Synthesis of (S)-7-amino-5-azaspiro[2.4]heptane via highly enantioselective hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropanecarboxylates

Article abstract of DOI:10.1021/jo2002165

Highly effective asymmetric hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropane carboxylates in the presence of [RuCl(benzene)(S)-SunPhos]Cl was realized, and high enantioselectivities (up to 98.7% ee) were obtained. This asymmetric hydrogenation provides a key intermediate for the enantioselective synthesis of (S)-7-amino-5-azaspiro[2.4] heptane moiety of quinolone antibacterial agents.

Full text of DOI:10.1021/jo2002165

ARTICLE
pubs.acs.org/joc
Synthesis of (S)-7-Amino-5-azaspiro[2.4]heptane via Highly
Enantioselective Hydrogenation of Protected Ethyl
1-(2-Aminoaceto)cyclopropanecarboxylates
Ying Yao,† Weizheng Fan,† Wanfang Li,† Xin Ma,† Lvfeng Zhu,‡ Xiaomin Xie,† and Zhaoguo Zhang†,§,*
†School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
‡School of Chemical Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing 210094, China
§Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
S Supporting Information
b
ABSTRACT: Highly effective asymmetric hydrogenation
of protected ethyl 1-(2-aminoaceto)cyclopropane carboxy-
lates in the presence of [RuCl(benzene)(S)-SunPhos]Cl was
realized, and high enantioselectivities (up to 98.7% ee) were
obtained. This asymmetric hydrogenation provides a key inter-
mediate for the enantioselective synthesis of (S)-7-amino-5-
azaspiro[2.4]heptane moiety of quinolone antibacterial agents.
’ INTRODUCTION
have also been examined intensively for the hydrogenation of
β-keto esters.8 In contrast, there are limited substrates being
investigated, usually restricted to simple β-alkyl or aryl substit-
uents. Since notably lower enantioselectivities were usually
observed due to the competitive coordination to the catalyst,
only a few investigations have been dedicated to the use of subs-
trates bearing adjacent coordinating groups, such as a benzyloxyl
group,9 alkoxyl group,10 halogen atoms,8c,11 tert-butoxycarbony-
lamino group,11d or a double bond11e in the vicinity of the keto
group. Consequently, asymmetric hydrogenation of β-ketoesters
bearing adjacent functional coordinating groups is still a
challenging work.
Recently we designed new biaryl phosphine ligands and
exploited their applications in ruthenium-catalyzed asymmetric
hydrogenation of simple β-keto esters,12a,b R-keto esters12cꢀg
and β-keto sulfones12h with excellent enantioselectivities. In this
paper, we disclose a highly enantioselective hydrogenation of
ethyl 1-(2-aminoaceto)cyclopropanecarboxylates with a variety
of amino-protecting groups.
Asymmetric reactions catalyzed by transition metals represent
one of the most powerful tools for the synthesis of enantiomeri-
cally pure pharmaceuticals, agrochemicals, flavoring agents, and
other fine chemicals.1 In particular, asymmetric hydrogenation
has attracted significant interest both in industry and in academia
for its synthetic utility.2 The therapeutic use of certain pyrido-
[1,2-a]pyrimidine and quinolone antibacterial agents, such as
Sitafloxacin and Olamufloxacin (Figure 1), are well-known.3
Both molecules contain the (S)-7-amino-5-azaspiro[2.4]heptane
moiety, which can be synthesized from an optically active tartrate
ester intermediate or stereoselective microbial reduction of
5-benzyl-4,7-dioxo-5-azaspiro[2.4]heptane.4 However, both syn-
thetic routes suffer either low enantioselectivity or efficiency.
Abbott reported a more efficient process for enantioselective
synthesis of 3-aminopyrrolydine derivatives by using enantio-
merically pure ethyl 1-(2-{[(benzyloxy)carbonyl]amino}-1-hy-
droxyethyl)cyclopropanecarboxylate as a key intermediate.5
Accordingly, the search for effective, highly enantioselective,
and practical approaches to optically synthesize pure ethyl
1-(2-amino-1-hydroxyethyl)cyclopropanecarboxylate is of
significance.
’ RESULTS AND DISCUSSION
Subtle changes in geometric, steric, and/or electronic proper-
ties of chiral ligands can lead to dramatic variations of reactivity
and enantioselectivity.8a,13 To test these effects, Ru-catalyzed
Asymmetric hydrogenation of β-keto esters has been exten-
sively studied, especially with ruthenium catalysts.6 It has been
proven that several Ru-BINAP complexes give high enantios-
electivities for a wide variety of β-keto esters.7 Ruthenium cata-
lysts with structurally similar chiral atropisomeric biaryl ligands
Received: January 28, 2011
Published: March 17, 2011
r
2011 American Chemical Society
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|

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Table 2. Effects of Solvent and Temperaturea
entry
solvent
T (°C)
convn (%)
ee (%)b
1
2
3
4
5
6
7
MeOH
EtOH
i-PrOH
DCM
THF
70
70
70
70
70
50
90
100
100
100
100
79.1
100
100
95.1
97.1
95.0
29.7
4.3
Figure 1. Structures of Sitafloxacin and Olamufloxacin.
EtOH
95.9
EtOH
95.1
a All reactions were carried out with a substrate (0.5 mmol) concentra-
tion of 0.2 M in ethanol under 20 bar of H2 for 18 h, substrate/[Ru-
(benzene)Cl2]2/(S)-SunPhos
=
100/0.5/1.1. b ee values were
determined by HPLC on a Chiralpak OD-H column.
Table 3. Effectsof AdditivesonCatalytic Hydrogenationof1aa
Figure 2. Strutures of chiral bidentate ligands.
Table 1. Catalytic Asymmetric Hydrogenation of 1a with
[RuCl(benzene)L]Cla
entry
additive
1 M HCl
ee (%)b
1
76.4
85.3
89.6
77.7
85.0
95.8
81.4
93.9
96.1
83.2
2
1 M HBr
3
1 M HI
4
1 M H2SO4
1 M CF3COOH
1 M H3BO3
1 M CSA
H2O
5
entry
ligand
ee (%)b
6
1
2
3
4
5
6
7
(R)-BINAP
(S)-C3-TunePhos
(S)-SEGPhos
(S)-SunPhos
L5
92.5
94.4
95.3
97.1
96.5
95.2
95.5
7
8c
9
CeCl3 7H2O
3
10
I2
a All reactions were carried out with a substrate (0.5 mmol) concentra-
tion of 0.2 M in EtOH under 20 bar of H2 at 70 °C for 18 h,
substrate/[Ru(benzene)Cl2]2/(S)-SunPhos/additive = 100/0.5/1.1/6.
