One-pot sequential organocatalysis: Highly stereoselective synthesis of trisubstituted cyclohexanols

Article abstract of DOI:10.1002/chem.201203104

A highly diastereoselective (d.r. >99:1) and enantioselective (ee value up to 96 %) synthesis of trisubstituted cyclohexanols was achieved by using a one-pot sequential organocatalysis that involved a quinidine thiourea-catalyzed tandem Henry-Michael reaction between nitromethane and 7-oxo-hept-5-en-1-als followed by a tetramethyl guanidine (TMG)-catalyzed tandem retro-Henry-Henry reaction on the reaction products of the tandem Henry-Michael reaction. Through a mechanistic study, it has also been demonstrated that similar results may also be achieved with this one-pot sequential organocatalysis by using the racemic Henry product as the substrate. Copyright

Full text of DOI:10.1002/chem.201203104

DOI: 10.1002/chem.201203104
One-Pot Sequential Organocatalysis: Highly Stereoselective Synthesis of
Trisubstituted Cyclohexanols
Qipu Dai, Hadi Arman, and John Cong-Gui Zhao*[a]
Abstract: A highly diastereoselective
(d.r. >99:1) and enantioselective (ee
value up to 96%) synthesis of trisubsti-
tuted cyclohexanols was achieved by
using a one-pot sequential organocatal-
ysis that involved a quinidine thiourea-
catalyzed tandem Henry–Michael reac-
tion between nitromethane and 7-oxo-
hept-5-en-1-als followed by a tetra-
methyl guanidine (TMG)-catalyzed
tandem retro-Henry–Henry reaction
on the reaction products of the tandem
Henry–Michael reaction. Through
a
mechanistic study, it has also been
demonstrated that similar results may
also be achieved with this one-pot se-
quential organocatalysis by using the
racemic Henry product as the sub-
strate.
Keywords: cyclohexanol · domino
reactions · Henry reaction · Michael
addition · organocatalysis
Introduction
hept-5-en-1-als.[6] Although organocatalyzed tandem Mi-
chael–Henry reactions have been used for the synthesis of
cyclohexane derivatives,[2i,q,t,z] to our knowledge, an organo-
catalyzed tandem Henry–Michael reaction has never been
used for this purpose. Herein, we wish to report our study
on a highly stereoselective synthesis of trisubstituted cyclo-
hexanols by using a quinidine thiourea-catalyzed tandem
Henry–Michael reaction followed by a one-pot tetramethyl
guanidine (TMG)-catalyzed tandem retro-Henry–Henry re-
action. The diastereomeric mixture obtained in the quini-
dine thiourea-catalyzed tandem Henry–Michael reaction
was successfully converted in situ to a single diastereomeric
product by a TMG-catalyzed tandem retro-Henry–Henry re-
action with high ee values. Thus, a highly diastereo- and
enantioselective synthesis of trisubstituted cyclohexanols
was achieved by using a one-pot sequential organocataly-
sis.[7]
Organocatalyzed tandem reactions have been widely used
for the quick assembly of complex structures from relatively
simple starting materials in recent years.[1] The major advan-
tages of using organocatalysts in tandem reactions lie in the
fact that they are tolerant of many functional groups, and as
a result the use of protecting groups is largely avoided, and
that organocatalyzed reactions are mild and easy to oper-
ate.[1] Organocatalyzed tandem reactions are especially
useful for constructing substituted cyclohexane,[2] a moiety
that may be found in many natural products.[3] By using or-
ganocatalyzed tandem reactions, cyclohexane derivatives
with up to six contiguous stereogenic centers have been suc-
cessfully obtained.[1,2] In practice, the Michael addition,
Henry reaction, and aldol reaction have often been used in
a cascade fashion for the synthesis of cyclohexane deriva-
tives, especially substituted cyclohexanols and cyclohexenes.
For example, Enders et al.[2a] and Wang et al.[2b] recently de-
scribed organocatalyzed one-pot Michael/Michael/aldol and
Michael/Michael/Henry reactions for the synthesis of cyclo-
hexanols with six contiguous stereocenters. Earlier, Enders
et al. also achieved the synthesis of substituted cyclohexenes
through a three-component domino reaction.[2z]
Results and Discussion
Using the enal 1a[8] and nitromethane as the model sub-
strates, we first tested several organic bases as the catalyst
for the desired tandem Henry–Michael reaction for the syn-
thesis of the trisubstituted cyclohexanol derivative 2a. The
results are summarized in Table 1.
