Synthesis of spherical polyols from itaconic acid

Article abstract of DOI:10.1055/s-0029-1218764

The Diels-Alder reaction of some bromo derivatives of the itaconic acid with cyclopenta-1,3-diene gave a simple access to precursors of spherical polyols of synthetic interest. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218764

PAPER
1787
Synthesis of Spherical Polyols from Itaconic Acid
S
ynthesis of Sphe
é
rical
P
olyo
l
ls ine Reynaud,a Henri Doucet,*b Maurice Santelli*a
a
Laboratoire Chimie Provence, associé au CNRS, UMR 6264, Faculté des Sciences de Saint Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Fax +33(4)91289112; E-mail: m.santelli@univ-cezanne.fr
Institut Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes ‘Catalyse et Organometalliques’,
Campus de Beaulieu, 35042 Rennes, France
b
Fax +33(2)23236939; E-mail: henri.doucet@univ-rennes1.fr
Received 22 January 2010; revised 10 March 2010
Br
CO2Me
Abstract: The Diels–Alder reaction of some bromo derivatives of
the itaconic acid with cyclopenta-1,3-diene gave a simple access to
precursors of spherical polyols of synthetic interest.
CO2Me
DMSO
1. Br2, CH2Cl2
2. Et3N
CO2Me
CO2Me
40 °C, 20 h
O
CO2Me
O
Key words: bicyclic compounds, Diels–Alder reaction, ozonoly-
sis, stereoselective synthesis, protecting groups
1
2, 80%
3, 65%
CO2Me
O
O
+
Among the most prominent reactions able to construct
carbon frameworks through carbon–carbon bond-forma-
tion reactions, the Diels–Alder reaction presents the ad-
vantage to have a good control of the stereochemistry.1
For ten years, we studied the synthesis of chelating poly-
phosphine ligands as useful tools for stabilizing unusual
geometries in transition-metal complexes in order to ob-
tain efficient organometallic catalysts.2 For this purpose,
we developed a strategy based on the use of the Diels–
Alder reaction involving cyclopentadiene derivatives and
a suitable dienophile, followed by an ozonolysis reaction
and a reductive treatment to give stereochemically con-
trolled polyols. These polyols are useful precursors of
polydentate ligands. They might also serve as the initia-
tors of some polymers such as polyurethane or polyesters.
CH2Cl2
O
MeO2C
O
exo
endo 4:1
4, 90%
O
O
OH
OH
LiAlH4
Et2O
OMe
H+
endo-4
OH
6, 100%
OH
5, 80%
HO
HO
HO
HO
OH
O
OH
OH
H+
1. O3, CH2Cl2
2. NaBH4
O
OH
7, 95%
8, 96%
Here, we report on new results concerning the Diels–
Alder reaction involving itaconic acid derivatives, allowing
the synthesis of some polyols of predetermined structure.
TsO
TsO
OTs
OTs
TsCl
pyridine–CH2Cl2
Methyl aconate (3) was obtained in a fairly good yield of
65% by simply heating dimethyl bromocitraconate (2) in
DMSO at a moderate temperature (40 °C; at 100 °C, the
yield of 3 was only 29%).3,4 The Diels–Alder reaction of
3 with cyclopentadiene was found to be quite selective, as
mainly the endo-isomer, endo-4, was formed (ratio endo-
4/exo-4 = 4:1) (Scheme 1) (endo is defined by the rela-
tionship of the lactone to the bicyclo[2.2.1] system). The
adduct endo-4 was easily obtained in pure form by simple
crystallization of the crude reaction mixture from Et2O.
Structure of endo-4 was confirmed by X-ray crystallo-
graphic analysis (Figure 1). The high selectivity in favor
of the endo-isomer is not observed with the 2-acylbuteno-
lides, which led mainly to the exo-isomers.5
OTs
9, 20%
Scheme 1 Synthesis of the pentaol 8
SYNTHESIS 2010, No. 11, pp 1787–1792
x
x.
x
x
.
2
0
1
0
Advanced online publication: 29.04.2010
DOI: 10.1055/s-0029-1218764; Art ID: T01810SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 ORTEP drawing of endo-4; non-hydrogen atoms are
drawn with 50% probability thermal ellipsoids

1788
C. Reynaud et al.
PAPER
Subsequent reduction of endo-4 with lithium aluminum The pentaol 8 was obtained in seven steps with an overall
hydride gave the triol 5 in 80% yield. Compound 5 was yield of 34% from the cheap reagent dimethyl itaconate
also purified by simple crystallization of the crude mix- (1) and other cheap usual reagents. This pentaol is charac-
ture. Next, 5 was protected as the acetonide 6 using an ex- terized by a globular structure, which might serve as the
cess of 2-methoxypropene.6 This protection makes the precursor for dendrimers or hyperbranched polymers.9
workup of the following step easier, as pentaol 8 is very Then, in order to obtain a precursor of polydentate
water soluble. It should be noted that, in the course of this ligands, we performed the tosylation of 8 using an excess
reaction, only the 1,3-dioxane derivative was obtained in of tosyl chloride. Unfortunately, the pentatosylation to
quantitative yield. No formation of 1,3-dioxepane deriva- form 9 occurs in a relatively low yield of 20% due to the
tive was detected. The structure of the acetonide 6 was se- formation of some cyclized ethers as the by-products. We
cured by an X-ray crystallographic analysis of its tosylate also examined the protection of the residual hydroxy
10 (Scheme 2 and Figure 2).
group of 6 using benzyl bromide as the reactant. The reac-
tion led to the fully protected triol 11, which might be use-
ful to prepare some polymer-supported ligands, in good
yield. We also observed that classical substitution or elim-
ination reactions to give 12 and 13 occurred easily from
the tosylate 10 prepared by tosylation of 6 (Scheme 2).
