Total
Synthesis
New
Methodology
MacMillan Group Meeting
3-31-10
an opinion by
Anthony Casarez
What Classifies as Innovative?
Innovation \i-nə-ˈvā-shən\ n: 1. The act of introducing something new.
2. A new idea, method, or device.   Would introducing a new method in a total synthesis make it innovative?
Yes but…
  Some innovations are considered to be more significant than others. How
do we qualify these?
  In my view an innovation must dramatically change the landscape of our
field or provide a method that is widely applicable.
How Our Field was Born: UREA
O
H2N
NH2
  Isolated in 1773 from human urine (hence the name) by Hilaire M. Rouelle
  Intriguing to scientists who were eager to understand the mysteries of bodily functions .
How Our Field was Born: UREA
  Friedrich Wöhler: 1800-1882; student of Jöns Jakob Berzelius.   The synthesis of urea is known as the event that begot the field of
synthetic organic chemistry.
  “I cannot, so to say, hold my chemical water, and must tell you
that I can make urea, without thereby needing to have kidneys,
or anyhow, an animal, be it human or dog.”
  Wöhlerʼs discovery shouldʼve refuted vitalism, the belief that organic
molecules can only come from life which possesses a “vital force,”
but the skeptics remained because he did not synthesize a C–C
bond.
AgNCO
O
NH4Cl
H2N
NH2
AgCl
How Our Field was Born: UREA
  As if the birth of synthetic organic chemistry wasnʼt enough…
  Wöhler thought he was using AgOCN (silver cyanate) instead of
AgNCO (silver isocyanate), both possessing the same formula as
AgCNO (silver fulminate), studied by Justus von Liebig, but having
different chemical properties.
  This gave rise to the notion of isomerism.
AgNCO
O
NH4Cl
H2N
NH2
AgCl
Convincing the Skeptics
  15 years later Hermann Kolbe silenced (most) skeptics by synthesizing
acetic acid, literally from elements.
FeS2
C
2Cl2
CS2
2CCl4
pyrolysis
CS2
Fe
CCl4
2S
Cl
Cl
2Cl2
Cl
Cl
Cl
Cl
O
pyrolysis
3HCl
Cl
Cl
O
Cl3C
O
3H2
OH
OH
Cl3C
H3C
OH
3HCl
Retrosynthetic Application: Tropinone
“By the imaginary hydrolysis at the points indicated by the dotted
lines, the substance may be resolved into succinaldehyde,
methylamine, and acetone, and this observation suggested a
line of attack of the problem which has resulted in a direct
synthesis.” –Sir Robert Robinson J. Chem. Soc. 1917, 762.
Sir Robert Robinson
  Sir Robertʼs analysis was one of the simplest yet most
powerful suggestions of its time. The fact that it worked was a
testament to his intuition.
NMe
CO
Tropinone
Retrosynthetic Application: Tropinone
“In Searching for a method of synthesis of any substance it is
always convenient to be able to recognize the formation of
traces of the desired product…tropinone is obtained in small
yield by the condensation of succinaldehyde with acetone and
methylamine in aqueous solution.”
–Sir Robert Robinson J. Chem. Soc. 1917, 762-8.
  The forward synthesis only required a slight modification of starting materials.
Me
CO2H
CHO
H2NMe
O
CaCO3
CO2CaX
H2O
CHO
CO2H
Me
N
XCaO2C
O
N
HCl
H2O
O
Tropinone, 42%
Tropinone: Mechanism
CO2CaX
CO2H
CHO
H2NMe
O
CaCO3
CO2H
N
Me
OH
Me
N
CO2CaX
O
N
CO2CaX
OH
CO2CaX
XCaO2C
OH
CO2CaX
OH
CO2CaX
Me
Me
H2O
CHO
Me
N
O
CO2CaX
N
HCl
2CO2
O
“We have here a case where three rather simple molecules spontaneously unite into a complicated system,
which earlier we could only build up step by step through a long series of reactions (13). We may suppose
that here Sir Robert has found the key to natureʼs own way of working.” –A. Fredga: Robinsonʼs Nobel presentation speech (1947).
