Enantioselective vinylogous aldol reaction of Chan's diene catalyzed by hydrogen-bonding

Article abstract of DOI:10.1016/j.tetlet.2006.11.159

Hydrogen-bonding activation of aromatic aldehydes by a TADDOL-derivative promotes the vinylogous aldol reaction of Chan's diene in moderate efficiency and enantioselectivity. Electron-poor aromatic aldehydes show an enhanced reactivity and a competing asy

Full text of DOI:10.1016/j.tetlet.2006.11.159

Tetrahedron Letters 48 (2007) 891–895
Enantioselective vinylogous aldol reaction of Chan’s diene
catalyzed by hydrogen-bonding
Rosaria Villano,* Maria Rosaria Acocella, Antonio Massa,
Laura Palombi and Arrigo Scettri*
`
Dipartimento di Chimica, Universita di Salerno, Via Ponte Don Melillo 84084 Fisciano (Salerno), Italy
Received 26 October 2006; revised 15 November 2006; accepted 17 November 2006
Available online 19 December 2006
Abstract—Hydrogen-bonding activation of aromatic aldehydes by a TADDOL-derivative promotes the vinylogous aldol reaction of
Chan’s diene in moderate efficiency and enantioselectivity. Electron-poor aromatic aldehydes show an enhanced reactivity and a
competing asymmetric hetero-Diels–Alder reaction takes place in comparable (or higher) yields and enantiomeric excesses.
Ó 2006 Elsevier Ltd. All rights reserved.
Chan’s diene 11 and Brassard’s diene 22 represent
masked forms of acetoacetate ester and, in spite of their
close structural analogy they can exhibit a very different
reactivity with aldehydes in metal-catalyzed processes.
In fact, Brassard’s diene 2 was found to react with
aliphatic and aromatic aldehydes, respectively, in the
presence of chiral Eu(hfc)33 and Ti(IV)/tridentate Schiff-
base complexes,4 to give the corresponding d-lactones 4
through a hetero-Diels–Alder (HDA) reaction with a
good efficiency and high enantioselectivity. Conversely,
in the presence of Ti(IV)/BINOL complexes both ali-
phatic, unsaturated, heteroaromatic and aromatic alde-
hydes showed to suffer a vinylogous aldol reaction by
Chan’s diene 1 leading to chiral polyketide derivatives
3 in high yields and ees (Scheme 1).5
OTMS OTMS
OH
O
O
cat
RCHO
+
OCH3
R
OCH3
1
3
OCH3
OCH3 OTMS
cat
RCHO
+
OCH3
R
O
O
2
4
Scheme 1.
Taking in mind the different reactivities of dienes 1 and 2
in metal-catalyzed reactions with aldehydes (Scheme 1),
we decided to investigate the viability of an enantioselec-
tive vinylogous aldol reaction of Chan’s diene 1 under
organocatalytic conditions.
In these last years an ever increasing interest has been
devoted to the organocatalysis6 and, particularly, car-
bonyl activation by hydrogen bonding has been conve-
niently exploited for the achievement of a variety of
preparatively important enantioselective procedures,7
such as aldol reactions, HDA reactions, epoxidations,
conjugate addition. Very interestingly, the conversion
2 ! 4 has been recently reported to take place in mod-
erate to good yields and high enantioselectivity by using
5a (Fig. 1).8
In order to verify the possibility of a competing non-
asymmetric reaction, a control experiment was per-
formed on benzaldehyde, chosen as the representative
substrate, in the absence of any chiral activator. Chan’s
diene 1 confirmed its notable nucleophilic properties so
that, under the conditions reported in Scheme 2 and
Table 1 (entry 1), the formation of vinylogous aldol
3a, as an exclusive product, took place in non-negligible
way (25% yield).
Keywords: Asymmetric synthesis; Vinylogous aldol reaction; Hydro-
gen-bonding; Chan’s diene; Organocatalysis.
