A synthesis of novel N-sulfonylated β-amino acids

Article abstract of DOI:10.1016/j.tet.2005.11.052

Novel N-sulfonyl β-amino acids were efficiently prepared in a seven-step synthesis starting from Boc protected methanesulfonamide and terminal epoxides. A zinc-mediated allylation of cyclic N-sulfonyl imines readily derived from these building blocks serv

Full text of DOI:10.1016/j.tet.2005.11.052

Tetrahedron 62 (2006) 1799–1805
A synthesis of novel N-sulfonylated b-amino acids
†
Dirk Freitag and Peter Metz
*
¨
¨
Technische Universitat Dresden, Institut fur Organische Chemie, Bergstraße 66, D-01069 Dresden, Germany
Received 16 September 2005; revised 17 November 2005; accepted 21 November 2005
Available online 20 December 2005
Abstract—Novel N-sulfonyl b-amino acids were efficiently prepared in a seven-step synthesis starting from Boc protected
methanesulfonamide and terminal epoxides. A zinc-mediated allylation of cyclic N-sulfonyl imines readily derived from these building
blocks served as a key operation of this sequence.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In the last decade, b-amino acids and their derivatives have
been studied intensively.1 They represent major structural
features of a large number of bioactive compounds such
as the antifungal agent jasplakinolide2a and the
antitumor drug taxol.2b Moreover, b-amino acid
derivatives are of high value as precursors for peptidomi-
Scheme 1. Envisaged access to b-lactam-sulfonamide hybrids 1 by
metics3a and b-lactams,3b–d and the free amino acids can
cyclization of b-amino acids 2.
display useful biological effects as well.4
As part of a program launched into the development of
novel methods for the preparation of cyclic sulfonic acid
derivatives,5 we have recently developed an access to a
range of bicyclic b-lactam-sulfonamide hybrids6 by ring
closing metathesis and hydrogenation.5a,b However, the
carbapenam–monobactam hybrids 1a,b featuring a
g-sultam moiety were not available using this methodology.
Since cyclization of b-amino acids 2 was envisioned as an
alternative approach to 1 (Scheme 1), we investigated their
synthesis. Here, we report an efficient protocol for the
preparation of the N-sulfonylated b-amino acids 2a and 2b.
According to our retrosynthetic analysis (Scheme 2), acids 2
should be available by an allylation/oxidative cleavage
Scheme 2. Retrosynthetic analysis for b-amino acids 2.
sequence from cyclic N-sulfonyl imines 3. Heterocycles 3
might be obtained by deprotection/condensation from
2. Results and discussion
carbonyl compounds 4, which in turn should be accessible
by regioselective ring opening of epoxides 5 with the
dianion of 6 followed by oxidation.
2.1. Synthesis of cyclic N-sulfonyl imines 3
Deprotonation of Boc protected methanesulfonamide 67
using an excess of LDA gave rise to dianion 7,8 which was
used in ring opening reactions of ethylene oxide (5a),
propylene oxide (5b), and styrene oxide (5c) (Scheme 3).
Nucleophilic addition of 7 to 5 delivered primary alcohol 8a
and secondary alcohols 8b,c in good yields.
Keywords: b-Amino acids; g-Sultams; Sulfonyl imines; Sulfonamides;
Allylation; Oxidative cleavage.
*
Corresponding author. Tel.: C49 351 463 37006; fax: C49 351 463
33162; e-mail: peter.metz@chemie.tu-dresden.de
† New address: Chemisches Labor fu¨r Umwelt- und Produktanalytik,
Drebnitzer Weg 4, D-01877 Bischofswerda, Germany.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.052

1800
D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
2.2. Allylation of cyclic N-sulfonyl imines 3 and oxidative
cleavage
Among the large variety of reaction conditions for allylation
of imines,12 reactions in aqueous media are of particular
importance,13 since they are easily performed and environ-
mentally friendly. We allylated imines 3 according to
conditions published by Lu and Chan14 using a large excess
of zinc and allyl bromide (Scheme 6). Activation of the
metal surface15 by ultrasonication of the reaction mixture
shortened the reaction times and improved the yields of
g-sultams 10a,b.
Scheme 3. Nucleophilic addition of dianion 7 to epoxides 5.
For oxidation of alcohols 8, the chromium reagent PCC9
gave the best results (Scheme 4). While hemiaminal 9 was
isolated after oxidation of 8a, reactions of 8b and 8c with
PCC smoothly afforded ketones 4b and 4c, respectively, in
high yields.
Scheme 6. Allylation of cyclic N-sulfonyl imines 3a and 3b.
As anticipated, allylation of 3a proceeded much faster than
allylation of 3b. Nevertheless, sultam 10b was obtained in
good yield. In contrast, phenylsubstituted analog 3c was
not allylated under these conditions, probably due to the
steric hindrance caused by the phenyl substituent. Likewise,
attempted alkylation of 3c with other nucleophilic agents
(MeMgBr, MeLi) met with no success.
Scheme 4. PCC oxidation of 8.
Trifluoroacetic acid (TFA) is a standard reagent for the
cleavage of Boc protecting groups.10 In our approach to
heterocycles 3, TFA has two additional functions as an
acidic catalyst, namely to promote intramolecular nucleo-
philic attack at the carbonyl moiety of 4 as well as
subsequent dehydration (Scheme 5). Much to our delight, all
tasks were readily fulfilled by TFA, and the N-sulfonyl
imines 3 could be isolated as crystalline compounds in
good (3a) to excellent (3b,c) yields.11 For deprotection/
˚
dehydration of 9, the use of molecular sieves 4 A was
essential in order to achieve a synthetically useful yield
of 3a.
Scheme 5. Deblocking/dehydration to give cyclic N-sulfonyl imines 3.
Scheme 7. Formation of b-amino acids 2a and 2b.

