and Regioselectivity in the Palla-dium-Catalyzed Asymmetric Allylic C

A dehydrative cyclization by exposure of 8a and 8b to a mixture of methanesulfonyl chloride (MsCl) and triethylamine (Et3N) resulted in the formation ...
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Nucleophile-Dependent Z/E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C–H Alkylation of 1,4-Dienes Hua-Chen Lin, Pei-Pei Xie, Zhen-Yao Dai, Shuo-Qing Zhang, PuSheng Wang, Yu-Gen Chen, Tian-Ci Wang, Xin Hong, and Liu-Zhu Gong J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13582 • Publication Date (Web): 13 Mar 2019 Downloaded from http://pubs.acs.org on March 13, 2019

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Journal of the American Chemical Society

Nucleophile-Dependent Z/E- and Regioselectivity in the PalladiumCatalyzed Asymmetric Allylic C–H Alkylation of 1,4-Dienes Hua-Chen Lin‡,1, Pei-Pei Xie‡,2, Zhen-Yao Dai1, Shuo-Qing Zhang2, Pu-Sheng Wang*,1, Yu-Gen Chen1, Tian-Ci Wang1, Xin Hong*,2, Liu-Zhu Gong*,1,3 1Hefei

National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China 2Department

of Chemistry, Zhejiang University, Hangzhou, 310027, China

3Collaborative

Innovation Center of Chemical Science and Engineering (Tianjin), China

ABSTRACT: The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- and step-economic than the classical allylic functionalizations, thus can be considered a transformative variant. However, asymmetric allylic C–H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E- and regioselectivity in the Pd-catalyzed asymmetric allylic C–H alkylation of 1,4-dienes is highly dependent on the type of nucleophiles. A highly stereoselective allylic C–H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio- and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C−H cleavage and reveal that the Z/E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

■ INTRODUCTION The stereoselective carbon-carbon bond forming reactions enabled by transition metal catalysis have long been the mainstay in organic chemistry.1 Among extremely versatile approaches, the palladium-catalyzed asymmetric allylic alkylation reaction2 (Tsuji−Trost allylation3) stands out for construction of C(sp3)−C(sp3) bonds (Scheme 1a). The flexibility and efficiency of this method for rapidly accessing alkene-bearing structural complexity have been enabled by nucleophile diversity, good functional group tolerance and abundantly available chiral ligand library.2d Tsuji−Trost allylic alkylation basically employs active allylic substrates, including allylic carbonates, carboxylates and halides to ensure its synthetic repertoire. Although it is highly reliable and has historical significance in organic synthesis and asymmetric catalysis, the installation of allylic leaving groups unavoidably brings additional workup and related processes to erode either the step- or atom-economy. The allylic C−H alkylation of readily accessible olefins4 allows the carbon-carbon bond formation with minimal pre-oxidation and functionality manipulations, and hence can be considered as a transformative alternative of traditional allylic alkylation processes. In the past decades, continuous endeavors have been directed toward the development of palladium-catalyzed allylic C–H

functionalization, providing a diverse range of protocols for assembling carbon-carbon and carbon-heteroatom bonds.5 However, it still remains a formidable challenge to address the stereochemical control issue in the asymmetric allylic C−H alkylation. The multiple and somehow incompatible roles of the palladium catalyst in the catalytic elementary reactions, including allylic C–H cleavage, nucleophilic substitution and oxidative Pd(II) regeneration, lead to the paucity of chiral ligands capable of accelerating all these individual steps (Scheme 1b).4a,4b,4d,4f,4m,6 We have found that sterically demanding chiral phosphoramidite ligands7 nicely fit the requirement of Pd-catalyzed asymmetric allylic C–H functionalization reaction.4i,6, 8 Using benzoquinone as an external oxidant, phosphoramiditepalladium catalyst and 1,4-diene undergo allylic C–H cleavage to generate a terminal π-allyl-Pd intermediate, which can equilibrate to an internal π-allyl-Pd intermediate through π-σ-π isomerization.9 The nucleophilic substitution of these allyl-Pd intermediates, in principle, generates three regiomeric allylation products and each regiomer can exhibit different Z/E- and stereoselectivities. As a consequence, the simultaneous control of regio-, Z/Eand stereoselectivities is extremely challenging. Previous studies found that the regioselectivity seemingly depends on the nature of nucleophiles. For example, the allylic C–H alkylation of 1,4-dienes with pyrazol-5-ones4i greatly

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favored branched diene products. In contrast, linear products were obtained upon using 5-alkylthiazol-4(5H)ones as nucleophiles, but branched diene products became dominant again when the 5-substituent of thiazol-4(5H)ones was switched from alkyl to aryl.8c Here, we will report an asymmetric allylic C−H alkylation of 1,4-dienes with azlactones,10 leading to branched, but unusual Z-dienyl products. Highly enantioenriched α,α-disubstituted αamino acid surrogates bearing thermodynamically unfavorable Z-dienyl moiety were prepared under mild conditions. Lepadiformine marine alkaloids were catalytically and stereoselectively synthesized based on this reaction. The integration of experimental and computational studies on reaction mechanism reveals a novel concerted proton and two-electron transfer process for the allylic C−H cleavage and clarifies the correlation of Z/E- and regioselectivities with the nucleophiles. Scheme 1. Palladium-Catalyzed Asymmetric Allylic Alkylation a). Typical features of palladium-catalyzed asymmetric allylic alkylation (Tsuji-Trost allylation). L L L L LG Nu Nu Nuor carbon  R2 R1 R2 R1 R2 R1  R1 = Pd nucleophiles LG = leaving group • Flexibility and efficiency • Well-established chiral ligand library good functional group tolerance more than 200 chiral ligands alkenyl group for late-stage functionalization • Abundant preoxidized allylic precursor nucleophile versatility carbonates, carboxylates, halides, etc.

