Model studies towards the total synthesis of GKK1032s, novel antibiotic anti-tumor agents: Enantioselective synthesis of the alkyl aryl ether portion of GKK1032s

Article abstract of DOI:10.1055/s-2005-917112

An enantioselective synthesis of an alkyl aryl ether portion of GKK1032s, novel antibiotic anti-tumor agents, was achieved via Mitsunobu reaction between a sterically congested indenol derivative and a p-substituted phenol derivative. The indenol derivati

Full text of DOI:10.1055/s-2005-917112

LETTER
2599
Model Studies towards the Total Synthesis of GKK1032s, Novel Antibiotic
Anti-Tumor Agents: Enantioselective Synthesis of the Alkyl Aryl Ether
Portion of GKK1032s
E
nantioselective Synth
o
e
sis of the
A
r
lkyl
A
ry
i
l
Ether
t
P
ortion
e
of
G
K
K
10
r
32s u Asano,a Munenori Inoue,*a,b Tadashi Katoh*c
a
b
c
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Fax +81(22)2752013; E-mail: katoh@tohoku-pharm.ac.jp
Received 30 July 2005
Me
H
Me
H
1
Abstract: An enantioselective synthesis of an alkyl aryl ether
portion of GKK1032s, novel antibiotic anti-tumor agents, was
achieved via Mitsunobu reaction between a sterically congested
indenol derivative and a p-substituted phenol derivative. The inde-
nol derivative, the key substrate for the Mitsunobu reaction, was
efficiently synthesized starting from the known indanone derivative
through regio- and stereoselective methylation, Saegusa oxidation,
and carbonyl transposition as the pivotal steps.
5
Me
Me
Me
O
Me
O
Me
A
9
6
A
3
14
C
B
C
B
15
X
NH
OH
NH
OR
13
H
H
11
O
O
Y
H
H
O
O
Me
Me
3: pyrrocidine A ( X,Y = C=CH )
1: GKK1032A1 ( R = Me )
2: GKK1032A2 ( R = H )
4: pyrrocidine B ( X,Y = CH–CH2 )
Key words: GKK1032s, antibiotic, anti-tumor agent, natural prod-
ucts synthesis, Mitsunobu reaction, Saegusa oxidation
Me
Me
Me
Me
Me
9
H
O
Me
7
12
A
14
6
C
3
O
13
C
B
GKK1032A1 (1) and A2 (2, Figure 1), isolated from a
strain of Penicillium sp. in 2001, exhibit prominent
biological properties such as antimicrobial and anti-tumor
activities.1,2 Pyrrocidines A (3) and B (4), subsequently
isolated from the culture broth of a fungus, display antimi-
crobial activity against Gram-positive bacteria including
drug-resistant strains.3 Structurally, these natural products
consist of a tricyclic decahydrofluorene nucleus (ABC-
ring) appended to an unusual 13-membered macrocycle
containing ether, phenyl, pyrrolidinone, and carbonyl
functionalities. These rather unique structure features to-
gether with the attractive biological properties have made
GKK1032s and pyrrocidines exceptionally intriguing and
timely targets for total synthesis. Synthetic studies of
these natural products have been recently disclosed by
several research groups;4 however, no total synthesis has
been reported to date.
S
15
11
CO2Me
H
H
O
Me
S
H
OH
5
6
Figure 1 Structures of GKK1032A1 (1), A2 (2), pyrrocidines A (3),
B (4), the tricyclic decahydrofluorene nucleus 5, and the alkyl aryl
ether portion 6
compound 6 (Figure 1), which contains the alkyl aryl
ether portion as well as the fully substituted C-ring moiety
present in GKK1032s and pyrrocidines.