D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
1801
The next step in our synthetic plan was oxidative cleavage
of the alkene. Using a Lemieux–von-Rudloff oxidation16
with ruthenium tetroxide generated in situ from ruthenium
trichloride in the presence of excess sodium periodate,
formation of the desired products was detected by mass
spectrometric analysis of the reaction mixture. However,
isolation of the very polar acids 2 from the aqueous reaction
medium could not be achieved. This problem was
eventually overcome by Boc protection of g-sultams 10 to
afford derivatives 11. Lemieux–von-Rudloff oxidation of 11
and subsequent oxidation with sodium chlorite delivered
Boc protected acids 12. Finally, TFA promoted removal of
the Boc protecting group gave rise to the desired acids 2a
and 2b (Scheme 7).
purification. Diazomethane was prepared as an approxi-
mately 0.35 M solution in diethyl ether from commercially
available Diazaldw according to a procedure published by
Hudlicky.20 Solvents were dried according to standard
procedures. Analytical TLC was performed on precoated
Merck Si 254 F plates, and the products were visualized
with a solution of KMnO4. Merck silica gel 60 (40–63 mm)
was used for flash chromatography. Melting points were
determined on a Kofler microscope desk. IR spectra were
1
measured with a ThermoNicolet AVATAR 360 FT-IR. H
and 13C NMR spectra were recorded on a Bruker AC-300
using either CDCl3 or DMSO-d6 as the solvent and are
1
reported in ppm downfield from TMS (dZ0) for H NMR
and relative to the central CDCl3 resonance (dZ77.7) or
DMSO-d6 resonance (dZ40.8) for 13C NMR. 13C multi-
plicities were determined using DEPT pulse sequences.
Mass spectra were recorded with a Hewlett Packard
Esquire-LC (LC/MS) and an Agilent GC 6890N coupled
to an Agilent MSD 5973 (GC/MS). Elemental analysis were
carried out with a EuroVector EA-3000.
Similar to the cyclization of b-amino acids, conversion of
their methyl esters to b-lactams promoted by organometallic
agents such as Grignard reagents17 and organolithium
compounds18 is a commonly applied process. With this
aim in mind, we also transformed the Boc protected
b-amino acid 12b into methyl ester 13. Removal of the
Boc protecting group by TFA then smoothly delivered
b-amino acid methyl ester 14 (Scheme 8).
4.2. Nucleophilic opening of epoxides 5
4.2.1.
tert-Butyl-N-[(3-hydroxypropyl)sulfonyl]-
carbamate (8a). To a cooled (K78 8C) solution of
diisopropylamine (1.12 mL, 8.00 mmol) in THF (8 mL)
was added n-BuLi (5.00 mL, 8.00 mmol, 1.6 M in
n-hexane). After stirring the resulting mixture for 10 min,
a solution of carbamate 6 (0.78 g, 4.00 mmol) in THF
(8 mL) was added dropwise over a period of 20 min and
stirring was continued for additional 20 min. The resulting
white suspension was treated successively with 0.5 mL
portions of a solution of ethylene oxide (5a) (0.22 g,
5.00 mmol) in THF (5 mL) over a period of 30 min. The
reaction mixture was slowly warmed to 0 8C and stirred for
2 h. After additional stirring at ambient temperature for 2 h,
the mixture was poured onto an ice-cold saturated aqueous
NH4Cl solution (10 mL). The resulting precipitate was
dissolved by addition of water, and the mixture was acidified
with 2 N HCl to pH 3. The aqueous layer was extracted 3!
with CH2Cl2 (20 mL), and the organic extracts were dried
over anhydrous MgSO4. After concentration in vacuo, the
residue was finally purified by flash chromatography
(CH2Cl2/Et2O 20:1) to afford 8a. Yield 77% (735.0 mg,
3.08 mmol); white solid; mp 98–99 8C; Rf 0.21 (CH2Cl2/Et2O
Scheme 8. Synthesis of b-amino acid methyl ester 14.
Despite extensive experimentation, we were not able to find
suitable conditions for cyclization of free acids 2a,b or
methyl ester 14 to give bicyclic b-lactams 1. Apparently, the
highly strained nature of the ring system to be formed and
the low nucleophilicity of the sulfonamide moiety19 in 2a,b
and 14 preclude b-lactam formation.
5:1); IR (neat) 3458, 1743, 1332, 1126 cmK1 1H NMR
;
(CDCl3) d 1.51 (s, 9H), 2.08–2.15 (m, 2H), 3.54–3.59 (m,
2H), 3.81 (t, 2H, JZ5.9 Hz); 13C NMR (CDCl3) d 26.27,
27.94, 50.13, 60.27, 84.49, 149.65; MS (LC/MS) m/z (%) 278
(8) [MCKC], 262 (100) [MCNaC], 257 (7) [MCNHC4 ].
Anal. Calcd for C8H7NO5S: C, 40.15; H, 7.16; N, 5.85; S,
13.40. Found: C, 40.25; H, 7.14; N, 5.87; S, 13.57.
3. Conclusion
An efficient seven-step route to novel b-amino acids 2 bearing
a g-sultam moiety has been developed starting from Boc
protected methanesulfonamide (6) and terminal epoxides 5
via a zinc-mediated allylation of cyclic N-sulfonyl imines 3
readily derived from building blocks 6 and 5.
4.2.2. tert-Butyl-N-[(3-hydroxybutyl)sulfonyl]-carbamate
(8b). To a cooled (K78 8C) solution of diisopropylamine
(5.60 mL, 40.0 mmol) in THF (40 mL) was added n-BuLi
(25.0 mL, 40.0 mmol, 1.6 M in n-hexane). After stirring the
resulting mixture for 10 min, a solution of carbamate 6
(3.90 g, 20.0 mmol) in THF (40 mL) was added dropwise
over a period of 20 min and stirring was continued for
additional 20 min. The resulting white suspension was
treated with a solution of propylene oxide (5b) (1.75 mL,
25.0 mmol) in THF (25 mL) over a period of 30 min.
