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Collective Synthesis of Natural Products by Means of
Organocascade Catalysis
Spencer B. Jones, Bryon Simmons, Anthony Mastracchio, David W. C. MacMillan Nature 2011, 475, 183
Nate Ware, Wipf Group Current Literature 08/06/11
Nate Ware @ Wipf Group Page 1 of 15 8/7/2011
Organocascade Catalysis• Follows the “blueprints of biosynthesis”
– cascade reaction sequences – avoidance of protecting groups – molecular complexity is built quickly and efficiently using simple key building
blocks
C. Grondal, M. Jeanty, D. Enders Nature Chem. 2010, 2, 167 D. Enders, C. Grondal, M. Huttl, ACIE, 2007, 46, 1570
Nate Ware @ Wipf Group Page 2 of 15 8/7/2011
Imine/Enamine Tandem Cascade
Y. Yoshitomi, H. Arai, K. Makino, Y. Hamada Tetrahedron 2008, 64, 11568
MeO2C CHO
NHTs
OBocHN
NH
Ph
OTES
Ph
MeCN, -20 ºC, 1 dayquant, 99% ee
NHBoc
N
Ph
OTES
Ph
MeO2C CHO
NHTs
NHBoc
N
Ph
OTES
Ph
MeO2C
NTs
O
IM EN
NTs
CHO
NHBoc
MeO2C
Formal Synthesisof
Martinelline
10 steps
NTs
NH2
MeO2C
HN3 HCl
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Coupled Imine/Enamine Organocascade
B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su, J.-H. Liao JOC, 2007, 72, 8459
O
N
O
O
H
N
AcO
AcO
O
O
AcO
N
O
O
H
NAcO
OO
AcO AcO
AcO
N
HO2C
N
O2C
AcO
AcO
CHO
70%, 95% ee
NH
CO2H
MeCN,-20 ºC, 8 h
IM IMEN EN
(+)-Palitantin
9 steps
OAc
O
HO
OH
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Bronsted-Acid Catalysed Cascade
M. Rueping; A.P. Antonchick; T. Theissmann, ACIE, 2006, 45, 3683
N
O
OP
OH
O
Ar
Ar
Ar = 9-phenanthryl
Benzene, rt, 12 h88%, 90% ee
NH
EtO2C CO2Et NH
1. HCHO, AcOH
2. NaBH479%
N
N C5H11N C5H11
H
N
EtO2C CO2Et
P
O
ArO
OAr
OH
H
P
O
ArO
OAr
ON
EtO2C CO2Et
NH
C5H11
NH
EtO2C CO2Et
P
O
ArO
OAr
OH
NH
C5H11
N
EtO2C CO2Et
H
P
O
ArO
OAr
O
N
EtO2C CO2Et
NH
EtO2C CO2Et
NH
C5H11
P
O
ArOOAr
OP
O
ArOOAr
O
(-)-Angustureine
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Biosynthetic Intermediates to Title Paper Targets
S.B. Jones; B. Simmons; A. Mastracchio; D.W.C. MacMillan, Nature, 2011, 475, 183
NH
NH2
OMeO2C
OGluc
CHO
N
N
H
MeO2C
OH
Preakuammicine
Tryptamine Secologanin
NH
N
H
Norfluorocurarine
CHO
NH
CO2Me
N
Et
Didehydrosecodine
N
N
OO
H
H
H
Strychnine(Strychnos)
H NH
N
CO2Me
Vincadifformine(Aspidosperma or Kopsia)
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Natural Products Derived from a Common Intermediate
S.B. Jones; B. Simmons; A. Mastracchio; D.W.C. MacMillan, Nature, 2011, 475, 183
N
N
OO
H
H
H
NH
N
H
NH
N
CO2Me
NH
N
CO2Me
NH
N
CO2MeNH
NO
NP
X
NHBoc
NP
NBoc
CHO
(-)-strychnine (+)-aspidospermidine
(-)-kopsinine
(-)-akuammicine
(+)-vincadifformine
(-)-kopsanone
H
Organocascade
Nate Ware @ Wipf Group Page 7 of 15 8/7/2011
Mechanism of Organocascade cycles
N
N
O Me
t-Bu
NPg
NBoc
CHO
N
NH
OMe
t-Bu
• HA
NPg
N XBoc
NPg
N XBoc
A
NPg
NH
XBoc
A
N
NH
OMe
t-Bu
• HA
NPg
NH
OBoc
ANPg
OR1N
R1 = Boc
NPg
NR2R1N
R1 = Boc
A
NPg
NH NR2
Boc
A
ANPg
NH NR2
Boc
A
SeMe
NPg
SeMe
NHBoc
A
1-Nap
1-Nap 1-Nap
endo[4+2]
NPg
SeMe
NHBoc
O
X =
Path B
X = OH
Path A
N
N
OMe
t-Bu
1-Nap
Cycle 1 Cycle 2
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Synthesis Towards Strychnine and Akuammicine
NH
NBoc
NPMB
CHO
1. PMB-Cl, NaH, DMF
2. SeO2, dioxane, H2O, 100 ºC
NHBoc
(EtO)2P
O
SeMe
18-c-6, KHMDS,THF, -78 ºC to rt
63% (3 steps)
NPMB
NHBoc
N
NH
OMe
1-Napt-Bu
• TBA
-40 ºC to rt, PhMe82%, 97% ee
O
H
N
NBoc
CHO
PMB
N
NH
PMB CO2MeH
N
NBoc
PMB CO2Me
1. Wilkinson's Catalyst, PhCN, PhMe, 120 ºC
2. COCl2, Et3N, PhMe, -45 ºC to rtthen MeOH, -30 ºC to rt
DIBAL-H,DCM, -78 ºC to rt
thenTFA, -78 ºC to rt61% (3 steps)
overall commonintermidiate
SeMe
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Completion of (-)-Strychnine
DBU, K2CO3, DMF
Br
I
OAc
2. DIBAL-H, DCMDCM, -78 ºC76% (2 steps)
1.
