Synthesis of xestobergsterol A from dehydroepiandrosterone

Article abstract of DOI:10.1016/j.tetlet.2005.07.042

Xestobergsterol A, a potent inhibitor of histamine release, has been synthesized from dehydroepiandrosterone in a route that used introduction of a novel 15-oxygen functionality, side-chain construction via the orthoester Claisen rearrangement and TBAF-pr

Full text of DOI:10.1016/j.tetlet.2005.07.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6373–6376
Synthesis of xestobergsterol A from dehydroepiandrosterone
Atsuko Nakamura, Yuko Kaji, Kana Saida, Michiko Ito, Yumi Nagatoshi,
Noriyuki Hara and Yoshinori Fujimoto*
Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received 19May 2005; revised 27 June 2005; accepted 1 July 2005
Available online 28 July 2005
Abstract—Xestobergsterol A, a potent inhibitor of histamine release, has been synthesized from dehydroepiandrosterone in a route
that used introduction of a novel 15-oxygen functionality, side-chain construction via the orthoester Claisen rearrangement and
TBAF-promoted epimerization–aldol condensation.
Ó 2005 Elsevier Ltd. All rights reserved.
Xestobergsterols A (1) and B (2) were isolated in 1992
from the Okinawan marine sponge Xestospongia berg-
quistia, as unique polyhydroxy-steroids having a cis C/
H
O
R1
R2
OH
D-ring junction and an additional carbocyclic E-ring.1
Subsequently, xestobergsterol C (3) was isolated from
the Okinawan sponge, Ircinia sp., and the full structures,
including the C-23 configuration, of these sterols were
established.2 Xestobergsterols A and B are strong inhibi-
tors of histamine release from rat mast cells induced by
anti-immunoglobulin E.1 It was further shown that
xestobergsterol A exerts its action by inhibiting phos-
phatidylinositol phospholipase C.3 In addition, xesto-
bergsterols A and C were shown to exhibit cytotoxicity
against L-1210 murine leukemia cells.2 The unique
structures and potent biological activities of xestoberg-
sterols prompted our and other groups to study the syn-
thesis of xestobergsterols.4–6 In the previous paper, we
reported a model synthesis of 3-epi-6,7-dideoxyxesto-
bergsterol A from dehydroepiandrosterone (4) in a route
that used a novel C-15 functionalization followed by a
side-chain construction via an orthoester Claisen rear-
rangement.7 Herein, we report the synthesis of naturally
occurring xestobergsterol A by applying this methodol-
ogy. The first synthesis of 1 has been described by Jung
and Johnson8 who employed Breslow et al.ꢀs remote oxi-
dation for the C-15 functionalization.9
H
O
H
H
HO
OH
HO
HO
1: R1, R2 = H
2: R1, R2 = OH
3: R1 = H, R2 = OH
4
Before beginning the total synthesis of 1 itself, we first
examined the feasibility of the order of introduction of
the C-6/C-7 glycol and the C-15 oxygen functions. The
study suggested that the C-15 oxygen functionality
(and the side-chain construction) should be introduced
before the C-6/C-7 glycol formation, since epoxidation
of an androst-15-en-17-one derivative having
a
protected C-6/C-7 glycol moiety failed to proceed. Thus,
we chose a compound that bears a protected 3b-ol
function and the D5-double bond as well as C-15 and
C-23 oxygen functions as a key intermediate. Retrosyn-
thesis of 1 along this line is shown in Scheme 1. The E-
ring of 1 could be formed from the diketone A according
to the base-catalyzed epimerization–aldol condensation
originally developed by Jung and Johnson.6 The suitably
protected pentanol B, in which the R1 protecting group
needs to be removed in the presence of the R3 and R4
protecting groups, could be a precursor of the diketone
A. We anticipated a possible use of compound B for the
synthesis of 2 and 3, since the introduction of the A-ring
functionalities in 2 and 3 might be possible from it.
The D5-double bond of compound C is a good clue for
the introduction of the C-6/C-7 glycol moiety. In the
Keywords: Xestobergsterol A; Steroid; Dehydroepiandrosterone;
Orthoester Claisen rearrangement.
*
Corresponding author. Tel./fax: +81
fujimoto@cms.titech.ac.jp
3 5734 2241; e-mail:
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.042

