Synthesis of enantiomerically pure (2S)-2-endo-hydroxymethyl-5- norbornene by Diels-Alder reaction based on a new fructose-derived auxiliary

Full text of DOI:10.1021/jo982023q

1412
J . Org. Chem. 1999, 64, 1412-1414
Sch em e 1
Syn th esis of En a n tiom er ica lly P u r e
(2S)-2-en d o-Hyd r oxym eth yl-5-n or bor n en e
by Diels-Ald er Rea ction Ba sed on a New
F r u ctose-Der ived Au xilia r y
Robert Nouguier,* Vale´rie Mignon, and J ean-Louis Gras
Faculte´ des Sciences Saint J e´roˆme, Avenue Normandie
Niemen 13397 Marseille Cedex 20, France
Sch em e 2
Received October 7, 1998
In tr od u ction
During our previous work1 on the use of carbohydrate
derivatives for asymmetric induction,2 we showed that
methyl methylene-arabinoside A was an efficient tem-
plate in the asymmetric Diels-Alder reaction of an
acrylate with cyclopentadiene (CPD)1b (Scheme 1). How-
ever, â-D- or R-L-arabinopyranosides are relatively ex-
pensive, and the synthesis of A involves a direct methyl
glycosylation during the methylenation of arabinose,
which is not selective.3 Tedious separation of the anomers
is only possible on the corresponding acrylates.
Sch em e 3
We needed an auxiliary suitable for large scale ap-
plications as, for example, the synthesis of enantiomeri-
cally pure (2S)-2-endo-5-norbornene derivatives.4 Then,
we turned our attention toward the design of a more
accessible sugar-derived acrylate having the same favor-
able conformational structure as arabinose for efficient
asymmetric Diels-Alder reactions.
Resu lts a n d Discu ssion
Because the relative configuration of adjacent C-3, C-4,
and C-5 carbons of D-fructose is the same as for C-2,
C-3, and C-4 in D-arabinose, we decided to synthesize a
4,5-O-methylene acetal of D-fructose with the equatorially
attached 3-OH remaining free. We have shown5 that
direct methylenation of D-fructose led to 2,3:4,5-di-O-
methylene-â-D-fructopyranose and not to 1,2:4,5-di-O-
methylene-â-D-fructopyranose. Consequently, we first
protected the anomeric and the 2-OH positions to obtain
spirotriol 3. Then, methylenation of 3 led to the desired
stable and crystalline tricyclic product 4 with the requi-
site structural pattern (Scheme 2).
76% yield, through a well-established three-step sequence
without isolation of the intermediates.5 Nevertheless, we
have shown that after the first step a 80/20 mixture of
the trimethoxymethyl ether (tri-MOM ether) of 3 and the
MOM ether of 4 was obtained. This mixture was entirely
transformed into the MOM ether of 4 during the diox-
olane-forming second step, and finally, the last MOM
ether protection was cleaved during the third step.
The synthesis of spiro 3 was carried out as described
in the literature.6 Methylenation of 3 was achieved in
Alcohol 4 was transformed into acrylate 5 with acryloyl
chloride in the presence of Et3N. The Diels-Alder reac-
tion with CPD was carried out at 0 °C with 2 equiv of
SnCl4 as Lewis acid. The acrylate was consumed in 40
min (TLC). After workup and rapid purification through
a short pad of silica, adduct 6 was isolated in quantitative
yield. 1H NMR and HPLC analysis1c showed the presence
of only 2% of the exo adduct along with endo-6 as a major
diastereomer (Scheme 3). This result and those employ-
ing EtAlCl2 as Lewis acid are presented in Table 1. The
(1) (a) Gras, J .-L.; Poncet, A. Nouguier, R. Tetrahedron Lett. 1992,
33, 3323. (b) Nouguier, R.; Gras, J .-L.; Giraud, B. Virgili, A. Tetrahe-
dron Lett. 1991, 32, 5529; (c) Tetrahedron, 1992, 48, 6245. In these
papers (b,c) the drawn 4C1 conformation of D-arabinose is not the correct
one, see A in Scheme 1 for the correct 1C4 conformation.