*
Successively, a set of chiral hydrogen bond donors has
Corresponding authors. Tel.: +39 089969583; fax: +39 089969603;
e-mail addresses: rvillano@unisa.it; scettri@unisa.it
been used as organocatalysts in the reaction of diene 1
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.159

892
R. Villano et al. / Tetrahedron Letters 48 (2007) 891–895
Table 1. Vinylogous aldol reaction of Chan’s diene 1 on PhCHO
promoted by organocatalysts
HO
OH
Ar
Ar
Ar
Ar
Entry
Catalyst
Reaction
time (h)
3a Yielda
(%)
3a eeb
(%)
5a: Ar = 1-naphthyl
5b: Ar = 1-phenyl
1
2
3
4c
5d
6d
7e
—
72
72
72
48
24
72
24
25
25
43
40
42
42
32
—
8 (S)
O
O
(R)-BINOL
(R,R)-5b
(R,R)-5b
(S,S)-5a
(S,S)-5a
(S,S)-5a
11 (S)
11 (S)
61 (R)
58 (R)
65 (R)
R
R
Figure 1.
a In all entries 1/1.3/0.1 aldehyde/1/catalyst ratios were used under
solvent-free conditions. All the yields refer to isolated chromato-
graphically pure compounds, whose structures were confirmed by
spectroscopic data (1H NMR, 13C NMR, MS, IR).
with benzaldehyde. As reported in Table 1, very poor
results both in terms of efficiency and enantioselectivity
were obtained with (R)-BINOL and (R,R)-phenyl-TAD-
DOL 5b (respectively entries 2 and 3) and no improve-
ment was observed by using an increased amount of
activator (entry 4). Furthermore, the employment of a
poorly acidic hydrogen bond donor, as (2R,3R)-(ꢀ)-
2,3-butanediol, led to a completely racemic 3a in 33%
yield.
b Determined by chiral-phase HPLC analysis (CHIRALPAK AD,
Hexane/EtOH 95/5 + 0.1% TFA, 1 ml/min, k = 254 nm). Absolute
configurations of 3a were assigned by comparison of the signs of the
optical rotation with the ones reported in the literature.5d
c The experiment was performed with a catalyst loading of 30 mol %.
d The experiment was performed at room temperature.
e The experiment was performed at 0 °C.
A more interesting result was afforded by the employ-
ment of TADDOL derivative (S,S)-5a, as catalyst: in
fact, although the reaction was preferentially carried
out at room temperature because of the high viscosity
of the reaction mixture at lower temperature, the forma-
tion of the vinylogous aldol 3a, again as only product,
took place with a notable enhancement of the level of
enantioselectivity (entry 5). Comparable yields and ees
were observed after more prolonged reaction times
(entry 6). The sense of asymmetric induction observed
by using (S,S)-5a can be explained through the involvement
of a highly ordered transition state, generated by hydro-
gen-bonding between TADDOL derivative and the
aldehydic oxygen, according to the general models
developed by Ding and co-workers8 and Rawal and
co-workers.7e,9 As known,7e,8,9 temperature often repre-
sents a determining factor for the achievement of a high
enantioselectivity in processes promoted by organo-
catalysts. Consequently, the reaction of entry 5 was
repeated at 0 °C in the presence of toluene (0.1 ml) in
order to circumvent the disadvantage of the high viscos-
ity of the reagents mixture. However, a slight increase of
ee was obtained at the expense of the efficiency of the
reaction (entry 7).
Table 2. Vinylogous aldol reaction of Chan’s diene 1 on RCHO
promoted by 5a10,11
Entry
R
Product
3 Yielda (%)
3 eeb (%)
1
2
3
4
5
6
Ph
p-Tol
2-Furyl
p-MeOC6H4
o-MeOC6H4
n-C9H19
3a
3b
3c
3d
3e
3f
42
39
40
18
57
—
61
57
37
11
40
—
a In all entries 1/1.3/0.1 aldehyde/1/5a ratios were used under solvent-
free conditions. All the yields refer to isolated chromatographically
pure compounds, whose structures were confirmed by spectroscopic
data (1H NMR, 13C NMR, MS, IR).
b ees were determined by HPLC with a CHIRALPAK AD column.
Absolute configuration of compounds 3a,5d 3b,12 3c12 and 3d5d was
assigned as (R) by comparison of the sign of the optical rotation with
the one reported in the literature.
Conversely, aliphatic aldehydes showed to be com-
pletely unreactive, so that, for example, decanal (entry
6) was recovered completely unchanged after more
prolonged reaction times too. The results reported in
entries 4 and 5 pointed out a strong dependence of
the efficiency and enantioselectivity on the pattern of
substitution of the aromatic nucleus. A similar discrep-
ancy in the reactivity of o- and p-anisaldehyde has
been recently observed by Rawal in the Mukaiyama
aldol reaction of O-silyl-N,O-ketene acetals promoted
by the cyclohexylidene TADDOL-derivative of type 5
[R = –(CH2)5–].9
Therefore, the experimental conditions used in entry 5
were chosen to assess the scope of the reaction.
