A general and concise asymmetric synthesis of sphingosine, safingol and phytosphingosines via tethered aminohydroxylation

Article abstract of DOI:10.1039/c0ob00117a

A novel, practical and efficient enantioselective synthesis of sphingoid bases, l-threo-[2S,3S]-sphinganine (safingol), l-threo-[2S,3S]-sphingosine, l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C₁₈-phytosphingosine is described. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation (TA) as the key steps.

Full text of DOI:10.1039/c0ob00117a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A general and concise asymmetric synthesis of sphingosine, safingol and
phytosphingosines via tethered aminohydroxylation†
Pradeep Kumar,*a Abhishek Dubeya and Vedavati G. Puranikb
Received 13th May 2010, Accepted 21st July 2010
DOI: 10.1039/c0ob00117a
A novel, practical and efficient enantioselective synthesis of sphingoid bases,
L-threo-[2S,3S]-sphinganine (safingol), L-threo-[2S,3S]-sphingosine, L-arabino-[2R,3S,4R] and
L-xylo-[2R,3S,4S]-C18-phytosphingosine is described. The synthetic strategy features the Sharpless
kinetic resolution and tethered aminohydroxylation (TA) as the key steps.
goid base structures12 are known, the most abundant sphingoid
Introduction
base in nature is D-erythro-C18-sphingosine, i.e. (2S,3R,4E)-2-
Sphingolipids are structurally diverse constituents of membranes
aminooctadec-4-ene-1,3-diol. Phytosphingosine exists in nature as
in mammals, plants, fungi, yeast and in some prokaryotic organ-
one of the molecular species of sphingolipids in microorganisms,
isms and viruses.1 Sphingolipids and some of their metabolites
plants and many mammalian tissues such as brain, hair, intestine,13
exhibit essentially all types of cell regulation such as cell prolifera-
uterus,14 liver,15 skin,16 kidney,17 and in blood plasma18 (Fig. 1).
tion, differentiation, immune response, cell recognition, apoptosis,
Phytosphingosine is a potential heat stress signal in yeast cells19a,b
adhesion and signal transduction.2 Studies have shown that defects
and some of its derivatives exhibit important physiological activity.
in sphingolipid metabolism lead to several inherited and most
a- and b-galactosyl and glucosylphytoceramides are highly potent
common human diseases, including diabetes,3 cancers,4 infection
against tumors.19c Natural sphingoid bases occur in the D-erythro-
by microorganisms,5 Alzheimer’s disease,6 heart disease and an
(2S,3R) configuration, but three additional unnatural isomers
array of neurological syndromes.7
have also been reported.20 Among the unnatural sphingoid bases,
In recent times, there has been a tremendous upsurge of
L-threo-(2S,3S)-dihydrosphingosine (safingol) is of particular in-
interest in the synthesis of structurally modified sphingosines
terest due to its medicinal importance. Safingol is an antineo-
and phytosphingosines, as some of their analogues have been
plastic, antipsoriatic drug21 and an inhibitor of protein kinase C
shown to bring morphological changes in neuronal cells8 and
(PKC)22 andis knowntoactsynergistically withanticancer drugs.23
behave as enzyme inhibitors.9 The most important sphingolipids
Structurally, sphingolipids24 are formed from two different
are sphingosine and phytosphingosine (Fig. 1).
units: a polar head group (carbohydrates) and a ceramide. The
Sphingosines10 are known inhibitors of protein kinase C11
ceramide moiety consists of a sphingoid base (amino alcohol)
and they are the backbone of glycosphingolipids and phospho-
sphingolipids. Although a number of structurally related sphin-
linked through an amide bond to a fatty acyl chain. These
have long-chain bases as the backbone, i.e. sphingosine (1),
phytosphingosine (3) and the biosynthetic precursor of both,
aDivision of Organic Chemistry, National Chemical Laboratory, Pune
sphinganine (2) (Fig. 1) which are most abundant long-chain
411008, India. E-mail: pk.tripathi@ncl.res.in; Fax: +91–20–25902050;
amino alcohols with generally 18 or 20 carbon atoms.
Tel: +91–20–25902629
Due to their wide variety of biological activities, and unique
structure with an array of functionalities, sphingolipids have been
targets of synthetic interest, and therefore a great deal of effort
has been devoted towards their synthesis.25 Most synthetic studies
have been focused either starting from the chiral pool materi-
als, particularly serine26 and carbohydrate,27 or by asymmetric
bCenter for Materials Characterization, National Chemical Laboratory,
Pune 411008, India
† Electronic supplementary information (ESI) available: 1H NMR, 13C
NMR spectra of compounds 16, 18, 19, 20, 9, 23, 25, 26, 28, 10, 33–39,
12, X-ray crystallographic data, and the ORTEP diagram for compounds
27. CCDC reference number 773906. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob00117a
Fig. 1
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synthesis.28 Asymmetric syntheses reported mainly involve the use
of chiral auxiliaries, such as sulfoxides,29 chiral aziridines,30 chiral
sulfur31 and nitrogen32 ylides. The asymmetric catalytic procedures
employ Sharpless asymmetric epoxidation33 and dihydroxylation
reactions.34,35 Also, the aldol reaction36 and organocatalytic pro-
cedures have also been described.37 Although several procedures
for the target compound have been reported,38–41 most of these
methods suffer either from a large number of steps, low yields or
from low stereo- or regioselectivity. Therefore, a practical, concise
expeditious and high yield synthesis of these target molecules is
highly desirable. A literature search revealed that there has been no
synthesis of these compounds using tethered aminohydroxylation
(TA) as a source to generate both the amino and hydroxyl
functionality. The tethered aminohydroxylation42 has recently
emerged as a powerful method of preparing vicinal amino alcohols
in a regio- and stereoselective manner. This method overcomes
the problem of low regioselectivity mainly encountered during the
asymmetric aminohydroxylation (AA)43 of unsymmetrical olefins,
a recent discovery of Sharpless to introduce amine and alcohol
functionality in a single step in an enantio- and stereoselective way.
Donohoe et al. have extended the scope of the AA reaction and
solved the problem of regioselectivity by tethering the nitrogen
source (typically a carbamate unit) to an allylic alcohol, thus
constituting a tethered aminohydroxylation (TA). A variety of
TA protocols were developed to improve the yield and efficacy
of the reaction. Initially, allylic carbamates were oxidised with
t-BuOCl using the Sharpless original AA reaction conditions
(TA protocol A, hereafter).42a–d However, it was observed that the
chlorination of the alkene unit was a competing side reaction
responsible for lowering the yield of the product. Subsequent
replacement of N-halocarbamate salt by the N-mesitylsulfonyloxy
derivatives (N–Cl → N–O–SO2Mes) (TA protocol B)42e proved
capricious and substrate specific. A recent modification of the TA
protocol by Donohoe et al. relies on the acyl-based leaving group,
in which the hydroxycarbamate derived from an allylic alcohol is
treated with different acid chlorides to yield the corresponding O-
derivatized hydroxyl carbamates which were subjected to the new
TA conditions (TA protocol C, hereafter).42f
As a part of our research interest in the asymmetric synthesis
of bioactive molecules such as lactones44 and amino alcohols45a–d
including sphingolipids,45e–j we became interested in developing
a new and highly concise route to sphingoid bases. Herein,
we report a general and efficient synthesis of L-threo-[2S,3S]-
sphinganine, L-threo-[2S,3S]-sphingosine, L-arabino-[2R,3S,4R]
and L-xylo-[2R,3S,4S]-C18-phytosphingosine employing Sharpless
kinetic resolution and tethered aminohydroxylation as the key
steps.
Synthetic plan
Our retrosynthetic analysis is outlined in Scheme 1.
Our synthetic approach for the synthesis of sphingoid bases
was envisioned through the retrosynthetic analysis as shown in
Scheme 1. We visualized compound 8 as an important precursor
from which all the target sphingoid bases (9–12) could be
constructed. The amino stereocenter in 8 could be introduced
by tethered aminohydroxylation, which in turn would be obtained
from carbamate 7. The carbamate 7 could be prepared from an
allylic alcohol 6 which in turn would be derived from the Sharpless
kinetic resolution. In this strategy, the amino center could be
installed using tethered aminohydroxylation in a highly regio- and
stereoselective manner while the hydroxyl centre would be derived
from Sharpless kinetic resolution.
Results and discussion
Synthesis of L-threo-sphinganine (Scheme 2)
The synthesis of L-threo-[2S,3S]-sphinganine (safingol) started
from commercially available hexadecanol 13. Compound 13 was
oxidized using DMSO–pivaloyl chloride46 to give the aldehyde
14, which on Grignard reaction with vinyl magnesium bromide
furnished the allylic alcohol 15 in 82% yield. The treatment of
15 with titanium tetraisopropoxide and tert-butylhydroperoxide
in the presence of (-)-DIPT under Sharpless asymmetric kinetic
resolution conditions47 provided the epoxy alcohol 17 and chiral
allylic alcohol 16 in 47% yield and 97% ee (determined from the
Scheme 1 Retrosynthetic route to various sphingoid bases.
