Practical syntheses of both enantiomers of cyclopropylglycine and of methyl 2-cyclopropyl-2-N-Boc-iminoacetate

Article abstract of DOI:10.1002/adsc.200606038

A facile three-step synthesis of racemic cyclopropylglycine in multigram quantities from inexpensive cyclopropyl methyl ketone has been elaborated. Enzymatic hydrolysis of the N-Boc-protected methyl ester of cyclopropylglycine 9 with the inexpensive enzyme papain from Carica papaya affords both enantiomers of cyclopropylglycine (8) with enantiomeric excesses of 99% or better after deprotection under acidic conditions. Furthermore, the new cyclopropyl group-containing building block methyl 2-cyclopropyl-2-N-Boc-iminoacetate (13) was prepared by N-chlorination and subsequent dehydrochlorination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Addition of nucleophiles to 13 offers a ready access to an unusual, orthogonally bisprotected α,α-diamino acid derivative and interesting components of rigid peptide backbones.

Full text of DOI:10.1002/adsc.200606038

FULL PAPERS
DOI: 10.1002/adsc.200606038
Practical Syntheses of Both Enantiomers of Cyclopropylglycine
and of Methyl 2-Cyclopropyl-2-N-Boc-iminoacetate[1]
Oleg V. Larionova and Armin de Meijerea,*
a
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Gçttingen, Tammannstrasse 2, 37077
Gçttingen, Germany
Fax : (+49)-551-399-475; e-mail: Armin.deMeijere@chemie.uni-goettingen.de
Received: February 2, 2006; Accepted: March 25, 2006
Dedicated to Professor Dieter Enders on the occasion of his 60th birthday.
Abstract: : A facile three-step synthesis of racemic 2-cyclopropyl-2-N-Boc-iminoacetate (13) was pre-
cyclopropylglycine in multigram quantities from in- pared by N-chlorination and subsequent dehydro-
expensive cyclopropyl methyl ketone has been elabo- chlorination with 1,8-diazabicyclo[5.4.0]undec-7-ene
G
rated. Enzymatic hydrolysis of the N-Boc-protected (DBU). Addition of nucleophiles to 13 offers a
methyl ester of cyclopropylglycine 9 with the inex- ready access to an unusual, orthogonally bisprotected
pensive enzyme papain from Carica papaya affords a,a-diamino acid derivative and interesting compo-
both enantiomers of cyclopropylglycine (8) with en- nents of rigid peptide backbones.
antiomeric excesses of 99% or better after deprotec-
tion under acidic conditions. Furthermore, the new Keywords: amino acids; cyclopropanes; enantiomeric
cyclopropyl group-containing building block methyl resolution; enzymes; furans; small rings
Introduction
2-Substituted 2-cyclopropylideneacetates have dem-
onstrated their synthetic utility as multifunctional
building blocks with unique features.[2] They signifi-
cantly excel simple acrylates in their reactivity to-
wards nucleophiles and cyclophiles.[3] Alkyl 2-chloro-
2-cyclopropylideneacetates, for which an advanced
simple synthesis has recently been developed by our
group,[4] have emerged as most prolific of this unrival- Scheme 1.
led family. Their high reactivity combined with their
four compactly arranged functionalities make them
suitable precursors to various valuable complex mole-
cules such as natural product analogues, unusual het-
The alternative potential precursor to 1 would be 3,
erocyclic compounds and conformationally rigid pep- a derivative of the naturally occurring amino acid
tidomimetics.[5] An even more facile access to the cleonin, for which a new synthesis has recently been
latter would be possible if 2-(acylamino)-2-cyclopro- reported.[6] The route via 3 appeared to be considera-
pylideneacetates of type 1 were available as starting bly longer than that starting from the N-substituted
materials. At the outset of our work it was not known cyclopropylglycine 2, provided that a facile and effi-
whether such compounds would be stable under basic cient protocol for the preparation of 2 would be de-
conditions or would tautomerize to the potentially veloped.
more stable 2-(acylimino)-2-cyclopropylacetates 4.
Since 4 also might exhibit interesting reactivities, we
first tested the possibility of accessing 1 by base-pro- Results and Discussion
moted elimination from an N-protected N-haloamino-
cyclopropylacetate 2 with subsequent isomerization Cyclopropylglycine (8) had previously been prepared,
(Scheme 1).
e.g., from cyclopropanecarboxaldehyde by a Strecker
Adv. Synth. Catal. 2006, 348, 1071 – 1078
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1071

Oleg V. Larionov and Armin de Meijere
FULL PAPERS
reaction,[7] and by reaction of an electrophilic glycine oped protocol, which features efficiency, simplicity
equivalent, with cyclopropylmagnesium bromide.[8] and easy availability of the starting materials, could
However, both of these approaches have certain easily be performed on a 100 g scale. By analogy, the
shortcomings, e.g., the toxicity of KCN, the volatility Cbz-protected methyl ester rac-10 was prepared in a
of cyclopropanecarboxaldehyde, as well as the low one-pot procedure employing N-benzyloxycarbonyl-
yield in the first case, and expensive starting materials
ACHTREUNG
in the second protocol. Therefore, a short route to 8
from inexpensive cyclopropyl methyl ketone (5) was hand, an enzymatic deracemization was considered as
conceived and executed. First, 5 was oxidized with an efficient route to both enantiomers of 8, employing
aqueous KMnO4 at 508C (Scheme 2) to give the po- papain as an inexpensive and efficient enzyme
(Scheme 3).
