First enantiocontrolled synthesis of sceletium alkaloid A-4: Determination of the absolute configuration

Article abstract of DOI:10.1039/a709212a

Sceletium A-4, a pyridine alkaloid isolated from the Sceletium species, has been synthesized for the first time in an enantiocontrolled manner along with (-)-mesembrine, an alkaloid isolated from the same plant, starting from a chiral cyclohexadienone synthon to determine the absolute configuration.

Full text of DOI:10.1039/a709212a

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First enantiocontrolled synthesis of sceletium alkaloid A-4: determination of
the absolute configuration
Takashi Kamikubo and Kunio Ogasawara*†
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Sceletium A-4, a pyridine alkaloid isolated from the
Sceletium species, has been synthesized for the first time in
an enantiocontrolled manner along with (2)-mesembrine,
an alkaloid isolated from the same plant, starting from a
chiral cyclohexadienone synthon to determine the absolute
configuration.
workup, which on thermolysis afforded the cyclohexenone 9,
[a]2D8 +64.2 (c 1.38, CHCl3). To transpose its 5,5-disubstituted
cyclohex-2-enone structure to the 4,4-disubstituted cyclohex-
2-enone structure 14, 9 was first transformed into the
a-diketone monothioketal 11 via the cyclohexanone 10, by
sequential 1,4-reduction,11 debenzylation, silylation and a,a-
thioketalization.12 On reduction of the ketone functionality,
followed by the thioketal–methyl ketal exchange reaction,13 11
furnished the secondary alcohol 12 which was then transformed
to the methyl xanthate 13 after acid hydrolysis. Finally, 13 was
heated to give the 4,4-disubstituted cyclohex-2-enone 14, [a]2D9
221.7 (c 0.62, CHCl3).
The alkaloid (+)-sceletium A-41,2 1 is a minor constituent of
various Sceletium species of the family Aizonaceae and was
OMe
OMe
OMe
OMe
OMe
OMe
To produce (2)-mesembrine 3, 14 was first transformed into
the ketal alcohol 16 via 15. Employing the Mitsunobu
reaction,14 16 was next converted to the secondary amine 19, via
the imide 17, and the carbamate 18. Finally, 18 was treated with
perchloric acid in THF to give (2)-mesembrine 3, [a]2D9 255.4
(c 1.16, MeOH) [lit.,5b [a]3D0 257.5 (c 0.146, MeOH) (Scheme
2).
Me
N
R
N
Me
N
N
N
O
Me
H
H
3 (–)-mesembrine
Having obtained (2)-mesembrine 3, we investigated the
transformation of the same enone 14 into (+)-sceletium A-4 1 to
correlate the stereochemistry (Scheme 3). The enenone 14 was
exposed to I2 in CH2Cl2 containing pyridine15 to furnish the
a-iodo ketone 21. Palladium-mediated cross-coupling reac-
tion16 between the iodo ketone 21 and N-tert-butylcarbamoyl-
prop-1-yne yielded the enyne 22 which was converted into the
ketal 24 via 23 by sequential ketalization and desilylation.
Employing a five-step sequence including the Mitsunobu
