1,2-Bond shift of the Fe(CO)3 moiety in the 1,5-O-heterocyclization of (1,3-dienyl)-tricarbonyliron diols: Application to the synthesis of novel phosphocholines

Article abstract of DOI:10.1560/WGVK-AU3Q-5VJV-REXD

A novel concept of intramolecular cationic 1,5-O-heterocyclization of ψ-exo-/ψ-endo-(1,3-dienyl)tricarbonyliron diols has been demonstrated to occur under acid catalysis with a quite unusual 1,2-migration of the complexation site. This cationic cyclization has been shown to be stereoselective when involving homochiral precursor diols. It allowed straightforward access to new racemic and optically active conformationally locked alkylphosphocholines as potential anticancer agents.

Full text of DOI:10.1560/WGVK-AU3Q-5VJV-REXD

1,2-Bond Shift of the Fe(CO)3 Moiety in the 1,5-O-Heterocyclization
of (1,3-Dienyl)-Tricarbonyliron Diols: Application to the Synthesis of
Novel Phosphocholines
a
a,b,
ALAIN BRAUN AND JEAN-PAUL (MOSHE) LELLOUCHE
*
aCEA, CE-Saclay, DBCM, Service des Molécules Marquées, Bât 547, F-91191 Gif-sur-Yvette, France
bDepartment of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel
(Received 5 December 2001)
Abstract. A novel concept of intramolecular cationic 1,5-O-heterocyclization of
ψ-exo-/ψ-endo-(1,3-dienyl)tricarbonyliron diols has been demonstrated to occur
under acid catalysis with a quite unusual 1,2-migration of the complexation site.
This cationic cyclization has been shown to be stereoselective when involving
homochiral precursor diols. It allowed straightforward access to new racemic and
optically active conformationally locked alkylphosphocholines as potential antican-
cer agents.
INTRODUCTION
center at Cβ in transoid-3 trapped in situ by the pendant
Through our strong involvement in the field of (1,3- tethered OH-nucleophile. Providing a direct entry to the
dienyl)tricarbonyliron complexes for the last decade, constrained 2,3-disubstituted 1,4-dioxane unit, this in-
previous works from our laboratory as well as from novative cationic 1,5-O-heterocyclization has been ap-
others demonstrate clearly that the complexing Fe(CO)3 plied sucessfully toward the preparation of two confor-
unit possesses powerful protecting and stereodirecting mationally locked racemic and optically active
properties.1 Additionally, its potent capability to stabi- phosphocholines of type 8 (Fig. 2).
lize anchimerically carbocations close to the coordina-
Due to the potent anticancer action of the pro-inflam-
tion site is well-established.1 Such stabilized cations can matory mediator Paf-Acether 5, numerous alkylphos-
be generated under mild acidic conditions from appro- pholipids have been synthesized and tested for their
priate alcohol precursors (dehydration), and trapped in- antitumor properties.3 Among them, rac-edelfosine 6
tramolecularly by a tethered pendant nucleophile to and rac-ilmofosine 7 appeared as the most potent com-
afford diverse O-, N-, and S-heterocycles, even pounds, not only active in vitro but also in vivo.3
medium-sized ones.2 Interestingly, these heterocy-
These compounds selectively accumulate in the
clizations occur without migration of the complexation membranes of tumor cells, perturbing membrane-local-
site. On the contrary, iron-complexed diols 1 (Fig. 1) ized vital enzymic processes. However, the molecular
should undergo a novel acid-mediated intramolecular basis of this selective accumulation remained elusive
1,5-O-heterocyclization toward complexed dioxanes 4 until now. Interestingly, these phosphocholines are
concomitant with a 1,2-shift of the complexing unit. based on a conformationally mobile glycerol skeleton.
Worthy of mention are the in situ generation of the Novel alkylphosphocholines 8, which will be con-
transoid cation transoid-2 from 1 under acid-catalyzed strained conformationally by the 2,3-disubstituted 1,4-
dehydration (electronic deficiency at Cα) and isomer- dioxane unit, could find useful applications as locked
ization of the complexation site by 1,2-migration of the
Fe(CO)3 unit, thus revealing the second electrophilic Bar-Ilan University. E-mail: lellouj@mail.biu.ac.il
*Author to whom correspondence should be addressed, at
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2001 pp. 329–338

330
Fig. 1. O-Heterocyclization concept.
Fig. 2. Retrosynthesis towards conformationally-locked phosphocholines.
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structural probes of their mechanism of action.
formation of a more stable secondary transoid cation
The main purposes of our present work are (1) to transoid-3 (R1 = H), which will cyclize with the ex-
describe our design of conformationally locked pected 1,2-shift of the Fe(CO)3 unit.4 Indeed, our previ-
phosphocholines 8 with potential anticancer properties ous results showed that racemic diastereoisomeric dis-
(Fig. 2); (2) to demonstrate that an innovative intramo- ubstituted dienyl-Fe(CO)3 diols ψ-exo-/ψ-endo-14a–
lecular nucleophilic 1,5-O-heterocyclization of (1,3- 16a/14b–16b4 (Scheme 1, 14a/b: R3 = nC16H33, 15a/b:
dienyl)-Fe(CO)3 diols 11 is the key stereoselective step R3 = CH2Cl, 16a/b: R3 = CH2OBn) prepared from rac-
for their synthesis; (3) to provide evidence that the 12 in three steps (a–c) can be selectively cyclized using
O-heterocyclization affords optically active derivatives Amberlyst resin (H+ form) to give ψ-exo-cis-/ψ-exo-
when involving homochiral precursors; (4) to empha- trans-2,3-disubstituted dioxanes 17c–19c/17t–19t (step
size the synthetic equivalency of the complexed ester d: CH2Cl2, 20 °C, 3–12 h, 17c–19c: 10–38%, 17t–19t:
aldehyde 12 with the 3C-homochiral monofunctional 50–91%), respectively.1d,2,4,5 1H/13C NMR data of the
2,3-dicationic synthon 13; and, finally, (5) to provide cyclized monosubstituted iron-complexed adducts and
full experimental and analytical/spectroscopic data of crystallographic structures obtained for rac-cis- and
new compounds that were not described previously.
trans-19c/19t (R3 = CH2OBn) supported the described
structures and, more particularly, the ψ-exo-diastereo-
isomeric relationship of the newly formed C(2)-O(1)
bond versus the Fe(CO)3 unit (anti-nucleophilic
attack).4,6
DESIGN AND RETROSYNTHESIS TOWARD THE
LOCKED PHOSPHOCHOLINES rac-25 AND
(–)-(2R,3R)-38
Further chemical processing of rac-17t (R3
=
We envisioned that the 2-methoxy group of rac-
edelfosine 6 can be linked to the C(1) of the glycerol
backbone to afford conformationally locked phospho-
cholines 8 containing a 2,3-disubstituted dioxane het-
erocycle (Fig. 2). Phosphocholines 8, where X = O and
n = 15, contain an added methylene inserted into the
C(1)–O bond of 6 to improve metabolic stability. Addi-
tionally, the dioxane moiety should also provide enzy-
mic stability toward phospholipases C and D.
