(S)-Mandelic acid enolate as a chiral benzoyl anion equivalent for the enantioselective synthesis of non-symmetrically substituted benzoins

Article abstract of DOI:10.1016/j.tet.2010.12.012

A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol reaction of the lithium enolate of the 1,3-dioxo

Full text of DOI:10.1016/j.tet.2010.12.012

Tetrahedron 67 (2011) 881e890
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Tetrahedron
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(S)-Mandelic acid enolate as a chiral benzoyl anion equivalent for the
enantioselective synthesis of non-symmetrically substituted benzoins
*
ꢀ
ꢀ
ꢀ
Gonzalo Blay, Isabel Fernandez, Belen Monje, Marc Montesinos-Magraner, Jose R. Pedro
ꢁ
ꢁ
ꢁ
Departament de Química Organica, Facultat de Química, Universitat de Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic
acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol re-
action of the lithium enolate of the 1,3-dioxolan-4-one derived from (S)-mandelic acid and pivalaldehyde
with aromatic aldehydes, which gives the corresponding aldols in good yields. Subsequent hydroxyl group
Received 4 November 2010
Received in revised form 3 December 2010
Accepted 6 December 2010
Available online 10 December 2010
protection as MEM ethers, basic hydrolysis of the dioxolanone ring, oxidative decarboxylation of the a-
hydroxy acid moiety, and hydroxyl group deprotection provides chiral non-symmetrically substituted
benzoins with high enantiomeric excesses.
Keywords:
Umpolung
Aldol reaction
Dioxolanone
Hydroxy ketones
Decarboxylation
Ó 2010 Elsevier Ltd. All rights reserved.
3
O
2
4
O
1. Introduction
H
t
LDA
H
H
Bu CHO
HO2C
HO
5
t
O1
2
Bu
Ph
During the last years, we have reported several highly diaster-
eoselective reactions of the (S)-mandelic acid enolate with different
electrophiles and the transformation of the corresponding adducts
into highly enantioenriched compounds.1 In this context we have
Ph
(S)-(+)-1
O
R1
O
described the Michael reaction using a,b-unsaturated ketones as
3
O
O
R1
R2
H
H
acceptors and the transformation of the resulting adducts into
chiral non-racemic 2-substituted-1,4-diketones,2 which formally
involves the use of (S)-mandelic acid as a source of a chiral benzoyl
anion (Scheme 1).
O
O
R2
Ph
t
t
O
O
Bu
Bu
Ph
4
The preservation of the chiral information of (S)-mandelic acid
is based on Seebach’s principle of self-regeneration of stereo-
centers3 whilst its use as an ‘Umpoled’ equivalent of the benzoyl
from Michael acceptor
R1
O
1. Hydrolysis
anion is based on an oxidative decarboxylation of
developed in our laboratory.4 According to this principle (Scheme
1), chiral -hydroxy acids, such as (S)-mandelic acid (1), are
a-hydroxy acids
Ph
R2
2. Oxidative
a
O
decarboxylation
5
transformed by acetalization with pivalaldehyde into cis-1,3-diox-
olan-4-ones 2, which can be isolated in enantiomerically pure form.
The dioxolanone is transformed into a non-racemic enolate by
deprotonation at the original sterogenic center C5 with a base such
as lithium diisopropylamide (LDA) at low temperatures. Sub-
from "benzoyl anion"
Scheme 1. Synthesis of chiral non-racemic 1,4-diketones from mandelic acid.
sequent reaction of the enolate with an electrophile (an a,b-un-
saturated ketone 3, for example) proceeds under the influence of
the temporary acetal stereogenic center C2, yielding a dioxolanone
derivative 4 resulting from the exclusive anti approach of the
electrophile with respect to the tert-butyl group. Therefore, the
chirality of the starting stereocenter of (S)-mandelic acid is regen-
erated. 2-Substituted-1,4-dicarbonyl compounds 5 were obtained
with very high enantiomeric excesses from compounds 4, by
* Corresponding author. Tel.: þ34963544329; fax: þ34963544328; e-mail
address: jose.r.pedro@uv.es (J.R. Pedro).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.012

882
G. Blay et al. / Tetrahedron 67 (2011) 881e890
hydrolysis of the dioxolanone ring and subsequent aerobic oxida-
tive decarboxylation of the
-hydroxy acid moiety.2
reaction. However, the absence of stereochemical control at C5 for
the addition reactions of (2S,5S)-1,3-dioxolan-4-one derived from
(S)-lactic acid and pivalaldehyde to linear aliphatic aldehydes and
benzaldehyde has been reported by Battaglia.23
a
In this paper wewish to report the use of a similar strategy (Fig.1)
for the enantioselective synthesis of non-symmetrically substituted
benzoins 11 through the diastereoselective addition of the (2S,5S)-
1,3-dioxolan-4-one 2 enolate to aromatic aldehydes 6 and the sub-
sequent transformation of the resulting aldol products 7.
OH
O
O
1. LDA
H
H
O
H
O
Ar
t
t
O
Bu
Ph
2. ArCHO (6)
O
Bu
Ph
7
2
OMEM
Ar
O
1, Separation
H
O
t
O
Bu
Ph
2. MEMCl, DIPEA
8
Fig. 1. Retro-synthetic analysis for benzoins.
OMEM
Ar
Chiral non-symmetrically substituted benzoins are a valuable
class of building blocks in organic and pharmaceutical chemistry
due to their bifunctional nature and especially to the fact that they
have a stereogenic center amenable to further synthetic manipu-
lation.5 Generally, the racemic compounds are prepared by cross-
benzoin condensation from aromatic aldehydes in a reaction
catalyzed by cyanide ions6 or quaternary thiazolium salts derived
ylides.7 This condensation involves a masked acyl anion equivalent
as intermediate and in fact several kinds of masked acyl anions,
OMEM
t
O2, Bu CHO
Ph
KOH
HO2C
Ar
Co complex
Ph
O
EtOH-H2O
HO
9
10
OH
Ar
TiCl4
such as O-protected cyanohydrins,8
cyanophosphates,10 and dithioacetals11 have been also used in ad-
dition reactions to carbonyl compounds to give -hydroxy ketones.
a
-(dialkylamino)nitriles,9
Ph
O
a
However, only few efficient enantioselective synthesis of benzoins
have been described so far. Enders12 and co-workers developed
several new chiral triazolium salts as precatalysts in the synthesis
of benzoins, Leeper13 and Bach14 introduced novel thiazolium salts
as precatalysts, Davis15 and Xu16 showed that thiazolium and imi-
dazolium ion-based ionic liquids also promote the benzoin con-
densation. Iwamoto17 carried out the reaction in water and
Degani18 developed a microwave-assisted benzoin condensation in
aqueous media. In addition, cross-benzoin condensations usually
yield mixtures of all possible symmetrically and non-symmetrically
substituted benzoins, and only a very few examples of synthesis of
enantiopure non-symmetrically substituted benzoins have been
reported so far. Mullersbib19b and co-workers have described the
first asymmetric cross-benzoin condensation with high selectiv-
ities and enantiomeric excesses utilizing thiamine diphosphate
11
Scheme 2. Synthesis of chiral non-symmetrically substituted benzoins.
In our case, we studied the reaction of (2S,5S)-1,3-dioxolan-
4-one 2 with benzaldehyde (6a) in order to optimize the reaction
conditions. The best results in terms of yield and diaster-
eoselectivity were obtained in the following conditions: compound
2 was deprotonated by addition to a freshly prepared solution of
LDA (1.25 equiv) in THF at ꢀ78 ꢁC, and then benzaldehyde (6a)
(1.25 equiv) in THF was added to the resulting enolate. Stirring for
1 h at ꢀ78 ꢁC and quenching with aqueous NH4Cl at ꢀ78 ꢁC, gave
product 7a in 84% yield.24 1H NMR analysis of the reaction mixture
revealed the presence of three out of four possible diastereomers
for 7a in a 76:14:10:0 ratio (Table 1, entry 1). Flash chromatography
allowed to obtain pure the two major aldols 7a-A and 7a-B (Fig. 2).
The stereochemical structures of these two diastereomers were
elucidated by NOE experiments. Irradiation in compound 7a-A of
0.96 corresponding to the tert-butyl group enhanced
7.47 corresponding to the ortho-protons of the phenyl
group derived from mandelic acid. Besides, irradiation of the signal
at 5.72 corresponding to proton H2 of the dioxolanone ring en-
hanced the signal at 5.23 corresponding to the proton geminal to
the hydroxyl group. Thus, in compound 7a-A the phenyl group
derived from mandelic acid remains syn to the tert-butyl group.
Consequently the absolute stereochemistry of the newly formed
quaternary carbon was assigned to be R upon the consideration that
the absolute configuration of the dioxolanone carbon C5 bearing
the tert-butyl group in 2 is S and it keeps unaltered from 2 to 7a-A.
(ThDP)-dependent enzymes by taking advantage of
a new
donoreacceptor concept for enzymatic cross-coupling reactions of
aldehydes. Johnson20 has reported a cross-silyl benzoin conden-
sation catalyzed by cyanide in which the starting acylsilanes acted
as good acyl anion precursors avoiding the usual problem of self-
condensation. The same authors have also developed an enantio-
selective version using metallophosphites as catalysts.21 A new
strategy for the enantioselective synthesis of benzoins based on an
oxidative kinetic resolution of racemic benzoins has been reported
recently.22
the signal at
the signal at
d
d
d
d
2. Results and discussion
The synthesis of enantiomerically enriched non-symmetrically
substituted benzoins is outlined in Scheme 2. The first step involves
the addition of the enolate of (2S,5S)-2-tert-butyl-5-phenyl-1,3-
dioxolan-4-one (2) to aromatic aldehydes 6. According to Seebach’s
principle of self-regeneration of stereocenters,3 the configuration of
the starting (S)-mandelic acid should be regenerated during this
In compound 7a-B irradiation of the signal at
to the tert-butyl group enhanced the signal at
to the proton geminal to the hydroxyl group and irradiation of the
signal at 5.02 corresponding to proton H2 of the dioxolanone ring
enhanced the signal at 7.38 corresponding to the ortho-protons of
d
0.90 corresponding
5.22 corresponding
d
d
d

G. Blay et al. / Tetrahedron 67 (2011) 881e890
883
Table 1
Aldol reaction of (2S,5S)-1,3-dioxolan-4-one (2) with several aromatic aldehydes 6
Entry
Ar
6
Yielda (%)
Ratiob A/B/C/D
Ratioc (AþC)/(BþD)
Ratiod (AþB)/(CþD)
1
2
3
4
5
6
7
Ph
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3,4-OCH2OeC6H3
4-CF3C6H4
6a
6b
6c
6d
6e
6f
84
86
60
71
69
70
59
76:14:10:0
70:22:8:0
61:22:17:0
53:19:25:3
73:19:7:1
68:28:4:0
33:23:40:4
86:14
78:22
78:22
78:22
80:20
72:28
73:27
90:10
92:8
83:17
72:28
92:8
96:4
56:44
6g
a
Combined yield of all four diastereomers.
