Retrosynthe*cAnalysis
A11-StepTotalSynthesisofMagellaninethroughaGold(I)-CatalyzedDehydroDiels-AlderReac*on
PhilippeMcGee,GenevièveBétournay,FrancisBarabé,andLouisBarriault*
N
O
OHHAB C
D
(+/-)Magellanine (7)
Ka#eBoknevitzProfessorS.-Y.Liu
02/23/2017
Angew.Chem.Int.Ed.2017,56,Earlyview.
• Alkaloidisolatedfromtheclubmoss,LycopodiumMagellanicum
• Tetracyclicangularcarbonframework• Sixcon*nguousstereogeniccenters• Applica*onofGold-catalyzedDDAreac*on
1
N
O
OHHAB C
D
NTsA
B
TIPSO
E EE
E
E = CO2Et
NTs
O
HO NH
Ts
(+/-)Magellanine (7)15
17
161918
Au(I)-DDA 1,4-addition
Mitsunobu/Diels-Alder
oxidation/aldol
2
ForwardSynthesisOverview
NH
Ts
HO
NH
H
TsN OTs
a) TMAD, TBP
then 150 °C70 %
b) OsO4, NMO, NaIO4
c) Piperidine, HOAc, MePh58% over 2 steps
d) TIPSOTf, DMS then
LiHMDS, THF, –78 °C81%
EE
NTs
TIPSO
E E
E = CO2Et
N
TIPSO
Ts H EE
e) [L6AuNCMe][SbF6](1 mol%)then CSA91%
f) TBAF, 60 °Cthen LiOH, 140 °C
92%
g) DMP, CH2Cl287%NTs H
O
CO2H
h) PtO2, H2,
EtOAc84%NTs H
O
CO2H
i) iPrC(O)Cl, NMM,Et3N, Toluene, 0 °C
N
S
OH
S
NTs H
O
OO
NS
S
LED (365nm), O2
CH3(CH2)8C(CH3)2SHthen PPh3
26% (27) + 29% (28)NTs H
O
YX
27 X=H, Y=OH28 X=OH, Y=H
N H
O
OH
k) Na, C10H8,THF
then HOAc, CH2O,NaBH3CN
74%N H
O
OH
l) LDA, TMSCl
then LDA,
64%N
StBuCl
Ph
j) DIAD, HCO3H, Ph3Pthen LiOH, 59%
NTs
18
19
20
21 16
2324
25
26 29 30
1715
22
(+/-)Magellanine (7)
ForwardSynthesisMechanisms
3
E
E Br
Pd(PPh3)4 (2 mol%)
CuI (4 mol%), DIPEATHF
EE
Pd0R–X
R–PdII–X
CuX
R'H
R'Cu
R–PdII R'
NH(iPr)2(Et)XN(iPr)2(Et)
R'RSynthesis of 17: Sonogashira Coupling
17E = CO2Et
OA
TM
RE
O
Oethyl sorbate
1) LDA, THF, HMPA
2) LiAlH4
OH
18
O
O
H
NLi
O
O
PONN
N
HMPA
H+
O
O
1)
2) H–OH
18
Determines selectivity of enolate formation
Synthesis of 18: Isomerization/Reduction
O
OHtautomerization
NH
Ts
HO
NH
H
Ts
a) TMAD, TBP
then 150 °C70 %
1:1.6 mixture ofdiastereomers
b) OsO4, NMO, NaIO4
18
19
21
N OTs
16
c) Piperidine, HOAc, MePh
58% over 2 stepsN
H
H
Ts
21aO
O
TMAD: TetramethylazodicarboxamideTBP: Tributylphosphine
NNO
NO
N
18 to 21: Mitsunobu/Diels-Alder
NNO
NO
NPR3
R3P
ROH H
NNO
NO
NPR3
RO
ROPR3
18
NH
Ts
NTs
20–H+
NH
H
Ts
21
4
21 to 21a: Lemieux-Johnson protocol
OsO
O
O
O
R
R
R
R
O OsO
OO
OsO
OH
O
HO
N
O
O
N
O+ H2O
2 H2O
R
R
OHOH
NaIO4R
R
O IO
HO OOHO
Na
