Effective methods for the synthesis of N-methyl β-amino acids from all twenty common α-amino acids using 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones

Article abstract of DOI:10.1002/hlca.200690235

N-Methyl β-amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N-methyl α-amino acids. Starting from α-amino acids, two approaches were used to prepare the corresponding N-methyl β-amino acids. First, α-amino acids were converted to N-methyl α-amino acids by the so-called '1,3-oxazolidin-5-one strategy', and these were then homologated by the Arndt-Eistert procedure to afford N-protected N-methyl β-amino acids derived from the 20 common α-amino acids. These compounds were prepared in yields of 23-57% (relative to N-methyl α-amino acid). In a second approach, twelve N-protected α-amino acids could be directly homologated by the Arndt-Eistert procedure, and the resulting β-amino acids were converted to the 1,3-oxazinan-6-ones in 30-45% yield. Finally, reductive cleavage afforded the desired N-methyl β-amino acids in 41-63% yield. One sterically congested β-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N-methyl β-amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N-methyl β-amino acids derived from the 20 proteinogenic α-amino acids.

Full text of DOI:10.1002/hlca.200690235

Helvetica Chimica Acta – Vol. 89 (2006)
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Effective Methods for the Synthesis of N-Methyl b-Amino Acids from All
Twenty Common a-Amino Acids Using 1,3-Oxazolidin-5-ones and
1,3-Oxazinan-6-ones
by Andrew B. Hughes* and Brad E. Sleebs
Department of Chemistry, La Trobe University, Victoria 3086, Australia
(phone: +619-9479-1353; e-mail: a.hughes@latrobe.edu.au)
N-Methyl b-amino acids are generally required for application in the synthesis of potentially bioac-
tive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxa-
zolidin-5-ones to synthesise N-methyl a-amino acids. Starting from a-amino acids, two approaches were
used to prepare the corresponding N-methyl b-amino acids. First, a-amino acids were converted to N-
methyl a-amino acids by the so-called ꢀ1,3-oxazolidin-5-one strategyꢁ, and these were then homologated
by the Arndt–Eistert procedure to afford N-protected N-methyl b-amino acids derived from the 20 com-
mon a-amino acids. These compounds were prepared in yields of 23–57% (relative to N-methyl a-amino
acid). In a second approach, twelve N-protected a-amino acids could be directly homologated by the
Arndt–Eistert procedure, and the resulting b-amino acids were converted to the 1,3-oxazinan-6-ones in
30–45% yield. Finally, reductive cleavage afforded the desired N-methyl b-amino acids in 41–63% yield.
One sterically congested b-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%)
of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived
N-methyl b-amino acid 61 in 71% yield (Scheme 2).
Thus, our protocols allow the ready preparation of all N-methyl b-amino acids derived from the 20
proteinogenic a-amino acids.
Introduction. – There is a large and rapidly growing body of research concerning b-
amino acids, of which representative structures occur in numerous naturalproducts
[1–3]. b-Amino acids, as a-amino acid homologues and as precursors for b-lactams,
are the subject of synthetic studies in the development of novel therapeutics and in
the synthesis of various natural products. Especially two research groups, those of See-
bach and Gellman, have contributed greatly in recent times to the body of knowledge
about b-amino acids. Their work centres on two aspects of these compounds: i) the syn-
thesis of b-amino acid derivatives [4–6] and ii) the incorporation of b-amino acids into
oligomeric structures and delineation of general rules for the folding and 3D structure
imposed by b-amino acids in these oligomers [7][8].
Of further note is the occurrence of such residues in antibiotics [9]. One criticalres-
idue is present, e.g., in taxol, and the extensive elaboration of taxol analogues has been
reviewed [10]. Juaristi has presented much discussion of many aspects of the biological
activity of b-amino acids [11]. The high biological-activity potential of b-amino acid res-
idues is exemplified by compounds such as bestatin [12] and amastatin [13], which are
quite small compounds (Mr <500 Da). Consequently, the development of libraries of b-
amino acid derived structures, and the associated synthetic methods, is an active
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
research area in which many compounds are being developed for incorporation into
lead therapeutic peptide and peptidomimetic structures [5].
Our previous papers focussed on the methodology of synthesis of N-methyl a-
amino acids (NMA) [14–17]. The chemistry described exploits intermediate 1,3-oxazo-
lidin-5-ones to prepare the N-methylderivatives of al20 common a-amino acids. In the
course of elaborating this methodology, its extension into the area of b-amino acids was
an ingenuous and attractive one for the aforementioned reasons. We also know that b-
amino acids, like N-methyl a-amino acid residues, will confer proteolytic resistance and
increased lipophilicity on peptides in which they are incorporated [11]. We now wish to
describe the results of extending the ꢀ1,3-oxazolidin-5-one strategyꢁ to the synthesis of a
range of N-methyl b-amino acids. It should be noted that some preliminary results of
this project have already been published [18].
Two strategies were conceived for the synthesis of N-methyl b-amino acids. In pre-
vious work, N-protected a-amino acids were converted to 1,3-oxazolidin-5-ones, which,
in turn, were used as precursors for N-methyl a-amino acids [15–17]. A similar
approach to the b-compounds required the N-protected a-amino acids to be homolo-
gated to the corresponding N-protected b-amino acids. An established method for
the homologation of carboxylic acids is the Arndt–Eistert reaction [19], which has
also been applied to amino acids [20][21]. The original homologation procedure
involves reaction of an acid chloride with diazomethane (CH2N2) to effect formation
of a diazoketone. A Wolff rearrangement of the diazoketone then forms the homolo-
gated acid. However, the homologation of amino acids via acid chlorides is complicated
by the formation of cyclic oxazolones [22] from the reaction of the acid chloride with
the N-acylprotecting group. Carbamate-protected a-amino acids also undergo a cyclis-
ing side reaction with the acid chloride to form N-carboxyanhydrides [20]. This prob-
lem has been overcome by the use of the so-called ꢀmixed-anhydride methodꢁ [23],
which allows the use of amides and urethanes. Thus, the N-protected b-amino acids
from the homologation would then be converted into 1,3-oxazinan-6-ones, and subse-
quent reductive cleavage would yield the target N-methyl b-amino acids.
Results and Discussion. – 1. Route via 1,3-Oxazinan-6-ones. The benzylcarbamates
2–12 were treated with ethylchloroformate and N-methylmorpholine (NMM) to form
the corresponding mixed anhydrides, which were reacted, in turn, with CH2N2 [24] to
afford the corresponding diazoketones 14–24 in yields of 72–85% (Scheme 1). The for-
mation of the diazoketones and their Wolff rearrangement to the b-amino acids 25–36
(50–90% yield) is known to proceed without racemisation of the asymmetric centre
[25], except in the case of phenylglycine. The procedure employed in the present
study is based on the work of Müller et al. [26] who reported: ꢀthe base-free, Ag+-cata-
lysed Wolff rearrangement … proceeds smoothly within minutes at room temperature on
sonication using an ultrasound cleaning bathꢁ. This method was used for all the Wolff
rearrangements in this report. In addition, it was noted that previous workers employ-
ing Ag+ salts for the Wolff rearrangement had used silver(I) oxide [27] and silver(I)
benzoate [28]. More recently, the use of silver(I) trifluoroacetate was reported by See-
bach and co-workers [29]. We found that, indeed, this reagent is best suited for the rear-
rangement, with the benefit that the trifluoroacetate anion can be easily removed dur-
ing workup.

Helvetica Chimica Acta – Vol. 89 (2006)
2613
Scheme 1
a) 1. ClCOOEt, N-methylmorpholine (NMM); 2. CH2N2. b) CF3COOAg, H2O, sonication. c)
(CH2O)n, camphorsulfonic acid (CSA; cat.), AcOH (cat.), benzene, reflux, 3 h. d) CF3COOH (TFA),
Et3SiH, CH2Cl2.
A
The b-amino acids 25–36 were next converted into the corresponding 1,3-oxazinan-
6-ones 37–48 in 30–45% yield by reaction with paraformaldehyde in the presence of
camphorsulfonic acid (CSA)/AcOH as catalysts. The 1,3-oxazinan-6-ones then under-
went reductive cleavage when exposed to trifluoroacetic acid (TFA) and triethylsilane
(Et
ACHTREUNG
tive route via the ꢀ1,3-oxazinan-6-one pathwayꢁ (Scheme 2). We prepared the required
b-amino acid 62 in high yield by a modification of a literature procedure [30]. Thus,
urea and 3-methylbut-2-enoic acid were heated to effect a Michael addition, followed
by dehydration to form the dihydropyrimidine dione 63, which was hydrolysed to 3-
amino-3-methylbutanoic acid (64) [30], and protected as the desired carbamate 62
[31]. Reaction of 62 then afforded 4,4-dimethyl-1,3-oxazinan-6-one (65) in 95%
yield. Finally, reductive cleavage of this compound also proceeded well affording the
target compound 61 in 71% yield.
The N-Cbz-protected (Cbz=benzyloxycarbonyl) aminoisobutyric acid (Aib) 66
could be converted into the diazoketone 67 (70% yield); however, the latter failed to
form 62 in severalattempted Wolff rearrangements [32]. Further, although accessible
via the ꢀ1,3-oxazinan-6-one routeꢁ outlined in Scheme 1, the overall yields of N-methyl
b-amino acids did not meet our expectations.
2. Route via 1,3-Oxazolidin-5-ones. The second approach was to homologate the N-
methyl a-amino acids as previously described [14][16]. Accordingly, the sequence
depicted in Scheme 3 was undertaken. A broad range of N-Cbz a-amino acids 1–12
and 68–70, including some with side chains that we have not used before, were con-
verted into the corresponding 1,3-oxazolidin-5-ones 71–85 by the established proce-
dure [16]. Reductive cleavage with Et3SiH and TFA provided the N-methyl a-amino
A

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2
a) 1. ClCOOEt, NMM; 2. CH2N2. b) CF3COOAg, H2O, sonication. c) (CH2OH)2, 1908, 1 h. d) 1. aq.
NaOH; 2. aq. HCl. e) Cbz-Succinimide, Et3N, DMF. f) (CH2O)n, CSA (cat.), AcOH (cat.), benzene,
reflux, 3 h. g) TFA, Et3SiH, CH2Cl2.
AHCTREUNG
AHCTREUNG
acids 86–100. All the acids were submitted to the same mixed-anhydride-forming con-
ditions as in Scheme 1, and subsequent treatment with CH2N2 [24] gave the expected
diazoketones 101–115. Wolff rearrangements were performed by treatment of the
diazoketones with CF3CO2Ag, which afforded the expected N-methyl b-amino acids
G
49–60 and 116–118 in 45–92% yield.
3. Aspartic Acid, Glutamic Acid, Asparagine, and Glutamine. The transformation of
aspartic and glutamic acid varied from the basic sequence shown in Scheme 3 due to
interference by the side chain COOH groups. Aspartic acid (119) and glutamic acid
(120) were converted under standard conditions to the oxazolidinones 121 and 122,
respectively, without protection of the side-chain functions, and the latter were isolated
as their dicyclohexylamine (DCHA) salts. It was found that this expedient gave crystal-
line material that was easy to handle. Additionally, the benzylation reactions to provide
the esters 123 and 124 gave the highest yields when the reaction was performed with the
respective DCHA salts. Other lower-yielding methods to obtain the benzyl esters 123
and 124 involved reaction of Et3N and benzylbromide with the acids 121 and 122, fol-
U
lowed by reaction with either benzyl alcohol and dicyclohexylcarbodiimide (DCC) or
with benzyl chloroformate, 4-(dimethylamino)pyridine (DMAP), and DCC. As shown
in Scheme 3, the 1,3-oxazolidin-5-ones 123 and 124 were reductively cleaved to the N-
methylated a-amino acids 125 and 126, respectively. Then, the diazoketones 127 and
128 were prepared, and their Wolff rearrangement afforded the desired b-amino
acids 129 and 130.
The synthesis of the asparagine- and glutamine-derived b-amino acids also started
from the corresponding carboxylic acids. Compounds 121 and 122 were treated with
thionylcholride (SOCl 2), and the resulting acid chlorides were quenched with 2
equiv. of dibenzylamine (Bn2NH) to afford the tertiary amides 131 and 132. These
N

Helvetica Chimica Acta – Vol. 89 (2006)
2615
Scheme 3
a) (CH2O)n, CSA (cat.), toluene, reflux. b) TFA, Et3
d) CF3COOAg, H2O, sonication. e) (C6H11)2NH, Et2O. f) BnBr, Et3
(2 equiv.), CH2Cl2. i) NH4I, Me2S, TFA, CH2Cl2.
ACHTREUNG
A
G
A
ACHTREUNG
AHCTREUNG
amides were readily cleaved reductively to afford the N-methylamino acids 133 and
134, respectively. Arndt–Eistert homologation via the diazoketones 135 and 136 finally
gave the expected b-amino acids 137 and 138 with ease.

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Helvetica Chimica Acta – Vol. 89 (2006)
4. Cysteine and Methionine. In the case of cysteine and methionine, we have already
described methods for the conversion of the protected analogues 139 and 140 (Scheme
3) to the corresponding 1,3-oxazolidin-5-ones 141 and 142, respectively [16]. These 1,3-
oxazolidin-5-ones can be reductively cleaved to the N-methylamino acids 143 and 144
[16]. The mixed-anhydride procedure afforded the diazoketones 145 and 146 in mod-
erate yields (50 and 52%, resp.). Ag+-Catalysed Wolff rearrangement of the diazoke-
tones was uneventfulin the case of cysteine, providing the b-N-methyl-S-benzyl-cys-
teine 147 in 87% yield. Seebach noted high yields in the Wolff rearrangements of
methionine derivatives [33][34]. However, in our hands, the conversion of 146 to 148
proceeded in only 44% yield, which was attributed to catalyst poisoning by the sulfur
functionality.
5. Tyrosine. O-Methyl-tyrosine (149; Scheme 4) was readily available by double
methylation followed by ester hydrolysis of N-Cbz-tyrosine (150) [35][36]. This mate-
rialformed the 1,3-oxazolidin-5-one 151 in good yield (80%). The latter was reductively
cleaved to form the N,O-dimethyl-tyrosine 152 (84% yield; CHA salt). Formation of
the diazoketone 153 proceeded uneventfully, and the Wolff rearrangement gave the
expected N-methyl b-amino acid 154 in 87% yield as the tert-butylammonium salt.
In one of our previous papers [16], we noted that tyrosine presents certain problems
in terms of the desired 1,3-oxazolidin-5-one manipulations. This was also the case in the
current b-amino acid sequence. Attempts were made to prepare the b-amino acid start-
ing with 155, but these reactions were low-yielding. Accordingly, O-benzyl-tyrosine
(156) [37] was converted into the 1,3-oxazolidin-5-one 157 [38]. However, the subse-
quent reductive cleavage did not provide the O-benzyl-N-methyl-tyrosine 158. Instead,
the debenzylated compound 159 and the rearrangement product 160 [39] were isolated.
6. Proline. Lin et al. [40] converted L-proline to N-methyl-L-proline using aqueous
formaldehyde in MeOH under hydrogenating conditions. In the present investigation,
N-methyl-L-proline could not be directly homologated to the corresponding b-amino
acid due to its low solubility. It was possible though to convert the carbamate 161
[31] to the diazoketone 162 [31] (Scheme 5). Wolff rearrangement then provided the
b-amino acid 163 [31]. Lastly, the N-Cbz group was removed by hydrogenolysis over
Pd/C, followed by in situ treatment with aqueous formaldehyde to effect N-methyla-
tion. Upon workup, the proline-derived b-amino acid 164 was isolated in 95% yield
(isolated as the hydrochloride salt) [41].
7. Arginine and Histidine. In a previous paper [14], we described the preparation of
the intermediate 98 in the synthesis of N-methyl-arginine. Thus, 98 was converted to the
corresponding diazoketone 113 (Scheme 6). Wolff rearrangement in 1,4-dioxane/H2O
afforded the b-amino acid 116, which was converted into the t-Bu ester 165. Alterna-
tively, 165 could be obtained directly from 113 by Wolff rearrangement in 1,4-diox-
ane/t-BuOH as solvent. The use of the t-Bu ester was advantageous for the ultimate
deprotection step in that it suppressed aminolytic side reactions observed with the cor-
responding Me ester. Thus, ester 165 was treated with ethane-1,2-diamine to effect
deprotection of the phthalimide moiety. The resulting primary amine 166 was then gua-
nylated with the reagent 167 to afford the fully protected arginine-derived b-amino acid
168 in 62% yield (Scheme 6).
The synthesis of the b-N-methylamino acid derived from histidine began with the
N-methyl a-amino acid 169 (Scheme 7), which was described earlier [15][16]. Conver-

Helvetica Chimica Acta – Vol. 89 (2006)
2617
Scheme 4
a) (CH2O)n, CSA (cat.), toluene, reflux. b) TFA, Et3SiH, CH2Cl2. c) 1. ClCOOEt, NMM; 2. CH2N2.
A
d) CF3COOAg, H2O, sonication.
sion of 169 using ethyl chloroformate and the less-nucleophilic base 2,4,6-collidine
(=2,4,6-trimethylpyridine) at ꢀ208, followed by treatment with CH2N2 [24], gave the

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 5
a) 1. ClCOOEt, NMM; 2. CH2N2. b) CF3COOAg, H2O, sonication. c) 1. H2, Pd/C, MeOH; 2. aq.
CH2O, H2, Pd/C.
Scheme 6
a) 1. ClCOOEt, NMM; 2. CH2N2. b) CF3COOAg, H2O/1,4-dioxane, sonication. c) 4-(Dimethylami-
no)pyridine (DMAP; cat.), anh. t-BuOH, (Boc)2O. d) CF3COOAg, 1,4-dioxane/anh. t-BuOH, sonica-
G
tion. e) Ethane-1,2-diamine/t-BuOH 4:1, 908, 16 h. f) i-Pr2NH, CH2Cl2.
desired diazoketone 170 in 50% yield1). Wolff rearrangement of 170 in the presence of
1,4-dioxane/H2O then afforded the expected acid 171, but this materialwas difficult to
handle and purify. However, the expedient of using anhydrous 1,4-dioxane/MeOH
instead of 1,4-dioxane/H2O as solvent allowed the isolation of the Me ester 172 in
82% yield.
Conclusions. – An Arndt–Eistert approach has been successfully applied to the syn-
thesis of N-methyl b-amino acids derived from the 20 common a-amino acids. As with
our previous experience [16], the derivatives varied in their ease of synthesis. In general
though, the solutions found for the synthesis of the corresponding N-methyl a-amino
acids were mostly compatible with the Arndt–Eistert chemistry used to prepare the
1
)
When employing N-methylmorpholine as base, a dark-red colour was observed, probably due to
removal(though unproven) of the 2,4-dinitrophenyl(DNP) protecting group, and the overaltrans-
formation was unsuccessful.

