Synthesis of β,β′-diamino acids from α-amino acid-derived β-lactams by ring opening with nucleophiles. Utilization in the synthesis of peptidomimetics

Article abstract of DOI:10.1016/j.tet.2008.07.006

Ring opening of protected 3-aminoalkyl-substituted azetidin-2-ones with O-, N- or S-nucleophiles led to β,β′-diaminocarboxylic esters, amides and thioesters, respectively. The reaction outcome is improved by the addition of catalytic amounts of sodium azide. Utilization of a glycine derivative with unprotected amino function as nucleophile was possible. When bulkier amino acid esters were used, the intermediate acid azide underwent a Curtius rearrangement. The isocynates formed were trapped as the corresponding urea derivatives. Reduction of β-lactam's amide moiety led to diaminoalcohols.

Full text of DOI:10.1016/j.tet.2008.07.006

Tetrahedron 64 (2008) 8659–8667
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of b,b a-amino acid-derived b-lactams by ring
0-diamino acids from
opening with nucleophiles. Utilization in the synthesis of peptidomimetics
,
Alexander A. Taubinger a, Dieter Fenske b, Joachim Podlech a
*
a Institut fu¨r Organische Chemie, Universita¨t Karlsruhe, Karlsruher Institut fu¨r Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
b Institut fu¨r Anorganische Chemie, Universita¨t Karlsruhe, Karlsruher Institut fu¨r Technologie (KIT), Engesserstraße 15, 76131 Karlsruhe, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring opening of protected 3-aminoalkyl-substituted azetidin-2-ones with O-, N- or S-nucleophiles led to
b,b
0-diaminocarboxylic esters, amides and thioesters, respectively. The reaction outcome is improved by
Received 21 May 2008
Accepted 1 July 2008
Available online 5 July 2008
the addition of catalytic amounts of sodium azide. Utilization of a glycine derivative with unprotected
amino function as nucleophile was possible. When bulkier amino acid esters were used, the intermediate
acid azide underwent a Curtius rearrangement. The isocynates formed were trapped as the corresponding
Keywords:
urea derivatives. Reduction of
b-lactam’s amide moiety led to diaminoalcohols.
Amino acids
Diazo compounds
Lactams
Ó 2008 Elsevier Ltd. All rights reserved.
Amino alcohols
Peptidomimetics
1. Introduction
acids should be useful as synthetic intermediates and as unnatural
amino acids,13 e.g., for the preparation of peptidomimetics.
b
-Lactams are not only eminent parts of antibiotics,1 but were
also used as precursors for the production of polyamides2 and for
Reductive ring opening would lead to g,g
0-diaminoalcohols, which
could be used as three-dentate ligands14 or therapeutics.15
the preparation of
b-amino acids, a class of compounds, which
found substantial attention during the last decades.3 The side chain
of the antitumour agent TaxolÒ (Paclitaxel)4 is preferentially pre-
2. Results and discussion
pared by nucleophilic ring opening of suitably substituted
b-lac-
tams.5
b-Lactams are usually prepared by Staudinger reaction, in
2.1. Preparation of
b-lactams
which in situ generated ketenesdpreferentially prepared from acid
chlorides with tertiary basesdare reacted with imines.6 Recently,
we presented a new variation of the Staudinger reaction, in which
ketenes were prepared in situ via a photochemical rearrangement
Synthesis of the herein used
b
-lactams is simply achieved by
photolysis of amino acid-derived diazo ketones 4–6 in the presence
of imines 7–9 (Scheme 1, Table 1).8 Photochemical Staudinger
reaction was performed in a quartz immersion photoreactor at
ꢀ25 ꢁC, while the thermal reaction was performed by heating at
160 ꢁC in dichlorobenzene. Selectivities were ruled by the steric
hindrance of amino acid’s side chain and ranged from 2:1 (alanine,
of diazo ketones synthesized from
stereoselectively with imines to yield exclusively trans-arranged7
aminoalkyl-substituted
-lactams.8 With this method 4-aryl- or
4-styryl-substituted -lactams are accessible, while a change to
a-amino acids. These react dia-
b
b
R¼Me) to 7:1 (valine, R¼iPr). Starting with
L-amino acids the major
thermal conditions in the decomposition of diazo ketones addi-
tionally allows the preparation of 4-vinyl- and 4-crotyl-substituted
derivatives.9
product was 3R,4S-configured; the diastereoisomers were separa-
ble by flash chromatography or medium pressure liquid chroma-
tography (MPLC). Z protection at the N-terminus was chosen to
allow for UV detection at any time of the proposed syntheses.
Furthermore, it is an orthogonal protecting group to the tert-
butyloxycarbonyl (Boc) group, which will be introduced at a later
stage of the synthesis. It has to be kept in mind that the Z group is
In this paper, we wish to describe a nucleophilic ring opening of
thus obtained b-lactams leading to b,b
0-diamino acid derivatives.10
These compounds, though interesting building blocks, have hardly
been investigated.11 A stereoselective synthesis has been reported
only once using the ring opening of pyrazolidines.12 0-Diamino
b,b
hardly useful in
b-lactam synthesis, since a b-lactam (with aryl
substituent in position C-4) is cleaved with hydrogenolytic condi-
tions,16 but is fully applicable when the
the here proposed reactions.
b-lactam is cleaved as it is in
* Corresponding author. Tel.: þ49 721 608 3209; fax: þ49 721 608 7652.
E-mail address: joachim.podlech@ioc.uka.de (J. Podlech).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.006

8660
A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
O
1) NEt3
H
H
N
H
H
N
1) K2OsO4·2 H2O
NaIO4, 2,6-lutidine
Z
Ph
Z
2) ClCO2Et
3) CH2N2/Et2O
R1
R1
O
N
H
N
H
Z
2) glycol, TosOH·H2O
Dean-Stark trap
Z
PMB
PMB
N
H
CO2H
1−3
N
H
N2
O
O
O
H
12a
14a
4−6
Scheme 3. Oxidative degradation of the styryl group and acetal formation.
R1
R1
O
PMB
N
R2
H
H
N
H
N
Z
R2
Z
R2
substrates. It has to be kept in mind that these oxidative conditions
are not compatible with highly electron-rich aromatic rings. Con-
sequently, we tested besides the parent phenyl group a slightly
electron-deficient para-chlorophenyl (pCP) group as substituents of
7−9
N
H
N
H
+
hν or Δ
PMB
PMB
O
10−18a/b
Scheme 1. Preparation of
dinger reaction.
b
-lactams in a photochemically or thermally induced Stau-
the b-lactam. b-Lactams with an aliphatic substituent or without
substituent at the nitrogen are hydrolyzed only with strongly acidic
conditions.18 A mild ring opening is best achieved with an electron-
withdrawing group at the nitrogen. The Boc group is an easy to
handle protecting group fulfilling this requirement. Introduction of
Table 1
Synthesis of
b-lactams
the Boc protection group at b-lactam’s nitrogen was achieved with
No. Diazo ketone Imine R1
R2a
b
-Lactamb Yield [%] d.r.
standard conditions using di-tert-butyl dicarbonate (Boc2O), tri-
ethyl amine and catalytic amounts of 4-(dimethylamino)pyridine
(DMAP).19 Most of the Boc-protected substrates were obtained as
crystalline products (Table 2).
1
2
3
4
5
6
7
4
4
4
5
5
6
6
7
8
9
7
8
7
8
Me Ph
Me pCP
Me (E)–CH]CHPh 12a,b
iPr Ph
iPr pCP
Bn Ph
Bn pCP
10a,b
11a,b
59c
49
48
57
43
43c
42
56:44
66:34
62:38
87:13
81:19
55:45
57:43
15a,b
16a,b
17a,b
18a,b
2.2. Ring opening of b-lactams
a
b
c
pCP: 4-chlorophenyl.
