Synthesis of new C-glycosyl aza-β3-amino acids building blocks

Article abstract of DOI:10.1016/j.tetlet.2012.03.072

New C-glycosylated N^β-protected aza-β³- amino acid building blocks have been prepared from C-glycosyl aldehydes of gluco and galacto configuration by reductive amination and subsequent N-alkylation. These moieties were elaborated to

Full text of DOI:10.1016/j.tetlet.2012.03.072

Tetrahedron Letters 53 (2012) 2702–2705
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new C-glycosyl aza-b3-amino acids building blocks
Manuel Andreini, Anne-Sophie Felten, Hoang-Trang Tran Thien, Claude Taillefumier ,
⇑
Nadia Pellegrini-Moïse, Yves Chapleur
UMR 7565 SRSMC, Nancy Université-CNRS, Groupe S.U.C.R.E.S, BP 239, F-54506 Nancy Vandoeuvre, France
a r t i c l e i n f o
a b s t r a c t
New C-glycosylated Nb-protected aza-b3-amino acid building blocks have been prepared from C-glycosyl
aldehydes of gluco and galacto configuration by reductive amination and subsequent N-alkylation. These
moieties were elaborated to b-dipeptides by elongation at the C- or the N-terminus establishing their
ability to be incorporated in original glycosylated foldamers.
Article history:
Received 7 February 2012
Revised 16 March 2012
Accepted 20 March 2012
Available online 25 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-amino-acid
Aza-b-peptide
C-glycosyl compounds
Chiral building block
Organized molecular structures have always fascinated chem-
ists and the construction of representatives of this class of com-
pounds is still a challenge. Nature offers a number of models of
highly organized molecules among which the helix occupies a
prominent place. This tridimensional folding pattern found in
nucleic acids and in proteins plays an important role in molecular
recognition and in cellular communication. The construction of
artificial oligomers able to adopt such an organized shape without
external help has long been a holy grail. The discovery by Gellman1
and Seebach2 that analogs of amino acids can be assembled into
oligomers, the so-called foldamers,3 showing a strong tendency to
spontaneously arrange in ordered tridimensional structures such
as helices4 has prompted many groups to design such oligomers
and to examine their spatial arrangements. In this regard, b-pep-
tides have been the subject of intense interest, and their oligomers
or mixed oligomers are able to adopt diverse helical structures. It
has been shown that stable 14-, 12-, and mixed 10/12-helices are
formed in short oligomers of acyclic- or cyclic b-amino acids.5 Var-
ious b-amino acid monomers have been used including b-amino-
acids derived from sugars as building blocks.6 In-depth studies by
Sharma et al. showed that 5-amino furanose derived amino acid
oligomers also adopt helical structures.7 We have shown for exam-
ple that small oligomers (6 to 8-mers) of conformationally re-
stricted anomeric b-amino acids8 can adopt organized structures.9
As glycosylation is an important post-translational process which
HO
HO
NH
*
HO
HO
NH
O
O
N
( )n
( )n
CO
CO
HO
OH
HO
OH
II
I
Figure 1. Sugar amino acid building blocks.
seems to play a role in protein structuration, it would be of interest
to examine the behavior of oligopeptides bearing a glucidic part not
necessarily embedded in the peptidic backbone. Organized struc-
tures built with such glycosylated units would be of interest as
glycopeptides mimics10 or as multivalent carbohydrate presenting
structure.
Thus we decided to investigate the creation of new building
blocks incorporating a glucidic part—a glucose or galactose unit
linked to a b-amino-acid by a stable C-glycosidic linkage. Ample
precedents from literature show that a spacer arm of two methy-
lene groups should be suitable.11 (Fig. 1) This sugar b-amino-acid
should retain the properties of a carbohydrate, for example in
recognition process and the properties of the b-amino-acid when
incorporated into an oligomer. If the synthesis of C-glycosidic
a
-amino acids has been thoroughly investigated,11 the synthesis
of C-glycosyl b3-amino-acids (Compound I Fig. 1) remains scarcely
explored,6d and is still challenging mainly due to the difficulty to
create stereoselectively a stereocenter remote from the chiral
sugar template.
⇑
Corresponding author.
E-mail address: yves.chapleur@sucres.uhp-nancy.fr (Y. Chapleur).
