Synthesis of 3- and 4-hydroxy-2-aminocyclohexanecarboxylic acids by lodocyclization

Article abstract of DOI:10.1002/ejoc.200500297

Starting from cis-7-azabicyclo[4.2.0]oct-4-en-8-one, novel routes have been developed for the synthesis of 2-amino-4-hydroxycyclohexanecarboxylic acid and its 3-hydroxy-substituted analog via iodooxazine, iodooxazoline or iodolactone intermediates. After CAL-B-catalyzed enzymatic transformation of the starting β-lactam, the iodolactone method was applied to the synthesis of 3-hydroxy-substituted β-amino acid enantiomers. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500297

FULL PAPER
Synthesis of 3- and 4-Hydroxy-2-aminocyclohexanecarboxylic Acids by
Iodocyclization
Zsolt Szakonyi,[a] Szilvia Gyónfalvi,[a] Enikö Forró,[a] Anasztázia Hetényi,[a]
Norbert De Kimpe,[b] and Ferenc Fülöp*[a]
Keywords: Amino acids / Iodocyclization / Iodolactone / Stereoselectivity / Enantioselectivity
Starting from cis-7-azabicyclo[4.2.0]oct-4-en-8-one, novel
routes have been developed for the synthesis of 2-amino-4-
tion of the starting β-lactam, the iodolactone method was ap-
plied to the synthesis of 3-hydroxy-substituted β-amino acid
hydroxycyclohexanecarboxylic acid and its 3-hydroxy-sub- enantiomers.
stituted analog via iodooxazine, iodooxazoline or iodolactone
intermediates. After CAL-B-catalyzed enzymatic transforma-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The number of investigations on β-amino acids, and es-
pecially alicyclic compounds, has increased exponentially
because of their growing chemical and biological applica-
tions.[1] Various new synthetic strategies involving transfor-
mations to heterocycles[2] or peptides and peptidomimet-
ics[3] have been developed. Although alicyclic saturated
amino acids have also proved to be of great importance,
their partially saturated analogs provide scope for further
functionalization of the alicyclic ring, for example, one or
two hydroxy groups have been incorporated.
Hydroxyamino acids may serve as building blocks in the
synthesis of peptide analogs and heterocycles; they can take
part in enzymatic transformations and can be used as a
scaffold in combinatorial chemistry.[4]
While the chemistry and pharmacology of hydroxy-sub-
stituted α-amino acids have been widely studied,[5] less at-
tention has been paid to their β analogs.[6] The hydroxy-β-
amino acid unit is the essential moiety of several well-
known, naturally occurring products that possess powerful
biological activity. For example, Taxol derivatives,[7] the im-
munological response modifier dipeptide bestatin,[8] and the
highly potent HIV-1 protease inhibitor kynostatins[9,10] con-
tain an α-hydroxy-β-amino acid unit.
Figure 1. The structure of oryzoxymycin.
Since hydroxy-substituted β-amino acids are of both
pharmacological and synthetic chemical interest, our aim
was to synthesize saturated analogs of oryzoxymycin via
iodooxazine or iodolactone intermediates. The enantiomer-
ically pure forms of the hydroxy-β-amino acids may serve
as chiral auxiliaries or additives; therefore we set out to pre-
pare the enantiopure form of the 3-hydroxy-substituted β-
amino acid derivative.
Results and Discussion
To achieve the desired iodocyclization of the unsaturated
β-amino acid derivatives in the synthesis of 3- or 4-hydroxy
derivatives, two pathways are available.[12] The cyclization
reaction can be accomplished by attack of the activated
double bond by the amide carbonyl of 3, resulting in O,N-
heterocycles (Scheme 1). Similarly, a five- or six-membered
lactone ring can be produced by starting from N-Boc-pro-
tected amino acid 11 (Scheme 2). Recently we reported the
regio- and diastereoselective functionalization of cis- and
trans-2-amino-4-cyclohexenecarboxylic acids, regioisomers
of compounds 3 and 11, in the synthesis of 4- and 5-hy-
droxy-substituted 2-aminocyclohexanecarboxylic acids via
1,3-oxazine or γ-lactone intermediates.[13]
The first alicyclic hydroxy-β-amino acid to be isolated
was oryzoxymycin (Figure 1), which was extracted from a
Streptomyces species by Hashimoto and co-workers and has
been found to exhibit moderate activity in vitro against
Xanthomonas oryzae.[11]
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
P. O. Box 121, 6701 Szeged, Hungary
Fax: +36-62-545705
E-mail: fulop@pharm.u-szeged.hu
[b] Department of Organic Chemistry, Faculty of Agricultural and
Applied Biological Sciences, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
Eur. J. Org. Chem. 2005, 4017–4023
DOI: 10.1002/ejoc.200500297
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Z. Szakonyi, S. Gyónfalvi, E. Forró, A. Hetényi, N. De Kimpe, F. Fülöp
FULL PAPER
Scheme 1. Reagents and conditions: (i) 12% HCl, EtOH, reflux, 2 h, 76%; (ii) MeCOCl, Et3N, CHCl3, room temp., 2 h, 98%; (iii) NaI,
I2, NaHCO3, CH2Cl2, 0 °C, 20 h, 4: 27%, 5: 63%; (iv) Bu3SnH, AIBN, toluene, 60 °C, 6 h, N2, followed by chromatography, 6: 65%, 8:
58%; (v) 10% HCl, H2O, reflux, 30 h, 7: 88%, a mixture (1:2) of 9 and 10: 85%.