O
O
NaH
TsCl
6
O
O
pyridine
BnBr
O
OTs
THF
11, 65%
10, 95%
Saponification of endo-4 led to the lactone acid 14 in very
high yield (Scheme 3). Surprisingly, the chemoselective
reduction of the lactone 14 did not occur using lithium
aluminum hydride or lithium borohydride under various
reaction conditions.10
KCN
KOt-Bu
DMF
DMSO
O
O
O
O
CO2Me
CO2H
C
N
13, 55%
12, 80%
1. KOH, EtOH
2. HCl
Scheme 2 Synthesis of various bornene derivatives from alcohol 6
O
O
O
O
endo-4
14, 86%
Scheme 3 Saponification of the lactone endo-4.
Similarly, itaconic anhydride (15), after a bromation step
followed by a basic treatment (K2CO3 appeared to give
better yield than 2,6-lutidine) gave 16.11 Then, 16 reacted
with cyclopentadiene leading nearly quantitatively to the
expected and interesting Diels–Alder adduct 17. Only the
crystallized endo-isomer was obtained, and it can be used
in the following steps without further purification
(Scheme 4). The endo structure of 17 was confirmed by
the reduction of the anhydride to the known endo diol
18.12 In order to prepare a potential precursor of polymer-
supported ligand, we required the bromo diol 19. Interest-
ingly, a chemoselective reduction of 17 occurred with
DIBAL to give 19 in 62% yield. On the other hand, the re-
duction of 17 with lithium aluminum hydride at a low re-
action temperature, afforded the lactone 20, resulting
from the selective reduction of the less hindered carbonyl
group of the anhydride of 17. A further reduction of 20 at
low temperature led to the bromodiol 19 in 56% yield.13
Figure 2 ORTEP drawing of 10; non-hydrogen atoms are drawn
with 30% probability thermal ellipsoids
It should be pointed out that the neopentyl-type bromide
17 is almost inert towards nucleophiles (e.g., CuCN in
MeCN; NaN3 in DMF). Anhydrous sodium methoxide in
the presence of tetrabutylammonium iodide (TBAI) led
mainly to a Grob fragmentation reaction14 and to the ste-
reoselective formation of the dehydrosantalene analogue
21 (only endo-isomer) in a moderate yield of 66% [36%
overall yield from itaconic anhydride (15)].15
Acetonide 6 was ozonolyzed at –60 °C in the presence of
an ozonizable red dye (sudan III, Eastman Kodak) as the
internal standard.7 After treatment with an ethanolic solu-
tion of sodium borohydride, the protected spherical penta-
ol 7 was isolated in very good yield.8 The deprotection
was performed using ion exchange resin Amberlite IR®
120 hydrogen form in the presence of water. After filtra-
tion and elimination of water in vacuo, the pentaol 8 was
dried by three azeotropic distillations with toluene.
Synthesis 2010, No. 11, 1787–1792 © Thieme Stuttgart · New York

PAPER
Synthesis of Spherical Polyols
1789
13C NMR (75 MHz, CDCl3): d = 165.2 (s), 165.0 (s), 142.7 (s),
Br
O
O
Br
O
128.3 (d), 53.0 (q), 52.2 (q), 22.4 (t).
O
1. Br2, CH2Cl2
2. K2CO3
O
3-Methoxycarbonyl g-Crotonolactone (Methyl Aconate, 3)3
A solution of the bromo ester 2 (36.2 g, 0.15 mol) in DMSO (250
mL) was stirred at 40 °C for 20 h. H2O (250 mL) and CH2Cl2 (250
mL) were added to the solution and stirred for 1 h. The organic layer
was washed with H2O (4 ×) and the aqueous layer extracted with
CH2Cl2. The combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo to give an oil, which was dissolved in
PE–Et2O (70:30) to give white flakes of 3 (14.2 g, 0.10 mol, 65%);
mp 86 °C.
1H NMR (300 MHz, CDCl3): d = 6.72 (t, J = 2.3 Hz, 1 H), 5.02 (d,
J = 2.3 Hz, 2 H), 3.90 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.8 (s), 161.5 (s), 154.7 (s),
126.5 (d), 70.7 (t), 52.9 (q).
CH2Cl2
O
O
O
O
15
16, 85%
17, 95%
LiAlH4, THF
OH
OH
−10 °C to 25 °C
18, 90%
19, 62%
Br
DIBAL-H, CH2Cl2
–80 °C to 25 °C
OH
OH
17
Br
LiAlH4, THF
–25 °C
LiAlH4, Et2O
2-Methoxycarbonyl-4-oxatricyclo[5.2.1.02,6]dec-8-en-5-one (4)
A solution of cyclopentadiene (28.4 g, 0.43 mol) and lactone 3 (34.5
g, 0.243 mol) in CH2Cl2 (400 mL) was stirred at 25 °C for 24 h.
Concentration in vacuo gave a mixture of endo- and exo-isomers
(80:20) in 87% (44 g) yield.
O
19, 56%
–35 °C to 25 °C
O
20, 45%
OMe
O
endo-416
MeONa, TBAI
THF
+
The crude product was crystallized from Et2O to give white crystals
of endo-4 (26.4 g, 0.127 mol); mp 56 °C.
1H NMR (300 MHz, CDCl3): d = 6.43 (AB, d, J = 5.7, 2.9 Hz, 1 H),
6.35 ( AB, d, J = 5.7, 3.2 Hz, 1 H), 4.36 (AB, J = 10.2 Hz, 1 H), 3.92
(AB, J = 10.2 Hz, 1 H), 3.80 (s, 3H), 3.63 (d, J = 4.7 Hz, 1 H), 3.41
(m, 1 H), 3.36 (m, 1 H), 1.71 (m, 2 H).
O
CO2Me
O
21, 66%
22, 20%
Scheme 4 Synthesis of norbornene derivatives.