Scheme 2. New practical synthesis of cyclopropylglycine (8)
and derivatives thereof.
tassium salt 6 of cyclopropyloxoacetic acid which,
after concentration of the aqueous phase, was con-
verted with hydroxylamine hydrochloride into the
corresponding oxime 7 in 73% yield over 2 steps. The
potassium salt 6 and the oxime 7 can be stored at
room temperature for at least 6 months without de-
composition. The oxime 7 raises an additional interest
as it is the key structural constituent of a potent (IC50
ꢀ 50 mM) KSP kinesin inhibitor.[9]
Scheme 3. The papain-catalyzed deracemization of rac-9 as
an efficient route to both enantiomers of 8.
Indeed, papain had previously been used for suc-
Upon attempted hydrogenation of 7 over Pd/C, cessful deracemizations of N-protected amino esters
norvaline (n-propylglycine) was obtained instead of in a few cases,[11] and one of them comprised the opti-
the expected cyclopropylglycine (8). Since several cal resolution of ethyl N-Boc-vinylglycinate.[12] Grati-
other oxime reduction methods also proved fruitless, fyingly, the papain-catalyzed ester hydrolysis yielded
attention was turned to reduction with zinc in glacial (R)-9 and (S)-11 in 49 and 43% yields, respectively,
acetic acid which had previously been shown to be and with high enantiopurity (>99%).[13] Although no
compatible with the cyclopropane ring.[10]
pH control was necessary, the use of McIlvaineꢁs
Indeed, the reduction proceeded cleanly to give 8 buffer consisting of citric acid, disodium hydrogen
in 93% yield after DOWEX ion-exchange chroma- phosphate and a 1.5 mM aqueous solution of the diso-
tography. The crude reduction product which, accord- dium salt of ethylenediamine-N,N,N’,N’-tetraacetic
ing to the 1H NMR spectrum had an approximate acid (EDTA) buffer with pH 6.2 as an aqueous com-
composition 8·HOAc·2Zn(OAc)2, can be directly ponent furnished the best results in terms of enantio-
A
transformed into the corresponding Boc-protected selectivity and catalyst activity (Scheme 3). Also, uti-
methyl ester 9 in 98% yield over 2 steps. The devel- lization of dimethylformamide as an organic cosolvent
1072
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1071 – 1078

Cyclopropylglycine and Methyl 2-Cyclopropyl-2-N-Boc-iminoacetate
FULL PAPERS
with acetonitrile played a beneficial role. rac-Thio- small fraction of the non-chlorinated precursor 9 (ca.
threitol was added to prevent oxidative deactivation 3 – 5%) was also present and could not be separated
of the enzyme. Ethanethiol can also be employed in- from the Boc-imino ester 13. As the N-chlorinated
stead of rac-thiothreitol, although a slight decrease of starting material 12 did not contain 9, its presence in
the hydrolysis rate was observed. The free amino the final product can only be rationalized on the basis
acids (R)- and (S)-8 were then liberated by acidic hy- of a chlorine transfer onto the tertiary amine moiety
drolysis and purified by subsequent ion-exchange in DBU, as had previously been suggested for other
chromatography on DOWEX Monosphere 650C, in N-chloro derivatives.[16] The N-Boc-iminoacetate 13
close analogy to the previously described procedure appears to be the first such compound that does not
for the purification of 3-(trans-2-nitrocyclopropyl)ala- readily tautomerize to the corresponding N-Boc-ami-
nine.[14]
noacrylate in spite of its having a b-hydrogen substitu-
The N-Boc-protected methyl ester rac-9 was cleanly ent.[17] This must be due to the additional strain that
chlorinated to yield the corresponding N-chloro deriv- a double bond experiences when it is attached to a
ative 12 with calcium hypochlorite on moist alumina, three-membered ring.[18,19]
as has recently been described.[15]
To test the reactivity of the N-Boc-imino ester 13, it
A screening of the reaction conditions for the dehy- was treated with benzylamine in tetrahydrofuran. This
drochlorination of 12 showed that the choice of an ap- afforded the 2,2-diamino-2-cyclopropylacetate deriva-
propriate base was crucial for achieving high yields. tive 15 in 63% yield. Since a-substituted cyclopropyl-
Whereas potassium tert-butoxide and potassium car- glycines appear to be key constituents of many bio-
bonate led to a rapid charring of the reaction mixture, logically active compounds,[20] the derivative 15, pos-
triethylamine brought about only a very sluggish reac- sessing an a-heteroatom substituent may be of partic-
tion to an elimination product and a number of un- ular interest as a building block for the preparation of
identified by-products. On the other hand, 1,8- novel analogues.
diazabicyclo
A
a
Although a number of [4+2] cycloadditions of ac-
much cleaner dehydrochlorination, which was com- ceptor-substituted imines are known,[21] 13 did not un-
plete within 1 h and could successfully be performed dergo Diels–Alder reactions with cyclopentadiene, cy-
on an up to 250 mmol scale without decreases in yield clohexa-1,3-diene, isoprene, or Danishefskyꢁs diene
(Scheme 4). The elimination product turned out to be under various conditions, including high pressure (10
the 2-cyclopropyl-(N-Boc-imino)acetate 13 and not kbar). With furan and substituted furans 16-R under
the 2-(N-Boc-amino)-2-cyclopropylideneacetate 14. A boron trifluoride-etherate catalysis, however, 13 react-
ed smoothly to give the corresponding Friedel–Crafts
aminoalkylation products 17-R in 68 – 91% yields.
The structures of these products were unambiguously
established on the basis of HMBC/HSQC NMR spec-
tra. The adducts 17 comprise a-furyl-a-cyclopropyl-
glycine derivatives, which are difficult to access along
other routes, and might be of interest as constituents
for rigid peptide frameworks.[22]
Conclusions
In conclusion, a facile and easily scalable synthesis of
cyclopropylglycine and several interesting derivatives
thereof, from inexpensive starting materials, has been
developed.
