Highly diastereoselective Michael reaction of (S)-mandelic acid enolate. Chiral benzoyl carbanion equivalent through an oxidative decarboxylation of α-hydroxyacids

Article abstract of DOI:10.1016/S0040-4039(02)02099-3

The reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and high dias

Full text of DOI:10.1016/S0040-4039(02)02099-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8463–8466
Highly diastereoselective Michael reaction of (S)-mandelic acid
enolate. Chiral benzoyl carbanion equivalent through an
oxidative decarboxylation of a-hydroxyacids
Gonzalo Blay, Isabel Ferna´ndez, Bele´n Monje, Jose´ R. Pedro* and Rafael Ruiz
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Universitat de Vale`ncia, E-46100 Burjassot (Vale`ncia), Spain
Received 21 June 2002; revised 23 September 2002; accepted 24 September 2002
Abstract—The reaction of the 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 high diastereoselectivity. Subsequent basic hydrolysis of the acetal and oxidative decarboxylation of the a-hydroxyacid
moiety provides chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. © 2002 Elsevier Science Ltd.
All rights reserved.
The Michael reaction1 is a convenient and useful reac-
tion for carbonꢀcarbon bond formation that affords
two potential contiguous stereogenic centers in the
resulting molecule. However, despite the recent
advances in this area there is still a great need to
develop new methodologies to construct those stereo-
genic centers in a diastereo- and enantioselective fash-
ion.2 In this context, the strategies employed to exert
stereocontrol in the newly created stereogenic centers
involve the introduction of chiral information at the
Michael acceptor or at the enolate as well as the use of
chiral catalysts.3
(S)-mandelic acid enolate to a,b-unsaturated carbonyl
compounds and the transformation of the resulting
adducts into enantioenriched 1,4-dicarbonyl com-
pounds, in an overall sequence where mandelic acid is
used as a chiral benzoyl carbanion equivalent.
Mandelic acid is readily available in both enantiomeri-
cally pure forms, although deprotonation at the a-car-
bon to give the corresponding enolate results in loss of
the stereochemical information. Yet, it is possible to
carry out the alkylation of enolates derived from opti-
cally active (S)-mandelic acid (1) without racemiza-
tion,5 through its previous conversion into a (S,
S)-cis-1,3-dioxolan-4-one 2 with pivalaldehyde (See-
bach principle of self-regeneration of stereocenters)
(Scheme 1).6
We have recently reported the use of methyl mandelate
as an umpoled masked synthon for nucleophilic ben-
zoylation of alkyl halides.4 In this letter we wish to
report the highly stereoselective Michael addition of
The enolate derived from 2 also reacted with saturated
and a,b-unsaturated carbonyl compounds, such as 2-
cyclohexenone, to give the 1,2-adducts with good yields
and diastereoselectivities, while the 1,4-addition
product was not observed at all.5 On the other hand,
the Michael addition of 2 to ethyl crotonate, with low
yield and diastereoselectivity,7 and a highly diastereose-
lective 1,4-addition of the enolate of (R,R)-cis-1,3-diox-
olan-4-one (ent-2) to cyclopentenone, in a synthesis of a
muscarinic receptor antagonist,8 have been reported.
Scheme 1.
Herein we report our results on the highly diastereose-
lective Michael reaction of the lithium enolate of the
(S,S)-cis-1,3-dioxolan-4-one 2 with some a,b-unsatu-
rated carbonyl compounds 4 to give the corresponding
* Corresponding author. Tel.: +34-963864329; fax: +34-963864328;
e-mail: jose.r.pedro@uv.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02099-3

