A flexible synthesis of privileged structural motifs using the Ollis-Sweeney ammonium ylid rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.08.055

The Ollis-Sweeney ammonium ylid rearrangement has been effectively utilized to provide access to hitherto unknown hybrid privileged structural motifs. The rearrangement of didehydropiperidinium salts containing tethered olefins at the 4-position afforded, after subsequent ring closing metathesis, novel spirocyclic scaffolds suitable for further elaboration and incorporation of final structures into HTS sets.

Full text of DOI:10.1016/j.tetlet.2008.08.055

Tetrahedron Letters 49 (2008) 6286–6288
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A flexible synthesis of privileged structural motifs using the Ollis–Sweeney
ammonium ylid rearrangement
Alan F. Gasiecki a, Jeffrey L. Cross b, Rodger F. Henry b, Vijaya Gracias a, Stevan W. Djuric a,
*
a Medicinal Chemistry Technologies, Abbott Laboratories, R4CP, AP10-2, 100 Abbott Park Road, Abbott Park, IL 60064, USA
b Structural Chemistry, Abbott Laboratories, R418, AP-9LL, 100 Abbott Park Road, Abbott Park, IL 60064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Ollis–Sweeney ammonium ylid rearrangement has been effectively utilized to provide access to hith-
erto unknown hybrid privileged structural motifs. The rearrangement of didehydropiperidinium salts
containing tethered olefins at the 4-position afforded, after subsequent ring closing metathesis, novel
spirocyclic scaffolds suitable for further elaboration and incorporation of final structures into HTS sets.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 13 June 2008
Revised 13 August 2008
Accepted 14 August 2008
Available online 22 August 2008
The judicious identification and synthesis of compounds for
inclusion in the corporate screening collections of pharmaceutical
companies remains a formidable undertaking. Several approaches
to the selection of compounds have been adopted. One such ap-
proach consists of the targeting of compound libraries to specific
protein families, such as kinases, G-protein coupled receptors
and ion channels. In this context, it has become apparent that cer-
tain classes of chemical structures, namely privileged structures,
have a higher chance of eliciting pharmacological activity than
other ‘random’ chemotypes. The term ‘privileged structure’ was
first introduced in 1988.1 A privileged structure was defined as ‘a
single molecular framework able to provide ligands for diverse
receptors’. It was envisaged that the privileged structures could
be a valuable alternative in the search for new receptor ligands
by suitably decorating these substructures. Since then, an increas-
ing number of substructural frameworks have been described as
privileged structures,2 including indoles, aryl piperazines, spiro
piperidines, biphenyls, and 3-phenyl pyrrolidines (Fig. 1).
These structures have since then been used extensively in
medicinal chemistry programs to identify new ligands, especially
for G-protein coupled receptors (GPCRs). As part of our efforts to
elaborate novel variants of privileged motifs as quality lead struc-
tures, we took advantage of the underutilized Sweeney3 protocol
for the [2,3]-sigmatropic rearrangement of didehydropiperidinium
ylids to provide 3-vinyl-substituted pyrrolidines. Our initial targets
are shown in Figure 2, and all incorporate privileged structural
motifs.
From a design perspective, it was envisioned that by incorpo-
rating a suitable olefinic handle at the 4-position of the starting
pyridines, a final ring-closing metathesis step would access the
H
Cl
NHSO2R
N
N
NH2
O
O
N
O
OH
N
N
N
N
N
SO2CH3
NH
N
WO2007118899
D3 receptor antagonist
Losartan
A2 receptor antagonist
MK-0677
Growth Hormone secretagogue
Figure 1.
* Corresponding author. Tel.: +1 847 935 4170; fax: +1 847 935 0548.
E-mail address: stevan.w.djuric@abbott.com (S. W. Djuric).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.055

A. F. Gasiecki et al. / Tetrahedron Letters 49 (2008) 6286–6288
6287
We next turned our attention to the synthesis of the completely
novel ‘hybrid’ privileged structure. Our main concern in this cam-
paign centered on whether we could coax the requisite [2,3] sig-
matropic rearrangement to occur with a functionalized 4-phenyl
substituent present on the didehydropiperidinium ring, given the
anticipated steric congestion present in the transition state.4 Grat-
ifyingly, the rearrangement proceeded smoothly and rapidly at
50 °C to provide the desired product. Interestingly, the cis and
trans products (vinyl and benzoyl group relative stereochemistry)
were isolated after silica gel chromatography, and each pure iso-
mer was found to equilibrate on standing to reprovide the mixture.