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A. Nakamura et al. / Tetrahedron Letters 46 (2005) 6373–6376
23
O
OR3
OR3
OR3
15
O
1
14
OR3
H
OR4
H
H
3
7
R5O
R1O
R1O
6
OR4
OR4
OR4
C
B
A
O
17
CHO
OH
OR2
16
O
4
15
OR2
H
H
H
R1O
R1O
R1O
F
E
D
Scheme 1. Retrosynthesis of 1.
intermediate C, the C-15 and C-23 alcohol groups were
intentionally protected with the same group (R3). This
required a selective removal of the C-15 hydroxy pro-
tecting group (R2) in the presence of the C-3 alcohol-
protecting group (R1). Use of a single C-23 epimer
would be convenient from the viewpoint of synthetic
simplicity, although the C-23 chiral center in compound
C disappears at a later stage. The full side-chain struc-
ture in compound C can be readily prepared from the
C-23 aldehyde D, which can be obtained in reactions
involving the orthoester Claisen rearrangement of the
allylic alcohol E with a suitably protected (R2) C-15
alcohol group. At the outset of this study, we developed
a method to attain such an allylic alcohol by titanium
tetraisopropoxide-mediated ring-opening of a 15,16-
epoxy-17(20)-ene,7 which is available from the epoxy-
ketone F. The synthesis of the epoxide F from dehydro-
epiandrosterone appeared to be straightforward
according to the known procedure.10,11
alcohols, the less polar (23S)-ol 14b (30%) and the more
polar (23R)-ol 14a (36%) together with the reduced C-23
primary alcohol (17%). Reaction of 13 with isobutylli-
thium at À78 °C gave an improved result, yielding 14b
(25%) and 14a (58%) together with the C-23-alcohol
(6%). The (23S)-ol 14b was found to be readily con-
verted to (23R)-ol 14a in 83% yield via a protocol
reported by Corey et al., that is, mesylation followed
by KO2 treatment (80% combined yield from 13 to
14a).13 The configuration at the C-23 stereocenter for
14a and b was determined by application of the modified
Mosherꢀs ester method.14 Chemoseletive desilylation of
the C-15 TES group in 14a was achieved by a brief treat-
ment of 14a with BF3ÆEt2O (2 equiv) in CH2Cl2 at 0 °C,
although TBAF or acidic treatment deprotected the two
silyl groups without selectivity. The 15,23-diol thus ob-
tained was now protected as the dibenzoate 15.
The stage was now set for the B-ring modification. It
was found that N-hydroxyphthalimide-catalyzed air oxi-
dation15 of 15 in the presence of dibenzoyl peroxide fol-
lowed by decomposition of the resulting peroxy product
with CuCl2 in pyridine afforded the corresponding 5-
ene-7-one in a better yield than other oxidation methods
such as RuCl3/TBHP and PCC. Luche reduction of the
C-7 ketone with NaBH4 gave the 7b-ol 16 stereo-
selectively.16 Hydroboration–oxidation of 16 gave the
6a,7b-diol which was protected as the methylenedioxy
compound 17 (corresponding to compound B). The
modest yield (51%) of this step was mainly due to partial
removal of the C-15 benzoate group. The C-3 silyl group
was removed with TBAF, and the orientation of the C-3
alcohol was inverted via an oxidation–reduction
sequence using L-Selectride as a reducing agent5 to yield
the 3a-alcohol 18. Protection of the hydroxyl group of
18 as tert-butyldimethylsilyl ether and reductive removal
of the benzoyl group gave the C-15,C-23-diol. This diol
was smoothly oxidized to the corresponding diketone 19
with Dess–Martin periodinane. We found that TBAF
treatment of the diketone 19 effected deprotection of
the TBS group as well as epimerization–aldol condensa-
tion to furnish the 6,7-methylal derivative 20 of xesto-
bergsterol A in good yield. The new epimerization–
aldol condensation method could be used as an alterna-
The TBDPS ether was selected as the R1 protecting
group of 4 in the hope of a selective removal of the C-
15 protecting group. The ether 5 was converted to the
enol TMS ether, which was then gently heated in
CHCl3–DMSO in the presence of 0.1 equiv of Pd(OAc)2
under oxygen atmosphere to yield the enone 6.12 Epox-
idation of 6 with TBHP/triton B afforded the b-epoxide
7 stereoselectively.10 Wittig reaction of 7 gave exclu-
sively the (E)-olefin 8 [(E):(Z) = 10:1].5 The epoxide-
ring-opening of 8 with acetic acid (3 equiv) and
Ti(OiPr)4 (1.5 equiv) gave 15b-hydroxy-16a-acetate 9
in 84% yield, as we reported previously.7 Protection of
the C-15 hydroxyl group as TES ether followed by
deacetylation afforded the protected allylic alcohol 10,
a substrate for the side-chain introduction. Compound
10 was subjected to the standard conditions of the
orthoester Claisen rearrangement using triethyl ortho-
propionate to give the rearranged ester 11 as a single iso-
mer in 88% yield. The D16-olefinic bond in 11 was
selectively hydrogenated with Pt–C as a catalyst to give
the ester 12 with the correct C-17 configuration.11 Com-
pound 12 was converted to the aldehyde 13 via the
corresponding C-23 alcohol. Reaction of 13 with
isobutylmagnesium bromide gave the C-23 epimeric

