14-Membered cyclodepsipeptides with alternating β-hydroxy and α-amino acids by cyclodimerization

Article abstract of DOI:10.1016/j.tet.2005.11.002

The cyclodimerization (twinning) of β-hydroxy acid amides of type 1 under 'direct amide cyclization' (DAC) conditions is described. Although other coupling methods also gave moderate results, best yields were obtained via DAC, reaching 88% for the cyclodi

Full text of DOI:10.1016/j.tet.2005.11.002

Tetrahedron 62 (2006) 1079–1094
14-Membered cyclodepsipeptides with alternating b-hydroxy
and a-amino acids by cyclodimerization
*
Boyan Iliev, Anthony Linden, Roland Kunz and Heinz Heimgartner
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Received 6 October 2005; revised 28 October 2005; accepted 2 November 2005
Available online 28 November 2005
Abstract—The cyclodimerization (twinning) of b-hydroxy acid amides of type 1 under ‘direct amide cyclization’ (DAC) conditions is
described. Although other coupling methods also gave moderate results, best yields were obtained via DAC, reaching 88% for the cyclodimer
10. In all cases, when starting with racemic material, only the trans-substituted cyclodepsipeptides were isolated. Simple molecular modeling
revealed that the formation of the cyclodimer is thermodynamically slightly more favorable than that of the cyclomonomer. The proposal that
cyclodimer formation is preferred because of the presence of intramolecular H-bonds could not be confirmed by X-ray crystallography. The
influence of substituents, both in the amino acid and in the hydroxy acid moieties, was also studied. It is shown, that cyclodimerization was
successful only when the hydroxy acid moiety is a,a-disubstituted.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Cyclic 14-membered depsipeptides with the same ring
skeleton as 3 have been known since the 1960s, and the
dimerization process is not as surprising as it seems at first.
Since the discovery, isolation, and identification of
serratamolide (4: RZH, R0Z(CH2)6CH3, Scheme 2) from
Serratia marcescens in 1961,11 the proof of its antibiotic
activity,12 and its first total synthesis by Shemyakin et al.,13
the interest in depsipeptides containing b-hydroxy acids has
increased significantly, mainly because of their antibiotic
properties. The other important biological role of the same
compound is its use as a surface-active agent under the
name of serrawettin W1,14 and it has been patented for use
as a pesticide as well.15
In a recent paper,1 we reported that amides 1, when
subjected to the conditions of the ‘direct amide cyclization’
reaction,2–9 yielded only the dimerized product 3. The 14-
membered cyclodepsipeptide 3 was isolated as the sole
product and none of the expected seven-membered
monomer 2 could be detected (Scheme 1).
In order to explain this unexpected result, we investigated
some other lactonization methods with derivatives of 1,
including that described by Richard et al.,10 which, in the
case of ethyl 6-hydroxyhexanoates, had resulted in the
formation of seven-membered lactones. Again, in all
experiments with derivatives of 1, where a defined product
could be isolated, we obtained only the dimeric product 3.
The synthetic pathways to serratamolide (4) and its
derivatives are numerous, but the approaches can be divided
Scheme 1.
Keywords: Cyclodepsipeptides; Cyclodimerization; Twinning; 2H-Azirin-3-amines; 1,3-Oxazole-5(4H)-ones.
*
Corresponding author. Tel.: C41 44 6354282; fax: C41 44 6356836; e-mail: heimgart@oci.unizh.ch
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.002

1080
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
Scheme 2.
into three main groups: classical ring closure of linear
precursors, usually by lactam bond formation (5/4), ring
enlargement (6/7/4), and cyclization by twinning
(8/4) (Scheme 2).
tetrameric structures of the b-hydroxy acid.1 Therefore,
most probably the dimerization is not a result of the amide
bond rigidity.
In order to further investigate the cyclodimerization of
dipeptide analogues of type 1 under the conditions of the
‘direct amide cyclization’ we synthesized some other amide
precursors, which differ in the substitution in the a-amino
acid as well as in the b-hydroxy acid moiety, including
chiral compounds. Furthermore, we tried to get some
information from computer modeling of key compounds.
The main feature of the last-mentioned method is that the
cyclization is performed with the monomeric linear
precursor, and the twinning, or cyclodimerization, takes
place during the course of the reaction. Some basic theories
have been offered as an explanation of this dimerization.
One of the most popular proposals states that it is mainly
due to intermolecular hydrogen bonding between carbonyl
and amine groups that are formed during the reaction.16,17 In
the case of 4, the two planar trans-amide groups form a
trans-annular hydrogen bond (intramolecular) and thus
favor the formation of a 14-membered ring. That no
monomeric product was formed in the reaction can probably
be explained by the fact that such an intramolecular
interaction would not be possible within a seven-membered
ring. However, the contribution of hydrogen bonding tends
to be overestimated as some dimerizations also take place in
polar solvents, which could interfere with such an
intramolecular interaction.17 Another theory proposed by
Ovchinnikov et al.18 is that the cyclization is preceded by a
linear polycondensation, which results in linear dimers and
oligomers, which, under the conditions of high dilution,
may undergo cyclization. The extent of the ring closure is
determined principally by the most stable conformation of
a given linear peptide, being close to that of the cyclic
product. On the other hand, the formation of trimers seems
to be statistically unfavorable.
2. Results and discussion
It is known from previous experiments5–7,19,20 that
dipeptides of type 1, in which the two methyl groups
in the amino acid residue are replaced by a cyclopentane
ring (i.e., the compounds contain 1-aminocyclopentane
carboxylic acid instead of 1-aminoisobutyric acid (Aib)),
react in a very similar way to 1. Therefore, our first
target was amide 9, which was conveniently prepared by
the coupling of 3-hydroxy-2,2-dimethylpropanoic acid
with N,N-dimethyl-1-azaspiro[2.4]hept-1-en-2-amine in
analogy to Ref. 1 (‘azirine/oxazolone method’; see also
Ref. 21). After bubbling HCl gas through a solution of 9
in toluene (20 mM) at 100 8C for 4 min, 88% of the
corresponding 14-membered cyclodepsipeptide 10 was
obtained (Scheme 3). Similarly, the linear racemic
dipeptides 11a,b22 carrying two different substituents on
the C(a) atom, were also synthesized by the ‘azirine/
oxazolone method’. ‘Direct amide cyclization’ of 11b
yielded, upon cyclization, 68% of the dimeric meso-
compound 12 as the sole product.
The reason for the preferred dimerization in the case of 1 is
most probably a defined conformation of the linear
precursor and the stability of the transition state. Another
reason could be the rigidity of the amide bond in 1, although
the reactions with an ester analogue of compound 1 showed
that again oligomerization occurred to give tri- and
1
This was clearly indicated by the H and 13C NM spectra,
which show only one set of signals. The structures of 10 and
12 were established by X-ray crystallography (Fig. 1).

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1081
again sits about a crystall0ographic centre of inversion.
Therefore, 12 has the (7RS,7 SR)-configuration, that is, 12 is
the trans-isomer. The hydrogen bonding pattern in the
crystals of 12 is the same as for 10.
The nature of the cyclodimerization in the case of 11 is
remarkable. Starting with a racemic precursor 11, one would
expect that a mixture of cis- and trans-substituted
cyclodimers would be obtained, but only the trans-isomer
12 has been formed in 68% yield.
As mentioned before, factors that might influence the
cyclization are not only the type, but also the number of
substituents in the amino acid moiety. Therefore, a
cyclization experiment was carried out with an analogue
of 11, which contains a monosubstituted amino acid. Direct
amide cyclization was not an option in this case, since the
intermediate oxazolone does not form smoothly in the case
of monosubstituted substrates.25 Therefore, we used the
base catalyzed lactonization described in Ref. 10. When a
solution of the enantiomerically pure 13 was heated in
toluene (200 mM) in the presence of 1 equiv of NaH, the
14-membered cyclic depsipeptide trans-14 was obtained as
the only isolable product in 44% yield. In order to compare
the configurations of the two stereogenic centers, the
analogous cyclization was performed with a racemic
starting material, that is, methyl ester 15 (Scheme 4).
Surprisingly, a single cyclodepsipeptide was again obtained
in 24% yield and was identical with trans-14 in all respects.
Scheme 3.
Scheme 4.
1
The H NMR spectrum of the cyclized product obtained
Figure 1. ORTEP plots23 of the molecular structures of (a) 10 and (b) 12
(50% probability ellipsoids, arbitrary numbering of atoms).
from 13 using a shift reagent (Pirkle reagent) and HPLC on
a chiral adsorbent (Chiracel OD-H, Merck Whelk-O 1)
showed the presence of only one compound, which was
identical with the product obtained from the cyclization of
15. X-ray crystallography of both products confirmed their
identical structure and proved that the benzyl groups are
trans-oriented (Fig. 2). The space group of trans-14 is
centrosymmetric and the molecule sits about a crystallo-
graphic centre of inversion, so the two stereogenic centres
have inverted configurations, that is, (7RS,70SR). The
hydrogen bonding pattern is again analogous to that of
12 and 10.
The backbones of the two structures are very similar and
also resemble the structures of the previously reported
tetramethyl analogue 3.1 In the case of 10, the molecule sits
about a crystallographic centre of inversion. The cyclo-
pentane ring has an envelope conformation with the spiro
C-atom as the envelope flap. Each amide NH group forms
an intermolecular hydrogen bond with a lactone carbonyl
O-atom of an adjacent molecule. The molecular symmetry
results in there being two parallel hydrogen bonds running
in opposite directions between each molecule. These
interactions link the molecules into extended double-
bridged chains, which run parallel to the [1 0 0] direction.
Taken individually, the repeat unit in the chain generated by
one of the interactions has a graph set motif24 of C(5). The
pair of hydrogen bonds linking two adjacent molecules
forms a loop with a graph set motif of R22(16). In the case of
12, the space group is centrosymmetric and the molecule
As the precursor 13 was optically active ([a]2D5 C44.6 (c 1,
CHCl3)), an inversion of the configuration at one of the
stereogenic centers has taken place during the cyclization
step. With the aim of avoiding this inversion, another
cyclization was attempted with the corresponding free
hydroxy acid 16, which was obtained from the basic

1082
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
10.9 min, respectively. The HPLC diagram of a mixture of
the two compounds under the same conditions also showed
two peaks, proving once more their different structure.
Furthermore, it was shown, that (S,S)-14 is optically active.
For this reason, we expected that it is the cis-isomer with the
(S,S)-configuration, which was subsequently proven by
X-ray crystallography (Fig. 2).
In the crystal structure of (S,S)-14, there are two symmetry-
independent molecules A and B in the asymmetric unit, but
the conformations of the two molecules are almost identical.
The space group permits the compound in the crystal to be
enantiomerically pure, but the absolute configuration of the
molecule has not been determined. The enantiomer used in
the refinement was based on the expected (S)-configuration of
each chiral centre in the molecule. The crystal is merohed-
rally twinned, with twin operator [1 0 0/0 K1 0/0 0 K1] and
the major twin domain has a volume fraction of 0.640(1).
Each amide group in molecule A forms an intermolecular
hydrogen bond with an amide O-atom of an adjacent
molecule A. This results in there being two parallel
hydrogen bonds running in opposite directions between
each molecule. The interactions link the molecules into
extended double-bridged /A/A/A/ chains, which run
parallel to the [1 0 0] direction. Taken individually, the
repeat unit in the chain generated by one of the interactions
has a graph set motif24 of C(4). The pair of hydrogen bonds
linking two adjacent molecules forms a loop with a graph
set motif of R22(18). The molecules of type B are similarly
linked into extended double-bridged /B/B/B/ chains,
which also run parallel to the [1 0 0] direction.
Figure 2. ORTEP plots23 of the molecular structures of (a) trans-14 and
(b) molecule A of (S,S)-14 (50% probability ellipsoids, arbitrary numbering
of atoms).
hydrolysis of 13. Cyclization of both rac-16 and (S)-16 was
achieved under neutral conditions using I2 as a catalyst,26
which has previously proven to be efficient for the synthesis
of depsipeptide 3.1 The product obtained from rac-16
was again the meso-compound trans-14a, while the
enantiomerically pure acid (S)-16, obtained by a milder
hydrolysis of its methyl ester 17, yielded also only one
cyclodepsipeptide, namely (S,S)-14 (Scheme 5).
From these results it could be concluded that mono-
substituted amino acids in amides of type 1 do not prevent
thecyclodimerization. Next, the influenceofthe disubstitution
of C(a) of the b-hydroxy acid should be investigated and,
therefore, analogous dipeptides containing a a-monosubsti-
tuted b-hydroxy acid were synthesized and subjected to
cyclization procedures. Tropic acid (3-hydroxy-2-phenylpro-
panoic acid) turned out to be an interesting starting material
Analytical HPLC of both of these compounds on a chiral
column (Whelk-O 1 column, hexane/EtOH 10:1) clearly
shows two different peaks with retention times of 10.8 and
Scheme 5.

