Asymmetric synthesis of α,β-diamino acid derivatives with an aziridine-, azetidine- and γ-lactone-skeleton via Mannich-type additions across α-chloro-N-sulfinylimines

Article abstract of DOI:10.1039/c2ob06637h

The efficient asymmetric synthesis of new chiral γ-chloro-α, β-diamino acid derivatives via highly diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters across a chiral α-chloro-N-p-toluenesulfinylimine was developed. The influence of the base, LDA or LiHMDS, used for the formation of the glycine enolates, was of great importance for the anti-/syn-diastereoselectivity of the Mannich-type reaction. The γ-chloro-α,β-diamino acid derivatives proved to be excellent building blocks for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters, and subsequent ring transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives and α,β-diamino-γ-butyrolactones. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06637h

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PAPER
Asymmetric synthesis of α,β-diamino acid derivatives with an aziridine-,
azetidine- and γ-lactone-skeleton via Mannich-type additions across α-chloro-
N-sulfinylimines†
Gert Callebaut,‡a Sven Mangelinckx,§a Loránd Kiss,b Reijo Sillanpää,c Ferenc Fülöpb and
Norbert De Kimpe*a
Received 26th September 2011, Accepted 8th December 2011
DOI: 10.1039/c2ob06637h
The efficient asymmetric synthesis of new chiral γ-chloro-α,β-diamino acid derivatives via highly
diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters across a chiral
α-chloro-N-p-toluenesulfinylimine was developed. The influence of the base, LDA or LiHMDS, used for
the formation of the glycine enolates, was of great importance for the anti-/syn-diastereoselectivity of the
Mannich-type reaction. The γ-chloro-α,β-diamino acid derivatives proved to be excellent building blocks
for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters, and subsequent ring
transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives and α,β-diamino-
γ-butyrolactones.
and heterocyclic compounds starting from SAM, γ-chloro-
Introduction
α-amino acids also constitute excellent precursors for the prep-
aration of these molecules.3 Moreover, γ-chloro-α-amino acids
Nature uses α-amino acid derivatives with a leaving group at the
γ-position as versatile building blocks in the biosynthesis of a
broad range of biologically important natural products. For
example, (S)-adenosylmethionine (SAM) is a biological sulfo-
nium compound that is involved in many biological processes.
SAM is the second most common co-enzyme in the human
body, after ATP, and it is known as the major biological methyl
donor in reactions catalyzed by methyltransferases.1 Enzymolo-
gical studies have demonstrated that SAM is not only used as a
methyl donor in biological reactions, but that SAM is also a pre-
cursor for a variety of natural products such as 1-aminocyclopro-
pane-1-carboxylic acid (α-ACC), precursor of the plant hormone
ethylene, N-acylhomoserine lactones (AHLs), signal molecules
involved in bacterial quorum sensing, and L-azetidine-2-car-
boxylic acid (L-Aze), a non-proteinogenic amino acid homol-
ogue of proline.1c,2 Besides the biosynthesis of these carbocyclic
are involved in the biosynthesis of a wide range of natural pro-
ducts such as cytotrienins (apoptosis-inducing Streptomycete
metabolite),3a coronatine (phytotoxin),3b,3c and bactobolins
(antibiotic activity).4
Some γ-chloro-α-amino acids are also biologically active as a
free amino acid, such as armentomycin, a non-proteinogenic
amino acid with antibiotic properties,3a,5 and 4-chloro-L-threo-
nine, which is biologically active as a serine hydroxymethyl-
transferase-inhibitor,3d and as a herbicidal antimetabolite.6 4-
Chloro-L-threonine is also a constituent of naturally occurring
syringomycins (antifungal compound),7 and actinomycins (cyto-
toxic and antibacterial compound).8
Next to γ-chloro-α-amino acid derivatives, β-amino acids9 and
α,β-diamino acid derivatives have also gained a lot of attention
as non-proteinogenic amino acids for different reasons. Several
of these biologically important compounds, such as β-(N-
oxalyl)-L-α,β-diaminopropionic acid (neurotoxin),10 β-methyla-
mino-L-alanine (neurotoxin),11 L-quisqualic acid (vermicide),12
L-mimosine (cell proliferation blocker),13 and L-willardine
(agonist of AMPA and kainate receptor)14 are found in this
group of atypical amino acids.
α,β-Diamino acids can also serve as building blocks for the
synthesis of new heterocyclic compounds and peptides.15 Pre-
viously published results disclosed the successful racemic syn-
thesis and elaboration of γ-chloro-α,β-diamino acid derivatives
via a Mannich-type addition of ‘benzophenone imine glycinates’
across N-(p-toluenesulfonyl) α-chloroaldimines.16 Results
aDepartment of Sustainable Organic Chemistry and Technology, Faculty
of Bioscience Engineering, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium. E-mail: norbert.dekimpe@UGent.be; Fax: +32
(0)9 264 62 21; Tel: +32 (0)9 264 59 51
bInstitute of Pharmaceutical Chemistry, University of Szeged, H-6701
Szeged, P.O. Box 427, Hungary
cDepartment of Chemistry, University of Jyväskylä, Fin-40351
Jyväskylä, Finland
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob06637h
‡Aspirant of the “Institute for the Promotion of Innovation through
Science and Technology – Flanders (IWT-Vlaanderen)”.
§Postdoctoral Fellow of the Research Foundation – Vlaanderen (FWO)
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1
discussed within the present paper demonstrate the first asym-
metric synthesis and elaboration of γ-chloro-α,β-diamino acid
derivatives, as new building blocks for heterocyclic scaffolds,
which incorporate the biologically interesting γ-chloro-α-amino
acid moiety as well as the α,β-diamino acid moiety.
equivalents of LiHMDS. H NMR of the crude reaction mixture
indicated that the resulting syn-γ-chloro-α,β-diamino ester syn-
5a was obtained with good syn-selectivity (dr = 93 : 7). The syn-
adduct syn-5a was isolated as a single diastereomer in a yield of
63% after purification by column chromatography and sub-
sequent recrystallization. Repeating the reaction with 1.1 equiva-
lents of LiHMDS (entry 2) led to the formation of syn-γ-chloro-
α,β-diamino ester syn-5a in an excellent syn-selectivity (dr =
99 : 1) after recrystallization in 88% yield. When 1.1 equivalents
of the enolate were used, column chromatography to purify the
syn-adduct syn-5a could be avoided which resulted in an
improved yield. The use of methyl glycinate 4b using the same
(entry 3) conditions resulted in a similar syn-selectivity (dr =
97 : 3) and yield (86%). In the following reaction (entry 4), the
Mannich-type addition was performed with 1.1 equivalents of
LDA, resulting in γ-chloro-α,β-diamino ester anti-5a with good
anti-selectivity (dr = 87 : 13). The anti-γ-chloro-α,β-diamino
ester anti-5a was obtained in 79% yield as a mixture of two dia-
stereomers (dr 89 : 11) after purification by column chromato-
graphy. Unfortunately, the anti-adduct anti-5a was not
crystalline and could not be obtained as a single diastereomer. In
order to improve the diastereoselectivity, the reaction was con-
ducted with 1.6 equivalents of LDA (entry 5), according to a
procedure as reported for the synthesis of anti-ethyl diamino-3-
phenylpropanoates from N-(benzylidene)-p-toluenesulfinamide
and glycine enolates.18a These conditions led to a slightly better
diastereoselectivity (dr 90 : 10), but unfortunately the anti-
γ-chloro-α,β-diamino ester anti-5a was obtained in a lower yield
of 55% as a mixture of two diastereomers (dr 90 : 10) after
purification by tedious column chromatography. Next, tert-butyl
glycinate 4c was subjected to the Mannich-type reaction con-
ditions with α-chloro-N-p-toluenesulfinyl isobutyraldimine 3
using 1.6 equivalents of LDA (entry 6). The resulting anti-
γ-chloro-α,β-diamino ester anti-5c was obtained with moderate
anti-selectivity (dr = 72 : 28) and was isolated in 52% yield as a
mixture of two diastereomers (dr 81 : 19) after purification by
column chromatography.
Results and discussion
The new chiral α-chloro-N-sulfinylimine 3 was efficiently pre-
pared by condensation of α-chloroisobutyraldehyde 1 with (S)-
(+)-p-toluenesulfinamide 2 in dichloromethane in the presence
of Ti(OEt)4 (Scheme 1).17
The stereoselective synthesis of chiral azaheterocyclic α,β-dia-
mino acid derivatives was performed via a Mannich-type
addition of N-protected glycine esters 4 across chiral α-chloro-N-
sulfinylimine 3 and was optimized by systematically changing
the reaction conditions (Scheme 2, Table 1) in the synthesis of
γ-chloro-α,β-diamino esters 5a. It was found that the base, LDA
or LiHMDS, used for the deprotonation of the glycine ester 4a,
had a dramatic influence on the syn- or anti-selectivity of the
reaction (Table 1).
