective additions of nucleophiles to 1,4disubstituted dienes are rare because of their reactivity is low and controlling the regioselectivity is challenging.2d,3b,19 Therefore, we also tested our method with several internal 1,3-dienes bearing aryl and alkyl groups (Table 5). We found that both the yields and the diastereoselectivities were lower for these dienes than for terminal dienes, but the

CO2Me

Ph

Me

H2 N

Me

(2S,3R)-3qa, 45% yield dr = 10:1, 98% ee OBn

nPr CO2Me

Ph

NH2

Me

NH2

(2R,3R)-3oa, 56% yield (2R,3R)-3pa, 47% yield dr = 5:1, >99% ee dr = 7:1, >99% ee

Me CO2Me

Ph

Me

CO2Me

Ph

Me OBn

CO2Me

Et

Ph

(2R,3R)-3eq, 92% yield dr >20:1, >99% ee

Me

aSee

Ph

Ph

Ph

H2 N

(2S,3R)-3oa, 55% yield (2S,3R)-3pa, 44% yield dr = 14:1, >99% ee dr = 10:1, >99% ee

CO2Me

m-F-C6H4

Ph

(2S,3R)-3eq, 94% yield dr >20:1, >99% ee

H2 N

(2R,3R)-3am, 93% yield dr = 13:1, >99% ee

Me

Me

CO2Me

R1

nPr CO2Me

Ph

N

Me

CH2R2

(R, Rp)-L2

2a

Et CO2Me

Ph

NH2

Me

Me

Cu

(2S,3R)-3am, 90% yield dr > 20:1, >99% ee

CO2Me

NH2

Me

(2R,3R)-3fa, 66% yield dr = 14:1, >99% ee

Pd-6 CO2Me

N

CO2Me

R1 H2 N

+ Ar

Ph

Me CO2Me

CO2Me N

(2S,3R)-3ja, 73% yield dr >20:1, >99% ee

(S, Sp)-L2

1

Ph

Me

Page 4 of 7

CO2Me

Ph Me

NH2

(2R,3R)-3qa, 47% yield dr = 5:1, 97% ee


In summary, we have developed a protocol for stereodivergent coupling reactions between 1,3-dienes and aldimine esters with synergistic catalysis by Pd and Cu. This protocol has a wide substrate scope and could be used to prepare all four possible stereoisomers of synthetically useful amino acid esters with two vicinal stereogenic centers (at the α- and β-positions) with high diastereo- and enantioselectivities, simply by varying the configurations of the two chiral metal catalysts. Our work represents the first example of stereodivergent coupling reaction catalyzed by Pd-H and insights from this study can be expected to shed light on other Pd-H related synergistic catalysis.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental procedures for all reactions and characterization data for all products, including 1H and 13C NMR spectra, HPLC spectra, crystal data (PDF), and X-ray crystallographic data for (2S,3R)-3ga (CIF).

AUTHOR INFORMATION Corresponding Author *Email：[email protected]

Author Contributions ‡ These authors contributed equally to this work.


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Notes

The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by the National “Young Thousand Talents Plan,” the National Natural Science Foundation of China (no. 21871150) and Fundamental Research Funds for Central University. We gratefully acknowledge the State Key Laboratory of Elemento-organic Chemistry and the College of Chemistry of Nankai University for generous financial support. We thank Professor F. Dean Toste for insightful discussions. This work is dedicated to the 100th anniversary of Nankai University.

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R2

R

Ar

Pd-H +

N

R3O

CO2R3

R1 H2N

R4 O

R1

Cu

Stereodivergent coupling

R4

(R,R) (R,S) (S,R) (S,S)

regioselective diastereoselective enantioselective


7

Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters Enabled

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