Cyclopropanation of enantiopure metal alkenyl carbenes with 2-methoxyfuran: A practical route to carboxycyclopropylglycine precursors

Article abstract of DOI:10.1002/chem.200601332

We have examined the reactivity of enantiopure alkenyl Fischer carbene complexes 1, readily available from the chiral pool, with 2-methoxyfuran 4. In this reaction, polyfunctionalised cyclopropylcarbenes 5 are obtained under very mild conditions and with

Full text of DOI:10.1002/chem.200601332

DOI: 10.1002/chem.200601332
Cyclopropanation of Enantiopure Metal Alkenyl Carbenes with
2-Methoxyfuran: A Practical Route to Carboxycyclopropylglycine Precursors
JosØ Barluenga,* Ana de Prado, Javier Santamaría, and Miguel Tomµs[a]
Abstract: We have examined the reac-
tivity of enantiopure alkenyl Fischer
carbene complexes 1, readily available
from the chiral pool, with 2-methoxy-
furan 4. In this reaction, polyfunction-
alised cyclopropylcarbenes 5 are ob-
tained under very mild conditions and
with high selectivity, the major stereo-
isomer being isolated in an enantiopure
form. The reaction involves the conju-
gate nucleophilic addition of 2-methox-
yfuran 4 to the carbene complexes 1
followed by ring closure of the result-
ing zwitterionic intermediate species.
The oxidation of the carbene 5a results
in the formation of the enantiopure cy-
clopropane diester 6. Further elabora-
tion of the cyclopropane 6 allows for
an efficient enantioselective access to
alcohols or diols 7–9 as well as to cy-
clopropanecarbaldehydes 10–12. The
protocol described herein provides a
very simple entry to interesting enan-
tiopure precursors of carboxycyclopro-
pylglycine derivatives from readily
available starting materials. In order to
test this potential as carboxycyclopro-
pylglycine precursors, the aminocyana-
tion of the cyclopropanecarbaldehyde
10 was undertaken and the a-amino-
cyano derivative 13 was isolated as a
single diastereosiomer.
Keywords: asymmetric synthesis ·
carbenes · chiral pool · cyclopropa-
nation · diastereoselectivity
Introduction
benes proved to be excellent acceptor substrates for the Mu-
kaiyama–Michel addition reaction of 2-trimethylsilyloxyfur-
an 2 to produce new functionalised carbene complexes 3, as
summarised in Scheme 1.[5] In this case, the conjugate addi-
Cyclopropane rings have emerged as an important target in
modern organic synthesis. This skeleton is found as a basic
structural element in a wide range of naturally occurring
compounds and analogues with important biological and
pharmacological applications.[1] Additionally, functionalised
cyclopropanes play a prominent role as synthetic key inter-
mediates in different processes.[2] In this sense, searching for
new methods in the synthesis of enantiopure cyclopro-
panes[3] represents a field with increasing interest.
À
tion of 2 is followed by the cleavage of the O Si bond to
generate the butenolide skeleton.
On the other hand, as part of our study into the synthetic
potential of group 6 Fischer carbene complexes, we recently
initiated the study of the potential of enantiopure Fischer
carbene complexes 1a,b, prepared by condensation of [pen-
tacarbonyl methoxy(methyl)carbene]tungsten(0) complex
G
and aldehydes readily available from the chiral pool,[4] in
diastereoselective synthesis. Gratifyingly, these metal car-
Scheme 1. Stereoselective Mukaiyama–Michael addition of carbene 2-tri-
methylsilyloxyfuran 2 to carbene complexes 1.
This result prompted us to investigate the behaviour of 2-
[a] Prof. Dr. J. Barluenga, Dr. A. de Prado, Dr. J. Santamaría,
Prof. Dr. M. Tomµs
À
methoxyfuran 4, a reagent that lacks the labile O Si bond,
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C., Universidad de Oviedo
33006 Oviedo (Spain)
Fax : (+34)98-510-3450
E-mail: barluenga@uniovi.es
but is still reactive for conjugate addition. In this sense, iso-
lated examples reveal that 2-methoxyfuran 4 is able to cy-
clopropanate highly electron-deficient alkenes and can be
thus considered as a synthetic equivalent of the crotylcar-
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Chem. Eur. J. 2007, 13, 1326 – 1331

FULL PAPER
bene species A (Figure 1).[6] In such cases, the cyclopropana-
tion involves nucleophilic addition and furan ring opening
(Michael-initiated cyclopropanation reaction, MICR). On
the basis of these findings, we decided to study the reaction
9:1, face selectivity >98:2). It is noteworthy that by simply
purifying the crude mixture of cyclopropylcarbenes 5a,b by
conventional flash column chromatography the major cyclo-
adduct could be isolated in good yield and high purity (5a,b
>98% de; 5a: 69% yield; 5b: 75% yield). It should be
noted that both chiral appendages lead to cycloadducts 5a
and 5b with complementary absolute configuration at the
three stereogenic centres of the cyclopropane ring. Recrys-
tallization of cyclopropylcarbenes 5a and 5b from a 5:1 mix-
ture of pentane/CH2Cl2 gave single crystals suitable for X-
ray analysis (see Figures 2and 3).