Reserpine
MeO
N
N
H H
H
O
H
OMe
O
MeO2C
OMe
(-)-reserpine
OMe
OMe
R. B. Woodward
  Known as one of the hallmarks of synthetic manipulation by a master of the field.
  One of the greatest achievements of Woodwardʼs career especially considering only IR and
elemental analysis were used as guides.
  The dramatic conclusion taught chemists an invaluable lesson of thermodynamic engineering. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J; Kierstead, R. W. J. Am. Chem. Soc., 1956, 78, 2023.
Reserpine: Retrosynthetic Analysis
MeO
N
H
N
MeO
H
H
BischlerNapieralski MeO2C
OMe
O
OMe
(+)-reserpine
OMe
O
H
H
p-benzoquinone
O
H
OAc
MeO2C
H
CO2Me
OAc
OMe
OMe
Diels–Alder
O
H
MeO2C
O
O
H
Lactamization
O
H
O
N
H
Reductive
amination
N
OMe
CO2Me
CO2Me
MeO
N
H
NH2
6-methoxytryptamine
Reserpine
O
MeO2C
OH
H
PhH, !
O
H
Al(Oi-Pr)3
H
i-PrOH
O
O
H
CO2Me
O
H
O
endo-TS
H
H
H
MeONa
O
 
H
A Diels–Alder
O
H
O
MeOH
Br
sets the first three
O
  Meerwein–Pondorff–Verley reduction creates the next two causing a
spontaneous lactonization with the nearby ester.
H
H
H
O
O
Br
H
stereocenters
O
O
H
Br2
H
O
H
OMe
O
Br
H
O
O
NBS
H
OMe
H
O
H2SO4 (aq)
H
HO
O
H
OMe
H
O
Reserpine: Molecular Judo
O
MeO2C
OH
H
PhH, !
O
H
Al(Oi-Pr)3
H
i-PrOH
O
O
H
CO2Me
O
H
O
endo-TS
H
H
H
MeONa
O
  Bromoetherification sets the next two.
O
MeOH
Br
H
H
O
O
O
H
H
H
H
O
OMe
O
Br
H
O
H
Br
H
O
O
Br2
H
O
O
NBS
H
OMe
H
O
H2SO4 (aq)
H
HO
O
H
OMe
H
O
Reserpine: Molecular Judo
O
MeO2C
OH
H
PhH, !
O
H
Al(Oi-Pr)3
H
i-PrOH
O
O
H
CO2Me
O
H
O
endo-TS
H
H
H
MeONa
O
O
MeOH
Br
H
O
H
H
O
H
O
OMe
O
Br
H
H
H
H
Br2
H
O
O
O
H
O
O
Br
H
O
H
OMe
H
H
  NBS
Substitution of methoxide occurs with
HO
OMe
retention
of configuration.
H
H2SO
4 (aq)
O
O
O
Reserpine: Molecular Judo
O
MeO2C
OH
H
PhH, !
O
H
Al(Oi-Pr)3
H
i-PrOH
O
O
H
CO2Me
O
H
O
endo-TS
H
H
H
MeONa
O
O
MeOH
Br
H
H
O
O
O
H
H
H
H
O
OMe
O
Br
H
O
H
Br
H
O
O
Br2
H
O
O
NBS
H
OMe
H
O
H2SO4 (aq)
H
HO
O
H
OMe
H
O
Reserpine
H
H
Br
H
O
HO
O
H
OMe
H
Br
O
O
AcOH
OsO4
NaClO3,
H2O
HO
OAc
H
O
H
Zn
H
OMe
H
AcOH
H
O
Zn
O
H
H
O
H
OAc
1. CH2N2
H
O
H
2. Ac2O
OMe
CO2Me
O
H
Br
OMe
CO2H
H
H
OH
O
Zn
O
H
H
H2Cr2O7
OMe
CO2Me
H
1. HClO4
2. CH2N2
OAc
H
MeO2C
H
OMe
CO2Me
OH
H
O
H
OMe
CO2H
MeO
1. PhH, 1
2. NaBH4,
MeOH
N
H
N
O
H
H
MeO2C
OAc
OMe
Reserpine
MeO
N
H
N
O
1. POCl3, !
H
MeO
2. NaBH4,
MeOH
H
MeO2C
N
N
H H
H
H
MeO2C
OAc
OAc
OMe
OMe
(+)-methyl-O-acetylisoreserpate
H
H iminium ion happens on the convex face providing the undesired epimer.
