Synthesis of (?)-(R)-Sitagliptin by RhI-Catalyzed Asymmetric Hydroamination

Article abstract of DOI:10.1002/ejoc.202100832

We report of a concise synthesis of (R)-sitagliptin monophosphate – a drug predominantly applied in the treatment of type 2 diabetes. Utilizing our recently developed Rh^I-catalyzed hydroamination of allenes for the stereoselective construction of the inherent chiral amino function, a new approach to (R)-sitagliptin monophosphate on a 3.5 mmol scale was established.

Full text of DOI:10.1002/ejoc.202100832

Communications
doi.org/10.1002/ejoc.202100832
Synthesis of (À )-(R)-Sitagliptin by RhI-Catalyzed
Asymmetric Hydroamination
Dino Berthold[a] and Bernhard Breit*[a]
In memory of Klaus Hafner
hydrogenation[9] and enantioselective or auxiliary controlled
We report of a concise synthesis of (R)-sitagliptin mono-
phosphate – a drug predominantly applied in the treatment of
type 2 diabetes. Utilizing our recently developed RhI-catalyzed
hydroamination of allenes for the stereoselective construction
of the inherent chiral amino function, a new approach to (R)-
sitagliptin monophosphate on a 3.5 mmol scale was estab-
lished.
Mannich reaction[10] (Figure 1).
However, the best and most elegant synthesis until today
was developed by Merck, Sharp & Dohme (DSM) itself in
cooperation with Codexis, providing 1 by a biocatalytic route
utilizing an engineered transaminase enzyme.[9d] The latter
enabled a tandem amination/asymmetric hydroamination proc-
ess as a one-pot procedure avoiding hazardous and expensive
hydrogenation conditions (Scheme 1).
Type 2 diabetes mellitus (T2DM) is a major and rapidly growing
disease, which affects millions of people worldwide every
year.[1] In this context the treatment by drugs, e.g. (R)-sitagliptin
(1) – an orally active, safe and selective DPP-IV inhibitor – is of
ever growing interest. 1, originally discovered by Merck, Sharp
& Dohme (MSD) in 2005, inhibits the proteolytic activity of
dipeptidyl peptidase-4, an enzyme that breaks down the
incretins, which play a key role in glucoregulation by increasing
insulin secretion and suppressing glucagon release.[2] The
significance of sitagliptin as the active pharmaceutical ingre-
dient in commercial drugs such as Januvia® and Janumet® is
best illustrated by the fact, that it is present in the top 200 best-
selling drugs since its first approval by the FDA in 2006.[3]
For this reason the synthesis of (R)-sitagliptin (1) has been
established as a benchmark target for chiral amine synthesis
and therefore, attracted the attention of many different
research groups and pharmaceutical companies reporting of
extensive efforts on its asymmetric synthesis. The key methods
employed to install the chiral primary amine include auxiliary
controlled alkylation of amides followed by Arndt-Eistert
homologation,[2,4] intramolecular Pd-catalyzed [2,3]-sigmatropic
rearrangement,[5] asymmetric aza-Michael addition,[6] auxiliary
controlled amination of enolates,[7] auxiliary controlled reduc-
tion or (transfer-)hydrogenation,[8] asymmetric (transfer-)
Although especially the synthetic routes containing the
construction of the chiral amine by asymmetric hydrogenation,
transamination and Michael addition are straightforward and
efficient, there is still interest in convenient, atom efficient and
synthetically applicable alternatives to the mentioned method-
ologies.
In the recent past our research group developed a broad
variety of inter- and intramolecular hydroamination reactions of
allenes and alkynes employing different N-nucleophiles such as
N-heterocycles, sulfonylamines and anilines. These method-
ologies can be seen as an atom economic alternative to allylic
substitution.[12] Among the above mentioned methods for
asymmetric preparation is a RhI/Josiphos J003-catalyzed hydro-
amination of benzophenone imine of allenes of further interest
since this procedure provides an efficient access towards free or
protected chiral primary allylic amines in a highly enantioselec-
tive fashion.[12g]
Herein, we report such an alternate approach exploiting our
above mentioned methodology to accomplish the asymmetric
installation of the chiral amine. We initiated our synthetic study
by preparing fluorinated allene 30 via a CuI-catalyzed Grignard
addition of benzylic bromide 29 to propargylic bromide. This
reaction, carried out on a 75 mmol scale, provided allene 31 in
74% yield. Next, we were able to optimize the original
[a] Dr. D. Berthold, Prof. Dr. B. Breit
Institut für Organische Chemie and Freiburg, Albert-Ludwigs-Universität
Freiburg
Albertstraße 21, 79104 Freiburg im Breisgau, Germany
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100832
Part of the “Special Collection in Memory of Klaus Hafner”.
© 2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or adap-
tations are made.