In a first reaction (Table 1, entry 1), the Mannich-type addition
of ethyl glycinate 4a across chiral α-chloro-N-p-toluenesulfinyl
isobutyraldimine 3 was performed at −78 °C using five
Both the syn- and anti-addition products 5 were subsequently
cyclized to the corresponding N-sulfinylaziridines 6 (Scheme 2)
upon treatment with K2CO3 in acetone under reflux in good to
excellent isolated yields (73–99%). The syn-N-sulfinylaziridine
syn-6a could also be prepared directly in 72% yield via a
Scheme 1 Synthesis of chiral N-(2-chloro-2-methylpropylidene) p-
toluenesulfinamide 3.
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Scheme 2 Synthesis of syn-and anti-N-sulfinylaziridines 6.
Table 1 Addition of N-(diphenylmethylene) glycine esters 4 across N-p-toluenesulfinylimine 3 producing syn-and anti-addition products 5
Entry
Ester
Base
Equiv. Enolate
Time/Temp
syn/anti ratioa
Product
Yield (%)
1
2
3
4
5
6
7
8
4a
4a
4b
4a
4a
4c
4a
4a
LiHMDS
LiHMDS
LiHMDS
LDA
LDA
LDA
5
15 min, −78 °C
15 min, −78 °C
15 min, −78 °C
5 min, −90 °C
93 : 7
syn-5a
syn-5a
syn-5b
anti-5a
anti-5a
anti-5c
syn-6a
syn-6a
63b
88b
86b
79d
55e
52f
72b
—
1.1
1.1
1.1
1.6
1.6
1.1
1.1
99 : 1c
97 : 3c
13 : 87
10 : 90
28 : 72
>99 : 0
>99 : 0
5 min, −90 °C
5 min, −90 °C
15 min, −78 °C; 2 h, rt
5 min, −90 °C; 2 h, rt
LiHMDS
LDA
a Determinated via 1H NMR of crude reaction mixtures with syn-5 or syn-6 as standard b Isolated yield of single diastereomer (dr >97 : 3)
c Determinated via 1H NMR after recrystallisation of crude reaction mixtures d Isolated yield of anti- and syn-diastereomers (dr 89 : 11) e Isolated yield
of anti- and syn-diastereomers (dr 90 : 10) f Isolated yield of anti- and syn-diastereomers (dr 81 : 19)
single-step reaction starting from ethyl glycinate 4a, if the reac-
tion mixture from the Mannich-type addition across imine 3 after
15 min at −78 °C was subsequently stirred for two hours at
room temperature (Table 1, entry 7). This procedure was not
applicable for the synthesis of anti-N-sulfinylaziridines anti-6 as
the anti-adducts are the kinetically favored diastereomers which
isomerize to the thermodynamically more stable syn-isomers
(entry 8). The absolute stereochemistry of the anti-N-p-toluene-
sulfinylaziridine anti-6a and syn-adduct syn-5a were unambigu-
ously determined by means of X-ray diffraction analysis (Fig. 1).
The dramatic influence of the base, LDA or LiHMDS
(Scheme 2), on the stereochemical outcome of the Mannich-type
reaction across α-chloro-N-sulfinylimine 3 under kinetic con-
ditions (for example −90 °C, 5 min) is rationalized on the basis
of the enolate geometry of the anions derived from the
deprotonation of N-(diphenylmethylene) glycine esters 4. As
reported in the literature, the enolates obtained via deprotonation
of N-(diphenylmethylene) glycine esters 4 with LDA are
expected to have the Z-geometry (Scheme 3), which is favoured
by intramolecular chelation.18 As commonly performed in the
assignment of enolate geometry, in contrast to conventional E/Z-
nomenclature, the highest priority designation is allocated to the
O-metal group of the enolate substituents. Alternatively, we
suggest that upon deprotonation of N-(diphenylmethylene)
glycine esters 4 with the less basic LiHMDS in THF, a shift
towards the formation of the E-enolate occurs (Scheme 3).
Unfortunately, the enolate geometry could not be determinated
via trapping experiments with TMSCl.19 Reaction of the Z- and
E-enolates via TS-7a and TS-7b (Scheme 3) results in the for-
mation of anti-5 and syn-5, respectively.18a
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Fig. 1 X-ray diffraction analysis of anti-N-sulfinylaziridine anti-6a and syn-adduct syn-5a.
Scheme 3 Transition state model for the reaction of Z- and E-enolate of glycine esters 4 in the Mannich-type addition across chiral N-(2-chloro-2-
methylpropylidene) p-toluenesulfinamide 3.a
The N-protective groups of anti-aziridine 6a (Scheme 4) were
readily removed by treatment with five equivalents of trifluoro-
acetic acid in acetone/water (2 : 1) at room temperature for
15 min, resulting in the N-deprotected anti-β,γ-aziridino-
α-amino ester 8 in 78% yield after a basic workup with
NH4OH.20
The N-sulfinyl β,γ-aziridino moiety of aziridine anti-6a could
be functionally equivalent to the γ-chloro substituent of natural
Scheme 4 Deprotection of anti-aziridine anti-6a with TFA.
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Scheme 5 Synthesis of aziridine anti-9 and further transformation into 3-amino-1,5-dihydropyrrol-2-one 11.
Table 2 Different reaction conditions for the ring transformation of aziridine anti-9
Entry
Solvent
Equiv. base
Base
Temp
Time
Result
Yield
1
2
3
4
5
THF
THF
EtOH
DMSO
DMSO
1
1
3
3
KOtBu
NaH
K2CO3
K2CO3
NaH
Δ
Δ
Δ
Δ
2.5 h
1 h
22 h
22 h
2 h
11
11
11
87%a
45%b
98%a
—
Complex mixture
11
2.5
80 °C
56%b
a Yield after precipitation of dihydropyrrol-2-one 11 in diethyl ether b Yield after recrystallization from diethyl ether
Scheme 6 Reaction mechanism for the synthesis of 3-amino-1,5-dihydropyrrol-2-one 11.
γ-chloro-α-amino acids,3 or the adenosyl-S+-CH3 cation of
SAM,1 in activating the γ-carbon as an electrophile. Eventually,
this reactivity could be used in a ring transformation via intramo-
lecular N-alkylation to the corresponding trans-β-aminoazeti-
dine-2-carboxylate 10. The N-diphenylmethylene group of anti-
N-sulfinylaziridine anti-6a (Scheme 5) was reduced with
NaCNBH3 in the presence of acetic acid in MeOH, resulting in
aziridine anti-9 containing a nucleophilic α-amino function
(68% yield). Several attempts were made to achieve the ring
transformation of N-sulfinylaziridine anti-9 into trans-β-amino-
azetidine-2-carboxylate 10, albeit without success (Scheme 5,
Table 2). A possible explanation for this failure is the poorer
electron-withdrawing character of the p-toluenesulfinyl group,
relative to the p-toluenesulfonyl group. Previously, the latter sul-
fonyl group allowed to achieve an intramolecular ring opening
towards the corresponding azetidines.16b
increased reaction times and temperatures, did not lead to the
desired conversion. Reaction with one equivalent of BF3·Et2O at
room temperature for 20 h resulted in a complex reaction
mixture, in which the trans-β-aminoazetidine-2-carboxylate 10
was not detected. Also the use of one equivalent LiHMDS led to
a complex reaction mixture after heating at reflux for 2.5 h.
When aziridine 9 was treated with one equivalent KOtBu in
THF at reflux temperature for 2.5 h (Table 2, entry 1), the selec-
tive formation of 3-amino-1,5-dihydropyrrol-2-one 11 was
observed and isolated in 87% yield.
The proposed reaction mechanism begins with deprotonation
at the α-position of the ester, which leads to an antiperiplanar
elimination resulting in ring opening of the aziridine anti-9
(Scheme 6). The secondary amide group of alkenoate 12 then
attacks the ester group leading to γ-lactam 13. The p-toluene-
sulfinyl group of the ring-closed product 13 was subsequently
cleaved by attack of the expelled ethoxide anion, resulting in
dihydropyrrol-2-one 11.