  Reduction of the
N
H
H
N
CO2Me
H
H
N
H
OMe
MeO
OAc
CO2Me
HN
OMe
OAc
MeO
Reserpine
MeO
N
O
N
H
1. POCl3, !
H
MeO
2. NaBH4,
MeOH
H
MeO2C
N
N
H H
H
H
MeO2C
OAc
OAc
OMe
OMe
(+)-methyl-O-acetylisoreserpate
H
H
H
H
N
CO2Me
H
N
H
OMe
MeO
N H
OAc
CO2Me
HN
OMe
OAc
MeO
  Thermodynamics favors the wrong conformation for an acid catalyzed epimerization.
Reserpine
MeO
N
O
N
H
1. POCl3, !
H
MeO
2. NaBH4,
MeOH
H
MeO2C
N
N
H H
H
H
MeO2C
OAc
OAc
OMe
OMe
(+)-methyl-O-acetylisoreserpate
H
H
H
H
H
H
N
N
H H
CO2Me
N
N
H
OMe
N
H H
N H
N
H
N
H
OAc
N
HCO2Me
HN
MeO
H
OMe
OAc
N
H H
N
N
H H
N
MeO
H
Reserpine: Molecular Judo
  Hydrolysis and lactone formation lock the molecule in the thermodynamically unfavorable conformation.
H
H
H
N
H
N H
H
N
H
OAc
CO2Me
HN
OMe
MeO
CO2Me
OMe
OAc
MeO
H
H
MeO
H
N H
OAc
CO2Me
HN
MeO
N H
H
O
1. KOH, MeOH
MeO
2. DCC, pyr
O
HN
MeO
Reserpine: Molecular Judo
H
H
N H
H
N
H
O
O
HN
MeO
O
t-BuCO2H
O H HN
MeO
xylenes, !
OMe
MeO
NaOMe,
MeOH, !
  Epimerization is now favored, correcting the stereochemistry
MeO
N
N
H H
Pyridine
H
O
H
MeO2C
OMe
(+)-reserpine
O
OMe
O
H
OMe
Cl
OMe
OMe
OMe
OMe
MeO
N
N
H H
H
H
MeO2C
OH
OMe
Reserpine
H
H
N H
H
N
H
O
O
HN
MeO
O
t-BuCO2H
O H HN
MeO
xylenes, !
OMe
MeO
NaOMe,
MeOH, !
MeO
N
N
H H
Pyridine
H
O
H
O
OMe
O
MeO2C
OMe
OMe
(+)-reserpine
OMe
Cl
OMe
OMe
OMe
MeO
N
N
H H
H
H
MeO2C
OH
OMe
Reserpine
(+)-reserpine
1. (+)-CSA
2. NaOH
MeO
N
N
H H
H
O
H
OMe
O
MeO2C
OMe
(-)-reserpine
Woodward: Organic
OMe
OMe
Ninja
  When defeated by both kinetics and thermodynamics, Woodward manipulated the system so
that it worked in his favor. “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).
Progesterone
O
Me
Me
H
Me
H
H
H
O
(+)-progesterone
W. S. Johnson
  A synthesis inspired by the polyene cyclization of squalene oxide to dammaradienol in the
biosynthesis of lanosterol.
  Displayed a synthetically useful domino reaction and demostrated the utility of the Johnson–
Claisen rearrangement.
Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am. Chem. Soc., 1973, 95, 20, 6832.
