Facile synthesis of 5-hydroxy-l-lysine from d-galactose as a chiral-precursor

Article abstract of DOI:10.1039/c4ob01220h

A concise synthesis of (2S,5R) and (2S,5S)-5-hydroxy-lysine was achieved by utilizing d-galactose as a chiral-precursor with stereo retention. This synthetic strategy showcased the potential of utilizing carbohydrates as starting materials to prepare amino acids. Using the diazido intermediate, the derived β-d-galactopyranosyl and α-d-glucopyranosyl-(1→2)- β-d-galactosyl moieties were synthesized. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01220h

Organic &
Biomolecular Chemistry
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Facile synthesis of 5-hydroxy-L-lysine from
D-galactose as a chiral-precursor†
Cite this: Org. Biomol. Chem., 2014,
12, 7310
Lina Guo,a Taibao Liu,a Kai Chen,b Tianbang Song,a Peng George Wang*a,c and
Wei Zhao*a
Received 13th June 2014,
Accepted 23rd July 2014
A concise synthesis of (2S,5R) and (2S,5S)-5-hydroxy-lysine was achieved by utilizing D-galactose as a
chiral-precursor with stereo retention. This synthetic strategy showcased the potential of utilizing carbo-
hydrates as starting materials to prepare amino acids. Using the diazido intermediate, the derived
β-D-galactopyranosyl and α-D-glucopyranosyl-(1→2)-β-D-galactosyl moieties were synthesized.
DOI: 10.1039/c4ob01220h
www.rsc.org/obc
A polypeptide fragment of CII (256–270) which contains residues
of 3 and 4 has been recently recognized as an immunodomi-
Introduction
Rheumatoid arthritis (RA), an autoimmune inflammatory nant T cell epitope in murine,3 and has been used to study the
disease initiated from self-tissue antigens, is characterized by degradation of skin and bone collagen.4 Thus, the hydroxy-
hyperplasia of the synovium, destruction of joint cartilage and lated or glycosylated lysine residues in collagens as a cartilage-
irreversible bone erosion. Type II collagen (CII) is the major specific autoantigen candidate implicated in the pathogenesis
protein component of articular cartilage and has been of rheumatoid arthritis (RA) have become an important topic.5
suggested to be an autoantigen associated with RA.1 In col-
Recently, Webby stated that another post-translational lysyl-
lagen and protein-like collagen sequences, especially in CII 5S-hydroxylation (2) of nuclear proteins, which exists in both
of humans, L-lysines can be modified with hydroxyl (1) and the cytoplasm and nucleoplasm, is ubiquitous and widely
subsequently glycosylated with β-D-galactopyranosyl (3) or α-D- affects the proteins and protein biosynthesis through oxygen
glucopyranosyl-(1→2)-β-D-galactopyranosyl moieties (4)2 (Fig. 1). tension elicit systems.6 2-Oxoglutarate-dependent dioxygenase
Jumonji domain-6 protein (Jmjd6) and Fe(II) could catalyse the
post-translational lysyl-5-hydroxylation in the splicing factor
U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodal-
ton subunit (U2AF65), a ubiquitous protein important for pre-
mRNA splicing. In 2012, the important bioactivity of this post-
translational modification and synthesis of (5R)-L-Hyl and
glycosylated Hyl were summarized by Brimble.7
From natural resources, compound 1 and the glycosylated
derivatives (3, 4) were isolated from hydrolysates of various
soluble proteins like collagen, marine sponges and ver-
tebrates.8 However, these alkaline hydrolysis reactions pro-
duced mostly a mixture of isomers that were difficult to
separate. The natural structure of (2S, 5R)-5-hydroxylysine (Hyl)
was first determined in 1950,9 and the first synthesis of D,L-5-
Hyl was reported by Sheehan.10 Because of the chirality of C-α
Fig. 1 The structures of L-lysine derivatives.
and C-δ positions, it was hard to separate pure enantiomers
from the mixture of four isomers by fractionated crystallization
aState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy,
of derivatives.11 Recently, stereoselective synthesis of 5-Hyl
Tianjin Key Laboratory of Molecular Drug Research, Nankai University,
isomers has been investigated. In general, William’s glycine
template was applied to introduce the stereogenic center at C-α
in amino acids.12 However, it was hard to effectively create the
second stereogenic center at the C-δ position from α-amino
acids. As shown in Scheme 1, there were two strategies (A and B)
to realize this objective goal. According to strategy A,
Tianjin 300071, PR China. E-mail: wzhao@nankai.edu.cn, pwang@nankai.edu.cn;
Fax: +86 22 23507760
bLaboratory of Computational Chemistry and Drug Design, Laboratory of Chemical
Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055,
PR China
cThe Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob01220h
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Scheme 1 The reported synthesis of L-hydroxylysine from William’s
glycine template.
through an epoxidation and a nucleophilic reaction, the stereo-
isomeric pure (5S)- and (5R)-L-Hyl stereoisomers were
obtained.13 Stereoselective synthesis of L-Hyl was achieved by
synthesizing an optically pure hydroxylysine side chain (strat-
egy B), but toxic NaCN was necessary and then volatile toxic
HCN was formed.14 In contrast, Kihlberg’ method, regioselec-
tive reductive opening of a p-methoxybenzylidene acetal of
triol which was obtained by reduction of (R)-malic acid, was
more convenient.15 The α-stereogenic centre could also be
introduced by Schöllkopf’s strategy,16 and utilizing this
method, Kunz17 reported the synthesis of (5S)-L-Hyl based on
Sharpless asymmetric aminohydroxylation18 to introduce the
second stereogenic center at the C-δ position. Another strategy
was C-α chirality retention of the natural amino acid to
produce L-Hyl. Allevi reported the synthetic approach starting
from D-,L-glutamic acid to obtain four optically pure stereo-
Scheme 2 Synthesis of 5S-L-hydroxylysine from D-galactoside. (a) TsCl,
pyridine, −50 °C, 6 h; (b) (i) p-TSA, trimethyl orthoformate, DCM, reflux;
(ii) Zr(OH)4, Ac2O, 135 °C, 9 h; (c) 10% Pd/C, H2, ethyl acetate–methanol,
rt, 8 h; (d) NaN3, DMF, 100 °C, 5 h; (e) NaOMe, dry MeOH, rt, 5 h; (f) (i),
Tf2O, pyridine, DCM, −30 °C, 2 h; (ii) NaN3, DMF, rt, 36 h; (g) (i) 80%
HCOOH, 90 °C, 3 h; (ii) PCC, silica gel, DCM, rt, 24 h; (h) Dowex
50W-X2, H2O, reflux, 4 h; (i) 10% Pd/C, H2, H2O, rt, 15 h.
