A new procedure for the enantioselective vinylogous aldol reaction of Chan's diene

Article abstract of DOI:10.1016/j.tetasy.2006.12.016

Chiral δ-hydroxy-β-ketoesters are easily available through the enantioselective vinylogous aldol reaction of Chan's diene promoted by a SiCl₄/chiral phosphoramide catalytic system. The procedure is conveniently exploited for a very rapid approach to (+)-kavain, a natural bio-active α-pyrone compound.

Full text of DOI:10.1016/j.tetasy.2006.12.016

Tetrahedron: Asymmetry 17 (2006) 3332–3334
A new procedure for the enantioselective vinylogous
aldol reaction of Chan’s diene
Rosaria Villano,* Maria Rosaria Acocella, Antonio Massa, Laura Palombi and Arrigo Scettri*
`
Dipartimento di Chimica, Universita di Salerno, 84084 Fisciano (Salerno), Italy
Received 30 November 2006; accepted 18 December 2006
Available online 16 January 2007
Abstract—Chiral d-hydroxy-b-ketoesters are easily available through the enantioselective vinylogous aldol reaction of Chan’s diene
promoted by a SiCl4/chiral phosphoramide catalytic system. The procedure is conveniently exploited for a very rapid approach to
(+)-kavain, a natural bio-active a-pyrone compound.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
positive nonlinear effects allowed the attainment of chiral
aldols 2 in high yields and enantiomeric excesses (ees) by
using enantioenriched Ti(OiPr)4/BINOL catalysts.5
Over the last few years, the nucleophilic properties of
Chan’s diene 1,1 a synthetic equivalent of acetoacetate
dianion, have been widely exploited in a variety of
procedures for C–C bond formation, leading to d-hydroxy-
b-ketoesters, c-alkylidenebutenolides, 2-alkylidenetetra-
hydrofurans, functionalized cyclopent-2-en-1-ones, 6-methoxy-
bicyclo [4.3.0]non-9-en-8-ones, methyl 2-hydroxybenzoate,
tetraline derivatives, 4,5-benzotropones, oxabicyclo-
[3.2.1]octan-3-ones, anthraquinones, etc.2
More recently, our interest was focused on the reactivity of
silyloxydiene 1 in the presence of non-metallic catalysts and
SiCl4, a very poor Lewis acid, which proved to be capable
of promoting the conversion 1 ! 2 in very satisfactory
way, so that, for example, benzaldehyde, submitted to
treatment with 1 for 10 min in the presence of SiCl4
(1 equiv) in CH2Cl2 solution at ꢀ78 °C, afforded vinylo-
gous aldol 2a (R = –Ph) in >99% yield.6
Less nucleophilic reagents than silyloxydiene 1 (such as
silyl ketene acetals, enolsilanes, dioxanone-derived silyl
dienolate, amide-derived silyl enol ethers) have been
conveniently employed by Denmark in an impressive series
of procedures7 for highly enantioselective C–C bond for-
mation previa activation of SiCl4 with suitable chiral
ligands.
2. Results and discussion
Chiral aldols of type 2 (Scheme 1), key-intermediates in the
synthesis of important bio-active natural and unnatural
products,3 proved to be easily accessible through a highly
efficient and enantioselective modification of the original
Sato’s procedure, based on the use of Ti(OiPr)4/BINOL
complexes, as catalysts.4 Furthermore, the detection of
In particular, the SiCl4/(R,R)-3 system (Fig. 1) was recently
found to promote the vinylogous aldol reaction of linear
OH
O
OTMS OTMS
OMe
cat
+
RCHO
COOMe
Me
Me
N
N
R
O
P
O
P
1
2
N
N
Me
N
Me
N
Me
Scheme 1.
Me
(R,R)-3
*
Corresponding authors. Tel.: +39 089969583; fax: +39 089969603;
e-mail addresses: rvillano@unisa.it; scettri@unisa.it
Figure 1.
