Switching diastereoselectivity in proline-catalyzed aldol reactions

Article abstract of DOI:10.1021/jo3020352

The choice of the anion of an achiral TBD-derived guanidinium salt, used as cocatalyst for proline, allows reacting cycloketones with aromatic aldehydes and preparing either anti- or syn-aldol adducts with very high enantioselectivity. As a proof of princ

Full text of DOI:10.1021/jo3020352

Article
pubs.acs.org/joc
Switching Diastereoselectivity in Proline-Catalyzed Aldol Reactions
́
̃
́
Angel Martínez-Castaneda, Humberto Rodríguez-Solla, Carmen Concellon,* and Vicente del Amo*
́ ́ ́
Departamento de Química Organica e Inorganica, Universidad de Oviedo, C/Julian Clavería 8, 33006, Oviedo, Spain
*
S Supporting Information
ABSTRACT: The choice of the anion of an achiral TBD-
derived guanidinium salt, used as cocatalyst for proline, allows
reacting cycloketones with aromatic aldehydes and preparing
either anti- or syn-aldol adducts with very high enantiose-
lectivity. As a proof of principle, we show how the judicious
choice of an additive allows individual access to all possible
products, thus controlling the stereochemical outcome of the asymmetric aldol reaction. The origin of the syn diastereoselectivity
unfolds from an unusual equilibrium process coupled to the enamine-based catalytic cycle standard for proline.
INTRODUCTION
Scheme 1. General Scheme for a Direct Aldol Reaction
between a Ketone and an Aldehyde: Structures of
Organocatalyst 5, TBD 6, and Additives 7 and 8
■
Carboligation processes (C−C bond-forming reactions) are
essential for assembling the backbone of complex organic
molecules from small and simple building blocks. Among the
dozens of possible reactions available to the organic chemist,
the catalytic asymmetric aldol reaction constitutes one of the
most powerful methodologies for the stereocontrolled for-
mation of carbon−carbon bonds in the synthesis of
1
enantiopure compounds. Although impressive metal-based
methodologies were known, the breakthrough discovery of the
first proline-catalyzed intermolecular aldol reaction, due to List,
2
Lerner and Barbas, encouraged researchers to find out novel
3
organocatalytic protocols for such transformations.
Ordinarily a classical direct aldol reaction between a ketone
and an aldehyde affords an aldol adduct bearing two additional
stereogenic centers on its α- and β- position (Scheme 1). This
fact offers the potential for stereodivergent product generation,
as multiple stereoisomeric products can be derived from a
common pair of synthetic precursors. Four products 1−4 can
be drawn for the reaction sketched in Scheme 1. For every pair
of ketone and aldehyde substrates, it would be ideal to have at
hand a single chiral catalyst that would allow addressing
individually the full matrix of products 1−4. In principle, all
mirror image products can be individually provided if both
enantiomers of a chiral catalyst are available or can be
(
S) and (R) enantiomers of proline are both readily available,
the choice of the proline configuration and the nature of the
additive (7 or 8), allows access to individually to all possible
products 1−4 represented in Scheme 1.
4
chemically prepared. Fulfilling this requirement is not always
trivial (i.e., cinchona-based alkaloids, commonly used organo-
catalysts, do not present an accessible enantiomeric form). It is
still more challenging controlling the relative stereochemical
RESULTS AND DISCUSSION
■
5
The ability of proline to catalyze aldol reactions, rendering anti-
aldol adducts, is widely recognized. However, proline itself
presents some major drawbacks: poor performance in direct
aldol reactions with aromatic aldehydes, rather limited solubility
and reactivity in nonpolar organic solvents, and potential
parasitic side processes. In a previous contribution, we have
shown that the addition of a catalytic amount of tetrafluor-
disposition of aldol adducts (diastereoselectivity) using a single
chiral catalyst. To our knowledge, only one recent example has
appeared in the literature reporting a stereochemical switch in
organocatalyzed aldol reactions, employing the synthetic chiral
6
diamine 5.
Herein, we demonstrate the ability of different achiral
triazabicyclo[4.4.0]dec-5-ene (TBD, 6)-derived guanidinium
salts (7 and 8) to modulate the reactivity of proline in direct
aldol reactions between cyclic ketones and aromatic aldehydes,
giving rise to diastereodivergent pathways. Considering that the
Received: September 26, 2012
Published: October 26, 2012
©
2012 American Chemical Society
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oborate TBD-derived guanidinium salt 7 accelerates the
reaction rate, and increases the diastereo- and enantioselectivity
of anti-aldols, in proline-catalyzed aldol reactions between
entries 2−4). Products 10b−d display a preferential syn-
stereochemistry, peaking the syn/anti ratio at 75:25, and have
an enantiomeric excess above 90% (for the syn-adducts). It has
to be noted that only limited work has been done on the
catalytic direct asymmetric aldol reaction of cyclohexanone with
aldehydes to afford syn products. To expand the scope of our
reaction, we also explored cyclopentanone as ketone donor.