An initial attempt using similar reaction conditions as in our
previously reported ring transformation into racemic anti-N-
tosylazetidines, via heating in acetonitrile in the presence of one
equivalent Et3N,16b did not result in the formation of trans-
β-aminoazetidine-2-carboxylate 10. Also, use of more equiva-
lents of triethylamine, other solvents (EtOH, DMSO), and/or
Repeating the reaction with one equivalent NaH for one hour
(Table 2, entry 2), also afforded the 3-amino-1,5-dihydropyrrol-
2-one 11 however in a lower yield (45%). Performing the reac-
tion in EtOH for 22 h at reflux temperature in the presence of
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Scheme 7 Synthesis of aziridines 14 and 15 and further ring transformation to trans-N-tosylazetidine 16.
three equivalents of K2CO3 (entry 3), afforded the 3-amino-1,5-
dihydropyrrol-2-one 11 in an excellent yield of 98%. Repeating
the reaction in DMSO led to a complex reaction mixture (entry
4), while the use of 2.5 equivalents of NaH in DMSO at 80 °C
for two hours (entry 5), resulted in the 3-amino-1,5-dihydro-
pyrrol-2-one 11 in a yield of 56%. When aziridine anti-9 was
treated with one equivalent of DBU in toluene for 24 h at room
temperature, no reaction was observed. Reaction of aziridine
anti-9 with two equivalents of LiClO4 in acetonitrile at reflux
temperature for 24 h, resulted only in a complex reaction
mixture. In an additional series of attempts, a microwave (MW)
reactor was used for the ring transformation of aziridine anti-9 to
trans-β-aminoazetidine-2-carboxylate 10, albeit without success.
An initial reaction, performed in acetonitrile at 120 °C for
10 min, led to degradation of the starting material anti-9. Lower-
ing reaction times and temperatures resulted in degradation or no
reaction, without formation of the desired azetidine 10. In a final
attempt, NaI was added to the reaction mixture, but no conver-
sion of the starting material into the envisaged product was
achieved.
tosylaziridine 15 to racemic anti-N-tosylazetidine 16, it was
expected that the targeted ring transformation of aziridine 14 to
optically pure azetidine 16 should be straightforward.16b The N-
diphenylmethylene moiety of this anti-N-sulfonylaziridine 14
was subsequently reduced with NaCNBH3, resulting in the for-
mation of anti-N-sulfonylaziridine 15 in 92% yield. It was found
that the anti-N-sulfonylaziridine 15 is an excellent precursor for
an easy ring transformation towards trans-3-(N-tosylamino)azeti-
dine-2-carboxylate 16 via simple heating in acetonitrile at
120 °C for 10 min under microwave (MW) conditions. Note-
worthy, the latter transformation as reported for the racemic aze-
tidine 16 required heating at 70 °C in acetonitrile for 20 h under
conventional heating conditions.16b The enantiomeric excess of
trans-3-(N-tosylamino)azetidine-2-carboxylate 16 (ee > 98%)
was determined via chiral HPLC involving comparison to a
racemic mixture of azetidine 16 (see Supporting Information).
In a series of follow up experiments, in order to extend the
potential applicability of the synthesized 3-aminoazetidine-2-car-
boxylic acid derivative 16 as building block for the synthesis of
peptides, azetidine 16 (Scheme 8) was subjected to several
deprotection reactions. In an initial reaction, the ester group was
hydrolyzed under basic conditions in 2 M NaOH in aq. metha-
nol, resulting in trans-3-(N-tosylamino)azetidine-2-carboxylic
acid 17 in 69% yield after acidic workup with aqueous HCl.
Subsequently, the N-(diphenylmethyl)amino group of the azeti-
dine 17 was N-deprotected by hydrogenolysis in the presence of
Subsequently, the p-toluenesulfinyl group of N-sulfinylaziri-
dine anti-6a (Scheme 7) was selectively oxidized with 3-chloro-
perbenzoic acid (mCPBA), resulting in enantiomerically pure
anti-N-sulfonylaziridine 14 containing a strong electron-with-
drawing activating group at the aziridine nitrogen. Based on
our previously reported ring transformation of racemic anti-N-
Scheme 8 Synthesis of the deprotected azetidines 17, 18 and 19.
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Scheme 9 Benzylation and further attempted detosylation of azetidine 16.
Pd(OH)2/C.21 After precipitation in diethyl ether, the trans-3-(N-
tosylamino)azetidine-2-carboxylic acid 18 was obtained in 92%
yield. The hydrogenolysis of the N-(diphenylmethyl)amino
group could be directly applied on the ethyl ester 16, affording
ethyl 3-(N-tosylamino)azetidine-2-carboxylate 19 in 87% yield,
also after precipitation from diethyl ether.
Furthermore, some efforts were made to cleave the N-tosyl
group from trans-3-(N-tosylamino)azetidine-2-carboxylic ester
16 (Scheme 8), unfortunately without success. In an initial
attempt, treatment of azetidine 16 with Mg turnings in MeOH,22
gave no reaction. When azetidine 16 was treated with sodium or
lithium naphthalenide in THF at −78 °C or at −20 °C,23,24 no
reaction occurred and the starting material was totally recovered.
Performing the reaction with sodium naphthalenide at room
temperature for 30 min led to a complex mixture of unidentified
products. The use of phenol and 48% HBr in H2O,18,25 or the
use of sodium amalgam and disodium hydrogen phosphate in
dry methanol,26 both under reflux conditions gave rise to
complex reaction mixtures. Application of conditions reported
for the deprotection of tertiary sulfonamides using trimethylsilyl
chloride in the presence of sodium iodide,27 failed also to depro-
tect azetidine 16.
The procedure for the deprotection of tertiary sulfonamides
using TMSCl in the presence of NaI is reported as straight-
forward.27 Thus this strategy was used and azetidine 16 was
N-benzylated with benzyl bromide in the presence of K2CO3 in
DMF (Scheme 9).28 Next, the trans-N-benzyl-N-tosylazetidine
21 was stirred under reflux for 48 h with 1.5 equivalents TMSCl
in the presence of 1.5 equivalents NaI, but unfortunately without
formation of the trans-(3-N-benzylamino)-azetidine 22.
As the synthesis of the racemic cis-isomer of azetidine 16
starting from the syn-isomer of aziridine 14 was not possible, but
racemic syn-aziridine could be transformed into a racemic
α,β-diamino-γ-butyrolactone,16b a similar ring transformation of
syn-N-sulfinylaziridine syn-6a to chiral α,β-diamino-γ-butyrolac-
tones was evaluated (Scheme 10). (2R,3R)-2,3-diamino-4,4-
dimethylbutyrolactone 23 was prepared via acid-mediated syn-
thesis in quantitative yield. The reaction required careful optimiz-
ation and final reaction conditions involved stirring aziridine
syn-6a in 0.5 M HCl in H2O/EtOAc for 30 min at room tempera-
ture (Scheme 10). The optically pure lactone 23 is of interest in
further applications towards the synthesis of new β-amino-substi-
tuted analogues of N-acyl homoserine lactones acting as quorum
sensing interfering molecules.29
Scheme 10 Transformation of syn-N-sulfinylaziridine syn-6a into
(2R,3R)-2,3-diamino-butyrolactone 23.
aziridine anti-6a under the same reaction conditions led to
unprotected aziridine 8 (Scheme 4).
In conclusion, it was demonstrated that new chiral syn- and
anti-γ-chloro-α,β-diamino esters are formed in high yield and in
excellent diastereomeric ratios via stereoselective Mannich-type
reactions of N-(diphenylmethylene) glycine esters across a chiral
α-chloro-N-p-toluenesulfinylimine. The base used for the depro-
tonation of the glycine ester had a dramatic and unexpected
influence on the diastereoselectivity of the Mannich-type reac-
tion, with LDA leading selectively to anti-diastereomers,
whereas the use of LiHMDS leads to syn-diastereomers. The
γ-chloro-α,β-diamino esters proved to be versatile building
blocks in asymmetric synthesis as demonstrated by several selec-
tive transformations to new syn- and anti-β,γ-aziridino-α-amino
esters, trans-3-aminoazetidine-2-carboxylates and an α,β-dia-
mino-γ-butyrolactone.
General methods
Flame-dried glassware was used for all non-aqueous reactions.
Commercially available solvents and reagents were purchased
from common chemical suppliers and used without further
Similarly, syn-γ-chloro-α,β-diamino ester syn-5a was treated
with 5 equivalents of trifluoroacetic acid in acetone/water (2 : 1)
for 15 min (Scheme 11). Following basic workup with NH4OH,
the syn-γ-chloro-α,β-diamino ester syn-24 was isolated in 83%
yield. The fact that the N-sulfinyl group is not removed under
these conditions is remarkable, as the deprotection of anti-
Scheme 11 Deprotection of syn-γ-chloro-α,β-diamino ester syn-5a
with TFA.
