Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib

Article abstract of DOI:10.1016/j.cclet.2018.10.023

We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H₂O₂ as oxidant in the presence of carboxylic acid (e.g., acetic acid).

Full text of DOI:10.1016/j.cclet.2018.10.023

Accepted Manuscript
Title: Bioinspired manganese complexes catalyzed
epoxidation for the synthesis of the epoxyketone fragment of
carfilzomib
Authors: Bin Qiu, Chungu Xia, Wei Sun
PII:
DOI:
Reference:
S1001-8417(18)30410-8
https://doi.org/10.1016/j.cclet.2018.10.023
CCLET 4687
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
29-9-2018
15-10-2018
22-10-2018
Please cite this article as: Qiu B, Xia C, Sun W, Bioinspired manganese complexes
catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib,
Chinese Chemical Letters (2018), https://doi.org/10.1016/j.cclet.2018.10.023
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Communication
Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the
epoxyketone frag ment of carfilzomib
Bin Qiua,b, Chungu Xiaa, Wei Suna,
a Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, China
b University of Chinese Academy of Sciences Beijing 100049, China
Graphical abstract
We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-
2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib.
ARTICLE INFO
ABSTRACT
We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone
(tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an
important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes
bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H2O2
as oxidant in the presence of carboxylic acid (e.g., acetic acid).
Article history:
Received 29 September 2018
Received in revised form 16 October 2018
Accepted 17 October 2018
Available online
Keywords:
Catalytic Epoxidation
Bioinspired Manganese Complexes
Hydrogen Peroxide
Epoxyketone
Carfilzomib
Carfilzomib is a proteasome inhibitor for the treatment of multiple myeloma (MM) which is the second common type of malignancy
and a progressive B-cell tumour [1-3]. In 2012, carfilzomib (marketed under the brand name Kyprolis) was approved as cancer drug by
the U.S. Food and Drug Administration (FDA) and then followed by Europe in 2015, and Japan in 2016. As shown in Fig. 1, carfilzomib
derived from epoxomicin and YU-101 is made up of a tetrapeptide, and the elimilation of three chiral centers from epoxomicin to
carfilzomib greatly simplifies the synthetic routes [4]. Apart from the original medicinal chemistry route developed by Crews group and
Proteolix, much more efforts have been taken to exploit potential manufacturing and alternate routes to carfilzomib [5-10]. Among these
synthetic routes, the last step always involved the reaction of a tripeptide with the epoxyketone fragment (as marked in Fig. 1). Presently,
the synthesis of epoxyketone remained to be the major challenge, and when using the vinyl ketone 1 as substrate, the yield of the
epoxyketone 2 was always not satisfactory (Scheme 1). In 1999, Crews first reported that epoxidation of 1 with hydrogen peroxide in
the presence of diisopropyl ethylamine (DIPEA) and cyanobenzene led to the formation of epoxyketone 2, but a long reaction time of
43 h was needed to acquire 76% yield with a 1.7:1 (2a:2b) ratio of diastereomers (Scheme 1) [7]. In Proteolix and Onyx patents,
epoxidation of 1 was conducted in aqueous N-methyl pyrrolidone, and the using of Ca(OCl)2 as a terminal oxidant, leading to 41% yield
of 2 at 0-15 ºC [8,9]. Under the same conditions, it afforded a dr ratio of 2:1 in a subsequent patent and the epoxidation of the bis-Boc-
protected substrate gave a higher diastereoselectivity with 64% yield [10]. The development of efficient catalytic oxidation method is
highly desirable [11,12], in particular, with earth-abundant metal catalyst (e.g., Mn, Fe) [13].
———
 Corresponding author.
E-mail address: wsun@licp.cas.cn

