Tetrahedron Letters
Convergent synthesis of (R)-silodosin via decarboxylative cross-coupling
Tie-Gen Chen a, Lucas Mele b, Olivier Jentzer b, Dominique Delbrayelle b,
Pierre-Georges Echeverria b, Julien C. Vantourout a, Phil S. Baran a,
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a Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
b Minakem Recherche, 145 Chemin des Lilas, 59310 Beuvry-la-Forêt, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2021
Revised 9 July 2021
Accepted 16 July 2021
Available online 24 July 2021
A new approach to Silodosin capitalizing on a radical retrosynthetic strategy to dissect the molecule into
two halves is reported. Using a reductive decarboxylative cross-coupling, a simple indoline can be cou-
pled to a chiral pool-derived fragment to arrive at the target in only seven steps (LLS). This route avoids
the use of resolution strategies or asymmetric hydrogenation that requires a subsequent Curtius rear-
rangement to install a key amino functionality.
Ó 2021 Elsevier Ltd. All rights reserved.
Silodosin (1, FDA-approved and sold as RapafloTM in the USA,
Figure 1) is a medicine for the treatment of benign prostatic hyper-
plasia [1], a disorder that afflicts roughly 105 million people world-
wide per year. Discovered by Kissei Pharmaceutical and Daiichi
Sankyo in 2006 and approved by the FDA in 2008, it functions as
As shown in Table 1, a proof-of-concept study for the key cou-
pling was carried out using various haloindolines and RAEs. Opti-
mized conditions (entry 1) were obtained when using RAE 3 (2
equiv), iodoindoline 4 (1 equiv), NiI2 (10 mol%), L1 (10 mol%), Zn
(2 equiv), and LiBr (1 equiv) in DMA at 60 °C for 12 h affording
the desired coupled product 5 in 77% yield. When bromoindoline
was used instead of iodoindoline 4 the yield was significantly
decreased to 35% (entry 2). Similarly, the use of TCNHPI RAE
instead of NHPI 3 afforded less than 10% of the desired coupled
product (entry 3). NiI2 proved by far to be the optimum nickel
source to be employed (entry 4 and see SI for details) and was
essential for the reductive decarboxylative cross-coupling to occur
(entry 5). The yield of the reaction was slightly diminished when
Mn powder was used as a reductant instead of Zn (entry 6). Both
the Zn and LiBr were critical for the reaction to result in high yield
(entries 7 and 8). In addition, running the reaction at room temper-
ature instead of 60 °C only afforded traces of the desired product
(entry 9). Finally, an extensive ligand screening highlighted the
importance of the ligand class employed in such a reductive
cross-coupling and L1, originally uncovered by the Weix/Pfizer
team [8], was found to be the best ligand to use amongst all the
ligands tested (entries 10 to 12 and see SI for details).
a selective
a1-adrenergic receptor antagonist and has an annual
revenue of approximately 636 million dollars per year [2]. Several
routes to prepare this indoline-containing structure have been
reported as illustrated in Fig. 1A, all of which proceed in a linear
fashion focused on the installation of the chiral amine stereocenter
[3]. This has been achieved by either a hydrogenation/Curtius path-
way of acrylate 2 [3a] or various reductive amination tactics
(enzymatic [3b], diastereoselective [3c], resolution [3d]). As part
of a collaboration between Scripps and Minakem, exploration
into a more economical route was initiated with the goal of
developing a chiral pool strategy that would perhaps be more
convergent and orthogonal to prior reports. Specifically, using the
logic of radical retrosynthesis [4], a plan was devised (Fig. 1B) that
would dissect the molecule into two equally complex halves that
could be unified via decarboxylative cross-coupling [5,6]. In this
Letter, we describe the successful execution of this strategy to
access 1 through a modification of Weix’s reductive decarboxyla-
tive coupling protocol [7] to couple an iodoindoline with a chiral
redox-active ester (RAE) (Fig. 1C).
With optimum conditions in hand, application to the synthesis
of 1 was pursued as outlined in Fig. 2. To prepare the key RAE 6,
alkyl halide 7 was cleanly alkylated with amine 8 in 60% yield fol-
lowed by Boc-protection, hydrolysis, and RAE formation (34% yield
over 3 steps). The iodoindoline fragment 4 was synthesized via a
Dedicated to Professor Dale Boger on the occasion of his receipt of the Tetrahedron
Prize for Creativity
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simple sequence commencing from indoline
9
involving
Corresponding author.
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Baran, Phil S.