Ratio determined by 1H NMR.
See text. A and C are Seebach aldols, B and D are non-Seebach aldols.
b
c
d
See text. Aldols A and B lead to (S)-benzoin, aldols C and D would lead to (R)-benzoin.
OH
O-Li+
Ph
O
O
H
H
H
H
O
O
t
ArCHO
LDA/ THF
TS II
O
5S
Ar
t
t
O
O
Bu
Ph
Bu 2S
O
Bu
Ph
2S
6
(2S,5S)-2
7
TS I
TS IV
TS III
Li
O
Ph
Li
O
Li
Li
O
O
O
H
H
H
H
O
H
O
Ar
t
O
O
O
O
O
H
O
Ar
O
t
t
t
Ph
O
Bu
Bu
O
Bu
Ph
Bu
Ph
H
Ar
Ar
H
OH
O
OH
O
O
O
H
H
H
H
Ph
Ph
O
O
t
O
O
Ar
Ar
Ar
Ar
t
t
t
O
O
Bu
Bu
O
O
Bu
Ph
Bu
Ph
OH
OH
D (2S,5S,1'R)
B (2S,5S,1'S)
A (2S,5R,1'S)
C (2S,5R,1'R)
Fig. 2. Possible TS for the approach of aldehyde 6 to the enolate of compound 2.
the phenyl group derived from mandelic acid. Therefore, in com-
pound 7a-B the phenyl group derived from mandelic acid and the
tert-butyl group are anti. Consequently the absolute stereochem-
istry of the newly formed quaternary carbon was assigned to be S
for aldol 7a-B.
The absolute configuration of the hydroxyl-supporting carbon
atom in the side chain could not be determined at this stage, but it
was shown to be S in both major aldols, 7a-A and 7a-B after con-
version of these compounds separately into (S)-(þ)-benzoin and
comparison of the specific rotations sign with that of an authentic
commercially available sample (see further on).25 Consequently,
the stereochemistry of this hydroxyl-supporting carbon atom
should be R in both minor diastereomers 7a-C and 7a-D, which
would differ in the stereochemistry of the quaternary carbon of the
dioxolanone ring.26
The optimized conditions were then applied to other
substituted aromatic aldehydes (6beg), bearing either electron-
donating or electron-withdrawing groups. The reaction of 2 with
aldehydes 6bef gave the corresponding aldol products 7bef in
good yields and with high diastereoselectivities, in particular the
high facial diastereoselectivity with respect to the aldehyde car-
bonyl (last column, Table 1). However, in the case of aldehyde 6g,
bearing a strong electron-withdrawing substituent, the facial dia-
stereoselectivity was very low.
Interestingly, in the addition of compound 2 to p-chlor-
obenzaldehyde (6c) and also in the case of p-bromobenzaldehyde
(6d), all three diastereomers could be isolated. The stereochemical
structures of these three diastereomers were elucidated by NOE
experiments. Compounds 7c-A and 7c-B showed the same ste-
reochemical pattern as 7a-A and 7a-B. With regards to the third
diastereomer 7a-C, the NOE experiments showed that the phenyl
group derived from mandelic acid remained syn to the tert-butyl
group and consequently the absolute stereochemistry of the newly
formed quaternary carbon was assigned to be R (as in 7c-A), and the
hydroxyl-supporting carbon atom in the side chain should be R.
All the diastereomers obtained in the addition reaction of 2 with
the different aldehydes (6aef) show a very good correlation between
the chemical shifts of the signals corresponding to proton H2 of
the dioxolanone ring and to the tert-butyl group, and the stereo-
chemistry of the diastereomer compounds. So, in type A di-
astereomers, H2 appears at
appears at 0.95e0.97 ppm; in type B diastereomers, H2 appears at
5.01e5.02 ppmandthetert-butyl group appears at 0.90e0.94 ppm.
Finally, in type C diastereomers, H2 appears at 4.60e4.80 ppm and
the tert-butyl group appears at 0.83e0.86 ppm.
d 5.71e5.73 ppm and the tert-butyl group
d
d
d
d
d
The stereochemical outcome of the reaction can be explained
according to the transition states formulated by Battaglia23 to
explain the diastereoselectivity observed in a related reaction,

884
G. Blay et al. / Tetrahedron 67 (2011) 881e890
namely the addition of the enolate of cis-1,3-dioxolan-4-one de-
rived of (S)-lactic acid and pivalaldehyde to aldehydes. Type A and
C diastereomers could be formed through the kinetically favored
transition states TS I and TS II, respectively, which result from the
approach of the aldehyde to the less hindered Re face of the
enolate, according to Seebach’s principle of self-regeneration of
stereocenters (Seebach products). On the other hand, type B and D
diastereomers could be formed through transition states TS III and
TS IV, respectively, which result from the approach to the Si face of
the enolate (non-Seebach products). So, the facial diaster-
eoselectivity with respect to the enolate would be (AþC)/(BþD),
which indicates the extent of compliance with Seebach’s principle
of self-regeneration of stereocenters.
However, as the final objective of our synthesis is the prepara-
tion of enantioenriched non-symmetrically substituted benzoins,
and since the quaternary stereogenic center in the dioxolanone ring
is lost in further stages of our synthesis, the overall enantiose-
lectivity of the synthetic sequence does not depend on the facial
stereoselectivity with respect the enolate but with respect to the
aldehyde carbonyl, that is, the ratio (AþB)/(CþD) (last column of
Table 1), since 6a-A and 6a-B yield both the (S)-benzoin, while 6a-C
and 6a-D would both lead to the (R)-benzoin.
-
O
O
O
N
N
N
N
+
Co
NMe4
O
Me Me
Fig. 3. Co(III) ortho-phenylene-bis(N0-methyloxamidate) complex.
However, in the cases of MEM-protected benzoins 10eef, which
bear strong electron-donating substituents, the yields were lower,
probably due to a benzylic oxidative cleavage. For example, when
a
-hydroxy acid 9e-A was subjected to the oxidative de-
carboxylation three products were obtained: MEM-protected
benzoin 10e (54%), MEM-protected p-methoxybenzoic acid (18%)
and p-methoxybenzaldehyde (14%). The structure of all MEM-
protected benzoins 10a-f was determined by spectroscopic
methods, particularly 1H and 13C NMR and mass spectrometry. In
the 1H NMR spectra the signals corresponding to the proton gem-
inal to the MEMO-group appeared at
13C NMR spectra the signals corresponding to the carbonyl group
and the MEMO-supporting carbon appeared at 196.2e196.6 ppm
and 79.1e80.0 ppm, respectively. Hydroxy acids 9a-A and 9a-B
d 6.03e6.09 ppm and in the
With the aldol products 7 in our hands we carried out the pro-
tection of the hydroxyl group in order to avoid the retro-aldol re-
action during the basic hydrolysis of the 1,3-dioxolan-4-one moiety
and a possible over-oxidation27 during the oxidative decarboxylation
d
d
yielded both the same MEM-protected benzoin 10a. The materials
obtained from both hydroxy acids showed identical spectroscopic
features and values of specific optical rotations [
CHCl3), which were also identical to those of the product obtained
upon MEM protection of commercial (S)-(þ)-benzoin. In this way,
the absolute configuration of the chiral stereocenter in compound
10a was established to be S. Similarly, the MEM-protected benzoins
10e obtained separately from compounds 9e-A and 9e-B were
of the a-hydroxy acid moiety. This protection was carried out by
25
a
]
þ11.0 (c 0.8,
D
the reaction of aldols 7 with MEM-chloride and diisopropylethyl-
amine (DIPEA) in acetonitrile at reflux temperature to afford MEM
derivatives 8, with good yields (Table 2).28 The structure of all
MEM-protected aldols 8aef was determined by spectroscopic
methods, particularly 1H and 13C NMR and mass spectrometry.
As with aldols 7, the 1H NMR spectra signals corresponding to proton
H2 and the tert-butyl group in compounds 8 showed characteristic
chemical shifts. Thus, for type A diastereomers, H2 appeared
shown to be identical with the same value of specific optical rota-
22
tions [
a]
þ126.1 (c 0.9, CHCl3). On the assumption of a uniform
D
reaction mechanism for the aldol reaction between dioxolanone 2
and aromatic aldehydes 6, the absolute configuration for all MEM-
protected benzoins 10a-f was assigned as S.
at
d
d
5.71e5.73 ppm and the tert-butyl group appeared at
0.97e0.98 ppm, whilts for type B diastereomers they appeared at
5.01e5.04 ppm and 0.74e0.80 ppm, respectively.
d
d
Table 2
Synthesis of (S)-benzoins from aldols 7
Entry
7
Hydroxyl protection
Hydrolysis
Product
Oxidative decarboxylation
MEM cleavage
Product
Yielda (%)
Yielda (%)
Product
Yielda (%)
Product
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Ph
Ph
7a-A
7a-B
7b-A
7c-A
7d-A
7e-A
7e-B
7f-A
8a-A
8a-B
8b-A
8c-A
8d-A
8e-A
8e-B
8f-A
70
89
75
69
66
80
90
75
9a-A
9a-B
9b-A
9c-A
9d-A
9e-A
9e-B
9f-A
97
86
96
80
90
98
89
92
10a
10a
10b
10c
10d
10e
10e
10f
62
60
66
62
70
54
59
39
11a
11a
11b
11c
11d
11e
11e
11f
85
85
90
80
91
35
35
60
99
99
99
99
99
40
40
54
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
3,4-OCH2OeC6H3
a
Yields refer to isolated product.
