Aziridines as precursors for chiral amidie-containing surfactants

Article abstract of DOI:10.1021/jo962298a

Optically active aziridines can be used as precursors in the synthesis of several enantiopure amide-containing surfactants. Acylation of the aziridines is a convenient method for both the activation of the aziridine ring and the introduction of the hydrocarbon chain. The regioselectivity of the ring-opening reactions using dibenzyl phosphate could be controlled by varying the reaction temperature. In this way both regioisomers of the phospholipid analogues could be obtained. In the course of these experiments, an unprecedented rearrangement of α-acylamino phosphotriesters was observed. A mechanism for this group exchange reaction was proposed based on the compared reactivities of related compounds and FT-IR spectroscopic data. Application of high pressures (12 kBar) for the ring opening of the activated aziridines with imidazole led to the efficient formation of the desired surfactant with complete regioselectivity.

Full text of DOI:10.1021/jo962298a

J . Org. Chem. 1997, 62, 4955-4960
4955
Azir id in es a s P r ecu r sor s for Ch ir a l Am id e-Con ta in in g Su r fa cta n ts
N. A. J . M. Sommerdijk, P. J . J . A. Buynsters, H. Akdemir, D. G. Geurts, R. J . M. Nolte,* and
B. Zwanenburg*
Department of Organic Chemistry, NSR-Institute for Molecular Structure, Design and Synthesis,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received December 10, 1996X
Optically active aziridines can be used as precursors in the synthesis of several enantiopure amide-
containing surfactants. Acylation of the aziridines is a convenient method for both the activation
of the aziridine ring and the introduction of the hydrocarbon chain. The regioselectivity of the
ring-opening reactions using dibenzyl phosphate could be controlled by varying the reaction
temperature. In this way both regioisomers of the phospholipid analogues could be obtained. In
the course of these experiments, an unprecedented rearrangement of R-acylamino phosphotriesters
was observed. A mechanism for this group exchange reaction was proposed based on the compared
reactivities of related compounds and FT-IR spectroscopic data. Application of high pressures (12
kBar) for the ring opening of the activated aziridines with imidazole led to the efficient formation
of the desired surfactant with complete regioselectivity.
Sch em e 1
In tr od u ction
Following the discovery that phospholipid molecules
can form tubular, rodlike, and even helical structures,1
it has been demonstrated that chiral synthetic surfac-
tants can also be used to construct similar superstruc-
tures.2 The formation of these types of structures
requires a high degree of organization within the ag-
gregate in order to transfer the molecular chirality to the
supramolecular level. Interconnecting the surfactant
molecules by means of hydrogen bonding or π-π stacking
was shown to be most useful in achieving and stabilizing
these highly organized aggregates.2-4 In particular the
formation of hydrogen-bonded chains of secondary amides,
the so-called amide polymers, has been utilized success-
fully.4
introduce both the amide and phosphate moiety in
successive steps. The acylation of an aziridine function
served both as a peptide-coupling reaction and as an
activation step for the introduction of the phosphate
group by opening of the aziridine ring. This particular
reaction offers prospects for the synthesis of amide-
containing surfactants. Starting from a suitable aziri-
dine, only two reaction steps would suffice, in principle,
for the introduction of both a hydrocarbon chain and a
(protected) head group as depicted in Scheme 1 in a
retrosynthetic manner.
A synthetic pathway for the preparation of amide-
containing surfactants was developed in order to explore
the use of amide functions in the construction of chiral
aggregates. The synthesis of a series of new chiral
surfactant molecules based on a C3-skeleton having an
amide-linked hydrocarbon chain on the C(2)-position was
accomplished (Scheme 1). An ester or an ether group can
be present on the primary position, and a variety of polar
head groups can be introduced. A chiral precursor to
which different hydrocarbon chains and polar head
groups can be attached is required for the preparation
of these lipids. In this respect the synthesis of phospho-
peptides described by Okawa and co-workers is of inter-
est.5,6 These authors used the chemistry of aziridines to
Syn th esis of N-Acyla zir id in es
An established procedure for the synthesis of chiral
aziridines was employed,7-9 starting from the corre-
sponding epoxides (Scheme 2). In this process the
nucleophilic ring opening of the glycidyl derivatives 1
using sodium azide in 2-methoxyethanol/water10 gave a
mixture of the two regioisomeric azido alcohols in 77-
92% yield. The distilled mixture of azido alcohols was
transformed into only one stereoisomer of the aziridine,
however, by reaction with triphenylphosphine. In this
so-called Staudinger reaction,11 both azido alcohols react
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) (a) Bangham, A. D.; Horne, R. W. J . Mol. Biol. 1964, 8, 660-
668. (b) Papahadjopoulos, D.; Vail, W. J .; J acobson, K.; Poste, G.
Biochim. Biophys. Acta 1975, 394, 483-491. (c) Inoue, K.; Suzuki, K.;
Nojima, S. J . Biochem. 1977, 81, 1097-1106.
(2) Fuhrhop, J .-H.; Helfrich, W. Chem. Rev. 1993, 93, 1565 and
references cited therein.
(3) (a) Singh, A.; Burke, T. G.; Calvert, J . M.; Georger, J . H.;
Herendeen, B.; Price, R. R.; Schoen, P. E.; Yager, P. Chem. Phys. Lipids
1988, 47, 135. (b) Yanagawa, H.; Ogawa, Y.; Furuta, H.; Tsuno, K. J .
