Total synthesis of vineomycin B2

Article abstract of DOI:10.1021/ja407827n

The first total synthesis of vineomycin B₂ (1) has been accomplished. The aglycon segment, a vineomycinone B₂ derivative, and the glycon segment, an α-l-acurosyl-l-rhodinose derivative, were prepared via C-glycosylation using an unprotected sugar and powerful chemoselective O-glycosylation using a 2,3-unsaturated sugar, respectively, as the key steps. Furthermore, effective and simultaneous introduction of the two glycon moieties to the aglycon part by concentration-controlled glycosylation led to the total synthesis of 1.

Full text of DOI:10.1021/ja407827n

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Article
Total Synthesis of Vineomycin B2
Shunichi Kusumi, Satoshi Tomono, Shunsuke Okuzawa, Erika Kaneko,
Takashi Ueda, Kaname Sasaki, Daisuke Takahashi, and Kazunobu Toshima
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Sep 2013
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Total Synthesis of Vineomycin B2
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Shunichi Kusumi, Satoshi Tomono, Shunsuke Okuzawa, Erika Kaneko, Takashi Ueda, Kaname Sasaki,
Daisuke Takahashi and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yoko-
hama 223-8522, Japan
ABSTRACT: The first total synthesis of vineomycin B2 (1) has been accomplished. The aglycon segment, a vineomycinone B2
derivative, and the glycon segment, an -L-acurosyl-L-rhodinose derivative, were prepared via C-glycosylation using an unprotect-
ed sugar and powerful chemoselective O-glycosylation using a 2,3-unsaturated sugar, respectively, as the key steps. Furthermore,
effective and simultaneous introduction of the two glycon moieties to the aglycon part by concentration-controlled glycosylation
led to the total synthesis of 1.
oxygen and the ease of -elimination of the tert-hydroxy
group  to the carbonyl group.4 Indeed, model studies in our
laboratories have shown that even without the -oxo moiety,
homobenzylic tertiary alcohols are challenging to use as gly-
cosyl acceptors showing a propensity to undergo dehydration
under standard Lewis acid-mediated glycosylation conditions.5
Therefore, any synthesis of 1 is going to require a careful
strategy to tune the glycosyl donor and acceptor's inherent
reactivity to allow the desired bond formation without dehy-
dration. Herein, we report the first total synthesis of 1, utiliz-
ing our powerful chemoselective O-glycosylation methodolo-
gy employing 2,3-unsaturated and 2,3-saturated deoxysugars.6
To the best of our knowledge, this is the first example of a
total synthesis of a natural product that possesses an oligosac-
charide attached to a tert-alcohol.7
1. INTRODUCTION
Vineomycin B2 (1), an anthracycline antibiotic, was isolated
by Ōmura et al. from the culture broth of Streptomyces maten-
sis subsp. vineus.1 1 is active against Gram-positive bacteria
and sarcoma 180 solid tumors in mice.1a The key structural
features of 1 are an aryl C-glycoside scaffold with a side chain
containing a -oxo-tert-alcohol subunit in the aglycon and two
identical deoxydisaccharides, -L-acurosyl--L-rhodinoses, in
the glycon.1b Because of its important biological activity and
novel molecular architecture, 1 is a prime target for chemical
synthesis. Indeed, six elegant syntheses of the aglycon,
vineomycinone B2 methyl ester (2), have been reported so far.2
In addition, synthetic studies of the deoxyoligosaccharide por-
tion of vineomycin family and related antibiotics have also
been reported.3 However, the total synthesis of 1 with its two
deoxydisaccharides has not been accomplished to date (Figure
1). One of the major tasks in the synthesis of 1 is the introduc-
tion of the highly deoxygenated and acid-labile deoxydisac-
charide (-L-acurosyl--L-rhodinose) to the -oxo-tert-alcohol
in the aglycon. It is well known that -oxo-tert-alcohols are
difficult to glycosylate due to both the intramolecular hydro-
gen bonding between the hydroxy group and the carbonyl
2. RESULTS AND DISCUSSION
As illustrated in our retrosynthetic analysis (Figure 2), we
planned to simultaneously introduce two deoxydisaccharide
(-L-acurosyl--L-rhodinose) moieties 4 to the suitably pro-
tected aglycon derivative 3 by glycosylation under mild condi-
tions. Furthermore, we expected that the temporary silyl ether
at the side chain in 3, which could be converted to the carboxy
function originally found in 1, would enhance the nucleo-
philicity of the tert-alcohol on the side chain and prevent -
elimination in the glycosylation of 3 and 4. The aglycon deriv-
ative 3 could be prepared in a few short steps by a modified
version of Suzuki’s synthesis of vineomycinone B2 methyl
ester (2)2d involving C-glycosylation using unprotected D-
olivose8 and 1,2-addition of the chiral aldehyde 5 and the aryl
C-glycoside 6. The glycon derivative 4 would be synthesized
utilizing a powerful chemoselective glycosylation methodolo-
gy6 with 2,3-unsaturated deoxysugar 7 and 2,3-saturated deox-
ysugar 8.
