metal-catalyzed heterocyclization of allenes

Metal-Catalyzed Heterocyclization of Allenes

Chris M. Yates

What Makes an Allene an Interesting Substrate?

Entrance into large number of highly functionalized heterocycles

Cyclization products retain an olefin that can be further manipulated

Cyclization products can be varied by changing metal and or reaction conditions

Many intramolecular heterocyclizations can be done with high diastereoselectivity

Reactions can be catalyzed by Silver, Palladium, Lanthanides, Cobalt, Ruthenium, Iron, and Gold

Discovery of Metal-Catalyzed Cyclization

First discovered by Alf Claesson and co-workers when attempting to purify allenic amines by GLC at 210 °C

Noticed complete conversion of allenic amine 1 into two new compounds, 2 and 3

Lead to the discovery of a metal-catalyzed cyclization using Silver (I)

HN

•

N N

HN

•

N

1 2 3

1 2 (90 % yield)

AgBF4 (5 mol %)CH3Cl

Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. 1979, B33, 309-310.

Extension to Oxygen Heterocycle Formation

Synthesis of 2,5-Dihydrofurans

Synthesis of 5,6-Dihydro-2H-pyrans

•

OHR1

R2

R4

R3

OR1

R3

R4

R2

•R3

R2

HO

R1OR1

R2

R3

AgNO3(10 mol %)H2O/Acetone

CaCO3

1 2 (55-61 % yield)

3 4 (53-60 % yield)

AgBF4 (30 mol %)CH3Cl

Olsson, L. I.; Claesson, A. Synthesis 1979, 743-745.

Diastereoselective Tetrahydropyran Formation

Synthesis of cis-2,6-disubstituted tetrahydropyrans

•O

AgNO3 (1-2 equiv)H2O/AcetoneOR

HR OR

HO•

R

HH

Ag+ HO+

Ag

HH

R

1 2 3

Ag+

A B% Yield

1 2 3

R = Me 71 4

R = t-Bu 50 Trace

R = cyclohexyl 90 7

R = Ph 90 3

R = CH=CH2 50 Trace

Gallagher, T. J. Chem. Soc., Chem. Comm. 1984, 1554-1555.

Diastereoselective Pyrrolidine Formation Synthesis of cis-2,5-disubstituted pyrrolidines

Synthesis of trans-2,3-disubstituded pyrrolidines

NH•

R

EtO2CNEtO2C

R

NEtO2C

R

1 2 3

AgBF4 (1 equiv)CH2Cl2

NH•

Ts

N

Ts

4 5 (86 % yield)


Ph Ph

NAg

H

EtO2CN

AgEtO2C

H

R

H H

R

A B

1 2:3 % Yield

R = tosyl >50:1 100

R = Bn >50:1 93

R = Boc >50:1 70

R = H 1:1 60

δ+ δ+

δ+ δ+

Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J. Chem. Soc., Chem. Comm. 1987, 243-244.

Gallagher, T.; Jones, S. W.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Perkin Trans. 1 1991, 2193-2198.

Formation of Nitrones Trans-2,6-disubstituted piperidines by trapping nitrone with styrene

Trans-2,5-disubstituted pyrrolidines by trapping nitrone with styrene

7-Member nitrones can also be formed by this same method

N

N

N

OH

OH

OH

•

•

•

N

NO

N

O

O




Ph

Ph

N

N

O

O

Ph

Ph

H

H

E/Z - 1a 2a 42 % yield

E - 1b 2b 42 % yield

Z - 1b 3b (34 % yield)

Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1989, 2415-2424.

Cyclization of Allenyl Aldehydes and Ketones to Furans

•

OR3

R2

R1

HAgNO3 (1 equiv)

acetone

1 2

R1 = H, Me, CH2OBn 65-99% yield

R2 = H, n-C7H15

R3 = H, Me, CO2Me, CH2OAc, CH2OTBS, CH2OMOM

OR1 R3

R2

•

OR3

R2

R1

H

OR1 R3

R2Ag+

H

Ag

OR1

R2

R3

Ag

H-Shift H+H+

-Ag+

OR1 R3

R2AgH-Ag+

OR1

R2

R3

•

OR3

R2

R1

H

Ag+

A B C

1 D 2

-H+

Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.