Progesterone: Retrosynthetic Analysis
O
O
Me
Me
Me
H
Me
H
Me
Me
H
Me
H
O
H
O
Me
O
H
H
H
Me
H
H
H
O
Aldol/dehydration
Cation-!cyclization
Me
Me
Me
Me
Me
O
H
Ozonolysis
Me
(+)-progesterone
Me
Me
Me
Me
Me
Me
O
O
Aldol/dehydration
OH
Me
Me
O
O
O
O
Me
O
Me
PPh3
CHO
Me
O
I
Wittig/Schloser
modification
O
O
Me
Cyclization of Squalene Oxide
Me
  Stork and Eschenmoser independently yet
concomitantly proposed that the trans olefins in the
substrate controlled stereoselectivity. Me
Me
Me
H
O
H
Me
  Eschenmoser states: “It seems that with polyenes of
this complexity (below), acid-catalyzed cyclization
ceases to be a useful reaction from the preparative
point of view.”
enzyme catalyzed
Me
Me
Me
Me
Me
Me
Me
HO
Me
Me
dammaradienol
Me
further enzymatic steps
5-10%
Me
OH
Me
H
Me
Me
H
H
H
Me
CO2Me
Me
Me
Me
H
Me
Me
CO2Me
Me
HO
Me
Me
lanosterol
Progesterone: Right Half
Me
Me
BrMg
CHO
138 °C,
CH3C(OEt)3,
C2H5CO2H,
55% 2-steps
HO
Me
Me
Me
Me
Me
1. LiAlH4
CHO
Me
2. CrO3,
pyr, 77%
EtO
O
EtO
O
Me
  Johnson–Claisen rearrangement sets the γ,δ-usaturation Me
Progesterone: Left Half
Me
Me
nBuLi, THF
–30 °C
O
HO(CH2)2OH,
p-TsOH
O
—20 to 23 °C, 75%
Br
O
Br
Br
O
Me
I
O
PPh3
PPh3, PhH
hydroquinone, PhH,
reflux, 71%
O
Me
I
O
O
O
  Furan starting material installs the 1,4-diketo relationship.
O
Me
O
NaI, MgO
C2H5COCH3,
80 °C, 99%
80 °C, 94%
O
O
O
Br
Progesterone: Converging Two Halves
Me
O
Me
I
O
Me
Me
PPh3
O
Me
CHO
O
O
PhLi, –70 to –30 °C
then MeOH, -30 °C
O
Me
O
O
Me
Me
Me
Me
EtOH, reflux
2% NaOH (aq)
Me
40%
O
Me
O
0.1 N HCl (aq),
MeOH (3:10),
40 °C
O
  Schlosser modification of the Wittig provides the requisite E-olefin.
  Deprotection and cyclization installs the final unsaturation.
Progesterone: Cation-π-Cylization
Me
Me
Me
Me
MeLi, ether
99%
Me
Me
O
Me
O
Me
Me
Me
OH
O
Me
O
O
Me
Me
O
H
H
Cl(CH2)2Cl,
O
TFA, 0°C
O
O
O
H
Me
Me
O
K2CO3,
H2O/MeOH,
71%
Me
Me
H
Me
H
H
Me
H
Progesterone
O
Me
O
Me
O3, MeOH/CH2Cl2
–70 °C
H
Me
H
H
Me
H
O
then Zn, AcOH, H2O,
–15 °C to rt, 88%
H
Me
Me
Me
H
H
H
O
Me
O
Me
Me
H
Me
H
H
KOH, H2O
51%
H
O
(+)-progesterone
  Cation-π-cylization forges all six stereocenters in a tandem operation from the crude tertiary alcohol.
  Though biomimetic cation-π-cylizations had been previously demonstrated by Stork, Eschenmoser,
and van Tamlen, this is the most elegant and highest yielding example applied to a total synthesis.
Prostaglandin A2
O
CO2H
Me
H
OH
PGA2
Elias James Corey
  The first example of a total synthesis using the TBS protecting group, which also directs a SN2selective organocuprate addition.
  Addition of a chiral organocuprate facilitates convergence within the synthesis.
  Introduction of the TBS protecting group has been one of the most enabling innovations of the
20th century.
Corey, E. J.; Mann, J. J. Am. Chem. Soc., 1973, 95, 20, 6832.