In summary, various polyfunctionalized norbornene de-
rivatives and cyclopentane derivatives were prepared in
good yields from itaconic acid and usual reagents. Some
of these compounds should be useful precursors for the
preparation of polydentate ligands or dendrimers, or
might serve as the starting point for polymeric polyols.
13C NMR (75 MHz, CDCl3): d = 176.2 (s), 174.0 (s), 138.9 (d),
134.9 (d), 71.7 (t), 57.6 (s), 52.9 (d), 52.3 (d*, q*), 50.9 (q*, d*),
50.6 (t), 45.9 (d). * The assignments are exchangeable.
Anal. Calcd for C11H12O4 (208.21): C, 63.45; H, 5.81. Found: C,
63.61; H, 6.02.
exo-4
Mp 78 °C.
THF was freshly distilled from sodium-benzophenone; CH2Cl2,
Et3N, and pyridine from CaH2 under N2. Other reagents and sol-
vents were obtained from commercial sources and used as received.
Flash column chromatography (FC): Merck 230–400 Mesh silica
gel; EtOAc, Et2O, and petroleum ether (PE, bp 40–65 °C) as elu-
ents. TLC: Macherey-Nagel silica gel UV254 analytical plates. NMR
spectroscopy: Bruker AC 300 (1H at 300 MHz, 13C at 75 MHz);
chemical shift d in parts per million relative to CDCl3 [signals for
residual CHCl3 in the CDCl3: 7.26 ppm for 1H NMR and 77.00 ppm
(central) for 13C NMR]; in the case of CD3OD as solvent, d = 3.34
1H NMR (300 MHz, CDCl3): d = 6.33 (AB, d, J = 5.6, 3.1 Hz, 1 H),
6.12 (AB, d, J = 5.6, 3.0 Hz, 1 H), 4.46 (AB, J = 10.2 Hz, 1 H), 4.18
(AB, J = 10.2 Hz, 1 H), 3.72 (m, 2 H), 3.71 (s, 3 H), 3.34 (br s, 1 H),
3.18 (br s, 1 H), 3.04 (br s, 1 H), 1.63 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 176.0 (s), 173.0 (s), 138.5 (d),
136.0 (d), 73.6 (t), 59.3 (s), 52.6 (d), 51.7 (q), 51.6 (d), 47.3 (d), 44.8
(t).
5,5,6-Tris(hydroxymethyl)bicyclo[2.2.1]hept-2-ene (5)
To a cold and stirred suspension of LiAlH4 (5.10 g, 0.134 mol) in
anhyd Et2O (150 mL) at –20 °C was added dropwise endo-4 (13.62
g, 0.065 mol) in anhyd Et2O (50 mL). The mixture was warmed to
20 °C and stirred for 12 h and then refluxed for 5 h. After cooling to
–20 °C, H2O (5.1 mL), aq 1 M NaOH (5.1 mL), and then H2O (15.3
mL) were added successively and the jelly was stirred for 2 h and
filtered. The residue was stirred with a mixture of CH2Cl2–MeOH
(93:7) several times and filtered. The combined filtrates were con-
centrated in vacuo to give 5 as a white powder (9.57 g, 52 mmol,
80%); mp 193 °C.
1H NMR (300 MHz, CDCl3): d = 6.12 (m, 2 H), 3.88–3.60 (m, 5 H),
3.32 (t, J = 11.1 Hz, 1 H), 2.76 (br s, 1 H), 2.65 (br s, 1 H), 2.10 (dt,
J = 11.1, 3.2 Hz, 1 H), 1.61 (d, J = 8.7 Hz, 1 H), 1.38 (dt, J = 8.7,
1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 136.1 (s), 134.9 (s), 70.1 (t), 65.7
(t), 64.0 (t), 51.4 (s), 49.2 (d), 48.3 (d), 47.3 (t), 46.3 (d).
1
for H NMR and 49.0 for 13C NMR. C–H couplings were deter-
mined by DEPT sequence experiments. MS: Applied Biosystems
SCIEX QStar Elite. Mp: not corrected, Büchi capillary apparatus.
The reactions were performed under argon atmosphere. Usual
workup means aqueous treatment, extraction with an organic sol-
vent (Et2O or CH2Cl2 as indicated), washing the organic layer with
H2O, drying (MgSO4), and evaporation of the solvent.
Dimethyl 2-Bromomethylmaleate (2)3
Br2 (10 mL, 0.19 mol) was added dropwise to a stirred solution of
dimethyl itaconate (1; 30.2 g, 0.19 mol) in CH2Cl2 (200 mL) at r.t.
The solution was refluxed for 4 h. After cooling to –10 °C, Et3N (40
mL, 0.28 mol) was added dropwise and the solution was stirred at
r.t. for 12 h. After usual workup (Et2O), the residue was flash chro-
matographed on silica gel (PE–Et2O, 70:30) to give a yellow oil of
2 (35.5 g, 0.15 mol, 80%).
1H NMR (300 MHz, CDCl3): d = 6.80 (s, 1 H), 4.70 (s, 2 H), 3.85
(s, 3 H), 3.8 (s, 3 H).
Synthesis 2010, No. 11, 1787–1792 © Thieme Stuttgart · New York

1790
C. Reynaud et al.
PAPER
Anal. Calcd for C10H16O3 (184.23): C, 65.19; H, 8.75. Found: C,
65.41; H, 8.80.
1H NMR (300 MHz, CDCl3): d = 7.74 (d, J = 8.4 Hz, 10 H), 7.36–
7.30 (m, 10 H), 3.98–3.80 (m, 10 H), 3.6–3.2 (m, 7 H), 2.43 (s, 15
H), 2.4–2.25 (m, 4 H), 1.76 (m, 2 H), 1.20 (m, 2 H).