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Scheme 2 Reagents and conditions: (a) [i] pivaloyl chloride, DMSO, Et3N, -78 ◦C; [ii] vinyl bromide, Mg, 0 ◦C, 2 h, 82% yield of two steps; (b)
(-)-DIPT, Ti(O- Pr)4, TBHP, dry CH2Cl2, molecular sieves, 3 A, -20 ◦C, 4 d, 47% for 16 and 48% for 17; (c) CDI, then NH2OH·HCl, pyridine, rt, 85%;
i
˚
(d) 2,4,6-trichlorobenzoyl chloride, Et3N, Et2O, 0 ◦C, 85%; (e) potassium osmate t-BuOH : H2O, 20 min, 75%; (f) [i] K2CO3, MeOH, rt, 6 h; [ii] Boc2O,
dioxane, 72%.
1H NMR of the corresponding Mosher’s ester). For introduction
of the amino functionality, we then applied the new modified
tethered aminohydroxylation procedure (TA protocol C).42e Thus,
the alcohol 16 was reacted with CDI in pyridine, followed by the
addition of hydroxylamine hydrochloride to afford the hydroxy
carbamate 18 in excellent yield. The resulting hydroxycarbamate
18 was then treated with pentafluorobenzoyl chloride in ether
to yield the pentafluorobenzoyl O-derivatized hydroxycarbamate,
which was found to decompose during the reaction and purifi-
cation on column chromatography. We then decided to explore
yet another reagent, trichlorobenzoyl chloride, for tethering the
substrate 18. To our delight the reaction proceeded smoothly
to furnish the trichlorobenzoyl O-derivatized hydroxycarbamates
19 in 85% yield. The trichlorobenzoyl O-derivatized hydroxy-
carbamates 19 were subjected to TA reaction to furnish the
protected aminoalcohol 20 in 75% yield with complete regio-
and excellent diastereoselectivity (syn : anti 15 : 1, determined from
1H NMR). The diastereomeric mixture could easily be separated
by column chromatography, which on hydrolysis with K2CO3
in methanol afforded the crude aminoalcohol. Subsequent Boc
protection using Boc2O in the presence of dioxane furnished
the enantiomerically pure N-Boc-L-threo-sphinganine 938b in 72%
yield. The overall yield of the target compound 9 was found to be
15% from seven steps. Our synthesis of 9 proved to be efficient in
comparison with a literature report38g of its synthesis in 10 steps
in overall ~4% yield.
The treatment of 22 with titanium tetraisopropoxide and tert-
butylhydroperoxide in the presence of (-)-DIPT under Sharpless
asymmetric kinetic resolution conditions provided the epoxy
alcohol 24 and chiral allylic alcohol 23 in 45% yield and 96%
ee (determined from the 1H NMR of the corresponding Mosher’s
ester). Then we used trichloroacetyl isocyanate reagent for tethered
aminohydroxylation (TA protocol A).42a
Alcohol 23 was then reacted with trichloroacetyl isocyanate in
CH2Cl2 to give the corresponding isocyanate, which on treatment
with aq. K2CO3 and methanol furnished the carbamate 25 in
85% yield. The carbamate was converted into the oxazolidinone
derivative 26 by a tethered aminohydroxylation protocol42a using
tert-butylhypochlorite as the oxidant, potassium osmate, NaOH,
iPr2EtN and propanol as the solvent. The reaction proceeded
smoothly to furnish the protected aminoalcohol 26 in 65% yield
with complete regio- and good diastereoselectivity (syn : anti 13 : 1,
1
determined from H NMR). The diastereomeric mixture could
easily be separated by column chromatography. The desired syn-
diastereomer was subjected to hydrolysis with K2CO3 in methanol
to furnish the crude aminoalcohol 27. Subsequent Boc protection
using Boc2O in the presence of dioxane gave the Boc protected
28 in 82% yield, which was finally converted to the crystalline,
enantiomerically pure N-Boc-L-threo-sphingosine 1026a in 65%
yield by selective reduction of the C–C bond with Red-Al in
Et2O, followed by its subsequent conversion into N-Boc-L-threo-
sphinganine 9 in 85% yield by reduction of the double bond
under Pd(OH)2/H2 conditions. The overall yield of the target
compound 10 was found to be 14% from seven steps. Our synthesis
of 10 proved to be efficient in comparison with literature reports
(Kitagawa et al.,40l 7 steps, 12% yield; Griengl et al.40f 14 steps,
12% yield; Hudlicky et al.40h 10 steps, 9% yield).
Synthesis of N-Boc-L-threo-sphingosine (Scheme 3)
The synthesis of L-threo-sphingosine (Scheme 3) started from
commercially available pentadec-1-yne 21. Treatment of 21 with
n-BuLi in THF at -78 ◦C followed by addition of freshly
distilled acrolein furnished the allylic alcohol 22 in 70% yield.
The relative stereochemistry of the TA product was confirmed
by single crystal X-ray crystallography of compound 27 (Fig. 2),
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Scheme 3 Rea◦gents and conditions: (a) n-BuLi, freshly distilled acrolein, THF, -78 ◦C, 2 h, 70%; (b) (-)-DIPT, Ti(O-iPr)4, TBHP, dry CH2Cl2, molecular
i
˚
sieves, 3 A, -20 C, 3 d, 45% for 23 and 49% for 24; (c) Cl3CCONCO, K2CO3, CH2Cl2–CH3OH (1.5 : 1), 4 h, 85%; (d) NaOH, t-BuOCl, Pr2EtN, potassium
osmate, propanol, 2.5 h, 65%; (e) K2CO3, MeOH, rt, 6 h; (f) Boc2O, dioxane, 82%; (g) Red-A1/Et2O, 0 ◦C–r.t. 65%; (h) H2/Pd, EtOAc, 85%.
Fig. 2 ORTEP diagram of 27.
which shows that the amino and alcohol functional groups are syn
to each other.
The required erythro-isomer 34 could easily be separated by col-
umn chromatography in 90% yield. Epoxide 34 was treated with ex-
cess dimethylsulfonium methylide48 (generated from trimethylsul-
fonium iodide and n-BuLi) to furnish the allylic alcohol 35 in 75%
yield. Alcohol 35 was then reacted with trichloroacetyl isocyanate
in the presence of CH2Cl2 to give the corresponding isocyanate,
which on treatment with aq. K2CO3 and methanol furnished the
carbamate 36 in 90% yield. The carbamate was converted into
the oxazolidinone derivative 37 by a tethered aminohydroxylation
protocol using tert-butyl hypochlorite as the oxidant, potassium
osmate, NaOH, iPr2EtN and propanol as the solvent (TA protocol
A). The reaction proceeded smoothly to furnish the protected
aminoalcohol 37 in 66% yield with complete regio- and excellent
diastereoselectivity (syn : anti 12 : 1, determined from H NMR).
The diastereomeric mixture could easily be separated by column
chromatography.
The key step in the TA as depicted in Fig. 3 is the intramolecular
addition of the RN Os O fragment across the alkene leading
to syn or anti relative stereochemistry. Generally the 1,3-allylic
interaction plays a major role in determining the stereoselective
outcome of the reaction. Between the two possible conforma-
tions, A and B of tethered [3 + 2] cycloaddition, the 1,3-allylic
Synthesis of L-arabino-[2R,3S,4R]-C18-phytosphingosine and
L-xylo-[2R,3S,4S]-C18-phytosphingosine (Scheme 4)
The tethered aminohydroxylation route was then further extended
to the synthesis of a few selected isomers of phytosphingosine.
As depicted in Scheme 4, the synthesis of L-arabino-[2R,3S,4R]-
C18-phytosphingosine started from commercially available pen-
tadecanol 29. Subsequent oxidation of alcohol 29 using DMSO–
pivaloyl chloride followed by Grignard reaction with vinyl
magnesium bromide furnished the allylic alcohol 31 in 88%
yield. Compound 31 was treated with titanium tetraisopropoxide
and tert-butylhydroperoxide in the presence of (-)-DIPT under
Sharpless asymmetric kinetic resolution conditions to provide the
epoxy alcohol 32 and chiral allylic alcohol 33 in 46% yield and
97% ee (determined from 1H NMR of the corresponding Mosher’s
ester). The epoxide 32 was found to be a mixture of erythro and
threo (96 : 4), which was subsequently treated with TBSOTf in the
presence 2,6-lutidine to furnish the silylated derivative 34 in good
yield.
1
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Scheme 4 Reagents and conditions: (a) [i] pivaloyl chloride, DMSO, Et3N, -78 ◦C; [ii] vinyl bromide, Mg, -78 ◦C, 2 h, 88%; (b) (-)-DIPT, Ti(O-iPr)4,
TBHP, dry CH2Cl2, molecular sieves, 3 A, -20 ◦C, 4 d, 49% for 32 and 46% for 33; (c) TBSOTf, 2,6-lutidine, dry CH2Cl2, 15 min, -10 ◦C, 90%;
˚
◦
(d) (CH3)3S+I-, n-BuLi, -20 C, 75%; (e) Cl3CCONCO, K2CO3, CH2Cl2–CH3OH (1.5 : 1), 4 h, 90%; (f) NaOH, t-BuOCl, Pr2EtN, potassium osmate,
i
propanol, 2.5 h, 66%; (g) TsOH (cat.), MeOH, 78%; (h) (i) K2CO3, MeOH, rt, 6 h; (ii) Ac2O, pyridine, DMAP (cat), overnight, 82%.
phytosphingosine26j 4 in 82% yield. Our synthetic approach proved
to be efficient as the overall yield of the target compound 11 was
found to be 11% from eight steps in comparison with a literature
report26j of overall yield of ~7% in three steps.
