Synthesis of novel, chiral bicyclo[3.1.0]hex-2-ene amino acid derivatives as useful synthons in medicinal chemistry

Article abstract of DOI:10.1002/hlca.201500163

A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex-2-ene amino acid derivatives 13 and 14 has been developed. The key step is a stereo- and regioselective allylic amination of exo- and endo-methyl bicyclo[3.1.0]hex-2-ene-6-carboxylates 8 and 9, which were prepared from 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one (1). These amino acid derivatives are useful building blocks in medicinal chemistry and can be prepared as chiral compounds by using either (+)-1 or (-)-1 as starting material.

Full text of DOI:10.1002/hlca.201500163

Helvetica Chimica Acta – Vol. 98 (2015)
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Synthesis of Novel, Chiral Bicyclo[3.1.0]hex-2-ene Amino Acid Derivatives as
Useful Synthons in Medicinal Chemistry
by Heinz Stadler
Roche Pharma Research and Early Development, Small Molecule Research, Roche Innovation Center
Basel, F. Hoffmann-La Roche Ltd., Picassoplatz, Lautengartenstrasse 6, CH-4070 Basel
(phone: þ 41-62-6875752; e-mail: heinz.stadler@hotmail.ch)
A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex-2-ene amino acid derivatives 13 and
14 has been developed. The key step is a stereo- and regioselective allylic amination of exo- and endo-
methyl bicyclo[3.1.0]hex-2-ene-6-carboxylates 8 and 9, which were prepared from 7,7-dichlorobicy-
clo[3.2.0]hept-2-en-6-one (1). These amino acid derivatives are useful building blocks in medicinal
chemistry and can be prepared as chiral compounds by using either (þ)-1 or (À)-1 as starting material.
1. Introduction. – Conformationally restricted a-amino acids A and B (Scheme 1)
are useful tools for synthetic and medicinal chemists for the preparation of
peptidomimetics, biologically active compounds, natural products, and organocatalysts
[1]. (2-Carboxycyclopropyl)glycines A are of interest primarily as conformationally
restricted analogs of glutamic acid, the major excitatory neurotransmitter in the central
nervous system [2]. Proper choice of stereochemistry places the desired functional
groups in such a way that the conformation of glutamate is fixed either in an extended
or folded form [3], which allows the assessment of the spatial requirements for a wide
range of ionotropic- (iGluRs) and metabotropic-glutamate receptors (mGluRs) [4], as
well as different classes of transporters [5]. For example, A (R1 ¼ H, R2 ¼ COOH,
Scheme 1
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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DCG-IV) [6] is a potent mGluR2 agonist, A (R1 ¼ H, R2 ¼ MeOCH2, trans-MCG-IV)
is a kainic acid agonist (iGluR), and A (R1 ¼ MeOCH2, R2 ¼ H, cis-MCG-IV) is an N-
methyl-d-aspartic agonist (iGluR) [7]. Proline derivatives B (R2 or R1 ¼ COOMe) are
members of the bicyclic amino acid family [8]. More specifically, they are a sub-class of
proline-glutamic acid chimeras [9], in which backbone flexibility is restricted by the
proline, and the conformation of the glutamate side chain is also locked, making them
interesting building blocks for peptide synthesis [10]. Common precursors for the
synthesis of A and B are the pyroglutamic acid derivatives C (R1 ¼ H, R2 ¼ COOMe;
R1 ¼ COOMe, R2 ¼ H) [11], which by themselves are unique chiral synthons offering a
wide variety of possible synthetic transformations [12]. Building block C (R1 ¼ H, R2 ¼
COOMe), synthezised from Garnerꢁs aldehyde [13] in some 20 steps, is an intermediate
in the first synthesis of DCG-IV (17) by Ohfune [6a] and is formed as a result of a
spontaneous lactamization of the corresponding dicarboxylic amino acid D. To shorten
the synthesis of the important building block C, we thought it should be possible to
synthesize D from an amino substituted bicyclo[3.1.0]hex-2-ene derivative E by
oxidative cleavage of the C¼C bond. The g-amino acid derivatives E (R1 ¼ H, R2 ¼
COOMe; R1 ¼ COOMe, R2 ¼ H) are conformationally restricted g-amino butyric acid
(GABA) analogs [14]. g-Amino butyric acid, like glutamic acid, is present in the
central nervous system [15], but in contrast to the latter, it acts through different
receptors and transporters and functions as the major inhibitory neurotransmitter [16].
For the synthesis of building block E, we envisioned an allylic amination of methyl
bicyclo[3.1.0]hex-2-en-6-carboxylates F as a possible route. In addition, these building
blocks are interesting due to their relatively high level of saturation (Fsp3) and number
of stereogenic centers [17], making them attractive novel synthons in medicinal
chemistry [18]. Herein, we report the synthesis of building blocks E (R1 ¼ COOMe,
R2 ¼ H; R1 ¼ H, R2 ¼ COOMe) in racemic and optically active form, their conversions
into pyroglutamate derivatives C, and the preparation of (2-carboxycyclopropyl)gly-
cines A.
2. Results and Discussion. – 2.1. Syntheses of exo- and endo-Methyl Bicyclo[3.1.0]-
hex-2-ene-6-carboxylates 8 and 9. From the known syntheses of exo- and endo-
bicyclo[3.1.0.]carboxylic acids 3 and 4 [19], we decided to follow the route described by
Brook et al. [19c], because the starting material 7,7-dichlorobicylco[3.2.0]hept-2-en-6-
one (1) is readily available in both enantiomeric forms [20], making the synthesis of our
building blocks in homochiral form straightforward. To test and possibly refine our
synthetic plan (Scheme 2), we first used commercially available racemic 7,7-dichloro-
bicylco[3.2.0]hept-2-en-6-one (1) as the starting material. Reduction with Zn in AcOH
and distillation afforded the reported endo-chloroketone 2 [21], which then underwent
a Favorski ring contraction upon treatment with KOH in dioxane/H2O to produce a 6 :4
mixture of exo- and endo-acid 3 and 4, which were separated via iodolactonization
[19a][19c]. Thus, treatment of this mixture with I2/KI under basic conditions delivered
g-iodolactone 5 together with d-iodolactone 6 in a ratio of 3 :7 and exo-acid 3 [19a].
Subsequent treatment of these iodolactones with Zn under acidic conditions delivered
not only the expected and already described endo-acid 4 (64%) [19a], but also a bicyclic
lactone 7 (25%), which was identified by comparison of the 1H- and 13C-NMR, and IR
spectra with those described in [22]. We hypothesized (Scheme 3) that the undesired

Helvetica Chimica Acta – Vol. 98 (2015)
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Scheme 2
a) Zn, AcOH [21]. b) KOH, Dioxane/H2O [19c]. c) I2, KI, NaHCO3 [19a]. d) 2,2-Dimethoxypropane,
TsOH, MeOH [24]. e) Zn, AcOH, THF [19a]. f) BTCEAD, ClCH2CH2Cl, 858. g) Zn, AcOH, acetone,
then MeOH, Et3N, (tBoc)2O.
