Diastereo- and enantioselective synthesis of 2-substituted 1-aminocyclopropane-1-carboxylic acids. Application to the synthesis of protected 2,3-methano analogs of ornithine and glutamic acid

Article abstract of DOI:10.1055/s-2005-870007

An enantiodivergent synthesis of protected 2,3-methano amino acid analogs is described. (R)-2-benzyloxyethyloxirane, prepared from (S)-aspartic acid, was reacted with tert-butyl hydrogen malonate and further transformed into an enantiomeric pair of interm

Full text of DOI:10.1055/s-2005-870007

PAPER
1751
Diastereo- and Enantioselective Synthesis of 2-Substituted 1-Aminocyclo-
propane-1-Carboxylic Acids. Application to the Synthesis of Protected
2,3-Methano Analogs of Ornithine and Glutamic Acid
S
ynthesis
e
of 2-Substi
f
tuted 1-A
f
minocy
r
c
lopropa
e
ne-1-Carbo
y
xylic
A
cids A. Frick,*a,b John B. Klassen,a Henry Rapoporta
a
Department of Chemistry, University of California at Berkeley, Berkeley, CA, 94720, USA
Department of Chemistry, Illinois Wesleyan University, PO Box 2900, Bloomington, IL, 61702-2900, USA
Fax +1(309)5563864; E-mail: jfrick@iwu.edu
b
Received 28 July 2004; revised 16 December 2004
Dedicated to the memory of Professor Henry Rapoport
which all four stereochemistries of isomeric 1,1,2-trisub-
stituted cyclopropanes, including ACC’s, could be diaste-
reo- and enantiospecifically prepared from a common
precursor derived from the chiral pool. The 2-hydroxyeth-
Abstract: An enantiodivergent synthesis of protected 2,3-methano
amino acid analogs is described. (R)-2-benzyloxyethyloxirane, pre-
pared from (S)-aspartic acid, was reacted with tert-butyl hydrogen
malonate and further transformed into an enantiomeric pair of inter-
mediate cyclopropane-fused-lactones, 1-carboxy-2-oxo-3-oxabicy- yl group was chosen as a key substituent on the cyclopro-
pane, in contrast to most of the reported syntheses6–8 that
clo[4.1.0]heptane. Each of these enantiomers allowed
differentiation of the carboxy functions and generation of a 2-hy-
use a single carbon side chain. Thus, further manipulation
droxyethyl group on the cyclopropanes, thus affording access to any
into a variety of functional groups could be effected with
or all four stereoisomers. The two-carbon pendant allowed for the
minimal involvement of the neighboring cyclopropane.
direct synthesis of protected 2,3-methano analogs of glutamic acid
and ornithine and can be used for other useful transformations.
The results of the application of this methodology to the
construction of various 1,1,2-trisubstituted cyclopropanes
are presented.
Key words: amino acids, asymmetric synthesis, chemoselectivity,
chiral pool, protecting groups, cyclopropanes
Previously, we reported the simple synthesis of enantio-
merically pure epoxide 2 from (S)-aspartic acid (1)12 and
its further elaboration to lactone 6a via intermediate 3
(Scheme 1).13
Polysubstituted cyclopropanes of defined stereochemistry
are of considerable interest as reflected in a number of nat-
ural products and as conformationally constrained ana-
logs of biologically active compounds. Among the latter
are the aminocyclopropanecarboxylic acids (ACC’s)
which have been used as conformationally constrained
amino acid components of peptides,1 as artificial sweeten-
ers,2 and as enzyme inhibitors.3 Cyclopropane amino acid
analogs of arginine have been incorporated into short he-
lical peptides4 and into spirocyclic peptidomimetics5 in
order to study the impact of these well-defined stereoiso-
mers on secondary structures. The intense activity in this
area of synthesis has been delineated in three recent re-
view articles.6 In particular, Burgess and co-workers have
developed an entry point into a variety of cyclopropane
amino acid analogs using malic acid as a chiral starting
material.7 Charette and coworkers have focused on the de-
velopment of a method which uses a benzylated b-D-glu-
copyranose to induce a diastereoselective methylation of
allylic alcohols.8a Other cyclopropane amino acid analogs
have been prepared via metal-catalyzed reactions,9 from a
chiral glycine equivalent,10 and from (D)-serine.11
Mitsunobu inversion14 of alcohol 3 using 3,5-dinitroben-
zoic acid resulted in the formation of triester 4 in 91%
yield (Scheme 1). The use of a carboxylic acid bearing
electron withdrawing groups provided a molecule with a
leaving group in place for subsequent cyclopropane for-
mation. Consideration was also given to the use of 2,4-
dinitrobenzoic acid since the 2,4-dinitrobenzoate should
be a better leaving group; however, purification of the 2,4-
dinitrobenzoate ester by column chromatography was
possible, but much more difficult. Furthermore, the 2,4-
dinitrobenzoate and the 3,5-dinitrobenzoate underwent
ring closure at nearly the same rate.
