Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic acid enolate and α,β-enones

Article abstract of DOI:10.1016/j.tet.2006.07.036

An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalal

Full text of DOI:10.1016/j.tet.2006.07.036

Tetrahedron 62 (2006) 9174–9182
Enantioselective synthesis of 2-substituted-1,4-diketones
from (S)-mandelic acid enolate and a,b-enones
a
Gonzalo Blay, Isabel Fernandez, Belen Monje, M. Carmen Munoz,
a
a
b
ꢀ
Jose R. Pedro and Carlos Vila
˜
a,
a
*
ꢀ
a
´
ꢁ
´
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia,
ꢁ
Dr. Moliner, 50, E-46100 Burjassot, Valeꢁncia, Spain
b
´
Departamento de Fısica Aplicada, Universidad Politecnica de Valencia, E-46071 Valeꢁncia, Spain
´
Received 15 June 2006; revised 10 July 2006; accepted 11 July 2006
Available online 31 July 2006
Abstract—An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic acid and a,b-enones has been
developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with
a,b-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereo-
selectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction
mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to
explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding a-hydroxy acids (in hemiacetal
form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me2opba complex as catalyst give chiral
2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic acid acts as an umpoled chiral
equivalent of the benzoyl anion.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
1,4-dicarbonyl compounds has not been studied thoroughly.9
During the last years, we have reported the use of different
mandelic acid derivatives as umpoled masked d1-synthons
for the nucleophilic benzoylation of alkyl and aryl halides
to give aryl alkyl ketones10 and nitrobenzophenones, respec-
tively.11 In both syntheses, the key step is the aerobic
oxidative decarboxylation of an a-hydroxy acid, which is
carried out with oxygen in the presence of pivalaldehyde
and a Co(III) complex as catalyst. In this paper we described
a highly diastereoselective addition of (S)-(+)-mandelic
acid enolate to a,b-enones and the transformation of the
resulting adducts into chiral non-racemic 2-substituted-1,4-
diketones.12 This strategy, based on the Seebach principle
of self-regeneration of stereocenters,13 formally involves
the use of (S)-mandelic acid as a source of the benzoyl anion
and also as a source of chiral information. Similar Michael
additions to ethyl crotonate14 and cyclopentenone15 have
been reported previously.
1,4-Diketones are important and valuable precursors for the
synthesis of substituted cyclopentenones,1 such as jasmones,
cuparenones, and prostaglandins, and for the synthesis of
five-membered heterocyclic compounds.2 Althoughavariety
of synthetic methods have been developed for the prepara-
tion of 1,4-diketones,3 the most widely used approach is the
Michael addition to a,b-unsaturated ketones of either
unmaskedacylanionssuchasacyllithium4 andacyl-transition
metal complexes,5 or, specially, of masked acyl anions and
their equivalents,6 thiazolinium salts, alkoxyvinylcuprates,
cyanohydrins, nitronate anions, and anions of 1,3-dithians.
The conjugate addition reactions often result in generation
of new stereocenters, and accordingly a number of new
methods to construct these stereogenic centers in a diastereo-
and enantioselective fashion have been developed in the last
decade.7 In fact excellent results on the asymmetric Michael
addition of enolate carbon nucleophiles to a,b-unsaturated
ketones leading to 1,5-dicarbonyl compounds have been
reported.8 However, the asymmetric conjugate addition
of acyl anion equivalents leading to the less accessible
2. Results and discussion
The synthesis of enantiomerically pure 2-substituted-1,4-
diketones is outlined in Scheme 1. The first step involves
the conjugate addition of (S)-(+)-mandelic acid enolate to
a,b-enones. Although the formation of the mandelic acid
* Corresponding author. Tel.: +34 963544329; fax: +34 963544328; e-mail:
jose.r.pedro@uv.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.036

G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
9175
enolate leads to the loss of chirality at the stereogenic center,
according to the Seebach principle of self-regeneration
of stereocenters,13 it is possible to regenerate the chiral
information if (S)-(+)-mandelic acid (1) is previously trans-
formed into (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxolan-
4-one (2) derived from pivalaldehyde.16
ratio 30:70) were produced (entry 2). The effect of the
enolate aggregation state was also examined. In most reac-
tions involving the participation of carbanions, the use of
HMPA as an additive increases the reactivity as well as
modifies the selectivity.18 In our case, when 3 equiv of
HMPA were used (entries 3 and 4) in the Michael addition
of the lithium enolate of 2 to enone 3a an improvement of
the reaction yield, specially with the inverse addition proto-
col (85%, entry 4), together with an increase and full rever-
sion of the diastereoselectivity were observed. Thus, only
compound 4a was obtained (de>99%). Addition of more
HMPA (6 equiv) (entries 5 and 6) did neither further
enhanced the yield of the reaction nor modified the dia-
stereoselectivity, while the use of 1.5 equiv of HMPA
decreased the diastereoselectivity (entry 7). The use of
TMEDA18 (entry 8) as substitutive for HMPA decreased
both the yield and the diastereoselectivity. Therefore, the
inverse addition protocol together with the use of HMPA
(3 equiv) as additive seemed to be the optimal reaction con-
ditions to get a good yield and a high diastereoselectivity
(entry 4).
O
R1
R2
O
H
H
t
H
O
3
HO2C
HO
Bu CHO
O
H+
Bu
t
LDA, THF-HMPA
Ph
Ph
1
2
R1
O
O
H R1
O
H
O
H
H
O
O
R2
R2
+
O
O
t
t
Ph
Ph
Bu
Bu
4
epi-4
O
H
R1
R
Ph
OH
R2
1 O
Co complex
1. KOH
2. HCl
Ph
4
R2
t
HO2C
Bu CHO, O2
O
H
6
5
In order to verify the generality of the effect of HMPA as an
additive in this reaction, that is, increasing of the reaction
yield and specially the full reversion of the diastereoselectiv-
ity, we carried out a comparative study with two more
enones (3b and 3c) using the inverse addition protocol in the
absence of HMPA (Table 2, entries 1, 3, and 5) and in
the presence of 3 equiv of HMPA (entries 2, 4, and 6). In
both cases, the results were very similar to those obtained
with enone 3a, without practically any influence of the
aliphatic or aromatic nature of the substituents R1 and R2.
R1
R2
a
b
c
d
e
f
CH3
C2H5
CH3
C6H5
CH3
CH3
CH3
CH3
O
Ph
H
C6H5
HO2C
C6H5
Ph
n-C5H11
(CH3)2CH
Ph
5c
HO
p-MeO-C6H4
p-Cl-C6H4
g
Scheme 1. Synthesis of chiral non-racemic 1,4-diketones from mandelic
acid.
In order to optimize the reaction conditions for the conjugate
addition, we studied the reaction of 1,3-dioxolan-4-one 2
with enone 3a (Table 1). Compound 2 was deprotonated
by addition to a freshly prepared solution of LDA (1.5 equiv)
in THF at ꢀ78 ꢁC, and then enone 3a (1 equiv) was added to
the resulting enolate solution (direct addition protocol). This
process provided a fair yield (49%) of a separable diastereo-
mer mixture of 4a and epi-4a, with moderate diastereoselec-
tivity (4a:epi-4a ratio 35:65) (entry 1). In a modification of
the experimental procedure we carried out the formation
of enolate in the presence of the Michael acceptor since it
is known that similar enolates may suffer some decomposi-
tion even at low temperatures.17 So, LDAwas added to a mix-
ture of dioxolan-4-one 2 and enone 3a in THF at ꢀ78 ꢁC
(inverse addition protocol). In this way, slight increases in the
yield (60%) as well as in the diastereoselectivity (4a:epi-4a
Finally the scope of the reaction using the inverse addition
protocol and HMPA was studied with several different
enones, bearing either aliphatic (3d and 3e) or aromatic (3f
and 3g) substituents. In all the three cases of enones where
substituents R1 and R2 were both aliphatic, the reaction pro-
ceeded with good yields (73–85%) and high diastereoselec-
tivities (from 95:5 to 100:0 ratios) (entries 2, 7, and 8). In
a similar way, the reaction proceeded also with good yields
(76–93%) and high diastereoselectivities (from 94:6 to 99:1
ratios) with enones having R1 aromatic and R2 aliphatic
substituents (entries 4, 9, and 10). In the case of chalcone
3c the reaction proceeded also with good yield (70%) and
full diastereoselectivity (100:0 ratio, entry 6).
