Biomimetic synthesis of isoindolinones related to the marilines

Article abstract of DOI:10.1055/s-0034-1380700

The non-enzymatic formation of the racemic isoindolinone core structure during the biosynthesis of the marine natural products mariline A and B was mimicked by employing structurally closely related model substrates. Thus, condensation of 2-formyl-3,5-dim

Full text of DOI:10.1055/s-0034-1380700

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
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-
2
0
9
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1395–1397
letter
1395
D. Augner, H.-G. Schmalz
Letter
Synlett
Biomimetic Synthesis of Isoindolinones Related to the Marilines
Daniel Augner
AcOH
1,4-dioxane–H2O
r.t., 10 min
OMe
OMe
MeO
NH2
O
Hans-Günther Schmalz*
OHC
O
+
MeO
N
University of Cologne, Department of Chemistry,
Greinstrasse 4, 50939 Köln, Germany
schmalz@uni-koeln.de
73%
OMe
OMe
O
O
Received: 24.02.2015
Accepted after revision: 09.04.2015
Published online: 11.05.2015
et al. suggested a non-enzymatic transformation as the chi-
rogenic (i.e., racemogenic) step of mariline biosynthesis.1
More specifically, they proposed that these natural prod-
ucts are formed in nature by condensation of an ortho-
formyl-acetophenone of type 3 with a primary amine, ac-
cording to the isoindolinone synthesis recently discovered2
and applied3 in our laboratory. As briefly shown in Scheme
1, this transformation would involve the reaction of an
amine component R2-NH2 with an ortho-formyl-arylketone
3 to generate (via A) a hydroxyisoindole intermediate (B),
which finally tautomerizes in a stereo-uncontrolled fashion
to the more stable (chiral) isoindolinone (rac-4).
DOI: 10.1055/s-0034-1380700; Art ID: st-2015-b0130-l
Abstract The non-enzymatic formation of the racemic isoindolinone
core structure during the biosynthesis of the marine natural products
mariline A and B was mimicked by employing structurally closely relat-
ed model substrates. Thus, condensation of 2-formyl-3,5-dimethoxy-4-
methyl-acetophenone with different primary amines in the presence of
AcOH afforded the isoindolinone products in up to 73% yield.
Key words natural products, biomimetic synthesis, heterocycles, iso-
indolinones, aromatic compounds.
OMe
OMe
In 2012, G. König et al. reported the discovery of the ma-
rilines, a group of natural isoindolinones produced by a
sponge-derived marine fungus (Stachylidium sp.). Mariline
A (rac-1) was shown to inhibit the human leucocyte elas-
tase (IC50 = 0.86 μM), which constitutes an important cellu-
lar switch in relevant inflammatory processes.1 All marili-
nes share a characteristically functionalized isoindolinone
core structure with a methyl substituent at C3 (Figure 1).
O
OHC
O
R2 NH2
– H2O
R2
N
OR1
OR1
non-enzymatic
biosynthesis
3
rac-4
R2 NH2
OMe
OMe
HO
HO
H
OMe
O
R2
N
R2
N
– H2O
MeO
N
OR1
OR1
3
HO
O
A
B
O
rac-1
Scheme 1 Proposed non-enzymatic step in the biosynthesis of the iso-
indolinone core of the marilines (rac-4) through condensation of an or-
tho-formyl-acetophenone (3) with a primary amine
OMe
O
N
The goal of the study disclosed herein was to probe the
proposed biosynthetic pathway in vitro, by employing sub-
strates that exhibit substitution patterns that are typical of
the marilines. As a model substrate of type 3, we selected
the ortho-formyl-arylketone 10, which carries a simplified
OR1 substituent (methoxy instead of geranyloxy). This com-
pound was synthesized starting from the commercially
available acid 5 as outlined in Scheme 2. At first, treatment
of 5 with an excess (3 equiv) of MeLi in Et2O gave methyl
HO
O
rac-2
Figure 1 Structure of marilines A (rac-1) and B (rac-2); the isoindoli-
none unit is highlighted in red
Remarkably, the marilines occur in nature as racemic
mixtures. Having proven (for mariline A) that the stereocen-
ter possesses a high degree of configurative stability, König
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1395–1397

