Rapid access to trans-2,6-disubstituted piperidines: Expedient total syntheses of (-)-solenopsin A and (+)-epi-dihydropinidine

Article abstract of DOI:10.1055/s-2005-871956

Expedient syntheses of (-)-solenopsin A and (+)-epi-dihydropinidine are reported, the key step in both being the one-pot multicomponent aza-silyl-Prins condensation reaction to yield a trans dihydropyridine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871956

LETTER
2101
Rapid Access to trans-2,6-Disubstituted Piperidines:
Expedient Total Syntheses of (–)-Solenopsin A and (+)-epi-Dihydropinidine
Rapid
A
ccess totra
d
ns-2, 6-Disu
r
bstituted
i
Piper
i
a
dines n P. Dobbs,* Sebastien J. J. Guesné
Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
Fax +44(1392)263434; E-mail: A.Dobbs@exeter.ac.uk
Received 4 May 2005
We have previously reported the aza-silyl-Prins reaction
Abstract: Expedient syntheses of (–)-solenopsin A and (+)-epi-di-
hydropinidine are reported, the key step in both being the one-pot
multicomponent aza-silyl-Prins condensation reaction to yield a
trans dihydropyridine.
(ASPR; Scheme 1) as an efficient method for the prepara-
tion of tetrahydropyridines.5 The ASPR involves the reac-
tion of an aldehyde with a silylated homoallylic amine in
the presence of a mild Lewis acid; the easy-to-handle and
moisture-tolerant indium trichloride being the one of
choice in the majority of our work. Furthermore, the reac-
tion is completely diastereoselective and gives only the
2,6-trans-substituted product when a R1 substituent is in-
troduced in the homoallylic amine component. Given this
complete diastereocontrol, it occurred to us that (–)-sole-
nopsin A and (+)-epi-dihydropinidine would be excellent
targets to showcase this novel methodology in total syn-
thesis and hence reduce the number of steps in the overall
synthesis of these important synthetic targets.
Key words: total synthesis, (–)-solenopsin A, (+)-epi-dihydropini-
dine, multicomponent condensation, aza-silyl-Prins reaction, trans
dihydropyridine
The piperidine ring system is one of the most common
motifs found in numerous natural products, drugs and
drug candidates. Accordingly, the important bioactivities
of piperidines have stimulated the development of new
synthetic approaches and considerable efforts have been
devoted to the enantioselective preparation of these com-
pounds. An excellent review of the synthesis of pipe-
ridines has recently appeared.1 Trans-2,6-disubstituted
piperidines represent a subclass of naturally occurring al-
kaloids that have also been the targets of many synthetic
efforts, not only due to their range of pharmacological ac-
tivities but also the difficulty in establishing the trans sub-
stitution pattern across the nitrogen atom. Notable
examples include (–)-solenopsin A (1), a constituent of
fire-ant venom from Solenopsis species, the venom of
which is characterised by a predominance of 2-alkyl-6-
methylpiperidines.2 These have appeared as novel drug
candidates for the treatment of Alzheimer’s disease. The
structurally related (+)-epi-dihydropinidine has been iso-
lated from pine and spruce species such as Picea pungens
or Pinus ponderosa (Figure 1).3
R1
NHR
O
InCl3
MeCN, reflux
TMS
R2
H
R1
N
R
R2
R = alkyl, aryl, benzyl, CBz
R1 = alkyl
R2 = alkyl, aryl, benzyl, cycloalkyl
Scheme1 The aza-silyl-Prins reaction
We envisaged efficient total syntheses of 1 and 2 using a
common strategy from an intermediate tetrahydropyri-
dine, prepared via the ASPR.
Racemic syntheses of both compounds were first per-
formed. The two aldehydes required were dodecyl alde-
hyde and butyraldehyde, both of which are commercially
available. The required N-benzyl-substituted secondary
amine was prepared in four steps from 4-pentyn-2-ol: si-
lylation, DiBAL-H reduction, tosylation and displace-
ment with benzylamine, to give 4 in 48% yield over the
four steps.5 The ASPR reaction proceeded in good yields
to give the trans-substituted tetrahydropyridines 5 and 6
in 72% and 58% yield, respectively. The trans-configura-
tion of both compounds was determined by NOE studies,
with enhancement observed between the axial methyl
group and axial hydrogen atom.
CH3
( )10
CH3
( )2
Me
N
R
Me
N
R
(–)-solenopsin A (1)
(+)-epi-dihydropinidine (2)
Figure 1
There are too many synthetic approaches to these and oth-
er trans-2,6-disubstituted piperidines to be able to report
them all here, so the reader is directed to several recent
reviews for a comprehensive coverage.1,4
Having carefully chosen the benzyl protecting group, it
was now possible, in one step, both to deprotect the benzyl
group and hydrogenate the double bond using catalytic
hydrogenation on a palladium hydroxide catalyst in
quantitative yield after four hours. Thus, it was possible
SYNLETT 2005, No. 13, pp 2101–2103
1
9
.0
8
.2
0
0
5
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871956; Art ID: D12005ST
© Georg Thieme Verlag Stuttgart · New York

