Asymmetric alkylation of 5-alkyl-2-aminothiazolones using a C 2-symmetric chiral tetraamine base

Article abstract of DOI:10.1016/j.tetlet.2011.08.073

The diastereoselective alkylation of a series of 5-alkyl-2-aminothiazolones utilizing a C₂-symmetric chiral tetraamine base is reported.

Full text of DOI:10.1016/j.tetlet.2011.08.073

Tetrahedron Letters 52 (2011) 5613–5616
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric alkylation of 5-alkyl-2-aminothiazolones
using a C2-symmetric chiral tetraamine base
Matthew J. Frizzle a, , Roger R. Nani a,à, Michael J. Martinelli b,§, George A. Moniz a,
⇑
,–
a Chemical Process R&D, Amgen, Inc., 1 Kendall Square, Building 1000, Cambridge, MA 02139, United States
b Chemical Process R&D, Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective alkylation of a series of 5-alkyl-2-aminothiazolones utilizing a C2-symmetric chiral
tetraamine base is reported.
Received 28 July 2011
Accepted 13 August 2011
Available online 24 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric
Alkylation
Koga
Thiazolone
Chiral
Introduction
Results and Discussion
AMG 221 (1a, Scheme 1) is an inhibitor of 11b-hydroxysteroid
dehydrogenase type 1 (11b-HSD1). Inhibitors of 11b-HSD1 are po-
tential therapeutic agents for the treatment of type 2 diabetes.1
The first-generation synthesis of 1 involved alkylation of 5-iso-
propylthiazolone 2 (>98% ee for the norbornyl moiety) using LDA
as base to afford a 1.1:1 mixture of diastereomers which were sep-
arated by chiral chromatography.1a Importantly, this procedure
afforded the 5,50-dialkylthiazolones 1a and 1b in the absence of
O-, N- and N0-alkylated by-products. While this procedure was suf-
ficient to support early preclinical studies, an asymmetric process
was sought to control the stereochemical outcome of the C–C bond
forming event. We hoped to use a chiral lithium amide base to
introduce facial selectivity into this already chemo- and regioselec-
tive reaction.
In 1990, Koga reported that a chiral lithium amide base (e.g., 8)
could be used to direct the approach of an electrophile selectively
to one face of an achiral tetralone enolate.2 We sought to explore a
similar approach for alkylation of 2.3
As shown in Table 1, an initial screen of chiral bases (3–8,
Scheme 1) revealed that the dilithium enolate of (S,S)-8 afforded
significant selectivity for the desired isomer (1a).4 Further optimi-
zation studies focused on the base structure revealed that the initial
base 8 was optimal for selectivity. Modifying the length of the
tether (Table 1, entries 10 and 11) afforded worse selectivity, as
did replacement of the piperidine ring in 8 with a tetrahydroiso-
quinoline (Table 1, entry 12). Alkyl iodides afforded better selectiv-
ity than the corresponding bromide and sulfate (Table 1, entries 13
and 14). Finally, a significant improvement in both rate and selec-
tivity was observed by the use of TMEDA as an additive, presumably
by affecting the active lithium aggregate.5 Other ethylenediamine
ligands (i.e., TMPDA and TMBDA, entries 18 and 19) did not produce
a similar effect. One drawback to the use of methyl iodide as alkyl-
ating agent was the methylation of (S,S)-8 itself during the course of
the reaction, which rendered recycle of (S,S)-8 impossible. In an
effort to avoid alkylation of the chiral base and enable recycle, we
evaluated the alkylation with isopropyl iodide, 5-methylthiazolone
12, and the antipode of the chiral base, (R,R)-8 (Scheme 2).
⇑
Corresponding author. Tel.: +1 617 817 2794.
E-mail address: gmoniz@aya.yale.edu (G.A. Moniz).
Present address: Alphora Research, Inc., 2395 Speakman Drive, Suite 201,
Mississauga, Ontario, Canada L5K 1B3.
à
To our delight, the alkylation proceeded with a similar level of
selectivity and without alkylation of (R,R)-8, which could now be
recycled via a simple acid/base extraction procedure followed by
crystallization.4 The success of the alkylation of 12 led us to
Present address: Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, CA 91125, United States.
§
Present address: Fibrogen, Inc., 409 Illinois Street, San Francisco, CA 94158,
United States.
–
Present address: Eisai, Inc., 4 Corporate Drive, Andover, MA 01810, United States.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.073

