Novel glycine like amino acids from glyco-α-aminonitriles as building blocks for peptide synthesis

Article abstract of DOI:10.1016/j.tetasy.2007.11.038

Our interest in the glycoaminocyanation reaction led us to apply this methodology to introduce amino acids on a monosaccharide using the N-terminal position. The GAAs described in this paper are characterized by having the amino and carboxylic acid functionalities on a disubstituted position of the saccharide backbone leading to α,α-disubstituted glycines. These new sugar amino acids showed a restricted conformation involving a spontaneous intramolecular cyclization between the C- and N-terminal positions during hydrolysis or hydrogenolysis to give the corresponding oxopiperazine. Tripeptide mimics were obtained by the introduction of an additional amino acid using one-pot conditions starting from these cyclic by-products under basic media. We demonstrated that these pseudo tripeptides are good candidates for extension of the peptidic scaffold and cyclization.

Full text of DOI:10.1016/j.tetasy.2007.11.038

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 67–81
Novel glycine like amino acids from glyco-a-aminonitriles as
building blocks for peptide synthesis
*
`
´
Helene Ducatel, Albert Nguyen Van Nhien and Denis Postel
Laboratoire des Glucides, UMR 6219, Universite´ de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
Received 30 October 2007; accepted 30 November 2007
Available online 26 December 2007
Abstract—Our interest in the glycoaminocyanation reaction led us to apply this methodology to introduce amino acids on a monosac-
charide using the N-terminal position. The GAAs described in this paper are characterized by having the amino and carboxylic acid
functionalities on a disubstituted position of the saccharide backbone leading to a,a-disubstituted glycines. These new sugar amino acids
showed a restricted conformation involving a spontaneous intramolecular cyclization between the C- and N-terminal positions during
hydrolysis or hydrogenolysis to give the corresponding oxopiperazine. Tripeptide mimics were obtained by the introduction of an addi-
tional amino acid using one-pot conditions starting from these cyclic by-products under basic media. We demonstrated that these pseudo
tripeptides are good candidates for extension of the peptidic scaffold and cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
[3,3]-sigmatropic rearrangement of an allylic thiocyanate.25
Moreover, the synthesis of unnatural glycopeptides was
extensively studied. In this case, the amino acid functional-
ity was implemented on the anomeric position.
Among the natural products, amino acids and carbohy-
drates are two of the most potent compounds for biological
interactions. Over the last decade, an increased interest in
unnatural a-amino acids has been noted in the litera-
ture.1–5 Such compounds have been used to study enzy-
matic reaction mechanisms and as optically active
starting materials for a variety of synthetic applications.
Hybrids of sugars and amino acids (SAAs), also termed
as glycosamino acids (GAAs), are molecules that combine
the structural features of simple amino acids (amino and
carboxylic acid functions) with those of simple carbohy-
drates (cyclic polyols, which may contain additional acet-
amido or amino functions).1,6 The resulting hybrid is a
highly substituted polyfunctionalized monomer, which
can be used for the synthesis of compound libraries by
means of combinatorial synthesis.7,8 This class of confor-
mationally restricted building block has been used exten-
sively for the preparation of unnatural glycopeptides,9–14
oligomer, and foldamers15–19 or cyclic peptides and macro-
cycles,20–22 among others. Their predisposition to induce
novel secondary structures is well established.21,23,24
2. Results and discussion
In keeping with our earlier work, we have studied the scope
and limitations of the aminocyanation reaction26–30 to
elaborate glycopeptide mimics by introducing an a-amino
acid segment onto a saccharide moiety such that the N-
terminal group is directly linked to a sugar carbon atom
(amino sugar–amino acid hybrid) (Fig. 1).
R1O
O
OR2
H2N
OR2
HOOC
NH
AA
Figure 1. General structure of target glycoamino acids.
Thus, L- and D-amino acids were first protected by conver-
sion into their methyl esters using classical conditions
[(MeO)2C(Me)2; HCl; H2O] and then stereoselectively cou-
pled with uloses 1, 2, and 3 using our aminocyanation pro-
cedure, which employs Ti(OiPr)4 as a mild and effective
´
Recently Martinkova described a novel furanoid a-substi-
tuted amino acid as a potent b-turn mimic, applying a
*
Corresponding author. E-mail: denis.postel@sc.u-picardie.fr
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.038

68
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
Lewis acid (Scheme 1).26–30 Relatively low yields of the a-
substituted L-amino acid derivatives 5–10, 12, and 14
(15–31%) were obtained. In contrast, higher yields were
afforded for the glycine derivatives 4, 11, and 13 (56%,
53%, and 78%, respectively) and of the phenylalanine
derivative 15 (57%).
and D-phenylalanine in 40% and 62%, respectively (vs
30% and 40% in the L-series). These differences in the reac-
tivity could be attributed to an enhancement of the steric
constraint on the Ti-complexed transition state induced
by the a- substituent for the L- versus the D-series (Fig. 3).
-CN
O
O
O
-CN
O
O
O
H
i) ii)
R
O
O
Ti
Ti
NC
O
O
O
NH
O
O
L- series
R2OOC
D- series
R
4-10
H
1
R1
H3CO
H3CO
Figure 3.
4- R1= H, R2=CH3 (56%)
5- R1= CH3, R2=CH3 (18%)
6- R1= CH2CH(CH3)2, R2=CH3 (20%)
7- R1= CH2CH2SCH3, R2=CH3 (16%)
8- R1= CH2CH2COOCH3, R2=CH3 (15%)
9- R1= CH2Ph, R2=CH3 (30%)
10-R1= H, R2=tBu (35%)
To extend the peptidic scaffold, selective reduction of the
CN group of compounds 4–15 with NaBH4–CoCl2 was
effected.
R2O
R2O
O
In all cases, the derivatives were obtained, which cyclized
spontaneously to the corresponding oxopiperazines 20–29
with good yield (Scheme 2). Removal of CoII derivatives
was achieved by filtration through a silica gel pad. Com-
pound 20 was also obtained (82%) from t-butyl ester pro-
tected amino acid derivative 10 that is less prone to
aminolysis (Scheme 2).
O
i) ii)
O
O
NC
O
O
O
NH
H3COOC
2 (R3 =Trt)
3 (R3 = Bn)
11-15
R1
11- R1= H, R2= Bn (63%)
12- R1= CH2CH(CH3)2, R2= Bn (20%)
13- R1= H, R2=Trt (78%)
To avoid spontaneous intramolecular aminolysis aided by
the formation of a stable piperazine ring, we chose to use
the dipeptide glycylglycine instead of a monomeric amino
acid. Thus, the corresponding glycopeptidonitrile 30 was
obtained from 1 in 38% yield. Selective reduction of the
cyano group of 30 was achieved in the same fashion as used
for 4–15. Contrary to previous experiments, the CoII–
glycopeptide complex appeared to be relatively stable, such
that filtration through a layer of silica gel was found to be
inefficient in removing the cobalt moiety. However, extrac-
tion using aqueous HCl (5 M) resulted in cyclization to give
piperazine 20 in low yield (34%). These results demonstrate
the effective and selective reduction of the cyano group
without affecting the carbonyl group and the capability
of the subsequent amines to efficiently cyclize and to give
the required piperazine derivative. A hypothesis for the
high reactivity is the formation of a cobalt–amino acid
complex involving the oxygen and nitrogen atoms of the
same amino acid unit. Displacement of the peptide deriva-
tive from the complex by adding KCN followed by extrac-
tion into CHCl3 led successfully to the amino glycopeptide
31 in 35% yield. Nevertheless, 31 gave piperazine 20 quan-
titatively by silica gel chromatography (Scheme 3).
14- R1= CH3, R2=Trt (31%)
15- R1= CH2Ph, R2=Trt (57%)
Scheme 1. Reagents and conditions: (i) Ti(OiPr)4 (1.2 equiv), R2OOC–
CHR1–NH2ꢀHCl, TEA (1.1 equiv), MeOH (24 h); (ii) TMSCN (1 equiv)
(12 h).
Many attempts involving modifications in the equivalents
of aminoacid, the nature and equivalents of Lewis acid
[Ti(OiPr)4, TiCl4] and/or an excess of amino acids, the sol-
vents (MeOH, CH3CN, Et2O, CH2Cl2) and an increasing
temperature did not permit an improvement in the yield.
D-Amino acids led to better reactivities (Fig. 2).
R2
O
O
NC
O
NH
H3COOC
R1
(L- series)
(D- series)
O
O
5- R1 = CH3 (18%)
16- R1 = CH3 (33%)
R2=
9- R1 = CH2Ph (30%) 17- R1 = CH2Ph (40%)
To circumvent the oxopiperazine formation, the reduction
step was carried out in the presence of an acylating agent
(Boc2O or Ac2O) to quench the amino methyl ester as a
carbamate or an amide. Under these conditions, compound
4 yielded the N-Boc and N-Ac compounds 32 and 33 in
54% and 45% yield, respectively. Oxopiperazine 20 was
additionally formed in 33% yield using the acetylating con-
ditions. Finally, the replacement of Boc2O/Ac2O by an
14- R1 = CH3 (31%)
18- R1 = CH3 (58%)
R2= CH2OTrt
Figure 2.
15- R1 = CH2Ph (57%) 19- R1 = CH2Ph (62%)
Thus, D-alanine was introduced on uloses 1 and 2 in 33%
and 58%, respectively (vs 18% and 31% in the L-series)

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
69
R2
R2
O
O
O
O
a)
NC
HN
O
O
O
NH
R1
NH
R1
MeOOC
R2 = CH2OBn
O
O
20- R1= H, (78%)
26- R1= H (54%)
R2 =
21- R1= CH3 (75%)
27- R1= CH2CH(CH3)2 (69%)
22- R1= CH2CH(CH3)2 (70%)
23- R1= (CH2)2SCH3 (75%)
24- R1= (CH2)2COOCH3 (67%)
25- R1= CH2Ph (56%)
R2 = CH2OTrt
28- R1= H (60%)
29- R1= CH3 (50%)
Scheme 2. Reagents and conditions: (a) CoCl2ꢀ4H2O (2 equiv), NaBH4 (10 equiv), MeOH (30 min).
Piperazines 21–25 were unreactive under the same condi-
tions or using Ba(OH)2, known to be efficient for the
hydrolysis of spirohydantoin rings.28 Surprisingly, acidic
displacement (IRA 120) of 35 to get the corresponding car-
boxylic acid 36 yielded the starting oxopiperazine 20
(Scheme 5). This phenomenon was also observed when
we realized the hydrolysis of 4 to 37 (89%) followed by a
subsequent hydrogenation step using H2–Pd/C. Spiro oxo-
piperazine 20 was formed in 59% and 83% yield, respec-
tively, using AcOEt or MeOH as solvent (Scheme 6).
O
O
O
O
O
O
O
O
a
c
1
H2N
NC
O
O
O
O
NH
31 (35%)
NH
N
H
OMe
N
30 (38%)
O
O
H
OMe
d
b
20
(34%) from b
O
O
O
O
(quantitative) from c
O
O
a)
b)
O
Scheme 3. Reagents and conditions: (a) (i) Ti(OiPr)4 (1.2 equiv) MeOOC-
Gly-Gly-NH2, HCl (1.1 equiv), TEA (1.1 equiv), MeOH; (ii) TMSCN
(1 equiv); (b) (i) CoCl2ꢀ4H2O (3 equiv), NaBH4 (10 equiv), MeOH; (ii)
HCl (0.5 M); (c) (i) CoCl2ꢀ4H2O (3 equiv), NaBH4 (10 equiv), MeOH; (ii)
KCN, H2O; (d) silica gel chromatography.
O
20
H2N
-OOC
H2N
HOOC
O
O
NH
NH
R1
35 R1= H (quantitative)
R1
36 R1= H
amino acid anhydride such as L-glycine symmetrical anhy-
dride [N-Z-Gly; DDC (0.5 equiv); CH2Cl2; 0 °C; 65%] gave
the target compound 34 in modest yield (18%) together
with oxopiperazine 20 (56%) (Scheme 4).
Scheme 5. Reagents and conditions: (a) NaOH (3 N) dioxane–H2O, reflux
(12 h); (b) IR 120 resin.
Because of his stability in basic media, carboxylate 35 has
been exploited as an intermediate to introduce further ami-
no acid units. When 20 was treated with NaOH (3 equiv)
and p-nitrophenyl esters of amino acids (Gly; Ala; Leu;
Phe), the tripeptide mimic compounds 38–41 were obtained
in 42–56% yield. Starting from 38, methylated L-alanine
was coupled using DCC to afford the pseudotetrapeptide
42 in 67% yield (Scheme 7).
This poor result prompted us to explore the route to syn-
thesize the target compounds starting from the oxopiper-
azine. Firstly, the hydrolysis of the spiro-ring was
performed from 20 using aqueous NaOH (3 equiv) in
refluxing dioxane/H2O mixture overnight. Acyclic sodium
carboxylate 35 was formed exclusively from 20 in quantita-
tive yield (Scheme 5).
O
O
O
O
O
O
a)
O
O
R
+
20 (33-56%)
N
H
NC
O
O
O
O
NH
NH
MeO
MeO
4
32 R= Boc (54%)
33 R= Ac (45%)
34 R= ZNHCH2C(O) (18%)
Scheme 4. Reagents and conditions: (a) CoCl2ꢀ4H2O (2 equiv), Boc2O, Ac2O or (ZNH-Gly-CO)2O (3 equiv), MeOH and then NaBH4 (10 equiv).

70
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
O
O
O
O
O
O
O
O
O
a
b
O
O
O
NaOH (1M)
H2, Pd/C, solvent
O
42
NC
4
20(44-71%)
O
NH
O
N
H
O
dioxane, 1 hr
O
O
HN
NH
H2N
NH
CH3
HO
37 (89%)
HN
O
HN
CH3
N
H
O
HOOC
44
(56%)
43
quantitative
Scheme 6. Reagents and conditions: (a) NaOH (1 M), dioxane (40 min);
(b) H2, Pd/C MeOH or AcOEt (12 h).
O
Scheme 8. Reagents and conditions: (a) (i) K2CO3, MeOH, H2O; (ii) H2,
Pd/C MeOH or AcOEt (12 h); (b) DPPA (1.2 equiv), TEA (2 equiv),
DMF.
Expecting to benefit from the spontaneous cyclization be-
tween the N-terminal position and the methyl ester group
previously observed in the formation of the oxopiperazine,
we afforded the cleavage of the benzyloxycarbonyl protect-
ing group. Hydrogenolysis of 42 followed by deprotection
of the C-terminal position quantitatively gave 43, which
cyclized using DPPA as a coupling agent to give the cyclic
pseudotetrapeptide 44 in 56% yield (Scheme 8).
3. Conclusion
In conclusion, we have demonstrated that a-amido nitriles
derived from sugar templates are key intermediates for
accessing restricted disubstituted glycine like compounds.
A series of L- and D-amino acids have been used to explore
the scope and limits of the aminocyanation reaction. Fur-
thermore, extension on the C- and N-terminal position
was achieved to obtain acyclic and cyclic pseudotetrapep-
tide. Further works concerning the synthesis of cyclic pep-
tides incorporating SAAs are currently in progress and will
be reported in due course.
Removal of the isopropylidene groups in 38 and 42–44 un-
der classical conditions (TFA/H2O 9:1) gave pseudotripep-
tide 45, acyclic pseudo tetrapetide 46, 47 and cyclic
tetrapeptide 48 in 92% to quantitative yields.
OH
OH
O
O
HO
O
O HO
4. Experimental
OH
N
N
OH
ZHN
H3C
OH
ZHN
H
H
NH
OH
NH
O
Melting points were determined on a digital melting point
apparatus (Electrothermal) and are uncorrected. Optical
rotations were recorded in CHCl3, H2O with a digital
polarimeter model 343 (Perkin Elmer) using a 1 mL cell.
1H NMR and 13C NMR spectra were recorded in CDCl3,
MeOD-d3, Me2SO, D2O (internal Me4Si), respectively, at
300.13 MHz and at 75.47 MHz (Bruker Avance-300).
TLC was performed on Silica F254 (Merck) and detection
by UV light at 254 nm or by charring with phosphomolyb-
dic acid–H2SO4 reagent. Column chromatography was ef-
fected on Silica Gel 60 (Merck, 230 mesh). Elemental
analyses have been carried out in Madrid (IQOG, CSIC).
46
(92%)
45
NH
HOOC
qunatitative
MeOOC
OH
OH
O
O
HO
NH
HO
O
CF3COO-
+H3N
O
N
OH
OH
OH
HN
HN
H
OH
NH
O
H3C
HOOC
HN
NH
O
48
(94%)
47
(92%)
O
CH3
O
O
O
O
O
O
O
O
O
O
a)
b)
20
N
H
N
O
O
ZHN
ZHN
NH
H
NH
R
HO
38 -R =H (56%)
O
HN
Me
O
O
42 (67%)
MeO
39 -R CH (49%)
=
3
40
41
=
-R CH2CH(CH3)2 (42%)
-R CH Ph (44%)
=
2
Scheme 7. Reagents and conditions: (a) NaOH (3 equiv), H2O–dioxane, ZNH-gly-CO–O–Ph–NO2 (1.2 equiv); (b) L-Ala-OMe (2 equiv), DCC (2 equiv),
N-hydroxysuccinimide (2 equiv), DMF, MeCN ꢁ10 °C to ambient temperature (24 h).

