Enantioselective aldol condensation of O-silyldienolates derived from alkyl-substituted 2,2-dimethyl-[1,3]-dioxin-4-ones

Article abstract of DOI:10.1016/j.tetasy.2004.07.020

Vinylogous aldol condensation of masked alkylated acetoacetates proceeds with good to excellent yields and enantiomeric excesses in the presence of a chiral Ti(O-i-Pr)₄/BINOL complex. The presence of positive nonlinear effects are also pointed out.

Full text of DOI:10.1016/j.tetasy.2004.07.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3029–3033
Enantioselective aldol condensation of O-silyldienolates
derived from alkyl-substituted 2,2-dimethyl-[1,3]-dioxin-4-ones
Margherita De Rosa, Maria R. Acocella, Michele F. Rega and Arrigo Scettri*
`
Dipartimento di Chimica, Universita di Salerno, 84081, Baronissi (Salerno), Italy
Received 27 May 2004; revised 21 July 2004; accepted 23 July 2004
Available online 15 September 2004
Abstract—Vinylogous aldol condensation of masked alkylated acetoacetates proceeds with good to excellent yields and enantio-
meric excesses in the presence of a chiral Ti(O-i-Pr)4/BINOL complex. The presence of positive nonlinear effects are also pointed out.
Ó 2004 Elsevier Ltd. All rights reserved.
1.Introduction
functionality proceeds in high yields and enantiomeric
excesses (eeÕs) in the presence of reduced amounts of a
chiral Cu(II)/pybox complex,3a while a more general,
highly enantioselective procedure is based on the use
of (R)- or (S)-Tol-BINAP/Cu(OTf)2/n-Bu4NPh3SiF2
system (2mol%),3c,d although in this latter case, a poor
efficiency is usually observed with aliphatic aldehydes.
Furthermore, very good yields and eeÕs have been ob-
tained by performing the aldol reaction of 1a in the pres-
ence of Ti(IV)/BINOL4 and Ti(IV)/Schiff base4b
complexes.
Asymmetric Mukaiyama aldol condensation of dienol-
silyl ethers of type 1 (Scheme 1) represents one of the
most useful approaches for the stereoselective synthesis
of C-5 polyfunctional subunits 3, key-intermediates in
the preparation of bioactive compounds.1
O
O
OH
O
O
OH
O
O
cat.
R
OR3
OSiMe3
R
O
RCHO
R1 R2
R1 R2
R1 R2
Finally, a very recent report concerning the employment
of a chiral Cr(Salen) complex,5 which is particularly effi-
cient in the promotion of the asymmetric aldol reaction
on aliphatic aldehydes, while a quite different approach
involves the use of a chiral bis-phosphoramide, as neu-
tral coordinate organo-catalyst, in a SiCl4-catalyzed
process.6
2
3
1
a: R1=R2=H
b: R1=Me; R2=H
c: R1=H; R2=Me
Scheme 1.
The conversion 1a ! 2a usually takes place under chiral
Lewis acid catalysis with the most relevant results being
obtained by using chiral B(III),2 Cu(II)3 and Ti(IV)4
catalysts.
In spite of this interest, it should be noted that the reac-
tivity of silyloxydienes of type 1b and 1c (Scheme 1),
bearing a substituent at the 5 or 6 positions, has scarcely
been explored, although their successful employment
could have allowed an easy access to branched polyols.
So, for example, a chiral tartaric acid-derived acyl bor-
ane (CAB) proved to be capable of promoting the for-
mation of aldols of type 2a: however, high catalyst
loadings (50–100mol%) were required to reach only
moderate levels of efficiency and enantioselectivity. An
aldol reaction of 1a on aldehydes bearing a suitable
chelating substituent at the a-position to the carbonyl
Taking advantage of the results of an intense investiga-
tion on SatoÕs protocol,4a based on the use of a Ti(O-i-
Pr)4/BINOL complex, we have achieved a significantly
improved catalytic procedure for the conversion of
1a ! 2a. Furthermore, we have clarified some interest-
ing mechanistic aspects, such as the presence of positive
nonlinear effects (NLE)7 and the involvement of an
auto-inductive process.4h
*
Corresponding author. Tel.: +39 089 965374; fax: +39 089 965296;
e-mail: scettri@unisa.it
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.020

3030
M. De Rosa et al. / Tetrahedron: Asymmetry 15 (2004) 3029–3033
Consequently, we have decided to verify the possibility
of extending our procedure (optimized for silyloxydiene
1a) to 5- and 6-substituted derivatives of type 1b and 1c.
viously prepared in more concentrated solution (see
Table 1, footnote e). In fact lower yields and eeÕs were
observed so that anti-2b could be isolated in its almost
completely racemic form.
