Synthesis of D-erythro-sphinganine through serine-derived α-amino epoxides

Article abstract of DOI:10.1021/jo500493c

A total synthesis of d-erythro-sphinganine [(2S,3R)-2-aminooctadecane-1,3- diol] starting from commercial N-tert-butyloxycarbonyl-l-serine methyl ester is described. The approach is based on the completely stereoselective preparation of an α-amino epoxide obtained by treating a protected l-serinal derivative with dimethylsulfoxonium methylide. The oxirane synthon is obtained with an anti configuration fitting the (2S,3R) stereochemistry of the 2-amino-1,3-diol polar head of d-erythro-sphinganine. The synthetic procedure afforded the target compound in a 68% overall yield based on the initial amount of the starting l-serine material.

Full text of DOI:10.1021/jo500493c

Note
pubs.acs.org/joc
Synthesis of D-erythro-Sphinganine through Serine-Derived α‑Amino
Epoxides
Carlo Siciliano,*,† Anna Barattucci,‡ Paola Bonaccorsi,‡ Maria Luisa Di Gioia,† Antonella Leggio,†
Lucio Minuti,§ Emanuela Romio,† and Andrea Temperini∥
†Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Universita
Arcavacata di Rende (CS), Italy
̀
della Calabria, Edificio Polifunzionale, I-87030
‡Dipartimento di Scienze Chimiche, Universita
̀
di Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy
§Dipartimento di Chimica, Universita
̀
di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy
∥Dipartimento di Chimica e Tecnologia del Farmaco, Universita
̀
di Perugia, Via del Liceo 1, 06123 Perugia, Italy
S
* Supporting Information
ABSTRACT: A total synthesis of D-erythro-sphinganine [(2S,3R)-2-aminooctadecane-1,3-diol] starting from commercial N-tert-
butyloxycarbonyl-L-serine methyl ester is described. The approach is based on the completely stereoselective preparation of an α-
amino epoxide obtained by treating a protected L-serinal derivative with dimethylsulfoxonium methylide. The oxirane synthon is
obtained with an anti configuration fitting the (2S,3R) stereochemistry of the 2-amino-1,3-diol polar head of D-erythro-
sphinganine. The synthetic procedure afforded the target compound in a 68% overall yield based on the initial amount of the
starting L-serine material.
-erythro-Sphinganine [(2S,3R)-2-aminooctadecane-1,3-
diol] (1, Scheme 1) is involved in the biosynthesis of
and 3-OH groups display a reciprocal anti configuration,
defining a (2S,3R) stereochemistry of the chiral carbons. The
stereoselective synthesis of the 2-amino-1,3-diol subunit by
asymmetric approaches7 is often troublesome. The main
drawbacks are low levels of stereoselection and the chromato-
graphic separation of stereoisomers. Otherwise, the use of
carbohydrates and serine as chiral pool8 has been proposed to
provide 1 in satisfactory overall yields and high chiral purity.
Although most of these routes are of comparable length, they
do not show the same level of stereocontrol. The creation of
two stereogenic centers in the headgroup with high stereo-
selectivity is the major difficulty. The total synthesis of 1
proceeds also through a stereoselective nucleophilic addition to
the Garner’s aldehyde CHO group.9 The low reactivity of the
Garner’s aldehyde to Grignard and other aliphatic long-chain
organometallic reagents limits the effectiveness of these
applications. Moreover, a incomplete stereoselection is
observed, and in many cases, the syn isomers are preferentially
formed, while the opposite anti relative stereochemistry is
required to build up the backbone of 1. The use of sacrificial
bases to deprotonate a serine-derived Weinreb amide10 could
be used for the preparation of 1. Nevertheless, these approaches
D
Scheme 1. Retrosynthetic Approach to D-erythro-
Sphinganine (1)
ceramides, sphingomyelin, cerebrosides, and gangliosides,
which are ubiquitous components of cell membranes.1 These
compounds regulate signaling, cellular recognition, cell
proliferation, growth, differentiation, and apoptosis.2 D-erythro-
Sphinganine is also a structural constituent in a large class of
biologically active natural products.3 It inhibits protein kinase
C4 and exerts a potent immunoregulatory activity.5 A defect of
D-erythro-sphinganine could determine diabetes, degenerative
diseases, and neurological syndromes.6 The biological role of D-
erythro-sphinganine justifies the interest in targeting synthetic
access to this sphingoid base. Structurally, D-erythro-sphinga-
nine (1, Scheme 1) features a 2-amino-1,3-diol subunit as polar
head inserted in a C18 saturated hydrocarbon chain. The 2-NH2
Received: March 1, 2014
© XXXX American Chemical Society
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Scheme 2. Preparation of the L-Serinal Derivative 6
require chromatography to isolate the diastereomers with the
appropriate relative configuration. Hence, the preparation of 1
and its stereomers with high levels of stereocontrol is still
attractive today because they cannot readily be obtained from
natural sources. In the ambit of the synthesis of biologically
important compounds,11 and in a survey of possible approaches
that could provide 1, we have developed a striking stereo-
selective route to D-erythro-sphinganine in which its anti
configuration could easily be accessible.
latter with hydrides should generate 6. The reaction of 5 with
lithium hydroxide in THF/water at room temperature14 gave 8
in an almost quantitative yield, without need for chromatog-
raphy. The 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide/
1-hydroxybenzotriazole (EDC/HOBt)-mediated coupling15 of
8 to N,O-dimethylhydroxylamine hydrochloride in DCM at
room temperature afforded 9 which was isolated, without
chromatography, in 96% yield and high purity as assessed by 1H
and 13C NMR spectroscopy. Exposure of 9 to lithium
aluminum hydride in THF at room temperature gave
exclusively 6 in 93% yield, avoiding chromatography. In this
case, no formation of 7 was observed.
