One-pot organocatalytic enantioselective Michael-Michael-aldol-Henry reaction cascade. A facile entry to the steroid system with six contiguous stereogenic centers

Article abstract of DOI:10.1021/ol501011t

An expedited method has been developed for the enantioselective synthesis of highly functionalized steroid systems containing six contiguous stereogenic centers with high enantioselectivities (99% ee). The one-pot methodology comprises a cascade of organocatalytic Michael-Michael-aldol-Henry reactions of 7-nitrohept-3-en-2-one and 5-(1-methyl-2,5-dioxocyclopentyl)pent-2-enal. The structure and absolute configuration of the products were confirmed by X-ray analyses of appropriate products.

Full text of DOI:10.1021/ol501011t

Letter
pubs.acs.org/OrgLett
One-Pot Organocatalytic Enantioselective Michael−Michael−Aldol−
Henry Reaction Cascade. A Facile Entry to the Steroid System with
Six Contiguous Stereogenic Centers
Dai-Huei Jhuo,† Bor-Cherng Hong,*,† Chun-Wei Chang,† and Gene-Hsiang Lee‡
†Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621, Taiwan R.O.C
‡Instrumentation Center, National Taiwan University, Taipei, 106, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: An expedited method has been developed for the enantioselective synthesis of highly functionalized steroid
systems containing six contiguous stereogenic centers with high enantioselectivities (99% ee). The one-pot methodology
comprises a cascade of organocatalytic Michael−Michael−aldol−Henry reactions of 7-nitrohept-3-en-2-one and 5-(1-methyl-2,5-
dioxocyclopentyl)pent-2-enal. The structure and absolute configuration of the products were confirmed by X-ray analyses of
appropriate products.
teroids have long played a pivotal role in medicinal
chemistry due to their definitive polycyclic structures and
various biological activities (Figure 1). The interest in the wide
extensive applications of the Hajos−Wiechert−Parrish ketone
and Wieland−Miescher ketone11 in traditional steroid
syntheses, the demonstration of a modern asymmetric
organocatalytic cascade for the synthesis of the steroid
framework has garnered little attention and examples remain
rare.12
S
Prompted by the aforementioned background and in an
effort to extend our studies on organocatalyzed annulations,13,14
we envisioned that a cascade of organocatalytic reactions15
might provide a useful protocol for the formation of a highly
functionalized steroid system containing multiple contiguous
stereogenic centers (Scheme 1). Retrosynthetic disconnection
of estrene-3-one or tetradecahydrophenanthren-3-ene-2-one via
aldol and Michael transforms led to the 13-oxotetradeca-2,11-
Figure 1. Selected examples of natural and biologically active steroids.
Scheme 1. Retrosynthetic Analysis
ranging investigations of steroids and their preparation in the
mid-20th century continues to the present day. The synthesis of
these polycyclic compounds still attracts the attention of
chemists1 and pharmacologists,2 with particular focus on the
processes that control steroid synthesis. These intriguing
synthetic methodologies for constructing the steroidal skeleton
include transition-metal-catalyzed reactions,3 polyolefin carbo-
cyclizations,4 Diels−Alder reactions,5 and enantioselective
approaches.6
Asymmetric organocatalysis has undergone a resurgence of
interest,7 especially as inspired by the pioneering Hajos−
Parrish−Eder−Sauer−Wiechert reaction8 and the Wieland−
Miescher ketone synthesis.9 After decades of dormancy,10
asymmetric organocatalyzed reactions have become a burgeon-
ing topic in contemporary synthetic chemistry. Despite the
Received: April 7, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
dienal derivative (Scheme 1). Subsequently, aldol trans-
formation disconnection of the derivative, with an aldehyde
serving as the electron-withdrawing group, and the trans-
formation of the functional group by protection of the aldehyde
would provide 7-[(trimethylsilyl)oxy]hepta-2,6-dienal and 8-
[(trimethylsilyl)oxy]octa-3,7-dien-2-one. Alternatively, Henry
transform disconnection of the intermediate, with the nitro
group as the electron-withdrawing group, may give rise to the
7-nitrohept-3-en-2-one and 5-(2-oxocyclopentyl)pent-2-enal.
