Asymmetric Hetero-Diels-Alder Reactions Catalysed by Chiral (Salen)Chromium(III) Complexes

Full text of DOI:10.1021/jo971758c

J . Org. Chem. 1998, 63, 403-405
403
important transformation that requires only 2 mol % of
readily available chiral catalyst and affords 2 with good
enantioselectivity.
Asym m etr ic Heter o-Diels-Ald er Rea ction s
Ca ta lyzed by Ch ir a l (Sa len )Ch r om iu m (III)
Com p lexes
Resu lts a n d Discu ssion
Scott E. Schaus, J onas Brånalt, and Eric N. J acobsen*
Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138
Several parameters were found to influence the rate
and enantioselectivity of the condensation reaction.
Reactions performed in noncoordinating ethereal solvents
such as Et2O and TBME afforded the dihydropyranone
in the highest yield and enantioselectivity. The reaction
of 1 with benzaldehyde in the presence of 2 mol % (R,R)-3
at room temperature yielded (R)-2a in 96% isolated yield
and 56% ee.4 With an initial substrate concentration of
1.0 M, the reaction required 8 h to attain >90% conver-
sion. At 5-fold higher concentration the reaction was
complete in 4 h with a slight increase in enantioselec-
tivity (60% ee). A further increase to 64% ee was
obtained with 68% isolated yield in reactions carried out
at -30 °C, although substantially longer reaction times
were also required (70% conversion of 1 after 24 h with
[1]0 ) 5 M).
Received September 19, 1997
In tr od u ction
The formal hetero-Diels-Alder reaction between
1-methoxy-3-[(trimethylsilyl)oxy]-1,3-butadiene (1, “Dan-
ishefsky’s diene”) and aldehydes provides useful access
to dihydropyranones (2, eq 1), a class of compounds with
The identity of the catalyst counterion was also re-
vealed to be a critical parameter for the attainment of
high enantioselectivity. For example, azide complex 4
displayed significantly higher enantioselectivity (81% ee)
and yield (86%) at -30 °C relative to chloride catalyst 3
in the model reaction with benzaldehyde. Catalyst 5,
bearing the more electronegative fluoride counterion,
afforded even higher enantioselectivity (86% ee) but lower
product yield (56%). Catalysts bearing less coordinating
counterions [X ) BF4, PF6, B(Arf)4 (Arf ) 3,5-C6H3(CF3)2)]
proved to be much less reactive and less enantioselective.
However, the addition of oven-dried powdered 4 Å
molecular sieves to reactions with these catalysts led to
increased yield and enantioselectivities in each case with
the best result obtained with the tetrafluoroborate cata-
lyst 6a , which afforded 2a in 87% ee and 85% isolated
yield at -30 °C (Table 1, entry a). A brief screen of
substitution of the salicylidene component of the salen
ligand showed that catalyst 6a , derived from the com-
mercially available tert-butyl-substituted salen ligand,
was the most effective, although the methoxy-substituted
catalyst 6b conferred measurably higher enantioselec-
tivity and yield in select cases (entries e and f).
extensive utility in organic synthesis.1 Recently, several
groups have reported enantioselective catalytic versions
of this reaction.2 In most cases, these condensations have
been shown not to involve a formal cycloaddition reaction
but rather to proceed via a Mukaiyama aldol condensa-
tion followed by cyclization under the influence of acid
catalysis to generate 2.2a,b Recently we have found that
chiral chromium- and cobalt-containing salen complexes
catalyze the highly enantioselective reaction of nucleo-
philes with epoxides.3 In an effort to ascertain whether
other classes of nucleophile-electrophile reactions are
promoted by such catalysts, we evaluated a series of
chiral (salen)metal complexes for the hetero-Diels-Alder
reaction shown in eq 1, and identified that (salen)Cr(III)-
Cl complex 3 does indeed catalyze the reaction. Optimi-
The scope of the asymmetric condensation of 1 with
aldehydes proved to be quite broad (Table 1). Although
enantioselectivity in excess of 90% was achieved only in
one case (entry b), several of the dihydropyranone
products could be recrystallized to enantiomeric purity
(entries d-g). The simplicity of the experimental pro-
cedure and the ready accessibility of the catalysts thus
renders this an experimentally attractive method for the
preparation of enantioenriched dihydropyranone deriva-
tives.
zation of the catalyst and reaction conditions has led to
the development of a protocol for this synthetically
(1) For reviews, see: (a) Danishefsky, S. J . Chemtracts 1989, 273.