For the synthesis of L-xylo-[2R,3S,4S]-C18-phytosphingosine,
the allylic alcohol 33 obtained by the chiral resolution of 31
was subjected to Sharpless asymmetric epoxidation to give the
epoxide 39 in 75% yield as a single diastereomer, which was
converted into the tetraacetate derivative of L-xylo-[2R,3S,4S]-
C18-phytosphingosine 5 following the same sequence of reactions
as described for 4 (Scheme 4). The physical and spectroscopic data
of 12 were in accordance with those described in literature.41,45e
Fig. 3 Proposed transition states for the syn/anti selectivity observed
during the TA reaction.
interactions are minimised in conformation A, while such in-
teractions are significant in conformation B. One would predict
Conclusions
conformation A to be lower in energy and therefore the equilibrium
is shifted towards the more stable conformation A, thus leading to
major syn product.
The compound 37 was desilylated using p-TSA and methanol
to give the alcohol 38 in 78% yield, which on hydrolysis with
K2CO3 in methanol furnished the crude aminoalcohol. Subse-
quent acylation using Ac2O in the presence of pyridine and
catalytic amount of DMAP produced the tetraacetate derivative of
In summary, we have developed a facile and practical enantioselec-
tive synthesis of sphingoid bases in high overall yields. The main
advantage of this strategy is its versatility, leading to the synthe-
sis of N-Boc-L-threo-sphinganine, N-Boc-L-threo-sphingosine, L-
arabino-[2R,3S,4R]-C18-phytosphingosine and L-xylo-[2R,3S,4S]-
C18-phytosphingosine. The synthetic strategy is flexible and would
permit the synthesis of not only the stereoisomers of sphingoid
bases but also the other lipids bearing skeleton-modified sphingoid
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base backbones with different chain lengths and substitution
patterns.
80.6 mmol) was added dropwise over 30 min and the Grignard
reagent thus formed was cooled to 0 ◦C. Aldehyde 14 (9.7 g,
40.3 mmol) in dry THF (10 mL) was added dropwise to the above
reaction mixture over 20 min. After 2 h stirring at 0 ◦C the reaction
mixture was quenched with saturated NH4Cl solution (10 mL),
and the aqueous layer was extracted with EtOAc (4 ¥ 20 mL) and
the combined organic layers were washed with brine and dried
over Na2SO4. The extracts were concentrated to near dryness and
purified by silica gel column chromatography using petroleum
ether–EtOAc (96 : 4) as eluent to give 15 (9.08 g, 82% yield) as a
pale yellow solid: mp 46–48 ◦C.
Experimental section
General Methods
All reactions requiring anhydrous conditions were performed
under a positive pressure of argon using oven-dried glassware
(110 ◦C), which was cooled under argon. Solvents used for
chromatography were distilled at their respective boiling points
using known procedures. All commercial reagents were obtained
from Sigma-Aldrich Chemical Co. and Lancaster Chemical Co.
(UK). The progress of the reactions was monitored by TLC
using precoated aluminium plates (Merck silica gel 60 F254).
Column chromatography was performed on silica gel 60–120/100–
200/230–400 mesh obtained from S. D. Fine Chemical Co. India
or Spectrochem India. Typical syringe and cannula techniques
were used to transfer air- and moisture-sensitive reagents. IR
spectra were recorded on a Perkin-Elmer infrared spectrometer
model 599-B and model 1620 FTIR. 1H NMR spectra were
recorded on Bruker AC-200 MHz, Bruker AV-400 MHz and
Bruker DRX–500 MHz instruments using deuterated solvent.
Chemical shifts are reported in ppm. Proton coupling constants (J)
are reported as absolute values in Hz and multiplicity (brs, broad; s,
singlet; d, doublet; t, triplet; m, multiplet). 13C NMR spectra were
recorded on Bruker AC-200, Bruker AV-400 and Bruker DRX-
500 instruments operating at 50 MHz, 100 MHz, and 125 MHz,
respectively. 13C NMR chemical shifts are reported in ppm relative
to the central line of CDCl3 (d 77.0). Mass spectra were recorded
on PE SCIEX API QSTAR pulsar (LC-MS). HRMS was taken
by EI method using DIP. Microanalytical data were obtained
using a Carlo–Erba CHNS-0 EA 1108 elemental analyzer. All the
melting points were recorded on a Bu¨chi B-540 electrothermal
melting point apparatus. Yields refer to chromatographically
and spectroscopically pure compounds. Enantiomeric excess was
determined using Mosher analysis.
3-(S)-Octadec-1-en-3-ol (16)
i
˚
To a mixture of 3 A molecular sieves (225 mg) and Ti( -PrO)4
(1.34 mL, 4.50 mmol) in dry CH2Cl2 (40 mL) (-)-DIPT (1.2 mL,
5.73 mmol) was added dropwise over 10 min at -20 ◦C. The
mixture was stirred for 20 min at -20 ◦C and a solution of 15
(1.1 g, 4.09 mmol) in dry CH2Cl2 (5 mL) was added over 10 min.
The reaction mixture was stirred for an additional 30 min at -20 ◦C
and TBHP (3.4 mL, 3 M solution in toluene, 10.24 mmol) was
added dropwise over 15 min. The reaction mixture was kept at
◦
-20 C by constant temperature bath and after 4 d the reaction
was warmed to 0 ◦C, and quenched with H2O (30 mL) and the
mixture was stirred for 30 min, and then precooled (0 ◦C) freshly
prepared ferrous sulfate heptahydrate (278 mg, 1 mmol) in 10 mL
of water was added and the reaction mixture stirred for 30 min
at rt. The two phases were separated and the aqueous phase was
extracted with CH2Cl2 (2 ¥ 30 mL). The combined organic layers
were treated with 6 mL of a precooled (0 ◦C) solution of 30%
NaOH w/v in saturated brine. The two phase mixture was stirred
vigorously for 1 h at 0 ◦C, followed by dilution with 50 mL of
water. The phases were separated and the aqueous layer extracted
with CH2Cl2 (2 ¥ 50 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated to dryness. The
crude product was then purified by flash chromatography on silica
gel using petroleum ether–EtOAc (96 : 4) as eluent to give chiral
hydroxy olefin 16 (0.52 g, 47% yield, based on 50% conversion)
as a white solid. mp 46–48 ◦C; [a]D25: +8.3 (c 0.32, CHCl3); Anal.
Calcd for C18H36O (268.48): C, 80.53; H, 13.52%; Found: C, 80.43;
H, 13.49%; IR (CHCl3, cm-1): nmax 3499, 1611; 1H NMR (CDCl3,
200 MHz): d 0.88 (3H, t, J = 6.1 Hz), 1.26 (26H, brs), 1.41–1.55
(2H, m), 1.59 (1H, brs), 4.05–4.15 (1H, m), 5.07–5.27 (2H, m),
5.79–5.96 (1H, m); 13C NMR (CDCl3, 50 MHz): d 14.1, 22.7,
25.3, 25.7, 29.3, 29.7, 31.9, 37.0, 73.2, 114.4, 141.3. MS(ESI): m/z
269.44 (M+H)+, 291.48 (M+Na)+.
1-Hexadecanal (14)
To a stirred solution of pivaloyl chloride (10.14 mL, 82.4 mmol)
in dry CH2Cl2 (100 mL) cooled to -78 ◦C was added dropwise
dry DMSO (8.77 mL, 123.6 mmol) in dry CH2Cl2 (20 mL) over
20 min. The reaction mixture was stirred for 30 min. Alcohol 13
(10 g, 41 mmol) in dry CH2Cl2 (20 mL) was added dropwise to
the above reaction mixture over 20 min. After consumption of the
starting material (2 h), Et3N (28.7 mL, 206 mmol) was added and
stirred at -78 ◦C for further 30 min. The reaction mixture was
brought to room temperature slowly and stirred for 30 min. The
reaction mixture was poured into H2O (150 mL) and the organic
layer separated. The aqueous layer was extracted with CH2Cl2 (2 ¥
50 mL) and combined organic layers were washed with H2O (3 ¥
50 mL), brine (50 mL), dried (Na2SO4) and passed through short
pad of silica gel. The filtrate was concentrated to give the aldehyde
14 (9.7 g) as pale yellow oil, which was used as such for the next
step without purification.
Further elution with petroleum ether–/EtOAc (92 : 8) gave the
epoxide 17 as a white solid.
1-Oxiranyl-hexadecan-1-ol (17)
(0.56 g, 48% yield, based on 50% conversion): mp 56–57 ◦C; [a]D25
:
-6.3 (c 1.3, CHCl3); Anal. Calcd for C18H36O2 (284.48): C, 76.0;
H, 12.76%; Found: C, 75.89; H, 12.64%; IR (CHCl3, cm-1): nmax
3482, 2854, 1211; 1H NMR (CDCl3, 200 MHz): d 0.89 (3H, t, J =
6.1 Hz), 1.26 (26H, brs), 1.49–1.59 (2H, m), 2.71–2.84 (2H, m),
3.04–3.21 (1H, m), 3.86–3.94 (1H, m), 4.48 (1H, brs); 13C NMR
(CDCl3, 50 MHz): d 13.9, 21.6, 22.5, 25.2, 29.2, 31.8, 33.4, 43.4,
54.6, 68.4, 70.1, 72.1; MS(ESI): m/z 307.48 (M+Na)+.
