Studies on reactivity of azidoamides, intermediates in the synthesis of tetrahydroxypipecolic acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.03.018

Azido group reduction was observed by the treatment of a 2-azido-3-triisopropylsilyloxy heptonamide derivative with NaI in DMSO. The process allowed us to obtain a tetrahydroxypipecolic acid amide derivative. The same azido amide was treated with LiCl in DMSO, but desilylation occurred to give 3,6-anhydro-2-azido heptonamide.

Full text of DOI:10.1016/j.tetasy.2008.03.018

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 932–937
Studies on reactivity of azidoamides, intermediates in the synthesis
of tetrahydroxypipecolic acid derivatives
*
´
´
M.-Soledad Pino-Gonzalez, Carmen Assiego and Noe Ona
˜
Departamento de Bioquı´mica, Biologı´a Molecular y Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Ma´laga, 29071 Ma´laga, Spain
Received 15 February 2008; accepted 20 March 2008
Abstract—Azido group reduction was observed by the treatment of a 2-azido-3-triisopropylsilyloxy heptonamide derivative with NaI in
DMSO. The process allowed us to obtain a tetrahydroxypipecolic acid amide derivative. The same azido amide was treated with LiCl in
DMSO, but desilylation occurred to give 3,6-anhydro-2-azido heptonamide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
R´´
N
OR´
CONEt2
OH
O
HO
HO
CONEt2
O
[N]
Iminoalditols (also known as iminosugars or azasugars) are
valuable glycosidase inhibitors.1,2 They have attracted
interest as potential therapeutic agents against HIV infec-
tion,3 cancer,4 diabetes5 and other genetic or metabolic dis-
orders.6 However, at the moment, their use is limited
because of a lack of commercially viable syntheses. Addi-
tionally, new structures with higher selectivities are
needed.7
O
OH
4
5
TrO
OR´
OR´
TrO
OR
X
CONEt2
CONEt2
O
O
O
O
O
[N]
[N]
As part of our ongoing work on the preparation of glyco-
sidase inhibitors, we are interested in stereoselective meth-
ods for synthesizing iminoalditols from 2,3-epoxyamides.8
In 2,6-iminoheptitols, the presence of an additional a- or
b-hydroxymethyl group often leads to an increase in either
their potency and/or specificity as inhibitors. Polyhydroxy
pipecolic acid analogues have attracted a number of
approaches to their synthesis because of their potential bio-
logical properties.9 In a communication,8a we described a
route to form the piperidine framework from an epoxide
1, obtained from a D-ribose derivative. This strategy was
based on the regioselective epoxide opening by nitrogen
nucleophiles, followed by selective hydroxyl group protec-
tion (Scheme 1). Intermediates of type 2 gave us the possi-
bility of synthesizing C-6 epimers 3 and 4. In order to
obtain the 6-(R) isomers, an azido epoxide of type 5 was
obtained, but its reduction and subsequent cyclization led
to a mixture of imino derivatives with different ring sizes.
6
2
R´´
N
H
CONEt2
OH
OH
O
H
TrO
HO
CONEt2
[N]
HO
O
OH
3
1
Scheme 1. Retrosynthetic analysis of 2,6-dideoxy-2,6-imino-heptonamides
(pipecolic acid amide derivatives).
Thus, polyhydroxy piperidine and azepane derivatives
could be obtained.8a We then planned other transforma-
tions to change the configuration at C-6 in an intermediate
of type 2.8e
We chose an azido derivative because azides have several
advantages as amino protecting groups. Azido groups offer
low steric hindrance, uncomplicated NMR spectra and
*
Corresponding author. Tel.: +34 952134260; fax: +34 952131941;
e-mail: pino@uma.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.018

M.-Soledad Pino-Gonza´lez et al. / Tetrahedron: Asymmetry 19 (2008) 932–937
933
good solubility. Moreover, azides are resistant to many
reaction conditions and can be easily reduced to amines.
