Hexahydro-1 H -Isoindolinone-Like Scaffolds from Electronically Deactivated and Sterically Hindered Dienes: Synthesis in the Context of Muironolide A

Article abstract of DOI:10.1055/s-0034-1380221

Initial synthetic efforts toward muironolide A based upon an intramolecular Diels-Alder strategy were hampered by a conjugate reduction rather than the desired half-reduction. An intermolecular Diels-Alder strategy was initiated that utilized electronically deactivated and sterically hindered dienes. The [4+2] cycloadditions were successful, but only with highly reactive dipolarophiles such as N-phenylmaleimide and 4-phenyl-1,2,4-triazoline-3,5-dione thus establishing the scope of these dienes. Although limited, installation of the α,β-unsaturated lactam embedded in the hexahydro-1H-isoindolinone is noteworthy.

Full text of DOI:10.1055/s-0034-1380221

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 2756–2766
2756
special topic
Synthesis
C. A. Olson et al.
Special Topic
Hexahydro-1H-Isoindolinone-Like Scaffolds from Electronically
Deactivated and Sterically Hindered Dienes: Synthesis in the
Context of Muironolide A
Christopher A. Olson
Courtnay E. Shaner
Sydney C. Roche
N
O
O
O
O
N
O
O
N
N
BocN
BocN
H
Ph
O
Ph
H
N
N
O
BocN
O
Gregory M. Ferrence
T. Andrew Mitchell*
Me
O
CH2Cl2, 23 °C
4% yield
PhMe, 100 °C, 6 d
BHT (20 mol%)
Me
O
N
Me
N
9
Ph
Ph
7
6% yield
Department of Chemistry, Illinois State University, Normal,
IL 61790-4160, USA
tmitche@ilstu.edu
Received: 30.04.2015
Accepted after revision: 05.06.2015
Published online: 05.08.2015
performed on very small scale.1a Upon completion of the
enantioselective total synthesis in which 25 mg was ob-
tained, data for the revised structural assignment was in
DOI: 10.1055/s-0034-1380221; Art ID: ss-2015-c0283-st
complete agreement with the isolated natural product (Fig-
Abstract Initial synthetic efforts toward muironolide A based upon an
intramolecular Diels–Alder strategy were hampered by a conjugate re-
duction rather than the desired half-reduction. An intermolecular
Diels–Alder strategy was initiated that utilized electronically deactivat-
ed and sterically hindered dienes. The [4+2] cycloadditions were suc-
cessful, but only with highly reactive dipolarophiles such as N-phenyl-
maleimide and 4-phenyl-1,2,4-triazoline-3,5-dione thus establishing
the scope of these dienes. Although limited, installation of the α,β-un-
saturated lactam embedded in the hexahydro-1H-isoindolinone is
noteworthy.
ure 2).8 In addition to the unknown biological potential,
unique structural features make this an exciting synthetic
target: 1) a hexahydro-1H-isoindolinone core with three
contiguous stereocenters (including one all-carbon quater-
nary); 2) a macrocyclic diester fused to the hexahydro-1H-
isoindolinone; 3) a trisubstituted alkene flanked with ste-
reocenters on either side; 4) a trichloromethylcarbinol es-
ter; 5) a chlorocyclopropylcarbinol ester possessing three
contiguous stereocenters; and 6) remote arrangement of
these eight total stereocenters.
Key words cycloaddition, Diels–Alder reaction, muironolide A, natu-
ral products, total synthesis
Me
Me
OMe
O
Me
OH
OH
MeO
Me
O
Muironolide A is a novel marine natural product with
HN
H
O
H
1
Me
O
O
very intriguing structural features. Molinski isolated
1a
Me
Cl
H
HO
muironolide A from the same specimen of Phorbas that
Me
O
O
Me
2
3
Me
afforded the phorbasides and the phorboxazoles, which
have become prominent targets of recent total synthesis
O
O
CCl3
phorbaside A
4
endeavors (Figure 1). Exquisite structural elucidation was
accomplished with just 90 μg of muironolide A, but only
minimal biological activity could be ascertained. Thus, to-
O
H
1a
H
OH
H
O
5
muironolide A
original assignment)
(
N
O
Cl
tal synthesis represents the sole access point toward biolog-
ical investigation of muironolide A. Molinksi1b and
Zakarian have both disclosed elegant approaches based on
1c
Me
O
O
Br
OMe
O
O
6
intramolecular Diels–Alder cycloadditions.
Recently,
7
Zakarian accomplished the total synthesis of the originally
proposed structure of muironolide A only to discover that it
was in fact the epimer of the natural product. He subse-
quently proposed a revised structure based on a hypothesis
that this inconsistency arose from the degradation studies
MeO
N
Me
Me
O
O
H
OH
Me
OH
phorboxazole A
Figure 1 Natural products isolated from the marine sponge Phorbas
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2756–2766

2
757
Synthesis
C. A. Olson et al.
Special Topic
9
O
O
nation was anticipated as a route to provide the CBz-pro-
10
tected amine (not shown) that could then be acylated to
give the Diels–Alder precursor 3. Thus, lactam-ester 5 was
proposed as the first synthetic building block necessary in
order to investigate the desired half-reduction toward the
aminal 4 (Scheme 1).
HN
H
O
HN
H
O
Me
Me
Me
Cl
H
Me
Cl
H
Me
O
Me
O
O
CCl3
O
CCl3
Allylamine 6 was protected as the CBz derivative11 and
treated with methyl malonyl chloride (7) to afford amide 8
(Scheme 2). Treatment with 4-acetamidobenzenesulfonyl
azide (p-ABSA, 17) and Et N gave the α-diazo amide (not
shown), which was subjected to refluxing benzene to de-
O
O
H
H
C21-epi-muironolide A
original assignment)
(+)-muironolide A
(revised assignment)
(
12
3
Figure 2 Original and revised assignments of muironolide A
13
liver the desired α,β-unsaturated lactam 5 (vide supra) in
37% yield over four steps. Transformation of the diazo func-
tionality into the α,β-unsaturated lactam 5 likely proceeds
via [3+2] cycloaddition to the bicyclic lactam 10 and then
through a cyclopropane intermediate 11 followed by a 1,2-
hydride shift (Scheme 3).14
Our original synthetic strategy also focused on an intra-
molecular Diels–Alder cycloaddition, but was altered in or-
6
der to investigate an intermolecular variant. Previously, we
showed proof of principle within the intermolecular con-
text demonstrating that an electronically deactivated and
sterically hindered diene was capable of undergoing Diels–
1d
O
O
Alder cycloaddition with N-phenylmaleimide. Herein, we
report a full account of these investigations within the con-
text of the attempted synthesis of the hexahydro-1H-isoin-
dolinone core of muironolide A. We show several ‘dead-
end’ pathways and intriguing by-products, optimized syn-
thesis and manipulation of several dienes, and we firmly
demarcate the scope and limitation of these electronically
deactivated and sterically hindered dienes (vide infra). Al-
though capable of [4+2] cycloaddition, unfortunately these
dienes are incapable of Diels–Alder cycloadditions that are
synthetically useful toward the hexahydro-1H-isoindoli-
none core of muironolide A.
1) CBzCl, K2CO3
EtOAc–H2O, 0 °C
1) p-ABSA, Et3N
MeCN, 0 to 23 °C
NH2
MeO
NCBz
5
2
)
O
O
6
8
2) PhH, reflux
7
Cl
37% yield (4 steps)
MeO
PhH, reflux
Scheme 2 Synthesis of lactam 5 from allylamine 6
O
O
O
O
PhH, reflux, 2 d
6%
MeO
NCBz
MeO
NCBz
9
N
N
6
Me
–
5
Initially, we proposed that cyclohexene-lactam 1 could
serve as a productive form of the hexahydro-1H-isoindoli-
none core. Thus, cyclohexene-lactam 2, upon opening of
the lactam followed by capture of the ester with the result-
ing CBz-protected amine, could then be converted to the
hexahydro-1H-isoindolinone 1. Intramolecular Diels–Alder
of diene 3 was expected to provide efficient access to cyclo-
hexene-lactam 2. Manipulation of aminal 4 via Wittig olefi-
intramolecular
3+2] cycloaddition
1
,2-hydride shift
[
MeO C
N
2
O
O
MeO C
2
N
NCBz
10
NCBz
H
N2
11
H
Scheme 3 Mechanistic rationale for the synthesis of lactam 5
intramolecular
Diels–Alder
O
CBzN
Several attempts to synthesize the aminal 4 by half-
reduction15 of α,β-unsaturated lactam-ester 5 were unsuc-
cessful (Scheme 4). However, a saturated amide ester 12
O
H
MeO
Me
1d
muironolide A
O
O
Me
H
was isolated, presumably resulting from conjugate addition
Me
H
CBzN
Me
by the hydride source. LiAlH(t-BuO) proved to be the most
3
O
1
2
efficient reducing agent, albeit unoptimized, and provided
the ester 12 in 38% yield as a mixture of diastereomers (dr
O
O
Me
16
6:1).
