A concise and scalable formal synthesis of the enantiopure side-chain diester of homoharringtonine

Article abstract of DOI:10.3184/174751915X14189228913336

The enantiopure side-chain diester of homoharringtonine (HHT) has been prepared in 38% overall yield, from cheap L-aspartic acid by a linear sequence of 10 chemical operations (mean yield per step: 91%). The experimental operation in each step is convenient, economic and prone to scale up. About 7-10 g of the side-chain diester of HHT is easily prepared within one week from 5 g of L-aspartic acid.

Full text of DOI:10.3184/174751915X14189228913336

26 RESEARCH PAPER
VOL. 39 JANUARY, 26–29
JOURNAL OF CHEMICAL RESEARCH 2015
A concise and scalable formal synthesis of the enantiopure side-chain
diester of homoharringtonine
Moran Sun, Xin Jia, Yaowen Lai and Hua Yang*
School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, P.R. China
The enantiopure side-chain diester of homoharringtonine (HHT) has been prepared in 38% overall yield, from cheap L-aspartic
acid by a linear sequence of 10 chemical operations (mean yield per step: 91%). The experimental operation in each step is
convenient, economic and prone to scale up. About 7–10 g of the side-chain diester of HHT is easily prepared within one week
from 5 g of L-aspartic acid.
Keywords: homoharringtonine, regioselective, large-scale production
Homoharringtonine (HHT, 1), accompanied by several
congener alkaloids, was extracted from the leaves and stems of
plum yew Cephalotaxus harringtonia, an evergreen tree native
of the southern provinces of China.1–3 HHT is the main natural
ester of cephalotaxine (2) in the tree, and also the most potent
in this family of antitumor alkaloids (Fig. 1). Indeed nowadays,
HHT may be marketed alone or in multi-drug associations to
treat orphan blood diseases such as chronic myeloid leukaemia
(CML) or refractory acute promyelocytic leukaemia (AML).
After successful clinical trials, HHT has been submitted to a
marketing authorisation application (MAA) and a new drug
application (NDA).4–6 Although cephalotaxine (2) accounts
for approximately 50% of the crude alkaloid extract mixture,
it itself does not exhibit any interesting antitumour activity.
Accordingly, the most practical path for obtaining large
quantities of HHT at present is through semi-synthesis by
coupling the carboxyl group of the ester side-chain to the C-3
hydroxyl group of cephalotaxine (2).
As shown in Table 1, six synthetic routes have been
reported and the retrosynthetic analysis is categorised as a
bond disconnection strategy (entries 1–5) and a functional
group connection strategy (entry 6). By bond a disconnection,
Robin and coworkers achieved a moderate diastereoselectivity
(65/35) by hydroxyalkylation of the hindered tert-butyl
ketoester 4 with the chiral lithium anion of (R)-2-hydroxy-
1,2,2-triphenylethyl acetate 5. Chromatography of the
diastereomeric mixture, followed by crystallisation, gave the
enantiopure hydroxyalkylation product only in 30% yield and
the overall yield of 4+5ꢀ→ꢀ6 was 19.5% (entry 1).7 The bond b
disconnection strategy was based upon Seebach’s procedure,
which was called ‘self-regeneration of stereogenic centres’.8
D-malic acid derivative 8 was alkylated with 7 in moderate
yield (80%) and with high enantiomeric excess (>95%). The
overall yield of 7+8ꢀ→ꢀ9 was 32%, higher than others. However,
using a stoichiometric amount of SeO2 for the introduction of
the necessary hydroxyl group by an allylic oxidation might
lead to serious environmental pollution if operated on a large
scale (entry 2).9 Gin and coworkers utilised the same strategy to
obtain 12 in 17% yields from 9 to 11 and the necessary hydroxyl
group was introduced through the Grubbs alkene metathesis
reaction (entry 3).10 The bond c disconnection strategy was
applied successfully to the synthesis of the side chain ester
of deoxyharringtonine and deoxyhomoharringtonine, but
unsuccessfully to the coupling of 13 and 14 (entry 4).11 The
bond d disconnection strategy originated from the resolution of
citric acid derivatives, and the resolved product was converted
into 16 in 63% yield. Using the Grignard reagent 15 the yield of
16ꢀ→ꢀ6 was 22% and so the overall yield from the resolved citric
acid derivative 6 was 13.8%. If we calculated the overall yield
from citric acid, the value is only 1.6% (entry 5).12 Based on
their synthetic methodology, d’Angelo adopted the functional
group connection strategy (entry 6) and reached a 4.3% total
yield of 18 from the starting 2-benzyloxycyclohexanone
by a linear sequence of 12 chemical operations (mean yield
per step: 77%) via the intermediate 17.13,14 Admittedly, each
synthetic route naturally has its own value from an academic
view, but for a large-scale production, expensive reagents (e.g.
