P-nitrophenyl ethylthioester in enantioselective organocatalytic Michael additions: Different behaviour of β-aryl and β-alkyl enals

Article abstract of DOI:10.1002/ejoc.201300934

Although several nucleophiles derived from arylacetic acids have been described in catalysis via iminium activation, none have presented good enantioselectivity and reactivity with both β-alkyl and β-aryl enals. This study on the Michael addition of p-nit

Full text of DOI:10.1002/ejoc.201300934

Job/Unit: O30934
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Date: 19-09-13 16:28:36
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201300934
p-Nitrophenyl Ethylthioester in Enantioselective Organocatalytic Michael
Additions: Different Behaviour of β-Aryl and β-Alkyl Enals
Sara Duce,[a] María Jorge,[a] Inés Alonso,[a] José Luis García Ruano,[a] and M. Belén Cid*[a]
Dedicated to the memory of Christian Claessens
Keywords: Asymmetric catalysis / Organocatalysis / Michael addition
Although several nucleophiles derived from arylacetic acids
have been described in catalysis via iminium activation, none
have presented good enantioselectivity and reactivity with
both β-alkyl and β-aryl enals. This study on the Michael ad-
dition of p-nitrophenylacetic thioesters suggests that this be-
havior is due to the different reactivity and distinct tendency
to reversibility exhibited by these types of enal. Independent
optimization of the conditions for β-alkyl and β-aryl enals
provide good yields and enantioselectivities with both sub-
strates, affording Michael adducts that are versatile building
blocks for the preparation of an interesting variety of aryl-
acetic acid derivatives.
Because the simple arylacetic ester is not able to partici-
pate in this process due to the low acidity of the methylenic
protons,[4] this approach has mainly been applied starting
from two types of precursors, trifluoroethyl thioesters[4] and
p-nitrophenyl derivatives[5–7] (Figure 1), with higher acidi-
ties than the corresponding benzyl ester.
Introduction
Substituted 2-phenylacetic acids and their derivatives are
important synthetic building blocks for agrochemicals and
active pharmaceutical ingredients[1] such as nonsteroidal
anti-inflammatory drugs. Because enantioselective organo-
catalysis involving iminium activation[2] provides an excel-
lent procedure for the incorporation of nucleophiles to the
β-position of α,β-unsaturated aldehydes,[3] the use of syn-
thetic equivalents of 2-phenylacetic acids as nucleophiles in
these processes is very promising for the preparation of
highly functionalized 2-phenylacetic acids (Scheme 1).
Figure 1. Design of a hybrid nucleophile based on the structure of
other nucleophiles.
A detailed analysis of the results provided in these papers
seems to indicate that the behavior of β-alkyl and β-aryl
enals under the optimized conditions for each precursor is
different. β-Alkyl enals exhibit low or moderate reactivity
and enantioselectivity with trifluoroethyl thioester 1a[4] but
provide very good yields and ee values with nitrile 1b,[5]
ketone 1c,[6] and ester 1d,[7] whereas β-aryl enals give good
yields and ee values with 1a but erratic and lower enantio-
selectivity with 1b–d (Figure 1).
Scheme 1. Approach to enantiomerically pure substituted aryl-
acetic acid.
[a] Department of Organic Chemistry, Universidad Autónoma de
Madrid,
Cantoblanco, 28049, Spain
E-mail: belen.cid@uam.es
Optimization studies for nucleophile 1a were performed
on the trans-cynamic aldehyde, whereas trans-crotonalde-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300934.
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S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid
FULL PAPER
hyde was used with 1b–d. Because the optimal conditions Table 1. Optimization of the reactions of 1e with 2a and 2b.[a]
established in each case are different, we hypothesized that
this indiscriminate optimization could be a possible cause
of the failures of yield and enantioselectivity for nucleo-
philes 1 with either aromatic or aliphatic enals.[8] The results
reported for the ester 1d under different conditions with
different enals corroborate our hypothesis.[7,9] Those re-
ported by Duce et al.[7] were appropriate for obtaining good
results with β-alkyl enals but erratic ee values were obtained
Entry
R
Catalyst Solvent Additive t [h] Conv. ee (4)
with the β-aryl enals, whereas conditions reported by Seo
and Kim[9] were suitable for the latter enals but not for β-
alkyl enals. This suggests that an independent optimization
of both types of electrophiles could improve the results for
every nucleophile.
[%][b] [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me II
Me
Me II
Me II
Me II
Me II
Me II
I
II
I
II
I
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
EtOH
–
–
–
–
–
–
6
6
5
90
–
10
87
60
87
Ͻ5
74
86
90
94
–
0.25 50
0.25 91
3.5
3.5
95
95
Ͼ95
Ͼ95
95
95
Ͻ5
70
36
61
To confirm this interesting practical question, we investi-
gated the reactions of ethyl thioester 1e, derived from p-
nitrophenyl acetic acid (Figure 1). The selection of this new
pronucleophile, with structural features of 1a and 1d, was
based on the synthetic usefulness of the nitro group for in-
troducing different functions to the aromatic ring, and also
on the chemical versatility of the thioester group. The latter
characteristic allows this moiety to be used as mild acyl
transfer reagent[10] in the preparation of a variety of carbox-
ylic acid derivatives and has been used in medicinal chemis-
try[11] and as key intermediates in various biological pro-
cesses.[12] We present herein the results obtained in the or-
ganocatalytic Michael addition of thioester 1e to enals; by
changing the reaction conditions this approach is satisfac-
tory for both β-aryl and β-alkyl derivatives. Moreover, some
synthetic transformations illustrating the chemical versatil-
ity of the resulting compounds are also presented.
II
I
EtOH TBAB[d] 3.5
I
EtOH LiOAc
EtOH PhCO2H 3.5
EtOH PhCO2H 36
3.5
9
I
10[e]
11
12
13
14
15
16
17
18
I
I
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
–
–
–
–
–
6
6
6
6
48
3
–
I
75
75
75
80
68
74
85
EtOH TBAB[d]
EtOH LiOAc
EtOH PhCO2H
Ͼ95
95
6
6
35
[a] Reactions were carried out at room temp. on a 0.2 mmol scale
with 2 (1.5 equiv.) and [1e] = 0.5 m. [b] Determined by 1H NMR
analysis of the crude material from the Michael addition. [c] Deter-
mined by chiral-phase HPLC analysis of alcohol 4 resulting in the
reduction of the major syn-3 diastereoisomer. [d] 1 equiv. was used.
[e] Reaction performed at –20 °C.
ee than TBAB and LiOAc (compare entries 7, 8 and 9).
This analysis suggests that the best conditions for reacting
1e with β-aryl enals are those involving the use of catalyst
Results and Discussion
Independent optimization of reactions of 1e with cinna- I in the presence of PhCO2H as additive. Finally, an im-
maldehyde (2a) and crotonaldehyde (2b) are depicted in provement in the ee value was achieved by decreasing the
Table 1. The role of the catalyst (I and II), solvent (CH2Cl2 temperature (entry 10).
and EtOH), and additive (PhCO2 H, TBAB, and LiOAc)
on the reactivity and stereoselectivity was studied.
Reactions carried out with crotonaldehyde 2b (entries
11–18) were slower than those with cinnamaldehyde (2a)
In all the cases, Michael reactions afforded mixtures of under similar conditions. The influence of the catalyst and
two diastereomers (3 and 3Ј, epimers at C-2), with dr values the solvent on the reaction rate was less significant in the
ranging between 1:1 and 2.3:1.[13] Concerning the reactions case of 2b, although reactions catalyzed by II were still
with cinnamaldehyde (2a), it is clear that EtOH is more slightly faster (entries 11–14).
efficient as solvent than CH2Cl2, and that catalyst II leads
Nevertheless, the main difference regarding aromatic en-
to faster reaction than catalyst I (compare Table 1, entries als is that the reaction time had no influence on the ee val-
1 and 2 with 3 and 4). However, the influence of the catalyst ues with catalyst II (Table 1, entries 14 and 15), which sug-
on the enantioselectivity is remarkable. In the case of cata- gests that reactions with 2b are less prone to reversibility
lyst I, the enantioselectivity is higher and remains almost than those with 2a. As a consequence, catalyst II was se-
constant with longer reaction times (compare entries 3 and lected to continue the optimization process. To compare the
5), whereas the ee is lower with catalyst II and significantly influence of additives on the reaction with the aromatic en-
decreases with time (compare entries 4 and 6). This behav- als (entries 7–10), the reactions were performed in EtOH.[14]
ior suggests that the decrease of the ee could be due to It was observed that reaction times decreased with the ad-
the reversibility of the process in reactions catalyzed by II. dition of TBAB and LiOAc (entries 16 and 17) and in-
Therefore, catalyst I, although it is less effective in terms of creased with the inclusion of PhCO2H (entry 18). The best
reactivity, should be chosen for these reactions because it is reactivity/enantioselectivity balance for aliphatic enals was
less prone to reversibility. Finally, we studied the effect of achieved by using catalyst II in the presence of TBAB (en-
additives in these reactions, with PhCO2H providing better try 16).