2x PT
NH
H
Ts
21a OO
NaIO3H2O
21a to 22: Aldol Condensation
PT N OTs
16
R
R
21aO
OH
R
R
O
OHHN
– H2O R
R
O
N
R
R
OH
NR
ROH
N
H – H2O
R
R
N + H2O
– amine
5
R
TIPSO
E ER
[Au]+
R
TIPSO
E ER
[Au]
R
R
TIPSO
E E
[Au]
R
R
TIPSO
H E E
[Au]
HH
R
R
TIPSO
H E E
[Au]
N
TIPSO
Ts H E E
22
15
15 to 22: Gold-catalyzed Dehydro-Diels Alder
R
R
TIPSO
E E
[Au]
H
MeO PAr Ar
OMe
iPr
iPriPr
JackiePhos (L6)
*Diastereoselec#vetransforma#on(>95:5)
N OTs d) TIPSOTf, DMS then
LiHMDS, THF, –78 °C81%
EE
NTs
TIPSO
E E
E = CO2Et
1617 15
N
TIPSO
Ts H E E
22
e) [L6AuNCMe][SbF6](1 mol%)
then CSA91%
O
16
R
R
SiOTf
S
OR
RS
TIPS
EE
EE
17
H
NTs
TIPSO
E E
15LiHMDS
16 to 15: 1,4-addition
N
TIPSO
Ts H E E
f) TBAF, 60 °C
then LiOH, 140 °C92% NTs H
O
CO2H
h) PtO2, H2,
EtOAc84% NTs H
O
CO2H23 2422
g) DMP, CH2Cl2
87%NTs H
HO
CO2H22a
OR
RSi
N 4F
22
OR
R= O
RO
OEtOOEt
+ 2 LiOHO
RO
OOO
∆
– CO2NTs H
O
OO
NTs H
O
CO2 NTs H
O
CO2NTs H
HO
CO2H22a
2 H+
– 2 EtOH
22 to 22a: One-pot desilylation/saponification/decarboxylation
HOR
R
22a
OI
O
OAcOAc
AcO
OI
O
OAcO
AcO
RR
H
– H+
OAc
– HOAc– AcO– NTs H
O
CO2H23
22a to 23: Dess-Martin oxidation
6
NTs H
O
CO2H24
i) iPrC(O)Cl, NMM,Et3N, Toluene, 0 °C
N
S
OH
S
25
NTs H
O
OO
NS
S
26
LED (365nm), O2
CH3(CH2)8C(CH3)2SHthen PPh3
26% (27) + 29% (28)NTs H
O
YX
27 X=H, Y=OH28 X=OH, Y=H
j) DIAD, HCO3H, Ph3Pthen LiOH, 59%
HO
RR
R
i-PrO N NO
Oi-Pr
ODIAD
PPh3
i-PrO N NO
Oi-Pr
O
PPh3
HO OH
O
i-PrO NH
NO
Oi-Pr
O
PPh3
HO O
O
27
i-PrO NH
HN
OOi-Pr
O
O
RR
R
PPh3 OH NTs H
O
OH
28
27 to 28: Mitsunobu reaction
7
R
RR
OOH
Cl
OR
RR
OO
O24
HO
N
O
N HCl
R
RR
OO
O
N
S
HO
S
OO
NS
S
26
RR
R
HO
O
C9H19 S
R
S
OO
RR
R– CO2
RR
R
O O
RR
R O O
H
RR
R O OH
R
S
PPh3
RR
R O
O PPh3
HNTs H
O
YX
27 X=H, Y=OH28 X=OH, Y=H
O=PPh3
24 to 27/28: Radical oxidative decarboxylation
PT
NTs H
O
N H
O
OH
k) Na, C10H8,THF
then HOAc, CH2O,NaBH3CN
74%N H
O
OH
l) LDA, TMSCl
then LDA,
64%N StBu Cl
Ph
29 (+/-)Magellanine (7)28
OH
NS
RR
O
ONa2
N
RR
SO2Na
O
O HO
HH
O
HH
H
N
RR
OH
H
N
RR
OH2 H2O
N
RR
H BH2CNNa
N H
O
OH
29
28 to 29: One-pot detosylation/reductive amination
N H
O
OH
29
NLi
H
N H
O
OH
SiCl
N H
O
OH
Si
NS tBuCl
Ph
N H
O
OH
SN
Ph
tBuCl H
NLi
N H
O
OH
(+/-)Magellanine (7)
29 to 7: Oxidation
8Conclusion:Finaltargetachievedin11stepsfromknowncompounds.