An expeditious synthesis of the MDM2-p53 inhibitor AM-8553

Article abstract of DOI:10.1021/ja305123v

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.

Full text of DOI:10.1021/ja305123v

Article
pubs.acs.org/JACS
An Expeditious Synthesis of the MDM2−p53 Inhibitor AM-8553
Brian S. Lucas,*,† Benjamin Fisher,† Lawrence R. McGee,† Steven H. Olson,† Julio C. Medina,†
and Eugene Cheung‡
†Department of Medicinal Chemistry, Amgen, Inc., 1120 Veterans Boulevard, S. San Francisco, California 94080, United States
‡Department of Pharmaceutics, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: The development of the structurally complex
MDM2/p53 inhibitor AM-8553 was impeded by the low yield
of the initial synthesis. A second generation synthesis is
described that features a Noyori dynamic kinetic resolution, a
highly diastereoselective allylation, and a novel oxazoline-
assisted piperidinone forming reaction to provide AM-8553 in
35.6% yield and 11 steps.
enantiomer. The installation of the quaternary center (Figure
1b) occurred with modest 3.9:1 diastereoselectivity, while the
installation of the side chain (Figure 1c) did not show any
diastereoselectivity. The use of the piperidinone as a
nucleophile to install the side-chain fragment (Figure 1d)
required the use of strong electrophiles. Lastly, our initial co-
crystal structures of AM-8553 and MDM2 were not able to
unequivocally distinguish between the oxygen and methyl
group at the secondary alcohol (Figure 1e), rendering the
configuration at that site ambiguous.
Our retrosynthesis for an improved route to 1 is shown in
Scheme 1. Key to our approach was the desire to replace the
difficult intermolecular amide alkyation (Figure 1, issues c,d)
with a more facile intramolecular N−C6 bond-forming reaction
(Scheme 1). Bicyclic iminium ether 2, an intermediate similar
INTRODUCTION
■
Over the past decade, there has been considerable interest in
the discovery of molecules that disrupt the protein−protein
interaction between p53 and MDM2 as a potential treatment
for human cancer.1 In the presence of cellular stress, the tumor
suppressor protein p53 is known to play a pivotal role in
controlling cell cycle arrest, DNA repair, senescence, and
apoptosis.2 The MDM2 protein is transcriptionally activated by
p53 and, once expressed, serves as a master regulator of p53 by
controlling its activity and degradation.3 Molecules which bind
to MDM2 and neutralize the MDM2−p53 protein−protein
interaction can disrupt the autoregulatory feedback loop
between the two proteins, leading to increased p53
concentration and, eventually, tumor growth inhibition and
apoptosis in cancer cells containing wild-type p53.4
We recently described a class of high-affinity inhibitors of the
MDM2−p53 interaction, exemplified by piperidinone AM-
8553 (1),5 a 0.4 nM (Kd) inhibitor with demonstrated efficacy
in xenograft studies. As our interest in AM-8553 grew, it
became clear that further development of this compound would
be limited by our ability to secure it on scale. The initial
synthesis of AM-8553 comprised 17 steps and 0.37% overall
yield and suffered from a number of deficiencies as outlined in
Figure 1. In our previous synthetic route, the trans-aryl
piperidone core was prepared as a racemate (Figure 1a) and
required chiral chromatography to obtain the desired
́
to that employed by Aube for lactam synthesis via the
intramolecular Schmidt reaction,6 was proposed to accomplish
this goal. In our approach, it was conceived that a transient
side-chain-derived oxazoline would render the amide of 3
nucleophilic at nitrogen, resulting in the displacement of a
simultaneously activated C6 benzylic alcohol to assemble the
lactam framework. The amide 3, bearing a fully elaborated side
chain, was envisioned to arise from a simple ring-opening of a
cis-aryl lactone 4 with a readily available chiral amino alcohol.
