Stereoselective synthesis of both enantiomers of trans-2- (diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool approach and their incorporation in dipeptides

Article abstract of DOI:10.1016/j.tet.2012.09.078

The stereoselective synthesis of (1R,2R)- and (1S,2S)-trans-2- (diphenylmethylideneamino)cyclopropanecarboxylic acid has been accomplished in six steps starting from (2S)- and (2R)-β-benzyl N-(tert-butoxycarbonyl) aspartate, respectively. The key-step in

Full text of DOI:10.1016/j.tet.2012.09.078

Tetrahedron 68 (2012) 9566e9571
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Stereoselective synthesis of both enantiomers of trans-2-
(diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool
approach and their incorporation in dipeptides
y
*
Tamara Meiresonne, Sven Mangelinckx , Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Received in revised form 14 September 2012
Accepted 16 September 2012
Available online 23 September 2012
The stereoselective synthesis of (1R,2R)- and (1S,2S)-trans-2-(diphenylmethylideneamino)cyclo-
propanecarboxylic acid has been accomplished in six steps starting from (2S)- and (2R)-
butoxycarbonyl)aspartate, respectively. The key-step in the reaction sequence is a stereoselective base-
induced ring closure with a good trans diastereoselectivity. These novel trans- -ACC derivatives could
be incorporated in dipeptides employing a standard peptide coupling technique.
b-benzyl N-(tert-
b
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
remains rather scarce. An enantiomerically enriched cis-2-
aminocyclopropanecarboxylic acid derivative (63% ee) was syn-
thesized using a chemoselective hydrolysis of a cyclopropane meso-
diester with Pig Liver Esterase (PLE) followed by appropriate
functional group transformation.12 Enamides have proved to serve
as valuable precursors in the synthesis of unsubstituted N-stabi-
b-Aminocyclopropanecarboxylic acid (
b
-ACC) 1 is a carbocyclic
-ACC 1 itself
analogue of -alanine possessing a severe ring strain.
b
b
has never been synthesized due to the inherent instability of this
small-membered ring caused by its 1,2-donor-acceptor substituted
cyclopropane structure.1,2 Therefore, a suitable stabilizing group at
nitrogen is essential to avoid spontaneous ring opening of the cy-
clopropane core, which complicates the synthesis of
rivatives and their incorporation in peptides.3e9 Moreover, due to
the presence of two stereogenic centres in the cyclopropane ring,
lized b-ACC derivatives via a cyclopropanation reaction using ethyl
diazoacetate as a carbene source in the presence of a catalyst, which
is of great importance for the diastereoselective outcome of this
reaction.13,14 An asymmetric cyclopropanation reaction of styrene
b-ACC de-
b
-
with ethyl diazoacetate afforded an unsubstituted trans-b-ACC
aminocyclopropanecarboxylic acid 1 exists as four stereoisomers
(Fig. 1). This entails an extra challenge in the development of
derivative (90% ee) in five steps using a chiral (salen)Ru(II) cyclo-
propanation catalyst.15 Noteworthy, only one synthetic route to-
a strategy for the synthesis of enantiopure
b
-ACC derivatives.
wards an unsubstituted chiral b-aminocyclopropanecarboxylic acid
using a chiral pool approach has been described in the literature,
more specifically starting from the expensive chiral building block
benzyl (S)-(þ)-glycidyl ether.16,17 The only other synthesis starting
from a chiral building block,
tiomerically pure trans-1-methyl-
Next to their synthesis, also the incorporation of cis-,10,18e22 and
to a lesser extent trans-
-aminocyclopropanecarboxylates10 in
peptides, allowing to influence their structural conformation, has
received a lot of attention in recent years. The synthesis of a cis-
D-glyceraldehyde, leads to an enan-
b
-ACC derivative in nine steps.12
b
Fig. 1. The four stereoisomers of b-ACC 1.
b
-
Although different asymmetric synthetic approaches towards
2-aminocyclopropanecarboxylates have been reported,10,11 the
ACC-containing pseudopeptide, starting from a meso-anhydride
and (S)-prolinate is the only example that can be mentioned re-
elaboration of synthetic pathways towards
b-ACC derivatives
garding the incorporation of an unsubstituted
b-ACC building block
with no extra functionalization of the cyclopropane core
in peptides.23,24
In view of these important gaps in the chemistry of chiral
herein, the synthesis of a new enantiopure unsubstituted (ꢀ)-trans-
-aminocyclopropanecarboxylic acid via a stereoselective base-
induced ring closure is described, starting from an S-aspartic acid
b-ACCs,
* Corresponding author. Tel.: þ32 (0)9 264 59 51; fax: þ32 (0)9 264 62 21; e-mail
b
address: norbert.dekimpe@UGent.be (N. De Kimpe).