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purification, unless stated otherwise. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were freshly distilled under a nitrogen
atmosphere from sodium/benzophenone ketyl. Petroleum ether
is representative. To a flame dried round-bottomed flask with
freshly distilled diisopropylamine (1.1 equiv, 6.76 mmol, 0.67 g)
in dry THF (15 mL) was added n-BuLi (1.21 equiv, 7.43 mmol,
2.5 M in hexane, 2.97 mL) under nitrogen atmosphere. The reac-
tion mixture was stirred for 5 min at 0 °C and was subsequently
cooled to −78 °C. After 5 min, a solution of N-(diphenylmethy-
lene) glycine ethyl ester 4a (1.1 equiv, 6.76 mmol, 1.81 g) in dry
THF (5 mL) was slowly added and the resulting solution was
stirred for 1 h at −78 °C. After deprotonation, the reaction
mixture was cooled to −90 °C and a solution of (SS)-α-chloro-N-
p-toluenesulfinyl isobutyraldimine 3 (1.0 equiv, 6.14 mmol,
1.50 g), in dry THF (20 mL) was added dropwise and the reac-
tion mixture was stirred at −90 °C for 5 min. To the reaction
mixture was added a saturated solution of NH4Cl (40 mL) while
stirring was continued at −90 °C for 2 min. The reaction mixture
was brought to room temperature, followed by an extraction with
EtOAc (3 × 40 mL). The combined organic phases were dried
(MgSO4), filtered and evaporated in vacuo. The crude product
was purified by column chromatography to yield 2.48 g
(4.85 mmol) of (SS,2S,3R)-ethyl 2-(diphenylmethyleneamino)-4-
chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate anti-5a
as a 89 : 11 mixture with syn-adduct syn-5a.
1
refers to the 40–60 °C boiling fraction. H NMR (300 MHz),
13C NMR (75 MHz) spectra were recorded in deuterated solvents
with tetramethylsilane (TMS, δ = 0 ppm) as internal standard
unless specified otherwise. Mass spectra were recorded using a
direct inlet system (ESI, 4000 V). IR spectra were obtained from
samples in neat form with an ATR (Attenuated Total Reflec-
tance) accessory. Elementary analyses were performed using a
CHNS/O elementary analyzer. HRMS analysis was performed
using an Agilent 1100 series HPLC coupled to an Agilent 6220
TOF-Mass Spectrometer equipped with ESI/APCI-multimode
source. Melting points of crystalline compounds were deter-
mined in open-end capillary tubes using a hot stage apparatus
and were not corrected. The purification of the reaction mixtures
was performed by column chromatography with silica gel (par-
ticle size 0.035–0.070 mm, pore diameter ca. 6 nm). Thin layer
chromatography (TLC) was performed on glass plates coated
with silica gel 60 F254, using UV and KMnO4 as a visualizing
agent. (SS)-p-Toluenesulfinamide is commercially available
(>98% ee).
(SS,2S,3R)-Ethyl 2-(diphenylmethyleneamino)-4-chloro-4-
methyl-3-(p-toluenesulfinylamino)pentanoate anti-5a
Experimental section
Synthesis of (SS)-α-chloro-N-p-toluenesulfinyl isobutyraldimine 3
Rf 0.23 (petroleum ether/EtOAc: 3/1). White crystals, yield
79%, dr 89 : 11. Mp 52.7 0.3 °C. IR (cm−1): νmax 1624, 1731,
3280. H NMR (300 MHz, CDCl3): δ 1.19 (3H, t, J = 7.15 Hz),
To a flame dried round-bottomed flask charged with α-chloroiso-
butyraldehyde 1 (3.43 g, 32.21 mmol) in dry CH2Cl2 (100 mL)
was added Ti(OEt)4 (4 equiv, 29.40 g, 128.85 mmol) and (SS)-p-
toluenesulfinamide 2 (5.00 g, 32.21 mmol) under nitrogen
atmosphere. The reaction mixture was stirred for 18 h at room
temperature. After completion, the reaction mixture was poured
into water (100 mL) while rapidly stirring. The suspension was
filtered over Celite® and the solids were washed with CH2Cl2
(2 × 20 mL). Subsequently, the filtrate was extracted with
CH2Cl2 (3 × 30 mL) and the combined organic phases were
dried (MgSO4), filtered and evaporated in vacuo. The crude
product was purified by column chromatography to yield 7.25 g
(29.74 mmol) of pure (SS)-α-chloro-N-p-toluenesulfinyl iso-
butyraldimine 3.
1
1.62 (3H, s), 1.64 (3H, s), 2.37 (3H, s), 3.90 (1H, d × d, J = 8.81
Hz, 3.30 Hz), 3.99–4.16 (2H, m), 4.58 (1H, d, J = 3.30 Hz),
5.47 (1H, d, J = 8.81 Hz), 7.14–7.77 (14H, m). 13C NMR
(75 MHz, CDCl3): δ 14.0, 21.5, 30.6, 30.8, 61.5, 66.4, 67.2,
73.0, 125.6 (2C), 127.8 (2C), 128.2 (2C), 128.7 (2C), 128.9,
129.4 (2C), 129.6 (2C), 130.8, 136.0, 139.3, 141.3, 142.9,
170.7, 172.6. MS (ES, pos. mode) m/z (%): 511/513 (M + H+,
100). HRMS (ES) calcd for C28H31ClN2O3S: 511.1817 MH+;
found: 511.1825.
(SS,2S,3R)-tert-Butyl 2-(diphenylmethyleneamino)-4-chloro-4-
methyl-3-(p-toluenesulfinylamino)pentanoate anti-5c
Rf 0.29 (petroleum ether/EtOAc: 3/1). White crystals, yield
52%, dr 81 : 19. Mp 57.2 0.5 °C. IR (cm−1): νmax 1624, 1725,
3284. 1H NMR (300 MHz, CDCl3): δ 1.35 (9H, s), 1.64 (3H, s),
1.69 (3H, s), 2.37 (3H, s), 3.82 (1H, d × d, J = 8.53 Hz, 2.5 Hz),
4.44 (1H, d, J = 2.20 Hz), 5.62 (1H, d, J = 8.81 Hz), 7.15–7.78
(14H, m). 13C NMR (75 MHz, CDCl3): δ 21.3, 27.8, 30.4, 30.8,
66.6, 67,3, 73.0, 82.2, 125.7 (2C), 127.9 (2C), 128.0 (2C), 128.5
(2C), 128.7, 129.3 (2C), 129.4 (2C), 130.5, 136.0, 139.4, 141.0,
142.5, 169.5, 172.3. MS (ES, pos. mode) m/z (%): 539/541 (M
+ H+, 100). HRMS (ES) calcd for C30H35ClN2O3S: 539.2130
MH+; found: 539.2114.
(SS)-α-chloro-N-p-toluenesulfinyl isobutyraldimine 3
Rf 0.25 (petroleum ether/EtOAc: 5/1). White crystals, yield
92%. Mp 54.6 1.0 °C. IR (cm−1): νmax 816, 1086, 1071, 1621.
1H NMR (300 MHz, CDCl3): δ 1.70 (3H, s), 1.77 (3H, s), 2.41
(3H, s), 7.31 (2H, d, J = 8.0 Hz), 7.55 (2H, d, J = 8.0 Hz), 8.17
(1H, s). 13C NMR (75 MHz, CDCl3): δ 21.5, 29.0, 29.1, 66.6,
124.7 (2C), 129.9 (2C), 141.0, 142.0, 165.9. MS (ES, pos.
mode) m/z (%): 288/290 (100), 244/246 (M + H+, 80). HRMS
(ES) calcd for C11H14ClNOS: 244.0557 MH+; found: 244.0548
(<1%), 219.1737 (100%).