3,5-Dinitrobenzoate ester 4 underwent cyclization when
treated with NaH in THF–t-BuOH to produce cyclopro-
pane 5a in 81% yield. Hydrogenolysis of the benzyl ether
of 5a proceeded smoothly in methanol with a 10% Pd/C
catalyst. Comparison of the optical rotation for 5b with its
enantiomer13 showed that the Mitsunobu reaction pro-
ceeded with clean inversion in this system. When cyclo-
propane 5b was treated with an excess of TFA, d-lactone
6b was formed in quantitative yield (Scheme 1). With
enantiomers 6a and 6b in hand, selective elaboration al-
lowed for the stereospecific preparation of various 1,1,2-
trisubstituted cyclopropane derivatives.
Although many protocols exist for the construction of
such cyclopropanes, methods leading to the asymmetric
synthesis of all four stereoisomers of these compounds are
limited. Our goal was to develop a general method by
Efforts next were turned to the selective conversion of the
exocyclic carboxyl group into another functionality, e.g.,
a protected amine. The Curtius reaction was chosen as the
SYNTHESIS 2005, No. 11, pp 1751–1756
Advanced online publication: 29.06.2005
DOI: 10.1055/s-2005-870007; Art ID: M05604SS
x
x.
x
x
.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

1752
J. A. Frick et al.
PAPER
O
O
O
HO2C
H
H
O
Ref. 13
O
Ref. 13
tBuO
OtBu
OH
BnO
2
6a
OBn
3
Ref. 12
3,5-dinitrobenzoic acid,
Ph3P, DEAD
91%
O
NH2
OH
HO
1
O
O
O
O
O
tBuO
OtBu
OR
NaH
tBuOH, THF
tBuO
OtBu
OR
5a, R = Bn, 81%
5b, R = H, 97%
OBn
H2/Pd-C
4 R = 3,5-dinitrobenzoate
TFA, CH2Cl2
quant.
O
HO2C
H
O
6b
Scheme 1 Synthesis of enantiomeric 1-carboxy-2-oxo-3-oxabicyclo[4.1.0]heptanones
method of choice for the conversion of 6 into 7. The use
H
N
O
O
O
of diphenylphosphoryl azide (DPPA),15 a common re-
H
N
1. LiOH
2. Me
93%
1.
Cbz
OEt
O
Cl
agent for the one-pot transformation of carboxylic acids
into amines, gave poor results with this system. After ex-
amining a variety of carboxylic acid-activating agents in-
cluding 1,1¢-carbonylbis(3-methylimidazolium) triflate
(CBMIT)16 and diphenyl chlorophosphate,17 ethyl
chloroformate18 was found to be the reagent of choice.
Carboxylic acid 6a was treated with ethyl chloroformate
in acetone at 0 °C and the resulting mixed anhydride was
then treated with NaN3 in acetone–water to provide the in-
termediate acyl azide. Rearrangement of the acyl azide to
the isocyanate was accomplished by heating in toluene.
After the isocyanate formation was complete, benzyl alco-
hol was added to form the Cbz-protected amine 7a in an
overall 90% yield after silica gel chromatography
(Scheme 2).
OMe
OH
6a
Cbz
2. NaN3
3. heat
4. BnOH
90%
8a
H
7a
1. MsCl
2. NaN3
95%
O
O
H
N
H
N
H2/Pd-BaSO4
(Boc)2O
75%
OMe
OMe
Cbz
Cbz
9
N3
NH
10
Boc
O
tBuO2C
O
tBuO2C
NH3
93%
O
NH2
tert-butyl isourea
CH2Cl2
6a
OH
89%
H
12
11
Further functional group modification involved hydroly-
sis of the d-lactone (LiOH) to hydroxy carboxylate, and
esterification (MeI) to afford protected amino acid 8a in
93% yield. Elaboration of the pendant hydroxyethyl group
continued by treatment of 8a with MsCl in methylene
chloride to produce in quantitative yield the mesylate
which was converted into azide 9 with NaN3 in DMF
(95% yield) (Scheme 2).