Octadec-1-en-3-ol (15)
To a stirred solution of Mg (2.94 g, 120.9 mmol) in dry THF
(30 mL), vinyl bromide (40.32 mL, 2.0 M solution in dry THF,
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[a]2D5: -9.8 (c 1.0, CHCl3); Anal. Calcd for C19H37NO3 (327.50): C,
69.68; H, 11.39; N, 4.28%; Found: C, 69.56; H, 11.33; N, 4.38%; IR
(CHCl3, cm-1): nmax 3438, 2949, 1710; 1H NMR (CDCl3, 500 MHz):
d 0.88 (3H, t, J = 5.9 Hz), 1.26–1.91 (28H, m), 3.53–3.83 (3H, m),
4.31–4.40 (1H, m), 6.41 (1H, s); 13C NMR (CDCl3, 125 MHz): d
14.1, 22.7, 24.6, 29.3, 29.6, 29.7, 31.9, 34.8, 59.5, 63.5, 79.2, 160.4;
MS(ESI): m/z 350.3427 (M+Na)+.
(S)-Octadec-1-en-3-ylhydroxycarbamate (18)
N,N-Carbonyldiimidazole (1.81 g, 11.16 mmol) was added to
alcohol 16 (2 g 7.44 mmol) in pyridine (30 mL) at 40 ◦C. After
complete adduct formation between the alcohol and N,N-
carbonyldiimidazole (~4 h), hydroxylamine hydrochloride (1.29 g,
18.61 mmol) was added and the reaction mixture stirred for 24 h
at 40 ◦C. The reaction was quenched with 1 M hydrochloric acid
(10 mL), partitioned, and the aqueous layer extracted with Et2O
(35 mL) and EtOAc (3 ¥ 30 mL). The combined organic layers
were then washed sequentially with H2O (30 mL) and brine (2 ¥
30 mL), dried (Na2SO4), filtered and the solvent was azeotropically
removed with toluene. The crude product was then purified by
flash chromatography on silica gel using petroleum ether–EtOAc
(85 : 15) as eluent to give hydroxyl carbamate 18 (2.07 g, 85%
yield) as a white crystalline solid: mp 72–74 ◦C; [a]D25 : -4.3 (c 1.0,
CHCl3); Anal. Calcd for C19H37NO3 (327.50): C, 69.68; H, 11.39;
N, 4.28%; Found: C, 69.87; H, 11.31; N, 4.38%; IR (CHCl3, cm-1):
tert-Butyl-(2S,3S)-1,3-dihydroxyoctadecane-2-yl)carbamate (9)
To a stirred solution of TA product 20 (300 mg, 0.92 mmol)
in MeOH (5 mL) was added K2CO3 (379 mg, 2.74 mmol) and
the reaction mixture was stirred until completion of the starting
material (6 h), and methanol was removed in vacuo. Water was
added to the crude product and extracted with EtOAc (3 ¥ 10 mL),
dried over sodium sulfate and concentrated to near dryness.
The residue was subsequently treated with Boc2O (0.32 mL,
1.38 mmol) in dioxane and the reaction mixture stirred until
consumption of the starting material (8 h), and the solvent was
removed by vacuum evaporation. Purification by silica gel flash
chromatography (MeOH–CH2Cl2, 5 : 95) gave 9 (265 mg, 72%
yield for two steps) as a white solid: mp 80–81 ◦C; [a]D25: +18.8 (c
1.0, CHCl3); lit.38b [a]D21: +19.8 (c 1.0, CHCl3); IR (CHCl3, cm-1):
n
max 3482, 2854, 1716; 1H NMR (CDCl3, 200 MHz): d 0.88 (3H, t,
J = 6.1 Hz), 1.26 (26H, brs), 1.53–1.68 (2H, m), 5.16–5.31 (3H, m),
5.69–5.86 (1H, m), 7.20 (1H, brs); 13C NMR (CDCl3, 50 MHz):
d 14.1, 22.7, 24.9, 29.3, 29.6, 31.9, 34.2, 77.1, 117.1, 136.1, 159.1;
MS(ESI): m/z 350.43 (M+Na)+, 366.3549 (M+K)+.
n
max 3400, 2970, 1690; 1H NMR (CDCl3, 400 MHz): d 0.88 (3H, t,
(S)-Octadec-1-en-3-yl-2,4,6-trichlorobenzoyloxycarbamate (19)
J = 6.5 Hz), 1.26 (26H, brs), 1.46 (9H, s), 1.50–1.56 (2H, m), 2.10
(2H, brs), 3.53 (1H, brs), 3.75–3.80 (2H, m), 4.01 (1H, dd, J = 3.5,
11.5 Hz), 5.32–5.48 (1H, brs); 13C NMR (CDCl3, 100 MHz): d
14.1, 22.7, 25.9, 28.4, 29.4, 29.7, 31.9, 34.5, 54.6, 62.6, 74.5, 79.7,
156.0; MS(ESI): m/z 424.33 (M+Na)+.
To an ice-cold solution of hydroxycarbamate 18 (2.2 g, 6.71 mmol)
in Et2O (4 : 1; 5 mL mmol-1) was added Et3N (1.02 mL,
7.38 mmol), before the addition of the 2,4,6-trichlorobenzoyl
chloride (1.03 mL, 6.71 mmol) in small portions. The reaction
was quenched with HCl (1 M aq. sol., 20 mL) and the aqueous
layer was extracted with Et2O (3 ¥ 20 mL). The combined organic
layers were washed sequentially with H2O (30 mL), NaHCO3 (aq.
sat. sol., 30 mL) and brine (30 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The crude product was purified by flash col-
umn chromatography on silica gel using petroleum ether–EtOAc
(96 : 4) as eluent to give O-trichloro substituted hydroxycarbamate
Octadec-1-en-4-yn-3-ol (22)
n-BuLi (1.6 M solution in hexane, 6.6 mL, 10.56 mmol) was
added dropwise over 10 min to a solution of 1-pentadecyne 21
◦
(2 g,◦9.6 mmol) in dry THF (50 mL) at -78 C. After stirring at
-78 C for 30 min, a solution of acrolein (2.15 g, 38.39 mol) in
abs. THF (20 mL) was added. The reaction mixture was stirred at
-78 ◦C for 30 min, and allowed to warm to -20 ◦C for 2 h, then
quenched by the addition of sat. NH4Cl (10 mL) and extracted
with Et2O (3 ¥ 50 mL). The combined organic layers were washed
with brine, dried (Na2SO4) and concentrated. Filtration through
a silica gel column using petroleum ether as the solvent to recover
excess 1-pentadecyne followed by elution with petroleum ether–
EtOAc (96 : 4) gave 22 (1.77 g, 70% yield) as a low melting
solid.
◦
19 (3.05 g, 85% yield) as a white solid compound: mp 46–47 C;
[a]2D5: -8.8 (c 1.0, CHCl3); Anal. Calcd for C26H38Cl3NO4 (534.94):
C, 58.38; H, 7.16; N, 2.62%; Found: C, 58.30; H, 7.02; N, 2.55%;
1
IR (CHCl3, cm-1): nmax 3420, 2982, 1745, 1710, 1660; H NMR
(CDCl3, 200 MHz): d 0.88 (3H, t, J = 5.9 Hz), 1.25 (26H, brs),
1.55–1.78 (2H, m), 5.20–5.36 (3H, m), 5.72–5.89 (1H, m), 7.41
(2H, s); 13C NMR (CDCl3, 50 MHz): d 14.1, 22.7, 24.9, 29.3, 29.7,
31.9, 34.2, 78.4, 117.7, 128.3, 128.6, 133.6, 135.5, 137.7, 155.4,
163.1; MS(ESI): m/z 556.317 (M+Na)+, 558.33 (M+2+Na)+.
(R)-Octadec-1-en-4-yn-3-ol (23)
(4R,5R)-4-(Hydroxymethyl)-5-pentadecyloxazolidine-2-one (20)
i
˚
To a mixture of 3 A molecular sieves (1.2 g) and Ti( -PrO)4
To a solution of O-trichlorobenzoyl-substituted hydroxycarba-
mate 19 (0.50 g, 0.93 mmol) in t-butanol and H2O (18 mL, 3 : 1,
20 mL mmol-1) was added dropwise a solution of potassium
osmate dihydrate (13.7 mg, 4 mol%) in H2O (0.5 mL) over
10 min. The reaction was quenched by addition of sodium sulfite
(200 mg mmol-1) and the solvent azeotropically removed with
toluene. The crude product was found to be a mixture of ratio
(6.19 mL, 20.79 mmol) in dry CH2Cl2 (40 mL), (-)-DIPT (5.23 mL,
24.96 mmol) was added dropwise over 10 min at -20 ◦C. The
mixture was stirred for 20 min at -20 ◦C, and a solution of mixture
of 22 (5.5 g, 20.79 mmol) in dry CH2Cl2 (20 mL) was added
over 15 min. The reaction mixture was stirred for an additional
30 min at -20 ◦C and TBHP (2.27 mL, 5.5 M solution in toluene,
12.48 mmol) was added dropwise over 15 min. The reaction
mixture was kept at -20 ◦C by constant temperature bath and
after 3 days the reaction was warmed to 0 ◦C, quenched with
H2O (100 mL) and the mixture was stirred for 30 min, and then
precooled (0 ◦C) freshly prepared ferrous sulfate heptahydrate
1
syn : anti 15 : 1 (determined from H NMR of crude compound),
which was purified by flash column chromatography on silica
gel using petroleum ether–EtOAc (6 : 4) as eluent to give the
aminoalcohol 20 (230 mg, 75% yield) as white solid: mp 87–89 ◦C;
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(1.44 g, 5.19 mmol) in 10 mL of water was added and reaction
mixture is stirred for 30 min at rt. The two phases were separated
and the aqueous phase was extracted with CH2Cl2 (2 ¥ 50 mL). The
combined organic layers were treated with 30 mL of a precooled
(0 ◦C) solution of 30% NaOH w/v in saturated brine. The two
phase mixture was stirred vigorously for 1 h at 0 ◦C, followed
by dilution with 50 mL of water. The phases were separated and
the aqueous layer was extracted with CH2Cl2 (2 ¥ 50 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated to dryness. The crude product was then purified
by flash chromatography on silica gel using petroleum ether–
EtOAc (96 : 4) to give chiral hydroxy olefin 23 as a white solid
compound (2.48 g, 45% yield, based on 50% conversion): mp 35–
(4R,5S)-4-(Hydroxymethyl)5-(pentadec-1-ynyl)oxazolidin-2-one
(26)
A fresh aqueous solution of sodium hydroxide (18 mL, 0.08M,
58 mg, 1.46 mmol) was prepared. All but a few drops of this was
added in one portion to a stirred solution of the allylic carbamate
25 (0.50 g, 1.62 mmol) in propan-1-ol (19.44 mL, 12 mL mmol-1).