However, when the mixture of isomers was exposed to ring clos-
ing-metathesis conditions, once again using Grubbs 2 catalyst, a
single product 5d was observed (Scheme 2).5
X
X
N
X
O
O
N+
R
Y-
N
R
R1
R1
X
X
N
N
O
R
O
R
X=O, NBoc
Figure 2.
The structure of this compound was confirmed by X-ray struc-
tural analysis (Fig. 3), and was found to be, not unexpectedly, the
isomer where the phenyl and benzoyl group exhibited a trans
relationship. Summarily, we have used the Sweeney–Ollis [2,3]-
rearrangement of didehydropiperidinium ylids to provide the
hitherto unknown privileged spirocyclic motifs and the structur-
ally intriguing hybrid structure 5d. The protocol has been shown
desired spirocycles. As minimal prior work had been done on the
investigation of the [2,3]-sigmatropic rearrangement of didehydro-
piperidinium ylids derived from 4-substituted pyridines, we were
anxious to determine the relative stereochemistry of substituents
in the final products. Construction of the requisite intermediates
for the simple oxa- and aza-spirocycles proceeded uneventfully
and in good yield as outlined in Scheme 1. Based on literature prec-
edent for the rearrangement reactions of ylides derived from 4-
unsubstituted didehydropiperidinium salts, we anticipated that
the rearrangement would occur via an endo transition state to pro-
vide products, where the 3-vinyl and 2-benzoyl groups resided in
the cis configuration. This presupposition proved to be correct as,
in both cases, the cis product was obtained upon exposure of the
salts to sodium hydride in warm DME. After purification on silica
gel, 3c and 4c were both subjected to ring-closing metathesis using
the Grubbs 2 catalyst to provide the anticipated spirocycles. Inter-
estingly, the reaction to produce the azaspirocycle 4d also pro-
duced a small amount of the isomer 4e, presumably formed by
scrambling of the C2 stereogenic center due to the high acidity of
the C-2 proton (3:1 ratio of products). This scrambling was not a
problem in our environment, where a major goal is to produce
and evaluate, in a biological setting, as many different structural
types as possible. It should be noted that we were not able to iso-
late any of the corresponding regioisomers in the oxacyclic case.
NBoc
N
NHBoc
a,b,c
Boc
d,e
N
N
N
O
CH3
CH3
5a
5c
5b
f
Boc
N
N
O
CH3
5d
Scheme 2. Reagents and conditions: (a) NaN(TMS)2, allyl bromide, 55 °C, 2 h, 56%;
(b) CH3I, CH3CN, 38 °C, 12 h, 90%; (c) NaBH4, CH3OH, 0 °C, 69%; (d) bromoaceto-
phenone, CH3CN, 65 °C, 4 h, 95%; (e) NaH, 1 equiv, DME, 85 °C, 2.5 h, 55%; (f) Grubbs
II, pTsOHꢀH2O, CH2Cl2, reflux, 30 min, 28%.
X
X
X
a,b,c
d,e
N
N
N
R
O
f
R
3c
4c
X=OH,
3a
3b
4b
X=NHBoc, 4a
X
X
+
N
N
O
R
O
R
3e
4e
3d
4d
Scheme 1. Reagents and conditions: X = OH, R = (CH2)2Ph, (a) Ph(CH2)2Br, CH3CN,
reflux, 12 h, 81%; (b) NaBH4,CH3OH, 0 °C, 41%; (c) NaH, THF, allyl iodide, 16 h, 22%;
(d) bromoacetophenone, CH3CN, 40 °C, 12 h, 90%; (e) NaH,1 equiv, DME, 85 °C, 3 h,
40%; (f) Grubbs II, p-TsOHꢀH2O, CH2Cl2, reflux, 30 min, 70%. X = NHBoc, R = CH3, (a)
NaNTMS2, allyl bromide, 55 °C, 16 h, 53%; (b) CH3I, CH3CN, 40 °C, 20 h, 90%; (c)
NaBH4, CH3OH, 0 °C, 77%; (d) bromoacetophenone, CH3CN, 70 °C, 4 h, 95%; (e) NaH,
1 equiv, DME, 85 °C, 8 h, 76%; (f) Grubbs II, pTsOHꢀH2O, CH2Cl2, reflux, 1 h, 91%, 3:1
ratio of 3d–e.
