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Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)-Myrioneurinol Anthony J. Nocket and Steven M. Weinreb Angew. Chem. Int. Ed. 2014, 53, 1 – 5 �
Ruiting Liu Wipf Group Current Literature
11/08/2014 �
N
O
OHH
H
HHN O
OHHH
Ruiting Liu @ Wipf Group Page 1 of 13 12/6/2014
The Myrioneuron alkaloid �1 �
Ø Isolated from southeast asian plant Myrioneuron nutans, Schoberine, Mytioxazine A, Mytioxazine B have been synthesized by Bernard Bodo
N O
OHHH
Myrioneurinol
N N N ON
O
NO
NHO
HNN
O
Schoberine Mytioxazine A Mytioxazine B
Myrobotinol Myrionine
The Myrioneuron alkaloid
Ruiting Liu @ Wipf Group Page 2 of 13 12/6/2014
Myrioneurinol �2 �
Ø New member of the Myrioneuron alkaloid,
isolated from leaves of Myrioneuron nutans Ø significant antimalarial activity against
Plasmodium falciparum (IC50: 11 mg/mL) Ø Four tightly fused, rigid array of chair six-
membered rings
Tetrahedron 63 (2007) 11244–11249 Tetrahedron Letters 43 (2002) 7565–7568 J. Org. Chem. 2008, 73, 7565–7573
N O
OHHH
Myrioneurinol
Ruiting Liu @ Wipf Group Page 3 of 13 12/6/2014
Biosynthesis �3 �
Nat. Prod. Rep., 2010, 27, 32–56 �
Plausible biosynthetic pathway to myrioneurinol
N
O
NH
HN N
O
-H2Oreduction
N
N
N N
1. H2O2. oxidative deamination
N
OMannich
HN
O
OO
Lysine derived key intermediate
reduction
HCHO
cyclizationN O
OHHH
reduction
Ruiting Liu @ Wipf Group Page 4 of 13 12/6/2014
Retrosynthesis �4 �
NH
H OMOM
OMOM
Intramolecular Sulfonyliminium
Aza-Sakurai Reaction
N
HO N
OH
HBn
CO2MeCO2Me
Conjugate Addition to Nitrosoalkene
NO
Cbz
CO2Me
NH
O
Micheal Addition
N
O
OHH
H
HHN O
OHHH
a
bcd
75
9106
Ruiting Liu @ Wipf Group Page 5 of 13 12/6/2014
a/d Ring – Michael addition �5 �
NH
O
n-BuLi (2 equiv.)THF, 0°C
Br NH
O
n-BuLiTHF, -78 °C
CbzCl
89%2 steps
N O
O3, CH2Cl2-78 °C, PPh3-78 °C to rt
90%
N OCHO
(EtO)2POCH2CO2MeLiCl, DBU, MeCN, rt
82%
Cbz
CbzN
OCbz
CO2Me TiCl4NEt3
CH2Cl20 °C to rt, 86%
NO
Cbz
OMeO
Ti ClCl Cl
NO
Cbz
CO2MeH
NO
Cbz
CO2MeH
Alkylation
J. Org. Chem. 1991, 56, 5750 Tetrahedron Lett. 1989, 30, 6511
Ruiting Liu @ Wipf Group Page 6 of 13 12/6/2014
C7-Pains and gains �6 �
NO
Cbz
CO2MeH 1) H2, Pd/C, rt
EtOAc, 98%
2) BnBr, rt, Ag2O, TBAI CaSO4, 73%
NO
Bn
CO2MeH
Me(OMe)NH2Cl
Me2AlClCH2Cl2
0°C to rt, 90%
NO
Bn
H O
NOMe
Me
NO
Bn
HLiAlH4, THF- 40 °C
91%
CHO
PyrolidineCHCl3, 0°C
4 A M.S.
100% NO
Bn
HN
1) NCS, 65 °C Et2O.CHCl3
2) HOAc/H2O 82%
NO
Bn
HCHO
Cl
NO
Bn
HN
OTBSTBSONH2PPTS
CH2Cl2, rt85% LiHMDS, THF
-78 ° Cthen TBAF, 0 °C
93%
CO2MeCO2Me
N
HO
NOBn
Micheal addition
Cl
Ruiting Liu @ Wipf Group Page 7 of 13 12/6/2014
Conjugate Addition to a Nitrosoalkene �
N
HO N
OH
HBn
CO2MeCO2Me
TiCl4, Zn0THF, 0° C
63%N
HCHOO
HBn
CO2MeCO2Me
NaBH4MeOH0 °C81%
N
HO
HBn
OO
CO2Me
LiClDMSO/H2O155 - 160 °C
90% N
HO
HBn
OO Me(OMe)NH2Cl
Me2AlCl
N
HO
HBn
OR
ON OMeMe
CH2Cl20 °C to rt
LiAlH4THF, -40 °C
N
HO
HBn
OMOM
CHO
Tetrahedron Lett. 2010, 51, 2032 Org. Lett. 2011, 13, 1258.
7 �
Ruiting Liu @ Wipf Group Page 8 of 13 12/6/2014
Sulfonyliminium Sakurai Reaction �
N
HO
HBn
OMOM
CHO
Me3Si PPh3
I
PhLi, THF, rt
74% (2 steps) N
HO
HBn
OMOM
SiMe3
Na/NH3 Et2O-78°C
N
HO
HR
OMOM
SiMe3
R=H (79%)
R=Ts (87%)
LHMDSTsCl, THF
DMAP
DIBALHCH2Cl2-78 °C
then FeCl3 warm to 5 ° C
N
HOH
HTs
OMOM
SiMe3
N
H
HTs
OMOM
SiMe3
J. Organomet. Chem. 1979, 181, 293. J. Org. Chem. 2006, 71, 2078
8 �
Ruiting Liu @ Wipf Group Page 9 of 13 12/6/2014
N
H OMOM78%
29 R=H (92%, 2 steps)
30 R=MOM (80%)
MOMClDIEA
THF, 0°C
1) O3, CH2Cl2 -78 °C, PPh3
2) NaBH4 MeOH, 0 °C
N
H OMOM
OR
Li/NH3 Et2O-78°C
81%Ts Ts
NH
H OMOM
OMOM N O
OHHH
6N HClTHF/H2O
50 °C75%
9 �
Ruiting Liu @ Wipf Group Page 10 of 13 12/6/2014
Conclusion �
10 �
Ø Fisrt total synthesis (±)-Myrioneurinol Ø 28 steps, 1.8% yield Ø Three highly diastereoselective reactions to install the
correct configuration at the C5/C6, C7, C9/C10 configuration �
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11 �
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12 �
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