Organocatalytic Asymmetric Tandem α-Aminooxylation–Henry Reactions for the Synthesis of 1,2-Diols: Total Synthesis of (–)-l-threo-Sphinganine

Article abstract of DOI:10.1002/ejoc.201701289

A new and rapid asymmetric synthesis of anti- and syn-β,γ-dihydroxynitroalkanes through an organocatalytic tandem α-aminooxylation–Henry reaction is described. The target diol derivatives were synthesized in good yields, with excellent enantioselectivitie

Full text of DOI:10.1002/ejoc.201701289

A Journal of
Accepted Article
Title: Organocatalytic Asymmetric Tandem α-Aminooxylation-Henry
Reactions for the Synthesis of 1,2-Diols: Total Synthesis of (-)-L-
threo-Sphinganine
Authors: Satyendra Kumar Pandey, Yuvraj Garg, and Ramandeep
Kaur
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701289
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10.1002/ejoc.201701289
European Journal of Organic Chemistry
Full Paper
Organocatalytic Asymmetric Tandem α-Aminooxylation-Henry
Reactions for the Synthesis of 1,2-Diols: Total Synthesis of (-)-
threo-Sphinganine
L-
Yuvraj Garg,[a] Ramandeep Kaur[a] and Satyendra Kumar Pandey*[a]
Abstract: A novel and rapid asymmetric syntheses of 1,2-diol
derivatives anti- and syn-β,γ-dihydroxynitroalkanes via
organocatalyzed tandem -aminooxylation-Henry reactions are
Nitromethane and base DIPEA were used in the second step
and were added to α-aminooxylation reaction mixture until all the
nitrosobenzene was consumed. Pleasingly, the tandem reaction
proceeded smoothly with product anti-5a and syn-5b in 42%
yield along with expected O-NHPh protected derivative of 5 in
low yield (12%). It is also known that in situ partial N-O bond
cleavage may occur during α-aminooxylation reaction.2i It is also
worthy to mention that removal of N-phenylamino group could
be achieved by either catalytic hydrogenation2n or by Cu(II)
catalyzed reactions.6 The separation of anti-5a and syn-5b on
α
described. The targeted diol derivatives are synthesized in good
yields, with excellent enantio- and low to moderate
diasteroselectivities under mild conditions. Synthesis of an
antineoplastic and antipsoriatic drug (-)-L-threo-sphinganine
demonstrate the synthetic utility of the fragments generated in the
title reaction.
silica
gel
column
chromatography
indicated
no
Enantiopure 1,2-diols are versatile chiral building blocks and
have been used widely as starting materials for the asymmetric
synthesis of drugs and bioactive natural products.1 Various
methods for the synthesis of 1,2-diols have been documented in
the literature.2,3 The Sharpless asymmetric dihydroxylation (AD)
of trans-olefins3 is one of the most efficient reactions leading to
syn-1,2-diols in high enantiomeric excesses (ee’s) while cis-
olefins give rise to anti-1,2-diols showing low enantioselectivity.3b
Recent developments in asymmetric catalysis have included
organocatalysis involving α-aminooxylation directed tandem
reactions which demonstrate a rapid and atom-economical one
pot catalytic process that provides enantiopure compounds.4 We
envisioned that reactive α-aminooxy aldehyde intermediate 2
generated from the organocatalyzed α-aminooxylation2l-n of
aldehydes 1 on in situ trapping with nitromethane under a Henry
reaction conditions5 followed by cleavage of phenylamine moiety
would provide β,γ-dihydroxynitroalkane 3 (eq 1).
diastereoselectivity in the second step (anti-5a/syn-5b 1:1), but
excellent enantioselectivities were found (>99% ee for each of
anti-5a and syn-5b) in one pot tandem α-aminooxylation-Henry
reactions.
Guided by our favorable results, we then focused on using a
chiral catalyst in the Henry reaction to improve the
diastereoselectivity and chemical yield. After the first report of
Shibasaki and co-workers,5y many efforts have been made
continuously in the literature for asymmetric induction into the
Henry reaction, using prochiral aldehydes and nitromethane in
the presence of chiral metal complexes and organocatalysts.5
Among them, Henry reaction catalyzed by the stable Cu(II)-
salen complex has received more attention during the recent
years.5i-s Towards this end, a stable copper (II)-salen complex (-
)-7 was prepared by the treatment of commercially available
(R,R)-Jacobsen’s ligand7 (-)-6 with copper (II) acetate in
methanol (Scheme 2) which was then used in tandem α-
aminooxylation-Henry reactions. Initial result was not
encouraging, as the tandem reaction proceeded with no
improvement in anti-5a/syn-5b diastereomeric ratio even though
with no loss in enantiomeric excess (ee’s).
Based on this, herein we describe a highly enantioselective one-
pot tandem approach to
a
non-terminal 1,2-diol unit
β,γ−dihydroxynitroalkanes involving the organocatalyzed α-
aminooxylation of aldehydes followed by an in situ Henry
reaction. Our preliminary experiments were initiated by using 3-
We next envisioned that, due to the strong basicity and
coordination capability of the secondary diamine ligands could
affect the catalytic activity in the Cu catalyzed Henry reaction. 5i-
l,n,p,r Therefore, we have performed the reduction of ligand (-)-6
with NaBH4/acetic acid in DCE to diamine ligand (-)-8 in
excellent yield of 99% which was used further for controlling the
stereoselectivity (Scheme 2).
phenylpropionaldehyde
4
as
the
model
substrate,
nitrosobenzene, DMSO as the solvent and
catalyst (Scheme 1).
L
-proline as the
Scheme 1. Strategy for in situ trapping of the reactive
aldehyde intermediates.
α-aminoxylated
[a]
Y. Garg, R. Kaur and Dr. S. K. Pandey
School of Chemistry and Biochemistry
Thapar University, Patiala-147001 (India)
E-mail:skpandey@thapar.edu
Scheme 2. Synthesis of (-)-7/copper (II) complex and tetrahydrosalen ligand (-
)-8 from (-)-6.
https://sites.google.com/site/satyendraresearchgroup/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201701289
European Journal of Organic Chemistry
Full Paper
Serendipitously, ligand (-)-8 on complexation with Cu(OAc)2.H2O
led to more promising outcome in the Henry reaction step to
furnish relatively good yield of anti-5a/syn-5b in 52% without
affecting the enantioselectivity. To further improve the
diastereoselectivity and chemical yield, a series of other Cu (I)
catalysts, such as CuI, CuBr, CuCl, CuCN, CuOAc and Cu (II)
catalysts, such as CuCl2.2H2O, Cu(OTf)2, CuSO4.5H2O were
surveyed in the presence of ligand (-)-8. Out of copper (I) and
(II) catalysts, Cu(OAc)2.H2O turned out to be the best choice for
subsequent reactions which provided the highest anti/syn ratio.
