Synthetic efforts toward the isoindolinone core of muironolide A

Article abstract of DOI:10.1055/s-0033-1339327

Studies directed toward the isoindolinone core of muironolide A are described. An initial plan to implement an intramolecular Diels-Alder cycloaddition was thwarted by an undesired conjugate addition during the attempted preparation of the Diels-Alder substrate. A revised retrosynthetic analysis revealed a direct, albeit challenging, intermolecular Diels-Alder disconnection. Toward this end, a sterically hindered and electronically deactivated diene was utilized with N-phenylmaleimide to achieve a Diels-Alder cycloaddition. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339327

LETTER
▌1861
lSetyternthetic Efforts toward the Isoindolinone Core of Muironolide A
The Isoindolinone Core of Muironolide A
Courtnay E. Shaner, Gregory M. Ferrence, T. Andrew Mitchell*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Fax +1(309)4385538 (department); E-mail: tmitche@ilstu.edu
Received: 27.05.2013; Accepted after revision: 07.06.2013
EtO
EtO
Me
O
O
Abstract: Studies directed toward the isoindolinone core of
muironolide A are described. An initial plan to implement an intra-
molecular Diels–Alder cycloaddition was thwarted by an undesired
conjugate addition during the attempted preparation of the Diels–
Alder substrate. A revised retrosynthetic analysis revealed a direct,
albeit challenging, intermolecular Diels–Alder disconnection. To-
ward this end, a sterically hindered and electronically deactivated
diene was utilized with N-phenylmaleimide to achieve a Diels–
Alder cycloaddition.
P
HWE olefination
Me
O
HN
H
O
BocN
H
O
H
Me
Me
H
TESO
CCl3
Me
Me
4
Mitsunobu
Cl
CCl3
O
OH
O
O
OH OMe
2
Cl
O
O
macrolactonization
H
H
muironolide A (1)
3
Key words: cycloaddition, Diels–Alder reaction, muironolide A,
natural products, total synthesis
electronic
deactivation
O
Diels–Alder
O
H
BocN
O
O
2
BocN
Muironolide A was recently isolated by Molinski and co-
workers1 from the same marine sponge that delivered
phorboxazole A,2 which is an extremely potent bioactive
natural product with promising anticancer activity.3 Only
90 μg of muironolide A was isolated, which meant that to-
tal synthesis was the only viable means available to under-
take a detailed biological evaluation.4 Molinski disclosed
an intramolecular, organocatalytic approach to an isoin-
dolinone core5 that utilized imidazolidinone precatalysts.6
Herein, we describe preliminary synthetic efforts toward
the isoindolinone, leading to an intermolecular Diels–
Alder strategy utilizing a diene that is sterically hindered
and electronically deactivated7 (Scheme 1). Retrosynthet-
ic analysis reveals three key fragments, isoindolinone 2,
chlorocyclopropylcarbinol 3, and protected trichloro-
methylcarbinol 4 resulting from Horner–Wadsworth–
Emmons (HWE) olefination,8 Mitsunobu,9 and
macrolactonization10 disconnections. Isoindolinone 2 can
be further disconnected to reveal a second isoindolinone
5, which could be accessible through Diels–Alder cyclo-
addition to provide diene 6 and 2-methylfuran-derived di-
enophile 7.11
O
+
Me
O
H
H
Me
Me
Me
6
7
5
steric
hindrance
Scheme 1
lactamization
O
O
Diels–Alder
O
MeO
CBzN
H
Me
1
O
Me
H
Me
H
Wittig
olefination
Me
CBzN
O
9
8
CH2=PPh3
+
O
O
Me
O
MeO
O
O
OH
MeO
MeO
NCBz
NCBz
Me
O
Me
Me
N
12
11
10
acylation
O
BnO
Scheme 2
Toward this end, CBz-allylamine 1316 was subjected to
acylation with methyl malonyl chloride followed by diazo
transfer17 with p-acetamidobenzenesulfonyl azide (p-ABSA)18
to provide diazo ester 14 (Scheme 3). Upon heating in
benzene, cyclization provided α,β-unsaturated lactam-
ester 12 in moderate yield.19
Our first-generation strategy centered on an intramolecu-
lar Diels–Alder cycloaddition (Scheme 2).12 Initial retro-
synthetic analysis revealed that isoindolinone 8 could be
accessed from bicyclic lactam 9, which, in turn, could be
obtained from diene-dienophile 10 through an intramolec-
ular Diels–Alder cycloaddition. Wittig olefination13 of
aminal 11, which would be achieved through half-
reduction14 of lactam-ester 12, followed by acylation15
was proposed for the synthesis of the Diels–Alder cyclo-
addition precursor 10. Thus, lactam-ester 12 was viewed
as a crucial synthetic intermediate toward this goal.
O
O
O
O
1) MeO
Cl
O
O
NHCBz
PhH
PhH, 80 °C
MeO
NCBz
MeO
NCBz
80 °C
66%
2) p-ABSA, Et3
N
N2
13
14
MeCN, 23 °C
Me
12
57%
SYNLETT 2013, 24, 1861–1864
Advanced online publication: 10.07.2013
Scheme 3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339327; Art ID: ST-2013-S0489-L
© Georg Thieme Verlag Stuttgart · New York