At the outset of the study, as shown in Scheme 1, reaction of
7-[(trimethylsilyl)oxy]hepta-2,6-dienal (1) and 7-oxooct-5-enal
with the Jørgensen−Hayashi catalyst (I)16 and acetic acid under
various reaction conditions gave a complicated mixture of
products, arising from the self-condensation of dienal (1).17
When we focused our attention on the nitro derivatives
(Scheme 2), the results were more promising. Reaction of enal
Figure 2. Stereoplots of the X-ray crystal structures of (+)-9, (+)-16,
and (+)-17: C, gray; O, red; Br, purple.
Table 1. Screening of the Catalysts, Solvents, and Conditions
a
for the Double Michael Reactions
Scheme 2. Reactions toward Tetradecahydrophenanthren-3-
ene-2-one System
b
c
time
(h)
yield
dr
entry
cat.−additive
I−PhCO2H
solvent
(%)
(syn/anti)
d
1
2
CHCl3
CDCl3
CHCl3
CHCl3
CHCl3
3
0
na
d
I
48
30
24
18
0
na
e
f
3
I−DBU
I−DIPEA
14
nd
4
5
53
48
54:46
55:45
I−DIPEA−
PhCO2H
6
I−DIPEA
I−DIPEA
I−DIPEA
I−DIPEA
I−DIPEA
I−DIPEA
I−DIPEA
I−DIPEA
I−Et3N
Toluene
EtOH
108
23
17
28
96
96
56
48
48
44
35
21
33
nr
50:50
47:53
47:53
48:52
na
7
8
CH3CN
CH2Cl2
THF
9
10
11
DMF
13
63
69
56
16:84
56:44
52:48
55:45
e
12
CHCl3
CHCl3
CHCl3
eg
,
13
14
118 and nitroenone 219 with 20 mol % of the Jørgensen−
e
Hayashi catalyst (I), benzoic acid (10 mol %), and Hunig base
̈
a
Unless otherwise noted, the reactions were performed with 0.2 M of
(DIPEA, 30 mol %) in CHCl3 at ambient temperature for 48 h
afforded an inseparable diastereoisomeric mixture of the
ketoaldehyde 3 in 75% yield in a ca. 3:2 ratio.20 Treatment
of the ketoaldehyde 3 with pyridinium p-toluenesulfonate
(PPTS) and L-Pro in CH3CN at 40 °C for 5 h led to the
deprotection of enolsilyl ether, followed by a subsequent aldol
condensation to give an 86% yield of decalines 4 and 5, after
two reaction steps. Alternatively, exposure of 3 to L-Pro in
DMSO at ambient temperature for 24 h gave a 57% yield of an
inseparable diastereoisomeric mixture of nitroenone 6, after a
two-step reaction starting from enal 1 and nitroenone 2.
Deprotection of the enolsilyl ether group of 6 (TsOH, CH3CN,
rt, 30 min) provide a 47% yield of nitroaldehyde 7 and a 29%
yield of 8. Henry reaction of 7 was conducted with Amberlyst-
A21 in THF at rt for 38 h to give a diastereomeric mixture of 9
and 10 (45% and 23% yield, with 94 and 93% ee, respectively).
The structure of (+)-9 was ascertained by single-crystal X-ray
analysis (Figure 2). Surprisingly, attempted Henry reactions of
8 under the same conditions did not proceed but resulted in
the recovery of 8 after a few days of reaction.
