Direct stereoselective synthesis of enantiomerically pure anti -β-amino alcohols

Article abstract of DOI:10.1021/jo500481j

Enantiomerically pure anti-β-amino alcohols were synthesized from optically pure α-(N,N-dibenzylamino)benzyl esters, derived from α-amino acids, by the sequential reduction to aldehyde with DIBAL-H at -78 °C and subsequent in situ addition of Grignard reagents. Besides anti-β-amino alcohols, anti-2-amino-1,3-diols and anti-3-amino-1,4-diols were obtained in good yields (60-95%) and excellent stereoselectivity (de > 95%). Our technique is compatible with free hydroxyl groups present in the substrate. To demonstrate the versatility of the method, spisulosine and sphinganine were synthesized in two steps from the appropriate N,N-dibenzyl-l-aminobenzyl ester in 42% and 45% yield, respectively.

Full text of DOI:10.1021/jo500481j

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pubs.acs.org/joc
Direct Stereoselective Synthesis of Enantiomerically Pure anti-β-
Amino Alcohols
Gaston Silveira-Dorta,† Osvaldo J. Donadel,‡ Víctor S. Martín,† and Jose M. Padron*,†
́
́
́
†Instituto Universitario de Bio-Organ
(CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco San
́
ica “Antonio Gonzal
́
ez” (IUBO-AG), Centro de Investigaciones Biomed
́
icas de Canarias
́
chez 2, 38206 La Laguna, Spain
‡INTEQUI-CONICET, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco y Pedernera,
5700 San Luis, Argentina
S
* Supporting Information
ABSTRACT: Enantiomerically pure anti-β-amino alcohols were
synthesized from optically pure α-(N,N-dibenzylamino)benzyl esters,
derived from α-amino acids, by the sequential reduction to aldehyde
with DIBAL-H at −78 °C and subsequent in situ addition of
Grignard reagents. Besides anti-β-amino alcohols, anti-2-amino-1,3-
diols and anti-3-amino-1,4-diols were obtained in good yields (60−
95%) and excellent stereoselectivity (de > 95%). Our technique is
compatible with free hydroxyl groups present in the substrate. To
demonstrate the versatility of the method, spisulosine and
sphinganine were synthesized in two steps from the appropriate
N,N-dibenzyl-L-aminobenzyl ester in 42% and 45% yield, respectively.
There is a close structural relationship between long-chain
amino alcohols, including SLs, and cytotoxic properties, which
make this type of compounds an attractive scaffold for
anticancer drug discovery programs.
INTRODUCTION
■
β-Amino alcohols have received much attention in the scientific
community due to their versatility. They can be used as chiral
ligands in asymmetric synthesis,1,2 as chiral synthons in the
synthesis of natural products,3,4 as well as in the synthesis of
products with diverse biological activities.5−7 In addition, long-
chain amino alcohols exhibit promising activity as antitumor
agents.8 An important class of amino alcohols is the
sphingolipids (SLs)9 represented by dihydrosphingosine (1a)
and sphinganine (1b), which show a 2-amino-1,3-diol fragment
with an anti-2S,3R configuration (Figure 1).5 Another relevant
To shed light on the above compounds and their associated
bioactive properties, and as part of our interest in synthesis of
nitrogen-containing bioactive molecules,18−23we were engaged
in the development of a more versatile and efficient
methodology to synthesize anti-β-amino alcohols in order to
obtain new SL analogues and test their antiproliferative activity.
We pondered a general one-pot methodology for the
synthesis of functionalized anti-β-amino alcohols based on the
in situ DIBAL-H reduction of α-(N,N-dibenzylamino)benzyl
esters (4, 6, 10, and 11, Tables 1−4) to their corresponding
aldehyde, followed by the sequential addition of commercially
available Grignard reagents. This methodology is an extension
of the well-known Reetz protocol, but avoiding the three-step
sequence, namely reduction of the ester to alcohol and later
oxidation to aldehyde and addition of the organometallic
reagent.24−26 A related one-pot process has been explored in
the literature, using N-Boc-protected amino esters but
obtaining syn-β-amino alcohols.27−29 We found also a
precedent in the synthesis of anti-β-amino alcohols using
benzostabase (BSB) as the N-protecting group.30 However, this
methodology has never been further used, maybe due to the
difficulty in preparing N-BSB-protected amino esters. In this
paper, we describe how our one-pot approach is a very
attractive form to generate anti-β-amino alcohols (1), anti-2-
Figure 1. Dihydrosphingosine, sphinganine, and related 1-deoxy-
sphingolipids.
group of long-chain amino alcohols are the 1-deoxysphingoli-
pids from marine origin, such as the clavaminols A (2a), C
(2b), and H.10,11 These compounds have an anti-2R,3S amino
alcohol motif, opposite to that of SLs, and have shown
cytotoxic and pro-apoptotic properties.6 Furthermore, spisulo-
sine12 (2c) having the same anti-2S,3R configuration as SLs was
initially a promising antiproliferative agent against diverse
human tumor cell lines.13 However, clinical studies were
discontinued in phase I.14 In the literature, there are many SLs
reported with antiproliferative activity,15−17 and the number is
still growing.
Received: February 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500481j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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addition of Grignard reagents using serine and threonine
derivatives without O-protecting groups.
Table 1. Reaction Parameters for the Synthesis of 5a
In addition, to test the applicability of this new methodology,
we describe the synthesis of the naturally occurring compounds
spisulosine and sphinganine.
reduction
a
EtMgBr
(equiv)
DIBAL-H
(equiv)
anti/
b
yield
(%)
RESULTS AND DISCUSSION
■
entry
time (h)
solvent
syn
Synthesis of anti-β-Amino Alcohols. The key step of this
one-pot reaction is the DIBAL-H reduction of a N,N-dibenzyl-
α-amino ester (synthesized by perbenzylation of the corre-
sponding α-amino acid)39,40 to its corresponding aldehyde, at
−78 °C, followed by the in situ sequential addition of the
suitable Grignard reagent. First, we studied the influence of the
reaction conditions taking into account the effect of solvents on
the nucleophilicity, basicity of organomagnesium, and reducing
ability of DIBAL-H.28−30 We also evaluated the amount of
DIBAL-H equivalents, as well as reduction time, using 3 equiv
of EtMgBr. The ratio of Grignard reagent used was chosen
based on literature precedents,41 and it is consistent with our
observations. The results obtained using the benzyl ester of
N,N-dibenzyl-L-alanine (4a) as starting material are summar-
ized in Table 1.
We observed that Et2O was the best solvent, and we also
determined that DIBAL-H amount and reduction time were a
contributing factor in the yield of the reaction. When 3.6 equiv
of DIBAL-H during 1 h was used, a complete over-reduction to
the alcohol was observed (entries 2 and 9, Table 1). After the
amount of DIBAL-H was decreased to 1.4 equiv and the
reduction time was increased to 2 h, a better yield (70%) was
1
1
1
2
2
2
2
2
2
1
2
2
2
2
3
3
3
3
1
2
4
3
3
3
3
3
3
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
DCM
DCM
DCM
THF
toluene
2.5
3.6
2.5
1.4
1.4
1.4
1.4
1.1
3.6
2.5
1.4
1.4
1.4
>95/1
35
2
3
>95/1
>95/1
>95/1
>95/1
>95/1
>95/1
55
70
26
33
68
48
4
5
6
7
8
9
10
11
12
13
>95/1
>95/1
>95/1
>95/1
28
13
38
63
a
Delay time between the addition of DIBAL-H and the Grignard
b
1
reagent. Diastereoisomeric ratio as determined by H NMR analysis
of the crude product 5a.
amino-1,3-diols (2), and anti-3-amino-1,4-diols (3) (Figure 2),
reducing the number of chemical steps when compared to the
methods reported in the literature for the synthesis of similar
compounds31−38 (Figure 2).