The solution was allowed to stir for 5 min, before freshly prepared
tert-butyl hypochlorite (0.176 g, 1.62 mmol) was added. The
mixture was again allowed to stir for 5 min, to this was added
iPr2EtN (14 mg, 5 mol%) in one portion. The mixture was allowed
to stir for a further 5 min before the final addition of a solution of
potassium osmate (23 mg, 4 mol%) in the remainder of the NaOH
solution made earlier. The reaction was monitored by TLC and
halted when no further change was detected. The reaction was
quenched by the addition of sodium sulfite (100 mg mmol-1), and
allowed to stir for 30 min. The mixture was extracted with EtOAc
(5 ¥ 25 mL). The combined organics were washed with brine, dried
over sodium sulfate and concentrated under reduced pressure to
give the crude product which was found to be a mixture of ratio
◦
37 C; [a]2D5: -3.76 (c 1.0, CHCl3); IR (CHCl3, cm-1): nmax 3440,
2210, 1611; 1H NMR (200 MHz, CDCl3): 0.88 (3H, t, J = 6.1 Hz),
1.26–1.52 (22H, m), 1.89 (1H, d, J = 6.1 Hz), 2.20–2.27 (2H, t, J =
6.9 Hz), 4.84–4.90 (1H, m), 5.17–5.49 (2H, m), 5.9–6.01 (1H, m);
13C NMR (50 MHz, CDCl3): 14.1, 18.7, 22.6, 28.5, 28.8, 29.1, 29.3,
29.6, 31.9, 63.3, 78.9, 87.3, 115.9, 137.6; MS(ESI): m/z 287.477
(M++Na). HRMS, (EI/DIP) for (M+): calc. 264.24729, Found:
264.24697.
1
syn : anti 13 : 1 (determined from H NMR of crude compound).
Purification by flash column chromatography on silica gel using
petroleum ether–EtOAc (1 : 1) as eluent gave the carbamate 26
◦
(0.34 g, 65% yield) as a white solid: mp 53–55 C; [a]2D5: -8.39
(R)-1-((S)-Oxirane-2-yl)hexadec-2-yn-1-ol (24)
(c 0.9, CHCl3); IR (CHCl3, cm-1): nmax 3400, 2922, 2100, 1653;
1H NMR (200 MHz, CDCl3): 0.88 (3H, t, J = 6.0 Hz), 1.24–
1.52 (22H, m), 1.84 (1H, brs) 2.18–2.25 (2H, m), 4.20–4.25 (1H,
m), 4.47–4.68 (2H, m), 5.45 (1H, d, J = 7.9 Hz), 6.73 (1H, brs);
13C NMR (50 MHz, CDCl3): 14.4, 18.7, 22.8, 28.1, 28.9, 29.1,
29.3, 29.5, 31.9, 58.4, 65.0, 68.6, 74.6, 90.8, 157.9; MS(ESI): m/z
346.561 (M+Na)+; HRMS, (EI/DIP) for (M+): calc. 323.24354,
Found: 323.24346.
(2.85 g, 49% yield, based on 50% conversion); m.p. 48–49 ◦C; [a]D25:
-16.31 (c 1.0, CHCl3); Anal. Calcd for C18H32O2 (280.45): C, 77.09;
H, 11.50%; Found: C, 77.19; H, 11.44%; IR (CHCl3, cm-1): nmax
1
3482, 3100, 2900, 2200; H NMR (200 MHz, CDCl3): 0.88 (3H,
t, J = 6.1 Hz), 1.26–1.58 (22H, m), 2.11 (1H, d, J = 5.0 Hz), 2.23
(2H, dt, J = 6.9, 14.0 Hz), 2.82 (1H, q, J = 3.9, 4.9 Hz), 2.92 (1H,
q, J = 2.6, 5.0 Hz), 3.25 (1H, dt, J = 2.7, 3.9 Hz), 4.63 (1H, sextet,
J = 2.1, 4.9, 7.0 Hz); 13C NMR (50 MHz, CDCl3): 14.0, 18.6, 22.6,
28.4, 28.9, 29.0, 29.4, 29.6, 31.8, 44.3, 53.9, 61.1, 76.1, 87.6.
(2S,3S)-2-Aminooctadec-4-yne-1,3-diol (27)
To a stirred solution of TA product 26 (900 mg, 2.78 mmol)
in MeOH (10 mL) was added K2CO3 (1.15 g, 8.35 mmol) and
the reaction mixture was stirred for 6 h at room temperature
until consumption of the starting material and methanol was
removed in vacuo. H2O was added to the crude product, which
was extracted with EtOAc (3 ¥ 30 mL) and dried over sodium
sulfate, concentrated to near dryness and crystallised from DCM–
petroleum ether to give 27 (703 mg, 85% yield) as white shiny
crystal. mp 81–83 ◦C; lit.26k mp 82–83 ◦C; IR (CHCl3, cm-1): nmax
(R)-Octadec-1-en-4-yn-3-ylcarbamate (25)
Trichloroacetyl isocyanate (0.54 mL, 4.54 mmol) was added
dropwise over 10 min to a solution of alcohol 23 (1.0 g, 3.78 mmol)
◦
in dry CH2Cl2 (5.67 mL, 1.5 mL mmol-1) at 0 C. After stirring
for 2 h, or until TLC showed no starting material present, the
mixture was concentrated under reduced pressure. The residue
was dissolved in MeOH (7.56 mL, 2 mL mmol-1), cooled to
0
◦C and an aqueous K2CO3 solution (1.56 g, 11.34 mmol,
2 mL mmol-1) was added. The cooling bath was removed and
the mixture was allowed to stir for 4 h, by which time TLC showed
complete conversion. The solvent was evaporated under reduced
pressure and the aqueous residue was extracted with CH2Cl2 (3 ¥
25 mL). The combined organics were washed with brine (10 mL),
dried over Na2SO4 and concentrated under reduced pressure to
yield the crude carbamate, which was purified by flash column
chromatography on silica gel using petroleum ether–EtOAc (8 : 2)
as eluent to give carbamate 25 (0.98 g, 85% yield) as a white solid:
mp 50–51 ◦C; [a]D25: -3.67 (c 1.2, CHCl3); IR (CHCl3, cm-1): nmax
3346, 1654; 1H NMR (200 MHz, CDCl3): 0.87 (3H, t, J = 6.0 Hz),
1.25–1.55 (22H, m), 2.19–2.27 (2H, m), 5.07 (2H, brs), 5.24–5.57
(2H, dd, J = 1.2, 18.0 Hz), 5.78–5.96 (2H, m); 13C NMR (50 MHz,
CDCl3): 14.1, 18.7, 22.6, 28.4, 28.8, 29.0, 29.4, 29.6, 31.9, 65.6,
75.4, 88.4, 118.1, 133.8, 155.9; HRMS, (EI/DIP) for (M+): calc.
307.25074, Found: 307.25068.
1
3460, 3300, 2184; H NMR (500 MHz, CDCl3): 0.88 (3H, t, J =
6.1 Hz), 1.15–1.72 (22H, m), 1.98–2.5 (2H m), 3.4–5.5 (5H, m),
7.79 (2H, brs); 13C NMR (50 MHz, CDCl3): 14.1, 18.9, 22.7, 28.7,
29.3, 29.4, 29.7, 29.8, 31.9, 58.9, 60.2, 65.6, 76.5, 88.9; HRMS,
(EI/DIP) for (M+): calc. 297.2649, found 297.2643.
tert-Butyl(2S,3S)-1,3-dihydroxyoctadec-4-yn-2-ylcarbamate (28)
Compound 27 (500 mg, 1.68 mmol) was treated with Boc2O
(0.58 mL, 2.52 mmol) in dioxane and the reaction mixture stirred
until consumption of the starting material (8 h) and solvent was
removed by vacuum evaporation. The crude material was purified
by flash column chromatography on silica gel using petroleum
ether–EtOAc (6 : 1) as eluent to give 28 (547 mg, 82% yield) as
a colorless oil: [a]D25: -14.8 (c 0.5, CHCl3); lit.26a [a]2D5 - 14.0 (c
1
0.5, CHCl3); IR (CHCl3, cm-1): nmax 3485, 2187, 1675; H NMR
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(200 MHz, CDCl3): 0.88 (3H, t, J = 5.9 Hz), 1.25–1.63 (31H, m),
2.21 (2H, t, J = 6.8 Hz), 2.57 (2H, brs), 3.79–3.92 (3H, m), 4.58–
4.61 (1H, m), 5.17 (1H, brs); 13C NMR (50 MHz, CDCl3): 14.1,
18.7, 22.6, 28.3, 28.5, 28.9, 29.1, 29.3, 29.5, 29.6, 31.9, 55.9, 62.9,
63.4, 80.0, 87.3, 156.4; MS(ESI): m/z 420.22 (M+Na)+.
