Cross-metathesis of chiral N-tert-butylsulfinyl homoallylamines: Application to the enantioselective synthesis of naturally occurring 2,6-cis-disubstituted piperidines

Article abstract of DOI:10.1055/s-0028-1083535

The synthesis of piperidine alkaloids (+)-dihydropinidine (1), (+)-isosolenopsin (2a), (+)-isosolenopsin A (2b), and (2R,6R)-6-methylpipecolic acid (3a) hydrochlorides, based on cross-metathesis of chiral N-tert-butylsulfinyl homoallylamines with methyl vinyl ketone, is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083535

LETTER
2777
Cross-Metathesis of Chiral N-tert-Butylsulfinyl Homoallylamines: Application
to the Enantioselective Synthesis of Naturally Occurring 2,6-cis-Disubstituted
Piperidines
C
ross-Met
o
a
thesisof
C
h
s
iral
N
-
te
r
é
t
-Butylsulfinyl
H
o
C
moallylamines . González-Gómez, Francisco Foubelo,* Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax +34(965)903549; E-mail: foubelo@ua.es; E-mail: yus@ua.es
Received 18 July 2008
cis stereoselectivity is a consequence of the stereoelec-
Abstract: The synthesis of piperidine alkaloids (+)-dihydropini-
tronically preferred axial approach of the hydride to the
dine (1), (+)-isosolenopsin (2a), (+)-isosolenopsin A (2b), and
(2R,6R)-6-methylpipecolic acid (3a) hydrochlorides, based on
cross-metathesis of chiral N-tert-butylsulfinyl homoallylamines
most stable half-chair conformation of the iminium inter-
mediate.7 In this context, a novel sequence of cross-meta-
with methyl vinyl ketone, is presented.
thesis (CM) of chiral homoallyl amines and
vinylalkylketones followed by reductive cyclization has
been recently exploited in a number of enantioselective
syntheses of 2,6-cis-disubstituted piperidine containing
alkaloids.8 A crucial finding for this approach was the
Hoveyda–Blechert modification of the Grubbs II catalyst,
which allows highly selective cross-coupling reactions
between terminal alkyl-substituted and electron-deficient
olefins (Scheme 1).9
Key words: cross-metathesis, piperidine alkaloids, pipecolic acid
derivatives, stereoselective allylation
Piperidine-containing alkaloids are commonly found in
nature and exhibit a wide range of interesting biological
activities.1 These reasons have motivated considerable ef-
forts on the enantioselective preparation of mainly 2,6-
cis-disubstituted piperidines.2 Among the numerous natu-
rally occurring piperidines, simple 2-methyl-6-alkyl-
piperidines constitute an important class of alkaloids.
R1
R1
N
R2
N
R2
_
H
H
H
H
Representative examples are dihydropinidine
1
H
(Figure 1), a defense alkaloid of the Mexican bean beetle
Epilachna varivestis,3,4 and isosolenopsins 2 (Figure 1),5
venom alkaloids of fire ants. Structurally related cis-6-
alkylpipecolic acids 3 (Figure 1), have also attracted the
attention of synthetic chemists because they are key con-
stituents of bioactive molecules and useful building
blocks for asymmetric synthesis.6
O
1. CM
2. [H]
O
R2
R2
+
R1
NH
PG
R1
NH
PG
An attractive strategy for the stereoselective synthesis of
2,6-cis-disubstituted piperidines is the reductive amina-
tion of d-aminoketones. The usually excellent observed
N
N
Mes
Mes
Cl
Cl
Ru
Hoveyda–Blechert catalyst
O
( )n
N
H
N
H
1, dihydropinidine
2a, n = 8, isosolenopsin
Scheme 1
2b, n = 10, isosolenopsin A
2c, n = 12, isosolenopsin B
2d, n = 14, isosolenopsin C
In most of the reported enantioselective synthesis of cis-
2,6-disubstituted piperidines using the CM-reductive
amination sequence, chiral N-Cbz homoallyl amines were
used to ensure hydrogenation of the double bond; N-de-
protection and reductive amination were performed in the
same synthetic operation. Due to its suitability for large-
scale synthesis, the opening of chiral oxiranes by vinyl-
magnesium bromide followed by several functional group
manipulations (usually six steps) has been the favorite ap-
proach to the necessary enantioenriched protected homo-
allylamines.10 Since we have previously reported a simple
HO2C
N
R
H
3, cis-6-alkyl pipecolic acids
Figure 1
SYNLETT 2008, No. 18, pp 2777–2780
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083535; Art ID: D27208ST
1
4
.1
1
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

