Nathan Wilde
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Brigham Young University
Some BYU alumni you might know:
Napoleon
Dynamite
Jeopardy
Guy
Twilight
author
not the
president
superbowl
champ
All photos stolen from wikipedia
Emeritus Professors in Organic Chemistry
Photo credit: Pastelitodepapa on wikipedia.
-Private university owned and run by the Church of Jesus Christ of Latter
Day Saints (LDS Church or Mormon Church)
-At ~34,000 on-campus students it is the 3rd-largest private university in
the US.
-BYU started as a small academy in 1865 at Provo, Utah.
-The College of Physical and Mathematical Sciences wasn't founded until
1949.
Edward G. Paul
K. LeRoi Nelson
Richard T. Hawkins
Jerald S. Bradshaw
Angus U. Blackham
Morris J. Robins
Brigham Young
Et
Me
Jerald S. Bradshaw
Born 1933, maybe
PhD: at UCLA with Donald Cram (the Cram's rule guy)
Post-doc: at CalTech with George S. Hammond (the Hammond's postulate
guy). Started around 1963.
Researcher at Chevron Research Company until about 1966
Professor at BYU starting around 1967.
Racemization of carbanions JACS 1963, 85, 1108 (with Cram)
Ph
Ph
Ts
H
N N
H
H
Ts
Et
Me
N NH 2
Ph
Et
Me
base
H or H
Ph
[O]
retention
H
N NH 2
Ph
Et
Me
or racemate
Ph
3
3
1
3
3
1
R
Dielectric
constant (ε ºC)
Et
Me
74% ret.
78% ret.
68% ret.
60% ret.
44% ret.
37% ret.
44% ret.
32% inv.
Oxidant [Base] (M)
Steric
course
KIO 4
Br 2
none
KIO 4
Br 2
none
0.30
0.30
0.30
9.70
9.70
9.70
32% inv.
33% inv.
5% inv.
12% inv.
77% ret.
70% ret.
Me Et
ROH
N2
Ph
Ph
symmetrically
solvated carbanion
Et
Me
H
asymmetrically
solvated carbanion
H
H
racemization
mechanism
Et
Me
Ph
Ph
Ph
HOR
inversion
mechanism
Water explanations
Steric
course
2.2
11
18
27
34
35
49
80
Me Et
ROH
HOR
R
retention
mechanism
1,4-dioxane
t-BuOH
n-BuOH
EtOH
MeOH
ethylene glycol
DMSO
water
Substrate
O
H
inversion
3
Solvent
O
base
2
Et
Me
M+
solvated intimate ion pair
1
OR
N N H
Ph
Me Et N 2
Et
Me
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
It doesn't matter if it's
oxidation or simply basecatlyzed; all that matters
is the solvent and the
identity and concetration
of the base (alkoxide &
hydroxide bases). No
base gives 100%
racemization.
These are all in water
using KOH.
Et
Me
N N H
Ph
inversion
mechanism
Et
Me
H H
N N LG
Ph
This azamine would
favor retention
because of proximity
of the proton.
Et
Me
H
N N LG
Ph
Et
Me
Ph
N N
H
R4
Irradiation of Carbonyl Compounds
JOC 1966, 31, 237
w/ Chevron Research Company
Properties of Crown-ether-type macrocycles JACS 1980, 102, 467
O
R1
R1
HO
R2
O
R1
R4
R4
R1
*
O
crossing
R1
R2 s
Carbonyl
Compound
Olefin
Compound
% Conv.
