Total synthesis of marine diterpenoid stolonidiol

Article abstract of DOI:10.1016/S0040-4039(01)02032-9

Marine dolabellane diterpenoid stolonidiol was synthesized from L-ascorbic acid. The method for this total synthesis involves formation of the bicyclo[2.2.1]heptane derivative using a diastereoselective sequential Michael reaction, formation of cyclopentane derivative by the retro-aldol reaction and construction of an 11-membered carbocyclic ring through the intramolecular Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1016/S0040-4039(01)02032-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9233–9236
Total synthesis of marine diterpenoid stolonidiol
Hiroaki Miyaoka, Tomohiro Baba, Hidemichi Mitome and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 2 October 2001; revised 24 October 2001; accepted 26 October 2001
Abstract—Marine dolabellane diterpenoid stolonidiol was synthesized from L-ascorbic acid. The method for this total synthesis
involves formation of the bicyclo[2.2.1]heptane derivative using a diastereoselective sequential Michael reaction, formation of
cyclopentane derivative by the retro-aldol reaction and construction of an 11-membered carbocyclic ring through the intramolec-
ular Horner–Wadsworth–Emmons reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Stolonidiol and stolonitriene, isolated from the Oki-
nawan marine soft coral Clavularia sp. by this labora-
tory, are dolabellane-type diterpenoids.1,2 Most
dolabellane-type diterpenoids possess trans-bicy-
clo[9.3.0]tetradecane and exhibit antimicrobial, antitu-
mor and antiviral activity.3,4 Stolonidiol is unique for
multi biological activity and has been found to express
potent cytotoxic activity toward P388 leukemia cells
(IC50 0.015 mg/mL) and ichthyotoxic activity toward
killifish Oryzias latipes (minimum lethal concentration:
10 mg/mL).1 Stolonidiol was recently noted to exhibit
potent choline acetyltransferase (ChAT) inducible activ-
ity in primary cultured basal forebrain cells and clonal
septal SN49 cells, suggesting a potent neurotrophic
factor-like agent to be possibly present in the cholinergic
nervous system.2 These features prompted the present
study for devising a method for the total synthesis of
stolonidiol. The total synthesis5,6 of, and synthetic
studies7 on, dolabellane-type diterpenoid have been
reported, but no method is presently available for obtain-
ing stolonidiol. The total synthesis of stolonidiol through
application of the sequential Michael reaction, retro-
aldol reaction and intramolecular Horner–Wadsworth–
Emmons reaction as key steps is presented here.
The authors have been engaged in the synthesis of
natural products using a bicyclic compound, prepared by
sequential Michael reaction, as a chiral building
RO
O
4
1
O
12
14
11
10
10
18
H
12
7
8
O
OHC7
(EtO)2(O)P
7
H
O
10
OH
O
OH
H
OR
8
O
18
OH
stolonidiol
OH
stolonitriene
B
CO2R
A
O H
OR
O
14
19
OR
O
12
12
O
O
1
CO2R
OR
OR
1
CO2R
O
+
O
O
G
O
O
O
F
O
O
O
D
C
E
Scheme 1.
Keywords: antitumor compounds; marine metabolites; terpenes and terpenoids.
* Corresponding author. Tel.: +81-426-76-3046; fax: +81-426-76-3069; e-mail: yamaday@ps.toyaku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02032-9

9234
H. Miyaoka et al. / Tetrahedron Letters 42 (2001) 9233–9236
block.5,8 This method was applied in this study for the
total synthesis of stolonidiol. It was considered that the
diastereoselective sequential Michael reaction of lithium
enolate of cyclopentenone derivative F and chiral (Z)-
retro-aldol reaction followed by epimerization at the
C-12 position of diketone C would produce tetra-
substituted cyclopentane derivative B. Compound B
would be converted to phosphono aldehyde A and