y
Postdoctoral Fellow of the Research Foundation-Flanders (FWO).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.078

T. Meiresonne et al. / Tetrahedron 68 (2012) 9566e9571
9567
derivative as chiral building block. The (þ)-trans-
b
-ACC enantiomer
The same synthetic pathway was applied on (2R)-
b
-benzyl N-
could be synthesized via the same pathway starting from the R-
aspartic acid derivative. Surprisingly, S-aspartic acid, one of the
(tert-butoxycarbonyl)aspartate 2b and afforded (3R)-benzyl 3-
diphenylmethylideneamino-4-iodobutanoate 6b in 39% overall
yield (Scheme 1).
twenty proteinogenic amino acids and a naturally occurring
amino acid, has never been used as a chiral building block in the
synthesis of enantiopure -aminocyclopropanecarboxylic acids.
Moreover, the incorporation of these new trans- -amino-
b-
With
g-iodo b-amino esters 6aeb in hand, the base-induced
b
ring closure of these precursors towards the envisaged chiral
benzyl cyclopropanecarboxylates was investigated and optimized
(Table 1 and 2).
b
cyclopropanecarboxylic acids in dipeptides was studied as well.
Initially, (3S)-benzyl 4-iodobutanoate 6a was treated with
1.05 equiv of KOtBu in THF for 1 h at room temperature. After
work-up, four reaction products could be detected in the crude
reaction mixture (based on 1H NMR analysis). To our satisfaction,
2. Results and discussion
the intended b-aminocyclopropanecarboxylic ester 7 was formed
By using acyclic aspartic acid derivatives as chiral building
under the present reaction conditions, albeit as a mixture of two
diastereomers in moderate diastereomeric ratio (dr trans:cis
74:26) (Table 1, entry 1) from which (1R,2R)-trans-2-(diphe-
nylmethylideneamino)cyclopropanecarboxylate 7a could be iso-
lated in 26% yield (dr>99:1). Due to a reaction conversion of only
73%, iodide 6a was still present in the crude reaction mixture and
via 1H NMR analysis of the reaction mixture, a tert-butyl cyclo-
propanecarboxylate resulting from transesterification could ten-
tatively be identified as a side product, which was not isolated. In
an attempt to drive the ring closure reaction to completion, io-
dide 6a was treated with 1.5 equiv KOtBu in THF at room tem-
perature for 1 h (Table 1, entry 2). In this case, a reaction
conversion of 100% was noticed, but again cyclopropane 7 was
obtained in a moderate diastereomeric ratio (dr trans:cis 79:21).
Furthermore, the formation of the side product mentioned above
could not be avoided under these modified reaction conditions.
After extensive column chromatography and subsequent re-
crystallization, (1R,2R)-trans-cyclopropane 7a (24%) and a very
small amount of (1S,2R)-cis-cyclopropane 7b (2%) could be iso-
lated in pure form (dr>99:1). In order to suppress the occurrence
of the side reaction, the ring closure reaction was performed at
a lower temperature. Unfortunately, the use of KOtBu at 0 ꢁC did
not lead to better results (Table 1, entry 3). Following these
moderate results, the use of another base, more specifically the
strong nitrogen base potassium hexamethyldisilazide (KHMDS),
was evaluated in the ring closure reaction of iodide 6a. When
(3S)-benzyl 4-iodobutanoate 6a was reacted with 1.1 equiv
KHMDS in THF for 5 min at ꢀ78 ꢁC, 92% of the starting product
was converted towards cyclopropane 7, with no formation of side
products. Moreover, an improvement of the diastereomeric ratio
of cyclopropane 7 could be observed (dr trans:cis 88:12) (Table 1,
entry 4). Prolongation of the reaction time to 10 min led to a full
blocks for the synthesis of b-ACCs, the introduction of the cyclo-
propane core is envisaged to proceed via a 1,3-cyclization reaction.
Therefore, the synthesis of an eligible precursor, bearing a leaving
group in
position, starting from these aspartic acid derivatives had to be
developed. Similar -aminobutanoates have already been used as
precursors in the synthesis of another class of -amino acids with
g-position and a suitably stabilized amino group in b-
b
b
a three-membered ring as a core structure, more specifically 2-
carboxymethylaziridines.25e27 In the literature, the conversion of
(2S)-b-benzyl N-(tert-butoxycarbonyl)aspartate 2a towards the
functionalized iodide 4a has been reported. The carboxylic acid
moiety of aspartate 2a was converted into the alcohol 3a by re-
duction using NaBH4 after activation with isobutyl chloroformate.28
Conversion of b-amino alcohol 3a into iodide 4a was achieved using
a PPh3/I2 complex using triphenylphosphine instead of a polymer
bound triaryl phosphine (Scheme 1).29,30 In theory, this N-Boc
protected iodide could serve as a direct precursor in the synthesis of
b
-ACCs, although competition with formation of the corresponding
aziridines is expected.31 However, it has been demonstrated that
the presence of only one electron-withdrawing group at nitrogen in
such type of precursors is not sufficient to allow cyclization to 1,2-
donoreacceptor substituted cyclopropanes.32,33 Therefore, another
group at nitrogen was introduced, more specifically a diphenylme-
thylidene group, which has already been used previously as a sta-
bilizing group in the synthesis of donoreacceptor substituted
cyclopropanes.7,32 Boc-deprotection of the amino group of
ester 4a under acidic conditions afforded -iodoammonium salt 5a.
