Stereoselective synthesis of 2,6-cis-and 2,6-trans-piperidines through organocatalytic aza-Michael reactions: A facile synthesis of (+)-myrtine and (-)-epimyrtine

Article abstract of DOI:10.1021/ol103064f

Both 2,6-cis-and 2,6-trans-piperidines were prepared from common substrates through organocatalytic aza-Michael reactions promoted by the gem-disubstituent effect in conjunction with dithiane coupling reactions. The organocatalytic aza-Michael reaction en

Full text of DOI:10.1021/ol103064f

ORGANIC
LETTERS
2011
Vol. 13, No. 4
796–799
Stereoselective Synthesis of 2,6-cis- and
2,6-trans-Piperidines through
Organocatalytic Aza-Michael Reactions:
A Facile Synthesis of (þ)-Myrtine
and (-)-Epimyrtine
Yongcheng Ying, Hyoungsu Kim, and Jiyong Hong*
Department of Chemistry, Duke University, Durham, North Carolina 27708,
United States
jiyong.hong@duke.edu
Received December 17, 2010
ABSTRACT
Both 2,6-cis- and 2,6-trans-piperidines were prepared from common substrates through organocatalytic aza-Michael reactions promoted by the
gem-disubstituent effect in conjunction with dithiane coupling reactions. The organocatalytic aza-Michael reaction enabled a facile synthesis of
(þ)-myrtine and (-)-epimyrtine from a common substrate.
Structurally complex piperidines are found in a wide
range of biologically interesting natural products. In par-
ticular, 2,6-disubstituted piperidines have attracted con-
siderable interest because of their therapeutic potential.1
Although an increasing amount of interest has focused on
the generation of 2,6-disubstituted piperidines,2,3 there are
few methods that enable the synthesis of both 2,6-cis- and
2,6-trans-piperidines from a common substrate. More-
over, it is surprising that the organocatalytic aza-Michael
reaction has rarely been used for the stereoselective synthe-
sis of piperidines.4,5
(3) For recent examples of the synthesis of 2,6-disubstituted piper-
idines, see: (a) Gnamm, C.; Krauter, C. M.; Broedner, K.; Helmchen, G.
Chem. Eur. J. 2009, 15, 2050–2054. (b) Gnamm, C.; Broedner, K.;
Krauter, C. M.; Helmchen, G. Chem. Eur. J. 2009, 15, 10514–10532.
(c) Kumar, R. S. C.; Sreedhar, E.; Reddy, V. G.; Babu, K. S.; Rao, J. M.
Tetrahedron: Asymmetry 2009, 20, 1160–1163. (d) Kumar, R. S. C.;
Reddy, G. V.; Babu, K. S.; Rao, J. M. Chem. Lett. 2009, 38, 564–565. (e)
(1) (a) Struntz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.;
Academic: New York, 1985; Vol. 26, pp 89-193. (b) Schneider, M. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S.W., Ed.;
Pergamon: Oxford, 1996; Vol. 10, pp 155-299.
(2) For reviews on the synthesis of 2,6-disubstituted piperidines, see:
(a) Weintraub, J. S.; Sabol, P. M.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953–2989. (b) Buffat, M. G. P. Tetrahedron 2004,
60, 1701–1729. (c) Cossy, J. Chem. Rec. 2005, 5, 70–80.
ꢀ
Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond,
S.; Cossy, J. Org. Lett. 2010, 12, 1808–1811.
r
10.1021/ol103064f
Published on Web 01/20/2011
2011 American Chemical Society

