Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic acid enantiomers

Article abstract of DOI:10.1016/j.tetasy.2009.09.001

An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (-)-6 and (-)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyclohexanecarboxylic acids (-)-15 and (-)-18 was develope

Full text of DOI:10.1016/j.tetasy.2009.09.001

Tetrahedron: Asymmetry 20 (2009) 2220–2225
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic
acid enantiomers
a
a
a
a
a
a,b,
*
}
Gabriella Benedek , Márta Palkó , Edit Wéber , Tamás A. Martinek , Eniko Forró , Ferenc Fülöp
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2009
Accepted 2 September 2009
Available online 25 September 2009
An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycycloh-
exanecarboxylic acids (ꢀ)-6 and (ꢀ)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyc-
lohexanecarboxylic acids (ꢀ)-15 and (ꢀ)-18 was developed by using the OsO4-catalyzed oxidation of
Boc-protected (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and (1R,2S)-2-aminocyclohex-3-ene-
carboxylic acid (+)-11. Good yields were obtained. The stereochemistry of the synthesized compounds
was proven by NMR spectroscopy.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
corresponding dihydrooxazine or oxazoline derivatives.24–29 An-
other method involves the hydroxylation of the 2-aminocyclohex-
Alicyclic b-amino acids1,2 derived from b-lactams3,4 have at-
tracted the interest of a number of synthesis research groups as a
consequence of their useful biological effects and occurrence in
many pharmacologically relevant compounds.5 Peptides contain-
ing b-amino acids can increase and modify biological activities
and are not degradable by proteases, which can lead to peptide-
based synthetic targets.6 These compounds can be found in natural
products, for example, cispentacin, (1R,2S)-2-aminocyclopentane-
carboxylic acid, an antifungal antibiotic, as is amipurimycin, which
was isolated from Streptomyces novoguineensis.5,7–9 The synthetic
4-methylene derivative of cispentacin (Icofungipen, PLD-118) is
active in vitro against Candida species.10,11 In recent years, the
preparation of enantiopure b-amino acids has come into the fore-
ground of interest, because of their widespread use in peptide, het-
erocyclic and combinatorial chemistries and drug research.12–15
Among the b-amino acids, the hydroxy-functionalized deriva-
tives are of considerable importance in medicinal chemistry, be-
cause they occur in many important products, such as paclitaxel
(Taxol) and docetaxel (Taxotere), which have chemotherapeutic ef-
fects.16–18 Some cyclic hydroxylated b-amino acid derivatives have
antibiotic (oryzoxymycin)19–22 or antifungal activities, and are
used as building blocks for pharmaceutically significant natural
substances.23
enecarboxylic acid by functionalization of the olefinic bond
through epoxidation.29–31
The OsO4-catalyzed dihydroxylation of olefins provides one of
the most efficient methods for the preparation of vicinal diols.32–38
The KMnO4-induced oxidation of the double bond is another well-
known route to dihydroxy derivatives.39
Our present aim was the dihydroxylation of the olefinic bond of
enantiopure and racemic, cis- and trans-2-amino-4-cyclohexene-
carboxylic acids and cis- and trans-2-amino-3-cyclohexenecarb-
oxylic acids, and the structural analysis of the new dihydroxy-
substituted derivatives.
2. Results and discussion
The starting (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-
2 and (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11 were
synthesized from b-amino ester ( )-1 and b-lactam ( )-10 by highly
enantioselective CAL-B-catalyzed hydrolysis with one equivalent of
H2O in i-Pr2O at 65 °C.40,41 The enantiopure amino acids (+)-2 and
(+)-11 (ee >99%) were esterified in the presence of EtOH and SOCl2
to give amino ester hydrochlorides, which were reacted with tert-
butoxy pyrocarbonate to afford the N-Boc-protected amino esters
(+)-4 and (+)-13, respectively (Schemes 1 and 2).
The isomerization of (+)-4 and (+)-13 with NaOEt at room tem-
perature resulted in trans-N-Boc amino esters (ꢀ)-7 and (+)-16. The
trans-configuration was confirmed by the NOE signal of relatively
low intensity between H-1 and H-2 and the large 3J(H-1, H-2) cou-
pling at around 9–10 Hz.
A number of methods have recently been published for the ster-
eoselective introduction of a mono-hydroxy functionality onto the
cyclohexane or cyclopentane ring, for example, by iodolactoniza-
tion of cis- and trans-2-aminocyclohexenecarboxylic acids or
cis- and trans-2-aminocyclopentenecarboxylic acids, or via the
Dihydroxylation of protected esters (+)-4, (ꢀ)-7 and (+)-13,
* Corresponding author. Tel.: +36 62 545562; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
(+)-16 with a catalytic amount of OsO4 and 4-methylmorpholine
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.001

G. Benedek et al. / Tetrahedron: Asymmetry 20 (2009) 2220–2225
2221
1S
the amino group. In this case, H-1 and H-2 are in a trans-diaxial
position, and the NOE signals between H-1 and the axial H-5 and
between H-1 and the axial H-3 indicate the orientation of the hy-
droxy groups for (ꢀ)-8 and (ꢀ)-17, respectively. This selectivity
can be interpreted in terms of the steric bias of the substituents.
The bulkier N-Boc-protecting group interacts unfavourably with
the forming hydroxy groups, and hence osmylation will occur from
the sterically less-hindered face.32
COOH
NH2
1R
COOEt
NH2
COOEt
NH2
i
2R
2S
( )-1
ii, iii
(+)-2
(–)-3
1S
2R
5S 1S
1S
5S
COOEt
NHBoc
HO
HO
COOEt
HO
HO
COOH
v
vi, vii
viii
NHBoc
R NH2
4R
2R
4R
2
(–)-6.HCl
(–)-6
(+)-4
(+)-5
It is relevant that dihydroxylation by KMnO4 results in the same
diastereoselectivity as for osmylation, but the yields are not so
good.42
iv
5S 1R
1R
5S
1R
HO
HO
COOEt
NHBoc
COOEt
NHBoc
HO
HO
COOH
NH2
v
vi, vii
viii
The acidic hydrolysis of (ꢀ)-14 and (ꢀ)-17 resulted in the corre-
sponding dihydroxy-amino acid hydrochlorides (ꢀ)-15ꢁHCl and
(ꢀ)-18ꢁHCl in moderate yields.
