Preparation of enantiopure long chain threo-2-amino-3-hydroxyesters via chiral morpholinone-derived azomethine ylids

Article abstract of DOI:10.1139/V06-121

The synthetic approach to threo-2-amino-3-hydroxyesters possessing long alkyl chains outlined herein centres on the generation of chiral azomethine ylids by reaction of (5R)-5-phenyl-morpholin-2-one, (R)-(1), with long chain aldehydes. In the presence of

Full text of DOI:10.1139/V06-121

1448
Preparation of enantiopure long chain threo-2-
amino-3-hydroxyesters via chiral morpholinone-
derived azomethine ylids1
Victoria A. Brome, Laurence M. Harwood, and Helen M.I. Osborn
Abstract: The synthetic approach to threo-2-amino-3-hydroxyesters possessing long alkyl chains outlined herein centres
on the generation of chiral azomethine ylids by reaction of (5R)-5-phenyl-morpholin-2-one, (R)-(1), with long chain al-
dehydes. In the presence of a second equivalent of aldehyde, the azomethine ylid can be trapped to afford a
cycloadduct with three new stereodefined centres. Degradation of the cycloadduct allows entry to β-substituted-α-amino
acid derivatives, which have potential as building blocks for sphingosine synthesis.
Key words: sphingosine, morpholinone, chiral azomethine ylid, dipolar cycloaddition.
Résumé : On a mis au point une approche à la synthèse de thréo-2-amino-3-hydroxyesters d’acides à longues chaînes
alkyles qui est centrée sur la génération d’ylures d’azométhines chiraux par la réaction de la (5R)-5-phénylmorpholin-2-
one, (R)-(1) avec des aldéhydes à longues chaînes. En présence d’un deuxième équivalent d’aldéhyde, l’ylure
d’azométhine peut être piégé pour conduire à la formation d’un cycloadduit comportant trois nouveaux centres stéréo-
définis. La dégradation du cycloadduit permet d’obtenir des dérivés d’acides α-aminés et β-substitués qui peuvent servir
de blocs dans la synthèse de sphingosines.
Mots clés : sphingosine, morpholinone, ylure d’azométhine chiral, cycloaddition dipolaire.
[Traduit par la Rédaction] Brome et al. 1455
Introduction
derived building blocks for accessing this family of com-
pounds (7).
Glycosphingolipids have been isolated from a variety of
natural sources, including marine sponge species of Agelas
and Axinella (1, 2). Such compounds demonstrate interesting
immunostimulatory activity, for example, the modulation of
protein kinase C activities and the regulation of hormone re-
ceptors and nerve cells (3). The glycosphingolipid structure
may be considered in two parts, namely, a sphingosine-
related component and a carbohydrate component (Fig. 1).
Generally, throughout the literature, the syntheses of the two
constituent units are considered independently.
Developments in the synthesis of the sphingolipid moiety
and its analogues have been recently reviewed (4), and since
the first nonstere ocontrolled synthesis of sphinganine by
Grob and Gadient (5), synthetic strategies have frequently
utilized various carbohydrate precursors (6) or serine-
The sphingosines can be looked upon as 3-hydroxy-2-
amino acid derivatives, and detailed examples of enantio-
and stereo-selective syntheses of β-hydroxy-α-amino acids
have been reviewed by Duthaler (8). Drawing on the find-
ings of Dellaria and Santarsiero’s investigation into the
alkylation of chiral glycine synthon equivalents in α-amino
acid synthesis (9), much work carried out within our group
has focused on the use of (R)- and (S)-5-phenyl-3,4,5,6-
tetrahydro-2H-1,4-oxazin-2-one (1) (referred to herein as 5-
phenylmorpholin-2-one) as a chiral relay system and its use
as a chiral template in the area of α-amino acid synthesis
(10). During the cycloaddition studies in which the ylid was
generated using paraformaldehyde, a minor product was
sometimes obtained, which neither corresponded to any of
the possible cycloadducts nor the diketopiperizine resulting
from dimerization of the template. Spectroscopic evidence
pointed to the minor product being 2a, a result of trapping
the azomethine ylid by a second equivalent of formaldehyde.
Confirmation that this was indeed the case was obtained
when reaction between the (S)-morpholin-2-one template
and excess paraformaldehyde yielded 2a in essentially quan-
titative yield. As the trapping of the azomethine ylid with a
second equivalent of aldehyde does not compete efficiently
with electron deficient alkenes and alkynes, it was concluded
that the rate of this reaction is appreciably slower than with
carbon–carbon dipolarophiles. When aldehydes other than
paraformaldehyde were used, a single adduct was observed
in every case, and these adducts (2b–2g) could be decons-
tructed to liberate enantiomerically pure threo-β-hydroxy-α-
Received 2 February 2005. Accepted 7 March 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 8 November 2006.
Dedicated with our best respects to Alfred Bader.
V.A. Brome, L.M. Harwood,2 and H.M.I. Osborn.3 School
of Chemistry, University of Reading, Whiteknights, Reading,
Berkshire, RG6 6AD, UK.
1This article is part of a Special Issue dedicated to Dr. Alfred
Bader.
2Corresponding author (e-mail: l.m.harwood@reading.ac.uk).
3Current address: School of Pharmacy, University of Reading,
Whiteknights, Reading, Berkshire, RG6 6AD, UK.
Can. J. Chem. 84: 1448–1455 (2006)
doi:10.1139/V06-121
© 2006 NRC Canada

Brome et al.
1449
Fig. 1. Representative structure for a galactosylsphingolipid.
Scheme 2. Reagents and conditions: (i) Excess (S)-
glyceraldehyde acetonide, 53%; (ii) 1 mol/L HCl, MeOH, reflux;
(iii) H2 (5 atm), Pd(OH)2/C, TFA (1 equiv.), aq. MeOH; (iv) ba-
sic ion-exchange resin, 95% over 3 steps.