2.Results and discussion
Since positive nonlinear effects (NLE) have been de-
tected in several processes promoted by Ti(IV)/BINOL
complexes,7b,10 benzaldehyde, chosen as the representa-
tive substrate, was submitted to reaction with 1b in the
presence of an enantiomerically enriched Ti(O-i-Pr)4/BI-
NOL system under the standard conditions while the
presence of a positive NLE was observed for both syn-
and anti-2b (Fig. 1).
Compound 1b, easily accessible starting from 6-ethyl-
2,2-dimethyl-dioxin-4-one as an inseparable mixture of
E and Z geometrical isomers (E/Z = 3:5), was chosen
as representative of silyloxydiene and submitted to aldol
reaction in the presence of catalytic amounts of Ti(O-i-
Pr)4/(R)-BINOL complex (8mol%) under the typical
conditions of the catalytic conversion 1a ! 2a (Scheme
2).
100
80
Aldol condensation was shown to take place in good
yields with aromatic, heteroaromatic and unsaturated
aldehydes to afford, after in situdesilylation at À78°C,
a syn/anti diastereoisomeric mixture, with the syn-aldol
2b being the major product (Table 1, entries 1–4). A
much lower efficiency was observed with aliphatic
aldehydes.
60
40
In entries 1–4, however, the syn-aldols were obtained in
very good enantiomeric excesses, while the formation of
anti-aldols were shown to occur with a reduced level of
enantioselectivity. This stereochemical outcome is in
agreement with a preliminary result, reported previously
by Sato et al.,4a concerning the aldol condensation of 1b
with benzaldehyde.
20
(+)-NLE syn -2b
(+)-NLE anti -2b
0
0
20
40
60
80
100
ee BINOL
The strong well-documented dependence of the catalytic
properties of Ti(IV)/BINOL complex on the experimen-
tal conditions, especially with regards to the concentra-
tion8 and the mode of preparation of the catalyst,9 is
confirmed in entry 5, using the same procedure as in en-
try 1 but with the exception of the use of a catalyst pre-
Figure 1.
The degree of the asymmetric amplification proved once
again to be strongly influenced by the mode of catalyst
preparation: in fact, when the aldol condensation was
1) Ti(OiPr)4/(R)-BINOL
OH
O
O
O
O
OH
O
O
+ RCHO
+
2) CF3COOH
R
O
OSiMe3
R
O
Me
anti-2b
Me
Me
syn-2b
E/Z=3/5
1b
Scheme 2.
Table 1. Ti(O-i-Pr)4/(R)-BINOL-catalyzed aldol reaction of 1b
Entry
R
2
Yield (%)a
syn/antib
syn Ee (%)c,d
anti Ee (%)c,d
1
Ph–
2ba
2bb
2bc
2bd
2ba
75
81
98
26
68
80:20
85:15
85:15
87:13
79:21
94
86
94
99
89
42
16
56
54
ꢀ0
2
PhCH@CH–
2-Furyl–
Ph–CH2CH2–
Ph–
3
4
5e
a All the yields refer to isolated chromatographically pure compounds.
b The relative configurations and diastereomeric ratios were determined by 1H NMR analysis.
c EeÕs were determined by HPLC analysis using a CHIRALPAK AD column.
d The absolute configuration in Scheme 2 was established by comparison of the specific rotation to literature values4 for 2ba or by conversion to the
corresponding MTPA esters for 2bc. The absolute configurations of products 2bb and 2bd have been assigned (see Section 4) by assuming the same
asymmetric induction by Ti(O-i-Pr)4/(R)-BINOL complex as in entries 1 and 3.
e The catalytic system was initially prepared in 1mL. The final volume of the reaction was 6mL.