We also demonstrate that our method can be applied to
serine and threonine derivatives without the need to use
protecting groups for the hydroxyl moiety. This reaction
proceeds in good yields and high enantioselectivity (de > 95%).
Therefore, we report the first one-pot diastereoselective
1
obtained (entry 4). The anti/syn ratio was determined by H
NMR (400 MHz) of the crude reaction. The anti-
diastereoisomer was always formed as the major stereoisomer,
and the ratio was not affected either by the reaction solvent, the
amount of DIBAL-H, or the reduction times.
The stereochemical course of the process is consistent with
the generation of a free aldehyde, while the nucleophilic attack
of the Grignard reagent on the carbonyl follows a nonchelating
Felkin−Anh model.42 An SN2-like mechanism involving
elimination of a metalalkoxy group could explain the
intermediate aldehyde.41 In agreement with this proposal, the
identity of the alkoxy group of the aluminoxy acetal should not
affect the stereoselectivity of the alkylation reaction. To test this
hypothesis, a series of alanine esters (synthesized using different
procedures)43,44 were analyzed by H NMR to determine the
1
effect of increasing the steric bulk of the alkoxy group of the
ester on the stereoselectivity of the DIBAL-H reduction in Et2O
and subsequent EtMgBr addition (Table 2). From the results,
Table 2. Influence of the Alkoxy Group Bulkiness in Esters
of N,N-Dibenzyl-L-alanine
a
entry
compd
R
anti/syn
yield (%)
1
2
3
4
4a
4b
4c
4d
Bn
>95/1
92/8
70
68
65
66
t-Bu
Et
94/6
Me
>95/1
a
Diastereoisomeric ratio determined by 1H NMR analysis of the crude
products.
Figure 2. One-pot synthesis of anti-β-amino alcohols.
B
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The Journal of Organic Chemistry
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we inferred that there is no correlation between the bulkiness of
the ester group and the stereoselectivity of the reaction. We
also concluded that the ester did not affect the yield of the
reaction. The benzyl ester was the best choice because it is
synthesized in one step by the direct perbenzylation of the free
α-amino acid.
Scheme 2. Synthesis of Spisulosine (2c)
Once we had adjusted the conditions, we studied the scope.
Thus, 4 and 6 (synthesized by perbenzylation of the α-amino
acids L-alanine and L-phenylalanine, respectively) were
submitted, at −78 °C, to our one-pot sequence using
commercially available ethyl-, vinyl-, and ethynylmagnesium
bromide solutions affording the corresponding amino alcohols
5a−c and 7a−c (Table 3).
submitted both commercially available DL-phenylalanine and
L-phenylalanine to our one-pot procedure using as Grignard
reagent ethylmagnesium bromide. The resulting compounds
rac-7a and 7a were analyzed by chiral HPLC to check their
enantiomeric purity. The results showed that no loss of
enantiomeric purity was observed (see the Supporting
Information).
Table 3. Synthesis of anti-β-Amino Alcohols 5 and 7
Preparation of anti-2-Amino-1,3-diols. We wondered if
our technique could be extended to the synthesis of more
substituted β-amino alcohols and, more importantly, if it is
compatible with free hydroxyl groups present in the substrate.
To test this idea, we selected N,N-dibenzylamino esters 10 and
11, which were prepared by conventional methods using L-
serine and L-threonine, respectively.45 Gratifyingly, the syn-
thesis of amino alcohols 12a−c and 13a−c were carried out
using the same one-pot approach described above with good
yields and excellent stereoselectivity (Table 4).
a
entry
compd
R1
R2
anti/syn
yield (%)
1
2
3
4
5
6
5a
5b
5c
7a
7b
7c
Me
Me
Me
Bn
Bn
Bn
Et
>95/1
>95/1
87/13
>95/1
>95/1
90/10
70
60
65
72
63
70
vinyl
ethynyl
Et
vinyl
Table 4. Synthesis of anti-2-Amino-1,3-diols 12 and 13
ethynyl
a
Diastereoisomeric ratio determined by 1H NMR analysis of the crude
products.
The anti diastereoselectivity (>95/1) of the reaction was
determined by 1H NMR spectroscopy (400 MHz). We
observed that the diastereoselectivity was not affected by the
size of the substituent R1 (Table 3), while the Grignard reagent
produced a small influence. In this particular context, we
observed a lower diastereomeric ratio using ethynylmagnesium
bromide (entries 3 and 6). Fortunately, pure diastereoisomers
of compounds 5 and 7 were obtained in good yields by flash
column chromatography. The pure compounds showed good
physical and spectroscopic data compliance, within the limits of
experimental error, with those reported previously for 5a,31−33
5c,35 7a,31,32 and 7c35 (see the Supporting Information). To
the best of our knowledge, products 5b and 7b are described
for the first time in this work. To corroborate their structures,
we synthesized the amino alcohols 8 and 9 by N-deprotection
and double-bond reduction of 5b and 7b respectively, with
Pearlman’s catalyst under hydrogen pressure (Scheme 1). The
physical and spectral data of these compounds agree with those
reported for 8 and 9 (Scheme 2)31 (see the Supporting
Information).
a
entry
compd
R1
R2
anti/syn
yield (%)
1
2
3
4
5
6
12a
12b
12c
13a
13b
13c
H
Et
>95/1
>95/1
>95/1
>95/1
>95/1
>95/1
60
70
63
60
63
58
H
vinyl
H
ethynyl
Et
Me
Me
Me
vinyl
ethynyl
a
Diastereoisomeric ratio determined by 1H NMR analysis of the crude
products.
In this particular case, we needed to fine-tune the reaction
conditions to improve the yield of 12 and 13. We found that by
using the general conditions described above, namely 1.4 equiv
of DIBAL-H in ether (−78 °C, 2 h) and 3 equiv of Grignard
reagent, we could obtain 12 and 13 although in low yields
(∼40%). The contaminating products were the carbinols
resulting of the undesired addition of Grignard reagents to
the ester groups. We suspected that because of the presence of
the free hydroxy group, an additional amount of DIBAL-H
should be used. Fortunately, when we added, after 1 h, an extra
amount of 0.7 equiv of DIBAL-H allowing the reduction time
to reach 2 h, the Grignard reagent addition produced the anti-
diols 12 and 13 in good yields as shown in Table 4. It should be
pointed out that necessarily the DIBAL-H addition must be
done in two portions. When 2.1 equiv of the reducing agent
was added in one portion and maintained during 2 h, a
substantial amount of the primary alcohol was produced. In all
cases, the reaction took place with a good yield and excellent
It has been described in the literature that during the DIBAL-
H treatment it is possible that some racemization of the
enantiomerically pure aldehydes occurs. Therefore, we
Scheme 1. Synthesis of Amino Alcohols 8 and 9
C
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stereoselectivity (anti/syn > 95/1). Once again, the stereo-
chemical course of the reaction could be explained by a Felkin−
Anh model where the presence of a free hydroxy group did not
affect the stereoselectivity. Finally, it is important to mention
that our approach avoids the use of O-protecting groups, the
latter being used in all previously reported procedures for the
synthesis of related compounds.46−48
The relative configuration of 17a−c was determined by
converting them to the lactones 18a−c with tetrapropylammo-
nium perruthenate (TPAP) and N-methylmorpholine N-oxide
1
(NMO) (Figure 4). The H NMR vicinal coupling constant
between the protons H-3 and H-4 in the lactones 18a−c
showed a J3,4 = 4.3 Hz, indicating an anti-configuration.31,55,56
In order to determine the relative configuration of the
obtained 1,3-diols, the six-membered acetonides 14a−c and
15a−c were synthesized (Figure 3) by treatment of diols 12a−
c and 13a−c, respectively, with 2,2-dimethoxypropane (DMP)
in the presence of pyridinium p-toluensulfonate (PPTS) in
DCM.
