Synthetic studies toward cyathin diterpenoids: Approach to the tricyclic system through intramolecular Heck-type cyclization

Article abstract of DOI:10.1016/S0040-4039(02)00570-1

The enantioselective synthesis of a model of the core ring system of cyathin diterpenes is described. The key tricyclic acetate 4 was assembled via an intramolecular Heck-type cyclization of the chiral triflate 8. Acetate 4 was taken through to model cyat

Full text of DOI:10.1016/S0040-4039(02)00570-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4107–4110
Synthetic studies toward cyathin diterpenoids: approach to the
tricyclic system through intramolecular Heck-type cyclization
Cyrille Thominiaux,a Ange`le Chiaronib and Didier Desmae¨lea,*
aUnite´ de Chimie Organique Associe´e au CNRS, Faculte´ de Pharmacie, 5, rue J.-B. Cle´ment, 92290 Chaˆtenay-Malabry, France
bInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Accepted 21 March 2002
Abstract—The enantioselective synthesis of a model of the core ring system of cyathin diterpenes is described. The key tricyclic
acetate 4 was assembled via an intramolecular Heck-type cyclization of the chiral triflate 8. Acetate 4 was taken through to model
cyathan ketones 3a and 3b by a one-carbon ring expansion. © 2002 Elsevier Science Ltd. All rights reserved.
Stimulators of nerve growth factor (NGF) synthesis
have been expected as medicine for degenerative neu-
ronal disorders such as Alzheimer’s disease and periph-
eral nerve regeneration.1 Recently two classes of related
diterpenoid natural products isolated from fungi, the
erinacines2 and scabronines3 have been shown to have
significant NGF synthesis stimulating activity (Fig. 1).
ration of 4 into ketones 3a,b, which display the correct
stereochemistry of the cyathin family. Intramolecular
Heck reactions using prochiral dienes tethered to
vinylic halide or triflate moieties, are powerful tools for
the rapid construction of polycyclic compounds.5 Thus,
we first planned to elaborate a model of the cyathane-
ring system by palladium-catalyzed cyclization of the
triflate 9 possessing a cycloheptadiene moiety. How-
ever, we faced a number of difficulties to prepare the
required ester 7, and we also failed to alkylate
efficiently other seven-membered ring derivatives (such
as 2-methyl-1,3-cycloheptanedione or 2-methyl-cyclo-
heptenone) with the iodo derivative 5. An alternative
plan was therefore designed, targeting a C-nor-cyathane
derivative such as the acetate 4. The seven-membered
C-ring would ultimately be derived through a one-car-
bon ring enlargement reaction.6 Accordingly, the cru-
cial coupling of the chiral A-ring synthon with the
C-ring subunit would simply be performed by alkyla-
tion of the enolate of the cyclohexadiene ester 6 with
iodide 5 (Scheme 1).
The structural novelty and the biological activity dis-
played by the cyathins have drawn much attention to
their synthesis. However, to date no enantioselective
synthesis of cyathins has been accomplished.4 The cen-
tral synthetic challenge in the design of a route to
cyathins is the control of the anti relative stereochem-
istry between the rings A and C. In this letter, we wish
to describe a sound solution to this problem, involving
the enantioselective synthesis of the tricyclic acetate 4
by Heck-type cyclization of triflate 8, and further elabo-
The chiral synthon 5 was prepared from the known
keto ester (R)-10, which is easily accessible with a high
enantiomeric purity via the deracemizing Michael addi-
tion reaction involving the chiral imine derived from
1-methylcyclopentanone and (S)-1-phenylethylamine.7
Temporary shielding of the keto group was first under-
taken. To this aim, 10 was reduced with sodium boro-
hydride, and the mixture of epimeric alcohols obtained
was protected as t-butyldimethysilyl ethers. Saponifica-
tion of the ester group of 11 delivered the correspond-
ing acid 12 in 72% overall yield from 10.
Iododecarboxylation of the propionic side chain was
Figure 1.
Keywords: terpene; Heck reactions; ring transformation; dienes;
diastereoselection.
