Baran GM
Henry Rapoport
Klement Foo
-born in Brooklyn, New York, of Russian descent
Preparation of demethoxycolchicine (colchicide)
-B.S. in chemistry in 1940; M.S. in 1941; Ph.D in
MeO
MeSH,
Ni(R)
1943 (MIT)
NHAc ZnCl2
EtOH
-worked briefly during WWII at Heyden Chemical
Corporation on penicillin
MeO
(72%)
O (40%)
-1945 studied morphine syntheis at NIH
OMe
-1946 appointed as instructor in UC Berkeley
SMe
O
-trained 253 students, out of which 103 were grad
Me
NH
students.
2
colchicine
Ni(R)
OMe
-Coauthored with James Cason an organic chemistry
acetone
lab textbook.
1918-2002
(61%)
Professor of Chemistry, Emeritus -436 papers and 33 patents.
-noted for TS of heterocyclic drugs like morphine,
H2,
Berkeley
codeine, camptothecin and structural determination
Pd/BaSO4
of saxitoxin.
O
-been a consultant to at least 43 companies
O
NMe2
-students have commented that he is too fast to
same activity
keep up as he writes with both hands.
JACS 1955, 77, 667
OH
O
but less toxic
1940s-1960s -structure elucidation; isolation; biosynthetic discussion, NaBH4 reduc- Total synthesis: Prodigiosin (at this time structure was not fully established)
Pent
tion of esters; methods to make heterocycles.
CO2Et 1. base
EtO2C
E
OMe
2. CH2N2
Modified procedure to organolithium species
Anal.Chem. 1948, 20, 635
Me
EtO
N
(15:1:12) MeO
E
N
N
N
CO2Et
NH H
Me
A
CO2Et
H
E
OMe
E
OMe
N
OMe
OMe
c. H SO
2
NH
N
H
5% Pd/C
(82%)
E EtOH,
N
H
150 ºC
(13%,
49% SM)
4
then heat
E
(42%)
E
N
H
C (35%)
OMe
OMe
NH
N
H
E
Me
1 drop c. HCl
(55%)
B
E
Pent
1. MacFayden-Stevens
Pent
2.
N
H
N
Me
Me
N
NH
N
H
JACS 1962, 84, 635
Page 1
Henry Rapoport
Baran GM
O
1. NaNO2, HCl
2. LAH
O
N
H
(70%)
O
N
Ph
apo- -erythroidine
N
NH2
1. ethyl benzoyl
acetate
2. H2SO4, EtOH
(90%)
OH
HO
N
OH 2 steps
O
N
CO2Me
1. KOtBu
2.-CO2
3. O
OtBu
NH (52%) O
N
JACS 1965, 87, 1397
(20%)
OMe
OMe
OMe
Aberrant Alkaloid Biosynthesis- In-vitro synthesis of unnatural nicotine analogs
JACS 1971, 93, 7021
Stereochemistry of SeO2 oxidation-application to squalene synthesis
H(R) SeO
2
OH
cis or trans
H
R
O
OH
OH
O
H
H
cyclic TS favored
Se
HO
N
NAr
NH2
CHO
trans
O
COOH
Ac2O,
145 ºC
(84%)
1. SeO2, AcOH
2. K2CO3, MeOH AcO
OH
N
O
(58%)
(43%)
1. SeO2, AcOH
2. 2N H2SO4glyme
O
N
N
O
N
N
(72%)
O
CO2Me
R
N
Mechanism?
1. cat. PrOH, 145 ºC (ref 2)
2. [O]
3.
N
N
OH O
campothecin
2
ref. 1 HO
COOH (85%)
then
NaBH4
(86%)
E O
1970s - Obtained Xray structure of saxitoxin JACS 1975, 97, 6008
Review on Solid phase in organic synthesis Acc. Chem. Res. 1976, 9, 135
(H)R
HOOC
C N
D
O
1. Corey-chaykovsky
2. H2, 5% Pd-BaSO4
NP
(14%)
B
N
O
(20%)
CO2tBu
O
A
H
2
all trans
O
OMe
PBu3Br
3. Li/MeNH2
(46%)
H
JACS 1971, 93, 5311
JACS 1971, 93, 1758
O
1. SeO2 (48%)
2. NaBH4 (85%)
Ph
1. HN3
2. OH-
(10-15%)
nBuLi,
DMSO,
acetone
1. CBr4, PPh3
2.
CO2Et
O
N
H
CH2NH2
PPh3Br
BrPh3P
(83%)
1.H2SO4,
wet EtOH
2. acetylation
N
Klement Foo
CuCl2DMF-O2
(100%)
O
ref 3
1. JACS 1972, 94, 8613; 2. JOC 1976, 41, 535
NP
3. Chem. Ber. 1972, 105, 2126
this work: JACS 1972, 94, 8615. see Ke Chen GM "Campothecin" for more.
