Synthesis of the four stereoisomers of 1-amino-2-(hydroxymethyl)-cyclobutanecarboxylic acid and their biological evaluation as ligands for the glycine binding site of the NMDA receptor

Article abstract of DOI:10.1002/ejoc.200200673

A synthesis of all four stereoisomers [{1S,2S)-, {1R,2R)-, (1S,2R)-, (1R,2S)-] of 1-amino-2-(hydroxymethyl)cyclobutanecarboxyclic acid is presented. The synthesis is based on the chiral glycine equivalent 1, employed in both enantiomeric forms. The key step involves the cyclization of the silyl-protected iodohydrins 5a-d to the corresponding spiro derivatives 6a-d with the aid of the phosphazenic base tBu-P₄. The final compounds were found to display moderate potency as ligands for the glycine binding site of the NMDA receptor. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200200673

FULL PAPER
Synthesis of the Four Stereoisomers of 1-Amino-2-(hydroxymethyl)-
cyclobutanecarboxylic Acid and Their Biological Evaluation as Ligands for the
Glycine Binding Site of the NMDA Receptor
Claus-Jürgen Koch,[a] G. Höfner,[a] Kurt Polborn,[b] and Klaus Theodor Wanner*[a]
Dedicated with the best wishes to Prof. Gotthard Wurm on the occasion of his 65th birthday
Keywords: Amino acids / Aminocyclobutanecarboxyclic acid derivatives / Asymmetric synthesis / Glycine equivalent /
NMDA receptor
A synthesis of all four stereoisomers [(1S,2S)-, (1R,2R)-,
atives 6a−d with the aid of the phosphazenic base tBu-P4.
(1S,2R)-, (1R,2S)-] of 1-amino-2-(hydroxymethyl)cyclobu- The final compounds were found to display moderate po-
tanecarboxyclic acid is presented. The synthesis is based on tency as ligands for the glycine binding site of the NMDA re-
the chiral glycine equivalent 1, employed in both enantiom-
ceptor.
eric forms. The key step involves the cyclization of the silyl-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
protected iodohydrins 5a−d to the corresponding spiro deriv- Germany, 2003)
1. Introduction
quaternary carbon and so the compound may be subjected
repeatedly to deprotonation for alkylation reactions with-
out the risk of racemization.
1-Aminocycloalkanecarboxylic acids, especially those
with three-, four-, or five-membered rings, have attracted
much attention, which may be regarded as a result of the
particular conformational characteristics to which they give
rise when incorporated in peptides.[1,2] Although numerous
asymmetric syntheses of 1-aminocyclopropane- and 1-ami-
nocyclopentanecarboxylic acids have been developed, no
asymmetric syntheses of 1-aminocyclobutanecarboxyclic
acids are yet known, according to a recent review and to
the best of our knowledge.[3] Moreover, only a few racemic
syntheses of 1-aminocyclobutanecarboxylic acids have been
published,[4Ϫ6] this being indicative of the unfavorable situ-
ation in four-membered ring syntheses with respect both to
small-angle strain and to entropy.
As part of a study directed towards the development of
new ligands for the glycine site of the NMDA-receptor
complex we have recently performed the asymmetric syn-
theses of 1-aminocyclopropanecarboxyclic acid derivatives,
based on the chiral glycine equivalent 1 (Figure 1).[7] This
compound is especially useful for the construction of α,α-
disubstituted amino acids, as the chirality in 1 arises from a
Figure 1. Chiral glycine equivalent for the synthesis of disubstituted
amino acids
Together with 1-aminocyclopropanecarboxylic acid, 1-
aminocyclobutanecarboxylic acid[8] (9) is also well known
as a ligand for the glycine site of the NMDA receptor, so
derivatives of this amino acid 9 were of great interest to us.
We now present an asymmetric synthesis of the four
stereoisomeric 1-amino-2-(hydroxymethyl)cyclobutanecar-
boxylic acids 8a/b and (ent)-8a/b and the biological evalu-
ation of these compounds as ligands for the glycine binding
site of this receptor.
2. Results and Discussion
[a]
Department für Pharmazie, Zentrum für Pharmaforschung,
Ludwig-Maximilians-Universität München,
Butenandtstr. 5Ϫ13, Haus C, 81377 München, Germany
Fax: (internat.) ϩ 49(0)89/2180-77247
2.1 Synthesis of the Four Stereoisomeric 1-Amino-
2-(hydroxymethyl)cyclobutanecarboxylic Acids 8a/b and
(ent)-8a/b
E-mail: klaus.wanner@cup.uni-muenchen.de
[b]
Department für Chemie, Ludwig-Maximilians-Universität
Our synthetic approach commenced with the chiral gly-
cine equivalent 1, which is available in both enantiomeric
München, Butenandtstr. 5Ϫ13, Haus F, 81377 München,
Germany
Eur. J. Org. Chem. 2003, 2233Ϫ2242
DOI: 10.1002/ejoc.200200673
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2233

C.-J. Koch, G. Höfner, K. Polborn, K. T. Wanner
FULL PAPER
forms, (R)-1 (Figure 1) and (S)-1. This is a major advan- peared to be poor and, furthermore, the side product 2c
tage, as it allows the synthesis of both enantiomers of a was also found in all cases. Finally, the best results were
target compound simply by performing enantiomorphic obtained when sBuLi was used for the deprotonation and
synthetic sequences. This feature was also utilized in the but-3-enyl triflate (generated in situ) was employed as alkyl-
current study, to accomplish the synthesis of the stereoiso- ating agent. In this case the yield of 2a/2b rose to almost
mers 8a/b and of their enantiomers (ent)-8a/b.
70%, the diastereoselectivity remained as high as that seen
Various synthetic concepts were used for the construction for the previously described reaction with tBu-P4 (ds,
of the spirocyclic derivatives 7aϪd, which were intended to 95.5:4.5), and, most interestingly, the reaction product was
function as direct precursors for the desired amino acids. now devoid of the undesired by-product 2c (Scheme 1).
Treatment of 1 with 1,3-biselectrophiles to establish the de-
sired ring system was considered to be one of the most di-
rect approaches. The introduction of a but-3-enyl side chain
in the 3-position of 1 also seemed quite promising, as a
double bond would also easily allow a functional group
suitable for ring closure to be established.
As various attempts at the double alkylation of (R)-1
with appropriately substituted 1,3-biselectrophiles did not
meet with any success, we turned our attention to the se-
cond route, based on the introduction of a butenyl side
Scheme 1. Alkylation of (R)-1; reagents and conditions see Table 1
chain.
Next, the terminal double bond of the butenyl side chain
The first series of reactions was performed with 4-bromo- in 2a/2b had to be transformed into a functional unit suit-
but-1-ene as alkylating agent. When (R)-1 was treated at able for the desired ring closure. To this end, the dia-
Ϫ78 °C with sBuLi, followed by 4-bromobut-1-ene and NaI stereomeric mixture 2a/2b was treated with a catalytic
(to increase the reactivity), the desired product was ob- amount of OsO4 in combination with ONMe3 as a co-oxi-
tained, but in poor yield (2a ϩ 2b ϭ 15%, see Table 1) and dant to convert the double bond into a diol. Although the
with low diastereoselectivity (2a/2b ϭ 75:25). Interestingly, overall yield was good (76%), surprisingly, a mixture of the
significant amounts of the double alkylation product 2c four diastereomeric dihydroxy derivatives 3aϪ3d was
1
were also isolated, indicating that the intermediate lithium formed in a ratio of ca. 4:4:1:1 (determined by H NMR),
enolate had undergone some aggregate formation. There- indicating that epimerization at the 3-position of the oxa-
fore, to attenuate this aggregate formation in further experi- zine ring must have occurred. The cause of this isomeriz-
ments, LiN[Si(CH3)3]2, NaN[Si(CH3)3]2 and KN[Si(CH3)3]2} ation is most probably NMe3 generated during the dihy-
were employed in combination with appropriate crown droxylation reaction. As the mixture of diastereomers
ethers (see Table 1) for the deprotonation step.