Determined by chiral HPLC.
b
Once the hydroxyl group was protected as MEM derivative, we
carried out the basic hydrolysis of the dioxolanone moiety to obtain
the corresponding -hydroxy acids 9. The reaction was carried out
at room temperature, by treatment with 5% ethanolic KOH. In all
the cases the reaction yields were equal or higher to 80% (Table 2).
Finally the MEM-protected benzoins were treated with TiCl4 in
order to remove the MEM protecting group: the reaction proceeded
with good yields to provide highly enantioenriched benzoins
11aed (99% ee). However, in the cases of benzoins 11eef, bearing
strong electron-donating substituents, the yields and the enantio-
meric excesses were lower, due probably to the formation of
a benzylic carbocation facilitated by the presence of the strong
electron-donating group. In the 1H NMR spectra of all benzoins
11aef the signal corresponding to the proton geminal to the hy-
a
The oxidative decarboxylation of the a-hydroxy acid moiety was
carried out using a catalytic procedure developed in our laboratory,
which employs oxygen as terminal oxidant in the presence of
pivalaldehyde and of a catalytic amount of the Co(III) ortho-phe-
nylene-bis(N0-methyloxamidate) complex (Fig. 3).4 Under these
conditions the MEM-protected benzoins 10aed were obtained
with fair to good yields (Table 2).
droxyl group appeared at
spectra the signals corresponding to the carbonyl group and the
hydroxyl-supporting carbon appeared at 198.5e199.0 ppm and
d
5.84e5.94 ppm and in the 13C NMR
d

G. Blay et al. / Tetrahedron 67 (2011) 881e890
885
d
75.4e76.2 ppm, respectively. At this point, the absolute configu-
þ125.9 (c 1.5, CHCl3); HRMS m/z (EI, 70 eV) 326.1526 (Mþ, 1.0),
C20H22O4 requires 326.1518, 220 (100.0, Mþꢀ106); 1H NMR
ration of benzoin 11a was confirmed again to be S by comparison of
its specific optical rotation and the retention time in chiral HPLC
with those of an authentic sample of enantiomerically pure (S)-
(þ)-benzoin.25,29 Also the absolute configuration of benzoin 11c
was found to be S by comparison with literature data.22
In summary, we have developed a strategy for the enantiose-
lective synthesis of non-symmetrically substituted benzoins. This
strategy is based on a diastereoselective aldol reaction of a masked
benzoyl anion equivalent with aromatic aldehydes that formally
involves the use of (S)-mandelic acid as the source of chiral in-
formation and as source of benzoyl anion. This strategy appears as
a convenient method for the synthesis of enantioenriched non-
symmetricalbenzoins substituted with moderateelectron-donating
or electron-withdrawing groups.
(400 MHz, CDCl3)
d
0.90 (s, 9H), 3.00 (d, J¼2.4 Hz, 1H, OH), 5.02 (s,
1H), 5.22 (d, J¼2.0 Hz, 1H), 7.24 (m, 5H), 7.38 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 23.4 (q), 34.1 (s), 77.2 (d), 84.5 (s), 108.1 (d), 126.6
(d), 127.6 (d), 127.9 (d), 128.2 (d), 128.5 (d), 129.1 (d), 131.7 (s), 136.5
(s), 172.6 (s).
3.2.3. (2S,5R,10S)-2-(tert-butyl)-5-phenyl-5-[10-hydroxy-10-(4-metyl-
25
phenyl)methyl]-1,3-dioxolane-4-one (7b-A). [
a]
ꢀ20.4 (c 0.8,
D
CHCl3); m/z (FABþ) 363.1572 (Mþ, 100.0), C21H24O4Na requires
363.1572; 1H NMR (300 MHz, CDCl3)
d 0.95 (s, 9H), 2.25 (s, 3H), 2.59
(br s,1H, OH), 5.16 (br s,1H), 5.72 (s,1H), 6.92 (AA0 system, J¼8.2 Hz,
4H), 7.23 (m, 3H), 7.47 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 21.1 (q),
23.4 (q), 35.0 (s), 80.7 (d), 85.2 (s),111.2 (d),125.3 (d),127.7 (d),127.8
(d), 127.9 (d), 128.3 (d), 134.3 (s), 135.5 (s), 137.9 (s), 173.4 (s).
3. Experimental section
3.1. General procedures
3.2.4. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(4-meth-
25
ylphenyl)methyl]-1,3-dioxolan-4-one (7b-B). [
a
]
þ120.6 (c 1.4,
D
CHCl3); HRMS m/z (FABþ) 363.1577 (Mþ, 100.0), C21H24O4Na re-
quires 363.1572; 1H NMR (300 MHz, CDCl3)
0.91 (s, 9H), 2.30 (s,
3H), 2.99 (br s,1H, OH), 5.01 (s, 1H), 5.16 (br s,1H), 7.04 (m, 4H), 7.36
(m, 5H); 13C NMR (75 MHz, CDCl3)
21.1 (q), 23.4 (q), 34.1 (s), 77.1
All melting points are uncorrected. Column chromatography was
performed on silica gel (Merck, silica gel 60, 230e400 mesh). Optical
rotations were measured on a PerkineElmer 243 polarimeter. NMR
spectra were recorded on a Bruker Avance 300 DPX spectrometer
(300 MHz for 1H NMR and 75 MHz for 13C NMR) or a Varian Unity
400 (400 MHz for 1H 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. Chiral HPLC analyses were
performed in Hitachi chromatograph equipped with a UV diode-
array detector using chiral stationary columns from Daicel.
(2S,5S)-2-tert-Butyl-5-phenyl-1,3-dioxolan-4-one (2) was prepared
according to the literature.30 All new compounds were determined
to be >95% pure by 1H NMR spectroscopy.
d
d
(d), 84.4 (s), 108.0 (d), 126.6 (d), 127.8 (d), 128.2 (d), 128.4 (d), 128.9
(d), 131.8 (s), 133.4 (s), 137.8 (s), 172.6 (s).
3.2.5. (2S,5R,10S)-2-(tert-Butyl)-5-[10-(4-chlorophenyl)-10-hydrox-
25
ymethyl]-5-phenyl-1,3-dioxolan-4-one (7c-A). [
a]
ꢀ28.1 (c 0.6,
D
CHCl3); HRMS m/z (EI, 70 eV) 362.1102/360.1154 (Mþ, 0.7/2.2),
C20H21O4Cl requires 362.1099/360.1128, 220 (100.0, C13H16O3), 134
(24.3), 70 (58.4); 1H NMR (300 MHz, CDCl3)
d 0.95 (s, 9H), 2.80 (br s,
1H, OH), 5.20 (br s, 1H), 5.73 (s, 1H), 6.91 (d, J¼8.5 Hz, 2H), 7.11 (d,
J¼8.5 Hz, 2H), 7.25 (m, 3H), 7.44 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
23.4 (q), 35.1 (s), 80.2 (d), 85.1 (s), 111.4 (d), 125.2 (d), 127.7 (d),
128.0 (d), 128.2 (d), 129.1 (d), 134.0 (s), 135.1 (s), 135.8 (s), 173.2 (s).
3.2.6. (2S,5S,10S)-2-(tert-Butyl)-5-[10-(4-chlorophenyl)-10-hydrox-
3.2. General experimental procedure for the aldol addition
ymethyl]-5-phenyl-1,3-dioxolan-4-one (7c-B). Mp 132e134 ꢁC
25
(CH2Cl2); [
a
]
þ123.5 (c 0.7, CHCl3); HRMS m/z (EI, 70 eV)
D
A solution of (2S,5S)-2-(tert-butyl)-5-phenyl-1,3-dioxolane-4-
one (2) (220 mg, 1 mmol) in dry THF (0.85 mL) was added slowly to
a fresh solution of LDA (1.25 mmol) in dry THF (5 mL) at ꢀ78 ꢁC
under Ar. After stirring for 45 min, a solution of the corresponding
aldehyde 6 (1.25 mmol) in dry THF (0.39 mL) was added at ꢀ78 ꢁC
and the mixture was stirred for 1 h at ꢀ78 ꢁC. The reaction was
quenched with a saturated aqueous solution of NH4Cl and was
extracted with diethyl ether (3ꢂ30 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4), and
evaporated and the residue was purified by flash chromatography
to afford aldols 7. Yields are included in Table 1. From the di-
astereomeric mixtures, the following diastereomers could be
obtained in pure form by flash column chromatography (eluting
with hexaneediethyl ether or hexaneedichloromethane mixtures).
362.1050/360.1312 (Mþ, 0.6/2.1), C20H21O4Cl requires 362.1099/
360.1128, 220 (100.0, C13H16O3), 134 (22.8), 70 (47.9); 1H NMR
(300 MHz, CDCl3)
(s, 1H), 7.09 (d, J¼8.5 Hz, 2H), 7.20 (d, J¼8.6 Hz, 2H), 7.35 (m, 5H);
13C NMR (75 MHz, CDCl3)
23.4 (q), 34.1 (s), 77.0 (d), 84.1 (s), 108.1
d 0.93 (s, 9H), 3.17 (br s, 1H, OH), 5.02 (s, 1H), 5.16
d
(d), 126.6 (d), 127.7 (d), 128.5 (d), 129.1 (d), 129.2 (d), 131.2 (s), 134.0
(s), 134.9 (s), 172.5 (s).
3.2.7. (2S,5R,10R)-2-(tert-Butyl)-5-[10-(4-chlorophenyl)-10-hydrox-
ymethyl]-5-phenyl-1,3-dioxolan-4-one (7c-C). Mp 174e176 ꢁC
(CH2Cl2); [
a
]
25 þ21.7 (c 0.8, CHCl3); HRMS m/z (EI, 70 eV) 362.1117/
D
360.1346 (Mþ, 1.0/3.3), C20H21O4Cl requires 362.1099/360.1128, 220
(100.0, C13H16O3), 134 (18.4), 70 (61.6); 1H NMR (300 MHz, CDCl3)
d
0.85 (s, 9H), 2.28 (d, J¼2.5 Hz, 1H, OH), 4.78 (s, 1H), 5.07 (d,
J¼2.4 Hz, 1H), 7.27 (m, 4H), 7.37 (m, 3H), 7.67 (m, 2H); 13C NMR
3.2.1. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-(10-phenyl-10-hydrox-
(75 MHz, CDCl3) d 23.4 (q), 35.3 (s), 78.9 (d), 85.1 (s), 110.6 (d), 125.7
25
ymethyl)-1,3-dioxolan-4-one (7a-A). Mp 112e114 ꢁC (CH2Cl2); [
a
]
(d), 128.3 (d), 128.4 (d), 128.6 (d), 129.1 (d), 134.6 (s), 135.1 (s), 135.4
(s), 171.3 (s).
