Glycoluril as an efficient molecular template for intramolecular Claisen-type condensations

Article abstract of DOI:10.1039/a706855g

The readily prepared 3,4,7,8-tetramethylglycoluril 1 acts as a template to promote efficient intramolecular Claisen-like condensations between two acyl groups which are attached to the N-1 and N-6 positions. Thus, two sequential acylations of 1 give symmetric or unsymmetric diacylglycolurils 9-18 in good yield. Treatment of 9-18 with lithium tert-alkoxides furnishes N-(β-ketoacyl)glycolurils 19-27 under mild conditions and in high yields; rate-limiting deprotonation, predominantly on the least substituted of the two acyl groups, precedes a fast intramolecular Claisen-type condensation. Reduction of the keto group in 19 and 26, followed by elimination of water gives alk-2-enoylglycolurils 6 and 7; conjugate hydride addition (L-Selectride) then gives alkanoylglycoluril 5. Compounds 5-7 undergo further rounds of N-acylation then intramolecular condensation. Linear chains can thus be constructed on 1 by repetitive sequences of acylation-condensation-functional group transformation. N¹-Alk-2-enoyl-N⁶-alkanoylglycolurils 14-17 also afford condensation products with high selectivity upon treatment with L-Selectride, effecting a method for net reversal of the regioselectivity observed in the base-promoted rearrangement. The synthesized chains can be readily removed from the template, regenerating 1. The efficiency of the condensation reaction, the sequence of transformations and the ability to grow linear carbon chains in a repetitive manner mimic these aspects of the catalytic cycle of fatty acid synthases and polyketide synthases.

Full text of DOI:10.1039/a706855g

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Glycoluril† as an efficient molecular template for intramolecular
Claisen-type condensations
Sengen Sun, Louise Edwards and Paul Harrison*
Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton,
ON, Canada L8S 4M1
The readily prepared 3,4,7,8-tetramethylglycoluril 1 acts as a template to promote efficient intramolecular
Claisen-like condensations between two acyl groups which are attached to the N-1 and N-6 positions.
Thus, two sequential acylations of 1 give symmetric or unsymmetric diacylglycolurils 9–18 in good yield.
Treatment of 9–18 with lithium tert-alkoxides furnishes N-(â-ketoacyl)glycolurils 19–27 under mild
conditions and in high yields; rate-limiting deprotonation, predominantly on the least substituted of the
two acyl groups, precedes a fast intramolecular Claisen-type condensation. Reduction of the keto group
in 19 and 26, followed by elimination of water gives alk-2-enoylglycolurils 6 and 7; conjugate hydride
addition (L-Selectride) then gives alkanoylglycoluril 5. Compounds 5–7 undergo further rounds of
N-acylation then intramolecular condensation. Linear chains can thus be constructed on 1 by
1
6
repetitive sequences of acylation–condensation–functional group transformation. N -Alk-2-enoyl-N -
alkanoylglycolurils 14–17 also afford condensation products with high selectivity upon treatment with
L-Selectride, effecting a method for net reversal of the regioselectivity observed in the base-promoted
rearrangement. The synthesized chains can be readily removed from the template, regenerating 1. The
efficiency of the condensation reaction, the sequence of transformations and the ability to grow linear
carbon chains in a repetitive manner mimic these aspects of the catalytic cycle of fatty acid synthases
and polyketide synthases.
1
–4
Introduction
which occurs on FAS and PKS. Thus a growing linear chain
would be generated which is extended by two carbon atoms
each cycle. Further, the full array of oxidation states found at
C-1 of each unit within the growing chain in different metabol-
ites should be accessible; these include β-keto groups generated
in the condensation steps, as well as β-hydroxy, enoyl and satur-
ated units which are formed by functional group manipulations
on the surface of the synthases prior to addition of the next
An array of natural products are derived in vivo from multiple
Claisen-like ‘head-to-tail’ condensations of acyl units which are
1,2
provided as coenzyme A thioesters. In comparison with the
highly efficient biosynthetic process occurring on the surface of
2,3
2–4
the fatty acid synthases (FAS), polyketide synthases (PKS),
3
and thiolases which catalyze the assembly of these metabolites,
the chemical synthesis of these fatty acids and polyketides
poses a considerable challenge to the organic chemist. The
preparation of small di-, tri- and oligo-ketides in isotopically
labeled form for biosynthetic incorporation experiments has
1,2
acyl unit. Finally, the newly synthesized chain would be
released from the template.
Modeling of all of the aspects of the reactions which are
catalyzed by these multi-functional enzyme complexes presents
a substantial challenge. We have chosen to focus on developing
a bifunctional template approach to mimic some aspects of
FAS and PKS, specifically: (a) the efficiency of the conden-
sation between acyl units; (b) the ability to grow acyl chains by
a repetitive sequence of acyl addition then C᎐C bond form-
ation between acyl units, without the growing chain leaving
the template surface; and (c) the control of regioselectivity
that occurs during incorporation of alkanoates into poly-
ketides. In addition we wished to develop chemical reactions
which parallel the biochemical functional group transform-
ations which occur within each cycle of FAS, with the aim of
developing this approach as synthetically useful methodology.
We have previously reported that 3,4,7,8-tetramethylglycoluril 1
provides a template effect to promote intramolecular Claisen-
type condensations between two acyl units attached to the two
NH sites, and that this approach can be used in an iterative
5
also proved demanding. The desire for an efficient synthetic
method for the preparation of these classes of compound led
6
us to investigate a biomimetic approach to the sequential
7
assembly of acyl moieties.
In 1975, Scott et al. illustrated that catechol acetate malon-
ate undergoes intramolecular decarboxylative condensation
8
to give acetoacetylcatechol. Thus catechol provides a template
effect to mimic that present in FAS and PKS, where two
active site sulfhydryl groups hold the acetate and malonate
units from acetyl-coenzyme A (Ac-CoA) and malonyl-CoA
through covalent attachment prior to decarboxylative conden-
sation. In both enzymes, as well as in the catechol derivative, the
two acyl moieties are thus presumably oriented so that, after
decarboxylation of the malonyl entity, the resulting formal
acetyl enolate nucleophile is trapped by the electrophilic acetyl
group to give the acetoacetyl derivative.
An analogous template-directed intramolecular Claisen-type
condensation, in which two acyl groups undergo reaction, can
effect the same net transformation as occurs in vivo, since the
malonyl units required for the enzymic chain extension are
derived directly from AcCoA by carboxylation using the biotin-
7
manner for the synthesis of natural products. Herein, we
report in detail on these results, as well as on studies of the
mechanism of the condensation step and a novel method for
reversing the regiochemistry obtained in the crossed-Claisen
approach.
9
dependent AcCoA carboxylase. This Claisen-like approach
could prove useful in synthesis if it were extended to mimic the
repetitive ‘head-to-tail’ addition of acetyl or propanoyl units
Results and discussion
Preparation and acylation of 3,4,7,8-tetramethylglycoluril 1
†
IUPAC name: perhydroimidazo[4,5-d]imidazole-2,5-dione.
Tetramethylglycoluril 1 is readily prepared according to the
J. Chem. Soc., Perkin Trans. 1, 1998
437

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a
Table 1 Yields for the preparation of monoacylglycolurils 3–7 from 1
Yield
(%)
Yield of
by-product (%)
1
b
c
d
Entry
Product
R
Method
1
2
3
4
5
6
3
3
4
5
6
7
MeCO
MeCO
EtCO
Pr CO
MeCH᎐CHCO
A
B
A
A
B
B
78
89
83
70
68
15
1
ND
9
3
e
n
f
e
NDe
᎐
᎐
g
Me(CH᎐CH) CO
ND
2
a
b
c
d
All yields are for products after purification by column chromatography. See Scheme 1. See text. The by-products are the symmetric diacyl-
e
f
g
glycoluril in each case. ND: none detected. E. E, E.
H
N
This method provides a marginally better yield than method A
for 3 (Table 1), and requires only a slight excess of acylating
agent. Again, little or no diacyl products were obtained. Treat-
ment of a mixture of 1 and 2 using acetyl chloride and method
B gives a mixture of monoacetyl derivatives 3 and 8 which are
readily separable by column chromatography. Together, these
results show that monoacylation at one of the two NH groups
of 1 can be easily accomplished; the method chosen for a given
acyl group depends on availability of the respective activated
acyl derivatives.
NH
H +
N
N
N
O
O
2
O
O
O +O
O
NH
H
N
H
N
H
N
H
N
1
2
1
n
(
R )2O or
Bu Li
n
1
Bu Li, R Cl
AcCl
H
N
3
4
8
7
N
N
N
N
n
N
N
O
N
Bu Li
The monoacyl derivatives are readily converted to diacylgly-
colurils under more forcing conditions by treatment with base
O
O
O
O
O
1
N 6
R2Cl
N
N
N
n
R1
R2
R1
(Bu Li or LDA, 1 equiv.), followed by an acyl halide (Scheme
H
O
1
). Table 2 gives the yields of the diacyl derivatives 9–18 pre-
9
–18
3–7
8
pared in this way. Thus, the glycoluril 1 lends itself to the prep-
aration of both symmetric and asymmetric diacyl derivatives.
This is an ideal situation for setting up the proposed crossed-
Claisen-like condensation reaction.
n
Bu Li
R1
R2
AcCl
9
MeCO
MeCO
3
3
3
4
5
3
3
3
3
5
6
7
O
1
3CH313CO
9
9
1
1
1
1
1
1
1
1
1
a MeCO
d MeCO
0 EtCO
CD CO
3
N
N
N
N
Condensation reactions of diacetylglycolurils
MeCO
O
O
n
In early experiments on this system, the diacetylglycoluril 9 was
1 Pr CO
MeCO
n
t
treated with LDA or Bu Li in THF. Although the desired con-
2 MeCO
3 MeCO
4 MeCO
5 MeCO
Bu CO
MeOCO
CH =CHCO
CH =CMeCO
CH =CHCO
densation product 19 is obtained under these conditions the
yields are low (Table 3 and Scheme 2). Subsequently, it was
O
2
9e
2
n
6 Pr CO
2
7 MeCH=CHCO
8 Me(CH=CH)2CO
MeCO
MeCO
N
N
N
N
t
N
N
N
N
N
N
Bu OLi
O
O
O
O + O
O
Scheme 1
N
H
N
H
10
O
O
R4
O
O
method of Biltz (Scheme 1). Thus, reaction of monomethyl-
urea with butane-2,3-dione in ethanol in the presence of cata-
lytic aqueous HCl affords a mixture of isomers 1 and 2, which
can be either used directly (see below), or separated by
recrystallization to afford pure 1. Compound 1 is thus available
in one step from readily available starting materials, allowing
preparation in hundred-gram quantities.
Selective monoacylation of the glycoluril 1 with a variety of
acylating agents can be accomplished in one of two ways
Scheme 1). In method A, the glycoluril is heated to reflux in
neat alkanoic anhydride, following the procedure of Biltz. In
R3
O
R4
R3
R4
R3
O
R3
R3
R3 R4
9
d
0
H
D
H
H
H
19
19
9
D
19d
20
19e
1
Me
Et
Me Me
21ab
23ab
–
11
22
24
12
(
Scheme 2
10
this way, pure 1 affords the mono-acetyl, -propanoyl, and
shown that treatment of 9 with lithium tert-butoxide in THF
results in superior yields. In this case, the reaction is observed
by TLC to proceed to completion within 20 min at 0 ЊC. Work-
up under non-buffered aqueous conditions, however, results in
a yield that is well below quantitative. Further investigations
showed that 19 undergoes decomposition during aqueous
work-up; however, the use of solid ammonium hydrogen
carbonate, or aqueous sodium hydrogen sulfate to quench the
reaction mixture avoids this decomposition. All subsequent
experiments have used one of these methods of work-up. Com-
pound 19 can thus be prepared from 9 and is obtained in quan-
titative yield as an apparently pure solid by NMR after removal
of solvent. In order to ensure complete purity, and the absence
of lithium ion in the product (which potentially could act as a
lithium ion chelant), 19 was subjected to column chromato-
graphy, giving an isolated yield of 93%.
-
(
butanoyl derivatives 3, 4 and 5, respectively in good yields
Table 1). Alternatively, the mixture of isomers 1 and 2 gives the
desired acyl derivatives by method A, along with recovered 2,
which does not react under these conditions. Acetylglycoluril 3
was conveniently prepared on a large scale in this manner. Only
small amounts of diacyl derivatives, which are readily removed
by column chromatography, are formed in this method: pre-
sumably, steric hindrance by the first acyl unit reduces the rate
of acylation at the second site. Method A is convenient for
large-scale synthesis of the monoacyl derivatives when a large
excess of the anhydride can be used.
n
In method B, pure 1 was treated with either Bu Li or LDA (1
equiv.) and heated at reflux; treatment of the resulting suspen-
sion with an acyl chloride then work-up gives the monoacyl
derivatives. Compounds 3, 6 and 7 were prepared in this way.