3aϪ3d appeared to be hardly separable by chromatography
When the thus generated enolates of (R)-1 were sub- and as there was no need for the pure stereoisomers, the
sequently treated with the electrophile, the results were product was used unchanged for the subsequent reactions.
again disappointing. The yield and the diastereoselectivity In the next step the primary hydroxy group present in
for 2a/2b were still poor (see Table 1, yield ഠ 20%, ds ഠ 3aϪ3d was selectively protected[12,13] as a tert-butyldimeth-
70:30) and, moreover, the amount of the undesired doubly ylsilyl ether by use of tBuMe2SiCl, imidazole, and DMAP,
alkylated product 2c had even increased (13Ϫ29%). When producing 4aϪ4d in a yield of 88%. Then, on treatment of
the phosphazenic base tBu-P4 {tBuNϭP[NϭP(NMe2)3]3} 4aϪ4d with PPh3, iodine, and imidazole for selective re-
was used for deprotonation, however, a clear improvement placement of the secondary hydroxy group with
in the results occurred.[9Ϫ11] The yield of 2a/2b rose to 60% iodide,[14Ϫ16] the desired silylprotected iodohydrins 5aϪ5d
and the diastereoselectivity to 96.5:3.5 (ds). As a major were obtained in high yield (90%). During these two steps
drawback, though, the reproducibility of this reaction ap- (the syntheses of 4aϪ4d and of 5aϪ5d) the ratio of stereo-
Table 1. Alkylation of (R)-1
Yield (%)
2a ϩ 2b / 2c
ds
2a / 2b
Base
Electrophile
Additives
Temperature
sBuLi
BrCH2CH2CHϭCH2
BrCH2CH2CHϭCH2[a]
BrCH2CH2CHϭCH2
BrCH2CH2CHϭCH2
BrCH2CH2CHϭCH2
TfOCH2CH2CHϭCH2
NaI
Ϫ80 °C Ǟ 0 °C
Ϫ80 °C Ǟ 10 °C
Ϫ50 °C
15/7
ഠ 75:25[b]
ഠ 70:30[b]
ഠ 70:30[b]
ഠ 70:30[b]
96.5:3.5[c]
95.5:4.5[c]
LiN[Si(CH3)3]2
NaN[Si(CH3)3]2
KN[Si(CH3)3]2
tBu-P4
12-crown-4
15-crown-5
18-crown-6
Ϫ
23/29
15/13
13/17
60/13
69/Ϫ
Ϫ80 °C Ǟ Ϫ50 °C
Ϫ80 °C
sBuLi
Ϫ
Ϫ80 °C
[a]
[b]
1
[c]
DME was used as solvent instead of THF.
cal HPLC.
Selectivity determined by H NMR spectroscopy. Selectivity determined by analyti-
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Synthesis of the Four Stereoisomers of 1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic Acid
1
FULL PAPER
isomers remained unchanged (ഠ 4:4:1:1, determined by H
A stereomodel for alkylation reactions of 1 has been pro-
NMR). Finally, as the crucial step of our synthesis, the posed. According to this, the tert-butyl group, by shielding
cyclization of 5aϪ5d to 6aϪ6d had to be performed. This one face of the oxazine moiety, causes the electrophile to
was expected to be tedious, as a sterically strongly encum- approach the molecule from the opposite side.[7] The results
bered secondary iodide Ϫ beside a CH2OSiMe2tBu group both for the alkylation reaction of (R)-1 (Ǟ 2a/2b) and for
Ϫ was involved. In addition, to the best of our knowledge, the cyclization reaction of 5aϪd (Ǟ 6a؊d) proceeded with
no precedence for related cyclization reactions to cyclo- the same sense of asymmetric induction and in line with the
butanes exists. In order to generate a highly reactive enolate, model described above. Furthermore, the diastereoselec-
phosphazenic base tBuP4 was chosen for the deprotonation tivity found for the butenylation reaction was quite pleasing
reaction.[9Ϫ11] Upon treatment of 5aϪ5d with this base (for (Ͼ 95:5, see Table 1), whereas the selectivity for the cycliza-
three hours at Ϫ80 °C in DME/THF, 5:1) the desired cycli- tion reaction was far less satisfying (ഠ 8:2, determined from
zation indeed occurred and a mixture of the four dia- the ratios observed for 6aϪd and 7a-d). It seems likely that
stereomeric spirocyclic compounds 6aϪ6d was isolated. The the stereoselectivity observed in the spirocyclization (stereo-
ratio of the diastereomers amounted to ഠ 45:35:15:5 and chemistry at C-4) arises mainly from the asymmetric induc-
the total yield to 72%.
tion caused by the chiral auxiliary and that the chiral center
Scheme 2. Synthesis of the stereoisomeric 1-aminocyclobutanecarboxylic acids 8a/b and (ent)-8a/b
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Eur. J. Org. Chem. 2003, 2233Ϫ2242
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2235

C.-J. Koch, G. Höfner, K. Polborn, K. T. Wanner
FULL PAPER
located in the side chain of 5aϪd has only a minor influ-
ence.
The removal of the silyl protective group was ac-
complished by treatment of 6aϪ6d with tetrabutylam-
monium fluoride. The resulting crude product was sepa-
rated by preparative HPLC, providing 7aϪ7d each as a sin-
gle isomer in a ratio of 48:31:18:3 (7a/7b/7c/7d) and in a
total yield of 81% (see Scheme 2).
For evaluation of the biological activity, the whole set of
stereoisomeric amino acids 8a, 8b, (ent)-8a, and (ent)-8b
was required. However, the minor diastereomers 7cϪ7d, as
precursors to (ent)-8a and (ent)-8b, were available only in
small amounts. The whole synthetic sequence described so
far was therefore also performed with the enantiomeric gly-
cine equivalent (S)-1, to afford the enantiomeric spirocyclic
compounds (ent)-7a, (ent)-7b, (ent)-7c, and (ent)-7d. The
chemical yields and diastereoselectivities for each step in
this sequence corresponded well to those described above.
In the final step for each of the two enantiomorphic
series, the two major diastereomers [7a and 7b, and (ent)-
7a and (ent)-7b] had to be hydrolyzed to provide the free
amino acids. This was accomplished in a two-step se-
quence,[7] by application first of aqueous TFA for the cleav-
age of the lactim ether function and then of a NaOH solu-
tion for the hydrolysis of the ester group. Thus, after purifi-
cation by ion-exchange chromatography on an acidic ion-
exchange resin (DOWEX 50Wx8), the four desired 1-
aminocyclobutanecarboxylic acids 8a, 8b, (ent)-8a, and
(ent)-8b were obtained in yields between 70 and 80%
(Scheme 2).
Figure 2. X-ray structure of 7a
2.2 Assignment of the Stereochemistry to 7a؊7d, 8a, 8b,
(ent)-8a, and (ent)-8b
The stereochemical assignment started with the spiro-
cyclic derivative 7a, which, having formed crystals, was sub-
jected to an X-ray diffraction analysis.[17] From the results
of this analysis and by taking into account the absolute
configuration of the chiral auxiliary present in 7a (exhibit-
ing R configuration), the stereocenters at C-1 and C-4 of
7a must be of S stereochemistry.
With the stereochemistry for 7a being known, the abso-
lute configurations of the remaining stereoisomers could be
determined. This was accomplished mainly with the aid of
NOE measurements carried out on 7aϪ7d. Irradiation of
the signal of the tert-butyl group (δ ഠ 1.00 ppm) of the
diastereomers 7aϪ7b resulted in each case in an enhance-
Figure 3. NOEs observed for the stereoisomers 7aϪd
As 7c and 7d were diastereomers of 7a and 7b, all orig-
ment of the signals arising from the protons in the 3-posi- inating from the same chiral glycine equivalent (R)-1, their
tion (7a, 4.0 and 2.6%; 7b, 3.4 and 1.5%; see Figure 3). Al- stereochemistry at C-4 and at C-7 had to be as indicated,
though this was to be expected for 7a, because of the stereo- except that the configuration at C-1 was still unresolved. To
chemistry found by the X-ray analysis presented above, it provide this missing information, which was only a question
also demonstrated that 7b could differ from 7a only in the of the relative stereochemistry, 7c was hydrolyzed to the free
1
stereochemistry at C-1 and so must therefore possess the amino acid (ent)-8a. The H NMR spectrum of this amino
stereochemistry shown. These results were fully supported acid (ent)-8a was identical with that of 8a derived from 7a.
by NOE measurements performed with the remaining dia- Therefore, the hydroxymethyl group and the imidate func-
stereomers 7cϪ7d. For these, upon activation of the tert- tion in 7c, and also in (ent)-7c, must be located trans to
butyl group, enhancement of H-1 and of the protons of the one another with respect to the cyclobutane ring. As a
exocyclic methylene group was seen in both cases (Fig- consequence, 7c and 7d, and the same is of course true for
ure 3).
