Natural Product Synthesis via Palladium-Catalyzed Carbonylation

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JOCSynopsis

Natural Product Synthesis via Palladium-Catalyzed Carbonylation Yu Bai, Dexter C Davis, and Mingji Dai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00009 • Publication Date (Web): 07 Feb 2017 Downloaded from http://pubs.acs.org on February 10, 2017

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The Journal of Organic Chemistry

Natural Product Synthesis via Palladium-Catalyzed Carbonylation Yu Bai, Dexter C. Davis, and Mingji Dai* Department of Chemistry and Center for Cancer Research, Purdue University West Lafayette, Indiana, IN 47907 [email protected]

O

Me N

O

OMe O

O

N

O

OMe H

HN

MeO

Me

O O O

O

Me

O

Me

N

O

MeO

Me

H

O

H MeO

O

OH O

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Br

O H

Me O MeCl

Me 2N Me

Cl O

CH H Me 2 B

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H O NH

NH

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H Me

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HO

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O O

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OMe Me OMe OMe

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O Me Me O

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HO O H

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Me O

A

O

Me

O HO

Me

H Me

N CO2Me H H

Me

O

Cl

Me Me

Me

Me

N H

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Me

Me H

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H O

Me

Me

Me N

Me

Me O H H Me

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Pd CO

N O Me

Me

O

H

O

MeO

O

O

H MeO 2C

OH OH

O

H/Me

Me Me

H Me

NH H

O

O MeO

Me

CH 2 Me Me HH

O

N H

OH Me OH

Me

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Me Me N

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ABSTRACT: Carbon monoxide is an important one-carbon source and can be incorporated in complex molecules via various transition metal-catalyzed carbonylation reactions. In particular, palladiumcatalyzed carbonylation reactions have found broad application in total synthesis of natural products. Examples are presented in this Synopsis to highlight recent progress in this area including our own work in macrolide and spirocyclic molecule synthesis. In these selected cases, carbon monoxide functions as a one-carbon linchpin to facilitate building structural complexity and improving synthetic efficiency.

ACS Paragon Plus Environment


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Carbon monoxide is a cheap and abundant one-carbon source in organic synthesis. It reacts with various transition metals to form highly reactive acyl-metallo species which can be intercepted to form multiple carbon-carbon and/or carbon-heteroatom bonds. In general, carbonyl-containing products such as ketones, esters, amides, and aldehydes are produced from these carbonylation reactions.1 Among various transition metal catalysts used in carbonylative transformations, palladium-based catalysts have played important roles. 2 Since Heck’s seminal discoveries of palladium-catalyzed carbonylation of aryl and vinyl halides for the syntheses of esters, amides, acyl chlorides, and aldehydes (often referred as the Heck carbonylation) in 1974,3 many versions of palladium-catalyzed carbonylation reactions have been developed and utilized in making fine chemicals, pharmaceutical molecules, and natural products. Herein, we highlight the use of palladium-catalyzed carbonylation reactions in facilitating total syntheses of complex natural products, including our recent contributions. This Synopsis is organized according to the following reaction types: the carbonylative Stille/Suzuki reaction, carbonylative lactone/lactam formation, the Semmelhack reaction, cascade palladium-ene cyclization/carbonylation, carbonylative C-H functionalization, carbonylative macrocyclization, and carbonylative spirolactonization.

Carbonylative Stille/Suzuki reaction Palladium-catalyzed carbonylative Stille 4 or Suzuki 5 reactions involve a viable three-component coupling of organotin/boron nucleophiles, organic electrophiles (halides, triflates, etc) and carbon monoxide to rapidly synthesize unsymmetrical ketones. When both vinyl electrophiles and nucleophiles are used, divinyl ketones, important intermediates in organic synthesis, can be produced. A follow-up Nazarov cyclization could convert the resultant divinyl ketones to substituted cyclopentenones. Stille and co-workers used such an effective strategy in their total synthesis of ∆9(12)-capnellene (Scheme 1).6 The palladium-catalyzed carbonylative coupling of triflate 1 and (trimethylsilyl)vinylstannane 2 gave divinyl ketone 3. Notably, this transformation requires the addition of 2-3 equiv of LiCl and high pressure of carbon monoxide. Lowering the reaction temperature resulted in the formation of a considerable quantity of the non-carbonylated coupling product. Divinyl ketone 3 underwent a silicondirected Nazarov cyclization 7 to provide enone 4 in 70% yield. The second combination of the ACS Paragon Plus Environment

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carbonylative coupling and silicon-directed Nazarov reaction afforded tricyclic enone 6 efficiently, which eventually led to ∆9(12)-capnellene after double bond reduction and Wittig olefination.

Me Me

BF3. OEt2

2

3 mol% Pd(PPh 3)4 CO (15 psi), LiCl THF, 55 oC 87%

Me 1

Me Me H

Me Me O

SiMe3

Me3Sn OTf

O

Me

5

CH2 Me Me HH

O Me Me HH

ii. BF3.OEt2 toluene, 25 oC 80%

2

i. 3 mol% Pd(PPh3)4 CO (15 psi), LiCl THF, 55 oC 86%

Me

76%

SiMe3

Me3Sn

OTf

ii. Tf2NPh Me 4

toluene, 100 oC 70%

3

Me Me H

i. L-Selectride

SiMe3

Me Me

H

H

9(12) -capnellene (7)

6

Scheme 1. The Stille synthesis of ∆9(12)-capnellene (1984)

In 2008, Chen and coworkers reported an elegant total synthesis of nakiterpiosin (Scheme 2).8 One of the key steps in their synthesis involves an efficient carbonylative Stille reaction to unite two complex moieties 8 and 9. Under the condition of Pd(PPh3)4/CuCl in DMSO with 1 atm of carbon monoxide, the carbonylation product was produced in 62% yield. The CuCl additive and DMSO solvent are critical for this transformation. The successful coupling of two highly acid and base-sensitive parts 8 and 9 is a strong testimony of the generality, reliability, and efficacy of the carbonylative Stille reaction. The resultant aryl vinyl ketone was then subjected to a photo-Nazarov cyclization to produce cyclopentanone 10 in 60% yield after epimerization of the undesired C9-epimer. The total synthesis of nakiterpiosin was completed in four more steps.