(b) Danishefsky, S. J .; De Ninno, M. P. Angew. Chem., Int. Ed. Engl.
1987, 26, 15. (c) Danishefsky, S. J . Aldrichimica Acta 1986, 19, 59.
(2) (a) Keck, G. E.; Li, X. Y.; Krishnamurthy, D. J . Org. Chem. 1995,
60, 5998. (b) Corey, E. J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett.
1992, 33, 6907. (c) Ghosh, A. K.; Mathivanan, P.; Cappiello, J .
Tetrahedron Lett. 1997, 38, 2427. (d) Matsukawa, S.; Mikami, K.
Tetrahedron Asymm. 1997, 8, 815. (e) Gao, Q.; Maruyama, T.; Mouri,
M.; Yamamoto, H. J . Org. Chem. 1992, 57, 1951. (f) Togni, A.
Organometallics 1990, 9, 3106.
(3) (a) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E.
N. J . Am. Chem. Soc. 1995, 117, 5897. (b) Larrow, J . F.; Schaus, S. E.;
J acobsen, E. N. J . Am. Chem. Soc. 1996, 118, 7420. (c) J acobsen, E.
N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J . F.; Tokunaga, M. Tetra-
hedron Lett. 1997, 38, 773. (d) Tokunaga, M.; Larrow, J . F.; Kakiuchi,
F.; J acobsen, E. N. Science 1997, 277, 936.
(4) The absolute stereochemistry was assigned by comparison of the
optical rotation with literature values (ref 2a,b).
S0022-3263(97)01758-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/07/1998

404 J . Org. Chem., Vol. 63, No. 2, 1998
Notes
Ta ble 1. Asym m etr ic Heter o-Diels-Ald er Rea ction s of
mg (0.99 mmol, 99%) of a brown solid, which was used without
further purification: IR (KBr, cm-1) 2952, 1621, 1534, 1436,
1392, 1361, 1319, 1255, 1171, 1062; exact mass (FAB) calcd for
Dien e 1 Ca ta lyzed by 6a a n d 6ba
cat. 6a
cat. 6b
C
36H52N2O4Cr [M - BF4]+ 596.3434, found 596.3450.
temp
(°C)
ee
(%)b
yield
(%)c
ee
(%)b
yield
(%)c
P r ep a r a tion of (R,R)-6b. Under a nitrogen atmosphere,
entry
R
CrCl2 (86 mg, 0.70 mmol) was added to (R,R)-2,2′-[(1,2-cyclo-
hexanediyl)bis(nitrilomethylidyne)]bis[4-methoxy-6-(1,1-dimeth-
ylethyl)phenol]7 (ligand of 6b, 285 mg, 0.580 mmol) in dry,
degassed THF (10 mL). The resulting mixture was stirred under
nitrogen for 3 h, at which time the flask was opened to air and
allowed to stir for an additional 16 h at room temperature. The
solution was diluted with TBME and rinsed with saturated NH4-
Cl (5 × 50 mL) and saturated NaCl (1 × 50 mL). The organic
phase was separated, dried over Na2SO4, filtered, and concen-
trated in vacuo. The resulting residue was dissolved in TBME
(7 mL) and treated with solid AgBF4 (105 mg, 0.537 mmol). The
reaction flask was wrapped with aluminum foil and stirred at
rt for 5 h. The resulting mixture was filtered through Celite.
Solvent removal by rotary evaporation afforded 328 mg (0.520
mmol, 90%) of 6b as a brown solid which was used without
further purification: IR (KBr, cm-1) 2949, 1623, 1546, 1459,
1422, 1345, 1313, 1175, 1062, 821; exact mass (FAB) calcd for
C30H40N2O4Cr [M - BF4]+ 544.2393, found 544.2394.