Present address: (1) Clermont Université, Université Blaise Pascal, Institut de
Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France. (2) CNRS,
UMR 6296, ICCF, BP 80026, F-63171 Aubiere, France
The use of aza-b3-amino acids12 as a surrogate of amino acids in
the construction of peptidomimetics13 and foldamers14 proved
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.072

M. Andreini et al. / Tetrahedron Letters 53 (2012) 2702–2705
2703
useful. Thus we devised glycosylated aza-b3-amino acids (Com-
pound II Fig. 1). We describe in this Letter the synthesis of these
chiral building blocks and selected dipeptides resulting from their
coupling with b-alanine.
Two biologically significant model sugars were chosen as glyco-
sidic moieties. The first, of b anomeric configuration was derived
BnO
BnO
NHBoc
CO2iPr
O
BnO
N
OBn
6
iv
i
CF3CO2
O
from glucose while the second, of
a anomeric configuration was
BnO
BnO
BnO
BnO
NH3
N
NHBoc
O
derived from galactose. This gave us the opportunity to examine
the influence of the anomeric configuration and two different types
of sugar protecting groups.
BnO
CO2iPr
BnO
COOH
N
OBn
OBn
10
v
7
The known b-C-glucosyl derivative 1 was prepared as a single
anomer from commercially available 2,3,4,6-tetra-O-benzylgluco-
pyranose by a Wittig-type reaction.15 The reduction of the ethyl es-
ter by reaction with DIBAL-H in toluene led to corresponding
aldehyde 2 (Scheme 1). On treatment of 2 with N-tert-buty-
loxycarbonylhydrazine in refluxing toluene, the hydrazone 3 was
formed in 90% yield as a single isomer.16 The reduction of the C–
N double bond with sodium cyanoborohydride afforded the hydra-
zine derivative 4 in excellent yield.17 The N2 alkylation of 4 with
ethyl and isopropylbromoacetates was carried out in toluene in
the presence of K2CO3 leading to 1-tert-butoxycarbonyl-2-carboxy
alkyloxyhydrazine derivatives 5–6 in 82 and 70% yields respec-
tively.18 The deprotection of N1-tert-butyloxycarbonyl group of
the ethyl derivative 5 proved difficult giving a modest yield of
the pure compound. The glycosylated aza-b-aminoester 6 gave bet-
ter results and was selected as the chiral building block for further
peptidic coupling.
The ability of compound 6 to be incorporated in a b-peptidic
chain was then tested by chain elongation either at the C- or at
the N-terminus (Scheme 2). First, compound 6 was converted into
the corresponding hydrazinium salt 7 on exposure to TFA in CH2Cl2
at 0 °C (84% yield). The coupling between 7 and the N-Boc-b-ala-
nine in the presence of isobutylchloroformate and N-methyl mor-
pholine at room temperature led to the desired aza-b-dipeptide 8
in 60% yield.19
ii
O
NHBoc
RO
BnO
BnO
HN
BocNH
N
O
O
O
RO
RO
CO2iPr
BnO
N
NH
OR
OBn
MeOOC
11
8 R = Bn
9 R = H
iii
Scheme 2. Reagents and conditions: (i) TFA, CH2Cl2, 0 °C, 84%. (ii) N-Boc-b-AlaOH,
NMM, IBCF, THF, 60%. (iii) Pd(OH)2/C, H2, CH2Cl2, MeOH, 90%. (iv) KOH, MeOH, 80%.
(v) H-b-Ala-OMe, NMM, IBCF, THF, 73%.
The C-allyl-
commercially available peracetyl-
the major compound (
/b: 9/1).20 Ozonolysis of compound 12 per-
formed in CH2Cl2 gave the -aldehyde 13 in 90% yield (Scheme 3).
The latter was treated with benzyloxycarbonyl-hydrazine to give
the hydrazone compound 14 in 72% yield.16 The hydrazine deriva-
tive 15 was obtained by reduction of 14 in 70% yield.17 In this case,
N-alkylation was carried out with tert-butylbromoacetate giving
the new building block 16 in 68% yield.18
The chain elongation at the C-terminus of 16 was first explored.
