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atisine nominine
Me
N
H
N
H
OH
H
OMeHHO
HOH
O
talatisamine
Me
N
H HOH
Jonathan R. Scheerer
Me
C20-Diterpene Alkaloids
A Friday Afternoon Seminar
25 March 2005
Leading References:Stern, The Alkaloids, Vol. 4 (Eds.: R.H.F. Manske, H.L. Holmes), Academic Press, New York, 1954, pp. 275.Stern, The Alkaloids, Vol. 7, 1960, pp. 473. Pelletier, The Alkaloids, Vol. 12, 1970, pp. 1-206. Pelletier, The Alkaloids, Vol. 18, 1981, pp. 1-103. Wang, X.-T., The Alkaloids, Vol. 59, 2002, pp. 1-280.
Keywords: Alkaloids, Total Synthesis
MeO
OMe
Diterpene Alkaloids: Impressive Diversity
H
Me
N
hetisaneskeleton
RN
MeH delphinine
skeleton
atisineH
Me
H
N
O
H
Me
N
HOH
O
veatchine
281 known (2002)
(103)
H
Me
H
RN
(40)
H
Me
RN H
(34)
(50)
(6)
Biosynthetically dividedinto atisine-type and veatchine-type alkaloids.
OH
H
Me
H
RN
H
Me
RN
H
(8)
napellineskeleton
hetidineskeleton
Vary Significantly in Oxidation.
H
Diterpene Alkaloids
Isolated from flowering plants of two genera:Aconitum and Delphinium
Ranunculaceae Family (Buttercup)
H
Me
OHN
HMe
HOH
N
O
EtN
MeO
OMe
H
MeO
OMe
OBz
OH
OH
OH
HO
aconitine1833, toxic!
nominineatisine
Delphinium scaposum
Wolfsbane, Aconitumnapellus
atisine
Diterpene Alkaloids: Biosynthesis
Me
Me MeH
Me
OPP
ent-CPP
OPP
Me
Me MeH
(–H+)
Me
Me MeH
H
H
H
H
H
(–H+)
veatchineH
Me
N
H OH
O
HMe
N
HOH
O
[2.2.2] [3.2.1]
atisineskeleton
Diterpene Alkaloids: Biosynthesis
MeH
H
Me
RN
H
Me
Me MeH
O
H
O
H
MeH
O
H
O
H
MeH
O
H
O
H
O
O
H
Me
RN
HH2NR
H2NR
H2NR
H
Me
RN
O
H
Me
N
OH
H
Me
RN
H
O
H
oxidation
(P450)
Introduction of Nitrogen
hetsineskeleton
H2NR
Mannich
Mannich
hetidineskeleton
H
Me
N
H
Me
RN
H
Mannich
H
Me
RN
O
denudatineskeleton
atisine
H
Me
OHN
nominime
Me
N
H HOH
HMe
HOH
N
O
O
talatisamine
Me
N
H HOH
Diterpene Alkaloids: Structural Comparision
delphinine-type
[3.3.1]aza-bridgedpreserved
[3.2.1]
[2.2.2] [2.2.2][3.2.1]
[3.2.1]
hetisine-typeatisane-type
EtN
H
OMe
N
H
Me
OH
H
OMeHHO
OH
OH
H
MeO
MeO
OMe
OMe
Other Diterpene Alkaloids
H
Me
Nhetisaneskeleton
H
Me
N
HN
H
OH
H
Me
N
O
MeN
Me
MeO
staphisine(bisditerpene alkaloid)
O
HO
OH
delnudine
OH
O
NH2
racemulosine-type
RN
MeH
delphinineskeleton
Different Diterpene Alkaloids from Skeletal Rearrangements and Oxidation
HMe
N HOH
Me
N
H HOH
H
Me
HOH
N
O
O
O
HOH
HMe
N
O
WiesnerCorey
NagataMuratakeFukumoto
Perspective Comparision of Atisine
3-D12
3
4
5
6
7
8
9
10
1112
13
1415
1617
18
19
20
Synthetic Efforts:
Masamune, JACS, 1964, 288-292. (four articles)Pelletier, JACS, 1956, 4144. TL, 1963, 205.Mander, Aust. J. Chem, 1971, 343.Wiesner, TL, 1966, 4645.Nagata, JACS, 1967, 1483. (full paper)Fukumoto, JACS, 1988, 1963.Tahara, TL, 1966, 1453. Tet, 1965, 2133.Okamoto, CPB, 1970, 2135.van der Baan, Rec. Trav. Chim. Pays-Bas, 1975, 109.Kametani, JACS, 1976, 8185.