LiHMDS), low temperature conditions (–60 °C to –78 °C) and
other troublesome operations should be circumvented as much
as possible.
More recently, we have demonstrated that the three-
step sequence (i.e. Wittig reaction, [2,3]-Meisenheimer
rearrangement15 and catalytic hydrogenation) served as unique
convenient tactics for the construction of the chiral tertiary
alcohol.16,17 Moreover, the absolute configuration of the tertiary
alcohol can be predicted according to the configuration of the
starting amino acid. In continuation of our efforts, we report
here a more concise and scalable synthesis of the enantiopure
side-chain diester of HHT, each step of which can be performed
in 7–10 g scale in the laboratory and no expensive or deleterious
reagents or cryogenic conditions (<5ꢀ°C) were required.
O
N
O
Results and discussion
5
The synthetic sequence commenced with the conversion of
L-aspartic acid into N,N-bibenzyl protected dialcohol 21
(Scheme 1). Although the regioselective Grignard reaction
betweenꢀ theꢀ α-(N,N-dibenzylamino) substituted ester group
and a simple ester group has no available literature precedents,
to our great delight, the production of intermediate 1918 and
subsequentꢀregioselectiveꢀGrignardꢀreactionꢀtoꢀγ-butyrolactone
20 were accomplished in almost quantitative yield and with
great ease. According to usual practice, the Grignard reagent
should be added to the ether solution of a substrate in order
to achieve excellent regioselectivity. Nevertheless, in the case
6'
HO
Me
H
3
O
R
=
1:
O
HO
O
Me
H
OMe
H
R
OMe
2: R =
homoharringtonine
Cephalotaxine
Fig. 1 Structure of homoharringtonine (HHT, 1).
* Correspondent. E-mail: yanghua@zzu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 27
Table 1 Enantiopure synthesis of 3 or its other forms from 1999 to 2009
b
d
c
OH
CO2H
a
HO
CO2Me
3
Final form of side
Reagents connection
(conditions, yield)
chain
(total yield)
Entry Retrosynthetic analysis
Reagents
O
CO2But
OLi
OH
CO2H
O
CO2H
LiHMDS, –70 oC,
4
1
30
%
HO
CO2Me
Ph
CO2Me
a disconnection
6
O
5
Ph
Ph
19.5%
HO
OH
H
CO2H
O
Br
H
O
LiHMDS, –78 oC,
80
O
O
CO2H
CO2H
2
%
HO
9
7
O
CO2Me
CO2H
8
b disconnection
OH
CO2H
CO2Me
b disconnection
32%
CO2H
i) LiHMDS, –78 oC,
59%
Br
O
O
O
OBn
3
+
+
OBn
10
12
HO
ii) Grubbs II, 23 o
C
11
O
O
61
%
CO2H
8
17%
O
H
CO2H
O
–78 –60 o
C
H
―
CO2
4
5
0
%
0
%
BnO
HO
14
2
e
M
CuLi
CO2
CO2Me
13
c disconnection
OH
CO2H
CO2Me
d disconnection
O
O
CO2H
O
O
OHC
MgBr
15
–40 oC
16
HO
CO2Me
47%, 2 steps
CO2Me
6
22
%
OH
OTMS
OH
1'
OH
6'
1'
HO
–78 oC
CO2H
CO2Me
CO2Me
6'
6
HO
35%, 4 steps
18
4.3%
CO2Me
CO2Me
17
C1'–C6' connection
of this regiocontrolled Grignard reaction of diester 19, no
deterioration of the chemical yield and purity were observed
when reversing this addition order under ice bath conditions.
