Enantioselective catalysis of the hetero-diels-alder reaction between Brassard's diene and aldehydes by hydrogen-bonding activation: A one-step synthesis of (S)-(+)-dihydrokawain

Article abstract of DOI:10.1002/chem.200400515

The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding δ-lactone derivatives in modera

Full text of DOI:10.1002/chem.200400515

FULL PAPER
Enantioselective Catalysis of the Hetero-Diels–Alder Reaction between
Brassardꢀs Diene and Aldehydes by Hydrogen-Bonding Activation:
A One-StepSynthesis of ( S)-(+)-Dihydrokawain
Haifeng Du, Dongbo Zhao, and Kuiling Ding*[a]
Abstract: The first catalytic enantiose-
lective hetero-Diels–Alder reaction be-
tween Brassardꢀs diene and aldehydes
has been achieved through hydrogen-
bonding activation using TADDOL de-
rivatives as catalysts to afford the cor-
responding d-lactone derivatives in
moderate-to-good yields and with high
enantioselectivities (up to 91% ee).
The reactions can be carried out either
under solvent-free conditions or in tol-
uene. On the basis of the absolute con-
figurations of the products and the hy-
drogen-bonding interaction pattern be-
tween TADDOL (a,a,a’,a’-tetraaryl-
1,3-dioxolan-4,5-dimethanol) and the
carbonyl group disclosed by X-ray dif-
fraction analysis, a possible mechanism
for the catalytic reaction has been pro-
posed. To demonstrate the usefulness
of the methodology, a natural product,
(S)-(+)-dihydrokawain, has also been
prepared in 50% isolated yield and
with 69% enantioselectivity in one step
starting from3-phenylpropionaldehyde
by using this methodology. Therefore,
this catalytic systemis one of the most
direct approaches to the construction
of d-lactone units, which will make the
methodology very attractive for the
synthesis of a variety of biologically
important compounds and natural
products.
Keywords: asymmetric catalysis
·
·
·
·
hetero-Diels–Alder
hydrogen-bonding
reactions
activation
lactones
·
organo catalysis
TADDOL
Introduction
developments is the 1-naphthyl-TADDOL-promoted
hetero-Diels–Alder (HDA) reaction of 1-amino-3-siloxybu-
tadiene with aldehydes reported by Rawal and co-workers
(TADDOL=a,a,a’,a’-tetraaryl-1,3-dioxolan-4,5-dimetha-
nol), which affords the corresponding 2-substituted 2,3-dihy-
dro-4H-pyran-4-ones in excellent yields and enantioselectivi-
ties.[5b] Although a variety of catalytic asymmetric HDA re-
actions between dienes and carbonyl compounds have been
reported to give dihydropyrones,[6] that can be converted to
the corresponding d-lactone derivatives, a type of heterocy-
cle with extensive synthetic applications in biologically im-
portant natural and unnatural products,[7] the enantioselec-
tive HDA reaction of electron-rich 1,3-dimethoxy-1-(trime-
thylsiloxy)butadiene (Brassardꢀs diene) with aldehydes to di-
rectly give d-lactones has not yet been successful. Herein,
we report our results on the development of the catalytic
enantioselective HDA reaction of Brassardꢀs diene with al-
dehydes through asymmetric hydrogen-bonding activation,
as well as a one-step synthesis of (S)-(+)-dihydrokawain.
Since the pioneering work of List, Barbas, and MacMillan
and their co-workers in 2000,[1] the enantioselective catalysis
of organic reactions involving small organic molecules as
catalysts has become a rapidly growing area of research in
the field of chiral chemistry because these reactions mimic
enzyme processes.[2] In most of the asymmetric reactions in-
volving carbonyl compounds, a central tenet is the selective
activation of the carbonyl group by the catalyst through the
coordination of its lone pair with a Lewis acid.[3] In princi-
ple, the proton can be considered the smallest hard Lewis
acid. Accordingly, carbonyl activation by hydrogen bonding
could be a viable strategy for catalysis and pave the way for
asymmetric carbonyl reactions.[4] Several catalytic enantiose-
lective reactions have been achieved very recently by hydro-
gen-bonding activation.[5] Of these, one of the most exciting
[a] H. Du, D. Zhao, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Results and Discussion
354 Fenglin Road, Shanghai 200032 (China)
Fax : (+86)21-6416-6128
This research was inspired by our recent discovery during
the optical resolution of the anti head-to-head coumarin
dimer through molecular complexation with the diol host
E-mail: kding@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200400515
Chem. Eur. J. 2004, 10, 5964 – 5970

5964 – 5970
molecule, (R,R)-(À)-trans-4,5-bis(hydroxydiphenylmethyl)-
2,2-dimethyl-1,3-dioxacyclopentane (TADDOL, (R,R)-
basis of the interaction between TADDOL (1a) and DMF
mentioned above, we decided to investigate the viability of
the catalytic enantioselective HDA reaction between 3 and
4 using TADDOL[8] as the catalyst. The reaction was carried
out at room temperature with 0.5 mmol of 3 and 2.5 mmol
of benzaldehyde (4a) using 20 mol% of (R,R)-1a under sol-
vent-free conditions. The reaction proceeded enantioselec-