Removal of the tert-butyl ester was performed by treatment with
TFA in MeOH (1/1) leading to the corresponding aza-b-aminoacid
17 in quantitative yield. The coupling reaction between 17 and b-
alanine tert-butyl ester21 in the presence of N-methyl-morpholine
a
-galacto derivative 12 prepared by allylation of the
a-D-galactose was obtained as
a
a
The removal of the sugar benzyl groups was tested on com-
pound 8. Catalytic hydrogenation under hydrogen pressure in the
presence of Pd(OH)2/C in a mixture of CH2Cl2/MeOH gave the free
derivative 9 in 90% yield.
For C-terminus expansion, the removal of the isopropyl group of
6 was carried out by treatment with potassium hydroxide in
MeOH. The resulting free acid 10 was coupled with H-b-alanine-
OMe under the above described reaction conditions and led to 11
in 73% yield.
OAc
OAc
AcO
AcO
AcO
AcO
O
O
ii
NHCbz
N
AcO
AcO
X
An analogous sequence of reactions was tested in the
series bearing acetates as hydroxyl protecting groups.
a-galacto
12 X = CH2
13 X = O
14
i
iii
BnO
BnO
BnO
BnO
BnO
OAc
O
OAc
AcO
AcO
O
i
AcO
AcO
O
iv
O
BnO
COOEt
OBn
CHO
NHCbz
NH
OBn
NHCbz
2
3
1
AcO
AcO
N
CO2R
ii
15
16 R = tBu
17 R = H
BnO
BnO
BnO
BnO
BnO
BnO
v
O
iii
O
BocHN
NH
NHBoc
N
OBn
iv
OBn
vi
4
OAc
CO2tBu
AcO
AcO
O
CbzHN
N
HN
BnO
BnO
BnO
AcO
18
O
NHBoc
N
5 R = Et
6 R = iPr
O
OBn
CO2R
Scheme 3. Reagents and conditions: (i) O3, CH2Cl2, ꢀ78 °C, 90%; (ii) CbzHN–NH2,
toluene, reflux, 72%; (iii) NaBH3CN, MeOH, CH2Cl2, 70%; (iv) BrCH2COOtBu, toluene,
K2CO3, 0 °C, reflux for 12 h, 68% ; (v) TFA/MeOH(1/1), quantitative. (vi) H-b-Ala-
OtBu, IBCF, NMM, THF, 50%.
Scheme 1. Reagents and conditions: (i) DIBAL-H, toluene, ꢀ78 °C, 2 h, 83%; (ii)
BocHN–NH2, toluene, reflux, 90%; (iii) NaBH3CN, MeOH, CH2Cl2, 90%; (iv)
BrCH2COOR, toluene, K2CO3, 0 °C, reflux for 12 h, R = Et, 82%, R = iPr, 70%.

2704
M. Andreini et al. / Tetrahedron Letters 53 (2012) 2702–2705
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13
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22
ii
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iv
NHCBz
3''
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v
OAc
2''
AcO
6
OAc
8
AcO
AcO
7
4 O
1''
1'
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1
24
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Scheme 4. Reagents and conditions: (i) SOCl2, MeOH, 0 °C then rt, 12 h, 95%. (ii)
NH2–NH2ꢁH2O, EtOH, reflux, 75%. (iii) Toluene, reflux, 55%. (iv) NaBH3CN, MeOH,
CH2Cl2, quantitative. (v) BrCH2COOtBu, toluene, K2CO3, 0 °C, reflux, 75%.
and isobutylchloroformate was performed at room temperature
and allowed us to obtain compound 18 in 50% yield.
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Whatever the experimental conditions (H2, Pd/C-5%, in MeOH,
EtOAc or THF, and atmospheric pressure), used to remove the
Cbz protecting group of compound 16, an inseparable mixture of
the desired hydrazine and the amino derivative resulting from
the cleavage of the N–N bond was obtained. To overcome this
problem, we reasoned that the b-alanine residue could be intro-
duced first. (Scheme 4). Thus N-benzyloxycarbonyl-b-alanine
hydrazide 21 was prepared starting from the commercially avail-
able N-benzyloxycarbonyl-b-alanine. Compound 19 was converted
to the corresponding methyl ester by treatment with thionyl chlo-
ride in methanol to give 20 which was treated with hydrazine
monohydrate to provide 21 in 75% yield. The treatment of alde-
hyde 13 with 21 in refluxing toluene followed by NaBH3CN reduc-
tion allowed us to obtain the expected derivative 23. Finally,
substitution–alkylation of 23 with tert-butylbromoacetate afforded
the expected aza-b-dipeptide 24.22
New C-glycosyl aza-b3-amino acids have been prepared in a few
steps from commercially available 2,3,4,6-tetra-O-benzyl-
D-gluco-
pyranose and 1,2,3,4,6-penta-O-acetyl- -galactose. Both chiral
D
building blocks have been efficiently coupled at both ends with
properly protected b-alanine derivatives. This allowed the synthesis
of yet unknown glycosylated aza-b-dipeptides. In view of the recent
developments of synthetic molecules able to adopt organized struc-
tures, this study demonstrated that these building blocks could be
easily expanded and led to a new family of hybrid structures con-
taining glycosylated aza-b-amino acids and b-amino acids.
