Proline-catalyzed, asymmetric Mannich reactions in the synthesis of a DPP-IV inhibitor

Article abstract of DOI:10.1021/jo0519458

A highly stereoselective L-proline-catalyzed, asymmetric direct Mannich reaction between a glyoxalate-derived imine and phenyl acetaldehyde was employed for the formation of a syn substituted β-phenyl homoserine. This Mannich adduct was then readily elabo

Full text of DOI:10.1021/jo0519458

SCHEME 1. Key Mannich Disconnection
SCHEME 2. l-Proline-Catalyzed Mannicha
Proline-Catalyzed, Asymmetric Mannich
Reactions in the Synthesis of a DPP-IV Inhibitor
Jacob M. Janey,* Yi Hsiao, and Joseph D. Armstrong III
Department of Process Research,
Merck Research Laboratories, Merck and Co., Inc.,
Rahway, New Jersey 07065
jacob_janey@merck.com
ReceiVed September 16, 2005
a (a) 17 mol % L-Pro, THF, -5 °C, 20 h; (b) added 3 equiv of AcOH
and then 1 equiv of NaBH4; (c) 20 mol % K2CO3, THF 50 °C, 2 h.
A highly stereoselective L-proline-catalyzed, asymmetric
direct Mannich reaction between a glyoxalate-derived imine
and phenyl acetaldehyde was employed for the formation
of a syn substituted â-phenyl homoserine. This Mannich
adduct was then readily elaborated to a functionalized
â-phenyl aspartic acid derivative through a series of mild
and efficient transformations.
To date, there are limited examples of the proline-catalyzed
Mannich reaction as applied to aryl acetaldehydes.5 This may
be, in part, due to the difficulty in their synthesis and their
inherent instability as they are quite prone to oxidation and
polymerization to poly(styreneoxide). The reaction between a
p-methoxyphenyl (PMP) protected imine derived from ethyl
glyoxalate (2)6 and phenylacetaldehyde catalyzed by 17 mol %
L-proline provides the desired syn-â-phenyl-substituted ho-
moserine with excellent levels of stereoselection (typically 92:8
syn/anti and >90% ee) after reduction of the crude aldehyde to
the amino alcohol 3 (Scheme 2). Immediate reduction is
necessary as the crude product aldehyde 5 is an unstable
intermediate that slowly undergoes epimerization and/or po-
lymerization upon standing at room temperature, thus neces-
sitating reaction temperatures of -5 °C (Scheme 3). Reduction
with NaBH4 alone gave slow epimerization of alcohol 3 (∼80:
20 syn/anti) along with some lactonization (6). Upon workup
with saturated aqueous NaHCO3, lactone 6 could be obtained
as the major product along with enhanced diastereomeric purity
There has been intense research focused upon glucagon-like
peptide 1 (GLP-1) and its potential for treating type 2 diabetes.1
This hormone, released in the gut in response to food, stimulates
insulin biosynthesis, while inhibiting the release of glucagon.
In addition, GLP-1 regulates insulin in a glucose-dependent
manner, thus reducing the risk of hypoglycemia. GLP-1 is
readily degraded in vivo by dipeptidyl peptidase IV (DPP-IV),
a serine protease. Identification of an orally available small
molecule capable of inhibiting the DPP-IV enzyme and thereby
increasing the amount of GLP-1 could yield a new and useful
therapy for type 2 diabetes.2 In that context, efforts by Merck
medicinal chemists led to the identification of molecules with
the general structure of 1 as novel inhibitors of DPP-IV.3
A retrosynthetic analysis of this challenging molecule revealed
a possible Mannich reaction as a useful bond-forming reaction
to set both stereocenters (Scheme 1). In particular, we were
drawn to the proline-catalyzed direct Mannich reaction reported
by List, Barbas, and co-workers as a potential way to address
the stereochemistry and functionality of this molecule.4,5 We
report herein an efficient synthesis of a â-phenyl aspartic acid
derivative 1, which features a proline-catalyzed Mannich
reaction.
(4) For proline cat. Mannich of N-PMP glyoxylate imines, see: (a)
Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507-
2510. (b) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett
2003, 1906-1909. (c) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N.
S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem.
2003, 68, 9624-9634. (d) Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz,
W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866-1867. (e)
Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923-1926.
(f) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III.
J. Am. Chem. Soc. 2002, 124, 1842-1843.
(5) For other proline cat. Mannich and aldol reactions, see: (a)
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541-
3544. (b) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem.