1862
C. E. Shaner et al.
LETTER
In pursuit of aminal 11, α,β-unsaturated lactam-ester 12
was subjected to a variety of reduction conditions (Table
1).14 Aminal 11 was not detected, but saturated amide-
ester 15 was observed as a result of conjugate addition.20 Re-
duction with Li(t-BuO)3AlH (entry 4) provided the best,
albeit unoptimized, isolated yield of 15 (38%) as a mix-
ture of diastereomers. Treatment of 12 with NaBH4 and
CeCl3 provided a complex mixture (analyzed by 1H NMR
spectroscopy) in which aminal 11 was not detected.
Me Me
O
O
18
O
O
O
O
Me
BocHN
1) DIBAL-H, toluene
1) xylenes, 140 °C
Me
BocN
BocN
O
2) POCl3, Et3N
10%
2) SiO2 column
50%
Me
Me
Me
19
6
17
Scheme 5
Initial investigation toward intermolecular Diels–Alder
cycloaddition between diene 6 and 2-methylfuran-derived
dienophile 7 catalyzed by imidazolidinone 16 was unsuc-
cessful (Scheme 6). Several solvents were screened under
ambient conditions, however, these did not lead to any re-
action; increased temperature resulted in decomposition.
Table 1 Reduction of Lactam 12 to Lactam 15
O
O
O
O
OH
NCBz
O
reduction
conditions
H
H
MeO
MeO
MeO
+
NCBz
NCBz
Me
Me
Me
12
11
15
Entry Reductant
Conv. 11 (%) Conv. 15 (%) dr 15
O
BocN
H
16 (20 mol%)
O
no reaction
O
+
1
2
3
4
DIBAL-H
LiAlH4
ND
ND
ND
ND
77
74
2.0:1
2.3:1
6.8:1
6.0:1
solvent–H2O (95:5)
23 °C, 24 h
Me
Me
7
6
solvent: MeCN, MeNO2, DMF, or MeOH
LiEt3BH
>95
>95
Scheme 6
Li(t-BuO)3AlH
To demonstrate reactivity in a more fundamental way, di-
ene 6 was subjected to a thermal Diels–Alder cycloaddi-
tion with N-phenylmaleimide (20; Table 2). Ambient
conditions provided no reaction, as anticipated (entry 1).
Upon heating in the presence of a radical scavenger
(BHT), Diels–Alder adduct 21 was observed with signifi-
cant amounts of starting diene 6 remaining (entry 2). Pro-
longed heating at 100 °C for six days provided complete
conversion into the desired adduct 21 (entry 4). Heating to
120 °C did not improve the rate of conversion to any ap-
preciable degree (entry 5) and heating to 150 °C resulted
in significant Boc-deprotection (entry 6). Fortuitously,
deprotected isoindolinone 22 was amenable to single
crystal X-ray crystallographic analysis,24 which con-
firmed both the expected endo adduct and the crucial α,β-
unsaturated lactam moiety (Figure 1). Not only does the
stereochemical outcome demonstrate the feasibility of
this direct intermolecular Diels–Alder cycloaddition with
diene 6, but construction of the α,β-unsaturated lactam
embedded within the isoindolinone allows access to a crit-
ical structural feature that have proven difficult to obtain
by using the approach developed by Flores and Molinski.5
Finally, the optimized conditions were utilized for the
synthesis of isoindolinone 21, providing 76% yield of the
desired product as a single diastereomer (Scheme 7).25
In light of our retrosynthetic analysis for isoindolinone 5,
which was further disconnected to reveal diene 6 and di-
enophile 7 (cf. Scheme 1), we envisioned an organo-
catalytic, intermolecular Diels–Alder cycloaddition6a
catalyzed by imidazolidinone 16 as an attractive strategy
with which to construct the highly functionalized isoindo-
linone 5 with high diastereo- and enantioselectivity
(Scheme 4).
O
O
BocN
O
BocN
H
Me
BocN
H
O
O
6
7
Me
H
H
Me
O
H
H
Me
Me
O
O
5
O
OH
Me
‡
2
H
O
H
H
H
Me
NH
Bn
Me
Me
O
Me
BocN
Me
N
VIA:
+N
H
Me
16
N
Me
Me
H
H
O
Ph
proposed endo TS
O
Scheme 4
O
O
BHT (20 mol%)
toluene
Toward this end, Boc-protected amino acetone 1721 was
treated with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (18)22
in xylenes at reflux to provide a β-ketoamide (not shown)
that underwent intramolecular aldol cyclization when
subjected to silica gel column chromatography23 to pro-
vide lactam 19 in moderate yield (Scheme 5). Unopti-
mized reduction and elimination delivered the requisite
diene 6.
O
BocN
H
H
BocN
O
+
N
100 °C, 6 d
76% yield
Me
O
Me
Ph
N
O
Ph
6
20
21 (dr >19:1)
Scheme 7
Synlett 2013, 24, 1861–1864
© Georg Thieme Verlag Stuttgart · New York

