C20-Diterpene Alkaloids

HO

Me

N
O

H
HO

Me

OH

MeO
N

N
Me

atisine

nominine

OMe H

HO

OMe

talatisamine

A Friday Afternoon Seminar

Jonathan R. Scheerer
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

Diterpene Alkaloids: Impressive Diversity

281 known (2002)
RN

RN

Biosynthetically divided
into atisine-type and
veatchine-type alkaloids.

H
H
Me

(50)

H
H

(8)

Me
O

O
N
OH

H
H

Vary Significantly in Oxidation.

H
H

atisine

Me

Me

RN

RN
H
H
Me

(40)

hetidine
skeleton

H
Me

(103)

veatchine

RN

OH

hetisane
skeleton

delphinine
skeleton

H
Me

(6)

napelline
skeleton

H
Me

(34)

Diterpene Alkaloids
Isolated from flowering plants of two genera:
Aconitum and Delphinium
Ranunculaceae Family (Buttercup)

O
N
H

Me

OH

OH

atisine
OMe

N
H
Me
OBz
OH
OMe

EtN
OH
OH
HO
MeO

H
MeO

aconitine
1833, toxic!

nominine

Wolfsbane, Aconitum
napellus
Delphinium scaposum

Diterpene Alkaloids: Biosynthesis

Me
Me
OPP
OPP
Me

H
Me

ent-CPP
H

H
H

[2.2.2]

[3.2.1]
(H+)

(H+)
O

O
Me

N
H

Me

H
Me

Me

atisine

Me

OH

Me

veatchine

OH
Me

H
Me

Diterpene Alkaloids: Biosynthesis

Introduction of Nitrogen
H
H

RN

RN

H2NR

oxidation

(P450)
H

RN

Mannich

H2NR

Me

atisine
skeleton

Me

RN

Me

Me

H
Me

H
Me

Me

denudatine
skeleton

H
O

Me

H
Me O

O
H

H2NR

H2NR

OH
O

H
Me

H
Me

Mannich
Me

RN

RN
H

Mannich
H

H
Me

hetsine
skeleton

Me

hetidine
skeleton

Diterpene Alkaloids: Structural Comparision

atisane-type

hetisine-type

delphinine-type

atisine

nominime

talatisamine
OH

OMe

OMe
EtN

N
OH

OH

H
Me

OH

Me
MeO

HO

Me

H
Me

HO

H
H

N
Me

[2.2.2]
[3.3.1]
aza-bridged
preserved

OH

MeO
N

OMe H

[2.2.2]
[3.2.1]

HO

[3.2.1]
[3.2.1]

OMe

Other Diterpene Alkaloids

RN
N

hetisane
skeleton

delphinine
skeleton

H
Me

Me

Different Diterpene Alkaloids from Skeletal Rearrangements and Oxidation

O

Me
N

O
NH2

Me

OH
HN

HO
N

OH
H
Me

MeO

OH

delnudine
N
H
Me

staphisine
(bisditerpene alkaloid)

racemulosine-type

Perspective Comparision of Atisine

H

HO

Me

13

O
N
O

20

3-D

16

12
14

9
10

19

17

15

OH

Standard Terpene
Nomenclature and
Numbering

11

7
4

Me
N

Me

HO

OH

Nagata
Muratake
Fukumoto

N
O

Wiesner
Corey

Me

18

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.

Atisine Aminal Interconversions

isoatisine
H

HO

Me

N
H

OH

H
H

Me

MeOH, !

HO

N
O

H
Me

base

atisine

base

HCl
HO

Me

HO

Me

DMSO, !

Cl

HCl

Cl

HO
OH

all synthetic
efforts have
intercepeted
the Pelletier
intermediate

HN

N
H

OH

HO

H
Me

OH

OsO4, 3 days;
KOH, EtOH

H
Me

Pelletier, JACS, 1956, 4144. TL, 1963, 205.