Helvetica Chimica Acta – Vol. 89 (2006)
2619
Scheme 7
a) 1. ClCOOEt, collidine, ꢀ208; 2. CH2N2. b) CF3COOAg, H2O/1,4-dioxane, sonication. c)
CF3COOAg, MeOH/1,4-dioxane, sonication.
b-amino acids. Thereby, two approaches were studied. In the preferred ꢀ1,3-oxazolidin-
5-one sequenceꢁ, the Arndt–Eistert homologation was applied generally to previously
described N-methyl a-amino acids [14–16], the desired N-methyl b-amino acids
being obtained in yields of 23–57% from the N-protected N-methyl a-amino acids.
Alternatively, the homologation could be applied to N-protected a-amino acids. The
resulting b-amino acid products were then converted to 1,3-oxazinan-6-ones, which
were reductively cleaved to the desired b-N-methylamino acids, though in lower over-
all yield than in the case of the 1,3-oxazolidin-5-ones.
An interesting observation was that the ketene intermediates in the Wolff rear-
rangements to form the b-amino acids could be intercepted by various alcohols to
afford Me and t-Bu esters, which solved some handling problems with certain com-
pounds. It was also noted that the synthesis and reductive cleavage of 1,3-oxazinan-
6-ones, though not efficient for mono-b-substituted b-amino acids, worked well for a
b,b-dimethyl b-amino acid to afford the sterically congested b-amino acid 61. This
might well be a general phenomenon. While the yields of the b-amino acids prepared
via the 1,3-oxazinan-6-one intermediates were not the highest, the 1,3-oxazinan-6-ones
are versatile intermediates for the synthesis of more-complex and valuable b-amino
acid derivatives and, thus, studies are continuing to optimise the yields of these com-
pounds, as will be reported in due course.
We thank La Trobe University and the Australian Government for the provision of a Post-Graduate
Scholarship (to B. E. S.). The authors are also grateful to J. A. Reiss for his interest and assistance in the
preparation of this manuscript.

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Helvetica Chimica Acta – Vol. 89 (2006)
Experimental Part
General. AcOEt and hexane used for chromatography were distilled prior to use. All solvents were
purified by distillation. For anh. solvents, procedures from Perrin and Armarego [42] were followed. Anh.
CH2Cl2 was distilled and stored over Linde-type 4-Š molecular sieves. All other reagents and solvents
were purified or dried as described in the literature [42]. The following compounds were prepared pre-
viously: 68 [43], 69 [44], 70 [45], and 150 [37]. All melting points (m.p.) are uncorrected and were
recorded on a microscope hot-stage apparatus. Infrared (IR) spectra were recorded on an FT-IR spec-
trometer, using a diffuse reflectance accessory with KBr background; in cmꢀ1. NMR Chemicalshifts d
and coupling constants J are reported in ppm (rel. to Me4Si) and in Hz, resp. Electrospray mass spectra
G
(ESI-MS) were obtained on a triple quadrupole mass spectrometer using H2O/MeOH/AcOH 0 :99 :1:0
or 50 :50 :1 as the mobile phase. Low- and high-resolution mass spectra (l.s.i.m.s.) were recorded at the
University of Tasmania by Dr. Noel Davies and co-workers.
General Procedure for the Preparation of the Diazoketones 14–24 and 67 of N-(Benzyloxycarbonyl)-
Protected L-Amino Acids. The Cbz-protected L-a-amino acid (1 mmol) was dissolved in anh. THF (25 ml)
and cooled to ꢀ158. To this soln., ethyl chloroformate (1.05 mmol) and N-methylmorpholine (NMM, 1.05
mmol) were added successively, and the mixture was stirred for 15 min. Then, an anh. soln. of CH2N2 (5
mmol; CAUTION!) [24] in CH2Cl2 was added slowly, and the yellow soln. was allowed to warm to r.t.
Stirring was continued untilthere was no acid remaining (TLC contro)l. Excess CH 2N2 was destroyed
by addition of AcOH. The mixture was concentrated under reduced pressure, and the residue was
taken up in AcOEt. The org. phase was washed successively with sat. aq. NaHCO3 soln., 10% aq. citric
acid, and brine. The org. layer was dried (MgSO4), filtered, and evaporated to dryness in vacuo. The prod-
uct was of sufficient purity to be directly used in the next reaction. An anal. sample was purified by flash
chromatography (FC) for characterization. The anal. data of 14 [46], 16 [47], 17 [48], 18 [49], 19 [50], 20
[51], 21 [52], and 22 [51] were identicalto those previousyl described.
Phenylmethyl [(1S)-3-Diazo-1-ethyl-2-oxopropyl]carbamate (15). Yield: 65%. Clear yellow oil.
[a]1D9 =ꢀ19.4 (c=1.7, CH2Cl2). IR (NaCl): 3319, 3091, 2936, 2108, 1713, 1637, 1525, 1366, 1258, 1084,
1
738. H-NMR (300 MHz, CDCl3; rotamers): 7.27 (s, 5 H), 5.81–5.78 (m, 1 H); 5.40 (m, 1 H); 5.00 (s, 2
H); 4.17–4.11 (m, 1 H); 1.82–1.49 (m, 2 H); 0.90–0.85 (t, J=7.4, 3 H). 13C-NMR (75 MHz, CDCl3):
193.6; 155.8; 136.1; 128.2; 127.9; 127.7; 66.6; 58.9; 53.7; 25.3; 9.4. HR-MS: 262.1182 ([M+H]+, C13
A
G
G
(2S)-4-Diazo-3-oxo-2-({[(phenylmethyl)oxy]carbonyl}amino)butyl Acetate (23). Yield: 85%. Pale-
yellow solid. M.p. 66–698. [a]1D8 =ꢀ3.9 (c=2.8, CH2Cl2). IR (KBr): 3325, 3093, 3034, 2956, 2112, 1811,
1
1789, 1742, 1639, 1524, 1455, 1368, 1230, 1045, 741, 699. H-NMR (300 MHz, CDCl3; rotamers): 7.30
(s, 5 H); 5.85–5.82 (m, 1 H); 5.52 (s, 1 H); 5.07 (s, 2 H); 4.52–4.46 (m, 1 H); 4.26 (br. s, 2 H); 1.98 (s, 3
H). 13C-NMR (75 MHz, CDCl3): 190.2; 170.5; 155.8; 135.9; 128.4; 128.2; 128.0; 67.1; 63.5; 56.8; 54.6;
13.8. HR-MS: 306.1092 ([M+H]+, C14
A
G
N
(1R,2S)-4-Diazo-1-methyl-3-oxo-2-({[(phenylmethyl)oxy]carbonyl}amino)butyl Acetate (24). Yield:
76%. Clear yellow oil. [a]2D3 =+2.5 (c=2.16, CH2Cl2). IR (NaCl) 3324, 3093, 2985, 2111, 1789, 1730,
1
1640, 1522, 1370, 1234, 1027, 741, 699. H-NMR (300 MHz, CDCl3; rotamers): 7.31 (s, 5 H); 5.72–5.69
(br. s, 1 H); 5.56 (s, 1 H); 5.31–5.28 (m, 1 H); 5.09 (s, 2 H); 4.35–4.28 (m, 1 H); 1.94 (s, 3 H); 1.22 (d,
J=3.2, 3 H). 13C-NMR (75 MHz, CDCl3): 190.4; 169.5; 156.2; 135.9; 128.4; 128.2; 128.0; 69.5; 67.2;
61.0; 54.6; 20.8; 16.6. HR-MS: 320.1243 ([M+H]+, C15
A
G
N
Phenylmethyl (3-Diazo-1,1-dimethyl-2-oxopropyl)carbamate (67). Yield: 70%. Pale-yellow oil. IR
1
(NaCl): 3332, 2986, 2106, 1714, 1643, 1517, 1454, 1353, 1259, 1152, 1088, 857, 739. H-NMR (300 MHz,
CDCl3; rotamers): 7.33 (s, 5 H); 5.49 (br. s, 2 H); 5.06 (s, 2 H); 1.46 (s, 6 H). 13C-NMR (75 MHz,
CDCl3; rotamers): 196.4; 154.7; 136.2; 128.5; 128.4; 128.2; 128.1; 68.0; 59.6; 52.2; 25.0. HR-MS:
262.1184 ([M+H]+, C13
A
G
N
General Procedure for the Preparation of the N-(Benzyloxycarbonyl)-Protected b-Amino Acids
25–36 (as ammonium salts). The diazoketone (1 mmol) was dissolved in 50 ml of 1,4-dioxane/H2O 9:1
(v/v). On addition of CF3CO2Ag (0.01 mmol), the mixture was sonicated in an ultrasound bath for 30
min or untilno diazoketone remained, as indicated by TLC (AcOEt/hexane). The mixture was then con-
centrated in vacuo. The residue was dissolved in Et2O and washed with 10% aq. citric acid. The org. layer
N

Helvetica Chimica Acta – Vol. 89 (2006)
2621
was extracted with sat. aq. NaHCO3 soln. (3”). The combined aq. layers were acidified to pH 2 with
dilute aq. HCl, and then re-extracted with AcOEt (3”). The combined org. extracts were dried
(MgSO4) and evaporated in vacuo. The residue was subjected to column chromatography (CC) for anal-
ysis, but for ease of handling the tert-butylammonium salt was made in the usualmanner. The free acid
was taken up in a minimum of anh. Et
slowly formed. Dropwise addition of hexane can aid the precipitation process. Stirring was generally con-
tinued for 16 h. The solid was suction-filtered, and the filter cake was washed with cold Et2O/hexane to
G
AHCTREUNG
obtain the product as a white colorless solid. The anal. data of 26 [53], 28 [47], 29 [54], 31 [55], 33 [47],
and 34 [47] were identicalto those previousyl described.
(3S)-3-({[(Phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (27). Yield: 87%. Colourless solid.
[a]1D9 =ꢀ9.56 (c=0.3, CH2Cl2). M.p. 110–1138. IR (KBr): 3329, 3064, 2966, 1696, 1537, 1451, 1286,
1
1247, 1097, 924, 733, 668. H-NMR (300 MHz, CDCl3; rotamers): 9.70–9.30 (m, 5 H); 5.21 (br. s, 1 H);
5.08 (s, 2 H); 3.90–3.85 (m, 1 H); 2.56 (s, 2 H); 1.60–1.55 (m, 2 H); 0.94–0.89 (t, J=7.1, 3 H). 13C-
NMR (75 MHz, CDCl3): 176.8; 156.1; 136.4; 128.5; 128.1; 128.0; 66.8; 49.4; 38.4; 27.3; 10.5. HR-MS:
252.1232 ([M+H]+, C13
N
N
(3S)-3-({[(Phenylmethyl)oxy]carbonyl}amino)heptanoic Acid (30). Yield: 67%. Colourless solid.
M.p. 97–998. [a]D21 =ꢀ17.3 (c=1.0, CH2Cl2). IR (KBr): 3331, 2956, 2927, 1694, 1537, 1293, 1072, 731,
695. 1H-NMR (300 MHz, CDCl3; rotamers): 7.32 (s, 5 H); 5.28–5.25 (m, 1 H); 5.12–5.07 (m, 2 H);
3.94 (br. s, 1 H); 2.60–2.52 (m, 2 H); 1.52 (s, 2 H); 1.29 (s, 2 H); 0.90–0.82 (m, 3 H). 13C-NMR (75
MHz, CDCl3; rotamers): 176.6; 156.0; 136.4; 128.4; 128.1; 128.0; 66.7; 48.0; 38.8; 34.0; 28.2; 22.3; 13.8.
HR-MS: 280.1557 ([M+H]+, C15
N
N
(3R,4S)-4-Methyl-3-({[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (32). Yield: 70%. Clear,
colourless oil. An anal. sample was converted to the tert-butylammonium salt: M.p. 102–1068.
[a]2D0 =ꢀ7.1 (c=1.0, MeOH). IR (KBr): 3400, 2966, 2933, 2747 2635, 2626, 1698, 1632, 1552, 1401,
1
1253, 1028, 697. H-NMR (300 MHz, CDCl3; rotamers): 7.27 (m, 5 H); 6.32 (s, 3 H); 6.12–6.09 (m, 1
H); 5.06–4.95 (m, 2 H); 3.78–3.71 (m, 1 H); 2.66 (s, 2 H); 1.59–1.00 (m, 3 H); 1.23 (s, 9 H); 0.82–0.80
(m, 6 H). 13C-NMR (75 MHz, CDCl3; rotamers): 178.5; 156.3; 136.8; 128.3; 127.8; 66.2; 53.4; 50.9;
39.3; 38.5; 27.7; 25.5; 15.2; 11.5. HR-MS: 280.1545 ([M+H]+, C15
N
N
(3R)-4-(Acetyloxy)-3-({[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (35). Yield: 90%. Col-
ourless solid. M.p. 111–1128. [a]2D3 =+0.73 (c=0.83, CH2Cl2). IR (KBr): 3352, 3144, 2585, 1720, 1692,
1
1540, 1447, 1377, 1272, 1217, 1067, 857, 638. H-NMR (300 MHz, CDCl3; rotamers): 10.20–9.80 (br. s,
1 H); 7.32 (s, 5 H); 5.48–5.46 (br. s, 1 H); 5.08 (s, 2 H); 4.23–4.12 (m, 3 H); 2.62 (s, 2 H); 2.01 (s, 3 H).
13C-NMR (75 MHz, CDCl3): 175.6; 170.9; 155.8; 136.1; 128.5; 128.2; 128.1; 67.2; 65.0; 46.8; 35.5; 16.6.
Anal. calc. for C14H17N2O6 (295.11): C 56.94, H 5.80, N 4.74; found: C 56.81, H 5.77, N 4.90.
(3R,4R)-4-(Acetyloxy)-3-({[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (36). Anal. data of
tert-butylammonium salt. Yield: 85%. Colourless solid. M.p. 103–1058. [a]1D9 =+7.2 (c=1.45, CH2Cl2).
IR (KBr): 3400, 2984, 2834, 2545, 2230, 2131, 1727, 1641, 1547, 1502, 1399, 1247, 1110, 1040, 753, 699.
1H-NMR (300 MHz, CDCl3; rotamers): 7.81 (br. s, 3 H); 7.30 (s, 5 H); 5.79–5.75 (br. s, 1 H); 5.12–4.94
(m, 3 H); 4.05–4.00 (m, 1 H); 2.34–2.32 (m, 2 H); 1.91 (s, 3 H); 1.25 (s, 9 H); 1.18 (d, J=3.1, 3 H).
13C-NMR (75 MHz, CDCl3): 176.8; 170.3; 156.2; 136.6; 128.4; 128.0; 71.8; 66.5; 52.5; 50.9; 39.7; 27.8;
21.0; 17.1. Anal. calc. for C19H30N2O6 (382.45): C 59.67, H 7.91, N 7.32; found: C 59.47, H 8.04, N 7.40.
General Procedure for the Preparation of the 1,3-Oxazinan-6-ones 37–48 and 65 of N-(Benzyloxycar-
bonyl)-Protected b-Amino Acids. To the b-amino acid (1 mmol) in toluene (150 ml) was added camphor-
sulfonic acid (CSA; 0.1 mmol) and AcOH (0.1 mmol). The mixture was heated at 908 for 3–5 h, during
which time an excess of paraformaldehyde was added in small portions down the condenser. The reaction
was monitored by TLC until no trace of the acid remained. The mixture was hot-filtered through a glass
frit, and the filtrate was concentrated in vacuo. The residue was taken up in AcOEt, the org. phase was
washed with sat. aq. NaHCO3 soln., dried (MgSO4), and evaporated under reduced pressure. The residue
was purified by CC (20–45% AcOEt/hexane) to afford the 1,3-oxazinan-6-one.
Phenylmethyl 6-Oxo-1,3-oxazinane-3-carboxylate (37). Yield: 36%. Colourless oil. IR (NaCl): 1764,
1714, 1454, 1276, 1153, 1012, 755, 699. 1H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.49 (s, 2 H);
5.18 (s, 2 H); 3.78 (t, J=10.8, 2 H); 2.75 (t, J=10.8, 2 H). 13C-NMR (75 MHz, CDCl3): 168.5; 153.6; 135.1;
128.3; 128.2; 127.9; 74.0; 67.9; 39.1; 29.3. HR-MS: 235.0644 (M+, C12
N
N

