On the structure of PHB (=Poly[(R)-3-hydroxybutanoic acid]) in phospholipid bilayers: Preparation of trifluoromethyl-labeled oligo[(R)-3-hydroxybutanoic acid] derivatives

Article abstract of DOI:10.1002/hlca.200490222

Oligomers of (R)-3-hydroxybutanoate (OHB) have previously been shown to transport cations through lipid bilayers. The ion-transport activity has been attributed to the formation of hydrophobic aggregates or pores, which have been identified by fluorescenc

Full text of DOI:10.1002/hlca.200490222

Helvetica Chimica Acta Vol. 87 (2004)
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On the Structure of PHB (ˆ Poly[(R)-3-hydroxybutanoic Acid])
in Phospholipid Bilayers: Preparation of Trifluoromethyl-Labeled
Oligo[(R)-3-hydroxybutanoic Acid] Derivatives
by Magnus Rueping1), Matthias Albert1), and Dieter Seebach*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, ETH-Hˆnggerberg,
CH-8093 Z¸rich
Oligomers of (R)-3-hydroxybutanoate (OHB) have previously been shown to transport cations through
lipid bilayers. The ion-transport activity has been attributed to the formation of hydrophobic aggregates or
pores, which have been identified by fluorescence-microscopy measurements of membrane-incorporated
fluorescence-labeled OHBs. To obtain more information about these aggregates, we describe here the synthesis
of the specifically F-labeled HB oligomers II IV for structural investigation by means of solid-state 19F-NMR
spectroscopic techniques.
1. Introduction. Poly[(R)-3-hydroxybutanoic acid] (PHB) is a linear homopol-
ymer which occurs as a high-molecular-mass storage material (sPHB) [1] and in a low-
molecular-mass form, complexed to other macromolecules such as proteins [2],
polynucleotides [3], and polyphosphates, and is then referred to as cPHB2). cPHB has
been detected in eucaryotic and procaryotic cells, in human aorta tissue, and in blood
plasma. In E. coli, cPHB and CaPPi form a complex that functions as an ion channel
[5]. The existence of this ion channel has been established in patch-clamp experiments
by comparing a complex from E. coli membranes with that formed from synthetic
oligo(3-hydroxybutanoic acid) (OHB) and Ca2‡ polyphosphate [6]. OHBs alone have
been shown to transport cations across bulk membranes in U-tubes [7] and to form
conductive, nonselective ion channels through lipid bilayers [8] (Fig.,a). Furthermore,
OHBs of 32 or more residues cause concentration-driven Ca2‡ transport when incorpo-
rated into liposomes [9]. From kinetic analysis, it was proposed that three 32mers
aggregate to form an ionophoric pore (Fig.,b). The structures of the channels and pores
consisting of or containing PHB are not known. Structures have been proposed [6][9]
that are derived from modeling, or form the structure of PHB in stretched fibers [10], in
lamellar crystallites [11], and in single crystals of cyclic oligomers [12]. Although the
conformation of PHB and linear OHB in the solid state is known to be a 21 helix, the
structure in solution has not yet been determined. While NMR- [13] and fluorescence-
spectroscopic measurements support the fact that the polyester has a flexible
conformation, CD spectroscopy provides hints regarding the presence of a secondary
structure in solution and in lipid bilayers [14].
1
)
Part of the Ph.D. theses of M. R. (Diss. ETH No. 14677, 2002) and M. A. (Diss. ETH No. 14869, 2002),
ETH Z¸rich.
For review articles, see [4].
2
)
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

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Helvetica Chimica Acta Vol. 87 (2004)
Figure. Hairpins of OHB 32mers have been proposed to form aggregates for ion transport through lipid bilayers
by a) a single channel or b) a pore mechanism. c) Scanning confocal fluorescence intensity image of a liposome
containing fluorescence-labeled OHB 32mers showing formation of aggregates. d) F-Labeled OHB oligomers
incorporated in the membrane should allow the determination of internuclear distances r and the orientation of the
OHBs with respect to the membrane normal N
Fluorescence-microscopic studies of liposomes containing fluorescence-labeled
OHBs demonstrated that OHBs with 32 residues tend to form aggregates [14]. This is
seen by bright spots in the membrane (Fig.,c), and it is compatible with the kinetic
analysis of Ca2‡ transport through the vesicle walls (Fig.,b) [9].
To obtain more-detailed information about the structure and conformation of the
OHB aggregates or pores in lipid bilayers, we describe here the synthesis of trifluoro-
labeled OHBs (i.e., precursor 31) and II IV for structural investigation by means of
solid-state 19F-NMR techniques. From such measurements, we hope to deduce the
orientation of the oligomers with respect to the membrane, as well as the internuclear
distances and orientation between the labeled nuclei, which in turn may lead to
information about the aggregates (pores), which mediate ion transport through
membranes (Fig.,d).
2. Synthesis of the Trifluoromethyl-Labeled OHBs.
We are interested in
monodisperse oligomers of 3-hydroxybutanoic acid (HB) for a variety of reasons.
These include their use in obtaining more-detailed information about inter- and
intracellular degradation by enzymes [15] and their study with regard to structural and

Helvetica Chimica Acta Vol. 87 (2004)
2475
functional properties in solution, in lipid bilayers, and in the solid state. To this end, we
have previously reported the synthesis and structural investigation of various linear and
cyclic OHB derivatives [16], including OHBs with attached fluorescent dyes [14][17],
2
with specific isotope labeling (13C and H) [13], and specific side chains (b-depsides
with side chains of alanine, valine, and leucine) [18].
The synthesis of linear oligomers C of HB up to a chain length of 128 residues has
been accomplished by a fragment-coupling procedure [16]3). This method is based on
the segment condensation, in which two orthogonal protecting groups at a fully
protected oligomer can be selectively removed (Scheme 1) and the resulting fragments
A and B be coupled ((COCl)2 activation, then pyridine in CH2Cl2, with warming from
À 788). Following this procedure, we prepared the building blocks 1 22, required for
the synthesis of the mono(trifluoromethyl)-labeled target molecules II IV.
For the synthesis of the all-trifluorohydroxybutanoic acid oligomers of type I and
the oligomers II IV containing one 4,4,4-trifluoro-3-hydroxybutanoic acid unit at
different positions in the OHB chains, orthogonally protected (S)-4,4,4-trifluoro-3-
hyroxybutanoic acid derivatives 26 and 27 had to be prepared (Scheme 2). The
synthesis of enantiomerically pure (S)-4,4,4-trifluoro-3-hydroxybutanoic acid (25) was
accomplished following the procedure previously developed by us [20]. Starting from
ethyl 4,4,4-trifluoro-3-oxobutanoate (23), the corresponding racemic trifluorohydroxy
acid rac-25 was obtained by reduction with NaBH4 and hydrolysis of the ester 24. Either
enantiomer could be obtained by crystallization with one of the enantiomers of
phenethylamine. The enantiomerically pure (S)-4,4,4-trifluoro-3-hydroxybutanoic acid
(25) was transformed to the benzyl ester 26, which was either used in the coupling
t
reaction or protected by BuMe2Si4) at its OH group (O-terminus), with subsequent
debenzylation (H2, Pd/C) to give the hydroxy-protected acid 27 (Scheme 2).
Thus the O-silyl-protected hydroxy acid 27 and the benzyl ester 26 were coupled to
the dimer 28 in 40% yield (Scheme 3); C- or O-terminal deprotection resulted in 29 and
30, respectively, and further coupling gave the tetramer 315) in 32% yield (Scheme 3).
The lower yields in the coupling steps, as compared to the coupling of the
nonfluorinated HB units, may be due to the sterically more demanding trifluoromethyl
t
group (16.8 ä3 vs. 42.6 ä3), and the more-labile BuMe2Si protecting group.
3
)
)
)
The syntheses started from (R)-3-hydroxybutanoic acid, as obtained from commercial PHB [19].
The protection with BuPh2Si-Cl gave low yields, which might be due to steric hindrance.
The all-trifluoro tetramer 31 is a light oil, compared to the HB tetramer, which is a viscous oil.
t
4
5

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 1. Synthesis of Oligo[(R)-3-hydroxybutanoates] (OHB) by a Fragment-Coupling Procedure [16].
Preparation of OHB building blocks for the synthesis of specifically trifluoro-labeled OHB derivatives II IV.
Acid A
m
Alcohol B
n
Oligomer C
n ‡ m
Yield [%]
1
4
7
10
13
7
10
10
1
2
4
8
16
4
2
5
8
1
2
4
3
6
9
12
15
16
17
19
2
4
8
16
32
2070
24
28
77
88
91
83
73
11
14
14
14
18
20
21
22
8
16
16
16
20
24
28
32
8
8
77
83
Therefore, no further attempts towards the synthesis of longer all-trifluoro-HB
oligomers were carried out; instead, we turned our attention to the preparation of HB
oligomers containing one (S)-4,4,4-trifluoro-3-hydroxybutanoic acid unit at different
positions in the OHB chain II IV (Scheme 3). Hence, the tetramer acid 7 and the

