An Asymmetric Suzuki-Miyaura Approach to Prostaglandins: Synthesis of Tafluprost

Article abstract of DOI:10.1021/acs.orglett.0c00745

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo- and enantioselective Rh-catalyzed Suzuki-Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio- and diastereoselective Pd-catalyzed Tsuji-Trost reaction with an enolate surrogate.

Full text of DOI:10.1021/acs.orglett.0c00745

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Letter
An Asymmetric Suzuki−Miyaura Approach to Prostaglandins:
Synthesis of Tafluprost
̌
Roman Kucera, F. Wieland Goetzke, and Stephen P. Fletcher*
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ABSTRACT: We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates
a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and
relative stereochemistry of the cyclopentyl core. Key steps include a diastereo- and enantioselective Rh-catalyzed Suzuki−Miyaura
reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio- and diastereoselective Pd-catalyzed Tsuji−Trost
reaction with an enolate surrogate.
Allylic substitution reactions are powerful tools for the
construction of complex organic molecules.13 In this context,
our group has developed a series of asymmetric rhodium-
catalyzed Suzuki−Miyaura coupling reactions between racemic
allylic chlorides and (hetero)aryl- and alkenylboronic acids.14
Recently, we have shown that racemic bicyclic allylic chlorides
undergo highly enantio- and diastereoselective cross-coupling
with boronic acids.15 Enantioconvergence in these reactions is
believed to occur via a DYKAT mechanism with a pseudo-meso
Rh−π-allyl intermediate.14,15 We envisioned that this method
could be used to construct a key carbon−carbon bond and set
the absolute and relative stereochemistry of the cyclopentyl
core of prostaglandins in a single reaction (Figure 2). We were
intrigued by the complexity of the side chain of Tafluprost (1)
and thought it was a highly demanding test of our method.
Our synthesis commenced with the preparation of suitable
coupling partners for the asymmetric Suzuki−Miyaura
coupling. The allyl halide ( )-2 was prepared from cyclo-
pentadiene in five steps, and alkenylboronic acid 3 was
prepared from 2-phenoxyethanol in 35% overall yield in eight
steps following literature procedures (for details, see the
Supporting Information).15−17 The two coupling partners were
subjected to reaction conditions previously used to couple
alkenylboronic acids to ( )-2 giving 4 in 87% yield and >20:1
rostaglandins are hormone-like lipid compounds that elicit
Pan unusually diverse array of physiological responses. For
example, they play a role in the origin of pain and fever and
have several regulatory functions.1 All prostaglandins contain
20 carbon atoms arranged in a five-membered core bearing two
aliphatic side chains and differ in the oxidation state of this
core and unsaturation of the side chains.2 Because of their
versatile properties, many prostaglandins and analogues are
used clinically, and the development of new synthetic strategies
for those natural products has been a vibrant area of chemical
research.2,3
Corey’s synthesis of PGE2 and PGF2α 50 years ago was a
true landmark in complex molecule synthesis.4,5 Indeed, many
contemporary routes to prostaglandin derivatives still rely on
the Corey aldehyde benzoate as a key intermediate.2 While
many stereospecific and diastereoselective approaches to
prostaglandins have been developed, so far catalytic asym-
metric approaches in which the asymmetry is exclusively
controlled by a chiral catalyst are rare (Figure 1).2 Those
include Aggarwal’s and Hayashi’s syntheses via asymmetric
aldol and Michael reactions,6,7 Feringa’s enantioselective 1,4-
addition followed by enolate tapping,2,8,9 and Nicolaou’s
asymmetric allylic alkylation approach.10
Tafluprost, developed by Asahi Glass Co., Ltd., and Santen
Pharmaceutical Co., is Santen’s and Merck Sharp & Dohme’s
prostaglandin PGF2α analogue for the treatment of intraocular
pressure in open-angle glaucoma and ocular hypertension.11
Previous syntheses of Tafluprost (1) have relied on the Corey
lactone to access the densely functionalized cyclopentane
core.4,12
Received: February 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00745
© XXXX American Chemical Society
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Table 1. Asymmetric Suzuki−Miyaura Coupling of Bicyclic
a
Allyl Halide
b
c
d
entry
ligand
yield (%)
ee (%)
dr
1
2
3
4
5
L1
L2
L3
L4
L5
L6
87
79
83
83
79
80
77
80
78
77
90
90
>20:1
>20:1
>20:1
11.5:1
7.2:1
e
6
7.2:1
a
Reactions run on a 0.20 mmol scale. Reagents and conditions:
