Total Synthesis of Proposed Structure of Yuremamine and All Diastereomers Using [3+2]-Cycloaddition of Platinum-Containing Azomethine Ylide

Article abstract of DOI:10.1002/asia.201500491

Total synthesis of the proposed structure of yuremamine has been achieved for the first time based on the intermolecular [3+2]-cycloaddition reaction of the platinum-containing azomethine ylide. All the possible diastereomers of yuremamine were also synthesized via the common intermediate. Through these syntheses, it was confirmed that the proposed structure of yuremamine and the diastereomers differ from the natural product. The total synthesis of the proposed structure of yuremamine and its diastereomers has been achieved based on the [3+2]-cycloaddition reaction of the platinum-containing azomethine ylide. Its basic core skeleton, pyrrolo[1,2-a]indole skeleton, was efficiently constructed by this method at an early stage of the synthesis and a straightforward, short-step synthesis of the target products has been achieved.

Full text of DOI:10.1002/asia.201500491

DOI: 10.1002/asia.201500491
Communication
Total Synthesis
Total Synthesis of Proposed Structure of Yuremamine and All
Diastereomers Using [3+2]-Cycloaddition of Platinum-Containing
Azomethine Ylide
Tomoya Ohyama,[a] Masako Uchida,[a] Hiroyuki Kusama,[b] and Nobuharu Iwasawa*[a]
Abstract: Total synthesis of the proposed structure of yur-
emamine has been achieved for the first time based on
the intermolecular [3+2]-cycloaddition reaction of the
platinum-containing azomethine ylide. All the possible
diastereomers of yuremamine were also synthesized via
the common intermediate. Through these syntheses, it
was confirmed that the proposed structure of yurema-
mine and the diastereomers differ from the natural prod-
uct.
Figure 1. Proposed and revised structures of yuremamine.
Yuremamine was isolated from the root bark of Mimosa tenui-
flora and was reported to have pyrrolo[1,2-a]indole skeleton
1,[1] which is commonly seen in biologically active compounds
such as mitomycins, flinderoles, isoborreverins, and PKC inhibi-
tor JTT-010.[2] We have been carrying out research on the total
synthesis of this natural product based on the [3+2]-cycloaddi-
tion of platinum-containing azomethine ylides generated from
o-alkynylanilines with a catalytic amount of platinum(II) chlo-
ride, which was developed in our laboratory.[3] In this study, we
report the synthesis of the proposed structure of yuremamine
2, along with its three diastereoisomers, and this resulted in
Scheme 1. [3+2] cycloaddition reaction of platinum-containing azomethine
the conclusion that the proposed structure of yuremamine dif-
fers from the natural product. Quite recently, Calvert and
Sperry reported the structural revision of this natural product
based on their bioinspired synthetic study,[4] which also coin-
cides with our conclusion (Figure 1).
ylides.
gen to the alkyne moiety, generating the platinum-containing
azomethine ylides 5. The electron-withdrawing nature of the
platinum–carbene moiety of 5 decreases the LUMO level of
the ylide and promotes [3+2]-cycloaddition with electron-rich
alkenes to afford the tricyclic carbene complex intermediate 6,
and finally, 1,2-migration of the substituent R2 takes place to
give the pyrrolo[1,2-a]indole derivatives 7 with regeneration of
the platinum catalyst. This reaction can be applied to a broad
range of substrates and is expected to be useful for the syn-
thesis of biologically active compounds bearing the pyrro-
lo[1,2-a]indole skeleton.
We previously reported an efficient method for the construc-
tion of the pyrrolo[1,2-a]indole skeleton through the intermo-
lecular [3+2]-cycloaddition of platinum-containing azomethine
ylides (Scheme 1).[3,5] Treatment of the imine derivatives 4 de-
rived from o-alkynylanilines with a catalytic amount of platinu-
m(II) chloride promotes nucleophilic attack of the imino nitro-
[a] T. Ohyama, M. Uchida, Prof. Dr. N. Iwasawa
Department of Chemistry
We then decided to apply our method to the total synthesis
of the proposed structure of yuremamine.[6] The synthetic plan
is shown in Scheme 2. The basic core skeleton of 2 would be
constructed by platinum-catalyzed [3+2]-cycloaddition of
imine 8 and vinyl ether and the cycloadduct 9 would be easily
converted into the corresponding ketone 10. Stereoselective
a-oxygenation of the carbonyl moiety and introduction of a re-
sorcinol unit followed by stereoselective reduction of the re-
Tokyo Institute of Technology
2-12-1, O-okayama, Meguro-ku, Tokyo, 152-8551 (Japan)
E-mail: niwasawa@chem.titech.ac.jp
[b] Prof.Dr. H. Kusama
Department of Chemistry, Faculty of Science
Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500491.