2622
Helvetica Chimica Acta – Vol. 89 (2006)
Phenylmethyl (4S)-4-Methyl-6-oxo-1,3-oxazinane-3-carboxylate (38). Yield: 43%. Clear colourless
oil. [a]2D0 =+143.4 (c=1.0, MeOH). IR (NaCl): 2900, 2800, 1766, 1713, 1454, 1266, 1159, 988, 771, 750,
1
699. H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.82–5.79 (br. s, 1 H); 5.16 (s, 2 H); 5.04 (d,
J=10.5, 1 H); 4.24 (br. s, 1 H); 2.81 (dd, J=6.7, 16.0, 1 H); 2.47 (dd, J=10.3, 16.0, 1 H); 1.30 (d,
J=6.3, 3 H). 13C-NMR (75 MHz, CDCl3; rotamers): 169.4; 153.8; 135.1; 128.3; 128.1; 127.8; 71.5; 67.8;
46.0; 36.8; 20.6. Anal. calc. for C13H15NO4 (249.26): C 62.64, H 6.07, N 5.62; found: C 62.92, H 6.27, N 5.87.
Phenylmethyl (4S)-4-Ethyl-6-oxo-1,3-oxazinane-3-carboxylate (39). Yield: 35%. Clear colourless oil.
[a]2D0 =+135.4 (c=0.4, MeOH). IR (NaCl): 2969, 2880, 1761, 1713, 1455, 1414, 1260, 1156, 1005, 770, 743,
1
698. H-NMR (300 MHz, CDCl3; rotamers): 7.31 (s, 5 H); 5.82 (d, J=9.8, 1 H); 5.14 (s, 2 H); 4.95 (d,
J=10.7, 1 H); 4.11–4.05 (m, 1 H); 2.78 (dd, J=7.0, 16.1, 1 H); 2.47 (dd, J=10.0, 16.1, 1 H); 1.76–1.54
(m, 2 H); 0.90–0.85 (t, J=11.2, 3 H). 13C-NMR (75 MHz, CDCl3): 169.5; 154.2; 135.2; 128.3; 128.1;
127.9; 127.7; 127.3; 72.0; 67.7; 50.7; 34.4; 27.5; 8.7. HR-MS: 263.1152 (M+, C14
N
N
Phenylmethyl (4S)-6-oxo-4-propyl-1,3-oxazinane-3-carboxylate (40). Yield: 45%. Clear colourless
oil. [a]2D0 =+135.5 (c=0.4, MeOH). IR (NaCl): 2960, 2934, 1762, 1713, 1414, 1261, 1244, 1156, 1109,
997, 772, 740, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.82 (d, J=9.9, 1 H); 5.15 (s, 2
H); 4.96 (d, J=10.8, 1 H); 4.19 (br. s, 1 H); 2.80 (dd, J=7.0, 16.2, 1 H); 2.45 (dd, J=9.8, 16.2, 1 H);
1.70–1.47 (m, 2 H); 1.33–1.26 (m, 2 H); 0.89 (t, J=10.8, 3 H). 13C-NMR (75 MHz, CDCl3): 169.5;
154.2; 135.2; 128.3; 128.1; 127.9; 127.8; 71.9; 67.8; 49.4; 36.8; 35.0; 17.8; 13.4. HR-MS: 277.1310 (M+,
C
N
N
Phenylmethyl (4R)-4-(1-methylethyl)-6-oxo-1,3-oxazinane-3-carboxylate (41). Yield: 45%. Clear col-
ourless oil. [a]2D0 =+147.8 (c=1.0, MeOH). IR (NaCl): 2964, 2800, 1761, 1714, 1455, 1262, 1155, 1130,
1
1009, 990, 772, 738, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.89 (br. s, 1 H); 5.16 (s,
2 H); 4.89 (d, J=10.8, 1 H); 4.12–4.05 (m, 1 H); 2.72 (dd, J=7.0, 16.1, 1 H); 2.54 (dd, J=10.5, 16.1, 1
H); 2.10–1.99 (m, 1 H); 0.92–0.88 (m, 6 H). 13C-NMR (75 MHz, CDCl3; rotamers): 169.9; 154.7;
135.1; 128.3; 128.3; 127.8; 72.8; 67.9; 54.5; 31.7; 31.3; 18.2; 16.3. 277.1309 (M+, C15
N
N
277.1314).
Phenylmethyl (4S)-4-Butyl-6-oxo-1,3-oxazinane-3-carboxylate (42).Yield: 38%. Clear colourless oil.
[a]2D0 =+64.8 (c=0.1, MeOH). IR (NaCl): 2957, 2932, 2861, 1762, 1713, 1455, 1264, 1155, 1000, 771, 751,
698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.86 (d, J=9.9, 1 H); 5.13 (s, 2 H); 4.98 (br. s, 1
H); 4.25–4.15 (m, 1 H); 2.83 (dd, J=7.0, 16.2, 1 H); 2.46 (dd, J=9.7, 16.2, 1 H); 1.78–1.48 (m, 2 H); 1.28
(br. s, 4 H); 0.86 (t, J=9.7, 3 H). 13C-NMR (75 MHz, CDCl3): 169.4; 154.2; 135.2; 128.3; 128.1; 128.0;
127.8; 71.9; 67.9; 49.6; 35.0; 34.4; 26.6; 22.0; 13.5. Anal. calc. for C16H21NO4 (291.34): C 65.96, H 7.27,
N 4.81; found: C 65.87, H 7.11, N 4.64.
Phenylmethyl (4S)-4-(2-Methylpropyl)-6-oxo-1,3-oxazinane-3-carboxylate (43). Yield: 31%. Clear
colourless oil that crystallised on standing. M.p. 30–328. [a]1D8 =+120.1 (c=0.3, MeOH). IR (NaCl):
2957, 2871, 1761, 1714, 1414, 1260, 1157, 998, 771, 752, 698. 1H-NMR (300 MHz, CDCl3; rotamers):
7.33 (s, 5 H); 5.85 (d, J=10.4, 1 H); 5.16 (s, 2 H); 4.98 (d, J=10.7, 1 H); 4.28 (s, 1 H); 2.86 (dd, J=7.2,
16.2, 1 H); 2.40 (dd, J=9.2, 16.2, 1 H); 1.68–1.52 (m, 2 H); 1.40–1.31 (m, 1 H); 0.90–0.88 (m, 6 H).
13C-NMR (75 MHz, CDCl3): 169.3; 154.1; 135.1; 128.3; 128.2; 127.9; 71.7; 67.9; 47.9; 44.1; 35.5; 24.0;
22.6; 21.4. Anal. calc. for C16H21NO4 (291.34): C 65.96, H 7.27, N 4.81; found: C 65.83, H 7.44, N 4.74.
Phenylmethyl (4R)-4-[(1S)-1-Methylpropyl]-6-oxo-1,3-oxazinane-3-carboxylate (44). Yield: 30%.
Clear colourless oil. [a]2D0 =+111.6 (c=0.5, MeOH). IR (NaCl): 2964, 2934, 1762, 1714, 1455, 1261,
1
1158, 1133, 1001, 772, 742, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.90 (br. s, 1 H);
5.16 (s, 2 H); 4.91 (d, J=10.5, 1 H); 4.14–4.08 (m, 1 H); 2.67–2.52 (m, 2 H); 1.93–1.86 (m, 1 H);
1.33–1.06 (m, 2 H); 0.90–0.87 (m, 6 H). 13C-NMR (75 MHz, CDCl3): 170.1; 154.6; 135.1; 128.3; 128.1;
127.9; 127.7; 73.0; 67.9; 53.3; 37.8; 30.3; 25.1; 12.6; 11.2. Anal. calc. for C16H21NO4 (291.34): C 65.96, H
7.27, N 4.81; found: C 66.14, H 7.41, N 4.64.
Phenylmethyl 6-Oxo-4-phenyl-1,3-oxazinane-3-carboxylate (45). Yield: 35%. Colourless solid. M.p.
70–748. IR (KBr): 3039, 2931, 1763, 1704, 1407, 1267, 1144, 997, 877, 807, 754, 698. 1H-NMR (300
MHz, CDCl3; rotamers): 7.36–7.24 (m, 10 H); 6.93 (br. s, 1 H); 6.05 (br. s, 1 H); 5.29 (d, J=10.2, 1
H); 5.10 (s, 2 H); 3.07–2.79 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 168.7; 145.5; 134.9; 128.8; 128.1;
127.9; 127.6; 124.9; 73.0; 67.9; 53.5; 37.1. Anal. calc. for C18H17NO4 (311.33): C 69.44, H 5.50, N 4.50;
found: C 69.43, H 5.61, N 4.42.

Helvetica Chimica Acta – Vol. 89 (2006)
2623
Phenylmethyl (4S)-6-Oxo-4-(phenylmethyl)-1,3-oxazinane-3-carboxylate (46). Yield: 40%. Clear col-
ourless oil that crystallised on standing. M.p. 47–508. [a]2D0 =+94.7 (c=1.1, MeOH). IR (NaCl): 3030,
1
2800, 1765, 1714, 1413, 1260, 1154, 1001, 833, 739, 700. H-NMR (300 MHz, CDCl3; rotamers): 7.37 (s,
5 H); 7.33–7.09 (m, 5 H); 5.76 (br. s, 1 H); 5.21 (s, 2 H); 4.66 (d, J=10.5, 1 H); 4.39 (m, 1 H);
3.00–2.50 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 169.5; 154.0; 135.1; 129.3; 128.8; 128.4; 128.2; 127.9;
126.9; 72.2; 68.0; 50.6; 39.7; 33.7. HR-MS: 325.1219 (M+, C19
N
N
Phenylmethyl (4R)-4-[(Acetyloxy)methyl]-6-oxo-1,3-oxazinane-3-carboxylate (47). Yield: 40%.
Clear colourless oil that crystallised on standing. M.p. 63–648. [a]1D9 =+101.0 (c=0.2, MeOH). IR
1
(NaCl): 3065, 3035, 1765, 1744, 1715, 1415, 1265, 1238, 1157, 1045, 1002, 771, 753, 699. H-NMR (300
MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.82 (br. s, 1 H); 5.16 (s, 2 H); 5.04 (d, J=9.9, 1 H); 4.42–4.40
(m, 1 H); 4.34–4.04 (m, 2 H); 2.76 (d, J=9.0, 2 H); 2.02 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 170.0;
168.8; 153.9; 134.9; 128.3; 128.2; 127.9; 127.8; 72.6; 69.4; 64.1; 48.5; 31.5; 20.3. HR-MS: 308.1130
([M+H]+, C15
N
N
Phenylmethyl (4R)-4-[(1R)-1-(Acetyloxy)ethyl]-6-oxo-1,3-oxazinane-3-carboxylate (48). Yield:
43%. Clear colourless oil that crystallised on standing. M.p. 69–718. [a]2D0 =+129.0 (c=0.6, MeOH).
IR (NaCl): 2986, 1761, 1737, 1718, 1455, 1263, 1135, 1152, 1027, 993, 829, 755, 699. 1H-NMR (300
MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.85 (br. s, 1 H); 5.16 (s, 2 H); 5.05–4.99 (m, 2 H); 4.39 (br. s, 1
H); 2.77 (dd, J=7.7, 16.3, 1 H); 2.60 (dd, J=9.5, 16.3, 1 H); 1.96 (s, 3 H); 1.21 (d, J=6.1, 3 H). 13C-
NMR (75 MHz, CDCl3): 169.6; 168.5; 154.6; 134.8; 128.3; 128.2; 128.0; 73.2; 70.8; 68.2; 51.9; 31.2;
20.5; 15.6. Anal. calc. for C16H19NO6 (321.33): C 59.81, H 5.96, N 4.36; found: C 59.66, H 5.69, N 4.48.
Phenylmethyl 4,4-Dimethyl-6-oxo-1,3-oxazinane-3-carboxylate (65). Yield: 95%. Colourless solid.
1
M.p. 70–718. IR (KBr): 3030, 2970, 1769, 1712, 1410, 1359, 1312, 1265, 1116, 1026, 698. H-NMR (300
MHz, CDCl3; rotamers): 7.29 (s, 5 H); 5.42 (s, 2 H); 5.10 (s, 2 H); 2.65–2.62 (m, 2 H); 1.46 (s, 6 H).
13C-NMR (75 MHz, CDCl3; rotamers): 170.0; 153.0; 135.4; 128.3; 128.1; 128.0; 127.8; 127.6; 72.8; 67.3;
54.7; 44.5; 26.7. HR-MS: 264.1231 ([M+H]+, C14
N
N
General Procedure for the Preparation of the N-Methyl b-Amino Acids 49–60 and 61 from 1,3-Oxa-
zinan-6-ones. The 1,3-oxazinan-6-one (1 mmol) was dissolved in the minimum volume of CH2Cl2/
CF3CO2H 1:1 (v/v). Et3SiH (3 mmol) was added, and the mixture was stirred for 24–48 h, until no
G
1,3-oxazinan-6-one remained (TLC control). Toluene was added to the soln., and the solvent was evapo-
rated in vacuo. This procedure was repeated three times to remove traces of CF3CO2H. The residue was
taken up in Et2
A
Et2O. The aq. fraction was adjusted to pH 2 with dilute aq. HCl, and the aq. layers were re-extracted with
AHCTREUNG
AcOEt (3”). The combined org. phases were dried (MgSO4) and evaporated under reduced pressure.
When there was any trace of CF3CO2H, the product was purified by CC on a short plug of silica gel
(5–10% MeOH/CH2Cl2). For analysis and ease of handling, the free acid could be converted to the
tert-butylammonium salt in the usual manner. The free acid was taken up in the minimum volume of
anh. Et
A
hexane sometimes aided the precipitation process. Stirring was generally continued for 16 h. The precip-
itate was suction-filtered and washed with cold Et
solid.
A
3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic Acid (49). Yield: 50%. Clear colourless
oil. Anal. data of dicyclohexylammonium salt: M.p. 116–1198. IR (KBr): 3438, 3028, 2936, 2853, 2807,
1
2521, 2420, 2363, 1698, 1636, 1556, 1397, 1305, 1200, 1137. H-NMR (300 MHz, D2
A
(s, 5 H); 5.01 (s, 2 H); 3.45–3.41 (m, 2 H); 3.12–3.11 (m, 2 H); 2.77 (s, 3 H); 2.27 (t, J=10.8, 2 H),
1.91–1.00 (m, 20 H). 13C-NMR (75 MHz, D2
AHCTREUNG
45.9; 35.8; 35.5; 34.0; 33.7; 24.1; 23.6; 28.7. Anal. calc. for C24H38N2O4 (418.57): C 68.87, H 9.15, N
6.79; found: C 68.86, H 9.16, N 6.79.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (50). Yield: 50%. Clear colour-
less oil. Anal. data of tert-butylammonium salt: M.p. 101–1068. [a]2D0 =+11.0 (c=3.0, MeOH). IR
1
(KBr): 2976, 2743, 2612, 2226, 1684, 1562, 1398, 1330, 1202, 1143, 1019, 737, 700. H-NMR (300 MHz,
CDCl3; rotamers): 7.38 (s, 3 H); 7.31–7.24 (m, 5 H); 5.07 (s, 2 H); 4.57 (q, J=9.3, 1 H); 2.78 (s, 3 H);