tively to give 4-methoxy-6-phenyl-5,6-dihydropyran-2-one
[(À)-5a] in 30% yield although the enantioselectivity was
low (Table 1, entry 1). This result encouraged us to improve
the enantioselectivity of the reaction by tuning the structure
of the catalysts and the reaction conditions. As shown in
Table 1, the use of catalyst (R,R)-1b, which was found to be
highly efficient in Rawalꢀs system,[5b] enhanced the yield and
enantioselectivity of the reaction (Table 1, entry 2) under
the same experimental conditions. By lowering the reaction
temperature to À308C, the enantioselectivity was further
improved to 71% with a yield of 70% if the reaction time
was extended to 24 h (Table 1, entry 3). When the catalyst
loading was reduced to 10 mol%, the enantioselectivity of
the reaction remained constant although the yield dropped
to 50% (Table 1, entry 4). In contrast, the use of 2-naphthyl-
TADDOL derivative (R,R)-1c as catalyst gave the racemic
product (Table 1, entry 5), which clearly demonstrates that
aryl groups have a significant impact on the efficiency of
asymmetric induction. Moreover, changing the R group in
the backbone of TADDOL frommethyl [( R,R)-1b] to 1,4-
butylene (R,R)-1d] (Scheme 1) affected the enantioselectivi-
ty only slightly, but resulted in a lower yield (Table 1,
entry 6). Therefore, fromthe performances of catalysts
(R,R)-1a–d, the TADDOL derivative (R,R)-1b is evidently
the best choice for the present reaction systemin terms of
both enantioselectivity and reactivity. Because the solvent-
free reaction systemwas very viscous at a low reaction tem-
perature (the melting point of benzaldehyde is À568C), tol-
uene was added to the reaction systemin order to reduce
1a).[8,9] Decomposition of the molecular crystals formed be-
tween (R,R)-1a and the coumarin dimer in N,N-dimethylfor-
mamide (DMF) results in the formation of a new molecular
complex, (R,R)-1a·DMF (2), and releases the enantiopure
coumarin dimer. X-ray crystal structural analysis of the mo-
lecular crystal 2 showed that intramolecular hydrogen bond-
ing exists between the two hydroxy groups of TADDOL
and that a DMF molecule is included in the TADDOL host
molecule through an intermolecular hydrogen-bonding in-
teraction between one of the hydroxy groups and the lone
pair of electrons of the carbonyl oxygen atomin DMF
(Figure 1).[10] This structural information encouraged us to
Figure 1. Molecular structure of (R,R)-1a·DMF (2).
Table 1. Enantioselective hetero-Diels–Alder reaction between Brassardꢀs diene (3) and benzaldehyde (4a).[a]
carry out further asymmetric
reactions involving activation of
the carbonyl group through hy-
drogen bonding by replacing
the DMF in the molecular com-
plex with other carbonyl sub-
strates, such as aldehydes or ke-
tones.
Entry
Catalyst
Solvent
[mL]
Temp.
Time
[h]
Yield
[%][b]
ee
[8C]
[%][c]
Although the synthesis of op-
tically active d-lactones through
the reaction of Brassardꢀs diene
(3) with optically active alde-
hydes has been achieved in the
presence of Lewis acid cata-
lysts,[11] to the best of our
knowledge, no successful cata-
lytic enantioselective HDA re-
actions of 3 with aldehydes (4),
by using either organometallic
catalysts or organocatalysts,
1
2
3
1a
1b
1b
1b
1c
1d
1b
1b
1b
1b
1b
free
free
free
free
free
free
toluene (0.05)
toluene (0.1)
toluene (0.2)
toluene (0.4)
toluene (0.2)
RT
RT
12
12
24
24
24
24
24
24
48
48
48
30
40
70
50
40
37
70
68
67
50
26
7
50
71
72
0
74
75
76
83
86
89
À30
À30
À30
À30
À30
À30
À60
À60
À78
4[d]
5[d]
6[d]
7
8
9
10
11
[a] All the reactions were carried out with 2.5 mmol of benzaldehyde and 0.5 mmol of Brassardꢀs diene.
[b] Yield of isolated product based on Brassardꢀs diene. [c] The enantiomeric excesses of the products were de-
termined by HPLC on a Chiralpak AD column; the sign of the optical rotation is “À”. [d] 10 mol% of catalyst
have been reported. On the was used.
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K. Ding et al.
FULL PAPER
Table 3. The reaction of Brassardꢀs diene with aldehydes catalyzed by
1b.[a]
Entry
Ar
Toluene
[mL]
Temp.
[8C]
Yield
[%][c]
ee
[%][d]
Scheme 1. The chiral diol catalysts employed in asymmetric catalysis.
1[b]
2[b]
3
4
5
6
7
8
Ph 5a
furyl 5b
0.2
0.2
0.2
0.4
0.4
0.4
0.4
0.2
À60
À60
À30
À30
À30
À60
À60
À60
67
80
54
85
72
67
75
45
83 (S)
87 (S)
68 (R)
76 (R)
78 (R)[e]
89 (R)
82 (R)
91[f]
o-MeC6H4 5c
p-ClC6H4 5d
p-BrC6H4 5e
m-BrC6H4 5 f
o-BrC6H4 5g
m-MeOC6H4 5h
the viscosity of the mixture. It was found that the addition
of a small amount of toluene was favorable for the enantio-
selectivity (Table 1, entries 7 and 8), and it also allowed the
reaction temperature to be further decreased to À608C,
which afforded (À)-5a with 83–86% ee without a significant
reduction in yield (Table 1, entries 9 and 10). Although the
enantioselectivity of the reaction could be improved to 89%
by reducing the reaction temperature to À788C, the yield of
(À)-5a was poor (Table 1, entry 11).
