Synthetic (±)-Axinellamines Deficient in Halogen Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

Eric E. Buck Current Literature

March 31, 2012

NNH

HN NH2

H

OH

HN

NH2

HN NHO

NH

Br

O

HN

Br

HOH

2 • CF3CO2

Eric Buck @ Wipf Group Page 1 of 16 3/31/2012

Isolation and biological activity

•  Axinellamines A-D were isolated from the Australian marine sponge, Axinella sp (pictured right).

•  Axinellamine A was not bactericidal at 1000 µM.

•  Axinellamine B-D exhibited MIC for bactericidal action against H. pylori (a gram negative bacterium associated with peticular and gastric cancer) at 1000 µM

Cl

NHOHN

O

HN

NHBr

Br

Br Br

N

HNHO NH

HNNHH

HONH

(-)-axinellamine A (OH, H = β)(-)-axinellamine B (OH, H = α)

H

J. Org. Chem. 1999, 64, 731-735

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Biosynthesis

O

NH HN

NH

NH2

HN

X

Y

1: clathrodin (X, Y = H)2: hymenidin (X = H, Y = Br)3: oroidin (X, Y = Br)

HN

HN

O

O

NH

HN

Br

Br

NHHN

HN NH

NH2

NH2

Cl

O

(-)-Sceptrin

NH

NHHO

NH2

Cl

NHOHN

O

HN

NHBr

Br

Br Br

N N

NH2

pre-axinellamine

J. Am. Chem. Soc. 1981, 103, 6772-6773

Eric Buck @ Wipf Group Page 3 of 16 3/31/2012

Biosynthesis

J. Am. Chem. Soc. 1993, 115, 3376-3377 (12,17-epi-13)

NHHN

OH

Cl

H3N

N

N

NH

HN

O

NH2

H

HH

NH

(-)-palau'amine

X

NHOHN

O

HN

NHBr

Br

Br Br

(-)-massadine (X = !")(-)-massadine chloride (X = Cl)

NHN

NH

O

HN NHHO

NH2

H

Org. Lett. 2003, 5, 2255-2257

Cl

NHOHN

O

HN

NHBr

Br

Br Br

N

HNHO NH

HNNHH

HONH

(-)-axinellamine A (OH, H = β)(-)-axinellamine B (OH, H = α)

H

J. Org. Chem. 1999, 64, 731-735

Eric Buck @ Wipf Group Page 4 of 16 3/31/2012

Synthetic efforts towards pyrrole-imidazole alkaloids

•  Synthesis of 1,9-Dideoxy-pre-axinellamine

•  Total syntheses of (±)-massadine and massadine chloride

•  Total synthesis of (-)-palau’amine

•  The Baran Group’s full paper detailing their efforts towards (-)-palau’amine, (-)-axinellamines, and massadines.

•  A review on the biosynthesis, assymetric synthesis, and pharmacology of pyrrole-2-aminoimidazole alkaloids.

Yamaguchi, J.; Seiple, I. B.; Young, I. S.; O’Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580

Su, S.; Seiple, I. B.; Young, I. S.; Baran, P. S. J. Chem. Soc. 2008, 130, 16490-16491

Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2010, 49, 1095-1098

J. Chem. Soc. 2011, 133, 14710-14726

Al-Mourabit, A.; Zancanella, M, A.; Tilvi, S.; Romo, D. Nat. Prod. Rep., 2011, 28, 1229-1260

Eric Buck @ Wipf Group Page 5 of 16 3/31/2012

The Baran Group’s synthesis of (±)-axinellamines

DMDO

ClN3

N3HN

NHH

NH2 • TFA

H2ON

N NH2ClN3

N3HN

NHH

NH22 • TFA

N

N NH2

OH

HO

ClN3

N3HN

NHH

NH2 • TFA

N

HN NH2

HO

H

HO

1) TFA

2) AgII, H2O

N

HNNH

NH2

H

HO

HN NH2NH

NH

O

NHBr

O

NH

Br

HO

H

Cl

Br

Br

40 %

2 • TFA

axinellamine A

45 %

O’Malley, D. P.; Yamaguchi, J.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47,

3581-3583

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Title paper: Two new ring systems