(Table 1). The tandem reaction furnished the adducts in low to
moderate diastereoselectivities of anti/syn ratio (from 1.10:1 to
6.34:1), excellent enantioselectivity (up to >99% ee’s) and good
overall yields (up to 70%). The described tandem reaction does
not require oxygen free or anhydrous conditions and was
completed in 12 h at room temperature. The stereochemistry of
this tandem transformation was assigned via 1H-NMR
determination of the anti- and syn-diastereomers which are in
accordance with the previously established absolute
configuration of the α-aminooxylated aldehyde.2l-n
As evident from Table 1 results that there is preference of
Table 1. Asymmetric synthesis of
β,γ-dihydroxynitroalkane derivatives
(1R,2R)-ligand
(-)-8/Cu(II)
complex
to
give
anti-β,γ-
α-
under optimized conditions.
dihydroxynitroalkane
derivatives
during
tandem
aminooxylation-Henry reactions approach. This implies that
nitronate ion attack at the si face of the α-aminooxylated
aldehyde synthesized using the
L-proline; to rationalize the
outcome, a transition state 16 is proposed in Figure 1. In the
proposed model, substrates are coordinated to (-)-8/Cu(II)
complex under the bicyclic framework and C-C bond formation
taking place from the less hindered side due to two
simultaneously NH hydrogen bonding, one with O-NHPh of α-
aminooxylated aldehyde and another with the nitronate ion.
Since, in complex (-)-7 this hydrogen bonding was absent leads
to low or no diastereoselectivity.
entry
product
R
Yield[a]
(%)
67
64
67
64
62
67
70
68
62
65
67
dr[b]
(anti/syn)
ee[c]
(anti/syn, %)
1
2
3
4
5
6
7
8
5
9
10
11
12
13
14
Bn
i-Pr
Me
C4H9
C5H11
C7H15
C10H21
C15H31
Bn
1.37:1
1.35:1
1.75:1
1.23:1
6.34:1
1.10:1
3.30:1
1.20:1
1.10:1
1.10:1
1.64:1
99/92
>99/98
98/94
92/96
98/82
90/>99
>99/98
80/>99
>99/96
70/96
15
9
10
11
5[d]
14[d]
15[d]
C10H21
C15H31
86/97
[a]All were for isolated anti+syn products. [b]The anti/syn diastereomeric ratio
was determined by chiral HPLC. All diastereomers were separable from the
silica gel column chromatography. [c]The ee’s were determined by HPLC on
Chiralpak IA, AD-H and Chiralcel OJ-H columns (see Supporting Information).
Figure 1. Plausible transition state for the tandem
α-aminooxylation-Henry
reactions.
[d]The
which furnished the anti-(R,S) and syn-(S,S) diastereomers (entry 9-11). The
-aminooxylated aldehydes are known to present in the form of oligomer in
α-aminooxylation reaction was performed via using D-proline as catalyst
As a probe to the mechanism, the α-aminooxylated aldehyde
synthesized from -proline was subjected to in situ treatment
D
α
with nitromethane under the above optimized Henry reaction
conditions which furnished the anti-selective diastereomer (re
face attack) of β,γ-dihydroxynitroalkane in good yield and anti-
5c/syn-5d 1.10:1 diastereomeric ratio (Table 1, 5[d]). The results
imply that the NH hydrogen bonding with O-NHPh of α-
aminooxylated aldehyde furnished the more anti-selective
solution.2m
After establishing the choice of catalyst, we moved further to
screen the reaction solvents for tandem α-aminooxylation-Henry
reactions. Previously, Guofu Zhong2n reported that DMSO acts
as best solvent for α-aminooxylation in terms of yield and
enantioselectivity. However, among the solvents (DMSO,
CH3CN, MeOH, EtOH, DCM, IPA, DMF, Toluene, THF, 1,4-
dioxane) screened for Henry reaction on α-aminooxylated
aldehyde intermediates, polar protic solvent methanol was found
to be best with respect to optical purity and chemical yield.
It is well known that a base could be employed in Henry reaction
to generate the nitronate ion from nitromethane and to increase
the reactivity of the catalyst.5s Among the screened bases (aq
NaOH, aq KOH, K2CO3, K-OtBu, DIPEA, DMAP, NEt3, NMM and
DBU) for Henry reaction of nitromethane with α-aminooxylated
aldehyde intermediates in methanol, aq NaOH was found to
show the best reactivity for the anti-5a/syn-5b.
diastereomeric ratio from both L- and D-proline.
Based on our study and literature reports, a catalytic cycle that
would incorporate a transition state 16 is proposed in Scheme 3.
In the first cycle, the aldehyde 1 on α-aminooxylation would
provide the enantiopure α-aminooxylated aldehyde intermediate
2 via reactive intermediates 17 and 18 which then undergo
stereocontrolled Henry reaction. In the second cycle, ligand
exchange of tetrahydrosalen (-)-8 for acetic acid would afford
complex 19, which on further progress via Cu (II) complex 20
and transition state 16 complete the cycle while generating the
β,γ-dihydroxynitroalkane derivative 3.
We next explored the synthetic application of the β,γ-
dihydroxynitroalkane fragments produced in the tandem α-
aminooxylation-Henry reactions. The 1,2-diols and vicinal
amino-alcohols motifs are found in various drugs and bioactive
natural products such as antineoplastic and antipsoriatic drug
With optimal reaction conditions in hand, we further explored the
scope of this one-pot tandem approach to a variety of α-
aminooxylated aromatic and aliphatic aldehyde intermediates
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10.1002/ejoc.201701289
European Journal of Organic Chemistry
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25
target
L
-threo-sphinganine 21 in 81% yield {[α]D -7.5 (c 0.09,
C2H5OH) Lit.10a -7.6 (c 0.09, C2H5OH)}.
i) NaNO2, AcOH
OH
DMSO, 35 o
24 h
C
OH
O
C14H29
C14H29
NO2
OEt
ii) TMSCl, EtOH
rt, 12h, 64%
OH
OH
15c
26
O
NaN3, DMF
80 oC, 12 h
SOCl2, NEt3
DCM, 0 oC, 1 h
C14H29
OEt
O
O
95%
91%
S
O
27
OH
OH
O
LiAlH4, THF
reflux, 12 h
C14H29
C14H29
OH
OEt
81%
NH2
N3
21
Lꢀthreoꢀsphinganine
28
Scheme 4. Asymmetric synthesis of
L
-threo-sphinganine.