4R 2R
2R
2R
4R
(–)-7
(–)-9.HCl
(–)-9
(–)-8
For (+)-5, (ꢀ)-8, ( )-5 and ( )-8, a different deprotection method
was used in the last step of the synthesis: reaction first with LiOH
in THF to deprotect the carboxylic group, followed by hydrolysis
with HCl/H2O. The yields were obviously the same.
Scheme 1. Reagents and conditions: (i) CAL-B, H2O (1 equiv), i-Pr2O, 65 °C; (ii)
SOCl2, EtOH, 0 °C– , 97%; (iii) Et3N, Boc2O, CH2Cl2, 2 h, rt, 89%; (iv) NaOEt, EtOH,
24 h, rt, 43%; (v) 2.0 w/w% OsO4 solution in t-BuOH, NMO, acetone, 4 h, rt, 78–85%;
D
In order to improve the yields of the final products, a new
deprotection protocol was applied: dihydroxy compounds (+)-5,
(ꢀ)-8, (ꢀ)-14 and (ꢀ)-17 and their racemic counterparts were sub-
jected to microwave irradiation in H2O at 150 °C for 1 h.43,44
Due to the possible isomerization after hydrolysis, we analyzed
the structures of the deprotected dihydroxy-amino acids (ꢀ)-6,
(ꢀ)-9, (ꢀ)-15 and (ꢀ)-18 as well. Because of the higher conforma-
tional flexibility of the compounds, some of the NMR signals were
broadened; consequently the smaller coupling constants could not
be determined exactly. For (ꢀ)-9 and (ꢀ)-18, the small NOE signal
between H-1 and H-2 and the large coupling 3J(H-1, H-2) = 11–
12 Hz suggest a trans-orientation for the carboxyl and amino
groups, while for (ꢀ)-6 and (ꢀ)-15, the small NOE couplings and
the large NOE signals between H-1 and H-2 indicate cis-substitu-
ents. The orientations of the hydroxy groups can be deduced from
the couplings and the NOE patterns of their vicinal hydrogens.
For (ꢀ)-6, whose conformational flexibility was pronounced,
the stereochemistry was proved unequivocally by measurements
in CD3OD and in DMSO. In this case, the coupling constants suggest
axial H-2 and H-5 and equatorial H-4. This would involve hydroxy
groups on the opposite side of the ring from the amino group,
which is supported by the absence of NOE signals between H-2
and H-4 and by the NOE cross peak between H-2 and one of the hy-
droxyl groups (Fig. 1).
(ꢀ)-6ꢁHCl, (ꢀ)-9ꢁHCl: (vi) LiOH, H2O/THF, rt, 5 h, 92–96%; (vii) 10% HCl/H2O, 24 h,
D,
45–47%; (ꢀ)-6, (ꢀ)-9; (viii) microwave irradiation, H2O, 150 °C, 1 h, 70–77%.
1R
O
O
COOH
NH2
1S
i
NH
NH
2S
6R
( )-10
(+)-11
(+)-12
ii, iii
1R
1R
1R
COOEt
COOEt
COOH
v
vi
vii
4R
4R
2R
2R
NHBoc
HO
NHBoc
HO
NH2
2S
3S
3S
OH
OH
(+)-13
(–)-14
(–)-15.HCl
(–)-15
iv
1S
1S
1S
COOEt
NHBoc
COOEt
NHBoc
COOH
v
vi
vii
4R
4R
2R
HO
HO
NH2
2R
2S
3S
3S
OH
OH
(+)-16
(–)-18.HCl
(–)-18
(–)-17
Scheme 2. Reagents and conditions: (i) CAL-B, H2O (1 equiv), i-Pr2O, 65 °C; (ii)
SOCl2, EtOH, 0 °C– , 90%; (iii) Et3N, Boc2O, CH2Cl2, 2 h, rt, 82%; (iv) NaOEt, EtOH,
24 h, rt, 65%; (v) 2.0 w/w% OsO4 solution in t-BuOH, NMO, acetone, 4 h, rt, 72–74%;
D
(ꢀ)-15ꢁHCl, (ꢀ)-18ꢁHCl: (vi) 10% HCl/H2O, 24 h,
D
, 43–49%; (ꢀ)-15, (ꢀ)-18; (vii)
microwave irradiation, H2O, 150 °C, 1 h, 72–74%.
N-oxide (NMO) as the stoichiometric co-oxidant afforded the
desired products (+)-5, (ꢀ)-8 and (ꢀ)-14, (ꢀ)-17 as single diaste-
reomers in good yields.
The dihydroxylations of (+)-4 and (+)-13 exhibit anti selectivity
with regard to the ester and protected amino groups, on the steri-
cally less-hindered side of the ring. The orientation of the hydroxy
groups was deduced from the couplings and NOEs of their vicinal
hydrogens. For (+)-5, H-4 and H-1 display large couplings (3J = 9–
10 Hz), indicating their axial positions. The singlet of H-5 suggests
its equatorial position. NOE signals were observed between the ax-
ial 5-OH and the axial H-1 and H-3ax. Moreover, the signal be-
tween H-4 and the amide hydrogen confirms the trans
orientation of the hydroxy groups relative to the ester and amide
groups. For (ꢀ)-14, the coupling constants suggest equatorial H-3
and axial H-4 and H-1, and the NOEs prove the stereochemistry:
the signal between 3-OH and H-1, H-4 and H-6ax and between
the amide hydrogen and H-4 and H-6x.