M. De Rosa et al. / Tetrahedron: Asymmetry 15 (2004) 3029–3033
3031
carried out by employing enantioenriched catalysts pre-
viously prepared in concentrated solutions (according
the procedure depicted in Table 1, entry 5) a very poor
deviation from linearity was observed until a value of
35% ee was reached for (R)-BINOL, after which a pos-
itive NLE could be again detected until enantiopure (R)-
BINOL was used (Fig. 2).
the final concentration of the catalyst and the reagents,
the corresponding aldol was obtained in a very poor
yield (14%) and high ee (>99%). A more satisfactory
preparative result (57% yield) was obtained by reducing
drastically the overall solvent volume (entry 3), although
a not neglectable decrease of the level of enantioselectiv-
ity (84% ee) was observed.
The same procedure has afforded promising results with
other aromatic and heteroaromatic aldehydes (entries 4–
6), while in the case of aliphatic aldehydes (entry 7),
aldol condensation showed to proceed in low yield and
good ee.
100
80
60
3.Conclusions
Through an appropriate choice of experimental condi-
tions, the aldol condensation of O-silyldienolates
derived from masked alkylated acetoacetates 1b and 1c
took place in the presence of a chiral Ti(O-i-Pr)4/BINOL
complex to afford the corresponding aldols with very
satisfactory efficiency and enantioselectivity. In the case
of 1b the reaction proceeded in good diastereoselectivity
affording syn-aldols 2b as the far more predominant dia-
stereoisomers. Furthermore, experiments performed in
the presence of enantioenriched catalytic species pointed
out the presence of a positive NLE, whose size was
found to strongly depend on the mode of the catalyst
preparation.
40
(+)-NLE syn- 2b
20
0
0
20
40
ee BINOL
60
80
100
Figure 2.
Successively, the reactivity of silyloxydiene 1c (easily
accessible from t-butyl 2-methyl-3-oxo-butanoate)4a,11
was investigated and, rather surprisingly, the optimized
procedure for unsubstituted derivatives 1a was found to
be completely unsuccessful in the first attempt of an
aldol condensation on benzaldehyde (Table 2, entry 1).
4.Experimental
4.1. General methods
Table 2. Ti(O-i-Pr)4/(R)-BINOL-catalyzed aldol reaction of 1cd
All reactions were performed using oven dried glassware
under an atmosphere of dry nitrogen. Tetrahydrofuran
(THF) was distilled from CaH2 and then from LiAlH4.
i-Pr2NH was freshly distilled from CaH2. 1H NMR and
13C NMR spectra were recorded in solutions of CDCl3
with Bruker DRX 400 (400.135MHz for 1H and
Entry
R
2
Yield (%)a
Ee (%)b,c
1
2
3
4
5
6
7
8
Ph–
Ph–
2ca
2ca
2ca
2cb
2cc
2cd
2ce
2cf
––
14
57
74
62
76
21
62
––
>99
84
Ph–
p-NO2C6H4–
2-Furyl–
p-CNC6H4–
Ph–CH2CH2–
p-OMeC6H4–
66
71
1
100.03MHz for 13C) spectrometers. Data for H are re-
>99
72
ported as follows: chemical shift (d in ppm), multiplicity
(s singlet, d doublet, t triplet, dd doublet of doublets, m
multiplet) and coupling constant (J in Hz). Optical rota-
tions were measured on a JASCO DIP-1000 polarimeter
operating at the sodium D line at room temperature.
Concentration is given in g/100mL. The mass spectra
were recorded on a VG TRIO 2000 spectrometer. Col-
umn chromatographic purification of products was car-
ried out using Silica gel 60 (70–230mesh, Merck). HPLC
analyses were performed with Waters Associates equip-
ment and a Hewlett–Packard SP4400 Chromojet inte-
grator using a CHIRALPAK AD column with solvent
mixtures of hexane/isopropanol and flow rates as
indicated.
22
a All the yields refer to isolated chromatographically pure compounds.
b EeÕs were determined by HPLC analysis using a CHIRALPAK AD
column.
c Absolute configuration of 2ca was established as R by conversion to
the corresponding MTPA esters. The absolute configurations of
products 2cb–cf have been assigned (see Section 4) by assuming the
same asymmetric induction by Ti(IV)/(R)-BINOL complex as in
entries 2–3.
d The catalytic system was initially prepared in 5mL of THF (entry 1)
or in 0.5mL of THF (entries 2–8). The final volume of the reaction
was 6mL in entries 1 and 2, while it was 1mL in entries 3–8.