A. Nakamura et al. / Tetrahedron Letters 46 (2005) 6373–6376
6375
O
O
O
a
c
b
d
O
O
4
H
H
H
H
TBDPSO
7
6
8
5
CO2Et
OTES
CO2Et
OTES
OAc
OH
OH
e
f, g
h
i
OTES
H
H
H
H
9
10
11
12
CHO
OBz
OBz
m, n
o, p
OH
l
j, k
OTES
OTES
H
H
H
TBDPSO
23R: 14a
23S: 14b
13
15
OBz
OBz
OBz
OBz
OBz
OBz
q, r
s, t, u
H
O
H
O
H
OH
HO
TBDPSO
TBDPSO
O
O
16
17
18
H
O
O
v, w, x
TBSO
y
z
1
OH
H
H
O
H
O
O
HO
O
O
20
19
Scheme 2. Synthetic route to 1. Reagents and conditions: (a) TBDPSCl, Im, 99%; (b) LDA, TMSC1; O2, Pd(OAc)2, 84%; (c) TBHP, Triton B, 83%;
(d) EtPPh3I, KHMDS, 83%; (e) AcOH, Ti(OiPr)4, 84%; (f) TESOTf, lutidine; (g) LiAlH4, 70% (two steps); (h) EtC(OEt)3, EtCO2H, 88%; (i) H2, Pt–
C, 96%; (j) LiAIH4; (k) TPAP, NMO, 83% (two steps); (l) isobutyllithium; (m) BF3ÆEt2O, 90%; (n) BzCl, Py, 91%; (o) N-hydroxyphthalimide, O2,
Bz2O2; CuCl2, Py, 75%; (p) NaBH4, CeCl3, 89%; (q) BH3ÆTHF; H2O2, NaOH, 51%; (r) CH2(OMe)2, P2O5, 85%; (s) TBAF, 95%; (t) Dess–Martin,
91%; (u) L-Selectride, 90%; (v) TBSOTf, lutidine, 63%; (w) LiAlH4, 90%; (x) Dess–Martin, 60%; (y) TBAF; (z) 6 N HCl/THF, 60% (two steps).
tive to the known base-catalyzed one in the synthesis of
the other xestobergsterols. Final deprotection of the
methylal group under acidic conditions furnished 1
(Scheme 2). The spectroscopic data of synthetic 1 were
in complete accord with those of natural xestobergsterol
A.
versity) for providing 1H and 13C NMR spectra of
natural xestobergsterol A.
References and notes
1. Shoji, N.; Umeyama, A.; Shin, K.; Takeda, K.; Arihara,
S.; Kobayashi, J.; Takei, M. J. Org. Chem. 1992, 57, 2996–
2997.
2. Kobayashi, J.; Shinonaga, H.; Shigemori, H.; Umeyama,
A.; Shoji, N.; Arihara, S. J. Nat. Prod. 1995, 58, 312–318.
3. Takei, M.; Umeyama, A.; Shoji, N.; Arihara, S.; Endo, K.
Experintia 1993, 49, 145.
4. Krafft, M. E.; Chirico, X. Tetrahedron Lett. 1994, 4511–
4514; Krafft, M. E.; Shao, B.; Dasse, O. A. Tetrahedron
1998, 54, 7033–7044.
5. Krafft, M. E.; Dasse, O. A.; Fu, Z. J. Org. Chem. 1999, 64,
2475–2485.
In summary, we have achieved the synthesis of xesto-
bergsterol A from dehydroepiandrosterone in a route
that used introduction of a novel 15-oxygen functional-
ity, side-chain construction via the orthoester Claisen
rearrangement, and TBAF-promoted epimerization–
aldol condensation. This paper constitutes the second
synthesis of xestobergsterol A. As an extension of this
work, the synthesis of xestobergsterols B and C is in
progress utilizing the intermediate 17.
6. Jung, M. E.; Johnson, T. W. J. Am. Chem. Soc. 1997, 119,
12412–12413.
7. Kaji, Y.; Koami, T.; Nakamura, A.; Fujimoto, Y. Chem.
Pharm. Bull. 2000, 48, 1480–1483.
Acknowledgments
8. Jung, M. E.; Johnson, T. W. Org. Lett. 1999, 1, 1671–
1674; Jung, M. E.; Johnson, T. W. Tetrahedron 2001, 57,
1449–1481.
We thank Professor Akemi Umeyama (Tokushima Bun-
ri University) and Junꢀichi Kobayashi (Hokkaido Uni-

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A. Nakamura et al. / Tetrahedron Letters 46 (2005) 6373–6376
9. Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu,
13. Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.; Machida, Y.;
Shiner, C. S. Tetrahedron Lett. 1975, 3183–3186.
14. Ohtani, I.; Kusumi, T.; Kashman, K.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
15. Jones, S. R.; Selinsky, B. S.; Rao, M. N.; Zhang, X. H.;
Kinney, W. A.; Tham, F. S. J. Org. Chem. 1998, 63, 8599–
8603.
S.; Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251–
3262.
10. Takahashi, T.; Ootake, A.; Tsuji, J.; Tachibana, K.
Tetrahedron 1985, 41, 5747–5754.
11. Liu, D.; Stuhmiller, L. M.; McMorris, T. C. J. Chem. Soc.,
Perkin Trans. 1 1988, 2161–2167.
12. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.;
Zheng, D. Tetrahedron Lett. 1995, 36, 2423–2426.
16. Kumar, V.; Amann, A.; Qurisson, G.; Luu, B. Synth.
Commun. 1987, 17, 1279–1286.