desired 3,4-dideoxy compound 6.23 In this step, hydrous zirco-
nium oxide was chosen as the Lewis acid catalyst, which was
activated by microwave instead of being calcined at 300 °C.24
Hydrogenation of 6 afforded compound 7, which was sub-
jected to SN2 nucleophilic attack with sodium azide to obtain
compound 8, followed by deacetylation in the presence of
NaOCH3 to give the key intermediate compound 9 with 72%
isomers of 5-Hyl.19 Guichard and coworkers reported
a
synthesis of (5S)-, (5R)-L-Hyl and their mimetics by
diastereoselective hydroxylation of 6-substituted piperidin-2-
ones from the corresponding aspartic acid derivatives.20
Brimble and coworkers synthesized an azido precursor of 5R-L-
Hyl from aspartic acid derivatives by a highly stereoselective
asymmetric organocatalytic α-chlorination of an aldehyde.21
Recently, a strategy using the acyl nitroso Diels–Alder reaction
to obtain structurally diverse amino acids including δ-hydroxy-
lysine was reported.22 Herein we developed a concise and
stereo-controlled synthesis of (5S)- and (5R)-L-Hyl starting from
D-galactose and demonstrated a convenient synthesis of two
glycosylated L-Hyl derivatives using the diazido intermediate.
1
yield. The H NMR spectra showed the characteristic signal of
the anomeric proton at δ = 4.71 with J1,2 = 3.6 Hz. After trifla-
tion to the α-hydroxy group and SN2 substitution reaction, the
stereogenic center of C-α was reconstructed smoothly, and the
anomeric proton of compound 10 resonates at 4.63 as a
singlet. For the oxidation step, we chose pyridinium chloro-
chromate (PCC) as the oxidation reagent to convert the hydro-
lysates of compound 10 to lactone 11. Subsequently, the
lactone was subjected to hydrolysis reaction under H+/H2O to
obtain the acid (12) without any detectable amount of α-epi-
merization (1H NMR and 13C NMR analysis in D2O at 393 K),
followed by hydrogenation using Pd/C as a catalyst to afford
the resulting (5S)-Hyl (2) with 42% overall yield from methyl-
α-D-galactoside.
Results and discussion
As depicted in Scheme 2, treatment of methyl α-D-galactoside
For the structure of compound 10, the methoxyl substitute
with tosyl chloride in pyridine afforded the desired mono-tosy- is likely to be in an equatorial or axial position, as shown in
lated compound 5 with 90% yield after crystallization. Under Fig. 2. The anomeric proton resonating at 4.63 as a singlet
acidic conditions, the tosylated compound 5 was converted to showed that conformation A may be more stable in chloro-
the ortho ester by trimethyl orthoformate, followed by a reduc- form, and this hypothesis was consistent with the results of
tive elimination reaction in acetic anhydride to obtain the calculation. By rotating the side chains, several conformations
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Fig. 2 Two possible conformations of compound 10: (A) methoxyl
group at the axial position; (B) methoxyl group at the equatorial position.
Scheme 4 Synthesis of Gal-Hyl building block. (a) Dowex 50W-X2,
MeOH, reflux, 4 h; (b) TMSOTf, 3 Å MS, DCM, 0 °C, 45 min.
were generated for conformation A and conformation B. Each
conformation was optimized by density functional theory at
the b3lyp/6-31+g* theoretical level. The solvent effect of chloro-
form was considered with the SMD25 solvent model, and fre-
quency was calculated to confirm a stable minimum. All the
calculation was performed using Gaussian 09.26 The most
stable structure of conformation A is about 2.8 kcal mol−1
lower in free energy than that of conformation B, which means
conformation A is dominant in solvent, to the best of our
knowledge.
The stereoisomer (5R)-Hyl (1) was obtained from compound
16 by hydrogenation with Pd/C. It was worth mentioning that
15 synthesized by intramolecular SN2 nucleophilic reaction
inverses the chirality of the C-δ position of compound 14 as
shown in Scheme 3. In this step, Cs2CO3 was chosen as the
base for alkaline hydrolysis of hexanoate (14), and the
obtained cesium carboxylate at 0 °C was used for intramole-
cular SN2 nucleophilic reaction at 40 °C to obtain the desired
compound 15, but due to the alkaline conditions (pH ≤ 10)
from the produced CsHCO3, the caprolactone (15) was hydro-
lyzed to carboxylate, which should be treated with acid before
purification. In this step, no α-epimerization was detected.
Encouraged by the results mentioned above, we decided to
explore a possible extension to synthetic glycosylated amino
acid building blocks to make versatile glycopeptide moieties.