When DABCO (5, Figure 1) was used as the catalyst
(Table 1, entry 1), the reaction of 1a and nitromethane at
RT in CH2Cl2 gave a mixture of three diastereomers, from
which compound 2a was isolated in 23% yield. The other
two diastereomers (3a and 4a) were not separable by
column chromatography, and they were obtained in a ratio
of 80:20 (3a/4a) with a total yield of 65%. These three dia-
stereomers differ in their stereochemistry of the hydroxy-
and nitro-substituted C1 and C2 stereogenic centers. Their
individual stereochemistry was established according to X-
ray crystallographic analysis or NOE experiments (see
We are interested in the development of new tandem re-
actions by using cinchona alkaloid derivatives as the cata-
lysts.[4,5] During our recent work, we envisioned that trisub-
stituted cyclohexanols may be obtained from a tandem
Henry–Michael reaction between nitromethane and 7-oxo-
[a] Dr. Q. Dai, Dr. H. Arman, Prof. Dr. J. C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio
One UTSA Circle, San Antonio, TX 78249 (USA)
Fax : (+1)210-458-7428
E-mail: cong.zhao@utsa.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203104.
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FULL PAPER
Table 1. Organocatalyzed tandem Henry–Michael reaction of 1a and ni-
comparison to the use of DABCO (Table 1,
entries 3 and 4). Poor results were also ob-
tromethane.[a]
tained when cupreidine (9) was used as the
catalyst (Table 1, entry 5). Similarly, the use
of 9-O-protected cupreidine derivatives 10–
12 led to undesirable results (Table 1, en-
tries 6–8). In contrast, when the quinidine
Cat. Yield of 2a ee of 2a Yield of 3a/4a[d] ee of 3a ee of 4a
[%][b]
[%][c]
3a+4a
[%][c]
[%][c]
thiourea catalyst 13 was applied in this reaction, the prod-
ucts were obtained in much-improved ee: 2a, 3a, and 4a
were obtained in 97, 91, and 88% ee, respectively. However,
the reaction still generated very low diastereoselectivity for
these three products (Table 1, entry 9). Similarly, high ee
values and low d.r. values of the products were also ob-
tained from the use of the cinchonine thiourea (14), quinine
thiourea (15), and cinchonidine thiourea (16) catalysts
(Table 1, entries 10–12). Interestingly, the quinine-derived
6’-thiourea catalyst 17, which is a known highly enantiose-
lective catalyst for the Henry reaction,[9] gave much worse
results: Both a low ee value and low d.r. of the products
were obtained (Table 1, entry 13). It should be pointed out
that the major enantiomers obtained with catalysts 7, 13,
and 14 were the opposite of those obtained with catalysts 8,
9, 11, 12, and 15–17.