This interesting reverse addition should be accredited to the
poor solubility of 20 in diethyl ether, wherein 20 was deposited
as soon as it formed. The regioselective Grignard reaction of
19ꢀ→ꢀ20 could be operated on a 5–30 g scale with no problem
in our laboratory.
reduction of lactone 20 by LiAlH4 readily yielded dialcohol
21 in quantitative yield.19 This concise three-step sequence
acts as an exceptionally convenient strategy to access the key
intermediate 21 from L-aspartic acid on a multi-gram scale, in
greater than 92% yield. Compared with the present method,
our published procedure involved additional Boc protection
and deprotection steps. Furthermore, the Grignard reaction
requires proceeding at a low concentration and is unfavourable
to scale-up production due to a complicated handling in the
course of removing the magnesium salt that sticks to the
product16.
The crude product 20 thus obtained contained only small
amounts of impurities, and was therefore taken directly into
the next step without further purification. Subsequently,

28 JOURNAL OF CHEMICAL RESEARCH 2015
CO2Me
CO2H
O
MeO2C
HO2C
b
a
c
NBn2
19
NH2
O
L-aspartic acid
NBn2
20
O
O
HO
HO
e
d
OH
f
OH
O
23
NBn2
NBn2
NBn2
22
21
26
O
O
HO
HO
HO
OH
27
+
HO
CO2Me
CO2Me
CO2H
CO2H
g
h
OH
OH
CO2Me
OH
29
18
OH
28
O
O
O
Ph3P
CO2Me
CO2Me
Ph3P
P
CO2Me
CO2Me
(EtO)2
25
24
23
Reagents and conditions: (a) (i) SOCl2, MeOH, (ii) BnBr, K2CO3, CH3CN, two steps, 95%; (b) MeMgl, ether, 93%; (c) LiAlH4,
THF, 5 °C, 97%; (d) Py SO3, DMSO 95%; (e) Toluene, reflux, 72%; (f) (i) m-CPBA, DCM, 5 °C, (ii) H2, Pd/C, 60 psi, 5 °C,
MeOH, then 60 °C, two steps 75%; (g) TEMPO, NaClO2, NaClO, 90%; (h) TMSCI, 2,2-dimethoxylpropane, DCM, 95%.
Scheme 1 Synthesis of side-chain diester 18.
We are now in a position to elaborate the alcohol 21 into a
form suitable for coupling with an ylide. A Swern oxidation
of 21 led to hemiacetal 22 in almost quantitative yield, as
described in our first generation route16. Considering that the
temperature conditions of below –60 °C and that the expensive
oxidant IBX was unaffordable for large-scale production, the
Parikh–Doering oxidation was also attempted. The reaction
finished rapidly at room temperature in quantitative yield
through an extremely convenient operation, just requiring
adding the pre-mixed solution of SO3·Pyꢀ inꢀ DMSOꢀ toꢀ theꢀ
DMSO solution of hemiacetal 22. Although the masked
aldehyde 21 proved unreactive towards ylide 24 or 25 in all
instances, it underwent a smooth condensation with Wittig
reagent 23 to furnish the desired trans-olefin 26 in 65% yield.
The removal of by-product Ph3P=O by column chromatography
or recrystallisation is universally recognised as troublesome
and we ultimately developed an effective method to resolve this
issue. When dry HCl gas was accessed to a dichloromethane
solution of 26 and Ph3P=O, a white hydrochloride precipitate
of compound 26 was formed immediately with no Ph3P=O
contamination and then Ph3P=O was removed through a
simple filtration. Therefore, the Meisenheimer rearrangement
precursor 26 could also be conveniently prepared in large-scale
within a short time. The followed conversion of 26ꢀ→ꢀ18 via
intermediates 27–29 was similar to that described in literature
16. If calculated from L-aspartic acid, the second-generation
synthesis is accomplished by a linear sequence of 10 chemical
operations (mean yield per step: 91%) in 38% overall yield,
which is the highest yield up to present.
