Reaction of γ-hydroy-N-[1-(dimethylcarbamoyl)ethyl]butanamides under the 'direct amide cyclization' conditions

Article abstract of DOI:10.1002/hlca.200690008

The preparation of the title compounds was achieved via the 'azirine/oxazolone method' starting from the corresponding γ-hydroxy acids. Upon subjecting the γ-hydroxy-N-[1-(dimethylcarbamoyl)-ethyl] butanamides 4 to the so-called 'direct amide cyclization' (DAC) conditions, chlorinated acids 11 or imino lactones 12 were obtained as the sole products instead of the expected cyclodepsipeptides A or their cyclodimers (Scheme 4). Variation of the substituents in 4 did not affect the outcome of the reaction and a mechanism for the formation of both products from the intermediate oxazolone 13 has been proposed. Under the acidic conditions of the DAC, the imino lactones are formed as their HCl salts 12, which, in polar solvents or on silica gel, reacted further to give the chlorinated acids 11. Stabilization of the imino lactones was achieved by increasing the substitution in the five-membered ring, and their structure, in the form of the hydrochlorides, was established independently by X-ray crystallography (Fig. 4). A derivative 15 of the imino lactone 12a was prepared by the reaction with the 2H-azirin-3-amine 10a; its structure was also established by an X-ray crystal-structure determination (Fig. 3). Furthermore, the structures of the ω-chloro acids 11a and 11b were determined by X-ray crystallography (Fig. 2).

Full text of DOI:10.1002/hlca.200690008

Helvetica Chimica Acta – Vol. 89 (2006)
153
Reaction of g-Hydroxy-N-[1-(dimethylcarbamoyl)ethyl]butanamides under
the ‘Direct Amide Cyclization’Conditions
by Boyan Iliev1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The preparation of the title compounds was achieved via the ‘azirine/oxazolone method’ starting
from the corresponding g-hydroxy acids. Upon subjecting the g-hydroxy-N-[1-(dimethylcarbamoyl)-
ethyl]butanamides 4 to the so-called ‘direct amide cyclization’ (DAC) conditions, chlorinated acids 11
or imino lactones 12 were obtained as the sole products instead of the expected cyclodepsipeptides A
or their cyclodimers (Scheme 4). Variation of the substituents in 4 did not affect the outcome of the reac-
tion and a mechanism for the formation of both products from the intermediate oxazolone 13 has been
proposed. Under the acidic conditions of the DAC, the imino lactones are formed as their HCl salts 12,
which, in polar solvents or on silica gel, reacted further to give the chlorinated acids 11. Stabilization of
the imino lactones was achieved by increasing the substitution in the five-membered ring, and their struc-
ture, in the form of the hydrochlorides, was established independently by X-ray crystallography (Fig. 4).
A derivative 15 of the imino lactone 12a was prepared by the reaction with the 2H-azirin-3-amine 10a; its
structure was also established by an X-ray crystal-structure determination (Fig. 3). Furthermore, the
structures of the w-chloro acids 11a and 11b were determined by X-ray crystallography (Fig. 2).
1. Introduction. – Cyclic depsipeptides, i.e., heterodetic cyclopeptides which contain
ester (depside) bonds as part of their backbone, have been found in many natural prod-
ucts, and show a wide spectrum of biological activity [1]. They are, therefore, sought
after as promising lead compounds for drug design and discovery. Nature is a rich
source of fascinating cyclodepsipeptides, and, although the significance of incorporat-
ing a depside bond is still not clear, it appears to be essential for biological activity,
since all-amide analogues are often inactive [2]. The depside bond is recognized as
being more difficult to incorporate into the backbone than the amide bond, although
macrolactonizations have been studied extensively [2–6], and is, therefore, usually
pre-formed in the linear precursor prior to the cyclization via amide-bond formation
to give cyclic depsipeptides.
The most-well-known structures in this class of natural products belong to the ion-
selective antibiotics, such as valinomycin [7], the closely related enniatin family [8], the
actinomycins [9], and others. The reduction in the conformational freedom brought
about by cyclization often results in higher-receptor binding affinity. Frequently, in
these cyclic compounds, extra conformational restrictions are also built in, such as -
D
amino acids, N-alkylated amino acids or a,a-disubstituted amino acids.
1
)
Part of the Ph. D. thesis of B.I., University of Zürich, 2005.
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

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A very efficient method for the incorporation of the latter into depsipeptide rings,
the so called ‘direct amide cyclization’ (DAC), has been developed in our research
group in recent years. It has been used successfully for the synthesis of 6-, 9-, 12-,
and 15-membered cyclodepsipeptides from a-hydroxy acids [10–12], as well as larger
ring systems from a- and b-hydroxy acids [13–15]. Therefore, we were interested to
investigate reactions of dipeptides, containing b-, g-, and d-hydroxy acids, and an a-
amino acid, with the aim of synthesizing seven- to nine-membered analogues. As we
reported earlier, the cyclization of b-hydroxy acid amides 1, the linear precursors of
the desired seven-membered rings, yielded only cyclodimers 3 by the dimerization
process [16][17] (Scheme 1, Table 1).
Scheme 1
Monosubstitution at C(a) of the amino acid moiety (R3 =H) did not prevent dime-
rization, although the cyclization was carried out under different conditions [17]2). If,
however, the hydroxy acid moiety in 1 was monosubstituted at C(a), no cyclic depsi-
peptides were obtained, although the formation of the intermediate 1,3-oxazol-
5(4H)-one 2 has been monitored by IR spectroscopy. Instead, H2O elimination occur-
red, to give derivatives of a,b-unsaturated acid amides.
In the present paper, we describe the results of reactions of the higher homologues
of 1 containing g-hydroxy acids, which were carried out with the aim of obtaining either
8- or 16-membered cyclodepsipeptides.
2. Results and Discussion. – The linear amides 4 were synthesized in five steps from
the g,d-unsaturated aldehydes 5 (Scheme 2 and Table 1). Reduction gave the pentenols
6, which were acetylated to give 73). The introduction of the COOH group was achieved
by oxidative cleavage of the C=C bond of 7, either with RuIVoxide/NaIO4 [19] or with
oxone/acetone [20], although purification proved to be easier in the first case, thus lead-
ing to 8 in higher yields. The protection of the OH group prevents the formation of the
lactone under these oxidation conditions [21]. The coupling of 8 with the respective
2
)
The DAC conditions were not applicable in this case because of the sluggish formation of the 1,3-
oxazol-5(4H)-one intermediate (cf. [18]).
The need for protection of the OH group arises from the fact that attempts to obtain the desired g-
hydroxy acids from the corresponding easily available lactones (e.g., 4,4-dimethyltetrahydropyran-2-
one) by alkaline hydrolysis failed. Upon acidification of the sodium salt, spontaneous lactonization
occurred, and only the starting lactone could be isolated.
3
)

Helvetica Chimica Acta – Vol. 89 (2006)
155
Scheme 2
a) NaBH4, MeOH, 08, 1 h. b) Ac2O, Pyr, Et2O, reflux, 1 h. c) NaIO4, RuIVoxide, MeCN, CCl4, H2O,
r.t., 14 h. d) 10, THF, r.t., 24 h. e) LiOH, THF/H2O, r.t., 2 h.
amino acid to give 9 was performed by the reaction with 2,2,N,N-tetramethyl- or 2,2,N-
trimethyl-N-phenyl-2H-azirine-3-amine (10a or 10b, resp.), and N,N-dimethyl-1-aza-
spiro[2.4]hept-1-en-2-amine (10c), respectively, at room temperature (‘azirine/oxazo-
lone method’ [22][23]). Deprotection of the hydroxy group by treatment with LiOH
in THF/H2O led to the linear precursors 4.
Table 1. Synthesized g-Hydroxy Amides 4
4
R1
R2
R3
R4
R5
R6
R7
a
b
c
d
e
f
Me
H
Me
Me
H
Me
Me
Me
Me
H
Me
Me
Ph
Ph
Me
Me
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
À(CH2)À
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
g
h
Unexpectedly, the reactions of 4a–4c (Table 1) under the conditions of the ‘direct
amide cyclization’ yielded neither the eight-membered nor the 16-membered cyclodep-
sipeptides. Instead, after chromatographic workup, the chlorinated acids 11a–11c were
isolated as the sole products (Scheme 3 and Table 2). If the N-methyl-N-phenylamide
4d was used instead of the N,N-dimethylamides 4a–4c, the product formed could be
isolated after evaporation of the solvent and washing the residue with CH2Cl2. The iso-
lated product was identified as the imino lactone hydrochloride 12a (Scheme 3).
At first, it seems that R5 is determining the product of the reaction. Indeed, it has
been shown that in some DAC reactions N,N-dimethyl- and N-methyl-N-phenyl amides
behave quite differently [15]. Therefore, the cyclization of 4e and 4f was attempted
under DAC conditions. Surprisingly, in both cases the product was not the imino lac-
tone of type 12, but the chlorinated acid of type 11. Therefore, the presence of the

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 3
Table 2. Synthesized Chlorinated Acids 11
11
R1
R2
R5
R6
a
b
c
e
f
Me
H
Me
H
Me
H
Me
Ph
Ph
Me
Me
Me
Me
À(CH2)4À
Me
Me
Me
Me
Me
PhN residue can not be the reason for the different behavior of 4d under DAC condi-
tions.
The explanation lies in the purification process. Since N-methylaniline hydrochlo-
ride is soluble in CH2Cl2 [16][17], and the products of the reaction are not, the crude
residue in the case of 4d was just washed with CH2Cl2, and thus the imino lactone
was isolated as its hydrochloride 12a in pure form. On the other hand, Me2NH·HCl
is insoluble in CH2Cl2, so that chromatographic workup was necessary in the case of
4a–4c, which led to the formation of the corresponding chloro acids 11. In the case
of 4e, and 4f, due to the presence of the Ph substituent in the hydroxy acid moiety,
the product of the reaction was soluble in CH2Cl2, and no precipitate was formed.
For this reason, chromatographic purification was required leading to chlorinated
acids 11 as the sole product (Scheme 3).
1
It is worth mentioning, that the H-NMR spectrum of 12a in (D6)DMSO changes
with time. After just 1/2 h at room temperature, the appearance of signals at 1.00,
1.31, 2.09, 3.59, and 8.05 ppm was observed, which grew stronger with time, while the
signals at 1.15, 1.56, 3.13, and 4.56 ppm diminished (Fig. 1).
The new signals were sharp and well-defined, indicating the formation of a single
compound, rather than decomposition. After ca. 12 h at room temperature, the ratio
of both compounds was roughly 1:1, while, after 3 d, only traces of the starting com-
pound 12a could be observed. The spectrum of the newly formed substance coincides
with the spectrum of 11a. The same process was also observable in the 13C-NMR spec-
trum, the isomerization proceeding in a variety of polar solvents such as DMF and ace-
tone. In the latter, the ratio 12a/11a reached 1:1 in about a week and then remained
constant. Flash chromatography of a mixture 11a/12a allowed the isolation of analytical
amounts of 12a. Finally, the instability of 12a in solution was established in a control

