Studies toward the total synthesis of (-)-kampanol A: An efficient construction of the ABCD ring system

Article abstract of DOI:10.1016/S0040-4039(02)01859-2

The optically active tetracyclic ABCD ring system 2 of (-)-kampanol A (1), a novel Ras farnesyltransferase inhibitor from a microorganism, was efficiently synthesized starting from the known ketol 4 as a model study. The synthetic method involves conjugate addition reaction of the Grignard reagent of the bromobenzene derivative 14 to the α-methylene ketone 10 to form the coupling product 15 and phenylselenium-mediated cyclization reaction of the phenol derivative 17 to stereoselectively construct the requisite tetracyclic intermediate 18 as the pivotal steps.

Full text of DOI:10.1016/S0040-4039(02)01859-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7937–7940
Studies toward the total synthesis of (−)-kampanol A:
an efficient construction of the ABCD ring system
Katsuhiko Iwasaki,† Mari Nakatani, Munenori Inoue and Tadashi Katoh*
Sagami Chemical Research Center, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
Received 9 August 2002; revised 26 August 2002; accepted 30 August 2002
Abstract—The optically active tetracyclic ABCD ring system 2 of (−)-kampanol A (1), a novel Ras farnesyltransferase inhibitor
from a microorganism, was efficiently synthesized starting from the known ketol 4 as a model study. The synthetic method
involves conjugate addition reaction of the Grignard reagent of the bromobenzene derivative 14 to the a-methylene ketone 10 to
form the coupling product 15 and phenylselenium-mediated cyclization reaction of the phenol derivative 17 to stereoselectively
construct the requisite tetracyclic intermediate 18 as the pivotal steps. © 2002 Elsevier Science Ltd. All rights reserved.
Kampanol A (1), isolated from the culture broth of
Stachybotrys kampalensis by the Merck research group
in 1998, has been shown to be a novel and specific
inhibitor of Ras protein farnesyltransferase.1,2 This
enzyme catalyzes the farnesylation of Ras p21 protein
on the cysteine residue of the C-terminal CAAX-tetra-
peptide sequence (C: cysteine, A: aliphatic amino acid,
X: serine or methionine); this post-translational modifi-
cation is essential for plasma membrane association
that is a critical step in ras-mediated oncogenesis.3
Figure 1. Structures of kampanol A (1) and the model com-
Therefore, kampanol A (1) is anticipated to be a
pound 2.
promising agent for novel cancer therapeutics. The
gross structure of 1 including the relative stereochem-
compound 2 will particularly be useful in the structure–
activity studies of kampanol A and related compounds.
To the best of our knowledge, synthetic studies of 1
have not been reported to date6 (Fig. 1).
istry was revealed by extensive spectroscopic studies to
have
a
novel pentacyclic 1H-benzo[a]furo[3,4-
h]xanthen-3(6H)-one skeleton (ABCDE ring system)
with five asymmetric carbons.1,4,5 Its remarkable biolog-
ical properties and unique structural features prompted
us to undertake a project directed toward the total
synthesis of optically active 1. In this communication,
we wish to disclose our preliminary results concerning
an efficient and facile synthetic method for the model
compound 2 possessing the tetracyclic ABCD ring sys-
tem with the requisite substituents and asymmetric
carbons contained in 1. The present study was con-
ducted to explore our synthetic strategy for this fasci-
nating natural product 1. And furthermore, the model
Our synthetic plan for the model compound 2 is out-
lined in Scheme 1. We envisioned that the target com-
pound 2 would be elaborated by the stereocontrolled
cyclization of the phenol derivative A applying the
related protocols previously described in the
literature6a–g followed by manipulation of the C-3 and
the phenolic hydroxy protecting groups. The cyclization
precursor A would be prepared through the conjugate
addition reaction7 between the a-methylene ketone B
and the Grignard reagent of the ortho-disubstituted
bromobenzene derivative C, where we expected that the
C-8 substituent in the coupling product should be
placed in an equatorial orientation under thermody-
namically and/or kinetically controlled reaction condi-
tions.8 The key segments B and C, in turn, would be
obtained from the known trans-decalone D9 and the
Keywords: kampanol A; Ras farnesyltransferase inhibitor; conjugate
addition; phenylselenium-mediated cyclization.
* Corresponding author. Tel.: +81-467-76-9295; fax: +81-467-77-4114;
e-mail: takatoh@alles.or.jp
† Graduate student from Department of Electronic Chemistry, Tokyo
Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01859-2

