An unexpected formation of a 14-membered cyclodepsipeptide

Article abstract of DOI:10.1002/hlca.200390262

The treatment of diluted solutions of the hydroxy diamides 6a and 6b in toluene with HCl gas at 100° gave the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3). The same product was formed from the linear dimer of 6b, the depsipeptid

Full text of DOI:10.1002/hlca.200390262

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An Unexpected Formation of a 14-Membered Cyclodepsipeptide
by Boyan Iliev1), Anthony Linden, and HeinzHeimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
The treatment of diluted solutions of the hydroxy diamides 6a and 6b in toluene with HCl gas at 1008 gave
the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3). The same product was formed
from the linear dimer of 6b, the depsipeptide 11, under the same conditions (cf. Scheme 4). All attempts to
prepare the cyclic seven-membered monomer 9, starting with different precursors and using different
lactonization methods failed, and 10 was the only product which was isolated (cf. Scheme 6). For example, the
reaction of the ester 20 with NaH in toluene at 808 led exclusively to the cyclodimer 10. On the other hand, the
base-catalyzed cyclization of the hydroxy diester 22, which is the −O-analogue× of 20, yielded neither the seven-
membered dilactone, nor the 14-membered tetralactone, but only the known trimer 23 and tetramer 24 of 2,2-
dimethylpropano-3-lactone (cf. Scheme 7).
1. Introduction. The continuous and current interest in cyclic depsipeptides is a
result of their well-known biological activity. A large number of them have been
isolated from natural sources, mainly from marine or surface cultures of the
corresponding microorganisms (cf. [1 8]). Typical examples are the antibiotics
valinomycin [9 11] and the enniatins [12], which act as ionophores [13]. The most
demanding step in the synthesis of such compounds is the cyclization. As they contain
amide groups and at least one ester group in the core, the cyclic depsipeptides could be
prepared by the formation of either the amide or ester bonds as the ring-closure step.
The cyclization via amide-bond formation (lactamization; e.g., [14 16]) is usually
carried out by following protocols for the synthesis of cyclopeptides with coupling
reagents. On the other hand, successful cyclizations via ester-bond formation
(lactonization; e.g., [17 19]) have also been described. In the last few years, the
number of reports on the use of macrolactonizations in the preparation of cyclo-
depsipeptides has increased remarkably [6 8][20][21]. A useful method for the ring
closure of depsipeptides, which contain a,a-disubstituted a-amino acids, is the so-called
−direct amide cyclization× method, developed in our laboratory [22 28]. The basic
concept is that an amide of type 1 in a toluene solution or suspension is treated with dry
HCl gas. Cyclization by elimination of the corresponding ammonium chloride leads to
the intermediate 1,3-oxazol-5(4H)-one of type 2. In the absence of other nucleophiles,
the oxazolone undergoes a ring enlargement via intramolecular nucleophilic attack of
the OH group at the CˆO C-atom of the neighboring lactone group, leading to the
depsipeptide 3 (Scheme 1).
As reported earlier, this method has been used efficiently for the synthesis of
morpholine-2,5-diones (i.e., six-membered cyclic depsipeptides) [23][29] as well as for
1
)
Part of the planned Ph.D. thesis of B. I., Universit‰t Z¸rich.

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Scheme 1
some 9-, 12-, 15- [23], 16- [27], and 19-membered rings [30]. For the preparation of the
6-, 9-, 12-, and 15-membered rings of type 3, the linear precursors 1 have been prepared
by coupling a-hydroxy acids with 2H-azirin-3-amines, whereas b-hydroxy acids and 2H-
azirin-3-amines led to the precursors of the 16- and 19-membered cyclodepsipeptides.
The azirines themselves have been a target of our studies for some years [31 36],
mainly because they proved to be useful synthons for a,a-disubstituted a-amino acids
in peptide synthesis [31][33][34][37 40].
Because the reaction of a-hydroxy acids with 2H-azirin-3-amines, followed by the
−direct amide cyclization×, proved to be a convenient access to morpholine-2,5-diones,
we intended to generalize this reaction sequence. Therefore, we carried out the reaction
under similar conditions with some b-hydroxy acids in order to obtain seven-membered
cyclic depsipeptides. In the present paper, we report the results of the reaction of 2H-
azirin-3-amines with 3-hydroxy-2,2-dimethylpropanoic acid (4).
2. Results and Discussion. 2.1. Direct Amid Cyclization. As a model b-hydroxy
acid, we chose 3-hydroxy-2,2-dimethylpropanoic acid (4), mainly due to its commercial
availability and its previous use in this type of reaction [26][27]. The linear dipeptides 6
were prepared by the standard procedure [26] of coupling 4 with the corresponding 2H-
azirin-3-amine (5a or 5b; cf. [31] and refs. cit. therein), to yield 6a and 6b, respectively,
in excellent yields and without side products (Scheme 2).
Scheme 2
Although the general protocol proposed MeCN as a solvent [26], THF turned out
to be a better solvent in this particular case. In addition to the spectroscopic
characterization of 6a and 6b (cf. [27]), their structures were established by X-ray
crystallography (Fig. 1).
The conformations of the backbones of 6a and 6b are very similar, with the
exception of the orientation of the OH group. In 6a, the NH group forms an

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Fig. 1. ORTEP Plots [41] of the molecular structures of a) 6a and b) one of the two symmetry-independent
molecules of 6b (arbitrary numbering of the atoms; 50% probability ellipsoids)
intermolecular H-bond with its adjacent amide O-atom from a neighboring molecule
(N(4) ¥¥¥ O(6'') 2.885(1) ä; N(4)ÀH ¥¥¥ O(6'') 161(1)8). This interaction links the
molecules into extended chains, which run parallel to the y-axis and have a graph set
motif [42] of C(5). The OH group forms an intermolecular H-bond with its adjacent
amide O-atom from a different neighboring molecule (O(1) ¥¥¥ O(3') 2.770(2) ä;
O(1)ÀH ¥¥¥ O(3') 169(2)8) and thereby also links the molecules into infinite chains,
which run parallel to the y-axis and have a graph set motif of C(6). The combination of

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the intermolecular interactions links the molecules into a two-dimensional network,
which lies parallel to the xy-plane.
In the case of 6b, there are two symmetry-independent molecules in the asymmetric
unit and they have almost identical conformations. The NH group in each molecule
forms an intramolecular H-bond with the OH group (e.g., N(4) ¥¥¥ O(7) 2.728(2) ä;
N(4)ÀH ¥¥¥ O(7) 142(1)8 in molecule A) to yield a six-membered loop with a graph set
motif of S(6). The OH group of molecule A forms an intermolecular H-bond with the
primary amide O-atom of molecule B (O(7) ¥¥¥ O(25') 2.684(1) ä; O(7)ÀH ¥¥¥ O(25')
173(2)8), while the OH group of molecule B has a similar interaction with a different
molecule A (O(27) ¥¥¥ O(5'') 2.692(1) ä; O(27)ÀH ¥¥¥ O(5'') 174(2)8). These interac-
tions link the molecules into infinite chains in which both symmetry-independent
molecules are incorporated in an alternating ÁÁÁAÁÁÁBÁÁÁAÁÁÁB ¥¥¥ sequence. These
chains run parallel to the y-axis and have a binary graph set motif of C22(12).
The dipeptide 6b was subjected to the reaction conditions of the −direct amide
cyclization×, i.e., dry HCl gas was bubbled through a toluene suspension of 6b at 1008. It
was expected that 6b would react in an analogous manner to the amide 7, which gave
3,3,6,6-tetramethylmorpholine-2,5-dione (8) in up to 60% yield [43] (Scheme 3).
Surprisingly, only the dimer of the expected seven-membered ring 9, namely the
14-membered
3,3,6,6,10,10,13,13-octamethyl-1,8-dioxa-4,11-diazacyclotetradecane-
2,5,9,12-tetraone (10), was formed in 72% yield (Scheme 3).
Scheme 3
1
The H-NMR spectrum of 10 showed no signal for OH groups and confirmed the
presence of NH groups. Two singlets for Me groups and a singlet for CH2 were also
clearly distinguished. The 13C-NMR spectra showed the presence of two CˆO groups
(174.3 and 178.2 ppm in (D6)DMSO), which was further confirmed by the IR spectrum
(KBr; 1723 and 1673 cmÀ1). Furthermore, the 13C-NMR spectrum indicated two