4
38
J. Chem. Soc., Perkin Trans. 1, 1998

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a
Table 2 Yields for the preparation of diacylglycolurils from 3–7
a
Starting
Material
Yield
(%)
1
b
2 b
Entry
Product
R
R
1
2
3
4
5
6
7
8
9
3
3
3
4
5
3
3
3
3
5
6
7
9
9a
9d
10
11
12
13
14
15
16
17
18
MeCO
MeCO
MeCO
EtCO
MeCO
13
78
80
68
54
61
52
84
41
36
36
62
38
1
3
CH3 CO
CD CO
3
MeCO
MeCO
n
Pr CO
t
MeCO
MeCO
MeCO
MeCO
Bu CO
MeOCO
CH ᎐CHCO
2
᎐
CH CMeCO
2
n
1
1
1
0
1
2
Pr CO
CH ᎐CHCO
2
᎐
c
MeCH᎐CHCO
Me(CH᎐CH) CO
MeCO
MeCO
᎐
᎐
d
2
a
b
c
d
All yields are for products after purification by column chromatography. See Scheme 1. E. E, E.
a
b
Table 3 Yields and isomer ratios for the condensation of diacylglycolurils 9–18
a
Starting
material
Yield
(%)
3
c
4 c
5 d
b
Entry
Base
Product(s)
R
R
R
Ratio
1
2
3
9
LDA
19
H
H
D
H
H
D
—
—
—
43
93
80
—
—
t
9
Bu OLi
19
t
9d
Bu OLi
19d
83:17
83:17
81:19
60:40
67:33
75:25
86:14
1
9
t
4
5
6
7
8
9
10
11
11
11
11
11
Bu OLi
20
H
H
H
H
H
H
Me
Et
Et
Et
Et
Et
—
—
—
—
—
—
81
88
56
80
80
80
2
1ab
t
Bu OLi
22
2
3ab
t
Bu ONa
22
2
3ab
t
Bu OK–18-crown-6
22
2
3ab
t
Bu OLi–12-crown-4
22
2
3ab
EtC(Me) OLi
22
2
2
3ab
t
1
1
1
1
1
1
0
1
2
3
4
5
12
13
13
13
17
18
Bu OLi
24
25
25
25
26
27
Me
—
—
—
—
—
Me
—
—
—
—
—
—
79
82
85
63
60
60
—
—
—
—
—
—
t
Bu OLi
OMe
OMe
OMe
MeCH᎐CH
Me(CH᎐CH)
᎐
2
EtC(Me) OLi
2
LiHMDS
t
e
Bu OLi
᎐
t
f
Bu OLi
a
d
b
c
All yields are for products after purification by column chromatography. Determined by integration of the proton NMR spectrum. See Scheme 2.
See Scheme 5. E. E, E.
e
f
In contrast with 9, derivative 9e (Scheme 1), which was pre-
n
pared from 8 using Bu Li then AcCl, and in which the two
acetyl units are located on opposite sides of the glycoluril tem-
plate, fails to give any condensation product under the reaction
conditions. Instead, the acyl groups are slowly cleaved to give
monoacetyl derivative 8 and ultimately recovered 2.
N
N
N
N
N
N
N
N
O
O
ButOLi
O
O
Li+
O
O
O –
O
Comparison of these two very different outcomes suggests
that the enhanced efficiency in 9 is the result of an intra-
molecular condensation. Deprotonation of one acetyl group
would generate an enolate which can be oriented appropriately
for nucleophilic attack at the electrophilic carbonyl of the other,
9
N
N
N
‘acceptor’ acetyl moiety (Scheme 3).
O
O
There are, of course, numerous examples of efficient inter-
N
H
molecular Claisen-like condensations where an enolate is pre-
generated with a strong base prior to addition of an acyl donor.
However, the appropriate comparison in the current case is with
addition of a weak base to a carbonyl compound followed by
intermolecular condensation. Such classical Claisen conden-
sations generally proceed much more slowly under similar
conditions, usually requiring elevated temperature and longer
O
O
1
9
Scheme 3 Proposed mechanism for the intramolecular Claisen-like
condensation of diacetylglycoluril 9 to give 19
11
reaction times. Comparison may also be drawn with inter-
molecular acylations of the enolates derived from N-acyloxazol-
idones, although these enolates are usually generated with
system is the use of catechol by Scott et al. as a template in the
conversion of catechol acetate malonate to acetoacetylcatechol,
which proceeded in 30% yield. The superior yield and milder
12,13
strong bases at low temperature.
Glycoluril 1 may be viewed
8
as a bifunctional variant of these oxazolidones, where an
N-CH group replaces the ring oxygen. Another analogous
conditions for condensation of diacetylglycoluril compared
3
J. Chem. Soc., Perkin Trans. 1, 1998
439

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sample is shown in Fig. 1 (b); the results show that the product
13
is comprised of a mixture of the two [ C ]-isotopomers 19a, as
2
13
12
well as 14% of [ C ]-isotopomer 19b, but no [ C ]-isotopomer
4
4
1
9c. The ratio of 19a:19b in the product is identical within
experimental error to the ratio of 9a:9b in the starting material.
Hence, the condensation is entirely intramolecular within the
limits of detection (ca. 3%), since any intermolecular reaction,
or indeed acyl group exchange between molecules of 9a, would
1
2
result in some [ C ]-product, as well as a change in distribution
4
13
13
of [ C ]- and [ C ]-isotopomers.
2
4
Rearrangement of 9d gives a mixture of 19 and 19d as the
sole product isotopomers within limits of detection (Scheme 2).
In this case, product 19e which results from deprotonation at
2
the [ H ]acetyl group, exchanges the remaining two deuterons
Fig. 1 Molecular ion region of the mass spectrum of (a) 9a and (b) 19
3
1
3
13
derived from 9a, corrected to 100%. The ratio of [ C ]-, [ C ]- and
during work-up to give 19 (also see below). The ratio of 19:19d
was determined to be 1:4.6 by MS and by NMR spectral
integration. This reaction therefore exhibits a primary kinetic
isotope effect of 4.6, favoring deprotonation over deuterium
0
2
13
[
C ]-isotopomers (m/z 282, 284 and 286, respectively) remains
4
unchanged during the reaction. The data were corrected for the relative
abundance of ions in unlabeled 9 and 19 to obtain percentages of each
isotopomer in the mixtures.
2
2
loss. The distribution of isotopomers (i.e. only [ H ] and [ H ]) is
0
3
consistent with rate-limiting deprotonation followed by efficient
internal trapping of the resulting enolate, which out-competes
enolate proton exchange by either intermolecular or intra-
molecular pathways. This exchange can occur in this experi-
ment since the tert-butoxide was generated from Bu Li and
excess tert-butyl alcohol.
with the catechol case suggest that the six-membered cyclic
transition state which would be formed on the glycoluril is more
readily achieved than the seven-membered ring in the catechol.
Alternatively, or as well, the number of available conformations
of the enolate from 9, which is probably restricted due to orbital
n
13,14
overlap requirements,
compared to that for the catechol
enolate, could explain the efficiency of the former process.
However, Scott’s study did not reveal which step is rate-limiting
for the catechol derivative; thus, these comparisons remain
tenuous. The reaction may also be assisted by the relatively high
electrophilic reactivity of the acyl group of glycolurils, com-
pared to normal amides, as has been demonstrated by Tice and
Crossed-Claisen condensations
Treatment of the asymmetric acetyl propanoyl and acetyl
butanoyl glycolurils 10 and 11 with Bu OLi under similar con-
t
ditions efficiently affords mixtures of the regioisomeric conden-
sation products 20/21 and 22/23 respectively (Scheme 2). The
yield and ratio of products, determined by NMR, is given
for each case in Table 3. None of the putative products from
condensation between two acetyl, or between two alkanoyl
moieties was observed in any of these reactions, again showing
the reaction to be entirely intramolecular within the limits of
detection. There was no evidence for formation of O-acyl enol
ethers. Therefore the condensation process is of general utility;
however the yields fall somewhat as the size of either of the
acyl units increases, probably reflecting increased difficulty
for approach of the base. Of the two possible regioisomers,
the major results from enolate formation on the less hindered
acyl group, consistent with the rate-limiting step involving
deprotonation as is the case for 9. In both these cases, the
minor regioisomer is produced as a mixture of two diastereom-
ers 21ab and 23ab, which were distinguishable in the proton
NMR spectrum. One diastereomer was observed to be major;
however, the ratios were not determined accurately due to the
small amounts present in the mixture (see below for further
discussion). While the formation of the minor regioisomer
reduces the yield of this reaction from a synthetic standpoint,
the results compare favorably with the mixture of four regio-
isomers expected for an intermolecular crossed-Claisen con-
densation.
For the acetyl butanoyl derivative 11, the presence of com-
plexing agents such as a crown ether, or the use of sodium or
potassium as counter-ion, had relatively little influence on
either the yield or the ratio of products (Table 3). From the
mechanistic standpoint, these marginal effects reveal little. The
somewhat enhanced yield for lithium as opposed to sodium or
potassium bases is suggestive of some role for the counter-ion
in the reaction. Whether this effect involves chelation (see
above) remains an open question. However, a significant
and consistent improvement was observed by using the more
hindered base, lithium 1,1-dimethylpropoxide: the ratio of
regioisomers 22:23 was increased to 6:1 in this case.
15
Ganem.
The lack of any evidence for formation of the O-acetyl-enol
ether, which could be formed by nucleophilic attack of the
oxygen of the ambident enolate on the acceptor carbonyl, also
suggests that the condensation reaction proceeds through an
oriented enolate. Chelation of the lithium counter-ion by the
enolate and urea oxygens, a process well-documented by Evans
12–14,16
and co-workers in the N-acyloxazolidone enolates,
could
explain this result, since this effect would enforce an orientation
in which intramolecular condensation could occur only by
carbon attack.
With these considerations in mind, further investigations of
the mechanism of this condensation reaction were undertaken.
Isotopically labeled diacetylglycolurils 9a and 9d were prepared
13
from 3 as described above, using [ C ]acetyl chloride and
2
2
[
H ]acetyl chloride, respectively. For 9a, mass spectrometry as
3
well as proton and carbon-13 NMR revealed that the sample
13
contained 84% of the desired [ C ]-isotopomer, as well as 16%
2
13
of the unexpected [ C ]-isotopomer 9b. However, the amount
4
12
of the [ C ]-isotopomer 9c was below the limits of detection
4
[
Fig. 1 (a)]. The slow exchange of acyl groups which must lead
to 9b has not been observed in any of the other acylation reac-
tions described herein, and remains anomalous.
Treatment of the mixture of 9a and 9b with Bu OLi as above
t
gives labeled 19 (Scheme 4). The mass spectrum of the resulting
N
N
N
N
t
N
N
N
N
N
N
Bu OLi
O
O
O
O + O
O
N
H
N
H
*
O
O
O
O
*
*
*
*
O
*
O
•
*
1
3
3
3
12
9
a
b
c
C
C
C
C
19a
19b
19c
Acetyl pivaloyl derivative 12 gives the expected 24 as sole
product; however, a reaction time of 5 h was required. Thus
bulky substituents do not prevent the condensation process. It is
unclear whether the reduced rate in this case reflects increased
1
1
13
9
9
C
12
C
Scheme 4
4
40
J. Chem. Soc., Perkin Trans. 1, 1998

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1
8
steric hindrance for approach of the base, or involvement of the
pivaloyl group in the rate-limiting step.
corresponding oxazolidone cases. Thus, this system should
be of use for effecting selective 1,2-additions of enolates to
unsaturated acyl moieties.
In order to test the feasibility of using glycoluril 1 to promote
decarboxylative condensation, hence more closely resembling
the process in FAS and PKS, a malonate derivative of 1 was
prepared. Since direct reaction of 1 with malonyl chlorides
failed to provide any identifiable products, an indirect approach
was used. The glycoluril 13, bearing a methoxycarbonyl- and
Taken together, the above results demonstrate a highly effi-
cient process in which two acyl groups attached to the glycoluril
template 1 undergo rate-limiting deprotonation by weak bases,
followed by a facile intramolecular Claisen-like condensation
which out-competes the many potential side-reactions, resulting
in high product yield. Deprotonation occurs at the smaller, least
hindered acyl group, while a range of acyl groups including
alkanoyl, alk-2-enoyl and methoxycarbonyl can act as the elec-
trophilic moiety.
t
an acetyl-group readily undergoes deprotonation by Bu OLi
followed by transfer of the methoxycarbonyl group to give
malonate derivative 25 (Scheme 5). The influence of reaction
N
N
N
N
t
N
N
N
Functional group manipulations on â-ketoacylglycolurils
Bu OLi
O
O
O
O
In order to achieve a chemical reaction sequence that parallels
the events that occur on FAS, namely the net reduction of the
β-carbonyl group to methylene, the following manipulations
were carried out. Treatment of the β-ketoalkanoyl derivatives
N
H
O
O
O
R5
1
9, 21ab and 26 with sodium borohydride in methanol furnishes
O
R5
R5
β-hydroxyalkanoyl derivatives 28 (93%), 29 (77%) and 30 (44%
19
plus 51% recovered 26), respectively (Scheme 6). It was found
that work-up with glacial acetic acid immediately after com-
pletion of the reaction was necessary, otherwise loss of acyl
groups occurred: methyl β-hydroxybutanoate was formed from
1
1
1
3
OMe
25
26
27
7
8
MeCH CH
Me(CH CH)2
Scheme 5
1
13
1
9. For 28 and 30, H and C NMR showed a ca. 1:1 ratio
conditions was also investigated for this conversion; the results
are given in Table 3. Again, there was little effect on the reaction
as a result of additives or changing counter-ion. This intra-
molecular condensation is reminiscent of the reaction of bound
acetyl-CoA with carboxybiotin in the active site of acetyl-CoA
of two diastereomers, while 29 is comprised of all four pos-
sible diastereomers in approximately equal proportions. Due
to extensive overlap of resonances, accurate ratios were not
determined. Thus little diastereoselectivity is observed in these
reductions. Stereoselective reductions are under active investig-
ation; however, sodium borohydride remains the most effective
agent to date in terms of yield. The issue of stereoselectivity in
this reduction is of course moot when the products are to be
dehydrated as described below.