Proposed mechanistic pathways

Mechanism for Conversion of Allenones to Furans

Possible pathways are determined by deuterium using labeled allenes and/or deuterated solvents

No incorporation or loss of deuterium upon treatment of 1 or 2 to reaction conditions with no AgNO3 present

•D

Bu

Me

OC6H13

1 2

O

D

Bu C6H13

Me AgNO3 (1 equiv)

solvent

entry D:H in 1 solvent % yield D:H in 2

1 91:9 Me2CO 92 50:50

2 91:9 Me2CO-H20 91 22:78

3 91:9 Me2CO-D20 88 95:5

4 0:100 Me2CO-d6 91 5:95

5 0:100 Me2CO-D20 92 72:28

Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.

Pd(II)-Catalyzed Cyclization

All Ag(I) cyclizations are limited to cycloisomerization

Pd(II) allows for further functional group incorporation

Can achieve arylations, vinylations, and allylations of cyclization products

Can achieve CO insertion to obtain ketones and acrylates

Palladium-Catalyzed Intramolecular Hydroamination of Allenes

Cyclization is achieved with catalytic Pd(II) and 1 equivalent of acetic acid

This method can also be applied to six member

NH•

Tf

N

Tf

1 2 (80 % yield) 94:6 cis:trans

Ph Ph[(η3-C3H5)PdCl]2 (5 mol %)

dppf (10 mol %)

acetic acid (1 equiv)

dppf = 1,1’-bis(diphenylphosphino)ferrocene

•NH2Ph NH

Ph

3 3 (52 % yield) 95:5 cis:trans

[(η3-C3H5)PdCl]2 (5 mol %)

dppf (10 mol %)

acetic acid (15 mol %)

Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.

Proposed Possible Catalytic Cycle

AcOH

PdH

OAc

L

L

Pd(0)L

L

NH•

Tf

Ph

AcOH

N•

Tf

PhPdL2

H

N

Tf

Ph

N

Tf

Ph

PdL2

H

Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.

Allylation, Vinylation, Arylation

Aryl, vinyl, and allyl palladium(II) complexes can be formed in situ and trigger cyclization

These reactions seem to be tolerable to various substitution

Cyclization can be completed by a variety of oxygen and nitrogen nucleophiles

NHTs

•

NTs

Pd(II)baseRBr

R R

NTs

OH

•

O

Pd(II)baseRBr

R R

O

Palladium-Catalyzed Allylamination

Stereoselective cyclization of carbamates to form oxazolidinones

All reactions proceeded to give trans-selectivity

ONHTs

O

R •

O NTs

R

O

1 2

PdCl2(PhCN)2 (10 mol %)Et3N (1 equiv)

Cl (10-20 equiv)THF

entry R reaction time (h) % yield

1 H 19 53

2 Me 17 65

3 Et 23 62

4 n-Pr 19 80

5 t-Bu 21 74

Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1992, 57, 6377-6379.

Mechanism and Stereochemical Model

Reaction is proposed to proceed through either pathway A or B

Stereochemistry can be rationalized according to pathway A

ONHTs

O

t-Bu •

O NTs

t-Bu

O

PdCl L

-HCl

PdL2 -PdL4

O NTs

t-Bu

O

Pathway A

Pathway B

ONHTs

O

t-BuPd

Cl

LPdCl L

-PdL4-HCl

O NTs

t-Bu

O

i 2

ii 2

1

O N

H

O

•

PdH R

Tscis

•

Pd

O N

O

Ts

HHR trans

Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 3764-3772.

Scope of Aryl and Vinyl Pd(II) Cyclization

Structurally and electronically diverse aryl and vinyl Pd(II) groups can trigger cyclization

R-X, Pd(PPh3)4

K2CO3, DMF

70 °C, 1-3 h

NH•

TsN

Ts1 2

R

Me

Me

Me

Me

entry aryl/vinyl Substrate % yield

1 PhOTf 78

2 p-MePhI 78

3 m-MeOPhBr 72

4 1-bromonaphthalene 80

6 E-PhCH=CHBr 84

7 PhC(Br)=CH2 66

Davies, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85-87.

Formation of Arylated Pyrrolines and Pyrroles

The number of carbons between the nucleophile and allene can affect the cyclization product

Additives and reaction conditions can be used to control product formation

•

n-BuN

Me

Me

H

DMF, K2CO3, RT, 20h

Pd(PPh3)4, PhI, nBu4NCl

DMF, K2CO3, 70 oC, 14h

Pd(PPh3)4, PhI

N

n-Bu Ph

Me

N

n-Bu Ph

Me

Me

1

2 (50 % yield)

3 (71 % yield)

Me

Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.

