Enantioselective direct aldol reaction of α-keto esters catalyzed by (Sa)-binam-d-prolinamide under quasi solvent-free conditions

Article abstract of DOI:10.1039/c2ob25224d

(S_a)-Binam-d-prolinamide (20 mol%), instead of (S _a)-binam-l-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.

Full text of DOI:10.1039/c2ob25224d

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PAPER
Enantioselective direct aldol reaction of α-keto esters catalyzed by
(Sa)-binam-D-prolinamide under quasi solvent-free conditions†‡
Santiago F. Viózquez,a Abraham Bañón-Caballero,a Gabriela Guillena,*a Carmen Nájera*a and
Enrique Gómez-Bengoa*b
Received 31st January 2012, Accepted 22nd March 2012
DOI: 10.1039/c2ob25224d
(Sa)-Binam-D-prolinamide (20 mol%), instead of (Sa)-binam-L-prolinamide, in combination with
chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto
esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions,
providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.
derived from 1,1′-binaphthyl-2,2′-diamine (binam) 110,14 and 211
Introduction
(Fig. 1), or even using polystyrene supported binam-prolinamide
312 for the inter-10,14 and intramolecular11 aldol reactions under
these reaction conditions, has allowed the synthesis of interesting
chiral compounds9e,11c,d in high levels of enantioselectivity. In
all these cases, the best results, for the aldol reaction between
aldehydes and ketones or the cross aldol reaction between alde-
hydes, in terms of diastereo- and enantioselectivities were
achieved by using catalyst 1a [(Sa)-binam-L-prolinamide] or
2 [N-tosyl-(Sa)-binam-L-prolinamide].
Only recently the use of solvent-free reaction conditions for
the aldol reaction between acetone and α-keto esters using as
organocatalyst a primary–tertiary diamine derived from L-serine
has been reported.15 However, chiral prolinamides have been not
used for this type of transformation.1e Therefore, continuing with
our work, we describe here the application of binam-prolin-
amides in the aldol reaction between α-keto esters and ketones to
The use of organocatalysed protocols in the enantioselective
direct aldol reaction is well recognised nowadays due to the prac-
tical advantages of these compared to other bio- or metal cata-
lysed procedures.1 The level of expertise gained in these types of
reactions has promoted the application of organocatalysed
methods to other enantioselective C–C2 and C–heteroatom pro-
cesses.3 While the organocatalysed aldol reaction with aldehydes
as electrophiles is well established, the use of ketones as accep-
tors has rarely been reported, probably due to the poor electro-
philic character of these compounds. Only a few reports using
highly active non-enolizable ketones as electrophiles are found
in the literature. This reaction has been mainly performed using
proline4 and proline derivatives.5 In this transformation, very
interesting chiral tertiary alcohols,6 which are key pharmaceutical
intermediates,4b are formed. In most cases, the use of a large
excess of the nucleophilic ketone counterpart is required in order
to shift the equilibrium involved to the formation of the corre-
sponding aldol products, diminishing the atom efficiency of the
reaction7 and hampering the general use of this type of trans-
formation. The application of solvent-free reaction conditions8 to
perform the organocatalysed direct aldol by several groups9
including ours10–13 has allowed reduction of the excess of the
aldol donor and facilitated the use of valuable ketones as starting
materials to perform this transformation. The use of prolinamides
aDpto. Química Orgánica and Instituto de Síntesis Orgánica,
Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain.
E-mail: gabriela.guillena@ua.es, cnajera@ua.es;
Fax: +34-965903549; Tel: +34-965903549
bDepartamento de Química Orgánica I, Universidad del País Vasco,
Apdo.1072, 20080 San Sebastián, Spain.
E-mail: enrique.gomez@ehu.es; Fax: (+) 34-943015270
†Dedicated to the memory of Prof. Balbino Mancheño.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25224d
Fig. 1 Binam-prolinamides used as organocatalyst in the aldol
reaction.
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Table 1 Optimization of the reaction conditions between acetone (4a) and 2-phenyl-2-oxoacetate (5a)a
Entry
Cat.