9
carboxylase, and provides an interesting model of this process.
Indeed, glycoluril has been compared with biotin; both mol-
17
ecules have similar ureido rings. N-Acylation of these malonyl
derivatives is currently being investigated.
Compounds 17 and 18 containing α,β-unsaturated acyl
Elimination of water from the β-hydroxyalkanoyl derivatives
28 and 30 yields the alk-2-enoyl derivatives 6 (83%) and 7 (86%)
respectively (Scheme 6). A variety of conditions were investi-
t
groups were treated with Bu OLi to test their capability to
undergo intramolecular Claisen condensations. Compounds 26
and 27 were the sole products, resulting from deprotonation at
the saturated acyl group to give the products of linear chain
growth. The potential product derived from deprotonation at
the γ-position of the α,β-unsaturated moiety, followed by
nucleophilic attack on the acetyl group, was not detected.
Nor was there any conjugate addition of the acetyl enolate to
the α,β-unsaturated moiety, a process which occurs readily in
gated for this reaction. In the event, use of TFAA and Et N
3
20
proved to give the best yields. For 6, the E:Z ratio was 98:2
(by H NMR spectroscopy), while for 7, the E,E isomer was the
1
only product observed. In each case, the products had spectro-
scopic properties that were identical to material prepared
directly from 1 and the appropriate acylating agent, except that
6 prepared in the latter manner had an E:Z ratio of 93:7. The
N
N
N
N
N
N
N
N
N
N
N
N
i
ii
iii
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
O
R4
R5
R4
R5
R4
R5
R4
R5
HO
R4
R5
H
1
9
H
28
30
29
6
7
–
5
–
–
2
2
6
H
CH CHMe
H
1ab
Me
ii
N
N
O
O
N
N
H
O
O
O
CF3
31
Scheme 6 Reagents and conditions: i, NaBH , MeOH, 10 min, then AcOH; ii, TFAA, Et N, CH Cl , 20 min; iii, -Selectride, THF, Ϫ78 to 0 ЊC, 2 h,
4
3
2
2
NH HCO3
4
J. Chem. Soc., Perkin Trans. 1, 1998
441

View Article Online
a
b
same conditions on 29 give only the trifluoromethyl ester 31.
This observation suggests that in this case 31 cannot attain a
suitable conformation for elimination; this is in accord with
observations on N-(α-alkyl-β-ketoacyl)oxazolidones, which
Table 4 Yields and isomer ratios for the -Selectride-induced
condensation of N-(alk-2Ј-enoyl)-NЈ-acylglycolurils 14–17
a
Starting
Entry material
Yield
(%)
6 c
7 c
8 c
b
Product
R
R
R
Ratio
12–14
show low acidity at the α-position,
as well as results with
(
α-alkyl-β-ketoacyl)glycolurils (see below).
A variety of reducing agents was investigated for effecting
1
2
3
4
14
15
16
17
21ab
32
33ab
23ab
H
Me
H
H
H
H
Me
H
H
Et
H
60
68
66
52
2.1:1
—
2.2:1
1.5:1
conjugate addition of hydride to the alk-2-enoyl derivatives. In
our hands, use of -Selectride in THF proved most satisfactory;
under these conditions, followed by quenching with NH HCO ,
H
4
3
a
All yields are for products after purification by column chrom-
6
furnished the saturated compound 5 (74%) (Scheme 6). The
b
atography. Determined by integration of the proton NMR spectrum.
c
product had spectroscopic properties that were identical to 5
prepared directly from 1 and butanoic anhydride. Alternatively,
the crude mixture from the -Selectride reduction was
quenched with acetyl chloride prior to work-up, resulting in 11
directly without the requirement for isolation of 5. This process
is useful in reducing the number of steps to be performed when
a series of condensation–functional group manipulation–
acylation sequences are to be strung together (see below).
The results demonstrate that transformations equivalent to
each of the steps in the FAS cycle can be effected on the
glycoluril. Since 5, 6 and 7 can undergo further acetylation then
condensation (see above), these processes constitute the first
examples to our knowledge of growth of a linear fatty acid
chain by a repetitive biomimetic sequence while the growing
See Scheme 8.
oate (83%) and recovered 1 (92%). The corresponding reaction
with but-2-enoyl derivative 6 gives recovered 1 (86%) and
benzyl but-2-enoate (55%). The reaction regenerates the
glycoluril in high yield, ready for recycling. Reasonable to good
yields of the benzyl esters are obtained. As well, the observation
of formation of methyl β-hydroxybutanoate from 19 when
treatment with NaBH4 is not followed by quenching with
AcOH shows that methoxide can also be used as a nucleophile
to cleave β-hydroxyacyl chains. These methods allow com-
pletion of the glycoluril ‘cycle,’ and mimic the role of thioester-
ases which cleave fatty acyl and in some cases polyketide chains
1,2
from the FAS/PKS surface to regenerate the free enzyme.
7
chain remains attached to the template. Scheme 7 illustrates an
Hydride addition to alkenoyl-alkanoylglycolurils and reversal of
regiochemistry
i
ii
iii
N
N
N
N
N
N
N
N
While the above reactions present many facets for continued
development, which are currently being investigated further,
we initially focussed on the question of regiochemistry in the
condensation reaction. Thus, while condensation reactions of
diacylglycolurils proceed with high efficiency and moderate
regioselectivity favoring deprotonation at the less hindered of
the two possible α-positions, we wished to develop a process in
which reversal of the regiochemical outcome was obtained,
resulting in the nett equivalent of deprotonation at the more
hindered acyl moiety.
O
O
O
O
H
H
H
H
O
1
3
9
19
iv
iii
ii
v
N
N
N
N
N
N
N
N
O
O
O O
O
Reaction of the N-alk-2-enoyl NЈ-alkanoylglycolurils 14, 15,
6 and 17 with -Selectride in THF gives 21ab, 32, 33ab and
3ab, respectively (Scheme 8). Yields and diastereomer ratios
H
H
H
OH
1
2
O
N
N
N
N
L-Selectride
N
N
N
N
N
N
26
17
6
28
O
O
O
O +O
O
iv
N
H
N
H
O
O
O
O
R6
O
R6
O
v
ii
iii
R6
R7
R7
R8
H
N
N
N
N
N
N
N
N
O
O O
O
O
R7
R8
R8
H
H
H
HO
O
R6 R7 R8
1
4
5
6
7
H
H
H
H
Et
H
21a
21b
32
33b
23b
1
1
1
Me
H
H
32
2
H
Me
33a
23a
H
3
0
7
18
27
Scheme 8
n
Scheme 7 Reagents and conditions: i, Ac O, neat, reflux, 20 h; ii, Bu Li,
THF, 1 h, then AcCl; iii, Bu OLi, THF, 0 ЊC, 20 min; iv, NaBH ,
2
t
4
are given in Table 4. For 14 and 17, minor side-products which
were separated and characterized include the saturated com-
pounds 10 (3%) and 11 (19%), respectively, as well as 3 (6% and
9%, respectively) from loss of one acyl group. The major prod-
ucts are consistent with the conjugate addition of hydride to
the alk-2-enoyl group, generating enolates as intermediates.
The enolates then undergo nucleophilic attack on the alkanoyl
moiety. These enolates correspond to deprotonation at the
more hindered of two acyl groups, a process which is difficult to
achieve by other methods. Compound 15 gives the enolate of
2-methylpropanoylglycoluril. The corresponding N-(2-methyl-
propanoyl)oxazolidone failed to undergo deprotonation even
MeOH, 10 min, then AcOH; v, TFAA, Et N, CH Cl , 20 min. The
stylised circle represents the glycoluril template.
3
2
2
example in which an eight-carbon polyketide chain containing
C᎐C bonds is assembled from four acetate units, using reactions
᎐
described above. The creation of chains adorned with hydroxy
groups and poly-β-keto acids using this methodology is
currently under investigation.
Cleavage of acyl groups from the glycoluril template
Treatment of butanoyl derivative 5 with lithium benzalkoxide
(
C H -CH OLi) in THF, using the method developed by Evans
6 5 2
14,16
14
and co-workers for N-acyloxazolidones,
gives benzyl butan-
under forcing conditions. No products derived from intra- or
4
42
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
inter-molecular proton transfer from the more acidic alkanoyl
group to the presumed transient enolate followed by conden-
sation were detected in any of the cases investigated, providing
further evidence of the efficiency with which the carbon᎐carbon
bond forming step takes place. Since neither proton transfer
process occurs, it is likely that the small amounts of 10 and 11
observed as products are formed during work-up, where
residual reducing agent remains and the medium provides an
efficient proton trap for the enolates.
quartet, m = multiplet), coupling constant(s) (J in Hz), assign-
ment]. Fourier transform (FT) infrared spectra were recorded
on a Bio-Rad SPC 3200 spectrophotometer. Ultraviolet spectra
were obtained on a Perkin-Elmer Lambda 9 UV–VIS–NIR
spectrophotometer. Mass spectra were recorded on a VG
analytical ZAB-E mass spectrometer using electron impact
(EI). High resolution mass spectra were also recorded on the
same spectrometer. Microanalyses were performed by Guelph
Chemical Laboratories Ltd., Guelph, Ontario, Canada.
For 21ab, 33ab and 23ab, the mixtures of diastereomeric
α-epimers are separable by flash chromatography. While treat-
10
3,4,7,8-Tetramethylglycoluril 1
ment of 19 with D O results in slow exchange of the hydrogens
To a stirred suspension of monomethylurea (7.6 g, 103 mmol)
in absolute ethanol (120 ml) was added concentrated hydro-
chloric acid (4 drops) and freshly distilled butane-2,3-dione (4.5
ml, 4.5 g, 52 mmol). The solution clarified as the exothermic
reaction proceeded. Product appeared as a precipitate after ca.
15 min. The mixture was stirred for a further 30 min, then
cooled to 0 ЊC for 1 h. The solid product was collected by
vacuum filtration, washed with cooled ethanol (2 × 5 ml) then
exhaustively with dichloromethane and dried to give 5.2 g
(51%) of a 1:1 mixture of 1 and 2. The crude product was
recrystallized twice from ethanol (60 ml ethanol per 1 g solid).
Compound 1 (2.1 g, 21%) was obtained as colorless crystals;
2
at C-2 of the acyl chain, the mixture 21ab fails to undergo H–D
exchange during 2 weeks under these conditions. The observed
low kinetic acidity in these H–D exchange experiments
resembles that for (α-alkyl-β-ketoalkanoyl)oxazolidone deriv-
12–14
atives which was reported by Evans and co-workers,
again
emphasizing the similarities between the two systems. However,
the pure diastereomers, 21a and 21b, and 23a and 23b, were
t
converted upon treatment with Bu OK to a mixture with the
same composition as for the products from the condensation
reactions. This result suggests that the immediate product in
the condensation reaction is the enolate of the β-ketoacyl
group. The observed diastereomer ratio in the latter reaction is
thus controlled by the enolate reprotonation step. Hence, any
diastereoselectivity in the actual condensation step is masked.
In conclusion, the glycoluril template 1 provides a frame-
work onto which two different acyl groups can be attached.
Generation of an enolate at one acyl site allows efficient
intramolecular Claisen-type condensation onto the other,
mimicking the proposed process in FAS and PKS. The enolates
may be generated directly by deprotonation, in which case
asymmetrically substituted diacylglycolurils give predomin-
antly the product from deprotonation at the least hindered
position; alternatively, an indirect method of enolate generation
by addition of hydride to α,β-unsaturated acyl groups can be
used to effect net regiochemical reversal of the process. The
resulting β-ketoacylglycolurils can be chemically modified in
steps which parallel those in FAS and PKS to give N-alk-2-
enoyl- and N-alkanoyl-glycolurils. As in FAS and PKS, these
compounds can undergo further rounds of acylation, conden-
sation and functional group manipulation to give extended
carbon chains without the growing chain leaving the enzyme
or template surface. The synthetic application of this method-
ology to products which can be derived from such a crossed-
Claisen approach, as well as other aspects of this interesting
system, are currently the subject of further investigations.
10
Ϫ1
mp >300 ЊC (lit., >300 ЊC); νmax(FT, KBr pellet)/cm 3282
(NH), 2920 (C᎐H), 1683 (C᎐O), 1506, 1441, 1414, 1389, 1263,
1230, 1120, 1087, 1003, 963, 768, 721; δ (200 MHz, CD OD)
H
3
2.77 (6H, s, NCH ), 1.48 (3H, s, CH ), 1.39 (3H, s, CH ); δ (50
3
3
3
C
MHz, CD OD) 161.0 (C᎐O), 83.1 (CNN), 74.7 (CNN), 26.8
3
ϩ
(NCH ), 22.1 (CH ), 15.9 (CH ); m/z (EI) 198.1121 (M .
