M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Graduate Work:
Biography
- Born 1936 in San Antonio, TX
for complete bio
(http://heathcock.org/CHHJr/)
Iodine isocyanate as a reagent: JOC, 1967, 32, 540
Education
- Abilene Christian College; B.S., 1958
- University of Colorado; Ph.D., 1963
(A. Hassner)
- Columbia University; Postdoc, 1963-64
(G. Stork)
H
N
INCO
ROH
I
OR
H
N
heat
O
O
O
R
I-
KOH
Professional Experience:
-Champion Paper & Fibre Company, Pasadena, TX; Supervisor, Chemical Tests, 1958-60
-University of California; Berkeley, CA
Assistant Professor, 1964-70; Associate Professor, 1970-75; Professor, 1975-present
Vice-Chairman, 1972-77; Chairman, 1986-89; Dean, College of Chemistry, 1999-2005;
Gilbert Newton Lewis Professor, 2003-05; Chief Scientist, QB3 Berkeley, California Institute
for Quantitative Biosciences, 2005-present
-Merck, Sharp & Dohme, Rahway, NJ; Consultant, 1968-78
-Abbott Laboratories, Abbott Park, IL; Scientific Advisory Committee, 1986-present
-Medicinal Chemistry A Study Section (NIH); Member, 1979-81; Chairman, 1981-83
-Organic Chemistry Division of the American Chemical Society
Executive Committee, 1976-79, 1984-86; Chairman, 1985; Ex officio 1986-present
-Organic Syntheses Editorial Board, 1980-88; Editor-in-Chief, 1986;
Board of Directors, 1992-present
-Chairman, 1986 Gordon Conference on Stereochemistry
-Editor-in-Chief, Journal of Organic Chemistry, 1989-1999
-Advisory Board, Bulletin of the Chemical Society of Japan
-Chair, Chemistry Division, American Association for the Advancement of Science, 2000
Honors and Awards:
-National Science Foundation Predoctoral and Postdoctoral Fellow, 1961-64
-Alfred P. Sloan Foundation Fellow, 1967-69
-Humboldt United States Senior Scientist Award, 1978
-Miller Research Professor, UC Berkeley, 1982-83, 1991-92
-Ernest Guenther Award, American Chemical Society, 1986
-Allan R. Day Award, Philadelphia Organic Chemists Club, 1989
-Award for Creative Work in Synthetic Organic Chemistry, American Chemical Society, 1990
-A. C. Cope Scholar Award, American Chemical Society, 1990
-Prelog Medal, ETH, 1991
-American Academy of Arts and Sciences, 1991
-Pfizer Award in Synthetic Organic Chemistry, 1993
-National Academy of Sciences, 1995
-Centenary Medal, Royal Society of Chemistry, 1996
-H. C. Brown Award, American Chemical Society, 2002
-Paul Gassman Award for Distinguished Service, American Chemical Society, 2004
H
N
NH
O
O
aziridines
2-oxazolidones
Independent Research:
First paper as PI: JACS, 1965, 87,5264
Me
hv
CO2Et
Me
Me
CO2Et
-
O
OEt
-CH2CH2
H
CO2Et
Me
O
OEt
Me
Me
-
O
OEt
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
- As a result, several reagents were developed
Aldol Reaction
Used for erythro selectivity: Z-enolate
First paper on aldol: JACS, 1977, 99, 247.
O
- Conformation of Dubois results: Kinetic stereoselection
Z-enolates -> erythro (syn)
E-enolates -> threo (anti)
- Main contributions focuses on Li enolates utilizing bulky substituents
OTMS
a. LDA
-78 oC
b. PhCHO
OH
O
OTMS
Ph
Me
- Synthetic Untility of reagent
OH
t-Bu
Ph
OLi
O
JOC, 1980, 45, 1066
Ph
-78 oC
OLi
OH
O
OH
H
o
-78 C
Me
t-Bu
Me
OH
Ph
COOH
R
H
O
Mes
OH
H5IO6
MeOH
O
O
Mes
Me
92% E
8% Z
Me
92%
OH
a. LAH
b. NaIO4
CHO
R
JOC, 1980, 45, 3846
Me
Mes
Ph
OTMS
R
+
Ph
O
Me
a. DHP, H+
b. n-BuLi
8%
OH
R
c. NaIO4
JOC, 1981, 46, 191
-Stereochem can be explained through Zimmerman-Traxler
O
n-Bu
Me
Used for threo selectivity: E-enolate
Me
O
H
O
R
Li
Me
O
vs.
