Dr. Gordon W. Gribble
Baran GM
Born: July 28, 1941 San Francisco, CA
Gianatassio
10/25/2014
Hobbies: Winemaking and Scuba Diving
Education:
A.A. San Francisco City College, 1961
B.S. University of California at Berkeley, 1963
Ph.D. University of Oregon, 1967
Advisor: Lloyd J. Dolby
Post - doc: UCLA, 1967-68
Advisor: Frank A. L. Anet
Academic Positions:
Assistant Professor of Chemistry, Dartmouth College
Associate Professor of Chemistry, Dartmouth College
Visiting Associate, California Institute of Technology
Professor Gribble's basement winemaking lab
Professor of Chemistry, Dartmouth College
Chair, Department of Chemistry, Dartmouth College
Visiting Professor of Chemistry, University of Hawaii
Professional Societies:
American Chemical Society
Career Stats:
International Society of Heterocyclic Chemistry
American Wine Society (Certified Wine Judge)
42 years of teaching experience
325 research publications
Research Interests:
46 graduate students (Ph.D. and M.A.) supervised
Synthesis of Biologically Active Natural Products
190 papers presented at meetings
Heterocyclic Chemistry
29 postdoctoral research associates supervised
Organic Synthetic Methodology
289 invited seminars
New Indole Chemistry
>140 undergraduate research assistants
Anticancer Drug Design
49 books reviewed for 11 journals/publishers
Chemopreventive Synthetic and Natural Triterpenoids
65 review articles and book chapters
Natural Organohalogen Compounds
810 manuscripts refereed for 71 different journals
New Antimalarial Compounds
185 research proposals refereed for 20 agencies
3 books/monographs
1968-1974
1974-1980
1977-1978
19801988-1991
1991-1992
Lithiation of Indole: Like a Boss!
Baran GM
JOC, 47, 5, 1982, 757-761
Inverse-addition apparatus
120 Citations
Generation and Reactions of 3-Lithio-1-(phenysulfonyl)indole
I
I
1. n-BuLi
2. φSO2Cl
N
H
N
SO2φ
What is going on here?
THF
N
E = φSO2Cl, CH3COCl
N
Li
E
Li
I
E
t-BuLi (2 eq.)
E = CH3I,ClCO 2Et,
PhCHO,TMSCl,(PhS) 2,
PhCOCl, HCON(CH 3)2,
"E+"
THF, -100 °C
N
66% without
E+
n-BuLi
N
H
88% with inverse
addition funnel
1. LDA, -78 °C
2. I 2
N
H
N
N
SO2φ
SO2φ
SO2φ
light yellow color
I
t-BuLi
Li
-100 °C to 20 °C
THF
SO2φ
CH3I
CH3
N
N
N
SO2φ
SO2φ
What is going on here?
LDA
N
SO2φ
THF
Li
N
SO2φ
"E+"
E
N
SO2φ
Gianatassio
10/25/2014
2
Here's How It's Done - Gribble Style
Baran GM
Gianatassio
10/25/2014 3
HO 2C
JOC, 50, 26, 1985, 5451-5457.
O
111 Citations
Topic: Acylation of Indoles and Ellipticine
O
R
(RCO) 2O/RCOCl
X
N
SO2Ph
K 2CO3
X
AlCl3
O
O
81-99%
SO2Ph
N
H
79-96%
H+
N
69%
(COCl) 2, AlCl3
X
DCM
N
O
X
N Me
N
H
R
R
Also,
NaBH 4
N
TFA
SO2Ph 96-99%
R= Me,Et,Ph
O
Ar
N
SO2Ph
H 3C
N
Li
O
N
H
"isoellipticine"
O
POCl 3, PhH
Δ
94%
OH NaBH 4
TFA
CO 2Me
O
N 2. HCl
O
Me
N
SO2Ph
N
N
AlCl3
SO2Ph
TFA
Synthesis 1978, 763
Synthesis 1977, 172
N
SO2Ph
N
O
Ar
H 3C
Ph
1.