3
3
3
C H N O requires 198.1117), 183, 140, 126, 125, 111, 85, 65
8
14
4
2
(base).
1,4,7,8-Tetramethylglycoluril 2
A mixture of 1 and 2 (2.0 g, 1:1) was heated at reflux with
acetic anhydride (20 ml) for 20 h. After cooling to room temp-
erature, the solid material was collected and washed with
CHCl , THF and cold ethanol, to give 2 (810 mg, 81% based on
3
the amount of 2 present in the starting material); δ (200 MHz,
H
CD OD) 2.61 (6H, s, NCH ), 1.40 (6H, s, CH ); m/z (EI)
3
3
3
ϩ
198.1111 (M . C H N O requires 198.1117).
8
14
4
2
General procedures for monoacylglycolurils 3–7
Method A. A mixture of 1 and the carboxylic anhydride (10
ml per g 1) was heated at reflux for 20 h, at which point the
starting material had completely dissolved. Most of the remain-
ing anhydride was removed on the rotary evaporator. The res-
idue was cooled and chloroform (10 ml per g 1) was added.
The mixture was filtered and the filtrate was concentrated. To
the residue in a minimum amount of CHCl was added ethyl
3
Experimental
acetate (10 ml per g 1) and the mixture was cooled to 4 ЊC
overnight. The crystals were collected, washed with diethyl
ether and recrystallized or purified by flash chromatography.
Method B. To a stirred suspension of finely powdered
glycoluril 1 in dry THF (200 ml per g 1) at room temperature
General
All reactions were performed in flame-dried glassware, under a
positive pressure of nitrogen, unless otherwise noted. Air- and
moisture-sensitive compounds were transferred by syringe.
Concentration of organic solutions was performed on the
rotary evaporator (ca. 25 Torr), followed by evacuation to con-
stant weight (<0.05 Torr). Flash column chromatography was
performed on Kieselgel 60 (230–400 mesh ASTM) according
n
was added Bu Li (1.1 equiv.). The mixture was heated at reflux
for 2 h. After cooling to room temperature, 1.5 equiv. of the
acyl chloride was added. The resulting clear solution was
heated at reflux for 30 min, cooled and filtered. The filtrate was
concentrated to give crude product. Recrystallization or flash
chromatography gave the pure products.
21
to the method of Still et al. THF was freshly distilled under
nitrogen protection from potassium–benzophenone, diiso-
propylamine from calcium hydride and tert-butyl alcohol
10
1-Acetyl-3,4,7,8-tetramethylglycoluril 3. Glycoluril 1 (2 g,
10 mmol) was heated with acetic anhydride (20 ml) to give 3
(1.89 g, 78%) by method A. Glycoluril 1 (2 g, 10 mmol) in THF
n
from sodium. n-Butyllithium (Bu Li) was titrated using 2,5-
22
dimethoxybenzyl alcohol in THF. All other reagents were
used as purchased except where indicated.
n
(200 ml) was treated with Bu Li (1.6 , 7.0 ml, 11 mmol) then
Melting points are uncorrected. Proton and carbon-13
nuclear magnetic resonance (NMR) spectra were recorded on
Bruker AC 200, Bruker AC 300 or Bruker AC 500 NMR
acetyl chloride (1.07 ml, 1.18 g, 15 mmol) according to method
B to give 3 (2.15 g, 89%) as a white solid after recrystallization
(CHCl –EtOAc); mp 178–180 ЊC (Found: C, 50.27; H, 6.85; N,
3
spectrometers. Proton chemical shifts (δ scale) refer to SiMe
23.16. C H N O requires C, 49.99; H, 6.71; N, 23.32%);
νmax(FT, KBr pellet)/cm 3250 (NH), 2980 (CH), 2940 (CH),
4
10 16
4
3
13
Ϫ1
and those of C to CDCl . Data are given as chemical shift
3
[
integral, multiplicity (s = singlet, d = doublet, t = triplet, q =
1723 (C᎐O), 1689 (C᎐O), 1487, 1416, 1326, 1117, 943; δ (200
᎐
᎐
H
J. Chem. Soc., Perkin Trans. 1, 1998
443

View Article Online
MHz, CDCl ) 6.00 (1H, br s, NH), 3.02 (3H, s, NCH ), 2.87
General procedure for preparation of diacylglycolurils 9–18
Either Bu Li in hexane or freshly prepared LDA in THF (1
3
3
n
(
3H, s, NCH ), 2.48 (3H, s, COCH ), 1.69 (3H, s, CH ), 1.56
3
3
3
(
3H, s, CH ); δ (50 MHz, CDCl ) 171.0 (MeC᎐O), 157.2
equiv.) was added to a stirred solution of the monoacyl-
glycoluril 3–7 in THF (80 ml per g starting material) at 0 ЊC.
After stirring for 30 min, the acyl chloride (1.2–1.5 equiv.) was
added. After stirring for 1 h at room temperature, the resulting
solution was concentrated to remove most of the THF. Chloro-
form (30 ml g ) was added to the residue, and the mixture was
stirred, cooled and filtered. The filtrate was concentrated and
separated by flash column chromatography (1% MeOH in
3
C
3
(
NNC᎐O), 153.0 (NNC᎐O), 78.5 (CNN), 76.4 (CNN), 27.0,
᎐
᎐
ϩ
2
6.3, 24.8, 19.5, 15.6; m/z (EI) 240.1231 (M . C H N O
10 16 4 3
requires 240.1222), 225, 210, 198, 183, 168, 156, 140, 125 (base).
-Propanoyl-3,4,7,8-tetramethylglycoluril 4. Compound 1 (2
g, 10 mmol) was heated with propanoic anhydride (20 ml)
according to method A. Purification by flash column chrom-
atography (2% MeOH in CHCl ) gave 4 (2.14 g, 83%) as a white
solid; mp (from CHCl ) 160–162 ЊC; νmax(FT, KBr pellet)/cm
1
Ϫ1
3
Ϫ1
CHCl ) to give the pure diacylglycoluril and recovered starting
3
3
3
265 (NH), 3108, 3000, 2942, 1730 (C᎐O), 1718 (C᎐O), 1685
material.
᎐
᎐
(
C᎐O), 1461, 1411; δ (200 MHz, CDCl ) 6.29 (1H, s, NH), 3.01
1,6-Diacetyl-3,4,7,8-tetramethylglycoluril 9. 1-Acetyl-3,4,7,8-
᎐
H
3
(
1
3H, s, NCH ), 2.87 (3H, s, NCH ), 3.00–2.74 (2H, m, CH ),
tetramethylglycoluril 3 (910 mg, 3.79 mmol) was treated with
Bu Li (1.6 , 2.5 ml, 4 mmol) followed by AcCl (0.4 ml, 5.6
3
3
2
n
.70 (3H, s, CH ), 1.58 (3H, s, CH ), 1.11 (3H, t, J 7.3,
3
3
CH CH ); δ (50 MHz, CDCl ) 174.5, 157.0, 152.7, 78.4, 77.2,
mmol) to give recovered 3 (17%) and 9 (834 mg, 78%) as a white
solid; mp 194–196 ЊC; νmax(FT, KBr pellet)/cm 2975, 2920,
3
2
C
3
ϩ
Ϫ1
2
9.6, 26.7, 26.1, 19.3, 15.4, 7.9; m/z 254.1370 (M . C H N O
11
18
4
3
requires 254.1379), 197, 180, 168, 156, 140, 125 (base).
-Butanoyl-3,4,7,8-tetramethylglycoluril 5. Glycoluril 1 (2.6
g, 13 mmol) was heated with butanoic anhydride (20 ml)
according to method A. Purification by flash column chrom-
1705 (C᎐O), 1688 (C᎐O), 1399, 1358, 1314, 1248, 1082, 1035,
994, 930, 869, 744, 696; δ (200 MHz, CDCl ) 2.97 (6H, s, 2
H 3
᎐ ᎐
1
NCH ), 2.48 (6H, s, 2 COCH ), 1.95 (3H, s, CH ), 1.51 (3H, s,
3
3
3
CH ); δ (50 MHz, CDCl ) 170.5 (MeC᎐O), 153.1 (NNC᎐O),
3
C
3
atography (2% MeOH in CHCl ) gave 5 (2.48 g, 70%) as a white
80.4 (NNC), 77.3 (NNC), 26.7, 26.0, 19.0, 14.5; m/z (EI)
3
ϩ
solid; mp (from CHCl ) 125–126 ЊC (Found: C, 53.63; H, 7.22;
282.1336 (M . C H N O requires 282.1328), 240, 225, 210,
3
12 18
4
4
N, 20.64. C H N O requires C, 53.71; H, 7.51; N, 20.88%);
198, 183, 168, 156, 141, 125 (base).
12
20
4
3
Ϫ1
13
νmax(FT, KBr pellet)/cm 3252 (NH), 2998, 2956, 2875, 1710
C᎐O), 1689 (C᎐O), 1458, 1408; δ (200 MHz, CDCl ) 6.01 (1H,
1-([ C ]Acetyl)-6-acetyl-3,4,7,8-tetramethylglycoluril
9a.
2
n
(
Compound 3 (1.53 g, 6.38 mmol) was treated with Bu Li (1.49
᎐
᎐
H
3
13
s, NH), 3.01 (3H, s, NCH ), 2.87 (3H, s, NCH ), 2.96–2.75 (2H,
, 4.3 ml, 6.40 mmol) and then [ C ]acetyl chloride (0.6 g, 7.45
3
3
2
m, CH CO), 1.68 (3H, s, CH ), 1.56 (3H, s, CH ), 1.70–1.50
mmol) to give 9a with some 9b (1.44 g, 80%); δ (200 MHz,
2
3
3
H
(
2H, m, CH CH ), 0.96 (3H, t, J 7.4, CH CH ); δ (50 MHz,
CDCl ) 2.99 (6H, s, 2 NCH ), 2.47 (6H, s and dd, J 130, 6.8;
2
3
3
2
C
3
3
13
13
CDCl ) 174.1, 157.2, 153.0, 78.6, 76.5, 38.2, 27.1, 26.4, 19.6,
1
2
integration ratio of s:dd = 1:1.25, COCH and CO CH ),
3
3
3
ϩ
7.7, 15.7, 13.6; m/z (EI) 268.1526 (M . C H N O requires
1.95 (3H, s, CH ), 1.55 (3H, s, CH ); δ (200 MHz, CDCl ) 170.0
3 3 C 3
13
12
20
4
3
68.1535), 253, 240, 211, 199, 183, 168, 156, 141, 125 (base).
-(But-2-enoyl)-3,4,7,8-tetramethylglycoluril 6 from 1. Glyco-
(enhanced d, J 52.4, C᎐O), 152.7, 80.0, 77.5, 25.7 (enhanced
13 ϩ
1
d, J 52.2), 18.6, 14.1; m/z (EI) 286 (3.2, [ C ]M 9b), 285
4
13 ϩ 13
luril 1 (2.50 g, 12.6 mmol) in THF (100 ml) was treated with
Bu Li (1.8 , 7 ml, 12.6 mmol) then but-2-enoic anhydride (3
(4), 284.1385 (10.4, [ C ]M 9a. C10 C H N O requires
2 2 18 4 4
n
284.1396), 242 (20.2), 240 (14.5), 198 (12.8), 168 (20), 156
ml, 3.1 g, 20 mmol) according to method B to give 6 (2.3 g,
(31.2), 141 (48), 125 (100).
2
6
8%) as a white solid after purification by flash column chrom-
1-([ H ]Acetyl)-6-acetyl-3,4,7,8-tetramethylglycoluril
9d.
3
n
atography (2% MeOH in CHCl ); mp 163–165 ЊC (Found: C,
Compound 3 (1.18 g, 4.92 mmol) was treated with Bu Li (1.6 ,
3.0 ml, 4.8 mmol) and then [ H ]acetyl chloride (0.35 ml, 4.72
mmol) to produce 9d (0.948 g, 68%); δ (200 MHz, CDCl ) iden-
3
2
5
3.92; H, 6.78; N, 20.79. C H N O requires C, 54.12; H, 6.81;
12
18
4
3
3
3
Ϫ1
Ϫ1
N, 21.04%); λmax(CH OH)/nm 229 (ε/dm mol cm 12 000);
νmax(FT, KBr pellet)/cm 3310 (NH), 2990, 1722 (C᎐O), 1667
3
H
3
Ϫ1
tical to 9, except δ 2.48 (3H, s, COCH ); δ (77 MHz, CHCl ,
3 D 3
ϩ
(
C᎐O), 1627; δ (200 MHz, CDCl ) 7.27 (1H, dq, J 15.2, 1.4,
reference CDCl3 δ 7.248) 2.43 (s); m/z 285.1515 (M .