To obtain the template compounds 3 and 4, Gal-Hyl and Glc-
Gal-Hyl building blocks 19 and 24 were synthesized. As shown
in Scheme 4, the monosaccharide substituted amino acid
building block intermediate 17 was chosen as the glycosylation
acceptor to avoid the tedious protection and deprotection
steps of amino groups. Moreover, due to neighboring group
participation, the acetyl protecting C-2 position of trichloro-
acetimidate (18)27 contributed to forming only β-linked com-
pound 19, whose anomeric proton resonates at 4.55 ppm with
the coupling constant J1,2 = 8.0 Hz.
The synthesis of another glycosylated amino acid building
block 24 is shown in Scheme 5.28 First, β-linked compound 21
Scheme 3 Preparation of (5R)-L-hydroxylysine by intramolecular SN2
nucleophilic reaction. (a) Dowex 50W-X2, MeOH, reflux, 4 h; (b) MsCl,
TEA, DCM, rt, 1 h; (c) Cs2CO3, dioxane–H2O, 0 °C→40 °C, 36 h;
(d) Dowex 50W-X2, H2O, reflux, 4 h; (e) 10% Pd/C, H2, H2O, rt, 15 h.
Scheme 5 Synthesis of the Glc-Gal-Hyl building block. (a) ref. 28;
(b) TMSOTf, 3 Å MS, DCM, 0 °C, 45 min; (c) AcCl, MeOH, 10 h, rt;
(d) TMSOTf, 3 Å MS, DCM, 0 °C, 45 min.
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was obtained by coupling of 2,3,6-tribenzyl-2-acetyl-galactosyl- (DCM) and 3 mL 6 N HCl was added to afford an amorphous
1-trichloracetimidate (20)29 with the diazido acceptor 17. Due white solid. After filtering and washing with methanol, DCM
to the neighboring group participation of the acetyl of the C-2 and ether sequentially, target compound 5 (30 g, 90.0%) was
position, no α-linked product was isolated and the chemical afforded and can be directly used for the next reaction without
shift signal of the anomeric proton was at 4.40 ppm with J1,2
=
further purification.
8.0 Hz. Subsequent removal of the 2-O-acetyl group by metha-
nolysis30 in the presence of MeCOCl–MeOH–CH2Cl2 afforded
acceptor 22 with high yield (85%). Glycosylation of 22 using
Methyl 2-O-acetyl-6-O-p-tolsulfonyl-3,4-dideoxy-α-D-erythro-
hex-3-enopyranoside (6)
tetrabenzylated galactopyranosyl trichloracetimidate in the To a suspension of methyl 6-O-p-tolsulfonyl-α-D-galactopyrano-
presence of TMSOTf gave the target compound 23 in a 46% side 5 (30 g, 86.00 mmol) in 500 mL DCM, p-toluenesulfonic
yield. The chemical shift of two anomeric protons of com- acid (p-TSA, 195 mg, 1.70 mmol) and trimethyl orthoformate
pound 23 was confirmed by HMQC experiment.
(47 mL, 430.00 mmol) were added. The mixture was stirred at
45 °C for 2 h until the reaction was clear. The reaction mixture
was washed with sat. NaHCO3 solution, water, brine, and dried
over Na2SO4. After concentration in vacuo, a colorless syrup
was prepared. Without purification, the syrup and hydrous
zirconium (8.5 g, activated by microwave) were heated to and
kept at 135 °C in acetic anhydride (400 mL) for 9 h. TLC ana-
lysis showed complete conversion of the starting material. The
mixture was cooled to room temperature. After removal of the
solvent, the residue was diluted in 500 mL DCM and filtered.
The filtrate was concentrated and chromatographed (petroleum
ether–DCM (1 : 1)→100% DCM) to afford a colorless syrup 6
Conclusions
In summary, we have developed a new, concise and highly
stereo-controlled synthesis of optically pure (5S)- and (5R)-L-
Hyl stereoisomers from methyl-α-D-galactoside. Lewis acid
catalyzed reductive elimination and intramolecular SN2
nucleophilic reaction are the key steps. Its utility was illus-
trated by amino acids’ stereogenic centers derived from the
chiral-precursors of the corresponding carbohydrates. This
synthetic strategy showcased the potential application in the
preparation of unnatural amino acids utilizing naturally occur-
ring carbohydrates as starting materials.
1
(23.5 g, 77.0% in two steps). H NMR (CDCl3, 400 MHz) δ 7.80
(d, J = 8 Hz, 2H), 7.36 (d, J = 8 Hz, 2H), 5.77 (d, J = 10.8 Hz,
1H), 5.70 (d, J = 10.8 Hz, 1H), 5.18 (brs, 1H), 4.99 (d, J = 4 Hz,
1H), 4.36 (brs, 1H), 4.12 (dd, J = 4.2, 10.6 Hz, 1H), 4.07 (dd, J =
4.8, 10.6 Hz, 1H), 3.42 (s, 3H), 2.46 (s, 3H), 2.10 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 170.48, 145.02, 132.92, 129.87,
Experimental
All reagents were purchased from commercial sources and 128.00, 126.74, 124.99, 95.74, 70.66, 66.34, 66.28, 56.13,
were used without further purification. All solvents were avail- 21.68, 20.95. HRMS Calcd for C16H24NO7S (m/z): 374.1273
able commercially, dried or freshly dried and distilled prior to [M + NH4]+, found: 374.1269.
