total synthesis of ( )-nakadomarin...
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1
Total Synthesis of (−)-Nakadomarin A
Darren Dixon, Oxford J. Am. Chem. Soc. 2009, 131, 16632.
Angew. Chem. Int. Ed. 2010, 49, 2830.Chemistry World 2009, 6, 12.
NO
H
NH
H
Contents
2
• Biosynthesis • Previous Approaches
Furstner Magnus Tius Williams Funk Zhai
• Previous Synthesis Nishida 1st approach Nishida 2nd approach Kerr
• Methodology Organocatalytic Michael addition of malonate esters to nitro olefins Nitro-Mannich/ lactamisation cascade
• Synthesis
Introduction
3
• Isolated 1996 from the Amphimedon sp. sea sponge off the coast of Kerama Islands#• Member of the manzamine family of alkaloids, only one to poses a furan#• Range of bioactivities blah blah blah…..#• Limited availability, extraction & synthesis have produced 8.5 mg#• Hexacyclic alkaloid 8/5/5/5/15/6 ring system#• Tetracyclic core containing 3 different heterocycles#• 4 stereogenic centers, 1 quaternary#• Z-olefin in macrocycle#
NO
H
NH
H
(-)-Nakadomarin A
Biosynthesis
4
Baldwin-Whitehead hypothesis for manzamine biosynthesis
Tetrahedron Lett. 1992, 33, 2059. Chem. Eur. J. 1999, 5, 3154.
Biosynthesis
5
• Proposed synthesis from Iricinal (isolated natural product) • Iricinal very similar to intermediate proposed by Baldwin
J. Org. Chem. 1997, 62, 9236.
Previous Approach - Furstner
6
NO
NH
H
H
NHO N
H+
OX
O HY
RCM
Diyne metathesisthen Lindlar reduction
J. Am. Chem. Soc. 1999, 121, 11108.
PhSO2SO
NH
O PhSO2SO
HN
O
(tBuO)W CCMe3
PhSO2SO
HN
O
H2, Lindlar
NO
O
H
N
OH
ON
H
O
HCl
(PCy3)2Cl2Ru=CHPh
90% 97%
76%
C6H5Cl, 80 oC
Chem. Eur. J. 2001, 7, 4811.
NMeO2C O
BocN
N
O
PMBO
CO2tBu
N
N
O
PMBO
CO2tBu
H
Ru
PCy3
PCy3
Cl
ClPh
98%
A
D
8 Steps
E
Previous Approach - Magnus
7 Tetrahedron Lett. 2002, 43, 947.
NO
NH
H
H
A B
DRN
NR'HO
R'N RN
Pauson-Khand
NBoc
O
NBocOHC 2 Steps3 Steps
NBoc
TsNTsN
NBoc
OH
Co2(CO)8
nBuSMe, DCE, reflux
69%
TsN
NBoc
OH
TsN
NBoc
OH
+
H H
65% 30%
Pd/C, H2
EtOAc
Previous Approach - Tius
8 Org. Lett. 2003, 5, 1171.
NO
NH
H
H
NRO
HN
H
HO
HO
R3
R2R1
O
OSiMe3OMeO
OMeO
Li
MeOH
OPh
nBuLI
O
NMe
PhO
74%
O
Ph
Me
O71%
Hg(OCOCF3)2,TFA, CH2Cl2 rt
Previous Approach - Williams
9 Org. Lett. 2004, 6, 4539.
NO
NH
H
H
NO
NH
H
HO
A BC
D
EN
N
O
Boc
OCO2MeE
D
A
N
NBoc
OCO2Me
O
N
ON
O O
HO
Boc
ADPh
PhH
H
O
NH
O OPh
Ph+ H
O
OO +
N
O
Boc
N
O OPh
Ph
OO
N
ON
O O
HO
Boc
Ph
PhH
H
-H2O
35%
NBocO
Pd(OH)2/CH2, MeOH, EtOAc
92%
HNN
O O
HO
Boc
H
HO2C 5 Steps
N
N
O
Boc
OCO2Me
H
O
10
Previous Approach - Funk
NO
NH
H
H
N
O
N OtBuO
O
MeO2C H MeO
O
O
O
N
NCO2tBu
Org. Lett. 2006, 8, 3833.
