Highly stereoselective synthesis of trisubstituted cyclohexanols using a guanidine-catalyzed tandem Henry-Michael reaction

Article abstract of DOI:10.1021/jo4001806

A highly diastereoselective (dr >99:1) and enantioselective (ee value up to 98%) synthesis of trisubstituted cyclohexanols was achieved by using a tandem Henry - Michael reaction between nitromethane and 7-oxo-hept-5-enals catalyzed by the Misaki-Sugimura guanidine.

Full text of DOI:10.1021/jo4001806

Note
pubs.acs.org/joc
Highly Stereoselective Synthesis of Trisubstituted Cyclohexanols
Using a Guanidine-Catalyzed Tandem Henry−Michael Reaction
Qipu Dai,† Huicai Huang, and John Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, United States
S
* Supporting Information
ABSTRACT: A highly diastereoselective (dr >99:1) and
enantioselective (ee value up to 98%) synthesis of trisub-
stituted cyclohexanols was achieved by using a tandem
Henry−-Michael reaction between nitromethane and 7-oxo-
hept-5-enals catalyzed by the Misaki−Sugimura guanidine.
n recent years, organocatalyzed tandem reactions have
Using (E)-7-oxo-7-phenylhept-5-enal (1a) as the substrate,
Iwidely been used for constructing complex structures from we first screened several reported guanidine derivatives as the
relatively simple starting materials.1 Besides their green nature,
catalyst (Scheme 2). The results are summarized in Table 1. As
the data in Table 1 show, when the pseudo-C2-symmetric
guanidine catalyst 310 was used in CH2Cl2 at rt, the desired
tandem Henry−Michael product 2a was obtained as a single
diastereomer in 98% yield and 60% ee (entry 1). This
compound has identical relative and absolute stereochemistry
as that obtained in the sequential catalysis5 according to its
NMR and optical rotation data. Similarly, Feng’s guanidine
catalyst 411 gave 2a in 48% ee (entry 2). On the other hand,
guanidine catalyst 512 led to the formation of the opposite
enantiomer of 2a in 95% yield and 59% ee (entry 3). When
Misaki−Sugimura guanidine catalysts 6 and 7 were applied,9
slightly improved ee values were obtained for the product 2a
(65% and 73% ee, respectively, entries 4 and 5). It should be
pointed out that only a single diastereomer was obtained with
all the above catalysts. Together with t-BuOK, the Ooi’s
phopshonium salt 8 has been reported to be a very good
catalyst for the Henry reaction.13 Thus, we also screened this
combination in our reaction. However, with this catalyst
combination in THF at −78 °C, no desired tandem Henry−
Michael product was observed. Instead, the S-enantiomer of the
Henry product 9a5 was obtained in 97% yield and 55% ee
(entry 6, eq 1). The desired tandem reaction product was not
generally these reactions are also very easy to perform. More
importantly, organocatalyzed tandem reactions can tolerate
many functional groups so that the use of protecting groups is
largely unnecessary.1 Since cychohexane is a very common
structural motif in many natural products,2 there has been a lot
of interest in developing novel organocatalyzed tandem
reactions for the stereoselective synthesis of cyclohexane
derivatives recently.1,3 Among the reported methods,1,3 Michael
addition, Henry reaction, and/or aldol reaction are often used
in a tandem fashion for obtaining the desired cyclohexane
derivatives. Our own interest in organocatalyzed tandem
reactions4 led to our recent realization5 of a highly diastereo-
and enantioselective synthesis of trisubstituted cyclohexanols 2
using a tandem Henry−Michael reaction between (E)-7-oxo-
hept-5-enals (1) and nitromethane. As shown in Scheme 1,
using a quinidine thiourea-catalyzed tandem Henry−Michael
reaction of (E)-7-oxo-hept-5-enals (1) and nitromethane, a
mixture of three cyclohexanol diastereomers was first obtained
with high ee values, and the disatereomers were then converted
in situ to a single diastereomer in high ee values using a 1,1,3,3-
tetramethylguanidine (TMG)-catalyzed tandem retro-Henry−
Henry reaction.5 Although eventually high product stereo-
selectivities were achieved using this one-pot sequential
catalysis,6 two catalysts had to be used in the reaction.