Scheme 2 Differentiation of the carboxyl groups and synthesis of
the protected 2,3-methanoornithine analog
intramolecular reaction of the amine as it formed. This
problem was overcome by exposing azide 9 to H2 in the
presence of 5% Pd/BaSO4 and (Boc)2O in ethyl acetate. A
75% yield of the fully differentiated, protected 2,3-meth-
anoornithine analogue 10 was isolated following silica gel
chromatography; no Cbz cleavage was observed under
these conditions.
Conversion of the azide into an amine proved to be non-
trivial. Reagents such as 1,3-propanedithiol,19 trieth-
ylphosphite,20 as well as triphenyl- and tributylphos-
phine,21 useful for azide reduction and known to be
compatible with the Cbz-protected nitrogen, were ineffi-
cient for reduction of 9. In general, incomplete consump-
tion of 9 was observed along with the d-lactam formed by
In another direction, carboxylic acid 6a was esterified
with O-tert-butyl-N,N¢- diisopropylisourea22 to form tert-
butyl ester 11 in 89% yield. Selective reaction with am-
monia induced lactone opening in isopropyl alcohol at
Synthesis 2005, No. 11, 1751–1756 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 1-Aminocyclopropane-1-Carboxylic Acids
1753
Melting points are uncorrected. NMR spectra were taken in CDCl3
and are referenced to internal TMS; coupling constants are reported
in Hertz. Proton and carbon spectra were recorded at 300 MHz and
75 MHz, respectively. Solvents were dried and purified prior to use:
THF was distilled from Na/benzophenone; CH2Cl2, DMF, and hex-
ane were distilled from CaH2; MeCN was distilled from P2O5. Re-
actions were conducted under Ar or N2. For isolation, the organic
phase was dried over MgSO4 before evaporation under reduced
pressure. TLC analysis was performed on aluminum-backed silica
gel 60 F254 0.2 mm plates. Chromatography was carried out using
230–400 mesh silica gel. Elemental analyses were performed by the
Microanalytical Laboratory, University of California, Berkeley.
room temperature and resulted in the formation of hy-
droxy amide 12 in 93% yield. This example establishes
that the lactone carboxyl group is amenable to elaboration
into other derivatives while the ester carboxyl remains un-
changed.
Protected amino acid 8b was prepared from acid lactone
6b in the same manner as described for the conversion of
6a into 8a. Oxidation of alcohol 8b to aldehyde 13, how-
ever, proved to be quite troublesome, since the cyclopro-
pylacetaldehyde readily enolizes and rearranges to the
ring-opened a,b-unsaturated aldehyde 15 (Scheme 3).23
Oxidation24 with NCS/(CH3)2S resulted in consumption
of 8b, but no evidence for aldehyde formation was found.
Oxidation with PCC resulted in a disappointing mixture of
13/15 (~15:85). A modified Collin’s oxidation25 resulted
in a 99:1 mixture of 14/13; however, unreacted alcohol 8b
was observed and the overall mass recovery was poor
(35%). Oxalyl chloride/DMSO oxidation26,27 gave a 1:1
mixture of 13/14 along with some unreacted alcohol 8b. It
is interesting to note that the tetrapropylammonium perru-
thenate (TPAP)28 catalyzed oxidation of 8b, reported to be
mild and effective for a wide range of alcohols, resulted in
a complex mixture of 8b, 13, 15, and several other uniden-
Di-tert-butyl [(2S)-4-Benzyloxy-2-(3,5-dinitrobenzoyloxy)] Bu-
tylmalonate (4)
A solution of diester 3 (5 g, 12.7 mmol) in THF (55 mL) was chilled
in an ice/water bath and the following reagents were added sequen-
tially: PPh3 (6.7 g, 25.4 mmol), 3,5-dinitrobenzoic acid (5.4 g, 25.4
mmol), and, dropwise, DEAD (3.9 mL 24.8 mmol). The reaction
mixture was stirred for 15 min, the ice bath was removed, the reac-
tion proceeded overnight. Then the solvent was evaporated, and the
residue was adsorbed onto silica gel. The product was then eluted
with a solvent gradient of hexane, EtOAc–hexane (1:6), and then
EtOAc–hexane (1:5) to yield 6.8 g (91%) of 4.
