3-4′-Bipiperidines via sequential [4 + 4]-[3,3]-retro-mannich reactions

Article abstract of DOI:10.1021/ol901743p

An approach to assembling unsymmetrically coupled piperidines is described, involving initial [4 + 4] photocycloaddition of 2-pyridones, followed by Cope rearrangement and retro-Mannich reaction. In these reactions, four stereogenic centers set during cyc

Full text of DOI:10.1021/ol901743p

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4540-4543
3-4′-Bipiperidines via Sequential
[4 + 4]-[3,3]-Retro-Mannich Reactions
Peiling Chen,† Patrick J. Carroll,‡ and Scott McN. Sieburth*,†
Department of Chemistry, Temple UniVersity, 1901 North 13th Street, Philadelphia,
PennsylVania 19122, and Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
scott.sieburth@temple.edu
Received July 30, 2009
ABSTRACT
An approach to assembling unsymmetrically coupled piperidines is described, involving initial [4 + 4] photocycloaddition of 2-pyridones,
followed by Cope rearrangement and retro-Mannich reaction. In these reactions, four stereogenic centers set during cycloaddition are relayed
or erased during the subsequent steps. Two methods for retro-Mannich reaction are demonstrated.
Piperidine rings, unsymmetrically coupled at C3 and C4′,
are a structural motif widely distributed among alkaloids.
The tetra- and pentacyclic examples in Figure 1 are arche-
this ring system, but with additional points of cyclization
between the piperidines, are also known.3 Biosynthesis of
these alkaloids has been proposed to involve dimerization
of dihydropyridines, and biomimetic studies have confirmed
the viability of this pathway.4 Among the challenges
presented by these molecules is the control of the stereo-
chemistry where the piperidine rings are joined. Synthesis
also has the potential to define the unknown 3′ stereocenter
of the saraines.5
We report here a novel method for assembling these
structures from aromatic 2-pyridones, beginning with two
efficient pericyclic reactions that set and then migrate the
key stereogenic centers.
Pyridones such as 1 (Scheme 1) are commercially available
or easily prepared and, while relatively unreactive in thermal
cycloadditions, will undergo [4 + 4]-photodimerization under
Figure 1. Coupled piperidine natural products.
types,1 and important biological activities have been found
for a number of these structures.2 Natural products containing
(2) Charan, R. D.; Garson, M. J.; Brereton, I. M.; Willis, A. C.; Hooper,
J. N. A. Tetrahedron 1996, 52, 9111–9120.
(3) Tsuda, M.; Inaba, K.; Kawasaki, N.; Honma, K.; Kobayashi, J.
Tetrahedron 1996, 52, 2319–2324. de Oliveira, J. H. H. L.; Grube, A.;
Koeck, M.; Berlinck, R. G. S.; Macedo, M. L.; Ferreira, A. G.; Hajdu, E.
J. Nat. Prod. 2004, 67, 1685–1689. Lebrun, B.; Braekman, J.-C.; Daloze,
D.; Kalushkov, P.; Pasteels, J. M. Tetrahedron Lett. 1999, 40, 8115–8116.
(4) Gil, L.; Baucherel, X.; Martin, M. T.; Marazano, C.; Das, B. C.
Tetrahedron Lett. 1995, 36, 6231–6234.
† Temple University.
‡ University of Pennsylvania.
(1) Torres, Y. R.; Berlinck, R. G. S.; Magalhaes, A.; Schefer, A. B.;
Ferrieira, A. G.; Hajdu, E.; Muricy, G. J. Nat. Prod. 2000, 63, 1098–1105.
Jaspars, M.; Pasupathy, V.; Crews, P. J. Org. Chem. 1994, 59, 3253–3255.
Guo, Y. W.; Madaio, A.; Trivellone, E.; Scognamiglio, G.; Cimino, G.
Tetrahedron 1996, 52, 14961–14974.
(5) Guo, Y. W.; Madaio, A.; Trivellone, E.; Scognamiglio, G.; Cimino,
G. Tetrahedron 1996, 52, 8341–8348.
10.1021/ol901743p CCC: $40.75
Published on Web 09/11/2009
 2009 American Chemical Society