the reaction to occur smoothly with stereoselectivity. For instance, the use of L2 resulted in the formation of branched product 3aa in 84% yield, 73% ee with excellent regio-, Z/E- and diastereoselectivities of >20:1 (entry 3). Surprisingly, the thermodynamically unfavorable Z-isomer appeared to be the major product. Fine-tuning of the amine moiety in the phosphoramidite ligands revealed that the presence of pentafluorophenyl and 1-naphthyl group offered the best results of 99% yield and 99% ee, together with excellent regio- and Z-selectivities (entries 4-6). Fine tuning of the 3,3’-substituents of the binaphthyl moiety revealed that the electronically deficient substituent might not be essential for the catalytic activity of chiral palladium complexes (entries 7-9). Unlike the observations reported previously,4i in this case the addition of phosphoric acid as co-catalyst resulted in only trace amounts of product (entry 10), and the presence of carboxylic acids to some degree eroded either the yield or the stereoselectivity (entries 1112). Table 1. Optimization of Reaction Conditionsa O

R2 O PMP

Typical

Me +

L* L*

R

[BQ] + Readily accessible

R

Ar

N N

branch

R

N Me

Me R

2

Gong 2016 JACS

• Limited nucleophile versatility pyrazol-5-ones 5H-thiazol-4-ones ...

This work Detailed mechanistic investigation

when R1 = Ph

O

1

Ar

R2 N

Features

R1

O

Ph

S

Gong 2018 OL

N Ar

S

N R2 R

3

up to 99% yield, 99% e.e., >20:1 d.r. >20:1 Z/E, >20:1 b/l when R1 = CH2Ar' R2 O

R2

N branch

S

Ar

• Undefined mechanism unidentified allylic C-H cleavage mechanism indistinct role of benzoquinones uncertainty factor for Z/E- and regioselectivity

Ar' linear Unsolved Problems

■ RESULTS AND DISCUSSION Asymmetric Allylic C−H Alkylation of 1,4-Dienes with Azlactones. The different regioselectivity between the allylic C–H alkylation reactions of pyrazol-5-ones4i and 5Hthiazol-4-ones8c prompted us to investigate another similar nucleophiles, azlactone derivatives, to get more insight into the selectivity issue. More importantly, the manipulation of azlactone derivatives provides a library of unnatural amino acids surrogates holding great practical potential in organic synthesis. The initial investigation was focused on the reaction of azlactone 1a with (E)-1,4-octadiene 2a in the presence of 2 mol % of Pd(dba)2, 2 mol % of ligand, and stoichiometric amounts of 2,5-dimethylbenzoquinone (2,5DMBQ) in toluene at 25 °C (Table 1). However, neither PPh34d,4h nor simple BINOL-derived phosphoramide ligand4f L1 enabled the desired reaction to proceed (entries 1 and 2). As reported previously,4i,6, 8c the installation of sterically demanding 3,3’-substituents at the binaphtnyl backbone of the chiral phosphoramidite ligands6,7 significantly improved the catalytic efficiency and allowed

Pr 2a

O P N O

O R1

n

R1

R2 R3

R1

branch

O

+

L (2 mol%) Pd(dba)2 (2 mol%) 2,5-DMBQ (110 mol%)

entry

L

O O

toluene (0.2 M) 25 C, 20 h 1

Useful synthon for chemical synthesis

azlactone (1)

allyl-Pd

O N N

R1

internal allyl-Pd

L*

allylic C-H cleavage

O R1

O

R terminal allyl-Pd

= Pd

Ar

O

L*

H

N 1a

b). Unsolved problems of asymmetric allylic C-H alkylation of 1,4-dienes with stabilized nucleophiles. R 1,4-diene (2)

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2

PMP

N Me nPr 3aa

3

L1, R = H, R = C6H5, R = C6H5 L2, R1 = 4-NO2C6H4, R2 = C6H5, R3 = C6H5 L3, R1 = 4-NO2C6H4, R2 = C6H5, R3 = 2-Naphthyl L4, R1 = 4-NO2C6H4, R2 = C6F5, R3 = 2-Naphthyl L5, R1 = 4-NO2C6H4, R2 = C6F5, R3 = 1-Naphthyl L6, R1 = 3,5-(CF3)2C6H3, R2 = C6F5, R3 = 1-Naphthyl L7, R1 = 4-CF3C6H4, R2 = C6F5, R3 = 1-Naphthyl L8, R1 = C6H5, R2 = C6F5, R3 = 1-Naphthyl

yield (%)b

e.e. (%)c

1

PPh3

trace

-

2

L1

20/1, dr >20/1, Z/E >20/1, which were determined by 1H NMR spectroscopic analysis. cThe e.e. value was determined by chiral HPLC analysis. dIn the presence of (PhO)2PO2H (5 mol%). eIn the presence of HOAc (5 mol%). fIn the presence of OFBA (5 mol%). OFBA = 2-fluorobenzoic acid. 2,5-DMBQ = 2,5-dimethyl-1,4benzoquinone.