intramolecular Horner–Wadsworth–Emmons reaction
of phosphono aldehyde A would give dolabellane-type
diterpenoid stolonitriene, a potential biogenetic precur-
sor of stolonidiol. Finally, stereoselective epoxidation
a,b-unsaturated ester
G
would provide bicy-
clo[2.2.1]heptane derivative E. Bicyclic compound E
would be converted to b-hydroxyketone D. Cleavage of
the C(14)ꢀC(19)9 bond in b-hydroxyketone D by a
OMOM
OMOM
O
OMOM
OTBDMS
OMOM
O
1
b
a
1
1
EtO2C
+
CO2Et
CO2Et
O
O
O
CO2Et
O
1
O
O
O
O
O
3a
3b
4
2
3a : 3b = 1 : 7.5
OMOM
OTBDMS
OH
O
BnO
O
14
12
1
d
c
e
OBn
CO2Et
1
H
12
O
10
H
O
O
O
O
O
H
O
5
18
6
7
BnO
BnO
HO
PhO2S
14
2
H
h
g
f
H
OMe
H
OMe
10
10
18
18
18
O
O
Me
Me
OMOM
TBDMSO
8
9
10
2
j
3
i
7
7
TBDPSO
OHC
(EtO)2(O)P
9
TBDPSO
I
TBDMSO
OMOM
OMOM
7
3
8
11
12
CO2Et
13
k
l
m
stolonitriene
stolonidiol
10
7
OMOM
OH
14
14 : 7Z -14 = 9 : 2
Scheme 2. Reagents and conditions: (a) LDA, THF, −78°C, then 2, −78°C to rt, 85%; (b) (1) NaBH4, MeOH, 0°C; (2) TBDMSCl,
imidazole, DMF, 97% (two steps); (c) LDA, THF, MeI, −78°C to rt, 86%; (d) (1) LiAlH4, THF, 0°C; (2) BnBr, NaH, THF/DMF,
86% (two steps); (3) TBAF, DMF, 50°C; (4) BzCl, pyridine, rt; (5) TsOH, acetone, rt, 92% (three steps); (6) LiAlH4, Et2O, 0°C;
,
(7) PDC, 4 A MS, CHCl3, rt, 85% (two steps); (e) K2CO3, MeOH, 40°C, 92%; (f) (1) TsOH, MeOH, rt, 98%; (2) H2NNH2,
O(CH2CH2OH)2, 130°C, then KOH, 205°C, 92%; (g) (1) TsCl, DMAP, ClCH2CH2Cl, rt; (2) DBU, toluene, reflux, 91% (two
steps); (h) (1) Na, liq. NH3/THF, −78°C, 88%; (2) PhSSPh, n-Bu3P, pyridine, 40°C, 94%; (3) PPTS, THF/H2O, rt; (4) MeLi, THF,
−78°C, 80% (two steps); (5) TBDMSCl, imidazole, DMF, rt; (6) MOMCl, i-Pr2NEt, ClCH2CH2Cl, rt; (7) TPAP, NMO, CH3CN,
rt, 85% (three steps); (i) (1) KHMDS, THF, 0°C, then 11, 82%; (2) Na–Hg, MeOH, NaH2PO4, rt, 82%; (j) (1) PPTS, MeOH, rt,
81%; (2) NaH, Ph3P, CBr4, THF, then (EtO)2P(O)CH2CO2Et, 75%; (3) TBAF, THF, rt; (4) Dess–Martin periodinane, NaHCO3,
CH2Cl2, rt, 68% (two steps); (k) (1) DBU, LiCl, 18-crown-6, CH3CN, rt; (2) DIBAL-H, toluene, −78°C, 69% (two steps);
(l) AcOH/H2O (4:1), 40°C, 99%; (m) (1) Ac2O, pyridine, rt; (2) TBHP, VO(acac)2, CH2Cl2, rt; (3) K2CO3, MeOH, rt, 87% (three
steps); (4) TBHP, L-(+)-DIPT, Ti(O-i-Pr)4, CH2Cl2, −20°C, 95%.

H. Miyaoka et al. / Tetrahedron Letters 42 (2001) 9233–9236
9235
hydroxy group to phenyl sulfide with PhSSPh and
n-Bu3P in pyridine; (3) hydrolysis of methyl acetal to
hemiacetal; (4) methylation with MeLi; (5) protection
of the primary hydroxy group as TBDMS ether; (6)
protection of the tertiary hydroxy group as MOM ether
and (7) oxidation of sulfide to sulfone with TPAP and
NMO.13
of two olefins in stolonitriene would afford stolonidiol
(Scheme 1).
Sequential Michael reaction of the enolate of cyclopen-
tenone 1 with chiral (Z)-a,b-unsaturated ester 2,10 pre-
pared from
L
-ascorbic acid, in THF at −78°C, gave
bicyclo[2.2.1]heptane 3a and 3b11 (3a:3b=3: 1) in 73%
yield (Scheme 2). A rise in reaction temperature from
−78°C to rt produced bicyclo[2.2.1]heptane 3a and 3b
(3a:3b=1:7.5) in 85% yield. In this reaction, bicy-
clo[2.2.1]heptane 3a was initially obtained at low tem-
perature and bicyclo[2.2.1]heptane 3a was isomerized to
3b by thermodynamic control with a rise in reaction
temperature, as confirmed by chemical conversion.
Bicyclo[2.2.1]heptane 3a was treated with LDA at
−78°C and, with assumption of rt, bicyclo[2.2.1]heptane
3b was obtained. Stereoselectivity in the sequential
Michael reaction of 1 with the a,b-unsaturated ester 2
can be explained based on the transition state leading
to 3a: the dienolate of 1 approaches 2, having a stable
conformation, from the less hindered side with coordi-
nation between the lithium cation of dienolate of 1 and
the carbonyl oxygen of 2 (Fig. 1).