Scheme 2. Reagents and conditions: (i) Boc2O, Et3N, DMAP, THF, room temp., 3 h, then LiOH, H2O/THF, room temp., 5 h, 90%; (ii)
I2, NaI, NaHCO3, CH2Cl2, 0 °C, 20 h, 91%; (iii) Bu3SnH, AIBN, toluene, 60 °C, 20 h, N2, 98%; (iv) HCl/H2O, room temp., 12 h; (v)
HBr/H2O, room temp., 12 h; (vi) Me3SiBr, phenol, CH2Cl2, room temp., Ar, 2 h, 65%; 9 and 10: X = Cl; 14 and 15: X = Br.
The ring-opening reaction of β-lactam ( )-1,[14–16] de- H and 6eq-H. The NOESY spectrum reveals a 5ax-H NOE
rived from cyclohexadiene, with ethanolic hydrogen chlo- cross-peak for 7-H, which proves that the relative position
ride resulted in the corresponding amino ester hydrochlo- of the iodine atom is equatorial. The structures were con-
ride salt 2.[17] After the acylation of 2, the iodocyclization firmed by molecular modeling. The conformational proto-
of N-acylamino ester 3 with iodine and sodium iodide in a col comprised a stochastic search using the Merck molecu-
two-phase solvent system proved to be unselective, resulting lar force field (MMFF94). Figure 2 depicts stereoviews of
in a 30:70 mixture of iodooxazine 4 and iodooxazoline 5. typical minimum-energy molecular structures of 4 and 5.
Isomers 4 and 5 were successfully separated and fully char- Compound 4 was deiodinated with tributyltin hydride in
acterized by NMR measurements. The relative positions of the presence of a catalytic amount of azobis(isobutyronitr-
the iodine atoms were deduced from the J couplings and ile) (AIBN) under nitrogen. Hydrolysis of oxazine 6 re-
the NOESY spectra. For 4, the J values for the 9-H atom sulted in 4-hydroxyamino acid 7 in a low overall yield.
are 3.0 and 4.3 Hz, which are typical for an equatorial–
When the deiodination of 5 was attempted, the oxazoline
equatorial hydrogen arrangement between 9-H and 1-H and moiety proved unstable and only the ring-opened product
between 9-H and 5-H. The NOESY spectrum shows only 8 could be isolated. Hydrolysis of N-acetylamino ester 8
1-H and 6-H NOE cross-peaks for 9-H, which proves that under acidic conditions furnished a mixture of hy-
the relative position of the iodine atom is axial. For 5, the droxyamino acid ( )-10 and amino lactone 9 (Scheme 1).
J values for the 7-H atom are 4.5, 7.1, and 10.6 Hz, which Lactone 9 proved to be very stable under acidic conditions
shows an axial–axial and an axial–equatorial hydrogen ar- (even when it was refluxed in 25% hydrogen chloride solu-
rangement between 7-H and 7a-H, 7-H and 6ax-H, and 7- tion for several hours).
4018
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3- and 4-Hydroxy-2-aminocyclohexanecarboxylic Acids by Iodocyclization
FULL PAPER
Figure 2. Stereoviews of typical minimum-energy structures of 4
and 5.
Since the above procedure was not selective, even in two
reaction steps, and only gave the 4-hydroxy derivative ( )-7
Scheme 3. Reagents and conditions: (i) LiOH, H2O, THF, room
temp., 5 h, 98%; (ii) Me3SiBr, phenol, CH2Cl2, room temp., 2 h, Ar
atmosphere, 76%.
in a low overall yield, we next focused on an iodolactoni-
zation protocol (Scheme 2). N-Boc protection of azetidi-
none ( )-1 followed by hydrolysis with aqueous LiOH in
THF gave N-Boc-amino acid ( )-11[16] in an excellent yield.
The iodolactonization step was achieved under the same
conditions as those used in the synthesis of iodooxazine,
resulting in iodolactone ( )-12 in 91% yield.[18] It appears
that the chances of a five- or six-membered lactone ring
being formed are the same, but in our case only the five-
membered iodolactone ( )-12 was obtained stereo- and re-
gioselectively. The conversion of iodolactone ( )-12 to N-
Boc-lactone ( )-13 was nearly quantitive in 20 h.
thesized following a procedure similar to that used for the
synthesis of the racemic compound ( )-15.
When ring-opening of the N-Boc-lactone ( )-13 was at-
tempted using different acidic reagents, similar to the hy-
drolysis of amido ester 8 (Scheme 1), a variable mixture of
hydroxyamino acid ( )-10 or 15 and deprotected stable
amino lactone ( )-9 or 14 was observed (Table 1). Depro-
tection of ( )-13 with a mixture of bromotrimethylsilane
and phenol under argon led to the formation of only the
amino lactone 14.
Table 1. Deprotection and hydrolysis of N-Boc-amino lactone ( )-
13.
Reagents[a]
( )-9 or 14 [%]
( )-10 or 15 [%]
iv
v
vi
23
15
100
77
85
0
Scheme 4. Reagents and conditions: (i) CAL-B, H2O (1 equiv.),
iPr2O, 65 °C; (ii) 18% HCl.
[a] Reagents and conditions: (iv) 10% HCl/H2O, room temp., 12 h;
(v) 10 % HBr/H2O, room temp., 12 h; (vi) Me3SiBr, phenol,
CH2Cl2, room temp., Ar, 2 h (see Scheme 2).
