Asymmetrie synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor

Article abstract of DOI:10.1021/jo902573q

Chemical Equetion Presentation A practical asymmetric synthesis of a novel aminopiperidine-fused Imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl₃ is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to < 0.5% by utilizing a trace amount of HCl generated from RhCl₃. The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

Full text of DOI:10.1021/jo902573q

pubs.acs.org/joc
Asymmetric Synthesis of a Potent, Aminopiperidine-Fused
Imidazopyridine Dipeptidyl Peptidase IV Inhibitor
Feng Xu,* Edward Corley, Michael Zacuto, David A. Conlon, Brenda Pipik,
Guy Humphrey, Jerry Murry, and David Tschaen
Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065
feng_xu@merck.com
Received December 4, 2009
A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl
peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component
cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective
Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functiona-
lized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven
process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly
crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide
16b in the presence of RhCl3 is achieved without any epimerization of the acid/base labile stereogenic
center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate
is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl3. The amino lactam
4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the
reaction solution directly, as such intramolecular transamidation has been dramatically suppressed
via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the
tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale
preparation, is accomplished in 23% overall yield.
Introduction
advantages such as lack of body weight gain and decreased
incidence of hypoglycemic episodes over other existing anti-
diabetic agents. In addition, DPP-4 inhibitors could poten-
tially alter the disease progress by restoring the β-cell
function of the pancreas.3
The biological mechanism by which DPP-4 inhibitors oper-
ate involves stabilization of incretin hormones glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotro-
pic polypeptide (GIP). GLP-1 and GIP are secreted by
intestinal L-cells and K-cells in response to meal ingestion,
respectively.5 To date, it is well recognized that both GLP-1
and GIP can stimulate insulin secretion from β-cells. In
addition, GLP-1 can also inhibit glucagon secretion and
Type 2 diabetes mellitus (T2DM) is a progressive disease.
The worldwide prevalence of T2DM is growing at a contin-
uous rate and could reach a total of 220 million cases by
2010.1,2 Recently, protease dipeptidyl peptidase IV (DPP-4)
inhibitors have emerged as a new class of antihyperglycemic
agents for the treatment of T2DM3,4 and offer several
(1) (a) International Diabetes Federation (IDF). Diabetes Atlas, 3rd ed.;
December 2006, http://www.iotf.org/diabetes.asp. (b) Andrews, M. U.S. News
World Rep., 2009, Feb 9.
(2) Zimmet, P.; Alberti, K. G. M. M.; Shaw, J. Nature 2001, 414, 782–787.
(3) For leading references, see: (a) Thornberry, N. A.; Weber, A. E. Curr.
Topics Med. Chem. 2007, 7, 557–568. (b) Gwaltney, S. L. II; Stafford, J. A.
slow gastric emptying, which are all beneficial in controlling
3,6
ꢀ
Annu. Rep. Med. Chem. 2005, 40, 149–165. (c) Ahren, B.; Landin-Olsson, M.;
blood glucose and hemoglobin A1C
.
Unfortunately, the
Jansson, P. A.; Svenson, M.; Holmes, D.; Schweizer, A. J. Clin. Endocrinol.
Metab. 2004, 89, 2078–2084. (d) Weber, A. J. Med. Chem. 2004, 48, 4135–
4141.
(4) (a) Florentin, M.; Liberopoulos, E. N.; Mikhailidis, D. P.; Elisaf, M.
S. Expert Opin. Pharmacother. 2008, 9, 1705–1720. (b) Matikainen, N.;
(5) For review, see: Holst, J. J. Diabetogoia 2006, 49, 253–260.
(6) For lead references, see: (a) Chia, C. W.; Egan, J. M. Drug Discovery
Today: Disease Mech. 2005, 2, 295. (b) Holst, J. J. Curr. Opin. Endocrin.
Diabetes Obesity 2005, 12, 56–62.
€
Manttari, S.; Schwizer, A. Diabetologia 2006, 49, 2049–2057.
€
DOI: 10.1021/jo902573q Published on Web 02/03/2010
r
J. Org. Chem. 2010, 75, 1343–1353 1343
2010 American Chemical Society

Xu et al.
SCHEME 1. Retrosynthetic Analysis of Aminopiperidine-
Fused Imidazopyridine 1
JOCFeatured Article
half-life of GLP-1 in human is very short (<2 min) as the
N-terminal amino acids are selectively clipped off by DPP-4.
Therefore, inhibition of DPP-4 can stabilize GLP-1 and GIP
and thus increase circulating levels of endogenous intact
GLP-1 and GIP to allow their therapeutic benefits to be
realized. This is a clinically proven, therapeutically novel
approach to the treatment of T2DM.2,3
Aminopiperidine-fused imidazopyridine 1 is a potent, se-
lective DPP-4inhibitor and a drug candidate for the treatment
of T2DM. The key challenge to synthesize 1 is to construct
its piperidine moiety enantioselectively and efficiently. The
piperidine ring is fused in a tricyclic system and has two
adjacent stereogenic centers in a trans relationship. Asym-
metric synthesis of this unique skeleton, as well as similar
structures, was lacking at the inception of this work.7 The
previously described synthesis of 1 was racemic and required
chromatographic resolution of a late-stage racemic intermedi-
ate.7 Therefore, to develop a practical synthesis of 1 that is
suitable for large-scale preparation to support the develop-
ment of this drug candidate, we required an efficient asym-
metric approach to the piperidine-fused imidazopyridine
skeleton with the desired stereochemistry and functionality.
Application of multiple component couplings to synthe-
size organic molecules efficiently and practically is a desir-
able synthetic strategy,8 since multiple transformations can
be achieved through a series of cascade reactions in one-pot.
The piperidine-fused imidazopyridine skeleton in 1 could be
constructed via a convergent, transition-metal-assisted cou-
pling7a,9 of intermediates 3 and 4 (Scheme 1). We envisioned
that the key intermediate 410 could be derived from nitro
piperidinone 5. Through a cascade coupling11 of 7 with a
suitable imine species 6, which arises from a condensation of
a primary amine and formaldehyde, piperidinone 5 could in
turn be accessed. Although at the time of this work the
literature precedence for this type of cascade coupling trans-
formation to build up intermediates such as 5 was un-
known,11 enantiomerically pure substrate 7 could be ob-
tained in one-step by taking advantage of recent methodol-
ogy for the asymmetric Michael addition of malonates to
nitrostyrenes.12 In this paper, we report a target-oriented,
reaction mechanism-guided, asymmetric synthesis of 1 via a
novel cascade coupling to realize the synthetic strategy
described above.
Results and Discussion
(7) (a) Edmondson, S. D.; Mastracchio, A.; Cox, J. M.; Eiermann, G. J.;
He, H.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Wu, J.
K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Roy, R. S.; Weber, A. E. Bioorg. Med.
Chem. Lett. 2009, 19, 4097–4101. (b) Cox, J. M.; Edmondson, S. D.; Harper, B.;
Weber, A. E. PCT Int. Appl. WO2006039325, 2006.
(8) For recent reviews, see: (a) Lelais, G.; MacMillan, D. W. C.
Aldrichim. Acta 2006, 39, 79–87. (b) Palomo, C.; Mielgo, A. Angew. Chem.,
Int. Ed. 2006, 45, 7876–7880.
Preparation of Coupling Precursor 7. Starting from com-
mercially available 2,4,5-trifluorobenzaldehyde (8), nitro-
styrene 10 was prepared through a Henry reaction.13
Although the Henry alcohol 11 could be easily obtained in
near-quantitative yield in the presence of a catalytic amount
of base, dehydration of 11 through activation of the OH
group under the reported conditions14 resulted in formation
of a dark product with decomposition, which led to a
difficult isolation of the crystalline solid 10.15 After several
attempts, we were glad to find that slowly quenching sodium
aci salt16 9 into aqueous HCl-ZnCl2 at 0 °C over 2-4 h
could effectively yield the desired nitrostyrene 10 as the
major product, which crystallized directly during the
quench. The sodium aci salt 9 was easily obtained in almost
quantitative yield by treating 2,4,5-trifluorobenzaldehyde
(9) For a lead reference on metal-assisted coupling for the formation of
amides, see: Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421–7428.