Figure 1. Molecular structure of (ꢀ)-6.
For (ꢀ)-9, H-1 and H-2 are in a trans-diaxial position (concluded
from 3J(H-1, H-2) = 12 Hz) and H-5 should also be axial, while H-4
is equatorial. NOE signals can be observed between H-1 and H-5
and between H-3ax and H-1 and H-5, which suggest that the hy-
droxy groups are cis relative to the carboxyl group (Fig. 2).
For (ꢀ)-15, whose spectra were measured in D2O because of the
overlapping signals in DMSO, the coupling constants indicate axial
H-2 and H-3, and equatorial H-4, which requires trans-hydroxy
groups relative to the amino and carboxyl groups. The NOE signal
Following the osmylation of the double bond in (ꢀ)-7 or (+)-16,
where the ester and amino groups are on opposite sides of the ring,
the hydroxy groups project on the ester side, that is, anti relative to

2222
G. Benedek et al. / Tetrahedron: Asymmetry 20 (2009) 2220–2225
5
l
column (0.46 cm ꢂ 25 cm) was used at room temperature; the
mobile phase was 0.1% aqueous triethylammonium acetate
(TEEA)/EtOH = 20/80; flow rate 0.5 mL/min; detection at 205 nm;
retention time (min): 22.77 (antipode: 21.08).46 The ee values for
compounds (ꢀ)-6, (ꢀ)-9, (ꢀ)-15 and (ꢀ)-18 were determined by
the above-mentioned methods; the samples were derivatized with
concentrated HCl.
4.2. Ethyl (1R,2S)-2-tert-butoxycarbonylaminocyclohex-3-ene-
carboxylate, (+)-13
At first, SOCl2 (1.47 g, 12.4 mmol) was added dropwise with
stirring to dry EtOH (11 mL) at ꢀ15 °C. To this mixture, (+)-11
(2.00 g, 14.17 mmol) was added in one portion, followed by stirring
for 30 min at 0 °C. After further stirring for 3 h at room tempera-
ture, the mixture was refluxed for an additional 1 h and then evap-
orated. The residue was recrystallized from EtOH/Et2O to give a
colourless crystalline product.
Figure 2. Molecular structure of (ꢀ)-9.
between H-3 and H-5ax is in accordance with this structure. For
(ꢀ)-18, similar couplings and NOE signal patterns were observed
for H-2, H-3 and H-4, which indicates that the hydroxy groups
are on the opposite side of the cyclohexane ring from the amino
group.
To the product (2.00 g, 9.7 mmol) in CH2Cl2 (50 mL), Et3N
(1.97 g, 19.4 mmol) and di-tert-butyl dicarbonate (2.33 g,
10.7 mmol) were added at 0 °C. The mixture was stirred at room
temperature for 2 h, and then washed with water (2 ꢂ 20 mL).
The aqueous layer was extracted with EtOAc (2 ꢂ 20 mL). The com-
bined organic phase was dried (Na2SO4) and the solvents were
evaporated off. The residue was recrystallized from n-hexane to
3. Conclusions
An effective route has been devised for the preparation of enan-
tiopure 2-amino-4,5-dihydroxycyclohexanecarboxylic acids and 2-
amino-3,4-dihydroxycyclohexanecarboxylic acids. Catalytic osmy-
lation with OsO4 and NMO as co-oxidants was used to introduce
the dihydroxy functionality on the cyclohexene ring. After micro-
wave irradiation of the protected amino acids, the appropriate
products were obtained. These new b-amino acid derivatives can
be used as enantiopure building blocks to produce peptides or het-
erocycles. The synthesis of further substances is also to be
expected.
give a white solid. Yield: 2.25 g (74%), mp 82–84 °C, ½a D20
¼
ꢃ
þ165:2 (c 0.55, EtOH). 1H NMR (500 MHz, DMSO, 27 °C): d = 1.16
(t, J = 7.1 Hz, 3H, CH2CH3), 1.36 (s, 9H, t-Bu), 1.61–1.68 (m, 1H, H-
6eq), 1.76–1.84 (m, 1H, H6-ax), 1.88–1.96 (m, 1H, H-5ax), 2.02
(dt, J = 17.8, 5.4, 5.2 Hz, 1H, H-5eq), 2.62 (ddd, J = 12.4, 4.6,
3.0 Hz, 1H, H-1), 3.96–4.02 (m, 2H, CH2CH3), 4.35–4.39 (m, 1H,
H-2), 5.53–5.59 (m, 1H, H-3), 5.73–5.78 (m, 1H, H-4), 6.73 (d,
J = 9.4 Hz, 1H, NH) ppm. 13C NMR (125 MHz, DMSO, 27 °C):
d = 13.5, 18.4, 23.4, 27.8, 43.2, 44.6, 59.1, 77.5, 126.0, 128.8,
154.6, 172.5 ppm. Anal. Calcd for C14H23NO4 (269.34): C, 62.43;
H, 8.61; N, 5.20. Found: C, 62.34; H, 8.59; N, 5.27.
4. Experimental
4.1. General
The 1H NMR spectra were recorded at 500 MHz or at 600 MHz
while the 13C NMR spectra at 125 MHz or at 150 MHz in DMSO-
d6, except for (ꢀ)-6 (CD3OD) and (ꢀ)-15 (D2O), which were re-
corded at ambient temperature, with Bruker DRX 500 and AV
600 spectrometers, respectively. Chemical shifts are given in d
(ppm) relative to TMS as the internal standard. Elemental analyses
were performed with a Perkin–Elmer CHNS-2400 Ser II Elemental
Analyzer. Melting points were measured with a Kofler melting
point apparatus and are uncorrected. Optical rotations were mea-
sured with a Perkin–Elmer 341 polarimeter. Microwave reactions
were performed in a CEM Discover MW reactor. Ester ( )-1 was
prepared by hypochlorite-mediated Hoffman degradation of the
carboxamide obtained by the ammonolysis of cis-1,2,3,6-tetra-
hydrophthalic anhydride,47 while b-lactam ( )-10 was formed by
the addition of chlorosulfonyl isocyanate to 1,3-cyclohexadiene.25
Amino acid (+)-2 was esterified in the presence of EtOH and SOCl2,
and the amino group was then protected with di-tert-butyl dicar-
bonate to give Boc-protected ester (+)-4.26 The ee values for the
starting (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and
(1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11 (>99%) were
determined after a simple and rapid double derivatization by using
GC instrumentation equipped with CP-Chirasil L-Val columns.45
The ee values for the final products were determined by HPLC.