A set of aldehydes was submitted to the usual treatment
and the procedure was found to be successful with aro-
matic and heteroaromatic aldehydes affording the corre-
sponding vinylogous aldols 3 as exclusive products
(Table 2, entries 1–5).
1. Organocatalyst,
neat, -20 ºC
2. TFA
OTMS OTMS
OH
O
O
PhCHO
+
OCH3
Ph
OCH3
1
3a
Scheme 2.

R. Villano et al. / Tetrahedron Letters 48 (2007) 891–895
893
O
1. Organocatalyst,
neat, rt
OH
*
O
+
ArCHO
+
1
COOMe
2. TFA
Ar
*
Ar
O
OMe
3
6
Scheme 3.
Table 3.
Entry
Ar
Product 3
Yielda (%)
eeb (%)
Product 6
Yielda (%)
eeb (%)
1
2
3c
4
p-NO2C6H4
o-NO2C6H4
o-NO2C6H4
p-CF3C6H4
o-CNC6H4
3g
3h
3h
3i
39
30
32
52
46
54
21
46
31
56
6g
6h
6h
6i
32
64
30
38
39
57
53
60
51
59
5
3j
6j
a In all entries 1/1.3/0.1 aldehyde/1/5a ratios were used under solvent-free conditions. All the yields refer to isolated chromatographically pure
compounds, whose structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS and IR).
b Determined by chiral-phase HPLC analysis.
c Reaction conditions: 72 h/ꢀ20 °C and 0.1 ml of toluene.
The presence of an electron-withdrawing substituent on
the aromatic ring caused a notable modification in the
behaviour of the aldehydic substrates (Scheme 3).
In fact, when the reaction of entry 2 was carried out at
ꢀ20 °C for 72 h in the presence of toluene (0.1 ml) (entry
3), 3h and 6h were isolated in comparable yields (respec-
tively 32% and 30%) and a notable enhancement of the
ees could be observed (with respect to entry 2).
In fact, under the usual conditions p-nitrobenzaldehyde
exhibited an enhanced reactivity and afforded a mixture
of the expected vinylogous aldol 3g and pyrone 6g in a
rather good overall yield and moderate ees (Table 3,
entry 1).
Through the usual treatment under solvent-free condi-
tions at room temperature, other electron-poor alde-
hydes were smoothly converted in the mixture of the
corresponding vinylogous aldols and HDA adducts (en-
tries 4 and 5) in a rather good yield and satisfactory ees.
It is noteworthy that this organocatalytic procedure
allowed the first synthetic approach to products of type
6, whose unusual 2-alkoxy-pyrone moiety represents the
main structural feature of Tridachiahydropyrone 7
(Fig. 2),13 isolated in 1996 by Ortea and co-workers
from the mollusc Tridachia crispata.
The formation of 6g could be reasonably explained
through the occurrence of a competing hetero-Diels–
Alder (HDA) reaction leading to a cycloadduct of type
A, whose evolution to pyrone 6 took place by the acidic
treatment (Scheme 4). On the ground of this result, the
alternative attainment of pyrones 4 or 6 by the same
organocatalyst (S,S)-5a showed to depend on the pro-
tecting group R (and consequently on the use either of
Chan’s or Brassard’s diene).
Furthermore, these preliminary results confirm the not-
able synthetic versatility of Brassard’s and Chan’s
dienes, since different mechanistic pathways (leading to
different classes of compounds) can be favoured by a
marginal structural modification.
As already observed in the case of p- and o-anisalde-
hyde, o-nitrobenzaldehyde exhibited an enhanced reac-
tivity (with respect to p-nitrobenzaldehyde) so that the
corresponding products 3h and 6h could be isolated in
an overall 94% yield, being the HDA reaction the pre-
vailing process (entry 2).
In conclusion, simple aromatic aldehydes, suitably
hydrogen-bonding activated by the (S,S)-TADDOL
derivative 5a under solvent-free conditions, are shown
to suffer a vinylogous aldol condensation by Chan’s
diene 1, characterized by a complete c-selectivity and
The experimental conditions proved to exert a deep
influence on the preparative and stereochemical aspects.
OMe
OR'
O
H+
H+
OSiMe3
R'= -Me
R'= -SiMe3
*
*
*
Ar
O
O
Ar
O
Ar
O
OMe
OMe
4
6
A
Scheme 4.