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different types of Me2C groups, in addition to a CH2O group. With this set of data, the
distinction between the monomeric lactone 9 and the dimer 10 was not possible.
However, the mass spectra (CI and ESI mode) indicated a molecular weight of 370,
which corresponds to the 14-membered depsipeptide 10. Finally, its structure was
confirmed by X-ray crystallography (Fig. 2).
Fig. 2. ORTEP Plot [41] of the molecular structure of 10 (arbitrary numbering of the atoms; 50% probability
ellipsoids)
The molecule is oriented across a crystallographic center of inversion. The
symmetry-unique NH group forms a very weak intermolecular H-bond with the amide
O-atom from the same amide group of an adjacent molecule (N(4) ¥¥¥ O(5') 3.483(2) ä;
N(4)ÀH ¥¥¥ O(5') 1708). This interaction links the molecules into extended chains,
which run parallel to the z-axis and have a graph set motif of C(4). The other amide
group in the molecule participates in an identical intermolecular interaction of
necessity because of the centrosymmetric nature of the molecule. The chains thereby
formed also run parallel to the z-axis, but in the opposite direction. The molecules
themselves bridge adjacent chains, so that the combination of both interactions links
the molecules into two-dimensional networks which lie parallel to the (100) plane. The
cross-linking of the chains also builds H-bonded loops involving four molecules and
yields the graph set motif of R44(26).
To obtain the seven-membered, monomeric cyclodepsipeptide 9 (Scheme 3), we
repeated the reaction with varying concentrations of the starting material 6b and
different reaction times. However, under all conditions 10 was formed as the sole
product, although in variable yields. Thus, the maximum yield of 72% was obtained at a

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concentration of 20 mm, whereas with a concentration of 2 mm the yield dropped to
35%, and at a concentration of 40 mm the yield was only 61%.
The rate-determining step of the −direct amide cyclization× is assumed to be the
formation of the oxazolone ring (see Scheme 1), a process favored by the precipitation
of the corresponding ammonium salt. Thus, the formation of the lactone is a function of
the salt×s solubility in toluene2). As a result, N,N-dimethyl amides of type 6a should
react more easily than N-methyl-N-phenyl amides like 6b under the conditions of the
−direct amide cyclization×, because the initially formed Me2NH ¥ HCl is less soluble in
toluene than Ph(Me)NH ¥ HCl.
Therefore, we also used 6a as a starting material. The cyclization with HCl gas in
toluene at 1008 gave again the product 10. The lower yield (32%) is mainly caused by
purification difficulties (see Exper. Part).
To prepare 10 by a specific synthesis, we synthesized the open-chain precursor, the
linear depsipeptide 11, according to standard procedures, starting from the commer-
cially available methyl ester 12. After protection of the OH group by benzylation to
give 13 and deprotection of the COOMe group, the intermediate 14 was coupled with
5b to yield the diamide 15. The product of its acid-catalyzed hydrolysis 16 was coupled
with 6b to give 17, which, after deprotection, gave 11 in a total yield of 24% (Scheme 4).
Crystallization from a mixture of CH2Cl2, i-PrOH, and hexane gave crystals, which
were suitable for an X-ray crystal-structure determination (Fig. 3).
Fig. 3. ORTEP Plot [41] of the molecular structure of 11 (arbitrary numbering of the atoms; 50% probability
ellipsoids)
2
)
It has been shown previously that the formation of a 16-membered cyclic depsipeptide, which was
obtained in toluene (heterogeneous conditions) in 60% yield, does not occur in homogeneous solution in
DMF [26].

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Although the molecule is achiral, the crystal structure is chiral. The absolute
structure has not been determined and was defined arbitrarily. The amide NH group
closest to the OH group forms an intramolecular H-bond with the OH O-atom
(N(4) ¥¥¥ O(1) 2.709(3) ä; N(4)ÀH ¥¥¥ O(1) 135(3)8). This gives rise to a six-membered
loop with a graph set motif of S(6), analogous to compound 6b (Fig. 1). The other
amide group forms an intermolecular H-bond with the adjacent amide O-atom from a
neighboring molecule (N(11) ¥¥¥ O(13'') 2.932(3) ä; N(11)ÀH ¥¥¥ O(13'') 155(3)8). This
interaction links the molecules into infinite chains, which run parallel to the y-axis and
have a graph set motif of C(5). The OH group forms an intermolecular H-bond with its
adjacent amide O-atom from a different neighboring molecule (O(1) ¥¥¥ O(3')
2.655(3) ä; O(1)ÀH ¥¥¥ O(3') 158(4)8) and thereby also links the molecules into
infinite chains, which run parallel to the y-axis and have a graph set motif of C(6). The
combination of intermolecular interactions links the molecules into a two-dimensional
network, which lies parallel to the yz-plane.
Compound 11 was subjected to cyclization under the standard conditions of the
−direct amide cyclization×. Once more, the 14-membered cyclodepsipeptide 10 was the
only product that could be isolated, with the moderate yield of 42%.
2.2. Other Lactonization Methods. After all attempts to obtain the seven-membered
ring 9 by the −direct amide cyclization× failed, even after a ten-fold dilution of the
reaction mixture, we were faced with a number of classical lactonization options,
starting mainly with the corresponding hydroxy acid 18, which was obtained easily from
either of the amides 6 by hydrolysis in an acidic medium. The crystal structure of 18 is
shown in Fig. 4.
The NH group forms an intermolecular H-bond with the O-atom of the OH group
of a neighboring molecule (N(4) ¥¥¥ O(7''') 3.086(2) ä; N(4)ÀH ¥¥¥ O(7''') 165(2)8).
This interaction links the molecules into extended chains, which run parallel to the y-
axis and have a graph set motif of C(6). The OH group forms an intermolecular H-bond
with CˆO of the COOH group from a different neighboring molecule (O(7) ¥¥¥ O(2'')
2.746(2) ä; O(7)ÀH ¥¥¥ O(2'') 170(2)8). This interaction also links the molecules into
infinite chains, which run parallel to the y-axis and have a graph set motif of C(9). The
OH group of COOH forms an intermolecular H-bond with the amide O-atom of a third
neighboring molecule (O(1) ¥¥¥ O(5') 2.606(2) ä; O(1)ÀH ¥¥¥ O(5') 172(2)8). Again,
this interaction links the molecules into infinite chains, which run parallel to the y-axis
and have a graph set motif of C(7). The combination of all H-bonding interactions links
the molecules into a two-dimensional network, which lies parallel to the xy-plane.
The variety of lactonization methods is enormous, and we could try only a few of
them. As starting point, we used the review by Nicolaou [44] where the classical
methods of Yamaguchi and co-workers [45], Corey and Nicolaou [46], and Mukaiyama
et al. [47] are mentioned. Unfortunately, none of the above reactions yielded the
desired product, and the only products obtained were the activated acid derivates,
namely the Yamaguchi mixed anhydride and the Corey active ester. Some modern
variations of these methods [48] were also tried, but they also failed to give the desired
product. The most common cyclization methods, with DCC or its water-soluble
derivatives and analogues, gave as the only product 2-(2-hydroxy-1,1-dimethylethyl)-
4,4-dimethyl-1,3-oxazol-5(4H)-one (19) in 36% yield (Scheme 5). This is the postulated
intermediate of the prospected −direct amide cyclization× 6 ! 9. Even after addition of