(ent)-7c and (ent)-7d, must have the stereochemistry as indi-
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Synthesis of the Four Stereoisomers of 1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic Acid
FULL PAPER
Table 2. Potency of 8a, 8b, (ent)-8a, and (ent)-8b, together with reference compound 9, at the glycine binding site of the NMDA receptor
[a]
Means Ϯ standard error of the mean from three independent experiments each carried out in triplicate.
cated (see Scheme 2 and Figure 3). Of course, the stereo- site of the NMDA receptor, but the potencies displayed by
chemistry of the final products, the 1-aminocyclobutane- these derivatives were lower than the affinity exhibited by
carboxylic acids, had also become evident from this assign- the parent compound 9. So far this method has been used
ment.
for the preparation of the free amino acids 8a, 8b, (ent)-8a,
and (ent)-8b, but it should also easily provide access to re-
lated amino acids with different substituents in the 2-posi-
tion of the cyclobutane ring. Further studies in this direc-
tion are underway.
3. Biological Test Results
The amino acids 8a, 8b, (ent)-8a, and (ent)-8b were evalu-
ated for their in vitro activity on the glycine binding site of
the NMDA receptor by a radioreceptor assay.[18] The bind-
ing affinities were determined on pig cortical brain mem-
branes with [3H]MDL 105,519 as a specific ligand.
5. Experimental Section
5.1 General Procedure
As a reference compound, 1-aminocyclobutanecarboxylic
acid (9) was included in this process.[19] As depicted in
Table 2, the derivatives 8a, 8b, (ent)-8a, and (ent)-8b ap-
peared to be distinctly less potent than the parent com-
pound 9. Moreover, the potencies of compounds 8a, 8b,
(ent)-8a, and (ent)-8b were only weakly influenced by their
stereochemistry. It should be noted, though, that the two
most potent stereoisomers Ϫ 8a and 8b Ϫ have the same
configuration at C-1 of the cyclobutane ring. Accordingly,
the stereochemistry at this stereocenter has a greater effect
on the potencies of these compounds than that at C-2.
Compounds 8b and (ent)-8b were also evaluated for their
ability to modulate [3H]MK-801 binding under non-equilib-
rium conditions. The two compounds 8b and (ent)-8b gave
rise to a distinct increase in binding of [3H]MK-801, indicat-
ing that these derivatives are partial or possibly even full
agonists.
All experiments were carried out in oven-dried glassware under dry
N2 atmosphere. Standard vacuum techniques were used for the
handling of air-sensitive materials. Solvents were dried and kept
under N2 and freshly distilled before use. Reagents were used as
commercially available. Solvents used for HPLC were degassed
prior to use. For the ion exchange chromatography doubly distilled
H2O was used; the NH3 solution was freshly prepared prior to use
by bubbling NH3 through bidest H2O. The phosphate buffer (pH ϭ
7) was prepared by dissolving NaH2PO4·H2O (12.17 g) and
Na2HPO4·2 H2O (21.35 g) in H2O (200 mL). M.p. (uncorrected
values): Melting point apparatus Electrothermal IA9100. Optical
1
rotation: Polarimeter 241 MC (PerkinϪElmer). H NMR spectra:
J NMR-GX 400 (400 MHz, Jeol) and J NMR-GX 500 (500 MHz,
Jeol), chemical shifts (δ) in ppm, TMS as internal standard. IR:
FT-IR spectrometer Paragon 1000 (PerkinϪElmer, Software Spec-
trumTM), liquids were recorded as films, solids as KBr pellets. MS:
5989 A mass spectrometer with 59980 B particle beam LC/MS in-
terface (HewlettϪPackard). Combustion analysis: Elementarana-
lysator Vario EL. Column chromatography (CC): Flash chroma-
tography on silica gel (Merck Si60 0.040Ϫ0.063 mm). TLC: Merck
Si60 F-254, detection with UV (λ ϭ 254 nm) or with ammonium
cerium()heptamolybdate [5% (NH4)xMo7O24 and 0.2% Ce(SO4)2,
dissolved in 400 mL of a 5% H2SO4 solution]. Analytical HPLC;
Pump: L-6200 intelligent-pump (MerckϪHitachi) or L-7100
(MerckϪHitachi). UV/Vis detectors: L-7400 (MerckϪHitachi); In-
tegrators: D-2500 (MerckϪHitachi) or D-7500 (MerckϪHitachi),
Software MerckϪHitachi HSM D-7000 (PC); Columns: LiChro-
Cart with LiChrospher Si 60 cartridge (5 µm, 250 ϫ 4 mm with
precolumn 4 ϫ 4 mm, Merck). Preparative HPLC; Pump: L-6000
(MerckϪHitachi), UV/Vis detectors: L-4000 (MerckϪHitachi); In-
tegrator: D-2000 Chromato integrator (MerckϪHitachi); Column:
Hibar (prepacked) LiChrosorb Si 60 (7 µm, 250 ϫ 25 mm,
4. Conclusions
In summary, an asymmetric synthesis of all four stereo-
isomers of 1-amino-2-(hydroxymethyl)cyclobutanecar-
boxylic acid, based on the chiral glycine equivalents (R)-1
and (S)-1, has been presented. The cyclization of the silyl-
protected iodohydrins 5aϪ5d, derived from (R)-1, to the
corresponding spirocyclic derivatives 6aϪ6d with mediation
by the phosphazenic base tBu-P4 should be considered the
key step of the synthetic sequence.
The final compounds, amino acids 8a, 8b, (ent)-8a, and
(ent)-8b, were found to be ligands for the glycine binding Merck).
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C.-J. Koch, G. Höfner, K. Polborn, K. T. Wanner
FULL PAPER
5.2 Experimental Data
added at Ϫ10 °C to but-3-en-1-ol (2.14 g, 2.55 mL, 29.7 mmol) in
THF (22 mL). After 15 min this solution was slowly (15 min) ad-
ded by cannula at Ϫ78 °C to TfCl (5.0 g, 29.7 mmol) in THF
(39 mL). After 30 min the resulting mixture was allowed to warm
to Ϫ50 °C over 1 h. This solution was finally added over 20 min,
by cannula, to another solution that had been prepared by treat-
ment of (S)-1 (1.186 g, 5.92 mmol) in THF (30 mL) at Ϫ80 °C with
sBuLi (1.3  in cyclohexane, 5.02 mL, 6.51 mmol, 1.1 equiv.) and
had been allowed to react for 1 h. After 18 h at Ϫ80 °C, NEt3
(9.86 mL, 7.17 g, 71.0 mmol, 12 equiv.) was added, followed after
3 h at Ϫ80 °C by phosphate buffer (pH ϭ 7, 100 mL). After the
mixture had warmed to room temperature, the organic phase was
separated and the aqueous phase was extracted with Et2O (4 ϫ
100 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by CC
(petroleum ether/ethyl acetate, 90:10; Rf ϭ 0.27) to give (ent)-2a/
(ent)-2b (884 mg, 59%) as a colorless oil. The diastereoselectivity
was determined on the crude product by analytical HPLC (n-hep-
tane/ethyl acetate, 95:5; 1.50 mL/min): ds (ent)-2a/(ent)-2b ؍ 95:5.
(ent)-2a: tRet ϭ 12.78 min; (ent)-2b: tRet ϭ 14.98 min. TLC: Rf ϭ
(3S,6R)-3-But-3-enyl-6-tert-butyl-5-methoxy-6-methyl-3,6-dihydro-
2H-1,4-oxazin-2-one (2a), (3R,6R)-3-But-3-enyl-6-tert-butyl-5-
methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one (2b), and (6R)-
3,3-Di(but-3-enyl)-6-tert-butyl-5-methoxy-6-methyl-3,6-dihydro-2H-
1,4-oxazin-2-one (2c): A) Compound (R)-1 (87 mg, 0.436 mmol) in
THF (2.5 mL) was treated at Ϫ80 °C with tBu-P4 (458 µL, c ϭ 1.0
 in n-hexane, 0.458 mmol, 1.05 equiv.). After 30 min, a precooled
solution (Ϫ78 °C) of 4-bromobut-1-ene (177 mg, 1.31 mmol, 3
equiv.) in THF (0.8 mL) was added by cannula and the reaction
mixture was stirred for 68 h. After addition of phosphate buffer
(pH ϭ 7, 3 mL), the reaction mixture was allowed to warm to room
temperature. The organic phase was separated and the aqueous
phase was extracted with Et2O (4 ϫ 5 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The crude
product was purified by CC (petroleum ether/ethyl acetate, 92:8,
Rf ϭ 0.28) to give 2a/2b (66 mg, 60%) as a colorless oil, together
with 2c (Rf ϭ 0.42, 17 mg, 13%), also as a colorless oil. The dia-
stereoselectivity was determined on the crude product by analytical
HPLC (n-heptane/ethyl acetate, 95:5; 1.50 mL/min): ds 2a/2b ؍
96.5:3.5. 2a: tRet ϭ 12.57 min; 2b: tRet ϭ 14.69 min. For analytical
purposes a sample of 2a/2b was separated by preparative HPLC (n-
heptane/ethyl acetate, 96:4; 15.0 mL/min): 2a: tRet ϭ 21.74 min; 2b:
tRet ϭ 28.51 min.