4.3. General procedure for isomerization of Boc-protected cis
amino esters, (+)-4 and (+)-13
Freshly prepared NaOEt (0.25 g, 3.7 mmol) was added to a solu-
tion of (+)-4 or (+)-13 (1.00 g, 3.7 mmol) in dry EtOH (12 mL), and
the mixture was stirred for 24 h at room temperature. It was then
concentrated under reduced pressure, taken up in EtOAc and
washed with H2O (2 ꢂ 20 mL). The combined organic phase was
dried (Na2SO4) and the solvent was evaporated off. The residue
was purified by column chromatography (n-hexane/EtOAc, 9:1)
to give a white solid.
4.3.1. Ethyl (1R,2R)-2-tert-butoxycarbonylaminocyclohex-4-
enecarboxylate, (ꢀ)-7
Yield: 0.43 g (43%), mp 45–47 °C, ½a D20
ꢃ
¼ ꢀ23:7 (c 0.5, EtOH). 1H
NMR (500 MHz, DMSO, 27 °C): d = 1.17 (t, J = 7.1 Hz, 3H, CH2CH3),
1.36 (s, 9H, t-Bu), 1.95–2.02 (m, 1H, H-3ax), 2.17 (dt, J = 17.3, 4.5,
4.5 Hz, 1H, H-3eq), 2.23–2.27 (m, 2H, H-6), 2.53 (dt, J = 10.7, 8.0,
8.0 Hz, 1H, H-1), 3.64–3.74 (m, 1H, H-2), 4.03 (q, J = 7.1 Hz, 2H,
CH2CH3), 5.56–5.59 (m, 2H, H-4, H-5), 6.79 (d, J = 8.7 Hz, 1H, NH)
ppm. 13C NMR (125 MHz, DMSO, 27 °C): d = 13.5, 27.1, 27.4, 31.1,
44.8, 46.5, 59.1, 77.9, 124.4, 124.8, 154.8, 174.3 ppm. Anal. Calcd
for C14H23NO4 (269.34): C, 62.43; H, 8.61; N, 5.20. Found: C,
62.27; H, 8.71; N, 5.17.
For (ꢀ)-9ꢁHCl, (ꢀ)-15ꢁHCl and (ꢀ)-18ꢁHCl, a Chirobiotic TAG 5
l col-
umn (0.46 cm ꢂ 25 cm) was used at room temperature; the mobile
phase was MeOH containing 0.1% TEA and 0.1% AcOH; flow rate
1 mL/min; detection at 205 nm; retention times (min): (ꢀ)-9ꢁHCl,
11.37 (antipode: 18.77); (ꢀ)-15ꢁHCl, 16.11 (antipode: 14.43);
(ꢀ)-18ꢁHCl, 12.16 (antipode: 13.41). For (ꢀ)-6ꢁHCl, a Chirobiotic T
4.3.2. Ethyl (1S,2S)-2-tert-butoxycarbonylaminocyclohex-3-
enecarboxylate, (+)-16
Yield: 0.65 g (65%), mp 75–78 °C, ½a D20
¼ þ103:6 (c 0.53, EtOH).
ꢃ
1H NMR (600 MHz, DMSO, 27 °C): d = 1.17 (t, J = 7.1 Hz, 3H,

G. Benedek et al. / Tetrahedron: Asymmetry 20 (2009) 2220–2225
2223
CH2CH3), 1.63–1.69 (m, 1H, H-6ax), 1.82–1.89 (m, 1H, H-6eq), 1.36
(s, 9H, t-Bu), 1.95–2.02 (m, 2H, H-5), 2.42–2.47 (m, 1H, H-1), 3.97–
4.11 (m, 2H, CH2CH3), 4.21 (d, J = 8.4 Hz, 1H, H-2), 5.42 (d,
J = 9.8 Hz, 1H, H-3), 5.67–5.72 (m, 1H, H-4), 6.96 (d, J = 8.7 Hz,
1H, NH) ppm. 13C NMR (150 MHz, DMSO, 27 °C): d = 14.0, 23.3,
24.2, 28.2, 45.1, 48.0, 59.9, 77.7, 127.7, 128.7, 155.0, 173.8 ppm.
Anal. Calcd for C14H23NO4 (269.34): C, 62.43; H, 8.61; N, 5.20.
Found: C, 62.45; H, 8.67; N, 5.22.
(150 MHz, DMSO, 27 °C): d = 13.7, 20.2, 26.3, 27.8, 39.4, 52.6,
59.2, 65.8, 70.9, 78.1, 155.2, 174.0 ppm. Anal. Calcd for
C14H25NO6 (303.35): C, 55.43; H, 8.31; N, 4.62. Found: C, 55.49;
H, 8.37; N, 4.65.
4.4.4. Ethyl (1S,2R,3S,4R)-2-tert-butoxycarbonylamino-3,4-
dihydroxycyclohexanecarboxylate, (ꢀ)-17
Yield: 349 mg (72%), mp 153–156 °C, ½a D20
¼ ꢀ12 (c 0.28, EtOH).