Standard TerpeneNomenclature andNumbering
HMe
HOH
N
O
Atisine Aminal Interconversions
Me
N
H HOH
O
Me
N
H HOH
O
MeOH, !
Me
N
H HOH
Me
N
H HOH
DMSO, !
OHHO
HClbaseHClbaseatisine
=
HMe
HOH
N
HO
OsO4, 3 days;KOH, EtOH
HMe
HOH
HN
isoatisine
Cl Cl
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
all syntheticefforts haveintercepetedthe Pelletierintermediate
Masamune, JACS, 1964, 288-292. (four articles)
BnO
OH
O
HO
H H
OTHP
Br
O
O
H
OTHP
H
Br
H
THPO
H
O
Br
H
H
THPO
KOt-Bu, t-BuOH, !
Does not react
30%
O
H
OTHP
H
H
H2, Pd-CaCO3
1) Ph3CNa, CO2; MeI2) ethylvinyl ketone
3) MeI, base
H
OTHP
H
H
O
MeO2C
Me Me
Synthesis of Atisine: Masamune
60%
H
H
HO2C
Me Me
O
H
H
H
MeO2C
Me MeH
OTHP
H
OH2, Pd/C steps
kaurene
alkaloids,e.g. atisine
Masamune, JACS, 1964, 288-292. (four articles)
H
H
HO2C
Me Me
O
H
H
H
Me MeH
O
O
O
H2NHN1) (COCl)2; H2NNH22) TsOH, (HOCH2)2
1) HNO2, h!, –10 °C
2) LiAlH43) Ac2O
H
H
H
O
OAcN
Me
5%
H
H
H
AcN
Me
Me
H
H
H
EtN
Me
OAc
1) h!, O22) LiAlH4
3) Ac2O
BrCNVon Braun
H
H
H
N
Me
OAc
N
Synthesis of Garryine: Masamune
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
(±)-garryine
O
HMe
N
HOH
H
3 steps
via acylazide andnitrene
Masamune, JACS, 1964, 288-292. (four articles)
H
H
H
HN
Me
OH
Synthesis of Atisine: Masamune
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
(±)-garryine
atisine
HMe
HOH
N
O
H
H
AcN
Me
CO2Me
H
H
AcN
Me
CO2Me
O
H
H
AcN
Me
CO2Me
CO2Me
H
H
AcN
Me
CO2Me
CO2Me
HMe
H
CO2Me
O
AcN
HMe
H
AcN
1) CrO3, H2SO42) CH2N2
3) NaOMe, MeOH4) NaOH
CO2H
1) (COCl)22) Me2Cd3) mCPBA
O
Me
1) NaOH2) CrO33) NaOMe, (MeO)2CO
4) NaBH45) TsCl, pyr
1) H2, Pd/C2) NaOH
3) (COCl)24) CH2N2
NaOMe, !xylene
1) NaOH; H+, !2) NaH, MeI, DMSO
3) AcOH, HBr4) NR3, !5) NaBH4
OH
6 steps
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
6 steps
Masamune, JACS, 1964, 288-292. (four articles)
O
H
OTHP
H
30%
H
O
N2
BF3•OEt2MeNO2
30%Mander, Aust. J. Chem, 1971, 343.
HO
OH
ON
N
O
O
HO
H
OTHP
Br
OH
Br
H
THPO
H
OH
Br
H
H
THPO
KOt-Bu, t-BuOH, !
Does not react
Aryl Alkylations: a Contribution by Mander
Mander's Solution: Use a trigonal carbon bridge with a better electrophile (N2+)
The Masamune Precedent
H
[3.2.1]
[2.2.2]
OMe
Me
O
HO2C
H
OMe
Me
O
N
H
•O1) EtO2CCl, NEt3
2) NaN3; ! TsOH
56%
1) (HSCH2)2, BF3•OEt22) Raney Ni, H2
3) Li, NH3; H+
h", allene
–78 °C
StereoselectivityDiscussion
4 steps
HN
HMe
OMe
O
O
HN
HMe
O
O H
HN
HMe
O
O H
AcN
HMe
HO
O
O
65%, 3 steps80%
Synthesis of Atisine: Wiesner
Wiesner, TL, 1966, 4645.
