Toward the total synthesis of vineomycin B2: application of an efficient glycosylation methodology using 2,3-unsaturated sugars

Article abstract of DOI:10.1016/j.tetlet.2007.07.145

The application of an efficient glycosylation methodology using 2,3-unsaturated sugars to synthesize critical precursors required for the total synthesis of an antibiotic, vineomycin B₂ (1), was demonstrated. The required disaccharide, the acur

Full text of DOI:10.1016/j.tetlet.2007.07.145

Tetrahedron Letters 48 (2007) 6982–6986
Toward the total synthesis of vineomycin B2: application of an
efficient glycosylation methodology using 2,3-unsaturated sugars
Kaname Sasaki, Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 4 July 2007; revised 23 July 2007; accepted 24 July 2007
Available online 27 July 2007
Abstract—The application of an efficient glycosylation methodology using 2,3-unsaturated sugars to synthesize critical precursors
required for the total synthesis of an antibiotic, vineomycin B2 (1), was demonstrated. The required disaccharide, the acurosyl rho-
dinose derivative of 1, was prepared by chemoselective glycosylation using a 2,3-saturated glycosyl acetate corresponding to the rho-
dinose moiety and a 2,3-unsaturated glycosyl acetate corresponding to the acurose portion. Further, the right-hand side chain of 1,
consisting of b-oxo-tert-alcohol and rhodinose, was constructed by a powerful glycosylation approach using a 2,3-unsaturated gly-
cosyl acetate in an ionic liquid under reduced pressure.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Many structurally complex oligosaccharides are found
in naturally occurring bioactive compounds such as
antibiotics, and it is known that these oligosaccharides
play very important roles in biological events. Much
effort by synthetic organic chemists to effectively synthe-
size such complex oligosaccharides1 has highlighted the
need to develop an efficient glycosylation methodology
in order to address these challenging tasks.2 In this con-
text, we have recently developed a chemoselective and
powerful glycosylation methodology using 2,3-unsatu-
rated sugars.3 Our previous work demonstrated that gly-
cosylation using a 2,3-unsaturated sugar and the
corresponding 2,3-saturated sugar proceeded chemo-
selectively to provide a disaccharide possessing a hex-
2-enosyl hexose structure. Furthermore, the tertiary
alcohols, which show low reactivity, underwent efficient
glycosylation using 2,3-unsaturated sugars. As expected,
the 2,3-unsaturated glycosides obtained are synthetically
equivalent to the 2,3-dideoxy glycosides. Based on these
earlier findings, the aim of the present study was to syn-
thesize critical building blocks required for the total syn-
thesis of vineomycin B2 in order to demonstrate the
usefulness and generality of this glycosylation methodol-
ogy using 2,3-unsaturated sugars.
Vineomycin B2 (1), an anthracycline antibiotic, was iso-
lated by Omura et al. from the culture broth of Strepto-
ꢀ
myces matensis subsp. Vineus. Vineomycin B2 is active
against Gram-positive bacteria and against sarcoma
180 solid tumors in mice.4 Compound 1 has a hexenosyl
hexose disaccharide (acurosyl rhodinose) at the C4 posi-
tion of olivose and at the C3 position of the right-hand
side chain moiety. Although elegant syntheses of the
aglycon moiety, vineomycinone B2 methyl ester (2), were
reported by four groups,5 the complete synthesis of 1
has not been reported to date. One of the most difficult
aspects in the synthesis is the introduction of the glycon
moiety to the aglycon moiety, which involves the intro-
duction of the highly deoxygenated sugar, rhodinose,
into the b-oxo-tert-alcohol at the side chain. It has been
reported that even b-oxo-sec-alcohols are difficult to be
glycosylated due to stabilization by intramolecular
hydrogen bonds between the hydroxy group and the
carbonyl oxygen.6 Herein, we report the successful
application of our previously reported glycosylation
methodology using 2,3-unsaturated sugars to the syn-
thesis of critical vineomycin B2 building blocks, and
demonstrate the effective construction of vineomycin
B2 glycoside structures (see Fig. 1).