R
OH
O
HO
HO
O
Me
m
NH OH
O
HO
O
Me
n
H
H
N
O
OH
Ph
O
H
ii), iii),
iv)
O
i)
H
Ph
N
O
Scheme 1. Reagents and conditions: (i) RCHO (excess), reflux;
(ii) 1 mol/L HCl, MeOH, reflux; (iii) H2 (5 atm), Pd(OH)2/C,
TFA (1 equiv.), aq. MeOH; (iv) basic ion-exchange resin.
O
O
H
H
O
O
(2h)
OH
H
R
H
H
N
Ph
Ph
N
O
CO2H
i)
HO
OH NH2
O
O
O
(3h)
(1)
Scheme 3. Reagents and conditions: See Table 1.
R
R
O
O
OH
H
N
H
ii), iii), iv)
R
Ph
R
Ph
N
CO2H
Ph
N
i)
R
H
O
H
H
NH2
O
O
O
O
O
R = H, (3a)
R = Phenyl,
p
R = Furyl,
R = Propyl,
R = Butyl, (3f)
R = Cyclohexyl, (3g)
(1)
-
R
R = H, (2a)
R = Phenyl, (2b)
R = C15H31 (4a)
(3b)
R = -OMe Phenyl,
(3d)
(3c)
R = -OMe Phenyl, (2c)
p
R = Furyl, (2d)
R = Propyl, (2e)
(3e)
Table 1. Effect of the number of equivalents of the added alde-
hyde on reaction yield and time.
(2f)
R = Butyl,
R = Cyclohexyl,
(2g)
Hexadecanal (equiv.) Reaction time Isolated yield of 4a (%)
3.0
1.5
1.1
48 h
72 h
5 d
18
34
65
amino acids (3b–3g) (Scheme 1) in good yields (11). The
value of this route was subsequently illustrated by a concise
synthesis of (+)-polyoxamic acid (3h) (Scheme 2) (12).
Results and discussion
NMR data were in agreement with those of cycloadducts
2e–2f, derived from lower homologue aliphatic aldehydes
(12), the hexadecanal-derived cycloadduct was tentatively
assigned as 4a (Scheme 3). It was clear that use of excess al-
dehyde in the cycloaddition reaction was not only wasteful
but was also hampering isolation and purification of the de-
sired product. The reaction conditions were therefore exam-
ined with the objective of achieving higher yields of the
pure hexadecanal-derived cycloadduct. To this end, the
number of equivalents of hexadecanal to (5R)-5-
phenylmorpholin-2-one was reduced from 3.0 to 1.5, the ra-
tionale being that reduced aldehyde contamination of the
crude product could simplify isolation of the cycloadduct.
TLC analysis of the reaction mixture after 72 h indicated
that the starting material had been almost completely con-
sumed and the crude reaction mixture was therefore purified,
resulting in the isolation of 34% of pure cycloadduct. Fur-
ther reduction to 1.1 equiv. of aldehyde required a reaction
time of 5 days before all starting morpholinone had been
consumed, but this resulted in a greatly improved yield of
65% of pure cycloadduct (4a) after a single purification
(Table 1).
To extend this methodology to allow preparation of long
chain hydroxyamino acids, which could act as precursors to
sphingosine analogues, preliminary investigations focused
on hexadecanal as a representative substrate, in terms of
alkyl chain length. Following our previous protocol, 3 equiv.
of the aldehyde were added to (5R)-5-phenylmorpholin-2-
one ((R)-(1)) (i.e., 6 mmol aldehyde : 1 mmol (R)-(1)) in to-
luene and the mixture was heated to reflux for 48 h, after
which time, TLC analysis indicated that all of the
morpholinone had been consumed. As the hexadecanal
proved to be far less polar than previous aldehydes em-
ployed in this reaction, the eluent chosen for chromato-
graphic purification had to reflect this; a system of 19:1
petroleum – diethyl ether proving the most efficient. Unfor-
tunately, only low yields (18%) of pure cycloadduct (4a)
were isolated under these conditions, with much of the re-
maining product being contaminated with residual
hexadecanal. NOE investigations of cycloadduct 4a failed to
determine conclusively the stereochemistry of the adduct,
the very large signal representing the aliphatic protons mask-
ing important regions in the 1H NMR spectrum. Addi-
tionally, the pure product was isolated as a waxy solid,
Thus, although reducing the number of equivalents of al-
dehyde in the reaction mixture necessitated an increase in
1
which was unsuitable for X-ray analysis. However, as H
© 2006 NRC Canada

1450
Can. J. Chem. Vol. 84, 2006
Table 3. Methanolysis of the cyloadducts
Table 2. Optimized yields of the cycloadducts of
(4b–4e).
(4a–4e)
Aldehyde
Yield of (cycloadduct) (%)
Cycloadduct
Yield of (methyl ester) %
Tetradecanal
Pentadecanal
Heptadecanal
Octadecanal
58 (4b)
68 (4c)
56 (4d)
62 (4e)
4a
4b
4c
4d
4e
81 (5a)
79 (5b)
82 (5c)
68 (5d)
56 (5e)
Scheme 4. Reagents and conditions: (i) MeOH, 5 mol/L HCl, re-
flux 1 h.
Scheme 5. Reagents and conditions: (i) H2 (5 atm), Pearlman’s
catalyst, TFA, MeOH (aq), 48 h.
R
OH
O
H
R
Ph
N
i)
Ph
N
OH
H
R
MeO2C
H
H
O
Ph
N
CO2Me
i)
R
HO
H
H2N
O
OH
R
CO2Me
HO
(4a)
(4b)
(5a)
(5b)
R = C15H31
R = C13H27
R = C14
R = C16H33 (4d)
R = C17 35 (4e)
R = C15H31
R = C13H27
(6a)
(6b)
29 (6c)
33 (6d)
35 (6e)
R = C15H31
R = C13H27
R = C15H31 (5a)
H29 (4c)
R = C14
R = C16H33 (5d)
R = C17 35 (5e)
H29 (5c)
R = C13
R = C14
R = C16
H27 (5b)
H29 (5c)
H33 (5d)
R = C14
R = C16
R = C17
H
H
H
H
H
(5e)
R = C17H35
reaction time, it resulted in a greater than three-fold increase
in yield and involved less wastage of aldehyde.
Table 4. Hydrogenolysis of the methyl esters
(5a–5e).