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Helvetica Chimica Acta – Vol. 89 (2006)
2.43–2.23 (m, 2 H); 1.27 (s, 9 H); 1.14 (d, J=6.8, 3 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers):
176.6; 155.7; 136.7; 128.7; 128.0; 127.8; 127.5; 127.4; 127.2; 66.5; 50.5; 49.4; 42.4; 28.2; 27.6; 17.6. Anal.
calc. for C17H28N2O4 (324.42): C 62.94, H 8.70, N 8.64; found: C 62.87, H 8.74, N 8.70.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (51). Yield: 50%. Clear colour-
less oil. Anal. data of tert-butylammonium salt: M.p. 92–978. [a]1D8 =+1.3 (c=1.2, MeOH). IR (KBr):
3417, 2973, 2915, 2834, 2746, 2634, 2545, 2433, 2379, 2227, 1697, 1645, 1560, 1450, 1143, 763, 736, 696.
1H-NMR (300 MHz, D2
ACHTREUNG
AHCTREUNG
55.5; 51.5; 40.8; 40.6; 27.5; 27.3; 26.2; 24.4; 24.2; 9.6. Anal. calc. for C18H30N2O4 (338.22): C 63.88, H
8.93, N 8.28; found: C 63.84, H 8.78, N 8.29.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (52). Yield: 41%. Clear colour-
less oil. Anal. data of tert-butylammonium salt: M.p. 96–1008. [a]1D8 =+4.3 (c=3.2, MeOH). IR (KBr):
1
3440, 2959, 2500, 2240, 1694, 1553, 1457, 1403, 1336, 1218, 1145, 1001, 762, 702. H-NMR (300 MHz,
CDCl3, 318 K; rotamers): 7.31–7.28 (m, 5 H); 6.38 (s, 3 H); 5.10–5.06 (m, 2 H); 4.48 (m, 1 H); 2.77 (s,
3 H); 2.40–2.32 (m, 2 H); 1.48–1.44 (m, 2 H); 1.34–1.20 (m, 2 H); 1.27 (s, 9 H); 0.90–0.84 (m, 3 H).
13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 176.3; 156.3; 136.7; 128.0; 127.3; 127.1; 66.5; 53.5; 50.3;
40.8; 40.4; 34.2; 29.2; 28.8; 27.9; 19.0; 13.4. Anal. calc. for C19H32N2O4 (352.24): C 64.74, H 9.15, N
7.95; found: C 64.74, H 9.15, N 7.95.
(3S)-4-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (53). Yield: 63%.
Anal. data of tert-butylammonium salt: M.p. 99–1018. [a]2D1 =ꢀ7.5 (c=1.1, MeOH). IR (KBr): 3408,
2937, 2928, 2742, 2635, 2361, 2341, 2224, 1689, 1638, 1543, 1406, 1324, 969, 700, 672. 1H-NMR (300
MHz, D
ACHTREUNG
H); 2.44–2.10 (m, 2 H); 1.65–1.57 (m, 1 H); 1.20 (s, 9 H); 0.76–0.60 (m, 6 H). 13C-NMR (75 MHz, D2
AHCTREUNG
rotamers): 180.2; 180.1; 158.2; 157.7; 136.5; 136.3; 128.4; 128.3; 127.9; 127.5; 127.2; 67.2; 66.9; 60.6; 51.6;
38.8; 38.7; 29.9; 28.5; 26.3; 18.7; 18.6; 18.5. HR-MS: 278.1396 ([MꢀH]–, C15
N
N
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)heptanoic Acid (54). Yield: 57%. Clear colour-
less oil. Anal. data of tert-butylammonium salt: M.p. 88–918. [a]2D1 =+5.5 (c=3.1, MeOH). IR (KBr):
2927, 2636, 2550, 2236, 1687, 1640, 1542, 1424, 1410, 1345, 1212, 1129, 1115, 1032, 966, 768, 745, 700.
1H-NMR (300 MHz, CDCl3, 318 K; rotamers: 7.31 (s, 8 H); 5.10–5.04 (m, 2 H); 4.48–4.43 (m, 1 H);
2.76 (s, 3 H); 2.40–2.25 (m, 2 H); 1.46 (m, 2 H); 1.35–1.20 (m, 4 H); 1.25 (s, 9 H); 0.83 (m, 3 H). 13C-
NMR (75 MHz, CDCl3, 318 K; rotamers): 176.4; 156.2; 136.8; 128.0; 127.3; 127.1; 66.5; 53.8; 50.0;
41.3; 40.8; 31.7; 28.2; 28.1; 22.0; 13.9. Anal. calc. for C20H34N2O4 (366.49): C 65.54, H 9.35, N 7.64;
found: C 65.67, H 9.05, N 7.66.
(3S)-5-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (55). Yield: 58%.
Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 97–1018. [a]1D8 =+7.5 (c=1.1,
1
MeOH). IR (KBr): 2927, 2628, 2549, 2227, 1690, 1638, 1539, 1408, 1321, 1218, 1118, 963, 753, 698. H-
NMR (300 MHz, CDCl3; rotamers): 7.30–7.26 (m, 5 H); 7.03 (s, 3 H); 5.13–5.04 (s, 2 H); 4.57 (m, 1
H); 2.76 (s, 3 H); 2.39–2.21 (m, 2 H); 1.46–1.44 (m, 2 H); 1.34–1.16 (m, 1 H); 1.26 (s, 9 H); 0.87–0.85
(m, 6 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 176.5; 156.1; 136.7; 127.9; 127.3; 127.1; 66.4;
51.9; 50.0; 41.6; 41.1; 28.0; 24.6; 22.9; 21.5. Anal. calc. for C20H34N2O4 (366.45): C 65.54, H 9.35, N
7.64; found: C 65.51, H 9.29, N 7.71.
(3R,4S)-4-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (56). Yield: 45%.
Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 94–978. [a]2D0 =ꢀ1.0 (c=2.0,
MeOH). IR (KBr): 3400, 2965, 2928, 2747, 2635, 2361, 2342, 2227, 1689, 1638, 1543, 1409, 1323, 1134,
699, 669. 1H-NMR (300 MHz, CDCl3; rotamers): 7.31–7.27 (m, 5 H); 6.40 (s, 3 H); 5.11–4.98 (m, 2
H); 4.21–4.13 (m, 1 H); 2.79 (s, 3 H); 2.50–2.31 (m, 2 H); 1.55 (m, 1 H); 1.41–1.00 (m, 2 H); 1.27 (s, 9
H); 0.89–0.80 (m, 6 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 176.6; 156.5; 136.8; 127.9;
127.3; 127.0; 66.5; 58.7; 50.0; 38.2; 38.0; 37.0; 36.5; 29.9; 29.2; 28.4; 25.3; 15.5; 10.5. Anal. calc. for
C20H34N2O4 (366.49): C 65.54, H 9.35, N 7.64; found: C 65.74, H 9.07, N 7.77.
3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-phenylpropanoic Acid (57). Yield: 44%. Clear
colourless oil. Anal. data of tert-butylammonium salt: M.p. 116–1198. IR (KBr): 3520, 3502, 3405,
2972, 2836, 2738, 2635, 2429, 2350, 2229, 1692, 1639, 1552, 1393, 1277, 759, 739, 698, 654. 1H-NMR

Helvetica Chimica Acta – Vol. 89 (2006)
2625
(300 MHz, D2
ACHTREUNG
9 H). 13C-NMR (75 MHz, D2
AHCTREUNG
67.3; 56.5; 51.6; 39.0; 29.9; 29.1; 26.3. Anal. calc. for C22H30N2O4 (386.48): C 68.37, H 7.82, N 7.25;
found: C 68.38, H 7.75, N 7.26.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-phenylbutanoic Acid (58). Yield: 60%.
Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 105–1088. [a]1D8 =ꢀ6.7 (c=1.4,
MeOH). IR (KBr): 3428, 2979, 2633, 2538, 2466, 2242, 1687, 1620, 1404, 1339, 1204, 1119, 979, 742,
699. 1H-NMR (300 MHz, CDCl3, 318 K; rotamers): 7.26–7.15 (m, 10 H); 7.06 (s, 3 H); 5.00–4.91 (m, 2
H); 4.61 (m, 1 H); 2.83–2.69 (m, 5 H); 2.50–2.41 (m, 2 H); 1.22 (s, 9 H). 13C-NMR (75 MHz, CDCl3,
318 K; rotamers): 176.6; 155.7; 138.4; 136.7; 129.1; 128.7; 127.9; 127.8; 127.2; 127.0; 125.8; 66.5; 66.1;
56.4; 55.6; 50.1; 40.9; 40.3; 38.5; 38.1; 30.3; 29.6; 28.2. Anal. calc. for C23H32N2O4 (400.51): C 68.97, H
8.05, N 6.99; found: C 68.87, H 8.06, N 7.02.
(3R)-4-(Acetyloxy)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (59). Yield: 56%.
Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 101–1048. [a]2D2 =+10.3 (c=3.2,
MeOH). IR (KBr): 2974, 2897, 2838, 2743, 2632, 2555, 2361, 2342, 2217, 1739, 1702, 1686, 1562, 1432,
1
1389, 1327, 1236, 1121, 758, 701. H-NMR (300 MHz, D2
A
2 H); 4.87 (br. s, 1 H); 4.36–4.28 (m, 2 H); 2.99 (s, 3 H); 2.61–2.57 (m, 2 H); 2.08 (s, 3 H); 1.54 (s, 9
H). 13C-NMR (75 MHz, D2
AHCTREUNG
63.6; 53.2; 52.0; 36.9; 29.3; 26.6; 20.0. Anal. calc. for C19H30N2O6 (382.45): C 59.67, H 7.91, N 7.32;
found: C 59.39, H 7.67, N 7.57.
(3R,4R)-4-(Acetyloxy)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (60). Yield:
50%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 94–988. [a]2D0 =+28.4 (c=3.2,
MeOH). IR (KBr): 3422, 2987, 2983, 2845, 2653, 2552, 2362, 2341, 1736, 1697, 1637, 1557, 1403, 1331,
1251, 1150, 743, 699. 1H-NMR (300 MHz, D2
ACHTREUNG
AHCTREUNG
136.7; 128.7; 128.2; 127.9; 127.7; 71.3; 67.6; 67.3; 58.0; 51.9; 37.1; 37.0; 30.1; 29.6; 26.7; 20.4; 16.5.
Anal. calc. for C20H32N2O6 (396.48): C 60.59, H 8.14, N 7.07; found: C 60.31, H 8.35, N 7.19.
3-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (61). Anal. data of dicyclo-
hexylammonium salt: Yield: 71%. Colourless solid. M.p. 102–1058. IR (KBr): 2937, 2859, 2538, 2454,
1
2361, 1685, 1622, 1544, 1457, 1391, 1337, 1267, 1120, 1074, 857, 741, 709. H-NMR (300 MHz, CDCl3;
rotamers): 8.43 (s, 3 H); 7.27 (s, 5 H); 5.02–4.98 (m, 2 H); 2.94 (s, 3 H); 2.90–2.68 (m, 4 H); 1.93–1.12
(m, 26 H). 13C-NMR (75 MHz, CDCl3; rotamers): 176.7; 176.4; 155.8; 137.2; 128.2; 128.0; 127.9; 127.7;
127.5; 127.5; 66.3; 57.0; 52.4; 47.3; 31.8; 27.6; 26.4; 29.3; 25.1; 24.7. HR-MS: 264.1243 ([MꢀH]–, C14
G
G
General Procedure for the Preparation of the 1,3-Oxazolidin-5-ones 71–85, 141, 142, 151, and 157.
These compounds were prepared according to the method of Aurelio et al. [14][16]. The anal. data of
the following compounds were identical with those reported in the literature (for data of other com-
pounds, see below): phenylmethyl 5-oxo-1,3-oxazolidine-3-carboxylate (71) [56], phenylmethyl (4S)-5-
oxo-4-methyl-1,3-oxazolidine-3-carboxylate (72) [57], phenylmethyl (4S)-5-oxo-4-ethyl-1,3-oxazolidine-
3-carboxylate (73) [58], phenylmethyl (4S)-5-oxo-4-phenyl-1,3-oxazolidine-3-carboxylate (79) [14], phe-
nylmethyl (4S)-5-oxo-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate (80) [57], phenylmethyl (4S)-4-
[(acetyloxy)methyl]-5-oxo-1,3-oxazolidine-3-carboxylate (81) [16], phenylmethyl (4S)-4-[(1R)-1-(acetyl-
oxy)ethyl]-5-oxo-1,3-oxazolidine-3-carboxylate (82) [16], phenylmethyl (4S)-4-[4-(1,3-dihydro-1,3-
dioxo-2H-isoindol-2-yl)butyl]-5-oxo-1,3-oxazolidine-3-carboxylate (84) [14], phenylmethyl (4S)-4-[(1-
formyl-1H-indol-3-yl)methyl]-5-oxo-1,3-oxazolidine-3-carboxylate (85) [15][16], phenylmethyl (4R)-5-
oxo-4-{[(phenylmethyl)sulfanyl]methyl}-1,3-oxazolidine-3-carboxylate (141) [16], phenylmethyl (4S)-4-
[2-(methylsulfinyl)ethyl]-5-oxo-1,3-oxazolidine-3-carboxylate (142) [14][16], and phenylmethyl (4S)-5-
oxo-4-({4-[(phenylmethyl)oxy]phenyl}methyl)-1,3-oxazolidine-3-carboxylate (157) [38].
Phenylmethyl (4S)-5-Oxo-4-propyl-1,3-oxazolidine-3-carboxylate (74). Yield: 66%. Clear colourless
oil. [a]2D0 =+72.9 (c=1.0, CH2Cl2). IR (NaCl): 2962, 2931, 1801, 1716, 1415, 1358, 1254, 1131, 1047, 752,
698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.35 (s, 5 H); 5.51 (br. s, 1 H); 5.23–5.03 (m, 3 H); 4.31–4.28

