The iodolactone approach to enantiopure oxiranes of constrained chiral cyclic β-amino acids

Article abstract of DOI:10.1016/j.tetasy.2008.09.005

A simple and efficient method has been developed for the synthesis of enantiopure epoxide derivatives of some constrained chiral cyclic β-amino acids via iodolactonization and alkaline de-iodation. Lower stereoselectivities were observed when the classical method using mCPBA was used when a bicyclic β-amino acid was involved leading to a quasi-inseparable mixture of two epoxides.

Full text of DOI:10.1016/j.tetasy.2008.09.005

Tetrahedron: Asymmetry 19 (2008) 2135–2139
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Tetrahedron: Asymmetry
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The iodolactone approach to enantiopure oxiranes of constrained
chiral cyclic b-amino acids
Olivier Songis a, Claude Didierjean b, Jean Martinez a, Monique Calmès a,
*
a Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2, Université Montpellier 2, Bâtiment Chimie (17), Place E. Bataillon, 34095 Montpellier Cedex 5, France
b Laboratoire de Cristallographie et de Modélisation des Matériaux Minéraux et Biologiques, UMR UHP-CNRS 8036, BP 239, 54506 Vandoeuvre les Nancy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method has been developed for the synthesis of enantiopure epoxide derivatives of
some constrained chiral cyclic b-amino acids via iodolactonization and alkaline de-iodation. Lower stereo-
selectivities were observed when the classical method using mCPBA was used when a bicyclic b-amino
acid was involved leading to a quasi-inseparable mixture of two epoxides.
Received 11 July 2008
Accepted 3 September 2008
Available online 9 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Consequently, the development of efficient methods for the ste-
reochemical control of the epoxidation of unsaturated cyclic b-
Over recent years, the chemistry of b-amino acids and their use
in medicinal chemistry have become areas of intense research
activity.1,2 In particular, there has been increasing interest with
regards to the structure and function of conformationally con-
strained chiral cyclic b-amino acids and their oligomers. These
compounds are present in many natural products and biologically
active peptides. They are also useful starting materials in the syn-
thesis of alkaloids and b-lactam antibiotics. Moreover, incorpora-
tion into peptides or peptidomimetics of cyclic b-amino acids
induce conformational restriction and provides significant struc-
tural effects that can be used for structural and biomechanistic
investigations.3
The availability of a large number of regio- and stereoisomers,
together with the possibility of various ring sizes provide a signif-
icant structural diversity of chiral cyclic b-amino acids for design-
ing therapeutic agents or new materials. This diversity has been
further increased by additional substitutions on the amino acid
ring and has found interesting applications. For example, in the
foldamer field, the appending functionality in oligomers composed
of chiral cyclic b-amino acids, which have an important effect on
both their folding propensity and their biological activity.4
A valuable synthetic route to prepare various functionalized
chiral cyclic b-amino acids consists of the ring opening of the cor-
responding chiral epoxide derivatives, because of their ring strain
and high reactivity. The reaction of chiral epoxides with various
nucleophiles (hydrides, organometallic reagents, oxygen and nitro-
gen containing derivatives) generally leads to high regio- and ster-
eoselective ring opening products.
amino acids is of great interest.
Since Prilezhaev’s discovery in 1910,5 the interaction of peroxy
acids with different olefins is the basis of a synthetic method that
leads to the formation of the corresponding epoxides. Among its
numerous applications, epoxidation of cyclic aminoalkenes con-
taining a NH-carbamate protecting group with peracids [mainly
metachloroperbenzoic acid (mCPBA)] is known to generally pro-
cess with a high degree of cis-selectivity, presumably via a hydro-
gen binding interaction in the transition state during the reaction
between the carbamate and the peracidic reagent.6 Conversely, it
has been reported that very high levels of trans-selectivity are
obtained from the epoxidation of both N-diprotected cyclic allylic
amines6d containing electron-withdrawing groups (e.g., Boc, Ts)
or N-Boc protected cyclopentenyl lactams.6h In this case, the stereo-
selectivity is governed by steric factors as a consequence of the
limited possibility of hydrogen bonding with peracid.
