An alternative synthesis for iloprost via a key bicyclic aldehyde intermediate

Article abstract of DOI:10.1016/j.tetlet.2020.152627

An alternative synthesis for iloprost has been accomplished in 14 steps via a convergent synthesis starting from commercially available (?)-Corey lactone diol. The syntheses employ a new and key chiral bicyclic aldehyde (4) intermediate, which is primed for attachment of the required α-side chain and ω-side chain.

Full text of DOI:10.1016/j.tetlet.2020.152627

Journal Pre-proofs
An alternative synthesis for iloprost via a key bicyclic aldehyde intermediate
Yinbo Chen, Jinhui Shi, Liang Li, Fei Liu, Xiquan Zhang, Yulei Yang
PII:
S0040-4039(20)31132-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152627
TETL 152627
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 July 2020
26 October 2020
31 October 2020
Please cite this article as: Chen, Y., Shi, J., Li, L., Liu, F., Zhang, X., Yang, Y., An alternative synthesis for
iloprost via a key bicyclic aldehyde intermediate, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2
020.152627
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Tetrahedron Letters
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An alternative synthesis for iloprost via a key bicyclic aldehyde intermediate
a
b
a
b
b
a,
Yinbo Chen , Jinhui Shi , Liang Li , Fei Liu , Xiquan Zhang , Yulei Yang 
a
Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203,
China
b
Chia Tai Tianqing Pharmaceutical Group Co., Ltd., 1099 Fuying Road, Nanjing, Jiangsu Province 211122, China
ARTICLE INFO
ABSTRACT
Article history:
Received
An alternative synthesis for iloprost has been accomplished in 13 steps via a
convergent synthesis starting from commercially available (-)-Corey lactone diol.
The syntheses employ a new and key chiral bicyclic aldehyde (4) intermediate,
which is primed for attachment of the required α-side chain and ω-side chain.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Iloprost
Chiral bicyclic aldehyde
(-)-Corey lactone diol

1
. Introduction
Prostacyclin (1) (Fig. 1), which plays an important role in the vascular and central
nervous system and in inflammation, has attracted the attention of chemistry, biology,
and medicine[1-3]. Unfortunately, its medicinal application is hampered by the inherent
[4]
chemical and metabolic instability . Therefore, intensive efforts have been made to
[5]
find new and stable analogues as alternatives to the natural prostacyclin . Iloprost (2)
(Fig. 1) is a biologically highly potent and chemically stable alternative that has been
[6]
developed by Bayer Schering Pharma . Currently, iloprost has already been
marketed as Ilomedin for the treatment of severe thrombo-angiitis obliterans and as
Ventavis for the treatment of pulmonary arterial hypertension[7-11]
.
COOH
COOH
O
OH
iloprost 2
OH
OH
OH
prostacyclin 1
Figure 1. Structures of prostacyclin (1) and iloprost (2).
Structurally, the iloprost (2) consisted of three main parts: α-side chain, chiral
bicyclic core and ω-side chain (Scheme. 1). Among them, the building blocks of
α-side chain and ω-side chain can be commercially purchased or easily synthesized in
[12]
a few steps , while the construction of the appropriately substituted chiral C6-C13
bicyclic core is the key-step of the iloprost synthesis. Previously, one of the most
attractive synthetic methods to prepare the chiral C6-C13 bicyclic core mainly started
from achiral bicyclic ketone via a enantioselective synthesis to establish the
enantiopure functional groups at C12 of iloprost[13-15]. Although these synthetic
methods are imaginative, some drawbacks still remained, such as harsh conditions
(-100C), expensive chiral reagents, lengthy synthetic sequences. Thus, it would be
highly interesting to have an easy access to chiral C6-C13 bicyclic core, which allows
an efficient and alternative synthesis for iloprost (2).