Figure 1. Schematic representations of crotylcarbene A and enantiopure
cyclopropanes B. FG=functional group.
of 1 with 4 as it might provide enantiopure cyclopropanes of
type B with very attractive structural features such as
1) three stereogenic centres, 2) a highly versatile functionali-
zation and 3) three contiguous orthogonal functional groups
attached to the cyclopropane ring. Herein, we report our re-
sults on this cyclopropanation reaction and the elaboration
of the individual functionalities of the resulting cycloadduct
without breaking the cyclopropane ring.[7]
Results and Discussion
Figure 2. ORTEP view of enantiopure cyclopropylcarbene complex 5a.
Synthesis of cyclopropylcarbene complexes: The Fischer car-
bene complex 1a was found to smoothly react with 2-me-
thoxyfuran 4 (toluene, À558C) affording the cyclopropylcar-
bene complex 5a in high yield (93%). In terms of stereose-
lectivity, the trans/cis ratio was 4.5:1, while the face stereose-
lectivity was 96:4 (Scheme 2). Similarly, the reaction of the
carbene complex 1b with 2-methoxyfuran
4 (toluene,
À608C) resulted in the formation of the cyclopropylcarbene
5b in high yield (86%) and with higher selectivity (trans/cis
Figure 3. ORTEP view of enantiopure cyclopropylcarbene complex 5b.
A mechanistic proposal for the formation of the cyclopro-
pylcarbene complexes 5 is shown in Scheme 3. In a general
view, the process would involve conjugate nucleophilic addi-
tion of 2-methoxyfuran to the carbene complex to generate
a zwitterionic intermediate which would evolve by cyclopro-
pane ring closure. First, the stereochemical reaction course
of the attack to carbene complexes 1a and 1b, a process
that has been previously well established in the case of the
Mukaiyama–Michael addition of 2-trimethylsilyloxyfuran,[5,8]
would provide intermediates
I
and II, respectively
(Scheme 3). Therefore, this first step is common for both
furan reagents, 2-trimethylsilyloxyfuran 2 and 2-methoxyfur-
Scheme 2. Stereoselective cyclopropanation of carbene complexes 1 with
2-methoxyfuran 4.
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1327

J. Barluenga et al.
Scheme 3. Mechanistic proposal for the cyclopropylcarbene formation.
Scheme 5. Synthesis of the enantiopure cyclopropanecarbaldehydes 10,
11 and 12. a) HCl (6n), THF, 258C, 96%; b) NaIO4, CH2Cl2, H2O,
pH 7.2, 258C, 89%; c) i) O3, CH2Cl2, MeOH, À788C, ii) SMe2, À78 to
258C, 93%; d) LiAlH4, THF, À508C, 87%; e) PCC, CH2Cl2, 2 58C, 91%.
PCC=pyridinium chlorochromate.
an 4. Whereas, the intermediate resulting from the addition
À
of silyloxyfuran evolves through the O Si cleavage (vide
supra). Furan ring opening by intramolecular nucleophilic
displacement was found to be the most favourable way to
follow the intermediate I. Thus, the nucleophilic attack from
the upper face of the furan ring accounts well for the forma-
tion of the major isomer 5a from the intermediate I. In the
same way, ring closure of II permits us to rationalise the
preferential formation of cyclopropane 5b.
alkenyl function of 6 directly afforded the cyclopropanecar-
baldehyde 11 with ester and ketal motifs. Aldehyde func-
tionalization of the third carbon of the cyclopropane to pro-
duce 12 was effected by reduction of 6 to give 7 (vide supra)
followed by PCC oxidation. In terms of overall yields, the
cyclopropanecarbaldehydes 10, 11 and 12 were prepared
enantiomerically pure in 57, 62and 53% yields, respectively,
from 1a and 4.
Taking in mind the additional interest of structures 10 and
11 as direct precursors of carboxycyclopropylglycine deriva-
tives,[10] the Strecker reaction on compound 10 was evaluat-
ed. The use of (R)-(À)-2-phenylglycinol and trimethylsilyl
cyanide[11] led to a reaction mixture from which the a-ami-
nocyano adduct 13 was isolated in 60% yield as a pure ste-
reoisomer (>98% de, determined by NMR spectroscopic
analysis; Scheme 6). X-ray analysis of a single crystal of 13
collected from a mixture (5:1) of pentane/Et2O enabled us
to determine the absolute configuration of the new stereo-
centre (Figure 4).
Elaboration of the enantiopure cyclopropyl carbene com-
plex 5a: Once this mild and selective cyclopropanation had
been set up, selective and efficient elaboration of the cyclo-
propane functionalities was attempted on the enantiopure
adduct 5a. Among a number of useful transformations of
the metal carbene into organic moieties,[9] the oxidation to
the corresponding ester 6 was found to occur in nearly quan-
titative yield (Scheme 4). Moreover, the reduction of the
diester 6 with LiAlH4 at À508C or at room temperature pro-
duced the monoalcohol 7 (87% yield) and the diol 8 (94%
yield) which features a cis-allylic alcohol motif, respectively.
The potential of cyclopropane 6 was finally checked by its
ready elaboration into three different cyclopropanecarbalde-
hydes (Scheme 5). For instance, the ketal hydrolysis provid-
ed diol 9, which in turn was efficiently oxidised to the cyclo-
propanecarbaldehyde 10, featuring two different ester func-
tionalities. On the other hand, the oxidative cleavage of the
Scheme 6. Strecker aminocyanation on aldehyde 10. a) i) (R)-(À)-2-phe-
nylglycinol, MeOH, 258C, ii) TMSCN, À108C. TMSCN=trimethylsilyl
cyanide.