Table 2. Michael reaction of 1,3-dioxolan-4-one 2 with a,b-enones 3
(inverse addition protocol)
Entry Enone 3 R1
R2
HMPA Yield 4:epi-4b
(equiv) (%)a
Table 1. Michael reaction of 1,3-dioxolan-4-one 2 with enone 3a
1
2
3
4
5
6
7
8
9
10
3a
3a
3b
3b
3c
3c
3d
3e
3f
CH3
CH3
C6H5
C6H5
C6H5
C6H5
n-C5H11
(CH3)2CH
p-MeOC6H4 CH3
C2H5
C2H5
CH3
0
3
0
3
0
3
3
3
3
3
60
85
34
85
58
70
80
73
76
93
30:70
100:0
35:65
98:2
30:70
100:0
95:5
98:2
99:1
94:6
Entry
Addition
Additive (equiv)
Yield (%)a
4a:epi-4ab
1
2
3
4
5
6
7
8
Direct
Inverse
Direct
Inverse
Direct
Inverse
Inverse
Inverse
None
None
49
60
64
85
53
82
85
16
35:65
30:70
97:3
100:0
98:2
99:1
CH3
HMPA (3)
HMPA (3)
HMPA (6)
HMPA (6)
HMPA (1.5)
TMEDA (3)
C6H5
C6H5
CH3
CH3
84:16
30:70
3g
p-ClC6H4
CH3
a
a
Yields refer to isolated products.
Yields refer to isolated products.
Diastereomeric ratios determined by H NMR prior to chromatographic
purification.
1
Diastereomeric ratios determined by 1H NMR prior to chromatographic
purification.
b
b

9176
G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
It is important to note that under the optimized conditions
(inverse addition protocol and 3 equiv of HMPA as additive)
the Michael adducts were obtained practically as only one
diastereomer out of the four possible ones, attending to the
configuration of the two newly created stereogenic centers.
The stereochemical structures of the Michael adducts 4a–4g
were elucidated by NOEs. These experiments showed in all
of the cases the cis-relationship between the t-Bu group and
the phenyl group from the starting 1,3-dioxolan-4-one. The
absolute configuration of the newly formed quaternary
carbon atom was then assigned to be S, upon the consider-
ation that the absolute configuration of the carbon bearing
the t-Bu group in 2 is S and it remains unaltered from 2 to
4.13 Furthermore, in the case of the adduct 4c the absolute
stereochemistry was unambiguously determined by single
X-ray diffraction (Fig. 1).19 According to this, the absolute
configuration of the tertiary carbon atom bearing the aryl
group was assigned to be S.
normally results in an increase in the nucleophilicity and
reactivity of the carbanion. However, this effect is not suffi-
cient to explain the change in the diastereomer distribution
with HMPA. According to the findings by Biddle and
Reich,20 this substantial change in diastereoselectivity in
the formation of the 1,4-adduct may be attributed to a change
in mechanism from lithium catalyzed reaction to one where
catalysis has been suppressed by the coordination of HMPA
to lithium. Thus, in the absence of HMPA, the reaction is
expected to proceed through an eight-membered chelated
transition state (TSs C and E, Fig. 2)21 with lithium being
coordinated to the enolate and enone carbonyl oxygens
with TS C being the preferred one as it minimizes any repul-
sion between the benzoyl group and the dioxolanone ring
(Fig. 2). Addition of HMPA suppresses the lithium catalyzed
mechanism and the reaction may proceed through a different,
nonchelated TS D, which minimizes the gauche interactions
between the enolate and enone substituents. Also, the lower
stereoselectivity found in the absence of HMPA can be
explained by a competition of these two mechanisms, che-
lated with contact ion pairs, and nonchelated with separated
ion pairs, in low concentration but more reactive, if the reac-
tion is governed by Curtin–Hammet kinetics.
For the other adducts the assignment of the stereochemistry
at the tertiary stereocenter in the side chain was established
later, after hydrolysis of the 1,3-dioxolan-4-one ring and
cyclization to hemiacetals 5 (see below). The configuration
of this carbon was S in all of the cases, except in compounds
4a and 4d as a consequence of a change of priority when
applying the Cahn–Ingold–Prelog rules. The stereochemical
structures of the Michael adducts epi-4a, epi-4b and epi-4c
were also elucidated by NOEs. These experiments showed
again in all of the cases the cis-relationship between the
t-Bu group and the phenyl group from the starting 1,3-
dioxolan-4-one, indicating that compounds 4 and epi-4
have the same configuration at the quaternary stereocenter
and differ only on the stereochemistry of the tertiary stereo-
genic center of the side chain.
The next step in our synthetic sequence was the cleavage of
the 1,3-dioxolan-4-one moiety present in compound 4 (and
also in compound epi-4a for comparison purposes), which
was achieved upon basic hydrolysis with ethanolic KOH
and reprotonation to give the corresponding a-hydroxy-d-
oxocarboxylic acids. Interestingly, all these compounds
were obtained as cyclic hemiacetal acid 5, and only the prod-
uct resulting from the hydrolysis of 4c was obtained as an
open a-hydroxy-d-oxocarboxylic acid 5c. In all the cases
the reaction yields were equal or higher to 90% (Table 3).
As the results in Tables 1 and 2 show, the addition of HMPA
causes a dramatic change in the diastereomer distribution
of the Michael products. HMPA is a highly polar aprotic
solvent frequently used to accelerate organolithium reac-
tions and, in some cases, to alter the course of the reaction.
Its usefulness stems from its ability to coordinate very
strongly to lithium to give separated ion pairs, in which
the carbanion and lithium counterion are separated. This
The stereochemical structures of the cyclic hemiacetal acids
5 were established by NOEs. As a representative example,
irradiation in compound 5a of the signal at d 7.49 corre-
sponding to the ortho-protons of the phenyl group enhanced
the signal at d 0.76 corresponding to the methyl group. On
the other hand, irradiation in epi-5a of the signal at d 7.70
corresponding to the ortho-protons of the phenyl group
gave NOE with the signal at d 2.50 corresponding to the
TS leading to epi-4
Li+
O
R1
O
O
O
O
O
O
R2
O
H
O
O
R1
H
R2
Ph
Ph
O
O
H
Ph
R1
C
R2
A
B
TS leading to 4
Li+
O
H
O
O
O
O
R2
O
R1
Ph
O
O
H
R1
R2
O
O
Ph
H
O
O
Ph
R1
R2
D
E
F
Figure 2. Possible TS for the approach of the enone to the Re-face of the
enolate of 2.
Figure 1. ORTEP drawing for compound 4c.

G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
9177
Table 3. Hydrolysis of the Michael adducts 4 and oxidative decarboxylation
of hydroxy acids 5
benzoyl anion. The preservation of the chiral information
of the (S)-mandelic acid is based on the Seebach principle
of self-regeneration of stereocenters whilst its use as an
‘Umpoled’ equivalent of the benzoyl anion is based on an
oxidative decarboxylation of a-hydroxy acids developed
in our laboratory. This strategy appears as a convenient
method for the synthesis of highly enantioenriched chiral
non-racemic 2-substituted-1,4-diketones.
Entry Adduct 4 R1
R2
Yield 5 (%)a,b Yield 6 (%)a,c
1
2
3
4
5
6
7
8
4a
CH3
CH3
C6H5
C6H5
C2H5 90
C2H5 94
CH3 90
C6H5 95
CH3 90
CH3 90
75
78
60
82
75
82
72
69
epi-4a
4b
4c
4d
4e
n-C5H11
(CH3)2CH
p-MeOC6H4 CH3 90
p-ClC6H4 CH3 95
4f
4g
3. Experimental
3.1. General
a
b
c
Yields refer to isolated products.