5614
M. J. Frizzle et al. / Tetrahedron Letters 52 (2011) 5613–5616
O
O
O
Me
Me
Me
Me
Me
Me
Me-I
Base
N
N
N
Me
Me
+
S
S
S
NH
NH
NH
Conditions
2
1a
1b
Me Me
Me
t-Bu
Ph
NLi
N
Li
N
N
Li
(S)-3
(S,S)-5
(R)-6
Me
Me Me
O
NLi
Ph
Ph
NLi
N
Li
N
N
LiO
N
Ph
4
5
7
(R)-
(S,S)-
(R,R)-
LiN
LiN
NLi
LiN
NLi
N
N
N
Ph Ph
Ph Ph
(R,R)-8
(S,S)-8
Li
N
Li
N
LiN
N
N
N
Ph
N
Ph
Ph
(S,S)-10
Ph
(S,S)-9
LiN
NLi
N
N
Ph Ph
(S,S)-11
Scheme 1. Chiral bases screened for asymmetric alkylation of 2.
Table 1
Alkylation of 2 under various conditions
Entry
Basea
Conditions
Electrophile
Additive
1a Diastereoselectivityb (%)
% Conversion (HPLC)
1
2
3
4
5
6
7
8
LDA
(S)-3
(S,S)-4
(S,S)-5
(R,R)-5
(R)-6
Toluene, ꢀ45 to 0 °C
THF, ꢀ78 to 0 °C
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeBr
Me2SO4
MeI
MeI
MeI
MeI
MeI
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5
0
>95
79
42
85
90
94
42
90
93
87
83
75
88
89
>95
>95
>95
89
84
THF, ꢀ78 to 0 °C
ꢀ1.5
THF, ꢀ78 to 0 °C
9
THF, ꢀ78 to 0 °C
ꢀ24
ꢀ5
12
32
58
19
0
20
49
34
66
86
64
64
59
THF, ꢀ78 to 0 °C
(R)-7
THF, ꢀ78 to 0 °C
(S,S)-8
(S,S)-8
(S,S)-9
(S,S)-10
(S,S)-11
(S,S)-8
(S,S)-8
(S,S)-8
(S,S)-8
(S,S)-8
(S,S)-8
(S,S)-8
THF, ꢀ78 to 0 °C
9
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
Toluene, ꢀ45 to 0 °C
10
11
12
13
14
15
16
17
18
19
TMEDA (1.0 equiv)
TMEDA (2.0 equiv)
TMEDA (4.0 equiv)
TMPDA (2.0 equiv)
TMBDA (2.0 equiv)
a
3 equiv of chiral bases 3–7 were used, 2 equiv of chiral bases 8–1 were used.
Determined by Chiral HPLC.
b
explore other substrates under similar conditions. As can be seen
from Table 2, (R,R)-8 affords good selectivity with a range of substi-
tuted 5-alkylthiazolones.6 In general, secondary alkyl iodides affor-
ded better selectivity than primary alkyl iodides.
In conclusion, C2-symmetric chiral base (R,R)-8 enables efficient
reagent-controlled alkylation of 5-alkyl-2-aminothiazolones with a
high degree of regio-, chemo-, and stereochemical control,
overriding any intrinsic stereocontrol element. Importantly, use