Retrosynthetically, disconnection of the phospho-
choline residue in 8 (O–P linkage) reveals the
hydroxymethylated-2,3-disubstituted 1,4-dioxane 9.
The hydroxymethyl itself can arise from the oxidative
treatment of a monosubstituted (1,3-dienyl)-Fe(CO)3
residue present in the monosubstituted tricarbonyliron
complex 10. Disconnecting further the critical C–O
ether bond close to the Fe(CO)3 moiety unravels the
disubstituted (1,3-dienyl)tricarbonyliron diol 11 as its
logical precursor. In turn, this diol should cyclize via our
original acid-catalyzed intramolecular 1,5-O-hetero-
cyclization as the key step of our retrosynthesis. As
described later, uneventful chemistry can be used to
transform the (1,3-dienyl)-Fe(CO)3-ester aldehyde 12
into the required diol 11.
nC16H33) to the two targeted racemic phospholipids rac-
23/rac-25 has been performed in the following manner.
Its oxidative decomplexation affords the corresponding
trans-dioxane diene rac-20 (step e: Ce(NH3)4(NO3)6,
EtOH/AcOEt 2/1, –20 °C, 87%), which is ozonized
leading to the trans-dioxane alcohol rac-21 after an
ozonide reductive quench by NaBH4 (steps e–f: com-
bined yield 85%). Introduction of the phosphocholine
moiety into rac-21 toward the phospholipid rac-25 can
be performed with a similar global efficiency using the
two synthetic methodologies of (1) Hirt7 or of (2)
Thuong8 (32–36% combined yield after preparative
HPLC purification, VYDAC-C8 reverse-phase column,
solvent A/B 3/2, solvent A: CH3COCH3/MeOH/THF/
CH3CO2H 700/250/50/50, solvent B: H2O containing
5% CH3CO2H, tr = 8.5 min, 1.5 mL/min, He gas-operated
DEDL-light diffusion detector, purity ≥ 99%). The first
step involves the intermediate brominated phosphate
rac-24 while the second one makes use of the cyclic
1,3,2-dioxaphospholane rac-22. In each case, NMe3
quaternization terminates the synthetic sequence (steps
h and k: 36% combined yield; steps g and i: 32% com-
bined yield). Additionally, the chemoselec-tive basic
hydrolysis of rac-24 afforded the unsymmetrical phos-
phate diester rac-23 (step j: NaOH, DME/H2O 1/1, 20 °C,
60%), useful for biological evaluation.
RESULTS
The above retrosynthesis emphasizes nicely the well-
We also demonstrated that the key intramolecular
known protecting and/or stereodirecting properties as- 1,5-O-heterocyclization of complexed diols 11 can lead to
sociated with the complexing Fe(CO)3 unit, as well as optically active derivatives when involving homochiral
the strong stabilization by anchimeric assistance of tricarbonyliron complexed diol precursors (Scheme 2).
carbocations close to the coordination site.1 More The synthesis of the optically active (–)-(2R,3R) trans-
specifically, the key step of the intramolecular phosphocholine 38 starts from the known resolved
O-heterocyclization 11 → 10 will involve the preferred complexed ester aldehyde (+)-(2S,5R)-26 (ee ≥ 95%),9
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332
Scheme 1. Reagents: (a) R3Li or R3MgBr, THF, –78 °C, 1 h, 77–97% (chromatographic separation of ψ-exo-/ψ-endo-
diastereoisomers ~ 3/1); (b) N2CHCO2Et, cat. [Rh2 (OAc)4], CH2Cl2, 20 °C, 1 h, 46–80%; (c) DIBAL-H, CH2Cl2, –78 °C, 1 h,
63–82%; (d) Amberlyst resin (acid form), CH2Cl2, 20 °C, 3–12 h; (e) Ce(NH3)4(NO3)6, EtOH/AcOEt 2/1, – 20 °C, 0.5 h, 87%; (f)
O3, Et2O, –78 °C, 0.5 h; NaBH4, EtOH, 0 °C, 1 h, 98%; (g) 2-chloro-1-[1,3,2]-dioxaphospholane 2-oxide, benzene, Et3N, 20 °C,
2 h, 90%; (h) 2-bromoethyl phosphorodichloridate, Et2O, Pyr, 20 °C, 18 h, MeOH quench, 62%; (i) NMe3, TMSOTf, CH2Cl2,
20 °C, 6 h, 35%; (j) 1N NaOH, DME/H2O 1/1, 20 °C, 4 h, 60%; (k) NMe3, PhMe, 20 °C, 24 h, 58%.
which is submitted to similar steps a–c toward the ψ- λUV = 230 nm). Under the same conditions, the racemic
endo-diol 30.
compound rac-trans-19t (Scheme 1, R3 = CH2OBn) is
The diol 30 affords the (–)-(2R,3S)-trans-dioxane perfectly resolved into two baseline-separated picks
complex 31 in a similar global yield of 8% from eluted at 7.0 and 12.5 min. To the best of our knowledge,
(+)-(2S,5R)-26 after Amberlyst resin (H+ form)-cata- this cationic cyclization of (1,3-dienyl)-Fe(CO)3 diols is
lyzed O-heterocyclization. Removal of paramagnetic a unique case of stereoselective intramolecular 1,5-O-
impurities from the crude compound (silica gel pad, heterocyclization occurring with migration of the site of
ether) followed by high-field NMR analyses did not complexation.5 With (–)-(2R,3S)-31 at hand, the opti-
allow us to detect any other diastereoisomer besides 31 cally active phospholipid (–)-(2R,3R)-38 can be pre-
(1H/13C NMR, 300 MHz, CDCl3, and C6D6, diastereoi- pared uneventfully (Scheme 2), including some minor
someric purity ≥ 98%). Moreover, the optical purity of synthetic variations of Scheme 1. Worthy of note are (1)
(–)-(2R,3S)-31 has been assayed to be 96% by chiral the preparation of the diversely functionalized dioxane
HPLC using a Chiracel OD column eluted by the mixture aldehyde (–)-(2S,3R)-trans-34, which opens an easy
n-hexane/isopropanol 95/5 (0.8 mL/min, tr = 12.5 min, access to structurally different phosphocholines, and (2)
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Scheme 2. Reagents: Steps a–f, h, and k (Scheme 1); (a) BnOCH2Li,10 THF, 0 °C, 0.25 h, 97% (chromatographic separation of
ψ-exo-/ψ-endo-diastereoisomers ~65/35); (b): 52%; (c): 69%; (d) 72%; (e): 92%; (f): 87%; (h) 75%; (k): 44% (l) O3, Et2O,
–78 °C, 0.25 h, Me2S quench, 65%; (m) NaH, DMF/HMPT 95/5, 20 °C, 6 h, 66%, (n) H2, Raney Ni, EtOH, 20 °C, 24 h, 92%.
