Total Synthesis of Nakadomarin A. · PDF fileWilliams 2004 Funk 2006. ... 20 mol% Pd(OH)2/C H2...
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Total Syntheses of Nakadomarin A
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Transcript of Total Synthesis of Nakadomarin A. · PDF fileWilliams 2004 Funk 2006. ... 20 mol% Pd(OH)2/C H2...
Total Syntheses of Nakadomarin A
Nakadomarin A: The FactsNakadomarin A: The Facts
• Isolated in 1997 from an Amphimedon sea sponge by Kobayashi
N
N H
Isolated in 1997 from an Amphimedon sea sponge by Kobayashioff the coast of the Kerama Islands, Okinawa
• Only member of the manzamine family containing a furan ring
ON
• Bioactivity includes anticancer, antifungal and antibacterial
• Limited availability: 6 mg isolated from 1 kg of wet sponge
• Initially the absolute stereochemistry was unknown
Structural Features:
• Tetracyclic core contains fused 6/5/5/5 ring system
• 3 different heterocycles
• 4 stereogenic centers, 1 quaternary
• Z-olefin
Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem. 1997, 62, 9236-9239.
Nakadomarin A: Proposed BiosynthesisNakadomarin A: Proposed Biosynthesis
NH OH
N NH
HN
H OHH
OH
N
HOH
OH
N
NH
N
NH
N
NH
Manzamine AIrcinal
Completed Syntheses:(+)-Nakadomarin: Nagata, Nakagawa and Nishida 2003
Young and Kerr 2007
(-)-Nakadomarin: Ono, Nakagawa and Nishida 2004HN( ) , g
Published Approaches:Furstner 1999Magnus 2002
O
NH
gTius 2003Williams 2004Funk 2006
Nakagawa’s Retrosynthetic Analysis of Nakadomarin Ag y y
Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003, 125, 7484-7485.
Nakagawa’s Total Synthesis of Nakadomarin Ag y
O
NO
O
SO
PhCO2H
1. BnNH2, 91%2. cat. OsO4, NMO3 NaIO
NO
O
SO H
NBn
1. DBU, EtOH (3.3:1 dr)2. 2N NaOH3. AcCl, EtOH54% for 8 steps
NO
O
SO
OPh NBn
O
OPh 3. NaIO44. Ph3P=CHCO2Et
SOPh
O
Bn 54% for 8 steps
O
OH
EtO
OEtO
O1. LiBH4, 99%2. 70% HClO4 91%3. DHP 91%
OOi LiN(TMS)2O
OTfO
PdCl2(dppf), K3PO4O
EtO2C
NS
O
OPh NBn
H
i. LiN(TMS)2
ii. PhNTf2, 87%
NS
O
OPh NBn
H
EtO2C
PdCl2(dppf), K3PO4
95%NS
O
OPh NBn
O
O
THPOO
BO
OMeMe
H THPOTHPO
THPO
Nakagawa’s Total Synthesis of Nakadomarin Ag y
Grieco Elimination
Nakagawa’s Total Synthesis of Nakadomarin Ag y
38 steps, 0.44% yield
Acid Coupling with EDC and HOBtp g
Nakagawa’s Retrosynthetic Analysis of (-)-Nakadomarin Ag y y ( )
P
ON O
H
N
H
O
H
NHN
NBs
HP
O
N
NBs
HP
O
NBs
H
NBs
HO
OTBSBsN
+ Bs
NBs
OP
Bs
O
NBs
M
MeOMeO
O
NBs
Me
+OO
MeMeMe
Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43, 2020-2023.
Nakagawa’s Retrosynthetic Analysis of (-)-Nakadomarin Ag y y ( )
Nakagawa’s Retrosynthetic Analysis of (-)-Nakadomarin Ag y y ( )
HH
OH
HN
NBs
HO
TMS
O2, h ,Rose Bengal
quant. 1.2:1 drHN
NBs
HO
OO
TMS t-BuOK
then 6M HClHN
NBs
HO
O
TMS
OTBDPS
Bs
OTBDPS OH1. DMP, 90%2. TMSCH2MgCl83% 2:1 dr 61%83% 2:1 dr3. BF3OEt24. K2CO3, MeOH81% for 2 steps
H
61%
1 B O DMAP 93%HH
HN
NBs
HO
O1. Boc2O, DMAP 93%2. DIBAL3. Et3SiH, BF3OEt284% for 2 steps
BocN
NBs
H
OBocN
NH
O
O
1. Na/napthalene
2. 5-hexenoyl chlorideE N 92% f 2 BsEt3N 92% for 2 steps
Nakagawa’s Retrosynthetic Analysis of (-)-Nakadomarin Ag y y ( )
36 steps, 0.42% yield
Kerr’s Retrosynthetic Analysis of Nakadomarin Ay y
Young, I.; Kerr, M. J. Am. Chem. Soc. 2007, 129, 1465-1469.
