Syntheses of sugar-related pyrrolidine derivatives by reductive amination reactions

Article abstract of DOI:10.1016/j.tetasy.2004.11.054

Several pyrrolidine iminosugar derivatives have been stereoselectively synthesised from a chiral keto-epoxyamide, by reductive amination procedures. An unexpected cyanide addition was observed when a mixture of SnCl₂ and NaCNBH₃ was employed.

Full text of DOI:10.1016/j.tetasy.2004.11.054

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 199–204
Syntheses of sugar-related pyrrolidine derivatives by
reductive amination reactions
*
M. S. Pino-Gonzalez and C. Assiego
´
´ ´ ´ ´
Departamento de Bioquımica, Biologıa Molecular y Quımica Organica, Facultad de Ciencias, Universidad de Malaga,
´
´
29071 Malaga, Spain
Received 30 October 2004;accepted 22 November 2004
Available online 5 January 2005
´
Dedicated to the memory of Dr. Fidel Jorge Lopez Herrera
Abstract—Several pyrrolidine iminosugar derivatives have been stereoselectively synthesised from a chiral keto-epoxyamide, by
reductive amination procedures. An unexpected cyanide addition was observed when a mixture of SnCl2 and NaCNBH3 was
employed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Iminosugars (or azasugars) represent an important class
of transition state analogue inhibitors of glycosidases
and glycosyl transferases.1–3 These compounds can be
considered as useful biological tools for a better under-
standing of glycoconjugate function, because of the key
role of carbohydrates in cellular recognition and signal-
ling phenomena. Some iminosugars are arousing great
interest as potential therapeutic agents against HIV
infection,4,5 cancer,6,7 diabetes8 and other genetic or
metabolic disorders.9 Some of them have already found
clinical application10,11 but efforts are still required to cre-
ate novel structures with improved potency and selecti-
vity towards a target enzyme. Many syntheses of
polyhydroxylated pyrrolidines and piperidines have
been focused on derivatives of D-gluco, D-manno or D-
Scheme 1. Reagents and conditions: (a) DMSO, Ac2O, 24 h;(b)
BnNH2, ZnCl2, NaBH3CN, EtOH, 7 h;(c) Ac 2O, py, 48 h.
galacto configurations because their targeting enzymes
are essential for living organism, but there are few re-
ports on L-derivatives and other diastereomers.12
iminosugars have been described previously using this
reaction,15,16 and a number of them were based in a dou-
These antecedents encouraged us to develop our own
ble reductive amination,17,18 with the possibility of ste-
synthetic approach to these compounds, from chiral
epoxyamides as starting materials.13,14 Among the strat-
egies followed by our group to reach several iminosugar
types, the most direct synthesis employed reductive amin-
ation as the key step (Scheme 1). Several approaches to
reoisomer mixtures being formed. We planned to
combine reductive amination with intramolecular epox-
ide opening.
2. Results and discussion
*
Our strategy starts with the oxidation of the epoxyamide
1a to the ketone 2. The best results were obtained
Corresponding author. Tel.: +34-952134260;fax: +34-952131941;
e-mail: pino@uma.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.054

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M. S. Pino-Gonzalez, C. Assiego / Tetrahedron: Asymmetry 16 (2005) 199–204
200
treating 1a with DMSO and Ac2O, although a small
quantity of methylthiomethylether 4 was isolated with
the oxidation product 2. Both products could be struc-
turally determined by spectroscopy. To test a possible
C-5 epimerisation in the oxidation product, we reduced
2 obtaining an inseparable mixture of 1a and its C-6 epi-
mer 5a in approximately 1:1 relation. The epimers were
acetylated giving the mixture of 1b,19 and 5b. Thus, it
was confirmed that 2 had not epimerised (Scheme 2).
In an experiment, the ethanol addition product 60
(R = Et) was detected.
To study the influence of the catalyst we repeated the
reaction of 2 with BnNH2 and NaCNBH3 using SnCl2
(Scheme 3), isolating 3a as major product (42%) along
with an a-aminonitrile 7a (12%) that could be formed
by cyanide addition to the imine intermediate before
cyclisation. The spectroscopy data confirmed this struc-
ture, (13C NMR: 117.5 ppm, C„N;quaternary C-6 in
SEFT), but not the absolute configuration at C-6. To
our knowledge this subproduct type has been not de-
scribed in literature in reductive amination reactions
with NaCNBH3 as reductor. The a-aminonitriles are
useful as a-aminoacids precursors and among the wide
range of synthetic routes to a-aminoacids, the related
Strecker synthesis is the most predominant (Table 1).
Scheme 2.