We reasoned that a synthetic strategy to 1 could implicate
the preparation of the anti-α-amino epoxide 2 (Scheme 1). In
this approach, 2 should be obtained by the stereocontrolled
epoxidation of a Garner-like aldehyde elaborated from 3 after
its protection as a UV-detectable N,O-acetal. The choice of the
4,4′-dimethoxybenzophenone hemiaminal protection as an
alternative to the commonly used acetone hemiaminal moiety
as in the Garner’s aldehyde was addressed by several
considerations. The bulky diaryl chromophore group, remov-
able under mild acid conditions, could also affect the
stereoselectivity of the epoxidation. Then, 2 would need only
the regioselective oxirane ring opening with a C14 organo-
metallic reagent. The protection of 3 as N-Boc-N,O-acetal with
two acid-labile groups seemed appealing. In fact, they should
globally be cleaved to give the target compound 1 with benefit
in terms of total yield. N-tert-Butyloxycarbonyl-L-serine methyl
ester (3) was chosen as a source of chirality because both
enantiomers are commercially available and inexpensive, and
the three functionalities can selectively be manipulated,
maintaining the optical integrity of the starting material.
The procedure leading to the serinal intermediate 6 is
depicted in Scheme 2. A slightly modified protocol already
reported for carbohydrates12 was applied to obtain 5. The acid-
catalyzed treatment of 3 with the acetal 4 in refluxing toluene
afforded 5 in 92% yield and was pure enough to be used in the
next step without further purification.
The reactivity of 5 toward hydrides was thus exploited. The
preparation of 6 was first attempted by using DIBALH at low
temperature. Although reduction of 5 with DIBALH could
directly afford 6, this step was more problematic than expected.
In fact, 6 was isolated in unsatisfactory yield (27%) after
chromatography, while the serinol 7 was the prevalent product
(68%). We concluded that 6 suffered from over-reduction, and
this unwanted reaction cannot completely be avoided unless
freshly purchased DIBALH is used for the transformation.13
Therefore, we reasoned that 6 could more conveniently be
prepared through the basic hydrolysis of 5 to give the carboxylic
acid 8, precursor of the Weinreb amide 9. Treatment of the
We thus envisaged the conversion of 6 into the desired α-
amino epoxide 2 (Scheme 3) by using sulfur ylides,16 a reaction
Scheme 3. Preparation of the anti-α-Amino Epoxide 2
well-documented for the Garner’s aldehyde.17 Nevertheless, to
the best of our knowledge, the synthesis of 1 through the
stereoselective preparation of chiral α-amino epoxides, followed
by the oxirane ring opening with long-chain Grignard reagents,
has not been attempted yet.
The preparation of 2 was the key step of the procedure.
Initially, 6 (1 equiv) was reacted with dimethylsulfonium
methylide (1 equiv) in THF at room temperature to give 2 and
11 in 95% crude yield and in an approximately 1:1 ratio, as
demonstrated by 1H NMR (Figure 1). No other products were
detected. Chemical shifts and proton coupling constants18
suggested the anti and syn configurations for 2 and 11,
respectively. The three signals appearing at 2.79, 2.89, and 3.12
ppm were attributable to the anti-α-amino epoxide 2 (J = 6.9,
4.0, and 2.6 Hz) and the other three at 2.61, 2.74, and 3.34 ppm
to the syn isomer 11 (J = 4.7, 4.6, and 2.0 Hz) (Figure 1). This
assignment was supported by the comparison with findings
already published for a series of similar N-protected α-amino
epoxides.19 In fact, the two anti and syn diastereomers should
show distinguishable resonances for the respective oxirane
protons. In accord with the literature, 2 featured better resolved
and less spread out signals than for anti-α-amino epoxides.
The absence of stereoselection observed for the treatment of
6 with dimethylsulfonium methylide was in stark contrast with
the results already reported for Garner’s aldehyde.17 As an
alternative, 6 (1 equiv) was reacted with dimethylsulfoxonium
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1
Figure 1. H NMR spectral regions of the oxirane protons in 2 and 11 (crude products).
Scheme 4. Nucleophilic Ring Opening of 2 and Global Deprotection of 12 to 1
Scheme 5. Use of N-Boc-D-Serine Methyl Ester
methylide (1 equiv) in THF at room temperature. Unpredict-
ably, epoxidation was totally diastereoselective, providing only 2
in 90% yield and high purity, without need for chromatography.
elemental composition and the definitive confirmation of the
structure of 12 were obtained by ESI-TOF HRMS and MS/MS
experiments. With construction of the skeletal framework
complete, the solid obtained from trituration was treated with
perchloric acid in DCM/CH3OH at room temperature20 to
globally deprotect 12. D-erythro-Sphinganine (1) was isolated in
92 and 68% overall yields, referring to the starting amounts of 2
and 3, respectively. 1H and 13C NMR spectroscopy in
methanol-d4 gave spectral data in strong agreement with
those reported for the same compound synthesized by another
route.21 The anti configuration of the 2-amino-1,3-diol frame
was indicated by the coupling constant (J = 5.4 Hz) between
the H-2 and H-3 protons. Within the limits of NMR
techniques, no syn diastereomer was detected. The stereo-
chemical outcome of this total synthesis was confirmed by the
specific rotation of 1 ([α]D 7.9, c 1.0, CH3OH) which agreed
with the literature values, within the limits of experimental
error.21 NMR spectroscopy and the comparison with already
reported data suggested that the configuration of 3 was totally
retained in all steps of the procedure. As a consequence, the
absolute (2S,3R) stereochemistry was finally assigned to 1. This
1
The H NMR spectrum of 2 displayed a unique series of
resonances for the oxirane protons (Figure 1), with chemical
shifts identical to those displayed by the mixture of 2 and 11
obtained as described. As a consequence, we postulated the anti
configuration for 2, corresponding to the (S,S) stereochemistry.