C H D N O requires 285.1513), 267, 241, 213, 168, 156, 140,
᎐
H
3
CH᎐CHMe), 7.08 (1H, dq, J 15.2, 6.4, MeCH᎐CH), 6.13 (1H,
᎐
᎐
12 15
3
4
4
s, NH), 3.02 (3H, s, NCH ), 2.87 (3H, s, NCH ), 1.93 (3H, dd,
125, 83 (base).
3
3
J 6.5, 1.3, CH᎐CHCH ), 1.71 (3H, s, CH ), 1.57 (3H, s, CH );
1-Propanoyl-6-acetyl-3,4,7,8-tetramethylglycoluril 10. 1-Prop-
᎐
3
3
3
δ (50 MHz, CDCl ) 165.2, 157.1, 152.6, 144.8, 123.0, 78.2, 76.2,
anoyl-3,4,7,8-tetramethylglycoluril 4 (2.52 g, 9.92 mmol) was
treated with Bu Li (1.3 , 8.0 ml, 10.4 mmol) and then acetyl
C
3
ϩ
n
2
1
6.7, 26.0, 19.3, 18.0, 15.3; m/z (EI) 266 (M , base), 251, 192,
68, 142, 125.
chloride (0.75 ml, 15.5 mmol) to produce recovered 4 (19%) and
10 (1.59 g, 54%); mp 180–182 ЊC (Found: C, 52.83; H, 6.60; N,
19.26. C H N O requires C, 52.96; H, 6.80; N, 18.91%);
1
-(Hexa-2,4-dienoyl)-3,4,7,8-tetramethylglycoluril 7 from 1.
Glycoluril 1 (2.0 g, 10 mmol) in THF (120 ml) was treated with
13
20
4
4
n
23
Ϫ1
Bu Li (1.6 , 7.9 ml, 11 mmol) then hexa-2,4-dienoyl chloride
νmax(FT, KBr pellet)/cm 2975, 2942, 1758 (C᎐O), 1722 (C᎐O),
1445, 1411; δ (200 MHz, CDCl ) 3.08–2.70 (2H, m, CH ), 2.99
(
1.45 g, 11.1 mmol) according to method B to give 7 (320 mg,
H
3
2
1
5%) after purification by flash column chromatography (2%
(3H, s, NCH ), 2.98 (3H, s, NCH ), 2.47 (3H, s, CH ), 1.95 (3H,
3
3
3
MeOH in CHCl ) as a white solid (Found: C, 57.41; H, 6.98; N,
s, CH ), 1.54 (3H, s, CH ), 1.13 (3H, t, J 7.3, CH CH ); δ (50
3 3 2 3 C
3
1
8.81. C H N O requires C, 57.52; H, 6.90; N, 19.16%);
MHz, CDCl ) 174.1, 170.1, 152.8 (2 C᎐O), 80.2, 77.6, 30.8, 26.4
14
20
4
3
3
3
Ϫ1
Ϫ1
ϩ
λmax(CH OH)/nm 319 (ε/dm mol cm 26 000); νmax(FT, KBr
pellet)/cm 3289, 3089, 2915, 1731, 1712, 1668, 1597; δ (200
(2 CH ᎐N), 25.8, 18.8, 14.2, 8.2; m/z (EI) 296.1497 (M .
3
3
Ϫ1
C H N O requires 296.1484), 254, 241, 225, 199, 183, 168,
H
13 20
4
4
MHz, CD Cl ) 7.37 (1H, dd, J 15.3, 9.4, CH᎐CHCO), 7.23 (1H,
156, 141, 125 (base).
2
2
d, J 15.3, CH᎐CHCO), 6.39–6.12 (2H, m, CH᎐CH), 2.99 (3H,
1-Butanoyl-6-acetyl-3,4,7,8-tetramethylglycoluril 11. 1-Buta-
᎐
᎐
s, NCH ), 2.82 (3H, s, NCH ), 1.86 (3H, d, J 5.6, CH CH᎐CH),
noyl-3,4,7,8-tetramethylglycoluril 5 (1.20 g, 4.48 mmol) was
treated with Bu Li (2.8 ml, 4.48 mmol) and then acetyl chloride
3
3
3
n
1
1
2
.68 (3H, s, CH ), 1.54 (3H, s, CH ); δ (50 MHz, CD Cl ) 166.4,
3
3
C
2
2
57.6, 153.3, 145.5, 140.4, 130.8, 120.4, 78.9, 77.1, 27.3, 26.5,
(0.5 ml, 7.6 mmol) to produce 12 (0.85 g, 61%) (with 20%
recovered 9); mp 130–132 ЊC (Found: C, 54.05; H, 7.07; N,
17.81. C H N O requires C, 54.18; H, 7.15; N, 18.06%);
ϩ
0.0, 18.9, 15.9; m/z (EI) 292 (M ), 218, 168, 125 (base).
1
-Acetyl-3,6,7,8-tetramethylglycoluril 8. Glycoluril 2 (510
14
22
4
4
n
Ϫ1
mg, 2.57 mmol) in THF was treated with Bu Li then acetyl
chloride according to method B. Purification by flash column
νmax(FT, KBr pellet)/cm 2980, 2945, 1756, 1735, 1722, 1410;
δ (200 MHz, CDCl ) 2.99 (6H, s, 2 NCH ), 2.97–2.66 (2H, m,
H
3
3
chromatography (1% MeOH in CHCl ) gave 8 (310 mg, 50%) as
CH CO), 2.47 (3H, s, CH CO), 1.95 (3H, s, CH ), 1.55 (3H, s,
CH ), 1.75–1.59 (2H, m, CH CH ), 0.95 (3H, t, J 7.4, CH CH );
3 2 3 3 2
3
2
3
3
a white solid; δ (200 MHz, CDCl ) 6.19 (1H, s, NH), 2.98 (3H,
H
3
s, NCH ), 2.85 (3H, s, NCH ), 2.51 (3H, s, COCH ), 1.84 (3H, s,
δ (50 MHz, CDCl ) 173.1, 170.1, 152.71, 152.66, 80.1, 77.5,
C 3
3
3
3
CH ), 1.51 (3H, s, CH ).
39.1, 26.4, 26.3, 25.8, 18.7, 17.4, 14.1, 13.3; m/z (EI) 310.1633
3
3
4
44
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
ϩ
(
M . C H N O requires 310.1641), 282, 268, 241, 199, 183,
CDCl ) 7.09–7.02 (1H, m, CH᎐CHCO), 6.96 (1H, d, J 15.3,
3
᎐
14
22
4
4
1
68, 156, 141, 125 (base).
-Trimethylacetyl-6-acetyl-3,4,7,8-tetramethylglycoluril 12.
-Acetyl-3,4,7,8-tetramethylglycoluril 3 (550 mg, 2.3 mmol) was
CH᎐CH), 2.95 (6H, s, 2 NCH ), 2.48 (3H, s, COCH ), 1.98 (3H,
s, CH ), 1.91 (3H, d, J 6.6, CH᎐CHCH ), 1.47 (3H, s, CH );
3 3 3
᎐
3
3
1
1
δ (50 MHz, CDCl ) 170.5, 165.6, 153.2, 153.1, 144.6, 124.9,
C
3
n
treated with Bu Li (1.6 , 1.5 ml, 2.4 mmol) and then trimethyl-
acetyl chloride (0.350 ml, 2.8 mmol) to give 12 (273 mg, 52%);
mp 180–182 ЊC; νmax(FT, KBr pellet)/cm 2985, 2924, 1748,
1
1
80.5, 77.8, 26.7 (2 CH N), 26.0, 19.1, 18.3, 14.6; m/z (EI) 308
3
ϩ
(M ), 280, 241, 192, 167, 124, 125 (base).
Ϫ1
1-(Hexa-2,4-dienoyl)-6-acetyl-3,4,7,8-tetramethylglycoluril
18. Compound 7 (160 mg, 0.54 mmol) in THF (30 ml) was
treated with LDA (1.1 equiv.) and acetyl chloride (0.05 ml, 0.7
mmol) to give 18 (68 mg, 38%, with 45% recovered 7);
733, 1710, 1690, 1449, 1411, 1386, 1327, 1274, 1229, 1113,
093, 945, 886, 811, 760, 740, 683, 603, 587; δ (200 MHz,
H
CDCl ) 3.02 (3H, s, NCH ), 2.90 (3H, s, NCH ), 2.50 (3H, s,
COCH ), 1.91 (3H, s, CH ), 1.56 (3H, s, CH ), 1.32 [9H, s,
3
3
3
3
Ϫ1
Ϫ1
λmax(CH OH)/nm 275 (ε/dm mol cm 9300); νmax(FT, KBr
3
3
3
3
Ϫ1
(
CH ) C]; δ (50 MHz, CDCl ) 183.3, 170.5, 153.6, 152.8, 80.5,
pellet)/cm 2939, 1735 (C᎐O), 1702 (C᎐O); δ (500 MHz,
3
3
C
3
H
7
8.4, 43.7, 27.2, 27.0, 26.9, 25.2, 19.5, 15.4; m/z (EI) 325
CDCl ) 7.37 (1H, dd, J 15.0, 10.9, CH᎐CH), 6.97 (1H, d, J 15.1,
CH᎐CHCO), 6.26 (1H, dd, J 14.9, 11.4, CH᎐CH), 6.15 (1H,
3
ϩ
(
M ϩ1), 269, 211, 225, 198, 168, 141, 126 (base), 125.
-Methoxycarbonyl-6-acetyl-3,4,7,8-tetramethylglycoluril 13.
-Acetyl-3,4,7,8-tetramethylglycoluril 3 (715 mg, 2.97 mmol) in
1
dq, J 14.8, 6.6, CH᎐CHMe), 2.97 (3H, s, NCH ), 2.96 (3H, s,
᎐
3
1
NCH ), 2.49 (3H, s, COCH ), 1.99 (3H, s, CH ), 1.84 (3H, d,
3 3 3
n
THF (28 ml) at 0 ЊC was treated with Bu Li (1.5 , 1.98 ml, 2.97
mmol) and then methyl chloroformate (0.30 ml, 3.9 mmol). The
crude material was purified by MPLC using a 1 inch diameter
J 6.8, CH CH᎐CH), 1.51 (3H, s, CH ); δ (50 MHz, CDCl )
3
3
C
3
170.6, 166.1, 153.2, 145.3, 139.8, 130.5, 121.1, 80.7, 77.8, 26.9,
ϩ
26.7, 26.2, 19.2, 18.7, 14.7; m/z (EI) 334.1646 (M . C H N O
16
22
4
4
Ϫ1
silica LOBAR column, eluted with ethyl acetate at 4 ml min
requires 334.1641), 293, 241, 149, 125 (base).
to give 13 (758 mg, 84%); δ (200 MHz, CDCl ) 3.86 (3H, s,
H
3
OCH ), 2.98 (3H, s, NCH ), 2.89 (3H, s, NCH ), 2.44 (3H, s,
General procedures for condensations of diacylglycolurils 9–18 to
3
3
3
COCH ), 1.88 (3H, s, CH ), 1.49 (3H, s, CH ).
give â-ketoacylglycolurils 19–27
3
3
3
t
1
-Propenoyl-6-acetyl-3,4,7,8-tetramethylglycoluril
14.
A solution of Bu OLi was prepared by adding dry tert-butyl
n
t
1
-Acetyl-3,4,7,8-tetramethylglycoluril 3 (9.6 g, 40 mmol) was
alcohol (1.5 equiv.) then Bu Li or Bu Li in hexane (1.1 equiv.) to
n
n
treated with Bu Li (1.6 , 25 ml, 40 mmol) and then propenoyl
chloride (4.5 ml, 55 mmol) to give 14 (4.9 g, 41%) (Found: C,
THF (3 ml per mmol Bu Li) with stirring at 0 ЊC. Other alkox-
ides were prepared similarly from the corresponding alcohol
5
3.14; H, 6.00; N, 19.10. C H N O requires C, 53.05; H, 6.16;
[EtC(CH ) OLi], or were used as commercially available solids
13
18
4
4
3 2
3
Ϫ1
Ϫ1
t
t
N, 19.04%); λmax(CH OH)/nm 226 (ε/dm mol cm 9930);
νmax(FT, KBr pellet)/cm 3033, 2943, 1754, 1729, 1706, 1619,
(Bu ONa, Bu OK) dissolved in THF. The solution was stirred at
room temperature for 5–10 min and then added to a vigorously
stirred solution of the diacylglycoluril (1 equiv.) in THF (80 ml
3
Ϫ1
1
452, 1399, 1338; δ (200 MHz, CDCl ) 7.23 (1H, dd, J 16.9,
H
3
Ϫ1
1
0.3, CH᎐CH ), 6.45 (1H, dd, J 17.0, 1.9, CH᎐CHH), 5.78 (1H,
g ) at 0 ЊC, and, in some cases, the appropriate crown ether (1.3
᎐
2
dd, J 10.3, 1.8, CH=CHH), 2.98 (6H, s, 2 NCH ), 2.49 (3H, s,
equiv.). After the reaction was complete by TLC, work-up
ensued. Either a large excess of ammonium hydrogen carbonate
powder was added, the mixture was stirred for 5 h, filtered
through Celite and the filtrate was concentrated; or sodium
hydrogen sulfate (1 , 7 equiv.) was added, the product was
extracted into chloroform (2 × 5 volumes) and the combined
organic layers were washed sequentially with water (15 ml) and
brine (15 ml) and dried over sodium sulfate prior to filtration
and concentration. The resulting solid was purified by flash
3
COCH ), 1.99 (3H, s, CH ), 1.53 (3H, s, CH ); δ (50 MHz,
3
3
3
C
CDCl ) 170.4, 165.5, 153.0, 130.4, 129.7, 80.5, 77.9, 26.8, 26.7,
3
ϩ
1
9.0, 14.6; m/z (EI) 294 (M ), 252, 168, 125 (base).