2102
A. P. Dobbs, S. J. J. Guesné
LETTER
Me
3
HO
1. 2 equiv n-BuLi, 2 equiv TMSCl, THF, –78 °C followed by dil. HCl
2. 3 equiv DiBAL-H, Et2O 0 °C to reflux, followed by dil. H 2SO4
3. TsCl, Et3N, DMAP, CH2Cl2, 0 °C
4. BnNH2, EtOH, 80 °C
overall 48%
O
InCl3
( )10
H
H
MeCN, reflux
72%
( )10
( )10
Me
Me
N
Me
Me
N
Me
Bn
5
H
7
H2, Pd(OH)2/C
TMS
NHBn
4
EtOH, r.t.
4 h
100%
O
InCl3
( )2
MeCN, reflux
58%
( )2
( )2
N
N
Bn
H
6
8
Scheme 2 Total syntheses of racemic solenopsin A and epi-dihyropinidine
( )-trans-1-Benzyl-2-methyl-6-undecyl-1,2,3,6-tetrahydropyri-
dine (5)
to obtain both racemic solenopsin A and racemic epi-di-
hydropinidine in six linear steps and 35% and 28% overall
yields, respectively.6
Following the general procedure, ( )-N-benzyl-N-(Z)-(1-methyl-4-
trimethylsilylbut-3-enyl)amine (4) (250 mg, 1.00 mmol) and dode-
cyl aldehyde (244 mL, 1.00 mmol), were reacted and TLC indicated
full consumption of starting materials after 24 h of stirring at reflux
temperature. The work up gave a yellow oil, which was purified by
flash column chromatography (95% hexane, 4% EtOAc, 1% Et3N)
to give the title compound (243 mg, 0.71 mmol, 72%) as a colour-
The racemic syntheses described were readily modified
to enantiospecific ones simply by the introduction of
an additional step at the start of the synthetic schemes:
commencing with the ring opening of either (R)-(+) or
(S)-(–)-propylene oxide with trimethylsilylacetylene and
boron trifluoride etherate afforded enantiomerically pure
samples of both stereoisomers of 4. Completion of the
reaction sequence as described gave enantiopure samples
of both the natural and unnatural isomers of 7 and 8
(Scheme 2). No racemisation was observed during the
reaction sequence.7
1
less oil. IR (neat) nmax = 2925, 1602 cm–1. H NMR (300 MHz,
CDCl3): d = 7.40–7.36 (2 H, m, ArH), 7.31–7.26 (2 H, m, ArH),
7.23–7.19 (1 H, m, ArH), 5.79–7.75 (1 H, m, H-C4), 5.61–5.57 (1
H, m, H-C5), 3.69 (1 H, d, J = 13.8 Hz, CHH-Ph), 3.48 (1 H, d, J =
13.8 Hz, CHH-Ph), 3.16–3.11 (1 H, m, H-C2), 2.91 (1 H, br s, H-
C6), 2.04–1.91 (1 H, m, H-C3), 1.90–1.80 (1 H, m, H-C3), 1.50–
1.36 (2 H, m, H-C9), 1.34–1.13 (18 H, m, H-C10–C18), 1.12 (3 H,
t, J = 6.7 Hz, H-C8), 0.89 (3 H, t, J = 6.6 Hz, H-C19). 13C NMR
(75.5 MHz, CDCl3): d = 141.4 (ArC), 129.9 (C5), 128.9 (ArCH),
128.1 (ArCH), 126.5 (ArCH), 124.8 (C4), 56.8 (C6), 50.8 (C7),
46.7 (C2), 33.9 (C9), 32.1 (C10), 29.8 (C11–C16), 29.5 (C3), 26.0
(C17), 22.8 (C18), 16.8 (C8), 14.3 (C19). MS (CI): m/z (%) = 342
(100) [MH+], 186 (54). HRMS: m/z calcd for C24H40N: 342.3161;
found [MH+]: 342.3155. Anal. Calcd for C24H39N: C, 84.39; H,
11.51; N, 4.10. Found: C, 84.45; H, 11.36; N, 4.19. For (–)-(2R,6R)-
trans-1-benzyl-2-methyl-6-undecyl-1,2,3,6-tetrahydropyridine:
[a]D30 –40.9 (c 1.1, CHCl3).
In summary, we have reported the first successful applica-
tion of the ASPR reaction in enantioselective total synthe-
sis and have completed the syntheses of both racemic,
natural and unnatural solenopsin A and epi-dihydropini-
dine.
Typical Experimental Procedure for the Indium Trichloride
Mediated ASPR
( )-trans-1-Benzyl-2-methyl-6-propyl-1,2,3,6-tetrahydropyri-
dine (6)
The secondary amine (1.0 mmol) was added dropwise to a solution
of indium trichloride (221 mg, 1.0 mmol) and an aldehyde (1.0
mmol) in anhydrous MeCN (20 mL) at reflux temperature. Once the
reaction was completed (monitored by TLC) the solution was
cooled, concentrated and the residue obtained was partitioned be-
tween CH2Cl2 (20 mL) and 1 M NaOH (20 mL). The aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with 1 M NaOH, H2O, dried (MgSO4) and concentrated un-
der reduced pressure. The residue obtained was then purified by
flash chromatography to give the corresponding tetrahydropyridine.
Following the general procedure, ( )-N-benzyl-N-Z-(1-methyl-4-
trimethylsilylbut-3-enyl)amine (250 mg, 1.00 mmol) and butyralde-
hyde (89 mL, 1.00 mmol) were reacted and TLC indicated full con-
sumption of starting materials after 24 h of stirring at reflux
temperature. The work up gave a brown oil, which was purified by
flash column chromatography (97% hexane, 2% EtOAc, 1% Et3N)
to give the title compound (133 mg, 0.57 mmol, 58%) as a yellow
oil. IR (neat) nmax = 2959, 1601 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.38–7.36 (2 H, m, ArH), 7.31–7.29 (2 H, m, ArH), 7.23–7.21
(1 H, m, ArH), 5.81–5.74 (1 H, m, H-C4), 5.62–5.56 (1 H, m, H-
C5), 3.69 (1 H, d, J = 14.0 Hz, CHH-Ph), 3.47 (1 H, d, J = 14.0,
CHH-Ph), 3.14 (1 H, br s, H-C2), 2.92 (1 H, br s, H-C6), 2.05–1.94
Synlett 2005, No. 13, 2101–2103 © Thieme Stuttgart · New York