P r ep a r a tion of (R,R)-5. To a solution of (R,R)-6a (684 mg,
1.00 mmol) in acetonitrile (10 mL) was added NaF (84 mg, 2.00
mmol). The reaction mixture was stirred at room temperature
for 24 h, solvent was removed by rotary evaporation, and the
residue was suspended in TBME and washed three times with
water. The organic phase was dried, filtered through Celite, and
evaporated to give 568 mg (0.92 mmol, 92%) of 5 as a brown
solid which was used without further purification: IR (KBr,
cm-1) 2954, 1623, 1533, 1463, 1436, 1392, 1361, 1321, 1256,
1170, 1083, 837; exact mass (FAB) calcd for C36H52N2O4Cr [M
- F]+ 596.3434, found 596.3423.
a
b
c
d
e
f
Ph
-30 87
-20 93
-40 83
85
71
86
65
85
62
98
C6H11
n-C5H11
2-furyl
(E)-PhCHdCH
p-BrC6H4CH2OCH2 -30 79
o-ClC6H4CO2CH2
76
85
80
-10 76 (99) 89 (63) 68
0
70
65
67
73 (99) 96 (64)
84 (99)d 94 (70)d
g
-20 83 (99)d 92 (67)d 72
86
a
Unless noted otherwise, all reactions were run at 5.0 M in
TBME using 2 mol % catalyst, 1.0 mmol of aldehyde, 1.0 mmol of
diene 1, and 300 mg of oven-dried 4 Å molecular sieves for 24 h.
b
Enantiomeric excesses in parentheses were obtained after re-
crystallization (see Experimental). c Yields in parentheses refer
d
to recrystallized yields. Reactions were run on 10.0 mmol scale.
An important question arises regarding the mechanism
of the (salen)Cr-catalyzed condensation of 1 with alde-
hydes. A Mukaiyama aldol condensation mechanism has
been identified in the highly effective asymmetric ver-
sions of this reaction developed by Keck and by Corey,
whereas a concerted [4 + 2] cycloaddition pathway was
indicated in the Eu(hfc)3-catalyzed reaction reported by
Danishefsky.5 In the present (salen)Cr catalytic system,
1
the H NMR spectrum of the crude reaction product of 1
with benzaldehyde catalyzed by complex 3 revealed the
exclusive presence of cycloadduct 7 (eq 2). To test the
Rep r esen ta tive P r oced u r e for th e Heter o-Diels-Ald er
Rea ction of 1 w ith Ald eh yd es. (R)-2-P h en yl-2,3-d ih yd r o-
4H-p yr a n -4-on e (2a ). A 10 mL oven-dried flask equipped with
a stir bar was charged with (R,R)-6a (13 mg, 0.02 mmol) and
0.3 g of oven-dried powdered 4 Å molecular sieves. The flask
was sealed with a rubber septum and purged with N2. The
catalyst was dissolved in TBME (200 µL), and benzaldehyde (100
µL, 1.0 mmol) was added via syringe at rt. The reaction was
then cooled to -30 °C followed by the addition of 1-methoxy-3-
[(trimethylsilyl)oxy]butadiene (1) (195 µL, 1.0 mmol). The
mixture was allowed to stir at - 30 °C for 24 h, at which time
it was removed from the bath, diluted with 2 mL of CH2Cl2, and
treated with a drop of TFA. After stirring 10 min at rt, the
reaction was concentrated in vacuo and the crude residue was
purified by flash chromatography (7:3 hexanes:EtOAc) to yield
2a 8 (151 mg, 0.85 mmol, 85% yield) as a clear oil. The isolated
material was determined to be in 87% ee by chiral GC analysis
(Cyclodex-B, 155 °C, 20 min, isothermal, tR(minor) ) 15.4 min,
possible intermediacy of a Mukaiyama aldol condensation
adduct, silyl ether 8 was synthesized independently6 and
subjected to the conditions of the Cr(salen)-catalyzed
condensation reaction. However, no detectable cycliza-
tion of 8 to 7 was observed after exposure to 2 mol % of
catalyst 3 for 6 h at room temperature. These results
point toward a concerted [4 + 2] mechanism for the
(salen)Cr catalysts and thus extend the scope of enanti-
oselective reactions catalyzed by these complexes to the
important arena of cycloaddition chemistry.
tR(major) ) 15.7 min). [R]26 -96° (c 0.58, CH2Cl2); lit2b -83°
D
for 82% ee material (c 0.5, CHCl3).
