Novel synthetic approach to alfaprostol key intermediates via Stille coupling with an alkyne

Article abstract of DOI:10.1016/j.tetlet.2017.04.091

Novel intermediates based on the Corey skeleton for preparation of the ω-chain of non-halogenated unnatural prostaglandin analogues containing a triple bond at position 13–14 (PG numbering) were synthesized. The utilization of a novel synthetic approach towards a new tin intermediate, and subsequent Stille coupling opens up new possibilities for preparing these important pharmaceutical intermediates.

Full text of DOI:10.1016/j.tetlet.2017.04.091

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthetic approach to alfaprostol key intermediates via Stille
coupling with an alkyne
a
a,
a
b
⇑
´
Sara Monteiro , Aleš Imramovsky , Karel Pauk , Jan Pavlík
a Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
b Cayman Pharma Ltd., Práce 657, 277 11 Neratovice, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel intermediates based on the Corey skeleton for preparation of the
x-chain of non-halogenated
Received 3 February 2017
Revised 19 April 2017
Accepted 24 April 2017
Available online xxxx
unnatural prostaglandin analogues containing a triple bond at position 13–14 (PG numbering) were syn-
thesized. The utilization of a novel synthetic approach towards a new tin intermediate, and subsequent
Stille coupling opens up new possibilities for preparing these important pharmaceutical intermediates.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Prostaglandin intermediates
Corey intermediates
Stille coupling
Tin intermediates from the Corey skeleton
Propargyl ketones synthesis
The synthesis of natural or synthetic analogs of prostaglandin
(PG) has been of significant interest to synthetic chemists since
its discovery by Von Euler.1,2 Their use in human and veterinary
practice and the complexity of their preparation is one reason for
the continued fascination of organic chemists. Synthetic analogs
moreover show greater biological activity, better stability, or allow
for more preferred methods of application to the organism.3–5 The
basis for the synthesis of natural PG was first reported by Corey
and co-workers, and this approach still forms the basis for labora-
tory synthesis as well as industrial applications.6 Recent studies
have described the synthesis of PG without Corey intermediates;
fewer steps are the main advantage of these approaches.7–9 Despite
these promising studies, there is still scope for optimizing existing
routes, as well as for the application of modern approaches to the
synthesis of PG using Corey intermediates.
ing the structure of AP with PGF2 , position 13–14 (PG numbering)
a
contains a triple bond instead of an alkene. Additionally, the
chain of AP is terminated by a saturated six-membered ring and
the -chain contains a carboxylic acid methyl ester (Fig. 2).
Due to the presence of the triple bond, a specific approach for
x-
a
the synthesis of this molecule is required. In this case, it is not
appropriate to simply apply Horner-Wadsworth-Emmons reaction
O
O
OH
O
O
Phase 2
Phase 1
(CH2)3
COOH
14
13
O
15
HO
O
O
PG
H
PG
HO
HO
Corey aldehyde
Intermediate with complete ω-chain Prostaglandin F2α
The synthesis of natural PGs and their synthetic analogues
based on Corey intermediates can be divided into two phases, each
involving several synthetic steps. Individual phases include con-
Fig. 1. Representative example of a general approach towards prostaglandins using
natural PGF2 .
a
struction of the
the -chain (Phase 2). The
Wittig reaction (Fig. 1).6,9,10
In this study, attention was focused on synthesis of the
x
-chain (Phase 1) and subsequent synthesis of
a
a-chain of PGs is connected using the
OH
O
OH
Z
S
x
-chain
S
R
R
R
COOH
O
of the non-halogenated synthetic PG derivative alfaprostol (AP). AP
14
15
13
HO
is used in veterinary practice, however, compared to PGF2 it is
13
a
HO
characterized by greater stability and specific activity.11 Compar-
14
HO
Alfaprostol
HO
Prostaglandin F2α
⇑
Corresponding author.
E-mail address: ales.imramovsky@upce.cz (A. Imramovsky´).
Fig. 2. Comparison of PGF2 and AP structures.
a
http://dx.doi.org/10.1016/j.tetlet.2017.04.091
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Monteiro S., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.04.091

