Skeletal and appendage diversity as design elements in the synthesis of a discovery library of nonaromatic polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas

Article abstract of DOI:10.1016/j.tet.2008.02.033

Amino-acid derived cross-conjugated trienes were used as a starting point for the synthesis of a discovery library of over 200 polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas. The main feature of this library synthesis is a triple branching

Full text of DOI:10.1016/j.tet.2008.02.033

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6997e7007
www.elsevier.com/locate/tet
Skeletal and appendage diversity as design elements
in the synthesis of a discovery library of nonaromatic polycyclic
5-iminooxazolidin-2-ones, hydantoins, and acylureas
*
S. Werner , D.M. Turner, P.G. Chambers, K.M. Brummond
Center for Chemical Methodologies and Library Development (UPCMLD), University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 18 November 2007; received in revised form 8 February 2008; accepted 11 February 2008
Available online 15 February 2008
Abstract
Amino-acid derived cross-conjugated trienes were used as a starting point for the synthesis of a discovery library of over 200 polycyclic
5-iminooxazolidin-2-ones, hydantoins, and acylureas. The main feature of this library synthesis is a triple branching strategy, which provides
efficient access to five skeletally diverse scaffolds. In addition, four sets of building blocks were applied in both a front end and a back end
diversification strategy. Multiple fused rings were obtained by cyclization of diamides with phosgene and stereoselective DielseAlder reactions
with maleimides. The 5-iminooxazolidin-2-one scaffold was rearranged into the isomeric hydantoin scaffold through a sequence of ring-opening
and ring-closing reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Library design; Skeletal diversity; Appendage diversity; Polycycles; DielseAlder reaction
1. Introduction
fragmentation processes13 in the library design. Polymorphic
scaffolds14 and sigma-elements that contain appendages with
pre-encoded skeletal information as defined by Schreiber15
have been described as alternative strategies to obtain skeletal
diversity.
Distributing compounds into chemical descriptor space can
be achieved best by combining several diversity elements.
For the discovery library of polycyclic nonaromatic 5-imino-
oxazolidin-2-ones, hydantoins, and acylureas presented here,
a triple branching strategy (see Scheme 1) allowing for the
combination of appendage and skeletal diversity elements
was employed (Fig. 1).
The amino-acid derived d-lactam A containing an electron
deficient cross-conjugated triene system and diamide function-
alities provides a densely functionalized key intermediate,
which serves as a starting point in the skeletal diversity strat-
egy for the generation of multiple scaffolds. The amide func-
tionalities are cyclized with phosgene to form a sterically
biased and electronically tuned 5-iminooxazolidin-2-one tri-
ene system. This second generation triene undergoes a single
cycloaddition reaction with dienophiles followed by the newly
The search for new biological probes capable of modula-
ting biological pathways has led to the rapid development of
diversity oriented synthesis (DOS), a strategy used to access
larger numbers of structurally unique compounds.1e3 In addi-
tion to occupying new chemical space, these molecules need
to bind to proteins, be of a defined molecular complexity,4
be structurally rigid, and possess three-dimensionality.5
Many DOS libraries are inspired by natural products because
of their richness in stereochemical and three-dimensional
structural diversity.6,7 Although it is not easy to measure the
diversity of a certain collection of compounds,8,9 four diversity
elements have been described: building block, stereochemical,
appendage, and skeletal.10 Recently, skeletal diversity has
evolved as the most powerful element in the design of
small molecule discovery libraries.11 It can be generated
through branching strategies12 or through rearrangement and
* Corresponding author.
E-mail address: werner-stefan@gmx.net (S. Werner).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.033

6998
S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
1. LiOH/THF
2.R2NH2 2{1-6},
HOBt, DMAP,
EDCI, DCM, r.t.
O
O
HN
R1
HN
MeOOC
O
18-93%
R1
1{1-2}
5{1-2,1-6}
phosgene
(20% in toluene),
NEt3, DCM
R2 NH
-20 °C to r.t.
-10 °C to 0 °C
O
O
O
O
NEt2
O
N
N
O
O
R1
6{1-2,1-5}
7{1-2,1-5}
3{1-5}
R1
R2
N
R2
N
R3
N
R3
N
3{1-5}
O
O
O
O
toluene, 90 °C
toluene, 90 °C
0-33%
0-35%
5-72%
O
O
O
O
O
O
O
NEt2
O
O
N
H
N
H
O
H
N
R3
O
N
H
R1
R1
R2
N
O
R2
N
R1
O
R2
N
O
O
9{1-2,1-5,1-5}
N
N
8{1-2,1-5,1-5}
10{1-2,1-5,1-5}
R3
O
R3
N
O
R3
O
if maleimide in excess
H2, Pd/C,
THF, r.t.
H2, Pd/C,
THF, r.t.
23-99%
17-85%
O
O
Et
H
O
11{1-2,1-5,1-5}
O
NEt2
Et
N
O
O
N
R1
H
O
R2
N
O
R1
R2
N
N
O
R3
O
N
12{1-2,1-5,1-5}
R3
O
R4NH2,
CHCl3, r.t.
0-43%
10-99%
R4
O
O
NH
N
O
Et
O
N
Et
R2
N
H
H
H
R2
N
R1
R1
O
O
O
O
N
R3
13{1-2,1-5,1-5}
N
O
R3
14{1-2,1-5,1-5,1-6}
O
wet MeOH, r.t. 85-89%
Scheme 1. Synthesis of polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas.
formed diene moiety reacting with another dienophile in a
second DielseAlder reaction or it can undergo a hetero-
DielseAlder reaction involving the carbonyl group.16
Further diversification of the 5-iminooxazolidin-2-one
moiety can potentially be achieved by ring-opening reactions
with amines and rearrangement into the isomeric hydantoin
scaffold, an important pharmacophore.17 Although 4-imino-
oxazolidin-2-ones are of interest as fungicides,18 little is
known about the isomeric 5-iminooxazolidin-2-ones.19 There-
fore it was appealing to synthesize a discovery library based

S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
6999
O
H
H2N
H2N
H2N
O
O
OMe
2{2}
COOMe
2{3}
N
H
N
R3
O
2{1}
F
R1
O
R2
N
H2N
H2N
H2N
R4
NH
O
N
O
O
NH
N
O
H
N
Et
N
R3
O
O
Et
H
H
O
2{4}
2{5}
2{6}
R2
N
R1
R1
R2
N
Figure 3. Building blocks 2{1e6} used in the library synthesis.
O
O
O
O
N
N
R3
O
B
E
HN
R1
R3
O
O
O
O
O
NH
N Me
N Et
R2
NH
O
A
O
H
O
O
O
O
N
O
NEt2
Et
O
3{1}
3{2}
3{3}
Et
N
R2
N
O
O
H
O
COOMe
R1
R1
O
N
Ph
N
R2
N
O
O
N
O
O
N
3{4}
3{5}
R3
O
C
R3
O
D
Figure 4. Building blocks 3{1e5} used in the library synthesis.