Am. Chem. Soc. 1989, 111, 4567. (c) Yamada, N.; Sasaki, T.; Murata,
H.; Kunitake, T. Chem. Lett. 1989, 205. (d) Frankel, D. A.; O’Brien, D.
F. J . Am. Chem. Soc. 1991, 113, 7436.
(4) (a) Pfannemu¨ller, B.; Welte, W. Chem. Phys. Lipids 1985, 37,
227. (b) Yamada, K.; Ihara, H.; Ide, T.; Fukumoto, T.; Hirayama, C.
Chem. Lett. 1984, 1713. (c) Nakashima, N.; Asakuma, S.; Kunitake,
T. J . Am. Chem. Soc. 1985, 107, 509. (d) Imae, T.; Takahashi, Y.;
Muramatsu, H. J . Am. Chem. Soc. 1992, 114, 3414.
(5) Okawa, K.; Yuli, M.; Tanaka, T. Chem. Lett. 1979, 1085.
(6) Okawa, K.; Nakajima, K. Biopolymers 1981, 20, 1811.
(7) Thijs, L.; Porskamp, J . J . M.; van Loon, A. A. W. M.; Derks, M.
P. W.; Feenstra, R. W.; Legters, J .; Zwanenburg, B. Tetrahedron 1990,
46, 2611.
(8) Legters, J .; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1987,
30, 4881.
(9) Legters, J .; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 1.
(10) Tanner, D.; He, H. M. Tetrahedron 1982, 48, 6079.
S0022-3263(96)02298-0 CCC: $14.00 © 1997 American Chemical Society

4956 J . Org. Chem., Vol. 62, No. 15, 1997
Sommerdijk et al.
Sch em e 2
crystallization from ethyl acetate, the acylated aziridines
5 were isolated as white solids in almost quantitative
yields.
Rin g Op en in g of N-Acyla zir id in es w ith Diben zyl
P h osp h a te
The synthesis of phosphopeptides by ring opening of
acylated aziridines using either dibenzyl phosphate or
phosphoric acid as the reagent has been reported to lead
to the respective products in good yields (64-92%).5
When dibenzyl phosphate was added to a solution of 5
in dichloromethane, a mixture of two products was
obtained (Scheme 3). Both compounds were isolated
using column chromatography and identified as the two
regioisomers 6 and 7, which arise from nucleophilic
attack on either (a) the primary C(1) or (b) the secondary
C(2) carbon atom. The ratio of 6 and 7 amounted to 1:1.
Different reaction temperatures were used with the
aim of improving the regioselectivity of the ring opening.
It was found that the product ratio could be changed from
6:7 ) 1:1 at room temperature to 6:7 ) 6:1 at -15 °C. At
temperatures lower than -30 °C, no reaction took place.
After column chromatography the two regioisomers could
always be isolated in pure form in a combined yield of
70-80%.
Surprisingly, it was found that butyrate derivatives
6b,c, after storage for several weeks, partially rearranged
to give 7b,c (Scheme 3, path c), whereas pure 6a did not
show any change during this period.14 Application of
longer reaction times or temperatures higher than room
temperature did not change the product ratio, indicating
that under the conditions of phosphorylation no rear-
rangement takes place.
This rearrangement of 6b,c into 7b,c, after their
isolation, can be avoided by immediate removal of the
benzyl groups by catalytic hydrogenation and subsequent
conversion into the respective disodium salts 8b,c (Scheme
4). Compound 8a and compounds 9 were obtained from
6a and 7, respectively, in an analogous manner.
Mech a n istic Asp ects of th e Rea r r a n gem en t of
with triphenylphosphine with concomitant extrusion of
nitrogen to form a regioisomeric mixture of phosphazo
compounds. Intramolecular addition of the hydroxyl
group leads to the formation of oxazaphospholidines,
which in related cases, have been isolated and character-
ized.12 Thermal cleavage of the P-N bond leads to the
intramolecular substitution of the triphenylphosphine
oxide group, resulting in the formation of an aziridine.
The stereochemistry at either carbon atom in the aziri-
dine ring is inverted compared with the stereochemistry
at the starting epoxide. The inversion of the stereogenic
center at C(2) takes place either during the epoxide ring
opening or when the Ph3PO group is displaced during
the Staudinger reaction, depending on the site of the
initial nucleophilic attack.
r-Acyla m in o P h osp h a te Tr iester s
The rearrangement in R-acylamino phosphate triesters
6b,c into 7b,c, described in the preceding section, has
no precedent in the literature. It is important to note
that no byproducts of any sort were observed during this
rearrangement. That the phenoxy derivative 6a does not
show this group exchange reaction is relevant for the
mechanism. The findings suggest that a neighboring
group participation of the butyrate ester group may be
involved in the rearrangement. However, a nucleophilic
displacement of the amido group by intramolecular
attack of the ester carbonyl group either in an SN1 or
SN2 fashion should lead to the formation of a dioxolenium
ion, and as a consequence a product resulting from a shift
of the butyrate to the C(2) carbon atom may be expected.
No such product was observed, which makes the above
When the reaction was carried out on a gram scale,
the aziridines 4 could be isolated in 55-75% yield.13 The
obtained (S)-(-)-aziridines 4 were acylated using differ-
ent fatty acid chlorides in dichloromethane with triethyl-
amine as the base. After column chromatography and
(13) When the reaction was carried out using larger quantities, the
yield of isolated product decreased drastically, probably due to
decomposition of the product during chromatography. Attempts to
improve the yield of the reaction on
a multigram scale, viz. by
distillation of the reaction mixture or acid-base extraction, were not
(11) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437.