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Journal of the American Chemical Society Scheme 2. Scope of 1,4-Pentadienes and Azlactones L5 (2 mol%) Pd(dba)2 (2 mol%) 2,5-DMBQ (110 mol%)

O O

toluene (0.2 M) 25 C, 20 h

N

Ar

1

2 O

3ab 99% yield, 97% e.e.

3af 91% yield, 98% e.e.

Cl

N Me

O

O

O N Me

Me N

O 3aj 84% yield, 95% e.e. O

PMP

O N Me

O 3ak 92% yield, 97% e.e. O

N H

Ar

PMP

O 3al 87% yield, 96% e.e. O

O N Me

N Me

N Me Me

Me Me

3ba 99% yield, 97% e.e. O

Me F

3ca 95% yield, 98% e.e. O

O

3da 91% yield, 97% e.e. O

O N Me

O N Me

Me

Me

O

O

PMP

3ga 90% yield, 96% e.e. O

O

O

3ha 94% yield, 98% e.e.

Me

3fa 76% yield, 94% e.e.

O

N Me

Cl

Me

3ea 96% yield, 98% e.e.

Me

S

O

O

O

N Me

N Me

O

O

PMP

O

3am', Ar = C6H5, 94% yield, 96% e.e. 3an', Ar = 4-MeC6H4, 86% yield, 96% e.e. 3ao', Ar = 4-ClC6H4, 86% yield, 93% e.e. 3ap', Ar = 3-ClC6H4, 82% yield, 94% e.e. 3aq', Ar = 2-MeC6H4, 95% yield, 96% e.e.

O Me CO2Me

Cl

O O

N Me N Me PMP PMP OH CO2Et CONHBn 3ag 3ah 3aia 99% yield, 98% e.e. 99% yield, 97% e.e. 95% yield, 96% e.e.

PMP

O

PMP

Ph

3ae 76% yield, 97% e.e.

O

O PMP

N Me

PMP

O

O N Me

N Me

3ad 89% yield, 93% e.e.

O

O

O O

PMP Me

3ac 90% yield, 98% e.e.

O

PMP

O O

N Me

PMP

R1 CO2Me N H

R2 3', alcoholysis with MeOH/K2CO3

3

O

N MeMe

O or Ar

N R1 R2

Ar

O

O PMP

O O

+ R2

R1

O

O N Ph

Me

3ia 85% yield, 94% e.e.

PMP

N

i

PMP

Pr Me

3ja 45% yield, 94% e.e.

N Me

3ka 62% yield, 91% e.e.

Reaction conditions: unless indicated otherwise, reactions of 1 (0.20 mmol), 2 (0.24 mmol), Pd(dba)2 (0.0040 mmol), L5 (0.0040 mmol) and 2,5-DMBQ (0.22 mmol) were carried out in toluene (1 mL) at 25 °C for 20 h; >20:1 b/l, >20/1 d.r., >20/1 Z/E, which were determined by 1H NMR spectroscopic analysis; Isolated yields; The e.e. value was determined by chiral HPLC analysis; Due to the unstability on silica gel, 3am-3aq were alcoholyzed with K2CO3-MeOH to the corresponding methyl ester 3’; The absolute stereochemistry of 3ao’ was assigned based on X-ray crystallography, and the other compounds were assigned by analogy. a8:1 d.r.

(3am’-3aq’) in high yields and with excellent regio- and stereoselectivities after alcoholysis with MeOH. A diverse range of azlactones were next examined under the standard reaction conditions. The protocol was highly general for the azlactone nucleophiles. Azlactones bearing either a paraor meta-substituted phenyl group at the C2 underwent the asymmetric allylic C−H alkylation reaction in high yields and with excellent regio- and stereoselectivities, regardless of the electronic feature (3ba-3ga). The variation of alkyl substituents at the C4 position of azlactones was also permitted to undergo the desired reaction cleanly, delivering the branched alkylation products (3ha-3ka) in good to high yields and with high levels of regio- and stereoselectivities. Applications to the Enantioselective Synthesis of Lepadiformine Marine Alkaloids. Lepadiformines are tricyclic marine alkaloids bearing perhydropyrrolo[1,2j]quinoline ring frameworks, in which the trans-1azadecalin A/B ring system distorts the B ring into an unusual twist boat form. Lepadiformine A was first isolated by Biard’s group11 from the tunicate Clavelina lepadiformis in 1994, while lepadiformines B and C were isolated by Sauviat’s group12 from another marine tunicate Clavelina moluccensis in 2006 (Figure 1). The structure of lepadiformine A was initially proposed based on NMR spectroscopy, but was convinced to be incorrect and the revised structure was established through total synthesis by Kibayashi.13 Similarly, although the chemical structure of lepadiformine C was assumed to be similar to that of lepadiformine A, its absolute configuration was recently assigned by Morimoto on the basis of total synthesis.14 All of the lepadiformine marine alkaloids exhibit strong effect on the cardiovascular systems, in particular, lepadiformine A shows extra moderate cytotoxic activity against a variety of cell lines.11,15 The diverse spectrum of biological effects and the synthetic challenge imparted by lepadiformines have stimulated several groups to devote their efforts to the synthetic studies.16 Figure 1. Chemical Structures of Lepadiformine Marine Alkaloids A

