One-pot synthesis of vicinal aminoalkanols from sugar aldehydes

Article abstract of DOI:10.1016/j.tet.2013.02.072

A novel synthetic method of carbohydrate derived vicinal aminoalcohols, from sugar aldehydes and bromonitroalkanes, has been developed. It involves an indium-catalyzed one-pot Henry reaction and nitro group reduction, and proceeds with a remarkably high anti-selectivity. The reaction of the intermediate aminoalcohols with alkylating agents furnished the corresponding carbohydrate-based tertiary aminoalcohols with excellent stereoselectivity. This very simple methodology allows easy access to families of N,N-dialkylated vicinal aminoalkanols, useful intermediates in the synthesis of derivatives of biological interest and sugar-based stereodifferentiating agents for asymmetric catalysis.

Full text of DOI:10.1016/j.tet.2013.02.072

Tetrahedron 69 (2013) 3425e3431
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of vicinal aminoalkanols from sugar aldehydes
*
*
Raquel G. Soengas , Artur M.S. Silva
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic method of carbohydrate derived vicinal aminoalcohols, from sugar aldehydes and
bromonitroalkanes, has been developed. It involves an indium-catalyzed one-pot Henry reaction and
nitro group reduction, and proceeds with a remarkably high anti-selectivity. The reaction of the in-
termediate aminoalcohols with alkylating agents furnished the corresponding carbohydrate-based ter-
tiary aminoalcohols with excellent stereoselectivity. This very simple methodology allows easy access to
families of N,N-dialkylated vicinal aminoalkanols, useful intermediates in the synthesis of derivatives of
biological interest and sugar-based stereodifferentiating agents for asymmetric catalysis.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 18 December 2012
Received in revised form 15 February 2013
Accepted 21 February 2013
Available online 26 February 2013
Keywords:
Carbohydrates
Indium
Henry reaction
Vicinal aminoalkanols
One-pot
1. Introduction
but also for their potential as stereodifferentiating agents in
asymmetric catalysis.7 Taking into account their importance in
In the past several years there has been increased pressure on
the synthetic community to use environmentally benign or ‘green’
methods in synthesis. In this regard, the interest in the de-
velopment of one-pot reactions for the sustainable synthesis of
organic compounds has grown exponentially.1 The use of one-pot
conversions, reactions taking place without intermediate recovery
steps, drastically reduces operating time and costs as well as con-
sumption of solvents and energy.2 In this context, reductive one-
pot reactions involving carbonyl compounds and nitronates as
carbon nucleophiles would be particularly attractive in assembling
carbonecarbon bonds around the carbonyl group and directly
generating a 1,2-aminoalkanol function.
The 1,2-aminoalkanol moiety is a structural component, which
can be found in many naturally occurring molecules. For example,
the vicinal aminoalkanol functionality is found in polyoxamic acid,
a structural constituent of the nucleoside antibiotic polyoxin,3 in
indolizine alkaloids, such as 1,2-dihydroxyindolizine,4 and in the
potent antifungal sphingosine.5 On other hand, chiral 1,2-
aminoalkanols serve as useful intermediates in the synthesis of
several natural products, as well as chiral auxiliaries and ligands for
asymmetric synthesis.6
synthesis and biology, a short and reliable procedure for the mul-
tigram preparation of carbohydrate-based vicinal aminoalkanols
would be of great interest. Although sugar-derived 1,2-
aminoalcohol building blocks are present in the literature,8 more
efficient and practical routes that allow large-scale preparations
reducing the environmental impact are still needed.9
In connection with our interest in the application of Barbier-
type reactions to carbohydrate chemistry,10 we have recently de-
scribed11 the efficient preparation of nitrosugars by means of the
indium promoted addition of bromonitroalkanes to sugar alde-
hydes.12 We have also described an indium-catalyzed version of
the reaction, in which an excess of zinc was used as secondary
reducing agent.13 It is known that, in the presence of a proton
source, zinc alone or in the presence of a catalytic amount of in-
dium can reduce the nitro group to an amino group.14 Then, we
reasoned that adding a proton source to the reaction mixture, we
could complete the one-pot Henry reaction-nitro reduction and
obtain homologated aminosugars from sugar aldehydes. Herein
we report the one-pot synthesis of several aminosugars, poten-
tially useful as synthetic intermediates and ligands for metal
catalysis.
Sugar-derived 1,2-aminoalkanols are a particularly relevant
family of compounds, not only for their usefulness as intermediates
in the preparation of carbohydrate derivatives of biological interest,
2. Results and discussion
In order to set up the optimal conditions to carry out the syn-
thesis of aminosugars, we started our study with the reaction of
sugar aldehyde 1a and bromonitromethane 2a (Scheme 1). A
* Corresponding authors. Tel.: þ351 234 370714; fax: þ351 234 370084; e-mail
addresses: rsoengas@ua.pt (R.G. Soengas), artur.silva@ua.pt (A.M.S. Silva).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.072

3426
R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
L
L
O2N
HO
O
In
O
O
H
O
OTBDPS
OTBDPS
In/Zn
THF
O
O
+
N
Br
NO2
O
O
O
O
O
H
Fig. 1. FelkineAhn model for the attack of the indium nitronate on sugar aldehydes
1aef.
1a
2a
3a
H2N
HO
HOHN
HO
proton
source
would cause, in the first instance, the formation of the nitroalcohol
from the alkoxide. Then, the indium(0) in the presence of the
proton source would reduce the nitro group to the corresponding
amine. In the presence of zinc(0), the required indium(0) would be
regenerated to continue the reduction until total conversion of the
nitroalcohol into the corresponding aminoalcohol.
With the optimal conditions established, we studied the prep-
aration of different aminosugars (Scheme 2) by reaction of sugar
aldehydes 1aeg with bromonitroalkanes 2aec (Fig. 2). The reaction
is of general application regarding both the sugar aldehydes and the
bromonitroalkanes, affording in all the cases the corresponding
aminoalkanols as diastereomeric mixtures in which the anti-
isomer is the major product, as predicted by the FelkineAhn
model (Table 2).
O
O
OTBDPS
OTBDPS
+
O
O
4a
O
O
5a
Scheme 1. One-pot synthesis of vicinal aminoalkanol 4a from aldehyde 1a.
mixture of aldehyde 1a (1 equiv), bromonitromethane 2a
(1.2 equiv), indium (0.13 equiv), and zinc (10 equiv) was sonicated
for 4 h. Then, after the formation of the corresponding nitrosugar,
different conditions for the in situ nitro group reduction were in-
vestigated (Table 1).
Table 1
O
OH
OH
Conditions for the in situ reduction of the nitro group
R
R
In/Zn
NO2
1. THF
NH2
NH2
+
H
+
Entry
Proton source
Conditions
4a:5aa
Yieldb (4a)
Br
R
R
R
R
O
O
O
2. aq. HCl/IPA
1
2
3
4
5
6
NH4Cl satd
NH4Cl satd
HCl 1 M/IPA
HCl 1 M/IPA
HCl 1 M/IPA
HCl 1 M/IPA
rt/3 h
0:1
1:1
1:0
2:1
1:0
1:0
d
Major isomer anti
Minor isomer syn
Reflux/3 h
Reflux/3 h
rt/3 h
n.d.
31%
n.d.
52%
64%
1a-f
2a-c
4a-i
Scheme 2. One-pot synthesis of aminoalkanols 4aei from sugar aldehydes 1aef.
rt/12 h
rt/12 hc
IPA¼isopropyl alcohol.
O
O
O
a
Determined by 1H NMR.
O
O
O
b
O
O
OR
After filtration over silica gel.
O
c
O
Zinc (5 equiv) were added along with the proton source.