Rf 0.42 (petroleum ether–EtOAc, 4:1).
[a]D23 +1.72 (c 1.46, CHCl3).
1H NMR: d = 8.95–9.3 (m, 3 H), 7.13 (s, 5 H), 5.45 (m, 1 H), 4.35
(d, J = 5 Hz, 2 H), 3.65 (t, J = 6 Hz, 2 H), 3.25 (t, J = 6 Hz, 1 H),
1.8–2.2 (m, 4 H), 1.45 (s, 9 H), 1.41 (s, 9 H).
13C NMR: d = 168.167.9, 162.2, 148.2, 137.7, 134.1, 129.3, 128.0,
127.6, 127.3, 122.0, 82.0, 92 0, 73.4, 73.1, 67.1, 50.5, 34.7, 33.2,
27.8.
29
tified products. When 8b was treated with pyridine·SO3
(600 mol%), in methylene chloride at 0 °C, complete con-
sumption of 8b was effected and formation of ring-opened
aldehyde 15, which did occur to a slight extent under these
conditions at room temperature, was suppressed. Even on
standing at room temperature, a slow conversion of 13
into 15 took place; therefore, crude 13 should be used for
subsequent transformations immediately upon isolation.
Oxidation of 13 to the protected 2,3-methanoglutamate 14
was accomplished with sodium chlorite29 in 80% yield
(Scheme 3).
Anal. Calcd for C29H36N2O6: C, 59.2; H, 6.2; N, 4.8. Found: C, 59.3;
H, 6.3; N, 4.7.
Di-tert-butyl (2R)-2-[2-Benzyloxy)ethyl]cyclopropane-1,1-di-
carboxylate (5a)
To a solution of the 3,5-dinitrobenzoate 4 (3.46 g, 5.88 mmol) in
THF (90 mL) and t-BuOH (4.5 mL), chilled in an ice/water bath,
was added NaH (760 mg, 57%, 17.5 mmol). After stirring for 15
min, the ice bath was removed, the reaction was continued at r.t. for
2 d, and the reaction mixture was partitioned between Et2O (75 mL)
and sat. NaHCO3 (50 mL). The organic phase was washed with sat.
NaHCO3 (2 × 50 mL) and brine (50 mL), dried, and evaporated.
In summary, we have demonstrated that total steric and
enantiomeric control can be effected to synthesize a vari-
ety of 1,1,2-trisubstituted, functionalized cyclopropanes.
Stereochemical control is driven by the influence of the
initial chiral center of aspartic acid. Structural diversity is
achieved through a pendant 2-hydroxyethyl group.
O
H
N
O
H
N
Cbz
O
Cbz
OMe
6b
96%
77%
H
OH
8b
pyr.SO3
7b
O
O
O
H
N
H
NaClO2
N
+
Cbz
OMe
CO2H
H
CO2Me
NHCbz
Cbz
OMe
CHO
80% from
8b
14
13
15
Scheme 3 Synthesis of the protected glutamate analog
Synthesis 2005, No. 11, 1751–1756 © Thieme Stuttgart · New York

1754
J. A. Frick et al.
PAPER
The dark red residue was chromatographed (hexane–EtOAc, 10:1)
Rf 0.34 (hexane–EtOAc, 1:1).
to yield 1.78 g (81%) of 5a.
1H NMR: d = 7.29–7.40 (m, 5 H), 5.88 (br s, 1 H), 5.10 (s, 2 H),
4.22–4.27 (m, 1 H), 3.99–4.16 (m, 1 H), 2.38–2.45 (m, 1 H), 1.91–
2.04 (m, 2 H), 1.73 (t, J = 6.3 Hz, 1 H), 1.37 (t, J = 7.9 Hz, 1 H).
13C NMR: d = 171.3, 156.5, 136.0, 129.4, 128.0, 127.9, 66.9, 65.1,
35.1, 24.3, 21.2, 16.0.
