Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

Article abstract of DOI:10.1021/jacs.5b08528

A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β′-enones and substituted β,β′-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ⁵-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.

Full text of DOI:10.1021/jacs.5b08528

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Article
Concise Enantioselective Synthesis of Oxygenated
Steroids via Sequential Copper(II)-Catalyzed Michael
Addi-tion/Intramolecular Aldol Cyclization Reactions
Nathan Cichowicz, Will Kaplan, Iaroslav Khomutnik, Bijay Bhattarai, Zhankui Sun, and Pavel Nagorny
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08528 • Publication Date (Web): 22 Oct 2015
Downloaded from http://pubs.acs.org on October 28, 2015
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Journal of the American Chemical Society
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Concise Enantioselective Synthesis of Oxygenated Steroids
via Sequential Copper(II)-Catalyzed Michael Addi-
tion/Intramolecular Aldol Cyclization Reactions
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Nathan R. Cichowicz, Will Kaplan, Iaroslav Khomutnik, Bijay Bhattarai, Zhankui Sun, and Pavel
Nagorny.*
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109
Steroids, Enantioselective Catalysis, Michael Reaction, Aldol Cyclization, Synthesis
ABSTRACT: A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is
based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of
cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II)
salts as highly active catalysts for Michael reaction of the traditionally unreactive β,β-enones and substituted β,β-ketoesters
that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The
Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or
unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising
from the presence of the Δ5-unsaturation are key controling elements for the formation of the natural cardenolide scaffold.
The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well
as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.
INTRODUCTION
relies on tandem asymmetric diastereoselective Michael
addition/intramolecular aldol reactions to achieve expedi-
ent assembly of steroids.8-10 It requires simple and readily
available building blocks 5 and 6, and achieves the synthe-
sis of functionalized steroidal core 9 and the C13, C14-
epimeric core 8 in only 4-5 steps (Figure 1). In addition,
our method tolerates modifications in 5 and 6, which al-
lows accomplishing rapid alterations in the ring size and
C13-substituents of 8 and 9. The scaffolds 8 and 9 are pre-
sent in a variety of bioactive steroids (i.e. 1–4, Figure 1)
and their quick generation provides exciting opportunities
for the synthesis of these and many other natural and un-
natural diterpenes.
Steroids play an important role in drug discovery, me-
dicinal chemistry, and chemical biology. These compounds
are responsible for the regulation of vital biological func-
tions in animals and plants, and, not surprisingly, the ste-
roidal scaffold is a privileged motif that is present in many
FDA-approved drugs.1 Developing means to access syn-
thetic and natural steroids was one of the triumphs of last
century’s chemists, and the first total synthesis of a steroi-
dal sex hormone, equilenin by Bachmann dates back to
1939.2 Despite major advances in the total synthesis of
steroids, most steroid-based drugs are obtained by semi-
synthesis using feedstock isolated from plant or animal
sources.3 Recent developments in the field of asymmetric
catalysis have enabled the efficient preparation of simple
enantioenriched steroids such as estrones.4 However, few-
er asymmetric catalytic strategies for the construction of
more complex steroids are available. In particular, despite
the significant efforts invested in developing scalable syn-
thetic routes to cardenolides, an asymmetric total synthe-
sis of the steroids of this family still represent a formidable
challenge.4-7 Considering recent interests in developing
safer versions of existing medicines as well as the growing
demand for cardenolide-based therapeutics, a concise,
scalable and modular synthetic route to the cardenolide
skeleton bearing necessary functionalization is highly de-
sired.5c
Figure 1. Approach Summary
O
O
CN
strophanthidin
(cardiotonic)
O
O
Me
13
Me
18
Me
19
5
HO
Me
OH
Me
H
H
H
11
17
17
O
19
13
14
Me
H
H
H
H
H
1
H
H
O
7
HO
H
OH
H
OH
3
5
1
3
7
HO
2
4
HO
OH
aromatase
inhibitor
GABAA modulator
rostafuroxin (hypertension)
O
R
Enantioselective Michael/Double Aldol Approach
13
H
E
base
m
chiral
catalyst
n
n
O
n
H
OH
O
O
5
R
m
E
8
5
E
6
O
OH
E
13
O
This article describes a conceptually new asymmetric
approach to steroids that enables rapid stereoselective
synthesis of various cardenolide scaffolds. This approach
R
R
O
O
m
Me
13
H
O
7
m
Me
O
base
Δ
5
E = -CO2Me
OH
O
H
5
9
O
R = Me or Et
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Journal of the American Chemical Society
Page 2 of 9
groups describe the formation of these motifs with suffi-
ciently high levels of enantiocontrol.14 However, the evalu-
ation of the aforementioned methods using catalysts 10–
12 (Table 1)12 did not result in significant formation of 7a,
probably, due to the substantially lower reactivity of unac-
tivated 6-membered β-ketoester 6a. While catalyst 12
could indeed promote the previously reported reaction of
6a and methyl vinyl ketone to provide the corresponding
Michael adduct in 77% yield, 36% ee (cf. Supporting In-
1
2
3
4
5
6
7
8
Finally, the formation of the sterically strained chiral
Michael adducts is described using a new variant of Cu(II)-
catalyzed Michael reactions under solvent-free conditions.