EXPERIMENTAL SECTION
Generalities about the experimental section have been de-
scribed elsewere.11,12
the optical purity of the monobenzylated (–)-(2R,3R)-
trans-33 better than 97%, as measured under the same
conditions as for (–)-(2R,3S)-31 (0.8 mL/min, tr = 10.5
min, λUV = 230 nm).
rac-trans-2-(Buta-1,3-dienyl)-3-hexadecyl-[1,4]dioxane rac-20
To a solution of the ψ-endo-iron complexed diene 17t (1.6 g,
3.17 mmol) in a mixture of C2H5OH (8 mL)/AcOEt (24 mL), the
oxidizing Ce(IV) salt dissolved in C2H5OH (Ce(NH3)4(NO3)6,
17.0 g, 31.0 mmol, 44 mL) is added at –20 °C. The reaction
mixture is stirred 30 min at – 20 °C, at which time the medium
is hydrolyzed by deionized water (50 mL), and immediately
extracted by ethyl ether (5 × 30 mL). After drying (anhydrous
In conclusion, the acid-catalyzed intramolecular 1,5-
O-heterocyclization of (1,3-dienyl)tricarbonyliron diols
has been shown to be a key stereoselective step toward
racemic and optically active conformationally locked
phosphocholines. Accordingly, the starting complex
(+)-(2S,5R)-26 can be viewed as a 3C-homochiral func-
tional dicationic synthon of type 13 (Fig. 1).
Braun and Lellouche / 1,5-O-Heterocyclization of Iron Complexed Diols

334
MgSO4) and filtration (5-µm Buchner filter), the neutral com- gas, the reaction is vigorously stirred for 6 h at 20 °C. The
bined organic extracts are concentrated under reduced pres- organic volatiles are eliminated (reduced pressure) to afford
sure. The crude decomplexed diene is purified by flash chro- crude rac-25, which is purified by flash chromatography (silica
matography (silica gel column, hexane/ethyl ether gel column, CHCl3/MeOH/H2O 60/30/04) to give the pure
9/1) to give the corresponding pure compound (1.0 g).
Solvent mixture (SM): hexane/ethyl ether 9/1, Rf 0.3 (white
solid, 87%); 1H NMR (CDCl3, 300 MHz) δ 6.37–6.28 (m, 2H),
5.57 (q, 1H, J = 7.2 Hz), 5.23–5.18 (m, 1H), 5.11 (dd, 1H, J=
1.7 and 8.1 Hz), 3.79–3.67 (m, 5H), 3.19 (t, 1H, J = 8.2 Hz),
1.44–1.38 (m, 2H), 1.36–1.17 (m, 28H), 0.86 (t, 3H, J = 6.8
Hz); 13C NMR (CDCl3, 75 MHz) δ [136.0, 134.3, 129.5,
118.1] (C=C diene), 80.3 (C–H–O), 79.2 (CH–O), 66.5 (CH2–
O), 66.1 (CH2–O), [31.6, 31.2, 29.4 29.1, 24.9, 22.4] (CH2),
13.8 (CH3); MS (CI, NH3) m/z 382 (100%) [M+18]+, 364
(9.7%) [M]+, 310 (30.0%); Anal. Calcd for C24H44O2: C, 64.28;
H, 8.79. Found: C, 64.11; H, 8.61.
phospholipid (182.8 mg, pulverulent white powder, 35%).
Preparation from rac-24. The brominated phosphate rac-
24 (141.0 mg, 0.26 mmol) is dissolved under nitrogen in
anhydrous toluene (10 mL), and cooled at –20 °C. The me-
dium saturated by trimethylamine gas at the same temperature
is agitated for 24 h at 20 °C. The organic phase is then
concentrated to give the crude dioxane-phosphocholine rac-
25. Flash chromatography (silica gel column, CHCl3/MeOH/
H2O 60/30/4) gives the pure ncetyl phosphocholine rac-25
(77.0 mg, 58%).
Analytical HPLC on a column VYDAC C8 250-4.6 (column
temperature 35 °C), solvent A acetone/methanol/THF/acetic
acid 700/250/50/50, solvent B H2O containing 5% CH3CO2H,
isocratic elution solvent A/solvent B 6/4, 1.5 mL/min, light-
scattering DEDL-evaporating detector (SEDEX Ltd, He nebu-
lizing gas at a pressure of 1.75 bar), retention time of rac-25
5.91 min, chemical purity greater than 96.0%; IR (KBr) 3402,
2919, 2851 (νCH), 1247, 1082, 970; 1H NMR (CDCl3, 300 MHz)
δ 4.32 (s, 2H), 4.00-3.91 (m, 1H), 3.88–3.76 (m, 4H), 3.75–3.59
(m, 4H), 3.52–3.40 (m, 1H), 3.34 (s, 9H, NMe3), 2.00 (m, 2H),
1.54–1.37 (m, 2H), 1.32–1.17 (m, 26H), 0,87 (t, 3H, J = 6.4 Hz);
13C NMR (CDCl3, 75 MHz) δ 78.9 (CH–O), 66.3 (CH2–O), 65.1
(CH2–N), 59.0, 58.1, 54.3 (NMe3), [31.7, 31.2, 29.5, 29.1,
24.7, 22.4, 18.2] (CH2), 13.8 (CH3); MS (CI, NH3) m/z 508
(100%) [M]+, 449 (87.2%), 360 (34.5%), 196 (36.9%).
rac-trans-(3-Hexadecyl-[1,4]dioxan-2-yl)-methanol rac-21
After dissolution of the above dioxane-diene rac-20
(300.0 mg, 0.83 mmol) in anhydrous ethyl ether (50 mL), it is
ozonized at –78 °C until its disappearance (TLC monitoring).
Residual ozone is evacuated from the medium by nitrogen
bubbling (15 min). The in-situ-prepared ozonide is reduced by
addition of NaBH4 dissolved in ethanol (156.0 mg, 4.15 mmol,
10 mL, 5 min reaction). After hydrolysis by saturated aqueous
NH4Cl (20 mL), the medium is extracted by ethyl ether
(3 × 20 mL). After drying (anhydrous MgSO4) and filtration
(5-µm Buchner filter), the neutral combined organic phases
are concentrated. The crude dioxane alcohol 21 is purified by
flash chromatography (silica gel column, hexane/ethyl ether
1/1) to afford the corresponding pure compound (280.0 mg).