Synthesis of Atisine: Masamune

H
THPO
H
BnO

HO
O
H

OTHP

Does not react

KOt-Bu,
t-BuOH, !

O
THPO

OH

Br

H
H

Br

Br

30%
H
H

1) Ph3CNa, CO2; MeI

2) ethylvinyl ketone

H
H
OTHP

H2, Pd-CaCO3

OTHP

3) MeI, base

60%

H
H
MeO2C

MeO2C

OTHP

Me

HO2C

OTHP

steps

O
Me

H
Me

O
H

H2, Pd/C
Me

H
H

H
O

Me

H
Me

alkaloids,
e.g. atisine
kaurene

Masamune, JACS, 1964, 288-292. (four articles)

Synthesis of Garryine: Masamune

H
HO2C

O
H

1) (COCl)2; H2NNH2
2) TsOH, (HOCH2)2

1) HNO2, h!,
10 C

O
H

2) LiAlH4
3) Ac2O

H
Me

Me

1) h!, O2
2) LiAlH4

EtN

O
AcN
O

3) Ac2O

OAc

3 steps

H
Me

Me

via acyl
azide and
nitrene

H
Me

AcN

Von Braun

H2NHN

H
Me

Me

5%

Me

BrCN
H

N
H
OAc
H

Me

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

OH
Me

()-garryine
Masamune, JACS, 1964, 288-292. (four articles)

Synthesis of Atisine: Masamune

H

CO2H

HN

6 steps

()-garryine

OH

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

CO2Me

AcN

CO2Me

AcN
H

CO2Me

3) NaOMe, MeOH
4) NaOH

Me

1) H2, Pd/C
2) NaOH

AcN

1) CrO3, H2SO4
2) CH2N2

3) (COCl)2
4) CH2N2

CO2Me

CO2Me

1) (COCl)2
2) Me2Cd
3) mCPBA

H
Me

1) NaOH
2) CrO3
3) NaOMe,
(MeO)2CO

O
AcN

O
H

4) NaBH4
5) TsCl, pyr

Me

Me

CO2Me

H
Me

NaOMe, !
xylene
CO2Me
AcN
H
H
Me

Me

atisine
1) NaOH; H+, !
2) NaH, MeI,
DMSO

6 steps

AcN

3) AcOH, HBr
4) NR3, !
5) NaBH4

H
H
Me

OH

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

OH

H
Me

Masamune, JACS, 1964, 288-292. (four articles)

Aryl Alkylations: a Contribution by Mander

The Masamune Precedent

H
THPO
H

HO
OTHP

Br

Does not react

KOt-Bu,
t-BuOH, !

OH
THPO

H
H

Br

H
H

Br

OTHP

[3.2.1]
OH

30%

Masamune, JACS, 1964, 288-292. (four articles)

Mander's Solution: Use a trigonal carbon bridge with a better electrophile (N2+)

HO

BF3OEt2
MeNO2

O
N

O
N2

OH

Mander, Aust. J. Chem, 1971, 343.

30%

[2.2.2]

Synthesis of Atisine: Wiesner

OMe

HO2C

1) EtO2CCl, NEt3
2) NaN3; !
O
Me

TsOH

OMe

Me

56%

Stork, JACS, 1956, 5128.

O
HN

h", allene

78 C

OMe

1) (HSCH2)2, BF3OEt2
2) Raney Ni, H2

80%

3) Li, NH3; H+

HN

H
Me

65%, 3 steps

Me

Stereoselectivity
Discussion
H

O
HN

Me
O
O

N
H

AcN
H

Facially distinct LUMO

See Fleming for further commentary

4 steps

H
Me

H
Me

Wiesner, TL, 1966, 4645.

Synthesis of Atisine: Wiesner

OH
O

1) NaBH4
2) HCl, THF, !

