Synthesis of highly functionalized enantiopure halocyclopropanes derived from carbohydrates

Article abstract of DOI:10.1002/ejoc.201300322

A chromium-mediated synthesis of enantiopure sugar-based halocyclopropanecarboxamides is reported. This reaction can be stereospecifically carried out on (E)- or (Z)-α,β-unsaturated amides and takes place with the formation of a new C-Hal stereogenic center, which is generated with total stereoselectivity. Synthetic applications of the obtained halocyclopropanecarboxamides are also reported. The structure of the halocyclopropanes and derivatives were established by X-ray analysis. A mechanism to explain these transformations is proposed. Copyright

Full text of DOI:10.1002/ejoc.201300322

FULL PAPER
DOI: 10.1002/ejoc.201300322
Synthesis of Highly Functionalized Enantiopure Halocyclopropanes Derived
from Carbohydrates
Humberto Rodríguez-Solla,*[a] Carmen Concellón,[a] Vicente del Amo,[a]
Ainhoa Díaz-Pardo,[a] Elena G. Blanco,[a] Santiago García-Granda,[a] M. Rosario Díaz,[a]
Ricardo Llavona,[a] and Raquel G. Soengas[b]
Keywords: Small ring systems / Carbohydrates / Amides / Carbenoids / Chromium
A chromium-mediated synthesis of enantiopure sugar-based
halocyclopropanecarboxamides is reported. This reaction
can be stereospecifically carried out on (E)- or (Z)-α,β-unsatu-
rated amides and takes place with the formation of a new C-
Hal stereogenic center, which is generated with total stereo-
selectivity. Synthetic applications of the obtained halocyclo-
propanecarboxamides are also reported. The structure of the
halocyclopropanes and derivatives were established by X-
ray analysis. A mechanism to explain these transformations
is proposed.
The incorporation of cyclopropanes into a carbohydrate
scaffold provides a combination of strained and reactive cy-
clopropanes with the well-defined stereochemistry inherent
of carbohydrates. However, although there are several re-
ports on the synthesis of cyclopropane units on the fur-
anosyl and pyranosyl rings of carbohydrates,[7] construction
of cyclopropanes on acyclic sugars[8] or in acyclic chains of
pyranoses and furanoses,[9] has been much less studied.
Chromium dichloride (CrCl2) has become an important
reagent in synthetic organic chemistry because of its versa-
tility in electron transfer reactions, and this reagent has
been applied to a multitude of organic transformations,
which generally proceeded with high selectivity.[10] In par-
ticular, previous contributions by us (the stereospecific cy-
clopropanation of α,β-unsaturated amides,[11] the highly
stereoselective tert-butyl- and silyl-cyclopropanation,[12]
and the chloro- and bromocyclopropanation of α,β-unsatu-
rated amides with total or high stereoselectivity[13]) and
other[14] laboratories, have demonstrated the utility of CrCl2
for the cyclopropanation of unsaturated compounds.
In this communication we report a stereoselective prepa-
ration of sugar-based chloro and bromocyclopropanes in
moderate to good yields by means of the reaction of α,β-
unsaturated amides derived from sugar aldehydes and chro-
mium carbenoids.
Introduction
A great deal of attention has been focused on the prepa-
ration of cyclopropanes because of their fascinating struc-
ture. The highly strained nature of the cyclopropane rings
makes them very reactive and useful synthetic building
blocks in organic chemistry.[1] Additionally, cyclopropane
moieties are present in a wide range of natural products.
While non-activated cyclopropanes have limited use in
chemical synthesis, activated derivatives, such as cyclo-
propanes substituted with electron-withdrawing or electron-
donating groups, have been used extensively as precursors
in several chemical syntheses.[2] In particular, it is known
that the presence of a carbonyl or imine group further acti-
vates cyclopropanes towards ring-enlargement and cycload-
dition reactions.[3] Cyclopropanes have been extensively
used to introduce a conformational restriction in drugs to
enhance their activity and avoid undesired effects. In this
regard, chiral cyclopropanes substituted at all three ring
carbon atoms are of great interest.[4] Moreover, much effort
has been devoted to substitution of the cyclopropane moi-
ety by means of either the formation of organometallic cy-
clopropanes or palladium cross-coupling reactions. For this
purpose, halocyclopropanes have proven to be useful start-
ing materials.[5]
An important advance in cyclopropane chemistry has
been the integration of cyclopropanes and carbohydrates.[6]
Results and Discussion
[a] Departamento de Química Orgánica e Inorgánica and Química
Física y Analítica, Facultad de Química, Universidad de
Oviedo,
The (E)- and (Z)-α,β-unsaturated amides used as starting
materials were easily prepared from sugar aldehydes 1, and
N,N-diethyl-(dimethylphosphono)acetamide (2) through
the Horner–Wadsworth–Emmons protocol.[15] By using the
method described in the Experimental Section, it was pos-
sible to isolate α,β-unsaturated amides 3 and 4 as a stereo-
Julián Clavería 7, 33006 Oviedo, Spain
E-mail: hrsolla@uniovi.es
[b] Departamento de Química & QOPNA, Universidade de Aveiro,
3810-193 Aveiro, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300322.
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H. Rodríguez-Solla et al.
FULL PAPER
isomeric mixture, which was easily separated by simple col- Table 2. Synthesis of halocyclopropanecarboxamides 5 derived
from (E)-α,β-unsaturated amides 3.
umn chromatography (Table 1).
Table 1. Synthesis of (E/Z)-α,β-unsaturated amides 3/4.
1
[a] Only one stereoisomer was observed by H NMR spectroscopic
analysis of the crude reaction mixture. [b] Isolated yield of analyti-
cally pure 5 based on 3.
[a] E/Z ratio determined by 1H NMR spectroscopic analysis of
crude reaction mixtures. [b] Isolated yield of analytically pure E/Z
mixtures and, in parentheses, percentage yield of the isolated E-
and Z-stereoisomer (3 and 4, respectively), after column purifica-
tion.
Table 3. Synthesis of halocyclopropanecarboxamides 6 derived
from (Z)-α,β-unsaturated amides 4.
On the basis of the results of the halocyclopropanation
of (E)-α,β-unsaturated amides previously reported by our
group,[13] we initially tested the same reaction conditions to
perform the chlorocyclopropanation of the (E)-α,β-unsatu-
rated amide derived from galactose 3a. Thus, when a mix-
ture of CrCl2 (3 equiv.) and CCl4 (1 equiv.) in tetra-
hydrofuran (THF) was heated to reflux for 16 h in the pres-
ence of (E)-α,β-unsaturated amide 3a, chlorocyclopropana-
mide 5a was obtained, after hydrolysis, in high yield and
with total stereoselectivity (Table 2, entry 1). These reaction
conditions were used to generalize the process, with the re-
action being performed on various (E)-α,β-unsaturated
amides 3 (Table 2).
In the case of the synthesis of bromocyclopropane 5f, a
similar process was carried out. In this case, a mixture of
CrBr2[13]/CBr4 was employed instead CrCl2/CCl4. Carben-
oid sources, CCl4 and CBr4, are both commercially avail-
able.
When this reaction was performed on (Z)-α,β-unsatu-
rated amides 4, no significant differences were observed
when compared with the same process carried out on (E)-
α,β-unsaturated amides 3. Table 3 summarizes the results
obtained on the chloro- and bromocyclopropanation of
sugar-based (Z)-α,β-unsaturated amides 4.
Analysis of the results compiled in Tables 2 and 3 indi-
analysis of the crude reaction mixture. [b] Isolated yield of analyti-
cates that: (a) all halocyclopropanation reactions took place cally pure 6 based on 4.