Moreover, since an incomplete conversion of compound 1 in
the first step would lower the final product ee value, a longer
reaction time was needed for the first step in order to ensure a
full conversion of this substrate. Nonetheless, during the study
we also noticed that a single diastereomer of the racemic
products may be obtained by using TMG alone as the catalyst
(Scheme 1).5 Based on this observation, we envisioned that an
appropriate optically active guanidine derivative7,8 should be a
good catalyst for this reaction. In this paper, we report our
finding on a highly stereoselective synthesis of trisubstituted
cyclohexanols using the Misaki−Sugimura guanidine catalyst.9
obtained probably because this catalytic system was not basic
enough. Since Misaki−Sugimura catalyst 7 generated the
highest enantioselectivity among these screened catalysts, it
was chosen for further optimizations. First the solvent effects
on the reaction were evaluated. It was found that in CHCl3, the
Received: January 30, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4001806 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Organocatalyzed synthesis of Trisubstituted Cyclohexanols Using a Tandem Henry−Michael Reaction
Scheme 2. Catalysts Screened in the Tandem Henry−
Michael Reaction of 1a and Nitromethane
Table 1. Catalyst Screening and Reaction Condition
Optimization
a
b
d
T
(°C)
time yield
ee
c
entry catalyst
solvent
CH2Cl2
(h)
(%)
dr
(%)
1
3
4
5
6
7
8
7
7
7
7
7
7
7
7
7
7
rt
rt
4
4
98
98
95
99
99
>99:1
>99:1
>99:1
>99:1
>99:1
60
48
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
e
3
rt
4
59
4
rt
4
65
73
5
rt
4
f
g
6
−78
rt
24
4
0
7
CHCl3
ClCH2CH2Cl
CCl4
99
99
97
99
95
99
99
99
99
99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
84
70
65
66
38
67
91
98
95
89
8
rt
4
9
rt
4
10
11
12
13
14
15
16
THF
rt
4
product ee value was slightly improved to 84% (entry 7), while
the other halogenated and nonhalogenated solvents screened
all led to inferior results (entries 8−12). Gratifyingly, when the
reaction was conducted at 0 °C, the enantioselectivity of this
reaction was improved to 91% ee (entry 13), although the
reaction became a little slower at this temperature. Further
dropping the reaction temperature to −15 °C, an even higher
ee value of 98% was obtained for compound 2a (entry 14). No
further improvement in the asymmetric induction was observed
when the reaction temperature was lowered further (data not
shown). On the other hand, reducing the loading of the catalyst
was found to cause some minor loss of the product ee values
(entries 15 and 16).
Once the reaction conditions were optimized, the scope of
this reaction was established. The results are presented in Table
2. It was found that the electronic nature of the substituent on
the phenyl ring of (E)-7- aryl-7-oxohept-5-enals (1a−k) has
almost no influence on either the diastereoselectivity or the
enantioselectivity of this reaction (entries 1−8). The
corresponding tandem Henry−Michael products 2 were
consistently obtained as a single diastereomer in high ee
values. Similarly, the position of these substituents on the
phenyl ring is of almost no influence on the stereoselectivities
of this reaction (entries 3, 9, and 10; 4 and 11). In contrast,
when 7-methyl- and 7-cyclopropyl-substituted enals (1l and
1m) were used as the substrates, the products were obtained in
much lower enantioselectivities, although the high diastereose-
lectivity of this reaction was retained (entries 12 and 13).
Nevertheless, a high ee value of 90% was achieved when a tert-
butyl-substituted enal 1n was applied. These results indicate
that the enantioselectivity of the 7-alkyl-substituted substrates is
Et2O
rt
4
toluene
CHCl3
CHCl3
CHCl3
CHCl3
rt
4
0
12
12
12
12
−15
−15
−15
h
i
a
Unless otherwise noted, all reactions were carried out with 1a (0.10
mmol), nitromethane (0.20 mmol), and the catalyst (0.010 mmol, 10
mol %) in the indicated solvent (0.2 mL). Yield of isolated product
after column chromatography. Determined by H NMR analysis of
the crude product. Determined by HPLC analysis on ChiralPak AD-
H column. The absolute configuration of the product was determined
by comparison of the measured optical rotation with the reported data
(ref 5). The opposite enantiomer was obtained. t-BuOK (10 mol %)
was used together with 8 in this reaction as the catalyst. The R-
b
c
1
d
e
f
g
enantiomer of the Henry reaction product was obtained (see text).
h
i
The loading of the catalyst was 5 mmol %. The loading of the
catalyst was 2 mmol %.