2 and with 1.5 equiv of 11 at 28 °C, using 20 mol % of the catalyst and
b
additive at 28 °C in a vial containing the appropriate solvent. Isolated
c
1
yields of 12. Determined by H NMR of the crude reaction mixture.
d
e
Decomposition of 11 with no products observed. Reaction at 10 °C.
f
g
Along with a 37% yield of 13. Reactions were performed on a scale of
0.2 M of 2 and with 2.2 equiv of 11. nd = not determined. na = not
available. nr = no reaction.
catalyst I−PhCO2H (20 mol %) in CHCl3 at rt for 3 h afforded
the self-dimerization and decomposition of 1117 and provided
no observed product 12 (Table 1, entry 1). A similar
observation was obtained for the reaction in the absence of
the benzoic acid additive (Table 1, entry 2). To minimize the
self-dimerization of 11 and to increase the nucleophilicity of
nitroalkane 2, several organic bases were screened. As shown in
Table 1, entry 3, the reaction with I−DBU (20 mol %) in
CHCl3 at 10 °C for 30 h afforded 14% of the product 12,
however, along with a 37% yield of a side product 13 arising
from the intramolecular Michael reaction of 11. The yield of
adduct 12 was increased to 53% by substituting DIPEA, a less
basic base, for DBU (Table 1, entry 4). However, addition of
the combinatorial additive DIPEA−PhCO2H in the reaction
mixture did not help in increasing the yield (Table 1, entry 5).
We conducted further attempts to optimize the double-Michael
reaction with I−DIPEA in various solvents, but the results were
fruitless (Table 1, entries 6−11). To our delight, lowering the
After the success of the approach to tetradecahydrophen-
anthren-3-ene-2-one system, 1121 was selected for the reaction
with nitroenone 2. The double Michael reaction of 2 and 11
was screened with a variety of organocatalysts to obtain the
cyclohexane adducts 12 (Table 1). The optimization conditions
are briefly summarized in Table 1. Reaction of 2 and 11 with
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Letter
reaction temperature to 10 °C diminished the decomposition
of 11 and resulted in increasing the yield to 63% after 56 h of
reaction (Table 1, entry 12). Nevertheless, a further decrease in
the reaction temperature to 0 °C did not improve the yield but
required a longer time (72 h) to complete the reaction. With
2.2 equiv of 11, the reaction could be completed in 48 h,
providing 69% of the product (Table 1, entry 13). Replacement
of DIPEA by Et3N in the reaction did not improve the yield
(Table 1, entry 14). Finally, screening of the other catalysts (II
to VII) with DIPEA in the reaction gave no reaction or
provided only trace amounts of products.
Et3N, rt, 1.5 h; 76%). The structure and absolute configuration
of the product (+)-17 were assigned unambiguously by the
single-crystal X-ray analysis (Figure 2).
To account for the stereoselectivity of the transformation, we
propose a plausible mechanism (Scheme 4). Initially, iminium
Scheme 4. Proposed Mechanism for the One-Pot
Transformation
With the best reaction conditions in hand (Table 1, entry
13), an efficient one-pot operation of the double Michael−aldol
reaction was attempted, and the results were promising with a
higher overall isolated yield than the stepwise operation.
Reaction of 11 and 2 with I−DIPEA (20 mol %) at 10 °C in
CHCl3 for 48 h, followed by the addition of p-TsOH (1.8
equiv), and stirring for an additional 24 h at rt provided 75%
yields of a 56:44 ratio of nitro ketones 14 and 15, with 98% and
99% ee, respectively (Scheme 3). A Henry reaction of the
formation of the enamine from 11 occurs, followed by the
nucleophilic attack of nitroenone 2 (from either the Si- or Re
face of the nitroalkane) on the iminium activated aldehyde 11
via the Re face under the control of the catalyst (TS A or TS
B), giving the intermediate, which spontaneously undergoes an
additional Michael reaction to afford 12. A subsequent aldol
reaction of the adducts with p-TsOH would give the trans-
decalines 14 and 15. The mechanism of the Henry reaction of
the trans-decaline diones 14 and 15 with TBAF leading to
steroid 16 is elucidated in Scheme 3 (vide supra).
