The use of the aza-Diels-Alder reaction in the synthesis of pinidine and other piperidine alkaloids

Article abstract of DOI:10.1016/S0040-4039(01)02149-9

The imine Ph₂CHN=CHCO₂Et, generated from benzhydrylamine and ethyl glyoxylate, provides a Diels-Alder adduct with 1,3-pentadiene from which a range of cis-2,6-disubstituted piperidines can be accessed; the benzhydryl group confers high diastereocontrol for derivatising the six-membered ring, allowing access to 2,5,6-trisubstituted piperidines, and to 2,6-disubstituted piperidines such as pinidine.

Full text of DOI:10.1016/S0040-4039(01)02149-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1071–1074
The use of the aza-Diels–Alder reaction in the synthesis of
pinidine and other piperidine alkaloids
Patrick D. Bailey,* Peter D. Smith, Keith M. Morgan and Georgina M. Rosair
Department of Chemistry, Heriot-Watt University, Edinburgh EH14 4AS, UK
Received 4 September 2001; revised 2 November 2001; accepted 8 November 2001
Abstract—The imine Ph2CHNꢀCHCO2Et, generated from benzhydrylamine and ethyl glyoxylate, provides a Diels–Alder adduct
with 1,3-pentadiene from which a range of cis-2,6-disubstituted piperidines can be accessed; the benzhydryl group confers high
diastereocontrol for derivatising the six-membered ring, allowing access to 2,5,6-trisubstituted piperidines, and to 2,6-disubstituted
piperidines such as pinidine. © 2002 Elsevier Science Ltd. All rights reserved.
The piperidine ring is widespread in nature, and these
alkaloids possess potent biological properties.1 Of par-
ticular interest to us are pinidine (1),2 and carpamic
acid (2).3 In the previous paper, we described aza-
blocking the 2,6-equatorial positions (Fig. 1). Molecu-
lar modelling studies10 were consistent with the NMR
and X-ray observations. As indicated in Figs. 2 and 3,
whilst an N-benzyl auxiliary can accommodate two
flanking equatorial substituents, the bulkier N-benzhy-
dryl auxiliary cannot, forcing adjacent substituents into
axial positions. This is particularly apparent when the
conformation of the global minimum is compared with
representative local minima, from which it is apparent
that the one phenyl ring can rotate away from steric
clashes with adjacent 2,6-diequatorial substituents (N-
benzyl, Fig. 2), whereas an additional phenyl ring is
unable to avoid such a steric interaction (N-benzhydryl,
Fig. 3). This has dramatic stereochemical consequences
on subsequent transformations, which can be exploited
to good effect. Thus, whilst the hydroboration/oxida-
tion sequence used to convert 4“5 provided the Me/
OH anti isomer due to the pseudoaxial methyl group,
oxidation followed by ‘hydride’ reduction generated the
Me/OH-syn isomer of the carpamic acid series, with
complete stereocontrol, again conferred by the methyl
group due to the influence of the N-benzhydryl auxil-
Diels–Alder
reactions
with
benzhydryl
imine
Ph2CHNꢀCHCO2Et 3, which is a stable white solid
dienophile that reacts with acyclic dienes to generate
piperidines in yields of ca. 70%, with complete control
of regio- and diastereochemistry.4 In this letter, we
focus on the use of the penta-1,3-diene adduct,5 isolated
as a single regio- and diastereoisomer (even using an
E/Z mixture of diene), as shown in Scheme 1.
An unexpected feature of these cycloadducts was their
conformations. Structural analysis by NMR spec-
troscopy revealed that cis-2,6-substituents in analogues
of 4 occupied diaxial (or pseudodiaxial) positions.6 This
led to high diastereocontrol for subsequent transforma-
tions, as indicated in Scheme 2, for which hydrobora-
tion/oxidation of 4 gave 57 as the sole diastereoisomer.
The X-ray crystal structure of the TBDMS protected
derivative 78 revealed an all-axial chair conformation of
the C-substituents, due to the bulky N-benzhydryl
Scheme 1. Reagents and conditions: (i) penta-1,3-diene (2 equiv.), TFA (1 equiv.), TFE, −40°C (62%).
Keywords: alkaloids; Diels–Alder reaction; piperidines.
* Corresponding author. Present address: Department of Chemistry, UMIST, PO Box 88, Manchester M60 1QD, UK. Tel.: 0161 200 4448; fax:
0161 200 4559; e-mail: p.bailey@umist.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02149-9