Conversion: 100%. b ee values were determined by HPLC on a
Chiralpak OD-H column. c 0.03 mL of H2O.
L6
L7
a All reactions were carried out with a substrate (0.5 mmol) concentra-
tion of 0.2 M in EtOH under 20 bar of H2 for 18 h, substrate/[Ru-
(benzene)Cl2]2/ligand = 100/0.5/1.1. Conversion: 100%. No ring-
opening product was detected. b ee values were determined by HPLC
on a Chiralpak OD-H column.
ee values of reduced product 2a were increased with the
reduction of the dihedral angles of the chiral ligands: (R)-BINAP
(92.5% ee, dihedral angle:13d 86°), (S)-C3-TunePhos (94.4% ee,
dihedral angle:13b 77°), (S)-SEGPhos (95.3% ee, dihedral
angle:13d 67°). We were pleased to see that the highest ee was
obtained with (S)-SunPhos (97.1%), which may because the bite
angle of the [Ru((S)-SunPhos)(benzene)Cl]Cl (73°) was smal-
ler than that of (S)-SEGPhos (75°).12a With L5ꢀL7 as ligands,
the corresponding ee values of 96.5%, 95.2%, and 95.5% were
achieved (Table 1), which revealed that the modifications of
SunPhos on P atom did not impose a remarkable change in
enantioselectivity in the asymmetric hydrogenation of 1a.
Results of the optimization of solvents and reaction tempera-
tures are summarized in Table 2. Solvent is important for the
efficiency and enantioselectivity of the asymmetric hydrogenation
(Table 2, entries 1ꢀ5). Protonic solvents resulted in high catalytic
asymmetric hydrogenation of ethyl 1-{2-[(benzyloxycarbonyl)-
amino]acetyl}cyclopropanecarboxylate (1a) with the chiral bi-
dentate ligands (S)-SunPhos, L5ꢀL7, and three commercially
available chiral bidentate phosphines, (R)-BINAP, (S)-SEG-
Phos, and (S)-C3-TunePhos (Figure 2), were performed under
the same reaction conditions (Table 1). The catalyst was
prepared from [Ru(benzene)Cl2]2 and a diphosphine ligand
by refluxing them in degassed ethanol/dichloromethane for 1 h
and then dried under reduced pressure.12 The asymmetric
hydrogenation was carried out under 20 bar of H2, at 70 °C in
EtOH for 18 h with 1 mol % of Ru(II) catalyst. While these
ligands show similar reactivity, the enantioselectivity was greatly
dependent on the ligand employed. As illustrated in Table 1, the
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Table 4. Asymmetric Hydrogenation of 1 with
Scheme 1. Synthesis of (S)-7-Amino-5-azaspiro[2.4]heptane
dihydrochloride
[RuCl(benzene)(S)-SunPhos]Cla
entry
R
ee (%)
97.1b
1
Cbz (1a)
2
Phth (1b)
84.7b
82.4b
97.5c
3
Bz (1c)
4
Ms (1d)
5
Ts (1e)
98.1b
98.3b
97.0b
94.8c
98.2c
96.6c
6
Fmoc (1f)
PhOCO (1g)
Cl3CCH2OCO (1h)
EtOCO (1i)
i-BuOCO (1j)
Boc (1k)
7
hydrogenated, as presented in Table 4. Noyori et al. had reported
that using electron-withdrawing amino-protecting groups may
reduce the competitive directing effects of the amino group
versus the ester group within one molecule.11d,15 Therefore we
employ electron-withdarwing rather than electron-donating
amino groups in our study (when dibenzyl was used as amino-
protecting group, ee dropped to 11%; see Supporting In-
formation). In all cases, complete conversions were obtained.
The enantioselectivities were highly influenced by amino-pro-
tecting groups: phthaloyl-protected substrate (1b) and benzoyl-
protected substrate (1c) gave moderate enantioselectivities: 2b
of 84.7% ee and 2c of 82.4% ee were obtained, respectively
(entries 2, 3). When sulfonyls were employed as amino-protect-
ing groups, enantioselectivities for the hydrogenation turned out
to be very high: product 2d was obtained at 97.5% ee and 2e at
98.1% ee (entries 4, 5). The presence of carbamate-protecting
group gave even better ee values, ranging from 94.8% to 98.7%
(entries 6ꢀ11). The employment of tert-butyloxycarbonyl group
had accomplished the highest enantioselectivity (up to 98.7%
ee). When 1a was hydrogenated with [RuCl(benzene)(S)-
SunPhos]Cl (S/C = 500/1) under the same reaction conditions,
2a was also isolated in full conversion and 96.2% ee (entry 12),
and via recrystallization, 2a can be upgraded to 98.9% ee with
95% recovery.
8
9
10
11
12d
98.7c
96.2 (98.9)e
Cbz (1a)
a All reactions were carried out with a substrate (0.5 mmol) concentra-
tion of 0.2 M in EtOH under 20 bar of H2 at 70 °C for 18 h,
substrate/[Ru(benzene)Cl2]2/(S)-SunPhos = 100/0.5/1.1. Conver-
sion: 100%. b ee values were determined directly by HPLC. c ee values
were determined through their corresponding p-nitrobenzoyl deriva-
tives 3d, 3h, 3i, 3j, 3k (see Experimental Section). d S/C = 500/1, 24 h.
e The second ee value was examined after one recrystallization.
activities and enantioselectivities, providing complete conversions of
1a to 2a with ee values ranging from 95.0% (entry 3) to 97.1% (entry
2). Aprotonic solvents such as dichloromethane gave only 29.7% ee
(entry 4), while THF gave even poorer ee of 4.3% and 79.1%
conversion (entry 5). Temperatures can also influence the enantios-
electivities (entry 2 vs 6, 7). Higher or lower the temperature may
also slightly reduce the ee values.
It has been reported that additives play a crucial role in
improving the reactivity and enantioselectivities in many asym-
metric reactions.14 In our preliminary work, we used aqueous
solutions of Brønsted acids or Lewis acids as additives and
achieved better results.12 Accordingly, we evaluated a number
of commonly used additives for the asymmetric hydrogenation of
1a by using 1 mol % of [RuCl(benzene)(S)-SunPhos]Cl as
catalyst and 6 mol % of additives in an attempt to promote the
enantioselectivity (Table 3). Unfortunately, the results did not
turn out as we had expected. Using aqueous solutions of
Brønsted acids as additives (entries 1ꢀ7), ee values decreased
greatly, ranging from 76.4% to 89.6%, except for H3BO3, where
the enantioselectivity remained. To find out what caused the
enantioselectivity decrease, control test was performed (entry 8).