Helvetica Chimica Acta – Vol. 89 (2006)
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experiment in which a mixture 12a/11a in CH2Cl2 containing 10% of MeOH was stirred
at room temperature. After 14 h, only the chlorinated acid 11a was isolated. Appa-
rently, under the DAC conditions, the initially formed product is the imino lactone hy-
drochloride 12a, which, in polar solvents, undergoes an isomerization to give 11a
(Scheme 4).
Scheme 4
A reaction mechanism for the formation of 11a and 12a is shown in Scheme 4. Treat-
ment of 4d with HCl gas leads to the corresponding 1,3-oxazol-5(4H)-one 13. When no
external nucleophiles are present, the OH group acts as a nucleophile and attacks one
of the two electrophilic centres in the ring. If the attack occurs at the C=O group
(pathway a), the eight-membered cyclodepsipeptide A would be formed. On the
other hand, the OH attack at the C=N group (pathway b) would lead to the opening
of the oxazolone ring to yield the imino lactone hydrochloride 12a. The latter can be
isolated if no chromatographic workup is necessary. In a polar solvent, the ClÀ ion
apparently attacks the CH2 group adjacent to the O-atom, which leads to the open-
chain w-chloro acid 11a4).
Due to its instability in solution, no crystals of 12a suitable for an X-ray crystal
structure determination could be obtained, but the structures of the chlorinated acids
11a and 11b were confirmed by X-ray crystallography (Fig. 2)5).
The OH group in 11a forms an intermolecular H-bond with the amide O-atom of a
neighboring molecule, thereby linking the molecules into extended chains which run
parallel to the [0 1 0] direction and can be described by a graph set motif [25] of
C(7). The amide group forms an intermolecular H-bond with the carboxylate carbonyl
4
)
We expected that, in the presence of a better nucleophile, a competition with the attack of ClÀ should
be possible, which would lead to a mixture of products, but all reactions in the presence of CsI,
Bu4NI, and PhSNa, respectively, led to the formation of 11 exclusively.
The structure of 11c has also been established by an X-ray crystal-structure determination. The qual-
ity of the crystals and, subsequently, the results of the structure determination were poor, although
unambiguous. The results are not reported here, but have been deposited at the CCDC (see Footnote
6).
5
)

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159
Fig. 2. ORTEP Plots [24] of the molecular structures of a) 11a and b) one of the disordered conforma-
tions of one of the two symmetry-independent molecules of 11b (arbitrary numbering of the atoms;
50% probability ellipsoids)
O-atom of a different neighboring molecule, thus also linking the molecules into
extended chains. These chains run parallel to the [1 0 0] direction and can be described
by a graph set motif of C(5). The combination of both interactions generates a two-
dimensional network, which lies parallel to the (0 0 1) plane.
In the case of 11b, there are two symmetry-independent molecules in the asymmet-
ric unit. The most significant difference between the independent molecules is in the
orientation of the Cl-atom. Furthermore, each of the two symmetry-independent mol-
ecules is disordered over the Cl(CH2)3 section of the molecule. Two positions were
defined for these atoms in each molecule, except for the Cl-substituted C-atom,
which is common to both conformations. The major conformation is present in ca. 65
and 80% of molecules A and B, respectively. Except for the orientations of the Cl-
atoms, the major conformation of molecule A is almost identical to that of the minor
conformation of molecule B and vice versa. The OH group of each molecule in 11b
forms an intermolecular H-bond with the amide O-atom of an adjacent molecule of
the same type. These interactions link the molecules into extended chains composed
entirely of molecules of type A or entirely of type B. These chains run in the [1 0 1]
direction and can be described by a graph set motif of C(7). The amide group of
each molecule forms an intermolecular H-bond with the carbonyl O-atom of the car-
boxy group of an adjacent symmetry-independent molecule. These interactions link

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Helvetica Chimica Acta – Vol. 89 (2006)
the molecules into extended ···A···B···A···B··· chains which run in the [0 0 1] direc-
tion and can be described by a binary graph set motif of C22(10). The combination of all
H-bonding interactions links the molecules into extended two-dimensional networks
which lie parallel to the (0 1 0) plane.
To isolate the crucial intermediate 12a, extraction with aq. Na2CO3 solution [26] and
deprotection by treatment with polyvinylpyridine were attempted, but neither proce-
dure gave satisfactory results. Although esterification of 12a with CH2N2 yielded the
corresponding crude methyl ester hydrochloride 14a (Scheme 5), the product was
also not stable in polar solvents and isomerized partially to the corresponding chloro
ester.
Scheme 5
Finally, the reaction of 12a with 2H-azirin-3-amine 10b yielded the diamide 15,
which was stable in solution, and whose structure was confirmed by X-ray crystallogra-
phy (Fig. 3). This is the first direct proof of the tetrahydrofuran-2-imine structure.
Fig. 3. ORTEP Plot [24] of the molecular structure of 15 (arbitrary numbering of the atoms; 50%
probability ellipsoids)
The central amide group (N(4)H) of 15 has a weak intramolecular H-bonding inter-
action with the imine N-atom (N(7)), which results in a five-membered loop that can be
described by a graph set motif [25] of S(5).

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When the hydroxy-protected amide 9d was subjected to the DAC conditions, the
corresponding protected 1,3-oxazol-5(4H)-one 16a (Scheme 6) was isolated in good
yield, which indicated that an oxazolone, i.e., 13 in Scheme 4, is most probably the
first intermediate from which the imino lactones 12 and the chloro acids 11 are formed.
Therefore, we decided to prepare 9i–9l with different protecting groups, which could
potentially allow the deprotection and isolation of the oxazolone with a free OH
group as a precursor for the cyclization to give A.
We planned to prepare 9i–9l analogously to 9d (Scheme 2). The benzyl (Bn), (ben-
zyloxy)methyl (Bom), and (9H-fluoren-9-yl)methoxycarbonyl (Fmoc) protecting
groups could be introduced before the oxidative clevage of the double bond and
yield the protected acids of type 8, which could then be reacted with 2H-azirin-3-
amine 10b to give the protected diamides 9. Because of the instability of the protecting
group under the oxidation conditions, direct protection of the hydroxy amide 4d was
preferred (Scheme 6). Unfortunately, the deprotection of 16b–16d failed in all cases.
Scheme 6
Since the DAC method failed to give cyclic depsipeptides, we attempted to synthe-
size the hydroxy esters of type 17 from amides 4 and to subject them to the NaH cyc-
lization procedure, as described earlier [16][17]. Unexpectedly, treatment of 4d and 4f
with HCl gas in toluene containing 20% EtOH as an external nucleophile did not yield
the desired esters 17, but gave as the main products the imino lactone esters 14 in mod-
erate yields together with the corresponding w-chloro esters 18 (Scheme 7).
Further experiments with 4d in the presence of MeOH showed that the ester could
also be formed directly from the imino lactone 12a, either under DAC conditions or by
treatment with CH2N2 (Schemes 5 and 7).
If instead of the hydroxy amides 4, the protected alcohols 9d or 9f were subjected to
the DAC conditions in the presence of MeOH, the unprotected linear esters 17 were
formed (Scheme 8). We believe that again oxazolones are the intermediates, and,
since the OH group in 9 is protected, it is to be expected that protected oxazolones
of type 16 (Scheme 6) are the intermediates. Nucleophilic addition of MeOH to the

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 7
Scheme 8
oxazolone, followed by ring opening, leads to the ester group in 17. The deacetylation
could be explained by trans-esterification, via formation of AcOMe, which is a common
reaction under acidic conditions.
The esters 17 were subjected to the conditions of the NaH-catalyzed cyclization, i.e.,
they were treated with NaH in toluene at 808 [16][27], but no cyclic products were
obtained. As in previous studies [16][17], the rigidity of the amide bond was considered
to be the reason for the failure. Therefore, the amino ketone 19 was synthesized, as
depicted in Scheme 9, and subjected to the same reaction conditions. Again, no cyclic
products could be identified in the mixture.
Scheme 9
a) HCHO, NaOH; 72%. b) Br2; 88%. c) Ethyl 2-amino-2-methylpropanoate hydrochloride, Et3N;
39%.

Helvetica Chimica Acta – Vol. 89 (2006)
163
If indeed the formation of the cyclic products 12 and 14 occurs via the attack of the
OH group at the imminium C-atom of the oxazolone 12 (see Scheme 4, path b), a-sub-
stitution in the hydroxy diamide 4 might present sufficient steric hindrance in order to
direct the nucleophilic attack onto the ester group (Scheme 4, path a). Therefore, the
amides 4g and 4h were prepared analogously to Scheme 2. Treatment of amides 4g
and 4h with HCl gas in toluene at 1008 (DAC conditions) yielded imino lactones as
sole products (Scheme 10).
Scheme 10
Unlike their analogues 12a–12c, compounds 12g and 12h are stable in solution. The
higher substitution of the ring apparently stabilizes it, i.e., the gem-dimethyl effect,
(Thorpe–Ingold effect [28]) makes the ring opening thermodynamically unfavorable.
Thanks to their stability in solution, crystals suitable for an X-ray crystal structure
determination could be grown for both hydrochlorides 12g and 12h (Fig. 4).
Since the space group of 12g is centrosymmetric, the compound in the crystal is rac-
emic. The OH group forms a H-bond with a neighboring ClÀ ion, while the imminium
group forms a H-bond with a different ClÀ ion. Thus, each ClÀ ion accepts two H-bonds.
These interactions link two cations and two anions in a cyclic manner into a tetrameric
unit and can be described by a graph set motif [25] of R24(14).
Similar H-bonding interactions occur in 12h, but this time the interactions link the
ions into extended chains, which run parallel to the [1 0 0] direction and can be descri-
bed by a graph set motif of C12(7).
Conclusions. – When g-hydroxy diamides 4 were subjected to the DAC reaction
conditions, neither the 8-membered nor the 16 membered depsipeptides were formed.
Depending on the workup procedure, either the chlorinated acids 11 or the imino lac-
tone hydrochlorides 12 with a COOH group were obtained as the sole products in good
yields. Both products are formed via the intermediate oxazolones by an attack of the
OH group at the iminium C-atom, instead of at the C=O group of the oxazolone
(Scheme 4). This attack leads to the five-membered ring, instead of the desired eight-
membered ring. The former are obviously more stable than the latter.
Compounds 12, with a-H atoms next to the C=O group, are unstable in solution
and isomerize to the corresponding w-chloro acids 11. Increased substitution of the
imino lactone stabilizes the five membered ring and prevents isomerization. A few
other cyclization methods were also tried, but they all failed to give cyclic depsipepti-
des.