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P. D. Bailey et al. / Tetrahedron Letters 43 (2002) 1071–1074
Scheme 2. Reagents and conditions: (i) BH3·THF, then H2O2, HO− (33%); (ii) TPAP, NMO, CH2Cl2, then L-Selectride (65%); (iii)
TBDMS·OTf, DMF (89%); (iv) LiAlH4, Et2O, then Swern oxidation (64%); (v) n-C7H15PPh3+·Br−, KHMDS, PhMe/THF (74%).
iary; the resulting hydroxyester underwent spontaneous
cyclization to the lactone 6, whose structure was confi-
rmed by NOE studies. Access to the carpamic acid
skeleton was demonstrated by the model sequence of
reactions shown in Scheme 2. Starting from the pro-
tected hydroxyester 7, reduction with LiAlH4, followed
by Swern oxidation, gave the aldehyde 8; condensation
of this with the heptyl triphenylphosphonium ylid gave
exclusively the Z-alkene 9, containing the full C/N
skeleton of protected carpamic acid, and with control
of all three chiral centres.
We have also applied the new aza-Diels–Alder reaction
to the synthesis of members of the pinidine family,2 as
summarised in Scheme 3. Thus, the cycloadduct 4 could
be reduced to 10 in a single step, which could be
Figure 1. X-Ray crystal structure of 7.8
converted into the protected aldehyde 11 in high overall
Figure 2. Molecular modelling10 of the N-benzyl analogue of 5. Each point represents a minimised structure from the
conformational search. Examples of local minima structures are shown, as well as the global minimum (Gmin).

P. D. Bailey et al. / Tetrahedron Letters 43 (2002) 1071–1074
1073
Figure 3. Molecular modelling of the N-benzhydryl derivative 5 (see Fig. 2 for details).
Scheme 3. Reagents and conditions: (i) H2, Pd–C, EtOH (70%); (ii) (a) (Boc)2O, NEt3, H2O/dioxan, then (b) LiBH4, Et2O, rt, then
(c) TPAP, NMO, CH2Cl2 (61% overall); (iii) 2-(ethylsulfonyl)benzothiazole, KHMDS, THF, −78°C (34%, E/Z 6:1); (iv)
Ph3PEt·Br, KHMDS, THF, rt (91%, all Z); (v) UV, I2, 1,2-epoxypropane, hexane, rt (E:Z 1:1 after 6 h).
yield. The E-alkene 12 could be prepared with good
stereoselectivity (but poor yield) using modified Julia
coupling conditions;12 alternatively, the Z-isomer 13a
could be formed in high yield using Wittig chemistry,
and isomerised to the E-isomer. Acidic removal of the
Boc protection generates Z- or E-pinidine.
4. Bailey, P. D.; Smith, P. D.; Pederson, F.; Clegg, W.;
Rosair, G. M.; Teat, S. J. Tetrahedron Lett. 2002, 43,
1067; adduct 4 should allow access to numerous 6-Me-2-
substituted piperidines.
5. 1-Benzhydryl-4,5-didehydro-2-ethoxycarbonyl-6-methyl-
piperidine 4: Pale yellow oil; 1H NMR (200 MHz,
CDCl3): l 0.96 (3H, d, J=6.1 Hz, C6-Me), 1.36 (3H, t,
J=7.1 Hz), 2.27 (1H, m, C3-CH2), 2.42 (1H, m, C3-
CH2), 3.52 (1H, m, C6-CH); 3.66 (1H, dd, J=6.1 Hz, 1.6
Hz, C2-CH), 4.13 (2H, q, J=7.1 Hz), 5.33 (1H, s,
CHPh2), 5.57 (1H, m, C5-CH), 5.82 (1H, m, C4-CH),
7.11–7.31 (6H, m), 7.47–7.56 (4H, m); 13C NMR (50
MHz, CDCl3): l 14.19 (CH3), 16.38 (CH3), 24.97 (CH2),
49.73 (CH), 52.44 (CH), 60.23 (CH2), 70.76 (CH), 122.41
(CH alkene), 126.93 (CH alkene), 127.89 (CH), 128.20
(CH), 128.45 (CH), 128.50 (CH), 129.99 (CH), 130.46
(CH), 132.35 (CH), 142.90 (C), 143.47 (C), 175.04 (CꢀO);
IR w (thin film, cm−1): 3060.6, 3027.7, 2980.2, 2932.5,
1728.7, 1452.4; MS m/z (EI): 334.8 (0.09%, M+), 320.8
(0.25%, M−CH3+), 261.9 (14.66% M−CO2Et+), 166.8
(81.12%, CHPh2+), 121.0 (100%), 107.1 (100%), 48.9
(21.34%); HRMS calcd for C22H25NO2: 335.1885; found:
335.1891.
The imine 3 therefore not only provides a reliable and
efficient aza-dienophile, but the cycloadduct 4 (from its
Diels–Alder reaction with penta-1,3-diene) allows rapid
access to alkaloids of the pinidine and carpamic acid
families, with the N-benzhydryl auxiliary conferring
excellent diastereocontrol. We thank Dr. A. S. F. Boyd
and Dr. R. Ferguson for NMR and mass spectra, and
Quintiles (Scotland) for financial support.
References
1. For example, see: Bailey, P. D.; Millwood, P. A.; Smith,
P. D. Chem. Commun. 1998, 633.
2. Tawara, J. N.; Blokhin, A.; Foderaro, T. A.; Stermitz, F.
R.; Hope, H. J. Org. Chem. 1993, 58, 4813.
3. (a) Coke, J. L.; Rice, W. Y., Jr. J. Org. Chem. 1965, 30,
3420; (b) Smalberger, T. M.; Rall, G. J. H.; de Wall, H.
L.; Arndt, R. R. Tetrahedron 1968, 24, 6417.
6. Although poly-axial conformations of cyclohexanes are
rare, N-alkyl piperidines can show axial or equatorial
preference for 2/6-substituents. See: Bonin, M.; Romero,