According to the results of the above screening, cinchona
alkaloid thiourea catalysts 13–16 are the best catalysts for
this reaction in terms of the ee values obtained for the prod-
ucts. Nevertheless, very low diastereoselectivities were ob-
tained with all of these catalysts and, therefore, these results
are not yet synthetically useful. To solve the diastereoselec-
tivity problem, we then re-examined our results. As men-
tioned before, only a single diastereomer (3a) is formed
with TMG (6, Table 1, entry 2). Our results also indicate
that products 2a, 3a, and 4a only differ in their stereochem-
istry of the hydroxy-substituted C1 and the nitro-substituted
C2 stereogenic centers. Because the Henry reaction is rever-
sible, we speculated that these three diastereomers may be
interconvertable. On the basis of this assumption, we hy-
pothesized that diastereomer 3a is the thermodynamically
most stable among these three diastereomers and, therefore,
the results obtained with TMG (6) may be explained by
conversion of the other two less stable diastereomers, 2a
and 4a, to the more stable 3a by equilibrium under the
action of a stronger base catalyst. To test our hypothesis, we
first treated the isolated diastereomer 2a (97% ee), which
was obtained from the quinidine thiourea catalysis (Table 1,
entry 9), with TMG (6). As the results presented in
Scheme 1 show, diastereomer 3a was indeed obtained as a
single diastereomer after 2a was treated with catalyst 6 for
6 h at RT. More importantly, diastereomer 3a was also ob-
tained in 97% ee, which indicates a complete retention of
the product ee in this process.[10] Then the diastereomeric
mixture of 3a and 4a (a 60:40 mixture, 91 and 88% ee, re-
spectively; Table 1, entry 9) was similarly treated, and again
the single diastereomer 3a was obtained in 90% ee
(Scheme 1). The results also indicate the complete retention
of the ee value after the treatment. It should be pointed out
that, because the same enantiomer of 3a was obtained after
[%][b]
1
2
3
4
5
6
7
8
9
5
6
7
8
9
10
11
12
13
23
0
–
–
65
99
84
76
53
trace
80
80
66
84
80:20
>99:1
91:9
–
–
–
–
10
14
19
19
trace
13
19
23
11
10
8
31[e]
40
30
91:9
50[e]
50[e]
15[e]
n.d.[f]
60[e]
60[e]
88
13[e]
n.d.[f]
72[e]
70[e]
97
60:40 12[e]
n.d.[f]
nd[f]
89:11 60[e]
93:7
60:40
70:30
62[e]
91
81
10 14
11 15
12 16
13 17
96
90
94[e]
99[e]
20[e]
87
87
26
75:25 85[e]
73:27 91[e]
66:34 20[e]
90[e]
86[e]
20[e]
3
[a] Unless otherwise specified, all reactions were carried out at RT with
1a (0.10 mmol), nitromethane (0.20 mmol), and the catalyst (0.010 mmol,
10 mol%) in CH2Cl2 (0.2 mL) for 12 h. [b] Yield of the isolated product
after column chromatography. [c] Determined by HPLC analysis on a
ChiralPak AD-H column. [d] Determined by 1H NMR analysis of the iso-
lated product. [e] The opposite enantiomer was obtained as the major
product. [f] Not determined.
Figure 1. Structure of the catalysts screened in the tandem reaction (Ar=
3,5-(CF3)2C6H3-; Nap=naphthyl).
below). Interestingly, when 1,1,3,3-tetramethyl guanidine
(TMG; 6) was used as the catalyst, the same reaction led to
the formation of 3a in 99% yield as a single diastereomer
(Table 1, entry 2). Encouraged by these results, we then
screened
some
cinchona-alkaloid-derived
catalysts
(Figure 1) to test their capability in inducing the desired dia-
stereo- and enantioselectivity in this reaction. As the results
in Table 1 show, when quinine (7) and quinidine (8) were
used, a mixture of 2a, 3a, and 4a was again obtained, and
the ee values of these three diastereomers were also low,
although the d.r. ratios of 3a/4a were slightly improved in
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1667

J. C.-G. Zhao et al.
diastereomer (Table 2, entry 1). Similarly, high yields, excel-
lent d.r. values, and high ee values were also obtained with
the use of catalysts 14–16 (Table 2, entries 2–4). Because the
catalyst combination of 13/6 generated the product in the
highest ee (Table 2, entry 1), this combination was adopted
for further optimization of the reaction conditions. It was
found that the product ee could be improved to 94% when
xylene was used as the solvent (Table 2, entry 12), whereas
the other screened solvents (Table 2, entries 5–11) or no sol-
vent (Table 2, entry 13) all led to lower product ee values.
Finally, the highest ee value of 96% was achieved for prod-
uct 3a when the tandem Henry–Michael reaction was con-
ducted at 08C for 36 h before the reaction mixture was
treated with TMG (6; Table 2, entry 14).
Scheme 1. TMG-catalyzed conversion of compound 2a and a mixture of
3a and 4a to compound 3a.
the treatment in these two reactions, diastereomers 2a, 3a,
and 4a must share the same absolute stereochemistry at the
C3 stereogenic center.