1
0.31 (petroleum ether/ethyl acetate, 90:10). The H NMR and IR
data were in agreement with those described above for the pure
isomers 2a and 2b.
(3S,6R)-6-tert-Butyl-3-[(R)-3,4-dihydroxybutyl]-5-methoxy-6-
methyl-3,6-dihydro-2H-1,4-oxazin-2-one (3a), (3S,6R)-6-tert-Butyl-
3-[(S)-3,4-dihydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-
oxazin-2-one (3b), (3R,6R)-6-tert-Butyl-3-[(R)-3,4-dihydroxybutyl]-
5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one (3c), and
(3R,6R)-6-tert-Butyl-3-[(S)-3,4-dihydroxybutyl]-5-methoxy-6-
methyl-3,6-dihydro-2H-1,4-oxazin-2-one (3d): The synthesis was ac-
complished analogously to the preparation of (ent)-3aϪd, by em-
ployment of OsO4 (0.206 mmol) in H2O (1.31 mL; 5 mol %), tri-
methylamine N-oxide (600 mg, 5.35 mmol, 1.3 equiv.), and 2a/2b
(95.5:4.5 mixture of diastereomers, 1.04 g, 4.10 mmol) in THF/H2O
(5:2, 39 mL). The crude product was purified by CC (petroleum
ether/ethyl acetate, 10:90; Rf ϭ 0.15) to give 3aϪd (897 mg, 76%)
as a colorless oil (ratio of isomers determined by 1H NMR: ഠ
Compound 2a: Colorless crystals, m.p. 37 °C. [α]2D0 ϭ Ϫ76.1 (c ϭ
0.85, CHCl3). TLC: Rf ϭ 0.31 (petroleum ether/ethyl acetate,
90:10). 1H NMR (CDCl3): δ ϭ 1.01 [s, 9 H, C(CH3)3], 1.50 (s, 3
H, CH3), 1.89Ϫ1.99 (m, 1 H, CH2), 2.07Ϫ2.24 (m, 3 H, CH2), 3.72
(s, 3 H, OCH3), 4.13 (dd, J ϭ 7.3/4.6 Hz, 1 H, CHCH2), 4.96Ϫ5.09
(m, 2 H, CHϭCH2), 5.78Ϫ5.90 (m, 1 H, CHϭCH2). IR: ν˜ ϭ 2964
cmϪ1, 1737, 1704, 1462, 1374, 1334, 1323, 1257, 1102, 989, 910.
MS (CH4, CI): m/z (%) ϭ 254 (69) [M ϩ Hϩ], 212 (23), 201 (13),
200 (100), 175 (14), 149 (23), 113 (15), 101 (23). C14H23NO3 (253.3):
calcd. C 66.37, H 9.15, N 5.53; found C 66.41, H 9.20, N 5.44.
Compound 2b: Colorless crystals, m.p. 35Ϫ36 °C. [α]2D0 ϭ Ϫ3.8 (c ϭ
0.26, CHCl3). TLC: Rf ϭ 0.31 (petroleum ether/ethyl acetate,
4:4:1:1, stereochemistry not assigned). TLC: Rf ϭ 0.15 (petroleum
90:10). 1H NMR (CDCl3): δ ϭ 1.04 [s, 9 H, C(CH3)3], 1.52 (s, 3 ether/ethyl acetate, 10:90). H NMR, MS and IR as described for
H, CH3), 1.71Ϫ1.82 (m, 1 H, CH2), 2.12Ϫ2.22 (m, 1 H, CH2), (ent)-3aϪd. C14H25NO5 (287.4): calcd. C 58.52, H 8.77, N 4.87;
2.23Ϫ2.40 (m, 2 H, CH2), 3.71 (s, 3 H, OCH3), 4.15 (dd, J ϭ 9.0/ found C 58.06, H 8.88, N 4.71.
4.4 Hz, 1 H, CHCH2), 4.98Ϫ5.12 (m, 2 H, CHϭCH2), 5.81Ϫ5.92
1
(m, 1 H, CHϭCH2). IR: ν˜ ϭ 2963 cmϪ1, 1739, 1697, 1462, 1375,
1332, 1257, 1126, 1096. C14H23NO3 (253.3). MS (CH4, CI): m/z
(%) ϭ 254 (100) [M ϩ Hϩ].
(3R,6S)-6-tert-Butyl-3-[(S)-3,4-dihydroxybutyl]-5-methoxy-6-
methyl-3,6-dihydro-2H-1,4-oxazin-2-one (ent)-3a, (3R,6S)-6-tert-
Butyl-3-[(R)-3,4-dihydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-
2H-1,4-oxazin-2-one (ent)-3b, (3S,6S)-6-tert-Butyl-3-[(R)-3,4-di-
hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(ent)-3c, and (3S,6S)-6-tert-Butyl-3-[(S)-3,4-dihydroxybutyl]-5-
methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one (ent)-3d: OsO4
(0.168 mmol) in H2O (1.03 mL; 5 mol %) and trimethylamine N-
oxide (527 mg, 4.7 mmol, 1.4 equiv.) were added to (ent)-2a/(ent)-
2b (95:5 mixture of diastereomers, 851 mg, 3.36 mmol) in THF/
H2O (5:2, 33 mL) and the mixture was stirred for 6 h at room tem-
perature. Solid Na2S2O3·5 H2O (1 g) and phosphate buffer (pH ϭ
7, 10 mL) were added. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (4 ϫ 25 mL). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by CC (ethyl acetate, Rf ϭ
0.20) to give 800 mg (84%) of (ent)-3aϪd as a colorless oil (ratio
of isomers determined by 1H NMR: ഠ 4:4:1:1, stereochemistry not
Compound 2c: Colorless oil. [α]2D0 ϭ Ϫ19.4 (c ϭ 1.22, CHCl3). TLC:
Rf ϭ 0.42 (petroleum ether/ethyl acetate, 92:8). 1H NMR (CDCl3):
δ ϭ 1.04 [s, 9 H, C(CH3)3], 1.53 (s, 3 H, CH3), 1.75Ϫ2.15 (m, 8 H,
CH2), 3.71 (s, 3 H, OCH3), 4.91Ϫ5.07 (m, 4 H, CHϭCH2),
5.71Ϫ5.87 (m, 2 H, CHϭCH2). IR: ν˜ ϭ 3078 cmϪ1, 2961, 1731,
1694, 1842, 1454, 1373, 1310, 1221, 1153, 1101, 994, 911Ϫ MS
(CH4, CI): m/z (%) ϭ 308 (100) [M ϩ Hϩ]. C18H29NO3 (307.4):
calcd. C 70.32, H 9.51, N 4.56; found C 70.45, H 9.72, N 4.34.
B) This was analogous to the synthesis of (ent)-2a/b, but starting
from (1.18 g, 5.92 mmol) of (R)-1. Yield of 2a/b: 1.04 g (69%),
HPLC: ds 2a/2b ؍ 95.5:4.5).
(3R,6S)-3-But-3-enyl-6-tert-butyl-5-methoxy-6-methyl-3,6-dihydro-
2H-1,4-oxazin-2-one [(ent)-2a] and (3S,6S)-3-But-3-enyl-6-tert-bu-
tyl-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one [(ent)-2b]:
1
assigned). TLC: Rf ϭ 0.20 (ethyl acetate). H NMR (CDCl3): δ ϭ
1.02 (s, 0.8 ϫ 9 H, C(CH3)3], 1.05 (s, 0.2 ϫ 9 H, C(CH3)3], 1.51 (s,
sBuLi (1.3  in cyclohexane, 24.0 mL, 31.18 mmol, 1.05 equiv.) was 0.4 ϫ 3 H, CH3), 1.52 (s, 0.4 ϫ 3 H, CH3), 1.53 (s, 0.1 ϫ 3 H, CH3),
2238  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2233Ϫ2242

Synthesis of the Four Stereoisomers of 1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic Acid
FULL PAPER
1.54 (s, 0.1 ϫ 3 H, CH3), 1.57Ϫ2.02 (m, 3 H, CH2), 2.22Ϫ2.50 (m,
1 H, CH2), 3.45Ϫ3.54 (m, 1 H, CHOH or CH2OH), 3.61Ϫ3.68 (m, ν˜ ϭ 3469 cmϪ1, 2955, 2930, 2858, 1746, 1695, 1463, 1314, 1252,
1 H, CHOH or CH2OH), 3.73 (s, 0.1 ϫ 3 H, OCH3), 3.740 (s, 0.4
1103, 838, 778. MS (CH4, CI): m/z (%) ϭ 402 (100) [M ϩ Hϩ], 344
4.2 Hz, 0.4 ϫ 1 H, NCH), 4.09Ϫ4.21 (m, 0.2 ϫ 1 H, NCH). IR:
ϫ 3 H, OCH3), 3.748 (s, 0.1 ϫ 3 H, OCH3), 3.753 (s, 0.4 ϫ 3 H, (48). C20H39NO5Si (401.6): calcd. C 59.81, H 9.79, N 3.49; found
OCH3), 3.70Ϫ3.85 (m, 1 H, CHOH or CH2OH), 4.10 (dd, J ϭ 8.5/ C 59.40, H 9.40, N 3.50.