Reagents and catalyst concentration proved once again
to be an important factor both for the efficiency and
enantioselectivity of the process. In fact, when the cata-
lytic system was prepared in very concentrated solution
(Table 2, entry 2) and the reaction performed under the
same conditions used in entry 1 (Table 2), in regards to
4.2. General procedure for the enantioselective dienolates
1b and 1c addition to aldehydes
A
mixture of (R)-(+)-1,10-bi-2-naphthol (23mg,
0.08mmol), titanium tetraisopropoxide (24lL,

3032
M. De Rosa et al. / Tetrahedron: Asymmetry 15 (2004) 3029–3033
˚
0.08mmol) and molecular sieves 3A (350mg) in THF
(5mL for 1b, 0.5mL for 1c) was stirred at room temper-
ature under an inert atmosphere for 1h to yield a red-
brown solution. The mixture was cooled to À78°C
and the aldehyde (1mmol) added dropwise followed,
after 20min, by a solution of the dioxinone derivative
dienolate (2mmol) in THF (1mL for 1b, 0.5mL for
1c). The whole mixture was then stirred at À78°C for
2h and then at rt for 16h. After cooling the mixture at
À78°C, TFA (0.4mL) was added and the solution
warmed to rt stirring for 1h. A saturated aqueous solu-
tion of NaHCO3 was added until the evolution of gas
ceased. After stirring for 30min, it was extracted with
Et2O. The organic layer was washed with brine, dried
over MgSO4 and concentrated in vacuo. Purification
by chromatography on silica gel using 9:1 CHCl3/Et2O
afforded the aldol adducts.
4.2.4. 6-((1R,2R)-2-Furan-2-yl-2-hydroxy-1-methyl-eth-
yl)-2,2-dimethyl-[1,3]dioxin-4-one syn-2bc. [Found: C
61.77; H 6.50; C13H16O5 requires C, 61.90; H, 6.39%];
25
½aŠ ¼ À2:8 (c 1.0, CHCl3), ee 94% determined by
D
HPLC analysis (hexane/isopropanol 95:5, 0.8mL/min,
major enantiomer 26.63min, minor enantiomer
36.01min; dH (400MHz, CDCl3) 7.37 (d, 1H,
J = 1.5Hz), 6.33 (t, 1H, J = 3.1Hz), 6.28 (d, 1H,
J = 3.2Hz), 5.25 (s, 1H), 4.83 (d, 1H, J = 6.8Hz), 2.87
(m, 1H), 1.48 (s, 3H), 1.60 (s, 3H), 1.26 (d, 3H,
J = 5.0Hz); dC (100.03MHz, CDCl3) 172.5, 161.7,
154.5, 142.4, 110.5, 107.5, 106.7, 94.0, 68.9, 43.5, 25.1,
12.9; m/z (EIMS) 252 (M+).
4.2.5. 6-((1S,2R)-2-Furan-2-yl-2-hydroxy-1-methyl-eth-
yl)-2,2-dimethyl-[1,3]dioxin-4-one anti-2bc. [Found: C
61.81; H 6.47; C13H16O5 requires C, 61.90; H, 6.39%];
25
½aŠ ¼ þ27:2 (c 1.0, CHCl3), ee 56% determined by
D
4.2.1. 6-((1R,2R)-2-Hydroxy-1-methyl-2-phenyl-ethyl)-
2,2-dimethyl-[1,3]dioxin-4-one syn-2ba and 6-((1S,2R)-2-
hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-[1,3]di-
oxin-4-one anti-2ba. The physical and spectroscopic
data of compounds 2ba match those described in
literature.4a
HPLC analysis (hexane/isopropanol 95:5, 0.8mL/min,
major enantiomer 31.62min, minor enantiomer
36.01min); dH (400MHz, CDCl3) 7.40 (s, 1H); 6.35 (s,
1H), 6.32 (d, 1H, J = 3.8Hz), 5.36 (s, 1H), 4.71 (d, 1H,
J = 11.7Hz), 2.88 (m, 1H), 1.43 (s, 3H), 1.25 (s, 3H),
1.00 (d, 3H, J = 9.36Hz); dC (100.03MHz, CDCl3)
173.0, 162.0, 154.3, 142.4, 110.5, 107.8, 106.9, 93.9,
69.0, 44.5, 24.8, 13.3; m/z (EIMS) 252 (M+).