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Fig. 4. ORTEP Plots [41] of the molecular structures of a) 18 and b) one of the two symmetry-independent
molecules of 19 (arbitrary numbering of the atoms; 50% probability ellipsoids)
Scheme 5
4-(dimethylamino)pyridine (DMAP) to a mixture of 18 and N,N'-dicyclohexylcarbo-
diimide (DCC), a procedure suitable for the synthesis of medium sized lactones [49],

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the reaction path did not change, and 19 was isolated as the only product, although in
moderate yield.
In general, 1,3-oxazol-5(4H)-ones are reactive species; in the case of 19, the
geminal dimethyl group seems to stabilize it, so that it could be isolated in crystalline
form. In the IR spectrum (KBr), 19 showed a characteristic strong CˆO absorption at
1836 cmÀ1, and in the 13C-NMR spectrum, the singlets for CˆO and CˆN appeared at
182.8 and 166.6 ppm, respectively. The structure of 19 was established by X-ray
crystallography (Fig. 4).
The asymmetric unit contains two symmetry-independent molecules, the confor-
mations of which differ only in the orientation of the OH group. The OH group of
molecule A forms an intermolecular H-bond with the N-atom of molecule B
(O(7)ÁÁÁN(21') 2.891(2) ä; O(7)ÀHÁÁÁN(21') 159(3)8). In turn, molecule B has an
identical interaction with another molecule A. These interactions link the molecules
into extended ÁÁÁAÁÁÁBÁÁÁAÁÁÁBÁÁÁ chains, which run parallel to the y-axis and have a
graph set motif [42] of C22(12).
As 19 is expected to be the intermediate in the −direct amide cyclization× 6 ! 9, we
attempted to transform 19 to the depsipeptide 9 in polar, aprotic solvents (AcOEt,
MeCN), but all attempts failed. After two days of heating 19 under reflux, only the
starting material was isolated. Another way of converting 19 to the depsipeptide 9 was
the −direct amide cyclization×. This reaction yielded again only product 10 in excellent
yield (86%; Scheme 6).
Scheme 6
The next step on the way to the synthesis of the seven-membered 9 was to try out
some reactions involving salts of metals, such as Sb [50], Sn [51], Ag [52], Sc [53], and
Ru [54], which are known to catalyze the formation of small- and medium-sized
lactones. Most of these attempts failed in the case of 18, and only few led to a definite
product, namely once more the dimeric cyclodepsipeptide 10 (Scheme 6). Surprisingly,
the reaction with I2 in boiling MeCN, which was initially used to cyclize terpene-like
hydroxy acids [55], gave again the 14-membered ring 10 in moderate yield (Scheme 6).

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Recently, Richard et al. have reported the synthesis of seven-membered lactones,
containing an amino group in their basic structure, by treatment of the corresponding
hydroxy esters with NaH in a toluene suspension [56]. Therefore, we treated the ester
20 under the same conditions. To our disappointment, this reaction yielded again the
dimeric compound 10 as the sole product.
The discrepancy between the reactions of 6-hydroxy-4-azahexanoates [56] and 6 is
very surprising. One of the possible reasons for the failure of this method in the case of
6 could lie in the presence of the amide bond and its rigidity. With the aim of verifying
this hypothesis, the ester analogue of the amide 6, i.e., the diester 22, was synthesized in
the same way as compound 11 (Scheme 7).
Subjecting compound 22 to the reaction conditions described in [56] led to a
mixture of products, among which the tri- and tetralactones 23 and 24, respectively,
were isolated as the main products. None of the expected seven-membered dilactone
could be detected. As an additional product, 2-hydroxyisobutanoic acid was also
obtained. The structures of 23 and 24, i.e., the cyclic tri- and tetramers, respectively, of
3-hydroxy-2,2-dimethylpropanoic acid (4) were confirmed by X-ray crystal-structure
analyses (Fig. 5). It turned out that these compounds are already known, and the
crystal-structure of 24 has been published previously [57]. They have been prepared by
oligomerization of b-lactone 25. Therefore, we propose that, in the reaction of 22 with
NaH, 25 is formed by the intramolecular nucleophilic attack of the OH group at the
central ester group and cleavage of this ester. Then, 25 undergoes the oligomerization.
Apparently, the alternative nucleophilic attack at the terminal ester group of 22, which
would lead to the seven-membered dilactone, cannot compete with the formation of the
b-lactone.
3. Conclusions. In conclusion, our attempts to prepare the seven-membered cyclic
depsipeptide 2,3,4,5,6,7-hexahydro-3,3,6,6-tetramethyl-1,4-oxazepine-2,5-dione (9) by
the −direct amide cyclization× starting with 3-hydroxy-2,2-dimethyl-N-[1-methyl-1-(N-
methyl-N-phenylcarbamoyl)ethyl]propanamide (6b) failed. The only product obtained
was the dimeric 14-membered cyclodepsipeptide 10, which was formed in a very good
yield. Furthermore, the attempts to prepare the monomeric lactone 9 by various
classical lactonization procedures also failed, and in almost all cases 10 was obtained as
the main product in yields of 28 72%. Six different methods for the synthesis of 10
were developed. Despite all the variations in reaction conditions and the knowledge of
the crystal structures of the starting materials and some of the intermediates, there is no
convincing explanation for this unexpected result, and additional experiments are
required.
We thank the analytical units of our institute for spectra and analysis, and the Swiss National Science
Foundation and F. Hoffmann-La Roche AG, Basel, for financial support.

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Fig. 5. ORTEP Plots [41] of the molecular structures of a) one of the two symmetry-independent molecules of 23 and b) 24 (arbitrary numbering of the atoms; 50%
probability ellipsoids)