Unprecedented Michael reactions with unreactive enones
and ketoesters were achieved under these conditions, and
applied to the preparation of chiral products with vicinal
all-carbon quaternary centers and with vicinal quaternary
and tertiary stereocenters is described. Development of this
transformation not only enabled the four-step assembly of
steroids, but also the asymmetric synthesis of functionalized
Hajosh-Parrish and Wieland-Miescher ketones that are chal-
lenging to generate using existing methods.
1
formation), only 6% of 7a was detected by H NMR analy-
9
sis of the crude mixture after 72 h when ketone 5a was
employed as an electrophile (entry 2).
10
11
12
13
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16
17
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Considering that the prior methods were not suitable
for the approach outlined in Figure 1, our further attempts
were focused on identifying a new, more reactive catalytic
system. Our initial efforts to form 7a with amine bases
(entries 4–5) or LHMDS (not shown) were unsuccessful.
However, in the following screening of the Lewis acid-
based catalysts, we discovered that Cu(OTf)2 can promote
an efficient Michael reaction15 between 6a and 5a in 86%
yield, 4:1 d.r. (Table 1, entry 8) under solvent free condi-
tions.15e Interestingly, Cu(OTf)2 was unique in catalyzing
the formation of 7a. Thus, Zn(OTf)2 (entry 6) did not pro-
mote any reaction, and the use of Sc(OTf)3 (entry 7) led to
decomposition of the starting materials. Furthermore, the
diastereoselectivity of Cu(OTf)2-catalyzed reaction could
be increased without affecting the yield if the reaction was
run at 0 ºC (entry 9).
RESULTS AND DISCUSSION
Initial studies on Michael reaction. As the asymmet-
ric Michael reaction resulting in 7 is key to this approach,
our studies commenced with investigating the addition of
ketoester 6a to enone 5a (Table 1). Intermolecular Mi-
chael reactions of 2-substituted β-ketoesters and β-
substituted enones resulting in vicinal quaternary and ter-
tiary stereocenters are challenging.11–13
Table 1. Initial evaluation of the conditions for the for-
mation of Michael product 7a
O
Developing asymmetric variant of Michael reaction. With
the racemic variant of this reaction in hand, we investigated
the enantioselective variant of this transformation by employ-
ing chiral Cu(II) Box and PyBox complexes (Table 2).17 Such
complexes have been previously employed as the catalysts for
the conjugate additions of carbon and oxygen-based nucleo-
philes17 as well as Mukaiyama Michael reactions.18 The at-
tempts of utilizing Cu(II) Box complexes for the direct Michael
reactions of 1,3-dicarbonyls and enones are also document-
ed;19 however, racemic products were observed in such cases.
Thus, the only successful example of enantioselective Michael
reaction catalyzed by Cu(II) Box complexes relied on activa-
tion of chelating electrophiles such as β,γ-unsaturated α-
ketoesters.20
O
CO2Et
Me
O
O
catalyst
Me
EtO2C
Me
H
O
conditions, T, time
O
6a
5a
7a
O
Me
O
2+
OMe
OH
Tol2
P
OH2
OH2
H
N
BnO
2TfO–
Pd
P
N
NH
Tol2
N
N
H
S
NH
10
11
NH2
12
entry catalyst catalyst conditions T, °C time conversion d.r.
(yield)%a
mol %
h
20
10
1
2
3
4
5
6
7
8
9
10
11
87
72
72
48
72
3
0
0
6
0
1 M in CH2Cl2 rt
–
–
The optimization results for the enantioselective reaction of
6a and 5a resulting in chiral 7a are summarized in Table 2.
