.
Angewandte
Communications
DOI: 10.1002/anie.201209380
Asymmetric Reactions
Pot Economy in the Synthesis of Prostaglandin A1 and E1 Methyl
Esters**
Yujiro Hayashi* and Shigenobu Umemiya
Dedicated to Professor E. J. Corey
The efficient total synthesis of natural products has always
been a critical issue for organic chemists, especially when the
molecule to be prepared possesses important biological
activity and is difficult to obtain from natural sources. A lot
of effort has been devoted to the development of the ideal
synthesis.[1] Recently, when synthesizing molecules we not
only have to consider efficiency but also sustainability, as
indicated by terminology such as atom economy,[2] step
economy[3] and redox economy.[4] Protecting-group-free[5]
and toxic-metal-free syntheses would also contribute to
sustainability, and catalytic reagents (as selective as possible)
are regarded as superior to stoichiometric reagents according
to the 12 principles of green chemistry.[6]
A one-pot reaction is an efficient method to achieve
several transformations and form several bonds, while at the
same time cutting out several purifications, minimizing the
generation of waste chemicals, and saving time. Thus, a one-
pot reaction can also be regarded as environmentally benign,
and “pot economy” should be considered when planning
a synthesis.[7]
challenge to synthesize a molecule of this complexity, that is,
with three contiguous stereogenic centers, in a small number
of steps and by a sustainable process. Moreover, the synthesis
of the D and E series of prostaglandins, which contain a b-
hydroxyketo moiety, is very difficult owing to their instability
and facile dehydration resulting in their conversion into A-
type and B-type prostaglandins in acidic and basic media,
respectively.[11] Herein, we have accomplished a three-pot
synthesis of prostaglandin E1 methyl ester (1; see Scheme 1)
and A1 methyl ester (2; see Scheme 2) by using an organo-
13]
catalyst.[12,
During the preparation of this manuscript,
a short (seven steps) synthesis of prostaglandin PGF2a has
been described, for which the total yield is 2.2–3.3%.[14]
Our strategy is completely different from any previous
synthesis of prostaglandins: The first one-pot operation
involves construction of a key chiral intermediate that
contains all the carbon atoms of prostaglandin from three
simple molecules, and subsequent reactions consist of only
functional-group transformations.
The first key reaction relied on the use of diphenylprolinol
silyl ether (3),[15] an effective organocatalyst developed
independently by our research group[16] and that of Jørgen-
sen.[17] The asymmetric Michael reaction of an aldehyde and
an nitroalkene can be catalyzed by 3, and this reaction has
already been successfully employed in our two-pot synthesis
of (À)-Oseltamivir[18] and one-pot synthesis of ABT-341.[19]
Chiral cyclohexane derivatives can be synthesized by
a domino reaction consisting of a Michael reaction mediated
by organocatalyst 3 and a Henry reaction of aqueous
tetrahydro-2H-pyran-2,6-diol.[20] We applied this domino
reaction to the synthesis of the cyclopentane framework.
Starting from the three simple fragments nitroalkene 4,
succinaldehyde (5), and Horner–Wadsworth–Emmons
reagent 6, the prostaglandin skeleton 7, containing all the
necessary carbon atoms, is constructed in a one-pot operation
in good yield (81%) with good diastereoselectivity and
excellent enantioselectivity (Scheme 1). Of the eight possible
diastereomers, three were generated in the ratio of 76:17:7.
Although the relative stereochemistry was not determined at
this stage, the relative and absolute configurations at C8 and
C12 are highly controlled, as shown after conversion into the
cyclopentene derivative 10 (see Scheme 2). This crucial
sequence requires some elaboration: the first reaction is
The prostaglandins are known to act as local hormones;
only trace amounts can control a multitude of important
physiological processes, and some of their derivatives are used
as medicines.[8] The scientific community has put a great deal
of effort and ingenuity into their efficient synthesis because of
their biological importance and limited availability from
natural sources.[9] These molecules have inspired the chemical
community to devise many different synthetic strategies,
beginning with Coreyꢀs landmark synthesis[10] and continuing
with more than 40 subsequent syntheses, but all the previous
syntheses require many operations. Thus, it is still a synthetic
[*] Prof. Dr. Y. Hayashi,[+] S. Umemiya[+]
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
[+] Present address: Department of Chemistry
Graduate School of Science, Tohoku University
Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yhayashi@m.tohoku.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Orga-
nocatalysts” from The Ministry of Education, Culture, Sports,
Science and Technology (Japan). The authors thank Prof. Hayato
Ishikawa at Kumamoto University, Dr. Takuya Seko, and Dr. Toru
Maruyama at Ono pharmaceutical Co., Ltd. for their helpful
discussions.
a
Michael reaction mediated by diphenylprolinol silyl
ether.[16] The sequential intramolecular Henry reaction is
slow but is facilitated by iPr2EtN, and subsequent addition of
Horner–Wadsworth–Emmons reagent 6 to the same pot
affords 7, having the complete skeleton of the prostaglandins.
Supporting information for this article is available on the WWW
3450
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3450 –3452