Scheme 3
(in our case) bicylic lactone 7 stems from the d-lactone 6, since formation of a C¼C
bond and opening of the three-membered ring (Path a) is not possible from the g-
lactone 5, whereas formation of a C¼C bond and liberation of the endo-acid 4 (Path b)

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is possible from both lactones. The so-formed bridged lactone i is not stable under these
conditions and rearranges readily to lactone 7 [23]. To test this hypothesis, we
separated the g-iodolactone 5 from the d-iodolactone 6 by column chromatography
and subjected each iodolactone individually to the Zn reduction conditions. Indeed,
whereas a mixture of endo-acid 4 (61%) and bicyclic lactone 7 (31%) was obtained
when starting with 6, only endo-acid 4 (86%) was formed using 5 as starting material.
Esterification [24] of these two acids afforded then exo-ester 8 (81%) [25] and endo-
ester 9 (93%) [26], respectively.
2.2. Allylic Amination. With exo- and endo-ester 8 and 9 in hand, we turned our
attention to the allylic amination [27]. Of particular concern was the level of regio- and
stereoselectivity, which we might achieve in this process. Since our synthesis plan called
for a trans relationship between the newly introduced N-function and the three-
membered ring and complete control of the regiochemistry (to avoid any racemization
in the chiral series), we selected the method reported by Leblanc et al. [28], namely
an allylic amination of olefins with bis(2,2,2-trichloroethyl) azodicarboxylate
(BTCEAD). Since the aza-ene reaction with olefins is thought to be a concerted,
suprafacial process [29], and attack of the azodicarboxylate should occur from the less
hindered side, we were confident of achieving the desired stereo- and regioselectivity.
An additional advantage of that protocol are the mild conditions (Zn, AcOH, acetone)
needed for the cleavage of the hydrazine to the amine. Besides the original procedure
[28], which calls for running the reaction in benzene at different temperatures, two
more variations are described in the literature: i) using different Lewis acids as catalysts
in CH2Cl2 at room temperature [30], and ii) running the reaction ꢂon waterꢁ [31]. To
find the best conditions for our case, we performed a short optimization with 8, which is
summarized in Table 1.
Table 1. Allylic Amination
Entry
Solvent
Catalyst
Temp.
Time [h]
Yield [%]a)
8
10
11
1
2
3
4
5
6
Benzene
Toluene
CH2Cl2
CH2Cl2
ClCH2CH2Cl
H2O
none
none
none
(TfO)2Cu
none
808
1108
r.t.
r.t.
858
508
16
16
48
48
16
10
11
–
43
19
–
77
84
50
40
93
83
–
14
–
–
–
none
–
–
a) Yield of isolated product.

Helvetica Chimica Acta – Vol. 98 (2015)
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Running the reaction in benzene for 16 h at reflux temperature (Entry 1) yielded 10
(77%) and starting material 8 (11%). Increasing the temperature to 1108 by using
toluene (Entry 2) drove the reaction to completion (84%), but 11 was formed as an
additional product, which can be explained by an azo-ene reaction of toluene and
BTCEAD. Comparing the results using the conditions of Jorgenson et al. [30] (Entry 4)
vs. running the reaction in CH2Cl2 without catalyst at room temperature (Entry 3) led
us to conclude not to use a Lewis acid as catalyst, but to use 1,2-dichloroethane as
solvent and perform the reaction at 858 (Entry 5). We were pleased to see that the
reaction was finished after 16 h and yielded 10 in 93% yield. To complete our small
study, we also tested the protocol described by Sharpless et al. [31] (Entry 6). These
conditions delivered 10 after 10 h in 83% yield. The drawback of this method was the
formation of a white lump embedded with yellow particles, which contained not only 10
but also BTCEAD. To drive the reaction to completion, it was found necessary to break
up this lump after 6 h and 8 h. Taking account of these findings, for the reaction of the
endo-ester 9 with BTCEAD we also used 1,2-dichloroethane as solvent and employed a
reaction temperature of 858, which enabled 12 to be obtained in 79% yield after 16 h
(Scheme 1). To obtain an orthogonally protected building block, the last step of the
protocol in [28] was modified slightly. Instead of protecting the amine, which is released
after reductive treatment (Zn, AcOH, acetone), as an acetate, we employed (tBoc)2O
as an acylating reagent to afford Boc-protected 13 (74%) and 14 (80%), respectively.
The expected trans relationship between HÀC(4) and HÀC(5) could not be
unequivocally confirmed, since the coupling constant between these two H-atoms in
1
the H-NMR spectrum could not easily be determined. Although the width at half
maximum of the corresponding signals indicated that the coupling constant values were
rather small, suggesting a trans relationship as evidenced in [32], the final proof of the
configuration stemmed from the preparation of rac-DCG-IV (17; Scheme 4). Improved
Sharpless conditions [33] applied to 13 and 14 delivered pyroglutamate derivatives 15
(88%) and 16 (82%) after spontaneous lactamization [6a] of the initially formed
dicarboxylic amino acid [34]. The 1H-NMR coupling constants J(HÀC(2),HÀC(1)) ¼
6.0 Hz in 15 and J(HÀC(2),HÀC(1)) ¼ 6.4 Hz in 16 were in agreement with a cis
relationship as reported in [35]. This, together with the conversion of 15 into rac-DCG-
IV 17 (80%) [6] by acidic hydrolysis, corroborated the stereochemical outcome of the
azo-ene reaction. Applying the same conditions to 16 produced, for the first time, the
all cis-substituted cyclopropyl glycine derivative 18 in 84% yield (Scheme 4).
2.3. Chiral Series. For the synthesis of our chiral bicyclo[3.1.0]hex-2-ene building
blocks, we modified our strategy in such a way that we decided not to separate the endo-
acid 4 from the exo-acid 3 via iodolactonization, but to carry the mixture through the
esterification and allylic amination steps and then isolate 13 and 14 as enantiomerically
pure compounds by column chromatography. The results, using either (1S,5R)-7,7-
dichlorobicyclo[3.2.0]hept-2-en-6-one ((À)-1) [20] or the enantiomer (þ)-12 [20] as
starting material, are shown in Table 2. The absolute configurations of these building
blocks were initially deduced by assuming that the azo-ene reaction proceeds through a
[p2S þ p2S þ s2S] process according to the WoodwardÀHoffmann notation [36]. The
absolute configurations were subsequently confirmed by the synthesis of (2R,2’S,3’S)-
2-(2’,3’-dicarboxylcyclopropyl)glycine (ent-DCG IV) ((þ)-17) [a]D ¼ þ22.3, (À)-17
[a]D ¼ À20.2 [6a]) from (þ)-13 by the reactions outlined above (Scheme 4).