(12) Smits, J . M. M.; Beurskens, P. T.; Thijs, L.; van Loon, A. A. W.
M.; Zwanenburg, B. J . Crystallogr. Spectrosc. Res. 1988, 18, 625.
successful.
(14) The product isolated after the rearrangement gave the same
optical rotation as the one obtained initially from the phosphorylation
reaction.

Synthons for Chiral Amide-Containing Surfactants
J . Org. Chem., Vol. 62, No. 15, 1997 4957
Sch em e 3
Sch em e 4
broadening of the PdO vibration was also observed,
suggesting a hydrogen bond between the N-H of the
amide and the PdO of the phosphate group. The
formation of such a hydrogen bond would again enhance
the nucleophilic character of the amide nitrogen atom.
Attack on the primary carbon atom bearing the phos-
phate group is not possible due to the induced syn
orientation of the phosphate with respect to the amide,
and no rearrangement takes place (Scheme 4).
Rin g Op en in g of N-Acyla zir id in es w ith Im id a zole
The nucleophilic ring opening of acylated aziridines 5a
and 5b by imidazole was first carried out by using sodium
imidazolate in DMF at 80 °C. After 2 days, TLC analysis
of the mixture showed the formation of several products.
In both cases 11 could be obtained in only 12-15% yield,
after column chromatography.
proposal less likely. A different role for the ester should
therefore be considered. The following proposal for the
rearrangement could account for the observations. It is
assumed that the ester carbonyl group forms an intramo-
lecular bond with the amide hydrogen (Scheme 4). In
this manner the nucleophilicity of the amide nitrogen will
be enhanced, and a displacement of the dibenzyl phos-
phate anion is now feasible via the formation of an
intermediate aziridine ring. Subsequent ring opening of
this three-membered ring by the dibenzyl phosphate
anion, which is still favorable, then leads to the observed
rearrangement products 7b,c.
The phosphorylation of 5 is carried out under acidic
conditions since a 2-fold excess of dibenzyl phosphate is
used. This is in agreement with the proposed mecha-
nism, because intermolecular protonation of the ester
carbonyl will prevent the formation of hydrogen bonds
and accordingly the rearrangement.
In order to substantiate the role of hydrogen bonding,
FT-IR spectra of a chloroform solution of 6b were
recorded. This revealed the presence of two ester car-
bonyl vibrations at 1744 and 1729 cm-1; the former is
typical for a free ester function, and the latter is indica-
tive of a hydrogen-bonded ester carbonyl.
Furthermore, the appearance of the amide I vibration
at relatively high wavenumbers (1681 cm-1) indicates the
presence of an electron-rich amide group, supporting the
increased nucleophilic character of the nitrogen atom.
The FT-IR spectra of 6a showed the amide I vibration at
high wavenumbers (1681 cm-1); however, in addition a
In spite of the poor nucleophilicity of imidazole,15 the
use of this agent without the addition of a base was
considered. A ring-opening reaction should proceed via
the dipolar transition state 10 (Scheme 5). The formation
of such a transition state will cause the solvent molecules
to align their dipoles in a manner that electronically
compensates the separation of charges. This will lead
to a higher degree of organization and hence to a
contraction of the volume of the reaction mixture. This
negative volume of activation offers possibilities for the
use of high pressure in accelerating product formation.16
A series of experiments was performed using equimolar
amounts of 5c and imidazole in different solvents at 12
kBar.17 It was found that the reaction in chloroform
showed the highest degree of conversion. However, even
after 48 h, only 50% of the starting material had been
consumed. The reaction was still incomplete after 4 days
(15) (a) Grimett, M. R. Advances in Imidazole Chemistry. Advances
in Heterocyclic Chemistry; Academic Press: New York, 1972; Vol. 12.
(b) Grimett, M. R. In Comprehensive Heterocyclic Chemistry; Katrizky,
A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon Press: New York, 1984;
Vol. 5. (c) Yamauchi, K.; Kinoshita, M. J . Chem. Soc., Perkin Trans. 1
1973, 2506.
(16) Asano, T. In Organic Synthesis at High Pressures; Matsumoto,
K., Morrin Acheson, R., Eds.; Wiley: New York, 1991; pp 7-76.
(17) Aben, R. W. M.; Smit, R.; Scheeren, J . W. J . Org. Chem. 1987,
52, 365.

4958 J . Org. Chem., Vol. 62, No. 15, 1997
Sommerdijk et al.
Exp er im en ta l Section
Sch em e 5
Gen er a l. Most common procedures and instrumentation
have been previously described.7 (2R)-(-)-Glycidyl butyrate
was purchased from Aldrich Chemical Co.; (S)-Glycidyl-3-
nitrobenzenesulfonate was a kind gift from Mr. Z. van Eupen
(LGSS, Nijmegen). Solvents were dried and distilled prior to
use according to standard procedures.20
(2R)-1-Azid o-3-p h en oxyp r op a n -2-ol (2a ) a n d (2S)-2-
Azid o-3-p h en oxyp r op a n -1-ol (3a ). To a solution of (R)-
(phenoxymethyl)oxirane (1a )13 (10.0 g, 66.7 mmol) in 130 mL
of methoxyethanol/water (10/3, v/v) were added sodium azide
(8.67 g, 133 mmol) and ammonium sulfate (10.7 g, 80 mmol).