(2) (a) Kunz, H.; Ru¨ck, K. Angew. Chem. 1993, 105, 355. (b) Hultin,
P. G.; Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53, 14823. (c)
Seyden-Penne, J . In Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; J ohn Wiley: New York, 1995.
(3) Nouguier, R.; Gras, J .-L.; Giraud, B. Virgili, A. Bull. Soc. Chim.
Fr. 1991, 128, 945.
(4) For the synthesis of enantiopure norbornene adducts see, for
exemple: (a) Bezuidenhoudt, B. C. B.; Castle, G. H.; Geden, J . V.; Ley,
S. V. Tetrahedron Lett. 1994, 35, 7451. (b) Kitagawa, O.; Izawa, H.;
Taguchi, T. Tetrahedron Lett. 1997, 38, 4447. (c) Poll, T.; Sobczak, A.;
Hartmann, H.; Helmchen, G. Tetrahedron Lett. 1985, 26, 3095. (d)
Helmchen, G.; Ihrig, K.; Schindler, H. Tetrahedron Lett. 1987, 28, 183.
(e) Helmchen, G.; Abdel Hady, A. F.; Hartmann, H.; Karge, R.; Krotz,
A.; Sartor, A.; Urmann, M. Pure Appl. Chem. 1989, 61, 409.
(5) Nouguier, R.; Mignon, V. Gras, J .-L. Carbohydr. Res. 1995, 277,
339.
1
diastereomeric ratios were determined by 400 MHz H
NMR analyses by integrating the signals of the ethylenic
protons of the norbornene moiety.1c
(6) Chan, J . Y. C.; Cheong, P. P. L.; Hough, L.; Richardson, A. C. J .
Chem. Soc., Perkin Trans. 1 1995, 1447.
10.1021/jo982023q CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1413
for SnCl4-mediated asymmetric Diels-Alder reaction
with CPD.
The transformation of cheap and abundant D-fructose
into the 1,2-O-ethylene-fructose 3 and the protection as
the methylene acetal 4 are very easy, highly selective and
can be scaled up to large quantities. These protections
are very stable toward an excess of SnCl4 at 0 °C. The
auxiliary 4 is crystalline and easily handled and recov-
ered and can be used for the synthesis of pure (2S)-2-
substituted-5-norbornene derivatives.
Exp er im en ta l Section
F igu r e 1. CSC Chem3Dpro drawing of chelates B and C.
Only the geometry of the sugar acrylate 5 has been optimized
by MM2 calculations.
Gen er a l Meth od s. Unless otherwise noted, starting materi-
als were obtained from commercial suppliers and used as
received. All reactions were carried out under argon atmosphere.
Tetrahydrofuran (THF) was distilled under argon from sodium/
benzophenone prior to use. MeOH-free CH2Cl2 was distilled over
P2O5, and Et3N was distilled over KOH. Melting points are
uncorrected. Coupling constants (J ) are reported in Hz.
1,2-O-eth ylen e-â-D-fr u ctop yr a n ose (3). To a solution of
acetyl chloride (5 mL) in 2-chloroethanol (200 mL) was added
portionwise anhydrous powdered D-fructose (27 g, 0.15 mmol).
The mixture was stirred for 2 h at room temperature. The solid
was filtered off and washed twice with EtOH and then with
Et2O. After drying under vacuum, 2 (27.3 g, 75%) was obtained
as a white solid, mp 148 °C. Crude fructoside 2 (25.5 g, 105
mmol) was added to a 1 M solution of MeONa in MeOH (200
mL). The mixture was heated under reflux for 45 min, cooled,
and neutralized by Amberlite IR-120 resin (prior to use, the resin
was washed with distilled water and then with hexanes). After
filtration, the solution was decolorized for 20 min with activated
carbon Norit A. Filtration and evaporation led to a slightly
yellowish syrup; crystallization for 12 h in 2-propanol (100 mL)
gave 18.4 g (85%) of a white solid, mp 133 °C. Concentration of
the filtrate and purification of the residual syrup by chroma-
tography on silica gel with 10% f 40% MeOH in CHCl3 as eluent
gave 2 g (9%) of a second crop of 3. If the 2-propanol used for
crystallization was not dried, 3 crystallized as a semihydrate.