solubility of the bis-2-pyridone 9 in nonpolar solvents,
controlling relative stereochemistry during the cycloaddition,
and providing a stereochemical reference center for the
cyclobutane cleavage reaction. Photocycloaddition of 9 in
toluene using a medium-pressure mercury lamp leads to a
completely cis-selective cycloaddition producing 10. The cis
stereoselectivity of the cycloaddition stems from the forma-
tion of an intermolecular hydrogen bonded dimer of 9.7c The
single stereogenic center of 9 was expected to control the
four new stereocenters of 10 by adopting a pseudoequatorial
conformation on the tether during the cycloaddition. When
the photochemistry was performed in the absence of ice-
cooling, cyclobutane 11 was obtained directly, in 68% yield,
without the need for isolation of cyclooctadiene 10. In
principle, the electronically very different alkenes of 11 could
be reduced selectively, but for the purposes of this model
system, both alkenes were hydrogenated to give 12. The
stereogenic centers of the rearrangement product 11 were
confirmed with an X-ray crystal structure of 12 (see Figure 2).10
Scheme 1
.
[4 + 4]-Cycloaddition-Cope Rearrangement-
Retro-Mannich Sequence
a rather broad set of conditions, including the use of
sunlight.6 The [4 + 4]-photocycloaddition of two 2-pyridones
proceeds with a high degree of solvent-insensitive, head-to-tail
regioselectivity and sets four new stereogenic centers. Stereo-
selectivity can be more variable, with both trans 2 and cis 3
cycloadducts observed, and methods have been developed for
selection of either isomer.7 These cycloadducts are quite
strained, and the cis isomer 3 of this functionalized 1,5-
cyclooctadiene will undergo a [3,3]-rearrangement at 50 °C to
quantitatively yield divinylcyclobutane 4.8 Notably, the head-
to-tail regioselectivity of the cycloaddition leads to a Cope
rearrangement product in which one bond of the cyclobutane
of 4 is flanked by an amide nitrogen and an amide carbonyl. It
was therefore anticipated that a retro-Mannich reaction9 of 4
might give a coupled piperidine product 6, with defined
stereochemistry at the 3- and 4′-positions.
We have explored this reaction sequence using the model
system 9 (Scheme 2), readily prepared from alcohol 7 and
Scheme 2
.
cis-Selective [4 + 4]-Photocycloaddition and Cope
Rearrangement
Figure 2. Crystal structures of 12, 16, and 22.
Initially the retro-Mannich reaction was expected to
involve simple treatment with a suitable base, but 12 proved
to be inert to a variety of basic conditions. The secondary
amides were, therefore, modified to promote cleavage, and
their substantially different steric environment led to straight-
forward selectivity. Treatment of 12 with di-tert-butyl
dicarbonate gave a single derivative, 13 (Scheme 3).11 The
activated carbonyl was then reduced with lithium borohy-
dride, yielding aminal 14. This sensitive structure underwent
chloropyridine 8. Williamson etherification followed by
hydrogenolysis of the benzyl ethers yields 9. The isobutyl
group of 7 plays three roles in this study: increasing the
(8) Nakamura, Y.; Kato, T.; Morita, Y. J. Chem. Soc., Perkin Trans. 1
1982, 1187–1191.
(9) (a) Schauble, J. H.; Hertz, E. J. Org. Chem. 1970, 35, 2529–2532.
(b) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836–4842. (c)
Schell, F. M.; Cook, P. M. J. Org. Chem. 1984, 49, 4067–4070. (d) Winkler,
J. D.; Scott, R. D.; Williard, P. G. J. Am. Chem. Soc. 1990, 112, 8971–
8975. (e) Risch, N.; Langhals, M.; Hohberg, T. Tetrahedron Lett. 1991,
32, 4465–4468. (f) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring,
R. R. Org. Lett. 1999, 1, 229–231. (g) Kwak, Y.; Winkler, J. D. J. Am.
Chem. Soc. 2001, 123, 7429–7430. (h) Aitken, D. J.; Gauzy, C.; Pereira,
E. Tetrahedron Lett. 2004, 45, 2359–2361. (i) White, J. D.; Ihle, D. C.
Org. Lett. 2006, 8, 1081–1084.
(6) Sieburth, S. McN. CRC Handbook of Organic Photochemistry and
Photobiology; Horspool, W., Lenci, F., Eds.; CRC Press: Boca Raton, FL,
2004; pp 103/1-103/18.
(7) (a) Sieburth, S. McN.; Lin, C.-H. J. Org. Chem. 1994, 59, 3597–
3599. (b) Sieburth, S. McN.; McGee Jr., K. F.; Al-Tel, T. H. J. Am. Chem.
Soc. 1998, 120, 587–588. (c) Sieburth, S. McN.; McGee, K. F. J. Org.
Lett. 1999, 1, 1775–1777.
Org. Lett., Vol. 11, No. 20, 2009
4541

