An efficient preparation of novel epoxyketone intermediates for the synthesis of carfilzomib and its derivatives

Article abstract of DOI:10.3184/174751916X14539789662063

A novel and efficient preparation of epoxyketone intermediates for the synthesis of carfilzomib and its derivatives has been developed. Compared to reported methods, this highly stereoselective, environmentally friendly, low-cost method can be used in scaling up the synthesis of carfilzomib and its derivatives.

Full text of DOI:10.3184/174751916X14539789662063

82 RESEARCH PAPER
VOL. 40 FEBRUARY, 82–86
JOURNAL OF CHEMICAL RESEARCH 2016
An efficient preparation of novel epoxyketone intermediates for the synthesis
of carfilzomib and its derivatives
Xiao Dua, Hao-yang Zhanga, Meng Leib*, Zi-yuan Lic and Yong-qiang Zhua*
ªCollege of Life Science, Nanjing Normal University, Nanjing 210023, P.R. China
bCollege of Science, Nanjing Forestry University, Nanjing 210037, P.R. China
cDepartment of Chemistry, Huazhong University of Science and Technology, Wuhan 430074, P.R. China
A novel and efficient preparation of epoxyketone intermediates for the synthesis of carfilzomib and its derivatives has been developed.
Compared to reported methods, this highly stereoselective, environmentally friendly, low-cost method can be used in scaling up the
synthesis of carfilzomib and its derivatives.
Keywords: carfilzomib, epoxyketone derivatives, vanadium(III) acetylacetonate
The ubiquitin-proteasome pathway (UPP) is responsible
for the intracellular protein degradation and regulation of
pivotal transduction pathways associated with cell growth,
survival, differentiation and apoptosis.1,2 In this pathway, the
26S proteasome, consisting of a catalytic 20S particle and
a 19S regulator particle, is the main proteolytic ingredient in
eukaryotes. Three different proteolytic activities are localised to
β-subunits of the 20S proteasome, namely β1, β2 and β5, which
are responsible for cleaving the chain after acidic amino acids,
basic amino acids and hydrophobic amino acids respectively.3,4
Based on this target, there has been a great deal of interest in
developing structurally diverse proteasome inhibitors. Among
these, a tripeptidyl epoxyketone, carfilzomib has been approved
for the treatment of patients with relapsed and refractory
multiple myeloma (MM) and mantle cell lymphoma (MCL).5,6
peroxomonosulfate. Finally the hydroxyl group of epoxide F was
oxidised to give the epoxyketone G. This method had several
serious disadvantages. For example, a very expensive and unstable
isopropenylmagnesium bromide was used in the production of
intermediate C from B. Furthermore, a strong reducing agent
NaBH4/CeCl3·7H2O was employed in the reduction of the α,β-
unsaturated ketone of intermediate C to a hydroxyl group, which
led to the production of two diastereoisomers D and E. Hence
flash chromatography was needed to purify the useful isomer D.
From the viewpoint of drug economy, this synthetic route was
not suitable for industrial scaling up of the preparation of a key
intermediate for carfilzomib synthesis.
To avoid the above drawbacks, we describe here an economic
and efficient method to produce the key intermediates under
mild conditions.
Carfilzomib represents
a new generation of highly
Results and discussion
stereoselective and irreversible proteasome inhibitor and
was approved on July 20, 2012 by the US Food and Drug
Administration (FDA). Compared with bortezomib, carfilzomib
(Fig. 1) can cause fewer side effects, especially lower rates
of peripheral neuropathy. At the same time, it has enhanced
tolerability and safety profiles.7 Hence, it is considered to be a
promising anticancer agent.
Epoxyketone fragments are extremely useful building blocks in
the synthesis of carfilzomib and its derivatives. Several synthetic
routes have been reported for the preparation of such key
intermediates.8–11 One representative method is shown in Scheme
1: firstly, condensation of N-Boc-protected leucine A with N,
O-dimethylhydroxylamine hydrochloride gave the Weinreb
amide B, which was then treated with isopropenylmagnesium
bromide to give an α,β-unsaturated ketone C. After reducing
the ketone in C with sodium borohydride and cerium chloride, to
obtain the allylic alcohols D and E. Olefin D was epoxidised to
give F using 3-chloroperoxybenzoic acid (mCPBA) or potassium
An epoxyketone is an important intermediate in carfilzomib
synthesis. In a typical preparation of this key intermediate
(Scheme 1), the formation of the unsaturated ketone C
from amide B is a critical step, in which a four-fold excess of
isopropenylmagnesium bromide was used. However, the high
cost and difficulty in obtaining large amounts of the Grignard
reagent made this an uneconomic route and encouraged us to
find a more economic method. We have designed a novel process
for the synthesis of the key intermediate for carfilzomib synthesis
without the use of expensive reagents. As shown in Scheme 2, we
chose the cheap and readily available ethylmagnesium bromide
as a Grignard reagent to prepare the ethyl ketone 3 based on the
literature method.12 The reaction used 1 equiv. of the Grignard
reagent to give a high yield (92%). An aldol condensation of
compound 3R1 with paraformaldehyde formed product 4R1 in a
yield of 92% (see experimental section). Aluminium isopropoxide
and isopropanol were then employed to selectively reduce the
O
O
H
H
O
N
N
O
OH
B
N
N
N
H
H
H
N
N
N
O
O
O
O
OH
N
H
O
Bortezomib
Carfilzomib
Fig. 1 Structures of bortezomib and carfilzomib.