After the mixture was stirred for 16 h, water (50 mL) and
diethyl ether (90 mL) were added. The layers were separated,
and the water layer was extracted with diethyl ether (2 × 50
mL). The combined organic layers were washed with brine
and dried over Na2SO4. After evaporation of the solvent and
distillation under reduced pressure, a colorless oil was obtained
in 92% yield (bp 107 °C, 0.04 mmHg). From GLC the ratio of
2a and 3a was determined to be 7.7:1: 1H NMR (CDCl3) 2a δ
1.98 (s, 1H), 3.46 (d, 2H, J ) 5.1 Hz), 4.03 (m, 2H), 4.13 (m,
1H), 6.76-7.37 (m, 5H); 3a δ 1.98 (s, 1H), 2.77 (d, 2H, J ) 5.2
Hz), 4.03 (m, 2H), 4.57 (m, 1H), 6.76-7.37 (m, 5H); IR (CCl4)
3440, 3040, 2920, 2860, 2100, 1580 cm-1
.
(2R)-3-Azid o-2-h yd r oxyp r op -1-yl Bu ta n oa te (2b) a n d
(2S)-2-Azid o-3-h yd r oxyp r op -1-yl Bu ta n oa te (3b). A mix-
ture of 2b and 3b was synthesized starting from (2R)-(-)-
glycidyl butyrate {[R]20D -26.3 (c 1.0, CHCl3)} using the same
procedure as described for compounds 2a and 3a . After
distillation a colorless oil was obtained in 77% yield: bp 82
at 50 °C. The use of higher imidazole concentrations
improved the rate of conversion, whereas the use of
higher concentrations of 5c did not. These observations
suggest that at higher pressures the precipitation of
aziridine 5c may limit the progress of the reaction. When
the reaction was carried out with 2 equiv of imidazole in
chloroform at 12 kBar and 55 °C for 2 days, the complete
conversion of 5b,c into the desired imidazolyl surfactant
11 was accomplished, without the formation of any
byproducts. Column chromatography of the depressur-
ized reaction mixture resulted in the isolation of 11 in
30-50% yield.18
1
°C (0.05 mmHg); H NMR (CDCl3) 2b δ 0.97 (t, 3H, J ) 7.4
Hz), 1.67 (m, 2H), 2.69 (s, 1H), 2.34 (t, 2H, J ) 7.4 Hz), 3.38
(m, 2H), 4.07 (m, 1H), 4.17 (m, 2H); 3b δ 0.96 (t, 3H, J ) 7.4
Hz), 1.67 (m, 2H), 1.80 (s, 1H), 2.34 (t, 2H, J ) 7.4 Hz), 3.51
(d, 2H, J ) 5.4 Hz), 3.77 (d, 2H, J ) 4.9 Hz), 5.02 (m, 1H); IR
(CCl4) 3440, 2920, 2110, 1725 cm-1; MS (CI+) m/z 188 (M +
1), 170 (18), 145 (3).
(2S)-(+)-2-(P h en oxym eth yl)a zir id in e (4a ). A mixture of
(R)-2a and (S)-3a (5.8 g, 30.5 mmol) was added to a solution
of triphenylphosphine (8.4 g, 32.1 mmol) in acetonitrile (150
mL). The reaction mixture was stirred until nitrogen evolution
had ceased and subsequently heated under reflux for 6 h. After
removal of the solvent under reduced pressure, the mixture
was dissolved in hexane/ethyl acetate (1/1, v/v) from which
triphenylphosphine oxide crystallized. Column chromatogra-
phy (silica, methanol/ethyl acetate ) 5/95, v/v) yielded the pure
Con clu d in g Rem a r k s
The results described in this paper show that optically
active aziridines can be used as precursors in the
synthesis of several enantiopure amide-containing sur-
factants. Acylation of the aziridines is a convenient
method for both the activation of the aziridine ring and
the introduction of the hydrocarbon chain. The regiose-
lectivity of the ring-opening reactions using dibenzyl
phosphate was found to be satisfactory when low reaction
temperatures were applied, and even complete when
imidazole was used.
In the course of the synthesis of these phospholipids,
an unprecedented rearrangement of R-acylamino phos-
photriesters was observed. A mechanism for this group
exchange reaction was proposed on the basis of the
compared reactivities of related compounds and FT-IR
spectroscopic data.
The fact that both regioisomers of the phospholipid
analogues could be obtained extends the possibility to
study the relation between molecular structure and the
expression of chirality on the supramolecular level in two
closely related substrates.19 A detailed study of the
aggregation behavior of the chiral surfactants described
above will be published elsewhere.
aziridine as a colorless oil in 55% yield: [R]20 +5.63 (c 1.0,
D
1
CHCl3); H NMR (CDCl3) δ 0.7 (s, 1H), 1.64 (d, 1H, J ) 3.4
Hz), 1.93 (d, 1H, J ) 6.0 Hz), 2.46 (m, 1H), 3.80-4.27 (m, 2H),
6.84-7.38 (m, 5H); IR (CCl4) 3300, 3050, 2950, 1590 cm-1; MS
(CI+) m/z 299 (2M + 1), 150 (M + 1), 133 (26), 105 (11), 94
(13), 77 (5).
(2S)-(+)-Azir id in -2-ylm et h yl Bu t a n oa t e (4b ). Com-
pound 4b was synthesized starting from a mixture of 2b and
3b using the same procedure as described for compound 4a .
A colorless oil was obtained in 64% yield: [R]20 +9.6 (c 1.0,
D
1
CHCl3); H NMR (CDCl3) δ 1.0 (t, 3H, J ) 7.4 Hz), 0.9-1.0
(br s, 1H), 1.5-2.0 (m, 4H), 2.2-2.5 (m, 3H), 3.9 (AA′X, 1H),
4.2 (AA′X, 1H); IR (CCl4) 3285, 1735 cm-1
.