b-amino
b
Subsequent transimination of 5a with benzophenone imine
yielded enantiopure benzyl (3S)-3-diphenylmethylideneamino-
4-iodobutanoate 6a, as a direct precursor for the synthesis of
novel chiral unsubstituted
(Scheme 1).
b-aminocyclopropanecarboxylates
Scheme 1. Synthesis of (3S)-benzyl 4-iodobutanoate 6a and (3R)-benzyl 4-iodobutanoate 6b.

9568
T. Meiresonne et al. / Tetrahedron 68 (2012) 9566e9571
Table 1
Ring closure of (3S)-benzyl 3-(diphenylmethylideneamino)-4-iodobutanoate 6a
Entry
Reaction conditions
dr trans:cisa
Yield (%) trans 7ab
1
2
3
4
5
6
7
8
9
1.05 equiv KOtBu, THF, rt, 1 h
1.5 equiv KOtBu, THF, rt, 1 h
74:26c
79:21d
61:39e
88:12f
91:9
95:5
99:1
99:1
93:7
26
24
22
70
79
81
80
74
65
1.05 equiv KOtBu, THF, 0 ꢁC, 2 h
1.1 equiv KHMDS, THF, ꢀ78 ꢁC, 5 min
1.1 equiv KHMDS, THF, ꢀ78 ꢁC, 10 min
1.1 equiv KHMDS, THF, ꢀ78 ꢁC, 1 h
1.1 equiv KHMDS, THF, ꢀ78 ꢁC, 2 h
1.1 equiv KHMDS, THF, 0 ꢁC, 5 min
1.5 equiv KHMDS, THF, ꢀ78 ꢁC, 1 h
a
Determinated by 1H NMR spectroscopy of the crude reaction mixture.
b
c
d
e
f
dr trans:cis>99:1.
73% conversion.
cis-7b was isolated in 2% yield (dr>99:1).
82% conversion.
92% conversion.
Table 2
Ring closure of (3R)-benzyl 3-(diphenylmethylideneamino)-4-iodobutanoate 6b
Entry
Reaction conditions
dr trans:cisa
Yield(%) trans 7cb
1
2
1.1 equiv KHMDS, THF, ꢀ78 ꢁC, 1 h
97:3
87:13
75
56
1.1 equiv KHMDS, THF, rt, 1 h
a
Determinated by 1H NMR spectroscopy of the crude reaction mixture.
dr trans:cis>99:1.
b
conversion of the starting material towards cyclopropane 7 in
a good diastereomeric ratio (dr trans:cis 91:9) (Table 1, entry 5).
In an attempt to improve the diastereomeric ratio, the reaction
time was prolonged towards 1 and 2 h, with some improvement
of the diastereomeric ratio (up to 99:1), but no improvement of
the yield of cyclopropanecarboxylate 7a (Table 1, entry 6e7).
From these attempts, (1R,2R)-trans-cyclopropanecarboxylate 7a
could be isolated in a good yield of 81% (resp. 80%) (dr>99:1).
When (3S)-benzyl 4-iodobutanoate 6a was reacted with KHMDS
at a higher temperature, a similar variable diastereomeric ratio
was observed (dr trans:cis up to 99:1) and (1R,2R)-trans-benzyl 2-
(diphenylmethylideneamino)cyclopropanecarboxylate 7a was
isolated in 74% yield (dr>99:1) after recrystallization (Table 1,
entry 8). The use of more equivalents of the base was also eval-
uated but did not lead to an improvement of the diastereomeric
ratio or the yield (Table 1, entry 9). Noteworthy, treatment
of pure trans-benzyl 2-(diphenylmethylideneamino)cyclo-
propanecarboxylate 7a with KHMDS under similar reaction con-
ditions (THF, ꢀ78 ꢁC, 1 h) only led to degradation of this
cyclopropane derivative.