SM: hexane/ethyl ether 1/1, Rf 0.24 (white solid, 98%); IR
(KBr) 3520 (νOH), 2916 (νCH); 1H NMR (CDCl3, 300 MHz) δ
3.81–3.64 (m, 5H), 3.60–3.51 (m, 1H), 3.37–3.30 (m, 2H),
1.98 (t, 1H, OH), 1.50–1.21 (m, 30H), 0.87 (t, 3H, J= 6.9 Hz);
13C NMR (CDCl3, 75 MHz) d 79.4 and 76.1 (2 CH–O), 66.4
(CH2–O), [62.3, 31.7, 31.1, 29.4, 29.1, 24.7, 24.7, 22.4] (CH2),
13.9 (CH3); MS (CI, NH3) m/z 360 (100%) [M+18]+; Anal.
Calcd for C21H42O3: C, 73.63; H, 12.36. Found: C, 73.71; H,
12.06.
rac-trans-[Phosphoric acid 2-bromo-ethyl ester 3-hexadecyl-
[1,4]dioxan-2-ylmethyl ester methyl ester] rac-24
2-Bromoethyl phosphorodichloridate (410.0 mg,
1.7 mmol) is dissolved in 5 mL of anhydrous ethyl ether
containing anhydrous pyridine (0.35 mL). The medium is
added under nitrogen with the cyclic dioxane-alcohol 21
(300 mg, 0.87 mmol) dissolved in anhydrous ethyl ether
(10 mL). After one night reaction at room temperature, the
medium is quenched by excess methanol (2.0 mL), then agi-
tated for 1 h. Ethyl ether extraction (4 × 25 mL), drying of the
organic extracts (anhydrous MgSO4), and filtration (5-µm
Buchner filter) allow the recovery of the crude brominated
phospholipid rac-24 after vacuum concentration. Its purifica-
tion on a silica gel column (MeOH/CH2Cl2 60/40) affords pure
rac-24 as a white powder (270.0 mg, 62%).
IR (KBr) 2926 (νCH), 2852, 2500, 2073, 1241, 1122, 978;
1H NMR (CDCl3, 300 MHz) δ 4.45–4.26 (m, 2H, CH2–Br),
4.15–4.07 (m, 2H, OPO(OMe)–CH2), 3.80–3.60 (m, 6H,
CH–O, and CH2–O–C), 3.58–3.50 (m, 2H, CH2–OP), 3.40 (s,
3H, OMe), 1.46–1.23 (m, 28H), 0.86 (t, 3H, CH3, J = 7.0 Hz);
13C NMR (CDCl3, 75 MHz) δ 80.4, 80.3, 78.0, 68.3, 68.1,
33.4, 32.7, 32.2, 32.1, 31.2, 30.8, 26.1, 24.1, 15.3 ( CH2–CH3);
MS (CI, NH3) m/z 559 (78.7%), 545 (100%) [M + 18]+.
rac-trans-2-Hexadecyl-3-(2-oxo-2λ5-[1,3,2]dioxaphospholan-
2-yloxymethyl)-[1,4]dioxane rac-22
The dioxane-alcohol rac-21 (117.1 mg, 1.0 mmol) is dis-
solved in 15 mL of anhydrous benzene, cooled at 0 °C, and
slowly added dropwise with freshly distilled triethylamine
(0.16 mL) and 2-chloro-1-[1,3,2]-dioxaphospholane-2-oxide
(142.5 mg, 1.0 mmol). The reaction medium is gently stirred at
20 °C for 2 h. The precipitated triethylammonium chloride
is filtered (5-µm Buchner filter), and washed with benzene
(2 × 10 mL). The organic extracts are concentrated to afford the
white crude cyclic dioxane-phosphate rac-22, which is used in
the next step without any further purification (200.8 mg, 90%).
Racemic ncetyl phosphocholine rac-25
Preparation from rac-22. In a sealed glass tube (35 mL rac-trans-[Phosphoric acid 3-hexadecyl-[1,4]dioxan-2-
internal volume), rac-22 (161.5 mg, 0.36 mmol) and tri- ylmethyl ester 2-hydroxy-ethyl ester] rac-23
methylsilyl triflate (0.2 mL, 0.36 mmol) in anhydrous CH2Cl2
The brominated phosphate diester rac-24 (260.0 mg,
(10 mL). After saturation of the medium by trimethylamine 0.5 mmol) is dissolved in a mixture of DME/H2O 1/1 (10 mL),
Israel Journal of Chemistry
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335
and added with 5 mL of 1N NaOH. The hydrolysis lasts 4 h at 7.38–7.30 (m, 5H, aromatics), 5.84 (dd, 1H, J = 4.8 and 7.8
room temperature. The medium is extracted with ethyl ether Hz), 5.51 (dd, 1H, J= 5.1 and 8.7 Hz), 4.57 (s, 2H, OCH2-Ph),
(3 × 20 mL). The combined organic extracts are dried (dry 3.73–3.65 (m, 4H, CH-OH and OMe), 3.59 (dd, 1H, J = 9.4
MgSO4) and filtered (5-µm Buchner filter) to afford the crude and 12.6 Hz), 3.41 (dd, 1H, J = 7.2 and 9.0 Hz), 2.67 (d, 1H,
rac-23. Its purification is performed by flash chromatography OH, J = 3.0 Hz), 1.19 (t, 1H, J = 7.8 Hz), 1.05 (d, 1H, J = 8.1
(silica gel column, CHCl3/MeOH/H2O 60/30/04). Pure rac-23 Hz); 13C NMR (CDCl3, 75 MHz) δ 209.0 (m, 3 CO complex),
is obtained as a white powder (135.0 mg).
172.1 (s, C=O ester), [137.2, 128.3, 127.7, 127.6] (aromatics),
SM: CHCl3/MeOH/H2O 60/30/04 Rf 0.42 (white pulveru- 84.5 and 84.3 (CH diene), 74.3, 73.2, 71.6, 60.7, 51.5, 46.1;
lent solid, 60%); IR (KBr) 3419 (large, νOH), 2922, 2852 (νCH), MS (CI, NH3) m/z 420 (92.6%) [M+18]+, 402 (3.1 %) [M]+,
1467, 1261, 1124, 1085; 1H NMR (CD3OD + CDCl3 1/1, 300 385 (100%) [M–OH]+, 280 (47.1%), 264 (22.1%); Anal. Calcd
MHz) δ 3.77 (q, 2H, CH2–OH, J = 6.8 Hz), 3.58–3.54 (m, 1H), for C18H18FeO7: C, 53.75; H, 4.51. Found: C, 54.01; H, 4.69;
3.53–3.50 (m, 1H), 3.45–3.38 (m, 2H), 3.36–3.27 (m, 2H), [α]D = +149 (C = 2.0 g/100 mL, MeOH, 26 °C).
