Res., 1994, 33, 239–328; (d) J. Hajdu, Recent Res. Dev. Lipids Res., 1999,
3, 165–189.
16 The two fluorophores incorporated at the chain-terminals of compound
7 comprise a donor–acceptor pair suitable for fluorescence resonance
energy transfer (FRET) studies, including real time monitoring of phos-
pholipase A2 activity,11 since the emission peak of the 2-naphthylacetyl
group (kmax = 340 nm) shows substantial overlap with the excitation
spectrum of 7-mercapto-4-methylcoumarin group (kmax = 335 nm).
2 Y. Barenholz and G. Cevc, Structure and Properties of Membranes
in Physical Chemistry of Biological Interfaces, ed. A. Baskin and
W. Norde, Marcel Dekker, New York, 2000, pp. 171–242.
3 L. McPhail, in Biochemistry of Lipids, Lipoproteins and Membranes,
ed. D. E. Vance and J. E. Vance, Elsevier Science, Amsterdam, 4th edn,
2002, pp. 315–340.
4 (a) E. J. Goetzl and S. An, FASEB J., 1998, 12, 1589–159; (b) V. A.
Sciorra and A. J. Morris, Biochim. Biophys. Acta, 2002, 1582, 45–
51.
5 (a) J. P. Bradshaw, R. J. Bushby, C. C. D. Giles and M. R. Saunders,
Biochemistry, 1999, 38, 8393; (b) W. Dowhan and M. Bogdanov, in
Biochemistry of Lipids, Lipoproteins and Membranes, ed. D. E. Vance
and J. E. Vance, Elsevier Science, Amsterdam, 4th edn, 2002, pp. 1–35;
(c) A. S. Muresan, H. Diamant and K. Y. Lee, J. Am. Chem. Soc., 2001,
123, 6951–6952.
6 (a) A. G. Lee, Biochim. Biophys. Acta, 2003, 1612, 1–40; (b) M. Carrillo-
Tripp and S. E. Feller, Biochemistry, 2005, 44, 10164–10169; P. Wang,
D. H. Blank and T. A. Spencer, J. Org. Chem., 2004, 69, 2693–2702.
7 O. G. Berg, M. H. Gelb, M. D. Tsai and M. K. Jain, Chem. Rev., 2001,
101, 2613–2653.
1
17 All new compounds were characterized by IR, H NMR, 13C NMR,
HRMS and elemental analysis. Selected data: Compound 3: IR
(CHCl3): 3330 br, 2857 cm−1 1H NMR (CDCl3, 200 MHz) d 1.49–
;
1.92 (br m, 6H, 3CH2), 3.27 (m, 1H, CH2CHH(OCH)), 3.53 (m, 3H,
CHCH2O and CH2CHH(OCH)), 3.82 (m, 1H, CH2CH(CH2)OH),
3.99 (m, 2H, CH2OH), 4.87 (br m, 1H, OCH(OCH2)CH2). 13C
NMR (CDCl3, 50 MHz) d 19.15 (CH2CH2CH2), 26.74 (CH2CH2CH2),
37.35 (CHCH2CH2), 62.07 (OCH2CH2), 67.06 (OCH2CH), 73.46
(CHCH2O), 87.42 (CH2CH(O)CH2), 111.66 (OCH(O)CH2). Rf
(CHCl3–EtOAc, 1 : 1) 0.23. Anal. Calcd for C8H16O4: C, 54.53; H,
9.15; Found: C, 54.43; H, 9.49%; MS MH+ C8H16O4H Calcd: 177.1127,
1
Found: 177.1121. Compound 4: H NMR (CDCl3, 200 MHz) d 1.28
(m, 10H, 5CH2), 1.42–1.72 (br m, 10H, 5CH2), 2.29–2.47 (br m, 5H,
=
CH2CH2C O and CH3), 2.82 (br m, 1H, CHH), 2.96 (t, 2H, J =
6Hz, SCH2), 3.55 (m, 2H, CH2O), 3.66 (d, 2H, J = 5 Hz, CH2CH),
3.94 (m, 1H, CHH), 4.14 (d, 2H, J = 5 Hz, OCH2CH), 4.55 (m, 1H,
CH2CHCH2), 6.18 (s, 1H, CH), 7.10–7.14 (m, 2H, CH-aromatic), 7.44
(d, 1H, J = 8.8 Hz, CH-aromatic). Rf (CHCl3–EtOAc 4 : 1) 0.41. Anal.