Much effort has been devoted to obtain efficient azido
reduction methods,10 and some of them have found appli-
cation in carbohydrate area.11 Besides the well-known
methods such as hydrogenation, or the use of hydrides or
triphenyl phosphine, there are a variety of reagents de-
formed by treating 12 with different nucleophiles and sol-
vents. With NaI in acetone or LiCl in THF, after 48 h at
rt, the starting material was recovered. With NaI in
DMSO, after 48 h at rt, a new, more polar product 13
was observed, which was isolated and purified by column
chromatography. NMR data (d ppm) of compound 13 al-
lowed us to confirm a pyrimidine ring (C-6: 50.8 and C-2:
53.4). The protons H-6, 7–70 and 2 appeared at higher field
(2.94, 3.03 and 3.74) compared with the data of the previ-
ous compound 12. Acetylation of 13 gave the N-acetylated
14 with higher values of d for H-6, 7–70 and 2. The slow
rate of the acetylation reaction (several days) can be attrib-
uted to steric hindrance with nearby trityl and amide
group. The cis-configuration of the substituents at C-5
and C-6 was assigned by a comparison with the detritylated
C-6 epimer 15,19 obtained from epoxide 5 (R0: TIPS, [N]:
N3).8a Compound 13 showed NMR data different to that
of 15, confirming the direct displacement of –OSO2CH2Cl
by [N]. Whereas the epimer 15 had J5,6 = 8.6 Hz (trans-ax-
ial relationship); in 13 the smaller coupling constant could
not be measured directly but it could be in the acetylated 14
(J5,6 = 4.8 Hz).
scribed in the literature for the reduction of azides, includ-
ing FeSO4/NH3,12 SmI2 or Sm/I2,13 Sm/NiCl2
and
14
FeCl3/Zn.15 The inexpensive NaI has usually been em-
ployed in combination with other halides: FeCl3/NaI16 or
TMSCl/NaI.17 Additionally, the treatment of arylazides
with NaI in acetic acid or formic acid gave N-arylaceta-
mides or N-arylformamides, respectively.18 To the best of
our knowledge the use of NaI in DMSO has not previously
been reported for the reduction of the azide functionality.
Herein, we report the unexpected results obtained in
displacement reactions with 2-azido amide derivatives,
containing suitable nucleofuges at C-6, when they were
treated with halides. The conditions which provoked azido
reduction and/or internal displacement are described.
In Scheme 3 the formation of 13 is shown. Firstly, the io-
dide causes azido group reduction and thus, [N] is free to
attack at C-6, provoking the cyclization to the piperidine
13. The reduction mechanism is unknown; it is not clear
if an intermediate amine is formed or another reduced spe-
cies. The evidence is that the chloromesylate group is dis-
placed to give the iminosugar derivative. Kamal et al.
employed FeCl3/NaI or TMSCl/NaI combinations to re-
duce azides to amines.16,17 The role of NaI in these pro-
cesses is unclear and it could involve the participation of
in situ generated FeI3 or TMSI, respectively. But in our
case, there is no additional halide added, but only DMSO.
2. Results and discussion
2-Azido amide 7 was obtained by regioselective epoxide
opening of epoxiamide 1, with NaN3 in DMF, with acetic
acid as catalyst. Next, we had to selectively protect the hy-
droxyl group at C-3 in 7. The best results were obtained
with TIPSOTf (triisopropyl silyl triflate) and lutidine giving
8 as the principal isomer (Scheme 2). With the appropriate
substrate 8 in hand, the next stage was the conversion of
the free hydroxyl group into a good leaving group. The
C-6 hydroxyl group was mesylated giving 10, but unfortu-
nately, it could not be displaced by nucleophiles such as
Brꢀ, Iꢀ or AcOꢀ.
On the other hand, the reaction of 12 with LiCl in DMSO
gave, after 30 h at rt, a new, more polar product 16, which
was isolated and purified by column chromatography.