Under the optimized reaction conditions, the generality of the asymmetric allylic C−H alkylation for 1,4-pentadienes was first explored (Scheme 2). Notably, various 1,4pentadienes were nicely tolerated to give the branched products in excellent yields and selectivities. Both primary and secondary alkyl substituted dienes underwent the desired reaction and offered the branched products with high levels of enantioselectivity (3ab-3ae). It is noteworthy that a chloroalkyl substituted diene is also suitable for the reaction (3af). Moreover, the alkyl substituted diene containing ester, amide, alcoholic hydroxyl and heteroaromatic functional groups were also tolerated (3ag3al). Although aryl substituted dienes smoothly participated in the allylic C−H alkylation, the resultant branched products were highly acid-sensitive and cannot be isolated. Fortunately, they could be directly converted into the corresponding α,α-disubstituted α-amino esters

A

A B R 13 H N 2 R2 H 1

13

CN B

B 2

R1 R2 (-)-lepadiformine A: R1 = CH2OH, R2 = nC6H13 1 2 (-)-lepadiformine B: R = CH2OH, R = nC4H9 (+)-lepadiformine C: R1 = H, R2 = nC4H9 (original structure) (-)-Lepadiformine A exhibits strong effect on the cardiovascular system and moderate cytotoxic activity against various cell lines:

2

NC 13

R (+)-lepadiformine C: R = nC4H9 (revised structure)

IC50 = 9.20 g/mL (KB) IC50 = 0.75 g/mL (HT29) IC50 = 3.10 g/mL (P388) IC50 = 6.30 g/mL (P388 doxorubicin-resistant) IC50 = 6.10 g/mL (NSCLS-N6)

The presented reaction provides an efficient access to a diverse range of densely functionalized chiral skeletons that can be further applied to building up complex structures, as exemplified by enantioselective synthesis of lepadiformine marine alkaloids (Scheme 3). A scale-up reaction of 1l with 2r and 2s under the optimized conditions gave 3lr and 3ls in excellent yields and enantioselectivities, together with excellent regio-, diastereo- and Z/Eselectivities. Reduction of 3lr and 3ls with sodium borohydride (NaBH4), and followed by Dess-Martin

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oxidation, produced enantioenriched aldehydes 4a and 4b. Subsequent Wittig olefination by the treatment of 4a and 4b with in situ formed methylenetriphenylphosphorane afforded the desired terminal alkenes 5a and 5b, respectively. Ring-closing metathesis (RCM) with the second-generation Grubbs catalyst at low concentration successfully transformed 5a and 5b into cyclohexa-1,3dienes 6a and 6b.17 Hydrogenation of the C−C double bonds and hydrogenolysis to remove the O-benzyl protecting group enabled by Pd(OH)2/C catalysis, and followed by reduction of the amide functionality with lithium aluminium hydride (LiAlH4) gave amines 7a and 7b. A reaction sequence, including catalytic hydrogenolysis of 7a and 7b over Pd/C to cleave N-p-methoxybenzyl protecting group, removal of ketal protecting group by HCl-mediated hydrolysis, and neutralization with aqueous NaOH, yielded iminium intermediates, which were subsequently hydrogenated by Pd/CaCO3 catalysis to afford alkanolamines 8a and 8b with good diastereoselectivity at C-2. A dehydrative cyclization by exposure of 8a and 8b to a mixture of methanesulfonyl chloride (MsCl) and triethylamine (Et3N) resulted in the formation of a tricycle 9a and (−)-lepadiformine C 9b, respectively. Interception of the Rychnovsky’s route18 at compound 9a and 9b established the formal synthesis of lepadiformine A and B. The spectral data of 9a are identical to those reported in the literature18 and the spectral data of 9b hydrochloride salt are consistent with those reported for the natural product in the literature.14 Scheme 3. Asymmetric Synthesis of Lepadiformine Marine Alkaloids

O PMP

O

+

O

N



toluene, 25 C b/l >20/1 dr >20/1 Z/E >20/1

R OBn

1l

2r: R = nC6H13 2s: R = nC4H9

O

ii. DMP, DCM, rt

R

O

N H

THF, 0 °C

O HN

DCM (0.004 M), rt

i. Pd(OH)2/C, H2, EtOAc, rt

BnO

ii. LiAlH4, THF, 60 °C

O 6a (86%) 6b (95%)

i. Pd/C, H2, EtOH

O

R

Pd/CaCO3 H2, EtOH, rt

HO N

ii. 4M HCl in 1,4-dioxane then 2M NaOH

d). Effect of [BQ]

(H)D D(H) + 1a

Ph 2m or 2m-d2

optimized condition

HO O R

HO R

DCM -20 °C to 0 °C

our synthetic sample: 9b•HCl (-)-lepadiformine C hydrochloride []D25 = -7.9 (c 0.23, CHCl3)

Rychnovsky's route N

N R 9a (54%, 4 steps) 9b (41%, 4 steps)

HO

R

10a: lepadiformine A 10b: lepadiformine B

azlactone 1a + 2,5-DMBQ L5 (100 mol%) Pd(dba)2 (100 mol%) toluene-d8, 25 °C, 2 h

92% recovery of 2,5-DMBQ 28% recovery of 1a

O

Pd(dba)2 (2 mol%) 2,5-DMBQ (110 mol%) toluene-d8, 25 C kH/kD = 2.79

R [BQ] = R O

O

D(H)

O PMP

N Me Ph 3am or 3am-d1

f). Nonlinear effect (NLE) and Hammett studies

8a (5:1 d.r.) 8b (6:1 d.r.)