When the hydrolysis of ( )-13 was carried out with aque-
ous LiOH in THF, the expected N-Boc-hydroxyamino acid
( )-16 was obtained in an excellent yield. Deprotection of
( )-16 with bromotrimethylsilane and phenol resulted in
Conclusions
In summary, we have devised novel pathways to synthe-
the desired 2-amino-3-hydroxycyclohexanecarboxylic acid size the 4-hydroxy-β-amino acid and its 3-hydroxy-substi-
( )-15 as the hydrobromide salt (Scheme 3).[19]
tuted analog from 1,3-cyclohexadiene. Iodocyclization via 3
In order to synthesize the enantiopure hydroxy-substi- was not selective and gave only a low overall yield of 2-
tuted β-amino acids (+)-15 and (–)-15, highly enantioselec- amino-4-hydroxycyclohexanecarboxylic acid 7. On the
tive CAL-B-catalyzed ring-opening of β-lactam ( )-1 was other hand, iodolactonization proved to be an excellent
performed (E Ͼ 200) (Scheme 4) following the literature protocol for the synthesis of either racemic or enantiomeric
procedure.[20] The enantiomers (+)-1 and (+)-17 obtained 2-amino-3-hydroxycyclohexanecarboxylic acid 15. The β-
were transformed with 18% HCl into β-amino acid hydro- amino acids that have been prepared are good starting ma-
chlorides (+)-18 and (–)-18. After Boc protection, the hy- terials for the synthesis of peptides and different heterocy-
droxyamino acid enantiomers (+)-15 and (–)-15 were syn- cles with potential biological activity.
Eur. J. Org. Chem. 2005, 4017–4023
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Z. Szakonyi, S. Gyónfalvi, E. Forró, A. Hetényi, N. De Kimpe, F. Fülöp
FULL PAPER
reaction mixture was washed with water (2×20 mL). The combined
aqueous layers were extracted with chloroform (2×30 mL), and the
combined organic layers were dried (Na2SO4) and the solvent re-
moved by evaporation under reduced pressure to afford 3. Color-
Experimental Section
1H and 13C spectra were recorded with a Bruker Avance DRX 400
spectrometer [400 MHz, δ = 0 (TMS), in D2O, DMSO, or CDCl3].
Chemical shifts are expressed in ppm (δ relative to TMS as internal
reference). J values are given in Hz. FTIR spectra were recorded
with a Perkin–Elmer model 1000 spectrophotometer in KBr pellets.
Microanalyses were determined with a Perkin–Elmer 2400 elemen-
tal analyzer.
less crystals, 98% yield, m.p. 84–86 °C. IR: νmax = 1724, 3257 cm–1.
˜
1H NMR (CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.88
(d, J = 6.3 Hz, 1 H, 6-H), 1.91 (d, J = 6.3 Hz, 1 H, 6-H), 1.93 (s,
3 H, Me), 2.00–2.07 (m, 2 H, 2×5-H), 2.80–2.86 (m, 1 H, 1-H),
4.06–4.16 (m, 2 H, CH2CH3), 4.82–4.89 (m, 1 H, 2-H), 5.56–5.62
(m, 1 H, 4-H), 5.76–5.81 (m, 1 H, 3-H) ppm. 13C NMR (CDCl3):
δ = 14.5 (CH2CH3), 22.6 (6-C), 23.5 (5-C), 23.8 (Me), 43.4 (1-C),
45.2 (2-C), 61.0 (CH2CH3), 127.7 (4-C), 129.7 (3-C), 169.7
(NHCOMe), 173.9 (COO) ppm. C11H17NO3 (211.26): calcd. C
62.54, H 8.11, N 6.63; found C 62.62, H 8.23, N 6.54.
Compounds (+)-1, (+)-17, (+)-18, and (–)-18 were prepared by fol-
lowing literature methods.[18] Lipolase (lipase B from Candida ant-
arctica), produced by submerged fermentation of a genetically
modified Aspergillus oryzae microorganism and adsorbed onto a
macroporous resin, was from Sigma–Aldrich (Catalog No. L4777).
The ee values were determined by gas chromatography on a
Chrompack Chirasil-Dex CB column (25 m) [without derivati-
zation for (+)-1, (+)-12, (–)-12, (+)-13, and (–)-13; after derivati-
zation with diazomethane for (+)-11 and (–)-11; after double
derivatization with diazomethane and acetic anhydride in the pres-
ence of 4-(dimethylamino)pyridine and pyridine for (+)-15, (–)-15,
(+)-16, (–)-16, (+)-17, (+)-18, and (–)-18]. Optical rotations were
measured with a Perkin–Elmer 341 polarimeter. Melting points
were determined with a Kofler apparatus and are uncorrected.
Iodocyclization of Carboxamide 3: A 0.5  aqueous solution of
NaHCO3 (300 mL), NaI (34.48 g, 0.23 mol), and I2 (14.83 g,
117.0 mmol) were added to a solution of carboxamide 3 (8.24 g,
39.0 mmol) in dry dichloromethane (200 mL) at 0 °C. After stirring
for 20 h at room temperature, the excess of I2 was decomposed with
an aqueous 1  Na2S2O3 solution. The phases were separated and
the organic phase was washed with H2O and brine, dried (Na2SO4),
and concentrated in vacuo to give a mixture of iodooxazine 4 and
1
iodooxazoline 5 (in a ratio of 30:70, based on H NMR measure-
ments), which were separated by column chromatography (dichlo-
romethane/ethyl acetate, 10:1).
(1R*,6S*)-7-Azabicyclo[4.2.0]oct-4-en-8-one (1): Compound 1 was
synthesized following a modified literature method.[16a] 1,3-Cyclo-
hexadiene (7.00 g, 87.0 mmol) in dry diethyl ether (100 mL) was
Ethyl
(1S*,5R*,6R*,9S*)-9-Iodo-3-methyl-2-oxa-4-azabicyclo-
[3.3.1]non-3-ene-6-carboxylate (4): Yellowish crystals, 27% yield,
added dropwise to
a solution of chlorosulfonyl isocyanate
1
m.p. 93–95 °C. IR: ν
= 1031, 1225, 1655, 1731, 2930 cm–1. H
˜
(7.70 mL, 88.6 mmol) in dry diethyl ether (100 mL) over 10 min.
