Synthesis of the carboline disaccharide domain of shishijimicin A

Article abstract of DOI:10.1021/ol201444t

A synthetic route to the carboline disaccharide domain (2) of shishijimicin A (1) has been developed. The convergent synthesis relies on a novel application of the Reetz-Mueller-Starke reaction to form the central, sulfur-bearing quaternary carbon center

Full text of DOI:10.1021/ol201444t

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3924–3927
Synthesis of the Carboline Disaccharide
Domain of Shishijimicin A
K. C. Nicolaou,*,† J. L. Kiappes,† Weiwei Tian,† Vijaya B. Gondi,‡ and Jochen Becker†
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
United States, and The Department of Chemistry and Biochemistry, University of
California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
kcn@scripps.edu
Received May 27, 2011
ABSTRACT
A synthetic route to the carboline disaccharide domain (2) of shishijimicin A (1) has been developed. The convergent synthesis relies on a novel
€
application of the ReetzꢀMuller-Starke reaction to form the central, sulfur-bearing quaternary carbon center and addition of the carboline
structural motif as a dianion to a disaccharide aldehyde fragment.
The enediyne class of natural products has captured the
imagination of chemists, biologists and clinicians because
of their novel molecular architectures, potent biological
properties, and medical potential. Thus, investigations of
members of this family of compounds led to important
advances in fundamental science and practical applica-
tions in cancer chemotherapy.1
Isolated from the thin encrusting orange ascidian Di-
demnum proliferum, shishijimicin A (1, Figure 1) has joined
its siblings (B and C)2 and namenamicin3 as the only
members of the enediyne class that originate from marine
sources. All three shishijimicins carry the same enediyne
core as the one found in namenamicin and calicheamicin
γ1 (known as calicheamicinone).4 What sets the shishiji-
I
micins apart from all other enediynes, however, is their
unique carboline structural motif. Indeed, β-carboline is
known to intercalate into double-stranded DNA,5 and a
number of β-carbolines have been shown to cleave DNA
under photoirradiation conditions.6 Shishijimicin A (1) is
the most potent of the shishijimicin family, exhibiting IC50
values of 2.0, 1.8, and 0.47 pM cytotoxicities against 3Y1,
HeLa, and P388 cell lines, respectively.2 In light of these
observations and the extreme scarcityofshishijimicin A, its
total synthesis and that of its carboline disaccharide do-
main are deemed important. In this letter, we report the
† The Scripps Research Institute.
‡ University of California.
(1) For selected reviews on the chemistry, biology and medicinal
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Wogan, G. N.; Hecht, S. M. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
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r
10.1021/ol201444t
Published on Web 06/28/2011
2011 American Chemical Society