MsCl, Et3N

3am 92% yield

toluene-d8, 25 °C, 2 h

3ab + 1a toluene, 25 °C, 20 h 2b R = Me, 99% yield, 97% e.e., >20:1 b/l, >20/1 d.r., >20/1 Z/E R = tBu, 97% yield, 92% e.e., >20:1 b/l, >20/1 d.r., >20/1 Z/E R = Ph, 78% yield, 96% e.e., >20:1 b/l, 4:1 d.r., 14:1 Z/E e). Kinetic studies L5 (2 mol%) Me

HN R

L5 (100 mol%) Pd(dba)2 (100 mol%) 2,5-DMBQ (100 mol%)

L5 (2 mol%) Pd(dba)2 (2 mol%) [BQ] (110 mol%)

PMB HN

O 7a (90%, 2 steps) 7b (90%, 2 steps)

1a + 2m

toluene-d8, 25 °C, 2 h

20/1 d.r., >20/1 Z/E

2b + 1a

N

PMP

O O i. NaBH4, MeOH, rt

Scheme 4. Mechanistic Studies towards the Allylic C–H Alkylation

O

L5 (2 mol%) Pd(dba)2 (2 mol%) 2,5-DMBQ (110 mol%)

O

Page 4 of 9

ref. 12: nature sample of (+)-lepadiformine C hydrochloride []D25 = +11.0 (c 1.00, CHCl3)

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3ab

+ 1a X

2 X = Me2N, MeO, Me, H, Cl, CF3

optimized condition

3

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Journal of the American Chemical Society

Scheme 5. DFT-Computed Free Energy Changes of the Most Favorable Pathway Computed free energy profile

Ph

G(kcal/mol), B3LYP-D3(BJ)/6-311+G(d,p)-SDD-SMD(toluene)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ O

Pd

H

L

HO

L

N

H

O Pd

Pd

O

O

L

Ph

Ph

L

10.8

14

Ph L

15

O

L

Pd

17

2.6 18 Ph N

N O

H

HO

Pd

14

H

H L

Pd

HO

15

O L

O

O H

Ph

Ph O

HO

Pd

17

L

TS23

3.8 21

1.0 20

L

12

O

L Pd

11.5

Pd

O

0.0 12

HQ O

6.9 TS19

6.8

O

HQ

O

N

Pd

HQ

O HQ

9.0 TS16

L

N

Pd

11.4

Ph

Ph

Ph

Pd

OH

HQ = HO

Ph

16.5 TS13 1b

O Me P N Me O

L=

O

N

1.4 22

N

O

N

Ph

N

O

O

O HQ

O

L Pd

18

Mechanistic Studies towards the Allylic C–H Alkylation. Although the palladium catalyzed allylic C–H functionalization has been well established,1b,5d,19 mechanistic investigations are still limited.20 To understand the intriguing nucleophile-dependent Z/Eand regioselectivity in the allylic C–H functionalization of 1,4dienes, a series of control experiments were conducted. The Pd-catalyzed allylic alkylation with allyl carbonate 11 led to identical regio-, stereo- and Z/E-selectivities to the allylic C–H alkylation (Scheme 4a), indicating that these reactions might proceed via similar π-allyl-Pd intermediates. Interestingly, the use of stoichiometric amount of Pd(OAc)2 alone was unable to promote the allylic C–H alkylation reaction, resulting in 97% recovery of 1,4-diene 2m and 35% recovery of azlactone 1a. The consumption of azlactone 1a was presumably attributed to a Pd(II)-mediated oxidative homocoupling.21 However, a stoichiometric amount of Pd(dba)2 combined with stoichiometric amount of 2,5DMBQ allowed the formation of 3am in a 92% yield, which implied that 2,5-DMBQ was critical in the success of the allylic C–H alkylation (Scheme 4b). Treatment of 1,4-diene 2m with a stoichiometric mixture of L5, Pd(dba)2 and 2,5DMBQ in d8-toluene at room temperature for 2 h led to nearly complete conversion of 2m and 2,5-DMBQ, suggesting that L5, Pd(dba)2 and 2,5-DMBQ could form a reactive intermediate that participated in the allylic C−H cleavage. Treatment of azlatone 1a with the stoichiometric mixture of L5, Pd(dba)2 and 2,5-DMBQ found that 2,5DMBQ was almost completely recovered, whereas the 1a was consumed in a large amount presumably due to the coupling22 of Pd(dba)2 and 1a (Scheme 4c). These facts suggested that the combination of Pd(0) and 2,5-DMBQ was unable to oxidize azlactone 1a to generate a reactive intermediate. A bulky 2,5-di-tert-butyl-p-benzoquinone rendered the reaction to give excellent regio-, Z/E- and diastereoselectivities, but a slightly decreased