O
O
O
OH
NCBz
MeO
MeO
MeO
O
O
O
O
OH
NCBz
O
NCBz
Me
H
LiAlH(Ot-Bu)3
Me
Me
O
MeO
MeO
MeO
N
5
4
3
NCBz
NCBz
THF, – 78 °C
Me
Me
Me
BnO
O
H
5
acylation
4
(not observed)
12 (38% yield)
Scheme 1 Intramolecular retrosynthetic analysis of muironolide A
Scheme 4 Attempted half-reduction with LiAlH(Ot-Bu) to aminal 4
3
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Synthesis
C. A. Olson et al.
Special Topic
We next pursued a substrate without the ester (Scheme
) in order to reduce the electrophilicity of the alkene and
and macrolactonization,21 and synthetic intermediates
from these disconnections were proposed: hexahydro-1H-
isoindolinone 25, phosphonate 26, and chlorocyclopropyl
carbinol 27. Further retrosynthetic disconnection of hexa-
hydro-1H-isoindolinone 25 afforded hexahydro-1H-isoin-
dolinone 28, which could be accessible via an intermolecu-
lar Diels–Alder cycloaddition. Although electronically deac-
tivated and sterically hindered,22 diene 29a could
potentially undergo Diels–Alder cycloaddition with a highly
5
potentially to provide an avenue toward a simpler variant of
aminal 4 (vide supra) that could perhaps undergo a late-
stage allylic oxidation. Acylation of the CBz-protected allyl-
11
amine 13 delivered the necessary amide 14, but treat-
ment with p-ABSA and NaHMDS afforded hydantoin 2017
(
vide infra) rather than the desired α-diazo amide 15. This
unexpected result may arise from an enolate-azide [3+2]
18
23
cycloaddition and subsequent attack upon the CBz pro-
tecting group (Scheme 6). Unfortunately, attempts to gener-
alize this hydantoin formation or a more general α-amina-
tion proved unsuccessful since neither α-amino amides 22
or 24 were observed under similar conditions (Scheme 7).
Oxazolidinone 24 would presumably be less likely to un-
dergo capture akin to the CBz-protecting group.
reactive dienophile such as the fumarate derivative 30. Al-
though this route harbored risk, if successful would give di-
rect access to the crucial hexahydro-1H-isoindolinone core.
EtO
Me
O
O
EtO
O
P
olefination
Me
O
HN
H
O
BocN
H
Me
H
Me
H
TESO
CCl3
Me
O
Me
O
26
O
O
Me
Cl Me
p-ABSA
Me
Mitsunobu
Cl
O
CCl3
O
OH
NCBz
OH OMe
NHCBz
NCBz
25
Cl
NaHMDS
THF, – 78 °C
NaHMDS
N
14
O
macrolactonization
O
13
–N
15
H
H
27
66% yield
(
+)-muironolide A
not observed
Scheme 5 Attempted synthesis of α-diazo amide 15
electronic
deactivation
O
intermolecular
Diels–Alder
Since the intramolecular approach was leading further
away from muironolide A, potential intermolecular routes
were investigated (Scheme 8). Three disconnections of
O
H
BocN
O
O
25
BocN
+
O
Me
O
H
19
20
Me
Me
Me
muironolide A were envisioned: olefination, Mitsunobu,
29a
30
H
28
steric
hindrance
O
Scheme 8 Intermolecular retrosynthetic analysis of muironolide A
O
Me
i) NaHMDS, THF, –78 °C
N
Me
NCBz
N
Our first attempt within this strategy relied on a direct
synthesis of β,γ-unsaturated amides 33 and 35 (Scheme 9).
Coupling of but-3-enoic acid 31 and allylamine with
ii) p-ABSA, THF, –78 °C
AcHN
S
O
14
20
3
6% yield
O
O
NaOBn
i) NaHMDS
24
EDCI·HCl gave β,γ-unsaturated amide 32. While Boc-pro-
tection was realized, conversion to the α-diazo-β,γ-unsatu-
rated amide 34 was unsuccessful. A small quantity of isom-
erized by-product (i.e., α,β-unsaturated amide correspond-
ing to 33, not shown) was observed. Also, a styrene variant
35 afforded the α-diazo-β,γ-unsaturated amide 36, albeit in
poor yield. Unfortunately, diazoalkene [3+2] cyclization to
diene 37 was also unsuccessful.
N2
O–Na+
O
Me
enolate-azide
Na+–O NCbz
Me
NCBz
N
Na+
intermol. [3+2] Me
–N
N
16
O
Ar BnO
–
N
N
NH
Ar
19
N
18
N
AcHN
ii)
S
O
O
We then attempted to utilize α-diazo-β-keto amides
17
3
1
3
8a,b in order to access the requisite dienes (Scheme
Scheme 6 Proposed mechanism of the formation of hydantoin 20
13,14
0).
The syntheses of these β-keto-α-diazo amides
8a,b were straightforward, but cyclization proved to be in-
efficient. Although the CBz-protected variant 38a showed
some potential, the yield dropped drastically upon increas-
ing the scale. The Boc-protected version 38b gave only trace
lactam-ketone 40. At this point, we abandoned this diazo-
mediated approach in favor of an aldol-based strategy.
O
O
O
Me
Me
N
O
N
O
O
O
2
3
21
Me
p-ABSA
Me
N
N
O
NaHMDS
THF, –78 °C
NaHMDS
THF, –78 °C
NHAr
NHAr
α-amination?
not observed
24
2
2
Scheme 7 Attempted α-amination utilizing p-ABSA and NaHMDS
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759
Synthesis
C. A. Olson et al.
Special Topic
O
Therefore, a scalable synthesis of the unsaturated lact-
am-diene 29a was developed in order to investigate this in-
H2N
O
EDCI·HCl,
Boc2O, DMAP
HN
(
i-Pr)2NEt, DMF, –10 °C
0% yield
CH2Cl2, 23 °C
50% yield
termolecular Diels–Alder strategy (Scheme 13). Boc-protec-
HO
3
2
28
3
1
tion of the amino alcohol 44 followed by oxidation gave α-
4
25
26
amino ketone 42. Acylation with dioxinone 43 and opti-
O
O
O
mized aldol cyclization delivered enone 40. CeCl -mediated
3
p-ABSA, DBU
BocN
29
BocN
BocN
Luche reduction followed by POCl -mediated elimination
BocN
3
MeCN, 23 °C
N2
3
3
Me
afforded diene 29a. This route proved to be dependable in
order to deliver multi-gram quantity of requisite diene 29a.
34
29a
not observed
O
NH2
BocHN
O
BocHN
O
Boc O, 23 °C, 2 h
2
PDC, DMF
OH
OH
Ph p-ABSA
Ph PhH
reflux
Ph
O
BocN
THF–H O (5:3)
2
BocN
0 → 23 °C, 16 h
Me
Me
DBU
N2
Me
92%
67%
Me
44 (100 mmol)
3
5
21% yield
36
45
42
37
not observed
Me Me
Scheme 9 Attempted direct synthesis of diene 29
O
O
O
O
O
43
O
Me 10% aq NaOH, 0 °C
O
Me
Me
O
BocN
BocN
O
O
O
O
THF–MeOH, 15 min
85%
O
O
xylene, 150 °C, 10 min
99%
Me
PhH
R
PhH
Me
Me
N
Me
Me
41
40
CBzN
BocN
reflux
N2
reflux
Me
Me
HO
3
9
38a: R = CBz
8b: R = Boc
40
trace
O
O
3
NaBH , CeCl ·7H O
POCl3, CH2Cl2
Et3N, 0 °C, 4 h
47%
2
3% yield
lower upon scale-up)
4
3
2
Me
(
BocN
BocN
MeOH, 0 °C, 4 h
1%
Scheme 10 Attempted diazo-mediated approach to enones 39,40
Me
Me
9a (10 mmol)
4
46
2
Scheme 13 Scalable synthesis of Boc-lactam diene 29a
While an aldol condensation presented an obvious ap-
proach (Scheme 11) toward α,β-unsaturated lactam 40, it
had also demonstrated significant shortcomings with sev-
eral substrates (i.e., R = Cbz, Boc, Bn, H). However, we com-
mitted to the aldol strategy and chose the Boc variant for
further investigation. Thus, Boc-protected aminoacetone
Upon accessing the necessary diene 29a, several Diels–
Alder strategies were envisioned (Schemes 14–17). Our ini-
30
tial strategy centered on imidazolidinone catalysts (i.e.,
48) with fumarate derivative 30, which was readily accessi-
25
23
4
2
was acylated with 2,2,6-trimethyl-4H-1,3-dioxin-4-
ble from 2-methylfuran (Scheme 14). However, a variety
26
27
one 43 and, upon exposure to silica gel, gave the desired
aldol adduct 40 (Scheme 12). Although minor quantity of
diene 29a could be accessed (vide infra), this route was not
dependable or amenable to large scale.