Soc. 2003, 125, 11208-11209. (c) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (d) Notz, W.;
Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett. 2001,
42, 199-201. (e) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.
(6) N-PMP imine 2 formed by slow addition of 1 equiv of ethyl
glyoxylate to a stirring solution of 1 equiv of p-anisidine and 3 Å MS in
toluene. The solution was stirred 1 day at room temperature (rt), with
additional ethyl glyoxylate added as needed to consume p-anisidine.
Treatment with Na2SO4 (s) followed by filtration gave >95% pure 2 in
89% yield.
(1) For a review of GLP-1, see: Knudsen, L. B. J. Med. Chem. 2004,
47, 4128-4134.
(2) For a review of DPP-IV mode of action and inhibitors, see: Weber,
A. E. J. Med. Chem. 2004, 47, 4135-4141.
(3) Edmondson, S. D.; Mastracchio, A.; Duffy, J. L.; Eiermann, G. J.;
He, H.; Ita, I.; Leiting, B.; Leone, J. F.; Lyons, K. A.; Makarewicz, A. M.;
Patel, R. A.; Petrov, A.; Wu, J. K.; Thornberry, N. A.; Weber, A. E. Bioorg.
Med. Chem. Lett. 2005, 15, 3048-3052.
10.1021/jo0519458 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/18/2005
390
J. Org. Chem. 2006, 71, 390-392

SCHEME 3. Aldehyde Reduction and Lactonization
amino alcohol 4. The final coupling reaction with dimethylamine
was >90% complete after 1 h, but allowing the reaction to run
overnight gave some epimerization (83:17 syn/anti). A final
recrystallization from MTBE gave material with >99% optical
purity.
A concise, stereoselective synthesis of a diamide-function-
alized â-phenyl aspartic acid derivative has been accomplished,
highlighted by the use of a proline-catalyzed direct Mannich
reaction. Also examined was the mild, selective removal of a
PMP nitrogen-protecting group using PhI(OAc)2. Despite
limitations imposed by the nitrogen-protecting group and
inherent instability of the aryl acetaldehyde starting materials
and crude aldehyde products, this proline-catalyzed Mannich
reaction represents a rapid and highly stereoselective method
for the preparation of syn â-substituted R-amino acid derivatives.
SCHEME 4. Amino Alcohol 4 Elaborationa
Experimental Section
(2S,3S)-4-Hydroxy-2-(4-methoxyphenylamino)-3-phenyl-1-
pyrrolidin-1-yl-butan-1-one (4). To a stirring solution of imine 2
(7.11 g, 34.3 mmol, 1 equiv) in 100 mL of THF at -5 °C was
added freshly distilled phenylacetaldehyde (3.99 mL, 35.7 mmol,
1.04 equiv) followed by l-proline (684 mg, 5.94 mmol, 0.17 equiv).
The reaction was held at -5 °C for 24 h, then acetic acid was
added (6.70 mL, 116 mmol, 3.4 equiv) followed by a portionwise
addition of NaBH4 (1.46 g, 38.6 mmol, 1.13 equiv). The reaction
was allowed to slowly warm to room temperature over 3 h, after
which time 50 mL of EtOAc was added along with 150 mL of
saturated aqueous NaHCO3. This biphasic mixture was stirred for
1 h at room temperature. The organic layer was then separated,
washed with brine (∼150 mL), dried with Na2SO4, filtered, and
concentrated in vacuo giving crude alcohol 3. To this crude material
(3) dissolved in 60 mL of THF was added pyrrolidine (2.98 mL,
35.7 mmol, 1.04 equiv) and Na2CO3 (630 mg, 5.94 mmol, 0.17
equiv). This mixture was heated to 50 °C for 2 h. After cooling to
room temperature, 50 mL of EtOAc was added. The organics were
then washed with 50 mL of saturated aqueous NaHCO3 and 50
mL of brine, dried with Na2SO4, filtered, and concentrated in vacuo
giving 12.45 g of 70.6 wt % 4 (8.78 g of 4, 72% yield from 1,
96:4 syn/anti by HPLC). This material was upgraded to >99%
optical purity after recrystallization from MTBE (6.93 g, 57% yield
from 2). mp 104.3-106.1 °C (MTBE); [R]25D +0.3 (c 1.02, CHCl3);
1H NMR (400 MHz, CDCl3): δ 7.35-7.25 (m, 5H), 6.77 (d, J )
8.8 Hz, 2H), 6.66 (d, J ) 6.9 Hz, 2H), 4.52 (d, J ) 5.5 Hz, 1H),
4.11-4.02 (m, 2H), 3.75 (s, 3H), 3.52-3.40 (m, 2H), 3.38-3.31
(bm, 2H), 3.03-2.95 (bm, 1H), 1.84-1.67 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 171.3, 153.0, 141.5, 139.0, 128.9, 128.8, 127.6,
116.1, 115.1, 63.4, 59.9, 55.9, 49.9, 46.7, 46.3, 26.2, 24.2; Anal.
