Multifaceted interception of 2-chloro-2-oxoacetic anhydrides: A catalytic asymmetric synthesis of β-lactams

Article abstract of DOI:10.1039/c2sc21240d

Aziridine-2-carboxylic acids will react with oxalyl chloride to give morpholin-2,3,5-trionones, cyclic N-carboxyanhydrides or β-lactams depending on the nature of the substituent at the 3-position. All substrates can be diverted to β-lactams upon treatment with a Vilsmeier reagent. The three to four membered ring expansion is stereospecific and proceeds with high yields and diastereoselection. This method provides for an asymmetric synthesis of β-lactams from simple aldehydes via a multi-component catalytic asymmetric aziridination reaction. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2sc21240d

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Multifaceted interception of 2-chloro-2-oxoacetic
anhydrides: a catalytic asymmetric synthesis of
Cite this: Chem. Sci., 2013, 4, 622
b-lactams†
*
Li Huang, Wenjun Zhao, Richard J. Staples and William D. Wulff
Aziridine-2-carboxylic acids will react with oxalyl chloride to give morpholin-2,3,5-trionones, cyclic N-
carboxyanhydrides or b-lactams depending on the nature of the substituent at the 3-position. All
substrates can be diverted to b-lactams upon treatment with a Vilsmeier reagent. The three to four
membered ring expansion is stereospecific and proceeds with high yields and diastereoselection. This
method provides for an asymmetric synthesis of b-lactams from simple aldehydes via a multi-component
catalytic asymmetric aziridination reaction.
Received 12th August 2012
Accepted 8th October 2012
DOI: 10.1039/c2sc21240d
www.rsc.org/chemicalscience
Introduction
It has been 83 years since Fleming’s discovery of penicillin and
b-lactams are still widely used in combating bacterial infec-
tions.1 The last two decades have seen modications of the
b-lactam ring that have yielded a plethora of pharmacological
activities ranging from cholesterol absorption inhibitory activity
to anticancer activity.2 Perhaps as a response to the diverse
structures involved, there has been an increase in the develop-
ment of methods for the synthesis of b-lactams and the last
decade has seen an increased emphasis on catalytic asymmetric
methods.3 These methods include CO insertion into aziridines
with kinetic resolution of the aziridine,4 the kinetic resolution
of b-lactams,5 intramolecular C–H insertion reactions of diaz-
oacetamides,6 the reaction of alkynes with nitrones (Kinugasa
reaction),7 and the amide catalyzed addition of ester enolates to
imines.8 By far the most important method is the addition of
imines to ketenes (Staudinger reaction).9
Scheme 2 Interception of 2-chloro-2-oxoacetic anhydrides.
catalytic asymmetric aziridination of aldehydes, amines and a-
diazoesters10 with a chloride assisted ring expansion of the
resultant aziridine-2-carboxylate derivative (Scheme 1). There
are two previous reports of the conversion of aziridines to b-
lactams via a chloride induced ring-expansion of aziridine-2-
carboxylic acids.11,12 In the course of the investigation of this
ring-expansion we found that in addition to b-lactams, this
reaction can also produce morpholin-2,3,5-triones and cyclic N-
carboxyanhydrides depending on reaction conditions and on
the nature of the substrate (Scheme 2).
We sought to develop a new catalytic asymmetric synthesis of
b-lactams that couples our recently developed multi-component
Scheme 1 Synthesis of b-lactams via aziridines.