O
R
Li
R
R
OH
O
Me
a. LDA
-78 oC
O
R
R
R
O
b. PhCHO
OH
Ph
R
O
O
Me
Chiral Reagent: Unfortunately less popular than Evans: JOC, 1991, 56, 2499
H
O
O
Li
Me
H
O
R
R
OH
O
vs.
Li
Me
R
O
R
H
O
O
Me
OTMS
Bu2BOTf, R3N
OH
t-Bu
R
TMSO
t-Bu
R
R
LDA, TMEDA, RCHO
Me
O
OH
t-Bu
TMSO
R
Me
M. R. Luzung
Clayton H. Heathcock
-Application of aldol and erythro reagent: JOC, 1980, 45, 1066
Aldol Reaction cont'd
Double Diastereoselectivity: JACS, 1979, 101, 7076
CHO
OH
OLi
+
O
R
OTMS
1
2
5
OH
OLi
R CHO +
OH
R'
R'
R'
OH
4
+
ephedrine
O
NHMe
Ph
NH
Ph
R
O
O
R'
a. LDA
:
OH
Me
BHTO2C
b.
1
OBn
BnO
OHC
- Real example:
O
O
HO
OHC
O
O
O
O
O
O
HO
O
OBn
O
R*
61%
R*
O
TMSO
28%
OH O
OH O
O
O
O
O
O
OHC
O
O
- Application of aldol reaction C8 to C15 of Erythromycin A:
JOC, 1988, 53, 4730
1
BHTO
25
LAH
R'
OH
+
O
O
OH
R
:
R'
Me
Ph P N3
Ph
1
+
O
R
COOH
Ph
R'
OH
R'
OH
b. PhCHO
c. HIO4
MeOH
O
R
O
5
1
+
:
R
a. LDA
-78 oC
O
- Matched and mismatched aldols
- Best way to have excellent dr is through double diastereoselection
(BOTH components chiral)
R
Baran Group Meeting
06/03/2008
HO
O
O
O
HO
O
O
R* 97%
R*
3%
BnO
H
OBHT
Me
R
vs.
BnO
R
H
O
15
OBHT
Me
O
BnO
8
M. R. Luzung
Clayton H. Heathcock (some completed syntheses)
O
O
Me
H
copaene (1966)
ylangene (1967)
Me
N
O
N
N
O
O
OH
N
(+)-occidentalol (1972)
H
Me
O
O
HN
HN
lycodine (1979)
O
lycododine (1981)
OH
O
O
O
S
N
bukittinggine (1992)
S
(-)-alloaristoteline (1992)
Me
MeHN
N
N
O
SMe
Ph
H
H
O
(-)-papuamine (1996)
petrosin (1994)
H
OAc
N
Me
Me
O
O
Me
CO2H
OH
O
O
MeO
O
(-)-haliclonadiamine (1996)
N
N
Cl
isoschizogamine (1999)
zaragozic acid A (1996)
H
N
O
CO2H
CO2H
Et
O
O
Me
O
Ph
H
H
ACRL toxin IIIb (1994)
Me
MeO
H
H
O
S
(-)-thiangazole (1994)
NH
HO
O
OMe
Me
S
O
H
H
N
H
OH
OH
S
methyl homosecodaphniphyllate (1988)
HN
O
OH
OH
Me
N
a-bulnesene (1971)
H
N
N
O
Me
diplamine (1994)
HN
Me
N
O
NH
O
N
NHAc
CO2Me
norsecurinine (1987)
(-)-serratoline (1992)
(+)-aristotelone (1992)
O
(+)-methyl homodaphniphyllate (1986)
N
HN
H
N
H
(+)-dihydromevinolin (1986)
O
H
N
H
N
(-)-mirabazole C (1992)
fawcettimine (1986)
Me
Me
O
HO
H
N
AcO
O
(+)-compactin (1985)
N
HN
S
O
N
HO
O
Me
N
N
O
proto-dapniphylline (1990)
N
O
OH
(-)-secodapniphylline (1990)
Me
O
ritosamine R = H
megalosamine R = Me (1983)
O
O
O
parthenin (1982)
S
O
NR2
O
lycopodine (1978)
isovelleral (1990)
OH
N
O
O
Et
vallesamidine (1989)
HO
O
O
CHO
daphnilactone (1989)
HO
CHO
N
Me N
nor-ketoagarofuran (1968)
Me
HO
N
H
O
OH
B-eudesmol (1968)
Me
H
Baran Group Meeting
06/03/2008
N
H
C 6H13
cylindricine A (1999)
aspidospermidine (2000)
O
preussomerin G (1999)