D
ꢀ20.2 (c 0.7, CHCl3); HRMS m/z (CI, methane) 325.3467 (MþꢀH,
2.0), C20H21O4 requires 325.3402, 220 (49.1, Mþꢀ106); 1H NMR
(400 MHz, CDCl3)
d
0.96 (s, 9H), 2.46 (d, J¼3.8 Hz, 1H, OH), 5.23 (d,
3.2.8. (2S,5R,10S)-5-[10-(4-Bromophenyl)-10-hydroxymethyl]-2-(tert-
J¼3.6 Hz, 1H), 5.72 (s, 1H), 7.02 (dd, J¼7.2, 0.8 Hz, 2H), 7.23 (m, 6H),
butyl)-5-phenyl-1,3-dioxolan-4-one (7d-A). Mp 58e60 ꢁC (CH2Cl2);
7.47 (dd, J¼7.2, 3.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d
23.5 (q), 35.1
[
a
]
25 ꢀ28.4 (c 0.6, CHCl3); HRMS m/z (EI, 70 eV) 276.9854/274.9928
D
(s), 81.0 (d), 85.1 (s), 111.3 (d), 125.3 (d), 127.7 (d), 127.8 (d), 127.9 (d),
128.1 (d), 128.3 (d), 135.5 (s), 137.3 (s), 173.3 (s).
(MþꢀC6H11O3, 2.9/3.1), C10H12O4Br requires 276.9898/274.9919,
220 (100.0, C13H16O3), 105 (26.4, C7H5O), 70 (49.4, C5H10); 1H NMR
(300 MHz, CDCl3)
d
0.95 (s, 9H), 2.69 (d, J¼4.1 Hz, 1H, OH), 5.20 (d,
3.2.2. (2S,5S,10S)-2-(tert-butyl)-5-phenyl-5-(10-phenyl-10-hydrox-
J¼3.9 Hz, 1H), 5.73 (s, 1H), 6.85 (d, J¼8.5 Hz, 2H), 7.26 (m, 3H), 7.27
25
ymethyl)-1,3-dioxolane-4-one (7a-B). Mp 86e88 ꢁC (CH2Cl2); [
a
]
(d, J¼8.5 Hz, 2H), 7.45 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 23.4 (q),
D

886
G. Blay et al. / Tetrahedron 67 (2011) 881e890
35.1 (s), 80.2 (d), 85.0 (s), 111.4 (d), 122.3 (s), 125.3 (d), 128.0 (d),
128.2 (d), 129.4 (d), 130.7 (d), 135.1 (s), 136.3 (s), 173.1 (s).
(s), 77.0 (d), 84.5 (s), 100.9 (t), 107.4 (d), 108.1 (d), 108.6 (d), 121.5 (d),
126.6 (d), 128.5 (d), 129.1 (d), 130.4 (s), 131.7 (s), 147.0 (s), 147.4 (s),
172.6 (s).
3.2.9. (2S,5S,10S)-5-[10-(4-Bromophenyl)-10-hydroxymethyl]-2-(tert-
butyl)-5-phenyl-1,3-dioxolan-4-one (7d-B). Mp 125e127 ꢁC
3.2.15. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(4-tri-
fluoromethylphenyl)methyl]-1,3-dioxolan-4-one (7g-A). HRMS m/z
(EI, 70 eV) 263.0665 (MþꢀC6H11O3, 12.6), C15H10OF3 requires
263.0684, 220 (100.0, C13H16O3), 105 (61.4, C7H5O), 70 (77.2, C5H10);
(CH2Cl2); [
a
]
25 þ117.1 (c 0.7, CHCl3); HRMS m/z (EI, 70 eV) 276.9824/
D
274.9922 (MþꢀC6H11O3, 6.0/6.2), C10H12O4Br requires 276.9898/
274.9919; 220 (100.0, C13H16O3),105 (25.4, C7H5O), 70 (63.3, C5H10);
1H NMR (300 MHz, CDCl3)
d
0.93 (s, 9H), 3.17 (d, J¼2.3 Hz, 1H, OH),
1H NMR (300 MHz, CDCl3)
d
0.96 (s, 9H), 2.65 (d, J¼4.1 Hz, 1H, OH),
5.02 (s, 1H), 5.14 (d, J¼2.1 Hz, 1H), 7.02 (d, J¼8.5 Hz, 2H), 7.34 (d,
5.31 (d, J¼4.1 Hz, 1H), 5.75 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 23.4
J¼8.5 Hz, 2H), 7.35 (m, 5H); 13C NMR (75 MHz, CDCl3)
d
23.4 (q),
(q), 35.1 (s), 80.2 (d), 85.0 (s), 111.5 (d), 173.0 (s).
34.1 (s), 76.6 (d), 84.0 (s), 108.1 (d), 122.2 (s), 126.6 (d), 128.5 (d),
129.2 (d), 129.5 (d), 130.6 (d), 131.1 (s), 135.4 (s), 172.5 (s).
3.2.16. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(4-tri-
fluoromethylphenyl)methyl]-1,3-dioxolan-4-one (7g-B). HRMS m/z
(EI, 70 eV) 263.0670 (MþꢀC6H11O3, 10.8), C15H10OF3 requires
263.0684, 220 (100.0, C13H16O3), 105 (53.8, C7H5O), 70 (64.9,
3.2.10. (2S,5R,10R)-5-[10-(4-Bromophenyl)-10-hydroxymethyl]-2-
(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (7d-C). Mp 178e180 ꢁC
(CH2Cl2); [
a
]
25 þ20.9 (c 0.9, CHCl3); HRMS m/z (EI, 70 eV) 276.9842/
C5H10); 1H NMR (300 MHz, CDCl3)
d 0.92 (s, 9H), 3.18 (d,
D
274.9920 (MþꢀC6H11O3, 6.1/6.3), C10H12O4Br requires 276.9898/
J¼2.4 Hz, 1H, OH), 5.03 (s, 1H), 5.26 (d, J¼2.3 Hz, 1H); 13C NMR
274.9919, 220 (100.0, C13H16O3), 105 (46.8, C7H5O), 70 (43.2, C5H10);
(75 MHz, CDCl3)
172.4 (s).
d 23.4 (q), 34.1 (s), 76.6 (d), 84.1 (s), 108.2 (d),
1H NMR (300 MHz, CDCl3)
d 0.85 (s, 9H), 2.29 (br s, 1H, OH), 4.79 (s,
1H), 5.05 (br s, 1H), 7.19 (br d, J¼8.5 Hz, 2H), 7.37 (m, 3H), 7.44 (br d,
J¼8.5 Hz, 2H), 7.67 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 23.4 (q),
35.3 (s), 78.9 (d), 85.0 (s), 110.6 (d), 122.8 (s), 125.7 (d), 128.4 (d),
128.7 (d), 129.4 (d), 131.2 (d), 135.0 (s), 135.9 (s), 171.3 (s).
3.3. General procedure for the protection of the hydroxyl
group
3.2.11. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(4-me-
A solution of compound 7 (0.5 mmol) and diisopropylethyl-
amine (0.43 mL, 2.4 mmol) in dry CH3CN (1.6 mL) under argon was
treated with 0.18 mL (1.6 mmol) of MEMCl. The mixture was stirred
and heated at reflux for 1e2 h. The reaction was quenched with
water and extracted with CH2Cl2 (3ꢂ20 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4), and
evaporated and the residue was purified by flash chromatography
(silica gel, hexaneediethyl ether), to afford adducts 8. Yields are
included in Table 2.
25
thoxyphenyl)methyl]-1,3-dioxolan-4-one (7e-A). [
a
]
ꢀ20.7 (c 0.6,
D
CHCl3); HRMS m/z (EI, 70 eV) 356.1618 (Mþ, 0.9), C21H24O5 requires
356.1624, 220 (33.4, C13H16O3), 137 (100.0, C9H13O), 105 (16.0,
C7H5O); 1H NMR (300 MHz, CDCl3)
d
0.96 (s, 9H), 2.46 (d, J¼3.8 Hz,
1H, OH), 3.73 (s, 3H), 5.17 (d, J¼3.8 Hz, 1H), 5.71 (s, 1H), 6.68 (d,
J¼8.9 Hz, 2H), 6.95 (d, J¼8.9 Hz, 2H), 7.24 (m, 3H), 7.47 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 23.4 (q), 35.0 (s), 55.1 (q), 80.5 (d), 85.2 (s),
111.2 (d), 113.0 (d), 125.3 (d), 127.8 (d), 127.9 (d), 129.0 (d), 129.5 (s),
135.6 (s), 159.4 (s), 173.5 (s).
3.3.1. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-phenyl-10-(2-methox-
25
3.2.12. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(4-me-
thoxyphenyl)methyl]-1,3-dioxolan-4-one (7e-B). Mp 89e91 ꢁC
yethoxymethoxy)methyl]-1,3-dioxolan-4-one (8a-A). [
a
]
þ103.3
D
(c 1.0, CHCl3); HRMS m/z (CI, methane) 415.2121 (Mþþ1, 8.1),
(CH2Cl2); [
a
]
25 þ108.5 (c 0.9, CHCl3); HRMS m/z (EI, 70 eV) 356.1550
C24H31O6 requires 415.2121, 309 (20.3), 195 (21.0), 167 (66.2), 105
D
(Mþ, 0.4), C21H24O5 requires 356.1524, 220 (20.1, C13H16O3), 137
(14.2, C7H5O), 89 (100.0, C7H5); 1H NMR (300 MHz, CDCl3)
d 0.97 (s,
(MþꢀC13H16O3,100.0, C8H9O2), 70 (22.9, C5H10); 1H NMR (300 MHz,
9H), 3.39 (s, 3H), 3.56 (m, 3H), 3.90 (m, 1H), 4.63 (d, J¼7.0 Hz, 2H),
CDCl3)
d
0.93 (s, 9H), 3.01 (d, J¼2.5 Hz, 1H, OH), 3.77 (s, 3H), 5.01 (s,
5.21 (s, 1H), 5.73 (s, 1H), 6.96 (dd, J¼8.4, 1.6 Hz, 2H), 7.0e7.2 (m,
1H), 5.15 (d, J¼2.5 Hz, 1H), 6.76 (d, J¼8.9 Hz, 2H), 7.09 (d, J¼8.7 Hz,
6H), 7.45 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 23.5 (q), 35.0 (s),
2H), 7.37 (m, 5H); 13C NMR (75 MHz, CDCl3)
d
23.5 (q), 34.1 (s), 55.2
59.0 (q), 67.4 (t), 71.7 (t), 83.4 (d), 84.9 (s), 92.9 (t), 110.9 (d), 125.4
(d), 127.4 (d), 127.8 (d), 128.0 (d), 128.2 (d), 129.0 (d), 134.0 (s), 135.3
(s), 173.1 (s).