HQ

O

0.0 24

Ph

Ph

L

O

Pd

20

HQ Pd

21

HQ

O

HQ

O

O

L Pd

L

O Ph

22

BQ + 2b

L Pd

S

R

HQ + 12

18.1 3bb

N

24

enantioselectivity. The use of 2,5-diphenyl-pbenzoquinone led to much more attenuated Z/E- and diastereoselectivities (Scheme 4d), implying that the benzoquinones or the corresponding hydroquinones might interact with the Pd catalyst to thereby exert effect on the C−C bond formation step, which affects stereochemistry. In addition, kinetic studies toward understanding the individual allylic C-H cleavage step were also performed. A significant kinetic isotope effect (KIE, kH/kD = 2.79) was observed for the reaction of 1a and 2m(d2) (Scheme 4e), suggesting that the allylic C−H cleavage is involved in the rate-determining step. On the other hand, the correlation between the reaction rate and the concentration of azalactone 1a showed a slightly inverse relationship, implying that the carbon-carbon bond formation step was faster than the allylic C−H cleavage step. In addition, the high concentration azalactone 1a might slightly inhibit the catalytic activity by coordination with palladium species. A linear relationship between the enantiomeric excesses of the ligand L5 and product 3ab suggested that only one molecule of chiral ligand bonded to the active palladium catalyst (Scheme 4f). Surprisingly, a negative slope (ρ = −0.36) of the Hammett plot (Scheme 4f) was obtained, which is contrary to the positive slope (ρ = +0.37) of Hammett studies on the sulfoxide-palladium catalyzed allylic C−H alkylation.4a,4b Generally, a positive slope suggested a proton abstraction mechanism and buildup of a partial negative charge in the allylic C−H cleavage process,20 while the negative slope in our case might imply a different allylic C−H cleavage. Computational Studies towards the Reaction Mechanism and Origins of Selectivities. To elucidate the reaction mechanism and origins of selectivities at the molecular level, we next studied the catalytic cycle with density functional theory (DFT) calculations. The free energy profile of the operating catalytic cycle with a model

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phosphoramidite ligand is shown in Scheme 5. From the substrate-coordinated complex23 12, the initial allylic C–H bond activation occurs via TS13. This process involves both a two-electron transfer and proton transfer, and its concertedness is confirmed by intrinsic reaction coordinate (IRC) calculation (see Supporting Information for more details). Thus, Pd(0) is oxidized to Pd(II) intermediate 14 via TS13, in addition to the proton transfer. Subsequent deprotonation of azlactone through TS16 leads to the ion pair complex 17, and 17 isomerizes to the more stable allylPd species 18. 18, which has an s-trans geometry of the coordinating diene fragment, undergoes a facile isomerization via TS19 to generate intermediate 20 with the s-cis geometry. 20 isomerizes to 22 with a 3-coordination of allyl fragment, and 22 undergoes the C–C bond formation through TS23 to produce the observed product 3bb. Based on the computed free energy profile, the oncycle resting state is the alkene-coordinated Pd(0) complex 12. The rate-determining step is the C–H bond activation via TS13 with an overall barrier of 16.5 kcal/mol, which is consistent with the experimental kinetic studies (Scheme 4). We have also considered a number of alternative mechanistic pathways, and the details of these unfavorable pathways are included in the Supporting Information. Scheme 6. DFT-Optimized Structures and Free Energies of the C–C Bond Formation Transition States and Allyl-Pd(II) Intermediates A) Competing CC bond formation transition states b). branch and E-, conjugated diene

a). branch and Z-, conjugated diene Ph

Ph L

HQ

O

Ph

L

HQ

O

L

O

N

Pd

Pd

Pd

HQ

Ph

L

O

N

Pd

HQ

TS23 G = 11.5 kcal/mol c). linear and Z-, conjugated diene

TS25 G = 12.7 kcal/mol d). linear and E-, conjugated diene L Pd

Ph Pd

L

HQ Ph

HQ

N Ph L

Pd

O

O

Pd

L

N O

Ph

O

HQ

HQ

TS26 G = 20.5 kcal/mol e). branch and non-conjugated diene

TS27 G = 15.8 kcal/mol

HQ Ph

HQ Pd

Ph

Ph

O

L

O

N

Pd

Ph

O

HQ

L

N

HQ O

L Pd

Pd L

TS28 G = 20.2 kcal/mol

TS29 G = 21.2 kcal/mol

B) Preceding intermediates of CC bond formation Ph N

Ph

L HQ

HQ

Ph O

O

Pd

H H

N

Ph

O

L

L Pd

Pd HQ

22 G = 1.4 kcal/mol

HQ

O

L Pd

18 G = -2.6 kcal/mol

* Free energies are compared to the substrate-coordinated complex 12.

Due to the facile isomerization between the allyl-Pd(II) intermediates (18, 20 and 22), the C–C reductive elimination step determines the Z/E as well as

Page 6 of 9

regioselectivity of product. The optimized structures and free energies of the related transition states and intermediates are summarized in Scheme 6. The six competing transition states (TS23, TS25 to TS29) determine the Z/E and regioselectivity. The formation of branched and Z-, conjugated diene via TS23 is at least 1.2 kcal/mol more favorable than the other transition states, which is consistent with the observed selectivities (Table 1). The controlling factor for the regioselectivity is the conjugation of coordinating diene moiety. In TS26, TS27, TS28 and TS29, all four transition states have partial break of conjugation of the diene moiety to accommodate the C–C bond formations. This change of conjugation is supported by the highlighted C–C bond length in the competing transition states (Scheme 6A). The favored transition states TS23 and TS25 have the highlighted C–C distance of 1.39 Å, while the same distance elongates significantly in the other four competing transition states. Comparing the two transition states that determine the Z/E selectivity, TS23 is 1.2 kcal/mol more favorable than TS25. This is due to the stretch of the Pd–O bond in TS25. The s-trans geometry of the diene fragment is intrinsically more stable than the corresponding s-cis geometry because of steric effects, and 4.0 kcal/mol free energy difference exists between the preceding intermediates in favor of the s-trans geometry (22 vs. 18, Scheme 6B). However, the s-trans diene fragment is longer than the corresponding s-cis fragment. The highlighted C–C distance in 18 is 4.88 Å while the same distance in 22 is 4.46 Å (Scheme 6B). This long C–C distance in 18 requires significant distortion of the palladiumnucleophile complex to reach the terminal C–C bond formation, which is reflected in the change of Pd–O bond length from 18 to TS25. This distortion is released in TS23 due to the s-cis geometry, and the Pd–O bond does not have to dissociate that much to allow the desired C–C bond formation. Therefore, the geometric distortion in the C–C bond formation transition states overcome the intrinsic thermodynamic differences of allyl moiety and favors the production of Z-alkenes. We also studied these competing C–C bond formation transition states using the experimental oxidant 2,5-DMBQ, and the same trend was observed (See supporting information). This suggests that the methyl substituents of oxidant have limited effects on the Z/E- and regioselectivity. Our computations highlight the importance of nucleophile in the determination of the Z/E-selectivity, because the geometry of nucleophile is closely related to the required distortion of palladium complex in C–C bond formation. Our hypothesized catalytic cycle provides a mechanistic basis for understanding the stereoselectivity. Scheme 7 shows the optimized structures and relative energies of the four competing stereoselectivity-determining C–C bond formation transition states using the experimental chiral phosphoramidite ligand L5. (R,S)-TS23 is more favorable than the other three competing transition states by at least 2.1 kcal/mol, which is consistent with the excellent diastereo- and enantioselectivity in experiments. Two controlling factors lead to the excellent stereoselectivity. The π-stacking interaction between hydroquinone and the