reaction,14 24 was transformed into the bis-carbamate 27 via the
imide enyne 25 and the imide diene 26. On standing in diluted
hydrochloric acid in THF at room temperature, 27 collapsed
gradually to the pyridine 30 through a concurrent deketaliza-
tion, chemoselective decarbamoylation, double cyclization and
dehydrogenation, presumably through the allyl amine 28 and
the dihydropyridine 29. The pyridine 30 was exposed to TFA to
give the secondary amine 31, which was immediately subjected
1(+)-sceletium A-4
2a R = H (–)-tortuosamine
b R = CHO(–)-N-formyltortuosamine
isolated with congeners such as (2)-tortuosamine2b,d 2a,
(2)-N-formyltortuosamine2d 2b and (2)-mesembrine1 3.
(+)-Sceletium A-4 1 afforded (2)-tortuosamine 2a on hydroge-
nolysis2b,d while the latter afforded (2)-N-formyltortuosamine
2b on formylation, indicating that they possess the same
absolute configuration at the benzylic quaternary centers. The
structure determination, both by a single-crystal X-ray analy-
sis2c and by racemic syntheses,3 revealed that (+)-sceletium A-4
1 possesses the same relative stereochemistry as (2)-mesembr-
ine 3 with respect to two stereogenic centers. However, the
absolute configuration of the former alkaloid has not been
correlated to the latter, whose absolute configuration has been
determined both by X-ray analysis4 and by enantioselective
syntheses.5
In order to determine the absolute configuration of (+)-scele-
tium A-4 1 as well as of the two congeners 2 by correlation to
the stereochemistry of (2)-mesembrine 3, we examined
enantiocontrolled synthesis of Sceletium A-4 1 along with
(2)-mesembrine 3 using the common tricyclic chiral building
block (+)-4, serving as a chiral cyclohexadienone.6,7 We report
here the first enantiocontrolled synthesis of (+)-sceletium A-4 1
and a new synthesis of (2)-mesembrine 3 leading to the
unambiguous determination of the absolute configuration of
(+)-sceletium A-4 1 and its two congeners, (2)-tortuosamine 2a
and (2)-N-formyltortuosamine 2b.
O
OTBDMS
i
+
(+)-4
PPh3
TfO–
5
We have recently demonstrated8 that the tricyclic enone 4
may be b-alkylated to furnish the b-substituted enone 7 by a
single-flask sequential Michael–Wittig process9 via the phosp-
honium trifrate 5 and the 1,3-diene 6 (Scheme 1). Employing
this procedure, we prepared the b-substituted enone‡ 7
(R = CH2OBn), [a]2D8 +164.3 (c 1.13, CHCl3), in 71% yield
from (+)-4 and 2-benzyloxyacetaldehyde. Reaction of 7 with
3,4-dimethoxyphenylmagnesium bromide in the presence of
copper(i) bromide–dimethyl sulfide complex10 proceeded from
the convex face to give the b,b-disubstituted ketone 8 after acid
OTBDMS
O
R
R
H
6
7
Scheme 1 Reagents and conditions: i, PPh3, TBDMSOTf, THF, 278 °C,
then BunLi, 278 °C, then RCHO, 10% HCl
Chem. Commun., 1998
783

