Simple modifications of enantiopure 1,2-oxazines leading to building blocks for carbohydrate and peptide mimetics

Article abstract of DOI:10.1055/s-2007-984907

Starting from easily available enantiopure pyran derivatives we prepared bicyclic γ-lactam 6, azide 10, and alkyne 18 using simple procedures. These compounds were crucial intermediates for the synthesis of γ-amino acid 8 and dipeptide 9 as well as triazo

Full text of DOI:10.1055/s-2007-984907

LETTER
2069
Simple Modifications of Enantiopure 1,2-Oxazines Leading to Building Blocks
for Carbohydrate and Peptide Mimetics
M
odifications
h
of Enantiopu
a
re 1,2-Oxa
h
zines la Yekta, Vladimir Prisyazhnyuk, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 24 May 2007
versatile and allows us to generate a wide range of highly
functionalized and diverse compounds with potential
biological activity.
Abstract: Starting from easily available enantiopure pyran deriva-
tives we prepared bicyclic g-lactam 6, azide 10, and alkyne 18 using
simple procedures. These compounds were crucial intermediates
for the synthesis of g-amino acid 8 and dipeptide 9 as well as
triazoles 13, 14, and 19, all containing a carbohydrate-mimicking
aminopyran moiety. The generation of triazoles was particularly
efficient by use of a recently reported modification of the click
reaction.
Bicyclic pyran derivative 4a – obtained via the reduction
of the corresponding ketone 2 with sodium borohydride –
upon hydrogenation in the presence of Pd on charcoal, led
to enantiopure aminopolyol 7 in 80% yield (Scheme 2).3,4
Similarly, hydrogenation of 4b5 with one equivalent of
Boc2O present for in situ protection of the amino group,
afforded aminopyran derivative 5 with three different
protecting groups. Using these simple methods various
substituents or functionalities can be placed at differing
positions of the compounds as desired. The substrates are
therefore excellent precursors for the synthesis of novel
enantiopure amino acids with a carbohydrate-like back-
bone.1b
Key words: pyrans, carbohydrates, peptides, sugar amino acids,
oxidations, 1,3-dipolar cycloadditions
Due to their importance as building blocks, synthetic
targets and biological tools, and their potential as drug
targets, research toward facile and rapid access to carbo-
hydrate and peptide derivatives has taken a crucial role in
organic synthesis.1 We previously reported the stereo-
divergent synthesis of enantiopure 1,2-oxazines such as 1
(Scheme 1) from the [3+3] cyclization of lithiated alkoxy-
allenes and glyceraldehyde-derived nitrones.2 It was
further demonstrated that 4-(2-trimethylsilyl)ethoxy-sub-
stituted 1,2-oxazines undergo Lewis acid mediated re-
arrangements, followed by fragmentation to generate
bicyclic ketones 2 which can be available in gram quan-
tities. The N–O bond cleavage of these compounds leads
to diverse and highly functionalized enantiomerically
pure aminopyrans which are regarded as carbohydrate
mimetics 3.3 Several changes are possible at various
positions on either compound 2 or 3.
We were interested in the oxidation of the remaining
free primary hydroxyl group of 5 to the corresponding
carboxylic acid as a precursor for peptide coupling with
proteinogenic amino acids. All our efforts to perform this
oxidation so far led to g-lactam 6 which is apparently
formed upon in situ cyclization of the Boc-protected
amine with the carbonyl moiety formed during initial
oxidation of the primary alcohol to an aldehyde
(Scheme 2). After screening several reaction conditions,
chromium-mediated oxidation resulted in 79% yield of
g-lactam derivative 6.6
O
OR2
OR1
O
H2, Pd/C,
Boc2O, MeOH,
r.t., 12 h
OR1
R
R
OR1
R
H
H
R
O
O
O
NHBoc
O
OTBS
73%
O
OH
NH2
R
H
N
OH OR2
R
O
Bn
H
N
4a, R1, R2 = H
4b, R1 = TBS, R2 = Bn
5 R1 = TBS, R2 = Bn
O
Bn
N
OH OH
O
Bn
1
3
2
PDC, Ac2O,
DMF, r.t., 12 h
R1 = TMSE (CH2CH2SiMe3)
H2, Pd/C,
MeOH, r.t., 3 d
R1, R2 = H
Scheme 1 Synthesis of enantiopure carbohydrate mimetics 3 from
3,6-dihydro-2H-1,2-oxazines 1
79%
80%
O
OR1
OR2
O
OH
Herein we report a series of simple modifications of our
building blocks that allow rapid access to a variety of
carbohydrate and peptide mimetics. This methodology is
H
H
NH2
N
OH OH
Boc
O
7
6 R1 = TBS, R2 = Bn
SYNLETT 2007, No. 13, pp 2069–2072
Advanced online publication: 17.07.2007
DOI: 10.1055/s-2007-984907; Art ID: G17207ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7
Scheme 2 Synthesis of g-lactam 6 by oxidation of pyran
derivative 5