Rf 0.36 (petroleum ether–EtOAc, 9:1).
[a]D23 –29.3 (c 10.6, CH2Cl2).
1H NMR: d = 7.26 (s, 5 H), 4.51 (s, 2 H), 3.57 (d, J = 6.6 Hz, 2 H),
1.45–1.95 (m, 3 H), 1.47 (s, 9 H), 1.45 (s, 9 H), 1.23 (d, J = 6.8 Hz,
2 H).
Benzyl [(1S,6S)-2-Oxo-3-oxabicyclo[4.1.0]hept-1-yl]carbamate
(7a)
The same procedure used to prepare 7b was applied to acid 6a (312
mg, 2 mmol) to yield 470 mg (90%) of 7a. This compound was
chromatographically and spectroscopically identical to 7b.
13C NMR: d = 169.6, 167.5, 138.3, 128.3, 127.6, 127.5, 81.3, 81.1,
72.9, 69.3, 35.8, 28.8, 28.0, 27.0, 23.9, 19.9.
Anal. Calcd for C22H32O5: C, 70.2; H, 8.6. Found: C, 70.1; H, 8.4.
Di-tert-butyl (2S)-2-(2-Hydroxyethyl)cyclopropane-1,1-dicar-
boxylate (5b)
Anal. Calcd for C14H15NO4: C, 64.4; H, 5.8; N, 5.4. Found: C, 64.2,
H, 5.8, N, 5.2.
To a solution of 5a (1.37 g, 3.64 mmol) in MeOH (10 mL) was add-
ed 10% Pd/C (150 mg) and the reaction mixture was purged with H2
at atmospheric pressure. After 1.5 h, the reaction mixture was fil-
tered through celite and evaporated to yield chromatographically
and spectrally pure 5b: 1.05 g (97%).
Methyl (1R,2R)-1-{[(Benzyloxy)carbonyl]amino}-2-(2-hy-
droxyethyl)cyclopropanecarboxylate (8b)
To a solution of carbamate 7b (322 mg, 1.23 mmol) in THF (12 mL)
was added an aq LiOH solution (1 M, 1.5 mL, 1.5 mmol, 120 mol%)
and the mixture was stirred overnight at r.t. The reaction mixture
was acidified by the addition of Bio-Rad AG 50W-X4 acid cation
exchange resin (600 mg, 3.1 mmol, 250 mol%) and stirred for 30
min, then filtered after which the resin was washed with CHCl3
(2 × 10 mL). The combined filtrate was dried, filtered, and evapo-
rated. The residue of hydroxy acid was dissolved in a mixture of
MeCN (12 mL) and DMF (2.4 mL), and K2CO3 (340 mg, 2.46
mmol) and MeI (0.77 mL, 12.3 mmol) were added. This mixture
was stirred overnight and then partitioned between EtOAc (25 mL)
and H2O (25 mL). The aqueous phase was extracted with EtOAc
(2 × 25 mL), and the combined EtOAc extracts were washed with
brine. After drying and filtering, the organic solution was evaporat-
ed and the residue was chromatographed (hexane–EtOAc, 1:1) to
yield 346 mg (96%) of 8b.
Rf 0.32 (hexane–EtOAc, 4:1).
[a]D23 –49 (c 3.30, CHCl3).
1H NMR: d = 3.72 (d, J = 6.5 Hz, 2 H), 1.51–1.88 (m, 3 H), 1.45 (s,
9 H), 1.43 (s, 9 H), 1.23 (m, 2 H).
13C NMR: d = 169.7, 167.6, 81.5, 81.4, 62.0, 35.7, 31.6, 27.9, 23.8,
19.6.
Anal. Calcd for C15H26O5: C, 62.9; H, 9.1. Found: C, 62.7; H, 9.1.
(1R,6R)-2-Oxo-3-oxabicyclo[4.1.0]heptan-1-carboxylic Acid
(6b)
Cyclopropane 5b was dissolved in CH2Cl2 (100 mL/g), trifluoro-
acetic acid (1000 mol%) was added, the reaction mixture was re-
fluxed overnight, and the solvent was evaporated leaving a white
solid in quantitative yield. Although this material was generally
used directly in the next transformation, the acid can be chromato-
graphed and crystallized from Et2O–hexane.
Rf 0.33 (hexane–EtOAc, 1:1).