(10) In fact, piperidinones such as 4 are pharmaceutically useful inter-
mediates. For examples, see: (a) Cox, J. M.; Harper, B.; Mastracchio, A.;
Leiting, B.; Roy, R. S.; Patel, R. A.; Wu, J. K.; Lyons, K. A.; He, H.; Xu, S.;
Zhu, B.; Thornberry, N. A.; Weber, A. E.; Edmondson, S. D. Bioorg. Med.
Chem. Lett. 2007, 17, 4579–4583. (b) Pei, Z.; Li, X.; von Geldern, T. W.;
Longenecker, K.; Pireh, D.; Stewart, K. D.; Backes, B. J.; Lai, C.; Lubben, T.
H.; Ballaron, S. J.; Beno, D. W. A.; Kempf-Grote, A. J.; Sham, H. L.;
Trevillyan, J. M. J. Med. Chem. 2007, 50, 1983–1987. (c) Edmondson, S. D.;
Mastracchio, A.; Cox, J. M. PCT Int. Appl. WO2006058064, 2006. (d)
Ashwell, S.; Gero, T.; Ioannidis, S.; Janetka, J.; Lyne, P.; Su, M.; Toader, D.; Yu,
D.; Yu, Y. PCT Int. Appl. WO2005066163, 2005. (e) Cody, W. L.; Holsworth, D.
D.; Powell, N. A.; Jalaie, M.; Zhang, E.; Wang, W.; Samas, B.; Bryant, J.; Ostroski,
R.; Ryan, M. J.; Edmunds, J. J. Bio. Med. Chem. 2004, 13, 59–68.
(11) For a preliminary communication on cascade coupling, see: Xu, F.;
Corley, E.; Murry, J. A.; Tschaen, D. M. Org. Lett. 2007, 9, 2669–2672.
(12) For examples, see: (a) Terada, M.; Ube, H.; Yaguchi, Y. J. Am.
Chem. Soc. 2006, 128, 1454–1455. (b) Evans, D. A.; Seidel, D. J. Am. Chem.
Soc. 2005, 127, 9958–9959. (c) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125. (d) Li, H.; Wang, Y.;
Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 127, 9906–9907. (e) Watanabe,
M.; Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004,
126, 11148–11149. (f) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger,
S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215–10216. (g) Hynes, P. S.;
Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389–1391. (h) Zhu, Q.; Huang,
H.; Shi, D.; Shen, Z.; Xia, C. Org. Lett. 2009, 11, 4536–4539.
(13) One-pot synthesis led to a low yield of fluoro-substituted styrenes;
see: Jacobo, R.; Cota, A.; Rogel, E.; Garcia, J. D.; Rivero, I. A.; Hellberg,
L. H.; Somanathan, R. J. Fluorine Chem. 1994, 67, 253–255.
(14) For examples, see: (a) Denmark, S. E.; Marcin, L. R. J. Org. Chem.
1993, 58, 3850–3856. (b) Saikia, A. K.; Barua, N. C.; Sharma, R. P.; Ghosh,
A. C. Synthesis 1994, 685–686.
(15) Attempts to accomplish the dehydration with TMSCl, MsCl, t-
BuCOCl/Et3N, i-Pr2NEt, DBU, and tetramethylguanidine in various sol-
vents resulted in unsatisfactory results.
(16) (a) Anderson, W. K.; Dabrah, T. T.; Houston, D. M. J. Org. Chem.
1987, 52, 2945–2947. (b) Worrall, D. E. et al. Organic Synthesis; Wiley: New
York, 1941; Collect. Vol. 1, p 413.
1344 J. Org. Chem. Vol. 75, No. 5, 2010

Xu et al.
JOCFeatured Article
TABLE 1. Selected Results for the Preparation of Nitrostyrene 10
through aci Salt 9
TABLE 2. Optimization of Michael Addition
ratio
of 10:11
isolated yield
of 10a (%)
entry
additives
equiv
1
2
3
4
5
None
MgCl2
ZnCl2
ZnCl2
ZnCl2
2.5:1
3.6:1
3:1
3.5:1
7:1
63
70
N/A
69
5
1
2
5
81
aThe aci salt 9 was quenched with aq HCl at 5 °C over 2-4 h.
SCHEME 2. Preparation of Nitrostyrene 10 through aci Salt 9
and Plausible Pathways
temp (°C)
-20 °C
95.5
0.05
94
-15 °C
93
0.2
-10 °C
90
0.4
20 °C
85.4
1
eea,b (%)
H2O in THF (%)
eea,c (%)
89.9
87.4
80.3
aUnless otherwise mentioned, the enantiomeric excess (ee) was de-
termined by high-performance liquid chromatography (HPLC): Chir-
alcel OD-H column, 4.6 ꢀ 250 mm, 5 μm particle size, 20 °C, isocratic
10% i-PrOH in hexane; flow rate: 1.5 mL/min; UV detection: 215 nm.
bIn the presence of 2 mol % of DMQ in dry THF reaction solution. cIn
the presence of 1 mol % of DMQ at -15 °C.
of the reaction depends on both reaction temperature and
water content (Table 2). Regarding the former, lower reac-
tion temperatures resulted in higher ee. However, the reac-
tion became sluggish below -25 °C. With respect to the
latter, the presence of a small amount of water significantly
decreased the enantioselectivity (Table 2), while keeping the
reaction system dry at -20 °C yielded 7 in >95% ee repro-
ducibly.
To isolate 7, a straightforward process was developed.
After the reaction was complete, the crude reaction solution
was solvent-switched to i-PrOH. Water was then added
to the reaction mixture and 7 directly crystallized from aq
i-PrOH in 88% isolated yield with about 1% ee upgrade.
One-Pot Cascade Coupling. Various methods have been
developed for the preparation of lactams and cyclic amines;
however, efficient asymmetric synthesis of functionalized
piperidinones with the stereochemistry setup such as 419-21
has been lacking. Interestingly, the core structure of our
retro-synthetic precursor piperidinone 4 also exists in a
number of pharmaceutically important compounds.10
As shown in our retrosynthetic analysis (Scheme 1), we
required the use of nitro malonate 7 to trap an active,
unstable alkyl imine species in order to form the desired
corresponding nitro piperidinone precursor. Condensation
of a primary alkyl amine and formaldehyde led to instanta-
neous formation of the imine species 6 (Scheme 3), which
could be masked as its corresponding trimer 1222 during the
reaction. However, at the time of this work, the literature
(8) and nitromethane with NaOH in aqueous MeOH. The
use of ZnCl217 to significantly improve the ratio of 10 and 11
is unprecedented and proved to be robust and reproducible
(Table 1, entry 5). Presumably, Lewis acid ZnCl2 promoted
the dehydration (Scheme 2, path a) of the initially quenched
enolized intermediate rather than the Henry alcohol 11 since
attempts to convert the isolated Henry alcohol 11 to nitro-
stryene 10 under acidic conditions such as in aq HCl or HCl/
ZnCl2 were unsuccessful (path c) and a good recovery of 11
was obtained under these conditions.
Thus, the desired 10 was directly obtained from the
quenched reaction mixture as a yellowish crystalline solid
in >80% yield and >98 area% purity (HPLC) through
simple filtration, while the Henry alcohol 11 was effectively
rejected in the mother liquors.
With nitrostyrene 10 secured, we turned our attention to
enantioselective Michael addition of dimethyl malonate on
nitrostyrene 10 to set up the desired tertiary stereogenic
center of the key intermediate 7. Several catalysts have been
reported to achieve this type of Michael addition with high
enantioselectivity.12 Our studies on this step focused on the
use of readily obtained demethyl quinidine (DMQ).12d,18
After optimization, the desired product 7 was obtained in
99% conversion and ca. 95% ee between -20 and -15 °C in
the presence of 1.1 equiv of dimethyl malonate and 0.5-1
mol % of catalyst (vs typical 10 mol % loading in literature).