use. Reactions were monitored by Thin Layer Chromatography
Methyl 2-O-acetyl-6-O-p-tolsulfonyl-3,4-dideoxy-
α-D-galactopyranoside (7a) and methyl 6-O-p-tolsulfonyl-
3,4-dideoxy-α-D-galactopyranoside (7b)
(TLC) using silica gel GF254 plates with detection by short
wave UV light (λ = 254 nm) and staining with 10% phosphomo-
lybdic acid in EtOH. Column chromatography was conducted
by silica gel (200–300 mesh) with ethyl acetate and petroleum A mixture of compound 6 (20.2 g, 56.20 mmol) and 10% Pd/C
ether (60–90 °C) or dichloromethane and methanol as an (2 g) in ethyl acetate–methanol (4 : 1, 200 mL) was vigorously
eluent. Compounds 1, 2 were purified by C-18 reverse phase stirred at room temperature for 8 h under a hydrogen atmos-
1
silica gel (200–300 mesh) with pure water and MeOH. H NMR phere. The mixture was filtered through a pad of Celite and
and 13C NMR were recorded with a Bruker AV 400 spectrometer the Celite pad was washed thoroughly with ethyl acetate. The
at 400 MHz (1H NMR), 100 MHz (13C NMR) using CDCl3, filtrate and washings were combined and concentrated to give
DMSO-d6 or CD3OD-d4 as solvents. Chemical shifts were compound 7a as a colorless syrup (19.0 g, Rf = 0.5, petroleum
reported in δ (ppm) from TMS internal standard (0.00 ppm). ether–ethyl acetate, 2 : 1) and 10–15% deacetyl compound 7b
Coupling constants were reported in hertz. Optical rotations: (Rf = 0.2, petroleum ether–ethyl acetate, 2 : 1). 7a. 1H NMR
Perkin Elmer 341 polarimeter (Na D line, λ = 589 nm), temp- (CDCl3, 400 MHz) δ 7.79 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz,
erature 25 °C.
2H), 4.73–4.70 (m, 2H), 4.00 (s, 1H), 3.99 (brs, 1H), 3.95–3.91
(m, 1H), 3.35 (s, 3H), 2.45 (s, 3H), 2.06 (s, 3H), 1.95–1.88
(m, 1H), 1.86–1.78 (m, 1H), 1.71–1.65 (m, 1H), 1.47 (ddd, J =
Methyl 6-O-p-tolsulfonyl-α-D-galactopyranoside (5)31
Methyl α-D-galactopyranoside (20 g, 47.20 mmol) was dissolved 4.0, 13.2, 24.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 170.45,
in dry pyridine (100 mL), and the solution was kept at −50 °C 144.90, 132.96, 129.83, 127.96, 96.76, 71.54, 69.90, 65.72,
for 1 h under a nitrogen atmosphere. p-Toluene sulfonyl chlor- 55.00, 26.22, 22.63, 21.66, 21.13. HRMS calcd for C16H26NO7S
ide (24 g, 56.70 mmol) was added to the cooled solution and (m/z): 376.1430 [M + NH4]+, found: 376.1424. 7b. 1H NMR
the reaction was stirred at −50 °C for another 6 h. 10 mL (CDCl3, 400 MHz) δ 7.81 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,
MeOH was added to quench the reaction. The solvent was 2H), 4.62 (d, J = 3.6 Hz, 1H), 4.00 (s, 1H), 3.99 (s, 1H),
removed in vacuo, and then a mixture of 100 mL dichloromethane 3.90–3.84 (m, 1H), 3.60–3.55 (m, 1H), 3.39 (s, 3H), 2.46 (s, 3H),
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1.91–1.86 (m, 2H), 1.70 (d, J = 4.0, 12.8 Hz, 1H), 1.66–1.62 dried, and concentrated to afford a crude residue, which was
(m, 1H), 1.46–1.35 (m, 1H); 13C NMR (CDCl3, 100 MHz) chromatographed (petroleum ether–ethyl acetate, 20 : 1) to
δ 144.88, 132.99, 129.84, 127.98, 99.16, 71.71, 67.70, 65.93, afford a colourless oil of compound 10 (7.8 g, 86.0% in two
55.17, 26.82, 26.21, 21.67. HRMS Calcd for C14H24NO6S (m/z): steps). 1H NMR (CDCl3, 400 MHz) δ 4.63 (s, 1H), 3.97–3.91
334.1324 [M + NH4]+, found: 334.1324.
(m, 1H), 3.54 (brs, 1H), 3.44 (s, 3H), 3.36 (dd, J = 7.6, 12.4 Hz,
1H), 3.14 (dd, J = 3.4, 12.4 Hz, 1H), 2.13–2.04 (m, 1H),
1.88–1.84 (m, 1H), 1.67 (ddd, J = 4.0, 13.2, 25.1 Hz, 1H),
Methyl 2-O-acetyl-6-azido-3,4,6-trideoxy-α-D-galactopyranoside (8)
To the solution of compound 7a (15.3 g, 50.00 mmol) in 1.44–1.41 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 98.40, 68.12,
100 mL DMF, NaN3 (15.3 g, 250.00 mmol) was added. The 58.74, 55.01, 54.83, 22.76, 22.42. HRMS Calcd for C7H13N6O2
reaction was kept at 100 °C for 5 h. TLC analysis showed com- (m/z): 213.1100 [M + H]+, found: 213.1094.
plete conversion of the starting material. The reaction mixture
(2S,5S)-2,6-Diazido-δ-caprolactone (11)
was filtered, concentrated and diluted with 50 mL ethyl
acetate. The crude residue was purified by flash column A solution of compound 10 (7.8 g, 36.8 mmol) in 150 mL 80%
chromatography (petroleum ether–ethyl acetate, 5 : 1) to afford HCOOH in water was heated at 90 °C for 3 h. The mixture was
a colorless syrup 8 (10.6 g, 93%), Rf = 0.63, (petroleum ether– concentrated to give the corresponding hemiacetal. After being
ethyl acetate, 2 : 1). 1H NMR (CDCl3, 400 MHz) δ 4.83–4.78 purified by chromatography (petroleum ether–ethyl acetate,
(m, 2H), 3.85 (ddd, J = 3.6, 7.2, 14.4 Hz, 1H), 3.46 (s, 3H), 3.29 2 : 1), the hemiacetal was dissolved in 100 mL dried DCM, and
(dd, J = 7.2, 12.8 Hz, 1H), 3.19 (dd, J = 3.6, 12.8 Hz, 1H), 2.09 then PCC (16.2 g, 75.0 mmol) and silica gel (16.2 g) were
(s, 3H), 1.95 (ddd, J = 4.0, 12.1, 25.1 Hz, 1H), 1.89–1.84 added. The suspension was stirred at room temperature for
(m, 1H), 1.74–1.69 (m, 1H), 1.58 (ddd, J = 4.2, 13.2, 25.0 Hz, 24 h. After removing the solvent, the solid was purified
1H); 13C NMR (CDCl3, 100 MHz) δ 170.44, 96.91, 70.10, 67.47, through a short chromatograph column with ether to afford
55.04, 54.50, 27.49, 22.79, 21.12. HRMS Calcd for C9H16N3O4 the lactone as a colorless oil (5.9 g, 82.0% in two steps), Rf =
(m/z): 230.1141 [M + H]+, found: 230.1137.