[a] All the reactions were carried with 2.5 mmol of benzaldehyde and
0.5 mmol of Brassardꢀs diene. [b] The catalyst employed in this case was
(R,R)-1b. [c] Yield of isolated product. [d] The enantiomeric excesses of
the products were determined by HPLC on a Chiralpak AD column. The
absolute configurations were assigned by comparing the Cotton effect of
the CD spectra with that of 5e. [e] The absolute configuration was deter-
mined by X-ray crystal structural analysis of 5e on the basis of the anom-
alous dispersion of the heavy bromine atom. [f] The absolute configura-
tion was not assigned.
BINOL-Ti and BINOL-Zn complexes have previously
been reported to be efficient catalysts in the enantioselec-
tive hetero-Diels–Alder reaction of Danishefskyꢀs diene and
aldehydes.[12] These organometallic catalysts were also em-
ployed in the asymmetric hetero-Diels–Alder reactions be-
tween Brassardꢀs diene (3) and benzaldehyde (4a) in order
to compare the two catalytic systems. The optimized results
are summarized in Table 2, and clearly demonstrate the ad-
a natural product, (S)-(+)-dihydrokawain (5i),[14] was ob-
tained in one step in 50% isolated yield and with 69% ee
(Scheme 2). Therefore, this catalytic system has provided
one of the most direct and con-
venient approaches to the syn-
thesis of d-lactone derivatives,
which are very useful in the
synthesis of natural products
and chiral drugs (for example,
all of the Statin drugs, such as
Lipitor, Zocor, and Pravacol,
contain the chiral b-hydroxy-d-
lactone subunit).[15] Hence, this
methodology will be very at-
tractive froma synthetic point
of view.
Table 2. Enantioselective HDA reactions between Brassardꢀs diene (3) with benzaldehyde (4a) using chiral
Lewis acids as the catalysts.[a]
Entry
Ligand
Metal
Solvent
Temp.
[8C]
Time
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
7
7
8
(R)-BINOL-Ti[d]
toluene
toluene
DME[g]
RT
RT
À30
24
24
24
38
50
50
70
17
62
(R)-BINOL-Ti[e]
(R)-6,6’-Br2-BINOL-Zn[f]
[a] The reactions were carried out with 0.25 mmol of benzaldehyde and 0.5 mmol of Brassardꢀs diene in
1.0 mL of solvent using 10 mol% of the catalyst. [b] Yield of isolated product of 5a. [c] The enantiomeric ex-
cesses of the products were determined by HPLC on a Chiralpak AD column. The optical rotation of 5a is
“+”. [d] BINOL/[Ti(OiPr)4]=2:1. [e] BINOL/[Ti(OiPr)4]=1:1. [f] 6,6’-Br2-BINOL/Et2Zn=1:1.4. [g] DME=
ethylene glycol dimethyl ether.
vantages of organocatalysis over organometallic catalysis in
this reaction system. Moreover, the reactions catalyzed by
the organometallic catalysts hardly gave reproducible yields,
which is probably due to the fact that Brassardꢀs diene (3)
decomposed in the presence of the Lewis acid before it re-
acted with the aldehydes.[13]
Scheme 2. One-step synthesis of (S)-(+)-dihydrokawain (5i).
Under the optimized conditions, the substrate scope of
this reaction systemwas then examined using 1b as the cata-
lyst. As shown in Table 3, this catalyst was effective for the
reactions of a variety of aromatic aldehydes to give the cor-
responding 6-substituted 4-methoxy-5,6-dihydropyran-2-ones
in 45–85% yields and with 68–91% ee. When solid alde-
hydes were employed as the substrates, it was necessary to
use more toluene to ensure that the reaction mixture was an
homogeneous solution (Table 3, entries 4–7). In particular,
when 3-phenylpropionaldehyde 4i was used as the substrate,
The absolute configuration of (+)-5e was determined un-
ambiguously by the Bijvoet method to be R with a Flack pa-
rameter of À0.004(15) on the basis of the anomalous disper-
sion of the bromine heavy atom (Figure 2). To determine
the absolute configurations of the other products, the CD
spectra of 5a–g and 5i were measured in CHCl3. As shown
in Figure 3, compounds (+)-5c–g exhibited a similar (+)
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Chem. Eur. J. 2004, 10, 5964 – 5970

Enantioselective Catalysis by Hydrogen-Bonding Activation
5964 – 5970
Figure 4. Possible mechanism for asymmetric induction in the enantio-
selective HDA reaction between Brassardꢀs diene and aldehydes.
Figure 2. Molecular structure of (R)-(+)-5e in the crystal.
action between the naphthyl ring and the carbonyl group of
the substrate all play important roles in the control of the
enantioselectivity of the catalytic reactions.[5b]
Conclusions
In conclusion, the first catalytic enantioselective hetero-
Diels–Alder reaction of Brassardꢀs diene with aldehydes has
been achieved by catalysis with TADDOL derivatives
through hydrogen-bonding activation to afford the corre-
sponding d-lactone derivatives in moderate-to-good yields
and with high enantioselectivities (up to 91% ee). On the
basis of the absolute configurations of the products and the
hydrogen-bonding interaction pattern between TADDOL
and the carbonyl group disclosed by X-ray diffraction analy-
sis, a possible mechanism for the enantioselective catalytic
reaction has been proposed. Moreover, a natural product,
(S)-(+)-dihydrokawain, has also been prepared in one step
by using this methodology. Therefore, this catalytic system
has provided one of the most direct and convenient ap-
proaches to the construction of d-lactone units, which will
make the methodology very attractive for the synthesis of a
variety of biologically important compounds and natural
products.[15]
Figure 3. CD spectra of compounds 5a–g and 5i (c=0.01m in CHCl3).