Me

O Me

Cl Me

O Me OTf

O

+

Cl

Bu3Sn

9

O O

Me

O H Br

ii. hv (350 nm) iii. iPr2NH

OTBS 8

Me

i. Pd(PPh3)4, CuCl CO, DMSO, 55 oC Me

Br

Me

O O

Cl Me

O

Cl

O O O

O

Me

Me HO

9

OTBS H

37%

10

Br

H

O

Cl Me

Cl

O O Me

9

OH H

Nakiterpoisin (11)

Scheme 2. The Chen synthesis of nakiterpiosin (2008)



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Recently, Smith and co-workers employed a similar strategy to build the cyclopentene ring of the polycyclic natural product calyciphylline N.9 As shown in Scheme 3, highly complex vinyl triflate 12 obtained by using an intramolecular Diels-Alder reaction to build the [2.2.2] bicyclic ring system was coupled with tetravinyltin under a carbon monoxide atmosphere using the conditions established by Stille to give divinyl ketone 13 in excellent yield. Nazarov cyclization of 13 with the aid of HBF4 gave 14 in 82% yield, which was subsequently elaborated to complete the first total synthesis of calyciphylline N with an intramolecular aldol condensation on the newly generated ketone (derived from carbon monoxide) to close the other cyclopentane ring as the key steps.

TBSO PhthN Me Ar

TBSO

O

(vinyl)4Sn Pd(PPh 3)4, LiCl, CO

OTf Si Me2

PhthN Me Ar

DMF, 90 oC 97%

Me

O

13 TBSO

PhthN

O

HBF4 . OEt2 82%

Me

Si Me2

Ar = p-OMeC6H4 12

Me Ar

O

O

Me

Si Me2 14

N

CO2Me H

Me HO

Me

Calyciphylline N (15)

Scheme 3. The Smith synthesis of calyciphylline (2014)

A combination of carbonylative Suzuki coupling and Nazarov reaction was employed by Ishikura and co-workers 10 to synthesize the bis-indole alkaloid yuehchukene which was isolated as a racemic mixture and has shown impressive anti-implantation activity and high binding affinity to estradiol receptor (Scheme 4). A directed ortho-metalation of N-Boc-indole 16 followed by treatment with triethylborane gave the lithiated “ate” complex 17, which was then coupled with vinyl triflate 18 and carbon monoxide without further purification under a catalytic amount of PdCl2(PPh3)2 in THF. Notably, due to the tetra-coordinated nature of “ate” complex 19, no additional base is required to promote the transmetalation step. Subsequent treatment of the carbonylative coupling product with TFA promoted the Nazarov cyclization as well as Boc-deprotection to give 20 in 70% yield, which was further


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advanced to yuehchukene via a sequence of ketone reduction and Lewis acid promoted indole alkylation.

Li

Et B Et N Et Boc

i. tBuLi, THF

16

N Boc

ii. BEt3

OTf

PdCl2(PPh3)2

+ Me Me

Me

CO (10 atm) THF, 60 oC 75%

18

17

Me Me

H

Me Me Me N O Boc

Me

H

TFA 70%

H Me

N H

Me H Me

N H

NH

O

19

20

Yuehchukene (21)

Scheme 4. The Ishikura synthesis of yuehchukene (2000)

Another classical application of the carbonylative Stille coupling lies in the total syntheses of strychnos alkaloids including akuammicine and strychnine by Overman and co-workers (Scheme 5).11 In these cases, carbon monoxide was used as a linker to connect triazone-protected ortho-iodoaniline 22 and vinylstannane 23. Again, lithium chloride and pressurized carbon monoxide were necessary for the carbonylation reaction. Additionally, triphenylarsine turned out to be the best ligand for this transformation. Carbonylation products 24 and 25 were then advanced to strychnine and akuammicine respectively with an aza-Cope-Mannich reaction 12 as the key transformation to form the desired pyrrolidine.

O Me

N

TIPSO N

Me

TIPSO

2.5 mol% Pd2dba3 22 mol% AsPh 3

+

N I

O

CO (50 psi), LiCl NMP, THF, 70 oC

Me3Sn 23

R

Me N

Me

N

R

80% (R = OtBu, 24) 85% (R = H, 25)

22

O

N

24/25

N

N H

N

H H

O O Strychnine (26) H

N H

Me H CO2Me

Akuammicine (27)

Scheme 5. The Overman synthesis of strychnine and akuammicine (1993)



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In these selected natural product syntheses via carbonylative Stille/Suzuki reactions, the desired unsymmetrical ketones were generated in one step from three components: an organotin/boron, an organic electrophile, and carbon monoxide. In comparison to conventional synthetic approaches, which mainly rely on acylation or Friedel-Crafts-type reaction, no carboxylate synthesis and the related functional group manipulations are required for the catalytic carbonylation process. The regioselectivity is predetermined by the positions of the stannane/boron and the halides/triflates on the coupling partners, but not by the electronic properties of the substrates.