The reductive amination process permitted us to obtain
the pyrrolidine products in a one-pot procedure. The ke-
tone 2 was treated with benzylamine and zinc chloride in
ethanolic solution in the presence of sodium cyanoboro-
hydride. The reduction of the imine with subsequent regio-
selective epoxide opening gave the pyrrolidine 3a by a 5-
exo intramolecular process. Surprisingly, only a pyrrol-
idine derivative with the (S)-configuration (L-series) was
isolated. The (R)-isomer was not detected. The 1H NMR
data showed the symmetrical structure of 3a, with simi-
lar coupling constants J3,4 = 6.3 Hz and J5,6 = 6.4 Hz.20
The complete connectivity of the carbon and hydrogen
atoms was ascertained by 2D NMR experiments.
These signals: C-3 = 67.6 ppm, C-6 = 66.4 ppm, C-4 =
80.56 ppm and C-5 = 78.69 ppm are consistent with a
pyrrolidine ring. Additionally, the acetylation of 3a giv-
ing 3b, confirmed the structural assignment. Our strat-
egy takes advantage on earlier procedures due to the
complete stereoselectivity in both processes: reduction
and subsequent oxirane opening.
Scheme 3.
Table 1. Isolated products in the reductive amination reactions of
Scheme 323
Amine
Catalyst 3 (%)
7 (%)
6 (%)
BnNH2
BnNH2
ZnCl2
SnCl2
3a (60)
—
(25)
3a (42) 7a (12) Not
determined
(3)
3c (42) 7c (15) Not
determined
(CH3)2CH(CH2)2NH2 ZnCl2
(CH3)2CH(CH2)2NH2 SnCl2
3c (67)
—
With the object of studying the influence of the nature of
protecting group in the stereoselectivity of the reduction
process, we tested the reaction with a bulky aliphatic
amine. Moreover, N-alkylated azasugars have been
demonstrated to be stronger glycosidase inhibitors than
the corresponding nonalkylated derivatives.21 Using
isoamylamine we obtained similar results to those of
the benzyl amine with ZnCl2 or SnCl2 as catalysts
(Scheme 3). The formation of the product 3c showed
that the complete stereoselectivity, in the reductive ami-
nation reaction, cannot be simply justified by a possible
The low yield in the synthesis of 3a could be due to the
formation of hemiacetal 6, formed from 2 after several
hours of reaction. This product was isolated in several
experiments. The chromatographic mobility of product
6 was similar to that of 2 (slightly more polar), it being
sometimes difficult to determine the completion of the
reaction with accuracy. NMR experiments permitted
us to elucidate the structure of 6 but not the absolute
configuration at C-6.

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M. S. Pino-Gonzalez, C. Assiego / Tetrahedron: Asymmetry 16 (2005) 199–204
201
p–p stacking interaction between the trityl and benzyl
groups as we supposed at first. The role of the free hy-
droxyl groups in the formation of D-products22 has been
previously noted and accordingly, the presence of iso-
propylidene group should favour the L-products. In
our case, the reaction could not be tested with the depro-
tected ketone to compare possible changes in the stereo-
selectivity because the hydrolysis of the protecting
groups could provoke secondary reactions. Addition-
ally, some results revealed a discrepancy between the
soluble hydride and catalytic hydrogenation methods.17
monitored by thin layer chromatography (TLC) on E.
Merck silica gel plates (0.25 mm) and visualised 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 chromatographic purification,
the formation of solid foam is favoured solving syrupy
products in some of Et2O and evaporating. NMR spec-
tra were recorded at on a Bruker WP200SY spectrome-
ter at room temperature. Chemical shifts (ppm) are
reported relative to the residual solvent peak. Multipli-
cities are designated as: singlet (s), doublet (d), triplet
(t) and multiplet (m). Coupling constants are expressed
as J values in Hertz units. Mass spectra (EI, CI and
FAB) were recorded with a Kratos MS-80RFA or a
Micromass AutoSpecQ instrument with a resolution of
1000 or 60,000 (10% valley definition). For the FAB
spectra, ions were produced by a beam of xenon atoms
(67 keV), using 3-nitrobenzyl alcohol or thioglycerol as
matrix and NaI as salt. Exact masses were recorded on
a Kratos MS-80RFAa instrument of the University of
Seville. Specific rotations were measured with a Per-
kin–Elmer 241 polarimeter.
In contrast, employing a combination of ammonium
formate and sodium cyanoborohydride in methanol,
(Scheme 4) we obtained the D-isomer 8a and the direct
reduction product 1a. The C-6 epimer was not detected.