Yield from 4.
Yield from 5.
All melting points are uncorrected. Column chromatography
was performed on silica gel (Merck, silica gel 60, 230–400
mesh). Optical rotations were measured on a Perkin–Elmer
243 polarimeter. NMR spectra were recorded on a Bruker
proton on the tertiary carbon atom (Fig. 3). According to
these experiments the absolute configuration of the tertiary
carbon atom bearing the methyl group in the side chain
was determined to be R in compound 5a and S in compound
epi-5a, upon the consideration that the absolute configura-
tion of the quaternary carbon bearing the phenyl and carboxy
groups was S in all the cases as explained earlier. These
experiments also allowed the assignment of the absolute
stereochemistry of the tertiary stereocenter of compound
4a, that is, the R configuration of this stereocenter in com-
pound 5a was assigned to this carbon in its Michael adduct
precursor 4a. The opposite configuration S was therefore
assigned to the adduct epi-4a.
1
Advance 300 DPX spectrometer (300 MHz for H NMR
and 75 MHz for 13C NMR) or a Varian Unity 400
1
(400 MHz for H NMR and 100 MHz for 13C NMR) as
indicated, and referenced to the residual non-deuterated
solvent as internal standard. The carbon type was determined
by DEPT experiments. Mass spectra were run by electron
impact at 70 eV or by chemical ionization using methane
as ionizing gas on a Fisons Instruments VG Autospec GC
8000 series spectrometer. (2S,5S)-cis-2-tert-Butyl-5-phenyl-
1,3-dioxolan-4-one (2) was prepared according to the litera-
ture.16 All new compounds were determined to be >95%
pure by 1H NMR spectroscopy.
Finally, the oxidative decarboxylation of the a-hydroxy acid
moiety present in compound 5, either in open form (5c) or as
cyclic hemiacetal (5a, 5b, 5d–5g) was carried out by using
a catalytic system developed in our laboratory that employs
oxygen as terminal oxidant in the presence of pivalaldehyde
and a catalytic amount of the Co(III)Me2opba complex
(Fig. 4).10 Under these conditions the 1,4-diketones were
obtained with fair to good yields. Much more importantly,
products highly enantiomerically enriched (ee>99%) were
3.2. General experimental procedure for the Michael
reaction (inverse addition protocol)
A solution of freshly prepared LDA (1.25 mmol) in dry
THF (1.3 mL) was slowly added to a solution of (2S,5S)-
cis-2-tert-butyl-5-phenyl-1,3-dioxolan-4-one (2) (220 mg,
1 mmol) and a,b-unsaturated carbonyl compound
3
1
obtained, as it was proven by H NMR experiments using
the chiral lanthanide shift reagent Eu(hfc)3 under conditions
previously optimized for racemic mixtures.
(1.25 mmol) in dry THF:HMPA (5 mL:0.53 mL) at ꢀ78 ꢁC.
The reaction was allowed to reach ꢀ40 ꢁC and it was
quenched with a saturated aqueous solution of NH4Cl at this
temperature, and extracted with diethyl ether (3ꢂ30 mL).
The combined organic extracts werewashed with brine, dried
(MgSO4), and evaporated and the residue was purified by
flash chromatography (silica gel, hexane:diethyl ether or
hexane:dichloromethane) to afford Michael adducts 4.
Yields are included in Table 2.
In summary, we have developed a strategy for the asymmet-
ric Michael reaction of a masked benzoyl anion equivalent to
a,b-enones that formally involves the use of (S)-mandelic
acid as a source of chiral information and as a source of
δ 7.70
δ 7.49
H
H
H
3.2.1. (2S,5S,10R)-2-(tert-Butyl)-5-(10-methyl-30-oxopen-
tyl)-5-phenyl-1,3-dioxolan-4-one (4a). An oil; [a]2D5 ꢀ9 (c
1.1, CHCl3); HRMS (EI) m/z 318.1833 (M+, 9, C19H26O4
requires 318.1831), 220 (62), 105 (100); 1H NMR
(300 MHz, CDCl3) d 0.86 (s, 9H), 0.90 (d, J¼7.0 Hz, 3H),
0.99 (t, J¼7.2 Hz, 3H), 2.21 (dd, J¼16.6, 8.9 Hz, 1H),
2.37 (dq, J¼14.8, 7.4 Hz, 2H), 2.51 (dd, J¼16.7, 4.3 Hz,
1H), 2.85 (m, 1H), 5.33 (s, 1H), 7.3–7.4 (m, 3H), 7.62 (dd,
J¼6.6, 1.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 7.6 (q),
14.5 (q), 23.3 (q), 35.2 (s), 36.6 (t), 37.5 (d), 43.9 (t), 84.1
(s), 109.5 (d), 125.8 (d), 127.9 (d), 128.0 (d), 136.2 (s),
172.6 (s), 209.1 (s).
δO2.50
δ 0.76
CH
Et
3O
OH
Et
HO2C
HO2C
OH
CH3
H
5a
epi-5a
Figure 3. Significant NOE in compounds 5a and epi-5a.
-
O
O
O
N
N
N
N
+
Co
NMe4
O
Me Me
3.2.2. (2S,5S,10S)-2-(tert-Butyl)-5-(10-methyl-30-oxopen-
tyl)-5-phenyl-1,3-dioxolan-4-one (epi-4a). An oil; [a]D25
Figure 4. Co(III) ortho-phenylene-bis(N0-methyloxamidate) complex.

9178
G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
+26 (c 1.4, CHCl3); HRMS (EI) m/z 318.1846 (M+, 7.2,
C19H26O4 requires 318.1831), 220 (27.8), 105 (100); H
3.2.7. (2S,5S,10R)-2-(tert-Butyl)-5-(10-n-pentyl-30-oxo-
butyl)-5-phenyl-1,3-dioxolan-4-one (4d). An oil; [a]D25
ꢀ30 (c 0.5, CHCl3); HRMS (EI) m/z 360.2286 (M+, 5.8,
C22H32O4 requires 360.2301), 247 (14), 220 (100), 141
(20), 105 (91); 1H NMR (300 MHz, CDCl3) d 0.84 (t,
J¼6.6 Hz, 3H), 0.87 (s, 9H), 1.20 (m, 7H), 1.81 (m, 1H),
2.12 (s, 3H), 2.18 (dd, J¼17.1, 4.7 Hz, 1H), 2.57 (dd,
J¼17.1, 6.8 Hz, 1H), 2.85 (m, 1H), 5.30 (s, 1H), 7.36 (m,
3H), 7.66 (dd, J¼7.7, 1.7 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 13.9 (q), 22.4 (t), 23.3 (q), 27.1 (t), 29.2 (t), 30.5
(q), 31.8 (t), 34.8 (s), 41.3 (d), 42.6 (t), 83.5 (s), 108.7 (d),
126.1 (d), 127.9 (d), 128.1 (d), 135.8 (s), 172.5 (s), 206.7 (s).
1
NMR (300 MHz, CDCl3) d 0.89 (t, J¼7.4 Hz, 3H), 0.91 (s,
9H), 1.04 (d, J¼6.8 Hz, 3H), 2.23 (m, 4H), 2.81 (m, 1H),
5.38 (s, 1H), 7.3–7.4 (m, 3H), 7.64 (dd, J¼8.5, 1.5 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 7.5 (q), 15.4 (q),
23.5 (q), 35.5 (s), 36.3 (t), 39.0 (d), 42.9 (t), 84.7 (s), 110.6
(d), 125.4 (d), 128.0 (d), 128.1 (d), 137.1 (s), 173.2 (s),
209.5 (s).