2
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p-Nitrophenyl Ethylthioester as a Pronucleophile
As a result of the optimization studies, two sets of condi- mized for aliphatic enals) in the reaction with cinnamal-
tions, Conditions A (Table 1, entry 10; catalyst I and dehyde, a fast reaction took place but very low ee was ob-
PhCO2H as additive) and Conditions B (Table 1, entry 16; served (entry 8), evolving to the racemic compound after
catalyst II and TBAB as additive), were established as opti- 3 h reaction (entry 9). When Conditions A (optimized for
mal for β-aryl and β-alkyl enals, respectively. The scope of aromatic enals) were employed with the aliphatic enals and
the reactions of 1e with conjugated aldehydes 2c–g was then 1e, the corresponding adducts were obtained with good
investigated; the results are collected in Table 2.
enantioselectivity but required remarkably longer reaction
times than when TBAB was used (compare entries 6 with
10 and 7 with 11).
Table 2. Scope of the Michael addition.[a]
We suspect that this behavior was not limited to nucleo-
phile 1e, because it was even more acute with the less reac-
tive ester 1d,[7–9] which did not afford the desired products
when catalyst I was used with aliphatic enals.
The reduction of the Michael adducts with NaBH4 was
optimized in the case of compounds 3a and 3b,[15] with the
use of low temperatures being necessary to avoid thioester
reduction. Reductions of the mixture of the two dia-
stereomers (epimers at C-2) provided a new mixture com-
posed of alcohol 4a or 4b and lactones 5 (Scheme 2).
Alcohols 4 resulted from the reduction of the major alde-
hydes 3, whereas lactones 5[16] were obtained by spontane-
ous cyclization of the alcohols[17] obtained from the minor
diastereomers 3Ј.[18] This reaction was general for the rest
of the aldehydes studied (Table 2), and the separation of the
corresponding alcohols 4a–g by chromatography allowed
the enantiomeric excesses to be determined (Table 1 and
Table 2).
Entry Enal
Cond
3
T
t
Yield ee
2
R
[°C] [h]
[%][b] [%][c]
1
2
3
4
2a
2d
2e
2f
Ph
A
A
A
A
A
B
B
B
B
A
A
3a –20 36
3d –20 60
3e 15
3f 15
3g r.t. 48
3b r.t.
3c r.t. 48
3a r.t. 15 min 50
3a r.t.
3b r.t. 96
3c r.t. 48
93
70
90
75
60
85
80
94
87
88
86
70
80
80
44
Ͻ5
83
92
pMeO-C6H4
oMeO-C6H4
pO2N-C6H4
2-furyl
Me
iPr
Ph
Ph
36
84
5
6
7
8
9
10
11
2g
2b
2c
2a
2a
2b
2c
6
3
85
80
50
Me
iPr
The relative configuration of alcohols 4a and 4aЈ[19] was
determined by comparison of the chemical shifts in their
[a] Reactions were carried out on 0.3 mmol scale with 3 equiv. of
the corresponding aldehyde and [1e] = 0.5 m. [b] Isolated yield of
3. [c] Determined by chiral-phase HPLC analysis of the corre-
sponding alcohol 4 resulting in the reduction of the major syn-3
diastereoisomer.
1
respective H NMR spectra with those generated by theo-
retical calculations at the DFT (B3LYP)[20] level by using
Gaussian 09.[21] Molecular structures of the most stable
conformer of each diastereomer are shown in Scheme 3.[13]
Interestingly, a hydrogen bond between the hydroxyl group
and the thioester group is only observed in the minor dia-
stereoisomer 4aЈ, which could explain the easy formation
of lactone 5a, preventing the isolation of 4aЈ (Scheme 3).
To illustrate the versatility of the thioester group, several
transformations were carried out. Formation of lactones 5
and the decarboxylation reaction had been previously opti-
mized in the adducts obtained from aldehydes with ali-
phatic substituents and the nitrile and ester nucleophiles
1b[5] and 1d,[7] respectively. Because these nucleophiles did
not afford high enantioselectivities with aromatic enals, we
optimized the reactions of lactonization and decarboxyl-
ation from alcohol 4a, featuring the thioester moiety, to ob-
Aryl derivative 2a and aryl-substituted enals 2d–f, react
with similar ee values (Ͼ86%) under Conditions A, regard-
less of the electron character of the substituents on the aryl
ring. Even the heteroaryl-substituted enal 2g reacted in a
similar way, albeit with a slightly lower stereoselectivity
(Table 2, entry 5). Concerning β-alkyl enals, an increase in
the size of the substituent did not significant influence the
stereoselectivity but clearly decreased the reactivity (com-
pare entries 5 and 6).
To confirm the importance of selecting appropriate reac-
tion conditions depending on the nature of the enal, we
employed the optimized conditions for aromatic enals with
the aliphatic enals and vice versa. The results (Table 2, en-
tries 8–11) clearly show this detrimental effect. When cata-
lyst II was used with TBAB as additive (Conditions B, opti-
Scheme 2. Reduction of adducts 3.
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S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid
FULL PAPER
shows that it is possible to prepare enantio and dia-
stereomerically pure α-aryl ketones. The alternative method
of α-arylation of ketones is not an evident transforma-
tion.[26] The reduction of the nitro group to the correspond-
ing amine also offers a plethora of possible transformations
through diazonium salt reactions, such as substitution by a
hydrogen atom[27] to afford 10.
Scheme 3. Molecular structures of alcohols 4a and 4aЈ. Representa-
tive distances [Å] H–O are indicated.
tain these compounds in high enantioselectivities. Thus,
these transformations allowed the absolute configuration of
adducts 3 to be unequivocally determined by chemical cor-
relation of lactone 5b.[22]
Diastereomerically pure lactones were formed by treat-
ment of the corresponding alcohols 4a and 4b with NaH,
indicating that reactions take place with complete inversion
of configuration at C-2 (Scheme 4). Decarboxylation of
alcohol 4a to give compound 6 converts pronucleophile 1e
into a masked reagent for the enantioselective β-benzylation
of enals, which is significant because the introduction of
functionalized benzylic substituents is not evident, even in
a racemic version.[23] Compound 6 was prepared by hydrol-
ysis of the thioester group to the acid under basic condi-
tions followed by decarboxylation (Scheme 4).
The reductive amination of aldehyde 3a/3aЈ and its sub-
sequent cyclization[24] led to the formation of lactams 7a/
7aЈ as a 67:33 diastereomeric mixture in 81% yield. Interest-
ingly, whereas lactone 5a was obtained in diastereomerically
pure form (Scheme 4), the afforded lactam 7 retained the
diastereoisomeric ratio of the starting material (70:30;
Scheme 5).
Scheme 6. Transformation of thioester and nitro groups of 4.
Conclusions
Thioester 1e can be used to efficiently transfer the aryl-
acetic residue in a highly stereoselective way to both β-alkyl
and β-aryl-substituted enals through iminium activation.
The corresponding adducts have proven to be very versatile
substrates. Interestingly, the independent optimization of
aromatic and aliphatic enals has highlighted very different
behavior of these types of enals with pronucleophile 1e. The
lower reactivity of aliphatic enals seems to be palliated with
the use of catalyst II and TBAB as additive; nevertheless,
these conditions were shown to be detrimental for aromatic
enals, which present problems of reversibility. This tendency
seems to decrease with the use of catalyst I and an acidic
additive. These findings can have important consequences
in the optimization of this kind of reaction; the causes and
generality of this behavior is being investigated in further
detail in our laboratory.
Experimental Section
Scheme 5. Reductive amination of 3a to prepare lactam 7.