-(2-Methylpropenoyl)-6-acetyl-3,4,7,8-tetramethylglycoluril
5. 1-Acetyl-3,4,7,8-tetramethylglycoluril 3 (1.35 g, 5.6 mmol)
1
1
n
was treated with Bu Li (1.6 , 3.5 ml, 5.6 mmol) and then
-methylpropenoyl chloride (0.65 ml, 6.65 mmol) to give 15
0.63 g, 36%); δ (200 MHz, CDCl ) 5.40 (2H, s, C᎐CH ), 3.00
2
(
H
3
2
(
3H, s, NCH ), 2.87 (3H, s, NCH ), 2.44 (3H, s, COCH ), 1.95
column chromatography (2% MeOH in CHCl ).
3
3
3
3
(
3H, s, CH ), 1.53 (3H, s, CH ); δ (50 MHz, CDCl ) 170.7,
1-(3-Oxobutanoyl)-3,4,7,8-tetramethylglycoluril 19. Com-
pound 9 (0.364 g, 1.29 mmol) was treated with lithium tert-
butoxide to give 19 (0.339 g, 93%); mp 154–156 ЊC (Found: C,
50.90; H, 6.35; N, 19.67. C H N O requires C, 51.05; H, 6.43;
3
3
C
3
1
1
3
69.8, 152.7, 152.4, 141.4, 121.7, 79.7, 77.9, 26.7, 26.5, 24.9,
ϩ
8.8, 18.2, 14.9; m/z (EI) 308.1485 (M . C H N O requires
14
20
4
4
08.1485), 266, 168, 142, 126 (base).
-Butanoyl-6-propenoyl-3,4,7,8-tetramethylglycoluril
-Butanoyl-3,4,7,8-tetramethylglycoluril 5 (0.728 g, 2.72 mmol)
12
18
4
4
3
Ϫ1
Ϫ1
1
16.
N, 19.85%); λmax(CH OH)/nm 211 (ε/dm mol cm 7600),
3
Ϫ1
1
272 (970); νmax(FT, KBr pellet)/cm 3224 (NH), 3095, 2931,
n
was treated with Bu Li (1.6 , 1.7 ml, 2.72 mmol) and then
propenoyl chloride (0.27 ml) to give 16 (0.312 g, 36%); mp 143–
1
1760–1690 (C᎐O, br), 1500, 1415, 1394, 1385, 1341, 1312,
1264, 1215, 1167, 1108, 1088, 998, 970, 901, 789, 761, 652, 591,
544; δ (200 MHz, CDCl ) 13.45 (0.09H, s, enol OH), 6.51
45 ЊC (Found: C, 56.00; H, 6.95; N, 17.43; C H N O
15 22 4 4
H
3
requires C, 55.88; H, 6.88; N, 17.38%); λ (CH OH)/nm 224
(0.09H, s, enol CH᎐C), 5.95 (1H, s, NH), 4.31 (0.91H, d, J 16.4,
max
3
᎐
3
Ϫ1
Ϫ1
Ϫ1
(
ε/dm mol cm 11 700); νmax(FT, KBr pellet)/cm 2965,
935, 1754, 1731, 1706, 1401; δ (300 MHz, CDCl ) 7.19
COCHHCO), 3.59 (0.91H, d, J 16.4, COCHHCO), 3.01
(0.27H, s, enol NCH ), 2.98 (2.73H, s, NCH ), 2.86 (3H, s,
2
H
3
3
3
(
1H, dd, J 17.0, 10.4, CH᎐CH ), 6.44 (1H, dd, J 17.0, 1.8,
NCH ), 2.25 (2.73H, s, CH CO), 2.02 (0.27H, s enol CH CO),
᎐
2
3
3
3
CH᎐CHH), 5.76 (1H, dd, J 10.3, 1.8, CH᎐CHH), 2.98 (3H, s,
1.74 (3H, s, CH ), 1.56 (3H, s, CH ); δ (50 MHz, CDCl , keto
3 3 C 3
᎐
᎐
NCH ), 2.96 (3H, s, NCH ), 3.01–2.71 (2H, m, CH CO), 1.99
form only) 201.3 (C᎐O ketone), 167.1, 157.1, 152.8, 78.7, 76.6,
52.2, 30.0, 27.1, 26.4, 19.2, 15.7; m/z (EI) 282.1319 (M .
3
3
2
ϩ
(
3H, s, CH ), 1.70–1.60 (2H, m, CH CH ), 1.51 (3H, s, CH ),
3
2
3
3
0
1
1
.95 (3H, t, J 7.4, CH CH ); δ (75 MHz, CDCl ) 173.6, 165.6,
C H N O requires 282.1328), 267, 240, 210, 183, 156, 140,
3
2
C
3
12 18
4
4
53.1, 130.6, 129.6, 80.7, 78.0, 39.4, 26.8 (2 CH N), 19.2, 17.9,
125.
1-(3-Oxo-[1,2- C ]butanoyl)-3,4,7,8-tetramethylglycoluril
3
ϩ
13
4.7, 13.6; m/z (EI) 322 (M ), 294, 253, 179, 125 (base).
2
1
3
1
-(But-2-enoyl)-6-acetyl-3,4,7,8-tetramethylglycoluril n
Compound 6 (700 mg, 2.63 mmol) was treated with Bu Li (1.6
, 1.5 ml, 2.4 mmol) and then acetyl chloride (0.3 ml). The
crude product was purified by flash column chromatography
17.
and 1-(3-oxo-[3,4- C ]butanoyl)-3,4,7,8-tetramethylglycoluril
2
13
19a, with 1-(3-oxo-[1,2,3,4- C ]butanoyl)-3,4,7,8-tetramethyl-
4

glycoluril 19b. This mixture (0.304 g, 87%) was obtained from
condensation of 9a and 9b (0.35 g); δ (200 MHz, CDCl ) 5.96
H
3
13
(
CHCl ) to give 17 (502 mg, 62%, with 12% recovered 6)
(1H, s, NH), 4.69–3.21 (2H, m, COCH CO and CO-
2
13
3
(
Found: C, 54.48; H, 6.88; N, 18.06. C H N O requires C,
CH CO), 2.98 (3H, s, NCH ), 2.86 (3H, s, NCH ), 2.25 (3H, s
2 3 3
14
20
4
4
3
Ϫ1
5
4.53; H, 6.54; N, 18.17%); λ (CH OH)/nm 206 (ε/dm mol
and dd, J 128.0, 6.1, integration ratio of s:dd 1:1.27, CH CO
3
13 13
max
3
Ϫ1
Ϫ1
cm 11 000); νmax(FT, KBr pellet)/cm 2939, 1749 (C᎐O), 1722
and CH3 CO), 1.74 (3H, s, CH ), 1.56 (3H, s, CH ); m/z 286
3 3
ϩ 13
᎐
(
C᎐O), 1703 (C᎐O), 1637 (C᎐O), 1408, 1341; δ (500 MHz,
(3.2%, 19b), 285 (3.2), 284.1385 (9.6, M , 19a. C C H N O
10 2 18 4 4
᎐
᎐
᎐
H
J. Chem. Soc., Perkin Trans. 1, 1998
445

View Article Online
requires 284.1396), 242 (4), 240 (3.2), 212 (17.6), 140 (24), 125
100).
-(3-Oxo-[4- H ]butanoyl)-3,4,7,8-tetramethylglycoluril 19d.
J 15.8, 6.6, enol CH CH᎐CH), 6.51 (1H, s, enol COCH᎐COH),
3
᎐ ᎐
(
6.16–6.12 (2H, m, NH and CH᎐CH), 5.90 (1H, d, J 15.3,
᎐
2
1
CH᎐CHCO), 4.47 (1H, d, J 16.2, COCHHCO), 3.75 (1H, d,
3
᎐
t
Compound 9d (310 mg, 1.09 mmol) was treated with Bu OLi to
J 16.2, COCHHCO), 3.00 (3H, s, enol NCH ), 2.97 (3H, s, keto
3
give 19d (247 mg, 80%), which contained 19 (17%); δ (500
NCH ), 2.86 (3H, s, NCH ), 1.93 (3H, dd, J 6.9, 1.7, keto
H
3
3
MHz, CDCl ) 5.97 (1H, s, NH), 4.30 (1H, d, J 16.4, COCH-
CH CH᎐CH), 1.88 (3H, dd, J 7.0, 1.6, enol CH CH᎐CH), 1.76
3
3
3
HCO), 3.60 (1H, d, J 16.5, COCHHCO), 2.98 (3H, s, NCH ),
(3H, s, CH ), 1.74 (3H, s, enol CH ), 1.56 (3H, s, CH ); δ (50
3 3 3 C
3
2
.86 (3H, s, NCH ), 2.25 (0.52H, s, CH CO in 19), 1.74 (3H, s,
MHz, CDCl , mixture of keto and enol forms) 192.9, 172.6,
3
3
3
CH ), 1.56 (3H, s, CH ); δ (77 MHz, CHCl ) 2.20 (s, CD CO);
171.5, 167.8, 157.2, 152.8, 144.2, 137.3, 131.2, 126.6, 90.8, 78.7,
3
3
D
3
3
ϩ
m/z 285.1512 (M , 19d. C H D N O requires 285.1513), 282
78.6, 76.8, 76.7, 49.0, 27.1, 26.4, 20.0, 19.3, 18.3, 15.7; m/z (EI)
12
15
3
4
4
ϩ
ϩ
(
M , 19), 267, 241, 213, 210, 125 (base).
-(3-Oxopentanoyl)-3,4,7,8-tetramethylglycoluril 20 and 1-(2-
methyl-3-oxobutanoyl)-3,4,7,8-tetramethylglycoluril 21ab from
0. Compound 10 (350 mg, 1.18 mmol) gave a mixture of 20
308 (M ), 236, 125 (base).
1
1-(3-Oxoocta-4,6-dienoyl)-3,4,7,8-tetramethylglycoluril 27.
t
Compound 18 (40 mg, 0.12 mmol) was treated with Bu OLi to
3
Ϫ1
Ϫ1
Ϫ1
1
give 27 (24 mg, 60%); λmax(CH OH)/nm 215 (ε/dm mol cm
3
Ϫ1
and 21ab (284 mg, 81%). For 20: νmax(FT, KBr pellet)/cm 3230
11 500), 280 (11 600), 319 (10 800); νmax(FT, KBr pellet)/cm
(
NH), 2991, 2940, 1743 (C᎐O), 1717 (C᎐O), 1689 (C᎐O), 1457,
3426 (NH), 2927, 1719 (C᎐O); δ (500 MHz, CDCl , contains
᎐
᎐
᎐
H
3
1
410; δ (200 MHz, CDCl ) 5.99 (1H, s, NH), 4.33 (1H, d,
46% enol form) 13.18 (0.46H, s, enol OH), 7.15–5.83 (4H, m,
CH᎐CH), 6.56 (0.46H, enol COCH᎐COH), 4.51 (0.54H, d,
H
3
J 16.4, COCHHCO), 3.56 (1H, d, J 16.4, COCHHCO),
.99 (3H, s, NCH ), 2.86 (3H, s, NCH ), 2.54 (2H, q, J 7.2,
᎐
᎐
2
J 16.1, keto COCHHCO), 3.74 (0.54H, d, J 16.1, keto COCH-
HCO), 3.02 (1.4H, s, enol NCH ), 2.97 (1.6H, keto NCH ), 2.86
3
3
CH CH ), 1.75 (3H, s, CH ), 1.56 (3H, s, CH ), 1.08 (3H, t,
2
3
3
3
3
3
J 7.2, CH CH ); δ (50 MHz, CDCl ) 204.4, 167.4, 157.3, 152.8,
(3H, s, NCH ), 1.87 (1.5H, d, J 5.0, CH CH᎐CH), 1.85 (1.5H,
3
2
C
3
3
3
7
2
2
8.8, 76.7, 51.2, 35.9, 27.1, 26.4, 19.3, 15.7, 7.4; m/z (EI)
d, J 6.7, CH CH᎐CH), 1.76 (1.5H, s, CH ), 1.74 (1.5H, s, CH ),
3 3 3
ϩ
96.1482 (M . C H N O requires 296.1484), 267, 254, 240,
1.56 (3H, s, CH ); δ (200 MHz, CDCl ) 193.3, 172.9, 167.9,
13
20
4
4
3 C 3
24, 168, 140, 125, 97, 86, 70.