3.3 Hz, 0.4 ϫ 1 H, NCH), 4.15 (dd, J ϭ 7.3/4.0 Hz, 0.4 ϫ 1 H,
NCH), 4.07Ϫ4.22 (m, 0.2 ϫ 1 H, NCH). IR: ν˜ ϭ 3368 cmϪ1, 2966,
1736, 1697, 1463, 1315, 1268, 1104. MS (CH4, CI): m/z (%) ϭ 288
(100) [M ϩ Hϩ]. C14H25NO5 (287.4): calcd. C 58.52, H 8.77, N
4.87; found C 58.38, H 8.59, N 4.69.
(3S,6R)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyloxy)-3-
iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(5a), (3S,6R)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(5b), (3R,6R)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(5c), and (3R,6R)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyl-
oxy)-3-iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-
2-one (5d): Imidazole (407 mg, 5.95 mmol, 2.2 equiv.), PPh3
(782 mg, 2.98 mmol, 1.1 equiv.), and I2 (792 mg, 3.12 mmol, 1.15
(3S,6R)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyloxy)-3-
hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(4a), (3S,6R)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(4b), (3R,6R)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
(4c), and (3R,6R)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyl- equiv.) were added at 0 °C to 4aϪd (4:4:1:1 mixture of dia-
oxy)-3-hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxa-
zin-2-one (4d): DMF (600 µL), imidazole (468 mg, 6.85 mmol, 2.2
equiv.), DMAP (19 mg, 0.156 mmol), and ClSiMe2tBu (520 mg,
3.44 mmol, 1.1 equiv.) were added to 3aϪd (4:4:1:1 mixture of dia-
stereomers, 891 mg, 3.10 mmol) in THF (31 mL). The reaction
mixture was stirred for 20 h at room temperature before being hy-
drolyzed by addition of phosphate buffer (pH ϭ 7, 4 mL). The
mixture was concentrated in vacuo. CC (petroleum ether/ethyl acet-
stereomers, 1.09 g, 2.71 mmol) in THF (27 mL). The reaction mix-
ture was stirred for 1.5 h at 0 °C and for 1.5 h at room temperature,
after which solid Na2S2O3·5 H2O (1 g) and phosphate buffer (pH ϭ
7, 25 mL) were added. The workup was performed as described
for (ent)-5aϪd. CC (petroleum ether/ethyl acetate, 95:5; Rf ϭ 0.32)
yielded 5aϪd (1.25 g, 90%) as a colorless oil (ratio of isomers deter-
mined by 1H NMR: ഠ 4:4:1:1, stereochemistry not assigned). TLC:
Rf ϭ 0.32 (petroleum ether/ethyl acetate; 95:5). 1H NMR, MS and
ate, 75:25; Rf ϭ 0.25) yielded 4aϪd (1.09 g, 88%) as a colorless oil IR as described for (ent)-5aϪd. C20H38NO4SiI (511.5): calcd. C
1
(ratio of isomers determined by H NMR: ഠ 4:4:1:1, stereochem-
istry not assigned). TLC: Rf ϭ 0.25 (petroleum ether/ethyl acetate,
75:25). 1H NMR, MS and IR as described for (ent)-4aϪd.
C20H39NO5Si (401.6): calcd. C 59.81, H 9.79, N 3.49; found C
59.36, H 9.84, N 3.33.
46.96, H 7.49, N 2.74; found C 47.22, H 7.49, N 2.27.
(3R,6S)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
[(ent)-5a], (3R,6S)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyl-
oxy)-3-iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-
2-one [(ent)-5b], (3S,6S)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsil-
anyloxy)-3-iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxa-
zin-2-one [(ent)-5c], and (3S,6S)-6-tert-Butyl-3-[(S)-4-(tert-butyl-
(3R,6S)-6-tert-Butyl-3-[(S)-4-(tert-butyldimethylsilanyloxy)-3-
hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one
[(ent)-4a], (3R,6S)-6-tert-Butyl-3-[(R)-4-(tert-butyldimethylsilanyl-
oxy)-3-hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxa-
zin-2-one [(ent)-4b], (3S,6S)-6-tert-Butyl-3-[(R)-4-(tert-butyldimeth- dimethylsilanyloxy)-3-iodobutyl]-5-methoxy-6-methyl-3,6-dihydro-
ylsilanyloxy)-3-hydroxybutyl]-5-methoxy-6-methyl-3,6-dihydro-2H- 2H-1,4-oxazin-2-one [(ent)-5d]: Imidazole (345 mg, 5.07 mmol, 2.2
1,4-oxazin-2-one [(ent)-4c], and (3S,6S)-6-tert-Butyl-3-[(S)-4-(tert-
equiv.), PPh3 (663 mg, 2.53 mmol, 1.1 equiv.), and I2 (677 mg,
butyldimethylsilanyloxy)-3-hydroxybutyl]-5-methoxy-6-methyl-3,6- 2.67 mmol, 1.15 equiv.) were added at 0 °C to (ent)-4aϪd (4:4:1:1
dihydro-2H-1,4-oxazin-2-one [(ent)-4d]: DMF (270 µL), imidazole
(397 mg, 5.83 mmol, 2.2 equiv.), DMAP (16 mg, 0.133 mmol), and
ClSiMe2tBu (440 mg, 2.92 mmol, 1.1 equiv.) were added to (ent)-
3aϪd (4:4:1:1 mixture of diastereomers, 762 mg, 2.65 mmol) in
THF (26 mL). The reaction mixture was stirred for 18 h at room
temperature before being hydrolyzed with 10 mL of phosphate
buffer (pH ϭ 7). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (4 ϫ 20 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. The
crude product was purified by CC (petroleum ether/ethyl acetate,
mixture of diastereomers, 929 mg, 2.31 mmol) in THF (23 mL),
and the mixture was stirred for 1.5 h at 0 °C. The reaction mixture
was then stirred for 1.5 h at room temperature, after which solid
Na2S2O3·5H2O (1 g) and phosphate buffer (pH ϭ 7, 5 mL) were
added. The organic layer was separated and the aqueous layer was
extracted with Et2O (4 ϫ 30 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo. The crude product
was purified by CC (petroleum ether/ethyl acetate, 90:10; Rf
ϭ
0.62) to give (ent)-5aϪd (1.067 g, 90%) as a colorless oil (ratio of
isomers determined by 1H NMR: ഠ 4:4:1:1, stereochemistry not
70:30; Rf ϭ 0.27) to give (ent)-4aϪd (942 mg, 88%) as a colorless assigned). TLC: Rf ϭ 0.62 (petroleum ether/ethyl acetate, 90:10).