Without altering conditions, 4-nitrobenzaldehyde 9a was
reacted, isolating the expected cyclopentyl aldol 11a in very
high yield, with good diastereoselectivity (77:23 syn to anti)
and excellent enantioselectivity (96% ee, for syn-11a). Again,
aldehydes 9b−d were tested as substrates (Table 1, entries 6−
8). Their reactions proceeded smoothly, affording the aldol
addcuts with high diastereo- and very high enantioselectivity,
confirming the robustness of this transformation. The absolute
stereochemistry of products syn-11 was assigned unambigu-
ously as (R,R) by comparison of the chiral HPLC chromato-
gram for compounds 11a and 11c with those previously
7
cyclic ketones and aromatic aldehydes. Additive 7 also allowed
carrying out proline-catalyzed direct aldol reactions employing
8
chloroacetone. The nature of the anion in the guanidinium
salts proved to be decisive in these studies. We observed an
intriguing behavior for the tetraphenylborate salt 8, which
rendered syn-aldols when it was used as cocatalyst for proline.
We aimed to explore further this feature, and the direct aldol
reaction between cyclohexanone and 4-nitrobenzaldehyde, 9a,
cocatalyzed by (S)-proline and salt 8, was studied as a model
system. In accordance to our previously developed method-
ologies, we decided to work under solvent-free conditions,
employing a moderate excess of ketone as reagent and reaction
media. A screening of reaction temperatures (Supporting
Information (SI), Table S1) and stoichiometries (SI, Table
S2) unveiled an optimum protocol: when a suspension of 4-
nitrobenzaldehyde 9a (1.0 equiv), (S)-proline (10 mol %) and
TBD-derived tetraphenylborate guanidinium salt 8 (15 mol %),
10
reported in the literature. The results of Table 1 are superior
in terms of enantioselectivity, and of comparable diastereose-
lectivity, to the sole example describing an additive-mediated
diastereoswitch in direct aldol reaction employing a synthetic
in cyclohexanone (10.0 equiv), was allowed to react for 120 h at
9
0
−3 °C, with no stirring, the corresponding aldol adduct 10a
6
was rendered in full conversion, with moderate syn-diaster-
eoselectivity (65:35 syn/anti) and excellent enantioselectivity
organocatalyst.
It is important to remark that, under rather closed reaction
conditions, replacing additive 8 by the tetrafluoroborate
guanidinium salt 7 in the experiments presented in Table 1
results in the preferential formation of the corresponding
products anti-10, or anti-11, with very high enatiomeric
excesses (see SI, Tables S3 and S4). It is relevant for
cyclopentanone-derived products 11, where the syn isomer is
usually obtained in organocatalyzed aldol reactions. Moreover,
when additives 7 or 8 do not participate in the proline-catalyzed
aldol reaction, under our reaction conditions, adducts 10a−d
and 11a−d are rendered with poor conversion and significantly
low diastereoselectivity (SI, Tables S5 and S6).
(
93% ee, for syn-10a) (Table 1, entry 1). The absolute
stereochemical configuration of product syn-10a was assigned
as (R,R) by comparison of the chiral HPLC trace of thi6s
compound with data previously reported in the literature.
Under the optimized conditions, other representative aldehydes
9
b−d were tested as substrates for this reaction (Table 1,
Table 1. (S)-Proline/Guanidinium Salt 8 Cocatalyzed
Synthesis of syn-Aldols Derived from Cyclohexanone or
a
Cyclopentanone
Taking as example aldol 10c, all four possible stereoisomers
of this compound were accessed by our methodology picking
out the appropriate combination of either (R)- or (S)-proline,
and either guanidinium salt 7 or 8 (Figure 1, and SI). While
proline exerts the enantiocontrol on the reaction, the
guanidinium salt additive controls the diastereoselection of
the process. It has to be emphasized that the chemistry of
different organocatalysts in aldol reactions has been explored to
extenuation, and that both anti- and syn-aldol products have
been separately studied and prepared with much better results
than those of Table 1 by choosing the right catalyst. It is far
from our objective of presenting a synthetic work, a novel
methodology for proline-catalyzed aldol reactions, but
introducing a proof of principle: the judicious choice of an
additive for the most widely known off-the-bench organo-
catalyst, proline, allows us to gain access to either stereoisomer
of an aldol product.
b
c
d
entry
ArCHO
product conversion [%]
d.r.
