Practical synthesis of the C-1027 aminosugar moiety

Article abstract of DOI:10.1055/s-0030-1258524

A concise and reliable synthetic route to the aminosugar moiety of the C-1027 chromophore was developed. The aminosugar moiety was synthesized from l-glutamic acid in 11 steps and 13% overall yield.

Full text of DOI:10.1055/s-0030-1258524

2156
LETTER
Practical Synthesis of the C-1027 Aminosugar Moiety
S
ynthesis of the
C
e
-1027
A
min
i
osuga
i
M
oiet
c
y
hiro Hirai,a Yukio Tamura,a Itaru Sato,*b Masahiro Hirama*a,b
a
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax +81(22)7956566; E-mail: isato@mail.tains.tohoku.ac.jp; E-mail: hirama@mail.tains.tohoku.ac.jp
b
Received 8 June 2010
route to 2. For the purpose of the stereoselective
glycosylation6b and global deprotection at the end of the
synthesis, 1,1,3,3,-tetraisopropoxydisiloxanylidene (TIPDS)
protection of 2 should be a suitable choice.
Abstract: A concise and reliable synthetic route to the aminosugar
moiety of the C-1027 chromophore was developed. The aminosugar
moiety was synthesized from L-glutamic acid in 11 steps and 13%
overall yield.
Key words: C-1027, enediyne, carbohydrate, natural products, The aminosugar moiety 2 features a gem-dimethyl at C5,
synthesis
a cis-dihydroxy group at C2 and C3, and an N,N-dimeth-
ylamino group at the C4 position. Stereoselective con-
struction of the three C2–C4 consecutive stereogenic
The enediyne antibiotic C-1027,1 isolated from the culture
supernatant of Streptomyces globisporus C-1027 in 1988,
possesses the most potent antitumor activity in the family
of chromoprotein antibiotics.2 C-1027 is composed of a
biologically active chromophore and a stabilizing apopro-
tein.3,4 Synthesis of chromophore 1, which has the highly
strained, labile nine-membered enediyne,5 has attracted
the attention of many chemists.6,7 In 1993, we reported the
synthesis of the aminosugar moiety via intramolecular
carbamate rearrangement and determined its absolute
configuration.3b,8 However, a recent synthetic study of 1
indicated that glycosylation at a relatively early stage was
preferable and it required an ample supply of the amino-
sugar moiety 2 (Figure 1). Unfortunately, our synthesis of
2 suffered from lengthy steps and a low overall yield.
Thus, we developed a more concise and reliable synthetic
centers was a major challenge in the synthesis
(Scheme 1). The synthesis began with L-glutamic acid (3).
According to the literature procedure, 3 was converted
into g-lactam ethyl ester.9 Selective methylation of the es-
ter functionality and subsequent trapping of the hydroxy
group as a trimethylsilyl ether gave 4 after tert-butoxycar-
bonyl (Boc) protection of the lactam nitrogen. Introduc-
tion of the double bond and subsequent dihydroxylation of
5 using osmium tetroxide and N-methylmorpholine N-
oxide provided cis-diol 6 as a single diastereomer.10 Alka-
line hydrolysis of the imide function selectively cleaved
the g-lactam, followed by the addition of p-toluenesulfon-
ic acid, to give desired d-lactone 7.
For the selective hydrolysis of the lactam, Boc protection
of the amide group was essential. When hydrolysis of the
O
O
NH2
a, b, c
BocN
d, e
f
BocN
OH
HO2C
TMSO
TMSO
O
L
-glutamic acid (3)
4
5
O
O
O
O
g
h, i
j
BocN
Me2N
OH
BocN
H
OH
O
TMSO
Me2N
OH
OH
OH
OH
6
7
8
O
O
O
Me2N
OH
k
O
O
O
O
Si(i-Pr)2
Si(i-Pr)2
(i-Pr)2Si
(i-Pr)2Si
O
O
9
2
Scheme 1 Reagents and conditions: (a) SOCl2, EtOH then 150 °C, 0.02 bar, 89%; (b) MeLi, THF, –78 °C then TMSCl, Et3N, r.t., 68%; (c)
(Boc)2O, Et3N, MeCN, 90%; (d) LiN(SiMe3)2, THF, –78 °C then PhSeCl; (e) 30% aq H2O2, pyridine, 79% (2 steps); (f) cat. OsO4, NMO, ace-
tone, H2O, 91%; (g) LiOH, THF, H2O then TsOH, CH2Cl2, 82%; (h) TFA–CH2Cl2 (1:1); (i) NaBH3CN, aq HCHO, formic acid, 79% (2 steps);
(j) TIPDSCl2, imidazole, DMF, 56%; (k) DIBAL-H, CH2Cl2, –78 °C, 90%.
SYNLETT 2010, No. 14, pp 2156–2158
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258524; Art ID: U0511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the C-1027 Aminosugar Moiety
2157
MeO
O
Acknowledgment
This work was supported financially by a Grant-in-Aid for Special-
ly Promoted Research from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT). A fellowship to Y.T.
from the Japan Society for the Promotion of Science (JSPS) is gra-
tefully acknowledged.
N
H
O
O
O
O
Me2N
O
OH
References and Notes
OH
OH
O
O
O
(1) (a) Otani, T.; Minami, Y.; Marunaka, T.; Zhang, R.; Xie,
M.-Y. J. Antibiot. 1988, 41, 1580. (b) Yoshida, K.; Minami,
