Synthesis of the pluramycins 1: Two designed anthrones as enabling platforms for flexible Bis-C-glycosylation

Article abstract of DOI:10.1002/anie.201308016

Two effective tricyclic platforms are reported for the installation of the two constituent sugars, l-vancosamine and d-angolosamine, in a regio- and stereoselective manner for the synthesis of the pluramycin class of bis-C-glycoside antitumor antibiotics. Two complementary protocols are now available that differ in the order in which the two sugar moieties are installed. Sc(OTf)3 was effective as the Lewis acid.

Full text of DOI:10.1002/anie.201308016

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Angewandte
Communications
DOI: 10.1002/anie.201308016
C-Glycosylation
Synthesis of the Pluramycins 1: Two Designed Anthrones as Enabling
Platforms for Flexible Bis-C-Glycosylation**
Kei Kitamura, Yoshio Ando, Takashi Matsumoto,* and Keisuke Suzuki*
Dedicated to Professor Teruaki Mukaiyama
Abstract: Two effective tricyclic platforms are reported for the
installation of the two constituent sugars, l-vancosamine and
d-angolosamine, in a regio- and stereoselective manner for the
synthesis of the pluramycin class of bis-C-glycoside antitumor
antibiotics. Two complementary protocols are now available
that differ in the order in which the two sugar moieties are
installed. Sc(OTf)3 was effective as the Lewis acid.
However, it is difficult to find a coherent solution for these
issues. The pioneering synthesis of isokidamycin by Martin
and co-workers has been the only example of a completed
total synthesis.[4]
Previous approaches for installing the bis-C-glycosides
can be classified in three categories: 1) In early-stage
approaches, simple mono- or bicyclic compounds are used
to regioselectively connect two sugars. An inevitable issue,
however, is that a linear strategy would be required for the
construction of the tetracyclic core.[5–7] 2) In late-stage
approaches, a pyranoanthracene tetracycle is used for bis-C-
glycosylation; in this case, problems arise in terms of
regioselectivity and/or yield.[8] 3) In their unique approach,
Martin and co-workers[4] used a C-glycosyl furan derivative,
which was converted into a tetracycle amenable to a second
C-glycosylation.
Among the aryl C-glycoside antibiotics, the pluramycins
share the unique structural feature of two amino C-glycosides
attached to an anthrapyranone chromophore (Scheme 1).[1]
Seeking a simple, general solution, we focused on tricycles.
Among other structures, anthrones 1 and 2 were considered as
potential platforms for bis-C-glycosylation according to the
following reasoning. First, anthraquinone A, the intact BCD
framework in the targets, was excluded by consideration of its
electron poorness, which would be inappropriate for a Frie-
del–Crafts reaction or O!C-glycoside rearrangement.[3,9]
Second, inspiration from type-II polyketide biosynthesis
[Scheme 2, Eq. (1)][10] suggested that anthrone B, which
lacks the C7 oxygen functionality, would be endowed with
the necessary reactivity. Omission of the C7 carbonyl group
would also help minimize the possible photodegradation
known for the pluramycins [Scheme 2, Eq. (2)].[11] However,
an issue in B was the equivalency of the B/D rings: Non-
selective, multiple C-glycosylation reactions may occur at
both rings. Finally, tricycles 1 and 2 emerged as the candidates
for further investigation. In these compounds, the non-
aromatic B ring would enable discrimination between the B/
D rings. Furthermore, the carbonyl group in the B ring would
be useful for the formation of the A ring. Herein, we report
the excellent performance of tricycles 1 and 2 as platforms for
the installation of two sugar groups in a complementary
fashion, thus providing a firm basis for the general synthesis of
the pluramycins.[12]
Scheme 1. Bis-C-glycoside antibiotics of the pluramycin-class. The
natural product numbering has been adopted herein.
The antitumor activity of these compounds is attributed to
intercalation with DNA, whereby the two C-glycosides are
responsible for the sequence selectivity.[2] The significant
bioactivity as well as the challenging structures of the
pluramycins have attracted considerable attention to their
synthesis.
Two key synthetic challenges are 1) the regio- and
stereoselective installation of two different C-glycosides[3]
and 2) the effective assembly of the tetracyclic framework.