The structural assignment of 8a and that of its acetate 8b
was by NMR data (J5,6 = 0). Compound 1a cyclised eas-
ily to the C-glycoside 9.19
4.2. N,N-Diethyl 2,3-anhydro-4,5-O-isopropylidene-7-O-
trityl-D-altro-6-heptulosonamide 2
To a solution of 1a19 (0.7 g, 1.3 mmol) in DMSO
(3.6 mL, 51.3 mmol) cooled with ice bath was added
Ac2O (2.4 mL, 25.6 mmol). The mixture was allowed
to reach room temperature and stirred for 24 h. TLC
(CHCl3–hexanes–MeOH, 10:10:1) showed the depletion
of 1a and the formation of two faster-running
compounds. Ethyl ether was added (10 mL) and the
reaction mixture washed with water and the aqueous
layer extracted with Et2O (2 · 10 mL). The combined
organic layers were dried over anhyd MgSO4 and con-
centrated. The residue was chromatographed (AcOEt–
hexanes, 4:6) to give 4 (123 mg, 27%) and the ketone 2
Scheme 4.
3. Conclusion
(430 mg, 61%) as a white foam. Compound 2:
26
½aŠ ¼ À20 (c 0.53, CHCl3). Rf: 0.6 (AcOEt–hexanes,
D
In conclusion, with substituted amines and ZnCl2 or
SnCl2, the hydride delivery is from the least hindered
face to afford, after cyclisation, the L-isomers. With
ammonium formate, a less hindered imine is formed,
which leads to the product 8a (D-series) with a 5,6-
trans-relationship.
4:6);0.7 (CHCl 3–hexanes–MeOH, 10:10:1). 1H NMR
d (400 MHz, CDCl3): 1.09 (t, 3H, CH2CH3), 1.19 (t,
3H, CH2CH3), 1.29 (s, 3H, C(CH3)2), 1.44 (s, 3H,
C(CH3)2), 3.18 (dd, 1H, H-3, J3,4 = 5.4, J3,2 = 2.1),
3.30–3.46 (m, 4H, CH2CH3), 3.49 (d, 1H, H-2), 4.04
(d, 2H, H-7, H-70, J7,7 ¼ 6:9), 4.39 (dd, 1H, H-4,
0
J4,5 = 7), 4.84 (d, 1H, H-5), 7.21–7.43 (m, 15H, Tr).
We have described a method to achieve pyrrolidine
derivatives in a highly stereocontrolled manner, in five
steps from D-ribose. Therefore, this methodology can
be extended to the synthesis of various pyrrolidine
azasugars having suitable side chains for further syn-
thetic elaborations. This research program is underway
in our laboratory.
13C NMR
d (100 MHz, CDCl3): 12.8 and 14.6
(2CH2CH3), 25.0 and 26.9 (C(CH3)2), 40.6 and 41.3
(2CH2CH3), 51.5 (C-2), 55.2 (C-3), 69.3 (C-4), 76.2 (C-
7), 80.1 (C-5), 88.1 (CPh3), 110.5 [C(CH3)2], 127.4,
128.1, 128.6, 142.9 (Ph), 165.1 (CONEt2), 203.1 (CO).
FAB HRMS m/z: 566.251641, [MNa+] C33H37NO6Na
requires 566.251858.
Compound 4: Rf: 0.7 (AcOEt–hexanes, 4:6)1H NMR d
(400 MHz, CDCl3): 1.14 (t, 3H, CH2CH3), 1.25 (t, 3H,
CH2CH3), 1.37 (s, 3H, C(CH3)2), 1.40 (s, 3H,
C(CH3)2), 2.10 (s, 3H, CH2SCH3) 3.37 (dd, 1H, H-3,
J3,4 = 6,3, J3,2 = 1.8), 3.4–3.52 (m, 6H, H-7, H-70,
2CH2CH3), 3.54 (d, 1H, H-2), 4.02 (t, 1H, H-4,
J4,5 = 6.4), 4.06 (m, 1H, H-6), 4.55 (dd, 1H, H-5,
4. Experimental
4.1. General
All reactions were carried out under argon or nitrogen
atmosphere using distilled solvents. Reactions were

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M. S. Pino-Gonzalez, C. Assiego / Tetrahedron: Asymmetry 16 (2005) 199–204
202
J5,6 = 8.2), 4.67 (2d, 2H, CH2SCH3), 7.22–7.49 (m, 15H,
Tr). 13C NMR d (50 MHz, CDCl3): 12.9 and 14.6
(2CH2CH3), 14.7 (CH2SCH3) 24.9 and 27.5 [C(CH3)2],
40.6 and 41.3 (2CH2CH3), 51.8 (C-2), 55.1 (C-3), 62.5,
73.8, 74.8, 75.8, 77.1, 86.6 (CPh3), 108.7 [C(CH3)2],
126.9, 127.7, 128.7, 143.7 (Ph), 165.9 (CONEt2).