* Correspondent. E-mail: zhyqscu@hotmail.com; hk-lm@163.com

JOURNAL OF CHEMICAL RESEARCH 2016 83
III
II
I
Boc
+
Boc
N
Boc
OH
Boc
Boc
N
O
N
N
N
H
H
H
H
OH
O
O
O
A
B
C
D
IV
V
Boc
O
Boc
O
N
N
N
H
H
H
OH
O
OH
E
F
G
Scheme 1 Synthesis of epoxyketone fragments G: I, isobutyl chloroformate, N-methylmorpholine, dichloromethane (DCM), N,O-dimethylhydroxylamine
hydrochloride; II, isopropenylmagnesium bromide, anhydrous tetrahydrofuran (THF); III, NaBH4,CeCl3·7H2O, MeOH; IV, mCPBA, DCM, or potassium
peroxomonosulfate, ethylenediaminetetraacetic acid (EDTA), NaHCO3, acetone, H2O; V, Dess–Martin, penodinane, MeCN.
R
R
R
R
II
III
H
O
I
Boc
Boc
N
Boc
Boc
N
N
O
N
N
H
H
H
H
O
O
O
O
–
–
4R1 4R5
1R1 1R5
–
–
2R1 2R5
3R1 3R5
R
R
R
IV
VI
V
O
Boc
Boc
Boc
O
N
N
N
H
H
H
OH
OH
O
–
6
R
5
–
R
6
5R1 5R5
–
7R1 7R5
1
:
R1
:
R2
:
R3
;
;
;
:
;
:
R5
R4
Scheme 2 Synthesis of epoxyketone fragments (7R1, 7R2, 7R3, 7R4 and 7R5): I, 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI), N,N-diisopropylethylamine (DIPEA), DCM, 0 °C; II, anhydrous THF, ethylmagnesium bromide, –20 °C;
III, piperidinium acetate, piperidine, paraformaldehyde, THF, 68 °C; IV, aluminium isopropoxide, isopropanol, toluene, 50 °C; V, tert-butyl
hydroperoxide solution, vanadium(III) acetylacetonate, DCM; VI, pyridine sulfur trioxide, DIPEA, dimethyl sulfoxide.
Experimental
α,β-unsaturated ketone of intermediate 4R1 to the alcohol 5R1
without the use of the strong reducing agent NaBH4/CeCl3·7H2O.
In this reduction, the S configuration of the intermediate 4R1
induces the generation of its neighbouring chiral centre. The
formation of two stereoisomers was avoided and the workup was
greatly simplified. Once the optically pure isomer 5R1 had been
obtained, the newly generated R configuration of 5R1 induced the
stereo-epoxidation. A single stereoisomeric epoxyl-alcohol 6R1
was obtained by oxidation with vanadium(III) acetylacetonate
and tert-butyl hydroperoxide. Finally, commercially available
pyridine:sulfur trioxide instead of the expensive Dess–Martin
reagent was employed to oxidise the alcohol 6R1 to the ketone
7R1. In order to widen the new method, we also synthesised
the aromatic compounds (4R2–7R2, 4R3–7R3) and aliphatic
compounds 4R4–7R4 (Scheme 2). The results showed that the
yields of the aliphatic substrates were generally higher than the
aromatic compounds. This may be due to the effect of both steric
and electronic factors in the reactions. However, more data are
needed to define the mechanism.
Commercially available reagents were used directly without any
purification unless otherwise stated. Reactions were monitored by
thin-layer chromatography (TLC) carried out on silica gel glass sheets
(GF-254) and RP-18 F254s using UV light as a visualising agent,
15% ethanolic phosphomolybdic acid and heat as a developing agent.
Column chromatography was performed on 200–300 mesh silica gel
and an ODS C-18 column. Analytical reverse phase high-performance
liquid chromatography (HPLC) was run using a Kromasil 100-5C18,
4.6 mm × 250 mm column eluting with a mixture of acetonitrile and
0.04% triflurooacetic acid. HPLC showed that the purity of all of the
final products was greater than 95%. 1H NMR spectra were measured
on a Bruker Avance 400 MHz spectrometer using TMS as an internal
standard and CDCl3 as the solvent. Mass spectra were determined
on an Agilent Thermo MSQ PLUS mass spectrometer operating at
an ionisation potential of 70 eV. High-resolution mass spectra were
recorded on a ZAB-HS instrument using an electrospray source (ESI).
Optical rotations were measured on a JASCO P-2000 polarimeter.
The general procedure for the preparation of fragments 7 followed
the route described in Scheme 2.
Conclusions
(S)-tert-Butyl{1-[methoxy(methyl)amino]-4-methyl-1-oxopentan-2-
yl}carbamate 2R1
A novel and efficient process for the synthesis of the epoxyketone
fragment of carfilzomib and its derivatives has been developed.
Compared with the conventional method, this new route is more
economic and environmentally friendly and can be used in
scaling up the synthesis of carfilzomib and its derivatives.
N-Boc-protected amino acid 1R1 (7.5 mmol) was dissolved in
dichloromethane (20 mL) and stirred at –10 °C. Then HOBt (7.5 mmol)
and EDCI (11.3 mmol) were added. The reaction was carried out for
15 min, then N, O-dimethylhydroxylamine hydrochloride (7.5 mmol)

84 JOURNAL OF CHEMICAL RESEARCH 2016
was added and after 15 min, DIPEA (18.9 mmol) was added. The
reaction temperature was allowed to rise to room temperature 25 min
later and the mixture was left overnight. The resulting mixture was
washed with 1 M HCl (20 mL), 5% NaHCO3 (20 mL) and saturated
brine (20 mL) respectively and dried over anhydrous Na2SO4. It was
filtered, and the solvent was evaporated to provide crude product 2R1
which was used without further purification in the next reaction.
m, 2H), 4.28 (–CH, dd, J = 9.0, 3.6 Hz, 1H), 5.04 (–CONH, d, J = 7.4
Hz, 1H). MS (ESI) m/z: 244.4 [M + H]+, 266.3 [M + Na]+; HRMS
calcd for C13H25NO3Na [M + Na]+:266.1726; found: 266.1732.