oil (ratio of isomers determined by 1H NMR: ഠ 4:4:1:1, stereo-
chemistry not assigned). TLC: Rf ϭ 0.27 (petroleum ether/ethyl
1H NMR (CDCl3): δ ϭ 0.06Ϫ0.09 [m, 6 H, Si(CH3)2], 0.90 (s, 0.8
ϫ 9 H, C(CH3)3], 0.91 (s, 0.2 ϫ 9 H, C(CH3)3], 1.01 (s, 0.8 ϫ 9 H,
acetate, 70:30). 1H NMR (CDCl3): δ ϭ 0.06 (s, 0.5 ϫ 6 H, C(CH3)3], 1.04 (s, 0.2 ϫ 9 H, C(CH3)3], 1.50 (s, 0.8 ϫ 3 H, CH3),
Si(CH3)2], 0.07 (s, 0.5 ϫ 6 H, Si(CH3)2], 0.89 (s, 0.5 ϫ 9 H,
1.54 (s, 0.2 ϫ 3 H, CH3), 1.60Ϫ2.20 (m, 3.6 H, CH2), 2.24Ϫ2.40
C(CH3)3], 0.90 (s, 0.5 ϫ 9 H, C(CH3)3], 1.01 (s, 0.8 ϫ 9 H, (m, 0.4 H, CH2), 3.40Ϫ3.63 (m, 1 H, CHI or CH2OSi), 3.68Ϫ3.80
C(CH3)3], 1.04 (s, 0.2 ϫ 9 H, C(CH3)3], 1.50 (s, 0.4 ϫ 3 H, CH3), (m, 1 H, CHI or CH2OSi), 3.69 (s, 0.1 ϫ 3 H, OCH3), 3.70 (s, 0.1
1.51 (s, 0.4 ϫ 3 H, CH3), 1.52 (s, 0.1 ϫ 3 H, CH3), 1.53 (s, 0.1 ϫ
ϫ 3 H, OCH3), 3.71 (s, 0.4 ϫ 3 H, OCH3), 3.72 (s, 0.4 ϫ 3 H,
3 H, CH3), 1.48Ϫ1.98 (m, 3.4 H, CH2), 2.14Ϫ2.30 (m, 0.6 H, CH2), OCH3), 3.85Ϫ3.93 (m, 1 H, CHI or CH2OSi), 4.05Ϫ4.28 (m, 1 H,
3.41Ϫ3.53 (m, 1 H, CHOH or CH2OSi), 3.58Ϫ3.72 (m, 2 H, NCH). IR: ν˜ ϭ 2955 cmϪ1, 2930, 2857, 1746, 1694, 1462, 1312,
CHOH or CH2OSi), 3.706 (s, 0.1 ϫ 3 H, OCH3), 3.712 (s, 0.1 ϫ 3
1253, 1104, 838, 778. MS (CH4, CI): m/z (%) ϭ 512 (22) [M ϩ
H, OCH3), 3.716 (s, 0.4 ϫ 3 H, OCH3), 3.720 (s, 0.4 ϫ 3 H, OCH3), Hϩ], 380 (100). C20H38NO4SiI (511.5): calcd. C 46.96, H 7.49, N
4.11 (dd, J ϭ 7.8/4.2 Hz, 0.4 ϫ 1 H, NCH), 4.17 (dd, J ϭ 6.5/
www.eurjoc.org
2.74; found C 47.30, H 7.41, N 2.28.
Eur. J. Org. Chem. 2003, 2233Ϫ2242
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2239

C.-J. Koch, G. Höfner, K. Polborn, K. T. Wanner
FULL PAPER
(1S,4S,7R)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-
equiv.). The reaction mixture was stirred for 2.5 h at room tempera-
methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one (6a), (1R, ture. Phosphate buffer (pH ϭ 7, 2 mL) was then added and the
4S,7R)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-meth- solvent was removed in vacuo. The residue was purified by CC
oxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one (6b), (1R,4R,7R)-
7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-methoxy-7-
methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one (6c), and (1S,4R,7R)-7-
tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-methoxy-7-
methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one (6d): tBu-P4 (1.0  in n-
(petroleum ether/ethyl acetate, 60:40; Rf ϭ 0.22Ϫ0.30) to give 7aϪd
(369 mg, 83%) as a mixture of diastereomers, which was separated
by prep. HPLC (n-heptane/ethyl acetate, 70:30; 15 mL/min; ds ϭ
48 (7a): 31 (7b): 18 (7c): 3 (7d); 7a: tR ϭ 34.81 min; 7b: tR
ϭ
28.80 min; 7c: tR ϭ 22.09 min; 7d: tR ϭ 21.46 min). Thus 173 mg
hexane, 2.68 mL, 2.68 mmol, 1.1 equiv.) was added at Ϫ80 °C to (39%) of 7a, 111 mg (25%) of 7b, 64 mg (14.5%) of 7c and 10 mg
5aϪd (4:4:1:1 mixture of diastereomers, 1.25 g, 2.44 mmol) in
DME/THF (5:1, 59 mL). The reaction mixture was stirred for 2 h
at Ϫ80 °C before being worked up as described for (ent)-6aϪd.
CC (petroleum ether/ethyl acetate, 90:10; Rf ϭ 0.45) yielded 6aϪd
(674 mg, 72%) as a colorless oil (ratio of isomers determined by 1H
NMR: ഠ 45:35:15:5, stereochemistry not assigned). TLC: Rf ϭ
0.38 (petroleum ether/ethyl acetate, 95:5). 1H NMR, MS and IR as
described for (ent)-6aϪd. C20H37NO4Si (383.6): calcd. C 62.62, H
9.72, N 3.65; found C 62.88, H 9.59, N 3.63.
(2.5%) of 7d were obtained [total yield: 358 mg (81%)].
Compound 7a: Colorless crystals, m.p. 121Ϫ122 °C. [α]2D0 ϭ Ϫ8.7
(c ϭ 0.71, CHCl3). 1H NMR, MS and IR as described for (ent)-
7a. C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20; found C
62.30, H 8.60, N 5.12.
Compound 7b: Colorless oil. [α]2D0 ϭ Ϫ56.1 (c ϭ 0.89, CHCl3). H
NMR, MS and IR as described for (ent)-7b. C14H23NO4 (269.3):
1
calcd. C 62.43, H 8.61, N 5.20; found C 62.10, H 9.05, N 5.10.
(1R,4R,7S)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-
methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one
(1S,4R,7S)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-
methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one [(ent)-6b],
(1S,4S,7S)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-6-
methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one [(ent)-6c],
[(ent)-6a], Compound 7c: Colorless crystals, m.p. 81Ϫ83 °C. [α]2D0 ϭ Ϫ70.8
(c ϭ 0.59, CHCl3). 1H NMR, MS and IR as described for (ent)-
7c. C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20; found C
62.49, H 8.61, N 5.03.
Compound 7d: Colorless crystals, m.p. 48 °C. [α]2D0 ϭ Ϫ8.4 (c ϭ
1.01, CHCl3). 1H NMR, MS and IR as described for (ent)-7d.
C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20; found C 62.66,
H 8.82, N 5.02.
and (1R,4S,7S)-7-tert-Butyl-1-(tert-butyldimethylsilanyloxymethyl)-
6-methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one [(ent)-6d]:
tBu-P4 (1.0  in n-hexane, 2.72 mL, 2.72 mmol, 1.1 equiv.) was ad-
ded at Ϫ80 °C to (ent)-5aϪd (4:4:1:1 mixture of diastereomers,
1.262 g, 2.47 mmol) in DME/THF (5:1, 59 mL), and the mixture
was stirred at Ϫ80 °C for 2.5 h. Phosphate buffer (pH ϭ 7, 20 mL)
was then added. The organic layer was separated and the aqueous
layer was extracted with Et2O (4 ϫ 50 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The crude
product was purified by CC (petroleum ether/ethyl acetate, 90:10;
Rf ϭ 0.45) to give (ent)-6aϪd (813 mg, 86%) as a colorless oil (ratio
of isomers determined by 1H NMR: ഠ 45:35:15:5, stereochemistry
not assigned). TLC: Rf ϭ 0.38 (petroleum ether/ethyl acetate, 95:5).
1H NMR (CDCl3): δ ϭ Ϫ0.03Ϫ0.03 [m, 6 H, Si(CH3)2], 0.83 (s,
0.35 ϫ 9 H, C(CH3)3], 0.84 (s, 0.45 ϫ 9 H, C(CH3)3], 0.85 (s, 0.05
ϫ 9 H, C(CH3)3], 0.86 (s, 0.15 ϫ 9 H, C(CH3)3], 0.96 (s, 0.8 ϫ 9
H, C(CH3)3], 1.00 (s, 0.05 ϫ 9 H, C(CH3)3], 1.01 (s, 0.15 ϫ 9 H,
C(CH3)3], 1.45 (s, 0.15 ϫ 3 H, CH3), 1.46 (s, 0.05 ϫ 3 H, CH3),
1.47 (s, 0.45 ϫ 3 H, CH3), 1.48 (s, 0.35 ϫ 3 H, CH3), 1.74Ϫ2.09
(m, 2.6 ϫ 1 H), 2.12Ϫ2.31 (m, 0.8 ϫ 1 H), 2.45Ϫ2.53 (m, 0.4 ϫ 1
H), 2.60Ϫ2.73 (m, 0.6 ϫ 1 H), 2.81Ϫ2.92 (m, 0.4 ϫ 1 H),
3.06Ϫ3.24 (m, 0.2 ϫ 1 H), 3.46Ϫ3.52 (m, 0.35 ϫ 1 H, CH2OSi),
3.57Ϫ3.69 (m, 0.50 ϫ 1 H, CH2OSi), 3.70 (s, 0.45 ϫ 3 H, OCH3),
3.72 (s, 0.15 ϫ 3 H, OCH3), 3.73 (s, 0.05 ϫ 3 H, OCH3), 3.76 (s,
0.35 ϫ 3 H, OCH3), 3.69Ϫ3.85 (m, 0.95 ϫ 1 H, CH2OSi),
3.88Ϫ3.94 (m, 0.20 ϫ 1 H, CH2OSi). IR: ν˜ ϭ 2950 cmϪ1, 2857,
1738, 1732, 1694, 1471, 1463, 1315, 1255, 1106, 832, 777. MS (CH4,
CI): m/z (%) ϭ 384 (100) [M ϩ Hϩ]. C20H37NO4Si (383.6): calcd.