The synthetic plan for the model compound 6 is outlined
in Scheme 2. The key feature in this scheme is envisioned
to be an uncommon Mitsunobu reaction6 between the
indenol 8 and p-substituted phenol 9 to construct the
requisite asymmetric carbon center at the C13 position
In the course of our ongoing project directed towards the
total synthesis of optically active GKK1032s, we have re-
cently reported the first entry to the tricyclic decahydro-
fluorene nucleus (ABC-ring, 5),5 which features a highly
diastereoselective intramolecular Diels–Alder reaction as
the key step (cf. 7 → 5, Scheme 1). To forward the next
stage of the projected total synthesis, we were strongly
required to develop a method for the construction of the
characteristic alkyl aryl ether portion of GKK1032s. In
this paper, we wish to report our further investigation
concerning an efficient and facile synthesis of the model
O
O
Me
H
OMe
Me
O
Me
Me
+
O
O
O
TMSO
O
Me
H
Me
Me
Me
toluene
Me
120 °C, 24 h
Me
A
C
B
S
S
S
70%
CO2Me
CO2Me
H
S
H
H
OH
OH
5
7
SYNLETT 2005, No. 17, pp 2599–2602
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917112; Art ID: U25705ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5
Scheme 1 Outline of our developed synthetic route to the tricyclic
decahydrofluorene nucleus 5

2600
M. Asano et al.
LETTER
(8 + 9 → 6). This coupling reaction is considerably pyridinium chlorochromate (PCC), furnishing the desired
challenging at a synthetic chemistry level because the C13 product 17 (57%, 2 steps). Finally, the carbonyl group in
hydroxy group present in the indenol 8 is placed in a 17 was steroselectivelly reduced under the Luche
sterically congested position. The precursor 8 would be conditions12 to provide the allyl alcohol 813 as a single
available from the indenone 10 via Saegusa oxidation7 diastereomer in 82% yield.14 The configuration of the
followed by carbonyl transposition and reduction. The newly generated C13 stereocenter was determined by
intermediate 10 would be derived from the enantiomeri- NOE experiments, wherein the clear interaction between
cally pure (–)-Hajos–Parrish ketone (11;8 >99% ee) C13-H and C7-Me was observed as pictured in 8A.
through regio- and stereoselective methylation.
OtBu
OtBu
Me
Me
O
Me
Me
Me
Me
9
O
ref. 9
a
7
O
O
O
O
H
H
HO
Me
Me
Me
Me
Me
H
Me
11 (>99% ee )
12
13
Me
O
9
Me
O
13
13
OtBu
Me
H
H
O
H
Me
O
9
OH
Me
Mitsunobu reaction
Me
Me
7
Me
e, f
OtBu
b–d
8
6
11
H
H
Me
H
NOE
O
Me
O
13A
Me
14
Me
OH
O
O
Me
Me
Me
Me
H
O
Me
g, h
Me
Me
Me
j
i
(–)-Hajos–Parrish ketone (11)
10
Scheme 2 Synthetic plan for the model compound 6
H
H
H
Me
Me
Me
10
15
16
At first, as shown in Scheme 3, we pursued the synthesis
of the indenol 8, the substrate for the key Mitsunobu
reaction, starting from the known enantiomerically pure
ketone 129 readily prepared from 11. Regio- and stereo-
selective methylation of 12 was successfully achieved by
treatment with lithium diisopropylamide (LDA) followed
by addition of iodomethane, which provided the requisite
dimethylketone 13 as a single diastereomer in 93% yield.
The configuration of the newly formed C9 stereocenter in
13 was confirmed by NOESY experiments as depicted in
13A, where clear NOE interactions between the angular
methyl group (C7–Me) and C9–H, C11–H were observed,
respectively. Removal of the carbonyl function in 13 was
carried out by sodium borohydride reduction followed by
deoxygenation of the resulting alcohol by employing the
Barton–McCombie protocol.10 The desired decarbonyl-
ation product 14 was obtained in 81% yield for the three
steps. After deprotection of the tert-butyl group in 14
under acidic conditions, the liberated hydroxy group was
then oxidized with Dess–Martin periodinane11 to afford