(q), 76.9 (d), 84.5 (s), 108.0 (d), 113.0 (d), 126.6 (d), 128.4 (d), 128.6
(s), 129.0 (d), 129.1 (d), 131.8 (s), 159.5 (s), 172.7 (s).
3.2.13. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(3,4-
3.3.2. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-phenyl-10-(2-methox-
25
25
methylendioxyphenyl)methyl]-1,3-dioxolan-4-one (7f-A). [
a
]
ꢀ40.1
yethoxymethoxy)methyl]-1,3-dioxolan-4-one (8a-B). [
a
]
þ134.4
D
D
(c 1.1, CHCl3); HRMS m/z (EI, 70 eV) 370.1405 (Mþ, 3.9), C21H22O6
(c 1.2, CHCl3); HRMS m/z (CI, methane) 413.1915 (MþꢀH, 1.5),
requires 370.1416, 220 (97.3, C13H16O3), 151 (100.0, C7H3O4), 93 (28.1,
C24H29O6 requires 413.1964, 223 (8.4), 195 (29.3, C14H11O), 167
C6H5O), 70 (58.9, C5H10); 1H NMR (300 MHz, CDCl3)
d
0.97 (s, 9H),
(93.7), 89 (100.0); 1H NMR (300 MHz, CDCl3)
d 0.74 (s, 9H), 2.70
2.40 (d, J¼3.7 Hz, 1H, OH), 5.15 (d, J¼3.7 Hz, 1H), 5.72 (s, 1H), 5.91 (d,
J¼1.4 Hz, 2H), 6.35 (dd, J¼8.0, 1.6 Hz, 1H), 6.54 (d, J¼8.0 Hz, 1H), 6.71
(d, J¼1.6 Hz, 1H), 7.26 (m, 3H), 7.49 (m, 2H); 13C NMR (75 MHz,
(m, 1H), 3.06 (m, 2H), 3.20 (m, 1H), 3.27 (s, 3H), 4.45 (d, J¼7.2 Hz,
2H), 5.01 (s, 1H), 5.27 (s, 1H), 7.2e7.4 (m, 8H), 7.66 (dd, J¼8.1 Hz,
1.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 23.4 (q), 33.9 (s), 58.9 (q),
CDCl3)
d
23.5 (q), 35.1 (s), 80.7 (d), 85.1 (s), 101.0 (t), 107.4 (d), 108.1
66.6 (t), 71.4 (t), 80.4 (d), 85.8 (s), 93.3 (t), 108.1 (d), 126.3 (d),
127.9 (d), 128.4 (d), 128.5 (d), 128.6 (d), 129.4 (d), 133.8 (s), 135.4
(s), 171.3 (s).
(d), 111.3 (d), 121.7 (d), 125.3 (d), 128.0 (d), 128.1 (d), 131.2 (s), 135.5
(s), 147.2 (s), 147.5 (s), 173.3 (s).
3.2.14. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-hydroxy-10-(3,4-
3.3.3. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-(4-methylphenyl)-10-
25
25
methylendioxyphenyl)methyl]-1,3-dioxolan-4-one
(7f-B). [
a
]
(2-methoxyethoxymethoxy)methyl]-1,3-dioxolan-4-one (8b-A). [a]
D
D
þ114.5 (c 0.6, CHCl3); HRMS m/z (EI, 70 eV) 370.1414 (Mþ, 15.3),
þ105.2 (c 0.8, CHCl3); HRMS m/z (EI, 70 eV) 401.1929 (MþꢀC2H3,
0.3), C23H29O6 requires 401.1964, 209 (11.0, C12H17O3), 105 (15.7,
C7H5O), 89 (100.0, C4H9O2), 59 (38.8, C3H7O); 1H NMR (300 MHz,
C21H22O6 requires 370.1416, 220 (100.0, C13H16O3), 151 (80.3), 105
(29.7, C7H5O); 1H NMR (300 MHz, CDCl3)
d
0.94 (s, 9H), 3.03 (d,
J¼2.5 Hz, 1H, OH), 5.02 (s, 1H), 5.11 (d, J¼2.4 Hz, 1H), 5.90 (s, 2H),
6.67 (m, 3H), 7.38 (m, 5H); 13C NMR (75 MHz, CDCl3)
23.5 (q), 34.1
CDCl3)
d 0.97 (s, 9H), 2.24 (s, 3H), 3.39 (s, 3H), 3.59 (m, 3H), 3.88
d
(m, 1H), 4.61 (d, J¼7.0 Hz, 2H), 5.18 (s, 1H), 5.72 (s, 1H), 6.84 (d,

G. Blay et al. / Tetrahedron 67 (2011) 881e890
887
J¼8.3 Hz, 2H), 6.91 (d, J¼8.2 Hz, 2H), 7.23 (m, 3H), 7.47 (m, 2H);
13C NMR (75 MHz, CDCl3)
21.1 (q), 23.5 (q), 34.9 (s), 58.9 (q),
123.2 (d), 125.3 (d), 127.6 (s), 127.8 (d), 128.0 (d), 135.3 (s), 147.1 (s),
147.4 (s), 173.1 (s).
d
67.3 (t), 71.7 (t), 83.2 (d), 84.9 (s), 92.6 (t), 110.7 (d), 125.4 (d),
127.8 (d), 127.9 (d), 128.2 (d), 128.9 (d), 130.8 (s), 135.4 (s), 137.8
(s), 173.2 (s).
3.4. General procedure for the hydrolysis of compounds 8
Compound 8 (0.28 mmol) was treated with a 5% KOH solution in
ethanol at room temperature until complete reaction of the starting
material (TLC) was achieved. The solution was poured into ice and
acidified with 1 M HCl until pH 2. The aqueous mixture was
extracted with EtOAc and the organic layers were washed with
brine until neutrality, dried (MgSO4), filtered, and concentrated
3.3.4. (2S,5R,10S)-2-(tert-Butyl)-5-[10-(4-chlorophenyl)-10-(2-me-
thoxyethoxymethoxy)methyl]-5-phenyl-1,3-dioxolan-4-one (8c-A).
[
a
]
25 þ94.0 (c 0.7, CHCl3); HRMS m/z (EI, 70 eV) 423.1325/421.1413
D
(MþꢀC2H3, 0.3/1.0), C22H26O6Cl requires 423.1388/421.1418, 105
(17.9, C7H5O), 89 (100.0, C4H9O2), 59 (41.3, C3H7O); 1H NMR
under reduced pressure to give
cluded in Table 2.
a-hydroxy acids 9. Yields are in-
(300 MHz, CDCl3)
d 0.97 (s, 9H), 3.39 (s, 3H), 3.5e3.9 (m, 4H), 4.61
(d, J¼7.0 Hz, 2H), 5.19 (s,1H), 5.72 (s,1H), 6.88 (d, J¼8.5 Hz, 2H), 7.09
(d, J¼8.5 Hz, 2H), 7.23 (m, 3H), 7.44 (m, 2H); 13C NMR (75 MHz,
3.4.1. (2R,3S)-2,3-Diphenyl-2-hydroxy-3-(2-methoxyethox-
CDCl3) d 23.5 (q), 35.0 (s), 59.0 (q), 67.5 (t), 71.6 (t), 82.6 (d), 84.6 (s),
ymethyoxy)propanoic acid (9a-A). [
a
]
25 þ14.5 (c 0.7, CH3OH); HRMS
D
92.9 (t), 110.9 (d), 125.3 (d), 127.7 (d), 128.0 (d), 128.2 (d), 130.2 (d),
132.6 (s), 134.1 (s), 135.0 (s), 172.8 (s).
m/z (CI, methane) 347.1487 (Mþþ1, 1.9), C19H23O6 requires
347.1495, 241 (19.5), 225 (12.2), 195 (16.0, C4H11), 105 (30.2, C7H5O),
89 (100.0, C7H5); 1H NMR (300 MHz, DMSO)
d 3.18 (s, 3H), 3.2e3.5
3.3.5. (2S,5R,10S)-5-[10-(4-Bromophenyl)-10-(2-methoxyethox-
(m, 3H), 3.66 (m, 1H), 4.52 (d, J¼6.6 Hz, 2H), 5.31 (s, 1H), 7.12 (m,
ymethoxy)methyl]-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (8d-A).
8H), 7.48 (d, J¼8.3, 1.7 Hz, 2H); 13C NMR (75 MHz, DMSO)
d 58.3 (q),
25
[
a
]
þ87.6 (c 0.6, CHCl3); HRMS m/z (EI, 70 eV) 309.1483/
D
66.8 (t), 71.3 (t), 80.8 (s), 82.3 (d), 93.1 (t), 126.5 (d), 127.1 (d), 127.2
(d), 127.3 (d), 127.5 (d), 127.7 (d), 129.6 (d), 136.9 (s), 175.1 (s).