Results and discussion
Department of Chemistry, Michigan State University, East Lansing, MI, USA. E-mail:
wulff@chemistry.msu.edu; Fax: +1 517-353-1793; Tel: +1 517-355-9715
† Electronic supplementary information (ESI) available: Protocols for procedures
and NMR analysis. CCDC reference numbers 884444–884446. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2sc21240d
The two previous reports on the chloride induced ring expan-
sion of aziridine-2-carboxylates to b-lactams begin with the
conversion of the carboxylic acid to its sodium salt.11,12 For
example, Sharma and coworkers reported that the sodium salt 5
was converted to the b-lactam 6 in 62% yield by treatment with
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either oxalyl chloride and triethylamine or with thionyl chloride carboxyanhydrides (NCAs) 33–40 (Table 1). A series of substrates
and sodium hydride (Scheme 3).12 In attempting to repeat the were screened with a bis-(3,5-di-tert-butylanisyl) methyl group
latter, we found that the b-lactam 6 was produced in 56% (BUDAM) as the nitrogen substituent since these aziridines can
yield.13 However, when we attempted to repeat the reaction of 5 be made with very high enantioselectivities.16,17 The N-carboxy-
with oxalyl chloride we found that instead the major product anhydride 34 has two carbonyl absorptions at 1847 and 1784
had three carbonyl absorptions in the infrared spectrum at cmꢀ1 and its structure and relative stereochemistry were
1830, 1780 and 1701 cmꢀ1 instead of just one as expected for the determined by X-ray diffraction (Table 1, entry 4). NCAs have
b-lactam 6. In fact, 6 could not be detected in the 1H NMR had a long history of applications in the synthesis of poly-
spectrum of the crude reaction mixture. The major product was peptides as they are very sensitive to polymerization.18 Those in
assigned the structure 7 and was formed in 34% yield (NMR). Table 1 however are stable to purication by silica gel and this is
The yield of 7 was increased to 82% if the acid 8 was reacted undoubtedly related to the bulky protecting group on
with oxalyl chloride.
nitrogen.19 A number of methods have been used to prepare
Morpholin-2,3,5-triones have only been reported14 on two NCAs but most common is the reaction of an a-amino acid with
previous occasions and both were from the reaction of an a-
amino acid with oxalyl chloride. Morpholin-2,3,5-triones are not
stable to silica gel and thus 7 could not be brought to a high
level of purity. A rmer assignment of structure could be made
for the morpholinetrione 11 obtained from the aziridine acid 10
(Scheme 4).15 Morpholinetrione 11 could be crystallized to give
high quality single crystals which were characterized by X-ray
diffraction. The related morpholinetriones 12 and 13 could be
obtained in the same manner from the proper aziridine-2-
carboxylic acid. Two likely mechanisms are the nucleophilic
addition of the aziridine nitrogen to the acyl chloride unit to
give the aziridinium ion 16 which is then opened by chloride,11
or the initial opening of the aziridine to give the b-chloroamine
17 which then closes to the morpholinetrione 11. The reaction
of the sodium salt 5 in the presence of Et3N would be expected
to occur via the former.
The reaction took a different turn with aziridine-2-carboxylic
acids in which the 2-position had an additional substituent.
These substrates reacted with oxalyl chloride to give the N-
Scheme 3 b-Lactam vs. morpholin-2,3,5-trione formation.
Table 1 Reaction of trisubstituted aziridine carboxylic acids with oxalyl chloridea
Entry
Aziridine ester
PGb
R1
R2
% Yield (acid)c
% Yield (NCA)d
1e
2e,f
3
4
5
6
7
8
9
9
9
9
18
19
20
21
22
23
24
Ph2CH
Ph2CH
Ph2CH
BUDAM
BUDAM
BUDAM
BUDAM
BUDAM
BUDAM
BUDAM
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
2-MeC6H4
4-BrC6H4
2-BrC6H4
1-Naphthyl
4-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
73 (25)
73 (25)
73 (25)
87 (26)
94 (27)
78 (28)
54 (29)
57 (30)
56 (31)
53 (32)
51 (33)
56 (33)
54 (33)
69 (34)
75 (35)
71 (36)
78 (37)
73 (38)
80 (39)
20 (40)
10
a
Alkylation was performed in THF by deprotonation with 2 equiv. LDA at ꢀ78 ꢁC followed by addition of methyl or ethyl iodide (3 equiv.). Aer 1 h at
ꢀ78 ꢁC, the temperature was increased to ambient. The hydrolysis was performed by reuxing the alkylated ester in THF–EtOH (1 : 1) with 0.8 M aq.