1
[a] Only one stereoisomer was observed by H NMR spectroscopic
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Highly Functionalized Enantiopure Halocyclopropanes
in moderate to good yields, with total stereoselectivity and
in the absence of epimerization of any chiral center; (b) this
process tolerated a broad range of sugar-derived (E)- or
(Z)-α,β-unsaturated amides bearing different protection on
the hydroxyl groups; (c) the determination of the structure
for compounds 5 and 6 has proven that the halocyclo-
propanation reaction took place with complete stereospeci-
ficity because the geometry of the C–C double bond of both
(E)- and (Z)-α,β-unsaturated amides was conserved during
the cyclopropanation process (see Tables 2 and 3), and (d)
no significant differences were observed in terms of yield or
stereoselectivities when the reaction was carried out using
CrCl2/CCl4 or CrBr2/CBr4.
Mechanism
This halocyclopropanation process could be explained by
assuming the formation of a chromium(III) geminal di-
carbenoid intermediate 8, after the reaction of CrX2
(4.0 equiv.) with CX4 (X = Cl, or Br; 1.0 equiv.). This chro-
mium(III) geminal dicarbenoid has been previously pro-
posed by Takai et al. for the halocyclopropanation of
acrylic esters using the CrCl2/CCl4 system.[17] In this sense,
dicarbenoid 8 could react with α,β-unsaturated amides 3b
or 4b through a similar mechanism to that proposed by
Houk for the addition of carbenoids to olefins.[18] Tenta-
tively, we propose the transition states A and B depicted in
Scheme 1, in which the formation of the new stereogenic
centers, with total stereoselectivity, could be explained on
the basis of steric hindrance between the halogen atom X
and the carboxamide group. The attack of carbenoid 8 to
olefins 3b and 4b would take place from the less hindered
si face. In the transition state, the halogen atom would oc-
cupy a trans relative position with respect to the carbox-
amide group as depicted in Scheme 1. Moreover, internal
coordination of the chromium(III) center with the amide
oxygen would play a crucial role because it would afford
an additional stabilization of intermediates 9 and 10.[17,19]
Hydrolysis of these intermediates during workup would
finally yield halocyclopropanes 5b or 6b, respectively. It is
noteworthy that when this process was carried out on sugar-
based (E)- or (Z)-α,β-unsaturated esters, no reaction took
place. In this sense, the presence of the amide group was
necessary to obtain sugar-based halocyclopropanes 5 and
6.
The total stereoselectivity of this process was established
by 1H NMR spectroscopic experiments with the crude reac-
tion mixtures. Analysis of the spectra showed that all halo-
cyclopropanes were isolated as single stereoisomers. The
structures of halocyclopropanes 5 and 6 were assigned
1
based on H, 13C, COSY, and HSQC NMR experiments.
Because the stereochemistry of the sugar backbone is fixed
in the starting material, and no epimerization of any chiral
center took place, the absolute configuration of 5 and 6
was established by means of NOESY and NOE difference
experiments. Furthermore, the assigned absolute configura-
tion of 5c, 6a, and 6e was unambiguously confirmed by
single-crystal X-ray diffraction analysis (Figure 1).[16] The
structure and the absolute configuration of other halocyclo-
propanes were assigned by analogy.
To demonstrate synthetic applications of the obtained
chlorocyclopropanecarboxamides 5 and 6, selected exam-
ples were readily transformed into enantiopure chlorocy-
Table 4. Synthesis of enantiopure chlorocyclopropylamines 11 and
12.
[a] Only one stereoisomer was observed by 1H NMR spectroscopic
analysis of the crude reaction mixture. [b] Isolated yield of analyti-
cally pure compound based on 5 or 6.
Figure 1. Ortep diagram for 5c and 6e.
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H. Rodríguez-Solla et al.
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Scheme 1. Mechanistic proposal.
clopropylamines (Table 4). Thus, 5b, 6a, or 6d in THF was unsaturated amides derived from carbohydrates. Studies
treated with lithium aluminum hydride at reflux for 12 h, aimed towards fully delineating the factors involved in this
affording the corresponding chlorocyclopropylamines 11, transformation and other synthetic applications of the
12a, or 12b, in good yields, without loss of stereoisomeric products obtained are under investigation in our laboratory.
purity (1H NMR spectroscopic analsysis of the crude reac-
tion products), following a previously described pro-
cedure.[12b] No significant differences in terms of yield or
stereoisomeric purity were observed when this transforma-
Experimental Section
General: Reactions requiring an inert atmosphere were conducted
under dry nitrogen, and the glassware was oven dried (120 °C).
THF was distilled from sodium/benzophenone immediately prior
to use. All reagents were purchased in the highest quality available
and were used without further purification. Flash column
chromatography was carried out on silica gel 230–400 mesh; com-
pounds were visualized on analytical thin-layer chromatograms
(TLC) by UV light (254 nm). 1H NMR spectra were recorded at
300 MHz; 13C NMR spectra and DEPT experiments were deter-
mined at 75 MHz. Chemical shifts are given in ppm relative to
tetramethylsilane (TMS), which was used as an internal standard,
and coupling constants (J) are reported in Hz. The diastereoiso-
meric ratios were obtained by 1H NMR analyses (300 MHz) of
crude products. GC–MS and HRMS were measured by using EI
tion was performed using different chlorocyclopropanecar-
boxamides. In the case of the reaction of 6d with LiAlH4,
O-deprotection took place under the reaction conditions
and the O-desilylated chlorocyclopropylamine 12b was ob-
tained.
Conclusions
We have described a general method for the synthesis of
highly functionalized sugar-based halocyclopropanecarbox-
amides in a stereospecific manner and in good yields. This
process is carried out through a stereospecific chromi-
um(III)-promoted halocyclopropanation of (E)- or (Z)-α,β- (70 eV) or FAB conditions. When HRMS could not be measured
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Highly Functionalized Enantiopure Halocyclopropanes
on the molecular ion, the HRMS of a significant fragment is given.
Only the most important IR bands (cm–1) and the molecular ions
and/or base peaks in MS are given.
m/z calcd. for C29H41NNaO4Si [M + Na]+ 518.2703; found
518.2710. IR (neat): ν = 3049, 1650, 1127, 824 cm–1.
˜
(Z)-N,N-Diethyl-6,7-dideoxy-1,2:3,4-di-O-isopropylidene-β-D-ga-
Synthesis of 3/4. General Procedure: To a solution of N,N-diethyl-
bromoacetamide (1.1 equiv.) in ethyl acetate was added trimethyl-
phosphite (1.1 mmol, 1.1 equiv.) at room temperature and the solu-
tion was heated to reflux for 72 h to give N,N-diethyl-(dimethyl-
phophono)acetamide (2). The solution of N,N-diethyl-(dimethyl-
phosphono)acetamide (1.1 mmol, 1.1 equiv.) in anhydrous THF
(3 mL) was treated under a nitrogen atmosphere with n-butyllith-
ium (1.6 m in hexanes, 1.05 mmol, 1.05 equiv.) at –78 °C. After stir-
ring for 10 min, the corresponding aldehyde (1.0 mmol, 1.0 equiv.)