3.2.3. (2S,5S,10S)-2-(tert-Butyl)-5-(30-oxo-10-phenyl-
butyl)-5-phenyl-1,3-dioxolan-4-one (4b). An oil; [a]D25
ꢀ75 (c 0.7, CHCl3); HRMS (EI) m/z 366.1811 (M+, 0.3,
C23H26O4 requires 366.1831), 220 (43), 147 (31), 105
3.2.8. (2S,5S,10S)-2-(tert-Butyl)-5-(10-isopropyl-30-oxo-
butyl)-5-phenyl-1,3-dioxolan-4-one (4e). Mp 78–81 ꢁC
(CH2Cl2); [a]2D5 ꢀ41 (c 0.5, CHCl3); HRMS (EI) m/z
332.1991 (M+, 2.3, C20H28O4 requires 332.1988), 221
1
(100); H NMR (300 MHz, CDCl3) d 0.73 (s, 9H), 1.95
(s, 3H), 2.76 (dd, J¼17.2, 4.1 Hz, 1H), 3.23 (dd, J¼17.2,
10.2 Hz, 1H), 3.88 (dd, J¼10.2, 4.3 Hz, 1H), 4.50 (s, 1H),
7.2–7.4 (m, 8H), 7.57 (dd, J¼8.1, 2.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 23.2 (q), 30.6 (q), 35.0 (s), 43.6 (t),
50.4 (d), 84.7 (s), 110.1 (d), 125.7 (d), 127.7 (d), 128.1
(d), 128.2 (d), 128.3 (d), 129.3 (d), 137.2 (s), 137.6 (s),
172.3 (s), 205.3 (s).
1
(14), 220 (100), 219 (28); H NMR (300 MHz, CDCl3)
d 0.51 (d, J¼6.8 Hz, 3H), 0.80 (d, J¼7.0 Hz, 3H), 0.83 (s,
9H), 2.07 (m, 1H), 2.12 (s, 3H), 2.26 (dd, J¼17.0, 4.4 Hz,
1H), 2.57 (dd, J¼17.0, 7.1 Hz, 1H), 2.84 (ddd, J¼7.2, 4.5,
1.9 Hz, 1H), 5.28 (s, 1H), 7.32 (m, 3H), 7.67 (dd, J¼7.9,
1.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 17.1 (q), 23.1
(q), 23.3 (q), 25.8 (d), 30.2 (q), 35.0 (s), 38.3 (t), 47.6 (d),
83.7 (s), 109.4 (d), 125.8 (d), 128.0 (d), 128.1 (d), 137.0
(s), 173.0 (s), 206.7 (s).
3.2.4. (2S,5S,10R)-2-(tert-Butyl)-5-phenyl-5-(30-oxo-10-
phenylbutyl)-1,3-dioxolan-4-one (epi-4b). Mp 136–138 ꢁC
(CH2Cl2); [a]2D5 +69 (c 1.4, CHCl3); HRMS (EI) m/z
366.1831 (M+, 0.4, C23H26O4 requires 366.1831), 220 (43),
1
105 (100); H NMR (300 MHz, CDCl3) d 0.82 (s, 9H),
3.2.9. (2S,5S,10S)-2-(tert-Butyl)-5-(10-p-methoxyphenyl-
30-oxobutyl)-5-phenyl-1,3-dioxolan-4-one (4f). Mp 110–
111 ꢁC (CH2Cl2); [a]D25 ꢀ71 (c 1.5, CHCl3); HRMS (EI)
m/z 396.1946 (M+, 0.3, C24H28O5 requires 396.1936), 177
(100), 135 (10), 105 (16), 77 (8); 1H NMR (300 MHz,
CDCl3) d 0.73 (s, 9H), 1.94 (s, 3H), 2.71 (dd, J¼16.8,
4.4 Hz, 1H), 3.17 (dd, J¼16.8, 10.2 Hz, 1H), 3.77 (s, 3H),
3.83 (dd, J¼10.2, 4.4 Hz, 1H), 4.58 (s, 1H), 6.78 (d,
J¼8 Hz, 2H), 7.12 (d, J¼8 Hz, 1H), 7.26–7.34 (m, 3H),
7.56 (dd, J¼8.1, 1.8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 23.2 (q), 30.5 (q), 35.0 (s), 43.7 (t), 49.6 (d), 55.1 (q),
84.7 (s), 109.9 (d), 113.6 (d), 125.7 (d), 128.0 (d), 128.1
(d), 129.4 (s), 130.3 (d), 137.2 (s), 158.9 (s), 172.2 (s),
205.4 (s).
1.83 (s, 3H), 2.40 (dd, J¼17.1, 4.4 Hz, 1H), 3.05 (dd,
J¼17.1, 10.6 Hz, 1H), 3.96 (dd, J¼10.6, 4.4 Hz, 1H), 4.53
(s, 1H), 7.2–7.4 (m, 8H), 7.79 (dd, J¼8.5, 1.5 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 23.5 (q), 30.2 (q), 35.2 (s), 42.7
(t), 49.5 (d), 85.3 (s), 110.4 (d), 125.5 (d), 128.1 (d), 128.2
(d), 128.3 (d), 128.7 (d), 129.4 (d), 137.2 (s), 137.3 (s),
172.6 (s), 205.8 (s).
3.2.5. (2S,5S,10S)-2-(tert-Butyl)-5-(10,30-diphenyl-30-oxo-
propyl)-5-phenyl-1,3-dioxolan-4-one (4c). Mp 116–118 ꢁC
(CH2Cl2:hexane); [a]2D5 ꢀ99 (c 1.0, CHCl3); HRMS (EI)
m/z 428.1980 (M+, 0.3, C28H28O4 requires 428.1988), 209
1
(32), 105 (100); H NMR (300 MHz, CDCl3) d 0.72 (s,
9H), 3.26 (dd, J¼17.3, 3.8 Hz, 1H), 3.84 (dd, J¼17.3,
10.4 Hz, 1H), 4.11 (dd, J¼10.2, 3.8 Hz, 1H), 4.45 (s, 1H),
7.2–7.6 (m, 11H), 7.64 (dd, J¼7.7, 1.5 Hz, 2H), 7.81 (dd,
J¼8.6, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 23.2 (q),
35.0 (s), 38.6 (t), 50.6 (d), 85.0 (s), 110.2 (d), 125.8 (d),
127.6 (d), 128.0 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.5
(d), 129.3 (d), 133.1 (d), 136.6 (s), 137.4 (s), 137.8 (s),
172.4 (s), 196.8 (s).
3.2.10. (2S,5S,10S)-2-(tert-Butyl)-5-(10-p-chlorophenyl-30-
oxobutyl)-5-phenyl-1,3-dioxolan-4-one (4g). An oil; [a]D25
ꢀ70 (c 0.9, CHCl3); HRMS (EI) m/z 400.1441 (M+, 0.3,
C23H25ClO4 requires 400.1441), 220 (20), 181 (13), 105
1
(100); H NMR (300 MHz, CDCl3) d 0.76 (s, 9H), 1.97 (s,
3H), 2.75 (dd, J¼16.8, 4.2 Hz, 1H), 3.17 (dd, J¼16.8,
10.2 Hz, 1H), 3.86 (dd, J¼10.2, 4.2 Hz, 1H), 4.72 (s, 1H),
7.11 (d, J¼8.7 Hz, 2H), 7.21 (d, J¼8.7 Hz, 1H), 7.27–7.31
(m, 3H), 7.53 (dd, J¼7.7, 1.95 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 23.2 (q), 30.5 (q), 35.2 (s), 43.6 (t),
49.8 (d), 84.4 (s), 110.2 (d), 125.6 (d), 128.1 (d), 128.3
(d), 128.4 (d), 130.6 (6), 133.4 (s), 136.1 (s), 136.9 (s),
172.0 (s), 204.9 (s).