General Methods and Materials: NMR spectra were acquired using
1
CDCl3 or C6D6 as solvents, recording at 300 and 75 MHz for H
We also performed a cross-coupling reaction[25] of the
protected alcohol with phenyl boronic acid, yielding ketone
and 13C, respectively. Chemical shifts (δ) are reported in ppm rela-
tive to residual solvent signals (CHCl3: δ = 7.26 ppm for 1H;
8 in 65% yield (Scheme 6). The synthesis of compound 8 CDCl3: δ = 77.0 ppm for 13C; C6H6: δ = 7.16 ppm for H; C6D6: δ
1
Scheme 4. Decarboxylation and lactonization reactions.
4
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p-Nitrophenyl Ethylthioester as a Pronucleophile
1
= 128.0 ppm for 13C). For thin layer chromatography (TLC), silica
gel plates were used, and compounds were visualized by irradiation
with UV light and/or by treatment with a solution of phosphomol-
ybdic acid (12 g), in EtOH (250 mL) followed by heating or treat-
ment with a solution of KMnO4 (1.5 g), K2CO3 (10 g), and 10%
NaOH (1.25 mL) in H2O (200 mL). Mass spectra were recorder in
positive electrospray ionisation (ESI+) or electron impact ionis-
ation (EI). Obtained data are expressed in mass/charge (m/z) units.
Values between parentheses indicate relative intensities with regard
to the base peak. Commercial grade reagents and solvents were
used without further purification.
from the major diastereomer. H NMR (300 MHz): δ = 9.41 (s, 1
H), 8.23 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.38–7.20
(m, 5 H), 4.20 (d, J = 11.1 Hz, 1 H), 4.07 (td, Jt = 11.1, Jd
=
4.0 Hz, 1 H), 2.75–2.48 (m, 3 H), 2.41 (dd, J = 17.1, 4.1 Hz, 1 H),
0.94 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 199.6
(CHO), 197.5 (C), 147.8 (C), 143.4 (C), 139.7 (C), 129.6 (2CH),
128.8 (2CH), 128.3 (2CH), 127.6 (CH), 124.2 (2CH), 65.5 (CH),
47.1 (CH2), 43.6 (CH), 23.81 (CH2), 14.3 (CH3) ppm. MS (ESI):
m/z (%) = 358 (4) [M + 1+], 279 (95), 149 (56). HRMS (ESI): Calcd.
for C19H20NO4S [M + 1] 358.1107; found 358.1101. The ee was
determined for the corresponding alcohol, obtained after reduction
with NaBH4 in EtOH at –20 °C. The crude compound was purified
by flash chromatography (n-hexane/EtOAc, 4:1).
Synthesis of Thioester 1e: Synthesized following a typical procedure
reported for thioester formation from the corresponding ester.[28]
A
solution of trimethylaluminum (2 m in hexane, 10.0 mL,
S-Ethyl (2S,3R)-5-Hydroxy-2-(4-nitrophenyl)-3-phenylpentanethio-
ate (4a): M.p. 134–135 °C. H NMR (300 MHz): δ = 8.21 (d, J =
1
20.0 mmol) was diluted with anhydrous CH2Cl2 (50 mL) followed
by ethane thiol (4.5 mL, 60 mmol) at –78 °C. Methane evolution
occurred and the solution was warmed to ambient temperature to
give a solution of Me2AlSEt. p-Nitrophenyl ethyl acetate (2.1 g,
10 mmol) was dissolved in CH2Cl2 (20 mL), cooled to –78 °C, and
treated with the aluminum thiolate. The reaction was warmed to
0 °C and stirring was continued for 6 h. The reaction was recooled
and quenched with saturated aqueous sodium potassium tartrate
(30 mL) and stirred vigorously for 1 h. The resulting solution was
transferred to a separatory funnel and the aqueous fraction was
extracted with CH2Cl2 (3ϫ 30 mL). The combined organics were
dried with anhydrous MgSO4, filtered, concentrated, and purified
by flash chromatography (n-hexane/EtOAc, 20:1) to give the title
8.7 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.35–7.18 (m, 5 H), 4.09
(d, J = 11.4 Hz, 1 H), 3.61 (td, Jt = 11.4, Jd = 3.0 Hz, 1 H), 3.43–
3.31 (m, 1 H), 3.30–3.18 (m, 1 H), 2.71–2.42 (m, 2 H), 1.73–1.54
(m, 2 H), 0.88 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (75 MHz): δ =
197.8 (C), 147.5 (C), 144.3 (C), 140.4 (C), 129.6 (2CH), 128.6
(2CH), 128.4 (2CH), 127.2 (CH), 124.0 (2CH), 66.5 (CH2), 60.2
(CH), 46.0 (CH2), 35.8 (CH), 23.7 (CH2), 14.2 (CH3) ppm. MS
(FAB): m/z (%) = 361 (5) [M + 1+], 360 (28), 298 (100). HRMS
(ESI): Calcd. for C19H22NO4S [M + 1] 360.1264; found 360.1277.
The enantiomeric excess was determined by HPLC using a Chi-
ralcel OD column [hexane/iPrOH, 90:10]; flow rate 1.0 mL/min; tR
= 19.1 (major), 15.4 (minor) min (94%ee). [α]2D0 = + 10.6 (c = 0.5,
CHCl3) [this compound was obtained using catalyst (S)-I instead
of (R)-I].
1
compound (1.5 g, 75%) as a yellow oil. H NMR (300 MHz): δ =
8.20 (d, J = 10.1 Hz, 2 H), 7.47 (d, J = 10.1 Hz, 2 H), 3.92 (s, 2
H), 2.92 (q, J = 6.9 Hz, 2 H), 1.25 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (75 MHz): δ = 196.0 (CO), 147.4 (C), 141.3 (C), 130.6
(2CH), 124.0 (2CH), 50.1 (CH2), 24.0 (CH2), 14.6 (CH3) ppm. MS
(FAB): m/z (%) = 226 (100) [M + 1+]. HRMS (ESI): Calcd. for
C10H12NO3S [M + 1] 226.0538; found 226.0535.
S-Ethyl (2R,3S)- and (2S,3S)-3-Methyl-2-(4-nitrophenyl)-5-oxo-
pentanethioate (3b/3bЈ): The title compound was obtained as a
62:38 mixture of diastereomers according to the general procedure
1
(72% yield). Data obtained from the mixture of diastereomers. H
NMR: δ = 9.75 (s, 1 H, minor), 9.57 (s, 1 H, major), 8.19 (d, J =
8.8 Hz, 2 H, minor), 8.17 (d, J = 8.7 Hz, 2 H, major), 7.51 [d, J =
8.8 Hz, 2 H (major), 2 H (minor)], 3.78 (d, J = 10.5 Hz, 1 H,
major), 3.74 (d, J = 10.2 Hz, 1 H, minor), 3.00–2.73 [m, 3 H
(major), 3 H (minor)], 2.58 (dd, Jd = 17.3, 3.6 Hz, 1 H, minor),
2.35 (ddd, J = 16.6, 8.6, 2.2 Hz, 1 H, minor), 2.18 (dd, J = 17.3,
3.6 Hz, 1 H, major), 2.05 (ddd, J = 17.4, 8.6, 2.2 Hz, 1 H, minor),
1.14 (t, J = 7.5 Hz, 3 H, major), 1.13 (t, J = 7.4 Hz, 3 H, minor),
1.07 (d, J = 6.6 Hz, 3 H, major), 0.73 (d, J = 6.6 Hz, 3 H,
minor) ppm. 13C NMR (75 MHz): δ = 200.5 (CHO), 200.4 (CHO),
198.7 (C), 198.5 (C), 147.6 (C), 147.5 (C), 144.2 (2CH), 129.5
(2CH), 124.0 (2CH), 124.0 (2CH), 65.4 (CH), 65.3 (CH), 48.4
(CH), 47.7 (CH), 32.4 (CH2), 31.9 (CH2), 18.5 (CH3), 17.9.3 (CH3),
14.4 (CH3), 14.3 (CH3) ppm. MS (IE): m/z (%) = 295 (1) [M+], 206
(100), 160 (5), 142 (40), 118 (25), 115 (40), 89 (28). HRMS (IE):
Calcd. for C14H17NO4S [M+] 295.0878; found 295.0891. The ee was
determined for the corresponding alcohol, obtained after reduction
with NaBH4 in EtOH at –20 °C. The crude compound was purified
by flash chromatography (n-hexane/EtOAc, 4:1).