in THF (2 mL) was added and the mixture was stirred for 2 h at
–78 °C. The reaction was quenched by the addition of saturated
NH4Cl solution, and extracted with ethyl acetate (3ϫ 5 mL). Usual
work-up and separation by column chromatography on silica gel
(hexane/EtOAc, 5:1) afforded pure compounds 3 and 4. Com-
pounds 3a, 3b, and 3d have previously been fully characterized.[20]
lacto-oct-6-enopyranosiduronamide (4a): Starting from 1a
(1.0 mmol, 258.3 mg), yield 99.5 mg (28%); white solid; m.p. 79–
81 °C (Et2O/Hex); [α]2D0 = –136.9 (c = 1.00, CHCl3); Rf = 0.45 (hex-
ane/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 6.15 (d, J =
11.6 Hz, 1 H), 5.97 (dd, J = 11.7, 7.6 Hz, 1 H), 5.47 (d, J = 5.1 Hz,
1 H), 5.08 (d, J = 7.6 Hz, 1 H), 4.57–4.51 (m, 2 H), 4.24 (d, J =
5.3 Hz, 1 H), 3.41–3.18 (m, 4 H), 1.46 (s, 3 H), 1.41 (s, 3 H), 1.27
(s, 6 H), 1.11 (t, J = 7.1 Hz, 3 H), 1.04 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 165.4 (C), 139.7 (CH), 122.7
(CH), 109.2 (C), 109.0 (C), 96.7 (CH), 73.9 (CH), 71.2 (CH), 70.6
(CH), 66.3 (CH), 42.9 (CH2), 40.4 (CH2), 26.3 (2 ϫCH3), 25.4
(CH3), 24.5 (CH3), 14.7 (CH3), 13.3 (CH3) ppm. MS (ESI+-TOF):
m/z (%) = 378 (100) [M + Na]+, 356 (31) [M + H]+, 379 (25).
HRMS: m/z calcd. for C18H29NNaO6 [M + Na]+ 378.1893; found
378.1892. IR (neat): ν = 3400, 1654, 1040, 756 cm–1.
˜
(E)-N,N-Diethyl-1-O-benzyl-5,6-dideoxy-2,3-O-isopropylidene-α-
D-
(Z)-N,N-Diethyl-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-
lyxo-hept-5-enofuranosiduronamide (3c): Starting from 1c
(1.0 mmol, 278.3 mg), yield 105.1 mg (28%); yellow oil; [α]2D0 = –5.0
(c = 1.00, CHCl3); Rf = 0.38 (hexane/EtOAc, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.29 (m, 5 H), 6.90 (dd, J = 15.2,
5.2 Hz, 1 H), 6.55 (d, J = 15.0 Hz, 1 H), 5.15 (s, 1 H), 4.72–4.69
(m, 1 H), 4.63 (d, J = 4.5 Hz, 1 H), 4.60–4.57 (m, 2 H), 4.44 (d, J
xylo-hept-5-enofuranosiduronamide (4b): Starting from 1b
(1.0 mmol, 278.3 mg), yield 150.2 mg (40%); yellow oil; [α]2D0 = –9.2
(c = 1.00, CHCl3); Rf = 0.54 (hexane/EtOAc, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.24–7.16 (m, 5 H), 6.18 (d, J = 11.4 Hz,
1 H), 6.08 (dd, J = 12.0, 7.2 Hz, 1 H), 5.90 (d, J = 3.15 Hz, 1 H),
5.26 (dd, J = 3.66, 3.0 Hz, 1 H), 4.55–4.50 (m, 3 H), 4.27 (d, J =
= 11.8 Hz, 1 H), 3.44–3.38 (m, 4 H), 1.42 (s, 3 H), 1.29 (s, 3 H), 2.7 Hz, 1 H), 3.44–3.17 (m, 4 H), 1.41 (s, 3 H), 1.23 (s, 3 H), 1.20–
1.26–1.18 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.7
(C), 137.8 (CH), 137.6 (C), 128.8 (2ϫCH), 128.3 (2ϫCH), 128.2
1.04 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9 (C),
138.2 (C), 138.0 (CH), 128.6 (2ϫCH), 127.9 (CH), 127.8 (2ϫCH),
(CH), 123.2 (CH), 113.2 (CH), 105.6 (C), 85.6 (CH), 81.3 (CH), 124.1 (CH), 111.9 (C), 105.4 (CH), 85.1 (CH), 83.8 (CH), 78.9
79.8 (CH), 69.4 (CH2), 42.6 (CH2), 42.4 (CH2), 26.4 (CH3), 25.3 (CH), 72.8 (CH2), 43.0 (CH2), 40.3 (CH2), 27.2 (CH3), 26.7 (CH3),
(CH3), 15.2 (CH3), 13.5 (CH3) ppm. MS (ESI+-TOF): m/z (%) =
14.7 (CH3), 13.4 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 376 (31)
376 (100) [M + H]+, 398 (78) [M + Na]+, 414 (31) [M + K]+. [M + H]+ , 398 (100) [M + Na]+ . HRMS: m/z calcd. for
HRMS: m/z calcd. for C21H30NO5 [M + H]+ 376.2124; found
376.2123. IR (neat): ν = 3056, 1720, 1657, 1620, 1086 cm–1.
C21H29NNaO5 [M + Na]+ 398.1943; found 398.1945. IR (neat): ν
˜
= 3440, 1745, 1240, 1101 cm–1.
˜
(E)-N,N-Diethyl-2,3-dideoxy-4,5:6,7-di-O-isopropylidene-
L
-xylo-
(Z)-N,N-Diethyl-1-O-benzyl-5,6-dideoxy-2,3-O-isopropylidene-α-D-
hept-2-enamide (3e): Starting from 1e (1.0 mmol, 230.1 mg), yield
lyxo-hept-5-enofuranosiduronamide (4c): Starting from 1c
49.1 mg (15%); yellow oil; [α]2D0 = +3.8 (c = 1.00, CHCl3); Rf =
(1.0 mmol, 278.3 mg), yield 161.4 mg (43%); yellow oil; [α]2D0
=
1
1
0.38 (hexane/EtOAc, 1:1). H NMR (300 MHz, CDCl3): δ = 6.92
–38.4 (c = 1.00, CHCl3); Rf = 0.62 (hexane/EtOAc, 1:1). H NMR
(300 MHz, CDCl3): δ = 7.25–7.19 (m, 5 H), 6.23 (d, J = 11.7 Hz,
(dd, J = 15.0, 5.9 Hz, 1 H), 5.58 (dd, J = 15.0, 1.2 Hz, 1 H), 4.58–
4.54 (m, 1 H), 4.18–4.09 (m, 2 H), 3.97–3.86 (m, 1 H), 3.73 (t, J = 1 H), 6.08 (dd, J = 11.7, 7.0 Hz, 1 H), 5.21–5.18 (m, 1 H), 5.04 (s,
7.1 Hz, 1 H), 3.47–3.31 (m, 4 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.39
(s, 3 H), 1.33 (s, 3 H), 1.25–1.11 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.5 (C), 142.4 (CH), 121.2 (CH), 110.3 (C), 110.1
(C), 81.4 (CH), 79.7 (CH), 76.9 (CH), 67.7 (CH2), 42.5 (CH2), 41.2
1 H), 5.03–5.01 (m, 1 H), 4.63–4.58 (m, 2 H), 4.39 (d, J = 11.9 Hz,
1 H), 3.36–3.25 (m, 4 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 1.15–1.05 (m,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4 (C), 138.9 (CH),
137.7 (C), 128.7 (2ϫCH), 128.2 (2ϫCH), 128.0 (CH), 123.2 (CH),
(CH2), 27.3 (CH3), 27.0 (2ϫCH3), 25.5 (CH3), 15.2 (CH3), 13.5 112.5 (C), 105.7 (CH), 85.5 (CH), 82.7 (CH), 78.3 (CH), 68.9
(CH3) ppm. MS (ESI+-TOF): m/z (%) = 328 (100) [M + H]+.
