a stereoselective synthesis of the bromopyrrole natural product ( …ccc.chem.pitt.edu/wipf/current...

A Stereoselective Synthesis of the BromopyrroleNatural Product (-)-Agelastatin A

Paul M. When and J. Du Bois, Angew. Chem. Int. Ed. 2009, 48, 3802-3805.

Melissa Sprachman

Current Literature: May 23, 2009

BocHN

O SNH2

OO

[Rh2(esp)2](0.06 mol%)

PhI(OAc)2MgO95%

BocHNN

HO S

O

O NBr

NH

O

NH

MeN OHO

Melissa Sprachman @ Wipf Group of 14 5/27/2009

Aziridines: General Methods

NR3

R1 R2

R1

HO R2

NHR3 R4P X

SOCl2

R1

Br Z

H2NR3NH

HN

+N

O

BuLi, THF-78 oC to rt

82%N

O

HN

R3

R2R

R1

R4-N=MLnNR4

R2

R3R

R1R3

R2R

R1

NH

R4LG

R3R2

R

R1NLG

R4

R1

R2

X-Nsinglet

NX

R1 R2

stereospecific

via

synchronous mechanism

R1

R2

X-Ntriplet

NX

R1 R2

non-stereospecific

via R1

R2HH

N

diradical mechanism

X

R1

R2HH

NX

N

O

O

NH2 +R2

R1 Pb(OAc)4 NPht

R1 R2

Tetrahedron Lett. 1999, 40, 5207-5210.

Aziridines and Epoxides in Organic Synthesis; Yudin, A. K.ed.; Wiley-VCH:Weinheim, 2006.

J. Chem. Soc. (C ), 1970, 576-582.


Synthesis of Aziridines via Metal-Catalyzed Nitrene Addition

Evans and Jacobsen: Enantioselective aziridination using chiral Cu catalysts:

Ph

CO2Ph CuOTf (5 mol%)

O

N

Me Me

N

O

Ph Ph

PhI=NTs TsN

H CO2Ph

HPh

64%, 97% ee

(6 mol%)

Aziridation Using TsN=IPh:

J. Chem. Soc., Chem. Commun. 1984, 1161-1163.

J. Am. Chem. Soc. 1993, 115, 5328-5329. J. Am. Chem. Soc. 1993, 115, 5326-5327.

PhI NTs +Ph Ph Fe(III)(TPP)Cl (0.05 mol%)

N

Ph Ph

Ts

+ PhI

TPP = tetraphenylporphyrin37% (63% TsNH2)

L=Cu PF6 PhI=NTs

PhI[L*Cu=NTs]PF6

R2R1

R3

TsN

R2

R1

R3

Aziridines and Epoxides in Organic Synthesis; Yudin, A. K.ed.; Wiley-VCH:Weinheim, 2006.

O

NC

PhI=NTs

CuOTf (10 mol%)

H HN NCl

Cl Cl

Cl

O

NCNTs

75%, > 98% ee

CH2Cl2


Rh-catalyzed Aziridination was developed in tandem with C-Hamination

SO O

NCl2Zn

cyclohexaneΔ

SO O

N SO O

NH

Tetrahedron Lett. 1968, 5349-5352.

n

[Rh2(OAc)4] (0.02 equiv)NsN=IPh (1 equiv)

(20 equiv) CH2Cl2, rt n

NHNs

+

nNs

a) n = 0 44% 9%

b) n = 1 70% 4%

c) n = 2 17% 24%d) n = 3 0% 54%

Mechanistic Aspects:OAc OAc

NHNs

+

OAc

NHNs

+ NNs

OAc

21% 4%

D D+

DNHNs

NHNs

(1:1)

Preliminary hope forenantioselective insertion:

[Rh2{R-BINAP}4]NsN=IPh

CH2Cl2

NHNs

71%, 31% ee

Helvetica Chim. Acta, 1997, 80, 1087-1105.


Du Bois Group Contributions: Early Developments andMechanistic Considerations

Conversion of Carbamates toOxazolidinones:

O NH2

O

[Rh2(tpa)4] (5 mol%)

PhI(OAc)2, MgOCH2Cl2, 40 oC, 12 h

OHN

O

77%, single diastereomer

OMeMe

NH2

O

[Rh2(O2CR)4]

PhI(OAc)2, MgO

HN O

O

MeMe

single enantiomer (GC)

O

NH2O

PhMeMeO2C

cat.

PhI(OAc)2MgO

O NH

O

Ph

MeMeCO2

cat.

[Rh2(OAc)4]: 2:1[Rh2(tpa)4]: 1:2.6

Evidence for direct insertion:

Evidence for a metallo-nitrene:

Angew. Chem. Int. Ed. 2001, 40, 598-560.

Me

Me Rh[tfacam)4 (2 mol%)H2NSO3CH2CCl3

PhI(OAc)2, MgOC6H6

MeNSO3CH2CCl3

72%

Aziridination Chemistry:

Me O2NConsumed preferentiallyJ. Am. Chem. Soc. 2002, 124, 13672-13673.