Synthesis of (SS,2S,3R)-alkyl 2-(diphenylmethyleneamino)-4-
chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoates anti-5
Synthesis of (SS,2R,3R)-alkyl 2-(diphenylmethyleneamino)-4-
chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoates syn-5
The synthesis of (SS,2S,3R)-alkyl 2-(diphenylmethyleneamino)-
4-chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate anti-5a
The synthesis of (SS,2R,3R)-ethyl 2-(diphenylmethyleneamino)-
4-chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate syn-5a
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2326–2338 | 2333

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is representative. A solution of N-(diphenylmethylene) glycine
ethyl ester 4a (1.1 equiv, 6.76 mmol, 1.81 g) in THF (20 mL)
was cooled to −78 °C under nitrogen atmosphere. A 1.0 M sol-
ution of LiHMDS (1.1 equiv, 6.76 mL, 6.76 mmol) in THF was
slowly added and the resulting solution was stirred for 1 h at
−78 °C. After deprotonation, a solution of (SS)-α-chloro-N-p-
toluenesulfinyl isobutyraldimine 3 (1.0 equiv, 6.14 mmol,
1.50 g) in THF (20 mL) was added dropwise and the reaction
mixture was stirred at −78 °C for 15 min. To the reaction
mixture was added a saturated solution of NH4Cl (40 mL) while
stirring at −78 °C for 2 min. The reaction mixture was brought
to room temperature followed by an extraction with EtOAc (3 ×
100 mL). The combined organic phases were dried (MgSO4),
filtered and evaporated in vacuo. The crude product was purified
is representative. To a solution of (SS,2S,3R)-ethyl 2-(diphenyl-
methyleneamino)-4-chloro-4-methyl-3-(p-toluenesulfinylamino)-
pentanoate anti-5a (1.50 g, 2.93 mmol) in acetone (35 mL) was
added K2CO3 (3.0 equiv, 8.80 mmol, 1.22 g) at room tempera-
ture. The reaction mixture was allowed to stir for 24 h at reflux
temperature. After 24 h, the K2CO3 was filtered off and the
solvent was evaporated in vacuo. The resulting oil was redis-
solved in EtOAc (40 mL) and washed with water (2 × 15 mL).
The organic phase was dried (MgSO4), filtered and evaporated
in vacuo. The crude product was purified by column chromato-
graphy to yield 1.02 g (2.14 mmol) of (SS,2S,2′R)-ethyl 2-
(diphenylmethyleneamino)-2-[3,3-dimethyl-1-(p-toluenesulfinyl)-
aziridin-2-yl]acetate anti-6a.
by recrystallization from diethyl ether to yield 2.76
g
(SS,2S,2′R)-Ethyl 2-(diphenylmethyleneamino)-2-[3,3-dimethyl-
1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-6a
(5.40 mmol) of pure (SS,2R,3R)-ethyl 2-(diphenylmethylenea-
mino)-4-chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate
syn-5a.
Rf 0.25 (petroleum ether/EtOAc: 3/1). White crystals, yield
73%. [α]D −24.1 (c 0.4, CHCl3). Mp 103.8 0.2 °C. IR (cm−1):
1
νmax 1613, 1732. H NMR (300 MHz, CDCl3): δ 1.01 (3H, t,
(SS,2R,3R)-Ethyl 2-(diphenylmethyleneamino)-4-chloro-4-
methyl-3-(p-toluenesulfinylamino)pentanoate syn-5a
J = 7.15 Hz), 1.06 (3H, s), 1.60 (3H, s), 2.36 (3H, s), 3.50 (1H,
d, J = 8.26 Hz), 3.53–3.66 (2H, m), 3.84 (1H, d, J = 8.81 Hz),
7.02–7.05 (2H, m), 7.22 (2H, d, J = 8.26 Hz), 7.30–7.41 (6H,
m), 7.55 (2H, d, J = 8.26 Hz), 7.59–7.63 (2H, m). 13C NMR
(75 MHz, CDCl3): δ 13.8, 20.9, 21.3, 21.7, 42.0, 44.6, 60.8,
65.4, 125.6 (2C), 128.0 (2C), 128.3 (2C), 128.9, 129.0 (2C),
129.2 (2C), 130.6, 135.8, 139.4, 140.8, 143.1, 170.1, 170.9. MS
(ES, pos. mode) m/z (%): 475 (M + H+, 100). Anal. calcd for
C28H30N2O3S: C 70.86; H 6.37; N 5.90; found: C 71.00; H
6.21; N 5.85.
Rf 0.21 (petroleum ether/EtOAc: 3/1). White crystals, yield
88%. [α]D +193.8 (c 0.6, CHCl3). Mp 144.2
1.0 °C. IR
(cm−1): νmax 815, 1070, 1088, 1259, 1621, 1721, 3312. 1H
NMR (300 MHz, CDCl3): δ 1.30 (3H, t, J = 7.15 Hz), 1.51 (3H,
s), 1.63 (3H, s), 2.45 (3H, s), 4.21–4.38 (3H, m), 4.66 (1H, d,
J = 1.10 Hz), 5.83 (1H, d, J = 8.26 Hz), 7.13–7.19 (2H, m),
7.26–7.46 (8H, m), 7.51–7.54 (2H, m), 7.74 (2H, d, J = 8.26
Hz). 13C NMR (75 MHz, CDCl3): δ 14.1, 21.4, 29.0, 30.6, 62.2,
65.6, 67,1, 72.6, 125.7 (2C), 127.1 (2C), 128.1 (2C), 128.6
(2C), 128.9 (2C), 129.0, 129.6 (2C), 130.7, 136.4, 138.8, 141.3,
143.6, 169.6, 171.7. MS (ES, pos. mode) m/z (%): 511/513 (M
+ H+, 100). HRMS (ES) calcd for C28H31ClN2O3S: 511.1817
MH+; found: 511.1838.
(SS,2S,2′R)-tert-Butyl 2-(diphenylmethyleneamino)-2-[3,3-
dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-6c
Rf 0.38 (petroleum ether/EtOAc: 3/1). White crystals, yield
79%, dr 81 : 19. Mp 92.2 0.1 °C. IR (cm−1): νmax 1149, 1619,
1741. 1H NMR (300 MHz, CDCl3): δ 1.23 (3H, s), 1.25 (9H, s),
1.60 (3H, s), 2.33 (3H, s), 3.41 (1H, d, J = 8.26 Hz), 3.86 (1H,
d, J = 7.71 Hz), 6.91–7.61 (14H, m). 13C NMR (75 MHz,
CDCl3): δ 21.25, 21.28, 21.8, 27.8 (3C), 42.2, 44.5, 65.5, 81.5,
125.9 (2C), 127.9 (2C), 128.1 (4C), 128.7, 128.9 (2C), 129.2
(2C), 130.3, 135.8, 139.7, 140.7, 143.3, 168.9, 170.1. MS (ES,
pos. mode) m/z (%): 503 (M + H+, 100). Anal. calcd for
C30H34N2O3S: C 71.68; H 6.82; N 5.57; found: C 72.05; H
6.79; N 5.57.
(SS,2R,3R)-Methyl 2-(diphenylmethyleneamino)-4-chloro-4-
methyl-3-(p-toluenesulfinylamino)pentanoate syn-5b
Rf 0.08 (petroleum ether/EtOAc: 4/1). White crystals, yield
86%. [α]D +224.1 (c 1.6, CHCl3). Mp 136.4
0.5 °C. IR
(cm−1): νmax 1071, 1092, 1261, 1727, 3319. 1H NMR
(300 MHz, CDCl3): δ 1.51 (3H, s), 1.63 (3H, s), 2.45 (3H, s),
3.83 (3H, s), 4.30 (1H, d × d, J = 8.53 Hz, 1.38 Hz), 4.70 (1H,
d, J = 1.10 Hz), 5.83 (1H, d, J = 8.81 Hz), 7.13–7.16 (2H, m),
7.28–7.45 (8H, m), 7.50–7.53 (2H, m), 7.74 (2H, d, J = 8.26
Hz). 13C NMR (75 MHz, CDCl3): δ 21.4, 29.0, 30.6, 53.1, 65.6,
67,2, 72.4, 125.7 (2C), 127.0 (2C), 128.1 (2C), 128.7 (2C),
128.9 (2C), 129.0, 129.6 (2C), 130.8, 136.4, 138.7, 141.3,
143.5, 170.2, 171.8. MS (ES, pos. mode) m/z (%): 497/499 (M
+ H+, 100). HRMS (ES) calcd for C27H29ClN2O3S: 497.1660
MH+; found: 497.1658.
(SS,2R,2′R)-Ethyl 2-(diphenylmethyleneamino)-2-[3,3-dimethyl-
1-(p-toluenesulfinyl)aziridin-2-yl]acetate syn-6a
Rf 0.23 (petroleum ether/EtOAc: 3/1). Colourless oil, yield 99%.