Figure 3.

6288
A. F. Gasiecki et al. / Tetrahedron Letters 49 (2008) 6286–6288
EA/hexane, Rf 0.2 5d, purified on silica gel, 1:4, EA/hexane, Rf 0.4 1H NMR spectra
were recorded at 500.5 MHz in DMSO-d6 or pyridine-d5, and data are reported as
follows; chemical shift in ppm from tetramethylsilane as an internal standard,
multiplicity (s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of
doublet of doublets, bd = broad doublet, t = triplet, dt = doublet of triplets,
td = triplet of doublets, and m = multiplet), integration value. 13C NMR were
recorded at 125.9 MHz in DMSO-d6 or pyridine-d5, and data are reported as
follows; chemical shift in ppm from tetramethylsilane as an internal standard.
Compound 3d: 1H NMR (DMSO-d6, 500.5 MHz, 30 °C) d 7.90 (d, J = 7.7 Hz, 2H),
7.56 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.4 Hz, 2H), 7.11 (d,
J = 7.4 Hz, 1H), 7.07 (d, J = 7.4 Hz, 2H), 5.53 (dt, J = 10.3 and 2.3 Hz, 1H), 5.28 (bd,
J = 10.3, 1H), 4.47 (s, 1H), 3.96 (dt, J = 16.8 and 2.3 Hz, 1H), 3.92 (dt, J = 16.8 and
2.3 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.39 (d, J = 10.8 Hz, 1H), 3.18 (td, J = 8.8 and
3.1 Hz, 1H), 2.87 (dt, J = 8.8 Hz, 1H), 2.79–2.64 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H),
1.87 (dt, J = 12.4 and 8.3 Hz, 1H), 1.75 (ddd, 12.4, 7.3 and 3.2 Hz, 1H). 13C NMR
(DMSO-d6, 125.9 MHz, 30 °C) d 202.4, 140.8, 138.5, 133.8, 129.9, 129.2 (4 C0s),
129.0 (4 C0s), 128.4, 126.6, 73.5, 73.0, 65.5, 54.7, 51.4, 46.8, 35.6, 35.1. Compound
4d: 1H NMR (Pyridine-d5, 500.5 MHz, 80 °C) d 8.10 (d, J = 7.5 Hz, 2H), 7.48 (t,
J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 5.60 (d, J = 10.2 Hz, 1H), 5.37 (dt, J = 10.2
and 3.1 Hz, 1H), 4.30 (s, 1H), 3.98 (d, J = 12.7 Hz, 1H), 3.84 (bd, J = 18.5 Hz, 1H),
3.74 (bd, J = 18.5 Hz, 1H), 3.31 (d, J = 12.7 Hz, 1H), 3.25 (td, J = 8.4 and 2.7 Hz,
1H), 2.78 (dt, J = 8.4 Hz, 1H), 2.39 (s, 3H), 2.06 (dt, J = 12.7 and 8.5 Hz, 1H), 1.85
(ddd, J = 12.7, 7.1 and 3.0 Hz, 1H), 1.56 (s, 9H). 13C NMR (Pyridine-d5, 125.9 MHz,
80 °C) d 201.3, 155.0, 139.3, 132.9, 131.7, 128.8 (4 C0s), 125.2, 79.5, 76.2, 54.1,
51.0, 48.9, 43.8, 39.9, 37.0, 28.8 (3 C0s). Compound 4e: 1H NMR (Pyridine-d5,
500.5 MHz, 80 °C) d 8.11 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.40 (t,
J = 7.5 Hz, 2H), 5.90 (dt, J = 10.1 and 2.3, 1H), 5.46 (dt, J = 10.1 and 3.1, 1H), 3.95
(s, 1H), 3.73 (bd, J = 18.7 Hz, 1H), 3.64 (bd, J = 12.7 Hz, 1H), 3.41 (bd, J = 12.7 Hz,
1H), 3.33 (bd, J = 18.7 Hz, 1H), 3.16 (td, J = 8.6 and 3.4 Hz, 1H), 2.47 (dt, J = 8.6 Hz,
1H), 2.29 (s, 3H), 2.04 (dt, J = 12.7 and 8.2, 1H), 1.74 (ddd, J = 12.7, 8.6 and 3.3 Hz,
1H), 1.46 (s, 9H). 13C NMR (Pyridine-d5, 125.9 MHz, 80 °C) d 198.6, 154.9, 139.2,