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2477
Scheme 2. Preparation of Orthogonally Protected (S)-4,4,4-Trifluoro-3-hydroxybutanoic Acid Derivatives for
the Fragment-Coupling Procedure
octamer acid 10 were coupled with the benzyl trifluorohydroxybutanoate6) 26 under
the segment-coupling conditions shown in Scheme 1, to obtain pentamer 32 and
nonamer 33, respectively, while the 32mer 22 was coupled with 3-O-protected
trifluorobutanoic acid 27 to give 36 (Scheme 4). Compound 36 was fully deprotected
(H2, Pd/C; HF ¥ pyridine) to give the target oligomer II, with the trifluorohydrox-
ybutanoic acid unit in the terminal position.
For the assembly of the trifluoro-labeled oligomers 37 and 38, the fully protected
oligomers 32 and 33 were debenzylated to yield the corresponding acids 34 and 35,
which were used in the coupling with hydroxybutanoates 21 and 20. Following
desilylation of oligomers 37 and 38 ( ! 39 and 40, resp.) and debenzylation gave the
desired oligomers III and IV, respectively, with one trifluorohydroxybutanoic acid unit
in the 5 and 9 positions, respectively.
Conclusions. In conclusion, the experiments described herein provide, for the first
time, trifluorohydroxybutanoate oligomers up to the tetramer. The results suggest that
use of a different hydroxy-protecting group should lead to better yields, which would in
turn allow the synthesis of longer-chain trifluorohydroxy oligomers with yet unknown
properties. Furthermore, using the segment-coupling procedure, we were able to
6
)
To circumvent potential problems with respect to the larger trifluoromethyl group, the coupling was first
carried out at the O-terminus of these oligomers.

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Scheme 3. Preparation of all-Trifluorohydroxybutanoate Dimer 28 and Tetramer 31
TBDMS ˆ tBuMe2Si
synthesize three specifically labeled HB oligomers II IV that contain one trifluoro-
hydroxy acid unit in position 1, 5, or 9 of the oligomer chain. These oligomers will now
enable us to investigate the OHB aggregates and pores (see Fig.) by using the trifluoro
group as a magnetic label that will provide further information about the structure and
function of OHB in lipid bilayers.

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Scheme 4. Synthesis of Specifically Labelled OHB Derivatives II IV with One Trifluorohydroxybutanoate
Residue at Position 1, 5, or 9 in the Oligomer Chain
TBDPS ˆ tBuPh2Si, TBDMS ˆ tBuMe2Si.
Experimental Part
1. General. All solvents used were either puriss p.a. quality or distilled over appropriate drying reagents.
CH2Cl2 and DMF were stored over 4ä-molecular sieves. All other reagents were used as received from Fluka or
Senn. Compounds 1 15, 17, and 20 were synthesized as described [16]. For high vacuum < 10À4 mbar, a
turbomolecular pump Balzers TSH065 was employed. TLC: Merck silica-gel 60 F254 anal. plates; detection

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Helvetica Chimica Acta Vol. 87 (2004)
either by UV or by dipping into a soln. of I2 (30g) and Kl (2 g) in EtOH/H 2O 1 :1 (400 ml) and drying in the air.
Flash chromatography (FC): Merck silica-gel 60 (40 63 mm). M.p.: Buechi 510. Optical rotation: 10-cm, 1-ml
cell, at r.t.; Perkin-Elmer 241 polarimeter. IR: Perkin-Elmer 1600-FT spectrophotometer. 1H-NMR: Bruker
AMX-II-500 (5001 MHz), AMX-400 (400 MHz), ARX-300 (300 MHz), or Varian Gem-200 (200 MHz)
spectrometer. 13C-NMR: Bruker AMX-II-500 (125 MHz), AMX-400 (100 MHz), ARX-300 (75 MHz), or
Varian-Gem-200 (50MHz) spectrometer; in CDCl 3 unless other specified. MS: VG ZAB2-SEQ for LSI (FAB)
with 3-nitrobenzyl alcohol as matrix, Bruker Reflex-MALDI-TOF spectrometer for MALDI-TOF, and IonSpec
Ultima MALDI FT-MS for high-resolution MS (HR-MS) in a 2,5-dihydroxybenzoic acid (DHB) matrix.
Elemental analysis were conducted by the Microanalytical Laboratorium f¸r Organische Chemie, ETH Z¸rich.
2. Preparation of Acid Chlorides: General Procedure 1 (GP 1). Similar to the reported procedure [16], the
carboxylic acid was dissolved in CH2Cl2, and oxalyl chloride (1.5 equiv.) and one drop of DMF were added. The
mixture was stirred at r.t. until the gas evolution ceased (2 8 h). The solvent was evaporated and the oily
residue dried under h.v.
3. Coupling of Acid Chlorides with an Alcohol: General Procedure 2 (GP 2). Similar to the reported