Furthermore, the cis disposition of aryl groups in lactone 4
serves to enable a highly diastereoselective installation of the
quaternary center at C3. Ultimately, we hoped to arrive at
lactone 4 as a single stereoisomer from the hydrogenolytic
dynamic kinetic resolution of ketone 5 using Noyori’s Ru
BINAP/diamine catalyst system.7
RESULTS AND DISCUSSION
■
Inspired by the application of the Noyori catalyst system for a
dynamic kinetic resolution (DKR) in Merck’s taranabant
Received: June 4, 2012
Published: June 26, 2012
Figure 1. Key issues from the first generation synthesis of AM-8553.
© 2012 American Chemical Society
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The synthesis of key lactone 4 using this methodology is
described in Scheme 3. Synthesis of methylated DKR substrate
Scheme 1. Retrosynthesis of AM-8553 (1)
Scheme 3. Synthesis of Lactone 4
synthesis,8 we sought to employ these conditions to set the
relative and absolute stereochemistry of the aryl groups
necessary for lactone 4. To avoid complicating our initial
investigation of the DKR process with diastereomers resulting
from the C3 methyl group in 5, we began our work with the
desmethyl variant as depicted in Scheme 2. Application of
5 was achieved in 99% yield from Michael addition of ketone 7
to methyl methacrylate. The higher yield of this reaction as
compared to the desmethyl case (8) is attributed to the slower
reaction rate, and ultimately, the absence of double-Michael
adduct. Application of the optimized Noyori conditions yielded
an inconsequential yet complex mixture of diastereomers and
carboxyl functionality. A purified aliquot showed that the
isopropyl ester product 10 was obtained in 96:4 er.11 To
maximize yields, the crude mixture was taken directly through a
two-step hydrolysis/lactonization sequence to converge on
lactone 11 as a 3:1 mixture of epimers at C3.
Scheme 2. Initial Exploration of the Dynamic Kinetic
Resolution
At this point we were ready to address a key deficiency of the
previous routethe diastereoselectivity of the allylation at C3.
We hypothesized that the enolate derived from 11 would react
predominately from the more sterically accessible β-face as
shown in Figure 2.
Buchwald’s ketone α-arylation conditions9 to acetophenone 6
facilitated the synthesis of ketone 7 in 94% yield. Conjugate
addition of 7 to methyl acrylate afforded the desmethyl DKR
substrate 8. Gratifyingly, catalytic hydrogenation in the
presence of 0.2% RuCl2[(S-xyl-BINAP)(S-DAIPEN) with
40% potassium tert-butoxide in isopropanol afforded compound
9 as a single diastereomer in 99:1 er, predominantly as the
transesterifed isopropyl ester 9a, with small amounts of methyl
ester 9b isolated as well. Lower er results were obtained using
either higher pressure (500 psi, 92:8 er), methanol as a solvent
(98:2 er), or use of Noyori’s RuCl2(S-BINAP)(S-DAIPEN)
catalyst (92:8 er).10 Lowering the temperature of the reaction
to 0 °C resulted in unacceptably long reaction times.
Figure 2. Diastereoselective allylation of 11.
Diastereoselective alkylations of cis-5,6 disubstituted δ-
lactones are well precedented to result in the C3 trans-
alkylated product,12 although little precedent exists for C3
alkyl-substituted lactones such as 11.13 Allylation of 11 using
LiHMDS and allylbromide afforded lactone 4 in 93% yield.
Analysis of the crude reaction mixture by H NMR indicated
that allylation had occurred in >95:5 dr and the crystalline
1
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lactone 4 could be recrystallized from heptane to improve the
er from 96:4 to 99.2:0.8 if desired.
second equivalent of triflic anhydride activates the benzylic
alcohol to nucleophilic displacement with inversion by the
oxazoline nitrogen. The resulting iminium ether triflate salt 13
is stable to chromatography but is typically hydrolyzed with
aqueous base to the piperidinone 15. At this point, due to the
amplification of er afforded by the covalent linking of two
highly enantioenriched fragments, the product 15 was obtained
as essentially enantiopure after silica gel chromatography.15
AM-8553 (1) can be obtained from compound 15 in 4 steps
according to our previously published route, completing a
formal synthesis of AM-8553 (1) in 13 steps and 23% overall
yield.
