Synthetic study of fomitellic acids: construction of the AB ring moiety

Article abstract of DOI:10.1016/j.tetlet.2009.04.039

Stereocontrolled synthesis of a fully functionalized AB ring moiety of fomitellic acids was accomplished. The tricyclic skeleton was stereoselectively constructed by means of titanium(III)-mediated radical cascade cyclization of epoxypolyene. The stereoch

Full text of DOI:10.1016/j.tetlet.2009.04.039

Tetrahedron Letters 50 (2009) 3849–3852
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Synthetic study of fomitellic acids: construction of the AB ring moiety
*
Makoto Yamaoka, Yuichi Fukatsu, Atsuo Nakazaki, Susumu Kobayashi
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereocontrolled synthesis of a fully functionalized AB ring moiety of fomitellic acids was accomplished.
The tricyclic skeleton was stereoselectively constructed by means of titanium(III)-mediated radical cas-
cade cyclization of epoxypolyene. The stereochemistry at C1 and C3 was controlled by a vinylogous
Mukaiyama aldol reaction and a Sharpless asymmetric epoxidation, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 March 2009
Revised 6 April 2009
Accepted 9 April 2009
Available online 14 April 2009
Keywords:
Titanium(III)-mediated radical cascade
cyclization
Epoxypolyene
Vinylogous Mukaiyama aldol reaction
Triterpenoid
Fomitellic acids, originally isolated by Sakaguchi et al.1 from the
mycelium of basidiomycete, Fomitella fraxinea, are potent
inhibitors of calf DNA polymerase , rat DNA polymerase b, and
selectivity and mild reaction conditions. Thus, we intended to
apply this methodology to the transformation of 7 to 6. The cycli-
zation precursor 7 was divided into two fragments, the aldehyde
part 8 and the vinyl iodide part 9. We planned to couple these
two parts by 1,2-addition of the vinyl lithium species derived from
9 to the aldehyde 8. The aldehyde 8 could be stereoselectively pre-
pared using a Sharpless asymmetric epoxidation (SAE)7 of 10, and
the latter could be obtained by a vinylogous Mukaiyama aldol reac-
tion (VMAR)8,9 of vinylketene silyl N,O-acetal 12 with enal 11.
At the outset, we examined the vinylogous Mukaiyama aldol
reaction between the vinylketene silyl N,O-acetal 12 and the enal
11 (Scheme 2). The enal 11 was readily prepared in five steps from
1,3-propanediol.10 Initial attempts using standard conditions, pre-
viously established in our laboratory (TiCl4, 0.1 M in CH2Cl2,
À50 °C), afforded an aldol adduct 1311 in low yield (43%). During
a survey of reaction conditions, a marked increase in yield was ob-
served by using toluene as solvent in high concentration (0.5 M),
a
a
human DNA topoisomerases I and II (Fig. 1).2 In recent years, these
DNA-dependent enzymes have been recognized as important
targets for cancer chemotherapy. Structurally, fomitellic acids
belong to the triterpenoid family of compounds, which are charac-
terized by a highly oxygenated steroidal AB ring moiety. The array
of hydrophilic groups in the AB ring along with a hydrophobic CD
ring and side chain moiety makes fomitellic acids potential lead
compounds for anti-cancer agents.3 With these considerations in
mind, we embarked on the total synthesis of fomitellic acids. Here,
we wish to report the stereocontrolled construction of the fully
fuctionalized AB ring moiety (5).
Retrosynthetic analysis of the AB ring moiety (5) is depicted in
Scheme 1. We simplified our target to the tricyclic compound 6
containing six stereogenic centers. There are several efficient
methodologies for constructing an AB trans-decaline ring system.
However, in view of the hydroxy group at C3, we favored a cascade
cyclization of an epoxypolyene. The tricyclic skeleton 6, or its
equivalent, could be formed either by cationic or by radical cascade
cyclization of epoxypolyene 7. However, there are very few exam-
ples of the cyclization of an epoxypolyene possessing an oxygen-
ated carbon at C1 (i.e., 7).4 Recently, titanium(III)-mediated
radical cascade cyclization of epoxypolyenes has attracted a great
deal of attention.5 Indeed, this reaction has been used in the
synthesis of several natural products6 due to its high degree of
11
R3
OH
A
HO
1
D
C
B
A
B
R1
R2
HO2C
3
HO
HO2C
O
O
7
H
H
R1
R2
OH OH
OH
OH OMe
R3
Fomitellic Acid A (1) :
B (2) :
H
H
H
AB Ring Moiety (5)
H
C (3) :
D (4) : OH
H
H
* Corresponding author. Tel./fax: +81 4 7121 3671.
E-mail address: kobayash@rs.noda.tus.ac.jp (S. Kobayashi).
Figure 1. Structures of fomitellic acids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.039

