Organocatalytic asymmetric formation of steroids

Article abstract of DOI:10.1002/anie.201400203

A novel and simple one-step approach for the construction of optically active steroids in a highly stereoselective manner by using organocatalysis is presented. The reaction of (di)enals with cyclic dienophiles in the presence of a TMS-protected prolinol catalyst leads to the construction of important 14 β-steroids. This new reaction allows an easy access to optically active steroids with a variety of substituents in the A ring in high yields and up to greater than 99 % ee. The reaction has been extended to include the construction of B- and D-homosteroids as well as steroids containing heteroatoms in the B ring. The angular substituent at C13 can be varied and alkyl, ester, and sulfone functionalities are introduced with excellent stereoselectivities. Simple synthetic procedures provide access to a range of naturally occurring steroids such as estrone and related analogues. Organocatalysis made it possible: The reported methodology gives 14 β-steroids, displaying a broad generality, in one step, and includes various substituents on the A ring, variations of the B ring, hydroxy or alkyl substituents in the 12-position of the C ring, and different substituents in the angular position at C13. Furthermore, the developed reaction concept includes reactions with quinones to form D-homosteroids in excellent yields and stereoselectivities.

Full text of DOI:10.1002/anie.201400203

Angewandte
Chemie
DOI: 10.1002/anie.201400203
Synthetic Methods
Organocatalytic Asymmetric Formation of Steroids**
Kim Søholm Halskov, Bjarke S. Donslund, Sebastian Barfꢀsser, and Karl Anker Jørgensen*
Dedicated to Professor Carl Djerassi on the occasion of his 90th birthday
Abstract: A novel and simple one-step approach for the
construction of optically active steroids in a highly stereose-
lective manner by using organocatalysis is presented. The
reaction of (di)enals with cyclic dienophiles in the presence of
a TMS-protected prolinol catalyst leads to the construction of
important 14b-steroids. This new reaction allows an easy
access to optically active steroids with a variety of substituents
in the A ring in high yields and up to greater than 99% ee. The
reaction has been extended to include the construction of B-
and d-homosteroids as well as steroids containing heteroatoms
in the B ring. The angular substituent at C13 can be varied and
alkyl, ester, and sulfone functionalities are introduced with
excellent stereoselectivities. Simple synthetic procedures pro-
vide access to a range of naturally occurring steroids such as
estrone and related analogues.
regard to these discoveries are mainly based on semisynthetic
strategies. A purely synthetic pathway to these compounds
would represent a highly interesting alternative to obtain
important related structures.
One synthetic approach towards steroids relies on the
formation of the core structure by a Diels–Alder reaction.[7]
In the 1930s, Dane attempted this strategy, which was based
on a cycloaddition between what became known as Daneꢀs
diene and a dienophile.[8] Later Quinkert et al. showed that
the Diels–Alder reaction could be promoted by the applica-
tion of a Lewis acid catalyst.[9] Recently, enantioselective
versions of this approach, based on the activation of different
dienophiles with chiral catalysts, have been reported (Sche-
me 1a).[10–13]
Organocatalysis has opened a new dimension in asym-
metric catalysis in the last decade.[14] During the gold rush
days a wide range of enamine-[15] and iminium-ion-cata-
lyzed[16] asymmetric transformations were developed. Sub-
sequently, emphasis on expanding organocatalysis with new
Steroids are among the most privileged structures, and the
impact of steroid-based research on modern society can
hardly be overestimated. Being one of the most competitive
research fields in the last century, steroids have a vital role in
the development of organic synthesis, but also in medicine
and biology.[1] A crucial task regarding steroids, as well as
other biologically relevant compounds, is to develop reliable
and general methods for their selective synthesis. This general
method will allow structural diversity which is crucial for
studies of biological activity.[2]
14b-Steroids are an important branch of the steroid family
and possess the less common stereochemical configuration at
C14. They are naturally found in the Cardenolide family, the
members of which are known to possess, for example,
inotropic activity and have found application in the treatment
of cardiac dysfunction,[3a,b] and more recently in cancer.[3c,d]
Furthermore, studies by Ehrenstein and Djerassi have
demonstrated that 19-nor-14b-progesterone exhibits potent
progestinal activity.[4,5] In recent years 14b-steroids have
attracted renewed attention as additional pharmaceutical
properties have been discovered.[6] The synthesis of the
analogues used in the structure–activity reactivity studies with
[*] K. S. Halskov, B. S. Donslund, Dr. S. Barfꢀsser, Prof. K. A. Jørgensen
Center for Catalysis, Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
[**] This work was financially supported by Aarhus University, FNU, and
the Carlsberg Foundation. Dr. Jacob Overgaard and Espen Eikeland
are acknowledged for performing X-ray analysis. Mette S. Haferbier
is acknowledged for assisting in starting material synthesis.