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1083
Scheme 6.
for this study. Thus, amides 18a and 18b were prepared by
coupling tropic acid with 2,2,N,N-tetramethyl-2H-azirin-3-
amine and 2,2, N-trimethyl-N-phenyl-2H-azirin-3-amine,
respectively, and subjected to the conditions of the ‘direct
amide cyclization’. Surprisingly, the cyclization failed and
only traces of the corresponding 1,3-oxazol-5(4H)-one were
identified in the crude reaction mixture by IR and NMR
spectroscopy. Column chromatography led to no identifiable
products. Furthermore, the corresponding ethyl ester 19,
derived from either of the amides 18 by treatment with HCl
gas inthepresenceofEtOH, didnot yieldcyclicproducts upon
treatment with NaH. Other lactonization procedures, proven
to be successful in the case of amide derivatives,1 also failed to
give the desired cyclic depsipeptide in this case (Scheme 6).
toluene/acetonitrile/acetone gave crystals suitable for X-ray
crystallography. The molecular structure of 24 is depicted
in Figure 3, showing that again the trans-isomer has been
obtained.
When tropic acid was coupled with L-phenylalanine
t-butylester.HCl, amide 20 was obtained as a mixture of
two diastereoisomers. They were separated on a Whelk-O 1
preparative HPLC column, and we attempted to cyclize
each of them, in order to determine the stereospecificity of
the NaH cyclization. Unfortunately both the racemic and the
enantiomerically pure substrates failed to give cyclic
depsipeptides (Scheme 6).
Scheme 7.
The reason for the failure of cyclization of 18–20 could be a
steric hindrance of the phenyl group in the a-position or its
electronic effect. To examine this possibility, 3-hydroxy-2-
methyl-2-phenylpropanoic acid was prepared27 and coupled
with the corresponding 2H-azirin-3-amines to give 21a,b.
The third explanation could be that the cyclization is
thermodynamically unfavorable when the substrate is
monosubstituted in the a-position of the b-hydroxy acid
moiety. Therefore, a-benzyl-b-hydroxypropanoic acid and
b-hydroxyisobutyric acid were synthesized according to
known procedures28 and coupled with 2,2,N,N-tetramethyl-
2H-azirin-3-amine to give amides 22 and 23, respectively,
as substrates for the cyclization (Scheme 7).
As expected, amide 21b cyclized under DAC conditions to
yield the 14-membered cyclodepsipeptide 24 in moderate
yield. This result suggests that amides of type 18/21 bearing
a phenyl group at C(a) of the hydroxy acids do cyclize when
a,a-disubstituted, that is, the phenyl group in 18 was not the
reason for its failure to give cyclic products. Compound 24
was isolated as a colorless solid, which showed only one set
of signals in the NMR spectra. Therefore it could be
suggested that only one stereoisomer, as a meso-compound,
has been obtained. Careful crystallization from a mixture of
Figure 3. ORTEP plot23 of the molecular structure of 24 (50% probability
ellipsoids, arbitrary numbering of atoms).
Since the space group is centrosymmetric, 24 is a meso-
compound. The molecule sits about a crystallographic centre
of inversion, so therefore has the (4RS,40SR)-configuration.
Remarkably, the amide groups are not involved in any

1084
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
hydrogen bonds. Although amide O-atoms in adjacent
molecules appear to be positioned correctly to accept a
hydrogen bond from the amide H-atom, the H/O distance
for 18, that is, oxazolone formation with HCl gas in toluene
(monitoring by IR, increasing absorption at 1826 cmK1) and
addition of methanol after saturation, the dehydrated ester
28 and the dehydrated amide 29 were obtained in addition to
27 (Scheme 9).
˚
of 2.98 A is much too long for it to be considered a hydrogen
bond. This is probably the result of molecular bulk preventing
the molecules packing close enough together for intermole-
cular hydrogen bonds to form.
This result suggests that when the reaction is carried out in
the presence of a nucleophile, such as methanol, oxazolone
26 is formed first and is immediately transformed into the
corresponding hydroxy ester 27. On the other hand, in the
absence of a nucleophile, the intermediate oxazolone 26
eliminates water, leading to 2-vinyl oxazolones and thus
preventing further cyclization. The formation of 28 and 29
can be explained by the competitive ring opening of 26 by the
nucleophiles methanol and N-methylaniline, respectively.
This result is an additional indication that the cyclodimeriza-
tion process occurs via an oxazolone intermediate.
Amides 22 and 23 failed to cyclize under the DAC reaction
conditions, as was the case with 18. Upon monitoring
the reaction of 18 by IR spectroscopy, the formation of
the corresponding 1,3-oxazol-5(4H)-one 25, which is the
expected intermediate in the cyclization reaction, was
observed (strong absorption at 1820–1830 cmK1),29 and
after addition of methanol to the reaction mixture, methyl
ester 26 was isolated in 58% yield (Scheme 8).
The formation of a methyl ester and the IR spectra strongly
suggest the presence of a 1,3-oxazol-5(4H)-one as an
intermediate. It seems that the oxazolone formation and
dehydration in the case of 18 are competitive reactions. In
order to get an indication of which reaction takes place first,
a similar set of experiments was carried out with benzyl
derivative 22. Upon bubbling HCl gas through a solution of
22 in toluene/methanol (20%), the only product obtained
was the corresponding hydroxy ester 27 (Scheme 9). When
the reaction was carried out under the conditions described
Another variation of the starting materials for the direct
amide cyclization (DAC) is the insertion of aromatic
b-hydroxy acids or b-hydroxycycloalkane carboxylic
acids. The first of these derivatives, salicylamide 30, was
obtained from salicylic acid by coupling with the
corresponding 2H-azirin-3-amine (Scheme 10).5,19
Compound 30 was subjected to the DAC conditions. The
starting material disappeared quickly (TLC), but even after
Scheme 8.
Scheme 9.
Scheme 10.

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1085
Scheme 11.
35 min the only product formed was the corresponding
oxazolone 31. After its isolation, further exposure to the
same reaction conditions did not propagate the reaction
further, and the oxazolone 31 was recovered. The stability
of the oxazolone is in this case extremely high, and
apparently a ring enlargement reaction is sterically
disfavored.
out some simple quantum mechanical calculations.
Especially surprising was the discrepancy with the lower
homologue 36, which under the DAC conditions gave
the cyclic monomer 39 exclusively. Assuming that the
reaction proceeds indeed via the oxazolone intermediates
(37 and 40, respectively), we compared the energies of the
corresponding monomeric and dimeric ring structures, both
in the cases of a-hydroxy acids and b-hydroxy acids
(Schemes 12 and 13).
Crystals of 31 suitable for X-ray crystal structure determina-
tion were grown from a mixture of deuterochloroform and
dichloromethane by slow evaporation of the solvent. The
five-membered heterocycle is planar and the phenyl residue
is almost coplanar with the ring. The hydroxy group forms
an intramolecular hydrogen bond with the imine N-atom.
The interaction can be described by the graph set motif24 of
S(6) (for crystallographic details see Section 4).
AM1 calculations30 with Ampac v.6.5.531 revealed that the
transition state required to achieve a nucleophilic attack of
the oxazolone hydroxy group on the carbonyl C-atom is
more favorable in the case of 40 than in 37, which is to be
expected, having in mind the length of the alkyl chain to
which the OH group is bound. Nevertheless, under the DAC
conditions, 36 gives 39, whereas 1 undergoes the twinning
process.
Next, the aromatic ring in 30 was replaced by a
cycloaliphatic one. The preparation of the precursors
33a,b was achieved in three steps according to Scheme 11.
The cyclization under the standard conditions led to a
mixture of two products, the oxazolone 34 and the
dehydrated amide 35, but no cyclodepsipeptide could be
detected.
Direct comparison of the heats of formation (DH) of 38 and
39, as well as those of 3 and 2, reveals that in the first case
(Scheme 12) the formation of the dimer 38 is energetically
more unfavorable than the formation of the monomer 39
(2E39!E38). In the second case (Scheme 12), formation
of the dimer 3 is energetically more favorable than the
formation of the monomer (2E2OE3), which suggests that
the cause for the different products formed is thermo-
dynamic. This crude modeling helps to understand why the
dimers of type 3 could be the main products of the direct
2.1. Computer modeling
As we were searching for an explanation for the preferred
cyclodimerization process of diamides of type 1, we carried
Scheme 12.

1086
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
Scheme 13.
amide cyclization of 1, but it does not explain why they are
the only products formed. An equilibrium between the
monomeric and dimeric forms under the strongly acidic
conditions of the DAC is to be expected in both cases
(between 2 and 3 on the one hand and between 39 and 38 on
the other). This equilibrium might be shifted almost
completely in one direction in the case of 3 and in the
other in the case of 39.
yielded trans-14, although not via DAC). Using I2 mediated
lactonization allowed for the selective synthesis of both
(S,S)-14 (starting with (S)-16) and trans-14 (starting with
rac-16). If, on the other hand, the hydroxy acid moiety is
monosubstituted (as in 18, 19, 27), although the formation
of the intermediate 1,3-oxazol-5(4H)-one has been moni-
tored by IR, dehydration occurs and no cyclic products
are formed. Therefore, the synthesis of b-hydroxy acid
containing cyclic depsipeptides via DAC is useful only if
the starting amides contain a,a-disubstituted acids.
3. Conclusions
Upon investigating the reasons for the cyclodimerization of
b-hydroxy acid amides of type 1 under various conditions,
we were able to isolate five different 14-membered
cyclodimers of type 3. Although other coupling methods
also gave moderate results, the best yields were obtained via
the ‘direct amide cyclization’ (DAC), reaching 88% for the
cyclodimer 10. It is worth mentioning that in all cases, when
starting with racemic material, only the trans-substituted
cyclodepsipeptides were isolated.
4. Experimental
4.1. General
Thin-layer chromatography (TLC): Merck TLC aluminium
sheets, silica gel 60 F254. Prep. TLC: Merck PLC plates
(glass), silica gel 60 F254, 2 mm and 40–63 mm. Flash
chromatography (CC): Uetikon-Chemie ‘Chromato-
graphiegel’ C-560. Mp: Bu¨chi 540 apparatus, uncorrected.
IR Spectra: Perkin-Elmer Spectrum one spectrometer; in
KBr, unless otherwise stated, absorption bands in cmK1. 1H
NMR (300 MHz) and 13C NMR (75.5 MHz) spectra: Bruker
ARX-300 or Bruker DRX-600 instrument; 1H NMR
(600 MHz) and 13C NMR (150 MHz); in CDCl3 at 300 K;
TMS as internal standard, unless otherwise stated; d in ppm,
coupling constants J in Hz. Mass spectrometry (MS):
Finnigan MAT-90 for electron impact ionization (EI),
Finnigan SSQ-700 for chemical ionization (CI, with NH3)
and electrospray ionization (ESI, in MeOHCNaI), unless
otherwise stated.
The cyclodimerization is most probably a result of the
greater thermodynamic stability of the 14-membered ring
compared with the seven-membered one. Another factor,
which might contribute to the cyclodimerization, as
suggested in the literature, is H-bond formation, which
would be more pronounced in the 14-membered ring,
although the structures of all cyclodepsipeptides, which
were characterized by X-ray crystallography, showed no
evidence of intramolecular H-bonding.
Molecular modeling using simple AM1 calculations shows
in the case of 1 that the formation of the dimeric
depsipeptide is indeed thermodynamically favored over
the formation of the monomer, but it does not explain why
the 14-membered ring is the only product formed. A mixture
of the monomeric and dimeric forms is to be expected.
Thus, the reason for the exclusive cyclodimerization of
compounds of type 1 remains unclear and further
investigation in this area is needed.
2,2,N,N-Tetramethyl-2H-azirin-3-amine, 2,2,N-trimethyl-
N-phenyl-2H-azirin-3-amine, 2-benzyl-2,N-dimethyl-
N-phenyl-2H-azirin-3-amine and N,N-dimethyl-1-azaspir-
o[2.4]hept-1-en-2-amine were prepared according to stan-
dard procedures (Refs. 5 and 7 and references cited therein).
3-Hydroxy-2-benzylpropanoic acid was prepared by the
method of Monteil et al.28 and methyltropic acid from
hydroptropic aldehyde by hydroxymethylation, followed
by oxidation, according to Geffken.27 Hydroxy acids 32
were synthesized by the method of Seebach et al.32 All other
products used were commercially available.
Variation in the substitution pattern of the starting
compounds showed that mono-substitution in the amino
acid moiety does not prevent twinning (13, 15, and 16