The 1H NMR spectrum of 2 isolated after the reaction workup
did not display signals attributable to 11 within the NMR
sensibility limits. Compound 2 was then employed without
further purification to produce 1 in two steps (Scheme 4).
Reaction of 2 (1 equiv) with tetradecylmagnesium bromide
in Et2O at room temperature occurred smoothly, and its
completion was reached provided that an excess (2 equiv) of
the organomagnesium species was used. For simplicity of
operation, 12 was recovered by simple trituration of the
reaction crude with cold n-pentane and used in the next step
without further purification. At this level, the complexity of the
1H NMR spectrum in CDCl3 hampered a complete structural
assignment, although signals in the spectral window between
3.70 and 4.50 ppm were assumed to be symptomatic of 12. The
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1
procedures and freshly distilled before use. H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, using CDCl3, DMSO-
d6, or CD3OD as solvents. For a better resolution of signals, all spectra
were recorded at 40 °C. Chemical shifts are reported in parts per
findings validated also the anti configuration previously
hypothesized for 2.
To expand the scope and further exploit the versatility of this
procedure, commercial N-Boc-D-serine methyl ester was finally
used to prepare the α-amino epoxide 19 (Scheme 3), which
could be considered a valuable precursor of L-erythro-
sphinganine (20). This isomer appears less attractive than 1
because it does not display the same biological activities as the
D-erythro form. Nevertheless, a potential high-yielding synthetic
access to 20 should be desirable for applications of this
compound in studies of biological recognition and response
mechanisms.22 Starting from the D-optical form of serine
material, repetition of the synthetic protocol provided 13 and
all other expected products in excellent yields and without need
for chromatography. Furthermore, compounds 14 and 16 were
also successfully used to confirm the retention of configuration
during the preparation of 6 and 8 (Scheme 2). Hence,
carboxylic acids 8 and 14 were coupled to enantiomerically
pure (S)-1-methylbenzylamine and converted into the
respective diastereomeric amides 10 (Scheme 2) and 15
million relative to residual solvent (CDCl3: H 7.25 ppm, 13C 77.0
1
ppm; DMSO-d6: 1H 2.50 ppm, 13C 40.0 ppm; CD3OD: 1H 3.30 ppm,
13C 49.9 ppm). Coupling constants (J) are reported in hertz. ESI-TOF
HRMS, GC-MS analysis, MS/MS and MALDI MS spectra were
performed under the conditions previously reported.24 Reactions were
monitored by TLC (silica gel 60-F254 precoated glass plates),
visualizing the spots by a UV lamp (254 nm) and staining with
0.2% ninhydrin. Staining with 20% sulfuric acid in ethanol and charring
gave yellow-orange colored spots for all compounds containing the
4,4′-dimethoxybenzophenone hemiaminal protection. Melting points
were determined with a Kofler hot-stage apparatus and are
uncorrected. Optical rotations were measured in MeOH on a digital
polarimeter. All reactions were carried out under an inert atmosphere
(dry N2) in preflamed glassware.
Dimethoxybis(4-methoxyphenyl)methane (4). Trimethyl
orthoformate (7.19 mL, 65.7 mmol) and concentrated H2SO4 (0.01
mL) were added to a solution of 4,4′-dimethoxybenzophenone (7.07
g, 29.2 mmol) in MeOH (50 mL). The mixture was stirred for 30 h at
rt, monitoring the conversion of the starting ketone by TLC.
Triethylamine was then added until neutralization, and 4 was
recovered by filtration under vacuum. White solid (16.1 g, 85%
yield): TLC (eluent AcOEt/petroleum ether 25:75) Rf 0.37; mp 125−
1
(Scheme 5). The H and 13C NMR analysis of 10 and 15, as
obtained after the reaction workup, displayed such a few
evident differences, while spectra of each diastereomer did not
show residual resonances attributable to the other one. Thus,
lithium hydroxide used in the preparation of 8 and 14 did not
affect the configuration of the respective starting serine
material. The completely stereoselective and high-yielding
synthesis23 of the diastereomeric (E)-imines 17 and 18
(Scheme 5) supplied evidence for the total retention of
configuration observed also during the preparation of 6 and 16.
Each imine was the only product recovered from the
corresponding preparation, and no traces of the respective
diastereomer were detected by 1H NMR analysis of the
respective reaction crude. The stereochemistry of the double
bond in 17 and 18 was attributed on the basis of the chemical
shift values observed for the respective iminic protons, which
are less shielded in the E isomers and according to literature
data.23 Compound 19 was finally produced in 92% yield and
high purity. Epoxidation was totally stereoselective also in this
case, as stated by 1H and 13C NMR spectroscopy. Spectroscopic
characteristics of 19 were identical to those recorded for 2,
confirming the enantiomeric relationship of the pair of α-amino
epoxides.