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Experimental Part
1. General. The starting materials 2,2,N,N-tetramethyl-N-phenyl-2H-azirin-3-amine (5a) and 2,2,N-
trimethyl-N-phenyl-2H-azirin-3-amine (5b) were prepared according to standard procedures (cf. [31] and refs.
cit. therein). All other products used were commercially available. 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 column
chromatography (CC): Uetikon-Chemie −Chromatographiegel× C-560. M.p.: B¸chi 540 apparatus, uncorrected.
IR Spectra: Perkin-Elmer Spectrum one spectrometer; in KBr, unless otherwise stated, absorption bands in
cmÀ1. 1H- (300 MHz) and 13C-NMR (75.5 MHz) spectra: Bruker ARX-300 instrument; in CDCl3 at 300 K; TMS
as internal standard, unless otherwise stated; d in ppm, coupling constants J in Hz. HSQC and HMBC spectra:
1
Bruker DRX-600 instrument; H- (600 MHz) and 13C-NMR (150 MHz). MS: Finnigan MAT-90 for electron-
impact ionization (EI), Finnigan SSQ-700 for chemical ionization (CI, with NH3) and electrospray ionization
(ESI, in MeOH ‡ NaI), unless otherwise stated.
2. Coupling with 2H-Azirin-3-amines. N-[1-(N,N-Dimethylcarbamoyl)-1-methylethyl]-3-hydroxy-2,2-dime-
thylpropanamide (6a). To a soln. of 3-hydroxy-2,2-dimethylpropanoic acid (4; 806 mg, 6.84 mmol) in dry THF
(5 ml), 5a (1.231 g, 7.52 mmol) was added dropwise. The mixture was stirred at r.t. for 36 h, the solvent was
evaporated, and the remaining solid was purified by CC (SiO2, MeOH/CH2Cl2 1:10) and dried in h.v. Yield:
1.200 g (76%) of 6a. Pale yellow crystals. M.p. 126.2 127.48. 1H-NMR: 1.10, 1.33 (2s, 2 Me2C); 3.22 (s, Me2N);
3.46 (s, CH2O); 3.90 (br. s, OH); 6.79 (br. s, NH). 13C-NMR: 22.1, 26.3 (2q, 2 Me2C); 41.6 (s, Me2C); 42.4
‡
(q, Me2N); 58.7 (s, Me2C); 70.4 (t, CH2O); 174.1, 177.2 (2s, 2 CO). CI-MS: 231 (68, [M ‡ 1] ), 186 (100).
3-Hydroxy-2,2-dimethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]propanamide (6b). To a soln.
of 4 (806 mg, 6.84 mmol) in dry THF (5 ml), 5b (1.309 g, 7.52 mmol) was added dropwise. The mixture was
stirred at r.t. for 24 h, the solvent was evaporated, and the remaining solid was purified by CC (SiO2, MeOH/
CH2Cl2 1:20) and dried in h.v. Yield: 1.86 g (93%) of 6b. White solid. M.p. 102.8 103.3 8 ([27]: 103.4 1048).
1H-NMR: 1.11, 1.38(2 s, 2 Me2C); 3.28( s, MeN); 3.44 (s, CH2O); 3.90 (br. s, OH); 6.77 (br. s, NH); 7.25 7.45
(m, 5 arom. H). 13C-NMR: 22.2, 26.3 (2q, 2 Me2C); 41.6 (s, Me2C); 43.6 (q, MeN); 58.7 (s, Me2C); 70.4
(t, CH2O); 128.2 (d, 1 arom. CH); 128.4, 129.5 (2d, 4 arom. CH); 144.4 (s, 1 arom. C); 174.1, 177.2 (2s, 2 CO).
3. Cyclizations to 3,3,6,6,10,10,13,13-Octamethyl-1,8-dioxa-4,11-diazacyclotetradecane-2,5,9,12-tetraone
(10). 3.1. Direct Amide Cyclizations. Procedure A. A suspension of 6b (584 mg, 2 mmol) in dry toluene
(100 ml) was heated to 1008, and HCl gas was bubbled through the suspension for 7 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 white
residue was washed with 3 Â 15 ml of CH2Cl2 and dried in h.v. Yield: 267 mg (72%) of 10. White powder. M.p.
299.2 300.48. IR: 3393vs (NH), 2990s, 2977s, 2935m, 1723vs (CˆO), 1673vs (CˆO), 1523vs, 1171vs (CÀO).
1H-NMR ((D7)DMF): 1.12, 1.40 (2s, 2 Me2C each); 4.00 (s, 2 CH2O); 7.64 (s, 2 NH). 13C-NMR ((D7)DMF):
22.1, 24.6 (2q, 2 Me2C each); 41.6, 55.4 (2s, 2 Me2C); 71.3 (t, CH2O); 174.3 (s, CˆO). 13C-NMR ((D6)DMSO):
20.9, 23.2 (2q, 2 Me2C each); 40.4, 54.4 (2s, 2 Me2C); 70.1 (t, CH2O); 173.0, 174.3 (s, CˆO). CI-MS: 388 (34,
‡
‡
‡
[M ‡ NH4] ), 371 (100, [M ‡ 1] ). ESI-MS: 393 (100, [M ‡ Na] ). Anal. calc. for C18H30N2O6 (370.45): C 58.36,
H 8.16, N 7.56; found C 57.94, H 8.18, N 7.47.
Procedure B. A suspension of 6a (230 mg, 1 mmol) in dry toluene (50 ml) was heated to 1008, and HCl gas
was bubbled through the suspension for 3 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 3 Â 10 ml of CH2Cl2, and
the remaining solid was recrystallized from MeCN to yield 60 mg (32%) of 10.
Procedure C. A suspension of 11 (see Sect. 4; 477 mg, 1 mmol) in dry toluene (50 ml) was heated to 1008,
and HCl gas was bubbled through the suspension for 3 min. Workup as described in Procedure A gave 92 mg
(49%) of 10.
3.2. Other Lactonization Methods. 2-[(3-Hydroxy-2,2-dimethylpropanoyl)amino]-2-methylpropanoic Acid
(18). To a soln. of 6b (2.00 g, 7.35 mmol) in THF (10 ml), 3n HCl (10 ml) was added dropwise at 08 under
constant stirring. After 8h at r.t., THF was removed i.v., and the H2O phase was extracted with AcOEt (5 Â
20 ml). The combined org. fractions were dried (MgSO4), and the solvent was evaporated. The remaining
brownish crystals were washed twice with Et2O/PrOH 100 :1. Yield: 1.312 g (92%) of 18. White crystals. M.p.
142.3 143.48 ([27]: 142.8 144.0 8). 1H-NMR ((D6)DMSO): 1.00, 1.35 (2s, 2 Me2C); 3.36 (s, CH2O); 5.00
(br. s, OH); 7.52 (br. s, NH); 12.12 (br. s, COOH).
Procedure D. A soln. of 18 (205 mg, 1 mmol) and I2 (15 mg, 0.06 mmol) in dry MeCN (15 ml) was heated to
reflux for 3 d. After evaporation of the solvent, the residue was washed with 5% Na2S2O3 soln. and extracted
with AcOEt, and the combined org. fractions were dried (MgSO4). Purification by CC yielded 89 mg (49%) of
10 as a white powder.