HRMS: m/z calcd. for C17H30NO5 [M + H]+ 328.2124; found
(CH2), 42.9 (CH2), 40.5 (CH2), 26.4 (CH3), 24.9 (CH3), 14.8 (CH3),
13.4 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 376 (100) [M + H]+,
398 (34) [M + Na]+, 377 (28), 400 (22). HRMS: m/z calcd. for
328.2127. IR (neat): ν = 2986, 2935, 1628, 1064 cm–1.
˜
C21H30NO5 [M + H]+ 376.2124; found 376.2119. IR (neat): ν =
˜
(E)-N,N-Diethyl-6-O-tert-butyldiphenylsilyl-2,3-dideoxy-4,5-O-iso-
propylidene-D-threo-hex-2-enamide (3f): Starting from 1f (1.0 mmol,
3056, 1720, 1657, 1620, 1086 cm–1.
398.2 mg), yield 128.9 mg (26%); yellow oil; [α]2D0 = –6.8 (c = 1.00,
CHCl3); Rf = 0.20 (hexane/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 7.71–7.65 (m, 4 H), 7.45–7.34 (m, 6 H), 6.89 (dd, J =
15.0, 5.3 Hz, 1 H), 6.51 (d, J = 14.9 Hz, 1 H), 4.68 (app. dd, J =
7.5, 5.4 Hz, 1 H), 3.92–3.76 (m, 3 H), 3.47–3.32 (m, 4 H), 1.47 (s,
3 H), 1.43 (s, 3 H), 1.25–1.12 (m, 6 H), 1.06 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.3 (C), 141.9 (CH), 136.0 (4ϫCH), 133.5
(Z)-N,N-Diethyl-O-tert-buthyldimehyilsilyl-5,6-dideoxy-2,3-O-iso-
propylidene-α-D-lyxo-hept-5-enofuranosiduronamide (4d): Starting
from 1d (1.0 mmol, 302.4 mg), yield 147.9 mg (37%); colorless oil;
[α]2D0 = –75.4 (c = 1.00, CHCl3); Rf = 0.78 (hexane/EtOAc, 1:1). 1H
NMR (300 MHz, CDCl3): δ = 6.26 (dd, J = 11.7, 1.3 Hz, 1 H),
6.06 (dd, J = 11.7, 7.3 Hz, 1 H), 5.32 (s, 1 H), 5.20 (dd, J = 7.3,
3.7 Hz, 1 H), 5.06 (dd, J = 5.8, 3.7 Hz, 1 H), 4.52 (d, J = 5.8 Hz,
(C), 133.4 (C), 130.1 (CH), 130.0 (CH), 128.1 (4 ϫ CH), 121.8 1 H), 3.47–3.28 (m, 4 H), 1.45 (s, 3 H), 1.28 (s, 3 H), 1.16 (t, J =
(CH), 110.1 (C), 81.4 (CH), 77.7 (CH), 63.3 (CH2), 42.6 (CH2), 7.1 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.09 (s, 3 H),
41.2 (CH2), 27.4 (CH3), 27.3 (3ϫCH3), 27.1 (CH3), 19.6 (C), 15.3 0.06 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9 (C),
(CH3), 13.5 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 518 (100) [M 138.7 (CH), 123.5 (CH), 112.4 (C), 102.0 (CH), 87.4 (CH), 82.9
+ Na]+, 519 (41), 487 (19), 496 (13) [M + H]+, 520 (13). HRMS: (CH), 78.2 (CH), 43.0 (CH2), 40.4 (CH2), 26.4 (CH3), 26.0
Eur. J. Org. Chem. 2013, 4953–4961
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4957

H. Rodríguez-Solla et al.
FULL PAPER
(3 ϫ CH3), 25.0 (CH3), 18.2 (C), 14.7 (CH3), 13.4 (CH3), –4.2
for C19H31ClNO6 [M + H]+ 404.1840; found 404.1834. IR (neat):
˜
(CH3), –5.1 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 400 (100) [M ν = 3420, 1637, 1041, 752 cm–1.
+ H]+, 473 (75), 422 (34) [M + Na]+. HRMS: m/z calcd. for
(1S,2S,3S)-2-Chloro-N,N-diethyl-3-[(4R)-3-O-benzyl-1,2-O-isoprop-
ylidene-β- -threofuran-4-C-yl]cyclopropanecarboxamide (5b): Start-
C20H38NO5Si [M + H]+ 400.2519; found 400.2513. IR (neat): ν =
˜
L
2976, 1721, 1114 cm–1.
ing from 3b (0.5 mmol, 187.7 mg), yield 112.4 mg (53%); yellow
oil; [α]2D0 = –18.5 (c = 1.00, CHCl3); Rf = 0.62 (hexane/EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): δ = 7.29–7.19 (m, 5 H), 5.87 (d, J =
3.9 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.58 (d, J = 3.9 Hz, 1 H),
4.54 (d, J = 12.0 Hz, 1 H), 4.04 (dd, J = 8.6, 3.2 Hz, 1 H), 3.92 (d,
J = 3.2 Hz, 1 H), 3.56 (dd, J = 7.5, 3.8 Hz, 1 H), 3.48 (q, J =
7.4 Hz, 1 H), 3.29 (hept, J = 6.8 Hz, 3 H), 2.11–2.03 (m, 2 H), 1.41
(s, 3 H), 1.26 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H), 1.03 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.5 (C), 137.6 (C),
128.8 (2ϫCH), 128.3 (CH), 128.1 (2ϫCH), 111.1 (CH), 104.9 (C),
83.3 (CH), 81.9 (CH), 80.6 (CH), 72.6 (CH2), 42.6 (CH2), 41.3
(CH2), 37.3 (CH), 28.5 (CH), 27.1 (CH), 26.5 (CH3), 24.8 (CH3),
15.2 (CH3), 13.5 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 446 (100)
[M + Na]+, 448 (50) [M + 2 + Na]+, 424 (16) [M + H]+. HRMS:
m/z calcd. for C22H30ClNNaO5 [M + Na]+ 446.1710; found
(Z)-N,N-Diethyl-2,3-dideoxy-4,5:6,7-di-O-isopropylidene-L-xylo-
hept-2-enamide (4e): Starting from 1e (1.0 mmol, 230.1 mg), yield
157.2 mg (48%); yellow oil; [α]2D0 = –26.5 (c = 1.00, CHCl3); Rf =
1
0.47 (hexane/EtOAc, 1:1). H NMR (300 MHz, CDCl3): δ = 6.21
(d, J = 12.3 Hz, 1 H), 5.85 (t, J = 9.0 Hz, 1 H), 4.89 (t, J = 8.6 Hz,
1 H), 4.25 (q, J = 6.0 Hz, 1 H), 4.13 (t, J = 8.1 Hz, 1 H), 3.95 (t,
J = 8.1 Hz, 1 H), 3.89–3.84 (m, 1 H), 3.40–3.26 (m, 4 H), 1.39–
1.37 (m, 9 H), 1.30 (s, 3 H), 1.11 (q, J = 8.4 Hz, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.3 (C), 136.9 (CH), 125.9 (CH),
109.7 (C), 109.1 (C), 80.4 (CH), 75.3 (CH), 75.1 (CH), 65.2 (CH2),
42.4 (CH2), 39.6 (CH2), 27.0 (CH3), 26.7 (CH3), 26.3 (CH3), 25.3
(CH3), 14.1 (CH3), 12.9 (CH3) ppm. MS (ESI+-TOF): m/z (%) =
328 (100) [M + H]+. HRMS: m/z calcd. for C17H30NO5 [M + H]+
328.2124; found 328.2126. IR (neat): ν = 2998, 1614, 1031,
˜
446.1705. IR (neat): ν = 2982, 1713, 997 cm–1.
701 cm–1.