Six-Membered Ring? Since α-amino allenes give lead to five-member endo-cyclization products, do β-amino allenes give

six-member endo-cyclization? No!

Scope of reaction: reaction also works in presence of allylating agents

•

1 2 (64 % yield)

NH

O

XN

OPh

PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)

K2CO3, Bu4NClMeCN, 3h, reflux

N

O Ph

•

3 4a 4b 97:3 a:b 72 % combined yield

NH

O

PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)K2CO3, Bu4NClMeCN, 3h, reflux

N

O Ph

H

N

O

H

Ph

•

7 8 (73 % yield)


•

5 6a 6b 88:12 a:b 46 % combined yield


N

Ph

H

NH

O O

N

H

O

Ph

N

BzO

O

N

BzO

OPh

H

Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.

Mechanism For Intramolecular Attack of Central Carbon of Allene

•

N

Ph

H

NH

O

O

N

H

O

Ph

PhIPd(0)

PhIPd(0)

•NH

O

•NH

O

PdLPhI

PdLPhI

-HX

-HX

N

PdL2PhO

N

O

PdL2Ph

N

O

PdL2Ph

-Pd(0)

-Pd(0)

1

i ii 2a

iii iv 2b

Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.

Palladium-Catalyzed Oxirane Formation

Intramolecular cyclization of 2,3-allenols yields attack at proximal carbon yielding 2,3-disubstituted oxiranes

This is a in contrast to the previously reported cyclization of α-aminoallenes that yield pyrrolines and pyrroles

•

HO

n-C4H9 Pd(PPh3)4 (5 mol %)

K2CO3, DMF

55 oC, 14 hO

R-1 R,R-2a (98 % ee)98 % ee 52 % yield

H

I

n-C4H9

n-C4H9n-C4H9

•

HO


K2CO3, DMF

55 oC, 14 hO

R-1 R,R-2b (96 % ee)95 % ee 85 % yield

H

n-C4H9

•

HO


K2CO3, DMF

55 oC, 14 hO

R-1 R,R-2c (97.5 % ee)98 % ee 74 % yield

H

n-C4H9

Me

MeO

Me

I

OMe

I

Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943-7944.

Palladium-Catalyzed Aziridination Switching solvents from DMF to 1,4-dioxane shifts attack on allene

•N

Me

Mts H

Pd(PPh3)4 (4-10 mol %)ArI (4 equiv), K2CO3 (4 equiv)

dioxane, reflux

R1H

H

(S,aS)-1 3a 3b

N

R1

H H

Ar Me

H

Mts

N

R1

H H

Ar Me

H

Mts

•N

Me

Mts H

Pd(PPh3)4 (4-10 mol %)ArI (4 equiv), K2CO3 (4 equiv)

dioxane, reflux

R1H

H

(S,aR)-2 3a 3b

N

R1

H H

Ar Me

H

Mts

N

R1

H H

Ar Me

H

Mts

Mts = SO2PhMe3

entry allene R1 ArI time (h) product ratio % yield

1 1 i-Pr PhI 2 3a:3b = 84:16 83

2 1 i-Pr p-MePhI 6 3a:3b = 91:9 64

3 1 Ph PhI 4.5 3a:3b = 85:15 79

4 2 i-Pr PhI 2.2 3a:3b = 2:90 79

5 2 i-Pr p-MePhI 3.5 3a:3b = 12:85 44

6 2 Ph PhI 4 3a:3b = 17:67 73

Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.

Stereochemical model


Me•RL

HH

PdI Ph

PdI

PhA

B

path A path B

Ph

RL

H

HPd

Me

Ph

Me

H

RL

PdH

Ph

RL Pd

MePh

MePd

RL

Ph

RL

MePh

Me

RLRL Me

Ph

Pd

MeRL

Ph

Pd

Me

Ph

R1

NH

HN

R1 Ph

Pd

Mts

Me

Pd

N N

R1 R1

HHH H

Pd

PdI

I

II

I

II I

I

I

major minor

MePh Ph Me

C A B D

Mts Mts3a (cis-E) 3b (trans-E)

1 (S,aS)

Mts

RL =R1

NHMts

Stereochemistry is controlled by irreversible olefin insertion to the less hindered face