Carbonylative lactone/lactam formation In addition to the use of organotin/boron as nucleophiles to form unsymmetrical ketones, as reported in the original Heck carbonylation,3 alcohols, amines, and hydride can be used to as nucleophiles to trap the acylpalladium species derived from the reaction of organic electrophiles and carbon monoxide to form esters, 13 amides, 14 and aldehydes 15 , respectively. These cases can be view as a one-carbon homologation process and have been used frequently in total synthesis. If the alcohol or amine nucleophile is properly tethered in the same molecule with the newly generated acylpalladium species, a lactone or lactam could be produced. 16 In a synthetic study toward the phomoiride molecules, Leighton 17 and co-workers designed and executed a beautiful cascade sequence of hemiketal formation, carbonylative lactonization, and Cope rearrangement to converted 27 to 29 in only one step (Scheme 6A). Hugelshofer and Magauer used the palladium-catalyzed carbonylative lactonization to synthesize α,β-unsaturated lactone 32 in 98% yield from readily available vinyl triflate 31. Notably, in this case, instead of using carbon monoxide from a cylinder, carbon monoxide was in situ generated by the reaction of formic acid with sulfuric acid using a connected reactor and formic acid functions as a carbon monoxide surrogate.18 The α,β-unsaturated lactone 32 was then coupled with 33 through a Hauser-Kraus-type annulation to give tricyclic intermediate 34, which was further advanced to several (nor)leucosceptroids (Scheme 6B).19


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A. The Leighton synthesis toward phomoirides

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OTBDPS

TESO

Me

OTf O OH Me

OTBDPS

TESO

Me Pd(PPh3)4 CO

4

4 O

O

iPr2NEt, PhCN 75 to 115 oC 71%

O

OH

Me

28

OH

27 O

HO [3,3]

2

O

2

OTES

O

O

O

Me

O

Me

O

Me

Me

5

O

5

O

O

CO2H 29

Phomoiride B (CP-263,114, 30)

OTBDPS

B. The Magauer synthesis of (nor)leucosceptroids (2014) O Pd(PPh3)4 CO (H2SO4/HCO2H)

TfO HO 31

Me

PMPO

O

LiHMDS, THF 32

O O

Me HO

H

OH Me Me OH norleucosceptroid A (35) O

O

Me H OH

PMPO

Me

Me

34 Me

Me Me H

H

O

Me

O

LiCl, (nBu)3N MeCN, 70 oC 98%

Me Me

33

O

O

HO

Me H

O O

Me H

Me O

H

OH Me O Me O norleucosceptroid B (36)

H Me O OH Me

O

leucosceptroid K (37) Me

Scheme 6. Carbonylative lactonization

The palladium-catalyzed carbonylative lactamization has not been used as frequently as the corresponding lactonization in total synthesis of natural product. Mori, Ban and co-workers developed a new synthesis of diazepam and the related 1,4-benzodiazepines by means of palladium-catalyzed carbonylative lactamization.20 The application of this method was demonstrated in their total synthesis of tomaymycin (Scheme 7), prothracarcin, and anthramycin. Pressurized carbon monoxide atmosphere was required to suppress the competitive carbon-nitrogen formation process.

MeO TsO MeO

O N Br

Pd(PPh3)4 CO (10 atm)

H HN

OMOM

38

nBu3N, toluene 110 oC 69%

MeO TsO

O

N

H N

MeO

OMOM

O 39

HO MeO

H N

OMe H N

Me

O Tomaymycin (40)

Scheme 7. The Mori and Ban synthesis of tomaymycin (1986)



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Semmelhack Reaction Tetrahydropyran(THP) and tetrahydrofuran(THF) rings exist in many pharmaceutical molecules and natural products including macrolides. Among many methods to synthesize these structural motifs, the Semmelhack reaction21 stands out due to its mild reaction conditions, broad substrate scope and high synthetic efficiency (Scheme 8). The Semmelhack reaction proceeds by an intramolecular addition of alcohol nucleophiles to π-alkene-palladium(II) complexes (oxypalladation) followed by carbon monoxide migratory insertion to the alkylpalladium(II) intermediates and quenching the highly reactive acylpalladium species with another alcohol either intermolecularly or intramolecularly (annulation) to form THP/THF-esters or THP/THF-fused lactone, respectively. Overall, at least two carbon-oxygen bonds and one carbon-carbon bond are constructed. Carbon monoxide is incorporated as the ester or lactone carbonyl group.

I. THP/THF-ester formation n

Pd(II), CO ROH, [O]

OH 41

O

n

n

O

O

O

n

Pd

O

OR 42

Pd

II. Carbonylative annulation OH n

OH 43

Pd(II), CO [O]

OH n

n

O

O

OH Pd O

O

n

O

O

Pd

44

Scheme 8. The Semmelhack reaction

The application of both types of Semmelhack reactions has been magnificently demonstrated in many natural product total syntheses,22 a few of which are highlighted in Schemes 9 and 10. In the Leighton23 synthesis of leucascandrolide A, the standard Semmelhack reaction conditions were used to convert 45 to THP-ester 46 in 75% yield and high stereoselectivity. The ester group was later converted to the desired THP-macrolide via the Yonemitsu-modified Yamaguchi protocol. In their formal synthesis of neopeltolide, She and co-workers24 used the Semmelhack alkoxycarbonylation to produce THP-ester 50 from C2-symmetric alcohol 49 derived from 1,3-propanediol via the Krische’s iridium-catalyzed asymmetric carbonyl allylation.

25

In the MacMillan’s total synthesis of callipeltoside C,

26

the

Semmelhack reaction was employed to build the central THP ring. Callipeltoside C, leucascandrolide A and neopeltolide all have a THP-bridged macrolide, but callipeltoside C differs from the other two by ACS Paragon Plus Environment

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having a hemiketal at C3. This higher oxidation level at C3 renders further challenges for total synthesis, which was overcome by choosing an alkynyl alcohol instead of alkenyl alcohol as the substrate for the Semmelhack reaction. Using the reaction conditions developed by Marshall27 and coworkers, MacMillan and co-workers successfully converted alkynyl alcohol 52 to 54 in 75% yield with 95:5 anomeric diastereocontrol at the C3 carbon center. The use of an alkynyl group allowed a direct introduction of the C3 ketal presumably via a palladium-catalyzed ketal formation from the initial intramolecular alkoxycarbonylation product 53. In these three cases, the Semmelhack reaction enables rapid construction of the THP ring in high stereoselectivity and yield. Carbon monoxide eventually ends as the carbonyl group of these biologically active and complex macrolides.