While Cu(OTf)2 complexes in some cases were found to pro-
mote enantioselective reaction (entries, 1 and 11), the com-
plexes with non-coordinating counterions were found to be
more reactive.(i.e. entry 1 vs. entry 2). Extensive evaluation
of various Box and PyBox ligands, helped to identify 2,2'-
(cyclopropane-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole)-
ligand 16b as the ligand of choice.21 Substantial ligand effects
were observed in these studies, and no reaction was observed
with Box ligands 13b and 13c despite our numerous attempts
to optimize these reactions. The copper(II) hexafluoroantimo-
nate complex of 16b promoted the formation of 7a at r.t. in
93% yield and good selectivity (5:1 dr, 84% ee). The enanti-
oselectivity of this reaction was improved at lower tempera-
ture (entries 13 and 14), and under the optimal conditions (en-
try 13) the desired Michael adduct 7a was obtained in excel-
lent yield and selectivity (89% yield, 5:1 dr, 92% ee).
rt
0
rt
rt
rt
rt
rt
0
1 M in PhMe
4 M in THF
5
12
–
1000
100
10
Et3N
DBU
–
0.4 M in MeCN
4 M in THF
neat
b
–
–
Zn(OTf)2
Sc(OTf)3
0
–
b
neat
10
3
–
–
neat
Cu(OTf)2
Cu(OTf)2
10
3
>95 (86)
>95 (81)
4:1
8:1
10
neat
4
aThese reactions were performed on 0.24–0.77 mmol scale with 1
equiv of 10 and 11, and the catalyst of choice (10 mol%).The
isolated yields that represent average of two runs are provided.
bNumerous side-products resulting from the decomposition of 5a
were detected.
Up to date, only the asymmetric catalytic transfor-
mations developed by Sodeoka’s, Wang’s, Ye’s and Deng’s
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Journal of the American Chemical Society
As the possibility of introducing substituents at the C13
of their cyclized products (Schemes 4 and 5). Thus, the abso-
lute configuration of the series of Michael adducts 7 depicted
in Scheme 2 can be achieved with (R,R)–16b. Importantly,
getting access to 7a–7i in a highly selective manner was key to
our synthetic plan outlined in Figure 1 and allowed us to fur-
ther pursue the enantioselective synthesis of steroid analogs
(Table 3).
1
2
3
4
5
6
7
8
position and changing A/D ring sizes in 7 is key to the ap-
proach outlined in Figure 1, the substrate scope of the enanti-
oselective Michael reaction was investigated next (Scheme 1).
With five-membered β-ketoesters, the reactions proceeded
significantly faster (24 h) and with higher levels of diastere-
ocontrol (7b, 7c, 7f, 7g). For both 5- and 6-membered ketoes-
ters, the alterations in the β-substituent of α,β-unsaturated
ketone portion of 5 were well tolerated, and substrates 7a–7i
were obtained in good yields, diastereo- and enantioselectivi-
ties.
Scheme 1. Substrate scope of the enantioselective Mi-
chael reactiona
9
2+
SbF6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
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49
50
51
52
53
54
55
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60
–
O
O
O
O
EtO2C
R
Table 2. Optimization of the conditions for the enantioselec-
tive Michael reaction
N
N
CO2Et
Me
16b
Cu
Ph
Ph
(10 mol%)
n
R
n
Me
O
O
O
O
5
neat, –10 ˚C, 24 or 48 h
CuX2•liganda
6
7
CO2Et
Me
O
O
Me
(10 mol%)
EtO2C
Me
O
O
O
Me
O
Et
O
H
O
Me
O
neat, T, time
6a
5a
7a
EtO2C
EtO2C
O
EtO2C
Me
O
O
Me
Me
O
O
Me
7ab
Me
O
7c
O
O
O
O
7b
O
O
O
Me
O
O
R1
R1
N
N
N
N
N
N
89% yield, 5:1 dr
92% ee
87% yield, > 20:1 dr
96% ee
82% yield, 19:1 dr
92% ee
14
R
R2
R
R2
16a, R1 =Ph, R2 = Ph
16b, R1 =H, R2 = Ph
O
13a, R = Ph
O
O
Et
O
O
13b, R = tBu
13c, R = Bn
13d, R = iPr
Me
N
Me
EtO2C
N
N
EtO2C
EtO2C
15
iPr
iPr
O
O
O
7d
7e
7f
entry
T, °C
time conversion d.r.
ee
%
Me
ligand
CuX2
O
O
Me
O
O
Me
O
O
h
(yield) %
93% yield, 4:1 dr
90% ee
88% yield, 7:1 dr
91% ee
86% yield, 20:1 dr
95% ee
rt
rt
2.5:1
2.5:1
–
1
2
13a
13a
13b
13b
13c
13c
13d
14
3
3
90 (83)
>95 (88)
0
74
74
–
Cu(OTf)2
Cu(SbF6)2
Cu(OTf)2
EtO2C
EtO2C
Me
Me
EtO2C
Me
rt
3
3
rt
–
Cl
4
3
0
–
Cu(SbF6)2
Cu(OTf)2
Me
O
Me
O
O
O
Me
O
O
rt
–
5
3
0
–
7g
7h
7i
rt
–
6
3
0
–
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(OTf)2
92% yield, > 20:1 dr
91% ee
95% yield, 10:1 dr
94% ee
94% yield, 14:1 dr
88% ee
rt
2.5:1
n.d.
n.d.