Isomer a: 3R,4S; b: 3S,4R.
Thermal conditions.
Ring opening of Boc-protected
methanolate in refluxing methanol led to a poor 33% yield of the
corresponding methyl
0-diaminocarboxylate 32a within 5 h.
b-lactam 26a with sodium
b,b
When performing the ring opening at rt in methanol with addition
of triethyl amine >97% of methyl esters were obtained, though
reaction times had to be extended to about one day. Only substrate
31b led to a moderate 61% yield caused by a laborious purification
procedure (Scheme 4, Table 3). These substrates are N,N0-protected
with orthogonal protecting groups allowing for a selective depro-
tection and utilization in further reactions. No detectable epime-
rization at any of the stereogenic centres occurred during these and
the following reactions.
Unfortunately, imines with electron-withdrawing protection
groups (e.g., carbamate protections), which would be useful for the
further reactions cannot be subjected to the herein used -lactam
synthesis.8a,b Therefore, a para-methoxybenzyl (PMB) group was
introduced with the imine yielding PMB-protected -lactams.
Oxidative cleavage of the PMB group is achieved with potassium
peroxodisulfate in a buffered (K2HPO4) mixture of acetonitrile and
water.8b,c,17 With this method, an overoxidation of the PMB group
(leading to a para-methoxybenzoyl group) is minimized (Scheme 2,
Table 2). Furthermore, this variation is compatible with an acid-
sensitive acetal group, which is obtained by oxidative degradation
of the styryl group and subsequent acetal formation (Scheme 3)
and with any of the other functional groups present in these
b
b
R1
R1 R2
2
Z
R2
3
4
1'
Et3N, MeOH
3
N
H
Z
Boc
N
H
N
H
N
rt
1
Boc
O
see Table 3
O
OMe
R1
R1
3R,4S
3S,4R
2R,1'S (isomer a)
2S,1'R (isomer b)
1) K2S2O8, K2HPO4
Z
R2
Z
R2
N
H
N
H
2) Boc2O, Et3N,
DMAP (cat.)
Scheme 4. Ring opening of b-lactams with methanol.
N
N
PMB
Boc
O
O
N-Unprotected b-lactams were similarly, albeit more sluggishly
opened by methanol in the presence of chlorotrimethylsilane as
Lewis acid according to a protocol of Palomo et al. (Table 3 entries
Scheme 2. Preparation of N-Boc-protected b-lactams suitable for ring opening.
Table 2
Protection group manipulations
Table 3
-Lactama R1 R2b
PMB cleavage
Boc protection
Ring opening with methanol (cf. Scheme 4)
No.
b
Yield [%] Producta Yield [%] Producta
No.
b
-Lactama R1
R2 b
Me Ph
Me pCP
PG
Time [h] Producta Yield [%]
1
2
3
4
5
6
7
8
9
10a
10b
11a
11b
14a
15a
16a
17a
17b
Me Ph
Me Ph
Me pCP
Me pCP
56
56
53
51
19a
19b
20a
20b
21a
22a
23a
24a
24b
25b
79
87
88
70
70
92
88
56
72
d
26a
26b
27a
27b
28a
29a
30a
31a
31b
d
1
2
3
4
5
6
7
8
26a
27a
28a
29a
31b
19a
25b
23a
Boc 21
Boc 24
32a
33a
34a
35a
36b
37a
38b
39ad
99
99
99
97
61
58
53
51
Me 1,3-Dioxolan-2-yl Boc 22
iPr Ph
Bn Ph
Me Ph
Bn
iPr pCP
Boc 16
Boc 24
H
H
H
Me 1,3-Dioxolan-2-yl 40
iPr Ph
iPr pCP
Bn Ph
Bn Ph
Bn pCP
36
47
32
40
34
66c
pCP
48c
24c
a
b
c
Isomer a: 3R,4S; b: 3S,4R; the products have accordant configuration.
pCP¼4-chlorophenyl.
10 18b
a
Isomer a: 3R,4S; b: 3S,4R.
pCP¼4-chlorophenyl.
Addition of ClSiMe as Lewis acid.
b
d
Amine 39a was Boc-protected (/40a) for analytical reasons.

A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
8661
6–8).18a,20 Thus obtained unprotected amines could, e.g., for rea-
Ph
Ph
Ph
S
sons of analysis, be protected with the Boc group using a standard
protocol. Nevertheless, they are reasonably stable and crystallized
in some cases. The structure of 38b was proven by X-ray crystal-
lographic analysis.21
Ring opening with pyrrolidine and morpholine was cleanly
achieved at elevated temperatures without addition of solvent. The
respective amides were obtained as analytically pure, crystalline
solids in about 80% yield (Scheme 5, Table 4, entries 2–5). Addition
of primary amines was very sluggish with similar conditions, but
proceeded cleanly at ambient temperatures when sodium azide
was added as catalyst (entries 11–13).22 The stereochemical in-
tegrity and the structure of thus obtained amides were proven by
X-ray crystallographic analysis of substrates 42a and 44a.21
H
H
N
Z
Boc
Z
Ph
Boc Cys OMe
N
H
N
H
N
H
DMF, 60 °C, 4 h
73%
CO2Me
NH
Boc
O
O
31a
48a
Boc
Scheme 6. Ring opening of b-lactams with a cysteine derivative.
peptidomimetics containing
pounds, obtained via the ring opening of 3-benzyloxy-substituted
-lactams have been synthesized and investigated by Palomo
et al.22a Since primary amines require the addition of a catalyst in
that reaction, we performed a ring opening of the -lactams with
b,b
0-diamino acids. Similar com-
b
b
amino esters in the presence of a catalytic amount of sodium azide.
The amino function was in situ liberated from the respective hy-
drochlorides by addition of triethyl amine. With these reaction
conditions addition of glycine methyl ester (H–Gly–OMe) was
achieved within 43 h with a 55% yield (Scheme 7). Due to the or-
thogonality of the protection groups in this compound an attach-
ment of further amino acids at any of the termini should be possible
without significant problems. The structure of this dipeptidomi-
metic was unambiguously determined by X-ray crystallographic
analysis (Fig. 1).21
R1
R1 R2
2
1'
3
NuH (NaN3)
Z
R2
3
4
Z
Boc
N
H
N
H
N
H
conditions
see Table 4
1
N
Boc
O
Nu
O
3R,4S
3S,4R
2R,1'S (isomer a)
2S,1'R (isomer b)
Scheme 5. Ring opening of b-lactams with N-nucleophiles.
Though N,O-dimethyl- and O-methylhydroxylamine (liberated
from the respective hydrochlorides by addition of triethyl amine)
Ph
H
are exceptionally good nucleophiles due to the
a
-effect, they could
-lactams, even in
Z
Boc
not be used successfully in the ring opening of
b
N
H
N
H
H
H
N
Z
Ph
the presence of sodium azide.23 While the former did not react at
all, the latter gave only traces of a hydroxamic acid within 5 d. The
aimed products (Weinreb amides) would have been useful for
further reactions, e.g., for the preparation of ketones.24
HCl·H2N
CO2Me
N
H
O
NH
NEt3, NaN3 (cat.)
DMF, rt, 43 h
O
Boc
55%
O
19a
53a
OMe
The ring opening with allyl mercaptane or with N,O-diprotected
cysteine (Scheme 6)25 leading to thiocarboxylates is achieved with
high yields in the presence of a base (triethyl amine) at slightly
elevated temperatures (Table 4, entries 6–8). The addition of the
bulky tert-butylthiol proceeded only in the presence of sodium
azide as catalyst and with a longer reaction time. With this varia-
tion similar yields were obtained as with primary thiols (entry 10).