carbonyl
oxetane
benzophenone
benzophenone
acetophenone
benzaldehyde
benzaldehyde
acetone
cyclohexene
1-hexene
cyclohexene
cyclohexene
1-hexene
cyclohexene
95
85
90
90
90
80
13
20
15
38
30
8
Aryne Chemistry JOC 1971, 36, 314
1
2
KOt-Bu
O
Cl
R2 t
R1
Products (%)
hydrocarbon
dimer
pinacol
alcohol
47
49
0
10
0
0
>6
>10
>10
>4
>4
>26
8.5
8.3
6.2
8.8
5.6
2.1
39.6
0
4.8
6.2
2.4
6.0
6.1
5.3
58.3
0
27
28
17
18
19
45
OR
OR
+
t-BuOH/DMSO
140ºC, 8 min
100
100
100
100
86.0
85.6
80.3
72.8
R2
27.8
27.5
25.5
14.4
9.8
9.8
0
48.3
8.5
10.6
6.2
18.1
13.9
13.4
0
49.6
0.37
0.33
0.35
0.36
0.35
0.32
only 1
only 2
O
N
O
O
O
O
n
OH
n
Rate of transport of various metal salts (mol / 24hr x 10 7) through
a membrane containing 10 -3 M ligand
n
O
Products (%)
Substitution
Ar-X % Conv. 1-Ot-Bu 1-OH 2-Ot-Bu 2-OH ratio (1/2)
1-Br
2-Br
1-I
2-I
1-Cl
2-Cl
1-F
2-F
O
N
HO
R3
hydrocarbon dimer
* intersystem
O
hν
R4
R3
R3
alcohol
X
R
R1
R2
R2
O
Cl
R3
HO
R1
R
R1
OH
R2
pinacol
oxetane
R4
R2
R2
R3
hν
+
O
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
R
3
H
3
Cl
3
OMe
4
OMe
5
OMe
18-C-6
Li
Na
K
0
0
0
0
0
0
2.7
1.6
3.9
3.9
8
11.3
93
71
156
23
6
277
Rb
Cs Mg
31 1.8
16
0
21 2.6
62 42
8 111
214 67
0
0
0
0
0
0
Ca
1.07
0
2.5
0
0
26.3
Sr
Ba
Ag
15
0
312
5.8
0
330
91 3.3 462
0 13.6 770
0
5.2 266
316 60 223
Nathan Wilde
BYU Emeritus Professors in Organic Chemistry
Baran Lab GM
November 2014
Angus U. Blackham
Born: 1926. Died: 2009.
PhD: University of Cincinnati with Charles E. Frank
Professor at BYU: about 1960 to about 2000.
Had 6 kids. Had 100 posterity when he died.
Spontaneous Ignition of Organic Compounds
Industrial and Engineering Chemistry 1952, 862.
-2 different mechanisms postulated
-metal of container doesn't matter
-different additives can drastically change
the ignition temp, even at 5 mol%.
-example: (t-BuO)2 lowers the ignition
temp of dodecane from 232 to 199ºC
Richard T. Hawkins
Born: 1929. Died: 2013.
Worked at Phillips Petroleum Company
Drafted for the Korean War, served as a chemist at Rocky Mountain Arsenal
PhD: University of Illinois with H. R. Snyder
Professor at BYU: 1959 to 1995.
Ortho-Lithiation JOC 1969, 34, 1173
NMe 2
MgBr
then H 2O
H
B O
Me
NBS,
activator
Me
– H 2O
ArB(OH)2 + Ar2BOH
ArB
O
28 : 1
Me
KOH
B
Ar
NMe 2
O
Me
B
messy
Ph
O
NMe 2
S
Thiophenyl methacrylates
On sabbatical at Fabrics and Finishes Department of E. I. duPont de
Nemours and Company. Journal of Heterocyclic Chemistry 1974, 11, 291
i. n-BuLi
could never
make this
B
B
HO
3
O
R
n-BuLi benzaldehyde
S
R
N
Nn-Bu
then H 2O
BAr
B O
Br
3
B(OH) 2
OH
O
HO
B O
Me
NMe 2
Nn-Bu n-BuLi B(OMe) 3
Me
B(OMe) 3
n-BuLi B(OMe) 3
then H 2O
Making Stable Boronic and Borinic Acids with Snyder
JACS 1960, 82, 3053 and JACS 1960, 82, 3863.
Me
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
S
iii. H 2O2, NaOH
ii. B(OMe) 3
R
B(OMe) 3-n
n
n = 3, 2, 1
S
R
57-70%
one-pot
63-76%
S
methacrolyl
chloride,
pyridine
Br
R
Hydroxy thiophenes and their
esters had been pretty rare in
the literature.
B(OH) 2
O
H 2N
B O
H 2N
Br
3
B O
H 2N
– H 2O
N
H
3
HN
B N
O
O
R
S
O
Me
K. LeRoi Nelson
Born: about 1926. He's still kickin' too.
PhD: at Purdue with H. C. Brown
Professor at BYU: 1956 to 1990.
Homomorphs of o-di-t-butylbenzene with Brown. JACS 1953, 75, 24
t-Bu
t-Bu
Mononitration of t-butylbenzene with Brown. JACS 1951, 73, 5605
R
HNO 3,
H 2SO 4
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
R
R
ortho meta para
Me 58.45 4.4 37.15
t-Bu 15.8 11.5 72.7
NO 2
But ... how do you get ratios of isomers in 1951? Fractional distillation!
~
~
NMe 3
NMe 3
CClMe2
t-Bu
NMe 3
CClMe2
NH 2 MeI
NMe 2 MeI
NMe 3
NH 2
NMe 2
NMe 2
NMe 2
MeI
t-Bu
Me
NMe 3
No reaction even after 84 days of
refluxing in acetonitrile
Me Me
HCl
Me
Me
NMe 3
t-Bu
OH
Me
NMe 3
MeI
OH
O
Me Me
No chlorides
observed.