Acid (mol%)
Solvent (mL)
T (°C)
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
ent-1a
1b
2
AcOH (150)
AcOH (150)
AcOH (20)
AcOH (150)
AcOH (150)
AcOH (150)
AcOH (150)
AcOH (150)
AcOH (100)
AcOH (300)
AcOH (100)
AcOH (100)
AcOH (100)
AcOH (100)
AcOH (100)
AcOH (100)
Me3CCO2H (100)
ICH2CO2H (100)
ClCH2CO2H (100)
BrCH2CO2H (100)
Cl2CHCO2H (100)
CF3CO2H (100)
ClCH2CO2H (100)
ClCH2CO2H (100)
ClCH2CO2H (100)
ClCH2CO2H (100)
Acetone (0.5)
—
—
—
—
—
—
—
25
25
25
0
0
0
0
−20
0
0
0
0
0
0
0
25
25
25
25
25
25
25
0
17
17
17
24
24
48
48
48
48
48
96
48
96
96
96
30
30
30
30
30
30
30
72
72
72
72
90
90
93
95
98
96
75
95
90
90
50
50
80
75
40
84
95
97
95
98
40
40
82
10
38
15
16 (R)
15 (R)
4 (R)
32 (R)
36 (S)
56 (S)
0
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
56 (S)
60 (S)
60 (S)
42 (S)
64 (S)
62 (S)
32 (S)
20 (S)
16 (S)
0
60 (S)
62 (S)
50 (S)
30 (S)
16 (S)
70 (S)
46 (S)
60 (S)
44 (S)
9
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d
25e
26f
H2O (0.125)
Hexane (0.125)
CH2Cl2 (0.125)
THF (0.125)
MeOH (0.125)
—
—
—
—
—
—
—
—
—
—
—
0
0
0
a The reaction was carried out using 5 equiv. of acetone (otherwise stated), 20 mol% of catalyst, the indicated amount of acid as co-catalyst at the
indicated temperature. b Isolated yield after column chromatography. c Determined by HPLC. d 1 equiv. of ketone was used. e 10% of catalyst 1b was
used. f 5% of catalyst 1b was used.
give the corresponding chiral tertiary alcohols. The scope of this
reaction would be extended to the use of enolizable α-functiona-
lized ketones, which as far as we know, have not been used
before as nucleophile for this type of transformations.
entries 4–8). Decreasing the temperature to 0 °C raised the enan-
tioselectivity up to 36% by using catalyst (Sa)-binam-L-prolin-
amide 1a (Table 1, entry 4), but the best enantioselectivity
(56% ee) was encountered, surprisingly, using the diastereomeric
compound (Sa)-binam-D-prolinamide 1b (Table 1, entry 6).
Remarkably, under the same reaction conditions, catalyst N-
tosyl-(Sa)-binam-L-prolinamide 2 led to the formation of the
product 6aa in lower yields and in racemic form (Table 1, entry
7). Therefore, catalyst 1b was chosen to optimize the rest of the
reaction conditions. Further decrease of the temperature to
−20 °C did not improve the results (Table 1, entry 8). Also
decreasing or increasing the amount of acid co-catalyst led only
to a slight increase of the enantioselectivities (Table 1, entries 9
and 10). The need for a stoichiometric amount of acid as co-cata-
lyst is probably due to the activation of the α-keto ester as elec-
trophile through hydrogen bonding between the two oxygen
atoms. The effect of the use of a small amount of solvent was
evaluated, finding that the use of non-polar solvents such as
hexane or dichloromethane gave better enantioselectivities than
the use of a polar solvent such as methanol (Table 1, compare
entries 11 to 15) with an increase in the reaction time needed for
the reaction completion being observed in all cases.
Results and discussion
The reaction between acetone (4a) and methyl 2-oxo-2-phenyl-
acetate (5a) as α-keto ester and catalyst 1a (Table 1) was selected
as a model for the optimization of the reaction conditions. As it
has been reported that the addition of acetic acid allowed the
efficient synthesis of aldols 6 using prolinamides as catalysts,5f
this acid was used as additive and its required amount was
studied in this optimization.
