baran lab syntheses of the axinellamines - …ccc.chem.pitt.edu/wipf/current...

Baran Lab Syntheses of the Axinellamines:

Synthesis of 1,9-Dideoxy-pre-axinellamine:Yamaguchi, J., Seiple, I. B., Young, I. S., O’Malley, D. P., Maue, M., Baran, P. S.;ACIE, Early View DOI: 10.1002/anie.200705913

Total Synthesis of (±)-Axinellamines A and B:O’Malley, D. P., Yamaguchi, J., Young, J. S., Seiple, I. B., Baran, P.S.;ACIE, Early View DOI: 10.1002/anie.200801138

Presented by: Melissa Sprachman March 29, 2008

Cl

NH

NNHO

HN

Br Br

HN

ONH

Br

BrN NHH

NH2

NH2

H

H TFA

TFA

N

NNH

NH

HN

NH TFA

HN NH2

TFAHOCl

HN

NH O

O

BrBr

Br

Br

H

HO

Melissa Sprachman @ Wipf Group of 15 3/30/2008

The Pyrrole-Imidazole Alkaloids

Mono-and Bicyclic Dimeric Pyrrole-Imidazole Alkaloids

Tetracyclic Pyrrole-Imidazole Dimers

Copied from: Baran et al. Angew. Chem. Int. Ed. 2007, 46, 6586.


The Pyrrole-Imidazole Alkaloids (continued)

Hexacyclic Pyrrole-Imidazole Dimers

Polycyclic Pyrrole-Imidazole Dimers

Copied from Baran et al. Angew. Chem. Int. Ed. 2007, 46, 6586.


Biosynthetic Analyses and Features of Pyrrole-Imidazole Alkaloids

NHNH

N

HN

O

H2N

Br

Br

HN

NH2N NH2

+HN CO2HBr

Br

HN

N CO2H

HN CO2H

NH2

Feeding studies by Kerr and coworkers using a cell culture from Teichaxinella morchalla indicated thatthese amino acids are indeed precursors of odiline (a simple pyrrole-imidazole alkaloid).

The duel reactivity of the 2-aminoimidazole moiety helps to explain the molecular diversity in this group of alkaloids.

N N

NH2

H N N

NH

HH N N

NH2

nucleophilic positionelectrophilic position

Tautomerism of the vinylogous 2-aminoimidazole also plays a key role in the metabolic route.

Mourabit et al. Eur. J. Org. Chem. 2001, 237-243.

N

NH2N

NHR

N

HN

H2NNHR

HN

NH2N

NHR

N

NH2N

NHR

ElectrophilicNucleophilic

Nucleophilic

Electrophilic


Baran’s Proposed Biosynthesis of the Pre-Axinellamines

Linear:

RingExpansion:

RingContraction:

Baran et al. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.

oroidin

sceptrin

ageliferin “pre-axinellamine”

NHN

RHN

NH2

NN

RHN

NH2H+

NH

NRHN

RHN

NHN

HN

NH2

OH

Cl

NH

NRHN

RHN

NHN

H2N

NH2

ClOH

NN

NH2

RHN

RHN

Cl

NH

N NH2

OH

RHN

RHNHN N

NHN

NH2

NH2

"O+"

RHN

RHN NH

N

HNN

NH2

NH2

OH

RHN

RHN N

N

HNN

NH2

NH2

OH

Cl

HN N

NH2

RHN

RHN

Cl

NH

N NH2

OH

tautomerization

HNN

RHN

RHN

NH2

N

HN

NH2

HNN

RHN

RHN

NH2

N

HN

NH2

OH

Cl

"O+"