mainly depending on the size of the substituent at the C7
position. This is in drastic contrast to the results obtained with
the quinidine thiourea-TMG sequential catalysis (Scheme 1), in
which the enantioselectivity was not sensitive to steric factors
for these substrates.5 Overall, except for substrates 1l and 1m,
the enantioselectivities obtained with this new catalytic system
is either better than or at least comparable to those of the
sequential catalysis.5
We believe the current reaction also follows our previously
reported tandem Henry−Michael mechanism.5 In order to
elucidate the reaction mechanism some control experiments
were carried out. According to the reported mechanism, the
B
dx.doi.org/10.1021/jo4001806 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
In summary, we have developed a new protocol for the
highly stereoselective synthesis of trisubstituted cyclohexanols
using a guanidine-catalyzed tandem Henry−Michael reaction
between 7-oxo-hept-5-enals and nitromethane. Misaki−Sugi-
mura guanidine catalyst 7 has been demonstrated to be the best
catalyst for this reaction and, after optimizations of the reaction
conditions, the desired trisubstituted cyclohexanols may be
obtained in both high enantioselectivities (up to 98% ee) and
diastereoselectivities (>99:1 dr).
Table 2. Scope of the Guanidine-Catalyzed Tandem Henry−
a
Michael Reaction
b
c
d
entry
R
1/2
yield (%)
dr
ee (%)
1
Ph
a
b
c
d
e
f
99
98
95
99
98
99
98
99
99
98
99
98
95
98
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98
96
96
97
98
92
97
98
96
96
96
60
76
90
2
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
Me
3
EXPERIMENTAL SECTION
■
4
General Information. 1H and 13C NMR spectra were recorded on
a 300 MHz spectrometer (75 MHz for 13C). Multiplicities are
indicated as s (singlet), d (doublet), t (triplet), q (quintet), and m
(multiplet), and coupling constants (J) are reported in hertz. Splitting
patterns that could not be easily interpreted are designated as multiplet
(m). TLC was performed with silica gel GF254 precoated on plastic
plates, and spots were visualized with UV. HPLC analysis was
performed on an HPLC instrument equipped with a UV−vis detector.
Dry solvents were freshly distilled under argon from an appropriate
drying agent before use. Catalysts were synthesized by following the
published procedures.9−13 (E)-7-Alkyl-7-oxohept-5-enals (1a−n) were
prepared according to literature procedures,14 which are known
compounds except for compounds 1e, 1i, 1m, and 1n.
5
6
7
g
h
i
8
9
10
11
j
k
l
e
12
13
14
c-C3H5
m
n
t-Bu
a
Unless otherwise noted, all reactions were carried out with 1a (0.10
mmol), nitromethane (0.20 mmol), and catalyst 7 (0.010 mmol, 10
(E)-7-(4-Cyanophenyl)-7-oxohept-5-enal (1e): colorless oil, 1.27 g,
b
1
mol %) in CHCl3 (0.2 mL) at −15 °C for 12 h. Yield of isolated
56% yield; H NMR (500 MHz, CDCl3) δ 9.79 − 9.75 (m, 1H),
c
product after column chromatography. Determined by 1H NMR
8.00−7.93 (m, 2H), 7.77−7.72 (m, 2H), 7.04 (dt, J = 15.4, 6.9 Hz,
1H), 6.88−6.80 (m, 1H), 2.52 (td, J = 7.1, 1.2 Hz, 2H), 2.40−2.33 (m,
2H), 1.90−1.82 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 201.4,
189.1, 150.1, 140.9, 132.4, 128.8, 125.8, 117.9, 115.8, 42.9, 31.9, 20.2;
IR νmax (neat, cm−1) 3054, 2863, 1724, 1673, 1622, 1264. Anal. Calcd
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.96; H, 5.64;
N, 6.19.
d
e
analysis of the crude product. Determined by HPLC analysis. The
reaction time was 24 h.