Compounds 3R2–3R5 were prepared following a similar procedure to
that described for the synthesis of 3R1.
(S)-tert-Butyl(3-oxo-1-phenylpentan-2-yl)carbamate 3R2
1
1
Colourless liquid; yield 77%; H NMR (400 MHz, CDCl3): δ 1.00
Colourless liquid; yield 97%; H NMR (400 MHz, CDCl3): δ 0.91
(–CH3, t, J = 7.2 Hz, 3H), 1.41 (–CH3, s, 9H), 2.38–2.34 (–CH2, m,
2H), 2.97 (–Ph–CH2, dd, J = 13.9, 6.3 Hz, 1H), 3.04 (–Ph–CH2, dd, J =
13.8, 6.9 Hz, 1H), 4.54 (–CH, dd, J = 14.0, 6.9 Hz, 1H), 5.13 (–CONH,
d, J = 7.4 Hz, 1H), 7.23–7.08 (–Ph, m, 5H); MS (ESI) m/z: 279.2 [M
+ H]+, 301.2 [M + Na]+; HRMS calcd for C16H23NO3Na [M + Na]+:
300.1570; found: 300.1579.
(–CH3, d, J = 6.7 Hz, 3H), 0.95 (–CH3, d, J = 6.5 Hz, 3H), 1.42 (–CH3,
s, 9H), 1.70 (–CH, dd, J = 13.0, 6.4 Hz, 1H), 3.19 (–CH3, s, 3H), 3.78
(–CH3, s, 3H), 4.71 (–CH, d, J = 4.3 Hz, 1H), 5.04 (–CONH, d, J = 9.1
Hz, 1H); MS (ESI) m/z: 275.2 [M + H]+, 297.3 [M + Na]+; HRMS calcd
for C13H26N2O4Na [M + Na]+:297.1784; found: 297.1782.
Compounds 2R2–2R5 were prepared from the corresponding amino
acids and carboxylic acids following a similar procedure to that
described for the synthesis of 2R1.
(S)-tert-Butyl(4-oxo-1-phenylhexan-3-yl)carbamate 3R3
1
Colourless liquid; yield 81%; H NMR (400 MHz, CDCl3): δ 1.06
(S)-tert-Butyl{1-[methoxy(methyl)amino]-1-oxo-3-phenylpropan-2-
yl}carbamate 2R2
(–CH3, t, J = 7.3 Hz, 3H), 1.45 (–CH3, s, 9H), 1.81–1.78 (–CH2, m, 1H),
2.19–2.16 (–CH2, m, 1H), 2.48–2.45 (–CH2, m, 2H), 2.64–2.60 (–Ph–
CH2, m, 2H), 4.38 (–CH, d, J = 4.2 Hz, 1H), 5.25 (–CONH, d, J = 7.4
Hz, 1H), 7.22–7.06 (–Ph, m, 5H); MS (ESI) m/z: 292.2 [M + H]+, 314.2
[M +Na]+; HRMS calcd for C17H25NO3Na [M + Na]+: 314.1726; found:
314.1735.
1
Colourless liquid; yield 90%; H NMR (400 MHz, CDCl3): δ 1.36
(–CH3, s, 9H), 2.87 (Ph–CH2, dd, J = 13.2, 7.2 Hz, 1H), 3.05 (–Ph–
CH2, dd, J = 13.4, 5.9 Hz, 1H), 3.17 (–CH3, s, 3H), 3.65 (–CH3, s,
3H), 4.95 (–CONH, d, J = 7.1 Hz, 1H), 5.16 (–CH, d, J = 7.8 Hz, 1H),
7.23–7.09 (–Ph, m, 5H); MS (ESI) m/z: 309.3 [M + H]+, 331.2 [M +
Na]+; HRMS calcd for C16H24N2O4Na [M + Na]+: 331.1628; found:
331.1630.
(S)-tert-Butyl(3-oxooctan-4-yl)carbamate 3R4
1
Colourless liquid; yield 75%; H NMR (400 MHz, CDCl3): δ 0.88
(–CH3, t, J = 7.0 Hz, 3H), 1.07 (–CH3, t, J = 7.3 Hz, 3H), 1.25–1.20
(–CH2, m, 2H), 1.34–1.30 (–CH2, m, 2H), 1.43 (–CH3, s, 9H), 1.50
(–CH2, ddd, J = 11.5, 10.6, 5.9 Hz, 1H), 1.81–1.77 (–CH2, m, 1H),
2.51–2.47 (–CH2, m, 2H), 4.31 (–CH, dd, J = 11.9, 7.2 Hz, 1H), 5.17
(–CONH, d, J = 6.4 Hz, 1H); MS (ESI) m/z: 244.4 [M + H]+, 266.3
[M + Na]+; HRMS calcd for C13H25NO3Na [M + Na]+: 266.1726; found:
266.1725.
(S)-tert-Butyl{1-[methoxy(methyl)amino]-1-oxo-4-phenylbutan-2-
yl}carbamate 2R3
Colourless liquid; yield 79%; H NMR (400 MHz, CDCl3): δ 1.45
(–CH3, s, 9H). 2.03–2.01 (–CH2, m, 2H), 2.71–2.68 (–CH2, m,
2H), 3.16 (–CH3, s, 3H), 3.62 (–CH3, s, 3H), 4.68 (–CH, s, 1H), 5.22
(–CONH, d, J = 8.7 Hz, 1H), 7.22–7.07 (–Ph, m, 5H); MS (ESI) m/z:
323.2 [M + H]+; HRMS calcd for C17H26N2O4Na [M + Na]+: 345.1784;
found: 345.1797.