Acknowledgment
We thank F. Dupire and B. Fernette for their skilful technical
assistance.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic data of intermediates and final compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.03.072.
15. Dheilly, L.; Frechou, C.; Beaupere, D.; Uzan, R.; Demailly, G. Carbohydr. Res.
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References and notes
16. General procedure for imine formation: To a stirred solution of Boc- (or Cbz)
carbazate (0.65 mmol) in dry toluene (1.3 mL) was added aldehyde 2 (or 13)
(0.65 mmol). The reaction mixture was heated to 50 °C for 1 h then allowed to
cool to room temperature and stirred for 24 h. The solvent was removed under
vacuum to give a white solid. The crude product was purified by column
chromatography (20% EtOAc/Hexane). Compound 3: Yield: 90% as a colourless
1. (a) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J.
Am. Chem. Soc. 1996, 118, 13071–13072; (b) Appella, D. H.; Christianson, L. A.;
Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, J. J. J.; Gellman, S. H. Nature 1997,
387, 381–384.

M. Andreini et al. / Tetrahedron Letters 53 (2012) 2702–2705
2705
oil. ½a 2D5
ꢂ
+2.8 (c 1.30, CHCl3). IR (thin film, cmꢀ1): 1711, 3249. 1H NMR (CDCl3,
(0.40 mmol) were successively added. The reaction was stirred for 2 h at 0 °C
then refluxed overnight. Filtration and evaporation of the solvent gave the
crude product which was purified by column chromatography (20% EtOAc/
250 MHz): d 1.50 (s, 9H, 3ꢃ CH3), 2.54 (m, 1H, H2a), 2.74 (m, 1H, H2b), 3.28–3.80
(m, 7H, H3, H4, H5, H6, H7, 2ꢃ H8), 4.49–4.91 (m, 8H, 4ꢃ CH2Ph), 7.14–7.38 (m,
20H, HAr), 7.54 (s, 1H, H1). 13C NMR (C3D6O, 62.9 MHz): d 28.0 (3ꢃ CH3), 35.1
(C2), 69.4 (C8), 73.2, 74.7, 74.8, 75.3 (4ꢃ CH2Ph), 77.6 (C3), 78.9 (C6), 79.3
(C(CH3)3), 79.4 (C7), 81.8 (C4), 87.3 (C5), 127.6–128.5 (CAr), 139.0, 139.1, 139.4
(4ꢃ Cipso), 144.0 (C1), 152.7 (C@O). HRMS (ESI+) calculated for C41H48N2O7Na
[M+Na]+: calcd: 703.3354, found:703.3361. Compound 14: Yield: 72% as a
Hexane). Compound 6: Yield: 70% as a colourless oil. ½a D25
ꢀ1.5 (c 1.48, CHCl3).