(R)-2-Cycloh exyl-2,3-d ih yd r o-4H-p yr a n -4-on e (2b). The
crude product mixture was purified by flash chromatography
(7:3 hexanes:EtOAc) to afford 2b in 71% yield (128 mg, 0.71
mmol) as a clear oil. The chromatographed material was
determined to be in 93% ee by chiral GC analysis (Cyclodex-B,
150 °C, isothermal, tR(minor) ) 18.7 min, tR(major) ) 19.3 min).
[R]26 -157° (c 1.03, CH2Cl2); lit2b -159° for 76% ee material (c
D
0.5, CHCl3); IR (thin film, cm-1) 3498, 2927, 2856, 1677, 1595,
1450, 1408, 1276, 1225, 1038, 992, 910, 794; 1H NMR (CDCl3,
400 MHz) δ 7.36 (d, 2H, J ) 6.0 Hz), 5.38 (dd, 1H, J ) 1.0 and
6.0 Hz), 4.16 (ddd, 1H, J ) 3.3, 5.6 and 14.5 Hz), 2.54 (dd, 1H,
J ) 14.5 and 16.7 Hz), 2.38 (ddd, 1H, J ) 1.0, 3.3 and 16.7 Hz),
1.64-1.81 (m, 6H), 1.00-1.27 (m, 5H); 13C NMR (CDCl3, 100
MHz) δ 193.3, 163.6, 106.9, 83.6, 41.4, 39.2, 28.2, 26.3, 25.9, 25.8;
exact mass (EI) calcd for C11H16O2 [M]+ 180.1150, found 180.1150.
The absolute stereochemistry was assigned as (-)-R based on
comparison of the measured rotation with the literature value.2b
Exp er im en ta l Section
P r ep a r a tion of (R,R)-6a . To a solution of (R,R)-3 (632 mg,
1.00 mmol) in TBME (10 mL) was added AgBF4 (195 mg, 1.00
mmol). The reaction flask was wrapped with aluminum foil and
stirred at rt for 5 h, after which it was filtered through Celite
and washed with TBME. Evaporation of the solvent gave 680
(5) (a) Bednarski, M.; Danishefsky, S. J . J . Am. Chem. Soc. 1983,
105, 3716. (b) Bednarski, M.; Danishefsky, S. J . J . Am. Chem. Soc.
1983, 105, 6968. (c) Bednarski, M.; Maring, C.; Danishefsky, S. J .
Tetrahedron Lett. 1983, 23, 3451.
(6) Compound 8 was prepared independently by the reaction of 1
with benzaldehyde in the presence of BF3•OEt2. Danishefsky, S. J .;
Larson, E.; Askin, D.; Kato, N. J . Am. Chem. Soc. 1985, 107, 1246.
(7) Pospisil, P. J .; Carsten, D. H.; J acobsen, E. N. Chem. Eur. J .
1996, 2, 974.
(8) Sher, F.; Isidor, J . L.; Taneja, H. R.; Carlson, R. M. Tetrahedron
Lett. 1973, 8, 577.

