Reactivity of Steroidal 1-Azadienes toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids

Article abstract of DOI:10.1021/acs.orglett.8b01783

The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an initial stereoselec

Full text of DOI:10.1021/acs.orglett.8b01783

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reactivity of Steroidal 1‑Azadienes toward Carbonyl Compounds
under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids
Susana M. M. Lopes,† Clara S. B. Gomes,‡ and Teresa M. V. D. Pinho e Melo*,†
†CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
‡
́
Centro de Química Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
S
* Supporting Information
ABSTRACT: The synthesis and reactivity of a steroidal N-
sulfonyl-1-azadiene, derived from 16-dehydropregnenolone
acetate, toward carbonyl compounds under enamine catalysis
is disclosed. An unexpected annulation reaction was observed
involving an initial stereoselective conjugate addition of the in
situ generated enamine to the steroidal 1-azadiene. The
developed diastereoselective synthetic methodology is a novel
approach to a new class of chiral pentacyclic and hexacyclic
steroids.
1-Azadienes, also called α,β-unsaturated imines, are useful and
versatile building blocks for the synthesis of cyclic and acyclic
nitrogen-containing compounds.1 The introduction of an
electron-withdrawing group on the nitrogen, such as the
sulfonyl group, enhances the electrophilic character of these
conjugated imines. Therefore, N-sulfonyl-1-azadienes partic-
ipate in inverse electron-demand hetero-Diels−Alder reactions
with electron-rich dienophiles,2 and diastereoselective2e and
enantioselective versions2f of this approach to six-membered
heterocycles have been reported. Nevertheless, N-sulfonyl-1-
azadienes react with electron-deficient vinyl ketones via
phosphine-catalyzed asymmetric [4 + 2] annulation.3 N-
Sulfonyl-1-azadienes, having two electrophilic carbons, can
undergo enantioselective conjugate additions4 but can also
participate in 1,2-additions.5 Nickel(II)-catalyzed cascade
conjugate addition of N-sulfonyl-1-azadienes with 2-silyloxyfur-
an leads to 3a,4,7,7a-tetrahydrofuro[3,2-b]pyridin-2(3H)-
ones.6 N-Sulfonyl-1-azadienes undergo other transformations,
namely, phosphine-catalyzed annulations with allenoates7 and
allene ketones8 to afford cyclopentenes and eight-membered
heterocycles, respectively, and enantioselective [6 + 4]
annulation with vinyl oxetanes to give ten-membered hetero-
cycles.9 Interesting reactivity was also observed for 3-styryl-1,2-
benzoisothiazole-1,1-dioxides, which incorporate a N-sulfonyl-
1-azadiene moiety. These conjugated imines have been used to
prepare spirocyclic,10a six-membered carboxyclic, and hetero-
cyclic compounds.10b−d
studies for prostate cancer treatment.12 Recently, we have
described the synthesis and anticancer activity of new chiral
heterocycle-fused steroids, derived from 16-dehydropregneno-
lone acetate (16-DPA) and other steroidal scaffolds, via
unprecedented [8π + 2π] cycloaddition reactions with
diazafulvenium methides.13
The rich reactivity pattern of N-sulfonyl-1-azadienes
combined with our interest in the modulation of steroidal
scaffolds13 led us to explore the reactivity of steroidal 1-azadiene
1, derived from 16-DPA, toward electron-rich dienophiles as an
approach to a new class of pentacyclic and hexacyclic steroids
(Scheme 1).
Scheme 1. Synthetic Strategy: Reactivity of Steroidal 1-
Azadiene 1 toward Electron-Rich Dienophiles
The direct condensation of 16-DPA with p-toluenosulfona-
mide, using different reaction conditions and dehydrating agents
such as molecular sieves, MgSO4, DCC/DMAP,14 Ti(Oi-Pr)4,15
or TiCl4,2f or even carrying out the reaction in refluxing toluene
with a Dean−Stark apparatus did not afford the desired 1-
azadiene. However, the synthesis of steroidal 1-azadiene 1 was
achieved following the general strategy used by Boger et al. for
Steroids are an important class of both naturally occurring and
synthetic compounds with a variety of biological activities.11
Synthetic modification of steroidal scaffolds is a strategy used to
modulate their biological properties. Successful transformations
include the introduction of side chains/heterocycles or
heterocycles fused at positions 16 and/or 17 of the D-ring.
Galeterone, is an example of a C-17 substituted N-heterocycle
steroid that has successfully completed phase III of clinical
Received: June 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01783
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Letter
the synthesis of N-sulfonyl-1-azadienes.2c First, 16-DPA was
converted into the corresponding oxime 2,16 by reaction with
hydroxylamine hydrochloride. Then, oxime 2 underwent a
radical rearrangement17 upon treatment with p-toluenesulfinyl
chloride18 in the presence of triethylamine to give steroidal 1-
azadiene 1 in 42% yield (Scheme 2).