ꢂ
IR (thin film, cmꢀ1): 2977, 1735, 1455. 1H NMR (CDCl3, 400 MHz): d 1.27 (d, 6H,
J3’-4’ = 6 Hz, 6ꢃ H4’), 1.43 (s, 9H, 3ꢃ CH3), 1.69 (m, 1H, H2a), 2.15 (m, 1H, H2b),
3.01 (m, 1H, H1a), 3.16 (m, 1H, H1b), 3.30 (dd, 1H, J3–4 = 8.5 Hz, J4–5 = 9.5 Hz, H4),
3.40–3.45 (m, 2H, H6, H7), 3.61–3.73 (m, 6H, 2H1’, H3, H5, 2ꢃ H8), 4.54–4.70 (m,
4H, 2ꢃ CH2Ph), 4.83–4.89 (m, 4H, 2ꢃ CH2Ph), 5.08 (m, 1H, H3’), 6.66 (s, 1H, NH),
7.18–7.32 (m, 20H, HAr). 13C NMR (CDCl3, 100 MHz): d 22.3 (C4’), 28.7 (3ꢃ CH3),
30.6 (C2), 53.7 (C1), 58.2 (C1’), 68.7 (C3’), 69.4 (C8), 73.8, 75.2, 75.6, 75.9 (4ꢃ
CH2Ph), 77.6 (C3), 79.1 (C6) 79.3 (C7), 80.2 (C(CH3)3), 89.9 (C4), 87.6 (C5), 127.9–
128.9 (CAr), 138.5, 138.6, 138.7, 139.1 (4ꢃ Cipso), 155.5 (C@O), 170.9 (C2’). HRMS
(ESI+) for C46H59N2O9 [M+H]+: calculated: 783.4215, found: 783.4243.
colourless oil. ½a D25
ꢂ
+46.0 (c 1.00, CHCl3). IR (thin film, cmꢀ1): 1739, 3466. 1H
NMR (CDCl3, 250 MHz) 1.99, 2.03, 2.08, 2.12 (s, 12H, 4ꢃ CH3), 2.52 (ddd, 1H,
J1–2a <1 Hz, J2a-3 = 4.7 Hz, Jgem = 6.2 Hz, H2a), 2.76 (ddd, 1H, J1–2b <1 Hz,
J2b-3 = 4.7 Hz, H2b), 4.03 (dd, 1H, J7–8a = 4.4 Hz, Jgem = 10.8 Hz, H8a), 4.16 (ddd,
1H, J6–7 = 2.9 Hz, J7–8b = 7.3 Hz, H7), 4.26 (m, 1H, H8b), 4.46 (ddd, 1H,
J3–4 = 10.6 Hz, H3), 5.19–5.28 (m, 2H, H4, H5), 5.23 (s, 2H, CH2Ph), 5.43
(pseudo t, 1H, J5–6 = 2.7 Hz, H6), 7.17 (s, 1H, NH), 7.34–7.41 (m, 5H, HAr), 7.98
(dd, 1H, H1), 8.31 (s, 1H, NH). 13C NMR (CDCl3, 62,9 MHz) d 20.7, 20.8, 20.9 (4ꢃ
CH3), 30.2 (C2), 61.3 (C8), 67.4 (CH2Ph), 67.6, 67.9, 68.1, 69.2 (C4, C5, C6, C7), 69.8
(C3), 128.3–128.8 (CAr), 135.8 (Cipso), 143.9 (C1), 153.2, 169.8, 169.9, 170.1,
170.7 (5ꢃ C@O). HRMS (ESI+) for C24H30NaN2O11 [M+Na]+: calculated:
545.1742, found: 545.1753.
Compound 16: Yield 68% as a colourless oil. ½a D25
ꢂ
+41.0 (c 1.10, CHCl3). I.R
(thin film, cmꢀ1):1749, 3412. 1H NMR (CDCl3, 250 MHz):1.47 (s, 9H, 3ꢃ CH3),
1.70 (m,1H, H2a), 1.87 (m, 1H, H2b), 2.05, 2.06, 2.07, 2.13 (4ꢃ s, 12H, 4ꢃ CH3),
2.92 (m, 1H, H1a), 3,10 (m, 1H, H1b), 3.56–3.62 (m, 2H, 2ꢃ H1’), 4.06–4.13 (m,
2H, 2ꢃ H8), 4.25 (m, 1H, H7), 4.44 (m,1H, H3), 5.14 (s, 2H, CH2Ph), 5.17 (dd, 1H,
J4–5 = 9.0 Hz, J5–6 = 3.0 Hz, H5), 5.27 (dd, 1H, J3–4 = 5.0 Hz, H4), 5.41 (m, 1H, H6),
6.97 (s, 1H, NH), 7.33–7.39 (m, 5H, HAr). 13C NMR (CDCl3, 62.9 MHz): 21.1, 21.2,
(4ꢃ CH3), 24.7 (C2), 28.5 (3ꢃ CH3), 53.2 (C1), 59.0 (C1’), 62.0 (C8), 67.3 (CH2Ph),
67.9 (C5), 68.4, 68.6, 69.0 (C4, C6, C7), 70.1 (C3), 82.6 (C(CH3)3), 128.6–129.0
(CAr), 136.6 (Cipso), 156.3, 170.2, 170.3, 170.5 (5ꢃ C@O), 170.9 (C2’). HRMS (ESI+)
for C30H42Na1N2O13 [M+H]+: calculated: 661.2579, found: 661.2572.
