Synthesis of functionalized cyclopentane for pactamycin, a potent antitumor antibiotic

Article abstract of DOI:10.1055/s-2004-837223

A tricyclic compound including a cyclopentane structure for pactamycin, an antitumor antibiotic, was constructed by Overman rearrangement and Pauson-Khand cyclization as key steps starting from diacetone-D-glucose. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-837223

LETTER
433
Synthesis of Functionalized Cyclopentane for Pactamycin, a Potent Antitumor
Antibiotic
S
ynthetic Studie
a
s
onPacta
k
mycin ashi Tsujimoto,a Toshio Nishikawa,*a,b Daisuke Urabe,b Minoru Isobe*b
a
PRESTO of Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: nisikawa@agr.nagoya-u.ac.jp
b
Received 11 November 2004
Our synthetic plan is illustrated in Scheme 1. The core
structure of pactamycin was envisaged to be synthesized
from a tricyclic compound 3; the amino group at the C-2
position would be installed by nucleophilic substitution in
SN2 manner, while the nitrogen function at the C-3 posi-
tion would be introduced by Curtius rearrangement of a
carboxylic acid, which could be obtained from oxidative
cleavage of the silylenolether. Methyl group (C-6) would
be introduced by addition of a methyl nucleophile to the
ketone at the C-5 position. Since the enolether 3 would be
obtainable from 4, the compound 4 was regarded as an im-
portant intermediate. The cyclopentenone of 4 would arise
from intramolecular Pauson–Khand reaction8 of enyne 5.
The acetylenic moiety could be introduced by addition of
acetylide to an aldehyde, while the vinyl group would be
prepared from diol. Thus, enyne 5 was retrosynthesized
into 6. The nitrogen function connected to a quaternary
carbon center would be introduced by Overman
rearrangement9 from the known exo-allylic alcohol 7.10
Abstract: A tricyclic compound including a cyclopentane structure
for pactamycin, an antitumor antibiotic, was constructed by Over-
man rearrangement and Pauson–Khand cyclization as key steps
starting from diacetone-D-glucose.
Key words: pactamycin, natural products, antibiotics, Overman
rearrangement, Pauson–Khand reaction
Pactamycin was isolated as a potent antitumor antibiotic
from a fermentation broth of Streptomyces pactum var
pactum.1 From the same fermentation broth was isolated
pactamycate, a derivative of pactamycin.2 The structure of
these compounds was elucidated in 1969 from NMR anal-
yses and chemical degradation.3 However, X-ray crystal-
lographic analysis of a derivative of pactamycate revised
the structure to be 1 and revealed the absolute stereochem-
istry (Figure 1).4 Pactamycin shows potent in vitro and in
vivo antitumor activity as well as antimicrobial activi-
ty.1a,5 The action mechanism is inhibition of protein
synthesis6 through binding to the ribosomal small sub-
unit.7 The structural feature of pactamycin is a densely
functionalized cyclopentane ring including three contigu-
ous quaternary carbons with oxygen or nitrogen function-
alities such as substituted benzoic acid, m-acyl aniline and
dimethyl urea. Surprisingly, despite their unprecedented
complex structures as well as potent biological activities,
little synthetic study on pactamycin has been reported
since its structure determination. We disclose herein our
efforts toward the synthesis of pactamycin.
OSiR'3
R
Ar
HN
H
[N]
PO
HN
OH
OH
H2N
H2N
3
2
5
O
OH
[CH3]
O
HO
O
core of pactamycin
3
O
R
H
HO
HO
HN
R
O
O
HN
OH
OH
O
O
O
O
4
5
HN
HN
O
O
O
O
OH
4
OH
OH
O
O
O
3
5
H
2
OH
OH
H2N
HN
H2N
H
O
O
9
O
H
1
7
N
O
O
N
6
H
Cl3C
N
OH
O
O
O
O
O
HO
8
O
pactamycin (1)
pactamycate (2)
6
HO
7
Figure 1 The structures of pactamycin and pactamycate.