30 min at -20 ◦C and TBHP (12.5 mL, 5.5 M solution in toluene,
68.75 mmol) was added dropwise over 10 min. The reaction
mixture was kept at -20 ◦C by constant temperature bath and
after 4 d was warmed to 0 ◦C, and quenched with H2O (100 mL).
The mixture was stirred for 60 min, and then precooled (0 ◦C)
freshly prepared ferrous sulfate heptahydrate (1.52 g, 5.5 mmol)
in 10 mL of water was added and the reaction mixture was
stirred for 30 min at room temperature. The two phases were
separated and the aqueous phase was extracted with CH2Cl2 (2 ¥
50 mL). The combined organic layers were treated with 30 mL
of a precooled (0 ◦C) solution of 30% NaOH w/v in saturated
brine. The two phase mixture was stirred vigorously for 1 h at
tert-Butyl-(2S,3S,E)-1,3-dihydroxyoctadec-4-en-2-ylcarbamate
(10)
A solution of 28 (0.20 g, 0.5 mmol) in abs. Et2O (5 mL) was
added dropwise over 10 min to Red-Al◦(3.5 M in toluene, 0.71 mL,
2.5 mmol) and abs. Et2O (3 mL) at 0 C. The clear solution was
stirred at room temperature for 24 h, then MeOH (1 mL) was
added dropwise at 0 ◦C. After dilution with Et2O (5 mL) and
addition of sat. potassium sodium tartrate (3 mL), the mixture
was vigorously stirred at room temperature for 3 h. The aq. layer
was separated and extracted with Et2O (2 ¥ 10 mL). The combined
Et2O extracts were washed with sat. potassium sodium tartrate and
sat. NaCl, dried over Na2SO4 and concentrated to near dryness.
The crude material was purified by flash column chromatography
on silica gel using petroleum ether–EtOAc (1 : 1) as eluent to give
10 (0.13 g, 65% yield) as a white solid: mp 58–60 ◦C; [a]D25: -0.56
(c 1.0, CHCl3); lit.26a [a]D25 - 0.4 (c 1.0, CHCl3); IR (CHCl3, cm-1):
nmax 3460, 2900, 1670; 1H NMR (200 MHz, CDCl3): 0.89 (3H, t,
J = 6.8 Hz), 1.26–1.46 (31H, m), 2.03–2.09 (2H, m), 2.65 (1H, brs)
3.58 (1H, brs), 3.70 (1H, dd, J = 3.5, 11.2 Hz), 3.94 (1H, dd, J =
3.5, 11.2 Hz), 4.31 (1H, t, J = 4.5 Hz), 5.31 (1H, d, J = 7.0 Hz),
◦
0 C, followed by dilution with 50 mL of water, the phases were
separated and the aqueous layer was extracted with CH2Cl2 (2 ¥
50 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated to dryness. The crude product
was then purified by flash chromatography on silica gel using
petroleum ether–EtOAc (95 : 5) as eluent to give chiral hydroxy
olefin 33 as a white solid. (3.22 g, 46% yield, based on 50%
conversion). Further elution with petroleum ether–EtOAc (9 : 1)
gave the epoxide 32 as a white solid (3.64 g, 49% yield, based on
50% conversion): mp 46–47 ◦C; [a]D25 +2.38 (c 1.0, CHCl3); Anal.
Calcd. for C17H34O (254.45): C, 80.24; H, 13.47%. Found: C, 79.95;
1
H, 13.73%; IR (CHCl3, cm-1) : nmax 3499, 2899, 1611; H NMR
(CDCl3, 200 MHz): d 0.89 (3H, t, J = 6.1 Hz), 1.26–1.55 (26H,
m), 4.05–4.15 (1H, m), 5.08–5.27 (2H, m), 5.79–5.96 (1H, m); 13
C
NMR (CDCl3, 50 MHz): d 14.1, 22.7, 25.3, 29.3, 29.7, 31.9, 37.0,
73.2, 114.4, 141.3.
5.53 (1H, q, J = 6.2, 15.5 Hz), 5.79 (1H, q, J = 6.5, 14.5 Hz); 13
C
NMR (50 MHz, CDCl3): 14.1, 22.7, 28.4, 29.1, 29.2, 29.3, 29.7,
31.9, 32.3, 55.4, 62.6, 74.8, 79.8, 128.9, 134.2, 156.2.
tert-Butyldimethyl((R)-1-((S)-oxiran-2-yl)pentadecyl)oxy) silane
(34)
Pentadecanal-1 (30)
To a solution of 32 (3.0 g, 11.09 mmol) in dry CH2Cl2 (10 mL)
was added 2,6-lutidine (2.08 mL, 17.88 mmol) at 0 ◦C and stirred
for 15 min. To this TBSOTf (2.18 mL, 13.31 mmol) was added
dropwise over 10 min and stirred for 10 min. After TLC diagnosis,
the ice-cooled solution was added to the reaction mixture and then
the aqueous layer was extracted with CH2Cl2 (3 ¥ 50 mL), dried
over anhydrous Na2SO4 and concentrated to near dryness. The
crude product was purified by silica gel column chromatography
using petroleum ether–EtOAc (99 : 1) as eluent to give 34 (3.84 g,
90% yield) as a colorless liquid: [a]2D5 -4.1 (c 1.0, CHCl3); Anal.
Calcd for C23H48O2Si (384.71): C, 71.81; H, 12.58%. Found: C,
Following the procedure as described for 14, the crude aldehyde
30 was prepared and used as such in the next reaction.
Heptadec-1-en-3-ol (31)
To a stirred solution of Mg (2.57 g, 106 mmol) in dry THF (30 mL),
vinyl bromide (29.4 mL, 3.0 M solution in dry THF, 88.33 mmol)
was added dropwise over 30 min and the Grignard reagent thus
formed was cooled to 0 ◦C. Aldehyde 30 (8 g, 35.3 mmol) in
dry THF (30 mL) was added dropwise o◦ver 20 min to the above
reaction mixture. After 2 h stirring at 0 C the reaction mixture
was quenched with saturated NH4Cl solution (20 mL), and the
aqueous layer was extracted with EtOAc (4 ¥ 50 mL) and the
combined organic layers were washed with brine and dried over
Na2SO4. The extracts were concentrated to near dryness and
purified by silica gel column chromatography using petroleum
ether–EtOAc (95 : 5) as eluent to give 31 (7.84 g, 88% yield) as a
pale yellow solid: mp 46–47 ◦C.
1
71.65; H, 12.73%; H NMR (200 MHz, CDCl3): d 0.07 (3H, s),
0.12 (3H, s), 0.85–0.93 (12H, m), 1.26 (24H, brs), 1.48–1.56 (2H,
m), 2.55 (1H, q, J = 2.7, 5.1 Hz), 2.76–2.81 (1H, m), 2.89–2.96
(1H, m), 3.21–3.30 (1H, m); 13C NMR (50 MHz, CDCl3): d -4.9,
-4.4, 14.1, 18.2, 22.7, 24.9, 25.7, 25.8, 29.4, 29.7, 31.9, 35.3, 44.7,
54.8, 71.3; MS(ESI): m/z 385.7 (M+H)+, 407.61 (M+Na)+.
(3S,4R)-4-((tert-Butyldimethylsilyl)oxy)octadec-1-en-3-ol (35)
(S)-Heptadec-1-en-3-ol (33)
To a suspension of trimethylsulfonium iodide (6.47 g, 31.71 mmol)
in dry THF (20 mL) at -20 ◦C was added n-BuLi (21.07 mL,
1.6 M solution in hexane, 31.71 mmol) dropwise over 20 min
and stirred for 30 min. Then the epoxide 34 (2.0 g, 5.19 mmol)
in dry THF (10 mL) was added to the above reaction mixture
and slowly allowed to warm to 0 ◦C over 1 h. The reaction
mixture was then stirred at ambient temperature for 2 h. After
i
˚
To a mixture of 3 A molecular sieves (1.5 g) and Ti( -PrO)4
(9.0 mL, 30.26 mmol) in dry CH2Cl2 (100 mL), (-)-DIPT (8.07 mL,
38.51 mmol) was added dropwise over 10 min at -20 ◦C. The
mixture was stirred for 20 min at -20 ◦C, and a solution of 31
(7.0 g, 27.5 mmol) in dry CH2Cl2 (25 mL) was added dropwise
over 10 min. The reaction mixture was stirred for additional
5082 | Org. Biomol. Chem., 2010, 8, 5074–5086
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consumption of the starting material the reaction mixture was
quenched with H2O (20 mL) and extracted with EtOAc (4 ¥
30 mL). The combined extracts were washed with brine (50 mL),
dried over Na2SO4, filtered and concentrated to near dryness. The
residue was purified by flash silica gel column chromatography
using petroleum ether–EtOAc (94 : 6) as eluent to give 35 (1.55 g,
75% yield) as a colorless liquid: [a]2D5 -2.5 (c 1.0, CHCl3); Anal.
