Enantioselective Total Synthesis of Beraprost Using Organocatalyst

Article abstract of DOI:10.1021/acs.orglett.7b00134

A convergent and enantioselective total synthesis of the most active isomer of beraprost was achieved in 17 pots. A unique tricyclic core in beraprost was synthesized efficiently by utilizing the asymmetric organocatalyst-mediated formal [3 + 2] cycloaddi

Full text of DOI:10.1021/acs.orglett.7b00134

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of Beraprost Using Organocatalyst
Shigenobu Umemiya,† Daisuke Sakamoto,† Genki Kawauchi, and Yujiro Hayashi*
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza, Aoba, Aoba-ku, Sendai, Miyagi
980-8578, Japan
S
* Supporting Information
ABSTRACT: A convergent and enantioselective total synthesis of the most active isomer of beraprost was achieved in 17 pots.
A unique tricyclic core in beraprost was synthesized efficiently by utilizing the asymmetric organocatalyst-mediated formal [3 +
2] cycloaddition reaction of succinaldehyde with nitroalkene as a key step. The synthesis of the optically active Horner−
Wadsworth−Emmons reagent for the construction of the ω-side chain was also established by means of the enantioselective
Michael reaction of crotonaldehyde with nitromethane catalyzed by the organocatalyst developed by our group.
he prostaglandins are essential natural products for human
life controlling a wide array of physiological processes as
On the other hand, a selective synthesis of 2a is highly
important for reducing undesired pharmacological activities
because these isomers in beraprost (2a, 2b, 2c, and 2d) have
different biological activities respectively, and 2a is known as
the most biologically active isomer.7f Toray’s group reported
the enantioselective synthesis of 2a, combining the tricyclic
core and side chain, but it required a total of 27 pots.7f
Requirements for an ideal synthesis of 2a are as follows: (1) A
suitable methodology for high yielding construction of the
tricyclic core is required. (2) A catalytic and asymmetric
reaction introducing the stereogenic center(s) in the core
skeleton must be developed. (3) An efficient and enantiose-
lective preparation of the ω-side chain unit is needed.
T
local hormones.1 Numerous chemical syntheses of prostaglan-
dins and derivatives have been reported owing to their
attractive biological activities.2
Prostaglandin (PG) I2 (1) is a physiologically active natural
product, which can inhibit platelet aggregation and vasodilation
(Figure 1).3 As PGI2 can also promote axonal remodeling of
Several asymmetric syntheses of the common tricyclic core in
2a have been developed, which are summarized in Scheme 1
including the number of pots for the synthesis of this moiety.
In Toray’s synthesis, an intramolecular SN2′ reaction with a
Grignard reagent and copper iodide furnished a tricyclic
product. An optical resolution produced enantiopure carboxylic
acid in 30% over two steps (Scheme 1a).7e,f Chandrasekhar and
co-workers took advantage of an enzymatic optical resolution,
and an intramolecular oxy-Michael reaction of an enone formed
a key benzofuran ring (Scheme 1b).8a The Takemoto group
demonstrated that an enantioselective intramolecular oxy-
Michael addition of an α,β-unsaturated amide by an organo-
catalyst afforded a chiral amide (Scheme 1c).8b An intra-
molecular C−H insertion of a diazo compound followed by
reduction gave a tricyclic substrate in a useful yield. Most
Figure 1. Structure of PGI2 (1) and beraprost (2).
injured neuronal networks,4 it is thus considered as a
fascinating drug candidate. However, 1 is highly unstable and
hydrolyzed even under neutral aqueous conditions because of
its highly reactive enol ether functionality.5 Since the
hydrolyzed product has no pharmacological activity,6 more
stable analogs of 1 have been pursued for decades.
Toray Industries Inc. have developed beraprost, which is a
mixture of four isomers (2a, 2b, 2c, and 2d), bearing six
stereogenic centers and a unique benzofuran ring system
instead of the sensitive enol ether moiety (Figure 1).7 Beraprost
is a more stable and less cytotoxic analog than PGI2 whose
sodium salt is used as an antiplatelet aggregation drug.