The result showed that H2O probably caused a slight decrease of
ee value. Therefore, Brønsted acids were unfavorable for this
(S)-7-Amino-5-azaspiro[2.4]heptane can be prepared from 2a
through a five-step transformation as outlined in Scheme 1. After
methanesulfonation and azidation, compound 4 was produced in
high yield. Reduction, deprotection, and cyclization of 4 was
realized in one step and gave 5 in 90% yield and 98.9% ee, which
was then converted to (S)-7-amino-5-azaspiro[2.4]heptane di-
hydrochloride (6) by reduction with LAH followed by salifica-
tion in methanol in 92% yield over two steps.
’ CONCLUSION
In conclusion, we have developed a convenient protocol for
highly enantioselective synthesis of protected ethyl 1-(2-amino-
1-hydroxyethyl)cyclopropanecarboxylate by hydrogenation of
protected ethyl 1-(2-aminoaceto)cyclopropanecarboxylate. This
established a potentially practical mean for the synthesis of (S)-7-
amino-5-azaspiro[2.4]heptane, which is a key intermediate of
quinolone antibacterial agents.
reaction. Lewis acid, for example, CeCl3 7H2O, wastried(entry9),
3
but the result was no better than those without additives. Using
iodine as additive, the ee value decreased to 83.2% (entry 10).
On the basis of these results, the optimized reaction conditions
were therefore set as the following: 1 mol % of [RuCl(benzene)(S)-
SunPhos]Cl as the catalyst, EtOH as the solvent with a substrate
concentration of 0.2 M, and 20 bar of H2 at 70 °C.
’ EXPERIMENTAL SECTION
Under the optimized reaction conditions, a variety of pro-
tected ethyl 1-(2-aminoaceto)cyclopropanecarboxylates were
General. Commercially available reagents were used throughout
without further purification other than those detailed below. Methylene
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ARTICLE
chloride was distilled over calcium hydride. Ethanol was distilled over
magnesium under nitrogen. All reactions were carried out under an
atmosphere of nitrogen using standard Schlenk techniques or in a
nitrogen-filled glovebox, unless otherwise noted. 1H NMR spectra were
recorded at 400 MHz, with TMS as internal standard. 13C NMR spectra
were obtained at 100 MHz and referenced to the central peak of 77.00
ppm for CDCl3. Coupling constants (J) are reported in hertz and refer to
apparent peak multiplications. Mass spectroscopy data were collected on
an HRMS-EI instrument. Flash column chromatography was performed
on silica gel (300ꢀ400 mesh). [R]D values are given in deg cm2 gꢀ1 and
were recorded at the D-line of sodium (589 nm) at 20 °C.
Preparation of Ethyl 1-Acetylcyclopropanecarboxylate
(S1)16. A mixture of ethyl acetoacetate (66.0 g, 0.51 mol), 1,2-
dibromoethane (141.0 g, 0.75 mol), and anhydrous K2CO3 (260.3 g,
1.88 mol) was stirred in 600 mL of DMSO at room temperature
overnight, after which it was diluted with an equal volume of water
and then extracted with ether (300 mL ꢁ 3). The ether extract was
washed with water and dried with anhydrous Na2SO4. After removal of
the ether by distillation, the residue was distilled in vacuo. Colorless
product was obtained (65.0 g, 82%). 1H NMR (400 MHz, CDCl3): 4.21
(q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.47 (s, 4H), 1.29 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3): 203.0, 170.9, 61.1, 34.9, 29.8, 19.0, 13.9.
Preparation of Ethyl 1-(2-Azidoacetyl)cyclopropanecar-
boxylate (S2). To a solution of ethyl 1-acetylcyclopropanecar-
boxylate (46.4 g, 0.30 mol) in EtOH (250 mL) was added Br2
(22.8 mL, 0.45 mol) dropwise over 20 min in an ice bath. After the
solution was warmed at 25ꢀ30 °C for 80 min, water (250 mL) was
added and the lower layer (organic layer) was separated. The upper layer
was concentrated in vacuo and extracted with AcOEt (100 mL ꢁ 3). The
organic layers were combined and washed with aqueous 10% Na2S2O3
solution, saturated aqueous NaHCO3 solution, and brine. The washed
organic solution was dried over anhydrous Na2SO4 and concentrated in
vacuo to give the product (52.0 g, 74.5%) as colorless oil, which was used
for the next reaction without further purification.
A 250 mL three-necked flask was charged with ethyl 1-(2-bromoa-
cetyl)cyclopropanecarboxylate (52.0 g, 221 mmol), acetonitrile
(150 mL), and sodium azide (15.8 g, 243 mmol) in the flowing nitrogen
gas and the mixture was stirred at room temperature for 20 h. The
produced sodium salt was separated by filtration and the solvent was
distilled under reduced pressure. The residue was dissolved into EtOAc
(150 mL) and washed with saturated brine (80 mL). The washed
organic solution was dried over anhydrous Na2SO4 and concentrated in
vacuo to obtain 47.0 g of a crude product, which was purified by column
chromatography (PE/EA = 20/1) to give the desired product (39.7
g, 91%). 1H NMR (400 MHz, CDCl3): 4.52 (d, J = 2.2 Hz, 2H), 4.20 (q,
J = 7.2 Hz, 2H), 1.63 (s, 4H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): 199.9, 170.1, 61.4, 58.2, 33.3, 21.1, 14.0. HRMS: calcd for
C8H11N3O3 (M þ H)þ 198.0879, found 198.0866.
over anhydrous Na2SO4 and concentrated in vacuo to give 6.7 g of crude
product, which was purified by column chromatography (PE/EA = 6/1)
to give the compound ethyl 1-[2-(benzyloxycarbonylamino)acetyl]-
cyclopropanecarboxylate (1a) (5.9 g, 76%). 1H NMR (400 MHz,
CDCl3): 7.36ꢀ7.29 (m, 5H), 5.47 (s, 1H), 5.11 (s, 2H), 4.59 (d, J =
5.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.58 (s, 4H), 1.29 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): 200.9, 170.1, 156.1, 136.3, 128.4,
128.0, 127.9, 66.8, 61.4, 50.9, 33.3, 20.9, 14.0. HRMS: calcd for
C16H19NO5 (M þ Na)þ 328.1161, found 328.1168.
Likewisely, compounds 1bꢀk were prepared from the corresponding
amino-protecting groups and ethyl 1-(2-aminoaceto)cyclopropane-
carboxylate.