[Rh(COD)OH]2 (2.5 mol %), ligand (6 mol %), boronic acid (1.5
b
equiv), 50 wt % aqueous CsOH (1.0 equiv), THF (0.25M). Isolated
c
yield of the major diastereomer. The ee values were determined by
d
SFC analysis of a chiral nonracemic stationary phase. The dr values
1
were determined by H NMR spectroscopy of the crude reaction
e
mixture. Performed on a 1.9 mmol scale.
Figure 1. Catalytic asymmetric syntheses of prostaglandins.
details about the formation of the minor regioisomer, see the
Supporting Information).18 Next, the malonate was trans-
formed into the carboxylic acid 7 via a hydrolysis/
decarboxylation sequence with 1,1′-carbonyldiimidazole
(CDI), and iodolactonization stereoselectively introduced the
second cyclopentyl hydroxy group in 73% yield over three
steps (for the structure, see compound S16 in the Supporting
Information).
The synthesis of Tafluprost (1) was completed following a
strategy with strong precedent in the prostaglandin literature.4
Radical deiodination using Bu3SnH in 79% yield and
subsequent lactone reduction gave rise to hemiacetal in 89%
yield, previously synthesized by Matsumura and co-work-
ers.12a,19 Finally, a Z-selective Wittig reaction of hemiacetal 8
with an excess of nonstabilized ylid followed by an
esterification with isopropyl iodide in the presence of DBU
afforded Tafluprost in 65% yield over two steps.12a
Overall, we established an asymmetric synthesis of
Tafluprost in 19 steps over the longest linear sequence in
6.7% overall yield. The synthesis features an asymmetric
rhodium-catalyzed Suzuki−Miyaura reaction of two complex
coupling partners to introduce the alkenyl chain with high
diastereoselectivity and a palladium-catalyzed allylic substitu-
tion to control the stereochemistry of the allyl chain. We
envision that our modular approach to Tafluprost will enable
the synthesis of prostaglandins and new prostaglandin
analogues.
Figure 2. Our strategy toward Tafluprost.
dr, albeit with only moderate (77% ee) enantioselectivity
(Table 1, entry 1).15 To improve the enantioselectivity of the
reaction, different bidentate phosphine ligands were tested
(entries 3−6). A 90% ee was obtained with only SEGPHOS
ligands L5 and L6 at the slight expense of diastereoselectivity
to set the absolute stereochemistry of Tafluprost.
The protected allylic alcohol moiety in 4 allowed for regio-
and diastereoselective introduction of the second side chain via
allylic substitution with an enolate surrogate. We used a cyclic
carbonate as a traceless activation strategy for the allylic
alcohol. The acetonide 4 was converted in two steps to the
corresponding cyclic carbonate 5 in 80% overall yield (Scheme
1). Palladium-catalyzed allylic substitution with diethyl
malonate afforded 6 as the major regioisomer in 89% yield
with overall retention of the relative stereochemistry (for
B
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Letter
Notes
Scheme 1. Synthesis of Tafluprost from Bicyclic
Alkenylcyclopentene 4
a
The authors declare the following competing financial
interest(s): Oxford University Innovation has filed a patent
application (PCT/GB2016/051612) with S.P.F. named as an
inventor. R.K. and F.W.G. declare no competing financial
interests.
ACKNOWLEDGMENTS
■
The authors thank Dr. Mike Mortimore (Vertex Pharmaceut-
icals) for helpful discussions and advice. F.W.G. is grateful to
the National Research Fund, Luxembourg, for an AFR Ph.D.
Grant (11588566), the EPSRC Doctoral Training Partnership
(DTP) for a studentship (EP/N509711/1), and Vertex
Pharmaceuticals for financial support. R.K. is supported by
the EPSRC Centre for Doctoral Training in Synthesis for
Biology and Medicine (EP/L015838/1), generously supported
by AstraZeneca, Diamond Light Source, Defense Science and
Technology Laboratory, Evotec, GlaxoSmithKline, Janssen,
Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex
Pharmaceuticals.
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00745.
General methods, detailed experimental procedure,
chromatograms, and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Stephen P. Fletcher − Department of Chemistry, University of
Oxford, Oxford OX1 3TA, U.K.; orcid.org/0000-0001-
7629-0997; Email: stephen.fletcher@chem.ox.ac.uk
Authors
̌
Roman Kucera − Department of Chemistry, University of
Oxford, Oxford OX1 3TA, U.K.
F. Wieland Goetzke − Department of Chemistry, University of
Oxford, Oxford OX1 3TA, U.K.; orcid.org/0000-0002-
8688-5609
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00745
C
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D
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