Experimental Section
General Remarks
1H and 13C NMR spectra were recorded at 250 as well as
300 (1H), and 62.9 MHz [13C, additional DEPT (distortion-
Scheme 4. Dehydrochlorination of the 2-(N-chloro-N-Boc-
amino)-2-cyclopropylacetate 12 and subsequent reactions of
the resulting N-Boc-iminoacetate 13.
less enhancement by polarization transfer)] on Bruker
Aspect 3000 and Varian Unity-300 instruments. For CDCl3
solutions CHCl3/CDCl3 was used as an internal reference; d
Adv. Synth. Catal. 2006, 348, 1071 – 1078
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1073

Oleg V. Larionov and Armin de Meijere
FULL PAPERS
in ppm, J in Hz. IR spectra of the compounds as oils be-
tween KBr plates were measured on a Bruker IFS 66 (FT-
IR) spectrometer. MS (EI) were recorded on a Finnigan
MAT 95 instrument. Enantiomeric purities were determined
by HPLC on a chiral column [Crownpak CR (+) or (À) for
the amino acid 8, and ChiralPak for the derivatives 9 and
11]. Moist alumina was prepared according to the published
protocol.[15] 0.1M (pH 6.2) McIlvaineꢁs buffer containing
1.5 mM of the disodium salt of ethylenediamine-N,N,N’,N’-
tetraacetic acid (EDTA) was prepared by dissolving citric
acid (0.6513 g, 3.39 mmol), Na2HPO4·12 H2O (4.735 g,
13.22 mmol) in water (98.5 mL), and adding 0.1M aqueous
organic extracts were dried over Na2SO4 and concentrated
under reduced pressure and then under vacuum (0.05 mbar)
to give the second crop (5.9 g) as a colorless oil, slowly sol-
idifying upon standing; total yield: 38.5 g (99%); mp 958C.
1H NMR (300 MHz, D2O): d=0.85 – 0.96 (4H, m), 1.97 –
2.06 (1H, m); 13C NMR (62.9 MHz): d=9.51 (CH2), 13.47
(CH), 162.38 (C), 171.04 (C).
Reduction of the Oxime 7 with Zinc. Synthesis of
Cyclopropylglycine[24] (rac-8) and Methyl
solution of the disodium salt of EDTA (1.5 mL). Zinc 2-(N-tert-Butoxycarbonylamino)-2-cyclopropylacetate
[Boc-cPrGly-OMe] (rac-9)[25]
powder (Merck) was activated by rinsing with 0.5 N aqueous
hydrochloric acid, then water, anhydrous ethanol, and dieth-
yl ether, then dried under vacuum (0.05 mbar) at 1508C
overnight, and cooled to room temperature under an atmos-
phere of Ar. All other chemicals were used as commercially
available (Merck, Acrðs, BASF, Bayer, Hoechst, Degussa
AG, and Hüls AG). Organic extracts were dried over
Na2SO4.
Activated zinc powder (see general remarks on reagents
and chemicals, 45.4 g, 0.69 mol) was added in portions
within 10 min to
a solution of the oxime 7 (11.2 g,
86.7 mmol) in glacial AcOH (260 mL), maintaining the reac-
tion temperature at 20 – 308C. The mixture was stirred at
room temperature for 30 min, and then filtered. The filtrate
was concentrated under reduced pressure at 408C to give a
1
glassy solid which, according to its H NMR spectrum, had
an approximate composition 8·HOAc·2Zn(OAc)2 (yield:
A
Potassium Cyclopropylglyoxylate (6)[23]
49 g). A sample of this (2.3 g) was applied onto a DOWEX
column, as described elsewhere,[14] to give, after recrystalli-
zation from ethanol/water, the amino acid rac-8 as a color-
less solid; yield: 0.44 g (93%); mp 2518C (lit. 2498C).
1H NMR (300 MHz, D2O): d=0.20 – 0.25 (1H, m), 0.35 –
0.43 (1H, m), 0.48 – 0.56 (2H, m), 0.92 – 0.98 (1H, m), 2.86
(1H, s); 13C NMR (62.9 MHz): d=4.8 (CH2), 5.6 (CH2),
To a mechanically stirred mixture of cyclopropyl methyl
ketone (5) (54.6 g, 0.65 mol) and a solution of Na2CO3
(0.8 g, 7.6 mmol) in water (360 mL) at 508C in a 4 L flask
equipped with an efficient reflux condenser and a 500 mL
dropping funnel, was added dropwise over 40 h a solution of
KMnO4 (145 g, 0.92 mol) in water (3 L). The mixture was
stirred for an additional 10 h, then cooled to room tempera-
ture, and MeOH (360 mL) was added. The solids were fil-
tered off and washed with warm (508C) water (3”200 mL).
The combined filtrates were concentrated under reduced
pressure at 508C. The solid residue was dried under vacuum
(0.05 mbar) to give the salt 6·KOH, which also contained ca.
10% potassium cyclopropanecarboxylate (due to partial de-
carboxylative overoxidation); yield: 75 g (ca. 74% based on
KMnO4 and taking in account, that KOH is formed as a by-
product according to the stoichiometry of the reaction); mp
~
13.7 (CH), 61.2 (CH), 176.0 (C); IR (KBr): n=3547, 3440,
3386, 1624, 1580, 1490, 1417, 1390, 1260, 1030, 710 cmÀ1
.
