Asymmetric Total Synthesis of Nakadomarin A Li Nan 2013.7.6.
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Transcript of Asymmetric Total Synthesis of Nakadomarin A Li Nan 2013.7.6.
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Asymmetric Total Synthesis ofNakadomarin A
Li Nan
2013.7.6
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Nakadomarin A 是日本科学家 Kobayashi于 1997年从日本冲绳县 (Okinawa)庆良间列 岛 (Kerama Islands) 的 一 种 海 绵Amphimedon sp.(SS-264) 中分离得到了一种新型Manzamine类海洋生物碱。它具有完全环状结构 6/5/5/5/8/15六环体系 ,其中一个环为呋喃环 ,并具有一定的生理活性。
NO
N
H
A BC
D
E
F
Nishida, A. Angew. Chem. 2004, 116, 2054.Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465.Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632.Evans, D. A. J. Am. Chem. Soc. ASAP
2
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NO
N
H
A BC
D
E
F
HN
O
O
NBs
P
H
HN
NBs
OP
O
H CHO
BsN
NBs
OP
O
BsN
O
O
BsN
O
BsN
O
ONBs
+
OTBS
OMe
L-serine
Nishada’s Asymmetric Total Synthesis of (-)-Nakadomarin A
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HN
O
PhSO2Cl,nBuLi, THF
- 78 to - 40 oCBsN
O
1a, LiN(TMS)2
THF, -78 oC BsN
O
OH
ONBs
1.MsCl, Et3N, -30 to 0 oC2.DBU, CH2Cl2, -10 oC
3.H2, 5% Pd-C, AcOEt,67%
BsN
O
ONBs
PhSO2SPh,LiN(TMS)2, THF
- 30 oC BsN
O
ONBs
SPhmCPBA, aq.NaHCO3
DCM, 0 oC then benzene reflux
BsN
O
ONBs
94% 72%
70% 87%
1. AcCl, MeOH,reflux
2. BsCl, Et3N, DCM, 76%
HOCO2Me
NHBs
1. dimethoxypropanepTsOH, benzene,
reflux
2. DIBAl, tol.-78 oC, 83%
ONBs
CHO
1a
HOCO2H
NH2
4
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BsN
O
ONBs
neat, 180 oCthen TFA, DCM RT
52% diastereomer 35%
BsN
O
OH
O
BsN
NaBH4, CeCl3, DCM/MeOH,
- 78 oC
HCl(6N), benzenereflux, 69%
2:1 dr
BsN
NBs
OH
O
H
1.TBDPSCl, imidazole
2.Na/anthraceneDME, -65 oC
74%
HN
NBs
OTBDPS
O
H1.O3, DCM, -78 oCthen Me2S, RT
2. N-methylanilinium trifluoroacetate, THF, reflux, 75%
HN
NBs
OTBDPS
O
H CHO
IPh3P(CH2)3CCTMS, NaH, THF, -78 oC- RT
76%
HN
NBs
OTBDPS
O
H
TMS
1.O2, halogen lamp, Rose Bengal, DCM/MeOH, 0 oC
2. tBuOK, THF, 78 oC then HCl(6N),RT, 88%
HN
O
O
NBs
TMS
H
OH
+
OTBS
OMe
5
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HN
O
O
NBs
H1. Dess-Martin oxidation
then TMSCH2MgCl, Et2O,RT
2. BF3 Et2O, DCM,3. K2CO3, MeOH
RT, 61%
1. Boc2O, DMAP, Et3N, CH2Cl2,
2. DIBAH, tol, -78 oC3. Et3SiH, BF3Et2O,
CH2Cl2, -78 oC78%
BocNO
NBs
H
1. Na/naphthalene, DME-65 oC
2. 5-hexenoylchl oride, Et3N, CH2Cl2,92%
BocNO
N
H
O
1. Co2(CO)8, CH2Cl2,
2. Grubbs II (25 mol%), CH2Cl2, reflux,
76%
BocNO
N
R
H
O
R=
Co2(CO)6MesN NMes
RuCl
ClPCy3
Ph
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1. nBu3SnH, benzene,
65 oC
2. TFA, CH2Cl2,3. 5-hexenoylchl oride,
Et3N, CH2Cl2, 69%
NO
N
H
OO
Grubbs I (20 mol%), CH2Cl2 , reflux,