1074
P. D. Bailey et al. / Tetrahedron Letters 43 (2002) 1071–1074
J. R.; Grierson, D. S.; Husson, H.-P. J. Org. Chem. 1984,
49, 2392.
7. Ethyl 1-benzhydryl-5-hydroxy-6-methylpipecolate
9. (a) XSCANS, Data Collection and Reduction Program,
1994, Version 2.2, Bruker AXS, Madison, Wisconsin,
USA; (b) Sheldrick, G. M. SHELXTL, Structure Deter-
mination and Refinement Programs, 1999, Version 5.1
Bruker AXS, Madison, Wisconsin, USA.
5:
1
White solid, mp 95–96°C; H NMR (200 MHz, C6D6): l
0.74 (3H, d, J=7.8 Hz, C6-Me), 0.87 (3H, t, J=7.1 Hz),
1.55 (1H, m, 1 of C3-CH2), 1.78–2.01 (3H, m, 1 of
C3-CH2, C4-CH2), 2.43 (1H, s, broad, OH), 3.14 (1H, dq,
J=7.1 Hz, 2.1 Hz, C6-CH), 3.36 (1H, s, broad, C5-CH),
3.53 (1H, t, J=3.4 Hz, C2-CH), 3.77 (2H, dq, J=7.2 Hz,
2.56 Hz), 5.72 (1H, s, CHPh2), 6.85–7.08 (6H, m), 7.35–
7.47 (4H, m); 13C NMR (50 MHz, C6D6): l 12.71 (CH3),
13.79 (CH3), 20.62 (CH2), 23.58 (CH2), 53.77 (CH), 54.82
(CH), 59.70 (CH2), 69.17 (CH), 70.25 (CH), 127.57 (CH),
127.69 (CH), 127.93 (CH), 128.14 (CH), 128.18 (CH),
128.51 (CH), 128.66 (CH), 143.16 (C), 143.28 (C), 174.50
(CꢀO); IR w (Nujol, cm−1): 3521.1, 3420.8, 1735.6, 1197.3;
MS m/z (EI): 354.2 (2.56%, MH+), 280.2 (22.84%, M−
CO2Et), 167.1 (100%, Ph2CH). Anal. calcd for
C22H27NO3: C, 74.75; H, 7.70; N, 3.96. Found: C, 74.71;
H, 7.74; N, 3.90%.
10. The molecular modelling illustrated in Figs. 2 and 3 was
performed on a Power Computing PowerCenter Pro with
a 604e RISC processor running at 210 MHz and using
the modified MM2 force field implemented in Chem3D
Pro version 3.5.1 from CambridgeSoft. Initial structures
for the Monte Carlo conformational searches were gener-
ated by a custom written Applescript which forced the
random rotation of selected torsional angles, prior to
crude energy minimisation, filtering and final minimisa-
tion of low energy conformations. Further modelling on
a Silicon Graphics workstation using XED-9811 also indi-
cated that the all-axial chair conformation was the global
minimum for 5 with the N-benzhydryl auxiliary (the
all-equatorial chair conformation being around 3 kcal/
mol higher in energy), whilst the N-benzyl derivative
prefers the all-equatorial conformation; these studies
revealed a relatively small energetic penalty for placing
the N-auxiliary also axial, as is observed in the crystal
structure of 7.
11. (a) Vinter, J. G. J. Comput. Aided Mol. Res. 1996, 10,
417; (b) Morley, S. D.; Jackson, D. E.; Sanders, M. R.;
Vinter, J. G. J. Comput. Chem. 1992, 13, 693; (c) Bailey,
P. D.; Everitt, S. R. L.; Morgan, K. M.; Brewster, A. G.
Tetrahedron 2001, 57, 1379.
12. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175; (b) Blakemore, P. R.;
Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.
8. X-Ray data for 7: A single crystal of 7 was covered in
Nujol and mounted with vacuum grease on a glass fibre
and transferred to a Bruker AXS P4 diffractometer,9a
and data were measured at 160 K using an Oxford
Cryosystems cryostream. Crystal data for 7:
C26H39NO2Si, MW=425.67, monoclinic, space group
,
P21lc, a=17.589(4), b=92380(10), c=16.121(4) A, i=
3
108.04(2)°, V=2490.7(9) A , Z=4, Dcalcd=1.135 mg m−3
,
,
v=0.115 mm−1, T=160(2) K. Crystal 0.14×0.68×0.44
mm3, independent reflections 4337 [R(int)=0.0363], R1=
0.0515, wR2=0.1036 for [I>2|(I)]. Solution and refine-
ment for 7 was performed using the SHELXTL suite of
programs.9b