Ethyl 1-[2-(1,3-Dioxoisoindolin-2-yl)acetyl]cyclopropa
1
necarboxylate (1b). H NMR (400 MHz, CDCl3): 7.88ꢀ7.84 (m,
2H), 7.75ꢀ7.70 (m, 2H), 5.09 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H),
1.69ꢀ1.63 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 198.0, 170.3, 167.8, 134.0, 132.1, 123.4, 61.5, 47.4, 33.5, 22.0,
14.1. HRMS: calcd for C16H15NO5 (Mþ) 301.0950, found 301.0947.
Ethyl 1-(2-Benzamidoacetyl)cyclopropanecarboxylate
(1c). 1H NMR (400 MHz, CDCl3): 7.83ꢀ7.80 (m, 2H), 7.54ꢀ7.42 (m,
3H), 6.95 (s, 1H), 4.86 (d, J = 4.8 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H),
1.67ꢀ1.60 (m, 4H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 201.1, 170.1, 167.2, 134.0, 131.6, 128.6, 127.0, 61.6, 50.0, 33.6,
21.1, 14.1. HRMS: calcd for C15H17NO4 (Mþ) 275.1158, found
275.1156.
Ethyl 1-[2-(Methylsulfonamido)acetyl]cyclopropaneca-
rboxylate (1d). H NMR (400 MHz, CDCl3): 5.12 (t, J = 4.8 Hz,
1
1H), 4.62 (d, J = 5.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.96 (s, 3H),
1.70ꢀ1.62 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 200.7, 167.0, 109.7, 61.6, 52.4, 40.7, 33.2, 21.9, 14.0. HRMS:
calcd for C9H15NO5S (M þ Na)þ 272.0582, found 272.0572.
Ethyl 1-[2-(4-Methylphenylsulfonamido)acetyl]cyclopro-
1
panecarboxylate (1e). H NMR (400 MHz, CDCl3): 7.76ꢀ7.73
(m, 2H), 7.31ꢀ7.29 (m, 2H), 5.37 (t, J = 5.0 Hz, 1H), 4.42 (d, J = 5.0 Hz,
2H), 4.17 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.59ꢀ1.56 (m, 2H),
1.46ꢀ1.43 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 199.8, 169.8, 143.6, 136.2, 129.6, 127.2, 61.5, 52.1, 33.2, 21.9,
21.5, 14.0. HRMS: calcd for C15H19NO5S (Mþ) 325.0984, found
325.0979.
Ethyl 1-(2-{[(9H-Fluoren-9-yl)methoxy]carbonylamino}
acetyl)cyclopropanecarboxylate (1f). 1H NMR (400 MHz,
CDCl3): 7.78ꢀ7.29 (m, 8H), 5.50 (s, 1H), 4.62 (d, J = 5.2 Hz, 2H),
4.39 (d, J = 7.2 Hz, 2H), 4.22 (q, J = 7.1 Hz, 3H), 1.62ꢀ1.60 (m, 4H),
1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 201.0, 170.1,
156.1, 143.8, 141.2, 127.6, 127.0, 125.0, 119.9, 67.0, 61.4, 50.9, 47.1, 33.4,
21.0, 14.0. HRMS: calcd for C23H23NO5 (Mþ) 393.1576, found
393.1573.
Ethyl 1-[2-(Phenoxycarbonylamino)acetyl]cyclopropa
1
Typical Procedure for the Preparation of 1. A 50 mL round
flask was charged with ethyl 1-(2-azidoacetyl)cyclopropanecarboxylate
(5.0 g, 25.4 mmol), EtOH (25 mL), 5 mL of 6 N aqueous hydrochloric
acid, and 100 mg of 10% palladiumꢀcarbon, and then the flask was taken
into an autoclave. The pressure of H2 was set to 30 psi. The autoclave
was stirred at room temperature for 2 h. After release of hydrogen, the
autoclave was opened, the palladiumꢀcarbon was separated by filtra-
tion, and the solvent was distilled under reduced pressure.
The residue was dissolved into CH2Cl2 (40 mL) and pyridine (6.0 g,
76.1 mmol) was added, then CbzCl (5.2 g, 30.4 mmol) was added
dropwise over 20 min in an ice bath. After the solution was stirred at
25ꢀ30 °C for 16 h, saturated aqueous NaHCO3 solution (25 mL) was
added and the organic layer was separated. The aqueous layer was
extracted with DCM (20 mL ꢁ 3). The organic layers were combined
and washed with 1 M aqueous hydrochloric acid, saturated aqueous
NaHCO3 solution and brine. The washed organic solution was dried
necarboxylate (1g). H NMR (400 MHz, CDCl3): 7.37ꢀ7.33 (m,
2H), 7.22ꢀ7.12 (m, 3H), 5.74 (t, J = 4.0 Hz, 1H), 4.68 (d, J = 5.1 Hz,
2H), 4.23 (q, J = 7.1 Hz, 2H), 1.63 (s, 4H), 1.30 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): 200.7, 170.1, 154.4, 150.8, 129.2, 125.3,
121.5, 61.5, 51.0, 33.4, 21.1, 14.0. HRMS: calcd for C15H17NO5 (M þ
H)þ 292.1185, found 292.1181.
Ethyl
1-{2-[(2,2,2-Trichloroethoxy)carbonylamino]-
acetyl}cyclopropanecarboxylate (1h). 1H NMR (400 MHz,
CDCl3): 5.72 (s, 1H), 4.74 (s, 2H), 4.66 (d, J = 5.1 Hz, 2H), 4.22 (q,
J = 7.2 Hz, 2H), 1.65ꢀ1.60 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 200.5, 170.1, 154.3, 95.3, 74.5, 61.5, 51.0, 33.3, 21.4,
14.0. HRMS: calcd for C11H14Cl3NO5 (M þ H)þ 346.0016, found
346.0007.
Ethyl 1-[2-(Ethoxycarbonylamino)acetyl]cyclopropane-
carboxylate (1i). H NMR (400 MHz, CDCl3): 5.36 (s, 1H), 4.57
1
(d, J = 5.2 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H),
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ARTICLE
1.62ꢀ1.56 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13
C
Ethyl 1-[1-Hydroxy-2-(4-methylphenylsulfonamido)ethyl]-
cyclopropanecarboxylate (2e). H NMR (400 MHz, CDCl3):
1
NMR (100 MHz, CDCl3): 201.1, 170.2, 156.4, 61.5, 61.1, 50.8, 33.4,
20.9, 14.5, 14.0. HRMS: calcd for C11H17NO5 (M þ H)þ 244.1185,
found 244.1173.