Stereochemical model


H•RL

HMe

PdI Ph

PdI

PhA

B

path A path B

Ph

RL

H

MePd

H Ph

Me

H

RLPd

H

Ph

RL Pd

MePh

MePd

RL

Ph

RL

MePh

Me

RLRL Me

Ph

Pd

MeRL

Ph

Pd

Me

Ph

R1

NH

HN

R1 Ph

Pd

Mts

Me

Pd

NN

R1R1

H HHH

Pd

PdI

I

II

I

II I

I

I

major minor

MePhPh Me

D E F C

MtsMts3a (cis-E)3b (trans-E)

2 (S,aR)

Mts

RL =R1

NHMts

Stereochemistry is controlled by irreversible olefin insertion to the less hindered face

Palladium-Catalyzed Formation of Azetidines

Surprisingly the best solvent for this reaction is DMF giving all cis product

•

H

Pd(PPh3)4 (10 mol %)

RX (4 equiv), K2CO3 (4 equiv)

DMF, 70 oC

H

1 2

R1

HNR2 N

R2

R1

H H

R

entry R1 R2 RX time (h) % yield

1 i-Bu Mts PhI 3.5 84

2 i-Bu Ts PhI 3.0 89

3 Bn Ts PhI 1.0 89

4 TBSOCH2 Mts PhI 1.5 53

5 MeO2C(CH2)2 Mts PhI 1.5 73

6 i-Bu Ts PhCH=CHBr 0.75 81

7 MeO2C(CH2)2 Mts PhCH=CHBr 0.5 75

8 Bn Ts p-MePhI 1.5 81


Stereochemical Model


Carbonylation and Alkoxide Coupling

Attempted previous cyclization reactions in the presence of CO and methanol to form acrylate esters

•R1O

RPdCl2 (0.1 equiv)CuCl2 (3.0 equiv)MeOH, CO (1 atm)

O R

O

MeOO R

O

MeO

1 2a 2b

entry R R1 yield cis:trans (2a:2b)

1 H H 51 N/A

2 Me H 72 50:50

3 Me SiMe2tBu 60 50:50

4 Me H 92 50:50

5 CH2COC(CH3)3 SiMe2tBu 90 50:50

6 CH2COCH3 H 44 50:50

7 CH2COCH3 SiMe2tBu 68 50:50

8 CH2CH(OH)CH3 SiMe2tBu 44 50:50

Walkup, R. D.; Park, G. Tetrahedron Lett. 1987, 28, 1023-1026.

Alternative Method With High Selectivity

Obtain same product, but by addition of Hg(II) first, then palladium catalyzed carbonylation/coupling reaction, high cis selectivity is realized

•R1O

R1. Hg(OCOCF3)2 (1 equiv)2. PdCl2 (0.1 equiv) CuCl2 (3.0 equiv) MeOH, CO (1 atm)

O R

O

MeOO R

O

MeO

1 2a 2b

entry R R1 yield cis:trans (2a:2b)

1 Me SiMe2tBu 53 94:6

2 CH2COC(CH3)3 SiMe2tBu 80 92:8

3 CH2COCH3 SiMe2tBu 70 50:50

4 CH2CH(OH)CH3 SiMe2tBu 67 92:8

Walkup, R. D.; Park, G. Tetrahedron Lett. 1987, 28, 1023-1026.

Source of Selectivity in Hg(II) Cyclization Selectivity is controlled by the bulky protecting group

•R

OSiMe2tBu

Hg(OCOCF3)2

R

OSiMe2tBu

+Hg HCF3COO

R

OSiMe2tBu

+Hg HCF3COO

1

A B

O H

R

SiR3

H

XHg

O H

R

H

XHg

SiR3

C D E F

O H

R

SiR3

HXHg

O H

RHXHg

SiR3

cis trans

δ+

δ+

δ+

δ+

δ+

δ+

δ+

δ+

Walkup, R. D.; Park, G. J. Am. Chem. Soc. 1990, 112, 5388.

Pd(II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction

When γ-hydroxy allenes are reacted with aryl halides in the presence of Pd(II) and CO one can obtain cyclization-carbonylation-coupling products

• RHO

ArIPd(PPh3)4 (10 mol %)

K2CO3, CO (1 atm)

DMF, 55-60 oC, 12-18 h

O R

OAr

1 2 3 (5 equiv)

entry R ArI (2) % yield cis:trans

1 Me PhI 63 23:77

2 Me p-MeOPhI 52 39:61

3 Me 1-iodonaphthalene 24 25:75

4 Et PhI 84 21:79

5 Et 1-iodonaphthalene 76 21:79

6 Et p-MeOPhI 87 27:73

7 Et p-NO2PhI 66 28:72

8 i-Pr PhI 72 16:84

9 i-Pr 1-iodonaphthalene 69 19:81

Walkup, r. D.; Guan, L.; Kim, Y. S.; Kim, S. W. Tetrahedron Lett. 1995, 36, 3805-3808.