1
(S)-tert-Butyl(4-oxohexan-3-yl)carbamate 3R5
1
Colourless liquid; yield 77%; H NMR (400 MHz, CDCl3): δ 0.87
(S)-tert-Butyl{1-[methoxy(methyl)amino]-1-oxohexan-2-yl}
carbamate 2R4
(–CH3, t, J = 7.5 Hz, 3H), 1.07 (–CH3, t, J = 7.3 Hz, 3H), 1.43 (–CH3,
s, 9H), 1.62–1.53 (–CH, m, 1H), 1.83 (–CH, dd, J = 14.0, 7.0 Hz, 1H),
2.59–2.42 (–CH2, m, 2H), 4.30 (–CH, dd, J = 11.9, 6.7 Hz, 1H), 5.22
(–CONH, s, 1H); MS (ESI) m/z: 216.3 [M + H]+, 238.2 [M + Na]+;
HRMS calcd for C11H21NO3Na [M + Na]+: 238.1413; found: 238.1412.
1
Colourless liquid; yield 82%; H NMR (400 MHz, CDCl3): δ 0.87
(–CH3, dd, J = 9.5, 4.3 Hz, 3H), 1.27–1.24 (–CH2, m, 2H), 1.34–1.31
(–CH2, m, 2H), 1.42 (–CH3, s, 9H), 1.51–1.48 (–CH2, m, 1H), 1.68–1.65
(–CH2, m, 1H), 3.19 (–CH3, s, 3H), 3.76 (–CH3, s, 3H), 4.66 (–CH, s,
1H), 5.13 (–CONH, d, J = 8.7 Hz, 1H); MS (ESI) m/z: 275.2 [M + H]+,
297.3 [M + Na]+; HRMS calcd for C13H26N2O4Na [M + Na]+: 297.1784;
found: 297.1791.
(S)-tert-Butyl(2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate 4R1
A solution of compound 3R1 (4 mmol) in anhydrous THF (10 mL)
was heated with piperidinium acetate (14.8 mmol), piperidine (9.9
mmol) and paraformaldehyde (39.6 mmol). The reaction mixture was
refluxed for 8 h at 68 °C. The solution was extracted with ethyl acetate
(3 × 15 mL) and washed with 1 M HCl (40 mL) and brine (40 mL) and
then dried over anhydrous Na2SO4. The solvent was evaporated and the
crude product was purified by flash column chromatography with ethyl
acetate and petroleum (V/V = 1:10) to give 4R1.
(S) -tert-Butyl{1-[methoxy(methyl)amino]-1-oxobutan-2-yl}
carbamate 2R5
1
Colourless liquid; yield 82%; H NMR (400 MHz, CDCl3): δ 0.92
(–CH3, t, J = 7.5 Hz, 3H), 1.42 (–CH3, s, 9H), 1.54 (–CH, dd, J = 20.2,
6.8 Hz, 1H), 1.80–1.70 (–CH, m, 1H), 3.19 (–CH3, s, 3H), 3.74 (–CH3,
d, J = 13.1 Hz, 3H), 4.61 (–CH, s, 1H), 5.17 (–CONH, d, J = 8.2 Hz,
1H); MS (ESI) m/z: 247.3 [M + H]+, 269.3 [M + Na]+; HRMS calcd for
C11H22N2O4Na [M + Na]+:269.1471; found: 269.1474.
1
Colourless liquid; yield 92%; H NMR (400 MHz, CDCl3): δ 0.89
(–CH3, d, J = 6.6 Hz, 3H), 0.99 (–CH3, d, J = 6.6 Hz, 3H), 1.32 (–CH,
ddd, J = 14.4, 9.6, 4.8 Hz, 1H), 1.42 (–CH3, s, 9H), 1.50–1.44 (–CH,
m, 1H), 1.76–1.71 (–CH, m, 1H), 1.89 (–CH3, s, 3H), 5.05 (–CH, dd,
J = 9.6, 3.6 Hz, 1H), 5.14 (–CH, d, J = 8.4 Hz, 1H), 5.87 (–CH, s, 1H),
6.07 (–CONH, s, 1H); MS (ESI) m/z: 256.3 [M + H]+, 278.3 [M + Na]+;
HRMS calcd for C14H25NO3Na [M + Na]+: 278.1726; found: 278.1734.
Compounds 4R2–4R5 were prepared following a similar procedure to
that described for the synthesis of 4R1.
(S)-tert-Butyl(2-methyl-5-oxoheptan-4-yl)carbamate 3R1
The Weinreb amide 2R1 (5.7 mmol) was dissolved in anhydrous THF
(6 mL) and stirred at –20 °C. Ethylmagnesium bromide (17.1 mmol)
was then added dropwise. The reaction was left for a further 20 min
and then the temperature was allowed to rise to room temperature and
the mixture was stirred overnight. The reaction was quenched with 1
M HCl (20 mL) at –20 °C and extracted with ethyl acetate (3 × 15 mL).
The combined organic layers were washed with brine (50 mL) and
dried over anhydrous Na2SO4, filtered and the solvent was evaporated
to provide the crude product 3R1, which was purified by flash column
chromatography with ethyl acetate and petroleum (V/V = 1:3).