Conclusions
In summary, the present work presents a scalable and highly
enantiopure synthetic approach toward the preparation of
side-chain diester of HHT (18) in the natural R configuration,
involving a minimum number of purifications and relatively
simple and inexpensive procedures. The key tactical element of
the strategy involved: (a) the regioselective Grignard reaction of
compound 19, which happen to exploit the insoluble character
ofꢀγ-lactoneꢀ20 in diethyl ether; (b) the stereospecific formation
of trans-olefin 26 via the coupling of the 5-membered
hemiacetal 22 with butyrolactone ylide 23; (c) the rapid and
efficient [2,3]-Meisenheimer rearrangement of allylamine 26
with complete chirality [1,3]-transfer. The easy manipulation
in each step of this sequence is an obvious advantage, which
make it attractive and useful in organic synthesis. Currently
we can prepare the enantiopure side-chain diacid of HHT (18)
in 7–10 g quantities from 5 g L-aspartic acid within one week.
Experimental
All solvents were purified and dried by standard techniques, and
distilled prior to use. IR spectra were recorded on a Nicolet IR200
instrument using KBr disks in the 400–4000 cm–1 region. HRMS
were obtained on a Waters Micromass Q-Tof MicroTM instrument
using the ESI technique. Melting points were determined using a
XT5A apparatus and were uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker AM-400 spectrometer with TMS as an internal
standard and CDCl3 as solvent.
(S)-3-(Dibenzylamino)-5,5-dimethyldihydrofuran-2(3H)-one (20): A
three-necked,ꢀround-bottomedꢀflaskꢀequippedꢀwithꢀaꢀrefluxꢀcondenserꢀ

JOURNAL OF CHEMICAL RESEARCH 2015 29
and a dropping funnel was charged with magnesium turnings (1.46 g,
60.93 mmol) and anhydrous ethyl ether (25 mL). A solution of
iodomethane (3.79 mL, 60.93 mmol) in anhydrous ethyl ether (50 mL)
was added dropwise to this suspension, maintaining slight boiling,
and the suspension was stirred for an additional 90 min at ca 20 °C. A
solution of diester 19 (5.20 g, 15.23 mmol) in anhydrous diethyl ether
(20 mL) was added dropwise at 5 °C to the Grignard reagent. The
dropping funnel was rinsed with ethyl ether (8 mL), and the white
suspension was stirred at ca 20 °C for a further 30 min. The reaction
mixture was cooled to 0 °C, cautiously quenched by saturated NH4Cl
(25 mL), and poured into a separating funnel. The aqueous phase
was extracted with EtOAc (3×70 mL). The combined extracts were
washed with brine, dried over MgSO4, and concentrated under reduced
pressure, giving 20ꢀ(4.38ꢀg,ꢀ93.0%)ꢀasꢀaꢀwhiteꢀsolid:ꢀm.p.ꢀ100.3−100.9ꢀ°C
(EtOAc); IR (KBr) 3065, 1772 cm–1;ꢀ [α]D20 =–28.4 (c=1.20, CHCl3);
1H NMR (400 MHz, CDCl3):ꢀδꢀ7.50−7.47ꢀ(m,ꢀ4H),ꢀ7.47−7.35ꢀ(m,ꢀ4H),ꢀ
7.35−7.29ꢀ(m,ꢀ2H),ꢀ4.05−3.65ꢀ(m,ꢀ1H),ꢀ3.99ꢀ(d,ꢀJ=13.8 Hz, 2H)，3.73 (d,
J=13.8 Hz, 2H), 2.23 (dd, J=ꢀ12.8,ꢀ9.2ꢀHz,ꢀ1H),ꢀ2.14−2.08ꢀ(m,ꢀ1H),ꢀ1.49ꢀ
(s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3):ꢀδꢀ175.5,ꢀ139.1,ꢀ128.7,ꢀ
128.5, 81.1, 59.4, 54.8, 37.4, 29.3, 27.7; HRMS (ESI-TOF) m/z: [M+Na]+
calcd for C20H23NO2Na 332.1626; found 332.1628.
