Temporary Restraints to Overcome Steric Obstacles: An Efficient Strategy for
the Synthesis of Mycalamide B
Christopher RosenkerWipf Group - Current Literature
October 23, 2010
John C. Jewett and Viresh H. RawalAngew. Chem. Int. Ed. Early View. Oct. 7, 2010
DOI: 10.1002/anie.201003361
X
O O O
N X
O O O
N OMeO OH H
N
O O O
O
H
OMeOH
OMe
mycalamide B
X2 steps
tie back"arms"
Chris Rosenker @ Wipf Group Page 1 of 13 12/5/2010
Pederin Family of Natural Products
OMeO OH H
N
O O O
O
H OMe
ORHO
ORO OH H
N
O OMe
O
H OH
OMeMeO
pederin (R = Me)pseudopederin (R = H)
mycalamide A (R = H)mycalamide B (R = Me)
OMeO OH H
N
O OMe
O
H O
OMeMeO
pederone
OMeO OH H
N
O
O
H OMe
OH
NH
O
HN
NH2
NH
HHO O
O O
Onnamide A
OMeO OH H
N
O
O
H OMe
OH
O O
NH
OHHO O
NHHN
NH2
icadamide B
OMeO OH H
N
O
O
H OMe
OH
O O
OH
icadamide A
OMeO OH H
N
O O O
O
H OMe
R
R = O
OH
OHMeO
O
O
O
OO
HO
A B C D E
theopederin A-E
Narquizian, R.; Kocienski, P. J. In The Role of Natural Products in Drug Discovery, Mulzer, J.; Bohlmann, R., Eds. Springer: Berlin, 2000; pp.25-56.
Chris Rosenker @ Wipf Group Page 2 of 13 12/5/2010
Isolation and Biological activity
• Isolated from a marine sponge of the genus Mycale off the coast of New Zealand.
• Pederin was isolated from a black beetle (Paederus)
• Pederin family of compounds show antiviral and antitumor properties
• Pederin family of natural products could come from uncultivated symbiotic bacteria
• Exhibit >1.5 nM activity towards human promyelocytic leukemia, lung, and colon cancer cells
• Biological activity attributed to ability to arrest protein synthesis by binding to 80S ribosome and preventing transfer of new peptide from the A site to the P site
• Capable of changing morphology of ras-transformed Normal Rat Kidney cells to normal cells by inhibiting the biosynthesis of p21
Perry, N. B.; Blunt, J.; Munro, M.; Pannell, L. J. Am. Chem. Soc. 1988, 110, 4850.Burres, N.; Clement, J. Cancer Res. 1989, 49, 2935.Perry, N. B.; Blunt, J.; Munro, M.; Thompson, A. J. Org. Chem. 1990, 55, 223.Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm. Bull. 1991, 39, 2152.Piel, J.; Butzke, D.; Fusetani, N.; Hui, D.; Platzer, M.; Wen, G.; Matsunaga, S. J. Nat. Prod. 2005, 68, 472.Narquizian, R.; Kocienski, P. J. In The Role of Natural Products in Drug Discovery, Mulzer, J.; Bohlmann, R., Eds. Springer: Berlin, 2000; pp.25-56.
OMeO OH H
N
O O O
O
H OMe
OHHO
mycalamide A
OMeO OH H
N
O O O
O
H OMe
OMeHO
mycalamide B
Chris Rosenker @ Wipf Group Page 3 of 13 12/5/2010
Syntheses of the Pederin Family of Natural Products
OMeO OH H
N
O O O
O
H OMe
OMeHO
mycalamide BKishi 1990
Kocienski 1998Rawal 2010
OMeO OH H
N
O OMe
O
H OH
OMeMeO
pederinMatsuda 1988Kocienski 2000Nakata 2002Rawal 2007
OMeO OH H
N
O
O
H OMe
OH
NH
O
HN
NH2
NH
HHO O
O O
onnamide AKishi 1991
OMeO OH H
N
O O O
O
H OMe
theopederin DKocienski 2000Floreancig 2008
OO
OMeO OH H
N
O O O
O
H OMe
OH
O
MeO
theopederin BNakata 2009
OMeO OH H
N
O O O
O
H OMe
OHHO
mycalamide AKishi 1990
Nakata 1996Roush 2000Trost 2004Rawal 2005Toyota 2006
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Highlights from Previous Synthetic Work in the Pederin Family
O
MeOOH
OH
OH
OH
methyl α-D-glucopyranoside$0.14/g
H2N
O O
O
H OMe
OMeAcO
not configurationally stable2:1 in basic or neutral conditions
1:4 in acidic conditions(favored:unfavored)
OMeO ODMPM
OH
O
pTsCl, DMAPCHCl2, rt
OMeO
ODMPMHN
O O O
O
H OMe
OMeAcO
59% desired26% undersired
(undesired could be empimerized to a 1:1 mixture)
mycalamide B
Kishi: First total synthesis of mycalamide B
Hong, C.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. Synlett 1998, 869.