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Helvetica Chimica Acta – Vol. 98 (2015)
Scheme 4
a) NaIO4, RuCl3, MeCN, CCl4, H2O. b) 10% HCl.
Table 2. Chiral Building Blocks
3. Conclusions. – In summary, we have developed a concise and fully stereo-
controlled synthesis of the novel, chiral, bifunctional bicyclo[3.1.0]hex-2-ene building
blocks 13 and 14. These building blocks provide not only a short access to (2,3-
dicarboxycyclopropyl)glycines 17 and 18, but should also allow straightforward
modification of the substituents at the 2 or 3 position of the three-membered ring.
Additionally, together with the highly functionalized pyroglutamate derivatives 15 and
16, they might be versatile building blocks in medicinal chemistry due to their chirality
and three-dimensional shape.

Helvetica Chimica Acta – Vol. 98 (2015)
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We thank the Analytical Departments of the Roche Innovation Center Basel for skillful measure-
ment of NMR, IR, MS, ORD, and chiral HPLC data. The careful reading of the manuscript by Dr. Roger
Norcross is gratefully acknowledged.
Experimental Part
General. All solvents and reagents were used from commercial sources without further purification
or prepared as described in the literature. Thin-layer chromatography (TLC): EMD pre-coated silica gel
60 F254 glass plates; visualization with UV light (254 nm) or chemical detection ((NH4)2Ce(MoO4)3 soln.
or KMnO4 soln.). Flash chromatography (FC): silica gel 60 (Merck, 230 – 400 mesh), with the eluent
mixtures given for the corresponding procedures. Enantiomeric purities: chiral HPLC with an Ultimate
3000 coupled with a Chiralizer (IBZ Messtechnik). Optical rotations (ORD): Anton Parr MCP 500 at
208. M.p.: Büchi B-540 instrument; uncorrected. FT-IR (solid state (ATR)): Nicolet i5S instrument; n˜ in
.
cmÀ1 1H- and 13C-NMR spectra: Bruker Avance II 300 or a Bruker Avance III 600 spectrometer, in
CDCl3, (D6)DMSO or D2O; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Applied Biosystem
API300; in m/z. HR-LC/MS: Agilent Q-TOF 6520 system; in m/z. Elemental analyses: Solvias AG
(Mattenstrasse, Postfach, CH-4002 Basel, Switzerland).
(1RS,5SR,6SR)-Bicyclo[3.1.0]hex-2-ene-6-carboxylic Acid (4) and (3aRS,6aSR)-3,3a,4,6a-Tetrahy-
dro-2H-cyclopenta[b]furan-2-one (7). To a soln. of a mixture (3 :7) of iodolactones 5 and 6 [19a][19c]
(7.50 g, 30 mmol) in THF (50 ml), AcOH (1.5 ml), and H2O (1.5 ml) was added Zn (3.3 g, 58.5 mmol) in
small portions at 08 (ice/water bath). Then, the ice/water bath was removed, and the mixture was stirred
for 1.5 h at ambient temp. After filtration through a pad of Celite, the filtrate was partially concentrated,
diluted with H2O (75 ml), and acidified with 25% HCl to pH ¼ 1. The aq. layer was extracted with Et2O
(3 Â 80 ml). The combined org. extracts were dried (Na2SO4) and concentrated to give 3.48 g of crude
product, which was purified by FC (heptane/AcOEt 4 :1) to give 7 (0.94 g, 25%) as colorless oil (IR, 1H-
and 13C-NMR spectra as described in [22]) and 4 (2.41 g, 64%) as colorless solid. M.p. 88 – 918 (90 – 918
[19a]).
Separation of exo-8-Iodo-2-oxatricyclo[3.3.0.04,6]octan-3-one (5) and exo-6-Iodo-4-oxatricy-
clo[3.2.1.02,7]octan-3-one (6). A mixture of the iodolactones 5 and 6 (4.81 g, 19.2 mmol) was separated
by FC (heptane/AcOEt 4 :1) to afford 5 (1.25 g; Rf (heptane/AcOEt 4 :1) 0.37) and 6 (3.38 g; Rf
(heptane/AcOEt 4 :1) 0.24).
Data of 5. M.p. 120.6 – 121.48 (cyclohexane). IR (ATR): 2914w, 2857w, 1758s, 1440m, 1360m, 1342m,
1320s, 1301m, 1276m, 1258w, 1209m, 1194m, 1030s, 1045m, 1005s, 991s, 964s, 920s, 897m, 868m, 824s, 798s,
783m, 667m, 619m, 591s. 1H-NMR (600 MHz, CDCl3): 5.08 (br. d, J ¼ 4.2, HÀC(1)); 4.29 (br. d, J ¼ 4.7,
HÀC(8)); 3.37 (td, J ¼ 6.1, 4.2, HÀC(5)); 2.69 (ddd, J ¼ 16.3, 6.4, 1.4, HÀC(7)); 2.52 (ddd, J ¼ 16.3, 4.7, 1.6,
HÀC(7)); 2.31 (ddd, J ¼ 8.4, 6.1, 1.5, HÀC(4)); 2.22 (ddd, J ¼ 8.4, 6.1, 1.6, HÀC(6)). 13C-NMR (75 MHz,
CDCl3): 174.1 (C(3)); 87.9 (C(1)); 35.8, 34.4, 34.0 (C(5,7,8)); 29.2 (C(4)); 27.1 (C(6)). GC/EI-MS: 250
(Mþ), 123 ([M À I]þ), 79 ([M À I À CO2]þ). Anal. calc. for C7H7IO2 (250.03): C 33.63, H 2.82, I 50.75;
found C 33.48, H 2.96, I 50.67.