1396
D. Augner, H.-G. Schmalz
Letter
Synlett
ketone 6, which was further converted into the protected
derivative 7 with ethylene glycol under standard condi-
tions. As several attempts to directly introduce a formyl
group into 7 failed, we first introduced a bromine substitu-
ent by reacting 7 with N-bromosuccinimide (NBS) in aceto-
nitrile.
Having successfully synthesized the model substrate 10
and the mariline A-related amino building block 13, the
stage was set to investigate the key question of the present
study; that is, whether isoindolinones of type rac-4 would
readily form by condensation of 10 with different amines
under mild conditions (cf. Scheme 1).
Under the mild and only slightly acidic conditions de-
veloped before in the course of our initial study,3a the reac-
tion of the keto-aldehyde 10 with either trimethoxyaniline,
ethanolamine or amine 13, smoothly afforded the desired
isoindolinones rac-14, rac-15, and rac-16, respectively,
within 10 minutes at room temperature.6 Notably, the high-
est yield (73%) was observed in the case of mariline A-relat-
ed product rac-16, whereas aniline itself (as the parent aro-
matic amine) only gave rise to a complex mixture that did
not contain significant amounts of the expected isoindoli-
none product. Thus, the success of the transformations
shown in Scheme 4 may reflect the existence of privileged
combinations (of 2-acylbenzaldehydes and amines) that
nature seems to exploit in the non-enzymatic biosynthesis
of certain isoindolinones.
OMe
OMe
OMe
a
b
85%
87%
OMe
OMe
HO2C
OMe
O
O
O
5
6
7
c
95%
OMe
OMe
OMe
OHC
O
OHC
O
Br
e
d
69%
53%
OMe
OMe
OMe
O
O
O
10
9
8
Scheme 2 Synthesis of the model substrate 10. Reagents and condi-
tions: (a) MeLi, Et2O, –78 °C to r.t.; (b) HO(CH2)2OH, cat. p-TsOH, ben-
zene, reflux; (c) NBS, MeCN, 0 °C to r.t.; (d) n-BuLi, THF, –78 °C, then
EtO2CH, –78 °C to r.t.; (e) CAN, borate/HCl buffer (pH 8), MeCN–H2O
(1:1), 60 °C.
OMe
O
MeO
MeO
MeO
N
48%
54%
OMe
Treatment of the resulting bromide 8 with n-BuLi (bro-
mine–lithium exchange) and addition of ethyl formate2 to
the solution of lithiated intermediate then generated the
formylated product 9. The cleavage of the acetal function
also turned out to be quite difficult. Whereas complex mix-
tures were formed under acidic aqueous conditions (due to
aldol-type side reactions), the deprotection was achieved
by treatment of 9 with cerium ammonium nitrate (CAN) at
pH 8 (according to the protocol of Marko4) to afford the
keto-aldehyde 10 in satisfactory yield (Scheme 2).
Aniline derivate 13, corresponding to the amine compo-
nent of mariline A (rac-1), was prepared from the known5
nitrophenol 11 by O-prenylation and reduction of the nitro
function of 12 through hydrogenation in the presence of
Raney-Ni (Scheme 3).
rac-14
OMe
OMe
O
OHC
O
N
HO
OMe
OMe
OMe
10
rac-15
OMe
O
MeO
N
73%
O
rac-16
Scheme 4 Synthesis of mariline-related isoindolinones under mild
standard conditions. Reagents and conditions: (a) amine (2 equiv), AcOH
(2.3 equiv), 1,4-dioxane–H2O, r.t., 10 min.
MeO
MeO
MeO
a
b
82%
49%
NO2
NO2
NH2
OH
O
O
In conclusion, we have elaborated reliable schemes for
the synthesis of the mariline-related building blocks 10 and
13 and demonstrated their tendency to smoothly condense
to the corresponding racemic isoindolinones under mild
conditions. We have thereby also paved the way for the
(biomimetic) synthesis of other mariline-related com-
pounds, which are of potential pharmacological interest.7
11
12
13
Scheme 3 Synthesis of the mariline A-related aniline derivative 13. Re-
agents and conditions: (a) NaH, prenyl bromide, DMF, 0 °C to r.t., 3.5 h;
(b) H2, cat. Raney-Ni, MeOH, r.t., 2.5 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1395–1397