NMe 2
N
Li
2. TMS2NLi
what is going on here?
ellipticine
H 3C
CH3
PhC 3H 7-i +
H 3C
N
MeO 2C
X
Ar
COCl
78%
N
73%
O
CO 2Me
CO 2H SOCl2
1. NaOMe
CN
NaBH 4
Ar
CH3
O
SO2Ph
K 2CO3,
MeOH
H 2O,Δ
84%
X
NMe 2
N
acylation of benzene ring
when X=5-OMe
CN
N
SO2Ph
97%
SO2Ph
name?
2. TMS2NLi
N
X
SO2Ph
O
NH(CH 3)3
tert-butylamine
N
75%
SO2Ph
EtO 2C
O
Cl
EtOH
AlCl3
1.
O
N
X
MeOH
N
N
O
R
O
N
SO2Ph
N
H
N
O
ellipticine quinone
N
H
CH3
JACS 96, 25, 1974, 7812-7814
Examples in Total Synthesis
Heterocycles, 27, 7, 1988, 1603 - 1606
94 citations
O
NaBH 4-HOAc
N
NaBH 3CN
HOAc
88%
N
H
CH 2CH3
CO 2Me
NaBH 4-HOAc
88%
O
CH 2CH3
NaBH 4
TFA
HO
Ac
71%
B
Na
C
H3
H
N-
Na
c
OA
ne
to
e
ac 59%
BH
NaB
N
50 °C, 1h
H
4-
c
OA
Chem. Soc. Rev. 27, 1998, 395-404.
68%
Br
CH3
O
CO
2H
N
52%
CH3
Mg
CH3
CH3
NaBH 4
TFA
O
F
N
CH3 then,
SO2Ph
SO2Ph
N
NaOH
N
CH3
SO2Ph
Me
N
Gribble Reduction Summary
NaBH 4-RCO 2H
Me
Ph
TFA
SO2Ph 75%
N
SO2Ph
Me
O
Me
HOAc
40 °C
99%
Amine alkylation, Indole reduction, Aryl carbinol reduction,
selective aldehyde reduction, Quinoline, isoquinoline reduction,
Arene alkylation, Amide and nitrile reduction, Acetal-ketal reductive
cleavage, oxime reduction and N-alkylation, β-hydroxyketone reduction
Ph
NaBH 4
NaBH 3CN
N
N
epi- 16, 17 -dihydroburnameine
N
CH 2CH3
H4-H
CO 2Me
N
dioxane, Δ
90%
N
N-
H
Tet. Lett., 37, 1996, 335 - 338
N
Chem. Soc. Rev. 27, 1998, 395-404.
3C
H
N
H
90%
key intermediate for
geissoschizine, isositsirikine,
and (+) - 16 - epiisositsirikine
N
BH
10 °C
+ trans (1:1)
name?
N
H
N
NaBH 4-HOAc
86%
N
H
Na
O
NaBH 4
HOAc
N
N
H
Me
Gianatassio
10/25/2014 4
Gribble....Breakin' it Down!!
Baran GM
Me
O
Me
FYI: OPRD, 2006, 10, 1062
Arynes and Indolyne: Neil.....this one's for you!!
Baran GM
Heterocycles, 1992, 34, 2095
The elusive 2,3-Indolyne
C.
Br
Br
n-Bu 4NF
1. LDA
TMS
2. TMSCl
82%
SO2Ph
N
N
H
A possible key intermediate toward ellipticine
N
H 3C
H 3C
Gribble's attempts to generate 2,3-Indolyne
A.
1. 2 eq. t-Buli
Br
-78 °C
2.
Br
N
SO2Ph
H 3C
O
Br
CH3
X
SO2Ph
E.
I
SO2Ph
Ph
I
N
SO2Ph
X
N
SO2Ph
SO2Ph
Perhaps an explanation: ACIEE 1991, 30, 1455.