The remaining crude product (46.7 g) was covered with
MeOH (100 mL). In a separate flask, a mixture of MeOH
(200 mL), and SOCl2 (50 mL) was prepared at –108C. This
was added into the flask with the crude product at –108C
within 5 min, and the resulting mixture was stirred at room
temperature for 20 h. It was then concentrated under re-
duced pressure. The glassy residue was dried under vacuum
(0.05 mbar), then covered with dioxane (140 mL) and water
(140 mL). Then K2CO3 (120 g, 0.87 mol) was added in por-
tions with vigorous stirring maintaining the reaction temper-
ature within 0 – 108C. Boc2O (19.8 g, 91.0 mmol), and
NH2OH·HCl (0.6 g, 8.63 mmol) were added, the mixture
was stirred at room temperature for 12 h, and then 3-dime-
thylaminopropylamine (5 mL) was added to scavenge the
excess of Boc2O. The mixture was stirred for an additional
1 h, then concentrated to ca. 50 mL under reduced pressure
1
2418C (decomp.). H NMR (300 MHz, D2O): d=0.97 – 1.35
(4H, m), 2.38 – 2.47 (1H, m); 13C NMR (62.9 MHz): d=
13.67 (2CH2), 19.57 (CH), 172.01 (C), 208.90 (C); IR (film):
~
n=3340, 1557, 1417, 1358, 1188, 1102, 1026, 884, 702,
624 cmÀ1
.
at room temperature and extracted with CH2Cl2 (4
”
200 mL). The extracts were washed with 1 N aqueous
KHSO4 (2 ” 200 mL), dried over Na2SO4 and concentrated
under reduced pressure. The oily residue solidified upon
standing to give the N-Boc-protected ester rac-9 as a color-
less waxy solid; yield: 18.5 g (98%); mp 498C. 1H NMR
(300 MHz): d=0.32 – 0.42 (1H, m), 0.44 – 0.58 (3H, m), 0.98
– 1.11 (1H, m), 1.42 (9H, s), 3.69 (1H, m), 3.74 (3H, s), 5.04
(1H, br s); 13C NMR (62.9 MHz): d=2.62 (CH2), 2.75
(CH2), 13.47 (CH), 27.51 (CH3), 51.99 (CH3), 56.50 (CH),
2-Cyclopropyl-2-hydroxyiminoacetic Acid (7)[7]
A mixture of the salt 6·KOH (66 g, ca. 0.3 mol) and water
(60 mL) in a 250 mL flask was stirred at 458C until a clear
solution had formed. Hydroxylamine hydrochloride
(NH2OH·HCl) (43.4 g, 0.62 mol) was added over 15 min in
small portions to avoid foaming. The mixture was stirred for
an additional 20 min, then at 08C for 2 h. The fine precipi-
tate was filtered off to give the first crop (32.6 g) of 7 as a
colorless solid. The filtrate was acidified to pH 2 with 12 N
HCl and extracted with CH2Cl2 (5”60 mL). The combined
~
79.57 (C), 155.14 (C), 172.69 (C); IR (film): n=3369, 2976,
1747, 1717, 1507, 1367, 1163, 1025, 784 cmÀ1; LR-MS (DCI):
m/z=247.3 (100) [M + NH4+], 230.2 (14) [M + H+], 191.2
1074
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1071 – 1078

Cyclopropylglycine and Methyl 2-Cyclopropyl-2-N-Boc-iminoacetate
FULL PAPERS
+
(5); HR-MS (ESI): m/z=230.1392, calcd for C11H20NO4
The combined NaHCO3/Na2CO3 buffer extracts were
[M + H+]: 230.1387.
cooled to 08C, acidified to pH 2, and then extracted with
Et2O (5”20 mL). The combined organic phases were dried
over Na2SO4 and concentrated under reduced pressure to
give the acid (R)-11; yield: 0.61 g (43%); mp 798C; [a]2D0:
Methyl rac-2-(N-Benzyloxycarbonylamino)-
2-cyclopropylacetate (rac-10)[26]
1
+0.38 (c 1.4, CHCl3). H NMR (300 MHz): d=0.43 (1H, dd,
J=5.3, 5.3 Hz),0.47 – 0.68 (3H, m), 0.98 – 1.15 (1H, m), 1.43
(9H, s), 3.69 – 3.80 (1H, m), 5.11 (1H, br s), 6.42 (1H, br s);
13C NMR (62.9 MHz): d=2.92 (CH2), 3.12 (CH2), 13.51
(CH), 28.24 (CH3), 56.76 (CH), 80.23 (C), 155.54 (C), 177.13
This ester was prepared as described for rac-9, except that
Cbz-OSu (N-benzyloxycarboxysuccinimide) was used in-
stead of Boc2O. rac-10: oxime 7 (1.18 g, 9.13 mmol) was re-
duced with the activated zinc powder (see general remarks
on reagents and chemicals, 4.78 g, 72.63 mol) in AcOH
(27 mL) as described for rac-9, and the obtained glassy solid
was covered with MeOH (10 mL). In a separate flask, a
mixture of MeOH (20 mL), and SOCl2 (5 mL) was prepared
at –108C. This was added into the flask with the crude prod-
uct at –108C within 5 min, and the resulting mixture was
stirred at room temperature for 20 h. It was then concentrat-
ed under reduced pressure. The glassy residue was dried
under vacuum (0.05 mbar), then covered with dioxane
(14 mL) and water (14 mL). Then K2CO3 (12 g, 0.087 mol)
was added in portions with vigorous stirring while maintain-
ing the reaction temperature within 0 – 108C. Cbz-OSu
(2.49 g, 10 mmol) was added, the mixture was stirred at
room temperature for 16 h, and then 3-dimethylaminopro-
pylamine (0.8 mL) was added to scavenge the excess of Cbz-
OSu. The mixture was stirred for an additional 1 h, then
concentrated to ca. 50 mL under reduced pressure at room
temperature and extracted with CH2Cl2 (4 ” 20 mL). The
~
(C); IR (film): n=3336, 3007, 2979, 1735 1683, 1528, 1303,
1167, 1050, 979, 784, 601 cmÀ1; LR-MS (DCI): m/z=247.3
(100) [M + NH4+], 230.2 (14) [M + H+], 191.2 (5); anal.
calcd. for C10H17NO4 (215.25): C 55.80, H 7.96, N 6.51;
found: C 55.96, H 8.11, N 6.59.