6.98 (m, 2H, CH2Ph), 7.15 (m, 3H, CH2Ph), 7.18–7.41
(m, 15H, Tr). 13C NMR d (100 MHz, CDCl3): 12.6
and 14.2 (2CH2CH3), 25.1 and 26.0 (C(CH3)2), 40.0
and 41.6 (2CH2CH3), 54.4 (CH2Ph), 61.6 (C-7), 66.4
(C-6), 67.5 (C-3), 67.7 (C-2), 78.7 (C-4), 80.6 (C-5),
86.8 (CPh3), 110.9 (C(CH3)2), 126.8, 127.6, 128.7,
137.0, 144.1 (Ph), 171.9 (CONEt2). FAB HRMS m/z:
635.3456 [MH+] C40H47N2O5 requires 635.3484.
Compound 6: 1H NMR d (400 MHz, CDCl3): 1.10
(t, 3H, CH2CH3), 1.18 (t, 3H, CH2CH3), 1.26 (s, 3H,
C(CH3)2), 1.28 (s, 3H, C(CH3)2), 3.04 (m, 1H,
CH2CH3), 3.16 (m, 1H, CH2CH3), 3.32 (d, 1H, H-7,
4.3. Reduction of 2 with NaBH4 and acetylation of 1a and
5a
To a cooled solution (0 ꢁC) of 2 (70 mg, 0.13 mmol) in
EtOH (0.5 mL) was added NaBH4 (4.8 mg, 0.13 mmol)
stirring for 15 min. The reaction mixture was diluted
with aq KHSO4 and extracted with Et2O. The organic
layer was dried over anhyd MgSO4, filtered and evapo-
rated. The residue was purified by preparative TLC
(AcOEt–hexanes, 1:1), yielding an inseparable mixture
of 1a and 5a (50 mg, 71%). A solution of the mixture
1a and 5a (42 mg, 0,08 mmol) and Ac2O (0.02 mL,
0.15 mmol) in pyridine (0.5 mL) was stirred at room
temperature for 24 h. The mixture was diluted with cold
water and extracted with Et2O. The organic layer was
dried over anhyd MgSO4, filtered and evaporated. The
residue was purified in preparative TLC (hexanes–
Et2O–NEt3, 5:10:2), yielding a mixture (Rf: 0.4) of the
acetylated products 1b19 and 5b (1:1, 30 mg, 65%). Se-
0
J7,7 ¼ 3:6), 3.83 (m, 1H, CH2CH3), 3.65 (m, 1H,
CH2CH3), 4.01 (dd, 1H, H-4, J4,3 = 3.6, J4,5 = 9.15),
4.47 (d, 1H, H-2, J2,3 = 5.5), 4.68 (d, 1H, H-5), 4.92
(dd, 1H, H-4), 7.16–7.41 (m, 15H, Tr). 13C NMR d
(100 MHz, CDCl3): 12.7 and 13.8 (2CH2CH3), 24.6
and 25.9 (C(CH3)2), 40.4 and 40.9 (2CH2CH3), 64.4
(C-7), 64.8 (C-2), 80.3, 81.4, 84.8 (C-3, C-4, C-5), 86.7
(CPh3), 104.5 (C-6), 112.5 (C(CH3)2), 127.2, 127.7,
128.6, 143.2 (Ph), 172.0 (CONEt2). FAB HRMS m/z:
561.270062, [MH+] C33H39N1O7 requires 561.272653.
4.6. Acetylation of 3a
A solution of 3a (100 mg, 0.16 mmol) and Ac2O
(0.5 mL) in 1.2 mL of pyridine was stirred for 48 h at
rt. After addition of cold water and extraction with
Et2O (2 · 5 mL), the combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Purifica-
tion by preparative TLC (AcOEt–hexanes, 1:1, Rf: 0.5)
1
lected H NMR data for compound 5a: 3.48 (d, H-2),
3.55 (m, H-3), 3.80 (t, H-4), 4.05 (m, H-6), 4.42 (dd,
H-5). Compound 5b: 4.72 (m, 2H, H-5 of 5a and 5b),
5.39 (m, H-6).