Our experimental results revealed that the enantioselectivity
(19) For examples, see: Kumar, S.; Flamant-Robin, C.; Wan, Q.;
Chiaroni, A.; Sasaki, N. A. J. Org. Chem. 2005, 70, 5946-5953 and
references therein
(20) For similar three-component couplings, see: (a) Nara, S.; Tanaka,
R.; Eishima, J.; Hara, M.; Takahashi, Y.; Otaki, S.; Foglesong, R. J.;
Hughes, P. F.; Turkington, S.; Kanda, Y. J. Med. Chem. 2003, 46, 2467–
2473. (b) Desai, M. C.; Lefkowitz, S. L. Bioorg. Med. Chem. Lett. 1993, 3,
2083–2086. (c) Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron
Lett. 1993, 34, 5831–5834. (d) Bhagwatheeswaran, H.; Gaur, S. P.; Jain, P. C.
Synthesis 1976, 615–616.
(21) For recent examples of multiple-component coupling involving
€
nitroalkane or amine/formaldehyde, see: (a) Enders, D.; Huttlm, M. R.
(17) To the best of our knowledge, the use of Lewis acids such as ZnCl2 to
enhance the selectivity of the formation of nitro styrenes has not been
reported.
(18) For an improved, practical preparation of DMQ without chromato-
graphic purification, see the Supporting Information.
ꢀ
M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. (b) Sunden, H.;
Ibrahem, I.; Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44,
4877-4880 and references therein.
(22) Overman, L. E.; Burk, R. M. Tetrahedron Lett. 1984, 25, 1635–1638.
J. Org. Chem. Vol. 75, No. 5, 2010 1345

Xu et al.
JOCFeatured Article
SCHEME 3. Cascade Three-Component Coupling in One Pot
precedence for this type of cascade coupling transformation
was unknown.11 Other similar three-component coupling
transformations were limited to the use of an aryl aldehyde to
form a stable imine species that was then captured by an
ester. The use of the nitro malonates such as 7 had not been
reported.20
and the C-3 H adjacent to the two ester groups were believed
to suppress the formation of potential competing products
via Mannich reaction on C-3. These Mannich products were
not observed under our reaction conditions. Without work-
up, the crude reaction mixture 14c was treated with NaOH
followed by decarboxylation of the resulting acid 15 upon
acidification to give a mixture of cis/trans 16a,b in one-pot.
However, our initial results showed that the cis/trans ratio
(16a:16b) changed significantly as the decarboxylation con-
ditions such as reaction time, pH, and temperature were
varied. In order to further understand this observation, we
screened various conditions to facilitate the epimerization of
the nitro group. Interestingly, the cis 16a isolated through
chromatography purification can be partially converted to
the trans isomer 16b after several weeks at ambient tempera-
ture; in comparison, the isolated trans isomer is stable for
several months under the same conditions, which also in-
dicates that the trans isomer is the more thermodynamically
stable form. More interestingly, the undesired cis piperidi-
none 16a, is always the dominant product in a homogeneous
reaction solution under acidic epimerization conditions.26
The ratio of 16a:16b27 could be as high as 97:3 if the
After several experiments,23 we found that the use of alkyl
amines, such as 4-methoxybenzylamine and 3,4-dimethoxy-
benzylamine, did give the desired corresponding coupling
products 14a,b (for more information, see the Supporting
Information). However, taking into consideration the ease of
operation as well as atom-economical efficiency to transform
14 into retro-synthetically desired precursor 4, allylamine
became our amine of choice for further development. The use
of allylamine offered advantages over the use of other amines
based on our recent studies on selective deprotection of the
N-allylamide.24 With further optimization, we were pleased
to find that 14c as a mixture of isomers could be obtained in
90% yield by treatment of malonate 7 with 1.3 equiv of
allylamine and 1.05 equiv of aqueous HCHO in i-PrOH at
50 °C (Scheme 3). The stoichiometric utilization of formal-
dehyde was important in this cascade reaction. In fact,
overcharging formaldehyde could lead to a lower yield, as
the excess formaldehyde could further react with 14 to form
bispidine derivatives.11 Nevertheless, the formation of bis-
pidine byproducts were easily suppressed under the above
optimized conditions.
(25) Presumably due to the less nucleophilic aryl amine nitrogen, the
cascade coupling stalled at intermediate 13 when aryl amines such as 4-
methoxyphenylamine were used. The formation of 13a thus further supports
the stepwise reaction pathway (Scheme 3).
Scheme 3 also outlines a plausible mechanism for this
cascade transformation.25 The steric hindrance and pKa
differences between the C-1 H adjacent to the nitro group
(23) For an alternative synthesis as well as optimization of the cascade
reaction using 4-methoxybenzyl amine, see the Supporting Information.
(24) For deprotection of N-allyl acyclic amides with cat. RhCl3, see:
Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72, 6298-6300. However,
deprotection of N-allyl lactams as described here gave a mixture of depro-
tected lactam 17 and N,O-acetal lactam 18.
(26) It is not very clear why the cis isomer is the major product through
acidic equilibrium. Presumably, the formation of the cis isomer is kinetically
favored under acidic conditions.
(27) Unless otherwise mentioned, the ratio of cis/trans or diastereomers
was determined by HPLC analysis (YMC Pack Pro C18, 5 μm particle size,
250 ꢀ 4.6 mm, mobile phase: 10 mM H3PO4/MeCN).
1346 J. Org. Chem. Vol. 75, No. 5, 2010

Xu et al.
JOCFeatured Article
TABLE 3. Selected Results of RhCl3-Catalyzed Isomerization
entry
solvents
RhCl3 (mol %)
temp (°C)
time (h)
ratio of 17:18:19
1
2
3
4
5
6
7
MeOH
EtOHa
n-PrOH
2
2
64
78
95
95
95
95
95
10
20
17
16
16
20
24
no reaction
1:1: 9
1:4-6:0.03
2-3
2
2.5
2.5
2.5
n-PrOHb
19 þ its epimer
80% aq n-PrOH
i-PrOH
H2O-DMF
(17 þ its epimer):(18 þ its epimer) = 1:2.4
1: 6: 1
19 only
aSluggish reaction. b0.25 equiv of i-Pr2NEt was used.
decarboxylation was carried out homogenously in aq HCl/
i-PrOH at 55 °C. By contrast, epimerization of the cis isomer
to its corresponding thermodynamically favored trans iso-
mer could be realized upon exposure to weak bases; however,
poor cis/trans ratios in favor of the trans isomer were
obtained. For example, the ratio of 16a:16b was only 1:2
after equilibrium between 16a and 16b was reached in aq
NaHCO3 in i-PrOH at 45 °C.
An efficient isolation of the desired trans isomer 16b was
eventually achieved by designing a base-catalyzed, dynamic
crystallization-driven process. The desired trans isomer 16b was
allowed to crystallize from the reaction solution, as the cis
isomer 16a in the supernatant was continuously converted to
the thermo-dynamically favored trans isomer 16b through a
base-promoted equilibrium of both isomers in the supernatant.
In practice, without any aqueous workup, the one-pot cascade
reaction mixture after decarboxylation was pH-adjusted to
pH = 7-8 by simply adding aq NaHCO3. Upon aging at
45 °C, the desired trans isomer of 16b gradually crystallized and
was isolated directly from crude aqueous i-PrOH solution by a
simple filtration in 76% overall isolated yield and >98 area%
purity (HPLC). Only about 1-2% of the undesired cis isomer
of 16a remained in the mother liquor.
Rh-Catalyzed Isomerization/Deallylation. With the de-
sired trans-piperidinone 16b in hand, we set forth to prepare
the precursor 4 through reduction of the nitro group and
removal of the N-allyl group. To realize this transformation,
one of the challenges was to select the proper order of events.