Figure 4. Lactones prepared to assign the relative configuration.
Synthetic Applications. In order to assess the wider
application of our methodology, we turned our attention to
spisulosine (2c). Using the same experimental procedure
described above for the synthesis of anti-β-amino alcohols, 2c
could be prepared in just two steps from 4a using
pentadecynylmagnesium bromide as the Grignard reagent
(Scheme 2). We observed that our one-pot methodology
Figure 3. Acetonides prepared to assign the relative configuration.
1
provided 19 as only one diastereomer (within limits of H
NMR detection in the crude reaction mixture) in good yield.
The N-deprotection and reduction of the triple bond using
hydrogenation with Pearlman’s catalyst provided spisulosine
(2c), in 42% overall yield.6,57,58
Similarly, the synthesis of sphinganine (1b) was carried out
using the same experimental procedure described for the
synthesis of compounds 12a−c, and it is shown in Scheme 3.
First, we obtained product 20 by the addition of pentadecy-
nylmagnesium bromide to the aldehyde previously formed from
10, in 75% yield and with high diastereoselectivity (anti/syn >
95/1), without using protecting groups.36 Further hydro-
genation of 20 with Pearlman’s catalyst provided sphinganine
(1b) in 45% overall yield.59
The acetonides 14a−c showed a J4,5 value of approximately
9.8 Hz which is in agreement with the anti-configuration
reported.49 −51 Moreover, in acetonides 15a and 15b the 1,3-
anti relation was established by 13C NMR analysis of methyl
(marked in bold face, Figure 3) signals (24.5 and 24.8 ppm for
15a and 24.6 and 24.9 ppm for 15b), and C-6 (100.3 and 100.4
ppm for 15a and 15b, respectively). In addition, the anti-
relation of H-4 and H-5 was determined by the value of the
coupling constant (J4,5 = 7.4 Hz for both) which is in agreement
with previous data reported.52 The relative configuration of
compound 15c was determined by the J5,6 = 4.8 Hz value,
which is in agreement with the anti-configuration data
reported.53
Synthesis of anti-3-Amino-1,4-diols. In a third applica-
tion of the methodology, we examined the addition of EtMgBr
to lactone 16 previously treated with DIBAL-H (Table 5).
CONCLUSION
■
In summary, a new general one-pot methodology has been
developed for the synthesis of enantiopure anti-β-amino
alcohols from α-dibenzylamino esters having their origin in
α-amino acids, in good yields and excellent diastereoselectivity.
Our results showed that optically active α-dibenzylamino esters
can be reduced and converted into β-amino alcohols by
subsequent addition of diverse Grignard reagents avoiding the
problem of instability of the aldehydes. Presumably, these
additions proceed under nonchelation control involving the
aldehyde formed in situ using DIBAL-H at −78 °C. Similarly,
anti-2-amino-1,3-diols and anti-3-amino-1,4-diols were ob-
tained. Our technique is compatible with free hydroxyl groups
present in the substrate. Considering the simplicity of preparing
these products, we tested this methodology synthesizing
spisulosine and sphinganine. Further studies on the synthesis
of other derivatives and related natural products are in progress.
The in vitro antiproliferative activity against human solid tumor
cells is being evaluated with promising results and will be
reported in due course.
Table 5. Synthesis of anti-3-Amino-1,4-diols 17a−c
a
entry
compd
R
anti/syn
yield (%)
1
2
3
17a
17b
17c
Et
>95/1
>95/1
>95/1
95
96
80
vinyl
ethynyl
a
Diastereoisomeric ratio determined by 1H NMR analysis of the crude
products.
Lactone 16 was synthesized using methionine as starting
material.54 For the synthesis of 17a, we decided to test the same
one-pot methodology as for the compounds 3a−c and 4a−c
(1.4 equiv of DIBAL-H, at −78 °C for 2 h and subsequently
addition of EtMgBr). Under the reaction conditions, the
desired product 17a was obtained in high yield and
stereoselectivity (95% yield and anti/syn > 95/1, Table 5).
Furthermore, we tested this reaction with diverse Grignard
reagents, allowing the synthesis of 17b and 17c.
EXPERIMENTAL SECTION
■
General Remarks. Reactions were performed using oven-dried
glassware under an atmosphere of argon. Reagent-grade chemicals
were obtained from diverse commercial suppliers and were used as
received. Optical rotations were measured with a polarimeter at the
sodium line at different temperatures in CHCl3. 1H/13C NMR spectra
D
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The Journal of Organic Chemistry
Featured Article
Scheme 3. Synthesis of Sphinganine (1b)
of the samples as CDCl3 solutions were recorded at 400/100 MHz or
at 500/125 MHz or 600/150 MHz, respectively, at 298 K. Chemical
shifts (δ) are quoted in ppm and referenced to internal TMS (δ = 0
ppm) for 1H NMR and CDCl3 (δ = 77.0 ppm) for 13C NMR;
coupling constants (J) are quoted in hertz. Data are reported as
follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet, sex,
sextet, sep, septet, m, multiplet; br, broad. 2D NMR techniques were
used to assist in structure elucidation. IR spectra were recorded neat
on a FT-ATR IR system and the data are reported in reciprocal
centimeters (cm−1). Accurate mass (HRMS) were determined by
electrospray ionization (ESI-TOF) and electronic impact (EI-TOF).
Reactions were monitored using thin-layer chromatography (TLC) on
aluminum packed percolated Silica Gel 60 F254 plates. Flash column
chromatography was carried out with silica gel 60 (particle size less
than 0.020 mm) by using appropriate mixtures of ethyl acetate and
hexanes as eluent. Compounds were visualized by use of UV light and
2.5% phosphomolybdic acid in ethanol. All reactions involving air- or
moisture-sensitive materials were carried out under argon atmosphere.
Anhydrous magnesium sulfate was used for drying solutions. Melting
points were measured with a micro melting point apparatus. Chemical
nomenclature was generated using Chem Bio Draw Ultra 13.0.
(2S,3R)-2-(Dibenzylamino)pentan-3-ol (5a).28−30 To a cooled
(−78 °C) solution of 4a (100 mg, 0.28 mmol) in dry Et2O (3 mL)
under argon was added DIBAL-H (0.4 mL, 0.4 mmol, 1 M in hexane).