5,5,6-Tris(hydroxymethyl)bicyclo[2.2.1]hept-2-ene Acetonide
(6)
13C NMR (75 MHz, CDCl3): d = 145.2 (s), 145.1 (s), 145.0 (s),
132.4 (s), 132.3 (s), 132.2 (s), 132.1 (s), 130.0 (d, 5 C), 129.9 (d, 5
C), 127.7 (d, 5 C), 127.66 (d, 5 C), 73.8 (t), 73.6 (t), 70.45 (t), 70.35
(t), 69.5 (t), 69.3 (t), 67.2 (t), 56.1 (s), 48.8 (d), 44.2 (d), 42.3 (d),
41.9 (d), 39.3 (d), 34.0 (t), 31.3 (t), 29.5 (t), 21.5 (q, 5 C).
p-Toluenesulfonic acid (1 g) was added to a stirred solution of 5
(9.57 g, 52 mmol) in CH2Cl2 (100 mL) and then 2-methoxypropene
(5.7 mL, 104.6 mmol) was added dropwise. After stirring for 1.5 h,
K2CO3 (1 g) was added and the mixture was stirred and filtered. The
filtrate was concentrated in vacuo to give a yellow oil of 6 (11.4 g,
98%, 51.0 mmol).
Anal. Calcd for C45H50O15S5 (991.20): C, 54.53; H, 5.08. Found: C,
54.59; H, 5.21.
1H NMR (300 MHz, CDCl3): d = 6.2 (m, 2 H), 3.92 (AB, J = 11.6
Hz, 1 H), 3.76–3.36 (m, 5 H), 2.82 (s, 1 H), 2.58 (m, 1 H), 2.27 (ddd,
J = 9.7, 4.8, 3.4 Hz, 1 H), 1.52 (d, J = 8.8 Hz, 1 H), 1.45 (s, 3 H),
1.40 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.1 (d), 135.0 (d), 97.9 (s), 71.4
(t), 64.3 (t), 64.0 (t), 51.8 (d), 49.3 (d), 46.6 (d), 46.6 (t), 44.0 (s),
26.5 (q), 20.8 (q).
5,5-Bis(hydroxymethyl)-6-tosyloxymethylbicyclo[2.2.1]hept-2-
ene Acetonide (10)16
Tosyl chloride (2.15 g, 11.2 mmol) was added to a solution of 6
(1.26 g, 5.62 mmol) in pyridine (100 mL) and the mixture was
stirred at 20 °C for 5 days. After addition of H2O (250 mL), the mix-
ture was extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were quickly stirred with aq 1 N HCl (50 mL) and H2O (2 ×
50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
crude product was flash chromatographed on silica gel (PE–Et2O,
50:50) to give white crystals of 10 (2.015 g, 5.33 mmol, 95%); mp
114 °C.
1H NMR (300 MHz, CDCl3): d = 7.80 (d, J = 8.2 Hz, 2 H), 7.34 (d,
J = 8.2 Hz, 2 H), 6.2 (dd, J = 5.8, 3.1 Hz, 1 H), 6.0 (dd, J = 5.6, 3.0
Hz, 1 H), 4.20 (dd, J = 9.4, 5.8 Hz, 1 H), 3.75 (AB, J = 11.6 Hz, 1
H), 3.71 (AB, J = 11.6 Hz, 1 H), 3.64 (t, J = 9.8 Hz, 1 H), 3.46 (AB,
d J = 12.0 Hz, 1 H), 3.34 (AB,d, J = 12.0 Hz, 1 H), 2.93 (br s, 1 H),
2.74 (br s, 1 H), 2.45 (s, 3 H), 2.12 (m, 1 H), 1.47 (t, J = 1.6 Hz, 2
H), 1.37 (s, 3 H), 1.27 (s, 3 H).
Anal. Calcd for C13H20O3 (224.30): C, 69.61; H, 8.99. Found: C,
69.50; H, 8.83.
1,2,2,3,4-Pentakis(hydroxymethyl)cyclopentane Acetonide (7)
Ozone in oxygen was bubbled through a stirred solution of 6 (5.4 g,
24 mmol) in CH2Cl2 (100 mL) containing some drops of a CH2Cl2
solution of Sudan III (Eastman Kodak)7 at –60 °C until the red color
disappeared. The mixture was flushed with argon and cooled to
–80 °C. A suspension of NaBH4 (1.83 g, 48 mmol) in EtOH (40 mL)
was slowly added. After stirring at r.t. overnight, the solution was
diluted with CH2Cl2 (50 mL) and stirred for 4 h after addition of tar-
taric acid (3.7 g, 24 mmol). The suspension was filtered and concen-
trated in vacuo to give white crystals of 7 (6.0 g, 23 mmol, 96%);
mp 97 °C.
1H NMR (300 MHz, CDCl3): d = 3.60 (m, 10 H), 3.17 (m, 2 H), 2.30
(m, 1 H), 1.81 (m, 2 H), 1.37 (s, 3 H), 1.32 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 100.6 (s), 63.7 (t), 63.6 (t), 63.6 (t),
63.5 (t), 63.5 (t), 50.7 (s), 48.9 (d), 44.2 (d), 44.1 (d), 31.6 (t), 25.6
(q), 21.8 (q).
13C NMR (75 MHz, CDCl3): d = 144.7 (s), 137.0 (d), 135.1 (d),
133.0 (s), 129.8 (d, 2 C), 127.9 (d, 2 C), 97.6 (s), 71.5 (t), 70.3 (t),
64.2 (t), 47.5 (s), 46.3 (d, t), 45.4 (d), 44.7 (d), 24.4 (q), 23.0 (q),
21.6 (q).
Anal. Calcd for C20H26O5S (378.48): C, 63.47; H, 6.92. Found: C,
63.60; H, 7.00.