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Helvetica Chimica Acta – Vol. 89 (2006)
Fig. 4. ORTEP Plots [24] of the molecular structures of a) 12g and b) 12h (arbitrary numbering of
the atoms; 50% probability ellipsoids)
Experimental Part
1. General. See [16].
2. Starting Materials. 2,2,N,N-Tetramethyl-2H-azirin-3-amine (10a), 2,2,N-trimethyl-N-phenyl-2H-
azirin-3-amine (10b), and N,N-dimethyl-1-azaspiro[2.4]hept-1-en-2-amine (10c) were prepared according
to standard procedures (cf. [16] and refs. cit. therein). 2,2-Dimethylpent-4-enal (5a) was prepared from
isobutyraldehyde according to Noack and Goettlich [29], 2-phenylpent-4-en-1-ol (6e) was obtained
from 2-phenylpropanal by following the method of Iqbal and Srivastava [30], and 2-methyl-2-phenyl-
pent-4-enal (5f) was synthesized from 2-phenylpropanal analogously to 5a. All spectra were in accord-

Helvetica Chimica Acta – Vol. 89 (2006)
165
ance with literature data [31]. 2,2,3-Trimethylpent-4-enal (5g) and 2,2,3,3-tetramethylpent-4-enal (5h)
were prepared according to Brannock and Burpitt [32] from crotyl bromide and 1-bromo-3-methylbut-
2-ene, resp. 1-Bromo-4-hydroxy-3,3-dimethylbutan-2-one was synthesized according to Mihelcic and
Moeller [33]. All other products used were commercially available.
3. Preparation of Pent-4-enyl Acetates. General Procedure 1 (GP 1). To a soln. of the corresponding
pent-4-enal 5 (5 mmol) in MeOH (20 ml) at 08, NaBH4 (760 mg, 20 mmol) was added in small portions
within 20 min, then the mixture was allowed to warm to r.t. and was stirred for a total of 1 h. The solvent
was evaporated i.v., and the residue was dissolved in H2O. Extraction with Et2O (5×30 ml), drying
(MgSO4), and evaporation i.v. yielded the pent-4-en-1-ols 6, which were acetylated without further puri-
fication. For this purpose, 6 (5 mmol) was dissolved in Et2O (50 ml) and pyridine (0.81 ml, 10 mmol) was
added. The mixture was heated to reflux, and a soln. of Ac2O (0.41 ml, 5.5 mmol) in Et2O (10 ml) was
added dropwise within 20 min. The mixture was stirred under reflux for another 1.5 h, cooled, the salt
was filtered off, the org. layer was washed with 10% aq. CuSO4 soln. and brine, dried (MgSO4), evapo-
rated i.v., and purified by column chromatography (CC, SiO2) to yield the desired pent-4-enyl acetates 7.
3.1. 2,2-Dimethylpent-4-enyl Acetate (7a). According to GP 1 from 2,2-dimethylpent-4-enal (5a, 560
mg, 5 mmol), CC (hexane/Et2O 10 :1). Yield: 593 mg, (79%) of 7a as a colorless oil. All spectra were in
accordance with literature data [34].
3.2. 2-Phenylpent-4-enyl Acetate (7e). To a soln. of 2-phenylpent-4-en-1-ol (6e, 5 mmol, 810 mg) in
Et2O (50 ml), pyridine (0.81 ml, 10 mmol) was added, the mixture was heated to reflux, and then a
soln. of Ac2O (0.71 ml, 5.5 mmol) in Et2O (10ml) was added dropwise over 20 min. The mixture was stir-
red under reflux for another 1.5 h, cooled, and the pyridinium acetate was filtered off, the org. layer was
washed with 10% aq. CuSO4 soln. and brine, dried (MgSO4), evaporated i.v., and purified by CC (hexane/
1
Et2O 15 :1) to yield 860 mg (84%) of 7e. Colorless oil. H-NMR: 1.98 (s, MeCO); 2.24–2.41 (m, CH2);
2.91–3.06 (m, PhCH); 4.11–4.26 (m, CH2O); 4.92–5.09 (m, CH2=CH); 5.62–5.83 (m, CH2=CH);
7.12–7.39 (m, 5 arom. H). 13C-NMR: 20.8 (q, Me); 36.8 (t, CH2); 44.4 (d, CH); 67.6 (t, CH2O); 116.6
(t, CH2=CH); 126.7, 127.4, 128.3 (3d, 5 arom. CH); 135.6 (d, CH2=CH); 141.3 (s, arom. C); 170.8 (s,
C=O). ESI-MS: 205 (100, [M+H]+).
3.3. 2-Methyl-2-phenylpent-4-enyl Acetate (7f). According to GP 1 from 2-methyl-2-phenylpent-4-
enal (5f; 870 mg, 5 mmol), CC (hexane/Et2O 20 :1). Yield: 785 mg (72%) of 7f. Colorless oil. IR:
3075s, 2962vs, 2860vs, 1745vs, 1636s, 1482s, 1432s, 1386s, 1334s, 1188s, 1076s, 1029s, 912m. 1H-NMR:
1.35 (s, Me); 2.05 (s, MeCO); 2.31–2.59 (m, CH2); 4.13–4.28 (m, CH2O); 4.87–5.11 (m, CH2=CH);
5.45–5.59 (m, CH2=CH); 7.14–7.44 (m, 5 arom. H). 13C-NMR: 20.7, 22.5 (2q, 2 Me); 41.0 (s,
C(Me)(Ph)); 43.4 (t, CH2); 71.4 (t, CH2O); 117.8 (t, CH2=CH); 126.1, 127.7, 128.1 (3d, 5 arom. CH);
133.3 (d, CH2=CH); 144.3 (s, arom. C); 170.9 (s, C=O). ESI-MS: 219 (100, [M+H]+).
3.4. 2,2,3-Trimethylpent-4-enyl Acetate (7g). According to GP 1, from 2,2,3-trimethylpent-4-enal (5g,
5 mmol, 630 mg), CC (hexane/Et2O 10 :1). Yield: 604 mg (71%) of 7g. Colorless oil. IR: 3077w, 2973vs,
1
2879s, 1744vs, 1637m, 1473m, 1377s, 1036s, 914m. H-NMR: 0.86, 0.90 (2s, Me2C); 0.98 (d, J=4.5, Me);
1.98 (s, MeCO); 2.11–2.23 (m, MeCH); 3.36 (s, CH2O); 4.90–5.04 (m, CH2=CH); 5.74–5.92 (m,
CH2=CH). 13C-NMR: 14.6, 20.8, 21.6 (3q, Me, Me2C, MeCO); 36.5 (s, Me2C), 40.9 (d, MeCH); 70.4 (t,
CH2O); 114.1 (t, CH2=CH); 141.5 (d, CH2=CH); 171.8 (s, C=O). ESI-MS: 193 (100, [M+H]+).
3.5. 2,2,3,3-Tetramethylpent-4-enyl Acetate (7h). According to GP 1, from 2,2,3,3-tetramethylpent-4-
enal (5h, 5 mmol, 700 mg), CC (hexane/Et2O 10 :1). Yield: 717 mg (78%) of 7h. Colorless oil. IR: 3072m,
2964vs, 2909s, 1746vs, 1635m, 1473m, 1414m, 1380s, 1315s, 1040s, 913s. 1H-NMR: 0.88, 0.99 (2s, 2 Me2C);
2.02 (s, MeCO); 3.90 (s, CH2O); 4.89–5.00 (m, CH2=CH); 5.87–5.96 (m, CH2=CH). 13C-NMR: 20.5 (q,
Me2C); 21.0 (q, MeCO); 22.6 (q, Me2C); 38.3, 40.8 (2s, 2 Me2C); 70.6 (t, CH2O); 112.0 (t, CH2=CH); 145.3
(d, CH2=CH); 171.3 (s, C=O). ESI-MS: 207 (100, [M+H]+).
4. 4-Acetoxybutanoic Acids 8. General Procedure 2 (GP 2). To a soln. of pent-4-enyl acetates 7 (5
mmol) in MeCN/CCl4/H2O 2 :2 :3 (70 ml), NaIO4 (2.28 g, 20 mmol) was added under stirring. After 10
min, a cat. amount of RuO2 ·H2O was added, and the mixture was stirred vigorously at r.t. for 4–12 h.
Filtration of the white residue over Celite, washing with CH2Cl2, extraction of the collected mother liquor
with CH2Cl2, drying (MgSO4), evaporation i.v., and purification by CC yielded 8 as colorless oils.
4.1. 4-Acetoxy-3,3-dimethylbutanoic Acid (8a). According to GP 2 from 7a (5 mmol, 780 mg), 6 h,
CC (CH2Cl2/MeOH 20 :1). Yield: 625 mg (73%) of 8a. Colorless oil. IR: 3284s (br), 2969s, 1739vs,