2. Results and discussion
In our previous studies,7 we explored the asymmetric Diels
Alder cycloaddition that involved the chiral acrylate (R)-1 and
several N-benzyloxycarbonyl (Z) protected aminodienes, that is,
1-(benzyloxycarbonylamino)butadiene 2,8 1-(benzyloxycarbonyl-
amino)cyclohexadiene 39 and N-benzyloxycarbonyl-1,2-dihydro-
pyridine 4.10
The resulting Diels–Alder cycloadducts were obtained in high
yield and in moderate to good selectivity using optimized condi-
tions, especially when carrying out the reaction under microwave
activation. In each case, using the acrylate with an (R)-configura-
tion, the main Diels–Alder cycloadduct obtained was that resulted
from an endo selective approach on the Ca Si face of the dienophile,
* Corresponding author.
E-mail address: Monique.Calmes@univ-montp2.fr (M. Calmès).
and was isolated in pure form after column chromatography on
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.005

2136
O. Songis et al. / Tetrahedron: Asymmetry 19 (2008) 2135–2139
O
O
O
O
N
O
N
H
N
O
N
H
O
O
O
BnO
3
(R)-1
2
4
O
silica gel. Removal of the chiral auxiliary afforded three enantio-
pure constrained cyclic b-amino acids, that is, (1R,2S)-2-(benzyl-
oxycarbonylamino)cyclohex-3-ene-1-carboxylic acid 5, (1S,2R,
4R)-1-benzyloxycarbonylaminobicyclo[2.2.2]oct-5-ene-2-carboxylic
acid 6 and (1R,4R,7R)-(2-benzyloxycarbonyl)-2-azabicyclo[2.2.2]-
oct-5-ene-7-carboxylic acid 7.
Although the reaction proceeded with high selectivity, isolation
by chromatography of the pure cis-epoxide in good yield from
the mixture containing mCPBA proved to be difficult. In the case
of the bicyclic amino acids 6 and 7, a lower selectivity was ob-
served affording a quasi-inseparable mixture of the two epoxides
in an 80:20 and 33:67 ratio, respectively.11 It can be assumed that
for these two compounds, steric and/or electronic effects were not
sufficient enough to exclusively provide one epoxide.
Consequently, we decided to explore an alternative route to oxi-
rane formation based on the stereoselective transformation of the
cyclic b-amino acid to its iodolactone that offered an excellent pos-
sibility for the exclusive formation of a single epoxide after basic
treatment.
Z
N
CO2H
CO2H
NHZ
ZHN
CO2H
(1R,4R,7R)-7
(1R,2S)-5
(1S,2R,4R)-6
The oxirane formation in two steps via iodolactolization has
previously been described to obtain intermediates involved in
a
-multistriatin,12 in some preparations of poly-
To prepare the functionalized derivatives, we first studied the
epoxidation of these three enantiopure constrained cyclic b-amino
acids 5, 6 and 7 having a Z amino protecting group, in the presence
of mCPBA in dichloromethane.
the synthesis of
unsaturated fatty acids,13 in the macrocyclic core synthesis of
salicylihalamides A an B14 as well as in the synthesis of 4,5-
epoxy-a
-amino acids from allyl or crotyl glycine.15 Likewise,
As expected, the reaction of the cyclic b-amino acid 5 with
mCPBA proceeded with high stereoselectivity, mainly providing
the cis-epoxide due to the stereodirecting effect of the Z amino
protecting group. The product was assigned as a cis-epoxide by
analogy with the known stereochemistry obtained during epoxida-
tion of 2-aminocyclohex-4-ene carboxylic acids.6b,g The trans-
isomer could not be detected in the crude reaction mixture.
unsaturated cyclic b-amino acids have also been previously sub-
jected to iodolactonization but rarely with the aim of oxirane
synthesis.6a,16
The reaction of the unsaturated cyclic b-amino acids 5, 6 and 7
in a biphasic mixture with I2/KI in a slightly alkaline medium,
overnight, at room temperature yielded the corresponding iodo-
lactones 8, 10 and 13 with excellent regio and stereoselectivity
(Schemes 1–3).