3:1
4:1
5:1
5:1
6:1
7
3
>95 (96)
n.d.
26
8
O
O
Me Me
Me Me
rt
8
3
CO2Et
7j
7k
CO2Et
O
Me
Ph
O
rt
62% yield
15% ee
71% yield
10% ee
9
15
3
n.d.
10
76
72
84
92
93
rt
10
11
12
13
14
16a
16b
16b
16b
16b
3
>95 (71)
>95 (88)
>95 (93)
>95 (89)
80
aReactions were performed on 0.82–1.3 mmol scale. The depicted
absolute stereochemistry of 7a-7h could be achieved with (R,R)-
17b. The yields and selectivities represent an average of two runs.
rt
3
rt
3
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
–10
–20
1
The d.r. is determined by H NMR analysis. bThis reaction was
48
72
also performed on 10.8 mmol scale (cf. Scheme 5 and SI)
aThese reactions were performed on 1.0 mmol scale with 1 equiv
of 5a and 6a, and the catalyst of choice (10 mol%). The isolated
yields that are calculated based on the average of two runs are
provided. The d.r. is determined 1H NMR analysis, and the minor
diastereomer of 7a was isolated and characterized (cf. SI).
The observations summarized in Table 1 suggest that
Cu(II) salts are among the most active catalysts for the
formation of sterically-strained Michael adducts such as
7a under solvent-free conditions. In order to further
demonstrate this point, Michael adducts 7j and 7k with
vicinal all-carbon quaternary stereocenters were generat-
ed in good yields using 16b as the catalyst (Scheme 1).
Due to the presence of unfavorable steric repulsions with
the second β-substituent of the enone, these adducts were
formed in lower enantioselectivities, and further optimiza-
tion of the ligand would be required. At the same time, the
ability to generate 7j and 7k using this method is of great
utility by itself, considering that the formation of such Mi-
Remarkably, the introduction of the vinyl chloride moiety
into 6-membered ketoesters was also tolerated and the corre-
sponding vinyl chloride-containing Michael adduct 7i was
generated in excellent yield and selectivity. The presence of
unsaturation resulted in significant enhancement in the d.r. of
this reaction as a 14:1 mixture of diastereomers of 7i was ob-
tained. The absolute and relative configurations of these ad-
ducts were later confirmed by X-ray crystallographic analysis
ACS Paragon Plus Environment

Journal of the American Chemical Society
chael adducts with vicinal quaternary stereocenters is un-
Page 4 of 9
O
Me
13
17a
O
1
2
3
4
5
6
7
8
precedented under normal conditions, and the only exist-
ing reports describing similar transformations utilize stoi-
chiometric base at ultra high pressures (15 kBar).16
EtO2C
9
14
Me
8
O
Me
10
H
OH
O
EtO2C
13
14
EtO2C
O
9
O
Me
Me
8
10
5
O
The proposed mechanism of Cu(II)-catalyzed Michael re-
action is provided in Figure 2. Thus, Cu(II) undergoes chela-
tion with the enol form of β-keto-ester 6a to provide com-
plex I. Such complexes have previously been detected by
ESI MS and proposed to be active complexes in Cu(II)-
catalyzed Michael reactions.19a This complex undergoes a
Michael reaction with enone 5 to provide complex II.
While some additional studies are required to clarify the
details for the formation of complex II, coordination of 5
to Cu(II) followed by an intramolecular conjugate addition
are proposed to be involved. The zwitterionic complex II
then undergoes a proton transfer to generate complex III,
which upon decomplexation regenerates 16b.
H
OH
O
Me
O
O
OH
EtO2C
9
8
7a
O
10
5
H
17b
O
OH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Moreover, the precedents established by the Deslong-
champs group6b suggest that if the aldol cascade proceeds
through 17b then the unnatural α-configuration of the C13 and
C14 stereocenters is most likely to be formed (i.e. pro-S ke-
tone attack in 17b is preferred).