In conclusion, we have developed a novel organocatalyzed
tandem α-aminooxylation-Henry reactions approach for the
asymmetric synthesis of anti- and syn-β,γ-dihydroxynitroalkane
derivatives in good yield (up to 70%) with excellent enantio-
(ee’s for anti- and syn up to >99%) and diastereselectivities (dr
anti/syn, up to 6.34:1). The (S)- and (R)- configuration of α-
aminooxylated aldehyde could be manipulated by simply
Scheme
3.
Proposed
catalytic
cycle
for
the
synthesis
of
β,γ−dihydroxynitroalkane derivatives.
L
-threo-sphinganine (safingol) 21,8a potent inhibitor of the
serine/threonine kinases protein kinase A, protein kinase C drug
(R,R)-balanol 22,8b antidepressant drug (S,S)-reboxetine 23,8c
hydroxylated piperdines with potent antimalarial drug febrifugine
24,8d and antibiotic (-)-galantinic acid 258e (Figure 2).
changing the
D-proline and L-proline, respectively, during
organocatalytic step and thus, in principle, all the four isomers of
β,γ-dihydroxynitroalkane derivatives could be accessed from this
developed tandem approach. The rapid and protecting group
free synthesis of an antineoplastic and antipsoriatic drug L-threo-
sphinganine demonstrates the synthetic utility of the chiral
building blocks furnished by the title reaction. This tandem
strategy, which is amenable to both anti- and syn-1,2-diols, has
significant potential for its further extension to the asymmetric
synthesis of a variety of natural- and natural-like bioactive
compounds.
Experimental Section
Figure 2. Some selected biologically active compounds.
General Experimental Details: The chemicals and solvents were
purchased from Merck and Sigma Aldrich chemical company. Progress
of the reactions was monitored by thin layer chromatography using
precoated aluminium plates of Merck kieselgel 60 F254. 1H and 13C NMR
spectra were recorded in CDCl3 (unless otherwise mentioned) on JEOL
ECS operating at 400 and 100 MHz, respectively. Chemical shifts are
reported in δ (ppm), referenced to TMS. IR spectra were recorded on
Agilent resolution Pro 600 FT-IR spectrometer, fitted with a beam-
condensing ATR accessory and peaks are reported in cm-1. HRMS were
recorded using Electron Spray Ionization. UV-vis spectrum was recorded
on UV 2600 Shimadzu spectrophotometer. Optical rotations were
measured on Automatic polarimeter AA-65 and concentrations of g/100
mL. Column chromatography was performed on silica gel (60-120 and
In continuation of our ongoing research programme towards the
asymmetric syntheses of bioactive compounds,9 we
demonstrated the synthetic application of the developed tandem
α-aminooxylation-Henry reactions towards the total synthesis of
L-threo-sphinganine 21.10
With enantiomerically pure anti-15c (Table 1, 15[d]) diastereomer
in hand, we then subjected it to NaNO2/acetic acid mediated
oxidation in DMSO to furnish acid1b,e which on spontaneous
treatment with TMSCl/EtOH11 afforded the α,β-dihydroxy ester
26 in 64% yield (Scheme 4). The diol 26 on treatment with
thionyl chloride under basic conditions at 0 oC furnished the
cyclic sulfite 27 in 95% yield. The regioselective nucleophilic
opening of cyclic sulfite 27 at the α-carbon position with
100-200 mesh) using
a
mixture of hexane/ethyl acetate and
dichloromethane/MeOH. All reactions were carried out under argon or
nitrogen atmosphere, in oven-dried glassware using standard glass
syringes, cannulas and septa (unless otherwise mentioned). Solvents
and reagents were purified and dried by standard methods prior to use
(unless otherwise mentioned). The diastereomer ratio (dr) and
o
NaN3/DMF at 80 C afforded the α-azido-β-hydroxy ester 28 in
91% yield. Finally, concomitant reduction of ester and azide
groups of derivative 28 with LiAlH4 in THF at 70 oC afforded the
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10.1002/ejoc.201701289
European Journal of Organic Chemistry
Full Paper
o
mobile phase of (9:1 hexane/i-PrOH, flow rate of 1 mL/min at 25 C,
enantiomeric purity (ee) were determined by Waters HPLC analysis
using Chiralpak IA, AD-H and Chiralcel OJ-H chiral columns.
UV detection at 215 nm): anti diastereomer (S,R)-enantiomer: tr =
11.202 min, (R,S)-enantiomer: tr = 12.012 min; syn diastereomer
(R,R)-enantiomer: tr = 8.866 min, (S,S)-enantiomer: tr = 10.652 min.
6,6'-((((1R,2R)-Cyclohexane-1,2-diyl)bis(azanediyl))bis(methylene))
bis(2,4-di-tert-butyl phenol) (8): To a dichloroethane (20 mL) solution of
(R,R)-Jacobsen’s ligand (-)-6 (2.0 g, 3.65 mmol) was added NaBH4 (278
mg, 7.30 mmol) followed by acetic acid (2 mL) at 0 oC. The reaction
mixture was stirred at room temperature for 2 h and then quenched with
saturated aqueous NaHCO3 solution. The aqueous phase was
extracted with EtOAc (3 x 20 mL), dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by silica gel column
chromatography (EtOAc/hexanes 1:1 v/v) as eluent to afford the
(2R,3R)-1-Nitro-4-phenylbutane-2,3-diol (5b): The above anti-/syn-
diastereomers 5 (142 mg) were separated and purified by silica gel
column chromatography using (EtOAc/hexane 1:9 v/v) as eluent to
furnish the syn-5b diastereomer as white solid in 28% yield (57 mg, 0.28
mmol) with with 97% ee. [α]D25 -25.4 (c 0.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ: 7.37-7.22 (m, 5H), 4.75-4.52 (m, 2H), 4.27-4.23 (m, 1H), 3.91-
3.86 (m, 1H), 3.07-3.03 (m, 1H), 2.95-2.88 (m, 1H), 2.69-2.75 (m, 1H),
1.97 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 136.5, 129.3, 128.9, 127.1,
77.6, 73.1, 71.2, 39.5. HRMS (ESI)+ m/z calcd for C10H13NO4Na+
([M+Na]+) 234.0737; found 234.0728. The enantiomeric purity (ee)
was determined by HPLC analysis using a Chiralcel AD-H chiral
ligand (-)-8
(1.99 g, 99%). {[α]D25 -14.0 (c 0.5, CH3OH); IR (CH2Cl2) ν:
3491, 3272, 2961, 2908, 2878, 1472, 1435, 1421, 1391, 1247, 991, 733
cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.21 (d, J = 2.76 Hz, 2H), 6.86 (d, J =
2.28 Hz, 2H), 4.04 (d, J = 13.2 Hz, 2H), 3.90 (d, J = 13.2 Hz, 2H), 2.47-
2.46 (m, 2H), 2.19-2.16 (m, 2H), 1.71-1.70 (m, 2H), 1.45-1.40 (m, 20H),
1.28-1.21 (m, 24H); 13C NMR (100 MHz, CDCl3) δ: 154.3, 140.5, 135.9,
123.1, 122.9, 122.3, 59.8, 50.8, 34.8, 34.1, 31.6, 30.7, 29.5, 24.1. HRMS
(ESI)+ m/z calcd for C36H58N2O2Na+ ([M+Na]+) 573.4390; found 573.4391.