The relative configuration of cyclopropane 7a was assigned
based on comparison of the coupling constants in the 1H NMR
signal corresponding to HA with literature values. The values of the
vicinal coupling constants trans-3JHA,HB (¼2.5 Hz), trans-3JHA,HC
(¼4.7 Hz) and cis-3JHA,HD (¼7.4 Hz) are comparable to the values of
the
observed
vicinal
coupling
constants
trans-3JHA,HB
(¼3.0e3.2 Hz), trans-3JHA,HC (¼4.7e4.9 Hz) and cis-3JHA,HD
(¼7.5e7.7 Hz) of the similar racemic trans-
9.34
b
-ACC derivatives 8,7 and
The reaction of (3R)-benzyl 3-(diphenylmethylideneamino)-4-
iodobutanoate 6b with KHMDS, performed under similar reaction
conditions (1.1 equiv KHMDS, ꢀ78 ꢁC, 1 h), afforded cyclopropane 7

T. Meiresonne et al. / Tetrahedron 68 (2012) 9566e9571
9569
in a good diastereomeric ratio (dr 97:3) from which (1S,2S)-benzyl
2-(diphenylmethylideneamino)cyclopropanecarboxylate 7c could
be isolated in 75% yield after recrystallization (dr>99:1) (Table 2,
entry 1). Enantiomer 6b was also treated with KHMDS at room
temperature for 1 h, which resulted in a lower diastereomeric ratio
(dr trans:cis 87:13) (Table 2, entry 2).
acid 10a with 1 equiv of methyl glycinate (HCl salt) in CH2Cl2 for
24 h at room temperature in the presence of EDC$HCl afforded
dipeptide 12a, which could be isolated, albeit in a very low yield of
2% (dr>99:1). Addition of the base N-methylmorpholine (NMM) to
the reaction mixture decreased the reaction time to 3 h and in-
creased the yield of peptide 12a up to 58% after column chroma-
tography (Scheme 2). Peptide 12b was formed under similar
reaction conditions and was isolated in 68% yield (Scheme 3).
When 2 equiv of (R)-4-(9-anthryl)-2,2,2-trifluoroethanol [(R)-
Pirkle alcohol] were added to a prepared mixture (1:1) of peptides
12a and 12b, spectral nonequivalences of the signals from the NH-
proton and NCH2-protons appeared in the 1H NMR spectrum
(300 MHz, CDCl3). When 2 equiv of (R)-Pirkle alcohol were added to
peptide 12a or peptide 12b, no chemical shift nonequivalences
could be observed in the 1H NMR spectrum, confirming the enan-
tiomeric purity of peptides 12a and 12b.
In an attempt to isolate (1S,2R)-cis-benzyl 2-(diphenylmethyli-
deneamino)cyclopropanecarboxylate 7b in a better yield, some
other reaction conditions were evaluated in order to invert the
diastereomeric ratio of cyclopropane 7. Addition of KCl (1 equiv) or
ZnCl2 (1.1 equiv) to the reaction of (3S)-benzyl butanoate 6a with
KHMDS in THF at ꢀ78 ꢁC or 0 ꢁC did not increase the amount of cis-
isomer 7b and resulted in a sluggish reaction with the formation of
unidentified side products. Also the addition of 18-crown-6,
a crown ether with affinity for potassium cations, to the cyclization
reaction did not lead to an inversion of the diastereomeric ratio and
only lowered the conversion of the reaction. By adding these ad-
ditives to the reaction, it was attempted to create a more ‘naked’
anion in the intermediate, so that internal solvation by the ben-
zophenone imine function might take place, which could lead to
preferential formation of the cis-cyclopropane.35
3. Conclusion
In conclusion, a stereoselective synthesis of novel trans-b-
aminocyclopropanecarboxylic acids 7 was developed, using a chi-
ral pool approach. The key step in the reaction sequence, more
specifically the base-induced ring closure was optimized and
afforded (1R,2R)- and (1S,2S)-trans-2-(diphenylmethylidene-
amino)cyclopropanecarboxylates 7a and 7c in very good diaster-
eoselectivity and high yield. These new unsubstituted N-stabilized
In a last step towards the synthesis of the unprotected C-ter-
minal
b-aminocyclopropanecarboxylic acids, a saponification re-
action of cyclopropanecarboxylic esters 7a and 7c was performed
by treatment with aqueous NaOH (in methanol). To our satisfaction,
this reaction proceeded smoothly and afforded cyclo-
propanecarboxylic acids 10aeb in 61e77% yield without observa-
tion of trans/cis isomerisation (based on detailed analysis of the
well-resolved signals in the 1H NMR spectrum) (Scheme 2 and
Scheme 3). Subsequently, the stability of cyclopropanecarboxylic
acids 10aeb towards a peptide coupling reaction with methyl
glycinate hydrochloride 11 was evaluated. In a first attempt,
(1R,2R)-trans-cyclopropanecarboxylic acid 10a was reacted with
glycinate 11 in the presence of 1.05 equiv dicyclohexylcarbodiimide
(DCC) and Et3N in EtOAc. After detailed analysis of the reaction
mixture, it could be concluded that carboxylic acid 10a had reacted
with DCC but the subsequent coupling of the activated acid with
methyl glycinate failed, and peptide 12a could not be detected. The
use of another coupling reagent, more specifically 1-ethyl-3-(3-
N,N-dimethylaminopropyl)carbodiimide (HCl salt) (EDC.HCl),
proved to be more successful. Reaction of cyclopropanecarboxylic
b
-ACC derivatives could be converted into the C-terminal un-
protected -ACCs 10aeb and were incorporated in dipeptides 12
using standard peptide coupling reaction conditions. The coupling
of the novel -aminocyclopropanecarboxylic acid derivatives 10
b
b
into peptides via the N-terminus is currently under investigation in
our group.