Cotton effect in their CD spectra. It can be deduced that
these compounds possess the same R configuration as (+)-
5e. On the other hand, compound (À)-5a and -5b, which
were obtained with the opposite enantiomer of catalyst
(R,R)-1b, exhibited a (À) Cotton effect and hence their ab-
solute configurations can be assigned as S. Accordingly, it
can be concluded that the reaction of the aromatic alde-
hydes afforded (R)-5,6-dihydropyran-2-one derivatives when
(S,S)-1b was used whilst the reaction of the aliphatic alde-
hyde 4i gave (S)-5i with the same catalyst.
On the basis of the observed absolute configurations of
the products and the hydrogen-bonding interaction pattern
in the crystal structure of 2, a possible mechanism for asym-
metric induction in this catalytic system can be outlined
(Figure 4). When (S,S)-1b was used as the catalyst, the
steric hindrance of the naphthyl moiety shields the Si face
of the aldehyde, while the Re face is available to accept the
attacking diene to give the products with the R configura-
tion as expected. Although this model cannot quantitatively
explain the impact of the aryl groups of TADDOL deriva-
tives on their asymmetric induction in HDA reactions, it is
evident that the strength of the intermolecular hydrogen
bonding between the catalyst and the substrate, the greater
steric hindrance of the 1-naphthyl group, and the p–p inter-
Experimental Section
General considerations: 1H NMR spectra were recorded on a Bruker
AM300 NMR spectrometer (300 MHz) with CDCl3 or [D6]DMSO as sol-
vent; chemical shifts are measured in ppm and coupling constants, J, in
hertz. Mass spectra (EI, 70 eV) were recorded on a HP5989A spectrome-
ter. HRMS data were measured on a Kratos Concept instrument. Ele-
mental analysis was preformed on an Elemental VARIO EL apparatus.
Melting points are uncorrected. Optical rotations were measured on a
Perkin-Elmer 341 automatic polarimeter; [a]D values are given in units
of 10À1 degcm2 gÀ1. CD spectra were recorded on a JASCO 810 spectrom-
eter in CHCl3 at roomtemperature. HPLC analyses were carried out on
a JASCO 1580 liquid chromatograph with a JASCO CD-1595 detector
(l=254 nm) and AS-1555 autosampler. Toluene and tetrahydrofuran
were distilled fromsodiumbenzophenone ketyl under argon and de-
gassed before use. All reactions were performed under argon.
Preparation of Brassardꢀs diene (3):[11c] A solution of anhydrous THF
(100 mL) and diisopropylamine (12.0 g, 118 mmol, 17.0 mL) was cooled
to 08C, and nBuLi (1.6m in hexane, 70 mL, 112 mmol) was added drop-
wise over 10 min. The pale yellow solution was stirred at 08C for 1 h and
then cooled to À788C. Methyl 3-methoxy-2-butenoate (12.0 g, 100 mmol)
was added slowly to the lithiumdiisopropylamide (LDA) solution, which
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K. Ding et al.
FULL PAPER
was then stirred for 30 min at À788C. Chlorotrimethylsilane (20.0 mL,
16.9 g, 156 mmol) was slowly added to the solution at À788C, and the so-
lution was stirred for 10 min. Then the mixture was allowed to warm to
roomtemperature over 1 h. The solution was diluted with hexane
(100 mL) and filtered. The solution was then concentrated to remove the
solvent and the residue was distilled in vacuo (60–628C/2 mmHg) to
afford Brassardꢀs diene (3) (13.6 g, 78% yield) as a colorless liquid
(E/Z>95%). 1H NMR (300 MHz, CDCl3): d=4.36 (d, J=1.5 Hz, 1H),
4.03 (d, J=1.2 Hz, 1H), 3.99 (d, J=1.2 Hz, 1H), 3.57 (s, 3H), 3.56 (s,
3H), 0.26 (s, 9H) ppm.
(18.65), 39 (17.47), 105 (16.18); HRMS (EI): calcd for C12H12O3:
204.0781; found: 204.0787; IR (KBr): n=3064, 2983, 2947, 2913, 1718,
1620, 1456, 1384, 1290, 1228, 1070, 1025, 997, 761, 702 cmÀ1
.
General procedure for the catalytic asymmetric hetero-Diels–Alder reac-
tion between Brassardꢀs diene and benzaldehyde using chiral metal com-
plexes as catalysts: A chiral diol ligand (7 or 8, 0.025 mmol), dried tolu-
ene or DME (1.0 mL), and a specific amount of [Ti(OiPr)4] or Et2Zn
were added to a dried Schlenk tube filled with argon (see Table 2). The
mixture was stirred at room temperature for 0.5 h and then freshly distil-
led benzaldehyde (4a) (26.5 mg, 25 mmol, 25 mL) was introduced. The
temperature of the reaction system was adjusted to the appropriate tem-
perature (see Table 2), and finally Brassardꢀs diene 3 (102 mg, 0.5 mmol,
100 mL) was quickly added. The reaction mixture was stirred for 24 h,
and then methanol (0.5 mL) was added to quench the reaction. Evapora-
tion of the solvent in vacuo gave the crude product which was purified by
flash chromatography on silica gel with hexanes/ethyl acetate (2:1) as
eluent to afford (R)-4-methoxy-6-phenyl-5,6-dihydropyran-2-one ((R)-
5a) as a white solid. The results are summarized in Table 2.