NMR data showed the disappearance of the silyl group
and the presence of a furanose ring. Lithium chloride pro-
voked the desilylation of 12 and the intramolecular cycliza-
tion. Product 16 was also obtained by the reaction of 17
with NaN3 in DMF. These 2-azido amides are valuable
products to obtain synthetic aminoacids,20 which can be
used for the modification of bioactive glycopeptides.
OH
OR´
TrO
OR
OH
TrO
CONEt2
CONEt2
a
b
1
N3
O
N3
O
O
O
7
8 R = H, R´ = TIPS
9 R = TIPS, R´ = H
TrO
OTIPS
OTIPS
CONEt2
TrO
OMs
CONEt2
3. Conclusion
X-
-
X
c
8
O
O
O
O
N3
N3
In conclusion, these results confirmed to us the importance
of the solvent in these transformations, DMSO being the
solvent that permits a better reactivity. To the best of our
knowledge, there has not been any previous description
of azido group reduction with NaI in DMSO. This combi-
nation is a mild, suitable and inexpensive system for the
efficient synthesis of 13. With regard to the role of LiCl
in DMSO, it promoted desilylation and further cyclization
by the internal displacement of the nucleofuge. The failed
attempts of direct substitution on C-6 by external nucleo-
philes may be due to the large steric hindrance of the trityl
group.
-
-
-
X = I , Br , AcO
11
10
Scheme 2. Reagents: (a) NaN3, DMF, cat. AcOH; (b) TIPSOTf, 2,6-
lutidine, CH2Cl2; (c) MsCl, py.
Different results were found with the chloromesylated
derivative 12, as it is depicted in Scheme 3. Compound
12 was easily obtained in 45 min and isolated after usual
work-up without the need for further purification. NMR
data confirmed its structure. Several reactions were per-

934
M.-Soledad Pino-Gonza´lez et al. / Tetrahedron: Asymmetry 19 (2008) 932–937
R
H
N
[N]
OR
TrO
N
O
CONEt2
OTIPS
HO
CONEt2
OTIPS
CONEt2
OTIPS
TrO
NaI
O
O
DMSO
O
O
O
OTIPS
13 R = H
14 R = Ac
15
TrO
OR
b
CONEt2
O
O
N3
N3
CONEt2
H
Si
O
OR´
TrO
c
O
8 R = H
12 R = SO2CH2Cl
O
TrO
a
LiCl
d
Cl-
OR
CONEt2
TrO
CONEt2
DMSO
O
H
O
O
O
O
O
N3
1 R = H
17 R = Ms
16
´
Scheme 3. Reagents: (a) chloromethanesulfonyl chloride, py; (b) Ac2O, py; (c) MsCl, py; (d) NaN3, DMF, cat. AcOH.
21
4. Experimental
rial). Rf: 0.5 (7:3 hexane/ethyl acetate), ½aꢁD ¼ ꢀ28 (c 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.60–7.20 (m,
15H, Ph), 4.36 (dd, 1H, J5,6 = 9.7, H-5), 4.15 (dd, 1H, H-
3), 4.04 (dd, 1H, J4,5 = 5.4, J4,3 = 10.0, H-4), 3.96 (m,
1H, H-6), 3.93 (d, 1H, J2,3 = 3.0, H-2), 3.51–3.32 (m, 5H,
4.1. General
All reactions were carried out under either an argon or
nitrogen atmosphere. Reactions were monitored by thin
layer chromatography (TLC) on E. Merck silica gel plates
(0.25 mm) and visualized using UV light (254 nm) and/or
heating with 7% ethanolic phosphomolybdic acid solution.
Flash chromatography was performed on E. Merck Silica
Gel (60, particle size 0.040–0.063 mm). After chromato-
graphic purification, the formation of solid foam is fa-
voured by dissolving syrupy products in some Et2O and
evaporating in vacuo. NMR spectra were recorded on a
Bruker WP200SY spectrometer at room temperature.