LETTER
Rapid Access to trans-2,6-Disubstituted Piperidines
2103
(1 H, m, H-C3), 1.94–1.82 (1 H, m, H-C3), 1.47–1.18 (4 H, m, H-
C9, H-C10), 1.12 (3 H, d, J = 6.4 Hz, H-C8), 0.77 (3 H, t, J = 7.2
Hz, H-C11). 13C NMR (100.6 MHz, CDCl3): d = 141.4 (ArC), 129.8
(C5), 128.8 (ArCH), 128.1 (ArCH), 126.5 (ArCH), 124.8 (C4), 56.7
(C6), 50.7 (C7), 46.7 (C2), 36.3 (C9), 39.5 (C3), 19.2 (C10), 16.9
(C8), 14.3 (C11). MS (CI): m/z (%) = 230 (42) [MH+], 186 (100),
91 (10). HRMS (CI): m/z calcd for C16H24N: 230.1908; found
[MH+]: 230.1917. Anal. Calcd for C16H23N: C, 83.79; H, 10.11; N,
6.11. Found: C, 83.88; H, 9.98; N, 6.14.
References
(1) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
(2) (a) Isolation of solenopsin A: Jones, T. H.; Blum, M. S.;
Fales, H. M. Tetrahedron 1982, 38, 1949. (b) Potential for
treatment of Alzheimer’s disease: Takadoi, M.; Yamaguchi,
K.; Terashima, S. Bioorg. Med. Chem. 2003, 11, 1169.
(3) Todd, F. G.; Stermitz, F. R.; Blokhin, A. V. Phytochemistry
1995, 40, 401.
(4) (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(b) Felpin, F. X.; Lebreton, J. Curr. Org. Chem. 2004, 83.
(5) (a) Dobbs, A. P.; Guesné, S. J. J.; Martinovic, S.; Coles, S.
J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880.
(b) Dobbs, A. P.; Guesné, S. J. J.; Coles, S. J.; Hursthouse,
M. B. Synlett 2003, 1740.
Acknowledgment
We gratefully acknowledge the EPSRC (studentship to SJJG) and
the Royal Society (small equipment grant) for funding of this
project.
(6) All compounds gave satisfactory analytical and
spectroscopic data. Data for 7 and 8 in agreement with
previously reported values.2,3
(7) The absence of racemisation of compounds 4–8 was judged
by NMR experiments using Eu(hfc)3 doping at each stage
and comparison with the racemic series, where separation
occurred.
Synlett 2005, No. 13, 2101–2103 © Thieme Stuttgart · New York