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A. The Leighton synthesis of leucascandrolide A (2000)

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Me

Me OTBDPS

O

OH

OTBDPS

10 mol% PdCl2 CuCl2, CO

OH

O

OH

MeOH:PhCN (1:1) 75%

O

MeO

45

46

O

Me O O

OMe O

O

O

N

HN

O

O

O OMe

Me

Leucascandrolide A (47)

Me

B. The She synthesis of neopeltolide (2011) OH

OH

[Ir(cod)Cl]2 OH

OH

PdCl2, CuCl2

(R)-Cl,OMe-BIPHEP OAc

48

OH

CO, MeOH

49

83%

O 50 O

70%

N

O

OMe

O

O HN

O O Me

MeO

O

O

MeO

Me

Neopeltolide (51)

C. The MacMillan synthesis of callipeltoside C (2008) OH OH

OH

Me

PdCl2(CH3CN)2 5 mol%

PMBO

O

Me Me

BQ, CO MeOH, 0 oC

Me 52

H PMBO

75%

Me

O

OH O

Me H PMBO

Me

O

OH OH

OMe

H

Me

O

3

Me OMe

54

OMe

53

MeO

Me

O

H

O

MeO

OH O

O

Me

Cl

Callipeltoside C (55)

Scheme 9. The Semmelhack reaction in total synthesis of THP-macrolides

The

intramolecular

trapping

of

the

acylpalladium

complexes

derived

from

intramolecular

alkoxycarbonylation to form THP/THF-fused small-sized lactones (usually five-membered lactones) has been broadly used in facilitating complex natural product synthesis as well. This annulation process provides expedient access of bicyclic lactones, which are frequently found in many natural products and can also be converted to other structural skeletons readily. Strong testimonies to the utility of the Semmelhack carbonylative annulation reaction are highlighted in Scheme 10. In their first total synthesis schindilactone A,

28

Yang and co-workers demonstrated an impressive use of the ACS Paragon Plus Environment

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Semmelhack carbonylative annulation in a very challenging and sophisticated case (cf. 56 →57). Upon treatment of 56 under their palladium/thiourea29 catalyst system in THF under a balloon pressure of carbon monoxide, polycyclic product 57 was produced in 78% yield. All the functional groups of 56 including silylether, hemiketal, ketone, enones, and lactone are well tolerated under the reaction condition. In 2012 and 2015, both the Wong group 30 and Carreira group 31 used the Semmelhack annulation to construct the bicyclic lactone ring system of the pallambins. The Wong’s synthesis of pallambin C and D started from the Wieland-Miescher ketone and Carreira’s synthesis initiated with a Diels-Alder reaction of pentafulvene and methylacrylate. Both of these syntheses used the modified carbonylative annulation reaction conditions developed by the Yang group.32



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A. The Yang synthesis of schindilactone A (2011)

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O

O Me

Me O

H

OTES

O

Pd(OAc)2, ligand (58)

H

O

O

H

OTES

H H O

O

OH

H

CuCl2, CO THF, 70 oC 78%

OH OBn

Me Me

Me

Me

O

H

O OBn

Me Me

56

O

H

57 O

O

H

O

HO

Me

Me

O

H

O O

Me Me

Me

H H O

O

Me N

O H

N

S ligand (58)

Me

Schindilactone A (59)

B. The Wong synthesis of pallambin C and D (2012) O

OH H Me

O Me

HO Me Me

O 60

OTBS

61

O H

Pd(OAc)2, TMTU CO, CuCl2

H

propylene oxide NH4OAc, THF 78%

O

H Me

O Me Me 62 OTBS

O O H

Me H

O H

H Me H

Me

O Me Me

O Pallambin C (63)

H Me

O Me Me

O Pallambin D (64)

C. The Carreira synthesis of pallambin A and B (2015) O

Me2N

H

i. LiAlH4 88%

H

H

CO2Me

HO Me Me

67

68

ii. MeI CO2Me 65

66 pentafulvene

then Et2AlCl

O

O

OH H

Me

HO Me Me

O H

Pd(OAc)2, TMTU CO, CuCl2

MgBr 90% (dr 60:40)

Me

H

H

propylene oxide NH4OAc, THF

O

55% (isomer: 26%)

69 O O H

Me H

H

O Me Me 70

Me

O

O H

O Me Me

O H

Me Me

O

Pallambin A (71)

H

H

O Me Me

Me

O

Pallambin B (72)

Scheme 10. The Semmelhack annulation in total synthesis of THP/THF-fused lactone

Cascade Palladium-Ene Cyclization/Carbonylation In a continuation of their interest in metallo-ene reactions, Oppolzer and co-workers pioneered a sequence of palladium-catalyzed intramolecular insertion of alkenes into π-allyl-palladium and carbonylation reaction (formally considered as a cascade palladium-ene cyclization/carbonylation) to build fused bicyclic ring systems. This cascade process forms multiple (three or four) carbon-carbon bonds with insertion of one or two carbon monoxide molecules into the products as carbonyl functional


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groups for further transformations.33 The utility of this cascade process has been demonstrated in their total syntheses of 3-isorauniticine34 and hirsutene35 (Scheme 11). For the 3-isorauniticine synthesis, the cascade process initiated with an intramolecular palladium-ene reaction upon treatment of allylic carbonate 73 with a catalytic amount of Pd(dba)2 to generate alkyl palladium species 74, which then underwent a sequence of carbon monoxide migratory insertion, double bond insertion, and β-hydride elimination to produce bicyclic enone 76 in 45-53% yield accompanied with 25% of two diastereomers with stereochemistry variations at the newly formed ring junction. Enone 76 was then converted to lactone 77 via a stereoselective hydrogenation from the less hindered convex face and a regioselective Baeyer-Villiger oxidation with stereochemistry retention at the newly generated carbon center. Lactone 77, already containing the key cis-6,6-fused ring system and three of the four stereocenters was then advanced to 3-isorauniticine. Another magnificent application of the cascade palladium-ene cyclization/carbonylation was demonstrated in their hirsutene synthesis. The cascade process was used to rapidly build the A,B-ring system of hirsutene including the construction of one all-carbon quaternary center. In this case, the cascade process initiated with an insertion of the tethered alkyne into the π-allyl-palladium derived from carbonated 79 and two carbon monoxide molecules were incorporated, one in the ketone and the other one in the ester group. The reaction gave 72% yield of the cyclized products as an 85:15-mixture of diastereomers favoring the desired product. The minor product has opposite stereochemistry at the newly generated all-carbon quaternary center. Both the resulting enone and ester groups serve as convenient handles for further transformations to complete the total synthesis of hirsutene.