[α]D +117.8 (c 0.7, CHCl3). IR (cm−1): νmax 695, 1072, 1092,
1
1624, 1735. H NMR (300 MHz, CDCl3): δ 1.07 (3H, s), 1.24
(3H, t, J = 6.9 Hz), 1.60 (3H, s), 1.95 (3H, s), 3.53 (1H, d, J =
9.36 Hz), 3.77 (1H, d, J = 9.36 Hz), 4.07–4.22 (2H, m),
6.54–6.72 (4H, m), 7.25–7.33 (5H, m), 7.39–7.50 (5H, m). 13C
NMR (75 MHz, CDCl3): δ 14.1, 20.4, 21.2, 22.6, 42.2, 45.4,
61.2, 64.4, 124.6 (2C), 127.7 (2C), 128.0 (4C), 128.3, 129.1
(2C), 129.2 (2C), 130.2, 135.6, 138.9, 141.0, 143.2, 169.8,
Synthesis of (SS,2′R)-alkyl 2-(diphenylmethyleneamino)-2-[3,3-
dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetates 6
The synthesis of (SS,2S,2′R)-ethyl 2-(diphenylmethyleneamino)-
2-[3,3-dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-6a
2334 | Org. Biomol. Chem., 2012, 10, 2326–2338
This journal is © The Royal Society of Chemistry 2012

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170.5. MS (ES, pos. mode) m/z (%): 475 (M + H+, 100). HRMS
allowed to stir for 6 h at room temperature. After completion, the
reaction was quenched with H2O (100 equiv, 78 mmol, 1.4 mL)
and concentrated in vacuo. The resulting precipitate was redis-
solved in EtOAc (4 mL) and washed with H2O (3 × 2 mL). The
organic phase was dried (MgSO4), filtered and evaporated
in vacuo. The crude product was purified by column chromato-
graphy to yield 0.25 g (0.53 mmol) of (SS,2S,2′R)-ethyl
2-(diphenylmethylamino)-2-[3,3-dimethyl-1-(p-toluenesulfinyl)-
aziridin-2-yl]acetate 9.
(ES) calcd for C28H30N2O3S: 475.2050 MH+; found: 475.2071.
(SS,2R,2′R)-Methyl 2-(diphenylmethyleneamino)-2-[3,3-
dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate syn-6b
Rf 0.26 (petroleum ether/EtOAc: 3/1). White crystals, yield
83%. [α]D +178.9 (c 1.6, CHCl3). Mp 108.0
0.3 °C. IR
(cm−1): νmax 698, 1070, 1091, 1622, 1741. 1H NMR (300 MHz,
CDCl3): δ 1.07 (3H, s), 1.60 (3H, s), 1.95 (3H, s), 3.53 (1H, d, J
= 9.1 Hz), 3.70 (3H, s), 3.80 (1H, d, J = 9.8 Hz), 6.54–6.86 (4H,
m), 7.25–7.35 (5H, m), 7.39–7.50 (5H, m). 13C NMR (75 MHz,
CDCl3): δ 20.4, 21.2, 22.5, 42.2, 45.4, 52.4, 64.3, 124.5 (2C),
127.7 (2C), 128.0 (4C), 128.3, 129.1 (2C), 129.2 (2C), 130.3,
135.5, 138.8, 141.0, 143.2, 170.4, 170.6. MS (ES, pos. mode)
m/z (%): 461 (M + H+, 100). HRMS (ES) calcd for
C27H28N2O3S: 461.1893 MH+; found: 461.1894.
(SS,2S,2′R)-Ethyl 2-(diphenylmethylamino)-2-[3,3-dimethyl-1-(p-
toluenesulfinyl)aziridin-2-yl]acetate 9
Rf 0.28 (hexane/Et2O: 10/1). White crystals, yield 68%. [α]D
+80.6 (c 1.9, CHCl3). Mp 99.8 0.5 °C. IR (cm−1): νmax 1742,
1
3287. H NMR (300 MHz, CDCl3): δ 0.99 (3H, t, J = 7.15 Hz),
1.21 (3H, s), 1.61 (3H, s), 2.22 (1H, br s), 2.37 (3H, s), 2.88
(1H, d, J = 9.36 Hz), 2.91 (1H, d, J = 8.81 Hz), 3.26 (1H, d × q,
J = 11.01 Hz, 7.15 Hz), 3.61 (1H, d × q, J = 10.46 Hz, 7.15 Hz),
Synthesis of (2S,2′R)-Ethyl amino-(3,3-dimethylaziridin-2-yl)-
acetate 8
4.63 (1H, s), 7.16–7.33 (12H, m), 7.50 (2H, d, J = 8.26 Hz). 13
C
NMR (75 MHz, CDCl3): δ 14.0, 20.7, 21.3, 21.8, 41.1, 45.3,
58.5, 60.4, 65.2, 125.3 (2C), 127.0 (2C), 127.3, 127.4, 127.7
(2C), 128.4 (2C), 128.5 (2C), 129.2 (2C), 140.9, 142.1, 142.8,
143.5, 172.7. MS (ES, pos. mode) m/z (%): 477 (M + H+, 100).
HRMS (ES) calcd for C28H32N2O3S: 477.2206 MH+; found:
477.2210.
To a solution of (SS,2S,2′R)-ethyl 2-(diphenylmethyleneamino)-
2-[3,3-dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-
6a (0.50 g, 1.05 mmol) in acetone/H2O: 2/1 (30 mL) was added
dropwise trifluoroacetic acid (5 equiv, 5.27 mmol, 0.41 mL) at
room temperature. The reaction mixture was stirred for 15 min at
room temperature and subsequently quenched with NH4OH in
H2O until pH = 10 and concentrated in vacuo. The residue was
redissolved in water (10 mL) and NH4OH was added until pH =
10. The aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The combined organic phases were dried (MgSO4), filtered and
evaporated in vacuo. The crude product was purified by rapid fil-
tration over a short silica column with petroleum ether and the
silica was subsequently extracted with CH2Cl2/MeOH: 4/1. The
latter phase was filtered and evaporated in vacuo to yield 0.14 g
(0.82 mmol) of (2S,2′R)-ethyl amino-(3,3-dimethylaziridin-2-yl)-
acetate 8.
Synthesis of 3-(diphenylmethylamino)-5,5-dimethyl-1,5-
dihydropyrrol-2-one 11
To a solution of (SS,2S,2′R)-ethyl 2-(diphenylmethylamino)-2-
[3,3-dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate 9 (0.10 g,
0.21 mmol) in ethanol (2 mL) was added K2CO3 (3.0 equiv,
0.63 mmol, 0.09 g) at room temperature. The reaction mixture
was stirred for 22 h at reflux. Subsequently, the K2CO3 was
filtered off and the solvent was evaporated in vacuo. Precipi-
tation in diethyl ether afforded 0.06 g (0.20 mmol) of 3-(diphe-
nylmethylamino)-5,5-dimethyl-1,5-dihydropyrrol-2-one 11.
(2S,2′R)-Ethyl amino-(3,3-dimethylaziridin-2-yl)acetate 8
3-(Diphenylmethylamino)-5,5-dimethyl-1,5-dihydropyrrol-2-one
11
Yellowish oil, yield 78%. [α]D + 131.5 (c 0.9, CHCl3). IR
(cm−1): νmax 831, 1027, 1187, 1382, 1729, 2957. 1H NMR
(300 MHz, CDCl3): δ 1.21 (3H, s), 1.23 (3H, t, J = 7.15 Hz),
1.25 (3H, s), 1.39 (3H, br s), 1.91 (1H, d, J = 8.81 Hz), 3.08
(1H, d, J = 8.81 Hz), 4.16 (2H, q, J = 7.15 Hz). 13C NMR
(75 MHz, CDCl3): δ 14.3, 19.7, 27.2, 35.6, 45.8, 55.6, 61.2,
174.6. MS (ES, pos. mode) m/z (%): 173 (M + H+, 100). HRMS
(ES) calcd for C8H16N2O2: 173.1285 MH+; found: 173.1282.
White crystals, yield 98%. Mp 213.2 1.0 °C. IR (cm−1): νmax
704, 1344, 1650, 1697, 3181, 3359. 1H NMR (300 MHz,
CDCl3): δ 1.24 (6H, s), 4.52 (1H, br d, J = 3.6 Hz), 4.91 (1H, d,
J = 1.65 Hz), 5.25 (1H, d, J = 3.6 Hz), 6.21 (1H, br s),
7.21–7.34 (10H, m). 13C NMR (75 MHz, CDCl3): δ 27.6, 57.5,
63.7, 115.2, 127.3 (4C), 127.4 (2C), 128.6 (4C), 136.6, 141.8
(2C), 169.0. MS (ES, pos. mode) m/z (%): 293 (M + H+, 100).
HRMS (ES) calcd for C19H20N2O: 293.1648 MH+; found:
293.1651.
