Enantioselective synthesis of a GPR40 agonist AMG 837 via catalytic asymmetric conjugate addition of terminal alkyne to α,β-unsaturated thioamide

Article abstract of DOI:10.1021/ol102998w

A concise enantioselective synthetic route to a potent GPR40 agonist AMG 837 is described. The crucial catalytic asymmetric conjugate addition of terminal alkyne was promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst, allowing efficient

Full text of DOI:10.1021/ol102998w

ORGANIC
LETTERS
2011
Vol. 13, No. 5
952–955
Enantioselective Synthesis of a GPR40
Agonist AMG 837 via Catalytic
Asymmetric Conjugate Addition of
Terminal Alkyne to r,β-Unsaturated
Thioamide
Ryo Yazaki,†,‡ Naoya Kumagai,*,† and Masakatsu Shibasaki*,†
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo
141-0021, Japan, and Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Received December 10, 2010
ABSTRACT
A concise enantioselective synthetic route to a potent GPR40 agonist AMG 837 is described. The crucial catalytic asymmetric conjugate addition of
terminal alkyne was promoted by a soft Lewis acid/hard Brønsted base cooperative catalyst, allowing efficient construction of the requisite stereogenic
center. The thioamide functional group is key to both activation in asymmetric alkynylation and facile transformation into carboxylic acid.
The G-protein coupled receptor GPR40 was regarded as
an orphan receptor until the discovery of its endogenous
agonists, freefatty acidsthatamplifyinsulin secretionfrom
pancreatic β-cells,1-3 indicating that GPR40 agonists and
antagonists are potential therapeutic targets for insulin-
involved disorders such as type 2 diabetes.4 Recently, a
β-alkynyl acid derivative AMG 837 (1) was identified as a
potent GPR40 agonist at Amgen.5
† Institute of Microbial Chemistry, Tokyo.
‡ Graduate School of Pharmaceutical Sciences, The University of Tokyo.
(1) Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.;
Fukusumi, S.; Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; Tanaka,
H.; Maruyama, M.; Satoh, R.; Okubo, S.; Kizawa, H.; Komatsu, H.;
Matsumura, F.; Noguchi, Y.; Shinohara, T.; Hinuma, S.; Fujisawa, Y.;
Fujino, M. Nature 2003, 422, 173.
(4) For a comprehensive review, see: Bharate, S. B.; Nemmani,
K. V. S.; Vishwakarma, R. A. Expert Opin. Ther. Pat. 2009, 19, 237
and references cited therein.
(5) (a) Akerman, M.; Houze, J.; Lin, D. C. H.; Liu, J.; Luo, J.;
Medina, J. C.; Qiu, W.; Reagan, J. D.; Sharma, R.; Shuttleworth, S. J.;
Sun, Y.; Zhang, J.; Zhu, L. Int. Appl. PCT, WO 2005086661, 2005.
(b) Xie, Y.; Tao, W.; Morrison, H.; Chiu, R.; Jona, J.; Fang, J.; Couchon, N.
J. Pharm. Sci. 2008, 362, 29.
(2) Briscoe, C. P.; Tadayyon, M.; Andrews, J. L.; Benson, W. G.;
Chambers, J. K.; Eilert, M. M.; Ellis, C.; Elshourbagy, N. A.; Goetz,
A. S.; Minnick, D. T.; Murdock, P. R.; Sauls, H. R., Jr.; Shabon, U.;
Spinage, L. D.; Strum, J. C.; Szekeres, P. G.; Tan, K. B.; Way, J. M.;
Ignar, D. M.; Wilson, S.; Muir, A. I. J. Biol. Chem. 2003, 278, 11303.
(3) Kotarsky, K.; Nilsson, N. E.; Flodgren, E.; Owman, C.; Olde, B.
Biochem. Biophys. Res. Commun. 2003, 301, 406.
r
10.1021/ol102998w
Published on Web 02/03/2011
2011 American Chemical Society