1
4.4. Typical procedure for reductive amination reaction
with metal chlorides
afforded pure 3b (74 mg, 80%) as a foam. H NMR d
(400 MHz, CDCl3): 0.91 (t, 3H, CH2CH3), 1.20 (t, 3H,
CH2CH3), 1.32 (s, 3H, C(CH3)2), 1.40 (s, 3H,
C(CH3)2), 2.06 (s, 3H, OCOCH3), 2.73 (m, 1H, H6),
3.06 (dd, 1H, H-3, J3,2 = 8.2, J3,4 = 4.6), 3.10–3.17 (m,
2H, CH2CH3), 3.29–3.35 (m, 3H, H-70, CH2CH3), 3.35
To a solution of the carbonyl compound 2 in EtOH was
added the amine and then a solution of NaCNBH3 and
the catalyst (ZnCl2 or SnCl2) in EtOH, stirring the mix-
ture at rt. After completion of the reaction, the mixture
was diluted with water and extracted with Et2O (2·).
The combined organic layers were dried over anhyd
MgSO4, filtered and evaporated and later purified.
0
(d, 1H, CH2Ph), 3.43 (t, 1H, H-7, J7,7 ¼ 8:3), 3.53 (d,
1H, CH2Ph), 3.70–3.77 (m, 1H, CH2CH3), 4.60 (dd,
1H, H-5, J5,4 = 6.0), 4.72 (dd, 1H, H-4), 5.51 (d, 1H,
H-2), 6.93 (m, 2H, CH2Ph), 7.14 (m, 3H, CH2Ph),
7.20–7.40 (m, 15H, Tr). 13C NMR d (100 MHz, CDCl3):
12.3 and 13.3 (2CH2CH3), 20.8 (OCOCH3) 25.4 and
26.1 (C(CH3)2), 40.9 and 42.2 (2CH2CH3), 54.2
(CH2Ph), 61.2 (C-7), 65.1 (C-2), 65.7 (C-6), 69.3 (C-3),
78.8 (C-4), 79.5 (C-5), 86.7 (CPh3), 110.8 (C(CH3)2),
126.8–144.1 (Ph), 168.7 (CONEt2), 170.1 (OCOCH3).
4.5. N,N-Diethyl 3,6-dideoxy-3,6-imino-N0-benzyl-4,5-O-
isopropylidene-7-O-trityl-L-glycero-D-manno-hepton-
amide 3a
To a solution of 2 (200 mg, 0.37 mmol) in EtOH
(1.2 mL) were successively added benzylamine
(0.16 mL 1.47 mmol) and a mixture of NaBH3CN
(23 mg, 0.37 mmol) and ZnCl2 (25 mg 0.18 mmol) in
EtOH (0.4 mL), stirring the mixture for 7 h at room
temperature. After following the work-up procedure
for reductive amination reactions, the residue was puri-
fied by preparative TLC (MeOH–AcOEt–hexanes,
4.7. Synthesis of 3a and N,N-diethyl 6(R or S)-cyano-
3-deoxy-3,6-imino-N0-benzyl-4,5-O-isopropylidene-7-O-
trityl-D-manno-heptonamide 7a
Following the general procedure were mixtured: 2
(100 mg, 0.18 mmol), EtOH (1 mL) and benzylamine
(0.2 mL 1.08 mmol) with a solution of NaBH3CN
(23 mg, 0.4 mmol) and SnCl2 (17.24 mg 0.08 mmol,
0.5 equiv) in EtOH (0.4 mL), stirring the resulting mix-
ture at room temperature. After 24 h, TLC (AcOEt–hex-
anes, 4:6) indicated the complete conversion of the
starting material. After work-up as usual, the residue
was subjected to flash chromatography on silica
(AcOEt–hexanes, 3:7) to afford 3a (49 mg, 42%) and
7a (15 mg, 12%) as white foams. Compound 7a: Rf:
1:1:8), obtaining pure 3a (120 mg, 60%) and 6 (28 mg,
26
D
25%) as white foams. Compound 3a: ½aŠ ¼ þ16 (c 1,
1
CHCl3). H NMR d (400 MHz, CDCl3): 1.08 (t, 3H,
CH2CH3), 1.07 (t, 3H, CH2CH3), 1.33 (s, 3H,
C(CH3)2), 1.41 (s, 3H, C(CH3)2), 2.66–2.72 (m, 2H,
H3, H-6), 3.06–3.21 (m, 3H, H-7, CH2CH3), 3.33–3.51
(m, 3H, H-70, CH2CH3, CH2Ph), 3.56 (d, 1H, CH2Ph),