Scheme 7. Azide-catalyzed ring opening with glycine methyl ester.
Ring opening with amino esters bulkier than glycine was not
successful. No significant reaction was observed with valine or
alanine derivatives and catalytic amounts of sodium azide. With
stoichiometric amounts of azide, a reaction was observed only at
60 ꢁC yielding urea derivatives 54a and 55a, respectively. Obvi-
ously, the intermediately formed acid azide suffers a Curtius
rearrangement at elevated temperature forming an isocyanate,
which is trapped by the amine yielding the observed urea de-
rivatives (Scheme 8). Nevertheless, these compounds are of
significant interest with view on their possible utilization as
peptidomimetics.26
2.3. Synthesis of peptidomimetics
The ring opening of b-lactams with amines was now applied to
the utilization of amino acid derivatives as nucleophiles aiming for
Table 4
Ring opening of
b-lactams with O-, N-, and S-nucleophiles (cf. Scheme 5 and 6)
No.
b
-Lactama
R1
R2b
NuH
Conditionsc
Producta
Yield [%]
1
2
3
4
5
6
7
8
26a
26a
27a
29a
30a
26a
27a
31a
30a
30a
26a
27b
31b
Me
Me
Me
iPr
iPr
Me
Me
Bn
iPr
iPr
Me
Me
Bn
Ph
Ph
pCP
Ph
pCP
Ph
pCP
Ph
pCP
pCP
Ph
Allyl–OH
Pyrrolidine
Pyrrolidine
Morpholine
Morpholine
Allyl–SH
60 ꢁC, 18 h
41a
42a
43a
44a
45a
46a
47a
48a
49a
49a
50a
51b
52b
68d
81
82
72
78
79
70
73
90 ꢁC, 1 he
90 ꢁC, 1 he
100 ꢁC, 1.5 he
100 ꢁC, 1.5 he
NEt3, 60 ꢁC, 4 h
NEt3, 60 ꢁC, 4 h
NEt3, 60 ꢁC, 4 h
NEt3, 60 ꢁC, 4 h
NEt3, 60 ꢁC, 24 h
rt, 23 h
Allyl–SH
Boc–Cys–OMe
tBuSH
9
0
10
11
12
13
tBuSH
68d
61d
79d
61d
nBuNH2
nBuNH2
Allyl–NH2
pCP
Ph
rt, 42 h
rt, 24 h
a
Isomer a: 3R,4S; b: 3S,4R; the products have accordant configuration.
b
c
pCP¼4-chlorophenyl.
In DMF.
d
e
Addition of sodium azide (cat.).
Neat, without DMF.

8662
A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
Ph
H
H
Z
Z
Ph
LiAlH4
Z
Z
Boc
Boc
N
H
N
H
N
H
THF, rt, 17 h
41%
N
Boc
O
O
OH
56b
26b
pCP
H
H
N
pCP
Boc
LiAlH4
N
H
N
H
N
H
THF, rt, 17 h
40%
OH
27a
57a
Scheme 9. Reductive ring opening of b-lactams.
3. Experimental section
3.1. General remarks
The synthesis of protected amino acids 1–3,19 diazo ketones 4,
531 and 6,32 imine 733 and -lactams 15a,b,8b 19a,8c 22a8b and 29a8b
b
Figure 1. Structure of 53a in the crystal.21
has been published elsewhere. Tetrahydrofuran (THF) and Et2O
were distilled from sodium benzophenone ketyl radical. Abbrevi-
ations: ethyl acetate, EA; para-chlorophenyl, pCP. All moisture-
sensitive reactions were carried out under oxygen-free argon or N2
using oven-dried glassware and a vacuum line. Photochemical re-
actions were performed in a Heraeus laboratory UV reactor system
2 (quartz, 150 W). Flash column chromatography34 was carried out
using Merck silica gel 60 (230–400 mesh) and thin layer chroma-
tography was carried out using commercially available Merck F254
pre-coated sheets. Medium pressure liquid chromatography
(MPLC): Pump (Labomatic MD-50), detection by UV absorption
R2
R1 pCP
H
R1
O
H
H
N
Z
Boc
R2
Z
pCP
Boc
HCl·H2N
CO2Me
N
H
N
N
H
H
NEt3, NaN3
DMF, 60 °C, 24 h
HN
HN
O
CO2Me
NaN3
R2
(Latek UVIS 200); Merck LiChroprep Si 60 (15–25 mm). HPLC: anal-
yses of diastereoisomer distributions were carried out with
a Merck-Hitachi LaChrom D7000 apparatus with a L7100 mixer and
H2N
CO2Me
R1 pCP
H
R1 pCP
H
diode-array detection (L7455) on a LiChrospher Si 60, 5 mm, Merck
(flow: 1–1.5 ml/min) chromatographic column. 1H and 13C NMR
spectra were recorded on a Bruker Cryospek WM-250, an AM-400
or a DRX 500. Chemical shifts are given in parts per million
downfield of tetramethylsilane. 13C NMR spectra were recorded
with broad band proton decoupling and were assigned using DEPT
135 and DEPT 90 experiments. Melting points were measured on
a Bu¨chi apparatus and were not corrected. IR spectra were recorded
on a Bruker IFS-88 spectrometer. Elemental analyses were per-
formed on a Heraeus, CHN-O-rapid or on an elementar vario MICRO.
Electrical ionization and high resolution mass spectra were recor-
ded on a Finnigan MAT-90. Optical rotations were recorded on a
Perkin Elmer 241 polarimeter (using the sodium D line, 589 nm) and
Z
Boc
Z
Boc
Δ, −N2
N
H
N
N
H
N
H
H
N
O
N3
O
R1 = Me, R2 = iPr, 63%: 27a
1 = iPr, R2 = Me, 41%: 30a
54a
55a
R
Scheme 8. Preparation of urea-containing peptidomimetics starting with
pCP¼4-chlorophenyl.
b-lactams.
We planned to use this Curtius rearrangement for the prepa-
ration of triamines with three orthogonal protecting groups.
Trapping of the intermediate isocyanate with allyl alcohol would
lead to an allyloxycarbonyl (Aloc)-protected amino function. Nev-
ertheless, reaction conditions leading to urea derivatives turned out
to be not suitable for the preparation of carbamates (urethanes).
Reaction of allyl alcohol with the acid azide (from 26a) was obvi-
specific optical rotations [a] .
D are given in units of 10ꢀ1 deg cm2 gꢀ1
3.2. Imine syntheses
ously fast; the respective allyl
b,b
0-diaminocarboxylate 41a was
3.2.1. N-(4-Methoxybenzyl)-4-chloro-benzaldimine (8)35
4-Methoxybenzylamine (790 l, 6.09 mmol), 4-chlorobenz-
aldehyde (853 mg, 6.07 mmol) and Al2O3 (3.03 g, activated, neutral,
mesh 50–200 m) were placed in a small flask and vigorously
isolated with 68% yield (Table 4, entry 1).
m
2.4. Reductive ring openings
m
shaken. After standing for 2 h, the heterogeneous mixture was
placed in a funnel blocked with cotton and CeliteÒ and was
extracted with CH2Cl2. The filtrate was concentrated and imine 8
was used without further purification (1.57 g, 6.04 mmol, quant.).