Thus, 20 mol% of catalyst 1a and 150 mol% of acetic acid
were used to promote the reaction at 25 °C. The convenience or
not of the use of a solvent was evaluated by carrying the reaction
using acetone as solvent and nucleophile (Table 1, entry 1) or
using only 5 equiv. of acetone in the absence of solvent
(Table 1, entry 2). Decreasing the amount of acid co-catalyst led
to a drop in the achieved enantioselectivity (Table 1, entry 3). As
the yield and enantioselectivity were not affected by the presence
of an excess of acetone, the catalytic activities of the organocata-
lysts 1 and 2 were tested in the absence of solvent (Table 1,
Finally, the use of other acids as co-catalysts in this transform-
ation was tested. When a weaker acid such as pivalic acid
4030 | Org. Biomol. Chem., 2012, 10, 4029–4035
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Table 2 Solvent-free aldol reaction between ketones and α-keto estersa
(pKa = 5.05) was used, the product was obtained in racemic
form (Table 1, compare entries 16 and 17). Stronger acids such
as iodoacetic acid (pKa = 3.12) or chloroacetic acid (pKa = 2.87)
gave better enantioselectivities compared to acetic acid under the
same reaction conditions (Table 1, entries 18 and 19) with a drop
in the enantioselectivities being observed by using acids of
lower pKa such as bromoacetic acid (pKa = 2.69, Table 1, entry
20), dichloroacetic acid (pKa = 1.29, Table 1, entry 21) or trifl-
uoroacetic acid (pKa = 0.23, Table 1, entry 22). After these
optimization studies, the best results were those achieved using
catalyst 1b (20 mol%) and chloroacetic acid (100 mol%) as
co-catalyst at 0 °C in the absence of solvent, giving product 6aa
in 82% yield and 70% ee (Table 1, entry 23). Under these
reaction conditions, the reduction of the amount of ketone
or the decrease of catalyst loadings to 10 or 5 mol% led to
poorer conversions and lower enantioselectivities (Table 1,
entries 24–26).
Once the best reaction conditions were established, these were
applied in the reaction of several aromatic and heteroaromatic
α-keto esters with acetone (Table 2). The substitution of the
alkoxy group in the α-keto esters has no influence in the results
with methyl 2-oxo-2-phenylacetate or ethyl 2-oxo-2-phenylace-
tate providing the corresponding products in high yields
and moderate enantioselectivities (Table 2, entries 1 and 2).
However, the use of an alkyl α-ketoester such as ethyl pyruvate
(5c) as electrophile led a drop in the enantioselectivity to 23% ee
(Table 2, entry 3). The use of an activated α-keto ester such as
ethyl 2-(4-nitrophenyl)-2-oxoacetate (5d) gave the corresponding
product 6ad in shorter reaction time with excellent yields and
improved enantioselectivity (Table 2, entry 4).
Entry Major product
1
t (h) Yieldb (%) 6/7c
drc
eed (%)
38e
24
84
75
17
18
95
84
90
90
92
—
—
—
—
—
—
2
3
4
5
—
—
—
—
69
68
22
71
6
7
72
26
93
89
—
—
54
9 : 1
1 : 1 68
The use of a heteroaromatic α-keto ester was also possible
giving product 6ae in good yield and 54% ee (Table 2, entry 5).
Ethyl 2-(4-nitrophenyl)-2-oxoacetate (5d) was chosen as the
electrophile to study the scope of the reaction with different
ketones including α-functionalized ones. These transformations
are more challenging due to the need to control the regio-, dia-
stereo- and enantioselectivity. For these nucleophiles longer reac-
tion times were generally required. With the exception of
α-methoxyacetone (4c), the major isolated products were the iso-
isomers 6, probably due to the steric hindrance around the ter-
tiary alcohol. The yields obtained were highly dependent on the
reactivity of the nucleophile.
Thus, butanone (4b), α-methoxyacetone (4c) and α-benzyl-
oxyacetone (4e) gave high yields (Table 2, entries 7, 8 and 10)
while less reactive α-chloroacetone (4d) and α-methylsulfanyl-
acetone (4e) gave lower yields (Table 1, entries 9 and 11). Also,
except for the case of ketone 4c, the enantioselectivities achieved
were around 70%. The use of α-methoxyacetone (4c) as nucleo-
phile led to the formation of mainly the anti-7cd isomers in a
high enantioselectivity (92% ee, Table 1, entry 8).