procedure [16], the well-dried acid chloride was dissolved under Ar in CH2Cl2 and cooled to À 788. After the
addition of a soln. of the appropriate alcohol (1 equiv.) in CH2Cl2, a soln. of pyridine (1 equiv.) in CH2Cl2 was
slowly injected. The mixture was allowed to warm to r.t. within 12 h and then stirred for another 10h.
Subsequent dilution with Et2O was followed by thorough washing with 1m HCl (2Â), sat. NaHCO3, and sat.
NaCl solns. The org. phase was dried (MgSO4) and evaporated.
4. Cleavage of Benzyl Ester: General Procedure 3 (GP 3). The benzyl ester protected oligoester was
dissolved in MeOH or CF3CH2OH, and a catalytic amount of 10% Pd/C was added. The apparatus was
evacuated and flushed three times with H2. After the mixture was stirred under H2 (balloon) for 18 h, filtration
through Celite and evaporation yielded the crude carboxylic acid.
5. (tert-Butyl)diphenylsilyl or (tert-Butyl)dimethylsilyl Ether Deprotection: General Procedure 4 (GP 4).
The appropriate silyl ether was dissolved in CH2Cl2 in a plastic flask and cooled to 08. A solution of 70% HF ¥
pyridine was added, and the biphasic system was vigorously stirred for 20min. After the emulsion was poured
into H2O, Et2O was added and the org. phase separated. The org. phase was washed subsequently with H2O
(2Â), sat. NaHCO3 (3Â), and sat. NaCl solns., dried (MgSO4), and evaporated.
6. Products. a-[(tert-Butyl)diphenylsilyl]-w-(benzyloxy)leicosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-
diyl]} (16). According to GP 1, 7 (0.670 g, 1.109 mmol) in CH2Cl2 (5 ml) was transformed to the acid chloride.
Subsequent coupling (GP 2) at À 788 with 14 (1.29 g, 0.739 mmol) and pyridine (2.0 equiv., in deviation from
GP 2) in CH2Cl2 (5 ml) yielded, after FC (CH2Cl2/Et2O 2 :1), 1.06 g (70%) of 16. White solid. M.p. 124.5
r:t:
D
125.58. ‰aŠ ˆ ‡0.37 (c ˆ 1.15, CHCl3). IR (CHCl3): 3620w, 2990m, 2936w, 1738w, 1458w, 1383w, 1305s, 1179s,
1136s, 1101m, 1060s, 979m. 1H-NMR (500 MHz, CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1, Me); 1.21 (d, J ˆ 6.3, Me);
1.24 (d, J ˆ 6.3, Me); 1.25 (d, J ˆ 6.3, Me); 1.25 1.28 (m, 16 Me); 2.34 2.62 (m, 39 H, CH2); 2.67 (dd, J ˆ 15.6,
7.7, 1 H, CH2); 4.22 4.28 (m, CH); 5.11 (s, PhCH2); 5.17 5.20( m, CH); 5.21 5.33 (m, 18 CH); 7.31 7.43
(m, 11 arom. H); 7.66 7.68 (m, 4 arom. H). 13C-NMR (125 MHz, CDCl3): 19.1; 19.6; 19.7; 19.8; 19.8; 19.9; 23.4;
26.9; 40.7; 40.8; 40.9; 40.9; 41.0; 44.6; 66.5; 66.7; 67.2; 67.4; 67.5; 67.7; 67.8; 78.6; 127.5; 127.6; 128.3; 128.6; 129.6;
129.7; 133.9; 134.2; 135.7; 135.8; 135.8; 169.1; 169.2; 169.2; 169.4; 169.9; 170.3. MALDI-TOF-MS (pos.): 2093.91
‡
‡
‡
(12, [M ‡ Na ‡ 4 H] ), 2092.9 (31, [M ‡ Na ‡ 3 H] ), 2091.9 (64, [M ‡ Na ‡ 2 H ]), 2090.9 (100, [M ‡ Na ‡
‡
‡
1 H] ), 2098.9 (79, [M ‡ Na] ), 2004.9 (2), 1747.7 (3), 1661.7 (3), 1575.7 (3), 1489.6 (3), 1403.6 (3), 1317.5 (4),
1231.5 (5), 1145.5 (5), 1059.4 (4), 973.4 (4). Anal. calc. for C103H146O41Si (2068.37): C 59.81, H 7.11; found: C
60.02, H 7.12.
a-Hydro-w-(benzyloxy)eicosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (18). According to GP 4, 16
(0.798 g, 386 mmol) in CH2Cl2 (5 ml) was deprotected with 70% HF ¥ pyridine (0.15 ml, 5.78 mmol, 15 equiv.) at
r:t:
D
08. Workup and washings with pentane afforded 0.590 g (83%) of 18. White solid. M.p. 135 1368. ‰aŠ ˆ À2.84
(c ˆ 1.04, CHCl3). IR (CHCl3): 3011w, 2986m, 2937w, 2878w, 1738s, 1458w, 1383w, 1306s, 1177s, 1135s, 1101m,
1059s, 979m. 1H-NMR (400 MHz, CDCl3): 1.22 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.26 1.29 (m, 17 Me);
1.30( d, J ˆ 6.3, Me); 2.36 2.63 (m, 39 H, CH2); 2.68 (dd, J ˆ 15.6, 7.6, 1 H, CH2); 3.08 (d, J ˆ 3.9, OH); 4.16
4.20( m, CH); 5.12 (s, PhCH2); 5.20 5.33 ( m, 19 CH); 7.31 7.38 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3):
19.7; 19.8; 19.8; 19.9; 22.5; 40.7; 40.8; 43.3; 64.4; 66.5; 67.5; 67.6; 67.7; 67.8; 77.2; 128.3; 128.6; 135.7; 169.1; 169.2;
‡
‡
169.4; 169.9; 172.0. MALDI-TOF-MS (pos.): 1855.8 (7, [M ‡ Na ‡ 4 H] ), 1854.8 (25, [M ‡ Na ‡ 3 H] ), 1853.8
‡
‡
‡
(60, [M ‡ Na ‡ 2 H] ), 1852.8 (100, [M ‡ Na ‡ 1 H] ), 1851.8 (97, [M ‡ Na] ), 1765.8 (3), 1661.7 (1), 1489.6
(1), 1403.6 (1), 1317.5 (2), 1231.5 (2), 1145.5 (2), 1059.4 (2). Anal. calc. for C87H128O41 (1858.03): C 57.10, H 7.05;
found: C 57.15, H 7.21.