Mono- and bidimensional experiments (SEFT, COSY
and gHMQC) were performed to elucidate the new struc-
tures. Chemical shifts (ppm) are reported relative to the
residual solvent peak. Multiplicities are designated as sin-
glet (s), doublet (d), triplet (t) and multiplet (m). Coupling
constants are expressed as J values in Hertz units. Optical
rotations were measured on a Perkin–Elmer 241 polarime-
ter. Elemental analyses were performed by the Microanal-
0
0
H-7 and 2CH2CH3), 3.26 (dd, 1H, J7 ,6 = 5.5, J7,7 = 9.7,
H-70), 1.25–1.17 (m, 12H, CH3). 13C NMR d (100 MHz,
CDCl3): 168.8 (CO), 144.1, 128.8, 127.7 and 126.8 (Ph),
108.8 (CMe2), 86.4 (CPh3), 77.7 (C-4, 5), 73.2 (C-3), 68.5
(C-6), 65.2 (C-7), 55.0 (C-2), 42.6 and 41.0 (CH2CH3),
27.9 and 25.2 [C(CH3)2], 14.2 and 13.0 (CH2CH3). HRMS
(FAB): m/z 611.2845 [M+Na]+ (C33H40N4NaO6 requires
611.2845). Elemental Anal. Calcd for C33H40N4O6: C,
67.33; H, 6.85; N, 9.52. Found: C, 67.47; H, 6.97; N, 9.15.
4.3. 2-Azido-N,N-diethyl-4,5-O-isopropylidene-3-O-triiso-
propylsilyl-7-O-trityl-D-glycero-D-allo-heptonamide 8 and 2-
azido-N,N-diethyl-4,5-O-isopropylidene-6-O-triisopropylsi-
lyl-7-O-trityl-D-glycero-D-allo-heptonamide 9
To a stirred solution of 7 (518 mg, 0.87 mmol) in anhy-
drous CH2Cl2 (2.5 mL) at 0 °C under an argon atmosphere
were added 2,6-lutidine (0.25 mL, 2.19 mmol) and triiso-
propylsilyl triflate (0.26 ml, 0.96 mmol). After 20 min
MeOH was added (5 mL). The reaction mixture was di-
luted with ethyl ether and washed with aq NH4Cl and then
with water. Organic solvents were evaporated in vacuo and
the residue was purified by column chromatography to give
silylated 8 (390 mg, 60%) and 9 (130 mg, 20%) as white so-
´
yses service of the University of Malaga. High resolution
mass spectra (HRMS) were recorded on a Micromass
AutoSpecQ instrument of the University of Granada or
on a Kratos MS-80RFAa of the University of Seville.
4.2. 2-Azido-N,N-diethyl-4,5-O-isopropylidene-7-O-trityl-D-
glycero-D-allo-heptonamide 7
lid foams. Compound 8 had Rf: 0.7 (6:1 hexane/ethyl ace-
22
tate). ½aꢁD ¼ ꢀ10 (c 0.3, CH2Cl2). 1H NMR (400 MHz,
To
a
stirred solution of epoxiamide 121,8a (2.58 g,
CDCl3) d: 7.60–7.20 (m, 15H, Ph). 4.98 (dd, 1H, H-3),
4.51 (d, 1H, J2,3 = 9.3, H-2), 4.34 (dd, 1H, J4,3 = 2.3, H-
4), 4.24 (dt, 1H, H-6), 3.95 (dd, 1H, J5,4 = 5.5, J5,6 = 9.9,
H-5), 3.65 and 3.54 (2m, 2H, CH2CH3), 3.43 (dd, 1H,
J7,6 = 2.1, H-7), 3.25 and 3.15 (2m, 2H, CH2CH3), 3.08