Conclusion
Scheme 4. Formation of cyclopropanecarboxylate 6 by oxidation of 5a
and its reduction to alcohols 7 and 8. a) Py+ÀOÀ, THF, H2O, 25 8C, 94%;
b) for 7: LiAlH4, THF, À508C, 87%; c) for 8: LiAlH4, THF, À50 to 258C,
94%.
Herein we report uncatalysed, efficient and diastereoselec-
tive cyclopropanations of enantiopure electron-poor olefins
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Chem. Eur. J. 2007, 13, 1326 – 1331

Carboxycyclopropylglycine Precursors
FULL PAPER
(CH), 121.3 (CH), 109.9 (C), 74.1 (CH), 69.6 (CH3), 69.1 (CH2), 57.5
(CH), 51.3 (CH3), 38.2(CH), 34.6 (CH), 26.8 (CH 3), 25.5 ppm (CH3);
HRMS (70 eV, EI): m/z: calcd for C19H20O10W: 592.0560 [M]+; found:
592.0557; elemental analysis calcd for C19H20O10W: C 38.54, H 3.40;
found: C 38.62, H 3.42.
Pentacarbonyl[1-((1S,2R,3S)-2-[(Z)-2-methoxycarbonylethenyl]-3-{(R)-
G
[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]}cyclopropyl)-1-methoxymethylidene]-
tungsten(0) (5b): Orange solid; yield: 75% (86% mixture of diastereo-
isomers); Rf =0.2(hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3,
258C, TMS): d=7.40 (m, 5H), 6.23 (dd, J
(d, J(H,H)=11.4 Hz, 1H), 5.47 (s, 1H), 4.56 (s, 3H), 4.29 (dd, J
11.4, 4.6 Hz, 1H), 3.96 (m, 3H), 3.78 (t, J(H,H)=4.6 Hz, 1H), 3.71 (s,
3H), 2.47 (m, 1H), 1.95 (ddd, J(H,H)=16.8, 12.2, 4.6 Hz, 1H), 1.67 ppm
(d, J
(H,H)=13.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, 2 58C, TMS): d=
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
322.9 (C), 203.4 (C), 197.3 (C), 166.6 (C), 145.1 (CH), 138.1 (C), 128.7
(CH), 128.2 (CH), 125.7 (CH), 120.6 (CH), 100.9 (CH), 74.5 (CH), 69.6
(CH3), 66.7 (CH2), 56.8 (CH), 51.1 (CH3), 39.9 (CH), 35.0 (CH),
30.7 ppm (CH2); HRMS (70 eV, EI): m/z: calcd for C24H22O10WNa:
677.0645 [M+Na]+; found: 677.0615; elemental analysis calcd (%) for
C24H22O10W: C 44.06, H 3.39; found: C 44.12, H 3.38.
Figure 4. ORTEP view of enantiopure a-aminocyano compound 13.
AHCTREUNG
a
with 2-methoxyfuran which provide 1,2,3-trisubstituted,
highly functionalised cyclopropanes.[12] The powerful elec-
tron-acceptor nature of the metalcarbene is responsible for
this Michael-initiated cyclopropanation.[13] This protocol ap-
pears to represent a flexible and short access to a number of
enantiopure cyclopropanecarbaldehydes.[14]
12 mL). Pyridine oxide (240 mg, 2.5 mmol) was added to this solution
and the mixture stirred at room temperature for 15 h. At this point, the
mixture was extracted with ethyl acetate (3”10 mL) and the solvents
were removed under reduced pressure. Chromatographic purification of
the residue (silica gel, hexane/ethyl acetate 3:1) yielded 133 mg (94%) of
the enantiopure cyclopropylester 6 as white solid. [a]2D0 =+66.0 (c=0.15
in CH2Cl2); Rf =0.18 (hexane/ethyl acetate 3:1); m.p. 67–698C; 1H NMR
(300 MHz, CDCl3, 2 85C, TMS): d=6.00 (dd, J
1H), 5.89 (d, J(H,H)=10.2Hz, 1H), 4.10 (dd, J(H,H)=8.0, 5.9 Hz, 1H),
3.92(dd, (H,H)=6.6, 5.9 Hz, 1H), 3.73 (m, 1H), 3.72(s, 3H), 3.68 (s,
3H), 3.53 (dt, (H,H)=9.7, 5.0 Hz, 1H), 2.02 (m, 1H), 1.80 (dd,
(H,H)=5.0, 4.9 Hz), 1.40 (s, 3H), 1.31 ppm (s, 3H); 13C NMR (75 MHz,
A
G
ACHTREUNG
J
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J
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Experimental Section
J
ACHTREUNG
CDCl3, 2 58C, TMS): d=171.6 (C), 166.2(C), 144.4 (CH), 121.1 (CH),
109.4 (C), 73.7 (CH), 69.0 (CH2), 51.8 (CH3), 50.9 (CH3), 30.2(CH), 26.8
(CH), 26.5 (CH3), 25.6 (CH), 25.3 ppm (CH3); HRMS (70 eV, EI): m/z:
calcd for C13H17O6: 269.1020 [MÀCH3]+; found: 269.1026; elemental
analysis calcd (%) for C14H20O6: C 59.14, H 7.09; found: C 59.02, H 7.06.
