Total synthesis of (+)-cylindradine A

Article abstract of DOI:10.1039/c4cc00137k

Cylindradines A and B, members of the polycyclic pyrrole-imidazole alkaloids (PIAs), are the only congeners bearing a 3-carbamoylpyrrole unit among the PIAs. In this communication, we described a total synthesis of (+)-cylindradine A based on intramolecular Friedel-Crafts type cyclization of pyrrole-aldehyde and oxidative cyclization of tricyclic pyrrolopyrrolidine- guanidine with hypervalent iodine to construct the cyclic guanidine structure including the N,N′-aminal moiety. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00137k

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Total synthesis of (+)-cylindradine A†
Makoto Iwata, Kyohei Kanoh, Takuya Imaoka and Kazuo Nagasawa*
Cite this: Chem. Commun., 2014,
50, 6991
Received 7th January 2014,
Accepted 4th May 2014
DOI: 10.1039/c4cc00137k
www.rsc.org/chemcomm
Cylindradines A and B, members of the polycyclic pyrrole-imidazole
alkaloids (PIAs), are the only congeners bearing a 3-carbamoylpyrrole
unit among the PIAs. In this communication, we described a total
synthesis of (+)-cylindradine A based on intramolecular Friedel–Crafts
type cyclization of pyrrole-aldehyde and oxidative cyclization of tricyclic
pyrrolopyrrolidine-guanidine with hypervalent iodine to construct the
cyclic guanidine structure including the N,N0-aminal moiety.
Polycyclic pyrrole-imidazole alkaloids (PIAs) are oroidin-derived
marine natural products1 with diverse and complex architec-
tures. They include monomeric oroidins as shown in Fig. 1, and
dimeric and tetrameric oroidins as exemplified by Palau’amine,
massadine, axinellamine (dimeric), and stylissadine A (tetrameric).2
Most of these alkaloids show multiple biological activities, including
antitumor and immunosuppressive activities, and adrenoceptor-
agonistic activity. Consequently, there has been considerable
synthetic interest,3 and total syntheses of several monomeric
and dimeric PIAs have been reported.4
Fig. 1 Structures of oroidin-derived tetracyclic pyrrole-imidazole alkaloids
(PIAs).
Recently, Kuramoto and co-workers isolated the (+)- and
(ꢀ)-enantiomers of cylindradines A (1) and B (2), which are PIAs of
a structurally novel type, from marine sponge Axinella cylindratus.5
All previously reported PIAs contain a 2-carbamoylpyrrole
unit, but cylindradines 1 and 2 possess an unusual 3-carb-
amoylpyrrole unit (4-carbamoylpyrrole based on the numbering
of cylindradines), formation of which cannot be explained
in terms of the usual biosynthetic pathways of PIAs from
oroidins.6 Kuramoto and co-workers thus proposed a unique
biosynthetic pathway for cylindradines involving an ‘‘ipso’’
rearrangement process from 9 via 8 (Scheme 1).5,6 We already
had synthetic interest in PIA-related alkaloids,7 and we were
fascinated by the extraordinary structure of cylindradines. We
Scheme 1 Proposed biosynthetic pathway to cylindradines via ‘‘ipso’’
rearrangement.
therefore designed a synthetic strategy for these compounds, and in this communication, we describe the first total synthesis
of (+)-cylindradine A (1).
Cylindradine A (1) possesses a characteristic N,N0-aminal moiety
Department of Biotechnology and Life Science, Faculty of Technology,
Tokyo University of Agriculture and Technology, Naka-cho 2-24-16, Koganei,
in the cyclic guanidine structure, like other members of monomeric
PIA families, such as phakellins and phakellstatins, and construc-
Tokyo 184-8588, Japan. E-mail: Knaga@cc.tuat.ac.jp; Fax: +81-42-388-7295;
Tel: +81-42-388-7295
tion of this aminal structure in an enantioselective manner is one
of the challenging issues4d,e,7 to be addressed for the synthesis of
† Electronic supplementary information (ESI) available: Experimental details;
1H and 13C NMR spectra of all products. See DOI: 10.1039/c4cc00137k
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Scheme 2 Synthesis of phakellins and phakellstatin by enamide-type
Overman rearrangement.7
Scheme 4 Synthetic plan for tetracyclic guanidine 22 via oxidative cycli-
zation of 20.
Scheme 3 Synthetic approach to 15 via enamide-type Overman
rearrangement.