3.2.6. (2S,5S,10R)-2-(tert-Butyl)-5-(10,30-diphenyl-30-oxo-
propyl)-5-phenyl-1,3-dioxolan-4-one (epi-4c). Mp 168–
170 ꢁC (CH2Cl2); [a]D25 +88 (c 0.8, CHCl3); HRMS (EI)
m/z 428.1980 (M+, 0.5, C28H28O4 requires 428.1988), 209
1
(32), 105 (100); H NMR (300 MHz, CDCl3) d 0.85 (s,
9H), 2.88 (dd, J¼17.3, 3.8 Hz, 1H), 3.70 (dd, J¼17.3,
10.7 Hz, 1H), 4.17 (dd, J¼10.7, 3.6 Hz, 1H), 4.59 (s, 1H),
7.2–7.5 (m, 11H), 7.69 (dd, J¼8.6, 1.5 Hz, 2H), 7.85 (dd,
J¼8.7, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 23.5
(q), 35.3 (s), 37.6 (t), 49.8 (d), 85.6 (s), 110.4 (d), 125.5
(d), 127.8 (d), 128.0 (d), 128.3 (d), 128.37 (d), 128.42 (d),
128.6 (d), 129.5 (d), 133.0 (d), 136.7 (s), 137.3 (s), 137.4
(s), 172.7 (s), 197.2 (s).
3.3. General experimental procedure for the basic
hydrolysis of the Michael adducts 4
The Michael adducts 4 (0.28 mmol) were treated with a 5%
KOH solution in ethanol (0.63 mL, 0.56 mmol) at room tem-
perature until complete reaction of the starting material
(TLC) is achieved. The solution was poured into ice and

G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
9179
acidified with 1 M HCl until pH 2. The aqueous mixture was
extracted with EtOAc (3ꢂ30 mL), and the organic layers
were washed with brine until neutrality, dried, filtered, and
concentrated under reduced pressure to give compound 5.
Yields are included in Table 3.
J¼8.6, 1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 13.9
(q), 18.5 (q), 22.5 (t), 26.4 (t), 30.7 (t), 31.5 (t), 41.2 (d),
42.6 (t), 88.9 (s), 111.3 (s), 125.7 (d), 128.1 (d), 128.2 (d),
131.3 (s), 173.5 (s).
3.3.6. (2S,3S,5R)-5-Hydroxy-3-isopropyl-5-methyl-2-
phenyltetrahydrofuran-2-carboxylic acid (5e). Mp 105–
107 ꢁC (CHCl3); [a]2D5 +123 (c 0.6, CHCl3); HRMS (EI)
m/z 228.1157 (M+ꢀ2H2O, 0.4, C15H16O2 requires
228.1150), 202 (42), 160 (34), 159 (100), 131 (13), 115
(17), 105 (94), 77 (60), 51 (19); 1H NMR (400 MHz,
CDCl3) d 0.60 (d, J¼6.8 Hz, 3H), 0.78 (d, J¼6.9 Hz, 3H),
1.80 (m, 1H), 1.91 (s, 3H), 1.97 (dd, J¼12.9, 4.6 Hz, 1H),
2.29 (dd, J¼12.9, 8.6 Hz, 1H), 2.47 (m, 1H), 7.46 (m, 3H),
7.52 (dd, J¼8.5, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 15.7 (q), 18.3 (q), 21.6 (q), 26.5 (d), 36.2 (t), 45.5 (d),
89.3 (s), 111.2 (s), 126.0 (d), 128.1 (d), 128.2 (d), 131.1
(s), 173.5 (s).
3.3.1. (2S,3R,5R)-5-Ethyl-5-hydroxy-3-methyl-2-phenyl-
tetrahydrofuran-2-carboxylic acid (5a). An oil; [a]D27
+89 (c 1.0, CHCl3); HRMS (CI) m/z 233.1153 (M++
1ꢀH2O, 100, C14H17O3 requires 233.1178), 215 (93), 188
1
(32); H NMR (300 MHz, CDCl3) d 0.76 (d, J¼6.8 Hz,
3H), 1.15 (t, J¼7.6 Hz, 3H), 1.62 (q, J¼6.8 Hz, 1H), 2.14
(q, J¼7.6 Hz, 2H), 2.50 (m, 2H), 7.3–7.4 (m, 3H), 7.49
(m, 2H); 13C NMR (75 MHz, CDCl3) d 7.6 (q), 17.0 (q),
25.4 (t), 35.4 (d), 42.8 (t), 88.7 (s), 113.8 (s), 125.7 (d),
128.17 (d), 128.22 (d), 131.2 (s), 173.6 (s).
3.3.2. (2S,3S,5S)-5-Ethyl-5-hydroxy-3-methyl-2-phenyl-
tetrahydrofuran-2-carboxylic acid (epi-5a). An oil; [a]D25
+91 (c 0.8, CHCl3); HRMS (EI) m/z 232.1090 (M+ꢀH2O,
0.6, C14H16O3 requires 232.1100), 105 (100); 1H NMR
(300 MHz, CDCl3) d 1.14 (t, J¼7.5 Hz, 3H), 1.18 (d,
J¼7.0 Hz, 3H), 1.78 (dd, J¼12.1, 4.5 Hz, 1H), 1.86 (br s,
1H, OH), 2.11 (q, J¼7.5 Hz, 2H), 2.41 (dd, J¼12.4,
10.2 Hz, 1H), 2.50 (m, 1H), 7.3–7.5 (m, 3H), 7.70 (dd,
J¼8.1, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 7.5 (q),
14.8 (q), 25.5 (t), 39.0 (d), 41.3 (t), 89.1 (s), 113.4 (s),
126.1 (d), 128.4 (d), 128.8 (d), 132.2 (s), 171.8 (s).
3.3.7. (2S,3S,5R)-5-Hydroxy-5-methyl-3-p-methoxy-
phenyl-2-phenyltetrahydrofuran-2-carboxylic acid (5f).
An oil; [a]2D5 +124 (c 1.1, CHCl3); HRMS (EI) m/z
310.1197 (M+ꢀH2O, 11, C19H18O4 requires 310.1205),
266 (5), 223 (7), 176 (100), 134 (12), 105 (80), 77 (19);
1H NMR (300 MHz, CDCl3) d 2.00 (s, 3H), 2.26 (dd,
J¼13.2, 4.2 Hz, 1H), 2.92 (dd, J¼13.2, 8.7 Hz, 1H), 3.60
(dd, J¼8.7, 4.2 Hz, 1H), 3.67 (s, 3H), 6.62 (d, J¼9.0 Hz,
2H), 6.99 (d, J¼9.0 Hz, 1H), 7.11–7.22 (m, 3H), 7.33 (dd,
J¼8.1, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 18.3
(q), 46.7 (d), 46.8 (t), 55.0 (q), 90.4 (s), 111.2 (s), 113.6
(d), 125.9 (d), 127.7 (d), 127.8 (d), 129.3 (d), 130.9 (s),
131.1 (s), 158.4 (s), 173.1 (s).
3.3.3. (2S,3S,5R)-5-Hydroxy-3-methyl-2,3-diphenyltetra-
hydrofuran-2-carboxylic acid (5b). An oil; [a]2D5 +104 (c
1.3, CHCl3); HRMS (EI) m/z 281.1176 (M++1ꢀH2O, 100,
C18H17O3 requires 281.1178), 264 (45), 263 (93), 253
(57), 236 (30), 193 (39), 176 (34), 105 (22); 1H NMR
(300 MHz, CDCl3) d 2.00 (s, 3H), 2.31 (dd, J¼13.2,
4.3 Hz, 1H), 2.93 (dd, J¼13.2, 8.6 Hz, 1H), 3.63 (dd,
J¼8.7, 4.4 Hz, 1H), 7.0–7.2 (m, 8H), 7.33 (dd, J¼7.9,
1.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 18.4 (q), 46.7
(t), 47.5 (d), 90.5 (s), 111.3 (s), 126.0 (d), 127.1 (d), 127.7
(d), 127.9 (d), 128.2 (d), 128.3 (d), 130.7 (s), 139.1 (s),
173.0 (s).