O
CHO 4 Steps
52%
O
H
OMeO
O
N
NBoc N
Boc
N
O
OSc
O
MeO
N
N
O
OSc
O
MeO
Boc
N
NBoc
H
O
O
OMe
OSc
Sc(OTf)3
CH2Cl2
80%
N
OSc
OO
N Boc
ON
NO
Boc
HCO2Me
O
HH
N
O
NBoc
O
MeO2CH
A BC
D
Previous Approach - Zhai
11 Org. Lett. 2008, 10, 1791.
NO
NH
H
H
N
N O
TsH
Boc
MeO2C
A
B CD
ONTsN Boc
CO2Me
OH2N
NOHC Boc
CO2Me
+
ONTsN Boc
CO2Me
N
N O
Ts
Boc
MeO2C
4 Steps
PtCl2 (18 mol%)PhMe, reflux
50%
N
N O
Ts
Boc
MeO2C
4 Steps H
51%
Previous Synthesis - Nishida
12 J. Am. Chem. Soc. 2003, 125, 7484.
NO
NH
H
H
NO
N PH
H
H
PO
PN
O
N
OP
EWG
H
H
PO
P
OP
OCO2R
(RO)2B +N
N
OP
PH
P
X
NO
AcOH
BsN
HO
1) p-TsOH,CH2Cl2
2) 1 N HCl
87%
Boc
4 Steps
73% NO
AcOH
BsN O
Grubbs ii
CH2Cl2 NO
AcOH
BsN
HO
70%
NO
O
Bs CO2H
11 Steps
NBs
OTf
N
O
BnOTHP
PdCl2(dppf),K3PO4
OEtO2C
NBs N
O
BnOTHP
O
EtO2C
NBs N
OAc
BocOTHP
O
AcO
HH
7 Steps
95%
(pin)B
Previous Synthesis - Nishida
13 J. Am. Chem. Soc. 2003, 125, 7484.
NO
AcOH
BsN
HO
5 StepsN
OH
NH
OO
Grubbs i
CH2Cl2
Z:E 2:326% isolated
NO
NH
H
HO
O
RedAl,PhMe, reflux 86% N
O
NH
H
H
(+)-Nakadomarin
Previous Synthesis – Nishida 2nd
14
NO
NH
H
H
HNO
N Bs
HP
O
HN
CHO
N Bs
H
OP
O
PN
O
H
O
NBs
N
OBs
O
NBs
10 Steps from L-serine47%, >99% ee
N
OBs
OH
O
NBs
52%
TBSO
OMei)
neat 180 oC
ii) TFA, CH2Cl2
4 Steps
N
OBs
H
N Bs
TBDPSO
1) O3, CH2Cl2then Me2S
2) N-methylaniliniumtrifluoroacetate, THF
75%
N
CHO
BsO NBs
TBDPSO
H
3 Steps
NBs
O NBs
TBDPSO
HO
SiMe3
5 Steps
NBs
O N
HO
O
Angew. Chem. Int. Ed. 2004, 43, 2020.
Previous Synthesis – Nishida 2nd
15
Grubbs iCH2Cl2
Z:E 1:1.826% isolated
NO
NH
H
HO
O NO
NH
H
H
92%
RedAl, PhMe
(-)-Nakadomarin
NBs
O N
HO
O
i) Co(CO)8, CH2Cl2 92%
ii) Grubbs iiCH2Cl2 83%
NBs
O N
HO
O
Co(CO)6
N
O N
HO
OO
i) nBu3SnH, C6H6 75%
ii) TFA, CH2Cl2iii) 5-hexanoyl chloride,NEt3, CH2Cl2 92%
Angew. Chem. Int. Ed. 2004, 43, 2020.
Previous Synthesis - Kerr
16
NO
NH
H
H
NO
NH
H
H
PGO
GPO
OPGPGO
MeO2C O
NH
H
PGO
GPO
PGO
H
MeO2CO
NO
Br
OPG
OPG
OPGMeO2C
MeO2C
ON
O
Br
OPG
OPG
OPGE
E
E = CO2Me
PGO NHOH
CO2MeCO2Me
O
BrOPG
J. Am. Chem. Soc. 2007, 129, 1465.
Previous Synthesis - Kerr
17
Angew. Chem. Int. Ed. 2003, 42, 3023; Org. Lett. 2004, 6, 139; Org. Lett. 2005, 7, 953.
