Synthesis of two labeled forms of proteasome inhibitor MLN273

Full text of DOI:10.1002/jlcr.1176

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 428–430.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1176
Short Research Article
Synthesis of two labeled forms of proteasome inhibitor MLN273y
MIHAELA PLESESCU*, YUEXIAN LI and SHIMOGA R. PRAKASH
Department of Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA
Received 11 August 2006; Revised 6 November 2006; Accepted 21 November 2006
Keywords: [14C]MLN273; morpholine-4-[14C]carbonyl chloride; [D8]MLN273; l-[D8]naphthylalanine
Introduction
presence of diisopropylethylamine to generate the
protected boronate 8. Boronic acid deprotection was
accomplished by two-phase transesterification with
isobutyl boronic acid.2 The desired product 9 was
isolated by extraction and solvent washings.
MLN273, (R)-3-methyl-1-[(S)-2-(morpholine-4-carbox-
amido)-3-(naphthalen-1-yl) propanamido]butylboronic
acid, is a potent proteasome inhibitor that is under pre-
clinical evaluation for the treatment of hematologic
Although there are numerous biocatalytic processes
to produce optically active phenylalanine analogs,5
there are no published reports for enantioselective
chemical synthesis of l-naphthylalanine. We chose to
utilize enantioselective hydrogenation of N-protected
dehydro amino acid to prepare key labeled precursor
l-naphthylalanine.
malignacies.1 14C]MLN273 9 was synthesized in three
[
radiochemical steps in order to support metabolite
profiling and whole body autoradiography studies in
experimental animals. [D8]MLN273 19 was required for
biotransformation and pharmacokinetic studies.
Commercially available [D10]1-methylnaphthalene
was used as the starting material for the synthesis of
[D8]1-methylnaphtalene. Treatment of [D10]1-methyl-
naphthalene 10 with N-bromosuccinimide in carbon
tetrachloride provided the bromide 11. Refluxing
11 with hexamethylenetetramine in water and acetic
acid yielded the aldehyde 12. The Horner-Emmons
olefination of aldehyde 12 with phosphonate 13 gave
14 with Z-configuration as the major product.6
The enantiomerically pure a-amino acid derivative
15 was synthesized by the use of Burk’s DuPHOS-
based Rh (I) catalyst.6 Successive steps of ester
hydrolysis and amine deprotection produced the de-
sired amino-acid l-[D8]naphthylalanine 16 which was
further utilized to prepare the required proteasome
inhibitor.
Results and discussion
[
14C]MLN273 was prepared via a modification of the
previously described procedure (Scheme 1).2 This
new synthetic route was designed to incorporate the
carbon-14 label at a later stage in the synthetic
sequence. (1S,2S,3R,5S)-Pinanediol leucine boronate
trifluoroacetate salt3 1 (prepared according to literature
procedures) was coupled with N-Boc protected
l-naphthylalanine 2 in the presence of TBTU. To
prepare the key intermediate 7, commercially available
[
14C]phosgene 5 was used as the starting material.
Treatment of 5 with morpholine 6 in tetrahydrofuran
provided morpholine-4-[14C]carbonyl chloride 7,4
which was reacted with the deprotected pinanediol
ester of b-(1-naphthyl)-l-leucine boronic acid 4 in the
As illustrated in Scheme 2, synthesis of [D8]MLN273
was completed by adaptation of the previously de-
scribed procedure.2 The stable isotope labeled
l-[D8]naphthylalanine 16 was N-acylated with 4-mor-
pholinecarbonyl chloride, followed by coupling with the
previously prepared R-aminoboronic ester 1 to provide
the dipeptide boronate ester 18. Boronic acid deprotec-
tion was accomplished by a procedure analogous to the
one that was described in Scheme 1 to get the final
product 19.
*Correspondence to: Mihaela Plesescu, Department of Drug Metabo-
lism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., 35
Landsdowne Street, Cambridge, MA 02139, USA. E-mail: plesescu@m-
pi.com
y
Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF TWO LABELED FORMS OF PROTEASOME INHIBITOR MLN273 429
TBTU,
DIPEA, DMF
4M HCl in dioxane
O
B
H3N+
TFA-
HCl-
H3N+
O
B
+
O
B
O
NH
NH
89%
O
OH
91%
BocHN
O
BocHN
O
O
O
2
3
4
1
O
B(OH)2
14C
O
THF
NH
+
14C
Cl
N
O
Cl
Cl
O
1N HCl, MeOH,
hexanes
O
5
7
6
OH
O
O
H
H
14C
14C
N
N
B
B
N
N
OH
N
N
O
H
70%
(iPr)2NEt, THF
40% over two steps
H
O
O
O
O
9
8
Scheme 1
D
O
D
D
D
D
CD2Br
D
D
CD3
(MeO)2P(O)CH(NHCbz)COOMe
D
D
D
D
D
D
(CH2)6N4
NBS, CCl4
D
D
D
D
13
AcOH/H2O
66%
D
93%
CH2Cl2,DBU
92%
D
D
D
D
12
10
11
Me2OC
D
H
CO2Me
HO2C
H
D
D
D
NHCbz
D
D
NHCbz
NH2
D
D
D
D
D
D
D
D
D
H2,MeOH, 50 psi , 24h
1. MeOH, 1N NaOH
D
2. 6 NHCl
76% 2 steps
Burk's catalyst
D
D
(S, S) (COD) Et-DuPHOS Rh(I) OTf
95% ee, (76%)
D
D
D
D
D
D
15
16
14
O
D
B(OH)2
D
D
D
D
N
D
D
Cl
D
D
O
1
D
D
1N HCl, MeOH,
hexanes
D
D
D
THF, 4.5M K2CO3
D
D
TBTU, DIPEA
DMF
D
D
D
D
O
44%
O
D
O
O
64%
74%
OH
D
NH
O
D
N
NH
B
N
NH
NH
D
B
O
OH
N
NH
CO2H
O
O
O
O
17
18
19
Scheme 2
Application of the enantioselective rhodium-
Conclusions
catalyzed hydrogenation of N-protected (Z)-dehydro-
aminoacids, followed by deprotection, offers an efficient
route for the synthesis of deuterium labeled chiral
amino-acids. The (S,S) catalyst afforded the stable
isotope labeled l-[D8]naphthylalanine derivative with
an absolute S configuration based on the selectivity
of the (S,S)-Et-DuPHOS ligand, with a high yield and
high ee.
Utilization of [14C]phosgene is a practical method for
the efficient preparation of labeled heterocyclic acid
chlorides. The labeled dipeptidyl boronic acid
[
14C]MLN273, with label in the morpholine portion of
the molecule, was prepared from [14C]phosgene in a
quick 3-step sequence affording product in a 28%
overall radiochemical yield.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 428–430
DOI: 10.1002.jlcr

430 M. PLESESCU ET AL.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 428–430
DOI: 10.1002.jlcr