O
O
O
RO
O
Addition of saturated aqueous ammonium chloride as proton
source and reaction at room temperature afforded hydroxylamine
5a as the only product, which is the intermediate product in the
reduction of a nitro group to an amino group (entry 1). Rising the
temperature to reflux, some of the desired nitroalkanol 4a was
obtained along with hydroxylamine 5a. The use of 1 M aqueous
hydrochloric acid as proton source has proven to be more conve-
nient (entries 3e6). The best procedure in terms of conversion and
cleanliness of the crude reaction consider the addition of isopropyl
alcohol and diluted hydrochloric acid and the reaction at room
temperature for 12 h (entries 5 and 6). Shorter reaction times
yielded significant amounts of hydroxylamine 5a (entry 4). On
other hand, heating to reflux afforded a rather sluggish reaction
crude, from which nitroalkanol was isolated in low yields (entry 3).
The complete reduction of the nitro group to an amino group re-
quires a catalytic amount of indium in the presence of an excess
(10 molar equiv) of metal. Considering that some zinc is consumed
in the formation of the nitronate, an extra amount of zinc could be
required for the reduction step. Accordingly, the yields are slightly
better when further 5 equiv of zinc were added together with the
proton source (entry 6).
1a: R=TBDPS
1b: R=TBS
1c: R=Bn
1d: R=Bn
1e: R=Me
1f
O
O
Br
NO2
2a
Br
NO2
2b
Br
NO2
2c
Fig. 2. Sugar aldehydes 1aef and bromonitroalkanes 2aec.
Table 2
Preparation of vicinal sugar-derived aminoalkanols 4aei
Entry
Sugar
aldehyde
Bromonitro-
alkane
Amino-
alkanol
anti/syna
Yieldb
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1e
1f
2b
2c
2a
2b
2c
2a
2a
2c
4b
4c
4d
4e
4f
4g
4h
4i
100:0
100:0
78:22
85:15
76:24
69:31
87:13
100:0
52%
54%
61%
49%
51%
62%
64%
52%
Using this methodology, a 90:10 diastereomeric mixture of
aminoalcohols 4a was obtained, being the anti-isomer the major
compound obtained. Under these conditions, the formation of the
intermediate hydroxylamine 5a was not observed. The anti-
selectivity comes from a CeO antibonding orbital energy lower-
ing bringing an increased stabilization of a FelkineAnh anti-
periplanar nucleophilic addition of the organoindium species to the
aldehyde carbonyl group (Fig. 1).15 The addition of aqueous acid
1f
Determined by 1H NMR.
After filtration over silica gel.
a
b
The preferential formation of the anti-isomers, as predicted by
the FelkineAhn model, was confirmed when pure nitroalkanol
3b11a was reduced by treatment with catalytic amount of indium

R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
3427
and an excess zinc in a mixture of 1 M HCl/IPA (Scheme 3). Under
these conditions, pure anti-isomer of aminoalkanol 4c was ob-
tained in good yield.
Given the obtained satisfactory results, the synthesis of a family
of tertiary aminoalcohol ligands was performed from aldehydes
1aef and bromonitroalkanes 2aec, via aminoalcohols 4aei
(Scheme 5). Following the same strategy as above, the corre-
sponding tertiary anti-aminoalkanols 7dek were isolated as pure
compounds (Table 3). Thus, this procedure constitutes a general
procedure for the straightforward preparation of carbohydrate-
derived enantiomerically pure N,N-dialkyl-1,2-aminoalkanols
7aek from sugar aldehydes 1aef in two steps with just one final
purification step.
Scheme 3. Reduction of nitroalkanol 3b to aminoalkanol 4c.
O
OH
R
R
In/Zn
1. THF
NH2
+
H
Br
NO2
R
4a-i
R
It is worth mentioning that this process tolerates a broad scope of
sugar derived aldehydes bearing different protection on the hydroxyl
groups. Also, all reactions took place with good stereoselectivities in
absence of epimerization of any chiral center. The novel one-pot
Henry reaction/nitro group reduction herein described has many
advantages when compared to the previously reported procedures
for the synthesis of sugar 1,2-aminoalkanols, usually prepared from
sugar 1,2-diols as starting materials.8 Firstly, the reaction is accom-
panied by concomitant formation of a CeC bond and homologation
of the sugar chain. On other hand, as opposed to the aminoalkanols
prepared from terminal diols, the amino group can be attached to
a quaternary carbon. Finally, the procedure is very simple from the
experimental point of view and the corresponding aminoalkanols
are prepared in just one step from the starting sugar aldehydes, thus
reducing waste and minimizing handling.
O
1a-f
O
2. aq. HCl/IPA
2a-c
N = NEt2
OH
EtI (6a) or I(CH2)5I (6b)
or I(CH2)2O(CH2)2I (6c)
N
N =
N =
N
N
K2CO3, CH3CN
R
7d-k
R
O
O
Anti isomer
Scheme 5. Synthesis of aminoalkanols 7dek from sugar aldehydes 1aef and bro-
monitroalkanes 2aec.
Table 3
Preparation of vicinal sugar-derived aminoalkanols
Entry Aldehyde Bromonitro alkane Iodoalkane Aminoalkanol Yield
Carbohydrate derived tertiary aminoalkanols constitute an in-
teresting family of ligands, which were used to promote a number
of asymmetric transformations.16 In order to obtain suitable in-
termediates for the synthesis of novel sugar-based ligands, we
decided to investigate the application of the former strategy to the
preparation of N,N-dialkyl vicinal aminoalkanols. Thus, after re-
action of sugar aldehyde 1a with 2-bromo-2-nitropropane 2b, in
the presence of zinc/indium, in situ nitro group reduction, by ad-
dition of diluted hydrochloric acid, and aqueous work-up, the crude
mixture of the obtained aminoalkanols was dissolved in acetoni-
trile and heated in the presence of ethyl iodide 6a and potassium
carbonate (Scheme 4). The corresponding tertiary anti-amino-
1
2
3
4
5
6
7
8
1a
1b
1b
1c
1d
1d
1f
2a
2c
2c
2a
2b
2c
2a
2a
6a
6a
6b
6a
6c
6b
6a
6b
7d
7e
7f
7g
7h
7i
40%
39%
42%
38%
42%
47%
40%
49%
7j
7k
1f
3. Conclusions
To sum up, we have developed a novel one-pot procedure
consisting on an indium catalyzed Henry reaction/nitro group re-
duction that allows the preparation of carbohydrate derived vicinal
aminoalkanols from sugar aldehydes. This process took place in
good to excellent stereoselectivities maintaining the stereochemi-
cal integrity of the sugar backbone. The resulting 1,2-aminoalkanols
can be directly employed in the synthesis of carbohydrate-based
N,N-dialkyl-1,2-aminoalkanols, useful for the preparation of car-
bohydrate derivatives of biological interest as well as sugar-based
tertiary aminoalcohol ligands. This methodology is very simple
from the experimental point of view and would allow easy access to
large families of N,N-dialkyl-1,2-aminoalkanols reducing the time
and costs as well as consumption of solvents and energy.
H2N
HO
O
O
O
OTBDPS
OTBDPS
In/Zn
1. THF
+
Br
NO2
O
O
O
O
2. aq. HCl/IPA
1a
2b
4b
7a: N = NEt2
N
EtI (6a) or I(CH2)5I (6b)
or I(CH2)2O(CH2)2I (6c)
O
OTBDPS
HO
7b: N =
7c: N =
N
N
K2CO3, CH3CN
O
O
O
It is also noteworthy that this is the first report of a sugar-based
exocyclic N,N-dialkyl-1,2-aminoalkanol in which the amino func-
tion is attached to a quaternary carbon. These structures are more
rigid, which is important for the development of effective ligands
for asymmetric catalysis.
Scheme 4. Preparation of aminokanols 7aec from sugar aldehyde 1a and 2-bromo-2-
nitropropane 2b.
alkanol 7a was easily isolated from the reaction mixture in 39%
yield. Similarly, reaction of the crude aminoalkanol with 1,2-
diiodopentane 6b or 2-iodoethyl ether 6c afforded enantiomeri-
cally pure tertiary amines 7b and 7c in 43% and 45% yield,
respectively.