Helvetica Chimica Acta Vol. 86 (2003)
3229
Procedure E. A soln. of 18 (103 mg, 0.5 mmol) and Bu2SnO (25 mg, 0.1 mmol) in dry xylene (25 ml) was
heated under reflux for 2 d in a DeanÀStark apparatus (N2 atmosphere). Then, the solvent was evaporated i.v.,
the solid residue was washed with Et2O (2 Â 10 ml) and then with warm acetone (5 Â 10 ml). The acetone
fraction was concentrated to 5 ml, cooled, and filtered to yield 36 mg (38%) of 10.
Ethyl 2-[(3-Hydroxy-2,2-dimethylpropanoyl)amino]-2-methylpropanoate (20). A soln. of 6b (584 mg,
2 mmol) in a 10% EtOH soln. in toluene (110 ml) was heated to 1008, and HCl gas was bubbled through the
suspension for 7 min. Then, the mixture was allowed to cool to r.t. while bubbling N2 through it (ca. 20 min). The
solvent was evaporated, and purification by CC (CH2Cl2/acetone 100 :1) yielded 397 mg (86%) of 20. Colorless
oil. 1H-NMR: 1.14 (s, Me2C); 1.28( t, MeCH2O); 1.43 (s, Me2C); 3.53 (d, CH2OH); 4.05 (q, MeCH2O); 6.79
(s, NH). 13C-NMR: 15.6 (q, Me); 22.1, 26.3 (2q, 2 Me2C); 41.6 (s, Me2C); 61.4 (t, CH2O); 69.1 (t, CH2O); 76.8
‡
(s, Me2C); 174.3, 178.6 (2s, 2 CO). ESI-MS: 254 (100, [M ‡ Na] ).
Procedure F. To a soln. of 20 (232 mg, 1 mmol) in dry toluene (5 ml), NaH (40 mg of a 60% suspension in
mineral oil, 1 mmol) was added slowly at 08 and under constant stirring (N2 atmosphere). After 4.5 h at 808, the
mixture was acidified with 0.1n HCl (ca. 6 ml) to pH 5, and extracted with CH2Cl2 and AcOEt. The combined
org. fractions were dried (MgSO4) and evaporated i.v. The crystalline residue was washed with CH2Cl2 to yield
52 mg (28%) of 10.
4. Synthesis of 2-Methyl-2-{N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}propyl 2-[(3-
Hydroxy-2,2-dimethylpropanoyl)amino]-2-methylpropanoate (11).
Methyl 3-Benzyloxy-2,2-dimethylpropanoate (13). To a suspension of NaH (440 mg of a 60% suspension in
mineral oil, 11 mmol) in dry THF (15 ml) methyl 3-hydroxy-2,2-dimethylpropanoate (1.322 g, 10 mmol) was
added dropwise at 08 under constant stirring. The mixture was stirred at r.t. for 1 h, then BzBr (1.710 g,
10 mmol) was added. After heating under reflux for 3 h, the mixture was cooled, washed with brine (2 Â 25 ml),
the brine fractions were extracted with AcOEt, and the combined org. fractions were dried (MgSO4).
Purification by CC (SiO2, hexane/Et2O 10 :1) yielded 1.05 g (47%) of 13. Colorless oil. IR (film): 2976m, 2863m,
1736vs (CˆO), 1475s, 1454s, 1363m, 1308s, 1226s, 1192s, 1152s (CÀO), 1100s (CÀO), 1029m, 738m, 698m.
1H-NMR: 1.37 (s, Me2C); 3.62 (s, CH2O); 3.84 (s, MeO); 4.68( s, PhCH2); 7.40 7.52 (m, 5 arom. H). 13C-NMR:
22.4 (q, Me2C); 43.6 (t, CH2); 51.7 (s, Me2C); 73.1 (q, MeO); 76.9 (t, PhCH2); 127.3, 127.6, 128.2 (3d, 5
.
‡
arom. CH); 138.4 (s, 1 arom. C); 176.8( s, CˆO). EI-MS: 222 (28, M ), 116 (26), 107 (20), 101 (20), 91 (100),
65 (8).
3-Benzyloxy-2,2-dimethylpropanoic Acid (14). To a soln. of 13 (1.00 g, 4.5 mmol) in EtOH (20 ml), 8ml of
2n KOH were added at 08. After 1 h stirring at r.t., the org. solvent was evaporated i.v., and the remaining soln.
was acidified with 1n HCl to pH 1 and extracted with Et2O. The org. fractions were dried (MgSO4) and
evaporated i.v. The residue was recrystallized from hexane. Yield: 830 mg (88%) of 14. White crystals. M.p.
62.1 63.88. IR: 2975m, 2861m, 1707vs (CˆO), 1454s, 1364m, 1163w, 1100s (CÀO), 738m, 698m. 1H-NMR
((D6)DMSO): 1.07 (s, Me2C); 3.42 (s, CH2O); 4.49 (s, PhCH2); 7.25 7.42 (m, 5 arom. H); 12.21 (s, COOH).
13C-NMR ((D6)DMSO): 22.2 (q, Me2C); 40.6 (s, Me2C); 72.3 (t, CH2O); 76.7 (PhCH2); 127.2, 127.3, 128.1
.
‡
(3d, 5 arom. CH); 138.4 (s, 1 arom. C); 177.3 (s, COOH). EI-MS: 208(7, M ), 107 (49), 91 (100), 79 (9), 65 (9).
3-Benzyloxy-2,2-dimethyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]propanamide (15). To a
soln. of 14 (800 mg, 3.85 mmol) in THF (10 ml), a soln. of 5b (670 mg, 3.85 mmol) in THF (2 ml) was added
dropwise. After 24 h, the solvent was removed i.v., and the residue was purified by CC (CH2Cl2/MeOH 40 :1).
Yield: 1.230 g (84%) of 15. White solid. M.p. 105.6 106.88. IR: 3339vs (NH), 2992m, 2956m, 2838m, 1644vs
(CˆO), 1593m, 1253s, 1103s (CÀO), 976w, 753m, 713m, 618w. 1H-NMR: 0.98, 1.31 (2s, 2 Me2C); 3.08
(s, CH2O); 3.14 (s, MeN); 4.31 (s, PhCH2); 6.96 (s, NH), 7.12 7.27 (m, 10 arom. H). 13C-NMR: 22.8, 26.4
(2q, 2 Me2C); 41.2 (q, MeN); 42.5, 57.4 (2s, 2 Me2C); 73.3 (t, CH2O); 76.4 (t, PhCH2); 127.4, 127.5, 127.7, 127.9,
128.3, 129.1 (6d, 10 arom. CH); 137.6, 145.1 (2s, 2 arom. C); 173.2, 175.2 (2s, 2 CˆO). ESI-MS: 405 (100, [M ‡
‡
Na] ).
2-[(3-Benzyloxy-2,2-dimethylpropanoyl)amino]-2-methylpropanoic Acid (16). To a soln. of 15 (1.200 g,
3.14 mmol) in THF (5 ml), 3n HCl (5 ml) was added dropwise at 08. The mixture was left overnight at r.t., the
org. solvent was evaporated i.v., and the residue was extracted with AcOEt. The combined org. fractions were
washed with brine and dried (MgSO4). After evaporation, the crystals were washed with Et2O/hexane 2 :1.
Yield: 818 mg (89%). White crystals. M.p. 109.4 110.28. IR: 3355vs (OH), 2989 2863s (br.), 1717vs (CˆO),
1620vs (CˆO), 1533vs, 1468s, 1397s, 1257s, 1162s, 1162s, 1092vs, 1012m, 930m, 8 29s, 753s, 704m, 693m. 1H-NMR:
1.17, 1.46 (2s, 2 Me2C); 3.44 (s, CH2O); 4.56 (s, PhCH2); 7.31 7.39 (m, 5 arom. H, NH). 13C-NMR: 22.8, 24.8
(2q, 2 Me2C); 42.5, 56.6 (2s, 2 Me2C); 73.6 (t, CH2O); 76.4 (t, PhCH2); 127.6, 127.9, 128.4 (3d, 5 arom. CH); 137.2
‡
(s, 1 arom. C); 177.2, 178.0 (2s, 2 CˆO). CI-MS: 295 (18), 294 (100, [M ‡ 1] ).