KOH (5 equiv.) for 17 h. Formation of the N-carboxyanhydride was effected by reaction of the acid with 2.3 equiv. of (COCl)2 in CH2Cl2 for 5 min at
0 ꢁC and 1 h at 25 ꢁC. b BUDAM ¼ [3,5-t-Bu2-4-MeOC6H2]2CH. c Isolated yield for 2 steps aer purication of the acid by chromatography on silica
d
e
f
gel. Isolated yield aer purication by chromatography on silica gel. Reaction with (COCl)2 performed at 25 ꢁC for 2 h. The acid 25 was
converted to the sodium salt before reaction with (COCl)2 (see ESI†).
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triphosgene. These are the rst examples of NCA synthesis with
oxalyl chloride in which one of the carbonyls of the oxalyl
chloride is incorporated into the cyclic anhydride.20 Two
mechanisms are possible for NCA formation that mimic those
shown in Scheme 4 for morpholinetriones. The reaction of the
sodium salt of 25 (Table 1, entry 2) would be expected to be
more likely to occur with a mechanism involving initial attack of
the aziridine nitrogen on the 1-position of the 2-chloro-2-oxo-
acetic anhydride (Scheme 2, path b).
The reaction took yet another turn with the nding that
aziridine-2-carboxylic acids with an alkyl substituent in the 3-
position give exclusively b-lactams upon reaction with oxalyl
chloride (Table 2). No detectable amount of N-carboxyanhy-
drides or morpholinetriones was observed. The reactions of cis-
substituted aziridines lead to the formation of cis-substituted
b-lactams with an expected single carbonyl absorption (1755 cmꢀ1
for 41) and the relative stereochemistry was conrmed for
b-lactam 41 by X-ray diffraction. This reaction can also provide
b-bromo-b-lactams with oxalyl bromide but some isomerization
Scheme 4 Morpholin-2,3,5-trione formation.
to the trans-b-lactam is observed. The reaction is faster with
oxalyl bromide (0 ꢁC, 15 min) giving the cis-bromo-lactam 44 in
83% yield along with a 12% yield of the trans-isomer 45 but only
if an aqueous quench at 0 ꢁC is employed. If the reaction
mixture is simply concentrated at 25 ꢁC without an aqueous
quench, a 1 : 2 mixture of cis–trans b-lactams is observed.
Extended reaction times or increased temperatures do not
enhance the proportion of the trans-isomer past 2 : 1. The
reaction is stereospecic with oxalyl chloride as the trans-
cyclohexyl aziridine 55 gives exclusively the trans isomer of the
b-chloro-b-lactam 56 (56 : 41 $ 100 : 1, Scheme 5) and the cor-
responding cis-cyclohexyl aziridine gives exclusively the cis
isomer of the b-chloro-b-lactam 41 (41 : 56 $ 50 : 1, Table 2).
The only example with oxalyl chloride where less than complete
diastereoselection was observed was with the tert-butyl-b-lactam
Table 2 Reactions of 3-alkylaziridine carboxylic acids with oxalyl chloridea
ꢁ
51. This was a very slow reaction and aer 24 h at 25 C a 9 : 1
mixture of cis and trans isomers was formed in 38 and 4%
yields, respectively, along with a 46% yield of the acid chloride
of the starting aziridine acid.21,22
a
Unless otherwise specied, all reactions were carried out in CH2Cl2 at
0.1 M in aziridine acid with 2.3 equiv. of (COCl)2 at 0 ꢁC for 5 min and
then at 25 ꢁC for 1 h. The solvent was then removed and the product
puried by chromatography on silica gel. MEDAM ¼ (3,5-Me2-4-
Scheme 5 Ring expansion of trans-aziridine 55.