chemical synthesis of the carboline disaccharide domain 2
€
Starke reaction to install the tetrasubstituted, sulfur-
bearing carbon center and a carboline dianion-aldehyde
coupling.
iodide derivative, which was also expected to undergo a
smoother halogen-metal exchange at the step of the anion-
aldehyde coupling. Toward this end, and capitalizing on the
reactivity of the hydroxypyridine moiety of compound 8, we
transformed the latter, first to its triflate (Tf2O, pyridine) and
then to its iodide in the same pot by iodide displacement
(NaI, TfOH) in 61% overall yield.8 Exchange of protecting
group within the so-obtained iodo-β-carboline 9 (BBr3,
demethylation; TBSOTf, silylation) led to the desired carbo-
line block 3 in 55% overall yield.
of shishijimicin A, whose features include a ReetzꢀMuller-
Scheme 1. Synthesis of Iodo-β-carboline 3
With the carboline coupling partner in hand, our atten-
tion turned to the synthesis of the central unit of the
molecule, namely the methylthio sugar 4. Our successful
construction of this intermediate commenced with differ-
entially protected glycoside 109 and proceeded as shown in
Scheme 2. Cleavage of the benzylidene group under acidic
conditions (TsOH) liberated the 1,3-diol system 11 (80%
yield), whose tosylation (TsCl, Et3N, DMAP cat.) furn-
ished monotosylate 12 in 89% yield. Subsequent reduction
of the tosylate 12 with LiAlH4 led smoothly to 6-deox-
ymethylpyranoside 13 in 94% yield. The remaining hydro-
xyl group within 13 was then oxidized with NMO in the
presence of TPAP (cat.), yielding ketone 14 (84% yield).
Aiming for the eventual installment of the quaternary
center bearing the methylthio and nitrile groups in the
growing molecule, ketone 14 was treated with TMSSMe
and TMSOTf in CH2Cl2 at ꢀ78 f 0 °C to furnish
dithioketal 15 in 94% yield. Careful monitoring of the
temperature for this reaction was important, as warming
above 0 °C resulted in the formation of a byproduct in
which the anomeric methoxy group was replaced with a
methylthio substituent.
Figure 1. Structures of shishijimicin A (1), carboline disacchar-
ide domain 2, and retrosynthetic analysis of 2.
Retrosynthetic rupture of the targeted disaccharide
fragment 2 as shown in Figure 1 revealed carboline deri-
vative 3, methylthio sugar 4, and N-alloc aminoglycosyl
fluoride 5 as the required building blocks.
Scheme 1 summarizes the developed expedient route to
carboline derivative 3startingwith5-methoxytryptamine6.
Thus, 6 was sequentially treated with triphosgene
(60ꢀ70 °C) and 30% HBr in glacial acetic acid (100 °C)
to afford the dihydrocarboline 7 in 72% overall yield. The
fully aromatized carboline 8 was obtained from the latter
compound through oxidation in the presence of 10% Pd/C
in refluxing cumene (68% yield). Previous studies7 with
carboline dianions employed bromide derivatives; however,
in this case, the bromide was obtained in rather low yield
(i.e., <40%), prompting us to target the corresponding
To complete the construction of the central carbon
center bearing the required methylthio and nitrile groups,
(8) Maloney, K. M.; Nwakpuda, E.; Kuethe, J. T.; Yin, J. J. Org.
Chem. 2009, 74, 5111–5114.
(9) (a) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang,
Y.-W.; Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896–
899. (b) Wang, C.-C.; Kulkarni, S. S.; Lee, J.-C.; Luo, S.-Y.; Hung, S.-C.
Nat. Protoc. 2008, 3, 97–113.
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12336. (b) Kuwada, T.; Fukui, M.; Hata, T.; Choshi, T.; Nobuhiro, J.;
Ono, Y.; Hibino, S. Chem. Pharm. Bull. 2003, 51, 20–23.
Org. Lett., Vol. 13, No. 15, 2011
3925

Scheme 2. Synthesis of Thiosugar 4
Scheme 3. Synthesis of Glycosyl Fluoride 5
The preparation of the remaining carbohydrate unit,
glycosyl fluoride 5, was prepared from the known amino
glycoside 17,11 as summarized in Scheme 3. The alloc
group was chosen as a protecting group for the secondary
amine moiety, instead of the Fmoc group employed in
previous work,12 due to the anticipated basic conditions of
the carboline coupling. Thus, treatment of 17 with allyl
chloroformate in the presence of K2CO3 and 18-crown-6
led to carbamate 18 (98% yield), whose exposure to
AcOH/H2O (5:1) at 95 °C liberated lactol 19 (70% yield;
90% based on recovered starting material). Finally, gly-
cosyl fluoride 5 was formed from the latter compound
through the action of DAST in 64% yield.
Scheme 4. Fragment Coupling and Completion of the Synthesis
of Carboline Disaccharide 2
we called upon the ReetzꢀMuller-Starke reaction.10 This
€
method had been successful previously on dithioketals but
not demonstrated on carbohydrates such as 15, where the
anomeric methoxy group may lead to complications.
Despite these fears, we were pleased to observe that, under
€
the conditions originally reported by Reetz and Muller-
Starke (i.e., TMSCN, SnCl4, CH2Cl2, 0 °C), dithioketal 15
reacted to afford the expected methylthio nitrile 16 as a ca.
2:1 diastereomeric mixture and in 75% combined yield.
The structures of the chromatographically separated iso-
mers 16 (major, desired) and 4-epi-16 (minor, undesired)
were assigned by 1H NMR spectroscopic analysis. Speci-
fically, the desired isomer 16 exhibited a diagnostic NOE
between the methylthio group protons and the C-2 proton,
whereas the undesired epimer did not (see chair structures
16 and 4-epi-16 in Scheme 2). In support of the stereo-
chemical assignment of 4-epi-16 were the NOE’s exhibited
between its methylthio group protons and those at C-3 and
C-5. All that remained to generate the targeted fragment 4
was the deallylation of intermediate 16, a reaction that
proceeded smoothly, and in 77% yield, in the presence of
Pd(PPh3)4.
€
(10) Reetz, M. T.; Muller-Starke, H. Tetrahedron Lett. 1984, 25,
3301–3304.
3926
Org. Lett., Vol. 13, No. 15, 2011