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
71
13C NMR resonances have been assigned by using stan-
dard NMR (DEPT, COSY, HSQC) experiments. FTIR
spectra were obtained on an AVATAR 320 neat using
ATR and are reported in cmꢁ1. Mass spectral data were ac-
quired on a WATERS Micromass ZQ spectrometer or a
WATERS Micromass Q-TOFF spectrometer.
4.5. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-[[(S)-
1-(methoxycarbonyl)ethyl] amino]-a-D-allofuranose 5
Following General Method A, 1 (0.6 g, 2.32 mmol),
L-MeOOCCH(CH3)NH2 (0.35 g, 2.51 mmol), TEA (0.36
mL, 2.50 mmol), and TMSCN (0.31 mL, 2.32 mmol) in
MeOH (5 mL) gave after flash chromatography (EtOAc/
4.1. General procedure for esterification of amino acids
hexane, 2:8) compound 5 (0.10 g, 18%) as a colorless syrup:
25
½aꢂD ¼ þ8:8 (c 1.09; CHCl3); IR (ATR): m 2988, 2901, 1740,
To a solution of amino acid (20 mmol) in 2,2-dimethoxy-
propane was added concentrated HCl (20 mL) dropwise.
The reaction mixture was stirred at room temperature
overnight and then evaporated to dryness. To the residue
was added a small amount of MeOH and Et2O (250 mL).
After one night at ꢁ4 °C, the crude was filtered to afford
the methyl protected aminoacids as the corresponding
hydrochloride salt.
1375, 1255, 1216, 1166, 1075, 1045 cmꢁ1 1H NMR
;
(CDCl3) d 5.83 (d, 1H, H-1, J1,2 3.6 Hz), 4.71 (d, 1H, H-
2), 4.28 (ddd, 1H, H-5, J5,6b 6.3 Hz), 4.10 (dd, 1H, H-6b,
J6a,6b 8.9 Hz), 3.96 (dd, 1H, H-6a, J5,6a 4.6 Hz), 3.81 (d,
1H, H-4, J5,4 8.1Hz), 3.77 (m, 1H, CH(ala)), 3.67 (s, 3H,
OCH3), 2.50 (s, 1H, NH), 1.49 (s, 3H, CH3), 1.40 (s, 3H,
CH3), 1.34 (d, 3H, CH3(ala), JH;CH ðalaÞ 7.0 Hz), 1.31 (s,
3
3H, CH3), 1.29 (s, 3H, CH3); 13C NMR (CDC13) d 174.8
(C@O), 117.2 (CN), 113.5 (CH3CCH3), 109.8 (CH3CCH3),
104.0 (C-1), 82.6 (C-2), 81.6 (C-4), 74.6 (C-5), 67.1 (C-6),
66.8 (C-3), 53.6 (CHNH), 51.9 (OCH3), 26.4 (CH3), 26.3
(CH3), 26.2 (CH3), 24.8 (CH3), 19.0 (CH3(ala)); HRMS:
calcd [M+Na]+ 393.1638; found, 393.1634. Anal. Calcd
for C17H26N2O7 (370.40 g/mol): C, 55.13; H, 7.08; N,
7.56. Found: C, 55.42; H, 6.95; N, 7.64.
4.2. General procedure for a-aminocyanation A
Ti(OiPr)4 (1.2 equiv) was added to a solution of ulose
derivative (1 equiv), H3COOC–CHR–NH2 (1.1 equiv) and
triethylamine (1.1 equiv) in MeOH. The reaction mixture
was stirred at room temperature for 5 h, and then TMSCN
(1 equiv) was added and the reaction mixture stirred for
12 h. A few drops of water and EtOAc were added until
oxidation of the titanium residue was complete. The sol-
vent was evaporated to dryness and the crude product
was purified by flash chromatography (EtOAc/hexane).
4.6. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-[[(S)-
1-(methoxycarbonyl)-3-methyl butyl]amino]-a-D-allofura-
nose 6
Following General Method A, 1 (1.06 g, 4.11 mmol), L-
MeOOCCH[CH(CH3)2]NH2 (0.89 g, 4.93 mmol), TEA
(0.69 mL, 4.93 mmol), and TMSCN (0.55 mL, 4.11 mmol)
in MeOH (8 mL) gave after flash chromatography (EtOAc/
4.3. General procedure for oxopiperazine synthesis B
To
a solution of compounds 20–25 (1 equiv) and
CoCl2ꢀ4H2O (2 equiv) in MeOH was added NaBH4
(10 equiv) portionwise. After stirring for 30 min, the reac-
tion mixture was filtered through a silica pad until decolor-
ization of the filtrate. The solvent was eliminated under
vacuum and the crude was purified by flash chromatogra-
phy (EtOAc/hexane).
hexane, 2:8) compound 6 (0.34 g, 20%) as a colorless syrup;
20
½aꢂD ¼ ꢁ2:0 (c 1.00, CHCl3); IR (ATR): m 2987, 2955, 1738,
1374, 1253, 1216, 1166, 1075, 1028 cmꢁ1
;
1H NMR
(CDCl3) d 5.89 (d, 1H, H-1, J1,2 3.5 Hz), 4.73 (d, 1H, H-
2), 4.35 (ddd, 1H, H-5, J5,6b 6.2 Hz), 4.2 (dd, 1H, H-6b,
J6a,6b 8.8 Hz), 3.98 (dd, 1H, H-6a, J5,6a 5.5 Hz), 3.93 (d,
1H, H-4, J5,4 7.9 Hz), 3.76 (s, 3H, OCH3), 3.74 (m, 1H,
CHNH), 2.59 (d, 1H, NH, JNH,CH 5.5 Hz), 1.68 (m, 1H,
4.4. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-
[[(methoxycarbonyl)methyl]amino]-a-D-allofuranose 4
CH), 1.60 (d, 2H, CH2 JCH;CH 7.1 Hz), 1.56 (s, 3H,
2
CH3), 1.45 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.35 (s, 3H,
Following General Method A, 1 (4.0 g, 16 mmol), MeO-
OCCH2NH2 (2.2 g, 18 mmol), TEA (2.47 mL, 18 mmol),
and TMSCN (2.15 mL, 16 mmol) in MeOH (33 mL) gave
CH3), 0.98 (d, 3H, CH3, JCH;CH 1.3 Hz), 0.96 (d, 3H,
3
CH3 JCH;CH 1.3 Hz); 13C NMR (CDCl3) d 175.2 (C@O),
3
117.6 (CN), 114.3 (CH3CCH3), 110.5 (CH3CCH3), 104.8
(C-1), 83 (C-2), 81.7 (C-4), 75.2 (C-5), 68.7 (C-3), 67.9
(C-6), 57.8 (CHNH), 52.4 (OCH3), 42.6 (CH2), 26.8
(3 ꢃ CH3), 25.5 (CH3), 25.0 (CH), 23.2 (CH3CH), 22.6
(CH3CH); HRMS: Calcd. [M+Na]+ 435.2107; found,
435.2092. Anal. Calcd for C20H32N2O7 (412.22 g/mol): C,
58.24; H, 7.82; N, 6.79. Found: C, 58.10; H, 7.57; N, 6.71.
after flash chromatography (EtOAc/hexane, 2:8) com-
25
pound 4 (3.17 g, 56%) as a colorless syrup: ½aꢂD ¼ þ30:8
(c 1.20; CHCl3); IR (ATR): m 2927, 1748, 1375, 1255,
1
1260, 1141, 1059 cmꢁ1; H NMR (CDCl3) d 5.85 (d, 1H,
H-1, J1,2 3.6 Hz), 4.66 (d, 1H, H-2), 4.30 (ddd, 1H, H-5,
J5,6b 6.1 Hz), 4.11 (dd, 1H, H-6b, J6a,6b 9.0 Hz), 3.96 (dd,
1H, H-6a, J5,6a 4.0 Hz), 3.84 (d, 1H, H-4, J5,4 9.0 Hz),
3.70 (s, 3H, OCH3), 3.58 (s, 2H, CH2NH), 2.93 (s, 1H,
NH), 1.50 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.31 (s, 3H,
CH3), 1.29 (s, 3H, CH3); 13C NMR (CDCl3) d 170.9
(C@O), 117.1 (CN), 114.1 (CH3CCH3), 110.3 (CH3CCH3),
104.4 (C-1), 82.5 (C-2), 80.8 (C-4), 75.0 (C-5), 68.0 (C-3),
67.6 (C-6), 52.1 (OCH3), 46.5 (CH2NH), 26.6 (2 ꢃ CH3),
26.5 (CH3), 24.9 (CH3); MS (ES) [M+Na]+ 379.16. Anal.
Calcd for C16H24N2O7 (356.37 g/mol): C, 53.92; H, 6.79;
N, 7.86. Found: C, 52.75; H, 6.24; N, 7.54.
4.7. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-[[(S)-
1-(methoxycarbonyl)-3-methyl thio-propyl]amino]-a-D-allo-
furanose 7
Following General Method A, 1 (1.06 g, 4.11 mmol), L-
MeOOCH(CH2SCH3)NH2 (0.98 g, 4.93 mmol), TEA
(0.69 mL, 4.93 mmol), and TMSCN (0.55 mL, 4.11 mmol)
in MeOH (8 mL) gave after flash chromatography (EtOAc/
hexane, 2:8) compound 7 (0.28 g, 16%) as a colorless syrup;