Reductive ring opening of
b-lactams to 1,3-aminoalcohols is
usually achieved either with lithium aluminium hydride,27 with
sodium borohydride28 or with lithium borohydride.29 We used
lithium aluminium hydride as reducing agent for b-lactams 26b
and 27a and obtained diaminoalcohols 56b and 57a. The carbamate
protecting groups were not reduced with these conditions. To re-
ceive filterable granulates after hydrolysis, a basic work-up pro-
cedure developed by Amundsen and Nelson was used.30 With this,
3.2.2. N-(4-Methoxybenzyl)-3-phenyl-propenaldimine (9)35
4-Methoxybenzylamine (1.26 ml, 9.71 mmol), cinnamaldehyde
(1.22 ml, 9.69 mmol) and Al2O3 (4.85 g, activated, neutral, mesh
50–200 mm) were placed in a small flask and vigorously shaken.
chiral, enantiomerically pure
g,g
0-diaminoalcohols with orthogonal
After standing for 2 h, the heterogeneous mixture was placed in
a funnel blocked with cotton and CeliteÒ and was extracted with
CH2Cl2. The filtrate was concentrated and the slowly crystallizing
protecting groups at the nitrogen atoms were obtained with
reasonable yields (Scheme 9).

A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
8663
product 9 (2.43 g, 9.67 mmol, quant.) was used without further
(20 ml), dried (Na2SO4) and concentrated. The residue was purified
purification.
by chromatography (100 g, silica gel, hexanes/EA, 2:1/1:4)
yielding 13a (396 mg, 999 mmol, 56%) as a colourless oil. Though the
product contained some impurities, it was sufficiently clean to be
used in the next step.
3.3.
b-Lactam syntheses
3.3.1. GP 1: general procedure for the thermally induced synthesis
of
-lactams9
A flask filled with diazo ketone (1 equiv) and imine (1.1–
1.3 equiv) in 1,2-dichlorobenzene is placed in a pre-heated bath
(160 ꢁC) and stirred for 30 min. After cooling to rt the mixture is
placed on top of a column (silica gel). The solvent is eluted with
hexanes and the products are eluted with mixtures of hexanes and
EA. The diastereomeric ratio is determined (1H NMR spectroscopy
or HPLC) and the isomers were separated by MPLC.
3.3.7. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-4-
[1,3]dioxolan-2-yl-1-(4-methoxybenzyl)-azetidin-2-one (14a)
b
Glycol (1.66 ml, 29.8 mmol) and p-TosOH$H2O (28 mg,147 mmol)
were added with stirring to a solution of aldehyde 13a (738 mg,
1.86 mmol) in toluene (47 ml) and the mixture was heated with
a Dean–Stark trap for 4 h (monitoring with TLC). CH2Cl2 (50 ml)
was added and the solution was extracted with H2O (40 ml) and
brine (40 ml), dried (MgSO4) and concentrated yielding a brownish
oil, which was purified by chromatography (70 g, silica gel, hex-
anes/EA, 2:1) yielding acetal 14a (529 mg, 1.20 mmol, 65%) as
a colourless solid.
3.3.2. GP 2: general procedure for the photochemically induced
synthesis of b
-lactams8b
A quartz photoreactor is charged with diazo ketone (1 equiv),
imine (1.5–2 equiv) and Et2O (300 ml), flushed with N2, cooled to
ꢀ25 ꢁC and irradiated with a UV lamp for 2–4 h (monitoring with
TLC) with vigorous stirring. The solution is warmed to rt and the
solvent is removed. Excess imine is removed by flash chromatog-
raphy (silica gel) and the diastereomeric ratio is determined
by 1H NMR spectroscopy. Separation and purification of the
diastereomers are achieved by MPLC.
3.3.8. (3R,4S,10S)- and (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-
2-methyl-propyl)-4-(4-chlorophenyl)-1-(4-methoxybenzyl)-
azetidin-2-one (16a,b)
According to GP 2 Z–Val–CHN2 (5, 1.70 g, 6.18 mmol) and imine
8 (2.47 g, 9.51 mmol) were reacted within 2 h. Excess imine was
removed (230 g, silica gel, hexanes/EA, 6:1/1:1) yielding a mix-
ture of isomers (16a/16b, 81:19), which was separated by MPLC
(hexanes/EA, 4:1) yielding 16a (1.11 g, 2.19 mmol, 35%) and 16b
(266 mg, 525 mmol, 8%) as yellowish waxy solid.
3.3.3. (3R,4S,10S)- and (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-
ethyl)-1-(4-methoxybenzyl)-4-phenyl-azetidin-2-one (10a,b)
According to GP 1 Z–Ala–CHN2 (4, 1.91 g, 7.72 mmol) and imine
7 (1.91 g, 8.48 mmol) were reacted in 1,2-dichlorobenzene (44 ml).
Filtrative chromatography on silica gel (250 g, hexanes/EA, 5:1/
1:2) yielded 10a and b (56:44, 1H NMR), which were separated by
MPLC (hexanes/iPrOH, 97:3) yielding 10a (1.19 g, 2.68 mmol, 35%)
and 10b (809 mg, 1.82 mmol, 24%) as colourless solids.
3.3.9. (3R,4S,10S)- and (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-
2-phenyl-ethyl)-1-(4-methoxybenzyl)-4-phenyl-
azetidin-2-one (17a,b)
According to GP 1 Z–Phe–CHN2 (6, 1.70 g, 5.26 mmol) and imine
7 (1.30 g, 5.77 mmol) were reacted in 1,2-dichlorobenzene (40 ml).
Filtrative chromatography on silica gel (200 g, hexanes/EA, 5:1/
1:1) yielded 17a and 17b (55:45, HPLC: hexanes/iPrOH, 98:2). Re-
crystallization (hexanes/EtOAc) gave 17a (650 mg, 1.25 mmol, 24%)
as a colourless solid and purification of the mother liquor by MPLC
(hexanes/iPrOH, 98:2) yielded 17b (524 mg, 1.01 mmol, 19%) as
a waxy yellowish solid.
3.3.4. (3R,4S,10S)- and (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-
ethyl)-4-(4-chlorophenyl)-1-(4-methoxybenzyl)-
azetidin-2-one (11a,b)
According to GP 2 Z–Ala–CHN2 (4,1.77 g, 7.16 mmol) and imine 8
(2.72 g, 10.5 mmol) were reacted within 2 h. Excess imine was
removed (250 g, silica gel, hexanes/EA, 5:1/1:2) yielding a mix-
ture of isomers (11a/11b, 66:34), which was separated by MPLC
(hexanes/iPrOH, 97:3) yielding 11a (1.06 g, 2.21 mmol, 31%) and 11b
(603 mg, 1.26 mmol, 18%) as colourless solids.
3.3.10. (3R,4S,10S)- and (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-
2-phenyl-ethyl)-4-(4-chlorophenyl)-1-(4-methoxybenzyl)-azetidin-
2-one (18a,b)
According to GP 2 Z–Phe–CHN2 (6, 1.65 g, 5.10 mmol) and imine
8 (2.12 g, 8.16 mmol) were reacted within 2 h. Recrystallization
(hexanes/EA) of the crude product (18a/18b, 57:43) gave 18a
(473 mg, 52 mmol, 17%) as a colourless solid and purification of the
mother liquor by chromatography (hexanes/EA, 5:1/2:1) and
MPLC (hexanes/iPrOH, 98:2) yielded 18a (687 mg, 1.24 mmol, 24%)
3.3.5. (E,3R,4S,10S)- and (E,3S,4R,10S)-3-(1-Benzyloxycarbonyl-
amino-ethyl)-1-(4-methoxybenzyl)-4-(2-phenyl-ethenyl)-
azetidin-2-one (12a,b)
According to GP 2 Z–Ala–CHN2 (4, 1.38 g, 5.58 mmol) and imine
9 (2.15 g, 8.55 mmol) were reacted within 4 h. Excess imine was
removed (200 g, silica gel, hexanes/EA, 5:1/1:2) yielding a mix-
ture of isomers (12a/12b, 62:38), which was separated by MPLC
(hexanes/iPrOH, 97:3) yielding 12a (703 mg, 1.49 mmol, 27%) as
a colourless solid and 12b (539 mg, 1.15 mmol, 21%) as a yellowish
waxy solid.
as a colourless solid and 18b (519 mg, 935 mmol, 18%) as a colourless
waxy solid.