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Ar
Ar
OTBDPS
X
Ar
i
iii
O
14
OBn
O
i
ii
O
7
O
R
Ar
21 R = I
22 R =
O
BnO
CH2NHBoc
NHBoc
8
9
23 X = OTBDPS
24X = OH
25 X = o-C6H4(CO)2N
iv
v
iii–v
OTBDPS
Ar
Ar
vi
OTBDPS
Ar
Ar
xi
Ar
ix
O
X
NH
Boc
N
Boc
O
N
O
N
14
Y
H
X
O
10 X = H2, Y = O
H2N
vi
29
28
NH
11 X = –S(CH2)3S–, Y = O
12 X = (OMe)2, Y = H, OH
13 X = O, Y = H, OCS2Me
Ar
vii, viii
ix, x
xii
Boc
26 X = o-C6H4(CO)2N
27 X = H, Boc
Ar
vii, viiii
Ar =
Ar
xi
N
X
OR
1
N
R
xiv
N
H
OMe
OMe
O
O
30 R = Boc
31 R = H
O
O
x
15 R = TBDPS
16 R = H
17 X = o-C6H4(CO)2
18 X = H, CO2Me
19 X = H, Me
xv, xvi
xvii
xiii
Scheme 3 Reagents and conditions: i, I2, Py, CH2Cl2 (97%); ii,
HC·CCH2NHBoc, PdCl2(PPh3)2 (cat), CuI, Et3N (91%); iii, (CH2OH)2,
TsOH, C6H6 (71%); iv, Bu4NF, THF (100%); v, phthalimide, PPh3,
DIPAD, THF (90%); vi, H2, Lindlar catalyst, MeOH (86%); vii,
hydrazine·H2O, EtOH, reflux; viii, Boc2O, Et3N, CH2Cl2 (85% from 26); ix,
10% HCl–THF (1:4) (42%); x, TFA, CHCl3; xi, 35% HCHO, HCO2H
(67%)
xviii
Ar
OMe
OMe
Ar =
3
HN
Me
O
20
2 (a) P. W. Jeffs, P. A. Luhan, A. T. McPhail and N. H. Martin, J. Chem.
Soc., Chem. Commun., 1971, 1466; (b) F. O. Snyckers, F. Strelow and
A. Wiechers, J. Chem. Soc., Chem. Commun., 1971, 1467; (c)
P. A. Luhan and A. T. McPhail, J. Chem. Soc., Perkin Trans. 2, 1972,
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and B. Rauckman, J. Org. Chem., 1974, 39, 2703.
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Scheme 2 Reagents and conditions: i, 3,4-(MeO)2C6H3MgBr, CuBr·SMe2,
Me3SiCl, HMPA, THF; ii, Ph2O, ca. 260 °C (77% from 7); iii, DIBAL-H,
CuI, HMPA, THF; iv, H2, 10% Pd–C; v, ButPh2SiCl, imidazole, DMF (72%
from 9); vi, TsS(CH2)3STs, ButOK, THF–ButOH (70%); vii, NaBH4,
CeCl3·7H2O; viii, (CF3CO2)IPh, MeOH (87% from 11); ix, NaH, CS2, MeI,
THF; x, 70% HClO4–THF (1:20); xi, o-C6H4Cl2, ca. 180 °C (77% from
12); xii, (CH2OH)2, TsOH, C6H6, (100%); xiii, Bu4NF, THF (94%); xiv,
phthalimide, PPh3, PriO2CNNNCO2Pri (DIPAD), THF (94%); xv, hydrazi-
ne·H2O, EtOH, reflux; xvi, ClCO2Me, Et3N, CH2Cl2 (79% from 17); xvii,
LiAlH4, THF, reflux; xviii, aq. HClO4, THF (66% from 18)
to the Eschweiler–Clarke reaction17 to afford (+)-Sceletium A-4
1, mp 153.5–154.5 °C, [a]2D7 + 120.5 (c 1.10, MeOH) (lit.,2a mp
153.5–154.5; lit.,2b 132–134 °C, lit.,2c [a]D +131 (MeOH);
lit.,2d [a]D +131 (EtOH)). The synthetic material had a circular
dichroism (CD) spectrum (in 95% EtOH) showing the first
cotton effect (positive) at 278 nm, the second (positive) at 274
nm and the third (negative) at 247 nm which was identical to
that reported2d for (+)-sceletium A-4 1 (positive at 278 nm,
positive at 274 nm and negative at 247 nm in 95% EtOH). Since
(+)-1 thus obtained has the same CD spectrum as the natural
product, the absolute configuration of natural (+)-Sceletium
A-4 1 as well as its two natural congeners, (+)-tortuosamine 2a
and (2)-N-formyltortuosamine 2b, has now been established as
that shown by correlation to (2)-mesembrine 3.
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Notes and References
† E-mail: konol@mail.cc.tohoku.ac.jp
‡ Satisfactory analytical (high resolution mass) and spectral (IR, 1H NMR
and mass) data were obtained for all new isolable compounds.
17 W. S. Emerson, Org. React., 1948, 4, 174.
1 A. Popelak and G. Lettenbauer, in The Alkaloids, ed. R. H. F. Manske,
Academic Press, New York, 1967, vol. IX, p. 467.
Received in Cambridge, UK, 23rd December 1997; 7/09212A
784
Chem. Commun., 1998