Anal. Calcd for C8H14O6‚0.5H2O: C, 44.65; H, 7.02. Found: C,
44.60; H, 7.00.
Ta ble 1. Rea ction of 5 w ith CP D (4 equ iv) in CH2Cl2
u n d er Differ en t Con d ition s: % of th e S, R, a n d exo
a d d u cts of 6
product (%)
Lewis acid reaction temp (2S)-6 (2R)-6 (2R + 2S)-6 yield
(2 equiv)
time
(°C)
endo
endo
exo
(%)
SnCl4
EtAlCl2
EtAlCl2
40 min
40 min
6 h
0
0
-78
>99
75
90
<1
25
10
2
5
1
>99
>99
96
As expected, the acrylate 5 proved excellent for asym-
metric induction in this reaction. It can favorably com-
pare with the previously used acrylate of arabinoside A,
with the advantage of cooling at 0 °C rather than at -78
°C. This seems to be due to the resemblance of the two
sugar templates: the acrylate is equatorial, and the
adjacent oxygen of the methylene acetal function is also
1
equatorial, in a C4 pyranoside chair conformation. This
geometry favors, with a bidentate Lewis acid7 like SnCl4,
the chelate B represented in Figure 1. The CPD ap-
proaches from the less hindered Re face of the chelate
with the acrylate in an s-cis conformation, and the de is
very high.
1,2-O-eth ylen e-4,5-O-m eth ylen e-â-D-fr u ctop yr a n ose (4).
A slurry of fructopyranose 3 (10.3 g, 50 mmol), dimethoxymethane
(DMM) (100 mL), and amberlyst 15 resin (5.1 g) was vigorously
stirred in a round-bottom flask topped with a Soxhlet containing
4 Å molecular sieves (200 g) and filled with DMM. The mixture
was refluxed for 12 h at such a temperature that refluxing DMM
returned in the reaction flask after percolation on the molecular
sieves. After filtration and evaporation of the DMM, the residue
was dissolved in CH2Cl2 (100 mL) containing 0.7 g of p-
toluenesulfonic acid, and the mixture was refluxed for 12 h. To
this solution was added 50 mL of MeOH containing 2% of water,
and the CH2Cl2 was slowly evaporated. MeOH (50 mL) and
p-TsOH (0.7 g) were added, and the mixture was refluxed for 6
h. The reaction mixture was neutralized with solid K2CO3 and
filtered. The solid was washed with CH2Cl2, and the filtrate was
concentrated. Purification by chromatography on silica gel with
0% f 5% MeOH in CH2Cl2 as eluent gave 8.2 g (76%) of a white
As already observed1b,8 with arabinose acrylates, when
EtAlCl2 is employed as Lewis acid, the de is not so high.
These results can be explained on the basis of the
complex C, shown to prefer a conformation where the Cd
O/CdC bonds of the acrylate are s-trans disposed.4c The
Re face of the chelate is less hindered by the methylene
acetal protection than the Si face by the spiro-2-dioxanyl
substitution.
The LiAlH4 reduction9 of the cycloadduct 6 led to the
desired norbornenol 7 and to recovered auxiliary 4.
Con clu sion
1
solid: mp10 173 °C; H NMR (CDCl3, 200 MHz) δ 5.20 (s, 1H),
We have shown that the acrylate of the protected
fructose derivative 4 is an efficient new chiral auxiliary
5.00 (s, 1H), 4.23-4.13 (m, 2H), 4.05-3.88 (m, 4H), 3.76-3.55
(m, 4H), 3.38 (t, J ) 7.9 1H), 2.40 (d, J ) 7.9, 1H); 13C NMR
(CDCl3, 50 MHz) δ 95.1, 94.8, 76.0, 74.5, 69.8, 68.5, 65.5, 60.2,
59.3. Anal. Calcd for C9H14O6: C, 49.54; H, 6.47. Found:10 C,
(7) a) Singh, D. K.; Springer, J . B.; Goodson, P. A.; Corcoran, R. C.