3.4. Oxidative cleavage of the PMB group
3.4.1. GP 3: general procedure for the oxidative cleavage of the PMB
group17
3.3.6. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-1-(4-
To PMB-protected b-lactam (1.00 mmol) in acetonitrile/H2O
methoxybenzyl)-2-oxo-azetidine-4-carbaldehyde (13a)
(1:1, 43 ml) was added K2HPO4 (600 mg, 3.44 mmol) and K2S2O8
(1.80 g, 6.66 mmol). The mixture was heated to 75 ꢁC and stirred for
70 min. The solution was concentrated in vacuo to half the volume
and extracted with EA (3ꢂ10 ml). The combined organic layers
were washed with saturated NaHCO3 solution (40 ml) and brine
(40 ml). The aqueous layers were re-extracted with EA (10 ml) and
the combined organic layers were dried (MgSO4), concentrated and
purified by chromatography (silica gel).
To a solution of
oxane/H2O (3:1,18 ml) was added at rt and with stirring 2,6-lutidine
(410 l, 3.52 mmol), NaIO4 (1.52 g, 7.11 mmol) and K2OsO4$2H2O
(13 mg, 35.3 mol). After stirring for 30 min (monitoring with TLC)
b-lactam 12a (837 mg, 1.78 mmol) in 1,4-di-
m
m
H2O (20 ml) and CH2Cl2 (40 ml) were added. The organic layers
were separated and the aqueous layers were extracted with CH2Cl2
(3ꢂ20 ml). The combined organic layers were washed with brine

8664
A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
3.4.2. (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-4-phenyl-
3.5.3. tert-Butyl (3S,4R,10S)-3-(1-benzyloxycarbonylamino-ethyl)-
azetidin-2-one (19b)
2-oxo-4-phenyl-azetidine-1-carboxylate (26b)
According to GP 3
reacted and purified (90 g, silica gel, hexanes/EA, 4:1/1:1) yield-
ing -lactam 19b (362 mg, 1.12 mmol, 56%) as a colourless solid.
b
-lactam 10b (893 mg, 2.01 mmol) was
According to GP 4
and purified (35 g, silica gel, hexanes/EA, 4:1) yielding
26b (223 mg, 525 mol, 87%) as a colourless solid.
b
-lactam 19b (195 mg, 601
m
mol) was reacted
b-lactam
b
m
3.4.3. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-
3.5.4. tert-Butyl (3R,4S,10S)-3-(1-benzyloxycarbonylamino-ethyl)-
4-(4-chlorophenyl)-azetidin-2-one (20a)
4-(4-chlorophenyl)-2-oxo-azetidine-1-carboxylate (27a)
According to GP 3
and purified (20 g, silica gel, hexanes/EA, 4:1/1:1) yielding
-lactam 20a (78 mg, 217 mol, 53%) as a colourless solid.
b
-lactam 11a (196 mg, 409
m
mol) was reacted
According to GP 4
and purified (20 g, silica gel, hexanes/EA, 5:1/4:1) yielding
-lactam 27a (78 mg, 170 mol, 88%) as a colourless solid.
b-lactam 20a (69 mg, 192 mmol) was reacted
b
m
b
m
3.4.4. (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-
3.5.5. tert-Butyl (3S,4R,10S)-3-(1-benzyloxycarbonylamino-ethyl)-
4-(4-chlorophenyl)-azetidin-2-one (20b)
4-(4-chlorophenyl)-2-oxo-azetidine-1-carboxylate (27b)
According to GP 3
ted and purified (55 g, silica gel, hexanes/EA, 4:1/1:1) yielding
-lactam 20b (243 mg, 677 mol, 51%) as a colourless solid.
b
-lactam 11b (641 mg, 1.34 mmol) was reac-
According to GP 4
and purified (20 g, silica gel, hexanes/EA, 5:1/4:1) yielding
-lactam 27b (127 mg, 277 mol, 70%) as a colourless solid.
b-lactam 20b (142 mg, 396 mmol) was reacted
b
m
b
m
3.5.6. tert-Butyl (3R,4S,10S)-3-(1-benzyloxycarbonylamino-ethyl)-
3.4.5. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-ethyl)-
4-[1,3]dioxolan-2-yl-2-oxo-azetidine-1-carboxylate (28a)
4-[1,3]dioxolan-2-yl-azetidin-2-one (21a)
According to GP 4
and purified (20 g, silica gel, hexanes/EA, 4:1) yielding
(115 mg, 274 mol, 77%) as a colourless solid.
b
-lactam 21a (114 mg, 356
m
mol) was reacted
According to GP 3
ted and purified (60 g, silica gel, hexanes/EA, 4:1/1:1) yielding
-lactam 21a (163 mg, 509 mol, 40%) as a colourless foam.
b-lactam 14a (562 mg, 1.28 mmol) was reac-
b-lactam 28a
m
b
m
3.5.7. tert-Butyl (3R,4S,10S)-3-(1-benzyloxycarbonylamino-2-
methyl-propyl)-4-(4-chlorophenyl)-2-oxo-azetidine-
1-carboxylate (30a)
3.4.6. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-2-methyl-propyl)-
4-(4-chlorophenyl)-azetidin-2-one (23a)
According to GP 3
and purified (100 g, silica gel, hexanes/EA, 6:1/4:1) yielding
-lactam 23a (404 mg, 1.04 mmol, 47%) as a colourless solid.
b-lactam 16a (1.13 g, 2.23 mmol) was reacted
According to GP 4
reacted and purified (100 g, silica gel, hexanes/EA, 6:1) yielding
-lactam 30a (447 mg, 918 mol, 88%) as a colourless foam.
b-lactam 23a (404 mg, 1.04 mmol) was
b
b
m
3.4.7. (3R,4S,10S)-3-(1-Benzyloxycarbonylamino-2-phenyl-ethyl)-
4-phenyl-azetidin-2-one (24a)
3.5.8. tert-Butyl (3R,4S,10S)-3-(1-benzyloxycarbonylamino-2-
phenyl-ethyl)-2-oxo-4-phenyl-azetidine-1-carboxylate (31a)
According to GP 3
and purified (30 g, silica gel, hexanes/EA, 4:1/2:1) yielding
-lactam 24a (122 mg, 305 mol, 32%) as a colourless solid.
b-lactam 17a (500 mg, 960 mmol) was reacted
According to GP 4
and purified (10 g, silica gel, hexanes/EA, 8:1) yielding
(71 mg, 142 mol, 56%) as a colourless solid.
b
-lactam 24a (102 mg, 255
m
mol) was reacted
b
-lactam 31a
b
m
m
3.4.8. (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-2-phenyl-ethyl)-
4-phenyl-azetidin-2-one (24b)
3.5.9. tert-Butyl (3S,4R,10S)-3-(1-benzyloxycarbonylamino-2-
phenyl-ethyl)-2-oxo-4-phenyl-azetidine-1-carboxylate (31b)
According to GP 3
and purified (60 g, silica gel, hexanes/EA, 4:1/2:1) yielding
-lactam 24b (191 mg, 477 mol, 40%) as a colourless solid.