Preparation of (R,R)-1-naphthyl-TADDOL [(R,R)-1b]:[16] Magnesium
(2.0 g, 84 mmol), anhydrous THF (24 mL), and a grain of iodine were
added to a flame-dried three-necked flask. 1-Bromonaphthane (16.6 g,
80 mmol) in THF (80 mL) was then added dropwise to prepare 1-naph-
thylmagnesium bromide. (R,R)-O,O’-Isopropylidene-l-tartaric acid dieth-
yl ester (2.46 g, 10 mmol) in THF (50 mL) was added dropwise to the so-
lution of 1-naphthylmagnesium bromide at room temperature over 1 h,
and then the reaction mixture was refluxed for an additional 6 h. The re-
action mixture was cooled to room temperature, and saturated NH4Cl
aqueous solution was added carefully to quench the reaction. The organic
layer was separated, and the aqueous phase was extracted with diethyl
ether (3”50 mL). The combined organic phase was then dried over
Na2SO4 and concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel using toluene as eluent to give (R,R)-
1b (3.3 g, 50% yield) as a white solid. 1H NMR (300 MHz, [D6]DMSO):
d=8.50 (brs, 1H), 8.36 (brs, 1H), 7.98–7.64 (brm, 18H), 7.27–6.98 (brm,
8H), 6.72 (brs, 2H), 5.20 (brs, 2H), 0.05 (brs, 6H) ppm; IR (KBr): n=
3569, 3352, 3047, 1598, 1509, 1395, 1381, 1370, 1235, 1216, 1168, 1057,
(S)-4-Methoxy-6-(2-furyl)-5,6-dihydropyran-2-one ((S)-5b): A white solid
prepared in 80% yield and 87% ee (determined by HPLC on a Chiral-
pak AD column using hexane/2-propanol (85:15) as eluent, flow rate=
1.0 mLminÀ1, tR1 =21.2 min (minor), tR2 =22.8 min (major)); [a]2D0 =À56.0
(c=0.95 in CHCl3); m.p. 124–1268C; 1H NMR (300 MHz, CDCl3): d=
7.44 (s, 1H), 6.45–6.44 (m, 1H), 6.40–6.38 (m, 1H), 5.47 (dd, J=11.4,
4.2 Hz, 1H), 5.22 (s, 1H), 3.76 (s, 3H), 3.13–3.03 (m, 1H), 2.68–2.61 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3): d=172.2, 166.2, 150.1, 143.0,
110.4, 108.9, 90.2, 70.3, 56.1, 31.0 ppm. EI-MS: m/z (%): 194 ([M]+,
16.83), 39 (100), 68 (83.59), 69 (45.55), 38 (25.45), 55 (24.19), 98 (16.15);
HRMS (EI): calcd for C10H10O4: 194.0574; found: 194.0572; IR (KBr):
n=3143, 3129, 3113, 3029, 2930, 1709, 1621, 1597, 1379, 1347, 1289, 1233,
778 cmÀ1
.
By following the same procedure as described above, TADDOL deriva-
tives 1a, 1c, and 1d were prepared and their spectral data are summar-
ized below.
(R,R)-1a: Yield 76%; m.p. 195–1968C (lit.[16] 195–1968C); 1H NMR
(300 MHz, CDCl3): d=7.20–7.60 (m, 20H), 4.60 (s, 2H), 3.95 (s, 2H),
1.00 (s, 6H) ppm; IR (KBr): n=3589, 3398, 3055, 2976, 2904, 2872, 1494,
1448, 1441, 1336, 1270, 1206, 1178, 1156, 1109 cmÀ1
1201, 1026, 1013, 823, 761 cmÀ1
.
(R)-4-Methoxy-6-(2-tolyl)-5,6-dihydropyran-2-one ((R)-5c): This product
was obtained by using (S,S)-1b as the catalyst: a white solid prepared in
54% yield and 68% ee (determined by HPLC on a Chiralpak AD
column using hexane/2-propanol (85:15) as eluent, flow rate=
1.0 mLminÀ1
, tR1 =12.6 min (major), t =
R2 =14.5 min (major)); [a]D20
+146.2 (c=1.17 in CHCl3); m.p. 96–988C; 1H NMR (300 MHz, CDCl3):
d=7.51–7.48 (m, 1H), 7.28–7.22 (m, 2H), 7.19–7.16 (m, 1H), 5.61 (dd,
J=12.3, 3.6 Hz, 1H), 5.25 (d, J=1.5 Hz, 1H), 3.79 (s, 3H), 2.86–2.76 (m,
1H), 2.54–2.47 (m, 1H), 2.36 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d=172.8, 167.1, 136.1, 134.7, 130.6, 128.4, 126.4, 126.0, 90.4, 74.6, 56.1,
33.8, 19.0 ppm; EI-MS m/z (%): 218 ([M]+, 5.33), 98 (100), 68 (88.54),
172 (75.07), 91 (59.59), 69 (58.52), 130 (39.40), 99 (38.06), 119 (36.97);
HRMS (EI): calcd for C13H14O3: 218.0937; found: 218.0940; IR (KBr):
n=2978, 2975, 1711, 1620, 1386, 1287, 1244, 1231, 1070, 1026, 991,
(R,R)-1c: Yield 82%; m.p. 213–2158C (lit.[16] 213–214.58C); 1H NMR
(300 MHz, [D6]DMSO):[16] d=8.21 (s, 2H), 7.97–7.91 (m, 8H), 7.80–7.72
(m, 6H), 7.65–7.43 (m, 12H), 7.32 (d, J=8.7 Hz, 2H), 4.78 (s, 2H), 1.13
(s, 6H) ppm; IR (KBr): n=3550, 3248, 3056, 2985, 1631, 1599, 1505,
1454, 1434, 1380, 1371, 1273, 1241, 1217, 1165, 1124, 1093, 1060, 1018,
886, 858, 815, 792, 756, 746 cmÀ1
.