4. Experimental section
4.1. General experimental
Thus, this procedure allowed the straightforward preparation of
carbohydrate-derived N,N-dialkyl-1,2-aminoalkanols 7aec from
sugar aldehyde 1a in two steps with just one final purification step.
Thin layer chromatography (TLC) was performed on aluminum
sheets coated with 60 F254 silica gel, visualized using a spray of 0.2%

3428
R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
w/v cerium(IV) sulfate and 5% ammonium molybdate in 2 M sulfuric
acid or 0.5% ninhydrin in methanol. Purification via flash column
chromatography was performed on Sorbsil C60 40/60 silica. Nuclear
magnetic resonance spectroscopy (NMR) spectra were recorded on
a Bruker Avance 300 spectrometer in the deuterated solvent stated.
Optical rotations were measured on a PerkineElmer 241 polarimeter
0.11, 0.10 (2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
¼112.3, 101.7
d
(2ꢁ eCe), 98.2, 85.9, 81.2, 78.2, 71.0 (5ꢁ eCHe), 67.9, 66.9 (2ꢁ
eCH2e), 52.2 (eCe), 28.3, 26.0 (2ꢁ CH3), 25.5 [eC(CH3)3], 24.6, 19.0
(2ꢁ CH3), 17.9 [eC(CH3)3], ꢀ4.8, ꢀ5.4 (2ꢁ CH3). MS (ESIþ) m/z (%)
434 ([MþH]þ, 100); HRMS (ESIþ) calcd for [C20H40NO7Si]þ, [MþH]þ
434.2561, found 434.2569.
with a path length of 10 cm. Concentrations are quoted in g 100 mLꢀ1
.
Low resolution mass spectra were recorded using electrospray ion-
ization (ESI), on Micromass BioQ II-ZS, Micromass 500 OAT, Micro-
mass TofSpec 2E, Micromass GCT, or Micromass Platform 1 mass
spectrometers. High resolution mass spectra (HRMS) were measured
on a Waters 2790-Micromass LCT by ESI.
4.2.4. 6-Amino-1-O-benzyl-6-deoxy-2,3-di-O-isopropylidene-a-D-
22
mannofuranose (4d). [
CDCl3):
a
]
ꢀ8.0 (c 0.8, CDCl3). 1H NMR (300 MHz,
D
d
¼7.63e7.26 (m, 5H, AreH), 5.08 (s, 1H, 1H), 4.87 (dd,
J3,2¼5.9 Hz, J3,4¼3.5 Hz, 1H, 3H), 4.70e4.47 (m, 3H, eCH2Ph, 2H),
4.23e4.20 (m, 1H, 5H), 4.02 (dd, J4,5¼7.2 and J4,3¼3.5 Hz, 1H, 4H),
3.77e3.59 (m, 2H, 6H, 60H), 2.12 (br s, 3H, eNH2, eOH), 1.45, 1.30
4.2. General procedure for the synthesis of aminoalcohols
4aei
(2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
¼137.5 (eCe), 128.4,
d
128.0, 127.9, 127.8 (5ꢁ eCHe), 112.5 (eCe), 105.6 (eCHe), 84.7,
81.4, 79.9 (3ꢁ eCHe), 69.2 (eCH2e), 64.6 (eCHe), 54.7 (eCH2e),
26.3, 24.5 (2ꢁ CH3). MS (ESIþ) m/z (%) 310 ([MþH]þ, 100); HRMS
(ESIþ) calcd for [C16H24NO5]þ, [MþH]þ 310.1654, found 310.1672.
Bromonitroalkane (1.2 mmol) was added to a suspension of
activated zinc powder (654 mg, 10.0 mol) and indium powder
(14.3 mg, 0.13 mmol) in THF (5 mL) and the mixture was sonicated
for 20 min. The corresponding aldehyde (1.0 mmol) was added and
sonication was continued for a further 4 h. Then, isopropyl alcohol
(11 mL), hydrochloric acid (8 mL, 1 M) and zinc (327 mg, 5.0 mmol)
were added and the reaction mixture was stirred at room tem-
perature for 14 h. The mixture was then neutralized with saturated
aqueous sodium hydrogen carbonate, filtered through a pad of
Celite and extracted with ethyl acetate (3ꢁ50 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and the
solvent was evaporated in vacuo. The residue was filtered through
a pad of silica gel eluting with CH2Cl2 to CH2Cl2/MeOH 9:1.
4.2.5. 5-[2-(Amino)propan-2-yl]-3-O-benzyl-1,2-O-isopropylidene-
a
-
D
-xylofuranose (4e). [
a
]
22 ꢀ3.8 (c 0.3, CDCl3). 1H NMR (300 MHz,
D
CDCl3):
d
¼7.38e7.28 (m, 5H, AreH), 5.99 (d, J1,2¼3.9 Hz, 1H, 1H),
4.72 (d, J¼11.8 Hz, 1H, eCHPh), 4.59 (d, J2,1¼3.9 Hz, 1H, 2H), 4.54 (d,
J¼11.8 Hz, 1H, eCHPh), 4.27 (d, J4,5¼3.8 Hz, 1H, 4H), 4.10 (d,
J5,4¼3.8 Hz, 1H, 5H), 4.02 (s, 1H, 3H), 1.51, 1.45, 1.31 (3s, 12H, 4ꢁ
CH3). 13C NMR (75 MHz, CDCl3):
d¼136.1 (eCe), 128.7, 128.3, 128.0
(5ꢁ eCHe), 112.2 (eCe), 104.9 (eCHe), 84.4, 81.6, 76.3, 72.6 (4ꢁ
eCHe), 72.1 (eCH2e), 57.9 (eCe), 26.9, 26.3, 23.6, 21.6 (4ꢁ CH3).
MS (ESIþ) m/z (%) 338 ([MþH]þ, 100); HRMS (ESIþ) calcd for
[C18H28NO5]þ, [MþH]þ 338.1957, found 338.1962.
4.2.1. 6-Amino-1-O-tert-butyldiphenylsilyl-6-deoxy-2,3-di-O-iso-
22
propylidene-
NMR (300 MHz, CDCl3):
a
-
D
-mannofuranose (4a). [
a]
þ0.6 (c 3.9, CDCl3). 1H
4.2.6. 5-(5-Amino-2,2-dimethyl-1,3-dioxan-5-yl)-3-O-benzyl-1,2-O-
D
d
¼7.65e7.61 (m, 4H, AreH), 7.45e7.39 (m,
isopropylidene-
dioxan-5-yl)-3-O-benzyl-1,2-O-isopropylidene-
(4f). 1H NMR (300 MHz, CDCl3):
7.36e7.33 (m, 10H, AreH), 5.99
a
-
D
-xylofuranose and 5-(5-amino-2,2-dimethyl-1,3-
6H, AreH), 5.35 (s, 1H, 1H), 4.94 (dd, J3,2¼5.8 and J3,4¼3.7 Hz, 1H,
3H), 4.70 (d, J2,3¼5.8 Hz, 1H, 2H), 4.04 (dd, J4,5¼8.5 Hz, J4,3¼3.7 Hz,
a-L
-arabinofuranose
d
0
1H, 4H), 3.96e3.89 (m, 1H, 5H), 2.98 (dd, J6,5¼3.3 and J6,6 ¼13.0 Hz,
(d, J1,2¼3.9 Hz, 1H, 1H), 5.90 (d, J1,2¼3.8 Hz, 1H, 1H), 4.76e4.51 (m,
3H), 4.16e3.90 (m, 4H), 3.72e3.46 (m, 4H), 2.41 (br s, 3H, eNH2,
eOH),1.46,1.43,1.42,1.40,1.32,1.30 (6s, 24H, 8ꢁ CH3). Major isomer
1H, 6H), 2.75 (dd, J6 ,5¼7.8 and J6 ,6¼13.0 Hz, 1H, 60H), 2.07 (br s, 3H,
0
0
eNH2, eOH), 1.40, 1.31 (2s, 6H, 2ꢁ CH3), 1.06 [s, 9H, C(CH3)3]. 13C
NMR (75 MHz, CDCl3):
d
¼135.6, 135.5 (4ꢁ eCHe), 132.9, 132.6 (2ꢁ
anti (
D
-xylo): 13C NMR (75 MHz, CDCl3):
d
¼137.3 (eCe), 128.7,
eCe), 130.0, 129.9, 127.8, 127.7 (6ꢁ eCHe), 112.6 (eCe), 101.6
(eCHe), 86.6, 80.8, 79.9, 77.2 (4ꢁ eCHe), 51.4 (eCH2e), 26.7
[eC(CH3)3], 25.9, 24.7 (2ꢁ CH3), 19.2 [eC(CH3)3]. MS (ESIþ) m/z (%)
458 ([MþH]þ, 100); HRMS (ESIþ) calcd for [C25H36NO5Si]þ, [MþH]þ
458.2357, found 458.2349.