of conditions at ambient temperature afforded no reaction
and heating the reaction only promoted decomposition or
led to complex mixtures. Alternatively, an oxazolidinone
chiral auxiliary-based approach was considered (Scheme
31
1
5). However, we postulated that the Boc protecting
O
O
O
O
O
group of the lactam could function as a competing imide
and detract from the ability of the oxazolidinone imide to
aldol
Me
Me
R
N
R
N
R N
O
inefficient
Me
Me
O
O
H
41
Me
40
29
R = H, Bn, CBz, Boc
48, 23 °C, 24 h
O
+
BocN
H
BocN
O
O
Scheme 11 Overview of the aldol cyclization strategy
solvent*–H O (95:5)
Me
Me
2
30
Me
O
H
H
29a
no reaction
Me
Me
NH
Bn
8 (20 mol%)
47
O
Me
Me Me
BocHN
O
H
H
i) xylenes, 150 °C, 4 h
O
Me
Me
N
O
O
O
H
BocN
H
Me
ii) SiO2 chromatography
0% yield (not scalable)
Me
O
BocN
42
Me
O
Me
Me
O
5
40
43
N
+
4
H
Me
Me
N
Me
H
H
Scheme 12 Initial synthesis of unsaturated Boc-lactam 40
*
MeCN, MeNO2, DMF, or MeOH
Ph
proposed endo TS
O
Scheme 14 Attempted imidazolidinone-catalyzed Diels–Alder reaction
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2
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Synthesis
C. A. Olson et al.
Special Topic
O
17). Again no reaction was observed, even at elevated tem-
peratures, further indicating the deactivated nature of
these hindered dienes regardless of protecting group (vide
supra). It should be noted that diene 29b was subjected to
identical conditions with similar outcomes.
Wacker
O
O
O
BocN
H
BocN
H
BocN
H
Me
H
Me
O
H
Me
O
H
Me
H
Xc
Wittig
O
OH
O
2
5
49
half-reduction
50
O
O
Et2AlCl, CH2Cl2
various temp
O
O
Si
N
no reaction
O
N
H
Ph
Et2AlCl2–
N
Me
O
Me
t-BuO
O
Me
O
N
H
H
29c
52
29a
Et2AlCl
Et
H
Al
BocN
Scheme 17 Attempted oxazolidinone–Et AlCl Diels–Alder reaction
2
O
toluene, – 78 °C
Ph
Et
O
H
O
Me
N
H
Several reactive dipolarophiles were investigated in or-
der to ascertain whether these dienes 29a–c were capable
of undergoing [4+2] cycloaddition (Schemes 18–21). Upon
heating Boc-lactam diene 29a with N-phenylmaleimide
proposed endo TS III
O
51
Scheme 15 Proposed oxazolidinone–Et AlCl Diels–Alder reaction
2
(
53) in toluene, a single diastereomer of the protected hexa-
hydro-1H-isoindolinone 54 was observed (Scheme 18, eq
1). Although heating to 150 °C resulted in Boc-deprotection
(Scheme 18, eq 2), this proved to be fortuitous since X-ray
crystallographic analysis1 was ascertained on this hexahy-
dro-1H-isoindolinone 55 thus confirming the expected ste-
reochemical outcome (Figure 3). Microwave (μW) irradia-
tion32 was attempted with mixed results (Table 1). Although
rate enhancement was significant, Boc-deprotection was
still observed. Alternative dienophiles such as dimethyl fu-
marate (56) and dimethyl acetylenedicarboxylate (57) gave
no reaction (Scheme 19, eq 1 and 2). Lactam-dienes 29b,c
afforded unsatisfactory results with N-phenylmaleimide
(Scheme 20); 29b gave poor yield of the cycloadduct 55
(Scheme 20, eq 1) and 29c gave no reaction (Scheme 20, eq
2).
chelate to the Et AlCl effectively. This would thereby inhibit
2
any productive lowering of the dienophile LUMO and pre-
sumably lead to no reaction. Indeed, when this reaction was
attempted with an achiral oxazolidinone (vide infra), no cy-
cloadduct and only Boc-deprotection was observed.
At this point, the Boc-protecting group had served the
purpose of aiding in the synthesis of a diene that could con-
ceivably be transformed to something more useful (Scheme
d
16). It was our hope to remove the Boc and replace it with a
variety of protecting groups. Unfortunately, this proved to
be exceptionally challenging. Upon successful deprotection
with 4 N HCl in 1,4-dioxane, attempted re-protection of the
lactam 29b as the Me, Bn, Ts, or MOM under a variety of
conditions led to no reaction or only to complex mixtures.
1
Crude H NMR analyses of these reactions suggest that the
O
proton α to the nitrogen is relatively acidic due to the im-
pending aromaticity. Attempts to synthesize dienes with
other protecting groups (i.e., CBz, Bn, PMB, etc.) from sim-
ple starting materials utilizing diazo-mediated routes or al-
dol-based approaches were very problematic. Fortunately, a
less common protecting group (i.e., TBS) was utilized for
the lactam, albeit in relatively poor yield. However, the TBS-
protected lactam 29c could be isolated as a pure compound
and it was subjected to the desired Diels–Alder cycloaddi-
O
BocN
O
PhMe, 100 °C, 6 d
BocN
H
H
+
(1)
N
O
BHT (20 mol%)
76% yield
Me
O
Me
Ph
O
N
H
54
2
9a
53
(dr >19:1)
Ph
O
O
PhMe, 150 °C, 24 h
HN
H
54 (21%)
BocN
+
(2)
(dr >19:1)
O
53, BHT (20 mol%)
Me
Me
N
tion conditions with oxazolidinone 52 and Et AlCl (Scheme
29a
2
O
Ph
5 (40%, dr >19:1)
5
O
O
O
Scheme 18 Successful Diels–Alder cycloadditions with 29a
O
4
N HCl
TBSCl
Si
N
N
HN
Treatment of lactam-diene 29a with 4-phenyl-1,2,4-tri-
azoline-3,5-dione (58) in CH Cl provided excellent yield of
t-BuO
EtOAc
(
i-Pr)2NEt
Me
Me
Me
2
2
7
5% yield
30% yield
29a
29b
29c
the desired cycloadduct 59a (Scheme 21). This highly reac-
tive dipolarophile 58 was treated with lactam-dienes 29b
and 29c under similar conditions and delivered the expect-
ed cycloadducts 59b and 59c in good yields. X-ray crystallo-
graphic analysis was also obtained on cycloadduct 59b (Fig-
attempted protection of 29b as the Me, Bn, Ts, or MOM under a variety
of conditions led to no reaction or complex mixtures
Scheme 16 Boc-deprotection and TBS-protection
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Synthesis
C. A. Olson et al.
Special Topic
ure 4). Interestingly, cycloadduct 59b adopts a significantly
different conformation as compared to hexahydro-1H-iso-
indolinone 55 (cf. Figure 3), presumably due to inversion at
the nitrogen atoms of triazolinedione 59b.