(S)-9: mp 528C; [a]2D0: –0.31 (c 0.9, CHCl3). The spectral
data (1H and 13C NMR, IR) of (S)-9 were identical to those
of rac-9.
General Procedure (GP1) for the Hydrolysis of (S)-9
and (R)-11, and Liberation of Enantiomerically Pure
(S)- and (R)-Cyclopropylglycine (8)
A solution of (S)-9 (0.46 g, 2 mmol) or (R)-11 (0.43 g,
2 mmol) in methanol (5 mL) and 12 N aqueous HCl (5 mL)
was heated under reflux for 8 h. It was then concentrated
under reduced pressure, and the residue was purified by ion
exchange chromatography on DOWEX Monosphere 650C
to give the cyclopropylglycine enantiomers (S)-8; yield:
0.20 g (86%); [a]2D0: +59 (c 0.3, CHCl3) or (R)-8; yield:
0.19 g (81%); [a]2D0: –60.1 (c 0.32, CHCl3)}, respectively. The
spectral data (1H and 13C NMR, IR) of the both enantio-
mers of 8 were virtually identical to those of rac-8.
extracts were washed with 1 N aqueous KHSO4 (2
”
20 mL), dried over Na2SO4 and concentrated under reduced
pressure to give the N-Cbz-protected ester rac-10 as a color-
less solid; yield: 2.27 g (94%); mp 558C. 1H NMR
(300 MHz): d = 0.25 – 0.62 (4H, m), 0.98 – 1.11 (1H, m),
3.74 (3H, s), 3.82 (1H, dd, J=7.6, 7.6 Hz), 5.08 (2H, s), 5.33
(1H, d, J=7.6 Hz), 7.27 – 7.39 (5H, m) ppm; 13C NMR
(62.9 MHz): d=2.97 (CH2), 13.86 (CH), 52.32 (CH3), 57.11
(CH), 67.00 (CH2), 128.11 (CH), 128.16 (CH), 128.49 (CH),
Methyl 2-(N-tert-Butoxycarbonyl-N-chloroamino)-
~
136.15 (C), 155.82 (C), 172.48 (C); IR (film): n=3347, 1734,
cyclopropylacetate (12)[15]
1710, 1522, 1275, 1235, 1056, 975, 758, 698, 668 cmÀ1
.
From 9 (57.4 g, 250.3 mmol), Ca(OCl)2 (108.5 g, 759 mmol),
A
and moist Al2O3 (398 g) in CHCl3 (700 mL), compound 12
was obtained according to the literature procedure[15] as a
colorless oil; yield: 62.5 g (95%). 1H NMR: d=0.40 – 0.46
(m, 1H), 0.51 – 0.59 (m, 1H), 0.61 – 0.68 (m, 1H), 0.78 – 0.85
(m, 1H), 1.37 – 1.45 (m, 1H), 1.49 (s, 9H), 3.78 (s, 3H), 3.95
(d, J=9.5 Hz, 1H); 13C NMR: d=3.38 (CH2), 5.72 (CH2),
11.55 (CH), 27.81 (CH3), 52.29 (CH3), 68.42 (CH), 83.39
Kinetic Resolution by the Papain-Catalyzed
Hydrolysis of rac-9
To a solution of rac-9 (1.52 g 6.63 mmol) in MeCN (7 mL)
and DMF (7 mL) was added 0.1M McIlvaineꢁs buffer, con-
taining 1.5 mm EDTA (7 mL, see general remarks on re-
agents and chemicals). In a separate flask, a solution of thio-
threitol (20 mg) and papain (10 mg) in the buffer (1 mL)
was prepared. This was added into the first flask, and the re-
sulting mixture was stirred at room temperature for 36 h. It
was then concentrated under reduced pressure at room tem-
perature. The residue was diluted with 10% citric acid
(10 mL) and Et2O (50 mL). The ethereal phase was extract-
ed with 0.1m pH 9.6 NaHCO3/Na2CO3 buffer (see general
remarks on reagents and chemicals, 7”10 mL). The com-
bined aqueous phases were washed with Et2O (10 mL). The
combined organic phases were dried over Na2SO4 and con-
centrated under reduced pressure to give the ester (S)-9;
yield: 0.75 g (49%).
~
(C), 154.88 (C), 169.94 (C); IR (film): n=2981, 1751, 1705,
1457, 1436, 1371, 1341, 1287, 1262, 1158, 1063, 1027, 969,
853, 752, 461 cmÀ1; MS (EI): m/z=263.3 (1) [M+], 160.2 (5),
104.1 (23), 57.1 (100), 41.0 (17).