Scheme 3
.
Boc-Activation of a Lactam and Reduction-
Scheme 4. Alternative Retro-Mannich Ring Opening
Solvolysis Retro-Mannich
retro-Mannich reaction under a variety of conditions, includ-
ing silica gel chromatography. Stirring 14 with silica gel
suspended in a methanol-methylene chloride mixture gave
the acyl-imine-enamide 15. The enolizable nature of all three
stereogenic centers in 15 made their preservation uncertain,
and the flexibility of this structure made NMR determination
of its structure problematic. A crystal structure of 15, grown
from methanol, however, confirmed that the stereochemical
relationship of these stereocenters was intact, as well as
formation of a new stereocenter resulting from addition of
methanol to the acylimine (Figure 2, 16).12
An alternative method for cleaving the cyclobutane also
took advantage of the divergent amide reactivities of 12
(Scheme 4). Treatment of 12 with sodium hydride and
iodomethane gave N-methylation of the less hindered amide.
The hindered nature of the remaining amide is evidenced
by the O-benzylation product 17 (2:1 O-benzyl:N-benzyl),
generated with sodium hydride and benzyl bromide. Treat-
ment of 17 with sodium cyanoborohydride reduced the
imidate to secondary amine 18. This amine was stable, but
when treated with sodium methoxide, a single product 20
was formed. This product had a new stereogenic center,
presumably set by kinetic protonation of 19. Reduction of
the imine 20 with sodium borohydride gave a 5:8 mixture
of two amines 21 and 22. The oxalate salt of 22 provided
an X-ray structure that defined the five stereogenic centers
resulting from this reaction sequence (Figure 2).13 Notably,
the three stereocenters originating in 12 remained in the same
relative configurations in product 22.
In these reaction paths, a [4 + 4]-photocycloaddition sets
four stereogenic centers in 10, fully controlled by the single
stereogenic center of the tether isobutyl group. None of these
four new stereocenters remain in the ultimate products 15,
16, 20, 21, or 22. Cope rearrangement of the [4 + 4] adduct
10 transfers two of those stereogenic centers to the cyclobu-
tane 11. The other two stereogenic centers disappear during
the retro-Mannich reactions. Nevertheless, in each case one
of the stereogenic centers that transiently disappear during
the retro-Mannich reaction is reformed with complete ste-
reocontrol (structures 16, 20). This control may be a function
of the seven-membered ether ring biasing the conformational
options during protonation of 19 and the addition of methanol
to imine 15. In the latter case, one can assume a reversible
addition to the imine, driven by either thermodynamics or
the crystallization, leads to formation of product 16, whereas
in the protonation of the amide enol(ate) 19, this stereo-
chemical outcome is most likely kinetic in origin. On the
other hand, the reduction of imine 20 to give a 5:8 mixture
of diastereomers 21 and 22 is more consistent with the
absence of stereochemical bias engendered by the seven-
membered ring. The crystal structures of 16 and 22 reveal
the rather open oxepin conformation (Figure 2).