3.3.8. (2S,3S,5R)-3-p-Chlorophenyl-5-hydroxy-5-methyl-
2-phenyltetrahydrofuran-2-carboxylic acid (5g). An oil;
[a]2D5 +99 (c 1.1, CHCl3); HRMS (EI) m/z 314.0710
(M+ꢀH2O, 0.3, C18H15O3Cl requires 314.0709), 270 (9),
1
176 (42), 105 (100), 77 (26); H NMR (300 MHz, CDCl3)
d 2.00 (s, 3H), 2.24 (dd, J¼13.5, 4.2 Hz, 1H), 2.94 (dd,
J¼13.5, 8.7 Hz, 1H), 3.61 (dd, J¼8.7, 4.2 Hz, 1H), 7.00
(d, J¼8.7 Hz), 7.06 (d, J¼8.7 Hz, 1H), 7.15–7.23 (m, 3H),
7.31 (dd, J¼7.5, 1.2 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 18.3 (q), 46.8 (t), 46.9 (d), 90.3 (s), 111.2 (s), 125. 8 (d),
127.9 (d), 128.1 (d), 128.4 (d), 129.5 (d), 130.4 (s), 132.9
(s), 137.7 (s), 172.7 (s).
3.3.4. (2S,3S)-2-Hydroxy-5-oxo-2,3,5-triphenylpentanoic
acid (5c). Mp 128–130 ꢁC (EtOAc); [a]2D5 ꢀ58 (c 0.7,
CH3OH); HRMS (EI) m/z 342.1261 (M+ꢀH2O, 7,
C23H18O3 requires 342.1256), 296 (67), 105 (100); 1H
NMR (300 MHz, DMSO-d6) d 3.16 (dd, J¼16.8, 2.5 Hz,
1H), 3.85 (dd, J¼17.0, 11.1 Hz, 1H), 4.24 (dd, J¼0.9,
2.5 Hz, 1H), 6.9–7.6 (m, 13H), 7.87 (d, J¼8.0 Hz, 2H);
13C NMR (75 MHz, DMSO-d6) d 41.5 (t), 48.9 (d), 81.3
(s), 126.1 (d), 126.2 (d), 126.9 (d), 127.3 (d), 127.6 (d),
128.2 (d), 129.1 (d), 130.2 (d), 133.5 (d), 137.0 (s), 140.1
(s), 142.2 (s), 176.1 (s), 198.5 (s).
3.4. General experimental procedure for the catalytic
aerobic decarboxylation of compound 5
A solution of compound 5 (0.11 mmol) in 0.2 mL of aceto-
nitrile was added to a stirred mixture of Co(III)Me2opba
complex (6.5ꢂ10ꢀ3 mmol) and pivalaldehyde (0.33 mmol)
in 0.2 mL of acetonitrile under a dioxygen atmosphere.
The mixture was stirred at room temperature until consump-
tion of the starting material as indicated by TLC. The reac-
tion product 6 was purified by flash column chromatography.
3.3.5. (2S,3R,5R)-5-Hydroxy-5-methyl-3-n-pentyl-2-phe-
nyltetrahydrofuran-2-carboxylic acid (5d). An oil; [a]D25
+74 (c 1.4, CHCl3); HRMS (EI) m/z 247.1709
(M+ꢀCO2H, 3, C16H23O2 requires 247.1698), 230 (67),
173 (85), 160 (42), 105 (100); 1H NMR (400 MHz,
CDCl3) d 0.82 (t, J¼7.2 Hz, 3H), 1.00 (m, 1H), 1.14 (m,
7H), 1.76 (dd, J¼12.6, 3.7 Hz, 1H), 1.89 (s, 3H), 2.36
(ddt, J¼7.8, 7.7, 3.5 Hz, 1H), 2.49 (dd, J¼12.6, 8.0 Hz,
1H), 7.38 (tt, J¼8.7, 1.4 Hz, 1H), 7.44 (m, 2H), 7.53 (dd,
3.4.1. (R)-2-Methyl-1-phenyl-1,4-hexanedione (6a). An
oil; [a]2D5 +16 (c 0.6, CHCl3); HRMS (EI) m/z 204.1159
(M+, 5, C13H16O2 requires 204.1150), 175 (51), 105 (100);
1H NMR (300 MHz, CDCl3) d 1.02 (t, J¼7.4 Hz, 3H),
1.16 (d, J¼7.4 Hz, 3H), 2.47 (q, J¼7.4 Hz, 2H), 2.54 (dd,
J¼17.9, 5.1 Hz, 1H), 3.12 (dd, J¼17.9, 8.7 Hz, 1H), 3.97

9180
G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
1
(m, 1H), 7.45 (m, 2H), 7.53 (m, 1H), 7.96 (dd, J¼8.4, 1.5 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 7.6 (q), 17.8 (q), 36.0 (t),
36.1 (d), 45.6 (t), 128.4 (d), 128.6 (d), 133.0 (d), 135.9 (s),
203.5 (s), 210.0 (s).
(19), 177 (100), 135 (21), 105 (88), 91 (11), 77 (51); H
NMR (300 MHz, CDCl3) d 2.18 (s, 3H), 2.73 (dd, J¼17.7,
4.2 Hz, 1H), 3.57 (dd, J¼17.7, 9.9 Hz, 1H), 3.73 (s, 3H),
5.06 (dd, J¼9.9, 4.2 Hz, 1H), 6.80 (d, J¼8.7 Hz, 2H), 7.17
(d, J¼8.7 Hz, 1H), 7.36 (d, J¼7.2 Hz, 2H), 7.46 (tt, J¼7.2,
1.5 Hz, 1H), 7.95 (dd, J¼7.2, 1.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 30.0 (q), 47.8 (d), 48.0 (t), 55.1 (q),
114.5 (d), 128.4 (d), 128.8 (d), 129.1 (d), 130.4 (s), 132.8
(d), 136.2 (s), 158.7 (s), 199.9 (s), 207.0 (s).
3.4.2. (S)-2-Methyl-1-phenyl-1,4-hexanedione (epi-6a).
An oil; [a]2D5 ꢀ15 (c 1.3, CHCl3); 1H and 13C NMR spectra
identical to those of compound 6a.
3.4.3. (S)-1,2-Diphenyl-1,4-pentanedione (6b). An oil;
[a]2D5 +263 (c 1.1, CHCl3). HRMS (EI) m/z 252.1155 (M+,
7.3, C17H16O2 requires 252.1150), 234 (2), 105 (100), 77
(24); 1H NMR (300 MHz, CDCl3) d 2.19 (s, 3H), 2.76 (dd,
J¼18.1, 4.0 Hz, 1H), 3.62 (dd, J¼17.9, 10.0 Hz, 1H), 5.11
(dd, J¼10.2, 4.0 Hz, 1H), 7.2–7.4 (m, 7H), 7.47 (tt, J¼6.4,
1.3 Hz, 1H), 7.96 (dd, J¼8.7, 1.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 28.7 (q), 48.1 (t), 48.8 (d), 127.3 (d),
128.1 (d), 128.4 (d), 128.9 (d), 129.2 (d), 132.9 (d), 136.3
(s), 138.6 (s), 198.9 (s), 206.8 (s).
3.4.8. (S)-2-p-Chlorophenyl-1-phenyl-1,4-pentanedione
(6g). An oil; [a]2D5 +13 (c 0.6, CHCl3); HRMS (EI) m/z
286.0760 (M+, 4, C17H15ClO2 requires 286.0760), 268 (1),
1
165 (1), 138 (3), 105 (100), 77 (25); H NMR (300 MHz,
CDCl3) d 2.19 (s, 3H), 2.74 (dd, J¼18.0, 4.2 Hz, 1H), 3.57
(dd, J¼18.0, 9.8 Hz, 1H), 5.09 (dd, J¼9.8, 4.2 Hz, 1H),
7.20 (d, J¼8.6 Hz, 2H), 7.25 (d, J¼8.6 Hz, 1H), 7.38 (d,
J¼7.5 Hz, 2H), 7.50 (tt, J¼7.2, 1.5 Hz, 1H), 7.93 (dd,
J¼7.5, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 30.0
(q), 47.8 (t), 47.9 (d), 128.5 (d), 128.8 (d), 129.3 (d), 129.4
(d), 133.1 (d), 133.2 (s), 136.0 (s), 137.0 (s), 198.5 (s),
206.5 (s).