M. J. Frizzle et al. / Tetrahedron Letters 52 (2011) 5613–5616
5615
O
Me
N
1) (S,S)-8 (2.2 equiv)
Me
S
NH
2) TMEDA (2.2 equiv)
3) MeI
O
Me
Me
2
-
15 °C, Toluene, 12h
N
Me
S
(79% yield)
86% de (93:7 dr)
NH
1a
O
Me
N
8
1) (R,R)- (2.2 equiv)
S
NH
2) TMEDA (2.2 equiv)
3) iPrI
12
-15 oC, Toluene, 12h
(75% yield)
83% de (92:8 dr)
Scheme 2. Use of (R,R)-8 with isopropyl iodide to alkylate 12.
Table 2
Syed, R.; Jordan, S.; Komorowski, R.; Chen, M. M.; Cupples, R.; Kim, K. W.; St.
Jean, D. J.; Johansson, L.; Henriksson, M. A.; Williams, M.; Vallgarda, J.; Fotsch, C.;
Wang, M. J. Med. Chem. 2010, 53, 4481; (b) Johansson, L.; Fotsch, C.; Bartberger,
M. D.; Castro, V. M.; Chen, M.; Emery, M.; Gustafsson, S.; Hale, C.; Hickman, D.;
Homan, E.; Jordan, S. R.; Komorowski, R.; Li, A.; McRae, K.; Moniz, G.;
Matsumoto, G.; Orihuela, C.; Palm, G.; Veniant, M.; Wang, M.; Williams, M.;
Zhang, J. J. Med. Chem. 2008, 51, 2933; (c) Fotsch, C.; Adams, J.; Bartberger, M.;
Bercot, E. A.; Cai, L.; Castro, V. M.; Chen, M.; Cupples, R.; Emery, M.; Fretland, J.;
Guram, A.; Gustafsson, S.; Hague, A.; Hale, C.; Han, N.; Hayashi, M.; Henriksson,
M.; Hickman, D.; Homan, E.; Hungate, R. W.; Johansson, L.; Jordan, S.; Kaiser, C.;
Komorowski, R.; Li, A.; Liu, Q.; Matsumoto, G.; McRae, K.; Moniz, G.; Palm, G.;
Pyring, D.; St. Jean, D. J., Jr.; Sun, Y.; Sydow-Backman, M.; Tedenborg, L.; Tu, H.;
Ursa, S.; Veniant, M.; Williams, M.; Xu, G.; Ye, Q.; Yuan, C.; Zhang, J.; Zhang, X.;
Wang, M. Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT,
March 22–26, 2009; MEDI-029.
Scope of 5-alkylthiazolone alkylations using (R,R)-8
O
O
O
Me
R'
Me
R'
8
1) (R,R)- (2.2 equiv)
Me
N
N
N
+
S
S
S
2) TMEDA (2.2 equiv)
3) R'-I
R
R
R
N
N
N
H
H
H
2, 13a-c
14a
% de 14aa
14b
Yieldb (%)
-15 °C, Toluene
Substrate
R
R0
12
2-Propyl
86
79
2. (a) Masatoshi, M.; Makoto, K.; Koga, K. Chem. Commun. 1990, 1657; (b)
Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999, 40, 2803; For a
recent application of (R,R)-8 in the asymmetric alkylation of arylacetic acids, see
(c) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2011, 133, 11936.
3. The initial disclosure of this work can be found in: Moniz, G. A.; Frizzle, M. J.;
Bernard, C.; Martinelli, M. J.; Faul, M. M.; Nani, R. R.; Larrow, J. F. PCT Int. Appl.
WO2009002445, 2008. This reference also describes the synthesis of 2.
4. For a large-scale preparation of the C2-symmetric tetraamine used to generate
(R,R)-8, see: Frizzle, M. J.; Caille, S.; Marshall, T.; McRae, K.; Guo, G.; Wu, S.;
Martinelli, M. J.; Moniz, G. A. Org. Process Res. Dev. 2007, 11, 215.
12
1-Propyl
2-Propyl
1-Propyl
27
81
43
76
86
71
13a
13a
5. (a) Gallano-Roth, A. S.; Collum, D. B. J. Am. Chem. Soc. 1989, 111, 6772; (b)
Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
6. A typical large-scale alkylation procedure is as follows: A 20 L reactor was
Me
Me
13b
13b
2-Propyl
1-Propyl
89
86
70
65
placed under
a nitrogen sweep. (R,R)-chiral amine (8, 1610 g, 3.59 mol,
2.2 equiv) was charged to the reactor. This was followed by a nitrogen sweep
for 50 min. Anhydrous toluene (5.42 L) was then charged and agitation was
initiated. The reaction mixture was allowed to stir under a nitrogen sweep for an
additional 10 min, after which the reaction mixture was cooled to ꢀ7.5 °C over
45 min. A dropping funnel was charged with n-BuLi solution (2.7 M in toluene,
2.66 L, 7.18 mol, 4.4 equiv), and dropwise addition of the n-BuLi was initiated.