These iodolactones were isolated in pure form in 75–80% yield
after column chromatography on silica gel using dichlorometh-
ane/ethyl acetate (9.5:0.5) as eluent. The structure of compounds
8, 10 and 13 was characterized by 1H and 13C NMR and by MS
analysis.
Treatment of iodolactone 8 with lithium hydroxide (3 equiv) in
a THF/H2O mixture for 4 h at room temperature resulted in the
quantitative formation of the epoxide 9, which was isolated in pure
form by recrystallization from ethyl acetate (98% yield) (Scheme 1).
O
CO2H
CO2H
NHZ
O
a
b,c
NHZ
NHZ
O
I
(1R,4R,5R,8R)-8
(1
R,2S
)-5
(1R,2R,3R,4S)-9
Scheme 1. Reagents and conditions: (a) I2, KI, NaHCO3, DCM, H2O; (b) LiOH, THF,
H2O, rt; (c) H3O+, H2O.
I
I
OH
O
O
b, c
d, e
a
O
CO2H
CO2H
ZHN
(1R,2R,3R,4R,6R)-11
CO2H
,4 ,6
ZHN
(1 ,2
ZHN
(1 ,2
ZHN
(1 ,2
S
R,4
R
)-6
R
R
,3
R,6
R,7
R)-10
R
R,3
S
R
R)-12
Scheme 2. Reagents and conditions: (a) I2, KI, NaHCO3, DCM, H2O; (b) LiOH, THF, H2O, rt; (c) H3O+, H2O; (d) LiOH, THF, H2O, 70 °C; (e) H3O+, H2O.
Z
Z
N
Z
N
I
N
a
b, c
O
O
HO2C
(1
CO2H
,4 ,5
O
R,
4R,7
R)-7
(1S
,2
R,3
R,6
R,7
S)-13
(1S
S
S
,6
R,7
R)-14
Scheme 3. Reagents and conditions: (a) I2, KI, NaHCO3, DCM, H2O; (b) LiOH, THF, H2O, rt; (c) H3O+, H2O.

O. Songis et al. / Tetrahedron: Asymmetry 19 (2008) 2135–2139
2137
The lactone ring opening intermediate was not detected by LC/MS
analysis in the reaction mixture due to the fast epoxide formation.
Under the same experimental conditions for 2 h, the iodolac-
tone 10 led to the corresponding iodo hydroxy-b-aminoacide 11
which was isolated in good yield (98%) after acidic treatment of
the reaction mixture (Scheme 2). On the other hand, epoxide 12
was quantitatively formed when compound 11 was treated with
an excess of lithium hydroxide (3 equiv) in a THF/H2O mixture at
70 °C for 4 h. It was isolated in pure form after column chromatog-
raphy on silica gel using dichloromethane/acetic acid (9.5:0.5) as
eluent in 81% yield.
I: H2O (0.1% TFA)/CH3CN (0.1% TFA) 60:40; eluent II: H2O (0.1%
TFA)/CH3CN (0.1% TFA) 70:30; column C: (S,S)-Welk 01, flow:
1 ml/min, hexane/2-propanol: 90:10; column D: Chiracel OD, flow:
1 ml/min, hexane/2-propanol: 70:30.
The enantiopure (1R,2S)-2-(benzyloxycarbonylamino)cyclohex-
3-ene-1-carboxylic acid 5, (1S,2R,4R)-1-benzyloxycarbonylamino-
bicyclo[2.2.2]oct-5-ene-2-carboxylic acid 6 and (1R,4R,7R)-(2-ben-
zyloxycarbonyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylic acid 7
were prepared as previously described.7
4.2. General procedure for synthesis of iodolactones 8, 10
and 13
Opening of the lactone ring of compound 13 with lithium
hydroxide (3 equiv) at room temperature was quantitative after
3 h, as determined by LC/MS analysis. The corresponding epoxide
14 was quantitatively formed overnight. Although the formation
of epoxide 14 was slow, in this case, we were unable to isolate
the iodo hydroxy-b-amino acid intermediate in its pure form.