Mp 90 °C (hexane–EtOAc).
[a]D23 +23.2 (c 0.56, CHCl3).
1H NMR: d = 7.31–7.39 (m, 5 H), 5.46 (s, 1 H), 5.15 (AB quartet,
JAB = 12.2 Hz, 2 H), 3.74–3.78 (m, 1 H), 3.71 (s, 3 H), 3.61–3.65
(m, 1 H), 1.98–2.04 (m, 1 H), 1.68–1.78 (m, 3 H), 1.47 (dd, J = 8.2,
4.9 Hz, 1 H), 1.25 (dd, J = 9.5, 4.9 Hz, 1 H).
Mp 90–91 °C.
[a]23 –63 (c 1.95, CHCl3).
1H NMR: d = 4.41 (dddd, J = 12.13, 5.93, 1.33, 1.32 Hz, 1 H), 4.25
(ddd, J = 12.85, 12.81, 3.69 Hz, 1 H), 2.68–2.72 (m, 1 H), 2.32 (tq,
14.0, 5.58, 2.97 1 H), 2.16–2.19 (m, 1 H), 2.13 (distorted t, J = 5.48
Hz, 1 H), 1.99 (dd, J = 8.38, 5.42 1 H).
13C NMR: d = 171.6, 157.7, 135.8, 128.5, 128.27, 128.12, 67.3,
61.7, 52.6, 37.9, 30.6, 29.4, 21.8.
13C NMR: d = 174.7, 169 7, 66.3, 26.7, 25.9, 21.66, 20.3.
Methyl (1S,2S)-1-{[(Benzyloxy)carbonyl]amino}-2-(2-hydroxy-
ethyl)cyclopropanecarboxylate (8a)
Anal. Calcd for C7H8O4: C, 53.8; H, 5.2. Found: C, 53.5; H, 4.8.
The same procedure used to prepare 8b was conducted using car-
bamate 7a (622 mg, 2.4 mmol) to yield 653 mg (93%) of 8a, chro-
matographically and spectroscopically identical to 8b.
Benzyl [(1R,6R)-2-Oxo-3-oxabicyclo[4.1.0]hept-1-yl]carbam-
ate (7b)
To a solution of acid 6b (608 mg, 3.9 mmol) in acetone (8 mL),
chilled with an ice bath, was added TEA (1.1 mL 7.8 mmol) and eth-
yl chloroformate (0.447 mL, 4.7 mmol). This solution was stirred
for 30 min during which of benzene (6 mL) was added and the re-
sulting cloudy mixture was filtered through celite and washed with
an additional amount of of benzene (10 mL). Then the combined fil-
trate was evaporated. To the residual oil, dissolved in acetone (8
mL) and cooled to 0 °C, was added sodium azide (0.51 g, 7.8 mmol)
dissolved in H2O (2 mL). After stirring for 30 min, the reaction mix-
ture was diluted with H2O (20 mL) and extracted with CH2Cl2
(3 × 20 mL). The combined organic phase was dried and evaporated
to an oil which was dissolved in toluene (20 mL) and refluxed for 2
h before benzyl alcohol (0.85 mL, 7.8 mmol) was added and reflux
was continued overnight. The solvent was evaporated and the resi-
due chromatographed (hexane–EtOAc, 1:1) to yield 0.78 g (77%) of
7b.
Mp 89–90 °C.
[a]D23 –26.9 (c 0.84, CHCl3).
Anal. Calcd for C15H19NO5: C, 61.3; H, 6.4; N, 4.8. Found: C, 61.3;
H, 6.4; N, 4.6.
Methyl (1S,2S)-2-(2-Azidoethyl)-1-{[(benzyloxy)carbonyl]ami-
no}cyclopropanecarboxylate (9)
To alcohol 8a (479 mg, 1.6 mmol) in CH2Cl2 (40 mL) at 0 %C, were
added TEA (0.56 mL, 4 mmol) and MsCl (0.25 mL, 3.2 mmol). Af-
ter 30 min, saturated NaHCO3 (50 mL) was added and the reaction
mixture was stirred for another 30 min, then the aqueous layer was
extracted with CH2Cl2 (2 × 50 mL). The combined organic phase
was dried, filtered, and evaporated, and the residue was chromato-
graphed to yield 593 mg (quant.) of mesylate.