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1087
General procedure 1 (GP1). To a solution of a hydroxy acid
(2–6 mmol) in dry THF (5–20 mL), 1.05 equiv of the
corresponding 2H-azirin-3-amine were added dropwise.
The mixture was stirred at rt for 12–36 h, the solvent
evaporated and the remaining solid purified by column
chromatography (CC) over silica gel and dried in h.v.
the suspension for 10 min. Then, the mixture was allowed
to cool to rt while bubbling N2 through it (ca. 20 min).
The solvent was evaporated and the oily residue was
purified by CC.
General procedure 10 (GP10). A suspension of an amide
(0.5 mmol) in dry toluene (25 mL) was heated to 100 8C,
and dry HCl gas was bubbled through the suspension for
10 min. Then, the mixture was allowed to cool to rt while
bubbling N2 through it (ca. 20 min). The solvent was
removed i.v. and MeOH (15 mL) was added to the residue
and stirred at rt for 1 h in the presence of 500 mg SiO2. The
silica gel was filtered, the solvent was evaporated and the
oily residue was purified by CC.
General procedure 2 (GP2). According to GP1, the reaction
was stirred overnight, the solvent evaporated, the solid
residue washed with Et2O and recrystallized from AcOEt.
General procedure 3 (GP3). To a solution of a hydroxy acid
(3 mmol) in dry THF (10 mL) was added the corresponding
phenylalanine ester hydrochloride (3.0 mmol) and 3-
(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
(DEPBT, 916 mg, 98%, 3.0 mmol). To the cooled mixture
were added dropwise 12 mmol (1.21 g) of Et3N. The
mixture was stirred at rt overnight, the solvent was partially
evaporated, AcOEt was added and the solution was washed
with 5% aq KHSO4 and with saturated aq NaHCO3
solutions. The combined organic fractions were dried over
MgSO4, evaporated, purified by CC, and dried in h.v.
4.2. Preparation of 3-hydroxy-2-methylpropanoic acid
To a solution of methyl (R)-3-hydroxy-2-methylpropanoate
(1.0 g, 8.38 mmol) in THF/water 75:10 (10 mL) LiOH
(1.55 g, 33.5 mmol) was added at 0 8C. The mixture was
stirred overnight, the organic solvent evaporated, the
residue acidified with 6 N HCl to pH 1 and extracted with
AcOEt. The colorless oil was used in the next reaction
without further purification. Yield: 768 mg (88%). Spectro-
scopic data in accordance with previously published data.33
General procedure 4 (GP4). To a solution of an ester
(2.0 mmol) in 10 mL EtOH was added LiOH$H2O (336 mg,
8 mmol). The reaction was stirred overnight at rt, acidified
with 6 N HCl, the organic solvent was evaporated in vacuo
and the residue extracted with AcOEt. The crude acids were
used in the next reaction step without further purification.
1
The optical purity has not been determined. H NMR((d6)-
DMSO): 1.04 (d, JZ5.9 Hz, CH3); 2.31–2.38 (m, CH);
3.38–3.44, 3.52–3.61 (2m, CH2); 4.62 (br s, OH); 11.95
(br s, COOH).
General procedure 5 (GP5). A suspension of an amide
(1 mmol) in dry toluene (50 mL) was heated to 100 8C, and
dry HCl gas was bubbled through the suspension for
5–15 min. Then, the mixture was allowed to cool to rt while
bubbling N2 through it (ca. 20 min). The solvent was
evaporated, the white residue was washed with 3!15 mL of
CH2Cl2 and dried in h.v.
4.3. Coupling of b-hydroxy acids with 2H-azirin-3-
amines
4.3.1. 3-Hydroxy-2,2-dimethyl-N-[1-(N,N-dimethyl-
carbamoyl)cyclopentyl]propanamide (9). According to
GP1, 3-hydroxy-2,2-dimethylpropanoic acid (806 mg,
6.84 mmol) in dry THF (10 mL), N,N-dimethyl-1-
azaspiro[2.4]hept-1-en-2-amine (1.037 g, 7.52 mmol),
18 h, CC (SiO2, acetone/CH2Cl2 1:20). Yield: 1.330 g
(76%) of 9. White solid. Mp 180.6–181.9 8C (AcOEt). IR:
3397vs, 3279s, 2960s, 2873m, 1644vs, 1542vs, 1469m,
1393s, 1309m, 1257m, 1212w, 1164m, 1119w, 1061s,
1011w, 983w, 911w, 817w, 669m. 1H NMR ((d6)-DMSO):
1.14 (s, Me2C); 1.71 (m, 2CH2); 1.81–2.00, 2.28–2.48 (2m,
2CH2); 2.99 (s, Me2N); 3.56 (br s, OH); 4.46 (s, CH2O);
7.42 (br s, NH). 13C NMR ((d6)-DMSO): 22.8 (q, Me2C);
24.2 (t, CH2); 37.2 (t, CH2); 37.7 (q, Me2N); 42.8, 66.2 (2s,
2C); 69.1 (t, CH2O); 172.7, 176.9 (2s, 2CO). CI-MS: 257
(21, [MCH]C), 212.3 (100, [MKNMe2]C). Anal. Calcd for
C13H24N2O3 (256.35): C 60.91, H 9.44, N 10.93; found: C
60.24, H 9.50, N 10.76.
General procedure 6 (GP6). According to GP5, after
bubbling N2 through the reaction mixture (ca. 20 min) the
solvent was evaporated, and the residue purified by CC.
General procedure 7 (GP7). To a solution of 13 or 15
(1 mmol) in dry toluene (5 mL), NaH (40 mg of a 60%
suspension in mineral oil, 1 mmol) was added slowly at 0 8C
and under constant stirring (N2-atmosphere). After 6 h at
80 8C, the mixture was acidified with 0.1 N HCl (w5 mL) to
pH 5 and extracted with CH2Cl2. The combined organic
fractions were dried (MgSO4) and evaporated i.v. The
crystalline residue was purified by CC (CH2Cl2/acetone
200:1) and dried in h.v.
General procedure 8 (GP8). To a solution of a hydroxy acid
(1 mmol) in acetonitrile (5 mL), I2 (25 mg, 0.1 mmol) was
added. After 2 days under reflux, the mixture was cooled
and the solvent evaporated. After addition of 20 mL of
AcOEt and washing with aq Na2S2O3, the combined organic
fractions were dried (MgSO4) and evaporated i.v.
The crystalline residue was purified by CC.
4.3.2. 3-Hydroxy-2,2-dimethyl-N-[1-methyl-1-(N,N-
dimethylcarbamoyl)-2-phenylethyl]propanamide (11a).
According to GP1, 3-hydroxy-2,2-dimethylpropanoic acid
(436 mg, 2.00 mmol) in dry THF (5 mL), 2-benzyl-2,N,
N-trimethyl-2H-azirin-3-amine (395 mg, 2.1 mmol), 24 h,
CC (SiO2, acetone/CH2Cl2 1:20). Yield: 538 mg (88%) of
11a. White powder. Mp 92.6–94.9 8C. 1H NMR ((d6)DMSO):
1.05 (s, Me2C); 1.29 (s, Me); 3.09 (s, Me2N); 3.13–3.38
(m, PhCH2); 3.54 (s, CH2O); 4.77 (br s, OH); 6.92 (br s, NH);
7.06–7.36 (m, Ph). 13C NMR ((d6)DMSO): 22.4 (q, Me2C);
24.8 (q, Me); 37.3 (q, MeN); 41.0 (s, Me2C); 43.8 (t, PhCH2);
General procedure 9 (GP9). A suspension of an amide
(1 mmol) in a toluene/20% ethanol solution (60 mL) was
heated to 100 8C, and dry HCl gas was bubbled through