Page 14 of 29

A. 3-Isorauniticine

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

O2 S

O N

SO2Ar N

Pd(dba)2, PBu3 CO, AcOH

OCO2Me

H

O Xc

SO2Ar N H

H

45-53% Me

H

Me 73 O

Xc

SO2Ar N H

H H

75

Pd CO

74 O Xc

SO2Ar N H

H

O

H

O

76

N H H H MeO2C

SO2Ar N H

H

ii. mCPBA

H

Pd

O Xc

i. Pd/C, H2

77

Me

O O

N H

Me

O

3-Isorauniticine (78)

B. Hirsutene Me

Me

i. Pd(dba)2, PPh3 CO, AcOH

Me OCO2Me

ii. CH2N2

O

72%

79

Me Me

H Me Pd-CO

Me Me

O H Me

OMe

O 81

80

Me Me

CH H Me 2 A

B

H

H Hirsutene (82)

Scheme 11. The Oppolzer syntheses of 3-isorauniticine (1991) and hirsutene (1994)

Carbonylative C-H functionalization C-H functionalization has become as a powerful tool in organic synthesis. The obvious advantage of direct C-H functionalization is that only one or even none of the coupling partners need to possess a pre-functionalized group, therefore it could significantly enhance synthetic efficiency by removing the pre-functionalization as well as the related protection/deprotection steps. While a significant amount of palladium-catalyzed C-H functionalization methods have been developed, palladium-catalyzed carbonylative C-H functionalizations have been quite limited.36 Their application in total synthesis is even more sporadical. The following three examples were selected to highlight the power of using palladium catalyzed C-H carbonylation in total synthesis. One pioneering example came from the Sames group in their synthesis of the teleocidin B-4 core structure (Scheme 12).37 A stoichiometric amount of PdCl2 first reacted with 83 to afford pure palladacycle 84 in 75% yield via a directed C-H activation of one of the methyl C-H bonds. Upon treatment with 85 in the presence of Ag2O, a carboncarbon bond formation took place with palladacycle 84 to furnish 86 in 86% yield with 3:1 E/Z selectivity. After a Friedel-Crafts cyclization, the resultant product was treated with PdCl2 again to form ACS Paragon Plus Environment

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palladacycle 87, which was converted to a methyl ester via addition of carbon monoxide and methanol. Removal of the Schiff base followed by lactam formation gave 88 in 65% yield. Notably, the direct C-H palladation of one of the two methyl groups can be quite stereoselective. At lower reaction temperature (70 oC), a 6:1 ratio was obtained. This stereoselectivity suggested that the isopropyl group occupied the pseudo-equatorial position in the favored transition state of the C-H palladation step and the anti pseudo-equatorial methyl group which is more accessible to the metal center was activated. Lactam 88 was then advanced to 89 via a palladium-catalyzed intramolecular alkenylation of the aromatic C-H bond to afford the core of teleocidin B-4. In principle, the carbon monoxide carbon could eventually become the terminal olefin carbon. While the first two C-H functionalizations require more than stoichiometric amounts of PdCl2, this conceptually new synthesis is thought-provoking and inspiring.

OMe

PdCl2, NaOAc N

ACOH 75%

Me

Me

OMe OMe

Me

Ag2O, DMF 86% (E/Z 3:1)

Pd O Cl Me 84

N Me O Me Me 86

Me

B(OH)2 85 Me

OMe

Me

Me

MeO

N Me O Me Me 83

Me

Me

OMe

OMe

i. MeSO3H 83% ii. PdCl2 NaOAc

Me

MeO

Me Me

i. CO (40 atm) MeOH

N Me

ii. SiO2, CHCl3

Pd O Cl Me

65% (dr 6:1)

87 Me

OMe

NH Me 88

OH

Br

Me Me Me

Me

Br i. tBuOK ii. BBr3

Me

Me Me Me

iii. Pd(OAc)2 O P(tBu) , Cs CO 3 2 3 57%

N Me

Me Me Me

O

Teleocdine B-4 core (89)

N

Me H N

OH

O N H Me

Teleocdine B-4 (90)

Scheme 12. The Sames synthesis of the teleocidine B-4 core (2002)

Another example is shown in Scheme 13. Hong 38 and co-workers demonstrated a sequential palladium-catalyzed intermolecular C-H arylation of chromone 91 and intramolecular C-H carbonylation of the resultant 2-phenolchromone 93 to complete a three-step total synthesis of frutinone A, a potent inhibitor of the CYP1A2 enzyme. This straightforward synthetic route allowed them to rapidly produce frutinone analogs for identifying new inhibitors of CYP1A2 enzyme for cancer prevention.


The Journal of Organic Chemistry O

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

OMe +

O

(HO)2B

H 92

91

i. Pd(OAc)2, Fe(OTf)3 DDQ, KNO2, PivOH 60 oC, 57% ii. BBr3, CH2Cl2 90% O

O OH

Pd(OAc)2 Cu(OAc)2, Na2CO3 CO PivOH, mesitylene 120 oC 86%

O 93

Page 16 of 29

O O

O Frutinone A (94)

Scheme 13. The Hong synthesis of frutinone A (2015)

Early 2016, the Gaunt group reported an elegant synthesis of K-252c (staurosporinone) by using the carbonylative C-H functionalization to construct the 5-membered lactam (Scheme 14, 95→ →96).39 To synthesize the C-H carbonylation precursor, they employed three impressive copper-catalyzed C-H functionalizations40 to build the two aryl-aryl carbon-carbon bonds and one carbon-nitrogen bond.