2626
Helvetica Chimica Acta – Vol. 89 (2006)
(m, 1 H); 1.94–1.66 (m, 2 H); 1.38–1.29 (m, 2 H); 0.94–0.89 (t, J=3.5, 3 H). 13C-NMR (75 MHz, CDCl3;
rotamers): 172.4; 152.8; 135.4; 128.6; 128.6; 128.2; 77.9; 67.8; 54.8; 32.7; 17.6; 13.6. HR-MS: 264.1240
([M+H]+, C14
N
N
Phenylmethyl (4S)-4-(1-Methylethyl)-5-oxo-1,3-oxazolidine-3-carboxylate (75). Yield: 90%. Colour-
less solid. M.p. 548. [a]2D0 =+89.2 (c=1.3, CH2Cl2). IR (NaCl): 2966, 1801, 1715, 1414, 1360, 1239, 1125,
1052, 752, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.56 (br. s, 1 H); 5.21–5.13 (m, 3 H);
4.20 (br. s, 1 H); 2.34 (br. s, 1 H); 1.06–1.04 (d, J=3.4, 3 H); 0.99 (d, J=3.4, 3 H). 13C-NMR (75 MHz,
CDCl3; rotamers): 171.4; 153.6; 135.3; 128.6; 128.5; 128.2; 78.4; 67.9; 60.1; 31.2; 17.8; 17.7. Anal. calc.
for C14H17NO4 (263.29): C 63.87, H 6.51, N 5.32; found: C 63.89, H 6.47, N 5.28.
Phenylmethyl (4S)-4-Butyl-5-oxo-1,3-oxazolidine-3-carboxylate (76). Yield: 70%. Clear colourless
oil. [a]2D0 =+81.1 (c=1.0, CH2Cl2). IR (NaCl): 2958, 2930, 1803, 1717, 1415, 1358, 1246, 1131, 1052,
1
750, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.50 (br. s, 1 H); 5.24–5.10 (m, 3 H);
4.30 (br. s, 1 H); 1.98–1.72 (m, 2 H); 1.29 (br. s, 4 H); 0.86 (br. s, 3 H). 13C-NMR (75 MHz, CDCl3; rotam-
ers): 172.4; 152.8; 135.4; 128.6; 128.5; 128.2; 77.9; 67.8; 54.9; 30.3; 26.2; 22.2; 13.7. HR-MS: 278.1395
([M+H]+, C15
N
N
Phenylmethyl (4S)-4-(2-Methylpropyl)-5-oxo-1,3-oxazolidine-3-carboxylate (77). Yield: 95%. Col-
ourless solid. M.p. 63–648. [a]2D0 =+79.2 (c=1.0, CH2Cl2). IR (NaCl): 2959, 1802, 1715, 1416, 1359,
1
1217, 1133, 1029. H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.55 (br. s, 1 H); 5.22–5.11 (m,
3 H); 4.32 (br. s, 1 H); 1.78–1.67 (m, 3 H); 1.06–1.04, 0.92–0.90 (2m, 6 H). 13C-NMR (75 MHz,
CDCl3; rotamers): 172.6; 153.1; 135.3; 128.6; 128.6; 128.3; 77.4; 68.0; 53.5; 39.5; 24.3; 22.4; 22.3. HR-
MS: 278.1393 ([M+H]+, C15
N
N
Phenylmethyl (4S)-4-[(1S)-1-Methylpropyl]-5-oxo-1,3-oxazolidine-3-carboxylate (78). Yield: 66%.
Colourless solid. M.p. 66–688. [a]2D3 =+97.7 (c=1.0, CH2Cl2). IR (NaCl): 2965, 1802, 1716, 1414, 1358,
1230, 1125, 1052, 761, 697. 1H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H); 5.53 (br. s, 1 H);
5.21–5.11 (m, 3 H); 4.25 (br. s, 1 H); 2.08 (br. s, 1 H); 1.63–1.35 (m, 2 H); 0.94–0.92 (m, 6 H). 13C-
NMR (75 MHz, CDCl3; rotamers): 171.1; 153.1; 135.3; 128.5; 128.4; 128.1; 78.2; 67.8; 58.9; 37.8; 24.8;
14.5; 11.6. Anal. calc. for C15H19NO4 (277.32): C 64.97, H 6.91, N 5.05; found: C 64.93, H 7.01, N 5.03.
Phenylmethyl (4S)-4-[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-5-oxo-1,3-oxazolidine-3-
carboxylate (83). The anal. data were identical with those reported in [59]. Yield: 70%. Clear colourless
oil. [a]2D4 =+52.9 (c=0.88, CH2Cl2). IR (NaCl): 2928, 1801, 1772, 1712, 1398, 1247, 1129, 1037, 749, 698.
1H-NMR (300 MHz, CDCl3; rotamers): 7.81–7.67 (m, 4 H); 7.31 (s, 5 H); 5.50 (br. s, 1 H); 5.21–5.08 (m,
3 H); 4.33 (br. s, 1 H); 3.66 (br. s, 2 H); 2.01–1.71 (m, 4 H). 13C-NMR (75 MHz, CDCl3; rotamers): 171.8;
168.1; 152.8; 135.2; 133.9; 131.91; 129.0; 128.6; 128.5; 128.2; 123.2; 77.8; 67.9; 54.4; 28.02; 23.8. HR-MS:
409.1387 ([M+H]+, C22
A
G
N
Phenylmethyl (4S)-4-{[4-(Methyloxy)phenyl]methyl}-5-oxo-1,3-oxazolidine-3-carboxylate (151).
Yield: 80%. Colourless solid. M.p. 64–668. [a]2D0 =182.0 (c=2.4, CH2Cl2). IR (KBr): 3033, 2958, 2914,
1
2837, 1800, 1715, 1613, 1513, 1417, 1249, 1125, 1051, 763, 699. H-NMR (300 MHz, CDCl3; rotamers):
7.38 (s, 5 H); 7.05–6.95 (m, 2 H); 6.74 (d, J=8.3, 2 H); 5.27–5.18 (m, 3 H); 4.49 (br. s, 1 H); 4.28–4.26
(m, 1 H); 3.74 (s, 3 H); 3.50–3.00 (m, 2 H). 13C-NMR (75 MHz, CDCl3; rotamers): 171.9; 158.9; 152.4;
152.0; 135.5; 125.9; 130.6; 128.6; 128.5; 128.4; 114.1; 78.0; 77.8; 67.7; 56.4; 55.1; 35.3; 34.1. HR-MS:
341.1267 (M+, C19
N
N
General Procedure for the Preparation of the N-Methyl a-Amino Acids 86–100, 125, 126, 133, 134,
143, 152, 158, 159, and 169. These compounds were prepared according to the procedure of Aurelio
et al. [16]. The anal. data of the following compounds were identical with those reported in the literature
(for other data, see below): (methyl{[(phenylmethyl)oxy]carbonyl}amino)acetic acid (86) [60],
(2S)-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic acid (88) [61], (2S)-2-(methyl{[(phenylmethyl)-
oxy]carbonyl}amino)pentanoic acid (89) [62], (2S)-3-methyl-2-(methyl{[(phenylmethyl)oxy]carbonyl}ami-
G
no)butanoic acid (90) [63], (2S)-4-methyl-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic acid
(92) [64], (2S)-(methyl{[(phenylmethyl)oxy]carbonyl}amino)(phenyl)ethanoic acid (94) [14], (2S)-2-
(methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-phenylpropanoic acid (95) [64], (2S)-3-(acetyloxy)-2-
(methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic acid (96) [16], (2S,3R)-3-(acetyloxy)-2-(meth-
yl{[(phenylmethyl)oxy]carbonyl}amino)butanoic acid (97) [16], (2S)-6-(1,3-dioxo-1,3-dihydro-2H-isoin-
dol-2-yl)-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic acid (99) [14], (2S)-3-(1-formyl-1H-

Helvetica Chimica Acta – Vol. 89 (2006)
2627
indol-3-yl)-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic acid (100) [15][16], (2S)-2-(meth-
yl{[(phenylmethyl)oxy]carbonyl}amino)-4-oxo-4-[(phenylmethyl)oxy]butanoic acid (125) [14], (2R)-2-
({2-oxo-2-[(phenylmethyl)oxy]ethyl}amino)-3-[(phenylmethyl)sulfanyl]propanoic acid (143) [16], (2S)-
2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-(methylsulfanyl)butanoic acid (144) [16], (2S)-2-
(methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-{4-[(phenylmethyl)oxy]phenyl}propanoic acid (158)
[66], (2S)-3-(4-hydroxyphenyl)-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic acid (159)
[14], and (2S)-3-[1-(2,4-dinitrophenyl)-1H-imidazol-4-yl]-2-(methyl{[(phenylmethyl)oxy]carbonyl}ami-
no)propanoic acid (169) [16].
(2S)-2-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic Acid (87). Yield: 89%. Colourless
solid. M.p. 54–568. [a]2D3 =ꢀ20.0 (c=1.0, CH2Cl2). IR (NaCl): 3446, 3034, 2947, 1740, 1698, 1456, 1404,
1319, 1211, 1162, 1096, 738, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 9.62 (br. s, 1 H); 7.33–7.31
(m, 5 H); 5.14 (s, 2 H); 4.91–4.71 (m, 1 H); 2.90 (s, 3 H); 1.45–1.42 (d, J=3.9, 3 H). 13C-NMR (75
MHz, CDCl3; rotamers): 177.0; 156.8; 156.1; 136.3; 128.4; 128.0; 128.8; 67.6; 54.2; 30.9; 30.4; 15.0;
14.5. HR-MS: 238.1071 ([M+H]+, C12
N
N
(2S)-2-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (91). Yield: 75%. Clear colour-
less oil. [a]2D1 =ꢀ26.4 (c=1.8, CH2Cl2). IR (NaCl): 3440, 3034, 2958, 1705, 1681, 1456, 1403, 1366,
1
1212, 1158, 1113, 735, 697. H-NMR (300 MHz, CDCl3; rotamers): 10.74 (s, 1 H); 7.36–7.31 (m, 5 H);
5.22–5.10 (s, 2 H); 4.88–4.63 (m, 1 H); 2.91–2.89 (s, 3 H); 2.03–1.72 (m, 2 H); 1.38–1.24 (m, 4 H);
0.93–0.86 (m, 3 H). 13C-NMR (75 MHz, CDCl3; rotamers): 176.6; 176.3; 157.3; 156.6; 136.2; 136.0;
128.3; 127.9; 127.6; 127.5; 67.6; 58.2; 30.6; 30.1; 28.2; 28.0; 27.9; 21.9; 13.7. Anal. calc. for C15H21NO4
(279.33): C 64.50, H 7.58, N 5.01; found: C 64.45, H 7.52, N 4.97.
(2S,3S)-3-Methyl-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (93). Yield: 78%.
Clear colourless oil. [a]2D1 =ꢀ52.0 (c=1.7, CH2Cl2). IR (NaCl): 3440, 3034, 2967, 1736, 1702, 1675,
1
1457, 1401, 1340, 1259, 1152, 1123, 735, 697. H-NMR (300 MHz, CDCl3; rotamers): 8.78 (s, 1 H); 7.34
(s, 5 H); 5.16 (s, 2 H); 4.57–4.41 (m, 1 H); 2.93 (s, 3 H); 2.03–1.99 (m, 1 H); 1.42–0.85 (m, 8 H). 13C-
NMR (75 MHz, CDCl3; rotamers): 175.4; 157.3; 156.6; 136.1; 128.4; 128.0; 127.7; 67.8; 63.1; 62.9; 33.3;
30.7; 25.0; 15.7; 10.5; 10.4. HR-MS: 280.1546 ([M+H]+, C15
N
N
(2S)-5-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-
pentanoic Acid (98). Yield: 63%. Clear colourless oil. [a]2D1 =0.0 (c=1.2, CH2Cl2). IR (NaCl): 3440, 2958,
1709, 1653, 1456, 1398, 720, 665. 1H-NMR (300 MHz, CDCl3; rotamers): 7.84–7.70 (m, 4 H); 7.34–7.28
(m, 5 H); 5.13 (s, 2 H); 4.84–4.70 (m, 1 H); 3.73–3.65 (m, 2 H); 2.87 (s, 3 H); 2.08–1.68 (m, 4 H). 13C-
NMR (75 MHz, CDCl3; rotamers): 175.8; 168.4; 157.3; 156.4; 136.2; 132.0; 134.0; 128.5; 128.0; 127.9;
127.8; 123.3; 67.8; 58.2; 58.0; 37.2; 37.1; 31.1; 30.8; 25.9; 25.7; 25.3. HR-MS: 411.1561 ([M+H]+, C22
A
A
ACHTREUNG
(2S)-2-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-oxo-5-[(phenylmethyl)oxy]pentanoic Acid
(126). Yield: 81%. Colourless oil. [a]2D1 =ꢀ21.1 (c=0.57, CH2Cl2). IR (NaCl): 3440, 3033, 2952, 1736,
1705, 1455, 1401, 1319, 1213, 1168, 738, 697. 1H-NMR (300 MHz, CDCl3; rotamers): 8.24 (s, 1 H);
7.33–7.28 (m, 10 H); 5.13–5.05 (m, 4 H); 4.80–4.65 (m, 1 H); 2.86 (s, 3 H); 2.41–2.08 (m, 4 H). 13C-
NMR (75 MHz, CDCl3; rotamers): 175.5; 172.4; 172.3; 156.1; 156.2; 136.2; 136.6; 128.2; 128.4; 128.0;
127.7; 67.7; 66.6; 58.3; 58.1; 31.7; 31.2; 30.7; 30.5; 24.0; 23.7. HR-MS: 386.1602 ([M+H]+, C21
N
N
calc. 386.1604).
(2S)-4-[Bis(phenylmethyl)amino]-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-oxobutanoic
Acid (133). Yield: 62%. Colourless solid. M.p. 129–1328. [a]2D0 =ꢀ4.8 (c=1.2, CH2Cl2). IR (KBr): 3065,
3031, 2933, 1735, 1700, 1652, 1604, 1453, 1214, 1154, 733, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 9.90
(s, 1 H); 7.34–7.06 (m, 15 H); 5.15–4.31 (m, 7 H); 3.28–2.82 (m, 5 H). 13C-NMR (75 MHz, CDCl3;
rotamers): 174.2; 174.0; 171.3; 171.0; 156.2; 155.6; 136.3; 136.0; 135.6; 128.7; 128.6; 128.4; 128.2; 127.8;
127.5; 127.2; 126.3; 126.0; 67.4; 67.2; 59.1; 58.0; 49.9; 49.7; 48.5; 48.3; 35.6; 35.4; 34.0; 33.4. HR-MS:
460.1989 (M+, C27
A
G
N
(2S)-5-[Bis(phenylmethyl)amino]-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-oxopentanoic
acid (134). Yield: 90%. Colourless solid. [a]D16 =ꢀ8.7 (c=2.0, CH2Cl2). IR (KBr): 3064, 3031, 2942, 1733,
1703, 1650, 1605, 1453, 1361, 1212, 1171, 734, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 10.35 (s, 1 H);
7.33–7.04 (m, 15 H); 5.10–5.08 (m, 2 H); 4.81–4.33 (m, 5 H); 2.87–2.84 (m, 3 H); 2.57–2.01 (m, 4 H).

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Helvetica Chimica Acta – Vol. 89 (2006)
13C-NMR (75 MHz, CDCl3; rotamers): 173.2; 172.7; 157.2; 156.9; 136.4; 135.9; 135.4; 128.7; 128.3; 128.1;
128.0; 127.7; 127.5; 127.3; 126.0; 67.3; 58.4; 49.6; 48.4; 31.2; 29.7; 29.2; 24.3. HR-MS: 475.2235 ([M+H]+,
C
A
G
N
[65]. Yield: 84%. Clear colourless oil. Anal. data of cyclohexylammonium salt: M.p. 96–1028.
[a]1D7 =ꢀ27.1 (c=1.3, CH2Cl2). IR (KBr): 3062, 2937, 2859, 2660, 2565, 1696, 1633, 1611, 1584, 1513,
1
1365, 1313, 1247, 1136, 1036, 697. H-NMR (300 MHz, CDCl3; rotamers): 7.73 (s, 3 H); 7.39–6.69 (m,
9 H); 5.17–4.80 (m, 2 H); 4.74–4.64 (m, 1 H); 3.74 (s, 3 H); 3.30–2.90 (m, 2 H); 2.85–2.78 (m, 3 H);
1.93–1.10 (m, 11 H). 13C-NMR (75 MHz, CDCl3; rotamers): 176.5; 158.1; 156.9; 137.1; 131.2; 129.7;
128.5; 128.1; 127.7; 127.3; 113.8; 66.8; 63.1; 55.2; 50.2; 35.0; 31.9; 31.4; 24.9; 24.5. HR-MS: 344.1500
([M+H]+, C19
N
N
General Procedure for the Preparation of the N-Methyl Diazoketones 101–115, 127, 128, 135, 136,
145, 146, and 153. To a soln. of the N-CBz-protected N-methyl a-L-amino acid (1 mmol) in anh. THF
(5 ml) at ꢀ158 were added successively ethyl chloroformate (1.05 mmol) and N-methylmorpholine
(NMM; 1.05 mmol). The mixture was stirred for 15 min, and then treated dropwise with an anh. soln.
of CH2N2 (5 mmol; CAUTION!) [24] in CH2Cl2. The yellow soln. was allowed to warm to r.t., and stirring
was continued untilthere was no acid remaining (TLC control). Excess CH 2N2 was destroyed by addition
of AcOH. The mixture was concentrated under reduced pressure, and the residue was taken up in
AcOEt. The org. phase was washed successively with sat. aq. NaHCO3 soln., 10% aq. citric acid soln.,
and brine. The org. layer was dried (MgSO4) and evaporated to dryness in vacuo. The product was of suf-
ficient purity to be used directly in the following reaction.
Phenylmethyl (3-Diazo-2-oxopropyl)methylcarbamate (101). Yield: 65%. Clear yellow oil. IR (KBr):
2967, 2109, 1743, 1703, 1456, 1362, 1225, 1146, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 5 H);
5.33–5.23 (m, 1 H); 5.12 (s, 2 H); 3.98–3.94 (m, 2 H); 2.96 (s, 3 H). 13C-NMR (75 MHz, CDCl3; rotam-
ers): 190.8; 156.6; 136.3; 128.4; 128.0; 127.9; 127.8; 127.7; 67.5; 56.3; 50.5; 36.1; 35.4. HR-MS: 248.1035
([M+H]+, C12
A
G
N
Phenylmethyl (3-Diazo-1-methyl-2-oxopropyl)methylcarbamate (102). Yield: 70%. Clear yellow oil.
[a]1D8 =ꢀ148.8 (c=1.1, CH2Cl2). IR (NaCl): 3091, 2985, 2944, 2107, 1741, 1700, 1647, 1356, 1307, 1162,
1
770, 753, 738, 699. H-NMR (300 MHz, CDCl3; rotamers): 7.28 (s, 5 H); 5.36–5.25 (m, 1 H); 5.09 (s, 2
H); 4.77–4.56 (m, 1 H); 2.78 (s, 3 H); 1.26 (d, J=7.2, 2 H). 13C-NMR (75 MHz, CDCl3): 192.9; 156.1;
155.5; 136.0; 128.1; 127.8; 127.5; 67.2; 58.5; 57.7; 53.1; 30.8; 29.3; 13.3; 12.7. HR-MS: 262.1183
([M+H]+, C13
A
G
N
Phenylmethyl (3-Diazo-1-ethyl-2-oxopropyl)methylcarbamate (103). Yield: 80%. Clear yellow oil.
[a]1D9 =ꢀ194.4 (c=1.4, CH2Cl2). IR (NaCl): 3067, 2984, 2944, 2107, 1741, 1700, 1647, 1356, 1307, 1162,
1
770, 753, 699. H-NMR (300 MHz, CDCl3; rotamers): 7.34 (s, 5 H); 5.40–5.27 (m, 1 H); 5.15 (s, 2 H);
4.69–4.43 (m, 1 H); 2.81 (s, 3 H); 1.98–1.58 (m, 2 H); 0.87 (t, J=10.6, 3 H). 13C-NMR (75 MHz,
CDCl3): 192.5; 156.9; 156.0; 136.3; 128.3; 127.9; 127.5; 67.4; 64.0; 63.1; 53.8; 30.1; 29.3; 20.4; 20.1; 10.1.
Phenylmethyl [(1S)-1-(Diazoacetyl)butyl]methylcarbamate (104). Yield: 61%. Clear yellow oil.
[a]2D0 =ꢀ194.7 (c=1.3, CH2Cl2). IR (NaCl): 2961, 2936, 2105, 1697, 1644, 1352, 1309, 1149, 783, 769,
742, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.12 (s, 5 H); 5.26–5.13 (m, 1 H); 4.94 (s, 2 H);
4.53–4.33 (m, 1 H); 2.59 (s, 3 H); 1.66–1.37 (m, 2 H); 1.07–1.02 (m, 2 H); 0.71 (t, J=10.6, 3 H). 13C-
NMR (75 MHz, CDCl3): 192.3; 156.5; 155.4; 136.5; 128.0; 127.5; 127.1; 66.8; 62.4; 61.5; 53.6; 30.2;
29.5; 29.1; 28.6; 18.5; 13.1. HR-MS: 290.1510 ([M+H]+, C15
A
G
N
Phenylmethyl [(1S)-3-Diazo-1-(1-methylethyl)-2-oxopropyl]methylcarbamate (105). Yield: 50%.
Clear yellow oil. [a]2D0 =ꢀ306.7 (c=1.2, CH2Cl2). IR (NaCl): 3106, 3068, 3034, 2964, 2875, 2102, 1696,
1
1644, 1470, 1399, 1371, 1338, 1226, 1170, 978, 791, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.14 (s,
5 H); 5.31 (s, 1 H); 4.97 (s, 2 H); 4.12–3.92 (m, 1 H); 2.64 (s, 3 H); 2.15–2.03 (m, 1 H); 0.76 (d, J=6.5,
3 H); 0.66 (d, J=5.2, 3 H). 13C-NMR (75 MHz, CDCl3): 191.0; 190.6; 156.4; 155.3; 136.2; 128.0; 127.7;
127.6; 127.5; 127.1; 66.9; 66.1; 54.6; 29.9; 29.4; 25.5; 25.1; 19.3; 19.1; 18.2; 18.1.
Phenylmethyl [(1S)-1-(Diazoacetyl)pentyl]methylcarbamate (106). Yield: 65%. Clear yellow oil.
[a]1D8 =ꢀ182.9 (c=1.1, CH2Cl2). IR (NaCl): 2957, 2932, 2105, 1698, 1645, 1497, 1398, 1353, 1150, 1130,
770, 751, 735, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.11–7.02 (m, 5 H); 5.26–5.16 (m, 1 H);
4.95 (s, 2 H); 4.51–4.30 (m, 1 H); 2.59 (s, 3 H); 1.67–1.39 (m, 2 H); 1.10–1.00 (m, 4 H); 0.66 (t,