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1709vs, 1475w, 1379s, 1243s, 1041s, 926w. 1H-NMR: 0.98 (s, Me2C); 1.98 (s, MeCO); 2.28 (s, CH2); 3.88 (s,
CH2O); 9.83 (br. s, COOH). 13C-NMR: 20.6 (q, Me); 24.9 (q, Me2C); 33.5 (s, Me2C); 42.8 (t, CH2); 71.6 (t,
CH2O); 171.1 (s, C=O); 177.7 (s, COOH). ESI-MS: 197 (100, [M+Na]+).
4.2. 4-Acetoxy-3-phenylbutanoic Acid (8e). According to GP 2, 7e (5 mmol, 1.020 g), 4 h, CC
(CH2Cl2/acetone 20 :1). Yield: 678 mg (61%) of 8e. Colorless oil. 1H-NMR: 1.99 (s, MeCO); 2.61–2.88
(m, CH2); 3.42–3.58 (m, PhCH); 4.09–4.36 (m, CH2O); 7.13–7.38 (m, 5 arom. H.); 10.63 (br. s,
COOH). 13C-NMR: 20.6 (q, MeCO); 37.1 (t, CH2); 40.7 (d, CH); 67.3 (t, CH2O); 127.2, 127.5, 128.6
(3d, 5 arom. CH); 139.8 (s, arom. C); 170.7 (s, C=O); 177.3 (s, COOH). ESI-MS: 245 (100, [M+Na]+).
4.3. 4-Acetoxy-3-methyl-3-phenylbutanoic Acid (8f). According to GP 2 from 7f (5 mmol, 1090 mg),
6 h, CC (CH2Cl2/MeOH 20 :1). Yield: 861 mg (73%) of 8f. Colorless oil. 1H-NMR: 1.31 (s, Me); 2.01 (s,
MeCO); 2.28–2.36 (m, CH2); 4.18–4.45 (m, CH2O); 7.08–7.38 (m, 5 arom. H). 13C-NMR: 20.9 (q,
MeCO); 26.6 (q, Me); 31.1 (s, Me2C); 45.7 (d, CH); 69.3 (t, CH2O); 127.3, 127.6, 128.9 (3d, 5 arom.
CH); 141.2 (s, arom. C); 171.4 (s, C=O); 176.1 (s, COOH). ESI-MS: 259 (100, [M+Na]+).
4.4. 4-Acetoxy-2,3,3-trimethylbutanoic Acid (8g). According to GP 2 from 7g (5 mmol, 850 mg ), 6 h,
CC (CH2Cl2/MeOH 20 :1). Yield: 771 mg (82%) of 8g. Colorless oil. IR: 3466s (br.), 2976s, 1738vs,
1
1710vs, 1467w, 1390s, 1245s, 1041s, 925w. H-NMR: 0.95, 0.99 (2s, Me2C); 1.18 (d, J=4.7, MeCH); 2.00
(s, MeCO); 2.48 (q, J=4.7, MeCH); 3.89 (s, CH2O); 10.11 (br. s, COOH). 13C-NMR: 15.6, 20.6 (2q, 2
Me); 21.8, 22.1 (2q, Me2C); 38.7 (s, Me2C); 45.1 (d, CH); 70.8 (t, CH2O); 171.0 (s, C=O); 181.3 (s,
COOH). ESI-MS: 211 (100, [M+Na]+).
4.5. 4-Acetoxy-2,2,3,3-tetramethylbutanoic Acid (8h). According to GP 2 from 7h (5 mmol, 920 mg),
4 h, CC (CH2Cl2/MeOH 20 :1). Yield: 524 mg (52%) of 8h. IR: 3290s (br.), 2972s, 1743vs, 1477m, 1377m,
1248s, 1214w, 1040s, 1021w, 926w. 1H-NMR: 0.99, 1.19 (2s, 2 Me2C); 2.03 (s, MeCO); 3.99 (s, CH2O); 9.63
(br. s, COOH). 13C-NMR: 20.6 (q, MeCO); 21.1, 21.4 (2s, 2 Me2C); 38.3, 46.9 (2s, 2 Me2C); 70.1 (t, CH2O);
171.1 (s, C=O); 183.3 (s, COOH). CI-MS: 203 (38, [M+H]+), 143 (100, [M – MeCO]+).
5. Coupling of 8 with 2H-Azirin-3-amines 10. General Procedure 3 (GP 3). Acids 8 were taken up in
dry THF (20 ml), and the corresponding aminoazirine 10 was added dropwise. The mixture was stirred
overnight at r.t., the solvent was evaporated i.v. , and the residue was purified by CC to yield acetoxy dia-
mides 9.
5.1. 3-{[1-Methyl-1-(N,N-dimethylcarbamoyl)ethyl]carbamoyl}-2,2-dimethylpropyl Acetate (9a).
According to GP 3 from 8a (348 mg, 2 mmol) in dry THF (20 ml) and 10a (235 mg, 2.1 mmol), CC
(CH2Cl2/MeOH 30 :1). Yield: 509 mg (89%) of 9a. White powder. M.p. 99.1–99.28. 1H-NMR: 0.98,
1.52 (2s, 2 Me2C); 2.05 (s, MeCO); 2.10 (s, CH2); 3.08 (br. s, Me2N); 3.98 (s, CH2O); 7.12 (s, NH). 13C-
NMR: 20.9 (q, MeCO); 24.5, 24.7 (2q, 2 Me2C); 34.1 (s, Me2C); 38.2 (q, Me2N); 45.5 (t, CH2); 56.8 (s,
Me2C); 71.8 (t, CH2O); 169.4, 171.2, 173.2 (3s, 3 C=O). ESI-MS: 309 (100, [M+Na]+).
5.2. 3-{[1-(N,N-Dimethylcarbamoyl)cyclopentyl]carbamoyl}-2,2-dimethylpropyl Acetate (9c).
According to GP 3 from 8a (348 mg, 2 mmol) in dry THF (20 ml) and 10c (290 mg, 2.1 mmol), CC
(CH2Cl2/MeOH 20 :1). Yield: 549 mg (88%) of 9c. White powder. M.p. 139.0–140.28. 1H-NMR: 1.02
(s, Me2C); 1.66–1.78, 1.83–1.93 (2m, 4 CH2); 2.07 (s, MeCO); 2.18–2.26 (m, CH2); 2.98 (br. s, Me2N);
3.96 (s, CH2O); 6.41 (br. s, NH). 13C-NMR: 21.0 (q, MeCO); 22.4 (t, CH2); 24.6 (q, Me2C); 34.3 (t,
CH2); 35.7 (s, Me2C); 38.2 (q, Me2N); 44.3 (t, CH2); 66.8 (s, Me2C); 71.9 (t, CH2O); 169.8, 171.4, 172.5
(3s, 3 C=O). CI-MS: 313 (40, [M+H]+), 268 (100, [MÀMe2N]+).
5.3. 3-{[1-Methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}-2,2-dimethylpropyl Acetate
(9d). According to GP 3 from 8a (348 mg, 2 mmol) in dry THF (20 ml) and 10b (365 mg, 2.1 mmol),
CC (CH2Cl2/MeOH 40 :1). Yield: 584 mg (84%) of 9d. White powder. M.p. 94.1–95.88. 1H-NMR:
0.99, 1.48 (2s, 2 Me2C); 2.03 (s, MeCO); 2.12 (s, CH2); 3.26 (s, MeN); 3.91 (s, CH2O); 6.38 (s, NH);
7.21–7.43 (m, 5 arom. H). 13C-NMR: 20.9 (q, MeCO); 24.4, 26.0 (2q, 2 Me2C); 34.0 (s, Me2C); 41.5 (q,
MeN); 46.0 (t, CH2); 58.3 (s, Me2C); 71.7 (t, CH2O); 127.9, 128.2, 129.3 (3d, 5 arom. CH); 144.5 (s,
arom. C); 169.6, 171.2, 173.4 (3s, 3 C=O). ESI-MS: 371 (100, [M+Na]+).
5.4. 3-{[1-Methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}-2-phenylpropyl Acetate (9e).
According to GP 3 from 8e (444 mg, 2 mmol) in dry THF (20 ml) and 10b (365 mg, 2.1 mmol), CC
1
(CH2Cl2/MeOH 50 :1). Yield: 689 mg (87%) of 9e. White powder. M.p. 133.3–134.28. H-NMR: 1.32,
1.38 (2s, Me2C); 2.09 (s, MeCO); 2.18–2.25, 2.43–2.50 (2m, CH2); 3.20–3.26 (m, MeN, CH);
3.72–3.77 (m, CH2O); 5.97 (s, NH); 7.17–7.36 (m, 10 arom. H). 13C-NMR: 21.1 (q, MeCO); 26.1, 26.2

Helvetica Chimica Acta – Vol. 89 (2006)
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(2q, Me2C); 40.9 (t, CH2); 41.3 (q, MeN); 44.5 (d, CH); 58.1 (s, Me2C); 67.0 (t, CH2O); 126.9, 127.5, 127.9,
128.6, 129.3 (5d, 10 arom. CH); 141.8, 144.4 (2s, 2 arom. C); 169.9, 171.0, 173.0 (3s, 3 C=O). ESI-MS: 419
(100, [M+Na]+).
5.5. 3-{[1-Methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}-2-methyl-2-phenylpropyl Ace-
tate (9f). According to GP 3 from 8f (472 mg, 2 mmol) in dry THF (20 ml) and 10b (365 mg, 2.1
1
mmol), CC (CH2Cl2/MeOH 50 :1). Yield: 689 mg (84%) of 9f. White powder. M.p. 135.1–136.68. H-
NMR: 1.08, 1.16, 1.36 (3s, Me, Me2C); 2.08 (s, MeCO); 2.11–2.17 (m, CH2); 3.16 (s, MeN); 4.21 (s,
CH2O); 5.64 (s, NH); 7.09–7.41 (m, 10 arom. H). 13C-NMR: 20.8 (q, MeCO); 22.4, 26.1, 26.6 (3q, Me,
Me2C); 30.8 (s, Me2C); 41.1 (q, MeN); 46.3 (t, CH2); 57.4 (s, Me2C); 71.1 (t, CH2O); 126.1, 127.6,
127.9, 128.5, 128.9, 129.3 (6d, 10 arom. CH); 143.6, 144.8 (2s, 2 arom. C); 168.9, 170.8, 172.9 (3s, 3
C=O). CI-MS: 411 (42, [M+H]+), 304 (100, [MÀMe(Ph)N]+), 175 (21).
5.6. 3-{[1-Methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}-2,2-dimethylbutyl Acetate (9g).
According to GP 3 from 8g (372 mg, 2 mmol) in dry THF (20 ml) and 10b (365 mg, 2.1 mmol), CC
1
(CH2Cl2/MeOH 50 :1). Yield: 637 mg (88%) of 9g. White powder. M.p. 139.6–140.98. H-NMR: 0.99,
1.00 (2s, Me2C); 1.05 (d, J=3.9, MeCH); 1.40, 1.41 (2s, Me2C); 2.05–2.12 (m, MeCO, CH); 3.19 (s,
MeN); 3.86 (q, CH2O); 6.66 (s, NH); 7.14–7.46 (m, 5 arom. H). 13C-NMR: 12.2 (q, Me); 20.8 (q,
MeCO); 21.6, 22.4, 24.8, 25.0 (4q, 2 Me2C); 35.9 (s, Me2C); 41.4 (q, MeN); 46.4 (d, CH); 58.5 (s,
Me2C); 71.3 (t, CH2O); 128.0, 128.4, 129.3 (3d, 5 arom. CH); 144.1 (s, arom. C); 170.9, 172.7, 173.7 (3s,
3 C=O). ESI-MS: 385 (100, [M+Na]+).
5.7. 3-{[1-Methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}-2,2,3-trimethylbutyl Acetate
(9h). According to GP 3 from 8h (404 mg, 2 mmol) in dry THF (20 ml) and 10b (365 mg, 2.1 mmol),
CC (CH2Cl2/MeOH 50 :1). Yield: 684 mg (91%) of 9g. White powder. M.p. 119.9–120.98. 1H-NMR:
0.93, 1.11, 1.47 (3s, 3 Me2C); 2.04 (s, MeCO); 3.26 (s, MeN); 3.98 (s, CH2O); 7.04 (s, NH); 7.18–7.41
(m, 5 arom. H). 13C-NMR: 21.0, 21.7, 24.9 (3q, 3 Me2C); 38.6 (s, Me2C); 41.7 (q, MeN); 47.2, 58.8 (2s,
2 Me2C); 70.7 (t, CH2O); 128.3, 128.6, 129.5 (3d, 5 arom. CH); 144.1 (s, arom. C); 171.1, 174.3, 176.9
(3s, 3 C=O). ESI-MS: 415 (20, [M+K]+), 399 (100, [M+Na]+), 377 (60, [M+H]+). Anal. calc. for
C21H32N2O4 (376.50): C 66.99, H 8.57, N 7.44; found: C 66.35, H 8.28, N 7.15.
6. Deprotection of 9 to Give Hydroxy-Diamides 4. General Procedure 4 (GP 4). The amides 9 were
treated with 4 equiv. of LiOH in THF/H2O 2 :1 at r.t. for 4–12 h. Evaporation of the solvent i.v., extrac-
tion of the residue with CH2Cl2, drying (MgSO4), evaporation i.v., and washing with Et2O yielded the hy-
droxy diamides 4 as white powders, which were used without further purification.
6.1. 4-Hydroxy-3,3-dimethyl-N-[1-methyl-1-(N,N-dimethylcarbamoyl)ethyl]butanamide (4a). Ac-
cording to GP 4 from 9a (858 mg, 3 mmol), 4 h. Yield: 677 mg (93%) of 4a. White powder. M.p.
1
138.6–139.98. H-NMR: 0.99, 1.64 (2s, Me2C); 2.14 (s, CH2); 3.12 (br. s, Me2N); 3.91 (s, CH2O); 7.02
(s, NH). 13C-NMR: 24.6, 24.8 (2q, 2 Me2C); 34.6 (s, Me2C); 38.8 (q, Me2N); 45.4 (t, CH2); 56.8 (s,
Me2C); 71.3 (t, CH2O); 171.4, 173.0 (2s, 2 C=O). CI-MS: 244 (32, [M+H]+]), 201 (100, [MÀMe2N]+).
6.2. 4-Hydroxy-N-[1-methyl-1-(N,N-dimethylcarbamoyl)ethyl]butanamide (4b). A soln. of sodium 4-
hydroxybutanoate (1.0 g, 7.9 mmol) in H2O (10 ml) was acidified with 3N HCl. Extraction with AcOEt
(5×30 ml), drying (MgSO4), and evaporation of the solvent i.v. yielded 520 mg (63%) of 4-hydroxybuta-
noic acid as a viscous fluid, which was used without further purification. All spectra were in accordance
with the data in [35]. 4-Hydroxybutanoic acid (600 mg, 5.77 mmol) was dissolved in dry THF (20 ml) and
10a (711 mg, 6.35 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred overnight at r.t., the sol-
vent evaporated i.v., and the residue was purified by CC (CH2Cl2/MeOH 10 :1). Yield: 1134 mg (90%) of
4b. White solid. M.p. 124.6–125.38. 1H-NMR: 1.48 (s, Me2C); 1.73–1.82 (m, CH2); 2.08 (t, J=6.2, CH2);
3.26 (s, Me2N); 3.65 (t, J=6.2, CH2O); 6.38 (s, NH); 7.24–7.32 (m, 5 arom. H). 13C-NMR: 24.4 (t, CH2);
26.0 (q, Me2C); 41.5 (q, Me2N); 46.0 (t, CH2); 58.3 (s, Me2C); 71.7 (t, CH2O); 127.9, 128.2, 129.3 (3d, 5
arom. CH); 144.5 (s, arom. C); 171.2, 173.4 (2s, 2 C=O). CI-MS: 279 (85, [M+H]+), 172 (100, [MÀ
Me2N]+).
6.3. 4-Hydroxy-3,3-dimethyl-N-[1-(N,N-dimethylcarbamoyl)cyclopentyl]butanamide (4c). According
to GP 4 from 9c (936 mg, 3 mmol), 6 h. Yield: 738 mg (91%) of 4c. White powder. M.p. 138.4–139.98. 1H-
NMR: 0.99 (s, Me2C); 1.62–1.76, 1.84–2.02 (2m, 4 CH2); 2.21–2.39 (m, CH2); 3.03 (br. s, Me2N); 3.38 (s,
CH2O); 6.61 (br. s, NH). 13C-NMR: 24.4 (t, CH2); 25.2 (q, Me2C); 35.7 (s, Me2C); 37.3 (t, CH2); 37.9 (q,
Me2N); 46.4 (t, CH2); 66.6 (s, C); 71.9 (t, CH2O); 172.2, 172.7 (2s, 2 C=O). ESI-MS: 309 (10, [M+K]+),
293 (100, [M+Na]+).