2070
S. Yekta et al.
LETTER
Hydrolysis of lactam 6 with LiOH in THF and water
smoothly furnished g-amino acid derivative 8 in 87%
yield. Carboxylic acid 8 could then be coupled with L-
alanine methyl ester hydrochloride in the presence of
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate7 (BOP) as an activating agent, using
conditions previously optimized in our group,8 yielding
the desired pyrano-substituted amino acid 9 in 57%
(Scheme 3). When N,N,N¢,N¢-tetramethylfluoroformami-
dinium hexafluorophosphate (TFFH) was used as the
activating agent, under the same reaction conditions, 8
was cyclized to obtain bicyclic lactam 6 as the only ob-
served product.
1) Nf-N3, K2CO3, CuSO4·5H2O
O
O
OAc
N3
OH
MeOH–H2O (1:2), 24 h
2) Ac2O, pyridine, DMAP
57% over two steps
NH2
OAc OAc
OH OH
10
7
alkyne, CuI, TBTA
Et3N, MeCN
Nf = SO2C4F9
alkyne =
40 °C, 24 h
OTMSE
11
12
O
Ph
OAc
N
N
N
OAc OAc
R
13, R = CH2OTMSE
14, R = Ph
93%
89%
O
OR2
OR1
O
OR1
LiOH, THF–H2O,
r.t., 12 h
H
H
O
Scheme 4 Copper-catalyzed cycloadditions of azido derivative 10
with terminal alkynes leading to triazoles 13 and 14
NHBoc
87%
N
OH OR2
Boc
O
6
8
HCl·Ala-OMe, BOP,
i-Pr2NEt, CH2Cl2,
r.t., 12 h
ment of the reaction mixture with sodium thiosulfate to
quench all DMP byproducts, the crude aldehyde was
directly converted into the dibromo-alkene 17 upon
reaction with carbon tetrabromide and triphenylphosphine
(66% yield over two steps).17
R1 = TBS
2 = Bn
R
57%
O
OMe
OR1
NHBoc
H
N
Direct lithiation of 17 with n-butyllithium gave the corre-
sponding alkyne in only 45% yield along with a series of
unidentifiable byproducts. In order to avoid possible nu-
cleophilic attack of the reagent on the carbonyl group, the
ketone was first reduced to the secondary alcohol with so-
dium borohydride (95% yield). Alkyne formation pro-
ceeded smoothly in the presence of n-butyllithium in THF
at –78 °C to give the desired product in 85% yield
(Scheme 5). Protection of the alcohol was therefore not
necessary, however, 3.5 equivalents of the base instead of
2.5 equivalents were used.
O
O
OR2
9
Scheme 3 Synthesis of pyrano-substituted amino ester 9 from
N-Boc-protected amino acid derivative 8
As a second new application of enantiopure carbohydrate
mimetics we wanted to apply the Sharpless–Meldal
variation of the 1,3-dipolar cycloaddition (Huisgen reac-
tion) of an azide with an alkyne providing triazole-linked
moieties.9 Hence, secondary azide 10 was prepared upon
treatment of aminopolyol 7 in the presence of copper
sulfate and nonafluorobutanesulfonyl azide10 (Nf-N3)
followed by in situ acetylation of the hydroxyl groups
with acetic anhydride (Scheme 4).11,12
O
O
O
O
OH
O
Dess–Martin periodinane
CH2Cl2, 0 °C to r.t.
H
H
H
H
N
N
Azide 10 proved to be highly versatile in the Cu(I)-cata-
lyzed [3+2] cycloaddition reactions with alkynes. After
extensive screening, the best reaction conditions were
found to be in the presence of CuI and tris(benzyl-
triazolylmethyl)amine (TBTA)13 in acetonitrile at 40 °C.14
Azide 10 was coupled with alkyne 11 to give the desired
triazole 13 in 93% yield. Similarly, in the presence of
phenyl acetylene 12, cycloadduct 14 was obtained in
excellent yield (Scheme 4).15 The use of aqueous media
afforded considerably lower conversion, presumably due
to poor substrate solubility.