O
1
-
+
α-side chain
acid (3)
BrPh3 P
OH
3
COOH
O
6
O
α
-side chain
O
O
O
6
1
2
O
bicyclic aldehyde
(4)
OH
1
2
15
16
13
13
OTBS
OH
OH
ω-side chain
O
OH
(
-)-Corey lactone diol
achiral
bicyclic ketone
chiral
bicyclic core
(6)
O
P
H3CO
H3CO
ω-side chain
phosphonate (5)
iloprost 2
O
Scheme 1. Retrosynthetic analysis for iloprost (2)
2
. Results and discussion
Our synthesis for iloprost (2) has the following key features (Scheme 1): (1)
Retrosynthetically, iloprost was disconnected into three main parts: α-side chain acid
3), chiral C6-C13 bicyclic aldehyde (4) as a new and key intermediate and ω-side
(
chain phosphonate (5). (2) Our synthetic method to prepare chiral C6-C13 bicyclic
aldehyde (4) started from commercially available (-)-Corey lactone diol (6), which
allowed an easy access to chiral bicyclic core. (3) We reported a short synthesis of
iloprost in 13 steps.
Initially, the synthesis of ω-side chain phosphonate (5) was carried out by the
[12]
known procedures (Scheme 2). The alkylation of commercially available diethyl
methylmalonate (7) with 1-bromobut-2-yne gave diester (8) in 91% yield. Then,
o
diester (8) was subjected to high temperature (170 C) with LiCl to generate the
monoester (9) in 78% yield, amidation of which with N,O-dimethylhydroxylamine
hydrochloride provided the corresponding amide (10) in 91% yield. Reaction of
amide (10) with dimethyl methylphosphonate in the presence of n-BuLi furnished the
phosphonate (5) in 85% yield. Therefore, the ω-side chain phosphonate (5) was
obtained in 55% overall yield over 4 steps.
O
O
CH3
N
C2H5O
C2H5O
2 5
C H O
a
b
c
d
O
P
CH3
C2H5O
H3CO
O
C H O
2
5
O
O
O
O
5
O
O
7
8
9
10
Scheme 2. Preparation of ω-side chain (5). Reagents and conditions: (a) 1-bromobut-2-yne,
o
o
t-BuOK, THF, 0 C, 30 mins, 91%; (b) LiCl, DMSO, H O, 170 C, 5 hrs, 78%; (c)
2
o
N,O-dimethylhydroxylamine hydrochloride, isopropylmagnesium chloride, THF, -20 C, 30 mins,
o
9
1%; (d) Dimethyl methylphosphonate, n-BuLi, THF, -78 C, 3 hrs, 85%.
The synthesis of the key chiral bicyclic aldehyde (4), as depicted in Scheme 3,

commenced from commercially available and optically pure (-)-Corey lactone diol (6),
which was silylated with TBSCl gave silyl ether (11) in 95% yield. The silyl ether (11)
was treated with dimethyl methylphosphonate in the presence of n-BuLi afforded
hemiketal (12) in 88% yield. A modified PCC oxidation of hemiketal (12) was
performed to give the desired diketone (13) in 86% yield, which was subsequently
cyclized by intramolecular Horner-Wadsworth-Emmons reaction to generate the
enone (14) in 75% yield. The hydrogenolysis of enone (14) in the presence of 10%
Pd/C provided octanone (15) in 90% yield. Subsequent treatment of octanone (15)
with PPTS allowed selective removal of the TBS-protecting group to give alcohol (16)
in 72% yield. The oxidation of alcohol (16) with oxidant DMP afforded the key chiral
bicyclic aldehyde (4) in 75% yield. Therefore, the chiral bicyclic aldehyde (4) was
obtained from (-)-Corey lactone diol (6) in 26% overall yield over 7 steps.
O
O
O
O
HO
O
P
O
P
O
O
O
O
O
a
b
O
c
O
OTBS
OH
OTBS
OTBS
OTBS
13
OH
OTBS
11
OTBS
12
6
O
O
O
O
d
e
f
g
OTBS
OTBS
OH
O
OTBS
OTBS
15
OTBS
16
OTBS
14
4
Scheme 3. Preparation of bicyclic aldehyde (4). Reagents and conditions: (a) TBSCl, imidazole,
o
o
o
DCM, 0 C-40 C, 24 hrs, 95%; (b) Dimethyl methylphosphonate, n-BuLi, THF, -78 C, 3 hrs, 88%;
o
(
c) PCC, sodium propionate, DCM, reflux, 6 hrs, 86%; (d) K CO , 18-crown-6, toluene, 75 C, 6
2
3
o
o
hrs, 75%; (e) 10% Pd/C, HCO H, Et N, toluene, 85 C, 1 hr, 90%; (f) PPTS, EtOH, 25 C, 24 hrs,
2
3
o
o
7
2%; (g) Dess-Martin periodinane, NaHCO , DCM, 0 C-10 C, 3 hrs, 75%.
3
And, the reaction conditions from hemiketal (12) to diketone (13) was optimized
in our lab. Firstly, the Collins condition of hemiketal (12) afforded the desired product
13) in 40% yield along with β-eliminated by-product (13-BP) in 40% yield following
(
[16]
the previous method . The main reason to generate 13-BP was due to acidic
condition of oxidation. So, a range of oxidants (DMP, PDC, and PCC) were screened
and PCC was more efficient than the others (Table 1, entry 4). In order to reduce the