For example, reduction of the nitro group in 16b prior to
N-allyl group removal would have limited our options to
those reduction methods that are not ideal for large scale
preparation,7,28 in order to prevent saturation of the N-allyl
moiety. Alternatively, deprotection of N-allylamide prior to
reduction of nitro group would have to avoid epimerization
of the labile nitro-bearing stereogenic center in 16b. While
various methods can be applied to deprotect N-allylamines,
the deprotection of N-allylamides is considerably more
challenging,29 and few methods are currently available.30,31
However, our recent studies on the deprotection of N-allyl
acyclic amides via isomerization/hydrolysis in the presence
of a catalytic amount of RhCl3 improved the attractiveness
of the allyl protecting group for amide synthesis.24
After several experiments, we found that the reaction tem-
perature of the rhodium-catalyzed isomerization of N-allyl-
amide clearly played an important role30b to effectively convert
16b to a mixture of 17 and N,O-acetal 18. Table 3 depicts some
selected results. The rhodium-catalyzed isomerization and
deprotection in refluxing EtOH gave the undesired enamine
1932 as a major product (Table 3, entry 2). By contrast, no
reaction was observed in refluxing MeOH (Table 3, entry 1).
However, when the reaction temperature was increased to 95 °C
in dry n-PrOH, two major products, the desired amino acetal 18
(R = n-Pr) and deallylated lactam 17, were formed in high yield
in the presence of 2 mol % of RhCl3, while the undesired
enamine 19 was reduced to <0.5% (Table 3, entry 3). Similar
results were obtained when the reaction was carried out in
MeOH or EtOH in a sealed-tube between 90 and 95 °C.
Reaction of RhCl3 with an alcohol not only provides a
rhodium hydride species, which is believed to be the active
species that catalyzes the isomerization of N-allylamide 16b,
but also generates a crucial catalytic amount of HCl.33,34
(31) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Org. Lett.
2001, 3, 3781–3784. (b) Alcaide, B.; Almendros, P.; Alonso, J. M. Tetra-
hedron. Lett. 2003, 44, 8693–8695. (c) For a report on the Ru-catalyzed
isomerization but not applied to N-allyl deprotection, see: Krompiec, S.;
Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-Bialon, J.; Kasperczyk, J.
Tetrahedron Lett. 2004, 45, 5257–5261.
(32) Attempts to hydrolyze 19 under acidic conditions resulted in epimer-
ization of the stereogenic center adjacent to nitro group. In addition,
subsequent hydrogenation would also reduce enamine 19 to the undesired
corresponding n-propyl lactam.
ꢀ
(28) Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; ACS
(33) For relevant observations, see: (a) Cramer, R. J. Am. Chem. Soc.
1967, 89, 1633-1639 and references therein. (b) Trebellas, J. C.; Olechowski, J.
R.; Jonassen, H. B.; Moore, D. W. J. Organomet. Chem. 1967, 9, 153. (c) Hirai,
H.; Sawai, H.; Ochiai, E.-I.; Makishima, S. J. Catal. 1970, 17, 119. (d) Su, A. C.
Adv. Organomet. Chem. 1979, 17, 269. These mechanistic studies, including
deuterium labeling experiments, suggest a Rh(I) hydride species is likely the active
catalyst, since Rh(III) is reduced to Rh(I) in the presence of olefins and alcohol
solvents.
Monograph 188; American Chemical Society: Washington, DC, 1996.
(29) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synth-
esis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999.
(30) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139–2145. (b)
Nemeto, H.; Jimenez, H. N.; Yamamoto, Y. Chem. Commun. 1990, 1304–6.
(c) Kanno, O.; Miyauchi, M.; Kawamoto, I. Heterocycles 2000, 53, 173–181.
(d) Cainelli, G.; Giacomini, D.; Galetti, P. Synthesis 2000, 289–294. (e)
Cainelli, G.; DaCol, M.; Galetti, P.; Giacomini, D. Synlett 1997, 923–924. (f)
Chiusoli, G. P.; Costa, M.; Fiore, A. Chem. Commun. 1990, 1303–1304.
(34) Liberation of HCl by treating RhCl3 with alcohol solvents was also
observed in our previous communication, cf. ref 24.
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SCHEME 4. Plausible Pathways of the RhCl3-Promoted Iso-
merization
(Table 3, entry 6), as expected. Replacing an alcohol with
other solvents (Table 3, entry 7) also made the isomerization
stall at the enamine stage. In summary, under our optimiza-
tion conditions, the formation of enamine 19 can be repro-
ducibly reduced to <0.5% (Table 3, entry 3) without epimeri-
zation of the acid/base labile stereogenic center adjacent to the
nitro group.
Hydrolysis and Isolation of 4. At this point, acidic depro-
tection of N,O-acetal 18 to nitro piperidinone 17 was not
practical, because hydrolysis of N,O-acetal 18 under acidic
conditions resulted in formation of the corresponding un-
desired, epimerized cis-piperidionone. This fully agrees with
our previous observation: the cis-nitropiperidinones such as
16a always become the dominant products upon exposure of
the corresponding trans isomers to acidic conditions.
Thus, without any workup, the crude rhodium-catalyzed
isomerization reaction mixture of 17/18 was subjected to
hydrogenation (Raney Ni, 90 psi, 40 °C, MeOH/n-PrOH) to
give a mixture of the corresponding amines cleanly. The
presence of RhCl3 did not have any adverse effects on
hydrogenation. After completion of the reduction of nitro
intermediates 17/18, the reaction mixture was then solvent
switched to aq n-PrOH and treated with p-toluenesulfonic
acid (pTSA) to hydrolyze acetal 22 to 4. The choice of using a
combination of n-PrOH/water (5:1) and pTSA was carefully
selected after evaluating several acids in various solvents, so
that the desired amine pTSA salt 4 crystallized directly from
the reaction mixture as the hydrolysis proceeded.
It is worthwhile to note that the direct crystallization of 4 as
its pTSA salt from the crude reaction mixture allowsfor further
harnessing the reaction pathways of hydrolysis of 22 to sup-
press formation of the rearranged byproduct 24 (Table 4). The
formation of transamidation byproduct 24 was presumably
formed through intermediate 23 via intramolecular nucleophi-
lic attack of the amide carbonyl group by the amino group in 4
and/or 22.35 The undesired side reactions to form 24 was
kinetically minimized/controlled by maintaining a low con-
centration of 4 in the supernatant as the pTSA salt 4 pre-
cipitated from the reaction mixture during the hydrolysis. By
contrast, if the hydrolysis was carried out in a homogeneous
solution in the presence of strong acids such as HCl or
MeSO3H in aqueous alcohol or DMSO, the formation of a
significant amount of rearranged pyrrolidinone 24 accompa-
nied with small amount of hydrolyzed acid 26 was inevitable.36
To understand the kinetic/dynamic equilibrium profile of
the intramolecular transamidation between 4 and 24 and,
therefore, to determine optimal reaction conditions to sup-
press the formation of byproducts, the isolated free base 4
was treated with excess of HCl (∼3.5 equiv) in aqueous
n-PrOH, as such the reaction could be carried out in a
homogeneous solution. After 24 h at 56 °C, a ratio of 4 to
24 (1:1.85 in favor of pyrrolidinone 24) at equilibrium was
achieved (Table 4, entry 5 and the Supporting Information).
The kinetic rate differences of the interconversion at differ-
ent concentrations of the free acid (Hþ) and the protonated 4
The existence of such a trace amount of HCl in the reaction
solution should not cause any epimerization of the labile
stereogenic center adjacent to the nitro group, and indeed,
the apparent pH of the reaction solution was observed
experimentally to be pH = 4. However, the catalytic amount
of HCl does play a pivotal role in converting the undesired
enamine intermediate 19, to the desired N,O-acetal interme-
diates 18 via a plausible iminium intermediate 20 (Scheme 4).
Enamine 19 is believed to be formed first24,31 through
rhodium-catalyzed isomerization. Furthermore, the trace
amount of HCl present in the reaction solution also pro-
motes the partial exchange of the N,O-acetal 18 to dipropyl
acetal 21 as the deprotected lactam 17 is liberated. The
formation of acetal 21 was observed during the reaction.
The plausible reaction pathways are depicted in Scheme 4.
Although a mixture of deallylated lactam 17 and N,O-acetal
18 was obtained, hydrogenation reduction of the mixture of
17 and 18 followed by aqueous acid treatment would result in
the desired precursor 4 without any epimerization.
