Synthesis of maremycins A and D1 via cycloaddition of a nitrone with (E)-3-ethylidene-1-methylindolin-2-one

Article abstract of DOI:10.1021/ol800515w

A concise synthesis of maremycins A and D₁ has been accomplished via cycloaddition of a chiral cyclic nitrone with (E)-3-ethylidene-1- methylindolin-2-one as a key step. This synthesis clarifies the stereochemistry of the maremycins and is suitable for large-scale synthesis for biological screening.

Full text of DOI:10.1021/ol800515w

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2043-2046
Synthesis of Maremycins A and D1 via
Cycloaddition of a Nitrone with
(E)-3-Ethylidene-1-methylindolin-2-one
Tohru Ueda, Mitsuhide Inada, Iwao Okamoto, Nobuyoshi Morita, and
Osamu Tamura*
Showa Pharmaceutical UniVersity, 3-3165 Higashi-tamagawagakuen,
Machida, Tokyo 194-8543, Japan
tamura@ac.shoyaku.ac.jp
Received March 7, 2008
ABSTRACT
A concise synthesis of maremycins A and D1 has been accomplished via cycloaddition of a chiral cyclic nitrone with (E)-3-ethylidene-1-
methylindolin-2-one as a key step. This synthesis clarifies the stereochemistry of the maremycins and is suitable for large-scale synthesis for
biological screening.
Maremycins A (1) and B (2) are diketopiperazine alkaloids
isolated from the culture broth of marine Streptomyces
species B 9173 (Figure 1).1 The stereochemistries of 1 and
2 were tentatively proposed to be as depicted in Figure 1 on
the basis of molecular mechanics calculations and spectro-
scopic data. An inseparable 1:1 mixture of maremycins C1
(3) and C2 (4) was obtained from Streptomyces sp. GT
051237, together with an inseparable 3:1 mixture of mare-
mycins D1 (5) and D2 (6).2 The stereochemistries of 3 and 4
were deduced by comparison of the NMR spectroscopic data
with those of 2, while the stereostructures of 5 and 6 were
assigned by comparison of the spectra with those of 1 and
2. Therefore, confirmation of the stereostructure of mare-
mycins A (1) and B (2) would also establish the stereochem-
Figure 1. Proposed structures of maremycins.
istries of 3-6.
We have now accomplished the first synthesis of mare-
mycins A (1) and D1 (5) and confirmed their stereostructures
to be as depicted in Figure 1.
The retrosynthetic analysis was as follows (Scheme 1).
Maremycin D1 (5) may be obtained from maremycin A (1)
by syn-elimination of a sulfoxide derived from 1. Discon-
nection of the diketopiperazine ring of 1 provides two amino
acids, S-methyl-L-cysteine (8) and an unusual amino acid 7
that possesses three contiguous stereogenic centers, including
(1) Balk-Bindseil, W.; Helmke, E.; Weyland, H.; Laatsch, H. Liebigs
Ann. 1995, 1291–1294.
(2) Tang, Y.; Sattler, I.; Thiericke, R.; Grabley, S. Eur. J. Org. Chem.
2001, 261–267.
10.1021/ol800515w CCC: $40.75
Published on Web 04/16/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis of Maremycin A (1)
Scheme 2. Cycloaddition of Indolinone 9 with Nitrone 10
a tertiary hydroxyl group at the 3-position (indoline number-
ing). The latter amino acid 7 would be available by reductive
cleavage of the N-O bond of spiro-(indoline isoxazolidine)
A, which might be formed by 1,3-dipolar cycloaddition of
nitrone B with (3E)-3-ethylidene-1-methylindolin-2-one (9).
