One-pot high-yielding synthesis of the DPP4-selective inhibitor ABT-341 by a four-component coupling mediated by a diphenylprolinol silyl ether

Article abstract of DOI:10.1002/anie.201006204

A dream come true: ABT-341 was synthesized in high yield with excellent diastereo- and enantioselectivity in a one-pot process mediated by a diphenylprolinol silyl ether (see scheme; TMS=trimethylsilyl). Thus, an asymmetric Michael reaction, a domino Mich

Full text of DOI:10.1002/anie.201006204

Communications
DOI: 10.1002/anie.201006204
Domino Reactions
One-Pot High-Yielding Synthesis of the DPP4-Selective Inhibitor
ABT-341 by a Four-Component Coupling Mediated by a
Diphenylprolinol Silyl Ether**
Hayato Ishikawa, Masakazu Honma, and Yujiro Hayashi*
In a “one-pot” reaction, several transformations are carried
out to form several bonds in a single flask.[1] Such reactions
remove the need for several purification steps, minimize the
generation of chemical waste, and save time; thus, they can be
viewed as “green” processes. However, there are several
challenges to be overcome in a one-pot reaction: 1) There are
reactions that are not suitable for a one-pot reaction. The
reaction has to be performed in the presence of the products
generated in the previous reactions. When A reacts with B to
generate C, along with D, the next reaction has to be carried
out in the presence of D, which might cause a problem. In the
Horner–Wadsworth–Emmons reaction, for example, a phos-
phoric acid derivative would be generated in an equimolar
amount as a side product. 2) As the number of transforma-
tions increases, the amount of other compounds present
increases. Furthermore, each transformation has to proceed in
high yield. 3) There is a limitation in terms of solvent usage.
When the best solvents for successive reactions are different,
a solvent with a high boiling point cannot be used for the
earlier reaction because of the difficulty of its removal under
reduced pressure. 4) The reagents that can be employed are
limited. If a reactive reagent remains, it might influence the
subsequent reaction. The exact stoichiometric amount of the
reagent has to be used, or a low-boiling reagent has to be
employed, in which case the excess reagent can be removed
under reduced pressure. Thus, there are several limitations in
a one-pot reaction, and a one-pot reaction is not a simple
connection of each optimized reaction.
turally, it possesses an amide part and, on the other side of the
carbonyl group, a cyclohexene moiety with a trifluorophenyl
and an amino forming two contiguous stereogenic centers.
Chiral ABT-341 (1) has been synthesized in 11 steps;[3] the
key chiral disubstituted methyl cyclohexenecarboxylate was
prepared by separation of the enantiomers by preparative
HPLC on a chiral phase. Thus, an efficient enantioselective
synthesis of ABT-341 (1) would be highly desirable.
Our strategy for the synthesis of ABT-341 (1) began with
the construction of a disubstituted cyclohexenecarboxylate
with the correct absolute and relative configurations. The rest
of the reactions were transformations of the functional groups
and amide-bond formation. Recently, we completed the
synthesis of (À)-oseltamivir through two one-pot reactions,[4]
which also involved a cyclohexenecarboxylate as a key
structure (Scheme 1). Although the synthetic approach to
ABT-341 (1) was similar to that used for our synthesis of (À)-
Scheme 1. Structures of ABT-341 (1) and oseltamivir.
Dipeptidyl peptidase IV (DPP4, also known as CD26), a
110 kDa serine protease that is ubiquitously distributed in the
body, deactivates glucose-regulating hormones, such as GLP-
1 and GIP. Thus, DPP4 inhibition has become a useful therapy
for type 2 diabetes.[2] ((4R,5S)-5-Amino-4-(2,4,5-trifluorophe-
nyl)cyclohex-1-enyl)-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341
(1)) is a highly potent, selective, and orally bioavailable
DPP4 inhibitor developed by Abbott Laboratories.[3] Struc-
oseltamivir, the synthesis of ABT-341 (1) through a one-pot
reaction is more challenging for several reasons. Although a
chiral trisubstituted cyclohexene was prepared in the first
one-pot reaction in the synthesis of (À)-oseltamivir, not only
the preparation of the chiral cyclohexene but also further
transformations, such as the formation of the amide bond and
functional-group manipulations, have to be performed in one
flask in the case of ABT-341 (1). That is, after the construction
of the chiral cyclohexene framework, several transformations
have to be carried out in the same flask in the presence of
several products, such as (EtO)2P(O)OH. Control of the
relative and absolute configurations at C4 and C5 of the
cyclohexene ring is another key issue.
The one-pot reaction to form ABT-341 (1) from four
components is summarized in Scheme 2. Thus, an initial
enantioselective Michael reaction of acetaldehyde (3) and
nitroalkene 2 in the presence of the diphenylprolinol silyl
ether organocatalyst 4,[5,6] followed by the successive addition
of vinyl phosphonate 5, trifluoroacetic acid (TFA), amine 6
[*] Dr. H. Ishikawa, M. Honma, Prof. Dr. Y. Hayashi
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[**] DPPA=dipeptidyl peptidase IV.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006204.
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Angew. Chem. Int. Ed. 2011, 50, 2824 –2827