ee [%]
1
2
3
4
5
6
7
8
9a 4-NO −C H
4
10a
10b
10c
10d
11a
11b
11c
11d
>99 (86)
>99 (87)
>99 (92)
>99 (98)
>99 (86)
>99 (89)
>99 (89)
>99 (88)
65:35
66:34
75:25
65:35
77:23
76:24
89:11
76:24
93
96
98
91
96
95
94
95
2
6
9b 3-NO −C H
2
6
4
9c 2-NO −C H
4
2
6
9d 4-CN−C H
6
4
9a 4-NO −C H
2
6
4
9b 3-NO −C H
4
2
6
9c 2-NO −C H
2
6
4
9d 4-CN−C H
Any mechanistic proposal for the reactions presented in
Table 1 must account for the unusual syn diastereoselectivity
observed for the resulting aldol adducts. To gain further insight
into these processes, we decided to follow the evolution of the
aldol reaction between cyclohexanone and 2-nitrobenzaldehyde
6
4
a
Reaction conditions: ketone (2.0 mmol), ArCHO (0.2 mmol), (S)-
proline (0.02 mmol), 8 (0.03 mmol), no solvent. The reaction mixture
was left to stand for 120 h inside a fridge (0−3 °C) with no stirring.
Determined by H NMR spectroscopy of the crude reaction
mixtures. Isolated yield of analytically pure products 10/11 is given
in brackets. Diastereoisomeric ratio of syn- to anti-10/11 determined
by H NMR spectroscopy of the crude reaction mixtures and identified
by comparison with data previously described in the literature.
Enantiomeric excess of aldol adducts syn-10/11 as determined by
b
1
9c, in the presence of (S)-proline and additive 8, to render
c
product 10c, under our finest reaction conditions (Table 1,
entry 3). Accordingly, a battery of reactions was set up in
parallel containing each 0.2 mmol of aldehyde 9c, and the
indicated quantity of the other reagents. These reactions were
1
d
1
chiral HPLC on analytically pure samples.
strictly quenched, worked up and analyzed by H NMR
1
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Figure 1. Combinations of either (S)- or (R)-proline, and additive 7 or 8, employed for the preparation of all possible stereoisomers of product 10c.
Figure 2. Concentration vs time profile for the formation of aldol adducts syn-10c and anti-10c from cyclohexanone and 2-nitrobenzaldehyde 9c,
and evolution of reaction conversion vs time. Every point is the average result of two individual reactions. All the experiments were carried out under
the following reaction conditions: cyclohexanone (2.0 mmol), aldehyde 9c (0.2 mmol), (S)-proline (0.02 mmol), 8 (0.03 mmol), no solvent. The
reaction mixture was left to stand inside a fridge (0−3 °C) with no stirring. Aldol syn-10c is represented in micromoles (left axis, filled diamonds).
Aldol anti-10c is represented in micromoles (left axis, filled squares). A maximum quantity of 200 micromoles can be reached by either aldol.
Conversion is represented in percentage (right axis, open circles).
1
1
spectroscopy and chiral HPLC after particular times.
gradually converted with time into aldol syn-10c, which after
around 70 h it is already the major product featured in the
reaction media. At ≈120 h the reaction reaches equilibrium, the
population of adducts syn- and anti-10c reflecting the
diastereoselectivity indicated in Table 1, entry 3. Importantly,
the enantiomeric excesses of aldols anti-10c (99% ee, (S,R)
configuration) and syn-10c (98% ee, (R,R) configuration) are
constant for every experiment represented in Figure 2,
independently of reaction conversion values. Intrigued by
these results, we decided to evaluate the relative stability of the
Deconvolution of the appropriate resonances allowed calculat-
ing and plotting the amount of adducts syn-10c and anti-10c
featured in this process against time, as well as the reaction
conversion (Figure 2).
Analyzing Figure 2, it can be concluded that at the start of
the reaction, adduct anti-10c is formed at a faster rate compared
to syn-10c. This observation is to be expected from the
admitted role of (S)-proline acting as organocatalyst in aldol
reactions selective for anti addcuts. Product anti-10c is
1
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Scheme 2. Experiments on Aldol Adduct (S,R)-anti-10c to Gain Insight into the Mechanism of the Proline/Guanidinium Salt 8
a
Catalyzed Synthesis of syn-Aldols
a
All the experiments were set up employing 0.2 mmol of aldol (S,R)-anti-10c as starting material. All the reaction mixtures were left to stand for 10
days inside a fridge (0−3 °C) with no stirring or mechanical agitation.