With all three required fragments available, their cou-
pling and elaboration to the targeted carboline disacchar-
ide domain 2 became the next task. Scheme 4 summarizes
theaccomplishment of thisgoal. Coupling of carbohydrate
fragment 4 with glycosyl donor 5 proceeded smoothly
following the Mukaiyama protocol.11a,13 Thus, in the pre-
sence of AgClO4 and SnCl2 under anhydrous conditions
The described chemistry provides a highly conver-
gent entry to the carboline disaccharide domain 2 of
shishijmicin A (1), paving the way for an eventual total
synthesis of the natural product itself, and for binding
and biological evaluation studies with the synthesized
domain 2 and its derivatives. This synthesis demon-
€
strated the application of the ReetzꢀMuller-Starke
(4 A MS), the mixture afforded, stereoselectively, dis-
reaction10 and of the carboline dianion coupling in
complex situations.
˚
accharide 20 in 85% yield (based on 4). Direct addition
of the dianion derived from carboline fragment 3 to
disaccharide nitrile 20 gave a complex mixture of pro-
ducts, necessitating the intermediacy of aldehyde 21.
The latter was produced from 20 by DIBAL-H reduction
(ꢀ78 °C, 88% yield). Reaction of this aldehyde with the
dianion generated from iodocarboline derivative 3 by
deprotonation (KHMDS, Et2O, ꢀ20 °C), followed by
halogen-metal exchange (t-BuLi, ꢀ78 °C), resulted in the
formation of the corresponding coupling product as a
mixture of diastereomeric alcohols (20, epi-20, not shown,
dr ca. 1:1; 70% yield based on 50% recovered starting
material 21).7a This mixture was then oxidized with MnO2
to afford the targeted ketone 2 in 74% yield.
Acknowledgment. Within The Scripps Research Insti-
tute, we thank Drs. D.-H. Huang and L. Pasternack for
NMR spectroscopy assistance and Dr. G. Siuzdak for
mass spectrometry assistance. Financial support for this
work was provided by the National Institutes of Health
(U.S.A.) (R01 CA100101) and the Skaggs Institute for
Research, as well as predoctoral fellowships from the
National Science Foundation and SkaggsꢀOxford Scho-
larship program (both to J.L.K.), and postdoctoral
fellowships from A*STAR (Singapore to W.T.) and
the Alexander von Humboldt Foundation (Germany,
to J.B.).
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P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron
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T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.;
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Chem. Soc., Perkin Trans. 1 1999, 545–557.
Note Added after ASAP Publication. The toc/abstract
graphic and Figure 1 contained an error in the version
published ASAP June 28, 2011, the correct version re-
posted June 30, 2011.
Supporting Information Available. Schemes with re-
spective reagents and conditions, experimental proce-
dures, and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) (a) Mukaiyama, T.; Hashimoto, Y.; Shoda, S. Chem. Lett. 1983,
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