4. Experimental
4.1. General methods
All reactions were carried out under argon atmosphere using
anhydrous solvents and flame-dried glassware. Commer-
cially available compounds were used without further

1802
D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
The reaction mixture was slowly warmed to ambient
temperature (16 h) and poured onto an ice-cold saturated
aqueous NH4Cl solution (50 mL). The resulting precipitate
was dissolved with water, and the mixture was acidified
with 2 N HCl to pH 3. The aqueous layer was extracted 3!
with CH2Cl2 (50 mL), and the organic extracts were washed
with brine and dried over anhydrous MgSO4. After
concentration in vacuo, the residue was finally purified by
flash chromatography (Et2O) to afford 8b. Yield 75%
(3.80 g, 15.0 mmol); colorless oil; Rf 0.33 (Et2O); IR (neat)
3513, 1734, 1340, 1127 cmK1; 1H NMR (CDCl3) d 1.26 (d,
3H, JZ6.2 Hz), 1.51 (s, 9H), 1.85–2.08 (m, 2H), 3.56 (dt,
2H, JZ6.5, 9.1 Hz), 3.96–4.02 (m, 1H); 13C NMR (CDCl3)
d 23.41, 27.92, 32.16, 49.88, 65.90, 84.34, 149.86; MS
(LC/MS) m/z (%)Z271 (68) [MCNHC4 ], 254 (18) [MC
HC], 198 (100) [MKC4H8CHC]. Anal. Calcd for
C9H19NO5S: C, 42.67; H, 7.56; N, 5.53; S, 12.66. Found:
C, 42.48; H, 7.78; N, 5.64, S, 12.35.
the analytically pure ketone 4b. Yield 93% (3.5 g,
14.0 mmol); white solid; mp 82–83 8C; Rf 0.40 (Et2O); IR
(neat) 1724, 1332, 1130 cmK1; 1H NMR (CDCl3) d 1.50 (s,
9H), 2.22 (s, 3H), 3.01 (t, 2H, JZ7.2 Hz), 3.67 (t, 2H, JZ
7.3 Hz); 13C NMR (CDCl3) d 27.92, 29.79, 36.68, 47.71,
84.61, 149.53, 203.52; MS (LC/MS) m/z (%)Z525 (100)
[2!MCNaC], 269 (32) [MCNHC4 ], 252 (9) [MCHC].
Anal. Calcd for C9H17NO5S: C, 43.01; H, 6.82; N, 5.57; S,
12.76. Found: C, 43.14; H, 6.92; N, 5.52; S, 12.77.
4.3.3. tert-Butyl-N-[(3-oxo-3-phenylpropyl)sulfonyl]-
carbamate (4c). To a solution of 8c (4.33 g, 13.8 mmol)
in CH2Cl2 (120 mL) was added PCC (6.20 g, 28.8 mmol).
The resulting dark-brown solution was stirred for 4.5 h at
ambient temperature. After addition of Et2O (100 mL) and
additional stirring (15 min), the mixture was filtered (Et2O)
through a pad of silica gel. Concentration in vacuo afforded
the analytically pure ketone 4c. Yield 96% (4.15 g,
13.22 mmol); white solid; mp 103–104 8C; Rf 0.56
4.2.3.
tert-Butyl-N-[(3-hydroxy-3-phenylpropyl)-
(CH2Cl2/MeOH 100:1); IR (neat) 1739, 1341, 1137 cmK1
;
sulfonyl]-carbamate (8c). The reaction was performed as
described for the preparation of 8b; starting materials: 6
(3.90 g, 20.0 mmol) and styrene oxide (5c) (2.85 mL,
25.0 mmol), flash chromatography: CH2Cl2/Et2O 20:1.
Yield 84% (5.30 g, 16.8 mmol); white solid; mp
98–100 8C; Rf 0.53 (CH2Cl2/Et2O 20:1); IR (neat) 3506,
1H NMR (CDCl3) d 1.51 (s, 9H), 3.56–3.60 (m, 2H),
3.86–3.91 (m, 2H), 7.14 (s, 1H), 7.47–7.52 (m, 2H),
7.59–7.64 (m, 1H), 7.96–8.00 (m, 2H); 13C NMR (CDCl3)
d 27.94, 32.31, 48.26, 84.68, 128.14, 128.84, 133.85,
135.79, 149.44, 195.15; MS (LC/MS) m/z (%)Z649 (100)
[2!MCNaC], 336 (30) [MCNaC], 280 (13) [MKC4H8C
NaC]. Anal. Calcd for C14H19NO5S: C, 53.66; H, 6.11; N,
4.47; S, 10.23. Found: C, 53.78; H, 6.11; N, 4.49; S, 10.35.
1
1723, 1339, 1128 cmK1; H NMR (CDCl3) d 1.47 (s, 9H),
2.21–2.28 (m, 2H), 3.50–3.55 (m, 2H), 4.88 (t, 1H, JZ
6.4 Hz), 7.27–7.39 (m, 5H); 13C NMR (CDCl3) d 27.89,
32.44, 49.75, 72.01, 84.43, 125.61, 128.13, 128.76, 142.90,
149.62; MS (LC/MS) m/z (%)Z653 (100) [2!MCNaC],
333 (21) [MCNHC4 ]. Anal. Calcd for C14H21NO5S: C,
53.32; H, 6.71; N, 4.44; S, 10.17. Found: C, 53.41; H, 6.99;
N, 4.39; S, 10.17.
4.4. Synthesis of cyclic N-sulfonyl imines 3
4.4.1. 4,5-Dihydro-isothiazole 1,1-dioxide (3a). TFA
˚
(0.11 mL, 1.41 mmol) and molecular sieves 4 A (100 mg)
were added to a solution of 9 (111 mg, 0.47 mmol) in
CH2Cl2 (14 mL). The resulting solution was heated to reflux
for 16 h, cooled to ambient temperature and filtered
(CH2Cl2/ethyl acetate 1:1) through a pad of silica gel.
Concentration in vacuo and purification by flash chroma-
tography (CH2Cl2/ethyl acetate 1:1) afforded imine 3a.
Yield 65% (36.4 mg, 0.31 mmol); white solid; mp
68–70 8C; Rf 0.41 (CH2Cl2/ethyl acetate 1:1); IR (neat)
1597, 1307, 1142 cmK1; 1H NMR (CDCl3) d 3.13–3.18 (m,
2H), 3.31–3.37 (m, 2H), 8.30 (s, 1H); 13C NMR (CDCl3) d
35.69, 40.70, 170.82; MS (GC/MS, EI, 70 eV) m/z (%) 119
(6) [MC], 75 (5), 66 (8), 65 (13), 64 (97), 59 (8), 58 (7), 57
(7), 55 (22), 54 (26), 52 (25), 51 (20), 50 (9), 49 (7), 48
(100), 46 (13), 45 (13), 43 (7), 40 (15), 39 (29), 38 (19), 37
(11). Anal. Calcd for C3H5NO2S: C, 30.24; H, 4.23; N,
11.76; S, 26.91. Found: C, 30.33; H, 4.19; N, 11.84;
S, 26.96.