With the procedure for preparing the hexadecanal-derived
cycloadduct optimized, a range of analogues derived from
aldehydes with chain lengths between 14 and 18 carbon at-
oms was synthesized, utilizing 1.1 equiv. of aldehyde. In
each case a single cycloadduct (4b–4e) was isolated in an
acceptable yield after purification by column chromatogra-
phy (Table 2).
Methyl ester
Yield of
precursor (5)
(hydroxyamino ester) (6) %
5a
5b
5c
5d
5e
53 (6a)
60 (6b)
54 (6c)
66 (6d)
69 (6e)
The subsequent step of the synthesis was the opening of
the cycloadduct to afford the corresponding amino esters
(5a–5e). The two-step hydrolysis and hydrogenolysis se-
quence, previously shown to be the optimal procedure for
aliphatic aldehyde-derived cycloadducts, was adopted. Previ-
ously, the hydrolysis had been carried out in methanol at re-
flux using 1 mol/L hydrochloric acid to release the amino
ester, but when applied to the hexadecanal-derived cyclo-
adduct (4a), the conditions failed to effect hydrolysis, leav-
ing the starting material intact. It was observed that the
starting material was only sparingly soluble in aqueous
methanol at room temperature but was more soluble in hot
methanol. Thus, the effect of the addition of 5 mol/L hydro-
chloric acid to a hot methanolic solution of the cycloadduct
was investigated, and this furnished the corresponding
methyl ester in 1 h. In the first instance, the lactone-opened
products 5a–5e were isolated for characterization purposes
and were obtained in moderate to good yield (Scheme 4, Ta-
ble 3). These derivatives were solids, as opposed to the oils
obtained when using the lower homologue aldehydes. The
proposed structure for the hexadecanal-derived methyl ester
5a, (a representative example) was supported by characteris-
Following the previously developed reaction protocol
(11b), it was envisaged that the crude hydrolysis reaction
mixture would be concentrated and subjected directly to
hydrogenolysis at 5 bar (1 bar = 100 kPa) using Pearlman’s
catalyst and TFA in methanol. The first complication en-
countered was the insolubility of the crude reaction mixture
in methanol. Therefore, to aid solubility, a 10:1 ratio of
methanol to ethyl acetate was used. Continuing with the
standardized conditions, the amino ester was subjected to
hydrogenolysis, but after 48 h there was no evidence of reac-
tion. Gratifyingly, when the hydrolysis products (5a–5e)
were purified by column chromatography prior to hydroge-
nation, the reactions proceeded efficiently. Presumably, com-
ponents of the crude reaction mixtures were poisoning the
catalyst. A further deviation from the original method when
applied to the longer aliphatic chain analogues was the final
purification procedure. The original method (11b) used ion
exchange chromatography to afford the free amino acids as
colourless solids in near quantitative yields, but the
hexadecanal analogue could not be treated in the same way,
as the hydrogenolysis product was insoluble in water, and so
more conventional silica gel chromatography was imple-
mented. As a result, the final product was isolated as the
methyl ester 6a (Scheme 5), as opposed to the free β-
hydroxy-α-amino acid. In this way, all the long chain
hydroxyamino esters (6a–6e) could be isolated in pure form
and in acceptable yields (Table 4). In all cases, detailed
1
tic H NMR data, which displayed a multiplet at 7.30 ppm
representing the five aromatic protons; a one proton doublet
at 3.17 ppm corresponding to the proton α to the amino
group and a one proton multiplet at 3.75–3.68 ppm for the
methane proton α to the hydroxyl functionality. A set of
overlapping multiplets, integrating to 30 protons, due to the
aliphatic hydrogens of the long alkyl chain, dominated the
spectrum.
© 2006 NRC Canada

Brome et al.
1451
units g 100 mL–1. Readings were measured using a
PerkinElmer 341 polarimeter.
Scheme 6. Reagents and conditions: (i) p-TsCl, imidazole,
DMAP, DCM, 43%; (ii) LiBH4, THF, rt, 74%.
Melting points were obtained using a Reichert Kofler
heated-stage microscope and are uncorrected. Flash column
chromatography was performed according to the method of
Still (13) with silica gel 60 (Merck 9385) using head pres-
sure by the means of hand bellows. TLC analyses were car-
ried out using 0.25 mm silica gel precoated aluminium or
glass-backed plates with fluorescent indicator UV254. Spots
were visualized either by the quenching of UV fluorescence
or by staining with an acidic ammonium heptamolydate so-
lution.
MeO2C
MeO2C
H
H
i)
ii)
H
H2N
OH
C14H29
H
TsHN
OH
14H29
C
(7)
(6c)
HO
H
H
TsHN
OH
C14H29
(8)
Reagents obtained from Acros Organics (Loughborough,
UK), Aldrich (Gillingham, UK), Avocado (Heysham, UK),
Fluka (Gillingham, UK), and Lancaster fine chemicals
(Morecombe, UK) suppliers were used directly as supplied
or following purification according to standard procedures.
Acetonitrile and dichloromethane were dried by distillation
from calcium hydride under nitrogen. Tetrahydrofuran was
dried by distillation from sodium-benzophenone ketyl under
nitrogen. Petrol refers to light petroleum ether in the boiling
point range 30–40 °C, which was fractionally distilled
through a Vigreux column prior to use. (5R)-5-Phenylmor-
pholin-2-one was synthesized according to the literature pro-
cedure (9). The long chain aldehydes were obtained in
quantitative yield from the corresponding commercially
available alcohols by oxidation using 4-methylmorpholine-
N-oxide (1.5 equiv.) and tetra-n-propylammonium perruthenate
(5 mol%) in dichlorormethane at room temperature in the
presence of 4A molecular sieves (14).
spectroscopic analysis showed these final products to be ho-
mogeneous with a resonance for the proton α- to the amino
group, appearing as a doublet between 3.52 and 3.45 ppm,
corresponding to the equivalent proton in the pentanal-
derived material (3.45 ppm).