Table 3. Double aldol cyclization studiesa
O
O
Me
Me
Figure 2. Tentative Mechanism of Cu(II)-Catalyzed Mi-
chael Reaction
EtO2C
H
EtO2C
H
O
Me
O
H
OH
O
H
OH
O
2+
SbF6
O
O
–
8b
EtO2C
8a
O
O
6a
OH
OH
OEt
O
N
N
O
X-Ray
Cu
conditions
O
O
Ph
Ph
Me
Me
Me
HO
Me
O
O
R
I
EtO2C
EtO2C
H
H
2+
SbF6
7a
OEt
5
–
O
O
H
OH
O
H
OH
O
N
N
9a
9b
Cu
Ph
Ph
X-Ray
O
16b
Me
OH
2+
–
SbF6
O
O
EtO2C
H
O
O
N
N
Cu
H
Ph
Ph
OEt
R
2+
SbF6
9c
II
HO
O
O
–
O
O
Me
OEt
R
N
O
N
O
7
O
Cu
Ph
Ph
Me
entry
conditions
conversion, %
(yield, %)
products
selectivity
III
O
OEt
R
1
2
D- or L-proline
DMF, rt, 24 h
0
–
–
–
–
Me
TiCl4, Et3N
THF, –78 to 0 ˚C
decomposition
O
Double aldol cyclization studies. With this key bond
formation achieved, the double aldol cyclization strategy
(Scheme 2) was investigated next. Depending on the sequence
of the cyclization events, the formation of 8 from Michael
adduct 7a can proceed via two different intermediates (i.e. 17a
and 17b). It is noteworthy that the formation of steroid 9 re-
sults in four new stereogenic centers at the C5, C8, C13 and
C14 positions. While the configuration of the C5 carbon will
most likely be dictated by the adjacent C10 stereocenter re-
gardless of the reaction pathway (i.e. 17a vs. 17b), the per-
spectives of achieving control over the configuration of the
three remaining centers were not as clear.
3b
4
p-TSA, toluene
reflux, 18 h
> 98
9a
8a
only
only
DBU, THF
reflux, 18 h
> 98 (94)
5
piperidine
THF, reflux, 18h
> 98
> 98
> 98
8a
only
6
piperidine, LiCl
THF, reflux, 18h
8a, 8b, 9a, 9b 10:8:43:39
7c
8c
9
KHMDS (1 equiv)
THF, rt, 24 h
8b, 9a, 9b
35:50:15
KHMDS (2 equiv)
THF, reflux, 30 min
> 98 (48)
> 98 (89)
9b, 9c
9b
1:2
Cs2CO3
DMF, 140 ˚C, 1 h
only
Scheme 2. Proposed double cyclization strategy
aPre-purified diastereomerically pure 7a was used for these stud-
b
ies. Unidentified product (c.a. 30%) was formed along with 9a;
cSignificant amounts of retro-Michael reaction products were
observed.
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stereomer 9b containing Δ5-unsaturation. These results are
consistent with the mechanistic pathway, in which the B-ring
is closed first. In the case of the reactions catalyzed by DBU
or p-TSA (entries 3 and 4), the second aldol addition proceeds
through 18a and 18b and leads to 8a or 8b, and the pathway
from 18a to 8a is energetically more favored. Indeed, compu-
tations (DFT, geometry optimization, B3LYP, 6-31+G*) sug-
gest that 8a is more stable than 8b by 1.8 kcal/mol. However,
the reaction promoted by Cs2CO3 at 140 ºC (entry 9) is likely
to proceed through a different mechanism, in which the inter-
mediate aldol adduct 18b undergoes elimination of water to
form the corresponding aldol condensation product 20 (cf. Eq.
1). This product then cyclizes via 19a and 19b to form 9a and
9b. With the Δ5-unsaturation, the natural configuration present
in 9b becomes more stable, and thus the pathway proceeding
through 19b becomes more energetically favored. The ob-
served preference for 9b can possibly be the result of not only
kinetic, but also thermodynamic control. Consistent with this
proposal, the computational studies suggest that the energy of
the enone 9b with natural configuration is 2.1 kcal/mol lower
than the energy of the unnatural enone 9a. We propose that
formation of the C5-C6 enone double bond in ring B, results in
increased torsional strain for the unnatural α-configuration,
and for the diastereomeric enones 9a/9b, the natural β-
diastereomer 9b becomes more stable.6h
However, with no other precedents for the cyclization of 7a
1
2
3
4
5
6
7
8
existing, we anticipated that the configuration at the C8, C13
and C14 carbons can be controlled with the proper selection of
the aldolization conditions. Therefore, the following studies
commenced with evaluation of various promoters and cata-
lysts of aldol reactions (Table 3). The cyclization of 7a was
unsuccessful under proline-catalyzed (entry 1) or soft
enolization (entry 2) conditions. However, under the acidic
conditions cyclization proceeded to provide enone 9a with
the unnatural α-configuration of the C13- and C14-
stereocenters (entry 3). Similarly, DBU- and piperidine-
promoted transformations resulted in a clean formation of
8a (entries 4 and 5). The use of LiCl as an additive in com-
bination with piperidine affected the outcome of this cy-
clization and enones 9a and 9b were formed along with
8a and 8b (entry 6). In our further attempts to improve
the formation of 8b and 9b, containing the desired natural
stereochemistry, we investigated KHMDS-promoted cycli-
zations (entries 7 and 8). Remarkably, the temperature
was found to be an important parameter, and when con-
ducted in refluxing THF, only the natural β-diastereomers