4.3. Oxidation of alcohols 8
4.3.1.
3-Hydroxy-1,1-dioxo-1l6-isothiazolidine-2-
carboxylic acid tert-butyl ester (9). To a solution of 8a
(239.0 mg, 1.00 mmol) in CH2Cl2 (8 mL) was added PCC
(453.0 mg, 2.10 mmol). The resulting dark-brown solution
was stirred for 9 h at ambient temperature. After addition of
Et2O (5 mL) and additional stirring (15 min), the mixture
was filtered (Et2O) through a pad of silica gel. Concen-
tration in vacuo afforded the analytically pure hemiaminal 9.
Yield 70% (167.0 mg, 0.70 mmol); white solid; mp
78–80 8C; Rf 0.43 (Et2O); IR (neat) 3467, 1719, 1317,
1129 cmK1; 1H NMR (CDCl3) d 1.56 (s, 9H), 2.30–2.38 (m,
1H), 2.47–2.58 (m, 1H), 3.31 (ddd, 1H, JZ12.7, 2.6,
6.9 Hz), 3.60 (ddd, 1H, JZ7.0, 7.0, 12.6 Hz), 3.95 (s, 1H),
5.65–5.68 (m, 1H); 13C NMR (CDCl3) d 26.16, 28.02,
46.94, 79.52, 85.30, 150.26; MS (LC/MS) m/z (%)Z255
(100) [MCNHC4 ], 238 (9) [MCHC]. Anal. Calcd for
C8H15NO5S: C, 40.50; H, 6.37; N, 5.90; S, 13.51. Found: C,
40.29; H, 6.39; N, 5.89; S, 13.46.
4.4.2. 3-Methyl-4,5-dihydro-isothiazole 1,1-dioxide (3b).
TFA (4.70 mL, 63.6 mmol) was added to a solution of
ketone 4b (4.00 g, 15.9 mmol) in CH2Cl2 (150 mL). The
solution was heated to reflux for 48 h, and EtOH (20 mL)
was added. Concentration of the reaction mixture in vacuo
to a volume of approximately 10 mL and subsequent
crystallization at K20 8C afforded imine 3b. Yield 91%
(1.93 g, 14.5 mmol); white solid; mp 81 8C; Rf 0.30
(CH2Cl2/ethyl acetate 1:1); IR (neat) 1618, 1308,
4.3.2. tert-Butyl-N-[(3-oxobutyl)sulfonyl]-carbamate
(4b). To a solution of 8b (3.80 g, 15.0 mmol) in CH2Cl2
(120 mL) was added PCC (6.90 g, 32.0 mmol). The
resulting dark-brown solution was stirred for 3 h at ambient
temperature. After addition of Et2O (30 mL) and additional
stirring (15 min), the mixture was filtered (Et2O) through
a pad of silica gel. Concentration in vacuo afforded
1
1146 cmK1; H NMR (CDCl3) d 2.27 (s, 3H), 3.11–3.23
(m, 4H); 13C NMR (CDCl3) d 21.90, 37.88, 44.33, 182.04;
MS (GC/MS, EI, 70 eV) m/z (%) 133 (5) [MC], 89 (2), 69

D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
1803
(75), 68 (9), 64 (9), 54 (7), 48 (15), 42 (100), 41 (11), 40 (8),
39 (7). Anal. Calcd for C4H7NO2S: C, 36.08; H, 5.30; N,
10.52; S, 24.08. Found: C, 35.87; H, 5.34; N, 10.33; S,
24.19.
was repeated 4! in 30 min intervals. Then ultrasonication
was stopped, the mixture was warmed to ambient
temperature, the resulting precipitate was dissolved with
water, and remaining Zn was removed by filtration. To the
filtrate 1 N H3PO4 (2 mL) and CH2Cl2 (100 mL) were
added, and the mixture was carefully acidified with 2 N
HCl. The layers were separated, and the aqueous layer was
extracted 5! with CH2Cl2 (50 mL). The combined organic
extracts were dried over anhydrous MgSO4, concentrated in
vacuo, and the residue was purified by flash chromatography
(Et2O) to afford g-sultam 10b. Yield 74% (1.87 g,
10.7 mmol); colorless oil; Rf 0.36 (Et2O); IR (neat)
4.4.3. 3-Phenyl-4,5-dihydro-isothiazole 1,1-dioxide (3c).
TFA (3.00 mL, 40.4 mmol) was added to a solution of 4c
(4.14 g, 13.2 mmol) in CH2Cl2 (100 mL). The solution was
heated to reflux for 35 h, cooled to ambient temperature
and filtered (CH2Cl2) through a pad of silica gel. After
concentration in vacuo and purification by flash chromato-
graphy (CH2Cl2), imine 3c was isolated. Yield 84% (2.16 g,
11.1 mmol); white solid; mp 175 8C; Rf 0.32 (CH2Cl2);
1
3265, 1293, 1136 cmK1; H NMR (CDCl3) d 1.29 (s, 3H),
IR (neat) 1592, 1310, 1141 cmK1 1H NMR (CDCl3) d
;
2.10–2.20 (m, 1H), 2.25–2.35 (m, 3H), 3.06–3.20 (m, 2H),
4.31 (s, 1H), 5.09–5.17 (m, 2H), 5.69–5.83 (m, 1H);
13C NMR (CDCl3) d 27.34, 34.54, 46.27, 47.63, 59.31,
120.25, 132.19; MS (GC/MS, EI, 70 eV) m/z (%) 176 (0.1)
[MCC1], 136 (9), 135 (11), 134 (100), 70 (33), 54 (4).
