Total synthesis and absolute configuration of marine bisnor-diterpenoid elisabethin C

Article abstract of DOI:10.1016/S0040-4039(02)01831-2

Total synthesis of marine bisnor-diterpenoid elisabethin C was successfully carried out by stereoselective construction of bicyclo[4.3.0]nonane ring system with Dieckmann cyclization as the key step. The absolute configuration of elisabethin C was determined based on this total synthesis.

Full text of DOI:10.1016/S0040-4039(02)01831-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7773–7775
Total synthesis and absolute configuration of marine
bisnor-diterpenoid elisabethin C
Hiroaki Miyaoka, Daichi Honda, Hidemichi Mitome and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 22 July 2002; revised 19 August 2002; accepted 23 August 2002
Abstract—Total synthesis of marine bisnor-diterpenoid elisabethin C was successfully carried out by stereoselective construction
of bicyclo[4.3.0]nonane ring system with Dieckmann cyclization as the key step. The absolute configuration of elisabethin C was
determined based on this total synthesis. © 2002 Elsevier Science Ltd. All rights reserved.
Elisabethin C (1) is a novel bisnor-diterpenoid which
was isolated from the gorgonian Pseudopterogorgia
elisabethae, obtained off San Andre´s Island, Colombia,
by Rodr´ıguez in 1998.1 Its structure is characterized by
a unique bicyclic carbon skeleton (bisnorseco-elisa-
bethane skeleton); its relative configuration was deter-
mined by NOESY though the absolute configuration
remains to be elucidated. Elisabethin C (1) was found
to have antituberculosis activity against Mycobacterium
tuberculosis H37Rv (42% inhibition) at 12.5 mg/mL.
Thus, its unique structure and biological activity
prompted the authors to undertake the total synthesis
of elisabethin C. The total synthesis of elisabethin C is
presented here for the first time, along with determina-
tion of its absolute configuration.
The synthesis of elisabethin C (1) involves stereoselec-
tive construction of the bicyclo[4.3.0]nonane ring sys-
tem in the Dieckmann cyclization as a key step, as
shown in Scheme 1. The authors used the key interme-
diate A, which undergoes transformation to elisabethin
C (1) via deoxygenation at C-82 position and elongation
Scheme 1. Retrosynthetic analysis of elisabethin C (1).
Keywords: biologically active compounds; marine metabolites; terpenes and terpenoids.
* Corresponding author. Tel.: +81-426-76-3063; fax: +81-426-76-3048; e-mail: yamaday@ps.toyaku.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01831-2