In a further illustrative extension of how these long chain
hydroxyamino esters could be converted into N-protected
sphingosine analogues, 6c was N-tosylated to yield 7 in 43%
isolated yield, and this was subsequently reduced to diol 8 in
74% yield using lithium borohydride in THF (Scheme 6).
Conclusions
In conclusion, we have developed protocols in which long
chain aliphatic aldehydes will undergo 1,3-dipolar cyclo-
additions with (5R)-5-phenyl-morpholin-2-one to furnish
cycloadducts containing three newly defined stereocentres in
good yield. Degradation of these cycloadducts affords
diastereomerically and enantiomerically pure β-substituted-
α-amino acid derivatives, and further modification can fur-
nish sphingosine analogues suitable for coupling to appro-
priate carbohydrate donors.
General method for preparation of cycloadducts (4a–4e)
The requisite aldehyde (2.2 mmol, 1.1 equiv.) was added
to a solution of (5R)-5-phenylmorpholin-2-one ((R)-(1),
1.0 mmol, 1 equiv.) in anhydrous toluene (40 cm3). The
flask was fitted with a magnetic stir.bar, a Soxhlet extractor
containing 4A molecular sieves, and a condenser. The reac-
tion mixture was heated to reflux under nitrogen for 5 d. The
solvent was removed in vacuo, and the resulting pale yellow
oil was subjected to column chromatography (diethyl ether –
petroleum ether, 1:19) to yield the corresponding
cycloadduct.
Experimental section
General techniques
1H NMR spectra were recorded on either a Bruker AMX
400 NMR (400 MHz) or a Bruker DPX 250 (250 MHz)
spectrometer in chloroform-d or dimethyl sulfoxide-d and
referenced to the residual solvent residual proton. Signal po-
sitions were recorded in δ ppm with the abbreviations s, d, t,
q, quint., br, and m denoting singlet, doublet, triplet, quartet,
quintet, broad, and multiplet, respectively. 13C NMR spectra
were recorded on the same spectrometers listed above at ei-
ther 100 or 62.5 MHz, respectively, and were referenced to
chloroform-d or dimethyl sulfoxide-d. All NMR chemical
shifts are quoted in ppm.
(2R,6R,7S,9R)-2-Phenyl-7,9-dipentadecyl-1-aza-4,8-
dioxabicyclo[4.3.01.6]nonan-5-one (4a)
Yield 65%; colourless needles; mp 53 to 54 °C. [α]20
–
D
4.8 (c 1.0, CHCl3). IR (KBr disc, cm–1) νmax: 2920, 1730
1
(lactone C=O). H NMR (250 MHz, CDCl3) δ: 0.94 (6H, t,
J = 6.5, alkyl CH3), 1.00–1.20 (60H, m, alkyl CH2), 3.73
(1H, d, J = 8.2, H-6), 3.84 (1H, dd, J = 3.6, J′ = 10.5, H-
3eq), 4.10 (1H, dt, J = 3.3, J′ = 9.6, H-7), 4.18 (1H, dd, J =
3.5, J′ = 10.3, H-2), 4.23 (1H, t, J = 10.3, J′ = 10.5, H-3ax),
4.32–4.26 (1H, m, H-9), 7.37–7.33 (5H, m, Ph-H). 13C NMR
(60 MHz, CDCl3) δ: 14.5 (alkyl CH3), 23.1, 24.8, 26.6, 29.6,
29.7, 29.8, 29.9, 30.1, 32.3, 35.3, 35.9 (alkyl CH2), 60.1 (C-
3), 63.7 (C-6), 72.9 (C-2), 79.2 (C-7), 97.3 (C-9), 128.5,
129.1, 129.2, 137.4 (Ar–C), 169.8 (C=O). CI-MS m/z (%):
640 ([M + NH4]+, 8), 400 (74), 252 (39), 216 (70), 104
(100). HR-MS calcd. for C42H77O3N2 ([M + NH4]+):
640.5669; found: 640.5665.
Infrared spectra were recorded on a PerkinElmer 1720-X.
Spectra were analysed as either thin films between sodium
chloride plates or as potassium bromide disks.
Mass spectra (m/z) and accurate mass (HR-MS) were re-
corded under conditions of electron impact (EI) or chemical
ionization using ammonia as the ionizing source (CI). The
instrument used was a Fisons VG Autospec mass spectrome-
ter.
Specific rotations ([α]20D) were recorded using the sodium
D line (589.3 nm) in the appropriate solvent and are quoted
in 10–1 deg cm2 g–1. Solution conentrations are given in the
© 2006 NRC Canada

1452
Can. J. Chem. Vol. 84, 2006
J = 3.5, J′ = 11.4, H-2), 4.31 (1H, dd, J = 10.5, J′ = 11.4, H-
3ax), 4.34–4.38 (1H, m, H-9), 7.33–7.39 (5H, m, Ph–H). 13C
NMR (60 MHz, CDCl3) δ: 14.5 (alkyl CH3), 22.7, 23.1,
24.8, 26.6, 29.6, 29.8, 29.9, 30.1, 32.3, 35.3, 35.9 (alkyl
CH2), 60.1 (C-3), 63.7 (C-6), 72.9 (C-2), 79.2 (C-7), 97.3
(C-9), 128.5, 129.1, 129.2, 137.5 (Ar–C), 169.7 (C=O). CI-
MS m/z (%): 696 ([MH]+, 7), 428 (100), 216 (51), 131 (12),
81 (22). HR-MS calcd. for C46H82O3N ([MH]+): 696.6294;
found: 696.6299.