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G. Blay et al. / Tetrahedron Letters 43 (2002) 8463–8466
known that similar enolates suffer some decomposition
even at low temperatures. So a mixture of the (S,S)-cis-
1,3-dioxolan-4-one 2 and enone 4a was treated in THF
at −78°C with LDA. In this way, both the yield as well
as the diastereoselectivity increased slightly to 60% and
to 5a–6a ratio 30:70, respectively (entry 2).
The effect of the enolate aggregation state was also
examined. In most cases, the use of HMPA as an
additive appreciably increases the reactivity as well as
substantially modifies the selectivity.11 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 4a an improvement of the reaction yield, spe-
cially with the inverse addition protocol (85%, entry 4),
together with an increase and a full reversion of the
diastereoselectivity were observed. Thus, only com-
pound 5a was obtained (de >99%). Addition of more
HMPA (6 equiv.) (entries 5 and 6) did not further
enhance the yield nor modified the diastereoselectivity.
Figure 1.
Michael adducts 5 and 6 with good yields and high
diastereoselectivities. These adducts upon basic hydroly-
sis of the acetal furnish compounds 7 and 8 which by
subsequent oxidative decarboxylation of the a-hydroxy-
acid moiety provide access to chiral 2-substituted 1,4-
dicarbonyl compounds 9 and 10 with high enantiomeric
excesses (Fig. 1).
Table 2 shows the results observed for the reaction of
the lithium enolate of 2 with some representative a,b-
unsaturated carbonyl compounds 4a–c using the inverse
addition protocol. In all the three cases the reaction
proceeded with high diastereoselectivity (entries 2, 4
and 6) and the resulting Michael adducts were obtained
as only one diastereoisomer out of the four possible
ones, attending to the configuration of the two newly
created stereogenic centers.
Initially, we performed the reaction of the lithium
enolate of 2 with enone 4a (Table 1) using a direct
addition protocol, that is to say, compound 2 was
deprotonated by addition to a freshly prepared solution
of LDA (1.25 equiv.) in THF at −78°C, and then enone
3a (1 equiv.) was added to the resulting enolate solu-
tion. This process provided a fair yield (49%) of a
separable diastereoisomer mixture of 5a and 6a; how-
ever, only moderate diastereoselectivity (5a–6a ratio
35:65) was obtained (entry 1).9 The reaction was also
performed using an inverse addition protocol10 as it is
With the Michael adducts 5 and 6 in our hands, we
carried out the basic hydrolysis of the acetal moiety to
obtain the corresponding a-hydroxy-d-oxocarboxylic
acids 7 and 8, respectively. Compound 7b was obtained
as an open a-hydroxyacid while the rest of the products
were obtained as cyclic hemiacetal-acids, 7a, 8a, and 8b,
or as lactone-acids 7c and 8c in almost quantitative
yield (Fig. 2). This fact strongly facilitated the stereo-
chemical assignments.12
Table 1. Michael reaction of 1,3-dioxolan-4-one 2 with
enone 4a
Entry
Addition
HMPA (equiv.)
Yielda (%)
5a:6ab
1
2
3
4
5
6
Direct
Inverse
Direct
Inverse
Direct
Inverse
0
0
3
3
6
6
49
60
64
85
53
82
35:65
30:70
97:3
100:0
98:2
The oxidative decarboxylation of the open a-hydroxy-
acid 7b and the cyclic hemiacetal-acids 7a, 8a, and 8b
was carried out using a catalytic procedure developed
recently in our laboratory for a-hydroxyacids which
employs oxygen as terminal oxidant in the presence of
pivalaldehyde and of a catalytic amount of the Co(III)
99:1
a Yields refer to isolated products.
b Ratios determined by 1H NMR.
ortho-phenylene-bis(N%-methyloxamidate)
complex
Table 2. Michael reaction of 1,3-dioxolan-4-one 2 with a,b-unsaturated carbonyl compounds 4 using the inverse addition
protocol
Entry
R1
R2
HMPA (equiv.)
Product
Yielda (%)
5:6b
30:70
100:0
65:35
2:98
1
2
3
4
5
6
Me
Me
Ph
Ph
Me
Me
Et
Et
Me
Me
OMe
OMe
0
3
0
3
0
3
5a–6a
5a–6a
5b–6b
5b–6b
5c–6c
5c–6c
60
85
34
83
40
74
40:60
0:100
a Yields refer to isolated products.
b Ratios determined by 1H NMR.

G. Blay et al. / Tetrahedron Letters 43 (2002) 8463–8466
8465
Typical experimental procedures
Michael reaction (inverse addition): A solution of freshly
prepared LDA (1.25 mmol) in dry THF (1.3 mL) was
slowly added to a solution of (S,S)-cis-1,3-dioxolan-4-
one 2 (220 mg, 1 mmol) and the a,b-unsaturated car-
bonyl compound 4 (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 (3×30 mL). The combined
organic extracts were washed 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 5
and 6. Yields are included in Table 2.
Figure 2.
(Fig. 3).13 Under these conditions the 1,4-dicarbonyl
compounds 9b, 9a, 10a and 10b were obtained, respec-
tively, with fair to good yields (Fig. 4, Table 3).14 Much
more important these products were obtained enan-
Basic hydrolysis of the Michael adducts: The Michael
adduct 5 or 6 (0.28 mmol) was treated with 5% ethano-
lic KOH (0.63 mL, 0.56 mmol) at room temperature
until complete reaction of the starting material (TLC).
The solution was poured into ice and acidified with 1 M
HCl until pH:2. The aqueous mixture was extracted
with EtOAc (3×30 mL), the organic layers were washed
with brine until neutrality was reached, dried, filtered
and concentrated under reduced pressure to give com-
pounds 7 or 8 in almost quantitative yield.
1
tiomerically enriched (ee >99%) as proven by H NMR
experiments using the chiral lanthanide shift reagent
Eu(hfc)3 under conditions previously optimized for a
racemic mixture.15
In summary, we have developed a strategy for the
asymmetric Michael reaction of a masked benzoyl
anion equivalent with a,b-unsaturated carbonyl com-
pounds that formally involves the use of (S)-mandelic
acid as the source of benzoyl anion and as source of
chiral information. This strategy appears as a conve-
nient method for the synthesis of highly enantioen-
riched 2-substituted 1,4-dicarbonyl compounds.
Oxidative decarboxylation of compounds 7 and 8: See
Ref. 4.
Acknowledgements
This work was financially supported by the Spanish
Government (MCYT, projects PB97-1411 and BQU
2001-3017) and in part by Generalitat Valenciana. R.R.
(Ramo´n y Cajal program) and B.M. (FPI program)
thank MCYT for a grant.
References
Figure 3.
Figure 4.
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Table 3. Oxidative decarboxylation of cyclic hemiacetal-
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a
Entry
S.m.
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R2
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1
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4
7a
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a Reaction time 24 h.

8466
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15. Racemic mixtures of 1,4-dicarbonyl compounds were pre-
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