acidic condition, several bases were investigated and the sodium propionate showed
the best efficiency, which could give diketone (13) in 86% yield (Table 1, entry 6).
Subsequently, the screening of the amount of oxidant and base revealed that
decreasing the amount of PCC and sodium propionate to 4.0 equivalents had no
influence on the isolated yield (Table 1, entry 8), while further decreasing the amount
to 2.0 equivalents led to lower yield (Table 1, entry 9). Therefore, 1.0 eq. of hemiketal
(12), 4.0 eq. of PCC, and 4.0 eq. of sodium propionate were selected as the optimal
reaction conditions.
Table 1. Optimization for the synthesis of intermediate (13).
O
O
O
P
O
P
P
O
HO
O
O
O
O
O
O
O
O
OTBS
OTBS
OTBS
OTBS
13
OTBS
12
OTBS
3-BP
1
Entry
Oxidant (eq.)
Base (eq.)
Yield (%)d
40%
1
2
3
4
5
6
7
8
9
Collins (6.0)
--
--
--
--
a
DMP (6.0)
38%
b
PDC (6.0)
45%
c
PCC (6.0)
60%
PCC (6.0)
PCC (6.0)
PCC (6.0)
PCC (4.0)
PCC (2.0)
Sodium acetate (6.0)
Sodium propionate (6.0)
Sodium Butyrate (6.0)
Sodium propionate (4.0)
78%
86%
82%
86%
Sodium propionate (2.0)
45%
a
b
c
DMP: Dess-Martin periodinane; PDC: Pyridinium dichromate; PCC: Pyridinium chlorochromate;
Isolated yield.
d
With two key fragments (4 & 5) in hand, we turned to the Horner-Wadsworth
Emmons reaction as a mean of constructing α,β-unsaturated ketone (17). Detailedly,
-
the ω-side chain phosphonate (5) was treated with NaH and to this was added the
chiral bicyclic aldehyde (4) to afford α,β-unsaturated ketone (17) in 78% yield. The
protection of α,β-unsaturated ketone (17) with 2,2-dimethylpropane-1,3-diol gave
intermediate (18) in 90% yield, which was converted to its corresponding enol (19)
[17]
through a diastereoselective reduction with R-(+)-Me-CBS with the yield of 75% .
The deprotection of enol (19) was achieved with p-TsOH to generate diol (20) in 90%

yield, which was further protected with TBSCl to generate silyl ether (21) in 85%
yield. Finally, the Wittig olefination and silyl deprotection of silyl ether (21) with
commercially available α-side chain acid (3) delivered a mixture of iloprost (2) and its
Z isomer in a ratio of 65:35, the separation of which by preparative HPLC afforded
iloprost (2) in 31% yield (Scheme 4). Thus, we have achieved an alternative synthesis
for iloprost (2).
O
O
O
O
O
O
O
P
b
a
c
O
O
O
O
OTBS
4
OTBS
O
OTBS
O
OTBS
OH
19
5
17
18
COOH
O
O
O
d
e
f
-BrPh3+
P
OH
OH
OH
OH
OH
OTBS
OTBS
21
20
3
iloprost 2
o
Scheme 4. Preparation of iloprost (2). Reagents and conditions: (a) NaH, THF, 25 C, 1 hr, 78%;
(b) 2,2-dimethylpropane-1,3-diol, PPTS, toluene, reflux, 45 min, 90%; (c) R-(+)-Me-CBS, borane
o
o
o
dimethyl sulfide, DCM, -5 C-10 C, 30 mins, 75%; (d) p-TsOH·H O, acetone, H O, 30 C, 12 hrs,
2
2
o
o
o
9
0%; (e) TBSCl, imidazole, DCM, 0 C-40 C, 24 hrs, 85%; (f) KHMDS, THF, 25 C, 24 hrs, 31%.
3
. Conclusion
In summary, an alternative synthesis for iloprost (2) was achieved in 13 steps via
a convergent synthesis starting from commercially available (-)-Corey lactone diol (6).
We have prepared a new and key chiral bicyclic aldehyde (4) intermediate, which
was subsequently elaborated to iloprost (2). To the best of our knowledge, the
synthetic route presented here is shorter than those previously reported. Further
studies on the application of this approach are in progress in our lab.
Acknowledgments
We are grateful to the Shanghai Rising-Star Program (NO. 19QB1406300) for
their financial support of this work.
Supplementary Material
Supplementary data associated with this article can be found. This material

1
includes detailed experimental procedures and analytical data ( H NMR and MS &
HRMS).
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An alternative synthesis for iloprost via a key bicyclic aldehyde
intermediate
a
b
a
b
b
a,
Yinbo Chen , Jinhui Shi , Liang Li , Fei Liu , Xiquan Zhang , Yulei Yang 
aShanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
2
85 Gebaini Road, Shanghai 201203, China
bChia Tai Tianqing Pharmaceutical Group Co., Ltd., 1099 Fuying Road, Nanjing, Jiangsu
Province 211122, China
Graphical abstract

COOH
O
O
O
O
O
P
H CO
3
-
+
BrPh3 P
OH
H CO
OH
O
3
O
OH
OTBS
OH
OH
bicyclic aldehyde
intermediate
(-)-Corey lactone diol
iloprost
1
8.
An alternative synthesis for iloprost via a key bicyclic aldehyde
intermediate
a
b
a
b
b
a,
Yinbo Chen , Jinhui Shi , Liang Li , Fei Liu , Xiquan Zhang , Yulei Yang 
aShanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
85 Gebaini Road, Shanghai 201203, China
2
bChia Tai Tianqing Pharmaceutical Group Co., Ltd., 1099 Fuying Road, Nanjing, Jiangsu
Province 211122, China
Highlights


An alternative synthesis for iloprost is presented.
The shortest synthetic approach for iloprost was achieved in 14 steps.
The synthesis started from commercially available (-)-Corey lactone diol.

1
9.