Methyl 2-(N-tert-Butoxycarbonylimino)-2-
cyclopropylacetate (13)
To a solution of 12 (4.47 g, 17 mmol) in CH2Cl2 (100 mL)
was added dropwise within 20 min at 08C a solution of
DBU (2.57 g, 16.9 mmol) in CH2Cl2 (5 mL), and the mixture
Adv. Synth. Catal. 2006, 348, 1071 – 1078
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1075

Oleg V. Larionov and Armin de Meijere
FULL PAPERS
was stirred at room temperature until the starting material
had completely disappeared (ca. 1 h, TLC, hexane/Et2O,
2:1). The solvent was then removed under reduced pressure
at ca. 10 – 158C. The residue was covered with hexane
(40 mL), the precipitate was filtered off and washed with
hexane (3 ” 10 mL). The combined filtrates were concen-
trated under reduced pressure, and the residue was immedi-
ately applied onto a column of neutral alumina [Brockmann
activity N 4, prepared by deactivation of alumina ICN,
Super I (40 g) with 10% (w/w, 4 g) of water]. This was
eluted with a hexane/Et2O, 5:1 mixture, to give, after con-
centration of the fraction with the product [Rf =0.25
(hexane/Et2O, 2:1)] the desired N-Boc-imino ester 13 as a
colorless oil. The product turned yellow on standing at room
temperature, and, therefore, should be stored at –188C. The
product contained some of the precursor 9 (ca. 3 mol%),
which could not be removed. Yield: 3.26 g (84%); bp 2408C
(0.05 mbar, bulb-to-bulb distillation). 1H NMR (300 MHz):
d=0.99 – 1.09 (2H, m), 1.10 – 1.21 (2H, m), 1.51 (9H, s),
2.06 – 2.22 (1H, m), 3.84 (3H, s); 13C NMR (62.9 MHz): d=
12.46 (CH2), 14.47 (CH) 27.90 (CH3), 52.82 (CH3), 82.32
General Procedure (GP2) for the Friedel–Crafts
Aminoalkylation of Furans 16-R with
N-Boc-iminoacetate 13
To a solution of the imino ester 13 (2.27 g, 10 mmol) and the
respective furan 16-R (22 mmol) in CH2Cl2 (5 mL) was
added at room temperature BF3·OEt2 (71 mg, 0.5 mmol, 5
mol%), and the mixture was stirred at room temperature
for 30 min (24 h without catalyst). The volatiles were re-
moved under reduced pressure, and the residue was purified
by column chromatography to give the corresponding amino
acid derivative 17-R.
Methyl 2-(N-tert-Butoxycarbonylamino)-2-cyclo-
propyl-2-furanylacetate (17-H)
According to GP2, 17-H (2.0 g, 68%) was obtained from
imino ester 13 (2.27 g, 10 mmol) and furan 16-H (1.5 g,
22 mmol), and purified by column chromatography (hexane/
Et2O, 6:1). Rf =0.5, (hexane/Et2O, 2:1). Light brown oil;
1H NMR (300 MHz): d=0.26 – 0.37 (1H, m), 0.38 – 0.69
(3H, m), 1.35 (4H, s, rotamers), 1.43 (5H, s, rotamers), 1.56
– 1.71 (1H, m), 3.76 (2H, s, rotamers), 3.89 (1H, s, rotamers),
5.05 (0.2H, br s, rotamers), 5.55 (0.8H, br s, rotamers), 6.35
(1H, s), 6.50 (1H, d, J=3.2 Hz), 7.33 (1H, br s); 13C NMR
(62.9 MHz): d=1.32 (CH2), 2.11 (CH2), 17.10 (C), 28.04
(CH3), 52.98 (CH3), 62.11 (C), 79.94 (C), 108.65 (CH),
110.36 (CH), 141.49 (CH), 151.34 (C), 154.08 (C), 171.05
~
(C), 160.58 (C), 164.62 (C), 219.29 (C); IR (film): n=3413,
2978, 1746, 1663 (-N=C), 1483, 1392, 1295, 1249, 1159,
857 cmÀ1; LR-MS (DCI): m/z=245.2 (44) [M + NH4+],
228.2 (100) [M + H+], 128.1 (21); HR-MS (ESI): m/z=
228.1233, calcd. for C11H18NO4+ [M + H+]; 228.1230.
Methyl 2-Benzylamino-2-(N-tert-butoxycarbonyl-
amino)-2-cyclopropylacetate (15)
~
(C); IR (film): n=3397 cm, 2978, 2522, 1714, 1490, 1367,
1258, 1164, 1052, 1023, 737, 599 cmÀ1; LR-MS (EI): m/z=
296.1 (5) [M + H+], 240.0 (24), 181.0 (100); HR-MS (ESI):
To a solution of benzylamine (1.5 g, 14 mmol) in THF
(15 mL) was added dropwise within 30 min at room temper-
ature a solution of 13 (2.27 g, 10 mmol) in THF (15 mL),
and the mixture was stirred at room temperature for 24 h.
The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (hexane/
Et2O, 4:1) to give an oil, which solidified on standing. This
was dissolved in boiling Et2O (6 mL), and hexane (6 mL)
was added. The mixture was stirred at 08C for 1 h, and the
precipitate was filtered off to give the product 15 as a color-
less solid; yield: 2.12 g (63%); mp 528C. 1H NMR
(300 MHz): d=0.36 – 0.54 (3H, m), 0.55 – 0.64 (1H, m), 1.27
– 1.40 (1H, m), 1.44 (9H, s), 3.01 (1H, br s), 3.47 (1H, d, J=
12.2 Hz), 3.68 (1H, d, J=12.2 Hz), 3.74 (3H, s), 5.59 (1H, s),
7.17 – 7.75 (5H, m); 13C NMR (62.9 MHz): d=1.6 (CH2),
2.1 (CH2), 18.4 (CH), 28.20 (CH3), 47.8 (CH2), 52.9 (CH3),
74.9 (C), 79.7 (C), 126.9 (CH), 128.3 (CH), 128.4 (CH),
+
m/z=296.1490, calcd. for C15H22NO5 [M + H+]: 296.1493.