Herein, we report the stereoselective synthesis of both
2,6-cis- and 2,6-trans-piperidines from common substrates
through the organocatalytic aza-Michael reaction pro-
moted by the gem-disubstituent effect and its application
to a facile synthesis of (þ)-myrtine and (-)-epimyrtine.
with pyrrolidine TFA (Scheme 1). As expected, the iminium
3
activation of 4 dramatically promoted the aza-Michael reac-
tion to successfully provide the desired 2,6-cis-piperidine 5.8
However, the stereoselectivity of the substrate-controlled aza-
Michael reaction was modest (5:6 = 4:1).
Scheme 2. Organocatalytic Aza-Michael Reactions for the
Synthesis of 2,6-cis- and 2,6-trans-Piperidines
Scheme 1. Synthesis of 2,6-cis-Piperidine 5 through an Intra-
molecular Aza-Michael Reaction
To test the feasibility of the tandem allylic oxidation/
aza-Michael reaction6 in the synthesis of 2,6-disubstituted
piperidines, we prepared substrate (Z)-3 by coupling7
allyl alcohol (Z)-16 with the readily available Ts-protected
chiral aziridine 2 and subjected it to MnO2-oxidation con-
ditions (Scheme 1). However, due to the poor nucleophilicity
of sulfonamide 4, the tandem allylic oxidation/aza-Michael
reaction of (Z)-3 in the presence of MnO2 failed to provide
the desired 2,6-cis-piperidine 5. Instead, it resulted in the
exclusive formation of the intermediate (Z)-enal 4 (80%).
We hypothesized that the activation of the conjugate
acceptor would help overcome the poor nucleophilicity of
4 in the aza-Michael reaction. To test this hypothesis, we
converted4 tothe corresponding iminium ion bytreatment
To further improve the stereoselectivity of the aza-Michael
reaction, we decided to test chiral organocatalysts.4,5,9 When
(R)-I10 or (R)-II10a was employed (Scheme 2), the desired 2,
6-cis-piperidine 5 was obtained with good stereoselectivity
(dr=11:1).11 The catalyst (2R,5R)-III12 also provided 5, but
in modest stereoselectivity (dr=4:1). When (S)-Iwas used for
the aza-Michael reaction of 4, the 2,6-trans-piperidine 6 was
obtained as the major diastereomer (dr=3:1), demonstrating
that the synthesis of both 2,6-cis- and 2,6-trans-piperidines
could be achieved from a common substrate through the
organocatalytic aza-Michael reactions.13 To the best of our
(9) For recent examples of organocatalytic aza-Michael reaction, see:
(a) Uria, U.; Vicario, J. L.; Badia, D.; Carrillo, L. Chem. Commun. 2007,
2509–2511. (b) Perdicchia, D.; Jørgensen, K. A. J. Org. Chem. 2007, 72,
3565–3568. (c) Li, H.; Zu, L.; Xie, H.; Wang, J.; Wang, W. Chem.
Commun. 2008, 5636–5638. (d) Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.;
Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.-Y.; Liu,
P.; Zhou, J. Org. Lett. 2009, 11, 1999–2002. (e) Enders, D.; Wang, C.;
Raabe, G. Synthesis 2009, 4119–4124. (f) Lv, J.; Wu, H.; Wang, Y. Eur.
J. Org. Chem. 2010, 11, 2073–2083.
(10) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794–797. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215.
(11) A variety of solvents were tested to further optimize the reaction
conditions, and CH2Cl2 proved to be the most effective for the reaction
(see the Supporting Information for details).
(4) For a review on the organocatalytic aza-Michael reaction, see:
Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058–
11076.
(5) For examples of the synthesis of monosubstituted or benzofused
piperidines by the organocatalytic aza-Michael reaction, see: (a) Takasu,
K.; Maiti, S.; Ihara, M. Heterocycles 2003, 59, 51–55. (b) Fustero, S.;
ꢀ
ꢀ
ꢀ
Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo, C. Org. Lett. 2007, 9,
5283–5286. (c) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.;
Carter, R. G. J. Org. Chem. 2008, 73, 5155–5158. (d) Fustero, S.;
Moscardo, J.; Jimenez, D.; Perez-Carrion, M. D.; Sanchez-Rosello,
M.; del Pozo, C. Chem. Eur. J. 2008, 14, 9868–9872.
(6) For an analogous tandem allylic oxidation/oxa-Michael reaction,
see: (a) Kim, H.; Park, Y.; Hong, J. Angew. Chem., Int. Ed. 2009, 48,
7577–7581. (b) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880–2883.
(7) (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2004, 6, 1493–1495. (b)
Smith, A. B., III; Kim, D.-S. Org. Lett. 2005, 7, 3247–3250. (c) Smith,
A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547–2557.
(8) The relative stereochemisry of the major diastereomer of the
reaction was determined to be cis by 2D NMR spectroscopy (see the
Supporting Information for details).
(12) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172–1173.
(13) To assess the effect of protecting groups on stereochemical
outcome, we prepared the corresponding Boc- and Cbz-carbamates of
4 and subjected them to the organocatalytic aza-Michael reaction
conditions. Both (R)-I and (S)-I provided 2,6-cis-piperidines as the
major diastereomer (dr = 2-20:1; see the Supporting Information for
details).
Org. Lett., Vol. 13, No. 4, 2011
797