C 62.62, H 9.72, N 3.65; found C 62.79, H 9.57, N 3.62.
(1R,4R,7S)-7-tert-Butyl-1-(hydroxymethyl)-6-methoxy-7-methyl-8-
oxa-5-azaspiro[3.5]non-5-en-9-one [(ent)-7a], (1S,4R,7S)-7-tert-Bu-
tyl-1-(hydroxymethyl)-6-methoxy-7-methyl-8-oxa-5-azaspiro[3.5]-
non-5-en-9-one
[(ent)-7b],
(1S,4S,7S)-7-tert-Butyl-1-(hydroxy-
methyl)-6-methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one
[(ent)-7c], and (1R,4S,7S)-7-tert-Butyl-1-(hydroxymethyl)-6-meth-
oxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one [(ent)-7d]: Com-
pounds (ent)-6aϪd (45:35:15:5 mixture of diastereomers, 747 mg,
1.95 mmol) were treated with Bu4NϩFϪ (1.0  in THF, 2.95 mL,
2.95 mmol, 1.5 equiv.). The mixture was stirred for 4 h at room
temperature, and phosphate buffer (pH ϭ 7, 3.5 mL) was then ad-
ded. The solvent was removed in vacuo and the residue was puri-
fied by CC (petroleum ether/ethyl acetate, 60:40; Rf ϭ 0.22Ϫ0.30)
to give (ent)-7aϪd (492 mg, 93%) as a mixture of diastereomers,
which was separated by prep. HPLC (n-heptane/ethyl acetate,
70:30; 15 mL/min; ds ϭ 48[(ent)-7a]:31[(ent)-7b]:18[(ent)-7c]:3[(ent)-
7d]; (ent)-7a: tRet ϭ 36.46 min; (ent)-7b: tRet ϭ 29.86 min; (ent)-7c:
tRet ϭ 22.74 min; (ent)-7d: tRet ϭ 21.89 min). Thus 233 mg (44.5%)
of (ent)-7a, 152 mg (29%) of (ent)-7b, 85 mg (16%) of (ent)-7c and
13 mg (2.5%) of (ent)-7d were obtained [total yield: 483 mg (92%)].
Compound (ent)-7a: Colorless crystals, m.p. 118Ϫ120 °C. [α]2D0
ϭ
ϩ3.5 (c ϭ 0.20, CHCl3). 1H NMR (CDCl3): δ ϭ 0.97 [s, 9 H,
C(CH3)3], 1.49 (s, 3 H, CH3), 1.83 (br. s, 1 H, OH), 1.95Ϫ2.05 (m,
1 H, CHCH2CH2), 2.09Ϫ2.19 (m, 2 H, CHCH2CH2), 2.54Ϫ2.62
(m, 1 H, CHCH2CH2), 2.81Ϫ2.89 (m, 1 H, CH), 3.71Ϫ3.76 (m, 1
H, CH2OH), 3.72 (s, 3 H, OCH3), 3.78Ϫ3.85 (m, 1 H, CH2OH).
(1S,4S,7R)-7-tert-Butyl-1-(hydroxymethyl)-6-methoxy-7-methyl-8-
oxa-5-azaspiro[3.5]non-5-en-9-one (7a), (1R,4S,7R)-7-tert-Butyl-1-
(hydroxymethyl)-6-methoxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-
en-9-one (7b), (1R,4R,7R)-7-tert-Butyl-1-(hydroxymethyl)-6-meth-
IR: ν ϭ 3410 cmϪ1, 2946, 1727, 1692, 1326, 1106. MS (CH4, CI):
m/z (%) ϭ 270 (100) [M ϩ Hϩ]. C14H23NO4 (269.3): calcd. C 62.43,
H 8.61, N 5.20; found C 62.72, H 8.54, N 5.06.
˜
oxy-7-methyl-8-oxa-5-azaspiro[3.5]non-5-en-9-one
(1S,4R,7R)-7-tert-Butyl-1-(hydroxymethyl)-6-methoxy-7-methyl-8-
oxa-5-azaspiro[3.5]non-5-en-9-one (7d): Compounds 6aϪd
(7c),
and
Compound (ent)-7b: Colorless oil. [α]2D0 ϭ ϩ54.4 (c ϭ 1.70, CHCl3).
1H NMR (CDCl3): δ ϭ 0.97 [s, 9 H, C(CH3)3], 1.52 (s, 3 H, CH3),
2.07Ϫ2.32 (m, 2 H, CHCH2CH2; 1 H, CHCH2CH2), 2.64Ϫ2.72
(45:35:15:5 mixture of diastereomers, 634 mg, 1.64 mmol) were
treated with Bu4NϩFϪ (1.0  in THF, 2.80 mL, 2.80 mmol, 1.7
2240
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2233Ϫ2242

Synthesis of the Four Stereoisomers of 1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic Acid
(m, 1 H, CHCH2CH2), 3.08Ϫ3.15 (m, 1 H, CH), 3.47 (br. s, 1 H, m/z (%) ϭ 146 (100) [M ϩ Hϩ], 128 (14). C6H11NO3 (145.2); calcd.
FULL PAPER
OH), 3.67 (dd, J ϭ 12.0/5.3 Hz, 1 H, CH2OH), 3.77 (s, 3 H, OCH3),
for C6H11NO3·0.25 H2O (149.7): calcd. C 48.15, H 7.74, N 9.36;
3.78 (dd, J ϭ 12.0/2.8 Hz, 1 H, CH2OH). IR: ν˜ ϭ 3438 cmϪ1, 2947, found C 48.20, H 7.38, N 9.70.
1734, 1697, 1331, 1220, 1105. MS (CH4, CI): m/z (%) ϭ 270 (100)
[M ϩ Hϩ]. C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20;
found C 62.56, H 8.84, N 5.11.
(1R,2S)-1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic
Acid
[(ent)-8b]: This compound was prepared by the GP, from (ent)-7b
(61 mg, 0.226 mmol). Yield: 26 mg [(ent)-8b·0.25 H2O, 77%]. Color-
less crystals, m.p. 185Ϫ187 °C (dec.). [α]2D0 ϭ ϩ34.3 (c ϭ 0.47,
H2O). 1H NMR (D2O): δ ϭ 1.77Ϫ1.86 (m, 1 H, CHCH2),
Compound (ent)-7c: Colorless crystals, m.p. 79Ϫ80 °C. [α]2D0
ϭ
ϩ68.4 (c ϭ 0.27, CHCl3). 1H NMR (CDCl3): δ ϭ 1.00 [s, 9 H,
C(CH3)3], 1.49 (s, 3 H, CH3), 1.98Ϫ2.09 (m, 2 H, CHCH2CH2),
2.33Ϫ2.42 (m, 1 H, CHCH2CH2), 2.58Ϫ2.65 (m, 1 H, CH),
2.67Ϫ2.76 (m, 1 H, CHCH2CH2), 3.74 (s, 3 H, OCH3), 3.80Ϫ3.85
(m, 2 H, CH2OH), OH not detectable. IR: ν˜ ϭ 3473 cmϪ1, 2949,
2859, 1707, 1332, 1104. MS (CH4, CI): m/z (%) ϭ 270 (100) [M ϩ
Hϩ]. C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20; found C
62.70, H 8.79, N 5.00.
2.00Ϫ2.09 (m,
CHCH2CH2), 2.85Ϫ2.93 (m, 1 H, CH), 3.62 (dd, J ϭ 12.0/7.0 Hz,
˜ ϭ
2 H, CHCH2CH2), 2.38Ϫ2.45 (m, 1 H,
1 H, CH2OH), 3.66 (dd, J ϭ 12.0/5.5 Hz, 1 H, CH2OH). IR: ν
3241 cmϪ1, 3067, 2946, 2924, 2849, 1594, 1403, 1258, 1072, 610.
MS (CH4, CI): m/z (%) ϭ 146 (100) [M ϩ Hϩ], 128 (15). C6H11NO3
(145.2); calcd. for C6H11NO3·0.25 H2O (149.7): calcd. C 48.15, H
7.74, N 9.36; found C 48.15, H 7.56, N 9.60.