Figure 1. d-Lactams A as key intermediates for a structurally diverse discovery
library.
their relatively small substituents, N-phenyl maleimide 3{4}
as an aromatic representative and methyl N-acetate maleimide
3{5} because of its more polar character. The last set of build-
ing blocks consisted of six amines 4{1e6} that were used
to open the 5-iminooxazolidin-2-one moiety (Fig. 5). Again,
the selection included small polar (4{1}, 4{6}) and lipophilic
(4{4}) aliphatic substituents as well as a polar (4{2}) and
lipophilic (4{5}) aromatic representatives. N-(2-Aminoethyl)-
morpholine 4{3} was chosen because of its basic nitrogen
and ethanolamine (4{1}) because of its ability to act as hydro-
gen bond donor.
on this new motif. Furthermore, targeted scaffolds BeF are all
nonaromatic and polycyclic in nature, a class of compounds of
interest because of their natural product like character.20
2. Results and discussion
2.1. Library design
In addition to five highly functionalized scaffolds differing
significantly in volume, flexibility, number of fused rings, and
their ability to donate and accept hydrogen bonds, the library
design involved four sets of building blocks. Two triene con-
taining methyl esters 1{1e2}16 (Fig. 2) and a set of six amines
2{1e6} (Fig. 3) were used for the essential conversion of
1{1e2} to 5{1e2,1e6} (Scheme 1). Cyclopropylmethyl-
amine 2{1} was chosen as a small lipophilic building block,
methoxyethylamine 2{2} and glycyl methyl ester 2{3} as
more polar substituents, benzylamine 2{4} and 2-amino-
methylpyridine 2{6} to include aromatic and heteroaromatic
systems, and tryptamine 2{5} because of its hydrogen bond
donor abilities. Five maleimides 3{1e5} were applied as sym-
metric dienophiles in a DielseAlder reaction in order to avoid
the formation of regioisomers (Fig. 4). Maleimide itself 3{1}
was selected to include a second hydrogen bond donor,
N-methyl and N-ethyl maleimide 3{2} and 3{3} because of
H2N
H2N
H2N
OH
N
O
N
4{1}
4{2}
4{3}
H2N
H2N
H2N
OMe
4{6}
4{4}
4{5}
Figure 5. Building blocks 4{1e6} used in the library synthesis.
2.2. Library synthesis
The cross-conjugated trienes 1{1e2} were obtained via
a Rh(I)-catalyzed Aldereene reaction of propiolamides.16,21
Saponification of the methyl esters 1{1e2} with lithium
hydroxide, followed by HOBt/DMAP/EDCI mediated amida-
tion with amines 2{1e6} provided amides 5{1e2,1e6} in
yields ranging from 18e93% (Scheme 1, Table 1) for the
two steps.
The reaction conditions for the cyclization reaction with
phosgene were optimized on small scale (0.1 mmol) with
diamide 5{1,4} prior to applying it on large scale to all di-
amides 5{1e2,1e6}. Diamide 5{1,4} was treated with 3 equiv
of phosgene and triethylamine in dichloromethane at ꢀ10 ꢁC
O
O
HN
MeOOC
HN
MeOOC
Me
1{1}
1{2}
Figure 2. Building blocks 1{1e2} used as starting points in the library
synthesis.

7000
S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
Table 1
Yields in % for the synthesis of amides 5{1e2,1e6} from methyl esters
1{1e2} and amines 2{1e6}
carbamates from phosgene and triethylamine has been
described.22
Assuming quantitative conversion in the cyclization step,
5-iminooxazolidin-2-ones 6{1e2,1e5} and 7{1e2,1e5}
were taken on to the next reaction. Heating each in a Radley’s
Carousel for 2 h at 90 ꢁC with 1.3 equiv of maleimide 3{1e5}
in toluene gave the DielseAlder cycloadducts, which could be
easily purified on an ISCO Optix 10 chromatography station.
The carbamates 8{1e2,1e5,1e5} were obtained in 0e33%
while the adducts 10{1e2e1e5,1e5} were isolated in 5e74%
yield (Table 2). In several cases a second DielseAlder
reaction occurred providing adduct 9{1e2,1e5,1e5} in
0e11% yield, which could also be separated by chromato-
graphy (Tables 2 and 3). It is thought that in those cases the
cyclization reaction did not go to completion and thus the
maleimide was present in excess. This hypothesis is supported
by the cyclization reaction of 5{2,2}, which was quenched at
ꢀ10 ꢁC, preventing completion of the reaction, and the crude
reaction mixture was applied to the DielseAlder reaction with
3{4}. In this case, carbamate 6{2,2,4} was not observed, but
the double DielseAlder adduct 9{2,2,4} was obtained in
35% yield (Table 2, footnote b). An isomerization of the
exocyclic double bond in 10{1e2,1e5,1e5} was noticed23
but the E/Z-isomers were not separated because the diene
system was reduced in the following step.
5{1e2,1e6}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
1{1}
1{2}
a
68
55
18
51
65
83
75
30
93
79
da
55
Not attempted as 5{2,6} did not undergo a selective reaction with
phosgene in the next step.
for 30 min. The reaction mixture was then warmed to 0 ꢁC
and quenched by adding a saturated ammonium chloride/brine
(1/10) solution. 5-Iminooxazolidin-2-one 7{1,4} was the only
observed product. When the reaction was carried out on larger
scale under otherwise identical conditions, the bicycle 7{1,4}
was immediately hydrolyzed back to 5{1,4} while quenching
with saturated ammonium chloride/brine (1/10) because of the
large amount of HCl that was generated during the quenching
process. This could be prevented by using 6 equiv of triethyl-
amine and quenching the reaction mixture with a saturated
sodium bicarbonate solution. All 5-iminooxazolidin-2-ones
7{1e2,1e5} were highly acid sensitive and converted back
into the starting material if a purification by chromatography
on silica was attempted. Thus, they were not purified and in-
stead used crude in the following DielseAlder reaction. The
pyridine containing diamide 5{2,6} was the only diamide
that did not undergo a cyclization reaction with phosgene.
Upon addition of phosgene, the reaction mixture turned black
and no product could be detected.
On large scale, it proved to be necessary to warm the
reaction mixture from ꢀ10 ꢁC to room temperature prior to
quenching it with saturated sodium bicarbonate to obtain
complete conversion. However, carbamate 6{1e2,1e5} was
now formed as a side product. Quenching the reaction at
ꢀ10 ꢁC or 0 ꢁC led to incomplete reactions but prevented
the carbamate formation (Table 2, footnotes b and c). Al-
though a rather unusual reaction, the formation of N,N-diethyl
Table 3
Purities in % for the double DielseAlder adducts 9{1e2,1e5,1e5}, purity
detection by ELS
Compound
Purity
9{1,1,3}
9{1,2,2}
9{1,4,2}
9{2,2,4}
9{2,2,5}
9{2,3,4}
9{2,5,4}
a
>99
64
71
90a
>99
99
>99
Purity estimated by 1H NMR.
Table 2
Yields in % for the synthesis of 5-iminooxazolidin-2-ones 8{1e2,1e5,1e5},
9{1e2,1e5,1e5}, and 10{1e2,1e5,1e5} from amides 5{1e2,1e5} and
maleimides 3{1e5}a
Because of concern for the reactivity24 of the exocyclic
double bond of the lactam, the diene in 8{1e2,1e5,1e5}
and 10{1e2,1e5,1e5} was reduced by hydrogenation with
Pd/C to give carbamates 11{1e2,1e5,1e5} in 23e99% yield
(Table 4) and lactams 12{1e2,1e5,1e5} in 17e85% yield
(Table 5). Most reactions were complete after 4 h, but the
indole containing substrates required reaction times of 24 h.