9b and 9c were formed. To avoid deconjugation of 9b
into 9c and to prevent retro-Michael pathway, a milder
base, Cs2CO3, was employed at an elevated temperature
(140 ºC, DMF). These conditions resulted in a fast for-
mation of the desired enone 9b with the β-configuration of
the C13- and C14-stereocenters of the CD-ring junction
(entry 9).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
Me
Me
N
H
LiHMDS
EtO2C
H
EtO2C
(1)
AcOH, EtOAc
O
7a
THF
H
OH
O
Scheme 3. Explaination of diastereoselectivity for the
formation of 8a–9b
H
30 ºC, 18 h
72% yield
9b
20 –78º to 60 ºC
O
59%, > 20 : 1 dr
O
O
Me
O
Me
O
O
Me
Me
EtO2C
Cs2CO3
H
EtO2C
H
EtO2C
EtO2C
H
H
EtO2C
H
(2)
Me
more stable
by1.8 kcal/mol
DMF, 140 ºC
9a:9b = 1:3
Favored
H
H
OH
O
OH
O
8a
H
OH
O
H
OH
O
HO
O
OH
O
OH
9b
9a
18a
8a
O
7a
Me
O
EtO2
C
Me
O
To validate the mechanistic proposal above, the experi-
EtO2C
H
HO
ments depicted in equations 1 and 2 were performed. Enone
20 was prepared by pyrrolidine-promoted monocyclization of
7a. This compound was treated with LiHMDS, which pro-
duced 9b as the only observed product (>20:1 dr after 30 min,
Eq. 1). In an additional control experiment, diastereomerically
pure adduct 8a was treated with Cs2CO3 at 140 ºC (Eq. 2). As
expected, 8a underwent elimination of water, and 1:3 mixture
of 9a:9b was observed under the reaction conditions. The out-
come of this experiment suggests that the formation of 9a and
9b may be reversible at 140 ºC. However, considering that
significant quantities of 9a were observed along with 9b, the
exclusive formation of 9b observed for the direct cyclization
of 7a (entry 9, Table 3) cannot be a sole result of the thermo-
dynamically controlled isomerization of 9a into 9b.
Application to the synthesis of natural and unnatural
cardenolides. The formation of unnatural steroids 8a–8g from
the corresponding Michael adducts (7a–7g) was investigated
next (Scheme 4). Based on the results summarized in Table 3,
DBU was selected as the base of choice to promote these cy-
clizations. Upon subjecting 7a–7f to DBU in refluxing THF,
the cyclizations proceeded cleanly and resulted in the for-
mation of the corresponding steroids with the epimeric α-CD-
H
OH
O
O
18b
OH
8b
O
Me
O
EtO2C
H
EtO2C
H
Me
H
OH
O
O
O
9a
19a
7a
140 ºC
O
Me
O
EtO2C
Favored
Me
O
EtO2C
H
H
OH
more stable
by 2.1 kcal/mol
O
O
19b
9b
The origins of diastereodivergence in double
aldol cyclization. The results summarized in Table 3 indi-
cate that in the case of the double aldol adducts 8a and 8b
there is a clear preference for the pathway leading to the un-
natural diastereomer 8a (Scheme 3). At the same time, elevat-
ed temperatures lead to the selective formation of natural dia-
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Page 6 of 9
ring junction. In all cases, the epimeric steroids were obtained eration of steroids with natural cardenolide configuration, chi-
1
2
3
4
5
6
7
8
in excellent yields and selectivities, and the formation of the
otherwise challenging to generate by semi-synthesis 8a, 8d
and 8e as well as C18-ethyl group containing products 8c and
8f was successfully achieved. The relative configurations of
compound 8a and the relative and absolute configuration of 8d
were assigned based on X-ray crystalographic analysis (cf.
Scheme 4). It is also noteworthy that all of these compounds
were generated via 4-step linear sequences from the commer-
cially available building blocks.
ral steroid 9b, as well as enones 21, and 22 were formed from
the corresponding Michael adducts (conditions A and B,
Scheme 5). It is noteworthy that the formation of 9b was car-
ried on 1.5 g scale without significant erosion in yield and
enantioselectivity, and its absolute and relative configuration
was confirmed by X-ray crystallographic analysis. Compound
9b possesses all of the necessary functionalities and stereo-
chemistry to be converted to cardenolides as well as other
steroids, and the efforts in this direction are ongoing in our
laboratories.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A two-step protocol (conditions B) was required for the clean
formation of 22 and 23 as the corresponding cyclizations with
Cs2CO3 at 140 ºC resulted in significant amounts of retro-
Michael products. To circumvent this problem, the Michael
adducts 7b and 7d were monocyclized with pyrrolidine acetate
(i.e. conditions resulting in the formation of enamine) to afford
a clean formation of the corresponding Δ5-enones. As in the
case of the cyclization described in equation 1, the following
treatment of the monocyclized enone with LiHMDS (22) or
NaHMDS (23) resulted in a clean diastereoselective formation
of the corresponding cardenolide analog with the natural con-
figuration.