Characterization of these three enantiopure epoxides 9, 11 and
14 allowed us to unambiguously establish the structure of the
main epoxide that was previously obtained when using mCPBA
by comparison of the NMR data of the crude mixtures obtained
using the two methods. As assumed, the cis-epoxide 9 was
obtained by reaction of mCPBA on the cyclic b-amino acid 5. In
the case of the bicyclic b-amino acid 6, the main product formed17
was the epoxide 12 (80% yield), probably the result of a stereo-
directing effect of the carboxyl group since an interaction in the
transition state between the carbamate and the peracid seems
improbable. Finally, epoxide 14 corresponds to the minor isomer18
formed in 33% yield during the epoxidation of the amino acid 7
with mCPBA. Taking into account that a tertiary amine should
not exert a stereodirecting effect,6d,h we assumed that in this case,
the stereoselectivity is mainly governed by steric factors.
To a solution of the N–Z b-amino acid (1 equiv) in CH2Cl2, KI
(6 equiv), NaHCO3 (3 equiv) and I2 (2 equiv) in H2O were added
at 0 °C. After stirring for 24 h at room temperature, a solution of
Na2S2O3 was added in order to destroy the excess iodine. The mix-
ture was then extracted with CH2Cl2 and the organic layer was
washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo to afford the expected iodolactone.
4.3. (1R,4R,5R,8R)-8-(Benzyloxycarbonylamino)-4-iodo-6-
oxabicyclo[3.2.1]octan-7-one (1R,4R,5R,8R)-8
Synthesized according to the general procedure from (1R,2S)-
2-(benzyloxycarbonylamino)cyclohex-3-ene-1-carboxylic acid
5
(605 mg, 2.2 mmol) in CH2Cl2 (20 ml), in the presence of KI
(2.19 g, 13.2 mmol), NaHCO3 (554 mg, 6.6 mmol) and I2 (1.11 g,
4.4 mmol) in H2O (15 ml). The expected pure iodolactone
(1R,4R,5R,8R)-8 was obtained as a white solid after column chro-
matography on silica gel with dichloromethane/ethyl acetate
(9.5:0.5) and precipitation using diethyl ether (662 mg, 75%);
mp 109 °C; ½a 2D0
¼ þ57 (c 0.8, CH2Cl2); tR (HPLC, column A)
ꢁ
9.6 min; tR (HPLC, column B: eluent I) 18.0 min; MS (ESI) m/z:
402.0 [(M+H)+]; 1H NMR (400 MHz, CDCl3, 25 °C) d 1.75–1.85
(m, 1H, 2-H), 1.85–2.00 (m, 2H, 2-H and 3-H), 2.15–2.25 (m, 1H,
3-H), 2.68 (s, 1H, 1-H), 4.40 (m, 1H, 4-H), 4.62 (s br, 1H, 5-H),
4.71 (d, J = 5.6 Hz, 1H, 8-H), 5.00 (s, 2H, CH2O), 5.48 (d,
J = 6.2 Hz, NH), 7.25 (m, 5H, CH-arom); 13C NMR (100 MHz, CDCl3,
25 °C) d 21.52 (C-4), 22.92 (C-2), 28.52 (C-3), 45.20 (C-1), 57.91
(C-8), 67.22 (CH2O), 83.73 (C-5), 128.26, 128.37, 128.49, 128.60
(CH-arom), 135.92 (C-arom), 155.57 (NHCOO), 176.15 (COO);
HRMS (FAB) calcd for C15H17INO4 (MH+) 402.0202, found
402.0204.
3. Conclusion
In conclusion, an effective approach to the enantiopure oxirane
derivatives of some constrained chiral cyclic b-amino acids has
been developed, based on a stereoselective epoxidation involving
the regio- and stereoselective iodolactonization, followed by open-
ing of the lactone ring by alkaline treatment. These syntheses con-
stitute the first preparation of these cyclic b-aminoacid derivatives
and further studies concerning their transformation are currently
in progress.