After stirring for 30 min at room temperature, the reaction mixture
was poured into a stirred solution of K2CO3 (35.93 g, 0.26 mol)
and Na2SO3 (1.10 g, 8.7 mmol) in water (300 mL). The organic
layer was separated, and the aqueous layer was washed with diethyl
ether (2×500 mL) and then with chloroform (2×500 mL). The
combined organic layers were dried with Na2SO4, and the solvents
evaporated to dryness under reduced pressure. Recrystallization
from ethyl acetate/n-hexane afforded pure compound 1. Colorless
crystals, 60% yield, m.p. 71–73 °C (ref.[16a] m.p. 70.5–71.5 °C). IR:
max
NMR (CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.71 (ddd,
J = 5.0, 14.1 Hz, 1 H, 7-H), 1.77–1.86 (m, 1 H, 7-H), 1.96 (s, 3 H,
Me), 2.03–2.11 (m, 1 H, 8-H), 2.40 (ddd, J = 1.8, 5.5, 14.9 Hz, 1
H, 8-H), 3.25 (ddd, J = 2.8, 4.5, 12.3 Hz, 1 H, 6-H), 4.11 (dd, J =
3.3, 5.8 Hz, 1 H, 5-H), 4.13–4.25 (m, 2 H, CH2CH3), 4.42–4.46 (m,
1 H, 1-H), 4.67 (dd, J = 3.0, 4.3 Hz, 1 H, 9-H) ppm. 13C NMR
(CDCl3): δ = 14.8 (CH2CH3), 18.3 (7-C), 21.4 (Me), 26.7 (9-C),
27.9 (8-C), 43.3 (6-C), 55.1 (5-C), 61.5 (CH2CH3), 74.3 (1-C), 160.2
(3-C), 173.9 (COO) ppm. C11H16INO3 (337.15): calcd. C 39.19, H
4.78, N 4.15; found C 39.51, H 4.52, N 4.45.
ν
˜
max = 1768, 3263 cm–1. 1H NMR (CDCl3): δ = 1.55–1.68 (m, 1 H,
2-H), 2.02–2.14 (m, 3 H, 2-H, 2×3-H), 3.45–3.53 (m, 1 H, 1-H),
4.01 (t, J = 4.8 Hz, 1 H, 6-H), 5.94 (dd, J = 4.5, 10.1 Hz, 1 H, 4-
H), 6.08–6.16 (m, 1 H, 5-H), 6.81 (br. s, 1 H, NH) ppm. 13C NMR
(CDCl3): δ = 22.2 (3-C), 22.3 (2-C), 44.7 (1-C), 50.1 (6-C), 126.6
(4-C), 134.7 (5-C), 172.8 (8-C) ppm. C7H9NO (123.15): calcd. C
68.27, H 7.37, N 11.37; found C 68.38, H 7.45, N 11.24.
Ethyl (3aR*,4R*,7R*,7aR*)-7-Iodo-2-methyl-3a,4,5,6,7,7a-hexahy-
drobenzoxazole-4-carboxylate (5): White crystals, 63% yield, m.p.
170–173 °C. IR: ν
= 1041, 1203, 1663, 1729, 2978 cm–1. 1H
˜
max
NMR (CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.66–1.96
(m, 3 H, 5-H, 2×6-H), 2.00 (d, J = 1.8 Hz, 3 H, Me), 2.19–2.29
(m, 1 H, 5-H), 2.99 (dt, J = 5.3, 12.3 Hz, 1 H, 4-H), 3.89 (ddd, J
= 4.5, 7.1, 10.6 Hz, 1 H, 7-H), 4.17–4.28 (m, 2 H, CH2CH3), 4.34–
4.40 (m, 1 H, 3a-H), 4.90 (dd, J = 7.3, 8.1 Hz, 1 H, 7a-H) ppm.
13C NMR (CDCl3): δ = 14.9 (CH2CH3), 15.2 (Me), 23.5 (6-C), 27.2
(7-C), 32.5 (5-C), 41.7 (4-C), 61.5 (CH2CH3), 66.5 (3a-C), 85.7 (7a-
C), 161.4 (2-C), 173.5 (COO) ppm. C11H16INO3 (337.15): calcd. C
39.19, H 4.78, N 4.15; found C 39.01, H 4.62, N 4.39.
Ethyl (1R*,2S*)-2-Aminocyclohex-3-enecarboxylate Hydrochloride
(2): A solution of 1 (1.50 g, 12.0 mmol) in ethanol containing 12%
HCl (50 mL) was refluxed for 2 h.[17] After removal of the solvent,
amino ester 2 was obtained as the hydrochloride salt, which was
recrystallized from ethanol/diethyl ether. Colorless crystals, 76%
yield, m.p. 157–159 °C. IR: νmax = 1718, 2860, 2902, 2977 cm–1. 1H
˜
NMR (D2O): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.87–1.99
(m, 1 H, 6-H), 2.04–2.13 (m, 1 H, 6-H), 2.17–2.24 (m, 2 H, 2×5-
H), 3.11 (dt, J = 3.5, 10.3 Hz, 1 H, 1-H), 4.13–4.29 (m, 3 H, 2-H,
CH2CH3), 5.71–5.79 (m, 1 H, 3-H), 6.11–6.18 (m, 1 H, 4-H) ppm.