General Procedure for the Catalytic Michael Addition of 1e to α,β-
Unsaturated Aldehydes 2a–g: To a solution of (R)-α,α-bis[3,5-bi-
s(trifluoromethyl)phenyl]-2-pyrrolidinemethanol
trimethylsilyl
ether (I; 0.1 equiv., 0.03 mmol) in EtOH (0.5 m) were sequentially
added the corresponding α,β-unsaturated aldehyde 2a–g (3 equiv.,
0.9 mmol) and benzoic acid (0.1 equiv., 0.03 mmol). The resulting
mixture was stirred at room temperature for 10 min, then thioester
1e (67 mg, 0.3 mmol) was added. The reactions were followed by
TLC until disappearance of the starting thioester 1e was observed.
The resulting Michael adducts were purified by flash column
chromatography (n-hexane/EtOAc, 10:1 for aliphatic aldehydes and
8:1 for aromatic aldehydes) to afford the corresponding aldehydes
3a–g in the yields indicated in Table 2.
General Procedure for the Reduction of Aldehydes 3a–g: To a cooled
solution (–20 °C) of the corresponding aldehyde 3a–g (0.3 mmol)
in EtOH (0.05 m), NaBH4 (1.2 equiv.) was added. The reaction
mixture was stirred at –20 °C for 4 h and quenched at the reaction
temperature with water (10 mL). The aqueous layer was extracted
with EtOAc (3ϫ 15 mL) and the combined organic layers were
washed with brine and dried with MgSO4. The solvent was finally
evaporated and the crude product was purified by flash column
chromatography using the eluent indicated in each case. The enan-
tiomeric excesses of the Michael addition were determined for the
major diastereomer of alcohols 4a–g by chiral HPLC analysis.
S-Ethyl (2R,3S)-5-Hydroxy-3-methyl-2-(4-nitrophenyl)pentanethio-
1
ate (4b): H NMR (300 MHz): δ = 8.17 (d, J = 8.4 Hz, 2 H), 7.51
(d, J = 8.4 Hz, 2 H), 3.62 (d, J = 9.1 Hz, 1 H), 3.67–3.49 (m, 2 H),
2.94–2.74 (m, 2 H), 2.56–2.44 (m, 2 H), 1.63–1.45 (m, 1 H), 1.42–
1.29 (m, 1 H), 1.19 (t, J = 7.6 Hz, 3 H), 1.07 (d, J = 6.5 Hz, 3
H) ppm. 13C NMR (75 MHz): δ = 198.9 (CO), 147.3 (C), 144.8
(C), 129.6 (2CH), 124.0 (2CH), 66.9 (CH2), 60.0 (CH), 36.4 (CH),
34.0 (CH2), 23.8 (CH2), 17.4 (CH3), 14.5 (CH3) ppm. MS (ESI):
m/z (%) = 326 (12) [M + 1+], 236 (100), 79 (47). HRMS (ESI):
Calcd. for C14H20NO4S [M + 1] 298.1107; found 298.1035. The
S-Ethyl (2R,3S)- and (2S,3S)-2-(4-Nitrophenyl)-5-oxo-3-phenylpent-
anethioate (3a/3aЈ): The title compound was obtained as a 70:30
mixture of diastereomers according to the general procedure
(Michael addition, 93% yield); m.p. 121–123 °C. Data obtained
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O30934
/KAP1
Date: 19-09-13 16:28:36
Pages: 10
S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid
FULL PAPER
enantiomeric excess was determined by HPLC using a Chiralcel
IA column [hexane/iPrOH, 90:10]; flow rate 1.0 mL/min; tR = 16.7
(major), 14.1 (minor) min (83%ee). [α]2D0 = –66.9 (c = 2.0, CHCl3).
obtained after reduction with NaBH4 in EtOH at –20 °C. The
crude compound was purified by flash chromatography (n-hexane/
EtOAc, 6:1).
S-Ethyl (2R,3S)-5-Hydroxy-3-(4-methoxyphenyl)-2-(4-nitrophenyl)-
pentanethioate (4d): M.p. 115–116 °C. 1H NMR (300 MHz): δ =
8.22 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.19 (d, J =
8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 4.06 (d, J = 11.2 Hz, 1 H),
3.81 (s, 3 H), 3.58 (td, Jt = 11.2, Jd = 3.6 Hz, 1 H), 3.44–3.33 (m,
1 H), 3.32–3.21 (m, 1 H), 2.72–2.47 (m, 2 H), 1.69–1.50 (m, 2 H),
0.93 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 198.0
(CO), 158.7 (C), 147.7 (C), 144.5 (C), 132.2 (C), 129.6 (2CH), 129.3
(2CH), 124.0 (2CH), 114.1 (2CH), 66.9 (CH), 60.2 (CH2), 55.3
(CH3), 45.2 (CH2), 35.9 (CH), 23.7 (CH2), 14.4 (CH3) ppm. MS
(ESI): m/z (%) = 390 (32) [M + 1+], 328 (100), 135 (45). HRMS
(ESI): Calcd. for C20H24NO5S [M + 1] 390.1369; found 390.1373.
The enantiomeric excess was determined by HPLC using a Chi-
ralcel IA column [hexane/iPrOH, 90:10]; flow rate 1.0 mL/min; tR
= 23.5 (major), 18.7 (minor) min (87%ee). [α]2D0 = –1.97 (c = 1.0,
CHCl3).
S-Ethyl (2R,3S)- and (2S,3S)-2-(4-Nitrophenyl)-5-oxo-3-isopropyl-
pentanethioate (3c/3cЈ): The title compound was obtained as a
68:32 mixture of diastereomers according to the general procedure
1
(50% yield). Data obtained from the mixture of diastereomers. H
NMR (300 MHz): δ = 9.63 (s, 1 H, minor), 9.24 (s, 1 H, major),
8.13 (d, J = 8.8 Hz, 2 H, minor), 8.09 (d, J = 8.8 Hz, 2 H, major),
7.47 [d, J = 8.8 Hz, 2 H (major), 2 H (minor)], 3.83 (d, J = 11.1 Hz,
1 H, major), 3.80 (d, J = 10.7 Hz, 1 H, minor), 3.04–2.96 (m, 1 H,
major), 2.88–2.68 (m, 5 H), 2.47–2.3958 (m, 1 H, minor), 2.32–2.18
(m, 2 H), 1.97–1.87 (m, 2 H), 1.37 (dsept, Jd = 3.2, Jsept = 6.8 Hz,
1 H, major), 0.87 (t, J = 5.8 Hz, 6 H), 0.78 (d, J = 6.8 Hz, 3 H,
major), 0.65 (d, J = 6.8 Hz, 3 H, minor) ppm. 13C NMR (75 MHz):
δ = 200. 9 (CHO), 199.9 (CHO), 198.8 (C), 198.6 (C), 147.6 (2 C),
144.4 (C), 144.0 (CH), 129.8 (2CH), 129.4 (2CH), 124.1 (2CH),
124.0 (2CH), 63.5 (CH), 63.1 (CH), 42.1 (CH), 41.8 (CH), 41.6
(CH), 41.4 (CH), 29.1 (CH2), 27.8 (CH2), 24.1 (CH2), 23.9 (CH2),
21.6 (CH3), 21.2 (CH3), 16.6 (CH3), 15.8 (CH3), 14.3 (CH3), 14.2
(CH3) ppm. MS (ESI): m/z (%) = 324 (20) [M + 1+], 262 (24), 216
(20), 79 (3). HRMS (ESI): Calcd. for C16H22NO4S [M + 1+]
324.1264; found 324.1273. The ee was determined in the corre-
sponding alcohol, obtained after reduction with NaBH4 in EtOH
at –20 °C. The crude compound was purified by flash chromatog-
raphy (n-hexane/EtOAc, 4:1).