The retrosynthetic analysis for 1, outlined in Figure 2, is
based on the disconnections of the disaccharide, acuro-
syl rhodinose 4, and the monosaccharide, acurose pre-
cursor 5, from 1. The Diels–Alder reaction of the
known bromo naphthoquinone 67 and the ketene silyl
Keywords: Glycosylation; 2,3-Unsaturated sugar; Chemoselectivity;
Ionic liquid; Vineomycin B2.
*
Corresponding author. Tel./fax: +81 45 566 1576; e-mail:
toshima@applc.keio.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.145

K. Sasaki et al. / Tetrahedron Letters 48 (2007) 6982–6986
6983
important because the resulting hemiacetal was acid-
sensitive and thus transformed into the corresponding
d-hydroxy-a,b-unsaturated aldehyde possessing an E-
olefin. Subsequent hydrogenation of the olefin in 5,
catalyzed by Rh/Al2O3 in a mixture of EtOAc and tolu-
ene, gave the hexopyranosyl acetate 13;10 deprotection
of the TPS group of 13 using TBAF yielded the dis-
armed glycosyl donor 14 corresponding to the rhodinose
moiety. The efficiency of our chemoselective glycosyla-
tion methodology using 2,3-unsaturated and 2,3-satu-
rated sugars was demonstrated in the next step of the
synthesis. Glycosylation of the 2,3-unsaturated sugar 5
(1.0 equiv) and the 2,3-saturated sugar 14 (1.5 equiv)
using TBSOTf as an activator11 chemoselectively pro-
ceeded at ꢀ98 ꢁC to give the disaccharide 15 in high
yield (82%) and with high stereoselectivity (a/b = 1:0).3
Disaccharide 15 was then converted into the fully func-
tionalized acurosyl rhodinose segment 412 by appropri-
ate deprotection and oxidation reactions, while
retaining the OAc leaving group at the C-1 position.
O
O
OH
COOR'
O
OR
RO
HO
OH
O
Vineomycin B2 (1): R =
, R' = H
O
O
O
Vineomycinone B2 methyl ester (2): R = H, R' = Me
Figure 1. Vineomycin B2 and vineomycinone B2 methyl ester.
acetal derived from 7 would proceed with debromina-
tional aromatization to afford anthraquinone 3;5d,8 this
synthesis would be preceded by glycosylation of b-oxo-
tert-alcohol 8 with the rhodinose equivalent 9 to afford
glycoside 7.
The synthesis of 7 was achieved as summarized in
Schemes 2 and 3. The 1,4-addition of a vinyl cuprate to
the known enone 1613 according to Roush’s protocol14
provided anti-adduct 17 in moderate yield, which was
then subjected to aldol reaction with EtOAc to afford
18. Diastereo-induction in the aldol reaction was not ob-
served and the resulting diastereomers were inseparable
at this stage; therefore, they were derived into hemiace-
tals 22 and 23 by sequential deprotection and protection
reactions followed by Swern oxidation via 19–21. Hemi-
acetals 22 and 23 were separable, and their configura-
tions were confirmed by NOE experiments on the
acetate derivatives 24 and 25. Although reduction of
Disaccharide 4 was synthesized following the retrosyn-
thetic analysis, as summarized in Scheme 1. Both the
armed glycosyl donor 5 and the disarmed glycosyl donor
14 were synthesized from the known p-methoxyphenyl
(MP) glycoside 10.9 Thus, silylation of the allylic alcohol
of 10 with the TPS group, followed by deprotection of
the MP group with CAN in the presence of NaHCO3,
gave the hemiacetal 12 which was subsequently
subjected to acetylation to give the armed glycosyl
donor 5, corresponding to the acurose moiety. The addi-
tion of NaHCO3 in the CAN-oxidation reaction was
1
Glycosylation
O
OAc
AcO
COOEt
OAc
O
O
O
O
AcO
AcO
O
OAc O
O
TPSO
5
3
O
OH
O
O
Diels-Alder reaction
O
4
O
MeO
COOEt
Br
O
AcO
AcO
O
OAc O
BnO
6
7
Glycosylation
OAc
OClAc
ClAcO
O
COOEt
OH
BnO
8
9
Figure 2. Retrosynthetic analysis of vineomycin B2.