Synthesis of (SS,2S,2′R)-ethyl 2-(diphenylmethylamino)-2-[3,3-
dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate 9
To a solution of (SS,2S,2′R)-ethyl 2-(diphenylmethyleneamino)-
2-[3,3-dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-
6a (0.37 g, 0.78 mmol) in methanol (4 mL) was added dropwise
acetic acid (1 equiv, 0.78 mmol, 0.05 g) at room temperature.
Subsequently, NaCNBH3 (2 equiv, 1.56 mmol, 0.10 g) was
added in portions during 5 min. The reaction mixture was
Synthesis of (2S,2′R)-ethyl 2-(diphenylmethyleneamino)-2-[3,3-
dimethyl-1-(p-toluenesulfonyl)aziridin-2-yl]acetate 14
To a solution of (SS,2S,2′R)-ethyl 2-(diphenylmethyleneamino)-
2-[3,3-dimethyl-1-(p-toluenesulfinyl)aziridin-2-yl]acetate anti-6a
(1.10 g, 2.32 mmol) in dry CH2Cl2 (40 mL) was added mCPBA
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2326–2338 | 2335

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(1.1 equiv, 2.55 mmol, 0.44 g) at room temperature. The reaction
mixture was allowed to stir for 2 min at room temperature and
was subsequently quenched with a saturated solution of
NaHCO3 (20 mL). The organic phase was dried (MgSO4),
filtered and evaporated in vacuo. The crude product was purified
by recrystallization from EtOAc to yield 1.02 g (2.09 mmol)
of (2S,2′R)-ethyl 2-(diphenylmethyleneamino)-2-[3,3-dimethyl-
1-(p-toluenesulfonyl)aziridin-2-yl]acetate 14. All spectroscopic
data were in good agreement with reported data of the racemate
of 14.16b White crystals, yield 90%. [α]D −137.1 (c 0.4, CHCl3).
Mp 128.4 0.5 °C.
(3 × 20 mL). The combined organic phases were dried
(MgSO4), filtered and evaporated in vacuo. Recrystallization
from diethyl ether/hexane: 1/1 afforded 0.24 g (0.52 mmol) of
(2S,3R)-1-diphenylmethyl-4,4-dimethyl-3-(p-toluenesulfonyla-
mino)azetidine-2-carboxylic acid 17.
(2S,3R)-1-Diphenylmethyl-4,4-dimethyl-3-(p-
toluenesulfonylamino)azetidine-2-carboxylic acid 17
White crystals, yield 69%. [α]D +61.0 (c 0.5, MeOH). Mp 121.0
0.2 °C. IR (cm−1): νmax 705, 1092, 1153, 1321, 1454, 1643,
1
1714, 3062. H NMR (300 MHz, CDCl3): δ 1.19 (3H, s), 1.24
(3H, s), 2.36 (3H, s), 3.65–3.73 (2H, m), 4.88 (1H, s), 6.33 (2H,
br s), 7.14–7.36 (10H, m), 7.53 (2H, d, J = 7.15 Hz), 7.70 (2H,
d, J = 7.71 Hz). 13C NMR (75 MHz, CDCl3): δ 16.5, 21.6, 29.7,
56.0, 66.7, 69.3, 70.3, 127.0 (2C), 127.7 (2C), 128.0, 128.6
(3C), 128.8 (2C), 129.1 (2C), 129.9, 136.8, 137.4, 140.2, 143.9,
170.7. MS (ES, pos. mode) m/z (%): 465 (M + H+, 100). HRMS
(ES) calcd for C26H28N2O4S: 465.1843 MH+; found: 465.1848.
Synthesis of (2S,2′R)-ethyl 2-(diphenylmethylamino)-2-[3,3-
dimethyl-1-(p-toluenesulfonyl)aziridin-2-yl]acetate 15
To a solution of (2S,2′R)-ethyl 2-(diphenylmethyleneamino)-2-
[3,3-dimethyl-1-(p-toluenesulfonyl)aziridin-2-yl]acetate 14 (1.33 g,
2.71 mmol) in methanol (15 mL) was added dropwise acetic
acid (1 equiv, 2.71 mmol, 0.16 g) at room temperature.
Subsequently, NaCNBH3 (2 equiv, 5.42 mmol, 0.34 g) was
added in portions during 5 min. The reaction mixture was stirred
for 6 h at room temperature. After completion, the reaction was
quenched with H2O (100 equiv, 271 mmol, 4.9 mL) and concen-
trated in vacuo. The resulting precipitate was redissolved in
EtOAc (15 mL) and washed with water (3 × 10 mL). The
organic phase was dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by recrystallization from
EtOAc/Et2O: 1/1 to yield 1.23 g (2.50 mmol) of (2S,2′R)-ethyl
2-(diphenylmethylamino)-2-[3,3-dimethyl-1-(p-toluenesulfonyl)-
aziridin-2-yl]acetate 15. All spectroscopic data were in good
agreement with reported data of the racemate of 15.16b White
crystals, yield 92%. [α]D −45.3 (c 0.9, CHCl3). Mp 95.8
1.0 °C.
Synthesis of (2S,3R)-4,4-dimethyl-3-(p-toluenesulfonylamino)-
azetidine-2-carboxylic acid derivatives 18 & 19
The synthesis of (2S,3R)-4,4-dimethyl-3-(p-toluenesulfonyla-
mino)azetidine-2-carboxylic acid 18 is representative. To a
solution of (2S,3R)-1-diphenylmethyl-4,4-dimethyl-3-(p-tolue-
nesulfonylamino)azetidine-2-carboxylic acid 17 (0.060 g,
0.13 mmol) in methanol (5 mL) was added Pd(OH)2/C (30%
mass fraction, 0.018 g) at room temperature. The mixture
was stirred for 64 h at room temperature under H2-atmosphere
(3 bar) and subsequently filtered through a short pad of Celite®.
The Celite® pad was washed exhaustively with CH2Cl2 and the
collected organic fractions were evaporated in vacuo. Precipi-
tation in diethyl ether afforded 0.035 g (0.12 mmol) of (2S,3R)-
4,4-dimethyl-3-(p-toluenesulfonylamino)azetidine-2-carboxylic
acid 18.
Synthesis of (2S,3R)-ethyl 1-diphenylmethyl-4,4-dimethyl-3-
(p-toluenesulfonylamino)azetidine-2-carboxylate 16
In a 10 mL microwave vial containing (2S,2′R)-ethyl 2-(diphe-
nylmethylamino)-2-[3,3-dimethyl-1-(p-toluenesulfonyl)aziridin-
2-yl]acetate 15 (0.40 g, 0.81 mmol) was added acetonitrile
(3 mL). The reaction mixture was stirred vigorously at 120 °C
for 10 min. Subsequently, the reaction mixture was concentrated
in vacuo and the residue was recrystallized from Et2O to afford
0.25 g (0.51 mmol) of (2S,3R)-ethyl 1-diphenylmethyl-4,4-
dimethyl-3-(p-toluenesulfonylamino)azetidine-2-carboxylate 16.
All spectroscopic data were in good agreement with reported
data of the racemate of 16 (ee > 98%).16b White crystals, yield
63%. [α]D +15.6 (c 0.2, CHCl3). Mp 188.1 0.5 °C.
(2S,3R)-4,4-Dimethyl-3-(p-toluenesulfonylamino)azetidine-2-
carboxylic acid 18
White crystals, yield 92%. [α]D +66.9 (c 0.4, MeOH). Mp 171.0
1.0 °C. IR (cm−1): νmax 665, 1094, 1159, 1326, 1620, 3063.
1H NMR (300 MHz, CD3OD): δ 1.47 (6H, s), 2.42 (3H, s), 3.87
(1H, d, J = 8.0 Hz), 4.27 (1H, d, J = 8.0 Hz), 7.38 (2H, d, J =
7.71 Hz), 7.76 (2H, d, J = 7.71 Hz). 13C NMR (75 MHz,
CD3OD): δ 21.3, 21.5, 26.5, 59.4, 60.4, 69.8, 128.2 (2C), 130.9
(2C), 138.9, 145.2, 171.4 (tentative assignment). MS (ES, pos.
mode) m/z (%): 299 (M + H+, 100). HRMS (ES) calcd for
C13H18N2O4S: 299.1060 MH+; found: 299.1066.