enantioselectivity of this reaction is generated in the intra-
molecular Michael addition step.5 Moreover, under base
catalysis, all of the diastereomers formed in the Michael
reaction step can be converted to the thermodynamically more
stable product 2.5 On the basis of this assumption, even if a
racemic Henry product is used as the starting material,
compound 2 should be obtained in similar diastereo- and
enantioselectivities.5 Indeed, when the reaction was carried out
with rac-9a using catalyst 7 under the optimized conditions, 2a
was obtained as a single diastereomer in 94% yield and 97% ee
(eq 2). In contrast, similar reaction conducted with the racemic
(E)-7-(2-Chlorophenyl)-7-oxohept-5-enal (1i): colorless oil, 1.65 g,
1
70% yield; H NMR (300 MHz, CDCl3) δ 9.76 (t, J = 1.3 Hz, 1H),
7.36 (dddd, J = 8.2, 7.6, 3.3, 1.4 Hz, 4H), 6.66 (dt, J = 15.8, 6.7 Hz,
1H), 6.47 (dt, J = 15.8, 1.3 Hz, 1H), 2.51 (td, J = 7.2, 1.2 Hz, 2H),
2.33 (td, J = 8.0, 1.3 Hz, 2H), 1.84 (dd, J = 14.7, 7.4 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 201.2, 193.8, 150.4, 138.6, 131.1, 130.9,
130.8, 130.0, 128.9, 126.6, 43.0, 31.8, 20.2; IR νmax (neat, cm−1) 2254,
1724, 1657, 1296. Anal. Calcd for C13H13ClO2: C, 65.97; H, 5.54.
Found: C, 65.90; H, 5.67.
(E)-7-Cyclopropyl-7-oxohept-5-enal (1m): colorless oil, 1.25 g,
1
75% yield; H NMR (300 MHz, CDCl3) δ 9.69 (t, J = 1.4 Hz, 1H),
6.77 (dt, J = 15.7, 6.9 Hz, 1H), 6.16 (dt, J = 15.8, 1.5 Hz, 1H), 2.44
(td, J = 7.2, 1.4 Hz, 2H), 2.28−2.16 (m, 2H), 2.06 (tt, J = 7.8, 4.6 Hz,
1H), 1.76 (dq, J = 14.6, 7.4 Hz, 2H), 1.04−0.95 (m, 2H), 0.88−0.80
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 201.3, 199.6, 144.8, 130.7,
42.8, 31.4, 20.3, 18.7, 11.0; IR νmax (neat, cm−1) 2830, 2253, 1723,
1680, 1659, 1625, 1443, 1391, 1207, 1090. Anal. Calcd for C10H14O2:
C, 72.26; H, 8.49. Found: C, 72.38; H, 8.54.
(E)-8,8-Dimethyl-7-oxonon-5-enal (1n): colorless oil, 1.31 g, 72%
1
yield; H NMR (300 MHz, CDCl3) δ 9.67 (d, J = 1.2 Hz, 1H), 6.78
(dt, J = 14.1, 6.9 Hz, 1H), 6.43 (dd, J = 15.2, 1.1 Hz, 1H), 2.41 (t, J =
7.2 Hz, 2H), 2.18 (q, J = 7.3 Hz, 2H), 1.73 (p, J = 7.4 Hz, 2H), 1.06
(d, J = 1.0 Hz, 9H); 13C NMR (75 MHz, CDCl3) δ 203.6, 201.3,
145.4, 124.6, 42.9, 42.7, 31.4, 26.0, 20.4; IR νmax (neat, cm−1) 2967,
2871, 2722, 1723, 1687, 1623, 1461, 1365, 1241, 1108, 1046. Anal.
Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.36; H, 9.97.
Representative Procedure for the Enantioselective Organo-
catalytic Tandem Reaction. A solution of catalyst 7 (6.1 mg, 0.010
mmol, 10 mol %) and (E)-7-oxo-7-phenylhept-5-enal (1a) (20.2 mg,
0.10 mmol) in CHCl3 (0.2 mL) was stirred at −15 °C for 10 min. To
the above mixture was added nitromethane (12.2 mg, 0.20 mmol) in
one portion. The reaction mixture was further stirred at this
temperature for 12 h (monitored by TLC). After the reaction was
completed, the volatile components were removed under reduced
pressure and the residue was purified by column chromatography on
Michael addition product (rac-10a) as the starting material led
to the formation of a mixture of all four possible diastereomers
2a, 11a,5 12a,5 and 13a in a ratio of 3:17:40:40. After column,
most of these diastereomers were also converted to the more
stable diastereomer 2a, which was isolated in 94% yield as a
racemic compound with a dr of 85:15 (eq 3). These results
clearly indicate our two-component reaction follows a tandem
Henry-Michael mechanism instead of a tandem Michael−
Henry reaction.
C
dx.doi.org/10.1021/jo4001806 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
silica gel (1:2 EtOAc/hexanes as the eluent) to afford the desired
product 2a.
(2) For a review, see: Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem., Int. Ed. 2006, 45, 7134−7186.
(1R,2R,3R)-2-Nitro-3-(2-oxo-2-phenylethyl)cyclohexanol (2a):5
26.0 mg, 99% yield.
