caldaphnidine o...(-)-caldaphnidine o. n h co. 2. me • 9 stereo centers • 3 quaternary centers....
TRANSCRIPT
(-)-Caldaphnidine O
Presented By: Dare E. George
NH
CO2Me
(-)-Caldaphnidine O
NH
CO2Me
• 9 Stereo centers
J. Am. Chem. Soc. 2019, 141, 13043−13048
(-)-Caldaphnidine O
NH
CO2Me
• 9 Stereo centers
• 3 Quaternary centers
J. Am. Chem. Soc. 2019, 141, 13043−13048
OTfOBn
NO
S S Ts
nBu3SnH, AIBNBarton-McCombie Deoxygenation NTs
H
OTf
OBn
H
1,5 HATand detosylation
OTfOBn
N
NaBH(OAc)3
90%
OTfOBn
HN
Key Inspiration: An unexpected detosylation by a Barton-McCombie deoxygenation
J. Am. Chem. Soc. 2019, 141, 13043−13048
HNR
H
N
OBn
BnO
H Biomimetic Diels-Alder /
Aza-Prins Cascade
R = CH2OBn
OBn
NH
O
O
Bukittinggine
NH
CO2Me
NHO
CO2Me
Caldaphnidine O Caldaphnidine P
Previously Synthesized Bikittinggine-Type Alkaloid
HNR
H
N
OBn
BnO
H Biomimetic Diels-Alder /
Aza-Prins Cascade
R = CH2OBn
OBn
NH
O
O
Bukittinggine
J. Am. Chem. Soc. 2019, 141, 13043−13048
Retrosynthesis
NH
CO2Me
Radical cyclizationcascade
N
CO2Me
H
Sm(II)/Fe(III)-mediatedKagan-Molander Coupling
OIBnO
NTs
IMAM & Ring expansion
OBnO
NH
TsO
O
O
Readily available chiral starting material
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisO
BnO
NH
TsO
OBnO
NH
TsO
BnO CHO
O O
333 mmol
(2 equiv)
DCM, 0 °C
Hantzsch ester (1 equiv)
NH
O
OH
L-proline (0.1 equiv)O OH
OBn
DCM, r.t, 14 hr82%
Hantzsch ester
O
O
NH
O
O
O OH
OBn
+O
250 mmol2 equiv
Et3N (0.1 equiv)
r.t, 24 hr DCM, 0 °C to r.t, 12 hr
NH
O
NH2
L-Prolinamide (1.0 equiv)
AcOH (1.0 equiv)
O
OOBn
J. Am. Chem. Soc. 2019, 141, 11713−11720
SynthesisO
BnO
NH
TsO
OBnO
NH
TsO
O
OOBn
201 mmol
+OMeMeO
OMe
1.5 equivTHF, r.t, 70 mins
p-TsOH H2O (0.2 equiv)
HN
PMB(2 equiv)
CH2O (4.0 equiv)
THF, r.t, 168 hr88%
O
OOBn
NPMB
PMB = p-methoxybenzyl
O
OOBn
NPMB
+ N
O
N
OO1,3-Dimethylbarbituric acid
2.2 equiv100 mmoldr = 3:1
DCM/THF (5:1), r.t, 4 hrPd(PPh3)4
(0.05 equiv)NaHCO3
(500 mL)
TsCl (2.0 equiv)
DCM/THF (5:1), r.t, 14 hr O
OOBn
NPMB
Ts82%, dr > 6:1
O
OOBn
NPMB
Ts
O
OOBn
NPMB
Ts
DCM, r.t, 3 hr
DBU (0.20 equiv)
1.00 mmol
95%, dr > 50:1
J. Am. Chem. Soc. 2019, 141, 11713−11720
SynthesisO
BnO
NH
TsO
OBnO
NH
TsO
O
OOBn
NPMB
Ts
LiBr + Ni(acac)210 equiv 0.1 equiv Et2O, 0 °C, 30 min
ZnMe2 (in toluene)
(5.0 equiv) (20.0 mmol, dr > 6:1)
THF, added over 30 minr.t, 40 hr
O
OOBn
NPMB
Ts
O
OOBn
NPMB
Ts
25.1 mmol
THF, -78 °C to -50 °C, 1h
SiN-Si
Li+
LHMDS (1.05 equiv)
THF, -78 °C, 1h
Cl
NS
(1.5 equiv)
O
OOBn
NPMB
Ts75%
J. Am. Chem. Soc. 2019, 141, 11713−11720
SynthesisO
BnO
NH
TsO
OBnO
NH
TsO
O
OOBn
NTs
PMB
CH3CN/H2O, 0 °C to r.t, 5h
CAN (4.0 equiv)
1.00 mmol
79%O
OOBn
NHTs
By Leyo - Own work based on: doi:10.1021/ic50062a020, Public Domain, https://commons.wikimedia.org/w/index.php?curid=18639807
NH4
NH4
CAN = Ceric ammonium nitrateJ. Am. Chem. Soc. 2019, 141, 11713−11720
Retrosynthesis
NH
CO2Me
Radical cyclizationcascade
N
CO2Me
H
Sm(II)/Fe(III)-mediatedKagan-Molander Coupling
OIBnO
NTs
IMAM & Ring expansion
OBnO
NH
TsO
O
O
Readily available chiral starting material
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
O
OOBn
NHTs
+ PhNTf2
8 mmol1.0 equiv