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Helvetica Chimica Acta Vol. 86 (2003)
2-Methyl-2-{N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]carbamoyl}propyl 2-[(3-Benzyloxy-2,2-
dimethylpropanoyl)amino]-2-methylpropanoate (17). To a soln. of 16 (1.00 g, 3.41 mmol) in dry THF
(15 ml), 1,1'-carbonyldiimidazole (CDI; 552 mg, 3.41 mmol) was added. After 2 h stirring at r.t., 6b (934 mg,
3.41 mmol) was added, followed by the dropwise addition of a Na-imidazolide suspension (73 mg imidazole,
45 mg of a 60% NaH suspension in mineral oil and 3 ml of THF). After stirring overnight, the org. solvent was
removed i.v., and the residue was purified by CC (CH2Cl2/acetone 60 :1). Yield: 1.276 g (66%) of 17. White solid.
M.p. 114.2 115.88. IR: 3353s (NH), 2980m, 2934m, 2873m, 1739vs (CˆO), 1702m, 1664vs (br., CˆO), 1594s,
1520s, 1494m, 1454m, 1385m, 1382m, 1150vs (CÀO), 1091m, 1023m, 923m, 904m, 738m, 705m. 1H-NMR: 1.13,
1.14 (2s, 2 Me2C); 1.44 (s, 2 Me2C); 3.27 (s, MeN); 3.42 (s, CH2OH); 4.03 (s, CH2O); 4.57 (s, PhCH2); 7.04
(s, NH); 7.21 7.41 (m, 10 arom. H, NH). 13C-NMR: 22.3, 22.9, 24.7, 25.2 (4q, 4 Me2C); 41.4 (q, MeN); 42.5, 42.7,
55.8, 58.3 (4s, 4 Me2C); 70.9 (t, CH2O); 73.5 (t, CH2O); 76.6 (PhCH2); 127.5, 127.7, 128.0, 128.3, 128.3, 129.3
(6d, 10 arom. H); 137.6, 144.3 (2s, 2 arom. C); 173.6, 173.7, 174.0, 175.8(4 s, 4 CˆO). CI-MS: 590 (100, [M ‡
‡
Na] ).
Compound 11. To a soln. of 17 (1.200 g, 2.11 mmol) in dry CH2Cl2 (15 ml), 150 mg of Pd/C were added, and
the mixture was stirred under an H2 atmosphere at r.t. overnight. The suspension was filtered over Celite, and
evaporated i.v. The product was used without further purification. Yield: 901 mg (89%) of 11. White crystals.
M.p. 139.2 140.38. IR: 3358vs (OH), 3281m, 2981m, 2886m, 1746vs (CˆO), 1664vs, 1623vs, 1592s, 1533vs,
1382s, 1264s, 1224m, 1144vs, 1140m, 1062m, 1024w, 78 1m, 708s. 1H-NMR ((D6)DMSO): 0.99, 1.04, 1.31, 1.38
(4s, 4 Me2C); 3.20 (s, MeN); 3.34 (d, 3J ˆ 6, CH2O); 3.91 (s, CH2O); 4.97 (t, 3J ˆ 6, OH); 7.16 7.28( m, 2 ar-
om. H, NH); 7.30 7.40 (m, 3 arom. H); 7.58( s, NH). 13C-NMR ((D6)DMSO): 21.9, 22.1, 24.6, 25.9
(4q, 4 Me2C); 41.6, 42.6, 54.8, 56.4 (4s, 4 Me2C); 67.5, 69.9 (2t, 2 CH2O); 126.3, 127.0, 128.7 (3d, 5 arom. CH);
‡
137.8( s, 1 arom. C); 172.3, 173.6, 173.7, 175.6 (4s, 4 CˆO). ESI-MS: 500 (100, [M ‡ Na] ).
5. Formation of 2-(2-Hydroxy-1,1-dimethylethyl)-4,4-dimethyl-1,3-oxazol-5(4H)-one (19).
Procedure F. A soln. of 18 (103 mg, 0.5 mmol) and N,N'-dicyclohexylcarbodiimide (DCC; 104 mg,
0.5 mmol) in AcOEt (10 ml) was stirred overnight at r.t., then filtered, washed with AcOEt, and the solvent was
evaporated i.v. Recrystallisation of the residue from MeCN yielded 33 mg (36%) of 19 as white crystals. M.p.
128.1 128.88. IR: 3327vs (OH), 2928vs, 2850vs, 1836vs, 1626vs, 1574vs, 1536vs, 1436m, 1311s, 1271m, 1243s,
1088s, 1045m, 8 92m, 641s. 1H-NMR ((D6)DMSO): 1.13, 1.30 (2s, 2 Me2C); 3.41 (d, 3J ˆ 6, CH2OH); 4.91 (t,3J ˆ
6, OH). 13C-NMR ((D6)DMSO): 21.3, 24.2 (2q, 2 Me2C); 64.9, 67.4 (2s, 2 Me2C); 166.6 (s, CˆN); 181.8
‡
‡
(s, CˆO). CI-MS: 204 (100, [M ‡ NH4] ), 186 (30, [M ‡ 1] ), 174 (10), 158(6).
Procedure G. A soln. of 18 (103 mg, 0.5 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (86 mg, 0.5 mmol) in AcOEt (10 ml) was stirred overnight at r.t., then washed with brine, and
extracted with AcOEt. The combined org. fractions were dried (MgSO4), the solvent was evaporated i.v., and
the residue was purified by CC (CH2Cl2/acetone 150 :1). Yield: 26 mg (28%) of 19.
Procedure H. A soln. of 18 (103 mg, 0.5 mmol) and 4-(dimethylamino)pyridine (DMAP; 66 mg, 0.5 mmol)
in CH2Cl2 (10 ml) was stirred for 15 min at r.t. Then, DCC (103 mg, 0.5 mmol) was added. The mixture was left
overnight, then filtered, washed with AcOEt, and the solvent was evaporated i.v. Purification by CC (CH2Cl2/
acetone 150 :1) yielded 42 mg (45%) of 19.
A suspension of 19 (185 mg, 1 mmol) in dry toluene (50 ml) was heated to 1008, and HCl gas was bubbled
through the suspension for 3 min. Workup as described in Procedure A gave 159 mg (86%) of 10.
6. Synthesis and Cyclization of 1-(Ethoxycarbonyl)-1-methylethyl 3-Hydroxy-2,2-dimethylpropanoate (22)
1-(Ethoxycarbonyl)-1-methylethyl 3-Benzyloxy-2,2-dimethylpropanoate (21). To
a soln. of 14 (1.00 g,
3.41 mmol) in dry THF (15 ml), CDI (552 mg, 3.41 mmol) was added, and the mixture was stirred at r.t. for
2 h. Then, methyl 2-hydroxy-2,2-dimethylethanoate (450 mg, 3.41 mmol) was added, followed by the dropwise
addition of 3 ml of a Na-imidazolide suspension (73 mg of imidazole, 45 mg of a 60% NaH suspension in
mineral oil, and 3 ml of THF). After stirring overnight, the org. solvent was removed i.v., and the residue was
purified by CC (CH2Cl2/acetone 100 :1). Yield: 780 mg (48%) of 21. Colorless oil. IR (film): 2983m, 1743vs
1
(CˆO), 1471w, 1383w, 1293m, 1179s (CÀO), 1130s (CÀO), 1028m, 738w, 698w. H-NMR: 1.21 (s ‡ t, Me2C,
MeCH2O); 1.52 (s, Me2C); 3.47 (s, CH2O); 3.76 (q, MeCH2O); 4.52 (s, PhCH2); 7.25 7.32 (m, 5 arom. H).
13C-NMR: 13.9 (q, Me); 22.2, 24.3 (2q, 2 Me2C); 43.4 (s, Me2C); 60.9 (t, MeCH2O); 73.2 (t, CH2O); 76.7
(t, PhCH2); 77.9 (s, Me2C); 127.2, 127.3, 128.1 (3d, 5 arom. CH); 138.5 (s, 1 arom. CH); 172.5, 175.1 (2s, 2 CˆO).
‡
ESI-MS: 345 (100, [M ‡ Na] ).
Compound 22. To a soln. of 21 (900 mg, 2.79 mmol) in dry CH2Cl2 (15 ml), 120 mg of Pd/C were added, and
the mixture was stirred under H2 atmosphere at r.t. overnight. The suspension was filtered over Celite, and
evaporated i.v. The product was used without further purification. Yield: 589 mg (91%) of 22. Colorless oil. IR
(film): 3528w (br.), 2885m, 2939m, 1743vs (CˆO), 1474m, 1296s, 1180m (CÀO), 1128s (CÀO), 1053m, 8 8 w2,