3850
M. Yamaoka et al. / Tetrahedron Letters 50 (2009) 3849–3852
OTBS
OH
Ti(III)-mediated
OTBS
PO
Ti(Oi-Pr)4, MS 3A
(+)-DET, TBHP
1) NaH, BnBr, NaI
THF, rt
OH
radical cyclization
OTBDPS
OTBDPS
1
H
3
CH2Cl2
2) TBAF, THF, 0 oC
91% (2 steps)
PO
O
HO
O
H
−30 o
C
H
HO2C
OH
OP
OP
90%
5
6
14 (95% ee)
15 (dr = 95:5)
OP
OTBS
OTBS
I
t-BuLi,
+
CHO
OH
DMP
9
OP
I
O
CHO
O
CH2Cl2
rt
Et2O
−78 o
84% (2 steps)
OP
9
O
O
OP
SAE
C
OBn
OBn
7
8
16
17
OP
OTBS
OTBS
Ac2O
VMAR
OTBDPS
Et3N, DMAP
+
CHO
N
O
OH
CH2Cl2
rt
OTBDPS
11
OAc
O
O
TBSO
O
OH
OBn
18
(diastereomeric mixture)
OBn
19
12
93%
10
Scheme 1. Synthetic strategy for the AB ring moiety (5).
Scheme 3. Preparation of epoxypolyene 19.
OTBS
(R)-CBS
TiCl4, H2O
.
BH3 THF
+
CHO
O
N
O
N
toluene
−50 o
76%
OTBDPS
11
OH
CH2Cl2
0 o
65%
O
C
TBSO
OTBDPS OH
O
O
O
OTBS
TEMPO
C
OBn
12
13
PhI(OAc)2
18a (dr = >20:1)
18
OTBS
1) TBSCl, imidazole, DMAP
CH2Cl2, rt
CH2Cl2
rt
O
O
OTBS
OTBDPS
(S)-CBS
OBn
20
81%
.
BH3 THF
OTBDPS OTBS
14 (95% ee)
OH
2) LAH, THF, 0 oC to rt
85% (2 steps)
CH2Cl2
OH
OH
O
0
oC
55%
OBn
Scheme 2. Vinylogous Mukaiyama aldol reaction.
18b (dr = 5:1)
Scheme 4. Selective preparation of 18a and 18b.14
although the reaction was slow and not particularly reproducible.
However, by adding a catalytic amount of water (10 mol %) the
reaction proceeded quite efficiently in a reproducible manner
without any decrease in yield.12 After protection of the secondary
hydroxyl group in 13 as the TBS ether, the chiral auxiliary was
removed with LiAlH4 to give allylic alcohol 14 in 85% yield with
95% ee.13
Scheme 3 shows the preparation of the cyclization precursor 19
from 14. Sharpless asymmetric epoxidation of 14 using the catalyst
derived from (+)-diethyl tartrate afforded 15 in 91% yield
(dr = 95:5).14 Protection of the primary alcohol in 15 as the benzyl
ether, followed by selective removal of the TBDPS group by treat-
ment with TBAF at 0 °C afforded homoallylic alcohol 16 in 91%
yield for the two steps. Oxidation of the resulting alcohol 16 using
Dess–Martin periodinane15 provided a key intermediate 17 in good
yield. The vinyl iodide 916 was treated with t-BuLi in Et2O at
À78 °C, and the resulting vinyl lithium was then reacted with the
aldehyde 17 giving a 1:1 diastereomeric mixture of 18 in 84% yield
(inseparable by silica gel column chromatography). Subsequent
acetylation of the secondary alcohol in 18 provided the cyclization
precursor 19 (1:1 diastereomeric mixture). Each isomer, 18a11 and
18b, could be obtained by sequential oxidation of 18 with TEMPO
and asymmetric reduction of the resulting ketone 20 with a chiral
borane reagent17 (Scheme 4).
afforded the desired tricyclic product 21 in 29% yield as a single
isomer, along with mixture of monocyclic and acyclic products.
The reaction was also carried out by changing the solvent and reac-
tion temperature as shown in Table 1. The desired 21 was best
obtained in 47% yield at elevated temperature (entry 2).19 In addi-
tion, the diastereomeric compounds 19a and 19b were separately
subjected to the same reaction to afford 21 in 43% and 45% yields,
respectively (entries 5 and 6). These results revealed that the con-
figuration of the acetoxy group at C7 position does not influence
Table 1
Titanium(III)-mediated radical cascade cyclization
TBSO
OTBS
Cp2TiCl
Solvent
H
7
HO
OAc
H
O
OBn
OBn
21
19 (diastereomeric mixture)
19a (7S isomer)
19b (7R isomer)
Entry
Substrate
Solvent
Temperature (°C)
Yield (%)
1
2
3
4
5
6
19
19
19
19
19a
19b
THF
THF
rt
29
47
45
41
43
45
60
60
80
60
60
Benzene:THF = 2:1
Toluene:THF = 2:1
Benzene:THF = 2:1
Benzene:THF = 2:1
With epoxypolyene 19 in hand, we then examined the tita-
nium(III)-mediated radical cascade cyclization of 19. Treatment
of 19 (diastereomeric mixture) with 3 equiv of Cp2TiCl,18 which
was prepared from Cp2TiCl2 and Zn, in THF at room temperature