Cu-catalyzed C-H functionalization 15 mol% Pd(OAc)2 50 mol% Cu(OAc)2

HN H N

O2 N Me

Me

O

HN

N

CO, air toluene, 110 oC 96%

O2N

Me

Me 96

95

i. P(OEt)3, 210 oC (MW) 86% ii. BCl3, TBAI, o-DCB 210 oC (MW) 78%

HN

O NH

HN

K-252c (97)

Scheme 14. The Gaunt synthesis of K-252c (2016)

Carbonylative Macrocyclization Macrocycles have been frequently found in many important drug molecules and natural products. It has always been challenging to form macrocycles mainly due to the entropic disadvantage. Among the macrocycles, macrocyclic ketone, macrolactam, and macrolide are three privileged structures. The application of palladium-catalyzed carbonylation in building these macrocycles has been very limited.41 One beautiful example of the application of carbonylative macrocyclization is from the Stille-Hegedus synthesis of jatrophone (Scheme 15A).42 They used an intramolecular carbonylative Stille coupling to build the macrocyclic ketone of the target molecule under 50 psi of carbon monoxide with 10 mol% of ACS Paragon Plus Environment

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Pd(CH3CN)2Cl2. The reaction is quite sensitive to the stereochemistry of the carbon center bearing the methyl group. With a β-substituted methyl group, the reaction yield (24%) is lower than the one with a α-substituted methyl group (53%). This transformation is highly efficient and forms two carbon-carbon bonds and one macrocycle with the incorporation of the carbon monoxide as the final ketone group in one step. In the Sames synthesis of rhazinilam (Scheme 15B),43 biaryl starting material 100 derived from a platinum-mediate dehydrogenation via a C-H activation process was converted to macrolactam 101 via a Pd/C-catalyzed hydro-carbonylative macro lactamization process. The reaction probably proceeded by an olefin migratory insertion to the Pd-H bond. The resultant alkyl-palladium intermediate underwent carbonylation and the acyl-palladium species was then trapped by the intramolecularly tethered aniline to form the desired macrocycle. Removal the methyl carboxylate completed an elegant total synthesis of rhazinilam.

A. The Stille-Hegedus synthesis of Jatrophone (1990) Me

O

Me Bu 3Sn

Me

OTf

Me 10 mol% Pd(CH 3CN) 2Cl 2

O

Me

Me O

CO (50 psi) LiCl, DMF,rt

Me 98a (β-Me) 98b (α-Me)

O

Me

Me Me O Jatrophone (β-Me: 24%, 99a) epi-Jatrophone (α-Me: 53%, 99b)

B. The Sames synthesis of Rhazinilam (2002) i. 5 mol% Pd/C, dppb CO (10 atm), HCO 2H DME, 150 oC 58%

Me

N NH 2 100

CO2Me

ii. NaOH, MeOH then HCl, 50 oC 90%

Me

N N H

O

Rhazinilam (101)

Scheme 15. Carbonylative macrocyclization in total synthesis

Since starting at Purdue in 2012, we have been interested in developing new catalytic carbonylation methods, particularly those using carbon monoxide as a one-carbon linchpin to stitch simple starting material into complex skeletons to streamline the total synthesis of complex natural products. Inspired by the Semmelhack chemistry, we have developed an efficient palladium-catalyzed cascade alkoxycarbonylative macrolactonization to construct THP/THF-containing macrolactones with different ring sizes and substituents (Scheme 16).44 This tandem catalytic transformation features mild reaction conditions and works for challenging tertiary alcohols. In comparison to other reported THP/THFACS Paragon Plus Environment


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Page 18 of 29

containing macrolactone synthesis, no carboxylate synthesis is required; therefore, the corresponding masking and unmasking steps are avoided. The highly reactive acylpalladium intermediate was generated in situ and trapped by the tethered primary, secondary, or tertiary alcohols. The metal center may have acted as a template to bring the remote alcohol into proximity to facilitate the macrolactonization. Overall, this one-step transformation accomplishes the formation of two carbonoxygen bonds, one carbon-carbon bond, and a bridged macrocyclic ring. Its application was further demonstrated by a total synthesis of the 9-demethylneopeltolide, 45 a potent anticancer analog of neopeltolide.46 Using Pd(OAc)2 as catalyst and CuCl2 as oxidant under a carbon monoxide balloon in 1,2-dichloroethane at room temperature, alkendiol 104 was converted to THP-bridged macrolactone 105 in 58% yield with excellent cis selectivity. Compound 105 was then converted to 9demethylneopeltolide in three steps.

R'

R' R R HO OH

X

X

R

n

m

Y

cis-103 (major)

O O O

O

O

64% (dr 7/1)

68% (dr 5/1)

O

trans-103

O

O

n

m

Y

O

R

O

O

O

O O

+ X

O

4A MS, DCE, rt

Y 102

R' R

O

CuCl2 (3.0 equiv) n

m

O R

10 mol% Pd(OAc)2 CO (balloon)

O

O

O

O

42% (dr 4/1) O Me

O O

O

O

O

Me Me

O 55% (cis only) O

69% (dr 5/1)

51% (dr 8/1) O

O

O

10 mol% Pd(OAc)2 CO (balloon) OH OH MeO

i) HCl O

CuCl2 (3.0 equiv) 4A MS, DCE, rt Me

58% (cis only)

O MeO

104

ii) NaBH4 72% (two steps)

O Me

105

OH N Mitsunobu reaction

O O MeO

O

HN

56% Me

106

O

O

O O O MeO

9

R MeO

O

O Me

9-Demethylneopeltolide (R = H, 107)

Scheme 16. The Dai synthesis of 9-demethylneopeltolide (2014)