After the solution was stirred for 2 h, ethylmagnesium bromide
solution (0.3 mL, 0.84 mmol, 3 M in Et2O) was carefully added at −78
°C, and the mixture was allowed to warm to −10 °C and stirred for 18
h. Then, the mixture was warmed to 0 °C and quenched with saturated
NH4Cl (8 mL). The mixture was extracted with Et2O (10 mL × 3).
The combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuum. The residue was purified
by flash chromatography on silica gel (eluent AcOEt/PE, 98:2) to give
5a (56.6 mg, 0.20 mmol, 70% yield) as a colorless oil: [α]25D +48.1 (c,
1.0, CHCl3).
6 (100 mg, 0.23 mmol) using vinylmagnesium bromide solution (0.69
mL, 0.69 mmol, 1 M in THF) to give 7b (51.8 mg, 0.15 mmol, 63%
yield) as a colorless oil: [α]25D = +3.6 (c, 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 2.76 (dd, 1H, J1 = 13.7, J2 = 8.1 Hz), 2.92 (d, 1H, J =
7.3 Hz), 3.10 (dd, 1H, J1 = 13.7, J2 = 6.5 Hz), 3.17−3.21 (m, 1H), 3.52
(d, 2H, J 13.6 Hz), 3.86 (d, J = 13.6 Hz), 4.04−4.05 (m, 1H), 5.17 (d,
J = 10.5 Hz), 5.38 (d, J = 17.3 Hz), 6.06 (ddd, 1H, J1 = 15.9, J2 = 10.5,
J3 = 5.0 Hz), 7.17−7.31 (m, 15H); 13C{1H} (100 MHz, CDCl3) δ
139.8, 139.5, 138.5, 129.3, 128.9, 128.5, 128.4, 127.2, 126.2, 115.5,
71.0, 63.2, 55.3, 31.7; IR (ATR-neat) νmax = 3435, 3026, 1641, 1602,
1453, 922, 920; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for
C25H28NO 358.2171, found 358.2160.
(3R,4S)-4-(Dibenzylamino)-5-phenylpent-1-yn-3-ol (7c).32
The procedure described for the synthesis of compound 7a was
applied to 6 (100 mg, 0.23 mmol), with ethynylmagnesium bromide
solution (1.38 mL, 0.69 mmol, 0.5 M in THF), to give 7c (57.2 mg,
0.161 mmol, 70% yield) as a colorless solid: mp = 131−132 °C; [α]25
D
= +63.1.0 (c, 1.0, CHCl3).
(2S,3R)-2-Aminopentan-3-ol (8).28 To a solution of 5b (100 mg,
0.36 mmol) in 5 mL of dry MeOH was added 10 mg of 20% Pd
(OH)2−C in one portion. The mixture was stirred under 1 atm of H2
at room temperature for 18 h. After completion of the reaction, the
catalyst was removed by filtration through Celite and washed with 20
mL of MeOH. The solvent was evaporated under reduced pressure to
afford 8 (36.2 mg, 0.32 mmol, 90% yield) as a colorless oil: [α]25
+14.6 (c, 1.0, CHCl3).
=
D
(2S,3R)-2-Amino-1-phenylpentan-3-ol (9).28 The procedure
described above was applied to 7b on a 0.28 mmol (100 mg) scale,
to give 9 (42.5 mg, 0.26 mmol, 92% yield) as a colorless solid: mp =
104−106 °C; [α]25 = +39.0 (c, 1.0, CHCl3).
D
(2S,3R)-2-(Dibenzylamino)pentane-1,3-diol (12a). To a cooled
(−78 °C) and stirred solution of N,N-aminobenzyl ester 10 (100 mg,
0.27 mmol) in dry Et2O (3 mL) under argon was added DIBAL-H in
two portions (0.38 mL, 0.38 mmol, 1 M in hexane; and 1 h later 0.19
mL, 0.19 mmol). One hour after the addition of the second portion of
DIBAL-H, ethylmagnesium bromide solution (0.27 mL, 0.81 mmol, 3
M in Et2O) was carefully added and the mixture was allowed to warm
to −10 °C and stirred for 18 h. Then, the mixture was warmed to 0 °C
and quenched with saturated NH4Cl (8 mL). The mixture was
extracted with Et2O (10 mL × 3), and the combined organic phases
were washed with brine, dried over MgSO4, filtered, and concentrated
in vacuum. The residue was purified by flash chromatography on silica
gel flash (eluent gradient AcOEt/PE, 8:2 to 7:3) to give 12a (48.5 mg,
(3R,4S)-4-(Dibenzylamino)pent-1-en-3-ol (5b). The procedure
described above was applied to 4a on a 0.28 mmol (100 mg) scale with
vinylmagnesium bromide solution (0.84 mL, 0.84 mmol, 1 M in THF)
to give 5b (47 mg, 0.17 mmol, 60% yield) as a colorless oil: [α]25
=
D
+5.99 (c, 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.05 (d, 3H, J
= 6.9 Hz), 2.76 (br, 1H), 2.87 (q, 1H, J = 6.6 Hz), 3.33 (d, 2H, J =
13.7 Hz), 3.73 (d, 2H, J = 13.7 Hz), 3.94 (br, 1H), 5.07 (d, 1H, J =
10.4 Hz), 5.26 (dd, 1H, J1 = 17.3, J2 = 1.3 Hz), 5.90 (ddd, 1H, J1 =
16.2, J2 = 10.5, J3 = 5.5 Hz); 13C{1H} (100 MHz, CDCl3) δ 139.8,
139.2, 128.9, 128.4, 127.1, 115.2, 73.8, 57.1, 54.9, 9.0; IR (ATR-neat)
νmax = 3409, 3031, 1644, 1605, 1455, 924; HRMS (ESI-TOF) (m/z)
[M + H+] = calcd for C19H24NO 282.1858, found 282.1861.
0.16 mmol, 60% yield) as a colorless oil: [α]25 = −7.5 (c, 1.2,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.82 (t, 3H, J = 7.4 Hz), 1.34
(sep, 1H, J = 7.5 Hz), 1.67 (m, 1H), 2.63 (q, 1H, J = 5.8 Hz), 3.64 (d,
2H, J = 13.7 Hz), 3.72−3.75 (m, 3H), 3.82 (m, 1H), 7.18−7.27 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 139.6, 129.0, 128.4, 127.1, 72.7,
61.9, 59.0, 54.6, 28.6, 9.9; IR (ATR-neat) νmax = 3371, 3062, 3028,
2962, 1493, 1453, 1365; HRMS (ESI-TOF) (m/z) [M + H+] = calcd
for C19H25NO2 300.1964, found 300.1968.
(3R,4S)-4-(Dibenzylamino)pent-1-yn-3-ol (5c).32 The proce-
dure described above was applied to 4a on a 0.28 mmol (100 mg)
scale with ethynylmagnesium bromide solution (1.68 mL, 0.84 mmol,
0.5 M in THF) to give 5c (50.8 mg, 0.18 mmol, 65% yield) as a solid:
mp = 54−55 °C; [α]25 = +31.0 (c, 0.6, CHCl3).