With lactone 4 in hand we could turn our attention toward
the proposed oxazoline-assisted piperidinone synthesis. Initially,
we chose to avoid the ambiguity surrounding the stereo-
chemistry of the secondary hydroxyl in 1 (Figure 1, issue e) by
intercepting our previous route to 1 at a late stage and installing
the hydroxyl as in our previous synthesis (Scheme 4).5 The
Scheme 4. Oxazoline-Assisted Cyclization and Formal
Synthesis of 1
Next, we sought to expand our synthetic route to obtain the
entirety of the side chain of 1 from a 3-amino-2-pentanol
building block. However, as the configuration of the secondary
hydroxyl in the side chain of 1 was originally obtained via a
substrate-directed ketone reduction using L-Selectride, the
stereochemistry was uncertain. Thus, we devised a sequence to
afford both possible diastereomers from a single amino alcohol
of known configuration, (2S,3S)-3-aminopentan-2-ol 16.16,17
We hoped that an understanding of the reaction mechanism of
the lactam-forming sequence would serve to elucidate the
absolute configuration of the side chain in 1.
Contrary to the relative ease with which 2-amino-1-butanol
opened the lactone 4 with simple heating, the freebase of
(2S,3S)-3-aminopentan-2-ol (16) required extended reaction
times and did not surpass 50% conversion even after 5 days at
100 °C (table 1). Addition of sodium hydride to a THF
solution of 16 prior to the addition of lactone 4 rapidly yielded
the product 3 in an optimized 78% yield, however, extreme care
must be taken to minimize adventitious water that leads to
significant formation of seco-acid 17. Moving to a strong
anhydrous base such as n-butyllithium likewise greatly
accelerated the rate of reaction, but promoted a competitive
ring contraction to afford ketone 19. Treatment of lactone 4
with a strong, non-nucleophilic base such as LiHMDS in the
absence of amino alcohol 16 could effect this rearrangement in
reasonable yields.18 The most practical synthesis of 3 was
achieved by heating lactone 4 directly with the hydrochloride
salt of 16 using triethylamine as base for 4 days at 100 °C, a
process which required no freebasing of 16 and was highly
reproducible.
necessary amide 12 was obtained in quantitative yield by simply
heating 4 with commercially available (S)-(+)-2-amino-1-
butanol. Treatment of 12 with triflic anhydride and 2,6 lutidine
at −78 °C resulted in the rapid formation of the desired bicylic
iminium ether 13 upon warming past −50 °C.14 Analysis of the
reaction performed with substoichiometric amounts of triflic
anhydride or less active sulfonylating agents such as nosyl-
fluoride show that oxazoline 14 is formed first. Addition of a
Table 1. Opening of Lactone 4 under Various Conditions; All Yields Are Isolated except Where Noted
base
equiv 16
t
T °C
3 (%)
17 (%)
18 (%)
4 (%)
19 (%)
a
none
3
5 d
4 d
100
100
<50
b
6 equiv Et3N
3
76
78
47
2.5
12
3.2
3.1 equiv NaH
2.8 equiv n-BuLi
1.2 equiv Li-HMDS
1.5
1.5
0
0.5 h
1 h
23
0−23
23−30
16
18
68
14 h
a
b
Not isolated. HCl salt of 16 was used.
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When amide 3 was subjected to triflic anhydride and 2,6
lutidine, (Scheme 5) the intermediate oxazoline 20 was formed
Scheme 6. Bicyclic Iminium Ether 2 As a Hydroxyl
Protecting Group and the Synthesis of 1
Scheme 5. Oxazoline-Assisted Cyclization Utilizing 2°
Hydroxyl Amino Alcohols
suggest structure 25 instead, where the newly formed carboxylic
acid moiety has trapped the iminium ether. Hydrolysis of the
crude oxidation product 25 with sodium bicarbonate afforded 1
in 81% overall yield. The readily hydrolyzed adduct 25 can be
regenerated from 1 in the presence of acid.