The structure of the carbamates was confirmed by an X-ray
structure analysis of 11{1,1,4} (Fig. 6a). Both DielseAlder
reactions took place in a diastereoselective fashion. The initial
DielseAlder cycloaddition reaction occurred with endo selec-
tivity from the opposite face of the R1 substituent as seen in
the X-ray structure analysis of 12{2,1,4} (Fig. 6b). Based on
comparison studies with a previously described double Dielse
Alder adduct16 the stereochemistry for 9{1e2,1e5,1e5} has
been tentatively assigned as resulting from an addition of
the second dienophile from the less hindered convex face in
endo mode.
8{1e2,1e5,1e5}/ 3{1}
9{1e2,1e5,1e5}/
3{2}
3{3}
3{4}
3{5}
10{1e2,1e5,1e5}
5{1,1}
5{1,2}
5{1,3}
5{1,4}
5{1,5}
5{2,1}
5{2,2}
14/d/13 22/d/58 20/5/38
13/d/13 12/3/17 13/d/18 10/d/17 17/d/13
20/d/7 22/d/35 24/d/46 32/d/31 27/d/30
27/d/33 28/8/42 28/d/47 25/d/53 27/d/32
11/d/13 15/d/18 16/d/60 22/d/39 20/d/39
18/d/5 25/d/43 27/d/53 28/d/42 22/d/37
24/d/37 21/d/37
18/d/29 17/d/39 13/d/51 33/d/61 12/7/29
d/35/36b
5{2,3}
5{2,4}
5{2,5}
a
20/d/12 25/d/58 27/d/40 18/3/50
d/d/32c d/d/61c d/d/74c d/4/19c d/d/68c
17/11/42 24/d/57 19/d/72 13/2/61 9/d/70
24/d/39
Yield in % for carbamate 8{1e2,1e5,1e5}/double DielseAlder adduct
9{1e2,1e5,1e5}/DielseAlder adduct 10{1e2,1e5,1e5}.
b
Phosgene reaction quenched at ꢀ10 ꢁC.
c
Phosgene reaction quenched at 0 ꢁC.

S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
7001
Table 4
Yields (purities) in % for the hydrogenation of 8{1e2,1e5,1e5}, purity detec-
tion by ELS
O
(a)
O
H
NEt2
Et
O
N
11{1e2,1e5,1e5} 3{1}
3{2}
3{3}
3{4}
3{5}
O
5{1,1}
5{1,2}
5{1,3}
5{1,4}
5{1,5}
5{2,1}
5{2,2}
5{2,3}
5{2,4}
5{2,5}
a
92 (>99) 99 (>99) 85 (99)
70 (>99) 90 (96)
75 (70)
70 (87)
Me
N
N
85 (>99) 51 (97)
73 (98)
70 (>99)
65 (93)
82 (93)
86 (99)
62 (>99)
99 (90)
O
59 (95)
d
O
89 (>99) 78 (97)
27 (86) 25 (>99)
69 (>99) 78 (90)
87 (>99) 70 (>99) 61 (96)
11{1,1,4}
96 (98)
80 (>99) 81 (98)
96 (99)
96 (98)
86 (98)
86 (86)
d
86 (70)
64 (98)
d
67 (98)
79 (96)
d
96 (97)
d
63 (94)
83 (96)
d
23 (>99) 38 (>99) 39 (90)a 41 (>99)
Purity estimation by 1H NMR.
Table 5
Yields (purities) in % for the hydrogenation of 10{1e2,1e5,1e5}, purity
detection by ELS
12{1e2,1e5,1e5} 3{1}
3{2}
48 (<50) 35 (82)
23 (>99) 35 (57) 52 (<50) 43 (<50) 44 (<50)
3{3}
3{4}
3{5}
5{1,1}
5{1,2}
5{1,3}
5{1,4}
5{1,5}
5{2,1}
5{2,2}
5{2,3}
5{2,4}
5{2,5}
a
51 (93)
57 (>95) 50 (<50)
(b)
O
Et
H
O
18 (91)
25 (88)
24 (93)
61 (99)
76 (78)
25 (98)
46 (90)
74 (97)
58 (95)
50 (77)
79 (94)
85 (97)
83 (94)
36 (93)
32 (75)
53 (94)
36 (91)
60 (98)
46 (87)
43 (93)
73 (80)
32 (95)
46 (84)a
53 (76)
29 (94)
N
23 (90)b 17 (84)
44 (>99) 46 (98)
O
Bn
N
N
63 (99)
83 (80)a 24 (80)
45 (95)
O
61 (77)a 37 (94)
34 (94)
33 (98)
O
17 (<50) 42 (95)b 53 (85)
12{2,1,4}
Purity detection by UV 254 nm.
b
Purity estimation by 1H NMR.
Although the 5-iminooxazolidin-2-ones 12{1e2,1e5,1e5}
are very stable compounds, e.g., stirring in 1 M HCl/MeOH
for 24 h did not result in any reaction or decomposition, the
5-iminooxazolidin-2-one ring system can be opened by reac-
tion with an excess primary amine in chloroform at room
temperature. This reaction tolerated a wide range of amines
and 87 acylureas 14{1e2,1e5,1e5,1e6} were prepared
(Table 6). The structure of those tricycles was confirmed by
an X-ray structure of 14{1,1,4,1},25 clearly showing the amide
as well as the acylurea functionality. In several cases a less
polar side product was observed, which could be easily
separated by chromatography on silica and was identified
as hydantoin 13{1e2,1e5,1e5} based on a characteristic
chemical shift change of a 13C NMR resonance from 147 to
173 ppm. The structure was later confirmed by the X-ray
structure analysis of 13{1,1,4} (Fig. 6c). Alternatively, stirring
the acylureas 14{1e2,1e5,1e5,1e6} in wet methanol for
24 h resulted in a selective conversion into the corresponding
hydantoins 13{1e2,1e5,1e5} in 85e89% yield. In all cases,
the substituent R2 on the amide was preserved in the molecule
while the substituent R4 on the acylurea was cleaved off. The
formation of hydantoins by an intramolecular nucleophilic at-
tack of an amide hydrogen on an ureido carbonyl,26 carbamoyl
carbonyl27 or benzotriazole carbonyl28 has been reported
previously, but in all cases a base was required. The intra-
molecular cyclization between the amide hydrogen and the
acylurea carbonyl of 14{1e2,1e5,1e5,1e6} took place under
O
O
(c)
Et
N
H
N
Me
O
O
N
O
13{1,1,4}
Figure 6. X-ray structures of 11{1,1,4}, 12{2,1,4}, and 13{1,1,4}.34
very mild conditions in wet methanol. As all library members
will be stored in the UPCMLD compound collection as
solution in DMSO at ꢀ78 ꢁC, it was important to investigate
the stability of the acylurea 14{1e2,1e5,1e5,1e6} in
DMSO-d6 under those conditions. While 14{2,5,2,1} had
a half life time in DMSO-d6 at room temperature of only
21 days and completely rearranged into 13{2,5,2,1} after

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S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
Table 6
Yields (purities) in % for the formation of the hydantoins 13{1e2,1e5,1e5} and acylureas 14{1e2,1e5,1e5,1e6} from the DielseAlder adducts 12{1e2,1e
5,1e5} and amines 4{1e6}, purity detection by ELSa
13{1e2,1e5,1e5}/
14{1e2,1e5,1e5,1e6}
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
12{1,1,1}
12{1,1,2}
12{1,1,3}
12{1,1,4}
12{1,1,5}
12{1,3,2}
12{1,3,3}
12{1,3,4}
12{1,3,5}
12{1,4,1}
12{1,4,2}
12{1,4,4}
12{1,4,5}
12{1,5,2}
12{1,5,3}
12{1,5,4}
12{1,5,5}
12{2,1,1}
12{2,1,2}
12{2,1,3}
12{2,1,4}
12{2,1,5}
12{2,2,3}
12{2,2,4}
12{2,3,4}
12{2,4,1}
12{2,4,2}
12{2,4,3}
12{2,4,4}
12{2,4,5}
12{2,5,2}
12{2,5,3}
12{2,5,4}
12{2,5,5}
a
43/22 (>99/>99)
d/87 (d/83)
d/94 (d/>99)
d/92 (d/>99)
dc/58 (dc/98)
16/56 (>99/>99)
d/85 (d/97)
6/38 (>99/71)