Scheme 1 Synthetic plan for pactamycin.
The exo-allylic alcohol 7, readily prepared from a com-
mercially available diacetone-D-glucose 8,11 was treated
with trichloroacetonitrile and DBU to give a labile allylic
SYNLETT 2005, No. 3, pp 0433–0436
Advanced online publication: 22.12.2004
DOI: 10.1055/s-2004-837223; Art ID: U31604ST
1
6.
0
2.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

434
T. Tsujimoto et al.
LETTER
O
trichloroacetimidate 9 (Scheme 2). The Overman re-
arrangement of 9 was carried out in refluxing xylene in
the presence of K2CO3 to afford the desired trichloro-
O
H
H
O
NOESY
NOESY
N
N
R
R
a
O
O
O
12
O
10
H
H
acetamide 6 as a single product in 90% yield from 7.13 The
configuration of the newly generated asymmetric center
of 6 was confirmed by the observation of NOESY corre-
lation between Ha and Hb as shown in Scheme 2. Since it
was reported the Overman rearrangement of 9 in the ab-
sence of K2CO3 failed to give 6,14 this experiment demon-
H
CH3
H
CH3
H
H
O
O
O
12
13
Figure 2 Reagents and conditions: a) DBU, CH2Cl2, r.t. (90%).
strates K2CO3 is a crucial additive for the successful and 11 was confirmed by the NOESY spectra of the cor-
Overman rearrangement.
responding oxazolidinones 12 and 13 derived from 11 and
10, respectively (Figure 2).18
O
O
O
We next elaborated two acetonides of 12 to precursors for
the cyclization (Scheme 4). After the benzylation of ox-
azolidinone 12, the terminal acetonide was converted to a
vinyl group in 2 steps; acidic deprotection of the acetonide
and reductive olefination according to the Tipson–Cohen
procedure.19 The other acetonide was removed with 80%
aqueous TFA. The resulting hemiacetal was reduced with
NaBH4 to give a triol, in which the vicinal diol was
cleaved with NaIO4 to afford unstable b-hydroxyaldehyde
15. To this aldehyde 14 was added (2-trimethylsilyl)ethy-
nyllithium to afford a mixture of diols 16a20 (55% yield in
3 steps) and 17 (6% yield in 3 steps). The configuration of
the C-5 position could not been determined at this stage.
However, we expected that the major product 16a had 5R-
configuration from the following consideration; a six-
membered chelation structure as A might be attacked by
the acetylide from the less hindered bottom side. The con-
figuration was finally confirmed by NOESY spectra of 19
H
O
H
O
a, b, c
O
O
O
O
O
O
HO
8
7
HO
O
O
H
O
O
O
O
Hb
O
O
e
d
H
O
N
Cl3C
O
HN
Ha
O
9
6
Cl3C
Scheme 2 Reagents and conditions: a) TPAP, NMO, MS 4 Å,
MeCN; b) Ph3P=CHCO2Et, toluene, 100 °C (73% from 8);
c) DIBALH, CH2Cl2, –20 °C (99%); d) Cl3CCN, DBU, CH2Cl2,
–78 °C; e) K2CO3, p-xylene, reflux (90% from 7).
A hydroxyl group at C-7 (pactamycin numbering) was in- (vide infra).
troduced as shown in Scheme 3. Ozonolysis15 of the vinyl
group of 6 gave neopentyl aldehyde (90% yield), which
was treated with methylmagnesium bromide to afford
carbinol 10 as a single product (95% yield).16 Since the
configuration at C-7 was opposite to that of pactamycin
judging from the NOESY spectra (vide infra), the config-
uration was inverted by oxidation of the alcohol with
DMSO and Ac2O followed by Luche reduction17 to pref-
erentially afford the desired isomer 11 in 70% yield along
with 10 in 10% yield. The stereochemistry of carbinol 10
O
O
H
O
H
O
H
O
O
O
b, c
O
O
d, e, f
BnN
RN
a
O
O
O
O
14
12 R = H
R = Bn
Ph
O
O
OH
N
g
O
O
O
O
O
BnN
CHO
H
H
Li
O
O
O
c, d
a, b
H
O
O
O
H
H
N
N
15
A
Cl3C
Cl3C
O
O
acetylide
7
O
HO
O
10
6
TMS
TMS
O
O
O
O
HO
HO
BnN
H
H
O
O
5
S
e
R
+
BnN
O
O
H
N
OH
OH
HN
Cl3C
O
O
O
O
O
O
7
O
O
O HO
16a
17
11
12
Scheme 4 Reagents and conditions: a) NaH, DMF, BnBr, TBAI, r.t.