6984
K. Sasaki et al. / Tetrahedron Letters 48 (2007) 6982–6986
OMP
OAc
OR
b
d
O
O
O
HO
TPSO
RO
13: R=TPS
14: R=H
12: R=H
5: R=Ac
10: R=H
11: R=TPS
e
c
a
AcO
O
g, h
f
4
5
14
O
+
O
TPSO
15
Scheme 1. Reagents and conditions: (a) TPSCl, imidazole, CH2Cl2, 0 ꢁC, 98%; (b) CAN, NaHCO3, MeCN/H2O (9:1), 0 ꢁC, 56%; (c) Ac2O, DMAP,
pyridine, 0 ꢁC, 85% (a:b = 8:1); (d) H2, Rh/Al2O3, EtOAc/toluene (9:1), 0 ꢁC, 89%; (e) TBAF, THF, 40 ꢁC, 87%; (f) TBSOTf, Et2O, MS 5A, ꢀ98 ꢁC,
82%; (g) TBAF, AcOH, THF, 40 ꢁC, 99%; (h) Dess–Martin periodinane, NaHCO3, CH2Cl2, 25 ꢁC, 94%.
O
O
a
b
O
O
O
OEt
O
OH
O
O
O
16 (E:
Z
= 2:1)
17
18
OR2
COOEt
OTBS
OTBS
O
c
R1O
OEt
f
O
OH
COOEt
OH
O
OH
22
23
19: R1=R2=H
20: R1=DMTr, R2=TBS
21: R1=H, R2=TBS
d
e
g
g
COOEt
OTBS
OH
HO
OTBS
O
h, i
OEt
O
H
H
H
H
22
4%
6%
H
OH
O
H
H
OAc
H
OAc
COOEt
26
10%
8%
4%
4%
j
4%
25
24
8
OMP
OR
l
O
O
HO
10: R=H
27: R=Bn
BnO
28: R=H
9: R=Ac
m
k
Scheme 2. Reagents and conditions: (a) CH2CHMgBr, CuBrÆSMe2, TMSCl, THF, ꢀ78 ꢁC, 64%; (b) EtOAc, LDA, THF, ꢀ78 ꢁC to 0 ꢁC, 91%; (c)
IR-120, MeOH/H2O (1:1), 60 ꢁC, 84%; (d) DMTrCl, TEA, DMF, 25 ꢁC, then, TBSCl, imidazole, 25 ꢁC, 89%; (e) montmorillonite K-10, CH2Cl2/
MeOH (9:1), 25 ꢁC, 91%; (f) (COCl)2, DMSO, TEA, ꢀ78 ꢁC to ꢀ20 ꢁC, 40% for 22, 40% for 23; (g) Ac2O, DMAP, pyridine, 0 ꢁC, 82% for 24, 63%
for 25; (h) NaBH4, MeOH, 0 ꢁC; (i) TBAF, THF, 25 ꢁC, 86% (two steps); (j) ClAcCl, pyridine, CH2Cl2, ꢀ78 ꢁC, 99%; (k) BnBr, NaH, DMF, 25 ꢁC,
99%; (l) CAN, NaHCO3, MeCN/H2O (9:1), 0 ꢁC, 78%; (m) Ac2O, DMAP, pyridine, 0 ꢁC, 69% (a:b = 17:3).