ꢃ
1H NMR (600 MHz, DMSO, 27 °C): d = 1.16 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.32 (d, J = 13.3 Hz, 1H, H-5ax), 1.35 (s, 9H, t-Bu), 1.42–
1.47 (m, 1H, H-6eq), 1.67 (ddd, J = 13.5, 6.9, 3.5 Hz, 1H, H-5eq),
1.81 (dq, J = 13.1, 12.9, 12.9, 3.3 Hz, 1H, H-6ax), 2.28 (dt, J = 12.3,
12.3, 3.7 Hz, 1H, H-1), 3.18–3.23 (m, 1H, H-3), 3.73 (q,
J = 10.20 Hz, 1H, H-2), 3.80 (s, 1H, H-4), 3.93–4.04 (m, 2H, CH2CH3),
4.20 (d, J = 7.0 Hz, 1H, OH), 4.45 (s, 1H, OH), 6.54 (d, J = 9.4 Hz, 1H,
NH) ppm. 13C NMR (150 MHz, DMSO, 27 °C): d = 14.5, 22.6, 28.7,
30.0, 48.5, 52.2, 60.1, 69.0, 73.6, 77.5, 155.7, 173.6 ppm. Anal. Calcd
for C14H25NO6 (303.35): C, 55.43; H, 8.31; N, 4.62. Found: C, 55.47;
H, 8.40; N, 4.69.
4.4. General procedure for dihydroxylation of N-Boc-protected
esters, (+)-4, (ꢀ)-7, (+)-13 and (+)-16
At first, OsO4 (1.02 mL 0.08 mmol; a 2.0% w/w solution in t-
BuOH) was added to a stirred solution of N-methylmorpholine N-
oxide (0.55 g, 4.7 mmol) and (+)-4, (ꢀ)-7, (+)-13 or (+)-16 (0.43 g,
1.6 mmol) in acetone (15 mL), and stirring was continued for a fur-
ther 4 h. When the reaction was completed (monitored by TLC), the
mixture was treated with aqueous Na2SO3 (20 mL). The aqueous
layer was extracted with EtOAc (3 ꢂ 20 mL), and the combined or-
ganic layer was dried (Na2SO4). The solvent was removed by evap-
oration under reduced pressure to afford crystalline products (+)-5,
(ꢀ)-8 and (ꢀ)-17, which were recrystallized from n-hexane/EtOAc
to give white crystalline solids. The oily compound (ꢀ)-14 was
purified by column chromatography on silica gel (n-hexane/EtOAc,
1:1) to afford white crystals.
4.5. General synthesis of stereoisomeric 2-amino-4,5-dihydroxy-
cyclohexanecarboxylic acid hydrochlorides, (ꢀ)-6ꢁHCl and
(ꢀ)-9ꢁHCl, and 2-amino-3,4-dihydroxycyclohexanecarboxylic
acid hydrochlorides, (ꢀ)-15ꢁHCl and (ꢀ)-18ꢁHCl
Dihydroxy ester (ꢀ)-14 or (ꢀ)-17 (364 mg, 1.2 mmol) was dis-
solved in aqueous HCl (10%; 20 mL) and the mixture was refluxed
for 24 h. The solvent was then evaporated off to afford the crude
amino acid hydrochloride, which was recrystallized from EtOH/
Et2O to give a pale-yellow crystalline solid. Compounds (+)-5 and
(ꢀ)-8 were first hydrolyzed with LiOH in H2O/THF at room temper-
ature for 5 h and subsequently treated with aqueous HCl by the
above-mentioned method.
4.4.1. Ethyl (1S,2R,4R,5S)-2-tert-butoxycarbonylamino-4,5-
dihydroxycyclohexanecarboxylate, (+)-5
Yield: 379 mg (78%), mp 136–137 °C, ½a D20
¼ þ27:3 (c 0.49,
ꢃ
EtOH). 1H NMR (600 MHz, DMSO, 27 °C): d = 1.14 (t, J = 7.1 Hz,
3H, CH2CH3), 1.36 (s, 9H, t-Bu), 1.51 (d, J = 11.8 Hz, 1H, H-3eq),
1.66 (ddd, J = 12.8, 5.0, 4.5 Hz, 1H, H-6eq), 1.73 (dd, J = 11.8,
9.4 Hz, 1H, H-3ax), 1.91 (dd, J = 12.8, 11.8 Hz, 1H, H-6ax), 2.75–
2.82 (ddd, J = 10.5, 5.0, 4.2 Hz, 1H, H-1), 3.69 (d, J = 9.4 Hz, 1H, H-
4), 3.72 (s, 1H, H-5), 3.93-4.04 (m, 2H, CH2CH3), 4.13 (s, 1H, H-2),
4.28 (s, 1H, OH), 4.35 (d, J = 2.5 Hz, 1H, OH), 6.79 (d, J = 5.9 Hz,
1H, NH) ppm. 13C NMR (150 MHz, DMSO, 27 °C): d = 13.9, 28.1,
28.3, 33.7, 39.9, 47.2, 59.5, 66.4, 67.2, 77.5, 154.9, 172.8 ppm. Anal.
Calcd for C14H25NO6 (303.35): C, 55.43; H, 8.31; N, 4.62. Found: C,
55.35; H, 8.29; N, 4.53.
4.5.1. (1S,2R,4R,5S)-2-Amino-4,5-dihydroxycyclohexanecarb-
oxylic acid hydrochloride, (ꢀ)-6ꢁHCl
Yield: 119 mg (47%), mp 240–243 °C (dec.),
½
a 2D0
ꢃ
¼ ꢀ7:3
(c = 0.324, H2O); ee >99%. 1H NMR (600 MHz, CD3OD, 40 °C):
d = 2.03–2.12 (m, 3H, H-3, H-3, H-6ax), 2.17 (dt, J = 13.6, 4.7,
4.7 Hz, H-6eq), 3.12 (q, J = 4.8 Hz, 1H, H-1), 3.74 (dt, J = 9.8, 4.7,
4.7 Hz 1H, H-2), 3.77 (d, J = 10.0 Hz, 1H, H-5), 3.99 (dt, J = 5.0, 2.9,
2.9 Hz, 1H, H-4) ppm. 13C NMR (150 MHz, MeOD, 40 °C): d = 28.5,
31.7, 39.6, 46.0, 67.0, 67.6, 174.2 ppm. Anal. Calcd for C7H14ClNO4
(211.64): C, 39.72; H, 6.67; N, 6.62. Found: C, 39.79; H, 6.57; N, 6.65.