Unlike azomethine ylides, a nitrone rarely undergoes cy-
cloaddition with a 2-oxoindolin-3-ylidene, probably because
of low reactivity.3–6 However, we considered that the nitrone
template 10,7a,b obtained from (S)-phenylglycinol within four
steps, corresponding to B might undergo cycloaddition with
9 because of the higher reactivity of 10 as a 1,3-dipole,
compared with usual nitrones.7
Our investigation was initiated by preparation of (E)-3-
ethylidene-1-methylindolin-2-one (9) from N-methylisatin
(11) using Lo´pez-Alvarado’s conditions (Scheme 2).8 The
crucial cycloaddition of 3-ethylideneindolin-2-one 9 with
cyclic nitrone 10 was next examined. The cycloaddition
proceeded in toluene at 60 °C for 48 h to give a 22:78
mixture of cycloadduct 12 and its regioisomer 13 in 94%
yield. It should be noted that only two of the possible eight
isomers were obtained, suggesting that the reaction occurs
via less hindered side attack of nitrone 10 with the endo-
oriented carbonyl group of the dipolarophile 9 (see C and D
in Scheme 2, as well as eq 1 in Scheme 3).7d The
stereostructures of cycloadducts 12 and 13 were determined
by X-ray diffraction analysis (for 12) and examination of
the NOE difference spectra (for 13) (Supporting Information).
It is worth noting that cycloadduct 12 has all elements,
including the three contiguous stereogenic centers, required
for the synthesis of amino acid 7.
Unfortunately, the desired cycloadduct 12 was the minor
isomer, so we further examined the reaction conditions. To
shorten the reaction time, neat conditions at various reaction
temperatures were first investigated (Table 1, entries 1-3).
Unexpectedly, it was found that higher reaction temperature
gave a higher ratio of cycloadduct 13. Thus, reaction of
nitrone 10 with 9 at -25 °C afforded a 47:53 mixture of 12
and 13 (entry 1), whereas reaction at 60 °C gave a 22:78
mixture (entry 3). Since a kinetically controlled reaction
(3) Raunak reported that N-phenyl-C-substituted phenyl nitrones undergo
cycloaddition with ethyl 2-oxo-3(2H)-indolylidene acetate under microwave
irradiation conditions. The use of conventional thermal conditions was much
less effective. See: Raunak, R.; Kumar, V.; Mukherjee, S.; Poonam; Prasad,
A. K.; Olsen, C. E.; Schaeffer, S. J. C.; Sharma, S. K.; Watterson, A. C.;
Errington, W.; Parmar, V. S. Tetrahedron 2005, 61, 5687–5697. To our
knowledge, this is the only report that refers to cycloaddition of a nitrone
with an indolyl-3-ylidene-2-one compound
.
(4) For selected examples of cycloaddition of azomethine ylide with
3-ylideneindolin-2-ones, see: (a) Palmisano, G.; Annunziata, R.; Papeo, G.;
Sisti, M. Tetrahedron: Asymmetry 1996, 7, 1–4. (b) Nyerges, M.; Gajdics,
L.; Szollosy, A.; Toke, L. Synlett 1999, 111–113. (c) Sebahar, P. R.;
Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666–5667. (d) Muthusamy,
S.; Babu, S. A.; Nethaji, M. Tetrahedron 2003, 59, 8117–8127. (e) Onishi,
T.; Sebahar, P. R.; Williams, R. M. Org. Lett. 2003, 5, 3135–3137. (f) Lo,
M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L.
J. Am. Chem. Soc. 2004, 126, 16077–16086. (g) Ding, K.; Wang, G.;
Deschamps, J. R.; Parrish, D. A.; Wang, S. Tetrahedron Lett. 2005, 46,
5949–5951. (h) Babu, A. R. S.; Raghunathan, R. Tetrahedron Lett. 2007,
48, 6809–6813
.
(5) For examples of nitrile oxides, see: (a) El-Ahl, A. A. S. Pol. J. Chem.
1997, 71, 27–31. (b) Risitano, F.; Grassi, G.; Foti, F.; Bruno, G.; Rotondo,
A. Heterocycles 2003, 60, 857–863
.
(6) For examples of trimethylenemethane, see: (a) Trost, B. M.; Cramer,
N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086–3087. (b) Trost,
B. M.; Cramer, N.; Silverman; Steven, M. J. Am. Chem. Soc. 2007, 129,
12396–12397
.
(7) (a) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.; Miyawaki,
T.; Sakamoto, M. Chem. Commun. 1996, 1861–1862. (b) Tamura, O.;
Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.; Kikuchi, M.; Miyawaki,
T.; Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org. Chem.