Once the reaction conditions were optimized, the sub-
strate scope of this reaction was then evaluated, and the re-
sults are collected in Table 3. As is evident from the data
With these results in hand, we envisioned that a one-pot
sequential organocatalysis with cinchona alkaloid thiourea
and TMG (6) would be able to solve the both the diastereo-
selectivity and enantioselectivity problems of this tandem
Henry–Michael reaction. Thus, the tandem Henry–Michael
reaction using 1a and nitromethane was conducted first with
the best cinchona thiourea catalysts 13–16. Upon the com-
pletion of this reaction, the reaction mixture was treated
with TMG (6) in situ for an additional 6 h at RT. The results
are compiled in Table 2. As the results show, when catalyst
13 was followed by the addition of TMG (6), the reaction
generated product 3a in 91% yield and 92% ee as a single
Table 3. Organocatalyzed stereoselective synthesis of trisubstituted cyclo-
hexanols.[a]
R
1/3
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
1a/3a
1b/3b
1c /3c
1d/3d
1e/3e
1 f/3 f
1g/3g
1h/3h
1i/3i
1j/3j
1k/3k
1l/3l
1m/3m
1n/3n
99
99
99
97
90
99
96
99
99
99
99
90
98
97
>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
96
96
96
95
93
96
93
95
96
95
94
70
67
92
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
Me
Table 2. One-pot sequential organocatalysis.[a]
d.r.[c]
ee
t-Bu
c-C3H5
Cat.
Solvent
Yield
[%][b]
[%][d]
[a] Unless otherwise specified, all reactions were carried out at 08C with
the enal 1 (0.10 mmol), nitromethane (0.20 mmol), and catalyst 13 (0.010
mol, 10 mol%) in xylene (0.2 mL) for 36 h. Upon completion of the reac-
tion, the reaction temperature was raised to RT and the reaction mixture
was further treated with TMG (6; 0.010 mmol, 10 mol%) for 6 h.
[b] Yield of the isolated product after column chromatography. [c] Deter-
mined by the 1H NMR analysis of the crude reaction product. [d] The ee
values were determined by Chiral HPLC analyses on a ChiralPak AD-H
or a ChiralPak IB column.
1
2
3
4
5
6
7
8
9
10
11
12
13
14[f]
13
14
15
16
13
13
13
13
13
13
13
13
13
13
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH3CN
DMF
91
95
91
95
91
76
68
80
84
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
>99:1
>99:1
>99:1
>99:1
92
89
88[e]
91[e]
92
57
20
56
90
93
93
94
92
THF
diethyl ether
benzene
toluene
xylene
–
shown in Table 3, the electronic nature of the substituent on
the phenyl ring of the enals has no effect on either the dia-
stereoselectivity or the enantioselectivity of this reaction,
and similar results were obtained for substrates with either
an electron-withdrawing or an electron-donating group (1a–
h; Table 3, entries 1–8). Furthermore, the location of the
substituent on the phenyl ring is not affecting the selectivity
of this reaction. For example, similar high d.r. and ee values
were obtained for enals with a 2-chlorophenyl (1i; Table 3,
entry 9), 3-chlorophenyl (1j; Table 3, entry 10), or 4-chloro-
xylene
96
[a] Unless otherwise specified, all reactions were carried out at RT with
1a (0.10 mmol), nitromethane (0.20 mmol), and the catalyst (0.010 mmol,
10 mol%) in the indicated solvent (0.2 mL) for 24 h. Then the reaction
mixture was further treated with TMG (6; 0.010 mmol, 10 mol%) for 6 h
at RT before workup. [b] Yield of the isolated product after column chro-
matography. [c] Determined by 1H NMR analysis of the crude reaction
mixture. [d] Determined by HPLC analysis on
column. [e] The opposite enantiomer was obtained as the major product.
[f] The first step of the reaction was conducted at 08C for 36 h.
a ChiralPak AD-H
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Stereoselective Synthesis of Trisubstituted Cyclohexanols
FULL PAPER
phenyl (1c; Table 3, entry 3) substituent. 4-Bromophenyl-
(1d; Table 3, entry 4) and 3-bromophenyl-substituted (1k;
Table 3, entry 11) enals also generate comparable results.