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Journal of the American Chemical Society naphthyl moiety of phosphoramidite ligand favors (R,S)TS23 and (S,S)-TS23, which determines the forming stereogenic center of azlactone. The proposed π-π interactions in these two transition states are also proven by IGM analysis;24 the green oval represents the favorable non-covalent interaction between the highlighted aryl fragments (Scheme 7). Comparing (R,S)-TS23 and (S,S)TS23, the steric repulsions between the azlactone and diene moiety lead to the preference of (R,S)-TS23. The Newman projection of the forming C–C bond is highlighted in Scheme 7. In (S,S)-TS23, the diene fragment is proximal to the five-membered ring of azlactone, which leads to steric repulsions that disfavor this transition state. Scheme 7. DFT-Optimized Structures and Relative Energies of Stereoselectivity-determining C–C Bond Formation Transition States

pyrazol-5-one undergoes the C–C bond formation in a similar fashion as compared to azlactone (TS30 and TS31). The palladium-oxygen bond in TS31 has to stretch significantly to allow the C–C bond formation for the strans diene fragment, leading to the similar stereoselectivity favoring Z-alkene product (TS30 vs. TS31). With the nitrogen coordination of pyrazol-5-one, no significant palladium-heteroatom bond stretch is required for the E-alkene product formation, the highlighted palladium-nitrogen distances are similar in TS32 and TS33. This allows the pyrazol-5-one nucleophile to exhibit the intrinsic preference towards s-trans geometry of diene fragment, and E-selectivity is observed. We also investigated the Z/E- and regioselectivity of thiazolone. The high acidity of thiazolone allows the C–C bond formation to proceed via an anionic process, leading to the linear Ediene product (See supporting information). Scheme 8. Origins of Reversed Z/E-Selectivity Between Azlactone and Pyrazol-5-one Nucleophiles. O

Pd

99% yield, >20:1 d.r. >20:1 b/l, >20:1 Z/E

1a + 2b

Pd 3.73Å

Ph

O

Pd

-stacking interaction

Pd(dba)2 (5 mol%) L9 (5 mol%) 2,5-DMBQ (110 mol%) toluene, 25 °C, 24 h

Ph L5

O

N

HQ

O O

N

L5

H

Me

O

Me

O alkenyl

Ph O alkenyl N O Me H Me

(R,S)-TS23 G sol = 0.0 kcal/mol

(S,R)-TS23 G sol = 2.1 kcal/mol

H sol = 0.0 kcal/mol

H sol = 1.2 kcal/mol

E



gas =

0.0 kcal/mol HQ

Ph

O N

O

E



gas =

Ph

HQ

(S,S)-TS23 G sol = 2.3 kcal/mol H sol = 2.0 kcal/mol E gas = 1.9 kcal/mol

L5

O Pd

Pd



Ph

Ph

Ph

sol

Me Me

3mb

N N

CF3

Ph

Ph L

Pd HQ

Ph

= 2.8 kcal/mol

HQ

L

Pd

Pd

TS25 G = 1.2 kcal/mol

Ph

Ph HQ

L

O

N N

L

Pd

Pd

Pd

HQ Ph

Pd

O HQ

Ph N

TS31 G = 5.3 kcal/mol L

L

N Pd

L Pd

TS30 G = 0.0 kcal/mol

L

HQ

O

E gas = 3.0 kcal/mol

-stacking interaction

L

O

Pd

HQ

N N

Ph

HQ

O N

TS23 G = 0.0 kcal/mol B) pyrazol-5-one nucleopile

(R,R)-TS23 G sol = 3.6 kcal/mol H

E

L

O

Pd





HQ

O

N

L HQ

O

P N O

O Ph

A) azlactone nucleophile

1.5 kcal/mol

N

L5

3ab O

99% yield, >20:1 d.r. >20:1 b/l, >20:1 E/Z

1m + 2b

CF3

L9 =

Pd

Ph N

N Me Me

PMP

HQ

Z

O

Pd HQ

Ph

O HQ

Ph N N

L Pd

Pd 3.63Å

TS32 G = 1.7 kcal/mol

To further understand the nucleophile-dependent Z/Eselectivity, a control experiment was conducted. Under the identical conditions, the use of azlactone 1a smoothly gave Z-alkene product 3ab, while pyrazol-5-one4i 1m afforded Ealkene product 3mb. Using the same model phosphoramidite ligand as in the computations of mechanism (Scheme 5), we investigated the origins of reversed Z/E-selectivity with azlactone and pyrazol-5-one nucleophiles (Scheme 8). TS23 and TS25 determine the Z/E-selectivity of azlactone, and TS23 is 1.2 kcal/mol more favorable due to the stretch of palladium-oxygen bond in TS25. The pyrazol-5-one nucleophile can coordinate to palladium with either the carbonyl oxygen or the hydrazone nitrogen. With the oxygen coordination,