OH
Me
C 5H11
O
HO
O
Me O
Me
O
O
O
Me
O
HO
HO
OH
N
H
Me
O
NH
HO
HO
OH
HO
O
Tricolorin A (1997)
O
O
O
Me
O
Me
X
N
OH
HO
O
OH
O
Br
Me
H
discorhabdin C X = Br
discorhabdin E X = H (1999)
HO
myxalamide A (1999)
O
Me
O
N
H
O
Me
O
O
O
HO
OH
O
O
O
OMe
O
HO
Cl
OH
Me
OAc
Me OH
H2N
Me
O
O
spongistatin 2 (2003)
O
O Me
Cl
Me
AcO
X
N
halichlorine (2004)
OH
pinnaic acid X = O- (2004)
tauropinnaic acid X = NH(CH2)2SO3-
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock (Early years)
Sesquiterpenes
Lycopodium Alkaloids
Copaene and Ylangene: JACS, 1967, 89, 4133
Lycopodine and Lycodoline: JACS, 1982, 104, 1054
Me
OTs
O
O
OTs
OBn
OBn
O
O
Me
O
O
Me
O
S
O
R
NC
O
O
O
NC
DMSO
Me
Me
O
Me
Me
R
OBn
O
+
R
NR'
O
copaene
HCl
R'
MeOH
14 days
O
Me
ylangene
O
OTs
i) H2SO4
ii) O3
iii) NH2OH
Me
AcOH
H
H
88%
N
NH
Lycodoline
O
heat
O
Me
R = homoallyl
R' = H
Bulnesene: JACS, 1971, 93, 1746
H
N
H
H
R
NR'
Me
R=H
R' = (CH2)3OBn
i) H2, Pd/C
ii) Ph2CO, tBuOK
iii) H2, Pt
O
N
Lycopodine
a-bulnesene
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Daphniphyllum Alkaloids
Proposed Biosynthesis (abbreviated)
- Isolated from Yuzuriha tree
- Vermicide and asthma cure early 1900's
- 38 members
JOC, 1992, 57, 2531
CO2Me
H
HN
HN
CO2Me
Squalene
H+
secodaphniphylline skeleton
methyl homosecodaphniphyllate (1988)
H
N
O
O
methyl homodaphniphyllate (1986)
H
N
O
N
O
O
HN
daphnilactone (1989)
daphniphylline skeleton
Key retrosynthetic step
HN
(-)-secodapniphylline (1990)
R
R
OHC
O
HN
O
N
bukittinggine (1992)
proto-dapniphylline (1990)
HN
NH3
OHC
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
"Classic" Synthesis of methyl homodaphniphyllate: JACS, 1986, 108, 5650; JOC, 57, 2531
OBn
O
O
O
N
a. Lawesson's
S
O
+
BnO
O
Me
d. LDA, 78%
N
S
BnO
b. H
c. HO(CH2)2OH
O
N
O
+
O
O
S
BnO
14%
46%
O
N
S
e. Et3OBF4
Me
f. Et3N, 80%
O
O
l. LDA
OBn
OBn
OBn
Me
CH3CHO
j. LTMP, PhSeCl
O
N
Me
k. mCPBA, 60%
N
O
OBn
only diastereomer
O
OBn
OBn
O
N
n. Me2CuLi
m. H2SO4
acetone
O
p. LDA
o. (EtO)2POCl
82%
N
H
Me
O
(EtO)2OPO
O
HO
OBn
OBn
r. Jones, 82%
s. MeOH, H+, 89%
1.1 % overall
methyl homodaphniphyllate
(EtO)2POCl
73%
N
O
CO2Me
N
O
N
O
O
O
Me
i. AcOH, HCl
H
H
Me
O
g. Me3OBF4
h. NaBH4
t. 1800 psi, H2
Pd(OH)2/C
120 oC, MeOH
81%, 1:1 dr
q. Li, EtNH2
N
64%
(EtO)2O2P
N
OPO(OEt)2
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Second Generation Biomimetic Synthesis JOC, 1992, 57, 2544
First Generation Biomimetic Synthesis
footnote (23): "This serendipitous discovery resulted from use of a lecture bottle
of methylamine that was mislabeled as ammonia by the vendor."