O
O
N
O
N
O
CH2Cl2, 23 °C, 1 h
R
N
R
N
+
N
N
N
O
Me
O
Me
Ph
N
2
2
2
9a: R = Boc
9b: R = H
9c: R = TBS
58
59a (R = Boc): 94% yield
59b (R = H): 71% yield
59c (R = TBS): 68% yield
Figure 3 ORTEP of Diels–Alder cycloadduct 55
Ph
Table 1 Microwave-Promoted Diels–Alder Cycloadditions with 29a
Scheme 21 Effective [4+2] cycloadditions with dipolarophile 58
O
O
BHT, 90 min
µW heat
BocN
H
HN
H
H
H
+
29a 53
+
O
O
Me
O
Me
F3C
N
N
O
Ph
Ph
5
4
55
Entry
Temp (°C)
Conv. (%)
Result
54 only
1
2
3
140
160
180
37
67
54 and 55
55 only
100
O
O
CO
2
Me
Figure 4 ORTEP of triazolinedione cycloadduct 59b
PhMe, 120 °C, 48 h
BHT (20 mol%)
BocN
H
(
1)
BocN
+
CO
2
Me
Me
CO Me
2
Me
H
In conclusion, our first-generation intramolecular
Diels–Alder strategy was unsuccessful (cf. Scheme 1) and a
second-generation intermolecular Diels–Alder strategy was
employed (cf. Scheme 8). Upon optimization of a scalable
synthesis of the Boc-lactam diene 29a (cf. Scheme 13), a
thorough investigation of this intermolecular Diels–Alder
cycloaddition strategy was undertaken. Although Diels–
Alder cycloadditions that could lead to muironolide A were
unsuccessful with dienes 29a–c (cf. Schemes 14, 15, 17),
proof of principle regarding potential [4+2] cycloadditions
was achieved when subjected to highly reactive species
such as the dienophile N-phenylmaleimide (53) (cf. Scheme
18) and the dipolarophile 4-phenyl-1,2,4-triazoline-3,5-di-
one (58) (cf. Scheme 21). Taken together, these results serve
to establish the scope and limitation of these electronically
deactivated and sterically hindered dienes 29a–c. Whereas
our initial report of the Diels–Alder cycloaddition with N-
phenylmaleimide demonstrated this important proof of
principle, the results henceforth obtained and reported in
this full account firmly demarcate the limits of these elec-
tronically deactivated and sterically hindered dienes. One
noteworthy feature of these [4+2] cycloadditions is the effi-
cient installation of the α,β-unsaturated amide that is em-
bedded within the hexahydro-1H-isoindolinone. Although
unfortunate that direct installation of the α,β-unsaturated
amide was not amenable toward Diels–Alder cycloadditions
that could lead to muironolide A, these developments will
2
CO Me
29a
56
not observed (NR)
O
2
CO Me
PhMe, 120 °C, 48 h
BHT (20 mol%)
BocN
(2)
2
9a
+
MeO
2
C
CO
Me
not observed (NR)
Me
2
Me
5
7
CO
2
Scheme 19 Unsuccessful Diels–Alder cycloadditions with 29a
O
O
HN
(1)
O
PhMe, 120 °C, 48 h
BHT (20 mol%)
HN
H
H
+
N
O
Me
O
Me
Ph
O
N
25% yield
55
29b
53
(
dr >19:1)
Ph
O
O
O
(2)
PhMe, 120 °C, 48 h TBSN
BHT (20 mol%)
H
H
TBSN
+
N
O
Me
Me
Ph
O
N
29c
53
not observed (NR)
O
Ph
Scheme 20 Attempted Diels–Alder cycloadditions with 29b,c
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Synthesis
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1
3
allow further innovations toward this important synthetic
target. Further investigation of alternative Diels–Alder
strategies toward muironolide A will be reported in due
course.
C NMR (125 MHz, CDCl ): δ = 166.9, 164.0, 162.2, 150.7, 135.2,
3
1
28.6 (2), 128.4, 128.0 (2), 124.4, 68.1, 53.1, 52.0, 15.6.
ESI-HRMS: m/z [M + H]+ calcd for C15H15NO : 290.1028; found:
2
5
90.1037.
Saturated CBz-Lactam Ester 12
All reactions were carried out under argon atmosphere in oven-dried
glassware. All commercially available anhydrous solvents and re-
agents were used as received. TLC was performed with glass plates
To a solution of CBz-lactam ester 5 (115 mg, 0.400 mmol) in THF (6.4
mL) was added LiAlH(t-BuO)3 (360 μL, 0.400 mmol) at –78 °C. The
solution stirred for 15 min at –78 °C before warming to 0 °C slowly
over a period of 2 h. The reaction mixture was stirred at 0 °C for 30
(silica gel F254, Art 5715, 0.25 mm), visualized by fluorescence
quenching under UV light, and stained with KMnO4 solution. Flash
column chromatography was performed with silica gel 60 (200–400
mesh). Mass spectral data was acquired using positive mode Electro-
spray Ionization (ESI+) and a high-resolution Time of Flight (TOF)
mass spectrometer. IR spectra were acquired on a FTIR spectrometer
min before quenching with H O (10 mL) and warming to 23 °C. The
2
mixture was filtered over a Celite pad with EtOAc and the filtrate was
washed with H O (10 mL). The organic layer was dried (Na SO ), de-
2
2
4
canted, and concentrated under reduced pressure. Purification by
flash column chromatography (hexanes–EtOAc, 60:40) delivered sat-
urated lactam ester 12 as a colorless oil; yield: 45 mg (38%); R = 0.47
–1
1
and reported as wavenumbers (cm ). H NMR spectra were recorded
13
at 400 or 500 MHz and C NMR spectra at 100 MHz or 125 MHz.
f
(
hexanes–EtOAc, 60:40).
IR (neat): 1724, 1700, 1273, 763, 697 cm–1
1H NMR (500 MHz, CDCl
): δ = 7.44–7.31 (m, 5 H), 5.30 (d, J = 12.4 Hz,
N-(Benzyloxycarbonyl)allylamine (13)
.
To a solution of allylamine (6; 3.7 mL, 50.0 mmol) in H O (75 mL) was
3
2
added K CO (17.30 g, 125 mmol) and EtOAc (75 mL). The reaction
1 H), 5.26 (d, J = 12.4 Hz, 1 H), 4.04 (dd, J = 10.7, 7.9 Hz, 1 H), 3.79 (s, 3
2
3
was then cooled to 0 °C and benzyl chloroformate (7.1 mL, 50.0
mmol) was added over a period of 15 min. The mixture was allowed
to warm to 23 °C and stirred for 2 h. The organic layer was separated
and washed with aq 10% HCl (2 × 50 mL), brine (50 mL), dried
H), 3.32 (dd, J = 10.7, 8.0 Hz, 1 H), 3.20 (d, J = 9.2 Hz, 1 H), 2.79 (m, 1
H), 1.18 (d, J = 6.7 Hz, 3 H).
13
C NMR (125 MHz, CDCl ): δ = 168.6, 168.4, 151.3, 135.2, 128.8 (2),
3
1
28.6, 128.3 (2), 68.5, 57.8, 53.0, 51.7, 30.7, 17.9.
ESI-HRMS: m/z [M + H]+ calcd for C15H17NO5 : 292.1185; found:
92.1190.
(
MgSO ), filtered, and concentrated under reduced pressure to afford
4
CBz-allylamine 13 as a clear oil; yield: 9.37 g (98%).
2
CBz-Allylamide 8
Propionyl Amide 14
To a solution of CBz-allylamine 13 (6.00 g, 32.0 mmol) in benzene (95
mL) was added methyl malonyl chloride (7; 6.9 mL, 64.0 mmol) at
To a solution of CBz allylamine 13 (3.50 g, 18.3 mmol) in THF (91 mL)
was added NaHMDS at –78 °C. After stirring for 1 h, propionyl chlo-
ride (2.0 mL, 22.0 mmol) was added and the mixture was allowed to
stir for 2 h at –78 °C. The mixture was then quenched with sat. aq
23 °C. This solution was refluxed at 80 °C, stirred for 2 h, and then
quenched with sat. aq NaHCO3 (200 mL) and stirred for 10 min. The
solution was diluted with Et O (400 mL), the combined organic ex-
tracts were separated, and washed with additional sat. aq NaHCO3
2
NH Cl (90 mL) and allowed to warm to 23 °C while stirring vigorously
4
for 10 min. The solution was diluted with EtOAc (300 mL), the com-
bined organic extracts were separated, and washed with sat. aq
NaHCO (100 mL), brine (100 mL), dried (Na SO ), decanted, and con-
(
200 mL), H O (200 mL) and brine (200 mL), and then dried (Na SO ),
2
2
4
decanted, and concentrated under reduced pressure. Purification by
flash column chromatography (hexanes–EtOAc, 80:20) delivered CBz-
allylamide 8 as a colorless oil; yield: 7.70 g (83%).