128.0, 127.8 (5ꢁ eCHe), 111.6 (eCe), 105.2 (eCHe), 98.1 (eCe),
82.7, 81.4, 78.8 (3ꢁ eCHe), 72.4 (eCH2e), 69.4 (eCHe), 67.6, 66.6
(2ꢁ eCH2e), 52.2 (eCe), 28.1, 26.8, 26.2, 18.9 (4ꢁ CH3). Minor
isomer syn (
L
-arabino): 13C NMR (75 MHz, CDCl3):
d
¼136.4 (eCe),
127.5, 128.3, 127.8 (5ꢁ eCHe), 111.6 (eCe), 105.2 (eCHe), 98.1
(eCe), 85.0, 81.7, 76.7 (3ꢁ eCHe), 72.0 (eCH2e), 70.7 (eCHe), 67.1,
66.4 (2ꢁ eCH2e), 51.9 (eCe), 26.9, 26.3, 25.4, 21.7 (4ꢁ CH3). MS
(ESIþ) m/z (%) 410 ([MþH]þ100); HRMS (ESIþ) calcd for
[C21H32NO7]þ [MþH]þ 410.2173, found 410.2198.
4.2.2. 5-[2-(Amino)propan-2-yl]-1-O-tert-butyldiphenylsilyl-2,3-di-
O-isopropylidene-
NMR (300 MHz, CDCl3):
a
-
D
-lyxofuranose (4b). [
a
]
22 þ4.0 (c 1.0, CDCl3). 1H
D
d¼7.68e7.60 (m, 4H, AreH), 7.41e7.35 (m,
6H, AreH), 5.35 (s, 1H, 1H), 4.98 (dd, J3,2¼5.8 and J3,4¼3.4 Hz, 1H,
3H), 4.65 (d, J2,3¼5.8 Hz, 1H, 2H), 4.58 (br s, 3H, eNH2, eOH), 4.19
(dd, J4,5¼8.9 and J4,3¼3.4 Hz, 1H, 4H), 3.75 (d, J5,4¼8.9 Hz, 1H, 5H),
1.42, 1.37 (2s, 6H, 2ꢁ CH3), 1.09e0.94 (m, 15H, 2ꢁ CH3, C(CH3)3),
4.2.7. 6-Amino-6-deoxy-1,2-O-isopropylidene-3-O-methyl-a-D-glu-
22
cofuranose (4g). [
CDCl3):
a]
þ2.8 (c 0.6, CDCl3). 1H NMR (300 MHz,
D
d
¼5.91 (d, J1,2¼3.7 Hz, 1H, 1H), 4.55 (d, J1,2¼3.7 Hz, 1H, 2H),
0.94, 0.91 (2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
d
¼135.5,
4.32e4.28 (m, 1H), 4.14e4.10 (m, 1H), 3.89 (d, J¼3.0 Hz, 1H), 3.46 (s,
3H, OCH3), 3.44e3.38 (m, 1H, 60H), 3.22e3.15 (m, 1H, 6H), 2.81 (br s,
1H, eOH), 1.48, 1.22 (2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
135.4 (4ꢁ eCHe), 133.1, 132.8 (2ꢁ eCe), 129.9, 129.8, 127.7, 127.6
(6ꢁ eCHe), 112.1 (eCe), 101.8 (eCHe), 85.8, 81.1, 80.0, 69.9 (4ꢁ
eCHe), 53.4 (eCe), 26.9 [eC(CH3)3], 25.9, 24.6, 19.4, 19.0 (4ꢁ CH3),
18.2 (eCe). MS (ESIþ) m/z (%) 486 ([MþH]þ, 100); HRMS (ESIþ)
calcd for [C27H40NO5Si]þ [MþH]þ 486.2676 found 486.2682.
d
¼111.8 (eCe), 105.1 (eCHe), 83.4, 81.5, 81.264.8 (4ꢁ eCHe), 58.1
(eCH3), 43.4 (eCH2e), 26.7, 26.2 (2ꢁ CH3). MS (ESIþ) m/z (%) 234
([MþH]þ, 100); HRMS (ESIþ) calcd for [C10H20NO5]þ, [MþH]þ
234.1336, found 234.1314.
4.2.3. 5-(5-Aminoethyl-2,2-dimethyl-1,3-dioxan-5-yl)-1-O-tert-bu-
22
tyldimethylsilyl-2,3-di-O-isopropylidene-
a
-
D
-lyxofuranose (4c). [
a
]
4.2.8. 7-Deoxy-7-amino-1,2:3,4-di-O-isopropylidene-D-glycero-b-D-
D
22
þ2.6 (c 0.32, CDCl3). 1H NMR (300 MHz, CDCl3):
d
¼5.31 (s, 1H, 1H),
galactoheptose (4h). [
CDCl3):
a
]
ꢀ6.2 (c 0.2, CDCl3). 1H NMR (300 MHz,
D
4.89 (dd, J3,2¼5.8 and J3,4¼3.7 Hz, 1H, 3H), 4.49 (d, J2,3¼5.8 Hz, 1H,
2H), 4.17 (dd, J4,5¼8.77 and J4,3¼3.7 Hz, 1H, 4H), 4.05e3.97 (m, 2H,
2ꢁ eOCHe), 3.69e3.60 (m, 3H, 2ꢁ eOCHe, 5H), 1.97 (br s, 3H,
eNH2, eOH), 1.48, 1.44, 1.33 (3s, 12H, 4ꢁ CH3), 0.88 [s, 9H, C(CH3)3],
d
¼5.52 (d, J1,2¼5.1 Hz, 1H, 1H), 4.63 (dd, J3,2¼2.4 and
J3,4¼8.0 Hz, 1H, 3H), 4.47 (dd, J4,5¼1.8 and J4,3¼8.0 Hz, 1H, 4H), 4.32
(dd, J2,1¼5.1 and J2,3¼2.4 Hz, 1H, 2H), 3.79e3.75 (m, 1H, 6H), 3.62
(dd, J5,4¼1.8 and J5,6¼8.7 Hz, 1H, 5H), 2.99 (dd, J7,6¼3.3 Hz,

R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
3429
J7,7 ¼13.0 Hz, 1H, 7H), 2.85 (dd, J7 ,6¼6.1 and J7 ,7¼13.0 Hz, 1H, 70H),
AreH), 7.46e7.38 (m, 6H, AreH), 5.35 (s,1H,1H), 5.00 (dd, J3,2¼5.8 and
J3,4¼3.3 Hz, 1H, 3H), 4.73 (d, J2,3¼5.8 Hz, 1H, 2H), 4.59e4.29 (m, 2H,
4H, 5H), 3.53e3.34 (m, 6H, 6H, 60H, 2ꢁ eCH2e), 2.73 (d, J¼14.3 Hz, 1H,
OH),1.42,1.33 (2s, 6H, 2ꢁ CH3), 1.30e1.26 (m, 6H, 2ꢁ CH3),1.07 [s, 9H,
0
0
0
1.96 (br s, 3H, eNH2, eOH),1.52,1.46,1.37,1.33 (4s,12H, 4ꢁ CH3). 13
C
NMR (75 MHz, CDCl3):
d
¼109.2, 108.5 (2ꢁ eCe), 96.4 (eCHe), 70.8,
70.6, 70.5, 69.4, 68.0 (5ꢁ eCHe), 43.8 (eCH2e), 26.0, 25.9, 24.9,
24.4 (4ꢁ CH3). MS (ESIþ) m/z (%) 290 ([MþH]þ, 100); HRMS (ESIþ)
calcd for [C13H24NO6]þ, [MþH]þ 290.1595, found 290.1598.