72
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
20
½aꢂD ¼ þ8:0 (c 1.60, CHCl3); IR (ATR): m 2988, 2936, 1739,
H-b, JHb,CH 8.2 Hz), 2.72 (1H, NH, JNH,CH 4.9 Hz), 1.54
(s, 3H, CH3), 1.32 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.24
(s, 3H, CH3); 13C NMR (CDCl3) d 174.1 (C@O), 136.0
(Cq), 129.8, 129.0, 127.5 (5C, Ph), 117.4 (CN), 114.3
(CH3CCH3), 110.5 (CH3CCH3), 104.8 (C-1), 83.0 (C-2),
81.8 (C-4), 75.0 (C-5), 68.7 (C-3), 67.9 (C-6), 60.1 (CH),
52.5 (OCH3), 39.2 (CH2), 26.7 (CH3), 26.9 (CH3), 26.8
(CH3), 25.3 (CH3); MS (ES) [M+Na]+ 469.4; [M+K]+
485.3, [2M+Na]+ 915.4. Anal. Calcd for C23H30N2O7
(446.21 g/mol): C, 61.87; H, 6.77; N, 6.27. Found: C,
61.59; H, 6.56; N, 6.01.
1375, 1253, 1217, 1165, 1076, 1028 cmꢁ1 1H NMR
;
(CDCl3) d 5.90 (d, 1H, H-1, J1,2 3.7 Hz), 4.77 (d, 1H, H-
2), 4.37 (ddd, 1H, H-5, J5,6b 6.2 Hz), 4.19 (dd, 1H, H-6b,
J6a,6b 8.8 Hz), 4.01 (dd, 1H, H-6a, J5,6a 5.4 Hz), 3.84 (m,
2H, CH, H-4, J5,4 7.4 Hz), 3.76 (s, 3H, OCH3), 2.6 (m,
3H, NH, CH2S), 2.11 (s, 3H, SCH3), 2.09 (m, 1H, H-a),
1.92 (m, 1H, H-b (CH–CH2(a,b))), 1.55 (s, 3H, CH3), 1.46
(s, 3H, CH3), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C
NMR (CDCl3) d 174.7 (C@O), 117.6 (CN), 114.2
(CH3CCH3), 110.5 (CH3CCH3), 104.6 (C-1), 83.1 (C-2),
82.4 (C-4), 75.0 (C-5), 67.8 (C-3), 67.6 (C-6), 58.0 (CH),
52.6 (OCH3), 33.2 (CH2), 30.5 (CH2SH), 27.1 (CH3), 27.0
(CH3), 26.8 (CH), 25.5 (CH3CH), 15.8 (SCH3); HRMS:
calcd [M+Na]+ 453.1671; found, 435.1657. Anal. Calcd
for C19H30N2O7S (430.18 g/mol): C, 53.01; H, 7.02; N,
6.51; S, 7.45. Found: C, 54.15; H, 7.03; N, 7.24; S, 7.80.
4.10. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-
[[(tert-butoxycarbonyl)methyl]amino]-a-D-allofuranose 10
Following General Method A, 1 (0.50 g, 1.94 mmol), L-
tBuOOCCH2NH2 (0.39 g, 2.15 mmol), TEA (0.30 mL,
2.13 mmol), and TMSCN (0.26 mL, 1.90 mmol) in MeOH
(5 mL) gave after flash chromatography (EtOAc/hexane,
4.8. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-[[(S)-
(1,3)-di-(methoxycarbonyl)propyl]amino]-a-D-allofuranose 8
1:9) compound 10 (0.27 g, 35%) as a colorless syrup;
28
Following General Method A, 1 (1.12 g, 4.34 mmol), L-
MeOOCH(CH2CH2COOMe)NH2 (1.10 g, 5.21 mmol),
TEA (0.73 mL, 5.21 mmol), and TMSCN (0.58 mL,
4.34 mmol) in MeOH (8 mL) gave after flash chromatogra-
½aꢂD ¼ þ18:7 (c 0.33, CHCl3); IR (ATR): m 2988, 1736,
1372, 1246, 1160, 1077, 1041, 1002, 839 cmꢁ1; H NMR
(CDCl3) d 5.90 (d, 1H, H-1, J1,2 3.6 Hz), 4.72 (d, 1H, H-
2), 4.31 (ddd, 1H, H-5, J5–6b 6.0 Hz), 4.20 (dd, 1H, H-6b,
J6b–6a 9.0 Hz), 4.00 (dd, 1H, H6a, J6a–5 4.0 Hz), 3.91 (d,
1
phy (EtOAc/hexane, 2:8) compound 8 (0.29 g, 15%) as a
20
colorless syrup; ½aꢂD ¼ þ22:0 (c 1.55, CHCl3); IR (ATR):
1H, H-4, J4–5 9.5 Hz), 3.50 (d, 2H, CH2, JCH ;NH 5.8 Hz),
2
m 2989, 2937, 1734, 1376, 1260, 1213, 1165, 1065,
2.90 (t, 1H, NH), 1.54 (s, 3H, CH3), 1.45 (s, 9H, t-Bu),
1.46 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.32 (s, 3H, CH3);
13C NMR (CDCl3) d 169.7 (C@O), 117.7 (CN), 114.5
(CH3CCH3), 110.8 (CH3CCH3), 104.8 (C-1), 83.1 (C-2),
82.3 (Cq t-Bu), 81.3 (C-4), 75.4 (C-5), 68.6 (C-3), 68.0 (C-
6), 47.9 (CH2NH), 28.4 (4C, CH3, 3 ꢃ CH3(t-Bu)), 27.1
(CH3), 26.9 (CH3), 25.4 (CH3); HRMS: calcd [M+Na]+
421.1951; found, 421.1967. Anal. Calcd for C19H30N2O7
(398.21 g/mol): C, 57.27; H, 7.59; N, 7.03. Found: C,
56.98; H, 7.45; N, 7.21.
1042 cmꢁ1 1H NMR (CDCl3) d 5.89 (d, 1H, H-1, J1,2
;
3.7 Hz), 4.76 (d, 1H, H-2), 4.35 (ddd, 1H, H-5, J5,6b
6.3 Hz), 4.19 (dd, 1H, H-6b, J6a,6b 8.7 Hz), 4.00 (dd, 1H,
H-6a, J5,6a 5.5 Hz), 3.83 (d, 1H, H-4, J5,4 7.5 Hz), 3.75
(m, 4H, OCH3, CH), 3.69 (s, 3H, OCH3), 2.58 (d, 1H,
NH, JNH,CH 8.5 Hz), 2.48 (m, 2H, CH2), 2.11 (m, 1H,
H0(CH2CO)), 1.96 (m, 1H, H00(CH2CO)), 1.55 (s, 3H,
CH3), 1.46 (s, 3H, CH3), 1.39 (s, 3H, CH3,), 1.36 (s, 3H,
CH3);13C NMR (CDCl3) d 174.7 (C@O), 173.6 (C@O),
117.5 (CN), 114.2 (CH3CCH3), 110.5 (CH3CCH3), 104.5
(C-1), 83.1 (C-2), 82.6 (C-4), 75.0 (C-5), 67.6 (C-3, C-6),
58.1 (CH), 52.6 (OCH3), 52.1 (OCH3), 30.5 (CH2), 28.7
(CH2CO), 27.1 (CH3), 26.9 (CH3), 26.8 (CH3), 25.5
(CH3); HRMS: calcd [M+Na]+ 465.1849; found,
465.1845. Anal. Calcd for C20H30N2O9 (442.20 g/mol): C,
54.29; H, 6.83; N, 6.33. Found: C, 54.15; H, 6.75; N, 6.17.
4.11. 5-O-Benzyl-3-C-cyano-3-deoxy-1,2-O-isopropylidene-
3-[[(methoxycarbonyl)methyl]amino]-a-D-ribofuranose 11
Following General Method A, 3 (5.81 g, 20 mmol), L-MeO-
OCCH2NH2 (2.87 g, 20 mmol), TEA (7.50 mL, 20 mmol),
and TMSCN (2.80 mL, 20 mmol) in MeOH (45 mL) gave
4.9. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-[[(S)-
1-(methoxycarbonyl)-2-phenylethyl]amino]-a-D-allofuranose
9
after flash chromatography (EtOAc/hexane, 1:9) com-
29
pound 11 (4.93 g, 63%) as a colorless syrup; ½aꢂD ¼ þ29:6
(c 0.63, CHCl3); IR (ATR): m 2989, 2868, 1742, 1376,
1
1255, 1217, 1165, 1097, 1026 cmꢁ1; H NMR (CDCl3) d
Following General Method A, 1 (1.02 g, 3.95 mmol), L-
7.33 (m, 5H, Ph), 5.91 (d, 1H, H-1, J1,2 3.7 Hz), 4.71 (d,
1H, H-2), 4.58 (s, 2H, CH2(Bn)), 4.16 (t, 1H, H-4, J4,5
6.1 Hz), 3.86 (dd, 2H, H-a (NHCH2(a,b)), H-5a, JH5a,H5b
9.3Hz), 3.62 (s, 3H, OCH3), 3.60 (dd, 2H, H-5b, H-b,
JHa,Hb 5.9Hz), 2.70 (t, 1H, NH, JNH,CH 6.3 Hz), 1.53 (s,
3H, CH3), 1.26 (s, 3H, CH3); 13C NMR (CDCl3) d 173.3
(C@O), 137.7 (Cq), 128.8–128.2 (5C, Ph), 117.3 (CN),
114.1 (CH3CCH3), 104.8 (C-1), 82.0 (C-4), 79.7 (C-2),
74.2 (CH2(Bn)), 69.4 (C-5), 67.7 (C-3), 52.4 (OCH3), 47.2
(CH2), 27.0 (CH3), 26.7 (CH3); HRMS: calcd [M+Na]+
399.1532; found, 399.1525. Anal. Calcd for C19H24N2O6
(376.16 g/mol): C, 60.73; H, 6.43; N, 7.44. Found: C,
60.74; H, 6.27; N, 7.19.
MeOOCH(CH2Ph)NH2
(1.02 g,
4.74 mmol),
TEA
(0.67 mL, 4.74 mmol), and TMSCN (0.53 mL, 3.95 mmol)
in MeOH (8 mL) gave after flash chromatography (EtOAc/
hexane, 2:8) compound 9 (0.52 g, 30%) as a colorless syrup;
20
½aꢂD ¼ þ16 (c 0.21, CHCl3); IR (ATR): m 2991, 2901, 1739,
1374, 1251, 1215, 1166, 1079, 1027 cmꢁ1
;
1H NMR
(CDCl3) d 7.29 (m, 5H, Ph), 5.86 (d, 1H, H-1, J1,2
3.6 Hz), 4.71 (d, 1H, H-2), 4.22 (ddd, 1H, H-5, JH5,H6a
6.3 Hz), 4.11 (dd, 1H, H-6a, JH6a,H6b 8.7 Hz), 4.04 (ddd,
1H, CH, JCH,Ha 5.9 Hz), 3.91 (dd, 1H, H-6b, J5,6a
5.2 Hz), 3.88 (d, 1H, H-4, J5,4 8.2 Hz), 3.70 (s, 3H,
OCH3), 3.14 (d, 1H, H-a, JHa,Hb 13.9 Hz), 3.05 (d, 1H,

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
73
4.12. 5-O-Benzyl-3-C-cyano-3-deoxy-1,2-O-isopropylidene-
3-[[(S)-1- (methoxycarbonyl)-3-methylbutyl]amino]-a-D-
ribofuranose 12
(dd, 1H, H-4, J4,5a = J4,5b 5.7 Hz), 3.74 (s, 4H, OCH3,
CHNH), 3.69 (dd, 1H, H-5a), 3.48 (dd, 1H, H-5b, J5a,5b
10.3 Hz), 2.58 (d, 1H, NH JNH,CH(ala) 5.5 Hz), 1.61 (s,
3H, CH3), 1.37 (s, 3H, CH3), 1.33 (d, 1H, CH3(ala)
Following General Method A, 3 (3.0 g, 10 mmol), L-MeO-
OCCH(CH2–iPr)NH2 (2.94 g, 20 mmol), TEA (2.27 mL,
20 mmol), and TMSCN (1.45 mL, 10 mmol) in MeOH
(25 mL) gave after flash chromatography (EtOAc/hexane,
JCH;CH ðalaÞ 7.0 Hz); 13C NMR (CDCl3) d 174.9 (C@O),
3
143.3 (3C, Cipso), 128.6, 127.9, 127.2 (15C, trity1), 116.9
(CN), 113.4 (CH3CCH3), 104.1 (C-1), 87.6 (Cq Ph3), 81.8
(C-2), 80.0 (C-4), 66.9 (C-3), 63.0 (C-5), 53.9 (CHNH),
52.1 (OMe), 26.6 (CH3), 26.4 (CH3), 19.5 (1C, CH3(ala)).
1:9) compound 12 (0.92 g, 20%) as a colorless syrup;
20
½aꢂD ¼ ꢁ11:0 (c 1.80, CHCl3); IR (ATR): m 2954, 2872,
1739, 1376, 1255, 1216, 1165, 1101, 1028, 740, 699 cmꢁ1
;
1H NMR (CDCl3) d 7.33 (m, 5H, Ph), 5.94 (d, 1H, H-1,
4.15. 3-C-Cyano-3-deoxy-1,2-O-isopropylidene-3-[[(S)-1-
(methoxycarbonyl)-2-phenylethyl]amino]-5-O-trityl-a-D-
ribofuranose 15
J1,2 3.7 Hz), 4.70 (d, 1H, H-2), 4.65 (d, 1H, H0(Bn), JH H
0
00
11.8 Hz), 4.57 (d, 1H, H00(Bn)), 4.08 (t, 1H, H-4, J4,5
5.5 Hz), 3.86 (d, 2H, 2 ꢃ H-5), 3.70 (s, 3H, OCH3), 3.61
(m, 1H, CHNH), 2.43 (d, 1H, NH, JNH,CH 7.9 Hz), 1.64
(m, 1H, CH), 1.55 (s, 3H, CH3), 1.45 (m, 2H, CH2), 1.36
Following General Method A, 2 (0.88 g, 2.05 mmol), L-
MeOOCCH(CH3)NH2
(0.57 g,
4.08 mmol),
TEA
(s, 3H, CH3), 0.88 (d, 6H, 2 ꢃ CH3 JCH;CH 6.6 Hz); 13C
(0.50 mL, 3.45 mmol), and TMSCN (0.27 mL, 2.05 mmol)
in MeOH (7 mL) gave after flash chromatography (EtOAc/
3
NMR (CDCl3) d 175.5 (C@O), 138.7 (Cq), 128.8, 128.3,
128.3 (5C, Ph), 117.3 (CN), 113.9 (CH3CCH3), 104.8 (C-
1), 82.2 (C-2), 80.6 (C-4), 74.3 (CH2(Bn)), 69.6 (C-5), 67.4
(C-3), 57.5 (CHNH), 52.4 (OMe), 42.9 (CH2), 27.1
(CH3), 26.8 (CH3), 24.9 (CH), 23.9 (CH3CH), 22.3
(CH3CH); HRMS: calcd [M+Na]+ 455.2158; found,
455.2162.
hexane, 1.5:8.5) compound 15 (0.35 g, 31%) as a colorless
20
syrup; ½aꢂD ¼ þ32:0 (c 0.21, CHCl3); IR (ATR): m 2988,
1741, 1491, 1449, 1377, 1218, 1164, 1078, 1056, 875, 737,
1
703 cmꢁ1; H NMR (CDCl3) d 7.49–7.03 (m, 20H, Ph(ala)
,
H trityl), 5.91 (d, 1H, H-1, J1,2 3.7 Hz), 4.65 (d, 1H, H-2),
3.88 (dd, 1H, H-4, J4,5a 5.8 Hz), 3.80 (m, 1H, CH, JCH;CH
2
6.9 Hz), 3.67 (s, 3H, OCH3), 3.65 (dd, 1H, H-5a), 3.42 (dd,
1H, H-5b, J4,5b 4.8 Hz, J5a,5b 10.5 Hz), 2.96 (dd, 1H,
H-a, CH2(Ph-ala) JHa–Hb 13.6 Hz), 2.90 (dd, 1H, H-b
(CH2(Ph-ala))), 2.50 (d, 1H, NH JNH,CH(Ph-ala) 7.4 Hz), 1.57
(s, 3H, CH3), 1.35 (s, 3H, CH3); 13C NMR (CDCl3) d
174.0 (C@O), 143.8 (3 ꢃ Cq), 136.5 (Cq), 131.3–127.2
(20C, trityl, Ph(ala)), 117.2 (CN), 113.8 (CH3CCH3), 104.6
(C-1), 88.1 (Cq Ph3), 82.1 (C-2), 80.5 (C-4), 67.5 (C-3),
63.8 (C-5), 60.2 (CH), 52.4 (OMe), 40.2 (CH2), 27.0
(CH3), 26.8 (CH3); MS (ES) [M+Na]+ 641.3.
4.13. 3-C-Cyano-3-deoxy-1,2-O-isopropylidene-3-
[[(methoxycarbonyl)methyl]amino]-5-O-trityl-a-D-ribo-
furanose 13
Following General Method A, 2 (2.0 g, 4.65 mmol), L-
MeOOCCH2NH2 (0.63 g, 5.12 mmol), TEA (0.72 mL,
5.11 mmol), and TMSCN (0.62 mL, 4.65 mmol) in MeOH
(16 mL) gave after flash chromatography (EtOAc/hexane,
2:8) compound 13 (1.91 g, 78%) as a colorless syrup;
25
½aꢂD ¼ þ20:6 (c 1.00, CHCl3); IR (ATR): m 2987, 1751,
1449, 1376, 1218, 1162, 1085, 1030, 761, 748, 704 cmꢁ1
;
1H NMR (CDCl3) d 7.56–7.34 (m, 15H, Ph, H trityl),
5.94 (d, 1H, H-1, J1,2 3.7 Hz), 4.76 (d, 1H, H-2), 4.13
(dd, 1H, H-4, J4,5a 5.5 Hz), 3.80 (dd, 1H, H-5b, J4,5b
7.0 Hz), 3.74 (s, 3H, OCH3), 3.68 (s, 2H, CH2NH), 3.56
(dd, 1H, H-5a, J5a,5b 10.1 Hz), 2.83 (t, 1H, NH
4.16. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-
[[(R)-1-(methoxycarbonyl)ethyl]amino]-a-D-allofuranose 16
Following General Method A, 1 (1.07 g, 4.13 mmol), D-
MeOOCCH(CH3)NH2
(0.87 g,
4.95 mmol),
TEA
JNH–CH NH 5.9 Hz), 1.62 (s, 3H, CH3), 1.38 (s, 3H, CH3);
(0.87 mL, 4.95 mmol), and TMSCN (0.55 mL, 4.13 mmol)
in MeOH (10 mL) gave after flash chromatography
2
13C NMR (CDCl3) d 170.4 (C@O), 143.1 (3C, Cipso),
128.5, 127.8, 127.1 (15C, trityl), 116.7 (CN), 113.5
(CH3CCH3), 104.1 (C-1), 87.7 (Cq Ph3), 81.7 (C-2), 79.2
(C-4), 67.3 (C-3), 63.1 (C-5), 51.8 (OCH3), 46.7
(CHNH), 26.4 (CH3), 26.3 (CH3); MS (ES) [M+Na]+
551.4.
(EtOAc/hexane, 1.5:8.5) compound 16 (0.49 g, 33%) as a
20
colorless syrup; ½aꢂD ¼ þ30 (c 0.26, CHCl3); IR (ATR): m
2989, 2929, 1740, 1375, 1255, 1216, 1167, 1072,
1036 cmꢁ1 1H NMR (CDCl3) d 5.81 (d, 1H, H-1, J1,2
;
3.6 Hz), 4.75 (d, 1H, H-2), 4.25 (ddd, 1H, H-5, J5,6a
6.1 Hz), 4.09 (dd, 1H, H-6a, J6a,6b 9.0 Hz), 3.92 (dd, 1H,
H-6b, J5,6b 4.2 Hz), 3.80 (d, 1H, H-4, J5,4 9.0 Hz), 3.69 (s,
3H, OCH3), 3.55 (m, 1H, CH(ala)), 3.09 (s, 1H, NH), 1.48
4.14. 3-C-Cyano-3-deoxy-1,2-O-isopropylidene-3-
[[(S)-1-(methoxycarbonyl)ethyl]amino]-5-O-trityl-
a-D-ribofuranose 14
(s, 3H, CH3), 1.39 (s, 3H, CH3), 1.29 (d, 3H, CH3(ala)
,
JH;CH 7.2 Hz), 1.28 (s, 6H, 2 ꢃ CH3); 13C NMR (CDCl3)
3
Following General Method A, 2 (0.88 g, 2.05 mmol), L-
d 175.1 (C@O), 117.7 (CN), 114.3 (CH3CCH3), 110.6
(CH3CCH3), 104.8 (C-1), 83.1 (C-2), 81.4 (C-4), 75.3 (C-
5), 68.0 (C-6), 67.9 (C-3), 53.8 (CHNH), 52.4 (OCH3),
27.0 (CH3), 26.9 (CH3), 26.8 (CH3), 25.3 (CH3), 20.4
(CH3(ala)); HRMS: calcd [M+Na]+ 393.1638; found,
393.1640. Anal. Calcd for C17H26N2O7 (370.40 g/mol):
C, 55.13; H, 7.08; N, 7.56. Found: C, 54.98; H, 6.99; N,
7.45.
MeOOCCH(CH3)NH2
(0.57 g,
4.08 mmol),
TEA
(0.50 mL, 3.45 mmol), and TMSCN (0.27 mL, 2.05 mmol)
in MeOH (7 mL) gave after flash chromatography (EtOAc/
hexane, 1.5:8.5) compound 14 (0.35 g, 31%) as a colorless
25
solid; mp = 133–135 °C; ½aꢂD ¼ ꢁ24:9 (c 1.18, CHCl3);
1H NMR (CDCl3) d 7.51–7.32 (m, 15H, Ph, H trityl),
5.91 (d, 1H, H-1, J1,2 3.7 Hz), 4.72 (d, 1H, H-2), 4.00