Data of 6. M.p. 114.6 – 115.18 (cylohexane). IR (ATR): 2978w, 2949w, 2858w, 1723s, 1711s, 1436w,
1374m, 1354m, 1329m, 1318w, 1275w, 1254w, 1210s, 1183w, 1160m, 1147m, 1096m, 1085m, 1025s, 987s,
967s, 952s, 924m, 886m, 854m, 838m, 809s, 783m, 762m, 713m, 649m, 598s. 1H-NMR (600 MHz, CDCl3):
4.69 – 4.67 (m, HÀC(5)); 4.14 (br. s, HÀC(6)); 2.68 (dt, J ¼ 13.7, 3.0, HÀC(8); 2.56 – 2.53 (m, HÀC(7));
2.32 – 2.28 (m, HÀC(1)); 2.00 (td, J ¼ 7.5, 0.8, HÀC(2)); 1.93 (dd, J ¼ 17.7, 0.7, HÀC(8)). 13C-NMR
(75 MHz, CDCl3): 168.3 (C(3)); 79.0 (C(5)); 27.7, 26.6 (C(1,7)); 25.6 (C(2)); 21.6, 20.1 (C(6,8)). GC/EI-
MS: 250 (Mþ), 123 ([M À I]þ), 79 ([M À I À CO2]þ). Anal. calc. for C7H7IO2 (250.03): C 33.63, H 2.82, I
50.75; found C 33.57, H 2.97, I 50.55.
(1RS,5SR,6SR)-Bicyclo[3.1.0]hex-2-ene-6-carboxylic Acid (4) and (3aRS,6aSR)-3,3a,4,6a-Tetrahy-
dro-2H-cyclopenta[b]furan-2-one (7). To a soln. of d-iodolactone 6 (2.50 g, 10 mmol) in THF (16 ml),
AcOH (0.5 ml), and H2O (0.5 ml) was added Zn (1.1 g, 19.5 mmol) in small portions at 08 (ice/water
bath). Then, the ice/water bath was removed, and the mixture was stirred for 1.5 h at ambient temp. After
filtration through a pad of Celite, the filtrate was partially concentrated, diluted with H2O (25 ml), and

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Helvetica Chimica Acta – Vol. 98 (2015)
acidified with 25% HCl to pH ¼ 1. The aq. layer was extracted with Et2O (3 Â 50 ml). The combined org.
extracts were dried (Na2SO4) and concentrated to give 1.24 g of crude product, which was purified by FC
(heptane/AcOEt 4 :1) to give 7 (0.38 g, 31%) and 4 (0.76 g, 61%).
(1RS,5SR,6SR)-Bicyclo[3.1.0]hex-2-ene-6-carboxylic Acid (4). To a soln. of g-iodolactone 5 (1.0 g,
4 mmol) in THF (10 ml), AcOH (0.3 ml), and H2O (0.3 ml) was added Zn (0.51 g, 7.8 mmol) in small
portions at 08 (ice/water bath). Then, the ice/water bath was removed, and the mixture was stirred for
1.5 h at ambient temp. After filtration through a pad of Celite, the filtrate was partially concentrated,
diluted with H2O (10 ml), and acidified with 25% HCl to pH ¼ 1. The aq. layer was extracted with Et2O
(3 Â 30 ml). The combined org. extracts were dried (Na2SO4) and concentrated to give 4 (0.43 g, 86%).
Methyl (1RS,5SR,6RS)-Bicyclo[3.1.0]hex-2-ene-6-carboxylate (8). To a soln. of 3 [19c] (8.69 g,
70 mmol) in MeOH (300 ml) and 2,2-dimethoxypropane (100 ml) was added TsOH (3.34 g, 17.6 mmol),
and the mixture was stirred for 24 h at ambient temp. The soln. was partly concentrated, then H2O
(200 ml) and Et2O (200 ml) were added. The layers were separated, and the aq. phase was extracted with
Et2O (2 Â 200 ml). The combined org. layers were washed with 0.5n NaOH (200 ml), H2O (200 ml), and
brine (200 ml), then dried (Na2SO4), and evaporated to give light-yellow oil (8.61 g), which was distilled
(Kugelrohr, 75 – 808, 0.5 Torr) to yield 8 (7.98 g, 81%). 1H-NMR Spectrum as described in [24].
Methyl (1RS,5SR,6SR)-Bicyclo[3.1.0]hex-2-ene-6-carboxylate (9). To a soln. of 4 (2.48 g, 20 mmol)
in MeOH (100 ml) and 2,2-dimethoxypropane (30 ml) was added TsOH (0.95 g, 5 mmol), and the soln.
was stirred for 24 h at 408. The soln. was partly concentrated, then H2O (120 ml) and Et2O (120 ml) were
added. The layers were separated, and the aq. phase was extracted with Et2O (2 Â 120 ml). The combined
org. layers were washed with 0.5n NaOH (120 ml), H2O (120 ml), and brine (120 ml), then dried
(Na2SO4) and evaporated to give light-yellow oil (2.89 g), which was distilled (Kugelrohr, 75 – 808,
1
0.5 Torr) to yield 9 (2.58 g, 93%). H-NMR Spectrum as described in [25][26].
Bis(2,2,2-trichloroethyl) 1-[(1RS,2SR,5SR,6RS)-6-(Methoxycarbonyl)bicyclo[3.1.0]hex-3-en-2-yl]-
hydrazine-1,2-dicarboxylate (10). i) In benzene: A soln. of 8 (691 mg, 5 mmol) and bis(2,2,2-
trichloroethyl) azodicarboxylate (2.28 g, 6 mmol) in benzene (25 ml) was heated for 16 h at 858 (oil
bath). The soln. was concentrated, and the residue (2.64 g) was purified by FC (heptane/AcOEt 10 :1) to
yield 8 (78 mg, 11%) as colorless oil and 10 (2.01 g, 77%) as light-yellow foam.
Data of 10. IR (ATR): 3310s, 3080w, 3069w, 3062w, 3001m, 2925s, 2854s, 1768s, 1731s, 1704s, 1503m,
1445s, 1403s, 1365m, 1347w, 1289s, 1253s, 1201s, 1179s, 1144s, 1106m, 1082w, 1058m, 1044m, 1024w, 981w,
963w, 918w, 897w, 853m, 820s, 791s, 754s, 711s, 650m, 606w, 570s. 1H-NMR (600 MHz, (D6)DMSO, 1208):
9.65 (br. s, NH); 6.20 (br. d, J ¼ 5.1, HÀC(4’)); 5.52 – 5.41 (m, HÀC(3’)); 5.09 – 5.07 (m, HÀC(2’)); 4.86 (s,
CH2O); 4.79 (br. s, CH2O); 3.59 (s, MeO), 2.51 – 2.47, 2.45 – 2.38 (2m, HÀC(1’,5’)); 1.03 (t, J ¼ 2.9,
HÀC(6’)). ESI-MS: 515 ([M À H]À).
ii) In toluene: A soln. of 8 (691 mg, 5 mmol) and bis(2,2,2-trichloroethyl) azodicarboxylate (2.28 g,
6 mmol) in toluene (25 ml) was heated for 16 h at 1108 (oil bath). The soln. was concentrated, and the
residue (2.76 g) was purified by FC (heptane/AcOEt 4 :1) to yield bis(2,2,2-trichloroethyl) 1-
benzylhydrazine-1,2-dicarboxylate (11; 0.34 g, 14%) as light-yellow solid and 10 (2.18 g, 84%) as light-
yellow foam.