Synthesis of (2S,3R)-1-diphenylmethyl-4,4-dimethyl-3-(p-
toluenesulfonylamino)azetidine-2-carboxylic acid 17
(2S,3R)-Ethyl 4,4-dimethyl-3-(p-toluenesulfonylamino)azetidine-
2-carboxylate 19
(2S,3R)-Ethyl 1-diphenylmethyl-4,4-dimethyl-3-(p-toluenesulfo-
nylamino)azetidine-2-carboxylate 16 (0.37 g, 0.80 mmol) was
dissolved in 2 M NaOH/MeOH: 1/1 (40 mL). The reaction
mixture was stirred for 24 h at reflux temperature and sub-
sequently washed with EtOAc (1 × 20 mL). The aqueous phase
was brought to pH = 4 with 2 M HCl and extracted with EtOAc
White crystals, yield 87%. [α]D +54.2 (c 0.9, MeOH). Mp 183.6
1.5 °C. IR (cm−1): νmax 664, 907, 1095, 1167, 1228, 1338,
1732, 2771. 1H NMR (300 MHz, CDCl3): δ 1.10 (3H, t, J = 6.9
Hz), 1.65 (3H, s), 1.68 (3H, s), 1.65–1.68 (1H, br s), 2.42 (3H,
s), 3.99–4.13 (3H, m), 5.36 (1H, d, J = 7.71 Hz), 7.29 (2H, d,
2336 | Org. Biomol. Chem., 2012, 10, 2326–2338
This journal is © The Royal Society of Chemistry 2012

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1
J = 8.0 Hz), 7.80 (2H, d, J = 8.0 Hz), 8.16 (1H, d, J = 8.81 Hz).
13C NMR (75 MHz, CD3OD): δ 14.2, 20.8, 21.5, 26.0, 57.9,
59.1, 64.0, 72.0, 128.2 (2C), 131.0 (2C), 139.2, 145.4, 167.5.
MS (ES, pos. mode) m/z (%): 327 (M + H+, 100). HRMS (ES)
calcd for C15H22N2O4S: 327.1373 MH+; found: 327.1379.
1787, 2857. H NMR (300 MHz, CD3OD, int. ref. H2O): δ 1.48
(3H, s), 1.59 (3H, s), 3.97 (1H, d, J = 10.46 Hz), 4.61 (1H, d,
J = 10.46 Hz). 13C NMR (75 MHz, D2O, int. ref. CH3CN): δ
21.7, 26.5, 52.3, 57.2, 84.9, 168.1. MS (ES, pos. mode) m/z (%):
145 (M + H+ − 2×HCl, 100). Anal. calcd for C6H14Cl2N2O2: C
33.19; H 6.50; N 12.90; found: C 33.55; H 6.51; N 12.66.
Synthesis of (2S,3R)-ethyl 1-diphenylmethyl-4,4-dimethyl-3-
[benzyl-(p-toluenesulfonyl)amino]azetidine-2-carboxylate 21
Synthesis of (SS,2R,3R)-ethyl 2-amino-4-chloro-4-methyl-3-(p-
toluenesulfinylamino)pentanoate syn-24
To a solution of (2S,3R)-ethyl 1-diphenylmethyl-4,4-dimethyl-3-
(p-toluenesulfonylamino)azetidine-2-carboxylate 16 (0.22 g,
0.45 mmol) in DMF (4 mL) was added K2CO3 (3 equiv,
1.35 mmol, 0.19 g) at room temperature. Subsequently, benzyl
bromide (1.4 equiv, 0.63 mmol, 0.11 g) was added dropwise and
the reaction mixture was stirred for 3.5 h at room temperature.
The reaction mixture was poured in diethyl ether (5 mL) and
washed with NH4Cl in H2O (2 mL) and brine (3 × 2 mL). The
organic phase was dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by column chromato-
graphy to yield 0.22 g (0.38 mmol) of (2S,3R)-ethyl 1-diphenyl-
methyl-4,4-dimethyl-3-[benzyl-(p-toluenesulfonyl)amino]azeti-
dine-2-carboxylate 21.
To a solution of (SS,2R,3R)-ethyl 2-(diphenylmethyleneamino)-
4-chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate syn-5a
(0.50 g, 0.98 mmol) in acetone/H2O: 2/1 (30 mL) was added
dropwise trifluoroacetic acid (5 equiv, 4.89 mmol, 0.38 mL) at
room temperature. The reaction mixture was stirred for 15 min at
room temperature and subsequently quenched with NH4OH in
H2O until pH = 10 and concentrated in vacuo. The residue was
redissolved in water (10 mL) and NH4OH in H2O was added
until pH = 10. The aqueous phase was extracted with CH2Cl2 (3
× 10 mL). The combined organic phases were dried (MgSO4),
filtered and evaporated in vacuo. The crude product was purified
by rapid filtration over a short silica column with petroleum
ether and the silica was subsequently extracted with CH2Cl2/
MeOH: 4/1. The latter phase was filtered and evaporated in
vacuo to yield 0.28 g (0.81 mmol) of (SS,2R,3R)-ethyl 2-amino-
4-chloro-4-methyl-3-(p-toluenesulfinylamino)pentanoate syn-24.
(2S,3R)-Ethyl 1-diphenylmethyl-4,4-dimethyl-3-[benzyl-(p-
toluenesulfonyl)amino]azetidine-2-carboxylate 21
Rf 0.18 (petroleum ether/EtOAc: 5/1). White crystals, yield
85%. [α]D +54.0 (c 0.2, CHCl3). Mp 165.5 0.5 °C. IR (cm−1):
νmax 671, 695, 706, 1157, 1216, 1332, 1720. 1H NMR
(300 MHz, CDCl3): δ 0.81 (3H, t, J = 7.15 Hz), 0.93 (3H, s),
1.18 (3H, s), 2.39 (3H, s), 3.38–3.49 (1H, m), 3.54–3.65 (1H,
m), 3.74 (1H, d, J = 7.71 Hz), 3.90 (1H, d, J = 16.2 Hz), 3.93
(1H, d, J = 7.71 Hz), 4.40 (1H, s), 4.64 (1H, d, J = 16.2 Hz),
7.06–7.37 (15H, m), 7.49 (2H, d, J = 7.15 Hz), 7.64 (2H, d, J =
8.26 Hz). 13C NMR (75 MHz, CDCl3): δ 13.6, 17.1, 21.5, 29.6,
51.4, 60.4, 62.0, 63.6, 68.6, 69.9, 127.2, 127.4, 127.5 (2C),
127.7, 128.0 (2C), 128.1 (4C), 128.3 (2C), 128.4 (2C), 128.9
(2C), 129.7 (2C), 135.5, 137.7, 140.7, 142.8, 143.6, 171.4. MS
(ES, pos. mode) m/z (%): 583 (M + H+, 100). HRMS (ES) calcd
for C35H38N2O4S: 583.2625 MH+; found: 583.2620.
(SS,2R,3R)-Ethyl 2-amino-4-chloro-4-methyl-3-(p-
toluenesulfinylamino)pentanoate syn-24
Yellowish oil, yield 83%. [α]D +155.2 (c 0.5, CHCl3). IR
(cm−1): νmax 811, 1064, 1090, 1224, 1734, 3208. 1H NMR
(300 MHz, CDCl3): δ 1.36 (3H, t, J = 7.15 Hz), 1.63 (3H, s),
1.69 (2H, br s), 1.74 (3H, s), 2.41 (3H, s), 4.07 (1H, d × d, J =
9.1 Hz, 1.10 Hz), 4.17 (1H, d, J = 1.10 Hz), 4.24–4.37 (2H, m),
5.40 (1H, d, J = 9.1 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J
= 8.0 Hz). 13C NMR (75 MHz, CDCl3): δ 14.2, 21.3, 29.2, 30.8,
53.3, 62.2, 65.3, 73.0, 125.4 (2C), 129.5 (2C), 141.4, 142.8,
173.0. MS (ES, pos. mode) m/z (%): 347 (M + H+, 100). HRMS
(ES) calcd for C15H23ClN2O3S: 347.1191 MH+; found:
347.1205.
Synthesis of (R,R)-2,3-diamino-4,4-dimethylbutyrolactone
Acknowledgements
dihydrochloride 23
The authors are indebted to the “Institute for the Promotion of
(SS,2R,2′R)-ethyl 2-(diphenylmethyleneamino)-2-[3,3-dimethyl-
1-(p-toluenesulfinyl)aziridin-2-yl]acetate syn-6a (0.14 g,
0.29 mmol) was dissolved in a mixture of 0.5 M HCl (aq.)/
EtOAc: 4/1 (10 mL) and the mixture was stirred for 30 min at
room temperature. Subsequently, the reaction mixture was con-
centrated in vacuo. Precipitation in diethyl ether afforded 0.06 g
(0.28 mmol) of (2R,3R)-2,3-diamino-4,4-dimethylbutyrolactone
dihydrochloride 23.
Innovation through Science and Technology
– Flanders”
(IWT-Vlaanderen) and the Research Foundation – Flanders
(FWO – Vlaanderen) for financial support.
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