dicobalt hexacarbonyl complexes of alkynyl imines …ccc.chem.pitt.edu/wipf/current...

Dicobalt Hexacarbonyl Complexes of AlkynylImines in a Sequential Staudinger/Pauson-Khand

Process. A Route to New Fused Tricyclic β-Lactams

Clarisse Olier, Nadia Azzi, Gérard Gil, Stéphane Gastaldi,and Michèle P. Bertrand

J. Org. Chem. 2008, 73, 8469–8473.

(CO)3Co Co(CO)3

EtO

OEtR

1. TMSOTf, ArNH2CH2Cl2

2. DIPEA, CH2Cl2

NClOCTs

3. PKR

NTsN

O

R

ArO

H

H

H + NTs

O

RH

HNO

HAr

Presented by Melissa Sprachman, December 20, 2008

Melissa Sprachman @ Wipf Group of 15 12/27/2008

The Pauson-Khand Reaction

R1 R2

R6 R5

R3R4

+Co2(CO)8

solvent, heatR1 > R2

O

R1

R2

R5

R6

R3

R4

R1 R2

R6 R5

R3R4

+

Co2(CO)8 (≤ 1 equiv)

promoter/solventCO atmosphere

Mechanism:

Other metal complexes used: Fe(CO)5, Ru2(CO)12, Cp2TiR2, Ni(COD)2, W(CO)6, Mo(CO)6, [RhCl(CO)2]2

Common promoters: NMO, high-intensity light/photolysis, “hard” Lewis bases

Kürti, L.; Czakó, B. Strategic Applications of Named Reactions inOrganic Synthesis; Elsevier: New York, 2005.

Co(CO)3(CO)3CoCO

CO

R1 R2 R2

R1

Co(CO)3Co(CO)3

- 2 CO - CO

R3

R2

R1

Co(CO)3Co

R3

COCO

+ CO

(alkene insertion)

R2

R1

Co(CO)3Co

R3

+ COR2

R1

Co(CO)3Co(CO)3

O

O

Co(CO)3Co(CO)3

R2R1

- [Co(CO)6] O

R1R2


The Pauson Khand Reaction: CO Labilization is Rate-Determining

Pure Appl. Chem. 2002, 74, 167-174.

DFT (VWN/PW91xc)


The Pauson-Khand Reaction in Natural Product Synthesis

J. Am. Chem. Soc. 1997, 119, 4353–4363.

Me H

HMe3Si

OEt

OH 1. CO2(CO)8, ether

2. TMSOTf, ether-78 oC

Me H

H

OH

(CO)3Co

Co(CO)3

> 20:1 d.r.(1:1 mixture of diastereomers)

91% (2 steps)

(91:9 site selectivityfor Lewis acid activation)

CH3CN, airreflux, 15 min

NMO, CH2Cl2rt, 12 h

85% (5:1 d.r.)

70% (11:1 d.r.)

Me H

HO

O

H

H

-or-

Key intermediate in thesynthesis of (+)-Epoxydictymene

Schreiber’s synthesis of (+)-epoxydictymene:

OTBSTBSOCo2(CO)8, CH2Cl2then Me2S. 45 oC, 12 h

89%

TBSO

TBSO

O

H TBSOSEMO

H

TMS

Co2(CO)8, CH2Cl2then Me2S, 18 oC, 4 d

79%OMOM

TBSOSEMO

H

O

HH

H

OMOM

Lycopodium Alkaloids

MeN

HHH

O

HMe

HO

(+)-paniculatine + otherJ. Org. Chem. 2007, 72, 10147–10154.


Advances in Pauson-Khand Reaction Methodology

Catalytic Pauson-Khand Reactions:

OTBS

n-PrCo2(Co)8 (35 mol%)

CyNH2, 60 mol%

DME, 70 oC, N2

15 h, 95%OTBS

n-Pr

O

Asymmetry by use of chiral auxiliaries orchiral metal complexes:

S*Co2(CO)8

80 oC O

H S*Zn, NH4Cl

O

H

96% ee60-65%92-95%

O O

Chem. Soc. Rev. 2004, 33, 32-42.