M. Yamaoka et al. / Tetrahedron Letters 50 (2009) 3849–3852
3851
to the quaternary nature of the adjacent carbon. Deprotection of
the benzyl group in 23b with LiAlH4, followed by oxidation of
the resulting diol with Dess–Martin periodinane provided ketoal-
dehyde 24 in 43% yield for two steps. The ketoaldehyde 24 was
then oxidized to carboxylic acid 25 with NaClO2. Finally, deprotec-
tion of two TBS ethers with concentrated HCl completed the syn-
thesis of the AB ring moiety (5).
In summary, we have demonstrated the synthesis of the fully
functionalized AB ring moiety of fomitellic acids. The stereoselec-
tive construction of the tricyclic core was achieved by tita-
nium(III)-mediated radical cascade cyclization of epoxypolyene,
and the stereochemistry at C1 and C3 was controlled by vinylogous
Mukaiyama aldol reaction and Sharpless asymmetric epoxidation,
respectively. The present strategy would be applicable to the total
synthesis of fomitellic acids using a suitable vinyl iodide part
instead of vinyl iodide 9. Preparation of the vinyl iodide part and
further studies toward the total synthesis of fomitellic acid B (2)
are in progress.
Figure 2. ORTEP drawing of cyclization product 21.
the cyclization. We also attempted the cyclization of epoxypolyene
possessing a silyloxy (TBSO) group instead of an acetoxy group to
result in the formation of a complex mixture of products.
The stereochemistry of 21 was unambiguously confirmed by
X-ray crystallographic analysis (Fig. 2).20 The cyclization product
21 was found to possess the desired stereochemistry and to be
formed via a trans-fused chair/chair-like transition state.
Transformation of 21 to the AB ring moiety (5) is illustrated in
Scheme 5. Protection of the secondary alcohol in 21 as the TBS
ether and subsequent epoxidation with mCPBA provided epoxide
22 in 97% yield for the two steps as an almost single isomer. Treat-
ment of 22 with TMSOTf and 2,6-lutidine,21 followed by removal of
the TMS group of the resulting allyl silyl ethers with TBAF afforded
allylic alcohols 23a11 and 23b in 35% and 38% yield, respectively
(separable by silica gel column chromatography). No regioselectiv-
ity was observed in this model reaction, although no attempt was
made to improve the selectivity. For total synthesis of fomitellic
acids, epoxide opening should proceed in the desired fashion due
Acknowledgments
This research was supported in part by a Grant-in-Aid for Scien-
tific Research (B) (KAKENHI No.18390010) from the Japan Society
for the Promotion of Science. We thank Professor Kazuo Miyamura
and Dr. Kazuaki Tomono (Department of Chemistry, Faculty of
Science, Tokyo University of Science) for the X-ray analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.039.
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90%
24
OH
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THF/MeOH
rt
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HO2C
O
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HO2C
O
H
H
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25
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Scheme 5. Synthesis of the AB ring moiety (5).

3852
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