6-Benzyloxymethyl-5,5-bis(hydroxymethyl)bicyclo[2.2.1]hept-
2-ene Acetonide (11)
Anal. Calcd for C13H24O5 (260.33): C, 59.98; H, 9.29. Found: C,
59.80; H, 9.21.
A solution of 6 (200 mg, 0.89 mmol) in anhyd THF (2 mL) was add-
ed dropwise to a stirred suspension of NaH (80 mg, 1.78 mmol) in
anhyd THF (2 mL) at 0 °C. After stirring at 20 °C for 6 h, Bu4NI (33
mg, 0.09 mmol) was added, followed by benzyl bromide (0.21 mL)
in anhyd THF (2 mL). The mixture was stirred for 3 days. After usu-
al workup (CH2Cl2), the crude product was flash chromatographed
on silica gel (PE–Et2O, 70:30) to give 11 (182 mg, 0.58 mmol,
65%).
1H NMR (300 MHz, CDCl3): d = 7.34 (s, 5 H), 6.28 (AB, d, J = 5.7,
3.1 Hz, 1 H), 6.11 (AB, d, J = 5.7, 3.0 Hz, 1 H), 4.51 (AB, J = 12.0
Hz, 1 H), 4.44 (AB, J = 12.0 Hz, 1 H), 3.96 (AB, J = 11.6 Hz, 1 H),
3.76 (AB, J = 11.7 Hz, 1 H), 3.64 (AB, d, J = 11.6, 1.8 Hz, 1 H),
3.42 (AB, d, J = 11.7, 1.85 Hz, 1 H), 3.31 ( AB, J = 12.0 Hz, 1 H),
3.18 (AB, d, J = 9.1, 7.9 Hz, 1 H), 3.07 (br s, 1 H), 2.89 (br s, 1 H),
1.91 (td, J = 7.7, 3.2 Hz, 1 H), 1.50 (br t, J = 1.4 Hz, 2 H), 1.41 (s,
3 H), 1.40 (s, 3 H).
cis,cis,cis-1,2,2,3,4-Pentakis(hydroxymethyl)cyclopentane (8)
To a solution of 7 (500 mg, 1.92 mmol) in THF (50 mL) and H2O
(5 mL) was added ion exchange resin Amberlite IR® 120 hydrogen
form (2.50 g). The mixture was refluxed for 2 h, filtered, and con-
centrated in vacuo. Toluene (20 mL) was added and removed in
vacuo (3 times) to give 8 as a colorless oil (400 mg, 1.82 mmol,
95%), which was used in the next step without further purification.
1H NMR (300 MHz, CD3OD): d = 3.66 (m, 1 H), 2.35 (m, 1 H), 2.10
(m, 1 H), 1.90 (m, 2 H), 1.34 (m, 1 H).
13C NMR (75 MHz, CD3OD): d = 68.1 (t), 64.5 (t), 62.6 (t), 61.1 (t),
60.1 (t), 52.8 (s), 50.3 (d), 48.1 (d), 41.6 (d), 32.5 (t).
cis,cis,cis-1,2,2,3,4-Pentakis(tosyloxymethyl)cyclopentane (9)
A solution of 8 (405 mg, 1.83 mmol) in pyridine (15 mL) was added
dropwise at –20 °C to a stirred solution of tosyl chloride (14 g, 73.5
mmol) in CH2Cl2 (40 mL) and the mixture was stirred at –20 °C for
48 h. After addition of H2O (20 mL), pyridine (6 mL) was added and
stirred. The mixture was extracted with CH2Cl2 (3 × 75 mL) and the
combined organic layers were quickly stirred with aq 20% HCl (100
mL), aq CuSO4 (50 mL) and H2O (2 × 75 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude product was flash chro-
matographed on silica gel (CH2Cl2–EtOAc, 97.5:2.5) to give white
crystals of 9 (362 mg, 0.37 mmol, 20%); mp 135 °C.
13C NMR (75 MHz, CDCl3): d = 138.4 (s), 137.1 (d), 135.2 (d),
128.3 (d, 2 C), 127.4 (d, 2 C), 97.6 (s), 72.9 (t), 70.4 (t), 69.5 (t), 64.5
(t), 47.0 (d), 46.9 (d), 46.4 (t), 45.4 (d), 43.9 (s), 26.6 (q), 21.1 (q).
Anal. Calcd for C20H26O3 (314.42): C, 76.40; H, 8.33. Found: C,
76.52; H, 8.47.
5,5-Bis(hydroxymethyl)-6-cyanomethylbicyclo[2.2.1]hept-2-
ene Acetonide (12)
Tosylate 10 (762 mg, 2 mmol) was added to a solution of KCN (651
mg, 10 mmol) and 18-crown-6 (1 mmol, 264 mg) in anhyd DMSO
Synthesis 2010, No. 11, 1787–1792 © Thieme Stuttgart · New York

PAPER
Synthesis of Spherical Polyols
1791
(15 mL). The solution was stirred and heated at 100 °C for 12 h. Af-
ter cooling and usual workup (Et2O), the crude product was flash
chromatographed on silica gel (CH2Cl2–MeOH, 99:1) to give 12
(376 mg, 1.61 mmol, 80%).
1H NMR (300 MHz, CDCl3): d = 6.25 (t, J = 1.2 Hz, 2 H), 3.84
(AB, J = 11.6 Hz, 1 H), 3.74 (AB, d, J = 11.6, 1.8 Hz, 1 H), 3.64
(AB, J = 12.1 Hz, 1 H), 3.34 (AB, d, J = 12.1, 1.8 Hz, 1 H), 3.09 (br
s, 1 H), 2.77 (dd, J = 16.7, 5.1 Hz, 1 H), 2.62 (br s, 1 H), 2.28 (ddd,
J = 11.3, 4.9, 3.3 Hz, 1 H), 1.95 (dd, J = 16.7, 11.3 Hz, 1 H), 1.55
(m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H).
cis-endo-2-Bromomethylbicyclo[2.2.1]hept-5-ene 2,3-dicarbox-
ylic Anhydride (17)
A solution of cyclopentadiene (120 g, 1.82 mol) and anhydride 16
(69.5 g, 0.36 mol) in CH2Cl2 (1 L) was stirred at 25 °C for 15 h.