Calcd for C21H26N2O3: C, 71.16; H, 7.39; N, 7.90. Found: C, 70.96;
H, 7.48; N, 7.71.
[(1S,2S)-3-Hydroxy-2-phenyl-1-(pyrrolidine-1-carbonyl)-pro-
pyl]-carbamic Acid tert-Butyl Ester (7). To a biphasic mixture
of amino alcohol 4 (425 mg, 1.20 mmol, 1 equiv) in 7.5 mL of
i-PrOAc and 7.5 mL of pH 5.9 (c 0.05 M) aqueous phosphate buffer
was added PhI(OAc)2 (1.55 g, 4.81 mmol, 4 equiv). After being
stirred for 2 h (HPLC indicates no 4), the reaction mixture was
diluted with 1 N HCl until acidic (pH ≈ 3) and organics were
separated and discarded. To the aqueous acidic layer was added
Na2CO3 (s) until pH ) 9-10 followed by 10 mL of THF. To this
mixture was added Boc2O (525 mg, 2.40 mmol, 2 equiv), and the
reaction was stirred overnight at room temperature. The mixture
was then diluted with 10 mL of EtOAc, the aqueous was separated,
and the remaining organic layer was washed successively with 20
mL of 1 N NaHSO4, 20 mL of water, and 20 mL of brine. The
organics were dried with Na2SO4, filtered, and concentrated in vacuo
giving 214 mg (51% yield) of crude 7. This material may be used
as is or can be further purified by recrystallization from MTBE.
a (a) 2 equiv of PhI(OAc)2, i-PrOAc/pH 5.9 aqueous buffer workup with
2 equiv of Boc2O, aqueous Na2CO3/THF; (b) 7 mol % TEMPO, 2 mol %
NaOCl, 2 equiv of NaClO2, CH3CN/pH 6.7 aqueous buffer, 35 °C, 20 h;
(c) 1.1 equiv of carbonyldiimidazole, 4 equiv of Me2NH, THF, rt, 20 h.
due to epimerization to the more stable trans-lactone 6 (96:4
syn/anti). The optimal reductive workup conditions involved
first treating the crude mixture with 3 equiv of AcOH followed
by addition of 1 equiv of NaBH4 (thereby generating NaBH-
(OAc)3 in situ). This protocol provided consistent purity of
amino alcohol 3 as the only product, with no lactone 6. Without
further purification, amino alcohol 3 was dissolved in THF and
heated with pyrrolidine and catalytic K2CO3 to efficiently
provide amide 4 in 72% yield over three steps from imine 2.
This material’s optical purity was upgraded to >99% de and
>99% ee by crystallization from MTBE. Presumably, this facile
amidation of 3 proceeds through lactone 6 as samples of 3 with
lower diastereomeric purity consistently provided amide 4 with
high diastereomeric purity.
One potential drawback to this methodology is the use of
PMP as a protecting group for the imine reaction partner.
Typically, harsh oxidation conditions involving highly toxic
reagents such as ceric ammonium nitrate are required to remove
PMP from nitrogen. A recent alternative reported by Hoveyda
and Snapper employs readily available PhI(OAc)2 as the
stoichiometric oxidant.7 Thus, treatment of N-PMP amino
alcohol 4 with PhI(OAc)2 under buffered biphasic conditions
followed by treatment with Boc2O gave N-Boc amino alcohol
7 in 51% yield (Scheme 4). Oxidation of alcohol 7 with catalytic
TEMPO and bleach along with 2 equiv of NaClO2 gave the
crude acid.8 This acid was then treated with carbonyldiimidazole
followed by dimethylamine to give the desired diamide aspartic
acid derivative 8 in 33% yield over three steps starting from
(7) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 10409-10410.
(8) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.
J. Org. Chem, Vol. 71, No. 1, 2006 391

1
mp 149.3-152.5 °C (MTBE); [R]25 +36.4 (c 0.72, CHCl3); H
concentrated in vacuo giving 79 mg (74% yield) of the crude acid.