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H. Miyaoka et al. / Tetrahedron Letters 43 (2002) 7773–7775
of carbon chains at C-10 and C-14 positions. Ketolac-
tone A is likely produced via Dieckmann cyclization of
ester lactone B. Ester lactone B can be obtained from
compound C via construction of lactone and hydrobo-
ration. Compound C can be prepared from commer-
cially available (+)-carvone through stereocontrolled
alkylation at C-1 position and stereocontrolled reduc-
tion of enone.
tected as TBS ether and the secondary hydroxy group
as MOM ether to give compound 4. Regio- and
stereoselective hydroboration of compound 4 using 9-
BBN5 afforded alcohol 5 as the sole product.6 The
hydroxy group in 5 was protected as a pivaloyl group
and the TBS group was removed by treatment with
TBAF to afford alcohol 6, which then underwent con-
version to ketolactone 7a by following four steps: (1)
ozonolysis of prenyl group; (2) PDC oxidation of hemi-
acetal; (3) removal of MOM group and (4) PCC oxida-
tion of secondary hydroxy group. Ketolactone 7a was
treated with K2CO3 in MeOH at 40°C to give a mixture
of ketolactone 7a and 7b (7a:7b=1:10)7 and following
the separation of which, the carbonyl group in 7b was
protected as exo-methylene by treatment with
TMSCH2Li and then 5N HCl.8 Removal of the pival-
oyl group with NaOMe gave alcohol 8. Esterification of
carboxylic acid obtained by oxidation of primary alco-
hol 8 using MeI and K2CO3 in acetone afforded ester 9.
Ester lactone 9 was treated with NaH in the presence of
15-crown-5 to give ketolactone 10 as the sole product9
by Dieckmann cyclization10 followed by isomerization
of the methyl group at C-7. The relative configuration
The synthesis of elisabethin C (1) was initiated using
(+)-carvone (Scheme 2). Lithium enolate of (+)-carvone
was treated with prenyl bromide to give a mono-prenyl-
ated compound, the subsequent treatment of which
with LDA in THF and then a solution of formaldehyde
in THF provided a diastereomeric mixture of alcohols
2a and 2b (2a:2b=9:1).3 Alcohols 2a and 2b were
separated and alcohol 2a was reduced with Na in liquid
NH3 in the presence of EtOH to give diol 3 as the sole
product.4 The methyl group at C-3 in diol 3 was found
to have b-configuration, thus being opposite that of
natural elisabethin C. The isomerization of the methyl
group at C-3 was consequently carried out in a later
step. The primary hydroxy group in diol 3 was pro-
Scheme 2. Reagents and conditions: (a) (1) LDA, THF, −42°C, then (CH3)2CꢀCHCH2Br, −42°C to rt, 89%, (2) LDA, THF,
−78°C, then HCHO, −78°C, 84%; (b) Na, liq. NH3, EtOH, −78°C, 70%; (c) (1) TBSCl, imidazole, DMF, rt, (2) MOMCl, iPr2NEt,
CH2ClCH2Cl, 50°C, 97% (two steps); (d) 9-BBN, THF, rt, then NaOH, H2O2, 92%; (e) (1) PivCl, pyridine, 0°C, (2) TBAF, THF,
,
50°C, 97% (two steps); (f) (1) O3, NaHCO3, MeOH, −78°C, then Me2S, −78°C to rt, (2) PDC, 4 A MS, CH2Cl2, rt, 92% (two
,
steps), (3) 1N HCl, THF, rt, 99%, (4) PCC, 4 A MS, CH2Cl2, rt, 99%; (g) K2CO3, MeOH, 40°C, 98%; (h) (1) TMSCH2Li, THF,
−78°C, then 5N HCl, rt, (2) NaOMe, MeOH, 50°C, then 1N HCl, 92% (two steps); (i) (1) Jones reagent, acetone, 0°C, (2) K2CO3,
MeI, acetone, rt, 80% (two steps); (j) NaH, 15-crown-5, benzene, reflux, 84%; (k) (1) NaBH4, MeOH, −42°C, 90%, (2) NaH, CS2,
n
MeI, THF, 0°C to rt, 81%, (3) Bu3SnH, Et3B, toluene, 0°C, 67%, (4) O3, NaHCO3, MeOH, −78°C, then NaBH4, −78°C to rt,
(5) TESOTf, 2,6-lutidine, CH2Cl2, 0°C, 84% (two steps); (l) (1) DIBAH, toluene, −78°C, (2) Ph3P+CH(CH3)2I−, PhLi, toluene, rt,
78% (two steps); (m) (1) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt, 99%, (2) EtMgBr, THF, rt, 67%; (n) (1) TBAF, THF,
rt, 99%, (2) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt, quant.

H. Miyaoka et al. / Tetrahedron Letters 43 (2002) 7773–7775
7775
of the methyl group at C-7 in ketolactone 10 was
regulated to the a-configuration through control of
thermodynamic factors. Deoxygenation11 at C-8 posi-
tion in 10 was carried out as follows: (1) NaBH4
reduction to give secondary alcohol; (2) treatment with
NaH, CS2, MeI to give xanthate and (3) radical reduc-
tion with nBu3SnH. exo-Methylene at C-2 was ozonated
followed by NaBH4 reduction to give a secondary
alcohol, whose secondary hydroxy group was protected
using TESOTf and 2,6-lutidine to give TES ether 11 as
a diastereomeric mixture (5:3). This mixture was used in
the following reaction without separation. Lactone 11
reduced to hemiacetal using DIBAH was subjected to
the Wittig reaction12 to afford alcohol 12. The oxidation
of alcohol 12 with Dess–Martin periodinane13 gave
aldehyde and which, by treatment with EtMgBr, gave
alcohol 13 and reductive product 12. Removal of TES
group in compound 13 gave diol. Finally, oxidation of
the two secondary hydroxy groups with Dess–Martin
periodinane provided elisabethin C (1), [h]2D5 −33.3° (c
0.3, CHCl3). Spectral data and the sign of optical
rotation of synthesized elisabethin C (1) were identical
with those of natural elisabethin C, [h]2D5 −31.2° (c 0.5,
CHCl3).1 Thus, the absolute configuration of elisabethin
C is clearly shown to be 1 by the present synthesis.
5. Liotta, R.; Brown, H. C. J. Org. Chem. 1977, 42, 2836–
2839.
6. The relative configuration of methyl group at C-7 in
alcohol 5 was determined by NOESY spectrum of lactone
5% which was prepared from alcohol 5 by following seven
steps: (1) PivCl, pyridine, 0°C; (2) TBAF, THF, 50°C,
97% (two steps); (3) O3, NaHCO3, MeOH, −78°C, then
,
Me2S, −78°C to rt; (4) PDC, 4 A MS, CH2Cl2, rt, 92%
(two steps); (5) NaOMe, MeOH, 50°C, 94%; (6) TsCl,
t
pyridine, 0°C, 99% and (7) BuOK, THF, 0°C, 92%.
7. The relative configuration of ketolactone 7b was con-
firmed by its NOESY spectrum.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from Ministry of Education, Cul-
ture, Sports, Science and Technology of Japan.
References
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