Calcd for C24H50O2Si (398.74): C, 72.29; H, 12.64%. Found: C,
mixture was stirred until consumption of the starting material
and was then quenched with sodium sulfite (100 mg mmol-1),
and subsequently diluted with EtOAc. The reaction mixture was
extracted with EtOAc (3 ¥ 10 mL), dried over Na2SO4 and
concentrated to near dryness. The crude product was found to
1
be a mixture of syn : anti 12 : 1 (determined from H NMR of
crude compound) and was purified by flash silica gel column
chromatography using petroleum ether–EtOAc (7 : 3) as eluent to
give 37 (0.36 g, 66% yield), as a thick syrupy liquid: [a]2D5 +28.47 (c
1.3, CHCl3); Anal. Calcd for C25H51NO4Si (457.76): C, 65.59; H,
11.23; N, 3.06%. Found: C, 65.35; H, 11.48; N, 3.36%; 1H NMR
(400 MHz, CDCl3): d 0.09 (3H, s), 0.10 (3H, s), 0.88–0.91 (12H,
m), 1.26 (24H, m), 1.39–1.53 (2H, m), 3.42–3.6 (1H, m), 3.65–3.8
(1H, m), 3.85–4.0 (2H, m), 4.32 (1H, m), 6.55 (1H, s); 13C NMR
(50 MHz, CDCl3): d -4.6, -4.4, 14.0, 17.9, 22.6, 24.9, 25.7, 29.3,
29.6, 31.8, 32.8, 54.3, 63.8, 71.9, 80.3, 160.3; MS(ESI): m/z Anal.
480.70 (M+Na)+.
1
72.27; H, 12.63%; IR (CHCl3, cm-1): nmax 3446, 1614; H NMR
(200 MHz, CDCl3): d 0.09 (3H, s), 0.10 (3H, s), 0.85–0.91 (12H,
m), 1.26–1.43 (26H, m), 2.27 (1H, brs), 3.66–3.71 (1H, m), 4.08–
4.12 (1H, m), 5.17–5.34 (2H, m), 5.77–5.94 (1H, m); 13C NMR
(50 MHz, CDCl3): d -4.5, -4.4, 14.1, 18.1, 22.7, 25.6, 25.7, 25.8,
29.4, 29.6, 29.7, 31.6, 31.9, 75.4, 75.9, 116.4, 136.5; MS(ESI): m/z;
421.72 (M+Na)+.
(3S,4R)-4-((tert-Butyldimethylsilyl)oxy)octadec-1-en-3-yl
carbamate (36)
(4S,5R)-4-(Hydroxymethyl)-5-((R)-1-hydroxypentadecyl)
oxazolidin-2-one (38)
Trichloroacetyl isocyanate (0.536 mL, 4.51 mmol) was added
dropwise over 10 min to a solution of alcohol 35 (1.5 g, 3.76 mmol)
in dry CH2Cl2 (1.7 mL) at 0 ◦C. After stirring for 2 h, or until TLC
showed no starting material present, the mixture was concentrated
under reduced pressure. The residue was dissolved in MeOH
(2.2 mL), cooled to 0 ◦C and aqueous K2CO3 solution (1.55 g,
3.4 mL, 11.28 mmol) was added. The cooling bath was removed
and the mixture was allowed to stir for 4 h, by which time TLC
showed complete conversion. The solvent was evaporated under
reduced pressure and the residue was extracted with CH2Cl2
(4 ¥ 25 mL). The extracts were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure to yield the
crude carbamate, which was purified by flash silica gel column
chromatography using petroleum ether–EtOAc (8 : 2) as eluent
to give 36 (1.49 g, 90% yield) as a colorless syrupy liquid: [a]D25
-27.5 (c 1.0, CHCl3); Anal. Calcd for C25H51NO3Si (441.76):
C, 67.97; H, 11.64; N, 3.17%. Found: C, 67.81; H, 11.69; N,
To a solution of TA product 37 (0.2 g, 0.43 mmol) in MeOH
(5 mL) was added catalytic amount of p-TSA. The reaction
mixture was stirred for 1 h and it was filtered and concentrated to
near dryness. The crude product was purified by silica gel column
chromatography using petroleum ether–EtOAc (3 : 7) as eluent to
afford 38 (0.117 g, 78% yield) as a white solid: mp 60–62 ◦C;
[a]2D5 +8.70 (c, CHCl3); Anal. Calcd for C19H37NO4 (343.50): C,
66.43; H, 10.86; N, 4.08%. Found: C, 66.38; H, 10.85; N, 4.03%;
1
IR (CHCl3, cm-1): nmax 3340, 2800, 1650; H NMR (200 MHz,
CDCl3): d 0.88 (3H, t, J = 6.1 Hz), 1.26–1.73 (26H, m), 2.30–2.37
(1H, m), 3.37–3.95 (4H, m), 4.10 (1H, t, J = 3.7 Hz), 4.24–4.28 (1H,
m), 6.99 (1H, brs); 13C NMR (50 MHz, DMSO-d6): d 14.5, 22.6,
25.5, 29.2, 29.5 31.8, 32.3, 54.9, 63.6, 70.9, 80.6, 159.1; MS(ESI):
m/z 344.48 (M+H)+.
1
3.25%; IR (CHCl3, cm-1): nmax 3446, 1644; H NMR (200 MHz,
CDCl3): d 0.06 (3H, s), 0.08 (3H, s), 0.88–0.91 (12H, m), 1.26–
1.41 (26H, m), 3.77–3.84 (1H, m), 4.79 (2H, brs), 5.01–5.06 (1H,
m), 5.24–5.34 (2H, m); 5.81–5.98 (1H, m); 13C NMR (50 MHz,
CDCl3): d -4.6, -4.4, 14.1, 18.2, 22.7, 25.4, 25.9, 29.3, 29.5,
29.7, 31.9, 33.6, 73.7, 78.8, 118.7, 132.9, 156.3. MS(ESI): m/z
442.39 (M+H)+.
(2R,3S,4R)-2-Acetamidooctadecane-1,3,4-triyltriacetate (11)
To a stirred solution of 38 (90 mg, 0.26 mmol) in MeOH (3 mL)
was added K2CO3 (72 mg, 0.39 mmol) and the reaction mixture
was stirred for 6 h until consumption of the starting material
and methanol was removed in vacuo. H2O was added to the
crude product and extracted with EtOAc (3 ¥ 10 mL), dried over
Na2SO4 and concentrated to near dryness. The crude material
was subsequently acetylated with acetic anhydride (0.053 g,
0.52 mmol), pyridine (0.043 g, 0.54 mmol) and DMAP (cat). After
overnight stirring, the solvent was evaporated and the residue was
purified on a silica gel column using petroleum ether–EtOAc (5 : 1)
as eluent to give tetraacetate 11 (104 mg, 82% yield) as a white
solid. Spectroscopic data of tetraacetate are in full agreement with
(4S,5R)-5-((R)-1-(tert-Butyldimethylsilyl)pentadecyl)-4-
(hydroxymethyl)oxazolidin-2-one (37)
A solution of sodium hydroxide (12.5 mL, 0.08M, 43 mg,
1.08 mmol) was prepared. A small amount of this solution was
used to dissolve potassium osmate dihydrate (17 mg, 4 mol%) in
a separate vial and the remaining sodium hydroxide solution was
added in one portion to a stirred solution of the allylic carbamate
36 (0.53 g, 1.2 mmol) in propan-1-ol (14.5 mL, 12 mL mmol-1).
To this reaction mixture was added freshly prepared t-butyl
hypochlorite (0.12 mL, 1.13 mmol) and the mixture was allowed
◦
those reported in literature.26j mp 48–49 C; [a]D20 - 25.95 (c 1.5,
1
CHCl3); lit.26j [a]D20 - 25.10 (c 1.5, CHCl3); H NMR (200 MHz,
CDCl3): 0.86 (3H, t, J = 6.0 Hz), 1.2–1.3 (24H, m), 1.55 (2H, m),
2.03 (3H, s), 2.04 (6H, s), 2.07 (3H, s), 3.95–4.05 (2H, m), 4.5
(1H, m), 5.02–5.18 (2H, m), 5.92 (1H, d, J = 10.0 Hz); 13C NMR
(50 MHz, CDCl3): d 14.6, 21.2, 21.4, 23.6, 25.5, 30.1, 32.4, 33.9,
47.5, 63.5, 71.4, 72.4, 170.3, 170.6, 170.7, 171.1; MS(ESI): m/z
486.645 (M+H)+, 508.641 (M+Na)+.
i
to stir for 5 min. To this was added Pr2EtN (10 mg, 5 mol%) in
one portion. The mixture was allowed to stir for a further 5 min
before the final addition of a solution of potassium osmate in
the remainder of the NaOH solution made earlier. The reaction
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(S)-1-((S)-Oxiran-2-yl)pentadecan-1-ol (39)
(3S,4S)-4-(tert-Butyldimethylsilyl)oxy)octadec-1-en-3-yl
carbamate (42)
i
˚
To a mixture of 3 A molecular sieves (600 mg) and Ti( -PrO)4
(3.57 mL, 11.79 mmol) in dry CH2Cl2 (50 mL) (-)-DIPT (2.46 mL,
11.79 mmol) was added dropwise over 10 min at -20 ◦C. The
mixture was stirred for 20 min at -20 ◦C, and a solution of 33 (3 g,
11.79 mmol) in dry CH2Cl2 (25 mL) was added slowly over 15 min.