column (4.6 x 250 mm) using mobile phase of (9:1 hexane/i-PrOH
,
flow rate of 1 mL/min at 25 oC, UV detection at 215 nm): (R,R)-
enantiomer: tr = 8.697 min, (S,S)-enantiomer: tr = 10.580 min.
(2S,3R)-1-Nitro-4-phenylbutane-2,3-diol (5a): After separation of
the syn-5b diastereomer, the anti-5a diastereomer was quickly eluted
(EtOAc/hexane 1:4 v/v) as white solid in 39% yield (84 mg, 0.39 mmol)
with >99% ee. [α]D25 -8.2 (c 0.6, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ:
7.36-7.21 (m, 5H), 4.65-4.46 (m, 2H), 4.29-4.25 (m, 1H), 3.83-3.82 (m,
1H), 2.95-2.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 136.7, 129.3,
129.2, 128.9, 127.0, 78.6, 72.5, 69.7, 39.9. HRMS (ESI)+ m/z calcd for
C10H13NO4Na+ ([M+Na]+) 234.0737; found 234.0735. The enantiomeric
purity (ee) was determined by HPLC analysis using a Chiralcel AD-
H chiral column (4.6 x 250 mm) using mobile phase of (9:1 hexane/i-
PrOH, flow rate of 1 mL/min at 25 oC, UV detection at 215 nm):
(S,R)-enantiomer: tr = 11.108 min, (R,S)-enantiomer: tr = 11.854
min.
General Procedure for tandem
a DMSO (1.5 mL) solution of aldehyde (1.0 mmol) and nitrosobenzene
(1.0 mmol), - or -proline (30 mol%) was added and stirred for about 20-
α-aminooxylation-Henry reaction: To
L
D
30 min at room temperature. The completion of the reaction was
monitored by its colour change from green to orange or by TLC until all
the nitrosobenzene was consumed and used as such for the next step
without further purification. The ligand (-)-8 (0.055 mmol, 5.5 mol%) and
Cu(OAc)2.H2O (0.05 mmol, 5 mol%) were added to methanol (1.5 mL)
and reaction mixture was stirred for 1 h at room temperature. To the
resulting dark blue solution of the catalyst, solvent (1.5 mL), nitromethane
(10.0 mmol), base (1.5 mmol), and above synthesized
α-
aminooxylatedaldehyde (1.0 mmol) were added. The reaction mixture
was stirred for 30 min then Cu(OAc)2.H2O (1.5 mmol) was added and
further stirred for 12 h at room temperature. After completion of the
reaction (monitored by TLC), the reaction mixture was evaporated,
diluted with water, extracted with EtOAc, dried over Na2SO4,
concentrated and purified by silica gel column chromatography.
(anti/syn)-1-Nitro-4-phenylbutane-2,3-diol (5c and 5d): Following
the general procedure for tandem
α-aminooxylated-Henry reaction, the
residue was purified by silica gel column chromatography using
(EtOAc/hexane 1:4 v/v) as eluent to afford the anti-5c and syn-5d
diastereomers as white solid in 62% yield (131 mg, 0.62 mmol), (>99%
ee for anti-5c, 96% ee for syn-5d) and as 1.10:1 anti:syn mixture of
diastereomers. 1H NMR (400 MHz, CDCl3) δ: 7.35-7.15 (m, 5H), 4.69-
4.42 (m, 2H), 4.26-4.21 (m, 1H), 3.89-3.77 (m, 1H), 3.01-2.65 (m, 3H);
13C NMR (100 MHz, CDCl3) δ: 136.8, 129.3, 129.3, 129.2, 128.8, 128.5,
126.9, 126.9, 78.6, 77.6, 73.3, 72.6, 71.3, 69.8, 39.8, 39.3. The
diastereomer ratio (dr) and enantiomeric purity (ee) were
determined by HPLC analysis using a Chiralcel AD-H chiral column
(4.6 x 250 mm) using mobile phase of (9:1 hexane/i-PrOH, flow rate
(-)-8/Cu(II) complex (19): To a MeOH (1.5 mL) solution of ligand (-)-8
(30 mg, 0.055 mmol) was added Cu(OAc)2.H2O (10 mg, 0.05 mmol) and
stirred for
1 h at room temperature under air atmosphere. After
completion of the reaction (as monitored by TLC), the reaction mixture
was evaporated, diluted with water, extracted with EtOAc, dried over
Na2SO4, concentrated and purified by silica gel column
chromatography using (EtOAc/hexane 1:4 v/v) as eluent to furnish the
complex 19 (30 mg, 95% yield) as green solid. {[α]D25 -558.4 (c 0.07,
CHCl3) [Lit.5j -558.8 (c 0.068, CHCl3)]; IR (CH2Cl2) ν: 3435, 3262, 3212,
2950, 2864, 2590, 2283, 1689, 1600, 1467, 1439, 1412, 1361, 1236,
o
of 1 mL/min at 25 C, UV detection at 215 nm): anti diastereomer
(S,R)-enantiomer: tr = 11.073 min, (R,S)-enantiomer: tr = 11.738
min; syn diastereomer (R,R)-enantiomer: tr = 8.353 min, (S,S)-
enantiomer: tr = 10.341 min.
1165, 1012, 926, 877, 827, 780, 738, 460 cm-1; UV-vis (CH2Cl2)
410, 292, 248 nm [Lit. 5j max: 623, 423, 290, 246 nm]; HRMS (ESI)+ m/z
calcd for C36H57N2O2Cu+ ([M+H]+) 612.3711; found 612.3724.