the desired hemiacetal 22 with NaBH4 took place with
migration of the TBS group, producing two alcohols,
both isomers could lead to the triol 26 by deprotection
of the TBS group using TBAF. Finally, protection of
the diol in 26 with chloroacetyl (ClAc) groups furnished
glycosyl acceptor 8. The 2,3-unsaturated glycosyl acetate

K. Sasaki et al. / Tetrahedron Letters 48 (2007) 6982–6986
6985
OClAc
ClAcO
a
COOEt
8
9
O
O
BnO
29
OClAc
ClAcO
OEt
O
O
O
O
O
a
O
8
4
O
O
O
30: 28%
O
31: 0%
OH
R
HO
b
c
COOEt
e
COOEt
29
7
O
O
O
O
BnO
d
BnO
32
33: R=CHO
34: R=CO2H
Scheme 3. Reagents and conditions: (a) HOTf (0.5 mol % to IL), C6mim[OTf], 25 ꢁC, 2 mmHg, 98% for 29; (b) pyridine/H2O (1:1), 25 ꢁC, 91%; (c)
NaIO4, CH2Cl2/H2O (1:1), 25 ꢁC; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (4:1), 25 ꢁC, 84% (two steps); (e) TMSCHN2, CH2Cl2/
MeOH (20:3), 25 ꢁC, 99%.
9 was prepared using a route similar to that used for 5,
except that a benzyl group was used as the C-4 protecting
group instead of the TPS group.
mediate from being derivatized into the corresponding
glycal. Deprotection of the di-ClAc groups of 29 in
aqueous pyridine, and oxidative cleavage of the result-
ing diol 32, afforded the unstable aldehyde 33. Subse-
quent immediate oxidation using NaClO2 followed by
methylation using TMSCHN2 gave 7,17 which is the pre-
cursor of the diene segment for the Diels–Alder reaction.
With both the b-oxo-tert-alcohol acceptor 8 and the gly-
cosyl donor 9 in hand, we next examined the glycosyla-
tion reaction using these key segments (Scheme 3). After
several attempts, we found that the glycosylation of 8
(1.0 equiv) with 9 (2.0 equiv) proceeded smoothly at
25 ꢁC under reduced pressure (2 mmHg) in the ionic
liquid 1-hexyl-3-methylimidazolium trifluoromethane-
sulfonate (C6mim[OTf]) containing the protic acid
HOTf (0.5 mol % to the ionic liquid). The desired glyco-
side 29 was obtained in high yield (98%) and with high
stereoselectivity (a/b = 1:0).15,16 These results confirmed
that the use of non-volatile C6mim[OTf] under reduced
pressure provided significant advantages for the glyco-
sylation reaction. A volatile by-product, HOAc, could
be removed from the reaction mixture during the reac-
tion, and the side-reaction between HOAc and the gly-
cosyl cation intermediate was prevented. To the best
of our knowledge, this is the first successful example
of chemical glycosylation for constructing the glycosidic
linkage between a highly deoxygenated sugar and a b-
oxo-tert-alcohol. In contrast, when the 2,3-saturated
glycosyl donor 4 was employed under the same condi-
tions, the glycal 30 was produced and the desired glyco-
side 31 was not detected. This result indicated that the
double bond installed at the C2 position of the glycosyl
donor worked well to prevent the oxocarbenium inter-
In conclusion, we synthesized three key segments, 4, 5
and 7, of vineomycin B2. The key steps were the prepa-
ration of the acurosyl rhodinose segment 4 by reduction
of the hex-2-enopyranosyl acetate 5 using Rh/Al2O3,
and the chemoselective glycosylation of the 2,3-unsatu-
rated sugar 5 with the 2,3-saturated sugar 14. Further-
more, the diene precursor 7 was synthesized by a
powerful glycosylation approach in which the b-oxo-
tert-alcohol acceptor 8 and the 2,3-unsaturated glycosyl
donor 9 were reacted in an ionic liquid. Studies toward
the total synthesis of vineomycin B2 using these seg-
ments are now in progress in our laboratories.
Acknowledgments
This research was supported in part by Grant-in-Aid for
the 21st Century COE Program ‘KEIO Life Conjugated
Chemistry’, for Scientific Research on Priority Areas
18032068, and for JSPS Fellows 18Æ6013 from the Min-
istry of Education, Culture, Sports, Science, and Tech-
nology, Japan.