d/67 (d/90b)
d/64 (d/>99)
d/96 (d/>99)
d/52 (d/60)
59/d (94/d)
d/76 (d/>99)
d/95 (d/88)
d/63 (d/98)
d/59 (d/90b)
d/63 (d/>99)
d/61 (d/87)
dd/70 (dd/>99)
d/73 (d/>99)
d/53 (d/99)
33/d (98/d)
d/51 (d/99)
d/5 (d/>99)
d
d
d
d
d
d/85 (d/82)
d
d
d
d
d/81 (d/84)
d/99 (d/>99)
d/94 (d/>99)
d/82 (d/95)
d/73 (d/97)
d/93 (d/98)
d/64 (d/96)
d/65 (d/95b)
d/80 (d/>99)
d/90 (d/>99)
d/52 (d/>99)
d/70 (d/98)
d/88 (d/98)
d/95 (d/>99)
d
d
17/47 (>99/90b)
d
d
d
d
d
d
d
d
d
d
d
d
d
19/46 (93/90b)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d/67 (d/98)
8/54 (91/95b)
d/80 (d/>99)
d/72 (d/>99)
d
d
d/40 (d/>99)
d
d
d
d/42 (d/>99)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d/7 (d/95b)
d
d/56 (d/90b)
d
d/79 (d/>99)
d
d
d
d
d
d
d
d/41 (d/90b)
d
d
d
d/52 (d/>99)
d/66 (d/>99)
d/36 (d/>99)
d/10 (d/>99)
d/54 (d/98)
d/86 (d/99)
16/62 (95/94)
22/55 (95/90b)
d/45 (d/>99)
d
28/37 (95b/99)
d/61 (d/97)
d/62 (d/99)
d
d/37 (d/90)
d
d
d
d
d/50 (d/95b)
d/16 (d/90b)
d
9/d (99/d)
d
d/60 (d/99)
d
d
d
d
d
d
d
d
d
d
41/50 (<50/90b)
d
d
d/54 (d/67e)
d
d
41/35 (95/95)
44/36 (86/>99)
16/36 (81/97)
d/89 (d/>99)
d/53 (d/90b)
d
d
d
d/19 (d/>99)
d/51 (d/92)
d/98 (d/99)
d/46 (d/77e)
d/65 (d/>99)
d/74 (d/79e)
d
d
d/42 (d/90)
d/85 (d/95b)
d
d/63 (d/90b)
d/71 (d/95b)
d
d/97 (d/>99)
d/66 (d/93)
d
d/73 (d/>99)
d
d
d
d
d/50 (d/99)
Yield (purity) in % for hydantoin 13{1e2,1e5,1e5}/acylurea 14{1e2,1e5,1e5,1e6}.
Purity estimated by 1H NMR.
b
c
d
e
Hydantoin 13{1,1,5} was synthesized from pure acylurea 14{1,1,5,1} by stirring in wet MeOH in 85% yield (purity >99%).
Hydantoin 13{2,1,3} was synthesized from pure acylurea 14{2,1,3,1} by stirring in wet MeOH in 89% yield (purity 95%).
Purity detected by UV 254 nm.
2 months, no rearrangement was observed if stored at ꢀ78 ꢁC
after 3 months.
In contrast to 12{1e2,1e5,1e5}, carbamates 11{1e2,1e
5,1e5} did not undergo ring-opening with amines. Carbamate
11{2,1,4} was irradiated in the microwave in chlorobenzene
with benzylamine 4{5} and after irradiation for 15 min at
180 ꢁC no reaction was observed.
accepted library members was 96.6% (Table 7). The Dielse
Alder adducts 12{1e2,1e5,1e5} contained the highest
number of rejected compounds and the accepted compounds
from this group had a slightly lower overall purity (94.6%)
Table 7
Number of compounds and purities in % for the five polycyclic scaffolds
Scaffold
Number of
compounds
in library
Number of
compounds with
purity ꢂ90%a
Average
puritya,b
2.3. Purity analysis
Altogether 7 double DielseAlder adducts 9{1e2,1e5,1e5},
44 carbamates 11{1e2,1e5,1e5}, 50 DielseAlder adducts
12{1e2,1e5,1e5}, 18 hydantoins 13{1e2,1e5,1e5}, and
87 acylureas 14{1e2,1e5,1e5,1e6} were synthesized. All
compounds were analyzed by LCeMS/ELSD (Tables 2e6).
One hundred sixty-seven compounds (81% of all compounds)
passed the purity criteria of 90% by ELSD for the UPCMLD
compound collection. The average purity by ELSD of the
9{1e2,1e5,1e5}
11{1e2,1e5,1e5}
12{1e2,1e5,1e5}
13{1e2,1e5,1e5}
14{1e2,1e5,1e5,1e6}
Complete library
a
7
44
5
40
97.8
97.3
94.6
96.8
97.0
96.9
50
18
30
15
87
206
77
167
Purity detected by ELS, for exceptions see Tables 2e6.
b
Average purity for all compounds that were accepted into the UPCMLD
compound collection (purity ꢂ90% by ELS).

S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
7003
because in several cases those compounds were contaminated
with small amounts of the corresponding double DielseAlder
adducts.
5-iminooxazolidin-2-one scaffold, which allowed excellent
stereocontrol in the following DielseAlder reactions. Although
the 5-iminooxazolidin-2-ones are very stable compounds, a
conversion into acylureas and hydantoins was accomplished.
The combination of skeletal and appendage diversity led to a
library of 206 tri- to hexacyclic 5-iminooxazolidin-2-ones,
acylureas, and hydantoins. The physicochemical profiling
of all compounds demonstrated a high degree of diversity
within each compound class and among the five scaffolds.
All compounds were analyzed by LCeMS and are currently
being evaluated in several high-throughput-screening pro-
grams. Results on their biological activities can be accessed
in PubChem (http://pubchem.ncbi.nlm.nih.gov).
2.4. Physicochemical profiling
3-D structures of all library members were built and mini-
mized using the MM2 force field in Macro Model 8.6. The
physicochemical profiling of the 206 library members was
analyzed computationally using QikProp 2.1.29 Besides slightly
elevated molecular weights in case of the double DielseAlder
adducts 9{1e2,1e5,1e5}, carbamates 11{1e2,1e5,1e5},
and acylureas 14{1e2,1e5,1e5,1e6}, all molecular descrip-
tors show values well within the range that is considered
tool-30 and drug-like31 (Table 8). Because of the combination
of skeletal and appendage diversity, distinct differences in the
physicochemical properties exist not only within the five
compound classes but also among the scaffolds. A difference
in the average molecular weight of around 160 Daltons can
be observed between the double DielseAlder adducts
9{1e2,1e5,1e5}, the DielseAlder adducts 12{1e2,1e5},
and the hydantoins 13{1e2,1e5,1e5}, which also have a
clearly smaller solvent-accessible volume. While the acylureas
14{1e2,1e5,1e5,1e6} attract attention because of their in-
creased ability to act as hydrogen bond donors, the double
DielseAlder adducts 9{1e2,1e5,1e5} are especially rich in
the number of hydrogen bond acceptors. The average log P
and log S values differ by almost an order of magnitude be-
tween the carbamates 11{1e2,1e5,1e5} and the DielseAlder
adducts 12{1e2,1e5,1e5}. The distinction is even more dra-
matic regarding the number of rotatable bonds with an average
of 4.7 for the relatively rigid hydantoins 13{1e2,1e5,1e5}
and 9.0 for the more flexible carbamates 11{1e2,1e5,1e5}.