Scheme 2. One-pot reaction for the synthesis of ABT-341 (1).
with a coupling reagent, and a reducing agent, provided ABT-
341 (1) in 63% yield over six steps in a highly diastereose-
lective and enantioselective manner.
ether 4, the Michael product 7 was obtained in good yield with
excellent enantioselectivity, even though the reaction was not
optimized.
The first step in the one-pot reaction is the Michael
reaction of acetaldehyde with a nitroalkene under the
catalysis of a diphenylprolinol silyl ether developed inde-
pendently by our research group[7] and List and co-workers.[8]
Our reported procedure with 10 equivalents of acetaldehyde
gave the product in good yield (74%) with excellent
enantioselectivity (94% ee); however, it is not suitable for a
one-pot reaction. Because this reaction is the first step, the
yield should be quantitative, and the generation of by-
products should be avoided as much as possible. Otherwise,
by-products will accumulate and interrupt subsequent reac-
tions. We optimized the reaction conditions and found that
the use of 2 equivalents of acetaldehyde was the key to
improving the yield to 93%; the reaction had to be quenched
at this point. The observed enantioselectivity was excellent
(97% ee). Excess acetaldehyde promotes the self-aldol reac-
tion, and the crotonaldehyde thus generated reacts further
with 7 to decrease the yield of 7. These optimized conditions
are suitable for the first step of the one-pot reaction, not only
because the yield and selectivity are excellent, but also
because the small excess of reactive acetaldehyde can be
removed readily under reduced pressure.
Compound 7 was prepared not only by the Michael
reaction of acetaldehyde and nitroalkene 2 [Eq. (1); TMS =
trimethylsilyl], but also by the Michael reaction of nitro-
methane and the a,b-unsaturated aldehyde 8 [Eq. (2)], which
was also developed by our research group.[9,10] When 8 and
nitromethane (9) were treated with the diphenylprolinol silyl
The next step, which involves several reactions, is the
preparation of the trans-substituted cyclohexenecarboxylate
10 (Scheme 3). When the isolated Michael adduct 7 and vinyl
phosphonate 5 were treated with Cs2CO3 in CH2Cl2 at 08C, a
Michael reaction of 7 and 5 was followed by an intramolecular
Horner–Wadsworth–Emmons reaction to afford two prod-
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Communications
ucts: the phosphonate ester
derivative 11 and the cis-
substituted cyclohexene 12.
The addition of EtOH to
the reaction mixture at
room temperature pro-
moted the retro-aldol reac-
tion and the subsequent
intramolecular
Horner–
Wadsworth–Emmons reac-
tion from 11 to 12. In this
way, the cis-substituted
cyclohexene
12
was
obtained in 87% yield. Iso-
merization of the cis isomer
12 to the trans isomer 10 did
not occur in the presence of
Scheme 3. Synthesis of 10 from 7.
Cs2CO3.
After
several
experiments, it was found
that iPr2EtN promoted
complete isomerization at
room temperature in 24 h to afford the trans isomer 10
quantitatively.
Since the separate reactions with isolated compounds
proceeded well, we investigated the one-pot reaction
(Scheme 2). After the first asymmetric Michael reaction,
excess acetaldehyde was removed under reduced pressure,
and the next domino[11] intramolecular Horner–Wadsworth–
Emmons reaction, a retro-aldol reaction, took place. The
reaction to form the cis-substituted cyclohexene 12 was
successful. Although the isomerization proceeded well for
isolated 12, it did not work with the crude mixture because of
the presence of Cs2CO3. As Cs2CO3 cannot be removed under
reduced pressure, we investigated its inactivation. Its con-
version into insoluble and neutral CsCl was examined, and
the reagent and temperature were found to be crucial. The
Nef reaction to afford the cyclohexanone was a major side
reaction when 4n HCl was used in 1,4-dioxane at 08C.
However, a reaction at À408C with TMSCl in the presence of
EtOH gave a good result. Thus, the reaction of 5 and 7 in the
presence of Cs2CO3 and the subsequent addition of EtOH
afforded 12. We then added TMSCl at À408C, whereupon
insoluble CsCl was generated, and the addition of iPr2EtN
promoted the isomerization to afford the trans isomer 10.
When we isolated 10 at this stage, the yield for the two steps
from 7 was 92%.
The transformation of the isolated tert-butyl ester 10 into
ABT-341 (1) was investigated in separate reactions [Eq. (3)].
Carboxylic acid 13, which was obtained when the isolated
ester 10 was treated with TFA, was coupled with amine 6 in
the presence of O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethy-
luronium tetrafluoroborate (TBTU) and Et3N in N,N-dime-
thylformamide (DMF)[3] to afford amide 14 in 93% yield over
two steps. The nitro group was successfully reduced to an
amine by treatment of the isolated compound 14 with Zn and
CH3CO2H in AcOEt at 08C to afford ABT-341 (1) in 98%
yield. In this reaction, the temperature is the key. ABT-341 (1)
was obtained in low yield when the reaction was performed at
room temperature because of overreduction of the triazole
moiety.
After removal of the volatile materials from the crude
product 10, the addition of CF3CO2H and CH2Cl2 trans-
formed the tert-butyl ester into the corresponding carboxylic
acid 13. The following coupling reaction of carboxylic acid 13
and amine 6 was expected to be one of the crucial steps. DMF
was employed in the reaction in Equation (3), but it cannot be
removed under reduced pressure and is not a preferred
solvent for the subsequent reduction of the nitro group.
Moreover, an equal amount of (EtO)2P(O)OH, which was
generated in the Horner–Wadsworth–Emmons reaction,
might act as a nucleophile with a coupling reagent. We
screened a range of reaction conditions and found that THF
can be used as a solvent and that the temperature is important
in this coupling reaction. When the reaction was performed
initially at 08C, and the temperature was then increased to
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Angew. Chem. Int. Ed. 2011, 50, 2824 –2827

