Exploration of ω-side chain addition strategies for the syntheses of isocarbacyclin and 15R-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin

Article abstract of DOI:10.1039/b611339g

We describe alternative access to prostacyclin analogues by means of two ω-side chain addition strategies: Grignard reagent addition to an α,β-unsaturated Weinreb amide, followed by diastereoselective reduction of the corresponding enone system, and imple

Full text of DOI:10.1039/b611339g

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Exploration of x-side chain addition strategies for the syntheses of
isocarbacyclin and 15R-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin†‡
Neil A. Sheddan* and Johann Mulzer*
Received 8th August 2006, Accepted 20th September 2006
First published as an Advance Article on the web 5th October 2006
DOI: 10.1039/b611339g
We describe alternative access to prostacyclin analogues by means of two x-side chain addition
strategies: Grignard reagent addition to an a,b-unsaturated Weinreb amide, followed by
diastereoselective reduction of the corresponding enone system, and implementation of Seebach’s
alkylation chemistry. These strategies have led to the syntheses of biologically active prostacyclin
analogues isocarbacyclin and 15R-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15R-TIC), with
modest to excellent diastereoselectivity.
CNS specific PGI2 ligand and its 15-deoxy-TIC (5) counterpart,9
both have exhibited an inhibitory effect on apoptosis of neuronal
Introduction
Discovered in 1976, prostacyclin (PGI2),1 (1), has shown diverse
biological activity ranging from being a potent vasodilator and
inhibitor of blood platelet aggregation to playing an important
role not only in the peripheral organs but also in the central
nervous system (CNS).2 Unfortunately, due to its chemical and
metabolic instability, resulting from the extremely labile nature
of the vinyl ether moiety to hydrolysis (t1/2 = 5 min at pH 7.4),
clinical applications have been severly hampered. This instability
has stimulated efforts towards the design and development of
various analogues (Fig. 1) with the aim of chemical and metabolic
stability combined with physiological activity.
cells induced by a high oxygen (50%) atmosphere.10 The most
challenging aspects associated with the syntheses of isocarbacylcin
and its analogues is the construction of the C6–C9a endo-
cyclic double bond and the flexible introduction of the x-side
chain allowing for a wider range of analogues to be prepared.
Through such a diversity orientated synthetic strategy, an array
of isocarbacyclin analogues could be obtained, allowing their
biological activity to be investigated further.
Fig. 1 Prostacyclin, isocarbacyclin and selected TIC derivatives.
Isocarbacyclin (2)3 is one such potent analogue, which
has shown promising application as a therapeutically use-
ful agent.4 15R-16-(m-Tolyl)-17,18,19,20-tetranorisocarbacyclin 3
(15R-TIC),5 a modified isocarbacyclin analogue has been used to
visualise the specific location of the IP2 receptor, a sub-type of
the prostacyclin (PGI2) receptor,2 for both in vitro and in vivo6
systems by autoradiography of rat brain slices and positron
emission tomography (PET),6,7 of a living rhesus monkey.8 This
Scheme 1 Diverse orientated isocarbacyclin analogue synthesis.
The focus of our research has been to develop a strategy
which would allow a large number of isocarbacyclin analogues
to be synthesized, from a common synthetic intermediate, with
only a minimum of synthetic steps. Typically, the x-side chain
for isocarbacyclin analogues is introduced via an (E)-selective
Horner–Wadsworth–Emmons olefination reaction (C13–C14),
where the yield varies from substrate to substrate,11 followed
by diastereoselective reduction of the C15 carbonyl functionality
under reagent control. To maximise diversity, it was envisaged that
via the addition of a suitable Grignard reagent to a,b-unsaturated
Weinreb amide building block 7 (available from methyl ester 6)9b
Institut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringerstrasse 38,
A-1090, Wien, Austria. E-mail: neil.sheddan@univie.ac.at, johann.mulzer@
univie.ac.at; Fax: +43-1-4277-52189; Tel: +43-1-4277-52190
† Electronic supplementary information (ESI) available: Experimental
procedures, data and NMR spectra for all new compounds. See DOI:
10.1039/b611339g
‡ Dedicated to Professor Manfred Christl on the occasion of his 65th
birthday.
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and subsequent diastereoselective reduction of the resulting enone,
a direct and reliable access to the carbon skeletons of a number
of isocarbacyclin analogues could be achieved. Alternatively,
by invoking Seebach’s alkylation method,12 with a,b-unsaturated
aldehyde 8, we also believe that a high d.e. for the C15 hydroxyl
group for a variety of functionalised isocarbacyclin analogues
could be accessed (Scheme 1).13
Results and discussion
Known aldehyde 9,9b was subjected to a Horner–Wadsworth–
Emmons olefination reaction, with Weinreb amide phosphonate
10 which delivered a,b-unsaturated Weinreb amide 7 in excellent
yield. Weinreb amide 7, containing the common C1–C15 carbon
skeleton of isocarbacyclin analogues, should act as a suitable
building block for the preparation of isocarbacyclin (2) and its
15R-TIC (3) analogue (Scheme 2).
Scheme 3 Grignard reagent addition to Weinreb amide. Reagents and