The synthesis of the aglycon derivative 3 is summarized in
Scheme 1. First, aryl C-glycoside 11 was synthesized by ste-
reo- and regioselective C-glycosylation using unprotected
Figure 1. Chemical structures of vineomycin B2 (1) and
vineomycinone B2 methyl ester (2).
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Scheme 1. Synthesis of aglyconderivative 3 and vineomyci-
none B2 methyl ester (2)a
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Figure 2. Retrosynthetic analysis of vineomycin B2 (1).
sugar, D-olivose (9), and 5,9,10-trimethoxyanthracen-1-ol (10)
in the presence of TMSOTf.2d,8,9 Meanwhile, optically pure
aldehyde 5 was synthesized from 12 in 4 steps (1. tetrahydro-
pyranylation; 2. benzylation; 3. detetrahydropyranylation; 4.
oxidation. See: Supporting Information). Compound 12 was
prepared from 3-methyl-3-buten-1-ol in 2 steps according to
Martin’s procedure.2e The aryl C-glycoside 11 was converted
to arylstannane 6 (Suzuki’s intermediate)2d in 3 steps (1. meth-
ylation; 2. silylation; 3. stannylation), which was then lithiated
and treated with aldehyde 5 to afford 13. Subsequent ben-
zoylation of the benzylic alcohol in 13 and treatment of the
resulting benzoate with CAN gave the corresponding anthra-
quinone derivative, whose benzyl ether was removed by hy-
drogenolysis, followed by deoxygenation at the benzylic posi-
tion using Na2S2O4 to provide diol 14. Deprotection of all the
silyl and methyl groups of 14 with BBr3 gave hexaol 15. At
this stage, the structure of 15 including the optical purity was
confirmed by the conversion of diol 14 to vineomycinone B2
methyl ester (2) in 3 steps (1. oxidation; 2. deprotection; 3.
methyl esterification. See: Supporting Information). Finally,
selective protection of the primary alcohol in 15 with a
TBDPS group, followed by selective protection of the C3 sec-
ondary alcohol in the D-olivose moiety with a chloroacetyl
(ClAc) group, furnished the suitably protected aglycon deriva-
tive 3.
aReagents and conditions: (a) TMSOTf, MeCN, rt, 45% (recov-
ered 6: 29%); (b) K2CO3, MeI, acetone, reflux, 95%; (c) TBSOTf,
2,6-lutidine, CH2Cl2, rt, 85%; (d) n-BuLi, t-BuOK, THF, -94 °C;
then Me3SnCl, -94 °C, 74%; (e) MeLi, toluene, -78 to 30 °C; then
5, 30 °C, 86% (dr 51:49); (f) BzCl, DMAP, pyridine, rt, 83%; (g)
CAN, MeCN/H2O (10/1, v/v), rt, 89%; (h) 10% Pd/C, H2, EtOH,
rt, 98%; (i) Na2S2O4, 1 N NaOH, dioxane/H2O (4/1, v/v), rt, 89%;
(j) BBr3, CH2Cl2, -78 °C, 94%; (k) TBDPSCl, imidazole, CH2Cl2,
rt, 99%; (l) Bu2SnO, MeOH, reflux; then ClAcCl, pyridine,
CH2Cl2, 0 °C, 50%.
thioglycoside structure as an armed sugar6 was obtained from
glycosyl acetate 17.11 Thus, conversion of the acetyl group in
17 to a thiophenyl group using PhSH and TMSOTf afforded
thioglycoside 18, whose TBDPS group was then removed
using TBAF to give 8. Chemoselective glycosylation of 8 (an
armed sugar) with 7 (a super-armed sugar) using TBSOTf as
an activator effectively proceeded at -98 °C under very mild
conditions to give the disaccharide 19 possessing a phenylthio
group at the C1 position in high yield with high -
stereoselectivity. On the other hand, it was found that
TBSOTf-mediated glycosylation of 8 and 2,3-unsaturated-4-
keto glycosyl acetate 20 (a disarmed sugar)6 did not proceed at
-98 °C, while glycosylation at a higher reaction temperature,
such as at -78 °C, produced considerable amounts of byprod-
uct 21 arising from the migration of the phenylthio group of 8.
In addition, it was confirmed that glycosylation of 8 and 2,3-
saturated glycosyl acetate 17 also did not proceed at -98 °C.