* Corresponding author. Fax: +33 (0) 146835752; e-mail:
didier.desmaele@cep.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00570-1

4108
C. Thominiaux et al. / Tetrahedron Letters 43 (2002) 4107–4110
nary stereogenic center to direct the reaction onto the
face opposite to the methyl group seemed unprece-
dented. This high stereoselectivity in the ring-closure
reaction could be related to steric interactions and/or
the introduction of conformational strain in the tether,
which does not favor a transition state that leads to the
angular substituents being on the same side of the
molecule. Thus, the tandem Heck reaction–acetate ion
capture process11 appears to be a viable method to
establish the crucial anti relationship of A and C rings
of the cyathane skeleton (Scheme 2).
The remaining task was the one-carbon expansion of
the C-ring. We first planned to introduce the C-14
hydroxyl group before implementing the ring enlarge-
ment. Thus, acetate 4 was treated with sodium methox-
ide in methanol, and the resulting allylic alcohol 1812
oxidized with MnO2 affording a 73% yield of 19. Base-
catalyzed epoxidation occurred exclusively by the con-
vex face, delivering keto-epoxide 20 in 90% yield.
Treatment of the latter with sodium (phenyl-
seleno)trimethoxy borate13 next provided the hydroxy
ketone 21 (75% isolated yield). The stereochemistry of
Scheme 1.
then achieved by treatment of acid 12 with Pb(OAc)4/I2
according to the Barton8 modification of the Kochi
reaction to provide 5 in 80% yield. The coupling
between the lithium enolate of the ester 69 and the iodo
derivative 5 turned out to be quite difficult, and
required heating in the presence of DMPU. In such
conditions the diene ester 13 was obtained in 83% yield.
Removal of the tert-butyldimethylsilyl group with
tetra-n-butylammonium fluoride in refluxing THF, fol-
lowed by Swern oxidation led to the ketone 14, which
was taken through enol triflate 8 by using triflic anhy-
dride in the presence of 2,6-di-tert-butylpyridine.10 At
this stage, we stood ready to check the crucial palla-
dium-catalyzed cyclization. In the event, treatment of
triflate 8 in standard Heck conditions (Pd(OAc)2 cat.,
K2CO3) was disappointing, giving rise to a mixture of
trienes 15, 16 and 17 in low yield (<15%), along with a
minute amount of allylic acetate 4 (<10%). Since the
latter product was formed by addition of acetate ions
from Pd(OAc)2 on the intermediate h3 palladium com-
plex, the influence of acetate ions was studied with the
hope to drive the reaction course toward the desired
acetate 4.11 Gratifyingly, treatment of triflate 8 with
Pd2dba3 as catalyst (5%) in the presence of 3 equiv. of
tetrabutylammonium acetate in DMSO at 60°C pro-
vided tricyclic acetate 4 in 85% yield. The stereochemi-
cal assignment of 4 was inferred from 1H NMR
spectroscopy including NOESY experiments. The
pseudo-axial configuration of the methine hydrogen at
C-9a (l=3.43) in respect to the C-ring, was deduced
from the coupling constants (J=14.5 and 3.5 Hz) with
vicinal H-9a and H-9b protons, respectively. Further-
more, a strong correlation between the H-10b proton
and the angular methyl group in the NOESY chart are
consistent only with the anti-cis configuration of 4. This
assignment was subsequently confirmed by X-ray crys-
tallography (vide infra). Interestingly, while the forma-
tion of the cis BC-ring junction could be anticipated in
view of the known steric course of such intramolecular
Heck reaction;5 however, the influence of the quater-
Scheme 2. Reagents and conditions: (a) NaBH4, MeOH, 0°C,
91%; (b) TBDMSCl, Im, DMF, 20°C, 12 h, 90%; (c) aq.
KOH, MeOH, 20°C, 89%; (d) Pb(OAc)4/I2, hw, refluxing
CCl4; (e) i. 6, LDA, THF, −78°C, 1 h, ii. DMPU, THF, 50°C,
3 h, 83%; (f) n-Bu4NF, THF, 60°C, 5 h, 78%; (g) (ClCO)2,
DMSO, CH2Cl2, −78°C, then Et3N, 95%; (h) 2,6-di-tert-
buylpyridine, Tf2O, CH2Cl2, 0°C, 79%; (i) PdOAc2 cat.,
K2CO3, n-Bu4NBr, DMA, 100°C, 8 h.