LETTER
The Isoindolinone Core of Muironolide A
1863
Supporting Information for this article is available online at
Table 2 Optimization of Diels–Alder Cycloaddition with Diene 6
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
O
O
BHT (20 mol%)
toluene
O
BocN
H
HN
H
H
H
6
+
References and Notes
N
O
O
+
temp, time
Me
O
Me
O
Ph
O
N
N
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20
Ph
Ph
21
22
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(b) While this manuscript was in press, the following was
published: Xiao, Q.; Young, K.; Zakarian, A. Org. Lett.
2013, 15, 3314.
Entry
Temp (°C) Time (d)
Conv. 21 (%) Conv. 22 (%)
1
2
3
4
5
6
23
100
100
100
120
150
1
1
4
6
3
1
ND
38
ND
ND
ND
ND
ND
58
78
>95
73
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Figure 1 ORTEP of Boc-deprotected Diels–Alder adduct 22
In conclusion, this investigation toward the natural prod-
uct muironolide A initially focused on an intramolecular
Diels–Alder cycloaddition as a key step. Undesired conju-
gate reduction of a precursor within the proposed intramo-
lecular approach led to a revised retrosynthetic analysis
that entailed a more direct intermolecular Diels–Alder cy-
cloaddition utilizing a sterically hindered and electroni-
cally deactivated diene. Initial investigation toward an
enantioselective, organocatalytic synthesis of the isoindo-
linone core was unsuccessful, but a challenging Diels–
Alder addition reaction was accomplished, which gives
credence to the viability of this novel diene for participa-
tion in Diels–Alder cycloaddition processes. Future stud-
ies utilizing this diene and others for the construction of
the isoindolinone core of muironolide A will be reported
in due course.
Acknowledgment
Financial support from the Research Corporation for Scientific Ad-
vancement - Cottrell College Science Award and the College of
Arts & Sciences and Department of Chemistry (ISU) are gratefully
acknowledged. The authors thank Dr. John Goodell for helpful
discussions and NSF-CHE (#1039689) for funding the X-ray dif-
fractometer.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1861–1864

1864
C. E. Shaner et al.
LETTER
data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html.
EtOAc, 60:40). IR (neat): 1769, 1705, 1147, 727, 691 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.39 (s, 3 H), 1.54 (s, 9 H),
2.71 (ddd, J = 2.8, 9.0, 17.8 Hz, 1 H), 3.10 (ddd, J = 1.3, 7.5,
17.8 Hz, 1 H), 3.36 (d, J = 8.9 Hz, 1 H), 3.49 (ddd, J = 1.3,
8.9, 9.0 Hz, 1 H), 3.63 (d, J = 11.6 Hz, 1 H), 4.73 (d,
J = 11.6 Hz, 1 H), 6.97 (dd, J = 2.8, 7.5 Hz, 1 H), 7.18–7.20
(m, 2 H), 7.38–7.48 (m, 3 H). 13C NMR (125 MHz, CDCl3):
δ = 24.5, 26.7, 28.1 (3), 35.8, 39.1, 47.8, 53.9, 83.3, 126.5
(2), 129.0, 129.3 (2), 131.4, 131.6, 139.9, 150.4, 163.7,
175.5, 177.5. HRMS (ESI): m/z [M + H]+ calcd for
C22H25N2O5: 397.1763; found: 397.1769.
(25) Experimental Procedure for the Synthesis of
Isoindolinone 21: N-Phenylmaleimide 20 (89 mg, 0.51
mmol), BHT (11 mg, 0.05 mmol), and diene 6 (56 mg, 0.25
mmol) were dissolved in toluene (1.0 mL). The solution was
sealed in a Teflon-capped vial, heated to 100 °C for 6 d,
cooled to 23 °C, and then concentrated under reduced
pressure. Purification by flash column chromatography
(hexanes–EtOAc, 60:40) delivered isoindolinone 21 (75 mg,
76%) as a white solid; mp 80–82 °C; Rf = 0.13 (hexanes–
Synlett 2013, 24, 1861–1864
© Georg Thieme Verlag Stuttgart · New York