asymmetric total synthesis of nakadomarin a li nan 2013.7.6
TRANSCRIPT
Asymmetric Total Synthesis ofNakadomarin A
Li Nan
2013.7.6
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
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
3
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
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
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
6
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
7
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
8
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
9
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
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%
11
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
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
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
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
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
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
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
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
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
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
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
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
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