Catalytic asymmetric torgov cyclization: A concise total synthesis of (+)-estrone

Article abstract of DOI:10.1002/anie.201404909

An asymmetric Torgov cyclization, catalyzed by a novel, highly Bronsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. This method was applied in a very short synthesis of (+)-estrone.

Full text of DOI:10.1002/anie.201404909

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Angewandte
Communications
DOI: 10.1002/anie.201404909
Organocatalyis
Catalytic Asymmetric Torgov Cyclization: AConcise Total Synthesis of
(+)-Estrone**
Sꢀbastien Prꢀvost, Nathalie Duprꢀ, Markus Leutzsch, Qinggang Wang, Vijay Wakchaure, and
Benjamin List*
Dedicated to the MPI fꢁr Kohlenforschung on the occasion of its centenary
Abstract: An asymmetric Torgov cyclization, catalyzed by
a novel, highly Brønsted acidic dinitro-substituted disulfon-
imide, is described. The reaction delivers the Torgov diene and
various analogues with excellent yields and enantioselectivity.
This method was applied in a very short synthesis of
(+)-estrone.
S
teroids have versatile and often powerful biological
C and C’; and 4) their isomerization and dehydration to give
dienone 2a (< Table 1). We hypothesized that the stereo-
determining step, possibly the cyclization of intermediate A
to cation B, could be catalyzed enantioselectively with
recently developed enantiopure Brønsted acid catalysts
through ketone activation.[7,8]
activities, as well as an elegant tetracyclic molecular archi-
tecture.[1] Their synthesis has captured the imagination of
chemists from the late 1930s until today, and has proven to be
a treasure trove of new synthetic methods, including the
Robinson annulation, proline-catalyzed intramolecular asym-
À
metric aldolizations, C H activations, cycloadditions, bio-
Indeed, when investigating the cyclization reaction of
diketone 1a in the presence of various enantiopure Brønsted
acid catalysts, we found that commercially available TRIP (3)
promoted the reaction to give diene 2a at 508C efficiently but
with a low enantiomeric ratio (e.r.; Table 1, entry 1).[9]
Remarkably, the more acidic chiral DSIs (4a–c) catalyzed
the transformation more rapidly and afforded diene 2a at
lower temperature and with higher enantioselectivity. Pre-
viously, our chiral DSI catalysts have mainly been applied as
precatalysts in silicon-based Lewis acid catalysis,[10] but
potential in asymmetric Brønsted acid catalysis has also
been reported.[11] DSI 4a, which bears electron-deficient aryl
substituents, delivered the Torgov diene at 08C with a prom-
ising 84:16 e.r. (Table 1, entry 2). An improvement of the
enantioselectivity was observed when novel DSI 4c, which
bears 3,5-(SF5)2-C6H3 substituents, was employed as the
catalyst (Table 1, entry 4). The pentafluorothio moiety has
previously been used as a bulkier and more electron-with-
drawing alternative to the common trifluoromethyl group in
medicinal chemistry and more recently also in organocatal-
ysis.[12] After an extensive screening of the reaction conditions
with this catalyst (see the Supporting Information), Torgov
diene 2a was obtained with 95:5 e.r. (Table 1, entries 5 and 6).
However, the reaction time was still rather long. To address
this issue, we designed the novel DSI catalyst 5, which bears
nitro groups in the 5 and 5’ positions to enhance its acidity
without affecting the steric environment of its active site.[13]
Indeed, DSI 5 proved to be a highly active catalyst although
under the same reaction conditions, product 2a was initially
obtained with lower enantioselectivity (Table 1, entry 7).
mimetic polyene cyclizations, and transition metal catalyzed
reactions.[2] The female sex hormone estrone is a prime
synthetic target and several total syntheses have been
described.[3] In 1963, Torgov et al. described a particularly
efficient synthesis based on the acid-catalyzed conversion of
diketone 1a into diene 2a, which is readily transformed into
racemic estrone.[4] However, while researchers from Schering
reported studies towards the development of a catalytic
asymmetric version of this reaction, which bears some
potential for the production of enantiopure steroid pharma-
ceuticals, high selectivity and turnover numbers have not been
achieved.[5,6] Herein, we report a highly enantioselective
Torgov cyclization, which is catalyzed by a novel chiral
disulfonimide (DSI), and its application in the shortest total
synthesis of (+)-estrone to date [Eq. (1)].
The Torgov reaction presumably involves four acid-
catalyzed steps: 1) the isomerization of olefin 1a to endocy-
clic compound A; 2) an intramolecular Prins reaction to give
stabilized carbocation B; 3) its deprotonation to give alcohols
[*] Dr. S. Prꢀvost, Dr. N. Duprꢀ, M. Leutzsch, Dr. Q. Wang,
Dr. V. Wakchaure, Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470, Mꢁlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[**] We gratefully acknowledge financial support from the Max-Planck-