4. Experimental
4.1. General
Commercially available solvents and reagents were purchased
from common chemical suppliers and used without further puri-
fication. Diethyl ether and tetrahydrofuran (THF) were freshly dis-
tilled from sodium/benzophenone ketyl. CH2Cl2 was freshly
Scheme 2. Saponification of ester 7a and peptide formation.
Scheme 3. Saponification of ester 7c and peptide formation.

9570
T. Meiresonne et al. / Tetrahedron 68 (2012) 9566e9571
distilled from CaH2. Petroleum ether refers to the 40e60 ꢁC boiling
fraction. 1H NMR (300 MHz), 13C NMR (75 MHz) spectra were
recorded in deuterated solvents with tetramethylsilane (TMS,
CHarom). 13C NMR (75 MHz, CDCl3):
d 10.9 (CH2I), 41.2 (CH2C]
O), 58.5 (CH), 66.1 (CH2O), 127.5, 127.9, 128.0, 128.3, 128.5,
128.7, 130.3 (CHarom), 135.6, 136.0, 139.3 (Cq,arom), 169.6 and
d¼0 ppm) as internal standard. Mass spectra were recorded using
170.6 (C]N and C]O). IR (ATR, cmꢀ1):
n
¼1737 (C]O), 1616
a direct inlet system (ESI, 4000 V). IR spectra were obtained from
samples in neat form with an ATR (Attenuated Total Reflectance)
accessory or on a PerkineElmer Spectrum One spectrophotometer.
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 com-
pounds were determined 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 (particle size 0.035e0.070 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.
(C]N). MS (ES, pos. mode): m/z (%): 484 (MþHþ, 100).
HRMS (ESI) calcd for C24H22INO2 484.0774 (MþHþ), found
484.0764.
4.2.3.2. (3R)-Benzyl 3-(diphenylmethylideneamino)-4-
iodobutanoate 6b. [
a]
D ꢀ40ꢂ1 (c 0.8, CH2Cl2).
4.2.4. Synthesis of (1R,2R)-benzyl 2-(diphenylmethylideneamino)cy-
clopropanecarboxylate 7a. A solution of (3S)-benzyl 3-(diphe-
nylmethylideneamino)-4-iodobutanoate 6a (0.15 g, 0.3 mmol,
1 equiv) in THF (3 mL) was cooled to ꢀ78 ꢁC and KHMDS (1 M in
THF) (0.33 mmol, 0.33 mL, 1.1 equiv) was added dropwise. Sub-
sequently, the reaction mixture was stirred for 1 h at ꢀ78 ꢁC, after
which it was quenched with 1 mL NH4Cl(aq,sat). The mixture was
poured in 10 mL NaOH (2 M in H2O), extracted with Et2O (3ꢃ
10 mL) and the organic layers were dried with MgSO4. After re-
moval of the drying agent and evaporation of the solvent in vacuo,
a mixture of trans- and cis-benzyl 2-(diphenylmethylideneamino)
cyclopropanecarboxylate 7a and 7b was obtained (dr 95:5)
from which (1R,2R)-benzyl 2-(diphenylmethylideneamino)cyclo-
propanecarboxylate 7a was isolated in 81% yield (dr>99:1) after
recrystallization from hexane.
4.2. Experimental procedures
4.2.1. Synthesis of (3S)-benzyl 4-iodo-3-N-(tert-butoxycarbonyl)bu-
tanoate 4a. (3S)-4-Iodobutanoate 4a was synthesized in two steps
following a slightly modified literature procedure starting from
(2S)-b-benzyl N-(tert-butoxycarbonyl)aspartate 2a using PPh3 in-
stead of polymer bound triphenylphosphine.28e30
4.2.2. Synthesis of (3S)-benzyl 3-amino-4-iodobutanoate hydrochlo-
ride 5a. (3S)-Benzyl 4-iodo-3-N-(tert-butoxycarbonyl)butanoate
4a (1.53 g, 3.4 mmol) was dissolved in 34 mL of a saturated so-
lution of HCl in Et2O at 0 ꢁC and stirred for 6 h at 0 ꢁC. After
stirring the reaction mixture for another 16 h at room tempera-
ture, the solvent was evaporated in vacuo. Subsequently, dry Et2O
(20 mL) was added and the solution was filtered. After washing
the filter cake with dry Et2O (20 mL), (3S)-benzyl 3-amino-4-
iodobutanoate hydrochloride 5a was obtained as white crystals
in a yield of 92%.