λmax: 612,
λ
(anti/syn)-4-Methyl-1-nitropentane-2,3-diol (9): Following the general
(anti/syn)-1-Nitro-4-phenylbutane-2,3-diol (5a and 5b): Following
the general procedure for tandem -aminooxylated-Henry reaction, the
procedure for tandem α-aminooxylated-Henry reaction, the residue was
α
purified by silica gel column chromatography using (EtOAc/hexane 1:6
v/v) as eluent to afford the anti-9a and syn-9b diastereomers as white
solid in 64% yield (104 mg, 0.64 mmol), (>99% ee for anti, 98% ee for
syn) and as 1.35:1 anti:syn mixture of diastereomers. IR (CH2Cl2) ν:
3574, 3512, 2975, 2904, 2714, 1545, 1471, 1413, 1373, 1289, 1182,
1085, 1054, 931, 770 cm-1; 1H NMR (400 MHz, CDCl3) δ: 4.66-4.42 (m,
3H), 3.47-3.15 (m, 2H), 2.36 (br s, 1H), 1.91-1.76 (m, 1H), 1.03-0.97 (m,
6H); 13C NMR (100 MHz, CDCl3) δ: 79.2, 77.5, 77.5, 76.9, 69.6, 68.7,
residue obtained was purified by silica gel column chromatography using
(EtOAc/hexane 1:5 v/v) as eluent to furnish the anti-5a and syn-5b
diastereomers as white solid in 67% yield (142 mg, 0.67 mmol), (99%
ee for anti-5a, 92% ee for syn-5b) and as 1.37:1 anti:syn mixture of
diastereomers. IR (CH2Cl2) ν: 3512, 3127, 2936, 1620, 1553, 1423, 1375,
791 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.35-7.21 (m, 5H), 4.72-4.45 (m,
2H), 4.28-4.21 (m, 1H), 3.90-3.79 (m, 1H), 3.05-2.67 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ: 136.7, 136.6, 129.3, 129.2, 128.9, 127.0, 127.0,
78.6, 77.6, 73.2, 72.5, 71.2, 69.8, 39.9, 39.4. The diastereomer ratio
(dr) and enantiomeric purity (ee) were determined by HPLC
analysis using a Chiralcel AD-H chiral column (4.6 x 250 mm) using
-
30.7, 29.6, 18.9, 18.7, 18.2, 17.4. HRMS (ESI)- m/z calcd for C6H12NO4
([M-H]+) 162.0772; found 162.0774. The diastereomer ratio (dr) and
enantiomeric purity (ee) were determined by HPLC analysis using a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701289
European Journal of Organic Chemistry
Full Paper
Chiracel OJ-H (4.6 x 250 mm) using mobile phase of (03:97 i-
o
propanol/n-hexane, flow rate of 1.5 mL/min at 25 C, UV detection
purified by silica gel column chromatography using (EtOAc/hexane 1:4
v/v) as eluent to furnish the anti-13a and syn-13b diastereomers as
white solid in 67% yield (146 mg, 0.67 mmol), (90% ee for anti, >99% ee
for syn) and as 1.10:1 anti:syn mixture of diastereomers. IR (CH2Cl2) ν:
3459, 3122, 2962, 2877, 1732, 1652, 1591, 1561, 1466, 1371, 1265,
1092, 770 cm-1; 1H NMR (400 MHz, CDCl3) δ: 4.62-4.48 (m, 2H), 4.26-
4.22 (m, 1H), 3.77-3.54 (m, 1H), 2.44 (br s, 2H), 1.58-1.21 (m, 12H), 0.88
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 78.7, 77.2, 72.8, 71.8,
71.7, 70.8, 33.4, 32.6, 31.7, 29.3, 29.1, 25.6, 25.4, 22.5, 14.0. HRMS
at 220 nm): anti diastereomer (R,S)-enantiomer: tr = 30.61 min,
(S,R)-enantiomer: tr
= 28.97 min; syn diastereomer (R,R)-
enantiomer: tr = 21.40 min, (S,S)-enantiomer: tr = 25.49 min.
(anti/syn)-1-Nitrobutane-2,3-diol (10): Following the general procedure
for tandem α-aminooxylated-Henry reaction, the residue was purified by
silica gel column chromatography using (EtOAc/hexane 1:3 v/v) as
eluent to furnish the anti-10a and syn-10b diastereomers as white
solid in 67% yield (90 mg, 0.67 mmol), (98% ee for anti, 94% ee for syn)
and as 1.75:1 anti:syn mixture of diastereomers. IR (CH2Cl2) ν: 3589,
3532, 2978, 2925, 1742, 1653, 1561, 1539, 1458, 1378, 1061, 771 cm-1;
1H NMR (400 MHz, CDCl3) δ: 4.64-4.49 (m, 2H), 4.24-4.16 (m, 1H), 3.97-
3.76 (m, 1H), 2.98 (br s, 1H), 2.14 (br s, 1H), 1.32-1.26 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ: 78.3, 77.2, 72.3, 72.0, 68.6, 67.8, 19.5, 18.7. HRMS
-
(ESI)- m/z calcd for C10H20NO4 ([M-H]+) 218.1398; found 218.1408. The
diastereomer ratio (dr) and enantiomeric purity (ee) were
determined by HPLC analysis using a Chirapak IA (4.6 x 250 mm)
using mobile phase of (2:98 i-propanol:n-hexane, flow rate of 1
mL/min at 25 oC, UV detection at 220 nm): anti diastereomer (S,R)-
enantiomer: tr = 76.80 min; syn diastereomer (R,R)-enantiomer: tr =
80.29 min, (S,S)-enantiomer: tr = 86.91 min.
-
(ESI)- m/z calcd for C4H8NO4 ([M-H]+) 134.0459; found 134.0489. The
diastereomer ratio (dr) and enantiomeric purity (ee) were
determined by HPLC analysis using a Chirapak AD-H (4.6 x 250
mm) using mobile phase of (05:95 i-propanol:n-hexane, flow rate of
1 mL/min at 25 oC, UV detection at 220 nm): anti diastereomer
(S,R)-enantiomer: tr = 41.52 min, (R,S)-enantiomer: tr = 44.67 min;
(anti/syn)-1-Nitrotridecane-2,3-diol (14a and 14b): Following the
general procedure for tandem
α-aminooxylated-Henry reaction, the
residue was purified by silica gel column chromatography using
(EtOAc/hexane 1:5 v/v) as eluent to furnish the anti-14a and syn-14b
diastereomers as white solid in 70% yield (182 mg, 0.70 mmol), (>99%
ee for anti, 98% ee for syn) and as 3.30:1 anti:syn mixture of
diastereomers. IR (CH2Cl2) ν: 3520, 3123, 2933, 1596, 1582, 1562, 1518,
1472, 1379, 1279, 1232, 1115, 1072, 772 cm-1; 1H NMR (400 MHz,
CDCl3) δ: 4.62-4.48 (m, 2H), 4.28-4.21 (m, 1H), 3.79-3.54 (m, 1H), 3.18
(s, 1H), 2.32 (s, 1H), 1.59-1.26 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 78.7, 77.2, 72.8, 71.8, 71.6, 70.8, 33.4, 32.6,
31.8, 29.5, 29.4, 29.4, 29.4, 29.2, 25.6, 25.4, 22.6, 14.0. HRMS (ESI)-
syn diastereomer (R,R)-enantiomer: tr
= 46.79 min, (S,S)-
enantiomer: tr = 56.15 min.