(R,R)-1d: Yield 60%; m.p. 187–1898C; [a]2D0 =À24.7 (c=1.0 in CHCl2);
1H NMR (300 MHz, [D6]DMSO): d=8.50 (brm, 2H), 8.47–7.71 (brm,
18H), 7.23–6.95 (m, 8H), 6.72–6.70 (brm, 2H), 5.17 (brs, 2H), 1.01–0.97
(brm, 4H), 0.45–0.40 (brm, 2H), 0.02 to À0.02 (brm, 2H) ppm;
MALDI-MS [M++Na): 715.3; HRMS (MALDI): calcd for C49H40O4Na:
715.2849; found: 715.2819; elemental analysis calcd. (%) for C49H40O4: C
84.94, H 5.82; found: C 84.64, H 5.79; IR (KBr): n=3569, 3350, 3047,
780 cmÀ1
.
(R)-4-Methoxy-6-(4-chlorophenyl)-5,6-dihydropyran-2-one ((R)-5d): This
product was obtained by using (S,S)-1b as the catalyst: a white solid pre-
pared in 85% yield and 76% ee (determined by HPLC on a Chiralpak
AD column using hexane/2-propanol (85:15), flow rate=1.0 mLminÀ1
t
,
2955, 1598, 1509, 1395, 1334, 1199, 1121, 964, 899, 778 cmÀ1
.
R1 =18.2 min (major), tR2 =21.9 min (minor)); m.p. 180–1828C; [a]D20
=
General procedure for the catalytic asymmetric hetero-Diels–Alder reac-
tion between Brassardꢀs diene and aldehydes using 1b as catalyst:
TADDOL derivative (R,R)-1b (66.6 mg, 0.1 mmol), freshly distilled ben-
zaldehyde (4a) (265 mg, 2.5 mmol), and toluene (0.2 mL) were added to
a dried Schlenk tube filled with argon. The Schlenk tube was then im-
mersed in a cooling bath for 30 min to attain a temperature of À608C,
and finally Brassardꢀs diene (3) (102 mg, 0.5 mmol) was quickly added.
The reaction mixture was stirred at À608C for 48 h, and then methanol
(0.5 mL) was added. Evaporation of the solvent in vacuo gave the crude
product which was purified by flash chromatography on silica gel with
hexanes/ethyl acetate (2:1) as eluent to afford (S)-4-methoxy-6-phenyl-
5,6-dihydropyran-2-one ((S)-5a) (68 mg, 67% yield) as a white solid with
83% ee (determined by HPLC on a Chiralpak AD column using hexane/
+141.0 (c=1.07 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.38 (s,
1H), 5.42 (dd, J=12.0, 3.9 Hz, 1H), 5.25 (d, J=1.5 Hz, 1H), 3.80 (s, 3H),
2.84–2.74 (m, 1H), 2.63–2.56 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3):
d=172.3, 166.5, 136.7, 134.3, 128.8, 127.3, 90.5, 76.3, 56.2, 34.9. EIMS m/z
(relative intensity): 238 ([M]+, 13.57), 98 (100), 68 (56.07), 69 (32.77), 139
(16.57), 111 (11.84), 127 (5.73); HRMS (EI): calcd for C12H11ClO3:
238.0392; found: 238.0390; elemental analysis calcd (%) for C12H11ClO3:
C 60.39, H 4.65; found: C 60.38, H 4.66; IR (KBr): n=3085, 3035, 2993,
2945, 2899, 1705, 1620, 1493, 1456, 1441, 1386, 1288, 1230, 1176, 1072,
1029, 1013, 999, 834 cmÀ1
.
(R)-4-Methoxy-6-(4-bromophenyl)-5,6-dihydropyran-2-one ((R)-5e): This
product was obtained by using (S,S)-1b as the catalyst: a white solid pre-
pared in 72% yield and 78% ee (determined by HPLC on a Chiralpak
2-propanol (85:15) as eluent, flow rate=1.0 mLminÀ1
, tR1 =13.5 min
AD column using hexane/2-propanol (85:15), flow rate=1.0 mLminÀ1
,
(minor), tR2=15.4 min (major)). [a]2D0 =À156.0 (c=1.17 in CHCl3); m.p.