b-lactam 17b (618 mg, 1.19 mmol) was reacted
According to GP 4
and purified (30 g, silica gel, hexanes/EA, 8:1) yielding
(161 mg, 322 mol, 72%) as a colourless solid.
b
-lactam 24b (179 mg, 447
m
mol) was reacted
b-lactam 31b
b
m
m
3.4.9. (3S,4R,10S)-3-(1-Benzyloxycarbonylamino-2-phenyl-ethyl)-
4-(4-chlorophenyl)-azetidin-2-one (25b)
3.6. Ring opening with O-nucleophiles
According to GP 3
and purified (40 g, silica gel, hexanes/EA, 4:1/2:1) yielding
-lactam 25b (135 mg, 310 mol, 34%) as a colourless solid.
b-lactam 18b (500 mg, 901 mmol) was reacted
3.6.1. Methyl (2R,3S,10S)-2-(amino-phenyl-methyl)-3-
benzyloxycarbonylamino-butanoate (37a)
b
m
TMSCl (158
ml, 1.24 mmol) was added at rt to a solution of
b-lactam 19a (80 mg, 247
mmol) in anhydrous MeOH (4.5 ml), the
3.5. Synthesis of N-Boc-protected
b
-lactams
mixture was stirred for 66 h (monitoring with TLC), volatile com-
ponents were removed in vacuo and CH2Cl2 (30 ml) was added. The
solution was extracted with saturated NaHCO3 solution (20 ml),
dried (MgSO4), concentrated and chromatographied (10 g, silica gel,
3.5.1. GP 4: general procedure for synthesis of N-Boc-protected
b
-lactams8b
To a solution of the
b
-lactam (500
mmol) in CH2Cl2 (10 ml) was
hexanes/EA 2:1/1:1) yielding 37a (51 mg, 143 mmol, 58%) of
added at rt Et3N (70
m
l, 503 mol), Boc2O (219 mg, 1.00 mmol) and
m
a slowly crystallizing oil.
a catalytic amount of DMAP. After stirring for 4 h brine (10 ml) and
Et2O (10 ml) were added. The organic layer was washed with sat-
urated NH4Cl solution (10 ml) and brine (10 ml), dried (MgSO4) and
concentrated. The residue was purified by chromatography (silica
gel).
3.6.2. Methyl (2S,3S,10R)-2-[amino-(4-chlorophenyl)-methyl]-3-
(benzyloxycarbonylamino)-4-phenyl-butanoate (38b)
TMSCl (88
ml, 689
mmol) was added at rt to a solution of b-lactam
25b (60 mg, 138
mmol) in anhydrous MeOH (10 ml) and the mixture
was stirred for 48 h (monitoring with TLC). The volatile compo-
nents were removed and the remnant was dissolved in CH2Cl2
(30 ml), washed with saturated NaHCO3 solution (20 ml), dried
(MgSO4) and concentrated. The residue was purified by chroma-
tography (6 g, silica gel, hexanes/EA, 3:1) yielding 38b (34 mg,
3.5.2. tert-Butyl (3R,4S,10S)-3-(1-benzyloxycarbonylamino-ethyl)-
2-oxo-4-phenyl-azetidine-1-carboxylate (26a)
According to GP 4
and purified (50 g, silica gel, hexanes/EA, 4:1) yielding
(238 mg, 561 mol, 79%) as a colourless solid.
b
-lactam 19a (230 mg, 709
m
mol) was reacted
b-lactam 26a
m
72.8 mmol, 53%) as a colourless solid.

A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
8665
3.6.3. Methyl (2R,3S,10S)-2-[amino-(4-chlorophenyl)-methyl]-3-
benzyloxycarbonylamino-4-methyl-pentanoate (39a)
TMSCl (114 l, 1.13 mmol) was added at rt to a solution of
-lactam 30a (87 mg, 225 mol) in anhydrous MeOH (2 ml) and
the mixture was stirred for 24 h (monitoring with TLC). The
volatile components were removed and the remnant was dis-
solved in CH2Cl2 (30 ml), washed with saturated NaHCO3 solu-
tion (20 ml), dried (MgSO4) and concentrated. The residue was
chromatographied (8 g, silica gel, hexanes/EA, 3:1) yielding 39a
3.6.9. Methyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-methyl]-4-methyl-
pentanoate (40a)
m
b
m
Crude amine 39a (48 mg, 115
4 within 4 d. Purification (6 g, silica gel, hexanes/EA, 5:1) yielded
40a (42 mg, 80.9 mol, 71%) as a colourless solid.
mmol) was reacted according to GP
m
3.6.10. Allyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-butanoate (41a)
(48 mg, 115
m
mol, 51%) as a yellowish oil containing significant
AllylOH (22
added at rt under an argon atmosphere to a solution of
26a (106 mg, 250 mol) in anhydrous DMF (1 ml). After stirring for
18 h (monitoring with TLC) at 60 ꢁC the mixture was poured after
cooling to brine (10 ml). The aqueous phase was extracted with
Et2O (3ꢂ10 ml) and the combined organic layers were dried
(MgSO4), concentrated at the rotary evaporator and purified by
chromatography (18 g, silica gel, hexanes/EA, 3:1) yielding 41a
m
l, 323
m
mol) and NaN3 (16 mg, 246
m
mol) were
amounts of non-identified side products. This material was
transferred into the Boc-protected derivative for analysis (vide
infra).
b
-lactam
m
3.6.4. Methyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-butanoate (32a)
(a) Et3N (100
ml, 718
mmol) was added to a solution of
b
-lactam 26a
(82 mg, 170 mmol, 68%) as a colourless oil.
(102 mg, 240
mmol) in anhydrous MeOH (7 ml) and the mixture
was stirred for 21 h at rt (monitoring with TLC), concentrated
and purified by chromatography (10 g, silica gel, hexanes/EA,
3.7. Ring opening with N-nucleophiles
3:1) yielding methyl ester 32a (109 mg, 239
mmol, 99%) as
3.7.1. (2R,3S,10S)-3-Benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-1-pyrrolidin-
1-yl-butan-1-one (42a)
a colourless wax.
(b) Methyl ester 32a is alternatively available by Boc protection of
amine 37a (45 mg, 126 mol) according to GP 4. Reaction (3 d)
and purification (5 g, silica gel, hexanes/EA, 3:1) yielded 32a
(36 mg, 78.9 mol, 62%) as a colourless wax.
m
A solution of b-lactam 26a (87 mg, 205 mmol) in pyrrolidine
(0.5 ml) was stirred for 1 h (monitoring with TLC) at 90 ꢁC. After
cooling to rt, the volatile components were removed at the rotary
evaporator and the residue was purified by chromatography (10 g,
m
silica gel, hexanes/EA, 3:1) to yield 42a (82 mg, 165 mmol, 81%) as
a colourless solid.
3.6.5. Methyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-methyl]-butanoate (33a)
Et3N (71
ml, 510
mmol) was added at rt to a solution of
b
-lactam
3.7.2. (2R,3S,10S)-3-Benzyloxycarbonylamino-2-[tert-butyloxy-
carbonylamino-(4-chlorophenyl)-methyl]-1-pyrrolidin-1-yl-
butan-1-one (43a)
27a (78 mg, 170
mmol) in anhydrous MeOH (5 ml) and the mixture
was stirred for 24 h (monitoring with TLC). The volatile compo-
nents were removed at the rotary evaporator and the residue was
purified by chromatography (8 g, silica gel, hexanes/EA, 3:1)
A solution of
b-lactam 27a (80 mg, 174 mmol) in pyrrolidine
(1 ml) was stirred for 1 h (monitoring with TLC) at 90 ꢁC. After
cooling to rt, the volatile components were removed at the rotary
evaporator and the residue was purified by chromatography (11 g,
yielding 33a (83 mg, 169 mmol, 99%) as a colourless wax.