eC(CH3)3]. 13C NMR (75 MHz, CDCl3):
d¼135.7, 135.6 (4ꢁ eCHe),
135.6, 132.3 (2ꢁ eCe), 129.9, 129.7, 127.7, 127.6 (6ꢁ eCHe), 112.7
(eCe),102.0 (eCHe), 86.7, 80.2, 79.2, 63.8 (4ꢁ eCHe),59.6 (eCH2e),
54.3 (2ꢁ eCH2e), 26.7 [eC(CH3)3], 26.2, 24.6 (2ꢁ CH3), 18.9
[eC(CH3)3], 7.7 (2ꢁ CH3). MS (ESIþ) m/z (%) 514 ([MþH]þ,100); HRMS
(ESIþ) calcd for [C29H44NO5Si]þ, [MþH]þ 514.2989, found 514.3001.
Rf¼0.34 (dichloromethane/methanol 19:1).
4.2.9. 6-(5-Amino-2,2-dimethyl-1,3-dioxan-5-yl)-1,2:3,4-di-O-iso-
propylidene-
NMR (300 MHz, CDCl3):
22
b
-D
-galactopyranose (4i). [
a
]
ꢀ2.1 (c 2.5, CDCl3). 1H
D
d
¼5.49 (d, J1,2¼5.1 Hz, 1H, 1H), 4.61 (dd,
J3,2¼2.4 and J3,4¼8.0 Hz, 1H, 3H), 4.45 (dd, J4,5¼1.7 and J4,3¼8.0 Hz,
1H, 4H), 4.30 (dd, J2,1¼5.1 and J2,3¼2.4 Hz, 1H, 2H), 4.08 (d,
J¼12.0 Hz, 1H, eCHOe), 4.04 (d, J¼12.0 Hz, 1H, eCHOe), 3.82 (dd,
J5,4¼1.7 and J5,6¼9.1 Hz,1H, 5H), 3.66e3.50 (m, 3H, 6H, 2ꢁ eCHOe),
2.58 (br s, 3H, eNH2, eOH), 1.55, 1.45, 1.44, 1.41, 1.36, 1.31 (6s, 18H,
4.3.3. 1-O-tert-Butyldimethylsilyl-5-(5-N,N-diethylamino-2,2-
dimethyl-1,3-dioxan-5-yl)-2,3-di-O-isopropylidene-a-D-lyxofuranose
(7e). Flash column chromatography eluting with dichloromethane/
6ꢁ CH3). 13C NMR (75 MHz, CDCl3):
d
¼109.0, 108.5, 98.0 (3ꢁ eCe),
methanol 39:1. [
a
]
23 þ3.6 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3):
D
96.3 (eCHe), 71.2, 70.5, 70.3, 69.9 (4ꢁ eCHe), 67.4, 66.7 (2ꢁ
eCH2e), 66.5 (eCHe), 52.4 (eCe), 28.7, 25.9, 25.8, 24.7, 24.3, 18.5
(6ꢁ CH3). MS (ESIþ) m/z (%) 390 ([MþH]þ, 100); HRMS (ESIþ) calcd
for [C18H32NO8]þ, [MþH]þ 390.2116, found 390.2122.
d
¼5.30 (s,1H,1H), 4.88 (dd, J3,2¼5.8 and J3,4¼3.6 Hz,1H, 3H), 4.48 (d,
J2,3¼5.8 Hz, 1H, 2H), 4.10e4.02 (m, 2H, eOCH2e), 3.98 (dd, J4,5¼9.3
and J4,3¼3.6 Hz, 1H, 4H), 3.69 (AB, J¼12.1 Hz, 2H, eOCH2e), 3.57 (d,
J5,4¼9.3 Hz, 1H, 5H), 3.00 (br s, 1H, eOH), 2.77e2.60 (m, 4H, 2ꢁ
eCH2e), 1.46, 1.40,1.34 (3s,12H, 4ꢁ CH3), 1.16e1.12 (m, 6H, 2ꢁ CH3),
0.88 [s, 9H, eC(CH3)3], 0.13, 0.11 (2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz,
4.3. General procedure for the synthesis of ligands 7a, 7d, 7e,
7g, and 7j
CDCl3):
d
¼112.3, 101.7 (2ꢁ eCe), 98.3, 85.9, 81.0, 78.7, 67.0 (5ꢁ
eCHe), 63.5, 63.0 (2ꢁ eCH2e), 55.3 (eCe), 36.3 (2ꢁ eCH2e), 28.9,
26.0 (2ꢁ CH3), 25.5 [eC(CH3)3], 24.6, 18.9 (2ꢁ CH3), 17.9 [eC(CH3)3],
15.91 (2ꢁ CH3), ꢀ4.8, ꢀ5.4 (2ꢁ CH3). MS (ESIþ) m/z (%) 490 ([MþH]þ,
100); HRMS (ESIþ) calcd for [C24H48NO7Si]þ, [MþH]þ 490.3200,
found 490.3219. Rf¼0.33 (dichloromethane/methanol 39:1).
Bromonitroalkane (1.2 mmol) was added to a suspension of ac-
tivated zinc powder (654 mg,10.0 mol) and indium powder (14.3 mg,
0.12 mmol) in THF (5 mL) and the mixture was sonicated for 20 min.
The corresponding aldehyde (1.0 mmol) was added and sonication
was continued for a further 4 h. Then, isopropyl alcohol (11 mL),
hydrochloric acid (8 mL, 1 M) and zinc (325 mg, 5.0 mmol) were
added and the reaction mixture was stirred at room temperature for
14 h. The mixture was then neutralized with saturated aqueous so-
dium hydrogen carbonate, filtered through a pad of Celite and
extracted with ethyl acetate (3ꢁ50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and the solvent was
4.3.4. 1-O-Benzyl-6-deoxy-6-N,N-diethylamino-2,3-di-O-iso-
propylidene-
phy eluting with dichloromethane/methanol 39:1. [
0.2, CHCl3); 1H NMR (300 MHz, CDCl3):
a-D-mannofuranose (7g). Flash column chromatogra-
23
a
]
þ37.6 (c
D
d
¼7.35e7.26 (m, 5H, AreH),
5.08 (s, 1H, 1H), 4.87 (dd, J3,2¼5.9 and J3,4¼3.5 Hz, 1H, 3H),
4.65e4.48 (m, 3H, eCH2Ph, 2H), 4.13e3.96 (m, 1H, 5H), 3.74 (dd,
J4,5¼8.3 and J4,3¼3.5 Hz, 1H, 4H), 2.98e2.93 (m, 1H, eOH),
2.65e2.24 (m, 4H, 6H, 60H, eCH2e), 2.04e1.99 (m, 2H, eCH2e),
evaporated in vacuo. Ethyl iodide (112 mL,1.35 mmol) and potassium
carbonate (9.5 mmol) were added to a solution of the obtained crude
aminoalcohol (0.5 mmol) in acetonitrile (4 mL) and the resulting
mixture was heated at 60 ꢂC for a total of 60 h. Further portions of
ethyl iodide were added after 10 h (56
0.45 mmol), 30 h (37 L, 0.45 mmol) and 54 h (20
reaction mixture was cooled, filtered, and evaporated under reduced
pressure and the residue was purified by flash column chromatog-
raphy in mixtures of dichloromethane/methanol.