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Very recently, we completed a total synthesis of spinosyn A using a palladium-catalyzed carbonylative Heck macrolactonization to form the 5,12-fused macrolactone in one step (Scheme 17).47 Spinosyn A is the major component of spinosad, an important natural insecticide that is widely used in agriculture.48 Our synthesis features a Corey-Fuchs-type 1,2-addition to unite dibromide 108 and aldehyde 109. The latter was synthesized by using the MacMillan chiral amine catalyzed intramolecular Diels-Alder reaction.49 Acetate 110 then underwent a one-step gold-catalyzed propargylic acetate rearrangement,50 oxidative selenide elimination, and TBS-removal to give α-iodoenone 111 in 58% yield. Upon treatment with 10 mol% of Pd(OAc)2 and 20 mol% of P(2-furyl)3 under carbon monoxide (3 atm) in toluene at 90 °C, 111 was converted to tetracyclic intermediate 114 in 43% yield in one step. This cascade palladium-catalyzed carbonylative Heck macrolactonization started with a regular Heck-type double bond insertion. β-Hydride elimination of newly generated alkylpalladium species 112 to give a regular Heck reaction product was suppressed presumably due to lack of the empty coordinate site on the metal center. Instead, a carbon monoxide migratory insertion took place to give acylpalladium 113,51 which was trapped by the remote secondary alcohol to form a 12-membered lactone. Overall, this efficient transformation constructed two carbon-carbon bonds and one carbon-oxygen bond and furnished a 5,12-fused macrolactone in only one operation. The carbonylation product was then advanced to spinosyn A with two deprotection steps and two glycosylation steps.


The Journal of Organic Chemistry PMBO

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

O

Br Me Me

Br

OTBDPS Me

then Ac2O

H

71% (dr 1:1)

SeAr

H

Me

PMBO

HH

Pd(OAc)2 (10%) P(2-furyl)3 (20%)

OTBDPS

Me I Me

58%

110

O

PPh3AuNTf2 (50%) AgNTf2 (3.0 eq.), NIS (2.5 eq.) acetone/H2O (800/1), -15 οC

SeAr

OTBS

109

108

Et4NCl, toluene, 90 οC CO (3 atm)

H

OH

43%

111

PMBO

PMBO

Me HH

OH

Me HH

OTBDPS

O Me

H Pd

H

Me

OH Pd

H O

Me2N

Me

Me

O

O

O

Me

OTBDPS 4 steps

HH

HH

OO

OMe Me OMe OMe

O

OO H

O

H

113

112

Me

OTBDPS

O

OC

PMBO

OTBDPS

nBuLi

+

OTBS

OAc HH

OPMB

HH

H

Page 20 of 29

H

Me

114

O

H

H

Spinosyn A (115)

Scheme 17. The Dai synthesis of spinosyn A (2016)

Carbonylative spirolactonization The oxaspirolactone motif occurs prominently in many bioactive natural products. During our ongoing efforts to develop catalytic carbonylative macrolactonization methodologies to build complex, biologically active molecules and to exploit cyclopropanols in ring opening cross coupling reactions,52 we have developed an efficient and general oxaspirolactone synthesis by using palladium-catalyzed cascade carbonylative spirolactonization of hydroxycyclopropanols (Scheme 18). 53 The use of [Pd(neoc)(OAc)]2(OTf)2, a cationic dimeric palladium catalyst developed in the Waymouth laboratory,54 is critical for this transformation. With 5 mol% of this catalyst and benzoquinone as oxidant, a variety of substrates can be converted to the corresponding oxaspirolactones including the spiro(4.4), (5,4), and (6,4) ring systems. In general, the stereoselectivity of the spiro(5.4) ring systems are excellent due to the anomeric effect.


Page 21 of 29

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The Journal of Organic Chemistry 5 mol% [Pd(neoc)(OAc)]2(OTf)2 CO (balloon)

HO

n

R

O O

benzoquinoe (2.0 equiv.) DCE (0.03 M), 50 oC

116

n

117

Br O

O O

Ph

O

O

117b (50%)

H

O

Me

Me

117e (65%; dr. >20:1)

O O H3C

H

O O H

O

H O

H

H 117f (57%; dr. >20:1) O

O O

O

O

O

F

H 117h (72%; dr. 4:1)

CH3

117g (70%; dr. 10:1)

O O O

O

H

H BzO

O

117d (51%) Ph

Me O O

O

O O

O O

Me

O

O

117c (88%; dr. 1.3:1)

O

117a (71%)

Me

H

O

O Br

O

R

OH

117i (75%; dr. > 20:1) 117j (52%)

F

117k (50%)

Scheme 18. Catalytic carbonylative oxaspirolactone synthesis

Mechanistically, as shown in Scheme 19, the proposed catalytic cycle involves a palladium(II)catalyzed β-carbon elimination to provide a palladium-homoenolate (cf. A→B). Intramolecular lactol formation followed by CO insertion and reductive elimination gave the spirolactone product and a Pd(0) complex. The latter was then oxidized back to Pd(II) complex for the next cycle. Some of the intermediates in the catalytic cycle have been observed by ESI-MS studies.

Pd cat. CO HO

OH

O

oxidant oxaspirolactone (119)

118 LPdII

oxidation

ligand exchange O

O O

LPd0

lactonization

PdII O O PdII

HO

O

A

β-carbon elimination

CO insertion OH O

D

PdII

B CO O O

PdII

C

Scheme 19. Proposed mechanism for the carbonylative oxaspirolactone



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Page 22 of 29

We also demonstrated the potential application of this catalytic carbonylative spirolactonization method by 2- and 4-step total syntheses of C12 oxygenated labdanolic diterpene α-levantanolide and αlevantenolide (Scheme 20), respectively, from commercially available (3aR)-(+)-sclareolide (120). Compound 120 was converted to unsymmetrical cyclopropanol 121 as a 4:1 mixture of diastereomers in 57% yield using the Kulinkovich protocol.55 The catalytic carbonylative spirolactonization occurred with high regioselectivity by cleaving the less substituted Walsh bond to afford a mixture of three diastereomeric oxaspirolactone products in 53% combined yield. The major diastereomer was identified as α-levantanolide (122). The mixture of 122 and 123 was then advanced to α-levantenolid (124) via a α-selenylation/oxidative elimination process.