133.3, 133.0, 128.9 (2 C0s), 128.5 (2 C0s), 124.0, 79.6, 77.9, 54.2, 48.8, 48.2, 43.6,
40.5, 37.3, 28.6 (3 C0s). Compound 5d: 1H NMR (DMSO-d6, 500.5 MHz, 30 °C) d
7.77 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.42 (d,
J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz,
1H), 5.33 (d, J = 11.7 Hz, 1H), 5.25 (d, J = 11.7 Hz, 1H), 4.86 (s, 1H), 4.53 (d,
J = 18.4 Hz, 1H), 3.37 (d, J = 18.4 Hz, 1H), 3.19–3.06 (m, 2H), 2.82 (dd, J = 13.3 and
6.4 Hz, 1H), 2.60 (dt, J = 13.3 and 10.0 Hz, 1H), 2.15 (s, 3H), 1.44 (s, 9H). 13C NMR
(DMSO-d6, 125.9 MHz, 30 °C) d 202.5, 142.4, 141.0, 139.4, 133.5, 132.2, 130.0,
129.3 (2 C0s), 129.0, 128.4 (2 C0s), 127.9, 127.5, 126.3, 80.9, 77.2, 53.6, 52.5, 46.7,
40.1, 37.5, 29.1 (3 C0s).
to work, for the first time, with a selection of 4-substituted dide-
hydropiperidines (other than 4-methyl and phenyl) and with a
variety of N-1 substituents for example, methyl and phenethyl.
The ultimate ring-closed products were also effectively designed
for further modification and for library production using differen-
tial chemofunctionalization of the molecules at their two reactive
sites (or three if the double bond is utilized). Further extensions
of this methodology, incorporating other functionalities and sub-
stituents on the starting 4-substituted pyridines, should provide
access to other novel structures for pharmacological interrogation.
Acknowledgments
Professor Joe Sweeney (University of Reading, UK) is thanked
for valuable discussions and insights at the onset of this work.
Drs. Ying Wang and Anil Vasudevan (Department of Medicinal
Chemistry Technologies, Abbott Laboratories) are thanked for
erudite input during the course of the work and valuable critique
of the Letter.
References and notes
1. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Friedinger, R. M., et al J. Med.
Chem. 1988, 31, 2235.
2. Patchett, A. A.; Nargund, R. Ann. Rep. Med. Chem. 2000, 35, 289.
3. Blackburn, G. M.; Ollis, W. D.; Smith, C.; Sutherland, I. O. J. Chem. Soc., Chem.
Commun. 1968, 168; Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F.
Tetrahedron 2002, 58, 10113; Sweeney, J. B.; Tavassoli, A.; Workman, J. A.
Tetrahedron 2006, 62, 11506; Coates, B.; Malone, J. F.; McCarney, M. T.;
Stevenson, P. J. Tetrahedron Lett. 1991, 32, 2827.
4. Soldatova, S. A.; Akbulatov, S. V.; Gimranova, G. S., et al Chem. Heterocycl. Compd.
2005, 41, 681. Rearrangement of a 4-phenyl didehydropiperidium ylid afforded
a mixture of the expected pyrrolidine and a tetrahydroazepine.
5. Analytical data for final compounds, 3d, purified on silica gel, 1:3, EA/hexane, Rf
0.4 4d, purified on silica gel, 1:1, EA/hexane, Rf 0.5 4e purified on silica gel, 1:1,