Table 1. Direct Catalytic Asymmetric Conjugate Addition of
TMS Acetylene 3aa
The first generation synthetic route to 1 developed by
Amgen relied on optical resolution to provide enantiopure
samples for toxicologic and clinical studies. Subsquently,
Cui and Walker at Amgen established a reliable and scal-
able enantioselective synthesis of 1 through asymmetric
conjugate addition of an alkynyl Grignard reagent to
Meldrum’s acid-derived acceptors.6 Although this second
generation route advanced the synthetic efficiency, the
use of more than stoichiometric amounts of cinchonidine,
Me2Zn, and propynylmagnesium chloride is essential to
construct the requisite stereogenic center with high yield
and excellent enantioselectivity, and there remains room
for further improvement.
Catalytic asymmetric conjugate addition of terminal
alkynes to R,β-unsaturated carboxylates offers the most
straightforward and efficient access to the optically active
β-alkynyl acid derivatives,7 but few methods exist for this
transformation in a catalytic asymmetric manner, likely
due to the diminished reactivity of in situ generated transi-
tion metal alkynylides. Recently, to address this issue, our
group focused on the simultaneous activation of both a
terminal alkyne and an acceptor to compensate for the low
reactivity of the transition metal alkynylide. R,β-Unsatu-
rated thioamides8,9 were selected as suitable acceptors to
engage the enantioselective coupling with terminal alkynes,
in which the Lewis basic nature of both the alkyne and
thioamide functional groups was exploited for simulta-
neous activation by a soft Lewis acid/hard Brønsted base
a 2a, 0.2 mmol. b Determined by 1H NMR of the crude mixture with
2-methoxynaphthalene as an internal standard. c 10 mol % of phosphine
oxide 6 was used. d Isolated yield.
cooperative catalyst. Based on this strategy, we developed
a direct catalytic asymmetric conjugate addition of termi-
nal alkynes to R,β-unsaturated thioamides that proceeds
under proton transfer conditions.10 Herein we report a
concise enantioselective synthesis of AMG 837 (1) via soft
Lewis acid/hard Brønsted base catalyzed11 asymmetric
conjugate addition of a terminal alkyne to R,β-unsaturated
thioamide.
(6) (a) Cui, S.; Walker, S. D.; Woo, J. C. S.; Borths, C. J.; Mukherjee,
H.; Chen, M. J.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 436. (b) Woo,
J. C. S.; Cui, S.; Walker, S. D.; Faul, M. M. Tetrahedron 2010, 66, 4730.
(c) Morrison, H.; Jona, J.; Walker, S. D.; Woo, J. C. S.; Li, L.; Fang, J.
Org. Process Res. Dev. 2011, 15, 104 and references cited therein.
(7) For copper catalyzed asymmetric conjugate additions of terminal
€
alkynes, see: (a) Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
€
125, 6054. (b) Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 9682. (c) Fujimori, S.; Carreira, E. M.
Angew. Chem., Int. Ed. 2007, 46, 4964. For rhodium catalyzed asym-
metric conjugate additions of terminal alkynes, see: (d) Nishimura, T.;
Guo, X.-X.; Uchiyama, N.; Katoh, T.; Hayashi, T. J. Am. Chem. Soc.
2008, 130, 1576. (e) Nishimura, T.; Tokuji, S.; Sawano, T.; Hayashi, T.
Org. Lett. 2009, 11, 3222. (f) Nishimura, T.; Sawano, T.; Hayashi, T.
Angew. Chem., Int. Ed. 2009, 48, 8057. (g) Fillion, E.; Zorzitto, A. K.
J. Am. Chem. Soc. 2009, 131, 14608. (h) Nishimura, T.; Sawano, T.;
Tokuji, S.; Hayashi, T. Chem. Commun. 2010, 46, 6837. For the catalytic
asymmetric conjugate addition of preactivated terminal alkynes, see: (i)
Kwak, Y.-S.; Corey, E. J. Org. Lett. 2004, 6, 3385. (j) Wu, T. R.; Chong,
J. M.; Corey, E. J. Org. Lett. 2010, 12, 300.
(8) For R,β-unsaturated thioamides as electrophile, see: Alkyllithium
or magnesium: (a) Tamaru, Y.; Harada, T.; Iwamoto, H.; Yoshida, Z.
J. Am. Chem. Soc. 1978, 100, 5221. (b) Tamaru, Y.; Kagotani, M.;
Yoshida, Z. Tetrahedron Lett. 1981, 22, 3409. (c) Tamaru, Y.; Harada,
T.; Nishi, S.; Yoshida, Z. Tetrahedron Lett. 1982, 23, 2383. Lithium
enolates: (d) Tamaru, Y.; Harada, T.; Yoshida, Z. J. Am. Chem. Soc.
Figure 1. Proposed catalytic cycle with Mtl-HMDS.
We began our studies using silyl acetylene as an acetylene
equivalent in the direct catalytic asymmetric conjugate
(10) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 10275.
€
(11) (a) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
(b) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7, 3757.
(c) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556.
For CuOtBu-catalyzed 1,2-addition of terminal alkynes, see: (d) Motoki,
R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997. (e) Asano, Y.;
Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901.
ꢀ
1979, 101, 1316. Nitroalkanes: (e) Sosnicki, J. G. Tetrahedron 2009, 65,
1336.
ꢀ
(9) For utility of thioamide functional group, see: Jagodzinski, T. S.
Chem. Rev. 2003, 103, 197.
Org. Lett., Vol. 13, No. 5, 2011
953