Notes
(R)-2-P en tyl-2,3-d ih yd r o-4H-p yr a n -4-on e (2c). Product 2c
J . Org. Chem., Vol. 63, No. 2, 1998 405
MHz) δ 7.48 (d, 2H, J ) 8.3 Hz), 7.37 (d, 1H, J ) 6.0 Hz), 7.21
(d, 2H, J ) 8.3 Hz), 5.42 (d, 1H, J ) 6.0 Hz), 4.56-4.62 (m, 3H),
3.66-3.74 (m, 2H), 2.74 (dd, 1H, J ) 14.2 and 16.8 Hz), 2.40
(dd, 1H, J ) 3.4 and 16.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
192.3, 162.8, 136.5, 131,6, 129.3, 121.8, 107.2, 107.1, 78.2, 72.8,
70.8, 38.3; exact mass (CI) calcd for C13H17BrNO3 [M + NH4]+
314.0392, found 314.0390. The absolute stereochemistry was
assigned as (-)-R by analogy to compounds 2a ,b,d .
was obtained in 86% yield (145 mg, 0.86 mmol) as a clear oil
after purification by flash chromatography (8:2 hexanes:EtOAc)
and in 83% ee by chiral GC analysis (Cyclodex-B, 120 °C, 21
min, 1 °C/min to 130 °C, tR(minor) ) 24.5 min, tR(major) ) 25.2
min): [R]26 -106° (c 0.500, CH2Cl2); IR (thin film, cm-1) 2933,
D
1
1680, 1596, 1407, 1272, 1230, 1039, 897, 791; H NMR (CDCl3,
400 MHz) δ 7.36 (d, 2H, J ) 6.0 Hz), 5.40 (dd, 1H, J ) 1.1 and
6.0 Hz), 4.36-4.43 (m, 1H), 2.52 (dd, 1H, J ) 13.4 and 16.7 Hz),
2.42 (dt, 1H, J ) 2.8 and 12.8 Hz), 1.79-1.83 (m, 1H), 1.64-
1.68 (m, 1H), 1.29-1.48 (m, 6H), 0.89 (t, 3H, J ) 7.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 192.8, 163.3, 106.9, 79.6, 41.8, 34.3,
31.4, 24.4, 22.5, 13.9; exact mass (EI) calcd for C10H16O2 [M]+
168.1150, found 168.1144. The absolute stereochemistry was
assigned as (-)-R by analogy to compounds 2a ,b,d .
(R)-2-{[(2-Ch lor ob en zoyl)oxy]m et h yl}-2,3-d ih yd r o-4H -
p yr a n -4-on e (2g). Using 1.99 g (10.0 mmol) of [(2-chloroben-
zoyl)oxy]acetaldehyde,10 the crude residue from the reaction was
purified by flash chromatography (7:3 hexanes:EtOAc) to yield
2g (2.44 g, 9.20 mmol, 92% yield) as a clear oil which solidified
upon standing. The chromatographed material was determined
to have 83% ee by chiral HPLC analysis (Chiralcel OD, 9:1
hexanes:IPA, 1 mL/min, tR(minor) ) 20.6 min, tR(major) ) 23.4
min). Recrystallization from a minimal amount of Et2O at 0 °C
yielded 1.78 g (67%) of opaque white crystals that were 99% ee
(R)-2-(2-Fu r yl)-2,3-dih ydr o-4H-pyr an -4-on e (2d). The crude
product mixture was purified by flash chromatography (7:3
hexanes:EtOAc) to yield 2d 5a in 89% yield (146 mg, 0.89 mmol)
as a clear oil which solidified upon standing. The chromato-
graphed material was determined to be 76% ee by chiral GC
analysis (Cyclodex-B, 130 °C, isothermal, tR(minor) ) 20.5 min,
tR(major) ) 21.1 min). A single recrystallization from 1:2 Et2O:
hexanes yielded 103 mg (63%) of white needlelike crystals in
by HPLC analysis: [R]26D -144° (c 0.508, CHCl3); IR (KBr, cm-1
)
3068, 2958, 1740, 1681, 1592, 1407, 1298, 1270, 1215, 1141,
1123, 1055, 1041, 1028, 977, 872, 799; 1H NMR (CDCl3, 400
MHz) δ 7.84 (d, 2H, J ) 6.0 Hz), 7.2-7.5 (m, 4H), 5.45 (dd, 1H,
J ) 0.9 and 6.0 Hz), 4.76 (m, 1H), 4.60 (dd, 1H, J ) 3.4 and
12.2 Hz), 4.53 (dd, 1H, J ) 5.6 and 12.2 Hz) 2.78 (dd, 1H, J )
99% ee by GC analysis. [R]26 -357° (c 0.805, CH2Cl2); lit2b
D
14.0 and 17.6 Hz), 2.53 (ddd, 1H, J ) 0.9, 3.6 and 17.6 Hz); 13
C
-255° for 67% ee material (c 0.5, CHCl3).