Table. Crystallographic Data of Compounds 6a, 6b, 10, 11, 18, 19, and 23
6a
6b
10
11
18
19
23
Crystallized from
CDCl3/AcOEt/acetone toluene/CH2Cl2/AcOEt CDCl3/MeOH
CH2Cl2/i-PrOH/hexane toluene/acetone/i-PrOH MeCN/acetone/CH2Cl2 CH2Cl2/acetone
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
Z
C
230.31
11H22N2O3
C16H24N2O3
292.38370.44
colorless, prism
0.18 Â 0.20 Â 0.25
160(1)
C18H30N2O6
477.60
colorless, prism
C25H39N3O6
203.24 5.22
colorless, prism
C9H17NO4
18
yellow, plate
C9H15NO3
C15H24O6
]
300.35
yellow, prism
0.12 Â 0.20 Â 0.25
160(1)
monoclinic
P21/c
colorless, prism
0.15 Â 0.15 Â 0.25
160(1)
monoclinic
P21/c
colorless, plate
0.02 Â 0.18 Â 0.23
160(1)
monoclinic
P21/c
0.10 Â 0.12 Â 0.20 0.10 Â 0.12 Â 0.20
0.02 Â 0.15 Â 0.17
160(1)
monoclinic
P21/c
160(1)
monoclinic
P21
160(1)
monoclinic
P21/n
4
triclinic
≈
P1
4
4
2
2
8
8
Reflections for cell determination
3944
9546
2273
3173
2004
3721
5976
2q Range for cell determination [8]
4
60
2
60
4
55
4
55
4
50
4
50
4 50
Unit cell parameters a [ä]
8.6612(1)
10.4339(2)
14.4276(2)
90
100.5340(6)
90
1281.85(3)
1.193
0.0863
8.9268(1)
11.9930(1)
16.4091(2)
99.0727(5)
92.8174(5)
108.5531(6)
1635.33(3)
1.187
9.1635(2)
9.6501(2)
10.8786(3)
90
103.3648(8)
90
935.93(4)
1.314
0.0981
f and w
55
9.3227(2)
11.1213(2)
12.8333(3)
90
99.6690(9)
90
1311.66(5)
1.209
0.0861
f and w
55
8.2708(2)
8.2429(2)
15.7690(4)
90
98.9548(9)
90
1061.95(5)
1.271
0.0992
w
11.7684(5)
10.5276(4)
16.1536(8)
90
90.464(2)
90
2001.3(2)
1.229
0.0918
f and w
50
9.8304(1)
11.9228(2)
27.7139(5)
90
97.1582(6)
90
3222.92(9)
1.238
0.0948
f and w
50
b [ä]
c [ä]
a [8]
b [8]
g [8]
V [ä3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.0820
f and w
60
f and w
60
2q(max) [8]
50
Total reflections measured
Symmetry independent reflections 3749
36257
68555
9576
21539
2140
32002
3177
14054
1859
30962
3521
51446
5680
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
30386579
3749
160
1713
21181330
1713
119
2425
1
398
6579
396
3176
329
1330
139
3521
252
5677
392
R [onF; I > 2s(I) reflections]
wR [onF; I > 2s(I) reflections]
wR [onF2; all indept. reflections]
0.0432
0.0500
0.0496
0.0412
0.0447
0.0410
0.0411
0.0379
0.0570
0.0436
0.1204
0.0965
0.1556
0.1120
a
Weighting parameter [p] )
Weighting parameters [a; b] )
0.005
0.005
0.005
1.865
0.0002
b
0.0527; 0.3914
1.046
0.029(5)
0.001
0.0436; 0
0.995
0.025(3)
0.001
0.0585; 0.9613
1.090
0.011(2)
0.001
0.0552; 0.1627
1.037
0.0036(6)
0.001
Goodness-of-fit
2.870
2.901
Secondary extinction coefficient
Final Dmax/s
2.7(3) Â 10À6
3.9(8) Â 10À6
0.0004
0.0004
D1 (max; min) [e äÀ3
]
0.34; À 0.36
0.28; À 0.22
0.25; À 0.20
0.18; À 0.19
0.18; À 0.21
0.22; À 0.22
0.20; À 0.21
b
a) wÀ1 ˆ s2(Fo) ‡ (pFo)2. ) wÀ1 ˆ s2(Fo2 ) ‡ (aP)2 ‡ bP where P ˆ (Fo2 ‡ 2F2c )/3.

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Helvetica Chimica Acta Vol. 86 (2003)
758w, 670w. 1H-NMR: 1.11 (s, Me2C); 1.22 (t, MeCH2O); 1.53 (2s, 2 Me2C); 3.53 (d, CH2OH); 4.13
(q, MeCH2O). 13C-NMR: 13.8( q, Me); 21.5, 24.4 (2q, 2 Me2C); 44.3 (s, Me2C); 61.3 (t, MeCH2O); 70.0
‡
(t, CH2O); 78.5 (s, Me2C); 172.6, 176.1 (2s, 2 CˆO). ESI-MS: 255 (100, [M ‡ Na] ).
3,3,7,7,11,11-Hexamethyl-1,5,9-trioxacyclododecane-2,6,10-trione (23) and 3,3,7,7,11,11,15,15-Octamethyl-
1,5,9,13-tetraoxacyclohexadecane-2,6,10,14-tetraone (24). To a soln. of 22 (232 mg, 1 mmol) in dry toluene
(5 ml), NaH (40 mg of a 60% suspension in mineral oil, 1 mmol) was added slowly at 08 and under constant
stirring (N2 atmosphere). After 5 h at 808, the mixture was acidified with 0.1n HCl (ca. 6 ml) to pH 5 and
extracted with CH2Cl2 . The combined org. fractions were dried (MgSO4) and evaporated i.v. The crystalline
residue was purified by CC (CH2Cl2/acetone 200 :1) to yield 24 mg (8%) of 23. (M.p. 132.1 134.28) [57] and
38mg (9.5%) of 24. M.p. 1446. 146.08) [57].
7. X-Ray Crystal-Structure Determination of 6a, 6b, 10, 11, 18, 19, and 23 (Table and Figs. 1 5)3). All
measurements were made on a Nonius KappaCCD diffractometer [58] with graphite-monochromated MoKa
radiation (l 0.71073 ä) and an Oxford Cryosystems Cryostream 700 cooler. The data collection and refinement
parameters are given in the Table and views of the molecules are shown in Figs. 1 5. Data reductions were
performed with HKL Denzo and Scalepack [59]. The intensities were corrected for Lorenz and polarization
effects, but not for absorption. The structures were solved by direct methods using SIR92 [60], which revealed
the positions of all non-H-atoms. There were two symmetry-independent molecules in the asymmetric units of
6b, 19, and 23. In each case, the atomic coordinates of the two molecules were tested carefully for a relationship
from a higher symmetry space group with the program PLATON [61], but none could be found. The non-H-
atoms were refined anisotropically. Except for 10, the amide and OH H-atoms in the structures were placed in
the positions indicated by difference-electron-density maps, and their positions were allowed to refine together
with individual isotropic displacement parameters. 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 of 6a, 11, 19, and 23). For 6b, 10, and 18,
each structure was refined on F using full-matrix least-squares procedures, which minimized the function
Sw(j Fo jÀj Fc j )2. Refinement of the remaining structures was carried out on F2 by minimizing the
corresponding function based on F2. Corrections for secondary extinction were applied with the exception of
18. In 6b, 10, 11, 18, and 23, six, two, one, three, and three reflections, respectively, were omitted from the final
refinement of each structure because their observed intensities were much lower than the calculated values as a
result of being partially obscured by the beam stop. Neutral-atom scattering factors for non-H-atoms were taken
from [62a] and the scattering factors for H-atoms were taken from [63]. Anomalous dispersion effects were
included in Fc [64]; the values for f ' and f '' were those of [62b]. The values of the mass attenuation coefficients
are those of [62c]. All calculations were performed using the teXsan crystallographic software package [65] for
6b, 10, and 18, and the SHELXL97 program [66] for 6a, 11, 19, and 23.
REFERENCES
[1] H. Vervoort, W. Fenical, R. de Epifanio, J. Org. Chem. 2000, 65, 782.
[2] N. Sitachitta, R. T. Williamson, W. H. Gerwick, J. Nat. Prod. 2000, 63, 197.
[3] F. D. Horgen, D. B. de los Santos, G. Goetz, B. Sakamoto, Y. Kan, H. Nagai, P. J. Scheuer, J. Nat. Prod. 2000,
63, 152.
[4] K. Fujii, K. Sivonen, E. Naganawa, K. Harada, Tetrahedron 2000, 56, 725.
[5] G. N. Belofsky, P. R. Jensen, W. Fenical, Tetrahedron Lett. 1999, 40, 2913.
[6] A. K. Gosh, A. Bischoff, Org. Lett. 2000, 2, 1573.
¬
[7] F. Sarabia, S. Chammaa, F. J. Lopez-Herrera, Tetrahedron Lett. 2002, 43, 2961.
[8] J. Hong, L. Zhang, Frontiers of Biotechnology & Pharmaceuticals 2002, 3, 193.
[9] K. Brockmann, G. Schmidt-Kastner, Chem. Ber. 1955, 88, 57.
3
)
CCDC-210670-210676 contain supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB12 1EZ, UK (fax : ‡44-(0)1223-336033; e-mail:
deposit@ccdc.cam.ac.uk))