Anal. Calcd for C7H13NO2S: C, 47.97; H, 7.48; N, 7.99; S,
18.30. Found: C, 47.99; H, 7.43; N, 8.14; S, 18.63.
3.35–3.40 (m, 2H), 3.59–3.63 (m, 2H), 7.42–7.48 (m, 2H),
7.55–7.61 (m, 1H), 7.94 (dd, 2H, JZ1.2, 8.4 Hz); 13C NMR
(CDCl3) d 33.47, 44.23, 129.03, 129.13, 130.87, 134.50,
175.86; MS (GC/MS, EI, 70 eV) m/z (%) 195 (15) [MC],
131 (8), 104 (15), 103 (100), 77 (9), 76 (12), 51 (6). Anal.
Calcd for C9H9NO2S: C, 55.37; H, 4.65; N, 7.17; S, 16.42.
Found: C, 55.31; H, 4.77; N, 6.94; S, 16.40.
4.6. Conversion of 10 to b-amino acids 2
4.5. Allylation of cyclic N-sulfonyl imines 3
4.6.1. Typical procedure for protection of g-sultams 10.
To a solution of g-sultam 10b (1.87 g, 10.7 mmol) in
CH2Cl2 (30 mL) were added triethylamine (1.70 mL,
11.7 mmol) and DMAP (127.0 mg, 1.07 mmol) followed
by dropwise addition of a solution of Boc2O (2.66 g,
12.3 mmol) in CH2Cl2 (20 mL) over 30 min. The reaction
mixture was stirred for 3 h and filtered (CH2Cl2) through
a pad of silica gel. After evaporation in vacuo, the crude
product was purified by flash chromatography (Et2O) to
give 11b.
4.5.1. 3-Allyl-isothiazolidine-1,1-dioxide (10a). Imine 3a
(0.40 g, 3.38 mmol) was dissolved in a mixture of THF
(7 mL) and saturated aqueous NH4Cl solution (33 mL). To
the solution was added Zn powder (1.10 g, 16.8 mmol), and
the mixture was ultrasonicated for 30 s. Then allyl bromide
(0.89 mL, 10.1 mmol) was added, and the temperature of
the mixture was carefully adjusted to 0–10 8C with ice-
cooling. After 30 min of ultrasonication, the mixture was
warmed to ambient temperature, the resulting precipitate
was dissolved with water, and remaining Zn was removed
by filtration. To the filtrate 1 N H3PO4 (0.5 mL) and CH2Cl2
(25 mL) were added, and the mixture was carefully acidified
with 2 N HCl. The layers were separated, and the aqueous
layer was extracted 5! with CH2Cl2 (20 mL). The
combined organic extracts were dried over anhydrous
MgSO4, concentrated in vacuo, and the residue was purified
by flash chromatography (CH2Cl2/ethyl acetate 4:1) to
afford g-sultam 10a. Yield 57% (308.0 mg, 1.91 mmol);
colorless oil; Rf 0.53 (CH2Cl2/ethyl acetate 4:1); IR (neat)
3261, 1289, 1137 cmK1; 1H NMR (CDCl3) d 2.10–2.20 (m,
1H), 2.37 (dd, 2H, JZ6.8, 6.8 Hz), 2.45–2.56 (m, 1H),
3.07–3.25 (m, 2H), 3.68 (ddd, 1H, JZ6.4, 12.9, 14.5 Hz),
4.12 (s, 1H), 5.16–5.22 (m, 2H), 5.70–5.84 (m, 1H); 13C
NMR (CDCl3) d 28.76, 39.84, 47.74, 53.95, 119.18, 132.77;
MS (GC/MS, EI, 70 eV) m/z (%) 162 (0.2) [MCC1], 122
(11), 121 (12), 120 (100), 68 (7), 56 (48), 54 (7). Anal. Calcd
for C6H11NO2S: C, 44.70; H, 6.88; N, 8.69; S, 19.89. Found:
C, 44.83; H, 6.92; N, 8.77; S, 19.77.
4.6.1.1.
3-Allyl-1,1-dioxo-1l6-isothiazolidine-2-
carboxylic acid tert-butyl ester (11a). Starting material:
10a (270.0 mg, 1.68 mmol), flash chromatography: Et2O.
Yield 100% (438.0 mg, 1.68 mmol); colorless oil; Rf 0.59
(Et2O); IR (neat) 1716, 1309, 1134 cmK1 1H NMR
;
(CDCl3) d 1.55 (s, 9H), 2.11–2.21 (m, 1H), 2.35–2.52 (m,
2H), 2.60–2.68 (m, 1H), 3.21–3.89 (m, 2H), 4.13–4.21 (m,
1H), 5.18 (dd, 1H, JZ1.3, 15.8 Hz), 5.18 (dd, 1H, JZ1.1,
11.4 Hz), 5.70–5.83 (m, 1H); 13C NMR (CDCl3) d 22.29,
28.04, 37.48, 47.62, 55.79, 84.19, 119.42, 132.39, 149.70;
MS (LC/MS) m/z (%) 545 (100) [2!MCNaC], 279 (88)
[MCNHC4 ], 262 (6) [MCHC], 223 (16) [MKC4H8C
NHC4 ], 206 (57) [MKC4H8CHC]. Anal. Calcd for
C11H19NO4S: C, 50.55; H, 7.33; N, 5.36; S, 12.27. Found:
C, 50.65; H, 7.36; N, 5.33; S, 12.20.
4.6.1.2. 3-Allyl-3-methyl-1,1-dioxo-1l6-isothiazolidine-
2-carboxylic acid tert-butyl ester (11b). Yield 99% (2.90 g,
10.5 mmol); colorless oil; Rf 0.53 (Et2O); IR (neat) 1717,
1309, 1143 cmK1; 1H NMR (CDCl3) d 1.51 (s, 3H), 1.53 (s,
9H), 2.00 (ddd, 1H, JZ6.8, 6.8, 13.6 Hz), 2.39 (ddd, 1H,
JZ8.1, 8.1, 14.4 Hz), 2.48 (dd, 1H, JZ7.7, 14.0 Hz), 2.83
(dd, 1H, JZ7.0, 14.0 Hz), 3.20–3.28 (m, 2H), 5.12–5.20
(m, 2H), 5.66–5.80 (m, 1H); 13C NMR (CDCl3) d 24.97,
28.06, 30.13, 42.71, 46.34, 63.37, 83.98, 119.97, 132.06,
149.41; MS (LC/MS) m/z (%) 298 (33) [MCNaC], 242
(100) [MKC4H8CNaC]. Anal. Calcd for C12H21NO4S: C,
52.34; H, 7.69; N, 5.09; S, 11.64. Found: C, 52.54; H, 7.74;
N, 5.25; S, 11.44.