To 75 mg of the crude acid (0.207 mmol, 1 equiv) in 1 mL of dry
THF was added CDI (carbonyldiimidazole) (37 mg, 0.228 mmol,
1.1 equiv). After being stirred for ∼30 min, dimethylamine was
added (207 µL, 0.414 mmol, 2 equiv). HPLC indicates that the
reaction was ∼90% complete after 1 h, but stirring was continued
overnight after which time 1 mL of EtOAc was added and the
organics were washed with ∼2 mL of 1 M NaHSO4, water, and
brine, dried with Na2SO4, filtered, and concentrated in vacuo giving
71 mg (88% yield) of the title compound 8. HPLC indicates some
epimerization had occurred (83:17 syn/anti), but optically pure syn-8
could be isolated after recrystallization from MTBE. mp 191.6-
192.8 °C (MTBE); [R]25D -157.1 (c 0.84, CHCl3); 1H NMR (400
MHz, CDCL3, ∼3.4:1 rotamer ratio at 300 K in CD3CN): δ 7.37-
7.29 (m, 5H), 5.15 (t, J ) 10.6 Hz, 1H), 4.70 (d, J ) 10.9 Hz,
1H), 4.23 (d, J ) 10.3 Hz, 1H), 4.02-3.96 (m, 1H), 3.70-3.65
(m, 1H), 3.50-3.40 (m, 2H), 2.91 (s, 3H), 2.87 (s, 3H), 2.03-
1.82 (m, 4H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 172.6,
170.6, 156.0, 137.4, 130.4, 129.4, 128.3, 79.6, 56.2, 51.7, 47.2,
46.7, 37.5, 35.7, 28.4, 26.7, 25.0; Anal. Calcd for C21H31N3O4: C,
64.76; H, 8.02; N, 10.79. Found: C, 64.50; H, 8.03; N, 10.50.
D
NMR (400 MHz, CDCl3): δ 7.31-7.23 (m, 3H), 7.08 (dd, J )
7.8, 1.7 Hz, 2H), 5.71 (d, J ) 7.9 Hz, 1H), 4.93 (dd, J ) 8.0, 4.0
Hz, 1H), 3.94 (dd, J ) 11.9, 10.1 Hz, 1H), 3.74 (dd, J ) 11.9, 4.9
Hz, 1H), 3.67-3.61 (m, 1H), 3.55-3.46 (m, 2H), 3.31 (ddd, J )
12.7, 6.6, 6.6 Hz, 1H), 3.23 (ddd, J ) 9.4, 4.5, 2.9 Hz, 1H), 2.02-
1.92 (m, 2H), 1.91-1.82 (m, 2H), 1.46 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 169.1, 157.1, 137.2, 128.7, 128.6, 127.8, 80.5,
62.8, 53.1, 49.9, 46.9, 46.2, 28.5, 26.3, 24.3; Anal. Calcd for
C19H28N2O4: C, 65.49; H, 8.10; N, 8.04. Found: C, 64.84; H, 8.11;
N, 7.71.
[(S)-1-((S)-Dimethylcarbamoylphenylmethyl)-2-oxo-2-pyrro-
lidin-1-ylethyl]carbamic Acid tert-Butyl Ester (8). To a mixture
of alcohol 7 (103 mg, 0.296 mmol, 1 equiv) in 1.5 mL of CH3CN
and 1.1 mL of pH 6.7 aqueous phosphate buffer (c 0.67 M) was
added TEMPO (3.3 mg, 0.021 mmol, 0.07 equiv), NaClO2 (53.3
mg, 0.592 mmol, 2 equiv) dissolved in 300 µL of water, and dilute
(0.04 M) NaClO (150 µL, 0.0059 mmol, 0.02 equiv). The mixture
was heated to 35 °C and stirred for 1 day. After cooling to room
temperature, 2 mL of water was added, and the pH was adjusted
to 8 with 2 N aqueous NaOH (∼400 µL). Next, a solution of Na2-
SO3 (90 mg in 1.5 mL of water) was added, and the reaction was
allowed to stir 30 min, after which time 1.5 mL of MTBE was
added. The organic layer was separated and discarded. To the
aqueous layer was added 3 mL of MTBE, and the pH was adjusted
to ∼4 with 2 N HCl (∼600 µL). The organic layer was separated
and washed with water and brine, dried with Na2SO4, filtered, and
Acknowledgment. We thank Ms. Lisa DiMichele for
assistance with NMR spectra and Ms. Mirlinda Biba and Mr.
Jimmy DaSilva for chiral-phase HPLC analysis.
JO0519458
392 J. Org. Chem., Vol. 71, No. 1, 2006