72%, Z;E = 1:1.8
NO
N
H
O
Red-Al, tol,reflux, 92%
Ru
PCy3
PCy3
Cl
Cl
Ph
NO
N
H
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NO
N
OPg
H
OPg
PgO
CO2Me
CO2MeO
N
OPg
OPg
OPgOPg
O
OPgBr
ON
OPg
OPg
CO2Me
MeO2C
O
OPgBr
ON
OPg
OPg
CO2MeMeO2C
PgO NHOH
MeO2C CO2Me
OPg O
OPgBr
O
H
NO
N
H
Kerr’s Asymmetric Total Synthesis of (+)-Nakadomarin A
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MeO2C CO2Me
OBn
O
TBDPSOBr
O
H
MeO
NHOH Yb(OTf)3, 4A MS,
tol, 100 oC
87%
1. DIBAL, CH2Cl2,
-78 oC
2. (MeO)2P(O)CH2CO2Me, tBuOK, THF, RT
81%
O
Br
ON OBnPMB
O
Br
ON OBn
CO2MeMeO2C
PMB
CO2Me
Pd(PPh3)4, Ag2SO4, NEt3, DMF, reflux,
87%CO2Me
O
ONPMB
OBn
CO2Me
MeO2C
OTBDPS
OTBDPS
TBDPSO
1. DDQ, CH2Cl2/H2O 9:1,
56%
2. ClC(O)(CH2)4OBn, NEt3, CH2Cl2,
89%
O ON
OBnCO2Me
MeO2C
TBDPSO
O OBn 0.1 M SmI2,
THF, 0 oC O OHNH
OBnCO2Me
MeO2C
TBDPSO
O OBn
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1. MsCl, NEt3, DMAP, CH2Cl2, 0
oC
2. tBuOK, THF, -25 oC
65%( 3 steps)CO2Me
CO2MeO
N
OTBDPS
OBn
OBn
ONiCl2 6H2O, NaBH4,
Na2CO3, MeOH/THF (10:1), -40 oC
67% (14:1 dr)CO2Me
CO2MeO
N
OTBDPS
OBn
OBn
O
1. LiAlH4, THF, 0 oC
2. MsCl, NEt3, DMAP,CH2Cl2, -78 oC- RT
79%
O
N
OTBDPS
OBn
O OBn
OMs
OMs
1. NH3, EtOH/THF (10:1), reflux;
2. ClC(O)(CH2)4OTBDPS, NEt3,CH2Cl2,0 oC -RT, 77%
O
N
OTBDPS
OBn
O OBn
N
O
OTBDPS
10
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1. MeOH,AcCl, RT2. Dess-Martin ,
CH2Cl2,
3. tBuOK, MePPh3Br, THF/tol, 70%
O
N
N
O
O1. 30 mol % Grubbs I,
CH2Cl2, reflux,
2. Red-Al, tol,reflux, 20%
NO
N H
1. BCl3, CH2Cl2,2. IBX, DMSO
3. tBuOK, MePPh3Br, THF/tol, RT
40%
O
N
OTBDPS
O
N
O
OTBDPS
20 mol % Grubbs II, CH2Cl2 , reflux,
O
N
OTBDPS
N
O
OTBDPS
O
84%
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NO
N
H
N
NO2O
O NO
O
NO
MeO2C
O2N N
O
MeO2C +O
NO
N
H
NO2
Dixon’s Asymmetric Total Synthesis of (-)-Nakadomarin A
12
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HNO OTs
+N N
NNNaS THF, reflux,
96%
HNO
N NN
NS2-(4-bromobutyl)-1,3-dioxolane,
NaH, Bu4NI, DMSO,RT
71%
NO
N NN
NS
O
O
mCPBA, CH2Cl2,
78%NO
N NN
NS
O
O
OO
HCl, THF,RT
98% NO
N NN
NSO
OO
Cs2CO3, DMF,THF, H2O, 70 oC
56%
N
O LHMDS, dimethylcarbonate, THF, -78 oC- 0 oC
82%
N
O
MeO2C
13
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POMe
OOMe
O
NaH, BuLi, THF, 0 oC, allylbromide,
then 2-oxopropane-1,3-diyl diacetate,
THF, RT,
42%AcO
OAcO
HCl, EtOH,
65 oC
69%
O
HO
(COCl)2, DMSO,
Et3N, CH2Cl2,
- 78 oC- RT
86% O
O
MeNO2, KOH, EtOH, 0 oC,
then MsCl, Et3N
- 15 oC - RT
88%
O
NO2
O N
O
MeO2C+
NH
N
NH
O
CF3
CF3
organocatalyst 20 (15 mol %),
tol, 30 oC
57%, 91:9 dr
O
NO
MeO2C
O2N
N
NO2
14
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O
NO
MeO2C
O2N
hex-5-enamine, CH2O, MeOH,
reflux