Rf 0.27 (hexanes–EtOAc, 1:1).
Synthesis 2005, No. 11, 1751–1756 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 1-Aminocyclopropane-1-Carboxylic Acids
1755
1H NMR: d = 7.30–7.36 (m, 5 H), 5.57 (br s, 1 H), 5.10 (br s, 2 H),
4.38–4.20 (m, 2 H), 3.72 (br s, 3 H), 2.99 (br s, 3 H), 2.01–2.17 (m,
2 H), 1 61–1.75 (m, 1 H), 1.51–1.56 (m, 1 H), 1.37–1.43 (m, 1 H).
stirred at r.t. for 48 h. The tube was cooled to –78 °C and opened,
the contents were warmed to r.t., and the solvent was evaporated.
Chromatography (hexane–EtOAc, 1:5) provided pure amide 12
(199 mg, 93%) as an oil
1H NMR: d = 8.15 (s, 1 H), 6.38 (s, 1 H), 3.59–3.36 (t, 2 H), 3.30 (s,
1 H), 1.72–1.81 (m, 2 H), 1.58–1.64 (m, 2 H), 1.40 (s, 9 H).
This mesylate was dissolved in DMF (70 mL) and to this solution
were added activated NaN3 (625 mg, 9.6 mmol) and NaI (24 mg,
0.16 mmol). The reaction flask was lowered into an oil bath at 80 °C
and the reaction was allowed to proceed with stirring for 18 h after
which it was diluted with EtOAc (100 mL) and washed with H2O
(100 mL). The aqueous phase was extracted with EtOAc (2 × 50
mL) and the combined organic extracts were washed with H2O (100
mL) and brine (100 mL), dried, and evaporated to an oil which was
chromatographed to yield 484 mg (95%) of azide 9.
13C NMR: d = 171.5, 171.0, 81.9, 61.6, 32.7, 30.5, 30.1, 27.8, 20.4.
Anal. Calcd for C11H19NO4: C, 57.2; H, 8.3; N, 6.1. Found: C, 57.4;
H, 8.0; N, 5.9.
Methyl (4E)-2-{[(Benzyloxy)carbonyl]amino}-6-oxohex-4-
enoate (15)
Mp 64–65 °C.
[a]D23 +3.9 (c 1.2, CHCl3).
1H NMR: d = 7.26–7.34 (m, 5 H), 5.50 (br s, 1 H), 5.12 (s, 2 H), 3.70
(br s, 3 H), 3.36 (br s, 2 H), 1.78–2.03 (m, 2 H), 1.52–1.63 (m, 2 H),
1.28–1.50 (m, 1 H).
To alcohol 8b (100 mg, 0.34 mmol) in CH2Cl2 (1 mL) and diisopro-
pylethylamine (0.350 mL 2.04 mmol) at 0 °C was added dropwise
a solution of pyridine·SO3 (0.35 g, 2.2 mmol) in DMSO (1 mL). The
reaction mixture was stirred for 15 min in the ice bath, allowed to
warm to r.t., diluted with H2O (10 mL), and extracted with ether
(3 × 15 mL). The combined organic extract was washed successive-
ly with 10% citric acid (2 × 15 mL), H2O (2 × 15 mL) and sat.
NaHCO3 (15 mL), then dried and evaporated to give crude aldehyde
13.
13C NMR: d = 171.7, 156.3, 136.1, 128.4, 128.1, 127.96, 66.8, 52.5,
50.8, 38.32, 29.2, 26.4, 22.8.
Anal. Calcd for C15H18N4O4: C, 56.6; H, 5.7; N, 17.6. Found: C,
57.0; H, S.8; N, 18.0.
1H NMR: d = 9.75 (br s, 1 H), 7.34 (br s, 5 H), 5.72 (br s, 1 H), 5.12
(s, 2 H), 3.67 (s, 3 H), 2.75–2.85 (m, 2 H), 1.69–2.22 (m, 1 H),
1.26–1.53 (m, 2 H).