J . Org. Chem. 1996, 61, 1436. (b) Springer, J . B.; Corcoran, R. C. J .
Org. Chem. 1996, 61, 1443. (c) Assfeld, X.; Garcia, J .; Garcia, J . I.;
Mayoral, J . A.; Proietti, M. G.; Ruiz-Lopez, M. F. Sanchez, M. C. J .
Org. Chem. 1996, 61, 1636. (d) Oppolzer, W.; Rodriguez, I.; Blagg, J .;
Bernardinelli, G. Helv. Chem. Acta 1989, 72, 123. (e) Hartmann, H.;
Abdel Hady, A. F.; Sartor, K.; Weetman, J .; Helmchen, G. Angew.
Chem., Int. Ed. Engl. 1987, 26, 1143. (f) Poll, T.; Metter, J . O.;
Helmchen, G. Angew. Chem., Int. Ed. Engl. 1985, 24, 112.
(8) Shing, T. M. K.; Lloyd-Williams, P. J . Chem. Soc., Chem.
Commun. 1987, 423. This reference was inadvertently omitted in ref
1b but quoted in ref 1c.
49.51; H, 6.49. [R]24.5 -150 (c 0.46, 95% EtOH).10
D
3-O-a cr yloyl-1,2-O-eth ylen e-4,5-O-m eth ylen e-â-D-fr u cto-
p yr a n ose (5). To a solution of 4 (1.1 g, 5 mmol) in MeOH-free
CH2Cl2 (12 mL) cooled at -40 °C were added Et3N (2 mL, 15
mmol) and acryloyl chloride (0.8 mL, 10 mmol), and the mixture
was stirred for 12 h at room temperature. The mixture was
cooled at 0 °C and acidified with 1 N HCl. The organic layer
was washed with 1 N HCl and saturated NaHCO3, dried over
Na2SO4, concentrated, and purified by chromatography on silica
(9) The adduct may be saponified without C-2 epimerization with
LiOH/H2O/THF at room temperature. See ref 4c for experimental
procedure.
(10) After second purification of a small amount on silica gel with
EtOAc as eluent.

1414 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
gel with Et2O as eluent to give 0.97 g (71%) of the acrylate: 1H
NMR (CDCl3, 200 MHz) δ 6.50 (dd, J ) 17.3, 1.4, 1H), 6.22 (dd,
J ) 17.3, 10.4, 1H), 5.92 (dd, J ) 10.4, 1.4, 1H), 5.20 (s, 1H),
4.98 (s, 1H), 4.88 (d, J ) 8.1, 1H), 4.40 (dd, J ) 8.1, 5.4, 1H),
4.21 (d, J ) 13.5, 1H), 4.06 (dd, J ) 5.3, 2.4, 1H), 4.0-3.9 (m,
1H), 3.90 (dd, J ) 13.5, 2.4, 1H), 3.75-3.70 (m, 1H), 3.65-3.55
(m, 3H), 3.38 (d, J ) 11.9, 1H); 13C NMR (CDCl3, 50 MHz) δ
165.9, 132.4, 127.5, 94.9, 94.6, 74.7, 73.2, 69.5, 68.0, 65.3, 60.3,
59.3. Anal. Calcd for C12H16O7: C, 52.92; H, 5.92. Found: C,
11.9, 9.3, 3.7, 1H), 1.45-1.38 (m, 2H), 1.29 (d J ) 8.2, 1H); 13C
NMR (CDCl3, 100 MHz) δ 174.4, 138.4, 132.0, 95.0, 94.7, 74.8,
73.5, 69.1, 68.2, 65.6, 60.4, 59.4, 50.0, 46.0, 43.4, 42.6, 28.5. Anal.
Calcd for C17H22O7: C, 60.33; H, 6.56. Found: C, 60.30; H, 6.52.