3
2
4
centrated under reduced pressure. Purification by flash column chro-
matography (hexanes–EtOAc, 95:5) delivered propionyl amide 14 as a
colorless oil; yield: 3.00 g (66%); R = 0.60 (hexanes–EtOAc, 80:20).
f
Diazo Amide 9
IR (neat): 1732, 1701, 1197, 736, 696 cm–1
.
To a solution of CBz-allylamide 8 (1.00 g, 3.43 mmol) and p-ABSA
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.35 (m, 5 H), 5.85–5.75 (m, 1 H),
(1.28 g, 5.15 mmol) in MeCN (41 mL) was added Et N (1.9 mL, 13.7
3
3
5.22 (s, 2 H), 5.13–5.08 (m, 2 H), 4.36 (dt, J = 5.7, 1.4 Hz, 2 H), 2.92 (q,
mmol) at 0 °C. The solution was stirred while warming to 23 °C for 66
h and then most (~80%) of the MeCN was removed under reduced
pressure using a rotary evaporator. The reaction mixture was then
J = 7.3 Hz, 2 H), 1.14 (t, J = 7.3 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 176.5, 154.4, 135.3, 133.3, 128.8 (2),
3
triturated with hexanes–Et O (1:1), filtered through a silica gel plug,
128.7, 128.4 (2), 117.0, 68.6, 46.4, 31.8, 9.4.
2
and concentrated again under reduced pressure to afford diazo amide
ESI-HRMS: m/z [M + H]+ calcd for C14H17NO : 248.1287; found:
3
9
as a yellow oil; yield: 753 mg (69%).
248.1282.
Unsaturated CBz-Lactam Ester 5
Hydantoin 20
A solution of diazo amide 9 (820 mg, 2.70 mmol) in benzene (27 mL)
was heated to reflux (80 °C) for 42 h. The reaction was allowed to cool
to 23 °C and then concentrated under reduced pressure. Purification
by flash column chromatography (hexanes–EtOAc, 30:70) delivered
CBz-lactam ester 5 as a yellow solid; yield: 569 mg (66%); mp 107 °C;
Rf = 0.38 (hexanes–EtOAc, 30:70).
To a solution of propionyl amide 14 (495 mg, 2.0 mmol) in THF (20
mL) cooled to –78 °C was added NaHMDS (2.0 mL of a 2 M solution,
4.0 mmol) dropwise. After 1 h, p-ABSA (481 mg, 2.0 mmol) was added
and allowed to stir for 5 h at –78 °C. The reaction was quenched with
sat. aq NH Cl (30 mL) and allowed to warm slowly to 23 °C. The mix-
4
ture was diluted with EtOAc (100 mL), the organic layer was separat-
ed, and washed with additional sat. aq NH Cl (30 mL), H O (30 mL)
IR (neat): 1751, 1699, 1187, 718, 697 cm–1
.
4
2
1
and brine (30 mL), dried (Na SO ), decanted, and concentrated under
reduced pressure. The crude solid was then triturated with hexanes–
EtOAc (90:10) to afford a solid. Purification by flash column chroma-
H NMR (400 MHz, CDCl ): δ = 7.47–7.34 (m, 5 H), 5.33 (s, 2 H), 4.33
2 4
3
(s, 2 H), 3.88 (s, 3 H), 2.40 (s, 3 H).
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Synthesis
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Special Topic
tography (CH Cl –MeOH, 90:10) delivered hydantoin 20 as an off-
corresponding β-keto amide (2.35 g, 59%) as a yellow oil. To a solution
of this β-keto amide (2.66 g, 11.0 mmol) in MeCN (55 mL) was added
2
2
white solid; yield: 250 mg (36%); mp 106 °C (dec.); R = 0.32 (CH Cl –
f
2
2
MeOH, 90:10).
p-ABSA (4.01 g, 16.5 mmol) and Et N (6.2 mL, 44.1 mmol) at 0 °C. The
3
IR (neat): 3345, 1747, 1266, 1163, 838 cm–1
reaction was allowed to warm to 23 °C and stirred for 16 h. The mix-
ture was concentrated and triturated with hexanes–EtOAc (1:1),
poured over silica gel, and concentrated under reduced pressure. Pu-
rification by flash column chromatography (hexanes–EtOAc, 80:20)
.
1
H NMR (500 MHz, CDCl ): δ = 7.91 (d, J = 8.9 Hz, 2 H), 7.73 (d, J = 8.9
3
Hz, 2 H), 7.43 (br s, 1 H), 5.85–5.75 (m, 1 H), 5.32–5.26 (m, 2 H), 4.62
(q, J = 6.8 Hz, 1 H), 4.21 (dt, J = 6.1, 1.3 Hz, 2 H), 2.23 (s, 3 H), 1.61 (d,
delivered 38b as a yellow oil; yield: 2.45 g (83%); R = 0.60 (hexanes–
f
J = 6.8 Hz, 3 H).
EtOAc, 70:30).
13
C NMR (100 MHz, CDCl ): δ = 169.5, 169.4, 151.1, 144.4, 131.2 (2),
IR (neat): 2128, 1726, 1657, 1141 cm–1
3
.
129.6 (2), 128.2, 120.0, 119.6, 55.9, 41.9, 24.9, 14.6.
1
H NMR (400 MHz, CDCl ): δ = 5.86 (m, 1 H), 5.18 (m, 2 H), 4.20 (dt,
3
ESI-HRMS: m/z [M + H]+ calcd for C15H17NO S: 352.0967; found:
5
J = 5.7, 1.4 Hz, 2 H), 2.43 (s, 3 H), 1.48 (s, 9 H).
352.0964.
13
C NMR (100 MHz, CDCl ): δ = 189.6, 163.8, 152.0, 133.3, 117.5, 84.0,
3
8
1.2, 48.4, 28.3, 27.9 (3).
β-Keto-α-Diazo Amide 38a
ESI-HRMS: m/z [M + Na]+ calcd for C12H17N O Na: 290.1117; found:
3
4
To a solution of CBz-allylamine 13 (2.87 g, 15.0 mmol) in p-xylene (15
mL) was added dioxinone 43 (3.3 mL, 22.5 mmol) at 23 °C. This solu-
tion was heated to reflux at 150 °C, stirred for 1.5 h, cooled to 23 °C,
and concentrated under reduced pressure. Purification by flash col-
umn chromatography (hexanes–EtOAc, 70:30) delivered the corre-
sponding β-keto amide (3.05 g, 74%) as a yellow oil. To a solution of
this amide (2.00 g, 7.3 mmol) in MeCN (36 mL) at 0 °C was added p-
290.1115.
Unsaturated Boc-Lactam 40
From Boc-aminoacetone 42: To a solution of Boc-aminoacetone 42
(4.21 g, 24.3 mmol) in p-xylene (24 mL) was added dioxinone 43 (7.1
mL, 48.6 mmol). The reaction was heated to reflux (150 °C) for 4 h,
cooled to 23 °C, and concentrated under reduced pressure to afford
the crude β-keto amide. Purification by flash column chromatogra-
phy (CH Cl –Et O, 90:10) provided mixed fractions of β-keto amide
and unsaturated Boc-lactam 40. Unsaturated Boc-lactam 40 was iso-
lated (1.37 g, 24%) as a yellow oil. The mixed fractions were re-intro-
duced to flash column chromatography (CH Cl –Et O, 90:10), which
ABSA (2.70 g, 10.9 mmol) and Et N (4.0 mL, 29.0 mmol). The reaction
3
was allowed to warm to 23 °C while stirring for 20 h and concentrated
under reduced pressure. The crude solid was triturated with
hexanes–EtOAc (1:1), filtered over silica gel, and concentrated under
reduced pressure. Purification by flash column chromatography
2
2
2
(hexanes–EtOAc, 80:20) delivered β-keto-α-diazo amide 38a as a
2
2
2
yellow oil (1.27 g, 58%).
provided an additional amount of lactam 40 (1.78 g, 31%) as a yellow
oil; combined total yield: 3.15 g (55%).