2
S. Monteiro et al. / Tetrahedron Letters xxx (2017) xxx–xxx
O
O
O
O
a) Protection
3
d) , K2CO3,
O
O
O
b) K2CO3, MeOH, 35 °C
38-72% over 2 steps
MeOH, RT, 5 h
25-35%
O
O
P
O
O
c) DMP, NaHCO3,
DCM, 0 °C - RT, overnight
60-97%
O
HO
N2
O
O
H
PG
PG
3
O
H
1
2
4a-c
Scheme 1. Synthesis of key intermediates for further modification. 4a PG = TBDPS; 4b PG = TBDMS; 4c PG = EOM.
O
O
O
O
O
O
O
H
O
O
a) NBS, AgNO3,
Acetone, RT, 3 h
b) i-PrMgBr, TMSCl,
THF, -78 °C, 1.5 h
79%
47%
c) TBAF,
THF, RT, overnight
7.5%
O
O
O
O
O
O
O
O
SiMe3
H
Br
HO
6
8
4c
5
Scheme 2. Application of the Chintareddy synthetic pathway (step c) to the novel Corey intermediates 4c, 5 and 6.
conditions which allow the Corey aldehyde to react with an appro-
priate phosphonate, yielding an E-alkene at position 13–14. This
reaction is commonly used for the synthesis of precursors of vari-
ous PGs containing double bonds at the mentioned position.6
Several methods to synthesize intermediates containing a triple
bond at position 13–14 for various PGs have been described.12–14
Gandolfi and co-workers reported a sequence utilizing a phospho-
nate reaction with the protected Corey aldehyde.12,13 In the first
step, the appropriate E-alkene was generated and subsequently
reacted with bromine. Double dehydrohalogenation followed to
yield the desired triple bond at position 13–14 of the future PG
trolling individual isomers. In general, these synthetic methodolo-
gies use a strong base, e.g. butyllithium, for activation of the triple
bond.19,20 The conditions of several studies were applied to the
reaction of 4a or 4b with cyclohexylpropanal. While the reaction
of 4a and cyclohexylpropanal in the presence of BuLi in THF21,22
resulted in starting material decomposition, the reaction in the
presence of diethylzinc and N-methylimidazole in DCM23 or chro-
mium(II) chloride in DMF24 did not proceed. See ESI, Table S1 for all
reaction conditions.
Persisting with our efforts to prepare propargylic alcohols,
Chintareddy and co-workers described the formation of propargyl
alcohols from the corresponding trimethylsilyl derivative in the
presence of TBAF.25 However, in order to carry out this approach
it was necessary to use a new protecting group. Ethyl methyl ether
(EOM) was chosen as a simple protecting group and compound 4c
x
-chain. A stereoselective reduction was also performed during
this synthesis to obtain the final -chain. Klar and co-workers
x
reported an alternative method, where a one-step reaction pro-
duced a ‘‘bromo-enone” derivative which was dehydrohalogenated
using CsOAc in the presence of 18-crown-6 ether.14 Both of these
studies involved reactions with phosphonates, a dehydrohalogena-
tion step, and stereoselective reduction of the carbonyl group.
Based on retrosynthetic analyses, we proposed an alternative
O
O
Pd(PPh3)Cl2
(2.5 mol%),
O
O
CuI (3 mol%), Et3N,
R-COCl
9a
9b
R = 4-MePh-, (23%)
R = cyclohexylethyl, (0%)
methodology for synthesis of the
x-chain containing a triple bond
at position 13–14. This approach included synthesis of the
protected Corey aldehyde, followed by Seyfert–Gilbert homologa-
tion. The targeted intermediate was synthesized via formation of
a new CAC bond; a scheme comparing our and Gandolfi and co-
workers synthetic approach can be found in the ESI.
THF, RT, 1 h
O
O
R
TBDMS
TBDMS
H
9a-b
O
4b
Scheme 3. Sonogashira coupling reaction with Corey intermediate 4b.
The starting gamma-lactone 1 (supplied by Cayman Pharma)
was first protected with tert-butyldimethylsilyl (other groups were
also tested for the protection of the Corey skeleton) and the ester
group hydrolyzed under basic conditions. The resulting Corey alco-
hol was oxidized using Dess-Martin periodinane to give the pro-
tected Corey aldehyde 2, which was the starting material for
further experiments (see ESI for detailed procedures as well as
compound characterization). In order to directly obtain the termi-
nal alkyne, alkynylation by treatment of the aldehyde with
lithiotrimethylsilyldiazomethane was attempted,15,16 but resulted
in substrate decomposition. Therefore, it was decided to use the
Ohira Bestmann reagent 3 which was prepared according to the lit-
erature procedure.17 The terminal alkynes 4a-c were prepared in
25–35% isolated yield (Scheme 1).18 tert-Butyldimethylsilyl