˜
(1S,2S,3S)-2-Chloro-N,N-diethyl-3-[(4R)-1-O-benzyl-2,3-O-isoprop-
ylidene-β-L-erythrofuran-4-C-yl]cyclopropanecarboxamide (5c):
(Z)-N,N-Diethyl-6-O-tert-butyldiphenylsilyl-2,3-dideoxy-4,5-O-iso-
propylidene-D-threo-hex-2-enamide (4f): Starting from 1f (1.0 mmol,
Starting from 3c (0.5 mmol, 187.7 mg), yield 146.3 mg (69%); col-
orless solid; m.p. 146–147 °C (Et2O/Hex); [α]2D0 = +13.2 (c = 1.00,
CHCl3); Rf = 0.32 (hexane/EtOAc, 3:1). 1H NMR (300 MHz,
CDCl3): δ = 7.34–7.19 (m, 5 H), 5.77 (d, J = 3.8 Hz, 1 H), 4.52 (d,
J = 3.8 Hz, 1 H), 3.84–3.78 (m, 1 H), 3.62–3.51 (m, 4 H), 3.19
(sext, J = 7.2 Hz, 2 H), 2.99 (sext, J = 7.2 Hz, 2 H), 2.25 (dd, J =
10.2, 3.6 Hz, 1 H), 2.13 (dt, J = 10.0, 4.6 Hz, 1 H), 1.30 (s, 3 H),
1.20 (s, 3 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.02 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6 (C), 137.7 (C),
128.9 (2ϫCH), 128.3 (CH), 128.2 (2ϫCH), 112.2 (CH), 105.1 (C),
83.1 (CH), 82.3 (CH), 77.6 (CH), 72.6 (CH2), 42.4 (CH2), 40.9
(CH2), 34.5 (CH), 28.8 (CH), 28.7 (CH), 27.2 (CH3), 26.9 (CH3),
14.7 (CH3), 13.0 (CH3) ppm. MS (ESI+-TOF): m/z (%) = 424 (100)
[M + H]+, 426 (44) [M + 2 + H]+, 496 (28), 446 (25). HRMS: m/z
calcd. for C22H31ClNO5 [M + H]+ 424.1891; found 424.1871. IR
398.2 mg), yield 228.0 mg (46%); colorless oil; [α]2D0 = +8.7 (c =
1.00, CHCl3); Rf = 0.33 (hexane/EtOAc, 3:1). 1H NMR (300 MHz,
CDCl3): δ = 7.76–7.72 (m, 4 H), 7.40–7.33 (m, 6 H), 6.16 (dd, J =
11.7, 1.0 Hz, 1 H), 5.85 (dd, J = 11.7, 8.4 Hz, 1 H), 5.05 (t, J =
7.6 Hz, 1 H), 3.97–3.86 (m, 3 H), 3.35 (q, J = 7.2 Hz, 2 H), 3.27
(c, J = 7.2 Hz, 2 H), 1.43 (d, J = 7.8 Hz, 6 H), 1.12 (t, J = 6.8 Hz,
3 H), 1.08–1.06 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.6 (C), 138.1 (CH), 136.1 (2ϫCH), 136.0 (2ϫCH), 134.0 (C),
133.8 (C), 130.0 (2ϫCH), 127.8 (4ϫCH), 125.8 (CH), 109.9 (C),
82.6 (CH), 74.3 (CH), 64.2 (CH2), 42.8 (CH2), 39.9 (CH2), 27.5
(CH3), 27.4 (CH3), 27.1 (3 ϫ CH3), 19.5 (C), 14.5 (CH3), 13.2
(CH3) ppm. MS (ESI+-TOF): m/z (%) = 518 (100) [M + Na]+, 519
(41), 520 (13), 496 (6) [M + H]+ . HRMS: m/z calcd. for
C29H41NNaO4Si [M + Na]+ 518.2703; found 518.2700. IR (neat):
ν = 3041, 1624, 1100, 1067 cm–1.
˜
(neat): ν = 2932, 1634, 1464, 1259, 1075 cm–1.
˜
Synthesis of Chlorocyclopropanecarboxamides 5a–e and 6a–d: To a
suspension of anhydrous CrCl2 (1.5 mmol, 3.0 equiv.) in THF
(5 mL) was added 3 or 4 (0.5 mmol, 1.0 equiv.) in THF (2 mL) and
CCl4 (0.5 mmol, 1.0 equiv.) at room temperature, under an inert
atmosphere. After stirring for 16 h at reflux, the reaction mixture
was quenched by the addition of 1.0 m aqueous HCl (5 mL), ex-
tracted with Et2O (3ϫ 10 mL) and washed with saturated NH4Cl
solution and water. Usual work-up and further purification by col-
umn chromatography on silica gel (hexane/EtOAc, 10:1) afforded
pure 5 and 6.
(1S,2S,3S)-2-Chloro-N,N-diethyl-3-[(4R)-1-O-tert-butyldimethylsil-
yl-2,3-O-isopropylidene-β-L-erythrofuran-4-C-yl]cyclopropanecarb-
oxamide (5d): Starting from 3d (0.5 mmol, 199.8 mg), yield
181.5 mg (81%); yellow oil; [α]2D0 = +39.9 (c = 1.00, CHCl3); Rf =
1
0.45 (hexane/EtOAc, 3:1). H NMR (300 MHz, CDCl3): δ = 5.29
(s, 1 H), 4.80–4.77 (m, 1 H), 4.55 (d, J = 5.8 Hz, 1 H), 4.00–3.96
(m, 1 H), 3.78–3.74 (m, 1 H), 3.58–3.26 (m, 4 H), 2.09–2.02 (m, 2
H), 1.44 (s, 3 H), 1.31 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.10 (t, J
= 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.08 (d, J = 4.5 Hz, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.2 (C), 112.4 (C), 100.8 (CH), 87.2
(CH), 79.8 (CH), 79.5 (CH), 42.0 (CH2), 40.9 (CH2), 36.9 (CH),
28.5 (CH), 26.0 (CH), 25.5 (3ϫCH3), 25.0 (CH3), 24.7 (CH3), 17.8
(C), 14.8 (CH3), 13.0 (CH3), –4.5 (CH3), –5.4 (CH3) ppm. MS (ESI-
TOF): m/z (%) = 448 (100) [M + H]+, 496 (94), 450 (38) [M + 2 +
H]+, 438 (22), 470 (16). HRMS: m/z calcd. for C21H39ClNO5Si [M
(1S,2S,3S)-2-Chloro-N,N-diethyl-3-[(5R)-1,2:3,4-di-O-isopropylid-
ene-β-L-arabinopyran-5-C-yl]cyclopropanecarboxamide (5a): Start-
ing from 3a (0.5 mmol, 177.7 mg), yield 173.7 mg (86%); yellow
oil; [α]2D0 = –37.5 (c = 1.00, CHCl3); Rf = 0.61 (hexane/EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): δ = 5.52 (d, J = 5.0 Hz, 1 H), 4.62
(dd, J = 7.9, 2.5 Hz, 1 H), 4.43–4.16 (m, 2 H), 3.75 (dd, J = 8.2,
2.8 Hz, 2 H), 3.60–3.25 (m, 4 H), 2.16–2.00 (m, 1 H), 1.98 (dd, J
= 5.8, 3.6 Hz, 1 H), 1.48 (s, 3 H), 1.46 (s, 3 H), 1.36 (s, 3 H), 1.32
(s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.10 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.3 (C), 109.3 (C), 108.5 (C),
+ H]+ 448.2286; found 448.2265. IR (neat): ν = 2976, 1721,
˜
1114 cm–1.