1088
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
70.1 (t, CH2O); 128.3, 128.8, 129.4 (3d, 5 arom. CH);
136.1 (s, arom. C); 173.1, 175.2 (2s, 2CO). CI-MS: 307
(100, [MCH]C), 262 (25, [MKNMe2]C).
(s, Me2C); 55.0 (d, CH); 67.3 (t, CH2O); 127.6, 127.7,
128.2, 128.5, 128.8, 129.1 (6d, 10 arom. CH); 136.7, 143.8
(2s, 2 arom. C); 173.1, 173.9 (2s, 2CO). ESI-MS: 363 (100,
[MCNa]C).
Recrystallization from DMSO/diethyl ether yielded crystals
of 11a, suitable for an X-ray crystal structure determination.
4.3.6. 3-Hydroxy-2-methyl-2-phenyl-N-[1-methyl-(N,
N-dimethylcarbamoyl)ethyl]propanamide (21a). Accord-
ing to GP1, 3-hydroxy-2-methyl-2-phenylpropanoic acid
(360 mg, 2.00 mmol) in dry THF (5 mL), 2,2,N,N-tetra-
methyl-2H-azirin-3-amine (249 mg, 2.1 mmol), 36 h, CC
(SiO2, acetone/CH2Cl2 1:10). Yield: 455 mg (78%) of 21a.
Colorless crystals. Mp 147.6–148.4 8C (toluene). IR: 3533s,
3280vs, 3054s, 2928vs, 1708vs, 1622vs, 1526vs, 1394s,
1264s, 1208s, 1118s, 1050m, 976m, 900w, 770m, 751m,
4.3.3. 3-Hydroxy-2,2-dimethyl-N-[1-methyl-1-(N-methyl-
N-phenylcarbamoyl)-2-phenylethyl]propanamide (11b).
According to GP1, 3-hydroxy-2,2-dimethylpropanoic acid
(436 mg, 2.00 mmol) in dry THF (5 mL), 2-benzyl-2,N-
dimethyl-N-phenyl-2H-azirin-3-amine (525 mg, 2.1 mmol),
28 h, CC (SiO2, acetone/CH2Cl2 1:30). Yield: 618 mg
(84%) of 11b. White powder. Mp 62.0–64.2 8C. IR: 3385vs,
3291vs, 3060m, 2941vs, 1701vs, 1634vs, 1591s, 1454s,
1386s, 1312s, 1238s, 1193m, 1165m, 1111m, 1053s, 886m,
1
802m. H NMR: 1.50 (s, Me2C); 1.61 (s, Me), 3.00 (s,
Me2N); 3.55–3.70, 4.05–4.19 (2m, CH2O); 4.45 (br s, OH);
7.18–7.41 (m, Ph, NH). 13C NMR: 21.4 (q, Me2C); 25.0 (q,
Me); 37.7 (q, Me2N); 51.5, 56.4 (2s, 2Me2C); 68.7 (t,
CH2O); 126.5, 126.9, 128.3 (3d, 5 arom. CH); 141.5
(s, arom. C); 172.6, 175.3 (2s, 2CO). CI-MS: 293 (88,
[MCH]C), 248 (100, [MKNMe2]C), 113 (28). Anal. Calcd
for C16H24N2O3 (292.38): C 65.73, H 8.27, N 9.58; found: C
65.69, H 8.40, N 9.59.
1
908w, 834w, 772s, 705s. H NMR: 0.98, 1.08 (2s, Me2C);
1.33 (s, Me); 3.29 (s, MeN); 3.41 (m, PhCH2); 3.54 (s,
CH2O); 3.77 (br s, OH); 6.89 (br s, NH); 7.12–4.10 (m,
2Ph). 13C NMR: 22.1 (q, Me2C); 24.1 (q, Me); 41.8 (q,
MeN); 43.4 (s, Me2C); 43.7 (t, PhCH2); 70.4 (t, CH2O);
127.1, 128.3, 128.8, 129.5, 130.1 (5d, 10 arom. CH); 136.1,
144.2 (2s, 2 arom. C); 173.0, 177.1 (2s, 2CO). CI-MS: 369
(30, [MCH]C), 262 (100, [MKN(Me)Ph]C), 234.2 (20),
160.1 (18), 134.1 (36), 107.1 (26). Anal. Calcd for
C22H28N2O3 (368.48): C 71.71, H 7.66, N 7.60; found: C
71.79, H 7.82, N 7.07.
4.3.7. 3-Hydroxy-2-methyl-2-phenyl-N-[1-methyl-1-(N-
methyl-N-phenylcarbamoyl)ethyl]propanamide (21b).
According to GP1, 3-hydroxy-2-methyl-2-phenylpropanoic
acid (360 mg, 2.00 mmol) in dry THF (5 mL) 2-benzyl-2,N-
dimethyl-N-phenyl-2H-azirin-3-amine (365 mg, 2.1 mmol),
28 h, CC (SiO2, acetone/CH2Cl2 1:20). Yield: 608 mg
(86%) of 21b. White solid. Mp 132.1–133.0 8C. IR: 3451s,
3282vs, 3057m, 2992s, 1709s, 1635vs, 1592s, 1445s, 1395s,
4.3.4. 3-Hydroxy-2-phenyl-N-[1-methyl-1-(N,N-dimethyl-
carbamoyl)ethyl]propanamide (18a). According to GP2,
3-hydroxy-2-phenylpropanoic acid (tropic acid, 332 mg,
2.00 mmol) in dry THF (5 mL), 2,2,N,N-tetramethyl-2H-
azirin-3-amine (249 mg, 2.1 mmol), 8 h. Yield: 440 mg
(79%) of 18a. White powder. Mp 160.8–161.3 8C (AcOEt).
IR: 3421m, 3296s, 3060m, 2936m, 1651vs, 1619vs, 1540s,
1491m, 1454w, 1396s, 1271m, 1219m, 1123s, 1068m,
1051m, 913w, 750m, 702m. 1H NMR: 1.88, 1.94 (2s,
Me2C); 3.28 (s, Me2N); 3.87–4.12 (m, CH2); 4.42 (br t, JZ
6.8 Hz, CH); 6.98 (s, NH); 7.50–7.62 (m, Ph). 13C NMR:
24.3, 24.5 (2q, Me2C); 38.0 (q, Me2N); 56.9 (s, Me2C); 54.7
(d, CH); 64.9 (t, CH2O); 127.7, 128.2, 129.0 (3d, 5 arom.
1
1262m, 1157m, 1123m, 1092s, 1026s, 921m. H NMR:
1.30, 1.38 (2s, Me2C); 1.48 (s, Me), 3.22 (s, MeN); 3.55–
3.61, 4.00–4.10 (2m, CH2O); 4.63 (br s, OH); 6.61 (br s,
NH); 7.18–7.41 (m, 2Ph). 13C NMR: 21.8 (q, Me2C); 25.7
(q, Me); 41.5 (q, MeN); 52.3, 58.8 (2s, 2Me2C); 69.2 (t,
CH2O); 126.3, 126.6, 126.9, 127.1, 127.2, 128.1, 128.3,
128.4, 128.6, 129.4 (10d, 10 arom. CH); 141.6, 144.2 (2s, 2
arom. C); 173.7, 176.0 (2s, 2CO). ESI-MS: 731 (48, [2MC
Na]C), 377 (100, [MCNa]C), 248 (16).
1
CH); 136.7 (s, arom. C); 171.9, 172.6 (2s, 2CO). H NMR
((d6)DMSO): 1.38, 1.32 (2s, Me2C); 2.71 (s, Me2N);
3.42–3.58, 3.60–3.69, 3.87–3.94 (3m, CH, CH2); 4.78 (t,
OH); 7.22–7.36 (m, Ph); 8.31 (s, NH). 13C NMR
((d6)DMSO): 25.5, 25.8 (2q, Me2C); 37.0 (q, Me2N); 53.9
(s, Me2C); 55.4 (d, CH); 63.2 (t, CH2O); 126.6, 127.7,
128.0 (3d, 5 arom. CH); 138.1 (s, arom. C); 170.2,
171.7 (2s, 2CO). CI-MS: 279 (80, [MCH]C), 234 (100,
[MKNMe2]C), 206 (22), 157 (18), 104 (8).
4.3.8. 3-Hydroxy-2-benzyl-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]propanamide (22). According to
GP2, 3-hydroxy-2-benzylpropanoic acid (360 mg,
2.00 mmol) in dry THF (5 mL), 2,2,N-trimethyl-N-phenyl-
2H-azirin-3-amine (365 mg, 2.1 mmol), 8 h. Yield: 560 mg
(79%) of 22. White powder. Mp 162.4–163.9 8C. IR:
3409m, 3277s, 3060w, 2932m, 1630vs, 1592s, 1544s,
1493s, 1395s, 1254m, 1188w, 1092s, 1070m, 769m,
743m, 703s, 617m. 1H NMR: 1.27, 1.33 (2s, Me2C);
2.38–2.42, 2.61–2.73, 2.88–3.01 (3m, CH2, CH); 3.27 (s,
MeN); 3.66–3.73 (m, OH); 6.18 (br s, NH); 7.11–7.41 (m,
2Ph). 13C NMR: 26.2, 27.0 (2q, Me2C); 34.3 (t, CH2); 41.5 (q,
MeN); 50.8 (d, CH); 59.0 (s, Me2C); 63.6 (t, CH2O); 126.3,
128.2, 128.3, 128.5, 129.0, 129.4 (6d, 10 arom. CH); 139.3,
144.4 (2s, 2 arom. C); 173.8, 174.0 (2s, 2CO). ESI-MS: 377
(100, [MCNa]C). Anal. Calcd for C16H24N2O3 (354.45): C
65.73, H 8.27, N 9.58; found: C 60.24, H 9.50, N 10.76.
4.3.5. 3-Hydroxy-2-phenyl-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]propanamide (18b). According
to GP2, 3-hydroxy-2-phenylpropanoic acid (tropic acid,
332 mg, 2.00 mmol) in dry THF (5 mL), 2,2,N-trimethyl-N-
phenyl-2H-azirin-3-amine (365 mg, 2.1 mmol), 9 h. Yield:
578 mg (85%) of 18b. White powder. Mp 128.6–129.9 8C
(AcOEt). IR: 3298s, 3274s, 3055m, 2940m, 1673vs,
16,124vs, 1545s, 1488m, 1462w, 1394s, 1270m, 1124s,
1099s, 1060m, 913m, 745m. 1H NMR: 1.76, 1.89 (2s,
Me2C); 3.31 (s, MeN); 3.91–4.19 (m, CH2); 4.36–4.42 (m,
CH); 7.05 (s, NH); 7.41–7.55, 7.60–7.87 (2m, 2Ph). 13C
NMR: 24.6, 24.8 (2q, Me2C); 41.1 (q, MeN); 57.4
4.3.9. 3-Hydroxy-2-methyl-N-[1-methyl-1-(N,N-dimethyl-
carbamoyl)ethyl]propanamide (23). According to GP1,
3-hydroxy-2-methylpropanoic acid (416 mg, 4.00 mmol)