894
R. Villano et al. / Tetrahedron Letters 48 (2007) 891–895
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10. General procedure for the preparation of compounds 3
(Table 2): In a dry vial (S,S)-5a (0.05 mmol), aldehyde
(0.5 mmol) and diene 1 (0.65 mmol) were added. The
resulting mixture was stirred for 24 h at room tempera-
ture, then dry THF (2 ml) was added. This solution was
cooled at ꢀ78 °C and TFA (0.2 ml) was added dropwise,
then it was permitted to warm to room temperature and
after completion of the desilylation reaction, it was
neutralized by addition of saturated aq NaHCO3. The
reaction mixture was extracted with AcOEt and the
combined organic phase was dried (MgSO4) and concen-
trated. The residue was purified by non-flash chromato-
graphy (CHCl3/Et2O 9/1) to give products 3.
promising level of enantioselectivity. The electronic
effects of the substituents on the aromatic nucleus played
a determining role on the reactivity of the examined sub-
strates, so that in the case of electron-poor aldehydes a
competing asymmetric HDA reaction, leading to pyrone
derivatives 6, was found to take place in comparable (or
higher) yields and ees with respect to the vinylogous
aldol reaction. Further studies, in order to rationalize
the product distribution in the case of electron-poor
aldehydes as well as to enlarge the substrate generality
of this reaction, are in progress.
Acknowledgement
We are grateful to MIUR for financial support.
11. All new compounds were fully characterized on the basis
1
of IR, H NMR, 13C NMR and mass spectroscopic data.
References and notes
Spectral data of selected compounds: Compound 3b:12
enantiomeric excess was determined by HPLC (Chiralpak
AD), hexane–EtOH 95:5 + 0.1% TFA, 1 ml/min major
enantiomer (R) tR = 23.3, minor enantiomer (S) tR = 30.3;
Compound 3c:12 enantiomeric excess was determined by
HPLC (Chiralpak AD), hexane–EtOH 95:5 + 0.1% TFA,
1 ml/min, major enantiomer (R) tR = 29.4, minor enan-
tiomer (S) tR = 42.3; Compound 3e:14 enantiomeric excess
was determined by HPLC (Chiralpak AD), hexane–EtOH
95:5 + 0.1% TFA, 1 ml/min minor enantiomer tR = 21.2,
major enantiomer tR = 23.5; Compound 3g:12 enantio-
meric excess was determined by HPLC (Chiralcel OD),
hexane–iPrOH 90:10, 0.8 ml/min, minor enantiomer (S)
tR = 48.0, major enantiomer (R) tR = 53.0; Compound 6g:
yellow oil, m/z: 250 [M+H]+, 272 [M+Na]+; IR (KBr,
1. Chan, T. H.; Brownbridge, P. J. Chem. Soc., Chem.
Commun. 1979, 578–579.
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4914.
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hedron: Asymmetry 2002, 13, 1949–1952; (d) Soriente, A.;
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Asymmetry 2000, 11, 2255–2258.
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sen, K. A. J. Am. Chem. Soc. 2006, 128, 12973–12980; (c)
1
neat) 2922, 1656, 1583, 1521, 1450, 1394, 1231; H NMR
(CDCl3, 400 MHz): d 8.28 (2H, d, J = 8.6 Hz), 7.59 (2H,
d, J = 8.6 Hz), 5.61 (1H, dd, J = 12.9, 3.9 Hz), 4.98 (1H,
s), 3.86 (3H, s), 2.77 (1H, dd, J = 16.8, 12.9 Hz), 2.68 (1H,
dd, J = 16.8, 3.9 Hz); 13C NMR (CDCl3, 400 MHz): d
190.6, 173.7, 148.0, 144.1, 126.6, 124.1, 82.8, 79.7, 56.2,
42.0; enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane–iPrOH 90:10, 0.8 ml/min, minor