124–1268C; H NMR (300 MHz, CDCl3): d=7.42–7.36 (m, 5H), 5.44 (dd,
t =
R1 =19.4 min (major), tR2 =23.6 min (minor)); m.p. 165–1678C; [a]D20
1
J=12.0, 3.6 Hz, 1H), 2.25 (d, J=0.9 Hz, 1H), 3.79 (s, 3H), 2.89–2.79 (m,
1H), 2.64–2.57 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): d=172.5,
166.8, 138.1, 128.6, 128.5, 125.9, 90.5, 77.4, 56.1, 35.0 ppm; EI-MS: m/z
(%): 204 ([M]+, 16.83), 98 (100), 68 (55.91), 69 (33.84), 40 (21.59), 77
+117.2 (c=1.09 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.56 (d, J=
8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 5.43 (dd, J=12.3, 4.2 Hz, 1H), 5.28
(s, 1H), 3.82 (s, 3H), 2.85–2.75 (m, 1H), 2.65–2.68 (m, 1H) ppm; 13C
NMR (75 MHz, CDCl3): d=172.3, 166.5, 137.2, 131.7, 127.6, 122.5, 90.4,
5968
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5964 – 5970

Enantioselective Catalysis by Hydrogen-Bonding Activation
5964 – 5970
76.3, 56.2, 34.8 ppm; EI-MS: m/z (%): 282 ([M]+, 11.93), 98 (100), 68
(54.94), 69 (31.96), 183 (12.03), 284 (11.78), 155 (7.91); HRMS (EI):
calcd. for C12H11BrO3: 281.9886; found: 281.9892; elemental analysis
calcd (%) for C12H11BrO3: C 50.91, H 3.92; found: C 50.76, H 3.84; IR
(KBr): n=3085, 2991, 2943, 2898, 1703, 1620, 1490, 1440, 1384, 1286,
0.71069 Š). A total of 3870 reflections were measured and 1933 were
unique [I>2.50s(I)]. The structure was solved by direct methods
(SHELX-97)[17] and refined by full-matrix least-squares to R=0.063,
wR=0.072. Crystal data for 2 (C34H37O5N): orthorhombic, P212121, a=
10.277(4), b=29.928(6), c=9.616(3) Š, a=b=g=908, V=2957(1) Š3,
1calcd =1.212 gcmÀ3, Z=4.
1230, 1177, 1072, 1029, 1010, 924, 842, 829 cmÀ1
.
X-ray crystallographic analysis of (R)-(+)-5e:[10] A single crystal of (+)-
5e was obtained by slow evaporation of its solution in dichloromethane/
hexane (1:2) at roomtemperature. X-ray crystallographic analysis was
performed with a Bruker SMART CCD-APEX at 208C using graphite
monochromated MoKa radiation (l=0.71073 Š). A total of 6832 reflec-
tions were measured and 2517 were unique (Rint =0.0800). The structure
was solved by direct methods (SHELX-97)[17] and refined by full-matrix
least-squares to R=0.0455, wR=0.1016. Crystal data for (+)-5e
(C12H11BrO3): orthorhombic, P212121, a=7.0582(9), b=8.4182(11), c=
19.142(2) Š, a=b=g=908, V=1137.3(3) Š3, 1calcd =1.653 gcmÀ3, Z=4.
The absolute configuration of (+)-5e was determined unambiguously by
the Bijvoet method to be R with a Flack parameter of À0.004(15) on the
basis of the anomalous dispersion of the bromine heavy atom.
(R)-4-Methoxy-6-(3-bromophenyl)-5,6-dihydropyran-2-one ((R)-5 f): This
product was obtained by using (S,S)-1b as the catalyst: a white solid pre-
pared in 67% yield and 89% ee (determined by HPLC on a Chiralpak
AD column using hexane/2-propanol (85:15), flow rate=1.0 mLminÀ1
,
t
R1 =14.0 min (major), t =
R2 =17.0 min (minor)); m.p. 88–908C; [a]D20
+162.2 (c=1.09 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.58 (s,
1H), 7.47 (d, J=8.4 Hz, 2H), 7.34–7.22 (m, 2H), 5.38 (dd, J=12.0,
0.9 Hz, 1H), 5.24 (s, 1H), 3.78 (s, 3H), 2.82–2.76 (m, 1H), 2.62–2.55 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3): d=172.3, 166.4, 140.4, 131.6,
130.2, 129.0, 124.5, 122.7, 90.5, 76.2, 56.2, 34.9 ppm; EI-MS: m/z (%): 282
([M]+, 11.94), 98 (100), 68 (47.51), 69 (29.18), 40 (11.64), 284 (11.55), 183
(7.99), 155 (5.17); HRMS (EI): calcd for C12H12O3: 204.0781; found:
204.0787; elemental analysis calcd (%) for C12H11BrO3: C 50.91, H 3.92;
found: C 51.11, H 3.92; IR (KBr): n=3106, 3014, 2942, 1712, 1626, 1568,
1386, 1355, 1227, 1174, 1072, 1028, 994, 877, 834, 802, 690 cmÀ1
.