R2

R1 R3+ H2NSO3CH2CCl3

1 equiv 1.1 equiv

1-2 mol%Rh2(tfacam)4

PhI(OAc)2, MgOC6H6-

NSO3CH2CCl3R1

R2 R3

For related work using Cu and PhIO, see J. Am. Chem. Soc. 2001, 123, 7707-7708 and Org. Lett., 2002, 4, 2481-3..

tfacam = CF3CONH

tpa = triphenylacetate


Rh-Catalyzed Amination Reactions of Chiral Sulfamates

OSOO

R3 R1

R2

H2N2 mol%Rh2(oct)4

PhI(OAc)2MgO, CH2Cl2

HN OS

R1R3

R2

OO

HN OS

MeMe

OOHN OS

CO2Bn

OOHN OS

CO2Et

OOHN OS

OO

88%, 3:1 dr 55%, 8:1 dr

Me

Me

91%, 15:1 dr 62%, 20:1 dr

SiMe3

HN OSOO

HN OSOO

HN OSOO

HN OSOO

HN OSOO

MeR

R = CF3, 70%, 20:1 drR = OMe, 85%, 20:1 dr

NTsN

Me

MeMe

84%, 20:1 dr

O

Me

65%, 20:1 dr

HN OSOO

NPhth OTBSONBoc

MeO

85%, 12:1 dr 77%, 10:1 dr

N

SMe

TBDPSO

92%, 20:1 dr

O

Ph

Org. Lett. 2003, 5, 4823-4826.


Aziridination Chemistry

Org. Lett. 2003, 5, 4823-4826.


Extensions of Rh-Catalyzed Amination Reactions

Ni-catalyzed cross-coupling of cyclic sulfamates:

NHMeMe

CO2tBu

H2NNTces

2 mol% Rh2(esp)2PhI(OAc)2, MgO

toluene, 40 oC91%

HN NH

NTces

CO2tBuMe

Me

Oxidative Cyclization of Urea and Guanidine Derivatives:

Org. Lett. 2005, 7, 4685-4688.

Org. Lett. 2006, 8, 1073-1076.

NH2S

O

O O

2 mol%Rh2(OAc)4

PhI(OAc)2MgO, CH2Cl2

NHS

O

O O

75%

1. nPrI, K2CO32. MeMgBr

5 mol%Ni(dppp)Cl2

72%

NHnPrMe

MeNS

O

OO

OMeMe2PhCH2MgCl

5 mol% Ni(dppp)Cl2C6H6, 55 oC

Ph

OMe

NHBn

Me Me

84%

Rh2(α,α,α’,α’-tetramethyl-1,3-benzenedipropionate)2


C-H Amination as an Application in Complex Molecule Synthesis

Org. Lett. 2007, 9, 5465-5468.


Synthesis of (-)-Agelastatin A

BocHN

O SNH2

OO

[Rh2(esp)2](0.06 mol%)

PhI(OAc)2MgO95%

BocHNN

HO S

O

OHN

O1. Boc2O2. NaBH4

93% BocHN

OH

ClSO2NH2

DMA83%

NaN3

iPrOHH2O71%

(EtO2C)2Ocat. DMAP

Ph2Se2NaBH4

93%

H N3O

BocHNS

NH

OO

H N3O

BocHNS

NO

O

EtO O

PhSe

N3

BocHN NHCO2Et

via

PhSe

PhSe

N3

BocHN NHCO2Et

NaIO4

aq. THFN

BocHN NHCO2Et

NN

[3.3]

N3

BocHN NHCO2Et

Problem with installation of the exocyclic olefin at this stage:


Synthesis of (-)-Agelastatin A

PhSe

N3

BocHN NHCO2Et

1. TFA

2.

BnO2C CHO

O

PPTS, DCE, 80 oC

CH2Cl2

85%

PhSe

N3

N NHCO2EtCO2Bn

Me3P, THF/H2O (10:1)then MeNCO

PhSe

NH

N NHCO2EtCO2Bn

NHMeO

PhSe

NH

N NHCO2EtCO2Bn

NHMeO

81%

1. m-CPBA, DCE, 0 oC,then Et3N, 89%2. OsO4then NaIO4, THF/H2O (1:1)45 oC, 81%

N NHCO2EtCO2Bn

NHNHO

OMe 1. KOtButAmOH45 oC, 77%

2.NBS, THF/MeOH (2:1)0 oC to 25 oC, 75%

NH

NHO OMe

NNH

O

Br

11 Steps, 15% overall yield (200 mg of natural product synthesized)


Other Routes to (-)-Agelastin A: A ComparisonNH

NHO OMe

NNH

O

Br

A B

CD

Weinreb (racemic synthesis):

J. Am. Chem. Soc. 1999, 121, 9574-9579.

+ SN

O

CO2Me N

OH

H

O

HH

SN

N

SES

SES

Boc

PhMe

Δ NBoc

O

H

H

O

SNH

N

SES

SES[2,3]

NBoc

O OH

HN

SNHSES

SES

Feldman (via alkynyliodonium salts):

J. Org. Chem. 2002, 67, 7096-7109.

Davis (sulfinimine methodologies):


Other Routes to (-)-Agelastin A: A ComparisonNH

NHO OMe

NNH

O

Br

A B

CD

NN

CuCl

Trost (Pd-catalyzed asymmetric allylic alkylation):

J. Am. Chem. Soc. 2006, 128, 6054-6055.


Summary and Outlook

-Rh-catalyzed selective C-H amination and olefin aziridinationmethods have been developed as useful tools for synthesis.

-Du Bois and co-workers have demonstrated the utility of theiraziridination methodology through installation of a critical chiral C-Nbond in the synthesis of (-)-Agelastatin A.


a stereoselective synthesis of the bromopyrrole natural product ( …ccc.chem.pitt.edu/wipf/current...

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