Stork, JACS, 1956, 5128.
Me
NH
H H
O
O
Facially distinct LUMOSee Fleming for further commentary
•
O
1) NaBH42) HCl, THF, !
(±)-atisine(±)-garryine
Synthesis of Atisine: Wiesner
Wiesner, TL, 1966, 4645.
AcN
HMe
H
O
OH
AcN
HMe
HO
O
O
AcN
HMe
H N
8 steps
O
N
AcN
HMe
H
Me
AcN
HMe
H
6 steps
N
HMe
H
O
OH
N2
OH
AcN
HMe
H
O N
HMe
HOH
H
H
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
Masamune, JACS, 1964, 288-292. Pelletier, ibid.
NaOEt, EtOH
Nagata, JACS, 1967, 1483.
OMe
O
OMe
O
Et2AlCl, HCN
OMe
O
CN
H
OMe
O
CN
H HCl equilibration
crystalline
OMe
CN
H
Me
CHO
1) Ph3PCHOAr2) H3O+
3) MeI, t-BuOK
equatorial alklylationsingle isomer
87%
OMe
HMe
HN1) HCl, !2) LiAlH4
1) Na, NH3, t-BuOH
2) MsCl3) HCl
59%
O
HMe
MsN
HEt2AlCl, HCN
O
HMe
MsN
H CN
HMe
MsN
H
1) TsOH, (HOCH2)22) MeLi; H+
3) KOHO
OH
Stork, JACS, 1947, 2936.
Synthesis of Atisine: Nagata
94%
56%, 3 steps
60%
47%
72%
HMe
MsN
H
OMs
OAc
HMe
MsN
H
O
HMe
MsN
H OMs
O
HMe
MsN
H
KOt-Bu
HMe
AcN
H
54%
KOH
1) Ph3PCH22) Li, NH3
3) Ac2O4) HCl
1) NBS, CCl4 (PhCOO)2
2) mCPBA3) Zn, EtOH
Wohl-Ziegler
6 steps
(±)-atisine
OMe
HMe
AcN
HOH
HMe
AcN
HOH
1) Jones Ox.2) NaBH4
Nagata, JACS, 1967, 1483.
Synthesis of Atisine: Nagata
HMe
N
HOH
Pelletier, JACS, 1956, 4144.
O
4 steps
O
HMe
MsN
H
OMs
OAc
Nagata, JACS, 1967, 1499.
HMe
MsN
H
OR
HMe
MsN
H
OH
OSO3Ar
HMe
MsN
H
O
HMe
HN
H OH
HMe
N
H OH
(±)-garryine
steps
XH+
Synthesis of Garryine and Veatchine: Nagata
collidine, !
HMe
N
H OH
O
(±)-veatchine
HMe
N
H OAc
HO
Pelletier, JACS, 1956, 4144. TL, 1963, 205.
OsO4;KOH, EtOH
HMe
N
H OAc
AcO
Cl
BnN
CO2Me
O
CO2Me
1) BnNH2,HCHO
2) MePPh3Br, t-AmOK
77%
OMe
CHPPh3
Na, NH3;EtOH, HCl
NaBH4, BF3•OEt2;NMO
LA coordinates to N,blocking bottom face.
Synthesis of Atisine: Fukumoto
Fukumoto, JACS, 1988, 1963.
NBn
MeO2C
CO2Me
NBn
Me
OMOM
H
OMOM
Me
MeO2CN
H
OH
MeMeO
MeO2CN
H
OH
MeO
MeO2CN
HMe
O
CO2Me
72%
OH
MeO2CN
CHOH
OMOM
Me
1) Pd/C, HCO2NH42) ClCO2Me
3) Swern
1) Wittig2) H2, Pd/C
3) HCl, MeOH
83%80%, 3 steps
1) Swern2) Ph3PCHCO2Me
LiHMDS,–78 to 0 °C
43%X-ray
1) KOH2) (COCl)2, DMF3) DMAP,
4) Bu3SnH, AIBN
N
S
NaO
1) TMSI2) AcCl, NaHCO3
48%63%
(±)-atisine
+8% stereoisomer
Me
NCO2Me
OO
Li
H
OMe
Synthesis of Atisine: Fukumoto
Fukumoto, JACS, 1988, 1963.