17. General procedure for imine reduction: To
a stirred solution of 3 (or 14)
(0.46 mmol) in MeOH/DCM (3/2, 4.5 mL) was added NaBH3CN (0.55 mmol).
The reaction mixture was acidified to pH = 3 by addition of 3 M HCl and stirred
for 30 min after which the pH was adjusted to 1. The reaction was stirred until
completion (monitored by TLC) then quenched with sat. NaHCO3, filtered and
evaporated to dryness. The residue was diluted with EtOAc and washed
successively with water and saturated aq. NaCl. The organic layer was dried
over MgSO4, filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography (30% EtOAc/Hexane).
19. NMR data for compound 8: 1H NMR (CD3OD, 400 MHz): d 1.24 (d, 6H, J3’-4’
=
6.0 Hz, 6ꢃ H4’),1.42, 1.43 (2s, 9H, 3ꢃ CH3), 1.59 (m, 1H, H2a), 2.02 (m, 1H, H2b),
2.21 (m, 1H, H2a’’), 2.45 (m, 1H, H2b’’), 2.09 (m, 1H, H1a), 3.13 (m, 1H, H1b), 3.17–
3.73 (m, 11H, H1a’, H1b’, H3, H3a’’, H3b’’, H4, H5, H6, H7, 2ꢃ H8), 4.48–4.69 (m, 4H,
2ꢃ CH2Ph), 4.75–4.96 (m, 4H, 2ꢃ CH2Ph), 5.02 (m, 1H, H3’), 7.18–7.31 (m, 20H,
Compound 4: Yield 90% as a colourless oil. ½a D25
ꢂ
+30.6 (c 1.10, CHCl3). IR
(thin film, cmꢀ1): 1700, 3249, 3330. 1H NMR (CDCl3, 400 MHz): d 1.43 (s, 9H,
3ꢃ CH3), 1.64 (m, 1H, H2a), 1.98 (m, 1H, H2b), 2.90–3.05 (m, 2H, 2ꢃ H1), 3.26–
3.47 (m, 3H, H4, H7, H8a), 3.58–3.75 (m, 4H, H3, H5, H6, H8b), 4.52–4.68 (m, 4H,
2ꢃ CH2Ph), 4.81–4.97 (m, 4H, 2ꢃ CH2Ph), 6.24 (s, 1H, NH), 7.16–7.37 (m, 20H,
H
Ar). 13C NMR (CD3OD, 100 MHz): d 22.1 (C4’), 28.7, 28.8 (3ꢃ CH3), 30.8 (C2),
35.6 (C2’’), 38.0 (C3’’), 54.0 (C1), 58.9 (C1’), 69.6 (C8), 70.3 (C3’), 74.4, 75.8, 76.1,
76.4 (4ꢃ CH2Ph), 77.8 (C(CH3)3), 78.1 (C3), 79.8, 79.9 (C6, C7), 83.6 (C4), 88.3
(C5), 128.7–129.4 (CAr), 139.4, 139.5, 139.6, 139.9 (Cipso), 158. 2 (C@O), 170.8,
170.9 (C2’), 172.5 (C1’’). HRMS (ESI+) for C49H64N3O10 [M+H]+: calculated:
854.4586, found: 854.4617.
H
Ar). 13C NMR (CDCl3, 100.6 MHz) d 28.3 (3ꢃ CH3), 30.0 (C2), 49.0 (C1), 69.0 (C8),
73.3, 74.9, 75.2, 75.4 (4ꢃ CH2Ph), 78.0 (C3), 78.5 (C6), 78.6 (C7), 80.0 (C(CH3)3),
82.0 (C4), 87.2 (C5), 127.5–128.4 (CAr), 138.0, 138.1, 138.5 (Cipso), 156.6 (C@O).
