total synthesis of the reserpine
TRANSCRIPT
Total Synthesis of the Reserpine
Valentin Soulard - Group RenaudNovember, 19 2015
Journal Club
R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, R. W. Kierstead, J. Am. Chem. Soc. 1956, 78, 2023–2025.R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, R. W. Kierstead, Tetrahedron 1958, 2, 1–57.
NH
OOMe
MeO2CH
NH
MeO
O
OMeOMe
OMe
H
Robert Burns Woodward
2
Born in 1917 - Boston, Massachusetts, USA
Attracted to chemistry at a very early age
1934 : Excluded from the MIT for negligence of his formal study
1936 : Bachelor degreee – MIT
1937 : PhD (James Flack Norris and Avery Adrian Morton) – MIT
1938 : Post-doctoral Fellow (Harvard) and then remained at Havard for the rest of his life
Died in 1979 (Heart Attack)
http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1965/woodward-bio.html
3
Woodward’s Era
> Work on the elucidation of the structure of natural products by UV spectroscopy
> Before his quinine synthesis, organic synthesis was still largely a matter of trial and error, and nobodythought that such complex structures could actually be constructed
> Main Area of research was the total synthesis of natural product.
4
Woodward’s Era
HOH
H
H
H
Cholesterol
N
OMeN
HOH
Quinine
NH
OOMe
MeO2CH
NH
MeO
O
OMeOMe
OMe
H
Reserpine
Nobel Prize in Chemistry in 1965Woodward-Hoffman rules
N
N
N
NCo+
ONH2
OH2N
OH2N
H2N
O
H
O NH2NH
O
OP O
HOO
O
NH2R
OHO
OH
N
N
R = -CN
Vitamin B12
And the strychnine, lysergic acid, cephalosporin, colchicine ….
N
N
N
N
OO
OHO
Mg
Chlorophyll
O
O
H
H
OH
H
O OH
Cortisone
5
(-)-Reserpine
NH
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
H
F
(-)-Reserpine
> First isolated in 1952 by Schlittler et al. from Rauwolfia serpentina
> The absolute configuration was found in 1955
> Use as a treatment of hypertensive nervous and mental disorder
> In the class of yohimbine (alkaloid)
> Epimerization possible at C3
> 5 contiguous stereocenter in the E ring
N
OMeMeO2C
E
DNH
MeO AB C
Yohimbine
6
Retrosynthetic Analysis
NH
OAcMeO
MeO2CEH
D
HN
MeOA
B
O
Lactamization
N
H
CO2MeH
MeO
AcOCO2Me
NMeO A
B
E
Imine formation
NMeO
NH2
A B
H
MeO2CH
OMeOAc
O
MeO2CE+
O
OCO2Me
+O
O
MeO2C
H
H
Diels-Alder
E
NH
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
HC-C bond formation
F
Nicolaou, K., C.; Sorensen, E., J.; Classics in Total Synthesis, VCH, 1996, pp 55-63
EEE
EE
O
OCO2Me
benzene+
O
OCO2MeHH
H
HH
endo
O
O
MeO2C
H
H
OHH
O
O
H
H
H
[4+2]
(flip)
Al(Oi-Pr)3
H
O
O
H
H
HO
Br
OO
Br+
H
H
HH
HO
rt, 2.5h84%
H
O
O
H
HO
MeO-
H
O
O
H
HO
OMeH
NBS, H2OH2SO4
H
O
O
H
HO
OMeH
OBr
H
OO H
HOMeO
H
Br+
H2O
H
O
O
H
HO
OMeH
HOBr
H2Cr2O7
reflux, 10h8%
i-PrOHreflux, 60 min
60%Br2
MeOHrt, 45 min
46%
60 to 90°C 40 min
AcOHrt, 10h
60% (2 steps)E
E
EE
MeONaMeOH
7
Ring E synthesis
Meerwein-Pondorff-Verley Reduction
R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, R. W. Kierstead, J. Am. Chem. Soc. 1956, 78, 2657–2657.
8
AlO
O O
AlO
OO
HO
R1 R2
AlO
OO
R1R2
R1 R2
O
O
R1 R2
OH
OH
Y
X
HH
Convex face
Concave face
O
O
MeO2C
H
H
OHH
O
O
H
H
HAl(Oi-Pr)3
i-PrOHreflux, 60 min
60%
EE
Meerwein-Pondorff-Verley Reduction
H. Meerwein, R. Schmidt, Justus Liebigs Ann. Chem.1925, 444, 221–238.
EEE
EE
O
OCO2Me
benzene+
O
OCO2MeHH
H
HH
endo
O
O
MeO2C
H
H
OHH
O
O
H
H
H
[4+2]
(flip)
Al(Oi-Pr)3
H
O
O
H
H
HO
Br
OO
Br+
H
H
HH
HO
rt, 2.5h84%
H
O
O
H
HO
MeO-
H
O
O
H
HO
OMeH
NBS, H2OH2SO4
H
O
O
H
HO
OMeH
OBr
H
OO H
HOMeO
H
Br+
H2O
H
O
O
H
HO
OMeH
HOBr
H2Cr2O7
reflux, 10h8%
i-PrOHreflux, 60 min
60%Br2
MeOHrt, 45 min
46%
60 to 90°C 40 min
AcOHrt, 10h
60% (2 steps)E
E
EE
MeONaMeOH
9
Ring E synthesis
Meerwein-Pondorff-Verley Reduction
IR spectroscopy5-membered ring : 1770 cm-1
6-membered ring : 1740 cm-1
OO
Br+
H
H
HH
HO
E
R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, R. W. Kierstead, J. Am. Chem. Soc. 1956, 78, 2657–2657.