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1089
in dry THF (5 mL), 2,2,N,N-tetramethyl-2H-azirin-3-amine
4.4. Preparation of dipeptide esters
(498 mg, 4.2 mmol), 38 h, CC (SiO2, acetone/CH2Cl2 1:20).
Yield: 790 mg (83%) of 23. Colorless crystals. Mp
118.7–120.0 8C. IR: 3418s, 1619vs, 1540s, 1397s, 1279m,
1226s, 1124s, 1077m, 1036m. 1H NMR: 1.09 (d, JZ6.1 Hz,
Me); 1.58 (s, Me2C); 2.59 (m, CH); 3.06 (s, Me2N); 3.63 (d,
CH2); 4.21 (br s, OH); 7.70 (s, NH). 13C NMR: 13.7 (q, Me);
25.5, 25.6 (2q, Me2C); 37.9 (q, MeN); 56.3 (s, Me2C); 42.3
(d, CH); 64.8 (t, CH2O); 173.0, 174.9 (2s, 2CO). ESI-MS:
455 (20, [2MCNa]C), 239 (100, [MCNa]C). Anal. Calcd
for C10H20N2O3 (216.28): C 55.53, H 9.32, N 12.95; found:
C 55.74, H 9.71, N 13.12.
4.4.1. tert-Butyl (S)-2-(3-hydroxy-2,2-dimethylpropanoyl-
amino)-3-phenylpropanoate (13). According to GP3,
3-hydroxy-2,2-dimethylpropanoic acid (654 mg, 3 mmol),
L-phenylalanine tert-butyl ester hydrochloride (774 mg,
3.0 mmol), CC (SiO2, acetone/CH2Cl2 1:30). Yield: 857 g
(89%) of 13. Colorless solid. Mp 82.7–84.1 8C. [a]2D5 C44.6
(c 1, CHCl3). IR: 3265vs, 3006s, 2982vs, 2867s, 1721vs,
1635vs, 1543vs, 1455s, 1392s, 1315s, 1165vs, 1102m, 963s,
850m. 1H NMR: 1.09 (s, Me2C); 1.45 (s, Me3C), 3.00–3.17
(m, PhCH2); 3.42–3.51 (m, CH2O); 3.72 (br s, OH);
4.63–4.78 (m, CH); 6.94 (br s, NH); 7.13–7.36 (m, Ph).
13C NMR: 22.3 (q, Me2C); 27.8 (q, Me3C); 37.6 (t, CH2);
43.1 (s, Me2C); 53. (d, CH); 69.9 (t, CH2); 82.3 (s, Me3C);
126.9, 128.3, 129.3 (3d, 5 arom. CH); 136.1 (s, arom. C);
170.8, 177.1 (2s, 2CO). CI-MS: 322 (88, [MCH]C), 266
(100, [MKtBu]C). Anal. calcd for C18H27NO4 (321.42): C
67.26, H 8.47, N 4.36; found: C 67.04, H 8.66, N 4.20.
4.3.10. 2-Hydroxy-N-[1-methyl-1-(N-methyl-N-phenyl-
carbamoyl)ethyl]benzamide (30). According to GP1,
salicylic acid (276 mg, 2.00 mmol) in dry THF (5 mL),
2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine (365 mg,
2.1 mmol), CC (SiO2, acetone/CH2Cl2 1:20). Yield:
565 mg (92%) of 30. Colorless crystals. Mp 146.1–
147.8 8C. IR: 3533s, 3280vs, 3054s, 2928vs, 1708vs,
1622vs, 1526vs, 1394s, 1264s, 1208s, 1118s, 1050m,
976m, 900w, 770m, 751m, 802m. 1H NMR: 1.43 (s,
Me2C); 3.22 (s, MeN); 6.68–6.74 (m, 1 arom. H); 6.76 (br s,
NH); 6.92–7.0 (m, 2H arom);7.11–7.28 (m, 4 arom. H);
7.31–7.42 (m, 2 arom. H); 12.1 (s, OH). 13C NMR: 26.4 (q,
Me2C); 41.4 (q, MeN); 58.4 (s, Me2C); 119.9 (s, arom. C);
126.6, 126.8, 127.3, 127.9, 128.2, 128.9, 129.3 (7d, 9 arom.
CH); 134.1, 142.2 (2s, 2 arom. C); 172.9, 177.5 (2s, 2CO).
ESI-MS: 335 (100, [MCNa]C).
4.4.2. Methyl (RS)-2-(3-hydroxy-2,2-dimethylpropanoyl-
amino)-3-phenylpropanoate (15). According to GP3,
3-hydroxy-2,2-dimethylpropanoic acid (654 mg, 3 mmol),
DL-phenylalanine methyl ester hydrochloride (639 mg,
3.0 mmol), CC (SiO2, acetone/CH2Cl2 1:30). Yield: 673 g
1
(80%) of 15. Pale yellow oil. H NMR: 1.03 (s, Me2C);
2.98–3.12 (m, PhCH2); 3.36–3.49 (m, CH2O); 3.67 (s,
MeO); 4.68–74 (m, CH); 6.50 (br s, NH); 7.13–7.38 (m, Ph).
13C NMR: 22.2 (q, Me2C); 37.6 (t, CH2); 43.0 (s, Me2C);
52.2 (d, CH); 52.9 (q, MeO); 69.5 (t, CH2); 127.0, 128.4,
129.1 (3d, 5 arom. CH); 135.8 (s, arom. C); 172.2, 177.3 (2s,
2CO). CI-MS: 280 (100, [MCH]C), 162 (18). Anal. Calcd
for C15H13NO4 (279.34): C 64.50, H 7.58, N 5.01; found: C
64.15, H 7.73, N 4.89.
4.3.11. (1R,2S)-2-Hydroxy-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]cyclopentanecarboxamide (33a).
According to GP1, (1R,2S)-2-hydroxycyclopentanoic
acid (32a, 260 mg, 2.00 mmol) in dry THF (5 mL), 2,2,
N-trimethyl-N-phenyl-2H-azirin-3-amine
(365 mg,
2.1 mmol), CC (SiO2, acetone/CH2Cl2 1:10). Yield:
530 mg (86%) of 33a. White powder. Mp 153.4–155.0 8C.
IR: 3289s, 2943s, 1708vs, 1636vs, 1593s, 1494s, 1390s,
1240s, 1092s, 1028m, 919m, 732s. 1H NMR: 1.42 (s,
Me2C); 1.57–1.68, 1.70–1.77, 1.79–1.96 (3m, 3CH2, CH);
3.27 (s, MeN); 4.35 (m, CHO); 6.38 (br s, NH); 7.24–7.41
(m, Ph, NH). 13C NMR: 21.9 (t, CH2); 26.1, 26.4 (2q,
Me2C); 26.8, 33.9 (2t, 2CH2); 41.4 (q, MeN); 50.2 (d, CH);
58.6 (s, Me2C); 74.2 (d, CHO); 128.1, 128.3, 129.4 (3d, 5
arom. CH); 144.2 (s, arom. C); 173.4, 176.1 (2s, 2CO).
ESI-MS: 327 (100, [MCNa]C).
4.4.3. Methyl (S)-2-(3-hydroxy-2,2-dimethylpropanoyl-
amino)-3-phenylpropanoate (17). According to GP3,
3-hydroxy-2,2-dimethylpropanoic acid (654 mg, 3 mmol),
L-phenylalanine methyl ester hydrochloride (639 mg,
3.0 mmol), CC (SiO2, acetone/CH2Cl2 1:30). Yield: 720 g
1
(86%) of 17. Pale yellow oil. H NMR: 1.05 (s, Me2C);
3.00–3.09 (m, PhCH2); 3.38–3.48 (m, CH2O); 3.69 (s,
MeO); 4.71 (t, JZ6.0 Hz, CH); 6.52 (s, NH); 7.14–7.36 (m,
Ph). 13C NMR: 22.3 (q, Me2C); 37.7 (t, CH2); 43.0 (s,
Me2C); 52.1 (d, CH); 53.0 (q, MeO); 69.6 (t, CH2); 127.0,
128.4, 129.1 (3d, 5 arom. CH); 135.9 (s, arom. C); 172.3,
177.5 (2s, 2CO). CI-MS: 280 (100, [MCH]C), 162 (18).
4.3.12. (1R,2S)-2-Hydroxy-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]cyclohexanecarboxamide (33b).
According to GP1, (1R,2S)-2-hydroxycyclohexanoic acid
(32b, 288 mg, 2.00 mmol) in dry THF (5 mL), 2,2,
N-trimethyl-N-phenyl-2H-azirin-3-amine (365 mg,
2.1 mmol), 12 h, CC (SiO2, acetone/CH2Cl2 1:10). Yield:
566 mg (89%) of 33b.White powder. Mp 171.2–172.9 8C.
IR: 3290s, 3020m, 2948s, 1711vs, 1635vs, 1599s, 1491s,
1421m, 1391s, 1239s, 1091s, 1022m, 919m, 731s. 1H NMR:
1.37, 1.42 (2s, Me2C); 1.43–1.52, 1.62–1.74, 1.77–1.83,
1.86–1.95 (4m, 4CH2, CH); 3.21 (s, MeN); 3.97 (m, CHO);
6.41 (br s, NH); 7.22–7.41 (m, Ph, NH). 13C NMR: 19.2,
24.4, 24.9 (3t, 3CH2); 25.9, 26.1 (2q, Me2C); 31.7 (t, CH2);
41.4 (q, MeN); 47.9 (d, CH); 59.4 (s, Me2C); 66.7 (d, CHO);
127.9, 128.2, 129.3 (3d, 5 arom. CH); 142.2 (s, arom. C);
172.1, 177.4 (2s, 2CO). ESI-MS: 341 (100, [MCNa]C).
4.4.4. tert-Butyl (R,S)-2-(3-hydroxy-2-phenylpropanoyl-
amino)-3-phenylpropanoate (20). According to GP3,
tropic acid (498 mg, 3 mmol), L-phenylalanine tert-butyl
ester hydrochloride (774 mg, 3.0 mmol), CC (SiO2,
acetone/CH2Cl2 1:30). Yield: 974 mg (88%) of 20. Pale
yellow crystals. Mp 117.4–119.1 8C. IR: 3426s, 3290s,
3059m, 1738vs, 1658vs, 1635s, 1551m, 1454m, 1368s,
1223s, 1154vs, 1059m, 1023m, 845m, 740m, 701s. 1H
NMR ((d6)DMSO): 1.28, 1.31 (2s, Me3C); 2.91–3.10 (m,
PhCH2); 3.50–3.62, 3.69–3.80 (2m, CH2O); 4.00–4.16,
4.60–4.78 (2m, 2CH); 5.81–6.00 (m, OH); 6.73 (d, JZ
3.7 Hz, NH); 6.93–7.27 (m, 2Ph). 13C NMR: 27.8, 27.9
(2q, Me3C); 37.7 (t, CH2); 53.1, 53.5, 54.3, 54.4 (4d, 2CH);
64.7, 64.8 (t, CH2O); 81.8 (s, Me3C); 127.7, 128.2, 128.3,
128.4, 129.0, 129.3 (6d, 10 arom. CH); 136.1, 136.8 (2s, 2