Helvetica Chimica Acta Vol. 86 (2003)
3233
[10] M. M. Shemyakin, N. A. Aldanova, R. I. Vinogradova, V. Y. Feigina, Tetrahedron Lett. 1963, 28, 1921.
[11] B. C. Pressman, E. J. Harris, W. S. Jagger, J. N. Johnson, Proc. Natl. Acad. Sci. U.S.A. 1967, 58, 1949.
[12] Y. A. Ovchinnikov, V. T. Ivanov, A. V. Evstratov, I. I. Mikhaleva, V. F. Bystrov, S. L. Portnova, T. A.
Balashova, E. N. Meshcheryakova, V. M. Tul×chinskii, Int. J. Pept. Protein Res. 1974, 6, 465.
[13] B. C. Pressman, Ann. Rev. Biochem. 1976, 45, 501.
[14] A. M. Sefler, M. C. Kozlowski, T. Guo, P. A. Bartlett, J. Org. Chem. 1977, 62, 93.
[15] Y. L. Dory, J. M. Mellor, J. F. McAleer, Tetrahedron Lett. 1996, 52, 1343.
[16] T. Imaeda, Y. Hamada, T. Shioiri, Tetrahedron Lett. 1994, 35, 591.
[17] K. W. Li, J. Wu, W. Xing, J. A. Simpson, J. Am. Chem. Soc. 1996, 118, 7237.
[18] Y. Hirai, K. Yokota, T. Momose, Heterocycles 1994, 39, 603.
[19] S. Cerini, E. Gavuzzo, G. Luisi, F. Pinnen, Int. J. Pept. Protein Res. 1993, 41, 282.
[20] T. K. Chakraborty, S. Ghosh, S. Dutta, Tetrahedron Lett. 2001, 42, 5085.
[21] M. Eggen, S. K. Nair, G. I. Georg, Org. Lett. 2001, 3, 1813.
[22] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1984, 67, 526.
[23] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1987, 70, 329.
[24] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1990, 73, 221.
[25] J. M. Villagordo, H. Heimgartner, Helv. Chim. Acta 1997, 80, 748.
[26] K. N. Koch, A. Linden, H. Heimgartner, Helv. Chim. Acta 2000, 83, 233.
[27] K. N. Koch, A. Linden, H. Heimgartner, Tetrahedron 2001, 57, 2311.
[28] H. Heimgartner, F. S. Arnhold, S. P. Fritschi, K. N. Koch, J. E. F. Magirius, A. Linden, J. Heterocycl. Chem.
1999, 36, 1539.
[29] A. Linden, F. Ghorbani-Salman Pour, R. A. Breitenmoser, H. Heimgartner, Acta Crystallogr., Sect. C 2001,
57, 634.
[30] K. N. Koch, H. Heimgartner, Helv. Chim. Acta 2000, 83, 18 8 1.
[31] H. Heimgartner, Angew. Chem., Int. Ed. 1991, 30, 238.
[32] C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1995, 78, 935; C. B. Bucher, H. Heimgartner,
Helv. Chim. Acta 1996, 79, 1903.
[33] R. Luykx, C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1996, 79, 527.
[34] G. Suter, S. Stoykova, A. Linden, H. Heimgartner, Helv. Chim. Acta 2000, 83, 2961.
[35] K. Brun, A. Linden, H. Heimgartner, Helv. Chim. Acta 2002, 85, 3422; K. Brun, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2001, 84, 1756 1777.
[36] R. A. Breitenmoser, T. R. Hirt, R. T. N. Luykx, H. Heimgartner, Helv. Chim. Acta 2001, 84, 972.
[37] P. Wipf, H. Heimgartner, Helv. Chim. Acta 1990, 73, 13.
[38] N. Pradeille, H. Heimgartner, J. Pept. Sci. 2003, in press.
[39] W. Altherr, Ph.D. Thesis, Universit‰t Z¸rich, 1994.
[40] R. T. N. Luykx, Ph.D. Thesis, Universit‰t Z¸rich, 2000.
[41] C. K. Johnson, −ORTEP II×, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge, Tennessee,
1976.
[42] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem., Int. Ed. 1995, 34, 1555.
[43] N. M. Mawad, F. Ghorbani-Salman Pour, A. Linden, H. Heimgartner, in preparation.
[44] K. C. Nicolaou, Tetrahedron 1977, 33, 683.
[45] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1976, 52, 1989.
[46] E. J. Corey, K. C. Nicolaou, J. Am. Chem. Soc. 1974, 96, 5614.
[47] T. Mukaiyama, M. Usui, K. Saigo, Chem. Lett. 1976, 49.
[48] M. Hikota, H. Tone, K. Horita, O. Yonemitsu, J. Org. Chem. 1990, 55, 7.
[49] G. E. Keck, E. P. Boden, M. R. Wiley, J. Org. Chem. 1989, 54, 896.
[50] Y. Kuroki, K. Ishihara, N. Hanaki, S. Ohara, H. Yamamoto, Bull. Chem. Soc. Jpn. 1998, 71, 1221.
[51] K. Steliou, A. Szczygielska-Nowosielska, A. Farve, M. A. Poupart, S. Hanessian, J. Am. Chem. Soc. 1980,
102, 7578.
[52] K. R. Buszek, Y. Jeong, N. Sato, P. C. Still, P. L. Muino, I. Ghosh, Synth. Commun. 2001, 31, 1781.
[53] K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J. Am. Chem. Soc. 1995, 117, 4413.
[54] B. M. Trost, J. D. Chisholm, Org. Lett. 2002, 4, 3743.
[55] T. Fujita, N. Hanyu, T. Mino, M. Sakamoto, Synthesis 2001, 12, 1846.
¬
√
[56] S. Richard, G. Prie, A. Guignard, J. Thibonnet, J.-L. Parrain, A. Duchene, M. Abarbri, Helv. Chim. Acta
2003, 86, 726.
[57] A. Matuszowicz, Z. Jedlinski, M. Gawron, Z. Kosturkiewicz, J. Org. Chem. 1995, 60, 6826.

3234
Helvetica Chimica Acta Vol. 86 (2003)
[58] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[59] Z. Otwinowski, W. Minor, in −Methods in Enzymology×, Vol. 276, −Macromolecular Crystallography×,
part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[60] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, SIR92, J.
Appl. Crystallogr. 1994, 27, 435.
[61] A. L. Spek, PLATON, J. Appl. Crystallogr. 2003, 36, 7.
[62] a) E. N. Maslen, A. G. Fox, M. A. O×Keefe, in −International Tables for Crystallography×, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh, W. J.
McAuley, in −International Tables for Crystallography×, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in −International Tables for
Crystallography×, Ed. A. J. C. Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3,
p. 200.
[63] R. F. Steward, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[64] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 78 1.
[65] teXsan: Single Crystal Structure Analysis Software, Version 1.10, Molecular Structure Corporation, The
Woodlands, Texas, 1999.
[66] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of Gˆttingen,
Germany, 1997.
Received May 22, 2003