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a-[(tert-Butyl)diphenylsilyl]-w-(benzyloxy)octacosakis{oxy[(1R)-1-methyl-3-oxoane-1,3-diylprop]} (19).
According to GP 1, 10 (0.304 g, 322 mmol) in CH2Cl2 (3 ml) was transformed to the acid chloride, and
subsequent coupling (GP 2) at À 788 with 18 (0.3 g, 161 mmol) in CH2Cl2 (3 ml) yielded, after FC (CH2Cl2/Et2O
r:t:
3 :1 ! 2 :1), 0.370 g (83%) of 19. White solid. M.p. 144 1458. ‰aŠ ˆ ‡0.05 (c ˆ 0.53, CHCl3). IR (CHCl3):
D
1
3015w, 2987m, 2934w, 1739w, 1457w, 1384w, 1305m, 1179m, 1136m, 1101m, 1060m, 979w. H-NMR (400 MHz,
CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1, Me); 1.21 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.25 (d, J ˆ 6.4, Me); 1.25
1.29 (m, 24 Me); 2.37 (dd, J ˆ 14.6, 7.7, 1 H, CH2); 2.37 2.63 (m, 54 H, CH2); 2.67 (dd, J ˆ 15.6, 7.6, 1 H, CH2);
4.23 4.28 (m, CH); 5.12 (s, PhCH2); 5.15 5.29 (m, CH); 5.20 5.32 ( m, 26 CH); 7.32 7.44 (m, 11 arom. H);
7.65 7.68 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 19.2; 19.6; 19.7; 19.8; 19.8; 20.0; 23.4; 26.9; 40.7; 40.8;
40.9; 41.1; 44.6; 66.5; 66.7; 67.2; 67.4; 67.5; 67.6; 67.7; 67.8; 77.2; 127.5; 127.6; 128.3; 128.6; 129.6; 129.7; 133.9;
‡
134.3; 135.7; 135.8; 169.1; 169.2; 169.9; 170.3. MALDI-TOF-MS (pos.): 2784.1 (12, [M ‡ Na ‡ 4 H] ), 2783.3
‡
‡
‡
‡
(31, [M ‡ Na ‡ 3 H] ), 2782.1 (64, [M ‡ Na ‡ 2 H] ), 2781.2 (100, [M ‡ Na ‡ 1 H] ), 2780.1 (79, [M ‡ Na] ).
Anal. calc. for C135H194O57Si (2757.07): C 58.81, H 7.09; found: C 58.87, H 7.09.
a-Hydro-w-(benzyloxy)octacosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (21). According to GP 4,
19 (0.350 g, 126 mmol) in CH2Cl2 (5 ml) was deprotected with 70% HF ¥ pyridine (42 ml, 1.65 mmol, 13 equiv.) at
r:t:
D
08. Workup and washings with pentane afforded 0.305 g (96%) of 21. White solid. M.p. 149 1508. ‰aŠ ˆ À2.07
(c ˆ 0.49, CHCl3). IR (CHCl3): 3015w, 2983m, 2939w, 2875w, 1740s, 1457w, 1381w, 1310m, 1180m, 1136m, 1098m,
1
1059m, 985w. H-NMR (400 MHz, CDCl3): 1.22 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.26 1.29 (m, 25 Me);
1.30( d, J ˆ 6.3, Me); 2.38 (dd, J ˆ 15.9, 8.3, 1 H, CH2); 2.40( dd, J ˆ 15.5, 5.8, 1 H, CH2); 2.42 2.63 (m, 53, 1 H,
CH2); 2.68 (dd, J ˆ 15.6, 7.6, 1 H, CH2); 3.09 (d, J ˆ 3.8, OH); 4.16 4.20( m, CH); 5.12 (s, PhCH2); 5.20 5.33
(m, 27 CH); 7.32 7.37 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 19.6; 19.7; 19.8; 19.9; 22.5; 40.7; 40.8; 41.1;
43.3; 64.4; 66.5; 67.4; 67.5; 67.6; 67.7; 67.8; 77.2; 128.3; 128.6; 135.7; 169.1; 169.2; 169.4; 169.9; 172.0. MALDI-
‡
‡
‡
TOF-MS (pos.): 2544.1 (13, [M ‡ Na ‡ 4 H] ), 2543.1 (44, [M ‡ Na ‡ 3 H] ), 2542.1 (80, [M ‡ Na ‡ 2 H] ),
‡
‡
2541.1 (100, [M ‡ Na ‡ 1 H] ), 2540.1 (71, [M ‡ Na] ), 1747.7 (1), 1661.7 (2), 1575.7 (2), 1489.6 (1), 1403.6 (1),
1317.6 (1), 1231.5 (2), 1145.5 (1), 1059.4 (1), 973.4 (1). Anal. calc. for C119H176O57 (2518.67): C 56.75, H 7.04;
found: C 56.74, H 6.92.
rac-4,4,4-Trifluoro-3-hydroxybutanoic Acid (rac-25) [20]. A mixture of NaBH4 (1.85 g, 49 mmol) in Et2O
(35 ml) was cooled to 08. At 08, 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (23; 30g, 163 mmol) was added,
and the soln. was stirred further for 3 h. The suspension was filtered over Celite and the filtrate acidified with 1m
HCl, stirred further for 0.5 h, and again filtered over Celite. The org. phase was washed with sat. NaCl soln.,
dried (MgSO4), and evaporated to give rac-4,4,4-trifluoro-3-hydroxybutanoic acid ethyl ester (24; 28.5 g, 95%)
as a light yellow oil. The crude ester was dissolved in a soln. of 1n NaOH (100 ml) and stirred for 1 h under
reflux. The soln. was extracted with Et2O (2Â), acidified to pH 1 with conc. HCl soln. and subsequently
extracted with Et2O (3Â). The Et2O phase was dried and evaporated: rac-25 (91%). White solid. 1H-NMR
(300 MHz, (D6)DMSO): 2.41 2.63 (m, CH2); 4.25 4.36 (m, CH); 6.7 (br. s, OH); 12.5 (br. s, COOH). 19F-
NMR (282 MHz): À 78 (d, J ˆ 7.5, CF3). All anal. data in agreement with those in [20].
(3S)-4,4,4-Trifluoro-3-hydroxybutanoic Acid (25) [20]. A soln. of (1R)-1-phenylethylamine (ˆ(aR)-a-
methylbenzenemethanamine; 19.14 g, 15.8 mmol) in EtOH (200 ml) was added to a soln. of rac-25 (25 g,
15.8 mmol) in EtOH (508). The mixture was cooled to r.t. and stirred for 12 h. The mixture was filtered and the
obtained white solid recrystallized twice from EtOH. After drying, the (1R)-1-phenyl-ethylammonium (3S)-
4,4,4-trifluoro-3-hydroxybutanoate was isolated as a white powder, which was subsequently dissolved in 2n HCl
and extracted with Et2O (5Â). The combined org. phase was evaporated: 5.25 g (21%) of 25. White oil, which
was used in subsequent transformations without purification. All anal. data in agreement with those in [20].
(3S)-4,4,4-Trifluoro-3-hydroxybutanoic Acid Benzyl Ester (26). To a soln. of 25 (18.05 g, 114.2 mmol) in
DMF were added benzyl bromide (13.6 ml, 1.2 equiv.) and Na2CO3 (70g, 5.8 equiv. The soln. was stirred for 12 h
and evaporated. FC (pentane/Et2O 3 :1) yielded 26 (22.5 g, 79%). Colorless oil. Rf (pentane/Et2O 3 :1) 0.3.
r:t:
‰aŠ ˆ À23.8 (c ˆ 1, CHCl3) IR (CHCl3): 3465w, 1725s, 1608w, 1498m, 962w. 1H-NMR (400 MHz, CDCl3):
D
2.69 2.81 (m, CH2); 3.34 (br. s, OH); 4.46 5.0( m, CH); 5.15 5.22 (dd, J ˆ 12, J ˆ 1, PhCH2); 7.35 7.41
(m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 170.4; 135.0; 128.7; 128.4; 125.7; 122.9; 67.3; 34.76. 19F-NMR
‡
(282 MHz, CDCl3): À 80.12 (d, J ˆ 6.4, CF3). FAB-MS: 249.3 ([M ‡ H] ). Anal. calc. for C11H11F3O3 (248.20):
C 53.23, H 4.47; found: C 52.97, H 4.50.
(3S)-3-(tert-Butyl)dimethylsilyl]oxy}-4,4,4-trifluorobutanoic Acid (27). A soln. of 26 (7.17 g, 29 mmol) in
DMF was cooled to 08. At 08, 1H-imidazole (4.91 g, 72.5 mmol) and tBuMe2SiCl (5.7 g, 37.7 mmol) were added,
and the soln. was stirred further for 24 h. The solvent was evaporated and the residue diluted with CH2Cl2. The
org. phase was washed subsequently with 1m HCl, sat. NaHCO3, and sat. NaCl soln., dried (MgSO4), and
evaporated. The resulting crude product was subsequently transformed according to GP 3 to give the crude