AcN
O

AcN
H

Me

Me

6 steps
8 steps
OH

AcN

AcN

N2

AcN

Me

NaOEt,
EtOH

H
N
H

H
Me

Me

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

Me

H
O
O

AcN
H

N
H

H
Me

Masamune, JACS, 1964,

288-292. Pelletier, ibid.

H
Me

OH

()-garryine

()-atisine

OH

H
Me

Wiesner, TL, 1966, 4645.

Synthesis of Atisine: Nagata

crystalline
OMe

OMe

OMe

OMe

CN

CN

Et2AlCl, HCN
Stork, JACS,
1947, 2936.

72%

HCl
equilibration

OMe

1) Na, NH3,
t-BuOH

OMe

1) HCl, !
2) LiAlH4

HN

CN
Me

2) MsCl
3) HCl
Me

87%

MsN

H
Me

1) Ph3PCHOAr
2) H3O+

equatorial alklylation

OH

MsN
H

94%

56%, 3 steps

single isomer

3) MeI, t-BuOK

H
CHO

59%

Et2AlCl, HCN

60%

CN

1) TsOH, (HOCH2)2
2) MeLi; H+

MsN
H
O

3) KOH

H
Me

Me

47%
Nagata, JACS, 1967, 1483.

Synthesis of Atisine: Nagata

OAc

MsN

MsN

MsN

KOH

4 steps

OMs

OMs
Me

H
Me

Me

Wohl-Ziegler
Me

1) NBS, CCl4
(PhCOO)2

1) Ph3PCH2
2) Li, NH3

AcN
H

2) mCPBA
3) Zn, EtOH
Me

MsN
H

3) Ac2O
4) HCl

KOt-Bu

Me

54%

O
AcN

AcN
H

Me

OH
H

1) Jones Ox.
2) NaBH4

Me

OH

6 steps

Pelletier, JACS,
1956, 4144.

Me

OH

()-atisine

Nagata, JACS, 1967, 1483.

Synthesis of Garryine and Veatchine: Nagata

OAc

OR

MsN

collidine, !

MsN
H

H
Me

HO

OSO3Ar

MsN

OMs
Me

OH

H+

Me

Me

OAc

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

OsO4;
KOH, EtOH

Me

MsN

HN

OH

steps

Me

O
N
AcO
H

O
Me

N
H

OH

()-garryine

Me

H
OAc

Cl

Me

OH

()-veatchine
Nagata, JACS, 1967, 1499.

Synthesis of Atisine: Fukumoto

OMOM
CO2Me
O

CO2Me

1) BnNH2,HCHO
2) MePPh3Br,
t-AmOK

CO2Me

NaBH4, BF3OEt2;
NMO
NBn

NBn

LA coordinates to N,
blocking bottom face.

77%

1) Wittig
2) H2, Pd/C

BnN

MeO2CN

OMe

OMOM

CHPPh3

3) HCl, MeOH

Me

CHO

MeO2CN
OH

Me

3) Swern

OMOM
OH
Me

MeO2CN
OH

Na, NH3;
EtOH, HCl
Me

MeO

1) Pd/C, HCO2NH4
2) ClCO2Me

83%

80%, 3 steps

MeO2CN

72%

Me

MeO2C

H
O

CO2Me

1) Swern
2) Ph3PCHCO2Me
Me

H
O

Fukumoto, JACS, 1988, 1963.

Synthesis of Atisine: Fukumoto

MeO2CN

CO2Me

LiHMDS,
78 to 0 C
Me

MeO2C

Li

O
Me

X-ray

43%
+8% stereoisomer

Me

1) KOH
2) (COCl)2, DMF
3) DMAP, NaO
AcN
H

Me

1) TMSI
2) AcCl, NaHCO3

MeO2CN

63%

N
CO2Me

MeO2CN

OMe

Me

4) Bu3SnH,
AIBN

48%

Barton Decarboxylation for younger members

Pelletier, JACS,
1956, 4144.
TL, 1963, 205.