2778
J. C. González-Gómez et al.
LETTER
straightforward preparation of chiral N-tert-butylsulfinyl
homoallyl amines,11 we considered of interest to explore
the use of these compounds in the CM-reductive amina-
tion sequence to obtain cis-2,6-disubstituted piperidines.
To the best of our knowledge, there are few reports of
ring-closing metathesis of dienes containing a N-sulfinyl
moiety,12 but no CM of N-sulfinyl homoallylamines, are
reported in the literature. At the outset of this work it was
unclear if the initial ‘ruthenacycle’ necessary for the met-
athesis would be poisoned by the N-sulfinyl moiety.
O
O
O
1. H2, 1 atm
(Ph3P)3RhCl (cat.)
EtOH, r.t.
[Ru] (cat.)
5a–d
CH2Cl2, 45 °C
2. 4 M HCl/dioxane
MeOH, 0 °C
3. NaBH3CN
buffer pH 5, r.t.
4. HCl, Et2O
R
NH
S
t-Bu
6a, 85%
6b, 72%
6c, 75%
6d, 85%
N-tert-Butylsulfinylamines13 5a–d were conveniently
prepared from the easily available (S)-N-tert-butyl-
sulfinimines14 4a–d by indium-mediated allylation under
Barbier reaction conditions (Scheme 2).15 Reactions were
run on a 5-mmol scale in excellent yields and only one di-
astereoisomer was observed by 1H NMR in all cases, ex-
cept for compound 5a where a 9:1 dr was observed. We
assume that the allylation takes place at the re-face of the
S-sulfinimine 4, using a six-membered ring chelation con-
trol model, as previously proposed for this reaction. Since
the newly created stereocenter would determine the abso-
lute stereochemistry of the final known compounds, we
decided to continue our synthesis hoping to confirm this
information at the end of the process.
⋅HCl
R
N
H
(+)-1, 85%
(+)-2a, 93%
(+)-2b, 95%
(+)-7, R = Ph, 94%
Scheme 3
sulfinyl group was removed using conventional acidic
conditions to furnish the corresponding imine (GC–MS),
which was reduced with NaCNBH3 in a citrate–phosphate
buffer medium (pH 5).18 The expected piperidines were
obtained in 85–95% yields over three steps and with a dr
of 95:5 for aliphatic free piperidines 1, 2a, and 2b, (GC–
MS), whereas only one diastereoisomer was observed for
7 (Scheme 3). Hydrochlorides of compounds 1, 2a, and
2b were crystallized using ethereal HCl and recrystalliza-
tion from EtOH–EtOAc (1:3) afforded the corresponding
pure products (>99:1, cis/trans ratio). Physical and spec-
troscopic data of hydrochlorides 1, 2a, and 2b were in
good agreement with those reported in literature. The
good correlation of the specific rotation of our synthetic
alkaloids 1, 2a, and 2b with the data reported for the cor-
responding natural products show that no racemization
occurred during the synthetic sequence and confirmed the
absolute stereochemistry of N-tert-butylsulfinyl homoal-
lylamines 5a–d.19
In
H
t-Bu
S
Br
R
NH
S
R
N
O
THF, 60 °C
t-Bu
O
(+)-4a, R = n-Pr
5a, 86%, dr 9:1
(+)-4b, R = n-C9H19
(+)-4c, R = n-C11H23
(+)-4d, R = Ph
5b, 80%, dr >95:5
5c, 76%, dr >95:5
5d, 94%, dr >95:5
t-Bu
H
S
N
O
[In]
R
Scheme 2
2-Phenyl-6-methylpiperidine (7) was conveniently pro-
tected, and oxidation of the phenyl group in the presence
of catalytic RuCl3 and an excess of NaIO4, followed by
methanolysis of the trifluoroacetamide, afforded crude
We were pleased to observe that the CM of N-tert-butyl-
sulfinylamines 5a–d with commercially available methyl
vinyl ketone took place smoothly when the Hoveyda–
Blechert ruthenium catalyst [Ru] was used to afford ex-
clusively the corresponding E-enones 6a–d (Scheme 3).