In conclusion, a new strategy for the satisfying-yield synthesis
of the biologically relevant D-erythro-sphinganine (1) was
developed. The procedure was based on the preparation of
the anti-α-amino epoxide 2 which was obtained through the
totally stereoselective epoxidation of the L-serinal derivative 6
with dimethylsulfoxonium methylide. The (S,S) stereochemis-
try of 2 was that required for the realization of the 2-amino-1,3-
diol scaffold of 1 with the appropriate (2S,3R) configuration.
The procedure is appealing because workup protocols are
reduced to a minimum, no chromatography is required to
isolate each compound in excellent yields and good purity, and
the configuration of the starting serine material is totally
maintained. The strategy also showed high potential for the
preparation of L-erythro-sphinganine, which should be obtained
by simply changing the configuration of the starting serine
material.
1
127 °C; H NMR (300 MHz, CDCl3) δ 3.09 (s, 6H), 3.77 (s, 6H),
6.81 (d, 4H, J = 7.9 Hz), 7.39 (d, 4H, J = 7.9 Hz); 13C NMR (75 MHz,
CDCl3) δ 49.1, 55.2, 102.7, 113.2, 128.0, 132.2, 158.7. Anal. Calcd for
C17H20O4: C, 70.81; H, 6.99. Found: C, 70.56; H, 7.01.
Synthesis of Methyl Esters 5 and 13. A modification of the
procedure already published12 was applied. Acetal 4 (108 mg, 0.374
mmol) was added to a solution of 3 (175 mg, 0.798 mmol) and (1S)-
(+)-10-canforsulfonic acid (4.25 mg, 0.08 mmol) in toluene (30 mL),
and the resulting mixture was refluxed under magnetic stirring for 45
min. Solvent was partially removed under reduced pressure, and
another portion of 4 (108 mg, 0.374 mmol) together with fresh
solvent (20 mL) was added. After being refluxed for further 45 min,
the above operations were repeated and the mixture was refluxed for 5
h (total time). Solvent was removed under reduced pressure to give a
solid which was dissolved in Et2O (15 mL) and partitioned with a 5%
aqueous solution of NaHCO3 (15 mL). The aqueous phase was
separated and extracted with Et2O (3 × 20 mL). The organic layers
were collected, dried (Na2SO4), filtered, and evaporated to dryness
under reduced pressure conditions. The oily residue was triturated
with Et2O, and the resulting mother liquor was evaporated to dryness
under vacuum to give 5, which was used in the next step without
further purification. White foam (326 mg, 92% yield): TLC (eluent
1
AcOEt/n-hexane 30:70) Rf 0.50; H NMR (DMSO-d6, 300 MHz) δ
1.18 (br s, 9H), 3.72 (s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 3.89 (m, 1H),
4.11 (dd, 1H, J = 9.1, 7.6 Hz), 4.62 (dd, 1H, J = 7.5, 4.8 Hz), 6.92 (d,
2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 8.0 Hz),
7.42 (d, 2H, J = 8.0 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 28.8, 52.3,
55.1, 59.0, 67.3, 80.7, 98.2, 112.8, 113.7, 129.5, 130.3, 133.1, 152.7,
159.3, 171.2. Anal. Calcd for C24H29NO7: C, 65.00; H, 6.59; N, 3.16.
Found: C, 65.18; H, 6.60; N, 3.16. Compound 13 was prepared by the
same protocol starting from commercial N-Boc-D-Ser-OMe (175 mg,
0.798 mmol) and obtained as a white foam (318 mg, 90% yield). Anal.
Calcd for C24H29NO7: C, 65.00; H, 6.59; N, 3.16. Found: C, 64.89; H,
6.58; N, 3.15.
Synthesis of Carboxylic Acids 8 and 14. To a solution of 5 (326
mg, 0.734 mmol) in a THF/H2O mixture (50:50, v/v; 20 mL) was
added LiOH monohydrate (92.4 mg, 2.20 mmol). The resulting
homogeneous solution was stirred overnight at room temperature, and
the conversion of 5 was monitored by TLC. The organic solvent was
removed under reduced pressure, and the aqueous residue was
extracted once with Et2O (5 mL). The aqueous phase was made acidic
(pH 2) with solid NaHSO4, extracted with AcOEt (3 × 5 mL), dried
(Na2SO4), filtered, and evaporated to dryness under reduced pressure
conditions to give 8. White foam (315 mg, quantitative yield): TLC
EXPERIMENTAL SECTION
General Experimental. All reagents were used without further
purification. All solvents were purified and dried according to standard
■
D
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(eluent AcOEt/n-hexane 50:50, with 5 drops of glacial acetic acid) Rf
0.33; 1H NMR (DMSO-d6) δ 1.18 (br s, 9H), 3.78 (s, 6H), 3.83 (dd,
1H, J = 9.0, 5.2 Hz), 4.10 (dd, 1H, J = 9.0, 7.6 Hz), 4.49 (dd, 1H, J =
7.6, 5.2 Hz), 6.88 (d, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.0 Hz), 7.18 (d,
2H, J = 8.0 Hz), 7.41 (d, 2H, J = 8.0 Hz), 12.4 (br s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 28.3, 55.6, 61.0, 67.9, 79.5, 98.1, 112.8, 113.7,
129.5, 130.9, 133.2, 152.3, 159.2, 173.0. Anal. Calcd for C23H27NO7:
C, 64.32; H, 6.34; N, 3.26. Found: C, 64.39; H, 6.33; N, 3.26.