O
Bn
O
Bn
15
16
CBr4, PPh3
CH2Cl2, 0 o
66% over
2 steps
C
O
OH
O
O
Br
1) NaBH4, EtOH
95%
Br
H
H
H
H
2) n-BuLi, THF, –78 °C
N
N
85%
O
Bn
O
Bn
18
17
Scheme 5 outlines the preparation of alkyne derivative 18.
The known alcohol 153 was oxidized with Dess–Martin
periodinane (DMP) to afford aldehyde 16.16 After treat-
Scheme 5 Conversion of enantiopure bicyclic 1,2-oxazinone
derivative 15 into alkynyl-substituted product 18
Synlett 2007, No. 13, 2069–2072 © Thieme Stuttgart · New York

LETTER
Modifications of Enantiopure 1,2-Oxazines
2071
(6) Typical Procedure for the Conversion of 5 into 6
With alkyne 18 and azide 10 in hand, the optimized
cycloaddition reaction in the presence of CuI and TBTA
as shown in Scheme 4 proceeded smoothly to give the
triazole-linked glycoconjugate 19 in excellent yield of
90% (Scheme 6).18 This result is remarkable considering
the high sterical congestion of both substrates.
Alcohol 5 (0.320 g, 0.629 mmol) was dissolved in anhyd
DMF (10 mL), then PDC (0.946 g, 2.52 mmol) and Ac2O
(0.24 mL, 2.5 mmol) were added. The mixture was stirred
for 12 h at r.t. Then, Et2O and H2O were added and the layers
were separated. The organic layer was successively washed
with H2O, dried (MgSO4), and the solvent was removed
under reduced pressure. Purification by column
Since selective deprotection and/or N–O bond cleavage
will allow connection to other substrates by various
methods, compounds such as 19 are versatile intermedi-
ates for the construction of oligosaccharide mimetics.
The 1,2-oxazine-derived aminopyran building blocks
presented in this communication will allow us to synthe-
size a wide range of conjugates with carbohydrates or
carbohydrate mimetics as well as peptides with potential
biological activity.19
chromatography (silica gel, hexane–EtOAc, 4:1 to 1:1)
yielded 0.250 g (79%) of 6 as a colorless solid.
Analytical Data for tert-Butyl (1S,4S,5R,8S)-8-Benzyl-
oxy-4-(tert-butyl-dimethylsiloxymethyl)-2,2-dimethyl-7-
oxo-3-oxa-6-azabicyclo[3.2.1]octane-6-carboxylate (6)
[a]D22 +14.1 (c 1.43, CHCl3); mp 64–65 °C. 1H NMR (500
MHz, CDCl3): d = 0.05, 0.06 (2 s, 3 H each, SiMe), 0.88 (s,
9 H, t-Bu), 1.29, 1.47 (2 s, 3 H each, Me), 1.51 (s, 9 H, t-Bu),
2.43 (dd, J = 1.6, 4.9 Hz, 1 H, 5-H), AB part of ABX system
(dA = 3.57, dB = 3.58, JA–X = JB–X = 6.5 Hz, JA–B = 10.6 Hz,
2 H, 4-CH2), 4.14 (t, J = 6.5 Hz, 1 H, 4-H), 4.15 (t, J = 4.9
Hz, 1 H, 8-H), 4.30 (dd, J = 1.6, 4.9 Hz, 1 H, 1-H), 4.60
(br s, 2 H, CH2Ph) 7.25–7.38 (m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): d = –5.3, –5.1 (2 q, SiMe), 18.1 (s,
t-Bu), 25.9 (q, t-Bu), 24.5, 29.0 (2 q, Me), 28.0 (q, t-Bu),
53.3 (d, C-5), 55.0 (d, C-1), 63.7 (t, 4-CH2), 68.1 (d, C-4),
71.8 (t, CH2Ph), 72.9 (s, C-2), 75.6 (d, C-8), 83.1 (s, t-Bu),
127.5, 128.1, 128.6, 136.8 (3 d, s, Ph), 149.4 (s, NCO2),
170.9 (s, NCO) ppm. IR (KBr): n = 3115–3030 (=C–H),
2955–2855 (C–H), 1790 (C=O), 1720 (NCO2) cm–1. Anal.
Calcd for C27H43NO6Si (505.3): C, 64.12; H, 8.57; N, 2.77.
Found: C, 64.22; H, 8.75; N, 2.78.
O
OH
O
AcO
H
H
N3
N
OAc
OAc
O
Bn
10
18
CuI, TBTA
Et3N, MeCN
40 °C, 24 h
90%
AcO
N
N
(7) (a) Campagne, J.-M.; Coste, J.; Jouin, P. J. Org. Chem. 1995,
60, 5214. (b) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C.
