A concise approach to the spiroiminal fragment of marineosins

Article abstract of DOI:10.1039/c3ob40208h

A concise approach to the spiroiminal fragment of marineosins A and B is described. The key steps involve an acid-catalyzed N-acyliminium ion cyclization and a Vilsmeier-Haack type reaction with Tf₂O. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40208h

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A concise approach to the spiroiminal fragment of
marineosins†
Cite this: Org. Biomol. Chem., 2013, 11,
2936
Guang Li,a Xun Zhang,a Qi Li,a Pengju Fenga and Yian Shi*a,b
Received 30th January 2013,
Accepted 12th March 2013
DOI: 10.1039/c3ob40208h
www.rsc.org/obc
A concise approach to the spiroiminal fragment of marineosins A synthetic targets. During our studies toward these two com-
and B is described. The key steps involve an acid-catalyzed N-acyli- pounds, two synthetic approaches were reported both in 2010.
minium ion cyclization and a Vilsmeier–Haack type reaction with Lindsley and co-workers reported their studies on the pro-
Tf2O.
posed inverse-electron-demand hetero Diels–Alder reaction
based biomimetic approach.3 Snider and co-workers proposed
an alternative biosynthesis of the marineosins and completed
the synthesis of the spiroiminal moiety.4 Herein, we wish to
report our own synthetic approach to the spiroiminal fragment
of marineosins A and B.
The spiroiminal core of marineosins A and B contains all
the stereogenic centers and appears to be important for bio-
activities. The construction of this moiety will pave the way for
the synthesis of the molecules and their derivatives for biologi-
cal studies. The retrosynthetic analysis is shown in Scheme 1.
The sensitive pyrrole was planned to be introduced in the late
stage via a Vilsmeier–Haack type reaction from spiroketal
lactam 4, which could be obtained from compound 5 through
an acid-catalyzed N-acyliminium ion cyclization.5 Compound 5
could be readily prepared from commercially available
reagents 6 and 7.
In 2008, Fencial and co-workers reported the isolation of two
novel spiroiminals, marineosins A (1) and B (2) (Fig. 1), from a
marine-derived Streptomyces-related actinomycete.1 These two
compounds are likely related to the prodigiosin class of bac-
terial pigments,2 and have been shown to possess significant
anticancer activities.1 Both 1 and 2 have a trans-fused macro-
cyclic ring and a spiro-tetrahydropyran-dihydropyrrole iminal
structure. Marineosins A and B differ in stereochemistry of the
spiroiminal center and the MeO group in the dihydropyrrole,
which leads to the significant difference in cytotoxicity toward
human colon carcinoma (HCT-116) (IC50 = 0.5 μM for 1 and
IC50 = 46 μM for 2). The unique structures as well as the prom-
ising biological activities of marineosins make them attractive
The synthesis of spiroketal lactam
4 is outlined in
Scheme 2. γ-Valerolactone (6) was reduced with DIBAL-H at
−78 °C to give hemiacetal 8 in 90% yield,6 which was treated
Fig. 1 Structures of marineosins A and B.
aBeijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
bDepartment of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
USA. E-mail: yian@lamar.colostate.edu; Fax: +1-970-4911801; Tel: +1-970-4917424
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, X-ray structure of 9, 4a, 4b, 4c, and 3b along with
NMR spectra. CCDC 919541–919545. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ob40208h
Scheme 1 Retrosynthetic analysis of spiroiminal fragment 3.
2936 | Org. Biomol. Chem., 2013, 11, 2936–2938
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Fig. 4 The X-ray structure of compound 4b.
Scheme 2 Synthesis of compounds 4a and 4b.
with 4-methoxy-3-pyrrolin-2-one (7) and 4 N NaOH in MeOH at
55 °C to give compound 5 in 55% yield.7 The cyclization of
compound 5 was investigated with various acids. The best
result was obtained by treating compound 5 with 10 mol%
p-TsOH·H2O in CHCl3 at 60 °C for 24 h, giving compound 9 as
a single isomer in 54% yield along with small amounts of 5. It
appears that an equilibrium between 9 and 5 was reached
under the reaction conditions and did not change with pro-
longed reaction time. The structure of compound 9 was con-
firmed by X-ray diffraction (Fig. 2). When compound 9 was
hydrogenated with Pd/C (10%) under 50 atmosphere pressure
of H2 at 60 °C, isomers 4a and 4b were isolated in 27% and Scheme 3 Synthesis of compounds 3a, 3b, and 3c.
64% yield, respectively, with silica gel buffered with Et3N (the
X-ray structures of 4a and 4b are shown in Fig. 3 and 4).
91% yield with Tf2O (Scheme 3).9,10 When 4b was subjected to
the reaction conditions, 3b and 3c (3 : 1) were obtained in 94%
yield (the X-ray structure of 3b is shown in Fig. 5). Compound
4b can be converted to 4c with p-TsOH·H2O (0.1 equiv.) in
CDCl3. The ratio of 4b to 4c is about 1 : 0.9 at equilibrium.11
However, compound 4c can be isolated in 85% yield when 4b
was loaded on a silica gel column and eluted with EtOAc (4b
was gradually converted to 4c on the silica gel) (the X-ray struc-
ture of 4c is shown in Fig. 6). Treating compound 4c with Tf2O
in pyrrole gave spiroiminal 3c in 89% yield (Scheme 3).
With compounds 4a and 4b in hand, the Vilsmeier–Haack
reaction was subsequently investigated. No desired product
was obtained when 4a was treated with POCl3 and pyrrole.8 To
our delight, spiroiminal fragment 3a was cleanly formed in
Fig. 7 lists four spiroiminal stereoisomers 3a–d. Three of
them were obtained. The anomeric effect12 and the electronic
repulsion between two oxygens are likely the contributing
Fig. 2 The X-ray structure of compound 9.
Fig. 3 The X-ray structure of compound 4a.
Fig. 5 The X-ray structure of compound 3b.
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Acknowledgements
The authors gratefully acknowledge the National Basic
Research Program of China (973 program, 2011CB808600) and
the Chinese Academy of Sciences for the financial support.
Fig. 6 The X-ray structure of compound 4c.
Notes and references
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Fig. 7 Stereoisomers of spiroiminal.
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factors for the stability of these isomers. In the case of marin-
eosin A (1) or B (2), the fused macrocyclic ring in the natural
product will likely make the MeO group stay away from it to
ensure a more stable configuration. The stereochemistry of the
MeO group will likely determine the configuration of the spiro-
iminal during the cyclization. Compounds 3a, 3b, and 3c
were previously reported by Snider and co-workers.4 Similar
discussion on the relative stability of these compounds has
also been described by them.
Conclusion
In summary, we have developed a concise strategy to construct
the spiroiminal fragment of marineosins A and B in five steps.
The key steps involve an acid-catalyzed N-acyliminium ion
cyclization and a Tf2O mediated Vilsmeier–Haack type reaction 11 A similar ratio was obtained when 4c was treated with
to introduce the pyrrole. The application of this strategy to the p-TsOH·H2O (0.1 equiv.) in CDCl3.
synthesis of marineosins A, B and their derivatives is currently 12 For leading review on the anomeric effect, see:
R. U. Lemieux, Pure Appl. Chem., 1971, 25, 527.
a
underway.
2938 | Org. Biomol. Chem., 2013, 11, 2936–2938
This journal is © The Royal Society of Chemistry 2013