Compound (ent)-7d: Colorless crystals, m.p. 50Ϫ52 °C. [α]2D0 ϭ ϩ8.5
(c ϭ 1.34, CHCl3). 1H NMR (CDCl3): δ ϭ 1.02 [s, 9 H, C(CH3)3],
1.50 (s, 3 H, CH3), 2.17Ϫ2.34 (m, 3 H, CHCH2CH2), 2.61Ϫ2.68
(m, 1 H, CHCH2CH2), 3.00Ϫ3.06 (m, 1 H, CH), 3.47 (br. s, 1 H,
OH), 3.66 (dd, J ϭ 12.3/4.2 Hz, 1 H, CH2OH), 3.76 (s, 3 H, OCH3),
3.83 (dd, J ϭ 12.3/2.8 Hz, 1 H, CH2OH). IR: ν˜ ϭ 3457 cmϪ1, 2961,
2850, 1716, 1694, 1336, 1100. MS (CH4, CI): m/z (%) ϭ 270 (100)
[M ϩ Hϩ]. C14H23NO4 (269.3): calcd. C 62.43, H 8.61, N 5.20;
found C 62.82, H 8.53, N 5.05.
5.3 Radioreceptor Assays
[3 H] MDL 105,519 binding to pig cortical brain membranes was
performed as described previously.[18] Modulation of [3H]MK-801
binding to pig cortical brain membranes in the presence of -gluta-
mate (100 µM) under non-equilibrium conditions was studied as
described previously.[20] Ki values for test compounds were calcu-
lated from competition experiments with at least six concentrations
of test compounds, by the use of Prism 2.01 (GraphPad Software,
San Diego, CA). If not stated otherwise, data are expressed as me-
ans Ϯ standard error of the means (SEM) of three experiments,
each carried out in triplicate.
General Procedure (GP) for the Preparation of the Free Amino Acids
by Hydrolysis of 7a, 7b, (ent)-7a, and (ent)-7b: TFA (5 equiv.) was
added to a 0.1  solution of the respective starting material (7a,
7b, (ent)-7a, or (ent)-7b) in H2O/MeCN (9:1) and the reaction mix-
ture was stirred for 48 h at 60 °C. The solvent was then removed
in vacuo and the residue was treated with methanolic NaOH solu-
tion (0.2 , 6 equiv.) and stirred at 60 °C for 24 h. The solvent was
removed in vacuo, H2O was added, and the alkaline solution was
washed with Et2O (2 ϫ 5 mL), adjusted to pH 2 by addition of 2
 HCl, and again washed with Et2O (2 ϫ 5 mL). Ion-exchange
chromatography of the aqueous phase with a DOWEX 50Wx8 re-
sin and removal of the solvent yielded the free amino acid as color-
less crystals.
Acknowledgments
Financial support of this work by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the BMBF is
gratefully acknowledged.
[1]
E. Gershonov, R. Granoth, E. Tzehoval, Y. Gaoni, M. Fridkin,
J. Med. Chem. 1996, 39, 4833Ϫ4843.
(1S,2S)-1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic
Acid
[2]
M. Gatos, F. Formaggio, M. Crisma, C. Tonolo, G. M.
(8a): This compound was prepared by the GP, from 7a (61 mg,
0.226 mmol). Yield: 24 mg (8a·0.25 H2O, 71%). Colorless crystals,
Bonora, E. Benedetti, B. Di Blasio, R. Iacovino, A. Santini,
M. Saviano, J. Karnphuis, J. Prot. Sci. 1997, 3, 110Ϫ122.
C. Cativiela, M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry
m.p. 179Ϫ180 °C (dec.). [α]2D0 ϭ ϩ50.8 (c ϭ 1.05, H2O). H NMR,
1
[3]
MS and IR as described for (ent)-8a. C6H11NO3 (145.2); calcd. for
C6H11NO3·0.25 H2O (149.7): calcd. C 48.15, H 7.74, N 9.36; found
C 48.30, H 7.49, N 9.72.
2000, 11, 645Ϫ732.
[4]
Y. Gaoni, Org. Prep. Proced. Int. 1995, 27, 185Ϫ212.
[5]
A. Burger, W. E. Coyne, J. Org. Chem. 1964, 29, 3079Ϫ3082.
[6]
A. Burger, S. E. Zimmerman, Arzneim. Forsch. 1966, 16,
(1S,2R)-1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic
Acid
1571Ϫ1572.
[7]
(8b): This compound was prepared by the GP, from 7b (51 mg,
0.189 mmol). Yield: 21.5 mg (8b·0.25 H2O, 76%). Colorless crystals,
ˇ
´
C.-J. Koch, S. Simonyiova, J. Pabel, A. Kärtner, K. Polborn,
K. Th. Wanner, Eur. J. Org. Chem. 2003, 1244Ϫ1263.
G. B. Watson, T. H. Lanthorn, Neuropharmacology 1990, 29,
727Ϫ730.
1
m.p. 186Ϫ188 °C (dec.). [α]2D0 ϭ Ϫ36.0 (c ϭ 0.41, H2O). H NMR,
[8]
MS and IR as described for (ent)-8b. C6H11NO3 (145.2); calcd. for
C6H11NO3·0.25 H2O (149.7): calcd. C 48.15, H 7.74, N 9.36; found
C 48.04, H 7.57, N 9.70.
[9]
R. Schwesinger, Nachr. Chem. Tech. Lab. 1990, 38, 1214Ϫ1226.
R. Schwesinger, H. Schlemper, C. Hasenfratz, J. Willaredt, T.
Dambacher, T. Breuer, C. Ottaway, M. Fletschinger, J. Boele,
H. Fritz, D. Putzas, H. W. Rotter, F. G. Bordwell, A. V. Satish,
G.-Z. Ji, E.-M. Peters, K. Peters, H. G. von Schnering, L.
Waltz, Liebigs Ann. 1996, 1055Ϫ1081.
[10]
(1R,2R)-1-Amino-2-(hydroxymethyl)cyclobutanecarboxylic
Acid
[(ent)-8a]: This compound was prepared by the GP, from (ent)-7a
(61.2 mg, 0.227 mmol). Yield: 26 mg [(ent)-8a·0.25 H2O, 76%]. Col-
orless crystals, m.p. 176Ϫ177 °C (dec.). [α]2D0 ϭ Ϫ52.1 (c ϭ 0.53,
H2O). 1H NMR (D2O): δ ϭ 1.69Ϫ1.79 (m, 1 H, CHCH2),
[11]
[12]
O. Legrand, Synlett 1999, 752.
M. Shimojo, K. Matsumoto, M. Hatanaka, Tetrahedron 2000,
56, 9281Ϫ9288.
1.94Ϫ2.12 (m,
2 H, CHCH2CH2), 2.30Ϫ2.38 (m, 1 H,
[13]
[14]
H. Makabe, H. Tanimoto, A. Tanaka, T. Oritani, Heterocycles
1996, 43, 2229Ϫ2248.
P. J. Garegg, B. Samuelson, J. Chem. Soc., Chem. Commun.
1979, 978Ϫ980.
CHCH2CH2), 2.65Ϫ2.74 (m, 1 H, CH), 3.45 (dd, J ϭ 11.2/7.5 Hz,
1 H, CH2OH), 3.55 (dd, J ϭ 11.2/7.2 Hz, 1 H, CH2OH). IR: ν˜ ϭ
3415 cmϪ1, 2999, 2951, 1601, 1401, 1278, 1031. MS (CH4, CI):
Eur. J. Org. Chem. 2003, 2233Ϫ2242
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2241

C.-J. Koch, G. Höfner, K. Polborn, K. T. Wanner
FULL PAPER
[15]
U. Berlage, J. Schmidt, U. Peters, P. Wetzel, Tetrahedron Lett.
Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ44Ϫ1223/
336Ϫ033; E-mail: deposit@ccdc.cam.ac.uk].
G. Höfner, K. Th. Wanner, Neurosci. Lett. 1997, 226, 79Ϫ82.
D. Kalvin, K. Ramalingam, R. Woodward, Synth. Commun.
1985, 14, 267Ϫ72.
1987, 28, 3091Ϫ3094.
U. Berlage, J. Schmidt, Z. Milkova, P. Wetzel, Tetrahedron Lett.
[16]
[18]
[19]
1987, 28, 3095Ϫ3098.
CCDC-192161 contains the supplementary crystallographic
[17]
[20]
data for structure 7a in this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12, Union
G. Höfner, K. Th. Wanner, J. Recept. Signal Transduct. Res.
1996, 16, 297Ϫ313.
Received December 1, 2002
2242
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2233Ϫ2242