As expected due to their size, the double DielseAlder adducts
9{1e2,1e5,1e5} have a lower predicted permeability than all
other scaffolds.
4. Experimental section
4.1. General
All solvents or reagents were used without further puri-
fication. Reactions were monitored by TLC analysis (EM
Science pre-coated silica gel 60 F254 plates, 250 mm layer
thickness) and visualization was accomplished with a
254 nm UV light and by staining with Vaughn’s reagent
(4.8 g (NH4)6Mo7O24$4H2O, 0.2 g Ce(SO4)2$4H2O in 10 mL
concd H2SO4 and 90 mL H2O), KMnO4 (1.0 g KMnO4,
1.0 g K2CO3, 2 mL 5% aqueous NaOH, 100 mL H2O), and
p-anisaldehyde (2.5 mL p-anisaldehyde, 2 mL acetic acid,
3.5 mL concd H2SO4, 92 mL EtOH). NMR spectra were
recorded in CDCl3 or DMSO-d6 (298 K) at 300.1 MHz (1H)
or 75.5 MHz (13C) using a Bruker Avance 300 with XWIN-
NMR software. Chemical Shifts (d) are reported in parts per
million (ppm). Tetramethylsilane (1H), chloroform-d (13C),
or DMSO-d6 (13C) were used as internal standards. Data are
reported as follows: chemical shift, multiplicity (s¼singlet,
d¼dublet, t¼triplet, q¼quartet, m¼multiplet, br s¼broad
singlet, app¼apparent), integration and coupling constants.
IR spectra were obtained on a Nicolet AVATAR 360 FTIR
E.S.P. Spectrometer. Mass spectra were obtained on a Micro-
mass Autospec double focusing instrument (EI) or a Waters
Q-Tof mass spectrometer (ESI). Melting points were obtained
using a heating rate of 2 ꢁC/min on a MelTemp melting point
apparatus with digital temperature reading and are reported
uncorrected.
3. Conclusions
Two amino-acid derived cross-conjugated trienes were
applied to the synthesis of a discovery library of nonaromatic
polycyclic small molecules. Those key building blocks were
converted into a sterically biased and electronically tuned
Table 8
Physicochemical profiling for the five scaffolds (averageꢃstandard deviation), calculated with QikProp 2.129
Scaffolds
9{1e2, 1e5,1e5}
11{1e2, 1e5,1e5}
12{1e2, 1e5,1e5}
13{1e2, 1e5,1e5}
14{1e2,1e5, 1e5,1e6}
MW [g/mol]
3
648ꢃ114
1724ꢃ302
837ꢃ138
6
586ꢃ60
1676ꢃ156
826ꢃ66
4
489ꢃ60
1371ꢃ160
687ꢃ71
4
490ꢃ52
1371ꢃ138
682ꢃ60
4
591ꢃ68
1699ꢃ180
847ꢃ79
3
˚
Volume [A ]
2
˚
SASA [A ]
Fused rings
HBD
HBA
0.1ꢃ0.4
12.1ꢃ2.0
3.9ꢃ2.4
ꢀ5.2ꢃ2.4
5.6ꢃ2.2
131ꢃ113
0.4ꢃ0.6
11.3ꢃ1.2
4.4ꢃ1.4
ꢀ5.1ꢃ1.5
9.0ꢃ1.4
729ꢃ544
0.4ꢃ0.6
8.6ꢃ1.2
3.5ꢃ1.5
ꢀ4.2ꢃ1.4
6.0ꢃ1.4
388ꢃ299
0.1ꢃ0.3
8.0ꢃ1.0
3.9ꢃ1.4
ꢀ4.4ꢃ1.1
4.7ꢃ1.4
503ꢃ317
1.5ꢃ0.8
10.2ꢃ1.4
3.8ꢃ1.4
ꢀ4.0ꢃ1.4
8.4ꢃ1.5
564ꢃ477
log P
log S
Rotatable bonds
Caco-Perm [nm/s]

7004
S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
1
Compounds were analyzed by reverse-phase HPLC (All-
(film) 2929, 1673, 1635, 1530, 1403, 1273 cmꢀ1; H NMR
(CDCl3) d 6.45e6.25 (m, 4H), 5.85 (s, 1H), 5.49 (dd, 1H,
J¼17.2, 1.5 Hz), 5.26 (dd, 1H, J¼10.8, 1.5 Hz), 3.18e3.00
(m, 2H), 2.31 (d, 3H, J¼7.5 Hz), 1.61 (s, 3H), 0.98e0.80
(m, 1H), 0.50e0.40 (m, 2H), 0.20e0.10 (m, 2H); 13C NMR
(CDCl3) d 171.8, 165.7, 137.5, 135.3, 133.3, 125.2, 123.4,
117.4, 61.1, 43.7, 26.6, 15.5, 10.1, 2.7, 2.7; MS (ESI) m/z
(rel intensity) 543 ([2 MþNa]þ, 15), 283 ([MþNa]þ, 100);
HRMS (EI) m/z calculated for C15H20N2O2Na 283.1422,
found 283.1419.
tech Prevail C-18, 100ꢄ4.6 mm, 1 mL/min, 50e70% MeCN,
50e30% H2O) with UV (210 and 254 nm), ELS (Nebulizer
45 ꢁC, Evaporator 45 ꢁC, N2 flow 1.25 SLM) and MS detec-
tion using a Thermo Finnigan Surveyor LC and LCQ
Advantage MS system (ESI positive mode).
4.1.1. General procedure for the formation of trienes
1{1e2} (protocol A)
A 1 L-three-necked round bottom flask equipped with a
stir-bar and condenser was charged with allenyne (1.00 equiv,
10.90 mmol) and toluene (400 mL). Argon was bubbled
through the solution for 5 min and [Rh(CO)2Cl]2 (0.05 equiv,
0.55 mmol) was added. The reaction was heated at 90 ꢁC
for 1 h, then a second portion of catalyst (0.025 equiv,
0.27 mmol) was added. After heating for additional 2.5 h at
this temperature the reaction was complete by TLC. The
reaction was allowed to cool to room temperature and the
solution was loaded directly onto a silica gel column, eluting
first with hexanes (200 mL) then 40% ethyl acetate/hexanes.