CClMe2
CClMe2
How do you tell when your methyl iodide is consumed in 1953? Have you
ever heard of the ebullioscopic technique?
They made a standard
curve of % MeI in MeOH
vs. refluxing temperature.
Used that to decide how far
the reaction had proceeded.
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
Edward G. Paul
Born: 1931. Died: 2014.
PhD: at University of Utah with W. J. Horton
Professor at BYU: 1965 to 1996
Studies Towards Isopimpinellin JOC 1959, 24, 2000
OMe
OMe
1. HCl, ZnCl ,
OMe NCCH Cl 2 MeO
2
MeO
2. HBr, AcOH
Cl
OMe O
OMe
1. AlCl3
2.
O
NC
OH
OMe
MeO
O
H
4.
Ph
O
O
OMe
OMe
O
OMe
N H , POCl 3
Me
NaHSO 3,
pyridine
OMe
OMe
O
O
OMe
O
HO 2C
O
O
1. NaOAc
2. LAH
3. H 2, Raney Ni
OH
all the oxidants
O
O
O
OMe
isopimpinellin
Baran Lab GM
November 2014
Biological activity, Cladribine J. Med. Chem 1972, 15, 735
Morris J. Robins
Born: maybe 1939.
PhD: Arizona State University with Roland Robins
Professor at University of Alberta in Edmonton: 1969 to 1986
Professor at BYU: 1987 to 2009
Has a 3.9/5.0 rating on ratemyprofessors.com.
NH 2
1. TrCl
2'-deoxy- 2. TsCl
adenosine
N
N
TrO
O
H
H
N
N
N
H
H
H
H
H
OTs H
H
Fusion of purines and sugars, NMR analysis JACS 1965, 87, 4934
NHAc
AcOH
H
O
H
H
H
AcO
H
N
OAc H
Cl
N
N
Cl
~1:1 anomeric ratio
NH 3
100
30
400
30
1000
1000
1000
800
1000
1000
30
5
100
0.07
100
8
100
100
100
100
Dichloro purine nucleosides w/o fusion Can. J. Chem. 1981, 59, 2601
adenosine
Cl
O
1. mCPBA
2. enzymatic HO
N
deamination
N
H
N
1. Ac2O
2. POCl 3
N
61% from Cl
adenosine
guanosine
1. Ac2O
2. POCl 3
N
H 2N
N
N
sugar(Ac's)
N
sugar(Ac's)
1. NH 3
2. NMe 2
NH 2
N
N
N
N
Cl
α-fused purines
Leukemia
L-1210
The Cl, β compound is now called Cladribine and is used to treat hairy cell
leukemia and multiple sclerosis. It was first designed by Dennis Carson
here at TSRI and Robins was the first to synthesize it.
H
H 2, Pd/C
N
20
50
1000
20
1000
1000
1000
1000
40
>1000
sugar
α-anomer
H
37.5%
H
OAc H
H
O
H
H
OAc
H
OAc H
2,6-dichloropurine,
chloroacetic acid,
neat
N
H
N
AcO
O
H
N
N
N
N
OH
H
NHAc
N
N
α or β
H
O
H
H
O
H
E. coli S. faecium
2-Cl-adenine
2-Cl-adenosine
α
Cl
β
Cl
α
OMe
β
OMe
α
SMe
β
SMe
NHNH 2 β
β
NH 2
N
N
HO
N
HO
R
anomer
R
N
N
NH 2
1. AcOH
2. EtSH,
NaOEt
3. "sponge Ni"
N
N
LC 50 (µM)
NH 2
First Synthesis of Dideoxy nucleosides at ASU. JACS 1964, 86, 3585
AcO
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
N
N
Me 2N
N
N
sugar
Selective reduction of C-3' sugar ketone JOC 1990, 55, 410
Non-aqueous diazotization Can. J. Chem. 1981, 59, 2608
N
t-BuONO
SbCl 3
N
NH 3
t-BuONO
HF•pyr
H 2N
N
sugar(Ac3)
N
N
N
N
sugar(Ac3)
F
N
DCE
O
H
H
OH
H
H
OH
O
i-Pr 2Si
O
H
O H
i-Pr 2Si O
Dess-Martin
H
OH
H
OTBS
HO
t-BuONO R
SbBr 3
N
CH2Br 2
N
Br
N
R = NH 2, Cl, F
base
O
base
NaBH 4
H
H
O
base
O
OH H
TBSO
H
OTBS
H
H
H
OTBS
TFA
base
1.