8
72
96
1 : 9
9 : 1 92
9
96
72
60
85
99 : 1
4 : 1
—
73
10
9 : 1 64
11
85
20
99 : 1
—
76
In an attempt to understand the formation of opposite enantio-
mers with catalysts 1a (R) and 1b (S), the better enantioperfor-
mance of catalyst 1b over catalyst 1a, and to get some insights
regarding the H-bonding network responsible for the catalytic
activity, we set out to study the reaction computationally.16 We
assumed that the reaction proceeds first by formation of an
enamine between the catalyst and acetone 4a, which upon proto-
nation with the acetic acid additive would render the quaternary
ammonium acetate salt 8a (or 8b from 1b) (Scheme 1).
a Reaction conditions: ketone 4 (5 equiv.), α-keto ester 5, 1b (20 mol%),
ClCH2CO2H (100 mol%),
0
°C. b Isolated yield after column
chromatography. c For the anti/syn-isomer determined by 1H NMR of
crude product. d Determined by HPLC (major isomer). e Catalyst 1a
(20 mol%) was used.
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Scheme 1 Formation of the enamine intermediate 8a.
Fig. 3 Transition state for the reaction with the catalyst 1b.
Conclusions
The use of nearly solvent free conditions has been applied in the
aldol reaction between α-keto esters and ketones, including func-
tionalized ones catalysed by binam-prolinamides using chloro-
acetic acid as catalyst. The highly functionalized corresponding
tertiary alcohols have been achieved in good yields and regio-
selectivities with enantioselectivities up to 92% ee, when (Sa)-
binam-D-prolinamide instead of (Sa)-binam-L-prolinamide was
used as catalyst. DFT computational studies indicate that steric
effects between the phenyl-keto ester 5a and the binaphthyl
portion of the bulky catalyst dictate the stereoselectivity.
Fig. 2 Transition state for the reaction with the catalyst 1a. Red-circled
atoms are those involved in the C–C bond formation.
Experimental section
We computed the reaction between 8a or 8b with keto ester
5a through the Re and Si faces of the electrophile. In each case,
several transition states with different H-bonding patterns were
screened and evaluated. The lowest in energy for each enantio-
mer are shown in Fig. 2 (catalyst 1a) and Fig. 3 (1b). In fair
agreement with the experimental results, the former shows a
slight preference (Fig. 2, ΔΔG‡ = 0.9 kcal mol−1) for the for-
mation of the R enantiomer, and a larger preference for the
S enantiomer is seen in the latter (Fig. 3, ΔΔG‡ = 1.5 kcal
mol−1). These values account for a theoretical 4 : 1 R-selectivity
with 1a, and 12 : 1 S-selectivity with 1b.
Interestingly, the H-bond network does not differ substantially
in each pair of diastereomeric transition states. In both TS-1a-R
and TS-1a-S, the reactive carbonyl oxygen of the keto ester is
activated by two H-bonds with two of the NH groups within the
catalyst (Fig. 2). Seemingly, in both TS-1b-R and TS-1b-S, a
single activation takes place with the amidic NH group. All these
NH-bonds present similar length, 1.9 Å in the case of TS-1b-R
and TS-1b-S (Fig. 3). Thus, the selectivity is not related to the
H-bond activation pattern, and must have a different origin.