Me O Me

O Me

Me

OH

Cp2ZrCl2

Me

n-PrMgCl, Tol.

Me

53% (0.5 gram)

121 O

Me

O

Me

O Me

Me 30%

α-Levantanolide (122)

O

O

i) LDA, PhSeCl

Me

ii) H2O2, AcOH

+ Me

Me 23% 123

O

Me

O

O Me

Me

benzoquinoe (2.0 equiv.) 50 oC, DCE, 18 h

Me

Me

120

(2 mol%) [Pd(neoc)(OAc)]2(OTf)2 CO (balloon)

Me

57%

Me

OH

46% (two steps)

Me

O Me

Me

Me

α-Levantenolide (124)

Scheme 20. The Dai syntheses of α-levantanolide and α-levantenolide (2016)

Summary We have highlighted the application of a series of palladium-catalyzed carbonylation reactions in facilitating the total syntheses of complex natural products. When well planned, these carbonylation reactions can significantly increase structural complexity and enhance synthetic efficiency. However, in comparison to other commonly used palladium-catalyzed cross-coupling reactions,56 the scope and potential of the palladium-catalyzed carbonylation reactions are still far from being fully explored, which will require collective effort to move the boundaries forward.

AUTHOR INFORMATION Corresponding Author ACS Paragon Plus Environment

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*E-mail: [email protected] Notes The authors declare no competing financial interest. Biographies

Yu Bai was born in Tianjin, China, in 1983. He received his B.Sc. degree from Nankai University in 2006, where he conducted research in the laboratory of Professor Zhongwen Wang. He joined Professor Mingji Dai’s group at Purdue University in 2012 and obtained his Ph.D. degree in August 2016. He is currently a postdoctoral research fellow in Professor Barry M. Trost group at Stanford University.

Dexter C. Davis was born in Madison, Wisconsin (USA) in 1989. He received his B.Sc. degree in chemistry from the University of Wisconsin-Eau Claire in 2012. He is currently a 5th year Ph.D. student in Professor Mingji Dai’s group at Purdue University. His research focuses on new palladium-catalyzed carbonylation reaction development and total synthesis of natural products.



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Page 24 of 29

Mingji Dai grew up in Sichuan, China, and received his B.S. from Peking University in 2002. After two years’ research with Professors Zhen Yang and Jiahua Chen in the same university, he went to New York in 2004 and pursued graduate study under the guidance of Professor Samuel J. Danishefsky and earned his Ph.D. degree in 2009. He then took a postdoctoral position in the laboratory of Professor Stuart L. Schreiber at Harvard University and the Broad Institute. In August 2012, he began his independent career as an assistant professor in the Chemistry Department of Purdue University. His lab currently focuses on developing new strategies and methodologies for the synthesis of complex natural products and other medicinally and biologically important molecules.

ACKNOWLEDGMENTS We thank the NSF CAREER Award (1553820), the ACS petroleum research foundation (PRF# 54896DNI1) for financial support and Purdue Center for Cancer Research for financial support.

REFERENCES 1

For reviews: (a) Kollár, L. Modern Carbonylation Methods; Wiley-VCH: Weinheim, 2008. (b) Beller,

M.; Wu, X.-F. Transition Metal Catalyzed Carbonylation Reactions; Springer: Berlin/Heidelberg, 2013. (c) Quintero-Duque, S.; Dyballa, K. M.; Fleischer, I. Tetrahedron Lett. 2015, 56, 2634. (d) Gehrtz, P. H.; Hirschbeck, V.; Ciszek, B.; Fleischer, I. Synthesis 2016, 48, 1573. 2

For palladium-catalyzed carbonylation reviews: (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev.

2013, 113, 1. (b) Fang, W.; Zhu, H.; Deng, Q.; Liu, S.; Liu, X.; Shen, Y.; Tu, T. Synthesis 2014, 46, 1689. (c) Kiss, G. Chem. Rev. 2001, 101, 3435. (d) Barnard, C. F. J. Organometallics 2008, 27, 5402. 3

(a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318. (b) Schoenberg, A.; ACS Paragon Plus Environment

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Heck, R. F. J. Org. Chem. 1974, 39, 3327. (c) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761. 4

(a) Tanaka, M. Tetrahedron Lett. 1979, 2601. (b) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie,

S. S.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417. 5

(a) Wakita, Y.; Yasunaga, T.; Akita, M.; Kojima, M. J. Organomet. Chem. 1986, 301, C17. (b)

Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1993, 1595. 6

Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 7500.

7

Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642.

8

Gao, S.; Wang, Q.; Huang, L. J.-S.; Lum, L.; Chen, C. J. Am. Chem. Soc. 2010, 132, 371.

9

Shvartsbart, A.; Smith, III, A. B. J. Am. Chem. Soc. 2014, 136, 870.

10

Ishikura, M.; Imaizumi, K.; Katagiri, N. Heterocycles, 2000, 53, 553.

11

(a) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, Jr. R. W.; Overman, L. E. J. Am. Chem. Soc.

1993, 115, 3966. (b) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776. 12

Overman, L. E. Acc. Chem. Res. 1992, 25, 352.

13

For selected application in total synthesis: (a) Li, H.; Chen, Q.; Lu, Z.; Li, A. J. Am. Chem. Soc. 2016,

138, 15555. (b) Camelio, A. M.; Johnson, T. C.; Siegel, D. J. Am. Chem. Soc. 2015, 137, 11864. (c) Kusaka, S.-i.; Dohi, S.; Doi, T.; Takahashi, T. Tetrahedron Lett. 2003, 44, 8857. (d) Herzner, H.; Palmacci, E. R.; Seeberger, P. H. Org. Lett. 2002, 17, 2965. (e) Rixson, J. E.; Skelton, B. W.; Koutsantonis, G. A.; Gericke, K. M.; Stewart, S. G. Org. Lett. 2013, 15, 4834. (f) Schuppe, A. W.; Newhouse, T. R. J. Am. Chem. Soc. 2017, 139, 631. 14

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