During this addition, the addition rate and jacket temperature were adjusted to
ensure that internal temperature did not rise above 0 °C. Once the addition was
complete, the dropping funnel was rinsed with anhydrous toluene (100 mL). The
reaction mixture was cooled to ꢀ15 °C and TMEDA (540 mL) was then added via
cannula. 5-methylthiazolone (13a, 361.6 g, 1.63 mol, 1.0 equiv) was slurried in
anhydrous toluene (1.45 L) in a separate 5 L, 3-neck round-bottom flask under a
nitrogen sweep for 30 min. The resulting slurry was charged portionwise to the
reactor via cannula, adjusting addition rate and jacket temperature so as to
maintain the internal temperature below 0 °C. The round-bottom flask used to
prepare the substrate slurry was rinsed with toluene (2 ꢁ 468 mL) and the
washes were charged to the reactor. The reaction mixture was warmed to 15 °C
over 1.5 h, and aged at this temperature for 30 min. The mixture was then re-
cooled to ꢀ15 °C over 1 h. 2-Iodopropane (1.3 L, 13.0 mol, 8.0 equiv) was
charged via cannula at such a rate as to maintain temperature below ꢀ12.5 °C,
adjusting the jacket temperature as needed to control the resulting exotherm.
The reaction mixture was allowed to age at ꢀ15 °C until >93% conversion was
obtained, and then quenched by dropwise addition of saturated NH4Cl solution
(3.62 L), again adjusting addition rate and jacket temperature to control the
resulting exotherm. The reaction mixture was warmed to room temperature and
agitation was halted. Phases were allowed to separate and the lower aqueous
layer was drained. 4.82 L of saturated NH4Cl solution was added and the mixture
agitated for 20 min. The phases were allowed to separate and the lower aqueous
a
Determined by Chiral HPLC.
Isolated yields as diastereomeric mixture.
b
of electrophiles more sterically hindered than methyl iodide pre-
vents alkylation of the chiral base itself, enabling facile recycle of
the chiral controller.
Acknowledgments
The authors acknowledge Ms. Kelly Nadeau for assistance with
chiral assays as well as Dr. M. Bhupathy and Ms. Roseann Price for
assistance with raw material procurement and logistics.
References and notes
1. (a) Veniant, M. M.; Hale, C.; Hungate, R. W.; Gahm, K.; Emery, M. G.; Jona, J.;
Joseph, S.; Adamsn, J.; Hague, A.; Moniz, G.; Zhang, J.; Bartberger, M. D.; Li, V.;

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M. J. Frizzle et al. / Tetrahedron Letters 52 (2011) 5613–5616
layer was drained. Acetic acid solution (2 M, 3 L) was charged to the reactor and
ratio of solvents 20:1 octane–toluene. After the desired solvent ratio was
reached, with a final volume of 3.9 L, the slurry was filtered through a medium-
porosity sintered glass funnel, rinsing with two portions of octane (1400 mL
total). The solids were dried on the filter for 1–1.5 h, and then transferred to a
drying dish and dried in a vacuum oven at 45–55 °C, 3–30 torr for 18–42 h.
Obtained 370 g of a white solid, 86% yield, 80.5% de.
the mixture agitated for 30 min. The phases were allowed to separate and the
lower aqueous layer was drained. The acetic acid wash was repeated. Saturated
NaHCO3 (3 L) was charged to the reactor slowly while agitating for 20 min. The
phases were allowed to separate (at least 20 min). The lower aqueous phase was
drained. The toluene layer was solvent-exchanged into octane, with the final