Concentration in vacuo gave white crystals of 17 (92.5 g, 0.36 mol,
99%), which were used in the following steps without further puri-
fication; mp 80 °C.
1H NMR (300 MHz, CDCl3): d = 6.37 (m, 2 H), 4.07 (d, J = 10.5
Hz, 1 H), 3.52 (s, 2 H), 3.41 (d, J = 10.5 Hz, 1 H), 3.11 (br s, 1 H),
1.92 (d, J = 9.7 Hz, 1 H), 1.77 (d, J = 9.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 137.2, 134.8, 119.7, 97.6, 70.8,
64.1, 48.1, 47.2, 46.4, 44.2, 43.7, 26.2, 21.1, 18.2.
13C NMR (75 MHz, CDCl3): d = 169.6 (s), 162.8 (s), 136.84 (d),
136.81 (d), 62.0 (s), 51.8 (d), 51.4 (d), 51.0 (t), 46.5 (d), 33.8 (t).
Anal. Calcd for C14H19NO2 (233.31): C, 72.07; H, 8.21. Found: C,
72.15; H, 8.30.
Anal. Calcd for C10H9BrO3 (257.08): C, 46.72; H, 3.53. Found: C,
46.61; H, 3.40.
5,5-Bis(hydroxymethyl)-6-methylenebicyclo[2.2.1]hept-2-ene
Acetonide (13)
Tosylate 10 (762 mg, 2 mmol) was added to a solution of t-BuOK
(336 mg, 3 mmol) in anhyd DMF (15 mL). The mixture was stirred
and heated at 80 °C for 18 h. After cooling and usual workup
(Et2O), the crude product was flash chromatographed on silica gel
(PE–Et2O, 70:30) to give 13 (227 mg, 1.11 mmol, 55%).
5,6-Bis(hydroxymethyl)-5-methylbicyclo[2.2.1]hept-5-ene
(18)12
To a stirred suspension of LiAlH4 (593 mg, 15.6 mmol) in anhyd
THF (40 mL) at –10 °C was added 17 (2 g, 5.2 mmol). After stirring
for 3 h and usual workup (CH2Cl2), the crude product was flash
chromatographed on silica gel (eluent: Et2O) to give white crystals
of 18 (791 mg, 4.71 mmol, 90%); mp 140 °C.
1H NMR (300 MHz, CDCl3): d = 6.27 (dd, J = 5.5, 3.0 Hz, 1 H),
6.15 (dd, J = 5.5, 3.1 Hz, 1 H), 5.03 (s, 1 H), 4.75 (s, 1 H), 3.96 (AB,
J = 11.9 Hz, 1 H), 3.675 (AB, J = 11.9 Hz, 1 H), 3.67 (AB, J = 11.8
Hz, 1 H), 3.35 (AB, d, J = 11.8, 2.3 Hz, 1 H), 3.25 (s, 1 H), 3.17 (s,
1 H), 1.64 (qt, J = 10.2, 1.7 Hz, 2 H), 1.48 (s, 3 H), 1.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 153.4 (s), 136.4 (d), 136.0 (d),
105.1 (t), 97.6 (s), 68.8 (t), 68.6 (t), 51.9 (d), 48.0 (t), 47.1 (s), 46.0
(d), 28.0 (q), 20.0 (q).
1H NMR (300 MHz, CDCl3): d = 6.10 (AB, d, J = 5.6, 3.0 Hz, 1 H),
6.01 (AB, d, J = 5.6, 2.8 Hz, 1 H), 3.61 (AB, d, J = 11.4, 4.0 Hz, 1
H), 3.54 (AB, J = 11.0 Hz, 1 H), 3.32 (AB, J = 11.0 Hz, 1 H), 3.28
(t, J = 11.3 Hz, 1 H), 2.68 (br s, 1 H), 2.32 (br s, 1 H), 2.04 (AB, t,
J = 11.0, 3.5 Hz, 1 H), 1.70 (d, J = 8.5 Hz, 1 H), 1.32 (dt, J = 8.5,
1.6 Hz, 1 H), 1.30 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.3 (d), 133.9 (d), 67.6 (t), 64.5
(t), 53.3 (d), 52.7 (d), 47.4 (t), 46.8 (d), 46.6 (s), 26.8 (q).
Anal. Calcd for C13H18O2 (206.28): C, 75.69; H, 8.80. Found: C,
75.75; H, 8.71.
5,6-Bis(hydroxymethyl)-5-bromomethylbicyclo[2.2.1]hept-5-
ene (19)
To a stirred solution of the anhydride 17 (2 g, 7.81 mmol) in anhyd
THF (40 mL) at –80 °C was added diisobutylaluminum hydride (3.1
g, 20.8 mmol). After stirring for 3 h, the mixture was warmed to
20 °C and stirred for 3 h. The mixture was cooled to 0 °C and
MeOH (20 mL) was added dropwise. The mixture was filtered, and
the solid washed with hot MeOH (2 × 20 mL), concentrated, and
flash chromatographed on silica gel (PE–Et2O, 10:90) to give white
crystals of 19 (1.19 g, 62%, 4.37 mmol); mp 112 °C.