1090
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
arom. C); 171.0, 173.2 (2s, 2CO). CI-MS: 370 (85, [MCH]C),
313 (100, [MKtBu]C).
3.51, (br s, OH); 3.71 (m, MeO, CH2); 6.50 (s, NH); 7.11–7.31
(m, Ph). 13C NMR: 26.3 (q, Me2C); 35.2 (t, CH2); 48.4
(s, MeO); 51.1 (d, CH); 55.1 (s, Me2C); 66.0 (t, CH2); 126.6,
128.4,128.9 (3d,5 arom. CH);138.0(s, arom. C);170.9, 172.9
(2s, 2CO). CI-MS: 281 (16), 280 (100, [MCH]C).
4.5. Saponification of dipeptide amides
4.5.1. (RS)-2-(3-Hydroxy-2,2-dimethylpropanoylamino)-
3-phenylpropanoic acid (rac-16). According to GP4, from
13 (642 mg, 2.0 mmol). Yield 454 mg (79%) of 13. White
4.7. Attempted cyclization reactions
1
solid. Mp 91.3–94.9 8C. H NMR: 0.99, 1.02 (2s, Me2C);
4.7.1. Direct amide cyclization.
4.7.1.1.
2.96–3.02, 3.08–3.14 (2m, PhCH2); 3.21–3.41 (m, CH2O);
4.66–4.78 (m, CH); 6.95 (br s, NH); 6.98–7.18 (m, Ph). 13C
NMR: 22.0 (q, Me2C); 37.0 (t, CH2); 43.3 (s, Me2C); 53.1
(d, CH); 69.3 (t, CH2); 127.0, 128.4, 129.3 (3d, 5 arom. CH);
135.8 (s, arom. C); 174.0, 178.1 (2s, 2CO). ESI-MS: 288
(100, [MCH]C).
8,8,19,19-Tetramethyl-10,21-dioxa-6,
17-diazadispiro[4.6.4.6]docosane-7,11,18,22-tetraone
(10). According to GP5, 9 (256 mg, 1 mmol) in dry toluene
(50 mL) for 15 min. Yield: 186 mg (88%) of 10. White
powder. Mp 344.8–346.4 8C (decomp.). IR: 3386vs, 3029w,
2989s, 2936s, 1715vs, 1668vs, 1519vs, 1470m, 1268vs,
1
1190m, 1126vs, 1012m, 804w, 699s. H NMR ((d7)DMF):
1.00 (s, 2Me2C); 1.46–1.54 (m, 4CH2); 1.75–1.82,
4.5.2. (S)-2-(3-Hydroxy-2,2-dimethylpropanoylamino)-
3-phenylpropanoic acid ((S)-16). According to GP4,
from 17 (558 mg, 2.0 mmol). Yield: 442 mg (79%) of (S)-
16. Colorless oil, [a]D25 C44.1 (c 1, CHCl3). IR: 3369vs,
3192s, 2963s, 1723vs, 1643vs, 1529vs, 1455s, 1394m,
1287m, 1254s, 1179m, 1111w, 1049s, 913w, 699s. 1H
NMR: 0.99, 1.01 (2s, Me2C); 2.88–2.94, 3.02–3.14
(2m, PhCH2); 3.38 (m, CH2O); 4.71–4.83 (m, CH); 6.71
(br s, NH); 6.98–7.18 (m, Ph). 13C NMR: 21.1 (q, Me2C);
36.1 (t, CH2); 42.4 (s, Me2C); 52.2 (d, CH); 68.5 (t, CH2);
126.1, 127.6, 128.4 (3d, 5 arom. CH); 134.9 (s, arom. C);
173.2, 177.2 (2s, 2CO). ESI-MS: 288 (100, [MCNa]C).
1.88–1.94 (2m, 4CH2); 3.94 (s, 2CH2O); 7.69 (s, 2NH). 13
C
NMR ((d7)DMF): 22.8 (q, 2Me2C); 24.7, 36.1 (2t, 8CH2);
41.3, 65.2 (2s, Me2C, 2C); 70.8 (t, 2CH2O); 173.9, 174.5 (2s,
4CO). CI-MS: 441 (21), 440 (90, [MCNa]C), 423 (100,
[MCH]C). Anal. Calcd for C22H34N2O6 (422.53): C 62.54,
H 8.11, N 6.63; found: C 61.89, H 8.07, N 6.56.
Recrystallization from DMF/toluene/ethyl acetate yielded
crystals of 10, suitable for an X-ray crystal structure
determination.
4.7.1.2. 3,10-Dibenzyl-3,6,6,10,13,13-hexamethyl-1,
8-dioxa-4,11-diazacyclotetradecane-2,5,9,12-tetraone
(12). According to GP 5, 11 (368 mg, 1 mmol) in dry
toluene (50 mL), for 15 min. Yield: 177 mg (34%) of 12.
White solid. Mp 288.1–290.5 8C (decomp.). IR: 3520m,
3460vs, 3057w, 2970s, 1744vs, 1660vs, 1527vs, 1483s,
1364s, 1260s, 1236m, 1121vs, 1020w, 719m, 701s. 1H
NMR: 1.11, 1.25, 1.46 (3s, 6Me); 3.28–3.38 (m, 2PhCH2);
4.09 (s, 2CH2O); 7.07 (s, 2NH); 7.21–7.31 (m, 10 arom. H).
13C NMR: 21.3, 21.8 (2q, 2Me2C); 28.7 (q, 2Me); 39.7 (s,
2Me2C); 41.3 (t, 2CH2); 58.4 (s, 2C); 70.2 (t, 2CH2O);
126.1, 127.3, 129.6 (3d, 10 arom. CH); 135.0 (s, 2 arom. C);
171.7, 173.2 (2s, 4CO). ESI-MS: 545 (100, [MCNa]C).
4.6. Solvolysis of dipeptide amides under DAC
conditions
4.6.1. Ethyl 2-(3-hydroxy-2-phenylpropanoylamino)-2-
methylpropanoate (19). According to GP9, 18 (278 mg,
1 mmol) in toluene/EtOH 80:20 (60 mL), CC (AcOEt/hexane
1:10). Yield: 209 mg (76%) of 19. Colorless oil. IR: 3237vs,
3068s, 2980s, 1734vs, 1642vs, 1557s, 1475s, 1383m, 1288s,
1164s, 1070m, 1037s, 872w, 751m, 699s. 1H NMR: 1.10 (t,
JZ6.1 Hz, Me); 1.42 (s, Me2C); 3.50–3.60, 3.63–3.72 (2m,
CH2); 3.91–4.13 (m, CH, CH2); 6.02 (s, OH); 7.11–7.29 (m,
Ph, NH). 13C NMR: 13.9 (q, Me); 24.5 (q, Me2C); 54.4 (d,
CH); 56.6 (s, Me2C); 61.5 (t, CH2); 65.1 (t, CH2O); 127.7,
128.3, 129.0 (3d, 5 arom. CH); 136.5 (s, arom. C); 172.8,
174.2 (2s, 2CO). ESI-MS: 280 (100, [MCH]C).
Recrystallization from DMF/benzene/CH2Cl2/hexane/i-
PrOH yielded crystals of 12, suitable for an X-ray crystal
structure determination.
4.6.2. Methyl 2-methyl-2-(2-phenylacryloylamino)-
propanoate (26). According to GP10, 18 (139 mg,
0.5 mmol) in toluene (30 mL), CC (AcOEt/hexane 1:10).
Yield:72 mg(58%)of26.Whitecrystals.Mp116.8–117.4 8C.
IR: 3328m, 3068m, 2960vs, 2861s, 1727vs, 1657s, 1533s,
1460s, 1382m, 1276vs, 1139s, 1073s, 944w, 731m. 1H NMR:
1.56(s, Me2C); 3.77(s, MeO); 5.60, 6.10(2s, H2C]);6.28(br
s, NH); 7.30–7.42 (m, Ph). 13C NMR: 24.6 (q, Me2C); 52.6 (s,
MeO); 56.7 (s, Me2C); 121.7 (t, H2C]); 127.9, 128.6, 128.9
(3d, 5 arom. CH); 136.8 (s, C]CH2); 144.7 (s, arom. C);
166.6, 174.7 (2s, 2CO). CI-MS: 265 (6, [MCNH4]C), 249
(14), 248 (100, [MCH]C).
4.7.1.3. 3,6,6,10,13,13-Hexamethyl-3,10-diphenyl-1,
8-dioxa-4,11-diazacyclotetradecane-2,5,9,12-tetraone
(24). According to GP6, 21a (292 mg, 1 mmol) in dry toluene
(50 mL), 15 min, (SiO2, acetone/CH2Cl2 1:60). Yield: 75 mg
(30%) of 24. White solid. Mp 251.6–253.1 8C (decomp.). IR:
3526m, 3435vs, 3023w, 2987s, 1736vs, 1665vs, 1519vs,
1
1384s, 1276s, 1142vs, 1081w, 998s, 770m, 699s. H NMR:
1.30, 1.51, 1.60 (3s, 6Me); 4.41–4.61 (m, 2CH2O); 7.07
(s, 2NH); 7.28–7.42 (m, 10 arom. H). 13C NMR: 22.6, 24.5
(2q,2Me2C);25.7(q, 2Me);50.6(s, 2Me2C);56.1(s, 2C);70.0
(t, 2CH2O); 126.4, 127.7, 128.9 (3d, 10 arom. CH); 141.0
(s, 2 arom. C); 172.9,173.5 (2s, 4CO). CI-MS: 513 (32), 512
(100, [MCNH4]C), 495 (28, [MCH]C).
4.6.3. Methyl 2-(2-benzyl-3-hydroxypropanoylamino)-2-
methylpropanoate (27). According to GP9, 22 (188 mg,
0.5 mmol) in toluene/MeOH 80:20 (30 mL), CC (AcOEt/
Recrystallization from toluene/MeCN/acetone yielded
crystals of 24, suitable for an X-ray crystal structure
determination.
1
hexane 1:10). Yield: 81 mg (58%) of 22. Colorless oil. H
NMR: 1.41, 1.44 (2s, Me2C); 2.59 (m, CH); 2.82 (m, CH2);