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K. Iwasaki et al. / Tetrahedron Letters 43 (2002) 7937–7940
the hydroxy group in 4 as its t-butyldimethylsilyl (TBS)
ether followed by oxidation of the resulting TBS ether
5 employing a combination of NaN(TMS)2 and 2-
phenylsulfonyl-3-phenyloxaziridine developed by Davis
et al.10,11 After protection of the hydroxy group in 6 as
its benzyloxymethyl (BOM) ether (98%), the resulting
BOM ether 7 was then subjected to Wittig methylena-
tion to provide the exo-olefin 8 in 91% yield. Removal
of the BOM protecting group in 8 under Birch condi-
tions (Li/liq.NH3/THF) followed by Dess–Martin
oxidation12 of the resulting alcohol 9, furnished the
desired decalin segment 10, mp 60–61°C, [h]2D0 −39.0° (c
1.02, CHCl3), in 78% yield for the two steps.
Next, the synthesis of the aromatic segment 14 (corre-
sponding to C) was carried out as shown in Scheme 3.
The starting material, 2-bromoresorcinol (12), was pre-
pared from the commercially available resorcinol (11)
in two steps according to the literature.13 The two
hydroxy groups present in 12 were differently pro-
tected; that is, monoprotection with a methoxymethyl
(MOM) group afforded the MOM ether 13 (41%),
which upon further protection as its BOM ether fur-
nished the requisite aromatic segment 14 in 96% yield.
Scheme 1. Synthetic plan for the model compound 2.
commercially available resorcinol (11, Scheme 3),
respectively.
We initially pursued the synthesis of the decalin seg-
ment 10 (corresponding to B) as shown in Scheme 2.
Although the compound 10 has been previously synthe-
sized by Seifert et al.8a starting with the (+)-Wieland
Miescher ketone in 21% overall yield in nine steps, we
sought an alternative, more efficient and reliable
method for the synthesis of 10. We have now found
that 10 can be synthesized starting from (+)-Wieland
Miescher ketone analogue 3 in 44% overall yield in a
ten-step sequence. Thus, the known ketol 49 (corre-
sponding to D), readily derived from (+)-3 (>99% ee) in
four steps according to the reported method,9 was first
converted to the a-hydroxy ketone 6 in 73% overall
yield via a two-step sequence involving protection of
Scheme 3. Synthesis of the aromatic segment 14. Reagents
and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, rt, 41%; (b)
BOMCl, i-Pr2NEt, CH2Cl2, rt, 96%.
Having obtained both the decalin segment 10 and the
aromatic segment 14, we next focused our attention on
the critical coupling reaction of these two segments. As
shown in Scheme 4, the conjugate addition of the
Grignard reagent, prepared from 14 and Mg turnings in
the presence of 1,2-dibromoethane in Et2O, to the
a-methylene ketone 10 proceeded smoothly without the
addition of any copper salts,14 leading to the formation
of the desired coupling product 15, [h]2D0 −26.3° (c 1.07,
CHCl3), in 95% yield with complete stereoselectivity at
the C-8 position. The coupling product 15 was further
converted to the phenol derivative 17 (corresponding to
A), [h]2D0 −12.6° (c 0.79, CHCl3), the key cyclization
precursor, through a two-step sequence of reactions
involving Wittig methylenation of the carbonyl func-
tion in 15 followed by reductive removal of the BOM
protecting group in the resulting exo-olefin 16, [h]D20
−20.6° (c 1.08, CHCl3), under the Birch conditions
(Li/liq.NH3/THF) (95%).
Scheme 2. Synthesis of the decalin segment 10. Reagents and
conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 99%; (b)
NaN(TMS)2, THF, −78°C, 2-phenylsulfonyl-3-phenylox-
aziridine, −78°C, 74%; (c) BOMCl, i-Pr2NEt, CH2Cl2, rt,
98%; (d) Ph3P+CH3Br−, t-BuOK, benzene, reflux, 91%; (e) Li,
liq. NH3–THF, 80%; (f) Dess–Martin periodinane, CH2Cl2,
rt, 98%.
With the key cyclization precursor 17 in hand, our next
efforts were directed toward the crucial stereocontrolled
cyclization reaction of 17 to construct the requisite
tetracyclic ABCD ring system. After several experi-
ments,15 to our delight, the cyclization reaction of the
phenol 17 was successfully achieved by the use of
organoselenenylating reagent.16 Thus, 17 was treated