74
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
20
4.17. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-
[[(R)-1-(methoxycarbonyl)-2-phenylethyl]amino]-a-D-allo-
furanose 17
syrup; ½aꢂD ¼ ꢁ22:0 (c 0.17, CHCl3); IR (ATR): m 2987,
1741, 1491, 1449, 1377, 1218, 1165, 1078, 1028, 910, 733,
1
704 cmꢁ1; H NMR (CDCl3) d 7.50–7.03 (m, 20H, Ph(ala)
,
H trityl), 5.90 (d, 1H, H-1, J1,2 3.3 Hz), 4.65 (d, 1H, H-2),
Following General Method A, 1 (1.00 g, 3.87 mmol), D-
MeOOCCH(CH2Ph)NH2 (1.00 g, 4.64 mmol), TEA
(0.65 mL, 4.64 mmol), and TMSCN (0.52 mL, 3.87 mmol)
in MeOH (10 mL) gave after flash chromatography
3.88 (dd, 1H, H-4, J4,5a 5.8 Hz), 3.78 (m, 1H, CH, JCH;CH
2
6.9 Hz), 3.67 (s, 3H, OCH3), 3.65 (dd, 1H, H-5a), 3.43 (dd,
1H, H-5b, J4,5b 4.7 Hz, J5a,5b 10.4 Hz), 2.96 (dd, 1H, H-a,
CH2(Ph-ala) JHa,Hb 13.6 Hz), 2.93 (dd, 1H, H-b, CH2(Ph-ala)),
2.50 (d, 1H, NH JNH,CH(Ph-ala) 7.3 Hz), 1.56 (s, 3H, CH3),
1.33 (s, 3H, CH3); 13C NMR (CDCl3) d 174.1 (C@O),
143.8 (3 ꢃ Cq), 136.5 (Cq), 129.7–127.2 (20C, trityl,
Ph(ala)), 117.2 (CN), 113.8 (CH3CCH3), 104.6 (C-1), 88.1
(Cq Ph3), 82.1 (C-2), 80.5 (C-4), 67.4 (C-3), 63.8 (C-5),
60.1 (CH), 52.4 (OCH3), 40.2 (CH2), 27.0 (CH3), 26.7
(CH3); HRMS: Anal. Calcd [M+Na]+ 641.2628; found,
641.2635.
(EtOAc/hexane, 2:8) compound 17 (0.69 g, 40%) as a col-
20
orless syrup; ½aꢂD ¼ ꢁ36:6 (c 0.50, CHCl3); IR (ATR): m
2991, 2901, 1740, 1374, 1251, 1215, 1167, 1078,
1
1032 cmꢁ1; H NMR (CDCl3) d 7.20 (m, 5H, Ph), 5.90
(d, 1H, H-1, J1,2 3.7 Hz), 4.75 (d, 1H, H-2), 4.35 (ddd,
1H, H-5, J5,6a 6.2 Hz), 4.13 (dd, 1H, H-6a, J6a,6b 9.1 Hz),
4.03 (dd, 1H, H-6b, J5,6a 3.7 Hz), 3.82 (d, 1H, H-4, J5,4
9.3 Hz), 3.80 (m, 1H, CH), 3.73 (s, 3H, OCH3), 3.02 (d,
1H, NH, JNH,CH 6.5 Hz), 2.98 (d, 2H, CH2, JCH;CH
2
8.5 Hz), 1.47 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.35 (s, 3H,
CH3), 1.29 (s, 3H, CH3); 13C NMR (CDCl3) d 174.1
(C@O), 137.1 (Cq), 128.9, 128.7, 127.0 (Ph), 118.1 (CN),
114.3 (CH3CCH3), 110.0 (CH3CCH3), 104.0 (C-1), 83.0
(C-2), 81.0 (C-4), 75.0 (C-5), 67.0 (C-6), 67.0 (C-3), 59.0
(CH), 52.4 (OCH3), 40.7 (CH2), 27.3 (CH3), 27.1 (CH3),
26.8 (CH3), 25.3 (CH3); MS (ES) [M+Na]+ 469.4;
[M+K]+ 485.4. Anal. Calcd for C23H30N2O7 (446.21 g/
mol): C, 61.87; H, 6.77; N, 6.27. Found: C, 61.59; H,
6.48; N, 6.30.
4.20. (3R)-1,2:5,6-Di-O-isopropylidenespiro[3-deoxy-a-D-
ribo-hexofuranose-3,50-piperazine]-20-one 20
Following General Procedure B, NaBH4 (0.34 g, 9.13
mmol) was added to a solution of 4 (0.34 g, 0.91 mmol)
and CoCl2ꢀ4H2O (0.23 g, 1.80 mmol) in MeOH (9 mL).
After flash chromatography (EtOAc/hexane, 5:5), com-
pound 20 (0.23 g, 78%) was isolated as a colorless syrup;
25
½aꢂD ¼ þ67:8 (c 1.19, CHCl3); IR (ATR): m 2994, 2931,
1672, 1373, 1250, 1213, 1165, 1073, 1010, 875, 846 cmꢁ1
;
1H NMR (CDCl3) d 7.40 (d, 1H, NH(CH2(a,b))), 5.81 (d,
1H, H-1, J1,2 3.8 Hz), 4.70 (d, 1H, H-2), 4.15 (dd, 1H, H-
6b, J6a,6b 8.2 Hz), 4.05 (ddd, 1H, H-5, J5,6b 5.9 Hz), 3.92
(dd, 1H, H-6a, J5,6a 5.0 Hz), 3.85 (d, 1H, H-4, J5,4
8.5 Hz), 3.70 (d, 1H, H-a, JH-a,H-b 12.3 Hz), 3.64 (d, 1H,
H-a), 3.50 (d, 1H, H-b, JH-a,H-b 18.1 Hz), 3.55 (dd, H-b,
JH-b,NH 4.4 Hz), 2.6 (s, 1H, NH), 1.60 (s, 3H, CH3), 1.44
(s, 3H, CH3), 1.34 (s, 3H, CH3), 1.29 (s, 3H, CH3); 13C
NMR (CDCl3) d 171.9 (C@O), 113.3 (CH3CCH3), 110.4
(CH3CCH3), 104.3 (C-1), 81.7 (C-2), 80.9 (C-4), 73.7 (C-
5), 68.6 (C-6), 62.6 (C-3), 46.8 (CH2(gly)), 44.1
(CH2(a,b)NH), 27.1 (CH3), 27.0 (CH3), 26.7 (CH3), 25.5
(CH3); HRMS: calcd [M+Na]+ 351.1532; found,
351.1534. Anal. Calcd for C15H24N2O6 (328.36 g/mol): C,
54.87; H, 7.37; N, 8.53. Found: C, 54.76; H, 7.54; N,
8.54.
4.18. 3-C-Cyano-3-deoxy-1,2-O-isopropylidene-3-[[(R)-1-
(methoxycarbonyl)ethyl]amino]-5-O-trityl-a-D-ribofuranose
18
Following General Method A, 2a (0.87 g, 2.01 mmol), D-
MeOOCCH(CH3)NH2
(0.34 g,
2.42 mmol),
TEA
(0.34 mL, 2.42 mmol), and TMSCN (0.29 mL, 2.01 mmol)
in MeOH (8 mL) gave after flash chromatography (EtOAc/
hexane, 1.5:8.5) compound 18 (0.64 g, 58%) as a colorless
20
syrup; ½aꢂD ¼ þ36:2 (c 0.50, CHCl3); IR (ATR): m 2989,
1741, 1491, 1449, 1376, 1218, 1168, 1079, 1012, 737,
1
706 cmꢁ1; H NMR (CDCl3) d 7.54–7.29 (m, 15H, Ph, H
trityl), 5.89 (d, 1H, H-1, J1,2 3.7 Hz), 4.89 (d, 1H, H-2),
4.12 (dd, 1H, H-4, J4,5a 4.9 Hz), 3.74 (dd, 1H, H-5a), 3.70
(s, 3H, OCH3), 3.63 (m, 1H, CH), 3.53 (dd, 1H, H-5b,
J4,5b 8.4 Hz, J5a,5b 9.6 Hz), 3.09 (d, 1H, NH JNH,CH(ala)
9.9 Hz), 1.60 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.38 (d,
4.21. (3R,30S)-1,2:5,6-Di-O-isopropylidene-30-methylspiro[3-
deoxy-a-D-ribo-hexofuranose-3,50-piperazine]-20-one 21
1H, CH3(ala) JCH;CH ðalaÞ 7.1 Hz); 13C NMR (CDCl3) d
3
174.9 (C@O), 143.6 (3 ꢃ Cq), 129.1, 128.4, 127.7 (trity1),
117.7 (CN), 114.2 (CH3CCH3), 104.8 (C-1), 88.5
(Cq Ph3), 82.9 (C-2), 79.7 (C-4), 67.7 (C-3), 63.5
(C-5), 54.2 (CHNH), 52.3 (OCH3), 27.1 (CH3), 26.9
(CH3), 20.6 (CH3(ala)); MS (ES) [M+Na]+ 565.4; [M+K]+
581.4.
Following General Procedure B, NaBH4 (0.10 g, 2.65
mmol) was added to a solution of 5 (0.10 g, 0.27 mmol)
and CoCl2ꢀ4H2O (0.07 g, 0.53 mmol) in MeOH (3 mL).
After flash chromatography (EtOAc/hexane, 5:5), com-
pound 21 (0.08 g, 75%) was isolated as a colorless syrup;
25
½aꢂD ¼ þ23:3 (c 0.54, CHCl3); 1H NMR (CDCl3) d 6.9
4.19. 3-C-Cyano-3-deoxy-1,2-O-isopropylidene-3-[[(R)-1-
(methoxycarbonyl)-2-phenylethyl]amino]-5-O-trityl-a-D-
ribofuranose 19
(d, 1H, NH(CH2(a,b))), 5.7 (d, 1H, H-1, J1,2 3.8 Hz), 4.35
(d, 1H, H-2), 4.12 (dd, 1H, H-6b, J6a,6b 7.8 Hz), 4.05
(ddd, 1H, H-5, J5,6b 5.9 Hz), 3.92 (dd, 1H, H-6a, J5,6a
5.0 Hz), 3.85 (d, 1H, H-4, J5,4 8.1 Hz), 3.72 (d, 1H, CH,
Following General Method A, 2 (0.95 g, 2.22 mmol), D-
MeOOCCH(CH2Ph)NH2 (0.57 g, 2.66 mmol), TEA
(0.37 mL, 2.66 mmol), and TMSCN (0.30 mL, 2.22 mmol)
in MeOH (8 mL) gave after flash chromatography (EtOAc/
hexane, 1.5:8.5) compound 19 (0.74 g, 62%) as a colorless
JCH;CH 6.8 Hz), 3.6 (d, 1H, H-a, JH-a,H-b 12.8 Hz), 3.15
3
(dd, H-b, JH-b,NH 4.3 Hz), 2.2 (s, 1H, NH), 1.60 (s, 3H,
CH3), 1.4 (s, 3H, CH3), 1.34 (d, 3H, CH3(ala)), 1.33 (s,
3H, CH3), 1.26 (s, 3H, CH3); 13C NMR (CDCl3) d 176.4
(C@O),113.1 (CH3CCH3), 110.1 (CH3CCH3), 103.3