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1091
4.7.1.4. Reaction of 22 under DAC conditions. A
suspension of 22 (188 mg, 0.5 mmol) in toluene (30 mL)
was heated to 100 8C, and dry HCl gas was bubbled through
the suspension for 20 min (IR monitoring). Then, the
mixture was allowed to cool to rt while bubbling N2
through it (ca. 20 min), MeOH was added to the solution
and stirred at rt for 1 h. The solvent was evaporated, the oily
residue was purified by CC (AcOEt/hexane 1:10) yielding
27 (13 mg, 9%), 28 (28 mg, 21%) and 29 (36 mg, 30%).
(d, CH]); 144.5 (s, arom. C); 169.0, 173.1 (2s, 2CO). ESI-
MS: 202 (100, [MCNa]C).
4.7.1.6.2. 2-(2-Hydroxycyclopentyl)-4,4-dimethyl-1,
3-oxazol-5(4H)-one (34a). White solid. Mp 98.0–102.1 8C
(decomp.). IR: 3080w, 2980m, 1822vs, 1642s, 1597s,
1472m, 1382w, 1216m, 1095s, 1018m, 916s. 1H NMR:
1.56 (s, Me2C); 1.54–1.75, 1.79–1.98 (2m, 3CH2, CH); 4.41
(m, CHO). 13C NMR: 22.4 (t, CH2); 25.4, 25.8 (2q, Me2C);
27.8, 31.1 (3t, 3CH2); 54.4 (d, CH); 62.3 (s, Me2C); 76.1 (d,
CHO); 162.5 (s, C]N); 173.1 (s, CO). CI-MS: 229 (100,
[MCNH4]C).
4.7.1.4.1. Methyl 2-(2-benzylacryloylamino)-2-
methylpropanoate (28). Colorless oil. IR: 3332m, 3069m,
2954vs, 2861s, 1727vs, 1661s, 1537s, 1454s, 1364m, 1282vs,
1241s, 1144s, 1073s, 1026m, 931w, 731m, 701m. 1H NMR:
1.46, 1.49 (2s, Me2C); 3.61 (s, CH2); 3.71 (s, MeO); 5.22, 5.79
(2s, H2C]); 6.32 (br s, NH); 7.14–7.32 (m, Ph). 13C NMR:
24.5 (q, Me2C); 38.5 (t, CH2); 52.4 (s, MeO); 56.4 (s, Me2C);
119.6 (t, H2C]); 126.4, 128.4, 128.8 (3d, 5 arom. CH); 138.2
(s, arom. C); 144.4 (s, C]CH2); 167.3, 174.8 (2s, 2CO). CI-
MS: 263 (18), 262 (100, [MCH]C).
4.7.1.7. Reaction of 33b under DAC conditions.
According to GP6, 33b (158 mg, 0.5 mmol) in dry toluene
(50 mL), 6 min, CC (SiO2, acetone/CH2Cl2 1:10). Yield:
51 mg (34%) of 35b and 31 mg (31%) of 34b.
4.7.1.7.1.
N-[1-Methyl-1-(N-methyl-N-phenyl-
carbamoyl)ethyl]cyclohex-1-enecarboxamide (35b).
White crystals. Mp 112.1–113.8 8C. 1H NMR: 1.46 (s,
Me2C); 1.52–1.62, 1.84–1.96, 2.01–2.14 (3m, 4CH2); 3.26
(s, MeN); 5.85 (m, CH]); 6.53 (br s, NH); 7.18–7.20,
7.30–7.36 (m, Ph). 13C NMR: 21.4, 21.9, 23.8, 25.2 (4t,
4CH2); 26.6 (q, Me2C); 41.3 (q, MeN); 57.6 (s, Me2C);
117.1 (s, CH]); 127.7, 129.1, 129.3 (3d, 5 arom. CH);
133.9 (d, CH]); 144.5 (s, arom. C); 169.6, 173.2 (2s, 2CO).
ESI-MS: 323 (100, [MCNa]C).
4.7.1.4.2.
2-Benzyl-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]acrylamide (29). White solid.
Mp 119.1–121.6 8C. IR: 3282s, 3060w, 2932m, 1634vs,
1598s, 1541s, 1481s, 1421m, 1390s, 1254m, 1172w, 1090s,
1
1079m, 769m, 703s. H NMR: 1.41 (s, Me2C); 3.20 (s,
MeN); 3.46 (s, CH2); 5.10, 5.53 (2s, H2C]); 6.18 (br s,
NH); 7.09–7.39 (m, 2Ph). 13C NMR: 26.1 (q, Me2C); 38.4 (t,
CH2); 41.3 (q, MeN); 58.1 (s, Me2C); 120.0 (t, H2C]);
126.5, 127.8, 128.1, 128.6, 129.0, 129.4 (6d, 10 arom. CH);
138.4, 143.4 (2s, 2 arom. C); 144.4 (s, C]CH2); 166.5,
173.1 (2s, 2CO). CI-MS: 237 (52, [MCH]C), 230 (100,
[MKN(Me)Ph]C), 108 (18).
4.7.1.7.2. 2-(2-Hydroxycyclohexyl)-4,4-dimethyl-1,
3-oxazol-5(4H)-one (34b). White solid. Mp 101.1–105.2 8C
(decomp.). IR: 3288w, 3017m, 29,619m, 1824vs, 1638s,
1595s, 1490m, 1421m, 1380m, 1092s, 917s. 1H NMR: 1.39,
1.43 (2s, Me2C); 1.44–1.56, 1.64–1.89, 1.90–1.98 (3m,
4CH2); 4.01 (m, CHO). 13C NMR: 19.8, 24.9, 26.6 (3t,
3CH2); 26.0, 26.1 (q, Me2C); 31.9 (t, CH2); 49.0 (d, CH); 64.0
(s, Me2C); 66.9 (d, CHO); 163.1 (s, C]N); 176.8 (s, CO).
CI-MS: 215 (100, [MCNH4]C).
4.7.1.5. 2-(2-Hydroxyphenyl)-4,4-dimethyl-1,3-oxazol-
5(4H)-one (31). According to GP6, 30 (156 mg, 0.5 mmol) in
dry toluene (50 mL), 5 min (SiO2, acetone/CH2Cl2 1:40).
Yield: 73 mg (74%) of 31. Colorless crystals. Mp
68.2–69.0 8C. IR: 3079m, 2977s, 1823vs, 1643vs, 1615vs,
1579s, 1478s, 1320vs, 1251s, 1206s, 1090s, 1016s, 915s,
735s. 1H NMR: 1.55 (s, Me2C); 6.84–7.08, 7.41–7.49,
7.68–7.73 (3m, 4 arom. H). 13C NMR: 24.8 (q, Me2C); 64.5
(s, Me2C); 108.8 (s, arom. C); 117.2, 119.3, 128.2, 134.5 (d, 4
arom. CH); 160.0 (s, C]N); 161.8 (s, arom. C); 178.6 (s,
CO). CI-MS: 206 (100, [MCNH4]C).
4.7.2. Other cyclizations.
4.7.2.1. trans-3,10-Dibenzyl-6,6,13,13-tetramethyl-
1,8-dioxa-4,11-diazacyclotetradecane-2,5,9,12-tetraone
(trans-14). According to GP7, 15 (321 mg, 1 mmol) or 13
(279 mg, 1 mmol). Yield of trans-14: 108 mg (44%) (from
13) and 60 mg (24%) (from 15), respectively. Colorless
crystals. Mp 232.9–234.6 8C (decomp.). [a]2D5 0 (c 1,
CHCl3). IR: 3374vs, 3024w, 2966m, 1732vs, 1645vs,
1531s, 1366m, 1282s, 1179s, 1108w, 1001m, 751m,
700m. 1H NMR: 0.90, 0.98 (2s, Me2C); 3.06 (d, JZ
5.8 Hz, CH2); 3.91–3.96 (m, CH2); 4.80–4.84 (m, CH); 5.89
(d, JZ3.9 Hz, NH); 6.97–6.99 (m, 6 arom. H); 7.10–7.25
(m, 4 arom. H). 13C NMR: 21.6, 22.7 (2q, Me2C); 37.6 (t,
2CH2); 42.2 (s, 2C); 52.5 (d, 2CH); 70.9 (t, 2CH2O); 127.2,
128.6, 129.3 (3d, 10 arom. CH); 135.7 (s, 2 arom. C); 170.0,
174.0 (2s, 4CO). ESI-MS: 517 (100, [MCNa]C), 444 (11).
CI-MS: 513 (30), 512 (100, [MCNH4]C), 496 (12), 495
(30, [MCH]C). Anal. Calcd for C28H34N2O6 (494.59): C
68.00, H 6.93, N 5.66; found: C 67.69, H 7.08, N 5.48.
Recrystallization from CDCl3/CH2Cl2 yielded crystals of
31, suitable for an X-ray crystal structure determination.
4.7.1.6. Reaction of 33a under DAC conditions.
According to GP6, 33a (152 mg, 0.5 mmol) in dry toluene
(50 mL), 6 min, CC (SiO2, acetone/CH2Cl2 1:10). Yield:
51 mg (34%) of 35a and 30 mg (28%) of 34a.
4.7.1.6.1.
N-[1-Methyl-1-(N-methyl-N-phenyl-
carbamoyl)ethyl]cyclopent-1-enecarboxamide (35a).
White solid. Mp 109.6–111.1 8C. 1H NMR: 1.53
(s, Me2C); 1.84–1.95, 2.22–2.26, 2.37–2.44 (3m, 3CH2);
3.26 (s, Me2N); 5.81 (m, CH]); 6.43 (br s, NH); 7.20–7.23,
7.29–7.34 (m, Ph). 13C NMR: 23.4 (t, CH2); 26.6 (q, Me2C);
31.0, 31.1, 32.8 (3t, 3CH2); 41.3 (q, MeN); 57.7 (s, Me2C);
117.9 (s, C]); 127.6, 127.8, 129.1 (d, 5 arom. CH); 139.4
Recrystallization from i-PrOH/CH2Cl2/hexane yielded
crystals of trans-14, suitable for an X-ray crystal structure
determination.

1092
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
According to GP8, rac-16 (287 mg, 1 mmol), CC (CH2Cl2/
acetone 200:1) yielded trans-14 as white crystals in 25%
yield (62 mg). [a]2D5 0 (c 1, CHCl3).
based of F. Corrections for secondary extinction were
applied.
Neutral atom scattering factors for non-hydrogen atoms
were taken from Ref. 39, and the scattering factors for
H-atoms were taken from Ref. 40. Anomalous dispersion
4.7.2.2. cis-(S,S)-3,10-Dibenzyl-6,6,13,13-tetramethyl-
1,8-dioxa-4,11-diazacyclotetradecane-2,5,9,12-tetraone
((S,S)-14). According to GP8, (S)-16 (1 mmol, 287 mg), CC
(CH2Cl2/acetone 200:1). Yield: 54 mg (22%) of (S,S)-14b.
Mp 212.1–214.4 8C (decomp.). [a]2D5 K26.3 (c 1, CHCl3).
1H NMR: 0.88, 1.08 (2s, 2Me2C); 3.13 (s, 2CH2O);
3.91–4.04, 4.11–4.22 (2m, 2CH2); 4.83–5.00 (m, 2CH);
5.83 (br s, 2NH); 7.03–7.14, 7.28–7.42 (2m, 2Ph). 13C
NMR: 21.5, 22.7 (2q, 2Me2C); 37.6 (t, 2CH2); 42.1 (s, 2C);
53.3 (d, 2CH); 71.0 (t, 2CH2); 127.3, 128.7, 129.4 (3d, 10
arom. CH); 136.1 (s, 2 arom. C); 169.7, 174.3 (2s, 4CO).
ESI-MS: 517 (100, [MCNa]C), 444 (11).
41
effects were included in Fc, the values for f0 and f00 were
those of Ref. 42. The values of the mass attenuation
coefficients are those of Ref. 43. All calculations were
performed using the SHELXL97 program44 with the
exception of 11a, where the teXsan crystallographic
software package45 was used.
Crystal data for 10. C22H34N2O6, MZ422.52, colorless,
plate, crystal dimensions 0.05!0.12!0.30 mm, triclinic,
space group Pbar, ZZ1, reflections for cell determina-
tion 2354, 2q range for cell determination 4–558,
˚
˚
˚
aZ6.0630(5) A, bZ9.5495(6) A, cZ10.7064(9) A,
Recrystallization from CH2Cl2/sec-BuOH yielded crystals
of (S,S)-14, suitable for an X-ray crystal structure
determination.
aZ66.451(3)8, bZ83.228(4)8, gZ71.733(5)8, VZ
3
539.61(7) A , TZ160 K, DxZ1.300 g cmK3, m(Mo Ka)Z
˚
0.0941 mmK1, 2q(max)Z558, total reflections measured Z
11,110, symmetry independent reflections Z2457, reflec-
tions with IO2s(I)Z1919, reflections used in refinement Z
2455, parameters refined Z143, R(F) [IO2s(I) reflections]
Z0.0473, wR(F2) [all data] Z0.1277 (wZ[s2(F2o)C
(0.0624P)2C0.093P]K1 where PZ(Fo2C2F2c)/3), goodness
of fit Z1.059, secondary extinction coefficient 0.09(2), final
4.8. X-ray crystal structure determination of 10, 11a, 12,
trans-14, (S,S)-14, 24, and 31
All measurements were made on a Nonius KappaCCD area-
detector diffractometer34 using graphite-monochromated
˚
Mo Ka radiation (l 0.71073 A) and an Oxford Cryosystems
K3
˚
D
max/sZ0.001, Dr (max; min) Z0.30; K0.28 e A
.
Cryostream 700 cooler. The data collection and refinement
parameters are given below35 and views of the molecules
are shown in Figures 1–3. Data reduction was performed
with HKL Denzo and Scalepack.36 The intensities were
corrected for Lorentz and polarization effects, but not for
absorption. Equivalent reflections were merged. Each
structure was solved by direct methods using SIR92,37
which revealed the positions of all non-hydrogen atoms.
Crystal data for 11a. C17H26N2O3, MZ306.40, colorless,
prism, crystaldimensions0.15!0.15!0.25 mm, monoclinic,
space group P21/n, ZZ4, reflections for cell determination
˚
4110, 2q range for cell determination 4–558, aZ8.1009(1) A,
˚
˚
bZ17.1770(3) A, cZ12.6459(2) A, bZ101.112(1)8, VZ
1726.67(5) A , TZ160 K, DxZ1.179 g cmK3, m(Mo Ka)Z
3
˚
0.0806 mmK1, 2q(max)Z558, total reflections measured Z
37,684, symmetry independent reflections Z3973, reflections
used in refinement [IO2s(I)]Z2947, parameters refined Z
208, R(F) Z0.0469, wR(F)Z0.0479 wZ[s2(Fo)C
(0.005Fo)2]K1, goodness of fit Z2.962, secondary extinction
coefficient Z3.3(5)!10K6, final Dmax/sZ0.0005, Dr (max;
In the case of 10, 12, trans-14 and 24, the molecule sits
about a crystallographic centre of inversion.
In the case of (S,S)-14, there are two symmetry-independent
molecules in the asymmetric unit. The atomic coordinates of
the two molecules were tested carefully for a relationship
from a higher symmetry space group using the program
PLATON,38 but none could be found. The crystal
is merohedrally twinned. Successful refinement of the
structure was achieved using the twin operator [1 0 0/
0 K1 0/0 0 K1] and the major twin domain has a volume
fraction of 0.640(1).
K3
˚
min)Z0.39; K0.27 e A
.
Crystal data for 12. C30H38N2O6, MZ522.64, colorless,
tablet, crystal dimensions 0.05!0.10!0.20 mm, mono-
clinic, space group P21/n, ZZ2, reflections for cell
determination 2439, 2q range for cell determina-
˚
˚
˚
tion 4–508, aZ6.0109(2) A, bZ17.3238(5) A, cZ
3
˚
12.9060(5) A, bZ91.855(2)8, VZ1343.22(8) A , TZ
160 K, DxZ1.292 g cmK3, m(Mo Ka)Z0.0896 mmK1
,
The non-hydrogen atoms were refined anisotropically. Any
amide or hydroxy H-atoms in the structures were placed in
the positions indicated by a difference electron density map
and their positions were allowed to refine together with
individual isotropic displacement parameters. All remaining
H-atoms were placed in geometrically calculated positions
and refined using a riding model where each H-atom was
assigned a fixed isotropic displacement parameter with a
value equal to 1.2Ueq of its parent C-atom (1.5Ueq for the
methyl groups). Except for 11a, the refinement of
each structure was carried out on F2 by using full-matrix
least-squares procedures, which minimized the function
Sw(F2oKF2c)2. The refinement of the structure of 11a was
carried out on F by minimizing the corresponding function
2q(max)Z508, total reflections measured Z17,323, sym-
metry independent reflections Z2359, reflections with IO
2s(I) Z1731, reflections used in refinement Z2358,
parameters refined Z180, R(F) [IO2s(I) reflections]Z
0.0540, wR(F2) [all data] Z0.1283 (wZ[s2(F2o)C
(0.0395P)2C0.6836P]K1 where PZ(Fo2C2F2c)/3), goodness
of fitZ1.129, secondary extinction coefficientZ0.013(2),
K3
˚
final Dmax/sZ0.001, Dr (max; min)Z0.35; K0.18 e A
.
Crystal data for trans-14. C28H34N2O6, MZ494.58, color-
less, needle, crystal dimensions 0.05!0.05!0.25 mm,
monoclinic, space group C2/c, ZZ4, reflections for cell
determination 2421, 2q range for cell determination 4–508,