0.56, (petroleum ether–ethyl acetate, 2 : 1). 1H NMR (CDCl3,
400 MHz) δ 4.42 (m, 1H), 4.13 (t, J = 7.2 Hz, 1H), 3.43 (brs, 1H),
3.42 (brs, 1H), 2.22–2.10 (m, 1H), 1.89–1.81 (m, 1H); 13C NMR
Methyl 6-azido-3,4,6-trideoxy-α-D-galactopyranoside (9)
To the solution of compound 8 (9.3 g) in 50 mL dried MeOH, (CDCl3, 100 MHz) δ 168.17, 77.54, 56.45, 53.94, 24.07, 22.76.
MeONa was added until the pH of the solution reached 9–10. HRMS Calcd for C6H97N6O2 (m/z): 197.0787 [M + H]+, found:
The reaction was kept at room temperature for 5 h. Dowex 197.0785.
50W-X2 resin was added and the suspension was stirred until
pH ≤ 7. The mixture was filtered, and the resin was washed
(2S,5S)-2,6-Diazido-5-hydroxyhexanoic acid (12)
with ethyl acetate. The filtrate and washings were combined, Dowex 50W-X2 resin (2 mg) was added to a solution of diazido
concentrated to obtain a colorless syrup compound 9 (7.5 g, lactone 11 (150 mg, 0.7 mmol) in H2O (7 mL) and the resulting
quant.). Rf = 0.3, (petroleum ether–ethyl acetate, 2 : 1). 1H NMR suspension was stirred at reflux temperature for 4 h. The resin
(CDCl3, 400 MHz) δ 4.71 (d, J = 3.6, Hz, 1H), 3.92 (ddd, J = 3.6, was then filtered off and the solvent was used in the next step
7.5, 14.5 Hz, 1H), 3.64 (ddd, J = 4.0, 4.8, 11.6 Hz, 1H), 3.48 without further purification (quant.). Rf = 0.30, (DCM–MeOH,
1
(s, 3H), 3.28 (dd, J = 7.2, 12.8 Hz, 1H), 3.18 (dd, J = 3.2, 10 : 1). H NMR (D2O, 400 MHz) δ 4.28 (t, J = 6.0 Hz, 1H), 3.89
12.8 Hz, 1H), 1.94–1.88 (m, 2H), 1.75–1.62 (m, 2H), 1.48 (ddd, (brs, 1H), 3.45 (d, J = 12.8 Hz, 1H), 3.33 (dd, J = 7.2, 12.8 Hz,
J = 4.0, 13.4, 25.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 99.27, 1H), 1.95 (dd, J = 7.0, 14.6 Hz, 2H), 1.69–1.57 (m, 2H);
67.87, 67.66, 55.26, 54.58, 27.52, 22.02. HRMS Calcd for 13C NMR (D2O, 100 MHz) δ 174.51, 68.78, 55.11, 44.86, 29.92,
C7H14N3O3 (m/z): 188.1035 [M + H]+, found: 188.1032.
28.59. HRMS Calcd for C6H9N6O3 (m/z): 213.0736 [M − H]−,
found: 213.0738.
Methyl-2,6-diazido-2,3,4,6-tetradeoxy-α-D-mannopyranoside (10)
(2S,5S)-5-Hydroxylysine (2)
Pyridine (8.0 g, 103.00 mmol) was dissolved in dry DCM
(200 mL) followed by addition of trifluoromethanesulfonic To the solvent of acid 12 in H2O as above, 10% Pd/C (15 mg)
anhydride (14.2 g, 51.2 mmol) and cooled to −30 °C. Com- was added and the mixture was stirred under a hydrogen
pound 9 (8.0 g, 42.70 mmol) was dissolved in DCM (25 mL) atmosphere at room temperature and atmospheric pressure
and added dropwise under anhydrous conditions to the cooled for 15 h. The solution was filtered through Celite and the
reaction mixture. After 2 h TLC showed almost complete con- filtrate was concentrated to dryness. The faint yellow solid
sumption of the starting material. The reaction was quenched obtained was purified by flash chromatography with C-18
with methanol and the organic layer was concentrated in vacuo silica gel (100% H2O→80% H2O in MeOH) to give the title
(<30 °C). The crude intermediate (oil) was dissolved in dry compound 2 (105 mg, 5.74 mmol, 92%) as a faint yellow solid.
