Formal synthesis of the piperidine alkaloid (±)-prosophylline using polymer-supported dihydro-2H-pyridin-3-one

Article abstract of DOI:10.1016/j.tetlet.2007.09.075

The use of polymer-supported 2,6-disubstituted-dihydro-2H-pyridin-3-one, as the 'polymorphic' core molecule for the formal synthesis of the piperidine alkaloid (±)-prosophylline is presented.

Full text of DOI:10.1016/j.tetlet.2007.09.075

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8227–8229
Formal synthesis of the piperidine alkaloid ( )-prosophylline
using polymer-supported dihydro-2H-pyridin-3-one
a
a,b
Elias A. Couladouros,a,b, Alexandros T. Strongilos and E. Neokosmidis
*
aChemistry Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 118 55, Greece
bNatural Products Synthesis and Bioorganic Chemistry Laboratory, Institute of Physical Chemistry,
NCSR ‘Demokritos’, 153 10 Ag. Paraskevi, Athens, Greece
Received 6 July 2007; revised 4 September 2007; accepted 12 September 2007
Available online 18 September 2007
Abstract—The use of polymer-supported 2,6-disubstituted-dihydro-2H-pyridin-3-one, as the ‘polymorphic’ core molecule for the
formal synthesis of the piperidine alkaloid ( )-prosophylline is presented.
Ó 2007 Elsevier Ltd. All rights reserved.
Combinatorial chemistry and solid-phase synthesis con-
stitute two strategies, which offer several advantages
compared with classic solution phase chemistry. Hence
they are used increasingly often for the synthesis of
simple or more complex designed bioactive structures
as well as natural products and derivatives thereof.1–3
Recently, our group has demonstrated the use of a
polymer-supported polymorphic core molecule for the
generation of libraries of pharmacophoric ‘privileged
structures’. Thus, 2H-pyran-3(6H)-one, after subjec-
tion to both skeletal and functional group mani-
pulations gave a number of structurally diversified
oxa-carbocycles.4
alkaloids, which have been found to possess significant
biological properties such as antibiotic and anaes-
thetic.7–9 Several total syntheses towards prosophylline,
both racemic and asymmetric, have been reported with
overall yield from 9.2% to 12%.5,10–13
According to Scheme 1, ( )-prosophylline (1) could be
derived from the solid supported advanced intermediate
2 after cleavage from the resin, reduction of the double
bonds and removal of all the protecting groups. Com-
pound 2 is closely related to the polymer-supported
1,2-dihydro-2H-pyridin-3-one 3, which can be prepared
through aza-Achmatowicz rearrangement of the corres-
ponding furylamide 4,5,14 using appropriate oxidants
(such as m-CPBA, PCC and NBS).15–18 The synthesis
of this furylamide would exploit previous experience in
our group involving the coupling of Merrifield resin with
azide 5 and subsequent reduction of the azide group.
The alkoxy-benzyl ether linker thus formed, could be
cleaved under mild conditions using DDQ at a later
stage of the synthesis.4,19
Here we report that the above concept can be expanded
to encompass aza-carbocycles, such as piperidines, by
exploiting polymer-supported 2,6-disubstituted-1,2-
dihydro-2H-pyridin-3-one as the key intermediate.
Substituted piperidines exhibit interesting biological
activities and have served as precursors for the synthesis
of various medicinally important piperidine alkaloids.5
In order to validate the above proposition, ( )-proso-
phylline (1) was selected as the target molecule. This
natural product has been isolated from various Prosopis
species6 among other 2,3,6-substituted piperidine
Thus, furyl alcohol 64 was treated with diphenyl phos-
phoryl azide (DPPA) in the presence of DBU to afford
the corresponding azide20 (Scheme 2). Cleavage of the
silyl ether using TBAF gave the desired furylazide 5,
quantitatively. Coupling of 5 with Merrifield resin,
reduction of the azide under Staudinger conditions
(PPh3, THF/H2O) and tosyl protection of the resulting
amine, afforded furylamide 4. This amide was then
subjected to oxidative cyclization using m-CPBA and
the solid supported dihydropyridinone so formed was
Keywords: Solid-phase synthesis; Piperidine alkaloids; Natural
products; Polymorphic scaffolds.
*
Corresponding author. Address: Chemistry Laboratories, Agricul-
tural University of Athens, Iera Odos 75, Athens 118 55, Greece.
Tel.: +30 210 650 3679; fax: +30 210 677 7849; e-mail: ecoula@
chem.demokritos.gr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.075