J. Org. Chem. 2001, 66, 3004-3020.

Tetrahedron: Asymmetry, 2000, 11, 797-808

Eur. J. Org. Chem. 2002, 2881-2889.

TsN

Co2(CO)8 (20 mol%)(S)-BINAP (20 mol%)

80 oC, 1 atm COTsN O

H

54% 94% ee

J. Am. Chem. Soc. 2000, 122,10242-10243.


β-Lactam Antibiotics

Eur. J. Org. Chem. 1999, 3223-3235

“The biologically active principle of all β-lactam antibiotics is the β-lactam ring, the reactivity and selectivity ofwhich towards biological substrates can be decisively influenced by substituents or fused rings.”

Angew. Chem. Int. Ed. Engl. 1985, 24, 180-202.

-->Motivation to diversify β-lactam scaffolds?


Construction of Polycyclic β-Lactams

Cycloadditions:

NO

OOMs

PMP

DBU, toluene

190 oC, 24 h88%

NO PMP

OH

HH

80 :10 :10 (mixture of diastereomers)

Tetrahedron Lett. 1999, 40, 1015-1018.

NO

HTBSO

H OO

CO2Bn

LiHMDS/THF

-78 oC to rt N

O

O

HTBSO H

CO2BnH

O

76%

Reaction of substituents on the azetidinone:

Tetrahedron Lett. 1997, 38, 5913-5916.

Precedence: Pauson-Khand Reactions:

NO

BnO 1. Co2(CO)8, toluene, rt2. toluene, reflux

95%N

O

BnO H

H

O

NPMPO

1. Co2(CO)8CH2Cl2, rt

2. TMNO, 0 oC to rtN

O PMP

O

HHH

80%

J. Org. Chem. 1998, 63, 6786-6796.


The Staudinger Reaction

The Staudinger Reaction:

Suggested mechanism and explanation of stereochemistry in the case of imines:

O

R1 R2O

R4 R5

R1 R2

R3

N

R1 R2

R3

Lewis Acidsolvent solvent

solvent

OO

R2

R1R4

R5

O

R2

R1R4

R5

R3

NO

R2

R1R4

R5

R3

Kürti, L.; Czakó, B. Strategic Applications of Named Reactions inOrganic Synthesis; Elsevier: New York, 2005.

J. Am. Chem. Soc. 2006, 128, 6060-6069.


Tandem Imine Formation-Staudinger Reaction

R1 CH(OEt)2

Co2(CO)6

+ArNH2

TMSOTf, CH2Cl2 rt, N2

O

ClAcO

DIPEA, CH2Cl2 rt, N2

R1

Co2(CO)6

N Ar

N

O

Ar

OAc

R1

Co2(CO)6

Entry R1 Ar Yield (%) Ratio cis:trans

1 H Ph 19 100:0

2 Me Ph 81 100:0

3 Me p-MeOC6H4 47 100:0

4 Me p-NO2C6H4 36 79:21

5 SiMe3 Ph 42 100:0

The observed stereoselectivities are consistent with the electronic effects of the zwitterionic model.


Tandem Staudinger-Pauson Khand Reactions

Me CH(OEt)2Co2(CO)6

1. TMSOTf, PhNH2CH2Cl2 rt, N2

2. DIPEA, CH2Cl2OClOC

N

O

Ar

O

R1

Co2(CO)6 PKR condnsNo Tricyclic ProductObserved

N

O

Ar

O

R1

CAN43%

Allyl ethers were not reactive toward the Pauson Khand Conditions

Only thiazolidin-3-ones formed when trying to replaceoxygen with sulfur:

Me

CH(OEt)2

(CO)6Co2


2. DIPEA, CH2Cl2SClOC

NS

O

Me

(85:15 mixture of diastereomers)3. CAN

48%

SClOC

C

S

O

Cl

Me

NAr

(CO)6Co2

[2,3]

NS

O

Me

Co2(CO)6


Pauson Khand Reactions with the Nitrogen Analog

Entry Conditions T (oC) Yield (%)(3 steps)