The reaction mixture was stirred for additional 30 min at -20 ◦C
and TBHP (4.2 mL, 5.5M solution in toluene, 23.58 mmol) was
Compound 42 was prepared following the procedure as described
for compound 36: Yield 90%; colorless syrupy liquid; [a]2D5 -27.5
(c 1.0, CHCl3); Anal. Calcd for C25H51NO3Si (441.76): C, 67.97;
H, 11.64; N, 3.17%. Found: C, 68.11; H, 11.67; N, 3.22%; IR
(CHCl3, cm-1): nmax 3446, 1644; H NMR (200 MHz, CDCl3): d
1
0.07 (3H, s), 0.10 (3H, s), 0.85–0.90 (12H, m), 1.26–1.43 (26H, m),
3.69–3.77 (1H, m), 4.60–4.77 (2H, brs), 5.07–5.35 (3H, m), 5.78–
5.95 (1H, m); 13C NMR (50 MHz, CDCl3): d -4.8, -4.4, 14.1,
18.2, 22.7, 25.4, 25.8, 29.5, 29.6, 29.7, 31.9, 33.6, 73.9, 79.8, 118.7,
132.9, 159; MS(ESI): m/z 442.39 (M+H)+.
◦
added over 15 min. The reaction mixture was kept at -20 C by
constant temperature bath and after 4 d the reaction was warmed
to 0 ◦C and quenched with H2O (100 mL). The mixture was stirred
for 40 min, and then precooled (0 ◦C) freshly prepared ferrous
sulfate heptahydrate (819 mg, 2.94 mmol) in 10 mL of water was
added and the reaction mixture was stirred for 30 min at rt. The
two phases were separated and the aqueous phase extracted with
CH2Cl2 (2 ¥ 20 mL). The combined organic layers were treated
with 20 mL of a precooled (0 ◦C) solution of 30% NaOH w/v
in saturated ◦brine. The two phase mixture was stirred vigorously
for 1 h at 0 C. Followed by dilution with 50 mL of water. The
phases were separated and the aqueous layer was extracted with
CH2Cl2 (2 ¥ 50 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated to dryness. The
crude product was then purified by flash chromatography on
silica gel using petroleum ether–EtOAc (9 : 1) as eluent to give
(4S,5R)-5-((S)-1-(tert-Butyldimethylsilyl)oxy)pentadecyl)-4-
(hydroxymethyl)oxazolidin-2-one (43)
Compound 43 was prepared following the procedure as described
for compound 37: Yield 55%, thick syrupy liquid; [a]2D5 +8.70 (c
1.0, CHCl3); Anal. Calcd for C25H51NO4Si (457.76): C, 65.59; H,
11.23; N, 3.06%. Found: C, 65.64; H, 11.28; N, 3.18%; 1H NMR
(200 MHz, CDCl3): d 0.09 (3H, s), 0.10 (3H, s), 0.87–0.92 (12H,
m), 1.26–1.55 (26H, m), 2.51 (1H, brs), 3.50–3.56 (1H, m), 3.70–
3.74 (1H, m), 3.91–3.98 (2H, m), 4.27–4.32 (1H, m), 6.14 (1H, s);
13C NMR (50 MHz, CDCl3): d -4.6, -4.4, 14.1, 18.0, 22.7, 25.0,
25.7, 25.8, 29.4, 29.6, 29.7, 31.9, 33.0, 54.0, 63.3, 72.0, 80.3, 159.8;
MS(ESI): m/z Anal. 480.70 (M+Na)+.
◦
epoxide 39 (2.39 g, 75%) as a white solid: mp 46–48 C; [a]D25
-3.83 (c 1.0, CHCl3); Anal. Calcd for C17H34O2 (270.45): C, 75.50;
1
H, 12.67%. Found: C, 75.65; H, 12.58%; H NMR (200 MHz,
CDCl3): 0.88 (3H, t, J = 6.0 Hz), 1.26–1.61 (26H, m), 1.78 (1H,
s), 2.72–2.78 (1H, m), 2.81–2.82 (1H, m), 3.01–3.06 (1H, m),
3.82–3.89 (1H, m); 13C NMR (50 MHz, CDCl3): d 14.1, 22.7,
25.3, 29.3, 29.5, 29.6, 31.9, 33.4, 43.4, 54.5, 68.4; MS(ESI): m/z
293.41 (M+Na)+.
(4S,5R)-4-(Hydroxymethyl)-5-((S)-1-hydroxypentadecyl)
oxazolidin-2-one (44)
Compound 44 was prepared following the procedure as described
◦
for compound 38: Yield 75%, white solid; mp 58–59 C; [a]D25
+43.48 (c 1.0, CHCl3); Anal. Calcd for C19H37NO4 (343.50): C,
66.43; H, 10.86; N, 4.08%. Found: C, 66.35; H, 10.85; N, 4.02%;
IR (CHCl3, cm-1): nmax 3378, 1675; 1H NMR (200 MHz, CDCl3):
d 0.88 (3H, t, J = 6.1 Hz), 1.26–1.75 (26H, m) 2.34 (1H, brs), 3.54–
3.94 (4H, m), 4.10 (1H, t, J = 3.7 Hz), 4.24–4.28 (1H, m), 6.97
(1H, s); 13C NMR (100 MHz, DMSO-d6): d 14.1, 22.7, 25.0, 29.3,
29.5, 29.6, 29.7, 31.9, 32.9, 53.4, 63.7, 73.4, 79.8, 158.4; MS(ESI):
m/z 344.47 (M+H)+.
tert-Butyldimethyl-((S)-1-((S)-oxiran-2-yl)pentadecyl)oxy) silane
(40)
Compound 40 was prepared following the procedure as described
for 34: Yield 85%; colorless liquid; [a]2D5 -4.16 (c 1.0, CHCl3);
Anal. Calcd for C23H48O2Si (384.71): C, 71.81; H, 12.58%. Found:
C, 71.73; H, 12.66%; 1H NMR (200 MHz, CDCl3): d 0.07 (3H, s),
0.12 (3H, s), 0.84–0.93 (12H, m), 1.26 (24H, s), 1.49–1.53 (2H, m),
2.55 (1H, q, J = 2.7, 5.1 Hz), 2.75–2.83 (1H, m), 2.87–2.97 (1H,
m), 3.19–3.33 (1H, m); 13C NMR (50 MHz, CDCl3): d -4.8, -4.4,
14.1, 18.1, 22.6, 24.8, 25.2, 25.6, 25.7, 25.9, 29.3, 29.5, 29.6, 29.7,
31.9, 35.2, 44.8, 54.7, 72.3; MS(ESI): m/z 385.73 (M+H)+, 407.54
(M+Na)+.
(2R,3S,4S)-2-Acetamidooctadecane-1,3,4-triyltriacetate (12)
Compound 12 was prepared following the procedure as described
◦
for compound 11: Yield 72%, white solid; mp 51–52 C; [a]D20
-
7.0 (c 1.2, CHCl3); lit.41,45e [a]D20 - 7.2 (c 1.2, CHCl3); H NMR
(400 MHz, CDCl3): 0.88 (3H, t, J = 6.2 Hz), 1.26 (24H, brs),
1.51–1.72 (2H, m), 2.05–2.09 (12H, m), 4.19–4.22 (1H, m), 4.40–
4.47 (2H, m), 4.55–4.57 (1H, m), 5.06–5.09 (1H, m); 13C NMR
(100 MHz, CDCl3): d 14.0, 20.6, 20.9, 22.6, 23.0, 24.9, 25.8, 29.2,
30.1, 31.8, 33.3, 46.9, 62.9, 70.4, 71.9, 169.7, 170.0, 170.1, 170.5;
MS(ESI): m/z 486.645 (M+H)+, 508.641 (M+Na)+.
1
(3S,4S)-4-(tert-Butyldimethylsilyl)oxy)octadec-1-en-3-ol (41)
Compound 41 was prepared following the procedure as described
for compound 35: Yield 70%; colorless liquid; [a]2D5 -1.78 (c 1.0,
CHCl3); Anal. Calcd for C23H50O2Si (398.74): C, 72.29; H, 12.64%.
Found: C, 72.36; H, 12.56%; 1H NMR (200 MHz, CDCl3): d 0.09
(3H, s), 0.10 (3H, s), 0.89–0.91 (12H, m), 1.26–1.52 (26H, m),
3.66–3.74 (1H, m), 4.08–4.12 (1H, m), 5.16–5.35 (2H, m), 5.77–
5.94 (1H, m); 13C NMR (50 MHz, CDCl3) d: -4.5, -4.4, 14.1, 18.1,
22.9, 25.6, 25.7, 25.8, 29.4, 29.5, 29.6, 29.7, 31.6, 31.9, 75.4, 75.8,
116.4, 136.6.
Acknowledgements
A.D. thanks CSIR, New Delhi for the award of a research
fellowship. Financial support from NCL, Pune (Project No.
MLP015826) is gratefully acknowledged.
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