Fig. 1. Structures of epoxomycin, YU-101 and carfilzomib.
Scheme 1. The synthesis of epoxyketone fragment 2 of carfilzomib.
Over the past decades, a great number of chiral manganese complexes with bioinspired tetradentate nitrogen ligands (N4 ligands), as
model compounds of nonheme enzymes, have been successfully synthesized and applied to enantioselective epoxidation of olefins [14-
20]. Further studies also proved that the addition of organic carboxylic acids, amino acids, even as well as inorganic acids demonstrated
important roles in these efficient asymmetric epoxidation methods [21-23]. In our previous study, the manganese catalyst (S-PEB-
Mn(OTf)2, Fig. 2, C1) bearing a chiral N4 ligand derived from L-proline and benzimidazole showed high reactivity (up to 99%) and high
enantioselectivity (up to 95%) in the epoxidation of α, β-unsaturated ketones. When using the vinyl ketone 1 as substrate, a nearly
quantitative yield of epoxyketone 2 was obtained while the ratio of dr (2a:2b) was only 1:7 [24]. Taking into account the excellent
performance of S-PEB-Mn(OTf)2 (C1), albeit with epoxyketone 2b as major product, therefore, we anticipate that the manganese
complex with opposite configuration or achiral catalyst will give better outcome in this reaction toward the synthesis of valuable
intermediate epoxyketone. Herein, a series of bioinspired manganese complexes with N4 supporting ligands, containing benzimidazole
motif [25], are carefully investigated in the epoxidation of enone precursor 1 with H2O2 as oxidant in the presence of carboxylic acid
(e.g., acetic acid). A gram-scale reaction was also performed under the optimized conditions.
Fig. 2. Structures of the N4 manganese complexes in this work.
As mentioned above, although the application of C1 produced epoxide in nearly quantitative yield, the proportion of the desired
epoxyketone 2a was very low [24]. Clearly, it was caused by the chirality of vinyl ketone 1, and its inherent chirality was mismatched
with manganese complex C1. Keep this in mind, a chiral ligand R-PEB derived from D-proline and its manganese complex was easily
synthesized based on our previous reported methods (Fig. 3) [24,25]. Single crystals of C3 (R-PEB-Mn(OTf)2) were obtained by diffusing
ether into the CH3CN solution. X-ray crystallographic analysis reveals that the ligand coordinates with manganese center in a cis-α

topology as that of manganese complex C3 [24]. Other manganese complexes C1,C2 and C4-C7 were also prepared as previously
methods [26,27].
Fig. 3. The synthesis of R-PEB-Mn(OTf)2 (C3) and crystal structure (CCDC 1870619, atom colors: Mn, pink; C, gray; N, blue; O, red; F, green;
S, yellow.).
Table 1
Catalytic epoxidation of the vinyl ketone 1 to epoxyketone 2 by manganese complex C3.a
Entry
Acid
AcOH
-
Temp (oC) Yield(%)b 2a:2bc
1
2
3
-20
-20
-20
97
NR
72
1:3.1
-
1:3.8
4
-20
75
1:3.7
5
-20
<8
-
6
-20
trace
-
7
8
-20
0
trace
77
-
AcOH
1:2.8
a Reaction conditions: all reactions were performed in CH3CN (1.0 mL) with substrates (0.5 mmol) in the presence of various acids (5 equiv.),
H2O2 (30% in 0.5 mL of CH3CN) was added dropwise through a syringe pump over 60 min, and an additional 60 min of stirring was allowed.
b Isolated yield.
c Determined by 1H NMR.
Initially, we evaluated the activity of C3 in the epoxidation of enone 1. Under the same conditions as our previous reported, in the
presence of 5 equiv. of acetic acid in acetonitrile at -20 ºC, manganese complex C3 showed excellent catalytic activity as that of C1 [24].
Epoxyketone 2 was obtained in 97% yield, as expected, and the ration of dr reached to 1:3.1 (Table 1, entry 1). More importantly, the
addition of organic carboxylic acid was proved to be effective way to tune the stereocontrol in manganese-catalyzed asymmetric
epoxidations through the formation of a carboxylate Mn-oxo intermediate [21-24,28]. Further, the influence of different organic
carboxylic acid was also studied, and the results were summarized in Table 1. When the reaction was performed in the absence of acid,
no reaction took place. We could find that the increase of the steric bulk at the α-carbon of the carboxylic acid decrease the reaction
activity apparently. For example, the addition of pivalic acid led to a yield less than 8% (Table 1, entry 5) and the addition of 2-
ethylbutanoic acid gave no yield of 2 (Table 1, entry 7). As a whole, the organic carboxylic acid played important roles in the epoxidation
of 1 to 2, and the best choice is acetic acid. Also, it was found that a higher temperature was adverse for this reaction that the yield of 2
decreased to 77% in the presence of acetic acid at 0 ºC (Table 1, entry 8).
Based on above results, clearly, we can see that the diamine backbone affects the ratio of epoxyketone 2 diastereoselectivity intensively
[24,29]. The catalyst C3 from D-proline let to better results than that of C1. These results further demonstrate that the variation in
diastereoselectivity is due to the inherent chirality and steric hindrance of vinyl ketone 1. We next investigated the different manganese
complexes C1-C7 (Fig. 2) with various diamines and substituted benzimidazole motifs. The use of achiral manganese complex C4
bearing a 1,2-ethanediamine led to a lower diastereoselectivity (Table 2, entry 4, 1:5.2). Among the tested catalysts, manganese complex
derived from (1R,2R)-cyclohexane-1,2-diamine gave better diastereoselectivity (up to 1:1.6) (Table 2, entries 5-7). On the other hand,
the catalytic reactivity and diastereoselectivity were also affected by the steric bulk of N-alkyl group in the benzimidazole of the N4