4.7 mmol) in DMF (31.5 mL) were added NaN3 (0.46 g,
7.1 mmol) and AcOH (0.13 mL, 2.3 mmol). The mixture
was left at rt and monitored by TLC. After 4 d, more Na-
N3(1.5 equiv) and AcOH (0.5 equiv) were added and the
reaction was left for 4 d.22 Then, the mixture was diluted
with ethyl ether and washed with aq NH4Cl and then with
water. The organic layer was dried over MgSO4 and the
solvents were evaporated in vacuo. Purification by column
chromatography gave 7 (1.71 g) as a white foam and
500 mg of 1 (80% total yield over recovered starting mate-
(dd, 1H, J7,7 = 9.2, J7 ,6 = 7.6, H70), 1.32 and 1.29 (s, 3H,
C(CH3)2), 1.22 (t, 3H, CH2CH3), 1.16 (t, 3H, CH2CH3),
1.07–1.12 (m, 21H, Si[CH(CH3)2]3). 13C NMR (100 MHz,
CDCl3) d: 166.3 (CO). 144.1, 128.8, 127.6 and 126.8 (Ph),
107.3 [C(CH3)2], 86.5 (CPh3), 78.12 (C-4), 77.1 (C-5),
70.4 (C-3), 68.9 (C-6), 65.3 (C-7), 58.7 (C-2), 42.5 and
0
0

M.-Soledad Pino-Gonza´lez et al. / Tetrahedron: Asymmetry 19 (2008) 932–937
935
41.4 (2CH2CH3), 27.4 and 25.3 [C(CH3)2], 18.3–18.0
(Si[CH(CH3)2]3), 14.9, 13.1 and 12.9 (Si[CH(CH3)2]3 and
2CH2CH3). HRMS (FAB): m/z 767.4180 [M+Na]+
(C42H60N4NaO6Si requires 767.4180). Elemental Anal.
Calcd for C42H60N4O6Si: C, 67.71; H, 8.12; N, 7.52.
45 min. The reaction was quenched by the addition of
methanol, diluted with ethyl ether and filtered through a
small amount of silica gel. The filtrated solution was
washed with water, dried over anhydrous MgSO4, and con-
centrated giving pure 12 (80 mg, 100%) as a white foam. Rf:
22
Found: C, 67.61; H, 8.12; N, 7.34. Compound 9 had Rf:
0.6 (hexane/ethyl acetate, 4:1). ½aꢁD ¼ þ26 (c 0.8, CHCl3).
22
0.6 (6:1 hexane/ethyl acetate). ½aꢁD ¼ ꢀ12:5 (c 0.2,
1H NMR (400 MHz, CDCl3) d: 7.50–7.20 (m, 15H, Ph).
5.39 (dt, 1H, H-6), 4.95 (dd, 1H, J3,2 = 7.0, H-3), 4.47 (t,
1H, J5,4 = 5.8, J5,6 = 3.5, H-4), 4.38 (d, 1H, H-2), 4.34
(dd, 1H, H-5), 4.16 (2d, 2H, SO2CH2Cl), 3.52 (m, 2H, H-
7, H-70), 3.32 (m, 4H, 2CH2CH3), 1.27 and 1.24 [s, 3H,
C(CH3)2], 1.15 and 1.08 (t, 3H, CH2CH3), 1.01–0.98 (m,
21H, Si[CH(CH3)2]3). 13C NMR d (100 MHz, CDCl3):
166.3 (CO), 142.7, 128.8, 127.8 and 127.2 (Ph), 107.4
[C(CH3)2], 87.3 (CPh3), 82.9 (C-6), 78.5 (C-4), 75.0 (C-5),
70.1 (C-3), 62.2 (C-7), 60.4 (C-2), 54.9 (OSO2CH2), 42.1
and 41.0 (2CH2CH3), 26.8 and 24.8 [C(CH3)2], 18.1
(Si[CH(CH3)2]3), 14.5, 13.0 and 12.8 (Si[CH(CH3)2]3 and
2CH2CH3). HRMS (FAB): m/z 879.3567 [M+Na]+.