Expansion to Nitrogen Nucleophiles

•ArI

Pd(PPh3)4 (5 mol %)

K2CO3, CO (20 atm)

CH3CN, 90 oC, 6 h

N O

Ar

1 2 3 n = 1,2 (5 equiv) n = 1,2

TsHNn n

Ts

entry substrate ArI (2) product % yield

1 PhI 83

2 p-MeOPh 91

3 PhI 61

4 p-MeOPh 65

•TsHN

•TsHN

•TsHN

•TsHN

N O

Ph

Ts

N OTs

OMe

O

OMe

NTs

O

Ph

NTs

Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.

Proposed Catalytic Cycle for Pd (II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction

PhI

PdI

Ph

L

L

LnPd(0)

CO

PdIL

L O

Ph

Ph

O

Pd

•

N O

Ph

TsHN

Ts

TsHN

HI

L

L

I

Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.

Organolanthanide-Catalyzed Intramolecular Hydroamination-Cyclization

•NHn

n

R

Cp'2LnCH(TMS)2 (3 mol %)BenzeneH2N

R

1 (n =1,2) 2

entry substrate Precatalyst Product % Conversion

(% Yield)

Z/E

1 Cp’2YCH(TMS)2 >95 (93) 86:14

2 Cp’2LuCH(TMS)2 >95 55:45

3 Cp’2SmCH(TMS)2 >95 67:33

4 Cp’2SmCH(TMS)2 >95 (91) 95:5

5 Cp’2LaCH(TMS)2 >95 (85) 72:28

•NH

NH2

• NH2

NH

•NH2

Me

H

C3H7

NH

C3H7 Me

Me

•NH2

H

•NH2

H

n-C5H11

NH

NH

H

C3H7

n-C5H11

Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-4872.

Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.

Kinetic and Mechanistic Studies of Organolanthanide-Catalyzed Reaction

catalyst ionic radius Nt, h-1 (23 °C)

Cp*2La 1.106 4

Cp*2Sm 1.079 13

Cp*2Y 1.019 31

Cp*2Lu 0.977 7

Ln CH(TMS)2

•

NH

NH2

R

R

•NH2

R

N

•Ln

H

R

HN

R

Ln

CH2(TMS)2


Stereochemical Model for trans-Pyrrolidines


Stereochemical Model for cis-Piperidines


Cobalt-Mediated Acylation-Cyclization of Allenes

RXNaCo(CO)4

CO, THF

O

Co(CO)4R

•Nuc

Nuc

O

RTHF, base

1 2 3

entry RX Nucleophile base % yield

1 MeI OH NaH 30

2 BnOCH2Cl OH i-Pr2NEt 25

3 MeI NHTs NaH 69

4 BnOCH2Cl NHTs NaH 80

5 EtO2CCH2Br NHTs i-Pr2NEt 23

6 PhCH2Br NHTs i-Pr2NEt 41

7 PhthCH2Br NHTs i-Pr2NEt 76

8 H2C=CHCH2Br NHTs i-Pr2NEt 27O

Co(CO)4•OH

O

THF, base

O

BnOBnO

4 5 (41 % yield)

O

O

Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.

Mechanism of Cobalt-Mediated Reaction

When using 1,3-disubstituted allenes, only E olefin products are observed

The reason for the stereochemical outcome has not yet been determined

•NHTs

R

H•

NHTs

HCo(CO)3

O

R

R O

HCo(CO)3

NHTs

O

HNHTs

R

(CO)3Co

NTs

O

R

1 A B

2 C

Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.

Ru-Catalyzed Cyclocarbonylation

Good yields are also obtained from β-sulfonamides to obtain δ-unsaturated lactams Reaction also works to yield seven and eight member rings Ru-catalyzed cyclocarbonylations also work for hydroxy-allenes

•R

NHTs

Ru3(CO)12 (1 mol %)

dioxane, 100 oC

CO (20 atm)

TsN

O

R

Me

1 2

entry substrate Time (h) product % yield

1 9 91

2 16 70

3 16 80

4 12 95

•NHTs

TsNO

Me

•NHTs TsN

O

Me

•NHTs

TsNO

Me

•NHTs

TsNO

MeS S

Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.

Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441-443.

Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett. 2001, 42, 5459-5461.

Ru-Catalyzed Cyclocarbonylation Catalytic Cycle

Ru(CO)4

•R

NHTs

•R

TsNRu H

(CO)4

TsN Ru(CO)3

R

C

O

TsN Ru(CO)3

R

O

CO

TsNO

R

Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.

Natural Product Synthesis Using Metal-Catalyzed Heterocyclization of Allenes

OCO2R

NHMe

EtOR

N

H

n-C7H15 MeH H

OMeH

NH2

OH

O

OOH

O

O

Me

(±)-Rhopaloic Acid A

Clavepictine A: R = Ac (+)-Xenovernine

Clavepictine B: R = H

(+)-Furanomycin (+)-Kallolide A

Synthesis of (±)-Rhopaloic Acid A

OCO2Me

Br

OH •

OCO2Me

4 steps

1

2 (55 % yield)

3 (50 % yield) 4 (6 % yield)

PdCl2 (0.1 equiv) CuCl2 (3.2 equiv) CO (1 atm) MeOH

NaOH (0.125 M1:1 t-BuOH:H2O

OCO2H

(97 % yield)

(±)-Rhopaloic Acid A

Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453-5454.

Synthesis of Clavepictine A and B

NH

Me

H

RO

OCOAr•

H

OR

(CH2)6Me

AgNO3

acetone:H20

NHMe (CH2)6Me

OR

ArOCO

H

1 2 (91 % yield)

OR

N

Me

H

AcO

HO

(CH2)6Me

1. N-Phenylthiophthalimide n-Bu3P2. Oxone; THF, heat 64 % yield (7:1 E:Z)

N

Me

H

AcO

(CH2)6Me

K2CO3MeOH

quantitativeN

Me

H

HO

(CH2)6Me

Clavepictine A 3 (88 % yield)

Clavepictine B

Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020.

Synthesis of (+)-Xenovernine

•n-C5H11OH

1. Swern (99 % yield)2.

Zn2 •n-C5H11OH

H

1. Ph3P, DEAD 2. LiAlH4, Et2O DPPA, rt reflux

•n-C5H11NH2

H

1 2 (37 % yield)

Ln N(TMS)2

NSi

Benzene, 45 oC

(5 mole %)

N

H

MeHH

n-C5H11 4 (80 % yield) 3 ( 57 % yield)

Pd/C, MeOHH2 (1 atm), rt

N

H

n-C7H15 MeHH

(97 % yield)

(+)-Xenovernine

Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639.

Synthesis of (+)-Furanomycin

O

H

O

N

Boc2 steps

OH

•Me

O

N

BocAgNO3/CaCO3

Acetone/H2OOMe

ON

H

Boc

1 2 (40 % yield) 3 (95 % yield)

TsOHMeOH

OMeOH

NH

H

Boc1. Dess-Martin

2. NaClO2, NaH2PO4

t-BuOH, H2O, 20 oC

OMe

NH

H

Boc

OH

O

TFACH2CH2

(76 % yield)

OMe

NH2

H

OH

O

(+)-Furanomycin 5 (77 % yield) 4 (95 % yield)

VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705-708.

Synthesis of Kallolide A

•H Me

ODPs O

OBz Ag(NO3)

O

Me

ODPS OBz

15 stepsO

Me

•

OHO

OSEM

Ag(NO3)

OOSEM

O

O

Me

HOAc, PPTS(82 % yield)

1 2 (88 % yield)

3 ( 11 % yield)

(+)-Kallolide A 4 (60 % yield)

OOH

O

O

Me

Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962-5970.

Summary

Hydroxy-allenes and Amino-allenes are versatile substrates that can be utilized to form a variety of heterocycles

Metal-catalyzed heterocyclization of allenes is tolerant to substitution

Many cyclizations of allenes are highly diastereoselective

A variety of metals can be utilized depending on the desired structure

Metal-catalyzed heterocyclization of allenes can be useful for natural product synthesis

Acknowledgements

Dr. Jeff Johnson

Johnson Group

UNC Chapel Hill

metal-catalyzed heterocyclization of allenes

Documents