Received: January 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00134
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Letter
core 3 and phosphonate 4. We proposed that the benzofuran
ring in aldehyde 3 could be prepared from β-hydroxyl ketone 5
through a diastereoselective reduction, followed by an intra-
molecular SNAr reaction. According to our previous synthesis of
prostaglandin E1 methyl ester,9 ketone 5 would be derived from
two simple starting materials, succinaldehyde (7) and
commercially available nitroalkene 8, by means of an
asymmetric formal [3 + 2] cycloaddition reaction10 catalyzed
by diphenylprolinol silyl ether.11
Scheme 1. Syntheses of the Tricyclic Core in Beraprost
On the other hand, we also envisioned that the optically
active Horner−Wadsworth−Emmons reagent 4 could be
synthesized by an organocatalyzed asymmetric reaction as a
key step. A simple nitroalkane 9 would be considered as a
suitable precursor toward 4. We assumed that nitroalkane 9
could be prepared from crotonaldehyde (11) and nitromethane
(12) with high enantioselectivity by utilizing our catalytic
enantioselective Michael reaction12 in the presence of
diphenylprolinol silyl ether.
The synthesis of the key tricyclic core 20, as outlined in
Scheme 3, commenced with succinaldehyde (7) which is easily
Scheme 3. Synthesis of the Key Intermediate 20
recently, Xie and co-workers described that a diolefin substrate
prepared from the commercially available (−)-Corey lactone
diol was converted into a tricyclic system via olefin metathesis
and oxidation (Scheme 1d).8c
These methods can produce the chiral common tricyclic
intermediate, but still require long sequences (over 14 pots)
and/or include low yielding manipulations, such as optical
resolutions. Moreover, a catalytic construction of the C-16
stereogenic center has not been reported. Only one method
controlling this stereocenter by using an optical resolution is
introduced by the Toray research group.7g Indeed, most of the
previous work did not control the C-16 stereogenic center.
There is thus a significant synthetic challenge to prepare the
complex tricyclic core and the ω-side chain unit in an efficient
and fully stereocontrolled fashion. Here, an enantioselective
total synthesis of 2a in 17 pots utilizing two organocatalyzed
asymmetric reactions and an amenable benzofuran ring
formation via an intramolecular SNAr reaction is described.
Our retrosynthetic analysis of 2a is illustrated in Scheme 2.
The desired product 2a could be disconnected into tricyclic
obtained from inexpensive 2,5-dimethoxytetrahydrofuran. The
formal [3 + 2] cycloaddition reaction afforded a highly
substituted cyclopentane 14 in good yield. After dimethylacetal
protection followed by dehydration under acetylation con-
ditions, nitroalkene 15 was obtained in 62% yield as single
isomer. In the acetalization step, the complete epimerization of
α-position of the formyl group occurred to furnish the trans
product. Notably, these three-step sequences can be engineered
in one pot13 and multigram scale.
Scheme 2. Retrosynthetic Analysis of 2a
An oxygen-promoted Nef reaction by DABCO produced
enone 16 in 55% yield,14 and the enantiomeric excess of 16 was
determined by HPLC analysis (93% ee). A base-mediated
epoxidation15a,b of 16 followed by a reductive epoxide opening
reaction using zinc powder under mildly acidic conditions gave
the corresponding unstable β-hydroxyketone. A successive L-
selectride reduction of this crude product was performed
immediately to give diol 17 in 50% yield over three steps.16 The
minor diastereomer generated in the epoxidation could be
B
DOI: 10.1021/acs.orglett.7b00134
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separated at this stage. Next, we conducted a crucial formation
of the benzofuran ring system. Fortunately, the desired product
18 was successfully afforded in excellent yield by simple
treatment of 17 with t-BuOK in 1,4-dioxane.17 The alkyl side
chain on the aromatic ring was subsequently installed by the
Suzuki−Miyaura coupling with alkylborane 19, prepared from
methyl but-3-enoate and 9-BBN to afford a key intermediate
20.18 The chiral functionalized tricyclic key intermediate 20 was
constructed in only seven pots.
As partial racemization was expected in the preparation of 4,
we confirmed the enantiomeric enrichment of 4 by conversion
into the corresponding enone using 3-phenylpropanal (28) as a
model (eq 2). The desired product 29 was obtained in 85%
In order to determine the absolute configuration of 20, a
known compound 21 in the Toray’s synthesis was accessed
through hydrolysis of dimethoxyacetal moiety and a sequential
reduction of the generated aldehyde (eq 1). All spectral data
and the optical rotation of our synthetic diol 21 matched those
in the reported literature.7f
yield along with 90% ee under standard conditions. No
racemization was observed under several acidic and basic
conditions (Nef reaction, benzyl esterification, Claisen-type
reaction, and Horner−Wadsworth−Emmons reaction).