The diastereomeric ratio was determined based on the well-
resolved signal of the benzylic protons in the 1H NMR spectrum.
4.2.4.1. (1R,2R)-Benzyl 2-(diphenylmethylideneamino)cyclopro-
panecarboxylate 7a. White crystals. Yield 81%. Mp¼102e103 ꢁC
[
a
]
ꢀ208ꢂ2 (c 0.6, CH2Cl2). 1H NMR (300 MHz, CDCl3):
D
d
1.52e1.63 (2H, m, CH2), 2.29 (1H, dxdxd, J¼8.6, 6.1, 2.5 Hz,
CHC]O), 3.37 (1H, dxdxd, J¼7.4, 4.8, 2.5 Hz, CHN), 5.08 (2H, s,
CH2O), 7.20e7.55 (15H, m, CHarom). 13C NMR (75 MHz, CDCl3):
d
18.6 (CH2), 25.2 (CHC]O), 45.7 (CHN), 66.4 (CH2O), 128.2,
128.3, 128.40, 128.43, 128.7, 128.9, 130.1 (CHarom), 136.1, 136.4,
4.2.2.1. (3S)-Benzyl 3-amino-4-iodobutanoate hydrochloride
139.6 (Cq,arom), 169.2 and 172.8 (C]N and C]O). IR (ATR, cmꢀ1):
5a. White crystals. Yield 92%. Mp¼129e130 ꢁC 1H NMR (300 MHz,
n
¼1714 (C]O), 1612 (C]N). MS (ES, pos. mode): m/z (%): 356
DMSO-d6):
d
2.77e2.92 (2H, m, CH2C]O), 3.46e3.61 (3H, m, CH2I
(MþHþ, 100). HRMS (ESI) calcd for C24H21NO2 356.1651 (MþHþ),
and CH), 5.15 (2H, s, CH2O), 7.32e7.43 (5H, m, CHarom), 8.51 (3H, br s,
NH3).13C NMR (75 MHz, DMSO-d6):
6.3 (CH2I), 37.3 (CH2C]O), 47.6
(CH), 66.2 (CH2O), 128.0, 128.1, 128.4 (CHarom), 135.5 (Cq,arom), 169.0
found 356.1644.
d
4.2.4.2. (1S,2S)-Benzyl 2-(diphenylmethylideneamino)cyclopro-
panecarboxylate 7c. [a]D 206 (c 1.6, CH2Cl2).
(C]O). IR (ATR, cmꢀ1):
n
¼3028 (NH3), 1731 (C]O). MS (ES, pos.
mode): m/z (%): 320 (MþHþꢀHCl, 100), 192 (MþHþꢀHClꢀHI, 46).
Optical rotation could not be determined due to instability of the
HCl salt in MeOH.
4.2.5. Synthesis of (1S,2R)-benzyl 2-(diphenylmethylideneamino)cy-
clopropanecarboxylate 7b. To solution of (3S)-benzyl 3-
a
(diphenylmethylideneamino)-4-iodobutanoate 6a (0.24 g,
0.5 mmol, 1 equiv) in THF (3 mL) was added KOtBu (0.084 g,
0.75 mmol, 1.5 equiv). Subsequently, the reaction mixture was
stirred for 1 h room temperature, after which it was filtered
through a path of CeliteÒ. Evaporation of the solvent in vacuo
affored a mixture of trans- and cis-cyclopropane 7a and 7b,
which could be separated using column chromatography (hex-
ane/Et2O 8/2), resulting in pure (1R,2R)-trans-cyclopropane 7a
in 24% yield. (1S,2R)-Benzyl 2-(diphenylmethylideneamino)
cyclopropanecarboxylate 7b was isolated after extra re-
crystallization in hexane, in 2% yield.
4.2.3. Synthesis of (3S)-benzyl 3-(diphenylmethylideneamino)-4-
iodobutanoate 6a. To
a solution of (3S)-benzyl 3-amino-4-
iodobutanoate hydrochloride 5a (0.23 g, 0.6 mmol, 1 equiv) in
CH2Cl2 (5 mL) was added benzophenone imine (0.11 g, 0.6 mmol,
1 equiv). After stirring the reaction mixture for 20 h at room tem-
perature, the solvent was evaporated in vacuo and the residue was
redissolved in dry Et2O (5 mL). Filtration of the solids and sub-
sequent removal of the solvent in vacuo afforded (3S)-benzyl 4-
iodobutanoate 6a in 97% yield.