In fact, we found that the position of the phenyl ring of 5a
during the transition states is an important factor that might
explain the R/S selectivity. As shown in Fig. 2, there is consider-
able steric hindrance between the phenyl group and the
binaphthyl portion of the catalyst in the S-TS, whereas in R-TS
the phenyl group points outwards, and is better positioned in a
fairly free area. The opposite is true for 1b in Fig. 3; the phenyl
ring is positioned in the less sterically demanding area in the
S-TS, and in the more congested one in R-TS.17
General
Catalysts were prepared following the previously described pro-
cedures.10b,11c,12 Dry DMF, dry toluene, dry CH2Cl2, piperidine
and triethylamine and all other reagents were commercially
available and used without further purification. Only the structu-
rally most important peaks of the IR spectra (recorded on a
Nicolet Impact 400D) are listed. 1H NMR (300 MHz, 400 MHz)
and 13C NMR (75 MHz) spectra were obtained on a Bruker
AC-300 using CDCl3 as solvent and TMS as internal standard,
unless otherwise stated. Optical rotations were measured on a
Perkin Elmer 341 polarimeter. HPLC analyses were performed
on a Agilent 1100 series equipped with a chiral column (detailed
for each compound below), using mixtures of n-hexane/isopro-
pyl alcohol (IPA) as mobile phase, at 25 °C. Analytical TLC was
performed on Schleicher & Schuell F1400/LS silica gel plates
and the spots were visualised under UV light (λ = 254 nm). For
flash chromatography we employed Merck silica gel 60
(0.063–0.2 mm). Elemental analysis was carried out in the
Research Technical Services of the University of Alicante.
General procedure for the solvent-free aldol reaction catalysed
by 1b
To a mixture of the corresponding α-keto ester 5 (0.25 mmol),
catalyst 1b (0.024 g, 0.05 mmol, 0.2 equiv.) and chloroacetic
acid (0.024 g, 0.25 mmol, 1 equiv.) at 0 °C was added the corre-
sponding ketone 4 (1.25 mmol, 5 equiv.). The reaction was
4032 | Org. Biomol. Chem., 2012, 10, 4029–4035
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(R)-Ethyl 2-hydroxy-4-oxo-2-(thiophen-2-yl)pentanoate (6ae)4f
stirred until the α-ketoester was consumed (monitored by TLC).
Then, CH2Cl2 (0.5 mL) was added to the mixture which was
purified by flash chromatography (hexanes–EtOAc) to yield the
pure product 6.
Colorless oil; Rf = 0.33 (hexanes–EtOAc 7 : 3); δH (300 MHz;
CDCl3, Me4Si) 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.20 (s, 3H,
CH3CO), 3.20 (d, J = 17.6 Hz, 1H, CH2), 3.51 (d, J = 17.6 Hz,
1H, CH2), 4.26 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.45 (s, 1H,
OH), 6.97 (dd, J = 3.6, 5.1 Hz, 1H, ArH), 7.06 (dd, J = 1.3, 3.6
Hz, 1H, ArH), 7.36–7.22 (m, 1H, ArH).; δc (75 MHz; CDCl3,
Me4Si) 13.9 (OCH2CH3), 30.5 (CH3CvO), 53.6 (CH2), 62.6
(OCH2CH3), 74.8 (COH), 123.7 (ArCH), 125.3 (ArCH), 127.0
(ArCH), 145.1 (ArC), 172.8 (CO2), 206.2 (CvO); HPLC (Chir-
alpak AD, n-hexane–i-PrOH: 90 : 10, 0.6 mL min−1), tR 21.218
(major), tR 26.330 (minor).
(S)-Methyl 2-hydroxy-4-oxo-2-phenylpentanoate (6aa)15
White solid; Mp = 56 °C (EtOAc); Rf = 0.35 (hexanes–EtOAc
7 : 3); δH (300 MHz; CDCl3, Me4Si) 2.21 (s, 3H, CH3CvO),
3.01 (d, J = 17.6 Hz, 1H, CH2), 3.56 (d, J = 17.6 Hz, 1H, CH2),
3.76 (s, 3H, CO2CH3), 4.43 (s, 1H, OH), 7.28–7.43 (m, 3H),
7.56 (d, J = 8.9 Hz, 2H, ArH); δc (75 MHz; CDCl3, Me4Si) 30.6
(CH3CvO), 52.9 (CH2), 53.1 (CO2CH3), 76.3 (C–OH), 124.8
(ArCH), 128.0 (ArCH), 128.4 (ArCH), 140.1 (ArC), 174.3
(CO2CH2CH3), 207.8 (CvO); HPLC (Chiralpak AD, n-hexane–
i-PrOH: 80 : 20, 0.8 mL min−1), tR 9.508 (minor), tR 11.189
(major).