308.1507 (MþꢀC4H9O3eBr, 3.2/3.4, C20H20O3 requires 309.1446/
308.1413), 89 (100.0); 1H NMR (300 MHz, CDCl3)
d 0.97 (s, 9H),
3.40 (s, 3H), 3.58 (m, 3H), 3.89 (m, 1H), 4.62 (d, J¼7.0 Hz, 2H),
3.4.2. (2S,3S)-2,3-Diphenyl-2-hydroxy-3-(2-methoxyethox-
5.18 (s, 1H), 5.71 (s, 1H), 6.81 (d, J¼8.5 Hz, 2H), 7.25 (m, 5H), 7.43
ymethoxy)propanoic acid (9a-B). [
a
]
25 þ61.9 (c 0.6, CH3OH); HRMS
D
(m, 2H); 13C NMR (75 MHz, CDCl3)
d 23.5 (q), 35.0 (s), 59.0 (q),
m/z (EI, 70 eV) 346.1424 (Mþ, 0.3), C19H22O6 requires 346.1416,
67.5 (t), 71.6 (t), 82.7 (d), 84.6 (s), 92.9 (t), 110.9 (d), 122.4 (s),
125.3 (d), 128.0 (d), 128.2 (d), 130.5 (d), 130.7 (d), 133.2 (s), 135.0
(s), 172.8 (s).
105 (31.0, C7H5O), 89 (100.0, C4H9O2); 1H NMR (300 MHz, DMSO)
d
2.9e3.3 (m, 4H), 3.14 (s, 3H), 4.28 (d, J¼7.0 Hz, 2H), 5.33 (s, 1H),
7.2e7.4 (m, 8H), 7.71 (br d, J¼7.2 Hz, 2H); 13C NMR (75 MHz,
DMSO)
d 58.4 (q), 66.5 (t), 71.2 (t), 81.0 (s), 81.1 (d), 92.6 (t), 126.8
3.3.6. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-(4-methoxyphenyl)-
(d), 127.3 (d), 127.5 (d), 127.6 (d), 128.0 (d), 129.9 (d), 137.6 (s),
141.5 (s), 173.8 (s).
10-(2-methoxyethoxymethoxy)methyl]-1,3-dioxolan-4-one (8e-A). Mp
69e71 ꢁC (CH2Cl2); [
a]
D
25 þ112.1 (c 0.6, CHCl3); HRMS m/z (EI, 70 eV)
339.1597 (MþꢀC4H9O3, 1.2), C21H23O4 requires 339.1596), 225
3.4.3. (2R,3S)-2-Phenyl-2-hydroxy-3-(4-methylphenyl)-3-(2-me-
(MþꢀC13H15O3, 15.2, C12H17O4, 105 (13.6, C7H5O), 89 (100.0, C7H5);
25
thoxyethoxymethoxy)propanoic acid (9b-A). [
a
]
D
þ25.9 (c 0.5,
1H NMR (300 MHz, CDCl3)
d 0.98 (s, 9H), 3.40 (s, 3H), 3.5e3.7 (m,
CH3OH); HRMS m/z (EI, 70 eV) 296.1438 (MþꢀCO2eH2OeH2), 0.1,
C19H20O3 requires 296.1413, 209 (17.4, C12H17O3), 105 (20.7, C7H5O),
89 (100.0, C4H9O2), 59 (58.9, C3H7O); 1H NMR (300 MHz, DMSO)
3H), 3.73 (s, 3H), 3.90 (m, 1H), 4.60 (d, J¼7.0 Hz, 2H), 5.16 (s, 1H), 5.72
(s, 1H), 6.65 (d, J¼8.7 Hz, 2H), 6.90 (d, J¼8.7 Hz, 2H), 7.23 (m, 3H),
7.46 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 23.5 (q), 35.0 (s), 55.0 (q),
d
2.15 (s, 3H), 3.20 (s, 3H), 3.36 (m, 3H), 3.71 (m, 1H), 4.49 (d,
58.9 (q), 67.3 (t), 71.7 (t), 82.9 (d), 84.9 (s), 92.5 (t),110.8 (d),112.9 (d),
125.4 (d), 125.9 (s), 127.8 (d), 127.9 (d), 130.2 (d), 135.5 (s), 159.4 (s),
173.2 (s).
J¼6.8 Hz, 2H), 5.29 (s, 1H), 6.87 (d, J¼7.9 Hz, 2H), 6.98 (d, J¼8.0 Hz,
2H), 7.16 (m, 3H), 7.49 (dd, J¼7.9, 1.1 Hz, 2H); 13C NMR (75 MHz,
DMSO) d 21.0 (q), 58.3 (q), 66.8 (t), 71.3 (t), 80.8 (s), 81.9 (d), 92.8 (t),
126.5 (d), 127.3 (d), 127.7 (d), 127.9 (d), 129.7 (d), 133.6 (s), 136.5 (s),
136.6 (s), 175.1 (s).
3.3.7. (2S,5S,10S)-2-(tert-Butyl)-5-phenyl-5-[10-(4-methoxyphenyl)-
25
10-(2-ethoxyethoxymethoxy)methyl]-1,3-dioxolan-4-one (8e-B). [
a]
D
þ138.9 (c 0.8, CHCl3); HRMS m/z (CI, methane) 443.2059 (MþꢀH,
3.4.4. (2R,3S)-3-(4-Chlorophenyl)-2-phenyl-2-hydroxy-3-(2-me-
0.3), C25H31O7 requires 443.2070, 339 (71.4, C21H23O4), 197 (81.2), 89
25
thoxyethoxymethoxy)propanoic acid (9c-A). [
a
]
þ5.7 (c 0.4,
D
(100.0); 1H NMR (300 MHz, CDCl3)
d 0.79 (s, 9H), 2.68 (m, 1H),
CH3OH); HRMS m/z (EI, 70 eV) 365.0617/363.0679 (MþꢀCH5, 0.1/
0.2), C18H16O6Cl requires 365.0606/363.0635, 105 (28.9, C7H5O),
89 (100.0, C4H9O2), 59 (62.1, C3H7O); 1H NMR (300 MHz, DMSO)
3.0e3.3 (m, 3H), 3.27 (s, 3H), 3.79 (s, 3H), 4.44 (d, J¼7.2 Hz, 2H), 5.01
(s, 1H), 5.21 (s, 1H), 6.82 (d, J¼8.9 Hz, 2H), 7.33 (d, J¼8.9 Hz, 2H), 7.35
(m, 3H), 7.65 (dd, J¼8.4, 1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 23.4
d
3.18 (s, 3H), 3.31 (m, 3H), 3.65 (m, 1H), 4.53 (d, J¼6.2 Hz, 2H),
(q), 33.9 (s), 55.2 (q), 58.9 (q), 66.5 (t), 71.4 (t), 80.0 (d), 85.9 (s), 93.0
(t), 108.0 (d), 113.2 (d), 126.2 (d), 127.2 (d), 127.4 (s), 128.5 (d), 130.7
(d), 133.9 (s), 159.6 (s), 171.3 (s).
5.29 (br s, 1H), 7.12 (m, 7H), 7.51 (d, J¼7.7 Hz, 2H); 13C NMR
(75 MHz, DMSO)
d 58.3 (q), 66.7 (t), 71.3 (t), 80.7 (s), 81.9 (d), 93.5
(t), 126.5 (d), 127.1 (d), 127.2 (d), 127.6 (d), 131.3 (d), 132.0 (s),
135.9 (s), 136.7 (s), 174.6 (s).
3.3.8. (2S,5R,10S)-2-(tert-Butyl)-5-phenyl-5-[10-(3,4-methylendiox-
yphenyl)-10-(2-methoxyethoxymethoxy)methyl]-1,3-dioxolan-4-one
3.4.5. (2R,3S)-3-(4-Bromophenyl)-2-phenyl-2-hydroxy-3-(2-me-
thoxyethoxymethoxy)propanoic acid (9d-A). Mp 125e127 ꢁC
(8f-A). [
a
]
25 þ76.7 (c 0.9, CHCl3); HRMS m/z (CI, methane) 457.1866
D
(MþꢀH, 0.6), C25H29O8 requires 457.1862, 353 (17.1, C18H25O7), 239
25
(EtOAc); [
a
]
þ5.3 (c 0.5, CH3OH); HRMS m/z (CI, methane)
D
(21.9), 211 (100.0); 1H NMR (300 MHz, CDCl3)
d 0.98 (s, 9H), 3.41 (s,
427.0589/425.0668 (Mþþ1, 0.3/0.3), C19H22O6Br requires 427.0579/
425.0600, 323/321 (3.4/3.7, C11H14O6Br), 305/303 (3.6/3.9,
C15H12O2Br), 277/275 (4.5/4.8, C14H12OBr), 187/185 (6.2/6.5,
C7H6OBr), 165 (7.0, C7H17O4), 89 (100.0, C4H9O2), 59 (45.1, C3H7O);
3H), 3.59 (m, 3H), 3.90 (m, 1H), 4.60 (d, J¼7.0 Hz, 2H), 5.12 (s, 1H),
5.71 (s, 1H), 5.90 (d, J¼1.5 Hz, 2H), 6.29 (dd, J¼8.1, 1.7 Hz, 1H), 6.49
(d, J¼7.9 Hz, 1H), 6.68 (d, J¼1.5 Hz, 1H), 7.24 (m, 3H), 7.48 (m, 2H);
13C NMR (75 MHz, CDCl3)
d 23.5 (q), 35.0 (s), 59.0 (q), 67.4 (t), 71.7
1H NMR (300 MHz, DMSO)
d
3.18 (s, 3H), 3.35 (m, 3H), 3.64 (m, 1H),
(t), 82.9 (d), 84.9 (s), 92.5 (t), 100.9 (t), 107.2 (d), 108.8 (d), 110.8 (d),
4.54 (d, J¼6.8 Hz, 2H), 5.29 (s, 1H), 7.02 (d, J¼8.5 Hz, 2H), 7.17 (m,

888
G. Blay et al. / Tetrahedron 67 (2011) 881e890
3H), 7.26 (d, J¼8.4 Hz, 2H), 7.49 (dd, J¼7.9, 1.1 Hz, 2H); 13C NMR
(EI, 70 eV) 314.1522 (Mþ, 0.1), C19H22O4 requires 314.1518, 209
(44.2, C12H17O3), 105 (28.9, C7H5O), 89 (100.0, C4H9O2), 59 (52.5,
(75 MHz, DMSO)
d 58.3 (q), 66.8 (t), 71.3 (t), 80.6 (s), 81.9 (d), 93.4
(t), 120.9 (s), 126.4 (d), 127.5 (d), 127.8 (d), 130.1 (d), 131.7 (d), 136.6
(s), 139.9 (s), 174.8 (s).