Importantly, 10 mol% of [Ru] catalyst and 48 hours were
necessary to achieve good yields (72–85%),16 probably
due to the intramolecular chelation of the intermediate ru-
thenium species. Although similar results have been re-
ported for N-Cbz homoallylamines, in our case it was not
necessary to change the N-protecting group.
cis-6-methylpipecolic
acid
after
acidification
(Scheme 4).20 The corresponding hydrochloride of the
crude cyclic amino acid was purified using Dowex 50W-
X8, followed by recrystallization from EtOH. The com-
20
pound thus obtained showed [a]D +10.5 (c 0.5, 0.1 M
HCl) and spectral data in good agreement with the litera-
ture.5a Although the desired compound 3a was isolated in
only 41% yield, the clean H and 13C NMR spectra ob-
1
tained just after elution through Dowex resin suggest that
the loading of the amino acid onto the resin was not quan-
titative and that optimization in this isolation is possible.
Most importantly, the specific rotation for the (2R,6R)-6-
methylpipecolic acid (3a) suggests that no racemization
has occurred during the synthetic sequence. With these re-
sults in hand, a general enantioselective synthesis of cis-
Although the sulfinyl group was proved to be tolerated
under the CM conditions, all attempts to hydrogenate
compound 6a with Pd or Pt catalysts in different solvents
were unsuccessful.17 However, quantitative hydrogen-
ation of the double bond of compounds 6a–d was ob-
served when the Wilkinson’s catalyst was used. The
Synlett 2008, No. 18, 2777–2780 © Thieme Stuttgart · New York

LETTER
Cross-Metathesis of Chiral N-tert-Butylsulfinyl Homoallylamines
2779
(7) (a) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983, Chap. 6.
(b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289; and
references therein. (c) Ryckman, D. M.; Stevens, R. V.
J. Org. Chem. 1987, 52, 4274.
6-alkylpipecolic acids, compounds with interesting bio-
logical activities,21 using compound 5d and different vinyl
alkyl ketones in the CM step can be readily envisaged.
1. TFAA, Et3N
(8) (a) Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879.
(b) Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45, 1167.
(c) Gebauer, J.; Blechert, S. Synlett 2005, 2826. (d) Dewi-
Wülfing, P.; Gebauer, J.; Blechert, S. Synlett 2006, 487.
(9) For recent reviews, see: (a) Connon, S. J.; Blechert, S.
Angew. Chem. Int. Ed. 2003, 42, 1900. (b) Hoveyda, A. H.;
Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.;
Garber, S. B.; Kingsburry, J. S.; Harrity, J. P. A. Org.
Biomol. Chem. 2004, 2, 8.
(10) (a) For ring opening of chiral oxiranes with vinylmagnesium
bromide, see: Fürstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J. Org. Chem. 2000, 65, 7990. (b) For
synthesis of chiral homoallylamines using this approach,
see: Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879.
(c) See also ref. 8d.
(11) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15,
3823.
(12) (a) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
(b) Dirscherl, G.; Rooshenas, P.; Schreiner, P. R.; Lamaty,
F.; König, B. Tetrahedron 2008, 64, 3005.
(13) For selected reviews, see: (a) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (b) Ellman,
J. A. Pure Appl. Chem. 2003, 75, 39. (c) Zhou, P.; Chen,
B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(14) N-tert-Butanesulfinylimines are readily prepared from
aldehydes and N-tert-butanesulfinamides (Ss and Rs are
commercially available in >99% ee), following the
procedure reported in: Liu, G.; Cogan, D. A.; Owens, T. D.;
Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
(15) Allylation of tert-butylsulfinimines has also been reported
by other authors using different metals and conditions. For
selected examples, see: (a) Cogan, D. A.; Liu, G.-C.;
Ellman, J. A. Tetrahedron 1999, 55, 8883. (b) Li, S.-W.;
Batey, R. A. Chem. Commun. 2004, 1382. (c) Kolodney,
G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew.
Chem. Int. Ed. 2007, 46, 9291.