4.57 (d, 1H, H-2, J2,3 = 5.3), 4.70 (dd, 1H, H-4,
J4,3 = 6.3, J4,5 = 5.2), 4.93 (dd, 1H, H-5, J5,6 = 6.4),

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M. S. Pino-Gonzalez, C. Assiego / Tetrahedron: Asymmetry 16 (2005) 199–204
203
22
D
0.6 (AcOEt–hexanes, 4:6), ½aŠ ¼ þ26 (c 0.54, CHCl3)
TLC (AcOEt–hexanes, 4:6) showed two new less polar
products than 2. The reaction was worked up as above
and the residue subjected to flash chromatography on
silica (AcOEt–hexanes, 4:6) to afford 3c (47 mg, 42%)
1H NMR d (400 MHz, CDCl3): 1.02–1.07 (m, 6H,
2CH2CH3), 1.28 (s, 3H, C(CH3)2), 1.30 (s, 3H,
C(CH3)2), 2.99–3.04 (m, 2H, H-70, H-3), 3.12–3.26 (m,
3H, H-7, CH2CH3), 3.35 (m, 1H, CH2CH3), 3.72–3.85
(2d, 2H, CH2Ph), 4.26 (d, 1H, –OH, JOH,2 = 9.32),
4.42 (dd, 1H, H-2, J2,3 = 3.5), 4.95 (d, 1H, H-5,
J5,4 = 6.4), 5.26 (dd, 1H, H-4, J4,3 = 4.1, J4,5 = 6.4),
7.09–7.34 (m, 20H, Tr). 13C NMR d (100 MHz, CDCl3):
12.7 and 14.4 (2CH2CH3), 25.3 and 25.7 (C(CH3)2), 40.3
and 41.7 (2CH2CH3), 53.3 (CH2Ph), 63.1 (C-7), 67.0 (C-
3), 67.8 (C-2), 71.5 (C-6), 80.6 (C-4), 81.9 (C-5), 87.3
(CPh3), 112.4 (C(CH3)2), 117.5 (CꢀN), 126.9, 127.7,
128.7, 138.6, 143.1 (Ph), 170.3 (CONEt2). FAB HRMS
m/z: 682.327324, [MNa+] C41H45N3O5Na requires
682.325692.
and 7c (18 mg, 15%) as white foams. Compound 7c;
22
D
Rf: 0.7 (AcOEt–hexanes, 4:6). ½aŠ ¼ þ7:5 (c 0.48,
1
CHCl3). H NMR d (400 MHz, CDCl3): 0.67 (2d, 6H,
–CH2CH2CH(CH3)2), 0.98 (m, 1H, –CH2CH2CH-
(CH3)2), 1.07–1.13 (m, 6H, 2CH2CH3), 1.17 (m, 1H,
–CH2CH2CH(CH3)2), 1.20 (s, 3H, C(CH3)2), 1.23 (s,
3H, C(CH3)2), 2.36 and 2.56 (2m, 2H, –CH2-
CH2CH(CH3)2), 2.81 (dd, 1H, H-3), 3.11 (d, 1H, H-70,
0
J7 ,7 ¼ 8:5), 3.21–3.42 (m, 4H, 2CH2CH3), 3.53 (d, 1H,
0
H-7, J7,7 ¼ 8:5), 4.30 (d, 1H, –OH, JOH,2 = 10.2), 4.43
(dd, 1H, H-2, J2,3 = 3.2), 4.81 (d, 1H, H-5, J5,4 = 6.4),
5.11 (dd, 1H, H-4, J4,3 = 4.3), 7.15–7.46 (m, 15H, Tr).
13C NMR
d (100 MHz, CDCl3): 12.8 and 14.5
4.8. N,N-Diethyl 3,6-dideoxy-3,6-imino-N0-(30-methyl-
butyl)-4,5-O-isopropylidene-7-O-trityl-L-glycero-D-
manno-heptonamide 3c
(2CH2CH3), 22.3 and 22.4 (CH2CH2CH(CH3)2), 25.3,
25.5 and 26.3 [C(CH3)2, CH2CH2CH(CH3)2], 37.9
[CH2CH2CH(CH3)2], 40.4 and 41.9 (2CH2CH3), 47.5
[CH2CH2CH(CH3)2], 62.9 (C-7), 66.0 (C-3), 68.0 (C-2),
70.4 (C-6), 80.6 (C-4), 82.3 (C-4), 87.5 (CPh3), 112.6
(C(CH3)2), 118.3 (CN), 127.1, 127.7, 128.7, 143.1,
144.1 (Ph), 170.3 (CONEt2). FAB HRMS m/z:
Isoamylamine (0.04 mL, 0.36 mmol) was added to a
solution of 2 (50 mg, 0.09 mmol) in EtOH (0.4 mL) with
stirring at room temperature. Then was added a solution
of NaBH3CN (5.8 mg, 0.09 mmol) and ZnCl2 (6.3 mg,
0.04 mmol, 0.5 equiv) in EtOH (0.4 mL). After stirring
for 3 h, TLC (AcOEt–hexanes, 4:6) showed a more fas-
ter-running compound (Rf: 0.45). The reaction was
worked up as above and the residue subjected to flash
chromatography on silica (AcOEt–hexanes, 3:7) to
662.357131
662.356992.