4.4.2. Ethyl (1R,2R,4R,5S)-2-tert-butoxycarbonylamino-4,5-
dihydroxycyclohexanecarboxylate, (ꢀ)-8
Yield: 413 mg (85%), mp 114–117 °C, ½a D20
¼ ꢀ25:2 (c 0.51,
ꢃ
EtOH). 1H NMR (600 MHz, DMSO, 27 °C): d = 1.15 (t, J = 7.1 Hz,
3H, CH2CH3), 1.34 (s, 9H, t-Bu), 1.40 (dd, J = 12.2, 13.0 Hz, 1H, H-
3ax), 1.55 (ddd, J = 12.4, 3.9, 3.6 Hz, 1H, H-6eq), 1.73 (ddd,
J = 13.0, 4.0, 3.8 Hz, 1H, H-3eq), 1.83 (q, J = 12.4 Hz, 1H, H-6ax),
2.31 (ddd, J = 12.4, 12.3, 3.4 Hz, 1H, H-1), 3.36 (ddd, J = 11.0, 6.5,
5.5 Hz, 1H, H-5), 3.73 (s, 1H, H-4), 3.81–3.88 (m, 1H, H-2), 3.93–
4.05 (m, 2H, CH2CH3), 4.42 (s, 1H, OH), 4.49 (d, J = 5.5 Hz, 1H,
OH), 6.63 (d, J = 9.3 Hz, 1H, NH) ppm. 13C NMR (150 MHz, DMSO,
27 °C): d = 14.5, 28.6, 30.9, 37.8, 45.8, 47.8, 60.0, 68.5, 69.7, 77.5,
155.2, 172.6 ppm. Anal. Calcd for C14H25NO6 (303.35): C, 55.43;
H, 8.31; N, 4.62. Found: C, 55.60; H, 8.35; N, 4.54.
4.5.2. (1R,2R,4R,5S)-2-Amino-4,5-dihydroxycyclohexanecarbox-
ylic acid hydrochloride, (ꢀ)-9ꢁHCl
Yield: 114 mg (45%), mp 222–225 °C (dec.), ½a D20
¼ ꢀ48:8 (c =
ꢃ
0.46, H2O); ee >99%. 1H NMR (500 MHz, DMSO, 27 °C): d = 1.58 (t,
J = 12.4 Hz, 1H, H-3ax), 1.67 (q, J = 12.2 Hz, 1H, H-6ax), 1.79–1.84
(m, 1H, H-6eq), 2.06 (dt, J = 12.6, 4.0, 4.0 Hz, 1H, H-3eq), 2.55 (t,
J = 12.4 Hz, 1H, H-1), 3.36–3.47 (m, 2H, H-2, H-5), 3.79 (s, 1H, H-4),
4.69–4.86 (m, 2H, OH), 8.06 (s, 3H, NH) ppm. 13C NMR (125 MHz,
DMSO, 27 °C): d = 30.3, 33.7, 43.9, 45.3, 66.9, 69.0, 173.8 ppm. Anal.
Calcd for C7H14ClNO4 (211.64): C, 39.72; H, 6.67; N, 6.62. Found: C,
39.77; H, 6.67; N, 6.58.
4.4.3. Ethyl (1R,2R,3S,4R)-2-tert-butoxycarbonylamino-3,4-
dihydroxycyclohexanecarboxylate, (ꢀ)-14
4.5.3. (1R,2R,3S,4R)-2-Amino-3,4-dihydroxycyclohexanecarb-
oxylic acid hydrochloride, (ꢀ)-15ꢁHCl
Yield: 359 mg (74%), mp 49–51 °C ½a D20
¼ ꢀ43:2 (c 0.54, EtOH).
ꢃ
1H NMR (600 MHz, DMSO, 27 °C): d = 1.13 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.36 (s, 9H, t-Bu), 1.39–1.48 (m, 2H, H-5), 1.49–1.56
(m, 1H, H-6eq), 1.76 (td, J = 12.4, 6.2, 6.2 Hz, 1H, H-6ax), 2.73 (td,
J = 12.2, 4.1, 4.1 Hz, 1H, H-1), 3.48 (s, 1H, H-3), 3.63 (dt, 1H, J =
10, 5.6, 5.6 Hz, H-4), 3.90–4.05 (m, 2H, CH2CH3), 4.10 (dt, J = 9.8,
4.5, 4.5 Hz, 1H, H-2), 4.28 (d, J = 5.7 Hz, 1H, OH), 4.72 (d,
J = 3.4 Hz, 1H, OH), 6.73 (d, J = 9.8 Hz, 1H, NH) ppm. 13C NMR
Yield: 109 mg (43%), mp 224 °C (dec.), ½a D20
¼ ꢀ84:8 (c = 0.55,
ꢃ
H2O); ee >99%. 1H NMR (600 MHz, D2O, 27 °C): d = 1.51–1.60 (dd,
J = 14.8, 12.0 Hz 1H, H-5ax), 1.74–1.79 (m, 1H, H-5eq), 1.87 (tt,
J = 14.2, 14.2, 4.2, 4.2 Hz, 1H, H-6ax), 1.93–2.01 (m, 1H, H6-eq),
3.11 (q, J = 4.2 Hz, 1H, H-1), 3.50 (dd, J = 10.7, 4.6 Hz, 1H, H-2),
3.99 (dd, J = 10.7, 3.20 Hz, 1H, H-3), 4.04 (q, J = 3.1 Hz, 1H, H-4)
ppm. 13C NMR (150 MHz, D2O, 27 °C): d = 20.6, 26.8, 41.3, 50.7,

2224
G. Benedek et al. / Tetrahedron: Asymmetry 20 (2009) 2220–2225
68.5, 68.5, 173.8 ppm. Anal. Calcd for C7H14ClNO4 (211.64): C,
39.72; H, 6.67; N, 6.62. Found: C, 39.65; H, 6.54; N, 6.71.