HN N

NH2

RHN

RHN

Cl

NH

N NH2

OH

"O+" N N

NH2

RHN

RHN

Cl

NH

N NH2

OH


Baran’s Proposed Biosynthesis of the Pyrrole-Imidazole Alkaloids

Cl

NH

NNHO

HN

R3 R4

HN

ONH

R2

R1

N

NH

NH

NH2

OH Cl

NH

NNHO

HN

R3 R4

HN

ONH

R2

R1N N

NH2

NH2

OH

HOH

H2O

- H2O

Cl

NN

HN

ONH

R3

R4

HN NH

O

R1

R2

NHNH

NH2OHH2N

Amide Hydrolysis

Cl

NN

H2N HN NH

O

R1

R2

NHNH

H2NOH

H2N

Cl

NN

HN

ONH

R3

R4

HNH

O HN

R2

R1

NHNH

NH2OHH2N

Amide Hydrolysis

Cl

NN

H2N HNH

O NH

R1

R2

NHNH

H2NOHH2N

ClNHO

HN

R3 R4

HN

ONH

R2

R1

O

N NH

NH2

N NHHHO

NH2

H

AziridineFormation

NHO

HN

R3 R4

HN

ONH

R2

R1

O

N

N NHHHO

NH2

H

NH

NH2

Axinellamines

Carteramine A

Styloguanidine

Konbu'acidins A and B

Palau'amine

Massadine Chloride

"Massadine Aziridine"

H2O

MassadineStylissadines A and B

Baran et al. Angew. Chem. Int. Ed. 2007,46, 6586-6594.


Isolation of Axinellamines

•Axinellamines A-D were isolated by Quinn and coworkers in 1999 from several species ofmarine sponge of genus Axinella.

•Axinellamines B-D show bactericidal activity against Helicobacter pylori; (MIC = 1000 µM)

Axinelle commune (Axinella polypoides)

subaqua.web.cern.ch/.../3.jpg

N

NNH

NH

HN

NH TFA

HN NH2

TFAROCl

HN

NH O

O

BrBr

Br

Br

HO

HR = H: Axinellamine A

R = Me: Axinellamine C

R = H: Axinellamine B

R = Me: Axinellamine D

** ***H * *

*

N

NNH

NH

HN

NH TFA

HN NH2

TFAROCl

HN

NH O

O

BrBr

Br

Br

HO

H

** ***H * *

*

Quinn et al. J. Org. Chem. 1999, 64, 731-735.


Synthetic Approaches to the Tetracyclic Core of the Axinellamines

Carreira: Enantioselective synthesis of the core of the tetracycle:N

NNH

NH

HN

NHTFA

HN NH2TFARO

ClHN

NH O

O

BrBr

Br

Br

HO

HH

Carreira et al. J. Am. Chem. Soc. 2000, 122, 8793-8794.

O

O

O

OTBS

HO

(racemic)

10 stepsquinine, MeOHCCl4, MePh

93 % ee CO2Me

CO2H

OTBS

1. LDA, Et2O, 0oC then 1 N NaHSO4, 73 % (2 steps)

2. LiAlH4, Et2O, 81 %3. pthalimide, DEAD, PPh3, 88%

OTBS

CH2NPhtCH2NPht

1. OsO4, (DHQD)2PyrNMO, tBuOH, 98 %2. NaIO4, K2CO3, 92 %

1. NaClO2, DMSO, tBuOH/H2O, pH =42. (COCl)2, CH2Cl23. NaN3, DMSO4. PhH, heat 67 % (4 steps)

OTBS

CH2NPht

CH2NPht

OH

OCN

OTBS

CH2NPht

CH2NPht

1. BnOH, BuLi,THF, 76 %2. O3/O2, CH2Cl2-then PPh3

OHC CHO

NPht NPht

TBSO NHCBz

1. K2CO3, 86 %2. 1,3 -propanediol, PPTS, 59 %3. KMnO4, pH = 7, tBuOH/H2Oquant.

NPht NPht

TBSO NHCBz

HO2C OO

EDC, DMAPthiopyridine-N-oxide, CCl4, 76 %

NPht NPht

TBSO NHCBz

Cl OO cyclopentane core

of the axinellamines


Synthetic Approaches: Oxidative Ring Contraction

N

NNH

NH

HN

NHTFA

HN NH2TFARO

ClHN

NH O

O

BrBr

Br

Br

HO

HH

Lovely et al. Org. Lett. 2007, 9, 3861.