Data of 11. 1H-NMR (600 MHz, (D6)DMSO, 1208): 9.88 (br. s, NH); 7.36 – 7.24 (m, 5 arom. H); 4.86,
4.78, 4.68 (3s, 2 Â CH2O, CH2N). ESI-MS: 469 ([M À H]À).
iii) In CH2Cl2: A soln. of 8 (691 mg, 5 mmol) and bis(2,2,2-trichloroethyl) azodicarboxylate (2.28 g,
6 mmol) in CH2Cl2 (25 ml) was stirred for 48 h at ambient temp. The soln. was concentrated, and the
residue (2.86 g) was purified by FC (heptane/AcOEt 10 :1) to yield 8 (298 mg, 43%) as colorless oil and
10 (1.31 g, 50%) as light-yellow foam.
iv) In CH2Cl2 with (TfO)2Cu: To a soln. of 8 (691 mg, 5 mmol) and bis(2,2,2-trichloroethyl)
azodicarboxylate (2.28 g, 6 mmol) in CH2Cl2 (25 ml) was added (TfO)2Cu (362 mg, 1 mmol), and the
mixture was stirred for 48 h at ambient temp. The soln. was concentrated, and the residue (3.12 g) was
purified by FC (heptane/AcOEt 10 :1) to yield 8 (132 mg, 19%) as colorless oil and 10 (1.06 g, 40%) as
light-yellow foam.
v) In ClCH2CH2Cl: A soln. of 8 (691 mg, 5 mmol) and bis(2,2,2-trichloroethyl) azodicarboxylate
(2.28 g, 6 mmol) in ClCH2CH2Cl (25 ml) was stirred for 16 h at 858 (oil bath). The soln. was concentrated,

Helvetica Chimica Acta – Vol. 98 (2015)
1197
and the residue (2.88 g) was purified by FC (heptane/AcOEt 10 :1) to yield 10 (2.42 g, 93%) as light-
yellow foam.
vi) ꢂOn waterꢁ: To a suspension of bis(2,2,2-trichloroethyl) azodicarboxylate (2.28 g, 6 mmol) in H2O
(25 ml) was added 8 (691 mg, 5 mmol), and the mixture was stirred for 6 h at 508 (oil bath). A light-
yellow lump formed and was broken up, and the suspension was stirred for another 2 h. The same
procedure was repeated, and the suspension was stirred for another 2 h. The mixture was cooled, and the
suspension was extracted with AcOEt (2 Â 80 ml). The combined org. layers were dried (Na2SO4) and
evaporated to give 2.67 g of crude product, which was purified by FC (heptane/AcOEt 10 :1) to yield 10
(2.16 g, 83%) as light-yellow foam.
Bis(2,2,2-trichloroethyl) 1-[(1RS,2SR,5SR,6SR)-6-(Methoxycarbonyl)bicyclo[3.1.0]hex-3-en-2-yl]-
hydrazine-1,2-dicarboxylate (12). A soln. of 9 (2.07 g, 15 mmol) and bis(2,2,2-trichloroethyl) azodicar-
boxylate (6.85 g, 18 mmol) in ClCH2CH2Cl (75 ml) was stirred for 16 h at 858 (oil bath). The soln. was
concentrated, and the residue (7.37 g) was purified by FC (heptane/AcOEt 10 :1) to yield 12 (6.21 g,
79%) as light-yellow foam. 1H-NMR (600 MHz, (D6)DMSO, 1208): 9.62 (br. s, NH); 5.89 (br. d, J ¼ 5.5,
HÀC(4’)); 5.56 (br. s, HÀC(2’)); 5.42 – 5.39 (m, HÀC(3’)); 4.86 (s, CH2O); 4.79 (br. s, CH2O); 3.50 (s,
MeO); 2.47 – 2.45 (m, 1 H) and 2.21 – 2.18 (m, 2 H) (HÀC(1’,5’,6’)). ESI-MS: 515 ([M À H]À).
Methyl (1RS,4RS,5SR,6SR)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate
(13). To a soln. of 10 (1.56 g, 3 mmol) in THF (13.5 ml), acetone (1.5 ml), and AcOH (3 ml) was
added Zn (4.68 g, 71.5 mmol) in small portions over 30 min. After 2 h, the mixture was filtered, and the
soln. was concentrated. MeOH (15 ml) and Et3N (1.38 ml, 9.9 mmol) were added, and the soln. was
cooled to 08. After addition of (tBoc)2O (720 mg, 3.3 mmol), the mixture was stirred for 5 h at ambient
temp. The soln. was concentrated, and the residue was dissolved in CH2Cl2 (50 ml). The org. phase was
washed with sat. NH4Cl soln. (2 Â 35 ml) and H2O (35 ml), dried (Na2SO4) and concentrated to give
689 mg of crude product, which was purified by FC (heptane/AcOEt 4 :1) to give 13 (563 mg 74%) as
colorless oil, which solidified on standing. An anal. sample was recrystallized (AcOEt, hexane). Rf
(heptane/AcOEt 4 :1) 0.41. M.p. 79.9 – 80.58. IR (ATR): 3355m, 3078w, 3055w, 2977w, 2933w, 1724m,
1680s, 1677s, 1505m, 1457w, 1435m, 1389w, 1366m, 1328w, 1321w, 1264m, 1254m, 1237m, 1172s, 1078w,
1046m, 1028m, 992w, 961w, 951w, 933w, 865m, 853w, 829w, 801w, 789w, 762w, 748w, 716w, 703w, 695w,
1
647w, 610w, 579w, 552w. H-NMR (600 MHz, CDCl3): 6.11 (dddd, J ¼ 5.5, 2.2, 1.3, 0.7, HÀC(2)); 5.50
(ddd, J ¼ 5.5, 1.8, 1.6, HÀC(3)); 4.64 – 4.51 (m, HÀC(4)), NH); 3.66 (s, MeO); 2.46 (dq, J ¼ 6, 2.2,
HÀC(1)); 2.30 – 2.25 (m, HÀC(5)); 1.46 (s, Me3C); 1.16 (br. dd, J ¼ 3.2, 2.2, HÀC(6)). 13C-NMR
(150 MHz, CDCl3): 171.6 (COOMe); 154.8 (NCOOC); 135.4 (C(2)); 130.2 (C(3)); 79.8 (NCOOC)); 57.2
(C(4)); 51.8 (MeO); 33.5, 33.1, 32.1 (C(1,5,6)); 28.4 (Me3C). ISP-MS: 270.9 ([M þ NH4]þ), 254.0 ([M þ
H]þ). Anal. calc. for C13H19NO4 (253.30): C 61.64, H 7.56, N 5.53; found C 61.66, H 7.50, N 5.55. Chiral
HPLC (Reprosil Chiral-NR): heptane/EtOH 90 :10, flow rate 1 ml/min, tR 8.00 min (À), tR 10.40 min (þ).