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D. Augner, H.-G. Schmalz
Letter
Synlett
Acknowledgment
under reduced pressure, the residue was purified by flash
column chromatography to give the pure isoindolinones.
This work was performed within the context of ‘SusChemSys’, a pro-
gram of the State of North Rhine-Westphalia (Germany), co-financed
by the European Union through ERDF funds.
Characteristic Data for rac-14: Rf = 0.18 (SiO2; cyclohexane–
EtOAc, 2:1). 1H NMR (500 MHz, CDCl3): δ = 6.79 (s, 2 H), 6.66 (s,
1 H), 5.02 (q, J = 6.6 Hz, 1 H,), 4.02 (s, 3 H), 3.92 (s, 3 H), 3.88 (s,
6 H), 3.84 (s, 3 H), 2.17 (s, 3 H), 1.44 (d, J = 6.6 Hz, 3 H). 13C NMR
(126 MHz, CDCl3): δ = 165.6 (s), 162.6 (s), 157.0 (s), 153.5 (s,
2C), 147.5 (s), 135.8 (s), 133.4 (s), 120.4 (s), 115.9 (s), 101.7 (d,
2C), 99.2 (d), 62.4 (q), 61.06 (q), 56.9 (d), 56.4 (q, 2C), 56.1 (q),
Supporting Information
Supporting information for this article is available online at
19.4 (q), 8.6 (q). FTIR (ATR): 1682 (s), 1590 (s), 1506 (s) cm–1
.
http://dx.doi.org/10.1055/s-0034-1380700.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
HRMS (ESI): m/z [M+H]+ calcd: 388.1755; found: 388.1753.
Characteristic Data for rac-15: Rf = 0.07 (SiO2; cyclohexane–
EtOAc, 1:3). 1H NMR (600 MHz, CDCl3): δ = 7.35 (1 H), 6.58 (s,
1 H), 4.48 (q, J = 6.7 Hz, 1 H), 3.98 (s, 3 H), 3.88 (s, 3 H), 3.84 (t, J
= 5.0 Hz, 2 H), 3.80–3.76 (m, 1 H), 3.53–3.50 (m, 1 H), 2.13 (s, 3),
1.44 (d, J = 6.7 Hz, 3 H). 13C NMR (151 MHz, CDCl3): δ = 168.7 (s),
162.2 (s), 156.4 (s), 148.5 (s), 119.9 (s), 115.5 (s), 99.3 (d), 62.7
(t), 62.3 (q), 57.1 (d), 56.0 (q), 44.6 (t), 18.9 (q), 8.6 (q). FTIR
(ATR): 3405 (br), 1659 (s), 1605 (s), 1130 (s) cm–1. HRMS (ESI):
m/z [M+H]+ calcd: 266.1387; found: 266.1387.
Characteristic Data for rac-16: Rf = 0.32 (SiO2; cyclohexane–
EtOAc, 2:1). 1H NMR (500 MHz, CDCl3): δ = 7.24 (d, J = 8.2 Hz,
1 H), 6.65 (s, 1 H), 6.55–6.53 (m, 2 H), 5.34 (t, J = 6.5 Hz, 1 H),
5.02 (q, J = 6.7 Hz, 1 H), 4.53–4.45 (m, 2 H), 4.06 (s, 3 H), 3.92 (s,
3 H), 3.82 (s, 3 H), 2.18 (s, 3 H), 1.71 (s, 3 H), 1.66 (s, 3 H), 1.30
(d, J = 6.8 Hz, 3 H). 13C NMR (126 MHz, CDCl3): δ = 166.3 (s),
161.9 (s), 159.8 (s), 156.7 (s), 155.7 (s), 148.9 (s), 137.3 (s), 130.9
(d), 119.8 (d), 119.4 (s), 118.9 (s), 115.9 (s), 104.7 (d), 101.0 (d),
99.2 (d), 65.8 (t), 62.4 (q), 57.1 (d), 56.0 (q), 55.7 (q), 25.8 (q),
19.2 (q), 18.4 (q), 8.6 (q). FTIR (ATR): 1686 (s), 1605 (s), 1510 (s),
1233 (s) cm–1. HRMS (ESI): m/z [M+H]+ calcd: 412.2118; found:
412.2117.
References
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(6) Synthesis of Isoindolinones; General Procedure (Scheme 4):
To a stirred solution of o-formyl-acetophenone 10 (111 mg,
1 mmol) in 1,4-dioxane (2 mL) were added aq AcOH (H2O–AcOH
= 9:1; 1.59 M, 0.8 mL, 2.3 mmol) and the respective amine (1
mmol). After 10 min, the reaction mixture was diluted with sat.
aq NH4Cl and extracted three times with MTBE. The organic
layers were dried with MgSO4. After removal of all volatiles
(7) For a recent review on the chemistry of isoindole natural prod-
ucts, see: Speck, K.; Magauer, T. Beilstein J. Org. Chem. 2013, 9,
2048.
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