(2R,6R,7S,9R)-2-Phenyl-7,9-ditridecyl-1-aza-4,8-
dioxabicyclo[4.3.01.6]nonan-5-one (4b)
Yield 58%; colourless solid; mp 46 to 47 °C. [α]20 –5.0
D
(c 1.0, CHCl3); IR (CHCl3, cm–1)νmax: 2955 (Ph–H), 2850
1
(C–H), 1730 (C=O). H NMR (250 MHz, CDCl3) δ: 0.88
(6H, t, J = 6.7, alkyl CH3), 1.01–1.62 (48H, m, alkyl CH2),
3.81 (1H, d, J = 8.2, H-6), 3.92 (1H, dd, J = 3.5, J′ = 10.7,
H-3eq), 4.17 (1H, dt, J = 3.2, J′ = 8.3, H-7), 4.18 (1H, dd,
J = 3.5, J′ = 11.4, H-2), 4.26 (1H, dd, J = 10.7, J′ = 11.4, H-
3ax), 4.31–4.34 (1H, m, H-9), 7.32–7.39 (5H, Ph–H). 13C
NMR (60 MHz, CDCl3) δ: 14.1 (alkyl CH3), 22.1, 22.7,
24.4, 26.2, 29.2, 29.4, 29.5, 29.6, 29.7, 31.9, 34.9, 35.5, 43.9
(alkyl CH2), 59.7 (C-3), 63.3 (C-6), 72.5 (C-2), 78.8 (C-7),
96.9 (C-9), 128.1, 128.3, 128.7, 128.8, 137.1 (Ar–C), 169.4
(C=O). CI-MS m/z (%): 584 ([MH]+, 24), 372 (100), 216
(44), 104 (47), 68 (27). HR-MS calcd. for C37H66O3N
([MH]+): 584.5042; found: 584.5052.
General procedure for the preparation of amino esters
(5a–5e)
Cycloadduct 4 (100 mg) was dissolved in methanol
(4 cm3), and 5 mol/L of hydrochloric acid (1 cm3) was
added. The reaction mixture was heated to reflux and left to
stir under nitrogen for 2 h. Saturated sodium carbonate solu-
tion (5 cm3) was added, and the aqueous layer separated and
extracted with ethyl acetate (5 × 5 cm3). The organic phases
were combined, washed with brine, dried (MgSO4), filtered,
and the excess solvent removed in vacuo to give a yellow
oil, which was subjected to column chromatography (eluent
petrol – diethyl ether, 4:1, then 10% methanol) to afford the
corresponding amino ester.
(2R,6R,7S,9R)-2-Phenyl-7,9-ditetradecyl-1-aza-4,8-
dioxabicyclo[4.3.01.6]nonan-5-one (4c)
Yield 68%; colourless solid; mp 57 to 58 °C. [α]20 –5.7
D
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 2920 (Ph–H), 2850
1
(C–H), 1730 (C=O). H NMR (250 MHz, CDCl3) δ: 0.87
(6H, t, J = 6.3, alkyl CH3), 1.25–1.65 (52H, m, alkyl CH2),
3.81 (1H, d, J = 8.2, C-6), 3.92 (1H, dd, J = 3.6, J′ = 10.5,
H-3eq), 4.16 (1H, dt, J = 3.3, J′ = 8.2, H-7), 4.24 (1H, dd,
J = 3.6, J′ = 11.5, H-2), 4.26 (1H, dd, J = 10.5, J′ = 11.5, H-
3ax), 4.35–4.38 (1H, m, H-9), 7.32–7.39 (5H, m, Ph–H). 13C
NMR (60 MHz, CDCl3) δ: 14.5 (alkyl CH3), 23.1, 24.8,
26.6, 29.6, 29.8, 29.9, 30.0, 30.1, 32.3, 35.3, 35.9 (alkyl
CH2), 60.1 (C-3), 63.7 (C-6), 72.9 (C-2), 79.2 (C-7), 97.3
(C-9), 128.5, 129.1, 129.2, 137.5 (Ar–C), 169.8 (C=O). CI-
MS m/z (%): 612 ([MH]+, 10), 386 (100), 216 (47), 81 (27).
HR-MS calcd. for C40H70O3N ([MH]+): 612.5355; found:
612.5368.
Methyl (2R,3S,1′R)-(2N-2′-hydroxy-1′-phenylethylamino)-
3-hydroxyoctadecanoate (5a)
Yield 81%; colourless solid; mp 61 to 62 °C. [α]20 –26.5
(c 1.0, MeOH). IR (KBr disc, cm1) νmax: 3335 (O–HD), 2920
(Ar–H), 2850 (C–H), 1740 (C=O). 1H NMR (250 MHz,
CDCl3) δ: 0.91 (3H, t, alkyl CH3), 1.40–1.18 (26H, m, alkyl
CH2), 2.00 (2H, bs, NH and OH), 3.17 (1H, d, J = 5.3,
CHCO2CH3), 3.48 (3H, s, CO2CH3), 3.66–3.64 (3H, m,
CH2OH and PhCH), 3.75–3.68 (1H, m, CHOH), 7.37–7.23
(5H, m, Ph–H). 13C NMR (60 MHz, CDCl3) δ: 14.9 (alkyl
CH3), 24.2, 27.1, 30.9, 31.0, 31.1, 31.2, 33.5, 35.2 (alkyl
CH2), 52.5 (CO2CH3), 67.2, 67.3 (CHCO2CH3 and CHOH),
68.0 (CH2OH), 74.0 (PhCH), 129.0, 129.4, 129.8, 142.3
(Ar–C), 176.0 (C=O). CI-MS m/z (%): 450 ([MH]+, 2), 210
(60), 178 (100). HR-MS calcd. for C27H48O4N ([MH]+):
450.3583; found: 450.3596.
(2R,6R,7S,9R)-2-Phenyl-7,9-dihexadecyl-1-aza-4,8-
dioxabicyclo[4.3.01.6]nonan-5-one (4d)
Yield 56%; colourless solid; mp 67 to 68 °C. [α]20 –14.1
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 2920 (Ph–HD), 2850
1
(C–H), 1730 (C=O). H NMR (250 MHz, CDCl3) δ: 0.88
(6H, t, J = 6.6, alkyl CH2), 1.13–1.70 (64H, m, alkyl CH2),
3.81 (1H, d, J = 8.2, H-6), 3.92 (1H, dd, J = 3.6, J′ = 10.4,
H-3eq), 4.18 (1H, dt, J = 3.3, J′ = 8.2, H-2), 4.24 (1H, dd,
J = 3.6, J′ = 11.4, H-2), 4.31 (1H, dd, J = 10.4, J′ = 11.4, H-
3ax), 4.34–4.40 (1H, m, H-9), 7.31–7.40 (5H, m, Ph–H). 13C
NMR (60 MHz, CDCl3) δ: 14.5 (alkyl CH3), 23.1, 24.8,
26.6, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 32.3, 35.3, 35.9
(alkyl CH2), 60.1 (C-3), 63.7 (C-6), 72.8 (C-2), 79.2 (C-7),
97.3 (C-9), 128.5, 129.1, 129.2, 137.5 (Ph–H), 169.7 (C=O).