MeO2CN
HMe
O
CO2MeMeO2CN
HMe
H
MeO2C
O
MeO2CN
HMe
HO
AcN
HMe
HO
HMe
N
HOH
OPelletier, JACS, 1956, 4144. TL, 1963, 205.
Barton Decarboxylation for younger members
R
RO
O
N
S
H
SnR3
R
RO
O
• R
R•
H•
H•
R
R
Reveiw: Sir D.H.R. Barton, Tet, 1992, 7083-130.
CH3
atisine
(–)-methyl dehydroabietate
Me
Me
MeO2C Me
Me
HMeO2C Me
Me
H
AlCl3
Wenkert, JACS, 1958, 211.
39%
MeO2C Me
Me
HOH
Pb(OAc)4I2, h!, 60 °C;KOH, MeOH
MeO2C MeH
O
O
Me
MeO2C
HMeO2C MeH
AcO
BF3•OEt2,Ac2O
HMe
O
O
O
HMe
AcN1) Urea, "2) LiAlH4
3) Ac2O; NaOH4) CrO3
O
steps
OH
Me
AcN1) HNO22) H2, Pd/C
3) NaNO2; H2O4) CH2N2
OMe
Nagata
Synthesis of Atisine: Tahara
MeO2C Me
Me
O
OAc
Tahara CPB, 1961, 655. TL, 1966, 1453. Tet, 1965, 2133.
Okamoto, CPB, 1970, 2135.
Synthesis of Atisine: Okamoto
H
Me
N OTHP
Me
H
HOTHP
Me
H
MeMe
N
OH
H
H
NOTHP
Me
H
Br
MeMe
OBrN3 h!
46%
O
H
H
NOTHP
Me
H
Br
MeMe
O• •
Me
CH3
RR
NO
BrMe
CH3
RR
Br
RO N••
R
Me RR
Br
RN
OH
Me
N O
R
R R
=
derived from GA15
EtN
Atisine Core: van der Baan
van der Baan, Rec. Trav. Chim. Pays-Bas, 1975, 109.
O
EtO2C
NC
O
NH2
OH
HN
CN
O
allylBrNaH
O
HN
CN
O
110 °C[3,3]
O
HN
O
CN
O
EtN
O
CN
OTHP
Br
CN
THPO
O
O
(±)-atisine
Synthesis of Atisine: Kametani
Kametani, JACS, 1988, 1963.
Br
NC
OMe
65%
OMe
NC
OMe
NC
MeMeO2C
OMe
NC
MeMeO2C
OMe
CN
HMeO2C Me
OMe
HMe
HN
Nagata, JACS,1967, 1483.
180–230 °Csealed tube
52%
NaNH2
single isomer
4! cyclization"con in"
Delphinine-type Alkaloids
N
H
OH
H
OMeHHO
N
H
OMe
OH
OH
H
talatisamine
Me
Me
MeO
MeO OMe
N
OMe
Me
HO
MeO
H
HO
H
H
Corey,Wiesner
EtN
H
OMe
OH
OH
H
MeOMeO
chasmanine
MeN
H
OMe
OH
OH
H
MeOMeO
X
x = OH, delphininex = H, 13-desoxydelphinine
EtN
H
OMe
OMe
OH
H
OMeO
OH
OMe OMe
H H
ONO
O
Me
methylcaconitine
Nicotinic-AcH receptor ligandhighly toxic!
= =
OMe OMe
H
Synthesis of Talatisamine: Wiesner
Wiesner, JACS, 1974, 4990.
AcN
H
H
O
OMe
AcN
H
H
OMe
O
O
OTs
NAc
H
XOTsH
OMe
NAc
H
OMe
OO
H
NAc
H
OMe
OO
H
EtN
H
OMe
N
H
OMe
OHH
H
Me
N
H
OMe
OHH
H
Me
N
H
Me
OH
H
OMeHHO
Hg(OAc)2
=
40%
40%
OH
OH=
H
(±)-talatisamine
40%
NR3, !