Methyl 2-(N-tert-Butoxycarbonylamino)-2-cyclo-
propyl-(5-methylfuran-2-yl)acetate (17-Me)
According to GP2, 17-Me (2.82 g, 91%) was obtained from
imino ester 13 (2.27 g, 10 mmol) and 2-methylfuran 16-Me
(1.8 g, 22 mmol), and purified by column chromatography
(hexane/Et2O, 4:1). Rf =0.45, (hexane/Et2O, 2:1). Light
1
brown oil. H NMR (300 MHz): d=0.26 – 0.63 (4H, m), 1.40
(4H, s, rotamers), 1.43 (5H, s, rotamers), 1.61 – 1.77 (1H,
m), 2.23 (3H, s), 3.73 (3H, s), 5.53 (1H, br s), 5.91 (1H, d,
J=5.0 Hz), 6.33 (1H, d J=5.0 Hz); 13C NMR (62.9 MHz):
d=1.21 (CH2), 2.15 (CH2), 13.70 (CH3), 16.87 (CH), 28.07
(CH3), 52.94 (CH3), 62.14 (C), 79.86 (C), 106.35 (CH),
109.27 (CH), 149.23 (C), 151.39 (C), 154.14 (C), 171.29 (C);
~
139.6 (C), 154.2 (C), 172.4 (C); IR (KBr): n=3347, 3088,
3009, 1745, 1685, 1616, 1534, 1384, 1365, 1260, 1165, 1072,
882, 788, 741, 698, 629 cmÀ1; LRMS (EI): m/z=334.2 (3)
[M+], 271.5 (22), 219.1 (100), 175.1 (9); anal. calcd, for
C18H26N2O4 (334.4): C 64.65, H 7.84, N 8.38; found: C
64.33, H 7.98, N 8.25.
~
IR (film): n=3447, 2926, 1734, 1707, 1363, 1158, 1094, 1020,
748, 668, 620 cmÀ1; LR-MS (EI): m/z=309.1 (5) [M+], 253.0
(12), 194.0 (90), 150.1 (40), 57.1 (100); HR-MS (ESI): m/z=
332.1471, calcd. for C16H23NNaO5+ [M + Na+]: 332.1468.
1076
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1071 – 1078

Cyclopropylglycine and Methyl 2-Cyclopropyl-2-N-Boc-iminoacetate
FULL PAPERS
[10] Two successful examples for the selective reduction of
the functional groups next to hydrogenolytically labile
cyclopropane rings with zinc under acidic conditions
have recently been described: a) R. P. Wurz, A. B.
Charette, J. Org. Chem. 2004, 69, 1262–1269; b) O. V.
Larionov, A. de Meijere, Org. Lett. 2004, 6, 2153–2156.
[11] a) M. Sypniewski, B. Peke, L. Simon, J. River, J. Org.
Chem. 2000, 65, 6595–6600; b) T. Miyazawa, H. Iwana-
ga, T. Yamada, S. Kuwata, Biotech. Lett. 1994, 16, 373–
378; c) T. Miyazawa, H. Iwanaga, T. Yamada, S.
Kuwata, Peptide Chem. 1991, 28, 57–60; d) J. L. Mori-
niere, B. Danree, J. Lemoine, A. Guy, Synth. Commun.
1988, 18, 441–444; e) J. L. Abernethy, R. Bobeck, A.
Ledesma, R. Kemp, J. Org. Chem. 1973, 38, 1286–
1291.
Methyl 2-N-tert-Butoxycarbonylamino-2-cyclo-
propyl-(5-methoxyfuran-2-yl)acetate (17-OMe)
According to GP2, 17-OMe (2.8 g, 86%) was obtained from
imino ester 13 (2.27 g, 10 mmol) and 2-methoxyfuran 16-
OMe (2.16 g, 22 mmol), and purified by column chromatog-
raphy (hexane/Et2O, 5:1). Rf =0.25, (hexane/Et2O, 2:1). Col-
1
orless solid; mp 708C. H NMR (300 MHz): d=0.31 – 0.67
(4H, m), 1.37 (9H, s), 1.61 – 1.74 (1H, m), 3.75 (3H, s), 3.80
(3H, s), 5.15 (1H, d, J=3.3 Hz), 5.48 (1H, br s), 6.37 (1H, d,
J=3.3 Hz); 13C NMR (62.9 MHz): d=1.27 (CH2), 2.05
(CH2), 16.63 (C), 28.11 (CH3), 52.98 (CH3), 57.75 (CH3),
61.78 (C), 79.79 (C), 80.28 (CH), 110.01 (CH), 140.91 (C),
~
154.02 (C), 160.7 (C), 171.14 (C); IR (KBr): n=3426, 3119,
2980, 2944, 1722, 1623, 1581, 1493, 1262, 1164, 1004, 962,
832, 777, 730, 666, 542 cmÀ1; LR-MS (EI): m/z=325.1 (6)
[M+], 266.1 (10), 210.0 (55), 166.0 (20), 114.0 (28), 57.1
[12] K. O. Hallinan, D. H. G. Crout, W. Errington, J. Chem.
Soc., Perkin Trans. 1 1994, 3537–3543.
+
[13] The absolute configurations of (À)- and (+)-cyclopro-
pylglycine (À)-8 and (+)-8 were assigned on the basis
of their signs of optical rotation as reported in ref.[12].
[14] O. V. Larionov, T. F. Savel’eva, K. A. Kochetkov, N. S.
Ikonnikov, S. I. Kozhushkov, D. S. Yufit, J. A. K.
Howard, V. N. Khrustalev, Yu. N. Belokon, A. de Mei-
jere, Eur. J. Org. Chem. 2003, 869–877.
(100); HR-MS (ESI): m/z=326.1599, calcd. for C16H24NO6
[M + H+]: 326.1598.
Acknowledgements
[15] O. V. Larionov, S. I. Kozhushkov, A. de Meijere, Syn-
This work was supported by the State of Niedersachsen and
the Fonds der Chemischen Industrie. O. V. L. is indebted to
the Degussa-Stiftung for a graduate fellowship. The authors
are grateful to the companies BASF AG, Bayer AG, Cheme-
tall GmbH, as well as Degussa AG for generous gifts of
chemicals, and to Dr. B. Knieriem, Gçttingen, for his careful
proof-reading of the final manuscript.
thesis 2003, 12, 1916–1919.