Figure 3. Mechanistic proposal for the (S)-proline/guanidinium salt 8 cocatalyzed direct aldol reaction between cyclohexanone and aromatic
aldehydes.
reaction products. The geometries of the anti and syn pair of
adducts 10c and 11a−c were fully optimized at the B3LYP/6-
syn) and 98% ee, a similar figure as that represented in Table 1,
entry 3. A comparable reaction outcome was experienced when
preformed aldol anti-10c (d.r. 96:4 anti/syn, 99% ee), was
treated with (S)-proline and additive 8 in the presence of
cyclopentanone under similar reaction conditions (Scheme 2,
reaction b). Aldols incorporating a cyclopentyl moiety were not
observed in this later experiment, thus ruling out an aldol/
retro-aldol process responsible for equilibrating species anti-10c
and syn-10c. Moreover, the experiments c and d from Scheme
2 confirm that neither the autonomous action of proline, nor
the action of additive 8, suffices for switching the stereo-
chemistry of aldol 10c.
3
1G* level of theory. To our wonder, these calculations showed
that the anti adducts are always more stable than their
corresponding syn partners (see SI).
Further experiments were designed and implemented to shed
light on the unanticipated equilibrium process that converts
aldol anti-10c into syn-10c (Scheme 2). A suspension of
preformed pure aldol anti-10c (0.2 mmol, d.r. 96:4 anti/syn,
12
99% ee), (S)-proline (0.02 mmol), tetraphenylborate guanidi-
nium salt 8 (0.03 mmol), in cyclohexanone (2.0 mmol) was
allowed to react for 10 days, at 0−3 °C, with no agitation or
stirring (Scheme 2, reaction a). Aldol (R,R)-syn-10c was
rendered as sole reaction product displaying a d.r. 25:75 (anti/
On the basis of the experimental observations, presented in
Figure 1 and Scheme 2, we adventure the following mechanistic
1
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scheme (Figure 3). On the one hand, as proposed by other
CONCLUSIONS
■
authors, the formation of anti-aldols could be explained
To conclude, we have succeeded in using proline as a single
chiral catalyst to control the stereochemical outcome of the
asymmetric direct aldol reaction between cyclohexanone, or
cyclopentanone, and aromatic aldehydes. The choice of the
anion of an achiral TBD-derived guanidinium salt, used as
cocatalyst for proline, allows preparation of either anti- or syn-
aldol adducts with very high enantioselectivity. The origin of
the syn diastereoselectivity unfolds from an unusual equilibrium
process coupled to the enamine-based catalytic cycle standard
for proline. This paper shows, as a proof of principle, how the
right choice of an additive for proline allows a diastereoswitch
in the aldol reaction. We are currently exploring different
additives and reactions that allow proline, or other natural
amino acids, for reversible diastereoswithcing.
13
considering a Zimmerman−Traxler-type transition state.
Therefore, we speculate that the establishment of a 1:1
complex between the guanidinium cation of additive 8 and
the corresponding enamine, formed from the cyclic ketone and
(
S)-proline, would stabilize the chairlike transition state TS-I
7
that leads to anti products. As we have previously studied, anti
aldols formed in this way present a very high diastereose-
lectivity and enantiomerical purity. On the other hand, syn
aldols would be slowly formed, in minimal quantity, through a
high-energy “misguided” transition state. While the anti aldols
seems to be more stable in the gas phase, according to the
calculations (SI, Figures S1, S2), the syn isomers possess lower
free energy under our reaction conditions. The data provided in
Figure 2 and Scheme 2 (experiment a) give a strong support for
this interpretation. As the possibility of a direct aldol/retro-
aldol sequence can be discarded (Scheme 2, reaction b), the
channel that connects both diastereoisomers most probably
consists of a common proline−enamine intermediate, followed
by hydrolysis. If this is the case, the high enantiopurity of the
isolated products 10 and 11 reflects the stereochemical integrity
of the C3 (C−OH) stereocenter. Anyhow, to give a clarification
for the equilibrium process, it remains to be established why syn
diastereoisomers could be more stable products under the
reaction conditions applied. The B3LYP76-31G* optimized
geometries of adducts (SI, Figures S1 and S2) show how the
anti compounds, particularly anti-10c, are stabilized by strong
intramolecular hydrogen bonds accounting for 6.3−12.5 kJ/
mol. Under the specified reaction conditions the rather weak
intramolecular interactions calculated for the syn compounds
are replaced with stronger intermolecular hydrogen bonds.