O
R
1
R
N
a. LDA, 1
b. 2
c. 3
R = (CH2)3OBn
2
R
N
OHC
O
MeO2C
87%
R
MeNH2
OHC
Me
N
MeO2C
d. DIBAL, 83%
e. KOH
f. HCl, 100%
g. LiAlH4, 96%
h. Swern
I
3
R = (CH2)3OBn
R
R
OHC
R
AcOH
NH4OAc
70 oC, 75%
i. NH3
H
R
N
N
Me
OHC
N
j, AcOH
NH4OAc
70 oC, 82%
R
[4+2]
R
R
aza-
N
prins
k. H2, Pd/C, 96%
l. Jones
m. MeOH, H+, 89%
R
H
H
N
HN
HN
a. Swern
b. MeNH2
c. AcOH, 65%
OH
R = CH2 -geranyl
CO2Me
(±)-methyl homosecodaphniphyllate
H
HN
HO
JOC, 1992,
57, 2554
dihydro-protodaphniphylline
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Daphnilactone A and methyl homodaphniphyllate: JOC, 1992, 57, 2585
OH
Br
CO2Me
a. CrO3, H+
Br
O O
Br
a. Zn, THF
O
OZnBr
O
HMPA
89%
b. MeOH, H+
60%
HN
HN
N firmly
protonated
in acidic
media
O
c. PhNCO
CO2Me
CO2Me
d. HCO2H
O
b. LAH, 90%
c. Swern
O
DIBAL, heat, 87%
OH
HN
HN
Bukittiggine: JOC, 1992, 57, 2575
OBn
g. CrO3, H+
h. CH2O, pH 7
50%
OBn
HN
OBn
OBn
Pd(TFA)2
Ph3P, quinone
N
CH3CN, 70%
71%
16%
O
O
O
O
O
O
N
N
N
bukittiggine
daphnilactone A
N
methyl homodaphniphyllate
OH
+
O
PhHN
O
d. NH3
e. AcOH
87%
f. H2, Py
100%
HN
50%
N
O
M. R. Luzung
Clayton H. Heathcock
Styelsamine B and Cystodytin J: Org. Lett., 2001, 3, 4323
Heterocycles
Aspidospermidine: JOC, 2000, 65, 2642
+
OH
H3N
OHC
Et
Cl
H
N
O
O
N
a. TFA
Cl
CeCl3
NH3+
Et
HN
b. NaI
c. AgOTf
Cl
N
H H
O
N
d. LAH
82%
H
Et
NH2
Ag(I)
O
O
N
N
H
aspidospermidine
NH2
-H2O
R
ArNH2
O
NH2
O
Et
O
Ag2O
N
H
H
CeIII
81%
O
N
O
OH
O
NHBoc
Baran Group Meeting
06/03/2008
O
N
H
R
OH
O
O
N
H
R
OH
R
-H2O
(-)-Thiangazole: JOC, 1994, 59, 4733
Me
MeHN
BnO
O
O
BnS
N
S
NH
N
N
S
Ph
styelsamine B
R
S
Ag(I)
N
S
N
N
N
O
N
H
N
d. TsOH
S
SBn
OH
O
N
HN
H
e. DDQ
c. DMP
O
N
R
a. Na, NH3
SBn b. TiCl4
HN
H
O
O
O
Ph
O
NH
O
NH
Me
MeHN
O
MeHN
N
H
O
S
Ph
cystodytin J
(-)-thiangazole
N
R
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Protecting Group Free Synthesis
Keys to Synthesis
(±)-Fawcettimine: JACS, 1986, 108, 5022, full account: JOC, 1989, 54, 1548
Michael Addition: 2 potential conformers, one diastereomer formed
1,4- vs. 1,6 addition
Me
O
Me
TMS
H
Me
a. (COCl)2
O
CN
R
c. TiCl4, DCM
100%
CN
O
CO2Et
CN
O
1,6 addition
O
H
Me
CO2Et
CN
g. NaOH, EtOH
h. (COCl)2
O
CO2Et
e. Ph3PCHCO2Et,
EtOH
OH
O
CN
H
O-
H
Me
p. O3, 95%
q. NaHCO3, 95%
m. Na, NaH, DME, 94%
OH
CN