(anti/syn)-1-Nitroheptane-2,3-diol (11): Following the general
procedure for tandem -aminooxylated-Henry reaction, the residue was
α
purified by silica gel column chromatography using (EtOAc/hexane 1:4
v/v) as eluent to furnish the anti-11a and syn-11b diastereomers as
white solid in 64% yield (113 mg, 0.64 mmol), (92% ee for anti, 96% ee
for syn) and as 1.23:1 anti:syn mixture of diastereomers. IR (CH2Cl2) ν:
3531, 3133, 2937, 1586, 1572, 1522, 1472, 1381, 1282, 1224, 1118,
1110, 770 cm-1; 1H NMR (400 MHz, CDCl3) δ: 4.62-4.48 (m, 2H), 4.27-
4.22 (m, 1H), 3.77-3.54 (m, 1H), 2.65 (br s, 2H), 1.59-1.25 (m, 6H), 0.92
(t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 78.7, 77.2, 72.9, 71.8,
71.7, 70.9, 33.0, 32.2, 27.7, 27.5, 22.4, 13.9. HRMS (ESI)- m/z calcd for
-
m/z calcd for C13H26NO4 ([M-H]+) 260.1867; found 260.1872. The
diastereomer ratio (dr) and enantiomeric purity (ee) were
determined by HPLC analysis using a Chirapak IA (4.6 x 250 mm)
using mobile phase of (5:95 i-propanol:n-hexane, flow rate of 1
mL/min at 25 oC, UV detection at 210 nm): anti diastereomer (S,R)-
enantiomer: tr = 17.51 min; syn diastereomer (R,R)-enantiomer: tr =
22.03 min, (S,S)-enantiomer: tr = 26.03 min.
-
C7H14NO4 ([M-H]+) 176.0928; found 176.0942. The diastereomer ratio
(dr) and enantiomeric purity (ee) were determined by HPLC
(anti/syn)-1-Nitrotridecane-2,3-diol (14c and 14d): Following the
analysis using a Chirapak IA (4.6 x 150 mm) using mobile phase of
o
(4:96:0.1 i-propanol:n-hexane:DEA, flow rate of 1 mL/min at 25 C,
general procedure for tandem α-aminooxylated-Henry reaction, the
residue was purified by silica gel column chromatography using
(EtOAc/hexane 1:5 v/v) as eluent to furnish the anti-14c and syn-14d
diastereomers as off white solid in 65% yield (170 mg, 0.65 mmol),
(70% ee for anti, 96% ee for syn) and as 1.10:1 anti:syn mixture of
diastereomers. 1H NMR (400 MHz, CDCl3) δ: 4.63-4.49 (m, 2H), 4.29 (d,
J = 5.04 Hz, 1H), 3.72-3.54 (m, 1H), 3.16 (br s, 1H), 1.58-1.24 (m, 18H),
0.85 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 78.7, 77.2, 72.8,
71.8, 71.6, 70.5, 33.4, 32.6, 31.8, 29.5, 29.5, 29.4, 29.4, 29.3, 25.6, 25.4,
22.6, 14.1. The above anti-/syn-diastereomers 14 were separated and
purified by silica gel column chromatography to furnish the anti-14c
(99% ee) and syn-14d (99% ee) diastereomers as white solid. The
diastereomer ratio (dr) and enantiomeric purity (ee) were
determined by HPLC analysis using a Chirapak IA (4.6 x 250 mm)
using mobile phase of (5:95 i-propanol:n-hexane, flow rate of 1
mL/min at 25 oC, UV detection at 210 nm): anti diastereomer (S,R)-
enantiomer: tr = 17.41 min, (R,S)-enantiomer: tr = 19.40 min; syn
diastereomer (R,R)-enantiomer: tr = 22.18 min, (S,S)-enantiomer: tr
= 26.17 min.
UV detection at 230 nm): anti diastereomer (S,R)-enantiomer: tr =
17.29 min, (R,S)-enantiomer: tr = 15.38 min; syn diastereomer
(R,R)-enantiomer: tr = 18.53 min, (S,S)-enantiomer: tr = 19.56 min.
(anti/syn)-1-Nitrooctane-2,3-diol (12): Following the general procedure
for tandem α-aminooxylated-Henry reaction, the residue was purified by
silica gel column chromatography using (EtOAc/hexane 1:4 v/v) as eluent
to furnish the anti-12a and syn-12b diastereomers as white solid in
62% yield (118 mg, 0.62 mmol), (98% ee for anti, 82% ee for syn) and as
6.34:1 anti:syn mixture of diastereomers. IR (CH2Cl2) ν: 3364, 3211,
1715, 1682, 1665, 1579, 1512, 1366, 1344, 1072 cm-1; 1H NMR (400
MHz, CDCl3) δ: 4.62-4.48 (m, 2H), 4.27-4.21 (m, 1H), 3.77-3.54 (m, 1H),
2.83 (br s, 2H), 1.57-1.32 (m, 8H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 78.7, 77.2, 72.8, 71.8, 71.7, 70.8, 33.3, 32.5, 31.5, 25.3,
-
25.1, 22.4, 13.9. HRMS (ESI)- m/z calcd for C8H16NO4 ([M-H]+)
190.1085; found 190.1095. The diastereomer ratio (dr) and
enantiomeric purity (ee) were determined by HPLC analysis using a
Chirapak AD-H (4.6 x 250 mm) using mobile phase of (5:95:0.1 i-
propanol:n-hexane:DEA, flow rate of 1 mL/min at 25 oC, UV
detection at 230 nm): anti diastereomer (S,R)-enantiomer: tr = 18.11
min, (R,S)-enantiomer: tr = 20.36 min; syn diastereomer (R,R)-
enantiomer: tr = 13.37 min, (S,S)-enantiomer: tr = 14.41 min.