(TBDMS), tert-butyldiphenylsilyl (TBDPS) and eventually the ethyl-
methyl ether (EOM) group were used for hydroxyl group
protection.
O
O
b) (Bu3Sn)2O,
TBAF (cat.),
a) i-PrMgBr,
TMSCl,
O
O
THF, -78 °C, 1.5 h
THF, 60 °C, 2.5 h
SiMe3
47%
11%
6
O
O
O
O
i-PrMgBr, (Bu)3SnCl
O
O
THF, -78 °C, 1 h
60%
Br
Sn(Bu)3
O
O
5
11
The synthesis of propargyl alcohols from terminal alkynes and
aldehydes is widely described and presents the possibility of con-
Scheme 4. Comparison of the literature approach to intermediate 11 via compound
6 and our novel one-step synthetic approach.
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S. Monteiro et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 1
Comparison of palladium catalysts for the reaction of tributyl tin derivative 11 with R-COCl.
O
O
O
O
Pd catalyst
R-COCl
O
O
O
R
SnBu3
O
O
11
12a-f
Entry
R-COCl
-Ph
Pd catalyst
Conditions
Product
Yield (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)4
1
2
1
2
1
2
1
2
1
2
1
2
12a
4a
40b
56a
45b
17a
29b
NFa
56b
5a
-Ph-4-CH3
-Ph-4-OCH3
-Ph-4-NO2
-Ph-4-Cl
12b
12c
12d
12e
12f
9
10
11
12
61b
17a
35b
-CH2CH2Ch
Pd(PPh3)2Cl2
a
Determined by HPLC.
b
Isolated yields, NF – not found, Reagents and conditions: (1) Pd(PPh3)4 (10 mol%), DMF, 65 °C, 2.5 h. (2) Pd(PPh3)2Cl2 (2.5 mol%), MeCN, reflux, 2 h.
was successfully transformed into bromo-derivative 5 in 79%
yield.26 Compound 6 was then reacted with 3-cyclohexylpropanal
7 in the presence of TBAF to afford the desired product 8
(PG = EOM, R = cyclohexylethyl) in 7.5% isolated yield (Scheme 2).
This result was not surpassed either upon repeated experiments
or after reaction condition optimisation. Experimental procedures
as well as characterisation data for compounds 5, 6 and 8 can be
found in the ESI.
yield a tin derivative 11 which was suitable for the Stille coupling
reaction. Under these conditions the desired ketone 12f was syn-
thesized which can be used as a key intermediate in the prepara-
tion of AP. This study may open up several possibilities for future
studies in the preparation of active PGs with a triple bond at posi-
tion 13–14.
Acknowledgments
Because we were not able to obtain the appropriate propargyl
alcohol in good yield, we then concentrated our efforts on propar-
gyl ketones which can be easily reduced to the desired alcohol. The
Sonogashira coupling reaction initially seemed ideal to apply to
our system.27 On the basis of this, compound 4b was reacted with
p-toluoyl chloride in presence of PdCl2(PPh)2, CuI and Et3N. The
expected ketone derivatives 9a was isolated in 23% yield; however,
the reaction with 3-cyclohexylpropanoyl chloride 10 did not pro-
ceed (Scheme 3).
The authors wish to acknowledge the institutional support from
the Faculty of Chemical Technology, University of Pardubice,
funded by the Ministry of Education, Youth and Sports of the Czech
Republic; project of the Technological Agency of Czech Republic
project No.: TA03010819 and to Cayman Pharma ltd. Neratovice
Czech republic.
A. Supplementary data
These disappointing results led us to select another type of reac-
tion which could produce the desired propargylic ketone. The Stille
coupling reaction has been reported as a useful method for the
preparation of propargylic ketones.28 In a first attempt, compound
6 was transformed into the appropriate tributyl tin compound 11
in 11% yield.29 Due to the low yield of the isolated tin compound,
a one-step synthetic approach was developed where compound 5
was directly transformed into tributyl tin compound 11 in 60%
yield (Scheme 4). The reaction of 11 with several substituted ben-
zoylchlorides (R-COCl) as well as cyclohexylpropanoyl chloride 10
was investigated using Pd(PPh3)4 and Pd(PPh3)2Cl2 as catalysts.
While Pd(PPh3)4 gave the desired product 12 in low yields, Pd
(PPh3)2Cl2 led to the targeted ketones 12a–f in moderate to good
yields (Table 1). The terminal alkyne was also detected by TLC
but not isolated.
General experimental information, experimental details, spec-
tral characterization data for compounds which are not cited in ref-
erences, their NMR and MALDI-TOF spectra. Supplementary data
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2017.04.091.
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