With an expeditious and high-yielding (11 steps, 35.6%
overall yield) approach to 1 accomplished, we turned our
attention to determining the absolute stereochemistry of the
side-chain hydroxyl in 1. While the stereochemical outcome of
the two oxazoline-forming protocols in Scheme 5 was
confirmed by NOE studies on iminium ethers 21 and 2, a
detailed understanding of the mechanism of iminium ether
hydrolysis was necessary to address the ambiguity of the
absolute stereochemistry of hydrolysis products 22 and 23, and
́
ultimately, 1. Aube and co-workers have previously dealt with
the ambident electrophilicity of these systems,22 and they found
through the use of 18O-labeling studies that hydroxide would be
expected to react via path A (retention), whereas nucleophiles
such as azide, cyanide, and benzenethiolate should react via
path B (inversion) (Scheme 5). However, the sterically
encumbered nature of our bicyclic iminium ether system23
warranted confirmation of these results.
with inversion of stereochemistry19 (vide infra) at the
secondary hydroxyl prior to the second cyclization to form
iminium ether 21. Upon basic hydrolysis of 21, the undesired
epimer 22 was obtained exclusively. Alternatively, formation of
oxazoline 18 by azeotropic dehydration in the presence of a
Two 18O-labeling experiments were performed as shown in
Scheme 7. Ring-opening of 50% 18O-labeled lactone 4 (see
Supporting Information) with (S,S)-amino alcohol 16 led to
50% labeled amide 3. When amide 3 was treated with triflic
anhydride/2,6-lutidine to form iminium ether 21 and then
hydrolyzed with unlabeled water, the 18O was transferred from
the carbonyl carbon of 3 to the hydroxyl position of 22 as
evidenced by an additional upfield signal at ∼71.1 ppm in the
13C NMR.24 Separately, unlabeled intermediate 21 was
hydrolyzed with ∼50% 18O-labeled aqueous NaHCO3 solution,
and in this case the label was clearly incorporated at the
carbonyl position of 22 (178.6 ppm). These results led us to
conclude that configuration of the side-chain hydroxyl is
inverted only once during the course of this sequence
(oxazoline formation) and the absolute configuration of
undesired epimer 22 is R. Subsequently, a small-molecule
crystal structure of compound 22 (Figure 3) confirmed our
assignment by this method.25
20
catalytic amount of (NH4)2MoO4 occurs with retention of
stereochemistry. Activation of the benzylic alcohol in 18 with
triflic anhydride/2,6-lutidine afforded iminium ether 2 and
desired piperidinone 23 upon hydrolysis.
To complete our synthesis of 1, only an oxidative cleavage of
the allyl group in 23 was formally required. We had anticipated
having to employ a hydroxyl protecting group or other
multistep sequence to avoid concomitant oxidation of the
side chain in 23 to arrive at 1. However, we ultimately chose to
investigate the possibility of leveraging the iminium ether for
this purpose and directly oxidize 2 to afford 1 after hydrolysis as
shown in Scheme 6. By subjecting iminium ether 2 to KMnO4
oxidation, we expected to observe intermediate 24 en route to
1. However, the spectral characteristics21 of a purified aliquot
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Scheme 7. 18O-Labeling Studies To Determine Stereochemical Outcome of the Iminium Ether Formation and Hydrolysis
side chain of AM-8553. The iminium ether was also shown to
be a competent alcohol protecting group that was stable to
oxidative conditions to complete an 11-step synthetic route to
AM-8553 in 35.6% overall yield. We expect to describe the
large-scale application of this iminium ether lactam synthesis in
due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed synthetic procedures, characterization data, and
1
images of H and 13C spectra for compounds 1−5, 7−15,
18−19, 21−23, and 25; syntheses and 13C spectra of 18O-
labeled 3, 4, 21, and 22. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*blucas@amgen.com
■
Notes
Figure 3. Crystal Structure of 22.
The authors declare no competing financial interest.
CONCLUSION
■
ACKNOWLEDGMENTS
■
The densely functionalized and stereochemically rich piper-
We thank Professor Samuel J. Danishefsky, Michael G.
idinone AM-8553 necessitated the development of a high-
Johnson, Felix Gonzalez Lopez de Turiso, Darin J. Gustin,
yielding synthetic approach to evaluate this biologically
and Brian M. Fox for helpful discussions related to this study.
intriguing molecule. An enantio- and diastereo-selective DKR
was used to set the relative and absolute stereochemistry of the
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