(93%); b) 50% aq HOAc, r.t. (85%); c) MsCl, Et3N, DMF, 0 °C then
NaI, Zn, 120 °C (86%); d) 80% aq TFA, r.t. (90%); e) NaBH4, MeOH,
0 °C; f) NaIO4, THF, H2O; g) n-BuLi, TMS-C≡CH, THF, 0 °C (16a:
55% in 3 steps, 17: 6% in 3 steps).
Scheme 3 Reagents and conditions: a) O3, CH2Cl2, –78 °C, then
Et3N, 0 °C (90%); b) MeMgBr, THF, 0 °C (95%); c) DMSO, Ac2O,
r.t. (96%); d) NaBH4, CeCl3·7H2O, CH2Cl2–MeOH, –10 °C (11: 70%,
10: 10%); e) DBU, CH2Cl2, r.t. (99%).
Synlett 2005, No. 3, 433–436 © Thieme Stuttgart · New York

LETTER
Synthetic Studies on Pactamycin
435
(4) Duchamp, D. J. American Crystallographic Association
Winter Meeting, Albuquerque, N. M. 1972, Abstracts, p. 23.
(5) Adama, E. S.; Rinehart, K. L. J. Antibiot. 1994, 47, 1456.
(6) Cohen, L. B.; Goldberg, I. H.; Herner, A. E. Biochemistry
1969, 8, 1327.
(7) The crystal structure of the complex of pactamycin with a
ribosomal 30S subunit was reported. See: (a) Brodersen, D.
E.; Clemons, W. M. Jr.; Carter, A. P.; Morgan-Warren, R. J.;
Wimberly, B. T.; Ramakrishnan, V. Cell 2000, 103, 1143.
(b) Dinos, G.; Wilson, D. N.; Teraoka, Y.; Szaflarski, W.;
Fucini, P.; Kalpaxis, D.; Nierhaus, K. H. Mol. Cell 2004, 13,
113.
(8) For reviews of Pauson–Khand reaction, see: (a) Pauson, P.
L. Tetrahedron 1985, 41, 5855. (b) Shore, N. E. Org. React.
1991, 40, 1.
(9) For reviews of the Overman rearrangement, see:
(a) Overman, L. E. Acc. Chem. Res. 1980, 13, 218.
(b) Ritter, K. Stereoselective Synthesis, In Houben-Weyl,
Vol. E21; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., Eds.; Thieme: Stuttgart, 1996, 5677.
(c) Sato, H.; Oishi, T.; Chida, N. J. Synth. Org. Jpn. 2004,
62, 693.
With the precursors for the cyclization in hand, we
examined intramolecular Pauson–Khand reaction
(Scheme 5).8,21 Enyne 16a was treated with Co2(CO)8 to
give the corresponding acetylene–cobalt complex, which
was heated in MeCN at 70 °C to afford an inseparable
mixture. Fortunately, when the crude material was treated
with Ac2O and pyridine at room temperature, the major
product was transformed to diacetate 1922 as a single dia-
stereomer in 55% yield from 16a after silica gel column
chromatography.23 The configurations of the C-3 and C-5
positions of 19 were determined by the observation of the
NOESY correlations as shown in Scheme 5. Interestingly,
the diacetate 16b and the bis-TMS ether 16c and the dia-
stereomeric isomer 17 did not undergo the Pauson–Khand
reaction under the same conditions.