the indanone 10 in 88% overall yield. Installation of the
enone system was next conducted by applying the Sae-
gusa procedure.7 Thus, treatment of 10 with LDA and
subsequent addition of trimethylsilyl chloride (TMSCl)
provided the corresponding silyl enol ether, which was
then oxidized with palladium(II) acetate to give the
desired indenone 15 in 77% yield for the two steps. The
carbonyl transposition of 15 was effectively achieved via
a two-step sequence involving 1,2-addition of methyl
lithium and oxidation of the resulting allyl alcohol 16 with
Me
Me
H
Me
Me
Me
Me
Me
7
Me
k
7
HO
H
13
13
H
Me
H
H
H
OH
O
Me
Me
NOE
17
8
8A
Scheme 3 Synthesis of the intermediate 8. Reagents and conditions:
(a) LDA, THF, –78 °C; MeI, –50 °C to 0 °C, 2 h, 93%; (b) NaBH4,
EtOH, –78 °C, 1 h, quant.; (c) NaN(SiMe3)2, CS2, –78 °C, 30 min,
MeI, –78 °C, 30 min, 90%; (d) n-Bu3SnH, AIBN, toluene, reflux, 12
h, 90%; (e) concd HCl, dioxane, reflux, 1 h; (f) Dess–Martine periodi-
nane, CH2Cl2, r.t., 2 h, 88% (2 steps); (g) LDA, THF, –78 °C, 1 h;
TMSCl, –78 °C to r.t., 1 h; (h) Pd(OAc)2, MeCN, 50 °C, 3 h, 77% (2
steps); (i) MeLi, Et2O, r.t., 1.5 h, quant.; (j) PCC, CH2Cl2, r.t., 12 h,
57%; (k) NaBH4, CeCl3·7H2O, 0 °C, 1 h, 82%
Having obtained the key intermediate 8 in an efficient
way, we next focused our attention on the synthesis of the
targeted model compound 6 by employing the Mitsunobu
reaction.6 As a preliminary experiment, we examined the
Mitsunobu reaction between 8 and simple p-substituted
phenols as shown in Table 1. When the reaction of 8 with
p-methoxyphenol was carried out under conventional
Mitsunobu conditions [diethyl azodicarboxylate (DEAD),
triphenylphosphine, THF, r.t.], the expected alkyl ether
18a was not detected in the reaction mixture, and the un-
reacted starting material 8 was recovered unchanged. Af-
ter several trials, to our delight, we found that the reaction
proceeded by heating at 100 °C in toluene for 12 hours;
Synlett 2005, No. 17, 2599–2602 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of the Alkyl Aryl Ether Portion of GKK1032s
2601
the expected coupling product 18a was produced in 11% allyl alcohol 8 and the phenol derivative 9 (1.2 equiv) was
yield (entry 1). Employing tributylphosphine instead of finally achieved under the same conditions described for
triphenylphosphine, the reaction gave 18a in an improved the model studies to furnish the targeted compound 618 in
yield (41%, 13a:13b = 10:1;15 entry 2). Additionally, the 46% yield (13a:13b = 10:115).
reaction of 8 with p-nitrophenol and p-cresol gave the
corresponding alkyl aryl ethers 18b and 18c in 41% yield
a
O
+
MeO
CuCNLi2
and 43% yield, respectively (entries 3 and 4). The newly
formed C13 stereocenter of the Mitsunobu coupling prod-
ucts 18a,c was confirmed by NOE experiments. Thus, as
shown in Figure 2, clear NOE correlations between C13–
H and C12–H, C11–Me were observed, while no NOE
interaction was observed between C13–H and C7–Me.
CO2Et
2
19
20
CO2Et
OH
O
b, c
O
MeO
HO
Table 1 Mitsunobu Reaction of the Indenol 8 with some p-Substi-
tuted Phenols
9
21
Scheme 4 Synthesis of the p-substituted phenol derivative 9.
Reagents and conditions: (a) BF3·OEt2, –78 °C, 30 min, 60%; (b)
camphor-10-sulfonic acid, benzene, reflux, 1 h, 91%; (c) BBr3,
CH2Cl2, 0 °C, 24 h, quant.
X
OH (1.2 equiv)
Me
Me
Me
Me
OH
phosphine (1.5 equiv)
DEAD (1.5 equiv)
Me
Me
13
toluene, 100 °C, 12 h
H
O
Me
18a–c
H
Me
O
Me
P(n-Bu)3 (1.5 equiv)
Me
Me
X
DEAD (1.5 equiv)
8
O
+
toluene, 100 °C, 12 h
46%
HO
Entry
X
Phosphine Product
Ratio
Yield
H
OH
(13a:13b)a (%)b
Me
8
9 (1.2 equiv)
1
2
3
4
OMe
OMe
NO2
Me
PPh3
18a
18a
18b
18c
10:1
10:1
10:1
10:1
11
41
41
43
Me
Me
H
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
Me
13
O
Me
O
a Determined by 500 MHz 1H NMR spectroscopy.