Scheme 4. Diastereoselective formation of steroids with
unnatural configuration
O
O
Me
R
DBU, THF
reflux, 12 ha
EtO2C
EtO2C
H
m
m
O
H
OH
O
H
n
7
O
n
9
O
Me
OH
Conditions A:
O
Me
Scheme 5. Diastereoselective formation of steroids with
the natural configurationa
EtO2C
H
H
OH
O
O
O
R
Me
8ab
OH
X-Ray
EtO2C
EtO2C
H
Conditions A–C
78% yield, > 20:1 dr
94% ee
(Relative Stereochemistry)
m
m
H
O
OH
O
H
n
O
Me
n
O
O
7
Me
9
EtO2C
H
X-Ray
(Absolute Stereochemistry)
Conditions A:b Cs2CO3, DMF 140 ºC
H
OH
O
8cb,c
O
Me
OH
9b
X-Ray
86% yield, > 20:1 dr
96% ee
EtO2C
H
(Absolute Stereochemistry)
H
OH
O
O
O
Et
Me
EtO2C
H
EtO2C
H
50% yield (1.5 g scale)
59% yield (350 mg scale)
> 20:1 dr, 90% ee
H
OH
O
H
OH
O
8db
8eb
OH
OH
Conditions B:c a) Pyrrolidine, HOAc; b) LiHMDS or NaHMDS
68% yield, > 20:1 dr
93% ee
86% yield, > 20:1 dr
99% ee
O
O
Et
21
Me
22
O
O
Me
Et
EtO2C
35% yield
(2 steps)
> 20:1 dr
89% ee
H
EtO2C
39% yield
(2 steps)
11:1 dr
H
EtO2C
H
EtO2C
H
H
OH
O
H
OH
O
92% ee
H
OH
O
H
OH
O
8gb
8fb
Conditions C:d Pyrrolidine, HOAc
OH
OH
65% yield, > 20:1 dr
99% ee
81% yield, > 20:1 dr
92% ee
C5H11
C5H11
23
24
EtO2C
EtO2C
63% yield
10:1 dr
94% ee
55% yield
>20:1 dr
90% ee
aSubstrates 7 were used as the diastereomeric mixtures of Michael
adducts (cf. Scheme 1) without pre-separation of the minor dia-
stereomers. 7 were treated with DBU, THF, reflux, 12 h. bThe
yields are reported for the isolated major diastereomer after puri-
fication by chromatography. (R,R)-enantiomer of 16b was used to
generate the depicted enantiomers of 8. c(S,S)-enantiomer of 16b
was used to generate the depicted enantiomers of 8c.
O
O
aSubstrates 7 were used as the diastereomeric mixtures of Michael
adducts (cf. Scheme 1) without pre-separation of the minor dia-
stereomers. The reactions were complete and the yields are based
on the isolated diastereomerically pure 9b, 21-24 after purifica-
b
tion. Condition A:. Cs2CO3, DMF, 140 ºC, 1 h; Condition B: i)
Pyrrolidine (1 equiv), AcOH (1 equiv), EtOAc, 30 ºC, 20 h; ii)
To demonstrate that our method could be used for the gen-
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LHMDS/THF (21) or NaHMDS/toluene (22), reflux; cCondition
C: Pyrrolidine (1 equiv), AcOH (1 equiv), THF, 30 ºC, 18 h.
This work was supported by NIGMS R01 grant
1
2
3
4
5
6
7
8
(1R01GM111476-01). PN is a Sloan Foundation Fellow. WK
is the AFPE fellow. We thank prof. Edwin Vedejs for the use-
ful suggestions during the preparation of this manuscript. We
acknowledge funding from NSF grant CHE-0840456 for X-
ray instrumentation.
As a result, the corresponding steroids 21 and 22 were ob-
tained in 35% and 39% (2 steps), correspondingly, starting
with the diastereomeric mixtures of the corresponding Michael
adducts. Importantly, the semi-synthetic methods based on the
modification of the natural steroids would not provide a
straightforward access to analogs such as 22 and 23, while our
current approach permitted an expedient generation of these
scaffolds in only 5 steps from the commercially available
starting materials.