Colourless liquid; yield 92%; 1H NMR (400 MHz, CDCl3): δ
0.88 (–CH3, d, J = 6.6 Hz, 3H), 0.92 (–CH3, d, J = 6.6 Hz, 3H), 1.03
(–CH3, t, J = 7.2 Hz, 3H), 1.34–1.25 (–CH, m, 1H), 1.39 (–CH3, s, 9H),
1.52–1.44 (–CH, m, 1H), 1.73–1.61 (–CH, m, 1H), 2.59–2.38 (–CH2,
(S)-tert-Butyl(4-methyl-3-oxo-1-phenylpent-4-en-2-yl)carbamate
4R2
1
Colourless liquid; yield 64%; H NMR (400 MHz, CDCl3): δ 1.38
(–CH3, s, 9H), 1.86 (–CH3, s, 3H), 2.91–2.86 (–Ph–CH2, m, 1H),
3.10–3.05 (–Ph–CH2, m, 1H), 5.26 (–CONH, s, 1H), 5.33–5.29 (–CH,
m, 1H), 5.85 (–CH2, d, J = 1.2 Hz, 1H), 6.01 (–CH2, s, 1H), 7.19–7.06
(–Ph, m, 5H); MS (ESI) m/z: 290.2 [M + H]+, 312.3 [M + Na]+; HRMS
calcd for C17H23NO3Na [M + Na]+:312.1570; found: 312.1589.

JOURNAL OF CHEMICAL RESEARCH 2016 85
(S)-tert-Butyl(5-methyl-4-oxo-1-phenylhex-5-en-3-yl)carbamate 4R3
(–CH3, s, 9H), 1.76 (–CH3, s, 3H), 2.23 (–OH, d, J = 7.7 Hz, 1H), 3.74
(–CH, s, 1H), 4.14 (–CH, s, 1H), 4.65 (–CONH, s, 1H), 4.95 (–CH2,
d, J = 1.3 Hz, 1H), 5.01 (–CH2, s, 1H); MS (ESI) m/z: 258.3 [M + H]+,
280.3 [M + Na]+; HRMS calcd for C14H27NO3Na [M + Na]+: 280.1883,
found: 280.1887.
1
Colourless liquid; yield 53%; H NMR (400 MHz, CDCl3): δ 1.46
(–CH3, s, 9H), 1.87 (–CH3, s, 3H), 2.05–2.01 (–CH2, m, 2H), 2.64–2.60
(–CH2, m, 2H), 5.06 (–CH, s, 1H), 5.35 (–CONH, s, 1H), 5.83 (–CH2,
s, 1H), 5.90 (–CH2, s, 1H), 7.22–7.07 (–Ph, m, 5H); MS (ESI) m/z:
304.4 [M + H]+, 326.4 [M + Na]+; HRMS calcd for C18H25NO3Na [M +
Na]+: 326.1726; found: 326.1724.
tert-Butyl[(3S,4S)-4-hydroxy-5-methylhex-5-en-3-yl] carbamate 5R5
1
Colourless liquid; yield 95%; H NMR (400 MHz, CDCl3): δ 0.94
(S)-tert-Butyl(2-methyl-3-oxooct-1-en-4-yl)carbamate 4R4
(–CH3, t, J = 7.4 Hz, 3H), 1.44 (–CH3, s, 9H), 1.54 (–CH, d, J = 3.4 Hz,
1H), 1.61 (–CH, d, J = 18.8 Hz, 1H), 1.76 (–CH3, s, 3H), 2.21 (–CH, d,
J = 7.4 Hz, 1H), 3.67 (–CH, s, 1H), 4.14 (–CH, s, 1H), 4.65 (–CONH,
s, 1H), 4.94 (–CH, s, 1H), 5.01 (–CH, s, 1H). MS (ESI) m/z: 230.3
[M + H]+, 252.2 [M + Na]+; HRMS calcd for C12H23NO3Na [M + Na]+
252.1570; found: 252.1570.
1
Colourless liquid; yield 90%; H NMR (400 MHz, CDCl3): δ 0.87
(–CH3, t, J = 7.0 Hz, 3H), 1.25 (–CH2, d, J = 2.5 Hz, 2H), 1.33–1.29
(–CH2, m, 2H), 1.43 (–CH3, s, 9H), 1.49–1.45 (–CH2, m, 1H), 1.76–1.72
(–CH2, m, 1H), 1.90 (–CH3, s, 3H), 5.01 (–CH, dd, J = 12.5, 6.4 Hz,
1H), 5.28 (–CONH, d, J = 8.1 Hz, 1H), 5.88 (–CH2, d, J = 0.9 Hz, 1H),
6.05 (–CH2, s, 1H); MS (ESI) m/z: 256.3 [M + H]+, 278.3 [M + Na]+;
HRMS calcd for C14H25NO3Na [M + Na]+: 278.1726; found: 278.1725.
tert-Butyl{(1S,2S)-1-hydroxy-4-methyl-1-[(R)-2-methyloxiran-2-yl]
pentan-2-yl}carbamate 6R1
(S)-tert-Butyl(5-methyl-4-oxohex-5-en-3-yl)carbamate 4R5
Compound 5R1 (0.7 mmol) in DCM (3 mL) was treated with
vanadium(III) acetylacetonate (0.14 mmol) at 0 °C under nitrogen.
tert-Butyl hydroperoxide solution (2.1 mmol) was then added. The
reaction mixture was allowed to warm to room temperature after
1 h and stirred overnight. The solution was extracted with DCM
(3 × 10 mL). The combined organic phases were washed with sodium
thiosulfate solution (3 × 20 mL) and brine (30 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated and the residue was
chromatographed with ethyl acetate and petroleum (V/V = 1:5) to give
6R1.