25
Compound syn-2ba: ½aŠ ¼ À10:5 (c 1.0, CHCl3), ee
D
96% (R) determined by HPLC analysis (CHIRAL-
PACK AD column, hexane/isopropanol 9:1, 0.5mL/
min, (R)-enantiomer 21.51min, (S) enantiomer
4.2.6. 6-((1R,2S)-2-Hydroxy-1-methyl-4-phenyl-butyl)-
2,2-dimethyl-[1,3]dioxin-4-one syn-2bd and 6-((1S,2S)-2-
hydroxy-1-methyl-4-phenyl-butyl)-2,2-dimethyl-[1,3]di-
oxin-4-one anti-2bd. The diastereoisomers are recov-
ered as an inseparable mixture after the usual purifica-
tion on silica gel column; [Found: C 70.45; H 7.73;
C17H22O4 requires C, 70.33; H, 7.64%]; dH (400MHz,
CDCl3) 7.31–7.18 (m, 10H), 5.30 (s, 1H, anti-2bd),
5.28 (s, 1H, syn-2bd), 3.75–3.79 (m, 1H, syn-2bd),
3.70–3.66 (m, 1H, anti-2bd), 2.86–2.79 (m, 2H), 2.72–
2.66 (m, 2H), 2.36–2.40 (m, 2H), 1.83–1.78 (m, 4H),
1.65 (s, 6H), 1.61 (s, 6H), 1.16 (d, 3H, J = 9.3Hz), 1.15
(d, 3H, J = 8.6Hz); dC (100.03MHz, CDCl3) 173.8,
161.7, 141.6, 129.26, 128.6, 128.4, 127.9, 126.2, 106.6,
93.6, 93.0, 72.0, 71.5, 44.1, 36.9, 32.5, 25.3, 24.6, 11.5;
m/z (EIMS) 290 (M+).
25
D
33.45min; anti-2ba: ½aŠ ¼ þ19:6 (c 0.6, CHCl3), ee
40% determined by HPLC analysis (CHIRAL-
PACK AD column, hexane/isopropanol 9:1, 0.5mL/
min, (R) enantiomer 29.27min, (S) enantiomer
35.78min.
4.2.2. 6-((E)-(1R,2S)-2-Hydroxy-1-methyl-4-phenyl-but-
3-enyl)]-2,2-dimethyl-[1,3]dioxin-4-one syn-2bb. [Found:
C, 70.95; H, 7.06; C17H20O4 requires C, 70.81; H,
25
6.99%]; ½aŠ ¼ À13:2 (c 0.6, CHCl3), ee 86% determined
D
by HPLC analysis (hexane/isopropanol 9:1, 0.8mL/min,
major enantiomer 19.46min, minor enantiomer 24.52
min; dH (400MHz, CDCl3) 7.36–7.24 (m, 5H), 6.63 (d,
1H, J = 15.8Hz), 6.19 (dd, 1H, J = 6.6, 15.8Hz), 5.34
(s, 1H), 4.44 (t, 1H, J = 5.8Hz), 2.55 (m, 1H), 1.66 (s,
3H), 1.65 (s, 3H), 1.22 (d, 3H, J = 7.0); dC
(100.03MHz, CDCl3) 172.8, 161.5, 136.3, 132.3, 129.2,
128.3, 126.7, 106.7, 94.2, 73.7, 44.4, 25.6, 25.0, 12.3;
m/z (EIMS) 288 (M+).
4.2.7. 6-((R)-2-Hydroxy-2-phenyl-ethyl)-2,2,5-trimethyl-
[1,3]dioxin-4-one 2ca. The physical and spectroscopic
data of compounds 2ca match those described in
literature.4f
4.2.3. 6-((E)-(1S,2S)-2-Hydroxy-1-methyl-4-phenyl-but-
3-enyl)-2,2-dimethyl-[1,3]dioxin-4-one
25
½aŠ ¼ þ25:8 (c 1.3, CHCl3), ee 84% (R), HPLC analysis
D
anti-2bb. The
(hexane/isopropanol 90:10, 0.8mL/min, minor enantio-
mer 11.82min, major enantiomer 12.95min.