With the two chiral fragments in hand, the total synthesis of
2a was completed in Scheme 5. Hydrolysis of dimethylacetal 20
Scheme 5. Completion of Enantioselective Total Synthesis
of 2a
Next, we carried out the enantioselective Michael reaction of
crotonaldehyde (11) with nitromethane, which was an essential
step for preparing the chiral Horner−Wadsworth−Emmons
agent 4 (Scheme 4). We selected secondary amine 22
Scheme 4. Preparation of Chiral Phosphonate 4
under the acidic conditions gave the corresponding aldehyde,
which was used directly after an aqueous workup. The
subsequent Horner−Wadsworth−Emmons reaction proceeded
smoothly to deliver enone 30 in 67% yield over two steps
together with perfect E-selectivity. A diastereoselective 1,2-
reduction of 30 using (−)-B-chlorodiisopinocampheylborane
(DIP-Cl) provided diol 31 (dr = >95:5 at C-15) possessing all
requisite stereogenic centers.24 Finally, hydrolysis of methyl
ester was achieved under basic conditions to afford beraprost
(2a) in 88% yield.
In summary, we have developed a concise, highly stereo-
selective, and short total synthesis of 2a, which is the most
biologically active isomer of beraprost, from simple starting
materials. The present synthesis has several notable features:
(1) A formal asymmetric [3 + 2] cycloaddition reaction
catalyzed by diphenylprolinol silyl ether 13 was suitable to
install stereogenic centers. (2) An asymmetric Michael addition
of crotonaldehyde with nitromethane in the presence of
diphenylprolinol silyl ether 22 furnished the appropriate chiral
building block toward the ω-side chain unit. This is the first
example controlling the C-16 stereogenic center in a catalytic
manner. It is noteworthy that diphenylprolinol silyl ether
catalysts facilitate two key asymmetric reactions that allow
assembling the complex setting of beraprost in 17 pots. (3) The
intramolecular SNAr reaction of 17 successfully provided the
tricyclic system in excellent yield. Moreover, our synthetic
developed by the Seebach group as the best catalyst,19 which
provided better asymmetric induction than the corresponding
TMS catalyst in Michael reactions via iminium ion
intermediates.12,20 The yield of 23 was dramatically improved
when the reaction was carried out in aqueous THF21 instead of
MeOH.12 Ultimately, the catalyst loading was able to be
reduced to only 5 mol % and the desired product was obtained
in 82% yield with 90% ee.
With an adequate amount of the optically active nitroalkane
23 accessible, we started to investigate transformations toward
phosphonate 4. Treatment of 23 with the Ohira−Bestmann
reagent 24 furnished the corresponding terminal alkyne 25 in
91% yield.22 Three-step transformations including a selective
methylation in 25, a Nef reaction,23 and a benzyl esterification
provided ester 26 in 32% yield over three steps. The resulted
benzyl ester was converted into the desired 4 by a Claisen-type
reaction with diethylmethane phosphonate (27) in 62% yield.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00134.
Experimental procedure, analytical data (1H and 13C
NMR, IR, HRMS) (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhayashi@m.tohoku.ac.jp.
ORCID
Yujiro Hayashi: 0000-0002-1838-5389
Author Contributions
†S.U. and D.S. contributed equally.
(20) Hayashi, Y.; Okamura, D.; Yamazaki, T.; Ameda, Y.; Gotoh, H.;
Tsuzuki, S.; Uchimaru, T.; Seebach, D. Chem. - Eur. J. 2014, 20, 17077.
(21) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.;
Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.;
Devine, P. J. Org. Chem. 2010, 75, 7829.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number
JP16H01128 in Middle Molecular Strategy.
■
(22) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Muller, S.;
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(25) Corey, E. J.; Cheng, X. The logic of chemical synthesis; John Wiley
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DOI: 10.1021/acs.orglett.7b00134
Org. Lett. XXXX, XXX, XXX−XXX