(R)-4-Methoxy-6-(2-bromophenyl)-5,6-dihydropyran-2-one
((R)-5 g):
This product was obtained by using (S,S)-1b as the catalyst: a white solid
prepared in 75% yield and 82% ee (determined by HPLC on a Chiral-
pak AD column with hexane/isopropanol (85:15), flow rate=
1.0 mLminÀ1, tR1 =11.0 min (major), tR2 =12.4 min (minor)); m.p. 142–
1448C; [a]2D0 =+210.4 (c=1.04 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.68 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.42 (t, J=7.5 Hz,
1H), 7.29–7.24 (m, 1H), 7.57 (dd, J=12.3, 3.6 Hz, 1H), 5.29 (s, 1H), 3.82
(s, 3H), 2.87–2.80 (m, 1H), 2.66–2.57 (m, 1H) ppm; 13C NMR (75 MHz,
CDCl3): d=172.5, 166.7, 137.6, 132.8, 129.9, 127.7, 121.0, 90.4, 76.4, 56.2,
33.7 ppm; EI-MS: m/z (%): 282 ([M]+, 6.23), 98 (100), 68 (59.58), 69
(36.49), 40 (24.66), 159 (22.97), 115 (7.36), 183 (6.04); HRMS (EI): calcd.
for C12H11BrO3: 281.9886; found: 281.9885; IR (KBr): n=3078, 2979,
Acknowledgements
Financial support fromthe National Natural Science Foundation of
China, the Chinese Academy of Sciences, the Major Basic Research De-
velopment Program of China (Grant no. G2000077506), and the Ministry
of Science and Technology of the Commission of Shanghai Municipality
is gratefully acknowledged.
[1] For leading references see: a) U. Eder, G. Sauer, R. Wiechert,
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2947, 2854, 1712, 1620, 1386, 1233, 1184, 1073, 1022, 996, 850, 775 cmÀ1
.
4-Methoxy-6-(3-methoxyphenyl)-5,6-dihydropyran-2-one (5h): This prod-
uct was obtained by using (S,S)-1b as the catalyst: a white solid prepared
in 45% yield and 91% ee (determined by HPLC on a Chiralpak AD
column using hexane/2-propanol (85:15), flow rate=1.0 mLminÀ1, tR1
=
17.6 min (major), tR2 =20.7 min (minor)); m.p. 90–928C; [a]2D0 =+167.2
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.31 (t, J=7.8 Hz,
1H), 6.99–6.97 (m, 1H), 6.91–6.88 (m, 1H), 5.41 (dd, J=12.3, 4.2 Hz,
1H), 5.26 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.83–2.78 (m, 1H), 2.64–2.56
(m, 1H) ppm; 13C NMR (75 MHz, CDCl3): d=172.6, 166.8, 159.8, 139.8,
129.7, 118.1, 114.1, 111.4, 90.5, 76.9, 56.1, 55.3, 35.0 ppm; EI-MS: m/z
(%): 234 (M+, 63.44), 98 (100), 68 (86.24), 69 (50.88), 135 (35.81), 77
(31.80), 176 (7.93); HRMS (EI): calcd for C13H12O4: 234.0887; found:
2234.0883; IR (KBr): n=3096, 3013, 2945, 2838, 1702, 1625, 1585, 1490,
1458, 1448, 1388, 1289, 1244, 1227, 1202, 1032, 998, 786 cmÀ1
.
(S)-4-Methoxy-6-(2-phenylethyl)-5,6-dihydropyran-2-one ((S)-5i): This
product was obtained by using (S,S)-1b as the catalyst: a white solid pre-
pared in 50% yield and 69% ee (determined by HPLC on a Chiralcel
OB-H column using hexane/isopropanol (85:15), flow rate=
1.2 mLminÀ1, tR1 =42.5 min (R, minor), tR2 =56.1 min (S, major)). The ab-
solute configuration of 5i was determined to be S by comparison of its
chiroptical rotation with that reported in the literature.[14] [a]D20 =+18.5
1
(c=0.97 in CHCl3); m.p. 56–588C; H NMR (300 MHz, CDCl3): d=7.33–
7.27 (m, 2H), 7.23–7.19 (m, 3H), 5.15 (d, J=1.5 Hz, 1H), 4.40–4.34 (m,
1H), 3.74 (s, 1H), 2.90–2.79 (m, 2H), 2.58–2.48 (m, 1H), 2.34–2.29 (m,
1H), 2.18–2.10 (m, 1H), 1.92 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3):
d=172.7, 167.3, 104.8, 128.5, 128.4, 126.1, 90.3, 74.7, 56.0, 36.3, 33.0,
30.9 ppm; EI-MS: m/z (%): 232 ([M]+, 30.04), 127 (100), 91 (70.87), 39
(55.20), 117 (43.82), 68 (37.02), 200 (23.23), 141 (20.00), 155 (16.30);
HRMS (EI): calcd. for C14H16O3: 232.1094; found: 232.1102; IR (KBr):
n=3087, 3063, 3028, 2943, 2857, 1708, 1625, 1605, 1497, 1456, 1444, 1396,
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.
X-ray crystallographic analysis of 2:[10] A single crystal of 2 was obtained
by recrystallization of TADDOL in DMF/H2O (5:1). X-ray crystallo-
graphic analysis was performed at 208C by using a Rigaku AFC7R dif-
fractometer with graphite monochromated MoKa radiation (l=
Chem. Eur. J. 2004, 10, 5964 – 5970
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5969

K. Ding et al.
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[10] CCDC-236876 (2) and CCDC-243247 ((R)-(+)-5e) contain the sup-
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Received: May 25, 2004
Published online: October 14, 2004
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Chem. Eur. J. 2004, 10, 5964 – 5970