1), 3.49 (t, 11.0 Hz, 1H, H-2), 3.74 (d, J = 10.5 Hz, 1H, H-3), 4.16
(s, 1H, H-4) ppm. 13C NMR (125 MHz, D2O, 27 °C): d = 22.6, 29.3,
46.8, 53.0, 68.8, 71.8, 174.7 ppm. Anal. Calcd for C7H13NO4
(175.18): C, 47.99; H, 7.48; N, 8.00. Found: C, 48.04; H, 7.35; N,
7.93.
4.5.4. (1S,2R,3S,4R)-2-Amino-3,4-dihydroxycyclohexanecarb-
oxylic acid hydrochloride, (ꢀ)-18ꢁHCl
Yield: 124 mg (49%), mp 214 °C (dec.), ½a D20
¼ ꢀ61:5 (c = 0.5,
ꢃ
H2O); ee >99%. 1H NMR (600 MHz, DMSO, 27 °C): d = 1.47 (s, 1H,
H-5ax), 1.62–1.69 (m, 1H, H-6), 1.69–1.74 (m, 2H, H-5eq, H-6),
2.47–2.51 (m, 1H, H-1), 3.23–3.29 (m, 1H, H-2), 3.45 (dd, J = 12.9,
4.2 Hz, 1H, H-3), 3.85 (s, 1H, H-4), 4.89 (s, 1H, OH), 5.42 (br s,
1H, OH), 7.90 (br s, 3H, NH), 12.70 (br s, 1H, COOH) ppm. 13C
NMR (150 MHz, DMSO, 27 °C): d = 22.5, 29.6, 44.6, 51.4, 67.4,
71.4, 173.7 ppm. Anal. Calcd for C7H14ClNO4 (211.64): C, 39.72;
H, 6.67; N, 6.62. Found: C, 39.55; H, 6.83; N, 6.64.
4.7. Racemic compounds
All the reactions for the racemic compounds were first opti-
mized. The 1H and 13C NMR spectroscopic data and elemental anal-
yses on the racemic derivatives are in accordance with those for
the enantiomers. Representative data on the racemates.
4.7.1. Ethyl (1S*,2R*,4R*,5S*)-2-tert-butoxycarbonylamino-4,5-
dihydroxycyclohexane-carboxylate, ( )-5
White crystals, mp 76–78 °C.
4.6. General synthesis of stereoisomeric 2-amino-4,5-dihydroxy-
cyclohexanecarboxylic acids (ꢀ)-6, (ꢀ)-9 and 2-amino-3,4-
dihydroxycyclohexanecarboxylic acids, (ꢀ)-15 and (ꢀ)-18
*
*
*
*
4.7.2. (1S ,2R ,4R ,5S )-2-Amino-4,5-dihydroxycyclohexane-
carboxylic acid hydrochloride, ( )-6ꢁHCl
Dihydroxy esters (+)-5, (ꢀ)-8, (ꢀ)-14 or (ꢀ)-17 (0.2 g, 0.66 mmol)
were dissolved in water (4 mL) in a CEM-Discover microwave pres-
sure tube. The reaction mixture was then stirred at 150 °C for 60 min
under a maximum microwave irradiation of 150 W. After cooling,
the mixtures were diluted with acetone (6 mL) and the products
crystallized out. The crude amino acids were recrystallized from
H2O/acetone to afford pale-yellow crystalline solids.
Pale-yellow crystals, mp 227 °C (dec.).
*
*
*
*
4.7.3. (1S ,2R ,4R ,5S )-2-Amino-4,5-dihydroxycyclohexane-
carboxylic acid, ( )-6
Pale-yellow crystals, mp 231 °C (dec.).
*
*
*
*
4.7.4. Ethyl (1R ,2R ,4R ,5S )-2-tert-butoxycarbonylamino-4,5-
dihydroxycyclohexane-carboxylate, ( )-8
White crystals, mp 99–101 °C.
4.6.1. (1S,2R,4R,5S)-2-Amino-4,5-dihydroxycyclohexanecarboxylic
acid, (ꢀ)-6
Yield: 81 mg (70%), mp 248–250 °C (dec.), ½a D20
¼ ꢀ11:7 (c = 0.35,
ꢃ
*
*
*
*
4.7.5. (1R ,2R ,4R ,5S )-2-Amino-4,5-dihydroxycyclohexane-
H2O); ee >99%. 1H NMR (500 MHz, D2O, 27 °C): d = 1.86–1.93 (m, 1H,
H-6), 1.96–2.08 (m, 3H, H-3, H-3, H-6), 2.78 (q, J = 4.7 Hz, 1H, H-1),
3.61 (dt, J = 9.8, 4.7, 4.7 Hz 1H, H-2), 3.70 (d, J = 8.7 Hz, 1H, H-5),
3.98–4.01 (m, 1H, H-4) ppm. 13C NMR (125 MHz, D2O, 27 °C):
d = 29.3, 31.8, 41.1, 46.7, 67.9, 67.9, 179.1 ppm. Anal. Calcd for
C7H13NO4 (175.18): C, 47.99; H, 7.48; N, 8.00. Found: C, 48.07; H,
7.62; N, 8.15.
carboxylic acid hydrochloride, ( )-9ꢁHCl
Pale-yellow crystals, mp 220 °C (dec.).