1.51e1.25 (m, 12H, 4ꢁ CH3). 13C NMR (75 MHz, CDCl3):
¼137.5
d
(eCe), 128.4, 128.0, 127.8 (5ꢁ eCHe), 112.6 (eCe), 106.0 (eCHe),
84.7, 81.5, 78.0 (3ꢁ eCHe), 69.3 (eCH2e), 64.6 (eCHe), 61.3, 54.8,
49.9 (3ꢁ eCH2e), 28.3, 26.4, 26.0, 24.6 (4ꢁ CH3). MS (ESIþ) m/z (%)
366 ([MþH]þ, 100); HRMS (ESIþ) calcd for [C18H32NO6]þ, [MþH]þ
366.2275, found 366.2288. Rf¼0.30 (dichloromethane/methanol
39:1).
m
L, 0.7 mmol), 22 h (37
mL,
m
mL, 0.25 mmol). The
4.3.1. 1-O-tert-Butyldiphenylsilyl-2,3-di-O-isopropylidene-5-[2-
4.3.5. 7-Deoxy-7-N,N-diethylamino-1,2:3,4-di-O-isopropylidene-
glycero- -galacto-heptose (7j). Flash column chromatography
eluting with dichloromethane/methanol 19:1. [
CHCl3); 1H NMR (300 MHz, CDCl3):
D-
(N,N-diethylamino)propan-2-yl]-
a-D-lyxofuranose (7a). Flash col-
b-D
23
umn chromatography eluting with dichloromethane/methanol
a
]
þ11.4 (c 0.9,
D
23
39:1. [
d
a
]
þ14.9 (c 3.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼5.51 (d, J1,2¼5.0 Hz, 1H, 1H),
D
7.68e7.61 (m, 4H, AreH), 7.42e7.35 (m, 6H, AreH), 5.36 (s, 1H,
4.65 (dd, J3,2¼2.4 and J3,4¼7.9 Hz, 1H, 3H), 4.47 (dd, J4,5¼1.8 and
J4,3¼7.9 Hz, 1H, 4H), 4.41e4.36 (m, 1H, 6H), 4.34 (dd, J2,1¼5.0 and
J2,3¼2.4 Hz, 1H, 2H), 3.83 (dd, J5,4¼1.8 and J5,6¼7.4 Hz, 1H, 5H),
3.50e3.26 (m, 6H, 7H, 70H, 2ꢁ eCH2e), 2.05e2.09 (m, 1H, eOH),
1.56e1.47 (m, 12H, 4ꢁ CH3), 1.33, 1.37 (2s, 6H, 2ꢁ CH3). 13C NMR
1H), 5.00 (dd, J3,2¼5.8 and J3,4¼3.5 Hz, 1H, 3H), 4.69 (d, J2,3¼5.8 Hz,
2H, 2H), 4.14 (dd, J4,5¼9.0 and J4,3¼3.5 Hz, 1H, 4H), 3.79 (d,
J5,4¼9.0 Hz, 1H, 5H), 2.80e2.78 [m, 4H, e(CH2CH3)2], 1.41, 1.35 (2s,
6H, 2ꢁ CH3), 1.19e1.07 [m, 21H, 2ꢁ CH3, (CH2CH3)2, C(CH3)3]. 13C
NMR (75 MHz, CDCl3):
d
¼135.5, 135.4 (4ꢁ eCHe), 133.0, 132.8 (2ꢁ
(75 MHz, CDCl3):
d
¼109.5, 109.0 (2ꢁ eCe), 96.1 (eCHe), 70.4, 70.3,
eCe), 129.9, 129.8, 127.7, 127.6 (6ꢁ eCHe), 112.3 (eCe), 102.1
(eCHe), 86.0, 81.1, 80.0, 69.9 (4ꢁ eCHe), 53.4 (eCe), 42.1 (2ꢁ
eCH2e), 26.6 [eC(CH3)3], 25.9, 24.7, 19.5, 19.4, 19.1 (6ꢁ CH3), 18.0
(eCe). MS (ESIþ) m/z (%) 542 ([MþH]þ, 100); HRMS (ESIþ) calcd for
[C31H48NO5Si]þ, [MþH]þ 542.3287, found 542.3296. Rf¼0.27
(dichloromethane/methanol 39:1).
69.9, 69.1, 64.7 (5ꢁ eCHe), 55.8, 50.0, 45.6 (3ꢁ eCH2e), 54.3 (2ꢁ
eCH2e), 26.2, 25.9, 24.7, 24.2 (4ꢁ CH3),10.0, 9.8 (2ꢁ CH3). MS (ESIþ)
m/z (%) 346 ([MþH]þ, 100); HRMS (ESIþ) calcd for [C17H32NO6]þ,
[MþH]þ 346.2224, found 346.2218. Rf¼0.32 (dichloromethane/
methanol 19:1).
4.4. General procedure for the synthesis of ligands 7b, 7f, 7i,
and 7k
4.3.2. 1-O-tert-Butyldiphenylsilyl-6-deoxy-6-N,N-diethylamino-2,3-
di-O-isopropylidene-a-D-mannofuranose (7d). Flash column chro-
23
matography eluting with dichloromethane/methanol 19:1. [
a
]
Bromonitroalkane (1.2 mmol) was added to a suspension of
activated zinc powder (654 mg, 10.0 mol) and indium powder
D
þ15.5 (c 2.2, CHCl3); 1H NMR (300 MHz, CDCl3):
¼7.67e7.61 (m, 4H,
d

3430
R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
(14.3 mg, 0.12 mmol) in THF (5 mL) and the mixture was sonicated
for 20 min. The corresponding aldehyde (1.0 mmol) was added and
sonication was continued for a further 4 h. Then, isopropyl alcohol
(11 mL), hydrochloric acid (8 mL, 1 M) and zinc (325 mg, 5.0 mmol)
were added and the reaction mixture was stirred at room tem-
perature for 14 h. The mixture was then neutralized with saturated
aqueous sodium hydrogen carbonate, filtered through a pad of
Celite and extracted with ethyl acetate (3ꢁ50 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and the
eCHe), 72.9 (eCH2e), 65.8 (eCHe), 62.3, 62.3 (2ꢁ eCH2e), 58.7
(eCe), 49.5 (2ꢁ eCH2e), 28.3 (CH3), 27.8 (2ꢁ eCH2e), 26.8, 26.3 (2ꢁ
CH3), 24.6 (eCH2e),19.4 (CH3). MS (ESIþ) m/z (%) 478 ([MþH]þ,100);
HRMS (ESIþ) calcd for [C26H40N2O7]þ, [MþH]þ 478.2790, found
478.2790. Rf¼0.27 (dichloromethane/methanol 39:1).
4.4.4. 7-Deoxy-7-(piperidin-1-yl)-1,2:3,4-di-O-isopropylidene-glyc-
ero-
ing with dichloromethane/methanol 19:1. [
CHCl3); 1H NMR (300 MHz, CDCl3):
b-D-galacto-heptose (7k). Flash column chromatography elut-
23
a
]
ꢀ16.4 (c 3.5,
D
solvent was evaporated in vacuo. 1,5-Diiodopentane (75
mL,
d
¼5.48 (d, J1,2¼5.0 Hz, 1H, 1H),
0.5 mmol) and potassium carbonate (70 mg, 0.5 mmol) were added
to a solution of the obtained crude aminoalcohol (0.5 mmol) in
acetonitrile (4 mL), and the resulting mixture was heated at 60 ꢂC
for a total of 12 h, and then at 80 ꢂC for 12 h. Further 1,5-
4.64e4.58 (m, 2H, 3H, eOH), 4.49 (dd, J4,5¼1.7 Hz, J4,3¼8.0 Hz, 1H,
4H), 4.31 (dd, J2,1¼5.0 and J2,3¼2.2 Hz, 1H, 2H), 4.29e4.22 (m, 1H,
6H), 4.71 (dd, J2,1¼5.0 Hz, J2,3¼2.3 Hz,1H, 2H), 3.16e2.95 (m, 6H, 7H,
70H, 2ꢁ eCH2e), 1.98e1.93 (m, 4H, 2ꢁ eCH2e), 1.66e1.62 (m, 2H,
eCH2e), 1.55, 1.45, 1.36, 1.32 (4s, 12H, 4ꢁ CH3). 13C NMR (75 MHz,
diiodopentane was added (38
mL, 0.25 mmol) and the mixture
was heated at 80 ꢂC for further 12 h, and then refluxed for 24 h. The
reaction mixture was cooled, filtered, and evaporated under re-
duced pressure and the residue was purified by flash column
chromatography in mixtures of dichloromethane/methanol.