1
Colourless liquid; yield 91%; H NMR (400 MHz, CDCl3): δ 0.86
(–CH3, t, J = 7.5 Hz, 3H), 1.43 (–CH3, s, 9H), 1.59–1.48 (–CH, m, 1H),
1.83 (–CH, dd, J = 12.5, 6.9 Hz, 1H), 1.90 (–CH3, s, 3H), 4.98 (–CH,
dd, J = 12.5, 7.4 Hz, 1H), 5.32 (–CONH, s, 1H), 5.88 (–CH, s, 1H), 6.05
(–CH, s, 1H); MS (ESI) m/z: 228.3 [M + H]+, 250.2 [M + Na]+; HRMS
calcd for C12H21NO3Na [M + Na]+: 250.1413; found: 250.1411.
tert-Butyl [(3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl]carbamate
5R1
A mixture of aluminium isopropoxide (1 mmol) and isopropanol
(9.5 mmol) in toluene (2 mL) was added dropwise to 4R1 (1 mmol)
in toluene (3 mL) at room temperature. The reaction mixture was
then stirred at 50 °C overnight. The solution was extracted with ethyl
acetate (3 × 5 mL). The combined organic phases were washed with 1
M HCl (20 mL) and brine (20 mL) and dried over anhydrous Na2SO4.
The solution was filtered and the solvent was evaporated to give a
yellow viscous oil, which was chromatographed with ethyl acetate and
petroleum (V/V = 1:4) to give 5R1.
1
Colourless liquid; yield 85%; H NMR (400 MHz, CDCl3): δ 0.90
(–CH3, d, J = 6.6 Hz, 3H), 0.91 (–CH3, d, J = 6.6 Hz, 3H), 1.11–1.04
(–CH, m, 1H), 1.36 (–CH3, s, 3H), 1.43 (–CH3, s, 9H), 1.48–1.44 (–CH,
m, 1H), 1.69–1.57 (–CH, m, 1H), 2.44 (–OH, s, 1H), 2.61 (–CH2, d,
J = 4.8 Hz, 1H), 2.97 (–CH2, d, J = 4.8 Hz, 1H), 3.82 (–CH, d, J = 3.0
Hz, 1H), 3.95–3.85 (–CH, m, 1H), 4.88 (–CONH, d, J = 9.6 Hz, 1H);
MS (ESI) m/z: 274.3 [M + H]+, 296.4 [M + Na]+; HRMS calcd for
C14H27NO4Na [M + Na]+ 296.1832; found: 296.1830.
Compounds 6R2–6R5 were prepared following a similar procedure to
that described for the synthesis of 6R1.
1
Colourless liquid; yield 96%; H NMR (400 MHz, CDCl3): δ 0.88
(–CH3, d, J = 6.6 Hz, 3H), 0.90 (–CH3, d, J = 6.6 Hz, 3H), 1.20–1.14
(–CH, m, 1H), 1.31–1.23 (–CH2, m, 2H), 1.43 (–CH3, s, 9H), 1.67–1.57
(–CH, m, J = 6.0, 3.6 Hz, 1H), 1.75 (–CH3, s, 3H), 2.42 (–OH, s, 1H),
3.82 (–CH, t, J = 9.6 Hz, 1H), 4.14 (–CH, s, 1H), 4.70 (–CONH, d, J =
7.8 Hz, 1H), 4.93 (–CH2, dd, J = 3.0, 1.2 Hz, 1H), 5.00 (–CH2, s, 1H);
MS (ESI) m/z: 258.3 [M + H]+, 280.3 [M + Na]+; HRMS calcd for
C14H27NO3Na [M + Na]+: 280.1883; found: 280.1888.
tert-Butyl{(1R,2S)-1-hydroxy-1-[(R)-2-methyloxiran-2-yl]-3-
phenylpropan-2-yl}carbamate 6R2
1
Colourless liquid; yield 76%; H NMR (400 MHz, CDCl3): δ 1.32
(–CH3, s, 9H), 1.38 (–CH3, s, 3H), 2.34 (–CH2, s, 1H), 2.60 (–CH2, d,
J = 4.6 Hz, 1H), 2.75 (–Ph–CH2, dd, J = 14.2, 9.5 Hz, 1H), 2.86 (–Ph–
CH2, dd, J = 14.0, 4.7 Hz, 1H), 3.01 (–OH, d, J = 4.6 Hz, 1H), 3.85
(–CH, d, J = 2.3 Hz, 1H), 4.12–4.08 (–CH, m, 1H), 4.87 (–CONH,
d, J = 9.4 Hz, 1H), 7.25–7.06 (–Ph, m, 5H); MS (ESI) m/z: 308.2 [M
+ H]+, 330.2 [M + Na]+; HRMS calcd for C17H25NO4Na [M + Na]+:
330.1675; found: 330.1690.
Compounds 5R2–5R5 were prepared following a similar procedure to
that described for the synthesis of 5R1.
tert-Butyl[(2S,3S)-3-hydroxy-4-methyl-1-phenylpent-4-en-2-yl]
carbamate 5R2
1
Colourless liquid; yield 96%; H NMR (400 MHz, CDCl3): δ 1.34
tert-Butyl{(1S,2S)-1-hydroxy-1-[(R)-2-methyloxiran-2-yl]-4-
phenylbutan-2-yl}carbamate 6R3
(–CH3, s, 9H). 1.81 (–CH3, s, 3H), 2.36 (–OH, s, 1H), 2.70 (–Ph–CH2, s,
1H), 2.89 (–Ph–CH2, dd, J = 14.3, 3.7 Hz, 1H), 3.98 (–CH, s, 1H), 4.20
(–CH, s, 1H), 4.64 (–CONH, s, 1H), 5.00 (–CH2, s, 1H), 5.08 (CH2, s, 1H),
7.24–7.10 (–Ph, m, 5H); MS (ESI) m/z: 292.2 [M + H]+, 314.2 [M + Na]+;
HRMS calcd for C17H25NO3Na [M + Na]+:314.1726; found: 314.1729.