Methyl (1S,2S)-1-{[(Benzyloxy)carbonyl]amino}-2-{2-[(tert-
butoxycarbonyl)amino]ethyl}cyclopropanecarboxylate (10)
Azide 9 (920 mg, 2.9 mmol) and (Boc)2O (1.9 g, 8.7 mmol) were
dissolved in EtOAc (25 mL), Pd/BaSO4 (5%, 180 mg, 20 wt%) was
added and the contents were stirred under H2 at atmospheric pres-
sure. After 2 h the reaction mixture was filtered through celite,
evaporated and the residue was chromatographed (1% TEA in hex-
ane–EtOAc, 4:1, then 1% TEA in hexane–EtOAc, 70:30) to yield
852 mg (75%) of 15.
The crude aldehyde was dissolved directly in a mixture of THF (7
mL), t-BuOH (7 mL), and 2-methyl-2-butene (1.8 mL) and a solu-
tion of sodium chlorite (280 mg, 3.06 mmol) and NaH2PO4·H2O
(324 mg, 2.35 mmol) in H2O (3.4 mL) was added dropwise. This
mixture was stirred for 15 min and then partitioned between saturat-
ed NaHCO3 (20 mL) and hexane (20 mL). The separated aqueous
phase was acidified to pH 3 with concd HCl and extracted with Et2O
(3 × 20 mL), the combined organic extract was dried, filtered, and
evaporated, and the residue was chromatographed (1% AcOH in
hexane–EtOAc, 2:1) to yield 84 mg (80%) of glutamate 14.
Rf 0.33 (hexane–EtOAc, 2:1).
[a]D23 –28.6 (c 0.7, CHCl3).
1H NMR: d = 7.28–7.35 (m, 5 H), 5.78 (br s, 1 H), 5.56 (br s, 1 H),
5.12 (s, 2 H), 3.69 (s, 3 H), 3.14–3.23 (m, 2 H), 1.87–1.90 (m, 1 H),
1.48–1.66 (m, 2 H), 1.43 (s, 9 H), 1.25–1.78 (m, 2 H).
13C NMR: d = 171.8, 156.8, 156.3, 136.3, 128.3, 127.95, 127.86,
78.7, 66.6, 52.3, 39.8, 38.0, 30.5, 28.4, 27.2, 22.4.
Rf 0.24 (1% AcOH in hexane–EtOAc, 21).
[a]D23 +17.8 (c 0.7, CHCl3).
1H NMR: d = 7.27 (s, 5 H), 5.56 (s, 1 H), 5.06 (s, 2 H), 3.63 (br s, 3
H), 2.78 (dd, J = 17.6, 4.9 Hz, 1 H), 2.67 (dd, J = 17.4, 8.98 Hz, 1
H), 1.67–1.74 (m, 1 H), 1.50–1.53 (m, 1 H), 1.40 1.47 (m, 1 H).
13C NMR: d = 175.7, 171.4, 156.9, l36.0, 128.52, 128.26, 128.11,
67.2, 52.7, 38.2, 32.2, 26.3, 23.0.
Anal. Calcd for C20H28N2O6: C, 61.2; H, 7.2; N, 7.1. Found: C, 61.0;
H, 7.3; N, 7.1.
Anal. Calcd for C15H17NO6: C, 58.6; H, 5.6; N, 4.6. Found: C, 58.7;
H, 5.8, N, 4.6.
tert-Butyl (1S,6S)-2-Oxo-3-oxabicyclo[4.1.0]heptane-1-carbox-
ylate (11)
To a solution of lactone 6a (429 mg, 2.75 mmol) in CH2Cl2 (25 mL)
was added O-tert-butyl-N,N¢-diisopropylisourea (1.5 g, 8.0 mmol)
and the reaction was stirred overnight. Then another portion of the
isourea (0.5 g, 2.6 mmol) was added and stirring was continued for
4 h. The reaction mixture was filtered through celite, the celite was
washed with Et2O–CH2Cl2 (50 mL, 2:1), and the combined filtrate
was evaporated to a yellow oil which was chromatographed to yield
515 mg (89%) of 17.
Acknowledgment
J.B.K. is grateful to St. John’s University, Collegeville, Minnesota,
for a sabbatical leave. We thank M.P. Parker, Undergraduate Re-
search Participant, for assistance in the preparation of a number of
intermediates.
Mp 70–72 °C.
[a]D23 +48.6 (c 2.5, CHCl3).
References
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Synthesis 2005, No. 11, 1751–1756 © Thieme Stuttgart · New York

1756
J. A. Frick et al.
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Synthesis 2005, No. 11, 1751–1756 © Thieme Stuttgart · New York