O
N

N
H

OH

O
R

R
SnR3

Me

()-atisine

R
R

Reveiw: Sir D.H.R. Barton,

Tet, 1992, 7083-130.

R
R

Fukumoto, JACS, 1988, 1963.

Synthesis of Atisine: Tahara

()-methyl dehydroabietate
Me
Me

Me

Me

Me

Me

AlCl3
39%
MeO2C

H
Me

Wenkert, JACS,
1958, 211.

MeO2C

H
Me

MeO2C

MeO2C

Me OAc

BF3OEt2,
Ac2O

steps
O
O
MeO2C

Me

H
Me

H
Me OH

Pb(OAc)4
I2, h!, 60 C;
KOH, MeOH

AcO

O
H
Me

MeO2C

H
Me
MeO2C

CH3
O

OMe

1) Urea, "
2) LiAlH4
3) Ac2O; NaOH
4) CrO3

1) HNO2
2) H2, Pd/C

AcN

H
Me

AcN

Nagata

3) NaNO2; H2O
4) CH2N2

atisine

H
Me

Tahara CPB, 1961, 655.

TL, 1966, 1453. Tet, 1965, 2133.

Synthesis of Atisine: Okamoto

OH

Me

Me

Br

H
Me

Me

h!

OTHP

OTHP

OTHP
H
Me

Me

BrN3

Me

Me

Br

H
Me

derived from GA15

Br

Me

R
N

46%

OH

Br

Me

R
CH3

Br

Me

R
CH3
O

H
R

Me

R
N

Me

OTHP
H

Me

Okamoto, CPB, 1970, 2135.

Atisine Core: van der Baan

O
OH

allylBr
NaH

EtO2C
NC
O

HN
NH2

HN
O

CN
CN

110 C
[3,3]
Br

THPO

EtN

O
OTHP
HN

EtN
O

O
CN

CN

CN

van der Baan, Rec. Trav. Chim. Pays-Bas, 1975, 109.

Synthesis of Atisine: Kametani

OMe

OMe

OMe

NaNH2
Br

65%

NC

NC

NC

MeO2C Me

4! cyclization
"con in"
OMe

OMe
CN

HN

Me

180230 C
sealed tube

MeO2C

H
Me

MeO2C

52%

Me

OMe

NC

single isomer
Nagata, JACS,
1967, 1483.

()-atisine

Kametani, JACS, 1988, 1963.

Delphinine-type Alkaloids
talatisamine
MeO

OH
H
OMe

OMe

Me

OH

HO

=
Me

HO

Me

OMe

OH

MeO

H
H

OMe H

HO

OMe

Corey,
Wiesner

H
OMe

MeO

OH
X

OH
OMe
EtN

OMe
MeN

OMe
OMe
H

MeO

H
MeO

chasmanine

MeO

H
MeO

x = OH, delphinine
x = H, 13-desoxydelphinine

EtN

H
H

OH

OH

OMe

OMe

Me

OH

O
O

H
MeO

OH

methylcaconitine
Nicotinic-AcH receptor ligand
highly toxic!

Synthesis of Talatisamine: Wiesner

prepared in a fashion
analogous to atisine core
OMe

OMe
O

OMe

OMe

AcN

MeO

OMe H

AcN
H

OTs

MeO

OTs

N
Ac

MeO

40%

40%
MeO

OH

OMe

Hg(OAc)2

MeO
N

OMe

OH

N
Ac

OMe

OMe

OMe
H

MeO
N

40%

OMe

OMe

NR3, !

OMe

N
Ac

MeO

OMe

steps

Me

Me
OH
H

OMe H

MeO

OMe

N
Me

EtN

OH

HO

OMe

OH

OMe

()-talatisamine

MeO

Wiesner, JACS, 1974, 4990.