General considerations: All operations were carried out under a nitrogen
atmosphere by using conventional Schlenck techniques. All common re-
agents were obtained from commercial suppliers and used without fur-
ther purification unless otherwise indicated. Toluene, and THF were dis-
tilled from sodium benzophenone and methanol, and methylene chloride
from calcium hydride, under a nitrogen atmosphere prior to use. Hexane,
ethyl acetate and triethylamine were distilled before use. TLC was per-
formed on aluminium-backed plates coated with silica gel 60, with F254 in-
dicator. Flash chromatographic columns were carried out on silica gel 60,
230–240 mesh. Optical rotations were determined with a Perkin–Elmer
241 polarimeter by using a Na lamp; data are reported as follows: [a]D20
(concentration in g per 100 mL in solvent). High-resolution mass spectra
were determined on a Finnigan MAT95 spectrometer. NMR spectra
were run on Bruker AV-400, NAV-400, DPX-300, AC-300 and AMX-400
spectrometers. Elemental analyses were carried out with a Perkin–Elmer
240 B microanalyser.
(Z)-Methyl 3-{(1R,2R,3R)-2-(hydroxymethyl)-3-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]cyclopropyl}propenoate (7): LiAlH4 (62mg, 1.6 mmol) was
added to a solution of the cyclopropane 6 (120 mg, 0.4 mmol) in THF
(20 mL) at À508C. After stirring for 15 min at this temperature, H2O
(1 mL) was carefully added and the reaction was filtered through a plug
of Celite. At this point, the mixture was extracted with diethyl ether (3”
10 mL) and the solvents were removed under reduced pressure. Chroma-
tographic purification of the residue (silica gel, ethyl acetate) gave 89 mg
(87%) of the enantiopure cyclopropane 7 as a colourless oil. [a]D20
=
À80.08 (c=0.25 in CH2Cl2); Rf =0.6 (ethyl acetate); 1H NMR (400 MHz,
CDCl3, 2 58C, TMS): d=6.19 (dd, J(H,H)=11.2, 9.1 Hz, 1H), 5.90 (dd,
A
J
C
(H,H)=7.9, 5.9 Hz, 1H), 3.84
General procedure for the preparation of the carbenes 5: 2-Methoxyfur-
an 2 (0.84 mL, 5 mmol) was added to a solution of tungsten carbene com-
plex 1a–b (1 mmol) in toluene (90 mL) at À55 or À608C (Scheme 2).
After stirring for 48 h at this temperature, the solvents were removed
AHCTREUNG
J
J
ACHTREUNG
1.22 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 2 58C, TMS): d=167.5
(C), 147.8 (CH), 120.2 (CH), 109.3 (C), 75.2 (CH), 69.3 (CH2), 64.8
(CH2), 51.19 (CH3), 29.2 (CH), 27.2 (CH), 26.8 (CH3), 25.61 (CH3),
22.14 ppm (CH); HRMS (70 eV, EI): m/z: calcd for C13H21O5: 257.1389
[M+H]+; found: 257.1397; elemental analysis calcd (%) for C13H20O5: C
60.92, H 7.87; found: C 61.10, H 7.85.
1
under vacuum. The residues were analysed by H NMR spectroscopy and
the major diastereoisomer was isolated by column chromatography
(silica gel, hexane/ethyl acetate 5:1) to give the enantiopure carbenes
5a–b.
Pentacarbonyl(1-{(1R,2S,3R)-3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
R
[(Z)-2-methoxycarbonylethenyl]cyclopropyl}-1-methoxymethylidene)-
tungsten(0) (5a): Orange solid; yield: 69% (93% mixture of diastereo-
isomers); Rf =0.28 (hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
(Z)-3-{(1R,2R,3R)-3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyme-
thylcyclopropyl}prop-2-en-1-ol (8): Cyclopropane 6a (120 mg, 0.4 mmol)
was dissolved in THF (20 mL) at À508C. LiAlH4 (31 mg, 0.8 mmol) was
added to this solution and the mixture was left to reach room tempera-
ture. After stirring for 2h at that temperature, the reaction was carefully
quenched with H2O (1 mL) and filtered though a plug of Celite. At this
point, the mixture was extracted with diethyl ether (3”10 mL) and the
CDCl3, 2 58C, TMS): d=6.13 (dd, J
ACHTREUNG
J
A
ACHTREUNG
4.05 (m, 1H), 3.95 (m, 1H), 3.73 (s, 3H), 3.55 (t, J(H,H)=4.7 Hz, 1H),
U
2.37 (m, 1H), 1.44 (s, 3H), 1.35 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3, 2 58C, TMS): d=322.2 (C), 203.2 (C), 197.3 (C), 166.5 (C), 144.1
Chem. Eur. J. 2007, 13, 1326 – 1331
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1329

J. Barluenga et al.
solvents were removed under reduced pressure. Chromatographic purifi-
cation of the residue (silica gel, ethyl acetate) yielded 80 mg (92%) of
the enantiopure diol 8 as a colourless oil. [a]2D0 =+59.7 (c=0.36 in
CH2Cl2); Rf =0.13 (ethyl acetate); 1H NMR (300 MHz, CDCl3, 2 58C,
(Z)-Methyl
3-{(1S,2R,3R)-2-formyl-3-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]cyclopropyl}propenoate (12): Pyridinium chlorochromate (215 mg,
1 mmol) was added to room temperature solution of (133 mg,
a
7
0.5 mmol) in methylene chloride (25 mL). After stirring for 2 h, the reac-
tion was concentrated under vacuum and diethyl ether (10 mL) was
added. The mixture was filtered through a plug of silica gel/Celite and
the solvents were removed under reduced pressure. A chromatographic
purification of the residue (silica gel, hexane/ethyl acetate 3:1) yielded
116 mg (91%) of the enantiopure diol 12 as a white solid. [a]2D0 =À13.11
(c=0.17 in methylene chloride); Rf =0.2(hexane/ethyl acetate 3:1); m.p.
