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Asymmetric Synthetic Access to the HetisineAlkaloids:Total Synthesis of (+)-Nominine
Kevin M. Peese and David Y. GinChem. Eur. J. 2008, 14, 1654 - 1665J. Am. Chem. Soc. 2006, 128, 8734
N
MeH
OH
H
H
H
N
Me
OR
Maciej Walczak @ Wipf Group Page 1 of 13 4/28/2008
C20 - Diterpenoid Alkaloids
Me
RN
Me
RN
Me
NR
Me
N
Me
RN
Me
RN
C20 - diterpenoids
atisane class kaurane class
veatchinetype
napellinetypeatisine
typedanudatine
type
hetidine type
hetisinetype
Me
N
R4
R3
R2
R5
H
R6
R1
Nominine
R1, R2, R3, R4, R6 = H, R5 =OH
Kobusine
R1, R2, R4, R6 = H, R3, R5 = OH
Pseudokobusine
R1, R2, R4 = H, R3, R5, R6 = OH
Hetisine
R3, R5, R6 = H, R1, R2, R4 = OH
Wang, Liang The Alkaloids 2002, 59, 1
Maciej Walczak @ Wipf Group Page 2 of 13 4/28/2008
• A subclass of C20-diterpenoid alkaloids consisting of >100members.
• Isolated predominantly from Aconitum and Delphinium genera,but also Rumex, Consolidia, and Spirea.
• Pharmacological Activity:– vasodialating– antiarrhythmic– immunomodulatory– analgesic
Hetisine Alkaloids
Wang, Liang The Alkaloids 2002, 59, 1
Maciej Walczak @ Wipf Group Page 3 of 13 4/28/2008
Proposed Biosynthesis of Hetisine Alkaloids
Wang, Liang The Alkaloids 2002, 59, 1
MeMe
Me
Me
Me
OPP
MeMe
Me
Me
OPP
H
MeMe
Me
H
copalyldiphosphate
synthase
copalyl diphosphateCPP
atis-16-ene
geranylgeranyldiphosphate
(GGPP)
Me
NR
Me
NR
Me
N
atisine type
hetidine type
hetisinetype
Maciej Walczak @ Wipf Group Page 4 of 13 4/28/2008
N
CO2Et
O
Br
Oi-Pr
OMe
MeMgBr, 94%3:2
N
CO2Et
Br
Oi-Pr
OMe
OHN
CO2Et
Oi-Pr
MeOO
+
steps
N
Br OAc
OMe
OH
AcO
AgO2C(NO2)3C6H2, MeNO2,53 %
N
OAc
OMe
OH
AcO
Studies towards the Total Synthesis of Hetisine Alkaloids
Williams, Mander Org. Lett. 2003, 5, 3499Williams, Mander, Bernhardt, Willis
Tetrahedron 2005, 61, 3759
Maciej Walczak @ Wipf Group Page 5 of 13 4/28/2008
Studies towards the Total Synthesis of Hetisine Alkaloids
HO
O
O
OMe
1. TBSCl, ImH
2. p-TsOH, Me2CO, 49%
3. Li, NH3, t-BuOH,
NCCO2Me, -78 oC, 69%TBSO
OMe
OH
CO2Me
TBSOOMe
H
1. NaH, MOMCl, 95%2. Li, NH3, t-BuOH, 69%
TBSOOMe
H
NH
MeO2C
1. Li, NH3, t-BuOH, 95%2. CDCl3, HCl, 60%
1. DDQ, HCl, 70%2. FeCl3, TMSCl, 21%
CO2H
OMe6 steps
TBSOO
H
NH
MeO2C
TBSOO
HN
CO2Me
H
H
HO
6 steps
Hutt, Mander J. Org. Chem. 2007, 72, 1030
Maciej Walczak @ Wipf Group Page 6 of 13 4/28/2008
Total Synthesis of (±)-Nominine
Summary:40 steps, 0.15% overall yieldMuratake, Natsume Tetrahedron Lett. 2002, 43, 2913Muratake, Natsume Angew. Chem. Int Ed. 2004, 43, 4646
NC O
OMOMO
H
OAc
1. LDA, TMSCl2. LAH, THF3. CbzCl, Et3N , 63%4. NaBH3CN, HCl, 90%
N
OMOMO
H
OH
Cbz
steps
N
OMOMO
H
Cbz
AIBN, Bu3SnH, PhMe,SiO2, 57%
N
OMOMO
H
CbzN
HO
H
Cbz
OAc
N
MeH
OH
HH
1. Pd(OAc)2, Et3N, Et3SiH2. SOCl2, Py, 80%3. K2CO3, MeOH, 95%
steps
Br
MeO
I
13 steps
Maciej Walczak @ Wipf Group Page 7 of 13 4/28/2008
Model Studies
TMS
OH1. Swern ox.2. BnNH2
TMS
NBn
MeO OTMS
ZnCl2, CH2Cl2, 61%(overall)
BnN
O
TMS
BnN
ORROTf Z
NBn
ROR
R
R = H, CO2Me, SO2PhYields: 20-43 %
OTf
Me
NH2
OTf
Me
N
TMS
O
Me
N
TMS
O
CO2Me
Me
N+
TMS
OMe
CO2Me
TfO-
TMSCHO, ZnCl2Danishefsky's diene
55%, 1.2:1 dr (Ph3P)4Pd, LiCl, 87%
Bu3SnCO2Me
MeOTf- stable and unreactive towards intramolecular cycloaddition
- underwent intermolecular addition with DMAD
Maciej Walczak @ Wipf Group Page 8 of 13 4/28/2008
Model Studies - 3-Oxidopyridinium Betains
3-Oxidopyridinium betains, introduced by Katritzky, are stable and isolable 1,3-dipolesundergoing cycloaddition reactions at positions 2 and 6.