Evidence to confirm the important role of HCl in this
transformation are also shown in Table 3. When Hunig’s
base (Table 3, entry 4) was introduced to the reaction
solution to neutralize the trace amount of HCl generated
from RhCl3 and keep the reaction under basic conditions, the
pathways to form the lactam 17 as well as N,O-acetal 18
through HCl promoted acetal formation and exchange were
shut down. This observation also confirmed that the path-
ways to form 17 and 18 are clearly not catalyzed by the active
rhodium species. In addition, epimerization of the labile
stereogenic center adjacent to the nitro group was also
observed in the presence of base. Increasing the steric bulki-
ness of the alcohol, which acted as a nucleophile during these
transformations, resulted in more unconsumed enamine 19
(35) For examples of intramolecular transamidation, see: (a) Tanaka,
K.-I.; Nemoto, H.; Sawanishi, H. Tetrahedron: Asymmetry 2005, 16, 809–
815. (b) Langlois, N. Org. Lett. 2002, 4, 185–187. (c) Langlois, N. Tetra-
hedron. Lett. 2002, 43, 9531–9533.
(36) Although isolation of 24 and 26 from the reaction mixture was
difficult, their structures could be unambiguously characterized by applying
NMR techniques.
1348 J. Org. Chem. Vol. 75, No. 5, 2010

Xu et al.
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TABLE 4. Selected Results of the Interconversion between 4, 24, and 26
entry
substrate
reaction conditions
conc (M)
products/results
1
2
4
4
MeOH/n-PrOH (1:1), 55 °C, 24 h
0.137a,b
0.27a,c
0.137a,c
0.02a,b
0.02a,b
0.02a,b
2% 24
1.2 equiv of pTSA, 83% aq n-PrOH, 53 °C, 24 h
6.4% 24, < 0.5% 26
3.5% 24, < 0.5% 26
2.4% 24, < 0.5% 26
10.6% 24, < 0.5% 26
15.3% 24, < 0.5% 26
3
4
4
4
1.5 equiv of pTSA, 83% aq n-PrOH, 53 °C 24 h
1.0 equiv of pTSA, 2.5 equiv of HCl,
83% aq n-PrOH, 53 °C 24 h
5
6
7
4
3.66 equiv of HCl, 50% aq n-PrOH, 56 °C, 24 h
0.082a,b
0.137a,b
43% 24, < 0.5% 26
64.9% 24, < 0.5% 26
by NMR: 4/24/26 = 2:1:0.1;
90% of 26 consumed.
4, 95% conversion; 24, not detected.
4/24/26 (1:1:1)
1.1 equiv of pTSA, DMSO-d6, rt, 7 days
26
pH ∼2, 85% aq n-PrOH, rt, overnight
aUnless otherwise mentioned, the product distribution profile was arbitrarily compared after 24 h under varied reaction conditions and did not
necessarily reach the equilibrium. For more information, see the Supporting Information. Homogenous solution. cSlurry, 1 g of 4 in 9 mL of 85%
n-PrOH in water.
b
in the solution or supernatant are also depicted in Figure 1.
In comparison with the kinetic profile of a HCl treated
homogeneous reaction solution, the profile of a pTSA-
treated reaction slurry (Figure 1, plot 1, line a vs lines b
and c; plot 2, line d vs lines e and f) clearly shows that the
intramolecular transamidation of 4 to 24 becomes signifi-
cantly slower as the majority of 4 is precipitated to maintain
lower concentration of 4 in the supernatant, while the
concentration of the free acid (Hþ) unneutralized by amine
4 and 24 also maintains low. The concentration of the Hþ in
the reaction mixture remained unchanged and no consumption
of acid was observed, as the concentration of acid unneutralized
by amine 4 or 24 could affect the reaction rate. This kinetics
observation is in line with the results of the concentration effects
on transamidation (Table 4, entries 2-5). The more dilute the
reaction is, the slower the formation of 24. In addition, as
expected, the less amount the acid (Table 4, entries 2 and 3)
used, the slower the conversion to 24. In the absence of an acid,
treatment of the free base 4 in MeOH/n-PrOH at 55 °C for 24 h
only resulted in ∼2% of 24 (Table 4, entry 1).
at 80 °C, in aq HCl/n-PrOH (pH = 2) at ambient temperature
overnight also gave kinetic favored cyclized 4 (Table 4, entry
7). These results are consistent with the observation that the
formation of hydrolyzed 26 was always low when 4 was
treated with anacid(Table 4 andthe Supporting Information).
Nevertheless, with a good understanding of the reaction
pathways, an easily operated, three-step through process was
finally developed (Scheme 5). Therefore, via direct crystal-
lization of 4 as its pTSA salt during the hydrolysis, a kinetic
control of the product distribution was gained and the
formation of undesired 24 was minimized. The hydrolysis
of the N,O-acetal 22 was observed to be faster than the
intramolecular transamidation. Typically, under our opti-
mized conditions, after 3-5 h age at 55 °C the hydrolysis of
N,O-acetal 22 is completed in the presence of 1.2 equiv of
pTSA and 4 was then isolated as its pTSA salt in 62% yield
over three steps (>99% purity and >98% ee). A significant
ee upgrade (e.g., upgrade from 93% ee to 98% ee) was also
achieved during the isolation of the pTSA salt 4.
Cu-Assisted Coupling and Endgame. Several options were
explored to finish the synthesis of 1. 4-Bromo-3-aminopyr-
idine (3)37 did undergo Cu-mediated coupling with the free
base amine 4 to give 1 directly. However, isolation and
purification of 1 from this reaction was challenging and it
was difficult to meet the pharmaceutical industry purity
Interestingly, NMR studies showed that after a mixture of
4/24/26(∼1:1:1) was aged inthe presenceof1.2 equivof pTSA
in DMSO-d6 at ambient temperature for a week, the ratio was
changed to 4/24/26 = 2:1:0.1. Pyrrolidinone 24 remained
unchanged while the open acid 26 was cyclized to 4 presum-
ably via intermediate 25, which is favored in terms of steric
hindrance in contrast to 27 (Table 4, entry 6). Exposure of
crude 26, which could be generated by treating 4 with NaOH
(37) (a) Stockmann, V.; Fiksdahl, A. Tetrahedron 2008, 64, 7626–7632.
(b) Tjosaas, F.; Kjerstad, I. B.; Fiksdahl, A. J. Heterocycl. Chem. 2008, 45,
559-562 and references cited therein.
J. Org. Chem. Vol. 75, No. 5, 2010 1349

Xu et al.
JOCFeatured Article
obtained in 88% assay yield after removal of the inorganic
salts, was directly subjected to the final deprotection step.
Treatment of the crude 29 with concd HCl in EtOH at
50 °C afforded 1. The tris-HCl salt 1 gradually crystallized
from the reaction solution as the deprotection proceeded. In
practice, this salt was conveniently isolated from EtOH/
i-PrOH (1:1) in 77% yield over two steps with >99.7%
purity and >97% ee. After a salt break of the tris HCl salt
with NaOEt, the free base 1 hydrate was crystallized from aq
EtOH, which further converted to the desired anhydrous
crystalline free base 1 upon drying at 60 °C overnight in 82%
yield (>99% purity).
Conclusion
We have developed a practical asymmetric synthesis
of potent, selective DPP-4 inhibitor 1, a drug candidate for
the treatment of T2DM. To achieve this target-oriented
synthesis, a novel three-component cascade coupling was
developed. Through a highly enantioselective malonate
addition to nitrostryene the first stereogenic center was set
up efficiently. Applying a selective cascade coupling allowed
for the effective assembling of the key piperidinone skeleton
with the desired stereochemistry setup. A simple base-
catalyzed, dynamic crystallization-driven process was devel-
oped to isolate the trans-piperidinone intermediate in one-
pot in high yield and purity, while the undesired cis piperdi-
none was fully utilized and converted to the desired trans
isomer. Further mechanistic studies on the rhodium-catalyzed
isomerization of allylamide led to an efficient synthetic strategy
for the preparation of the lactam 4. With a good understanding
of the kinetics of hydrolysis/intramolecular transamidation, the
desired hydrolyzed amine lactam 4 was directly isolated as its
crystalline pTSA salt from the crude reaction solution. Finally,
construction of the tricyclic core structure of 1 was hence
finished by a Cu(I)-catalyzed coupling-cyclization in one step.