Scheme 2. Synthesis of Steroidal 1-Azadiene 1
Figure 1. ORTEP-3 diagram of compound 4a, using 30% probability
level ellipsoids.
was explored (Table 1). The reaction with cyclohexanone or
cyclopentanone, in the presence of pyrrolidine (20 mol %), in
Table 1. Reaction of Steroidal 1-Azadiene 1 with in situ
Generated Enamines
Initially, we explored the reactivity of conjugated imine 1
toward electron-rich dienophiles expecting to obtain the
corresponding Diels−Alder cycloadducts, the pentacyclic, or
hexacyclic steroids. However, attempts to carry out the reaction
with enol ethers (e.g., ethyl vinyl ether, 2,3-dihydrofuran) only
led to the recovery of the starting steroidal 1-azadiene.
A very interesting and unexpected result was obtained when
we studied the reaction of steroidal 1-azadiene 1 with enamines
(Scheme 3). N-Tosyl-1-azadiene reacted with 1-pyrrolidino-1-
entry
reaction conditions
isolated yield (%)
a
1
2
3
4
reflux, Dean−Stark, 66 h
MW, 140 °C, 10 min
reflux, Dean−Stark, 65 h
MW, 140 °C, 10 min
4a 70
4a 65
4b 71
a
4b 62
a
5 equiv of ketone was used.
Scheme 3. Synthesis of Hexacyclic Steroids 4a−b
toluene under reflux gave steroids 4a or 4b in 70% and 71%
yields, respectively (entries 1 and 3). Compounds 4a and 4b
were obtained in slightly lower yields (65% and 62%,
respectively) in a reaction that was carried out under microwave
irradiation at 140 °C for 10 min (entries 2 and 4). Despite the
decrease in the efficiency, this method allows a significant
decrease in reaction time (from 65−66 h to 10 min) and in the
required amount of cyclohexanone (from 5 to 1.5 equiv).
The optimized reaction conditions were applied to the
synthesis of new chiral hexacyclic steroids 4c−4g, by reacting 1-
azadiene 1 with a selection of cyclic ketones (Scheme 4).
Cycloheptane-fused steroid 4c (50%) and cyclooctane-fused
steroid 4d (28%) could be obtained from the reaction of
conjugated imine 1 with cycloheptanone or cyclooctanone,
respectively, and in the presence of pyrrolidine.
The synthesis of hexacyclic steroids was also successful using
dihydro-2H-pyran-4(3H)-one, dihydro-2H-thiopyran-4(3H)-
one, and 1-methylpiperidin-4-one as the cyclic ketone, giving
the target compounds 4e−4g in 44%, 67%, and 60% yields,
respectively.
The reported results show that conjugated imine 1 does not
react with enamines via an aza-Diels−Alder cycloaddition.
Nevertheless, steroids 4 could result from a Diels−Alder
reaction of the enamines with diene 5 formed via imine−
enamine tautomerism (Scheme 5). However, this is very
unlikely since the cycloaddition of diene 5 with electron-rich
dienophiles would be very unfavorable. Furthermore, the
microwave irradiation of a solution of 1-azadiene 1 in toluene,
at 140 °C for 10 min, only led to the recovery of the reactant.
cyclohexene (3a), in dichloromethane under microwave
irradiation at 50 °C for 10 min, giving chiral hexacyclic steroid
4a in 67% yield as the only product (Scheme 3). The reaction of
1-pyrrolidino-1-cyclopentene (3b) also gave hexacyclic steroid
4b selectively, in moderate yield. These new chiral compounds,
with three new chiral centers, also incorporate a N-tosyl-1-
azadiene moiety.
The molecular structure of compound 4a was unambiguously
established by X-ray crystallography (Figure 1). This derivative
was crystallized as colorless needles in the orthorhombic system
within a P212121 space group, showing one molecule per
asymmetric unit. Its molecular structure consists of a hexacyclic
steroid bearing two methyls, an acetate, and a tosylimino
substituent at positions C18, C19, C3, and C20, respectively.
The newly formed chiral centers at positions C16, C17, and C27
display S configuration. All distances and angles are within the
expected values for similar compounds.19
The reaction of 1-azadiene 1 with carbonyl compounds under
enamine catalysis would make this synthetic methodology much
more versatile. In this context, the reaction of steroidal 1-
azadiene 1 with enamines generated in situ from the
corresponding ketones, using catalytic amounts of pyrrolidine,
B
DOI: 10.1021/acs.orglett.8b01783
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Organic Letters
Letter
enamine isomerization, followed by cyclization and subsequent
elimination of pyrrolidine, leading to the target compound. This
transformation can be considered a Robinson-type annulation
reaction.20
Scheme 4. Synthesis of Chiral Hexacyclic Steroids
This proposal is also consistent with the result observed in the
reaction of 1-azadiene 1 with acyclic ketone acetyl-1,2,3- triazole
6, which was prepared following a previously reported
procedure.21 The pyrrolidine catalyzed reaction gave steroids
7a and their isomeric derivative 7b in 56% overall yield (Scheme
7).
