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 Page 1 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.
Melissa Sprachman @ Wipf Group Page 2 of 15 3/30/2008
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.
Melissa Sprachman @ Wipf Group Page 3 of 15 3/30/2008
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
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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
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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.
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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.
Melissa Sprachman @ Wipf Group Page 7 of 15 3/30/2008
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
Melissa Sprachman @ Wipf Group Page 8 of 15 3/30/2008
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
Melissa Sprachman @ Wipf Group Page 9 of 15 3/30/2008
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
Melissa Sprachman @ Wipf Group Page 10 of 15 3/30/2008
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
Melissa Sprachman @ Wipf Group Page 11 of 15 3/30/2008
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
Melissa Sprachman @ Wipf Group Page 12 of 15 3/30/2008
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:
Melissa Sprachman @ Wipf Group Page 13 of 15 3/30/2008
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 %
+
Melissa Sprachman @ Wipf Group Page 14 of 15 3/30/2008
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.
Melissa Sprachman @ Wipf Group Page 15 of 15 3/30/2008