Scheme 3. Reactions toward Steroid System
Recently, self-disproportionation of enantiomers (SDE)23
has attracted much attention, as it demonstrates that the optical
purification of enantiomerically enriched compounds can be
achieved via achiral chromatography. Particularly, this subject
may be related to prebiotic chemistry, providing a possible
answer to a great mystery that has long puzzled scientists: what
is the origin of the chirality of the molecules of living systems?24
It is worth noting that the compounds at hand, e.g., 16, were
purified by an achiral silica-gel column with collection of all
fractions containing the designated product together for the
analyses, but not a single fraction from the separation.
Therefore, the ee analysis of each compound reflects the ee of
the sum of the designated product obtained. However, the
literature suggests that compounds capable of forming H-
bonding would be particularly prone to exhibit a significant
magnitude of SDE. We questioned if 16 possesses a substantial
SDE effect. In this context, an SDE test was performed on an
enantiomerically enriched 50% ee sample of 16, prepared by
mixing an adequate portion of (+)- and (−)-16,25 and a
significant magnitude (Δee ≈ 24.6%)26 was observed in the
seven fractions collected from the achiral silica-gel chromatog-
raphy. Logically, the intermolecular H-bonding interaction of
16 may play a key role in the SDE effect.
In summary, we have described a concise synthesis of
optically enriched steroids, with the multifunctionalized
tetracycles containing six stereogenic centers with a quaternary
carbon stereocenter with high enantioselectivities (99% ee) by
sequential organocatalytic double Michael/aldol/Henry reac-
tions. Particularly noteworthy is the one-pot operation of the
reactions at the key steps in the synthesis of estr-1-ene-3,17-
dione derivatives. The structures and the absolute configuration
of the products were unambiguously confirmed by single-crystal
X-ray crystallographic analyses of the appropriate adducts.
diastereomeric mixture 14 and 15 was achieved by treatment
with TBAF (0.5 equiv) in THF at −10 °C for 90 min to give 16
in 63% yield with 99% ee. It should be noted that the Henry
reaction of 14 was feasible with DBU (1.5 equiv) at rt to afford
16 in 89% yield, but required a much longer reaction time (24
h) than the reaction with TBAF.22 However, exposure of 15
with DBU (1.5 equiv) at rt gave no reaction after 4 days. The
result may be due to the fact that the large steric bulk of isomer
15 may encumber the Henry reaction (Scheme 3), as an
isomerization of 15 to 14 was observed upon addition of TBAF
to the reaction mixture, followed by the subsequent reaction to
give 16. Moreover, DBU was unable to trigger the isomer-
ization of 15 owing to the steric bulk of the substrate. The
structure of (+)-16 was confirmed by X-ray analysis (Figure 2).
Later, the three-step reaction was completed in a one-pot
process. Addition of the THF into the freshly prepared reaction
mixture of 14 and 15 in CHCl3, followed by the addition of
TBAF (4 equiv) with stirring at rt for 20 h, gave a 25% yield of
16, starting from 11 and 2. Subsequently, we observed that the
Henry reaction of 15 with TBAF in CHCl3 required a longer
reaction time than in THF. Consequently, evaporation of
CHCl3 in the freshly prepared reaction mixture of 14 and 15,
followed by the addition of THF, DBU (3.6 equiv, stirred at rt
for 2 h), and TBAF (3.6 equiv, stirred at 0 °C for 20 h)
afforded a 47% yield of 16, starting from 11 and 2. A bromo
steroid derivative 17 was prepared via a sequence of
bromination and elimination of 16 (Br2, CH2Cl2, 0 °C, 0.5 h;
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Letter
(13) For a recent review in organocatalyzed cycloadditions, see:
Hong, B.-C. In Enantioselective Organocatalyzed Reactions II; Mahrwald,
R., Ed.; Springer: Dordrecht, 2011; Chapter 3, pp 187−224.