Scheme 7. Synthesis of Pentacyclic Steroids 7
The structure of 7b was established based on bidimensional
NMR spectroscopy (see Supporting Information (SI)). The 13C
NMR spectrum of compound 7a shows the presence of an imine
carbon (C-20) at 178.8 ppm, while in the 13C NMR of
compound 7b, carbon C-20 is observed at 145.3 ppm. On the
other hand, the NOESY spectrum of compound 7b cross-peaks
were observed between proton H-21 (6.56 ppm) and proton H-
25 (7.97 ppm) as well as with NH proton (H-32, 5.88 ppm).
Furthermore, the HMBC spectrum shows a correlation between
carbon C-20 with protons H-21 and H-32.
a
Reaction time: 15 min.
Scheme 5. Imine−Enamine Tautomerism
Interestingly, the microwave irradiation at 140 °C for 10 min
of a solution of 1-azadiene 1 in toluene in the presence of
pyrrolidine (20 mol %) afforded steroid 8 in 52% yield. The 1H
and 13C NMR spectra allowed us to conclude that compound 8
Thus, the synthesis of hexacyclic steroids 4 can be rationalized
considering an initial stereoselective conjugate addition of the in
situ generated enamines to 1-azadiene 1 (Scheme 6). The
intermediate, generated in this way, undergoes an imine−
1
incorporates two steroidal moieties (see SI). The H NMR
spectrum shows signals corresponding to four methyl groups
(H-18, H-19, H-18′, and H-19′), two acetyl groups, and two
vinylic protons H-6 and H-6′. The molecule has only one N-
tosyl-1-azadiene group since signals corresponding to two
vinylic protons H-21 (7.35 ppm) and H-16′ (6.27 ppm) are
observed, but only one tosyl group is present. Additionally, the
13C NMR spectrum shows only one imine carbon (C-20), but
carbons corresponding to two acetyl groups are observed.
The formation of compound 8 can be explained by the general
mechanism presented in Scheme 8. In this case, enamine 5
generated in situ from steroidal 1-azadiene 1 via imine−enamine
tautomerism (see Scheme 5) acts as the nucleophile in the initial
conjugate addition with another molecule of steroidal 1-
azadiene 1. The imine−enamine tautomerism requires the
presence of pyrrolidine since heating a solution of 1-azadiene 1
in toluene in the absence of pyrrolidine only led to the recovery
of the starting compound.
Scheme 6. Mechanistic Proposal for the Synthesis of
Hexacyclic Steroids, Illustrated for the Reaction of Steroid 1
with Cyclohexanone
In summary, we have developed a pyrrolidine catalyzed
diastereoselective reaction of a steroidal N-sulfonyl-1-azadiene
with carbonyl compounds leading to novel chiral steroids. The
use of cyclic ketones allows the synthesis of hexacyclic steroids,
whereas with acyclic ketones, pentacyclic steroids are obtained.
The reported annulation reaction provides a simple, versatile,
C
DOI: 10.1021/acs.orglett.8b01783
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01783.
■
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Experimental details and NMR spectra for all new
compounds (PDF)
Accession Codes
CCDC 1847972 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tmelo@ci.uc.pt.
ORCID
(11) (a) Ibrahim-Ouali, M. Steroids 2008, 73, 775−797. (b) Ifere, G.
O.; Barr, E.; Equan, A.; Gordon, K.; Singh, U. P.; Chaudhary, J.;
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A. R.; Carvalho, J. F. S.; Neves, M. A. C.; Silvestre, S. M.; Leitao, A. J.;
Susana M. M. Lopes: 0000-0002-1580-5667
Teresa M. V. D. Pinho e Melo: 0000-0003-3256-4954
Notes
The authors declare no competing financial interest.
́
Silva, M. M. C.; Sa e Melo, M. L. Nat. Prod. Rep. 2013, 30, 324−374.
(f) Hanson, J. R. Nat. Prod. Rep. 2010, 27, 887−899. (g) Shagufta;
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M. S.; Vasaitis, T. S.; Kwegyir-Afful, A. K.; Ramalingam, S.; Ates-Alagoz,
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(13) (a) Lopes, S. M. M.; Correia, C. F. O.; Nunes, S. C. C.; Pereira, N.
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ACKNOWLEDGMENTS
Coimbra Chemistry Centre (CQC) and Centro de Quimica
■
́
Estrutural are supported by FCT and are cofunded by FEDER
and COMPETE 2020 through projects POCI-01-0145-
FEDER-007630 and UID/QUI/00100/2013. C.S.B.G. and
S.M.M.L. would like to thank FCT for the fellowships SFRH/
BPD/107834/2015 and SFRH/BPD/84423/2012, respec-
tively. We also acknowledge the UC-NMR facility for obtaining
the NMR data (www.nmrccc.uc.pt) and Vanessa Martins for her
contribution during her BSc project carried out at the
Department of Chemistry, University of Coimbra.
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