2. RuCl3⋅H2O (cat.), NaIO3
3. K2CO3, MeOH
Ph
N
H
HO2C
N
then 1 M HCl
H
7
(+)-3a, 41%
Scheme 4
In summary, we have reported here that enantioenriched
N-tert-butylsulfinyl homoallylamines (easily prepared on
the gram scale from inexpensive commercially available
starting materials) underwent a smooth CM reaction with
methyl vinyl ketone in the presence of the Hoveyda–
Bletchert ruthenium catalyst. Hydrogenation of the enone
intermediates in the presence of Wilkinson’s catalyst, fol-
lowed by reductive amination, allowed the efficient prep-
aration of (+)-dihydropinidine (1), (+)-isosolenopsin (2a),
and (+)-isosolenopsin A (2b) hydrochlorides. (2R,6R)-2-
Phenyl-6-methylpiperidine (7) was also prepared using
the same reaction sequence and was conveniently trans-
formed into (2R,6R)-6-methylpipecolic acid (3a). Appli-
cation of this approach to the synthesis of other natural
alkaloids is currently under progress.
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; Projects CTQ2007-65218/BQU and
Consolider Ingenio 2010 CDS2007-00006). J.C.G.-G. thanks the
Spanish MEC for a Juan de la Cierva contract.
References and Notes
(16) Preparation of Compound 6c: A solution of amine 5c (165
mg, 0.50 mmol), methyl vinyl ketone (140 mL, 1.65 mmol)
and Hoveyda–Blechert ruthenium catalyst (31 mg, 0.05
mmol) in anhyd CH2Cl2 (10 mL) was stirred for 60 h at
45 °C. The solvent was evaporated and the residue was
purified by flash chromatography (silica gel, hexane–
EtOAc) to give the title compound (137 mg, 0.37 mmol) as
a pale brown oil; [a]D28 +20.0 (c 0.32, CHCl3). IR (neat):
3226, 1673, 1626 cm–1. 1H NMR (300 MHz, CDCl3):
d = 6.83 (dt, J = 16.0, 7.5 Hz, 1 H), 6.15 (d, J = 16.0 Hz, 1
H), 3.33–3.42 (m, 1 H), 3.09 (d, J = 7.7 Hz, 1 H), 2.51–2.56
(m, 2 H), 2.27 (s, 3 H), 1.22–1.55 (m, 20 H), 1.21 (s, 9 H),
0.88 (t, J = 7.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3):
d = 198.3, 143.5 (CH), 133.9 (CH), 56.1, 56.0 (CH), 39.5
(CH2), 35.7 (CH2), 31.8 (CH2), 29.4 (CH2), 29.25 (CH2),
29.2 (CH2), 27.0 (Me), 25.6 (CH2), 22.55 (CH2), 22.5 (Me),
14.0 (Me). LRMS (MALDI): m/z = 372.281 [M + H],
394.286 [M + Na].
(17) Poisoning of Pd and Pt catalysts is well documented. See for
instance: (a) Bartholomew, C. H.; Agarwal, P. K.; Katzer,
J. R. Adv. Catal. 1982, 31, 135. (b) Barbier, J.; Lamy-
Pitara, E.; Marecot, P.; Boitiaux, J. P.; Cosyns, J.; Verna, F.
Adv. Catal. 1990, 37, 279.
(18) General Procedure for the Reductive Amination of
Cross-Metathesis Products: A flame-dried flask was
cooled under a stream of argon and charged with
(1) Schneider, M. In Alkaloids: Chemical and Biological
Perspectives, Vol. 10; Pelletier, S. W., Ed.; Pergamon:
Oxford, 1996, 55–299.
(2) For recent reviews on the stereoselective synthesis of
2,6-dialkylpiperidines, see: (a) Bates, R. W.; Sa-Ei, K.
Tetrahedron 2002, 58, 5957. (b) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
(3) Attygale, A. B.; Xu, S. C.; McCormick, K. D.; Meinwald, J.
Blankespoor, C. L.; Eismer, T. Tetrahedron 1993, 49, 9333.