A similar procedure was used to obtain 14 from 13 (300 mg, 0.676
mmol). The product was isolated as a white foam (290 mg,
quantitative yield). Anal. Calcd for C23H27NO7: C, 64.32; H, 6.34;
N, 3.26. Found: C, 64.28; H, 6.35; N, 3.25.
Synthesis of Weinreb Amide 9. To a solution of 8 (278 mg,
0.647 mmol) in DCM (8 mL) were added HOBt monohydrate (198
mg, 1.29 mmol), EDC hydrochloride (247 mg, 1.29 mmol), and DIEA
(0.49 mL, 2.59 mmol). The resulting mixture was stirred for 2 h at rt.
A solution of N,O-dimethylhydroxylamine hydrochloride (78.9 mg,
0.809 mmol) and DIEA (0.49 mL, 2.59 mmol) in DCM (8 mL) was
added dropwise. The resulting mixture was stirred overnight at rt, and
the conversion of 8 was monitored by TLC. The solvent was
evaporated under reduced pressure, and the oily residue was dissolved
in AcOEt (6 mL). The organic phase was washed with 5% aqueous
NaHSO4 (3 × 5 mL), 5% aqueous NaHCO3 (3 × 5 mL), and once
with brine (5 mL), dried (Na2SO4), filtered, and evaporated to dryness
under reduced pressure conditions to give 9. Pale yellow viscous oil
(293 mg, 96% yield): TLC (eluent AcOEt/n-hexane 50:50) Rf 0.59;
1H NMR (DMSO-d6, 300 MHz) δ 1.18 (br s, 9H), 3.15 (s, 3H), 3.73
(s, 3H), 3.75 (m, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 4.15 (dd, 1H, J =
9.1, 7.9 Hz), 4.98 (dd, 1H, J = 7.0, 5.6 Hz), 6.88 (d, 2H, J = 8.0 Hz),
6.90 (d, 2H, J = 8.0 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0
Hz); 13C NMR (DMSO-d6, 75 MHz) δ 28.0, 32.4, 55.5, 55.6, 57.3,
61.8, 66.4, 79.8, 98.1, 112.8, 113.3, 129.6, 130.8, 133.2, 151.7, 152.2,
159.3. Anal. Calcd for C25H32N2O7: C, 63.54; H, 6.83; N, 5.93. Found:
C, 63.51; H, 6.81; N, 5.94.
The same procedure was used to prepare the (R) enantiomer of 9
starting from 14 (278 mg, 0.647 mmol). Pale yellow viscous oil (287
mg, 94% yield). Anal. Calcd for C25H32N2O7: C, 63.54; H, 6.83; N,
5.93. Found: C, 63.59; H, 6.85; N, 5.92.
= 9.0, 7.7 Hz), 4.48 (m, 1H), 6.84 (d, 2H, J = 8.0 Hz), 6.86 (d, 2H, J =
8.0 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 9.71 (d,
1H, J = 2.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 27.8, 55.0, 63.8, 65.0,
81.2, 91.7, 98.2, 112.6, 112.7, 128.9, 129.1, 132.5, 132.6, 159.6, 159.7,
199.1. Anal. Calcd for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found:
C, 66.78; H, 6.60; N, 3.39.
The same protocol was used to prepare serinal 16 from the (R)
enantiomer of 9 (500 mg, 1.06 mmol).
16: Pale yellow viscous oil (395 mg, 90% yield). Anal. Calcd for
C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 67.01; H, 6.59; N,
3.38.
Synthesis of Amides 10 and 15. To a solution of the appropriate
carboxylic acid 8 or 14 (180 mg, 0.419 mmol) in DCM (5 mL) were
added HOBt monohydrate (128 mg, 0.838 mmol), EDC hydro-
chloride (161 mg, 0.838 mmol), and DIEA (0.152 mL, 1.68 mmol).
The resulting mixture was stirred at room temperature for 2 h before
(S)-(−)-1-α-methylbenzylamine (0.07 mL, 0.524 mmol) was added.
After being stirred at room temperature overnight, the solvent was
evaporated under reduced pressure to give a solid residue which was
dissolved in AcOEt (10 mL). The organic phase was washed with 5%
aqueous NaHSO4 (3 × 5 mL), 5% aqueous NaHCO3 (3 × 5 mL), and
once with brine (5 mL), then dried (Na2SO4), filtered, and evaporated
to dryness under reduced pressure conditions to afford the respective
amide 10 or 15.
10: Pale yellow viscous oil (210 mg, 94% yield); TLC (eluent
1
AcOEt/n-hexane 40:60) Rf 0.29; H NMR (DMSO-d6, 300 MHz) δ
1.15 (s, 9H), 1.40 (d, 3H, J = 7.0 Hz), 3.81 (s, 3H), 3.83 (s, 3H),
4.09−4.21 (m, 2H), 4.61 (m, 1H), 5.11 (quintet, 1H, J = 7.0 Hz),
6.81−6.92 (m, 4H), 7.12 (d, 2H, J = 8.0 Hz), 7.20−7.33 (m. 5H), 7.41
(d, 2H, J = 8.0 Hz), 7.52 (d, 1H, J = 7.0 Hz); 13C NMR (DMSO-d6, 75
MHz) δ 22.0, 28.0, 48.8, 55.2, 61.7, 66.5, 81.5, 98.6, 112.8, 112.9,
125.9, 127.1, 128.5, 129.1, 129.8, 133.2, 142.9, 153.0, 159.5, 159.6,
169.1. Anal. Calcd for C31H36N2O6: C, 69.90; H, 6.81; N, 5.26. Found:
C, 69.83; H, 6.80; N, 5.26.