Scheme 1. Industrial process for the synthesis of (R)-(À )-Sitagliptin (1)
developed by DSM and Codexis.
Eur. J. Org. Chem. 2021, 1–4
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published by Wiley-VCH GmbH
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Communications
doi.org/10.1002/ejoc.202100832
Figure 1. Retrosynthetic overview on key intermediates for the asymmetric synthesis of (À )-(R)-Sitagliptin (1) based on the synthetic strategies.[11]
conditions for asymmetric benzophenone imine addition to
allenes[12g] in terms of lowering the catalyst loading by
simultaneously obtaining a satisfying yield.[13] The reaction
sequence involved a RhI/Josiphos-catalyzed hydroamination
with benzophenone imine as an ammonia surrogate, cleaving
of the imine and BOC-protection. The desired BOC-protected
allylic amide 32 was thus obtained in one sequence on a
7.5 mmol scale in 78% yield and excellent enantioselectivity
(99.2% ee). Applying reaction conditions for anti-Markovnikov
selective Wacker oxidation developed by Feringa the corre-
sponding aldehyde 33 was obtained in 83% yield and good
linear/branched ratio.[14] Next, aldehyde 33 was then converted
in a three step sequence via Pinnick oxidation and EDC-
mediated amide coupling in (R)-Sitagliptin (1), which was
isolated after the third step as the phosphate salt in 72% yield.
A total of more than 1.4 g (3.5 mmol) of the phosphate salt of 1
was obtained in an overall yield of 47% over three isolated
intermediates avoiding stereochemical enrichment, such as
recrystallization, to obtain enantiomerically pure (R)-Sitagliptin
(1), as it is the case in many previously reported syntheses
(Scheme 2).
Scheme 2. Synthesis of (R)-Sitagliptin (1) employing a RhI/Josiphos J003-
catalyzed hydroamination of allenes. Reaction conditions: a) 1. Mg
°
(1.2 equiv.), Et2O (1.0 m), rt – 45 C, 4 h; 2. propargylic bromide (1.2 equiv.),
°
CuI (10 mol%), Et2O (1.0 m), 0 C – rt, 3 h, 74%; b) 1. 30 (1.0 equiv.), 31
(1.0 equiv.), [{Rh(cod)Cl}2] (0.50 mol%), Josiphos J003-2 (1.1 mol%), PPTS
°
(2.5 mol%), DCE (0.4 m), 80 C, 36 h; 2. HClaq (2.0 m, 5.0 mL/mmol), Et2O
(5.0 mL/mmol), rt, 12 h; 3. Boc2O (1.5 equiv.), NEt3 (4.0 equiv.), CH2Cl2 (0.2 m),
rt, 12 h, 78%, 99.2% ee; c) [Pd(MeCN)Cl2] (5.0 mol%), benzoquinone
(1.1 equiv.), tBuOH (0.25 m), rt, 18 h, 83%, linear/branched=91:9; d) 1.
NaOCl2 (1.5 equiv.), NaH2PO4 (3.0 equiv.), THF/H2O/2-methyl-2-butene/tBuOH
(10:6:3:3, 0.05 m), rt, 4 h; 2. 28 (1.2 equiv.), N-Me-morpholine (1.0 equiv.),
°
EDC·HCl (1.5 equiv.), MeCN (0.3 m), 0 C, 2 h; 3. H3PO4 (1.0 equiv.), iPrOH
(0.1 m), rt, 12 h, 72%.
Acknowledgements
In conclusion, the synthesis of (R)-Sitagliptin (1) demon-
strates an attractive application of our recently developed
hydroamination reaction, a method, which can be seen not
only as an atom economic alternative to allylic substitution, but
also as an approach for the synthesis of chiral amines
comparable to the asymmetric aza-Michael addition, stereo-
selective reduction and Mannich reaction. Applying this
methodology, 1 was synthesized over three isolated intermedi-
ates on a scalable and concise route highlighting the potential
of hydroamination of allenes. Its scope will be further extended
D.B. is grateful for a Feodor-Lynen Fellowship from the Alexander
von Humboldt Foundation. Furthermore, D.B. and Prof. Willem
van Otterlo thank Prof. Reinhard Brückner for admission to his
research group at short notice. We thank the analytical depart-
ment, especially Dr. Manfred Keller for NMR analysis and Joshua
Emmerich for ee determinations via HPLC. Open Access funding
enabled and organized by Projekt DEAL.
towards the asymmetric addition of unactivated N-nucleophiles, Conflict of Interest
such as aliphatic amines and amino acids to allenes and will be
reported in due course.
The authors declare no conflict of interest.
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Chaudhari, S. Achanta, A. Sud, V. Dahanukar, C. J. Cobley, F. Llewellyn-
Keywords: Allenes · Catalysis · Hydroamination · Rhodium ·
Sitagliptin
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Manuscript received: June 13, 2021
Revised manuscript received: August 31, 2021
Accepted manuscript online: September 3, 2021
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COMMUNICATIONS
Dr. D. Berthold, Prof. Dr. B. Breit*
1 – 4
Synthesis of (À )-(R)-Sitagliptin by
RhI-Catalyzed Asymmetric Hydroa-
mination
A concise, asymmetric synthesis of
(À )-(R)-Sitagliptin is presented
anti-Markovnikov selective Wacker
oxidation and subsequent Pinnick
oxidation. The synthesis of (À )-(R)-Si-
tagliptin proceeded over three
isolated intermediates providing
3.5 mmol in an overall yield of 47%.
utilizing a RhI/Josiphos-based hydroa-
mination strategy as a key step beside
allene preparation and amide
coupling. The unusual β-amino
function was accomplished by an