O
b Isolated yield by column chromatography on silica gel.
6
Scheme 5 Synthesis of the model compound 6
H
Me
Me
Me
12
7
In summary, we have developed a facile method for the
synthesis of the alkyl aryl ether portion 6 of GKK1032s in
an enantioselective manner by employing Mitsunobu
reaction of the functionalized indenol 8 and p-substituted
phenol 9 (8 + 9 → 6; Scheme 5). The key substrate 8 was
efficiently synthesized starting from the known ketone 12;
the method features a regio- and stereoselective methyla-
tion (12 → 13), Saegusa oxidation (10 → 15), and carbo-
nyl transposition (15 → 16 → 17) as the crucial steps.
Further investigation towards the total synthesis of
GKK1032s and pyrrocidines based on the present studies
is now in progress and will be reported appropriately in
due course.
11
H
H
13
H
Me
O
X
NOE
18a: X = OMe
18c: X = Me
X
Figure 2 Selected NOESY correlation of 18a,c
Having succeeded in the Mitsunobu reaction between 8
with some p-substituted phenolic compounds, we next in-
vestigated the synthesis of the targeted molecule 9 based
on the model studies. Toward this end, as shown in
Scheme 4, the required p-substituted phenol derivative 9
containing the d-lactone ring was initially prepared start-
ing from the known epoxide 19.16 Treatment of 19 with
the aryl cuprate reagent 20 (prepared from p-bromo-
anisole, n-BuLi, and CuCN) afforded the desired coupling
product 21 in 60% yield. Acid-catalyzed lactonization of
21 followed by deprotection of the methyl group by expo-
sure to boron tribromide in dichloromethane at 0 °C, pro-
vided the requisite phenol derivative 917 in 91% yield for
the two steps. The key Mitsunobu reaction between the
Acknowledgment
We are grateful to Dr. T. Mori (Tokyo Institute of Technology) for
his assistance in MS spectra measurements. This work was suppor-
ted in part by Grants-in-Aid for High Technology Research Pro-
gram and for Scientific Research on Priority Areas 17035073 from
the Ministry of Education, Culture, Sports, Science and Technology
of Japan.
Synlett 2005, No. 17, 2599–2602 © Thieme Stuttgart · New York

2602
M. Asano et al.
LETTER
1.00–1.08 (m, 1 H), 1.23 (d, J = 7.4 Hz, 1 H), 1.55–1.62 (m,
1 H), 1.65 (t, J = 1.8 Hz, 3 H), 1.68–1.75 (m, 1 H), 1.76–1.89
References
(m, 2 H), 4.47–4.54 (m, 1 H), 5.27 (t, J = 1.5 Hz, 1 H). 13
C
(1) (a) Koizumi, F.; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara,
M. Jpn. Kokai Tokkyo Koho, JP 2001247574, 2001.
(b) Hasegawa, A.; Koizumi, F.; Takahashi, Y.; Ando, K.;
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(4) (a) Arai, N.; Ui, H.; Omura, S.; Kuwajima, I. Synlett 2005,
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Spring Meeting of the Chemical Society of Japan,
Yokohama Japan 2005, Abstract 2, 874. (c) Hasegawa, D.;
Sakuma, Y.; Takagi, Y.; Uchiro, T. The 125th Annual
Meeting of the Pharmaceutical Society of Japan, Tokyo
Japan 2005, Abstract 4, 71.
(5) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 1539.
(6) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1967, 40, 935. (b) Mitsunobu, O.; Yamada, M.
Bull. Chem. Soc. Jpn. 1967, 40, 2380. (c) Mitsunobu, O.
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(7) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(8) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615. (b) Hajos, Z. G.; Parrish, D. R.; Oliveto, E. P.
Tetrahedron 1968, 24, 2039.
NMR (125 MHz, CDCl3): d = 12.3, 19.4, 20.7, 22.8, 28.3,
29.5, 43.3, 45.8, 48.0, 66.5, 77.7, 127.8, 152.6. HRMS (EI):
m/z calcd for C13H22O [M+]: 192.0786; found: 192.0790.
(14) This remarkable stereoselectivity can be rationalized by the
consideration that the hydride attack occurred exclusively
from a-face of the carbonyl group under an influence of
stereoelectronic effect, which may involve the so-called
‘product development control’.