1
dimethylformamide (250 mL) and sodium azide (8.2 g, [α]2D5 31.3 (c 1.03 in 6 M HCl). H NMR (D2O, 400 MHz): δ 3.74
126 mmol) was added to the solution. The reaction mixture (1H, m, 5–H), 3.49 (1H, t, J = 5.7 Hz, 2-H), 2.98 (1H, dd, J = 2.4,
was stirred at room temperature under argon for 36 h. The 13.2 Hz, 6-Ha), 2.78 (1H, dd, J = 13.2, 9.4, 6-Hb), 1.87–1.80 (1H,
solvent was removed, and the syrup was diluted with 100 mL m, 3-Ha), 1.78–1.71 (1H, m, 3-Hb), 1.62–1.53 (1H, m, 4-Ha),
ethyl acetate. The organic layer was washed with water, brine, 1.48–1.39 (1H, m, 4-Hb); 13C NMR (D2O, 100 MHz): δ 178.06
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(C-1), 68.48 (C-5), 55.01 (C-2), 44.76 (C-6), 29.88 (C-4), 28.29 (2S,5R)-2,6-Diazido-5-hydroxyhexanoic acid (16)
(C-3). HRMS Calcd for C6H15N2O3 (m/z): 163.1083 [M + H+],
Dowex 50W-X2 resin (20 mg) was added to a solution of
diazido lactone 15 (1.3 g, 7 mmol) in H2O (70 mL) and the
resulting suspension was stirred at reflux temperature for 4 h.
The resin was then filtered off and the solvent was used in the
next step without further purification (quant.). Rf = 0.30,
found: 163.1078.
(2S,5S)-Methyl-2,6-diazido-5-hydroxyhexanoate (13)
Dowex 50W-X2 resin (20 mg) was added to a solution of
diazido lactone 11 (4.0 g, 20.00 mmol) in MeOH (100 mL) and
the resulting suspension was stirred at reflux temperature for
4 h. The resin was then filtered off and the solvent evaporated
to give the title compound as a colorless liquid, which was
used in the next step without further purification (1.6 g,
quant.). Rf = 0.3, (100% DCM). 1H NMR (CDCl3, 400 MHz)
δ 3.96 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.81–3.76 (m, 1H), 3.40
(dd, J = 3.6, 12.4 Hz, 1H), 3.29 (dd, J = 7.6, 12.4 Hz, 1H), 2.20
(brs, 1H), 1.98–1.92 (m, 2H), 1.62–1.56 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 170.76, 69.80, 61.61, 57.05, 52.74, 29.98,
27.32. HRMS Calcd for C7H13N6O3 (m/z): 229.1049 [M + H]+,
found: 229.1045.
1
(DCM–MeOH, 10 : 1). H NMR (D2O, 400 MHz) δ 4.20 (dd, J =
5.0, 7.8 Hz, 1H), 3.76–3.69 (m, 1H), 3.30 (dd, J = 3.4, 13.0 Hz
1H), 3.17 (dd, J = 3.0, 13.0 Hz, 1H), 1.95–1.87 (m, 1H),
1.73–1.64 (m, 1H), 1.55–1.46 (m, 2H); 13C NMR (D2O,
100 MHz) δ 174.65, 69.98, 62.28, 55.87, 29.36, 27.23. HRMS
Calcd for C6H9N6O3 (m/z): 213.0736 [M
−
H]−, found:
213.0738.
(2S,5R)-5-Hydroxylysine (1)
To the solvent of acid 16 in water as above, 10% Pd/C (150 mg)
was added and the mixture was stirred under a hydrogen
atmosphere at room temperature and atmospheric pressure
for 15 h. Then the solution was filtered through Celite and the
filtrate was concentrated to dryness. The faint yellow solid was
purified by flash chromatography with C-18 silica gel (100%
H2O→80% H2O in MeOH) to give the title compound 1 (1.02 g,
6.30 mmol, 90%) as a faint yellow solid. [α]2D5 +18.8 (c 1.08 in
(2S,5S)-Methyl-2,6-diazido-5-((methylsulfonyl)oxy)hexanoate (14)
The colorless oil (13) was dissolved in dried DCM (50 mL) and
kept at 0 °C for 15 min, followed by addition of methane-
sulfonyl chloride and triethylamine dropwise. The reaction
was stirred at room temperature for 1 h. After evaporation of
the solvent, the residue was diluted with 100 mL ethyl acetate.
The organic layer was washed with water, brine, dried, and
concentrated to afford a crude residue, which was chromato-
graphed (petroleum ether–ethyl acetate, 5 : 1) quickly to afford
a colorless oil of compound 13 (5.9 g, 96.0% in two steps).
1H NMR (CDCl3, 400 MHz) δ 4.79 (brs, 1H), 4.00 (t, J = 7.2 Hz,
1H), 3.82 (s, 3H), 3.62 (dd, J = 3.4, 13.4 Hz, 1H), 3.47 (dd, J =
6.2, 13.4 Hz, 1H), 3.12 (s, 3H), 2.20–1.78 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 170.29, 78.96, 61.18, 53.91, 52.86, 38.71,
28.35, 26.65. HRMS Calcd for C8H18N7O5S (m/z): 324.1090
[M + NH4]+, found: 324.1082.
1
6 N HCl). H NMR (D2O, 400 MHz): δ 3.84–3.78 (1H, m, 5-H),
3.57 (1H, t, J = 6.2 Hz, 2-H), 3.04 (1H, dd, J = 13.2, 3.2 Hz,
6-Ha), 2.84 (1H, dd, J = 13.2, 9.2 Hz, 6-Hb), 1.99–1.90 (1H, m,
3-Ha), 1.84–1.74 (1H, m, 3-Hb), 1.63–1.50 (2H, 4-H); 13C NMR
(D2O, 100 MHz): δ 177.88 (C-1), 68.53 (C-5), 55.93 (C-2), 44.76
(C-6), 29.73 (C-4), 28.19 (C-3). HRMS Calcd for C6H15N2O7
(m/z): 163.1083 [M + H]+, found: 163.1078.
(2S,5R)-Methyl-2,6-diazido-5-hydroxyhexanoate (17)
Dowex 50W-X2 resin (20 mg) was added to a solution of
diazido lactone 15 (1.3 g, 7 mmol) in MeOH (70 mL) and the
resulting suspension was stirred at reflux temperature for 4 h.