MeOC6H2)2CH, BUDAM
¼
(3,5-t-Bu2-4-MeOC6H2)2CH. Yields are
b
isolated aer chromatography on silica gel. The ratio of cis : trans
$50 : 1. SOCl2 (2.0 equiv.) used instead of (COCl)2. Vilsmeier
c
d
e
reagent (2.3 equiv.) used instead of (COCl)2 (see Table 4). The
f
reaction was at 0 ꢁC for 10 min. This reaction was carried out with
(COBr)2 and also gave a 12% yield of the trans-b-lactam 45 (c–t ¼
g
7 : 1). The reaction was carried out at 0 ꢁC for 15 min and quenched
h
with sat aq. NaHCO3 at 0 ꢁC. Reaction was at 0 ꢁC for 5 min and 25
i
ꢁC for 30 min. Reaction at 25 ꢁC for 24 h and was quenched with
j
sat. aq. NaHCO3 before concentration. This reaction also gives a 4%
yield (NMR) of trans-b-lactam 52 (c–t ¼ 9 : 1) and a 46% yield of the
acid chloride 53 of the aziridine-2-carboxylic acid.
Scheme 6 Incorporation of chloride.
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The b-lactams presumably result from either attack of the
It is presumed that the b-lactam 65 is formed from the
nitrogen on the proximal carbonyl in intermediate 1 (Scheme reaction of acid 10 with the Vilsmeier reagent 61 via the
2, path c) or, aer collapse of 1 to the acid chloride 57, on the intermediacy of the acid chloride 14 (Scheme 4). Indeed, 14
acyl chloride carbonyl (Scheme 6). The resulting bicyclic acy- can be isolated (57% yield) from the reaction in entry 6 of
laziridinium ion 59 can account for the stereoselectivity Table 3, if aer a reaction time of 1 minute, the crude reaction
observed in the b-lactams and evidence has previously been mixture is directly loaded without concentration onto a silica
provided for this intermediate.11,23 It is also possible, but gel column. The question is then how is the acid chloride 14
perhaps less likely, that the normal penchant24 for aziridine-2- converted to the b-lactam 65. It is observed that when the
ꢁ
carboxylate esters of the type 9 to undergo nucleophilic reaction mixture in entry 6 of Table 3 is concentrated at 25 C
ꢁ
opening at C-3 is reversed for the corresponding acid chloride on a rotary evaporator aer 20 min at 0 C, the b-lactam 65 is
57 which gives the b-lactam via 58.25 While the b-lactam 51 may isolated in 83% yield. In contrast, the acid chloride 14 is
ꢁ
have been formed via an acid chloride, evidence suggests that relatively stable in CD2Cl2 solution: aer 24 h at 25 C there is
this may not be the case for the b-lactam 42. Reaction of the 72% of 14 remaining, a 5% yield of b-lactam 65 and 23%
corresponding acid with Vilsmeier reagent does appear to conversion toꢁ other compounds. Heating a sample of 14 in
generate an acid chloride as an intermediate, however, this CH2Cl2 at 80 C for 1 h resulted in an 8 : 1 mixture of 14 : 65
species can not be detected as an intermediate in the reaction with several unknown side-products. The preparation of the
with (COCl)2 thus suggesting that 42 arises from intermediate Vilsmeier reagent does lead to the generation of HCl, however,
1 via path c in Scheme 2 (see ESI†).
attempts to effect the conversion of the acid chloride 14 to b-
The formation of acid chlorides from acids and oxalyl chlo- lactam 65 by treatment with either dry HCl or HOTF in the
ride is known to be catalyzed by DMF (Scheme 7).26 This presence or absence of a chloride source in CH2Cl2 followed by
suggests that a competition can be set up to test the relative concentration gives only a low yield (6–20%) of 65 aer 15–240
ꢁ
rates of DMF and aziridine carboxylic acids towards oxalyl min at 25 C.