4.2.3.1. (3S)-Benzyl 3-(diphenylmethylideneamino)-4-
iodobutanoate 6a. Yellow crystals. Yield 97%. Mp¼82e83 ꢁC
4.2.5.1. (1S,2R)-Benzyl 2-(diphenylmethylideneamino)cyclopro-
[
a
]
41ꢂ1 (c 0.8, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
2.76 (1H,
panecarboxylate 7b. White crystals. Yield 2%. Mp¼136e138 ꢁC [
a]
D
D
dxd, J¼7.2, 15.3 Hz, CH(H)C]O), 2.81 (1H, dxd, J¼5.5, 15.1 Hz,
CH(H)C]O), 3.26 (1H, dxd, J¼6.1, 9.9 Hz, CH(H)I), 3.32 (1H, dxd,
J¼6.1, 9.6 Hz, CH(H)I), 3.84e3.92 (1H, m, CH), 5.06 (1H, d,
J¼12.4 Hz, CH(H)O), 5.10 (1H, d, J¼12.4 Hz, CH(H)O), 7.15e7.20
(2H, m, CHarom), 7.25e7.51 (11H, m, CHarom), 7.57e7.62 (2H, m,
20 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 1.31 (1H, dxdxd,
J¼7.8, 7.3, 5.1 Hz, CH(H)), 1.92 (1H, dxdxd, J¼6.6, 5.1, 5.1 Hz, CH(H)),
2.08 (1H, dxdxd, J¼7.8, 7.8, 6.6 Hz, CHC]O), 3.25 (1H, dxdxd, J¼7.8,
7.2, 5.1 Hz, CHN), 5.16 (1H, d, J¼12.4 Hz, CH(H)O), 5.29 (1H, d,
J¼12.4 Hz, CH(H)O), 7.19e7.52 (15H, m, CHarom). IR (KBr, cmꢀ1):

T. Meiresonne et al. / Tetrahedron 68 (2012) 9566e9571
9571
n
¼1730 (C]O), 1615 (C]N). MS (ES, pos. mode): m/z (%): 356
4.2.7.2. (10S,20S)-Methyl [(20-diphenylmethylideneaminocyclopro-
(MþHþ, 100).
pane)carbonyl]aminoacetate 12b. [
a]
151ꢂ1 (c 0.3, CH2Cl2).
D
Acknowledgements
4.2.6. Synthesis of (1R,2R)-2-(diphenylmethylideneamino)cyclopro-
panecarboxylic acid 10a. To an ice-cooled solution of (1R,2R)-benzyl
2-(diphenylmethylideneamino)cyclopropanecarboxylate 7a (0.21 g,
0.6 mmol, 1 equiv) in MeOH/H2O 5/1 (6 mL), aqueous 2 M NaOH
(3mmol,1.5 mL, 5 equiv)wasadded. Thereaction mixturewasstirred
at room temperature for 20 h. The organic solvent was evaporated
under reduced pressure and the residual aqueous phase was washed
with Et2O (2ꢃ 10 mL). Subsequently, the aqueous layer was carefully
acidified with a solution of 2 M HCl in H2O to pH 6, followed by an
extraction with CH2Cl2 (3ꢃ 10 mL). After drying (MgSO4), filtration
and evaporation, the pure carboxylic acid 10a was obtained in 61%
yield and dr>99:1.
The authors are indebted to Ghent University (GOA) and the
Research Foundation-Flanders (FWO) for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.09.078.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
4.2.6.1. (1R,2R)-2-(Diphenylmethylideneamino)cyclo-
1. Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151e1196.
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4. Mangelinckx, S.; De Kimpe, N. Synlett 2005, 1521e1526.
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8. Mangelinckx, S.; Courtheyn, D.; Verhe, R.; Van Speybroeck, V.; Waroquier, M.;
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10. Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603e1623.
propanecarboxylic acid 10a. White crystals. Yield 61%.