Tetrahedron Lett. 1975, 1219.
O
N
O
OH
(8) Veljkovic, I.; Zimmer, R.; Reissig, H.-U.; Brüdgam, I.;
Hartl, H. Synthesis 2006, 2677.
(9) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565;
Angew. Chem. 1963, 75, 604. (b) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596; Angew. Chem. 2002, 114, 2708.
AcO
H
H
AcO
N
O
Bn
19
Scheme 6 Synthesis of triazole-linked protected disaccharide
mimetic 19
(c) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057.
(10) (a) Zhu, S.-Z. J. Chem. Soc., Perkin Trans. 1 1994, 2077.
(b) Nonafluorobutanesulfonyl azide (Nf-N3) is a substitute
for the typically used trifluoromethanesulfonyl azide. Unlike
the latter, Nf-N3 is not explosive and is stable at r.t.
(11) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett.
1996, 37, 6029.
Acknowledgment
The authors thank the Deutsche Forschungsgemeinschaft, the
Alexander von Humboldt Foundation (post-doctoral fellowship for
SY), the Deutscher Akademischer Austauschdienst (PhD
fellowship for VP), the Fonds der Chemischen Industrie, and the
Schering AG for generous support.
(12) Typical Procedure for the Conversion of 7 into 10
To a solution of amino alcohol 7 (150 mg, 0.73 mmol) in
MeOH–H2O (2:1, 3 mL) at r.t. were added CuSO4·5H2O (18
mg, 0.073 mmol, 1 M solution in H2O) and K2CO3 (101 mg,
0.73 mmol), followed by slow addition of Nf-N3 (475 mg,
1.46 mmol) via syringe. The mixture was stirred for 24 h,
then glycine hydrochloride (554 mg, 5 mmol) was added in
order to quench the reaction mixture and the suspension was
stirred for another 24 h. The mixture was filtered and the
solvents were removed. The crude solid was dissolved in
pyridine (6 mL) and cooled to 0 °C. Then DMAP (3 mg, 0.02
mmol) and Ac2O (0.69 mL, 7.3 mmol) were added and the
mixture was stirred at r.t. for 12 h. The residue was taken up
in Et2O and washed with a 1 M solution of HCl and brine
followed by a sat. solution of NaHCO3. The organic layer
was dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash chromatography (silica gel,
hexane–EtOAc, 9:1 to 6:4) to give 10 (150 mg, 57% over
two steps) as a colorless oil.
References and Notes
(1) (a) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem. Int. Ed.
2001, 40, 1576; Angew. Chem. 2001, 113, 1624.
(b) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H.
Chem. Rev. 2002, 102, 491. (c) Schweizer, F. Angew. Chem.
Int. Ed. 2002, 41, 230; Angew. Chem. 2002, 114, 240.
(2) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
(b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-
Harrasi, A.; Fisera, L.; Hlobilová, I.; Zahn, G.; Reissig, H.-
U. Eur. J. Org. Chem. 2005, 1003.
(3) Al-Harrasi, A.; Reissig, H.-U. Angew. Chem. Int. Ed. 2005,
44, 6227; Angew. Chem. 2005, 117, 6383.
(4) Al-Harrasi, A. Dissertation; Freie Universität: Berlin, 2005.
(5) Compound 4b is obtained by the reduction of the
corresponding TBS-protected ketone (see ref. 3) followed by
protection of the secondary alcohol with BnBr.
Synlett 2007, No. 13, 2069–2072 © Thieme Stuttgart · New York

2072
S. Yekta et al.
LETTER
Analytical Data for (3S,4S,5R,6S)-Acetic Acid 3,6-Bis-
acetoxymethyl-5-azido-2,2-dimethyltetrahydropyran-4-
yl ester (10)
EtOAc, 6:4 to pure EtOAc) to give 14 (18 mg, 90% yield) as
a colorless solid.