4.5.2. 3-Allyl-3-methyl-isothiazolidine-1,1-dioxide (10b).
Imine 3b (1.94 g, 14.5 mmol) was dissolved in a mixture of
THF (30 mL) and saturated aqueous NH4Cl solution
(140 mL). To the solution was added Zn powder (4.70 g,
71.8 mmol), and the mixture was ultrasonicated for 30 s.
Then allyl bromide (3.80 mL, 43.5 mmol) was added, and
the temperature of the mixture was carefully adjusted to
0–10 8C with ice-cooling. After 30 min of ultrasonication,
additional amounts of Zn powder (2.40 g, 36.7 mmol) and
allyl bromide (2.00 mL, 22.9 mmol) were added, and this

1804
D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
4.6.2. Lemieux–von-Rudloff oxidation of 11.
(20 mL) was added, and the pH was adjusted to 10 with a
saturated aqueous Na2CO3 solution. The aqueous layer was
extracted 3! with Et2O (20 mL), acidified with 2 N HCl to
pH 2 and extracted again 3! with Et2O (20 mL). The
combined organic extracts were dried over anhydrous
MgSO4, and subsequent evaporation in vacuo afforded
pure acid 12b. Yield: 84% (2.60 g, 8.87 mmol); white solid;
IR (neat) 3243, 1719, 1314, 1125 cmK1; 1H NMR (CDCl3)
d 1.54 (s, 9H), 1.66 (s, 3H), 2.30 (ddd, 1H, JZ7.0, 7.0,
14.0 Hz), 2.70 (ddd, 1H, JZ7.7, 7.7, 13.9 Hz), 2.97 (d, 1H,
JZ15.0 Hz), 3.12 (d, 1H, JZ15.0 Hz), 3.22–3.35 (m, 2H);
13C NMR (CDCl3) d 24.79, 28.03, 30.49, 42.16, 46.16,
61.35, 84.59, 149.35, 175.00; MS (LC/MS) m/z (%) 311
(76) [MCNHC4 ], 294 (7) [MCHC], 260 (39) [MKC4H8C
NaC], 238 (57) [MKC4H8CHC], 216 (11) [MKC4H8–
CO2CNaC], 194 (100) [MKC4H8–CO2CHC]. Anal.
Calcd for C11H19NO6S: C, 45.04; H, 6.53; N, 4.77; S,
10.93. Found: C, 45.02; H, 6.78; N, 4.79; S, 10.58.
4.6.2.1. 3-Carboxymethyl-1,1-dioxo-1l6-isothiazo-
lidine-2-carboxylic acid tert-butyl ester (12a). Boc
protected g-sultam 11a (412.0 mg, 1.91 mmol) was
dissolved in a mixture of CCl4 (4 mL), CH3CN (4 mL),
and H2O (5.5 mL). To the vigorously stirred solution NaIO4
(1.63 g, 7.64 mmol) and RuCl3 (13.5 mg, 0.065 mmol) were
added. After stirring for 4 h, the resulting black mixture was
filtered, and H2O (20 mL) and ethyl acetate (20 mL) were
added. The layers were separated, and the aqueous layer was
extracted 3! with ethyl acetate (20 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
concentrated in vacuo. The black residue was dissolved in
CH2Cl2 (2 mL), t-BuOH (6 mL), and 2-methyl-2-butene
(2 mL). To the resulting mixture a solution of Na2HPO4
(0.65 g, 4.70 mmol) and NaClO2 (0.65 g, 7.18 mmol) in
H2O (6 mL) was added, and stirring was continued for 16 h.
After addition of 1 N H3PO4 (35 mL) and CH2Cl2 (20 mL),
the layers were separated, and the aqueous layer was
extracted 3! with CH2Cl2 (20 mL). The combined organic
extracts were dried over anhydrous MgSO4 and concen-
trated. The residue was dissolved in CH2Cl2 (20 mL), H2O
(10 mL) was added, and the pH was adjusted to 10 with a
saturated aqueous Na2CO3 solution. The aqueous layer was
extracted 3! with CH2Cl2 (20 mL), acidified with 2 N HCl
to pH 2 and extracted again 3! with CH2Cl2 (20 mL).
The combined organic extracts were dried over anhydrous
MgSO4, and subsequent evaporation in vacuo afforded pure
acid 12a. Yield: 59% (316.0 mg, 1.13 mmol); white solid;
4.6.3. Deprotection of Boc derivatives 12.
4.6.3.1. (1,1-Dioxo-1l6-isothiazolidin-3-yl)-acetic acid
(2a). Boc protected acid 12a (294.0 mg, 1.05 mmol) was
suspended in CH2Cl2 (15 mL), and TFA (0.33 mL,
4.50 mmol) was added. The clear solution was heated to
reflux for 24 h, cooled to ambient temperature, and all
volatile components were removed in high vacuo. The
resulting yellow oil was dissolved in a mixture of CH2Cl2
(10 mL) and H2O (10 mL) and stirred for 5 min. The layers
were separated, and the aqueous layer was evaporated
completely to afford pure b-amino acid 2a. Yield: 79%
(148 mg, 0.83 mmol); colorless oil; IR (neat) 3214, 1700,
IR (neat) 2981, 2876, 2740, 1721, 1710, 1310, 1133 cmK1
;
1H NMR (DMSO-d6) d 1.42 (s, 9H), 2.02–2.16 (m, 1H),
2.42–2.49 (m, 1H), 2.66 (d, 2H, JZ6.8 Hz), 3.45–3.62 (m,
2H), 4.27–4.30 (m, 1H), 12.50 (s, 1H); 13C NMR (DMSO-d6)
d 23.09, 27.47, 36.86, 46.49, 52.96, 82.92, 148.94, 171.26;
MS (LC/MS) m/z (%) 297 (100) [MCNHC4 ], 280 (5) [MC
HC], 241 (17) [MKC4H8CNH4C], 224 (48) [MKC4H8C
HC], 180 (27) [MKC4H8–CO2CHC]. Anal. Calcd for
C10H17NO6S: C, 43.00; H, 6.13; N, 5.01; S, 11.48. Found:
C, 43.02; H, 6.04; N, 5.06; S, 11.13.