C. Thominiaux et al. / Tetrahedron Letters 43 (2002) 4107–4110
4109
Scheme 3. Reagents and conditions: (a) MeONa, MeOH, 20°C, 3 h, 96%; (b) MnO2, toluene, 80°C, 3 h, 73%; (c) H2O2, NaOH,
MeOH, 20°C, 12 h, 90%; (d) PhSeSePh, NaBH4, MeOH, AcOH cat. 0°C, 3 h, 75%; (e) Li, NH3, t-BuOH–THF, −78°C; (f) PCC,
,
CH2Cl2, AcONa, 4 A sieves, 20°C, 78%; (g) i. TMSCHN2, AlMe3, −78 to 20°C, 3 h, ii: TFA, THF, H2O, 78%.
the four stereocenters in 21 was assigned by X-ray
diffraction analysis.14 This analysis confirmed the anti
relationship between the two angular substituents, as
previously established by NMR. At this point, inver-
sion and protection of the C-6 hydroxyl group were
required. Unfortunately, numerous attempts to address
this issue failed due to an extremely easy b-elimination
reaction of 21 reverting to enone 19, either under
conventional protection conditions, or employing Mit-
sunobu protocol. Given the potential difficulties to
perform the ring expansion reaction with 21, we
decided to evaluate the process with model ketone 24.
Accordingly, enone 19 was reduced with lithium in
liquid ammonia, and the crude alcohol obtained was
oxidized with PCC to give ketone 24. Treatment of this
material with (trimethylsilyl)diazomethane in presence
of Me3Al15 provided after acidic work-up a 1.5:1 mix-
ture of ketone 3a and 3b with a combined 78% yield
(Scheme 3). Since a higher selectivity could be expected
for more substituted compounds, this work constitutes
a useful stereocontrolled route for the construction of
the ABC rings of cyathins. Studies are now in progress
toward syntheses of erinacine A and other cyathin
derivatives, according to the present strategy.
hata, N.; Ohizumi, Y.; Takaya, Y.; Ojima, Y. Tetra-
hedron Lett. 1998, 39, 6229–6232; (b) Kita, T.; Takaya,
Y.; Ojima, Y.; Ohta, T.; Aizawa, K.; Hirano, T.;
Inakuma, T. Tetrahedron 1998, 54, 11877–11886.
4. For a review see: Wright, D. L.; Whitehead, C. R. Org.
Prep. Proc. Int. 2000, 32, 307–330.
5. (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1989, 54, 4738–4739; (b) Kagechika, K.; Shibasaki, M. J.
Org. Chem. 1991, 56, 4093–4094.
6. For a similar strategy: (a) Piers, E.; Boulet, S. L. Tetra-
hedron Lett. 1997, 38, 8815–8818; (b) Piers, E.; Gilbert,
M.; Cook, K. L. Org. Lett. 2000, 2, 1407–1410.
7. (a) Pfau, M.; Revial, G.; d’Angelo, J.; Guingant, A. J.
Am. Chem. Soc. 1985, 107, 273–274; (b) For a review, see:
d’Angelo, J.; Desmae¨le, D.; Dumas, F.; Guingant, A.
Tetrahedron: Asymmetry 1992, 3, 459–505.
8. Barton, D. H. R.; Faro, H.; Serebryakov, E. P.; Woosley,
N. F. J. J. Chem. Soc. 1965, 2438–2443.
9. Marshall, J. L.; Erickson, K. C.; Folsom, T. K. Tetra-
hedron Lett. 1970, 4011–4012.
10. Crips, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc.
1984, 106, 7500–7500.
11. Kagechika, K.; Ohshima, T.; Shibasaki, M. Tetrahedron
1993, 49, 1773–1782.
12. Compound 18: Colorless oil; [h]D −4.4 (EtOH, c=2); IR
(neat, cm−1) 3600–3100, 1728, 1640, 1460, 1430; 1H NMR
(CDCl3, 400 MHz): l 5.92 (ddd, J=9.9, 5.5, 1.4 Hz, 1H),
5.76 (d, J=9.9 Hz, 1H), 5.46 (m, 1H), 4.11 (ddd, J=5.5,
3.9, 2.0 Hz, 1H), 3.65 (s, 3H), 3.44 (dd, J=14.2, 2.8 Hz,
1H); 2.35–2.25 (m, 1H), 2.15 (dddd, J=15.9, 9.1, 3.1, 1.3
Hz, 1H), 2.08–2.01 (m, 1H), 2.00 (broad s, 1H), 1.92 (dt,
J=3.9, 14.2 Hz, 1H), 1.76–1.52 (m, 5H); 1.21 (dt, J=
14.2, 3.5 Hz, 1H), 1.06 (s, 3H); 13C NMR (CDCl3, 50
MHz): l 175.1 (C), 149.4 (C), 134.7 (CH), 128.1 (CH),
124.1 (CH), 63.1 (CH), 52.2 (CH3), 50.7 (C), 44.5 (C),
43.2 (CH2), 37.9 (CH2), 35.5 (CH2), 32.5 (CH), 29.1
(CH2), 27.5 (CH2), 25.1 (CH3); Anal. calcd for C16H22O3:
C, 73.25; H, 8.45. Found: C, 73.27; H, 8.61.