13C NMR (D2O): δ = 13.4 (CH2CH3), 20.6 (5-C), 23.5 (6-C), 40.9
(1-C), 46.2 (2-C), 62.4 (CH2CH3), 120.8 (3-C), 134.8 (4-C), 174.7
(C=O) ppm. C9H16ClNO2 (205.09): calcd. C 52.56, H 7.84, N 6.81;
found C 52.48, H 7.99, N 6.79.
Iodocyclization of N-Boc-Amino Acid Derivatives
(1R*,4R*,5R*,8R*)-8-(tert-Butoxycarbonylamino)-4-iodo-6-oxabi-
cyclo[3.2.1]octan-7-one [( )-12]: A 0.5  aqueous solution of
NaHCO3 (300 mL), NaI (34.48 g, 0.23 mol), and I2 (9.89 g,
78.0 mmol) were added to a solution of N-Boc-amino acid 11
(9.41 g, 39.0 mmol) in dry dichloromethane (200 mL) at 0 °C. After
stirring for 20 h, the mixture was poured into an aqueous 1 
Na2S2O3 solution (100 mL). The phases were separated and the
organic phase was washed with H2O and brine, dried (Na2SO4),
and concentrated in vacuo to give iodolactone 12. Colorless crys-
Ethyl (1R*,2S*)-2-Acetylaminocyclohex-3-enecarboxylate (3):
A
solution of 2 (1.00 g, 5.9 mmol) in dry chloroform (30 mL) was
treated with triethylamine (1.19 g, 11.8 mmol) and acetyl chloride
(0.56 g, 7.1 mmol). After stirring for 2 h at room temperature, the
tals, 91% yield (ethyl acetate/n-hexane), m.p. 132–134 °C. IR: ν
˜
max
= 1710, 2926, 3228 cm–1 1H NMR (CDCl3): δ = 1.46 (s, 9 H,
.
4020
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3- and 4-Hydroxy-2-aminocyclohexanecarboxylic Acids by Iodocyclization
FULL PAPER
OCMe3), 1.87–1.97 (m, 1 H, 2-H), 1.99–2.13 (m, 2 H, 2-H, 3-H),
2.25–2.39 (m, 1 H, 3-H), 2.74 (s, 1 H, 1-H), 4.53 (t, J = 4.5 Hz, 1 δ = 17.9 (2-C), 26.6 (3-C), 28.5 (4-C), 29.0 (OCMe3), 46.2 (1-C),
4.8 Hz, 1 H, 5-H), 4.84 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3):
H, 4-H), 4.71 (d, J = 4.0 Hz, 1 H, 5-H), 4.77 (br. s, 1 H, 8-H), 4.83
60.5 (8-C), 81.1 (OCMe3), 82.8 (5-C), 155.7 (COO), 177.7 (7-
C) ppm. C12H19NO4 (241.28): calcd. C 59.73, H 7.94, N 5.80;
(br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 22.2 (4-C), 23.5 (2-
C), 28.9 (3-C), 29.2 (OCMe3), 45.9 (1-C), 58.0 (8-C), 81.0 (OCMe3), found C 59.82, H 7.99, N 5.72.
84.3 (5-C), 155.4 (COO), 176.9 (7-C) ppm.
(1R,5R,8R)-8-(tert-Butoxycarbonylamino)-6-oxabicyclo[3.2.1]octan-
7-one [(+)-13]: The synthesis was accomplished according to the
general procedure, starting from (+)-12. Colorless crystals, 98%
yield (n-hexane), m.p. 143–144 °C, [α]2D0 = +7.0 (c = 0.5, MeOH);
ee = 99%. The H NMR spectroscopic data were similar to those
for ( )-13. C12H19NO4 (241.28): calcd. C 59.73, H 7.94, N 5.80;
(1R,4R,5S,8R)-8-(tert-Butoxycarbonylamino)-4-iodo-6-oxabicyclo-
[3.2.1]octan-7-one [(+)-12]: The synthesis was accomplished accord-
ing to the above procedure, starting from (+)-11. Colorless crystals,
89% yield (ethyl acetate/n-hexane), m.p. 134–135 °C, [α]2D0 = +6.8
(c = 0.5, MeOH). The 1H NMR spectroscopic data were similar to
those for ( )-12. C12H18INO4 (367.18): calcd. C 39.25, H 4.94, N
3.81; found C 39.34, H 5.06, N 3.75.
1
found C 59.81, H 8.01, N 5.70.
(1S,5S,8S)-8-(tert-Butoxycarbonylamino)-6-oxabicyclo[3.2.1]octan-
7-one [(–)-13]: The synthesis was accomplished according to the
general procedure, starting from (–)-12. Colorless crystals, 96%
yield (n-hexane), m.p. 143–144 °C, [α]2D0 = –6.9 (c = 0.5, MeOH);
(1S,4S,5R,8S)-8-(tert-Butoxycarbonylamino)-4-iodo-6-oxabicyclo-
[3.2.1]octan-7-one [(–)-12]: The synthesis was accomplished accord-
ing to the above procedure, starting from (–)-11. Colorless crystals,
86% yield (ethyl acetate/n-hexane), m.p. 134–135 °C, [α]2D0 = –7.0
(c = 0.5, MeOH). The 1H NMR spectroscopic data were similar to
those for ( )-12. C12H18INO4 (367.18): calcd. C 39.25, H 4.94, N
3.81; found C 39.33, H 5.05, N 3.75.
1
ee = 99%. The H NMR spectroscopic data were similar to those
for ( )-13. C12H19NO4 (241.28): calcd. C 59.73, H 7.94, N 5.80;
found C 59.80, H 7.97, N 5.71.