15: Pale yellow viscous oil (205 mg, 92% yield); TLC (eluent
1
AcOEt/n-hexane 40:60) Rf 0.28; H NMR (DMSO-d6, 300 MHz) δ
1.11 (s, 9H), 1.40 (d, 3H, J = 6.9 Hz), 3.78 (s, 3H), 3.79 (s, 3H), 3.82
(dd, 1H, J = 9.0, 5.6 Hz), 4.08 (dd, 2H, J = 9.0, 7.7 Hz), 4.64 (dd, 1H,
J = 7.7, 5.6 Hz), 4.99 (quintet, 1H, J = 6.9 Hz), 6.85 (d, 2H, J = 7.9
Hz), 6.91 (d, 2H, J = 7.9 Hz), 7.18 (d, 2H, J = 7.9 Hz), 7.20−7.36 (m,
5H), 7.50 (d, 2H, J = 7.9 Hz), 7.89 (d, 1H, J = 6.9); 13C NMR
(DMSO-d6, 75 MHz) δ 22.9, 28.1, 48.4, 55.5, 55.6, 61.4, 67.2, 79.8,
98.3, 113.1, 113.6, 126.5, 127.0, 128.3, 129.4, 130.5, 133.2, 144.2,
152.1, 159.4, 159.5, 168.9. Anal. Calcd for C31H36N2O6: C, 69.90; H,
6.81; N, 5.26. Found: C, 70.05; H, 6.79; N, 5.27.
Synthesis of Imines 17 and 18. A modification of the previously
reported procedure was used.21 The appropriate serinal 6 or 16 (250
mg, 0.605 mmol) was added to a suspension of L-valine methyl ester
hydrochloride (117 mg, 0.696 mmol) in DCM (10 mL) containing
DIEA (0.076 mL, 1.39 mmol) and anhydrous Na2SO4 (25.8 mg, 0.182
mmol). The mixture was stirred at room temperature for 10 min
before titanium(IV) isopropoxide (0.358 mL, 1.21 mmol) was added.
Magnetic stirring at room temperature was maintained until TLC
analysis of the reaction mixture indicated the complete conversion of
the starting serinal material. After paper filtration, the solvent was
removed under vacuum and the residue was suspended in AcOEt (10
mL). The white precipitate formed was filtered on a short pad of
Celite, and the mother liquor was washed once with 5% aqueous
NaHCO3 (10 mL). The organic phase was rapidly washed once with
5% aqueous NaHSO4 (10 mL) and once with brine (10 mL), dried
(Na2SO4), filtered, and evaporated to dryness under reduced pressure
conditions to give the respective (E)-imine 18 or 17.
Synthesis of Serinals 6 and 16 and Serinol 7. Reduction with
DIBALH. A commercial 1.0 M solution in DCM of diisobutylaluminum
hydride (DIBALH; 2.20 mL, 2.20 mmol) was added dropwise to a
solution of 5 (280 mg, 0.631 mmol) in DCM (10 mL) at −78 °C. The
resulting mixture was stirred for 15 min, then quenched with water (10
mL) and stirred vigorously for further 10 min. After filtration through
a short pad of Celite with DCM, the organic phase was separated,
washed once with brine (10 mL), dried (Na2SO4), filtered, and
evaporated to dryness under reduced pressure conditions. Short
column flash chromatography of the residue (AcOEt/n-hexane 40:60,
with the polar component reduced to 1/4) gave 6 (70.4 mg, 27%
yield) and 7 (178 mg, 68% yield).
7: Pale yellow viscous oil; TLC (eluent AcOEt/n-hexane 40:60) Rf
1
0.31; H NMR (CDCl3, 300 MHz) δ 1.10 (br s, 9H), 3.49 (m, 1H),
3.65 (m, 1H), 3.77 (s, 3H), 3.78−3.86 (m, 2H), 3.83 (s, 3H), 4.08
(dd, 1H, J = 8.8, 7.1 Hz), 4.50 (br s, 1H), 6.80 (d, 2H, J = 8.0 Hz),
6.86 (d, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.0
Hz); 13C NMR (CDCl3, 75 MHz) δ 28.0, 55.2, 55.3, 60.3, 65.5, 65.7,
81.3, 98.7, 112.9, 113.0, 129.5, 129.6, 132.5, 134.9, 155.0, 159.2. Anal.
Calcd for C23H29NO6: C, 66.49; H, 7.04; N, 3.37. Found: C, 66.51; H,
7.06; N, 3.36.