4. Experimental
4.4. (1R,2R,3R,6R,7R)-7-(Benzyloxycarbonylamino)-2-iodo-4-
oxa-8-tricyclo[4.3.1.03,7]decan-5-one (1R,2R,3R,6R,7R)-10
4.1. General remarks
Synthesized according to the general procedure from (1S,2R,4R)-
1-benzyloxycarbonylaminobicyclo[2.2.2]oct-5-ene-2-carboxylic
acid 6 (542 mg, 1.8 mmol) in CH2Cl2 (15 ml), in the presence of KI
(1.80 g, 10.8 mmol), NaHCO3 (445 mg, 5.4 mmol) and I2 (910 mg,
3.6 mmol) in H2O (10 ml). The expected pure iodolactone
(1R,2R,3R,6R,7R)-10 was obtained as a colourless oil after column
chromatography on silica gel with dichloromethane/ethyl acetate
All reagents were used as purchased from commercial suppliers
without further purification. Solvents were dried and purified by
conventional methods prior to use. Melting points were deter-
mined with a Kofler Heizbank apparatus and are uncorrected. Opti-
cal rotations were measured with a Perkin–Elmer 341 polarimeter.
1H or 13C NMR spectra (DEPT, 1H/13C 2D-correlations) were
recorded with a Bruker A DRX 400 spectrometer using the solvent
as the internal reference. Data are reported as follows: chemical
shifts (d) in parts per million, coupling constants (J) in hertz (Hz).
The ESI mass spectra were recorded with a platform II quadrupole
mass spectrometer (Micromass, Manchester, UK) fitted with an
electrospray source. HPLC analyses were performed with a Waters
model 510 instrument or a Beckman System Gold 126 instrument
(9.5:0.5) (615 mg, 80%); ½a D20
¼ ꢂ55 (c 0.9, CH2Cl2); tR (HPLC, col-
ꢁ
umn A) 10.2 min; tR (HPLC, column C) 29.4 min; MS (ESI) m/z:
428.0 [(M+H)+]; 1H NMR (400 MHz, CDCl3, 25 °C) d 1.66 (br m, 1H,
9-H), 2.05 (m, 2H, 1-H and 10-H), 2.18 (m, 4H, 9-H, 10-H, 8-H),
2.82 (br d, J = 8.7 Hz, 1H, 6-H), 4.28 (br s, 1H, 2-H), 4.99 (s, 2H,
CH2O), 5.09 (s, 1H, 3-H), 5.26 (br s, 1H, NH), 7.15–7.30 (m, 5H,
CH-arom); 13C NMR (100 MHz, CDCl3, 25 °C) d 26.14 (C-9), 27.80
(C-2), 28.36 (C-8 and C-10), 31.96 (C-1), 40.84 (C-6), 58.57 (C-7),
66.85 (CH2O), 87.35 (C-3), 128.17, 128.32, 128.61 (CH-arom),
135.91 (C-arom), 154.83 (NHCOO), 178.26 (COO); HRMS (FAB)
calcd for C17H19INO4 (MH+) 428.0359, found 428.0362.
with variable detector using column A: Symmetry Shield RP18
3.5
, (50 ꢀ 4.6 mm), flow: 1 ml/min, H2O (0.1% TFA)/CH3CN (0.1%
TFA), gradient 0?100% (15 min) and 100% (4 min); column B:
Chiracel OD-RH, C18, 5
, (150 ꢀ 4.6 mm), flow: 1 ml/min, eluent
,
l
l

2138
O. Songis et al. / Tetrahedron: Asymmetry 19 (2008) 2135–2139
4.5. (1S,2R,3R,6R,7S)-8-(Benzyloxycarbonyl)-2-iodo-4-oxa-8-
azatricyclo[4.3.1.03,7]decan-5-one (1S,2R,3R,6R,7S)-13
½
a 2D0
ꢁ
¼ ꢂ30 (c 0.8, CH2Cl2); tR (HPLC, column A) 9.8 min; MS
(ESI) m/z: 445.9 [(M+H)+]; 1H NMR (400 MHz, CD3CN, 25 °C) d
1.68 (br t, J = 10.2 Hz, 1H, 8-H), 2.00 (m, 4H, 8-H, 7-H, 5-H
and 4-H), 2.15 (m, 1H, 5-H), 2.28 (m, 1H, 7-H), 3.12 (m, 1H,
6-H), 4.30 (s, 2H, 2-H and 3-H), 4.98 (d, J = 13.0 Hz, 1H,
CH2O), 5.10 (d, J = 13.0 Hz, 1H, CH2O), 6.04 (s, 1H, NH), 7.40
(s, 5H, H-arom); 13C NMR (100 MHz, CD3CN, 25 °C) d 22.33 (C-
8), 28.28 (C-7), 28.84 (C-5), 35.01 (C-4), 37.94 (C-3), 39.93 (C-
6), 55.54 (C-1), 65.64 (CH2O), 80.95 (C-2), 127.62, 127.85,
128.46 (CH-arom), 137.28 (C-arom), 154.85 (NHCOO), 176.25
(COOH); HRMS (FAB) calcd for C17H21INO5 (MH+) 446.0464,
found 446.0474.