Methyl (1RS,4RS,5SR,6RS)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate
(14). To a soln. of 12 (5.19 g, 10 mmol) in THF (45 ml), acetone (5 ml), and AcOH (10 ml) was added
Zn (15.6 g, 23.9 mmol) in small portions over 45 min. After 6 h, the mixture was filtered, and the soln. was
concentrated. MeOH (50 ml) and Et3N (4.6 ml, 33 mmol) were added, and the soln. was cooled to 08.
After addition of (tBoc)2O (2.40 g, 11 mmol), the mixture was stirred for 5 h at ambient temp. The soln.
was concentrated, and the residue was dissolved in CH2Cl2 (200 ml). The org. phase was washed with sat.
NH4Cl soln. (2 Â 150 ml) and H2O (150 ml), dried (Na2SO4) and concentrated to give 2.46 g of crude
product, which was purified by FC (heptane/AcOEt 4 :1) to give 14 (2.05 mg, 80%) as colorless oil, which
solidified on standing. An anal. sample was recrystallized (AcOEt, hexane). Rf (AcOEt/heptane 1:4)
0.24. M.p. 98.5 – 99.08. IR (ATR): 3323w, 2980w, 2928w, 1724s, 1689s, 1521s, 1438m, 1386w, 1365m, 1300s,
1275w, 1263m, 1244w, 1206w, 1164s, 1148s, 1219s, 1084m, 1061m, 1041m, 1023m, 973m, 962m, 938w, 885m,
1
866w, 824w, 812w, 793w, 768w, 746m, 663m. H-NMR (600 MHz, CDCl3): 5.84 (br. d, J ¼ 5.5, HÀC(2));
5.68 (dtd, J ¼ 5.5, 1.8, 0.6, HÀC(3)); 4.93 (br. d, J ¼ 7.6, HÀC(4)); 4.51 (br. d, J ¼ 7.6, NH); 3.58 (s, MeO),
2.45 (ddt, J ¼ 8, 5.6, 2.4, HÀC(1)); 2.08 (tdd, J ¼ 8.0, 0.7, 0.6, HÀC(6)); 1.98 (br. dd, J ¼ 8.0, 5.6, HÀC(5));
1.46 (s, Me3C). 13C-NMR (75 MHz, CDCl3): 169.2 (COOMe); 154.8 (NCOOC); 132.3, 130.6 (C(2,3));
79.6 (Me3C); 55.1 (CN); 51.5 (MeO); 30.3, 29.6, 28.7 (C(1,5,6)); 28.4 (Me3C). ISP-MS: 270.1 ([M þ
NH4]þ), 254.1 ([M þ H]þ). Anal. calc. for C13H19NO4 (253.30): C 61.64, H 7.56, N 5.53; found C 61.41,

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Helvetica Chimica Acta – Vol. 98 (2015)
H 7.25, N 5.44. Chiral HPLC (Reprosil Chiral-NR): heptane/EtOH 90 :10, flow rate 1 ml/min, tR
10.00 min (þ), tR 10.49 min (À).
(1RS,2RS,5SR,6SR)-3-(tert-Butoxycarbonyl)-6-(methoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hex-
ane-2-carboxylic Acid (15). To a soln. of 13 (1.01 g, 4 mmol) in a mixture of MeCN (12 ml), CCl4 (12 ml),
and H2O (18 ml) was added NaIO4 (3.51 g, 16.4 mmol) followed by RuCl3 (18.3 mg, 0.088 mmol) at
ambient temp. After stirring for 4 h, the mixture was diluted with CH2Cl2 (25 ml) and H2O (10 ml). The
phases were separated, and the aq. phase was extracted with CH2Cl2 (2 Â 20 ml). The combined org.
extracts were dried (Na2SO4) and concentrated to give 1.06 g of light-red foam, which was purified by FC
(AcOEt/AcOH 95 :5) to give 15 (1.0 g, 88%) as white foam. An anal. sample was crystallized from
AcOEt. M.p. 126.5 – 127.38. IR (ATR): 3457w, 3188w (br.), 3086w, 2923s, 2853s, 2728w, 2614w, 1788s,
1730s, 1497w, 1396w, 1373w, 1306m, 1256m, 1150m, 1086m, 1058m, 1016m, 945w, 906w, 879w, 846w, 814w,
763w, 738w, 673w, 618w, 585w. 1H-NMR (600 MHz, CDCl3): 6.75 (br. s, COOH); 4.81 (d, J ¼ 6.0,
HÀC(2)); 3.72 (s, MeO); 2.70 (ddd, J ¼ 6.6, 6.0, 2.8, HÀC(1)); 2.59 (dd, J ¼ 6.6, 2.8, HÀC(5)); 2.40 (t, J ¼
2.8, HÀC(6)); 1.47 (s, Me3C). 13C-NMR (150 MHz, CDCl3): 172.9, 169.6, 169.0 (C(4), COOMe,
COOH)); 148.9 (NCO); 84.6 (Me3C), 58.2 (C(2)); 52.7 (MeO)); 29.3 (C(5)); 27.6 (Me3C); 22.0, 21.9
(C(1,6)). ISP-MS: 301.4 ([M þ H]þ). Anal. calc. for C13H17NO7 (299.28): C 52.17, H 5.73, N 4.68; found C
51.74, H 5.76, N 4.63.
(1RS,2RS,5SR,6RS)-3-(tert-Butoxycarbonyl)-6-(methoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hex-
ane-2-carboxylic Acid (16). To a soln. of 14 (507 mg, 2 mmol) in a mixture of MeCN (6 ml), CCl4 (6 ml),
and H2O (9 ml) was added NaIO4 (1.75 g, 8.2 mmol), followed by RuCl3 (9.92 mg, 0.044 mmol) at
ambient temp. After stirring for 4 h, the mixture was diluted with CH2Cl2 (15 ml) and H2O (5 ml). The
phases were separated, and the aq. phase was extracted with CH2Cl2 (2 Â 15 ml). The combined org.