Finally, the formation of substituted Hajosh-Parrish and
Wieland-Miescher ketones,22 by the cyclization of Michael
adducts 7g and 7h (conditions C) was performed to provide
enones 23 and 24. Such enones (and 24 in particular) contain
adjacent quaternary/tertiary stereocenters and to our
knowledge are not readily obtained enantioselectively.23
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SUMMARY AND CONCLUSIONS
In conclusion, a new method for a rapid assembly of natural
and unnatural cardenolide skeletons has been developed. This
method is enabled by developing a new chiral bis(oxazoline)
copper(II) complex-catalyzed enantioselective and diastere-
oselective Michael reaction of cyclic ketoesters and enones to
install vicinal quaternary and tertiary C9- and C10-
stereocenters. These products subsequently undergo base-
promoted diastereoselective aldol cascade reactions resulting
in the natural or unnatural steroid skeletons. The mechanistic
studies suggest that the stereodivergence in the cyclization
step arises from the torsional effects that favor a thermody-
namically more stable natural configuration-containing ring
system 9b at the elevated temperatures. The described method
enables expedient generation of polycyclic molecules includ-
ing modified steroidal scaffolds and challenging-to-synthesize
substituted Hajos-Parrish and Wieland-Mischer ketones. It is
also noteworthy that the developed in these studies Cu(II)-
catalyzed Michael reaction represents one of the most power-
ful transformations of this type displaying great tolerance to
steric bulk of both nucleophiles and electrophiles. Thus, the
described herein work suggests that this method is among the
best asymmetric methods for the formation of the Michael
adducts containing vicinal quaternary and tertiary stereocen-
ters. In addition, the application of this new protocol allowed
the unprecedented under normal conditions preparation of
Michael adducts 7j and 7k containing vicinal quaternary ste-
reocenters. The further application of this method to the syn-
thesis of natural and unnatural steroids and diterpenes is the
subject of ongoing studies in our laboratory.
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Supporting Information Available.
Experimental procedures, 1H and 13C NMR spectra, and X-ray
data are available free of charge via the Internet at
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Corresponding Author
* nagorny@umich.edu
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Funding Sources and Acknowledgement
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17) Reviews: (a) Desimoni, G.; Faita, G.; Jorgensen, K. A.
Chem. Rev. 2011, 111, PR284; (b) Alexakis, A.; Backvall, J.
E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008,
108, 2796; (c) Desimoni, G.; Faita, G.; Jorgensen, K. A.
Chem. Rev. 2006, 106, 3561; (d) Comelles, J.; Moreno-
Manas, M.; Vallribera, A. ARKIVOC 2005, 207.
18) Cu(II)•Box complex-catalyzed enantioselective Mukaiyama
Michael reactions: (a) Evans, D. A.; Rovis, T.; Johnson, J.
S.; Pure Appl. Chem. 1999, 71, 1407; (b) Evans, D. A.;
Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem.
Soc. 1999, 121, 1994; (c) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325; (d) Evans, D. A.; Scheidt, K. A.;
Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123,
4480. Cu(II)•Box complex-catalyzed enantioselective aza-
Michael reactions: (e) Palomo, C.; Oiarbide, M.; Halder, R.;
Kelso, M.; Gomez-Bengoa, E.; Garcia, J. M. J. Am. Chem.
Soc. 2004, 126, 9188; (g) Yamazaki, S.; Yamamoto, M.;
Sumi, A. Tetrahedron 2007, 63, 2320; (h) (i) Nakama, K.;
Seki, S.; Kanemasa, S. Tetrahedron Lett. 2002, 43, 829; (j)
Cornminboeuf, O.; Quranta, L.; Renaud, P.; Liu, M.; Jas-
perse, C. P.; Sibi, M. P. Chem.-Eur. J. 2003, 9, 29; (k) Sibi,
M. P. Liu, M. Org. Lett. 2001, 3, 4181.
19) Prior attempts to accomplish direct Cu(II)•Box complex-
catalyzed enantioselective Michael reactions of 1,3-
dicarbonyls and enones resulting in unselective reactions: (a)
Comelles, J.; Moreno-Manas, M.; Perez, E.; Roglans, A.;
Sebastian, R. M.; Vallribera, A. J. Org. Chem. 2004, 69,
6834; (b) Zhang, M.; Liu, N.; Tang, W. J. Am. Chem. Soc.
2013, 135, 12434.
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O
Me
2+
–
2SbF6
O
1)
EtO2C
O
O
H
CO2Et
N
N
OH
O
H
O
Cu
(10 mol%)
Ph
Ph
Me
OH
O
Me
or
neat, –10 ˚C, 24
Me
O
or 48 h
EtO2C
H
2) Base
(2 steps)
O
OH
O
H
9 examples
89–99% ee
5:1-20:1 dr
1.5 g scale
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