knowledge, the stereoselective synthesis of both 2,6-cis- and
2,6-trans-piperidines from a common substrate has not been
achieved for intramolecular organocatalytic aza-Michael
reaction, although it has been appeared in a few other
reactions such as Ir-catalyzed allylic substitutions.3a,b
modest to good stereoselectivities (up to 10:1 dr, entries
1-4). However, sterically hindered tertiary amine 8e did not
afford the desired piperidines (Table 1, entry 5). It is
noteworthy that higher stereoselectivities were observed
with (E)-enals compared with the corresponding (Z)-enals.
Table 1. Substrate Scope of the Organocatalytic Aza-Michael
Reaction
entry substrate conditionsa major product (yieldb)
drc
1
2
3
(Z)-8a
(E)-8a
(Z)-8b
(E)-8b
(Z)-8c
(E)-8c
(Z)-8d
(Z)-8e
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
9a (91%)
10a (82%)
9a (93%)
10a (86%)
9b (90%)
10b (75%)
9b (97%)
10b (80%)
9c (78%)
10c (78%)
9c (87%)
10c (79%)
9d (90%)
10d (86%)
NRd
11:1
1:3
Figure 1. Proposed mechanism of cyclization of (E)- and (Z)-
iminium ions.
15:1
1:5
>15:1
1:2
The origin of the higher stereoselectivity with (S)-I rela-
tive to (R)-I can be explained as illustrated in Figure 1. The
(E)-enal forms a “match pair”14 with (S)-I and proceeds
through conformer A to provide the 2,6-cis-piperidine with
excellent stereoselectivity. However, the combination of
(R)-I and (E)-enal produces a “mismatch pair”, which leads
to the formation of multiple competing transition states to
give 2,6-trans-piperidine with lower stereoselectivity (con-
former D). The reason for the higher stereoselectivity with
(E)-enals relative to (Z)-enals can be rationalized on the
basis that while the (Z)-iminium ion intermediates undergo
a cyclization to provide the corresponding 2,6-trans-piper-
idine (through conformer B in “match pair”) and 2,6-cis-
piperidine (through conformer C in “mismatch pair”),
competitive and rapid isomerization to the corresponding
(E)-iminium ion intermediates15 could occur to eventually
provide the opposite diastereomers, which results in lower
stereoselectivity relative to (E)-iminium ion intermediates.
We hypothesized that the 1,3-dithiane group would be
critical to overcome the low reactivity of sulfonamides by
promoting an ideal conformation for cyclization through the
gem-disubstituent effect.16 To test this hypothesis, we pre-
pared substrate 11 with no gem-disubstituent effect and
>20:1
1:4
10:1
1:8
12:1
1:10
15:1
1:1
NAe
NAe
4
5
NRd
a A: (1) MnO2, CH2Cl2, 25 °C, 3 h, filtration; (2) (S)-I BzOH (20
3
mol %), CH2Cl2, 0 °C, 7-45 h. B: (1) MnO2, CH2Cl2, 25 °C, 3 h, filtration;
(2) (R)-I BzOH (20 mol %), CH2Cl2, 0 °C, 9-67 h. b Combined yield of the
3
isolated 2,6-cis- and 2,6-trans-piperidines. c The diastereomeric ratio (2,6-cis-
piperidine:2,6-trans-piperidine) was determined by integration of the 1H
NMR spectrum of the crude product. d No reaction. e Not applicable.
To investigate the scope and stereochemical outcome of
the organocatalytic aza-Michael reaction with respect to
substituents at the C2 position, we prepared sulfonamides
8a-e by coupling 1 with the commercially or readily avail-
able chiral aziridines 7a-e and subjected them to the allylic
oxidation/organocatalytic aza-Michael reaction (Table 1).
We were pleased to find that the aza-Michael reaction of
8a-din the presence of (S)-Iproceeded smoothly to provide
the corresponding 2,6-cis-piperidines 9a-d with good to
excellent stereoselectivities (up to 20:1 dr, entries 1-4). In
addition, when (R)-I was used for the aza-Michael reaction
of 8a-d, 2,6-trans-piperidines 10a-d were obtained with
(14) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–30.
(15) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32–33.
(16) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
798
Org. Lett., Vol. 13, No. 4, 2011