2000, 65, 8544–8551. (c) Tamura, O.; Shiro, T.; Toyao, A.; Ishibashi, H.
Chem. Commun. 2003, 2678–2679. (d) Tamura, O.; Shiro, T.; Ogasawara,
M.; Toyao, A.; Ishibashi, H. J. Org. Chem. 2005, 70, 4569–4577. (e) See
also Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett. 1998,
39, 6819–6822. (f) Long, A.; Baldwin, S. W. Tetrahedron Lett. 2001, 42,
5345.
(8) Lo´pez-Alvarado, P.; Avendan˜o, C. Synthesis 2002, 104–110.
Org. Lett., Vol. 10, No. 10, 2008
2044

3-ethylideneindolin-2-one 9 (62%) and cycloadduct 15 of
methacrylate 14 (62%), along with recovery of 13 (38%)
(eq 3). Formation of 15 from 12 or 13 would involve
regeneration of nitrone 10 and indolinone 9. Thus, heating
12 or 13 would cause cycloreversion to indolinone 9 and
nitrone 10, which, in turn, could undergo re-cycloaddition
with methacrylate 14 to provide 15. These facts (eqs 2 and
3) also suggest that cycloadduct 13 may be thermodynami-
cally more stable than cycloadduct 12 because cycloadduct
13 exhibited lower cycloreversion reactivity on heating than
did 12.11 Therefore, we considered the conversion of
regioisomer 13 to the desired cycloadduct 12 via cyclorever-
sion-re-cycloaddition (eq 4). When a mixture of regioisomer
13 and ethylideneindolinone 9 was heated in toluene,
cycloreversion-re-cycloaddition occurred to give the desired
cycloaddition product 12 in 10% yield accompanied with
recovery of regioisomer 13 in 87% yield and ethylidenein-
dolinone 9 (90%). Thus, the yield of the desired cycloadduct
12 can be improved by recycling this reaction.
Table 1. Cycloaddition of Nitrone 10 with 3-Ethylidene-1-
methylindolin-2-one (9)
entry
solvent
temp (°C)
time (h)
12/13c (yield, %)d
1a
2a
3a
4a
5a
6b
7b
8b
neat
neat
neat
CH3CN
THF
MeOH
hexane
hexane
-25
rt
60
rt
rt
rt
11
11
11
11
11
11
8
47:53 (40)
45:55 (93)
22:78 (96)
42:58 (46)
50:50 (54)
26:74 (55)
47:53 (quant)
50:50 (quant)
rt
50
2.5
a Nitrone 10 (1 equiv) and ethylideneindolinone 9 (1 equiv) were used.
b Nitrone 10 (1 equiv) and ethylideneindolinone 9 (3 equiv) were used.
c The ratios of products 12 and 13 were estimated from the 1H NMR spectra.
d The yields were estimated from the 1H NMR spectra of the crude products.
should exhibit a higher ratio at lower temperature, these
results imply that the present cycloaddition at high temper-
ature might involve a thermodynamically controlled equilibi-
um cycloreversion9 of the cycloadducts 12 and 13 to the
starting 9 and 10. The effect of solvent polarity was next
examined. Although reactions in polar solvents such as
acetonitrile, tetrahydrofuran, and methanol did not go to
completion at room temperature (entries 4-6), the use of
hexane as a solvent, interestingly, accelerated the cycload-
dition at the same temperature to give a ca. 1:1 mixture of
12 and 13 in quantitative yield (entries 7 and 8).10 Taking
into account the distribution of products as well as the
solubility of the starting materials, neat conditions (entry 2)
may be convenient for a large-scale reaction.
Scheme 4. Synthesis of Maremycin A (1) and D1 (5)
We next decided to investigate cycloreversion of the
cycloadducts 12 and 13 (Scheme 3). It is known that methyl
methacrylate (14) reacts with nitrone 10 to exclusively afford
cycloadduct 15 in high yield (eq 1).7d Cycloadduct 12, on
heating with methacrylate 14 in toluene at 100 °C for 1 h,
released 3-ethylideneindolin-2-one 9 and afforded cycload-
duct 15 of methacrylate 14 in quantitative yield (eq 2).