addition to install the propyne unit of 1. Initial inves-
tigation revealed that the previously developed catalytic
system comprising [Cu(CH3CN)4]PF6, (R)-DTBM-Seg-
phos (R)-5,12 Li(OC6H4-p-OMe), and bisphosphine oxide
613 was less effective in an attempted reaction of R,β-
thioamide 2a and TMS acetylene 3a, likely because nucleo-
philic addition of in situ generated Cu acetylide was
hampered by the increased steric demand of 3a (Table 1,
entry 1). We envisioned using a catalytic amount of a stronger
base, LiHMDS, to generate Li acetylide A efficiently,
which would give Cu acetylide B through transmetalation
(Figure 1). Subsequently, enantioselective conjugate addi-
tion of Cu acetylide to Cu-activated 2a likely proceeds to
give Cu thioamide enolate C,14 which then would function
as a Brønsted base to drive the next catalytic cycle and
liberate the desired product 4a.15 The HMDS-type base of
a more electropositive alkali metal exhibited higher cata-
lytic efficiency (entries 2-4), affording 4a in 74% yield
with 92% ee with KHMDS (entry 4).16 The yield was
further improved by using 5 equiv of 3a (entry 5).17
thioamides bearing a p-oxy substituent were investigated
for the synthesis of 1 (Table 2). The reaction efficiency was
significantly different depending on the electronic charac-
ter of the p-oxy substituent. Substrate 2b, with an electron-
donating p-OMegroup, affordedonlytrace amountsof the
corresponding coupling product 4b, even with a 10 mol %
catalyst loading, presumably due to attenuated reactiv-
ity compared with nonsubstituted substrate 2a (Table 2,
entry 1 vs Table 1, entry 5). In contrast, R,β-unsaturated
thioamide 2a with an electron-withdrawing p-OAc group
afforded product 4c in moderate yield with 92% ee (entry 2),
which proved to be better than that obtained from the
analogous substrate bearing a p-OPiv group (entry 3).
Unexpectedly, a more electron-withdrawing p-OMs substi-
tuent did not afford the desired product (entry 4).18 Further
optimization of the reaction conditions using 2c revealed that
a higher concentration and extended reaction time contrib-
uted to give a higher yield (entry 5), and the catalyst loading
could be reduced to 5 mol % to afford 4c in 83% yield with
91% ee (entry 6). The absolute configuration of 4c prepared
by using (S)-DTBM-Segphos (S)-5 was determined to be
S by X-ray crystallographic analysis (Figure 2).19
Table 2. Direct Catalytic Asymmetric Conjugate Addition to
R,β-Unsaturated Thioamides Bearing a p-Oxy Substituenta
time
(h)
yieldb
(%)
ee
entry
R
2
x
product
(%)
1
2
3
4
5
6
OMe
OAc
OPiv
OMs
OAc
OAc
2b
2c
2d
2e
2c
2c
10
10
10
10
10
5
4b
4c
4d
4e
4c
4c
18
18
18
18
40
40
trace
58
;
92
;
;
90
91
Figure 2. X-ray crystal structure of 4c.
31
Due to the highly crystalline nature of 4c, enantioenrich-
ment was easily conducted in a CH2Cl2/n-hexane binary
solvent system to provide an enantiopure sample (>99% ee)
in 84% yield (Scheme 1). With enantiopure 4c bearing
the requisite stereogenic center of 1 in hand, we focused on
the enantioselective synthesis of 1. Facile conversion of a
thioamide functional group into the thioester was conducted
by treatment with MeI in the presence of H2O under acidic
conditions, giving the corresponding thioester 7.20 With-
out purification, 7 was subjected to Cs2CO3/MeOH to
remove the TMS group and acetyl group as well as to
transform the thioester to methyl ester to afford 8. Ether
ND
80
83c
a 2, 0.2 mmol; 3a, 1.0 mmol. b Determined by 1H NMR of the crude
mixture with 2-methoxynaphthalene as an internal standard. c Isolated
yield.
Having established the reaction conditions for TMS
acetylene 3a as the pronucleophile, β-aryl-R,β-unsaturated
(12) (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264. (b)
Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc.
Chem. Res. 2007, 40, 1385.
(16) With a Li(OC6H4-p-OMe) base (entry 1), retarded nucleophilic
addition would cause reprotonation of Cu acetylide by in situ generated
HOC6H4-p-OMe, leading to low catalytic performance. The higher
catalytic efficiency by using KHMDS is not clear at this stage.
(17) Sterically bulkier TES acetylene instead of TMS acetylene gave
an inferior result (63% yield, 92% ee). Even bulkier TBS or TIPS
acetylenes did not afford any product presumably due to considerable
steric repulsion in the transition state. The reaction using propyne was
not reproducible and is under investigation.
(13) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 5522.
(14) An attempted reaction of 2a and the Li acetylide of 3a prepared
from a stoichiometric amount of nBuLi did not afford 4a in the absence
of a Cu complex even at 50 °C, suggesting that transmetalation to Cu
acetylide is likely involved. Indeed, the reaction proceeded smoothly
with 5 mol % of a mesitylcopper/(R)-DTBM-Segphos catalyst, where
only the Cu acetylide of 3a can be formed, affording 4a in 91% yield and
90% ee under otherwise identical conditions.
(18) A thioamide bearing a β-p-trifluoroacetoxyphenyl substituent
was unstable and readily hydrolyzed.
(19) See Supporting Information for details.
(20) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron
1999, 55, 1187.
(15) The possibility that H-HMDS was deprotonated by intermedi-
ate C and the resultant Cu-HMDS functions as a Brønsted base for the
next catalytic cycle cannot be ruled out. Considering the proximity of 3a
and Cu thioamide enolate in intermediate C, the direct deprotonation as
depicted in Figure 1 is more likely.
954
Org. Lett., Vol. 13, No. 5, 2011