1
1301, 1135 cmK1; H NMR (DMSO-d6) d 1.84–1.97 (m,
1H), 2.43–2.63 (m, 3H), 2.94–3.04 (m, 1H), 3.13–3.21 (m,
1H), 3.75 (dd, 1H, JZ6.9, 13.6 Hz), 6.97 (d, 1H, JZ
6.3 Hz), 12.37 (s, 1H); 13C NMR (DMSO-d6) d 28.68,
39.92, 47.15, 50.29, 171.72; MS (LC/MS) m/z (%) 197 (12)
[MCNHC4 ], 180 (100) [MCHC]. Anal. Calcd for
C5H9NO4S: C, 33.51; H, 5.06; N, 7.82; S, 17.89. Found:
C, 33.41; H, 5.14; N, 7.66; S, 17.59.
4.6.3.2. (3-Methyl-1,1-dioxo-1l6-isothiazolidin-3-yl)-
acetic acid (2b). Boc protected acid 12b (2.93 g,
10.0 mmol) was dissolved in CH2Cl2 (140 mL), and TFA
(3.33 mL, 45.0 mmol) was added. The mixture was heated
to reflux for 48 h, cooled to ambient temperature, and all
volatile components were removed in high vacuo to afford
pure b-amino acid 2b. Yield: 86% (1.66 g, 8.60 mmol);
white solid; mp 110 8C; IR (neat) 3214, 1700, 1301,
4.6.2.2. 3-Carboxymethyl-3-methyl-1,1-dioxo-1l6-
isothiazolidine-2-carboxylic acid tert-butyl ester (12b).
Boc protected g-sultam 11b (2.90 g, 10.6 mmol) was
dissolved in a mixture of CCl4 (20 mL), CH3CN (20 mL),
and H2O (30 mL). To the vigorously stirred solution NaIO4
(9.05 g, 42.3 mmol) and RuCl3 (75.0 mg, 0.36 mmol) were
added. After stirring for 4 h, the resulting black mixture was
filtered, and H2O (50 mL) and ethyl acetate (50 mL) were
added. The layers were separated, and the aqueous layer was
extracted 3! with ethyl acetate (50 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
concentrated in vacuo. The black residue was purified by
filtration (Et2O) over a short pad of silica gel, the filtrate was
evaporated in vacuo, and the crude product was dissolved in
t-BuOH (30 mL) and 2-methyl-2-butene (10 mL). To the
resulting mixture a solution of Na2HPO4 (3.60 g,
26.0 mmol) and NaClO2 (3.60 g, 39.8 mmol) in H2O
(30 mL) was added, and stirring was continued for 16 h.
After addition of 1 N H3PO4 (200 mL) and Et2O (20 mL),
the layers were separated, and the aqueous layer was
extracted 5! with Et2O (20 mL). The combined organic
extracts were dried over anhydrous MgSO4 and concen-
trated. The residue was dissolved in Et2O (50 mL), H2O
1135 cmK1 1H NMR (DMSO-d6) d 1.32 (s, 3H), 2.14
;
(ddd, 1H, JZ7.0, 7.0, 13.9 Hz), 2.37 (ddd, 1H, JZ6.4, 6.4,
14.5 Hz), 2.48–2.56 (m, 2H), 3.08–3.25 (m, 2H), 6.98 (s,
1H), 12.31 (s, 1H); 13C NMR (DMSO-d6) d 26.68, 33.95,
45.47, 46.66, 56.88, 171.54; MS (LC/MS) m/z (%) 409 (96)
[2!MCNaC], 216 (19) [MCNaC], 211 (29) [MCNHC4 ],
194 (100) [MCHC], 176 (27) [MKH2OCHC]. Anal.
Calcd for C6H11NO4S: C, 37.30; H, 5.74; N, 7.25; S, 16.60.
Found: C, 37.03; H, 5.72; N, 7.20; S, 16.44.
4.7. Preparation of methyl ester 14
4.7.1. 3-Methoxycarbonylmethyl-3-methyl-1,1-dioxo-
1l6-isothiazolidine-2-carboxylic acid tert-butyl ester
(13). Boc protected acid 12b (1.47 g, 5.00 mmol) was

D. Freitag, P. Metz / Tetrahedron 62 (2006) 1799–1805
1805
Gorman, M., Eds.; Academic: New York, 1982: Vol. 1–3. (c)
For a recent review on the synthesis and chemistry of
azetidinones, see: Singh, G. S. Tetrahedron 2003, 59, 7631–
7649. (d) For a recent review on non-classical b-lactams, see:
´
Gomez–Gallego, M.; Manchen˜o, M. J.; Sierra, M. A.
Tetrahedron 2000, 56, 5743–5774.
dissolved in CH2Cl2 (20 mL), and the solution was cooled to
K20 8C. Diazomethane (ca. 0.35 M in diethyl ether) was
added until the mixture turned constantly yellow. The
mixture was warmed to ambient temperature and stirred
until the color completely faded. The solvents were
removed in vacuo, and the residue was purified by flash
chromatography (Et2O) to afford methyl ester 13. Yield:
100% (1.53 g, 4.98 mmol); colorless oil; Rf 0.38 (Et2O); IR
(neat) 1720, 1313, 1137 cmK1; 1H NMR (CDCl3) d 1.53 (s,
9H), 1.74 (s, 3H), 2.24 (ddd, 1H, JZ7.0, 7.0, 14.0 Hz), 2.67
(ddd, 1H, JZ7.7, 7.7, 13.9 Hz), 2.96 (s, 2H), 3.18–3.31 (m,
2H), 3.68 (s, 3H); 13C NMR (CDCl3) d 25.07, 28.03, 30.47,
42.19, 46.14, 51.90, 61.51, 84.31, 149.34, 170.29;
MS (LC/MS) m/z (%) 330 (24) [MCNaC], 274 (80)
[MKC4H8CNaC], 230 (100) [MKC4H8–CO2CNaC].