(S)-Ethyl 2-hydroxy-2-(4-nitrophenyl)-4-oxohexanoate (6bd)
Yellow solid; Mp = 55 °C (EtOAc); [α]2D5 = 47 (c 1.3, CHCl3);
Rf = 0.29 (hexanes–EtOAc 7 : 3); IR νmax/cm−1 (KBr) 3485,
3112, 2981, 1730, 1605, 1593, 1516, 1403, 1341, 1268, 1109,
855 cm−1; δH (300 MHz; CDCl3, Me4Si) 1.09 (t, J = 7.3 Hz,
3H, OCCH2CH3), 1.27 (t, J = 7.1 Hz, 3H, OCH2CH3),
2.40–2.66 (m, 2H, OCCH2CH3), 2.99 (d, J = 17.4 Hz, 1H,
CH2), 3.54 (d, J = 17.4 Hz, 1H, CH2), 4.26 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.60 (s, 1H, OH), 7.81 (d, J = 8.8 Hz, 2H, ArCH),
8.21 (d, J = 8.8 Hz, 2H, ArCH); δc (75 MHz; CDCl3, Me4Si)
7.2 (OvCCH2CH3), 13.8 (OCH2CH3), 36.5 (CH2), 51.6 (CH2),
63.3 (OCH2CH3), 76.2 (C–OH), 123.7 (ArH), 126.3 (ArH),
147.0 (Ar), 147.8 (Ar), 172.4 (CO2CH2CH3), 200.3 (CvO)
HRMS-DIP (m/z): [M+ − CO2Et] calcd for C13H12NO4 223.1;
found: 223.1. HPLC (Chiralcel ODH, n-hexane–i-PrOH: 90 : 10,
0.5 mL min−1), tR 26.766 (minor), tR 27.586 (major).
(S)-Ethyl 2-hydroxy-4-oxo-2-phenylpentanoate (6ab)15
White solid; Mp = 60 °C (EtOAc); Rf = 0.33 (hexanes–EtOAc
7 : 3); δH (300 MHz; CDCl3, Me4Si) 1.25 (t, J = 7.1 Hz, 3H,
OCH2CH3), 2.20 (s, 3H, COCH3), 3.02 (d, J = 17.6 Hz, 1H,
CH2), 3.55 (d, J = 17.6 Hz, 1H, CH2), 4.22 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.39 (s, 1H, OH), 7.27–7.41 (m, 3H), 7.51–7.65 (m,
2H, ArH); δc (75 MHz; CDCl3, Me4Si) 13.9 (OCH2CH3), 30.6
(CH3CvO), 53.0 (CH2), 62.2 (OCH2CH3), 76.5 (C–OH), 124.8
(ArCH), 128.0 (ArCH), 128.4 (ArC), 140.3 (ArC), 173.8
(CO2CH2CH3), 207.6 (CvO); HPLC (Chiralcel ODH,
n-hexane–i-PrOH: 90 : 10, 0.8 mL min−1), tR 21.090 (minor),
tR 26.470 (major).
(R)-Ethyl 2-hydroxy-3-methoxy-2-(4-nitrophenyl)-4-oxopentanoate
(7cd)
(S)-Ethyl 2-hydroxy-2-methyl-4-oxopentanoate (6ac)18
Brown oil; [α]2D5 = −124 (c 1.17, CHCl3); Rf = 0.30 (hexanes–
EtOAc 7 : 3); IR νmax/cm−1 (film) 3335, 3192, 2964, 2869,
1676, 1592; δH (300 MHz; CDCl3, Me4Si) 2.15 (s, 3H,
OvCCH3), 3.46 (s, 3H, OCH3), 4.20 (s, 1H, OH), 4.26 (s, 1H,
CHOCH3), 7.88 (d, J = 9.0 Hz, 2H, ArCH), 8.21 (d, J = 9.0 Hz,
2H, ArCH); δc (75 MHz; CDCl3, Me4Si) 14.1 (OCH2CH3), 27.7
(OvCCH3), 59.5 (OCH3), 63.6 (OCH2CH3), 80.0 (C–OH), 90.3
(HCOCH3), 123.2 (ArCH), 127.7 (ArCH), 145.1 (ArC), 147.8
(ArC), 171.1 (CO2CH2CH3), 209.8 (CvO); HRMS-DIP (m/z):
[M+ − CO2Et] calcd for C11H12NO5 238.0; found: 238.2. HPLC
(Chiralpak AD, n-hexane–i-PrOH: 90 : 10, 0.5 mL min−1),
tR 59.164 (minor), tR 31.471 (major).