B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
1093
˚
˚
˚
aZ18.6829(6) A, bZ14.5471(5) A, cZ10.0381(3) A,
National Science Foundation and F. Hoffmann-La Roche
AG, Basel, is gratefully acknowledged.
3
˚
bZ104.943(2)8, VZ2635.9(2) A , TZ160 K, DxZ
1.246 g cmK3, m(Mo Ka)Z0.0875 mmK1, 2q(max)Z508,
total reflections measuredZ18,709, symmetry independent
reflectionsZ2333, reflections with IO2s(I)Z1579, reflec-
tions used in refinementZ2333, parameters refinedZ170,
R(F) [IO2s(I) reflections]Z0.0456, wR(F2) [all data]Z
0.1156 (wZ[s2(Fo2)C(0.041P)2C1.0127P]K1 where PZ
(F2oC2F2c)/3), goodness of fitZ1.040, secondary extinction
coefficientZ0.0040(7), final Dmax/sZ0.001, Dr (max;
References and notes
1. Iliev, B.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2003,
86, 3215–3234.
K3
˚
min)Z0.18; K0.17 e A
.
2. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1984, 67,
526–533.
Crystal data for (S,S)-14. C28H34N2O6, MZ494.58, colorless,
prism,crystaldimensions0.13!0.13!0.30 mm,monoclinic,
spacegroupP21, ZZ4,reflectionsforcelldetermination7591,
3. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1987, 70,
329–338.
4. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1990, 73,
221–228.
˚
2q range for cell determination 4–608, aZ5.4181(2) A,
˚
˚
bZ35.569(1) A, cZ13.3108(4) A, bZ90.090(1)8, VZ
5. Villalgordo, J. M.; Heimgartner, H. Helv. Chim. Acta 1997, 80,
748–766.
2565.2(2) A TZ160 K, DxZ1.281 g cmK3, m(Mo Ka)Z
3,
˚
0.0899 mmK1, 2q(max)Z608, total reflections measuredZ
52,489, symmetry independent reflectionsZ7611, reflections
with IO2s(I)Z5073, reflections used in refinementZ7606,
parameters refinedZ675, R(F) [IO2s(I) reflections]Z
0.0446, wR(F2) [all data]Z0.0899 (wZ[s2(F2o)C
(0.036P)2]K1 where PZ(Fo2C2F2c)/3), goodness of fitZ
1.025, secondary extinction coefficientZ0.012(1), final
6. Koch, K. N.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
2000, 83, 233–257.
7. Koch, K. N.; Linden, A.; Heimgartner, H. Tetrahedron 2001,
57, 2311–2326.
8. Heimgartner, H.; Arnhold, F. S.; Fritschi, S.; Koch, K. N.;
Linden, A.; Magirius, J. E. F. J. Heterocycl. Chem. 1999, 36,
1539–1547.
K3
˚
D
max/sZ0.001, Dr (max; min)Z0.23; K0.21 e A
.
9. Linden, A.; Ghorbani-Salman Pour, F.; Breitenmoser, R. A.;
Heimgartner, H. Acta Crystallogr., Sect. C 2001, 57, 634–637.
10. Richard, S.; Prie, G.; Guignard, A.; Thibonet, J.; Luc Parrain,
J.; Duchene, A.; Abarbri, M. Helv. Chim. Acta 2003, 86,
726–732.
Crystal data for 24. C28H34N2O6, MZ494.58, colorless,
prism, crystal dimensions 0.22!0.25!0.32 mm, triclinic,
ꢀ
space group P1, ZZ1, reflections for cell determina-
tion 2078, 2q range for cell determination 4–508,
11. Wasserman, H.; Keggi, J.; McKeon, J. J. Am. Chem. Soc.
1961, 83, 4107–4108.
˚
˚
˚
aZ5.9467(3) A, bZ10.1233(5) A, cZ10.9664(5) A,
aZ73.363(3)8, bZ83.818(3)8, gZ76.704(3)8, VZ
12. Wasserman, H.; Keggi, J.; McKeon, J. J. Am. Chem. Soc.
1962, 84, 2978–2982.
3
614.97(5) A , TZ160 K, DxZ1.335 g cmK3, m(Mo Ka)Z
˚
0.0938 mmK1, 2q(max)Z508, total reflections measuredZ
8138, symmetry independent reflectionsZ2137, reflections
with IO2s(I)Z1796, reflections used in refinementZ2136,
parameters refinedZ171, R(F) [IO2s(I) reflections]Z
0.0390, wR(F2) [all data]Z0.1010 (wZ[s2(F2o)C
(0.043P)2C0.2587P]1 where PZ(Fo2C2F2c)/3), goodness
of fitZ1.067, secondary extinction coefficientZ0.052(9),
13. Shemyakin, M. M.; Antonov, V. K.; Shkrob, A. M.;
Schelokov, V. I.; Agadzhanyan, Z. E. Tetrahedron 1965, 21,
3537–3572.
14. Matsuyama, T.; Bhasin, A.; Harshey, R. J. Bacteriol. 1995,
177, 987–991.
15. Strobel, G., Morrison, S., Cassella, M. U.S. Pat. Appl.
US2001-858871, Publ. 2003.
K3
˚
final Dmax/sZ0.001, Dr (max; min)Z0.18; K0.25 e A
.
16. Hassall, C.; Martin, T.; Schofield, J. Tetrahedron Lett. 1964, 5,
3741–3743.
Crystal data for 31. C11H11NO3, MZ205.21, colorless,
prism, crystal dimensions 0.10!0.17!0.30 mm,
monoclinic, space group P21/n, ZZ4, reflections for
cell determination 2470, 2q range for cell determination
17. Hassall, C.; Martin, T.; Schofield, J. J. Chem. Soc., Sect. C
1967, 32, 997–1003.
18. Ovchinnikov, Y.; Ivanov, V.; Kiryushkin, A.; Shemyakin, M.
Dokl. Akad. Nauk SSSR 1963, 153, 122–125.
19. Philipova, I.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
2005, 88, 1711–1733.
˚
˚
˚
4–558, aZ5.6230(2) A, bZ8.9884(4) A, cZ20.2034(8) A,
3
˚
bZ93.985(3)8, VZ1018.65(7) A , TZ160 K, DxZ
1.338 g cmK3, m(Mo Ka)Z0.0982 mmK1, 2q(max)Z558,
total reflections measuredZ21,205, symmetry independent
reflectionsZ2333, reflections with IO2s(I)Z1834, reflec-
tions used in refinementZ2331, parameters refinedZ143,
R(F) [IO2s(I) reflections]Z0.0517, wR(F2) [all data]Z
0.1359 (wZ[s2(Fo2)C(0.0581P)2C0.2986P]K1 where PZ
(F2oC2F2c)/3), goodness of fitZ1.107, secondary extinction
coefficientZ0.032(6), final Dmax/sZ0.001, Dr (max;
20. Stoykova, S. A. Ph.D. Thesis, University of Zurich, 2004.
21. Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30,
238–265.
22. The crystal structure of 11a was established by X-ray
crystallography (see Section 4). Since the space group is
centrosymmetric, the crystals are racemic. The trans-amide
group is planar. The amide NH group forms an intramolecular
hydrogen bond with the hydroxy O-atom, while the hydroxy
group forms an intermolecular hydrogen bond with the O-atom
of the amide group in the centre of the molecule of a
neighboring molecule, thereby linking the molecules into
extended chains.
K3
˚
min)Z0.21; K0.22 e A
.
Acknowledgements
We thank the analytical sections of our institute for the
spectra and analyses. Financial support of the Swiss
23. Johnson, C. K., ORTEPII, Report ORNL-5138; Oak Ridge
National Laboratory: Oak Ridge, Tennessee, 1976.

1094
B. Iliev et al. / Tetrahedron 62 (2006) 1079–1094
24. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew.
Chem. 1995, 107, 1689–1708. Angew. Chem., Int. Ed. Engl.
1995, 34, 1555–1573.
36. Otwinowski, Z.; Minor, W. In Methods in Enzymology; Carter,
C. W., Jr., Sweet, R. M., Eds.; Macromolecular Crystallography;
Academic: New York, 1997; Vol. 276, pp 307–326; Part A.
37. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr.
1994, 27, 435.
25. Wipf, P.; Heimgartner, H. Helv. Chim. Acta 1987, 70,
354–368.
26. Fujita, T.; Hanyu, N.; Mino, T.; Sakamoto, M. Synthesis 2001,
12, 1846–1851.
38. Spek, A. L. PLATON, Program for the Analysis of Molecular
Geometry, University of Utrecht: The Netherlands, 2003.
39. Maslen, E. N.; Fox, A. G.; O’Keefe, M. A. In Wilson, A. J. C.,
Ed.; International Tables for Crystallography; Kluwer Aca-
demic: Dordrecht, 1992; Vol. C, pp 477–486; Table 6.1.1.1.
40. Stewart, R. F.; Davidson, E. R.; Simpson, W. T. J. Chem. Phys.
1965, 42, 3175–3187.
27. Geffken, D. Arch. Pharm. 1979, 312, 360–361.
28. Monteil,T.;Danvy,D.;Plaquevent,J.;Duhamel,L.;Duhamel,P.;
Gros, C.; Schwartz, J.; Lecomte, J. Synth. Commun. 2001, 31,
211–218.
29. Obrecht, D.; Heimgartner, H. Chimia 1982, 36, 78–81.
30. Dewar, M. J.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. P.
J. Am. Chem. Soc. 1985, 107, 3902–3909.
31. AMPAC 6.5.5, Semichem Inc., 7128 Summit, Shawnee,
KS66216.
41. Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17,
781–782.
42. Creagh, D. C.; McAuley, W. J. In Wilson, W. J. C., Ed.;
International Tables for Crystallography; Kluwer Academic:
Dordrecht, 1992; Vol. C, pp 219–222; Table 4.2.6.8.
43. Creagh, D. C.; Hubbell, J. H. In Wilson, A. J. C., Ed.;
International Tables for Crystallography; Kluwer Academic:
Dordrecht, 1992; Vol. C, pp 200–206; Table 4.2.4.3.
44. Sheldrick, G. M. SHELXL97, Program for the Refinement of
32. Herradon, D.; Seebach, D. Helv. Chim. Acta 1989, 72,
690–714.
33. Seebach, D.; Zimmermann, J. Helv. Chim. Acta 1986, 69,
1147–1152.
34. Hooft, R. KappaCCD Collect Software, Nonius BV: Delft, The
Netherlands, 1999.
¨
Crystal Structures, University of Gottingen: Germany, 1997.
35. CCDC 284106-284112 contain the supplementary crystallo-
graphic 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.
45. teXsan: Single Crystal Structure Analysis Software, Version
1.10, Molecular Structure Corporation: The Woodlands,
Texas, 1999.