*
*
*
*
4.7.6. (1R ,2R ,4R ,5S )-2-Amino-4,5-dihydroxycyclohexane-
carboxylic acid, ( )-9
Pale-yellow crystals, mp 251 °C (dec.).
*
*
4.7.7. Ethyl (1R ,2S )-2-tert-butoxycarbonylaminocyclohex-3-
4.6.2. (1R,2R,4R,5S)-2-Amino-4,5-dihydroxycyclohexanecarb-
oxylic acid, (ꢀ)-9
enecarboxylate, ( )-13
Yield: 89 mg (77%), mp 236–240 °C (dec.), ½a D20
¼ ꢀ56 (c = 0.37,
ꢃ
White crystals, mp 67–69 °C.
H2O); ee >99%. 1H NMR (500 MHz, DMSO, 27 °C): d = 1.40 (t,
J = 12.4 Hz, 1H, H-3ax), 1.47 (q, J = 12.4 Hz, 1H, H-6ax), 1.77 (dt,
J = 3.0, 12.4, 12.4 Hz, 1H, H-1), 1.88–1.95 (m, 2H, H-6eq, H-3eq),
2.98 (dt, J = 3.0, 11.7, 11.7 Hz,1H, H-2), 3.35 (dt, J = 11.6, 4.0.
3.4 Hz, 1H, H-5), 3.76 (s, 1H, H-4), 4.25–4.54 (m, 2H, OH), 8.51 (s,
2H, NH) ppm. 13C NMR (125 MHz, DMSO, 27 °C): d = 30.3, 36.6,
43.9, 47.0, 68.2, 70.5, 176.5 ppm. Anal. Calcd for C7H13NO4
(175.18): C, 47.99; H, 7.48; N, 8.00. Found: C, 47.55; H, 7.58; N, 8.05.
*
*
*
*
4.7.8. Ethyl (1R ,2R ,3S ,4R )-2-tert-butoxycarbonylamino-3,4-
dihydroxycyclohexane-carboxylate, ( )-14
White crystals, mp 123–125 °C.
*
*
*
*
4.7.9. (1R ,2R ,3S ,4R )-2-Amino-3,4-dihydroxycyclohexane-
carboxylic acid hydrochloride, ( )-15ꢁHCl
Pale-yellow crystals, mp 213 °C (dec.).
4.6.3. (1R,2R,3S,4R)-2-Amino-3,4-dihydroxycyclohexanecarb-
oxylic acid, (ꢀ)-15
4.7.10. (1R*,2R*,3S*,4R*)-2-Amino-3,4-dihydroxycyclohexane-
carboxylic acid, ( )-15
Yield: 86 mg (74%), mp 227–230 °C (dec.), ½a D20
¼ ꢀ81:4 (c = 0.35,
ꢃ
Pale-yellow crystals, mp 233 °C (dec.).
H2O); ee >99%. 1H NMR (500 MHz, D2O, 47 °C): d = 1.98 (dd, J = 14.8,
12.0 Hz 1H, H-5ax), 2.15–2.28 (m, 2H, H-5eq, H-6ax), 2.34–2.43 (m,
1H, H-6eq), 3.27 (s, 1H, H-1), 3.92 (d, J = 10.3, 4.7 Hz, 1H, H-2), 4.39
(d, J = 10.3 Hz, 1H, H-3), 4.50 (s, 1H, H-4) ppm. 13C NMR (125 MHz,
D2O, 47 °C): d = 21.6, 27.8, 42.6, 52.2, 69.3, 69.4, 174.9 ppm. Anal.
Calcd for C7H13NO4 (175.18): C, 47.99; H, 7.48; N, 8.00. Found: C,
48.12; H, 7.51; N, 7.89.
4.7.11. Ethyl (1S*,2S*)-2-tert-butoxycarbonylaminocyclohex-3-
enecarboxylate, ( )-16
White solid, mp 71–74 °C.
4.7.12. Ethyl (1S*,2R*,3S*,4R*)-2-tert-butoxycarbonylamino-
3,4-dihydroxycyclohexane-carboxylate, ( )-17
White crystals, mp 165–168 °C.
4.6.4. (1S,2R,3S,4R)-2-Amino-3,4-dihydroxycyclohexanecarb-
oxylic acid, (ꢀ)-18
Yield: 83 mg (72%), mp 258 °C (dec.), ½a D20
¼ ꢀ5:2 (c = 0.38,
ꢃ
4.7.13. (1S*,2R*,3S*,4R*)-2-Amino-3,4-dihydroxycyclohexane-
carboxylic acid hydrochloride, ( )-18ꢁHCl
H2O); ee >99%. 1H NMR (500 MHz, D2O, 27 °C): d = 1.66–1.76 (m,
Pale-yellow crystals, mp 225 °C (dec.).
2H, H-5, H-6), 1.96–2,02 (m, 2H, H-5, H-6), 2.38–2.44 (m, 1H, H-

G. Benedek et al. / Tetrahedron: Asymmetry 20 (2009) 2220–2225
2225
18. Nicolaou, K. C. Tetrahedron 2003, 59, 6683–6738.
19. Hashimoto, T.; Kondo, S.; Takita, T.; Hamada, M.; Takeuchi, T.; Okami, Y.;
Umezawa, H. J. Antibiot. 1968, 21, 653–658.
20. Hashimoto, T.; Takahashi, S.; Naganawa, H.; Takita, T.; Maeda, T. K.; Umezawa,
H. J. Antibiot. 1972, 25, 350–355.
*
*
*
*
4.7.14. (1S ,2R ,3S ,4R )-2-Amino-3,4-dihydroxycyclohexane-
carboxylic acid, ( )-18
Pale-yellow crystals, mp 275 °C (dec.).
21. Hashimoto, T.; Kondo, S.; Naganawa, H.; Takita, T.; Maeda, K.; Umezawa, H. J.
Antibiot. 1974, 27, 86–87.
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