3.19 (t, 2H, J = 6.3 Hz), 3.09–3.03 (m, 2H), 2.97 (q, 2H), 1.20–
ψ-endo-Tricarbonyl[(2S,5R)-7-Benzyloxy-6R-ethoxycarbonyl-
1.10 (m, 2H), 1.00–0.85 (m, 28H), 0.59 (t, 3H, CH3, J =
methoxy-hepta-2E,4E-dienoic acid methyl ester]iron 29
7.0 Hz); 13C NMR (CD3OD/CDCl3 1/1, 75 MHz) δ 80.0, 79.5,
The ψ-endo-iron complexed ester alcohol (+)–27 (1.2 g, 3.0
77.2, 67.3, 67.2, 66.0, 32.5, 31.8, 30.2, 29.9, 25.5, 23.2, 15.3
mmol) and the rhodium catalyst [Rh2(OAc)4] (165.0 mg, 0.36
(CH2–CH3); 31P NMR (CD3OD/CDCl3 1/1, 121.4 MHz, 85%
mmol) are mixed in anhydrous cooled dichloromethane (30 mL,
H3PO4 reference) δ 1.88 (s); MS (CI, NH3) m/z 466 (100%)
0 °C). The medium is added dropwise with ethyl diazoacetate
[M]+, 449 (70.3%) [M–OH]+.
(1.0 mL, 7.5 mmol), while maintaining the internal temperature
ψ-endo-Tricarbonyl[(2S,5R)-7-benzyloxy-6R-hydroxy-hepta-
2E,4E-dienoic acid methyl ester]iron 27 and ψ-exo-tricar-
bonyl[(2S,5R)-7-benzyloxy-6S-hydroxy-hepta-2E,4E-dienoic
acid methyl ester]iron 28
below 5 °C. TLC monitoring indicates that the reaction is com-
pleted within 1 h at 20 °C. After hydrolysis by saturated aqueous
NH4Cl (20 mL), and extraction by dichloromethane (3 × 25 mL),
the combined organic extracts are washed to neutrality by
deionized water, dried (anhydrous MgSO4), filtered (5-µm
Buchner filter), and concentrated. The crude iron-complexed
diester 29 is purified by flash chromatography (silica gel,
hexane/ethyl ether 1/1) to give pure (+)–29 (760.0 mg).
SM: hexane/ethyl ether 1/1, Rf 0.50 (orange oil, 52.0%); IR
(KBr) 2929 (νCH), 2060, 1990 (νCO complex), 1754, 1714
The optically active iron-complexed diene (+)-(2S,5R)-26
(2.80 g, 10.0 mmol) is dissolved in anhydrous tetrahydro-
furane (30 mL), cooled at –78 °C, and then slowly added
dropwise with a 1 M THF solution of the organolithium
BnOCH2Li10 (10.0 mL, 10.0 mmol). After completion of the
reaction (1 h at –78 °C, TLC monitoring), the medium is
hydrolyzed by saturated aqueous NH4Cl (30 mL), and ex-
tracted by ethyl ether (5 × 25 mL). The combined organic
extracts are washed to neutrality by deionized water, dried
(anhydrous MgSO4), filtered (5-µm Buchner filter), and con-
centrated. The two alcohols ψ-endo-/ψ-exo-27 and 28 are
well-resolved by flash chromatography on a silica gel column
(hexane/ethyl ether 1/1) to give the pure less polar/more polar
(+)–27 (1.37 g) and (+)–28 (2.53 g, global yield 97%).
1
(νCO ester), 1460, 1204, 1114, 612, 561; H NMR (CDCl3,
300 MHz) δ 7.34–7.28 (m, 5H, aromatics), 5.81 (dd, 1H, J =
5.1 and 7.7 Hz), 5.71 (dd, 1H, J= 5.2 and 8.7 Hz), 4.53 (s, 2H,
OCH2–Ph), 4.27–4.11 (m, 4H), 3.82 (q, 1H, CH–OH, J =
6.4 Hz), 3.63 (s, 3H, OMe), 3.58 (dd, 1H, J = 6.6 and 9.5Hz),
3.50 (dd, 1H, J= 4.5 and 9.8 Hz), 1.31–1.17 (m, 4H), 0.90 (d,
1H, J = 8.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 207.3 (3 CO
complex), 172.3 and 170.2 (CO ester), [137.5, 129.5, 127.5,
127.4] (aromatics), 83.9 and 82.7 (CH complex), 78.5, 75.1,
73.3, 67.6, 62.8, 60.5, 51.3, 45.2, 15.4 (CH2–CH3); MS
(CI, NH3) m/z 506 (100%) [M+18]+, 385 (36.2%) [M–
OCH2CO2Et]+; Anal. Calcd for C22H24FeO9: C, 54.10; H, 4.95.
Found: C, 54.17; H, 4.79; [α]D = +115 (C = 2.0 g/100 mL,
MeOH, 22 °C).
ψ-endo-27. SM: hexane/ethyl ether 1/1, Rf 0.49 (orange oil,
34.0%); IR (KBr) 3469 (νOH, large), 2925, 2858 (νCH), 2058,
1986 (νCO complex), 1712 (νCO ester), 1455, 1337, 1196, 1178,
1093, 611, 561; 1H NMR (CDCl3, 300 MHz) δ 7.38–7.30 (m,
5H, aromatics), 5.81 (dd, 1H, J= 4.8 and 8.0 Hz), 5.45 (dd, 1H,
J= 5.1 and 8.7 Hz), 4.56 (s, 2H, OCH2–Ph), 3.91–3.87 (m, 1H,
CH–OH), 3.65 (s, 3H, OMe), 3.58 (dd, 1H, J= 3.4 and 9.3 Hz),
3.33 (t, 1H, J = 8.9 Hz), 2.41 (d, 1H, OH, J = 2.7 Hz), 1.16 (dd,
1H, J = 8.4 and 6.3 Hz), 0.92 (d, 1H, J = 8.1 Hz); 13C NMR
(CDCl3, 75 MHz) δ 207.3 (m, 3 CO complex), 172.3 (s, C = O
ester), [137.3, 128.3, 127,6, 127,4] (aromatics), 84.4 and 83.7
(CH diene), 75.5, 73.3, 70.9, 63.5, 53.8, 45.4; MS (CI, NH3)
m/z 420 (100%) [M+18]+, 385 (8.0%) [M–OH]+, 280 (17.8%),
220 (8.7%); Anal. Calcd for C18H18FeO7: C, 53.75; H, 4.51.