Page 2
Henry Rapoport
Baran GM
MeO
MeO
MeO
MeO
MeO
1980s
A twist on Eschenmoser sulfide contraction
R1
OTf
S
CO2R2
R1
CO2R2/CN S
N
R
N
R
YH
MeO
O
O
O
MeN
O
MeN
MeN
Y- H
Y = ClO4- (rt)
4
Y = MsO- (< 0 ºC) 90
CH2N2
MeO
:
-both epimers can be assessed
MeO
MeO
1. BF3.Et2O
2. MsCl MeO
MeO
3. LiEt3BH
NMe
:
Y- H
96
10
H
-OMs
O
Decarbonylation of amino acids - iminium salts
-used for synthesis of berbines JOC 1978, 43, 2115.
H
N
O
N
Me
4:1 (3-product)
(55%)
1. Rh/Al2O3
H2, MeOH
2. Jones
anatoxin
N
Me
O
(69%)
(70%)
Me
N
1. HCl
2. POCl3
N
Me
O
E
D
NH2
R
R'
NH2
DBU,
DCM/DMF
rt
O
O
R
R'
N
ketone or
Me
aldehyde
trapped
in aq.
(77-94%)
phase
on w/u JACS 1982, 104, 4446
OMs
O
H
C
A
MeO
N
Me
O
CHO
O
O
MeO2C
B
O
O H
OBz
O
(1.5 eq)
MsO
O
JACS 1979, 101, 1259
Campbell, Can. J. Chem. 1977, 55, 1372
BzO
NH2
(83%)
MsO
H
aflatoxin B2
O
N
R1
R1
N
CO2Me
N
Me
H
1. Wolff-Kishner
slight xs
vit. B6
2. MeLi
-tried with alkyl, cycloalkylamines
3. Cl3CCOCl
amino acids...
4. NaOMe
O
hydrolysis R O C
2 2
R
R2O
OH
O
N
R
R
O
OMe
O
N
Me
MeO2C
O
Inspiration from nature
Cl
CO2R2
S
base
difficult to
monoalkylate
-modified Eschenmoser thiophile reagent to (3-morpholinylpropyl)2PPh
-vital to use triflate as bromide give little (R1 H) or low yield. JOC 1981, 46, 3230
MeN
H
R1
thiophile
difficult to vary R2
O
O DMSO
H
CHO
O
dihydrothebainone
(68% to codeine)
R = alkyl/aryl
R2= Bn, tBu, Me/Et
R1= Me/iPr
MeO
MeN
Klement Foo
MsO
N
O
(18:1 E/Z)
Page 4
Henry Rapoport
Baran GM
MsO
10 eq HCl
1.0M THF
R1O
OH
O(CH2)4Cl
(76%)
LiOH
O
MsO
O
R2O
OH
OH
R1 = Ms/H
R2 = H/Ms
Klement Foo
OH
hv/PhH
pyrex MeO
(71%)
Me
N
BnO
1. Et4NOH
2. Me2SO4
O
(84%) R2O
O
O
O
ZnCO3
MgCO3
JOC 1986, 51, 1006
made enantioselective (92% ee) in 1994
see: JOC 1994, 59, 3775
Br
CO2Et
NP
A quick look at Corey's 2005 synthesis of this molecule
H
O
MeO
cat.
O
O
Me
NH2
O
R
OMe
N
N B
H oTol
O
NH
O
Mitomycin A (R=OMe)
C (R=NH2)
O H
MeO
N
1. Me2SO4
2. hv/dioxane
Et3N
(61%)
3. HNO3
MeO
4 steps
O
potent analog
Pd(OAc)2
Et3N
(97%)
CO2Et
N
Me
O
JACS 1983, 105, 2859; JOC 1984, 49, 1671
for iminium salt strategy: JOC 1981, 46, 2745; JOC 1982, 47, 2404
for aziridine installation: JOC 1985, 50, 4515
1. base
2. RLi
3. H+
* variable on Br position
JOC 1986, 51, 5106
CO2Et
Base
RLi
% xchange
n/s-BuLi n/s-BuLi
0
tBuLi
tBuLi
15-90*
N MeLi
tBuLi
15-90*
H
NaH
tBuLi
30
MeMgBr
tBuLi
<15
KH
tBuLi
>90
Using 9-phenylfluorene as amine PG
O
O
KHMDS
O
1. nBuMgBr (xs)
RX
Pr
R
R
Pr
2. [O]
JACS 2005, 127, 11958 R
H
'
CO2Et
PhFlNH
R
O
NHPG
NHPG
major
isomer
>99/%
ee
MeO
Br
aminoaldehydes
R
=
1º
alkyl
for
PG=PhFl
undergo racemization
(77-94%)
-C normally depr otonated
rapidly when PG =
Me
N
dr (2.2-5):1
or
alkylation
on
N.