(1S,2S,3S)-2-Chloro-N,N-diethyl-3-(3-O-tert-butyldiphenylsilyl-1,2-
isopropilidene-
D-threitol-1-C-yl)cyclopropanecarboxamide (5e):
Starting from 3f (0.5 mmol, 247.9 mg), yield 198.7 mg (73%); col-
96.5 (CH), 71.9 (CH), 70.7 (CH), 70.4 (CH), 67.9 (CH), 42.2 (CH2), orless oil; [α]2D0 = –35.0 (c = 1.00, CHCl3); Rf = 0.33 (hexane/
40.8 (CH2), 37.6 (CH), 28.4 (CH), 26.1 (CH), 25.9 (2ϫCH3), 24.9 EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 7.75–7.66 (m, 4 H),
(CH3), 24.3 (CH3), 14.5 (CH3), 13.1 (CH3) ppm. MS (ESI+-TOF): 7.45–7.35 (m, 6 H), 4.14–4.08 (m, 1 H), 4.04–3.99 (m, 1 H), 3.92
m/z (%) = 404 (100) [M + H]+, 406 (11), 356 (4). HRMS: m/z calcd.
(dd, J = 11.4, 3.6 Hz, 1 H), 3.80 (dd, J = 11.4, 4.0 Hz, 1 H), 3.55
4958
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4953–4961

Highly Functionalized Enantiopure Halocyclopropanes
(dd, J = 7.5, 3.5 Hz, 1 H), 3.52–3.40 (m, 2 H), 3.39–3.30 (m, 2 H),
2.20 (dd, J = 5.9, 3.6 Hz, 1 H), 1.79 (td, J = 7.8, 5.8 Hz, 1 H), 1.42
(d, J = 2.7 Hz, 6 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.12 (t, J = 7.1 Hz,
3 H), 1.06 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.8
(C), 136.1 (4ϫCH), 133.6 (2ϫC), 130.0 (2ϫCH), 128.0 (4ϫCH),
109.5 (C), 82.7 (CH), 76.0 (CH), 63.1 (CH2), 42.6 (CH2), 41.3
(CH2), 37.9 (CH), 29.3 (CH), 27.6 (CH), 27.5 (CH3), 27.3 (CH3),
27.2 (3ϫCH3), 19.6 (C), 15.2 (CH3), 13.5 (CH3) ppm. MS (ESI-
TOF): m/z (%) = 566 (100) [M + Na]+, 568 (58) [M + 2 + Na]+,
569 (19), 582 (16). HRMS: m/z calcd. for C30H42ClNNaO4Si [M +
m/z (%) = 376 (100) [M + H]+ . HRMS: m/z calcd. for
C18H31ClNO5 [M + H]+ 376.1891; found 376.1888. IR (neat): ν =
˜
2986, 1634, 1069, 737 cm–1.
(1R,2S,3S)-2-Chloro-N,N-diethyl-3-(3-O-tert-butyldiphenylsilyl-1,2-
isopropilidene-D-threitol-1-C-yl)cyclopropanecarboxamide (6d):
Starting from 4f (0.5 mmol, 247.9 mg), yield 206.8 mg (76%); col-
orless oil; [α]2D0 = +9.5 (c = 1.00, CHCl3); Rf = 0.68 (hexane/EtOAc,
1
3:1). H NMR (300 MHz, CDCl3): δ = 7.75–7.71 (m, 4 H), 7.43–
7.37 (m, 6 H), 4.07–4.02 (m, 1 H), 3.85–3.70 (m, 3 H), 3.68–3.59
(m, 3 H), 3.29 (dq, J = 14.6, 7.2 Hz, 1 H), 3.12 (dq, J = 13.9,
7.0 Hz, 1 H), 2.24 (dd, J = 10.1, 3.6 Hz, 1 H), 1.80 (dt, J = 10.0,
4.0 Hz, 1 H), 1.40 (s, 3 H), 1.27 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H),
1.11–1.06 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4
(C), 136.0 (4ϫCH), 133.4 (C), 133.3 (C), 130.0 (2ϫCH), 128.0
(4ϫCH), 109.1 (C), 82.0 (CH), 75.0 (CH), 64.2 (CH2), 42.2 (CH2),
40.7 (CH2), 34.5 (CH), 33.0 (CH), 28.5 (CH), 27.7 (CH3), 27.1
(3ϫCH3), 26.9 (CH3), 19.5 (C), 14.6 (CH3), 12.8 (CH3) ppm. MS
(ESI-TOF): m/z (%) = 566 (100) [M + Na]+, 568 (56) [M + 2 +
Na]+, 569 (19), 582 (13), 553 (9). HRMS: m/z calcd. for
C30H42ClNNaO4Si [M + Na]+ 566.2469; found 566.2473. IR
Na]+ 566.2469; found 566.2473. IR (neat): ν = 2932, 1639, 1463,
˜
1428, 1381 cm–1.
(1R,2S,3S)-2-Chloro-N,N-diethyl-3-[(5R)-1,2:3,4-di-O-isopropylid-
ene-β-L-arabinopyran-5-C-yl]cyclopropanecarboxamide (6a): Start-
ing from 4a (0.5 mmol, 177.7 mg), yield 111.1 mg (55%); colorless
solid; m.p. 145–146 °C (Et2O/Hex); [α]2D0 = –175.4 (c = 1.00,
CHCl3); Rf = 0.38 (hexane/EtOAc, 3:1). 1H NMR (300 MHz,
CDCl3): δ = 5.38 (d, J = 5.1 Hz, 1 H), 4.58 (dd, J = 9.6, 1.8 Hz, 1
H), 4.25–4.20 (m, 2 H), 3.66 (t, J = 4.08 Hz, 1 H), 3.63–3.56 (m, 1
H), 3.54–3.45 (m, 2 H), 3.36–3.21 (m, 2 H), 2.22 (dd, J = 10.3,
3.6 Hz, 1 H), 2.14 (td, J = 9.9, 4.5 Hz, 1 H), 1.48 (s, 3 H), 1.46 (s,
3 H), 1.37 (s, 3 H), 1.27–1.23 (m, 6 H), 1.13 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.5 (C), 109.5 (C),
109.0 (C), 96.5 (CH), 72.8 (CH), 71.2 (CH), 70.6 (CH), 65.0 (CH),
42.6 (CH2), 40.7 (CH2), 34.4 (CH), 31.4 (CH), 28.6 (CH), 26.3
(CH3), 26.2 (CH3), 25.3 (CH3), 24.7 (CH3), 14.8 (CH3), 13.6
(CH3) ppm. MS (ESI-TOF): m/z (%) = 426 (100) [M + Na]+, 428
(56) [M + 2 + Na]+, 404 (16) [M + H]+, 429 (13). HRMS: m/z
calcd. for C19H30ClNNaO6 [M + Na]+ 426.1659; found 426.1652.
(neat): ν = 2932, 1639, 1463, 1428, 1381 cm–1.