D
(2S,3R)-2-(Dibenzylamino)-1-phenylpentan-3-ol (7a).28,29
The procedure described for the synthesis of compound 5a was
applied to 6 (100 mg, 0.23 mmol) using DIBAL-H (0.32 mL, 0.32
mmol, 1 M in hexane) and ethylmagnesium bromide solution (0.23
mL, 0.69 mmol, 3 M in Et2O), to give 7a (59.4 mg, 0.17 mmol, 72%
(2S,3R)-2-(Dibenzylamino)pent-4-ene-1,3-diol (12b). The
procedure described above for the synthesis of compound 12a was
applied to 10 on a 0.27 mmol (100 mg) scale using vinylmagnesium
bromide solution (0.81 mL, 0.81 mmol, 1 M in THF) to give 12b (56
mg, 0.19 mmol, 70% yield) as a colorless oil: [α]25 = −23.0 (c, 1.2,
D
1
yield) as a colorless oil: [α]25 = +21.0 (c, 1.0, CHCl3).
CHCl3); H NMR (400 MHz, CDCl3) δ 2.80 (q, 1H, J = 5.8 Hz),
D
(3R,4S)-4-(Dibenzylamino)-5-phenylpent-1-en-3-ol (7b). The
procedure described for the synthesis of compound 7a was applied to
3.67−3.79 (m, 5H), 3.84−3.87 (m, 1H), 4.41 (t, 1H, J = 5.8 Hz), 5.14
(d, 1H, J = 10.4 Hz), 5.25 (d, 1H, J = 17.3 Hz), 5.88 (ddd, J1 = 16.8, J2
E
dx.doi.org/10.1021/jo500481j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
= 10.4; J3 = 6.1 Hz), 7.18−7.27 (m, 10H); 13C{1H} (100 MHz,
CDCl3) δ 139.9, 139.5, 129.0, 128.6, 128.4, 127.2, 115.7, 72.0, 62.4,
59.0, 54.6; IR (ATR-neat) νmax = 3361, 3063, 3027, 1602, 1493, 1452,
1365; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for C19H23NO2
298.1807, found 298.1816.
1379, 1227, 1204, 1116; HRMS (ESI-TOF) (m/z) [M + H+] = calcd
for C22H30NO2 340.2277, found 340.2271.
(4R,5S)-N,N-Dibenzyl-2,2-dimethyl-4-vinyl-1,3-dioxan-5-
amine (14b). The procedure described above for the synthesis of
compound 14a was applied to 12b (20 mg, 0.067 mmol) to give 14b
(18.5 mg, 0.05 mmol, 82% yield) as a colorless oil: [α]25D = +19.7 (c,
(2S,3R)-2-(Dibenzylamino)pent-4-yne-1,3-diol (12c). The pro-
cedure described above for the synthesis of compound 12a was applied
to 10 on a 0.27 mmol (100 mg) scale using ethynylmagnesium
bromide solution (1.62 mL, 0.81 mmol, 0.5 M in THF) to give 12c
(50.2 mg, 0.17 mmol, 63% yield) as a colorless oil: [α]25D = −18.8 (c,
1
1.01, CHCl3); H NMR (500 MHz, CDCl3) δ 1.37 (s, 3H), 1.47 (s,
3H), 2.88 (ddd, 1H, J1 =9.5, J2 = 7.8, J3 = 5.6 Hz), 3.66 (d, 2H, J = 13.8
Hz), 3.88 (dd, 1H, J1 = 11.7, J2 = 5.6 Hz), 3.93 (d, 2H, J = 13.8 Hz),
3.97 (dd, 1H, J1 = 11.7, J2 = 7.8 Hz), 4.40 (dd, 1H, J1 = 9.8, J2 = 6.5
Hz), 5.32 (d, 1H, J = 10.5 Hz), 5.42 (d, 1H, J = 17.1 Hz), 5.93 (ddd,
1H, J1 = 17.1, J2 = 10.5, J3 = 6.5 Hz), 7.24−7.37 (m, 10H); 13C{1H}
(100 MHz, CDCl3) δ 139.5, 137.7, 128.7, 127.1, 117.5, 98.8, 71.4,
59.1, 57.4, 54.7, 27.6; IR (ATR-neat) νmax = 3503, 3063, 3027, 2989,
2936, 2887, 1602, 1493, 1453, 1200; HRMS (ESI-TOF) (m/z) [M +
H+] = calcd for C22H27NO2 338.2120, found 338.2117.
1
0.83, CHCl3); H NMR (400 MHz, CDCl3) δ 2.46 (d, 1H, J = 1.9
Hz), 3.04 (t, 1H, J = 6.1 Hz), 3.17 (br, 1H), 3.72 (d, 2H, J = 13.3 Hz),
3.81−3.84 (m, 1H), 3.92−3.98 (m, 3H), 4.46 (br, 1H), 7.19−7.27 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 139.1, 129.2, 128.5, 127.4, 83.8,
74.8, 61.8, 60.3, 59.6, 54.8; IR (ATR-neat) νmax = 3371, 3292, 3062,
3028, 1602, 1494, 1452, 1366; HRMS (ESI-TOF) (m/z) [M + Na+] =
calcd for C19H21NO2 318.1470, found 318.1474.
(4R,5S)-N,N-Dibenzyl-4-ethynyl-2,2-dimethyl-1,3-dioxan-5-
amine (14c). The procedure described above for the synthesis of
compound 14a was applied to 12c (20 mg, 0.068 mmol) to give 14c
(18.2 mg, 0.05 mmol, 80% yield) as a colorless oil: [α]25D = +29.2 (c,
(2R,3S,4R)-3-(Dibenzylamino)hexane-2,4-diol (13a). The pro-
cedure described above for the synthesis of compound 12a was applied
to 11 on a 0.26 mmol (100 mg) scale using ethylmagnesium bromide
solution (0.26 mL, 0.78 mmol, 3 M in Et2O) to give 13a (50.1 mg,
1
0.96, CHCl3); H NMR (500 MHz, CDCl3) δ 1.36 (s, 3H), 1.39 (s,
0.16 mmol, 60% yield) as a colorless oil: [α]25 = −43.0 (c, 1.0,
3H), 2.59 (d, 1H, J = 2.1 Hz), 3.18 (ddd, 1H, J1 = 9.8, J2 = 7.5, J3 = 5.6
Hz), 3.74 (d, 2H, J = 13.9 Hz), 3.79 (dd, 1H, J1 = 10.4, J2 = 5.6 Hz),
3.84 (dd, 1H, J1 = 10.4, J2 = 7.5 Hz), 3.97 (d, 1H, J = 13.9 Hz), 4.66
(dd, 1H, J1 = 9.8, J2 = 2.1 Hz), 7.22−7.40 (m, 10H); 13C{1H} (100
MHz, CDCl3) δ 139.4, 128.7, 128.3, 127.1, 99.4, 82.6, 74.3, 61.3, 60.2,
57.6, 54.7, 27.1, 20.8; IR (ATR-neat) νmax = 3288, 3062, 3028, 2991,
2124, 1703; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for
C22H25NO2 336.1964, found 336.1969.
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J = 7.6 Hz), 1.18
(d, 3H, J = 6.1 Hz), 1.67−1.58 (m, 2H), 2.10 (br, 1H), 2.36 (dd, 1H,
J1 = 7.1, J2 = 1.9 Hz), 3.48 (d, 2H, J = 13.5 Hz), 3.93−3.96 (m, 1H),
4.01 (d, 2H, J = 13.5 Hz), 4.13 (quin, 1H, J = 6.2 Hz), 7.16−7.29 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 139.4, 129.1, 128.4, 127.2, 70.9,
65.8, 64.9, 55.1, 30.2, 20.9, 18.8; IR (ATR-neat) νmax = 3415, 3062,
3026, 2968, 2922, 1496, 1455, 1374; HRMS (ESI-TOF) (m/z) [M +
H+] = calcd for C20H27NO2 314.2120, found 314.2118.