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Communication
with its phenolic hydroxy groups
protected as allyl ether, was
easily prepared as follows: Sono-
gashira coupling of the commer-
cially available o-iodoaniline with
4-triisopropylsiloxybut-1-yne fol-
lowed by condensation of the
resulting aniline with 3,4,5-trially-
loxybenzaldehyde afforded 8,
which was directly used for the
[3+2]-cycloaddition
reaction
without purification. Treatment
of the crude imine 8 with a cata-
lytic amount of platinum(II) chlo-
ride in the presence of tert-butyl
vinyl ether at 508C gave the de-
sired tricyclic indole derivative 9
in 84% yield as a diastereomeric
mixture (d.r.=7:3). Removal of
the tert-butyl group under acidic
conditions together with depro-
tection of the triisopropylsilyl
(TIPS) ether and MnO2 oxidation
of the resulting secondary alco-
hol followed by reprotection of
the primary hydroxy group with
Scheme 2. Synthetic plan.
tert-butyldimethylsilyl
chloride
(TBSCl) gave ketone 10 in 55%
yield in 3 steps. a-Oxygenation
of the ketone with Davis’ oxaziri-
dine[7] proceeded stereoselec-
tively to give secondary alcohol
11 as a single diastereomer and
the resultant hydroxy group was
protected using triethylsilyl tri-
fluoromethanesulfonate
(TESOTf). Introduction of the
allyl-protected resorcinol unit to
the ketone 13 smoothly pro-
ceeded to give the adduct 14 as
a diastereomeric mixture, and
then the stereoselective removal
of the resulting tertiary hydroxy
group was examined. After sev-
eral experiments, it was found
that treatment of 14 with an
excess amount of triethylsilane
in the presence of BF3·OEt2 at
Scheme 3. Total Synthesis of the proposed structure of yuremamine : a) PtCl2 (5 mol%), tBu vinyl ether (9.0 equiv),
toluene, 4 Š MS, 508C, 5 h, 84% (dr=7 :3) (2 steps from 2-(4-triisopropylsiloxybut-1-ynyl)aniline); b) TsOH·H2O
(1.7 equiv), acetone/water=2:1, RT, 1 day; c) MnO2 (20 equiv), CH2Cl2, RT, 2 days; d) TBSCl (3.0 equiv), imidazole
(5.0 equiv), DMF, RT, 2 h, 55% (3 steps); e) KHMDS (1.5 equiv), Davis’ oxaziridine (1.2 equiv), THF, À1008C, 1 h;
f) TESOTf (1.5 equiv), 2,6-lutidine (5.0 equiv), CH2Cl2, À788C, 1 h, 68% (2 steps); g) 1-bromo-2,4-bis(prop-2-en-1-
yloxy)benzene (3.0 equiv), nBuLi (3.0 equiv), THF, À1008C, 1 h, 89% (dr=88:12); h) BF3·OEt2 (1.1 equiv), Et3SiH
(30 equiv), CH2Cl2, À408C ~08C, 2 h; i) TBAF (12 equiv), THF, RT, 1 day, 91% (d.r.=87:13 (2 steps); j) 2-mesitylene-
sulfonyl chloride (1.1 equiv), 1,4-diazabicyclo[2.2.2]octane (DABCO) (2.2 equiv), CH2Cl2, 08C, 1 h; k) HNMe2 (2.0m
MeOH solution), MeOH, 408C, 2 h, 25% (2 steps); l) Ru catalyst (20 mol%), TFA (10 equiv), MeOH, RT, 1 day, 65%
(yield determined from H1 NMR spectroscopy).
sulting tertiary hydroxy group would give rise to diol 12. Final-
ly, substitution of the primary hydroxy group with a dimethyla-
mino group and deprotection of the five protecting groups on
the phenolic oxygen atoms would complete the synthesis of
the target compound 2.