THF, r.t, 1.5 hr
KHMDS (1.1 equiv)
NSiSi
K
THF,-78 °C, 1.5 hr
KHMDS (1.5 equiv)
NSiSi
K
THF,-78 °C, 1 hr
Davis oxaziridine(3 equiv)
TfO
OOBn
NTs
68%
OHON
SO
O
Davis oxaziridine
TfO
OOBn
NTs
Pd(OAc)2 (0.1 equiv)
PPh3 (0.2 equiv)
DIPEA (6.0 equiv)HCOOH (4.0 equiv)
DMF, 60 °C, 1 hr
OOBn
NTs
OHOH
88%
6.57 mmolJ. Am. Chem. Soc. 2019, 141, 13043−13048
Mechanism of Davis OxidationNH
CO2Me
NH
CO2Me
TfO
OOBn
NTs
ON
SO
O
BH
TfO
OOBn
NTs
TfO
OOBn
NTs
O Ph
NSO2Ph
TfO
OOBn
NTs
O
Ph
NSO2Ph
H+
TfO
OOBn
NTs
OH
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
OOBn
NTs
OH
CeCl3 THF, 0 °C, 1.5 hr
MgBr
6 equiv
6 equiv (5.0 mmol)
THF, 0 °C, 1.5 hr
OBn
NTs
OHOH
O
OBn
NTs
Pb(OAc)4
crude
DCM, r.t, 1 hr DCM, r.t, 1 hrNaHCO3 Residue
THF/MeOHNaBH4
OH
OBn
NTs
OHOH
75% (3 steps)
J. Am. Chem. Soc. 2019, 141, 13043−13048
Mechanism of Criegee oxidationNH
CO2Me
NH
CO2Me
R2
HO
R1
OH+ Pb(OAc)4
- 2 OAcR2
O
R1
OPb
OAcAcO
R1
O
R2
O+
O
OBn
NTs
Pb(OAc)4
crude
DCM, r.t, 1 hr DCM, r.t, 1 hrNaHCO3 Residue
THF/MeOHNaBH4
OH
OBn
NTs
OHOH
75% (3 steps)
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
O
OBn
NTs
OH
2.50 mmol
PPh3 (1.5 equiv)
NHN
(3.0 equiv)I2
(1.5 equivalent)O
OBn
NTs
I
93%THF, r.t, 1 hr
24%THF, r.t, 1 hr
NLi
(1.8 equiv)
OBn
NTs
O
OBn
NTs
O
45% (2 steps)
22% (2 steps)
** Not Isolated
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
OBn
NTs
O
1.0 mmol
BH
9-BBN (1.5 equiv)
THF, 0 °C, 5 hr THF, 0 °C to r.t, 0.5 hr
NaOMe (4.5 equiv)I2(s) (4.5 equiv)
OBn
NTs
O I
** Not Isolated
SmI2 + Fe(dbm)36.0 equiv 0.06 equiv THF, -78 °C to r.t, 17 hr
OBn
NTs
O I
** Not Isolated
OBn
NTs
OH
OBn
NTs
O
BH
9-BBN (1.5 equiv)
THF, 0 °C, 5 hr THF, 0 °C to r.t, 0.5 hr
NaOMe (4.5 equiv)I2(s) (4.5 equiv)
OBn
NTs
O I
** Not Isolated
SmI2 + Fe(dbm)36.0 equiv 0.06 equiv THF, -78 °C to r.t, 17 hr
OBn
NTs
O I
** Not Isolated
OBn
NTs
OH
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
OBn
NTs
OH
1.40 mmol
OBn
NTs
OH
1.44 mmol
SOCl2 (10.0 equiv)
Py, 0 °C to r.t, 1 hr55%
Burgess reagent (3.0 equiv)
CH3CN, 70 °C, 1.5 hr
60%
OBn
NTs
O OO
NS
NO
Burgess reagent
J. Am. Chem. Soc. 2019, 141, 13043−13048
Dehydration of alcohols using Burgress Reagent (20 and 3o Alcohols)N
H
CO2Me
NH
CO2Me
J. Indian Inst. Sci. 2013, 81(4), 461
O OO
NS
NO
OHR
R
OR
R
SO
N
O
O
OH
R
R
O OO
NS
NO
Burgess reagent
SynthesisNH
CO2Me
NH
CO2Me
20.0 mmol
Na(s)DME, r.t, 1 hr
sodium naphthalenide (Na-Naph.)
OBn
NTs
Na-Naph.
0.840 mmol
DME, -78 °C, 10min; r.t, 20 min,
EtOH, -78 °C to r.t
Br
(15 equiv)
N
OH
H66%
N
OH
H
The solution
PhMe, 90 °C, 1 hr
p-TsOH H2O (6 equiv)
DCM, r,t, 30 min N
OH
68%
nBu3SnH + NN
N
NAIBN
PhMe, 90 °C, 0.5 hrA solution
J. Am. Chem. Soc. 2019, 141, 13043−13048
SynthesisNH
CO2Me
NH
CO2Me
N
OH
ClCl
O
O
10 equiv
DCM, -78 °C, 1 hr
DMSO (20 equiv) 0.10 mmol
DCM, -78 °C, 1 hrEt3N (40 equiv)
DCM, -78 °C, 1.5 hr N
O
S S
PO OEt
OEt THF, -78 °C, 1 hr
4.4 equiv
n-BuLi (4.0 equiv)N
O
THF, -78 °C to 0 °C, 1.3 hr
p-TsOH H2O (6 equiv)
THF, r.t, 40 min
THF, r.t, 1 hr
NaOMe (100 equiv), MeOH
N
CO2Me
70% (2 steps)
H2, Pt/C (0.05 equiv)
MeOH, 12 hr70%
N
CO2Me
(-)-Caldaphnidine OJ. Am. Chem. Soc. 2019, 141, 13043−13048