68%N
NO2O
O NO
AIBN, Bu3SnH,tol. reflux
70%N
O
O NO
LiAlH4, tol, -20 oC
then HCOOH, RT
86%N
O
NO
DIBAL, tol, -20 oC
then HCl, 70 oC
41%N
O
N
H
15 mol % Grubbs I, (+) - CSA
CH2Cl2, reflux,
62%, 63:37 Z/E
NO
N
H
15
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NO
N
H
N
O
N
H
HH
N
O
N
H
HO
N
O
N
H
HO
O
O
N
O
N
HO
Evans’s Asymmetric Total Synthesis of (-)-Nakadomarin A
16
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O
CHO
nBuLi, morpholine, THF, - 78 oC
then sBuLi, then I2; O
CH(OMe)252%
1. CH(OMe)3, TsOH,
2. Pd(OAc)2, allyl alcohol, NaHCO3, DMF,50 oC
66%
KHMDS,BocNH(CH2)5PPh3I
then HCl
89%, >20:1 Z/E
CH3O2CCH2P(O)(OCH2CF3)2 18-crown-6, KHMDS, THF,
90%, >20:1 Z/E
O
O
CHO
O
CHO
I
NHBoc
O
NHBoc
CO2Me
1. NaOH, MeOH,H2O, RT
2. TFA, DCM, 0 oC - RT
3. HBTU, NEt3, CH3CN
50 oC, 73%
O
HN
O
NN
N
ON
N
PF6
HBTU
17
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O
StBu N
H
+ EtO Br
O Zn, LiCl, DMF, H2O
82%, >95:5 dr
EtO
OHN
StBu
O
H HCl, MeOH,then NaOH
86%
NH
O
H
NaH, 1-iodo-5-hexene, DMF;
85%
N
O
H
Grubbs I (1.5%),DCM
83%
N
O
H
O
HN
O
N
O
H
+
TBSOTf, 4a. iPr2NEt, DCE, RT, then 4b, DCE,
4a 4b
N
O
N
H
HO
O
79%, 9:1 dr
2,6-di-tert-butyl-4-methylpyridine,Tf2O, DCM, rt, then Red-Al,
69%
N
O
N
H
HH
18
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Matsumoto, M. Tetrahedron Lett. 1976, 17, 4363.
R
OH
O2, halogen lamp,
Rose Bengal,
DCM/MeOH, 0 oCR
OH
OO
tBuOK, THF, - 78 oC
then HCl(6N),RTR
OH
O
O
O
O
I
I I
I
HO OH
Cl
Cl
ClCl
Rose bengal
19
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Peterson, D. J. J. Org. Chem. 1968, 33, 780
Peterson Reaction
R1
R2M
SiR3
+O
R4R3
R3Si
OHR1R2
R4R3
base R2 R3
R4R1
R2 R4
R3R1
base
acid
R3Si
OHR1R2
R3R4
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Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
NOR1
R2
+
R3
CO2Me
CO2Me
Yb(OTf)3 NOR1
R2
CO2Me
R3
CO2Me
Ester manipulation NOR1
R2
R5
R3
R4
RaNi or SmI2 NHHOR1
R2
R5
R3
R4
MsCl NR1
R2
R5 R4
R3
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Kocienski Synlett 1998, 26Aissa, C. J. Org. Chem. 2006, 71, 360.
O
R2R1
NN N
N
tBu
SO2Me
Base = NaHMDSor Cs2CO3
R2R1
Julia-Kocienski Reaction
N
N
N
NSO2
CH2
Li
N
N
N
NSO2
CH2
O R1Li
N
N
N
NLi
SO2
O R1
N
N
N
NO R2R1
S
OLi
-SO2
N
N
N
NOLi
+R1
R2
tBu tBu tButBu
tBu
O
R2R1
R2
R2
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Ono, N. Tetrahedron Lett. 1981, 22, 1705. Fu, G. C. J. Org. Chem. 1998, 63, 5296.
R NO2 + Bu3SnXAIBN
benzene,reflux
R X + Bu3SnONO
X = H or D
AIBNheat
2C(CH3)2(CN)
Bu3SnH + 2C(CH3)2(CN) Bu3Sn
Bu3Sn + R-NO2 Bu3Sn +R-NO2
R-NO2 R + NO2
R Bu3SnH+ RH
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N
O
N
H
HO
O
N
O
N
H
HTfO
O
OTfN
O
N
H
H
O
OTf
Red-Al
N
O
N
H
HH