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Helvetica Chimica Acta Vol. 87 (2004)
product, which was purified by distillation: 27 (81%). Colorless oil. IR (CHCl3): 3646m, 3010m, 2953w, 1724s,
1607w, 1489w, 962m, 657m. 1H-NMR (400 MHz, CDCl3): 0.09 (s, Me); 0.13 (s, Me); 0.87 (s, tBu); 2.64 2.77
(m, CH); 4.45 4.51 (m, CH). 13C-NMR (100 MHz, CDCl3): 175.7; 128.7; 125.8; 123.0; 120.2; 68.1; 25.5; 18.0.
‡
19F-NMR (282 MHz, CDCl3): À 79.52 (d, J ˆ 6.5, CF3). HR-FT-MALDI-MS: 273.0394 ([M ‡ H] ). Anal. calc.
for C10H19F3O3Si (272.34): C 44.10, H 7.03; found: C 44.21, H 6.89.
(3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4,4,4-trifluorobutanoic Acid (1S)-3-(Benzyloxy)-3-oxo-1-(trifluoro-
methyl)propyl Ester (28). According to GP 1, 27 (8.5 g, 3.12 mmol) in CH2Cl2 (60ml) was transformed to the
acid chloride, and subsequent coupling (GP 2) at À 788 with 26 (7.75 g, 31.2 mol) in CH2Cl2 (60ml) yielded,
r:t:
D
after FC (CH2Cl2/pentane 3 :1), 6.23 g (40%) of 28. Colorless oil. Rf (pentane/Et2O 3 :1) 0.3. ‰aŠ ˆ À3.8 (c ˆ 1,
CHCl3). IR (CHCl3): 2933w, 2859w, 1768m, 1742m, 1463w, 1376w, 1309m, 1280m, 1177m, 1140s, 1036w.
1H-NMR (300 MHz, CDCl3): 0.13 (s, Me); 0.16 (s, Me); 0.89 (s, tBu); 2.62 2.86 (m, 2 CH2); 4.48 4.52
(m, CH); 5.16 (s, PhCH2); 5.82 5.86 (m, CF3CH); 7.33 7.40( m, 5 arom. H). 13C-NMR (100 MHz, CDCl3):
168.0; 135.4; 130.2; 128.9; 128.8; 128.7; 126.5; 125.2; 122.8; 121.4; 68.7; 67.3; 53.4; 33.4; 25.5. 19F-NMR (282 MHz,
t
‡
CDCl3): À 77.17 (d, J ˆ 6.5, CF3); À 78.89 (d, J ˆ 6.5, CF3). FAB-MS: 445 ([M À Bu] ). Anal. calc. for
C21H28F6O5Si (502.53): C 50.19, H 5.62; found: C 50.42, H 5.51.
(3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4,4,4trifluorobutanoic Acid (1S)-1-(Carboxymethyl)-2,2,2-trifluoro-
ethyl Ester (29). According to GP 3, 28 (1 g, 2 mmol) in CF3CH2OH (40ml) was debenzylated: 29 (quant.).
Colorless oil. IR (CHCl3): 1763w, 1455w, 1376w, 1356w, 1281m, 1177s. 1H-NMR (300 MHz, CDCl3): 0.09
(s, Me); 0.15 (s, Me); 0.86 (s, tBu); 2.64 2.89 (m, 2 CH2); 4.47 4.53 (m, CH); 5.77 5.83 (m, CF3CH); 11.44
(br., COOH). 13C-NMR (100 MHz, CDCl3); 174.8; 168.1; 128.4; 126.4; 125.1; 122.7; 121.3; 118.9; 68.8; 68.2;
66.7; 65.8; 36.4; 33.2; 25.5; 17.9. 19F-NMR (282 MHz, CDCl3): À 77.34 (d, J ˆ 6.5, CF3); À 78.96 (d, J ˆ 6.5 CF3).
‡
FAB-MS (435 ([M ‡ Na] ).
(3S)-4,4,4-Trifluoro-3-hydroxybutanoic Acid (1S)-3-(Benzyloxy)-3-oxo-1-(trifluoromethyl)propyl Ester
(30). According to GP 4, 28 (2 g, 3.98 mmol) in CH2Cl2 (60ml) was deprotected to give the crude product.
r:t:
D
FC (pentane/Et2O 3 :1) gave 30 in quant. yield. Colorless oil. Rf (pentane/Et2O 3 :1) 0.65. ‰aŠ ˆ 6.9 (c ˆ 1,
CHCl3). IR (CHCl3): 3312w, 3015w, 1743s, 1451w, 1303s, 1276s, 1170m, 1133m, 1053w, 953w. 1H-NMR
(400 MHz, CDCl3): 2.63 2.71 (m, CH2); 2.72 2.81 (m, CH2); 3.03 (br., OH); 4.39 4.47 (m, CH); 5.14
(s, PhCH2); 5.80 5.88 ( m, CF3CH); 7.34 7.39 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 168.3; 168.1;
134.9; 128.7; 128.6; 128.3; 127.1; 125.5; 122.7; 121.4; 67.5; 67.4; 53.4; 34.9; 33.3. 19F-NMR (282 MHz, CDCl3):
‡
À 77.83 (d, J ˆ 6.3, CF3); À 80.22 (d, J ˆ 6.4 CF3). FAB-MS: 389.0([ M ‡ H] ). Anal. calc. for C15H14F6O5
(388.26): C 46.40, H 3.63; found: C 46.56, H 3.75.
(3S)-3-{(S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4,4,4-trifluoro-1-oxobutoxy}-4,4,4-trifluorobutanoic Acid
(1S)-3-[(1S)-3-(Benzyloxy)-3-oxo-1-(trifluoromethyl)propoxy]-3-oxo-1-(trifluoromethyl)propyl
Ester
(ˆ(5S,9S,13S,17S)-2,2,3,3-Tetramethyl-7,11,15-trioxo-5,9,13,17-tetrakis(trifluoromethyl)-4,8,12,16-tetraoxa-3-si-
lanonadecan-19-oic Acid Benzyl Ester; 31). According to GP 1, 29 (0.825 g, 2 mmol) in CH2Cl2 (15 ml) was
transformed to the acid chloride, and subsequent coupling (GP 2) at À 780 with 30 (0.97 g, 2.5 mmol) in CH2Cl2
(25 ml) yielded, after FC (pentane/Et2O 3 :1), 0.5 g (32%) of 31. Colorless oil. Rf (pentane/Et2O 3 :1) 0.46.
r:t:
‰aŠ ˆ 13.7 (c ˆ 1, CHCl3). IR (CHCl3): 1777m, 1743m, 1404w, 1360w, 1309m, 1280m, 1177m, 1140s, 1040w,
D
1
963w. H-NMR (500 MHz, CDCl3): 0.11 (s, Me); 0.13 (s, Me); 0.87 (s, tBu); 2.67 2.95 (m, 4 CH2); 4.46 4.52
(m, CH); 5.09..5.19 (dd, J ˆ 12, J ˆ 8, PhCH2); 5.74 5.86 (m, 3 CFCH3); 7.32 7.39 (m, 5 arom. H). 13C-NMR
(100 MHz, CDCl3): 167.8; 167.6; 165.8; 134.9; 128.7; 128.4; 127.8; 126.3; 125.5; 124.0; 123.9; 123.3; 121.6; 121.7;
119.5; 68.1; 67.8; 67.3; 66.9; 66.5; 66.4; 66.2; 66.1; 65.9; 36.4; 32.9; 32.6; 25.4; 17.9. 19F-NMR (282 MHz, CDCl3):
À 77.70( d, J ˆ 6.5, CF3); À 77.84 (d, J ˆ 6.3, CF3); À 79.63 (d, J ˆ 6.4, CF3). HR-FT-MALDI-MS: 805.1638
‡
([M ‡ Na] ). Anal. calc. for C29H34F12O9Si (782.65): C 44.51, H 4.38; found: C 44.78, H 4.25.
(5R,9R,13R,17R,21S)-2,2,5,9,13,17-Hexamethyl-7,11,15,19-tetraoxo-3,3-diphenyl-21-(trifluoromethyl)-
4,8,12,16,20-pentaoxa-3-silatricosan-23-oic Acid Benzyl Ester (32). According to GP 3, 6 (2,3 g, 3.4 mmol) was
deprotected to yield 7, which was transformed to the acid chloride (GP 1). Subsequent coupling (GP 2) at À 788
with 26 (1.01 g, 4 mmol) in CH2Cl2 (25 ml) yielded, after FC (pentane/Et2O 3 :1), 1.92 g (68%) of 32. Colorless
oil. Rf (pentane/Et2O 3 :1) 0.31. IR (CHCl3): 3010w, 2982w, 2933w, 2858w, 1737s, 1456m, 1381m, 1306s, 1177w,
1
1138w, 1102w, 1061w, 1005w, 969w. H-NMR (500 MHz, CDCl3): 1.02 (s, tBu); 1.11 (d, J ˆ 6.2, Me); 1.20 1.25
(d, J ˆ 6.3, 3 Me); 2.34 2.64 (m, 4 CH2); 2.78 2.86 (m, CH2); 4.22 4.28 (m, CH); 5.10 5.27 ( m, PhCH2);
5.77 5.83 (m, CF3CH); 7.31 7.46 (m, 11 arom. H); 7.52 7.68 (m, 4 arom. H). 13C-NMR (125 MHz, CDCl3):
170.3; 169.2; 169.0; 167.8; 167.8; 135.7; 135.1; 134.2; 133.8; 129.6; 129.5; 128.6; 128.5; 127.5; 127.4; 124.2; 121.9;
119.7; 108.0; 67.4; 67.2; 67.1; 67.0; 66.7; 66.6; 66.3; 66.0; 65.8; 64.2; 58.4; 44.5; 40.8; 40.6; 39.9; 33.4; 26.8; 23.4;
19.7; 19.6; 19.5; 19.1. 19F-NMR (282 MHz, CDCl3): À 77.46 (d, J ˆ 6.4, CF3). 19F-NMR (282 MHz, CDCl3):