3.6.6. Methyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-[1,3]dioxolan-2-yl-methyl)-
butanoate (34a)
silica gel, hexanes/EA, 3:1) to yield 43a (76 mg, 143 mmol, 82%) as
a colourless solid.
Et3N (78
ml, 560
mmol) was added at rt to a solution of
b
-lactam
3.7.3. (2R,3S,10S)-3-Benzyloxycarbonylamino-2-(tert-butyloxy-
carbonylamino-phenyl-methyl)-4-methyl-1-morpholin-4-yl-
pentan-1-one (44a)
28a (79 mg, 188
m
mol) in anhydrous MeOH (4 ml) and the mixture
was stirred for 22 h (monitoring with TLC). The volatile compo-
nents were removed at the rotary evaporator and the residue was
purified by chromatography (10 g, silica gel, hexanes/EA, 3:1)
A solution of
b-lactam 29a (58 mg, 128 mmol) in morpholine
(1.1 ml) was stirred for 90 min (monitoring with TLC) at 100 ꢁC.
After cooling to rt, the volatile components were removed at the
rotary evaporator and the residual yellowish oil was purified by
chromatography (13 g, silica gel, hexanes/EA, 3:1) to yield 44a
yielding 34a (84 mg, 186 mmol, 99%) as a colourless oil.
3.6.7. Methyl (2R,3S,10S)-3-benzyloxycarbonylamino-
2-(tert-butyloxycarbonylamino-phenyl-methyl)-
4-methyl-pentanoate (35a)
(50 mg, 93 mmol, 72%) as a colourless solid.
Et3N (69
ml, 496
mmol) was added at rt to a solution of
b
-lactam
3.7.4. (2R,3S,10S)-3-Benzyloxycarbonylamino-2-[tert-butyloxy-
carbonylamino-(4-chlorophenyl)-methyl]-4-methyl-1-morpholin-
4-yl-pentan-1-one (45a)
29a (75 mg, 166
mmol) in anhydrous MeOH (5 ml) and the mixture
was stirred for 16 h (monitoring with TLC). The volatile compo-
nents were removed at the rotary evaporator and the residue was
purified by chromatography (8 g, silica gel, hexanes/EA, 5:1)
A solution of
b-lactam 30a (80 mg, 164 mmol) in morpholine
(1 ml) was stirred for 90 min (monitoring with TLC) at 100 ꢁC. After
cooling to rt, the volatile components were removed at the rotary
evaporator and the residue was purified by chromatography (10 g,
yielding 35a (78 mg, 161 mmol, 97%) as a colourless oil.
3.6.8. Methyl (2S,3S,10R)-3-benzyloxycarbonylamino-2-(tert-
silica gel, hexanes/EA, 3:1) to yield 45a (74 mg, 129 mmol, 78%) as
butyloxycarbonylamino-phenyl-methyl)-4-phenyl-butanoate (36b)
a colourless solid.
Et3N (58
31b (69 mg, 138
m
l, 417
mmol) was added at rt to a solution of b-lactam
mmol) in anhydrous MeOH (7 ml) and the mixture
3.7.5. (2R,3S,10S)-3-Benzyloxycarbonylamino-N-butyl-2-(tert-
was stirred for 24 h (monitoring with TLC). The volatile compo-
nents were removed at the rotary evaporator and the residue was
butyloxycarbonylamino-phenyl-methyl)-butanamide (50a)
nBuNH2 (15
at rt to a solution of
DMF (0.5 ml). The mixture was stirred for 23 h (monitoring with
ml, 152
mmol) and NaN3 (1 mg, 15
mmol) were added
purified by MPLC (hexanes/EA, 4:1) yielding 36b (45 mg, 85
mmol,
b
-lactam 26a (50 mg, 118
mmol) in anhydrous
61%) as a colourless solid.

8666
A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
TLC) under argon atmosphere and was poured on brine (5 ml). The
organic layer was extracted with Et2O (3ꢂ10 ml) and the combined
organic layers were dried (MgSO4), concentrated at the rotary
evaporator and purified by chromatography (10 g, silica gel, hex-
3.8.3. Methyl (2S,20R,30S,100S)-3-[3-benzyloxycarbonylamino-2-
(tert-butyloxycarbonylamino-phenyl-methyl)-4-phenyl-butyryl-
sulfanyl]-2-tert-butyloxycarbonylamino-propanoate (48a)
Et3N (25
were added under argon atmosphere to a solution of
(70 mg, 140 mol) in anhydrous DMF (1.5 ml). The mixture was
ml, 180
mmol) and Boc–Cys–OMe (43 mg, 183
mmol)
anes/EA, 4:1/2:1) yielding 50a (36 mg, 72.3
mmol, 61%) as a col-
b-lactam 31a
ourless solid.
m
heated to 60 ꢁC for 4 h (monitoring with TLC), hydrolyzed with
saturated NH4Cl solution (1 ml), and cooled to rt. The aqueous layer
was extracted with EA (3ꢂ5 ml) and the combined organic layers
were washed with saturated NaHCO3 solution (2ꢂ5 ml) and brine
(5 ml), dried (MgSO4) and concentrated at the rotary evaporator.
The residual yellowish oil was purified by chromatography (6 g,
3.7.6. (2S,3S,10R)-3-Benzyloxycarbonylamino-N-butyl-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-methyl]-
butanamide (51b)
nBuNH2 (23
ml, 233
mmol) and NaN3 (2 mg, 31
mmol) were added
at rt to a solution of
b
-lactam 27b (81 mg, 176
mmol) in anhydrous
silica gel, hexanes/EA, 8:1/6:1) to yield 48a (75 mg, 102 mmol,
73%) as a colourless oil.
DMF (1 ml). The mixture was stirred for 42 h (monitoring with TLC)
under argon atmosphere and was poured on brine (6 ml). The or-
ganic layer was extracted with Et2O (3ꢂ10 ml) and the combined
organic layers were dried (MgSO4), concentrated at the rotary
evaporator and purified by chromatography (16 g, silica gel, hex-
3.8.4. S-tert-Butyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-methyl]-4-methyl-
pentanethioate (49a)
anes/EA, 4:1/2:1) yielding 51b (74 mg, 139 mmol, 79%) as a col-
ourless solid.
Et3N (47
m
l, 338
mol) were added at rt under an argon atmosphere to
-lactam 30a (127 mg, 261 mol) in DMF (2.5 ml).
mmol), tBuSH (38 ml, 337 mmol) and NaN3
(17 mg, 261
m
a solution of
b
m
3.7.7. (2S,3S,10R)-N-Allyl-3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-4-phenyl-
butanamide (52b)
After stirring for 24 h (monitoring with TLC) at 60 ꢁC the mixture
was poured after cooling to brine (8 ml). The aqueous phase was
extracted with Et2O (3ꢂ10 ml) and the combined organic layers
were dried (MgSO4), concentrated at the rotary evaporator and
purified by chromatography (25 g, silica gel, hexanes/EA, 4:1)
AllylNH2 (8
ml, 107
mmol) and NaN3 (1 mg, 15
mmol) were added
at rt to a solution of
b
-lactam 31b (38 mg, 76
mmol) in anhydrous
DMF (1.5 ml). The mixture was stirred for 24 h (monitoring with
TLC) under argon atmosphere and was poured on brine (2 ml). The
organic layer was extracted with Et2O (3ꢂ10 ml) and the combined
organic layers were dried (MgSO4), concentrated at the rotary
evaporator and purified by chromatography (3 g, silica gel, hex-
yielding 49a (103 mg, 178 mmol, 68%) as a colourless solid.