Kocienski: Vinyl lithium addition to ester joins two fragments in mycalamide B
O O
O
H OMe
O
HO
OMeTBSO 1. DPPA, TMSCH2CH2OH, DIPEA
4 Å MS, toluene 65 °C (57%)
2. KHMDS; MeO2C-COCl -90 to -20 °C (70%)3. TBAF, AcOH, THF (82%)
O O
O
H OMeHN
OMeTBSO
O
O
MeO
O Li
SePh
4 equiv.
TMEDA, THF, -80 °CO O
O
H OMeHN
OMeTBSO
O
OO
SePh55%
mycalamide B
steps
Chris Rosenker @ Wipf Group Page 5 of 13 12/5/2010
Highlights from Previous Synthetic Work in the Pederin Family
Roush: Application of the aldol reaction to the synthesis of mycalamide A
Roush, W.; Pfeifer, L. Org. Lett. 2000, 2, 859.Sohn, J.-H.; Waizumi, N.; Zhong, H.; Rawal, V. J. Am. Chem. Soc. 2005, 127, 7290.
N
O O
O
H OMe
OO
O
Teoc
O
OBn
TiCl4, DIPEA, CH2Cl2-78 °C then
OTBSCHO
TBSO
N
O O
O
H OMe
OO
O
Teoc
O
OBn
OH
TBSO
OTBS
84%4 diastereomers
~1:1 syn:anti
mycalamide Asteps
O O
O
H OMeH2N
OAcAcO
1:1.4 mixtureof diasteromers
DCC, DMAP, CH2Cl2
rt, 12 h
OMeO OBz
OH
O
OMeO OBz H
N
O O O
O
H OMe
OAcAcO
56% (5:1 dr)
1 M LiOHTHF mycalamide A
78%
Rawal: Improved coupling of amine and acid fragments of mycalamide A
Chris Rosenker @ Wipf Group Page 6 of 13 12/5/2010
Retrosynthetic Analysis
OMeO OH H
N
O O O
O
H
OMeOH
OMe
mycalamide B
amide coupling
OMeO OBz
X
O
X=OH, pederic acid
H2N
O O
O
H
OR'OR
OMe
HN
O O
O
H
OR'OR
OMeRO
O
epimerizationof C10
?
HN
O O
O
H
OR'OR
OMeRO
O OMOM
O
H
OR'OR
OTBSMeO
O O
OR'OR
O
Mukaiyama-Michael
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
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Synthesis of Mycalamide B
Sohn, J.-H.; Waizumi, N.; Zhong, H.; Rawal, V. J. Am. Chem. Soc. 2005, 127, 7290.Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502.Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
OOMe
O
H1. NaOMe, Et2O, reflux; DMSO, Me2SO4
2. TBSOTf, Et3N, Et2O 0 °C to rt
OTBSMeO60%
OH
OO
HO
O
Ph
1. EDC, DMAP, CH2Cl2 (91%)
2. Cp2TiMe2, toluene 80 °C (85%)
OO
O
Ph 15% PdCl2benzoquinone
MeOH, HC(OMe)3
propylene oxideTHF/DMF (20/1)
OO
O
Ph
MeO
PdX
OO
O
Ph
MeO
5.7:1 dr
78%
1. Na, NH3, EtOH (93%)2. TESCl, DIPEA, CH2Cl2 (93%)
3. BzCl, DMAP, DIPEA, CH2Cl2 (94%)
OMeO OBz
OTES PDC, DMF OMeO OBz
OH
O
83%Pederic acid
Chris Rosenker @ Wipf Group Page 8 of 13 12/5/2010
Synthesis of Mycalamide B
O AlO
t-Bu t-Bu
t-Bu
t-Bu
Me
MAD
BnO OMgBr1. , CuI, THF, -78 to 0 °C
2. TIPSCl, imidazole, CH2Cl2
3. OsO4, NaIO4, 2,6-lutidine, H2O dioxane
BnOOTIPS
O H87% over
three steps$14.40/g TCI
1. MAD, A, TMSOTf, CH2Cl2 -78 °C to rt; HF, 0 °C (55%)
2. MeOTf, NaHMDS, THF -78 °C (76%)
O
O
OMeBnO
14:1
OTBSMeOA
O
O
OMeBnO
TBSO
OMeH
OMOM
, TBSOTf