(1R*,2S*,4S*)-2-Amino-4-hydroxycyclohexanecarboxylic Acid (7):
A solution of 6 (0.20 g, 0.9 mmol) and 10% HCl in H2O (20 mL)
was refluxed for 30 h. The aqueous solvent was evaporated to af-
ford the amino acid hydrochloride salt, which was purified on a
resin column (Dowex 50) to give 7. Colorless crystals, 88% yield
General Procedure for the Deiodination Reaction: Tributyltin hy-
dride (9.32 g, 32.0 mmol) and azobis(isobutyronitrile) (0.26 g,
1.60 mmol) were added to a solution of the iodo compound
(16.0 mmol) in dry toluene (200 mL) under nitrogen. After stirring
at 60 °C for 6 h under the inert atmosphere, the solvent was evapo-
rated in vacuo. Compounds 6 and 8 were purified by column
chromatography (toluene/ethanol 9:1), while 13 was crystallized
from n-hexane.
(ethanol/diethyl ether), m.p. 140–141 °C. IR: ν
= 1725, 3048,
˜
max
3452 cm–1. H NMR (D2O): δ = 1.41 (s, 1 H, 5-H), 1.55–1.67 (m,
1 H, 6-H), 1.78–1.91 (m, 2 H, 3-H, 5-H), 2.06 (dt, J = 3.5, 12.6 Hz,
1 H, 3-H), 2.10–2.22 (m, 1 H, 6-H), 2.58 (q, J = 4.4 Hz, 1 H, 2-
H), 3.49 (dt, J = 4.1, 13.6 Hz, 1 H, 1-H), 3.88 (m, 1 H, 4-H) ppm.
13C NMR (D2O): δ = 22.9, 30.8, 34.7, 42.6, 49.0, 67.5, 180.3 ppm.
C7H13NO3 (159.18): calcd. C 52.82, H 8.23, N 8.80; found C 52.84,
H 8.29, N 8.78.
1
Ethyl (1S*,5R*,6R*)-3-Methyl-2-oxa-4-azabicyclo[3.3.1]non-3-ene-
6-carboxylate (6): The synthesis was accomplished according to the
general procedure, starting from 4. A colorless oil, 65% yield. IR:
1
ν
= 1667, 1743, 2872, 2942 cm–1. H NMR (DMSO): δ = 1.18
˜
max
General Procedure for the Acidic Hydrolysis of 8 and 13: A solution
of amide 8 (1.0 mmol) or N-Boc-amino lactone 13 (1.0 mmol) and
10 % HCl in H2O (20 mL, for 9 and 10) or 10 % HBr in H2O
(20 mL, for 14 and 15) was stirred for 12 h at room temperature.
The solution was then evaporated to dryness to give a mixture of
9 and 10 or a mixture of 14 and 15. The ratio between the corre-
sponding amino lactone and hydroxyamino acid was determined
by NMR spectroscopy, based on integration of the 1-H singlets at
δ = 3.04 ppm for 14 and at δ = 2.87 ppm for 15. The attempted
separation of the products was not successful.
(t, J = 7.3 Hz, 3 H, CH2CH3), 1.26–1.38 (m, 1 H, 8-H), 1.45 (ddd,
J = 4.3, 12.6 Hz, 1 H, 7-H), 1.52–1.82 (m, 3 H, 7-H, 8-H, 9-H),
1.83 (s, 3 H, CH3), 1.89–1.97 (m, 1 H, 9-H), 2.68 (dt, J = 3.0,
12.1 Hz, 1 H, 6-H), 3.88 (s, 1 H, 5-H), 3.99–4.11 (m, 2 H,
CH2CH3), 4.43 (s, 1 H, 1-H) ppm. 13C NMR (DMSO): δ = 14.1
(CH2CH3), 17.9 (7-C), 21.0 (Me), 27.7 (8-C), 31.1 (9-C), 45.5 (6-
C), 48.1 (5-C), 59.7 (CH2CH3), 69.2 (1-C), 158.6 (3-C), 172.6
(COO) ppm. C11H17NO3 (211.26): calcd. C 62.54, H 4.11, N 6.63;
found C 62.52, H 4.15, N 6.67.
Ethyl (1R*,2R*,3S*)-2-Acetylamino-3-hydroxycyclohexanecarbox-
ylate (8): The synthesis was accomplished according to the general
procedure, starting from 5. Colorless crystals, 58% yield (ethyl ace-
(1R*,2S*)-2-(tert-Butoxycarbonylamino)cyclohex-3-enecarboxylic
Acid [( )-11]: Triethylamine (4.20 mL, 294.0 mmol), di-tert-butyl
dicarbonate (7.86 g, 36.0 mmol), and a catalytic amount of DMAP
were added to a stirred solution of azetidinone ( )-1 (4.0 g,
30 mmol) and dry THF (100 mL). After stirring for 12 h at room
temperature (the reaction was monitored by TLC), the mixture was
evaporated to dryness. The oily residue obtained was purified by
flash chromatography on a silica gel column (toluene/ethanol, 9:1),
and the resulting white crystalline product (7.2 g, 97%) was dis-
solved in THF (75 mL) and treated with aqueous LiOH (4.40 g in
50 mL of water) at room temperature. The mixture was stirred at
room temperature for 5 h. Then THF was removed in vacuo, water
(50 mL) was added, and the solution was acidified to pH 3.5–4.0
with acetic acid and extracted with ethyl acetate (3×80 mL). The
combined organic layers were dried (Na2SO4) and evaporated to
give ( )-11.[16a] Colorless crystals, 6.51 g, 90% yield (n-hexane),
tate/n-hexane), m.p. 125–128 °C. IR: νmax = 1223, 1551, 1654, 1734,
˜
1
2930, 3316 cm–1. H NMR (DMSO): δ = 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.37–1.66 (m, 6 H, 2×4-H, 2×5-H, 2×6-H), 1.81 (s, 3
H, Me), 2.45 (dt, J = 3.5, 12.1 Hz, 1 H, 1-H), 3.46–3.55 (m, 1 H,
3-H), 3.93 (dd, J = 7.6, 14.6 Hz, 2 H, CH2CH3), 4.48–4.51 (m, 1
H, 2-H), 7.30 (d, J = 9.8 Hz, 1 H, NH) ppm. 13C NMR (DMSO):
δ = 13.9 (CH2CH3), 21.3 (5-C), 21.8 (6-C), 22.8 (Me), 28.4 (4-C),
44.6 (1-C), 50.6 (2-C), 59.6 (CH2CH3), 69.3 (3-C), 169.6 (NHCO),
172.5 (COO) ppm. C11H19NO4 (229.27): calcd. C 57.62, H 8.35, N
6.11; found C 57.85, H 8.07, N 6.45.