(2S)-(-)-1-Oct a d eca n oyl-2-(p h en oxym et h yl)a zir id in e
(5a ). At -10 °C a solution of stearoyl chloride (3.25 g, 10.7
mmol) in dichloromethane (100 mL) was added to a solution
of 4a (1.60 g, 10.7 mmol) and triethylamine (1.91 g, 18.8 mmol)
in dichloromethane (100 mL). After 3 h the reaction mixture
was washed with 10% (w/w) aqueous citric acid, and the
organic layer was dried over MgSO4. Evaporation of the
solvent under reduced pressure and crystallization from ethyl
acetate gave 5a as a white solid in 97% yield: mp 61 °C; [R]20
D
1
-25.5 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.88 (t, 3H, J ) 6.8
(19) Sommerdijk, N. A. J . M.; Buijnsters, P. J . J . A.; Pistorius, A.
M. A.; Wang, M.; Feiters, M. C.; Nolte, R. J . M.; Zwanenburg, B. J .
Chem. Soc., Chem. Commun. 1994, 1941; 1994, 2739.
(20) Purification of laboratory Chemicals, 3rd ed.; Perrin, D. D.,
Armarego, W. L. F., Eds.; Pergamon: New York, 1988.
(18) A crude yield of ca. 90% was obtained. However, during the
chromatographic procedure a considerable portion of the product was
irriversibly bound to the silica.

Synthons for Chiral Amide-Containing Surfactants
J . Org. Chem., Vol. 62, No. 15, 1997 4959
Hz), 1.25 (m, 28H), 1.65 (m, 2H), 2.22 (d, 1H, J ) 3.3 Hz),
2.43 (t, 2H, J ) 7.6 Hz), 2.46 (m, 1H), 2.85 (m, 1H), 4.02 (dd,
1H, J ) 6.1 Hz, J ) 10.4 Hz), 4.13 (dd, 1H, J ) 10.4 Hz, J )
4.3 Hz), 6.91 (d, 2H, J ) 8.2 Hz), 6.98 (t, 1H, J ) 7.3 Hz), 7.27
(dd, 2H, J ) 21.7 Hz, J ) 8.2 Hz); IR (CCl4) 3060, 2905, 2840,
1630, 1600 cm-1; MS (CI+) m/z 416 (M + 1), 322 (40), 267 (44),
150 (15). Anal. Calcd for C27H45NO2: C, 78.02; H, 10.91; N,
3.37. Found: C, 77.34; H, 10.92; N, 3.21.
3300, 3200, 2950, 2850, 1740, 1680, 1260 cm-1; MS (CI+) m/z
326 (M - OPO(OBzl)2), 277 (6), 254 (12), 238 (13), 198 (41).
1
7b: Rf ) 0.31; [R]20 +1.1 (c 1.0, CHCl3); H NMR (CDCl3) δ
D
0.88 (t, 3H, J ) 7.0 Hz), 0.92 (t, 3H, J ) 7.4 Hz), 1.29 (m,
16H), 1.63 (m, 4H), 2.07 (t, 2H, J ) 7.6 Hz), 2.22 (t, 2H, J )
7.6 Hz), 3.31-3.38 (m, 1H), 3.56-3.62 (m, 1H), 4.08-4.20 (m,
2H), 4.59-4.53 (m, 1H), 5.03 (d, 4H, J ) 8.7 Hz), 6.33 (t, 1H,
J ) 5.3 Hz), 7.35 (m, 10H); IR (CCl4) 3300, 3200, 2950, 2850,
1740, 1680, 1260 cm-1; MS (CI+) m/z 326 (M - OPO(OBzl)2),
277 (16), 254 (13), 240 (15), 198 (70). Anal. Calcd for
C33H50O7NP‚2H2O: C, 61.95; H, 8.51; N; 2.19. Found: C,
62.03; H, 8.56; N, 2.19.
(2S)-(-)-2-[(Bu t yr yloxy)m e t h yl]-1-d od e ca n oyla zir i-
d in e (5b). Compound 5b was synthesized starting from 4b
and lauroyl chloride, using the same procedure as described
for the synthesis of compound 5a . A white solid was obtained
1
in 95% yield: mp 30 °C; [R]20 -21.7 (c 1.1, CHCl3); H NMR
Diben zyl (2R)-3-(Bu tyr yloxy)-2-(octa d eca n oyla m in o)-
p r op a n -1-yl P h osp h a te (6c) a n d Diben zyl (2R)-3-(Bu -
tyr yloxy)-1-(octa d eca n oyla m in o)p r op a n -1-yl P h osp h a te
(7c). Compounds 6c and 7c were synthesized starting from
5c using the same procedure as described for compounds 6a
and 7a . A colorless oil was obtained in 90% total yield. After
column chromatography (silica, ethyl acetate/hexane ) 3:1, v/v)
6c and 7c were isolated as colorless oils in 45% and 44% yield,
respectively. When the reaction was carried out at -15 °C,
6c and 7c were isolated in 79% and 14% yield, respectively.