According to the above synthetic plan, we first examined
the construction of the pyrrolo[1,2-a]indole skeleton
(Scheme 3). The substrate for the [3+2]-cycloaddition reaction,
À408C to 08C efficiently promoted the desired reaction and
the corresponding diol 12 was obtained in high yield with
good stereoselectivity (d.r.=87:13) after removal of the silyl
group by tetra-n-butylammonium fluoride (TBAF). The two dia-
stereomers were easily separated by silica-gel chromatography
and the relative stereochemistry of the major isomer 12 was
unambiguously determined to be the same as that of the
target compound 2 by X-ray crystallographic analysis (see the
Supporting Information). Then the primary hydroxy group of
N-[2-(4-triisopropylsiloxybut-1-ynyl)phenyl]imine derivative
8
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the major isomer 12 was selectively converted into a sulfonate
(Scheme 5),[15] and X-ray crystallographic analyses of the re-
maining three stereoisomers were successfully achieved to
assign the relative stereochemistry unambiguously (see the
Supporting Information).
ester and a substitution reaction with dimethylamine gave di-
1
methylamino derivative 15. Judging from the H NMR spectra
of the crude materials, this transformation proceeded in good
yield (ca. 70%), however, the product 15 was rather unstable
under purification conditions and the yield after silica-gel chro-
matography was 25% over 2 steps from 12. Removal of the
five allyl groups was also problematic because the highly oxy-
genated aromatic moieties of 2 were unstable toward oxygen
and basic conditions. After several examinations, we finally
found that the use of Kitamura’s ruthenium catalyst 16 under
acidic conditions[8,9] cleanly deprotected the allyl groups. The
product 2 was too labile to be isolated and decomposed even
under the reported isolation procedure of the natural prod-
uct.[10] Only Diol-silica gel chromatography allowed the isola-
Removal of the allyl groups of (1R*,2S*)-15 and (1R*,2R*)-15
smoothly proceeded again with Kitamura’s ruthenium catalyst,
although the deprotected (1R*,2S*)-2 and (1R*,2R*)-2 were not
isolated in completely pure form owing to their instability
(Scheme 6).[14]
Deprotection of (1S*,2S*)-15 was more problematic and was
achieved only with phenylsilane and a catalytic amount of
[Pd(PPh3)4].[16] The obtained product (1S*,2S*)-2 was exception-
ally unstable and the NMR spectrum was as a mixture of sever-
al unidentified products (Scheme 7).
Disappointingly, the 1H NMR spectra of the synthesized
three stereoisomers were not consistent with the reported
data either. Thus we concluded that the structure of yurema-
mine is different from the initially reported one, which is con-
sistent with the recent report on the structural revision by Cal-
vert and Sperry.[4]
1
tion of 2 in nearly pure form in our hands. However, H- and
13C-NMR spectra of the synthetic sample were apparently dif-
ferent from the reported data (Figure 2),[11] suggesting the pro-
In conclusion, the total synthesis of the proposed structure
of yuremamine was achieved in 14 steps from a commercially
available material based on the [3+2]-cycloaddition reaction of
the platinum-containing azomethine ylide. The spectral data of
the synthetic sample along with its diastereomers were differ-
ent from the reported one, supporting the recent report by
Calvert and Sperry that yuremamine has a flavonoidal skeleton.
We believe that this synthetic study demonstrates the utility of
our methodology for syntheses of highly-functionalized pyrro-
lo[1,2-a]indole derivatives.
Figure 2. Comparison of 1H NMR spectra measured in [D4]MeOH (the au-
thentic sample of yuremamine (above) and the synthetic sample 2 (below)).
posed structure of yuremamine
was not correct. At this stage,
we thought of the possibility
that the reported relative stereo-
chemistry on the three contigu-
ous stereogenic centers might
be assigned wrongly.
We then tried to synthesize
the other possible diastereomers
starting from the synthetic inter-
Scheme 4. Synthesis of Stereoisomers of Diol 12: a) TBSOTf (1.2 equiv), 2,6-lutidine (5.0 equiv), CH2Cl2, À788C,
76% b) DCC (4.5 equiv), pyridine-TFA (0.75 equiv), DMSO (45 equiv), toluene, RT,1.5 h; c) NaBH4 (3.0 equiv),
EtOH,08C, 1 h; d) TBAF (12 equiv), THF, RT, 1 day, (1S*, 2S*)-12 28%, (1R*, 2S*)-12 19%, (1R*, 2R*)-12 30%
(3 steps).
mediate 12 shown in Scheme 3.
Selective oxidation of the secon-
dary alcohol of 12 under Pfitz-
ner–Moffart conditions proceed-
ed with epimerization to give
ketone 17 as a mixture of two diastereomers.[12] For-
tunately, comparable amounts of all the other three
stereoisomers of the starting alcohol 12 were ob-
tained by the reduction of this diastereomer mixture
with NaBH4 (Scheme 4).[13,14] These stereoisomers
were separable by silica-gel chromatography and
subsequent amination reactions were carried out in-
dependently.