Br
Li O
-78 °C
O Li
Br
OiPr 2
SPh
N
2. (PhS) 2
SO2Ph
X = Br, I
X
N
SO2Ph
1. PhMgBr
diglyme
Δ 10 h
anthracene
2. H 2O
N
SO2Ph
m-CPBA
X
Indolynes that can be prepared: JACS, 2010, 132, 17933
4
5
5
N
H
SOPh
N
SO2Ph
*a distorted trans-dimer
and not conductive
to elimination of LiBr
Br OiPr 2
n-BuLi
O
1. LDA, -78 °C
via:
N
D
3. 25 to 55 °C
4. D 2O
* observed black tar
CO 2H
N
LDA
* Elimination of LiBr is 20X faster than LiCl
- LiI is ~100X faster
B.
CH3
CH3
Ph
I
several
conditions
O
black tar
+
unidentifiable
products
rt to reflux
CO 2H
SO2Ph
H 3C
H 3C
SO2Ph
N
N
SO2Ph
I
O
N
O
+
N
D.
N
Gianatassio
10/25/2014 5
4,5-Indolyne
6
N
H
5,6-Indolyne
6
N
H
7
6,7-Indolyne
via:
TMS
TfO
N
H
Gianatassio
10/25/2014
But Gribble is Still a Chemistry Jock!
Baran GM
JOC, 1985, 48, 1682
Chrysene - carcinogenic
OH
1
Br
2
10
X
9
+
3
X
4
+
X
Br
X
8
OH
7
Key SM
polyaromatic hydrocarbons - present in tobacco smoke, spinach, smoked ham
Synthesis of Chrysene - furan
OTs
Br
O
PhLi
51%
Br
OTs
Pd/C
O
O
HCl
O
O
Mg, MeOH
92%
EtOH
93%
41% overall
one isomer
R
Synthesis of chrysense tetramethylchrysene - pyrrole
R
R
OTs
Br
R
N
H
PhLi
Br
OTs
Me
R
R
R
N
Me
N
m-CPBA
Br
Br
what is going on here? R
R = H, Me
R = H, Me
87%, 93%
40%, 56%
Xn
R one isomer
X
2.
OH-
N CH3
name this heterocycle!
Br
R
R
Other Cool Stuff
F
F
X
Y
F
X=F, Y=Cl
X=Y=Cl
R
N
H
n-BuLi
R
N
R
F
Py
N
N
R
Py
N
X
CH3
F
R
R
F
N
X
n-BuLi
Xn
N
H 3C
X
Xn
TfO
+
R
R
1. CH3NHNH 2
N Me
Xn
N CH3
X
F
R
6
Welcome to Indole City!!
Baran GM
Synlett, 1991, 289
Chem. Commun. 2001, 805
H 3C
CHO
Li
O
MnO 2
CH3
SO2Ph
CH3
N
DCM, Δ
Cl
t-BuLi
2 eq.
O
TFA
N
H
N
H 3C
CH3
HO
OH
81%
SO2Ph
CH 2
O
N
THF, 0°C
97%
I
O
NH 2
Pb(OAc) 4
X
Y
N
1. NaOH, EtOH
MeI, acetone, rt
N
2. t-BuLi,
BrCl 2CCCl 2Br,
THF, -78 °C to rt
N
H
H 3C
N
O
N
Br
N
H 3C
PhH, Δ, 36h
Me
N
N
H
SO2Ph
Me
DDQ,
DCM
rt, 18 h
50%
X = N, Y = CH
X = CH, Y= N
55
ellipticine
CH3
N
H
CH3
:
H
N
54%
+
CH3
N
Bu 3SnH, AIBN
N
N
N
NaBH4
50% NaOH/MeOH
O
+
30% over 2 steps
H 3C
BuLi
piperidine
N
SO2Ph
SO2Ph
CF3
N
H
Et 2O, 0°C
87%
N
N
O
7
(CF3CO) 2O
OH
CH3CHO
N
2. t-BuLi
SO2Ph
CHCl3, Δ
H 3C
OLi
1. CH3Li
N
Gianatassio
10/25/2014
45
isoellipticine
O
N
H 3C
O
N
Ph 2NNH 2 HCl
O
N
HOAc Δ
Ph
name?