[*] Dr. K. Kitamura, Dr. Y. Ando, Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
E-mail: ksuzuki@chem.titech.ac.jp
Homepage: http://www.chemistry.titech.ac.jp/~org_synth/
Prof. Dr. T. Matsumoto
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences
1432-1, Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
The reactivity of tricyles 1 and 2[13] as C-glycosyl acceptors
was studied extensively under a variety of Lewis acidic
conditions. We employed three glycosyl donors for the
constituent sugars: d-angolosamine precursors 3a and
3b,[5b,14] and l-vancosamine precursor 4 (Scheme 3),[15] and
established two efficient protocols for their installation on the
tricyclic platforms.
[**] This research was supported by a Grant-in-Aid for Specially
Promoted Research (No. 23000006) from the JSPS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308016.
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Table 1: Mono-C-glycosylation of tricycle 1.
Entry
Lewis acid
Yield of 5 [%]
1
2
3
4
5
Sc(OTf)3
BF3·OEt2
SnCl4
21
14
30
21
67
[Cp2HfCl2]/AgOTf[a]
Me3SiOTf
[a] Tf=trifluoromethanesulfonyl.
Scheme 2. Design of the enabling platform for bis-C-glycosylation.
Scheme 3. Three glycosyl donors. Bn=benzyl.
Scheme 4. Protocol for the bis-C-glycosylation of tricycle 1.
Preliminary reactions of tricycle 1 with glycosyl donors 3a
and 3b were examined under a specified set of conditions
(50 mol% of a Lewis acid, 1,2-dichloroethane, Drierite,
ꢀ308C!RT). The azido acetate 3a failed to give any C-
glycoside products owing to reactivity mismatching: Donor
3a was rapidly activated by the Lewis acid at low temper-
ature, at which the nucleophilicity of 1 was insufficient for the
Friedel–Crafts reaction. Thus, donor 3a was completely
consumed, but did not take part in the productive pathway.
Instead only unidentified decomposition products were
obtained, with complete recovery of 1.
By contrast, 3b proved to be a viable glycosyl donor. The
first trial with Sc(OTf)3 gave the C8-linked C-glycoside 5,
albeit in 21% yield (Table 1, entry 1) along with decompo-
sition products derived from 3b and the recovery of 1.
Whereas other Lewis acids led to poor yields of 5 (Table 1,
entries 2–4), Me3SiOTf gave the C-glycoside 5 in promising
yield (67%; Table 1, entry 5). In all experiments, the anome-
ric configuration of 5 was entirely d-b (1H NMR and
2D ROESY spectroscopy).[16]
promote the second C-glycosylation. An idea was to first
remove the methyl protecting group in 5, in the hope that the
O!C-glycoside rearrangement would be effective.[9]
MgI2·OEt2 promoted this deprotection nicely:[17] The desired
phenol 6 was formed in 97% yield.[18] Pleasingly, the second
C-glycosylation was possible with phenol 6. The reaction of 6
and l-vancosamine precursor 4 (2 equiv) with Sc(OTf)3
occurred exclusively at the C10 position to give the bis-C-
glycoside 7 cleanly in 97% yield. The anomeric centers in 7
both had the b configuration.[16]
Thus, an efficient three-step protocol was established for
the bis-C-glycosylation of tricycle 1: 1) mono-C-glycosylation
at C8, 2) deprotection, 3) a second C-glycosylation at C10.
The generality of this approach was tested successfully in the
synthesis of C-glycosides 10a and 10b, in which the positions
of the two sugar moieties in 7 were exchanged (Scheme 5).
Notably, the second C-glycosylation proceeded well with both
glycosyl acetates, 3a and 3b. Such artificial bis-C-glycosides
are potentially useful for biological studies.
After further optimization, the reaction with Me3SiOTf
gave 5 in improved yield (82%; Scheme 4). Although it was
good that the reaction of 1 rigorously stopped at the stage of
mono-C-glycosylation at C8, we needed some means to
We next focused on another substrate, 2, with the C11
phenol unprotected. Tricycle 2 turned out to be much more
reactive than 1, and readily accepted two sugars at the C8 and
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Scheme 7. Mono-C-glycosylation of tricycle 2.