Reaction of the anion of sulfone 10, prepared from
sulfone 10 and KHMDS, with allylic iodide 11,14 corre-
sponding to the C(3)ꢀC(7) segment, at 0°C in THF
gave a coupling product and the phenylsulfonyl group
was removed by treatment with Na–Hg in MeOH in
the presence of NaH2PO4 to afford 12. Silyl ether 12
was converted to aldehyde 13 via a coupling reaction
with (EtO)2P(O)CH2CO2Et in four steps: (1) selective
deprotection of the TBDMS group with PPTS to give
allylic alcohol; (2) treatment with CBr4 and Ph3P in the
presence of NaH and then (EtO)2P(O)CH2CO2Et to
give a coupling product through in situ bromination;
(3) deprotection of TBDPS group with TBAF; and (4)
oxidation of the primary hydroxy group with Dess–
Martin
periodinane.15
Intramolecular
Horner–
Wadsworth–Emmons reaction of aldehyde 13 was
carried out by treatment with DBU in the presence of
LiCl and 18-crown-6 in CH3CN at rt to afford a
mixture of geometric isomers of a,b-unsaturated
esters.16 The mixture was treated with DIBAL-H to
give allylic alcohol 14 and the 7Z isomer of 14 (14: 7Z
isomer of 14=9:2) in 69% yield (two steps). Following
the separation of these compounds from each other,
removal of the MOM group in 14 was carried out by
treatment with AcOH/H2O (4:1) at 40°C to give
stolonitriene. Spectral data and the sign of optical
rotation of synthetic stolonitriene were identical with
those of natural stolonitriene.2 Finally, total synthesis
of stolonidiol was accomplished by following stepwise
stereoselective epoxidation of stolonitriene:17 (1) selec-
tive acetylation of the primary hydroxy group; (2)
diastereoselective epoxidation of the olefin at C-10 with
TBHP and VO(acac)2;18 (3) deacetylation with K2CO3
With 3a and 3b still together, the ketone of 3ab was
reduced with NaBH4 and the hydroxy group was pro-
tected as TBDMS ether to give silyl ether 4. Lithium
enolate of 4, prepared from ester 4 and LDA, was
reacted with MeI at −78°C to rt to give ester 5 as the
sole product. Ester 5 was converted to b-hydroxyketone
6 in the following seven steps: (1) LiAlH4 reduction to
primary alcohol; (2) protection of the hydroxy group as
Bn ether; (3) removal of TBDMS ether with TBAF to
give a secondary alcohol; (4) protection of the hydroxy
group as Bz ester; (5) removal of MOM ether with
TsOH in MeOH; (6) reductive deprotection of Bz ester
to a secondary alcohol; and (7) oxidation of this alco-
hol with PDC. Cleavage of the C(14)ꢀC(19) bond in
b-hydroxyketone 6 by retro-aldol reaction and then
isomerization at the C-12 position proceeded smoothly
by treatment with K2CO3 in MeOH at 40°C to give
diketone 7 as the sole product. Selective protection of
ketone at the C-18 position in 7 was then conducted by
treatment with TsOH in MeOH to give methyl acetal,
and ketone at the C-14 position was reduced by the
Wolff–Kishner procedure12 to afford alcohol 8. The
secondary hydroxy group of 8 was tosylated and subse-
quent treatment with DBU in toluene under reflux
afforded dihydropyrane 9 equipped with requisite E-
olefin. Dihydropyrane 9 was converted to sulfone 10,
which corresponds to the cyclopentane moiety of
stolonidiol, as follows: (1) removal of the Bn group
with Na in liq. NH3 to alcohol; (2) conversion of the
in MeOH; and (4) asymmetric epoxidation of the olefin
19
at C-7 with TBHP,
L
-(+)-DIPT and Ti(O-i-Pr)4 to
give stolonidiol, [h]D26 −32.0° (c 0.2, CHCl3). Spectral
data and the sign of optical rotation of synthetic
stolonidiol were identical with those for natural
stolonidiol, [h]D −31.6° (c 1.4, CHCl3).1
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research (Grant No. 11470473) from the Ministry
of Education, Science, Sports and Culture, Japan.
OMOM
O
References
Li
3a
H
O
H
H
1. (a) Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.;
Inouye, Y. Tetrahedron Lett. 1987, 28, 5673–5676; (b)
Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye,
Y. Chem. Pharm. Bull. 1988, 36, 2840–2852.
OEt
O
O
Figure 1.

9236
H. Miyaoka et al. / Tetrahedron Letters 42 (2001) 9233–9236
2. Yabe, T.; Yamada, H.; Shimomura, M.; Miyaoka, H.;
Lett. 1992, 33, 81–82; (e) Nagaoka, H.; Kobayashi, K.;
Yamada, Y. Tetrahedron Lett. 1988, 29, 5945–5946.