Analytical Data for (3S,4S,5R,6S)-Acetic Acid 4-
Acetoxy-6-acetoxymethyl-2,2-dimethyl-5-{4-phenyl-
[1,2,3]triazol-1-yl}tetrahydropyran-3-yl Methylester
(14)
[a]D22 +28.0 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 1.21, 1.37 (2 s, 3 H each, Me), 2.01 (mc, 1 H, 3-H), 2.08
(s, 6 H, COMe), 2.10 (s, 3 H, COMe) 3.60 (dd, J = 2.5, 3.8
Hz, 1 H, 5-H), 4.09–4.19 (m, 4 H, 3-CH2, 6-CH2, 4-H), 4.40
(dd, J = 6.5, 11.4 Hz, 1 H, 3-CH2), 5.35 (dd, J = 4.2, 5.2 Hz,
1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): d = 20.8, 20.9,
21.1 (3 q, COMe), 26.0, 26.3 (2 q, Me), 42.6 (d, C-3), 60.1
(d, C-5), 62.2 (t, 6-CH2), 63.7 (t, 3-CH2), 66.4 (d, C-4), 69.7
(d, C-6), 74.0 (s, C-2), 169.6, 170.6, 170.7 (3 s, CO) ppm. IR
(film): n = 2980–2715 (C–H), 2110 (N3), 1745 (C=O) cm–1.
MS (pos. FAB): m/z = 380 [M + Na]+, 358 [M + H]+. HRMS
(EI): m/z calcd for C13H20N3O6 [M – CH3CO]+: 314.1349;
found: 314.1352.
[a]D22 +75.2 (c 0.25, CHCl3); mp 136–138 °C. 1H NMR (500
MHz, CDCl3): d = 1.39, 1.42 (2 s, 3 H each, Me), 1.98, 2.00,
2.05 (3 s, 3 H each, COMe), 2.37 (mc, 1 H, 3-H), 3.72 (dd,
J = 7.3, 11.8 Hz, 1 H, 6-CH2), 3.81 (dd, J = 5.2, 11.8 Hz, 1
H, 6-CH2), 4.05 (dd, J = 5.2, 11.8 Hz, 1 H, 3-CH2), 4.25 (dd,
J = 5.8, 11.8 Hz, 1 H, 3-CH2), 4.47 (mc, 1 H, 6-H), 5.07 (dd,
J = 5.0, 7.0 Hz, 1 H, 5-H), 5.53 (dd, J = 7.0, 12.3 Hz, 1 H, 4-
H), 7.34 (mc, 1 H, Ph), 7.43 (mc, 2 H, Ph), 7.85 (mc, 2 H, Ph),
7.97 (s, 1 H, triazole) ppm. 13C NMR (125 MHz, CDCl3):
d = 20.6, 20.6, 20.9 (3 q, COMe), 23.5, 25.9 (2 q, Me), 44.3
(d, C-3), 61.2 (t, 3-CH2), 62.0 (t, 6-CH2), 65.2 (d, C-5), 67.9
(d, C-6), 71.8 (d, C-4), 118.3 (d, triazole), 125.9, 128.3,
128.8, 130.2 (3 d, s, Ph), 148.5 (s, triazole), 169.7, 170.2,
170.4 (3 s, CO) ppm. IR (KBr): n = 3030–3135 (=C), 2850–
2975 (C–H), 1745 (C=O) cm–1. HRMS (ESI): m/z calcd for
C23H30N3O6 [M + H]+: 460.2078; found: 460.2091.
(16) Peri, F.; Marinzi, C.; Barath, M.; Granucci, F.; Urbano, M.;
Nicotra, F. Bioorg. Med. Chem. 2006, 14, 190.
(17) Basak, P.; Lowary, T. L. Can. J. Chem. 2002, 80, 943.
(18) For examples of triazole-linked pseudo-oligosaccharides,
see: (a) Hotha, S.; Kashyap, S. J. Org. Chem. 2006, 71, 364.
(b) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007, 9, 1.
(19) These compounds are currently being tested as selectin
binding substrates in collaboration with J. Dernedde, R.
Tauber, Charité–Universitätsmedizin Berlin, CBF,
Zentralinstitut für Laboratoriumsmedizin und
(13) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853.
(14) Groothuys, S.; Kuijpers, B. H. M.; Quaedflieg, P. J. L. M.;
Roelen, H. C. P. F.; Wiertz, R. W.; Blaauw, R. H.; van Delft,
F. L.; Rutjes, F. P. J. T. Synthesis 2006, 3146.
(15) Typical Procedure for the Conversion of 10 into 14
To a solution of azide 10 (15 mg, 42 mmol) and phenyl
acetylene 12 (5.0 mL, 42 mmol) in MeCN (0.78 mL) were
added solutions of Et3N (840 mL, 8.4 mmol, 10 mM solution
in MeCN), TBTA (8.4 mmol, 840 mL of a 10 mM solution in
MeCN), and CuI (8.4 mmol, 840 mL of a 10 mM solution in
MeCN). Argon was bubbled through the mixture for 15 min
and the reaction was stirred for 24 h at 40 °C. Then H2O (5
mL) and EtOAc (5 mL) were added. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(2 × 3 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, hexane–
Pathobiochemie.
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