S-Ethyl (2S,3S)- and (2R,3S)-3-(2-Methoxyphenyl)-2-(4-nitro-
phenyl)-5-oxopentanethioate (3e/3eЈ): The title compound was ob-
tained as a 64:36 mixture of diastereomers according to the general
procedure (Michael addition, 90% yield). Data obtained from the
1
mixture of diastereomers. H NMR (300 MHz): δ = 9.54 (s, 1 H),
9.38 (s, 1 H), 8.20 (d, J = 8.7 Hz, 2 H), 7.95 (d, J = 8.7 Hz, 2 H),
7.62 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 8.7 Hz, 2 H), 7.19 (m, 2 H),
7.03 (m, 1 H), 6.95–6.85 (m, 3 H), 6.72–6.64 (m, 2 H), 4.57 (d, J
= 11.4 Hz, 1 H), 4.44 (d, J = 11.2 Hz, 1 H), 4.35 (td, Jt = 9.7, Jd
= 4.2 Hz, 1 H), 4.22 (td, Jt = 10.3, Jd = 4.2 Hz, 1 H), 3.92 (s, 3 H),
3.77 (s, 3 H), 3.04–3.74 (m, 5 H), 2.72–2.47 (m, 2 H), 2.35 (ddd, J
= 17.1, 4.4, 1.5 Hz, 1 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.90 (t, J =
7.4 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 200.6 (CHO), 200.5
(CHO), 198.7 (C), 197.8 (C), 157.4 (C), 156.8 (C), 147.7 (C), 147.1
(C), 144.1 (C), 143.8 (C), 130.7 (CH), 129.9 (CH), 129.8 (2CH),
129.2 (2CH), 128.8 (CH), 128.6 (CH), 127.1 (C), 126.9 (C), 123.9
(2CH), 123.2 (2CH), 120.8 (CH), 120.7 (CH), 111.1 (CH), 110.8
(CH), 63.3 (CH), 62.3 (CH), 55.4 (CH3), 55.2 (CH3), 46.6 (CH2),
45.3 (CH2), 40.8 (CH), 39.4 (CH), 24.0 (CH2), 23.5 (CH2), 14.3
(CH3), 14.2 (CH3) ppm. MS (ESI): m/z (%) = 388 (4) [M + 1+],
326 (8), 163 (6). HRMS (ESI): Calcd. for C20H22NO5S [M + 1+]
388.1213; found 388.1232. The ee was determined for the corre-
sponding alcohol, obtained after reduction with NaBH4 in EtOH
at –20 °C. The crude compound was purified by flash chromatog-
raphy (n-hexane/EtOAc, 6:1).
S-Ethyl (2R,3R)-5-Hydroxy-3-isopropyl-2-(4-nitrophenyl)pentane-
1
thioate (4c): M.p. 86–87 °C. H NMR (300 MHz): δ = 8.17 (d, J =
8.5 Hz, 2 H), 8.18 (d, J = 8.5 Hz, 2 H), 3.82 (d, J = 11.3 Hz, 1 H),
3.24–3.12 (m, 1 H), 3.11–2.98 (m, 1 H), 2.96–2.72 (m, 2 H), 2.41–
2.24 (m, 1 H), 1.94 (dsept, Jsept = 7.1, Jd = 2.8 Hz, 1 H), 1.67–1.42
(m, 2 H), 1.18 (t, J = 7.4 Hz, 3 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.95
(d, J = 6.7 Hz, 3 H) ppm. 13C NRM (75 MHz): δ = 199.3 (CO),
147.7 (C), 144.9 (C), 130.4 (2CH), 123.7 (2CH), 64.2 (CH2), 62.2
(CH), 43.7 (CH), 30.6 (CH2), 29.6 (CH), 23.9 (CH2), 21.2 (CH3),
16.8 (CH3), 14.2 (CH3) ppm. MS (ESI): m/z (%) = 326 (25) [M +
1+], 264 (100). HRMS (ESI): Calcd. for C16H24NO4S [M + 1]
326.1420; found 326.1418. The enantiomeric excess was determined
by HPLC using a Chiralcel AD column [hexane/iPrOH, 80:20];
flow rate 1.0 mL/min; tR = 8.8 (major), 5.8 (minor) min (92%ee).
[α]2D0 = –20.0 (c = 1.0, CHCl3).
S-Ethyl (2R,3S)- and (2S,3S)-3-(4-Methoxyphenyl)-2-(4-nitro-
phenyl)-5-oxopentanethioate (3d/3dЈ): The title compound was ob-
tained as a 64:36 mixture of diastereomers according to the general
procedure (Michael addition, 70% yield). Data obtained from the
S-Ethyl (2R,3S)-5-Hydroxy-3-(2-methoxyphenyl)-2-(4-nitrophenyl)-
1
pentanethioate (4e): H NMR (500 MHz, C2D2Cl4): δ = 8.13 (d, J
1
mixture of diastereomers. H NMR (300 MHz): δ = 9.55 (s, 1 H),
= 8.7 Hz, 2 H), 7.58 (d, J = 8.7 Hz, 2 H), 7.17 (td, Jt = 8.2, Jd
=
9.40 (s, 1 H), 8.22 (d, J = 8.6 Hz, 2 H), 8.00 (d, J = 8.8 Hz, 2 H),
7.61 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.6 Hz, 2 H), 7.19 (d, J =
8.7 Hz, 2 H), 6.89 (d, J = 8.9 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H),
6.64 (d, J = 8.9 Hz, 2 H), 4.14 (d, J = 11.1 Hz, 1 H), 4.08 (d, J =
11.4 Hz, 1 H), 4.00 (m, 2 H), 3.78 (s, 3 H), 3.68 (s, 3 H), 2.94–2.84
(m, 3 H), 2.74–2.53 (m, 4 H), 2.37 (dd, J = 17.1, 4.1 Hz, 1 H), 1.22
(t, J = 7.5 Hz, 3 H), 0.96 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz): δ = 199.9 (CHO), 199.8 (CHO), 198.4 (C), 197.6 (C),
158.9 (C), 158.5 (C), 147.8 (C), 147.2 (C), 143.7 (C), 143.5 (C),
131.6 (C), 131.1 (C), 129.6 (2CH), 129.4 (2CH), 129.3 (2CH), 128.9
(2CH), 124.2 (2CH), 123.5 (2CH), 114.2 (2CH), 114.1 (2CH), 65.7
(CH), 65.6 (CH), 55.2 (CH3), 55.1 (CH3), 48.0 (CH2), 47.2 (CH2),
43.1 (CH), 42.9 (CH), 24.1 (CH2), 23.8 (CH2), 14.4 (CH3), 14.2
(CH3) ppm. MS (ESI): m/z (%) = 388 (4) [M + 1+], 149 (56).
HRMS (ESI): Calcd. for C20H22NO5S [M + 1+] 388.1213; found
388.1216. The ee was determined for the corresponding alcohol,
1.7 Hz, 1 H), 7.11 (dd, J = 7.6, 1.7 Hz, 1 H), 6.86 (m, 2 H), 4.42
(d, J = 10.6 Hz, 1 H), 3.32–3.27 (m, 1 H), 3.23–3.19 (m, 1 H), 2.65–
2.58 (m, 1 H), 2.54–2.46 (m, 1 H), 1.78–1.71 (m 1 H), 1.54–1.48 (m
1 H), 0.80 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (125 MHz): δ =
198.0 (C), 158.1 (C), 148.0 (C), 144.9 (C), 129.9 (2CH), 128.6 (C),
128.3 (CH), 123.8 (2CH), 121.1 (CH), 111.9 (CH), 64.2 (CH), 60.6
(CH2), 55.9 (CH3), 34.9 (CH2), 29.6 (CH), 23.6 (CH2), 14.2
(CH3) ppm. MS (ESI): m/z (%) = 390 (14) [M + 1+], 328 (100), 149
(49), 135 (54), 64 (56). HRMS (ESI): Calcd. for C20H24NO5S [M
+ 1] 390.1369; found 390.1371. The enantiomeric excess was deter-
mined by HPLC using a Chiralcel OD column [hexane/iPrOH,
90:10]; flow rate 1.0 mL/min; tR = 13.8 (major), 18.9 (minor) min
(88%ee). [α]2D0 = –12.4 (c = 1.0, CHCl3).
S-Ethyl (2S,3S)- and (2R,3S)-2,3-bis(4-nitrophenyl)-5-oxopentane-
thioate (3f/3fЈ): The title compound was obtained as a 70:30 mix-
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30934
/KAP1
Date: 19-09-13 16:28:36
Pages: 10
p-Nitrophenyl Ethylthioester as a Pronucleophile
ture of diastereomers according to the general procedure (Michael
addition, 75% yield). Data obtained from the major diastereomer.