chloride. As the data in Table 3 shows, the amount of mor-
However, treatment of puried acid chloride 14 with 2.3
pholinetrione 11 steadily drops as increasing amounts of DMF equiv. Vilsmeier reagent 61 at 0 ꢁC for 20 min followed by
is employed from 92% with no added DMF to 6% yield with 4 concentration gives a 68% isolated yield of the lactam 65. To
equiv. of DMF. Even with a 1 : 1 ratio of 10 to DMF, a 28% yield account for the observed facilitation of the conversion of the
of morpholinetrione 11 is formed indicating that the acid can acid chloride 14 to the b-lactam 65 by the Vilsmeier reagent 61
compete with DMF for oxalyl chloride. When the Vilsmeier one can invoke an equilibrium of 14 and 61 with adduct 66
reagent 61 is generated separately and then added to the acid, (Scheme 8).27 An unfavorable equilibrium at normal concen-
only the b-lactam 65 is observed as expected (83% yield) since trations would be shied in the forward direction to 66 as the
formation of 11 is no longer possible (entries 6 and 7).
concentration is increased which could trigger the formation of
Table 4 Reactions of 3-arylaziridine carboxylic acids with Vilsmeier reagent 61a
Table 3 Reactions of 3-phenylaziridine 10 with (COCl)2 in the presence of DMFa
Vilsmeier
(COCl)2
DMF y
Entry reagent 61b x equiv. equiv.
% Yield 65c % Yield 11c
1
2
3
4
5
6
7
None
None
None
None
None
2.3 equiv.
4.6 equiv.
2.0
2.0
2.0
2.0
2.0
—
0
0
nd
7
20
47
83 (82)
83 (83)
92
69
28
18
6
0.1
1.0
2.0
4.0
—
0
0
—
—
a
The reaction was carried out by treatment of a 0.1 M solution of 10 (0.1
mmol) in CH2Cl2 with DMF (y equiv.) at 25 ꢁC followed by (COCl)2 (x
b
a
equiv.) at 0 ꢁC for 15 min. nd ¼ not detected. The pre-formed
Unless otherwise specied, all reactions were carried out in CH2Cl2 at
Vilsmeier reagent was prepared by reacting (COCl)2 with 1.24 equiv. of 0.05 M in aziridine acid with 2.3 equiv. of Vilsmeier reagent 61, prepared
c
DMF in CH2Cl2 at 25 ꢁC for 20 min. The yield was determined from as described in Table 3, for 15 min at 0 ꢁC. The solvent was removed and
the 1H NMR spectrum of the crude reaction mixture with the aid of the product puried by chromatography on silica gel. Yields are isolated
Ph3CH as internal standard. Yields in parentheses are isolated yields aer chromatography on silica gel. b Reaction at 0 ꢁC for 1 h. c Reaction
aer chromatography on silica gel.
with 4.6 equiv. 61.
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Scheme 10 Transformation of b-lactam 42.
Scheme 7 Catalysis by DMF.
We have recently developed a multi-component catalytic
asymmetric synthesis of aziridines from an amine, an aldehyde
and ethyl diazoacetate.10 For example, the aziridine 82, can be
prepared in 90% isolated yield and 96% ee from butanal with 5
mol% of a boroxinate catalyst prepared from VAPOL and
B(OPh)3 (Scheme 9). We have now found that b-lactam 48 can be
made from butanal in 58% overall yield where no unit operation
except the last is a purication. The overall yield of 48 for the
three steps when both intermediates are puried is 41%. Thus
the present method provides for a convenient and direct cata-
lytic asymmetric access to b-lactams from aldehydes.
Scheme 8 Assisted ring expansion with Vilsmeier reagent.
The synthetic utility of the 3-chloro-2-azetidinones was
probed with the cyclohexyl b-lactam 42 with a benzhydryl
protecting group (Scheme 10). Clean inversion was observed
upon reaction with sodium iodide in DMSO. The chlorine
could be reduced in near quantitative yield with tributyltin
hydride to give b-lactam 84 and the 1,3-amino alcohol 85
could be obtained in 90% yield by reduction with LAH. A free
radical introduction of an allyl group occurs with diaster-
eoselective control to give only the trans-b-lactam 86 in 89%
yield. Finally, the chlorine substituent can be replaced with an
azide group in 86% yield with complete inversion of stereo-
chemistry. The introduction of a nitrogen substituent in the 3-
position by SN2 substitution of a halide is a known but little
used process.29 Thus the method described here should
provide direct access to highly optically enriched b-lactams
from simple aldehydes, amines and ethyl diazoacetate via
aziridine intermediates.