TMS): d=5.75 (dt, J
1H), 4.25 (dd, (H,H)=12.4, 7.4 Hz, 1H), 4.14 (dd,
7.1 Hz, 1H), 4.05 (m, 1H), 3.71 (m, 2H), 3.61 (dd, J(H,H)=11.2, 5.6 Hz,
1H), 3.36 (dd, (H,H)=11.3, 7.4 Hz, 1H), 1.76 (dd, (H,H)=13.6,
ACHTREUNG
J
A
J
ACHTREUNG
AHCTREUNG
J
A
J
ACHTREUNG
8.5 Hz, 1H), 1.40 (s, 3H), 1.29 (s, 3H), 1.11 (m, 1H), 1.00 ppm (m, 1H);
13C NMR (75 MHz, CDCl3, 2 58C, TMS): d=131.2(CH), 130.1 (CH),
84–868C; 1H NMR (400 MHz, CDCl3, 2 58C, TMS): d=9.19 (d, J
4.9 Hz, 1H), 6.07 (dd, J(H,H)=11.2, 10.0 Hz, 1H), 5.95 (d, J
11.2Hz, 1H), 4.14 (dd, J(H,H)=8.1, 5.9 Hz, 1H), 4.02(dt, (H,H)=8.1,
6.4 Hz, 1H), 3.73 (s, 3H), 3.71 (m, 2H), 2.11 (m, 1H), 2.04 (dd, J(H,H)=
ACHTREUNG
109.2(C), 75.9 (CH), 69.3 (CH ), 64.7 (CH2), 58.1 (CH2), 26.7 (CH), 26.7
2
A
ACHTREUNG
(CH3), 26.2 (CH), 25.6 (CH3), 19.3 ppm (CH); HRMS (70 eV, EI): m/z:
calcd for C11H19O4: 213.1122 [MÀH]+; found: 213.1119; elemental analy-
sis calcd (%) for C12H20O4: C 63.14, H 8.83; found: C 63.16, H 8.86.
A
J
ACHTREUNG
ACHTREUNG
9.8, 4.9 Hz, 1H), 1.44 (s, 3H), 1.34 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3, 2 58C, TMS): d=196.7 (CH), 165.8 (C), 142.7 (CH), 121.1 (CH),
109.1 (C), 72.9 (CH), 68.5 (CH2), 50.6 (CH3), 35.5 (CH), 28.9 (CH), 26.0
(CH), 24.8 (CH3), 24.6 ppm (CH3); HRMS (70 eV, EI): m/z: calcd for
C13H17O5: 253.1071 [MÀH]+; found: 253.1071; elemental analysis calcd
(%) for C13H18O5: C 61.40, H 7.14; found: C 61.36, H 7.15.
A
lethenyl]cyclopropanecarboxylate (9): HCl (6n,1.5 mL) was added to a
solution of 6 (134 mg, 0.5 mmol) in THF (20 mL) at room temperature.
After stirring for 2h, the mixture was extracted with ethyl acetate (3”
10 mL) and the solvents were removed under reduced pressure. A chro-
matographic purification of the residue (silica gel, ethyl acetate) yielded
117 mg (96%) of the enantiopure diol 9 as a colourless oil. [a]2D0 =+110.5
(c=0.34 in CH2Cl2); Rf =0.36 (ethyl acetate); 1H NMR (200 MHz,
(1R,2R,3S)-Methyl 3-{(S)-[(R)-2-hydroxy-1-phenylethylamino]-(cyano)-
methyl}-2-[(Z)-2-methoxycarbonylethenyl]cyclopropanecarboxylate (13):
Cyclopropane 10 (112mg, 0.5 mmol) was dissolved in methanol (10 mL)
at room temperature. (R)-(À)-2-Phenylglycinol (75 mg, 0.55 mmol) was
added to this solution. After stirring for 2h, the mixture was cooled
down to À108C, followed by the addition of trimethylsilyl cyanide
(0.13 mL, 1 mmol). The mixture was stirred for 14 h at this temperature.