(1R*,5R*,8R*)-8-(tert-Butoxycarbonylamino)-6-oxabicyclo[3.2.1]-
octan-7-one [( )-13]: The synthesis was accomplished according to
the general procedure, starting from ( )-12. Colorless crystals, 98%
yield (n-hexane), m.p. 145–147 °C. IR: ν
= 1702, 1718, 3136,
m.p. 119–121 °C (ref.[16a] m.p. 110–118 °C). IR: ν
= 1710,
˜
˜
max
max
3249 cm–1. 1H NMR (CDCl3): δ = 1.44 (s, 9 H, OCMe3), 1.61–1.81
(m, 4 H, 2×2-H, 3-H, 4-H), 1.97–2.14 (m, 2 H, 3-H, 4-H), 2.67 (d, (m, 4 H, 2×5-H, 2×6-H), 2.89 (s, 1 H, 1-H), 4.57 (s, 1 H, 2-H),
J = 3.5 Hz, 1 H, 1-H), 3.80 (d, J = 6.3 Hz, 1 H, 8-H), 4.71 (d, J = 5.15 (d, J = 5.5 Hz, 1 H, NH), 5.60–5.86 (m, 2 H, 3-H, 4-H), 10.15
2932 cm–1. 1H NMR (CDCl3): δ = 1.44 (s, 9 H, OCMe3), 1.87–2.21
Eur. J. Org. Chem. 2005, 4017–4023
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4021

Z. Szakonyi, S. Gyónfalvi, E. Forró, A. Hetényi, N. De Kimpe, F. Fülöp
16, starting from (–)-13. Colorless crystals, 92% yield (n-hexane),
FULL PAPER
(br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ = 22.8 (5-C), 23.7 (6-
C), 29.0 (OCMe3), 44.0 (2-C), 47.0 (1-C), 80.3 (OCMe3), 128.2 (3- m.p. 128–129 °C, [α]2D0 = –22.8 (c = 0.5, MeOH); ee = 99%. The
C), 129.8 (4-C), 156.1 (COO), 179.3 (COOH) ppm. C12H19NO4
(241.28): calcd. C 59.73, H 7.94, N 5.80; found C 59.82, H 7.99, N
5.72.
1H NMR spectroscopic data were similar to those for ( )-15.
C12H13NO5 (251.23): calcd. C 55.58, H 8.16, N 5.40; found C
55.63, H 8.20, N 5.31.
(1R*,2R*,3S*)-2-Amino-3-hydroxycyclohexanecarboxylic Acid Hy-
drobromide [( )-15]: Compound ( )-16 (1.14 g, 4.6 mmol) in dry
dichloromethane (4 mL) was added to a solution of bromotrimeth-
ylsilane (1.04 g, 6.8 mmol) and phenol (0.03 g, 0.3 mmol) in dry
dichloromethane (5 mL) at room temperature under argon. After
stirring for 2 h, removal of the solvent afforded ( )-15 as the hydro-
bromide salt. Colorless crystals, 76% yield (ethanol/diethyl ether),
(1R,2S)-2-(tert-Butoxycarbonylamino)cyclohex-3-enecarboxylic
Acid [(+)-11]: An aqueous solution of NaOH (0.18 g, 4.5 mmol)
was added to a solution of amino acid hydrochloride (+)-18 (0.40 g,
2.3 mmol) in dioxane/water (2:1, 30 mL) at room temperature. Af-
ter cooling to 0 °C, the solution was treated with di-tert-butyl dicar-
bonate (0.55 g, 2.5 mmol). The reaction mixture was then left to
warm to room temperature and stirred for 4 h. The dioxane was
removed under reduced pressure and the aqueous residue was
acidified to pH 2.5 with dilute H2SO4 (10%). This solution was
extracted with ethyl acetate (3×30 mL), dried (Na2SO4), and the
solvent removed by evaporation. Colorless crystals, 88% yield (n-
m.p. 243–244 °C. IR: ν
= 1718, 3022, 3425 cm–1 1H NMR
.
˜
max
(D2O): δ = 1.37–1.52 (m, 2 H, 5-H, 6-H), 1.56–1.67 (m, 1 H, 4-H),
1.80–1.94 (m, 3 H, 4-H, 5-H, 6-H), 2.87 (dt, J = 3.5, 11.0 Hz, 1 H,
1-H), 3.82 (t, J = 3.0 Hz, 1 H, 2-H), 3.95–4.01 (m, 1 H, 3-H) ppm.
13C NMR (D2O): δ = 20.9 (5-C), 22.4 (6-C), 27.7 (4-C), 42.0 (1-C),
53.1 (2-C), 67.6 (3-C), 176.6 (COOH) ppm. C7H14BrNO3 (240.09):
calcd. C 35.02, H 5.88, N 5.83; found C 35.13, H 5.82, N 5.75.
hexane), m.p. 122–123 °C, [α]2D0 = +22.3 (c = 0.5, MeOH). The H
1
NMR spectroscopic data were similar to those for ( )-11.