formation of the resultant crude material containing 8
and 9 under basic conditions afforded terminal alkyne 10
in 48% yield in three steps. Installation of the methyl group
at the terminal alkyne was performed by Sonogashira
coupling with MeI using carbene precursor 11 to provide
12 in 64% yield.21,22 Basic hydrolysis of 12 delivered 1, a
potent GPR40 agonist.
Scheme 1. Enantioselective Synthesis of 1
In conclusion, we developed an enantioselective syn-
theticroute to a potentGPR40 agonist 1 via directcatalytic
asymmetric conjugate addition of a terminal alkyne to an
R,β-unsaturated thioamide. The initial formation of an
alkali metal acetylide with catalytic amounts of strong base
is key to using TMS acetylene, and the intermediate Cu
thioamide enolate served as base in the following catalytic
cycle. The facile transformation of a thioamide functional
group to a carboxylic acid derivative allowed efficient
access to 1. Further application of the present alkynylation
method to the catalytic asymmetric synthesis of biologi-
cally active compounds is now ongoing.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research (S) (M.S.) and
the Sumitomo Foundation (N.K.). R.Y. is thankful for a
JSPS predoctral fellowship. Dr. Motoo Shiro at Rigaku
Corporation is gratefully acknowledged for X-ray crystal-
lographic analysis of 4c.
Supporting Information Available. Characterization of
new compounds and experimental procedures. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(21) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(22) No racemization was observed at this stage as confirmed by
chiral-stationary-phase HPLC analysis.
Org. Lett., Vol. 13, No. 5, 2011
955