Introduction of the dimethylamino group was ac-
complished through an almost identical procedure Scheme 5. Synthesis of diastereomers of the amine 15.
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[3] a) H. Kusama, J. Takaya, N. Iwasawa, J. Am. Chem. Soc. 2002,
124, 11592–11593; b) J. Takaya, H. Kusama, N. Iwasawa,
Chem. Lett. 2004, 33, 16–17; c) H. Kusama, Y. Miyashita, J.
Takaya, N. Iwasawa, Org. Lett. 2006, 8, 289–292; d) J. Takaya,
Y. Miyashita, H. Kusama, N. Iwasawa, Tetrahedron 2011, 67,
4455–4466.
[4] M. B. Calvert, J. Sperry, Chem. Commun. 2015, 51, 6202–
6205.
[5] Other methods for constructing pyrrolo[1,2-a]indole skele-
ton, see: a) R. M. Wilson, R. K. Thalji, R. G. Bergman, J. A.
Ellman, Org. Lett. 2006, 8, 1745–1747; b) M. Tanaka, M. Ubu-
kata, T. Matsuo, K. Yasue, K. Matsumoto, Y. Kajimoto, T. Ogo,
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C. Liu, L. Wang, R. Wang, Chem. Eur. J. 2010, 16, 440–444.
[6] For synthetic studies of yuremamine, see: a) M. B. Johansen,
M. A. Kerr, Org. Lett. 2008, 10, 3497–3500; b) W.-B. Liu, X.
Zhang, L.-X. Dai, S.-L. You, Angew. Chem. Int. Ed. 2012, 51,
5183–5187; Angew. Chem. 2012, 124, 5273–5277; c) D. H.
Dethe, R. Boda, S. Das, Chem. Commun. 2013, 49, 3260–3262.
[7] L. C. Vishwakarma, O. D. Stringer, F. A. Davis, Org. Synth. 1988, 66, 203.
[8] a) H. Saburi, S. Tanaka, M. Kitamura, Angew. Chem. Int. Ed. 2005, 44,
1730–1732; Angew. Chem. 2005, 117, 1758–1760; b) S. Tanaka, H.
Saburi, M. Kitamura, Adv. Synth. Catal. 2006, 348, 375–378.
[9] In the absence of acid, the ruthenium catalyst was deactivated due to
the basic dimethylamino group of 15.
Scheme 6. Synthesis of (1R*,2S*)- and (1R*,2R*) À2.
[10] The natural yuremamine was isolated by reversed phase HPLC (water:a-
cetonitrile:trifluoroacetic acid=80:20:0.1),[1] but the synthetic sample 2
decomposed under the same purification conditions.
Scheme 7. Synthesis of (1S*,2S*)-2.
[11] The spectrum shown above in Figure 2 was kindly provided by Prof.
Vepsäläinen.
[12] D. P. Bradshaw, D. W. Jones, F. M. Nongrum, J. Chem. Soc. Perkin Trans.
1 1991, 19–23.
[13] In this reaction, it was confirmed that (1S*)-ketone 17 was selectively
reduced to (1S*,2S*)-alcohol 12, while reduction of (1R*)-ketone gave
a mixture of (1R*,2R*)- and (1R*,2S*)-isomers 12.
[14] Hereafter, the relative stereochemistry at only C1 and C2 positions is
described on the basis of the (3S*)-isomer for simplicity.
[15] Epimerization occurred during the reaction in case of (1S*,2S*)- and
(1R*,2R*)-isomers 12, although diastereomers 15 could be separated by
silica-gel chromatography. Probably, isomerization took place at the C1
position through the mechanism shown below.
Experimental Section
The synthetic procedures and characterization of the compounds
studied herein can be found in the Supporting Information.
CCDC 1400491 (14), 1400492 ((1R*, 2S*)-15), and 1400493 ((1S*,
2S*)-15) contain the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
Acknowledgements
We are grateful to Professor Jouko Vepsäläinen (Univ. of East-
1
ern Finland) for providing us with the H and 13C NMR spectra
and an authentic sample of yuremamine. We would like to
thank Prof. Kitamura (Univ. of Nagoya) for providing the ruthe-
nium catalyst and giving important suggestions on the reac-
tion conditions for the deallylation reaction using this catalyst.
This research was partly supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan.
Keywords: [3+2] cycloaddition · azomethine ylide · platinum ·
total synthesis · yuremamine
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Manuscript received: May 12, 2015
Accepted Article published: June 23, 2015
Final Article published: July 14, 2015
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