˜
Synthesis of Bromocyclopropanes 5f and 6e: Bromocyclopropanes
5f and 6e were synthesized following the same procedure used for
the synthesis of chlorocyclopropanecarboxamides 5a–e, and 6a–d
[13]
using anhydrous CrBr2
as the carbenoid source.
instead of CrCl2 and commercial CBr4
(1S,2S,3S)-2-Bromo-N,N-diethyl-3-[(5R)-1,2:3,4-di-O-isopropylid-
ene-β- -arabinopyran-5-C-yl]cyclopropanecarboxamide (5f): Start-
L
IR (neat): ν = 3420, 1637, 1041, 752 cm–1.
˜
ing from 3a (0.5 mmol, 177.7 mg), yield 141.2 mg (63%); colorless
oil; [α]2D0 = –23.6 (c = 0.50, CHCl3); Rf = 0.10 (hexane/EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): δ = 5.52 (d, J = 5.1 Hz, 1 H), 4.63
(dd, J = 7.9, 2.4 Hz, 1 H), 4.33 (m, 2 H), 3.69 (dd, J = 9.0, 1.9 Hz,
1 H), 3.63 (dd, J = 7.5, 4.2 Hz, 1 H), 3.58–3.26 (m, 4 H), 2.04–1.94
(m, 2 H), 1.51 (s, 3 H), 1.46 (s, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H),
1.27 (t, J = 7.1 Hz, 3 H), 1.11 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.9 (C), 109.8 (C), 109.0 (C), 97.0 (CH),
72.0 (CH), 71.1 (CH), 70.9 (CH), 70.4 (CH), 42.7 (CH2), 41.3
(CH2), 29.0 (CH), 26.4 (CH3), 26.3 (CH3), 25.9 (CH3), 25.8 (CH3),
25.4 (CH), 24.8 (CH), 15.0 (CH3), 13.6 (CH3) ppm. MS (ESI+-
TOF): m/z (%) = 470 (100) [M + Na]+, 472 (100) [M + 2 + Na]+,
4 7 3 ( 2 8 ) ; 4 4 8 ( 1 6 ) , 4 5 0 ( 1 6 ) . H R M S : m / z c a l c d . fo r
C19H30BrNNaO6 [M + Na]+ 470.1154; found 470.1162. IR (neat):
(1R,2S,3S)-2-Chloro-N,N-diethyl-3-[(4R)-3-O-benzyl-1,2-O-iso-
propylidene-β-L-threofuran-4-C-yl]cyclopropanecarboxamide (6b):
Starting from 4b (0.5 mmol, 187.7 mg), yield 135.7 mg (64%); yel-
low oil; [α]2D0 = –47.5 (c = 1.00, CHCl3); Rf = 0.52 (hexane/EtOAc,
3:1). 1H NMR (300 MHz, CDCl3): δ = 7.31–7.27 (m, 5 H), 5.77
(d, J = 4.7 Hz, 1 H), 4.62 (q, J = 12.0 Hz, 2 H), 4.53 (d, J = 4.9 Hz,
1 H), 3.82 (d, J = 5.7 Hz, 1 H), 371–3.43 (m, 2 H), 3.19 (dq, J =
14.6, 7.1 Hz, 2 H), 3.00 (dq, J = 13.9, 7.0 Hz, 2 H), 2.24 (dd, J =
9.8, 4.7 Hz, 1 H), 2.13 (td, J = 9.9, 4.4 Hz, 1 H), 1.30 (s, 3 H), 1.20
(s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.02 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.2 (C), 137.2 (C), 128.4
(2ϫCH), 127.9 (CH), 127.7 (2ϫCH), 111.8 (CH), 104.6 (C), 82.7
(CH), 81.9 (CH), 77.4 (CH), 72.2 (CH2), 42.0 (CH2), 40.5 (CH2),
34.1 (CH), 28.4 (CH), 28.3 (CH), 26.8 (CH3), 26.5 (CH3), 14.2
(CH3), 12.6 (CH3) ppm. MS (ESI-TOF): m/z (%) = 446 (100) [M
+ Na]+, 448 (44) [M + 2 + Na]+, 449 (13). HRMS: m/z calcd. for
C22H30ClNNaO5 [M + Na]+ 446.1710; found 446.1705. IR (neat):
ν = 3434, 2984, 1634, 1069, 737 cm–1.
˜
(1R,2S,3S)-2-Bromo-N,N-diethyl-3-[(5R)-1,2:3,4-di-O-isopropylid-
ene-β-L-arabinopyran-5-C-yl]cyclopropanecarboxamide (6e): Start-
ing from 4a (0.5 mmol, 177.7 mg), yield 134.5 mg (60%); colorless
ν = 2982, 1713, 997 cm–1.
˜
solid; m.p. 135–137 °C (Et2O/Hex); [α]2D0 = –78.5 (c = 0.50, CHCl3);
1
(1R,2S,3S)-2-Chloro-N,N-diethyl-3-(1,2:3,4-di-O-isopropylidene-
L-
Rf = 0.35 (hexane/EtOAc, 3:1). H NMR (300 MHz, CDCl3): δ =
xylitol-1-C-yl)cyclopropanecarboxamide (6c): Starting from 4e
5.31 (d, J = 5.0 Hz, 1 H), 4.52 (dd, J = 7.9, 2.4 Hz, 1 H), 4.16 (dt,
J = 6.6, 2.0 Hz, 1 H), 4.15 (s, 1 H), 3.60–3.39 (m, 4 H), 3.32–3.14
(0.5 mmol, 163.7 mg), yield 137.2 mg (73%); yellow oil; [α]2D0
=
1
–41.5 (c = 1.00, CHCl3); Rf = 0.78 (hexane/EtOAc, 1:1). H NMR (m, 2 H), 2.20 (dd, J = 10.1, 3.9 Hz, 1 H), 2.11 (td, J = 9.8, 4.8 Hz,
(300 MHz, CDCl3): δ = 4.13 (dd, J = 8.1, 5.9 Hz, 1 H), 4.01 (dt, J 1 H), 1.41 (d, J = 6.4 Hz, 6 H), 1.31 (s, 3 H), 1.18 (s, 3 H), 1.18 (t,
= 7.5, 5.4 Hz, 1 H), 3.94 (dd, J = 8.1, 4.9 Hz, 1 H), 3.81–3.77 (m,
J = 7.2 Hz, 3 H), 1.07 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
2 H), 3.77–3.54 (m, 3 H), 3.29 (sext, J = 7.1 Hz, 1 H), 3.13 (sext, (75 MHz, CDCl3): δ = 166.9 (C), 109.5 (C), 109.0 (C), 96.5 (CH),
J = 7.1 Hz, 1 H), 2.24 (dd, J = 10.0, 3.9 Hz, 1 H), 1.76 (dt, J = 72.8 (CH), 71.2 (CH), 70.6 (CH), 65.4 (CH), 42.6 (CH2), 40.8
9.7, 4.3 Hz, 1 H), 1.47 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H), 1.23 (s, 3 H), 1.07 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.4 (C), 109.6 (C), 108.8 (C), 81.4
(CH2), 31.6 (CH), 28.4 (CH), 26.4 (CH3), 26.3 (CH3), 25.3 (CH3),
24.7 (CH3), 20.3 (CH), 14.9 (CH3), 13.6 (CH3) ppm. MS (ESI-
TOF): m/z (%) = 470 (100) [M + Na]+, 472 (100) [M + 2 + Na]+,
(CH), 76.8 (CH), 76.3 (CH), 67.5 (CH2), 42.1 (CH2), 40.4 (CH2), 473 (22), 448 (9), 450 (9). HRMS: m/z calcd. for C19H30BrNNaO6
35.2 (CH), 32.8 (CH), 28.4 (CH), 27.1 (CH3), 26.6 (CH3), 26.5 [M + Na]+ 470.1154; found 470.1161. IR (neat): ν = 3434, 2984,
˜
(CH3), 25.0 (CH3), 14.2 (CH3), 12.4 (CH3) ppm. MS (ESI-TOF):
1634, 1069, 737 cm–1.