The product-containing fractions were combined and con-
centrated to afford triene 1{1} in 74% yield. The spectral
data matched to that previously reported.21
4.1.3. General protocol for 5-iminooxazolidin-2-one
formation and DielseAlder reaction of diamides
5{1e2,1e5} (protocol C)
Diamide 5{1e2,1e5} (1.00 equiv, 2.5e7.5 mmol) was dis-
solved in dichloromethane (100e200 mL), cooled to ꢀ10 ꢁC
and treated with triethylamine (6.00 equiv). Phosgene (20%
in toluene, 3.00 equiv) was slowly added while keeping the
temperature at ꢀ10 ꢁC. After stirring for another 30 min
at ꢀ10 ꢁC, the reaction mixture was allowed to warm up to
room temperature and stirred for an additional 30 min. The
reaction mixture was extracted with sodium bicarbonate
(100 mL), water (100 mL), and brine (100 ml). The combined
aqueous fractions were re-extracted with dichloromethane,
and all organic fractions were combined and dried over
sodium sulfate. Removal of all volatile components in vacuo
4.1.2. General protocol for the saponification and
amidation of esters 1{1e2} (protocol B)
The methyl ester 1{1e2} (1.00 equiv, 5.0e10 mmol) was
dissolved in THF (100e200 mL) and water (100e200 mL)
was added slowly to maintain a homogeneous solution. Lith-
ium hydroxide hydrate (2.00 equiv) was carefully added and
the solution was stirred for 5 min. After complete hydrolysis
a saturated solution of ammonium chloride was added
(100 mL), the reaction mixture was acidified to pH¼1 with
1 M-HCl, extracted with ethyl acetate (3ꢄ50 mL), and dried
over sodium sulfate. Removal of all volatile components
in vacuo gave the crude acid in quantitative yield, which
was used in the following step without further purification.
The crude acid was dissolved in dry dichloromethane
(150e300 mL) and treated with 1-hydroxybenzotriazole
(HOBt, 1.00 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride (EDCI, 1.00 equiv), and 4-dimethyl-
aminopyridine (DMAP, 1.05 equiv). The selected amine
2{1e6} (3.00 equiv of volatile 2{1} or 1.50 equiv of non-
volatile 2{2e6}) was added over 10 min while stirring at
room temperature. After 4 h the reaction mixture was extracted
with water (100 mL) and saturated ammonium chloride (2ꢄ
100 mL). The combined aqueous fractions were re-extracted
with dichloromethane (50 mL) and all organic fractions were
combined and dried over magnesium sulfate. Removal of
all volatile components in vacuo provided crude diamide
5{1e2,1e5}, which was purified on an ISCO Companion
chromatography station (40 g silica gel, hexane/ethyl acetate).
Compounds 5{1e2,1e5} were obtained in yields of 18e93%
(Table 1).
provided a mixture of crude 5-iminooxazolidin-2-ones
6{1e2,1e5} and 7{1e2,1e5} in toluene, which was used
immediately in the next step without further purification.
Acidic workup or chromatography over silica gel led to
the hydrolysis of the desired product to starting material
5{1e2,1e5}. Quenching the reaction at ꢀ10 ꢁC led to an
incomplete reaction, but prevented the formation of the
carbamate side product 6{1e2,1e5}.
A mixture of crude 5-iminooxazolidin-2-ones 6{1e2,1e5}
and 7{1e2,1e5} (1.00 equiv, 5.0e10 mmol assuming a quan-
titative conversion in the previous step) was dissolved in
toluene (50e100 mL) and divided into five batches of
equal volume. Using Radley’s Carousel Reaction Station (6
Place or 12 Place) maleimide 3{1}, N-methyl maleimide
3{2}, N-ethyl maleimide 3{3}, N-phenyl maleimide 3{4},
and methyl 2-(N-maleimide)acetate 3{5}32 (1.30 equiv) were
added at once to the five batches of 5-iminooxazolidin-2-one
and the reaction mixture was heated to 90 ꢁC for 1.5 h. After
cooling to room temperature all volatile components were
removed in vacuo and the residues were purified on an ISCO
Optix 10 parallel chromatography station (12 g silica gel,
hexane/ethyl acetate). In general, carbamates 8{1e2,1e5,1e5}
(first eluting), double DielseAlder adducts 9{1e2,1e5,1e5}
(second eluting), and DielseAlder adducts 10{1e2,1e5,1e
5} (third eluting, in most cases a mixture of E/Z-isomers33)
could be separated (Table 2). In some cases, a second chroma-
tography on an ISCO Companion chromatography station
(12 g silica gel, hexane/ethyl acetate) was necessary to obtain
pure material. If the reaction mixture was quenched at ꢀ10 ꢁC
during the formation of 5-iminooxazolidin-2-one 7{1e2,1e5}
(Table 2), no carbamate 6{1e2,1e5} was obtained. The double
4.1.2.1. (Z)-N-(Cyclopropylmethyl)-5-ethylidene-2-methyl-6-oxo-
4-vinyl-1,2,5,6-tetrahydropyridine-2-carboxamide (5{1,1}). IR

S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
7005
DielseAlder adduct 9{1e2,1e5,1e5} (Table 3) was espe-
cially observed if the formation of 5-iminooxazolidin-2-one
7{1e2,1e5} was incomplete and the maleimides 3{1e5}
were therefore present in greater excess.
J¼7.5 Hz), 2.30e2.20 (m, 1H); 13C NMR (CDCl3) d 177.5,
175.8, 166.0, 159.3, 150.2, 146.7, 140.6, 137.8, 134.8,
132.1, 129.8, 129.5, 128.5, 128.3, 128.0, 127.8, 127.0,
123.5, 65.6, 52.3, 51.6, 47.9, 41.0, 40.5, 39.3, 39.2, 24.9,
15.5; MS (ESI) m/z (rel intensity) 1157 ([2 MþNa]þ, 10),
590 ([MþNa]þ, 100), 568 ([Mþ1]þ, 10), 413 (40); HRMS
(ESI) m/z calculated for C32H29N3O7Na 590.1903, found
590.1877.
4.1.3.1. rac-(8aR,11aS,11bR,11cS,Z)-1-(Cyclopropylmethyl-
imino)-10-ethyl-11c-methyl-3,9,11-trioxo-6-vinyl-1,3,8,8a,9,10,
11,11a,11b,11c-decahydrooxazolo[4,3-a]pyrrolo[3,4-h]isoquino-
line-5-yl diethylcarbamate (8{1,1,3}). IR (film) 2979, 2936,
1811, 1735, 1697, 1379, 1346, 1254, 1145, 995 cmꢀ1
;
1H
4.1.4. General protocol for the hydrogenation of
NMR (CDCl3) d 6.18 (dd, 1H, J¼17.7, 11.4 Hz), 6.00 (ddd,
1H, 6.9, 4.2, 1.9 Hz), 5.42 (dd, 1H, J¼17.6, 1.7 Hz), 5.37
(dd, 1H, J¼11.4, 1.8 Hz), 3.83 (dd, 1H, J¼8.7, 4.6 Hz),
3.68e3.51 (m, 1H), 3.49e3.24 (m, 7H), 3.19 (app td, 1H,
J¼7.5, 0.9 Hz), 2.94e2.79 (m, 2H), 2.22 (dddd, 1H, J¼15.2,
7.4, 4.3, 0.9 Hz), 1.78 (s, 3H), 1.23 (app t, 3H, J¼7.1 Hz),
1.16 (app t, 3H, J¼7.1 Hz), 1.38e1.08 (m, 1H), 1.00 (app t,
3H, J¼7.2 Hz), 0.60e0.40 (m, 2H), 0.30e0.18 (m, 2H); 13C
NMR (CDCl3) d 178.8, 176.6, 153.1, 151.6, 148.0, 133.2,
132.8, 126.7, 122.5, 120.0, 110.6, 62.4, 52.5, 44.5, 42.3,
42.0, 41.3, 41.1, 33.7, 27.8, 25.7, 13.9, 13.0, 12.9, 11.5, 3.4,
3.2; MS (EI) m/z (rel intensity) 510 (15), 466 (7), 385 (61),
286 (20), 160 (23), 100 (100), 72 (84); HRMS (EI) m/z calcu-
lated for C27H34N4O6 510.2478, found 510.2485.