CH2Cl2). 1H NMR (400 MHz, CDCl3) d: 7.6–7.2 (Ph),
4.87 (d, 1H, OH, JOH,3 = 10), 4.53 (m, 1H, H-6), 4.41
(dd, 1H, H-5), 4.1 (dt, 1H, H-3), 3.92 (dd, 1H, J4,3 = 9.7,
J4,5 = 7.0, H-4), 3.62 (d, J2,3 = 3.1, 1H, H-2), 3.24–
3.52 (m, 6H, H-70, H-7, 2CH2CH3), 1.23–1.09 (m, 33H,
Si[CH(CH3)2]3, 2CH2CH3, C(CH3)2). 13C NMR (100
MHz, CDCl3) d: 168.7 (CO), 144.0, 128.8, 127.7 and
126.8, (Ph), 107.8 [C(CH3)2], 86.8 (CPh3), 80.4 (C-5), 77.2
(C-4), 71.9 and 72.0 (C-6 and C-3), 66.3 (C-7), 55.7 (C-2),
42.5 and 40.8 (2CH2CH3), 26.44 and 24.34 [C(CH3)2],
18.0–18.3 (Si[CH(CH3)2]3), 14.2 and 13.0 (2CH2CH3),
12.5 (Si[CH(CH3)2]3). HRMS (FAB): m/z 767.4182
[M+Na]+ (C42H60N4NaO6Si requires 767.4180). Elemental
Anal. Calcd for C42H60N4O6Si: C, 67.71; H, 8.12; N, 7.52.
Found: C, 67.68; H, 8.13; N, 7.44.
4.6. N,N-Diethyl-2,6-dideoxy-2,6-imino-4,5-O-isopropy-
lidene-3-O-triisopropylsilyl-7-O-trityl-L-glycero-D-allo-
heptonamide 13
4.4. 2-Azido-N,N-diethyl-4,5-O-isopropylidene-6-O-mesyl-3-
O-triisopropylsilyl-7-O-trityl-L-glycero-D-allo-heptonamide
10
To a solution of compound 12 (30 mg, 0.034 mmol) in
DMSO (0.5 mL) was added NaI (6.81 mg, 0.045 mmol,
1.3 equiv) with stirring. The reaction was monitored by
TLC. After 48 h, the solution was diluted with ethyl ether,
washed with water, dried over anhydrous MgSO4, and con-
centrated. Purification by column chromatography affor-
To a stirred solution of 8 (351 mg, 0.47 mmol) in anhy-
drous pyridine (1.2 mL) at 0 °C under an argon atmo-
sphere was added mesyl chloride (0.04 mL, 0.61 mmol).
The reaction mixture was left to reach rt. After 15 h,
TLC showed the completion of the reaction, and the reac-
tion mixture was diluted with methanol. The mixture was
partitioned between diethyl ether and water. The organic
solvents were dried over MgSO4 and evaporated in vacuo.
The residue was purified by column chromatography to
ded piperidine 13 (18.5 mg, 75%) as a white solid foam.
22
Rf: 0.4 (hexane/ethyl acetate, 4:1). ½aꢁD ¼ ꢀ10:5 (c 0.26,
1
CH2Cl2). H NMR (400 MHz, CDCl3) d: 7.40–7.10 (m,
15H, Ph), 4.47–4.44 (m, 3H, H-3, 4 and 5), 3.74 (d, 1H,
J2,3 = 8.80, H-2), 3.25 (m, 4H, 2CH2CH3), 3.04–2.95 (m,
3H, H-6, 7 and 70), 1.37 and 1.28 [2s, 2 ꢂ 3H, C(CH3)2],
1.11–0.98 (m, 21H, Si[CH(CH3)2]3, 2CH2CH3). 13C NMR
d (100 MHz, CDCl3): 171.9 (CO), 144.15, 128.8, 127.5
and 126.7 (Ph), 108.5 [C(CH3)2], 86.4 (CPh3), 75.7 (C-4),
74.5 (C-5), 68.7 (C-3), 63.5 (C-7), 53.4 (C-2), 50.8 (C-6),
41.9 and 40.9 (2CH2CH3), 26.3 and 23.9 [C(CH3)2], 17.9
(Si[CH(CH3)2]3), 14.8 and 12.7 (2CH2CH3), 12.6
(Si[CH(CH3)2]3). HRMS (FAB): m/z 701.4316 [M+H]+
(C42H61N2O5Si requires 701.4349).
give compound 10 (346 mg, 90%) as a white foam. Rf: 0.4
20
(4:1 hexane/ethyl acetate). ½aꢁD ¼ þ24 (c 0.37, CH2Cl2).
