A new enantioselective route to the Sceletium alkaloids via a cyclopentanone-cyclohexenone transformation

Article abstract of DOI:10.1016/S0040-4039(02)00033-3

An enantioselective route to the Sceletium alkaloids has been developed using the 2,3,4-trioxycyclopentanone chiral building block by carrying out its conversion into a 4,4-disubstituted cyclohexenone derivative.

Full text of DOI:10.1016/S0040-4039(02)00033-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1461–1464
A new enantioselective route to the Sceletium alkaloids via a
cyclopentanone–cyclohexenone transformation
Masato Hayashi, Tomohiro Unno, Michiyasu Takahashi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 29 November 2001; revised 24 December 2001; accepted 27 December 2001
Abstract—An enantioselective route to the Sceletium alkaloids has been developed using the 2,3,4-trioxycyclopentanone chiral
building block by carrying out its conversion into a 4,4-disubstituted cyclohexenone derivative. © 2002 Elsevier Science Ltd. All
rights reserved.
We have developed an efficient method for the prepara-
tion of the 2,3,4-trioxygenated cyclopentanone 2 having
a dioxabicyclo[3.3.0]heptane framework in both enan-
tiomeric forms by employing a lipase-mediated kinetic
resolution of racemic cis-4-cumyloxycyclopentenol ( )-1
as the key step.1 Because of its functionality and sterically
biased framework, the enantiopure cyclopentanone 2 has
already been used as a convenient chiral building block
allowing facile diastereocontrol1,2 in the enantio- and
diastereocontrolled synthesis of several natural products.
We have been trying for some time to develop the
enantio- and diastereocontrolled construction of less
accessible 4,4-disubstituted cyclohexenones 3 which pos-
sess versatile synthetic utility.3 Accordingly, we
attempted the conversion of the readily accessible enan-
tiopure cyclopentanone 2 into enantiopure 4,4-di-
substituted cyclohexenones 3. We wish to report here the
successful construction of the enantiopure 4,4-disubsti-
tuted cyclohexenone (R)-(−)-4 leading to four of the
Sceletium alkaloids,4 synthesized earlier by our group
from chiral cyclohexanoid precursors5,6 (Scheme 1).
steps, we hope to develop a more facile enantioselective
route to this compound from the chiral cyclopentanone
(−)-2, thereby, demonstrating its increased synthetic
potential and a more convenient enantioselective route
to the Sceletium alkaloids (Scheme 2).
The synthesis began with the reaction of the cyclopen-
tanone (−)-2 and 3,4-dimethoxyphenyllithium, prepared
in situ from 3,4-dimethoxyphenyl bromide with butyl-
lithium, to give the benzylic endo-alcohol 5. The reac-
tion proceeded diastereoselectively to furnish the
benzylic tertiary alcohol 5 as a single product. The
product
5
obtained was desilylated with tetra-
butylammonium fluoride (TBAF) to afford the diol 6,
[h]2D7 +27.5 (c 0.5, CHCl3). Oxidation of the diol 6 with
pyridinium chlorochromate (PCC) afforded the
hydroxy-ketone 7. Upon stirring in warm acetic acid,1
the hydroxy-ketone 7 furnished the cyclopentenone 8,
[h]3D0 +112.2 (c 2.4, CHCl3), through a b-elimination of
the tertiary hydroxyl functionality with the acetonide
functionality intact. Owing to the sterically biased
structure, the enone 8 allowed diastereoselective reduc-
tion of the ketone functionality with sodium borohy-
Since preparation of the key cyclohexene (R)-(−)-4, in the
previous syntheses, involved somewhat cumbersome
O
OH
R1
R2
O
ref. 1
O
O
O-TBS
O-cumyl
(+)- or (–)-3
(+)- and (–)-2
(±)-1
Scheme 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00033-3