Ratio A : B

1 SiO2, Ar, 18 h 40 53 65:35

2 SiO2, Ar 18 h 60 54 35:65

3 SiO2, Ar, 18 h 80 48 38:62

4 Basic Al2O3, Ar, 18 h 40 15 47:53

5 SiO2, H2O (10 equiv), Ar, 18 h 40 44 54:46

6 SiO2, O2, Ar, 18 h 40 44 58:42

7 DMSO (6 equiv), CH2Cl2, 18 h, rt 61 44:56

8 NMO•H2O (1.8 equiv), CH2Cl2,18 h

-20 53 52:48

9 NMO•H2O (1.8 equiv), DIPEA(2.7 equiv) CH2Cl2, 18 h

rt 49 35:65

10 NMO•H2O (1.8 equiv), DIPEA(2.7 equiv) CH2Cl2, 18 h

rt 32 30:70

11 Toluene, 18 h 110 33 71:29

Me

CH(OEt)2

(CO)6Co2


2. DIPEA, CH2Cl2

NClOCTs

N

O

Ar

N

Me

Ts

Co2(CO)6PKRcondns

NTs

N HH

PhO

OH

+ NTs

HO

OH

NH

Ph

A B


Mechanism for Formation of the Tricycle and Open Amide

Co

NPh O

NTs

Me

Co

Co

(CO)3

(CO)2

N

O

PhNTs

Me

Co

H

(CO)3

(CO)3

Co

NPhNTs

Me

Co

H

(CO)3

(CO)3O

migratoryinsertion

CO insertion

NPhNTs

Me

Co

H

(CO)3

OCo(CO)3

N

O O

O

Ph NTsH

O

MeCo

(CO)3(CO)3CoNTs

N HH

PhO

OH

HHH

H

H

H HH

H

H

Co

NOPh

NTsMe

Co

H

(CO)3

(CO)3

H

Co

NOPh

NTsMe

Co

H

(CO)3

(CO)3

H

[Co-H]

(CO insertion)Co

NTsMe

Co

H

(CO)3

(CO)3O

HNOPh

NTs

HO

OH

NH

Ph


Tandem Staudinger-Pauson Khand Scope

NTs

N HH

RO

O

Me

H

+ NTs

HO

O

Me

H

NH

R

Me

CH(OEt)2

(CO)6Co2

1. TMSOTf, RNH2CH2Cl2 rt, N2

2. DIPEA, CH2Cl2TsNClOC

A: SiO2, Ar, 40 oC

B: NMO•H2O, rt, 18 h

3.

A B

R = Ph, 53%, ratio A:B = 65:35; R = PMP, 15%, ratio A:B = 52:48


NTs

N HH

RO

O

TMS

H

+ NTs

HO

O

TMS

H

NH

R

TMS

CH(OEt)2

(CO)6Co2

1. TMSOTf, RNH2CH2Cl2 rt, N2


A: SiO2, Ar, 40 oC


3.

A B


R = Ph, 33%, only A isolated; R = PMP, 49%, ratio A:B = 55:45


Tandem Staudinger-Pauson Khand Scope

Me

CH(OEt)2

(CO)6Co2



A: SiO2, Ar, 40 oC


3.

NTsNPh

O

HH

O

H

30%

30%

NTs

N HH

PhO

O

H

H

+ NTs

HO

O

H

H

NH

Ph

H

CH(OEt)2

(CO)6Co2



A: SiO2, Ar, 40 oC


3.

A B

23%, ratio A:B = 29:71

14%, ratio A:B = 29:71


Summary

Novel tricyclic scaffolds were synthesized via a tandem Staudinger/Pauson-Khand process

Although overall yields are low, the methodology provides a route for rapid formation of complexsubstrates with possible utility in medicinal applications

The approach is limited to stoichiometric use of Co(CO)8, and cleavage of the β-lactam is an unsolvedproblem in this methodology. Suppression of N-C cleavage has been achieved, but the precedence isfor amines:

C DC D

J. Organomet. Chem. 2001, 624, 316-326.


dicobalt hexacarbonyl complexes of alkynyl imines …ccc.chem.pitt.edu/wipf/current...

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