Helvetica Chimica Acta Vol. 87 (2004)
2483
‡
À 77.46 (d, J ˆ 6.5, CF3). HR-FT-MALDI-MS: 853.047 ([M ‡ Na] ). Anal. calc. for C43H53F3O11Si (830.97): C
62.15, H 6.43; found: C 62.16, H 6.51.
(5R,9R,13R,17R,21R,25R,29R,33R,37S)-2,2,5,9,13,17,21,25,29,33-Decamethyl-7,11,15,19,23,27,31,35-oc-
taoxo-3,3-diphenyl-37-(trifluoromethyl)-4,8,12,16,20,24,28,32,36-nonaoxa-3-silanonatriacontanoic Acid Benzyl
Ester (33). According to GP 3, 9 (2,7 g, 2 mmol) was deprotected to give 10, which was transformed to the acid
chloride (GP 1). Subsequent coupling (GP 2) at À 788 with 26 (0.6 g, 2.4 mmol) in CH2Cl2 (40ml) yielded, after
FC (pentane/Et2O 2 :3), 1.71 g (73%) of 33. Colorless oil. Rf (pentane/Et2O 2 :3) 0.5. IR (CHCl3): 2984w, 1738s,
1382m, 1305m, 1260s, 1177m, 1102w, 1059w, 974w. 1H-NMR (500 MHz, CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1,
Me); 1.20 1.26 ( m, 7 Me); 2.34 2.66 (m, 8 CH2); 2.77 2.87 (m, CH2); 4.24 4.29 (m, CH); 5.10 5.39
(m, PhCH2, 6 CH); 5.76 5.83 (m, CF3CH); 7.30 7.45 ( m, 11 arom. H); 7.57 7.67 (m, 4 arom. H). 13C-NMR
(125 MHz, CDCl3): 170.3; 169.2; 169.1; 167.8; 167.7; 144.7; 135.8; 135.1; 134.2; 133.9; 129.6; 129.5; 128.6; 128.5;
128.3; 127.6; 127.5; 127.2; 126.5; 124.2; 122.0; 119.8; 110.9; 67.6; 67.5; 67.2; 67.1; 66.7; 66.4; 66.1; 65.8; 44.6; 40.9;
40.8; 40.6; 40.0; 33.4; 27.2; 26.9; 23.4; 19.7; 19.5; 19.1. 13F-NMR (282 MHz, CDCl3): À 77.81 (d, J ˆ 6.3, CF3).
Anal. calc for C59H77F3O19Si (1175.33): C 60.29, H 6.60; found: C 60.10, H 6.66.
(5R,9R,13R,17R,21S)-2,2,5,9,13,17-Hexamethyl-7,11,15,19-tetraoxo-3,3-diphenyl-21-(trifluoromethyl)-
4,8,12,16,20-pentaoxa-3-silatricosan-23-oic Acid (34). According to GP 3, 32 (700 mg, 843 mmol) in MeOH
(30ml) was debenzylated to yield 612 mg (98%) of 34. Viscous oil. IR (CHCl3): 3560w, 3010w, 2986m, 2937w,
1
2879w, 1740s, 1458m, 1381m, 1307m, 1125m, 980m. H-NMR (500 MHz, CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1,
Me); 1.20( d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.2, Me); 1.28 (d, J ˆ 6.3, Me); 2.36 2.77 (m, 5 CH2); 4.22 4.28
(m, CH); 4.83 (br. s, OH); 5.15 5.21 (m, 2 CH); 5.28 (br. s, CH); 5.81 (br. s, CH); 7.36 7.47 (m, 11 arom. H);
7.65 7.67 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 19.2; 19.6; 19.8; 19.8; 23.4; 26.9; 33.5; 40.0; 40.9; 41.1;
44.6; 58.5; 66.7; 67.4; 67.5; 68.3; 122.1; 124.3; 127.5; 127.6; 129.6; 129.7; 133.9; 134.2; 135.8; 135.8; 168.3; 169.2;
170.2; 170.7; 170.9. 19F-NMR (282 MHz, CDCl3): 77.38 (d, J ˆ 6.4). MALDI-TOF-MS (pos.): 786.3 (14, [M ‡
‡
‡
‡
‡
2 Na À H ‡ 1 H] ), 785.3 (14, [M ‡ 2 Na À H] ), 765.3 (14, [M ‡ Na ‡ 2 H] ), 764.3 (44, [M ‡ Na ‡ 1 H] ),
‡
763.3 (100, [M ‡ Na] ), 537.2 (15), 473.2 (20), 451.2 (22), 443.1 (20), 421.1 (14). Anal. calc. for C36H47F3O11Si
(740.84): C 58.37, H 6.39; found: C 58.27, H 6.14.
(5R,9R,13R,17R,21R,25R,29R,33R,37S)-2,2,5,9,13,17,21,25,29,33-Decamethyl-7,11,15,19,23,27,31,35-oc-
taoxo-3,3-diphenyl-37-(trifluoromethyl)-4,8,12,16,20,24,28,32,36-nonaoxa-3-silanonatriacontanoic Acid (35).
According to GP 3, 33 (650mg, 553 mmol) in Et 2O (30ml) was debenzylated to yield 615 mg (quant.) of 35.
Viscous oil. IR (CHCl3): 3553w (br.), 3010w, 2986m, 2938w, 2879w, 1740s, 1457m, 1383m, 1308m, 1125w, 980w.
1H-NMR (400 MHz, CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1, Me); 1.21 (d, J ˆ 6.4, Me); 1.24 (d, J ˆ 6.3, Me); 1.26
(d, J ˆ 6.6, Me); 1.26 (d, J ˆ 6.5, Me); 1.27 (d, J ˆ 6.3, Me); 1.28 (d, J ˆ 6.4, Me); 1.29 (d, J ˆ 6.2, Me); 2.39 (A),
2.50( B) (AB of ABX, JAB ˆ 14.6, JAX ˆ 6.7, JBX ˆ 5.8, CH2); 2.41 2.69 (m, 6 CH2); 2.59 (A), 2.72 (B) (AB of
ABX, JAB ˆ 16.2, JAX ˆ 8.8, JBX ˆ 4.4, CH2); 2.77 (A), 2.83 (B) (AB of ABX, JAB ˆ 16.4, JAX ˆ 9.8, JBX ˆ 3.7, CH2);
4.22 4.30( m, CH); 5.21 5.34 (m, 7 CH); 5.78 5.84 (m, CH); 7.35 7.42 (m, 11 arom. H); 7.65 7.68
(m, 4 arom. H). 13C-NMR (125 MHz, CDCl3): 19.2; 19.6; 19.7; 19.8; 19.8; 23.4; 26.9; 33.2; 39.9; 40.8; 40.9;
41.0; 44.6; 66.3; 66.6; 66.7; 67.2; 67.3; 67.6; 67.7; 67.7; 67.8; 68.4; 76.7; 77.0; 77.2; 77.3; 127.5; 127.6; 129.6; 129.7;
133.9; 134.3; 135.8; 135.8; 168.1; 169.0; 169.3; 169.3; 169.4; 169.5; 169.6; 170.1; 170.4. 19F-NMR (282 MHz,
‡
CDCl3): 77.38 (d, J ˆ 6.4). MALDI-TOF-MS (pos.): 1130.4 (10, [M ‡ 2 Na À H ‡ 1] ), 1129.4 (15, [M ‡ 2 Na À
‡
‡
‡
‡
H] ), 1109.4 (27, [M ‡ Na ‡ 2] ), 1108.4 (64, [M ‡ Na ‡ 1] ), 1107.4 (100, [M ‡ Na] ), 817.3 (7), 1765.3 (8),
731.3 (19), 709.3 (9), 679.2 (8), 645.2 (8), 593.2 (9), 559.2 (7), 529.1 (7), 507.1 (5), 473.2 (5). Anal. calc. for
C52H71F3O19Si (1085.20): C 57.55, H 6.59; found C 57.48, H 6.69.
a-{(3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4,4,4-trifluoro-1-oxobutyl}-w-(benzyloxy)dotriacontakis{oxy-
[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (36). According to GP 1, 27 (0.102 g, 0.375 mmol) was transformed to
the acid chloride, and subsequent coupling (GP 2) at À 788 with desilylated 15 (0.535 g, 0.187 mmol) ( ! 22) in
CH2Cl2 (15 ml) yielded, after FC (CH2Cl2/Et2O 3 :1), 0.34 g (59%) of 36. White solid. Rf (CH2Cl2/Et2O 3 :1)
0.25. IR (CHCl3): 3035w, 2984w, 2933w, 1737s, 1458w, 1382m, 1305m, 1177m, 1134w, 1100w, 1058m, 978w.
1H-NMR (500 MHz, CDCl3): 0.09 (s, Me); 0.13 (s, Me); 0.86 (s, tBu); 1.24 1.34 (m, 32 Me); 2.40 2.65
(m, 33 CH2); 4.46 4.49 (m, CH); 5.11 (s, PhCH2); 5.19 5.32 (m, 32 CH); 7.31 7.36 (m, 5 arom. H). 19F-NMR
‡
(282 MHz, CDCl3): À 79.09 (d, J ˆ 6.5, CF3). MALDI-TOF-MS: 3140.3 ([M ‡ Na] ). HR-FT-MALDI-MS:
‡
3140.234 ([M ‡ Na] ). Anal. calc. for C145H217F3O67Si (3117.35): C 55.87, H 7.02; found: C 55.82, H 7.07.
a-[(3S)-4,4,4-Trifluoro-3-hydroxy-1-oxobutyl]-w-hydroxydotriacontakis{oxy[(1R)-1-methyl-3-oxopro-
pane-1,3-diyl]} (II). According to GP 4 and GP 3, 36 (0.095 g, 0.035 mmol) was fully deprotected and the
product precipitated from CH2Cl2/pentane: II. White solid. IR (CHCl3): 3010w, 2986w, 2936w, 1737s, 1458w,
1382m, 1305m, 1263m, 1177w, 1134w, 1058m, 978w. 1H-NMR (500 MHz, CDCl3): 1.26 1.32 (m, 32 Me); 2.43
2.64 (m, 33 CH2); 3.61 (br. s, OH); 4.06 4.13 (m, CH); 5.11 5.25 (m, 31 CH); 5.62 5.72 (m, CH). 19F-NMR