CO2MeCO2Me
BnOO
BrTBDPSO
MeONHOH
CHO
Yb(OTf)3100 oC
87%
NO
CO2Me
PMBOBn
CO2MeO
BrOTBDPS
NOPMB
OBn
CO2MeO
BrOTBDPS CO2Me
Pd(PPh3)4,Ag2SO4, NEt3DMF
reflux
NOPMB
OBn
CO2Me
H
O
CO2MeOTBDPS
82%
B
NO
OBn
CO2Me
H
O
CO2MeOTBDPS
O
BnO i) 0.1 M SmI2, THFii) MsCl, DMAP, CH2Cl2
iii) tBuOK, THF
65%
CO2Me
H
O
CO2MeOTBDPS
NO OBn
OBnD
H
O
OTBDPS
NO OBn
OBn5 Steps
OMs
OMs
77%
H
O
OTBDPS
NO
OBn
OBn
N
H
OTBDPS
H
O
OTBDPS
NO
N
H
OTBDPS
3 Steps
A
i) NH3, EtOH/THF
ii) ClC(O)(CH2)4OTBDPSNET3, CH2Cl2
O O
Previous Synthesis - Kerr
18
H
O
OTBDPS
NO
N
H
OTBDPS
Grubbs iiO
CH2Cl2
H
O
OTBDPS
N
N
H
OTBDPS
OO
84%
3 Steps H
O
N
N
H
OO
i) Grubs i
ii) RedAlN
O
NH
H
H
Summary
• Many different approaches to the core • 3 Total syntheses (38, 36, 29 steps) • 8 & 15 membered rings made by RCM • Poor selectivity for Z-olefin
Methodology
19
MeO OMe
OO+ Ph
NO2
98%, 94%ee
Ph Ph
O O
PhNO2
(10 mol%)
CH2Cl2, -20 oC(2 eq.)
N
HNNN
HS
F3C
F3C
Organocatalytic Michael addition
Chem. Commun. 2005, 4481.
Org. Lett. 2008, 10, 1389.
Nitro-Mannich/lactamization
N
OMeO2C
O2N
Ph N
H2O, 70 oC N
ON
O
O2N Ph
76% dr > 99:1
One-pot combination of the above Org. Lett. 2008, 10, 4267.
Retrosynthesis
20
NO
NH
H
H
NO
N H
H
HN
NO2
N
O
OO
RCM reduction
cycisation
O2NO
NO
MeO2Cnitro-Mannich/lactamization
H2N4 Michael
O
O2N
+NMeO2C
O
H
Synthesis
21
OP
OMe
OOMe
OOAcAcO
then:
THF, rt
NaH, BuLi, THFallyl bromide
OOAc
OAc
HCl, EtOH, 65 oC
OHO
O
42% 69% 76%
1) (COCl)2, DMSO,NEt3, CH2Cl2
2) MeNO2, KOH, EtOH,then MsCl, NEt3
O2N
HNO
OTs + NN N
N
SNa HN
SN N
NNO
N
SN N
NNO
OTHF, reflux
96%
1) 2-(4-bromobutyl)-1,3-dioxolane,NaH, Bu4NI (cat), DMSO
2) m-CPBA, CH2Cl23) HCl, THF O
O54%
N
ON
O
MeO2C
Cs2CO3, DMFTHF, H2O
56%
LHMDS, dimethylcarbonate
THF
82%
Synthesis
22
O
O2N
N
O
MeO2C
+(15 mol%)
CH2Cl2, 30 oC, 8 days
N
HNNN
HS
F3C
F3CO2N
O
NO
MeO2C
57%, 91:9 dr
hex-5-enamine
CH2O, MeOHreflux
68%
O
NO
N
O
NO2
O
NO
N
60%
1) AIBN, Bu3SnHPhMe, reflux
2) LiAlH4, PhMe, -20 oCthen HCO2H
Grubbs i(+)-CSA, CH2Cl2reflux
62% Z:E 63:37
NO
NH
H
H
NO
NH
H
H
41%
(-)-Nakadomarin
DIBAL, PhMe, -20 oC
then HCl, 90 oC
Summary
23
• Short synthesis of (−)-Nakadomarin 12 linear steps (16 in total)
• Produced 69 mg in a single batch
• Uses asymmetric Mannich & nitro-Michael/lactamization developed within group
• Z-selective RCM in presence of CSA
• Unusual intramolecular Julia-Kocienski reaction to form 8-membered ring