Scheme 5 Synthesis of tricyclic structure by intramolecular Friedel–Crafts
type cyclization.
cylindradines. In our previous synthetic work on phakellins and
phakellstatins, we adopted an enamide-type Overman rearrange-
ment reaction7,8 to construct the N,N0-aminal moiety at C10 in
optically active form (10 to 12 in Scheme 2). Thus, we aimed to to give amide 27 (92% yield), whose N-Ts protective group was
apply a similar approach for the synthesis of cylindradine A (1) converted to N-Boc by deprotection with potassium hydroxide in
(Scheme 3). We planned to use an enamide-type Overman rearrange- methanol followed by reaction with (Boc)2O and triethylamine.12
ment reaction of 14 to construct the N,N0-aminal structure at C10 by The tert-butyldimethylsilyl (TBS) ether was removed with n-tetra-
transferring the chirality at C12 in 14, which would lead to the butylammonium fluoride (TBAF), and the resulting alcohol was
stereoselective construction of the cyclic guanidine moiety in cylin- oxidized with IBX to give aldehyde 28 in 65% yield from 27 (4 steps).
dradine A (1). However, when we examined the Overman rearrange- With the pyrrole-aldehyde 28 in hand, we investigated the construc-
ment process (14 to 15), we could not even obtain the necessary tion of tricyclic alcohol 29 by acid-promoted intramolecular Friedel–
precursor 16 (Scheme 3). Thus, we examined installation of the Crafts type cyclization. After investigation of various acidic
double bond using the aminal 17, which was obtained by IBX conditions, the Friedel–Crafts adduct 29 was obtained in 82%
oxidation of 18.9 In this reaction, however, unexpected dimerization yield as a diastereomeric mixture in a ratio of ca. 7:1 (29a :29b) by
reaction took place, and dimer 19 was obtained in 58% yield as a treatment with 0.1 equivalent of camphorsulfonic acid (CSA).13
single stereoisomer. This reaction was considered to proceed via a The stereochemistry at C6 in 29 was confirmed by examination of
1
homocoupling reaction between the enamine and enone moieties in the H NMR signals, especially the coupling constants between
16, which was generated in situ from 17 by treatment with methane- H6 and H10 (i.e., Ha and Hb in 29a). The diastereomers were easily
sulfonyl chloride and triethylamine. Unfortunately, we could not separated by silica gel column chromatography.
isolate either enone 16 or allylic alcohol 13 because of their instability.
Next, guanidine bearing different protective groups was
Next, we developed an alternative strategy to construct the cyclic stereoselectively introduced at C6 in 29a to give 32a–c
guanidine 22 from 20 under oxidative conditions via iminium (Scheme 6). Thus, stereoselective azidation of 29a with diphenyl-
cation 21, as originally demonstrated by Wang and Romo in their phosphoryl azide (DPPA) in the presence of 1,8-diazabicyclo-
synthesis of (+)-dibromophakellin (3) (Scheme 4).4e To obtain [5.4.0]undec-7-ene (DBU) (29% yield),14 followed by reduction of
precursor 20 for the oxidative cyclization, we planned to use the resulting azide under Staudinger’s conditions using trimethyl-
intramolecular Friedel–Crafts type reaction of 24 bearing aldehyde phosphine, gave amine 30. Then, guanidines 32a–c were synthe-
and 4-carbamoylpyrrole functional groups.
sized by reaction with bis-Boc-protected pseudo thiourea 31a,
Synthesis of tricyclic alcohol 29 via intramolecular Friedel–Crafts S-methyl N-(4-methoxyphenylsulfonyl)carbonchloroimidothioate
type reaction10 is depicted in Scheme 5. Condensation reaction of (31b),15 and S-methyl N-(2,2,2-trichloroethoxysulfonyl)carbon-
L-prolinol 25 with N-Ts-protected pyrrole-3-carboxylic acid 2611 was chloroimidothioate (31c)16 in 60, 50, and 53% yield, respectively.
carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Next, oxidative cyclization reaction of 32a–c to form tetra-
(EDCI) in the presence of N,N-dimethyl-4-aminopyridine (DMAP) cyclic compounds 33 was examined using hypervalent iodine
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Scheme 7 Synthetic approaches to cylindradine A (1) from 33c.
Scheme 6 Synthesis of guanidines 32 for oxidative cyclization reaction.