CBz-Lactam Ketone 39
Boc-1-Aminopropan-2-ol 45
A solution of 38a (820 mg, 2.7 mmol) in benzene (78 mL) was heated
to reflux (80 °C) for 60 h. The mixture was cooled to 23 °C and con-
centrated under reduced pressure. Purification by flash column chro-
matography (hexanes–EtOAc, 70:30) delivered CBz-lactam ketone 39
To a solution of 1-aminopropan-2-ol (44; 8.2 mL, 100 mmol) in THF–
H O (38 mL:38 mL) was added Boc O (23 mL, 100 mmol) in THF (25
2
2
mL). The mixture was stirred at 23 °C for 2 h and concentrated. The
organic layer was extracted with EtOAc (2 × 100 mL). The combined
as a yellow solid; yield: 172 mg (23%); mp 105–107 °C; R = 0.33
f
(hexanes–EtOAc, 60:40).
organic layers were washed with aq NH Cl (2 × 50 mL) and brine (100
4
IR (neat): 1738, 1716, 1679, 1313, 744, 699 cm–1
mL), dried (MgSO ), filtered, and concentrated to give 45 as a colorless
oil; yield: 16.0 g (92.0 mmol, 92%).
4
.
1
H NMR (500 MHz, CDCl ): δ = 7.46–7.34 (m, 5 H), 5.34 (s, 2 H), 4.32
3
(
1
s, 2 H), 2.56 (s, 3 H), 2.30 (s, 3 H).
Boc-Aminoacetone 42
3
C NMR (125 MHz, CDCl ): δ = 195.5, 166.8, 166.3, 1507, 135.2,
3
To a solution of PDC (68.9 g, 183 mmol) in DMF (50 mL) was added 45
1
30.5, 128.7 (2), 128.6, 128.4 (2), 68.3, 53.4, 30.5, 15.9.
(16.0 g, 92.0 mmol) in DMF (42 mL) at 0 °C. The reaction was allowed
ESI-HRMS: m/z [M + H]+ calcd for C15H15NO : 274.1079; found:
2
4
to stir for 16 h while warming to 23 °C. The reaction mixture was
poured over a plug of Celite with Et O, quenched with brine (200 mL),
74.1087.
2
and diluted with Et O (700 mL). The combined Et O layers were
2
2
β-Keto-α-diazo Amide (38b)
washed with aq NH Cl (2 × 200 mL), H O (2 × 200 mL), and brine
4
2
(
2 × 200 mL), dried (MgSO ), filtered, and concentrated to give Boc-
To a solution of allylamine (6; 3.0 mL, 39.8 mmol) in THF (20 mL) was
added i-Pr NEt (13 mL, 80.0 mmol) and Boc O (9.0 mL, 39.9 mmol).
4
aminoacetone 42 as a yellow oil; yield: 10.6 g (61.0 mmol, 61%).
2
2
After stirring 1 h, the reaction mixture was diluted with Et O (50 mL),
2
the organic layer was separated, and washed with sat. aq NH Cl
β-Keto Amide 41
4
(
3 × 20 mL), H O (20 mL) and brine (20 mL), dried (Na SO ), poured
2
2
4
To a round-bottomed flask was added 42 (10.6 g, 61.0 mmol), dioxi-
none 43 (8.9 mL, 61.0 mmol), and xylenes (61 mL), and heated to
over a silica gel plug, and concentrated under reduced pressure. Puri-
fication by flash column chromatography (hexanes–EtOAc, 90:10) de-
livered the corresponding Boc-allylamine (5.16 g, 81%) as a clear oil.
To a solution of this Boc-allylamine (2.60 g, 16.4 mmol) in p-xylene
150 °C for 10 min. The reaction was allowed to cool and the mixture
was concentrated under reduced pressure to give β-keto amide 41 as
a brown solid; yield: 15.54 g (60.4 mmol, 99%). Due to the propensity
to form the aldol adduct, this compound was not fully characterized.
1
(16 mL) was added dioxinone 43 (3.6 mL, 24.7 mmol). The reaction
mixture was heated to reflux (150 °C) for 1.5 h, then allowed to cool
to 23 °C, and concentrated under reduced pressure. Purification by
flash column chromatography (hexanes–EtOAc, 80:20) delivered the
H NMR (400 MHz, CDCl ): δ = 4.52 (s, 2 H), 4.05 (s, 2 H), 2.26 (s, 3 H),
3
2
.17 (s, 3 H), 1.44 (s, 9 H).
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2
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Synthesis
C. A. Olson et al.
Special Topic
Unsaturated Boc-Lactam 40
50.0 mmol). The ice bath was removed and the reaction was allowed
to warm to r.t. over 1 h. The solution was diluted with CH Cl2 (100
From β-Keto Amide 41: In a round-bottomed flask was added β-keto
amide 41 (15.54 g, 60.4 mmol), THF (92 mL), and MeOH (31 mL), and
cooled to 0 °C. Aq 10% NaOH (31 mL) was added to the mixture and it
was allowed to stir for 15 min. The mixture was concentrated and
then diluted with EtOAc (400 mL). The EtOAc layer was washed with
aq NH Cl (2 × 100 mL), H O (2 × 100 mL) and brine (2 × 100 mL), dried
2
mL), washed with sat. aq Na CO (2 × 50 mL), H O (2 × 50 mL) and
2
3
2
brine (2 × 50 mL), and dried (MgSO ). The resulting solution was
4
poured over a pad of silica gel with EtOAc (300 mL) and concentrated
to afford lactam diene 29b as a red solid; yield: 459 mg (75%); mp 84–
8
6 °C; R = 0.20 (hexanes–EtOAc, 10:90).
f
4
2
IR (neat): 1670, 1645 cm–1
.
(
MgSO ), filtered, and concentrated to give unsaturated Boc-lactam
4
4
0 as a brown solid, yield: 12.3 g (52.0 mmol, 85%). Immediate con-
1
H NMR (400 MHz, CDCl ): δ = 7.38 (br s, 1 H), 6.45 (dd, J = 17.7, 11.5
3
version to the subsequent allylic alcohol was generally employed due
to mild instability of the aldol adduct.
Hz, 1 H), 6.20 (dd, J = 17.7, 2.1 Hz, 1 H), 5.42 (dd, J = 11.5, 2.1 Hz, 1 H),
3
.85 (s, 2 H), 2.08 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 4.26 (s, 2 H), 2.56 (s, 3 H), 2.38 (s, 3 H),
13
3
C NMR (100 MHz, CDCl ): δ = 174.8, 151.1, 128.4, 125.8, 119.0, 49.9,
3
1.57 (s, 9 H).
1
3.7.
ESI-HRMS: m/z [M
24.0764.
+
H]+ calcd for C H NO: 124.0762; found:
7 9
Allylic Alcohol 46
1
CeCl ·7H O (38.3 g, 103 mmol) was dissolved in MeOH (130 mL) and
3
2
stirred for 5 min. Unsaturated Boc-lactam 40 (12.3 g, 52.0 mmol) was
TBS-Lactam Diene 29c
added, stirred for 5 min, and cooled to 0 °C. NaBH (3.89 g, 103 mmol)
4
To a round-bottomed flask was added 29b (123 mg, 1.0 mmol), i-
Pr NEt (348 μL, 2.0 mmol), and CH Cl (5 mL). The solution was cooled
was added slowly and the mixture was allowed to stir for 4 h at 0 °C.
The reaction was quenched with aq 1 M HCl (200 mL) and extracted
with EtOAc (3 × 300 mL). The combined organic layers were washed
2
2
2
to 0 °C and TBSCl (181 mg, 1.2 mmol) was added. The reaction was
allowed to stir at r.t. for 24 h. The resulting solution was diluted with
EtOAc (20 mL), washed aq NH Cl (10 mL), H O (10 mL) and brine (10
with brine (200 mL), dried (MgSO ), filtered, and concentrated. Purifi-
4
cation by flash column chromatography (hexanes–EtOAc, 40:60) de-
livered allylic alcohol 46 as a yellow oil; yield: 5.14 g (21.3 mmol,
4
2
mL), dried (Na SO ), and concentrated. Purification by flash column
2
4
chromatography (hexanes–Et O, 95:5) delivered TBS-lactam diene
4
2%); R = 0.23 (hexanes–EtOAc 40:60).
2
f
2
9c as a white solid; yield: 71 mg (30%); R = 0.27 (hexanes–Et O,
f
2
IR (neat): 3481, 1761, 1712, 1670 cm–1
.
90:10).
1
H NMR (500 MHz, CDCl ): δ = 4.66 (q, J = 6.7 Hz, 1 H), 4.12 (s, 2 H),
IR (neat): 1670, 1660 cm–1
3
.
3.47 (br s, 1 H), 2.03 (s, 3 H), 1.54 (s, 9 H), 1.45 (d, J = 6.7 Hz, 3 H).