Scheme 5. Synthesis of bis-C-glycosides 10 with the opposite sugar
substitution at C8 and C10 (with respect to 7).
In this case, the intermediary O-glycoside was neither
observed (TLC assay) nor isolated (early quenching). Elu-
siveness of the O-glycoside intermediate is a general trend for
reactions of substrates with a phenol group hydrogen-bonded
to a nearby carbonyl group,[5,9b] although the phenol appa-
rently plays a key role in the reactivity and regioselectivity of
the transformation. The mechanistic details of the process and
special reactivity of Sc(OTf)3 await further investigation.
A larger-scale reaction enabled the mono-C-glycoside 12
to be obtained in improved yield (89%). This product was
then subjected to the second C-glycosylation (Scheme 8). The
C10 positions, as exemplified by its reaction with glycosyl
donor 4 (3 equiv; Scheme 6). The reaction promoted by
Me3SiOTf (50 mol%) cleanly gave bis-C-glycoside 11 in 89%
yield, and Sc(OTf)3 was also effective, with the formation of
11 in 95% yield. The anomeric centers in 11 both had the l-
b configuration.[16]
Scheme 6. One-pot bis-C-glycosylation of tricycle 2.
Although this one-pot bis-C-glycosylation of tricycle 2
proceeded in similar yields with Me3SiOTf and Sc(OTf)3,
monitoring of the reaction by TLC suggested an interesting
difference between these Lewis acids: In the reaction with
Me3SiOTf, two sugar moieties appeared to be installed in
a random order, whereas the reaction with Sc(OTf)3 initially
led to glycosylation at C10. This observation was a promising
clue for the next goal: the regioselective installation of two
different sugars on tricycle 2.
Indeed, the reaction of tricycle 2 and acetate 4 in a 2:1
molar ratio led to completely different results with the two
Lewis acids. Me3SiOTf gave a mixture of regioisomeric mono-
C-glycosides 12 and 9, along with bis-C-glycoside 11
(Scheme 7). On the other hand, Sc(OTf)3 gave specifically
the mono-C-glycoside 12 as the sole product. The anomeric
configuration of 12 was l-b.[16,19]
Scheme 8. Protocol for the bis-C-glycosylation of tricycle 2.
treatment of 12 with azido acetate 3a in the presence of
Sc(OTf)3 led to smooth installation of the d-angolosamine
moiety at the C8 position to give bis-C-glycoside 13 in
excellent yield and stereoselectivity.[16]
In conclusion, two effective protocols have been estab-
lished for site-selective, stepwise bis-C-glycosylation by the
use of tricycles 1 and 2 as enabling platforms. These synthetic
methods provide flexible access to pluramycin-related com-
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Ben, T. Yamauchi, T. Matsumoto, K. Suzuki, Synlett 2004, 225;
see also Ref. [5].
[10] a) R. Thomas, Chembiochem 2001, 2, 612; b) A. Das, C. Khosla,
Acc. Chem. Res. 2009, 42, 631.
[11] a) A. Fredenhagen, U. Sꢀquin, Helv. Chim. Acta 1985, 68, 391;
b) A. Fredenhagen, U. Sꢀquin, J. Antibiot. 1985, 38, 236.
[12] See the following communication in this issue: K. Kitamura, Y.
Maezawa, Y. Ando, T. Kusumi, T. Matsumoto, K. Suzuki, Angew.
Chem., DOI: 10.1002/ange.201308017; Angew. Chem. Int. Ed.,
DOI: 10.1002/anie.201308017.
pounds and enabled the first total synthesis of saptomy-
cin B,[12] a member of this class of antibiotics.
Received: September 12, 2013
Published online: December 16, 2013
Keywords: amino sugars · bis-C-glycosides · C-glycosylation ·
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Lewis acids · pluramycins
[13] For the preparation of tricycles 1 and 2, see the Supporting
Information.
[1] a) K. Maeda, T. Takeuchi, K. Nitta, K. Yagishita, R. Utahara, T.