Starting from commercially available 2,4,5-trifluorobenzyalde-
hyde, the overall yield for the synthesis of aminopiperidine-
fused imidazopyridine 1 was 23%. The success of our synthesis,
as an example of target-oriented and mechanism-guided
development, clearly demonstrated the powerful impact of
the integration of synthetic and physical organic chemistry.
FIGURE 1. Selected kinetic profile of transamidation. For a full
picture of the reaction kinetic profile, see the Supporting Informa-
tion. Note the use of pTSA or HCl did result in a significant
difference of the concentration of the protonated 4 in the reaction
supernatant/solution, as the corresponding HCl salt did not result in
any precipitation. Plot 1, line a, and plot 2, line d: a slurry of free
base 4 in n-PrOH/H2O (5:1, 0.137 M) in the presence of 1.2 equiv
of pTSA was aged at 56 °C. Plot 1, line b, and plot 2, line e:
a homogeneous solution of free base 4 in n-PrOH/H2O (1:1,
0.082 M) in the presence of 3.5 equiv of HCl was aged at 56 °C.
Plot 1, line c, and plot 2, line f: a homogeneous solution of free base 4
in n-PrOH/H2O (1:1, 0.137 M) in the presence of 3.5 equiv of HCl
was aged at 56 °C.
Experimental Section
1,2,4-Trifluoro-5-((E)-2-nitrovinyl)benzene (10). To a solution
of MeOH (600 mL), water (300 mL), and 2.5 N NaOH (300 mL)
at 5 °C was added a solution of 2,4,5-trifluorobenzyaldehyde (8,
100 g, 0.6246 mol) and MeNO2 (40 mL, 0.7495 mol) in MeOH
(100 mL) dropwise over 30-60 min, while the internal tempera-
ture was maintained between 5 and 10 °C with external cooling.
The reaction solution was then agitated between 0 and 5 °C for
an additional 30 min, maintained between 0 and 5 °C, and added
dropwise to a solution of ZnCl2 (426 g, 3.123 mol) in concd HCl
(130 mL, 1.5615 mol) and water (170 mL) at 0-10 °C with
vigorous agitation over 2-4 h. The light yellow product pre-
cipitated during the addition. After addition, the slurry was
allowed to warm to ambient temperature and aged for 1 h before
filtration. The wet cake was washed with 40% MeOH in water
(3 ꢀ 300 mL). The wet cake was suction dried at ambient
temperature to give 103 g of light yellow product 10. 81%
standards as a final product. In comparison, use of the Boc-
protected lactam 28 led to higher conversions and an improved
assay yield. The ∼20% increase in yield was presumably due to
the suppression of side reactions as the free amino moiety was
protected with a Boc group. In addition, commercially avail-
able 4-chloro-3-aminopyridine as a coupling partner was also
extensively evaluated under various conditions. Although the
copper catalyst, base, solvents, ligands and additives were
varied, no conditions were identified that could give the coupled
product 29 in a yield comparable to that obtained with 3.
Thus, 4 was treated with Boc2O in the presence of Et3N in
aq THF to afford 28 in 95% isolated yield and >99.5%
purity (Scheme 6). Finally, the Boc lactam 28 was coupled
with pyridine 3 in the presence of CuI, K2CO3, and N,N0-
dimethylethylenediamine. The crude reaction product 29,
1
yield: >98% purity. H NMR (400 MHz, CDCl3) δ 7.96 (d,
J = 13.8 Hz, 1 H), 7.65 (d, J = 13.8 Hz, 1 H), 7.37 (m, 1 H),
7.09 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 157.6 (ddd, J =
243.5, 9.2, 2.5 Hz), 152.5 (ddd, J = 259.8, 14.7, 12.9 Hz), 147.5
1350 J. Org. Chem. Vol. 75, No. 5, 2010

Xu et al.
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SCHEME 5. Through Process To Prepare pTSA Salt 4
SCHEME 6. Preparation of 1 via Cu-Assisted Coupling
(ddd, J = 248.0, 13.0, 3.1 Hz), 140.0 d, J = 11.7, 2.4 Hz),
130.6, 118.4 (ddd, J = 20.3, 4.3, 1.9 Hz), 115.1 (ddd, J = 14.3,
5.8, 4.4 Hz), 107.2 (dd, J = 27.9, 21.3 Hz). Anal. Calcd for
C8H4F3NO2: C, 47.31; H, 1.98; N, 6.90. Found: C, 47.27; H,
1.74; N, 6.86.
Hz, 1 H), 3.79 (s, 3 H), 3.63 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 167.5, 167.0, 156.2 (ddd, J = 247.3, 10.4, 2.8 Hz),
150.3 (dt. J = 255.1, 12.7 Hz), 147.0 (ddd, J = 246.6, 12.4, 3.4
Hz), 119.7 (dt, J = 14.8, 4.8 Hz), 118.6 (dd, J = 19.4, 6.3 Hz),
106.6 (dd, J = 28.5, 20.8 Hz), 75.8, 53.5, 53.3, 52.9, 37.9. Anal.
Calcd for C13H12F3NO6: C, 46.58; H, 3.61; N, 4.18. Found: C,
46.62; H, 3.37; N, 4.08.
(4R,5R)-1-Allyl-5-nitro-4-(2,4,5-trifluorophenyl)piperidin-2-
one (16b). To a solution of nitro malonate 7 (100 g, 0.2983 mol)
and allylamine (22.14 g, 0.3878 mol) in i-PrOH (500 mL) and
water (100 mL) at 50 °C was added 37% HCHO (25.42 g, 0.3132
mol) dropwise over 1-2 h. The reaction solution was stirred for
additional 2-3 h at 50 °C. NaOH (5 N, 104.4 mL, 0.522 mol)
was added in one portion at 50 °C. The reaction solution was
stirred additional 1-2 h at 50 °C. Concentrated HCl (54.2 mL,
0.6563 mol) was added dropwise over 30 min between 50 and
60 °C. The reaction solution was stirred at 55-60 °C for 2-3 h
and then cooled to 45 °C, and 5% NaHCO3 (ca. 100 mL) was
added dropwise to pH = 7-8. Then, water (100 mL) was added
dropwise over 30 min. The resulting slurry was stirred at 45 °C
for 1-2 h and cooled to ambient temperature slowly. After
aging overnight, the slurry was filtered. The wet cake was
displacement washed with 50% aq i-PrOH (2 ꢀ 150 mL) and
2-[(R)-2-Nitro-1-(2,4,5-trifluorophenyl)ethyl]malonic Acid Di-
methyl Ester (7). To a solution of nitrostyrene 10 (100 g, 0.4923
mol), dimethyl malonate (91 g, 0.6842 mol), and THF (400 mL)
at -15 to -20 °C was added demethylquinidine (DMQ)18 (1.5 g,
4.9 mmol) in one portion, and the solution was stirred overnight
(about 15 h) at -20 °C. The reaction solution was then solvent
switched to i-PrOH (final volume: about 400 mL) in vacuum.
The batch was seeded with crystalline 7 (0.5 g) and agitated for
2-3 h at ambient temperature. Water (107 mL) was then added
dropwise over 2-3 h. After addition, the slurry was aged for
additional 1 h at ambient temperature. Then, the slurry was
slowly cooled to 5 °C and aged for 3 h before filtration. The wet
cake was displacement washed with cold 70% i-PrOH in water
(120 mL, 0-5 °C) followed by a displacement wash (50%
i-PrOH in water 150 mL, 0-5 °C). Suction dry at ambient
temperature afforded 145 g of off-white solid 7: 88% yield;
>98% purity; 95% ee; 1H NMR (500 MHz, CDCl3) δ 7.11 (m, 1
H), 6.96 (m, 1 H), 4.90 (m, 2 H), 4.38 (m, 1 H), 3.93 (d, J = 9.4
J. Org. Chem. Vol. 75, No. 5, 2010 1351

Xu et al.