CI-MS m/z (%): 668 ([MH]+, 21), 414 (100), 266 (38), 216
(55), 104 (55). HR-MS calcd. for C44H77O3N ([MH]+):
668.5981; found: 668.5972.
Methyl (2R,3S,1′R)-(2N-2′-hydroxy-1′-phenylethylamino)-
3-hydroxyhexadecanoate (5b)
Yield 79%; colourless solid; mp 52 to 53 °C. [α]20 –24.5
D
(c 1.0, MeOH). IR (thin film, cm–1) νma1x: 1740 (C=O), 2850
(C–H), 2920 (Ph–H), 3320 br (O–H). H NMR (250 MHz,
MeOD) δ: 0.80 (3H, t, J = 6.3, alkyl CH3), 1.19–1.36
(24H, m, alkyl CH2), 3.07 (1H, d, J = 5.9, CHCO2CH3),
3.26 (3H, s, CO2CH3), 3.51 (2H, dd, J = 4.1, J′ = 6.9,
CH2OH), 3.55–3.64 (2H, CHPh and CHOH), 7.13–7.20
(5H, m, Ph–H). 13C NMR (60 MHz, MeOD) δ: 14.6 (alkyl
CH3), 24.2, 27.1, 30.9, 31.0, 31.1, 31.2, 33.5, 35.2 (alkyl
CH2), 52.5 (CO2CH3), 67.2 (CHCO2CH3), 67.3 (CHPh),
68.1 (CH2OH), 73.9 (CHOH), 129.1, 129.4, 129.8, 142.4
(Ar–C), 176.1 (C=O). CI-MS m/z (%): 422 ([MH]+, 4), 210
(91), 178 (100), 118 (19). HR-MS calcd. for C25H44O4N
([MH]+): 422.3270; found: 422.3274.
(2R,6R,7S,9R)-2-Phenyl-7,9-diheptadecyl-1-aza-4,8-
dioxabicyclo[4.3.01.6]nonan-5-one (4e)
Yield 62%; colourless solid; mp 65 to 66 °C. [α]20 –9.1
D
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 2920 (Ph–H), 2850
1
(C–H), 1730 (C=O). H NMR (250 MHz, CDCl3) δ: 0.88
Methyl (2R,3S,1′R)-(2N-2′-hydroxy-1′-phenylethylamino)-
(6H, t, J = 6.4, alkyl CH3), 1.13–1.55 (68H, m, alkyl CH2),
3.81 (1H, d, J = 8.3, H-6), 3.92 (1H, dd, J = 3.6, J′ = 10.5,
H-3eq), 4.16 (1H, dt, J = 3.5, J′ = 8.3, H-7), 4.24 (1H, dd,
3-hydroxyheptadecanoate (5c)
Yield 82%; colourless solid; mp 56 to 57.5 °C. [α]20
–
23.6 (c 1.0, MeOH). IR (thin film, cm–1) νmax: 3370 (O–DH),
© 2006 NRC Canada

Brome et al.
1453
3025 (Ar–H), 2870 (C–H), 1735 (C=O). 1H NMR
(250 MHz, CDCl3) δ: 0.86 (3H, t, J = 7.0, CH2CH3), 1.25–
1.41 (6H, m, alkyl CH2), 3.12 (1H, d, J = 6.0, CHCO2CH3),
3.29 (3H, s, CO2CH3), 3.51–3.69 (4H, m, CH2OH, PhCH,
CHOH), 7.13–7.39 (5H, m, Ph–H). 13C NMR (60 MHz,
CDCl3) δ: 14.8 (alkyl CH3), 24.0, 29.4, 34.9 (alkyl CH3),
52.5 (CO2CH3), 67.3, 67.4 (CHCO2CH3 and CHOH), 68.1
(CH2OH), 73.9 (PhCH), 129.1, 129.4, 129.8, 142.2 (Ar–C),
176.1 (C=O). CI-MS m/z (%): 296 ([MH]+, 75), 264 (47),
210 (38), 178 (100), 118 (35). HR-MS calcd. for C16H26O4N
([MH]+): 296.1862; found: 296.1864.
Methyl (2R,3S)-2-amino-3-hydroxyoctadecanoate (6a)
Yield 53%; colourless solid; mp 74–76.5 °C. [α]20 –10.5
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3355 (N–HD), 3130
(O–H), 2915, 2840 (C–H), 1720 (C=O). 1H NMR
(250 MHz, D6 acetone) δ: 0.82 (3H, t, J = 6.4 alkyl CH3),
1.19–1.38 (28H, m, alkyl CH2), 3.45 (1H, d, J = CHNH2),
3.53 (3H, s, COOCH3), 3.62–3.74 (1H, m, CHOH). 13C
NMR (60 MHz, D6 acetone) δ: 14.8 (alkyl CH3), 23.7, 27.3,
29.3, 33.0, 36.2 (alkyl CH2), 52.9 (COOCH3), 66.2
(CHNH2), 81.5 (CHOH), 173.7 (C=O).
Methyl (2R,3S)-2-amino-3-hydroxyhexadecanoate (6b)
Yield 60%; colourless solid; mp 61–63 °C. [α]20D –14.3 (c
1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3345 (O–H), 2920,
2850 (C–H), 1680 (C=O). 13C NMR (250 MHz, D6 acetone)
δ: 0.75 (3H, t, J = 6.5, alkyl CH3, 1.16–1.40 (24H, m, alkyl
CH2), 3.52 (1H, d, J = 7.7, CHNH2), 3.60 (3H, s, CO2CH3),
3.64–3.72 (1H, m, CHOH). 13C NMR (60 MHz, D6 acetone)
δ: 14.8 (alkyl CH3), 23.7, 27.3, 29.3, 31.1, 33.0, 36.2 (alkyl
CH2),52.9 (COOCH3), 66.1 (CHNH2), 81.5 (CHOH), 173.5
(C=O). CI-MS m/z (%): 302 ([MH]+, 89), 242 (10), 89
(100). HR-MS calcd. for C17H36O3N ([MH]+): 302.2695;
found: 302.2708.