D
(CDCl3) δ 0.88 (t, 3H, J ) 6.8 Hz), 0.97 (t, 3H, J ) 7.4 Hz),
1.25 (m, 16H), 1.65 (m, 2H), 1.68 (m, 2H), 2.11 (d, 1H, J ) 3.3
Hz), 2.34 (t, 2H, J ) 7.6 Hz), 2.41 (d, 1H, J ) 5.8 Hz), 2.41 (t,
2H, J ) 5.3 Hz), 2.70 (m, 1H), 3.99 (dd, 1H, J ) 11.8 Hz, J )
6.6 Hz), 4.29 (dd, 1H, J ) 11.8 Hz, J ) 4.4 Hz); IR (CCl4) 2905,
2840, 1735, 1620 cm-1; MS (CI+) m/z 326 (M + 1), 254 (4), 170
(11). Anal. Calcd for C19H35NO3: C, 70.11; H, 10.84; N, 4.30.
Found: C, 70.08; H, 10.91; N, 4.17.
(2S)-(-)-2-[(Bu t yr yloxy)m et h yl]-1-oct a d eca n oyla zir i-
d in e (5c). Compound 5c was synthesized starting from 4b
using the same procedure as described for the synthesis of
6c: [R]20 -5.2 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3H,
D
J ) 7.0 Hz), 0.92 (t, 3H, J ) 7.4 Hz), 1.25 (m, 28H), 1.59 (m,
4H), 2.07 (t, 2H, J ) 7.6 Hz), 2.24 (t, 2H, J ) 7.6 Hz), 3.97-
4.14 (m, 4H), 4.35-4.36 (m, 1H), 4.98-5.02, (m, 4H), 6.07 (d,
1H, J ) 8.3 Hz), 7.35 (m, 10H); IR (CCl4) 3300, 3100-3000,
2905, 2840, 1735, 1675, 1260 cm-1; MS (FAB+) m/z 710 (M +
compound 5a . A white solid was obtained in 94% yield: mp
1
53.5 °C; [R]20 -30.4 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.88
D
(t, 3H, J ) 6.8 Hz), 0.97 (t, 3H, J ) 7.4 Hz), 1.25 (m, 28H),
1.65 (m, 2H), 1.68 (m, 2H), 2.11 (d, 1H, J ) 3.3 Hz), 2.34 (t,
2H, J ) 7.6 Hz), 2.41 (d, 1H, J ) 5.8 Hz), 2.41 (t, 2H, J ) 5.3
Hz), 2.70 (m, 1H), 3.99 (dd, 1H, J ) 11.8 Hz, J ) 6.6 Hz), 4.29
(dd, 1H, J ) 11.8 Hz, J ) 4.4 Hz); IR (CCl4) 2905, 2840, 1735,
1620 cm-1; MS (FB+) m/z 410 (M + 1), 818 (2M). Anal. Calcd
for C25H47NO3: C, 73.30; H, 11.56; N, 3.42. Found: C, 72.99;
H, 11.48; N, 3.41.
Na+), 688 (M + 1), 410 (100). 7c: [R]20 +1.2 (c 1.0, CHCl3);
D
1H NMR (CDCl3) δ 0.88 (t, 3H, J ) 7.0 Hz), 0.92 (t, 3H, J )
7.4 Hz), 1.29 (m, 28H), 1.63 (m, 4H), 2.07 (t, 2H, J ) 7.6 Hz),
2.22 (t, 2H, J ) 7.6 Hz), 3.31-3.38 (m, 1H), 3.56-3.62 (m, 1H),
4.08-4.20 (m, 2H), 4.53-4.59 (m, 1H), 5.03 (d, 4H, J ) 8.7
Hz), 6.33 (t, 1H, J ) 5.3 Hz), 7.35 (m, 10H); IR (CCl4) 3300,
3100-3000, 2950, 2850, 1740, 1680, 1260 cm-1; MS (CI+) m/z
710 (M + Na+), 688 (M + 1), 410 (100). Anal. Calcd for
C39H62NO7P: C, 68.10; H, 9.08; N, 2.04. Found: C, 67.77; H,
9.48; N, 2.08.
Diben zyl (2R)-3-P h en oxy-2-(octa d eca n oyla m in o)p r o-
p a n -1-yl P h osp h a te (6a ) a n d Diben zyl (2R)-3-P h en oxy-
1-(octa d eca n oyla m in o)p r op a n -2-yl P h osp h a te (7a ). At
room temperature a solution of dibenzyl phosphate (325 mg,
1.17 mmol) in dichloromethane was added to a solution of 5a
(405 mg, 0.98 mmol) in dichloromethane (50 mL). After 2.5 h
the reaction mixture was washed using saturated aqueous
NaHCO3, and the layers were separated. The organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The mixture of 6a and 7a was obtained as a white
solid in a total yield of 84%. The two regioisomers were
separated using flash column chromatography (silica, ethyl
acetate/hexane ) 3:2, v/v). Compounds 6a and 7a were
isolated in 43% and 29% yield, respectively. When the reaction
was carried out at -15 °C, 6a and 7a were isolated in 70%
Disod iu m (2R)-3-P h en oxy-2-(octa d eca n oyla m in o)p r o-
p a n -1-yl P h osp h a te (8a ). Phosphate triester 6a (225 mg,
0.32 mmol) was dissolved in methanol (100 mL) and subjected
to hydrogenation using palladium on carbon as a catalyst.