6986
K. Sasaki et al. / Tetrahedron Letters 48 (2007) 6982–6986
4.05 (1H, qd, J5,6 = 6.3, J4,5 = 1.5, H-5), 3.68 (1H, br ddd,
J4,5 = 1.5, H-4), 2.10 (3H, s, C(O)CH3), 2.17–1.91 (3H, m),
References and notes
1.67–1.60 (1H, m), 1.39 (3H, d, J5 ;6 ¼ 6:6, H-60), 1.22
(3H, d, J5,6 = 6.3, H-6); 13C NMR (75 Hz, CDCl3): (d,
CDCl3) d 196.6, 169.6, 142.8, 127.3, 95.3, 92.0, 75.8, 70.5,
68.3, 24.3, 23.1, 21.2, 17.1, 15.1; Anal. Calcd for
C14H20O6: C, 59.14; H, 7.09. Found: C, 58.96; H, 7.23.
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0
0
1. For recent reviews of synthesis of oligosaccharides of
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0
0
0
0
(5H, m, ArH), 6.09 (1H, dd, J2 ;3 ¼ 10:2, J3 ;4 ¼ 4:8, H-
30), 5.85 (1H, dd, J2 ;3 ¼ 10:2, J1 ;2 ¼ 3:3, H-20), 5.80 (1H,
0
0
0
0
ddd, J1 ;2 E ¼ 17:1, J1 ;2 Z ¼ 9:9, J2;1 ¼ 7:8, H-100), 5.33
00 00
00 00
00
(1H, d, J1 ;2 ¼ 3:3, H-10), 5.14 (1H, d, J1 ;2 E ¼ 17:1, H-
0
0
00 00
200E), 5.07 (1H, d, J1 ;2 Z ¼ 9:9, H-200Z), 4.64 and 4.54 (2H,
00 00
0
0
0
0
ABq, J = 12.0, ArCH2), 4.14 (1H, qd, J5 ;6 ¼ 6:6, J4 ;5
¼
2:4, H-50), 4.11 (2H, q, J = 6.9, OCH2CH3), 3.62 (3H, s,
OMe), 3.48 (1H, dd, J3 ;4 ¼ 4:8, J4 ;5 ¼ 2:4, H-40), 3.32
0
0
0
0
00
(1H, ddd, J2,3 = 9.6, J2;1 ¼ 7:8, J2,3 = 3.6, H-2), 2.78 and
11. TBSOTf was reported to be a milder activator than
TMSOTf, see: (a) Roush, W. R.; Narayan, S. Org. Lett.
1999, 1, 899–902; (b) Roush, W. R.; Hartz, R. A.; Gustin,
D. J. J. Am. Chem. Soc. 1999, 121, 1990–1991.
12. 1H NMR (300 MHz, CDCl3): (d, SiMe4; J Hz) d 6.88 (1H,
2.70 (2H, ABq, J = 14.4, H-5), 2.25 (1H, dd, J3,3 = 14.4,
J2,3 = 9.6, H-4), 1.89 (1H, dd, J3,3 = 14.4, J2,3 = 3.6, H-4),
1.41 (3H, s, CH3), 1.31 (3H, d, J5 ;6 ¼ 6:6, H-60), 1.25 (3H,
t, J = 6.9, OCH2CH3); 13C NMR (75 Hz, acetone-d6): (d,
acetone-d6) d 174.7, 170.9, 140.3, 138.4, 131.3, 129.0 (·2),
128.3 (·2), 128.1, 127.5, 116.3, 89.7, 77.1, 71.0, 70.4, 67.2,
60.7, 51.9, 46.5, 44.9, 42.9, 24.2, 16.7, 14.5; Anal. Calcd for
C25H34O7: C, 67.24; H, 7.67. Found: C, 67.10; H, 7.71.
0
0
dd, J2 ;3 ¼ 10:2, J1 ;2 ¼ 3:3, H-20), 6.16 (1H, br dd,
0
0
0
0
J1,2 = 1.8, H-1), 6.11 (1H, d, J2 ;3 ¼ 10:2, H-30), 5.25
0
0
(1H, d, J1 ;2 ¼ 3:3, H-10), 4.57 (1H, q, J4 ;5 ¼ 6:6, H-50),
0
0
0
0