JOCFeatured Article
suction dried at ambient temperature to give 72 g of off-white to
J = 6.4 Hz, 1 H), 2.72 (m, 1 H), 1.71 (m, 1 H), 1.57 (m, 2 H), 1.50
(m, 1 H), 0.92 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 168.4,
168.3, 156.2 (ddd, J = 245.5, 9.6, 3.1 Hz), 156.1 (ddd, J = 245.5,
9.6, 3.1 Hz), 150.4 (dt, J = 253.5, 13.5 Hz), 147.5 (ddd, J =
247.3, 9.8, 3.1 Hz), 147.4 (ddd, J = 247.3, 9.8, 3.1 Hz), 122.4 (dt,
J = 16.0, 4.9 Hz), 122.2 (ddd, J = 16.0, 4.9 Hz), 117.5 (dd, J =
19.7, 6.2 Hz), 117.3 (dd, J = 28.3, 20.9 Hz), 107.3 (dd, J = 28.3,
20.9 Hz), 107.1 (dd, J = 28.3, 20.9 Hz), 84.40, 84.39, 83.9 (d, J =
1.8 Hz), 83.5 (d, J = 1.8 Hz), 77.9, 71.1, 71.0, 41.8, 41.2, 37.7,
36.7, 35.7, 35.1, 26.0, 25.8, 23.2, 23.0, 11.0, 10.9, 10.4, 9.90, 9.88.
Anal. Calcd for C17H21F3N2O4: C, 54.54; H, 5.65; N, 7.48.
Found: C, 54.47; H, 5.52; N, 7.42.
(4R,5R)-5-Nitro-1-((E)-propenyl)-4-(2,4,5-trifluorophenyl)pi-
peridin-2-one (19): 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J =
14.4, 1.0 Hz, 1 H), 7.03 (m, 1 H), 7.01 (m, 1 H), 5.16 (m, 1 H), 5.13
(m, 1 H), 4.05 (dd, J = 12.9, 7.6 Hz, 1 H), 3.99 (dd, J = 9.6, 6.0
Hz, 1 H), 3.90 (dd, J = 12.9, 5.6 Hz, 1 H), 2.91 (dd, J = 18.1, 6.0
Hz, 1 H), 2.79 (dd, J = 18.1, 10.0 Hz, 1 H), 1.77 (dd, J = 6.4, 1.5
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.6, 156.0 (ddd, J =
245.7, 9.6, 2.4 Hz), 150.2 (dt, J = 254.0, 14.4 Hz), 147.4 (ddd,
J = 247.5,12.8, 4.0 Hz), 126.4, 121.1 (dt, J = 15.4, 4.9 Hz), 117.1
(ddd, J1= 20.0, 5.7, 1.5 Hz), 108.7, 107.0 (dd, J1= 28.2, 20.9
Hz), 82.6 (d, J = 1.8 Hz), 77.4, 46.1, 37.1, 35.1, 15.5. Anal. Calcd
for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.42;
H, 3.92; N, 8.73.
[(R)-6-Oxo-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamic
Acid tert-Butyl Ester (28). To a slurry of tosylate salt 4 (5.5 kg,
13.2 mol) in THF/water (33 L/16.5 L) at ambient temperature
was added Et3N (5.5 L, 39.6 mol) in one portion. Then, di-tert-
butyl dicarbonate (3.45 kg, 15.84 mol) was added to the resulting
clear solution over 30 min in portions. After aging for 15 h at
room temperature, the reaction mixture was extracted with
toluene (50 L). The organic phase was washed with water (2 ꢀ
25 L) and azetropically concentrated to a volume of 25 L. The
resulting slurry was aged at ambient temperature for 2-4 h
before filtration. The wet cake was washed with n-heptane (8 L)
and dried under vacuum to afford 4.236 kg of white solid 28
(97% ee): 95% yield; 1H NMR (400 MHz, CDCl3) major
rotomer38 δ 7.13 (m, 1 H), 7.07 (m, 1 H), 6.96 (m, 1 H), 4.83
(d, J = 6.7 Hz, 1 H), 4.18 (s, br 1 H), 3.57 (m, 1 H), 3.41 (m, 1 H),
3.22 (dd, J = 11.7, 9.9 Hz, 1 H), 2.72 (dd, J = 17.8, 5.8 Hz, 1 H),
2.58 (dd, J = 17.8, 10.8 Hz, 1 H), 1.33 (s, 9 H); 13C NMR (100
MHz, CDCl3) δ 170.8, 155.2, 156.1 (ddd, J = 244.5, 9.6, 2.4 Hz),
149.3 (dt, J = 252.2, 13.2 Hz), 147.2 (ddd, J = 245.4, 12.2, 2.8
Hz), 123.8 (m), 116.7 (dd, J = 20.1, 5.1 Hz), 105.9 (dd, J = 28.1,
21.0 Hz), 80.3, 48.4, 46.1, 37.5, 36.4, 28.3. Anal. Calcd for
C16H19F3N2O3: C, 55.81; H, 5.56; N, 8.14. Found: C, 55.95;
H, 5.49; N, 8.43.
1
yellowish solid 16b: 76% yield; H NMR (500 MHz, CDCl3)
δ 7.04 (m, 1 H), 7.01 (m, 1 H), 5.76 (m, 1 H), 5.26 (m, 2 H), 5.07
(m, 1 H), 4.13 (dd, J = 14.9, 6.2 Hz, 1 H), 4.02 (m, 2 H), 3.91 (dd,
J = 13.2, 6.9 Hz, 1H), 3.72 (dd, J = 13.2, 5.1 Hz, 1 H), 2.84 (dd,
J = 17.5, 6.2 Hz, 1 H), 2.72 (dd, J = 17.5, 9.8 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 166.7, 156.0 (ddd, J = 245.0, 10.0,
2.5 Hz), 150.1 (td, J = 251.3, 13.6 Hz), 147.3 (ddd, J = 246.3,
12.5, 3.8 Hz), 131.7, 121.6 (td, J = 15.0, 5.0 Hz), 119.6, 117.1
(ddd, J = 20.0, 6.3, 1.3 Hz), 106.9 (dd, J = 27.5, 21.3 Hz), 83.1
(d, J = 1.3 Hz), 49.4, 47.7, 36.7, 35.0. Anal. Calcd for C14H13F3-
N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.59; H, 4.12; N,
8.90.
(3R,4R)-6-Oxo-4-(2,4,5-trifluorophenyl)piperidin-3-ylammo-
nium Toluene-4-sulfonate (4). A N2-degassed solution of nitro-
piperidinone 16b (100 g, 0.3182 mol) and RhCl3 (1.8 g, 7.96
mmol) in n-PrOH (800 mL) was agitated at 90-95 °C for 17 h.
The reaction solution was then concentrated to a volume of ca.
500 mL in vacuo. MeOH (350 mL) and Raney Ni (50 g) were
charged, and the reaction mixture was hydrogenated (90 psig) at
40 °C for 5 h. The reaction mixture was cooled to ambient
temperature and filtered through a pad of Solka Floc to remove
the catalyst. The catalyst was washed with MeOH (300 mL). The
combined filtrate was solvent switched to n-PrOH in vacuo
(final volume: 750 mL). A solution of p-toluenesulfonic acid
(pTSA, 78.7 g of pTSA monohydrate, 0.4137 mol) in water (150
mL) was added in one portion. The reaction solution was seeded
with aminopiperidinone pTSA salt 4 (0.1 g), and the resulting
slurry was agitated for 30 min at ambient temperature and an
additional 3-5 h at 55-60 °C. The batch was slowly cooled to
ambient temperature. The slurry was filtered, and the wet cake
was washed with 90% aq n-PrOH (2 ꢀ 120 mL, displacement
wash followed by a slurry wash) and n-PrOH (100 mL). Suction
drying at ambient temperature gave 82.2 g of white solid 4: 62%
yield over three steps; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s,
3H), 7.78 (d, J = 2.6 Hz, 1 H), 7.61 (m, 2H), 7.48 (d, J = 8.1 Hz,
2 H), 7.12 (d, J = 8.1 Hz, 2 H), 3.80 (m, 1 H), 3.49 (m, 2H), 3.23
(dd, J = 12.1, 9.2 Hz, 1 H), 2.48 (d, J = 1.4 Hz, 1 H), 2.46 (s, 1
H), 2.29 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 168.5, 155.9
(ddd, J = 244.1, 10.4, 2.4 Hz), 148.7 (dt, J = 247.8, 13.7 Hz),
146.5 (ddd, J = 241.7, 16.1, 3.2 Hz), 144.9, 138.2, 128.3, 125.5,
123.1 (dt, J = 16.1, 4.8 Hz), 117.8 (dd, J = 20.1, 5.0 Hz), 106.4
(dd, J = 29.7, 21.7 Hz), 48.0, 43.0, 36.0, 35.3, 20.8. Anal. Calcd
for C18H19F3N2O4S: C, 51.92; H, 4.60; N, 6.73. Found: C, 51.67;
H, 4.27; N, 6.62.