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
75
(C-1), 83.6 (C-2), 83.1 (C-4), 73.8 (C-5), 68.7 (C-6), 63.6 (C-
3), 50.7 (CH(ala)), 42.7 (CH2(a,b)), 27.1 (CH3), 26.9 (CH3),
26.8 (CH3), 25.6 (CH3), 17.9 (CH3(ala)).
4.24. (3R,30S)-1,2:5,6-Di-O-isopropylidene-30-[2-(methoxy-
carbonyl)ethyl]spiro[3-deoxy-a-D-ribo-hexofuranose-3,50-
piperazine]-20-one 24
Following General Procedure B, NaBH4 (0.17 g, 4.30
mmol) was added to a solution of 8 (0.20 g, 0.43 mmol)
and CoCl2ꢀ4H2O (0.21 g, 0.88 mmol) in MeOH (7 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-
4.22. (3R,30S)-30-Isobutyl-1,2:5,6-di-O-isopropylidenespi-
ro[3-deoxy-a-D-ribo-hexofuranose-3,50-piperazine]-20-one 22
Following General Procedure B, NaBH4 (0.19 g, 5.12
mmol) was added to a solution of 6 (0.21 g, 0.51 mmol)
and CoCl2ꢀ4H2O (0.24 g, 0.10 mmol) in MeOH (10 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-
pound 24 (0.12 g, 67%) was isolated as a colorless syrup;
20
½aꢂD ¼ þ11 (c 0.17, CHCl3); IR (ATR): m 2987, 2901,
1
1733, 1674, 1374, 1250, 1216, 1166, 1073, 1015 cmꢁ1; H
NMR (CDCl3) d 7.47 (s, 1H, NH(CH2(a,b))), 5.70 (d, 1H,
H-1, J1,2 3.8 Hz), 4.28 (d, 1H, H-2), 4.10 (dd, 1H, H-6a,
J6a,6b 8.0 Hz), 4.02 (ddd, 1H, H-5, J5,6a 5.8 Hz), 3.86 (dd,
1H, H-6b, J5,6b 5.7 Hz), 3.78 (d, 1H, H-4, J5,4 8.4 Hz),
3.66 (m, 4H, OCH3, CH), 3.50 (dd, 1H, H-a, Ja,b
12.8 Hz, JHa-NH 3.1 Hz), 3.12 (dd, H-b, JHb,NH 3.1 Hz),
pound 22 (0.14 g, 70%) was isolated as a colorless syrup;
20
½aꢂD ¼ ꢁ13:0 (c 1.80, CHCl3); IR (ATR): m 2987, 2955,
1
1682, 1373, 1250, 1216, 1165, 1073, 1046 cmꢁ1; H NMR
(CDCl3) d 7.28 (s, 1H, NH(CH2(a,b))), 5.70 (d, 1H, H-1,
J1,2 3.8 Hz), 4.32 (d, 1H, H-2), 4.12 (dd, 1H, H-6a, J6a,6b
7.6 Hz), 4.08 (ddd, 1H, H-5, J5,6a 6.0 Hz), 3.90 (dd, 1H,
H-6b, J5,6b 5.8 Hz), 3.82 (d, 1H, H-4, J5,4 7.9 Hz), 3.62
2.50 (t, 2H, CH2–CO, JCH –Hða;bÞ 7.4 Hz), 2.18 (m, 2H,
2
NH, H-a), 1.98 (q, 1H, H-b, JCH,Hb = JCH,Ha 7.4 Hz),
1.54 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.31 (s, 6H,
2 ꢃ CH3); 13C NMR (CDCl3) d 174.9 (C@O), 174.5
(C@O), 112.8 (CH3 CCH3), 110.1 (CH3CCH3), 103.1 (C-
1), 84.0 (C-2), 83.3 (C-4), 73.6 (C-5), 68.9 (C-6), 63.0 (C-
3), 54.4 (CH), 51.8 (OCH3), 42.7 (CH2(a,b)), 30.9 (CH2(a,b)),
27.8 (CH2CO), 27.0 (CH3), 26.9 (CH3), 26.8 (CH3), 25.5
(CH3); HRMS: calcd for C19H30N2O8Na [M+Na]+
437.1900; found, 437.1897.
(dd, 1H, CH, JCH;CH 9.9 Hz), 3.58 (d, 1H, H-a, JH-a,H-b
12.9 Hz), 3.07 (dd, H-b, JH-b,NH 4.2 Hz), 1.92 (m, 1H,
2
NH, JNH,CH 3.9 Hz), 1.85 (m, 1H, CH, JCH;CH 6.4 Hz),
3
1.78 (m, 2H, CH2(leu)), 1.55 (s, 3H, CH3), 1.43 (s, 3H,
CH3), 1.34 (d, 3H, CH3), 1.32 (s, 3H, CH3), 0.92 (d, 3H,
CH3(leu)), 0.88 (d, 3H, CH3(leu)); 13C NMR (CDCl3) d
176.5 (C@O), 112.7 (CH3CCH3), 110.1 (CH3CCH3),
103.3 (C-1), 83.6 (C-2), 83.2 (C-4), 73.7 (C-5), 68.7 (C-6),
63.4 (C-3), 53.0 (CH), 42.5 (CH2(a,b)NH), 40.9 (CH2),
27.0 (CH3), 26.9 (CH3), 26.8 (CH3), 25.6 (CH3), 24.0
(CH(CH3)2), 23.8 (CH3(leu)), 21.7 (CH3(leu)); HRMS: calcd
[M+H]+ 385.2339; found, 385.2335. Anal. Calcd for
C19H32N2O6 (384.23 g/mol): C, 59.36; H, 8.39; N, 7.29.
Found: C, 59.16; H, 8.15; N, 7.60.
4.25. (3R,30S)-30-Benzyl-1,2:5,6-di-O-isopropylidenespiro[3-
deoxy-a-D-ribo-hexofuranose-3,50-piperazine]-20-one 25
Following General Procedure B, NaBH4 (0.19 g, 5.00
mmol) was added to a solution of 9 (0.22 g, 0.50 mmol)
and CoCl2ꢀ4H2O (0.24 g, 1.00 mmol) in MeOH (8 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-
4.23. (3R,30S)-1,2:5,6-Di-O-isopropylidene-30-(2-methylthio-
ethyl)spiro[3-desoxy-a-D-ribo-hexofuranose-3,50-piperazine]-
20-one 23
pound 25 (0.12 g, 56%) was isolated as a colorless syrup;
20
½aꢂD ¼ þ18:0 (c 0.32, CHCl3); IR (ATR): m 2966, 1680,
1375, 1254, 1210, 1165, 1073, 1041, 756, 733 cmꢁ1 1H
;
Following General Procedure B, NaBH4 (0.14 g, 3.69
mmol) was added to a solution of 7 (0.16 g, 0.37 mmol)
and CoCl2ꢀ4H2O (0.18 g, 0.74 mmol) in MeOH (7 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-
NMR (CDCl3) d 7.31 (m, 6H, NH(CH2(a,b)), 5H (Ph)),
5.70 (d, 1H, H-1, J1,2 3.8 Hz), 4.31 (d, 1H, H-2), 4.05 (m,
2H, CH, H-5, J5,6a 4.4 Hz), 3.94 (dd, 1H, H-6a, J6a,6b
9.5 Hz), 3.83 (dd, 1H, H-6b, J5,6b 6.6 Hz), 3.70 (d, 1H,
H-4, J5,4 7.3 Hz), 3.48 (dd, 1H, H-a, JH-a,H-b 12.5 Hz, JH-
pound 23 (0.11 g, 75%) was isolated as a colorless syrup;
20
½aꢂD ¼ ꢁ20:0 (c 1.40, CHCl3); IR (ATR): m 2987, 2935,
2.6 Hz), 3.38 (dd, 1H, H-a, JHa,Hb 13.8 Hz, JHa,CH
a,NH
1
1674, 1373, 1249, 1216, 1166, 1074, 1014 cmꢁ1; H NMR
3.4 Hz), 3.03 (dd, H-b, JH-b,NH 3.6 Hz), 2.82 (dd, 1H, H-
b, JHb,CH 9.6 Hz), 2.03 (s, 1H, NH), 1.50 (s, 3H, CH3),
1.34 (s, 3H, CH3), 1.30 (s, 6H, 2 ꢃ CH3); 13C NMR
(CDCl3) d 174.6 (C@O), 139.0 (Cq), 129.8, 128.7, 126.7
(Ph), 112.7 (CH3CCH3), 110.0 (CH3CCH3), 103.2 (C-1),
83.6 (C-2), 82.9 (C-4), 73.5 (C-5), 68.4 (C-6), 63.1 (C-3),
56.6 (CH), 43.1 (CH2(a,b)NH), 38.8 (CH2(a,b)), 27.0 (CH3),
26.9 (CH3), 26.7 (CH3), 25.5 (CH3). Anal. Calcd for
C21H28N2O6 (404.19 g/mol): C, 62.36; H, 6.98; N, 6.93.
Found: C, 62.27; H, 6.91; N, 6.99.
(CDCl3) d 7.15 (s, 1H, NH(CH2(a,b))), 5.70 (d, 1H, H-1,
J1,2 3.8 Hz), 4.32 (d, 1H, H-2), 4.13 (dd, 1H, H-6a, J6a,6b
7.9 Hz), 4.05 (ddd, 1H, H-5, J5,6a 6.0 Hz), 3.89 (dd, 1H,
H-6b, J5,6b 5.4 Hz), 3.82 (d, 1H, H-4, J5,4 8.3 Hz), 3.76
(dd, 1H, CH, JCH,Ha 4.6 Hz), 3.56 (dd, 1H, H-a, JH-a,H-b
12.8 Hz, JH-a,NH 2.7 Hz), 3.10 (dd, H-b, JH-b,NH 3.8 Hz),
2.70 (t, 2H, CH2S, JCH ;Ha ¼ JCH ;Hb 7.3 Hz), 2.12 (m, 4H,
2
2
CH3, H-a), 1.88 (ddt, 1H, H-b, JCH,Hb 8.0 Hz), 1.56 (s,
3H, CH3), 1.45 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.33 (s,
3H, CH3); 13C NMR (CDCl3) d 175.2 (C@O), 112.8
(CH3CCH3), 110.2 (CH3CCH3), 103.3 (C-1), 83.8 (C-2),
83.1 (C-4), 73.6 (C-5), 68.9 (C-6), 63.2 (C-3), 53.9 (CH),
42.0 (CH2(a,b)), 31.8 (CH2S), 31.0 (CH2(a,b)), 27.1 (CH3),
27.0 (CH3), 26.8 (CH3), 25.6 (CH3), 15.65 (SCH3); HRMS:
calcd [M+Na]+ 403.1903; found, 403.1896. Anal. Calcd for
C18H31N2O6S (402.18 g/mol): C, 53.71; H, 7.51; N, 6.96; S,
7.97. Found: C, 54.01; H, 7.52; N, 6.85; S, 6.74.
4.26. (3R)-5-O-Benzyl-1,2-O-isopropylidenespiro[3-deoxy-a-
D-erythro-pentofuranose-3,50-piperazine]-20-one 26
Following General Procedure B, NaBH4 (1.23 g, 32.66
mmol) was added to a solution of 11 (1.23 g, 3.26 mmol)
and CoCl2ꢀ4H2O (0.84 g, 6.52 mmol) in MeOH (40 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-

76
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
pound 26 (0.61 g, 54%) was isolated as a colorless syrup;
(C@O), 143.9 (3 ꢃ Cipso), 129.0, 128.4, 127.6 (15C, trityl),
112.7 (CH3CCH3), 104.4 (C-1), 87.7 (Cq), 80.1 (C-2), 79.7
(C-4), 62.6 (C-5), 62.3 (C-3), 47.0 (CH2(a,b)), 43.2 (CH2(a,b)
NH), 27.0 (CH3), 26.7 (CH3); HRMS: calcd [M+Na]+
523.2209; found, 523.2216. Anal. Calcd for C30H32N2O5
(500.59 g/mol): C, 71.98; H, 6.44; N, 5.60. Found: C,
71.54; H, 6.21; N, 5.34.
29
½aꢂD ¼ þ71:6 (c 0.38, CHCl3); IR (ATR): m 2986, 2926,
2865, 1672, 1380, 1255, 1213, 1164, 1074, 1051,
1001 cmꢁ1
;
1H NMR (CDCl3) d 7.69 (d, 1H, NH,
JNH–Hb 3.2 Hz), 7.27 (m, 5H, Ph), 5.75 (d, 1H, H-1, J1,2
3.9 Hz), 4.49 (d, 1H, H-2), 4.48 (s, 2H, CH2(Bn)), 3.88
(dd, 1H, H-4, J5a,4 3.0 Hz), 3.58 (m, 2H, H-a, H-5a,
J5a,5b 10.5 Hz), 3.45 (d, 1H, H-b, JH-a,H-b 17.5 Hz), 3.49
(dd, 1H, H-5b, J5b,4 6.8 Hz), 3.27 (d, 1H, H-a, JH-a,H-b
12.4 Hz), 2.79 (dd, 1H, H-b), 1.97 (s, 1H, NH), 1.49 (s,
3H, CH3), 1.27 (s, 3H, CH3); 13C NMR (CDCl3) d 171.2
(C@O), 138.0 (Cipso), 128.8, 128.2, 128.1 (5C, Ph), 112.6
(CH3CCH3), 104.4 (C-1), 80.3 (C-4), 79.4 (C-2), 73.9
(CH2(Z)), 68.3 (C-5), 62.7 (C-3), 46.9 (CH2(a,b)), 42.9
(CH2(a,b)), 26.9 (CH3), 26.7 (CH3).
4.29. (3R,30S)-1,2-O-Isopropylidene-30-methyl-5-O-trityl-
spiro[3-deoxy-a-D-erythro-pentofuranose-3,50-piperazine]-20-
one 29
Following General Procedure B, NaBH4 (0.16 g, 4.2 mmol)
was added to a solution of 14 (0.23 g, 0.42 mmol) and
CoCl2ꢀ4H2O (0.11 g, 0.84 mmol) in MeOH (4.5 mL). After
flash chromatography (EtOAc/MeOH, 5:5), compound 29
4.27. (3R,30S)-5-O-Benzyl-30-isobutyl-1,2-O- isopropyl-
idenespiro[3-deoxy-a-D-erythro-pentofuranose-3,50-piper-
azine]-20-one 27
(0.107 g, 50%) was isolated as
a
colorless syrup;
½aꢂD ¼ þ10:6 (c 0.39, CHCl3); IR (ATR): m 2987, 1680,
1373, 1213, 1161, 1080, 1012, 765, 747, 705 cmꢁ1 1H
27
;
NMR (CDCl3) d 7.20–7.52 (m, 15H, trityl), 7.11 (d, 1H,
NH, (CH2(a,b))), 5.84 (d, 1H, H-1, J1,2 3.9 Hz), 4.35 (d,
Following General Procedure B, NaBH4 (0.70 g, 18.50
mmol) was added to a solution of 12 (0.79 g, 1.85 mmol)
and CoCl2ꢀ4H2O (0.88 g, 3.70 mmol) in MeOH (25 mL).
After flash chromatography (EtOAc/MeOH, 9:1), com-
1H, H-2), 4.15 (q, 1H, CH, JCH;CH 7.1 Hz), 4.08 (dd, 1H,
3
H-4, J4,5a = J4,5b 5.4 Hz), 3.40 (dd, 1H, H-5b), 3.32 (m,
1H, H-a, JH-a,H-b 13.0 Hz), 3.24 (dd, 1H, H-5a, J5a,5b
10.3 Hz), 2.92 (dd, 1H, H-b, JH-b,NH 4.4 Hz), 2.12 (s, 1H,
NH), 1.60 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.27 (d, 3H,
CH3(ala)); 13C NMR (CDCl3) d 176.6 (C@O), 144.1
(3 ꢃ Cipso), 128.9, 128.6, 128.0 (trityl), 112.4 (CH3CCH3),
103.9 (C-1), 87.5 (Cq), 81.8 (C-2), 80.8 (C-4), 63.9 (C-5),
61.7 (C-3), 50.8 (CH), 44.8 (CH2(a,b)NH), 26.9 (CH3),
26,8 (CH3),17,2 (1C, CH3(ala)); HRMS: calcd [M+Na]+
537.2365; found, 537.2379. Anal. Calcd for C31H34N2O5
(514.61 g/mol): C, 72.35; H, 6.66; N, 5.44. Found: C,
72.47; H, 6.91; N, 5.48.
pound 27 (0.51 g, 69%) was isolated as a colorless syrup;
20
½aꢂD ¼ þ13:0 (c 0.85, CHCl3); IR (ATR): m 2957, 2901,
1674, 1383, 1250, 1216, 1166, 1076, 1066, 737, 699 cmꢁ1
;
1H NMR (CDCl3) d 7.50 (d, 1H, NH, JNH–Hb 4.4 Hz),
7.32 (m, 5H, Ph), 5.78 (d, 1H, H-1, J1,2 3.7 Hz), 4.55 (s,
2H, CH2(Bn)), 4.31 (d, 1H, H-2), 3.95 (dd, 1H, H-4, J5a,4
3.2 Hz), 3.71 (m, 1H, H-5a, J5a,5b 10.6 Hz), 3.60 (dd, 1H,
H-5b, J5b,4 6.0 Hz), 3.40 (m, 2H, CH, H-a, JH-a,H-b
13.3 Hz ), 3.00 (dd, 1H, H-b), 1.97 (s, 1H, NH), 1.76 (m,
3H, CH(CH3)2, CH2), 1.53 (s, 3H, CH3), 1.31 (s, 3H,
CH3), 0.94 (d, 3H, CH3(leu)), 0.87 (d, 3H, CH3(leu)); 13C
NMR (CDCl3) d 175.9 (C@O), 138.0 (Cipso), 128.8, 128.3,
128.2 (5C, Ph), 112.4 (CH3CCH3), 103.8 (C-1), 81.9 (C-
2), 81.2 (C-4), 74.0 (CH2(Bn)), 68.2 (C-5), 63.1 (C-3),
53.4 (CHNH), 42.2 (CH2(a,b)), 41.2 (CH2(leu)), 26.9 (CH3),
26.8 (CH3), 24.7 (CH), 23.9 (CH3(leu)), 21.4 (CH3(leu));
HRMS: calcd [M+Na]+ 427.2209; found, 427.2203. Anal.
Calcd for C22H32N2O5 (404.23 g/mol): C, 65.32; H, 7.97;
N, 6.93. Found: C, 65.08; H, 7.95; N, 6.82.
4.30. 3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-3-
[[[[(methoxycarbonyl)methyl]carbamoyl]methyl]amino]-a-D-
allofuranose 30
Following General Method A, 1 (1.00 g, 3.88 mmol), Gly-
Gly-OMe (0.78 g, 4.26 mmol), TEA (0.60 mL, 4.26 mmol),
and TMSCN (0.52 mL, 3.87 mmol) in MeOH (8 mL) gave
after flash chromatography (EtOAc/hexane, 1:9) com-
28
pound 30 (0.65 g, 41%) as a colorless syrup; ½aꢂD ¼ þ1:4
4.28. (3R)-1,2-O-Isopropylidene-5-O-trityl-spiro[3-deoxy-a-
D-erythro-pentofuranose-3,50-piperazine]-20-one 28
(c 0.38, CHCl3); IR (ATR): m 2988, 1747, 1683, 1531,
1446, 1375, 1213, 1165, 1076, 1034, 874, 841 cmꢁ1 1H
;
NMR (CDCl3) d 7.60 (t, 1H, NH, JNH;CH 5.4 Hz), 5,81
2a
Following General Procedure B, NaBH4 (0.31 g, 8.22
mmol) was added to a solution of 13 (0.43 g, 0.82 mmol)
and CoCl2ꢀ4H2O (0.21 g, 1.63 mmol) in MeOH (8 mL).
After flash chromatography (EtOAc/MeOH, 5:5), com-
(d, 1H, H-1, J1,2 3.6 Hz), 4.70 (d, 1H, H-2), 4.26 (ddd,
1H, H-5, J5,6b 6.2 Hz), 4.08 (dd, 1H, H-6b, J6a,6b 9.2 Hz),
3.95 (d, 2H, CH2a), 3.91 (dd, 1H, H-6a, J6a,5 4.4 Hz),
3.72 (d, 1H, H-4, J5,4 9.0 Hz), 3.60 (s, 3H, OCH3), 3.50
(dd, 1H, H-b gly JH-b,NH 6.1 Hz), 3.36 (dd, 1H, H-b0 gly,
pound 28 (0.24 g, 60%) was isolated as a colorless syrup;
27
0
0
½aꢂD ¼ þ51:1 (c 0.28, CHCl3); IR (ATR): m 2987, 2901,
JH-b;H-b 16.7 Hz), 2.8 (dd, 1H, NH, JNH;H-b 7.8 Hz), 1.46
(s, 3H, CH3), 1.35 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.23
(s, 3H, CH3). 13C NMR (CDCl3) d 170.7 (C@O), 170.3
(C@O), 117.3 (CN), 114.4 (CH3CCH3), 110.8 (CH3CCH3),
104.8 (C-1), 82.2 (C-2), 80.6 (C-4), 72.2 (C-5), 68.9 (C-3),
67.9 (C-6), 52.5 (OCH3), 48.7 (CH2b), 41.2 (CH2a), 26.9
(2 ꢃ CH3), 26.7 (CH3), 25.2 (CH3); HRMS: calcd
[M+Na]+ 436.1696; found, 436.1697. Anal. Calcd for
C18H27N3O8 (413.18 g/mol): C, 52.29; H, 6.58; N, 10.16.
Found: C, 52.41; H, 6.53; N, 9.97.
1671, 1393, 1250, 1226, 1066, 1056, 879, 750, 701 cmꢁ1
;
1H NMR (CDCl3) d 7.50–7.20 (m, 15H, trityl), 7.18 (d,
1H, NH(CH2(a,b))), 5.81 (d, 1H, H-1, J1,2 3.9 Hz), 4.50
(d, 1H, H-2), 4.00 (dd, 1H, H-4, J5a,4 6.4 Hz), 3.70 (d,
1H, H-a, JH-a,H-b 17.7 Hz), 3.45 (d, 1H, H-b), 3.40 (dd,
1H, H-5a, J5a,5b 10.1 Hz), 3.2 (dd, 1H, H-5b, J5b,4
4.6 Hz), 3.15 (d, 1H, H-a, JH-a,H-b 12.4 Hz ), 2.8 (dd, 1H,
H-b, JH-b,NH 4.4 Hz), 2.06 (s, 1H, NH), 1.59 (s, 3H,
CH3), 1.36 (s, 3H, CH3); 13C NMR (CDCl3) d 171.4