(CH), 60.2 (CH2), 39.3 (CH2), 34.0 (CH2), 23.7 (CH), 14.2
(CH3) ppm. MS (FAB): m/z (%) = 350 (22) [M + 1], 327 (67), 283
1H NMR (300 MHz): δ = 9.41 (s, 1 H), 8.23 (d, J = 8.8 Hz, 2 H), (100). HRMS (FAB): Calcd. for C17H20NO5 [M + 1] 350.1062;
8.17 (d, J = 8.6 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H), 8.50 (d, J = found 350.1058. The enantiomeric excess was determined by HPLC
8.8 Hz, 2 H), 4.21 (m, 2 H), 2.71 (m, 1 H), 2.61 (m, 2 H), 2.53 (m,
using a Chiralcel OD column [hexane/iPrOH, 90:10]; flow rate
1 H), 0.93 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 198.2
1.0 mL/min; tR = 13.8 (major), 18.9 (minor) min (70%ee). [α]D20
=
(CHO), 197.0 (C), 148.0 (C), 147.8 (C), 147.2 (C), 142.6 (CH), –10.8 (c = 2.0, CHCl3).
129.5 (2CH), 129.4 (2CH), 124.3 (2CH), 123.8 (2CH), 64.5 (CH),
(3S,4S)-3-(4-Nitrophenyl)-4-phenyltetrahydro-2H-pyran-2-one (5a):
To a solution of alcohol 4a (0.2 mmol) in anhydrous THF (0.03 m),
NaH (1.1 equiv.) was added. After stirring the resulting mixture at
room temperature for 1 h, the reaction was quenched by addition
of a saturated solution of NH4Cl (10 mL) and extracted with
EtOAc (2ϫ 15 mL). The organic extracts were washed with brine
and dried with anhydrous MgSO4. The solvent was evaporated and
47.0 (CH2), 42.9 (CH), 23.9 (CH2), 14.5 (CH3) ppm. MS (ESI): m/z
(%) = 403 (5) [M + 1+], 341 (50), 149 (100). HRMS (ESI): Calcd.
for C19H19N2O6S [M + 1] 402.0886; found 402,0896. The ee was
determined for the corresponding alcohol, obtained after reduction
with NaBH4 in EtOH at –20 °C. The crude compound was purified
by flash chromatography (n-hexane/EtOAc, 6:1).
S-Ethyl
(2R,3S)-5-Hydroxy-2,3-bis(4-nitrophenyl)pentanethioate the crude product was purified by flash chromatography (n-hexane/
(4f): M.p. 157–158 °C. 1H NMR (300 MHz): δ = 8.23 (d, J = EtOAc, 4:1) to afford the desired product (50% yield). 1H NMR
8.8 Hz, 2 H), 8.19 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 8.2 Hz, 2 H), (300 MHz): δ = 8.11 (d, J = 9 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H),
7.48 (d, J = 8.19 Hz, 2 H), 4.12 (d, J = 9.8 Hz, 1 H), 3.82 (td, Jt =
9.8, Jd = 5.1 Hz, 1 H), 3.44–3.33 (m, 1 H), 3.24–3.12 (m, 1 H),
7.19 (m, 3 H), 7.04 (d, J = 7.8 Hz, 2 H), 4.71 (m, 2 H), 4.02 (d, J
= 11.8 Hz, 1 H), 3.32 (m, 1 H), 2.39 (m, 2 H) ppm. 13C NMR
2.69–2.47 (m, 2 H), 1.71–1.54 (m, 2 H), 0.90 (t, J = 7.1 Hz, 3 (75 MHz): δ = 169.6 (CO), 141.2 (C), 133.4 (C), 133.3 (C), 128.8
H) ppm. 13C NMR (75 MHz): δ = 197.4 (CO), 148.5 (C), 147.8
(2CH), 128.6 (2CH), 127.5 (2CH), 127.2 (2CH), 126.0 (CH), 68.8
(C), 147.1 (C), 143.5 (C), 129.6 (2CH), 129.5 (2CH), 124.2 (2CH), (CH), 46.1 (CH), 45.3 (CH), 35.5 (CH2) ppm. MS (FAB): m/z (%)
123.8 (2CH), 65.6 (CH2), 59.4 (CH), 45.5 (CH2), 35.6 (CH), 23.8 = 298 (100) [M + 1], 154 (27), 136 (30), 55 (100). HRMS (FAB):
(CH2), 14.2 (CH3) ppm. MS (ESI): m/z (%) = 405 (13) [M + 1+],
343 (88), 282 (100), 225 (44), 149 (90), 79 (42), 64 (77). HRMS
(ESI): Calcd. for C19H21NO6S [M + 1] 405.1138; found 405.1114.
The enantiomeric excess was determined by HPLC using a Chi-
ralcel IC column [hexane/iPrOH, 90:10]; flow rate 1.0 mL/min; tR
= 56.9 (major), 43.6 (minor) min (86%ee). [α]2D0 = –14.5 (c = 0.7,
CHCl3).
Calcd. for C17H16NO4 [M + 1] 298.1079; found 298.1072.
(3S,4S)-4-Methyl-3-(4-nitrophenyl)-tetrahydropyran-2-one (5b): Fol-
lowing the same procedure described for 4a but starting from
alcohol 4b, lactone 5b was obtained as a single diastereomer (85%
yield). 1H NMR (300 MHz): δ = 8.23 (d, J = 8.8 Hz, 2 H), 7.38 (d,
J = 8.8 Hz, 2 H), 4.58–4.42 (m, 2 H), 3.38 (d, J = 11 Hz, 1 H),
2.33–2.22 (m, 1 H), 2.20–2.07 (m, 1 H), 1.74–0.98 (m, 1 H), 0.95
S-Ethyl (2S,3S)- and (2R,3S)-3-(Furan-2-yl)-2-(4-nitrophenyl)-5- (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 171.0 (CO),
oxopentanethioate (3g/3gЈ): The title compound was obtained as a
70:30 mixture of diastereomers according to the general procedure
(Michael addition, 60% yield). Data obtained from the mixture of
diastereomers. 1H NMR (300 MHz): δ = 9.60 (s, 1 H), 9.50 (s, 1
147.3 (C), 145.2 (C), 130.0 (2CH), 123.9 (2CH), 68.2 (CH2), 55.6
(CH), 34.3 (CH), 30.9 (CH2), 20.3 (CH3) ppm. MS (FAB): m/z (%)
= 236 (100) [M + 1], 219 (13), 107 (35), 71 (44), 57 (58), 55 (85).
HRMS (FAB): Calcd. for C12H13NO4 [M + 1] 236.0917; found
H), 8.20 (d, J = 8.8 Hz, 2 H), 8.05 (d, J = 8.8 Hz, 2 H), 7.53 (d, J 236.0923. The enantiomeric excess was determined by HPLC using
= 8.8 Hz, 4 H), 7.37–7.32 (m, 2 H), 6.28 (dd, J = 3.3, 1.9 Hz, 1 H),
6.14 (d, J = 3.3 Hz, 1 H), 6.05 (dd, J = 3.3, 1.9 Hz, 1 H), 5.49 (d,
a Chiralcel OD column [hexane/iPrOH, 90:10]; flow rate 1.0 mL/
min; tR = 30.3 (major), 26.4 (minor) min (83%ee). [α]2D0 = +20 (c
J = 3.3 Hz, 1 H), 4.29 (d, J = 10.3 Hz, 1 H), 4.25–4.08 (m, 2 H), = 1.0, CHCl3) {ref.[5] [α]2D0 = +25 (c = 1.0, CHCl3, 96%ee)]. IR
4.23 (d, J = 10.8 Hz, 1 H), 2.99–2.60 (m, 7 H), 2.41 (dd, J = 17.4,
3.9 Hz, 1 H), 1.22 (t, J = 7.5 Hz, 3 H), 1.09 (t, J = 7.4 Hz, 3
H) ppm. 13C NMR (75 MHz): δ = 199.2 (C), 199.1 (CHO), 197.6
(C), 192.9 (CHO), 152.4 (2C), 145.9 (2C), 142.8 (Cϫ2), 142.0
(CH), 141.9 (CH), 129.6 (2CH), 129.2 (2CH), 124.1 (2CH), 123.6
(2CH), 110.4 (CH), 110.2 (CH), 108.3 (CH), 108.1 (CH), 63.0
(CH), 62.7 (CH), 45.4 (CH2), 44.4 (CH2), 37.3 (CH), 36.7 (CH),
24.1 (CH2), 23.8 (CH2), 14.3 (CH3), 14.2 (CH3) ppm. MS (ESI):
m/z (%) = 370 (4) [M + Na+], 360 (12), 149 (4). HRMS (ESI):
Calcd. for C17H17NO5SNa [M + Na+] 370.0719; found 370.0724.