Intermediates 17, 18, and 19 could be isolated by silica gel
column chromatography (gradient 20% to 90% EtOAc in
hexane). (4R,5R)-5-Nitro-4-(2,4,5-trifluorophenyl)piperidin-2-
1
one (17): H NMR (400 MHz, CDCl3) δ 7.08 (m, 1 H), 7.01
(R)-7-(2,4,5-Trifluorophenyl)-5,6,7,8-tetrahydro-2,4b-diaza-
fluoren-6-ylamine (1). To a slurry of Boc piperidinone 28 (3.993
kg, 11.6 mol), 4-bromo-3-aminopyridine (2, 2.81 kg, 16.24 mol),
and potassium carbonate (3.527 kg, 25.52 mol) in toluene (30 L)
at ambient temperature was charged N,N0-dimethylethylenedia-
mine (1.25 L, 11.6 mol) dropwise. The resulting thick slurry was
degassed with nitrogen purge, and then CuI (221 g, 1.16 mol)
and toluene (8 L) were charged. The reaction mixture was
agitated at 100 °C until >96% conversion was achieved. Then,
the reaction mixture was cooled to 60 °C, and THF (40 L) was
added. The slurry was filtered through 10 kg of silica gel and
rinsed with 40 L of warm THF (60 °C). The combined filtrate
was solvent-switched to ethanol to a volume of 36 L in vacuum.
The assay yield of coupled product 29 was 88.4% (4.29 kg).
To the above ethanol solution of 29 at 50 °C was added concd
HCl (96 mol, 8 L) dropwise at such a rate as to maintain the
internal temperature between 50 and 60 °C. The tris-HCl salt 1
(m, 1 H), 6.65 (s, 1 H), 5.05 (m, 1 H), 4.04 (m, 1 H), 3.98 (td, J =
6.0, 2.0 Hz, 1 H), 3.80 (ddd, J = 13.3, 4.8, 2.8 Hz, 1 H), 2.83 (dd,
J = 17.7, 6.4 Hz, 1 H), 2.70 (dd, J = 17.7, 9.6 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 169.9, 156.0 (ddd, J = 246.5, 9.6, 3.2
Hz), 150.2 (dt, J = 253.5, 14.2 Hz), 147.4 (ddd, J = 243.8, 12.8,
3.5 Hz), 121.6 (dt, J = 15.3, 4.8 Hz), 117.3 (ddd, J = 19.9, 4.8
Hz), 107.0 (dd, J = 28.3, 21.0 Hz), 82.4, 77.4, 43.4, 37.4, 34.4.
Anal. Calcd for C11H9F3N2O3: C, 48.18; H, 3.31; N, 10.22.
Found: C, 48.06; H, 3.16; N, 10.08.
(4R,5R)-5-Nitro-1-(1-propoxypropyl)-4-(2,4,5-trifluorophenyl)-
piperidin-2-one (18): 1H NMR (500 MHz, CDCl3) (the ratio of
two isomers is about 1.5:1) for the major isomer, δ 7.07 (m, 1 H),
7.01 (m, 1 H), 5.63 (m, 1 H), 4.99 (m, 1 H), 4.00 (m, 1 H), 3.81
(dd, J = 13.5, 6.8 Hz, 1 H), 3.76 (dd, J = 13.5, 5.0 Hz, 1 H), 3.34
(m, 2 H), 2.87 (t, J = 6.4 Hz, 1 H), 2.76 (dd, J = 17.4, 9.2 Hz, 1
H), 1.71 (m, 1 H), 1.57 (m, 2 H), 1.50 (m, 1 H), 0.92 (m, 6 H); for
the major isomer, δ 7.07 (m, 1 H), 7.01 (m, 1 H), 5.63 (m, 1 H),
4.99 (m, 1 H), 4.11 (dd, J = 14.9, 7.2 Hz, 1 H), 4.00 (m, 1 H), 3.55
(dd, J = 14.1, 5.0 Hz, 1 H), 3.41 (m, 1 H), 3.34 (m, 1 H), 2.90 (t,
(38) For this specific compound, the sample concentration would also
affect the observed chemical shifts.
1352 J. Org. Chem. Vol. 75, No. 5, 2010

Xu et al.
JOCFeatured Article
started to crystallize at the completion of the HCl addition.
i-PrOH (32 L) was added dropwise, and the slurry was allowed
to cool to ambient temperature slowly and stirred overnight
prior to filtration. The wet cake was washed successively with
i-PrOH (2 ꢀ 4 L), i-PrOH/i-PrOAc (2:1, 8 L), and i-PrOAc (8 L).
Suction drying gave 3.8 kg of the tris-HCl salt 1 (99.78% purity,
97.2% ee) in 87% yield.
To a slurry of the tris-HCl salt 1 (3.8 kg, 8.89 mol) in
anhydrous ethanol (48 L) was added a solution of sodium
ethoxide (2.178 kg, 32 mol) in ethanol (24 L) dropwise. The
resulting sodium chloride was removed by filtration. The etha-
nol filtrate was concentrated to a volume of 16 L in vacuum. The
slurry of the free base 1 was then warmed to 50 °C. Water (30 L)
was added dropwise over 1 h. The slurry was stirred overnight at
ambient temperature before filtration. The wet cake was washed
with 10% aqueous ethanol (2 ꢀ 3 L) followed by water (5 L).
Vacuum oven drying at 60 °C gave the anhydrous free base 1
(2.327 kg) in 82% yield: 99.2% purity; 98.6% ee; 1H NMR (400
MHz, DMSO-d6) δ 8.84 (d, J = 0.8 Hz, 1 H), 8.31 (d, J = 5.5
Hz, 1 H), 7.60 (m, 1 H), 7.56 (dd, J = 5.5, 0.8 Hz, 1 H), 7.53 (m, 1
H), 4.45 (dd, J = 12.0, 5.3, 1 H), 3.79 (dd, J = 12.0, 9.8 Hz, 1 H),
3.58 (m, 1 H), 3.42 (m, 1 H), 3.27 (m, 2 H), 1.67 (s, 2 H); 13C
NMR (100 MHz, DMSO-d6) δ 155.9 (ddd, J = 242.5, 9.4, 2.2
Hz), 152.4, 147.8 (dt, J = 247.9, 14.5 Hz), 146.7 (ddd, J = 241.4,
12.5, 3.2 Hz), 140.8, 140.4, 140.2, 138.9, 125.9 (dt, J = 16.8, 4.9
Hz), 117.1 (dd, J = 19.5, 6.2 Hz), 105.8 (dd, J = 30.0, 20.9 Hz),
105.5, 49.3, 48.8, 38.8, 30.0. Anal. Calcd for C16H13F3N4: C,
60.37; H, 4.12; N, 17.60. Found: C, 60.24; H, 3.98; N, 17.37.
Acknowledgment. We thank Dr. R. Reamer, Dr. P. Dormer,
and Ms. L. DiMichele for assistance with NMR studies.
Supporting Information Available: Alternative synthesis,
experimental procedure, and kinetic profiles of intramolecular
transamidation. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1353