7.76ꢀ7.73 (m, 2H), 7.32ꢀ7.30 (m, 2H), 5.11 (dd, J = 8.6, 3.6 Hz, 1H),
4.12ꢀ4.04 (m, 2H), 3.29ꢀ3.22 (m, 2H), 3.27 (d, J = 3.5 Hz, 1H),
3.15ꢀ3.07 (m, 1H), 2.43 (s, 3H), 1.31ꢀ1.20 (m, 2H), 1.19 (t, J = 7.1 Hz,
3H), 0.97ꢀ0.92 (m, 1H), 0.87ꢀ0.82 (m, 1H). 13C NMR (100 MHz,
CDCl3): 174.1, 143.5, 136.9, 129.7, 127.0, 73.6, 60.9, 47.0, 25.8, 21.5,
14.9, 14.0, 12.7. HRMS: calcd for C15H21NO5S (M þ H)þ 328.1219,
found 328.1223.
Ethyl 1-(2-{[(9H-Fluoren-9-yl)methoxy]carbonylamino}-
1-hydroxyethyl)cyclopropanecarboxylate (2f). 1H NMR (400
MHz, CDCl3): 7.76 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.40 (t,
J = 7.3 Hz, 2H), 7.31 (td, J = 7.5, 1.1 Hz, 2H), 5.27 (s, 1H), 4.39 (d, J =
7.0 Hz, 2H), 4.21 (t, J = 7.1 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.60ꢀ3.54
(m, 1H), 3.43ꢀ3.26 (m, 3H), 1.34ꢀ1.22 (m, 2H), 1.24 (t, J = 7.1 Hz,
3H), 1.03ꢀ0.88 (m, 2H). 13C NMR (100 MHz, CDCl3): 174.3, 157.0,
143.8, 141.2, 127.6, 127.0, 125.0, 120.0, 74.3, 66.7, 60.8, 47.1, 45.3, 25.9,
14.7, 14.1, 12.5. HRMS: calcd for C23H25NO5 (M þ H)þ 396.1811,
found 396.1807.
Ethyl 1-[1-Hydroxy-2-(phenoxycarbonylamino)ethyl]cy-
clopropanecarboxylate (2g). 1H NMR (400 MHz, CDCl3):
7.38ꢀ7.33 (m, 2H), 7.21ꢀ7.18 (m, 1H), 7.13ꢀ7.10 (m, 2H), 5.58 (s,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.66ꢀ3.59 (m, 1H), 3.47ꢀ3.29 (m, 3H),
1.38ꢀ1.25 (m, 2H), 1.25 (t, J = 7.1, 3H), 1.05ꢀ0.90 (m, 2H). 13C NMR
(100 MHz, CDCl3): 174.3, 155.2, 150.9, 129.2, 125.3, 121.6, 74.4, 60.9,
45.5, 25.9, 15.0, 14.1, 12.6. HRMS: calcd for C15H19NO5 (M þ H)þ
294.1341, found 294.1346.
Ethyl 1-[2-(Isobutoxycarbonylamino)acetyl]cyclopropa
necarboxylate (1j). 1H NMR (400 MHz, CDCl3): 5.41 (s, 1H), 4.57
(d, J = 5.3 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.85 (d, J = 6.7 Hz, 2H),
1.95ꢀ1.88 (m, 1H), 1.58 (s, 4H), 1.30 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.7
Hz, 6H). 13C NMR (100 MHz, CDCl3): 201.1, 170.2, 156.5, 71.2, 61.4,
50.8, 33.3, 27.9, 20.8, 18.9, 14.0. HRMS: calcd for C13H21NO5 (M þ
H)þ 272.1498, found 272.1498.
Ethyl 1-[2-(tert-Butoxycarbonylamino)acetyl)cyclopro-
17
1
panecarboxylate (1k): . H NMR (400 MHz, CDCl3): 5.20 (s,
1H), 4.49 (d, J = 5.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.57 (s, 4H), 1.45
(s, 9H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 201.4,
170.2, 155.6, 79.6, 61.4, 50.5, 33.3, 28.2, 20.6, 14.0.
Typical Procedure for the Asymmetric Hydrogenation. To
a 20 mL Schlenk tube were added [Ru(benzene)Cl2]2 (5 mg, 0.01
mmol) and (S)-SunPhos (15 mg, 0.022 mmol). The tube was vacuumed
and purged with nitrogen three times before addition of freshly distilled
and degassed EtOH/DCM (2 mL/2 mL). The resulting mixture was
heated at 50 °C for 1 h and then cooled to room temperature. The
solvent was removed under vacuum to give the catalyst. This catalyst was
dissolved in degassed ethanol (10 mL) and distributed equally to four
vials. The β-ketoesters (0.5 mmol) were added to these vials, respec-
tively, and were transferred to an autoclave. The autoclave was purged
three times with H2, and the pressure of H2 was set to 20 bar. Then the
autoclave was stirred under specific reaction conditions. After 18 h, the
autoclave was then cooled to room temperature and the H2 was carefully
released. The autoclave was opened and the ethanol was evaporated.
The enantiomeric excess was determined by HPLC after passing the
residue through a short pad of silica gel column with petroleum ether
and ethyl acetate.
Ethyl 1-[2-(Benzyloxycarbonylamino)-1-hydroxyethyl]-
cyclopropanecarboxylate (2a). 1H NMR (400 MHz, CDCl3):
7.38ꢀ7.30 (m, 5H), 5.27 (s, 1H), 5.10 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H),
3.58ꢀ3.53 (m, 1H), 3.41ꢀ3.27 (m, 3H), 1.33ꢀ1.20 (m, 2H), 1.23 (t, J =
7.2 Hz, 3H), 1.02ꢀ0.88 (m, 2H). 13C NMR (100 MHz, CDCl3): 174.1,
156.9, 136.3, 128.4, 128.0, 127.9, 73.6, 66.6, 60.7, 45.2, 25.9, 14.1, 14.0,
12.4. HRMS: calcd for C16H21NO5 (M þ Na)þ 330.1304, found
330.1317.
Ethyl 1-{1-Hydroxy-2-[(2,2,2-trichloroethoxy)carbonyla-
mino]ethyl}cyclopropanecarboxylate (2h). 1H NMR (400
MHz, CDCl3): 5.52 (s, 1H), 4.72 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H),
3.62ꢀ3.56 (m, 1H), 3.44ꢀ3.29 (m, 3H), 1.39ꢀ1.27 (m, 2H), 1.25 (t, J =
7.1 Hz, 3H), 1.04ꢀ0.88 (m, 2H). 13C NMR (100 MHz, CDCl3): 174.2,
155.0, 95.5, 74.5, 74.1, 60.9, 45.3, 25.9, 14.7, 14.0, 12.5. HRMS: calcd for
C11H16Cl3NO5 (M þ H)þ 348.0172, found 348.0158.