Scheme 9 Sequential multi-component aziridination/b-lactam formation from
aldehydes.
the aziridinium ion 67 and then chloride opening to give 68
which collapses to the b-lactam 65. Aziridinium ion 67 would be
expected to be less strained than 59 (Scheme 6) due to the
absence of an sp2 carbon in the 3-membered ring.
This ring expansion for the 3-phenyl-2-carboxylic acid 10
mediated by Vilsmeier reagent 61 is general for a number of 3-
Conclusions
arylaziridine carboxylic acids (Table 4). The 3-chloro-4-aryl- We have reported here the rst examples where the reaction of
b-lactams are obtained as the cis-diastereomer with no evidence an a-amino acid in the form of an aziridine-2-carboxylic acid
for isomerization in any example. The b-lactams 69 and 72 are can give either morpholin-2,3,5-triones, cyclic N-carboxyanhy-
prepared from aziridines that can be made in highly matched drides or b-lactams via ring-expansion of the aziridine. Thus six,
double-stereodifferentiation with VAPOL and VANOL bor- ve and four membered rings can be obtained from reactions
oxinate catalyst.28 It is to be noted that the ring expansion of that incorporate two, one or zero carbons from oxalyl chloride.
aziridine-2-carboxylic acids is much more efficient with Vils- With proper control of reagents and conditions, all substrates
meier reagent 61 than it is with thionyl chloride. The yields for can be controlled to give b-lactams and coupled with the multi-
b-lactam 6 are 74% with Vilsmeier reagent (Table 4) and 56% component aziridination of aldehydes with amines and ethyl
with thionyl chloride (Scheme 3). The yields for b-lactam 42 are diazoacetate, a new and efficient catalytic asymmetric access to
100% and 62% in the same comparison (Table 2).
b-lactams is developed.
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Rt ¼ 7.06 min (major enantiomer, 48) and Rt ¼ 11.73 min (minor
enantiomer, ent-48). Rf ¼ 0.25 (hexane : CH2Cl2 : ethyl acetate
8 : 8 : 1). Spectral data for 48: 1H NMR (500 MHz, CDCl3) d0.80
(t, 3H, J ¼ 7.2 Hz), 1.04–1.16 (m, 1H), 1.24–1.36 (m, 1H), 1.42–
1.50 (m, 1H), 1.68–1.76 (m, 1H), 2.241 (s, 6H), 2.242 (s, 6H),
3.63–3.68 (m, 1H), 3.70 (s, 3H), 3.71 (s, 3H), 4.83 (d, J ¼ 5.5 Hz,
1H), 5.70 (s, 1H), 6.82 (s, 2H), 6.85 (s, 2H); 13C NMR (150 MHz,
CDCl3) d 13.65, 16.19, 16.20, 18.90, 31.43, 57.39, 59.01, 59.62,
59.63, 60.19, 128.13, 128.95, 130.84, 131.06, 132.92, 133.82,
156.44, 156.60, 163.99; IR (thin lm) 2934(w), 1767(s), 1485(w),
1221(w) cmꢀ1; HRMS calcd for C25H33NO3Cl (M + H, ESI+) m/z
Experimental section
Multi-component catalytic asymmetric aziridination of
butanal
To a 25 mL ame-dried Schlenck ask equipped with a stir bar
and lled with N2 was added (S)-VAPOL (13.7 mg, 0.025 mmol),
B(OPh)3 (21.8 mg, 0.075 mmol) and amine 79 (149.7 mg, 0.5
mmol). Dry toluene (1 mL) was added under an N2 atmosphere
to dissolve the reagents. The reaction mixture was stirred at
˚
room temperature for 1 h. Then 4 A molecular sieves (150 mg,
freshly ame-dried) were added. Aer the reaction mixture was
cooled to ꢀ10 ꢁC, butanal 80 (47.0 mL, 0.522 mmol, 1.04 equiv.)