10
Ring E synthesis
E E
Znglacial AcOH
H
O
O
H
HO
OMeH
OBrZn
+H
H
HO2C
H
HO
OMeH
OBr
H+
Zn
H
HO2C
H H
OMeH
O
OH17°C, 2 min
79%E
E
H
O
O
H
HO
OMeH
OBr
MeO2COMe
OAc
O
MeO2CE
CO2Me
CHOAcOMeO
MeO2C
pyr80-90°C, 2h
92%
Ac2OH
MeO2C
H H
OMeH
O
OH
H
MeO2C
H H
OMeH
O
OAc
CH2N2dioxane, Et2O
10°C 96%
CCl4rt, 8h46%
OsO4, H2ONaClO3H
MeO2C
H H
OMe
O
OAc
OHOH
Et2O 0°C, 3min
CH2N2
HIO4H2O
rt, 20 min
E E E
MeO2COMe
OAc
O
HO2CE
NMeO
NH2
A B
H
MeO2CH
OMeOAc
O
MeO2CE
1. benzene, rt, 3min2. NaBH4, MeOH, rt to reflux, 10 min
N
H
CO2MeH
MeO
AcOCO2Me
NMeO NH
HH
CO2MeMeO
AcON
MeO
O
OMe
AB
AB
E E
NH
OAcMeO
MeO2C
N
MeO
AB
E
O
H
D
N+
H
OAcMeO
MeO2CE
Cl
H
DPOCl3
HN
MeOA
BN+
H
OAcOMe
MeO2CEH
DNH
MeO AB CN
H
OAcOMe
MeO2CEH
DNH
MeO AB C
NaBH4
+81% (4 steps)
reflux, 2hMeOH, H2Ort, 5 min
70%
11
Ring C and D synthesis
Bicher-Napieralski
12
Total Synthesis of (±)-Reserpine
NH
OAcOMe
MeO2CEH
DNH
MeO AB C NH
OMeH
HH
OAcOMe
CO2MeY
N
HN
OMe
H
H
HXMeO
X = CO2MeY = OAc
ON
HN
OMe
H
H
H
MeO O
ON
HN
OMe
H
H
MeO OHN
H
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
H
1. NaOMe, MeOH, reflux, 90 min, 79%2. pyr.,
O
OMeOMe
OMeCl
AB
CD
E
AB
CD
E
AB
CD
E
ABC
D
E
1. KOH, MeOH, reflux, 2h, 100%2. DCC, pyr., 100°C, 2h, 67%
t-BuCO2Hxylenes
reflux, 16h74%
rt, 4d57%
F
(±)-reserpine
(±)-reserpic acid lactone
(±)-isoreserpic acid lactone
o-xylene m-xylene p-xylene
Xylene
13
NH
N
H
H+
NH+
N
H
H
33
A ADBC DB
C
NH+
N
H
H3A DB
C
NH
N
H3
A DBC
NH
NH
H+
3A DBC
-H+
Epimerization at C3
14
Total Synthesis of (±)-Reserpine
NH
OAcOMe
MeO2CEH
DNH
MeO AB C NH
OMeH
HH
OAcOMe
CO2MeY
N
HN
OMe
H
H
H
XMeO
X = CO2MeY = OAc
ON
HN
OMe
H
H
H
MeO O
ON
HN
OMe
H
H
MeO OHN
H
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
H
1. NaOMe, MeOH, reflux, 90 min, 79%2. pyr.,
O
OMeOMe
OMeCl
AB
CD
E
AB
CD
E
AB
CD
E
ABC
D
E
1. KOH, MeOH, reflux, 2h, 100%2. DCC, pyr., 100°C, 2h, 67%
t-BuCO2Hxylenes
reflux, 16h74%
rt, 4d57%
F
(±)-Reserpine
(±)-Reserpic acid lactone
(±)-isoreserpic acid lactone
15
Chiral Resolution of (±)-Reserpine to (-)-Reserpine
NH
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
H1. MeOH/CHCl3 (3/1), (+)-CSA2. Resolution3. 1N NaOH
F
(-)-Reserpine
NH
OOMe
MeO2CEH
DNH
MeO AB C
O
OMeOMe
OMe
H
F
(±)-Reserpine
16
Conclusion
Thank you for your attention
> Highly functionalized 6 members ring performed by a Diels-Alder reaction
> Epimerization under acidic condition to generate the good enantiomer
> Performed only with IR and elemental analysis were used as guides.
> Described as one of Woodward’s greatest contribution to organic synthesis.
“It is sometimes said that you have demonstrated that nothing is impossible in organic synthesis. This is perhaps a slight exaggeration. You have, however, in a spectacular way expanded and enlarged the domain of the possible.” –A. Fredga: Woodwardʼs Nobel presentation speech (1965).
Nicolaou, K., C.; Sorensen, E., J.; Classics in Total Synthesis, VCH, 1996, pp 55-63