9. Numbering of all compounds in this paper is accordance
with that of stolonidiol.
Yamada, Y. J. Nat. Prod. 2000, 63, 433–435.
3. Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1–49 and the
previous paper in this series.
4. Rodr´ıguez, A. D.; Gonza´lez, E.; Ram´ırez, C. Tetrahedron
10. (a) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh,
H. K.; Mikkilineni, A. B.; Wu, D. C.-J.; Saibaba, R.;
Panzica, R. P. J. Org. Chem. 1988, 52, 2598–2602; (b)
Hubschwerlen, C. Synthesis 1986, 962–964.
11. Structural assignments of all stable synthetic intermedi-
ates were made based on NMR, IR and HRMS spectra.
12. (a) Cram, D. J.; Sahyum, M. R. V.; Knox, G. R. J. Am.
Chem. Soc. 1962, 84, 1734–1735; (b) Minlon, H. J. Am.
Chem. Soc. 1946, 68, 2487–2488.
1998, 54, 11683–11729.
5. The authors have reported the total synthesis of claenone,
isolated from the same soft coral Clavularia sp.:
Miyaoka, H.; Isaji, Y.; Kajiwara, Y.; Kunimune, I.;
Yamada, Y. Tetrahedron Lett. 1998, 39, 6503–6506.
6. (a) Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39,
741–744; (b) Kato, N.; Higo, A.; Wu, X.; Takeshita, H.
Heterocycles 1997, 46, 123–127; (c) Corey, E. J.; Kania,
R. S. J. Am. Chem. Soc. 1996, 118, 1229–1230; (d) Jenny,
L.; Borschberg, H.-J. Helv. Chim. Acta 1995, 78, 715–731.
7. (a) Zhu, Q.; Qiao, L.; Wu, Y.; Wu, Y.-L. J. Org. Chem.
2001, 66, 2692–2699; (b) Zeng, Z.; Xu, X. Tetrahedron
Lett. 2000, 41, 3459–3461; (c) Zhu, Q.; Fan, K.-Y.; Ma,
H.-W.; Qiao, L.-X.; Wu, Y.-L.; Wu, Y. Org. Lett. 1999,
1, 757–759; (d) Zhu, Q.; Qiao, L.-X.; Wu, Y.; Wu, Y.-L.
J. Org. Chem. 1999, 64, 2428–2432; (e) Luker, T.;
Whitby, R. J. Tetrahedron Lett. 1996, 42, 7661–7664; (f)
Williams, D. R.; Coleman, P. J. Tetrahedron Lett. 1995,
36, 39–42; (g) Kato, N.; Higo, A.; Nakanishi, K.; Wu, X.;
Takeshita, H. Chem. Lett. 1994, 1967–1970; (h) Mehta,
G.; Karra, S. R.; Krishnamurthy, N. Tetrahedron Lett.
1994, 35, 2761–2762; (i) Williams, D. R.; Coleman, P. J.;
Henry, S. S. J. Am. Chem. Soc. 1993, 115, 11654–11655;
(j) Williams, D. R.; Coleman, P. J.; Navill, C. R.;
Robinson, L. A. Tetrahedron Lett. 1993, 34, 7895–7898.
8. (a) Mitome, H.; Miyaoka, H.; Yamada, Y. Tetrahedron
Lett. 2000, 41, 8107–8110; (b) Miyaoka, H.; Saka, Y.;
Miura, S.; Yamada, Y. Tetrahedron Lett. 1996, 37, 7107–
7110; (c) Nagaoka, H.; Shibuya, K.; Yamada, Y. Tetra-
hedron Lett. 1993, 34, 1501–1504; (d) Iwashima, M.;
Nagaoka, H.; Kobayashi, K.; Yamada, Y. Tetrahedron
13. Guertin, K. R.; Kende, A. S. Tetrahedron Lett. 1993, 34,
5369–5372.
14. Allylic iodide 11 was prepared from 5-hydroxypentan-2-
one in the following four steps: (1) protection of hydroxy
group as TBDMS ether; (2) Wittig reaction with
Ph3PꢁCH2 to give exo-olefin; (3) chlorination at allylic
position with Ca(COCl)2 and CO2 to give allylic chloride;
and (4) substitution reaction of chorine with NaI.
15. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,
113, 7277–7287; (b) Dess, D. B.; Martin, J. C. J. Org.
Chem. 1983, 48, 4155–4156.
16. (a) Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986,
108, 1035–1039; (b) Blanchette, M. A.; Choy, W.; Davis,
J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.;
Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
17. Epoxidation of two olefins in stolonitriene with TBHP
18
and VO(acac)2 gave the diastereomer of stolonidiol at
C-7, 8 epoxide as the sole product.
18. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136–6137.
19. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780 and references cited therein.