Similar treatment of cycloadduct 13 with 14 provided
Scheme 3. Cycloreversion of Cycloadducts 12 and 13
Cycloadduct 12 has the correct stereochemistry for mare-
mycins A (1) and D1 (5), and elaboration to 1 and 5 was
readily achieved (Scheme 4). Thus, hydrogenolysis of
cycloadduct 12 simultaneously caused reductive cleavage of
the N-O bond and the benzylic position, followed by
hydrolysis of the ester group to provide γ-hydroxy-R-amino
acid 7. Treatment of amino acid 7 with TMSCHN2 followed
by condensation with N-Boc-S-methyl-L-cysteine gave dipep-
tide 16. When dipeptide 16 was heated with silica gel in
Org. Lett., Vol. 10, No. 10, 2008
2045

boiling xylene for 30 min, removal of Boc group and
formation of the diketopiperazine ring occurred to afford
In conclusion, we have accomplished the first synthesis
of maremycins A (1) and D1 (5), featuring cycloaddition of
cyclic nitrone 10 with (E)-3-ethylidene-1-methylindolin-2-
one (9), and thereby conclusively determined the stere-
ochemistries of the natural products 1 and 5. In addition, 5
has been fully characterized for the first time. This short-
step synthesis is expected to be suitable for obtaining large
amounts of the natural products for biological screening.
maremycin A (1), mp 229.0-229.5 °C, [R]22 -110.2 (c
D
0.21, MeOH) [lit.1 mp 229 °C, [R]20 -120.95 (c 0.21,
D
MeOH)], whose 1H and 13C NMR spectra were identical with
those reported.1 The structure of maremycin A (1) has thus
been established to be as depicted in Scheme 4. The
methylthio group of 1 was oxidized to a methylsulfinyl group,
and then thermal elimination afforded maremycin D1 (5),
mp 224.0-226.0 °C (decomp), [R]22D -40.8 (c 0.1, MeOH),
Acknowledgment. We are grateful to Prof. I. Azumaya
and Dr. K. Katagiri (Tokushima Bunri University, Kagawa)
for measuring X-ray diffraction. Financial support of this
study by a Grant-in-Aid for Scientific Research on the
Priority Area “Creation of Biologically Functional Mol-
ecules” from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan is gratefully acknowl-
edged.
1
whose H and 13C NMR spectra were identical with those
reported.2
(9) For examples of cycloreversion of nitrone cycloadducts, see: (a)
Schultz, A. G.; McMahon, W. G.; Kullnig, R. K. J. Org. Chem. 1987, 52,
3905–3909. (b) Burdisso, M.; Gamba, A.; Gandolfi, R.; Oberti, R.
Tetrahedron 1988, 44, 3735–3748. (c) Giera, H.; Huisgen, R. Liebigs Ann.
1997, 1685–1689. (d) Williams, G. M.; Roughley, S. D.; Davies, J. E.;
Holmes, A. B. J. Am. Chem. Soc. 1999, 121, 4900–4901. (e) Pisaneschi,
F.; Cordero, F. M.; Brandi, A. Synlett 2003, 1889–1891. (f) Garcia Ruano,
J. L.; Fraile, A.; Martin Castro, A. M.; Martin, M. R. J. Org. Chem. 2005,
70, 8825–8834.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 12, 13, 7, 1,
(10) Nitrone 10 and 3-ethylidene-1-methylindolin-2-one (9) are highly
polar compounds whose oxygen atom may possess donating character, and
hence they would not undergo stabilization in hexane, which has low polarity
and low accepting ability. Since cycloreversion from cycloadducts 12 and
13 leading to nitrone 10 and indolinone 9 would become unfavorable in
hexane, dominance of cycloadduct 13 may be suppressed, affording a 1:1
mixture of 12 and 13.
1
and 5; their H NMR data; X-ray crystallography of 12;
6-31G* calculations of 12 and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Computation (6-31G*) indicated that cycloadduct 13 is more stable
by 1.47 kcal/mol than cycloadduct 12 (Supporting Information).
OL800515W
2046
Org. Lett., Vol. 10, No. 10, 2008