Helvetica Chimica Acta – Vol. 89 (2006)
2629
J=10.4, 3 H). 13C-NMR (75 MHz, CDCl3): 192.3; 156.3; 155.1; 136.0; 127.9; 127.5; 127.1; 66.84; 62.1;
61.3; 53.2; 29.8; 29.0; 27.4; 26.6; 26.2; 21.8; 13.3. HR-MS: 304.1664 ([M+H]+, C16 O3þ ; calc.
H22N3
304.1661).
A
N
ACHTREUNG
Phenylmethyl [(1S)-1-(Diazoacetyl)-3-methylbutyl]methylcarbamate (107). Yield: 54%. Clear yellow
oil. [a]1D8 =ꢀ161.8 (c=1.3, CH2Cl2). IR (NaCl): 2957, 2871, 2106, 1669, 1646, 1468, 1347, 1310, 1163, 1131,
771, 753, 736, 698. 1H-NMR (30 MHz, CDCl3; rotamers): 7.21–7.12 (m, 5 H); 5.30–5.18 (m, 1 H); 5.03 (s,
2 H); 4.70–4.49 (m, 1 H); 2.67 (s, 3 H); 1.54–1.49 (m, 2 H); 1.38–1.34 (m, 1 H); 0.81–0.68 (m, 6 H). 13C-
NMR (75 MHz, CDCl3): 192.5; 156.8; 155.9; 136.1; 135.8; 128.0; 127.7; 127.6; 127.2; 67.0; 60.1; 60.0; 53.3;
35.9; 35.5; 30.2; 29.2; 24.2; 24.0; 22.7; 21.2; 20.9. HR-MS: 304.1664 ([M+H]+, C16
304.1661).
A
G
N
Phenylmethyl [(1S,2S)-1-(Diazoacetyl)-2-methylbutyl]methylcarbamate (108). Yield: 50%. Clear yel-
low oil. [a]1D8 =ꢀ280.3 (c=0.58, CH2Cl2). IR (NaCl): 3066, 2964, 2932, 2104, 1697, 1646, 1454, 1346, 1304,
1139, 1115, 786, 767, 697. 1H-NMR (300 MHz, CDCl3; rotamers): 7.28 (s, 5 H); 5.39 (s, 1 H); 5.08 (s, 2 H);
4.31–4.11 (m, 1 H); 2.76 (s, 3 H); 2.04 (s, 1 H); 1.34–0.95 (m, 2 H); 0.84–0.78 (m, 6 H). 13C-NMR (75
MHz, CDCl3): 191.1; 190.6; 156.5; 155.5; 136.1; 136.0; 128.1; 128.0; 127.9; 127.8; 127.6; 127.2; 67.2;
67.1; 65.1; 64.6; 54.8; 30.9; 30.5; 29.5; 29.0; 24.2; 24.0; 15.2; 9.9.
Phenylmethyl [(1S)-3-Diazo-2-oxo-1-phenylpropyl]methylcarbamate (109). Yield: 71%. Clear yel-
low oil. IR (NaCl): 3090, 3065, 3032, 2950, 2106, 1696, 1650, 1496, 1453, 1353, 1146, 798, 754, 738, 700.
1H-NMR (300 MHz, CDCl3; rotamers): 7.26–7.12 (m, 10 H); 5.90 (br. s, 1 H); 5.18 (s, 1 H); 5.09 (s, 2
H); 2.69 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 191.3; 156.5; 141.3; 136.2; 129.3; 128.9; 128.7; 128.5;
128.4; 128.3; 128.1; 127.9; 127.7; 127.4; 67.6; 65.8; 54.6; 31.5. HR-MS: 324.1348 ([M+H]+, C18
A
G
N
calc. 324.1348).
Phenylmethyl [(1S)-3-Diazo-2-oxo-1-(phenylmethyl)propyl]methylcarbamate (110). Yield: 51%.
Clear, yellow oil. [a]1D8 =ꢀ128.8 (c=0.9, CH2Cl2). IR (NaCl): 3065, 3030, 2953, 2856, 2107, 1700, 1643,
1496, 1454, 1353, 1139, 769, 749, 699. 1H-NMR (300 MHz, CDCl3; rotamers): 7.45–7.08 (m, 10 H);
5.39–5.27 (m, 1 H); 5.13–4.92 (m, 2 H); 4.75–4.53 (m, 1 H); 3.37–2.89 (m, 2 H); 2.81 (s, 3 H). 13C-
NMR (75 MHz, CDCl3): 191.7; 156.3; 155.4; 137.1; 136.8; 136.2; 135.8; 128.6; 128.2; 127.9; 127.8;
127.8; 127.7; 127.3; 126.9; 126.7; 126.5; 126.3; 67.3; 67.0; 64.3; 62.8; 57.7; 56.4; 33.3; 33.1; 31.1; 30.2.
HR-MS: 338.1497 ([M+H]+, C19
A
G
N
(2S)-4-Diazo-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-oxobutyl Acetate (111). Yield: 51%.
Clear yellow oil. [a]1D8 =ꢀ142.2 (c=1.2, CH2Cl2). IR (NaCl): 3092, 3034, 2958, 2111, 1745, 1704, 1699,
1643, 1497, 1366, 1229, 1158, 1034, 786, 769, 739, 699. 1H-NMR (300 MHz, CDCl3; rotamers):
7.17–7.10 (m, 5 H); 5.48–5.31 (m, 1 H); 5.10–4.92 (m, 2 H); 4.84–4.66 (m, 1 H); 4.40–4.18 (m, 2 H);
2.73 (s, 3 H); 1.73 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 189.9; 169.8; 156.2; 155.2; 136.0; 135.7; 128.0;
128.0; 127.8; 127.7; 127.3; 67.2; 67.1; 61.2; 60.6; 60.6; 59.7; 54.1; 31.4; 30.5; 19.9. HR-MS: 320.1235
([M+H]+, C15
A
G
N
(1R,2S)-4-Diazo-1-methyl-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-oxobutyl
Acetate
(112). Yield: 60%. Clear yellow oil. [a]D18 =ꢀ142.4 (c=1.1, CH2Cl2). IR (NaCl): 2980, 2939, 2109,
1
1741, 1703, 1644, 1497, 1369, 1304, 1237, 1147, 1036, 770, 753, 739, 699. H-NMR (300 MHz, CDCl3;
rotamers): 7.25 (s, 5 H); 5.41–5.28 (m, 2 H); 5.16–5.00 (m, 2 H); 4.77–4.54 (m, 1 H); 2.79 (s, 3 H);
1.81–1.79 (m, 3 H); 1.17–1.11 (m, 3 H). 13C-NMR (75 MHz, CDCl3): 189.4; 189.3; 169.3; 169.2; 156.7;
155.5; 136.0; 135.9; 128.1; 127.9; 127.7; 127.4; 67.4; 67.3; 66.5; 64.9; 64.2; 54.8; 31.4; 30.6; 20.4; 17.3;
17.1. HR-MS: 334.1390 ([M+H]+, C16
A
G
N
Phenylmethyl [(1S)-1-(Diazoacetyl)-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]methylcarba-
mate (113). Yield: 53%. Clear yellow oil. [a]D18 =ꢀ117.3 (c=0.8, CH2Cl2). IR (NaCl): 3093, 3033, 2945,
1
2872, 2107, 1771, 1712, 1644, 1454, 1439, 1397, 1350, 1152, 1031, 721, 699. H-NMR (300 MHz, CDCl3;
rotamers): 7.78–7.65 (m, 4 H); 7.30–7.24 (m, 5 H); 5.40–5.25 (m, 1 H); 5.10 (s, 2 H); 4.78–4.60 (m, 1
H); 3.70–3.58 (m, 2 H); 2.77 (s, 3 H); 1.85–1.59 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 192.1; 168.0;
156.8; 155.8; 136.2; 131.8; 133.7; 128.3; 128.0; 127.9; 127.6; 123.0; 67.5; 61.6; 60.9; 54.0; 37.1; 36.8;
30.3; 29.5; 24.7; 24.3; 24.1. HR-MS: 435.1658 ([M+H]+, C23
A
G
N
Phenylmethyl [(1S)-1-(Diazoacetyl)-5-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)pentyl]methylcarba-
mate (114). Yield: 69%. Clear yellow oil. [a]D18 =ꢀ108.0 (c=1.1, CH2Cl2). IR (NaCl): 3091, 3007, 2943,
2864, 2106, 1771, 1711, 1644, 1454, 1397, 1351, 1147, 769, 721, 699. 1H-NMR (300 MHz, CDCl3; rotamers):

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Helvetica Chimica Acta – Vol. 89 (2006)
7.77–7.64 (m, 4 H); 7.29 (s, 5 H); 5.38–5.23 (m, 1 H); 5.08 (s, 2 H); 4.67–4.47 (m, 1 H); 3.60 (t, J=7.0, 2
H); 2.76 (s, 3 H); 1.89–1.17 (m, 6 H). 13C-NMR (75 MHz, CDCl3): 192.3; 168.1; 156.7; 155.8; 136.2; 131.9;
133.7; 128.3; 127.9; 127.6; 123.0; 67.4; 62.4; 61.4; 53.9; 37.4; 30.2; 29.5; 28.0; 26.7; 26.4; 20.8. HR-MS:
449.1831 ([M+H]+, C24
Phenylmethyl
C
G
R
1
2107, 1702, 1643, 1607, 1496, 1355, 1202, 1140, 792, 748, 698. H-NMR (300 MHz, CDCl3; rotamers):
9.31–8.34 (m, 2 H); 7.58–6.87 (m, 9 H); 5.43–5.31 (m, 1 H); 5.17–4.87 (m, 3 H); 3.39–2.93 (m, 2 H);
2.84 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 191.2; 158.9; 156.4; 155.2; 136.0; 135.5; 134.0; 130.8; 128.2;
128.1; 127.5; 125.1; 124.2; 123.7; 122.4; 119.4; 118.7; 118.5; 115.8; 109.3; 67.5; 67.4; 61.9; 60.6; 54.1;
30.7; 29.8; 22.9; 22.5. HR-MS: 376.1421 ([Mꢀ28]+, C22
A
G
N
Phenylmethyl (3S)-5-Diazo-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-oxopentanoate (127).
Yield: 50%. Clear yellow oil. [a]1D8 =ꢀ136.5 (c=0.45, CH2Cl2). IR (NaCl): 3091, 3009, 2953, 2109, 1734,
1702, 1644, 1454, 1366, 1306, 1146, 955, 768, 751, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.33 (s, 10
H); 5.42–5.24 (m, 1 H); 5.14–5.07 (m, 4 H); 4.92–4.83 (m, 1 H); 3.23–2.58 (m, 2 H); 2.92–2.82 (m, 3 H).
13C-NMR (75 MHz, CDCl3): 190.6; 170.0; 155.9; 155.0; 135.8; 135.7; 135.2; 128.2; 127.9; 127.6; 67.6; 67.5;
66.5; 66.3; 60.3; 58.7; 53.8; 33.0; 32.3; 31.9; 30.5.
Phenylmethyl (4S)-6-Diazo-4-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-oxohexanoate (128).
Yield: 70%. Clear yellow oil. [a]2D0 =ꢀ133.3 (c=1.0, CH2Cl2). IR (NaCl): 3040, 2950, 2108, 1737, 1732,
1
1703, 1697, 1644, 1497, 1351, 1317, 1138, 752, 739, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.32 (s,
10 H); 5.43–5.28 (m, 1 H); 5.20–5.03 (m, 4 H); 4.91–4.57 (m, 1 H); 2.83–2.79 (m, 3 H); 2.39–1.90 (m,
4 H). 13C-NMR (75 MHz, CDCl3; rotamers): 191.5; 188.0; 172.0; 136.4; 135.4; 128.2; 127.9; 127.5; 67.5;
66.1; 60.6; 53.7; 30.2; 29.5; 22.4; 22.1.
Phenylmethyl ((1S)-1-{2-[Bis(phenylmethyl)amino]-2-oxoethyl}-3-diazo-2-oxopropyl)methylcarba-
mate (135). Yield: 48%. Clear yellow oil. [a]D20 =ꢀ133.2 (c=0.8, CH2Cl2). IR (NaCl): 3088, 3064, 2955,
2926, 2107, 1704, 1698, 1650, 1644, 1495, 1469, 1398, 1149, 734, 699. 1H-NMR (300 MHz, CDCl3; rotam-
ers): 7.35–7.02 (m, 15 H); 5.48–5.22 (m, 1 H); 5.13–5.07 (m, 2 H); 4.65–4.32 (m, 5 H); 2.89–2.85 (m, 3
H); 2.66–2.16 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 190.0; 170.8; 155.7; 155.0; 136.7; 136.1; 135.9; 129.5;
129.2; 128.9; 128.3; 128.2; 127.9; 127.8; 127.6; 127.5; 127.1; 126.3; 126.1; 125.8; 125.4; 67.2; 60.2; 59.9;
53.8; 53.4; 49.5; 48.0; 47.7; 33.1; 32.0; 31.8; 31.5; 31.4. HR-MS: 485.2189 ([M+H]+, C28
485.2189).
A
G
N
Phenylmethyl {(1S)-4-[Bis(phenylmethyl)amino]-1-(diazoacetyl)-4-oxobutyl}methylcarbamate (136).
Yield: 65%. Clear yellow oil. [a]2D0 =ꢀ69.1 (c=1.0, CH2Cl2). IR (NaCl): 3088, 3063, 2948, 2106, 1738,
1700, 1646, 1495, 1467, 1348, 1192, 1080, 768, 734, 699. 1H-NMR (300 MHz, CDCl3; rotamers):
7.29–7.05 (m, 15 H); 5.42–5.25 (m, 1 H); 5.10 (s, 2 H); 4.86–4.32 (m, 5 H); 2.81–2.77 (m, 3 H);
2.44–1.98 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 192.0; 171.8; 156.6; 136.9; 136.1; 135.9; 128.6; 128.3;
128.2; 128.1; 128.0; 127.8; 127.7; 127.5; 127.4; 127.3; 126.0; 67.3; 67.0; 61.6; 61.1; 53.8; 53.5; 49.5; 48.0;
30.7; 29.8; 29.0; 28.7; 23.1; 22.7. HR-MS: 499.2334 ([M+H]+, C29
A
G
N
Phenylmethyl
((1R)-3-Diazo-2-oxo-1-{[(phenylmethyl)sulfanyl]methyl}propyl)methylcarbamate
(145). Yield: 50%. Clear yellow oil. [a]2D2 =182.2 (c=1.0, CH2Cl2). IR (NaCl): 3064, 3031, 2930, 2108,
1
1697, 1643, 1494, 1479, 1355, 1133, 1071, 766, 699. H-NMR (300 MHz, CDCl3; rotamers): 7.35–7.21
(m, 10 H); 5.39–5. 16 (m, 3 H); 4.87–4.53 (m, 1 H); 3.70–3.59 (m, 2 H); 2.96–2.60 (m, 2 H); 2.77 (s, 3
H). 13C-NMR (75 MHz, CDCl3): 191.0; 156.7; 137.6; 136.3; 128.7; 128.3; 127.9; 127.5; 126.9; 67.5; 62.0;
60.7; 54.0; 35.9; 29.5; 28.9. HR-MS: 384.1381 ([M+H]+, C20
A
N3
G
N
Phenylmethyl {(1S)-3-Diazo-1-[2-(methylsulfanyl)ethyl]-2-oxopropyl}methylcarbamate (146). Yield:
52%. Clear yellow oil. [a]2D2 =ꢀ168.2 (c=1.6, CH2Cl2). IR (NaCl): 3092, 3033, 2918, 2107, 1697, 1644,
1
1398, 1342, 1132, 697. H-NMR (300 MHz, CDCl3; rotamers): 7.27 (s, 5 H); 5.37–5.23 (m, 1 H); 5.09
(s, 2 H); 4.78–4.63 (m, 1 H); 2.76 (s, 2 H); 2.39–1.76 (m, 7 H). 13C-NMR (75 MHz, CDCl3): 192.0;
191.8; 156.2; 155.1; 136.0; 135.8; 128.2; 127.8; 127.4; 67.3; 61.3; 60.7; 53.8; 30.8; 29.8; 30.1; 26.5; 15.1;
15.0. HR-MS: 322.1225 ([M+H]+, C15
A
N3
G
N
Phenylmethyl ((1S)-3-Diazo-1-{[4-(methyloxy)phenyl]methyl}-2-oxopropyl)methylcarbamate (153).
Yield: 65%. Clear yellow oil. [a]2D0 =ꢀ137.8 (c=1.0, CH2Cl2). IR (NaCl): 3090, 2996, 2935, 2105, 1699,
1639, 1513, 1454, 1398, 1354, 1304, 1137, 823, 795, 766, 698. 1H-NMR (300 MHz, CDCl3; rotamers):