K. Iwasaki et al. / Tetrahedron Letters 43 (2002) 7937–7940
7939
Scheme 5. Synthesis of the model compound 2. Reagents and
conditions: (a) n-Bu3SnH, AIBN, toluene, reflux, 78%; (b) 6
M HCl, MeOH, 50°C, 96%; (c) Ac2O, DMAP, pyridine, rt,
85%; (d) t-BuOK, THF-t-BuOH (5:1), rt, 96%.
hydroxy group met with failure. Therefore, 20 was
transformed to 2 via a two-step sequence of reactions;
thus, acetylation of both the C-3 and phenolic hydroxy
groups in 20 furnished the corresponding diacetate 21
(85%), mp 144.5–146°C, [h]2D0 −8.3° (c 1.02, CHCl3),
which upon chemoselective removal of the phenolic
acetyl group by exposure to potassium t-butoxide (1.05
equiv.) in THF-t-butyl alcohol (5:1) at room tempera-
ture finally provided 2,17 mp 233–234°C, [h]2D0 −10.4° (c
0.98, CHCl3), in 96% yield.
Scheme 4. Synthesis of the tetracyclic key intermediate 18.
Reagents and conditions: (a) 14, Mg, 1,2-dibromoethane,
Et2O, reflux; 10, 0°C“rt, 95%; (b) Ph3P+CH3Br−, t-BuOK,
benzene, reflux, 97%; (c) Li, liq. NH3–THF, 95%; (d) N-
phenylselenophthalimide, SnCl4, CH2Cl2, −78°C, 98%.
In summary, we have achieved an enantioselective syn-
thesis of the ABCD ring system 2 of (−)-kampanol A
(1) as a model study. The explored method features a
conjugate addition reaction of the Grignard reagent,
prepared from the bromobenzene derivative 14, to the
a,b-unsaturated ketone 10 to obtain the coupling
product 15 and an organoselenium-mediated cycliza-
tion reaction of the phenol derivative 17 to construct
the requisite tetracyclic intermediate 18 with complete
stereoselectivity. Further investigation toward the total
synthesis of kampanol A and its analogues based on
this preliminary study, as well as biological evaluation
of the model compound 2 are now in progress and will
be reported appropriately in due course.
with N-phenylselenophthalimide (1.6 equiv.) in the
presence of tin(IV) chloride (1.4 equiv.) in
dichloromethane at −78°C for 2 h, resulting in the
formation of the desired cyclized product 18, [h]D20
+21.5° (c 1.04, CHCl3), as the single isomer in 98%
yield, which possesses the correct stereochemistry at the
C-7 position.6g This phenylselenium-mediated cycliza-
tion reaction would proceed through the transition
state such as selenonium ion intermediate 17A, where
the selenonium ion would be opened by the attack of
the inner phenolic hydroxy group to provide the 6-exo
cyclization product 18. The newly formed stereochem-
istry at the C-7 position in 18 was proven by NOESY
1
experiments in the 500 MHz H NMR spectrum; thus,
as depicted in the formula 18A, clear NOE interactions
between the signals due to Ha and Hb and between the
signals due to Ha and Hc were respectively observed.
Acknowledgements
The final route that led to completion of the synthesis
of the target compound 2 is summarized in Scheme 5.
Thus, removal of the phenylselenyl group in 18 by
reaction with tri-n-butyltin hydride in the presence of
2,2-azobis(isobutyronitrile) (AIBN) followed by com-
plete deprotection of the TBS and MOM groups in the
resulting product 19, [h]2D0 −13.8° (c 0.74, CHCl3),
afforded the diol 20, mp 108–109°C, [h]2D0 −40.6° (c
0.91, CHCl3), in 75% yield for the two steps. Direct
conversion of 20 to 2 by selective acetylation of the C-3
This work was supported in part by the Pfizer Award in
Synthetic Organic Chemistry, Japan.
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1
17. Spectral data for 2: H NMR (500 MHz, CDCl3): l 6.92
(1H, t, J=8.0 Hz), 6.37 (1H, d, J=8.0 Hz), 6.30 (1H, dd,
J=0.8, 8.0 Hz), 4.77 (1H, s), 4.50 (1H, dd, J=4.7, 11.7
Hz), 2.72(1H, d, J=17.9 Hz), 2.66 (1H, dd, J=7.5, 17.9
Hz), 2.12–2.21 (1H, m), 2.05 (3H, s), 1.91 (1H, dt, J=3.5,
13.2 Hz), 1.49–1.77 (5H, m), 1.38 (1H, d, J=7.5 Hz), 1.18
(3H, s), 1.09–1.21 (1H, m), 0.97–1.03 (1H, m), 0.90 (3H,
s), 0.86 (3H, s), 0.74 (3H, s); 13C NMR (125 MHz,
CDCl3): l 171.4, 155.8, 153.5, 126.6, 109.8, 109.5, 106.2,
81.1, 75.0, 54.4, 48.7, 40.5, 38.0, 37.8, 37.7, 28.4, 26.8,
23.4, 21.3, 17.8, 17.4, 16.8, 14.2; IR (KBr): 3447, 2946,
2361, 1699, 1616, 1595, 1468, 1377, 1277, 1169, 1136,
1084, 1030, 972, 905, 777, 561 cm−1; EI-MS (m/z): 372
(M+).