Methyl (2R,3S,1′R)-(2N-2′-hydroxy-1′-phenylethylamino)-
3-hydroxynonadecanoate (5d)
Yield 68%; colourless solid; mp 64–65.5 °C. [α]20 –21.7
(c 1.0, CHCl3). IR (KBr disc, cm1) νmax: 3351 (O–HD), 2920
(Ar–H), 2855 (C–H), 1740 (C=O). 1H NMR (250 MHz,
MeOD) δ: 0.80 (3H, t, J = 6.2 alkyl CH3), 1.36–1.19
(28H, m, alkyl CH2), 3.07 (1H, d, J = 5.9, CHCO2CH3),
3.25 (3H, s, CO2CH3), 3.48–3.51 (3H, m, CH2OH and
PhCH), 3.56–3.64 (1H, m, CHOH), 7.12–7.20 (5H, m, Ph-
H). 13C NMR (60 MHz, MeOD) δ: 14.9 (alkyl CH3), 24.2,
27.1, 30.9, 31.0, 31.1, 31.2, 33.5, 35.2 (alkyl CH2), 52.5
(CO2CH3), 67.2, 67.3 (CHCO2CH3 and CHOH), 68.1
(CH2OH), 74.0 (PhCH), 129.1, 129.4, 129.8, 142.4 (Ar–C),
176.1 (C=O). CI-MS m/z (%): 446 ([MH]+-H2O, 9), 414
(19), 210 (10), 178 (100), 118 (15). HR-MS calcd. for
C28H49O3N ([MH]+-H2O): 446.3634; found: 446.3448.
Methyl (2R,3S)-2-amino-3-hydroxyheptadecanoate (6c)
Yield 54%; colourless solid; mp 75–77.5 °C. [α]20 –16.8
D
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3135 (O–H), 2915,
1
2845 (C–H), 1735 (C=O). H NMR (250 MHz, D6 acetone)
δ: 0.75 (3H, t, J = 6.4, alkyl CH3), 1.25–1.45 (26H, m, alkyl
CH2), 3.48 (1H, d, J = 7.7, CHNH2), 3.57 (3H, s, COOCH3),
3.59–3.70 (1H, m, CHOH). 13C NMR (60 MHz, D6 acetone)
δ: 14.8 (alkyl CH3), 23.7, 27.3, 28.2, 33.0, 36.3 (alkyl CH),
52.8 (COOCH3), 66.4 (CHNH2), 81.7 (CHOH), 173.6
(C=O). CI-MS m/z (%): 316 ([MH]+, 100), 256 (10), 89
(50). HR-MS calcd. for C18H38O3N ([MH]+): 316.2852;
found: 316.2847.
Methyl (2R,3S,1′R)-(2N-2′-hydroxy-1′-phenylethylamino)-
3-hydroxyicosanoate (5e)
Yield 56%; colourless solid; mp 59–61 °C. [α]20 –23.8
(c 1.0, CHCl3). IR (CHCl3, cm1) νmax: 3315 (O-HD), 2920
(Ar–H), 2850 (C–H), 1740 (C=O). 1H NMR (250 MHz,
MeOD) δ: 0.80 (3H, t, J = 6.2, alkyl CH3), 1.19–1.36
(30H, m, alkyl CH2), 3.07 (1H, d, J = 5.9, CHCO2CH3),
3.26 (3H, s, CO2CH3), 3.48–3.51 (3H, m, CH2OH and
PhCH), 3.56–3.62 (1H, m, CHOH), 7.13–7.20 (5H, m, Ph-
H). 13C NMR (60 MHz, MeOD) δ: 14.9 (alkyl CH3), 24.2,
27.1, 30.9, 31.0, 31.1, 31.2, 33.5, 35.2 (alkyl CH2), 52.5
(CO2CH3), 67.2, 67.3 (CHCO2CH3 and CHOH), 68.1
(CH2OH), 74.0 (PhCH), 129.1, 129.4, 129.8, 142.4 (Ar–C),
176.1 (C=O). CI-MS m/z (%): 460 ([MH]+-H2O, 12), 428
(76), 268 (16), 216 (25), 178 (100), 104 (37). HR-MS calcd.
for C29H50O3N ([MH]+-H2O): 460.3790; found: 460.3799.
Methyl (2R,3S)-2-amino-3-hydroxynonadecanoate (6d)
Yield 66%; colourless solid; mp 84–86.5 °C. [α]20 –6.1
D
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3130 (O–H), 1720
1
(C=O). H NMR (250 MHz, acetone) δ: 0.75 (3H, t, J = 6.2,
alkyl CH3), 1.24–1.53 (30H, m, alkyl CH2), 2.76 (3H, br s,
NH2 and OH), 3.47 (1H, d, J = 7.7, CHNH2), 3.62 (3H, s,
COOCH3), 3.63–3.67 (1H, m, CHOH). 13C NMR (60 MHz,
D6 acetone) δ: 14.7 (alkyl CH3), 23.7, 27.3, 33.0, 36.3 (alkyl
CH2), 52.8 (COOCH3), 66.3 (CHNH2), 81.6 (CHOH), 173.6
(C=O). CI-MS m/z (%): 326 ([MH]+-H2O, 69), 266 (18),
115 (100), 82 (13), 56 (25). HR-MS calcd. for C20H39O2N
([MH]+-H2O): 326.3059; found: 326.3043.
General method for the preparation of long chain
amino acid methyl esters (6a–6e)
Amino ester (1 equiv.) was dissolved in methanol, and
water (10:1) and Pearlman’s catalyst were added (weight for
weight of amino ester) followed by the addition of
trifluoroacetic acid (1 equiv.). The system was degassed and
hydrogen introduced. The system was once again degassed
and hydrogen re-introduced. The reaction mixture was
warmed to 50 °C and left to stir for 16 h. The hydrogen was
released, and the reaction mixture filtered through Celite®
and the filtrate concentrated in vacuo. The residue was sub-
jected to column chromatography (eluent petrol – diethyl
ether, 1:1, then 10% methanol) to afford the amino acid
methyl ester.