The ee was determined for the corresponding alcohol, obtained
after reduction with NaBH4 in EtOH at –20 °C. The crude com-
pound was purified by flash chromatography (n-hexane/EtOAc,
4:1).
(film): ν = 2964, 1723, 1526, 1347 cm–1.
˜
(R)-4-(4-Nitrophenyl)-3-phenylbutan-1-ol (6): To
a solution of
alcohol 4a (36 mg, 0.1 mmol) in MeOH (0.5 mL) were added KOH
(1.2 equiv.) and water (2 mL). The reaction was stirred for 2 h until
the starting material was consumed. After this time, the solvent
was evaporated and K2CO3 (2.0 equiv.) and DMF (5 mL) were
added. The reaction was performed in an ultrasonic bath for 6 h at
room temperature, then water was added to the reaction mixture
and the aqueous phase was extracted with diethyl ether (3ϫ
20 mL). The combined organic extracts were washed with brine
and dried with anhydrous MgSO4. The solvent was finally evapo-
rated and the crude compound was purified by flash chromatog-
raphy (n-hexane/EtOAc, 4:1) to give 6 (80% yield). 1H NMR
(300 MHz, CDCl3): δ = 8.00 (d, J = 8.7 Hz, 2 H), 7.21 (m, 3 H),
7.08 (m, 4 H), 3.56 (m, 1 H), 3.44 (m, 1 H), 3.03 (m, 3 H), 1.95
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.2 (C), 146.4
(C), 142.9 (C), 129.9 (2 CH), 128.6 (2 CH), 127.7 (2 CH), 126.8
(CH), 123.3 (2 CH), 60.7 (CH2), 44.2 (CH), 43.5 (CH2), 38.5
S-Ethyl (2S,3S)- and (2R,3S)-3-(Furan-2-yl)-5-hydroxy-2-(4-nitro-
1
phenyl)pentanethioate (4g): H NMR (300 MHz): δ = 8.20 (d, J =
8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.24 (dd, J = 0.61, 1.71 Hz,
1 H), 6.29 (dd, J = 1.71, 3.20 Hz, 1 H), 6.17 (dd, J = 0.61, 3.20 Hz,
1 H), 4.21 (d, J = 10.7 Hz, 1 H), 3.79 (td, Jt = 10.7, Jd = 4.1 Hz, (CH2) ppm. MS (ESI): m/z (%) = 272 [M + 1], 149 (21), 79 (100),
1 H), 3.50–3.27 (m, 2 H), 2.81–2.58 (m, 2 H), 1.77–1.66 (m 1 H), 64 (22). HRMS (ESI): Calcd. C16H18NO3 [M + 1] 272.1281; found
1.54–1.42 (m 1 H), 1.05 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
272.1290. The enantiomeric excess was determined by HPLC using
(75 MHz): δ = 198.0 (CO), 153.3 (C), 147.5 (C), 143.7 (C), 142.0 a Chiralpak OD column [hexane/i-PrOH, 95:5]; flow rate 1.0 mL/
(CH), 129.7 (2CH), 124.0 (2CH), 110.2 (CH), 108.1 (CH), 64.1
min; tR = 20.1 (major), 17.9 (minor) min (90%ee).
Eur. J. Org. Chem. 0000, 0–0
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S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid
FULL PAPER
(3S,4S)- and (3R,4S)-1-Benzyl-3-(4-nitrophenyl)-4-phenylpiperidin-
2-one (7a/7aЈ): To a solution of 3a/3aЈ (72 mg, 0.2 mmol) in 1,2-
dichloroethane (166 mL) at 0 °C, benzylamine (3 equiv., 0.6 mmol),
acetic acid (12 μL, 0.2 mmol) and sodium triacetoxyborohydride
(5 equiv.) were added. The resulting mixture was stirred at room
temp. for 24 h. After this time, the reaction was quenched by the
addition of aqueous NaHCO3 (10 mL) and the product was ex-
tracted with CH2Cl2 (3ϫ 20 mL). The combined organic layers
were washed with brine and dried with anhydrous MgSO4. The
solvent was evaporated in vacuo to give the crude product, which
was purified by flash chromatography (n-hexane/EtOAc, 4:1) to af-
ford the lactam as a mixture of diastereomers (81% yield). 1H
490 μL) at 0 °C. After stirring at room temperature for 30 min, the
reaction mixture was filtered through Celite and the filtrate was
neutralized with a saturated solution of NaHCO3. The aqueous
layer was extracted with dichloromethane (3ϫ 15 mL) and the
combined organic layers were washed with brine and dried with
MgSO4. The solvent was evaporated to give pure amine 8a in quan-
titative yield. The crude material was treated with aqueous 50%
H3PO2 (2.5 mL), and NaNO2 (2.6 equiv., 54 mg) was added at
0 °C. After 2 h, K2CO3 was added to the reaction mixture and the
aqueous layer was extracted with Et2O (3ϫ 15 mL). The combined
organic layer was dried with MgSO4, filtered, and the solvents
evaporated. The residue was purified by flash chromatography
NMR (300 MHz): δ = 8.05 (d, J = 8.7 Hz, 2H, major), 7.90 (d, J (hexane/ethyl acetate, 6:1) to afford 9a (75% yield). 1H NMR
= 8.5 Hz, 2 H, minor), 7.45–7.31 [m, 6 H (major), 5 H (minor)], (300 MHz): δ = 7.46–7.27 (m, 10 H), 3.98 (d, J = 11.3 Hz, 1 H),
7.22–7.15 [m, 2 H (major), 3 H (minor)], 7.12 (d, J = 9.0 Hz, 2 H, 3.58 (dt, Jd = 11.3, Jt = 7.7 Hz, 1 H), 3.40–3.22 (m, 2 H), 2.69–
major), 6.98–6.93 (m, 2 H, major), 6.81 (d, J = 8.7 Hz, 2 H, minor),
6.77–6.73 (m, 2 H, minor), 5.03 (d, J = 14.3 Hz, 1 H, minor), 4.75
(d, J = 14.1 Hz, 1 H, major), 4.56 (d, J = 14.5 Hz, 1 H, major),
4.52 (d, J = 13.1 Hz, 1 H, minor), 4.21 (d, J = 5.7 Hz, 1 H, minor),
3.93 (d, J = 11.3 Hz, 1 H, major), 3.49–3.64 (m, 2 H, major), 3.48–
3.38 (m, 3 H, minor), 3.15 (td, Jt = 11.4, Jd = 4.1 Hz, 1 H, major),
2.44 (m, 2 H), 1.67–1.60 (m, 2 H), 0.88 (t, J = 7.6 Hz, 3 H) ppm.
13C NMR (75 MHz): δ = 198.9 (C), 141.4 (C), 137.1 (C), 128.8
(2CH), 128.6 (2CH), 128.5 (2CH), 128.4 (2CH), 127.8 (CH), 126.9
(CH), 66.9 (CH), 60.7 (CH2), 45.8 (CH), 36.2 (CH2), 23.4 (CH2),
14.3 (CH3) ppm. MS (ESI): m/z (%) = 315 (19) [M + 1+], 297 (45),
253 (100). HRMS (ESI): Calcd. for C19H23O2S [M + 1] 314.1346;
2.37–2.08 [m, 2 H (major), 2 H (minor)] ppm. 13C NMR (75 MHz): found 314.1356.
δ = 169.3 (CO), 169.1 (CO), 147.9 (C), 147.2 (C), 146.7 (C), 145.0
S-Ethyl (2R,3S)-5-Hydroxy-3-methyl-2-phenylpentanethioate (9b):
(C), 141.6 (C), 139.7 (C), 137.0 (C), 136.9 (C), 130.7 (2CH), 129.9
(2CH), 128.9 (2CH), 128.8 (2CH), 128.7 (2CH), 128.5 (2CH), 128.4
(2CH), 127.9 (2CH), 127.8 (2CH), 127.4 (2CH), 127.2 (2CH), 126.9
(2CH), 123.4 (2CH), 122.6 (2CH), 56.4 (CH2), 54.5 (CH), 50.9
(CH2), 50.7 (CH), 47.8 (CH2), 46.7 (CH2), 46.5 (CH), 43.2 (CH),
29.6 (CH2), 22.3 (CH2) ppm. MS (EI): m/z (%) = 386 (46) [M+], 91
(100). HRMS (EI): Calcd. for C24H22NO3 [M+] 386.1630; found
386.1647.