CDCl3):
d
¼109.1,108.7 (2ꢁ eCe), 96.0 (eCHe), 70.5, 70.2, 69.8, 69.2,
63.7 (5ꢁ eCHe), 61.1, 54.5 (3ꢁ eCH2e), 26.1, 25.8, 24.7, 24.0 (4ꢁ
CH3), 23.4, 22.3 (3ꢁ eCH2e). MS (ESIþ) m/z (%) 358 ([MþH]þ, 100);
HRMS (ESIþ) calcd for [C18H32NO6]þ, [MþH]þ 358.2217, found
358.2224. Rf¼0.32 (dichloromethane/methanol 19:1).
4.4.1. 1-O-tert-Butyldiphenylsilyl-2,3-di-O-isopropylidene-5-[2-(pi-
peridin-1-yl)propan-2-yl]-
a-
D-lyxofuranose (7b). Flash column
4.5. General procedure for the synthesis of ligands 7c and 7h
chromatography eluting with dichloromethane/methanol 19:1.
[
a
]
23 þ11.2 (c 3.8, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼7.69e7.62
Bromonitroalkane (1.2 mmol) was added to a suspension of
activated zinc powder (654 mg, 10.0 mol) and indium powder
(14.3 mg, 0.12 mmol) in THF (5 mL) and the mixture was sonicated
for 20 min. The corresponding aldehyde (1.0 mmol) was added and
sonication was continued for a further 4 h. Then, isopropyl alcohol
(11 mL), hydrochloric acid (8 mL, 1 M) and zinc (325 mg, 5.0 mmol)
were added and the reaction mixture was stirred at room tem-
perature for 14 h. The mixture was then neutralized with saturated
aqueous sodium hydrogen carbonate, filtered through a pad of
Celite and extracted with ethyl acetate (3ꢁ50 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and the
D
(m, 4H, AreH), 7.40e7.34 (m, 6H, AreH), 5.35 (s, 1H, 1H), 5.00 (dd,
J3,2¼5.8 and J3,4¼3.5 Hz, 1H, 3H), 4.70 (d, J2,3¼5.8 Hz, 1H, 2H), 4.12
(dd, J4,5¼9.1 and J4,3¼3.5 Hz, 1H, 4H), 3.77 (d, J5,4¼9.1 Hz, 1H, 5H),
2.69e2.42 (m, 4H, 2ꢁ eCH2), 1.62e1.44 (m, 4H, 2ꢁ eCH2e),
1.49e1.36 (m, 5H, eCH2e, CH3), 1.41 (s, 3H, CH3), 1.07 [s, 9H,
eC(CH3)3], 0.94, 0.87 (2s, 6H, 2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
d
¼135.5, 135.4 (4ꢁ eCHe), 133.0, 132.2 (2ꢁ eCe), 129.8, 129.7,
127.7, 127.5 (6ꢁ eCHe), 112.2 (eCe), 102.0 (eCHe), 86.1, 81.3, 80.0,
69.5 (4ꢁ eCHe), 53.7 (eCe), 46.2 (2ꢁ eCH2e), 26.6 [eC(CH3)3],
25.9 (2ꢁ eCH2e), 25.1, 24.7 (2ꢁ CH3), 24.4 (eCH2e), 19.3
[eC(CH3)3], 19.1, 17.4 (2ꢁ CH3). MS (ESIþ) m/z (%) 554 ([MþH]þ,
100); HRMS (ESIþ) calcd for [C32H48NO5Si]þ, [MþH]þ 554.3288,
found 497.3296. Rf¼0.34 (dichloromethane/methanol 19:1).
solvent was evaporated in vacuo. 2-Iodoethyl ether (71
mL,
0.5 mmol) and potassium carbonate (70 mg, 0.5 mmol) were added
to a solution of the obtained crude aminoalcohol (0.5 mmol) in
acetonitrile (4 mL) and the resulting mixture was heated at 60 ꢂC
for a total of 12 h, and then at 80 ꢂC for 12 h. Further 2-iodoethyl
4.4.2. 1-O-tert-Butyldimethylsilyl-2,3-di-O-isopropylidene-5-[2,2-
dimethyl-5-(piperidin-1-yl)-1,3-dioxan-5-yl]-
(7f). Flash column chromatography eluting with dichlor-
a
-
D
-lyxofuranose
ether was added (36 mL, 0.25 mmol) and the mixture was heated
at 80 ꢂC for further 12 h, and then refluxed for 24 h. The reaction
mixture was cooled, filtered, and evaporated under reduced pres-
sure and the residue was purified by flash column chromatography
in mixtures of dichloromethane/methanol.
omethane/methanol 39:1. [
a
]
23 ꢀ3.2(c3.5, CHCl3);1HNMR(300MHz,
D
CDCl3):
d
¼5.32 (s, 1H, 1H), 4.87 (dd, J3,2¼5.8 and J3,4¼3.6 Hz, 1H, 3H),
4.48 (d, J2,3¼5.8 Hz, 1H, 2H), 4.20 (d, J¼12.9 Hz, 1H, eOCHe), 4.08 (d,
J¼12.9 Hz, 1H, eOCHe), 3.97e3.89 (m, 3H, 2ꢁ eOCHe, 4H), 3.48 (d,
J5,4¼9.3 Hz,1H, 5H), 2.92e2.84 (m, 4H, 2ꢁ eCH2e), 1.68e1.55 (m, 4H,
2ꢁ eCH2e), 1.51e1.46 (m, 8H, eCH2, 2ꢁ CH3), 1.39, 1.34 (2s, 6H, 2ꢁ
CH3), 0.88 [s, 9H, eC(CH3)3], 0.12, 0.10 (2s, 6H, 2ꢁ CH3). 13C NMR
4.5.1. 1-O-tert-Butyldiphenylsilyl-2,3-di-O-isopropylidene-5-[2-
(morpholino)propan-2-yl]-a-D-lyxofuranose (7c). Flash column
chromatography eluting with dichloromethane/methanol 39:1.
23
(75 MHz, CDCl3):
d¼112.3 (eCe),101.6 (eCHe), 98.1 (eCe), 85.9, 81.1,
[a
]
þ11.0 (c 7.5, CHCl3); 1H NMR (300 MHz, CDCl3):
¼7.69e7.62
d
D
79.1, 66.7 (4ꢁ eCHe), 62.2, 62.0 (2ꢁ eCH2e), 58.3 (eCe), 49.5 (2ꢁ
eCH2e), 28.3 (eCH3), 27.7 (2ꢁ eCH2e), 26.0 (CH3), 25.5 [eC(CH3)3],
24.7 (CH3), 24.6 (eCH2e), 19.7 [eC(CH3)3], 17.9 (CH3), ꢀ4.7, ꢀ5.4 (2ꢁ
CH3). MS (ESIþ) m/z (%) 502 ([MþH]þ, 100); HRMS (ESIþ) calcd for
[C25H48NO7Si]þ, [MþH]þ 502.3189, found 502.3194. Rf¼0.28
(dichloromethane/methanol 39:1).