enantiomer tR = 84.9, major enantiomer tR = 113.6; Com-
pound 3h: yellow oil, m/z: 290 [M+Na]+; IR (KBr, neat)
3507, 2957, 1745, 1716, 1526, 1345–1077; 1H NMR
(CDCl3, 400 MHz): d 7.96 (1H, d, J = 8.2 Hz), 7.89 (1H,
d, J = 7.8 Hz), 7.67 (1H, m), 7.44 (1H, m), 5.70 (1H, dd,
J = 9.2, 1.9 Hz), 3.75 (3H, s), 3.55 (2H, s), 3.22 (1H, dd,
J = 17.7, 1.9 Hz), 2.87 (1H, dd, J = 17.7, 9.2 Hz); 13C

R. Villano et al. / Tetrahedron Letters 48 (2007) 891–895
895
NMR (CDCl3, 400 MHz): d 202.4, 167.1, 147.0, 138.0,
133.8, 128.4, 128.1, 124.4, 65.4, 52.5, 50.7, 49.2; enantio-
meric excess was determined by HPLC (Chiralcel OD),
hexane–iPrOH 90:10, 0.8 ml/min, minor enantiomer
tR = 28.0, major enantiomer tR = 31.4; Compound 6h:
yellow oil, m/z: 250 [M+H]+, IR (KBr, neat) 2923, 2853,
1659, 1590, 1527, 1449, 1395–1054; 1H NMR (CDCl3,
400 MHz): d 8.05 (1H, d, J = 8.2 Hz), 7.84 (1H, d,
J = 7.6 Hz), 7.74 (1H, m), 7.56 (1H, m), 6.15 (1H, dd, J =
13.4, 3.3 Hz), 4.99 (1H, s), 3.83 (3H, s), 2.94 (1H, dd,
J = 16.8, 3.3 Hz), 2.71 (1H, dd, J = 16.8, 13.4 Hz); 13C
NMR (CDCl3, 400 MHz): d 190.9, 173.7, 147.3, 134.7,
134.0, 129.6, 127.9, 124.9, 83.0, 65.4, 56.1, 41.7; enantio-
meric excess was determined by HPLC (Chiralcel OD),
hexane–iPrOH 90:10, 0.8 ml/min, minor enantiomer
tR = 40.4, major enantiomer tR = 44.0; Compound 3i:15
enantiomeric excess was determined by HPLC (Chiralpak
AD), hexane–EtOH 95:5 + 0.1% TFA, 1 ml/min, major
enantiomer tR = 15.9, minor enantiomer tR = 17.5; Com-
pound 6i: yellow oil, m/z: 273 [M+H]+, IR (KBr, neat)
pound 3j: yellow oil, m/z: 248 [M+H]+, 270 [M+Na]+; IR
(KBr, neat) 3465, 2955, 2226, 1745, 1716, 1325–1065; H
1
NMR (CDCl3, 400 MHz): d 7.65 (3H, m), 7.38 (1H, m),
5.52 (1H, dd, J = 9.5, 2.4 Hz), 3.74 (3H, s), 3.54 (2H, s),
3.08 (1H, dd, J = 17.7, 2.4 Hz), 2.94 (1H, dd, J = 17.7,
9.5 Hz); 13C NMR (CDCl3, 400 MHz): d 202.2, 167.0,
145.8, 133.2, 132.8, 128.0, 126.6, 117.1, 109.6, 67.6, 52.5,
50.2, 49.3; enantiomeric excess was determined by HPLC
(Chiralpak AD), hexane–iPrOH 80:20, 0.8 ml/min, major
enantiomer tR = 11.6, minor enantiomer tR = 14.3; Com-
pound 6j: yellow oil, m/z: 230 [M+H]+, 252 [M+Na]+; IR
1
(KBr, neat) 2923, 2853, 2226, 1658, 1586, 1449, 1254; H
NMR (CDCl3,400 MHz): d 7.69 (3H, m), 7.51 (1H, m),
5.83 (1H, dd, J = 13.6, 3.6 Hz), 5.00 (1H, s), 3.85 (3H, s),
2.84 (1H, dd, J = 16.7, 13.6 Hz), 2.70 (1H, dd, J = 16.7,
3.6 Hz); 13C NMR (CDCl3, 400 MHz): d 190.5, 173.6,
140.4, 133.4, 129.5, 126.9, 116.5, 110.9, 83.0, 78.8, 56.1,
41.1; enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane–iPrOH 95:5, 0.8 ml/min, minor
enantiomer tR = 97.0, major enantiomer tR = 101.5.
12. Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169–2186.
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1
2922, 2852, 1653, 1580, 1452, 1326, 1253–1124; H NMR
(CDCl3, 400 MHz): d 7.69 (2H, d, J = 8.0 Hz), 7.53 (2H,
d, J = 8.0 Hz), 5.56 (1H, dd, J = 13.4, 3.5 Hz), 4.97 (1H,
s), 3.84 (3H, s), 2.79 (1H, dd, J = 16.7, 13.4 Hz), 2.65 (1H,
dd, J = 16.7, 3.5 Hz); 13C NMR (CDCl3, 400 MHz): d
191.1, 173.8, 145.0, 141.1, 126.2, 125.8, 108.2, 82.8, 80.3,
56.0, 42.0; enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane–iPrOH 90:10, 0.8 ml/min, minor
enantiomer tR = 22.8, major enantiomer tR = 28.0; Com-
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