DielseAlder adducts 8{1e2,1e5,1e5} and
10{1e2,1e5,1e5} (protocol D)
The DielseAlder adducts 8{1e2,1e5,1e5} or 10{1e2,1e5
1e5} (1.00 equiv, 0.050e0.50 mmol), respectively, were dis-
solved in dry THF (10 mL) and treated with 20 wt % Pd/C
(10%). Using a Radley’s Carousel reaction station (12 Place)
a single balloon filled with hydrogen was attached and the
system was flushed five times with hydrogen. The reaction
mixtures were stirred in parallel for 4 h, after which the Pd/C
was removed through filtration over a plug of Celite, followed
by washing with dichloromethane (3ꢄ20 mL). In the case of
indole containing substrates 8{1e2,5,1e5} or 10{1e2,5,1e5}
another 20 wt % Pd/C (10%) was added after 4 h, the system
was flushed again five times with hydrogen and stirred for
an additional 20 h. All volatile components were removed
in vacuo and the residues were purified on an ISCO Optix
10 parallel chromatography station (12 g silica gel, hexane/
ethyl acetate) to afford the reduced DielseAlder adducts
11{1e2,1e5,1e5} or 12{1e2,1e5,1e5}, respectively (Tables
4 and 5).
4.1.3.2. rac-(3aS,3bR,3c1R,8R,8aS,11aR,11bS,12aR,E)-4-(Cyclo-
propylmethylimino)-2,10-diethyl-3c1,8-dimethyl-4,5,8,8a,11a,
11b,12,12a-octahydro-5-oxa-2,6a,10-triazatricyclopenta[a,e,j]-
phenalene-1,3,6,7,9,11(2H,3aH,3bH,3c1H,6aH,10H)-hexaone
(9{1,1,3}). IR (film) 2981, 2940, 1833, 1742, 1696, 1443,
;
1403, 1350, 1316, 1294, 1277, 1229 cmꢀ1 1H NMR
(CDCl3) d 3.95 (dd, 1H, J¼9.7, 5.5 Hz), 3.50e3.30 (m, 7H),
3.26 (dd, 1H, J¼8.7, 6.6 Hz), 3.06 (dd, 1H, J¼8.7, 5.7 Hz),
2.95 (app t, 1H, J¼3.9 Hz), 2.71 (ddd, 1H, J¼14.5, 13.0,
5.5 Hz), 2.63e2.57 (m, 1H), 2.53 (ddd, 1H, J¼14.5, 4.9,
2.4 Hz), 2.28e2.20 (m, 1H), 1.89 (d, 3H, J¼7.4 Hz), 1.56 (s,
3H), 1.10 (app t, 3H, J¼7.2 Hz), 1.05e0.95 (m, 1H), 0.98
(app t, 3H, J¼7.2 Hz), 0.53e0.42 (m, 2H), 0.28e0.15 (m,
2H); 13C NMR (CDCl3) d 177.9, 176.1, 175.7, 175.6, 155.9,
150.6, 150.0, 147.1, 131.9, 60.0, 52.6, 46.1, 42.6, 41.4, 39.4,
39.0, 35.4, 33.9, 33.9, 33.2, 29.8, 22.8, 15.4, 13.1, 12.9,
11.4, 3.4, 3.2; MS (ESI) m/z (rel intensity) 1095 ([2 MþNa]þ,
50), 1073 ([2 Mþ1]þ, 25), 975 (25), 559 ([MþNa]þ, 25), 537
([Mþ1]þ, 100), 483 (55), 412 (35); HRMS (ESI) m/z calcu-
lated for C28H33N4O7 537.2349, found 537.2341.
4.1.5. rac-(8aR,11aS,11bR,11cS,Z)-1-(Cyclopropylmethyl-
imino)-6-ethyl-10,11c-dimethyl-3,9,11-trioxo-1,3,8,8a,
9,10,11,11a,11b,11c-decahydrooxazolo[4,3-a]pyrrolo-
[3,4-h]isoquinolin-5-yl diethylcarbamate (11{1,1,2})
IR (film) 2973, 2935, 1810, 1734, 1699, 1431, 1383, 1255,
1
1140, 977 cmꢀ1; H NMR (CDCl3) d 5.85 (ddd, 1H, J¼7.0,
4.1, 2.2 Hz), 3.83 (dd, 1H, J¼8.7, 4.5 Hz), 3.70e3.59 (m,
1H), 3.43e3.18 (m, 6H), 2.87 (ddd, 1H, J¼15.4, 8.0, 1.3 Hz),
2.87 (s, 3H), 2.83e2.77 (m, 1H), 2.30e2.10 (m, 3H), 1.76
(s, 3H), 1.24 (app t, 3H, J¼7.1 Hz), 1.17 (app t, 3H,
J¼7.1 Hz), 1.15e1.05 (m, 1H), 0.97 (app t, 3H, J¼7.4 Hz),
0.53e0.40 (m, 2H), 0.27e0.20 (m, 2H); 13C NMR (CDCl3)
d 179.1, 176.9, 153.3, 152.0, 147.9, 132.9, 132.3, 120.0,
113.0, 62.2, 52.4, 43.9, 42.3, 42.0, 41.4, 41.3, 27.7,
25.5, 24.9, 17.4, 13.9, 13.0, 11.4, 3.4, 3.2; MS (ESI) m/z (rel
intensity) 1019 ([2 MþNa]þ, 25), 521 ([MþNa]þ, 100), 499
([Mþ1]þ, 45); HRMS (ESI) m/z calculated for C26H34N4O6Na
521.2376, found 521.2356.