Reduction with LiAlH4. A solution of 9 (500 mg, 1.06 mmol) in
THF (5 mL) was treated with LiAlH4 (141 mg, 3.71 mmol) under
magnetic stirring at rt. The reaction was monitored by TLC. After 12
min, the conversion of 9 was complete and 5% aqueous NaHCO3 (5
mL) was slowly added to the mixture. The solvent was removed under
reduced pressure, and the aqueous residue was extracted with AcOEt
(3 × 5 mL). The organic phase was washed once with brine (5 mL),
dried (Na2SO4), filtered, and evaporated to dryness under vacuum to
afford 6. Pale yellow viscous oil (408 mg, 93% yield): TLC (eluent
AcOEt/n-hexane 40:60) Rf 0.64; 1H NMR (CDCl3, 300 MHz) δ 1.21
(br s, 9H), 3.79 (s, 6H), 3.96 (dd, 1H, J = 9.0, 5.5 Hz), 4.14 (dd, 1H, J
18: Pale yellow viscous oil (283 mg, 89% yield); TLC (eluent
AcOEt/n-hexane 40:60) Rf 0.74; 1H NMR (CDCl3, 300 MHz) δ 0.82
(d, 3H, J = 6.7 Hz), 0.88 (d, 3H, J = 6.7 Hz), 1.18 (br s, 9H), 2.10
(octet, 1H, J = 6.7 Hz), 3.31 (d, 1H, J = 6.1 Hz), 3.72 (s, 3H), 3.80 (s,
3H), 3.81 (s, 3H), 3.91 (dd, 1H, J = 9.5, 7.0 Hz), 4.11 (dd, 1H, J = 9.5,
4.1 Hz), 4.61 (m, 1H), 6.79−6.90 (m, 4H), 7.18 (d, 2H, J = 7.8 Hz),
7.38 (d, 2H, J = 7.8 Hz), 7.66 (d, 1H, J = 2.8 Hz); 13C NMR (CDCl3,
75 MHz) δ 18.4, 19.3, 28.0, 34.5, 51.8, 51.9, 55.3, 59.9, 60.3, 65.9, 79.6,
E
dx.doi.org/10.1021/jo500493c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
98.3, 112.8, 112.9, 129.5, 129.7, 133.2, 152.6, 159.5, 167.8, 172.2. Anal.
Calcd for C29H38N2O7: C, 66.14; H, 7.27; N, 5.32. Found: C, 66.21;
H, 7.29; N, 5.31.
to dryness under reduced pressure conditions. The residue obtained
was dissolved in AcOEt (1 mL) and triturated with cold pentane. The
precipitate was separated from the mother liquor, washed rapidly with
cold pentane, dried, and directly analyzed by H NMR. The structure
of 12 was confirmed by MS experiments. The obtained compound was
used for the next treatment without further purification.
1
17: Pale yellow viscous oil (271 mg, 85% yield); TLC (eluent
AcOEt/n-hexane 40:60) Rf 0.72; NMR (CDCl3, 300 MHz) δ 0.82 (d,
3H, J = 6.8 Hz), 0.88 (d, 3H, J = 6.8 Hz), 1.19 (br s, 9H), 2.24 (octet,
1H, J = 6.8 Hz), 3.53 (d, 1H, J = 6.8 Hz), 3.71 (s, 3H), 3.80 (s, 3H),
3.81 (s, 3H), 3.94−4.06 (m, 1H), 4.07−4.18 (m, 1H), 4.76 (m, 1H),
6.80−6.89 (m, 4H), 7.20 (d, 2H, J = 7.9 Hz), 7.38 (d, 2H, J = 7.9 Hz),
7.77 (d, 1H, J = 2.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 18.4, 19.3,
28.0, 31.5, 51.9, 55.2, 60.7, 66.8, 67.7, 79.6, 98.3, 112.9, 129.5, 129.7,
133.2, 152.6, 159.5, 167.0, 172.0. Anal. Calcd for C29H38N2O7: C,
66.14; H, 7.27; N, 5.32. Found: C, 66.02; H, 7.28; N, 5.31.
Epoxidation of Serinals 6 and 16. Synthesis of α-Amino
Epoxides 2, 11, and 19. Method A. Trimethylsulfonium iodide (123
mg, 0.605 mmol) was added to a suspension of NaH (15.2 mg, 0.635
mmol) in THF (10 mL), and the resulting mixture was stirred at 0 °C
for 10 min, then at rt for 45 min until complete formation of the
ylide.15 A solution of 6 (250 mg, 0.605 mmol) in THF (10 mL) was
added dropwise, and the mixture was stirred at rt for 6 h, monitoring
the conversion of 6 by TLC. The mixture was quenched with 5%
aqueous NaHCO3 (10 mL), and the organic solvent was removed
under vacuum to give an aqueous residue which was diluted with brine
(5 mL) and then extracted with AcOEt (3 × 10 mL). The organic
layers were collected, dried (Na2SO4), filtered, and evaporated to
dryness under reduced pressure conditions to afford a crude material
which was directly analyzed by 1H NMR. Spectroscopy confirmed the
formation of an equimolar mixture of 2 and 11 (246 mg, 95% crude
yield): TLC (eluent AcOEt/n-hexane 30:70), unique spot, Rf 0.72; 1H
NMR (300 MHz, CDCl3), only resonances of the oxirane protons are
reported, as obtained from the spectrum recorded for the crude
mixture of 2 and 11, δ 2.61 (dd, 1H, J = 8.9, 4.0 Hz), 2.74 (t, 1H, J =
8.9 Hz), 3.34 (ddd, 1H, J = 4.7, 4.6, 2.0 Hz).
12 (crude): TLC (eluent AcOEt/n-hexane 30:70) Rf 0.81; ESI-TOF
+
HRMS calcd for C38H60NO6 626.4415, found 626.4443.
A slight modification of a previously reported acidolysis procedure20
was applied to globally deprotect 12. The crude product isolated from
the above treatment was dissolved in DCM (2 mL) and CH3OH (0.5
mL). A 60% aqueous solution of perchloric acid (0.1 mL) was added,
and the reaction mixture was stirred at room temperature for 5 min.