Romo et al. Org. Lett. 2005, 7, 1679.

N

N

DMAS

N

O

Ph

Ph

O

NNBn

PhMe

140-150oCONN

NN

DMAS

Bn

H

H O Ph

Ph

ON SO2PhH

O2N NH

N

N

N

N O

H

H

O

Ph

Ph

DMAS

Bn

SmI2, THF

EtOH, 73 % NH

N

NN

DMAS

Bn

H

H O Ph

Ph

OH

CHCl3

84 %84 % OH

TsvN

NDMBO

OH

NTIPSO Ts

O

+

Δ 96 h1.

2. TBDPSCl

48 % (2 steps)

N

N

N

HH

OTIPSO

OTBDPS

O

Ts

DMB

1. H2 Pd(OH)2/C, 93 %2. DMDO, 99 %3. chloramine-T, 65 %

N

H

OTIPSO

TseNN

H

TsTs

Cl

OTBDPS

O

O

DMB


Thermal Rearrangements within the Pyrrole Imidazole Alkaloids

NH

HN

NH

NH

NHHN

O

NH

Br

ONHBr

NH2

NH2

Cl-

Cl-

H2O, 195oC, 1 minmicrowave

Sceptrin

40 % (plus 52 % recovered Sceptrin)

NH

HNN

HHN

NH

NHN

HN Cl

ClO

O

HN

NH

Br

Br

Ageliferin

N

NNH

NH

HN

NHTFA

HN NH2TFARO

ClHN

NH O

O

BrBr

Br

Br

HO

HH

Baran et al. Angew. Chem. Int. Ed. 2004, 43, 2674.

Baran et al. J. Am. Chem. Soc. 2007, 129, 4762.

NH

HNN

HHN

NH

NHN

HN Cl

ClO

O

HN

NH

Br

Br

Ageliferin

MMPP, H2O

NH

HNN

HHN

NH2

NHHN

HN Cl

ClO

O

HN

NH

Br

Br

OH

OH

5 % NaHCO3 (aq)

microwave

NHHN

O

O

HN

NH

Br

Br

HN NH

NH2

NH

NHO

NH2

36 % overall


Synthesis of 1,9-Dideoxy-pre-axinellamine

OTIPS

MeO2C

CO2Me

150oC CO2Me

CO2MeOTIPS

(single diastereomer)

1. LAH, THF 2. MsCl, pyr3. NaN3, DMF, 100oC4. TBAF, THF RT

64% (5 steps)OH

N3N3

1. PMBCl, TBAIDMF2. O3, MeOHthen Me2S

PMBO

O O

85 % (2 steps)

1. TMSOTf, iPr2NEtthen NBS2. SiO2

N3

N3

57 % (2 steps) PMBO

N3

N3

Br

OHBr

O1. LiCl, DMF2. anisole, TFA/DCM (1/10)

HO

N3

N3

Cl

OHBr

O

78 % (2 steps)

SO2Cl22,6-lutidine

38-43%

N3

N3

ClO

Cl

Br

Key Intermediate

HO

N3

N3

Cl

OHBr

O

O

N3

N3

Cl

OBr

O

SO

O

SO2Cl22,6-lutidine

HElim.

O

N3

N3

Cl

Br

O

SOO

OCl

N3

N3

ClO

Cl

Br


Synthesis of 1,9-Dideoxy-Pre-Axinellamine

BocN

N

Cl

ClON3

N3 BaseN

BocN

OH

NBoc

N3

N3

Cl

Problem with Installation of the Final 2-Amino Imidazole:

NHBoc

N3

N3

ClO

Cl

Br

1. NaBH4CeCl3 7H2O

2. DBU,

NHBoc

H2N NBoc N3

N3

Cl

Cl

N55 % (2 steps)

HO

NHBoc

NHBoc

IBX, benzene

70%, dr = 1.3:1 NN

Cl

ClON3

N3

NHBocBoc

BocHN

H2NNH

1.