(4R,5S,6R)-N,N-Dibenzyl-4-ethyl-2,2,6-trimethyl-1,3-dioxan-
5-amine (15a). The procedure described above for the synthesis of
compound 14a was applied to 13a (20 mg, 0.064 mmol) to give 15a
(18.1 mg, 0.05 mmol, 80% yield) as a colorless oil: [α]25D = +27.2 (c,
(2R,3S,4R)-3-(Dibenzylamino)hex-5-ene-2,4-diol (13b). The
procedure described above for the synthesis of compound 12a was
applied to 11 on a 0.26 mmol (100 mg) scale using vinylmagnesium
bromide solution (0.78 mL, 0.78 mmol, 1 M in THF) to give 13b
(50.9 mg, 0.16 mmol, 63% yield) as a colorless oil: [α]25D = −42.7 (c,
1
0.3, CHCl3); H NMR (600 MHz, CDCl3) δ 0.83 (s, 3H), 1.26 (s,
3H), 1.33 (s, 3H), 1.27 (m, 1H), 1.40 (d, 1H, J = 7.0 Hz), 1.69 (dsext,
1H, J1 = 7.4, J2 = 2.8 Hz), 2.60 (dd, 1H, J1 = 7.4, J2 = 5.0 Hz), 3.68 (td,
1H, J1 = 7.4, J2 = 2.8 Hz), 4.01−4.03 (br + m, 3H), 7.19−7.27 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 140.5, 128.6, 128.2, 126.8, 100.3,
1
0.93, CHCl3); H NMR (400 MHz, CDCl3) δ 1.14 (d, 3H, J = 6.1
Hz), 2.52 (dd, 1H, J1 = 7.6, J2 = 2.2 Hz), 3.60 (d, 2H, J = 13.5 Hz),
4.03 (d, 2H, J = 13.5 Hz), 4.12 (quin, 1H, J = 6.3 Hz), 4.56 (br, 1H),
5.11 (d, 1H, J = 10.5), 5.27 (d, 1H, J = 17.2 Hz) 5.86 (ddd, 1H, J1
=16.7, J2 = 10.5, J3 = 5.2 Hz), 7.17−7.31 (m 10H); 13C{1H} (100
MHz, CDCl3) δ 140.4, 139.2, 129.1, 128.9, 128.5, 127.3, 114.8, 69.9,
66.4, 65.2, 55.3, 21.0; IR (ATR-neat) νmax = 3391, 3063, 3026, 1603,
1494, 1454; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for
C20H25NO2 312.1964, found 312.1972.
70.9, 68.6, 61.0, 55.8, 24.8, 24.5, 17.8, 10.3; IR (ATR-neat) νmax
=
3067, 2987, 2936, 2855, 1458, 1380, 1228; HRMS (ESI-TOF) (m/z)
[M + H+] = calcd for C23H31NO2 354.2433, found 354.2437.
(4R,5S,6R)-N,N-Dibenzyl-2,2,4-trimethyl-6-vinyl-1,3-dioxan-
5-amine (15b). The procedure described above for the synthesis of
compound 14a was applied to 13b (20 mg, 0.057 mmol) to give 15b
(15.8 mg, 0.05 mmol, 79% yield) as a colorless oil: [α]25 = −7.5 (c,
(2R,3S,4R)-3-(Dibenzylamino)hex-5-yne-2,4-diol (13c). The
procedure described above for the synthesis of compound 12a was
applied to 11 on a 0.26 mmol (100 mg) scale using ethynylmagnesium
bromide solution (1.56 mL, 0.78 mmol, 1 M in THF) to give 13c (46
D
1
0.30, CHCl3); H NMR (600 MHz, CDCl3) δ 1.29 (s, 3H), 1.39 (s,
3H), 1.37 (d, 3H, J = 6.9 Hz), 2.79 (dd, 1H, J1 = 7.4, J2 = 5.3 Hz), 3.89
(br, 2H), 4.07−4.11 (br + m, 3H), 4.46 (t, 1H, J = 7.4 Hz), 5.21 (d,
1H, J = 10.4 Hz), 5.32 (d, 1H, J = 17.2 Hz), 5.88 (ddd, 1H, J1 = 17.2,
J2 = 10.4, J3 = 6.6 Hz), 7.19−7.37 (m, 10H); 13C{1H} (100 MHz,
CDCl3) δ 140.1, 139.1, 128.6, 128.2, 126.8, 116.7, 100.4, 69.7, 67.9,
60.7, 55.4, 29.7, 25.0, 24.6, 17.4; IR (ATR-neat) νmax = 3330, 3063,
3027, 2925, 2852, 1603, 1494, 1454, 1224; HRMS (ESI-TOF) (m/z)
[M + H+] = calcd for C23H29NO2 352.2277, found 352.2268.
(4R,5S,6R)-N,N-Dibenzyl-4-ethynyl-2,2,6-trimethyl-1,3-diox-
an-5-amine (15c). The procedure described above for the synthesis
of compound 14a was applied to 13c (20 mg, 0.065 mmol), to give
15c (18.8 mg, 0.05 mmol, 83% yield) as a colorless oil: [α]25D = +3.5
(c, 0.34, CHCl3); 1H NMR (600 MHz, CDCl3) δ 1.34 (d, 3H, J = 6.5
Hz), 1.37 (s, 3H), 1.48 (s, 3H), 2.54 (d, 1H, J = 2.4 Hz), 2.87 (1H, t, J
= 4.8 Hz), 3.70 (d, 2H, J = 13.4 Hz), 4.16 (br, 2H), 4.29 (dq, 1H, J1 =
6.6, J2 = 4.8 Hz), 4.94 (dd, 1H, J1 = 4.8, J2 = 2.4 Hz), 7.20−7.36 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 139.8, 128.7, 128.3, 126.9, 100.7,
mg, 0.15 mmol, 58% yield) as a colorless oil: [α]25 = −33.8 (c, 1.02,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.25 (d, 3H, J = 6.0 Hz), 2.49
(d, 1H, J = 1.7 Hz), 2.77 (dd, 1H, J1 =8.9, J2 =4.9 Hz), 4.01 and 4.06
(2 × 2H, AB system, J = 13.1 Hz), 4.34−4.44 (m, 2H), 7.23−7.34 (m,
10H); 13C{1H} (100 MHz, CDCl3) δ 139.2, 129.5, 128.5, 127.3, 83.7,
74.7, 66.8, 65.6, 59.5, 55.5, 21.2; IR (ATR-neat) νmax = 3379, 3224,
3063, 3025, 1495, 1454, 1364; HRMS (ESI-TOF) (m/z) [M + H+] =
calcd for C20H23NO2 310.1807, found 310.1805.