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Helvetica Chimica Acta Vol. 87 (2004)
‡
‡
(282 MHz, CDCl3): À 79.52 (d, J ˆ 6.4, CF3). MALDI-TOF-MS: 2934.6 ([M ‡ Na À H] ), 2951.1 ([M ‡ K] ).
‡
HR-FT-MALDI-MS (pos.): 2935.1290(C 132H198F3NaO67; calc. 2935.1858).
a-[(3S,7R,11R,15R,19R)-7,11,15,19,22,22-Hexamethyl-1,5,9,13,17-pentaoxo-21,21-diphenyl-3-(trifluoro-
methyl)-4,8,12,16,20-pentaoxa-21-silatricos-1-yl]-w-(benzyloxy)octacosakis{oxy[(1R)-1-methyl-3-oxopropane-
1,3-diyl]} (37). According to GP 1, 34 (240mg, 221 mmol) was transformed to the acid chloride, and subsequent
coupling (GP 2) at À 788 with 21 (538 mg, 221 mmol) in CH2Cl2 (15 ml) yielded, after FC (CH2Cl2/Et2O 5 :1 !
3 :1), 580mg (81%) of 37. White solid. M.p. 138 1398. IR (CHCl3): 3010w, 2985m, 2936w, 1738w, 1457w, 1383w,
1
1306m, 1177m, 1136m, 1103m, 1059m, 984w. H-NMR (500 MHz, CDCl3): 1.03 (s, tBu); 1.11 (d, J ˆ 6.1, Me);
1.21 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.25 1.29 (m, 28 Me); 2.37 (dd, J ˆ 14.6, 6,9,
1 H, CH2); 2.40( dd, J ˆ 15.5, 9.0, 1 H, CH2); 2.42 2.65 (m, 30 CH2); 2.74 (A), 2.79 (B) (AB of ABX, JAB ˆ 16.6,
JAX ˆ 9.1, JBX ˆ 4.3, CH2); 4.23 4.29 (m, CH); 5.15 5.20( m, CH); 5.21 5.32 (m, 30CH); 5.75 5.81 ( m, CH);
7.31 7.44 (m, 11 arom. H); 7.65 7.68 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 19.2; 19.6; 19.7; 19.7; 19.8;
19.8; 19.9; 23.4; 26.9; 33.5; 40.1; 40.6; 40.6; 40.7; 40.8; 40.9; 41.1; 41.0; 44.6; 66.1; 66.4; 66.5; 66.7;67.2; 67.5; 67.5;
67.6; 67.7; 67.7; 67.8; 68.6; 77.2; 127.5; 127.6; 128.3; 128.6; 129.6; 129.7; 134.0; 134.3; 135.7; 135.8; 135.8; 167.1;
167.8; 168.9; 169.0; 169.1; 169.2; 169.9; 170.3. 19F-NMR (282 MHz, CDCl3): 77.26 (d, J ˆ 6.4). MALDI-TOF-MS
‡
‡
‡
(pos.): 3266.4 (37, [M ‡ Na ‡ 4 H] ), 3265.4 (68, [M ‡ Na ‡ 3 H] ), 3264.3 (98, [M ‡ Na ‡ 2 H] ), 3263.3 (100,
‡
‡
[M ‡ Na ‡ 1 H] ), 3262.3 (54, [M ‡ Na] ), 3176.3 (2), 2571.3 (1), 2117.7 (1), 1661.7 (2), 1575.7 (2), 1535.6 (2),
1317.6 (1), 1115.3 (2). Anal. calc. for C155H221F3O67Si (3241.49): C 57.43, H 6.87; found: C 57.55, H 6.85.
a-[(3S,7R,11R,15R,19R,23R,27R,31R,35R)-7,11,15,19,23,27,31,35,38,38-Decamethyl-1,5,9,13,17,21,25,29,33-
nonaoxo-37,37-diphenyl-3-(trifluoromethyl)-4,8,12,16,20,24,28,32,36-nonaoxa-37-silanonatriacont-1-yl]-w-(benzyl-
oxy)tetracosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (38). According to GP 1, 35 (435 mg, 587 mmol)
was transformed to the acid chloride, and subsequent coupling (GP 2) at À 788 with 20 (227 mg, 88 mmol) in
CH2Cl2 (5 ml) yielded, after FC (CH2Cl2/Et2O 4 :1 ! 2 :1), 230mg (81%) of 38. White solid. IR (CHCl3: 3010w,
2986m, 2934w, 1738w, 1384w, 1305m, 1179m, 1136m, 1103m, 1059m, 979w. 1H-NMR (500 MHz, CDCl3): 1.03
(s, tBu); 1.11 (d, J ˆ 6.1, Me); 1.21 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.26 1.29
(m, 28 Me); 2.37 (dd, J ˆ 14.6, 6.8, 1 H, CH2); 2.40( dd, J ˆ 15.5, 5.7, 1 H, CH2); 2.41 (dd, J ˆ 15.3, 6.5, 1 H, CH2);
2.44 2.62 (m, 59, 1 H, CH2); 2.68 (dd, J ˆ 15.6, 7.6, 1 H, CH2); 2.71 (dd, J ˆ 15.7, 7.5, 1 H, CH2); 2.74 (A), 2.79
(B) (AB of ABX, JAB ˆ 16.6, JAX ˆ 9.5, JBX ˆ 4.4, CH2); 4.23 4.29 (m, CH); 5.12 (s, PhCH2); 5.15 5.21
(m, CH); 5.22 5.32 (m, 30CH); 5.75 5.80( m, CH); 7.30 7.47 ( m, 11 arom. H); 7.66 7.69 (m, 4 arom. H).
13C-NMR (125 MHz, CDCl3): 19.2; 19.6; 19.7; 19.7; 19.8; 19.8; 19.9; 23.4; 26.9; 33.5; 40.0; 40.6; 40.6; 40.7; 40.7;
40.8; 40.9; 41.0; 44.6; 66.1; 66.4; 66.5; 66.7; 67.2; 67.5; 67.6; 67.7; 67.7; 67.8; 68.6; 77.2; 77.8; 78.0; 78.4; 78.8; 122.1;
127.5; 127.6; 128.4; 128.6; 129.6; 129.7; 134.0; 134.3; 135.7; 135.8; 135.8; 167.1; 167.8; 169.0; 169.1; 169.1; 169.2;
169.9; 170.3. 19F-NMR (282 MHz, CDCl3): 77.24 (d, J ˆ 6.4). MALDI-TOF-MS (pos.): 3266.4 (37, [M ‡ Na ‡
‡
‡
‡
‡
4 H] ), 3265.4 (66, [M ‡ Na ‡ 3 H] ) 3264.3 (97, [M ‡ Na ‡ 2 H] ), 3263.3 (100, [M ‡ Na ‡ 1 H] ), 3262.3 (53,
‡
[M ‡ Na] ), 3178.3 (3), 3129.4 (3), 3123.3 (3), 2768.5 (2), 2482.2 (2), 1661.7 (3), 1115 (3). Anal. calc. for
C155H221F3O67Si (3241.49): C 57.43, H 6.87; found: C 57.33, H 6.99.
a-[(3S,7R,11R,15R,19R)-19-Hydroxy-7,11,15-trimethyl-1,5,9,13,17-pentaoxo-3-(trifluoromethyl)-4,8,12,16-
tetraoxalicos-1-yl]-w-(benzyloxy)octacosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (39). According to
GP 4, 37 (540mg, 167 mmol) in CH2Cl2 (5 ml) was desilylated with HF ¥ pyridine (56 ml, 2.16 mmol, 13 equiv.) at
08 for 9 h. Workup and washings with hot pentane yielded 419 mg (84%) of 39. White solid. IR (CHCl3): 3010w,
1
2986m, 2937w, 2879w, 1740s, 1458w, 1382w, 1305m, 1136m, 1101m, 1059w, 980w. H-NMR (500 MHz, CDCl3):
1.22 (d, J ˆ 6.3, Me); 1.24 (d, J ˆ 6.3, Me); 1.26 1.29 (m, 28 Me); 1.30( d, J ˆ 6.3, Me); 1.31 (d, J ˆ 6.3, Me); 2.39
(dd, J ˆ 16.0, 8.5, 1 H, CH2); 2.40( dd, J ˆ 15.5, 5.8, 1 H, CH2); 2.43 2.65 (m, 30 CH2); 2.69 (dd, J ˆ 15.6, 7.6,
1 H, CH2); 2.72 (dd, J ˆ 15.7, 7.5, 1 H, CH2); 2.75 (A), 2.79 (B), (AB of ABX, JAB ˆ 16.5, JAX ˆ 9.1, JBX ˆ 4.3,
CH2); 3.07 (d, J ˆ 3.9, OH); 4.15 4.21 (m, CH); 5.11 (s, PhCH2); 5.15 5.34 (m, 31 CH); 5.76 5.80( m, CH);
7.31 7.38 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3): 19.6; 19.7; 19.7; 19.8; 19.8; 19.9; 22.5; 33.5; 40.1; 40.6;
40.6; 40.7; 40.7; 40.8; 41.0; 43.3; 64.4; 66.1; 66.4; 66.5; 67.2; 67.5; 67.5; 67.6; 67.7; 67.7; 67.8; 68.6; 77.2; 128.3; 128.6;
135.7; 167.2; 167.8; 169.0; 169.1; 169.2; 169.2; 169.4; 169.9; 172.0. 19F-NMR (282 MHz, CDCl3): 77.26 (d, J ˆ 6.4).
‡
‡
MALDI-TOF-MS (pos.): 3028.2 (23, [M ‡ Na ‡ 4 H] ), 3027.2 (51, [M ‡ Na ‡ 3 H] ), 3026.2 (89, [M ‡ Na ‡
‡
‡
‡
2 H] ), 3025.2 (100, [M ‡ Na ‡ 1 H] ), 3024.2 (61, [M ‡ Na] ). 2882.6 (2), 2771.8 (3), 2059.2 (4), 1747.7 (2),
1661.7 (3), 1575.7 (3), 1489.6 (3), 1227.5 (3), 1115.3 (4). Anal. calc. for C139H203F3O67 (3003.09): C 55.59, H 6.82;
found: C 55.67, H 6.87.
a-[(3S,7R,11R,15R,19R,23R,27R,31R,35R)-35-Hydroxy-7,11,15,19,23,27,31-heptamethyl-1,5,9,13,17,21,25,
29,33-nonaoxo-3-(trifluoromethyl)-4,8,12,16,20,24,28,32-octaoxahexatriacont-1-yl]-w-(benzyloxy)tetracosakis-
{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (40). According to GP 4, 38 (180mg, 55 mmol) in CH2Cl2 (9 ml)
was desilylated with HF ¥ pyridine (18 ml, 720mmol, 13 equiv.) for 7 h. Workup and washings with hot pentane