At this point, the reaction was extracted with methylene chloride (3”
10 mL) and the solvents were removed under reduced pressure. Chroma-
tographic purification of the residue (silica gel, hexane/ethyl acetate/trie-
thylamine 1:1:1) yielded 108 mg (60%) of the enantiopure 13 as a white
solid. [a]2D0 =+41.3 (c=0.38 in methylene chloride); Rf =0.6 (hexane/
ethyl acetate/triethylamine 1:1:1); m.p. 104–1068C; 1H NMR (400 MHz,
CDCl3, 2 58C, TMS): d=6.05 (dd, J
(H,H)=11.8 Hz, 1H), 3.50–3.80 (m, 3H), 3.73 (s, 3H), 3.69 (s, 3H), 3.37
(dt, J(H,H)=9.5, 4.6 Hz, 1H), 2.94 (brs, 2H), 2.02 (m, 1H), 1.89 ppm
(dd, J
(H,H)=5.3, 5.1 Hz); 13C NMR (75 MHz, CDCl3, 2 58C, TMS): d=
A
J
ACHTREUNG
ACHTREUNG
ACHTREUNG
172.3 (C), 167.0 (C), 145.3 (CH), 121.4 (CH), 70.6 (CH), 66.0 (CH2), 52.1
(CH3), 51.4 (CH3), 30.9 (CH), 27.4 (CH), 25.5 ppm (CH); HRMS (70 eV,
EI): m/z: calcd for C10H13O5: 213.0757 [MÀCH3O]+; found: 213.0757; el-
emental analysis calcd (%) for C11H16O6: C 54.09, H 6.60; found: C
54.11, H 6.56.
A
panecarboxylate (10): Cyclopropane 9 (213 mg, 1 mmol) was dissolved in
methylene chloride (10 mL). A buffer solution at pH 7.2(NaH 2PO4/
Na2HPO4, 5 mL) and NaIO4 (427 mg, 2 mmol) were added to this solu-
tion. After stirring at room temperature for 30 min, the mixture was ex-
tracted with ethyl acetate (3”10 mL) and the solvents were removed
under reduced pressure. Chromatographic purification of the residue
(silica gel, hexane/ethyl acetate 2:1) yielded 189 mg (89%) of the enan-
tiopure cyclopropane 10 as a colourless oil. [a]2D0 =+81.9 (c=0.27 in
methylene chloride); Rf =0.39 (hexane/ethyl acetate 2:1); 1H NMR
CDCl3, 2 58C, TMS): d=7.33 (m, 2H), 5.89 (dd, J
1H), 5.45 (dd, (H,H)=11.2, 10.3 Hz, 1H), 4.06 (dd,
3.9 Hz, 1H), 3.77 (m, 1H), 3.76 (s, 3H), 3.72(s, 3H), 3.61 (dd,
10.8, 9.3 Hz, 1H), 3.54 (m, 2H), 3.03 (d, J(H,H)=8.4 Hz, 1H), 2.31 (td,
(H,H)=9.3, 5.1 Hz, 1H), 1.84 ppm (t, J
(H,H)=5.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 2 58C, TMS): d=171.1 (C), 166.3 (C), 142.6 (CH),
137.8 (C), 128.9 (CH), 128.6 (CH), 127.9 (CH), 122.9 (CH), 118.5 (C),
66.9 (CH2), 63.0 (CH), 52.4 (CH3), 51.5 (CH3), 47.2(CH), 30.4 (CH), 28.0
(CH), 25.9 ppm (CH); HRMS (70 eV, EI): m/z: calcd for C19H24N2O5:
359.1607 [M+H]+; found: 359.1618; elemental analysis calcd (%) for
C19H23N2O5: C 63.67, H 6.19; found: C 63.69, H 6.21.
ACHTREUNG
J
G
J
ACHTREUNG
J
ACHTREUNG
AHCTREUNG
J
E
ACHTREUNG
(300 MHz, CDCl3, 2 58C, TMS): d=9.77 (d, J
(dd, J(H,H)=11.5, 10.1 Hz, 1H), 5.91 (d, J(H,H)=11.8 Hz, 1H), 3.97 (m,
1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.03 (m, 1H), 2.66 ppm (t, J(H,H)=
A
A
ACHTREUNG
AHCTREUNG
X-ray structure determination: The most relevant crystal and refinement
data for 5a are as follows: empirical formula=C19H20O10W; Mr =592.20;
T=293(2) K; l=1.54184 Š; crystal system=monoclinic; space group=
P21; unit cell dimensions: a=12.9282(2), b=9.7988(2), c=18.9921(3) Š;
5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 2 58C, TMS): d=196.5 (CH),
170.2 (C), 166.3 (C), 141.7 (CH), 122.4 (CH), 52.4 (CH3), 51.4 (CH3),
36.4 (CH), 30.1 (CH), 29.9 ppm (CH); HRMS (70 eV, EI): m/z: calcd for
C10H12O5: 212.0679 [M]+; found: 212.0675; elemental analysis calcd (%)
for C10H12O5: C 56.60, H 5.70; found: C 56.54, H 5.72.
a=90, b=107.4210(10), g=908; V=2295.58(7) Š3; Z=4, 1calcd
=
1.714 MgmÀ3
;
m=9.769 mmÀ1
;
F(000)=1152; crystal size =0.35”0.12”
A
A
0.05 mm; q range for data collection=2.44 to 67.708; index ranges=
À15ꢀhꢀ14, À10ꢀkꢀ11, 0ꢀlꢀ22; reflections collected/unique=14493/
7712( Rint =0.0606); completeness to q=67.70 (97.3%); absorption cor-
rection=semi-empirical from equivalents; max. and min. transmission=
1.479 and 0.707; refinement method=full-matrix least-squares on F2;
data/restraints/parameters=7712/1/541; goodness-of-fit on F2 =1.028;
final R indices [I>2s(I)]: R1 =0.0422, wR2 =0.1067; R indices (all data):
R1 =0.0435, wR2 =0.1087; largest difference peak and hole=2.201 and
À1.257 eŠÀ3. For 5b: empirical formula=C24H22O10W; Mr =654.27; T=
150(2) K; l=1.54183 Š; crystal system=monoclinic; space group=P21;
unit cell dimensions: a=10.3825(3), b=6.35170(10), c=18.7192(5) Š; a=
propanecarboxylate (11): A continuous flow of O3 was bubbled for 20 mi-
nutes through a solution of 6 (148 mg, 0.5 mmol) in a mixture of CH2Cl2/
MeOH (3:1, 90 mL) at À808C. After that period, Me2S (0.37 mL,
5 mmol) was added and the mixture was left to reach room temperature.