Nonetheless, when the phenyl group on the enal was re-
placed with an alkyl group such as methyl (1l) or tert-butyl
(1m), the corresponding products 3l and 3m were obtained
with much lower ee values (70 and 67% ee, respectively;
Table 3, entries 12 and 13), although the d.r. values re-
mained high. In contrast, when the phenyl group in the enal
was substituted with a cyclopropyl group (1n), high ee and
d.r. values of the product 3n were again obtained (Table 3,
entry 14). These improved results are most likely due to
some subtle electronic rather than steric effects, because our
results have shown that both smaller and larger alkyl groups
(Me, 1l, and t-Bu, 1m) lead to worse enantioselectivities in
this reaction.
chemistry of 4a was established by a NOE experiment,
which indicates that the compound has an all-cis configura-
tion. Based on the fact that the enantiomer of 4a that was
obtained from catalyst 13/6 can be converted to 3a with re-
tention of the ee (Scheme 1), 4a must have an absolute con-
figuration of (1R,2S,3R), as shown in Table 1.
In order to better understand the reaction mechanism,
some additional experiments were carried out. By using a
reported protocol,[13] we synthesized the individual enan-
tiomers of the Henry reaction product (19, 99% ee for each
enantiomer), which should be an intermediate in this
tandem Henry–Michael addition reaction. The intramolecu-
lar Michael addition of these Henry products under catalysis
(with the quinidine thiourea catalyst 13) was then investigat-
ed. As the results in Scheme 2 show, (R)-19 leads to the for-
The absolute stereochemistry of the products 2 and 3 was
determined by the X-ray crystallographic analyses of the
crystals grow from the products 2a (Figure 2)[11] and 3d
(Figure 3),[12] which show that they have the (1S,2R,3R) and
(1R,2R,3R) configurations, respectively. A crystal for prod-
uct 4 could not be obtained. Instead, the relative stereo-
Scheme 2. Quinidine thiourea-catalyzed intramolecular Michael addition
of the Henry reaction product 19.
mation of 3a as a single diastereomer with a complete reten-
tion of the stereochemistry, whereas (S)-19 leads to the for-
mation of a mixture of diastereomers of 2a, 3a, and 4a in a
ratio of 50:15:35, respectively. Most importantly, complete
retention of the stereochemistry is only observed during the
formation of the diastereomer 2a. In contrast, there is a
major loss of the optical purity during the formation of 3a
and a minor loss of the optical purity during the formation
of 4a (Scheme 2). It should be also pointed out that the
stereochemistry of the C1 stereogenic center is inverted in
compounds 3a and 4a due to a tandem retro-Henry–Henry
reaction. From these data, it is clear that the diastereomers
2a/4a and 3a that were obtained in the tandem reaction by
using catalyst 13 (Table 1, entry 9) are of different origins,
with the former (2a/4a) forming only from (S)-19, whereas
the latter forms mainly from (R)-19 and partly from (S)-19.
Thus, the mechanism of this sequential organocatalysis may
be summarized in Scheme 3: In the tandem Henry–Michael
reaction catalyzed by 13, the initial Henry reaction of nitro-
methane to 1a must produce a mixture of both enantiomers
of 19 in low ee. Under the further action of 13, these two
enantiomers cyclized through an intramolecular Michael ad-
dition reaction to give a mixture of 2a, 3a, and 4a. High ee
values of these products were also achieved in this process.
Luckily, the stereochemistry of the C3 stereogenic center is
Figure 2. ORTEP drawing of compound 2a; ellipsoids are shown at 50%
probability.
Figure 3. ORTEP drawing of compound 3d; ellipsoids are shown at 50%
probability.
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J. C.-G. Zhao et al.
Conclusion
In summary, although the cinchona alkaloid thiourea-cata-
lyzed tandem Henry–Michael reaction between nitrome-
thane and 7-oxo-hept-5-en-1-als generates a mixture of dia-
stereomers, we have demonstrated that the reaction may be
improved by an in situ treatment with a stronger base cata-
lyst, such as TMG (6). From this new sequential organoca-
talysis procedure, the corresponding trisubstituted cyclohex-
anols may be obtained in excellent yields and diastereose-
lectivities, as well as high enantioselectivities (up to
96% ee). Through a mechanistic study, it has also been dem-
onstrated that similar results may be achieved by using the
racemic Henry reaction product as the substrate.