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.016

R. Villano et al. / Tetrahedron: Asymmetry 17 (2006) 3332–3334
3333
OR'
O
O
O
OMe
SiCl4/chiral activator, CH2Cl2
DIPEA, -78 °C, 10 min
1 +
RCHO
COOMe
K2CO3/MeOH
MW, 10 min
Me2SO4, acetone
r.t., 15 hrs
R
(R)-2b
2: R' = -H
4: R' = -SiMe3
Ph
O
Ph
O
(+)-6
O
5
(not isolated)
Scheme 2.
Scheme 3.
and cyclic silyloxydienes (deriving, respectively, from
unsaturated esters, ketones, amides and 2,2,6-trimethyl-
4H-[1,3-dioxin]-4-one)7j,k,m with complete c-selectivity,
high yields and moderate to high ees.
the benzaldehyde was converted into a mixture of 2a and
O-trimethylsilyl protected aldol 4a in very high overall
yield (97%) and satisfactory ee, especially in consideration
of the strongly competing background reaction. As already
reported in a previous paper, the deprotection of 4a to 2a
can be performed by acidic treatment with quantitative
yield and no loss of enantiomeric excess.
From a general point of view, the occurrence of a compet-
ing background reaction in a relevant way can represent a
serious disadvantage for the achievement of an enantio-
selective process. Nevertheless, an investigation was
devoted to verify the possibility of employment of SiCl4/
chiral activator systems, as catalysts in asymmetric reac-
tions of type 1 ! 2.
Other aromatic, heteroaromatic and a,b-unsaturated alde-
hydes were submitted to the same treatment as benzalde-
hyde in entry 4 (entries 5 and 7–9) and moderate to high
yields and ees were obtained. As shown in entry 6, an
attempt to enhance the level of enantioselectivity by using
greater amounts of chiral ligand (0.025 equiv) proved to
be unsuccessful, since aldol 2b was isolated in comparable
yield, but in lower ee (69%) than in entry 5.
Keeping in mind recent reports on related topics pointing
out the capability of achiral and chiral sulfoxides to
increase the catalytic properties of SiCl4, the reactivity of
a SiCl4/(R)-pTolSOMe system was examined.
In the preliminary phase, benzaldehyde was chosen as the
representative substrate and submitted to a reaction with
1 under the experimental conditions reported in Scheme 2
and Table 1. However, in spite of a rather satisfactory effi-
ciency, the vinylogous aldol 2a was isolated in racemic
form (entry 1). The same result was obtained by using a
reduced amount of SiCl4 in the attempt to limit the occur-
rence of the competing background reaction (entry 2).
Moreover, poor yields and ees were observed by perform-
ing the reaction in THF (entry 3).
However, the result obtained in entry 5 was exploited for a
new approach to (+)-kavain 6,10,11 a member of a family of
natural products isolated from the Kava plant, known as
kavalactones and characterized by anxiolitic and soporific
properties.
Through a convenient modification of a known proce-
dure,11 involving in the first step (Scheme 3) a very rapid
process of lactonization carried out under microwave
(MW) irradiation, (R)-2b (75% ee) was converted into the
easy enolizable ketolactone 5. Next, the typical enol-ether-
ification by Me2SO4 treatment on crude 5 afforded (+)-
kavain 6 with an unchanged ee (75% ee) in 75% overall yield
from (R)-2b and in only two steps from cinnamaldehyde.12
More interesting results were afforded by the activation of
SiCl4 with the chiral bis-phosphoramide 3: in fact, in the
presence of only 0.01 equiv of 3 (with respect to aldehyde),
Table 1. Enantioselective vinylogous aldol addition realized via Scheme 28
Entry
R
Activator
Product
Yielda (%)
eeb (%)
1c
2d
3e
4
5
6
7
8
9
Ph
Ph
Ph
Ph
(R)-pTolSOMe
(R)-pTolSOMe
(R)-pTolSOMe
(R,R)-3
(R,R)-3
(R,R)-3
(R,R)-3
(R,R)-3
(R,R)-3
2a
2a
2a
2a
2b
2b
2c
2d
2e
76 (ꢀ)
52 (ꢀ)
43 (ꢀ)
67 (30)f
60 (24)f
62 (26)f
61 (8)f
61 (ꢀ)
80 (ꢀ)
0
0
22
67
75
69
95
75
54
PhCH@CH
PhCH@CH
p-MeOC6H4
3-Furyl
2-Furyl
a All the yields refer to isolated chromatographically pure compounds, whose structures were confirmed by spectroscopic data. In all entries aldehyde/1/
SiCl4/chiral activator/DIPEA 1/1.2/1.1/0.01/1.1 ratios were used. The reaction was performed on 1 mmol of aldehyde.