Synthesized according to the general procedure from (1R,
4R,7R)-(2-benzyloxycarbonyl)-2-azabicyclo[2.2.2]
oct-5-ene-7-
carboxylic acid 7 (224 mg, 0.78 mmol) in CH2Cl2 (6 ml), in the
presence of KI (776 mg, 4.7 mmol), NaHCO3 (196 mg, 2.3 mmol)
and I2 (406 mg, 1.6 mmol) in H2O (5 ml). The expected pure iodo-
lactone (1S,2R,3R,6R,7S)-13 was obtained as a white solid after
treatment and precipitation using diethyl ether (248 mg, 77%);
mp 124 °C; ½a 2D0
¼ þ43 (c 1.0, CH2Cl2); tR (HPLC, column A)
ꢁ
10.1 min; tR (HPLC, column D) 12.5 min; MS (ESI) m/z: 413.9
[(M+H)+]; 1H NMR (400 MHz, CDCl3, 25 °C) d 2.00 and 2.05 (2 m
(67/33)*, 1 H, 10-H), 2.14 and 2.21 (2 m (67/33)*, 1 H, 10-H), 2.28
and 2.34 (br m (67/33)*, 1 H, 1-H), 2.75 and 2.80 (2dd (67/33)*,
J = 10.2 Hz and 5.2 Hz, 1 H, 6-H), 3.33 (m, 1 H, 9-H), 3.95 (m, 1 H,
4.8. (1R,2R,3S,4R,6R)-1-(Benzyloxycarbonylamino)-2,3-
epoxybicyclo[2.2.2]octane-6-carboxylic acid (1R,2R,3S,4R,6R)-12
9-H), 4.31 (br s, 1 H, 2-H), 4.70 and 4.85 (2 t (67/33)*, J1 = J2
=
To a solution of iodo hydroxy b-amino acid (1R,2R,3R,4R,6R)-11
(140 mg, 0.32 mmol, 1 equiv) in THF (4 ml) was added an LiOH
solution (23 mg, 0.95 mmol, 3 equiv) in H2O (2 ml) and the mixture
was stirred for 4 h at 70 °C. The organic solvent was removed in
vacuo, the mixture diluted with water (10 ml) and acidified to
pH 2 and extracted with CH2Cl2 (4 ꢀ 10 ml). The organic layer
was then dried over anhydrous MgSO4 and concentrated in vacuo
to afford the iodo hydroxy b-amino acid (1R,2R,3S,4R,6R)-12 as a
colourless oil after column chromatography on silica gel with
5.2 Hz, 1 H, 7-H), 4.96 and 5.00 (2 d (67/33)*, J = 5.5 Hz, 2 H, 3-H),
5.14 (s, 2 H, OCH2), 7.27 (m, 5 H, H-arom); 13C NMR (100 MHz,
CDCl3, 25 °C) d 25.14 and 25.56 (C-2)*, 26.87 (C-10), 33.32 and
33.43 (C-1)*, 36.32 and 36.50 (C-6)*, 47.76 and 47.89 (C-9)*, 48.53
and 49.12 (C-7)*, 67.72 and 67.91 (OCH2)*, 83.47 and 83.68 (C-3),
127.93, 128.30, 128.52, 128.63 and 128.70 (CH-arom)*, 135.82
and 136.10 (C-arom)*, 154.72 and 155.50 (CO)*, 175.43 and
175.56 (CO)*; HRMS (FAB) Calcd for C16H17INO4 (MH+) 414.0202,
found 414.0196. (* The NMR of this compound is complicated by
the presence of carbamate rotamers.)