1H NMR (400 MHz, CDCl3) d: 7.47–7.22 (m, 15H, Ph).
5.36 (dt, 1H, H-6), 4.95 (dd, 1H, J3,2 = 2.5, J3,4 = 7.3, H-
3), 4.60 (t, 1H, J5,4 = 6.8, J5,6 = 7.1, H-5), 4.47–4.43 (m,
2H, H-4 and H-2), 3.63–3.54 (m, 3H, H-70, H-7 and
CH2CH3), 3.51–3.44 (m, 1H, CH2CH3), 3.39–3.30 (m,
2H, CH2CH3), 2.78 (s, 3H, OSO2CH3), 1.34 and 1.31 [2s,
2 ꢂ 3H, C(CH3)2], 1.22 and 1.15 (t, 2 ꢂ 3H, 2CH2CH3),
1.08 (m, 21H, Si[CH(CH3)2]3). 13C NMR (100 MHz,
CDCl3) d: 166.5 (CO), 127.1, 127.7, 129.0 and 143.1 (Ph),
107.4 [C(CH3)2], 87.0 (CPh3), 81.0 (C-6), 79.0 (C-4), 75.4
(C-5), 70.2 (C-3), 62.2 (C-7), 60.3 (C-2), 42.1 and 41.0
(2CH2CH3), 39.42 (OSO2CH3) 26.6 and 24.6 [C(CH3)2],
18.1 (Si[CH(CH3)2]3), 14.6, 13.1 and 12.7 (Si[CH(CH3)2]3
and 2CH2CH3). HRMS (FAB): m/z 845.3954 [M+Na]+
(C43H62N4NaO8SSi requires 845.3955). Elemental Anal.
Calcd for C43H62N4O8SSi: C, 62.74; H, 7.59; N, 6.81; S,
3.90. Found: C, 62.76; H, 6.69; N, 6.79; S, 3.76.
4.7. Acetylation of piperidine 13
To a stirred solution of piperidine 13 (13 mg, 0.018 mmol)
in dried pyridine (0.5 mL) was added acetic anhydride
(0.4 mL). The reaction was monitored by TLC which
showed the slow formation of a more polar product. After
6 d, the solvent is concentrated and the residue chromato-
graphed to give unreacted 13 (5 mg) and pure 14 (7 mg) as
a white solid foam, 82% total yield over recovered starting
1
material. Rf: 0.33 (4:1 hexane/ethyl acetate). H NMR d
(400 MHz, CDCl3): 7.42–7.12 (m, 15H, Ph), 5.10 (d, 1H,
J2,3 = 6.1, H-2), 4.60 (dd, 1H, J5,4 = 7.9; J5,6 = 4.8, H-5),
4.50 (m, 2H, J3,4 = 3.05. H-3 and 6), 4.30 (dd, 1H, H-4),
3.84 (dd, 1H, H-7), 3.53 (m, 4H, 2CH2CH3), 3.24 (m,
1H, H-70), 1.86 (s, 3H, COCH3), 1.38 [s, 3H, C(CH3)2],
1.31 [m, 6H, CH2CH3, C(CH3)2], 1.13 (t, 3H, CH2CH3),
1.06 (m, 21H, Si[CH(CH3)2]3). 13C NMR d (100 MHz,
4.5. Chloromesylation of compound 8
To a dried flask under an argon atmosphere with com-
pound
8 (70 mg, 0.093 mmol) were added pyridine
(0.7 mL) and chloromethanesulfonyl chloride (0.01 mL,
0.12 mmol) at 0 °C, and the solution was stirred for

936
M.-Soledad Pino-Gonza´lez et al. / Tetrahedron: Asymmetry 19 (2008) 932–937
CDCl3): 171.9 (CONEt2), 170.0 (COCH3), 143.7, 128.8,
127.7 and 126.9 (Ph), 109.6 [C(CH3)2], 86.9 (CPh3), 73.9
(C-4), 72.5 (C-5), 68.4 (C-3), 64.1 (C-7), 57.0 (C-2), 56.8
(C-6), 42.3 and 40.7 (2CH2CH3), 25.6 and 23.8
[C(CH3)2], 23.1 (COCH3), 17.9 (Si[CH(CH3)2]3), 14.1 and
12.8 (2CH2CH3), 12.7 (Si[CH(CH3)2]3). HRMS (FAB):
m/z 743.4453 [M+H]+ (C44H63N2O6Si requires 743.4455).