The resin was then filtered off and the solvent evaporated to
give the title compound as a colorless liquid, which was used
in the next step without further purification (1.6 g, quant.).
(2S,5R)-2,6-Diazido-δ-caprolactone (15)
To a cooled solution of compound 14 (5.9 g, 19.20 mmol) in
1,4-dioxacyclohexane–H2O 1 : 1 (v/v) (100 mL), Cs2CO3 (6.52 g
in 5 mL H2O, 20 mmol) was added dropwise. TLC (petroleum
ether–ethyl acetate, 5 : 1) showed complete conversion of hexa-
noate into cesium carboxylate. After the reaction mixture was
stirred for 36 h at 40 °C (pH ≈ 7–8), the mixture was treated
with 3 N HCl to pH 1–2 and ether (100 mL) was added. The
organic phase was collected and the aqueous phase was
extracted with an additional amount of ether (30 mL). The
combined organic layers were dried (Na2SO4) and concentrated
to the anhydrate product 15 (3.4 g, 91%, Rf = 0.60, petroleum
ether–ethyl acetate, 2 : 1), and compound 16 (352.0 mg, Rf =
1
Rf = 0.30, (100% DCM). H NMR (CDCl3, 400 MHz) δ 3.60 (dd,
J = 5.0, 8.6 Hz, 1H), 3.81 (s, 3H), 3.77 (td, J = 4.0, 8.0 Hz, 1H),
3.48 (s, 1H), 3.40 (dd, J = 3.6, 12.4 Hz, 1H), 3.29 (dd, J = 7.4,
12.2 Hz, 1H), 2.12–2.03 (m, 1H), 1.85–1.76 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 170.77, 70.22, 61.97, 57.10, 52.72, 30.22,
27.67. HRMS Calcd for C7H13N6O3 (m/z): 229.1049 [M + H]+,
found: 229.1045.
(2S,5R)-Methyl-2,6-diazido-5-(2,3,4,6-tetra-O-acetyl-
β-D-galactopyranosyloxy)hexanoate (19)
0.30, DCM–MeOH, 10 : 1). 15. 1H NMR (CDCl3, 400 MHz) A mixture of compound 17 (228 mg, 1.0 mmol), O-(2,3,4,6-tri-
δ 4.52 (ddd, J = 4.2, 8.2, 11 Hz, 1H), 4.13 (dd, J = 6.4, 11.2 Hz, O-acetyl-α-D-galactopyranosyl)trichloroacetimidate (18) (980 mg,
1H), 3.58 (dd, J = 4.4, 13.2 Hz, 1H), 3.44 (dd, J = 4.4, 13.2 Hz, 2.00 mmol), powdered molecular sieves (3 Å, 200 mg) and dry
1H), 2.32–2.25 (m, 1H), 2.05–1.97 (m, 1H), 1.96–1.77 (m, 2H); distilled DCM (10 mL) was kept at 0 °C for 30 min under
13C NMR (CDCl3, 100 MHz) δ 168.05, 79.55, 58.06, 54.13, argon. TMSOTf (23 μL, 0.1 mmol) was added. After stirring
26.07, 24.09. HRMS Calcd for C6H97N6O2 (m/z): 197.0787 for 45 min at 0 °C, triethylamine was added and the solvent
[M + H]+, found: 197.0785.
evaporated in vacuo. The residue was purified by flash chrom-
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atography (petroleum ether–ethyl acetate, 3 : 1) to give the title (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 170.92, 138.52, 138.06,
compound 17 (240 mg, 0.43 mmol, 43%) as a colorless syrup. 137.84, 128.54, 128.48, 128.22, 128.09, 127.88, 127.67, 103.82
Rf = 0.20, (petroleum ether–ethyl acetate, 2 : 1). 1H NMR (C-1′), 82.00, 78.53, 74.48, 73.88, 73.58, 72.86, 72.56, 71.28,
(CDCl3, 400 MHz) δ 5.37 (d, J = 2.8 Hz, 1H), 5.20 (dd, J = 8.0, 68.85, 61.96, 54.66, 52.72, 28.43, 27.24. HRMS Calcd for
10.4 Hz, 1H), 4.99 (dd, J = 3.6, 10.4 Hz, 1H), 4.55 (d, J = 8.0 Hz, C34H44N7O8 (m/z): 678.3251 [M + NH4]+, found: 678.3243.
1H, H-1′), 4.14 (ddd, J = 6.5, 11.2, 23.4 Hz, 1H), 3.91 (t, J =
(2S,5R)-Methyl-2,6-diazido-5-[(2,3,4,6-tetra-O-benzyl-
α-D-glucopyranosyl)-(1→2)-(3,4,6-tri-O-benzyl-
β-D-galactopyranosyloxy)]hexanoate (23)
6.8 Hz, 1H), 3.85 (dd, J = 5.2, 8.4 Hz, 1H), 3.79 (s, 3H),
3.72–3.67 (m, 1H), 3.45 (dd, J = 5.4, 12.6 Hz, 1H), 3.37 (dd, J =
4.6, 12.6 Hz, 1H), 2.13 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.97
(s, 3H), 1.95–1.88 (m, 1H), 1.70–1.62 (m, 3H); 13C NMR (CDCl3, A mixture of compound 22 (256 mg, 0.39 mmol), O-(2,3,4,6-
100 MHz) δ 170.52, 170.44, 170.30, 170.17, 169.34, 101.65, tetra-O-benzyl-α-D-glucopyranosyl)trichloroacetimidate (683 mg;
79.44, 70.86, 68.98, 61.94, 61.49, 54.59, 52.76, 28.87, 27.16, 1.00 mmol), powdered molecular sieves (3 Å, 100 mg) and
20.70, 20.67, 20.60. HRMS Calcd for C21H34N7O12 (m/z): dried DCM (10 mL) was kept at 0 °C for 30 min under argon.