(anti/syn)-1-Nitrooctadecane-2,3-diol (15a and 15b): Following the
general procedure for tandem
α-aminooxylated-Henry reaction, the
residue was purified by silica gel column chromatography using
(EtOAc/hexane 1:5 v/v) as eluent to furnish the anti-15a and syn-15b
diastereomers as white solid in 68% yield (225 mg, 0.68 mmol), (80%
ee for anti, >99% ee for syn) and as 1.20:1 anti:syn mixture of
diastereomers. IR (CH2Cl2) ν: 3591, 3586, 2931, 1632, 1575, 1532, 1474,
(anti/syn)-1-Nitrodecane-2,3-diol (13): Following the general
procedure for tandem α-aminooxylated-Henry reaction, the residue was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701289
European Journal of Organic Chemistry
Full Paper
1362, 1186, 1085, 773 cm-1; 1H NMR (400 MHz, CDCl3) δ: 4.62-4.48 (m,
2H), 4.26-4.23 (m, 1H), 3.78-3.55 (m, 1H), 2.96 (br s, 1H), 2.10 (br s, 1H),
1.60-1.25 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ: 78.6, 77.2, 72.8, 71.7, 71.6, 70.7, 33.5, 32.7, 31.9, 29.6, 29.6, 29.5,
29.4, 29.4, 29.3, 25.6, 25.4, 22.6, 14.1. HRMS (ESI)+ m/z calcd for
further purification. To an ethanolic (4.0 mL) solution of above crude was
added chlorotrimethylsilane (230 µL, 1.82 mmol) at room temperature
and stirred for 12 h. The reaction mixture was then concentrated on a
rotary evaporator and purified by silica gel column chromatography
using (EtOAc/hexane 1:4 v/v) as eluent to afford the diol ester 26
(200 mg, 64%) as white solid. {[α]D25 -13.8 (c 0.5, CH2Cl2); IR (CH2Cl2)
ν: 3551, 3349, 1731, 775 cm-1; 1H NMR (400 MHz, CDCl3) δ: 4.29 (q, J =
6.8, 14.2 Hz, 2H), 4.08 (d, J = 1.84 Hz, 1H), 3.90-3.86 (m, 1H), 1.63-1.58
(m, 2H), 1.49-1.25 (m, 29H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 173.7, 72.9, 62.1, 72.5, 33.8, 31.9, 29.6, 29.6, 29.5, 29.5, 29.4,
+
C18H38NO4 ([M+H]+) 332.2796; found 332.2798. The diastereomer
ratio (dr) and enantiomeric purity (ee) were determined by HPLC
analysis using a Chirapak IA (4.6 x 250 mm) using mobile phase of
(3:97 i-propanol:n-hexane, flow rate of 1 mL/min at 25 oC, UV
detection at 220 nm): anti diastereomer (S,R)-enantiomer: tr = 37.04
min, (R,S)-enantiomer: tr = 42.21 min; syn diastereomer (R,R)-
enantiomer: tr = 28.16 min, (S,S)-enantiomer: tr = 32.99 min.
+
29.3, 25.7, 22.6, 14.1; HRMS (ESI)+ m/z calcd for C20H41O4 ([M+H]+)
345.3000; found 345.2998.
(anti/syn)-1-Nitrooctadecane-2,3-diol (15c and 15d): Following the
Ethyl (4S,5S)-5-pentadecyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide
(27): To a stirred solution of diol 26 (200 mg, 0.58 mmol) in dry CH2Cl2 (5
mL) were added Et3N (160 µL, 1.16 mmol) and SOCl2 (51 µL, 0.696
mmol) at 0 oC over a period of 10 min. The reaction mixture was then
stirred for 1 h at 0 oC, quenched by adding water and extracted with
CH2Cl2. The organic layer was separated, washed with water followed by
brine, dried over Na2SO4, concentrated and purified by silica gel
column chromatography using (EtOAc/hexane 1:19 v/v) as eluent to
afford the sulfite ester 27 (215 mg, 95%) as yellow oil. {[α]D25 -31.2 (c
1, CH2Cl2); IR (CH2Cl2) ν: 1767, 1735, 1261, 723 cm-1; 1H NMR (400
MHz, CDCl3) δ: 5.12-5.08 (m, 1H), 4.49 (d, J = 7.8 Hz, 1H), 4.34-4.27 (m,
2H), 1.57-1.22 (m, 31H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 167.3, 82.6, 81.4, 62.5, 32.4, 31.9, 29.6, 29.5, 29.5, 29.4, 29.3,
29.2, 25.2, 22.6, 14.1, 14.0; HRMS (ESI)+ m/z calcd for C20H39O5S+
([M+H]+) 391.2513; found 391.2511.
general procedure for tandem
α-aminooxylated-Henry reaction, the
residue was purified by silica gel column chromatography using
(EtOAc/hexane 1:5 v/v) as eluent to furnish the anti-15c and syn-15d
diastereomers as off white solid in 67% yield (220 mg, 0.67 mmol),
(86% ee for anti, 97% ee for syn) and as 1.64:1 anti:syn mixture of
diastereomers. 1H NMR (400 MHz, CDCl3) δ: 4.60-4.46 (m, 2H), 4.24-
4.21 (m, 1H), 3.77-3.53 (m, 1H), 2.94 (br s, 1H), 1.58-1.23 (m, 28H), 0.86
(t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 78.3, 76.9, 72.4, 71.4,
71.3, 70.4, 33.2, 32.4, 31.5, 29.3, 29.3, 29.2, 29.1, 29.1, 29.0, 25.3, 25.1,
22.3, 13.8. The diastereomer ratio (dr) and enantiomeric purity (ee)
were determined by HPLC analysis using a Chirapak IA (4.6 x 250
mm) using mobile phase of (3:97 i-propanol:n-hexane, flow rate of 1
mL/min at 25 oC, UV detection at 220 nm): anti diastereomer (S,R)-
enantiomer: tr = 36.93 min, (R,S)-enantiomer: tr = 42.07 min; syn
diastereomer (R,R)-enantiomer: tr = 28.04 min, (S,S)-enantiomer: tr
= 32.37 min.