Keeping in mind the key effect played by the counteranions of
our additives, it can be reasoned that replacing the tightly
bound tetrafluoroborate anion with the large tetraphenylborate
allows the bicyclic guanidinium core of salt 8 to participate in
the hydrogen bonded networks with the syn-aldols. Also, it can
be added that although all of the reactions in which additive 8
participates are homogeneous to the naked eye, we can not rule
out the appearance of crystalline aggregates that would take syn
adducts away from the reaction media, hence favoring their
EXPERIMENTAL SECTION
■
General Remarks. All commercially available reagents and
solvents were used without further purification unless otherwise
stated. Flash chromatography of reaction products was carried out
using Silica 60A, particle size 230−400 μm. Analytical thin layer
chromatography (TLC) was performed on DC-Alufolien Kieselgel
6
0F254 0.2 mm plates, and compounds were visualized by UV
1
fluorescence or 5% phosphomolybdic acid in methanol. H NMR and
13
C NMR spectra were recorded on a 300 MHz spectrometer, using
deuterated solvents, and were referenced internally to the residual
solvent peak (δH = 7.26 ppm, δC = 77.36 ppm) signal. Coupling
constants (J-values) are given in hertzs (Hz). The DEPT 135
technique was used to assign methylene (CH ) signals. Chemical shifts
2
are reported as follows: value (number of protons, description of
absortion, coupling constant(s) where applicable). NMR spectra
assignation was aided by comparison with literature values for similar
compounds. Chiral HPLC analyses were performed according to the
conditions specified in the Supporting Information.
Standard Procedure for the Synthesis of anti-Aldols 10a−d
7
or 11a−d (SP1). Tetrafluoroborate guanidinium salt 7 (4.5 mg, 0.02
mmol), (S)-proline (3.5 mg, 0.03 mmol) and solid aldehyde 9a−d (0.2
mmol) were weighed together inside a screw-capped test tube. Either
cyclohexanone (196 mg, 0.21 mL, 2.0 mmol) or cyclopentanone (168
mg, 0.18 mL, 2.0 mmol) was added to the mixture, and the resulting
suspension, placed on a test tubes grid, was allowed to stay for 120 h
inside a standard fridge (temperature fixed at 0−3 °C) without
agitation of mechanical stirring. The mixture was then quenched with
NH Cl (aq. sat.) and extracted with DCM (2 × 15 mL), and the
4
organic liquors were dried (MgSO ). Solvents and excess of ketone
4
were eliminated under reduced pressure. Crude reaction mixtures were
filtered through a plug of silica gel to afford pure aldols anti-10a−d
(cyclohexanone) or anti-11a−d (cyclopentanone).
1
4
formation. While the mechanism illustrated in Figure 3 is only
a suggestion, it gives a full account for the experimental
observations presented in Figure 2 and Scheme 2.
Standard Procedure for the Synthesis of syn-Aldols 10a−d
17
or 11a−d (SP2). Tetraphenylborate guanidinium salt 8 (13.8 mg,
It is fair noting that the syn diastereoselectivity observed for
aldols 10, or 11, originated from an equilibrium as that showed
in Figure 2, could not be predicted taking into account the
nature of the catalysts used and the substrates involved. It is
however the consideration of the whole complex network
resulting from the simultaneous coexistence of anti-aldols, syn-
aldols, (S)-proline, guanidinium and guanidine species,
aromatic aldehyde, cyclic ketone, enamines, all featured in the
reaction media to some extent, their interactions (including
0
.03 mmol), (S)-proline (2.3 mg, 0.02 mmol) and solid aldehyde 9a−
d (0.2 mmol) were weighed together inside a screw-capped test tube.
The mixture of solids was finely grinded and homogenized before
either cyclohexanone (196 mg, 0.21 mL, 2.0 mmol) or cyclopentanone
(168 mg, 0.18 mL, 2.0 mmol) was added, and the resulting suspension,
placed on a test tubes grid, was allowed to stay for 120 h inside a
standard fridge (temperature fixed at 0−3 °C) without agitation of
mechanical stirring. The mixture was then quenched with NH Cl (aq.
4
sat.) and extracted with DCM (2 × 15 mL), and the organic liquors
were dried (MgSO ). Solvents and excess of ketone were eliminated
4
15
supramolecular interactions ) and competition, their different
solubility, solvation, etc., that makes it possible to figure out a
processes of the like. We believe that this kind of approach, a
under reduced pressure. Crude reaction mixtures were purified by flash
chromatography, when required, to afford pure aldols syn-10a−d
(
cyclohexanone) or syn-11a−d (cyclopentanone).
16
(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
systems chemistry strategy, the study of the properties
emerged from collections/systems of compounds (i.e., catalytic
systems), can be of great benefit for areas such as organo-
catalysis.
7
(
anti-10a). Prepared according to SP1. Obtained as a yellow solid, 46
1
mg, 92% isolated yield: H NMR (300 MHz, CDCl ) δ = 8.21−8.18
(
3
2H, m), 7.52−7.47 (2H, m), 4.89 (1H, dd, J = 8.4, 3.1 Hz), 4.07 (1H,
d, J = 3.1 Hz), 2.63−2.30 (3H, m), 2.15−2.07 (1H, m), 1.85−1.52
1
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1
3
(
(
5
4H, m), 1.45−1.30 (1H, m); C NMR (75 MHz, CDCl ) δ = 215.0
40 mg, 86% isolated yield. Purified by flash chromatography (Hex/
3
1
CO), 148.7, 147.9, 128.2 (2 x ArCH), 123.9 (2 x ArCH), 74.3,
EtOAc, 3:1): H NMR (CDCl , 300 MHz) δ = 8.22−8.18 (2H, m),
3
7.5, 43.0, 31.1, 28.0, 25.0.