[16] R. S. Coleman A. J. Carpenter, J. Org. Chem. 1993, 58,
4452–4461.
[17] a) H. Poisel, U. Schmidt, Angew. Chem. 1976, 9, 295–
297; Angew. Chem. Int. Ed. Engl. 1976, 15, 294–296;
b) H. Poisel, Chem. Ber. 1975, 108, 2547–2553; c) A. J.
Kolar, R. K. Olsen, Synthesis 1977, 457–459.
[18] In order to clarify this phenomenon. a computational
study (AM1) of the tautomeric pairs methyl 2-cyclo-
propyl-2-(N-methoxycarbonylimino)acetate and methyl
2-cyclopropylidene-2-(N-methoxycarbonylamino)ace-
tate, as well as the methyl 3,3-dimethyl-2-(N-methoxy-
carbonylamino)acrylate and its imine isomer methyl
3,3-dimethyl-2-(N-methoxycarbonylimino)acetate was
performed. In the latter tautomeric pair the 2-amino-
acrylate was found to be by 5.0 and 4.1 kcalmolÀ1, re-
spectively, more stable than the (Z)- and (E)-imine, re-
spectively. This correlates with the experimental and
spectral data, evincing that the compounds of this type
exist as 2-aminoacrylates, and add nucleophiles in the
1,4-manner. In contrast, in the former tautomeric pair,
the (Z)-imine diastereomer is by 2.1 kcalmolÀ1 more
stable than the (E)-imine, and by 4.5 kcalmolÀ1 than
the cyclopropylideneacetate. Thus, after elimination of
HCl from the N-chloro derivative 12, the system arrives
at the thermodynamically more stable tautomer.
[19] a) Y.-R. Luo, J. L. Holmes, J. Phys. Chem. 1992, 96,
9568–9571; b) R. B. Turner, P. Goebel, B. J. Mallon, W.
von E. Doering, J. F. Coburn, M. Pomerantz, J. Am.
Chem. Soc. 1968, 90, 4315–4322.
References
[1] Part 126 in the series “Cyclopropyl Building Blocks for
Organic Synthesis”; for part 125 see: M. Marradi, A.
Brandi, A. de Meijere, Synlett 2006, 1125–1127; part
124: S. Dalai, V. N. Belov, S. Nizamov, K. Rauch, D.
Finsinger, A. de Meijere, Eur. J. Org. Chem. 2006,
2753–2765.
[2] A. de Meijere, S. I. Kozhushkov, L. P. Hadjiarapoglou,
Topics Curr. Chem. 2000, 149–227, and references cited
therein.
[3] a) F. Seyed-Mahdavi, S. Teichmann, A. de Meijere, Tet-
rahedron Lett. 1986, 27, 6185–6188; b) A. de Meijere,
S. Teichmann, F. Seyed-Mahdavi, S. Kohlstruk, Liebigs
Ann. 1996, 1989–2000.
[4] M. Limbach, S. Dalai, A. de Meijere, Adv. Synth. Catal.
2004, 346, 760–766.
[5] V. N. Belov, C. Funke, T. Labahn, M. Es-Sayed, A. de
Meijere, Eur. J. Org. Chem. 1999, 1345–1356.
[6] A. Esposito, P. P. Piras, D. Ramazzotti, M. Taddei, Org.
Lett. 2001, 3, 3273–3275.
[20] See, for example: W. M. Kazmierski, C. J. Aquino, N.
Bifulco, E. E. Boros, B. A. Chauder, P. Y. Chong, M.
Duan, F. Deanda, C. S. Koble, E. W. Mclean, J. P. Peck-
ham, A. C. Perkins, J. B. Thompson, D. Vanderwall,
WO Patent 2004 054 974 A2, 2004.
[7] H. K. Chenault, J. Dahmer, G. M. Whitesides, J. Am.
Chem. Soc. 1989, 111, 6354–6364.
[8] S. I. Kozhushkov, M. Brandl, D. S. Yufit, R. Machinek,
A. de Meijere, Liebigs Ann. Recl. 1997, 2197–2204.
[9] D. E. Slaughter, R. Subramanian, M. E. Fraley, T.
Prueksaritanont, H. Shu, WO Patent 2004 087 050 A2,
2004.
[21] a) S. D. Larsen, P. A. Grieco, J. Am. Chem. Soc. 1985,
107, 1768–1769; b) K. Waldmann, Liebigs Ann. Chem.
Adv. Synth. Catal. 2006, 348, 1071 – 1078
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1077

Oleg V. Larionov and Armin de Meijere
FULL PAPERS
1989, 231; c) S. Kçrbe, A. de Meijere, T. Labahn, Helv.
Chim. Acta 2002, 85, 3161–3175.
[25] K. O. Hallinan, D. H. G. Crout, W. Errington, J. Chem.
Soc., Perkin Trans. 1 1994, 3537–3543.
[22] S. E. Gibson, N. Guillo, M. J. Tozer, Tetrahedron 1999,
55, 585–615.
[23] D. Laurie, E. Lucas, D. C. Nonhebel, C. J. Suckling, Tet-
rahedron 1986, 42, 1035–1046.
[26] a) A. L. Castelliano, S. Horne, G. J. Taylor, R. Bille-
deau, A. Krantz, Tetrahedron 1988, 44, 5451–5466;
b) A. L. Castelliano, S. Horne, R. Billedeau, A. Krantz,
Tetrahedron Lett. 1986, 27, 2435–2438.
[24] L. Wessjohann, N. Krass, D. Yu, A. de Meijere, Chem.
Ber. 1992, 125, 867–882.
1078
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1071 – 1078