Ethyl 1-[2-(Ethoxycarbonylamino)-1-hydroxyethyl]cyclo-
1
propanecarboxylate (2i). H NMR (400 MHz, CDCl3): 5.16 (s,
1H), 4.14 (q, J = 7.1 Hz, 2H), 4.11 (dd, J = 7.1, 14.2 Hz, 2H), 3.56ꢀ3.31
(m, 4H), 1.34ꢀ1.21 (m, 8H), 1.03ꢀ0.93 (m, 2H). 13C NMR (100
MHz, CDCl3): 174.3, 157.3, 74.0, 60.9, 60.7, 45.2, 25.9, 14.5, 14.4, 14.0,
12.5. HRMS calcd for C11H19NO5 (M þ Na)þ 268.1145, found
268.1149.
Ethyl 1-[1-Hydroxy-2-(isobutoxycarbonylamino)ethyl]-
cyclopropanecarboxylate (2j). 1H NMR (400 MHz, CDCl3):
5.22 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.83 (d, J = 6.6 Hz, 2H),
3.56ꢀ3.47 (m, 2H), 3.37ꢀ3.30 (m, 2H), 1.93ꢀ1.86 (m, 1H),
1.34ꢀ1.21 (m, 2H), 1.24 (t, J = 7.1, 3H), 1.04ꢀ0.89 (m, 2H), 0.92
(d, J = 6.7, 6H). 13C NMR (100 MHz, CDCl3): 174.2, 157.4, 73.6, 71.0,
60.6, 45.2, 27.8, 25.8, 18.9, 14.0, 13.9, 12.4. HRMS: calcd for
C13H23NO5 (M þ Na)þ 296.1474, found 296.1465.
Ethyl 1-[2-(1,3-Dioxoisoindolin-2-yl)-1-hydroxyethyl]-
cyclopropanecarboxylate (2b). H NMR (400 MHz, CDCl3):
1
7.88ꢀ7.83 (m, 2H), 7.75ꢀ7.70 (m, 2H), 4.26ꢀ4.19 (m, 3H), 3.94 (dd, J
= 14.1, 4.0 Hz, 1H), 3.38ꢀ3.35 (m, 1H), 3.29 (d, J = 10.3 Hz, 1H),
1.36ꢀ1.22 (m, 2H), 1.32 (t, J = 7.1, 3H), 1.01ꢀ0.89 (m, 2H). 13C NMR
(100 MHz, CDCl3): 173.7, 168.6, 134.0, 132.0, 123.3, 73.5, 61.0, 42.2,
25.9, 14.9, 14.1, 12.8. HRMS: calcd for C16H17NO5 (M þ H)þ
304.1185, found 304.1179.
Ethyl 1-[2-(tert-Butoxycarbonylamino)-1-hydroxyethyl]-
cyclopropanecarboxylate (2k). 1H NMR (400 MHz, CDCl3):
5.01 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.59ꢀ3.20 (m, 4H), 1.44 (s, 9H),
1.31ꢀ1.20 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.02ꢀ0.94 (m, 2H). 13C
NMR (100 MHz, CDCl3): 174.4, 156.7, 79.5, 74.1, 60.7, 45.0, 28.3, 25.9,
14.3, 14.1, 12.4. HRMS: calcd for C13H23NO5 (M þ Na)þ 296.1474,
found 296.1461.
Ethyl 1-(2-Benzamido-1-hydroxyethyl)cyclopropanecar-
1
boxylate (2c). H NMR (400 MHz, CDCl3): 7.80ꢀ7.77 (m, 2H),
7.52ꢀ7.41 (m, 3H), 6.76 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.94ꢀ3.88
(m, 1H), 3.81 (d, J = 7.9 Hz, 1H), 3.58ꢀ3.46 (m, 2H), 1.36ꢀ1.24 (m,
2H), 1.25 (t, J = 7.1 Hz, 3H),1.07ꢀ0.98 (m, 2H). 13C NMR (100 MHz,
CDCl3): 174.4, 168.4, 134.1, 131.5, 128.5, 126.9, 73.6, 60.8, 44.6, 26.1,
14.3, 14.0, 12.4. HRMS: calcd for C15H19NO4 (M þ H)þ 278.1392,
found 278.1382.
Typical Procedure for the Preparation of 3. A 25 mL round
flask was charged with 2d (1 mmol), pyridine (0.4 mL, 5 mmol),
4-nitrobenzoyl chloride (278 mg, 1.5 mmol), DMAP (6 mg) and
CH2Cl2 (10 mL). The mixture was stirred at 25ꢀ30 °C for 6 h,
saturated aqueous NaHCO3 solution (5 mL) was added and the organic
layer was separated. The organic layer was washed with 1 M aqueous
hydrochloric acid, saturated aqueous NaHCO3 solution and brine. The
washed organic solution was dried over anhydrous Na2SO4 and
Ethyl 1-[1-Hydroxy-2-(methylsulfonamido)ethyl]cyclopr-
opanecarboxylate (2d). 1H NMR (400 MHz, CDCl3): 5.07 (s, 1H),
4.14 (q, J = 7.1 Hz, 2H), 3.45ꢀ3.33 (m, 4H), 3.00 (s, 3H), 1.36ꢀ1.26
(m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.05ꢀ1.00 (m, 1H), 0.96ꢀ0.91 (m,
1H). 13C NMR (100 MHz, CDCl3): 174.1, 73.4, 60.9, 47.2, 40.3, 25.8,
14.3, 14.0, 12.7. HRMS: calcd for C9H17NO5S (M þ H)þ 252.0906,
found 252.0905.
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ARTICLE
concentrated in vacuo to obtain 410 mg of crude product, which
was purified by column chromatography (PE/EA = 1/1) to give comp-
ound 1-[1-(ethoxycarbonyl)cyclopropyl]-2-(methylsulfonamido)ethyl
(30 mL) and NaN3 (1.1 g, 17.2 mmol) was added. The resulting mixture
was heated at 80 °C for 1 h to effect a complete conversion. The reaction
mixture was diluted with water, and the mixture was extracted with ethyl
acetate. The extract was washed with brine and then dried over Na2SO4.
Concentration of the solvent in vacuo gave an oily residue, which was
purified by column chromatography (hexanes/ethyl acetate = 5/1) to give
4 (4.4 g, 85%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.39ꢀ7.23
(m, 5H), 5.15ꢀ5.07 (m, 3H), 4.15 (q, J = 7.0 Hz, 2H), 3.67ꢀ3.38 (m, 3H),
1.40ꢀ1.37 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.24ꢀ1.22 (m, 1H),
1.00ꢀ0.93 (m, 2H). 13C NMR (100 MHz, CDCl3): 172.3, 156.3, 136.2,
128.5, 128.1, 128.0, 66.8, 64.4, 61.0, 43.3, 24.9, 14.0, 13.8, 13.6.