Y.; Azuma, R.; Saeki, M.; Otani, T. Tetrahedron Lett. 1993,
34, 2637.
(2) For reviews, see: (a) Smith, A. L.; Nicolaou, K. C. J. Med.
Chem. 1996, 39, 2103. (b) Xi, Z.; Goldberg, I. H. In
Comprehensive Natural Product Chemistry, Vol. 7; Barton,
D. H. R.; Nakanishi, K., Eds.; Pergamon: Oxford, 1999, 553.
(3) (a) Minami, Y.; Yoshida, K.; Azuma, R.; Saeki, M.; Otani,
T. Tetrahedron Lett. 1993, 34, 2633. (b) Iida, K.; Ishii, T.;
Hirama, M.; Otani, T.; Minami, Y.; Yoshida, K.
Cl
NH2
1
O
O
Me2N
OH
O
Si(i-Pr)2
(i-Pr)2Si
O
Tetrahedron Lett. 1993, 34, 4079. (c) Iida, K.; Fukuda, S.;
Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro, M.; Yoshida,
K.; Otani, T. Tetrahedron Lett. 1996, 37, 4997.
2
Figure 1 Structures of C-1027 chromophore 1 and aminosugar
moiety 2
(4) Tanaka, T.; Fukuda-Ishisaka, S.; Hirama, M.; Otani, T.
J. Mol. Biol. 2001, 309, 267.
(5) For the structure and reactivity of nine-membered
enediynes, see: (a) Iida, K.; Hirama, M. J. Am. Chem. Soc.
1995, 117, 8875. (b) Hirama, M. Pure Appl. Chem. 1997,
69, 525. (c) Usuki, T.; Mita, T.; Lear, M. J.; Das, P.;
Yoshimura, F.; Inoue, M.; Hirama, M.; Akiyama, K.; Tero-
Kubota, S. Angew. Chem. Int. Ed. 2004, 43, 5249.
(d) Hirama, M.; Akiyama, K.; Das, P.; Mita, T.; Lear, M. J.;
Iida, K.; Sato, I.; Yoshimura, F.; Usuki, T.; Tero-Kubota, S.
Heterocycles 2006, 69, 83; and references therein.
(e) Myers, A. G.; Hurd, A. R.; Hogan, P. C. J. Am. Chem.
Soc. 2002, 124, 4583.
(6) (a) Sato, I.; Toyama, K.; Kikuchi, T.; Hirama, M. Synlett
1998, 1308. (b) Sato, I.; Akahori, Y.; Sasaki, T.; Kikuchi, T.;
Hirama, M. Chem. Lett. 1999, 867. (c) Inoue, M.; Sasaki,
T.; Hatano, M.; Hirama, M. Angew. Chem. Int. Ed. 2004, 43,
6500. (d) Inoue, M.; Hatano, S.; Kodama, M.; Sasaki, T.;
Kikuchi, T.; Hirama, M. Org. Lett. 2004, 6, 3833.
(e) Inoue, M.; Ohashi, I.; Kawaguchi, T.; Hirama, M.
Angew. Chem. Int. Ed. 2008, 47, 1777.
corresponding imide 10 protected by a carbobenzyloxy
(Cbz) group was attempted, the g-lactam was not cleaved
and instead the Cbz group migrated to the C5 hydroxy
group (Scheme 2). A similar migration of the alkoxycar-
bonyl group to the primary alcohol often occurred even if
the Boc group was used.11 In the hydrolysis of 6, steric
hindrance between the gem-dimethyl and the tert-butoxy-
carbonyl group suppressed intramolecular attack of the
alkoxide. Acidic removal of the Boc group followed by
reductive methylation of the resulting amine gave dimeth-
ylamine 8. Protection of the vicinal diol with TIPDSCl
provided 9.12 Reduction with DIBAL-H afforded desired
hemiacetal 2 together with a small amount (<10%) of
open-chain aldehyde.13
O
O
(7) Recent synthetic studies of related chromoprotein
antibiotics. For maduropeptin, see: (a) Komano, K.;
Shimamura, S.; Norizuki, Y.; Zhao, D.; Kabuto, C.; Sato, I.;
Hirama, M. J. Am. Chem. Soc. 2009, 131, 12072.
HN
CbzN
LiOH, aq THF
88%
OH
OH
CbzO
TMSO
OH
OH
(b) Norizuki, Y.; Komano, K.; Sato, I.; Hirama, M. Chem.
Commun. 2008, 5372. (c) Iso, K.; Inoue, M.; Kato, N.;
Hirama, M. Chem. Asian J. 2008, 3, 447. (d) Komano, K.;
Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc.
2007, 129, 14184. (e) Kato, N.; Shimamura, S.; Khan, S.;
Takeda, F.; Kikai, Y.; Hirama, M. Tetrahedron 2004, 60,
3161. (f) Nicolaou, K. C.; Koide, K.; Xu, J.; Izraelewicz,
M. H. Tetrahedron Lett. 1997, 38, 3671. For kedarcidin,
see: (g) Ogawa, K.; Koyama, Y.; Ohashi, I.; Sato, I.; Hirama,
M. Angew. Chem. Int. Ed. 2009, 48, 1110. (h) Ren, F.;
Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem.
Soc. 2007, 129, 5381. (i) Ren, F.; Hogan, P. C.; Anderson,
A. J.; Myers, A. G. Org. Lett. 2007, 9, 1923. (j) Lear, M. J.;
Hirama, M. Tetrahedron Lett. 1999, 40, 4897. (k) Vuljanic,
T.; Kihlberg, J.; Somfai, P. J. Org. Chem. 1998, 63, 279.
(l) Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc.
1997, 119, 12012. (m) Hornyak, M.; Pelyvas, I. F.;
Sztaricskai, F. J. Tetrahedron Lett. 1993, 34, 4087.
10
11
Scheme 2 Migration of carbobenzyloxy group of 10
In conclusion, we have developed a concise synthetic
route to the C-1027 aminosugar moiety 2. The present
synthesis (11 steps in 13% overall yield from L-glutamic
acid), superior to the previous route (18 steps, 0.49%),
will facilitate the synthetic study of the C-1027 chro-
mophore 1. Further studies directed toward the total syn-
thesis of 1 are currently under way in our laboratory.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 14, 2156–2158 © Thieme Stuttgart · New York