OMe
MeOMeO
MeO
MeO
steps
MeO
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
OMe OMe
prepared in a fashionanalogous to atisine core
OMe
H H
Me
O
Me
OMeMeO2C
Me
OMeMeO2C
OO
O
Me
OMeMeO2C
O
O
O
1) TMSN32) HOAc, Ac2O
Me
OH
O
Me
OMeMeO2C
MeOMe
R
H
HNH
H
O
Synthesis of Delphinine Alkaloids: Wiesner
Wieser, Pure Appl. Chem., 1979, 689.
OMe
Me
OAc
MeO2C
AcHN
O
Cl
AlCl3
85%
several days85 °C, 70%
(Ph3P)2Ni(CO)2
!
=
MeOMe
NAc
CO2Me
H
[4+2]
OMe
Me
OAc
NHAcMeO2C
OMe
Me
HN
MeO2CO
Me
R = CO2Me
HO
O
Me
H
O
HO
BrMg
MeO
OBn
1) RMgBr2) Ac2O3) H2, Pd/C4) PDC
K2CO3,MeOH, !
90%
OAc
h"
95%
OMe
Me
OAc
MeO2C1) Ce(NH4)2(NO3)62) mCPBA
3) K2CO3, MeOH
OMe
OH
OH
MeO2COMe
OMOM
OBn
OHC
RMgBr =
OMe
OMOM
O
O
MeO
OMe
OMOM
OMeO
OMe
OMOM
O
MeO
AcHN
AcOAcHN
MeO2C
OMe
OMOM
O
HN
MeO
OH
O
AcHN
AcHNAcO
AcHNHO
OMe
OMOM
O
MeO
AcOAcHN
OAc
H H
AcHN
Synthesis of Delphinine Alkaloids: Wiesner
Wieser, Pure Appl. Chem., 1979, 689.
NaOMe,MeOH, !
1) LiAlH(Ot-Bu)32) MeI, NaH
86%
OMe
OMOM
O
HN
MeO
O
H
selective demethylation
NaSEt,DMF120 °C
95%
OH
OMOM
OMe
MeN
MeO
OMe
H
H
OMe
OMOM
OMe
MeN
MeO
OMe
H
H
O
OH
OMe
MeN
MeO
OMe
H
HCO2H
O
OMe
MeN
MeO
OMe
H
H
O
OO
NBS
BnO
rt
exo
O
OMe
MeN
MeO
OMe
H
H
O
OO
OBn
O
OMe
MeN
MeO
OMe
H
H
OBnXX
Zn, HOAc18-c-6, !
Synthesis of Delphinine Alkaloids: Wiesner
Wieser, Pure Appl. Chem., 1979, 689.
x = H, Br
NMe
H
MeO
MeO
OMe
OMeOMOM
=
O
OMe
MeN
MeO
OMe
H
H
OBn
O
OMe
MeN
MeO
OMe
H
H
OAc
1) H2, Pd/C2) Ac2O
1) H2 (85 psi), Rh/Al2O3
2) CrO3•pyr
O
OMe
MeN
MeO
OMe
H
H
OAc
H
O
OMe
MeN
MeO
OMe
H
H
OMe
OMe
MeN
MeO
OMe
H
H
OMe
Br
O
O
MeN
MeO
OMe
H
H
MeO
OMe
X
MeN
MeO
OMe
H
H
MeO
OMe
OH
OH
Synthesis of Delphinine Alkaloids: Wiesner
Wieser, Pure Appl. Chem., 1979, 689.
=
==
=
1) Br2 dioxane
2) TsOH (HOCH2)2
5 steps
180 °CDBNDMSO
89%
X = (-OCH2)2
Delphonine
NMe
H
MeOMeO
OMe
OMe
H
O
NMe
H
MeOMeO
OMe
OMe
H
XBrH
NMe
H
OMeH
X
MeO
OMe
MeO
NMe
H
OMeHHO
MeO
OMe
MeO
OMeH
HMe
N HOH
H
Me
OHN
nominime
Me
N
H HOH
Hetisine-type Alkaloids
structurally the most simplelocal anesthetic, antinflammatory, antiarrhythmic
Mander MuratakeH
Me
OHN
H
Me
OHN
HO
HO
HO
hetisine
H
Me
OHN
HO
Winkler
kobusine
H
N
davisinol
HO
HO
H
N
HOOAc
OH
OAc
BzO
tadzhaconine
pronouncedantiarrhythmicED = <0.3 mg/kg
N
Me
HO
HO
HO
R N
O
O
NH2
NBoc
Me O
NBoc
Me
O
H
NBoc
Me
O
Boc N
Oh!