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The final reaction was the reduction of the nitro group to
an amine. The reaction proceeded as well as with the isolated
intermediate with Zn and AcOH in AcOEt to provide ABT-
341 (1). ABT-341 (1) was obtained in 63% overall yield from
nitroalkene 2 after purification by acid–base extraction
followed by column chromatography.
In summary, an efficient, enantioselective total synthesis
of ABT-341 (1) was completed in a one-pot reaction. This
approach demonstrates the power of asymmetric reactions
catalyzed by organocatalysts, and especially the diphenylpro-
linol silyl ether 4. The present synthesis has several notable
features: 1) the total yield is excellent (63% from nitroalkene
2); 2) the synthesis consists of six reactions, which were
conducted in a single flask; 3) four components were com-
bined to afford ABT-341, whereby all of these four compo-
nents were employed in nearly equimolar amounts, except for
inexpensive acetaldehyde (2 equiv); 4) a disubstituted chiral
cyclohexene carboxylate with the correct configuration was
synthesized from three starting materials by successive
reactions, including an asymmetric Michael reaction medi-
ated by a diphenylprolinol silyl ether, as developed by our
research group, a domino Michael reaction/Horner–Wads-
worth–Emmons reaction combined with a retro-aldol reac-
tion, and a base-catalyzed isomerization; 5) amide-bond
formation and functional-group manipulations can also be
performed in the same single flask by the appropriate choice
of reaction conditions, under which previous reagents and
products do not interfere with the desired reaction.
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Received: October 4, 2010
Published online: January 24, 2011
Keywords: asymmetric synthesis · domino reactions ·
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