The synthesis of glycon donor 4 was achieved as illustrated
in Scheme 2. Acurosyl segment 7 possessing the 2,3-
unsaturated glycosyl acetate as a super-armed sugar6 was pre-
pared from known p-methoxyphenyl (PMP) glycoside 16.10.11
Thus, silylation of the C4 secondary alcohol of 16 with a
TBDPS group, followed by deprotection of the PMP group
and acetylation at the C1 position gave the super-armed sugar
7. Hydrogenation of the olefin in 7 using Rh/Al2O3 in a mix-
ture of EtOAc and toluene afforded 2,3-saturated sugar 17.12
Rhodinose segment 8 possessing the 2,3-saturated
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These results clearly demonstrate the usefulness of the 2,3-
Table 1. Glycosylations using 3 and 4.
unsaturated sugar as a super-armed glycosyl donor.6 Finally,
deprotection of the TBDPS group in 19 and oxidation of the
resulting allyl alcohol afforded thiodisaccharide 4 as a source
of the glycon moiety of 1.
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Scheme 2. Synthesis of disaccharide donor 4a
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3. Deprotection of the TBDPS group in 22 using TASF, fol-
lowed by oxidation of the resulting primary alcohol, gave car-
boxylic acid 24. Finally, deprotection of the ClAc group in
24with thiourea14 gave vineomycin B2 (1). Synthetic vineomy-
cin B2 (1) was found to be identical in all respects with the
natural product (See: Supporting Information).
aReagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 oC,
o
98%; (b) CAN, NaHCO3, MeCN/H2O (9/1, v/v), 0 C; (c) Ac2O,
DMAP, pyridine, 0 oC, 91% (2 steps, : = 87:13); (d) 5%
o
Scheme 3. Completion of total synthesis of 1a
Rh/Al2O3, H2, EtOAc/toluene (9/1, v/v), 0 C, 87% ( only) (e)
PhSH, TMSOTf, CH2Cl2, -40 °C, 99% (: = 64:36); (e) TBAF,
THF, 40 °C, 95%; (f) 7, TBSOTf, MS 5A, Et2O, -98 °C, 74% (
only); (g) TBAF, THF, 40 °C, 98%; (h) Dess-Martin periodinane,
NaHCO3, CH2Cl2, rt, 76%.
With both the aglycon segment 3 and the glycon segment 4
in hand, we next examined the glycosylation reaction. After
many experiments including model studies,5 we found that the
use of NIS/TfOH as activator was effective compared with
other activators such as MeOTf, AgOTf, and NBS/TfOH.
Thus, glycosylations of acceptor 3 and donor 4 using
NIS/TfOH were carried out under several conditions. These
results are summarized in Table 1. When 3.0 eq. of 4 was used
under low concentration conditions (10 mM for 3), diglyco-
side 22 was not obtained, and only monoglycoside 23 was
produced in moderate yield. In contrast, when 3.0 eq. of 4 was
used under high concentration conditions (25 mM for 3), the
glycosylation effectively proceeded to afford the diglycoside
22 in high yield with -stereoselectivity. On the other hand,
when 1.5 eq. of 4 was used under high concentration condi-
tions (50 mM for 3), monoglycoside 23 was obtained in high
yield with -stereoselectivity. These results clearly indicate
that control of the concentration for the reaction substrates is
very important to obtain the desired glycoside in high yield.13
In all cases, cleavage of the glycosidic bond of the acurosyl
moiety was not observed due to the disarmed nature of the
acuroside possessing the 2,3-unsaturated-4-keto structure.6
aReagents and conditions: (a) TASF, DMF, rt, 80%; (b) Dess-
Martin periodinane, NaHCO3, CH2Cl2, rt; (c) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH/THF/H2O (4/4/3, v/v/v), rt, 93% (2
steps); (d) thiourea, 2,6-lutidine, DMF, 60 °C, 91%.
3. CONCLUSION
In summary, the first total synthesis of vineomycin B2 (1) was
achieved. Our synthesis highlights an efficient concentration-
Completion of the synthesis of 1 is summarized in Scheme
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Sasaki, K.; Takahashi, D.; Toshima, K. Org. Biomol. Chem.
controlled glycosylation strategy for introducing acid-labile
deoxydisaccharide moieties to the aglycon part. Furthermore,
the acid-labile deoxydisaccharide was effectively synthesized
by a powerful chemoselective glycosylation methodology
using 2,3-unsaturated and 2,3-saturated glycosyl donors. Syn-
thetic studies of other vineomycin family antibiotics are now
in progress in our laboratories.
2010, 8, 988-990. (c) Kusumi, S.; Sasaki, K.; Wang, S.;
Watanabe, T.; Takahashi, D.; Toshima, K. Org. Biomol. Chem.
2010, 8, 3164-3178.
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ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
K. Toshima, toshima@applc.keio.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We sincerely thank Professor Satoshi Ōmura at Kitasato Institute
for Life Sciences, Kitasato University for providing us useful
information of natural vineomycin B2. This research was support-
ed in part by the MEXT-supported Program for the Strategic Re-
search Foundation at Private Universities, 2012–2016, from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT).
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