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6.4. 4-Hydroxy-3,3-dimethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]butanamide (4d).
According to GP 4, from 9d (1044 mg, 3 mmol), 6 h. Yield: 845 mg (92%) of 4d. White powder. M.p.
1
138.4–139.98. H-NMR: 0.92, 1.44 (2s, 2 Me2C); 2.13 (s, CH2); 3.22 (s, MeN); 3.91 (s, CH2O); 6.32 (s,
NH); 7.16–7.41 (m, 5 arom. H). 13C-NMR: 25.2, 26.0 (2q, 2 Me2C); 35.6 (s, Me2C); 41.3 (q, MeN);
47.2 (t, CH2); 58.2 (s, Me2C); 71.4 (t, CH2O); 127.9, 128.2, 129.2 (3d, 5 arom. CH); 144.3 (s, arom. C);
171.6, 173.1 (2s, 2 C=O). ESI-MS: 345 (20, [M+K]+), 329 (100, [M+Na]+). Anal. calc. for
C17H26N2O3 (306.41): C 66.64, H 8.55, N 9.14; found: C 66.36, H 8.49, N 8.97.
6.5. 4-Hydroxy-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]-3-phenylbutanamide (4e).
According to GP 4, from 9e (1188 mg, 3 mmol), 8 h. Yield: 934 mg (88%) of 4e. White powder. M.p.
1
129.0–129.98. H-NMR: 1.28, 1.35 (2s, Me2C); 2.11–2.21, 2.34–2.46 (2m, CH2); 3.17 (br. s, MeN, CH);
3.64–3.79 (m, CH2O); 5.96 (s, NH); 7.10–7.41 (m, 10 arom. H). 13C-NMR: 26.1, 26.2 (2q, Me2C); 40.9
(q, MeN); 41.2 (t, CH2); 44.5 (d, CH); 58.2 (s, Me2C); 67.1 (t, CH2O); 126.8, 127.5, 127.9, 128.6, 129.3
(5d, 10 arom. CH); 141.7, 144.4 (2s, 2 arom. C); 171.1, 173.0 (2s, 2 C=O). CI-MS (i-butane): 355 (100,
[M+H]+).
6.6. 4-Hydroxy-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]-3-methyl-3-phenylbutanamide
(4f). According to GP 4 from 9f (820 mg, 2 mmol), 12 h. Yield: 587 mg (90%) of 4f. White powder.
M.p. 121.9–123.38. 1H-NMR: 1.22, 1.23, 1.24 (3s, Me, Me2C); 2.11–2.19, 2.31–2.38 (2m, CH2); 3.15 (s,
MeN); 3.51–3.59, 3.83–3.89 (2m, CH2O); 5.84 (s, NH); 7.11–7.43 (m, 10 arom. H). 13C-NMR: 23.6,
26.1, 26.2 (3q, Me, Me2C); 41.4 (q, Me2N); 42.7 (s, Me2C); 47.4 (t, CH2); 58.1 (s, Me2C); 70.6 (t,
CH2O); 126.1, 126.5, 127.8, 128.5, 129.3 (5d, 10 arom. CH); 144.5, 145.5 (2s, 2 arom. C); 170.9, 173.0
(2s, 2 C=O). CI-MS (i-butane): 327 (80, [M+H]+), 221 (100, [M – Ph(Me)N]+).
6.7. 4-Hydroxy-2,3,3-trimethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]butanamide (4g).
According to GP 4 from 9g (724 mg, 2 mmol), 4 h. Yield: 576 mg (90%) of 4g. White powder. M.p.
1
124.2–126.38. H-NMR: 1.00 (s, Me2C); 1.09 (d, J=4.6, MeCH); 1.40, 1.42 (2s, Me2C); 2.08 (q, J=4.6,
CH); 3.18 (s, MeN); 3.51–3.59 (m, CH2O); 6.96 (s, NH); 7.12–7.42 (m, 5 arom. H). 13C-NMR: 12.7 (q,
Me); 23.4, 24.2, 25.0 (3q, 3 Me2C); 37.6 (s, Me2C); 41.7 (q, MeN); 49.9 (d, CH); 58.9 (s, Me2C); 69.3 (t,
CH2O); 128.4, 128.6, 129.5 (3d, 5 arom. CH); 143.9 (s, arom. C); 173.8, 175.6 (2s, 2 C=O). ESI-MS:
343 (100, [M+Na]+).
6.8. 4-Hydroxy-2,2,3,3-tetramethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]butanamide
(4h). According to GP 4, from 9h (752 mg, 2 mmol), 4 h. Yield: 608 mg (91%) of 4h. White powder.
M.p. 129.9–131.38. 1H-NMR: 0.88, 1.15, 1.46 (3s, 3 Me2C); 3.29 (s, MeN); 3.44 (s, CH2O); 6.48 (s,
NH); 7.23–7.42 (m, 5 arom. H). 13C-NMR: 21.5, 21.9, 24.6 (3q, 3 Me2C); 39.6 (s, Me2C); 41.6 (q,
MeN); 47.6, 58.9 (2s, 2 Me2C); 70.7 (t, CH2O); 128.2, 128.4, 129.4 (3d, 5 arom. CH); 143.9 (s, arom.
C); 173.9, 177.8 (2s, 2 C=O). ESI-MS: 357 (100, [M+Na]+).
7. Attempted Direct Amide Cyclizations of Amides 4. General Procedure 5 (GP 5). A suspension of 4
(0.5 mmol) in dry toluene (50 ml) was heated to 1008, and HCl gas was bubbled through the suspension
for 4–6 min. Then, the mixture was allowed to cool to r.t. while bubbling N2 through it (ca. 20 min). The
solvent was evaporated, the white residue was washed with CH2Cl2 (3×15 ml) and dried in h.v. to yield
imino lactone hydrochlorides 12 as white powders.
General Procedure 6 (GP 6). A suspension of 4 was treated as described in GP 5. The solvent was
evaporated, and the oily residue was purified by CC to yield the w-chloro acids 11.
7.1. 2-[(4,4-Dimethyltetrahydrofuran-2-yliden)amino]-2-methylpropanoic Acid Hydrochloride (12a).
According to GP 5 from 4d (153 mg, 0.5 mmol). Yield: 101 mg (84%). M.p. 158.3–159.18. IR: 3431w,
2938s, 2804s, 1735vs, 1678vs, 1529s, 1414m, 1319m, 1194s, 1166s, 1003m, 946m, 754m. 1H-NMR
((D6)DMSO): 1.15, 1.56 (2s, 2 Me2C); 3.13 (s, CH2); 4.56 (s, CH2O); 13.2 (br. s, COOH). 13C-NMR
((D6)DMSO): 23.5, 24.1 (2q, 2 Me2C); 38.0, 60.1 (s, Me2C); 88.0 (t, CH2O); 162.0 (s, C=N); 180.2 (s,
C=O). CI-MS: 200 (100, [MÀCl]+).
7.2. 2-[(3,4,4-Trimethyltetrahydrofuran-2-yliden)amino]-2-methylpropanoic Acid Hydrochloride
(12g). According to GP 5 from 4g (160 mg, 0. 5mmol). Yield: 78 mg (73%). M.p. 152.4–153.68. IR:
3386w, 2986s, 2776s, 1739vs, 1671vs, 1514m, 1478s, 1240m, 1178s, 1165s, 997s, 773m. 1H-NMR
((D6)DMSO): 1.08 (d, J=4.9, Me); 1.21, 1.48 (2s, 2 Me2C); 2.18 (q, J=4.9, CH); 4.42 (s, CH2O); 10.0
(br. s, COOH). 13C-NMR ((D6)DMSO): 12.0 (q, Me); 21.1, 22.2 (2q, 2 Me2C); 36.5 (s, Me2C); 46.1 (d,
CH); 58.2 (s, Me2C); 87.2 (t, CH2O); 163.1 (C=N); 178.0 (s, C=O). CI-MS (i-butane): 214 (100, [M –