After the uptake of hydrogen had ceased the catalyst was
filtered off over a short RP-18 column. The solution was
concentrated under reduced pressure to a volume of ap-
proximately 50 mL, and 20 mL of water was added. This
mixture was passed through an ion-exchange column (Dowex
50W×2, sodium form) and the methanol evaporated under
reduced pressure. After lyophilization, 8a was isolated as a
white solid in 89% yield: mp 145-147 °C; [R]20 -20.1 (c 1.0,
and 15% yield, respectively. 6a : [R]20 -23.4 (c 1.0, CHCl3);
D
D
1H NMR (CDCl3) δ 0.88 (t, 3H, J ) 6.8 Hz), 1.29 (m, 28H),
1.72 (m, 2H), 2.14 (t, 2H, J ) 7.6 Hz), 3.96-4.34 (m, 4H), 4.42
(m, 1H), 5.02 (d, 4H, J ) 8.6 Hz), 6.22 (d, 1H, J ) 7.8 Hz),
6.80-6.97 (m, 5H), 7.32 (br s, 10H); IR (CCl4) 3015, 2925, 2850,
CHCl3); IR (AgCl) 3300, 3080, 2910, 2840, 1630, 1600, 1550
cm-1; MS (FAB+) m/z 580 (M + Na+), 558 (M + 1). Anal.
Calcd for C27H46NO6PNa2‚1.5H2O: C, 55.47; H, 8.45; N, 2.40.
Found: C, 55.41; H, 8.35; N, 2.32.
1675, 1240 cm-1; MS (CI+) m/z 694 (M + 1), 416 (46). 7a : mp
Disod iu m (2R)-3-P h en oxy-1-(octa d eca n oyla m in o)p r o-
p a n -1-yl P h osp h a te (9a ). Compound 9a was synthesized
from 7a using the same procedure as described for the
synthesis of compound 8a from 6a . A white solid was obtained
1
44 °C; [R]20 +24.5 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.88 (t,
D
3H, J ) 6.8 Hz), 1.17 (m, 28H), 1.80 (m, 2H), 2.09 (t, 2H, J )
7.6 Hz), 4.42 (m, 2H), 4.04 (d, 2H, J ) 5.0 Hz), 4.66-4.83 (m,
1H), 5.04 (d, 4H, J ) 8.4 Hz), 6.31 (t, 1H, J ) 5.3 Hz), 6.80-
6.97 (m, 5H), 7.27 (br s, 10H); IR (CCl4) 3015, 2925, 2850, 1675,
1240 cm-1; MS (CI+) m/z 694 (M + 1), 416 (40).
in 86% yield: mp 145-147 °C; [R]20 +6.1 (c 1.0, CHCl3); IR
D
(AgCl) 3500-3100, 3080, 2920, 2860, 1640, 1600, 1550 cm-1
;
MS (FAB+) m/z 580 (M + Na+), 558 (M + 1). Anal. Calcd for
C27H46NO6PNa2‚2H2O: C, 54.63; H, 8.49; N, 2.36. Found: C,
54.57; H, 8.35; N, 2.24.
Dib en zyl (2R)-3-(Bu t yr yloxy)-2-(d od eca n oyla m in o)-
p r op a n -1-yl P h osp h a te (6b) a n d Diben zyl (2R)-3-(Bu -
t yr yloxy)-1-(d od eca n oyla m in o)p r op a n -1-yl P h osp h a t e
(7b). Compounds 6b and 7b were synthesized starting from
5b using the same procedure as described for compounds 6a
and 7a . The mixture was obtained as a colorless oil in a total
yield of 81%. After column chromatography (silica, ethyl
acetate/hexane ) 3:1, v/v) 6b and 7b were isolated in 35% and
36% yield, respectively. When the reaction was carried out
at -15 °C, 6b and 7b were isolated in 71% and 13% yield,
respectively. 6b: Rf ) 0.37; [R]20D -4.2 (c 1.0, CHCl3); 1H NMR
(CDCl3) δ 0.88 (t, 3H, J ) 7.0 Hz), 0.92 (t, 3H, J ) 7.4 Hz),
1.25 (m, 16H), 1.59 (m, 4H), 2.07 (t, 2H, J ) 7.6 Hz), 2.24 (t,
2H, J ) 7.6 Hz), 3.97-4.14 (m, 4H), 4.35-4.36 (m, 1H), 4.98-
5.02 (m, 4H), 6.07 (d, 1H, J ) 8.3 Hz), 7.35 (m, 10H); IR (CCl4)
Disod iu m (2R)-3-P r op a n oyl-2-(d od eca n oyla m in o)p r o-
p a n -1-yl P h osp h a te (8b). Compound 8b was synthesized
starting from 6b using the same procedure as described for
compound 8a . A white solid was obtained in 78% yield: Rf )
0.33 (silica, CH3OH/H2O/CHCl3 ) 39/10/67, v/v/v); [R]20 -4.1
D
(c 1.0, CHCl3); IR (CHCl3) 3292, 2933, 2845, 1727, 1637, 1551
cm-1; MS (FAB+) m/z 469 (M + 2), 326 (M - OPO3Na2). Anal.
Calcd for C19H36NO7PNa2‚3H2O: C, 43.76; H, 7.73; N, 2.68.
Found: C, 43.78; H, 7.90; N, 2.55.
Disod iu m (2R)-3-P r op a n oyl-1-(d od eca n oyla m in o)p r o-
p a n -1-yl P h osp h a te (9b). Compound 9b was synthesized
starting from 7b using the same procedure as described for
compound 8a . A white solid was obtained in 80% yield: Rf )

4960 J . Org. Chem., Vol. 62, No. 15, 1997
Sommerdijk et al.