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
77
4.31. 3-C-Aminomethyl-3-deoxy-1,2:5,6-di-O-isopropyl-
idene-3-[[[(methoxycarbonyl)methyl]carbamoyl]-
methyl]amino]-a-D-allofuranose 31
(ATR): m 2981, 2936, 1658, 1544, 1373, 1250, 1167, 1071,
1014 cmꢁ1; 1H NMR (CDCl3) d 6.93 (m, 1H, NHCH2(a,b)),
5.65 (d, 1H, H-1, J1,2 3.7 Hz), 4.20 (d, 1H, H-2), 4.11 (dd,
1H, H-6a, J6a,5 6.0 Hz), 3.93 (dt, 1H, H-5, J6b,5 6.0 Hz),
3.84 (dd, 1H, H-6b, J6a,6b 8.4 Hz), 3.70 (d, 1H, H-4, J4,5
9.0 Hz), 3.70 (s, 3H, OCH3), 3.54 (s, 2H, CH2(gly)), 3.43
(dd, 1H, H-a, JHa,NH 6.3 Hz), 3.21 (dd, 1H, H-b, JHa,Hb
14.2 Hz, JHb,NH 3.5 Hz), 2.00 (s, 1H, NH), 1.98 (s, 1H,
CH3) 1.49 (s, 3H, CH3), 1.51 (s, 9H, CH3), 1.38 (s, 3H,
CH3), 1.30 (s, 3H, CH3), 1.27 (s, 3H, CH3); 13C NMR
(CDCl3) d 173.3 (C@O), 171.2 (C@O), 112.8 (CH3CCH3),
110.3 (CH3CCH3), 103.7 (C-1), 83.5 (C-2), 83.2 (C-4), 73.2
(C-5), 69.4 (C-6), 67.3 (C-3), 52.4 (OCH3), 45.1 (CH2(gly)),
38.4 (CH2(a,b)), 27.2 (CH3), 26.8 (2 ꢃ CH3), 25.7 (CH3),
23.5 (CH3); HRMS: calcd [M+Na]+ 425.1900; found,
425.1885. Anal. Calcd for C18H30N2O8 (402.20 g/mol): C,
53.72; H, 7.51; N, 6.96. Found: C, 54.01; H, 7.65; N, 6.79.
Following General Procedure B, NaBH4 (0.30 g, 7.94
mmol) was added to a solution of 30 (0.33 g, 0.79 mmol)
and CoCl2ꢀ4H2O (0.31 g, 2.38 mmol) in MeOH (8 mL).
After extraction with CH2Cl2 and water, the organic layer
was separated, dried, filtered, and evaporated to give com-
pound 31 (0.12 g, 35%) as a slightly yellow syrup; 13C
NMR (CDCl3) d 173.5 (C@O), 170.7 (C@O), 112.4
(CH3CCH3), 110.2 (CH3CCH3), 104.6 (C-1), 83.4 (C-2),
83.0 (C-4), 73.7 (C-5), 69.1 (C-6), 67.8 (C-3), 52.6 (OMe),
47.3 (CH2b), 41.7 (CH2NH2), 41.0 (CH2a), 27.2 (CH3),
27.0 (CH3), 26.7 (CH3), 25.7 (CH3). MS (ES) [M+Na]+
440.2.
4.32. 3-Deoxy-1,2:5,6-di-O-isopropylidene-3-[[(methoxy-
carbonyl)methyl]amino]-3-C-[(tert-butoxycarbonyl)-
aminomethyl]-a-D-allofuranose 32
4.34. 3-C-[[[(Benzyloxy)carbonyl]glycyl]aminomethyl]-3-
deoxy-1,2:5,6-di-O-isopropylidene-3-[[(methoxycar-
bonyl)methyl]amino]-a-D-allofuranose 34
To a solution of compound 4 (0.38 g, 1.07 mmol) and
CoCl2ꢀ4H2O (0.27 g, 2.14 mmol) in MeOH (10 mL) were
added successively Boc2O (0.69 g, 3.21 mmol) and NaBH4
(0.40 g, 10.7 mmol) portionwise. After stirring for 1 h, a
few drops of water were added followed by addition of
KCN until the reaction mixture became homogeneous
5 min later, the residue was extracted with CH2Cl2. After
the usual work-up and flash chromatography (EtOAc/hex-
To a solution of compound 4 (0.36 g, 1.00 mmol) and
CoCl2ꢀ4H2O (0.26 g, 2.00 mmol) in MeOH (10 mL) were
added successively ZNHCH2COOCOtBu(0.88 g, 3.00
mmol) and NaBH4 (0.38 g, 10.0 mmol) portionwise. After
stirring for 1 h, few drops of water were added followed
by addition of KCN until the reaction mixture became
homogeneous. After 5 min, the residue was extracted with
CH2Cl2. After usual work-up and flash chromatography
ance, 1:1), compound 32 was isolated (0.27 g, 54%) as a
32
slightly yellow solid; mp = 101–105 °C; ½aꢂD ¼ þ13:3 (c
(EtOAc/hexane, 8:2), compound 34 was isolated (0.15 g,
31
1.38; CHCl3); IR (ATR): m 2977, 2930, 1747, 1698, 1509,
28%) as a slight yellow syrup; ½aꢂD ¼ ꢁ1:7 (c 0.92, CHCl3);
1374, 1249, 1216, 1163, 1072, 1016 cmꢁ1
;
1H NMR
IR (ATR): m 2986, 2940, 1728, 1675, 1525, 1373, 1216,
1
(CDCl3) d 5.63 (d, 1H, H-1, J1,2 3.8 Hz), 5.50 (m, 1H,
NHCH2(a,b)), 4.25 (d, 1H, H-2), 4.08 (dd, 1H, H-6a, J6a-5
6.0 Hz), 3.92 (dt, 1H, H-5, J6b–5 6.1 Hz), 3.77 (dd, 1H, H-
6b, J6a–6b 8.3 Hz), 3.70 (1H, H-4, J4–5 8.7 Hz), 3.66 (s,
3H, OCH3), 3.60 (d, 1H, H-a, JH-a,H-b 17.3 Hz), 3.45 (d,
1H, H-b), 3.18 (m, 2H, CH2(a,b)), 2.18 (s, 1H, NH), 1.49
(s, 3H, CH3), 1.37 (s, 9H, CH3), 1.34 (s, 3H, CH3), 1.27
(s, 3H, CH3), 1.24 (s, 3H, CH3); 13C NMR (CDCl3) d
173.3 (C@O), 156.6 (C@O), 112.6 (CH3CCH3), 110.1
(CH3CCH3), 103.7 (C-1), 83.4 (C-2), 83.1 (C-4), 79.7
(Cq(t-Bu)), 73.2 (C-5), 69.2 (C-6), 67.3 (C-3), 52.2
(OCH3), 45.3 (CH2(gly)), 39.7 (CH2(a,b)), 28.7 (3 ꢃ CH3-
(t-Bu)), 27.2 (CH3), 26.7 (2 ꢃ CH3), 25.6 (CH3); HRMS:
calcd for C21H37N2O9 [M+H]+ 461.2499; found, 461.2480.
1165, 1070, 1049 cmꢁ1; H NMR (CDCl3) d 7.34 (m, 7H,
5H phenyl, 2 ꢃ NH), 5.69 (d, 1H, H-1, J1,2 3.7 Hz), 5.11
(s, 2H, CH2(Z)), 4.25 (d, 1H, H-2), 4.11 (dd, 1H, H-6a,
J6a,5 6.0 Hz), 3.90 (m, 4H, H-5, H-6b, CH2(gly-Z)), 3.72 (d,
1H, H-4, J4,5 8.9 Hz), 3.69 (s, 3H, OCH3), 3.54 (d,1H, H-
a, JH-a,H-b 17.5 Hz), 3.52 (d, 1H, H-b), 3.46 (dd, 1H, H-a,
JHa,NH 5.5 Hz), 3.23 (dd, 1H, H-b, JHa,Hb 14.0 Hz, JHb,NH
3.0 Hz), 2.30 (s, 1H, NH), 1.54 (s, 3H, CH3), 1.40 (s, 3H,
CH3), 1.29 (s, 6H, 2 ꢃ CH3); 13C NMR (CDCl3) d 173.9
(C@O), 169.8 (C@O), 156.9 (C@O), 136.6 (Cipso), 128.9,
128.8, 126.6 (phenyl), 112.9 (CH3CCH3), 110.4
(CH3CCH3), 103.7 (C-1), 83.4 (C-2, C-4), 73.3 (C-5), 69.3
(C-6), 67.5 (CH2(Z)), 67.4 (C-3), 52.4 (OCH3), 45.2
(CH2(a,b)), 44.9 (CH2(gly-Z)), 38.3 (CH2(a,b)), 27.3 (CH3),
26.9 (CH3), 26.8 (CH3), 25.6 (CH3); HRMS: calcd
[M+Na]+ 574.2377; found, 574.2358. Anal. Calcd for
C26H37N3O10 (555.59 g/mol): C, 56.61; H, 6.76; N, 7.62.
Found: C, 56.48; H, 6.74; N, 8.02.
4.33. 3-C-(Acetamidomethyl)-3-deoxy-1,2:5,6-di-O-isopro-
pylidene-3-[[(methoxycarbonyl) methyl]amino]-a-D-allofura-
nose 33
To a solution of compound 4 (0.19 g, 0.53 mmol) and
CoCl2ꢀ4H2O (0.14 g, 1.10 mmol) in MeOH (10 mL) were
added successively Ac2O (0.15 mL, 1.66 mmol) and NaBH4
(0.20 g, 5.33 mmol) portionwise. After stirring for 1 h, a
few drops of water were added followed by addition of
KCN until the reaction mixture became homogeneous.
After 5 min, the residue was extracted with CH2Cl2. After
the usual work-up and flash chromatography (EtOAc/
4.35. 3-[(Carboxymethyl)amino]-3-C-cyano-3-deoxy-1,2:5,6-
di-O-isopropylidene-a-D-allofuranose 37
To a solution of compound 4 (1.04 g, 3.04 mmol) in di-
oxane was added NaOH 1 M (58 mL). After stirring for
40 min at room temperature, the reaction mixture was neu-
tralized with acetic acid. The solvent was removed under
vacuo and the residue extracted with CHCl3 and water.
The organic layer was separated, dried over Na2SO4, and
evaporated. After flash chromatography (EtOAc), com-
MeOH, 1:1), compound 33 was isolated (0.10 g, 45%) as
20
a slight yellow syrup; ½aꢂD ¼ þ47 (c 0.16, CHCl3); IR