C3H7O); 1H NMR (300 MHz, CDCl3)
d 2.29 (s, 3H), 3.34 (s, 3H), 3.48
(t, J¼4.5 Hz, 2H), 3.71 (m, 2H), 4.83 (d, J¼7.0 Hz, 2H), 6.07 (s, 1H),
7.14 (d, J¼7.9 Hz, 2H), 7.37 (d, J¼7.9 Hz, 2H), 7.38 (m, 2H), 7.48 (tt,
J¼7.4, 1.3 Hz, 1H), 7.95 (dd, J¼8.7, 1.5 Hz, 2H); 13C NMR (75 MHz,
3.4.6. (2R,3S)-2-Phenyl-2-hydroxy-3-(4-methoxyphenyl)-3-(2-me-
thoxyethoxymethoxy)propanoic acid (9e-A). Mp 77e79 ꢁC (EtOAc);
CDCl3) d 21.1 (q), 58.9 (q), 67.3 (t), 71.6 (t), 79.6 (d), 93.8 (t),128.1 (d),
25
[
a]
þ30.3 (c 0.5, CH3OH); HRMS m/z (EI, 70 eV) 254.0903
128.4 (d), 128.9 (d), 129.6 (d), 132.8 (s), 133.1 (d), 135.1 (s), 138.5 (s),
196.4 (s).
D
(MþꢀC4H9O3eOH, 2.4), C16H14O3 requires 254.0943, 226
(MþꢀC4H9O3eCO2H, 28.3, C15H14O2), 121 (49.4), 89 (100.0, C7H5);
1H NMR (300 MHz, DMSO)
d
3.21 (s, 3H), 3.37 (m, 3H), 3.62 (s, 3H),
3.5.3. (2S)-2-(4-Chlorophenyl)-1-phenyl-2-(2-methoxyethox-
25
3.72 (m, 1H), 4.48 (d, J¼6.8 Hz, 2H), 5.28 (s, 1H), 6.63 (d, J¼8.7 Hz,
ymethoxy)ethanone (10c-A). [
a
]
D
þ89.8 (c 1.5, CHCl3); HRMS m/z
2H), 7.03 (d, J¼8.7 Hz, 2H), 7.15 (m, 3H), 7.49 (dd, J¼8.3, 1.5 Hz, 2H);
(EI, 70 eV) 336.0976/334.1011 (Mþ, 0.1/0.3), C18H19O4Cl requires
336.0942/334.0972, 229 (20.2, C13H9O4), 105 (45.1, C7H5O), 89
13C NMR (75 MHz, DMSO)
d 55.1 (q), 58.3 (q), 66.8 (t), 71.4 (t), 80.8
(s), 81.6 (d), 92.7 (t),112.7 (d), 126.5 (d), 127.3 (d),127.7 (d),128.5 (s),
128.6 (s), 130.9 (d), 158.7 (s), 175.1 (s).
(100.0, C4H9O2), 59 (59.1, C3H7O); 1H NMR (300 MHz, CDCl3)
d 3.33
(s, 3H), 3.47 (t, J¼4.5 Hz, 2H), 3.68 (m, 2H), 4.84 (d, J¼7.0 Hz, 2H),
6.05 (s, 1H), 7.31 (d, J¼8.5 Hz, 2H), 7.41 (d, J¼8.4 Hz, 2H), 7.3e7.5 (m,
2H), 7.51 (tt, J¼7.5, 1.3 Hz, 1H), 7.94 (dd, J¼8.7, 1.5 Hz, 2H); 13C NMR
3.4.7. (2S,3S)-2-Phenyl-2-hydroxy-3-(4-methoxyphenyl)-3-(2-me-
25
thoxyethoxymethoxy)propanoic acid (9e-B). [
a
]
þ68.9 (c 0.7,
(75 MHz, CDCl3) d 58.9 (q), 67.5 (t), 71.6 (t), 79.2 (d), 94.0 (t), 128.5
D
CH3OH); HRMS m/z (EI, 70 eV) 314.1509 (MþꢀCO2eH2O, 0.3),
(d), 129.0 (d), 129.1 (d), 129.3 (d), 133.4 (d), 134.4 (s), 134.6 (s), 134.9
(s), 196.6 (s).
C19H22O4 requires 314.1518, 225 (100.0, C15H13O2); 1H NMR
(300 MHz, DMSO)
d 2.9e3.5 (m, 4H), 3.15 (s, 3H), 3.73 (s, 3H), 4.25
(d, J¼6.8 Hz, 2H), 5.28 (s, 1H), 6.83 (br d, J¼8.6 Hz, 2H), 7.2e7.4 (m,
3.5.4. (2S)-2-(4-Bromophenyl)-1-phenyl-2-(2-methoxyethox-
25
3H), 7.32 (d, J¼8.6 Hz, 2H), 7.71 (br d, J¼7.1 Hz, 2H); 13C NMR
ymethoxy)ethanone (10d-A). Mp 75e77 ꢁC (CH2Cl2); [
a
]
þ77.1
D
(75 MHz, DMSO)
d
55.3 (q), 58.3 (q), 66.5 (t), 71.3 (t), 80.6 (d), 81.1
(c 0.5, CHCl3); HRMS m/z (CI, methane) 302.9875/300.9856
(Mþþ1ꢀC6H5, 13.5/14.0), C15H10O2Br requires 302.9844/
300.9864, 274/272 (MþꢀCOC6H5, 35.4/37.0, C11H13O3Br), 194
(MþꢀCOC6H5eBr, 41.2, C14H10O), 105 (17.4, C7H5O), 89 (100.0,
(s), 92.2 (t), 113.1 (d), 126.8 (d), 127.2 (d), 127.6 (d), 128.8 (s), 129.4
(s), 131.1 (d), 159.1 (s), 173.8 (s).
3.4.8. (2R,3S)-2-Phenyl-2-hydroxy-3-(3,4-methylendioxyphenyl)-3-
C4H9O2); 1H NMR (300 MHz, CDCl3)
d 3.34 (s, 3H), 3.47 (t,
(2-methoxyethoxymethoxy)propanoic acid (9f-A). [
a
]
25 þ11.4 (c 0.8,
J¼4.7 Hz, 2H), 3.69 (m, 2H), 4.84 (d, J¼7.1 Hz, 2H), 6.03 (s.1H),
D
CH3OH); HRMS m/z (EI, 70 eV) 372.1198 (MþꢀH2O, 1.0), C20H20O7
7.3e7.6 (m, 7H), 7.94 (dd, J¼8.7, 1.5 Hz, 2H); 13C NMR (75 MHz,
requires 372.1209, 239 (36.0, C12H15O5), 89 (100.0, C4H9O2); 1H
CDCl3) d 59.0 (q), 67.6 (t), 71.6 (t), 79.3 (d), 94.1 (t), 122.9 (s), 128.6
NMR (300 MHz, DMSO)
d
3.22 (s, 3H), 3.39 (m, 3H), 3.71 (m, 1H),
(d), 129.0 (d), 129.6 (d), 132.1 (d), 133.4 (d), 134.9 (s), 135.0 (s),
196.2 (s).
4.50 (d, J¼6.8 Hz, 2H), 5.26 (s, 1H), 5.89 (s, 2H), 6.44 (dd, J¼7.9,
1.3 Hz, 1H), 6.56 (d, J¼8.1 Hz, 1H), 6.82 (d, J¼1.3 Hz, 1H), 7.18 (m,
3H), 7.50 (dd, J¼8.5, 1.5 Hz, 2H); 13C NMR (75 MHz, DMSO)
d
58.4
3.5.5. (2S)-1-Phenyl-2-(4-methoxyphenyl)-2-(2-methoxyethox-
25
(q), 66.9 (t), 71.4 (t), 80.8 (s), 81.7 (d), 92.7 (t), 101.0 (t), 107.0 (d),
109.8 (d), 123.6 (d), 126.5 (d), 127.4 (d), 127.8 (d), 130.4 (s), 139.7 (s),
146.6 (s), 146.7 (s), 175.0 (s).
ymethoxy)ethanone (10e-A, 10e-B). [
a
]
þ126.6 (c 0.9, CHCl3);
HRMS m/z (EI, 70 eV) 330.1475 (MþD, 2.0), C19H22O5 requires
330.1467, 225 (50.4), 135 (20.6), 105 (19.1, C7H5O), 89 (100.0,
C4H9O2), 77 (11.4, C6H5), 59 (63.3, C3H7O); 1H NMR (300 MHz,
3.5. General procedure for the oxidative decarboxylation
CDCl3)
d
3.35 (s, 3H), 3.50 (t, J¼4.5 Hz, 2H), 3.6e3.8 (m, 2H), 3.76 (s,
3H), 4.83 (d, J¼7.1 Hz, 2H), 6.07 (s, 1H), 6.86 (d, J¼8.6 Hz, 2H), 7.39
To a stirred solution of a-hydroxy acid 9 (0.13 mmol) in aceto-
(m, 4H), 7.49 (tt, J¼7.4, 1.3 Hz, 1H), 7.95 (dd, J¼8.6, 1.5 Hz, 2H); 13C
nitrile (0.5 mL) were added 3.3 mg of Co(III)Me2opba complex
(6.5ꢂ10ꢀ3 mmol) and pivalaldehyde (0.39 mmol) and the mixture
was stirred for 5 min under air and then under oxygen atmosphere
at room temperature until consumption of the starting material as
indicated by TLC. The reaction was quenched with water and
extracted with diethyl ether. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated and the residue
was purified by flash chromatography (silica gel, hexaneediethyl
ether) to afford ketone 10. Yields are included in Table 2.
NMR (75 MHz, CDCl3) d 55.2 (q), 58.9 (q), 67.3 (t), 71.6 (t), 79.1 (d),
93.6 (t), 114.4 (d), 127.7 (s), 128.5 (d), 128.9 (d), 129.7 (d), 133.1 (d),
135.2 (s), 159.9 (s), 196.4 (s).