Methyl (2R,3S)-2-amino-3-hydroxyicosanoate (6e)
Yield 69%; colourless solid; mp 86 to 87 °C. [α]20 –7.1
(c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3140 (O–H),D2915,
1
2845 (C–H), 1720 (C=O). H NMR (250 MHz, D6 acetone)
δ: 0.75 (3H, t, J = 6.2, alkyl CH3), 1.28–1.54 (32H, m, alkyl
CH2), 2.76 (3H, br s, NH2 and OH), 3.47 (1H, d, J = 7.7,
CHNH2), 3.59 (3H, s, COOCH3), 3.62–3.65 (1H, m,
CHOH). 13C NMR (60 MHz, D6 acetone) δ: 14.8 (alkyl
CH3), 23.7, 27.3, 33.0, 36.3 (alkyl CH2), 52.8 (COOCH3),
66.3 (CHNH2), 81.6 (CHOH), 173.6 (C=O). CI-MS m/z (%):
358 ([MH]+, 26), 90 (100). HR-MS calcd. for C21H44NO3
([MH]+): 358.3321; found: 358.3313.
© 2006 NRC Canada

1454
Can. J. Chem. Vol. 84, 2006
Methyl (2R,3S)-3-hydroxy-2-(toluenesulfonyl-
amino)heptadecanoate (7)
References
Amino ester 6c (74 mg, 0.0.23 mmol) was dissolved in
anhydrous dichloromethane (5 cm3), and freshly recrystallized
p-toluenesulfonyl chloride (45 mg, 0.23 mmol, 1 equiv.) was
added followed by dimethylaminopyridine (2 drops). The re-
action mixture was left to stir under an atmosphere of nitro-
gen for 16 h. Water was added (5 cm3), the organic layer
was separated, and the aqueous phase extracted with di-
chloromethane (5 × 10 cm3). The organic fractions were
combined, dried (MgSO4), filtered, and the solvent removed
in vacuo. The residue was purified by column chromatogra-
phy, eluting with dichloromethane–acetone (10:1), to afford
the title compound as a colourless solid (47 mg, 43%), mp
85 to 86 °C. [α]20 –15.3 (c 1.0, CHCl3). IR (CHCl3, cm–1)
1. (a) V. Constantino, E. Fattorusso, and A. Mangoni. Tetrahe-
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1
(SO2). H NMR (250 MHz, CDCl3) δ: 0.81 (3H, t, J = 6.4,
alkyl CH3), 1.19–1.47 (26H, m, alkyl CH2), 2.22 (1H, br s,
O–H), 2.34 (3H, s, Ph–CH3), 3.45 (3H, s, COOCH3), 3.80–
3.85 (2H, m, CHOH, CHNHTs), 5.58 (1H, d, J = 9.6,
NHPhCH3), 7.21 (2H, d, J = 8.4, m-Ph–H), 7.65 (2H, d, J =
8.4, o-Ph–H). 13C NMR (60 MHz, CDCl3) δ: 14.5 (alkyl
CH3), 21.9 (Ph–CH3), 23.1, 25.8, 29.8, 29.9, 30.0, 30.1,
30.1, 32.3, 34.0 (alkyl CH2), 53.0 (COOCH3), 59.9
(CHNHTs), 72.8 (CHOH), 127.6 (m-Ar–C), 129.9 (o-Ar–C),
137.3 (p-Ar–C), 144.0 (i-Ar–C), 171.5 (C=O).
(2S,3R)-2-(Toluenesulfonylamino)heptadecan-1,3-diol (8)
The N-protected amino ester 7 (49 mg, 0.098 mmol) was
dissolved in anhydrous THF (5 cm3), and lithium
borohydride (2 mg, 0.36 mmol) was added. The reaction
mixture was left to stir under nitrogen for 16 h. Water
(5 cm3) was added, the organic phase separated, and the
aqueous phase extracted with ethyl acetate (5 × 5 cm3). The
organic fractions were combined, dried (MgSO4), filtered,
and the solvent removed in vacuo, to afford the title com-
pound as a colourless solid (32 mg, 74%), mp 80 to 81 °C.
[α]20 +10.6 (c 1.0, CHCl3). IR (CHCl3, cm–1) νmax: 3415
D
1
(O–H), 2910, 2840 (C–H), 1160 (SO2). H NMR (250 MHz,
CDCl3) δ: 0.81 (3H, t, J = 6.3, alkyl CH3), 1.04–1.27
(26H, m, alkyl CH2), 2.35 (3H, s, Ph–CH3), 2.87 (1H, br s,
O–H), 3.09–3.16 (1H, m, CHNHTs), 3.64 (2H, d, J = 3.7,
CH2OH), 3.71–3.79 (1H, m, CHOH), 5.57 (1H, d, J = 7.9,
NHTs), 7.22 (2H, d, J = 8.2, m-Ph–H), 7.71 (2H, d, J = 8.2,
o-Ph–H). 13C NMR (60 MHz, CDCl3) δ: 13.1 (alkyl CH3),
20.5 (Ph–CH3), 21.7, 24.4, 28.4, 28.5, 28.7, 28.7, 30.9, 32.8
(alkyl CH2), 55.7 (CHNHTs), 64.4 (CH2OH), 72.2 (CHOH),
126.1 (o-Ph–H), 128.7 (m-Ph–H), 136.6 (p-Ph–H), 142.5 (i-
Ph–H). CI-MS m/z (%): 442 ([MH]+, 100), 410 (15), 213
(15), 91 (7), 60 (10). HR-MS calcd. for C24H44O4SN
([MH]+): 442.2991; found: 442.2979.
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Acknowledgements
We are grateful to the University of Reading’s Research
Endowment Trust Fund for their financial support
(studentship to VAB).
© 2006 NRC Canada

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1455
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© 2006 NRC Canada