N+
OR
N+
O
OTf
Me
O
OClH3N
CN
Me
HN
OBr2, AcOH:H2O 1:1
65%
CN
Me
NO
PhMe, 170 oC,
5 d, 73%
NaBH4, MeOH, 99%
2. KCN, 18-crown-6 (Ph3P)4Pd, PhH, 75%
1.
CN
Me
N
OH
Maciej Walczak @ Wipf Group Page 9 of 13 4/28/2008
Model Studies - 3-Oxidopyridinium Betains
Me
NO
PhMe, reflux, 70%SO2Ph
N
O
Me
SO2Ph
H
Me
NO
PhMe, 120 oC, 67%SO2Ph
BnO
Me
NO
SO2Ph
BnOSO2Ph
N
Me OOBn
Me
NO N
O
MeH
NO2
NO2
H
H
PhMe, 170 oC (µW)
14% 81%
Maciej Walczak @ Wipf Group Page 10 of 13 4/28/2008
Intramolecular Cycloaddition
Due to lower Resonance Stabilization Energies (RSEs), 3-oxoisoquinolines are ideal partnersfor the cycloadditions reactions. Ground-state destabilization of the substrate may facilitateformation of the desired pentacycle.
N N
PhPh
AgMe
Me
Me
S
N N
PhPh
AgMe
Me
Me
S
O
OO
O
O
O
O
CO2Me
(CuOTf)2 PhH, Me2Zncat. then Tf2O, 88%, 84% ee
O
CO2MeMe
cat. =
CN
CN
OMe
O
MeO
OMeN3
OMe
O
MeO
MeOMe
HN
CN
Me
NOMe
O
CN
N
MeH
HO
OMe
CHOMe
PBu3, NaBH(OAc)3, 79%, 3:3:2:2 dr
TFA:CH2Cl293%
CN
N
MeH
H
OMeO180 oC, THF
A:B 1:3.6
AB
+
Maciej Walczak @ Wipf Group Page 11 of 13 4/28/2008
Completion of Synthesis
Completion of the synthesis involved adjustment of the oxidation state followed by Diels-Aldercyclization. Notably, the non-conjugate enone proved to be more stable thermodynamicisomer.
N
MeH
O
HH
CN
N
MeH
H
OMeO CN
N
MeH
H
OMe
1. NaBH4, EtOH, 23 oC
2. SOCl2, CH2Cl2, reflux
3. Bu3SnH, AIBN, PhH, reflux
68% (3 steps)
1. DIBAL-H, 85%2. Ph3P=CH2, 96%
N
MeH
H
OMe
Na, i-PrOH, THF, NH3 -78 oC
then HCl (aq), 97%
X-ray
1. Ph3P=CH2, 77%2. SeO2, t-BuO2H, CH2Cl2, 66%, 7:1 dr
N
MeH
H
O
9:1 MeOH/pyrrolidine,
60 oC, 78%
N
MeH
OH
H
H
H
X-ray
Maciej Walczak @ Wipf Group Page 12 of 13 4/28/2008
• Gin and Peese completed a total synthesis of (±)-nominine in 15 steps(longest linear sequence) and 6.1 % overall yield.
• Introduction of a chiral center via asymmetric conjugate addition allowed forcompletion of a synthesis of (+)-nominime in 16 steps and 1.3% overall yield.
• Convergent construction of the polycyclic core relied on a series ofcycloadditon (3+2 and 4+2) reactions demonstrating power of a well-plannedsynthesis.
Summary
N
MeH
OH
H
H
H
Maciej Walczak @ Wipf Group Page 13 of 13 4/28/2008