1
H NMR (500 MHz, CDCl ): δ = 6.45 (dd, J = 17.7, 11.6 Hz, 1 H), 6.23
3
13
C NMR (125 MHz, CDCl ): δ = 169.8, 149.5, 149.2, 134.3, 83.2, 63.7,
3
(dd, J = 17.7, 2.5 Hz, 1 H), 5.37 (dd, J = 11.6, 2.5 Hz, 1 H), 3.79 (s, 2 H),
53.3, 28.2 (3), 23.1, 13.2;
2
.06 (s, 3 H), 0.96 (s, 9 H), 0.31 (s, 6 H).
ESI-HRMS: m/z [M + H]+ calcd for C12H19NO : 242.1392; found:
4
13
C NMR (100 MHz, CDCl ): δ = 177.9, 152.1, 129.3, 125.9, 118.7, 54.5,
3
242.1397.
2
6.7 (3), 19.4, 13.5, -5.2 (2).
ESI-HRMS: m/z [M + H]+ calcd for C13H23NOSi: 238.1622; found:
38.1621.
Boc-Lactam Diene 29a
2
To a round-bottomed flask was added allylic alcohol 46 (5.14 g, 21.3
mmol), Et N (36 mL, 256 mmol), and CH Cl (375 mL). The solution
3
2
2
Boc-hexahydro-1H-isoindolinone 54
was cooled to 0 °C and a solution of POCl (8 mL, 85.0 mmol) in CH Cl
3
2
2
N-Phenylmaleimide (53; 89 mg, 0.500 mmol), butylated hydroxytolu-
ene (BHT; 11 mg, 0.050 mmol), and Boc-lactam-diene 29a (56 mg,
(50 mL) was added. The reaction mixture was allowed to stir for 4 h
while slowly warming to 23 °C. The resulting solution was diluted
with Et O (700 mL), washed with H O (3 × 300 mL) and brine (3 × 300
0.250 mmol) were dissolved in toluene (1 mL). The solution was
2
2
sealed in a Teflon capped vial with Teflon tape, heated to 100 °C for 6
days, cooled to 23 °C, and concentrated under reduced pressure to af-
mL), dried (MgSO ), filtered, and concentrated. Purification by flash
4
column chromatography (hexanes–EtOAc, 85:15) delivered lactam-
diene 29a as a white solid; yield: 2.23 g (10.0 mmol, 47%); mp 82 °C;
Rf = 0.20 (hexanes–EtOAc, 80:20).
1
ford 95% conversion (crude H NMR analysis). Purification by flash
column chromatography (hexanes–EtOAc, 60:40) delivered 54 as a
white solid; yield: 74 mg (74%); mp 80–82 °C; R = 0.13 (hexanes–
EtOAc, 60:40).
IR (neat): 1769, 1705, 1147, 727, 691 cm–1
f
IR (neat): 1726, 1712, 1655, 1151 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 6.41 (dd, J = 11.6, 2.2 Hz, 1 H), 6.29 (dd,
3
.
J = 17.7, 2.2 Hz, 1 H), 5.44 (dd, J = 17.7, 11.6 Hz, 1 H), 4.15 (s, 2 H), 2.11
1
H NMR (500 MHz, CDCl ): δ = 7.48–7.38 (m, 3 H), 7.20–7.18 (m, 2 H),
(
s, 3 H), 1.56 (s, 9 H).
3
6.97 (dd, J = 7.5, 2.8 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 3.63 (d, J = 11.6
13
C NMR (125 MHz, CDCl ): δ = 168.2, 150.5, 150.0, 128.5, 125.0,
3
Hz, 1 H), 3.49 (ddd, J = 9.0, 8.9, 1.3 Hz, 1 H), 3.36 (d, J = 8.9 Hz, 1 H),
120.2, 82.9, 52.7, 28.3 (3), 13.8.
3.10 (ddd, J = 17.8, 7.5, 1.3 Hz, 1 H), 2.71 (ddd, J = 17.8, 9.0, 2.8 Hz, 1
ESI-HRMS: m/z [M + Na]+ calcd for C12H17NO Na: 246.1115; found:
3
H), 1.54 (s, 9 H), 1.39 (s, 3 H).
246.1106.
13
C NMR (125 MHz, CDCl ): δ = 177.5, 175.5, 163.7, 150.4, 139.9,
3
1
2
31.6, 131.4, 129.3 (2), 129.0, 126.5 (2), 83.3, 53.9, 47.8, 39.1, 35.8,
8.1 (3), 26.7, 24.5.
Lactam Diene 29b
To a round-bottomed flask was added Boc-lactam diene 29a (1.12 g,
ESI-HRMS: m/z [M + H]+ calcd for C22H24N O : 397.1763; found:
2 5
5.0 mmol) and EtOAc (10 mL). The resulting solution was cooled to
°C followed by the addition of aq 4 N HCl in 1,4-dioxane (12.5 mL,
397.1769.
0
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2756–2766

2
765
Synthesis
C. A. Olson et al.
Special Topic
Isoindolinone (54)/Deprotected Isoindolinone 55
X-ray Crystal Data
N-Phenylmaleimide 53 (77 mg, 0.450 mmol), BHT (10 mg, 0.040
mmol), and Boc-lactam diene 29a (50 mg, 0.220 mmol) were dis-
solved in toluene (1.2 mL). The solution was sealed in a Teflon capped
vial with Teflon tape, heated to 150 °C for 24 h, cooled to 23 °C, and
concentrated under reduced pressure. Purification by flash column
chromatography (hexanes–EtOAc, 50:50) delivered Boc-hexahydro-
Crystals of 59b were obtained by slow evaporation and suspended in
mineral oil at r.t. and a suitable crystal was selected. A mineral oil
coated brown plate thereby obtained of approximate dimensions
0.205 mm × 0.148 mm × 0.117 mm was mounted on a 50 μm Micro-
Mesh MiTeGen Micromount and transferred to a Bruker AXS SMART
APEX CCD X-ray diffractometer. The X-ray diffraction data were col-
lected at 100(2) K using MoKα (λ = 0.71073 Å) radiation. A total of
3672 frames were collected. The total exposure time was 8.16 h. The
frames were integrated with the Bruker SAINT software package us-
1
H-isoindolinone 54 (19 mg, 21%) and deprotected hexahydro-1H-
isoindolinone 55 (27 mg, 40%) as white solids; mp 180–184 °C (dec.);
Rf = 0.13 (EtOAc).
33
ing a narrow-frame algorithm. The integration of the data using a
triclinic unit cell yielded a total of 28119 reflections to a maximum θ
angle of 32.028° (0.67 Å resolution), of which 4661 were independent
55
IR (neat): 1699, 1678, 1195, 758, 689 cm–1
.
(
average redundancy 6.033, completeness = 96.2%, Rint = 2.84%,
1
H NMR (400 MHz, CDCl ): δ = 7.46–7.17 (m, 5 H), 6.79 (br s, 1 H),
Rsig = 2.11%) and 3900 (83.67%) were observed with Fo > 2σ(Fo2). The
final cell constants of a = 7.8560(2) Å, b = 8.1380(2) Å, c = 11.2941(3)
Å, α = 74.704(2)°, β = 88.544(2)°, γ = 87.086(2)°, volume = 695.52(3)
2
3
6
.75 (dd, J = 7.4, 2.8 Hz, 1 H), 4.49 (d, J = 10.3 Hz, 1 H), 3.45 (ddd,
J = 8.8, 8.7, 1.3 Hz, 1 H), 3.32 (d, J = 8.8 Hz, 1 H), 3.22 (d, J = 10.3 Hz, 1
H), 3.05 (ddd, J = 17.5, 7.4, 1.3 Hz, 1 H), 2.68 (ddd, J = 17.5, 8.7, 2.8 Hz,
3
Å , are based upon the refinement of the XYZ-centroids of 9497 re-
1
H), 1.37 (s, 3 H).
flections above 20 σ(I) with 5.20° < 2θ < 63.48°. Limiting indicies were
as follows: –11 ≤ h ≤ 11, –12 ≤ k ≤ 12, –16 ≤ l ≤ 16. Data were corrected
for absorption effects using the multi-scan method (SADABS). The ra-
tio of minimum to maximum apparent transmission was 0.956 with
minimum and maximum SADABS generated transmission coeffi-
cients of 0.7135 and 0.7463. Solution and data analysis were per-
13
C NMR (100 MHz, CDCl ): δ = 177.8, 175.9, 168.1, 140.0, 131.6,
3
129.3 (2), 129.0, 127.6, 126.6 (2), 50.4, 48.1, 39.5, 39.3, 26.8, 24.3.