2. Boc2O

NN

Cl

N3

N3

NBoc2Boc

NBocN

N{Boc)2

33 % (2 steps)

1. Ph3P, then

NBr

Br

HO2CSEM

2. TFA41 % (2 steps)

Cl

NH

NNHO

HN

Br Br

HN

ONH

Br

BrN NHH

NH2

NH2

H

H TFA

TFA

1,9-dideoxy-pre-axinellamine


Synthesis of Axinellamines A and B

Cl

NH

NNHO

HN

Br Br

HN

ONH

Br

BrN NHH

NH2

NH2

H

H TFA

TFA

1,9-dideoxy-pre-axinellamine

N

HNNH

HNNH

HN

O

HN

BrBr

ONH

Br

Br

H

HO

NH

ClHO

NH2

TFA

TFA

Axinellamine A (H, OH = β)Axinellamine B (H, OH = α)

N

NNH

HNNH

HN

O

HN

BrBr

ONH

Br

Br

H

HO

NH

ClHO

NH2TFA

TFA

N3

N3

NH

HNCl NH2

HN N

NH2

TFA

TFAN3

N3

ClO

Br

Cl

Strategy based on Baran’s biosynthetic hypothesis:

Strategy used to avoid ring closures leading to other pyrrole-imidazole alkaloids:


Synthesis of Axinellamines A and B

BocN

N

N3

N3

NBocN

NBoc2

TFA

100 %

HN

NH

N3

N3

NHHN

NH

NBoc2 NH2

Cl Cl TFA

TFA

DMDO

N

NH

N3

N3

NHHN

NH

NH2

Cl TFA

TFA

OHHO

then TFA

acetone/H2O

N

NH

N3

N3

NHN

NH

NH2

Cl TFA

TFA

HO

N

NNH

N3

N3

H

HO

NH2TFA

HNCl NH2

TFAN

OOAg

O

N

O

H2O

40% (d.r. = 3:1)

N

NNH

N3

N3

H

HO

NHTFA

HN NH2

TFAHOCl

SH SH Et3N

MeOH

N

NNH

H2N

H2NH

HO

NHTFA

HN NH2

TFAHOCl

HN

Br

Br

Cl3C

O

iPr2NEtN

NNH

NH

HN

NH TFA

HN NH2

TFAHOCl

HN

NH

O

O

BrBr

Br

Br

HO

HN

NNH

NH

HN

NH2

HN NH2

HOCl

HN

NH

O

O

BrBr

Br

BrTFA

TFA

HO

H

Axinellamine A, 45 % Axinellamine B, 24 %

+


Summary and Outlook

•Baran and coworkers have completed the racemic synthesis of Axinellamines A and B as well as thesynthesis of the postulated species 1,9-dideoxy-pre-axinellamine. Both syntheses proceed through ahighly functionalized cyclopentene intermediate which dictates the stereochemistry of the final product.

•Baran’s synthesis is an achievement that marks the first synthesis of these marine natural products;however, several steps suffer from poor diastereoselectivities and low yields. .

•1,9-Dideoxy-pre-axinellamine was synthesized in 19 steps and 0.54 % overall yield (0.31 % based on themajor diastereomer from the spirocyclization).

•Axinellamines A and B were synthesized in 23 steps and 0.24 % and 0.12 % overall yields, respectively.

•Perhaps we can expect to see syntheses of the pyrrole-imidazole alkaloids derived from 1,9-dideoxy-pre-axinellamine. Yet, cyclization selectivities may prove difficult to control in the laboratory setting.

•The challenge to complete an asymmetric synthesis remains to be solved.


baran lab syntheses of the axinellamines - …ccc.chem.pitt.edu/wipf/current...

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