(3) For selected examples on the synthesis of cyclohexane derivatives,
see: (a) Enders, D.; Urbanietz, G.; Cassens-Sasse, E.; Keeß, S.; Raabe,
G. Adv. Synth. Catal. 2012, 354, 1481−1488. (b) Mao, Z.; Jia, Y.; Xu,
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(1R,2R,3R)-3-[2-(4-Fluorophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2b):5 27.6 mg, 98% yield.
(1R,2R,3R)-3-[2-(4-Chlorophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2c):5 28.3 mg, 95% yield.
(1R,2R,3R)-3-[2-(4-Bromophenyl)-2-oxoethyl]-2-nitrocyclohexanol
́
(e) Varga, S.; Jakab, G.; Drahos, L.; Holczbauer, T.; Czugler, M.; Soos,
(2d):5 33.8 mg, 99% yield.
T. Org. Lett. 2011, 13, 5416−5419. (f) Yu, D.-F.; Wang, Y.; Xu, P.-F.
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Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922−4925.
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(i) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am.
(1R,2R,3R)-3-[2-(4-Cyanophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2e):5 28.2 mg, 98% yield.
(1R,2R,3R)-2-Nitro-3-[2-(4-nitrophenyl)-2-oxoethyl]cyclohexanol
(2f):5 30.5 mg, 99% yield.
(1R,2R,3R)-3-[2-(4-Methylphenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2g):5 27.2 mg, 98% yield.
́
Chem. Soc. 2009, 131, 16016−16017. (j) Cabrera, S.; Aleman, J.; Bolze,
(1R,2R,3R)-3-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-nitrocyclohexa-
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121−125. For selected examples on the synthesis of cyclohexene
derivatives, see: (k) McGarraugh, P. G.; Jones, J. H.; Brenner-Moyer,
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Q.-Q.; Chen, P.-Q.; Chen, Y.-C. Angew. Chem., Int. Ed. 2011, 50,
8638−8641. (m) Enders, D.; Wang, C.; Mukanova, M.; Greb, A.
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Bats, J. W. Synlett 2009, 3175−3178. (o) García Ruano, J. L.; Marcos,
nol (2h):5 29.1 mg, 99% yield.
(1R,2R,3R)-3-[2-(2-Chlorophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2i):5 29.5 mg, 99% yield.
(1R,2R,3R)-3-[2-(3-Chlorophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2j):5 29.2 mg, 98% yield.
(1R,2R,3R)-3-[2-(3-Bromophenyl)-2-oxoethyl]-2-nitrocyclohexanol
(2k):5 33.9 mg, 99% yield.
(1R,2R,3R)-2-Nitro-3-(2-oxopropyl)cyclohexanol (2l):5 19.8 mg,
98% yield.
V.; Suanzes, J. A.; Marzo, L.; Aleman
́
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6576−6580. (p) Hong, B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje, R. Y.;
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(2m):5 21.5 mg, 95% yield.
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(1R,2R,3R)-3-(3,3-Dimethyl-2-oxobutyl)-2-nitrocyclohexanol
(2n):5 23.8 mg, 98% yield.
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̈
Gram-Scale Synthesis of Compound 2a. A solution of catalyst 7
(303.5 mg, 0.50 mmol, 10 mol %) and (E)-7-oxo-7-phenylhept-5-enal
(1a) (1.01 g, 5.0 mmol) in CHCl3 (10 mL) was stirred at −15 °C for
10 min. To the above mixture was added nitromethane (610 mg, 10.0
mmol) in one portion. The reaction mixture was further stirred at this
temperature for 12 h (monitored by TLC). After the reaction was
completed, the volatile components were removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (1:2 EtOAc/hexanes as the eluent) to afford product 2a (1.21
g, 92% yield).
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ASSOCIATED CONTENT
■
(6) For a review on sequential catalysis, see: Wende, R. C.; Schreiner,
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S
* Supporting Information
1H and 13C NMR spectra for the compounds obtained in this
study as well as HPLC chromatograms of the tandem Henry−
Michael products. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: cong.zhao@utsa.edu.
́ ́ ́
2005, 347, 1643−1648. (e) Chinchilla, R.; Najera, C.; Sanchez-Agullo,
Present Address
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†Department of Chemistry, University of Alabama at
Birmingham.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the Welch Foundation (Grant No. AX-1593) for
financial support of this project.
(9) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc. 2010,
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