Helvetica Chimica Acta – Vol. 89 (2006)
169
Cl]+), 108 (25). Anal. calc. for C11H20ClNO3 (249.74): C 52.90, H 8.07, N 5.61; found C 50.55, H 7.87, N
5.25.
7.3. 2-[(3,3,4,4-Tetramethyltetrahydrofuran-2-yliden)amino]-2-methylpropanoic Acid Hydrochloride
(12h). According to GP 5 from 4h (167 mg, 0.5 mmol). Yield: 79 mg (78%). M.p. 157.0–157.68. IR:
3390w, 3024s, 2938s, 2778s, 1738vs, 1669vs, 1476s, 1400s, 1313m, 1178s, 998m, 880m, 772m. 1H-NMR
((D6)DMSO): 0.97, 1.26, 1.56 (3s, 3 Me2C); 4.58 (s, CH2O); 12.9 (br. s, COOH). 13C-NMR
((D6)DMSO): 21.6, 22.5, 26.1 (3q, 3 Me2C); 42.8, 46.6, 60.7 (3s, 3 Me2C); 86.8 (t, CH2O); 168.1 (C=N);
183.2 (s, C=O). ESI-MS: 228 (100, [M+Na]+).
7.4. 2-[(4-Chloro-3,3-dimethylbutanoyl)amino]-2-methylpropanoic Acid (11a). According to GP 6
from 4a (122 mg, 0.5 mmol) or from 4d (153 mg, 0.5 mmol), CC (CH2Cl2/acetone 10 :1). Yield: 57 mg
(48%) of 11a from 4a and 62 mg (52%) from 4d. White powder. M.p. 116.1–117.38. IR: 3356vs, 2981s,
2605m, 1717vs, 1620vs, 1548vs, 1473s, 1393s, 1294m, 1221s, 1158s, 1023m, 895m, 791s. 1H-NMR
((D6)DMSO): 1.00, 1.31 (2s, 2 Me2C); 2.09 (s, CH2); 3.59 (s, CH2Cl); 7.12 (br. s, NH); 12.9 (br. s,
COOH). 13C-NMR ((D6)DMSO): 24.9, 25.8 (2q, 2 Me2C); 36.6 (s, Me2C); 44.9 (t, CH2); 55.3 (t,
CH2Cl); 60.3 (s, Me2C); 172.1, 181.1 (2s, 2 C=O). ESI-MS: 260 (32, [M(37Cl)+Na]+), 258 (100,
[M(35Cl)+Na]+).
7.5. 2-[(4-Chlorobutanoyl)amino]-2-methylpropanoic Acid (11b). According to GP 6 from 4b (140
mg, 0.5 mmol), CC (CH2Cl2/acetone 10 :1). Yield: 62 mg (66%) of 11b. White solid. M.p.
111.9–113.18. IR: 3318vs, 2988s, 1721vs, 1623s, 156s, 1467s, 1399m, 1230m, 1166s, 1050w, 945w, 787m.
1H-NMR: 1.57 (s, Me2C); 2.07–2.13 (m, CH2); 2.37 (t, J=6.1, CH2); 3.61 (t, J=6.1, CH2Cl); 7.29 (br.
s, NH). 13C-NMR: 24.7 (q, Me2C); 33.9 (t, CH2); 44.4 (t, CH); 55.6 (t, CH2Cl); 59.6 (s, Me2C); 171.8,
176.6 (2s, 2 C=O). CI-MS: 210 (10, [M(37Cl)+NH4]+), 208 (25, [M(35Cl)+NH4]+), 172 (100, [MÀCl]+).
7.6. 1-[(4-Chloro-3,3-dimethylbutylanoyl)amino]cyclopentanecarboxylic Acid (11c). According to
GP 6 from 4c (135 mg, 0.5 mmol), CC (CH2Cl2/acetone 10 :1). Yield: 69 mg (53%) of 11c. White powder.
1
M.p. 113.2–114.78. H-NMR: 1.02, 1.09 (2s, Me2C); 1.71–1.76, 1.94–2.02 (2m, 4 CH2); 3.22 (m, CH2);
3.63 (m, CH2Cl); 7.47 (br. s, NH). 13C-NMR: 24.8 (t, CH2); 25.3 (q, Me2C); 36.3 (q, Me2C); 37.5, 44.7
(2t, 2 CH2); 55.0 (t, CH2Cl); 66.1 (s, Me2C); 171.7, 176.4 (2s, 2 C=O). CI-MS: 264 (28, [M(37Cl)+H]+),
262 (72, [M(35Cl)+H]+), 226 (100, [MÀCl]+).
7.7. [2-(4-Chloro-3-phenylbutanoyl)amino]-2-methylpropanoic Acid (11e). According to GP 6 from
4e (184 mg, 0.5 mmol), CC (CH2Cl2/acetone 20 :1). Yield: 51 mg (43%) of 11e. White powder. M.p.
119.6–121.88 (dec.). IR: 3320vs, 2928s, 1722vs, 1626vs, 1606s, 1557s, 1496s, 1442s, 1315s, 1260m, 1170s,
1079m, 752s, 696s. 1H-NMR: 1.36, 1.39 (2s, Me2C); 2.53–2.60, 2.70–2.78 (m, CH2); 3.48–3.52 (m,
PhCH); 3.85–3.91 (m, CH2Cl); 7.24–7.32 (m, 5 arom. H); 7.45 (br. s, NH); 12.3 (br. s, COOH). 13C-
NMR: 24.8, 25.3 (2q, 2 Me2C); 40.2 (t, CH2); 45.3 (d, CH); 55.3 (t, CH2Cl); 59.6 (s, Me2C); 127.6,
128.7, 129.0 (3d, 5 arom. CH); 142.3 (s, arom. C); 171.1, 179.1 (2s, 2 C=O). CI-MS: 286 (15,
[M(37Cl)+H]+), 284 (39, [M(35Cl)+H]+), 248 (100, [MÀCl]+).
8. Synthesis of Dipeptide Esters. General Procedure 7 (GP 7). A suspension of 4 (0.5 mmol) in a mix-
ture of dry toluene (50 ml) and alcohol (5 ml) was heated to reflux, and HCl gas was bubbled through the
suspension for 6 min. Then, the mixture was allowed to cool to r.t. while bubbling N2 through it (ca. 20
min). The solvent was evaporated, and the oily residue was purified by CC to yield the products as color-
less oils.
General Procedure 8 (GP 8). To solid 12a (117 mg, 0.5 mmol), a 0.5M soln. of CH2N2 in Et2O (1 ml, 0.5
mmol) was added dropwise at 08. After the disappearance of the yellow color, another 1 ml of CH2N2 was
added, the mixture allowed to warm to r.t., stirred for 15 min, filtered, and the solvent was evaporated i.v.
The white solid 14a was used without further purification.
8.1. Methyl 2-[(4,4-Dimethyltetrahydrofuran-2-yliden)amino]-2-methylpropanoate (14a). Accordig
to GP 7 from 4d (153 mg, 0.5 mmol), 5 ml of MeOH, CC (CH2Cl2/acetone 20 :1). Yield: 50 mg (43%)
of 14a. White solid. M.p. 88.6–89.88. IR: 2961s, 2876m, 1736vs, 1706vs, 1567s, 1360m, 1271s, 1143s,
1
101m, 919m, 731s. H-NMR ((D6)DMSO): 1.05, 1.28 (2s, 2 Me2C); 2.24 (s, CH2); 3.56 (s, MeO); 3.83
(s, CH2O). 13C-NMR ((D6)DMSO): 23.6, 25.8 (2q, Me2C); 36.6 (s, Me2C); 42.4 (t, CH2); 50.1 (q,
MeO); 58.9 (s, Me2C); 80.3 (t, CH2O); 162.2 (s, C=N); 175.3 (s, C=O). CI-MS: 231 (100, [M+NH4]+).
An experiment according to GP 8 yielded 113 mg (98%) of 14a as a white solid.

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Helvetica Chimica Acta – Vol. 89 (2006)
8.2. Ethyl 2-[(4,4-Dimethyltetrahydrofuran-2-yliden)amino]-2-methylpropanoate (14b). According to
GP 7 from 4d (153 mg, 0.5 mmol), 5 ml of EtOH, CC (CH2Cl2/acetone 20 :1). Yield: 49 mg (43%) of 14b
and 51 mg of ethyl 2-[(4-chloro-3,3-dimethylbutanoyl)amino]-2-methylpropanoate 18a (38%) as colorless
oils.
1
Data of 14b: IR: 2965vs, 2893s, 1714vs, 1697vs, 1468s, 1380s, 1273s, 1166s, 1035m, 911m, 731s. H-
NMR: 1.11 (s, Me2C); 1.21 (t, J=7.1, MeCH2); 1.43 (s, Me2C); 2.33 (s, CH2); 3.82 (s, CH2O); 4.18 (q,
J=7.1, MeCH2). 13C-NMR: 14.3 (q, Me); 25.1, 26.6 (2q, Me2C); 37.1 (s, Me2C); 44.5 (t, CH2); 60.4 (t,
MeCH2); 60.5 (s, Me2C); 81.9 (t, CH2O); 163.7 (s, C=N); 176.5 (s, C=O). ESI-MS: 477 (15,
[2M+Na]+), 250 (100, [M+Na]+), 228 (12, [M+H]+).
Data of 18a: 1H-NMR: 1.05 (s, Me2C); 1.16 (t, J=7.2, MeCH2); 1.27 (s, Me2C); 2.24 (s, CH2); 3.81 (s,
CH2Cl); 4.02 (q, J=7.2, MeCH2); 6.02 (br. s, NH). 13C-NMR: 14.2 (q, Me); 24.7, 25.8 (2q, 2 Me2C); 35.8 (s,
Me2C); 38.4 (t, CH2); 54.9 (t, CH2O); 61.3 (t, MeCH2); 65.6 (s, Me2C); 170.4, 172.6 (2s, 2 C=O). ESI-MS:
288 (31, [M(37Cl)+Na]+), 286 (100, [M(35Cl)+Na]+).
8.3. Methyl 2-Methyl-2-[(4-methyl-4-phenyltetrahydrofuran-2-yliden)amino]propanoate (14c).
According to GP 7 from 4f (168 mg, 0.5 mmol), 5 ml of MeOH, CC (CH2Cl2/acetone 25 :1). Yield: 77
1
mg (56%) of 14c. Colorless oil. H-NMR: 1.45, 1.46, 1.49 (3s, Me, Me2C); 2.73–2.79, 2.97–3.02 (2m,
CH2); 3.68 (s, MeO); 4.31 (s, CH2O); 7.16–7.36 (m, 5 arom. H). 13C-NMR: 26.1, 26.7, 27.1 (3q, Me,
Me2C); 43.0 (t, CH2); 44.6 (s, Me2C); 51.3 (q, MeO); 60.1 (s, Me2C); 80.9 (t, CH2O); 127.3, 126.8, 128.7
(3d, 5 arom. CH); 144.5 (s, arom. C); 163.0 (s, C=N); 176.7 (s, C=O). CI-MS: 276 (100, [M+H]+),
108 (22).
8.4. Ethyl 1-[(4,4-Dimethyltetrahydrofuran-2-yliden)amino]cyclopentanecarboxylate (14d). Accord-
ing to GP 7 from 4c (135 mg, 0.5 mmol), 5 ml of EtOH, CC (CH2Cl2/acetone 20 :1). Yield: 71 mg
(28%) of 14d and 45 mg (31%) of ethyl 1-[(4-chloro-3,3-dimethylbutanoyl)amino]cyclopentanecarboxy-
late (18b) as colorless oils.
Data of 14d: 1H-NMR: 1.12 (s, Me2C); 1.21 (t, J=7.0, MeCH2); 1.81–1.94 (m, 4 CH2); 2.41 (s, CH2);
3.89 (s, CH2O); 4.14 (q, J=7.0, MeCH2). 13C-NMR: 14.3 (q, Me); 25.1 (q, Me2C); 37.3, 37.6, 38.4, 39.1 (4t,
4 CH2); 44.2 (s, Me2C); 44.9, 47.1 (2t, 2 CH2); 60.6 (s, Me2C); 82.2 (t, CH2O); 162.4 (s, C=N); 174.9 (s,
C=O). CI-MS: 254 (100, [M+H]+), 200 (18, [MÀEt]+), 158 (36).
1
Data of 18b: H-NMR: 1.09 (s, Me2C); 1.20 (t, J=6.9, MeCH2); 1.74–1.82, 1.84–1.94 (2m, 4 CH2,
Me2C); 2.16 (s, CH2); 3.56 (s, CH2O); 4.16 (q, J=6.9, MeCH2); 6.02 (br. s, NH). 13C-NMR: 14.2 (q,
Me); 24.7, 25.8 (2q, 2 Me2C); 35.8 (s, Me2C); 37.4, 37.7, 38.4, 39.1 (4t, 4 CH2); 44.2 (t, CH2); 54.9 (t,
CH2O); 61.3 (t, MeCH2); 65.6 (s, Me2C); 170.4, 172.6 (2s, 2 C=O). CI-MS: 292 (34, [M(37Cl)+H]+),
290 (100, [M(35Cl)+H]+), 254 (28).
8.5. Methyl 2-[(4-Hydroxy-3,3-dimethylbutanoyl)amino]-2-methylpropanoate (17a). According to
GP 7 from 9d (174 mg, 0.5 mmol), 5 ml of MeOH, CC (CH2Cl2/acetone 20 :1). Yield: 56 mg (48%) of
1
17a. Colorless oil. H-NMR: 0.98, 1.43 (2s, 2 Me2C); 2.11 (s, CH2); 3.29 (s, CH2O); 3.78 (s, MeO); 6.25
(s, NH). 13C-NMR: 24.6, 25.2 (2q, 2 Me2C); 35.7 (s, Me2C); 46.9 (t, CH2); 52.5 (q, MeO); 56.4 (s,
Me2C); 71.2 (t, CH2O); 171.9, 174.9 (2s, 2 C=O). ESI-MS: 254 (100, [M+Na]+).
8.6. Methyl 2-[(4-Hydroxy-3-methyl-3-phenylbutanoyl)amino]-2-methylpropanoate (17b). According
to GP 7 from 9f (205 mg, 0.5 mmol) with 5 ml MeOH, CC (CH2Cl2/acetone 20 :1). Yield 57 mg (38%) of
1
17b. Colorless oil. H-NMR: 1.38 (s, Me2C); 1.39 (s, Me); 2.47–2.51, 2.66–3.70 (2m, CH2); 3.65–3.69,
3.89–3.92 (2m, CH2O); 3.68 (s, MeO); 6.25 (s, NH); 7.19–7.42 (m, 5 arom. H). 13C-NMR: 23.3, 24.5,
24.6 (3q, 3 Me); 43.0 (t, CH2); 46.5 (s, C(Me)(Ph)); 52.3 (q, MeO); 56.1 (s, Me2C); 70.3 (t, CH2O);
126.0, 126.4, 128.4 (3d, 5 arom. CH); 145.4 (s, arom. C); 171.2, 174.7 (2s, 2 C=O). CI-MS (i-butane):
294 (100, [M+H]+).
9. Protection of the Hydroxy Amide 4d. 9.1. 4-(Benzyloxy)-3,3-dimethyl-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]butanamide (9i). To a soln. of 4d (1 mmol, 306 mg) in dry THF (20 ml), NaH (44
mg, 1.1 mmol, 60% suspension in mineral oil) was added at 08. After 1 h at r.t., BnBr (171 mg, 1 mmol)
was added, and the mixture was heated to reflux for 3 h. Washing with brine, extraction with Et2O, drying
(MgSO4), and evaporation i.v. yielded a colorless oil, which was purified by CC (CH2Cl2/acetone 40 :1).
Yield: 329 mg (73%) of 9i. Colorless oil. 1H-NMR: 0.99, 1.36 (2s, 2 Me2C); 2.18 (s, CH2); 3.12 (s, CH2O);
3.22 (s, MeN); 4.43 (s, PhCH2); 5.91 (br. s, NH); 7.12–7.43 (m, 10 arom. H). 13C-NMR: 25.4, 26.7 (2q, 2
Me2C); 34.8 (s, Me2C); 41.3 (q, MeN); 46.3 (t, CH2); 57.7 (s, Me2C); 73.1 (t, CH2O); 78.5 (t, PhCH2);