(4R,5S)-N,N-Dibenzyl-4-ethyl-2,2-dimethyl-1,3-dioxan-5-
amine (14a). To a solution of 12a (20.0 mg, 0.07 mmol) were added
DMS (0.8 mL, 0.85 mmol) and PPTS (5 mg, 0.02 mmol) in 2 mL of
dry DCM. The solution was stirred for 18 h at room temperature. The
solvent was then evaporated, and the residue was chromatographed on
silica gel flash (eluent AcOEt/PE, 95:5) to give 14a (19.0 mg, 0.06
mmol, 80% yield) as a colorless oil: [α]25 = +68.1 (c, 0.93, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.75 (t, 3H, J = 7.4 Hz), 1.22 (s + m
4H), 1.29 (s, 3H), 1.83 (dsext, 1H, J1 = 7.4, J2 = 2.6 Hz), 2.64 (td, 1H,
J1 = 9.6, J2 = 5.6 Hz), 3.45 (d, 2H, J = 14.3 Hz) 3.62 (dt, 1H, J1 = 9.6,
J2 = 2.6 Hz), 3.76 (dd, 1H, J1 = 11.9, J2 = 5.6 Hz), 3.83 (d + dd, 3H, J1
= 14.3, J2 = 11.9, J3 = 5.6 Hz) 7.13−7.26 (m, 10H); 13C{1H} (100
MHz, CDCl3) δ 139.7, 128.7, 128.0, 127.0, 99.0, 71.3, 58.2, 57.8, 54.8,
26.6, 25.6, 21.7, 9.7; IR (ATR-neat) νmax = 3068, 2938, 2880, 1457,
84.4, 74.6, 66.5, 59.6, 58.8, 55.3, 27.2, 23.4, 17.4; IR (ATR-neat) νmax
=
3400, 3063, 3028, 2925, 2336, 2963, 1734; HRMS (ESI-TOF) (m/z)
[M + H+] = calcd for C23H27NO2 350.2120, found 350.2129.
(3S,4R)-3-(Dibenzylamino)hexane-1,4-diol (17a). The proce-
dure described for the synthesis of compound 5a was applied to 16 on
a 0.7 mmol (200 mg) scale using ethylmagnesium bromide solution
(0.7 mL, 2.1 mmol, 3 M in Et2O). The residue was purified by flash
F
dx.doi.org/10.1021/jo500481j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
chromatography on silica gel (eluent gradient AcOEt/PE, 8:2 to 7:3)
(2S,3R)-2-(Dibenzylamino)octadec-4-yn-3-ol (19). To a sol-
ution of 1-nonyne (0.14 mL, 0.84 mmol) in dry Et2O (10 mL) was
added ethylmagnesium bromide solution (0.28 mL, 0.84 mmol, 3 M in
THF). The mixture was refluxed for 2.5 h, and then it was allowed to
cool to room temperature. In parallel, to a cooled (−78 °C) solution
of 4a (100 mg, 0.28 mmol) in dry Et2O (3 mL) was added DIBAL-H
(0.4 mL, 0.4 mmol, 1 M in hexane) under argon atmosphere. After
being stirred for 2 h, a solution of alkynylmagnesium bromide
previously formed was carefully added at −78 °C. The mixture was
allowed to warm to −10 °C and stirred for 18 h. Then, the mixture
was warmed to 0 °C and quenched with saturated NH4Cl (8 mL). The
mixture was extracted with Et2O (10 mL × 3), and the organic phases
were washed with brine, dried over MgSO4, filtered, and concentrated
in vacuum. The residue was purified by flash chromatography on silica
to give 17a (203.9 mg, 0.65 mmol, 95% yield) as a colorless oil: [α]25
D
= −34.0 (c, 1.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.82 (t, 3H,
J = 7.4 Hz), 1.30 (sep, 1H, J = 7.4 Hz), 1.43−1.56 (m, 1H), 1.96−2.05
(m, 1H), 2.60−2.64 (m, 1H), 3.46 (d, 2H, J = 13.6 Hz), 3.58 (br, 2H),
3.72−3.74 (d + m, 3H, J = 13.6 Hz), 7.50−7.24 (m, 10H); 13C{1H}
(100 MHz, CDCl3) δ 139.4, 129.1, 128.4, 127.2, 71.4, 62.4, 61.1, 54.5,
28.7, 27.2, 10.4; IR (ATR-neat) νmax = 3314, 3063, 3028, 2930, 2960,
1494, 1453, 1365; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for
C20H27NO2 314.2120, found 314.2119.
(3S,4R)-3-(Dibenzylamino)hex-5-ene-1,4-diol (17b). The pro-
cedure described for the synthesis of compound 5a was applied to 16
on a 0.7 mmol (200 mg) scale using vinylmagnesium bromide solution
(2.1 mL, 2.1 mmol, 1 M in THF) to give 17b (209.1 mg, 0.67 mmol,
1
96% yield) as a colorless oil: [α]25 = −31.4 (c, 1.26, CHCl3); H
gel (eluent AcOEt/PE, 9:1) to give 19 (77.5 mg, 0.17 mmol, 60%
D
1
yield) as a colorless oil: [α]25 = −10.2 (c, 0.89, CHCl3); H NMR
D
NMR (400 MHz, CDCl3) δ 1.59−1.68 (m, 1H), 2.10−2.19 (m, 1H),
2.88−2.92 (m, 1H), 3.68−3.72 (d + m, 4H, J = 13.5 Hz), 3.83 (d, 2H,
J = 13.5 Hz), 4.45 (br, 1H), 5.2 (d, 1H, J = 10.4 Hz), 5.33 (d, 1H, J =
17.2 Hz), 5.93 (ddd, 1H, J1 = 16.4, J2 = 10.4, J3 = 5.4 Hz), 7.28−7.37
(m, 10H); 13C{1H} (100 MHz, CDCl3) δ 140.1, 139.3, 129.1, 128.5,
127.3, 115.1, 70.9, 62.0, 60.8, 54.7, 27.2; IR (ATR-neat) νmax = 3337,
3063, 3027, 1602, 1494, 1452; HRMS (ESI-TOF) (m/z) [M + H+] =
calcd for C20H25NO2 312.1964, found 312.1964.
(400 MHz, CDCl3) δ 0.83 (t, 3H, J = 7.0 Hz), 1.14−1.25 (m, 23H),
1.39 (quin, 2H, J = 7.0 Hz), 2.13 (td, 2H, J1 = 7.0, J2 = 2.0 Hz), 2.95
(quin, 1H, J =6.6 Hz), 3.32 (d, 2H, J = 13.3 Hz), 3.89 (br, 1H), 4.14
(d + m, 3H, J = 13.3 Hz), 7.17−7.27 (m, 10H); 13C{1H} (100 MHz,
CDCl3) δ 139.4, 129.1, 128.4, 127.2, 86.8, 80.0, 63.2, 56.0, 54.7, 31.9,
29.7, 29.5, 29.4, 29.1, 28.9, 28.6, 22.7, 18.8, 14.1, 9.5; IR (ATR-neat)
νmax = 3425, 2925, 2853, 1332, 747, 699; HRMS (EI-TOF) (m/z) [M
− H2O+] = calcd for C32H47NO 443.3552, found 443.3541.