The reaction was extracted with methylene chloride (3”20 mL) and the
solvents were removed. The residue was purified by flash chromatogra-
phy (silica gel, hexane/ethyl acetate 2:1) to give 106 mg (93%) of the
enantiopure cyclopropane 11 as a colourless oil. [a]2D0 =+77.2( c=0.29 in
methylene chloride); Rf =0.38 (hexane/ethyl acetate 2:1); 1H NMR
(300 MHz, CDCl3, 2 58C, TMS): d=9.72(d,
(dd, J(H,H)=8.3, 6.0 Hz, 1H), 4.05 (dd, J(H,H)=14.7, 6.0 Hz, 1H), 3.73
(m, 1H), 3.72 (s, 3H), 2.68 (m, 1H), 2.49 (dd, J(H,H)=5.8, 5.0 Hz, 1H),
J(H,H)=3.0 Hz, 1H), 4.14
H
90, b=93.631(2), g=908; V=1231.99(5) Š3; Z=2; 1calcd =1.764 MgmÀ3
;
A
ACHTREUNG
m=9.174 mmÀ1; F
(000)=640; crystal size=0.17”0.10”0.05 mm; q range
AHCTREUNG
2.17 (m, 1H), 1.33 (s, 3H), 1.30 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3, 2 58C, TMS): d=196.7 (CH), 170.8 (C), 109.6 (C), 72.0 (CH), 68.8
(CH2), 52.3 (CH3), 34.0 (CH), 33.0 (CH), 26.7 (CH3), 25.3 (CH3),
24.9 ppm (CH); HRMS (70 eV, EI): m/z: calcd for C10H13O5: 213.0757
[MÀCH3]+; found: 213.0755; elemental analysis calcd (%) for C11H16O5:
C 57.88, H 7.07; found: C 57.65, H 7.09.
for data collection=2.37 to 68.358; index ranges=À12ꢀhꢀ12, À7ꢀkꢀ
6, 0ꢀlꢀ22; reflections collected/unique=6644/3845 (Rint =0.0561); com-
pleteness to q=68.35 (99.4%); absorption correction=semi-empirical
from equivalents; max. and min. transmission=1.236 and 0.771; refine-
ment method=full-matrix least-squares on F2; data/restraints/parame-
ters=3845/1/541; goodness-of-fit on F2 =1.244; final R indices [I>2s(I)]:
1330
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1326 – 1331

Carboxycyclopropylglycine Precursors
FULL PAPER
R1 =0.0329, wR2 =0.0799; R indices (all data): R1 =0.0356, wR2 =0.1005;
largest difference peak and hole=1.035 and À1.084 eŠÀ3. For 13: empiri-
cal formula=C19H22N2O5; Mr =358.39; T=298(2) K; l=1.54178 Š; crys-
tal system=tetragonal; space group=P41; unit cell dimensions: a=
9.47260(10), b=9.47260(10), c=39.7724(9) Š; a=90, b=90, g=908, V=
[6] a) G. Urrutia-Desmaison, G. Mloston, R. Huisgen, Tetrahedron Lett.
1994, 35, 4977–4980; b) G. Mloston, R. Huisgen, J. Heterocycl.
Chem. 1994, 31, 1279–1282; c) D. Cruz, F. Yuste, E. Díaz, B. Ortíz,
R. Sµnchez-Obregón, F. Walls, J. L García-Ruano, ARKIVOC 2005,
211–221; d) K. Itoh, S. Iwata, S. Kishismoto, Heterocycles 2006, 68,
395–400.
3568.78(10) Š3, Z=8, 1calcd =1.334 MgmÀ3, F
(000)=1520, crystal size=
A
0.18”0.10”0.05 mm; q range for data collection=3.33 to 73.088; index
ranges=À11ꢀhꢀ11, À11ꢀkꢀ11, À48ꢀlꢀ49; reflections collected/
unique=16928/6309 (Rint =0.0423); completeness to q=73.08 (99.1%);
absorption correction=semi-empirical from equivalents; refinement
method=full-matrix least-squares on F2; data/restraints/parameters=
6309/1/490; goodness-of-fit on F2 =1.032; final R indices [I>2s(I)]: R1 =
[7] For other diastereoselective cyclopropanations of alkenylcarbene
complexes see: a) With chloromethylllithium: J. Barluenga, P. L.
Bernad, Jr., J. M. Concellón, A. PiÇera-Nicolµs, S. García-Granda, J.
Org. Chem. 1997, 62, 6870–6875; b) with lithiated epoxides: V. Cap-
riati, S. Florio, R. Luisi, F. M. Perna, J. Barluenga, J. Org. Chem.
2005, 70, 5852–5858.