Helvetica Chimica Acta – Vol. 89 (2006)
171
127.4, 127.6, 127.7, 127.8, 128.3, 129.2 (6d, 10 arom. CH); 138.4, 145.0 (2s, 2 arom. C); 170.6, 173.2 (2s, 2
C=O). CI-MS (i-butane): 397 (100, [M+H]+).
9.2. (2,2-Dimethyl-3-{[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}propyl)[(9H-flu-
oren-9-yl)methyl] Carbonate (9k). To a soln. of 4d (306 mg, 1 mmol) in CH2Cl2 (20 ml), pyridine (3
ml), and FmocCl (284 mg, 1.1 mmol) were added. The mixture was stirred at r.t. for 3 h, diluted with
CH2Cl2 (30 ml), and washed with a 10% CuSO4 soln. and brine, and the org. fractions were dried
(MgSO4), evaporated i.v., and purified by CC (CH2Cl2/acetone 30 :1). Yield: 450 mg (88%) of 9k.
White powder. M.p. 108.9–110.68. IR: 3320vs, 2966s, 1745vs, 1678vs, 1650vs, 1599s, 1532s, 1441s, 1386s,
1
1316m, 1154m, 964m, 909s, 758m. H-NMR: 0.99, 1.39 (2s, 2 Me2C); 1.86 (s, CH2); 3.19 (s, MeN); 3.92
(s, CH2O); 1.15 (t, J=5.8, CH2CH); 4.36 (d, J=5.8, CH2CH); 6.12 (s, NH); 7.09–7.32, 7.50–7.80 (2m,
13 arom. H). 13C-NMR: 24.5, 25.5 (2q, 2 Me2C); 34.2 (s, Me2C); 41.3 (q, MeN); 45.3 (t, CH2); 58.0 (s,
Me2C); 69.7 (t, CH2O); 75.1 (t, CH2CH); 119.9 (d, CH); 125.0, 127.0, 127.7, 127.8, 127.9, 129.1 (6d, 13
arom. CH); 141.2, 143.3, 144.5 (3s, 5 arom. C); 155.2 (s, NC(O)O); 169.4, 173.1 (2s, 2 C=O). ESI-MS:
551 (100, [M+Na]+).
9.3. 4-[(Benzyloxy)methoxy]-3,3-dimethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]bu-
tanamide (9l). To a soln. of 4d (306 mg, 1 mmol) in CH2Cl2 (20 ml) was added (i-Pr)2NEt (142 mg, 1.1
mmol) and BnOCH2Cl (BomCl, 156 mg, 1 mmol). The mixture was stirred at r.t. for 12 h, diluted with
CH2Cl2 (30 ml), washed with NH4Cl soln. and brine, dried (MgSO4), evaporated i.v., and purified by
1
CC (CH2Cl2/acetone 40 :1). Yield: 375 mg (88%) 9l. Colorless oil. H-NMR: 0.99, 1.42 (2s, 2 Me2C);
1.84 (s, CH2); 3.22 (s, MeN); 3.32 (s, CH2); 4.51, 4.68 (2s, CH2); 5.94 (br. s, NH); 7.08–7.42 (m, 10
arom. H). 13C-NMR: 25.0, 26.3 (2q, 2 Me2C); 34.5 (s, Me2C); 41.2 (q, MeN); 45.9 (t, CH2); 57.8 (s,
Me2C); 69.3, 76.2, 94.8 (3t, 3 CH2); 127.6, 127.7, 127.8, 128.3, 129.0, 129.2 (6d, 10 arom. CH); 137.6,
144.6 (2s, 2 arom. C); 170.2, 173.1 (2s, 2 C=O). CI-MS: 427 (16, [M+H]+), 320 (100, [MÀPh(Me)N]+),
108 (16).
10. Synthesis of 1,3-Oxazol-5(4H)-ones. 10.1. 3-(4,5-Dihydro-4,4-dimethyl-5-oxo-1,3-oxazol-2-yl)-
2,2-dimethylpropyl Acetate (16a). According to GP 6 from 9d (153 mg, 0.5 mmol), 4 min HCl gas, CC
(CH2Cl2/acetone 40 :1). Yield: 123 mg (51%) of 16a. White solid. M.p. 99.5–101.78. Recovered starting
material: 33 mg (21%). IR: 3385m, 2976s, 2937s, 1820vs, 1739vs, 1672vs, 1525m, 1474s, 1379s, 1240vs,
1072s, 1041s, 966s, 897m. 1H-NMR: 1.05, 1.36 (2s, 2 Me2C); 2.04 (s, MeCO); 2.42 (s, CH2); 3.92 (s,
CH2O); 7.21–7.34 (m, 5 arom. H). 13C-NMR: 20.8 (q, MeCO); 24.4, 24.6 (2q, 2 Me2C); 34.3 (s, Me2C);
38.0 (t, CH2); 65.3 (s, Me2C); 71.6 (t, CH2O); 161.9 (s, C=N); 170.9, 181.4 (2s, 2 C=O). ESI-MS: 541
(100, [2(M+H2O)+Na]+), 371 (25), 282 (70, [M+H2O+Na]+).
10.2. 2-[3-(Benzyloxy)-2,2-dimethylpropyl]-4,4-dimethyl-1,3-oxazol-5(4H)-one (16b). According to
GP 6, from 9i (198 mg, 0.5 mmol), 4 min HCl gas, CC (CH2Cl2/acetone 50 :1). Yield: 49 mg (34%) of
16b. White powder. M.p. 104.2–106.08. Recovered starting material: 124 mg (31%). IR: 2951s, 1894s,
2565w,1822vs, 1723vs, 1612vs, 1534vs, 1458s, 1265s, 1101s, 1058m, 1040m, 911m. 1H-NMR: 1.01, 1.38
(2s, 2 Me2C); 2.48 (s, CH2); 3.14 (s, CH2O); 4.56 (s, PhCH2); 7.21–7.34 (m, 5 arom. H). 13C-NMR:
24.5, 24.9 (2q, 2 Me2C); 35.4 (s, Me2C); 38.3 (t, CH2); 65.2 (s, Me2C); 73.3 (t, CH2O); 78.6 (t, PhCH2);
127.5, 128.1, 128.3 (3d, 5 arom. CH); 138.5 (s, arom. C); 162.5 (s, C=N); 182.1 (s, C=O). CI – MS (i-bu-
tane): 290 (18, [M+H]+), 200 (100, [MÀBn]+).
10.3. [3-(4,5-Dihydro-4,4-dimethyl-5-oxo-1,3-oxazol-2-yl)-2,2-dimethylpropyl] [(9H-fluoren-9-yl)-
methyl] Carbonate (16c). According to GP 6 from 9k (169 mg, 0.33 mmol), 4 min HCl gas, CC
(CH2Cl2/acetone 80 :1). Yield: 64 mg (46%) of 16c. White powder. M.p. 93.8–95.28. Recovered starting
material: 66 mg (39%). IR: 3320s, 2966s, 1821vs, 1745vs, 1678vs, 1650vs, 1599s, 1532s, 1441s, 1386m,
1316m, 1156m, 909s. 1H-NMR: 1.01, 1.34 (2s, 2 Me2C); 2.32 (s, CH2); 3.87 (s, CH2O); 4.12 (t, J=6.0, CH2-
CH); 4.38 (d, J=6.0, CH2CH); 7.18–7.37, 7.53–7.81 (2m, 8 arom. H). 13C-NMR: 24.3, 24.8 (2q, 2 Me2C);
34.5 (s, Me2C); 37.9, 46.7 (2t, 2 CH2); 65.1 (s, Me2C); 65.9 (t, CH2O); 69.8 (t, CH2CH); 119.9 (d, CH);
125.0, 126.8, 127.1, 127.7 (4d, 8 arom. CH); 141.2, 143.3 (2s, 4 arom. C); 155.0 (s, NC(O)O); 161.6 (s,
C=N); 181.1 (s, C=O). CI-MS: 422 (16, [M+H]+), 200 (100, [M – Fmoc]+), 179 (44).
10.4.
2-{3-[(Benzyloxy)methoxy]-2,2-dimethylpropyl}-4,5-dihydro-4,4-dimethyl-1,3-oxazol-5-one
(16d). According to GP 6 from 9l (143 mg, 0.33 mmol), 5 min HCl gas, CC (CH2Cl2/acetone 60 :1).
Yield: 42 mg (36%). White solid. M.p. 104.1–105.88. Recovered starting material: 52 mg (35%). 1H-
NMR: 0.97, 1.36 (2s, 2 Me2C); 2.42, 3.36, 4.59, 4.73 (4s, 4 CH2); 7.14–7.43 (m, 5 arom. H). 13C-NMR:

172
Helvetica Chimica Acta – Vol. 89 (2006)
24.4, 24.7 (2q, 2 Me2C); 34.9 (s, Me2C); 45.5 (t, CH2); 56.8 (s, Me2C); 69.3, 76.1, 94.8 (3t, 3 CH2); 127.7,
128.3, 129.5 (3d, 5 arom. CH); 137.6 (s, arom. C); 162.4 (s, C=N); 172.6 (s, C=O). CI-MS (i-butane): 320
(100, [M+H]+).
10.5. 2,2-Dimethyl-3-(4-oxo-3-oxa-1-azaspiro[4.4]non-1-en-2-yl)propyl Acetate (16e). According to
GP 6 from 9c (156 mg, 0.5 mmol), 5 min HCl gas, CC (CH2Cl2/acetone 30 :1). Yield: 45 mg (34%) of
16e. White solid. M.p. 101.1–103.18. Recovered starting material: 33 mg (21%). IR: 3385w, 2976s,
2937s, 1820vs, 1739vs, 1672vs, 1474m, 1379s, 1240s, 1072s, 1041s, 966m. 1H-NMR: 1.01 (s, Me2C);
1.73–2.04 (m, MeCO, 4 CH2); 2.42 (s, CH2); 3.90 (s, CH2O). 13C-NMR: 20.8 (q, MeCO); 24.5 (q, Me2C);
25.8 (t, 2 CH2); 34.3 (s, Me2C); 38.0, 38.2 (2t, 3 CH2); 71.6 (t, CH2O); 73.9 (s, spiro-C); 161.8 (s, C=N);
170.9, 182.1 (2s, 2 C=O). ESI-MS: 593 (100, [2 M+H2O+Na]+), 324 (58, [M+H2O+K]+), 308 (64,
[M+H2O+Na]+), 286 (90, [M+H2O+H]+).
11. 2-Methyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]-2-[(2,3,4,5-tetrahydro-4,4-dime-
thylfuran-2-yliden)amino]propanamide (15). To solid 12a (100 mg, 0.42 mmol), a soln. of 10b (110 mg,
3 mmol, 1.5 equiv.) in CH2Cl2 (5 ml) was added under vigorous stirring. The solvent was immediately
removed i.v., and the suspension was left at r.t. overnight. CC (CH2Cl2/acetone 20 :1) yielded 102 mg
(64%) of 15. White powder. M.p. 142.1–143.38. IR: 3364vs, 2976s, 2937s, 1708vs, 1666vs, 1645vs, 1493s,
1
1380s, 1223m, 1111m, 1014s, 781m, 710s. H-NMR: 1.08, 1.42, 1.50 (3s, 3 Me2C); 2.26 (s, CH2); 3.21 (s,
MeN); 3.89 (s, CH2O); 7.06–7.29 (m, 5 arom. H); 8.07 (br. s, NH). 13C-NMR: 23.8, 24.9, 26.1 (3q, 3 Me2C);
36.5 (s, Me2C); 41.0 (q, MeN); 45.2 (t, CH2); 57.3, 60.6 (2q, 2 Me2C); 81.5 (t, CH2O); 127.3, 128.1, 129.4
(3d, 5 arom. CH); 144.8 (s, arom. C); 161.5 (s, C=N); 173.6, 176.3 (2s, 2 C=O). ESI-MS: 369 (100,
[M+Na]+).
12. Methyl 2-[(4-Hydroxy-3,3-dimethyl-2-oxobutyl)amino]-2-methylpropanoate (19). To a soln. of 1-
bromo-4-hydroxy-3,3-dimethylbutan-2-one (390 mg, 2 mmol) in Et3N (5 ml), methyl 1-amino-2-methyl-
propanoate hydrochloride (456 mg, 3 mmol) was added. The mixture was heated under reflux overnight,
cooled, diluted with CH2Cl2 (150 ml), and washed with a 10% CuSO4 soln. and brine. Drying (MgSO4),
evaporation of the solvent, and CC (CH2Cl2/acetone 30 :1) yielded 195 mg (42%) of 19. Yellow oil. IR:
2973m, 2884m, 1725vs, 1660vs, 1528m, 1471s, 1364s, 1192s, 1046m. 1H-NMR: 1.12, 1.46 (2s, 2 Me2C); 3.50,
3.54 (2s, 2 CH2); 3.71 (s, MeO); 6.74 (br. s, NH). 13C-NMR: 21.1, 25.1 (2q, 2 Me2C); 48.4 (s, Me2C); 49.9 (t,
CH2); 51.9 (q, MeO); 58.2 (s, Me2C); 69.4 (t, CH2O); 176.4, 212.6 (2s, 2 C=O). CI-MS (i-butane): 232 (70,
[M+H]+), 146 (100), 128 (40).
13. X-Ray Crystal-Structure Determination of 11a, 11b, 12g, 12h, and 15 (Table 3 and Figs. 2–4)6). All
measurements were performed on a Nonius KappaCCD area-detector diffractometer [36] using graph-
ite-monochromated MoKa radiation (l 0.71073 Å) and an Oxford Cryosystems Cryostream 700 cooler.
The data collection and refinement parameters are given in Table 3, and views of the molecules are
shown in Figs. 2–4. Data reduction was performed with HKL Denzo and Scalepack [37]. The intensities
were corrected for Lorenz and polarization effects and, in the cases of 11a, 12g, and 12h, an absorption
correction based on the multi-scan method [38] was applied. Each structure was solved by direct methods
using SIR92 [39], which revealed the positions of all non-H atoms. The non-H atoms were refined ani-
sotropically.
In the case of 11b, there are two independent molecules in the asymmetric unit. The atomic coordi-
nates of the two molecules were tested carefully for a relationship from a higher symmetry space group
using the program PLATON [40] but none could be found. Each molecule is disordered over two con-
formations. Two positions were defined for each atom of the ClÀ(CH2)3À section of each molecule,
except for the Cl-substituted C-atom, which is common to both conformations. Bond length restraints
were applied to all bonds involving disordered atoms so as to maintain reasonable geometry. The best
results were obtained with relative site occupation factors of 0.65 :0.35 and 0.80 :0.20 for the disordered
components of molecules A and B, respectively.
6
)
CCDC-286035–286040 contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre, via http://
www.ccdc.cam.ac.uk/data_request/cif

Helvetica Chimica Acta – Vol. 89 (2006)
173
Table 3. Crystallographic Data of Compounds 11a, 11b, 12g, 12h, and 15
11a
11b
12g
12h
15
Crystallized from
toluene/CH2Cl2/ xylene/AcOEt/ CH2Cl2/acetone/ CH2Cl2/i-PrOH/ CH2Cl2/Et2O/
MeCN/acetone MeOH
i-PrOH
acetone
hexane
Empirical formula
C10H18ClNO3
235.71
C8H14ClNO3
207.66
C11H20ClNO3
249.74
C12H22ClNO3
263.76
C21H31N3O3
373.49
Formula weight [g molÀ1
Crystal color, habit
]
colorless, prism colorless, plate colorless, prism colorless, prism colorless, tablet
0.07×0.17×0.25 0.02×0.15×0.20 0.13×0.20×0.25 0.18×0.20×0.25 0.12×0.15×0.30
160(1)
monoclinic
P21/c
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
Z
160(1)
160(1)
160(1)
monoclinic
P21/n
160(1)
monoclinic
P21/n
4
triclinic
triclinic
ꢀ
ꢀ
P1
P1
4
4
2
4
Reflections for cell
determination
2q Range for cell
determination [8]
Unit cell parameters
a [Å]
18016
4764
13668
49886
4258
4–60
4–55
4–55
4–60
4–52
5.8846(1)
10.5564(2)
19.0140(4)
90
91.887(1)
90
1180.51(4)
1.326
0.312
9.5502(2)
10.3588(2)
11.3586(3)
92.417(1)
90.584(1)
109.313(1)
1059.16(4)
1.302
8.1623(3)
8.8802(2)
9.0067(3)
86.145(2)
88.338(2)
79.602(2)
640.56(4)
1.295
7.0504(1)
15.0693(2)
13.0955(2)
90
90.7171(8)
90
1391.22(3)
1.259
0.272
10.1674(3)
19.4044(7)
11.5235(4)
90
112.515(2)
90
2100.2(1)
1.181
0.0794
w
b [Å]
c [Å]
a [8]
b [8]
g [8]
V [Å3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.338
f and w
55
0.291
f and w
55
f and w
60
f and w
60
2q(max) [8]
52
Transmission factors
(min; max)
0.887; 0.979
–
0.855; 0.968
0.864; 0.957
–
Total reflections measured 32539
26265
4824
15813
2932
37833
4054
37791
4135
Symmetry independent
reflections
3448
Reflections with I>2s(I) 2459
3464
4822
2535
2931
3375
4052
3006
4134
Reflections used in
refinement
3448
Parameters refined;
restraints
148; 0
0.0443
0.1158
309; 10
0.0667
0.2011
159; 0
0.0330
0.0833
169; 0
256; 0
R (on F; I>2s(I)
reflections)
0.0370
0.0472
wR (on F2; all indept.
reflections)
0.0960
0.1132
Weighting
0.0546; 0.3536 0.0996; 0.8346 0.0355; 0.2522
0.033; 0.7281
0.0406; 0.6032
parameters [a; b]a)
Goodness-of-fit
Secondary extinction
coefficient
1.046
–
1.069
–
1.055
0.019(5)
1.055
0.009(2)
1.048
0.015(2)
Final Dmax/s
0.001
0.26; À0.32
0.001
0.92; À0.89
0.001
0.30; À0.25
0.001
0.28; À0.23
0.001
0.18; À0.19
D1 (max; min) [e ÅÀ3
]
a) wÀ1 =s2(F2o)+(aP)2 +bP where P=(Fo2 +2F2c )/3

174
Helvetica Chimica Acta – Vol. 89 (2006)
The OH and ammonium H-atoms in 12g and 12h, as well as the amide H-atom in 15, and the amide
and OH H-atoms in 11a and 11b were placed in the positions indicated by difference electron-density
maps, and their positions were allowed to refine together with individual isotropic displacement para-
meters. All remaining H-atoms in all structures were placed in geometrically calculated positions and
each was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its parent
atom (1.5Ueq for the Me groups). The refinement of each structure F2 was carried out on using full-matrix
least-squares procedures, which minimized the function Sw(F2o –Fc2)2. Corrections for secondary extinc-
tion were applied, except in the cases of 11a and 11b. Neutral-atom-scattering factors for non-H atoms
were taken form [41], and the scattering factors for H-atoms were taken from [42]. Anomalous disper-
sion effects were included in Fc [43]; the values for f’ and f’’ were those of [44]. The values of the mass
attenuation coefficients are those of [45]. All calculations were performed using the SHELXL97 pro-
gram [46]
We thank the analytical sections of our institute for the spectra and elemental analyses. Financial
support of the Swiss National Science Foundation and F. Hoffmann-La Roche AG, Basel, is gratefully
acknowledged.
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Received October12, 2005