Society and the European Research Council (Advanced grant “High
Performance Lewis Acid Organocatalysis, HIPOCAT”). We thank
Daniela Kampen for early contributions as well as Marianne
Hannappel, Simone Marcus, Hendrik van Thienen, and Natascha
Wippich; and the members of our NMR, HPLC, and MS depart-
ments.
Nonetheless, the higher acidity of catalyst
5 enabled
a smooth cyclization even at À408C to afford product 2a
with 97.2:2.8 e.r. (Table 1, entry 8). Under these conditions,
a significant amount of intermediate C remained uncon-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404909.
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Chemie
Table 1: Catalytic asymmetric Torgov cyclization.[a]
Entry
Cat. [mol%]
T [8C]
t [d]
2a:C[b]
e.r.[c]
1
2
3
4
3 (20)
4a (20)
4b (20)
4c (20)
4c (20)
4c (10)
5 (10)
5 (5)
50
0
0
0
0
0
0
1
3
2
3
3
4
1
5
100:0
100:0
95:5
100:0
100:0
95:5
100:0
80:20
93:7
53.5:46.5
84:16
72.5:27.5
91:9
95:5
95.2:4.8
89:11
Scheme 1. Other products of the asymmetric Torgov cyclization.
[a] Reactions run on a 0.1 mmol scale. [b] Enantiomeric ratios were
determined by HPLC analysis on a chiral stationary phase. [c] The
reaction was performed at 0.1m.
5[d]
6[d]
7[d]
8[d]
9[d,e]
À40
97.2:2.8
97:3
5 (5)
À40, À5
1, 2
cyclic compound 2e was obtained with good selectivity, as was
the five-membered B ring product 2 f, which was synthesized
with excellent yield and enantioselectivity. This approach was
also suitable for the highly enantioselective synthesis of
tricyclic diene 2g, in which the B ring is absent, although
a higher reaction temperature was required in this case.
However, the more substituted diene 2h gave only moderate
results (24% yield, 72:28 e.r.). Interestingly, the six-mem-
bered D-ring analogue 1i was also converted, albeit with
lower enantioselectivity (75% yield, 62.5:37.5 e.r.).
To obtain a detailed insight into the mechanism of our
Brønsted acid catalyzed asymmetric Torgov cyclization, we
conducted an in situ NMR study. These experiments (includ-
ing a racemization study and a kinetic analysis) suggest that
the isomerization of intermediate C to Cꢀ by protonation and
deprotonation is rate determining. We also found that at
elevated temperatures, the intermediate steps prior to the
final dehydration are reversible, thus rendering the second
temperature utilized for the conversion of C to Cꢀ relevant for
the stereochemical outcome.[15]
[a] Reactions were run on 0.02 mmol scale. [b] Determined by 1H NMR
analysis of the crude reaction mixture after full conversion of 1a.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] Reac-
tions run with 4 ꢂ MS at 0.028m. [e] Reaction run at À408C for 1 day and
then at À58C for 2 days.
verted. Therefore, the optimal procedure involved raising the
temperature to À58C after full conversion of the starting
material (1 day at À408C).[14] This method furnished the
Torgov diene with a good 2a/C ratio (93:7) and an excellent
97:3 e.r. (Table 1, entry 9).
We also explored other substrates with our newly
developed cyclization method (Scheme 1). Various diketones
(1a–g) were subjected to the cyclization conditions and the
products (2a–g) were isolated with moderate to excellent
yield and enantioselectivity. Torgov diene 2a was obtained in
very good yield and with excellent enantioselectivity (87%
yield, 97:3 e.r.). Interestingly, product 2b, which has an ethyl
instead of a methyl group at the C–D junction and is an
intermediate in the synthesis of desogestrel,[3r] could also be
obtained in good yield but with somewhat lower enantiose-
lectivity (79% yield, 86.5:13.5 e.r.). An additional methoxy
group in the A ring was well tolerated and product 2c was
obtained with excellent enantioselectivity even at lower
temperature. However, the complete removal of the methoxy
group at the A ring provided a much less reactive substrate,
which was converted into the corresponding product 2d only
at room temperature and after 7 days. Modifications to the
B ring are also very well tolerated. For example, the hetero-
To illustrate the practical utility of our method, a gram-
scale Torgov cyclization and the concise synthesis of
(+)-estrone were realized (Scheme 2). Accordingly, diketone
1a (1.8 g, obtained in two steps from commercially available
6-Methoxy-1-tetralone) was subjected to slightly modified
asymmetric Torgov cyclization conditions (see the Supporting
Information) to furnish 1.61 g (95% yield) of the Torgov
diene 2a with an e.r. value of 96.5:3.5.
A single recrystallization provided the product with
essentially perfect enantiopurity (> 99.9:0.1 e.r.). Importantly,
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Keywords: disulfonimides · estrone · organocatalysis ·
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torgov cyclization · total synthesis
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