Colorless oil; Rf = 0.29 (hexanes–EtOAc 7 : 3); δH (300 MHz;
CDCl3, Me4Si) 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.39 (s, 3H,
CH3CvO), 2.17 (s, 3H, CH3COH), 2.81 (d, J = 17.6 Hz, 1H,
CH2), 3.13 (d, J = 17.6 Hz, 1H, CH2), 3.82 (s, 1H, OH), 4.23
(q, J = 7.1 Hz, 2H, OCH2CH3); δc (75 MHz; CDCl3, Me4Si)
14.0 (OCH2CH3), 26.1 (CH3COH), 30.5 (CH3CvO), 52.2
(CH2), 61.7 (OCH2CH3), 72.4 (COH), 175.7 (CO2CH2CH3),
207.7 (CvO); HPLC (Chiralpak AS, n-hexane–i-PrOH: 98 : 02,
0.6 mL min−1), tR 23.267 (minor), tR 29.345 (major).
(S)-Ethyl 2-hydroxy-2-(4-nitrophenyl)-4-oxopentanoate (6ad)18
White solid; Mp = 67 °C (EtOAc); Rf = 0.35 (hexanes–EtOAc
7 : 3); δH (300 MHz; CDCl3, Me4Si) 1.27 (t, J = 7.1 Hz, 3H,
OCH2CH3), 2.24 (s, 3H, CH3CvO), 3.01 (d, J = 17.6 Hz, 1H,
CH2), 3.57 (d, J = 17.6 Hz, 1H, CH2), 4.25 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.53 (s, 1H, OH), 7.80 (d, J = 8.9 Hz, 2H, ArH),
8.22 (d, J = 8.9 Hz, 2H, ArH); δc (75 MHz; CDCl3, Me4Si) 13.8
(OCH2CH3), 30.5 (CH3CvO), 52.8 (CH2), 62.8 (OCH2CH3),
76.1 (COH), 123.5 (ArCH), 126.0 (ArCH), 147.2 (Ar), 147.6
(ArC), 172.7 (CO2), 206.8 (CvO); HPLC (Chiralpak AD,
n-hexane–i-PrOH: 90 : 10, 0.6 mL min−1), tR 21.427 (minor),
tR 23.833 (major).
(S)-Ethyl 5-chloro-2-hydroxy-2-(4-nitrophenyl)-4-oxopentanoate
(6dd)
Colorless solid; Mp = 95 °C (EtOAc); [α]2D5 = −185 (c 1,
CHCl3); Rf = 0.29 (hexanes–EtOAc 7 : 3); IR νmax/cm−1 (film)
3475, 3108, 3077, 3000, 2939, 1734, 1722, 1686, 1593, 1516,
1403, 1341, 1268, 1101, 859; δH (300 MHz; CDCl3, Me4Si)
1.29 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.22 (d, J = 17.4 Hz, 1H,
CH2), 3.43 (s, 3H, OCH3), 3.63 (d, J = 17.4 Hz, 1H, CH2), 4.14
(s, 2H, ClCH2CO), 4.29 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.33
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(s, 1H, OH), 7.81 (d, J = 9.0 Hz, 2H, ArH), 8.24 (d, J = 9.0 Hz,
2H, ArH); δc (75 MHz; CDCl3, Me4Si) 13.9 (CH3), 48.3 (CH2),
49.3 (ClCH2), 62.7 (OCH2CH3), 77.1 (C–OH), 123.4 (ArCH),
126.1 (ArCH), 147.4 (ArC), 147.5 (ArC), 172.7 (CO2CH2CH3),
209.6 (CO); HRMS-DIP (m/z): [M+ − CO2Et] calcd for
C10H9ClNO4 243.6; found 243.1; HPLC (Chiralpak AD,
n-hexane–i-PrOH: 90 : 10, 1.0 mL min−1), tR 21.344 (minor),
tR 31.130 (major).