BOC/triyl
O
O
1. H2 Pd/C
Pr
CO2Et
HO
2.H5IO6, pH~ 6
>99% ee from
JACS 1987, 109, 236
R
single diastereomer
JACS 1988, 110, 7447
(92% ee)
(99% ee crystal.)
O
MeO
Br
Me
Br
O
7 steps
Me
O
NH2
N
N
H
4-7-bromoindole
H
HO
MeCN/DCM
(65%)
O
O
NTf 2-
O
Br
Ph
Ph
O
O
MeO
O R1 = Ms/Bn
R2 = Bn/Ms
1:8 mixture
Me
O
Br
OH
CO2Et
R1O
H2,
O Pd/C
(100%)
MeO
O
formal synthesis MeO
MeO
O
1. TsOH
2. BnBr, base
(71%)
OH
OH
Br
N
H
Page 5
Henry Rapoport
Baran GM
one example of radiochemistry - new reagent precursor of CH2TI
Previous:
T2, 10% Pd/C
HI, 150 ºC
Et3N
O
Cl
T
I
Cl
T
O
T
(80%)
(70%)
ultra pure needed
spec act. 29 Ci/mmol
bp -25 ºC
powerful carcinogen
S
Wuersch, J. Labelled Compd. Radiophar m.
1978, 14, 355
T2 (1 atm)
Cl 30% Pd/C
EtOAc/Et3N
S
T BnI, 48 h
140 ºC
S
New coupling reagents
O
MeOTf (2 eq)
N
N
N
N
MeNO
JOC 1989, 54, 4689
N
N
2OTf N
2
CDI
N
CBMIT
crashes out
with Et2O
esterification of
amino acids
proceed 85-98%
even with 2º ROH
minimal loss of
optical purity
JACS 1989, 111, 4856
another new reagent: see JOC 1994, 59, 7503
N
MeO
MeO
Br
N
O
15
2
N
Me
MeO
r acemization:
H
RACEMIC
SMe
N
N
Me
MeO
S
CH2TI (gas)
O
TsOH,
heat
(67%)
Bn
1 h, 95%
spec. act. =
28.5 Ci/mmol
(theoretical = 29)
Klement Foo
O
in the 2nd generation, they modified to make C14 nucleophilic and C2
electrophilic.
H N
1. KH, Ac2O
tBuOCl,
2. LDA, -78 ºC
then DBU
N
3. NaOMe, rt MeO
A
H
(75%)
(40%)
O
MeO2C
Cl
H N
H
N
MeO
MeO
N
H
MeO2C
O
N
H
MeO2C
O
CO2Me
OAc
1. NaBH3CN
N
MeO
N
N
N
CO2tBu
H
2. HCHO,
CO2Me
H
3 steps
(25% from p-cresol) (14% from aspartic acid)
N H OH
O NaBH3CN
O
NP
Me
(85%)
4 steps
vindoline
TFA
(65%)
CO2Me
N
N H CO2Me
MeO
MeO
to 4:1
Me
N
H
H N
19
steps
3.6%
overall
:
2 steps
>98%
ee
1:4
N
N
MeO
Me
JOC 1986, 51, 3882; JACS 1987, 107, 1603
H
A
also
discussed in Mitsos "Vindoline" GM
MeO
C
2
shown)
(
O
S
separable
for vincamine TS: see JOC 1985, 50, 1239; JOC 1990, 55, 3068
O
Page 6
Henry Rapoport
Baran GM
A quick look at Boger's 2006 synthesis
O
N
O
N
Me
MeO2C
4+2
N
N
Me
H2 (60psi)
N
5% Pd/C
1. LiBH4
H
60 h
N 2. HCl
(100%) HO C
CO2Me
88%
2
O
N
o-DCB, 180 ºC
(74%)
O
N
Me
CO2Me
3+2
O
JOC 1993, 58, 1159
N
O
N
-N2
JACS 2006, 128, 10596
E
N
R= H/Me
NMe
OTf-
reagent
-phloroglucinol in TsCl/pyr 60-70 ºC need days
to obtain 60-70% product.
-this condition allows 100% in hours.