-(3-Oxohexanoyl)-3,4,7,8-tetramethylglycoluril 22 and 1-(2-
ethyl-3-oxobutanoyl)-3,4,7,8-tetramethylglycoluril 23ab from
1. Compound 11 (270 mg, 0.87 mmol) gave a mixture of 22
157.2, 152.6, 144.3, 141.4, 138.5, 137.4, 130.6, 130.1, 126.6,
123.7, 91.9, 78.7, 77.7, 49.3, 27.1, 26.4, 20.0, 19.3, 18.8, 15.7;
1
ϩ
m/z (EI) 334.1633 (M . C H N O requires 334.1641), 319,
16
22
4
4
1
260, 198, 125, 83 (base).
Ϫ1
and 23ab (237 mg, 88%). For 22: νmax(FT, KBr pellet)/cm 3255
(
NH), 2962, 2941, 1745 (C᎐O), 1725 (C᎐O), 1692 (C᎐O), 1466,
General procedure for reduction of â-ketoacylglycolurils 19, 21ab
᎐
᎐
᎐
1
413; δ (200 MHz, CDCl ) 6.12 (1H, s, NH), 4.32 (1H, d,
and 26 with NaBH4
To a solution of the β-ketoacyl compound in MeOH (35 ml g )
H
3
Ϫ1
J 16.4, COCHHCO), 3.57 (1H, d, J 16.4, COCHHCO), 2.97
3H, s, NCH ), 2.86 (3H, s, NCH ), 2.61–2.46 (2H, m,
(
was added sodium borohydride (1.5–1.8 equiv) at 0 ЊC. This
mixture was stirred for 10 min at room temperature and glacial
acetic acid (10 ml) was added. The solution was concentrated to
give a solid mixture, to which was added dichloromethane (40
ml). The mixture was stirred for 5 min and solid material was
removed by filtration. The filtrate was concentrated and puri-
3
3
CH CH CO), 1.75 (3H, s, CH ), 1.57 (3H, s, CH ), 1.71–1.60
2
2
3
3
(
2H, m, CH CH CO), 0.93 (3H, t, J 7.4, CH ); δ (50 MHz,
2
2
3
C
CDCl ) 203.7, 167.3, 157.1, 152.7, 78.6, 76.5, 51.4, 44.6, 27.0,
2
requires 310.1641), 282, 267, 240, 199, 183, 125.
3
ϩ
6.3, 19.2, 16.7, 15.6, 13.5; m/z (EI) 310.1637 (M . C H N O
14 22 4 4
1
-(3-Oxo-4,4-dimethylpentanoyl)-3,4,7,8-tetramethyl-
fied by flash column chromatography (2% MeOH in CHCl ).
3
glycoluril 24. Compound 12 (100 mg, 0.308 mmol) in THF was
treated with Bu OLi at 0 ЊC using the standard procedure, but
the reaction was allowed to proceed for 5 h, producing the
1-(3-Hydroxybutanoyl)-3,4,7,8-tetramethylglycoluril
28.
t
Compound 19 (1.06 g, 3.76 mmol) was treated with NaBH4
(0.21 g, 5.55 mmol) to give 28 (0.985 g, 93%) as a mixture
of two diastereomers (Found: C, 50.42; H, 7.10; N, 19.65.
C H N O requires C, 50.69; H, 7.09; N, 19.71%); δ (200
condensation product 24 (79 mg, 79%); νmax(FT, KBr pellet)/
Ϫ1
cm 3268 (NH), 3104, 2961, 2924, 1737, 1711, 1692, 1491,
12
20
4
4
H
1
451, 1410, 1333, 1176, 1112, 1064, 760, 696, 664; δ (200 MHz,
MHz, CDCl ) 6.19 (1H, s, NH), 4.24 (1H, m, CHOH), 3.27–
H
3
CDCl ) 13.26 (s, enol OH), 6.64 (s, enol CH᎐C), 6.04 (1H, s,
2.80 (2H, m, CH ), 3.01 (3H, s, NCH ), 2.87 (3H, s, NCH ) 1.71
3
2
3
3
NH), 4.57 (1H, d, J 16.6, COCHHCO), 3.68 (1H, d, J 16.6,
COCHHCO), 3.02 (s, enol NCH ), 2.97 (3H, s, NCH ), 2.86
(3H, s, CH ), 1.56 (3H, s, CH ), 1.26 (3H, d, J 6.3, CH CHOH);
3
3
3
δ (50 MHz, CDCl ) 173.6, 157.1, 152.9, 78.7, 76.7, 64.1, 44.7,
3
3
C
3
ϩ
(
3H, s, NCH ), 1.76 (3H, s, CH ), 1.57 (3H, s, CH ), 1.20 [9H, s,
27.1, 26.4, 22.4, 19.7, 15.5; m/z (EI) 284.1492 (M . C H N O
3
3
3
12 20 4 4
keto (CH ) CO], 1.19 [s, enol (CH ) CO]; δ (50 MHz, CDCl )
requires 284.1485), 266, 240, 156, 140, 126 (base), 111, 86.
3
3
3
3
C
3
2
09.9 (ketone C᎐O), 189.8 (weak, OHC᎐CHCO), 171.6 (weak,
1-(2-Methyl-3-hydroxybutanoyl)-3,4,7,8-tetramethylglycoluril
29. A mixture of the two diastereomeric 1-(2-methyl-3-oxo-
butanoyl)-3,4,7,8-tetramethylglycolurils 21a and 21b (2.1:1
᎐
᎐
OHC᎐CHCO), 168.4, 157.2, 152.6, 86.6, 78.6, 76.6, 46.6, 44.3,
2
᎐
7.4, 27.1, 26.5, 26.4, 19.9 (enol), 19.2, 15.6; m/z (EI) 325
ϩ
(
M ϩ1), 267, 143, 125 (base).
-Methoxycarbonylacetyl-3,4,7,8-tetramethylglycoluril
ratio, 351 mg) was treated with NaBH (67 mg) to give 29 (210
4
1
25.
mg, 60%) as a mixture of four diastereomers; δ (500 MHz,
H
Compound 13 (29.0 mg, 0.097 mmol) and lithium 1,1-dimethyl-
propoxide (31.0 mg, 0.33 mmol) in THF (2 ml) gave a mixture
of 25 and 3 (27.3 mg, 94%, ratio of 25:3 8.5:1), which was
separated by chromatography on a Merck LOBAR MPLC
column (EtOAc). For 25: δ (200 MHz, CDCl ) 5.99 (1H, s,
CDCl ) 6.28, 6.16, 6.12 and 6.11 (total 1H, 4 × s, NH), 4.10–
3
3.65 (2H, m, CHOH and CHOHCHMe), 2.99 (3H, s, NCH ),
3
2.84 (3H, s, NCH ), 1.68, 1.67, 1.66 and 1.65 (total 3H, 4 × s,
3
CH ), 1.53 (3H, s, CH ), 1.23–1.08 (6H, 8 × d, CH CHOH and
3
3
3
CH CHCO); δ (50 MHz, CDCl ) 177.8, 177.4, 177.2, 157.4,
H
3
3
C
3
NH), 4.07 (1H, d, J 16.4, COCHHCO), 3.68 (1H, d, J 16.4,
COCHHCO), 3.70 (3H, s, OCH ), 2.98 (3H, s, NCH ), 2.84
157.3, 157.2, 153.3, 153.2, 78.5, 77.2, 76.8, 71.0, 70.0, 68.6, 67.4,
45.6, 43.6, 43.5, 27.2, 26.4, 21.5, 20.9, 20.6, 19.7, 19.6, 19.5,
19.1, 15.8, 15.7, 14.8, 14.4, 10.9, 10.3; m/z (EI) 299.1704
3
3
(
3H, s, NCH ), 1.70 (3H, s, CH ), 1.54 (3H, s, CH ).
3
3
3
ϩ
ϩ
1
-(3-Oxohex-4-enoyl)-3,4,7,8-tetramethylglycoluril 26. Com-
pound 17 (220 mg, 0.71 mmol) gave 26 (132 mg, 60%); mp 147–
50 ЊC (from CHCl ) (Found: C, 53.97; H, 6.63; N, 17.78.
(M ϩ 1. C H N O requires 299.1719), 280 (M Ϫ H O),
13 23 4 4 2
254, 125 (base).
1
1-(3-Hydroxyhex-4-enoyl)-3,4,7,8-tetramethylglycoluril 30.
Compound 26 (540 mg, 1.75 mmol) was reduced with NaBH4
(110 mg) to give 30 (240 mg, 44%, with 51% recovered 26) as a
3
C H N O requires C, 54.53; H, 6.54; N, 18.17%); λmax-
1
4
20
4
4
3
Ϫ1
Ϫ1
(
CH OH)/nm 304 (ε/dm mol cm 3500); νmax(FT, KBr
3
Ϫ1
Ϫ1
pellet)/cm 3223, 3094, 2948, 1741, 1717, 1690, 1668; δ (500
mixture of two diastereomers; νmax(FT, KBr pellet)/cm 3390
H
MHz, CDCl ) (shows 37% enol form) 13.2 (1H, s, enol OH),
(OH), 3322 (NH), 1721 (C᎐O); δ (200 MHz, CDCl ) 6.12 and
3
᎐
H
3
6
.96 (1H, dq, J 15.7, 6.7, keto CH CH᎐CH), 6.74 (1H, dq,
6.10 (1H, 2 × s, NH), 5.76–5.71 (1H, m, HC᎐CH), 5.58–5.53
᎐
3
4
46
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
(
1H, m, HC᎐CH), 4.4–4.6 (1H, m, CHOH), 3.30–3.00 (2H, m,
General procedure for L-Selectride-induced
reduction–condensation of 14–17
᎐
CH CO), 3.02 (3H, s, NCH ), 2.87 (3H, s, NCH ), 1.71 (3H, s,
2
3
3
CH ), 1.57 (3H, s, CH ), 1.69 (3H, d, J 7.2, CH CH᎐CH);
To a stirred solution of the N-alk-2-enoyl-NЈ-alkanoylglycoluril
in dry THF (150 ml g ) at Ϫ78 ЊC was added -Selectride (1
3
3
3
Ϫ1
δ (125 MHz, CDCl ) 173.0, 157.1, 152.1, 132.1, 127.1, 78.7,
C
3
7
6.7, 68.8, 43.5, 27.1, 26.4, 19.7, 19.6, 17.6, 15.7; m/z 310.1654
equiv.). The mixture was allowed to reach room temperature
over 2 h. Solid NH HCO was added, the mixture was stirred
ϩ
(
M . C H N O requires 310.1641), 292, 240, 199, 125 (base).
14 22 4 4
4
3
for 8 h and filtered through Celite. The filtrate was concentrated
1
-(But-2-enoyl)-3,4,7,8-tetramethylglycoluril 6 from 28
and purified by flash column chromatography (CHCl ).
3
To 1-(3-hydroxybutanoyl)-3,4,7,8-tetramethylglycoluril 28 (640
mg, 2.25 mmol) dissolved in CH Cl (15 ml) was added tri-
fluoroacetic anhydride (3 equiv.) at 23 ЊC. After stirring for 1 h,
a solution of Et N (2 equiv.) in CH Cl (5 ml) was added drop-
wise and 10 min later, Et N (2 ml) was added. The mixture was
heated at reflux for 20 min. The solution was concentrated and
the residue was purified by flash column chromatography (1%
1-(2-Methyl-3-oxobutanoyl)-3,4,7,8-tetramethylglycoluril
21ab from 14. Compound 14 (1.21 g, 4.1 mmol) was treated
with -Selectride to give a mixture of 21ab (71%, ratio 2.1:1).
Flash column chromatography gave: (1) 10 (3%); (2) 21a (340
mg, 28%); (3) a mixture of 21a and 21b (460 mg, 38%) in a 1:1
ratio; and (4) 21b (56 mg, 5%). The two pure single diastereo-
mers were obtained by recrystallization (CHCl –Et O) of frac-
2
2
3
2
2
3
3
2
MeOH in CHCl ) to give 6 (500 mg, 83%) with an E:Z ratio of
tions (2) and (4), respectively. For 21a: νmax(FT, KBr pellet)/
cm 3346 (NH), 3000, 2940, 1721 (C᎐O), 1689 (C᎐O), 1489,
3
Ϫ1
9
7.4:2.6.
1
457, 1411, 1353, 1309, 1245, 1160, 1110; δ (200 MHz, CDCl )
H
3
1
-(Hexa-2,4-dienoyl)-3,4,7,8-tetramethylglycoluril 7 from 30
5.94 (1H, s, NH), 4.48 (1H, q, J 7.3, COCHCO), 2.96 (3H, s,
NCH ), 2.86 (3H, s, NCH ), 2.29 (3H, s, CH CO), 1.74 (3H, s,
Compound 30 (194 mg, 0.626 mmol) was treated with tri-
fluoroacetic anhydride (0.25 ml) and triethylamine (0.1 ml and
then 2 ml), as for the preparation of 6 from 28, to give 7 (157
mg, 86%).