Notes and references
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(S)-Ethyl 5-(benzyloxy)-2-hydroxy-2-(4-nitrophenyl)-4-oxopenta-
noate (6ed)
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Brown oil; Rf = 0.29 (hexanes–EtOAc 7 : 3); 3 IR νmax/cm−1
(film) 3493, 2977, 2921, 2864, 1732, 1603, 1521, 1348, 1258,
1211, 1106; cm−1; δH (300 MHz; CDCl3, Me4Si) 1.27 (t, J = 7.1
Hz, 3H, OCH2CH3), 3.12 (d, J = 17.7 Hz, 1H, CH2), 3.54
(d, J = 17.7 Hz, 1H, CH2), 4.09 (s, 2H, OvCCH2OBn), 4.26
(q, J = 7.1 Hz, 2H, OCH2CH3), 4.40 (s, 1H, OH), 4.59 (s, 2H,
OCH2Ph), 7.29–7.41 (m, 5H, ArH), 7.82 (d, J = 9.0 Hz, 2H,
ArH), 8.22 (d, J = 9.0 Hz, 2H, ArH); δc (75 MHz; CDCl3,
Me4Si) 13.9 (CH3), 48.8 (OvCCH2COH), 63.0 (OCH2), 73.6
(CH2Ar), 75.2 (OvCCH2OBn), 76.0 (HOCAr), 123.6 (ArC),
126.3 (ArC), 128.0 (ArC), 128.2 (ArC), 128.6 (ArC), 136.7
(ArC), 147.4 (ArC), 147.7 (ArC), 172.7 (CO2CH2CH3), 206.9
(CO); HRMS-DIP (m/z): [M+ − CO2Et] calcd for C17H17NO5
314.1000; found 314.1034; HPLC (Chiralpak AD, n-hexane–i-
PrOH: 90 : 10, 1.0 mL min−1), tR 32.022 (minor), tR 46.248
(major).
(S)-Ethyl 2-hydroxy-5-(methylthio)-2-(4-nitrophenyl)-4-oxopenta-
noate (6fd)
Brown oil; [α]2D5 = −65 (c 1, CHCl3); Rf = 0.35 (hexanes–EtOAc
7 : 3); IR νmax/cm−1 (film) 3485, 3192, 2981, 2920, 1735, 1605,
1522, 1348, 1105, 856; δH (300 MHz; CDCl3, Me4Si) 1.28
(t, J = 7.1 Hz, 3H, OCH2CH3), 2.07 (s, 3H, SCH3), 3.22 (s, 2H,
SCH3CH2CO), 3.30 (d, J = 17.5 Hz, 1H, CH2), 3.72 (d, J = 17.5
Hz, 1H, CH2), 4.27 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.49 (s, 1H,
OH), 7.82 (d, J = 9.0 Hz, 2H, ArH), 8.22 (d, J = 9.0 Hz, 2H,
ArH); δc (75 MHz; CDCl3, Me4Si) 13.9 (CH3), 15.4 (SCH3),
43.2 (CH2), 49.3 (CH2), 62.9 (OCH2CH3), 76.1 (C–OH), 123.5
(ArH), 126.3 (ArH), 147.3 (Ar), 147.6 (Ar), 172.7
(CO2CH2CH3), 203.2 (CvO); HRMS-DIP (m/z): [M+] calcd for
C13H17NO7 327.1; found 327.1; HPLC (Chiralpak AD,
n-hexane–i-PrOH: 90 : 10, 0.9 mL min−1), tR 38.943 (minor),
tR 59.684 (major).
Acknowledgements
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This research was supported by the Ministerio de Ciencia e Inno-
vación (MICINN: Projects CTQ2007-62771/BQU, CTQ2010-
20387, and Consolider Ingenio2010 CSD2007-00006,), FEDER,
the Generalitat Valenciana (Project PROMETEO/2009/039), and
the EU (ORCA action CM0905). We also thank SGI/IZO-SGI-
ker UPV/EHU for allocation of computational resources.
A.B.-C. thanks the Spanish MICINN for a predoctoral fellow-
ship (FPU AP2009-3601).
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This journal is © The Royal Society of Chemistry 2012
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