conditions: (i) 3 equiv. 11, THF, −78 ◦C → 0 ◦C, 94%; (ii) 3 equiv. 12,
−78 ◦C → 0 ◦C, 90%.
failed to do so in our case, showing only a slight increase in d.r.
for both 13 and 14. Switching the method of reduction to Noyori’s
BINAL-H reducing agent,16 proved useful, although capricious,
without the aid of a stock solution of the reducing agent. Enone
13 when treated with (S)-BINAL-H, at −100 ◦C for 2 hours, gave
an impressive d.r. of over 35 : 1 (>94% d.e.). However, enone
◦
14, when treated with (R)-BINAL-H, also at −100 C, delivered
only a slightly improved d.r. of 8 : 1 compared to that obtained
with the CBS reagents (d.r. 7 : 1). It has been documented in the
literature that these enone systems and especially those leading
to the unnatural (R)-C15 configuration have led to a mismatched
case for the reduction.17 The allylic alcohols,18 resulting from enone
reductions, were both protected as the TBS ethers, to deliver 15
and 16 (Scheme 4).
Although this Grignard reagent addition and subsequent re-
duction strategy proved to be synthetically useful, the limiting
factor was the capricious diastereoselective reduction of the enone
moiety; resulting in the need for either column chromatography
or HPLC separation. Taking this under advisement, we thought
that we could instead form the C15–C16 bond and set the
C15 stereochemistry in one reaction by taking advantage of
Seebach’s alkylation method; the addition of a suitable dialkyl
zinc reagent to an a,b-unsaturated aldehyde catalysed by a Ti–
TADDOL complex. Reduction of Weinreb amide 7 with DIBAL-
H at −78 ◦C delivered the corresponding a,b-unsaturated aldehyde
8. Addition of dipentyl zinc 2019 to aldehyde 8, in the presence
of spirotitanate 17, proceeded in a diasteroselective manner to
give its corresponding allylic alcohol 21 with a d.r. of over 30 : 1
Scheme 2 Synthesis of Weinreb amide. Reagents and conditions: (i) NaH,
10, THF, 0 ◦C, 87%.
Slow addition of either n-pentyl magnesium bromide 11, or (3-
methylbenzyl)magnesium bromide 12 (3 equiv.), at −78 ◦C, to
Weinreb amide 7 delivered the corresponding enones 13 and 14
with yields of 94% and 90% respectively (Scheme 3).14
(R)-Me–CBS reduction of enone 13 was carried out according
to Snapper et al.15 which delivered the corresponding (S)-allylic
alcohol with a d.r. of 9 : 1 (Scheme 4, Table 1). Similarly,
enone 14 underwent reduction with (S)-Me–CBS to give the
unnatural (R)-configured C15 hydroxy group, albeit with a modest
diastereoselectivity (d.r. 6 : 1). Application of both the (R)- and
(S)-n-Bu–CBS reagents to enones 13 and 14 respectively, which
have been documented to give, in many cases, better selectivity
Table 1 Diastereoselective reduction of enones 13 and 14
Entry
Substrate
Reduction method
d.r.a
9 : 1
10 : 1
6 : 1
7 : 1
>35 : 1
8 : 1
Product
C15 configuration
Yieldb (%)
1
2
3
4
5
6
13
13
14
14
13
14
(R)-Me–CBS
(R)-n-Bu–CBS
(S)-Me–CBS
(S)-n-Bu–CBS
(S)-BINAL-H
(R)-BINAL-H
15
15
16
16
15
16
S
S
R
R
S
R
96
92
95
86
91
90
a Assigned from 1H NMR analysis. b Isolated yields.
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Scheme 4 Diastereoselective reduction of enone systems. Reagents and
conditions: (i) Reduction (see Table 1); (ii) TBSCl, DMF, r.t. Yields for
TBS protection of 15 and 16, 96–100% and 96%, respectively.
Scheme
6
Completion of isocarbacyclin and 15R-TIC syntheses.
Reagents and conditions: (i) DDQ, CH2Cl2–H2O (19 : 1); (ii) (COCl)2,
DMSO, NEt3, CH2Cl2, −78 ◦C; (iii) NaClO2, KH2PO4, 2,3-dimethyl-2-
butene, tBuOH, H2O; (iv) 0.5 N HCl, THF (over 4 steps for isocarbacyclin
(2) and 15R-TIC (3), 79% and 74%, respectively.
(Scheme 5).20 Changing the catalyst to 18 or 19 (documented to
sometimes give better selectivities) did not have any effect in our
case. The resulting allylic alcohol was protected with TBS to give
previously described isocarbacyclin skeleton 15. A similar strategy
was planned for 15R-TIC using bis(3-methylbenzyl)zinc 22.19 Un-
fortunately, dibenzyl zinc 22 proved to be sluggish and unselective,
compared to its alkyl analogue, due to its p-conjugation, resulting
in 1,2-addition (where a d.r. of 5 : 1 was obtained, comparable to
the reduction of enone 14). The use of selected amino alcohols,21 as
a source of catalytic asymmetric induction, was also investigated,
where diastereoselectivities obtained for both the isocarbacy-
clin and 15R-TIC substrates were inferior to those previously
mentioned.22
Conclusions
We have synthesised, both isocarbacyclin (2) and 15R-TIC (3)
via two x-side chain addition strategies taking advantage of
common synthetic intermediate 7; firstly, a Grignard reagent ad-
dition strategy and secondly, after reduction to its corresponding
aldehyde 8, implementation of Seebach’s highly diastereoselective
alkylation chemistry. These routes should allow for considerable
diversification of analogue synthesis; allowing the possibility to
explore and understand the usefulness of these CNS ligands.
Further research in our laboratories is currently ongoing, and
subsequent results will be published in due course.
Acknowledgements
Financial support from the Schering AG for N. A. S. is grate-
fully acknowledged. Valentin Enev and Wolfgang Felzmann are
thanked for helpful discussion (Universita¨t Wien). We also thank
Hanspeter Ka¨hlig for NMR (Universita¨t Wien).
References and notes
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Scheme 5 Diastereoselective Ti–TADDOL mediated addition. Reagents
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