7.54−7.50 (2H, m), 5.42 (1H, d, J = 2.9 Hz), 2.66 (1H, s), 2.51−1.65
(
R)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
(7H, m); 13C NMR (CDCl , 75 MHz) δ = 219.8 (CO), 150.4,
3
6,18
(syn-10a).
Prepared according to SP2. Obtained as a yellow solid,
147.5, 126.7 (2 x ArCH), 124.0 (2 x ArCH), 70.8, 56.4, 39.3, 22.8,
20.7.
4
2 mg, 86% isolated yield. Purified by flash chromatography (Hex/
1
EtOAc, 3:1): H NMR (300 MHz, CDCl ) δ = 8.21−8.18 (2H, m),
(S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclopentan-1-one
3
1
8
7
(
1
1
2
.52−7.47 (2H, m), 5.48 (1H, s), 3.20 (1H, d, J = 3.1 Hz), 2.66−2.59
(anti-11b). Prepared according to SP1. Obtained as a yellow solid,
36 mg, 77% isolated yield. Purified by flash chromatography (Hex/
1H, m), 2.52−2.33 (2H, m), 2.16−2.06 (1H, m), 1.89−1.80 (1H, m),
13
1
.76−1.48 (4H, m); C NMR (75 MHz, CDCl ) δ = 214.4 (CO),
CH Cl , 1:10): H NMR (CDCl , 300 MHz) δ = 8.25−8.15 (2H, m),
3
2
2
3
49.4, 147.4, 126.2 (2 x ArCH), 123.8 (2 x ArCH), 70.4, 57.1, 43.0,
7.72−7.66 (1H, m), 7.56−7.51 (1H, m), 4.83 (1H, d, J = 9.3 Hz),
13
8.2, 26.2, 25.1.
2.54−2.17 (3H, m), 2.08−1.98 (1H, m), 1.78−1.50 (3H, m);
NMR (CDCl
C
(
S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one
anti-10b). Prepared according to SP1. Obtained as a yellow solid,
3
, 75 MHz) δ = 222.7 (CO), 148.7, 144.0, 133.0,
1
8
(
4
8
=
1
129.8, 123.7, 122.0, 74.8, 55.4, 39.0, 27.3, 20.7.
1
9 mg, 98% isolated yield: H NMR (300 MHz, CDCl ) δ = 8.20−
(R)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclopentan-1-one
3
1
8
.11 (2H, m), 7.67−7.64 (1H, m), 7.53−7.48 (1H, m), 4.88 (1H, d, J
(syn-11b). Prepared according to SP2. Obtained as a yellow solid,
8.4 Hz), 4.13 (1H, s), 2.66−2.29 (3H, m), 2.14−2.06 (1H, m),
42 mg, 89% yield. Purified by flash chromatography (Hex/EtOAc,
13
1
.85−1.53 (4H, m), 1.44−1.31 (1H, m); C NMR (75 MHz, CDCl )
3:1): H NMR (CDCl
3
, 300 MHz) δ = 8.22−8.10 (2H, m), 7.70−7.66
3
δ = 215.1 (CO), 148.5, 143.6, 133.5, 129.6, 123.1, 122.3, 74.3, 57.4,
2.9, 31.0, 27.9, 24.9.
R)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one
(1H, m), 7.54−7.49 (1H, m), 5.41 (1H, d, J = 2.2 Hz), 2.52−1.93
13
4
(5H, m), 1.79−1.65 (2H, m); C NMR (CDCl , 75 MHz) δ = 220.0
3
(
(CO), 148.6, 145.3, 132.0, 129.7, 122.6, 120.9, 70.6, 56.4, 39.3, 22.7,
6,18
(syn-10b).
Prepared according to SP2. Obtained as a yellow solid,
20.7.
4
3 mg, 87% isolated yield. Purified by flash chromatography (Hexane/
(S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclopentan-1-one
1
19
EtOAc, 3:1): H NMR (300 MHz, CDCl ) δ = 8.18−8.10 (2H, m),
(anti-11c). Prepared according to SP1. Obtained as a yellow solid,
3
7
2
1
1
.67−7.65 (1H, m), 7.54−7.49 (1H, m), 5.48 (1H, s), 3.20 (1H, s),
38 mg, 80% isolated yield. Purified by flash chromatography (Hex/
1
.68−2.62 (1H, m), 2.51−2.34 (2H, m), 2.16−2.04 (1H, m), 1.88−
CH
Cl
2
2
, 1:10): H NMR (CDCl
3
, 300 MHz) δ = 7.84−7.78 (2H, m),
.49 (5H, m); 13C NMR (75 MHz, CDCl ) δ = 214.5 (CO), 148.6,
7.67−7.62 (1H, m), 7.46−7.41 (1H, m), 5.44 (1H, d, J = 8.6 Hz), 4.47
3
44.1, 132.3, 129.5, 122.4, 121.9, 70.2, 57.0, 42.9, 28.2, 26.2, 25.1.