1
4-nitrobenzoate (3d) (341 mg, 85%). H NMR (400 MHz, CDCl3):
8.33ꢀ8.29 (m, 2H), 8.23ꢀ8.20 (m, 2H), 5.14 (dd, J = 7.8, 4.0 Hz, 1H),
4.81 (t, J = 6.3 Hz, 1H), 4.22- 4.14 (m, 2H), 3.84ꢀ3.71 (m, 2H), 2.96 (s,
3H), 1.46ꢀ1.34 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.19ꢀ1.34 (m, 1H),
1.07ꢀ1.02 (m, 1H). 13C NMR (100 MHz, CDCl3): 172.1, 164.2, 150.6,
134.9, 130.9, 123.6, 75.4, 61.1, 45.2, 40.8, 24.9, 14.1, 13.9, 13.8. HRMS:
calcd for C16H20N2O8S (M þ Na)þ 423.0847, found 423.0838. HPLC
(Chiralcel AD-H column, hexane/i-PrOH = 80/20, 0.5 mL/min,
254 nm): t1 = 37.0 min, t2 = 46.3 min.
Preparation of (S)-7-Amino-5-azaspiro[2.4]heptan-4-one
(5). A mixture of 4 (4.4 g, 13.2 mmol) and 5% palladium on carbon (30%
wet) (1.0 g) in EtOH (50 mL) was hydrogenated at 75 °C under a
hydrogen pressure of 4 bar for 24 h. After completion of the reaction, the
catalyst was removed by filtration and the resulting filtrate was con-
centrated under a reduced pressure to obtain 5 (1.5 g, 90%) in the form
of colorless crystals. [R]20D ꢀ99.5 (c 1.0, MeOH); 1H NMR (400 MHz,
CDCl3): 6.43 (bs, 1H), 3.77 (ddd, J = 9.8, 7.1, 0.7 Hz, 1H), 3.50 (dd, J =
7.1, 4.5 Hz, 1H), 3.13 (ddd, J = 9.8, 4.5, 0.7 Hz, 1H), 1.37 (bs, 2H),
1.20ꢀ1.17 (m, 1H), 0.99ꢀ0.97 (m, 2H), 0.82ꢀ0.77 (m, 1H). 13C NMR
(100 MHz, CDCl3): 179.2, 51.7, 50.0, 29.1, 12.1, 8.1. Then 5 was
converted to tert-butyl (4-oxo-5-azaspiro[2.4]heptan-7-yl)carbamate
(derivative of 5) for chiral purity analysis by chiral HPLC. HPLC
analysis indicated an enantiomeric excess of 98.9% (ChiralPak AD-H
column, flow 0.5 mL/min, IPA/Hex =15/85, 210 nm, t1 = 10.6 min, t2 =
15.9 min). 1H NMR (400 MHz, CDCl3): 6.08 (s, 1H), 4.84 (d, J = 6.8
Hz, 1H), 4.18 (t, J = 6.2 Hz, 1H), 3.81 (dd, J = 10.3, 6.9 Hz, 1H), 3.32
(dd, J = 10.2, 2.3 Hz, 1H), 1.44 (s, 9H), 1.21ꢀ0.95 (m, 4H). 13C NMR
(100 MHz, CDCl3): 178.4, 155.2, 79.9, 51.4, 47.9, 28.3, 27.3, 14.5, 8.7.
HRMS: calcd for C11H18N2O3 (M þ Na)þ 249.1217, found 249.1215.
Preparation of (S)-7-Amino-5-azaspiro[2,4]heptane Dihy-
drochloride (6). LiAlH4 (182 mg, 4.8 mmol) was charged into a
50 mL 3-necked round-bottom flask and THF (20 mL) was added. The
resulting slurry was stirred and 5 (300 mg, 2.4 mmol) was added in
portions. The reaction was heated to 60 °C for 24 h. Completion of the
reaction was monitored by 1H NMR. Water (0.3 mL) was added
dropwise and stirred for 5 min. 15% NaOH solution (0.3 mL) was
added and stirred for 5 min. Water (0.9 mL) was added dropwise and the
white suspension stirred for 30 min, then filtered through a pad of Celite.
The Celite pad was rinsed with hot THF, and the filtrate was
concentrated to give an oily liquid. Then 1 M HCl in MeOH (3 mL)
was added and stirred for 20 min to obtain 6 (407 mg, 92%) as white
powder. [R]20 ꢀ44.7 (c = 1.0, H2O) ([R]20 ꢀ41.5 in H2O, c =
Likewisely, 3hꢀk were prepared from the corresponding alcohols
and 4-nitrobenzoyl chloride.
1-[1-(Ethoxycarbonyl)cyclopropyl]-2-[(2,2,2-trichloroeth-
oxy)carbonylamino]ethyl 4-Nitrobenzoate (3h). 1H NMR
(400 MHz, CDCl3): 8.32ꢀ8.19 (m, 4H), 5.34 (t, J = 6.3 Hz, 1H),
5.16 (dd, J = 8.3, 3.6 Hz, 1H), 4.68 (dd, J = 28.0, 12.0 Hz, 2H),
4.23ꢀ4.11 (m, 2H), 3.96ꢀ3.89 (m, 1H), 3.83ꢀ3.77 (m, 1H),
1.44ꢀ1.33 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.19ꢀ1.14 (m, 1H),
1.06ꢀ1.00 (m, 1H). 13C NMR (100 MHz, CDCl3): 172.1, 164.2, 154.6,
150.6, 135.0, 130.9, 123.5, 95.3, 75.4, 74.4, 61.0, 43.6, 24.9, 14.1, 13.9.
HRMS: calcd for C18H19N2O8Cl3 (M þ Na)þ 519.0090, found
519.0105. HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15,
0.5 mL/min, 254 nm): t1 = 26.0 min, t2 = 28.5 min.
1-[1-(Ethoxycarbonyl)cyclopropyl]-2-(ethoxycarbonyl-
amino)ethyl 4-Nitrobenzoate (3i). 1H NMR (400 MHz, CDCl3):
8.31ꢀ8.20 (m, 4H), 5.12 (dd, J = 8.3, 3.3 Hz, 1H), 4.96 (t, J = 5.8 Hz,
1H), 4.24ꢀ4.12 (m, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.87ꢀ3.71 (m, 2H),
1.43ꢀ1.31 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.22ꢀ1.14 (m, 3H),
1.06ꢀ0.83 (m, 2H). 13C NMR (100 MHz, CDCl3): 172.2, 164.2, 156.6,
150.6, 135.2, 130.9, 123.5, 76.0, 60.9, 43.3, 25.0, 14.5, 14.2, 14.1, 13.8.