ESI-HRMS: m/z [M + H]+ calcd for C17H16N O : 297.1239; found:
2
3
297.1237.
34
formed using the WinGX software package. The structure was
solved and refined in the space group P-1 (no. 2) with Z = 2.35 The
solution was achieved by charge-flipping methods using the program
Boc-Triazolinedione 59a
In a vial, 29a (112 mg, 0.500 mmol) and 4-phenyl-1,2,4-triazoline-
,5-dione (58; 105 mg, 0.600 mmol) were dissolved in anhydrous
CH Cl (2.5 mL). The reaction mixture was allowed to stir for 1 h at
3
36
SUPERFLIP and the refinement was completed using the program
2
2
SHELXL-2014/7. All non-H atoms were refined anisotropically. The
37
23 °C. The resulting solution was concentrated and purification by
H atom attached to N was freely refined isotropically after identifica-
tion by difference Fourier. All other H atoms were initially identified
by difference Fourier then included in the final refinement using the
riding-model approximation [C–H = 0.95, 0.98, 0.99 and 1.00 Å for
Ar–H, CH , CH , and CH; Uiso(H) = 1.2Ueq(C) except for methyl groups,
flash column chromatography (hexanes–EtOAc, 60:40) delivered Boc-
triazolinedione 59a as a white solid; yield: 187 mg (94%); mp 175–
1
77 °C; R = 0.25 (hexanes–EtOAc, 60:40).
f
IR (neat): 1756, 1701, 764, 697 cm–1
.
3
2
where Uiso(H) = 1.5Ueq(C)]. Full-matrix least-squares refinement on F2
1
H NMR (500 MHz, CDCl ): δ = 7.51–7.47 (m, 4 H), 7.41–7.38 (m, 1 H),
3
led to convergence, (Δ/σ)max = 0.001, (Δ/σ)
= 0.000, with
6.84 (dd, J = 3.2, 3.0 Hz, 1 H), 4.66 (dd, J = 19.1, 3.2 Hz, 1 H), 4.24 (m, 1
mean
2
2
R = 0.0399 and wR = 0.1108 for 4661 data with F > 2σ(Fo ) using 0
H), 4.19 (m, 1 H), 3.98 (dd, J = 10.9, 0.7 Hz, 1 H), 1.57 (m, 3 H), 1.56 (s,
1
2
o
restraints and 203 parameters. A final difference Fourier synthesis
9
H).
–
3
showed features in the range of Δρ
= 0.422 e /Å to Δρmin = –0.218
max
13
C NMR (125 MHz, CDCl ): δ = 162.4, 152.9, 152.0, 149.9, 136.7,
–
3
3
e /Å . All residual electron density away was within accepted norms
and was deemed of no chemical significance. Molecular diagrams
1
2
30.9, 129.4 (2), 128.6, 125.9, 125.3 (2), 84.3, 57.7, 55.1, 43.7, 28.2 (3),
0.5.
38,39
were generated using ORTEP-3.
ESI-HRMS: m/z [M + Na]+ calcd for C20H22N O Na: 421.1488; found:
4
5
421.1496.
TBS-Triazolinedione 59c
To a vial was added 29c (34 mg, 0.140 mmol) and 4-phenyl-1,2,4-tri-
Triazolinedione 59b
azoline-3,5-dione 58 (30 mg, 0.150 mmol) and dissolved in CH Cl2
2
In a vial, 29b (62 mg, 0.500 mmol) and 4-phenyl-1,2,4-triazoline-3,5-
dione (58; 105 mg, 0.600 mmol) were dissolved in CH Cl (2.5 mL).
The reaction mixture was allowed to stir for 1 h at 23 °C. The resulting
solution was concentrated and purification by flash column chroma-
tography (hexanes–EtOAc, 5:95) delivered triazolinedione 59b as a
(700 μL). The reaction mixture was allowed to stir for 1 h at 23 °C. The
resulting solution was concentrated and purification by flash column
chromatography (hexanes–EtOAc, 55:35) delivered TBS-triazolinedi-
one 59c as a white solid; yield: 40 mg (0.10 mmol, 68%); mp 131–
2
2
136 °C (dec.); R = 0.38 (hexanes–EtOAc, 60:40).
f
white solid; yield: 105 mg (71%); mp 214–216 °C; R = 0.30 (EtOAc).
IR (neat): 1712, 1694, 1682, 745, 692 cm–1
f
.
IR (neat): 3208, 1699, 1693, 747, 690 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 7.50–7.40 (m, 5 H), 6.61 (dd, J = 3.1, 3.0
3
1
H NMR (500 MHz, CDCl ): δ = 7.53–7.38 (m, 5 H), 6.70 (dd, J = 3.1, 3.0
Hz, 1 H), 4.63 (dd, J = 18.5, 3.1 Hz, 1 H), 4.18 (dd, J = 18.5, 3.0 Hz, 1 H),
3
Hz, 1 H), 6.36 (br s, 1 H), 4.66 (dd, J = 18.7, 3.1 Hz, 1 H), 4.20 (dd,
J = 18.7, 3.0 Hz, 1 H), 3.85 (d, J = 9.7 Hz, 1 H), 3.78 (d, J = 9.7 Hz, 1 H),
3.78 (d, J = 10.3 Hz, 1 H), 3.74 (d, J = 10.3 Hz, 1 H), 1.54 (s, 3 H), 0.99 (s,
9 H), 0.36 (s, 3 H), 0.33 (s, 3 H).
1
.59 (s, 3 H).
13
C NMR (125 MHz, CDCl ): δ = 170.9, 152.9, 152.0, 138.6, 131.1,
3
13
C NMR (125 MHz, CDCl ): δ = 166.9, 153.0, 152.0, 136.5, 131.0,
129.4 (2), 128.5, 125.4 (2), 121.3, 60.6, 56.2, 43.4, 26.7 (3), 20.5, 19.7,
–5.1, –5.2.
3
129.4 (2), 128.6, 125.4 (2), 122.7, 60.7, 51.9, 43.5, 20.5.
ESI-HRMS: m/z [M + H]+ calcd for C15H14N O : 299.1144; found:
ESI-HRMS: m/z [M + H]+ calcd for C21H28N O Si: 413.2009; found:
4
3
4
3
299.1128.
413.1987.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2756–2766

2
766
Synthesis
C. A. Olson et al.
Special Topic
(13) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(
b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev.
Acknowledgment
2003, 110, 704.
(
14) (a) Whitehouse, D. L.; Nelson, K. H.; Savinov, S. N.; Lowe, R. S.;
Austin, D. J. Bioorg. Med. Chem. Lett. 1998, 6, 1273. (b) Brown, D.
S.; Elliot, M. C.; Moody, C. J.; Mowlem, T. J.; Marion, J. P. Jr.;
Padwa, A. J. Org. Chem. 1994, 59, 2447.
15) (a) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.;
Ruano, J. L. G. Tetrahedron Lett. 1994, 35, 2053. (b) Langois, N.;
Rojas, A. Tetrahedron Lett. 1993, 34, 2477.
16) The anti-diastereomer 12 is presumed to be favored.
17) Liu, H.; Yang, Z.; Pan, Z. Org. Lett. 2014, 16, 5902; and references
cited therein.
18) Ramachary, D. B.; Shashank, A. B.; Karthik, S. Angew. Chem. Int.
Ed. 2014, 53, 10420; and references cited therein.
19) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
Financial support from the Research Corporation for Scientific Ad-
vancement (Cottrell College Science Award) and Illinois State Univer-
sity is gratefully acknowledged. Molecular assignments were
confirmed with assistance from high-resolution MS instrumentation
acquired through support by the National Science Foundation MRI
program (CHE 1337497) and Prof. Christopher Mulligan is gratefully
acknowledged for support and training. The authors thank the NSF-
MRI program (CHE 1039689) for funding the X-ray diffractometer, Dr.
John Goodell and Prof. Steven Peters for helpful discussions, and Bren-
dan Thompson for assistance with data acquisition.
(
(
(
(
(
Supporting Information
(b) Yue, X.; Li, Y. Synthesis 1996, 736. (c) Almeida, W. P.; Correia,
C. R. D. Tetrahedron Lett. 1994, 35, 1367.
Supporting information for this article is available online at
(
20) (a) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V.
P. P. Chem. Rev. 2009, 109, 2551. (b) Smith, A. B. III; Simov, V.
Org. Lett. 2006, 8, 3315.
http://dx.doi.org/10.1055/s-0034-1380221.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
(
(
(
(
21) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106,
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2756–2766