3
3
3
CH ), 1.55 (3H, s, CH ), 1.34 (3H, d, J 7.2, CH CHCO); δ (50
3
3
3
C
MHz, CDCl ) 205.9, 170.5, 157.2, 153.0, 78.9, 76.9, 53.8, 28.2,
3
ϩ
27.0, 26.4, 19.0, 15.7, 12.0; m/z (EI) 296.1495 (M . C H N O
13
20
4
4
requires 296.1485), 254, 222, 199, 180, 156, 140, 125 (base). For
Ϫ1
1
-Butanoyl-3,4,7,8-tetramethylglycoluril 5 from 6
Compound 6 (220 mg, 0.82 mmol) was dissolved in dry THF
100 ml) under N and cooled in an acetone–dry ice bath. -
21b: νmax(FT, KBr pellet)/cm 3319 (NH), 2989, 1720 (C᎐O),
1698 (C᎐O), 1490, 1412, 1302, 1112, 1089, 938, 762; δ (200
MHz, CDCl ) 6.05 (1H, s, NH), 4.60 (1H, q, J 7.2, COCHCO),
H
(
2
3
Selectride (1  in THF, 0.82 ml, 0.82 mmol) was added with
stirring. The mixture was allowed to reach room temperature
over 2 h. Solid NH HCO was added, and the mixture was
2.99 (3H, s, NCH ), 2.89 (3H, s, NCH ), 2.22 (3H, s, CH CO),
3
3
3
1.70 (3H, s, CH ), 1.57 (3H, s, CH ), 1.35 (3H, d, J 7.2,
3
3
CH CHCO); δ (50 MHz, CDCl ) 204.2, 171.1, 157.0, 153.0,
4
3
3
C
3
stirred for 4 h. The mixture was filtered through Celite and
the filtrate concentrated and purified by flash column chrom-
78.7, 76.6, 53.6, 28.3, 27.1, 26.6, 19.9, 15.8, 12.5; m/z (EI)
ϩ
296.1488 (M . C H N O requires 296.1485), 254, 125 (base).
13
20
4
4
atography (CHCl ) to give 5 (164 mg, 74%).
1-(2-Ethyl-3-oxobutanoyl)-3,4,7,8-tetramethylglycoluril 23ab
from 17. Compound 17 (377 mg, 1.22 mmol) was treated with
-Selectride (1 , 1.22 ml, 1.22 mmol) to give a mixture of
3
1
-Butanoyl-6-acetyl-3,4,7,8-tetramethylglycoluril 11 by
reduction of 6 and in situ acetylation
1
diastereomers 23a and 23b (1.6:1 by H NMR). Flash column
The above procedure was used for the -Selectride reduction of
chromatography gave: (1) 11 (71 mg, 19%); (2) 3 (26 mg, 9%);
(3) 23a; (4) a mixture of 23a and 23b; and (5) 23b (total yield
197 mg, 52%). For 23a: δ (200 MHz, CDCl ) 5.97 (1H, s, NH),
6
(100 mg, 0.385 mmol). Acetyl chloride (0.05 ml) was used to
quench the reaction instead of NH HCO to give 11 (73 mg,
4
3
H
3
6
3%).
4.42 (1H, dd, J 9.0, 3.9, COCHCO), 2.97 (3H, s, NCH ), 2.86
3
(
3H, s, NCH ), 2.28 (3H, s, CH CO), 1.97–1.90 (2H, m,
3 3
Benzyl butanoate and tetramethylglycoluril 1 from 5
CH CH ), 1.73 (3H, s, CH ), 1.55 (3H, s, CH ), 1.00 (3H, t,
2
3
3
3
1
6
A solution of lithium benzalkoxide (C H -CH OLi) was pre-
J 7.4, CH CH ); δ (50 MHz, CDCl ) 205.1, 169.8, 157.2, 153.0,
6
5
2
3 2 C 3
n
pared by addition of Bu Li (1.1 equiv.) to benzyl alcohol (1.5
equiv.) in THF (8 ml mmol ). To a solution of compound 5
78.7, 76.9, 60.8, 29.0, 27.1, 26.4, 20.6, 19.1, 15.7, 12.7. For 23b:
δ (200 MHz, CDCl ) 6.04 (1H, s, NH), 4.58 (1H, dd, J 8.0, 5.3,
Ϫ1
H
3
(
100 mg, 0.37 mmol) in THF (20 ml) was added the prepared
COCHCO), 2.99 (3H, s, NCH ), 2.88 (3H, s, NCH ), 2.21 (3H,
3
3
lithium benzalkoxide (1 equiv.) at room temperature. The mix-
ture was stirred for 12 h and glacial acetic acid (2 equiv.) was
s, COCH ), 1.99–1.81 (2H, m, CH CH ), 1.71 (3H, s, CH ), 1.57
3 2 3 3
(3H, s, CH ), 0.97 (3H, t, J 7.4, CH CH ); δ (50 MHz, CDCl )
3
3
2
C
3
added. The solution was concentrated and CHCl was added.
The mixture was stirred for a further 0.5 h, and the solid was
203.4, 170.5, 156.9, 153.0, 78.6, 76.6, 60.6, 28.9, 27.1, 26.6, 21.4,
19.9, 15.9, 12.4; m/z (EI) 311 (M ϩ1), 310.1627 (M . C H -
14 22
3
ϩ ϩ
collected by filtration, washed with CHCl and THF and dried
N O requires 310.1641), 268, 125 (base).
4 4
3
to give 1 (68 mg, 92%). The filtrate was concentrated and puri-
fied by flash column chromatography (hexane) to give benzyl
butanoate (55 mg, 83%); δ (200 MHz, CDCl ) 7.37 (5H, m,
1-(2,2-Dimethyl-3-oxobutanoyl)-3,4,7,8-tetramethylglycoluril
32. Compound 15 (148 mg, 0.48 mmol) was treated with
-Selectride (1 , 0.48 ml, 0.48 mmol) to give 32 (101 mg, 68%);
(Found: C, 54.05; H, 7.09; N, 17.98. C H N O requires C,
H
3
ArH), 5.11 (2H, s, CH Ar), 2.33 (2H, d, J 7.4, CH CO), 1.67
2
2
14 22
4
4
(
2H, sextet, J 7.4, CH CH ), 0.94 (3H, t, J 7.4, CH ); δ (50
54.18; H, 7.14; N, 18.05%); δ (200 MHz, CDCl ) 6.02 (1H, s,
2
3
3
C
H
3
MHz, CDCl ) 173.4, 136.1, 128.5 (2C), 128.1 (2C), 66.0, 36.1,
NH), 2.95 (3H, s, NCH ), 2.86 (3H, s, NCH ), 2.21 (3H, s,
3 3
3
ϩ
1
1
8.4, 13.6; m/z (EI) 178.1003 (M . C H O requires 178.0994),
08, 91 (base), 71, 43.
COCH ), 1.72 (3H, s, CH ), 1.55 (3H, s, CH ), 1.47 (3H, s,
11
14
2
3
3
3
CH ), 1.37 (3H, s, CH ); δ (50 MHz, CDCl ) 207.5, 173.8,
3 3 C 3
1
57.1, 152.3, 78.7, 77.2, 57.7, 27.0, 26.4, 25.0, 23.5, 22.5, 19.1,
ϩ
Benzyl but-2-enoate and tetramethylglycoluril 1 from 6
Reaction of 6 (165 mg, 0.62 mmol) as for 5 above gave 1 (69 mg,
15.7; m/z (EI) 311 (M ϩ1), 268, 199, 194, 125 (base).
1-(2-Methyl-3-oxohexanoyl)-3,4,7,8-tetramethylglycoluril
33ab. Compound 16 (168 mg, 0.52 mmol) gave 126 mg crude
product. Flash column chromatography gave: (1) 5 (15 mg, 9%);
(2) a mixture of 33ab (114 mg, 66%, diastereomer ratio 1:2.1).
The two diastereomers were separated in a second column
8
0%) and benzyl but-2-enoate (43 mg, 55%); νmax(FT, KBr
Ϫ1
pellet)/cm 3034, 2947, 1721, 1658, 1263, 1174, 1103, 1015,
9
7
69, 838, 738, 698; δ (200 MHz, CDCl ) 7.30 (5H, m, ArH),
H
3
.03 (1H, dq, J 15.5, 6.9, MeCH᎐CH), 5.89 (1H, dq, J 15.6, 1.5,
᎐
MeCH᎐CH), 5.17 (2H, s, ArCH ), 1.88 (3H, dd, J 6.9, 1.5,
chromatographic separation. For 33a: δ (200 MHz, CDCl )
᎐
2
H
3
CH CH᎐CH); δ (50 MHz, CDCl ) 166.3, 145.1, 136.1, 128.5,
5.96 (1H, s, NH), 4.46 (1H, q, J 7.4, COCHCO), 2.95 (3H, s,
NCH ), 2.85 (3H, s, NCH ), 2.68 (1H, dt, J 17.8, 7.1, CHHCO),
3
C
3
ϩ
1
28.1, 122.4, 65.9, 18.0; m/z (EI) 176 (M ), 158, 149, 131, 107,
3
3
9
1 (base), 77, 69, 65.
2.54 (1H, dt, J 17.8, 7.1, CHHCO), 1.74 (3H, s, CH ), 1.65–1.57
3
J. Chem. Soc., Perkin Trans. 1, 1998
447

View Article Online
(
2H, m, CH CH ), 1.33 (3H, d, J 7.3, CH CHCO), 0.92 (3H, t,
in the biosynthetic scheme is the last unit to be attached, and the
2
3
3
chain is grown in the opposite direction to that occurring on the
FAS/PKS surface; for other examples of intermolecular biomimetic
Claisen-like condensations, see: T. M. Harris and C. M. Harris,
Tetrahedron, 1977, 33, 2159; Y. Kobuke and J. Yoshida, Tetrahedron
Lett., 1978, 367; D. W. Brooks, D.-L. Lu and S. Masamune, Angew.
Chem., Int. Ed. Engl., 1979, 18, 72; for reviews of biomimetic
oligoketide cyclizations, see: M. Yamaguchi, Stud. Nat. Prod.
Chem., 1992, 11, 113; T. M. Harris and C. M. Harris, Pure Appl.
Chem., 1986, 58, 283.
S. Sun and P. Harrison, Tetrahedron Lett., 1992, 33, 7715; S. Sun and
P. Harrison, J. Chem. Soc., Chem. Commun., 1994, 2235; C. Cow,
D. Valentini and P. Harrison, Can. J. Chem., 1997, 75, 884.
8 A. I. Scott, C. J. Wiesner, S. Yoo and S. K. Chung, J. Am. Chem.
Soc., 1975, 97, 6277.
J 7.4, CH CH ); δ (50 MHz, CDCl ) 208.2, 170.8, 157.3, 152.9,
3
2
C
3
7
8.8, 77.2, 53.4, 42.5, 27.0, 26.4, 19.0, 16.7, 15.7, 13.7, 12.3. For
3
3b: mp 134–136 ЊC (Found: C, 55.79; H, 7.42; N, 17.44.
C H N O requires C, 55.54; H, 7.46; N, 17.28%); δ (300
15
24
4
4
H
MHz, CDCl ) 6.00 (1H, s, NH), 4.60 (1H, q, J 7.2, COCHCO),
3
2
7
.98 (3H, s, NCH ), 2.87 (3H, s, NCH ), 2.54 (1H, dt, J 17.5,
.4, CHHCO), 2.45 (1H, dt, J 17.5, 7.4, CHHCO), 1.69 (3H, s,
3
3
CH ), 1.65–1.53 (2H, m, CH CH ), 1.57 (3H, s, CH ), 1.34 (3H,
3
2
3
3
7
d, J 7.2, CH CHCO), 0.90 (3H, t, J 7.4, CH CH ); δ (75 MHz,
3
3
2
C
CDCl ) 206.1, 171.5, 157.0, 152.9, 78.6, 76.6, 53.1, 42.7, 27.1,
3
ϩ
2
6.5, 19.8, 16.9, 15.9, 13.6, 12.6; m/z (EI) 324 (M ), 281, 254,
1
99, 180, 152, 125 (base).
9
For a review, see: S. Numa and T. Tanabe in New Comprehensive
Biochemistry, ed. S. Numa, Elsevier, Amsterdam, 1984, vol. 7, p. 1.
Acknowledgements
This work was financially supported by the Natural Sciences
and Engineering Research Council of Canada and by Mc-
Master University.
10 H. Biltz, Chem. Ber., 1907, 40, 4806.
1
1 C. A. Brown, Synthesis, 1975, 326; for a review of the related
Dieckmann condensation, see: J. P. Schaefer and J. J. Bloomfield,
Org. React., 1967, 15, 1.
12 D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and G. S.
Sheppard, J. Am. Chem. Soc., 1990, 112, 866.
3 D. A. Evans, M. D. Ennis, T. Le, N. Mandel and G. Mandel, J. Am.
Chem. Soc., 1984, 106, 1154.
1
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1
1
4 For a review, see: D. A. Evans, Aldrichimica Acta, 1982, 15, 23.
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982, 104, 1737; M. P. Bonner and E. R. Thornton, J. Am. Chem.
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syntheses of oligoketides reported on oxazolidones, the ‘starter’ unit
1
1
8 cf. D. A. Evans, M. T. Bilodeau, T. C. Somers, J. Clardy, D. Cherry
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4
5
2
2
2
1 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
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6
2
3 J. L. Lee, A. R. Branfman, T. R. Herrin and K. L. Rinehart, Jr.,
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Paper 7/06855G
Received 22nd September 1997
Accepted 3rd November 1997
4
48
J. Chem. Soc., Perkin Trans. 1, 1998