HRMS: calcd for C18H22N2O8 (M þ Na)þ 417.1278, found 417.1274.
HPLC (Chiralcel OD-H column, hexane/i-PrOH = 85/15, 0.5 mL/min,
254 nm): t1 = 27.0 min, t2 = 31.0 min.
1-[1-(Ethoxycarbonyl)cyclopropyl]-2-(isobutoxycarbo-
nylamino)ethyl 4-Nitrobenzoate (3j). 1H NMR (400 MHz,
CDCl3): 8.31ꢀ8.10 (m, 4H), 5.13 (dd, J = 8.4, 3.4 Hz, 1H), 4.97 (t,
J = 5.8 Hz, 1H), 4.24ꢀ4.12 (m, 2H), 3.88ꢀ3.70 (m, 4H), 1.85ꢀ1.79 (m,
1H), 1.41ꢀ1.31 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.19ꢀ1.02 (m, 2H),
0.84 (dd, J = 6.7, 1.9 Hz, 6H). 13C NMR (100 MHz, CDCl3): 172.2,
164.3, 156.8, 150.6, 135.2, 130.9, 123.6, 76.0, 71.2, 61.0, 43.3, 27.9, 25.0,
18.9, 14.2 (2C), 13.9. HRMS: calcd for C20H26N2O8 (M þ Na)þ
445.1584, found 445.1587. HPLC (Chiralcel AD-H column, hexane/i-
PrOH = 85/15, 0.5 mL/min, 254 nm): t1 = 24.3 min, t2 = 26.7 min.
2-(tert-Butoxycarbonylamino)-1-(1-(ethoxycarbonyl)cyc-
lopropyl)ethyl 4-Nitrobenzoate (3k). 1H NMR (400 MHz,
CDCl3): 8.31ꢀ8.21 (m, 4H), 5.16 (dd, J = 8.4, 3.3 Hz, 1H), 4.83 (t,
J = 5.9 Hz, 1H), 4.24ꢀ4.12 (m, 2H), 3.82ꢀ3.62 (m, 2H), 1.36 (s, 9H),
1.28 (t, J = 7.1 Hz, 3H), 1.21ꢀ1.14 (m, 2H), 1.05ꢀ1.00 (m, 2H). 13C
NMR (100 MHz, CDCl3): 172.2, 164.2, 155.8, 150.6, 135.3, 131.0,
123.5, 79.6, 75.8, 60.9, 42.8, 28.2, 24.9, 14.2, 14.0, 13.8. HRMS: calcd for
C20H26N2O8 (M þ Na)þ 445.1584, found 445.1587. HPLC (Chiralcel
AD-H column, hexane/i-PrOH = 90/10, 0.5 mL/min, 254 nm): t1 =
36.8 min, t2 = 47.1 min.
Preparation of (S)-Ethyl 1-(1-Azido-2-{[(benzyloxy)car-
bonyl]amino}ethyl)cyclopropanecarboxylate (4)5. To a solu-
tion of 2a (4.8 g, 15.6 mmol) in CH2Cl2 (50 mL) was added Et3N
(4.4 mL, 31.2 mmol). The mixture was stirred and cooled to 5 °C. MsCl
(2.7 g, 23.4 mmol) was added via the addition funnel portionwise over a
period of 5 min, while maintaining the internal temperature below
10 °C. The mixture was stirred at 5 °C for 1 h, and diluted with CH2Cl2
(50 mL). The organic layer was washed with brine (20 mL), dried over
Na2SO4 and concentrated. The residue was dissolved into DMF
D
D
1.616).3f 1H NMR (400 MHz, D2O): 3.88 (dd, J = 13.8, 7.4 Hz, 1H),
3.59 (dd, J = 7.4, 3.2 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H), 3.45 (dd, J =
13.8, 3.2 Hz, 1H), 3.03 (d, J = 12.1 Hz, 1H), 1.01ꢀ0.76 (m, 4H). 13C
NMR (100 MHz, D2O): 55.0, 51.0, 49.2, 23.3, 14.7, 5.0. Compound 6
was converted to tert-butyl 7-[(tert-butoxycarbonyl)amino]-5-azaspiro-
[2.4]heptane-5-carboxylate (derivative of 6). HPLC analysis indicated
an enantiomeric excess of 98.9% (ChiralPak AD-H column, flow
0.5 mL/min, IPA/Hex =5/95, 210 nm, t1 = 15.2 min, t2 = 24.2 min).
1H NMR (400 MHz, CDCl3): 4.69 (s, 1H), 3.68ꢀ3.43 (m, 4H), 3.12
(dd, J = 25.6, 10.8 Hz, 1H), 1.46 (s, 9H), 1.44 (s, 9H), 0.84ꢀ0.54 (m,
4H). 13C NMR (100 MHz, CDCl3): 155.4, 154.5 (rotamer), 154.3, 79.7,
79.5, 56.2, 55.3 (rotamer), 53.0, 52.4 (rotamer), 52.1 (rotamer), 51.6,
28.4, 28.3, 25.8 (rotamer), 25.1, 13.1, 5.6. HRMS: calcd for C16H28N2O4
(M þ Na)þ: 335.1953, found 335.1947.
’ ASSOCIATED CONTENT
S
Supporting Information. Details of the preparations and
b
the NMR and/or HPLC data of compounds 1ꢀ6. This material
is available free of charge via the Internet at http://pubs.acs.org.
2812
dx.doi.org/10.1021/jo2002165 |J. Org. Chem. 2011, 76, 2807–2813

The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
Tetrahedron: Asymmetry 1991, 2, 51. (f) Kawano, H.; Ikariya, T.; Ishii,
Y.; Saburi, M.; Yoshikawa, S.; Uchida, Y.; Kumobayashi, H. J. Chem. Soc.,
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V.; Gen^et, J.-P. Eur. J. Org. Chem. 2004, 11, 2352. (b) Ratovelomanana-
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J.-P. Adv. Synth. Catal. 2003, 345, 261. (c) Kitamura, M.; Ohkuma, T.;
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Corresponding Author
*E-mail: zhaoguo@sjtu.edu.cn.
’ ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China,
the Science and Technology Commission of Shanghai Munici-
pality, and the Education Commission of Shanghai Municipality
for financial support.
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