Prostaglandin A2: Retrosynthetic Analysis
Wittig
O
HO
O
H
O
C5H11
C5H11
H
TBSO
CHO
(CH2)3CO2H
OH
OH
SN2 cuprate
addition
PGA2
elimination Iodoetherification
Baeyer–Villiger
H
O
H
Cl
Cl
O
O
O
HO
!-NH3MePh
CO2
Cl
H
Ketene
2+2
H
Prostaglandin A2
O
Cl
Cl
H
H
O
Zn, AcOH
Cl
Cl
NEt3, 0 °C, 75%
HO
!-NH3MePh
CO2
1. I2, 85%
2. TBS-Cl, DMF
imidazole, 72%
O
H
O
NaOH, H2O
0 °C, then
H
!-NH2MePh
TBSO
H
Cl
O
H2O2, H2O
AcOH, 90%
H
O
DBN, THF
70 °C, 94%
O
I
  Ketene 2 + 2 installs requisite lactone carbons.
TBSO
O
O
Prostaglandin A2
O
Cl
Cl
H
H
O
Zn, AcOH
Cl
Cl
NEt3, 0 °C, 75%
HO
!-NH3MePh
CO2
1. I2, 85%
2. TBS-Cl, DMF
imidazole, 72%
O
H
O
NaOH, H2O
0 °C, then
H
!-NH2MePh
TBSO
H
Cl
O
H2O2, H2O
AcOH, 90%
H
O
DBN, THF
70 °C, 94%
TBSO
O
I
  Baeyer-Villiger oxidation followed by hydrolysis and resolution furnishes the
enantioenriched hydroxy acid. O
O
Prostaglandin A2
O
Cl
Cl
H
H
O
Zn, AcOH
Cl
Cl
NEt3, 0 °C, 75%
HO
!-NH3MePh
CO2
1. I2, 85%
2. TBS-Cl, DMF
imidazole, 72%
O
H
O
NaOH, H2O
0 °C, then
H
!-NH2MePh
TBSO
O
H2O2, H2O
AcOH, 90%
H
O
O
H
Cl
DBN, THF
70 °C, 94%
TBSO
O
O
I
  Iodolactonization, TBS protection, and elimination provide the necessary precursor
for cuprate addition.
Prostaglandin A2
TBSO
TBSO
O
ether/pentane
C5H11
LiCu
O
OTBS
CO2H
C5H11
–70 ! –20 °C
2
H
O
O
O
O
HCl (aq),
acetone, 80%
DCM, PPTS
C5H11
H
OTBS
H
O
OTHP
1. DIBAlH, – 78 °C,
toluene
2. Ph3P=CH(CH2)3CO2,
DMSO
C5H11
99%
OH
O
HO
(CH2)3CO2H
C5H11
H
(CH2)3CO2H
1. Collins [O]
2. AcOH/H2O
C5H11
H
OH
OTHP
PGA2
  Organicuprate addition happens in an SN2 fashion
over SN2´ due to blocking from the –OTBS group. Prostaglandin A2
TBSO
TBSO
O
ether/pentane
C5H11
LiCu
O
OTBS
CO2H
C5H11
–70 ! –20 °C
2
H
O
O
O
O
HCl (aq),
acetone, 80%
DCM, PPTS
C5H11
H
OTBS
H
O
OTHP
1. DIBAlH, – 78 °C,
toluene
2. Ph3P=CH(CH2)3CO2,
DMSO
C5H11
99%
OH
O
HO
(CH2)3CO2H
C5H11
H
(CH2)3CO2H
1. Collins [O]
2. AcOH/H2O
C5H11
H
OH
OTHP
PGA2
  Olefination, deprotection, and oxidation complete
the synthesis of PGA2
Prostaglandin A2
O
CO2H
Me
H
OH
PGA2
  TBS protecting group is one of the most widely used protecting groups in synthesis (43,200
web hits, original paper cited 2,256 times). “Corey's most important syntheses are concerned with prostaglandins and related
compounds…No other chemist has developed such a comprehensive and varied assortment of
methods, often showing the simplicity of genius, which have become commonplace in organic
synthesis laboratories.
–S. Gronowitz: Coreyʼs Nobel presentation speech (1990).