78
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
pound 37 (0.89 g, 89%) was isolated as a white solid:
overnight. After cooling at room temperature,
ZNHCH(CH3)COOPhNO2 (1.49 g, 4.32 mmol) was added
slowly and stirred for 1 h. After elimination of the solvent,
the residue was extracted with EtOAc and a saturated solu-
tion of NaHCO3. The aqueous layer was acidified with HCl
1 M until pH 4 then extracted with EtOAc. The organic
layer was separated, dried over Na2SO4, filtered, and the
solvent eliminated under vacuum. After flash chromatogra-
phy (EtOAc/MeOH/CH3COOH, 90:9:1), compound 39
29
mp = 93–95 °C, ½aꢂD ¼ þ26:8 (c 0.47, CHCl3); IR (ATR):
m 2985, 2930, 1736, 1376, 1235, 1213, 1167, 1078,
1027 cmꢁ1 1H NMR (CDCl3) d 5.91 (d, 1H, H-1, J1,2
;
3.6 Hz), 4.73 (d, 1H, H-2), 4.35 (ddd, 1H, H-5, J5,6b
6.2 Hz), 4.18 (dd, 1H, H-6b, J6a,6b 9.0 Hz), 3.95 (dd, 1H,
H-6a, J5,6a 4.1 Hz), 3.85 (d, 1H, H-4, J5,4 9.0 Hz), 3.70
(d, 1H, H-a, CH2(gly), JHa,Hb 19.3 Hz), 3.62 (d, 1H, H-b),
2.03 (s, 1H, NH), 1.55 (s, 3H, CH3), 1.46 (s, 3H, CH3),
1.35 (s, 3H, CH3), 1.34 (s, 3H, CH3); 13C NMR (CDCl3)
d 174.2 (C@O), 117.3 (CN), 114.7 (CH3CCH3), 110.9
(CH3CCH3), 104.9 (C-1), 82.8 (C-2), 81.1 (C-4), 75.3 (C-
5), 68.4 (C-3), 68.0 (C-6), 46.9 (CH2(gly)), 26.7 (2 ꢃ CH3),
26.8 (CH3), 25.2 (CH3); HRMS: calcd [M+Na]+
365.1325; found, 365.1326. Anal. Calcd for C15H22N2O7
(342.14 g/mol): C, 52.63; H, 6.48; N, 8.18. Found: C,
52.48; H, 6.47; N, 7.99.
(0.97 g, 49%) was isolated as a solid; mp = 108–111 °C,
20
½aꢂD ¼ þ20 (c 0.11, CHCl3); IR (ATR): m 2989, 2899,
1
1722, 1678, 1515, 1383, 1249, 1164, 1073, 1027 cmꢁ1; H
RMN (CDCl3) d 8.84 (s, 1H, NH), 7.33 (m, 5H, Ph),
6.35 (m, 2H, NH), 5.87 (m, 1H, H-1, J1,2 3.1 Hz), 5.11
(d, 1H, H0, CH2(Z), JH ;H 11.9 Hz), 5.02 (d, 1H, H00,
CH2(Z)), 4.58 (d, 1H, H-2), 4.25 (m, 2H, H-6a, CH),
4.13–3.92 (m, 5H, H-4, H-5, H-6b, H-a, H-a), 3.72 (d,
1H, H-b, CH2COOH, JHa,Hb 15.7 Hz), 3.64 (d, 1H, H-b,
JHa,Hb 12.6 Hz), 1.55 (s, 3H, CH3), 1.44 (s, 3H, CH3),
0
00
4.36. 3-C-[[[(Benzyloxy)carbonyl]glycyl]aminomethyl]-3-
[(carboxymethyl)amino]-3-deoxy-1,2:5,6-di-O-isopropyl-
idene-a-D-allofuranose 38
1.34 (s, 6H, CH3, CH3(ala), JCH;CH 7.0 Hz), 1.27 (s, 3H,
3
CH3); 13C NMR (CDCl3) d 175.1 (C@O), 172.5 (C@O),
156.5 (C@O), 136.6 (Cipso), 128.9, 128.6, 128.3 (phenyl),
113.9 (CH3CCH3), 110.9 (CH3CCH3), 104.2 (C-1), 81.7
(C-2), 81.1 (C-4), 72.6 (C-5), 69.2 (C-6, C-3), 67.2
(CH2(Z)), 51.2 (CH), 46.7 (CH2(a,b)), 37.7 (CH2(a,b)), 26.9
(CH3), 26.5 (2 ꢃ CH3), 25.3 (CH3), 18.9 (CH3(ala)); MS
(ES) [M+Na]+ 574.4, [M+K]+ 590.4.
To a solution of compound 20 (0.68 g, 2.09 mmol) in
20 mL of (dioxane/H2O, 1:1) was added NaOH (0.25 g,
6.26 mmol). The reaction mixture was heated at 100 °C
overnight. After cooling at room temperature, ZNHCH2-
COOPhNO2 (1.38 g, 4.17 mmol) was added slowly and
stirred for 1 h. After elimination of the solvent, the residue
was extracted with EtOAc and a saturated solution of
NaHCO3. The aqueous layer was acidified with HCl 1 M
until pH 4 then extracted with EtOAc. The organic layer
was separated, dried over Na2SO4, filtered, and the solvent
eliminated under vacuum. After flash chromatography
(EtOAc/MeOH/CH3COOH, 80:19:1), compound 38
4.38. 3-C-[[[(Benzyloxy)carbonyl]-L-isoleucyl]aminomethyl]-
3-[(carboxymethyl)amino]-3-deoxy-1,2:5,6-di-O-isopropyl-
idene-a-D-allofuranose 40
To a solution of compound 20 (1.81 g, 3.60 mmol) in
18 mL of (dioxane/H2O, 1:2) was added NaOH (0.43 g,
10.81 mmol). The reaction mixture was heated at 100 °C
overnight. After cooling at room temperature,
ZNHCH(CH3)COOPhNO2 (1.49 g, 4.32 mmol) was added
slowly and stirred for 1 h. After elimination of the solvent,
the residue was extracted with EtOAc and a saturated solu-
tion of NaHCO3. The aqueous layer was acidified with HCl
1 M until pH 4 then extracted with EtOAc. The organic
layer was separated, dried over Na2SO4, filtered, and the
solvent eliminated under vacuum. After flash chromatogra-
phy (EtOAc/MeOH/CH3COOH, 90:9:1), compound 40
(0.45 g, 56%) was isolated as a solid; mp = 104–107 °C,
20
½aꢂD ¼ þ18 (c 0.12, CHCl3); IR (ATR): m 2989, 2931,
1728, 1666, 1530, 1382, 1267, 1223, 1166, 1071,
1
1050 cmꢁ1; H NMR (CD3OD) d 7.37 (m, 5H, phenyl),
5.85 (d, 1H, H-1, J1,2 3.5 Hz), 5.12 (s, 2H, CH2(Z)), 4.65
(d, 1H, H-2), 4.23 (m, 2H, H-5, H-6a), 3.89 (m, 2H, H-4,
H-6b), 3.82 (s, 2H, CH2(gly-Z)), 3.76 (d, 1H, H-a,
CH2COOH, JHa,Hb 16.5 Hz), 3.70 (d, 1H, H-a, CH2NH,
JHa,Hb 14.9 Hz), 3.58 (d, 1H, H-b), 3.55 (d, 1H, H-b),
1.57 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.37 (s, 3H, CH3),
1.34 (s, 3H, CH3); 13C NMR (CD3OD) d 172.6 (C@O),
172.2 (C@O), 158.1 (C@O), 137.0 (Cipso), 128.5, 128.1,
128.0 (phenyl), 113.3 (CH3CCH3), 110.6 (CH3CCH3),
104.3 (C-1), 82.0 (C-2), 81.8 (C-4), 72.8 (C-5), 68.6
(C-3), 68.4 (C-6), 66.9 (CH2(Z)), 46.0 (CH2(a,b)), 44.2
(CH2(gly-Z)), 37.2 (CH2(a,b)), 25.8 (CH3), 25.6 (CH3),
25.4 (CH3), 24.2 (CH3); HRMS: calcd [M+H]+
538.2401; found, 538.2401. Anal. Calcd for C25H35N3O10
(537.23 g/mol): C, 55.86; H, 6.56; N, 7.82. Found: C,
55.99; H, 6.71; N, 7.90.
(0.97 g, 49%) was isolated as a solid; mp = 92–95 °C,
20
½aꢂD ¼ þ27 (c 0.15, CHCl3); IR (ATR): m 1716, 1688,
1
1528, 1379, 1257, 1218, 1165, 1071, 1026 cmꢁ1; H NMR
(CDCl ) d 8.74 (s, 1H, NH
), 7.33 (m, 5H, Ph), 6.40
ðCH2a;b
Þ
3
(m, 1H, NH(leu)), 5.90 (m, 1H, H-1, J1,2 3.1 Hz), 5.68 (d,
1H, NH, JNH,CH 7.0 Hz), 5.08 (d, 1H, H0, CH2(Z), JH ;H
0
00
12.4 Hz), 4.98 (d, 1H, H00, CH2(Z)), 4.57 (d, 1H, H-2),
4.28 (m, 3H, H-6a, H-6b, CH), 4.00 (m, 4H, H-4, H-5,
H-a, H-a), 3.71 (d, 1H, H-b, CH2COOH, JHa,Hb
16.2 Hz), 3.38 (d, 1H, H-b, JHa,Hb 12.5 Hz), 1.64 (m, 3H,
CH2(leu), CH
, JCH;CH 6.0 Hz), 1.53 (s, 3H, CH3),
ðCH3Þ2
3
4.37. 3-C-[[[(Benzyloxy)carbonyl]-L-alanyl]aminomethyl]-3-
[(carboxymethyl)amino]-3-deoxy-1,2:5,6-di-O-isopropyli-
dene-a-D-allofuranose 39
1.41 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.21 (s, 3H, CH3),
0.94 (d, 6H, CH3(leu)); 13C NMR (CDCl3) d 175.0 (C@O),
172.8 (C@O), 156.7 (C@O), 136.6 (Cipso), 128.9, 128.5,
128.3 (phenyl), 113.7 (CH3CCH3), 110.8 (CH3CCH3),
104.3 (C-1), 81.8 (C-2), 81.3 (C-4), 72.8 (C-5), 69.2 (C-3),
69.1 (C-6), 67.3 (CH2(Z)), 54.3 (CH), 46.7 (CH2(a,b)), 41.8
(CH2(leu)), 38.0 (CH2(a,b)), 26.9 (CH3), 26.5 (2 ꢃ CH3),
To a solution of compound 20 (1.81 g, 3.60 mmol) in
18 mL of (dioxane/H2O, 1:2) was added NaOH (0.43 g,
10.81 mmol). The reaction mixture was heated at 100 °C

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
79
25.4 (CH3), 25.1 (CH), 23.4 (CH3(leu)), 22.4 (CH3(leu));
HRMS: calcd [M+Na]+ 616.2846; found, 616.2827. Anal.
Calcd for C29H43N3O10 (593.29 g/mol): C, 58.67; H, 7.30;
N, 7.08. Found: C, 58.54; H, 7.25; N, 7.20.
1375, 1217, 1167, 877, 844 cmꢁ1
7.71 (s, 1H, NH), 7.34 ( m, 5H, phenyl), 7.19 (s, 1H,
;
1H NMR (CDCl3) d
NHCH ), 5.80 (s, 1H, NHCH ), 5.77 (d, 1H, H-1, J1,2
2ða;bÞ
2ðc;dÞ
0
00
3.5 Hz), 5.10 (dd, 2H, CH2(Z), JH ;H 12.3 Hz), 4.60 (q,
1H, CH, JCH,NH 7.5 Hz), 4.30 (d, 1H, H-2), 4.15 (dd, 1H,
H-6a, J6a,5 5.9 Hz), 3.98–3.88 (m, 4H, H-6b, H-5, CH2(c,d)),
3.74 (s, 3H, CH3), 3.72 (m, 2H, H-4, H-a), 3.60 (d, 1H, H-a,
JHaHb 17.4 Hz), 3.45 (d, 1H, H-b), 3.22 (d, 1H, H-b, JHa,Hb
13.2 Hz, JHb,NH 3.2 Hz), 2.35 (s, 1H, NHCH2ða;bÞ ), 1.55 (s,
4.39. 3-C-[[[(Benzyloxy)carbonyl]-L-phenylalanyl]amino-
methyl]-3-[(carboxymethyl)amino]-3-deoxy-1,2:5,6-di-O-iso-
propylidene-a-D-allofuranose 41
To a solution of compound 20 (0.83 g, 2.52 mmol) in
30 mL of (dioxane/H2O, 1:1) was added NaOH (0.30 g,
7.56 mmol). The reaction mixture was heated at 100 °C
overnight. After cooling at room temperature, ZNH-
CH(CH2Ph)COOPhNO2 (2.12 g, 5.04 mmol) was added
slowly and stirred for 1 h. After elimination of the solvent,
the residue was extracted with EtOAc and a saturated solu-
tion of NaHCO3. The aqueous layer was acidified with HCl
1 M until pH 4 then extracted with EtOAc. The organic
layer was separated, dried over Na2SO4, filtered, and the
solvent eliminated under vacuum. After flash chromatogra-
phy (EtOAc/MeOH/CH3COOH, 90:9:1), compound 41
3H, CH3), 1.45 (s, 3H, CH3), 1.40 (d, 3H, CH3, JCH;CH
3
7.5 Hz), 1.35 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR
(CDCl3) d 174.9 (C@O), 172.3 (C@O), 170.4 (C@O),
156.9 (C@O), 136.6 (Cipso), 128.9, 128.6, 128.5 (5C, phe-
nyl), 112.9 (CH3CCH3), 110.5 (CH3CCH3), 103.8 (C-1),
83.6 (C-2), 83.4 (C-4), 73.2 (C-5), 69.4 (C-6), 68.0 (C-3),
67.5 (CH2(Z)), 53.1 (OMe), 47.9 (CH), 46.8 (CH2(a,b)),
44.8 (CH2(c,d)), 38.1 (CH2(a,b)), 27.3 (CH3), 26.9 (CH3),
26.8 (CH3), 25.6 (CH3), 18.5 (CH3(ala)); HRMS: calcd
[M+Na]+ 645.2748; found, 645.2760. Anal. Calcd for
C29H42N4O11 (622.09 g/mol): C, 55.94; H, 6.80; N, 9.00.
Found: C, 55.79; H, 6.84; N, 8.93.
(0.69 g, 44%) was isolated as a solid; mp = 92–93 °C,
20
½aꢂD ¼ þ21 (c 0.12, CHCl3); IR (ATR): m 2979, 1720,
4.41. [1S,3R,4R,5S,10S]-1-[(4R)(2,2-Dimethyl-[1,3]dioxo-
lan-4-yl)]-3,4-O-isopropylidene-10-methyl-2-oxa-6,9,12,15-
tetraaza-spiro[4.11]hexadecane-8,11,14-trione 44
1
1682, 1523, 1383, 1227, 1165, 1073, 1027 cmꢁ1; H NMR
(CDCl ) d 7.30 (m, 10H, phenyl), 5.78 (m, 2H, NH
H-1, J1,2 3.0 Hz), 5.61 (d, 1H, NH, JNHCH 6.9 Hz), 5.06
,
Þ
ðCH2a;b
3
0
00
(dd, 2H, CH2(Z), JH ;H 6.9 Hz), 4.45 (m, 2H, H-2, CH,
JCH,Hc 6.4 Hz, JCH,Hd 7.9 Hz), 4.16 (dd, 1H, H-6a, J6a,5
Compound 42 (169 mg, 0.30 mmol) and K2CO3 (46 mg,
0.33 mmol) were solubilized in 4 mL of a solution of
MeOH/H2O (9:1) and stirred at room temperature. After
neutralization with resin IRA-120 (pH 6), the reaction mix-
ture was filtered and the solvent removed under vacuo. To
the crude material solubilized in EtOAc (3.5 mL) and
EtOH (2 mL) were added 16 mg of Pd/C (10%) and stirred
under hydrogen overnight. After filtration through a Celite
pad and removal of the solvent, compound 43 was ob-
tained quantitatively and used in the next step without fur-
ther purification. To a solution of crude compound 43
(0.81 g, 1.70 mmol) in DMF (438 mL) at 0 °C under argon
were introduced TEA (0.48 mL, 3.40 mmol) and DPPA
(0.44 mL, 2.00 mmol). After 1 night, the solvent was elim-
inated and the residue extracted with EtOAc and a satu-
rated solution of NaCl. After separation, the organic
layer was dried over Na2SO4, filtered, and concentrated.
After flash chromatography (EtOAc), compound 44
5.2 Hz), 3.80–4.02 (m, 5H, H-4, H-5, H-a, NH
, H-
ðCH2a;b
Þ
6b, J6a,6b 10.9 Hz), 3.61 (d, 1H, H-b, CH2COOH, JHa,Hb
11.7 Hz), 3.35 (d, 1H, H-a, JHa,Hb 8.2 Hz), 3.14 (m, 2H,
H-b, H-c, JHc,Hd 13.8 Hz), 3.00 (dd, 1H, H-d), 1.49 (s,
3H, CH3), 1.44 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.16 (s,
3H, CH3); 13C NMR (CDCl3) d 173.2 (C@O), 172.8
(C@O), 156.4 (C@O), 136.7, 136.5 (2 ꢃ Cipso), 129.7,
129.0, 128.9, 128.5, 128.3, 127.4 (10C, phenyl), 113.6
(CH3CCH3), 110.8 (CH3CCH3), 104.2 (C-1), 82.0 (C-2),
81.6 (C-4), 72.8 (C-5), 69.1 (C-6), 68.8 (C-3), 67.3
(CH2(Z)), 58.8 (CH), 46.4 (CH2(a,b)), 38.6 (CH2(c,d)), 38.2
(CH2(a,b)), 26.9 (CH3), 26. (2 ꢃ CH3), 25.4 (CH3); HRMS:
calcd [M+Na]+ 650.2690; found, 650.2708. Anal. Calcd for
C32H41N3O10 (627.28 g/mol): C, 61.23; H, 6.58; N, 6.69.
Found: C, 61.15; H, 6.81; N, 6.74.
4.40. 3-C-[[[(Benzyloxy)carbonyl]glycyl]aminomethyl]-3-
deoxy-1,2:5,6-di-O-isopropylidene-3-[[[[(1S)-(methoxycar-
bonyl)ethyl]amino]carboxy]methylamino]-a-D-allofuranose
42
(0.43 g, 56%) was isolated as a white solid; mp = 143–
20
146 °C, ½aꢂD ¼ ꢁ13:0 (c 0.15, CHCl3); IR (ATR): m 2987,
1
1666, 1528, 1374, 1216, 1070, 1013, 842 cmꢁ1; H NMR
(DMSO-D6) d 7.48 (s, 1H, NHCH ), 7.20 (d, 1H, NH(ala)
,
2ðc;dÞ
JCH,NH 8.9 Hz), 6.39 (d, 1H, NHCH , JHa,NH 6.7 Hz),
2ða;bÞ
To a solution of compound 39 (2.92 g, 5.44 mmol) and
L-Ala-OMe (1.52 g, 10.9 mmol) in CH3CN/DMF (30 mL,
1:1) were added N-hydroxysuccinimide (1.25 g, 10.9 mmol)
and TEA (1.53 mL, 10.9 mmol). After cooling at ꢁ10 °C
under argon, DCC (2.25 g, 10.9 mmol) was added and
the reaction mixture was stirred at room temperature over-
night. After extraction with EtOAc and water, the organic
layer was successively washed with a saturated solution of
NaHCO3 and water. The organic phase was separated,
dried over Na2SO4, filtered, and evaporated. After flash
5.67 (d, 1H, H-1, J1,2 3.5 Hz), 4.63 (m, 1H, CH), 4.32 (d,
2H, H-2, H-c, JHc,Hd 13.8 Hz), 4.09 (m, 1H, H-5, J6a,5
6.4 Hz), 3.94 (dd, 1H, H-6a, J6a,6b 7.9 Hz), 3.83 (dd, 1H,
H-6b, J6b,5 5.0 Hz), 3.66 (d, 1H, H-4, J4,5 9.1 Hz), 3.50
(m, 3H, H-a, H-d, H-a), 3.44 (d, 1H, H-b, JHa,Hb
7.0 Hz), 3.09 (d, 1H, H-b, JHa,Hb 14.2 Hz), 2.60 (s, large,
1H, NHCH ), 1.51 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.34
2ða;bÞ
(d, 3H, CH3, JCH;CH 7.8 Hz), 1.32 (s, 3H, CH3), 1.29 (s,
3
3H, CH3); 13C RMN (DMSO-d6) d 175.9 (C@O), 172.8
(C@O), 170.9 (C@O), 113.1 (CH3CCH3), 110.3
(CH3CCH3), 104.0 (C-1), 84.3 (C-4), 82.7 (C-2), 73.0 (C-
5), 69.3 (C-6), 67.2 (C-3), 49.9 (CH), 47.4 (CH2(a,b)), 44.7
(CH2(c,d)), 39.8 (CH2(a,b)), 27.3 (CH3), 27.0 (CH3), 26.7
chromatography (EtOAc) compound 42 (2.28 g, 67%)
20
was isolated as a slight yellow syrup; ½aꢂD ¼ þ7:0 (c 0.10,
CHCl3); IR (ATR): m 2988, 2901, 1726, 1664, 1525, 1455,