Calcd for C28H40O7S: C, 64.59; H, 7.74; Found: C, 64.26; H, 7.58%;
MS MH+ C28H40O7SH Calcd: 521.2573, Found: 521.2595. Compound
5: Anal. Calcd for C52H71NO9S·H2O: C, 69.07; H, 8.14; Found: C,
68.99; H, 8.79%; MS MNa+ C52H71NO9SNa Calcd: 908.4742, Found:
8 (a) P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 3rd ed., 2004,
pp. 188–364; (b) J. Chevallier, N. Sakai, F. Robert, T. Kobayashi, J.
Gruenberg and S. Matile, Org. Lett., 2000, 2, 1859–1861; (c) A. Wang,
R. Loo, Z. Chen and E. A. Dennis, J. Biol. Chem., 1997, 272, 22030–
22036; (d) R. Rosseto and J. Hajdu, Tetrahedron Lett., 2005, 46, 2941–
2944; (e) S. D. Stamatov, M. Kullberg and J. Stawinski, Tetrahedron
Lett., 2005, 46, 6855–6859.
908.4789. Compound 6: IR (CHCl3): 3330, 1737 br, 1685 cm−1 1H
;
9 (a) M. Ostroski, B. Tu-Sekine and D. M. Raben, Biochemistry, 2005,
44, 10199–10207; (b) J. A. Jones, R. Rawles and Y. A. Hannun,
Biochemistry, 2005, 44, 13235–13245.
10 We believe that the mild conditions employed in this sequence for the
deprotection of the sn-3-alcohol function make this synthesis partic-
ularly attractive compared to the alternative protection–deprotection
strategies available,8a because 1) the 1,2-diacylglycerol intermediate is
obtained with complete regioselectivity (acyl migration is prevented),
and 2) the chain-terminal fluorescent reporter groups readily survive
the deprotection step as well.
11 (a) O. Wichmann and C. Schultz, Chem. Commun., 2001, 2500–2501;
(b) S. Mukherjee, H. Raghuraman, S. Dasgupta and A. Chattopadhyay,
Chem. Phys. Lipids, 2004, 127, 91–101.
12 N. M. Leonard, L. C. Wieland and R. M. Mohan, Tetrahedron,
2002, 58, 8373–8397. We have found, that selection of the counter-
ion of thebismuth salt used for the reaction is important; when
bismuth(III) triflate, is replaced with the corresponding bromide or
nitrate as catalysts, the reactions take longer, and the yields obtained
are significantly lower.
13 (a) W. Srisiri, Y.-S. Lee and D. F. O’Brien, Tetrahedron Lett., 1995, 36,
5911–5914; (b) N. Bibak and J. Hajdu, Tetrahedron. Lett., 2003, 44,
5875–5877; (c) F. S. Roodsari, D. Wu, G. S. Pum and J. Hajdu, J. Org.
Chem., 1999, 64, 7727–7737.
14 As has been pointed out, the phosphatidylcholine is usually obtained in
high yield from the ring-opening reaction, with only traces of byprod-
ucts formed, however, because chromatography of phospholipids on
silica gel often results in significant losses on recovery (most likely due
to irreversible adsorption to silica gel) isolated yields of 50–70% are
generally realized; cf. U. T. Kim and J. Hajdu, J. Chem. Soc. Chem.
Commun., 1993, 70–72.
15 The compound was completely hydrolyzed by bee-venom phospholi-
pase A2 yielding the corresponding sn-2-lysophospholipid as a single
phosphate positive spot on thin layer chromatography, with the same
Rf as the reference standard. For experimental details cf. C. Balet, K. A.
Clingman and J. Hajdu, Biochem. Biophys. Res. Commun., 1988, 150,
561–567.