0.18 (silica, CH3OH/H2O/CHCl3 ) 39/10/67, v/v/v); [R]20 +1.0
7.4 Hz), 2.18 (t, 2H, J ) 7.6 Hz), 2.35 (t, 2H, J ) 7.4 Hz), 4.04
(dd, 1H, J ) 14.8 Hz, J ) 5.9 Hz), 4.17 (d, 2H, J ) 5.0 Hz),
4.19 (dd, 1H, J ) 14.2 Hz, J ) 5.0 Hz), 4.40 (m, 1H, J ) 3.3
Hz), 5.82 (d, 1H, J ) 7.5 Hz), 6.94 (s, 1H), 7.08 (s, 1H), 7.49 (s,
1H); IR (CCl4) 3300, 2910, 2850, 1735, 1670 cm-1; MS (CI+)
m/z 394 (M + 1), 326 (21), 306 (21). Anal. Calcd for
C22H39N3O3‚1/2H2O: C, 65.64; H, 10.01; N, 10.43. Found: C,
65.62; H, 10.08; N, 10.30.
D
(c 1.0, CHCl3); IR (CHCl3) 3400-3300, 2922, 2840, 1733, 1663,
1520 cm-1; MS (FAB+) m/z 469 (M + 2), 326 (M - OPO3Na2).
Anal. Calcd for C19H36NO7PNa2‚1/2H2O: C, 47.89; H, 7.62; N,
2.94. Found: C, 47.73; H, 7.96; N, 2.37.
Disod iu m (2R)-3-P r op a n oyl-2-(oct a d eca n oyla m in o)-
p r op a n -1-yl P h osp h a te 8c. Compound 8c was synthesized
starting from 6c using the same procedure as described for
compound 8a . A white solid was obtained in 86% yield: Rf )
(R)-(+)-Bu tyr ic Acid 2-(Octa d eca n oyla m in o)-3-im id a -
zol-1-ylp r op yl Ester (11b). Compound 11b was synthesized
starting from 6c using the same procedure as described for
0.35 (silica, CH3OH/H2O/CHCl3 ) 39/10/67, v/v/v); [R]20 -5.2
D
(c 1.0, CHCl3); IR (CHCl3) 3292, 2933, 2845, 1727, 1637, 1551
cm-1; MS (FAB+) m/z 552 (M + Na+), 574 (M + 1). Anal.
Calcd for C25H48NO7PNa2‚3H2O: C, 49.58; H, 7.99; N, 2.31.
Found: C, 49.31; H, 8.08; N, 2.29.
compound 11a . A white solid was obtained in 50% yield: mp
1
66-69 °C; [R]20 +5.9 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.88
D
(t, 3H, J ) 6.8 Hz), 0.98 (t, 3H, J ) 7.4 Hz), 1.25 (m, 28H),
1.61 (m, 2H, J ) 7.2 Hz), 1.66 (m, 2H, J ) 7.4 Hz), 2.18 (t,
2H, J ) 7.6 Hz), 2.35 (t, 2H, J ) 7.4 Hz), 4.04 (dd, 1H, J )
14.8 Hz, J ) 5.9 Hz), 4.17 (d, 2H, J ) 5.0 Hz), 4.19 (dd, 1H, J
) 14.2 Hz, J ) 5.0 Hz), 4.40 (m, 1H, J ) 3.3 Hz), 5.82 (d, 1H,
J ) 7.5 Hz), 6.94 (s, 1H), 7.08 (s, 1H), 7.49 (s, 1H); IR (CCl4)
3300, 2910, 2850, 1735, 1670 cm-1; MS (CI+) m/z 478 (M + 1),
390 (50). Anal. Calcd for C28H51N3O3‚1/2H2O: C, 69.09; H,
10.77; N, 8.63. Found: C, 69.2; H, 10.35; N, 8.59.
Disod iu m (2R)-3-P r op a n oyl-1-(oct a d eca n oyla m in o)-
p r op a n -1-yl P h osp h a te (9c). Compound 9c was synthesized
starting from 7c using the same procedure as described for
compound 8a . A white solid was obtained in 84% yield: Rf )
0.20 (silica, CH3OH/H2O/CHCl3 ) 39/10/67, v/v/v); [R]20 +1.0
D
(c 1.0, CHCl3); IR (CHCl3) 3400-3300, 2922, 2840, 1733, 1663,
1520 cm-1; MS (FAB+) m/z 552 (M + Na+), 574 (M + 1). Anal.
Calcd for C25H48NO7PNa2: C, 54.44; H, 8.77; N, 2.54. Found:
C, 53.96; H, 9.22; N, 2.52.
Ack n ow led gm en t. The authors wish to thank J . W.
Scheeren and R. W. M. Aben for valuable discussions
and for the use of high-pressure equipment.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR spectra of
compounds 2-4 and 6 (7 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(R)-(+)-Bu tyr ic Acid 2-(Dod eca n oyla m in o)-3-im id a zol-
1-ylp r op yl Ester (11a ). A 10 mL ampoule was charged with
a chloroform solution containing 5b (215 mg, 0.66 mmol) and
imidazole (90 mg, 1.32 mmol) and kept at 12 kbar for 4 days
at 55 °C. After release of pressure the solvent was removed
in vacuo, and the reaction mixture was subjected to flash
column chromatography (silica, dichloromethane/ethanol/tri-
ethylamine ) 92:7:1 v/v/v). After purification 11a was isolated
1
as a colorless oil in 30% yield: [R]20 +9.6 (c 1.0, CHCl3); H
D
NMR (CDCl3) δ 0.88 (t, 3H, J ) 6.8 Hz), 0.98 (t, 3H, J ) 7.4
Hz), 1.25 (m, 16H), 1.61 (m, 2H, J ) 7.2 Hz), 1.66 (m, 2H, J )
J O962298A