4.10. Formation of compound 16 from mesylated epoxiamide
17
To a stirred solution of 17 (50 mg, 0.080 mmol) in DMF
(1 mL) were added NaN3 (18 mg, 0.277 mmol) and acetic
acid (0.04 mL). The reaction mixture was heated at 60 °C
for one week. Then, the mixture was diluted with ethyl
ether and washed with aq NH4Cl and then with water.
The organic layer was dried over MgSO4 and the solvents
were evaporated in vacuo. Purification by column chroma-
tography gave 16 (35 mg, 76%) which showed the same
spectroscopic data as above.
4.8. 3,6-Anhydro-2-azido-N,N-diethyl-4,5-O-isopropiliden-7-
O-trityl-L-glicero-D-allo-heptonamide 16
To a solution of 12 (50 mg, 0.058 mmol) in DMSO
(0.8 mL) was added LiCl (3.2 mg, 0.075 mmol) with stir-
ring at rt. After 30 h, a unique more polar product was ob-
served (TLC). The mixture was diluted with ethyl acetate
and washed with water. Organic solvents were concen-
trated in vacuo to give 16 (26.8 mg, 81%) as a white solid,
Acknowledgements
´
This research was supported with funds from Direccion
´
´
´
´
General de Investigacion Cientıfica y Tecnica of Spain
´
(Ref. CTQ2004-08141) and from Consejerıa de Educacion
which was characterized by NMR spectroscopy. mp:
21
´
y Ciencia, Junta de Andalucıa (FQM-158).
169 °C. Rf: 0.3 (hexane/ethyl acetate, 4:1). ½aꢁD ¼ þ7:5 (c
1.5, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.42–7.12
(m, 15H, Ph), 4.92 (dd, 1H, J4,5 = 6.3, H-4), 4.68 (dd,
1H, J 5,6 = 3.7, H-5), 4.35 (dd, 1H, J3,4 = 1.6, H-3), 4.11
(m, 1H, H-6), 3.92 (d, 1H, J2,3 = 6.9, H-2), 3.46 (m, 1H,
CH2CH3), 3.38–3.23 (m, 5H, H-7,70, CH2CH3), 1.28 [s,
3H, C(CH3)2], 1.24 [s, 3H, C(CH3)2], 1.18 and 1.10 (2t,
2 ꢂ 3H, CH2CH3). 13C NMR d (100 MHz, CDCl3): 166.3
(CO), 143.7, 128.8, 127.7 and 126.9 (Ph), 112.9
[C(CH3)2], 86.9 (CPh3), 84.3 (C-4), 82.6 (C-5), 81.7 (C-4),
81.3 (C-3), 62.5 (C-7), 58.7 (C-2), 42.0 and 41.0
(2CH2CH3), 26.3 and 25.3 [C(CH3)2], 14.8 and 12.9
(2CH2CH3). HRMS (FAB): m/z 593.2738 [M+Na]+
(C33H38N4NaO5 requires 593.2740).
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20
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M.-Soledad Pino-Gonza´lez et al. / Tetrahedron: Asymmetry 19 (2008) 932–937
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