(4) (a) For leading references on the enantioselective synthesis
of dihydropinidine, see: Ciblat, S.; Besse, P.; Papastergiou,
V.; Veschambre, H.; Canet, J. L.; Troin, Y. Tetrahedron:
Asymmetry 2000, 11, 2221; and references therein. (b) To
verify the NMR data, see: Wang, X.; Dong, Y.; Sun, J.; Xu,
X.; Li, R.; Hu, Y. J. Org. Chem. 2005, 70, 1897.
(5) (a) For the absolute configuration of isosolenopsins, see:
Leclerq, S.; Thirionet, I.; Broeders, F.; Daloze, D.;
Vander Meer, R.; Braeekman, J. C. Tetrahedron 1994, 50,
8465. (b) For leading references on the enantioselective
synthesis of isosolenopsins, see ref. 4.
(6) For leading references on cis-6-methylpipecolic acid, see:
(a) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J. Org.
Chem. 1999, 64, 1993. (b) Davis, F. A.; Zhang, H.; Lee,
S. H. Org. Lett. 2001, 3, 759. (c) Troin, Y.; Carbonnel, S.
Heterocycles 2002, 57, 1807.
Synlett 2008, No. 18, 2777–2780 © Thieme Stuttgart · New York

2780
J. C. González-Gómez et al.
LETTER
Wilkinson’s catalyst (50 mg, 0.05 mmol) and a solution of
the corresponding enone (1.10 mmol) in EtOH (5.0 mL). A
balloon of H2 was connected to the flask and the reaction
mixture was stirred at r.t. overnight. After changing the
solvent to n-hexane–t-BuOMe (1:1), the resulting
afforded pure products (cis/trans >99:1), having spectral
data identical with those reported in literature.4b
(19) Specific rotations obtained for hydrochlorides 1, 2a, and 2b:
(+)-Dihydropinidine hydrochloride: [a]D20 +14.2 (c 0.66,
EtOH) {Lit.4a [a]D20 +14.1 (c 1.0, EtOH)}.
suspension was filtered through a short pad of Celite to
remove the solid Ph3PO. The organic solution was
(+)-Isosolenopsin hydrochloride: [a]D20 +10.2 (c 0.93,
CHCl3) {Lit.4a [a]D20 +11.1 (c 0.92, CHCl3)\.
concentrated (15 Torr) and the crude aminoketone was
dissolved in MeOH (3 mL) and 4 M HCl in dioxane (1.5 mL)
was added at 0 °C. After 1 h stirring at the same temperature,
solvents were evaporated under vacuum. The residue was
dissolved in citrate–phosphate buffer (1.5 mL) and THF (1.5
mL), adjusting the pH to 5 with 1 M NaOH if necessary. To
this solution was added NaCNBH3 (50 mg, 0.80 mmol) at
0 °C and the mixture was stirred for 3 h at 23 °C. The
reaction mixture was basified with 15% NaOH (10 mL) and
extracted with CH2Cl2 (3 × 20 mL). The organic layer was
washed with brine, dried over K2CO3 and concentrated (15
Torr) to afford the desired piperidines as pale yellow oils.
The corresponding hydrochlorides were crystallized using
ethereal HCl and recrystallization from EtOH–EtOAc (1:3)
(+)-Isosolenopsin A hydrochloride: [a]D20 +11.0 (c 1.00,
CHCl3) {Lit.4a [a]D20 +10.0 (c 1.17, CHCl3)}.
(20) The procedure was adapted from: Larcheveque, M.;
Haddad, M. Tetrahedron: Asymmetry 1999, 10, 4231.
(21) For selected examples, see: (a) Mannaioni, G.; Alesiani, M.;
Carla, V.; Natalini, B.; Marinozi, M.; Pelliciari, R.; Moroni,
F. Eur. J. Pharmacol. 1994, 251, 201. (b) Skiles, J. W.;
Giannousis, P. P.; Fales, K. R. Bioorg. Med. Chem. Lett.
1996, 6, 963. (c) Ornstein, P. L.; Schoepp, D. D.; Arnold,
M. B.; Jones, N. D.; Deeter, J. B.; Lodge, D.; Leander, J. D.
J. Med. Chem. 1992, 35, 3111. (d) For a recent review
concerning pipecolic acids, see: Kadouri-Puchot, C.;
Comesse, S. Amino Acids 2005, 29, 101.
Synlett 2008, No. 18, 2777–2780 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.