aldol anti-2bb could not be isolated as a pure compound
but in mixture with syn-2bb; ee 16% determined by
HPLC analysis (hexane/isopropanol 9:1, 0.8mL/min,
major enantiomer 24.52min, minor enantiomer
32.10min); dH (400MHz, CDCl3) 7.39–7.24 (m, 5H),
6.63 (d, 1H, J = 15.8Hz), 6.16 (dd, 1H, J = 7.3,
15.7Hz), 5.36 (s, 1H), 4.34 (t, 1H, J = 7.5Hz), 2.55 (m,
1H), 1.65 (s, 6H), 1.16 (d, 3H, J = 7.2); dC
(100.03MHz, CDCl3) 173.5, 161.9, 136.2, 132.6, 129.4,
128.9, 127.9, 126.6, 106.7, 94.7, 74.2, 44.8, 25.2, 24.1,
13.4; m/z (EIMS) 288 (M+).
4.2.8. 6-[(R)-2-(4-Nitro-phenyl)-2-hydroxy-ethyl]-2,2,5-
trimethyl-[1,3]dioxin-4-one 2cb. The physical and
spectroscopic data of compounds 2cb match those de-
scribed in literature.4f
25
½aŠ ¼ þ33:6 (c 0.3, CHCl3), ee 66% (R), HPLC analysis
D
(hexane/isopropanol 95:5, 0.8mL/min, minor enantio-
mer 59.16min, major enantiomer 62.37min.

M. De Rosa et al. / Tetrahedron: Asymmetry 15 (2004) 3029–3033
3033
4.2.9.
methyl-[1,3]dioxin-4-one 2cc. [Found:
6-((R)-2-Furan-2-yl-2-hydroxy-ethyl)-2,2,5-tri-
61.77;
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H
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D
(hexane/isopropanol 90:10, 0.5mL/min, minor enantio-
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1
mer 22.92min, major enantiomer 22.44min); H NMR
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(m, 1H), 2.85 (dd, 1H, J = 14.1, 7.9Hz), 2.74 (dd, 1H,
J = 14.2, 6.1Hz), 1.72 (s, 3H), 1.57 (s, 3H), 1.52 (s,
3H); 13C NMR (CDCl3) d 162.78, 161.72, 155.05,
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25.05, 24.76, 9.93; m/z (EIMS) 252 (M+).
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[1,3]dioxin-4-yl)-ethyl]-benzonitrile 2cd. [Found:
C
67.01; 6.07; 5.01; C16H17NO4 requires C,
H
N
25
D
ee >99% (R) determined by HPLC analysis (hexane/
66.89; H, 5.96; N 4.88%]; ½aŠ ¼ þ25:9 (c 1.3, CHCl3),
isopropanol 90:10, 0.8mL/min, only enantiomer
21.52min; 1H NMR (CDCl3)
Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120,
¨
837; (d) Pagenkopf, B. L.; Kruger, J.; Stojianovic, A.;
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d
7.67 (d, 2H,
J = 8.2Hz), 7.52 (d, 2H, J = 8.1Hz), 5.08 (m, 1H), 2.85
(dd, 1H, J = 14.3, 8.9Hz), 2.59 (dd, 1H, J = 14.4,
4.4Hz), 1.78 (s, 3H), 1.66 (s, 6H); 13C NMR (CDCl3)
d 162.95, 161.99, 149.10, 132.39, 126.57, 118.75,
111.36, 105.22, 102.73, 70.58, 40.61, 25.66, 24.59,
10.28; m/z (EIMS) 287 (M+).
Carreira, E. M. Angew. Chem., Int. Ed. 1998, 37, 3124.
4. (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Hetero-
cycles 1995, 41, 1435; (b) Singer, R. A.; Carreira, E. M. J.
Am. Chem. Soc. 1995, 117, 12360; (c) Soriente, A.;
DeRosa, M.; Dovinola, P.; Sodano, G.; Scettri, A.
Tetrahedron: Asymmetry 1998, 9, 2197; (d) De Rosa, M.;
DellÕAglio, R.; Soriente, A.; Scettri, A. Tetrahedron:
Asymmetry 1999, 10, 3659; (e) DeRosa, M.; Soriente, A.;
Sodano, G.; Scettri, A. Tetrahedron 2000, 56, 2095; (f)
DeRosa, M.; Soriente, A.; Scettri, A. Tetrahedron: Asym-
metry 2000, 11, 3187; (g) Soriente, A.; DeRosa, M.;
Apicella, A.; Scettri, A.; Sodano, G. Tetrahedron: Asym-
metry 1999, 10, 4481; (h) DeRosa, M.; Acocella, M. R.;
Villano, R.; Soriente, A.; Scettri, A. Tetrahedron: Asym-
metry 2003, 14, 2499.