O
TMS
H
HO
TMS
RO
c, d
e
(10) Tadano, K.-I.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org.
Chem. 1987, 52, 1201.
BnN
BnN
OR
OH
O
O
O
O
(11) We have synthesized 6 according to the procedure described
by Tadano and co-workers except for oxidation of
diacetone-D-glucose(7); TPAP was employed instead of
PCC because of environmental consideration. See: Ley, S.
V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
16a R = H
16b R = Ac
16c R = TMS
18
a
b
NOESY
Ph
O
O
H
H
H
N
H
O
H
AcO
BnN
3
TMS
(12) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org.
Chem. 1998, 63, 188.
H3C
O
Ac
5
H
OAc
TMS
(13) Spectral data of 6: colorless crystalline solids, mp 116–
OAc
118 °C; [a]D26 +41.4 (c 1.05, CHCl3). IR (NaCl, film):
O
O
NOESY
O
19
nmax = 3312, 2990, 1720, 1507, 1375, 1248, 1216, 1164,
1081, 1007, 872, 844, 822 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.35, 1.37, 1.49, 1.57 (each 3 H, s, acetonide),
3.96 (1 H, t, J = 8 Hz, H-6), 4.06 (1 H, dd, J = 8.0, 6.5 Hz,
H6), 4.18 (1 H, d, J = 3.5 Hz, H-4), 4.56 (1 H, ddd, J = 8.0,
6.5, 3.5 Hz, H-5), 5.28 (1 H, d, J = 3.5 Hz, H-2), 5.43 (1 H,
d, J = 11.0 Hz, CH=CHH), 5.44 (1 H, d, J = 17.5 Hz,
CH=CHH), 5.92 (1 H, d, J = 3.5 Hz, H-1), 6.04 (1 H, dd,
J = 17.5, 11.0 Hz, CH=CH2), 8.54 (1 H, s, NH) ppm.
13C NMR (75 MHz, CDCl3): d = 25.8, 26.0, 26.5, 26.6, 66.0,
69.8, 75.4, 78.5, 83.7, 92.9, 103.9, 110.5, 112.4, 117.5,
131.0, 161.5 ppm. Anal. Calcd for C16H22NO6Cl3: C, 44.62;
H, 5.15; N, 3.25. Found: C, 44.63; H, 5.12; N, 3.23.
(14) (a) Gonda, J.; Bednárikova, M. Tetrahedron Lett. 1997, 38,
5569. (b) Eguchi, T.; Kakinuma, K. J. Synth. Org. Jpn. 1997,
55, 814.
Scheme 5 Reagents and conditions: a) Ac2O, pyridine (80%);
b) TMSOTf, i-Pr2NEt, CH2Cl2 (90%); c) Co2(CO)8, CH2Cl2, r.t.;
d) MeCN, 70 °C; e) Ac2O, pyridine, r.t. (55% in 3 steps).
In summary, tricyclic compound 19 including all the car-
bon atoms for the core cyclopentane of pactamycin has
been synthesized from diacetone-D-glucose. The product
also possesses suitable structure for installation of the re-
maining functionalities. Further studies toward the total
synthesis are in progress in this laboratory.
Acknowledgment
(15) Iio, H.; Isobe, M.; Kawai, T.; Goto, T. Tetrahedron 1979, 35,
941.
(16) All attempts to synthesize the desired diastereomer 10 failed.
(17) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454.
This work was financially supported by PRESTO of Japan Science
and technology Agency (JST), a Grant-in-Aid for Specially Promo-
ted Research (16002007) and the 21st COE grant from MEXT.
(18) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida,
N. Bull. Chem. Soc. Jpn. 2002, 75, 1927.
References
(1) (a) Bhuyan, B. K.; Dietz, A.; Smith, C. G. Antimicrob.
Agents Chemother. 1962, 184. (b) Argoudelis, A. D.;
Jahnke, H. K.; Fox, J. A. Antimicrob. Agents Chemother.
1962, 191.