Anal. Calcd for C12H21NO6S: C, 46.89; H, 6.89; N, 4.56;
S, 10.43. Found: C, 47.01; H, 6.99; N, 4.68; S, 10.17.
4. (a) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.;
Okazaki, H. J. Med. Chem. 1987, 30, 1458–1463. (b)
Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P. J. Org.
Chem. 1991, 56, 6523–6527.
5. (a) Freitag, D.; Schwab, P.; Metz, P. Tetrahedron Lett. 2004,
45, 3589–3592. (b) Karsch, S.; Freitag, D.; Schwab, P.;
Metz, P. Synthesis 2004, 10, 1696–1712. (c) Merten, S.;
¨
Frohlich, R.; Kataeva, O.; Metz, P. Adv. Synth. Catal. 2005,
347,754–758.(d)Freitag,D.;Drees,M.;Goutal,S.;Strassner,T.;
Metz, P. Tetrahedron 2005, 61, 5615–5621.
6. Turos and co-workers also reported several non-convention-
ally fused b-lactam-sulfonamide hybrids: (a) Ren, X.-F.;
Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.; Gonzalez, J.;
Turos, E. J. Org. Chem. 1998, 63, 8898–8917. (b) Turos, E.;
Konaklieva, M. I.; Ren, R. X.-F.; Shi, H.; Gonzalez, J.;
Dickey, S.; Lim, D. Tetrahedron 2000, 56, 5571–5578.
7. Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379–380.
8. Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58,
2900–2903.
4.7.2. (3-Methyl-1,1-dioxo-1l6-isothiazolidin-3-yl)-acetic
acid methyl ester (14). Ester 13 (2.61 g, 8.50 mmol) was
dissolved in CH2Cl2 (100 mL), and TFA (3.90 mL,
51.0 mmol) was added. The resulting mixture was stirred
for 30 h at ambient temperature, diluted with CH2Cl2
(100 mL) and carefully washed with saturated aqueous
NaHCO3 solution. After evaporation of the organic layer in
vacuo and purification of the crude product by flash
chromatography (CH2Cl2/MeOH 40:1), methyl ester 14
was isolated. Yield: 82% (1.45 g, 7.00 mmol); pale
yellow oil; Rf 0.37 (ethyl acetate); IR (neat) 1727, 1294,
1131 cmK1; 1H NMR (CDCl3) d 1.39 (s, 3H), 2.22–2.39 (m,
2H), 2.60 (AB pattern, 2H, JZ15.9 Hz, DdZ41.0 Hz),
3.07–3.21 (m, 2H), 3.66 (s, 3H), 5.12 (s, 1H); 13C NMR
(CDCl3) d 27.36, 34.94, 45.05, 46.75, 51.95, 57.19, 171.07;
MS (GC/MS, EI, 70 eV) m/z (%) 192 (12), 160 (6), 136 (4),
135 (6), 134 (100), 128 (22), 96 (5), 74 (11), 70 (9), 43 (7), 42
(17), 41 (5). Anal. Calcd for C7H13NO4S: C, 40.57; H, 6.32;
N, 6.76; S, 15.47. Found: C, 40.76; H, 6.43; N, 6.86; S, 15.05.
9. Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982,
245–258.
10. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999. (b)
´
Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart,
2004.
11. For a review on N-sulfonyl imines, see: Weinreb, S. M. Top.
Curr. Chem. 1997, 190, 131–184.
12. (a) For a review, see: Yamamoto, Y.; Asao, N. Chem. Rev.
1993, 93, 2207–2293. (b) For catalytic asymmetric allylation
of imines, see: Fernandes, R. A.; Yamamoto, Y. J. Org. Chem.
2004, 69, 735–738.
13. For a review on reactions in aqueous media, see: Li, C. J.
Chem. Rev. 2005, 105, 3095–3165.
Acknowledgements
14. Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589–8594.
15. For a review on metal-activation, see: Fu¨rstner, A. Angew.
Chem. 1993, 105, 171–197. Angew. Chem., Int. Ed. Engl.
1993, 32, 164–189.
Financial support of this work by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged.
16. Lemieux, R. U.; von Rudloff, E. Can. J. Chem. 1955, 33,
1701–1709.
17. (a) Kametani, T.; Huang, S.-P.; Yokohama, S.; Suzuki, Y.;
Ihara, M. J. Am. Chem. Soc. 1980, 102, 2060–2065. (b)
Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.;
Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6161–6163.
(c) Shono, T.; Tsubata, K.; Okinaga, N. J. Org. Chem. 1984,
49, 1056–1059. (d) Colvin, E. W.; McGarry, D.; Nugent, M. J.
Tetrahedron 1988, 44, 4157–4172. (e) Chuang, T. H.;
Sharpless, K. B. Org. Lett. 2000, 2, 3555–3557.
References and notes
1. For reviews, see: (a) Enantioselective Synthesis of b-Amino
Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds. Wiley-
VCH: New York, 2005. (b) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991–8035. (c) Abele, S.; Seebach, D. Eur. J. Org.
18. (a) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987,
28, 4331–4334. (b) Gennari, C.; Venturini, I.; Gislon, G.;
Schimperna, G. Tetrahedron Lett. 1987, 28, 227–230. (c)
Kobayashi, S.; Furuta, T.; Sugita, K.; Oyamada, H. Synlett
1998, 9, 1019–1022.
´
Chem. 2000, 1–15. (d) Juaristi, E.; Lopez-Ruiz, H. Curr. Med.
Chem. 1999, 6, 983–1004. (e) For a recent paper, see: Ege, M.;
Wanner, K. T. Org. Lett. 2004, 20, 3553–3556.
2. (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett.
1986, 27, 2797–2800. (b) Rowinsky, E. K.; Donehower, R. C.
Pharmacol. Ther. 1991, 52, 35–84.
19. For a successful cyclization of an N-sulfonyl b-amino
acid to give a monocyclic b-lactam, see: Vassiliou, S.;
Dimitropoulos, C.; Magriotis, P. A. Synlett 2003, 2398–2400.
20. Hudlicky, M. J. Org. Chem. 1980, 45, 5377–5378.
3. (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.;
Aquilar, M.-I. Curr. Med. Chem. 2002, 9, 811–822. (b)
Chemistry and Biology of b-Lactam Antibiotics, Morin, R. B.,