Synthesis of Delphinine Alkaloids: Wiesner

Me

Me
O

Me

Me

AlCl3
OH

O
Cl

MeO2C

MeO2C

OMe

OMe

[4+2]
O
O

NAc
CO2Me
Me

MeO

Me

Me

1) TMSN3
2) HOAc, Ac2O

MeO2C

OMe

(Ph3P)2Ni(CO)2

MeO2C

OMe

85%
H

H
N

R
Me

MeO

Me
MeO2C

H
N

R = CO2Me

MeO2C

NHAc

Me
H

Me

AcHN
MeO2C

O
OMe

several days
85 C, 70% HO

Me

OMe

Me
OMe

OAc

OAc

O
HO

Wieser, Pure Appl. Chem., 1979, 689.

Synthesis of Delphinine Alkaloids: Wiesner

Me

AcHN
MeO2C

OMe

1) Ce(NH4)2(NO3)6
2) mCPBA

OH

AcHN
MeO2C

OMOM

AcHN
OHC

OMe

OMe

3) K2CO3, MeOH
OAc

OAc

OH

OMOM

AcHN
HO

h"

K2CO3,
MeOH, !

OMe

95%

1) RMgBr
2) Ac2O
3) H2, Pd/C
4) PDC
BrMg

OMe
O

RMgBr =

MeO
OBn

MeO

OMOM

AcHN
AcO

OMOM

AcHN
AcO

90%

MeO

OBn

OMOM

AcHN
AcO

OMOM

OH
HN

OMe

OMe

OMe
O

MeO

MeO
O
OAc

MeO2C

NaOMe,
MeOH, !

H
MeO

Wieser, Pure Appl. Chem., 1979, 689.

Synthesis of Delphinine Alkaloids: Wiesner

OMOM

O
HN

OMe

H
MeO

OMOM

OMe
MeN

1) LiAlH(Ot-Bu)3
2) MeI, NaH

OMe

NaSEt,
DMF
120 C

OH

CO2H

OBn
X

MeO

BnO

OMe

OMe

OBn
O

MeN

O
H

O
H

OMe

MeO

OH

OMe

MeO

OMOM

OMe

MeN

95% selective
demethylation

MeN
H

OMe

OMe

MeO
N
Me

MeN

NBS

OMOM

H
MeO

OMe

OMe

MeO

OMe

86%

rt
exo

Zn, HOAc
18-c-6, !

MeN
H

O
H

MeO

OMe

H
OMe

MeO

OMe

x = H, Br
Wieser, Pure Appl. Chem., 1979, 689.

Synthesis of Delphinine Alkaloids: Wiesner

OBn

OAc
O

OMe
MeN
H

MeN
H

OMe

MeO
N
Me

180 C
DBN
DMSO
H

MeO

OMe

MeO

1) Br2
dioxane

MeN

=
MeO
H

MeO

OMe
X

MeN

=
N
Me

= (-OCH2)2

MeO

OMe

MeO
N
Me

OMe

OMe

OMe
H

Delphonine

OMe

MeN

=
H
H
MeO

OMe

OH

OMe

OMe

5 steps

OMe

2) TsOH
(HOCH2)2

89%

H
X

Br

OMe

OMe

MeO
OMe

MeN

H
H

OMe
O

Br X

OMe

OMe

MeO

MeO

MeO

OMe

MeN

2) CrO3pyr

OMe

1) H2 (85 psi),
Rh/Al2O3

H
MeO

OMe

1) H2, Pd/C
2) Ac2O

OAc

MeO

OH
H
MeO

MeO

MeO

OMe H

OMe

N
Me
HO

OMe

Wieser, Pure Appl. Chem., 1979, 689.

Hetisine-type Alkaloids
nominime
H
OH

HO

Me

OH
N

Mander

H
Me

Me

OH

Muratake

Me

Winkler

structurally the most simple

local anesthetic, antinflammatory, antiarrhythmic

HO
HO

HO

HO
OAc

HO

hetisine

H
Me

BzO

OH

OH

Me

kobusine

H
HO

HO

davisinol

OH

H
OAc

tadzhaconine
pronounced
antiarrhythmic
ED = <0.3 mg/kg

Approach to Hetisine Core: Winkler

HO

Hetisine
HO

O
R

NH2

Me

O
NBoc

Me

HO

h!