Following the same procedure described above for 9a, 9b was ob-
1
tained in 60% yield from 4b. H NMR (300 MHz): δ = 7.34–7.29
(m, 5 H), 3.65–3.48 (m, 2 H), 3.48 (d, J = 10.6 Hz, 1 H), 2.93–2.73
(m, 2 H), 2.56–2.42 (m, 1 H), 1.50–1.39 (m, 2 H), 1.19 (t, J =
7.4 Hz, 3 H), 1.07 (d, J = 6.6 Hz, 1 H) ppm. 13C NMR (75 MHz):
δ = 200.2 (C), 137.5 (C), 128.7 (2CH), 128.6 (2CH), 127.5 (CH),
67.4 (CH), 60.6 (CH2), 36.8 (CH2), 33.5 (CH), 23.6 (CH2), 18.0
(CH3), 14.5 (CH3) ppm. MS (ESI): m/z (%) = 253 (22) [M + 1+],
235 (43), 191 (100). HRMS (ESI): Calcd. for C14H21O2S [M + 1]
253.1256; found 253.1266.
(2R,3S)-4-(tert-Butyldiphenylsilyloxy)-2-(4-nitrophenyl)-1,3-di-
phenylbutan-1-one (8): A solution of alcohol 4a (36 mg, 0.10 mmol),
tert-butyl(choro)diphenylsilane (1.2 equiv., 0.12 mmol), triethyl-
amine (2.0 equiv., 0.20 mmol) and DMAP (6 mg, 0.05 mmol) in
dichloromethane (2 mL) was stirred overnight at room tempera-
ture. The resulting mixture was filtered through a short pad of silica
gel using CH2Cl2 as eluent to obtain the protected alcohol as a
single diastereomer in quantitative yield. The protected alcohol
(63 mg, 0.10 mmol), copper(I) thiophene-2-carboxylate (32 mg,
0.17 mmol), phenylboronic acid (13 mg, 0.11 mmol), tris(dibenzyl-
ideneacetone)dipalladium(0) (2.2 mg, 0.025 mmol), and triethyl-
phosphite (3.3 mg, 0.2 mmol) were placed in a sealed tube pre-
viously flushed with argon. DMF (300 μL) was added and the mix-
ture was stirred for 3 d at 100 °C. Et2O (10 mL) was added and the
suspension was washed with water (3ϫ 15 mL). The organic layer
was dried with anhydrous MgSO4, filtered, and the solvents evapo-
rated. The resulting solid was purified by column chromatography
(n-hexane/EtOAc, 12:1) to afford 8 (65% yield) as a single dia-
stereomer. 1H NMR (300 MHz): δ = 8.20 (d, J = 8.7 Hz, 2 H), 7.60
(dd, J = 8.6, 6.5 Hz, 3 H), 7.44 (t, J = 7.05 Hz, 6 H), 4.05 (d, J =
11.9 Hz, 1 H), 3.80–3.68 (m, 1 H), 3.40–3.20 (m, 2 H), 2.68–2.41
(m, 2 H), 0.99 (s, 9 H) ppm. 13C NMR (75 MHz): δ = 211.9 (CO),
152.4 (C), 151.9 (C), 147.2 (C), 145.3 (CH), 141.6 (CH), 137.0
(CH), 133.6 (C), 133.2 (2CH), 129.9 (2CH), 129.6 (2CH), 129.5
(2CH), 128.5 (2CH), 128.4 (2CH), 128.3 (2CH), 128.1 (2CH), 127.5
(2CH), 127.4 (2CH), 124.1 (2CH), 60.9 (CH), 59.5 (CH), 45.4
(CH2), 36.1 (CH), 26.7 (3CH3) ppm. MS (ESI): m/z (%) = 614 [M
+ 1], 242 (100), 149 (72). HRMS (ESI): Calcd. C39H40NO4Si [M +
1] 614.2721; found 614.26.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental data, computational details of the configura-
1
tional assignment of 4a and 4aЈ, H NMR and 13C NMR spectra;
chiral HPLC conditions; and computational details.
Acknowledgments
The authors thank the Spanish Government (CTQ-2012-35957)
and the Comunidad Autónoma de Madrid (CAM) (AVANCAT
CS2009/PPQ-1634) for financial support. S. D. thanks the Comun-
idad Autónoma de Madrid (CAM) for a predoctoral fellowship.
The authors also thank the Centro de ComputaciónCientífica de
la UAM for generous allocation of computer time.
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S-Ethyl (2R,3S)-5-Hydroxy-2,3-diphenylpentanethioate (9a): To a
solution of 4a (0.30 mmol, 110 mg) in CH2Cl2 (4 mL) was added
sequentially Zn dust (14 equiv., 270 mg) and AcOH (28 equiv.,
8
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p-Nitrophenyl Ethylthioester as a Pronucleophile
[6]
[7]
[8]
[18] We have confirmed that diastereomerically pure aldehyde 3a
afforded 4a quantitatively under the reduction conditions with
no epimerization.
[19] The same configuration was assigned to the rest of the
alcohols. The absolute configuration has been determined by
chemical correlation (see the Supporting Information and
ref.[22]).
S. Duce, M. Jorge, I. Alonso, J. L. García Ruano, M. B. Cid,
Org. Biomol. Chem. 2011, 9, 8253–8260.
S. Duce, A. Mateo, I. Alonso, J. L. García Ruano, M. B. Cid,
Chem. Commun. 2012, 48, 5184–5186.
Reaction conditions used for each nucleophile: 1a: catalyst I,
PhCO2H (ref.[4]); 1b: catalyst I, LiOAc (ref.[5]); 1c: catalyst I,
LiOAc (ref.[6]); 1d: catalyst II, TBAB (ref.[7]). It is important to
note that in the reactions of 1d with aromatic enals using
TBAB as additive only good enantioselectivities were obtained
with cat I controlling the reaction times (see also the ESI of
ref.[7]).
S. W. Seo, S.-G. Kim, Tetrahedron Lett. 2012, 53, 2809–2812.
Cat II and pNO2C6H4CO2H as additive were the conditions
used in this publication for aromatic enals and pronucleophile
1d. The authors do not describe the reaction of aliphatic enals,
presumably due to a lack of reactivity under these conditions
(see also ref.[7]).
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[22] Comparison of its spectroscopic parameters, sign of the specific
rotation, and chiral HPLC chromatogram with those obtained
for 5b in ref.[5] (the absolute configuration of which had been
unequivocally determined by X-ray diffraction analysis) al-
lowed the absolute configuration of adducts 3 to be assigned.
The absolute configurations of the other products were as-
signed by analogy.
[23] See, for example: a) A. Metzger, M. A. Schade, P. Knochel,
Org. Lett. 2008, 10, 1107–1110; b) A. Metzger, M. A. Schade,
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2010/085547.
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[9]
[10]
[11]
a) P. Metzner, A. Thuillier, Sulfur Reagents in Organic Synthesis
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489–491.
[13] For more details see the Supporting Information.
[14] No improvement in the reactivity was achieved by using
CH2Cl2 with other additives.
[15] The reduction of Michael adducts 3 to the corresponding
alcohols 4 was necessary to determine the enantioselectivity
of the addition because aldehydes 3 decompose in the HPLC
columns.
[16] Lactones 5a and 5b had been previously prepared by us in ref.[5]
[17] Traces of these alcohols were detected when the reactions were
performed on a large scale.
[27] K. Asakawa, N. Noguchi, S. Takashima, M. Nakada, Tetrahe-
dron: Asymmetry 2008, 19, 2304–2309.
[28] D. Swinnen, D. Hilvert, Org. Lett. 2000, 2, 2439–2442.
Received: June 25, 2013
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S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid
FULL PAPER
Organocatalysis
S. Duce, M. Jorge, I. Alonso,
J. L. G. Ruano, M. B. Cid* ............. 1–10
p-Nitrophenyl Ethylthioester in Enantiose-
lective Organocatalytic Michael Additions:
Different Behaviour of β-Aryl and β-Alkyl
Enals
Keywords: Asymmetric catalysis / Organo-
catalysis / Michael addition
S-Ethyl 4-nitrophenylthioacetate presents
excellent reactivity and enantioselectivity in
organocatalytic asymmetric Michael reac-
tions with both aromatic and aliphatic
enals under different conditions. The corre-
sponding adducts have proven to be versa-
tile intermediates.
10
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