2158
K. Hirai et al.
LETTER
25.7, 24.6 (C6), 31.4 (C6), 45.0 (NMe2), 68.7 (C4), 71.8
(C3), 76.7 (C2), 87.4 (C5), 169.3 (C1). ESI-HRMS: m/z
calcd for C21H43NNaO5Si2+ [M + Na+]: 468.2572; found:
468.2575.
(8) For the synthesis of the aminosugar moiety reported by
another group, see: Semmelhack, M. F.; Jiang, Y.; Ho, D.
Org. Lett. 2001, 3, 2403.
(9) (a) Saijo, S.; Wada, M.; Himizu, J.; Ishida, A. Chem. Pharm.
Bull. 1980, 28, 1449. (b) Hamada, Y.; Hara, O.; Kawai, A.;
Kohno, Y.; Shioiri, T. Tetrahedron 1991, 47, 8635.
(10) Schröder, M. Chem. Rev. 1980, 80, 187.
(11) Bunch, L.; Norrby, P.-O.; Frydenvang, K.; Krogsgaard-
Larsen, P.; Madsen, U. Org. Lett. 2001, 3, 433.
(12) Selected Data for 9
(13) Selected Data for 2
Colorless oil; [a]D27 –19.0 (c 1.00, CHCl3). FT-IR (film): n =
3386, 2867, 1465, 1386, 1364, 1248, 1137 cm–1. 1H NMR
(400 MHz, CDCl3): d = 1.03–1.13 (28 H, m, TIPDS), 1.30 (3
H, s, H6), 1.60 (3 H, s, H6), 2.46 (1 H, d, J = 2.4 Hz, H4),
2.55 (6 H, s, NMe2), 2.76 (1 H, br s, OH), 3.49 (1 H, dd,
J = 8.0, 3.2 Hz, H2), 4.73 (1 H, dd, J = 3.2, 2.4 Hz, H3), 5.01
(1 H, br d, J = 8.0 Hz, H1). 13C NMR (100 MHz, CDCl3):
d = 13.0, 13.1, 13.3, 13.6, 14.4, 17.1, 17.1, 17.4, 17.4, 17.5,
17.5, 17.6, 23.7 (C6), 30.8 (C6), 44.5 (NMe2), 69.4 (C4),
74.8 (C3), 78.1 (C2), 78.4 (C5), 90.5 (C1). ESI-HRMS:
m/z calcd for C21H46NO5Si2+ [M + H+]: 448.2909; found:
448.2910.
Colorless needles; mp 162–164 °C (EtOAc); [a]D29 +8.6 (c
1.00, CH2Cl2). FT-IR (film): n = 2944, 1742, 1458, 1275,
1179, 1114, 1041, 1014, 884, 801, 695 cm–1. 1H NMR (400
MHz, CDCl3): d = 0.94–1.15 (28 H, m, TIDPS), 1.45 (3 H,
s, H6), 1.61 (3 H, s, H6), 2.53 (6 H, s, NMe2), 2.71 (1 H, d,
J = 1.6 Hz, H4), 4.43 (1 H, d, J = 2.4 Hz, H2), 4.82 (1 H, dd,
J = 2.4, 1.6 Hz, H3). 13C NMR (100 MHz, CDCl3): d = 12.8,
13.3, 14.0, 14.3, 16.8, 16.9, 17.2, 17.2, 17.3, 17.6, 17.6, 17.9,
Synlett 2010, No. 14, 2156–2158 © Thieme Stuttgart · New York