Pyrex
MeCN
86%

EtOH,
PPTS, "

Me
NBoc

Me
Boc

NBoc

84%

Winkler, JACS, 2001, 7429.

Bridgehead Arylation: an Approach by Mander

Ar
XMg

MeN

Br

Br

R
CO2Et

N
Me

CO2Et

EtO2C

RMgBr
MgX

THF

O
N
Me

CO2Et

O
Br

R
Br

MeN

O
CO2Et

Br

Me
BrMg

Me
OMe

N
Me

EtO2C

OH

Me
OMe

64%

RMgBr =

OMe

NO2

OMe

SO3Ag

MeN
OAc

OH

Me

O2N

MeN

Br

NO2

53%

AcO

OAc

1) TMSOTf, Ac2O
2) Pd/BaSO4, H2
3) Reduction
4) Acylation (1 ROH)

OH
AcO

(AgBF4, 18%)
Williams and Mander, OL, 2003, 3499.

Synthesis of Nominine: Muratake and Natsume

MeO

OMe

OHC

OHC

OHC

PdCl2(PPh3)2,
Cs2CO3, THF, !

Br

OMe

TsOH
HO(CH2)2

65%

H
O

4:1
cis / trans

Muratake, Tet, 2004, 11783.

H
O

mixture subjected
to acetalization

mixture of
diastereomers
O

1) Me2NCH(OMe)2,
160 C

2) BH3NH3, BuLi
3) PivCl, NEt3, DMAP

MOMO
H

H
O

OPiv

H
O

34%

61%

20

OMe

2) TsOH, Me2CO

H
O

O
OPiv

1) BF3OEt2

66%

TsOH
35% (+SM)

~60%, 3 steps

OMe

1) Li, NH3; HCl

2) NaOMe, MeOH
3) NaBH4, CeCl3

H
O

65%, 3 steps

OH

PivO

LA
O
O

Muratake, TL, 2002, 2913.

Muratake, ACIE, 2005, 4646.

Synthesis of Nominine: Muratake and Natsume

O

HO

OPiv
H
H

MOMO

OAc

OH

1) TMSI, HMDS;
NBS
2) MOMCl
3) MeLi

RO

Me

1) Ac2O, pyr
2) PCC

OH

mixture at 3 ROH

Me

Et2AlCN

52%, 5 steps

94%
RO

RO

RO

OH

OH
H

NaBH3CN

OAc
H

H
Me

1) TMSCl, LDA
2) LiAlH4
3) CbzCl

90%

NCbz

Me

NCbz

63%

NC

H
Me O

SnBu3

1) PCC
2) Ohira
alkynlation

RO

RO

RO

Bu3SnH, AIBN,
toluene, !;

3) HCl
73%

SiO2

H
Me

NCbz

H
Me

NCbz

31%
R = -(CH2)2OH

Me

NCbz

57%
Muratake, TL, 2002, 2913.
Muratake, ACIE, 2005, 4646.

Synthesis of Nominine: Muratake and Natsume

RO
H

90%

H
Me

HO

1) SeO2
2) MnO2

Me

HO
H

3) Zn, NH4Cl

NCbz

R = -(CH2)2OH
R = -(CH2)2Br

1) NaBH4, CeCl3
2) Ac2O, pyr

NCbz

94%

OAc

H
Me

NCbz

MsCl; LiBr (97%)

HO

Me

OH
N

1) Pd(OAc)2, Et3SiH, NEt3

2) SOCl2, pyr
3) K2CO3, MeOH

N
Me

nominime

40 steps (0.15%)

Muratake, TL, 2002, 2913.

Muratake, ACIE, 2005, 4646.

fin