N
N
PMBH
OH
IOH
N
N
PMBH
OHO
H
H
NH
N
H
OHO
H
HN
N
OO
H
H
H
H
Pd(OAc)2 (25 mol%)
Bu4NCl, NaHCO3, EtOAc58%
PhSH,
TFA, 45 ºC66%
Wieland-Gumlichaldehyde
NaOAc, Ac2O, AcOH,
malonic acid, 120 ºC69%
(-)-strychnine
12 steps, 6.4% overall yield
N
NH
PMB CO2MeH
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Completion of (-)-Akuammicine
N
NH
PMB CO2MeH
PhSH,
TFA, 60 ºC91%
NH
NH
CO2MeH N
H
N
CO2MeH
I
NH
N
H
Pd(OAc)2 (25 mol%), Bu4NCl,
NaHCO3, MeCN, 65 ºC47%
CO2Me
DBU, K2CO3, DMF76%
Br
I
(-)-akuammicine
10 steps, 10% overall yield
Nate Ware @ Wipf Group Page 11 of 15 8/7/2011
Synthesis of (+)-Aspidospermidine and (+)-Vincadifformine
NH
NBoc
NCHO
1. BnBr, NaH, DMF
2. SeO2, dioxane, H2O, 100 ºC
NHBoc
(EtO)2P
O
SeMe
18-c-6, KHMDS,THF, -78 ºC to rt
61% (3 steps)
N
NHBoc
N
NH
OMe
1-Napt-Bu
• TBA
-40 ºC to rt, PhMe83%, 97% ee
O
H
N
NBoc
CHO
Bn
N
N
Bn
1. Ph3PCH3I, n-BuLi, THF, 0 ºCthen AcOH, NaCNBH3, 0 ºC
2. TFA, DCM
K2CO3, DMF73% (3 steps)
ent- overall commonintermidiate
SeMe
BnBn
H3. IBr
I
N
N
BnH N
H
N
H
NH
N
CO2Me
Pd(PPh3)4, Et3N,
PhMe, 80 ºC65%
Pd(OH)2, H2 (200 psi)
MeOH, EtOAc98%
1. (COCl)2, DMSO,DCM 65%
2. NCCO2Me, n-BuLi, THF, -78 ºC to rt
57%
(+)-aspidospermidine
9 steps, 24% overall yield
(+)-vincadifformine
11 steps, 8.9% overall yield
Nate Ware @ Wipf Group Page 12 of 15 8/7/2011
Synthesis of (-)-Kopsinine and (-)-Kopsanone
R
N
NBocCHO
Bnoverall common
intermidiate
N
N
Bn N
N
Bn CO2Me
N
N
Bn CO2MeR = SO2Ph
NH
N
CO2Me
NH
NO
(-)-kopsanone
11 steps, 10% overall yield
NH
N
CO2H
HB:
H
NH
HN
HO O
200 ºC
neat
1 N HCl
130 ºC
74%
2 steps
Raney Ni,
EtOH, 78 ºC83%
(-)-kopsinine
9 steps, 14% overall yield
TMS-I, Et3N, DCM, 0 ºC
then MeOH, 40 ºC
then KOt-Bu, DCM, THF 0 ºC58%
PPh3Br
1. COCl2, Et3N, PhMethen MeOH
2. H2, Pd/C, EtOAc, EtOH69% (2 steps)
PhH, 100 ºC86%
SO2Ph
Nate Ware @ Wipf Group Page 13 of 15 8/7/2011
Title Paper Syntheses vs. Previous Syntheses
N
N
OO
H
H
H
NH
N
H
NH
N
CO2MeNH
N
CO2Me
NH
N
CO2Me
NH
NO
(-)-strychnine
(+)-aspidospermidine
(-)-kopsinine(-)-akuammicine
(+)-vincadifformine
(-)-kopsanone
H
9 (24) 13 (NA1) 11 (1.7)
12 (6.4) 25 (3) 16 (0.15)
9 (14) NA 19 (2.6)10 (10) NA NA
11 (8.9) NA 10 (8.5)
11 (10) NA NA
Title Paper# steps
(overall yield)
PSAC(overall yield)
PSCA(overall yield)
Title Paper# steps
(overall yield)
PSAC(overall yield)
PSCA (overall yield)
PSAC = Previous Shortest Asymetric Catalytic SynthesisPSCA = Previous Shortest Chiral Auxiliary or Chiral Pool Synthesis
1 - unreported yields for some steps of the sequence
Nate Ware @ Wipf Group Page 14 of 15 8/7/2011
Summary
• An organo-catalyzed cascade was used to construct an advanced intermediate in the synthesis of a set of complex natural products.
• Six natural products were efficiently constructed enantioselectively from that advanced intermediate.
• All six syntheses represent some of the shortest routes to the respective targets.
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