8228
E. A. Couladouros et al. / Tetrahedron Letters 48 (2007) 8227–8229
SP
SP
OH
OH
O
O
OBz O
NTs
O
N
H
3
NTs
OMe
9
( )-prosophylline (1)
2
O
SP =
O
O
5
OH
NHTs
O
O
Cl
+
O
O
SP
4
5
N3
Scheme 1. Retrosynthetic analysis.
OTBS
OH
SP
O
O
TsHN
a, b
c, d, e
f, g
O
O
O
O
OH
N3
5
6
4
SP
SP
SP
O
O
OBz O
NTs
OBz O
NTs
OBz OH
NTs
h, i
j
k
NTs
OMe
OMe
3
7
8
9
Scheme 2. Reagents and conditions: (a) DPPA, DBU, toluene, 65%; (b) TBAF, THF, 0 °C, 99%; (c) Merrifield resin, Cs2CO3, Bu4NI, CH2Cl2, 3 d,
91%; (d) PPh3, THF/H2O 95:5, 60 °C; (e) p-TsCl, Et3N, CH2Cl2; (f) m-CPBA, CH2Cl2; (g) CH(OCH3)3, BF3ÆEt2O, THF, 0 °C to rt; (h) NaBH4,
CeCl3Æ7H2O, THF/MeOH 3:1, À30 to 0 °C; (i) Benzoic acid, PPh3, DIAD, THF; (j) allyltrimethylsilane, BF3ÆEt2O, CH2Cl2, À78 °C; (k) DDQ,
CH2Cl2/H2O 20:1.
treated with trimethyl orthoformate in the presence of a
Lewis acid to afford methyl ether 3. Reduction under
slightly modified Luche conditions at À30 °C21 followed
by Mitsunobu esterification yielded intermediate 7,
which was transformed into the corresponding allyl
derivative 8 in the presence of allyl trimethylsilane and
BF3ÆEt2O as a Lewis catalyst.ꢀ The relative stereo-
chemistry of allyl alcohol 922 (generated upon cleavage
from the resin using DDQ) was established by 2D-
NMR experiments and was in accordance with the
literature (Scheme 2).23
reaction on solid-phase.25,26 After extensive experimen-
tation,27 it was found that four reaction cycles (using
the Grubbs’ 1st generation catalyst) were necessary in
order to achieve optimum yields (Scheme 3).
Treatment of resin 11 with DDQ in a mixture of
CH2Cl2/H2O 20:1 not only resulted in the cleavage of
the desired product from the resin but also the removal
of the acetal protective group to afford (after reduction
of the double bonds) keto-alcohol 1228 (Scheme 3).
Conversion of the latter to ( )-prosophylline (1) has
been already published by Haroutounian et al.5 The
total yield for this nine step synthesis on solid-phase
was 12.8%.
With the advanced intermediate 8 in hand, the cross
metathesis reaction with alkene 1024 was the next crucial
step. The same approach was successfully followed by
Cossy et al. for the solution phase synthesis of (À)-
prosophylline.12 Our goal was to extend this method
by exploiting the advantages of the cross metathesis
In conclusion, we have developed a concise and effective
solid-phase strategy for the synthesis of the alkaloid ( )-
prosophylline. This strategy should be suitable for the
production of diverse derivatives of 1 either by using
different side-chains during the cross metathesis reaction
or by skeletal manipulations in the early stages of the
synthesis.
ꢀ The use of TiCl4 as a Lewis catalyst resulted in partial cleavage of 8
from the resin even at À78 °C.