Ph
N
Ph
O
N
1. LDA, MeI
2. CH3Li
11-24%
N
CH3
H
N
Ph
Me
FYI:
H 3C
O
Ph
N
SO2Ph
CH3
≅
N
SO2Ph
Not So Accelerated Serendipity
Baran GM
Heterocycles 1986, 24, 2127
Chem. Commun. 1996, 1909
C
NO 2
N
N
SO2Ph
expected
mechanism?
SO2Ph
observed
C
E+
°C
SO2Ph
N
0
N
N
-78 °C, THF
SO2Ph
-78 °C
C
E
Synthesis of expected
s-BuLi, THF
-78 °C to rt
Me
SO2Ph
N3
OEt
then COClCO 2Et
N
N
O
SO2Ph
31%
O
OEt
Ph 3P, THF, Δ
20 min, then
rt, 14 h
N
O
SO2Ph
NBS, CCl 4, AIBN,
3h then
NaN 3 aq. THF, 12h
87%
CO 2Et
N
N
65%
unexpected
SO2Ph
52-74%
expected
Synthesis of unexpected
NH
name?
N
NHSO 2Ph
Me
N
CH
C
N
C
C
N
SO2Ph
N3
NaOEt, EtOH
-10°C, 3.5 h
30%
CO 2Et
p-xylene, reflux
2h
43%
name?
O
SO2Ph
HN
N
SO2Ph
NH
N
O
Me
HO
HN
N
SO2Ph
converted to
ArNHSO2Ph
n-BuLi
N
N
Me
O
C
NH 2
NRR'
CO 2Et
N 3CH 2CO 2Et
C
NH 2
name?
94%
CHO
N
I
Cu
SO2Ph
Synthesis of isomer (observed)
8
Li
n-BuLi
N
NH
CO 2Et
N
DBU
SO2Ph
CO 2Et
NH
CO 2Et
N
-5
N
Gianatassio
10/25/2014
-78 °C, THF
CONRR'
NHSO 2Ph
Li
N
s-BuLi
TMEDA
-78 °C, THF
N
Me
OLi
CH3CHO
Ph
O
NPr i C NPri
O
N
Ph
150 °C
-CO 2
N
Ph
R
Ph
R
R = Me
R = Bn
O
O
R
Regiochemistry is oppositie to FMO predictions
O
O
CO 2Et
R
CH 2Ph
R = Me
R = Bn
N
H
THF, Δ
N
O
Ph
R
Ph
N
Bn
Bn
R
name?
O
+
R
R = H, Me, SO2Ph
R
R
N
CH 2Ph
R
N
SO2Ph
THF, Δ
94%
O
N
Me
FMO-predicted
Ph
Ph
Me
N
Bn
Me
DIPC, THF
83%
Ph + Me
N
DIPC
THF, Δ
-HNO 2
-CO 2
H
Ph
Ph
H
CO 2H
N
Bn
Bn
1
:
R1
O
N
CH 2Ph
via:
O
MeNO 2
NCH 2P
h
SO2Ph
H
Ph
Bn
NO 2
NH 4OAc/AcOH
R
N
1 - pot:
+
Me
THF
Heterocycles 2011, 82, 1617
N
N
H
Me
N
R
R
*EWG on indole nitrogen is needed
DFT - predicted and
experiementally observed
H
R
SO2Ph
H
DIPC
NO 2
50 % - quant.