[MNa+]
C39H49N3O5Na
requires
4.10. N,N-Diethyl 3,6-dideoxy-3,6-imino-4,5-O-isoprop-
ylidene-7-O-trityl-D-glycero-D-manno-heptonamide 8a
afford 3c (38 mg, 67%) and hemiacetal 6 (1.5 mg, 3%)
In a flask containing 14 mg of dried molecular sieves
were dissolved 100 mg (0.18 mmol) of 2 in dried MeOH
(1.7 mL). Ammonium formate was added (15.1 mg,
0.23 mmol) and the mixture stirred for 20 min. Then
was added NaCNBH3 (25.9 mg, 0.41 mmol). After
11 h TLC (Et3N–AcOEt–hexanes, 1:3:6) showed the
complete conversion of 2. The reaction mixture was fil-
tered through Celiteꢂ that was washed with methanol.
The filtrates were concentrated under vacuo and the res-
idue was subjected to flash chromatography on silica
(AcOEt–hexanes, 1:1) to afford product 6 (15 mg,
14%), pure 8a (40 mg, 40%) as white foam, and 10 mg
26
D
as white foams. Compound 3c: ½aŠ ¼ À25 (c 0.53,
1
CHCl3) H NMR d (400 MHz, CDCl3): 0.71–0.73 (2d,
6H, –CH2CH2CH(CH3)2), 0.98 (m, 1H, –CH2CH2-
CH(CH3)2), 1.07–1.13 (m, 6H, 2CH2CH3), 1.17 (m,
1H, –CH2CH2CH(CH3)2), 1.27 (s, 3H, C(CH3)2), 1.31
(s, 3H, C(CH3)2), 2.42–2.57 (m, 2H, –CH2CH2CH-
(CH3)2), 2.67 (dd, 1H, H-3), 2.74 (dd, 1H, H-6), 3.10
(dd, 1H, H-70, J7 ,6 ¼ 5:3, J7 ,7 ¼ 9:1), 3.23–3.4 (m, 3H,
CH2CH3), 3.48 (m, 1H, CH2CH3), 3.56 (dd, 1H, H-7,
J7,6 = 6.4), 4.09 (d, 1H, –OH, JOH,2 = 8.6), 4.49 (dd,
1H, H-2, J2,3 = 4.8), 4.63 (dd, 1H, H-5, J5,4 = 6.4,
J5,6 = 5.3), 4.92 (dd, 1H, H-4, J4,3 = 4.8), 7.15–7.45 (m,
15H, Tr). 13C NMR d (100 MHz, CDCl3): 12.7 and
14.3 (2CH2CH3), 22.5 and 22.7 (CH2CH2CH(CH3)2),
24.9, 25.7 and 26.6 [C(CH3)2, –CH2CH2CH(CH3)2],
31.3 [–CH2CH2CH(CH3)2], 40.5 and 41.6 (2C2CH3),
47.1 [–CH2CH2CH(CH3)2], 62.4 (C-7), 64.5 (C-6), 65.8
(C-3), 67.4 (C-2), 79.0 (C-5), 80.7 (C-4), 86.8 (CPh3),
110.9 (C(CH3)2), 126.8, 127.6, 128.7, 138.6, 144.1 (Ph),
171.7 (CONEt2). CI mass spectra: 614 [M+](<1), 615
[MH+](1), 484 (64), 485 (22), 243 (100). FAB HRMS
m/z: 637.361743 [MNa+] C38H50N2O5Na 637.357259.
0
0
(8a + degradation
products).
Compound
8a:
22
D
½aŠ ¼ þ17 (c 0.48, CH2Cl2). 1H NMR d (400 MHz,
CDCl3): 1.05 (t, 3H, CH2CH3), 1.12 (t, 3H, CH2CH3),
1.24 (s, 3H, C(CH3)2), 1.45 (s, 3H, C(CH3)2), 2.90–3.0
(m, 2H, H-70, H-6), 3.05–3.22 (m, 3H, CH2CH3, H-3),
3.55–3.78 (m, 3H, CH2CH3, –OH), 4.33 (d, 1H, H-5,
J5,4 = 5.9), 4.61 (dd, 1H, H-2), 4.69 (dd, 1H, H-4,
J4,3 = 5.37), 7.15–7.33 (m, 15H, Tr). 13C NMR d
(100 MHz, CDCl3): 12.9 and 14.1 (2CH2CH3), 24.3
and 26.0 (C(CH3)2), 40.2 and 41.6 (2CH2CH3), 62.7,
63.0 (C-7, C-6), 63.9 (C-3), 67.3 (C-2), 81.0 (C-4), 82.4
(C-5), 86.8 (CPh3), 111.36 (C(CH3)2), 127.08, 127.8,
128.4, 143.5 (Ph), 172.0 (CONEt2). CI mass spectra:
545 [MH+](1), 271 (3), 243 (100). FAB HRMS: m/z
545.301417, [M+H+] C33H41N2O5 requires 545.301548.