3.5.6. (2S)-1-Phenyl-2-(3,4-methylendioxyphenyl)-2-(2-methox-
25
yethoxymethoxy)ethanone (10f-A). [
a
]
þ115.7 (c 1.5, CHCl3);
D
HRMS m/z (EI, 70 eV) 344.1244 (Mþ, 0.6), C19H20O6 requires
344.1260, 239 (75.7, C12H15O5), 89 (100.0); 1H NMR (300 MHz,
CDCl3)
d
3.35 (s, 3H), 3.50 (t, J¼4.5 Hz, 2H), 3.71 (m, 2H), 4.83 (d,
J¼7.4 Hz, 2H), 5.92 (d, J¼1.3 Hz, 2H), 6.03 (s, 1H), 6.75 (d, J¼8.5 Hz,
3.5.1. (2S)-1,2-Diphenyl-2-(2-methoxyethoxymethoxy)ethanone
1H), 6.93 (m, 2H), 7.40 (m, 2H), 7.50 (tt, J¼7.4, 1.3 Hz, 1H), 7.96 (dd,
25
(10a-A, 10a-B). Mp 77e79 ꢁC (CH2Cl2); [
a]
þ111.0 (c 0.8, CHCl3);
J¼8.1, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 59.0 (q), 67.4 (t), 71.7
D
HRMS m/z (CI, methane) 301.1433 (Mþþ1, 0.1), C18H21O4 requires
(t), 79.2 (d), 93.6 (t),101.3 (t),108.4 (d),108.6 (d),122.4 (d),128.5 (d),
128.9 (d), 129.5 (s), 133.2 (d), 135.2 (s), 148.0 (s), 148.2 (s), 196.3 (s).
301.1439, 225 (29.5, C15H13O2), 195 (100.0, C10H11O4), 105 (16.3,
C7H5O), 89 (70.8, C7H5); 1H NMR (300 MHz, CDCl3)
d 3.34 (s, 3H),
3.48 (br t, J¼4.6 Hz, 2H), 3.70 (m, 2H), 4.85 (d, J¼7.1 Hz, 2H), 6.09
3.6. General procedure for the deprotection of the hydroxyl
group
(s, 1H), 7.2e7.5 (m, 8H), 7.96 (dd, J¼8.8, 1.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3)
d 59.0 (q), 67.4 (t), 71.6 (t), 80.0 (d), 94.0 (t), 128.1
(d), 128.5 (d), 128.7 (d), 128.9 (d), 129.0 (d), 133.2 (d), 135.1 (s),
135.8 (s), 196.5 (s).
To a solution of ketone 10 (0.11 mmol) in dry CH2Cl2 (0.64 mL)
cooled at ꢀ20 ꢁC was added dropwise a 1 M solution of TiCl4 in
CH2Cl2 (0.22 mL, 0.22 mmol) under argon. The reaction was stirred
for 5 min and then quenched with 9.3% aqueous NH4OH solution
(0.22 mL) at 0 ꢁC until pH 7. Water was added and the mixture was
3.5.2. (2S)-1-Phenyl-2-(4-methylphenyl)-2-(2-methoxyethox-
ymethoxy)ethanone (10b-A). [
a
]
25 þ134.0 (c 1.4, CHCl3); HRMS m/z
D

G. Blay et al. / Tetrahedron 67 (2011) 881e890
889
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic extracts
were washed with brine (20 mL), dried (MgSO4), and evaporated
and the residue was purified by flash chromatography (silica gel,
hexaneediethyl ether). Yields and enantiomeric excess of benzoins
11 are included in Table 2.
(s); enantiomeric excess (40%) was determined by HPLC (Chiralcel
OD-H), hexaneei-PrOH 90:10, 1 mL/min, major enantiomer (S)
tR¼14.2 min, minor enantiomer (R) tR¼19.3 min.
3.6.6. (2S)-1-Phenyl-2-hydroxy-2-(3,4-methylendioxyphenyl)etha-
none (11f). HRMS m/z (EI, 70 eV) 256.0701 (Mþ, 6.8), C15H12O4 re-
quires 256.0736,162 (33.0),151 (100.0, C8H7O3),149 (46.2), 93 (31.3);
3.6.1. (2S)-1,2-Diphenyl-2-hydroxyethanone (11a). Mp 134e136 ꢁC
(acetone); [
a
]
23 þ109.5 (c 1.3, acetone), commercially available (S)-
1H NMR (400 MHz, CDCl3)
d
4.47 (d, J¼6.0 Hz, OH), 5.84 (d, J¼6.0 Hz,
D
19
(þ)-benzoin:25
[a
]
þ115 (c 1.5, acetone); HRMS m/z (EI, 70 eV)
1H), 5.89 (d, J¼1.2 Hz, 2H), 6.73 (m, 2H), 6.83 (dd, J¼8.0, 1.6 Hz, 1H),
7.39 (t, J¼7.4 Hz, 2H), 7.52 (br t, J¼7.4 Hz, 1H), 7.89 (dd, J¼8.6, 1.2 Hz,
D
212, 0813 (Mþ, 0.6), C14H12O2 requires 212.0837, 107 (54.8), 105
(100.0, C7H5O), 79 (30.2, C6H7), 77 (53.4, C6H5), 51 (13.7); 1H NMR
2H); 13C NMR (75 MHz, CDCl3)
d 75.8 (d),101.3 (t),107.8 (d),108.8 (d),
(300 MHz, CDCl3)
d
4.53 (d, J¼6.1 Hz, 1H, OH), 5.93 (d, J¼6.2 Hz,1H),
121.9 (d), 128.7 (d), 129.1 (d), 132.9 (s), 133.4 (s), 133.9 (d), 147.9 (s),
148.2 (s), 198.8 (s); enantiomeric excess (54%) was determined by
HPLC (Chiralpak AD-H), hexaneei-PrOH 90:10, 1 mL/min, major
enantiomer (S) tR¼45.5 min, minor enantiomer (R) tR¼40.9 min.
7.31 (m, 5H), 7.38 (t, J¼7.8 Hz, 2H), 7.48 (tt, J¼7.5, 1.1 Hz, 1H), 7.90
(dd, J¼8.7,1.8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 76.2 (d),127.7 (d),
128.5 (d), 128.6 (d), 129.0 (d), 129.1 (d), 133.4 (s), 133.9 (d), 139.0 (s),
198.9 (s); enantiomeric excess (99%) was determined by HPLC
(Chiralpak AD-H), hexaneei-PrOH 90:10, 1 mL/min, major enan-
tiomer (S) tR¼26.6 min, minor enantiomer (R) tR¼21.0 min.29
Acknowledgements
This work was financially supported by the Spanish Government
and Generalitat Valenciana. B.M. thanks MCYT for a grant (FPI
program).
3.6.2. (2S)-1-Phenyl-2-hydroxy-2-(4-methylphenyl) ethanone (11b).
25
Mp 113e115 ꢁC (CH2Cl2); [
a
]
þ103.9 (c 1.0, acetone); HRMS m/z
D
(EI, 70 eV) 226.0989 (Mþ, 6.1), C15H14O2 requires 226.0994, 121
(100.0, C8H9O), 105 (19.9, C7H5O), 93 (26.3, C7H9), 77 (32.4, C6H5);
Supplementary data
1H NMR (400 MHz, CDCl3)
d
2.27 (s, 3H), 4.47 (d, J¼6.1 Hz, 1H, OH),
5.90 (d, J¼6.0 Hz, 1H), 7.10 (d, J¼8.2 Hz, 2H), 7.20 (d, J¼8.2 Hz, 2H),
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.12.012.
7.37 (t, J¼7.7 Hz, 2H), 7.50 (t, J¼7.6 Hz, 1H), 7.89 (d, J¼7.4 Hz, 2H);
13C NMR (75 MHz, CDCl3)
d 21.1 (q), 76.0 (d), 127.7 (d), 128.6 (d),
129.1 (d), 129.8 (d), 133.5 (s), 133.8 (d), 136.1 (s), 138.4 (s), 199.0 (s);
enantiomeric excess (99%) was determined by HPLC (Chiralcel OD-
H), hexaneei-PrOH 90:10, 1 mL/min, major enantiomer (S)
tR¼9.8 min, minor enantiomer (R) tR¼14.0 min.
References and notes
ꢀ
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ꢀ
2. (a) Blay, G.; Fernandez, I.; Monje, B.; Pedro, J. R.; Ruiz, R. Tetrahedron Lett. 2002,
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Vila, C. Tetrahedron 2006, 62, 9174e9182.
ꢀ
~
(11c). [a]
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246.0426 (Mþ, 0.4/1.3), C14H11O2Cl requires 248.0418/246.0448,
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143/141 (8.1/24.4, C7H6OCl), 105 (100.0, C7H5O), 77 (38.1, C6H5); 1H
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4H), 7.41 (br t, J¼7.5 Hz, 2H), 7.55 (tt, J¼7.5, 1.3 Hz, 1H), 7.89 (dd,
J¼8.5, 1.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 75.4 (d), 128.8 (d),
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4. (a) Blay, G.; Fernandez, I.; Formentín, P.; Pedro, J. R.; Rosello, A. L.; Ruiz, R.;
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(Chiralpak AS-H), hexaneei-PrOH 85:15, 1 mL/min, major enan-
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€
€
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d 4.57 (d,
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(d), 132.3 (d), 133.2 (s), 134.1 (d), 138.0 (s), 198.5 (s); enantiomeric
excess (99%) was determined by HPLC (Chiralpak AS-H), hexaneei-
PrOH 80:20, 1 mL/min, major enantiomer (S) tR¼9.5 min, minor
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3.6.5. (2S)-1-Phenyl-2-hydroxy-2-(4-methoxyphenyl)ethanone
25
25
(11e). [
a
]
þ47.8 (c 0.8, acetone), lit.21
[
a]
þ111 (c 1.1, acetone);
D
D
HRMS m/z (EI, 70 eV) 242.0933 (Mþ, 11.3), C15H14O3 requires
242.0943, 137 (100.0, C8H9O2), 135 (84.3, C8H7O2), 105 (7.7), 77
(14.5); 1H NMR (300 MHz, CDCl3)
d 3.74 (s, 3H), 4.47 (br s, 1H, OH),
5.89 (br s, 1H), 6.82 (d, J¼8.7 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H), 7.37 (br
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d 55.2 (q), 75.7 (d), 114.5 (d), 128.6
€
19. (a) Dunkelmann, P.; Kolter-Jung, D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen,
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