80
H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
(CH3), 25.5 (CH3), 14.9 (CH3(ala)); HRMS: calcd [M+Na]+
479.2118; found, 479.2130. Anal. Calcd for C20H32N4O8
(456.22 g/mol): C, 52.62; H, 7.07; N, 12.27. Found: C,
52.55; H, 7.07; N, 11.98.
MeOH/H2O (9:1) and stirred at room temperature. After
neutralization with resin IRA-120 (pH 6), the reaction mix-
ture was filtered and the solvent removed under vacuo. To
the crude material solubilized in EtOAc (3.5 mL) and
EtOH (2 mL) were added 16 mg of Pd/C (10%) and stirred
under hydrogen overnight. After filtration through a Celite
pad and removal of the solvent, compound 44 was ob-
tained quantitatively and used in the next step without fur-
ther purification. The crude compound 44 (0.40 g,
1.26 mmol) was solubilized in 6 mL of a solution of
TFA/H2O (9:1) and stirred at room temperature. After
one night, the solvent was removed under reduced pres-
sure. The residue was co-evaporated successively with
MeOH and toluene. Crystallization in diethyl ether gave
4.42. 3-C-[[[(Benzyloxy)carbonyl]glycyl]aminomethyl]-3-
[(carboxymethyl)amino]-3-deoxy-D-allopyranose 45
Compound 38 (0.51 g, 9.55 mmol) was solubilized in 6 mL
of a solution of TFA/H2O (9:1) and stirred at room tem-
perature. After one night, the solvent was removed under
reduced pressure, and the residue was co-evaporated suc-
cessively with MeOH and toluene. Crystallization in
diethyl ether gave after filtration compound 45 (0.44 g,
100%) as a white solid; mp = 200–203 °C; IR (ATR): m
1725, 1660, 1530, 1296, 1232, 1166 cmꢁ1; 45a: 13C NMR
(DMSO-d6) d 172.2 (C@O), 168.4 (C@O), 157.4 (C@O),
137.7 (Cq), 129.2–127.3 (phenyl), 92.7 (C-1), 68.8 (C-2),
67.6 (C-4), 66.5 (CH2(Z)), 65.9 (C-5), 65.3 (C-3), 61.7 (C-
6), 44.6 (CH2(a,b)), 41.2 (CH2(c,d)), 37.9 (CH2(a,b)). 45b:
13C NMR (DMSO-d6) d 172.2 (C@O), 170.7 (C@O),
157.4 (C@O), 137.7 (Cq), 129.2–127.3 (phenyl), 92.7 (C-
1), 69.0 (C-2), 67.9 (C-4), 66.5 (CH2(Z)), 66.2 (C-5), 65.5
(C-3), 61.7 (C-6), 45.5 (CH2(a,b)), 41.2 (CH2(c,d)), 38.4
(CH2(a,b)); MS (ES) [MꢁH] ꢁ456,4. Anal. Calcd for
C19H27N3O10 (457.17 g/mol): C, 49.89; H, 5.95; N, 9.19.
Found: C, 49.71; H, 5.88; N, 8.99.
after filtration compound 47 (0.59 g, 92%) as a white solid;
20
mp = 100–103 °C, ½aꢂD ¼ þ29 (c 0.25; H2O); IR (ATR): m
3394, 1670, 1556, 1434, 1198, 1135, 839, 800, 723 cmꢁ1
;
1H NMR (D2O) d 5.05 (d, 1H, H-1, J1,2 2.3 Hz), 4.36 (q,
1H, CHala, JCH;CH 7.2Hz), 4.05 (d, 1H, H-a, CH2(a,b),
3
JHa,Hb 15.7 Hz), 3.99 (d, 1H, H-b), 3.90 (d, 1H, H-2),
3.73 (d, 1H, H-a, CH2(a,b), JHa,Hb 8.9 Hz), 3.62–3.50 (m,
6H, H-4, H-5, H-b, H-6a, CH2(c,d)), 3.46 (m, 1H, H-6b,
J6a,6b 8.5Hz), 1.16 (d, 3H, CH3(ala)); 13C NMR (D2O) d
176.0 (C@O), 168.7 (C@O), 166.6 (C@O), 163.3, 162.8,
162.4, 161.9 (CF3COOꢁ), 122.1, 118.2, 114.4, 110.5
(CF3COOꢁ), 92.0 (C-1), 67.6 (C-2), 66.0 (C-4, C-3), 64.3
(C-5), 60.6 (C-6), 49.2 (CH), 44.9 (CH2(a,b)), 40.7 (CH2(c,d)),
37.0 (CH2(a,b)), 16.2 (CH3(ala)); HRMS: calcd for
C14H27N4O9 [M+H]+ 395.1778; found, 395.1768.
4.43. 3-C-[[[(Benzyloxy)carbonyl]glycyl]aminomethyl]-3-
deoxy-3-[[[[1-(methoxycarbonyl)ethyl]amino]carboxy-
methyl]amino]-a-D-allopyranose 46
4.45. [(1R,2R,4S,5S,11S)]-1,2,5-Trihydroxy-4-hydroxy-
methyl-11-methyl-3-oxa-7,10,13,16-tetraaza-spiro[5.11]hep-
tadecane-9,12,15-trione 48
Compound 42 (0.40 g, 6.43 mmol) was solubilized in 10 mL
of a solution of TFA/H2O (9:1) and stirred at room tem-
perature. After one night, the solvent was removed under
reduced pressure, and the residue was co-evaporated suc-
cessively with MeOH and toluene. Crystallization in
Compound 44 (0.118 g, 0.26 mmol) was solubilized in 2 mL
of a solution of TFA/H2O (9:1) and stirred at room tem-
perature. After 48 h, the solvent was removed under re-
duced pressure. The residue was co-evaporated
successively with MeOH and toluene. Crystallization in
diethyl ether led after filtration to compound 46 (0.32 g,
20
92%) as a white solid; mp = 102–104 °C, ½aꢂD ¼ þ21 (c
diethyl ether led after filtration to compound 48 (92 mg,
0.10, H2O); IR (ATR): m 3391, 3207, 1672, 1540, 1454,
20
1
1201, 1138, 1052 cmꢁ1; H NMR (D2O) d 7.32 ( m, 5H,
94%) as a white solid; mp = 204–207 °C, ½aꢂD ¼ þ76 (c
0.10, H2O); IR (ATR): m 3391, 3207, 1670, 1540, 1290,
Ph), 5.18 (d, 1H, H-1, J1,2 2.2 Hz), 5.03 (s, 2H, CH2(Z)),
1138 cmꢁ1 1H NMR (D2O) d 5.27 (d, 1H, H-1, J1,2
;
4.36 (q, 1H, CH, JCH;CH 7.3 Hz), 4.15 (m, 2H, CH2(a,b)),
3
2.3 Hz), 4.90 (q, 1H, CHala, JCH;CH 6.3 Hz), 4.05 (d, 1H,
3.90 (d, 1H, H-2), 3.75 (m, 4H,CH2(c,d), CH2(a,b)), 3.70
(m, 4H, 2 ꢃ H-6, H-5, H-4), 3.64 (s, 3H, OCH3), 1.31 (d,
3H, CH3(ala)); 13C NMR (D2O) d 174.9 (C@O), 173.4
(C@O), 166.8 (C@O), 158.4 (C@O), 136.9 (Cipso), 129.1,
128.8, 128.1 (phenyl), 92.1 (C-1), 67.7 (CH2(Z)), 67.6 (C-
2), 66.6 (C-4), 66.1 (C-3), 64.8 (C-5), 60.8 (C-6), 53.4
(OMe), 49.4 (CH), 45.1 (CH2(a,b)), 44.1 (CH2(c,d)), 37.6
(CH2(a,b)), 16.3 (CH3(ala)); HRMS: calcd [M+H]+
543.2302; found, 543.228. Anal. Calcd for C23H34N4O11
(542.22 g/mol): C, 50.92; H, 6.32; N, 10.33. Found: C,
50.89; H, 6.15; N, 10.21.
3
H-a, CH2(a,b), JHa,Hb 16.8 Hz), 3.92 (m, 2H, H-2, H-4,
J4,5 9.9 Hz), 3.78 (m, 4H, CH2(c,d), H-6a, H-6b), 3.69 (d,
H-b, CH2(a,b)), 3.64 (m, 1H, H-5), 3.10 (d, 1H, H-a, Ja,b
15.6 Hz), 3.01 (d, 1H, H-b), 1.13 (d, 3H, CH3(ala)); 13C
NMR (D2O) d 175.3 (C@O), 172.0 (C@O), 165.9 (C@O),
91.9 (C-1), 69.5 (C-2), 68.2 (C-4), 66.9 (C-3), 65.9 (C-5),
60.4 (C-6), 45.9 (CH), 44.9 (CH2(a,b)), 44.2 (CH2(c,d)), 41.2
(CH2(a,b)), 157 (CH3(ala)); MS (ES) [M+Na]+ 399.4,
[M+K]+ 415.3.
4.44. 3-Deoxy-3-[[[[1-(carboxy)ethyl]amino]carboxy-
methyl]amino]-3-C-[[[glycyl]amino]methyl]-a-D-allopyra-
nose. Trifluoroactetate 47
Acknowledgments
´
H.D. thanks the Conseil Regional de Picardie for a fellow-
´
ship. D.P. thanks the Conseil Regional de Picardie, the
`
Compound 42 (169 mg, 0.30 mmol) and K2CO3 (46 mg,
CNRS and the Ministere de la Recherche for financial
0.33 mmol) were solubilized in 4 mL of a solution of
support.

H. Ducatel et al. / Tetrahedron: Asymmetry 19 (2008) 67–81
81
16. Durrat, F.; Xie, J.; Valery, J.-M. Tetrahedron Lett. 2004, 45,
1477–1479.
References
17. Chakraborty, T. K.; Roy, S.; Kumar, S. K.; Kunwar, A. C.
Tetrahedron Lett. 2005, 46, 3065–3070.
18. Chakraborty, T. K.; Krishna Mohan, B.; Uday Kumar, S.;
Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2004, 45,
5623–5627.
1. Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 230–253.
2. Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem.
Rev. 2002, 102, 491–514.
3. LeTiran, A.; Stables, J. P.; Kohn, H. Bioorg. Med. Chem.
2001, 9, 2693–2708.
19. Chakraborty, T. K.; Srinivasu, P.; Sakunthala Madhavendra,
S.; Kiran Kumar, S.; Kunwar, A. C. Tetrahedron Lett. 2004,
45, 3573–3577.
4. Mazaleyrat, J.-P.; Boutboul, A.; Lebars, Y.; Gaucher, A.;
Wakselman, M. Tetrahedron: Asymmetry 1998, 9, 2701–
2713.
20. Billing, J. F.; Nilsson, U. J. Tetrahedron Lett. 2005, 46, 991–
993.
5. Gaucher, A.; Bintein, F.; Wakselman, M.; Mazaleyrat, J.-P.
Tetrahedron Lett. 1998, 39, 575–578.
21. Billing, J. F.; Nilsson, U. J. Tetrahedron 2005, 61, 863–874.
22. Van Well, R. M.; Overkleeft, H. S.; Overhand, M.; Vang
Carstenen, E.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 2000, 41, 9331–9335.
23. Claridge, T. D. W.; Long, D. D.; Baker, C. M.; Odell, B.;
Grant, G. H.; Edwards, A. A.; Tranter, G. E.; Fleet, G. W. J.;
Smith, M. D. J. Org. Chem. 2005, 70, 2082–2090.
24. Smith, M. D.; Claridge, T. D. W.; Sansom, M. S. P.; Fleet, G.
W. J. Org. Biomed. Chem. 2003, 1, 3647–3655.
25. Martinkova, M.; Gonda, J.; Raschmanova, J. Molecules
2006, 11, 564–573.
6. Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395–
4421.
7. Bornaghi, L. F.; Wilkinson, B. L.; Kiefel, M. J.; Poulsen, S.-
A. Tetrahedron Lett. 2004, 45, 9281–9284.
8. Schweizer, F.; Hindsgaul, O. Curr. Opin. Chem. Biol. 1999, 3,
291–298.
9. Gervay-Hague, J.; Weathers, T. M., Jr. J. Carbohydr. Chem.
2002, 21, 867–910.
10. Van Well, R. M.; Meijer, M. E. A.; Overkleeft, H. S.; van
Boom, J. H.; van der Marel, G. A.; Overhand, M. Tetra-
hedron 2003, 59, 2423–2434.
26. Ducatel, H.; Van Nhien, A. N.; Pilard, S.; Postel, D. Synlett
2006, 1875–1878.
11. Schweizer, F.; Hindsgaul, O. Carbohydr. Res. 2006, 341,
1730–1736.
27. Van Nhien, A. N.; Tomassi, C.; Len, C.; Marco-Contelles, J.
L.; Balzarini, J.; Pannecouque, C.; De Clercq, E.; Postel, D. J.
Med. Chem. 2005, 48, 4276–4284.
28. Van Nhien, A. N.; Ducatel, H.; Len, C.; Postel, D. Tetra-
hedron Lett. 2002, 43, 3805–3808.
12. Jayakanthan, K.; Vankar, Y. D. Tetrahedron Lett. 2006, 47,
8667–8671.
13. Xie, J. Carbohydr. Res. 2003, 338, 399–406.
14. Chakraborty, T. K.; Sudhakar, G. Tetrahedron Lett. 2005,
46, 4287–4290.
29. Postel, D.; Van Nhien, A. N.; Villa, P.; Ronco, G. Tetrahe-
dron Lett. 2001, 42, 593–595.
30. Postel, D.; Van Nhien, A. N.; Pillon, M.; Villa, P.; Ronco, G.
Tetrahedron Lett. 2000, 41, 6403–6406.
15. Chakraborty, T. K.; Reddy, V. R.; Sudhakar, G.; Uday
Kumar, S.; Reddy, T. J.; Kiran Kumar, S.; Kunwar, A. C.;
Mathur, A.; Sharma, R.; Gupta, N.; Prasad, S. Tetrahedron
2004, 60, 8329–8339.