Scheme 3. Mechanism of the sequential organocatalysis with catalysts 13
and 6.
the same in the major enantiomers of these diastereomers
and, therefore, they are all converted to the thermodynami-
cally most stable diastereomer, 3a, with a high ee when they
are treated with TMG (6).
From the above mechanism, it is evident that the enantio-
selectivity of this reaction is generated in the intramolecular
Michael addition step. Thus, a poor ee value of 19 is not a
problem for generating high ee values of 2a, 3a, and 4a. On
the basis of this analysis, we envisioned that the sequential
organocatalysis may also be carried out with a racemic
sample of 19. Indeed, when racemic 19 was used as the sub-
strate, the sequential organocatalysis with 13 and TMG (6)
also gave product 3a as single diastereomer in quantitative
yield and 96% ee (Scheme 4). The results are comparable
with those of the tandem Henry–Michael reaction (Table 3,
entry 1).
Experimental Section
Representative procedure: A solution of catalyst 13 (5.95 mg, 0.01 mmol,
10 mol%) and (E)-7-oxo-7-phenylhept-5-enal[8] (1a; 20.2 mg, 0.10 mmol)
in xylene (0.2 mL) was stirred at 08C for 15 min. Nitromethane (12.2 mg,
0.2 mmol) was then added to the mixture in one portion. The reaction
mixture was further stirred at 08C for 36 h and the progress of the reac-
tion was monitored by TLC until 1a was totally consumed. After the re-
action was complete, the reaction mixture was allowed to warm to room
temperature and TMG (6; 2.3 mg, 0.02 mmol, 10 mol%) was added with
stirring. After an additional 6 h of stirring, 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 give
the desired product 3a (26.05 mg, 99%, 96% ee) as a white solid. M.p.
117–1188C; [a]2D5 = +79.0 (c=1.0 in CHCl3, 96% ee); 1H NMR
(300 MHz, CDCl3, 258C) d=7.94–7.80 (m, 2H), 7.60–7.51 (m, 1H), 7.44
(t, J=7.5 Hz, 2H), 4.35 (dd, J=11.2, 9.7 Hz, 1H), 4.22–4.04 (m, 1H),
3.09 (d, J=5.4 Hz, 1H), 3.02–2.85 (m, 2H), 2.66 (ddd, J=11.4, 9.3,
5.6 Hz, 1H), 2.13 (d, J=5.1 Hz, 1H), 2.01–1.86 (m, 1H), 1.84–1.67 (m,
1H), 1.43 (dd, J=13.2, 6.7 Hz, 2H), 1.22–1.03 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3, 258C) d=197.3, 136.3, 133.3, 128.5, 127.9, 96.2, 71.9,
40.8, 36.9, 33.2, 30.0, 22.6 ppm; IR (neat): n˜max =3462 (br), 2972, 2073,
1683, 1594, 1553, 1542, 1446, 1285, 1186, 1115 cmÀ1; elemental analysis
calcd (%) for C14H17NO4: C 63.87, H 6.51, N 5.32; found: C 63.91, H
6.54, N 5.34. Enantiomeric excess of the product was measured by chiral
stationary phase HPLC analysis using a ChiralPak AD-H column (94:6
hexanes/iPrOH at 1.0 mLminÀ1, UV detection at 254 nm.): major enan-
tiomer: tR =45.9 min; minor enantiomer: tR =57.6 min.
Scheme 4. Sequential organocatalysis with catalysts 13 and 6 by using
rac-19 as the substrate.
The trisubstituted cyclohexanol compounds obtained in
this study are very useful in organic synthesis. For example,
product 3h can be converted to compound 20 in high yield,
with a complete retention of the stereochemistry, through
the Baeyer–Villiger oxidation (Scheme 5). The correspond-
Acknowledgements
The authors thank the Welch Foundation (Grant No. AX-1573) for the fi-
nancial support of this project.
Scheme 5. Further elaboration of the tandem Henry–Michael addition
product 3h.
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Stereoselective Synthesis of Trisubstituted Cyclohexanols
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Received: September 2, 2012
Published online: December 13, 2012
Chem. Eur. J. 2013, 19, 1666 – 1671
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1671