(14) (a) Hong, B.-C.; Lin, C.-W.; Liao, W.-K.; Lee, G.-H. Org. Lett.
2013, 15, 6258. (b) Dange, N. S.; Hong, B.-C.; Lee, C.-C.; Lee, G.-H.
Org. Lett. 2013, 15, 3914. (c) Hong, B.-C.; Liao, W.-K.; Dange, N. S.;
Liao, J.-H. Org. Lett. 2013, 15, 468 and references cited therein.
(15) Hong, B.-C.; Dange, N. S. Cascade Reactions in Stereoselective
Synthesis. In Stereoselective Synthesis of Drugs and Natural Products;
Andrushko, V., Andrushko, N., Eds.; Wiley-Blackwell: Hoboken, NJ,
2013; Chapter 21, p 581.
Further applications of this protocol in the synthesis of
elaborated steroid derivatives are currently underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for the new
compounds and X-ray crystallographic data for compound
(+)-9, (+)-16, and (+)-17. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) For recent reviews, see: Ensen, K. L.; Dickmeiss, G.; Jiang, H.;
Albrecht, Ł.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
(17) For the self-[3 + 3] and [4 + 2] reaction of aliphatic enal, see:
(a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006,
8, 2217. (b) Hong, B.-C.; Tseng, H.-C.; Chen, S. H. Tetrahedron 2007,
63, 2840.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chebch@ccu.edu.tw.
Notes
(18) For preparation, see Supporting Information.
(19) For preparation, see: Cornique, X. G.; Marsh, G. P.; Parsons, P.
J.; McCarthy, C. Org. Lett. 2007, 9, 2613.
The authors declare no competing financial interest.
(20) Ketoaldehyde 3, somewhat sensitive to the silica-gel
chromatography, decomposed to a certain extent during the
purification. For synthetic operation, these adducts were subjected
to the next reaction step without further purification.
(21) Prepared from the literature procedures: (a) Koech, P. K.;
Krische, M. J. Org. Lett. 2004, 6, 691. (b) Lavallee, J.-F.;
Deslongchamps, P. Tetrahedron Lett. 1988, 29, 6033.
(22) For a related Henry reaction: (a) Bernard, B.; Boivin, J.; Kaim,
L. E.; Elton-Farr, S.; Zard, S. Z. Tetrahedron 1995, 51, 1675.
(b) Barlaam, B.; Boivin, J.; Kaim, L. E.; Zard, S. Z. Tetrahedron Lett.
1991, 32, 623.
ACKNOWLEDGMENTS
■
We acknowledge the financial support for this study from the
Ministry of Science and Technology (MOST, Taiwan) and
thank the instrument center (MOST) for analyses of
compounds. Thanks to Mr. Wei-Lun Huang (NCCU) and
Dr. Nitin S. Dange (NCCU) for their assistance. We also thank
Professor Vadim A. Soloshonok (University of the Basque
Country) for the valuable suggestions.
(23) (a) Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766.
(b) Soloshonok, V. A.; Roussel, C.; Kitagawa, O.; Sorochinsky, A. E.
Chem. Soc. Rev. 2012, 41, 4180. (c) Han, J.; Nelson, D. J.; Sorochinsky,
A. E.; Soloshonok, V. A. Curr. Org. Synth. 2011, 8, 310. (d) Solo-
shonok, V. A.; Ueki, H.; Yasumoto, M.; Mekala, S.; Hirschi, J. S.;
Singleton, D. A. J. Am. Chem. Soc. 2007, 129, 12112. (e) Sorochinsky,
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(24) Guijarro, A.; Yus, M. The Origin of Chirality in the Molecules of
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(25) (+)-16 and (−)-16 were prepared from the catalyst (S)-I and
(R)-I, respectively.
(26) The result produced enantiomerically enriched (62.1% ee) first
and enantiomerically depleted (37.5% ee) last fractions.
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