5. Shimada, Y.; Matsuoka, Y.; Irie, R.; Katsuki, T. Synlett
2004, 57.
6. Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003,
125, 7800.
7. Recent reviews: (a) Jacobsen, E. N.; Pfaltz, A.; Yama-
moto, H. Comprehensive Asymmetric Catalysis I–III;
Sprinter: Berlin, 1999; (b) Girard, C.; Kagan, H. Angew.
Chem., Int. Ed. 1998, 37, 2922; (c) Guillaneux, D.; Zhao,
S. H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am.
Chem. Soc. 1994, 116, 9430; (d) Avalos, M.; Babiano, R.;
4.2.11. 6-((S)-2-Hydroxy-4-phenyl-butyl)-2,2,5-trimethyl-
[1,3]dioxin-4-one 2ce. [Found:
C 70.19; H 7.71;
25
D
1.2, CHCl3), ee 72% (S) determined by HPLC analysis
C17H22O4 requires C, 70.32; H, 7.64%]; ½aŠ ¼ þ3:0 (c
(hexane/isopropanol 95:5, 0.8mL/min, minor enantio-
mer 24.63min, major enantiomer 26.02min); H NMR
1
(CDCl3) d 7.17–7.29 (m, 5H), 3.93 (m, 1H), 2.81 (m,
1H), 2.69 (m, 1H), 2.52 (dd, 1H, J = 14.1, 8.1Hz), 2.41
(dd, 1H, J = 14.1, 4.2Hz), 1.82 (s, 3H), 1.62 (s, 3H),
1.6 (s, 3H); 13C NMR (CDCl3) d 163.22, 162.91,
141.61, 128.58, 128.50, 126.13, 105.04, 102.26, 68.81,
39.16, 39.08, 32.01, 25.33, 25.07, 10.49, m/z (EIMS)
290 (M+).
4.2.12. 6-[(R)-2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-
2,2,5-trimethyl-[1,3]dioxin-4-one 2cf. [Found: C 65.61;
H 6.98; C16H20O5 requires C, 65.74; H, 6.90%];
´
Cintas, P.; Jemenez, J. L.; Palacios, J. C. Tetrahedron:
25
Asymmetry 1997, 8, 2997; (e) Kagan, H. B. Synlett 2001,
22, 888.
½aŠ ¼ þ5:2 (c 1.1, CHCl3), ee 22% (R) determined by
D
HPLC analysis (hexane/isopropanol 90:10, 0.8mL/min,
minor enantiomer 22.47min, major enantiomer
8. (a) Mikami, K.; Terada, M. Tetrahedron 1992, 48, 5671;
(b) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc.
1995, 117, 2363; (c) Wang, B.; Feng, X.; Huang, Y.; Liu,
H.; Cui, X.; Jiang, Y. J. Org. Chem. 2002, 67, 2175.
9. (a) Iwasawa, N.; Hayashi, Y.; Sakurai, H.; Narasaka, K.
Chem. Lett. 1989, 22, 1581; (b) Keck, G. E.; Krishnamur-
thy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543; (c)
Brunel, J. M.; Luukas, T. O.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 1941.
10. Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.;
Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000, 112,
3532.
11. Grunwell, J. R.; Karapides, A.; Wigal, C. T.; Heinzman,
S. W.; Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.;
Daffner, M.; Stevens, J. J. Org. Chem. 1991, 56, 91.
24.25min); 1H NMR (CDCl3)
d 7.29 (d, 2H,
J = 8.6Hz), 6.89 (d, 2H, J = 8.6Hz), 4.94 (m, 1H), 3.81
(s, 3H), 2.83 (dd, 1H, J = 14.1, 8.3Hz), 2.61 (dd, 1H,
J = 14.2, 5.3Hz), 1.76 (s, 3H), 1.62 (s, 6H); 13C NMR
(CDCl3) d 162.96, 162.63, 159.43, 135.41, 127.12,
113.97, 105.03, 102.26, 71.2, 55.35, 40.57, 25.58, 24.69,
10.20; m/z (EIMS) 292 (M+).
Acknowledgements
We thank MIUR for financial support.