(1H, s), 2.57−2.23 (3H, m), 2.10−1.97 (1H, m), 1.80−1.65 (3H, m);
13
(
S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one
C NMR (CDCl
3
, 75 MHz) δ = 222.4 (CO), 148.8, 136.6, 133.5,
1
8
(anti-10c). Prepared according to SP1. Obtained as a yellow solid,
129.3, 128.9, 124.4, 69.4, 55.8, 39.0, 26.9, 20.8.
1
4
7
=
9 mg, 98% isolated yield: H NMR (300 MHz, CDCl ) δ = 7.84−
(R)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclopentan-1-one
3
1
9
.74 (2H, m), 7.65−7.59 (1H, m), 7.44−7.39 (1H, m), 5.43 (1H, d, J
(syn-11c). Prepared according to SP2. Obtained as a yellow solid,
7.1 Hz), 3.84 (1H, s), 2.79−2.71 (1H, m), 2.47−2.27 (2H, m),
42 mg, 89% isolated yield. Purified by flash chromatography (Hex/
13
1
2
.12−2.04 (1H, m), 1.89−1.54 (5H, m); C NMR (75 MHz, CDCl )
EtOAc, 3:1): H NMR (CDCl , 300 MHz) δ = 7.96 (1H, dd, J = 8.2,
3
3
δ = 215.2 (CO), 149.0, 136.9, 133.4, 129.3, 128.7, 124.4, 70.0, 57.6,
3.1, 31.4, 28.1, 25.3.
R)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one
1.2 Hz), 7.88 (1H, dd, J = 7.9, 1.2 Hz), 7.67−7.62 (1H, m), 7.45−7.39
1
3
4
(1H, m), 5.89 (1H, d, J = 2.9 Hz), 2.74−1.65 (7H, m); C NMR
(
(CDCl , 75 MHz) δ = 219.2 (CO), 147.2, 138.9, 133.7, 128.9,
3
6
,18
(syn-10c).
Prepared according to SP2. Obtained as a yellow solid,
128.3, 124.8, 66.9, 55.1, 38.9, 23.2, 20.5.
4
5 mg, 92% isolated yield. Purified by flash chromatography (Hex/
(S)-2-((R)-Hydroxy(4-cyanophenyl)methyl)cyclopentan-1-
1
18
EtOAc, 3:1): H NMR (300 MHz, CDCl ) δ = 8.01−7.98 (1H, m),
one (anti-11d). Prepared according to SP1. Obtained as a white
3
7
.84−7.81 (1H, m), 7.67−7.61 (1H, m), 7.45−7.39 (1H, m), 5.95
solid, 32 mg, 35% isolated yield. Purified by flash chromatography
1
(
1H, s), 3.29 (1H, d, J = 3.2 Hz), 2.91−2.84 (1H, m), 2.47−2.35 (2H,
(Hex/CH Cl , 1:10): H NMR (300 MHz, CDCl ) δ = 7.65 (2H, d, J
2
2
3
13
m), 2.14−2.04 (1H, m), 1.89−1.49 (5H, m); C NMR (75 MHz,
CDCl ) δ = 214.4 (CO), 147.4, 137.3, 133.5, 129.9, 128.2, 125.0,
= 8.3 Hz), 7.47 (2H, d, J = 8.2 Hz), 4.78 (1H, d, J = 9.2 Hz), 2.51−
13
2.18 (3H, m), 2.06−1.96 (1H, m), 1.81−1.51 (3H, m); C NMR (75
MHz, CDCl
3
6
7.0, 55.1, 42.9, 28.3, 26.8, 25.1.
3
) δ = 222.6 (CO), 147.0, 132.7 (2 x ArCH), 127.6 (2 x
(
S)-2-((R)-Hydroxy(4-cyanophenyl)methyl)cyclohexan-1-one
ArCH), 119.0, 112.2, 75.0, 55.4, 39.0, 27.2, 20.7.