Colourless liquid; yield 69%; 1H NMR (400 MHz, CDCl3): δ 1.26–1.21
(–CH3, m, 3H), 1.47 (–CH3, s, 9H), 1.73–1.68 (–CH2, m, 2H), 2.14
(–CH2, s, 1H), 2.60–2.55 (–CH2, m, 2H), 2.77–2.74 (–CH2, m, 1H),
2.95 (–OH, d, J = 4.8 Hz, 1H), 3.85 (–CH, s, 1H), 3.89 (–CH, d, J =
10.2 Hz, 1H), 4.96 (–CONH, d, J = 9.2 Hz, 1H), 7.25–7.09 (–Ph, m,
5H); MS (ESI) m/z: 322.3 [M + H]+, 344.2 [M + Na]+; HRMS calcd for
C18H27NO4Na [M + Na]+: 344.1832; found: 344.1844.
tert-Butyl[(3S,4R)-4-hydroxy-5-methyl-1-phenylhex-5-en-3-yl]
carbamate 5R3
1
Colourless liquid; yield 89%; H NMR (400 MHz, CDCl3): δ 1.45
(–CH3, s, 9H), 1.59 (–CH2, s, 1H), 1.65 (–CH3, d, J = 14.0 Hz, 3H),
1.80–1.76 (–CH2, m, 1H), 2.15 (–OH, s, 1H), 2.59–2.54 (–Ph–CH2, m,
1H), 2.75–2.70 (–Ph–CH2, m, 1H), 3.79 (–CH, s, 1H), 4.12 (–CH, dd,
J = 14.3, 7.2 Hz, 1H), 4.80 (–CONH, d, J = 8.8 Hz, 1H), 4.92 (–CH2,
dd, J = 2.7, 1.4 Hz, 1H), 5.01 (–CH2, s, 1H), 7.23–7.08 (–Ph, m, 5H);
MS (ESI) m/z: 306.3 [M + H]+, 328.4 [M + Na]+; HRMS calcd for
C18H27NO3Na [M + Na]+:328.1883; found: 328.1881.
tert-Butyl{(1R,2S)-1-hydroxy-1-[(R)-2-methyloxiran-2-yl]hexan-2-
yl}carbamate 6R4
1
Colourless liquid; yield 87%; H NMR (400 MHz, CDCl3): δ 0.88
(–CH3, t, J = 6.4 Hz, 3H), 1.23 (–CH2, ddd, J = 11.3, 4.6, 2.3 Hz, 2H),
1.31–1.27 (–CH2, m, 2H), 1.37 (–CH3, s, 3H), 1.38–1.34 (–CH2, m,
2H), 1.44 (–CH3, s, 9H), 2.34 (–OH, d, J = 10.0 Hz, 1H), 2.62 (–CH2, d,
J = 4.8 Hz, 1H), 2.97 (–CH2, d, J = 4.8 Hz, 1H), 3.75 (–CH, s, 1H), 3.80
(–CH, s, 1H), 4.90 (–CONH, d, J = 9.2 Hz, 1H); MS (ESI) m/z: 274.3
[M + H]+, 296.4 [M + Na]+; HRMS calcd for C14H27NO4Na [M + Na]+:
296.1832; found: 296.1830.
tert-Butyl[(3S,4S)-3-hydroxy-2-methyloct-1-en-4-yl]carbamate 5R4
1
Colourless liquid; yield 99%; H NMR (400 MHz, CDCl3): δ 0.88
(–CH3, t, J = 6.7 Hz, 3H), 1.25 (–CH2, s, 2H), 1.27 (–CH2, s, 2H), 1.44

86 JOURNAL OF CHEMICAL RESEARCH 2016
tert-Butyl{(1R,2S)-1-hydroxy-1-[(R)-2-methyloxiran-2-yl]butan-2-
yl} carbamate 6R5
1.34 (–CH2, d, J = 7.6 Hz, 2H), 1.42 (–CH3, s, 9H), 1.51 (–CH3, s, 3H),
1.59 (–CH, s, 1H), 1.75–1.70 (–CH, m, 1H), 2.88 (–CH, d, J = 5.0 Hz,
1H), 3.25 (–CH, d, J = 4.8 Hz, 1H), 4.27 (–CH, t, J = 8.0 Hz, 1H), 4.92
(–CONH, d, J = 8.3 Hz, 1H); MS (ESI) m/z: 272.3 [M + H]+, 294.3 [M
+ Na]+; HRMS calcd for C14H25NO4Na [M + Na]+: 294.1675; found:
294.1683.
1
Colourless liquid; yield 91%; H NMR (400 MHz, CDCl3): δ 0.94
(–CH3, t, J = 7.4 Hz, 3H), 1.24 (–CH, s, 1H), 1.37 (–CH3, s, 3H), 1.44
(–CH3, s, 9H), 1.56–1.48 (–CH, m, 1H), 2.27 (–CH, s, 1H), 2.63 (–CH,
d, J = 4.8 Hz, 1H), 2.96 (–CH, d, J = 4.8 Hz, 1H), 3.74 (–CH, t, J = 10.1
Hz, 1H), 3.81 (–CH, d, J = 2.7 Hz, 1H), 4.88 (–CONH, d, J = 9.1 Hz,
1H); MS (ESI) m/z: 246.3 [M + H]+, 268.2 [M + Na]+; HRMS calcd for
C12H23NO4Na [M + Na]+:268.1519; found: 268.1522.
tert-Butyl{(S)-1-[(R)-2-methyloxiran-2-yl]-1-oxobutan-2-yl}
carbamate 7R5
[a]
Colourless liquid; yield 90%;
24 = +61.6 (c = 0.5, CH3CN); 1H NMR
D
tert-Butyl{(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-
yl}carbamate 7R1
(400 MHz, CDCl3): δ 0.95 (–CH3, t, J = 7.4 Hz, 3H), 1.42 (–CH3, s,
9H), 1.48–1.45 (–CH, m, 1H), 1.53 (–CH3, s, 3H), 1.88–1.79 (–CH, m,
1H), 2.90 (–CH, d, J = 5.0 Hz, 1H), 3.25 (–CH, d, J = 4.7 Hz, 1H), 4.27
(–CH, dd, J = 12.5, 8.1 Hz, 1H), 4.99 (–CONH, d, J = 7.4 Hz, 1H); MS
(ESI) m/z: 266.2 [M + Na]+; HRMS calcd for C12H21NO4Na [M + Na]+:
266.1362; found: 266.1367.