(3S,4R)-3-(Dibenzylamino)hex-5-yne-1,4-diol (17c). The pro-
cedure described for the synthesis of compound 5a was applied to 16
on a 0.7 mmol (200 mg) scale using ethynylmagnesium bromide
solution (4.2 mL, 2.1 mmol, 0.5 M in THF) to give 17c (173.1 mg,
(2S,3R)-2-(Dibenzylamino)octadec-4-yne-1,3-diol (20).36 To
a solution of 1-nonyne (0.13 mL, 0.81 mmol) in dry Et2O (10 mL)
was added ethylmagnesium bromide solution (0.27 mL, 0.81 mmol, 3
M in THF). The mixture was refluxed for 2.5 h, and then it was
allowed to cool to room temperature. In parallel, to a cooled (−78 °C)
solution of 10 (100 mg, 0.27 mmol) in dry Et2O (3 mL) under argon
was added DIBAL-H in two portions (0.38 mL, 0.38 mmol, 1 M in
hexane; and 45 min later 0.19 mL, 0.19 mmol). After additional
stirring for 40 min at −78 °C, a solution of the alkynylmagnesium
bromide previously formed was carefully added at −78 °C and the
mixture was allowed to warm to −10 °C and stirred for 18 h. Then,
the mixture was cooled to 0 °C and quenched with saturated NH4Cl
(8 mL). The mixture was extracted with Et2O (10 mL × 3), and the
organic phases were washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel flash (eluent AcOEt/PE, 8:2) to give
20 (90.2 mg, 0.19 mmol, 70% yield) as a colorless oil: [α]25D = −37.6
(c, 0.94, CHCl3).
0.56 mmol, 80% yield) as a colorless oil: [α]25 = −13.7. (c, 1.03,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.78−1.86 (m, 1H), 2.01−
2.09 (m, 1H), 2.40 (d, 1H, J = 6.2 Hz), 3.55−3.57 (d + m, 3H, J = 13.3
Hz), 3.62−3.69 (m, 1H), 3.92 (d, 2H, J = 13.3 Hz), 4.38 (d, 1H, J =
4.4 Hz), 7.18−7.25 (m, 10H); 13C{1H} (100 MHz, CDCl3) δ 139.0,
129.3, 128.6, 127.4, 84.1, 74.6, 60.9, 60.7, 58.8, 54.8, 28.2; IR (ATR-
neat) νmax = 3379, 3296, 3066, 3032, 1498, 1456, 1370; HRMS (ESI-
TOF) (m/z) [M + H+] = calcd for C20H23NO2 310.1807, found
310.1813.
(4S,5R)-4-(Dibenzylamino)-5-ethyldihydrofuran-2(3H)-one
(18a.31 TPAP (32.0 mg, 0.09 mmol) was added to a stirred mixture of
17a (278.7 mg, 0.89 mmol), NMO (320.0 mg, 2.67 mmol), and
activated powdered molecular sieves (60 mg) in dry DCM (1 mL) at
room temperature under argon. After being stirred for 2 h, the reaction
mixture was purified by column chromatography flash (eluent AcOEt/
PE, 8:2) to give 18a (137.6 mg, 0.45 mmol, 50% yield) as a colorless
(2S,3R)-2-Aminooctadecan-3-ol (Spisulosine, 2c).6,53,54 The
procedure described for the synthesis of compound 8 was applied to
19 (50 mg, 0.11 mmol) to give 2c (25,1 mg, 0.09 mmol, 70% yield) as
oil: [α]25 = +84.3 (c, 0.4, CHCl3).
D
a white solid: mp = 65−67 °C; [α]25 = +25.3 (c, 0.94, CHCl3).
(4S,5R)-4-(Dibenzylamino)-5-vinyldihydrofuran-2(3H)-one
(18b). The procedure described for the synthesis of compound 18a
was applied to 17b (50 mg, 0.16 mmol) to give 18b (26.0 mg, 0.08
mmol, 51% yield) as a colorless oil: [α]25D = +27.8 (c, 0.7, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 2.60.(d, 2H, J = 7.1 Hz), 3.53 (ddd, 1H, J1
= 7.3, J2 = 6.7, J3 = 4.6 Hz), 3.57 (d, 2H, J = 13.8 Hz), 3.71 (d, 2H, J =
13.8 Hz), 4.98 (ddd, 1H, J1 = 5.4, J2 = 4.6, J3 = 1.4 Hz), 5.24 (dd, 1H,
J1 = 10.5, J2 = 1.0), 5.34 (dt, 1H, J1 = 17.2, J2 = 1.0 Hz), 5.76 (ddd, 1H,
J1 = 5.4, J2 = 4.6, J3 = 1.4 Hz), 7.25−7.34 (m, 10H); 13C{1H} (100
MHz, CDCl3) δ 175.6, 138.2, 134.8, 128.5, 127.5, 117.3, 81.7, 60.6,
54.3, 29.7; IR (ATR-neat) νmax = 3029, 2921, 1778, 1646, 1184, 1163,
987, 738, 700; HRMS (ESI-TOF) (m/z) [M + H+] = calcd for
C20H21NO2 308.1651, found 308.1651.
D
(2S,3R)-2-Aminooctadecane-1,3-diol (Sphinganine, 1b).55
The procedure described for the synthesis of compound 8 was
applied to 20 (50 mg, 0.10 mmol) to give 1b (19.0 mg, 0.06 mmol,
60% yield) as a white solid: mp = 70−72 °C; [α]25D = +0.62 (c, 0.57,
EtOH).
ASSOCIATED CONTENT
* Supporting Information
■
S
Full characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(4S,5R)-4-(Dibenzylamino)-5-ethynyldihydrofuran-2(3H)-
one (18c). The procedure described for the synthesis of compound
18a was applied to 17c (50 mg, 0.16 mmol) to give 18c (24.4 mg, 0.08
mmol, 49% yield) as a colorless oil: [α]25D = +25.0 (c, 0.3, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 2.57 (dd, 1H, J1 = 18.4, J2 = 4.4 Hz), 2.65
(d, 1, H, J = 2.2 Hz), 2.79 (dd, J1 = 18.4, J2 = 8.8 Hz), 3.63 (2 × 2AB
system, 4H, J = 13.8 Hz), 3.89 (qd, 1H, J1 = 4.3, J2 = 4.3 Hz), 5.13 (dd,
J1 = 4.3, J2 = 2.2 Hz), 7.26−7.34 (m, 10H); 13C{1H} (100 MHz,
CDCl3) δ 174.7, 137.7, 128.7, 128.6, 127.6, 79.4, 70.3, 62.6, 54.1, 29.7;
IR (ATR-neat) νmax = 3283, 2925, 2123, 1787, 1453, 1194, 970, 911,
736, 631 ; HRMS (ESI-TOF) (m/z) [M + Na+] = calcd for
C20H19NO2 328.1313, found 328.1316.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jmpadron@ull.es.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was co-financed by the EU Research Potential (FP7-
REGPOT-2012-CT2012-31637-IMBRAIN), the European Re-
gional Development Fund (FEDER), the Spanish Ministerio de
G
dx.doi.org/10.1021/jo500481j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Educacion (Programa Campus de Excelencia Internacional
CEI10/00018), and the Spanish MINECO (CTQ2011-28417-
C02-01 and Instituto de Salud Carlos III PI11/00840). G.S.-D.
thanks the EU Social Fund (FSE) and the Canary Islands
ACIISI for a predoctoral grant. This research was also
supported by CONICET (PIP 2012-2014-0360) and UNSL
(Project P-2-1412).
Featured Article
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dx.doi.org/10.1021/jo500481j | J. Org. Chem. XXXX, XXX, XXX−XXX