Scheme 1. Previous and current approaches towards the steroid skel-
eton using enantioselective Diels–Alder reactions. EWG=electron-
withdrawing group.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400203.
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activation modes evolved and SOMO activation,[17] dien-
amine,[18] and trienamine[19] catalysis were introduced, as well
as the concept of cascade reactions.[20] A more recent
development is the application of organocatalysis in target-
oriented synthesis. In this context, organocatalysis has been
utilized in the formation of biologically relevant molecules[21]
and in the total synthesis of complex natural products.[22]
Inspired by the application of organocatalysis for the
synthesis of important molecules, we envisioned a simple and
attractive approach for the formation of steroids (Sche-
me 1b). Previous reports, which focus on the activation of the
dienophilic partner of the reaction, are all shown to react with
Daneꢀs diene, which is electron rich because of the conjugated
methoxy substituent in the A ring.[8–13] Our novel approach is
based on the condensation of an aminocatalyst with an enal or
2,4-dienal to form either a dienamine or trienamine, respec-
tively, which consist of a diene moiety attached to an
activating and stereoinducing molecular handle. Because of
the electron donation from the catalyst the reaction can be
performed with a wide range of easily available substrates.
It will be demonstrated that electron-donating and
electron-withdrawing substituents can be present in the
A ring, while the B ring can contain both oxygen and sulfur
heteroatoms and can be of a different ring size. Hydroxy and
alkyl substituents can be incorporated into the C ring, and
furthermore, it will be shown that the size and substituents of
the D ring can be varied. Finally, methyl, ethyl, ester, and
sulfone functionalities are introduced as angular substituents
at C13. The access to these steroids has typically relied on
semisynthetic strategies, as opposed to purely synthetic
strategies, because of the relative complexity of the steroid
motif.[23] An important aspect of the developed reaction
concept is that it provides a simple procedure to the important
class of 14b-steroids. Furthermore, the approach also pro-
vides direct access to 12-hydroxy steroids. These are valuable
precursors for C-nor-d-homosteroids[24] and play a vital role in
the degradation of steroids.[25]
Preliminary experiments and optimization of the reaction
conditions (see the Supporting Information) identified the
diketone 2a, which was employed in the studies by Gçbel
et al.,[13b] as a suitable dienophile for the reaction with an E/Z
mixture of the enal 1 and the TMS-protected prolinol catalyst
3 in MeCN at 08C (Scheme 2).[26] With the optimal reaction
conditions in hand, we went on to investigate the scope of the
reaction. By the employment of the optimized reaction
conditions the 14b-steroids 4 are obtained in one step in
greater than 99% ee. Substrates with the methoxy substituent
in different positions on the A ring provided their respective
products in high yield and perfect stereoselectivity (4a–c).
Steroids carrying electron-neutral (4d,e) and electron-with-
drawing (4 f–h) substituents on the aromatic moiety are also
formed with the same excellent stereoselectivities. It should
be noted that fluoride and bromide can be present in the
A ring, the former is important from a medicinal chemistry
point of view[27] and the latter useful for, for example,
coupling reactions.
Scheme 2. Scope of the synthesis of 14b-steroids using the organo-
catalytic reaction of the enals 1 with diketones 2a,b. Reactions were
performed on a 0.1 mmol scale with 2.0 equiv of 2; see the Supporting
Information for experimental details and assignment of absolute
configuration. [a] The compounds 4a,c,d,l were formed by the employ-
ment of 20 mol% of the catalyst 3 and 20 mol% of PhCO2H. [b] The
yield within parentheses was obtained when the reaction was per-
formed on a 2 mmol scale. TMS=trimethylsilyl.
sulfur atom (4k) in the 6-position. These products were
formed in excellent stereoselectivities. Finally, we investi-
gated the possibility to vary the angular substituent in the C13
position. Since several commercially important steroid-based
compounds, such as desogestrel and levonorgestrel, contain
an ethyl substituent in this position, the organocatalytic
reaction was attempted with the corresponding dienophile 2b.
This resulted in the formation of the product 4l as a single
stereoisomer. Furthermore, it was found that the reaction
could be scaled up, thus maintaining yields and stereoselec-
tivities (4a,f).
Upon evaluation of the scope of the reaction, we decided
to pursue the application of the developed strategy beyond
the 14b-steroid structure to access a wider range of known
steroids and novel steroid analogues. To achieve this, a syn-
thetic procedure, inspired by the previous work of Gçbel
The method also allows for the formation of 14b-steroids
with interesting variations on the B ring. A seven-membered
ring can be incorporated (4i), as well as an oxygen (4j) or
2
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dienophiles other than the diketones 2a,b. Based on the
optimization process (see Table 1 in the Supporting Informa-
tion), we hypothesized that the observed low diastereoselec-
tivity in the reaction with the b-ketoester 2c (Scheme 5), as
opposed to the high diastereoselectivity observed with 2a,
Scheme 5. Organocatalyzed asymmetric Diels–Alder reaction between
the enal 1d and the sulfone dienophile 2d to form 4n. Reaction
performed on a 0.1 mmol scale using 1.2 equiv of 2. See the Support-
ing Information for details.