3.4.4. (S)-1,2,4-Triphenyl-1,4-butanedione (6c). Mp 153–
155 ꢁC (CH2Cl2); [a]D25 +50 (c 1.1, CHCl3); HRMS (EI)
m/z 314.1311 (M+, 10, C22H18O2 requires 314.1307), 209
(12), 111 (17), 105 (100), 97 (29), 77 (31); 1H NMR
(400 MHz, CDCl3) d 3.31 (dd, J¼18.1, 3.8 Hz, 1H), 4.22
(dd, J¼18.0, 10.0 Hz, 1H), 5.33 (dd, J¼10.0, 3.7 Hz, 1H),
7.23 (tt, J¼7.2, 2.3 Hz, 1H), 7.3–7.5 (m, 8H), 7.49 (tt,
J¼7.4, 2.1 Hz, 1H), 7.56 (tt, J¼7.3, 1.2 Hz, 1H), 7.99 (dd,
J¼7.1, 1.5 Hz, 2H), 8.03 (dd, J¼7.2, 1.5 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 43.9 (t), 48.7 (d), 127.4 (d),
128.1 (d), 128.2 (d), 128.5 (d), 128.6 (d), 128.9 (d), 129.2
(d), 132.9 (d), 133.3 (d), 136.3 (s), 136.4 (s), 138.6 (s),
198.1 (s), 198.9 (s).
Acknowledgements
Financial support from the Spanish Government MEC
(BQU2001-3017) and from Generalitat Valenciana (Grupos
03/168 and GV05/10) is acknowledged. B.M. thanks the
MEC for a grant (FPI program).
References and notes
3.4.5. (R)-2-Pentyl-1-phenyl-1,4-pentanedione (6d). An
oil; [a]2D5 +57 (c 0.5, CHCl3); HRMS (EI) m/z 246.1638
(M+, 1.2, C16H22O2 requires 246.1620), 176 (26), 133
(15), 105 (100), 77 (77); 1H NMR (300 MHz, CDCl3)
d 0.81 (t, J¼6.6 Hz, 3H), 1.21 (m, 6H), 1.41 (m, 1H), 1.63
(m, 1H), 2.13 (s, 3H), 2.58 (dd, J¼18.0, 4.1 Hz, 1H), 3.14
(dd, J¼18.1, 9.4 Hz, 1H), 3.90 (m, 1H), 7.45 (br t,
J¼7.7 Hz, 2H), 7.54 (tt, J¼7.1, 1.5 Hz, 1H), 7.97 (dd,
J¼8.7, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 13.9
(q), 22.4 (t), 26.8 (t), 30.1 (q), 31.7 (t), 32.3 (t), 41.3 (d),
45.1 (t), 128.4 (d), 128.6 (d), 132.9 (d), 136.8 (s), 203.4
(s), 207.4 (s).
1. (a) Ellison, R. A. Synthesis 1973, 397–412; (b) Bentley, P. H.
Chem. Soc. Rev. 1973, 2, 29–48; (c) Stetter, H.; Kulhmann,
H. Synthesis 1975, 379–382; (d) Sum, P. E.; Weiler, L. Can.
J. Chem. 1978, 56, 2301–2304; (e) Wenkert, E.; Buckwalter,
B. L.; Craveiro, A. A.; Sanchez, E. L.; Sathe, S. S. J. Am.
Chem. Soc. 1978, 100, 1267–1273; (f) Mussatto, M. C.;
Savoia, D.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem.
1980, 45, 4002–4005; (g) Wenkert, E.; Greenberg, R. S.;
Ragu, M. S. J. Org. Chem. 1985, 50, 4681–4685; (h)
Takahashi, K.; Aihara, T.; Ogura, K. Chem. Lett. 1987, 2359–
2362; (i) Pecuniso, A.; Menicagli, R. J. Org. Chem. 1988, 53,
2614–2617; (j) Fiandanese, V.; Marchese, G.; Naso, F.
Tetrahedron Lett. 1988, 29, 3587–3590; (k) Bergman, R.;
Nilsson, B.; Wickberg, B. Tetrahedron Lett. 1990, 31, 2783–
2786; (l) Yamashita, M.; Tashika, H.; Uchida, M. Bull. Chem.
Soc. Jpn. 1992, 65, 1257–1261; (m) Tsukasa, H. Biosci.
Biotechnol. Biochem. 1994, 58, 1181–1182; (n) Piancattelli,
G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867–889;
(o) Galopin, C. C. Tetrahedron Lett. 2001, 42, 5589–5591;
(p) Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem.
Soc., Perkin Trans. 1 2002, 1735–1742.
3.4.6. (S)-2-Isopropyl-1-phenyl-1,4-pentanedione (6e).
An oil; [a]2D5 +110 (c 0.7, CHCl3); HRMS (EI) m/z
218.1292 (M+, 2, C14H18O2 requires 218.1307), 161 (17),
1
133 (5), 105 (100), 77 (33), 51 (9); H NMR (300 MHz,
CDCl3) d 0.92 (d, J¼6.8 Hz, 3H), 1.04 (d, J¼6.9 Hz, 3H),
2.02 (m, 1H), 2.15 (s, 3H), 2.52 (dd, J¼18.0, 3.3 Hz, 1H),
3.18 (dd, J¼18.0, 10.5 Hz, 1H), 3.82 (ddd, J¼10.2, 4.8,
3.3 Hz, 1H), 7.44 (dt, J¼7.5, 1.2 Hz, 2H), 7.52 (tt, J¼7.2,
1.5 Hz, 1H), 7.96 (dd, J¼8.7, 1.8 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 18.5 (q), 21.2 (q), 29.7 (d), 30.1 (q),
41.1 (t), 47.0 (d), 128.4 (d), 128.5 (d), 132.7 (d), 137.4 (s),
203.1 (s), 207.7 (s).
2. (a) Gribble, G. W. Comprehensive Heterocyclic Chemistry;
Katrizky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon:
Oxford, 1996; Vol. 2, p 207; (b) Benassi, R. Comprehensive
Heterocyclic Chemistry; Katrizky, A. R., Rees, C. W.,
Scriven, E. F., Eds.; Pergamon: New York, NY, 1996; Vol. 2,
p 259; (c) Amarnath, V.; Anthony, D. C.; Amarnath, K.;
Valentine, W. M.; Wetterau, L. A.; Graham, D. G. J. Org.
Chem. 1991, 56, 6924–6931; (d) Hou, X. L.; Cheung, H. Y.;
3.4.7. (S)-2-p-Methoxyphenyl-1-phenyl-1,4-pentane-
dione (6f). An oil; [a]2D5 +39 (c 1.8, CHCl3); HRMS (EI)
m/z 282.1244 (M+, 66, C18H18O3 requires 282.1255), 264

G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
9181
Hon, T. U.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955–2020; (e) Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 1999, 2849–2866; (f) Ferreira, V. F.; de
Sousa, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira,
M. L. G. Org. Prep. Proced. Int. 2001, 33, 411–454; (g)
Raghavan, S.; Anuradha, K. Synlett 2003, 711–713.
Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004,
346, 1147–1168; (o) Ballini, R.; Bosica, G.; Fiorini, D.;
Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933–971;
(p) Zielinska-B1ajet, M.; Kowalczyk, R.; Skarz_ewski, J.
Tetrahedron 2005, 61, 5235–5240; (q) Evans, D. A.; Seidel,
D. J. Am. Chem. Soc. 2005, 127, 9958–9959; (r) Lattanzi,
A. Tetrahedron: Asymmetry 2006, 17, 837–841.
3. (a) Pecunioso, A.; Menicagli, R. J. Org. Chem. 1988, 53, 2614–
2617; (b) Freeman, F.; Kim, D. S. H. L.; Rodriguez, E. J. Org.
Chem. 1992, 57, 1722–1727; (c) Wedler, C.; Schick, H.