extracts were dried (Na2SO4) and concentrated to give 581 mg of light-red foam, which was separated by
FC (AcOEt/AcOH 95 :5) to yield 16 as white foam (491 mg, 82%). An anal. sample was crystallized from
AcOEt. M.p. 144.1 – 146.28. IR (ATR): 3276w (br.), 2967w, 1780s, 1752s, 1731m, 1685m, 1476w, 1435w,
1395w, 1369w, 1350m, 1336m, 1314m, 1301m, 1254w, 1211s, 1151s, 1093w, 1076m, 1054w, 1016m, 984m,
957m, 944s, 918w, 869w, 854m, 835w, 824m, 779m, 763w, 734w, 694m. 1H-NMR (600 MHz, CDCl3): 4.92
(d, J ¼ 6.4, HÀC(2)); 3.71 (s, MeO); 2.74 (br. s, COOH); 2.59 (dt, J ¼ 8.6, 6.4, HÀC(1)); 2.53 (dd, J ¼ 8.6,
6.4, HÀC(5)); 2.25 (t, J ¼ 8.6, HÀC(6)); 1.49 (s, Me3C). 13C-NMR (75 MHz, CDCl3/(D6)DMSO (1 drop)):
169.2, 169.0, 167.0 (C(4), COOMe, COOH); 147.9 (NCO); 82.5 (Me3C); 57.5 (C(2)); 51.7 (MeO); 27.3
(Me3C); 26.0, 24.7 (C(5,6)); 21.4 (C(1)). ISP-MS: 300.11 ([M þ H]þ). Anal. calc. for C13H17NO7 (299.28):
C 52.17, H 5.73, N 4.68; found C 51.79, H 5.61, N 4.60.
(1RS,2RS)-3-[(SR)-Amino(carboxy)methyl]cyclopropane-1,2-dicarboxylic Acid (17). A soln. of 15
(299 mg, 1 mmol) in 10% HCl (10 ml) was heated at 1008 (oil bath) for 3 h. The soln. was cooled to r.t.
and concentrated to give 281 mg of crude product, which was submitted to ion exchange chromatography
(Dowex 50WX4, elution with 12.5% NH3 · H2O) to give 17 (205 mg, 86%) as white, hygroscopic foam
(diammonium salt). 1H-NMR (600 MHz, D2O): 3.95 (d, J ¼ 9.9, HÀC(2’)); 2.09 (dd, J ¼ 9.5, 5.0,
HÀC(3)); 1.98 (dd, J ¼ 5.6, 5.0, HÀC(2)); 1.83 (ddd, J ¼ 9.9, 9.5, 5.6, HÀC(1)). 13C-NMR (150 MHz,
D2O): 178.8, 177.1, 173.5 (3 CO); 52.2 (C(2’)); 29.5, 28.4, 26.9 (C(1,2,3)). LC/HR-MS: 203.0439
(C7H9NOþ6 ; calc. 203.0429).
(1RS,2SR,3rs)-3-[(RS)-Amino(carboxy)methyl]cyclopropane-1,2-dicarboxylic Acid (18). A soln. of
16 (213 mg, 0.71 mmol) in 10% HCl (8 ml) was heated at 1008 (oil bath) for 3 h. The soln. was cooled to
r.t. and concentrated to give 253 mg of crude product, which was submitted to ion exchange
chromatography (Dowex 50WX4, elution with 12.5% NH3 · H2O) to give 18 (143 mg, 84%) as white,
hygroscopic foam (diammonium salt). 1H-NMR (600 MHz, D2O): 4.44 (d, J ¼ 10.9, HÀC(2’)); 2.17 – 2.08
(m, HÀC(1,2)); 1.64 (dt, J ¼ 10.9, 8.7, HÀC(3)). 13C-NMR (150 MHz, D2O): 176.1, 175.8, 174.6 (3 CO),
51.1 (C(2’)), 29.5, 28.4, 26.9 (C(1,2,3)). LC/HR-MS: 203.0448 (C7H9NOþ6 ; calc. 203.0429).
Methyl (1R,4R,5S,6S)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate ((À)-
13) and Methyl (1R,4R,5S,6R)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate
((À)-14). To a soln. of (1S,5R)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one ((À)-1; 4.43 g, 25 mmol;
[a]D ¼ À89.8 (c ¼ 1 in CHCl3) ([a]D ¼ À81.0 (c ¼ 0.75 in CHCl3) [20]) in AcOH (125 ml) was added with
stirring and cooling Zn (1.64 g, 25 mmol) in small portions over a period of 30 min. The soln. was diluted
with H2O (150 ml) and extracted with AcOEt (3 Â 120 ml). The org. layer was washed with H2O

Helvetica Chimica Acta – Vol. 98 (2015)
1199
(200 ml), sat. NaHCO3 soln. (2 Â 200 ml), dried (Na2SO4), and concentrated to give a mixture (92 :8) of
(1S,5R,7S)-7-chlorobicylo[3.2.0]hept-2-en-6-one and (1S,5R,7R)-7-chlorobicylo[3.2.0]hept-2-en-6-one
(3.56 g, 97%) as light-yellow oil, which was used for the next step without further purification.
A mixture (92 :8) of (1S,5R,7S)-7-chlorobicylo[3.2.0]hept-2-en-6-one and (1S,5R,7R)-7-chlorobicy-
lo[3.2.0]hept-2-en-6-one (3.46 g, 24.3 mmol) was added dropwise to a soln. of KOH (9.53 g, 170 mmol) in
a mixture of H2O (105 ml) and dioxane (45 ml) at ambient temp. After 30 min, the soln. was acidified to
pH ¼ 1 with 25% HCl. The aq. phase was extracted with CH2Cl2 (3 Â 100 ml), dried (Na2SO4), and
concentrated to give a 3 :1 mixture (HÀC(2) signal in 1H-NMR spectrum) of (1S,5R,6S)-bicyclo[3.1.0]-
hex-2-ene-6-carboxylate and (1S,5R,6R)-bicyclo[3.1.0]hex-2-ene-6-carboxylate (2.85 g, 94%) as white
solid, which was used directly for the next step.
To a soln. of a mixture (3 :1) of (1S,5R,6S)-bicyclo[3.1.0]hex-2-ene-6-carboxylate and (1S,5R,6R)-
bicyclo[3.1.0]hex-2-ene-6-carboxylate (2.85 g, 23 mmol) in MeOH (100 ml) and 2,2-dimethoxypropane
(35 ml) was added TsOH (1.09 g, 5.74 mmol), and the soln. was stirred for 24 h at 408. The soln. was
partly concentrated, then H2O (80 ml) and Et2O (80 ml) were added. The layers were separated, and the
aq. phase was extracted with Et2O (80 ml). The combined org. layers were washed with 0.5n NaOH
(80 ml), H2O (80 ml), and brine (80 ml), dried (NaSO4), and evaporated to give light-yellow oil (2.84 g),
which was distilled (Kugelrohr, 75 – 808, 0.5 Torr) to yield a 3 :1 mixture (MeO signal in 1H-NMR-
spectrum) of methyl (1S,5R,6S)-bicyclo[3.1.0]hex-2-ene-6-carboxylate and methyl (1S,5R,6R)-bicy-
clo[3.1.0]hex-2-ene-6-carboxylate as colorless oil (2.41 g, 76%).