576.2265 [M + NH4]+, found: 576.2253.
TMSOTf (10 μL, 0.04 mmol) was then added. After stirring at
0 °C for 45 min, triethylamine was added and the solvent was
evaporated in vacuo. The residue was purified by flash chrom-
atography (toluene–ethyl acetate, 20 : 1) to give the title com-
(2S,5R)-Methyl-2,6-diazido-5-(3,4,6-tri-O-benzyl-2-O-acetyl-
β-D-galactopyranosyloxy)hexanoate (21)
A mixture of compound 17 (228 mg, 1.00 mmol), O-(3,4,6-tri- pound 24 (214 mg, 0.18 mmol, 46%) as a colorless syrup. Rf =
O-benzyl-2-O-acetyl-α-D-galactopyranosyl)trichloroacetimidate 0.65, (petroleum ether–ethyl acetate, 2 : 1). 1H NMR (CDCl3,
(20) (1.27 g, 2.00 mmol), powdered molecular sieves (3 Å, 400 MHz) δ 7.36–7.04 (m, 35H), 5.58 (d, J = 3.6 Hz, 1H, H-1″),
100 mg) and dry distilled DCM (10 mL) was kept at 0 °C for 4.90 (d, J = 10.8 Hz, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.82 (d, J =
30 min under argon. TMSOTf (23 μL, 0.1 mmol) was added. 10 Hz, 2H), 4.78 (d, J = 13.2 Hz, 2H), 4.65 (d, J = 10.8 Hz, 1H),
After stirring at 0 °C for 45 min, triethylamine was added and 4.61 (d, J = 11.2 Hz, 1H), 4.60 (d, J = 7.6 Hz, 1H, H-1′), 4.56 (d,
the solvent was evaporated in vacuo. The residue was purified J = 11.6 Hz, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 10.8 Hz,
by flash chromatography (toluene–ethyl acetate, 50 : 1) to give 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H),
the title compound 21 (330 mg, 0.47 mmol, 47%) as a colorless 4.30–4.28 (m, 1H), 4.18 (dd, J = 3.6, 10.0 Hz, 1H), 4.00 (t, J =
1
syrup. Rf = 0.8, (petroleum ether–ethyl acetate, 2 : 1). H NMR 9.4 Hz, 1H), 3.95 (d, J = 3.0 Hz, 1H), 3.84–3.79 (m, 1H), 3.69
(CDCl3, 400 MHz) δ 7.34–7.26 (m, 15H), 5.34 (dd, J = 8.0, (s, 3H), 3.70–3.67 (m, 1H), 3.65–3.60 (m, 3H), 3.59 (brs, 3H),
10.0 Hz, 1H), 4.93 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H), 3.46 (dd, J = 5.0, 13 Hz, 1H), 3.39 (brs, 2H), 3.46 (dd, J = 4.2,
4.58 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.45 (d, J = 13.0 Hz, 1H), 1.73–1.59 (m, 4H); 13C NMR (CDCl3, 100 MHz)
11.2 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 8.0 Hz, 1H, δ 170.42, 138.90, 138.72, 138.43, 138.25, 137.85, 137.36,
H-1′), 3.92 (m, 1H), 3.88–3.78 (m, 4H), 3.65–3.54 (m, 4H), 3.49 128.51, 128.41, 128.32, 128.27, 128.19, 127.95, 127.84, 127.71,
(dd, J = 2.8, 10.0 Hz, 1H), 3.45 (dd, J = 4.4, 12.8 Hz, 1H), 3.37 127.60, 127.49, 127.31, 102.45 (C-1′), 95.95 (C-1″), 82.30, 81.41,
(dd, J = 12.6, 6.4 Hz, 1H), 2.03–1.88 (m, 4H), 1.72–1.58 (m, 3H); 79.66, 78.06, 75.82, 75.49, 74.81, 74.56, 73.64, 73.55, 73.36,
13C NMR (CDCl3, 100 MHz) δ 170.64, 169.40, 138.40, 137.85, 73.09, 72.95, 72.81, 69.93, 68.87, 68.15, 61.70, 53.77, 52.62,
137.79, 128.49, 128.46, 128.22, 128.16, 127.91, 127.81, 127.59, 27.44, 26.90. HRMS Calcd for C68H78N7O13 (m/z): 1200.5658
127.50, 101.98 (C-1′), 80.27, 78.89, 74.41, 73.79, 73.61, 72.47, [M + NH4]+, found: 1200.5646.
72.01, 71.40, 68.78, 62.03, 54.67, 52.63, 28.88, 27.16, 20.88.
HRMS Calcd for C36H46N7O9 (m/z): 720.3357 [M + NH4]+,
found: 720.3346.
Acknowledgements
We thank the 863 Program of China (No. 2012AA021505) and
the Natural Science Foundation of China (No. 21332006,
21372130) for financial support; Dr. Jianjun Zhang of CAU for
providing compound 20 (NKT R&D Program of China,
2012BAK25B03).
(2S,5R)-Methyl-2,6-diazido-5-(3,4,6-tri-O-benzyl-
β-D-galactopyranosyloxy)hexanoate (22)
To a solution of 21 (330 mg, 0.47 mmol) in dried MeOH
(10 mL), AcCl (200 μL) was added dropwise. After stirring for
10 h at room temperature, the solvent was evaporated in vacuo
and the residue was purified by flash chromatography
(toluene–ethyl acetate, 20 : 1) to give 22 (256 mg, 0.39 mmol,
85%) as a colorless syrup. Rf = 0.50, (petroleum ether–ethyl
acetate, 2 : 1).
Notes and references
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