Helvetica Chimica Acta – Vol. 89 (2006)
2631
7.38–6.72 (m, 9 H); 5.38–5.27 (m, 1 H); 5.14–4.70 (m, 3 H); 3.74 (s, 3 H); 3.27–2.84 (m, 2 H); 2.80 (s, 3
H). 13C-NMR (75 MHz, CDCl3): 190.9; 157.9; 156.3; 155.4; 136.1; 135.7; 129.5; 128.8; 128.6; 128.1; 127.9;
127.7; 127.6; 127.2; 113.5; 67.3; 67.0; 64.4; 62.8; 54.8; 53.9; 32.5; 32.3; 31.0; 30.1. HR-MS: 368.1621
([M+H]+, C20
A
G
N
General Procedure for the Preparation of the N-Methyl b-Amino Acids 49–60, 116–118, 129, 130,
137, 138, 147, 148, 154, and 171. To a soln. of the diazoketone (1 mmol) in 1,4-dioxane/H2O 9 :1 (v/v;
50 ml) was added CF3COOAg (0.1 mmol). The mixture was sonicated in an ultrasound bath for 30
min, or untilthe diazoketone had disappeared according to TLC (AcOEt/hexane). Then, sat. aq.
NaHCO3 soln. was added. The resulting precipitate was filtered off through a bed of Celite, the filter
cake being washed with sat. aq. NaHCO3 soln. and Et2
A
and the aq. layer was washed with Et2O (2”). The org. layer was extracted with sat. aq. NaHCO3 soln, and
AHCTREUNG
the combined aq. layers were acidified to pH 2 with dilute aq. HCl, and finally extracted with AcOEt
(3”). The org. extract was dried (MgSO4) and evaporated in vacuo, and the residue was subjected to
CC for analysis. For ease of handling, the corresponding tert-butylammonium salt may be prepared in
the usualmanner. The free acid was taken up in the minimum amount of anh. Et 2O and treated with
N
t-BuNH2 (1.05 mmol). A precipitate slowly formed. Dropwise addition of hexane sometimes aided the
precipitation process. Stirring was generally continued for 16 h. The solid was suction-filtered, and the
filter cake was washed with cold Et2O/hexane to afford the salt as a colourless solid.
N
3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)propanoic Acid (49). Yield: 70%. Clear colourless
oil. The anal. data of the dicyclohexylammonium salt were identical to those reported above.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (50). Yield: 72%. The anal. data
of the tert-butylammonium salt were identical to those reported above.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (51). Yield: 53%. The anal.
data of the tert-butylammonium salt were identical to those reported above.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (52). Yield: 60%. The anal. data
of the tert-butylammonium salt were identical to those reported above.
(3S)-4-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (53). Yield: 86%. The
anal. data of the tert-butylammonium salt were identical to those reported above.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)heptanoic Acid (54). Yield: 81%. The anal.
data of the tert-butylammonium salt were identical to those reported above.
(3S)-5-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (55). Yield: 72%. The
anal. data of the tert-butylammonium salt were identical to those reported above.
(3R,4S)-4-Methyl-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoic Acid (56). Yield: 58%.
The anal. data of the tert-butylammonium salt were identical to those reported above.
3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-3-phenylpropanoic Acid (57). Yield: 80%. The
anal. data of the tert-butylammonium salt were identical to those reported above.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-phenylbutanoic Acid (58). Yield: 45%. The
anal. data of the tert-butylammonium salt were identical to those reported above.
(3R)-4-(Acetyloxy)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (59). Yield: 92%.
The anal. data of the tert-butylammonium salt were identical to those reported above.
(3R,4R)-4-(Acetyloxy)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic Acid (60). Yield:
90%. The anal. data of the tert-butylammonium salt were identical to those reported above.
(3S)-6-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-
hexanoic Acid (116). Yield: 72%. Colourless oil. Anal. data of tert-butylammonium salt: M.p. 111–1168.
[a]2D1 =0 (c=1.7, MeOH). IR (KBr): 2985, 2909, 2628, 2557, 2235, 1773, 1716, 1684, 1545, 1435, 1393, 1329,
1204, 1155, 1020, 838, 770, 721. 1H-NMR (300 MHz, CDCl3, 318 K; rotamers): 7.80–7.66 (m, 4 H); 7.75
(s, 3 H); 7.27 (s, 5 H); 5.06–5.00 (m, 2 H); 4.46 (br. s, 2 H); 3.63 (br. s, 2 H); 2.75 (s, 3 H); 2.40–2.22 (m, 2
H); 1.55–1.28 (m, 4 H); 1.28 (s, 9 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 177.2; 168.2; 156.6;
136.9; 132.2; 133.8; 128.4; 127.8; 127.6; 123.1; 67.0; 54.0; 51.5; 42.2; 41.6; 37.8; 29.6; 29.2; 28.8; 27.6; 25.6.
Anal. calc. for C27H35N3O6 (497.25) C 65.17, H 7.09, N 8.44; found: C 65.08, H 6.96, N 8.39.
(3S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-
heptanoic Acid (117). Yield: 56%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p.
83–868. [a]2D1 =+2.6 (c=3.5, MeOH). IR (KBr): 2975, 2929, 2626, 2543, 2236, 1774, 1706, 1658, 1546,

2632
Helvetica Chimica Acta – Vol. 89 (2006)
1397, 1334, 1205, 1132, 1058, 755, 720. 1H-NMR (300 MHz, CDCl3; rotamers): 7.73 (s, 3 H); 7.78–7.62 (m,
4 H); 7.27 (s, 5 H); 5.11–4.98 (m, 2 H); 4.44–4.40 (m, 1 H); 3.64–3.59 (m, 2 H); 2.74 (s, 3 H); 2.33–2.21
(m, 2 H); 1.51–1.23 (m, 6 H); 1.25 (s, 9 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 177.1; 168.2;
156.6; 137.0; 132.2; 133.7; 128.4; 127.7; 127.5; 123.0; 66.9; 54.1; 51.0; 42.1; 41.6; 37.8; 31.8; 28.7; 28.3;
27.8; 23.6. HR-MS: 437.1709 ([MꢀH]ꢀ, C24
C
G
A
Acid
(118). Yield: 68%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 110–1148.
[a]2D1 =ꢀ25.4 (c=1.8, MeOH). IR (KBr): 3094, 2932, 2622, 2551, 2359, 2250, 1707, 1545, 1452, 1383,
1209, 1131, 762, 756, 733, 695. 1H-NMR (300 MHz, D2
O, 318 K; rotamers): 8.82–8.02 (m, 2 H);
U
7.44–6.86 (m, 9 H); 4.91–4.66 (m, 3 H); 2.84–2.69 (m, 5 H); 2.58–2.53 (m, 2 H); 1.37 (s, 9 H). 13C-
NMR (75 MHz, CDCl3; 318K): 178.6; 157.4; 161.2; 156.7; 136.4; 135.9; 133.5; 131.1; 128.2; 127.3;
126.7; 124.6; 124.2; 123.6; 121.8; 121.2; 120.3; 119.0; 115.3; 109.9; 67.0; 66.4; 54.1; 53.9; 51.8; 40.6;
28.6; 28.3; 27.1; 26.6; 26.5. Anal. calc. for C26H33N3O5 (467.56): C 66.79, H 7.11, N 8.99; found: C
66.70, H 7.05, N 8.89.
(3R)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-oxo-5-[(phenylmethyl)oxy]pentanoic Acid
(129). Yield: 68%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 101–1058.
[a]2D0 =+0.7 (c=1.0, MeOH). IR (KBr): 3412, 2974, 2840, 2636, 2557, 2221, 1724, 1699, 1641, 1546,
1
1399, 1306, 1239, 1158, 1129, 768, 736, 697. H-NMR (300 MHz, CDCl3, 318 K; rotamers): 7.28–7.27
(m, 10 H); 6.55 (s, 3 H); 5.04–4.96 (m, 4 H); 4.72 (br. s, 1 H); 2.82 (s, 3 H); 2.64–2.44 (m, 4 H); 1.21
(s, 9 H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 175.7; 170.5; 155.7; 155.0; 136.5; 135.5; 128.1;
128.0; 127.8; 127.7; 127.4; 127.2; 126.7; 66.6; 66.0; 52.3; 50.6; 39.7; 37.0; 30.7; 29.2; 27.6. Anal. calc. for
C25H34N2O6 (458.54) C 65.48, H 7.47, N 6.11; found: C 65.32, H 7.51, N 6.11.
(3S)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-6-oxo-6-[(phenylmethyl)oxy]hexanoic Acid
(130). Yield: 69%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 86–908.
[a]2D0 =+10.8 (c=3.2, MeOH). IR (KBr): 2944, 2838, 2628, 2549, 2360, 2343, 2238, 1738, 1688, 1538,
1
1408, 1356, 1224, 1117, 737, 728, 694, 668. H-NMR (300 MHz, D2
A
5.06–4.98 (m, 4 H); 4.52–4.50 (m, 1 H); 2.81–2.69 (m, 3 H); 2.48 (m, 2 H); 2.24 (m, 2 H); 1.87 (m, 2
H); 1.48 (s, 9 H). 13C-NMR (75 MHz, D2
AHCTREUNG
128.3; 127.9; 127.8; 127.7; 127.3; 67.2; 66.9; 66.2; 53.9; 51.9; 41.0; 30.7; 28.1; 27.9; 26.7; 26.5. Anal.
calc. for C26H36N2O6 (472.57): C 66.08, H 7.68, N 5.93; found: C 66.25, H 7.63, N 6.00.
(3S)-5-[Bis(phenylmethyl)amino]-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-oxopentanoic
Acid (137). Yield: 74%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 102–1058.
[a]1D8 =ꢀ15.1 (c=3.3, MeOH). IR (KBr): 2973, 2837, 2627, 2541, 2197, 1699, 1636, 1548, 1452, 1385,
1328, 1159, 1122, 964, 751, 707, 697. 1H-NMR (300 MHz, CDCl3, 318 K; rotamers): 7.47 (s, 3 H);
7.27–7.08 (m, 15 H); 5.02 (s, 2 H); 4.63–4.35 (m, 5 H); 3.11–2.48 (m, 4 H); 2.94 (br. s, 3 H); 1.19 (s, 9
H). 13C-NMR (75 MHz, CDCl3, 318 K; rotamers): 176.7; 171.6; 155.8; 137.4; 137.0; 136.7; 129.3; 128.8;
128.5; 128.4; 128.2; 127.7; 127.5; 127.3; 127.0; 126.7; 67.0; 66.7; 54.9; 53.3; 50.5; 50.2; 48.2; 41.5; 40.7;
37.4; 36.9; 36.1; 33.7; 33.0; 28.2. Anal. calc. for C32H41N3O5 (547.69): C 70.18, H 7.55, N 7.67; found: C
70.15, H 7.60, N 7.61.
(3S)-6-[Bis(phenylmethyl)amino]-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)-6-oxohexanoic
Acid (138). Yield: 85%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 108–1118.
[a]1D8 =+6.7 (c=3.2, MeOH). IR (KBr): 2972, 2634, 2547, 2234, 1698, 1640, 1547, 1400, 1335, 1209,
1
1152, 736, 696. H-NMR (300 MHz, CDCl3; rotamers): 7.70 (s, 3 H); 7.28–6.98 (m, 15 H); 5.12–4.87
(m, 2 H); 4.62–4.18 (m, 5 H); 2.69 (s, 3 H); 2.42–2.27 (m, 4 H); 1.90 (m, 2 H); 1.24 (s, 9 H). 13C-NMR
(75 MHz, CDCl3, 318 K; rotamers): 176.7; 172.9; 156.6; 137.4; 137.0; 136.5; 128.9; 128.5; 128.4; 128.2;
127.8; 127.5; 127.3; 126.5; 66.9; 53.9; 50.9; 50.1; 48.4; 41.6; 29.9; 28.6; 28.0; 27.7. Anal. calc. for
C33H43N3O5 (561.71): C 70.56, H 7.72, N 7.48; found: C 70.47, H 7.74, N 7.47.
(3R)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-4-[(phenylmethyl)sulfanyl]butanoic
Acid
(147). Yield: 87%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 89–908.
[a]2D3 =ꢀ39.0 (c=1.6, MeOH). IR (KBr): 2976, 2919, 2629, 2529, 1697, 1682, 1557, 1455, 1398, 1329,
1273, 698. 1H-NMR (300 MHz, CDCl3; rotamers): 7.31–7.18 (m, 10 H); 6.54 (br. s, 3 H); 5.25–5.00
(m, 2 H); 4.65–4.57 (m, 1 H); 3.70–3.65 (m, 2 H); 2.78–2.75 (m, 3 H); 2.67–2.40 (m, 4 H); 1.25 (s, 9