b ees have been determined by chiral-phase HPLC analysis (CHIRALPAK AD, hexane/EtOH 95/5 + 0.1% TFA, 1 ml/min, k = 254 nm). The (R)-
configuration was assigned to all the aldols 2a–e by comparing the signs of specific rotation with the ones reported in the literature.4b,9
c The experiment was performed by using 0.20 equiv of chiral sulfoxide.
d Reaction conditions: aldehyde/1/SiCl4/chiral activator/DIPEA 1/1.2/0.2/0.2/0.2 ratios and 1 h/ꢀ78 °C.
e Reaction conditions: aldehyde/1/SiCl4/chiral activator/DIPEA 1/1.2/0.2/0.4/0.2 ratios, THF and 3 h/ꢀ78 °C.
f Values in parentheses refer to the yields of trimethylsilyl-derivatives of type 4.

3334
R. Villano et al. / Tetrahedron: Asymmetry 17 (2006) 3332–3334
T. J. Org. Chem. 1998, 63, 918–919; (d) Denmark, S. E.;
3. Conclusion
Stavenger, R. A.; Wong, K. T.; Su, X. J. Am. Chem. Soc.
1999, 121, 4982–4991; (e) Denmark, S. E.; Fujimori, S.
Synlett 2001, 1024–1029; (f) Denmark, S. E.; Fan, Y. J. Am.
Chem. Soc. 2002, 124, 4233–4235; (g) Denmark, S. E.; Wynn,
T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405–13407;
(h) Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3477–
3480; (i) Denmark, S. E.; Heemstra, J. R., Jr. Org. Lett. 2003,
5, 2303–2306; (j) Denmark, S. E.; Beutner, G. L. J. Am.
Chem. Soc. 2003, 125, 7800–7801; (k) Denmark, S. E.;
Heemstra, J. R., Jr. Synlett 2004, 13, 2411–2416; (l)
Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682–4698; (m) Denmark, S. E.;
Heemstra, J. R., Jr. J. Am. Chem. Soc. 2006, 128, 1038–1039;
(n) Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.;
Wong, K. T.; Nishigaichi, Y. J. Org. Chem. 2006, 71, 3904–
3922.
In conclusion, in spite of the high reactivity of Chan’s diene
in aldol-type reactions promoted by SiCl4, the appropriate
combination of SiCl4/chiral phosphoramide proved to be
important for the achievement of an enantioselective
approach to vinylogous aldols 2 in good yields and moder-
ate to high ees.
By this procedure, a completely transition metal-free syn-
thetic sequence allowed the rapid and convenient access
to (+)-kavain, a bio-active natural product belonging to
a family of a-pyrone derivatives.
Acknowledgement
8. General procedure for the preparation of compounds 2 (Table
1): In a dry round bottom flask, a solution of ligand (R,R)-3
(0.01 mmol) in CH2Cl2 (3 ml) was prepared. This solution
was cooled at ꢀ78 °C and after 10 min DIPEA (1.1 mmol),
aldehyde (1 mmol), SiCl4 (1.1 mmol) and a solution of diene 1
(1.2 mmol) in CH2Cl2 (1 ml) were added dropwise. The
resulting mixture was stirred for 10 min at ꢀ78 °C, then it was
neutralized by the addition of saturated aq NaHCO3. The
reaction mixture was extracted with CH2Cl2 and the com-
bined organic phase dried over MgSO4 and concentrated. The
residue was purified by non-flash chromatography (CHCl3/
Et2O 9/1) to give products 2. The silylated aldol, when
present, was subjected to deprotection by treatment with
TFA at ꢀ78 °C according to Carreira’s procedure.13
9. Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169–2186.