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

Br

OMeO2C 1) MeOH, LiOH, 89 %

NH

OHNNH2

NN O

NH

HO2C2) (COCl)2

N

O

NH

SMe

NN O

NHN

O

O N

SMe (COCl)2, 55%

NN O

N

3) ClCH2OCH2CH2Si(CH3)3

RNN

O

O

60%

Eric Buck @ Wipf Group Page 7 of 16 3/31/2012

Title paper: Oxidative enolate coupling

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

Ryter, K.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 2658-2659

NN O

N RNN

O

O

1) [(iPrCp)2TiCl2], KHMDSCu(OTf)2, 55 %, d.r. = 1.2:1

NN O

N RNN

O

O

NN O

N RNN

O

O

Note: [(CF3CH2O)V(O)Cl2]"Livinghouse reagent" onlyother oxidant tried thatprovided comparable yield and regioselectivity to Cu(OTf)2

2) Rh1, H2, 600 psi, 3 d, 67%

3) NBS, 57%

Br Br

Br Br

H

H

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Exploring Symmetry-Based Logic for a synthesis of Palau’amine

NN O

N RNO

NN O

N RNO

Br Br

Br Br

H

H

N

N

Cy2BOTf;KHMDS

NN

O

NH

NH

O

NR

BrBr

NN

O

NH

HN O

NR

BrBr

3 isomers

50 %

Li, Q.; Hurley, P.; Ding, H.; Roberts, A. G.; Akella, R.; Harran, P. G. J. Org. Chem. 2009, 74, 5909-5919

Eric Buck @ Wipf Group Page 9 of 16 3/31/2012

Monomer forms targeted alkylidene

NN O

N RNN

O

O

NN O

N RNN

O

O

Br Br

Br Br

H

H

NN O

N RNN

O

O

Br Br

H

KHMDS

[18]crown-6N

NN

O

O

NH

O RN

Br

Br

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

Eric Buck @ Wipf Group Page 10 of 16 3/31/2012

Title paper: unexpected spiroaminal formation

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

NN O

N RNN

O

O

NN O

N RNN

O

O

Br Br

Br Br

H

H

N

O NR

Br

BrN NH

O N

O

N

O RN

Br

BrN NH

O N

OKHMDS (4.0 equiv)[18]crown-6, THF

39 % of major isomer (shown)

15% of other isomers

Note: Major isomer (shown) was treatedwith TFA and the corresponding salt wasrecrystalized. Relative stereochemistry was based on corresponding X-ray.

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Title paper: Isomerization to monoalkylidene-containing spirocycles

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

N

O NH

Br

BrN NH

O N

O

N

O HN

Br

BrN NH

O N

O1) TBD, THF

2) NH4OH, 120 oC, 90 min1,2-dimethoxyethane/H2O (4:1);

TFA; Et3N, MeOH

HN NHO

NH

Br

O

HN

Br

NHHN

O

NH

NH

NNH2

ON

N

NH

TBD =

43% over 2 steps

NN

O

HN

O NR Br

Br

NHN

O

NH

ONRBr

Br

O

N N

O

Br

Br

Eric Buck @ Wipf Group Page 12 of 16 3/31/2012

Title paper: Deoxygenation and isomerization

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

HN NHO

NH

Br

O

HN

Br

NHHN

O

NH

NH

NNH2

O

LAB; TFA

13% HN NHO

NH

Br

O

HN

Br

NHHN

O

NH

NH

NNH2

26% of other isomerNH

HNO

NH

NH

NNH2

Br

Br

Br

Br

Eric Buck @ Wipf Group Page 13 of 16 3/31/2012

Title paper: Oxidation and reduction

HN NHO

NH

Br

O

HN

Br

NHHN

O

NH

NH

NNH2

NNH

HN NH2

H

OH

HN

NH2

HN NHO

NH

Br

O

HN

Br

HOH

2 • CF3CO2

2) SmI2, THF/H2O

NO2

NO

PhO2S

Br

Br

26 %, d.r. = 4:1

45 %

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

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SmI2 preparation

•  Water, oxygen, and peroxide content in THF have little influence on the synthesis of SmI2

•  Most problems associated with SmI2 preparation are due to “inactive” samarium metal

•  “inactive” samarium metal can be activated by dry stirring under argon (similar to activating magnesium).

•  Solutions of SmI2 can be stored, however the solution should be stirred for 1 hr prior to use.

Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2012, ASAP

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Final thoughts

•  The synthesis of 2.0 mg of nonchlorinated (±)-Axinellamines was achieved in 13 steps in 0.016 % yield.

•  Interesting formation of spiroaminals and their base-mediated isomerization into monoalkylidene spriocycles.

•  The Haran Group mentions that there interest lie in synthesizing several halogenated analogs through this method and determine there impact on biological activity.

•  Essential to achieving their above goal is the refinement of spiroaminal formation and isomerization.

Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem. Int. Ed. 2012, 51, ASAP

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