PyrexMeCN
86%
EtOH,PPTS, "
84%
Winkler, JACS, 2001, 7429.
Approach to Hetisine Core: Winkler
Hetisine
MeN
O
Br
CO2Et
MeNBr
EtO2C
O
OMe
Me
Me
OH
NMe
Br CO2Et
O RXMg
NMe
Br CO2Et
R O
MgX
EtO2C
O
Ar
MeNBr
OH
OAc
OMe
AcO
(AgBF4, 18%)
53%
MeN
OH
AcO
OAc
OMe
Williams and Mander, OL, 2003, 3499.
NMe
Br CO2Et
O
O
OMe
Me
Me
BrMg
64%
Bridgehead Arylation: an Approach by Mander
RMgBr
THF
1) TMSOTf, Ac2O2) Pd/BaSO4, H23) Reduction4) Acylation (1° ROH)
RMgBr =
SO3Ag
NO2
NO2O2N
Muratake, TL, 2002, 2913.Muratake, ACIE, 2005, 4646.
MeO
Br
OHC
OO
mixture ofdiastereomers
Muratake, Tet, 2004, 11783.
OHC
OO
PdCl2(PPh3)2,Cs2CO3, THF, !
OMe
H
OHC
OO
OMe
H65% 4 : 1
cis / trans
OO
OMe
H
O O
34%OO
OMe
H
O O
61%
TsOHHO(CH2)2
35% (+SM)
OO
OH
H
O O
1) Li, NH3; HCl
2) NaOMe, MeOH3) NaBH4, CeCl3
H
OOH
O O
H OPiv1) BF3•OEt2
2) TsOH, Me2CO
1) Me2NCH(OMe)2, 160 °C
2) BH3•NH3, BuLi3) PivCl, NEt3, DMAP
H
OPiv
O
O
MOMOO O
H
O
O
LA
H
PivO
20
Synthesis of Nominine: Muratake and Natsume
mixture subjectedto acetalization
~60%, 3 steps
H
66%
TsOH65%, 3 steps
Muratake, TL, 2002, 2913.Muratake, ACIE, 2005, 4646.
H
H
OPiv
O
O
HO
H
OH
O
H
OAc
RO
OMeNCH
H
OH
RO
H
NCbzMe
H
OH
RO
H
NCbzMe
H
RO
H
NCbzMe
Bu3SnH, AIBN, toluene, !;
SiO2
H
RO
H
NCbzMe
H
RO
H
NCbzMe
SnBu3
1) TMSI, HMDS; NBS
2) MOMCl3) MeLi Et2AlCN
1) TMSCl, LDA2) LiAlH43) CbzClNaBH3CN
1) PCC2) Ohiraalkynlation
3) HCl
63%90%
73%
31% 57%
Synthesis of Nominine: Muratake and Natsume
H
OAc
RO
Me O
1) Ac2O, pyr
2) PCCMe OH
94%
MOMO
52%, 5 steps
R = -(CH2)2OH
mixture at 3° ROH
Muratake, TL, 2002, 2913.Muratake, ACIE, 2005, 4646.
H
Me
N
nominime
1) Pd(OAc)2, Et3SiH, NEt32) SOCl2, pyr3) K2CO3, MeOHOH
H
RO
H
NCbzMe
H
HO
H
NCbzMe
O
1) SeO22) MnO2
Synthesis of Nominine: Muratake and Natsume
1) NaBH4, CeCl32) Ac2O, pyr
3) Zn, NH4ClH
HO
H
NCbzMe
OAc
90%
94%
Me
N
HOH
R = -(CH2)2OHR = -(CH2)2Br
40 steps (0.15%)
MsCl; LiBr (97%)
fin