1
8
(anti-10d). Prepared according to SP1. Obtained as a white solid,
(R)-2-((R)-Hydroxy(4-cyanophenyl)methyl)cyclopentan-1-
1
18
4
7
5 mg, 98% isolated yield: H NMR (300 MHz, CDCl ) δ = 7.64−
one (syn-11d). Prepared according to SP2. Obtained as a white
3
.61 (2H, m), 7.44−7.41 (2H, m), 4.82 (1H, d, J = 8.4 Hz), 4.06 (1H,
solid, 38 mg, 88% isolated yield. Purified by flash chromatography
1
s), 2.60−2.29 (3H, m), 2.13−2.05 (1H, m), 1.86−1.51 (4H, m), 1.40−
(Hex/EtOAc, 3:1): H NMR (300 MHz, CDCl
3
) δ = 7.64−7.61 (2H,
1
1
.23 (1H, m); 13C NMR (75 MHz, CDCl ) δ = 215.1 (CO), 146.7,
m), 7.47−7.41 (2H, m), 5.35 (1H, d, J = 2.7 Hz), 2.73 (1H, s), 2.48−
3
13
32.4, 128.1, 119.0, 111.9, 74.5, 57.4, 42.9, 31.0, 27.9, 25.0.
1.88 (5H, m), 1.77−1.65 (2H, m); C NMR (75 MHz, CDCl ) δ =
3
(
R)-2-((R)-Hydroxy(4-cyanophenyl)methyl)cyclohexan-1-one
219.9 (CO), 148.5, 132.5 (2 x ArCH), 126.6 (2 x ArCH), 119.1,
6
,18
(syn-10d).
Prepared according to SP2. Obtained as a white solid,
111.4, 70.9, 56.3, 39.2, 22.7, 20.7.
4
5 mg, 98% isolated yield. Purified by flash chromatography (Hexane/
1
EtOAc, 3:1): H NMR (300 MHz, CDCl ) δ = 7.64−7.61 (2H, m),
3
ASSOCIATED CONTENT
■
7
2
1
1
2
.43−7.40 (2H, m), 5.42 (1H, s), 3.17 (1H, s), 2.63−2.53 (1H, m),
*
S
Supporting Information
.51−2.32 (2H, m), 2.16−2.03 (1H, m), 1.88−1.80 (1H, m), 1.74−
.48 (4H, m); 13C NMR (75 MHz, CDCl ) δ = 214.5 (CO), 147.3,
Supporting tables and figures. Copies of H and 13C NMR
spectra and HPLC plots for compounds 10a−d and 11a−d.
Conformational study of compounds 10c and 11a−c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
3
32.3 (2 x ArCH), 126.8 (2 x ArCH), 119.2, 111.1, 70.5, 57.1, 42.9,
8.2, 26.2, 25.1.
(
S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one
18
(
3
anti-11a). Prepared according to SP1. Obtained as a yellow solid,
9 mg, 84% isolated yield. Purified by flash chromatography (Hex/
CH Cl , 1:10): H NMR (CDCl , 300 MHz) δ = 8.21 (2H, d, J = 8.8
Hz), 7.54 (2H, d, J = 8.7 Hz), 4.84 (1H, d, J = 9.1 Hz), 4.75 (1H, s),
1
2
2
3
AUTHOR INFORMATION
■
13
2
.52−2.17 (3H, m), 2.07−1.97 (1H, m), 1.79−1.51 (3H, m);
C
Corresponding Author
E-mail: ccf@uniovi.es; vdelamo@uniovi.es.
NMR (CDCl , 75 MHz) δ = 222.5 (CO), 149.0, 148.0, 127.7 (2 x
3
*
ArCH), 124.1 (2 x ArCH), 74.8, 55.4, 39.0, 27.2, 20.7.
Notes
(
R)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one
18
(
syn-11a). Prepared according to SP2. Obtained as a yellow solid,
The authors declare no competing financial interest.
1
0380
dx.doi.org/10.1021/jo3020352 | J. Org. Chem. 2012, 77, 10375−10381

The Journal of Organic Chemistry
Article
Kellogg, R. M. Angew. Chem., Int. Ed. 2007, 46, 494−497 and
ACKNOWLEDGMENTS
■
references therein.
́
The authors thank Ministerio de Economia y Competitividad
(15) (a) Gasparini, G.; Martin, M.; Prins, L. J.; Scrimin, P. Chem.
(
CTQ2010-14959) for financial support. C.C. and V.d.A. thank
MICINN for a Juan de la Cierva contract and a Ramon y Cajal
contract, respectively. Dr. Francisco J. Gonzalez (Universidad
de Oviedo) is gratefully acknowledged for performing
calculations on structures 10 and 11, and for his valuable
advice during the preparation of the manuscript.
Commun. 2007, 1340−1342. (b) Orrillo, A. G.; Furlan, R. L. E. J. Org.
́
Chem. 2010, 75, 211−214.
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(
(
̃
́
(
(
1
0381
dx.doi.org/10.1021/jo3020352 | J. Org. Chem. 2012, 77, 10375−10381