Br
Me
OHC
N
N MeO2C
O
from L-aspartic
acid
O
pilocarpine
MeNH3Cl,
KSCN
HO
O
HO
CO2Me
OH
2
(57%)
Me
N
Zn(Ag)
Me2AlCl
N
(94%)
O
SH
N
O
(87%)
O
O
NHPf
(93%, 6.5:1 dr)
(68%, 98:2 dr recrystal.)
can put on other
functional groups
OH
OH
OH
NHBoc
OTBS
NHBoc
NHBoc
F
JOC 1995, 60, 4602
1. HNO3,
NaNO2
2. MnO2
(67%)
Me
N
NHPf
(2 eq)
1. H2, Pd/C
2. TBSCl, imid.
NBn
3. NaH, BnBr
OH
4. H2 Pd/C BnO
OTBS
1. Na/NH3
2. Boc2O, pyr
3. NaBH4
(93%)
R' include hinder ed
egs. like l-menthol.
pr oline or diisopr opylamine
JOC 1992, 57, 4775
(82%)
O
R'-OSO2Ar/
R'-NHSO2Ar
H
OtBu
1. PPh3, CBr4
NBn2. KHMDS
TBSO
R
BnO
Cl2(PrOi)2Ti
R'OH/R'NH2
N
O
NH2
E
H
O2
S
O
OH 4 steps
(67%)
NH2
D-serine
O
MeOTf
R
NH
carbovir
1990s
yet another new reagent
N
HO
HO
N O
Me
N
O
O
N
N
O
N
Me N
Me
N
.HCl
O
major isomer has right stereochem.
10 steps from L-aspartic acid (51% overall)
N
N
O2
S
Klement Foo
CO2Me
Me
N
Me
N
CO2Me
OCOPh
O
N
dr 91:9
cocaine
CO2H 1. BnOH/TsOH
2. Tf 2O, 2,6-lut,
HO
CO2H
either enantiomer
gives corresponding
enantiomer of cocaine
CO2Bn
TfO
CO2Bn
Page 7
Henry Rapoport
Baran GM
CO2Bn 1. H2, 10% Pd/C
NH4(HCOO)
2. MeOH, HCl
CO2Bn 3. BnBr, K CO
2
3
S
N
Bn
tBuO2C
then PPh3
N-Me piper.
(72%) tBuO2C
slow adn
HON
NBn
1. H2, Pd/C
Boc2O
2, TsNHNH2
3. NaH
(55%)
Boc
N
CO2Et
Cl
(xs)
THF/H2O
Na2CO3
(78%)
NBn
(79%)
(5.5:1 dr)
1. NaOH
2. heat
Boc CO Et 3. H2O2, Na2CO3
2
N
4. (PhCO)2O
N
(86%)
O
Boc
N
CO2Me
MeO2C
KHMDS
(90%)
Bn
N
O
NaI, pyr
heat
Bn
N
O
O
1. TFA
2. CH2O, NaBH3CN
CONH2 3. NaNO2, HOAc
Ac2O
OCOPh 4. CH N (60%)
2 2
CO2Me
10 steps
HO
OH
NH2
D-glutamic acid
(38%)
N
CO2Et
N
Bonus
Li
N
EtO2C
N
O
CO2Me
(31%)
N A
CO2Me
N
CO2Et
O
1
NBoc
O
CO2Et
N2
2
Br
Br
N
N
JOC 2001, 66, 7078
Rh2(OOct)4
CO2Et
Davies, JOC 1997, 62, 1095
CO2Me
N
CO2Me 1. Fe2(CO)9
2. H2, Pd/C
N
O
Br
O
Noyori, JACS 1978, 100, 1786
3
heat
CO2Me
N
CO2Et + A
Boc O Me
N
O
Me
O
O
Mannich/SN2
Other approaches:
N
EtO2C N
CO2Me
N
E
Dieckmann condensation
Br
I
CO2Me
LiDMP
N
CO2Et
R
N
NP
NaI, )))
ClCO2Et/AcCl
(10:1)
(93%)
I
Rapoport's favorite strategies:
- decarbonylation of amino acid derivative and alkylation of iminium salts
('Mannich')
- Dieckmann condensation
- -methylene lactam rearrangement
- Claisen rearrangement on (hetero)arenas
Not covered: synthesis of heterocycles like 1,4-disubstituted imidazoles,
thiocoumarins, azaindoles, benzofurans...
CO2Me also his contribution to structure elucidation, isolation of natural products, and
radiolabelling.
(90%)
Cl
Summary:
OH
JOC 1998, 63, 4069
2000s
Pyridyne!
Klement Foo
CO2Me
N
O
H2, Pd/C
CO2Me
H
N
OH
CO2Me
CO2Me
Tufariello, JACS 1979, 101, 2435
modified by Davis, OL 2010, 12 4118
Page 8
Henry Rapoport
Baran GM
Klement Foo
PhOCHN
4
O
Ph
N
O
Pr4N(IO4)
rt
5% Na(Hg)
O
N
Ph
HO
O
4 steps
Kibayashi, JOC 1985, 50 1818
5
O
CO2Me
O
OH
COPh
N
Bn
N
Et3N, 10 d
O
N
ClBn
O
RO
H
(mixture of diastereomers)
Charlton, JOC 1995, 60, 8057
Page 9