Ethyl (2R,3S)-2-azido-3-hydroxyoctadecanoate (28): To a solution of
cyclic sulfite 27 (200 mg, 0.51 mmol) in dry DMF (5 mL) was added NaN3
(100 mg, 1.53 mmol) under argon. The reaction mixture was stirred at
80 °C for 12 h under argon. The reaction mixture was diluted with water,
extracted with ether (3 x 100 mL), dried over Na2SO4, concentrated and
purified on a silica gel column chromatography using (EtOAc/hexane
(
2S,3S)-1-Nitrooctadecane-2,3-diol
(15d): The above anti-/syn-
diastereomers 15 (220 mg) were separated and purified by silica gel
column chromatography using (EtOAc/hexane 1:9 v/v) as eluent to
furnish the syn-15d diastereomer as white solid in 25% yield (84 mg,
0.25 mmol) with 98% ee. [α]D25 +35.2 (c 0.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ: 4.60-4.49 (m, 2H), 4.27-4.18 (m, 1H), 3.75-3.72 (m, 1H), 2.38
(br s, 2H), 1.59-1.40 (m, 2H), 1.37-1.20 (m, 26H), 0.88 (t, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 77.2, 72.8, 71.7, 32.7, 31.9, 29.6, 29.5,
29.4, 29.3, 25.6, 22.6, 14.1. The enantiomeric purity (ee) was
determined by HPLC analysis using a Chirapak IA (4.6 x 250 mm)
using mobile phase of (3:97 i-propanol:n-hexane, flow rate of 1
mL/min at 25 oC, UV detection at 220 nm): (R,R)-enantiomer: tr =
29.88 min, (S,S)-enantiomer: tr = 32.64 min.
1:40 v/v) as eluent to give azido ester 28 (166 mg, 91%) as white solid
{[α]D25 -43.1 (c 1.1, CH2Cl2); IR (CH2Cl2) ν: 3621, 2108, 1733, 735 cm-1;
1H NMR (400 MHz, CDCl3) δ: 4.32-4.26 (m, 2H), 3.95-3.90 (m, 2H), 1.58-
1.50 (m, 2H), 1.37-1.21 (m, 29H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 168.9, 71.9, 66.1, 62.0, 33.0, 31.9, 29.6, 29.5, 29.5, 29.4,
29.3, 29.3, 25.3, 22.6, 14.1, 14.1; HRMS (ESI)+ m/z calcd for
.
C
20H40N3O3+ ([M+H]+) 370.3064; found 370.3065.
(-)-L-threo-Sphinganine (Safingol) (21): To a freshly distilled THF (5
mL) solution of LiAlH4 (70 mg, 1.8 mmol) at 0 oC was added a solution of
azido ester 28 (120 mg, 0.3 mmol) in 5 mL THF. After stirring the reaction
mixture for 5 min, ice-cooled bath was removed and stirred the reaction
mixture at 70 °C for 12 h until the full consumption of the azido ester
(monitored by TLC). The reaction mixture was then diluted with 10 mL of
dry THF and filtered through a pad of silica gel slurry in hexane in a
sintered glass funnel to remove the impurities by gentle suction. The
silica pad was washed with a mixture of CHCl3/MeOH (1:4 v/v), dried
over Na2SO4, concentrated and purified by silica gel column
(
2R,3S)-1-Nitrooctadecane-2,3-diol (15c): After separation of the syn-
15d diastereomer, the anti-15c diastereomer was quickly eluted
(EtOAc/hexane 1:5 v/v) as white solid in 42% yield (136 mg, 0.42 mmol)
with 99% ee. [α]D25 +48.7 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ:
4.63-4.48 (m, 2H), 4.26-4.22 (m, 1H), 3.59-3.55 (m, 1H), 1.64-1.48 (m,
2H), 1.42-1.21 (m, 26H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 78.6, 71.7, 70.7, 33.5, 31.9, 29.6, 29.5, 29.4, 29.4, 29.3, 25.4,
22.6, 14.1. The enantiomeric purity (ee) was determined by HPLC
analysis using a Chirapak IA (4.6 x 250 mm) using mobile phase of
(3:97 i-propanol:n-hexane, flow rate of 1 mL/min at 25 oC, UV
detection at 220 nm): (S,R)-enantiomer: tr = 38.68 min, (R,S)-
enantiomer: tr = 43.44 min.
chromatography using
(CHCl3/MeOH/NH4OH 32:6:1) as eluent to give
the target -threo-sphinganine (safingol) 21 (73 mg, 81%) as white solid.
L
{[α]D25 -23.5 (c 0.5, CHCl3/MeOH 3:1) {[α]D25 -7.5 (c 0.09, C2H5OH) [Lit.10a
-7.6 (c 0.09, C2H5OH)]; IR (MeOH) ν: 3623, 3425, 1565, 756 cm-1; 1H
NMR (400 MHz, CDCl3) δ: 3.86-3.83 (m, 1H), 3.71-3.61 (m, 2H), 2.56 (br
s, 4H), 1.46-1.12 (m, 28H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 75.2, 62.6, 61.9, 34.1, 31.8, 30.2, 29.8, 29.6, 29.3, 29.2, 22.6,
14.0. HRMS (ESI)+ m/z calcd for C18H40NO2+ ([M+H]+) 302.3054; found
302.3035.
Ethyl (2S,3S)-2,3-dihydroxyoctadecanoate (26): A solution of anti-15c
diastereomer (300 mg, 0.91 mmol), sodium nitrite (190 mg, 2.73 mmol),
and acetic acid (0.54 mL, 9.1 mmol) in dimethyl sulfoxide (2 mL) was
stirred at 35 °C for 24 h. The reaction mixture was then diluted with water,
acidified with 10% aqueous solution of hydrochloric acid (10 mL),
extracted with ether (3
x 50 mL), dried over anhydrous Na2SO4,
concentrated in vacuo, and used as such for the next step without
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Acknowledgements
S.K.P. is thankful to Department of Science and Technology,
New Delhi, for generous funding of the project (Grant No.
EMR/2016/003649). Y.G. and R.K. thank UGC, New Delhi for
SRF and JRF, respectively.
Keywords: tandem• α-aminoxylation• Henry reaction• β,γ-
dihydroxynitroalkane• tetrahydrosalen
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10.1002/ejoc.201701289
European Journal of Organic Chemistry
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Entry for the Table of Contents
Full Paper
A novel and rapid asymmetric
Yuvraj Garg, Ramandeep Kaur and
syntheses of 1,2-diol derivatives anti-
and syn-β,γ-dihydroxynitroalkanes via
organocatalyzed tandem α-
Satyendra Kumar Pandey*
Page No. – Page No.
aminooxylation-Henry reactions are
described. The targeted diol
Organocatalytic Asymmetric Tandem
α-Aminooxylation-Henry Reactions
for the Synthesis of 1,2-Diols: Total
derivatives are synthesized in good
yields, with excellent enantio- and low
to moderate diasteroselectivities
under mild conditions. Synthesis of an
antineoplastic and antipsoriatic drug (-
Synthesis of (-)-L-threo-Sphinganine
Key words:α-aminooxylation, Henry
reaction
)-L-threo-sphinganine demonstrate the
synthetic utility of the fragments
generated in the title reaction.
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