Solid Na2CO3 was then added portionwise until pH 10. The
suspension was filtered through a short pad of Celite (MeOH as
eluent), and the mother liquor was evaporated to dryness under
reduced pressure conditions. The residue was dissolved in the minimal
amount of a 1:2 mixture of CH3OH/methyl-tert-butyl ether and
triturated with cold pentane. The precipitate was collected by filtration,
washed rapidly once with cold pentane, and dried under vacuum to
give D-erythro-sphinganine 1.
1: White powder (79.2 mg, 92% yield, referred to the initial amount
of 2; 68% overall yield, referred to the initial amount of 3); TLC
(eluent AcOEt/n-hexane 30:70) Rf 0.80; mp 82−84 °C, [α]D 7.9, c 1.0,
CH3OH), lit.21 [α]D 8.1, c 1.0, CH3OH); H NMR (CD3OD, 300
1
MHz) δ 0.89 (t, 3H, J = 7.0), 1.24−1.46 (m, 26H), 1.52 (m, 2H), 2.70
(ddd, 1H, J = 7.6, 5.4, 4.1 Hz), 3.46 (dd, 1H, J = 10.8, 7.6 Hz), 3.42−
3.55 (m, 1H), 3.71 (dd, 1H, J = 10.8, 4.1 Hz), 13C NMR (CD3OD, 75
MHz) δ 14.4, 23.7, 27.0, 30.1, 33.1, 34.4, 58.2, 64.4, 74.1; MALDI-MS
+
calcd for C18H40NO2 302.3054, found 302.3068. Anal. Calcd for
C18H39NO2: C, 71.70; H, 13.04; N, 4.65. Found: C, 71.83; H, 13.08;
N, 4.64.
ASSOCIATED CONTENT
Method B. Trimethylsulfoxonium iodide (133 mg, 0.605 mmol)
was added to a stirred suspension of NaH (15.2 mg, 0.635 mmol) in
THF (10 mL) at 0 °C. After 10 min, the mixture was refluxed for 2 h,
until complete formation of the ylide.15 After being cooled at rt, a
solution of the appropriate serinal 6 or 16 (250 mg, 0.605 mmol) in
THF (10 mL) was then added dropwise, and the mixture was stirred at
rt for further 12 h, monitoring the conversion of the aldehyde by TLC.
The mixture was quenched with 5% aqueous NaHCO3 (10 mL), and
the organic solvent was removed under vacuum. The aqueous residue
was diluted with brine (5 mL) and then extracted with AcOEt (3 × 10
mL). The organic layers were collected, dried (Na2SO4), filtered, and
evaporated to dryness under reduced pressure conditions to afford the
respective α-amino epoxide 2 or 19.
2: Pale yellow viscous oil (233 mg, 90% yield); TLC (eluent
AcOEt/n-hexane 30:70) Rf 0.72; 1H NMR (CDCl3, 300 MHz) δ 1.19
(s, 9H), 2.79 (dd, 1H, J = 9.1, 2.6 Hz), 2.88 (dd, 1H, J = 9.1, 4.0 Hz),
3.12 (ddd, 1H, J = 6.9, 4.0, 2.6 Hz), 3.76- 3.85 (m, 1H), 3.79 (s, 3H),
3.81 (s, 3H), 3.87 (m, 1H), 4.03 (dd, 1H, J = 6.9, 3.2 Hz), 6.81 (s, 2H,
J = 8.0 Hz), 6.86 (s, 2H, J = 8.0 Hz), 7.15 (m, 2H, J = 8.0 Hz), 7.41 (d,
2H, J = 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 28.0, 48.5, 52.6, 55.3,
59.4, 66.0, 80.6, 98.5, 112.9, 129.5, 129.8, 133.3, 133.5, 152.7, 159.4.
Anal. Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C,
67.38; H, 6.86; N, 3.27.
■
S
* Supporting Information
1
Copy of H and 13C NMR spectra for compounds 1, 2, 4−10,
15, 17−19. Copy of 1H NMR spectrum of the crude mixture of
2 and 11. Copy of 13C DEPT135 NMR spectrum of 7. Copy of
1H NMR and ESI-TOF HRMS and MS/MS spectra of 12
(crude). Copy of MALDI-MS and MS/MS spectra of 1. Copy
of GC-MS analysis of 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: carlo.siciliano@unical.it. Phone: +39 (0)984-493192.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by grants from MIUR (Ministero
■
dell’Istruzione, dell’Universita
Prof. Anna Napoli of the Dipartimento di Chimica e
Tecnologie Chimiche (CTC), Universita della Calabria
̀
e della Ricerca, ex-60% funds).
19: Pale yellow viscous oil (236 mg, 91% yield). Anal. Calcd for
C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.51; H, 6.82; N,
3.29.
̀
(Italy), is gratefully acknowledged for mass spectrometric
analyses.
Oxirane Ring Opening with Tetradecylmagnesium Bromide.
Preparation of D-erythro-Sphinganine [(2S,3R)-2-aminoocta-
decane-1,3-diol] (1). To a solution of tetradecylmagnesium bromide,
prepared from commercial tetradecyl bromide (159 mg, 0.154 mL,
0.562 mmol) and magnesium turnings (13.7 mg, 0.562 mmol) in Et2O
(5 mL), was added dropwise a solution of 2 (120 mg, 0.281 mmol) in
Et2O (5 mL). The resulting mixture was kept under magnetic stirring
at 0 °C for 15 min, then warmed to room temperature and stirred for
further 6 h. Saturated aqueous NH4Cl (5 mL) and brine (5 mL) were
added, and the mixture was extracted with Et2O (3 × 10 mL). The
organic layers were collected, dried (Na2SO4), filtered, and evaporated
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