dichloromethane/ethyl acetate (9.5:0.5) (81 mg, 81%); ½a D20
¼ ꢂ47
ꢁ
(c 0.5, CH2Cl2); tR (HPLC, column A) 8.1 min; MS (ESI) m/z: 318.1
[(M+H)+]; 1H NMR (400 MHz, CDCl3, 25 °C) d 1.61 (m, 3H, 8-H
and 5-H), 1.81 (m, 1H, 7-H), 2.12 (m, 2H, 4-H and 5-H), 1.30 (m,
1H, 7-H), 2.66 (dd, J = 12.3 and 4.8 Hz, 1H, 6-H), 3.32 (t,
J = 4.8 Hz, 1H, 3-H), 3.51 (d, J = 5.0 Hz, 1H, 2-H), 5.00 (s, 1H,
CH2O), 6.25 (s, 1H, NH), 7.21 (m, 5H, H-arom); 13C NMR
(100 MHz, CD3CN, 25 °C) d 24.27 (C-8), 25.92 (C-5), 26.90 (C-4),
27.50 (C-7), 44.86 (C-6), 54.46 (C-3), 54.63 (C-2), 55.88 (C-1),
66.48 (CH2O), 128.04, 128.50 (CH-arom), 136.50 (C-arom), 155.15
(NHCOO), 178.60 (COOH); HRMS (FAB) calcd for C17H20NO5
(MH+) 318.1341, found 318.1347.
4.6. (1R,2R,3R,4S)-2-(Benzyloxycarbonylamino)-3,4-
epoxycyclohexane-1-carboxylic acid (1R,2R,3R,4S)-9
To
a
solution of iodolactone (1R,4R,5R,8R)-8 (207 mg,
0.516 mmol, 1 equiv) in THF (4 ml) was added a LiOH solution
(1.55 mmol, 65.0 mg, 3 equiv) in H2O (2 ml) and the mixture stir-
red for 4 h at room temperature. The organic solvent was removed
in vacuo, the mixture diluted with water and acidified to pH 2, and
extracted with CH2Cl2. The organic layer was then dried over anhy-
drous MgSO4 and concentrated in vacuo.
The expected pure epoxide (1R,2R,3R,4S)-9 was obtained as a
white solid after crystallization with ethyl acetate (149.0 mg,
4.9. (1S,4S,5S,6R,7R)-2-(Benzyloxycarbonyl)-2-
azabicyclo[2.2.2]oct-5-ene-7-carboxylic acid (1S,4S,5S,6R,7R)-14
99%); mp 158 °C; ½a D20
¼ þ71 (c 0.7, EtOH); tR (HPLC, column A)
ꢁ
7.1 min; MS (ESI) m/z: 292.1 [(M+H)+]; 1H NMR (400 MHz,
DMSO-d6, 25 °C) d 1.40 (m, 1H, 6-H), 1.70 (m, 2H, 6-H and 5-H),
2.02 (m, 1H, 5-H), 2.48 (m, 1H, 1-H), 3.22 (m, 2H, 3-H and 4-H),
4.47 (m, 1H, 2-H), 5.03 (d, J = 12.7 Hz, 1H, CH2O), 5.08 (d,
J = 12.7 Hz, 1H, CH2O), 7.2 (d, J = 9.4 Hz, 1H, NH), 7.35 (m, 5H, H-
arom); 13C NMR (100 MHz, DMSO-d6, 25 °C) d 16.86 (C-6), 23.02
(C-5), 41.96 (C-1), 46.03 (C-2), 52.82 (C-4), 53.08 (C-3), 65.19
(CH2O), 127.65, 127.73, 128.25, 128.32 (CH-arom), 137.00 (C-
arom), 155.76 (NHCOO), 173.39 (COOH); HRMS (FAB) calcd for
C15H18NO5 (MH+) 292.1185, found 292.1160.