-exists in amino ketone exclusively;
closes only when C-4 is up (4S)
H
Me
-protonated amine serves as "protection" to ozonolysis
-base serves to deprotonate and epimerize C-4
to give exclusively fawcettimine
O
O
N
CO2Et
N
H
NH2 OH
H
HO
O
H
k. Ts2O, DMAP, 68%
l. nBu4NOH, 69%
Me
CO2Et
H
Me
O
n. CrO3, HOAc, 87%
o. HClO4
H
Me
CN
O
H
N
H
X
O
CN CO2Et
HO
H
10:1
CN
Me
-
E
R
LiAlH4, 95%
i. CH2N2
j. PhCO2Ag, Et3N
MeOH
47% from aldehyde
R
O
E
H
Me
Me
H
Me
H
X
d. CrO3, Py, 97%
f. NaOEt, EtOH
DMF
E
-
Na+
Me
Me
Me
H
OTMS
b. Zn(Ag)
MeOH, 93%
O
Me
(±)-fawcettimine, 15 steps
13.9% overall yield
N
H
ClO4-
H
M. R. Luzung
Clayton H. Heathcock
Protecting Group Free Synthesis cont'd
Keys to Synthesis
(±)-Vallesamidine: JACS, 1989, 111, 1528, full account: JOC, 1990, 55, 798
O
Baran Group Meeting
06/03/2008
O
a. CH2CHCN
NaOEt, THF
Et
58%
CN
O-
H
N
b. H2, Raney Ni
Et
Michael annulation
H
CO2H
N
H
KOH, MeOH, 95%
Ar
Ph
d. H2, PtO2
O
MeOH, 100%
NO2
N
Et
CO2H
H
Ar
Et
H
e. NBS (unstable)
NH2
f. AgNO3, H2O
MeOH
R = H (79%)
R = Me (20%)
N
RO
Ph
(±)-vallesamidine, 8 steps
18.5% overall yield
Et
O
O
Et
NH2
Br
NBS
N
O
Br
Et
N
N
H
O
NH
N
N
N
O
Me
Et
RO
N
H
Et
N
N
H
Et
h. LiAlH4
Et
N
Indoline Formation
N
O
Me
OH
N
EtCO2H
Et
92%
O
N
H
g. NaBH3CN
CH2O, HOAc
88%
N
Ar
Et
Et
N
Et
O-
HH
N
O
O
N
Et
c. dioxane, reflux, 42%
NO2
O
OH
N
Et
H
Ar
N
Br
AgNO3, H2O
MeOH
R = H (79%)
R = Me (20%)
Et
M. R. Luzung
Baran Group Meeting
06/03/2008
Clayton H. Heathcock
Protecting Group Free Synthesis
Protecting Group Free Synthesis
Aristotelia alkaloids: JOC, 1993, 58, 564
CN
Isovelleral: JOC, 1990, 55, 3004
OHC
a. Hg(NO3)2
b. NaBH4
+
HN
ClMg
39%
N
H
a. THF
b. KOH
+
HN
CO2Me
c.
(MeO)2OP
(+)-makomakine
(-)-ß-pinene
d. 235 oC
CO2Me
c. HCl, heat
59%
Me
HO
d. O2, Pt, EA
e. H2, Pt, 0 oC
HN
i. MeSO3H
50%
NH
(+)-aristoteline
H
O
COOH
g. (COCl)2
heat, 94%
Me
CO2Me
H
g. LiAlH4
96%
OH
HN
Me
CO2Me
j. Me2SOCH2, 65%
OTf
H
l. Pd(OAc)2, Ph3P
CO, Et3N, DMF
DMF, 93%
h. HCl
MeOH
87-94%
HN
H
k. LDA, PhNTf2, 97%
O
H
HN
(+)-aristotelone
f. O3
HN
f. NaOH,
MeOH
heat
97%
HN
H
Me
33%
(-)-serratoline
O
H
O
h. LiCH2CO2Me
N
e. KOH
100%
HN
HN
H
Me
CHO
m. DIBAL
H
Me
CO2Me
n. Swern, 83%
(-)-alloaristoteline
H
Isovelleral
CHO
H
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