N
sugar(Ac3)
H
PhO
H
OH
2. HSnBu 3
AIBN
3. TBAF
O
Cl
Buzzwords of yesteryear: "smooth and efficient" ...
H
base
H
H
H
OH H
overall yields:
adenosine: 78%
uridine: 68%
Sonogashira reactions of iodouracil
Tet. Lett. 1981, 22, 42. Tet. Lett. 1988, 29, 2855. J. Med. Chem 2005, 48, 4690.
alkyne,
O
O
O
R
CuI,
I 2,
I Pd(PPh ) Cl
3 2 2 HN
CAN HN
HN
R1 = O, NH 2
Et 3N
O
N
O
N
O
N
R
sugar(PGs)
sugar(PGs)
sugar(PGs)
R1
These types of compounds
have shown inhibitory
effects against varicellazoster virus (except omit the
sugar).
HN
O
N
sugar(PGs)
HO
base
base
H
H
O
H
OTBS
OH
O
NaBD 4
H
H
HO
S
O
D
Deoxygenations to make DNA from RNA
JACS 1981, 103, 932 Full paper: JACS 1983, 105, 4059
HO
TBSO
H
H
N
N
sugar(Ac3)
Cl
base
H
OTBS
Mechanism-based inhibition of ribonucleotide reductase
JACS 1999, 121, 1425 and references therein.
Robins made
the 2'-Cl and 2'OTs that helped
everyone figure
out what the
mechanism is.
Mechanism of ribonucleotide reductases
R
O
adenosine
Mechanism of
gemcitabine
t-BuONO
HF•pyr
N
NH 2
N
N
N
N
sugar(Ac3)
F
TBSO
R
R
N
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
PPO
O
base
PPO
O
base
O
H
F
H
H
OH
F
H
HO
H
F
O
F
Fluorine! JOC 1993, 58, 3800. JACS 1996, 118, 2519
H
H
Et 2NSF 3
(DAST),
SbCl 3
A
O
RS
H
F
H
H
(EtO)2OP
O
(2-pyr)O2S
H
U(Bz)
H
H
O
Me
Me
H
OAc OAc
H
OH
H
OH
(EtO)2OP
AcHN
F
O
(2-pyr)O2S
H
O
O
Me
Me
N
N
TMSCl
N N
NMe 2
N
R
N
nucleophile
N
N
sugar
N
N
sugar
N
N
Ar
ArB(OH)2,
Ni or Pd,
base
N
N
N
sugar(PGs)
N
N
N
N
N
sugar(PGs)
OAc
AcHN
H
7:9 = ~15:1
same as above
R = OMe, SMe, NMe 2
N
Cl
N
only the 9isomer was
observed!
NH 2
Cl
N
N
7:9 = ~3:1
N
N
sugar(Ac's)
Ph
N
N
N
N
N
sugar(Ac's)
AcHN
(p-tol)CO2
N
sugar
NPh 2
N
Ph
Ph
N
R = imidazol-1-yl, 1,2,4-triazol-4-yl, F,
S(alkyl), SO2(alkyl)
Ar = anything you want
O
NaH, MeCN, then
O
(p-tol)CO2
N
H
N
N
N
H
OAc OAc
N
H
N
N
N
This works for all kinds of purinyl-type amines.
Suzuki does all of the leaving groups
Org. Lett. 2004, 6, 3421. Org. Lett. 2005, 7, 1149.
R
NPh 2
N
N
N
O
O
AcHN
sugar(Ac's)
HN
O
NH 2
NN
2. TMSOTf,
O
AcO
H
Biochem. 1994, 33, 3758
Me 2N
N
H
H
N
NH 2
Me
9
O
OTMS
N
H
H
H
46%
N
U
Amine activated as a triazole leaving group
JACS 1994, 116, 9331. Full paper: JACS 1995, 117, 5951
N
1. TMSN
HN
This was used to study some biology.
H
7
O
A
O
H
O
~50% yields
H
1. KH,
selectfluor
2. NH 3, MeOH
H
The 7/9-regioselectivity problem with purines
JOC 1996, 61, 9207. JOC 2006, 71, 7773
A
O
RS
H
OAc OAc
F
Baran Lab GM
November 2014
BYU Emeritus Professors in Organic Chemistry
Nathan Wilde
N
H
NaH, MeCN, then
O
(p-tol)CO2
N
Cl
(p-tol)CO2
~100%
N
N
Cl
Ph
N
N-9 only!
Single anomer!
N
N
sugar(Ac's)
NH 3,
MeOH
a more efficient
way to make
cladribine
Cl
NH 2
N
N
N
N
sugar