(m, 4H, AreH), 7.44e7.35 (m, 6H, AreH), 5.35 (s, 1H, 1H), 5.00 (dd,
J3,2¼5.8 and J3,4¼3.5 Hz, 1H, 3H), 4.70 (d, J2,3¼5.8 Hz, 1H, 2H), 4.12
(dd, J4,5¼9.0 and J4,3¼3.5 Hz, 1H, 4H), 3.72e3.69 (m, 5H, 5H, 2ꢁ
eCH2Oe), 2.61e2.49 (m, 4H, 2ꢁ eCH2e), 1.60 (br s, 1H, eOH), 1.41,
1.36 (2s, 6H, 2ꢁ CH3), 1.06 [s, 9H, eC(CH3)3], 0.94, 0.91 (2s, 6H, 2ꢁ
CH3). 13C NMR (75 MHz, CDCl3):
d
¼135.5, 135.4 (4ꢁ eCHe), 133.1,
132.9 (2ꢁ eCe), 129.8, 129.7, 127.7, 127.6 (6ꢁ eCHe), 112.2 (eCe),
102.1 (eCHe), 86.1, 81.3, 79.7, 69.3 (4ꢁ eCHe), 67.7 (2ꢁ eCH2e),
59.3 (eCe), 45.4 (2ꢁ eCH2e), 26.6 [eC(CH3)3], 25.9, 24.7 (2ꢁ CH3),
19.1 [eC(CH3)3], 18.9, 17.0 (2ꢁ CH3). MS (ESIþ) m/z (%) 556 ([MþH]þ,
100); HRMS (ESIþ) calcd for [C31H46NO6Si]þ, [MþH]þ 556.3080,
found 556.3089. Rf¼0.27 (dichloromethane/methanol 39:1).
4.4.3. 3-O-Benzyl-1,2-O-isopropylidene-5-[2,2-dimethyl-5-(piper-
idin-1-yl)-1,3-dioxan-5-yl]-a-D-xylofuranose (7i). Flash column
chromatography eluting with dichloromethane/methanol 39:1.
[
a
]
24 ꢀ38.0 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.35e7.26 (m,
D
5H, AreH), 5.90 (d, J1,2¼3.7 Hz,1H,1H), 4.68 (s, 2H, eCH2Ph), 4.51 (d,
J2,3¼3.7 Hz,1H, 2H), 4.20e3.87 (m, 6H, 2ꢁ eOCH2e, 3H, 4H), 3.53 (d,
J5,4¼9.3 Hz, 1H, 5H), 2.93e2.84 (m, 4H, 2ꢁ eCH2e), 1.63e1.59 (m,
4H, 2ꢁ eCH2e),1.52e1.46 (m, 8H, eCH2e, 2ꢁ CH3),1.38,1.30 (2s, 6H,
4.5.2. 3-O-Benzyl-1,2-O-isopropylidene-5-[2-(morpholino)propan-2-
yl]-
with dichloromethane/methanol 39:1. [
NMR (300 MHz, CDCl3):
a-D-xylofuranose (7h). Flash column chromatography eluting
2ꢁ CH3). 13C NMR (75 MHz, CDCl3):
d¼137.8 (eCe), 128.4, 127.8 (5ꢁ
a]
D
23 ꢀ20.9 (c 1.3, CHCl3); H
1
eCHe), 111.7 (eCe), 105.3 (eCHe), 98.2 (eCe), 83.0, 81.9, 79.7 (3ꢁ
d
7.35e7.26 (m, 5H, HeAr), 5.90 (d,

R.G. Soengas, A.M.S. Silva / Tetrahedron 69 (2013) 3425e3431
3431
L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1993, 34, 5479; (d) Marshall, J. A.;
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H.; Choi, H. Chem. Commun. 1996, 1521; (h) Veeresa, G.; Datta, A. Tetrahedron
Lett. 1998, 39, 119.
J1,2¼3.7 Hz,1H, H-1), 4.72e4.45 (m, 5H), 4.88e4.76 (m, 2H), 3.79e3.51
(m, 3H), 2.30e2.70 (m, 4H, 2ꢁ eCH2),1.46,1.38,1.10, 0.92 (4s,12H, 4ꢁ
CH3).13C NMR(75MHz, CDCl3):
d¼137.4 (eCe),129.0,128.5,128.2 (5ꢁ
eCHe), 112.3 (eCe), 105.2 (eCHe), 84.8, 82.2, 77.4 (3ꢁ eCHe), 72.0
(eCH2e), 71.3 (eCHe), 68.3 (2ꢁ eCH2e), 59.7 (eCe), 46.7 (2ꢁ
eCH2e), 27.4, 27.0,19.6,19.2 (4ꢁ CH3). MS (ESIþ) m/z (%)408 ([MþH]þ,
100); HRMS (ESIþ) calcd for [C22H34NO6]þ, [MþH]þ 408.2381, found
408.2397. Rf¼0.27 (dichloromethane/methanol 39:1).
4. (a) Harris, T. M.; Harris, C. M. H.; Hill, J. E.; Ungemach, F. S.; Broquist, H. P.;
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Chem. 1989, 54, 2591.
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S. C. Tetrahedron 2000, 56, 2561.
7. Le, T. T.; Guillarme, S.; Saluzzo, C. Tetrahedron 2010, 66, 8893.
8. (a) Sudershan, K. S.; Thompson, D. S.; Akhtar, M. N. US 5360792 A 19941101.
(b) Sudershan, K. S.; Thompson, D. S.; Akhtar, M. N. WO 9313117 A2
19930708.
Acknowledgements
~
Thanks are due to the University of Aveiro, Fundac¸ ao para
ˇ
a Ciencia e a Tecnologia (FCT) and FEDER for funding the Organic
Chemistry Research Unit (project PEst-C/QUI/UI0062/2011) and the
Portuguese National NMR Network (RNRMN). R.S. thanks the FCT
for a ‘Investigador Auxiliar’ position.
ꢀ
ꢀ
ꢀ
9. Mancilla, G.; Duran-Patron, R. M.; Macías-Sanchez, A. J.; Collado, I. G. Bioorg.
Med. Chem. Lett. 2010, 20, 6820 and references cited herein.
10. (a) Soengas, R. G. Tetrahedron Lett. 2010, 51, 105; (b) Soengas, R. G. Tetrahedron:
ꢀ
Asymmetry 2011, 217, 2249; (c) Soengas, R. G.; Estevez, A. M. Synlett 2011, 2625;
ꢀ
(d) Soengas, R. G. Synlett 2011, 2547; (e) Soengas, R. G.; Segade, Y.; Jimenez, C.;
Rodríguez, J. Tetrahedron 2011, 67, 2617; (f) Soengas, R. G. Ultrason. Sonochem.
Supplementary data
2012, 19, 916.
ꢀ
11. (a) Soengas, R. G.; Estevez, A. M. Eur. J. Org. Chem. 2010, 5190; (b) Soengas, R. G.;
1H and 13C NMR spectra for vicinal aminoalkanols 7. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.02.072.
ꢀ
Estevez, A. M. Tetrahedron Lett. 2012, 53, 570; (c) Rodríguez-Solla, H.; Soengas,
R. G.; Alvaredo, N. Synlett 2012, 2083.
12. Reaction of bromonitromethane and aldehydes to give 2-bromo-2-nitroalkan-1-
ols has also been described. See Ref. 11c and: (a) Alcaide, B.; Almendros, P.; Luna,
ꢀ
A.; Torres, R. Org. Biomol. Chem. 2008, 6, 1635; (b) Concellon, J. M.; Rodríguez-
ꢀ
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