TS33 G = -2.3 kcal/mol

■ CONCLUSION In summary, we have established a chiral phosphoramidite ligand-palladium catalyzed highly regioand stereoselective allylic C–H alkylation of substituted 1,4pentadienes with azlactones. The protocol allows a wide range of α,α-disubstituted α-amino acid surrogates bearing thermodynamically unfavorable Z-alkenes to be accessed in high yields and with extremely high levels of enantioselectivity. This operationally simple reaction is highly reliable and scalable to deliver densely functionalized products, which are successfully applied to the enantioselective synthesis of lepadiformine marine alkaloids. The combination of experimental methods and DFT calculations suggests a novel concerted proton and two-electron transfer process for allylic C−H cleavage, and

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the DFT calculations highlight the critical role of nucleophile in determining the Z/E- and regioselectivities.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] *[email protected]

Author Contributions ‡These

authors contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Financial support was provided by MOST (973 project 2015CB856600) and NSFC (21602214, 21702182, 21873081).

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Journal of the American Chemical Society Isomers of Polycitorols by Reagent-Controlled Diastereoselective Reductive Amination Chem. Eur. J. 2014, 20, 17433. (18) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D. Total Synthesis of Lepadiformine Alkaloids using N-Boc alpha-Amino Nitriles as Trianion Synthons J. Org. Chem. 2012, 77, 3390. (19) Saint-Denis, T. G.; Zhu, R. Y.; Chen, G.; Wu, Q. F.; Yu, J. Q. Enantioselective C(sp(3))H bond activation by chiral transition metal catalysts Science 2018, 359. (20) Engelin, C.; Jensen, T.; Rodriguez-Rodriguez, S.; Fristrup, P. Mechanistic Investigation of Palladium-Catalyzed Allylic C–H Activation ACS Catal. 2013, 3, 294. (21) Curto, J. M.; Kozlowski, M. C. Chemoselective activation of sp(3) vs sp(2) C-H bonds with Pd(II) J. Am. Chem. Soc. 2015, 137, 18. (22) Liu, X.; Hartwig, J. F. Palladium-catalyzed alpha-arylation of azlactones to form quaternary amino acid derivatives Org. Lett. 2003, 5, 1915. (23) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. Chemistry of dibenzylideneacetone-palladium(0) complexes J. Organomet. Chem. 1974, 65, 253. (24) Lefebvre, C.; Rubez, G.; Khartabil, H.; Boisson, J. C.; Contreras-Garcia, J.; Henon, E. Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density Phys. Chem. Chem. Phys. 2017, 19, 17928.

(11) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K. Lepadiformine, a new marine cytotoxic alkaloid from Clavelina lepadiformis Müller Tetrahedron Lett. 1994, 35, 2691. (12) Sauviat, M. P.; Vercauteren, J.; Grimaud, N.; Juge, M.; Nabil, M.; Petit, J. Y.; Biard, J. F. Sensitivity of cardiac background inward rectifying K+ outward current (IK1) to the alkaloids lepadiformines A, B, and C J. Nat. Prod. 2006, 69, 558. (13) Abe, H.; Aoyagi, S.; Kibayashi, C. First total synthesis of the marine alkaloids (+/-)-fasicularin and (+/-)-lepadiformine based on stereocontrolled intramolecular acylnitroso-Diels-Alder reaction J. Am. Chem. Soc. 2000, 122, 4583. (14) Nishikawa, K.; Yamauchi, K.; Kikuchi, S.; Ezaki, S.; Koyama, T.; Nokubo, H.; Matsumura, K.; Kodama, T.; Kumagai, M.; Morimoto, Y. Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)(2)-Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities Chem. Eur. J. 2017, 23, 9535. (15) Jugé, M.; Grimaud, N.; Biard, J.-F.; Sauviat, M.-P.; Nabil, M.; Verbist, J.-F.; Petit, J.-Y. Cardiovascular effects of lepadiformine, an alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter) Toxicon 2001, 39, 1231. (16) Weinreb, S. M. Studies on total synthesis of the cylindricine/fasicularin/lepadiformine family of tricyclic marine alkaloids Chem. Rev. 2006, 106, 2531. (17) In, J.; Lee, S.; Kwon, Y.; Kim, S. Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine, Fasicularin, and

Table of Contents O

H R 1,4-dienes

L*

HQ

[BQ] +

R1

allylic C-H cleavage = Pd O

Experimental and computational studies

O

L*

R

O H

N L*

R concerted proton and twoelectron transfer process

O

up to 99% yield, 99% e.e. >20:1 d.r., >20:1 Z/E, >20:1 b/l R1

O

O

R2 N

R1

N R2 R 10 steps

HQ O

L

R2

R nucleophile geometry controlled Z- and branch-selectivity

R3 H N

H

R4

lepadiformine marine alkaloids

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