synthetic (±)-axinellamines deficient in halogenccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
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
Eric Buck @ Wipf Group Page 2 of 16 3/31/2012
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
Eric Buck @ Wipf Group Page 6 of 16 3/31/2012
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
Eric Buck @ Wipf Group Page 8 of 16 3/31/2012
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.
Eric Buck @ Wipf Group Page 11 of 16 3/31/2012
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
Eric Buck @ Wipf Group Page 14 of 16 3/31/2012
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
Eric Buck @ Wipf Group Page 15 of 16 3/31/2012
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
Eric Buck @ Wipf Group Page 16 of 16 3/31/2012