4.9. Synthesis of 3c and N,N-diethyl 6(R or S)-cyano-
3,6-imino-N0-(30-methylbutyl)-4,5-O-isopropylidene-7-O-
trityl-D-manno-heptonamide 7c
Isoamylamine (0.08 mL, 0.73 mmol) was added to a
solution of 2 (100 mg, 0.18 mmol) in EtOH (1 mL) with
stirring at room temperature. Then was added a solution
of NaBH3CN (11.5 mg, 0.18 mmol) and SnCl2 (17.3 mg,
0.09 mmol) in EtOH (0.4 mL). After stirring for 3 h,
4.11. Acetylation of 8a
To a solution of 8a (30 mg, 0.05 mmol) in pyridine
(1 mL) was added Ac2O (0.2 mL) with stirring at rt.
TLC showed the slow formation of a new compound.

´
M. S. Pino-Gonzalez, C. Assiego / Tetrahedron: Asymmetry 16 (2005) 199–204
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After 5 days, cold water was added and the mixture ex-
tracted with Et2O (2 · 5 mL). The organic layers were
dried (anhyd MgSO4) and concentrated to give a residue
that was subjected to flash chromatography on silica
(AcOEt–hexanes, 1:1) to afford 8b (25 mg, 80%) as a
1
white foam. Rf: 0.4 (AcOEt–hexanes, 1:1) H NMR d
(400 MHz, CDCl3): 1.10 (m, 6H, 2CH2CH3), 1.24 (s,
3H, C(CH3)2), 1.41 (s, 3H, C(CH3)2), 1.84 (s, 3H,
NCOCH3), 2.0 (s, 3H, OCOCH3), 3.12 (dd, 1H, H-70),
0
3.25 (dd, 1H, H-7, J7,7 ¼ 9:4), 3.36 (m, 3H, CH2CH3),
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3.62 (m, 1H, CH2CH3), 3.93 (dd, 1H, H-6, J6,7 = 5.9,
0
J6,7 ¼ 6:9), 4.49 (d, 1H, H-5, J5,4 = 5.37), 4.62 (dd, 1H,
H-4, J4,3 = 4.83), 6.35 (d, 1H, H-2, J2,3 = 8.6), 7.20–7.37
(m, 15H, Tr). 13C NMR d (100 MHz, CDCl3): 12.3
and 13.7 (2CH2CH3), 20.8 (OCOCH3), 22.7 (NCOCH3),
24.8 and 26.4 (C(CH3)2), 40.0 and 41.5 (2CH2CH3), 61.9
(C-7), 62.1 (C-3), 66.0 (C-6), 67.4 (C-2), 79.9 (C-5), 80.3
(C-4), 87.5 (CPh3), 111.3 (C(CH3)2), 126.8–143.2 (Ph),
167.6 (CONEt2), 168.7 and 169.7 (2Ac).
14. Assiego, C.;Pino-Gonzalez, M. S.;Lopez-Herrera, F. J.
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Acknowledgements
15. Izquierdo, I.;Plaza, M. T.;Franco, F.
Asymmetry 2004, 15, 1465–1469.
Tetrahedron:
This research was supported with funds from the Direc-
16. Chaudhari, V. D.;Kumar, K. S. A.;Dhavale, D. D.
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3185, and references cited therein.
´
´
´
´
cion General de Investigacion Cientıfica y Tecnica (Ref.
BQU2001-1576) and from the Direccion General de
´
´
´
´
´
Universidades e Investigacion, Consejerıa de Educacion
y Ciencia, Junta de Andalucıa (FQM 0158). We wish to
thank Dr. Antonio Gil and Unidades de Espectroscopıa
de Masas of the Universities of Seville and Granada for
mass spectral data.
18. Barili, P. L.;Berti, G.;Catelani, G.;D
Rensis, F.;Puccioni, L. Tetrahedron 1997, 53, 3407–
Õandrea, F.;De
´
3416.
´
19. Lopez-Herrera, F. J.;Pino-Gonza lez, M. S.;Sarabia
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´
´
´
´
´
Pedraza-Cebrian, M. G. Tetrahedron: Asymmetry 1996, 7,
2065–2071, corrected H NMR data of 1a in Ref. 13.
1
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