Found: C, 53.95; H, 4.68; [α]D = +149 (C = 2.0 g/100 mL,
MeOH, 26 °C).
ψ-endo-Tricarbonyl[(2S,5R)-7-benzyloxy-6R-(2-hydroxy-
ethoxy)-hepta-2E,4E-dien-1-ol]iron 30
The ψ-endo-iron complexed diester (+)–29 (1.46 g,
3.0 mmol) is dissolved in anhydrous dichloromethane
(30 mL) and cooled at –78 °C under nitrogen. The agitated
medium is added dropwise with 1 M DIBAL-H (15.0 mL,
15.0 mmol), and reacted during 1 h at –78 °C. The medium is
hydrolyzed sequentially by 3 mL of MeOH, and by a saturated
solution of sodium-potassium tartrate (9 mL). It is vigorously
agitated during 1 h at 20 °C. After extraction by ethyl ether
ψ-exo-28. SM: hexane/ethyl ether 1/1, Rf 0.22 (orange oil, (5 × 25 mL), the combined organic extracts are washed to
63.0%); IR (KBr) 3436 (νOH, large), 3032, 2951, 2862 (νCH), neutrality by deionized water, dried (anhydrous MgSO4),
2058, 1986 (νCO complex), 1713 (νCO ester), 1455, 1320, 1196, filtered (5-µm Buchner filter), and concentrated. The crude
1177, 1108, 743, 700, 612, 561; 1H NMR (CDCl3, 300 MHz) δ iron-complexed diol 30 is purified by flash chromatography
Braun and Lellouche / 1,5-O-Heterocyclization of Iron Complexed Diols

336
(silica gel, CH2Cl2/EtOH 95/05) to give pure (–)–ψ-endo-30 18]+, 401 (14.1%) [M + 1]+, 297 (12.0%), 280 (10.8 %); Anal.
(870.0 mg).
Calcd for C19H20FeO6: C, 43.87; H, 3.99. Found: C, 43.97; H,
SM: CH2Cl2/EtOH 95/05 Rf 0.51 (yellow solid, 69%); IR 4.00; [α]D = –48.2 (C = 2.0 g/100 mL, CH2Cl2, 23 °C).
(KBr) 2929 (νCH), 2060, 1990 (νCO complex), 1754, 1714
1
(2S,3S)-2-Benzyloxymethyl-3-buta-1E,3-dienyl-[1,4]dioxane
32
(νCO ester), 1460, 1204, 1114, 612, 561; H NMR (CDCl3,
300 MHz) δ 7.37–7.29 (m, 5H, aromatics), 5.27–5.18 (m, 2H,
CH complex), 4.55 (s, 2H, OCH2Ph), 3.76–3.60 (m, 7H), 3.53
(dd, 1H, J= 9.4 and 6.7 Hz), 3.45 (dd, 1H, J= 9.6 and 4.6 Hz),
2.68 (t, 1H, OH, J = 6.7 Hz), 1.63 (t, 1H, J = 7.0 Hz), 1.19 (q,
1H, CH complex, J = 7.3 Hz), 1.06 (dd, 1H, CH complex,
J= 5.6 and 7.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 210.7 (3 CO
complex), [137.3, 128.3, 127.6, 127.5] (aromatics), 82.6 and
81.4 (s, CH complex), 79.4, 74.6, 73.3, 72.2, 64.3, 62.7, 62.1,
60.5; MS (CI, NH3) m/z 436 (100 %) [M+18]+, 419 (7.4 %)
[M + 1]+, 401 (26%) [M–OH]+, 357 (99.7 %) [M–
OCH2CH2OH]+, 296 (20.7%), 93 (27.8); Anal. Calcd for
C19H22FeO7: C, 54.60; H, 5.30. Found: C, 54.53; H, 5.31;
[α]D = –9.5 (C = 2.0 g/100 mL, CH2Cl2, 26 °C).
The preparation of the optically active benzylated complex
(–)–(2S,3S)-32 (200.0 mg, 0.5 mmol) is carried out in the same
fashion as the preparation of the decomplexed rac-20. Purifi-
cation of crude (–)–32 is best accomplished by flash chroma-
tography (silica gel, hexane/ethyl ether 1/1) to give the pure
optically active (–)–(2S,3S)-32 (120.0 mg).
SM: hexane/ethyl ether 1/1 Rf 0.48 (colorless oil, 92%); IR
(KBr) 2857 (νCH), 1605 (νCH=CH), 1453, 1353, 1274, 1119,
1006, 904, 737, 698; 1H NMR (CDCl3, 300 MHz) δ 7.33–7.26
(m, 5H, aromatics), 6.32–6.23 (m, 2H, H-alkene), 5.54 (dd,
1H, H-alkene, J= 14.2 and 7.2 Hz), 5.22 (d, 1H, H-alkene, J=
14.8 Hz), 5.12 (d, 1H alkene, J= 11.0 Hz), 4.62 and 4.22 (2d,
2H, OCH2Ph, J= 12.2 Hz), 4.02 (t, 1H, J= 8.0 Hz), 3.83–3.72
(m, 4H, OCH2CH2O), 3.50 (t, 2H, J = 4.3 Hz), 3.43–3.39 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ [137.7, 135.9, 134.4,
128.8, 128.1] (aromatics), 118.3, 78.8, 73.4, 69.6, 66.6 and
66.0 (-OCH2CH2O-); MS (CI, NH3) m/z 278 (100%) [M+18]+,
261 (43.7%) [M + 1]+; Anal. Calcd for C16H20FeO3: C, 73.80;
H, 7.70. Found: C, 73.31; H, 7.98; [α]D = –37.5 (C = 2.0 g/100
mL, CH2Cl2, 24 °C).
ψ-exo-Tricarbonyl[(2S,3R)-2-Benzyloxymethyl-3-buta-1E,3-
dienyl-[1,4]dioxane]iron 31
The preparation of the optically active iron-complexed
trans-dioxane (–)–(2S,3R)–31 from the starting diol (–)–ψ-
endo-30 is carried out in the same fashion as described in ref 4.
Starting from (–)–30 (420.0 mg, 1.0 mmol), it allows the
obtention of the optically active (–)–31 (290.0 mg). Its analyti-
cal and spectroscopic data are detailed below.