R
O
+
N
Y
Org. Lett., 2013, 15, 5218
NO 2
-HNO 2
-CO 2
X = H, Y = NO 2
X = NO 2, Y = H
CO 2Et
O
NCH 2Ph
CH 2Ph
N O
X
O
R
O
N
R
NO 2
R = Bn, Ph,
4-MeOC6H 4, Bu t
name this heterocycle!
how are these made?
Tetrahedron 2000, 56, 10133
N
N
150 °C
-CO 2
N N
mechanism?
NO 2
R
N
hυ,
Ph
PhH,acetone
76%
Ph
O
(DIPC)
R
N
Ph
R
Ph
N
O
9
FYI: J. Chem. Soc. Chem. Comm., 1970, 760
Chem., Commun., 1997, 993
HO
Gianatassio
10/25/2014
Munchnones: The Heterocyclic Dessert
Baran GM
N
H
99
Bn
R2
N
R
Ph
Gribble's Street Cred. - Natural Products Made
Baran GM
O
O
O
O
O
O
O
O
N
H
Bruceolline D
N
N
(+) - Elaeokanine A
(+) - Elaeokanine C
N
N
H
N
H
HO
(+) - Elaeocarpidine
N
N
H
N
N
H
N
H
Me
Isoellipticine
O
Fascaplysin
N
O
H
H N
H
H N
Me
Me
MeO
Me
(+) - Aristoteline
H
Me
(-) - Hobartine
CO 2H
O
TP-151 (CDDO)
O
Homofascaplysin c
Me
NC
O
MeO
O
Me
H
N
H
N
H
O
Homofascaplysin B
N
H
Semperivine
(+) - Tarennine
N
ellipticine
N
H
N
H
Cl
Me
Me
N
NH
N
Cl Cl
Cl
Heptachloro-1'-methyl-1,2'bipyrrole
Lycogarubin C
N
Cl
N
O
O
N
H
N
H
N
H
Me
Bruceolline J
N
Cl
an Azamacrolide Allomone
Me
OMe
N
H
Bruceolline E
Me Cl
Cl
NH
Me
N
H
O
H
N
MeO
Me
Gianatassio
10/25/2014 10
Curtain Call: Gribble Magic
Baran GM
JOC, 1985, 50, 5900
Tet. Lett. 1996, 37, 2145
p-TSA
O
(2 eq.)
N
OH
O
Me
H
N
Me
O
NH
PhH
Δ, 3.5 h
56%
N
H
PPSE, DCM
Me
Δ
25%
name?
N
H
Me
H
Me
O
O
N
CO 2H
N
N
Li
O
SO2Ph
N
N
SO2Ph
JOC, 1988, 53, 3164
SO2Ph
O
H
N
OMe
MeO
pH = 5.5
then, pH = 1.5
28%
name (2nd step)?
ACIEE, 2002, 41, 1740
O
NCS
Me
Me
NaHCO 3
N
N
N
DCM, dark
rt, 4 h
O
Me
PCl 5,
POCl 3
O
N
N
N
N
H
H
N
Cl
Cl
N
H
N
H
TFA
N
H
rt, 30 min
+
N
N
H
Cl
Cl
N
Cl
Lycogarubin C
H
NH
OMe
N
H
N
H
who developed this?
mechanism?
NH 3Cl MeO
N
H
O
N N
then, Zn AcOH
N
PhO 2S
(-) Hobartine
H
HO
O
N N
Me
JOC, 1989, 54, 3264 - Ellipticine studies
Me
CO 2Me tol. Δ
PhH, Δ
5h
Me
Zn, HOAc
N
H
Tet. Lett. 2011, 52, 6772 (Bruceolline)
MeO 2C
Me
Me
H
N
Me
Me
H
N
H
Me
O
N
H
N+
Cu(OAc) 2
DCM, 0 °C
N
O
O
1. m-CPBA
Me
Me
Tet. Lett. 2011, 52, 6772 (Bruceolline)
O-
H 2. O (bubbling),
2
an Azamacrolide Allomone
N
H
Gianatassio
10/25/2014 11
Cl
Cl