ligands. We observe that the ratio of dr increases apparently, when changing the N-alkyl group from ethyl to H. The complex C7, without
substituent in benzimidazole, gave best dr ratio albeit with low yield under the optimized conditions (Table 2, entry 7, dr = 1:1.6). In
order to gain a high yield with a proper dr, 14 equiv of acetic acid was also used and C6 was proved to be the best catalyst by which the
yield reached 94% with a dr of 1:2.1. Finally, gram-scale reaction was carried out in order to verify the practical utility of this protocol.
As shown in Scheme 2, the epoxyketone 2 was obtained in high isolated (89%) yield and with good diastereoselectivity (1:2.3).
Table 2
Catalytic epoxidation of the vinyl ketone 1 to epoxyketone 2 by manganese complexes C1-C7.a
Entry
Catalyst
C1
C2
C3
C4
C5
C6
C7
Yield(%)b
98
87
97
73
2a:2b
1:7.7
1:5.3
1:3.1
1:5.2
1:2.9
1:2.1
1:1.6
1
2
3
4
5
6
7
91
77 (94)c
46 (70)c
a Unless otherwise mentioned, all reactions were performed in CH3CN (1.0 mL) with substrates (0.5 mmol) in the presence of AcOH (5 equiv.), H2O2 (30% in 0.5
mL of CH3CN) was added dropwise through a syringe pump over 60 min, and an additional 60 min of stirring was allowed.
b Isolated yield with adding 5 equiv. of AcOH.
c Isolated yield with adding 14 equiv. of AcOH.
Scheme 2. The gram-scale synthesis of epoxyketone 2.
For the manganese-catalyzed epoxidation method, presently, involvement of the high-valent Mn-oxo intermediates has been supported
experimentally and theoretically [21-23]. The acetic acid plays a key role during the formation of Mn-oxo, as shown in Scheme 3, acetic
acid binding to the metal center facilitates the heterolysis of the O-O bond of the intermediate (MnIII-OOH) [28,30].
Scheme 3. The proposed mechanism for the manganese-catalyzed epoxidation using H2O2 as the terminal oxidant.
In summary, we report an efficient catalytic epoxidation of the vinyl ketone 1 to the epoxyketone 2, which is the important active
component of carfizomib with good ratio of dr, and it could also extend to a gram-scale reaction. Through the study of various organic
carboxylic acids as the additives, acetic acid was the best choice for this catalytic system. Further, a series of chiral manganese catalysts
with N4 ligands were applied to further study the effects of the chiral ligands on the catalytic reactivity and diastereoselectivity which
were proved to be related with the diamine backbone and the steric hindrance. Though the diastereoselectivity of epoxyketone 2 was still
challenging, this study provided an alternative method for the synthesis of this key intermediate epoxyketone 2a.
Acknowledgments
We acknowledge financial support of this work from the National Natural Science Foundation of China (No. 21473226), Key Research
Program of Frontier Sciences, CAS (No. QYZDJ-SSW-SLH051) and Natural Science Foundation of Jiangsu Province (No. BK20161261
and BK20170420).
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