E. A. Couladouros et al. / Tetrahedron Letters 48 (2007) 8227–8229
8229
SP
OBz O
O
OBz
OH
OH
5
10
O
O
O
Ref. 5
b, c
NTs
8
OH
N
N
a
Ts
H
9
9
( )-prosophylline (1)
11
12
O
5
O
Scheme 3. Reagents and conditions: (a) Alkene 10, Grubbs’ 1st generation catalyst, CH2Cl2, 35 °C, four cycles; (b) DDQ, CH2Cl2/H2O 20:1, 12.8%
(for nine steps); (c) H2/Pd, MeOH, 99%.
20. Spectral data for TBSO-5: 1H NMR (500 MHz, CDCl3): d
Acknowledgements
7.4 (m, 1H), 6.94 (s, 2H), 6.35 (m, 2H), 4.68 (dd, 1H,
J = 7.5, 5.0 Hz), 4.47 (ABq, 2H, J = 11.6 Hz,
Dm = 24.8 Hz), 3.81 (dd, 1H, J = 10.1, 5.0 Hz), 3.78 (dd,
This project was co-financed by the European Social
Fund and National resources EPEAEK and YPEPTH.
1H, J = 10.1, 7.6 Hz), 2.21 (s, 6H), 1.04 (s, 9H), 0.19 (s,
6H); 13C NMR (125 MHz, CDCl3): d 142.8, 130.0, 128.5,
110.4, 108.4, 73.4, 70.5, 58.4, 26.1, 19.8, 17.8, À2.5.
References and notes
21. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–
2227.
1
1. Thomson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555–
600.
2. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
2091–2158.
3. Handbook of Combinatorial Chemistry; Nicolaou, K. C.,
Hanko, R., Hartwig, W., Eds.; Wiley-VCH, 2002.
4. Couladouros, E. A.; Strongilos, A. T. Angew. Chem., Int.
Ed. 2002, 41, 3677–3680.
5. Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869–6870.
6. Bourrinet, P.; Quevauviller, A. . Compt. Rend. Soc. Biol.
1968, 162, 1138–1140.
7. Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-
Huu, Q.; Goutarel, R. Bull. Soc. Chim. Fr. 1966, 2945–
2947.
8. Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 425–441.
9. Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 443–458.
10. Natsume, M.; Ogawa, M. Heterocycles 1981, 16, 973–977.
11. Yang, C.; Liao, L.; Xu, Y.; Zhang, H.; Xa, P.; Zhou, W.
Tetrahedron: Asymmetry 1999, 10, 2311–2318.
12. Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org.
Chem. 2002, 67, 1982–1992.
13. Cossy, J.; Willis, C.; Bellosta, V. Synlett 2001, 1578–1580.
14. Harris, J. M.; Padwa, A. Org. Lett. 2002, 4, 2029–2031.
15. Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwie-
rzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973–
1996.
22. Spectral data for 9: H NMR (500 MHz, CDCl3): d 7.66
(d, 2H, J = 7.9 Hz), 7.57–7.51 (m, 1H), 7.40–7.33 (m, 4H),
7.00 (d, 2H, J = 7.9 Hz), 6.16 (dd, 1H, J = 10.4, 3.6 Hz),
5.94–5.82 (m, 2H), 5.24 (d, 1H, J = 5.7 Hz), 4.49 (t, 2H,
J = 9.4 Hz), 4.38 (t, 1H, J = 7.8 Hz), 3.85–3.76 (m, 1H),
3.70–3.61 (m, 1H), 2.86–2.78 (m, 1H), 2.35 (ddd, 1H,
J = 18.9, 12.4, 9.6 Hz), 2.29 (t, 1H, J = 5.8 Hz), 2.15 (s,
3H); 13C NMR (125 MHz, CDCl3): d 166.1, 143.3, 137.5,
133.8, 133.1, 132.5, 129.7, 129.6, 128.1, 127.1, 120.1, 118.7,
65.4, 62.9, 56.9, 52.9, 42.8, 21.5; HRMS m/z: [M+Na+]
Calcd for C23H25NO5SNa: 450.1351; found, 450.1310.
23. Hopman, J. C. P.; van den Berg, E.; Ollero, L. O.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1995,
36, 4315–4318.
24. Compound 10 was prepared in the same manner as
reported in Ref. 12. Furthermore, the respective ketone
was protected as a ketal by treatment with 2-methyl-2-
propyl-1,3-dioxolane and a catalytic amount of CSA at
40 °C.
25. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900–1923.
26. Schuster, M.; Pernerstorfer, J.; Blechert, S. Angew. Chem.,
Int. Ed. 1996, 35, 1979–1980.
27. For the determination of conversion and yield of this
reaction, a sample was subjected to cleavage conditions
(DDQ, CH2Cl2/H2O 20:1) and after small column puri-
fication for the removal of the excess of 10 and its self
coupling product, the ratio of unreacted material vs
1
product was judged by H NMR.
16. Lefebvre, Y. Tetrahedron Lett. 1972, 133–136.
17. Piancatelli, G.; Scettri, A.; Auria, M. Synthesis 1982, 245–
258.
18. Couladouros, E. A.; Georgiadis, M. P. J. Org. Chem.
1986, 51, 2725–2727.
28. Spectral data for 12: 1H NMR (500 MHz, CDCl3): d 7.69–
7.52 (m, 5H), 7.40–7.32 (m, 2H), 6.95 (d, 2H, J = 8.4 Hz),
5.11 (m, 1H), 4.21 (m, 1H), 4.05 (m, 1H), 3.82 (d, 2H,
J = 7.3 Hz), 2.47–2.36 (m, 4H), 2.13 (s, 3H), 2.00–1.15 (m,
20H), 1.04 (t, 3H, J = 7.3 Hz); HRMS (as ketal with
ethylene glycol) m/z: [M+Na+] Calcd for C34H49NO7SNa:
638.3128; found, 638.3118.
19. Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J. A.,
Jr. Tetrahedron Lett. 1997, 38, 4973–4976.