(R)-2-(E)-Styr yl-2,3-d ih yd r o-4H-p yr a n -4-on e (2e). The
crude residue obtained from the reaction was purified by flash
chromatography (7:3 hexanes:EtOAc) to afford 2e8 in 96% yield
(191 mg, 0.96 mmol) as a clear oil which solidified after standing.
The isolated material was determined to have 84% ee by chiral
HPLC analysis (Chiralcel OD, 9:1 hexanes:IPA, 1.5 mL/min, tR-
(minor) ) 11.2 min, tR(major) ) 26.7 min). Recrystallization
from a minimal amount of 4:1 Et2O:hexanes at 0 °C yielded 128
mg (64%) of opaque needlelike crystals in 99% ee by HPLC
NMR (CDCl3, 100 MHz) δ 190.9, 165.0, 162.5, 133.8, 133.0, 131.6,
131.2, 129.1, 126.6, 107.3, 76.6, 65.2, 38.2; exact mass (CI) calcd
for C13H11ClO4 [M]+ 266.0346, found 266.0346. The absolute
stereochemistry was assigned as (-)-R by analogy to compounds
2a ,b,d .
Ack n ow led gm en t. This work was sponsored by the
NIH (GM43214). We gratefully acknowledge predoctoral
fellowship support to S.E.S. from the Ford Foundation
and postdoctoral fellowship support to J .B. from the
Knut and Alice Wallenberg Foundation and Stipendium
Berzelianum.
analysis: [R]26 -215° (c 0.36, CH2Cl2). The absolute stereo-
D
chemistry was assigned as (-)-R by analogy to compounds
2a ,b,d .
(R)-2-{[(4-Br om op h en yl)m eth oxy]m eth yl}-2,3-d ih yd r o-
4H-p yr a n -4-on e (2f). Using 2.29 g (10.0 mmol) of [(4-bro-
mophenyl)methoxy]acetaldehyde,9 the crude residue from the
reaction was purified by flash chromatography (7:3 hexanes:
EtOAc) to yield 2f (2.81 g, 9.39 mmol, 94% yield) as a clear oil,
which solidified upon standing, in 84% ee by chiral HPLC
analysis (Chiralcel OD, 9:1 hexanes:IPA, 1 mL/min, tR(minor)
) 11.3 min, tR(major) ) 12.8 min). Recrystallization from a
minimal amount of Et2O at 0 °C yielded 2.09 g (70%) of opaque
Su p p or t in g In for m a t ion Ava ila b le: Chromatographic
analyses of racemic and enantiomerically enriched dihydro-
1
pyranones, and copies of H NMR spectra of 2a -g, 7, 8, and
8 in the presence of (R,R)-3 (17 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
cube like crystals in 99% ee by HPLC analysis: [R]26 -112° (c
D
1.74, CHCl3); IR (KBr, cm-1) 2852, 1674, 1662, 1590, 1487, 1410,
1291, 1227, 1129, 1093, 1041, 890, 786; 1H NMR (CDCl3, 400
J O971758C
(9) Prepared by a procedure analogous to the one described for
[(4-methoxyphenyl)methoxy]acetaldehyde: England, P.; Chun, K. H.;
Moran, E. J .; Armstrong, R. W. Tetrahedron Lett. 1990, 31, 2669.
(10) Prepared by a procedure analogous to the one described for
[(4-chlorobenzoyl)oxy]acetaldehyde: Hashiguchi, S.; Maeda, Y.; Kish-
imoto, S.; Ochiai, M. Heterocycles 1986, 24, 2273.