Kerr’s Synthesis of Nakadomarin A:D l t f [3+2] Di l C l dditiDevelopment of [3+2] Dipolar Cycloaddition
Young, I.; Kerr, M. Angew. Chem. Int. Ed. 2003, 42, 3023-3026.
Kerr’s Synthesis of Nakadomarin A:D l t f [3+2] Di l C l dditiDevelopment of [3+2] Dipolar Cycloaddition
Kerr’s Synthesis of Nakadomarin A:I t f [3+2] Di l C l dditiImprovement of [3+2] Dipolar Cycloaddition
Three Component Coupling:
Young, I.; Kerr, M. Org. Lett. 2004, 6, 139-141.Young, I.; Williams, J.; Kerr, M. Org. Lett. 2005, 7, 953-955.
Kerr’s Synthesis of Nakadomarin A:yTetracyclic Core Model Studies
Ph
OMeO
PhNHOH
Ph
CO2Me
CO2Me
74%
NO Ph
O
1. DIBAL, 95%2. Horner Emmons, 73%
3 Heck 64%
NO Ph
PhPh
O CO2Me
10 mol% Yb(OTf)3
O
H
74%CO2Me
CO2Me
BrMeO
3. Heck, 64%
MeO2CMeO
2
1. NO Cleavage2. Pyrrolidine Formation66%, 2 Steps
PhPh PhPh Ph
O CO2Me
1. Double Bond Reduction, 66%2. Ester Reduction, 70%3. Bis-mesylation, 95%
NPh Ph
O
NPh
OMsBnNH2, 95%O
N
NBn
MeO2CMeO
2
MeOOMsMeO
Kerr’s Synthesis of Nakadomarin Ay
Kerr’s Synthesis of Nakadomarin Ay
Kerr’s Synthesis of Nakadomarin Ay
O
N
N
O Grubbs II75% O
N
N
O
3. t-BuOK, MePPh3I31% for 3 Steps
1. TBAF2. DMP
O
N
N
O
OTBDPSOTBDPS
OTBDPSOTBDPS
31% for 3 Steps
Grubbs I66%5:3 E:Z
NON
O N
Red-Al
5:4 mix E:Z80%
O
N
N
inseparable isomers inseparable isomers
Kerr’s Synthesis of Nakadomarin A:R i d E dRevised Endgame
23 steps, 0.29% yield
Approaches Toward Nakadomarin A:F tFurstner
Furstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108-11113
Approaches Toward Nakadomarin A:MMagnus
OON
NH
A B
CR1N
NR2
OH R1N
NR2
OH
R1N
NR2
O OO O
Pauson-Khand Approach: ChallangesNo previous examples of enamines as substrates
Creates a quaternary center
NBoc
OLiN(SiMe3)2
ClCO2MeTHF, -78 °C
NBoc
O
MeO
O
77-85%
1. DIBAL2. Quinolinium
Camphor SulfonicAcid
NBocH
O
77 85% Acid72-77%
NH3ClEt N MeOH NaBHEt3N, MeOH, NaBH4
HNTsClTsNTsN O
HCo2(CO)8
Sugihara conditions
NBocNBoc 70-75%for 2 Steps
NBoc
Hn-BuSMe63-69%
Magnus, P.; Fielding, M.; Wells, C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947-950.
Approaches Toward Nakadomarin A:TiTius
LecLerc, E.; Tius, M. Org. Lett. 2003, 5, 1171-1174
Approaches Toward Nakadomarin A:WilliWilliams
ON H
N
Boc
N
BocN
BocO
OPh H
N
NH N
H
O
O
CO2Me NH
H
OCO2H
O
OMe
Me
ON
Ph
O O
HH
Me Me
OPh O O OOPh O
N BocO
N
BocO
OPh H
NH
O
OO
N
Ph
Ph
O
H
Boc
+ +
MeMe
NPh
O
O
MeM
-H2OO
NPh
O O
H35%H
MeMe Me
20 mol% Pd(OH)2/CH2 (1 atm)
MeOH/EtOAc92%Boc
H
N
Boc
N
H
N
OCO M
NH
OCO2H
O
OMe
MeH
N
O
CO2Me
Ahrendt, K.; Williams, R. Org. Lett. 2004, 6, 4539-4541.
Approaches Toward Nakadomarin A:F kFunk
HN O H OMe
O
H
NH O
H
NH
Boc
N O
Boc
OHO
NO N
HNMe O
O O
HO
MeO
HO
MeO+
N
HO
N
N
Sc(OTf)3 N
N
O
O
Sc
O O Boc OBoc Boc O
OO
O OO H OMe
N
N
O
O
Sc
Boc
NO
O
O
Sc
N
HOO O
O
N
O
H
NH
Boc
N
H
O
ONBoc
N BocBoc
Nilson, M.; Funk, R. Org. Lett. 2006, 8, 3833-3836.
Syntheses of Nakadomarin A:SSummary