(2S)-en d o-2-Hyd r oxym eth yl-5-n or bor n en e (7). To a slurry
of LiAlH4 (0.35 g, 9 mmol) in anhydrous Et2O at 0 °C was slowly
added a solution of the adduct (3 g, 9 mmol) in THF, and the
reaction mixture was stirred at room temperature for 1 h and
refluxed for 1 h. Solid Na2SO4‚10H2O (6 g, 18 mmol) was added
to the cooled reaction mixture. After filtration, the solid was
washed twice with ether, and the ethereal layer was washed
with brine, dried over Na2SO4, concentrated, and purified by
chromatography on silica gel first with Et2O/CH2Cl2 2/8 as eluent
to give 1.02 g (93%) of the norbornenol 7 (>98% endo by 400
52.73; H, 6.01. [R]25 -178 (c 0.72, CHCl3).
D
Diels-Ald er Rea ction of 5 w ith Cyclop en ta d ien e. A
solution of the acrylate (2.72 g, 10 mmol) in MeOH-free CH2Cl2
(80 mL) was cooled at -40 °C. SnCl4 (2.34 mL, 20 mmol) was
added slowly, and the mixture was stirred for 15 min. The
cooling bath was replaced by an ice bath, and freshly distilled
cyclopentadiene (6.6 g, 40 mmol) was added. The mixture was
stirred at this temperature for 40 min (TLC) until the reaction
was complete, and then finely ground Na2CO3‚10H2O (12 g, 40
mmol) was added. The cooled (0 °C) reaction mixture was
filtered, the solid was washed with cooled CH2Cl2, and the excess
of CPD and solvent was evaporated under vacuum at 0 °C. The
residue was purified by chromatography on a short pad of silica
gel with 1% f 30% Et2O in CH2Cl2 as eluent to give 3.37 g
(>99%) of the adduct: 1H NMR (CDCl3, 400 MHz) δ 6.21 (dd, J
) 5.7, 3.1, 1H), 5.95 (dd, J ) 5.7, 2.8, 1H), 5.13 (s, 1H), 4.94
(s,1H), 4.70 (d, J ) 8.0, 1H), 4.33 (dd, J ) 8.0, 5.3, 1H), 4.01
(dd, J ) 5.3, 2.4, 1H), 4.16 (d, J ) 13.4, 1H), 3.97-3.90 (m, 1H),
3.88 (dd, J ) 13.4, 2.4, 1H), 3.8-3.7 (m, 1H), 3.60-3.55 (m, 2H),
3.54 (d, J ) 11.8, 1H), 3.33 (d, J ) 11.8, 1H), 3.37 (broad s, 1H),
3.05 (dt, J ) 9.3, 4.0, 1H), 2.90 (broad s, 1H), 1.92 (ddd, J )
MHz 1H NMR), [R]25 -93 (c 0.5, 95% EtOH), lit11 (endo) -95,
D
(exo) -23.9 and then with MeOH/CH2Cl2 1/9 to give 1.86 g (95%)
of recovered 4 identical to an original sample. 1H NMR of 7
(CDCl3, 200 MHz) δ 6.09 (dd, J ) 5.7, 3.0, 1H), 5.91 (dd, J )
5.7, 3.0, 1H), 3.36 (dd, J ) 10.5, 6.6, 1H), 3.18 (dd, J ) 10.5, 8.9,
1H), 2.88 (broad s, 1H), 2.76 (broad s, 1H), 2.4-2.1 (m, 2H), 1.76
(ddd, J ) 11.6, 9.2, 3.8, 1H), 1.40 (dq, J ) 8.4, 2.0, 1H), 1.21 (m,
1H), 0.46 (ddd, J ) 11.6, 4.4, 2.5, 1H).
Ack n ow led gm en t. This research was supported by
Roquette Fre`res, Lestrem, France.
J O982023Q
(11) Berson, J . A.; Walia, J . S.; Remanick, A.; Suzuki, S.; Reynolds-
Warnhoff, P.; Willner, D. J . Am. Chem. Soc. 1961, 83, 3986.