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M. Hayashi et al. / Tetrahedron Letters 43 (2002) 1461–1464
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
present
study
ref.5,6
:
:
(–)-2
N
Me
NHMe
N
N
H
N
Me
NMe
O
O
H
CO2Me
(R)-(–)-4
(–)-tortuosamine
(+)-sceletium A4
(–)-mesembrine
Scheme 2.
dride in the presence of cerium(III) chloride7 to give the
single cyclopentenol 9, [h]2D7 +75.4 (c 2.4, CHCl3), hav-
ing the all-cis oxygen stereochemistry, which is essential
for the next transformation. Thus, the Eschenmoser
reaction8 of the cyclopentenol 9 with dimethylac-
etamide dimethyl acetal in decalin at 220°C afforded
the single cyclopentene 10, [h]2D5 +52.1 (c 1.0, CHCl3),
which was hydrogenated to give the cyclopentane 11
having the acetic acid moiety cis to the acetonide
moiety. Due to the stereochemistry of the cyclopentane
ring, the amide 11 allowed consecutive facile deace-
tonization and lactonization under acidic methanolysis
conditions to give the d-hydroxy-g-lactone 12, [h]D30
+10.4 (c 0.7, CHCl3), as a single product. The overall
yield of the hydroxy-lactone 12 from the chiral
cyclopentenol (−)-2b was 39% in eight steps (Scheme 3).
ality of the g-lactone 12 was oxidized under Dess–Mar-
tin conditions9 to give the keto-lactone 13, [h]3D1 +20.8 (c
2.0, CHCl3), in good yield. Reaction of the keto-lactone
13 with the complex generated in situ from methyl-
lithium and cerium (III) chloride10 in THF at −20°C
allowed chemoselective reaction at the ketone carbonyl
center to yield the hydroxy-lactone 14 as a mixture of
two epimers with the lactone functionality intact. It was
also found that the same mixture 14 could also be
obtained in a comparable yield in THF in the absence
of the cerium salt at −78°C. The hydroxy-lactone 14
obtained was then exposed to the complex generated in
situ
from
methylamine
hydrochloride
and
trimethylaluminum11 in THF at reflux to give the dihy-
droxy-amide mixture 15. On sequential reduction with
lithium aluminum hydride and N-carbomethoxylation
with methyl chlorocarbonate, the amide 15 furnished
the carbamate 17 via the secondary amine 16. At this
stage, the 1,2-glycol functionality of the carbamate 17
was cleaved with sodium periodate in aqueous THF to
give the keto-aldehyde 18. Upon stirring in aqueous
After the neighboring two cis-secondary oxygen func-
tionalities that originated from the starting material
(−)-2 had been discriminated by regioselective lactone
formation, the remaining secondary hydroxy function-
MeO
OMe
MeO
MeO
OMe
iv
OMe
O
HO
HO
O
O
O
O
O
i
iii
O
O
v
O
OTBS
(–)-2
OR
O
O
5 : R = TBS
7
8
ii
6 : R = H
MeO
MeO
NMe2
MeO
OH
MeO
OMe
OMe
viii
OMe
OMe
vii
O
NMe2
vi
O
O
O
O
O
O
O
O
HO
O
12
11
10
9
Scheme 3. Reagents and conditions: (i) 6-bromo-3,4-dimethoxybenzene, butyllithium, THF, −78°C, (80%). (ii) TBAF, THF (94%).
(iii) PCC, NaOAc. (iv) AcOH, 40°C (81%, two steps). (v) NaBH4, CeCl3–7H2O, MeOH, −20°C (98%). (vi) MeCNMe2(OMe)2,
decalin, reflux (76%). (vii) H2, 10% Pd–C, AcOEt. (viii) p-TsOH (cat.), MeOH, reflux (85%, two steps).

M. Hayashi et al. / Tetrahedron Letters 43 (2002) 1461–1464
1463
MeO
MeO
MeO
OMe
OMe
OMe
MeHN O
HO
O
O
O
O
i
ii
iii
12
HO
HO
O
Me
15
Me
14
13
OMe
R
MeO
OMe
OMe
OMe
MeN
OMe
iv
vi
vii
HO
NMe
CO2Me
CHO
HO
O
Me
NMe
O
CO2Me
16 : R = H
17 : R = CO2Me
v
18
(R)-(–)-4
Scheme 4. Reagents and conditions: (i) Dess–Martin periodinane, CH2Cl2 (88%). (ii) MeLi, CeCl3, THF or MeLi, THF, −78°C.
(iii) MeNH3Cl, Me3Al, THF, reflux (62%, two steps). (iv) LiAlH4, dioxane, reflux. (v) ClCO2Me, Hu¨nig base, CH2Cl2 (73%, two
steps). (vi) NaIO4, THF–H2O (1:1). (vii) 10% KOH–MeOH (1:5) (49%, two steps).
methanol containing potassium hydroxide,12 the keto-
aldehyde 18 furnished, via a consecutive intramolecular
aldol reaction and dehydration, the cyclohexenone (R)-
(−)-4, [h]2D7 −34.2 (c 0.4, CHCl3) {Ref. 6: [h]2D7 −34.4 (c
0.4, CHCl3)}, which was used as the key intermediate in
the synthesis of the Sceletium alkaloids. The overall
yield of the key intermediate (R)-(−)-4 from the
hydroxy-lactone 12 was 20% in seven steps. Thus, a
new route to the key 4,4-disubstituted cyclohexenone
intermediate (R)-(−)-4 has been developed using the
readily accessible cyclopentane chiral building block
(+)-2. From the intermediate (R)-(−)-4, the Sceletium
alkaloids were obtained: (−)-mesembrine in one step,6
(−)-tortuosamine in five steps,6 and (+)-sceletium A4 in
six steps.6 Although it took 15 steps to convert the
starting chiral cyclopentane (+)-2 into the key cyclo-
hexenone (R)-(−)-4, the present synthesis may be more
easily carried out than the two previous ones since no
intractable reagents or difficult conditions are involved.
The present procedure may also be applicable to the
synthesis of the morphine alkaloids since we also have
developed13 the enantio- and diastereo-selective route to
morphinanone derivatives via the 4,4-disubstituted
cyclohexenone intermediate closely related to 4 (Scheme
4).
Acknowledgements
We are grateful to the Ministry of Education, Culture,
Sports, Science and Technology, Japan for support of
this research.
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a
cyclopentanone–cyclohexenone transformation path-
way. We have, thus, extended the utility of the
cyclopentane that we obtained as a chiral building
block.

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