Scheme 3. gem-Disubstituent Effect on Stereoselectivity and
Reaction Rate
Scheme 4. Synthesis of (-)-Epimyrtine and (þ)-Myrtine
subjected it to the reaction conditions (Scheme 3). Although
the organcatalytic aza-Michael reaction of 11 in the presence
of (R)-I provided 2,6-cis-piperidine 12 with good stereo-
selectivity (dr = 11:1), the yield was poor (<15%). The
organocatalytic aza-Michael reaction of 11 in the presence of
(S)-I failed to provide the corresponding 2,6-trans-piperi-
dine; instead, decomposition of 11 was observed. These data
clearly demonstrate that the gem-disubstituent effect by the
1,3-dithiane group is critical to overcoming the poor nucleo-
philicity of sulfonamides and improving the yield.
To demonstrate the versatility of the organocatalytic
aza-Michael reactions for the stereoselective synthesis of
2,6-disubstituted piperidines, we embarked on the facile
synthesis of (-)-epimyrtine (16) and (þ)-myrtine (18)
(Scheme 4).17,18 We envisioned that both 2,6-cis- and 2,6-
trans-piperidines embedded in 16 and 18, respectively,
could be constructed from a common substrate using the
organocatalytic aza-Michael reactions.
Final deprotection of 1,3-dithiane group in 15 in the
presence of bis(trifluoroacetoxy)iodo benzene19 completed
the synthesis of (-)-epimyrtine (16).
Starting from aninseparable mixture of 10b and 9b(4:1),
Still-Gennariolefination20 followed bya separation of the
resulting R,β-unsaturated esters provided (Z)-R,β-unsatu-
rated ester 17. Compound17was convertedto(þ)-myrtine
(18) following the procedures described above.
In summary, the organocatalytic aza-Michael reaction
was explored for the stereoselective synthesis of 2,6-disub-
stituted piperidines. The organocatalytic aza-Michael re-
actions allowed the synthesis of both 2,6-cis- and 2,6-trans-
piperidines from the common substrates. The reaction pro-
ceeded with modest to excellent stereoselectivities (up to 20:1
dr) and yields. The 1,3-dithiane group allowed for rapid
access to substrates and promoted the intramolecular aza-
Michael reaction via the gem-disubstituent effect. We also
demonstrated the utility of the combination of the organo-
catalytic aza-Michael reaction and the dithiane coupling
reaction in the concise synthesis of (-)-epimyrtine (16)
and (þ)-myrtine (18) from the common intermediate. This
synthetic method would be broadly applicable to the effi-
cient synthesis of a diverse set of bioactive natural products
with 2,6-disubstituted piperidines.
Witting reaction of aldehyde 9b with methyl (triphenyl-
phosphoranylidene)acetate followed by dissolving metal
reduction of the resulting (E)-R,β-unsaturated ester 13
afforded ester 14 with accompanying deprotection of the
Ts group. LiAlH4-reduction, mesylation, and subsequent
intramolecular N-alkylation provided quinolizidine 15.
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Acknowledgment. This work was supported by Duke
University. We are grateful to the NCBC (Grant No. 2008-
IDG-1010) for funding of NMR instrumentation.
Supporting Information Available. General experimen-
tal procedures including spectroscopic and analytical
data along with copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290. (b)
Fleming, F. F.; Funk, L.; Altundas, R.; Tu, Y. J. Org. Chem. 2001, 66,
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