Synthesis 1992, 543–544; (d) Katritzky, A. R.; Zhang, G. F.;
Jiang, J. L. J. Org. Chem. 1995, 60, 7605–7611; (e) Huang,
J.-T.; Su, T.-L.; Watanabe, K. A. J. Org. Chem. 1991, 56,
4811–4815; (f) Lu, X. Y.; Ji, J. G.; Ma, D. W.; Shen, W.
J. Org. Chem. 1991, 56, 5774–5778; (g) Bergman, R.;
Nilsson, R.; Wickberg, B. Tetrahedron Lett. 1990, 31, 2783–
2786; (h) Matsumoto, S.; Okubo, Y.; Mikami, K. J. Am.
Chem. Soc. 1998, 120, 4015–4016; (i) Yasuda, M.; Tsuji, S.;
Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc. 2002, 124, 7440–
7447; (j) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem.
2004, 69, 908–914; (k) Song Xue, A.; Li, L.; Liu, Y.; Guo, Q.
J. Org. Chem. 2006, 71, 215–218.
8. (a) Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033–8061; (b)
€
Krause, N.; Hoffman-Roder, A. Synthesis 2001, 171–196; (c)
Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2001,
3, 4251–4254; (d) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877–1894; (e) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748; (f)
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495;
(g) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580–591; (h) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138–5175; (i) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719–724; (j) Wang, J.; Li, H.;
Zu, L.; Wang, W. Adv. Synth. Catal. 2006, 348, 425–428.
9. (a) Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc.,
Chem. Commun. 1979, 591–592; (b) Colombo, L.; Gennari,
C.; Resnati, G.; Scolastico, C. Synthesis 1981, 74–76; (c)
Colombo, L.; Gennari, C.; Scolastico, C.; Guanti, G.;
Narisano, E. J. Chem. Soc., Perkin Trans. 1 1981, 1278–
1283; (d) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico,
C. J. Chem. Soc., Perkin Trans. 1 1981, 1284–1286; (e)
Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim.
Acta 1996, 79, 1899–1902; (f) Davis, J. H.; Forrester, K.
Tetrahedron Lett. 1999, 40, 1621–1622; (g) Enders, D.;
Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743–1745; (h)
4. Seyferth, D.; Hui, R. C. J. Am. Chem. Soc. 1985, 107, 4551–
4553.
5. (a) Cooke, M. P., Jr.; Parlman, R. M. J. Am. Chem. Soc. 1977,
99, 5222–5224; (b) Hegedus, L. S.; Perry, R. J. J. Org. Chem.
1985, 50, 4955–4960; (c) Corey, E. J.; Hegedus, L. S. J. Am.
Chem. Soc. 1969, 91, 4926–4928; (d) Hermanson, J. R.;
Hershberger, J. W.; Pinhas, A. R. Organometallics 1995, 14,
5426–5437; (e) Seyferth, D.; Hui, R. C. Tetrahedron Lett.
1986, 27, 1473–1476; (f) Lipshutz, B. H.; Elworthy, T. R.
Tetrahedron Lett. 1990, 31, 477–480; (g) Li, N.-S.; Yu, S.;
Kabalka, G. W. Organometallics 1998, 17, 3815–3818.
6. (a) Hassner, A.; Lokanatha Rai, K. M. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 2, p 541; (b) Stetter, H.; Kuhlmann, H. Org.
React. 1991, 40, 407–496; (c) Yadav, J. S.; Anuradha, K.;
Subba Reddy, B. V.; Eeshwaraiah, B. Tetrahedron Lett. 2003,
ꢀ
ꢀ
Vazquez, J.; Prieto, A.; Fernandez, R.; Enders, D.; Lassaletta,
J. M. Chem. Commun. 2002, 498–499; (i) Kerr, M. S.; de
Alaniz, J. R. J. Am. Chem. Soc. 2002, 124, 10298–10299; (j)
Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876–
8877; (k) Enders, D.; Balesiefer, T. Acc. Chem. Res. 2004,
37, 534–541; (l) Mennen, S. M.; Blank, J. T.; Tran-Dube,
M. B.; Imbriglio, J. E.; Miller, S. J. Chem. Commun. 2005,
ꢀ
ꢀ
195–197; (m) Vazquez, J.; Cristea, E.; Diez, E.; Lassaletta,
44, 8959–8962; (d) Anjaiah, S.; Chandrasekhar, S.; Gree, R.
ꢀ
Tetrahedron Lett. 2004, 45, 569–571; (e) Mattson, A. E.;
Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 2314–2315; (f) Johnson, J. S. Angew. Chem., Int. Ed.
2004, 43, 1326–1328; (g) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534–541; (h) Barrett, A. G. M.;
Andrew, C.; Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6,
3377–3380; (i) Myers, M. C.; Bharadwaj, A. R.; Milgram,
B. C.; Scheidt, K. A. J. Am. Chem. Soc. 2005, 127, 14675–
14680.
J. M.; Prieto, A.; Fernandez, R. Tetrahedron 2005, 61, 4115–
4128; (n) de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2005,
127, 6284–6289; (o) Nahm, M. R.; Potnick, J. R.; White,
P. S.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128, 2751–2756.
ꢀ
10. Blay, G.; Fernandez, I.; Formentin, P.; Monje, B.; Pedro, J. R.;
Ruiz, R. Tetrahedron 2001, 57, 1075–1081.
ꢀ
11. (a) Blay, G.; Cardona, L.; Fernandez, I.; Michelena, R.; Pedro,
J. R.; Ramırez, T.; Ruiz, R. Synlett 2004, 2325–2328; (b)
´
ꢀ
´
Barroso, S.; Blay, G.; Cardona, L.; Fernandez, I.; Garcıa, B.;
7. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (b)
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345;
(c) Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579–2581;
(d) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S.
Angew. Chem., Int. Ed. 2000, 39, 916–918; (e) Krause, N.;
Pedro, J. R. J. Org. Chem. 2004, 69, 6821–6829.
12. Preliminary results for this work have been published: Blay, G.;
ꢀ
Fernandez, I.; Monje, B.; Pedro, J. R.; Ruiz, R. Tetrahedron
Lett. 2002, 43, 8463–8466.
13. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. 1996, 35, 2708–2748.
€
Hoffmann-Roder, A. Synthesis 2001, 171–196; (f) Enders,
D.; Berner, O. M.; Vignola, N.; Bats, J. W. Chem. Commun.
2001, 2498–2499; (g) Hupe, E.; Knochel, P. Angew. Chem.,
Int. Ed. 2001, 40, 3022–3025; (h) Kacprzak, K.; Gawronski,
J. Synthesis 2001, 961–998; (i) Luchaco-Cullis, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192–8193; (j)
List, B. Tetrahedron 2002, 58, 5573–5590; (k) Molt, O.;
Schrader, T. Synthesis 2002, 2633–2670; (l) Duursma, A.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125,
3700–3701; (m) Ma, J. A.; Cahard, D. Angew. Chem., Int.
Ed. 2004, 43, 4566–4583; (n) Andrey, O.; Alexakis, A.;
14. Aitken, R. A.; Thomas, A. W. Synlett 1998, 102–103.
15. Mase, T.; Houpis, I. A.; Akao, A.; Dorziotis, L.; Emerson, K.;
Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.;
Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.;
Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.;
Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider,
P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775–6786.
16. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313–1324.
17. Kraus, G.; Dneprovskaia, E. Tetrahedron Lett. 2000, 41, 21–24.

9182
G. Blay et al. / Tetrahedron 62 (2006) 9174–9182
18. Handbook of Reagents for Organic Synthesis. Acidic and Basic
Reagents; Reich, J. H., Rigby, J. H., Eds.; Wiley: Chichester,
UK, 1999; pp 160 and 376.
19. Crystallographic data (excluding structure factors) for 4c
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC
607970. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax +44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
20. (a) Biddle, M. M.; Reich, H. J. J. Org. Chem. 2006, 71, 4031–
4039; (b) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001,
123, 6527–6535; (c) Reich, H. J.; Sikorski, W. H. J. Org. Chem.
1999, 64, 14–15.
21. Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55,
157–172.