NMR (CDCl3, 200 MHz) d 1.25 (m, 24H, 12CH2), 1.61 (m, 8H,
4CH2), 2.37 (m, 7H, 2CH2C(O) and CH3), 2.97 (t, 2H, J = 6.8 Hz,
SCH2), 3.20 (m, 2H, NHCH2), 3.73 (s, 2H, CCH2CO), 4.15 (m, 2H,
OCH2CH), 5.07 (m, 2H, OCH2CH), 5.60 (m, 1H, CH2CH(O)CH2),
6.19 (s, 1H, CH), 7.12–7.15 (m, 2H, CH-aromatic), 7.21–7.85 (m, 8H,
CH-aromatic). 13C NMR (CDCl3, 50 MHz) d 18.26 (CH3), 23.21 (CH2),
26.32 (CH2), 27.75 (CH2), 28.89 (CH2), 29.14 (CH2), 29.24 (CH2),
29.34 (CH2), 29.65 (CH2), 29.99 (CH2), 32.38 (CH2), 33.87 (CH2),
39.53 (SCH2), 42.37 (NHCH2), 62.07 (CHCH2OH), 63.79 (OCH2CH),
74.75 (CH2CH(O)CH2), 110.75 (CCHC), 113.09 (C-aromatic), 122.56
(C-aromatic), 124.54 (C-aromatic), 125.89 (C-aromatic), 126.51 (C-
aromatic), 127.32 (C-aromatic), 127.47 (C-aromatic), 128.02 (CH-
aromatic), 128.34 (C-aromatic), 128.57 (C-aromatic), 143.73 (C-
=
aromatic), 152.41 (C-aromatic), 154.75 (C-aromatic), 160.41 (OC O),
=
=
=
169.71 (NHC O), 173.04 (OC O), 173.37 (OC O). Rf (CHCl3–
1
EtOAc 4 : 1) 0.54. Anal. Calcd for C47H63NO8S· H2O: C, 69.60; H, 7.95;
2
N, 1.73; Found: C, 69.83; H, 8.22; N, 2.17%. MS MNa+ C47H63NO8SNa
Calcd: 824.4167, Found: 824.4187. [a]2D0 +9.2 (c 1.14, CHCl3–MeOH
3 : 2). Compound 7: Rf (CHCl3–MeOH–H2O 65 : 25 : 4) 0.42. Anal.
Calcd for C52H75N2O11PS·3H2O: C, 61.16; H, 7.99; N, 2.74; Found: C,
61.28; H, 7.47; N, 2.42%. MS MH+ C52H75N2O11PSH Calcd: 967.4902,
Found: 967.4928. [a]2D0 +5.7 (c 1.14, CHCl3–MeOH 4 : 1). Compound
8: 1H NMR (CDCl3, 200 MHz) d 0.87 (br t, 6H, 2CH3), 1.25 (m,
=
44H, 22CH2), 1.61 (m, 14H, 7CH2), 2.31 (br t, 4H, 2CH2CH2C O),
3.52 (m, 2H, OCH2CH2), 3.77 (m, 2H, CHCH2O), 4.18 (m, 1H,
OCHHCH), 4.35 (m, 1H, OCHHCH), 4.61 (m, 1H, OCH(OCH2)CH2),
5.22 (m, 1H, CH2CH(OC O)CH2). 13C NMR (CDCl3, 50 MHz) d
=
14.05 (CH3), 18.94 (CH3), 22.64 (CH2),24.85 (CH2), 24.93 (CH2), 25.31
(CH2), 29.04 (CH2), 29.08 (CH2), 29.25 (CH2), 29.31 (CH2), 29.44
(CH2), 29.61 (CH2), 29.65 (CH2), 30.2 (CH2), 30.25 (CH2), 31.87 (CH2),
34.08 (CH2CH2C O), 34.29 (CH2CH2C O), 61.75 (OCH2CH2), 62.68
(CHCH2O), 65.30 (OCH2CH), 70.11 (CH2CH(OC O)CH2), 98.71
=
=
=
=
=
(CH2OCHCH2(OCH2), 173.00 (CH2C O), 173.37 (CH2C O). Rf
(CHCl3) 0.47. Anal. Calcd for C40H76O6: C, 73.57; H, 11.73; Found:
C, 73.18; H, 11.72%; MS MNa+ C40H76O6Na Calcd: 675.5534, Found:
675.5550.
2360 | Org. Biomol. Chem., 2006, 4, 2358–2360
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