Mp¼194e195 ꢁC [
a
]
ꢀ256 (c 0.5, MeOH). 1H NMR (300 MHz,
D
CDCl3):
d
1.55 (1H, dxdxd, J¼7.4, 5.8, 4.4 Hz, CH(H)),1.63 (1H, dxdxd,
J¼8.8, 4.5, 4.4 Hz, CH(H)), 2.23 (1H, dxdxd, J¼8.5, 6.1, 2.5 Hz, CHC]
O), 3.38 (1H, dxdxd, J¼7.3, 4.8, 2.3 Hz, CHN), 7.24e7.55 (10H, m,
CHarom). 13C NMR (75 MHz, CD3OD)
d 17.7 (CH2), 24.6 (CHC]O),
ꢀ
45.4 (CHN), 128.3, 128.5, 128.6, 129.0, 130.5 (CHarom), 136.9, 139.8
(Cq,arom), 170.7 and 175.6 (C]N and C]O). IR (ATR, cmꢀ1):
(OH), 1698 (C]O), 1613 (C]N). MS (ES, pos. mode): m/z (%): 266
(MþHþ, 100). HRMS (ESI) calcd for C17H15NO2 266.1181 (MþHþ),
found 266.1176.
n
¼2850
11. For some selected examples, see: (a) Gu, P.; Su, Y.; Wu, X. P.; Sun, J.; Liu, W.; Xue,
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4.2.6.2. (1S,2S)-2-(Diphenylmethylideneamino)cyclo-
propanecarboxylic acid 10b. [a]D 247 (c 0.4, MeOH).
ꢁ
12. Martín-Vila, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.; Branchadell, V.;
ꢀ
~
Minguillon, C.; Giralt, E.; Ortuno, R. M. Tetrahedron: Asymmetry 2000, 11,
3569e3584.
4.2.7. Synthesis of (10R,20R)-methyl [(20-diphenylmethylideneamino-
cyclopropane)carbonyl]aminoacetate 12a. To stirred solution
a
13. Lu, T.; Song, Z.; Hsung, R. P. Org. Lett. 2008, 10, 541e544.
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of (1R,2R)-2-(diphenylmethylideneamino)cyclopropanecarboxylic
acid 10a (0.053 g, 0.2 mmol, 1 equiv) and methyl glycinate hydro-
chloride 11 (0.025 g, 0.2 mmol, 1 equiv) in dry CH2Cl2 (5 mL) were
added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDC$HCl) (0.038 g, 0.2 mmol, 1 equiv) and N-methyl-
morpholine (0.061 g, 0.6 mmol, 3 equiv), and the reaction mixture
was stirred at room temperature for 3 h. The reaction mixture was
poured into water (10 mL) and extracted with CH2Cl2 (3ꢃ 5 mL).
The combined organic layers were dried with MgSO4. The
drying agent was removed by filtration and the filtrate was con-
centrated in vacuo. This afforded pure (10R,20R)-methyl [(20-
diphenylmethylideneaminocyclopropane)carbonyl]aminoacetate
12a (58% yield) after column chromatography on silica gel (petro-
leum ether/EtOAc 1/1).
15. Miller, J. A.; Hennessy, E. J.; Marshall, W. J.; Scialdone, M. A.; Nguyen, S. T. J. Org.
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43, 511e514.
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Beck-Sickinger, A. G. Angew. Chem., Int. Ed. 2003, 42, 202e205.
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4.2.7.1. (10R,20R)-Methyl [(20-diphenylmethylideneaminocyclo-
€€
€ €
propane)carbonyl]aminoacetate 12a. Viscous oil. Yield 58%. [a]
D
ꢀ168ꢂ3 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 1.49 (1H,
dxdxd, J¼8.8, 4.4, 4.4 Hz, CH(H)), 1.56 (1H, dxdxd, J¼7.4, 5.8,
4.4 Hz, CH(H)), 2.11 (1H, dxdxd, J¼8.5, 5.9, 3.0 Hz, CHC]O), 3.36
(1H, dxdxd, J¼7.2, 4.8, 2.2 Hz, CHN), 3.75 (3H, s, CH3), 4.03 (2H, d,
J¼5.0 Hz, CH2NH), 6.28 (1H, t, J¼5.0 Hz, NH), 7.23e7.55 (10H, m,
CHarom). 13C NMR (75 MHz, CDCl3):
d 17.5 (CH2CHN), 26.9 (CHC]
31. Kwak, W.Y.; Kim, H.J.; Min, J.P.; Yoon, T.H.; Shim, H.J.; Yoo, M. U.S. Patent 2012/
0016126 2012.
O), 41.3 (CH2N), 44.8 (CHN), 52.4 (CH3), 128.1, 128.3, 128.4, 128.6,
128.8, 129.9 (CHarom), 136.3, 139.7 (Cq,arom), 168.7, 170.5 and 171.6
ꢀ
32. Díez, D.; García, P.; Fernandez, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.;
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1994, 1471e1475.
(C]N and 2ꢃ C]O). IR (ATR, cmꢀ1):
¼3299 (NH), 1752 (C]O),
n
1648 (C]O). MS (ES, pos. mode): m/z (%): 337 (MþHþ, 100).
HRMS (ESI) calcd for C20H20N2O3 337.1552 (MþHþ), found
337.1548.
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