Vernolepin/Vernomenin
OH
O
O
O
O
H
O
H
O
O
H
OH
H
O
vernolepin
vernomenin
Samuel Danishefsky
  First synthesis employing the synergistic diene: Danishefskyʼs diene (32,400 web hits, original
paper cited 431 times).
  Brought this concept to the scientific community, inspiring additional contributions e.g. Rawal
diene.
Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, S. J. J. Am. Chem. Soc., 1977, 99, 18, 6066.
Vernolepin: Retrosynthetic Analysis
Wittig
OH
O
H
O
H
OH
O
O
O
H
O
vernolepin
O
OH
O
CO2Me
O
O
Lactonization
OHC
O
O
O
H
H
Directed
epoxidation
Iodolactonization
Elimination
O
O
H
Diels–Alder
H
OMe
CO2Me
O
O
O
MeO2C
O
O
O
O
H
H
Epoxide
opening
Lactonization
O
O
OH
O
TMSO
O
CO2Me
Vernolepin/Vernomenin
OMe
CO2Me
CO2Me
MeO2C
TMSO
mesitlene,
reflux, 60%
O
H
O
O
O
H
NaHCO3,
I2, KI, 88%
I
NaOH (aq),
THF, quant
CO2H
O
H
O
PhH,
DBU,
87%
O
O
H
CO2H
NaOH (aq),
THF, quant
OH
O
H
  Sequential Diels–Alders, the second utilizing Danishefskyʼs Diene, forge the
quaternary decalone.
Vernolepin/Vernomenin
OMe
CO2Me
CO2Me
MeO2C
TMSO
mesitlene,
reflux, 60%
O
H
O
O
O
H
NaHCO3,
I2, KI, 88%
I
NaOH (aq),
THF, quant
CO2H
O
H
O
PhH,
DBU,
87%
O
O
H
CO2H
NaOH (aq),
THF, quant
OH
O
H
  Soponification followed by iodolactonization afford the tricyclic lactone. Vernolepin/Vernomenin
OMe
CO2Me
CO2Me
MeO2C
TMSO
mesitlene,
reflux, 60%
O
H
O
O
O
H
NaHCO3,
I2, KI, 88%
I
NaOH (aq),
THF, quant
CO2H
O
H
O
PhH,
DBU,
87%
O
O
H
CO2H
NaOH (aq),
THF, quant
OH
O
H
  E2 Elimination and a second sponification provide the allylic alcohol necessary
for epoxidation.
Vernolepin/Vernomenin
O
CO2H
O
OH
O
CO2H
dioxane, PhH,
m-CPBA
Ac2O, NaOAc
76%, 2-steps
O
H
OH
H
O
O
O
OHC
Pb(OAc)4, PhH
MeOH, 86%
MeO2C
H
HO
1. LiAl(Ot-Bu)3H
THF, –10 °C
2. Amberlite 105
PhH, !", 93%
O
HO
O
O
O
HO
O
O
O
O
H
H
OsO4, THF,
B(ClO3)2, H2O,
47 °C, 84%
O
OH
O
O
p-TsOH, PhH,
MgSO4, 66%
O
O
O
H
O
O
H
  Directed epoxidation installs the correct stereochemistry of the latent
alcohol and esterification regenerates the lactone.
O
O
Vernolepin/Vernomenin
O
CO2H
O
OH
O
CO2H
dioxane, PhH,
m-CPBA
Ac2O, NaOAc
76%, 2-steps
O
H
OH
H
O
O
O
OHC
Pb(OAc)4, PhH
MeOH, 86%
MeO2C
H
HO
1. LiAl(Ot-Bu)3H
THF, –10 °C
2. Amberlite 105
PhH, !", 93%
O
HO
O
O
O
HO
O
O
O
O
H
H
OsO4, THF,
B(ClO3)2, H2O,
47 °C, 84%
O
OH
O
O
p-TsOH, PhH,
MgSO4, 66%
O
O
O
H
O
O
H
O
  Dihydroxylation followed by oxidative diol cleavage prepares the molecule for
γ-lactone formation.