Compound 6R1 (0.5 mmol) dissolved in dimethyl sulfoxide (DMSO)
(3 mL) was treated with DIPEA (1.0 mmol). Pyridine:sulfur trioxide
(2 mmol) was then slowly added. The mixture was stirred at room
temperature overnight. The solution was extracted with ethyl acetate
(3 × 5 mL). The combined organic phases were washed with 1 M HCl
(10 mL) and saturated brine (10 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated and the residue was chromatographed with
ethyl acetate and petroleum (V/V = 1:5) to give 7R1.
Part of this work was supported by the following grants: the
National Natural Science Foundation of China (21302097),
Natural Science Fund for Colleges and Universities in Jiangsu
Province (14KJD350002), Technology Support Programme of
the Science and Technology Department of Jiangsu Province
(BE2014720), the National and Local Joint Engineering
Research Centre of Biomedical Functional Materials and
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD). Xiao Du and Hao-yang Zhang
are co-first authors of this paper.
[a]24
Colourless liquid; yield 91%;
= +54.4 (c = 0.5, CH3CN);
D
1H NMR (400 MHz, CDCl3): δ 0.92 (–CH3, d, J = 6.4 Hz, 3H), 0.95
(–CH3, d, J = 6.4 Hz, 3H), 1.21–1.11 (–CH, m, 1H), 1.39 (–CH3, s, 9H),
1.49–1.44 (–CH, m, 1H), 1.50 (–CH3, s, 3H), 1.83–1.64 (–CH, m, 1H),
2.87 (–CH, d, J = 4.8 Hz, 1H), 3.27 (–CH, d, J = 4.8 Hz, 1H), 4.30
(–CH, t, J = 9.6 Hz, 1H), 4.86 (–CONH, d, J = 8.0 Hz, 1H); MS (ESI)
m/z: 272.3 [M + H]+, 294.3 [M + Na]+; HRMS calcd for C14H25NO4Na
[M + Na]+:294.1675; found: 294.1678 (lit.10 294.1676).
Compounds 7R2–7R5 were prepared following a similar procedure to
that described for the synthesis of 7R1.
Received 10 October 2015; accepted 12 December 2015
Paper 1503648 doi: 10.3184/174751916X14539789662063
Published online: 29 January 2016
tert-Butyl{(S)-1-[(R)-2-methyloxiran-2-yl)]1-oxo-3-phenylpropan-2-
yl}carbamate 7R2
[a]24
Colourless liquid; yield 69%;
= +13.8 (c = 0.25, CH3CN);
D
1H NMR (400 MHz, CDCl3): δ 1.36 (–CH3, s, 9H). 1.50 (–CH3, s, 3H),
2.73 (–CH2, dd, J = 13.8, 7.7 Hz, 1H), 2.90 (–CH2, d, J = 4.9 Hz, 1H),
3.10 (–Ph–CH2, dd, J = 13.9, 5.0 Hz, 1H), 3.29 (–Ph–CH2, d, J = 4.9 Hz,
1H), 4.58 (–CH, dd, J = 13.2, 8.0 Hz, 1H), 4.93 (–CONH, d, J = 7.7 Hz,
1H), 7.25–7.09 (–Ph, m, 5H); MS (ESI) m/z: 306.2 [M + H]+, 328.2 [M
+ Na]+; HRMS calcd for C17H23NO4Na [M + Na]+: 328.1519; found:
328.1533.
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tert-Butyl{(S)-1-[(R)-2-methyloxiran-2-yl]-1-oxo-4-phenylbutan-2-
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Colourless liquid; yield 75%;
24 = +7.0 (c = 0.5, CH3CN); 1H NMR
[a]
D
(400 MHz, CDCl3): d 1.43 (–CH3, s, 9H), 1.49 (–CH3, s, 3H),
1.63–1.59 (–CH2, m, 1H), 2.14 (–CH2, s, 1H), 2.11–2.07 (–CH2, m,
1H), 2.69–2.65 (–CH2, m, 2H), 2.87 (–CH2, d, J = 5.0 Hz, 1H), 3.21
(–CH2, d, J = 4.8 Hz, 1H), 4.35 (–CH, d, J = 3.4 Hz, 1H), 5.02
(–CONH, d, J = 7.9 Hz, 1H), 7.24–7.09 (–Ph, m, 5H); MS (ESI) m/z:
320.3 [M + H]+; HRMS calcd for C18H25NO4Na [M + Na]+: 342.1675;
found: 342.1687.
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tert-Butyl{(S)-1-[(R)-2-methyloxiran-2-yl]-1-oxohexan-2-yl}
carbamate 7R4
Colourless liquid; yield 87%;
24 = +39.1 (c = 0.5, CH3CN); 1H NMR
[a]
D
(400 MHz, CDCl3): δ 0.90–0.86 (–CH3, m, 3H), 1.30 (–CH2, s, 2H),
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