(15) Since separation of 13a-form and 13b-form was very
difficult, the ratio was estimated by 1H NMR (500 MHz)
spectroscopy.
(16) Degenhardt, C. R. J. Org. Chem. 1980, 45, 2763.
(17) Data for 9.
White solid, mp 101–104 °C. IR (KBr): 652, 677, 818, 843,
972, 985, 1171, 1186, 1223, 1516, 1743, 3342 cm–1. 1H
NMR (500 MHz, CDCl3): d = 1.89–1.99 (m, 1 H), 2.21–2.30
(m, 1 H), 2.31–2.40 (m, 1 H), 2.41–2.51 (m, 1 H), 2.89 (dd,
J = 14.2, 5.9 Hz, 1 H), 2.97 (dd, J = 14.2, 6.0 Hz, 1 H), 4.67–
4.75 (m, 1 H), 5.05 (s, 1 H), 6.78 (d, J = 8.5 Hz, 2 H), 7.09
(d, J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 26.9,
28.7, 40.4, 81.1, 115.5 (2 C), 127.7, 130.7 (2 C), 154.8,
177.5. HRMS (EI): m/z calcd for C11H12O3 [M+]: 194.1671;
found: 194.1667.
(18) Data for 6.
Colorless viscous oil, [a]D20 +129.5 (c 0.16 CHCl3). IR
(neat): 607, 634, 806, 937, 1005, 1045, 1173, 1227, 1240,
1373, 1508, 1736, 1774, 2910, 2949 cm–1. 1H NMR (500
MHz, CDCl3): d = 0.54–0.65 (m, 1 H), 0.82 (t, J = 12.0 Hz,
1 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 1.18
(s, 3 H), 1.30 (dd, J = 11.6, 5.1 Hz, 1 H), 1.63 (dd, J = 11.6,
4.1 Hz, 1 H), 1.71 (s, 3 H), 1.80–1.88 (m, 1 H), 1.88–2.07 (m,
3 H), 2.18–2.27 (m, 1 H), 2.30–2.50 (m, 2 H), 2.85 (dd,
J = 14.1, 6.4 Hz, 1 H), 2.99 (dd, J = 14.1, 5.8 Hz, 1 H), 4.64–
4.73 (m, 1 H), 4.82–4.87 (m, 1 H), 5.67 (s, 1 H), 6.85 (d,
J = 8.5 Hz, 2 H), 7.09 (d, J = 8.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 12.8, 19.4, 22.0, 22.9, 26.7, 27.0, 28.1,
28.7, 40.40 (1/2 C), 40.39 (1/2 C), 43.1, 45.6, 48.2, 60.4,
78.896 (1/2 C), 78.868 (1/2 C), 81.1, 115.695 (1/2 C × 2),
115.703 (1/2 C × 2), 121.883 (1/2 C), 121.892 (1/2 C),
127.104 (1/2 C), 127.111 (1/2 C), 130.3 (2 C), 157.840 (1/2
C), 157.831 (1/2 C), 159.6, 177.155 (1/2 C), 177.172 (1/2 C).
HRMS–FAB: m/z calcd for C24H33O3 [M + H]+: 369.2430;
found: 369.2465.
(9) (a) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.;
Portland, L. A.; Scianmanna, W.; Scott, M. A.; Wehrli, P. A.
J. Org. Chem. 1975, 40, 675. (b) Nagao, K.; Yoshimura, I.;
Chiba, M.; Kim, S.-W. Chem. Pharm. Bull. 1983, 31, 114.
(10) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Izuhara, T.; Katoh, T. Org. Lett.
2001, 3, 1653.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
(12) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(13) Data for 8.
Colorless viscous oil, [a]D20 –52.2 (c 0.70 CHCl3). IR (neat):
644, 808, 993, 1039, 1049, 1140, 1205, 1377, 1439, 1456,
2839, 2868, 2906, 2949, 3317 cm–1. 1H NMR (500 MHz,
CDCl3): d = 0.51–0.61 (m, 1 H), 0.83 (s, 3 H), 0.85–0.94 (m,
1 H), 0.89 (d, J = 6.5 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H),
Synlett 2005, No. 17, 2599–2602 © Thieme Stuttgart · New York