-95 to -60 °C; Et3N to 0 °C;m-CPBA, NaHPO4, CH2Cl2
O
OTBS
OMeBnO
HOMOM
O
MeO
O
O
OMeBnO
HOMOM
O
MeO
isolation
O
OTBS
OMeBnO
HOMOM
O
MeO O
>9:1
72% of desiredstable to SiO2
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
Chris Rosenker @ Wipf Group Page 9 of 13 12/5/2010
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
HO
OTBS
OMeBnO
HOMOM
O
MeO O
P2O5, CH2(OMe)2, CH3CN
0 °C to rtO
O
OMeBnO
O
MeOO OH
56%
1. Al(i-PrO)3, i-PrOH, 45 °C
2. MeI, Ag2O, 42 °CO
OMe
OMeBnO
O
i-PrOO OH
86% overtwo steps
O OH
O
H
H
O
MeO O
OMe
HBnO
Synthesis of Mycalamide B
Chris Rosenker @ Wipf Group Page 10 of 13 12/5/2010
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
Synthesis of Mycalamide B
O
OMe
OMeBnO
O
i-PrOO OH
1. NaOH, MeOH
2. DPPA, Et3N, TMSCH2CH2OH 4 Å MS, THF, 65 °C
O
OMe
OMeBnO
HN
O OHTeoc
55% overtwo steps
base then BX O
MeO OBz HN
O O O
O
H OMe
OMeO OBz
Cl
O
OMeBnO
B
O
OTMS
OMeMeO
HN
OMeHTeoc
O
OTMS
OMeMeO
HMeO
HN Teoc
freerotation
pederin intermediate
O
OMe
OMeBnO
HN
O OHTeoc
lockedO
OMe
OMe
HN
O OH
OO
N-carbamateblocked
H
O OH
O
H
H
OMe
HBnOOMe
NH
TeocO
HO
H
OMe
MeO H
OHN
OOsteric repulsion
Chris Rosenker @ Wipf Group Page 11 of 13 12/5/2010
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, Early View. DOI: 10.1002/anie.201003361
O
OMe
OMeBnO
O
i-PrOO OH
86% overtwo steps
1. H2, Pd(OH)2, EtOH2. 10% NaOH, MeOH
3. DPPA, Et3N, THF 4 Å MS, rt to 70 °C
O
OMe
OMeHO
N
O OH
CO
O
OMe
OMe
HN
O OH
OO
44% overthree steps
LiHMDS, DMAP, THF;B, toluene, -78 to 0 °C
OMeO OBz
Cl
O
B
O
OMe
OMe
N
O OH
OO
O
OBzOMeO
45%73% based on rec.
carbamate
LiOH, LiCl, MeOH, 0 °C
OMeO OH H
N
O O O
O
H OMe
OMeHO
mycalamide B64%
(trace amide hydrolysis observed)
2.6% yield and 14 steps from commercially available materials
Synthesis of Mycalamide B
Chris Rosenker @ Wipf Group Page 12 of 13 12/5/2010
Conclusions
• Key steps include:
• one-pot Mukaiyama-Michael/epoxidation sequence introducing three contiguous stereocenters
• intramolecular trapping of an isocyanate, resulting from a Curtius rearrangement, to provide a cyclic carbamate, which allowed for the key coupling reaction to occur with no loss of stereochemical information
• selective carbamate hydrolysis in the presence of an amide
• Synthesis of mycalamide B in 14 steps from commercial material (longest linear sequence) with a 2.6% overall yield.
• Interesting solution to overcome the difficulty of a convergent stereocontrolled coupling of two fully functionalized halves of pederin-like natural products.
Chris Rosenker @ Wipf Group Page 13 of 13 12/5/2010