10. (a) Friese, J.; Gleitz, J. Planta Med. 1998, 64, 458–459; (b)
Wang, F.-D.; Yue, J.-M. Synlett 2005, 2077–2079.
11. For enantioselective synthesis of (+)-kavain, see: (a) Smith,
T. E.; Djang, M.; Velander, A. J.; Downey, C. W.; Carroll, K.
A.; Alphen, S. V. Org. Lett. 2004, 6, 2317–2323; (b) Wang,
F.-D.; Yue, J.-M. Synlett 2005, 13, 2077–2079; (c) Sabitha,
G.; Sudhakar, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47,
8599–8602.
12. General procedure for the preparation of (+)-kavain: Aldol
(R)-2b (0.4 mmol, ee = 75%), K2CO3 (0.8 mmol) and MeOH
(2 ml) were placed in an ACE pressure tube and submitted to
MW-irradiation in a kitchen oven for 10 min. Then, the
mixture was diluted with acetone (2 ml) and Me2SO4
(0.8 mmol) was added. The suspension was stirred overnight.
The reaction mixture was neutralized by the addition of 1 M
HCl and extracted with AcOEt. The combined organic phase
was dried over MgSO4 and concentrated. The residue was
purified by non-flash chromatography (petroleum ether/
AcOEt 1/1) to give product (+)-6 (whose structure was
confirmed by spectroscopic data) with unchanged ee (75% ee)
in 75% overall yield from (R)-2b.
We are grateful to MIUR for financial support.
References
1. Chan, T. H.; Brownbridge, P. J. Chem. Soc., Chem. Commun.
1979, 578–579.
2. For recent reviews, see: (a) Langer, P. Chem. Eur. J. 2001, 7,
3858–3866; (b) Langer, P. Synthesis 2002, 4, 441–459; (c)
Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A. Curr. Org.
Chem. 2004, 8, 993–1007.
3. (a) Hagiwara, H.; Kon-no, M.; Uda, H. J. Chem. Soc., Chem.
Commun. 1992, 866–868; (b) Hagiwara, H.; Kimura, K.; Uda,
H. J. Chem. Soc., Perkin Trans. 1992, 693–700; (c) Evans, D.
A.; Black, W. C. J. Am. Chem. Soc. 1992, 114, 2260–2262; (d)
Enders, D.; Burkamp, F.; Runsink, J. J. Chem. Commun.
1996, 609–610; (e) Lattman, E.; Coombs, J.; Hoffmann, H.
M. R. Synthesis 1996, 171–177; (f) Evans, D. A.; Carter, P.
H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens,
M. Angew. Chem., Int. Ed. 1998, 37, 2354–2359; (g) Soriente,
A.; De Rosa, M.; Apicella, A.; Scettri, A.; Sodano, G.
Tetrahedron: Asymmetry 1999, 10, 4481–4484.
4. (a) Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A.
Tetrahedron: Asymmetry 2000, 11, 2255–2258; (b) Soriente,
A.; De Rosa, M.; Stanzione, M.; Villano, R.; Scettri, A.
Tetrahedron: Asymmetry 2001, 12, 959–963.
5. (a) Villano, R.; De Rosa, M.; Salerno, C.; Soriente, A.;
Scettri, A. Tetrahedron: Asymmetry 2002, 13, 1949–1952; (b)
Villano, R.; Acocella, M. R.; De Rosa, M.; Soriente, A.;
Scettri, A. Tetrahedron: Asymmetry 2004, 15, 2421–2424.
6. Acocella, M. R.; De Rosa, M.; Massa, A.; Palombi, L.;
Villano, R.; Scettri, A. Tetrahedron 2005, 61, 4091–4097.
7. (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K. T. J.
Am. Chem. Soc. 1996, 118, 7404–7405; (b) Denmark, S. E.;
Wong, K. T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119,
2333–2334; (c) Denmark, S. E.; Stavenger, R. A.; Wong, K.
13. Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837–
838.