3.8.5. Methyl (20R,30S,100S)-[3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-butyrylamino]-
ethanoate (53a)
anes/EA, 4:1/3:1) yielding 52b (26 mg, 47 mmol, 61%) as a col-
ourless solid.
Gly–OMe$HCl (46 mg, 366
NaN3 (2 mg, 31 mol) were added at rt under a nitrogen atmo-
sphere to -lactam 26a (120 mg, 283 mol) in anhydrous DMF
mmol), Et3N (51 ml, 366 mmol) and
m
b
m
(1 ml), the mixture was stirred for 43 h (monitoring with TLC) and
poured into brine (8 ml). The aqueous phase was extracted with
Et2O (3ꢂ10 ml) and the combined organic layers were dried
(MgSO4) and concentrated at the rotary evaporator. The residue
was purified by chromatography (24 g, silica gel, hexanes/EA, 4:1/
3.8. Ring opening with S-nucleophiles
3.8.1. S-Allyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-(tert-
butyloxycarbonylamino-phenyl-methyl)-butanethioate (46a)
2:1) yielding 53a (80 mg, 156 mmol, 55%) as a colourless solid.
Et3N (28
289 mol) were added under argon atmosphere to a solution of
-lactam 26a (66 mg, 155 mol) in anhydrous DMF (1.5 ml). The
mixture was heated to 60 ꢁC for 4 h (monitoring with TLC), hy-
drolyzed with saturated NH4Cl solution (1 ml) and cooled to rt.
The aqueous layer was extracted with Et2O (3ꢂ5 ml) and the
combined organic layers were washed with saturated NaHCO3
solution (2ꢂ5 ml) and with brine (5 ml), dried (MgSO4) and
concentrated at the rotary evaporator. The residue was purified
by chromatography (8 g, silica gel, hexanes/EA, 3:1) to yield 46a
ml, 201 mmol) and AllylSH (technical grade, 23 ml,
m
3.8.6. Methyl (2S,10R,20S,100S)-2-(3-{2-benzyloxycarbonylamino-1-
[tert-butoxycarbonylamino-(4-chlorophenyl)-methyl]-propyl}-
ureido)-3-methyl-butanoate (54a)
b
m
Val–OMe$HCl (39 mg, 233
NaN3 (12 mg, 185 mol) were added at rt under a nitrogen atmo-
sphere to -lactam 27a (82 mg, 179 mol) in anhydrous DMF (1 ml),
mmol), Et3N (33 ml, 237 mmol) and
m
b
m
the mixture was stirred at 60 ꢁC for 24 h (monitoring with TLC) and
poured after cooling into brine (6 ml). The aqueous phase was
extracted with Et2O (3ꢂ10 ml) and the combined organic layers
were dried (MgSO4) and concentrated at the rotary evaporator. The
residue was purified by chromatography (16 g, silica gel, hexanes/
(61 mg, 122 mmol, 79%) as a colourless oil.
3.8.2. S-Allyl (2R,3S,10S)-3-benzyloxycarbonylamino-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-methyl]-
butanethioate (47a)
EA, 4:1/2:1) yielding 54a (68 mg, 112 mmol, 63%) as a colourless
solid.
Et3N (30
314 mol) were added under argon atmosphere to a solution of
-lactam 27a (77 mg, 168 mol) in anhydrous DMF (1.5 ml). The
mixture was heated to 60 ꢁC for 4 h (monitoring with TLC), hy-
drolyzed with saturated NH4Cl solution (1 ml) and cooled to rt. The
aqueous layer was extracted with EA (3ꢂ5 ml) and the combined
organic layers were washed with saturated NaHCO3 solution
(2ꢂ5 ml) and with brine (5 ml), dried (MgSO4) and concentrated at
the rotary evaporator. The residue was purified by chromatography
ml, 216 mmol) and AllylSH (technical grade, 25 ml,
3.8.7. Methyl (2S,10R,20S,100S)-2-(3-{2-benzyloxycarbonylamino-1-
[tert-butoxycarbonylamino-(4-chlorophenyl)-methyl]-3-methyl-
butyl}-ureido)-propionate (55a)
m
b
m
Ala–OMe$HCl (34 mg, 244
NaN3 (13 mg, 200 mol) were added at rt under a nitrogen atmo-
sphere to -lactam 30a (91 mg, 187 mol) in anhydrous DMF (1 ml),
mmol), Et3N (34 ml, 244 mmol) and
m
b
m
the mixture was stirred at 60 ꢁC for 24 h (monitoring with TLC) and
poured after cooling into brine (6 ml). The aqueous phase was
extracted with Et2O (3ꢂ10 ml) and the combined organic layers
were dried (MgSO4) and concentrated at the rotary evaporator. The
(17 g, silica gel, hexanes/EA, 3:1) to yield 47a (63 mg,118 mmol, 70%)
as a colourless solid.

A.A. Taubinger et al. / Tetrahedron 64 (2008) 8659–8667
8667
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b
b
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butyloxycarbonylamino-phenyl-methyl)-butan-1-ol (56b)
b
-Lactam 26b (68 mg, 160
added dropwise at rt under an argon atmosphere to a slurry of
LiAlH4 (19 mg, 501 mol) in anhydrous THF (0.5 ml). After stirring
mmol) in anhydrous THF (0.5 ml) was
m
for 14 h (monitoring with TLC), the mixture was carefully hydro-
lyzed by dropwise (!) addition of 25% aqueous NaOH (0.5 ml). The
aqueous phase was extracted with EA (3ꢂ5 ml) and the combined
organic layers were extracted with brine (10 ml), dried (MgSO4),
concentrated at the rotary evaporator and purified by chromato-
graphy (6 g, silica gel, hexanes/EA, 3:1/2:1) to yield 56b (28 mg,
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65 mmol, 41%) as a colourless solid.
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3.9.2. (2R,3S,10S)-3-Benzyloxycarbonylamino-2-[tert-
butyloxycarbonylamino-(4-chlorophenyl)-
methyl]-butan-1-ol (57a)
15. (a) Ng, J. S.; Przybyla, C. A.; Mueller, R. A.; Vasquez, M. L.; Getman, D. P.; Freskos,
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m
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165.
17 h (monitoring with TLC), the mixture was carefully hydrolyzed
by dropwise (!) addition of 25% aqueous NaOH (0.5 ml). The
aqueous phase was extracted with EA (3ꢂ5 ml) and the combined
organic layers were extracted with brine (10 ml), dried (MgSO4),
concentrated at the rotary evaporator and purified by chromato-
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Acknowledgements
21. X-ray crystallographic data of 38 (CCDC 668750), 42 (CCDC 668751) and 44
(CCDC 668749) have already been published.10 These and the data for the
structure of 53 (CCDC 682044) can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
22. (a) Palomo, C.; Aizpurua, J. M.; Cuevas, C. J. Chem. Soc., Chem. Commun. 1994,
1957–1958; (b) Palomo, C.; Aizpurua, J. M.; Cuevas, C.; Mielgo, A.; Galarza, R.
Tetrahedron Lett. 1995, 36, 9027–9030.
This work was supported by the Deutsche Forschungs-
gemeinschaft.
Supplementary data
23. Baldwin, J. E.; Adlington, R. M.; Gollins, D. W.; Schofield, C. J. J. Chem. Soc., Chem.
Commun. 1990, 720–721.
Experimental details and spectroscopic data of all new com-
pounds. X-ray-crystallographic data of compound 53a. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2008.07.006.
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