0.0358, wR2 =0.0929, R indices (all data): R1 =0.0361, wR2 =0.0930; larg-
[8] See also: a) J. Mulzer, M. Kappert, G. Huttner, I. Jibril, Tetrahedron
Lett. 1985, 26, 1631–1634; b) R. Casas, T. Parella, V. Branchadell,
A. Oliva, R. M. OrtuÇo, A. Guingant, Tetrahedron 1992, 48, 2659–
2680.
[9] Selected reviews: a) F. Z. Dçrwald, Metal Carbenes in Organic Syn-
thesis, Wiley-VCH, New York, 1999; b) J. W. Herndon, Coord.
Chem. Rev. 2006, 250, 1889–1964; c) J. Barluenga, F. Rodríguez, F. J.
FaÇanµs, J. Flórez, Top. Organomet. Chem. 2004, 13, 59–121; d) for
a review in cyclopropyl Fischer carbene complexes see: J. W. Hern-
don, Curr. Org. Chem. 2003, 7, 329–352.
À3
est difference peak and hole=0.251 and À0.220 eŠ
.
CCDC-615951 (5a), CCDC-615952( 5b) and -615952( 13) contain the
supplementary crystallographic data for this paper. These data can be ob-
tained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
[10] Carboxycyclopropylglycines are potent agonists or antagonists, de-
pending on their substitution pattern, of metabotropic glutamate re-
ceptors see: a) I. Collado, J. Ezquerra, A. Mazón, C. Pedregal, B.
Yruretagoyena, A. E. Kingston, R. Tomlison, R. A. Wright, B. G.
Johnson, D. D. Schoepp, Bioorg. Med. Chem. Lett. 1998, 8, 2849–
2854; b) I. Collado, C. Pedregal, A. Mazón, J. F. Espinosa, J. Blanco-
Urgoiti, D. D. Schoepp, R. A. Wright, B. G. Johnson, A. E. Kingston,
J. Med. Chem. 2002, 45, 3619–3629.
This research was partially supported by the Spain and Principado de As-
turias Governments (CTQ2004-08077-C2-01 and IB05-136, respectively).
A.P. acknowledges F.I.C.Y.T. (Principado de Asturias) for a fellowship.
We are also grateful to Dr. A. L. Suµrez-Sobrino (Universidad de
Oviedo) for his assistance in the X-ray analysis.
[11] For a similar approach see reference [10b].
[1] Selected examples: a) M. Yoshida, M. Ezaki, M. Hashimoto, M. Ya-
mashita, N. Shigematsu, M. Okuhara, M. Kohsaka, K. Horikoshi, J.
Antibiot. 1990, 18, 748–754; b) E. Ichikawa, K. Kato, Curr. Med.
Chem. 2001, 8, 385–423; c) F. Gnad, O. Reiser, Chem. Rev. 2003,
103, 1603–1623; d) L. A. Wesshohannm, W. Brandt, Chem. Rev.
2003, 103, 1625–1647; e) J. Pietruszka, Chem. Rev. 2003, 103, 1051–
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[2] Selected reviews: a) D. C. Nonhebel, Chem. Soc. Rev. 1993, 22, 347–
359; b) H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151–1196,
and references therein.
[3] For a very interesting review on stereoselective cyclopropane forma-
tion see: H. Lebel, J. F. Marcoux, C. Molinaro, A. B. Charette,
Chem. Rev. 2003, 103, 977–1050.
[4] Complexes 1a and 1b are prepared from readily available and
cheap starting materials, such as (R)-2,3-O-isopropylidene-d-glycer-
aldehyde and (S)-2,4-O-benzylidene-3-deoxyerythrose, respectively.
See: J. Barluenga, N. Panday, J. Santamaría, A. de Prado, M. Tomµs,
ARKIVOC 2003, 576–583.
[12] For a different approach using a sulfur ylide see: a) D. Ma, Y. Cao,
Y. Yang, D. Cheng, Org. Lett. 1999, 1, 285–287; b) D. Ma, Y. Cao,
W. Wu, Y. Jiang, Tetrahedron 2000, 56, 7447–7456.
[13] Treatment of the a,b-unsaturated methyl ester, derived from (S)-
glyceraldehyde acetonide, with 2-methoxyfuran in the presence of
BF3·OEt2 at room temperature for a long time results in the recov-
ery of the starting materials.
[14] A few methods are available for the synthesis of optically active cy-
clopropanecarbaldehydes by ring-forming reactions. For an elegant
piece of work on the enantioselective organocatalytic synthesis of
cyclopropanecarbaldehydes see: a) R. K. Kunz, D. W. C. MacMillan,
J. Am. Chem. Soc. 2005, 127, 3240–3241; b) for access to enantio-
pure cyclopropanecarbadehydes starting from hydroxyalquenyl car-
bamates see: R. Kalkofen, S. Brandau, B. Wibbeling, D. Hoppe,
Angew. Chem. 2004, 116, 6836; Angew. Chem. Int. Ed. 2004, 43,
6667–6669; c) reference [3] and references therein.
[5] J. Barluenga, A. de Prado, J. Santamaría, M. Tomµs, Angew. Chem.
2005, 117, 6741; Angew. Chem. Int. Ed. 2005, 44, 6583–6585.
Received: September 15, 2006
Published online: October 31, 2006
Chem. Eur. J. 2007, 13, 1326 – 1331
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1331