References
1. (a) Carswell, S. Exp. Neurol. 1993, 124, 36–42; (b) Riaz,
S. S.; Tomlinson, D. R. Prog. Neurobiol. 1996, 49, 125–
143; (c) Conner, J. M.; Tuszynski, M. H. Ment. Retard
Dev. Dis. 1998, 4, 212–222.
2. (a) Kawagishi, H.; Shimada, A.; Shirai, R.; Okamoto, K.;
Ojima, F.; Sakamoto, H.; Ishiguro, Y.; Furukawa, S.
Tetrahedron Lett. 1994, 35, 1569–1572; (b) Kawagishi,
H.; Shimada, A.; Hosokawa, S.; Mori, H.; Sakamoto, H.;
Ishiguro, Y.; Sakemi, S.; Bordner, J.; Kojima, N.;
Furukawa, S. Tetrahedron Lett. 1996, 37, 7399–7402.
3. (a) Ohta, T.; Kita, T.; Kobayashi, N.; Obara, Y.; Naka-
13. Miyashita, M.; Hoshino, M.; Yoshikoshi, A. Tetrahedron
Lett. 1988, 29, 347–350.

4110
C. Thominiaux et al. / Tetrahedron Letters 43 (2002) 4107–4110
14. Compound 21: Colorless crystal, mp 168–170°C; IR
group P212121, Z=4, a=8.902(3), b=12.533(3), c=
12.918(4) A, V=1441.2 A ,
F(000)=600, u (Mo Ka)=0.71073 A, v=0.091 mm
dcalcd=1.283 g
cm−3
,
.
1
3
(neat, cm−1) w 3500–3300, 1731, 1702; H NMR (CDCl3,
,
,
−1
,
400 MHz): l 5.49 (s, 1H), 4.36 (t, J=3.4 Hz, 1H), 3.71
(m, 4H), 2.78 (dd, J=14.8, 3.1 Hz, 1H), 2.58 (dd, J=
15.1, 13.1 Hz, 1H), 2.47 (ddd, J=14.8, 3.7, 2.4 Hz, 1H),
2.35 (ddd, J=15.1, 5.8, 2.3 Hz, 1H), 2.31 (m, 1H), 2.17
(ddd, J=16.1, 9.1, 3.1 Hz, 1H), 2.05–1.95 (m, 2H), 1.81
(dt, J=13.9, 3.4 Hz, 1H), 1.75 (dd, J=12.1, 7.0 Hz, 1H),
1.60 (t, J=12.1 Hz, 1H), 1.26 (m, 1H), 1.18 (s, 3H); 13C
NMR (CDCl3, 100 MHz): l 208.5 (C), 174.5 (C), 147.1
(C), 125.6 (CH), 75.5 (CH), 53.1 (C), 52.1 (CH3), 45.0
(C), 44.1 (CH2), 44.0 (CH2), 42.5 (C), 37.9 (CH2), 37.2
(CH), 29.1 (CH2), 26.0 (CH3), 25.4 (CH2). Crystallo-
graphic data: crystal of 0.100×0.275×0.375 mm,
C16H22O4, Mw=278.34, orthorhombic system, space
5609 data were measured with a Nonius Kappa-CCD
diffractometer. The structure was refined with program
SHELXL-93. Refinement of 187 parameters converged to
R1(F)=0.0325 for the 1631 observed reflections having
I]2|(I), and wR2(F2)=0.0741 for all the 1787 unique
data, with a goodness-of-fit S factor of 1.073. The resid-
ual electron density was found between −0.11 and 0.10
e A−3. Crystallographic results have been deposited (CIF
,
file) with the Cambridge Crystallographic Data Centre,
UK, and allocated the deposition number CCDC 179328.
15. Yang, S.; Hungerhoff, B.; Metz, P. Tetrahedron Lett.
1998, 39, 2097–2098.