(19) Tipson, R. S.; Cohen, A. Carbohydr. Res. 1965, 1, 338.
(20) Spectral data of 16a: colorless oil; [a]D26 +88.8 (c 0.16,
CHCl3). IR (NaCl, film): nmax = 3413, 2960, 2175, 1724,
1414, 1250, 1075, 845 cm–1. 1H NMR (300 MHz, CDCl3):
d = 0.13 (9 H, s, TMS), 1.52 (3 H, d, J = 7.0 Hz, CH3), 2.49
(1 H, br, -OH), 2.85 (1 H, br, -OH), 4.58 (2 H, s, CH2-Ph),
4.68 (1 H, br d, J = 5.0 Hz, CH2=CH-CH-OH), 4.94 (1 H, s,
C≡C-CH-OH), 4.97 (1 H, q, J = 7.0 Hz, CHCH3), 5.37 (1 H,
dt, J = 10.5, 1.5 Hz, CHAHB=CH), 5.52 (1 H, dt, J = 17.0, 1.5
Hz, CHAHB=CH), 5.99 (1 H, ddd, J = 17.0, 10.5, 5.0 Hz,
(2) Weller, D. D.; Rinehart, K. L. J. Am. Chem. Soc. 1978, 100,
6757.
(3) Wiley, P. F.; Jahnke, H. K.; MacKellar, F.; Kelly, R. B.;
Argoudelis, A. J. Org. Chem. 1970, 35, 1420.
Synlett 2005, No. 3, 433–436 © Thieme Stuttgart · New York

436
T. Tsujimoto et al.
LETTER
CH2=CH), 7.25–7.42 (5 H, m, Ph) ppm. 13C NMR (75 MHz,
CDCl3): d = –0.5, 15.9, 46.6, 65.0, 69.9, 72.3, 75.8, 94.9,
101.8, 119.6, 127.6, 128.5, 128.7, 135.1, 137.9, 159.0 ppm.
Anal. Calcd for C20H27NO4Si: C, 64.31; H, 7.29; N, 3.75.
Found: C, 64.28; H, 7.13; N, 3.71.
s, Ac), 2.33 (1 H, dd, J = 17.6, 6.8 Hz, CHAHB-C=O), 3.54
(1 H, m, CHCH2), 4.08 (1 H, d, J = 17.2 Hz, -CHAHB-Ph),
4.70 (1 H, q, J = 6.0 Hz, CHCH3), 5.24 (1 H, d, J = 5.6 Hz,
CH-CHOAc), 5.24 (1 H, d, J = 17.2 Hz, CHAHB-Ph), 6.04 (1
H, d, J = 1.6 Hz, C=C-CH-OAc), 7.41–7.24 (5 H, m, Ph)
ppm. 13C NMR (75 MHz, CDCl3): d = –1.6, 17.5, 20.3, 20.4,
38.9, 47.2, 48.5, 73.4, 74.9, 76.8, 77.8, 126.2, 128.1, 129.2,
137.1, 144.7, 158.2, 168.9, 169.1, 181.7, 211.2 ppm. HRMS
(FAB+): m/z calcd for C25H32NO7Si [M + H]: 486.1948;
found: 486.1930.
(21) Mukai, C.; Kim, J. S.; Uchiyama, M.; Sakamoto, S.;
Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1998, 2903.
(22) Spectral data of 19: [a]D26 +26.7 (c 0.55, CHCl3). IR (NaCl,
film): nmax = 2956, 1755, 1705, 1621, 1497, 1386, 1212,
1086, 976, 887 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.21
(9 H, s, TMS), 1.37 (3 H, d, J = 6.0 Hz, CH3), 1.77 (1 H, dd,
J = 17.5, 4.5 Hz, CHAHB-C=O), 1.97 (3 H, s, Ac), 2.13 (3 H,
(23) Another fraction contained an inseparable mixture of two
minor products, whose structures have not been elucidated.
Synlett 2005, No. 3, 433–436 © Thieme Stuttgart · New York