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DOI: 10.1055/s-0029-1218364
Solid-Supported Synthesis of Artificial Phospholipids
Publication History
Publication Date:
11 November 2009 (online)
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Abstract
A concise solid-supported synthesis of artificial phospholipids was developed. Functionalized phospholipids were prepared by introduction of a head group onto a solid-supported phospholipid framework in good overall yield and purity.
Key words
solid-phase synthesis - artificial phospholipid - Wang resin - Merrifield resin - oxime ligation
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References and Notes
Experimental Procedure
for 11c
Wang resin (80 mg, 1.2 mmol/g, 96 µmol)
placed in a syringe reactor was solvated with CH2Cl2,
and then CH2Cl2 was replaced with toluene.
To the resin in toluene (1.0 mL), was added Ph3P (25
mg, 96 µmol) and 5 (20 mg, 24
mmol). The suspension was shaken for 1 h at r.t., then DIAD (50 µL, 96 µmol)
was added, and the suspension was shaken for 3 h at r.t. The resin
was washed with toluene (3 × 3.0 mL), DMF (3 × 3.0
mL), CH2Cl2 (3 × 3.0 mL), and MeOH
(3 × 3.0 mL), and dried in vacuo to give the resin 6.
To the resin 6 in
toluene (1.0 mL), was added MeNHNH2 (3.8 µL,
72 µmol). The suspension was shaken for 15 min at r.t.,
then the resin was washed with toluene (3 × 3.0 mL), DMF
(3 × 3.0 mL), CH2Cl2 (3 × 3.0
mL), and MeOH (3 × 3.0 mL), and dried in vacuo to give
a resin 8. This step was repeated twice
to complete the deprotection.
To the resin 8 in
CH2Cl2 (1.0 mL), was added a solution of 2,3,4-trihydroxybenzaldehyde
(9c; 37 mg, 239 µmol) and p-anisidine (12 mg, 100 µmol).
The suspension was shaken for 17 h at r.t., then the resin was washed
with CH2Cl2 (3 × 3.0 mL), DMF (3 × 3.0
mL), CH2Cl2 (3 × 3.0 mL), and MeOH (3 × 3.0
mL), and dried in vacuo to give a resin 10c.
The
resin 10c was treated with 1% TFA
in CH2Cl2 (1.0 mL) for 30 min. The TFA solution
was collected, the resin was washed with CH2Cl2 (3 × 3.0
mL), the washes were collected, and the combined solutions were
dried in vacuo to give 11c (6.7 mg, 33% from 5).
Analytical
Data of 11c: [α]D
²4 +6.4
(c 0.3, CHCl3); ¹H
NMR (500 MHz, CDCl3): δ = 8.07 (s,
1 H), 6.62 (d, J = 8.6
Hz, 1 H), 6.50 (d, J = 8.6
Hz, 1 H), 5.30-5.20 (m, 1 H), 4.45-4.10
(m, 8 H), 2.40-2.20 (m, 4 H), 1.70-1.50
(m, 4 H), 1.40-1.10 (m, 48 H), 0.88 (t, J = 6.9 Hz,
6 H); ¹³C NMR (100 MHz, CDCl3): δ = 173.7,
173.4, 152.2, 147.0, 145.2, 131.4, 122.5, 109.3, 107.8, 72.8, 69.5,
66.6, 65.1, 61.9, 34.1, 34.0, 31.9, 29.70, 29.66, 29.5, 29.4, 29.3,
29.12, 29.07, 24.8, 22.7, 14.1; IR (neat): 3460, 2918, 2851, 1740
cm-¹; MS-FAB:
m/z = 843 [M - H]-;
HRMS-FAB: m/z [M - H]- calcd
for C44H77O12NP: 842.5184; found:
842.5167.
Experimental Procedure
for 11b: To Merrifield resin (3.6 g, 1.1 mmol/g, 4.0
mmol) in DMF (30 mL), were added 12 (2.0
g, 12 mmol), Cs2CO3 (3.8 g, 12 mmol), and
NaI (588 mg, 3.9 mmol), and the mixture was stirred for 40 h at
r.t. The resin was washed with DMF (3 × 15 mL), H2O
(3 × 15 mL), DMF (3 × 15 mL), CH2Cl2 (3 × 15
mL), DMF (3 × 15 mL), EtOAc (3 × 15 mL), CH2Cl2 (3 × 15
mL), and MeOH (3 × 15 mL), and then dried in vacuo to give
resin 13 (4.1 g, 4.0 mmol, quant.).
The
resin 13 (109 mg, 1.1 mmol/g,
120 µmol) placed in a syringe reactor was solvated with
CH2Cl2, and then CH2Cl2 was
replaced with toluene. To the resin 13 in
toluene (1.0 mL), were added Ph3P (25 mg, 96 µmol)
and 5 (20 mg, 24 µmol). The suspension
was shaken for 1 h then, DIAD (50 µL, 96 µmol)
was added and the suspension was shaken for 3 h at r.t. The resin
was washed with toluene (3 × 3.0 mL), DMF (3 × 3.0
mL), CH2Cl2 (3 × 3.0 mL), and MeOH
(3 × 3.0 mL), and then dried in vacuo to give resin 14.
To the resin 14 in
toluene (1.0 mL), was added MeNHNH2 (3.8 µL,
72 µmol). The mixture was shaken for 15 min, then the resin
was washed with toluene (3 × 3.0 mL), DMF (3 × 3.0
mL), CH2Cl2 (3 × 3.0 mL), and MeOH
(3 × 3.0 mL), and dried in vacuo to give resin 15. This step was repeated twice to complete
the deprotection.
To the resin 15 in
CH2Cl2 (1.0 mL), was added p-bromo-benzaldehyde
(9b; 31 mg, 239 µmol) and p-anisidine (12 mg, 100 µmol).
The suspension was shaken for 21 h at r.t., then the resin was washed
with CH2Cl2 (3 × 3.0 mL), DMF (3 × 3.0
mL), CH2Cl2 (3 × 3.0 mL), and MeOH
(3 × 3.0 mL), and dried in vacuo to give the resin 16. To the resultant resin 16 in
CH2Cl2 (1.0 mL), was added mCPBA
(29 mg, 167 µmol) and the mixture was shaken for 1 h at
r.t., and then washed with CH2Cl2 (3 × 3.0
mL), DMF (3 × 3.0 mL), CH2Cl2 (3 × 3.0
mL), and MeOH (3 × 3.0 mL), and dried in vacuo to give
the sulfone resin 17. After treatment of
resin 17 with a solution of Et3N
in CH2Cl2 (7%, 1.0 mL) for 16 h, the
filtrate was collected and dried in vacuo to give 11b as
a Et3N salt (11 mg). For desalting and purification,
TFA (10 µL) was added to a solution of 11b˙Et3N
salt in CHCl3-MeOH (4:1, 0.5 mL) then the solution
was dried in vacuo to give a residue, which was purified by preparative
TLC on silica gel (CHCl3-MeOH-TFA,
80:20:0.1) to give 11b (4.7 mg, 22% from 5).