(2R,3R)-(3-Benzyloxymethyl-[1,4]dioxan-2-yl)-methanol 33
The obtention of (–)–(2R,3R)-33 by the sequence ozoniza-
tion/NaBH4-mediated ozonide reduction is similar to the
preparation of rac-21. Accordingly, the benzylated diene
(–)–32 (260.0 mg, 1.0 mmol) affords the pure optically active
(–)–(2R,3R)–33 (190.0 mg) (flash chromatography on a silica
gel column, hexane/ethyl ether 1/1).
SM: hexane/ethyl ether 1/1 Rf 0.12 (colorless oil, 87%);
chiral analytical HPLC: same conditions as for (–)–(2S,3R)–
31, retention time 10.5 min, optical purity greater than 97.0%;
IR (KBr) 3456 (νOH), 2857 (νCH), 1721, 1454, 1366, 1262,
1116, 923, 847, 739, 699; 1H NMR (CDCl3, 300 MHz) δ 7.37–
7.25 (m, 5H, aromatics), 4.62 and 4.50 (2d, 2H, –OCH2Ph,
J= 12.2 and 18.1 Hz), 3.84–3.47 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ [137.3, 129.5, 128.3, 127.6] (aromatics), 77.6,
75.6, 73.5, 69.7, 66.6 and 66.3 (OCH2CH2O), 62.3; MS (CI,
NH3) m/z 256 (100%) [M+18]+, 239 (14.9 %) [M + 1]+; High
Resolution EI-MS m/z Calcd for C13H16O4, 238.1205. Found:
238.1208 [M]+. Calcd for C12H15O3, 207.1021. Found:
207.1021; Anal. Calcd for C18H18O3: C, 73.80; H, 7.70. Found:
C, 73.31; H, 7.98; [α]D = –12.5 (C = 2.0 g/100 mL, CH2Cl2,
23 °C).
SM: hexane/ethyl ether 1/1 Rf 0.44 (yellow solid, 72%);
chiral analytical HPLC on a Chiracel OD column (column
temperature 20 °C) eluted isocratically by the mixture hexane/
isopropanol 95/05, 0.8 mL/min, λUV 230 nm, retention time
12.5 min, optical purity greater than 96.0%; IR (KBr) 2885
(νCH), 2058 and 1965 (νCO carbonyl and νC=C aromatics), 1055;
1H NMR (C6D6, 300 MHz) δ 7.23–7.03 (m, 5H, aromatics),
5.28 (dd, 1H, internal CH complex, J = 4.9 and 8.6 Hz), 4.60
(ddd, 1H, internal CH complex, J = 4.9, 6.4 and 9.1 Hz), 4.35
(d, 1H, OCH2Ph, J = 12.1 Hz), 4.16 (d, 1H, OCH2Ph, J = 12.1
Hz), 3.70 (dd, 1H, CH complex, J = 2.0 and 8.6 Hz), 3.37 (t,
2H, J = 8.6 Hz), 3.32–3.24 (m, 4H, OCH2CH2O), 3.12–3.07
(m, 1H), 1.28 (dd, 1H, syn CH complex, J = 1.1 and 6.3 Hz),
1.01 (dd, 1H, J = 1.8 and 8.7 Hz), –0.13 (dd, 1H, anti CH
complex, J = 1.6 and 9.1 Hz); 1H NMR (CDCl3, 300 MHz) δ
7.36–7.25 (m, 5H, aromatics), 5.46 (dd, 1H, internal CH com-
plex, J= 4.9 and 8.6 Hz), 5.19 (ddd, 1H, internal CH complex,
J = 4.9, 6.5 and 9.1 Hz), 4.67 and 4.38 (d, 1H, OCH2Ph, J =
12.2 Hz), 3.82–3.79 (m, 1H), 3.76–3.57 (m, 4H), 3.56–3.46
(m, 2H), 3.30–3.25 (m, 1H), 1.60 (dd, syn CH complex, J= 1.7
and 6.8 Hz), 0.79 (dd, 1H, CH complex, J = 2.6 and 8.8 Hz),
–0.4 (dd, 1H, anti CH complex, J= 2.0 and 9.1 Hz); 13C NMR
(C6D6, 75 MHz) δ 210.2 (3 CO complex), [138.6, 128.6, (2S,3R)-3-Benzyloxymethyl-[1,4]dioxane-2-carbaldehyde 34
127.7] (aromatics), 84.3 and 80.7 (CH complex), 81.1 and The ozonization protocol is strictly identical to the one
76.7 (CH-O), 73.5 (OCH2Ph), [70.5, 66.8, 66.6] (CH2–O), developed toward rac-21, except that the ozonide is destroyed
60.7 (CH complex), 38.9 (CH2 complex); 13C NMR (CDCl3, by excess Me2S (0.5 mL) before similar processing. (–)–
75 MHz) δ 210.4 (3 CO complex), [137.5, 128.2, 127.8] (2S,3S)–32 (520.0 mg, 2.0 mmol) affords the pure (2S,3R)–
(aromatics), 83.8 (internal CH complex), 80.6 and 75.6 (CH– dioxane aldehyde 34 (300.0 mg) after flash chromatography
O), 80.5 (internal CH complex), 73.1 (OCH2Ph), [69.3, 66.7 (silica gel column, CH2Cl2/EtOH 95/05).
and 66.2] (CH2–O), 59.3 (CH complex), 38.6 (CH2 complex);
SM: CH2Cl2/EtOH 95/05 Rf 0.38 (colorless paste, 65%);
MS (CI, NH3) m/z 435 (100 %) [M+35]+, 418 (82.3%) [M + 1H NMR (CDCl3, 300 MHz) δ 9.56 (s, 1H, CHO), 7.32–7.26
Israel Journal of Chemistry
41
2001

337
(m, 5H, aromatics), 4.65–4.41 (m, 3H), 4.10–3.55 (m, 7H); the dioxane-alcohol (–)–(2R,3R)–36 (372.6 mg, 1.0 mmol),
13C NMR (CDCl3, 75 MHz) δ 198.2 (CHO), [137.3, 129.5, the chromatographically pure brominated phosphate (2R,3R)-
128.3, 127.6] (aromatics), 80.4, 74.3, 73.4, 68.8, 66.0, and 37 (430.1 mg, white paste) is obtained after flash chromatog-
65.8 (OCH2CH2O); MS (CI, NH3) m/z 254 (100%) [M+18]+, raphy (silica gel column, MeOH/CH2Cl2 60/40, 75% yield).
236 (21.9%) [M + 1]+; High Resolution EI-MS m/z Calcd for
C13H16O4, 236.1048. Found: 236.1055. Calcd for C12H15O3,
The preparation of (–)-(2R,3R)-38 has been performed in
207.1021. Found: 207.1021.
(–)-(2R,3R)-O-nCetyl phosphocholine 38
the same fashion as the preparation of rac-25 from rac-24.