4.1.3.3. rac-Methyl 2-((1Z,6Z,8aR,11aS,11bR,11cS)-11c-benzyl-
1-(benzylimino)-6-ethylidene-3,5,9,11-tetraoxo-1,5,6,8a,9,11,
11a,11c-octahydrooxazolo[4,3-a]pyrrolo[3,4-h]isoquinolin-10-
(3H,8H,11bH)-yl)acetate (10{2,4,5}). IR (film) 2928, 1838,
1742, 1712, 1421, 1365, 1300, 1223 cmꢀ1
;
1H NMR
4.1.5.1. rac-Methyl 2-((8aR,11aS,11bR,11cS,Z)-1-(benzyl-
imino)-6-ethyl-11c-methyl-3,5,9,11-tetraoxo-1,7,8,8a,9,11,11a,
11c-octahydrooxazolo[4,3-a]pyrrolo[3,4-h]isoquinolin-10(3H,
5H,11bH)-yl)acetate (12{1,4,5}). IR (film) 2953, 1833, 1741,
(CDCl3) d 7.40e7.18 (m, 8H), 6.84e6.80 (m, 2H), 6.61 (q,
1H, J¼7.4 Hz), 6.17e6.12 (m, 1H), 4.68 (d, 1H, J¼
14.1 Hz), 4.58 (d, 1H, J¼14.1 Hz), 4.15 (d, 1H, J¼17.2 Hz),
4.08 (d, 1H, J¼17.2 Hz), 3.92 (dd, 1H, J¼8.9, 5.3 Hz), 3.67
(s, 3H), 3.32e3.29 (m, 1H), 3.29 (d, 1H, J¼13.5 Hz), 3.15
(d, 1H, J¼13.5 Hz), 3.00e2.93 (m, 2H), 2.29 (d, 3H,
1
1708, 1420, 1326, 1281, 1220, 975 cmꢀ1; H NMR (CDCl3)
d 7.34e7.24 (m, 5H), 4.73 (d, 1H, J¼14.6 Hz), 4.63 (d, 1H,
J¼14.6 Hz), 4.15 (d, 1H J¼17.0 Hz), 4.05 (d, 1H,

7006
S. Werner et al. / Tetrahedron 64 (2008) 6997e7007
1
J¼17.0 Hz), 3.89 (dd, 1H, J¼9.5, 5.5 Hz), 3.69 (s, 3H), 3.17
(ddd, 1H, J¼9.6, 5.3, 2.4 Hz), 3.09 (d, 1H, J¼5.4 Hz),
2.67e2.59 (m, 2H), 2.52e2.40 (m, 1H), 2.37e2.22 (m, 2H),
2.16e2.02 (m, 1H), 1.74 (s, 3H), 0.95 (app t, 3H, J¼
7.4 Hz); 13C NMR (CDCl3) d 177.3, 175.7, 166.3, 158.3,
152.0, 146.9, 145.1, 138.3, 133.5, 128.5, 127.8, 127.2, 60.4,
52.6, 51.8, 40.9, 40.7, 39.9, 39.3, 29.7, 25.9, 19.9, 19.0,
12.2; MS (ESI) m/z (rel intensity) 516 ([MþNa]þ, 20), 494
([Mþ1]þ, 100), 333 (50); HRMS (ESI) m/z calculated for
C26H28N3O7 494.1927, found 494.1944.
1796, 1727, 1416, 1368, 1326, 1214 cmꢀ1; H NMR (CDCl3)
d 4.15 (d, 1H, J¼17.1 Hz), 4.05 (d, 1H, J¼17.0 Hz), 3.69 (s,
3H), 3.66 (dd, 1H, J¼9.5, 5.1 Hz), 3.53 (dd, 1H, J¼14.0,
6.8 Hz), 3.45 (dd, 1H, J¼14.0, 7.4 Hz), 3.24 (ddd, 1H, J¼9.5,
5.9, 3.1 Hz), 3.04 (d, 1H, J¼5.1 Hz), 2.70e2.59 (m, 2H),
2.51e2.23 (m, 3H), 2.16e2.08 (m, 1H), 1,67 (s, 3H), 1.28e
1.20 (m, 1H), 0.96 (app t, 3H, J¼7.5 Hz), 0.52e0.46 (m, 2H),
0.39e0.35 (m, 2H); 13C NMR (CDCl3) d 177.5, 175.1, 173.5,
166.4, 158.3, 151.6, 143.4, 134.3, 60.6, 52.7, 43.8, 41.2, 40.2,
39.6, 39.4, 28.0, 25.7, 20.1, 19.2, 12.5, 9.5, 3.9, 3.7; MS (ESI)
m/z (rel intensity) 480 ([MþNa]þ, 100), 458 ([Mþ1]þ, 10).
4.1.6. General protocol for the formation of acylureas
14{1e2,1e5,1e5,1e6} (protocol E)
4.2. Stability study of acylureas 14{1e2,1e5,1e5,1e6}
in DMSO
Using 16 mm test tubes, the reduced DielseAlder adducts
12{1e2,1e5,1e5} (1.0 equiv, 0.030e0.060 mmol) were dis-
solved in chloroform (1 mL), treated with amines 4{1e6}
(5.0 equiv) and stirred in parallel for 2 h at room temperature.
All volatile components were removed in vacuo and the resi-
dues were purified on an ISCO Optix 10 parallel chromato-
graphy station (4 g silica gel, hexane/ethyl acetate) to afford
amides 14{1e2,1e5,1e51e6}. In several cases, hydantoins
13{1e2,1e5,1e5} were observed as side product and could
be easily separated as the first eluting component (Table 6).
Acylurea 14{2,5,2,1} (0.0050 mmol) was dissolved in
DMSO-d6 (0.7 mL, Cambridge Isotope Laboratories, Inc, D
99.9%) and stored in an NMR tube at room temperature for
several weeks. The composition was determined regularly by
1H NMR studies. Complete and selective conversion of acyl-
urea 14{2,5,2,1} to hydantoin 13{2,5,2} was observed after
2 months. An identical sample was stored in a ꢀ78 ꢁC freezer
and no rearrangement was observed over 3 months.
4.1.6.1. rac-(3aR,9S,9aR,9bS)-9-Benzyl-N8,N9-bis(cyclopropyl-
methyl)-6-ethyl-2-methyl-1,3,7-trioxo-3,3a,4,5,7,9,9a,9b-octa-
hydro-1H-pyrrolo[3,4-h]isoquinoline-8,9(2H)-dicarboxamide
(14{2,1,2,4}). IR (film) 3324, 2960, 1699, 1542, 1437, 1385,
Acknowledgements
We gratefully acknowledge financial support provided by
NIGMS (P50-GM067082). The authors also thank Ms. Leslie
A. Twining for LCeMS/UV/ELSD analyses, Dr. Steven Geib
for performing several X-ray analyses, and Dr. Branko
Mitasev and Prof. Peter Wipf for stimulating discussions.
1319, 1287, 1170 cmꢀ1 1H NMR (CDCl3) d 9.18 (app t,
;
1H, J¼5.3 Hz), 7.93 (app t, 1H, J¼5.1 Hz), 7.18e7.14 (m,
3H), 7.04e7.01 (m, 2H), 4.02 (d, 1H, J¼14.4 Hz), 3.52 (d,
1H, J¼14.3 Hz), 3.52 (dd, 1H, J¼9.3, 3.6 Hz), 3.38e3.20
(m, 3H), 3.14e3.00 (m, 3H), 2.86 (s, 3H), 2.23e1.96 (m,
4H), 1.72e1.58 (m, 1H), 1.51e1.39 (m, 1H), 1.20e1.08 (m,
1H), 1.02e0.87 (m, 1H), 0.57 (app t, 3H, J¼7.4 Hz), 0.60e
0.51 (m, 2H), 0.48e0.42 (m, 2H), 0.34e0.28 (m, 2H),
0.21e0.16 (m, 2H); 13C NMR (CDCl3) d 178.5, 178.3,
170.3, 166.5, 154.6, 142.8, 138.4, 132.7, 129.8, 128.3,
126.8, 66.9, 45.5, 44.9, 44.7, 44.6, 42.2, 41.0, 25.0, 24.7,
20.5, 19.4, 12.5, 10.9, 10.2, 3.7, 3.6, 3.6, 3.2; MS (ESI) m/z
(rel intensity) 569 ([MþNa]þ, 25), 547 ([Mþ1]þ, 25), 518
(15), 476 (100), 472 (60); HRMS (ESI) m/z calculated for
C31H39N4O5 547.2920, found 547.2883.
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13{1e2,1e5,1e5} (protocol F)
Acylurea 14{1e2,1e5,1e5,1e6} (1.0 equiv, 0.030 mmol)
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methyl)-6-ethyl-11c-methyl-1,3,5,9,11-pentaoxo-2,3,7,8,8a,9,
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10(5H,11bH,11cH)-yl)acetate (13{1,1,5}). IR (film) 2953,

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