Scheme 3. Synthesis of Torgov’s diene (8), thus leading to a formal
synthesis of (+)-estrone from 4a. See the Supporting Information for
details. dppf=1,1’-bis(diphenylphosphanyl)ferrocene, HMDS=hexa-
methyldisilazide, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran.
et al.,[13b] was developed to convert the product 4a into
Torgovꢀs diene 8, which is a key intermediate in the synthesis
of naturally occurring steroids such as (+)-estrone. This
synthetic procedure is outlined in Scheme 3. First the enol in
4a is protected with simultaneous elimination of the hydroxy
substituent of the C ring and subsequent reduction to 6. This
sequence is followed by a double-bond transposition to form
7, which is reduced to 8 (Torgovꢀs diene), from which
(+)-estrone can be made.[10,13b,28] The formation of 8 proceeds
without deterioration of the enantiomeric excess.
With a reliable route to 8 in hand, we pursued the
synthesis of analogues of this class of steroids. Following the
same synthetic steps as presented in Scheme 3, compounds
4 f,i,j were converted into their respective Torgovꢀs diene
analogues 9a–c (Scheme 4). Each compound could be
synthesized in four steps in decent overall yields under non-
optimized reaction conditions and without deterioration of
the established enantiomeric excess.
might be explained by the ability of both the ester and ketone
carbonyl functionalities of 2c to separately participate in
interactions with the dienamine, thus promoting both an endo
and exo approach of the dienophile to the dienamine. As
a consequence, a similar substrate to 2c, one carrying
a noncarbonyl electron-withdrawing substituent, which we
expect to interact in the same manner as 2a,b, might be able
to participate in the reaction and form the steroid product
with high diastereoselectivity. The introduction of a sulfone
functionality in the dienophile (2d) provided the intended
product 4n as a single diastereoisomer in 61% yield and
96% ee (Scheme 5). This reaction shows that heteroatom
functionality, in form of a sulfone substituent, can be
introduced in the angular position at C13 of the steroid
skeleton.
We envisioned that the organocatalytic approach to the
stereoselective formation of steroids could be utilized with
alternative dienophiles to achieve further variations of the
D ring. In this regard, quinone-based dienophiles were
identified as suitable reaction partners leading to d-homoste-
roids (Scheme 6). This core structure is found in compounds
of the Withanolide family such as Salpichrolides and Nican-
drenon.[29] 2,6-Dimethylbenzoquinone (10a) was found to
react with the enals 1d,e to form their respective products
11a,b in high yields and excellent stereoselectivities in the
presence of 5 mol% of the catalyst 3.[18e,30] By the employ-
ment of 2,5-dimethylbenzoquinone (10b) and menadione
(10c) excellent results were also achieved (11c,d). However,
slightly higher catalyst and acid loadings were necessary for
the latter. The relative stereochemistry was assigned from an
X-ray structure of 11a (see the Supporting Information).
After the development of reliable methods which enable
variations of the A, B, and D rings of the steroid core, we
focused on the possibility to achieve variations on the C ring.
In this regard we envisioned that changing from a dienamine
catalysis strategy to the recently described trienamine catal-
ysis strategy[19] would facilitate the stereoselective incorpo-
ration of an alkyl substituent at the 12-position. The results of
these efforts are presented in Scheme 7. It was found that the
Having demonstrated the synthetic utility of the reaction,
we decided to pursue further variations of the formed steroid
products presented in Scheme 2 by expanding the scope to use
Scheme 4. Synthesis of Torgov’s diene analogues 9a–c under non-
optimized reaction conditions. See the Supporting Information for
details.
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Keywords: asymmetric synthesis · cycloaddition ·
.
organocatalysis · steroids · synthesis design
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Received: January 8, 2014
Published online: && &&, &&&&
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Communications
Synthetic Methods
K. S. Halskov, B. S. Donslund,
S. Barfꢁsser,
K. A. Jørgensen*
&&& — &&&
Organocatalytic Asymmetric Formation
of Steroids
Organocatalysis made it possible: The
reported methodology gives 14b-ste-
roids, displaying a broad generality, in
one step, and includes various substitu-
ents on the A ring, variations of the
B ring, hydroxy or alkyl substituents in the
12-position of the C ring, and different
substituents in the angular position at
C13. Furthermore, the developed reaction
concept includes reactions with quinones
to form D-homosteroids in excellent
yields and stereoselectivities.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!