Helvetica Chimica Acta Vol. 87 (2004)
2485
yielded 132 mg (80%) of 40. White solid. IR (CHCl3): 3010w, 2987m, 2937w, 2878w, 1740s, 1458w, 1382w, 1306s,
1
1179m, 1136m, 1103m, 1060w, 979w. H-NMR (500 MHz, CDCl3): 1.14 (d, J ˆ 6.3, Me); 1.22 (d, J ˆ 6.3, Me);
1.24 (d, J ˆ 6.3, Me); 1.26 1.29 (m, 27 Me); 1.30( d, J ˆ 6.3, Me); 1.31 (d, J ˆ 6.3, Me); 2.37 2.64 (m, 31 CH2);
2.68 (dd, J ˆ 15.6, 7.7, 1 H, CH2); 2.72 (dd, J ˆ 15.8, 7.6, 1 H, CH2); 2.75 (A), 2.80( B) (AB of ABX, JAB ˆ 16.6,
JAX ˆ 8.8, JBX ˆ 4.5, CH2); 3,07 (br. s, OH); 4.15 4.21 (m, CH); 5.12 (s, PhCH2); 5.21 5.33 (m, 31 CH); 5.76
5.81 (m, CH); 7.31 7.38 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3): 19.6; 19.6; 19.7; 19.8; 19.8; 19.9; 22.5;
29.7; 33.5; 40.0; 40.6; 40.6; 40.7; 40.8; 41.0; 43.2; 58.5; 64.4; 66.1; 66.3; 66.5; 67.2; 67.4; 67.5; 67.6; 67.7; 67.7; 67.8;
68.6; 77.2; 128.3; 128.6; 135.7; 167.2; 167.8; 169.1; 169.2; 169.4; 169.9; 172.0. 19F-NMR (282 MHz, CDCl3): 77.26
‡
‡
(d, J ˆ 6.4). MALDI-TOF-MS (pos.): 3028.2 (21, [M ‡ Na ‡ 4 H] ), 3027.2 (50, [M ‡ Na ‡ 3 H] ), 3026.2 (83,
‡
‡
‡
[M ‡ Na ‡ 2 H] ), 3025.2 (100, [M ‡ Na ‡ 1 H] ), 3024.2 (56, [M ‡ Na] ), 2882.5 (4), 2771.7 (5), 2669.0(5),
2413.6 (3), 2314.9 (3), 1896.6 (4), 1716.0(3), 1661.7 (3), 1575.7 (4), 1489.6 (3), 1227.5 (5), 115.3 (6). Anal. calc.
for C139H203O67F3 (3003.09: C 55.59, H 6.81; found: C 55.74, H 6.87.
a-[(3S,7R,11R,15R,19R)-19-Hydroxy-7,11,15-trimethyl-1,5,9,13,17-pentaoxo-3-(trifluoromethyl)-4,8,12,16-
tetraoxaeicos-1-yl]-w-hydrooctacosakis{oxy[(1R)-1-methyl-3-oxopropane-1,3-diyl (III). According to GP 3, 39
(190mg, 63 mmol) in Et2O (25 ml) was treated with Pd/C (100 mg) under H2 for 96 h. Workup resulted in 169 mg
(92%) of III. White solid. IR (CHCl3): 3610m (br.), 3010m, 2983m, 2941m, 2883m, 1740s, 1456m, 1384m, 1309w,
1179m, 1152m, 1055m, 983m. 1H-NMR (500 MHz, CDCl3): 1.09 (d, J ˆ 6.3, Me); 1.13 (d, J ˆ 6.3, Me); 1.15 1.26
(m, 28 Me); 1.27 (d, J ˆ 6.3, Me); 1.33 (d, J ˆ 6.3, Me); 2.33 2.63 (m, 63, 1 H, CH2); 2.66 (dd, J ˆ 15.5, 7.5, 1 H,
CH2); 2.69 (A), 2.72 (B) (AB of ABX, JAB ˆ 16.4, JAX ˆ 9.0, JBX ˆ 4.5, CH2); 3.71 (br. s, 2 OH); 4.08 4.15
(m, CH); 5.12 5.24 (m, 31 CH); 5.68 5.75 (m, CH). 13C-NMR (125 MHz, CDCl3): 19.2; 19.3; 19.4; 19.5; 19.5;
19.8; 22.2; 33.2; 39.7; 40.5; 40.6; 40.7; 42.9; 43.2; 64.1; 66.9; 67.2; 67.3; 67.4; 67.5; 67.6; 68.1; 69.4; 101.2; 156.2;
166.8; 167.4; 168.7; 168.8; 168.9; 169.0; 169.1; 169.2; 169.3; 170.1; 171.7; 213.9. 19F-NMR (282 MHz, CDCl3): 77.25
‡
‡
(d, J ˆ 6.4). MALDI-TOF-MS (pos.): 2938.2 (13, [M ‡ Na ‡ 4 H] ), 2937.2 (40, [M ‡ Na ‡ 3 H] ), 2936.2 (77,
‡
‡
‡
[M ‡ Na ‡ 2 H] ), 2935.2 (100, [M ‡ Na ‡ 1 H] ), 2934.2 (65, [M ‡ Na] ). HR-FT-MALDI-MS (pos.):
‡
2934.1903 (C132H197F3NaO67; calc. 2934.1858).
a-[(3S,7R,11R,15R,19R,23R,27R,31R,35R)-35-Hydroxy-7,11,15,19,23,27,31-heptamethyl-1,5,9,13,17,21,25,
29,33-nonaoxo-3-(trifluoromethyl)-4,8,12,16,20,24,28,32-octaoxahexatriacont-1-yl]-w-hydrotetracosakis{oxy-
[(1R)-1-methyl-3-oxopropane-1,3-diyl]} (IV). According to GP 3, 40 (63 mg, 21 mmol) in Et2O (10ml) was
treated with Pd/C (60mg) under H 2 fo r96 h. Workup resulted in 58 mg (90%) of IV. White solid. IR (CHCl3):
1
3574m (br.), 3007m, 2981m, 2891m, 1740s, 1455m, 1386m, 1311w, 1180m, 1055m, 945m. H-NMR (500 MHz,
CDCl3): 1.07 (d, J ˆ 6.4, Me); 1.12 (d, J ˆ 6.3, Me); 1.13 1.24 (m, 28 Me); 1.28 (d, J ˆ 6.3, Me); 1.33 (d, J ˆ 6.3,
Me); 2.30 2.61 ( m, 63, 1 H, CH2); 2.65 (dd, J ˆ 15.5, 7.5, 1 H, CH2); 2.68 (A), 2.72 (B) (AB of ABX, JAB ˆ 16.5,
JAX ˆ 9.1, JBX ˆ 4.5, CH2); 3.61 (br. s, OH); 4.08 4.15 (m, CH); 5.15 5.25 (m, 31 CH); 5.68 5.74 (m, CH).
13C-NMR (125 MHz, CDCl3): 19.2; 19.3; 19.4; 19.5; 19.6; 19.8; 22.2; 33.2; 39.7; 40.3; 40.5; 40.7; 42.9; 43.2; 64.1;
66.9; 67.2; 67.3; 67.4; 67.5; 67.6; 68.2; 69.3; 101.2; 156.2; 166.8; 167.4; 168.7; 168.8; 168.9; 169.0; 169.1; 169.2; 169.3;
170.0; 171.7; 213.9. 19F-NMR (282 MHz, CDCl3): 77.25 (d, J ˆ 6.4). MALDI-TOF-MS (pos.): 2938.2 (15, [M ‡
‡
‡
‡
‡
Na ‡ 4 H] ), 2937.2 (41, [M ‡ Na ‡ 3 H] ), 2936.2 (76, [M ‡ Na ‡ 2 H] ), 2935.2 (100, [M ‡ Na ‡ 1 H] ),
‡
‡
2934.2 (67, [M ‡ Na] ). HR-FT-MALDI-MS (pos.): 2934.1894 (C132H197F3NaO67; calc. 2934.1858).
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Received May 4, 2004