Table 1 Oxidative cyclization of 32 into 33
Entry Substrate R1
R2
Oxidant Temp. (1C) 33a–c (yield %)
1
2
3
4
5
6
7
32a
32a
32b
32b
32c
32c
32c
Boc Boc PIDA
Boc Boc PIFA
rt
rt
65
65
65
65
65
Decomp.
Decomp.
19
30
60
15
Decomp.
Mbs
Mbs
Tces
Tces
Tces
H
H
H
H
H
PIDA
PIFA
PIDA
PIFA
FPIFA
Scheme 8 Synthesis of (+)-cylindradine A (1) from 33c.
Boc groups were removed with TFA to afford (+)-cylindradine A
(1) in 58% yield, based on the recovered starting 37.19
In summary, we present the first synthesis of (+)-cylindradine
A (1), a PIA that possesses an unusual 3-carbamoylpyrrole tetra-
cyclic structure. Intramolecular Friedel–Crafts type cyclization of
pyrrole-aldehyde 28 and oxidative cyclization of guanidine 32c
with hypervalent iodine proved to be effective for stereoselective
construction of the cyclic guanidine structure in 1.
We thank Prof. Dr Makoto Kuramoto (Ehime University) for
his helpful suggestions concerning purification of cylindradine
A (1). We appreciate the reviewers for their valuable discussions
about the biosynthetic pathway of cylindradines. This study was
supported in part by a Grant-in-Aid for Challenging Exploratory
Research from JSPS (No. 21655060) and a Grant-in-Aid for
Scientific Research on Innovative Areas ‘‘Advanced Molecular
Transformations by Organocatalysts’’ from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
reagents (Table 1). In the case of 32a with two Boc protective
groups on guanidine, decomposition of the substrate was observed
upon reaction with either PIDA (phenyliodine diacetate) or PIFA
(phenyliodine bistrifluoroacetate) in the presence of magnesium
oxide as a base (entries 1 and 2). Mono-Mbs-protected 32b gave 33b
in 19% and 30% yield with PIDA and PIFA, respectively (entries 3
and 4). The best result was obtained with 32c: tetracyclic guanidine
33c was obtained in 60% yield by using PIDA in the presence of
magnesium oxide at 65 1C in acetonitrile (entry 5). Unfortunately,
lower yield or decomposition of the substrate was observed when
more reactive PIFA and FPIFA (pentafluorophenyliodine bistri-
fluoroacetate),17 respectively, were used (entries 6 and 7).
Completion of cylindradine A (1) synthesis from tetracyclic
guanidine 33c requires bromination at the C2 and C3 positions,
and deprotection of the Tces and Boc groups. Bromination or
deprotection of 33 took place to afford 34 or 35 in 60% and 98%
yield, respectively, but deprotection and bromination of the
resulting 34 or 35 (34 to 1, or 35 to 1, Scheme 7) was
unsuccessful. In particular, attempts to remove the Tces group
from 34 resulted in debromination.
Notes and references
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Thus, we decided to change the protective group in 33c from
Tces to a Boc group (Scheme 8). Reaction of 33c with hydrogen in
the presence of Pd(OH)2 in a mixed solvent system of methanol–
ethyl acetate followed by reaction with Boc-ON18 and triethylamine
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bicarbonate to give bis-Boc cylindradine A (37). Finally, the two
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¨
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quite labile to acids. During the concentration process using a rotary
evaporator, compound 1 was gradually decomposed even though a
small amount of acids was observed on TLC and NMR. To avoid the
decomposition of 1 during the concentration process, the freeze-dry
technique was essential. We deeply thank Prof. Makoto Kuramoto
(Ehime University) for his very helpful suggestions for concentration
and purification of cylindradine A (1).20 Detailed procedures for the
purification of 1 are provided in ESI†.
¨
R. A. Rodriguez, D. P. O. Malley, T. Gaich, M. Kock and P. S. Baran,
J. Am. Chem. Soc., 2011, 133, 14710–14726.
5 M. Kuramoto, N. Miyake, Y. Ishimaru, N. Ono and H. Uno, Org. Lett.,
2008, 10, 5465–5468.
6 A. Al-Mourabit, M. A. Zancanella, S. Tilvi and D. Romo, Nat. Prod. 20 The 1H and 13C NMR data for the synthetic cylindradine A (1) contain
Rep., 2011, 28, 1229–1260.
small amounts of impurities because of its acid-labile nature.
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This journal is ©The Royal Society of Chemistry 2014