(2R,3R)-2-Benzyloxymethyl-3-hexadecyloxymethyl-
[1,4]dioxane 35
Starting from the brominated phosphate (2R,3R)-37 (150.0 mg,
0.262 mmol), the pure optically active (–)-(2R,3R)-O-ncetyl
phosphocholine 38 (62.0 mg, colorless paste) is obtained after
flash chromatography (silica gel column, CHCl3/MeOH/H2O
60/30/4, 44% yield).
SM: CHCl3/MeOH/H2O 60/30/4 Rf 0.26 (colorless paste,
44%); Analytical HPLC on a column VYDAC C8 250–4.6
(column temperature 35 °C), solvent A—acetone/methanol/
THF/acetic acid 700/250/50/50, solvent B—H2O containing
5% CH3CO2H, isocratic elution solvent A/solvent B 6/4,
1.5 mL/min, light-scattering DEDL-evaporating detector
(SEDEX Ltd, He nebulizing gas at a pressure of 1.75 bar),
retention time of (–)-(2R,3R)-38 3.18 min, chemical purity
greater than 97.2%; IR (KBr) 3418 (large, νCH2N), 2921, 2852
NaH (26.0 mg, 1.1 mmol) suspended in anhydrous DMF
(5 mL) is added at 20 °C under nitrogen with the chiral
dioxane-alcohol (–)-(2R,3R)-33 (240.0 mg, 1.0 mmol, 5 mL
DMF). The medium is stirred for 1 h before adding 1-bromo
hexadecane dissolved in DMF (670.0 mg, 2.0 mmol, 3 mL).
The etherification reaction lasts 6 h at 20 °C, then the medium
is hydrolyzed by saturated aqueous NH4Cl (20 mL). After
extraction by ethyl ether (4 × 30 mL), the combined organic
extracts are washed to neutrality by deionized water, dried
(anhydrous MgSO4), filtered (5-µm Buchner filter), and con-
centrated. The crude benzylated ether 35 is purified by flash
chromatography (silica gel, hexane/ethyl ether 1/1) to give
pure (–)-(2R,3R)-35 (305.0 mg).
1
(νNMe3), 1738 (νCH2O), 1467, 1231 (νP=O), 1089, 971; H NMR
SM: hexane/ethyl ether 1/1 Rf 0.32 (colorless oil, 66%); IR
(KBr) 2925, 2854 (νCH), 1454 (νCH=CH aromatics), 1366, 1272,
1117, 926, 734, 697; 1H NMR (CDCl3, 300 MHz) δ 7.35–7.26
(m, 5H, aromatics), 4.62 and 4.48 (2H, –OCH2Ph, J = 12.2
Hz), 3.81–3.70 (m, 4H), 3.64–3.23 (m, 8H), 1.57–1.42 (m, 2H,
-OCH2CH2-), 1.32–1.17 (m, 26H), 0.86 (t, 3H, CH3-, J = 6.8
Hz); 13C NMR (CDCl3, 75 MHz) δ [137.8, 128.1, 127.6,
127.5] (aromatics), 76.1, 75.9, 73.3, 71.6, 70.3, 69.5, 66.6,
66.3, 31.7, 29.4, 29.2, 29.1, 25.8, 22.4, 13.9; MS (CI, NH3)
m/z 480 (100 %) [M+18]+, 463 (78.8%) [M + 1]+; Anal. Calcd
for C29H50O4: C, 75.34; H, 10.90. Found: C, 75.52; H, 11.24;
[α]D = –15.5 (C = 1.1 g/100 mL, CH2Cl2, 24 °C).
(CDCl3, 300 MHz) δ 4.33 (s, 2H), 4.00–3.87 (m, 2H), 3.86–
3.45 (m, 12H), 3.35 (s, 9H, –NMe3), 1.55–1.48 (m, 2H), 1.33–
1.17 (m, 28H), 0.86 (t, 3H, –CH2CH3, J = 7.0 Hz); 31P NMR
(CDCl3, 121.4 MHz, 85% H3PO4 reference) δ 0.47 (s);
13C NMR (CDCl3, 75 MHz) δ 82.3, 81.2 (d), 80.9, 77.2, 75.5,
71.7, 71.5, 70.2, 64.4, 59.5 (NMe3), 37.0, [34.7, 34.4, 31.1,
27.7] (CH2 alkyl chain), 19.1 (–CH2CH3); MS (CI, NH3) m/z
538 (100%) [M+1]+, 496 (72.8), 481 (63.7), 478 (43.5), 390
(17.5); [α]D = –9.0 (C = 1.0 g/100 mL, CH2Cl2, 24 °C).
Acknowledgments. The authors are grateful to Dr. Yves
Rolland for his interest during this work. A.B. thanks the
Servier Institute (Suresnes) for its financial support through a
research PhD fellowship.
(3R-Hexadecyloxymethyl-[1,4]dioxan-2R-yl)-methanol 36
The benzylated ether (–)–(2R,3R)–35 (230.0 mg, 0.5 mmol)
is dissolved in ethanol (10 mL) containing a suspension of
Raney nickel catalyst (30.0 mg), and agitated under H2 during
24 h at 20 °C. After filtration of the catalyst (Celite®-covered
5-µm Buchner filter) and washing of the filter by ethanol (2 ×
5 mL), the organic phase is concentrated affording the crude
debenzylated dioxane-alcohol 36. It is purified by flash chro-
matography (silica gel, hexane/ethyl ether 1/1) to afford pure
(–)-(2R,3R)-36 (170.0 mg).
SM: hexane/ethyl ether 1/1 Rf 0.10 (colorless oil, 92%); IR
(KBr) 3461 (large, νOH), 2923, 2854 (νCH), 1467, 1366, 1272,
1121, 922, 846, 733, 646; 1H NMR (CDCl3, 300 MHz) δ 3.81–
3.39 (m, 12H), 2.43 (s, 1H, OH), 1.61–1.49 (m, 2H, –CH2–OH),
1.39–1.15 (m, 26H), 0.86 (t, 3H, Me, J = 6.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 78.1, 75.7, 71.8, 70.6, 66.6, 66.4, 62.5, 31.7,
29.4, 29.3, 29.2, 29.1, 25.8, 22.4, 13.8; MS (CI, NH3) m/z 390
(100%) [M+18]+; [α]D = –1.5 (C = 2.0 g/100 mL, CH2Cl2,
24 °C), –11.0 (C = 2.0 g/100 mL, MeOH, 24 °C).
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Phosphoric acid 2-bromo-ethyl ester 3R-hexadecyloxy-
methyl-[1,4]dioxan-2R-ylmethyl ester methyl ester 37
The preparation of chiral (2R,3R)-35 has been performed
in the same fashion as the preparation of rac-24. Starting from
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