MS (ES+): m/z = 683 [(M+H)+, 52%], 705 [(M+Na)+, 100%]. Anal. calcd for
20. Cabaret, D.; Wakselman, M. J. Carbohydr. Chem. 1990, 10, 55–63.
21. Ruijtenbeek, R.; Kruijtzer, J. A. W.; Van de Wiel, W.; Fischer, M. J. E.; Fluck, M.;
Redegeld, F. A. M.; Liskamp, R. M. J.; Nijkamp, F. P. ChemBioChem 2001, 2, 171–
179.
C
41H50N2O7: C, 72.12; H, 7.38; N, 4.10, found: C, 71.92; H, 7.19; N, 4.10.
Compound 15: Yield 70% as a colourless oil. ½a D25
ꢂ
+40.1 (c 1.50, CHCl3). I.R (thin
film, cmꢀ1): 1750, 3331. 1H NMR (CDCl3, 250 MHz): 1.64 (m,1H, H2a), 1.84 (m,
1H, H2b), 2.03, 2.04, 2.08, 2.12 (4ꢃ s, 12H, 4ꢃ CH3), 2.91–3.07 (m, 2H, 2ꢃ H1),
4.03–4.13 (m, 2H, 2ꢃ H8), 4.26–4.39 (m, 2H, H3, H7), 5.14 (s, 2H, CH2Ph), 5.19–
5.27 (m, 2H, H4, H5), 5.41 (pseudo t, 1H, J5–6 = 2.6 Hz, J6–7 = 2.6 Hz, H6), 6,05 (s,
1H, NH), 6.37 (s, 1H, NH), 7.32–7.39 (m, 5H, HAr). 13C NMR (CDCl3, 62.9 MHz):
20.8, 20.9, 21.0 (4ꢃ CH3), 24.5 (C2), 48.4 (C1), 61.5 (C8), 67.2 (CH2Ph), 67.5, 68.0,
68.4, 68.8 (C4, C5, C6, C7), 70.3 (C3), 128.3–128.7 (CAr), 136.1 (Cipso), 157.4, 169.9,
170.1, 170.8 (5ꢃ C@O). Anal. calcd for C24H33N2O10: C, 54.96; H, 6.15; N, 5.34,
found: C, 54.91; H, 6.36; N, 6.60. HRMS (ESI+) for C24H33N2O11 [M+H]+:
calculated: 525.2079, found: 525.2087.
22. NMR data for compound 24: 1H NMR (CD3OD, 250 MHz): 1.44 (s, 9H, 3ꢃ CH3),
1.65–1.68 (m, 2H, 2ꢃ H2), 2.01, 2.03, 2.08, 2.10 (s, 12H, 4ꢃ CH3), 2.30–2.36 (m,
2H, 2ꢃ H1), 2.84–2.87 (m, 2H, 2ꢃ H2’’), 3.39–3.44 (m, 2H, 2ꢃ H3’’), 3.56–3.58 (m,
2H, 2ꢃ H1’), 4.01–4.42 (m, 4H, H3, H7, 2ꢃ H8), 5.07 (s, 2H, CH2Ph), 5.01–5.23 (m,
2H, H4, H5), 5.37 (s, 1H, H6), 7.23–7.48 (m, 5H, HAr). 13C NMR (CD3OD,
100 MHz): 20.5, 20.6, 20.7, 20.8 (4ꢃ CH3), 25.1 (C2), 28.4 (3ꢃ CH3), 35.6 (C2’’),
38.4 (C3’’), 53.6 (C1), 59.7 (C1’), 62.6 (C8), 67.4 (CH2Ph), 69.1 (C6), 69.4 (C4), 69.6
(C5), 69.7 (C7), 71.1 (C3), 82.8 (C(CH3)3), 128.8–129.5 (CAr), 138.3 (Cipso), 158.7
(C@O), 170.8 (C2’), 171.5, 171.6, 171.9, 172.3 (4ꢃ C@O), 172.5 (C1’’). HRMS
(ESI+) for C33H47Na1N3O14 [M+Na]+: calculated: 732.2950, found: 732.2952
18. General procedure for N2-alkylation: A solution of 4 (or 15) (0.31 mmol) in dry
toluene (3.0 ml) was cooled to 0 °C. K2CO3 (0.31 mmol) and alkyl bromoacetate