(10) Compound 12, crystallized from methanol as the hydrate,
j
C16H24N2O3·H2O, in the rhombohedral space group R3 with a ) 28.990(2)
Å, c ) 10.1877(7) Å, V ) 7415.0(9) Å3, Z ) 18, and dcalc ) 1.251 g/cm3,
determined from a 0.30 mm × 0.28 mm × 0.18 mm crystal. X-ray intensity
data were collected on a Rigaku Mercury CCD area detector employing
graphite-monochromated Mo Ka radiation (λ ) 0.71069 Å) at a temperature
of 143 K. Refinement converged to R1 ) 0.0372 and wR2 ) 0.1008 for
2455 reflections for which F > 4σ(F) and R1 ) 0.0432, wR2 ) 0.1053 and
GOF ) 1.075 for all 2920 unique, nonzero reflections, and 202 variables.
CCDC 714967 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(11) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424–2426.
(12) Compound 16, C21H31N2O4, crystallized from methanol in the
(13) The oxalic acid salt of compound 22, C21H38N2O7, crystallized from
j
j
triclinic space group P1 with a ) 8.8340(10) Å, b ) 10.278(2) Å, c )
ethanol/ethyl acetate in the triclinic space group P1 with a ) 10.3811(13)
13.298(2) Å, R ) 90.009(11)°, ꢀ ) 106.126(7)°, γ ) 98.122(9)°, V )
1147.3(3) Å3, Z ) 2, and dcalc ) 1.087 g/cm3, determined from a 0.38 ×
0.18 × 0.005 mm crystal. X-ray intensity data were collected on a Rigaku
Mercury CCD area detector employing graphite-monochromated Mo Ka
radiation (λ ) 0.71069 Å) at a temperature of 143 K. Refinement converged
to R1 ) 0.0459 and wR2 ) 0.0999 for 1925 reflections for which F > 4σ(F)
and R1 ) 0.0886, wR2 ) 0.1240 and GOF ) 0.984 for all 3553 unique,
nonzero reflections, and 269 variables. CCDC 714968 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Å, b ) 11.062(2) Å, c ) 11.7553(14) Å, R ) 109.649(2)°, ꢀ )
93.3740(10)°, γ ) 115.456(2)°, V ) 1114.6(2) Å3, Z ) 2, and dcalc ) 1.283
g/cm3, determined from a 0.40 × 0.23 × 0.06 mm crystal. X-ray intensity
data were collected on a Rigaku Mercury CCD area detector employing
graphite-monochromated Mo Ka radiation (λ ) 0.71069 Å) at a temperature
of 143 K. Refinement converged to R1 ) 0.0384 and wR2 ) 0.0983 for
2745 reflections for which F > 4σ(F) and R1 ) 0.0541, wR2 ) 0.1049 and
GOF ) 1.019 for all 3910 unique, nonzero reflections, and 278 variables.
CCDC 714969 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4542
Org. Lett., Vol. 11, No. 20, 2009

selective photodimerization of a single 3-alkyl-2-pyridone
23 (Scheme 5), a sequence that would provide the substitu-
tion needed for the natural products in Figure 1. Our
investigation of these chemistries is continuing.
Scheme 5. Dimerization/Rearrangement/Fragmentation of
3-Alkyl-2-pyridones Yielding the Natural Product Substitution
Acknowledgment. This research was supported by a TU-
NPUDEI grant.
Supporting Information Available: Experimental details,
CIF files, characterization data, and proton NMR spectra for
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
This model study relied on the use of tethered 2-pyridones
to induce cis-selective [4 + 4]-cycloaddition. Application
of the [4 + 4]-[3,3]-retro-Mannich sequence to the
substances in Figure 1 would ideally result from a cis-
OL901743P
Org. Lett., Vol. 11, No. 20, 2009
4543