Eur. J. Org. Chem. 2013, 4953–4961
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4959

H. Rodríguez-Solla et al.
FULL PAPER
Chlorocyclopropanamines 11 and 12[12b]
de Cristalización Consolider Ingenio 2010), the Portuguese Fun-
dação para a Ciencia e a Tecnologia (FCT), the European Union
(EU), Quadro de Referência Estratégico Nacional (QREN), Fundo
Europeu de Desenvolvimento Regional (FEDER) and Programa
Operacional Temático Factores de Competitividade (COMPETE)
(project PEst-C/QUI/UI0062/2011). C. C. and V. d. A. thank the
Ministerio de Ciencia e Innovación (MICINN) for a Juan de la
Cierva and Ramón y Cajal contract. A. D. P. thanks the Uni-
versidad de Oviedo for a predoctoral fellowship, and R. S. thanks
the FCT for an “Investigador Auxiliar” position.
(4R)-3-O-Benzyl-[(1S,2R,3S)-2-chloro-3-diethylaminomethylcyclo-
propanyl]-1,2-isopropylidene-β-L-threofuranose (11): Starting from
5b (0.4 mmol, 169.6 mg), yield 121.3 mg (74%); colorless oil; [α]2D0
= –143.3 (c = 0.50, CHCl3); Rf = 0.15 (hexane/EtOAc, 1:10). 1H
NMR (300 MHz, CDCl3): δ = 7.32–7.21 (m, 5 H), 5.87 (d, J =
3.9 Hz, 1 H), 4.68 (d, J = 12.0 Hz, 1 H), 4.56 (s, 1 H), 4.54 (d, J =
8.4 Hz, 1 H), 3.97–3.91 (m, 2 H), 2.90 (dd, J = 7.7, 4.0 Hz, 1 H),
2.66 (dd, J = 13.7, 5.4 Hz, 1 H), 2.58 (q, J = 7.2 Hz, 4 H), 2.30
(dd, J = 13.6, 7.4 Hz, 1 H), 1.41 (s, 3 H), 1.38–1.29 (m, 2 H), 1.26 (s,
3 H), 0.98 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 137.6 (C), 128.8 (2ϫCH), 128.3 (CH), 128.1 (2ϫCH), 111.7
(CH), 104.7 (C), 83.3 (CH), 82.1 (CH), 82.0 (CH), 72.6 (CH2), 54.3
(CH2), 46.8 (2ϫCH2), 36.4 (CH), 27.1 (CH), 26.5 (2ϫCH3), 21.0
(CH), 11.8 (2ϫCH3) ppm. MS (ESI-TOF): m/z (%) = 410 (100)
[M + H]+, 412 (38) [M + 2 + H], 413 (9). HRMS: m/z calcd. for
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C22H33ClNO4 [M + H]+ 410.2098; found 410.2096. IR (neat): ν =
˜
3419, 2973, 2936, 1634, 1005 cm–1.
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(5R)-[(1S,2R,3R)-2-Chloro-3-diethylaminomethylcyclopropanyl]-
1,2:3,4-di-O-isopropylidene-β-L-arabinopyranose (12a): Starting
from 6a (0.4 mmol, 161.6 mg), yield 110.7 mg (71%); yellow oil;
[α]2D0 = –52.5 (c = 0.60, CHCl3); Rf = 0.13 (hexane/EtOAc, 1:10).
1H NMR (300 MHz, CDCl3): δ = 5.54 (d, J = 5.2 Hz, 1 H), 4.59
(dd, J = 7.9, 2.3 Hz, 1 H), 4.27 (dd, J = 5.2, 2.3 Hz, 1 H), 4.23 (dd,
J = 7.9, 1.9 Hz, 1 H), 3.23 (dd, J = 7.9, 1.9 Hz, 1 H), 3.07 (dd, J
= 13.3, 3.3 Hz, 1 H), 2.64 (q, J = 6.0 Hz, 4 H), 2.11 (dd, J = 13.3,
9.6 Hz, 1 H), 1.48 (s, 3 H), 1.49 (s, 3 H), 1.36 (s, 3 H), 1.31 (s, 3
H), 1.16–1.07 (m, 1 H), 1.04 (t, J = 7.1 Hz, 6 H), 0.96–0.89 (m, 1
H), 0.18 (q, J = 5.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 109.4 (C), 108.4 (C), 97.1 (CH), 73.3 (CH), 71.4 (CH), 70.6 (CH),
69.2 (CH), 52.7 (CH2), 47.0 (2ϫCH2), 26.4 (2ϫCH3), 25.1 (CH3),
24.7 (CH3), 14.7 (CH), 13.9 (CH), 11.6 (2ϫCH3), 10.3 (CH2) ppm.
MS (ESI-TOF): m/z (%) = 392 (100) [M – Cl + H + K]+, 304 (90),
365 (53) [M – Cl + H + NH4 ]+ . HRMS: m/z calcd. for
C19H32KNO5 [M – Cl + H + K]+ 393.1918; found 393.1127. IR
(neat): ν = 3435, 2981, 2935, 1645, 1003 cm–1.
˜
(1S,2R,3R)-2-Chloro-3-diethylaminomethyl-1-(1,2-O-isopropylidene-
D
-threitol-1-C-yl)cyclopropane (12b): Starting from 6d (0.4 mmol,
217.7 mg); Yield: 58.36 mg (52%); colorless oil; [α]2D0 = –4.5 (c =
1.00, CHCl3); Rf
0.09 (hexane/EtOAc, 1:10). 1H NMR
=
(300 MHz, CDCl3): δ = 3.99 (dt, J = 8.2, 3.3 Hz, 1 H), 3.91 (dd, J
= 12.2, 3.3 Hz, 1 H), 3.68 (dd, J = 12.3, 3.4 Hz, 1 H), 3.60 (t, J =
8.4 Hz, 1 H), 3.00 (dd, J = 13.7, 4.8 Hz, 1 H), 2.96–2.93 (m, 1 H),
2.69 (dq, J = 7.1, 2.4 Hz, 4 H), 2.42 (dd, J = 13.6, 8.3 Hz, 1 H),
1.99 (br. s, 1 H), 1.58–1.42 (m, 2 H), 1.44 (s, 3 H), 1.38 (s, 3 H),
1.10 (t, J = 7.2 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
109.4 (C), 82.0 (CH), 75.0 (CH), 61.4 (CH2), 50.4 (CH2), 46.8
(2ϫCH2), 35.7 (CH), 28.4 (CH), 27.5 (CH3), 27.2 (CH3), 24.4
(CH), 11.6 (2ϫCH3) ppm. MS (ESI-TOF): m/z (%) = 292 (100)
[M + H]+, 294 (38) [M + 2 + H]. HRMS: m/z calcd. for
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˜
3435, 2983, 2935, 1641, 1381 cm–1.
Supporting Information (see footnote on the first page of this arti-
1
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Acknowledgments
The authors acknowledge financial support from the Spanish Min-
isterio de Economía y Competitividad (MINECO) (grant numbers
CTQ2010-14959, MAT2006-01997, MAT2010-15094 and Factoria
4960
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4953–4961

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Received: March 4, 2013
Published Online: June 17, 2013
Eur. J. Org. Chem. 2013, 4953–4961
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4961