O
Vernolepin/Vernomenin
O
CO2H
O
OH
O
CO2H
dioxane, PhH,
m-CPBA
Ac2O, NaOAc
76%, 2-steps
O
H
OH
H
O
O
O
OHC
Pb(OAc)4, PhH
MeOH, 86%
MeO2C
H
HO
1. LiAl(Ot-Bu)3H
THF, –10 °C
2. Amberlite 105
PhH, !", 93%
O
HO
O
O
O
HO
O
O
O
O
H
H
OsO4, THF,
B(ClO3)2, H2O,
47 °C, 84%
O
OH
O
O
p-TsOH, PhH,
MgSO4, 66%
O
O
O
H
O
O
H
  Reduction and cyclization forge the γ-lactone functionality and surprising
protection of this moiety via the orthoester happens under acetal forming
conditions.
O
O
Vernolepin/Vernomenin
O
O
1. DIBAlH, – 76 °C,
toluene, DME, 94%
O
O
O
O
O
H
2. Ph3P=CH2,
DME, 87%
O
OH
O
O
H
O
O
O
61%
O
H
OH
H
2. EtOAc, acetone,
CH2N2, 56%
O
p-TsOH,
PhH, !"
O
O
H
O
1. LDA, AcOH,
DME then Dowex
OH
OH
O
O
H
H
OH
31%
LDA, THF
Me2NCH2 I,
then MeI,
NaHCO3
OH
O
O
O
O
H
O
H
O
O
vernolepin
O
H
OH
H
vernomenin
CO2Me
Ambigiune H
Me
Me
Me
H
N
Me
Me
NH C
(+)-ambiguine H
Phil S. Baran
  Reintroduced the notion of protecting group free (PGF) synthesis with the completion of (+)hapalindole Q in 2004.
  Synthesized (+)-ambiguine H in 13 steps in a PGF manner. Provoked the chemical community
to rethink its approach toward synthesis. Do we rely on protecting groups as a crutch?
  Have protecting groups ultimately held us back regarding step efficiency and more importantly
development of new methodology?
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature, 2007, 446, 404.
Ambigiune H
Me
H
O
1. DIBALH, DCM
H
2. NaOMe, MeOH
61%
OH
Me
OMe
1. ClCOCCl3, Zn
ether, sonication
Me
CO2Me
Me
2. MsCl, pyr, then
AcOH/H2O, 73%
OH
Me
H
OMs
Me
Br
Me
Me
H
Me
O
N
H
O
Br
H
LiHMDS, THF,
Cu(II), –78 °C, 50%
NH
1. NaI, acetone
2. DBU, THF,
!, 87%
Me
Me
Pd(II),
NaOCHO,
65%
Me
Me
H
Me
O
NH
Me
NaBH3CN,
NH4OAc
HCO2H, CDMT,
COCl2, 60%
H
Me
N
NH
C
Ambigiune H
Me
Me
Me
Me
H
Me
t-BuOCl
prenyl-9-BBN
Me
N
H
Me
Me
60%
N
N
C
NH
Me
H
NH
N
C
B
Cl
Cl
Me
Me
Me
Me
H
Me
Me
Me
h!, TEA,
PhH, 41%
RN
N
H
H
Me
N Me
Cl
N Cl
B
B
Me
Me
H
Me
Me
Me
H
RN
N Cl
B
H
Me
N
Me
NH C
(+)-ambiguine H
Me
Me
Recap
  Urea: Gave birth to our field   Tropinone: Demonstrated retrosynthetic analysis and was one of the first
examples of a biomimetic synthesis.   Reserpine: Illustrated the power of diasteroselective transformations and
taught us a lesson about thermodynamic engineering.
  Progesterone: Exemplified how a bioinspired transformation can be
applied in the lab efficiently and aslo the utility of the Johnson-Claisen.
  PGA2: Gave us the TBS protecting group and demonstrated how it can be
used to control reactivity.
  Vernolepin: Demonstrated the concept of the synergistic diene in the
Diels–Alder reaction. Danishefskyʼs Diene has inspired other useful
variations.
  Ambigiune H: Reminded us why we should strive to develop protecting
group free syntheses. Presented an innovative example of said concept.