To a solution of iodolactone (1S,2R,3R,6R,7S)-13 (190 mg,
0.46 mmol, 1 equiv) in THF (4 ml) was added a LiOH solution
(1.38 mmol, 33 mg, 3 equiv) in H2O (2 ml) and the mixture was
stirred for 24 h at room temperature. The organic solvent was re-
moved in vacuo, the mixture diluted with water and acidified to
pH 2 and extracted with CH2Cl2. The organic layer was then dried
over anhydrous MgSO4, concentrated in vacuo, to afford the pure
epoxide (1S,4S,5S,6R,7R)-14 as a white solid (138 mg, 0 99%); mp
148 °C; ½a 2D0
¼ ꢂ104 (c 1.2, EtOH); tR (HPLC, column A) 7.7 min;
ꢁ
tR (HPLC, column B: eluent II) 12.5 min; MS (ESI) m/z: 304.3
[(M+H)+]; 1H NMR (400 MHz, CDCl3, 25 °C) d 1.59 (br m, 1H, 8-
H), 2.18 and 2.23* (2br m, 1H, 8-H), 2.38 and 2.42* (2br m, 1H, 4-
H), 2.65 (m, 1H, 7-H), 3.28 (m, 3H, 5-H and 3-H), 3.43 and 3.48*
(t, J1 = J2 = 4.6 Hz, 1H, 6-H), 4.88 and 5.00* (t, J1 = J2 = 4.0 Hz, 1H,
1-H), 5.10 (s, 2H, CH2O), 7.35 (m, 5H, H-arom); 13C NMR
(100 MHz, CDCl3, 25 °C) d 23.90 and 23.95* (C-8), 27.56 and
27.83 (C-4), 40.55 and 40.76 (C-7), 43.33 and 43.54* (C-3), 47.61
and 48.23* (C-1), 49.67 (C-5), 50.59 and 50.73* (C-6), 66.26 and
66.29* (CH2O), 126.89, 127.03, 127.12, 127.16, 127.52, 127.57
(CH-arom), 136.39 and 136.48* (C-arom), 155.16 and 155.61*
(COO), 177.53 and 177.59* (COOH); HRMS (FAB) calcd for
C16H18NO5 (MH+) 304.1185, found 304.1161. (* The NMR of
this compound is complicated by the presence of carbamate
rotamers.)
4.7. (1R,2R,3R,4R,6R)-1-(Benzyloxycarbonylamino)-2-
hydroxy-3-iodobicyclo[2.2.2]octane-6-carboxylic acid
(1R,2R,3R,4R,6R)-11
To
a solution of iodolactone (1R,2R,3R,6R,7R)-10 (180 mg,
0.42 mmol, 1 equiv) in THF (3 ml) was added a LiOH solution
(1.27 mmol, 30 mg, 3 equiv) in H2O (2 ml) and the mixture
was stirred for 2 h at room temperature. The organic solvent
was removed in vacuo, the mixture diluted with water (10 ml)
and acidified to pH 2 and extracted with CH2Cl2 (4 ꢀ 10 ml).
The organic layer was then dried over anhydrous MgSO4 and
concentrated in vacuo to afford the iodo hydroxy b-aminoacid
(1R,2R,3R,4R,6R)-11 as a colourless semi-solid (185 mg, 98%);

O. Songis et al. / Tetrahedron: Asymmetry 19 (2008) 2135–2139
2139
2003, 735–736; (d) O’Brien, P.; Childs, A.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.;
Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955–4957; (e)
Masesane, I. B.; Stell, P. G. Tetrahedron Lett. 2004, 45, 5007–5009; (f) Masesane,
I. B.; Batsanov, A. S.; Howard, J. AK.; Mondal, R.; Stell, P. G. Beilstein J. Org. Chem.
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2858; (h) Kiss, L.; Forro, E.; Sillanpaa, R.; Fulop, F. J. Org. Chem. 2007, 72, 8786–
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H and 1-H chemical shifts were, respectively, 1.92 and 1.98 ppm (2m)*; 3.00
and 3.06 ppm (2m)* and 4.74 and 4.85 ppm (2t)* for the major epoxide, and
1.59, 2.18 and 2.23 ppm (3m)*; 2.38 and 2.42 ppm (2br m)* and 4.88 and
5.00 ppm (2t)* for the minor epoxide. (*The NMR of this compound is
complicated by the presence of carbamate rotamers.)