was added followed by the addition of ethyl diazoacetate (EDA)
81 (125 mL, 1.00 mmol, 2.00 equiv.). The resulting mixture was
stirred for 24 h at ꢀ10 ꢁC. The reaction was diluted by addition
of hexane (6 mL). The reaction mixture was then ltered
through a Celite pad to a 100 mL round bottom ask. The
reaction ask was rinsed with EtOAc (3 mL ꢂ 3) and the rinse
was ltered through the same Celite pad. The resulting solution
was then concentrated in vacuo followed by exposure to high
vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine 82 as
a viscous yellow oil.
20
430.2149, meas. 430.2141; [a]D ꢀ13.7ꢁ (c 1.0, CH2Cl2) on 96%
ee material.
Acknowledgements
This work was supported by the National Institute of General
Medical Sciences (GM 094478).
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8 (a) H. Fujieda, M. Kanai, T. Kambara, A. Iida and
K. Tomioka, J. Am. Chem. Soc., 1997, 119, 2060–2061; (b)
T. Kambara and K. Tomioka, Chem. Pharm. Bull., 2000, 48,
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9 For representative examples, see: (a) A. E. Taggi, A. M. Hafez,
H. Wack, B. Young, W. J. Drury III and W. T. Lectka, J. Am.
Chem. Soc., 2000, 122, 7831–7832; (b) B. L. Hodous and
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Hydrolysis
To the solution of the crude aziridine 82 in ethanol (2 mL) was
added a solution of KOH (140.3 mg, 2.50 mmol, 5.00 equiv.) in
H2O (2 mL). The resulting mixture was reuxed for 1 h and then
cooled to rt. Then aq. citric acid (2 N, 2.5 mL) and ether (10 mL)
were added. The organic layer was separated and the aqueous
layer was extracted with ether (3 ꢂ 10 mL). The combined
organic extracts were dried (Na2SO4) and ltered. The ltrate
was concentrated to afford the crude aziridine acid as a yellow
foamy solid.
Ring-expansion
To a ame-dried round bottom ask equipped with a stir bar
and lled with N2 was added dry DMF (147.5 mL, 1.9 mmol, 3.8
equiv.) and dry CH2Cl2 (1 mL). The ask was tted with a rubber
septum and a nitrogen balloon. Then (COCl)2 (131 mL, 1.53
mmol, 3.06 equiv.) was added dropwise to the reaction ask
with stirring and the Vilsmeier salt precipitated out as a white
solid. The mixture was stirred for 20 min at room temperature
and cooled to 0 ꢁC. A solution of the crude aziridine acid in dry
CH2Cl2 (5 mL) was added dropwise to the reaction ask con-
taining the Vilsmeier salt (1.53 mmol, 3.06 equiv.) over 5 min.
The reaction mixture was stirred for 10 min at 0 ꢁC and
concentrated to afford a foamy crude product. The yield of
lactam 48 was 59% (over three steps) as determined from the 1H
NMR spectrum of the crude reaction mixture in CDCl3 with the
aid of Ph3CH as an internal standard. The product was puried
by column chromatography (silica gel, 25 ꢂ 210 mm, hex-
ane : CH2Cl2 : ethyl acetate 8 : 8 : 1) to afford b-lactam 48 (124
mg, 0.29 mmol) as a colorless semi-solid in 58% isolated yield
(over three steps); The optical purity was determined to be 96%
ee by HPLC analysis (Chiralcel OD-H column, 98 : 2 hexane–2-
propanol at 222 nm, ow-rate 1.0 mL minꢀ1); retention times:
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci., 2013, 4, 622–628 | 627

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628 | Chem. Sci., 2013, 4, 622–628
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