1H NMR (300 MHz, CDCl3): d = 6.1 (br s, 2 H), 3.98 (d, J = 10.2
Hz, 1 H), 3.72 (d, J = 11.2 Hz, 1 H), 3.54 (d, J = 9.9 Hz, 1 H), 3.46
(d, J = 11,4 Hz, 1 H), 3.33 (t, J = 11.0 Hz, 1 H), 2.86 (br s, 1H), 2.78
(br s, 1 H), 2.03 (dt, J = 10.2, 3.7 Hz, 1 H), 1.59 (AB, J = 9.0 Hz, 1
H), 1.40 (AB, t, J = 9.0, 1.6 Hz, 1 H).
4-Oxatricyclo[5.2.1.02,6]dec-8-en-5-one-2-carboxylic Acid (14)
Lactone endo-4 (2.16 g, 10 mmol) was added to a solution of KOH
(1.68 g, 30 mmol) in H2O (30 mL) and EtOH (30 mL) and then re-
fluxed for 6 h. After cooling to 0 °C, a solution of aq 20% HCl was
added dropwise until pH 1. After usual workup (Et2O), a white solid
of acid 14 was obtained (1.67 g, 8.6 mmol, 86%); mp 98 °C.
1H NMR (300 MHz CDCl3,): d = 6.44 (m, 1 H), 6.38 (m, 1 H), 4.45
(AB, J = 10.2 Hz, 1 H), 3.95 (AB, J = 10.2 Hz, 1 H), 3.65 (d, J = 4.4
Hz, 1 H), 3.42 (br s, 2 H), 1.80 (AB, J = 9.1 Hz, 1H), 1.72 (AB,
J = 9.1 Hz, 1 H).
13C NMR (75 MHz CDCl3,): d = 178.8 (s), 176.6 (s), 138.8 (d),
134.9 (d), 71.7 (t), 57.5 (s), 52.3 (d), 51.0 (d), 50.6 (t), 45.9 (d).
13C NMR (75 MHz, CDCl3): d = 135.7 (d), 135.1 (d), 63.7 (t), 62.5
(t), 52.1 (d), 51.4 (s), 49.0 (d), 46.7 (t), 46.6 (d), 41.5 (t).
Anal. Calcd for C10H10O4 (194.18): C, 61.85; H, 5.19. Found: C,
61.76; H, 5.25.
Anal. Calcd for C10H15BrO2 (247.13): C, 48.60; H, 6.12. Found: C,
48.39; H, 6.19.
2-Bromomethylmaleic Anhydride (16)11
Br2 (168 g, 1.05 mol) was added dropwise to a stirred solution of ita-
conic anhydride (15; 117 g, 1.05 mol) in anhyd CH2Cl2 (850 mL).
After stirring for 12 h, the mixture was cooled to –20 °C and anhyd
K2CO3 (218 g, 1.58 mol) was added. The mixture was stirred at
20 °C for 48 h, filtered, and concentrated in vacuo to give an orange
oil of 16 (170.0 g, 0.89 mol, 85%), which was used in the following
step without further purification.
1H NMR (300 MHz, CDCl3): d = 6.95 (t, J = 1.5 Hz, 1 H), 4.24 (d,
J = 1.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 163.3 (s), 162.4 (s), 148.1 (s),
131.8 (s), 18.5 (t).
2-Bromomethyl-4-oxatricyclo[5.2.1.02,6]dec-8-en-3-one (20)
The same procedure as that for the preparation of 18 was used, but
the reaction temperature was maintained at –25 °C; yield: 45%; mp
104 °C.
1H NMR (300 MHz, CDCl3): d = 6.33 (AB, d, J = 5.6, 2.8 Hz, 1 H),
6.28 (AB, d, J = 5.6, 2.9 Hz, 1 H), 4.26 (dd, J = 9.6, 8.6 Hz, 1 H),
3.96 (d, J = 10.0 Hz, 1 H), 3.76 (dd, J = 9.6, 2.7 Hz, 1 H), 3.40 (d,
J = 10.0 Hz, 1 H), 3.11 (br s, 1 H), 3.01 (ddd, J = 8.5, 4.06, 2.7 Hz,
1 H), 2.88 (sept, J = 1.4 Hz, 1 H), 1.73 (AB, t, J = 9.3, 1.6 Hz, 1 H),
1.65 (AB, t, J = 9.3, 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 177.9 (s), 137.3 (d), 135.8 (d), 69.9
(t), 61.8 (s), 51.3 (d), 49.8 (t), 46.5 (d), 45.8 (d), 34.5 (t).
Synthesis 2010, No. 11, 1787–1792 © Thieme Stuttgart · New York

1792
C. Reynaud et al.
PAPER
(2) (a) Laurenti, D.; Feuerstein, M.; Pèpe, G.; Doucet, H.;
Anal. Calcd for C10H11BrO2 (243.10): C, 49.41; H, 4.56. Found: C,
49.24; H, 4.39.
Santelli, M. J. Org. Chem. 2001, 66, 1633. (b) Reynaud, C.;
Fall, Y.; Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron 2009, 65, 7440. (c) Doucet, H.; Santelli, M.
Synlett 2006, 2001. (d) Lemhadri, M.; Battace, A.; Berthiol,
F.; Zair, T.; Doucet, H.; Santelli, M. Synthesis 2008, 1142.
(e) Lemhadri, M.; Fall, Y.; Doucet, H.; Santelli, M. Synthesis
2009, 1021.
endo-5-Methoxycarbonyl-6-methylenebicyclo[2.2.1]hept-2-ene
(21) and endo-2-Methoxymethylbicyclo[2.2.1]hept-5-ene 2,3-di-
carboxylic Anhydride (22)
To a stirred solution of NaOMe (210 mg, 3.89 mmol) and Bu4NI (52
mg, 0.19 mmol) in anhyd THF (10 mL) was added 17 (500 mg, 1.95
mmol) in anhyd THF (5 mL) at 0 °C. The mixture was stirred at
20 °C for 3 days. The solution was hydrolyzed and extracted with
CH2Cl2 (3 × 25 mL). After usual workup, the crude product was
flash chromatographed on silica gel (PE–EtOAc) to give a yellow
oil of 21 (211 mg, 1.29 mmol, 66%) and white crystals of 22 (69 mg,
0.39 mmol, 20%).