Osato, M. Ueda, S. Kondo, Y. Okami, H. Umezawa, J. Antibiot.
Ser. A 1956, 9, 75; for reviews, see: b) U. Sꢀquin, Prog. Chem.
Org. Nat. Prod. 1986, 50, 57; c) T. Bililign, B. R. Griffith, J. S.
Thorson, Nat. Prod. Rep. 2005, 22, 742.
[14] For the preparation of angolosamine donor 3b, see: a) P.
Bartner, D. L. Boxler, R. Brambilla, A. K. Mallams, J. B.
Morton, P. Reichert, F. D. Sancilio, H. Surprenant, G. Tomalesky,
G. Lukacs, A. Olesker, T. T. Thang, L. Valente, S. Omura, J.
Chem. Soc. Perkin Trans. 1 1979, 1600; for a review on the
synthesis of amino sugars, see: b) F. M. Hauser, S. R. Ellen-
berger, Chem. Rev. 1986, 86, 35.
[15] For the preparation of 4, see: a) D.-S. Hsu, T. Matsumoto, K.
Suzuki, Synlett 2006, 469; b) K. Kitamura, M. Shigeta, Y.
Maezawa, Y. Watanabe, D.-S. Hsu, Y. Ando, T. Matsumoto, K.
Suzuki, J. Antibiot. 2013, 66, 131; see also Ref. [14b].
[16] For structure assignment, see the Supporting Information.
[17] a) S. Yamaguchi, K. Sugiura, R. Fukuoka, K. Okazaki, M.
Takeuchi, Y. Kawase, Bull. Chem. Soc. Jpn. 1984, 57, 3607;
b) S. A. Snyder, Z.-Y. Tang, R. Gupta, J. Am. Chem. Soc. 2009,
131, 5744.
[2] For reviews on DNA recognition by the pluramycins, see: a) D.
Sun, M. Hansen, L. Hurley, J. Am. Chem. Soc. 1995, 117, 2430;
b) M. R. Hansen, L. H. Hurley, Acc. Chem. Res. 1996, 29, 249;
c) B. Willis, D. P. Arya, Curr. Org. Chem. 2006, 10, 663.
[3] For reviews on the synthesis of aryl C-glycosides, see:
a) M. H. D. Postema in C-Glycoside Synthesis; CRC Press,
Boca Raton, 1995; b) Y. Du, R. J. Linhardt, I. R. Vlahov,
Tetrahedron 1998, 54, 9913.
[4] a) B. M. OꢁKeefe, D. M. Mans, D. E. Kaelin, Jr., S. F. Martin, J.
Am. Chem. Soc. 2010, 132, 15528; b) B. M. OꢁKeefe, D. M. Mans,
D. E. Kaelin, Jr., S. F. Martin, Tetrahedron 2011, 67, 6524.
[5] a) T. Yamauchi, Y. Watanabe, K. Suzuki, T. Matsumoto, Synlett
2006, 399; b) M. Shigeta, T. Hakamata, Y. Watanabe, K.
Kitamura, Y. Ando, K. Suzuki, T. Matsumoto, Synlett 2010, 2654.
[6] a) D. E. Kaelin, Jr., O. Lopez, S. F. Martin, J. Am. Chem. Soc.
2001, 123, 6937; b) D. E. Kaelin, Jr., S. M. Sparks, H. R. Plake,
S. F. Martin, J. Am. Chem. Soc. 2003, 125, 12994.
[18] Other reagents (BBr3, BCl3, and CeCl3/NaI) induced side
reactions, such as debenzylation and/or decomposition of the
sugar moiety.
[19] BF3·OEt2 and [Cp2HfCl2]/AgOTf also gave mixtures of 12, 9, and
11 in varying ratios. No reaction occurred with Y(OTf)3 or
La(OTf)3.
[7] K. A. Parker, Y.-H. Koh, J. Am. Chem. Soc. 1994, 116, 11149.
[8] Z. Fei, F. E. McDonald, Org. Lett. 2007, 9, 3547.
[9] For the O!C-glycoside rearrangement, see: a) T. Matsumoto,
M. Katsuki, K. Suzuki, Tetrahedron Lett. 1988, 29, 6935; b) A.
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