A soln. of methyl (1S,5R,6S)-bicyclo[3.1.0]hex-2-ene-6-carboxylate and methyl (1S,5R,6R)-bicy-
clo[3.1.0]hex-2-ene-6-carboxylate (3 :1) (2.07 g, 15 mmol) and bis(2,2,2-trichloroethyl) azodicarboxylate
(6.85 g, 18 mmol) in ClCH2CH2Cl (75 ml) was stirred at 858 (oil bath) for 16 h. The mixture was
concentrated, and the residue was purified by FC (heptane/AcOEt 4 :1) to give bis(2,2,2-trichloroethyl)
1-[(1S,2R,5R,6S)-6-(methoxycarbonyl)bicyclo[3.1.0]hex-3-en-2-yl]hydrazine-1,2-dicarboxylate and
bis(2,2,2-trichloroethyl) 1-[(1S,2R,5R,6R)-6-(methoxycarbonyl)bicyclo[3.1.0]hex-3-en-2-yl]hydrazine-
1,2-dicarboxylate (6.18 g, 79%; 3 :1) as colorless foam.
To a soln. of bis(2,2,2-trichloroethyl) 1-[(1S,2R,5R,6S)-6-(methoxycarbonyl)bicyclo[3.1.0]hex-3-en-
2-yl]hydrazine-1,2-dicarboxylate and bis(2,2,2-trichloroethyl) 1-[(1S,2R,5R,6R)-6-(methoxycarbonyl)bi-
cyclo[3.1.0]hex-3-en-2-yl]hydrazine-1,2-dicarboxylate (3 :1 mixture) (3.11 g, 6 mmol) in THF (27 ml),
acetone (3 ml) and AcOH (6 ml) was added Zn (9.33 g, 143 mmol) in small portions over 30 min. After
5 h, the mixture was filtered, and the soln. was concentrated. MeOH (30 ml) and Et3N (2.76 ml,
19.8 mmol) were added, and the soln. was cooled to 08. After addition of (tBoc)2O (1.44 g, 6.6 mmol), the
mixture was stirred for 5 h at ambient temp. The soln. was concentrated, and the residue was dissolved in
CH2Cl2. The org. phase was washed with sat. NH4Cl soln. (2 Â 60 ml) and H2O (60 ml), dried (Na2SO4),
and concentrated to give 1.29 g of crude product, which was purified by FC (heptane/AcOEt 4 :1) and
crystallized (AcOEt, hexane) to give (À)-13 (0.89 g, 59%) as colorless needles, Rf (heptane/AcOEt 4 :1)
0.39. 1H-NMR spectrum identical to 13. M.p. 84.4 – 85.18, [a]D ¼ À195.7 (c ¼ 1 in CHCl3), chiral HPLC
(Reprosil Chiral-NR): heptane/EtOH 90 :10, flow rate 1 ml/min, tR 8.29 min (À) and (À)-14 (0.23 g, 15%)
as colorless needles. Rf (heptane/AcOEt 4 :1) 0.24. 1H-NMR spectrum identical to 14. M.p. 92.6 – 93.08,
[a]D ¼ À375.8 (c ¼ 1 in CHCl3), chiral HPLC (Reprosil Chiral-NR): heptane/EtOH 90 :10, flow rate
1 ml/min, tR 10.31 min (À).
Methyl (1S,4S,5R,6R)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate ((þ)-
13) and Methyl (1S,4S,5R,6S)-4-[(tert-Butoxycarbonyl)amino]bicyclo[3.1.0]hex-2-ene-6-carboxylate
((þ)-14). Using the same sequence as above but starting with (1R,5S)-7,7-dichlorobicyclo[3.2.0]hept-
2-en-6-one ([a]D ¼ þ87.1 (c ¼ 1 in CHCl3) ([a]D ¼ þ83.9 (c ¼ 0.75 in CHCl3) [20]) afforded (þ)-13
(1.46 g), Rf (heptane/AcOEt 4 :1) 0.40. 1H-NMR spectrum identical to 13. M.p. 83.8 – 84.48, [a]D ¼
þ181.5 (c ¼ 1 in CHCl3), chiral HPLC (Reprosil Chiral-NR): heptane/EtOH 90 :10, flow rate 1 ml/
1
min, tR 10.60 min (þ) and (þ)-14 (0.49 g) as colorless needles, Rf (heptane/AcOEt 4 :1) 0.24. H-NMR
spectrum identical to 14. M.p. 91.9 – 92.48, [a]D ¼ þ368.5 (c ¼ 1 in CHCl3), chiral HPLC (Reprosil Chiral-
NR): heptane/EtOH 90 :10, flow rate 1 ml/min, tR 9.79 min (þ) were obtained.
(1R,2R,5S,6S)-3-(tert-Butoxycarbonyl)-6-(methoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-
carboxylic Acid ((þ)-15). To a stirred soln. of (þ)-13 (506 mg, 2 mmol) in a mixture of MeCN (6 ml),
CCl4 (6 ml), and H2O was added NaIO4 (1.75 g, 8.19 mmol) followed by RuCl3 (9.91 mg, 0.044 mmol) at

1200
Helvetica Chimica Acta – Vol. 98 (2015)
ambient temp. After stirring for 4 h, the mixture was diluted with CH2Cl2 (15 ml) and H2O (10 ml). The
phases were separated, and the aq. phase was extracted with CH2Cl2 (2 Â 20 ml). The combined org.
extracts were dried (Na2SO4), filtered, and concentrated to give 0.565 g of light-red foam, which was
purified by FC (AcOEt/AcOH 95 :5 to give (þ)-15 (543 mg, 90%) as white solid. An anal. sample was
1
recrystallized (AcOEt), H-NMR spectrum identical to 15. M.p. 117.2 – 118.58. [a]D ¼ þ85.6 (c ¼ 1 in
CHCl3).
(1S,2S)-3-[(R)-Amino(carboxy)methyl]cyclopropane-1,2-dicarboxylate ((þ)-17). A soln. of (þ)-15
(150 mg, 0.50 mmol) in 10% HCl (5 ml) was heated at 1008 for 3 h. The soln. was cooled to r.t. and
concentrated to deliver 178 mg of crude product, which was submitted to ion exchange chromatography
(Dowex 50WX4, elution with 12.5% NH3 · H2O) to give (þ)-17 (98 mg, 82%) as white, hygroscopic foam
1
(diammonium salt), H- und 13C-NMR spectra identical to 17, [a]D ¼ þ22.3 (c ¼ 1 in H2O).
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Received June 26, 2015