Helvetica Chimica Acta – Vol. 89 (2006)
2633
H). 13C-NMR (75 MHz, CDCl3; rotamers): 176.9; 176.8; 156.5; 138.2; 138.1; 136.8; 136.7; 128.9; 128.4;
127.8; 127.8; 127.4; 126.8; 67.1; 66.8; 53.7; 50.7; 41.2; 40.8; 36.1; 36.0; 34.1; 33.9; 29.5; 27.8. HR-MS:
374.1442 ([M+H]+, C20
A
G
N
(3R)-3-(Methyl{[(phenylmethyl)oxy]carbonyl}amino)-5-(methylsulfanyl)pentanoic Acid (148).
Yield: 44%. Clear colourless oil. [a]2D3 =ꢀ1.74 (c=1.0, CH2Cl2). IR (KBr): 3032, 2918, 1732, 1701,
1454, 1404, 1341, 1212, 1145, 768, 698. 1H-NMR (300 MHz, CDCl3, 323 K; rotamers): 10.00 (br. s, 1
H); 7.31 (s, 5 H); 5.14 (s, 2 H); 4.82–4.47 (m, 1 H); 2.91–2.82 (m, 3 H); 2.63–1.75 (m, 9 H). 13C-NMR
(75 MHz, CDCl3, 323 K; rotamers): 175.5; 156.4; 136.6; 128.4; 127.9; 127.8; 127.7; 67.6; 67.2; 58.2;
57.8; 53.5; 52.6; 37.4; 31.8; 30.6; 28.4; 15.4; 15.2. HR-MS: 312.1270 ([M+H]+; C15
312.1270).
A
G
N
(3S)-4-[4-(Methyloxy)phenyl]-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)butanoic Acid (154).
Yield: 87%. Clear colourless oil. Anal. data of tert-butylammonium salt: M.p. 103–1088. [a]1D8 =ꢀ27.5
(c=3.4, MeOH). IR (KBr): 2982, 2931, 2835, 2632, 2548, 2242, 1690, 1640, 1611, 1549, 1513, 1406,
1344, 1247, 1200, 1120, 1032, 821, 763, 742. 1H-NMR (300 MHz, CDCl3, 318 K; rotamers): 7.83 (s, 3
H); 7.26–7.17 (m, 5 H); 7.05–6.72 (m, 4 H); 5.06–4.93 (m, 2 H); 4.57 (br. s, 1 H); 3.72 (s, 3 H); 2.76
(s, 3 H); 2.69 (s, 2 H); 2.48–2.39 (m, 2 H); 1.23 (s, 9 H). 13C-NMR (75 MHz, CDCl3; 318 K; rotamers):
177.1; 158.2; 156.4; 156.1; 137.2; 137.0; 130.9; 130.0; 129.7; 128.8; 128.3; 127.7; 127.4; 113.8; 66.9; 66.5;
57.0; 56.1; 55.2; 50.6; 41.6; 40.9; 38.0; 37.6; 30.7; 30.0; 28.0. Anal. calc. for C24H34N2O5 (430.25): C
66.95, H 7.96, N 6.51; found: C 66.95, H 8.01, N 6.46.
(1-Methylpyrrolidin-2-yl)acetic Acid (164) [41]. Yield: 95%. Clear orange oil. Anal. data of hydro-
chloride salt: M.p. 149–1618. [a]1D9 =ꢀ10.0 (c=1.8, MeOH). IR (KBr): 3105, 2961, 2728, 1710, 1550,
1
1464, 1402, 1192, 835, 611. H-NMR (300 MHz, D2
G
H); 2.91–2.61 (m, 5 H); 2.30–2.25 (m, 1 H); 2.02–1.90 (m, 2 H); 1.73–1.71 (m, 1 H). 13C-NMR (75
MHz, CDCl3, 318 K): 173.2; 64.9; 56.1; 39.6; 34.2; 28.8; 21.0. HR-MS: 144.1029 ([M+H]+, C7
calc. 144.1025).
Phenylmethyl (4S)-5-Oxo-4-{2-oxo-2-[(phenylmethyl)oxy]ethyl}-1,3-oxazolidine-3-carboxylate (123).
The anal. data were identical to those previously described [16].
Phenylmethyl (4S)-5-Oxo-4-{3-oxo-3-[(phenylmethyl)oxy]propyl}-1,3-oxazolidine-3-carboxylate (124).
To a soln. of 122 (2.0 mmol) in CH2Cl2 (10 ml) were added Et3N (2.0 mmol), benzyl chloroformate (2.0
G
mmol), and 4-(dimethylamino)pyridine (DMAP; 0.2 mmol) successively at 08, and the mixture was stir-
red at this temp. for 90 min. Then, the mixture was diluted with CH2Cl2, and the soln. was washed sequen-
tially with sat. aq. NaHCO3 soln., 10% aq. citric acid soln., and H2O. The org. layer was dried (MgSO4)
and concentrated under reduced pressure. The residue was purified by CC (35% AcOEt/hexane) to
afford the title compound. Yield: 70%. Oil. [a]2D4 =+55.6 (c=1.3, CH2Cl2). IR (NaCl): 3033, 2956,
1
2931, 1801, 1730, 1416, 1358, 1257, 1129, 1053, 751, 698. H-NMR (300 MHz, CDCl3; rotamers): 7.33
(s, 10 H); 5.48–5.46 (m, 1 H); 5.15 (br. s, 3 H); 5.08 (s, 2 H); 4.36–4.23 (m, 1 H); 2.50–2.19 (m, 4 H).
13C-NMR (75 MHz, CDCl3; rotamers): 171.7; 171.5; 152.9; 135.7; 135.3; 128.6; 128.4; 128.2; 77.7; 68.0;
66.4; 54.0; 29.4; 25.9. HR-MS: 384.1463 ([M+H]+, C21
N
N
General Procedure for the Preparation of the Oxazolidinones 131 and 132. The appropriate 1,3-oxa-
zolidin-5-one (8.0 mmol) in SOCl2 (6 ml) was heated at reflux for 15 min under an inert atmosphere. The
excess SOCl2 was removed at reduced pressure, the residue was dissolved in toluene, and the mixture was
evaporated in vacuo (3”). The acid chloride was then dissolved in anh. CH2Cl2, cooled to 08, and slowly
treated with anh. dibenzylamine (16.0 mmol). The mixture was stirred for 30 min while coming to r.t. The
resulting hydrochloride salt was filtered off, and the org. layer was washed successively with dilute aq.
HCl(2”), sat. aq. Na 2CO3 soln., and H2O. The org. layer was dried (MgSO4) and concentrated in
vacuo. The resultant oil derived from asparagine could be crystallised from AcOEt/hexane to yield
the dibenzylamide 131. The glutamine derivative 132 was purified by CC (30% AcOEt/hexane).
Data of Phenylmethyl (4S)-4-{2-[Bis(phenylmethyl)amino]-2-oxoethyl}-5-oxo-1,3-oxazolidine-3-car-
boxylate (131). Yield: 45%. Off-white solid. M.p. 80–858. [a]2D0 =+115.5 (c=1.6, CH2Cl2). IR (KBr):
1
3087, 3063, 2925, 1799, 1714, 1645, 1451, 1420, 1359, 1213, 1131, 732, 699. H-NMR (300 MHz, CDCl3;
rotamers): 7.36–7.12 (m, 15 H); 5.60–5.48 (m, 2 H); 5.18–5.02 (m, 2 H); 4.64–4.14 (m, 5 H);

2634
Helvetica Chimica Acta – Vol. 89 (2006)
3.60–3.04 (m, 2 H). 13C-NMR (75 MHz, CDCl3; rotamers): 172.1; 169.2; 152.3; 136.3; 135.3; 128.7; 128.4;
128.2; 127.9; 127.3; 126.2; 125.8; 78.4; 78.0; 67.3; 51.7; 49.5; 48.9; 47.8; 34.0; 33.2. HR-MS: 458.1846 (M+,
C
A
G
N
Data of Phenylmethyl (4S)-4-{3-[Bis(phenylmethyl)amino]-3-oxopropyl}-5-oxo-1,3-oxazolidine-3-
carboxylate (132). Yield: 52%. Clear colourless oil. [a]2D0 =+71.5 (c=1.1, CH2Cl2). IR (KBr): 3063,
3031, 2921, 1799, 1715, 1650, 1645, 1416, 1359, 1212, 1028, 733, 699. 1H-NMR (300 MHz, CDCl3; rotam-
ers): 7.37–7.09 (m, 15 H); 5.50 (s, 1 H); 5.18–5.10 (m, 3 H); 4.67–4.36 (m, 5 H); 2.64–2.24 (m, 4 H). 13C-
NMR (75 MHz, CDCl3; rotamers): 171.7; 171.4; 152.8; 136.8; 135.9; 135.1; 128.7; 128.4; 128.3; 128.0;
127.9; 127.3; 127.1; 126.1; 77.2; 67.6; 53.7; 49.5; 48.0; 27.9; 25.9. HR-MS: 472.1996 (M+, C28
A
G
N
calc. 472.1998).
Synthesis of 1,1-Dimethylethyl (3S)-6-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-(methyl{[(phenyl-
methyl)oxy]carbonyl}amino)hexanoate (165). Method 1 (via Wolff rearrangement of 113). To a soln. of
the diazoketone 113 (0.1 mmol) in 1,4-dioxane/t-BuOH 9:1 (v/v, 5 ml), CF3COOAg (0.01 mmol) was
added, and the mixture was sonicated in an ultrasound bath for 30 min, or until no diazoketone was
detected by TLC. The mixture was concentrated in vacuo. The residue was dissolved in AcOEt, and
the org. soln. was washed successively with 10% aq. citric acid soln., sat. aq. Na2CO3 soln., and H2O.
The org. layer was dried (MgSO4) and evaporated in vacuo. The residue was subjected to CC (40%
AcOEt/hexane) to afford 165 in 45% yield. Clear colourless oil. [a]1D9 =ꢀ11.38 (c=2.2, CH2Cl2). IR
(NaCl): 2976, 2937, 1772, 1713, 1397, 1367, 1305, 1213, 1087, 721, 698. 1H-NMR (300 MHz, CDCl3; rotam-
ers): 7.73–7.61 (m, 4 H); 7.24–7.09 (m, 5 H); 5.14–4.96 (m, 2 H); 4.49–4.43 (m, 1 H); 3.60–3.53 (m, 2
H); 2.78–2.70 (m, 3 H); 2.35–2.10 (m, 2 H); 1.55–1.02 (m, 6 H); 1.28 (s, 9 H). 13C-NMR (75 MHz,
CDCl3): 169.8; 169.7; 167.9; 155.9; 136.6; 136.4; 133.6; 131.8; 128.1; 127.7; 127.5; 127.5; 122.8; 80.4;
80.3; 66.9; 66.6; 52.9; 52.6; 39.5; 39.1; 37.3; 37.1; 29.4; 29.1; 28.5; 27.6; 25.1; 25.0. HR-MS: 481.2340
(M+, C27
Method 2 (via Esterification of 116). The carboxylic acid 116 (1.0 mmol) was dissolved in a minimum
of anh. t-BuOH. Then, DMAP (0.1 mmol) and di(tert-butyl) dicarbonate (Boc2O; 2.0 mmol) were added
A
N2
A
AHCTREUNG
at r.t., and the soln. was stirred for 20 h. The mixture was concentrated under reduced pressure, and the
residue was subjected to CC (80% AcOEt/hexane). The resultant oil was further purified by CC (45%
AcOEt/hexane) to furnish pure 165 in 43% yield. For anal. data, see above (Method 1).
Synthesis of 1,1-Dimethylethyl (3S)-6-Amino-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexa-
noate (166) and 1,1-Dimethylethyl (3S)-6-{[(Z)-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)({[(1,1-dime-
thylethyl)oxy]carbonyl}imino)methyl]amino}-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)hexanoate
(168). A soln. of 165 (0.4 mmol) in anh. t-BuOH (5 ml) and ethylenediamine (1 ml) was stirred at 908 for
16 h. The soln. was concentrated in vacuo, and then the residue was dissolved in toluene and further con-
centrated. This process was repeated three times. The residue was taken up in AcOEt, and the soln. was
washed with sat. aq. NaHCO3 soln. (2”). The org. layer was dried (MgSO4) and evaporated under
reduced pressure to afford 166. The latter was dissolved in CHCl3 (3 ml), treated with ꢀdi-boc-triflylgua-
nidineꢁ (167; 0.4 mmol) and then Hünig base (i-Pr2NEt; 0.6 mmol). The mixture was stirred at r.t. for 2 h,
A
and concentrated under reduced pressure. The residue was subjected to CC (CHCl3). The resultant oil
was further purified by CC (20% AcOEt/hexane) to afford 168 in 62% yield.
Data of 168. Colourless oil. [a]1D9 =ꢀ0.06 (c=0.6, CH2Cl2). IR (NaCl): 3334, 2978, 2934, 1723, 1640,
1616, 1415, 1367, 1333, 1156, 1134, 767. 1H-NMR (300 MHz, CDCl3; rotamers): 11.43 (s, 1 H); 8.21 (s, 1
H); 7.32–7.27 (m, 5 H); 5.08 (s, 2 H); 4.48–4.42 (m, 1 H); 3.36 (s, 2 H); 2.77 (s, 3 H); 2.48–2.18 (m, 2 H);
1.47–1.24 (m, 31 H). 13C-NMR (75 MHz, CDCl3, 325 K): 170.0; 163.6; 156.3; 156.1; 153.3; 136.8; 128.4;
128.0; 127.8; 83.0; 80.7; 79.1; 67.2; 53.3; 40.5; 39.8; 29.6; 28.9; 28.3; 28.1; 27.9; 25.9. Anal. calc. for
C30H48N4O8 (592.72): C 60.79, H 8.16, N 9.45; found: C 60.84, H 8.23, N 9.52.
Phenylmethyl [(1S)-3-Diazo-1-{[1-(2,4-dinitrophenyl)-1H-imidazol-4-yl]methyl}-2-oxopropyl]me-
thylcarbamate (170). To a soln. of 169 (1 mmol) in anh. THF (5 ml) was added at ꢀ308 ethylchol rofor-
mate (1.05 mmol) and collidine (1.05 mmol) successively. The mixture was stirred for 15 min. Then, an
anh. soln. of CH2N2 (5 mmol; CAUTION!) [24] in CH2Cl2 was added slowly. The yellow soln. was
allowed to warm to r.t., and stirring was continued until there was no acid remaining, as indicated by
TLC. Excess CH2N2 was destroyed by addition of AcOH. The mixture was concentrated under reduced
pressure, and the residue was dissolved in AcOEt. The org. phase was washed with sat. aq. NaHCO3 soln.

Helvetica Chimica Acta – Vol. 89 (2006)
2635
The org. layer was dried (MgSO4) and evaporated in vacuo, and the residue was subjected to CC (1.
AcOEt, 2. AcOEt/MeOH 95 :5) to afford the title compound in 50% yield. Clear orange gum.
[a]1D9 =ꢀ12.70 (c=0.38, MeOH). IR (NaCl): 3100, 2943, 2108, 1694, 1641, 1609, 1537, 1348, 1141, 1081,
1
742. H-NMR (300 MHz, DMSO; rotamers): 8.79–8.78 (m, 1 H); 8.51–8.49 (m, 1 H); 7.62–7.52 (m, 2
H); 7.30–7.23 (m, 6 H); 5.44–5.29 (m, 1 H); 5.15–4.86 (m, 3 H); 3.31–2.85 (m, 5 H). 13C-NMR (75
MHz, DMSO): 191.8; 156.7; 146.7; 144.2; 140.5; 134.9; 136.4; 136.3; 129.1; 128.2; 128.0; 127.8; 121.2;
117.0; 67.6; 63.0; 61.7; 54.3; 31.8; 30.7; 26.6; 26.1. HR-MS: 494.1436 ([M+H]+, C22
A
G
N
494.1424).
Methyl (3S)-4-[1-(2,4-Dinitrophenyl)-1H-imidazol-4-yl]-3-(methyl{[(phenylmethyl)oxy]carbonyl}-
ACHTREUNG
CF3CO2Ag (0.01 mmol), and the mixture was sonicated in an ultrasound bath for 30 min, or until no
diazoketone was detected by TLC. The mixture was concentrated in vacuo, the residue was dissolved
N
in AcOEt, and the org. phase was washed with sat. aq. Na2CO3 soln. The org. layer was dried
(MgSO4) and evaporated in vacuo. The residue was subjected to CC (AcOEt/MeOH 95 :5) to afford
the title compound in 82% yield. Clear yellow gum. [a]1D9 =0.00 (c=0.16, MeOH). IR (NaCl): 3116,
1
2952, 1735, 1695, 1610, 1542, 1343, 1213, 1145, 737. H-NMR (300 MHz, DMSO; rotamers): 8.82–8.81
(m, 1 H); 8.52–8.49 (m, 1 H); 8.10–9.90 (m, 1 H); 7.67–7.63 (m, 1 H); 7.31–7.17 (m, 6 H); 5.27 (s, 2
H); 4.75–4.65 (m, 1 H); 3.61 (s, 3 H); 3.05–2.49 (m, 7 H). 13C-NMR (75 MHz, DMSO): 171.3; 156.1;
147.0; 144.5; 141.0; 137.1; 136.3; 135.0; 129.2; 128.4; 128.1; 121.2; 119.2; 117.1; 67.0; 54.7; 51.7; 37.3;
37.6; 31.5; 31.2; 30.8. HR-MS: 498.1644 ([M+H]+, C23
A
G
N
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Received February 17, 2006