tert-Butyl
(4-hydroxy-4-methyl-1-(2-oxodihydrofuran-3-ylidene)
pentan-2-yl) carbamate (26): To a solution of lactol 22 (2.30 g,
7.43 mmol) in dry toluene (50 mL) was added 1-butyrolactonylidene
triphenylphosphorane 23 (6.41 g, 18.6 mmol). The mixture was
heated at reflux for 16 h. The solvent was removed under reduced
pressure and the residue was purified by chromatography on silica
gelꢀ(PE−EtOAc,ꢀ7ꢀ:ꢀ1)ꢀtoꢀyieldꢀolefinꢀ26 (2.04 g, 72%) as a white solid.
m.p.ꢀ 141.6−142.5ꢀ°C;ꢀ [α]D20ꢀ=ꢀ−32.6ꢀ (cꢀ=ꢀ1.0,ꢀ EtOH);ꢀ IRꢀ (KBr):ꢀ 3596,ꢀ
3481, 3298, 1751, 1675 cm−1; H NMR (400 MHz, CDCl3):ꢀδꢀ7.38−7.22ꢀ
1
(m,ꢀ 10H),ꢀ 7.09−6.97ꢀ (dt,ꢀ 1H,ꢀ J=ꢀ9.84ꢀHz),ꢀ 5.90ꢀ (s,ꢀ 1H),ꢀ 4.49−4.33ꢀ
(m, 2H), 4.11 (d, 2H, J=12.92 Hz), 3.82 (t, J=12.04 Hz, 1H), 3.28 (d,
Jꢀ=ꢀ12.92ꢀHz,ꢀ2H),ꢀ2.81−2.62ꢀ(m,ꢀ2H),ꢀ2.27−2.16ꢀ(m,ꢀ1H),ꢀ1.19ꢀ(s,ꢀ3H),ꢀ
1.22−1.11ꢀ(m,ꢀ1H),ꢀ0.81ꢀ(s,ꢀ3H);ꢀ13C NMR (100 MHz, CDCl3):ꢀδꢀ170.7,ꢀ
137.7, 136.2, 129.4, 128.7, 128.0, 127.7, 70.7, 65.4, 55.8, 54.2, 41.5, 31.5,
27.8, 25.2; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H29NO3Na
402.2045; found 402.2047.
This work was financially supported by the National Natural
Science Foundation (21302175, 21372205), which is gratefully
acknowledged.
(S)-2-(Dibenzylamino)-4-methylpentane-1,4-diol (21): To a stirred
suspension of LiAlH4 (635 mg, 16.73 mmol) in dry THF (20 mL), a
solution of lactone 20 (3.45 g, 11.15 mmol) in dry THF (25 mL) was
added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for
10 min and then quenched with EtOAc and saturated NaHCO3. The
resulting solution was dried over MgSO4 and filtered through a pad
of celite. The filtrate was concentrated under reduced pressure and
the residue was purified by chromatography on silica gel to afford 21
(3.39ꢀg,ꢀ97.0%)ꢀasꢀaꢀwhiteꢀsolid.ꢀm.p.ꢀ129.8−130.9ꢀ°C (EtOAc); IR (KBr)
Received 27 November 2014; accepted 8 December 2014
Paper 1403046 doi: 10.3184/174751915X14189228913336
Published online: 9 January 2015
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1
3315, 3025 cm–1;ꢀ [α]D20ꢀ=ꢀ−18.8ꢀ (cꢀ=ꢀ1.20,ꢀ CHCl3); H NMR (400 MHz,
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(4.81 g, 30.25 mmol) in dry DMSO (25 mL) at 0ꢀ°C. The reaction
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acid (2×25 mL), H2O (2×25 mL), saturated NaHCO3 (25 mL), brine
(25 mL), dried over MgSO4, and concentrated under reduced pressure.
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6:1) to afford 22 (2.98ꢀg,ꢀ95.0%)ꢀasꢀaꢀwhiteꢀsolid.ꢀm.p.ꢀ123.0−123.6ꢀ°C;
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Jꢀ=ꢀ4.0ꢀHz,ꢀ 0.62H),ꢀ 3.76−3.58ꢀ (m,ꢀ 3.88H),ꢀ 3.58−ꢀ 3.51ꢀ (m,ꢀ 0.36H),ꢀ
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1.22 (s, 2H). HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H25NO2Na
334.1783; found 334.1786.
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