C12H19NO4 (241.28): calcd. C 59.73, H 7.94, N 5.80; found C
59.82, H 7.99, N 5.72.
(1R,2R,3S)-2-Amino-3-hydroxycyclohexanecarboxylic Acid Hydro-
bromide [(+)-15]: The synthesis was accomplished as for ( )-15,
starting from (+)-16. Colorless crystals, 65% yield (ethanol/diethyl
ether), m.p. 240–241 °C, [α]2D0 = +14.0 (c = 0.5, H2O); ee Ͼ 98%.
(1S,2R)-2-(tert-Butoxycarbonylamino)cyclohex-3-enecarboxylic
Acid [(–)-11]: The synthesis was accomplished as for (+)-11, starting
from (–)-18. Colorless crystals, 85% yield (n-hexane), m.p. 122–
123 °C, [α]2D0 = –22.1 (c = 0.5, MeOH). The 1H NMR spectroscopic
data were similar to those for ( )-11. C12H19NO4 (241.28): calcd.
C 59.73, H 7.94, N 5.80; found C 59.82, H 7.99, N 5.72.
1
The H NMR spectroscopic data were similar to those for ( )-15.
C7H14BrNO3 (240.09): calcd. C 35.02, H 5.88, N 5.83; found C
35.17, H 5.80, N 5.73.
(1S,2S,3R)-2-Amino-3-hydroxycyclohexanecarboxylic Acid Hydro-
bromide [(–)-15]: The synthesis was accomplished as for ( )-15,
starting from (–)-16. Colorless crystals, 66% yield (ethanol/diethyl
ether), m.p. 240–241 °C, [α]2D0 = –14.2 (c = 0.5, H2O); ee = 99%.
The H NMR spectroscopic data were similar to those for ( )-15.
C7H14BrNO3 (240.09): calcd. C 35.02, H 5.88, N 5.83; found C
35.11, H 5.78, N 5.72.
(1R*,2R*,3R*)-8-Amino-6-oxabicyclo[3.2.1]octan-7-one Hydrobro-
mide [( )-14]: The Boc group was removed as in the synthesis of
( )-15 (see below), starting from ( )-13. Colorless crystals, 65%
yield, m.p. 259–260 °C. IR: νmax = 1718, 3132, 3245 cm–1. 1H NMR
˜
1
(D2O): δ = 1.48–1.62 (m, 1 H, 2-H), 1.76–1.95 (m, 3 H, 2-H, 3-H,
4-H), 1.98–2.08 (m, 1 H, 3-H), 2.11–2.20 (m, 1 H, 4-H), 3.04, (s, 1
H, 1-H), 3.85 (s, 1 H, 8-H), 5.08 (d, J = 4.03 Hz, 1 H, 5-H) ppm.
13C NMR (D2O): δ = 16.8 (2-C), 26.0 (3-C), 27.3 (4-C), 44.2 (1-
C), 59.2 (8-C), 81.5 (5-C), 178.9 (7-C) ppm. C7H12BrNO2 (222.08):
calcd. C 37.86, H 5.45, N 6.31; found C 37.78, H 5.52, N 6.24.
Acknowledgments
The authors acknowledge receipt of OTKA grants T 034901 and
TS 040888.
(1R*,2R*,3S*)-2-(tert-Butoxycarbonylamino)-3-hydroxycyclohex-
anecarboxylic Acid [( )-16]: N-Boc-lactone ( )-13 (11.82 g,
49.0 mmol) was dissolved in THF (200 mL) and treated with LiOH
(6.29 g, 0.15 mol) in water (150 mL). The mixture was stirred at
room temperature for 5 h. The THF was removed in vacuo, and
the aqueous residue was acidified to pH 3.5–4.0 with dilute acetic
acid (10%) and extracted with ethyl acetate (3×200 mL). Drying
(Na2SO4) and removal of the solvent in vacuo afforded ( )-16. Col-
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orless crystals, 98% yield (n-hexane), m.p. 128–129 °C. IR: ν
=
˜
max
1706, 2938, 3318 cm–1. H NMR (D2O): δ = 1.08–1.35 (m, 12 H,
4-H, 2×5-H, OCMe3), 1.47–1.63 (m, 3 H, 4-H, 2×6-H), 2.51 (d,
J = 12.0 Hz, 1 H, 1-H), 3.61 (s, 1 H, 2-H), 4.18 (s, 1 H, 3-H) ppm.
13C NMR (D2O): δ = 21.4 (6-C), 2×21.8 (4-C, 5-C), 27.9 (OCMe3),
45.4 (1-C), 52.5 (2-C), 70.4 (3-C), 81.0 (OCMe3), 158.4 (COO),
177.9 (COOH) ppm. C12H13NO5 (251.23): calcd. C 55.58, H 8.16,
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1
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(1R,2R,3S)-2-(tert-Butoxycarbonylamino)-3-hydroxycyclohexane-
carboxylic Acid [(+)-16]: The synthesis was accomplished as for ( )-
16, starting from (+)-13. Colorless crystals, 94% yield (n-hexane),
m.p. 128–129 °C, [α]2D0 = +23.2 (c = 0.5, MeOH); ee = 99%. The
1H NMR spectroscopic data were similar to those for ( )-15.
C
12H13NO5 (251.23): calcd. C 55.58, H 8.16, N 5.40; found C
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4022
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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2880.
Received: April 27, 2005
Published Online: August 4, 2005
Eur. J. Org. Chem. 2005, 4017–4023
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4023