(3) (a) Garbers, C. F.; Labuschagne, A. J. H.; Meyer, C. J.;
Schneider, D. F. J. Chem. Soc., Perkin Trans. 1 1973, 2016.
(b) See also: Beltaïef, I.; Besbes, R.; Amri, H.; Villiéras, J.
Tetrahedron Lett. 1997, 38, 813. (c) See also: Pelletier, S.
W.; Djamarti, Z.; Lajšić, S. D.; Mićović, I. V.; Yang, D. T.
C. Tetrahedron 1975, 31, 1659.
(4) For an efficient synthesis (90%) of 2 by the ring-closing
metathesis reaction, see: Selvakumar, N.; Kumar, P. K.;
Reddy, K. C. S.; Chary, B. C. Tetrahedron Lett. 2007, 48,
2021.
(5) Hoye, T. R.; Caruso, A. J.; Magee, A. S. J. Org. Chem. 1982,
47, 4152.
21
1H NMR (300 MHz, CDCl3): d = 6.47 (m, 2 H), 5.39 (d, J = 1.8 Hz,
1 H), 5.29 (d, J = 1.4 Hz, 1 H), 3.94 (s, 3 H), 3.73 (q, J = 2.35 Hz,
1 H), 3.52 (m, 2 H), 1.92 (d, J = 8.4 Hz, 1 H), 1.77 (d, J = 8.4 Hz, 1
H).
(6) For a selective protection of diol 5, see: Lee, J.; Barchi, J. J.
Jr.; Marquez, V. E. Chem. Lett. 1995, 299.
(7) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980,
13C NMR (75 MHz, CDCl3): d = 172.7 (s), 148.1 (s), 135.0 (d),
134.95 (d), 106.1 (t), 51.4 (q*, d*), 51.3 (d*, q*), 49.6 (d), 49.1 (t),
45.2 (d). * The assignments are exchangeable.
807.
Anal. Calcd for C10H12O2 (164.20): C, 73.15; H, 7.37. Found: C,
72.98; H, 7.24.
(8) Ozonolysis of a polyfunctionalized norbornene derivative
can lead to an ‘oxa bowl’ having a crownlike shape, see:
Mehta, G.; Vidya, R. J. Org. Chem. 2001, 66, 6905.
(9) (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A. III.
Angew. Chem., Int. Ed. Engl. 1990, 29, 138. (b) Rogunova,
M.; Lynch, T.-Y. S.; Pretzer, W.; Kulzick, M.; Hiltner, A.;
Baer, E. J. Appl. Polym. Sci. 2000, 77, 1207. (c) Fréchet, J.
Science 1994, 263, 1710.
(10) Lee, T. V.; Toczek, J. Tetrahedron Lett. 1985, 26, 473.
(11) (a) Greenlee, W. J.; Woodward, R. B. Tetrahedron 1980, 36,
3367. (b) Buttler, T.; Fleming, I.; Gonsior, S.; Kim, B.-H.;
Sung, A.-Y.; Woo, H.-G. Org. Biomol. Chem. 2005, 3, 1557.
(12) (a) Heissler, D.; Jung, F.; Vevert, J. P.; Riehl, J. J.
Tetrahedron Lett. 1976, 4879. (b) Ranganathan, S.;
Ranganathan, D.; Mehrotra, A. K. Tetrahedron 1977, 33,
807.
22
Mp 102 °C.
1H NMR (300 MHz, CDCl3): d = 6.48 (dd, J = 5.5, 2.8 Hz, 1 H),
6.26 (dd, J = 5.5, 3.0 Hz, 1 H), 4.48 (AB, J = 5.0 Hz, 1 H), 4.29
(AB, J = 5.0 Hz, 1 H), 3.61 (s, 3 H), 3.32 (d, J = 3.1 Hz, 1 H), 3.18
(br s, 2 H), 1.59 (AB, t, J = 9.0, 1.5 Hz, 1 H), 1.36 (AB, J = 9.0 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 171.8 (s), 170.7 (s), 137.8 (d),
133.2 (d), 71.6 (t), 65.2 (s), 55.2 (q), 51.8 (d), 51.1 (d), 47.4 (t), 44.2
(d).
Anal. Calcd for C11H12O4 (208.21): C, 63.45; H, 5.81. Found: C,
63.60; H, 5.70.
(13) Komarov, I. V.; Monsees, A.; Kadyrov, R.; Fisher, C.;
Schmidt, U.; Börner, A. Tetrahedron: Asymmetry 2002, 13,
1615.
Acknowledgment
(14) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(15) (a) Bertrand, M.; Monti, H.; Huong, K. C. Tetrahedron Lett.
1979, 20, 15. (b) Ismail, Z. M.; Hoffmann, H. M. R. J. Org.
Chem. 1981, 46, 3549. (c) Hoffmann, H. M. R.; Ismail, Z.
M.; Weber, A. J. Tetrahedron Lett. 1981, 22, 1953.
(16) X-ray crystallography: CCDC-767345 (for endo-4) and
CCDC-767346 (for 10) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; or e-mail: deposit@ccdc.cam.ac.uk].
C.R. thanks Dr. S. Goldstein for helpful comments and the Institut
de Recherche Servier (Suresnes, Fr 92150) for financial support.
This work was financially supported by the CNRS and the
Ministère de l’Enseignement Supérieur et de la Recherche.
References
(1) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels–Alder
Reaction; Wiley: New York, 1990. (b) Winkley, J. D.
Chem. Rev. 1996, 96, 167.
Synthesis 2010, No. 11, 1787–1792 © Thieme Stuttgart · New York