Biomimetic organocatalytic asymmetric synthesis of 2-substituted piperidine-type alkaloids and their analogues

Article abstract of DOI:10.1021/ol2017406

Natural substances such as pelletierine and its analogues have been prepared in up to 97% ee and good yield by a protective-group-free, biomimetic approach. Usage of benzonitrile or acetonitrile as solvents effectively prevents product racemization.

Full text of DOI:10.1021/ol2017406

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4546–4549
Biomimetic Organocatalytic Asymmetric
Synthesis of 2-Substituted Piperidine-
Type Alkaloids and Their Analogues
Mattia R. Monaco, Polyssena Renzi, Daniele M. Scarpino Schietroma,
and Marco Bella*
Dipartimento di Chimica, “Sapienza” University of Roma and Istituto di Chimica
Biomolecolare del CNR, P.le Aldo Moro 5, 00185 Roma, Italy
Marco.Bella@uniroma1.it
Received June 28, 2011
ABSTRACT
Natural substances such as pelletierine and its analogues have been prepared in up to 97% ee and good yield by a protective-group-free,
biomimetic approach. Usage of benzonitrile or acetonitrile as solvents effectively prevents product racemization.
Six-membered ring nitrogen heterocycle alkaloids are
widespread in nature, and given their useful biological
activity, significant effort has been devoted to their
preparation.1 In particular, (ꢀ)-pelletierine, ent-1a, isolated
in 1878,2 has been a popular target since its first total synthesis
reported in 1961, which confirmed its structure.3a Through
the years, new methodologies have been specifically
ideated to obtain this molecule and its analogues,3bꢀj and
one of the most effective strategies is the asymmetric
lithiation of N-protected heterocycles by means of chiral
amines and their subsequent functionalization with
electrophiles.4aꢀg This procedure requires noncommer-
cially available chiral bases, air- and moisture-sensitive
reagents such as organolithium species, and low tempera-
tures, generally below ꢀ50 °C. Recently, Carter and co-
workers accessed these structures in good enantioselectiv-
ity (up to 95% ee), in six steps and 37% yield starting from
an acyclic precursor5 via an asymmetric organocatalytic
approach. Significantly, the asymmetric preparation of the
core structure 1 would easily give access to a set of natural
substances via N-methylation and/or diastereoselective
partial or complete carbonyl reduction.6
(1) Dewik, P. M. Medicinal Natural Products; Wiley: Chicesterer,
U.K., 1997; Chapter 6. (b) Poupon, E.; Nay, B. Biomimetic Organic
Synthesis; Wiley-VCH: New York, USA, 2011; Chapter 1.
(2) (a) Tanret, C. Compt. Rend. 1878, 86, 1270. (b) Tanret, C. Compt.
Rend. 1880, 90, 695. (R)-(ꢀ)-Pelletierine, ent-1a, and rac-pelletierine,
but not (S)-(þ)-pelletierine 1a, have been isolated from natural sources.
(S)-(þ)-Methyl pelletierine, which biosynthesis derives from (S)-(þ)-1a,
has been found in nature: Chilton, J.; Partridge, M. W. J. Pharm.
Pharmacol. 1950, 2, 784.
Furthermore, chiral nonracemic pelletierine 1a (Figure 1)
could also be the starting material for the asymmetric
(4) Asymmetric lithiation of N-Boc heterocycles: (a) Beng, T. K.;
Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216. (b) Coldham, I.;
Leonori, D. J. Org. Chem. 2010, 75, 4069. Other lithiation of N-Boc
heterocycles: (c) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (d) Hoppe, D.; Hense,
T. Angew. Chem., Int. Ed. 1997, 36, 2282. (e) Whisler, M. C.; MacNeil,
S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
(f) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006,
2607 and references cited therein. (g) Dieter, R. K.; Topping, C. M.;
Kishan, R. C.; Lu, K. J. J. Am. Chem. Soc. 2001, 123, 5132.
(5) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter,
R. G. J. Org. Chem. 2008, 74, 5155.
(3) (a) Gilman, R. E.; Marion, L. Bull. Soc. Chim. Fr. 1961, 1993.
(b) Beyerman, H. C.; Maat, L. Recl. Trav. Chim. Pays-Bas 1963, 82,
1033. (c) Beyerman, H.; Maat, L. Recl. Trav. Chim. Pays-Bas 1965, 84,
385. (d) Beyerman, H. C.; Maat, L.; van Veen, A.; Zweistra, A. Recl.
Trav. Chim. Pays-Bas 1965, 84, 1367. (e) Quick, J.; Oterson, R. Synthesis
1976, 745. (f) Louis, C.; Mill, S.; Mancuso, V.; Hootele, C. Can. J. Chem.
1994, 72, 1347. (g) Takahata, H.; Kubota, M.; Takahashi, S.; Momose,
T. Tetrahedron: Asymmetry 1996, 7, 3047. Asymmetric addition of
alkynes to pyridine derivatives followed by reduction and application
to the synthesis of myrmicarin: (h) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J.
Am. Chem. Soc. 2007, 129, 9300. (i) Snyder, S. A.; Elsohly, A. M.;
Kontes, F. Angew. Chem., Int. Ed. 2010, 50, 9693. Asymmetric synthesis
employing Betti base as the chiral auxiliary:(j) Cheng, G.; Wang, X.; Su,
D.; Liu, H.; Liu, F.; Hu, Y. J. Org. Chem. 2010, 75, 1911.
(6) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192.
r
10.1021/ol2017406
Published on Web 08/04/2011
2011 American Chemical Society

The Mannich addition reaction of acetone and other
ketones to cyclic imines is reported only for two peculiar
substrate types, the 9-tosyl-3,4-dihydro-β-carboline by
Ohsawa and Itoh10aꢀc and, more recently, thiazines and
oxazines as described by Martens.10d The asymmetric
addition of nucleophiles to Δ1-piperideines is, to the best
of our knowledge, unreported.
We prepared Δ1-piperideine 5a (via piperidine N-chlor-
ination and base-mediated HCl elimination)11 and em-
ployed this electrophile in the reaction with carbonyl
compounds 9aꢀb (see Table 1, entries 1ꢀ2).
Figure 1. Structure of some six-membered ring alkaloids.
preparation of more complex alkaloid-type natural sub-
stances, such as rac-vertine, recently synthesized in 11 steps
Δ1-Piperideine 5a, such as other cyclic imines presented
later in this work, exists in solution as a complex diaster-
eoisomeric mixture of a trimeric (major component) and
monomeric form.11a However, during the reaction with
nucleophiles, the latter component is constantly removed
from the equilibrium, and the final reaction outcome is
consistent with if only the monomer would be present. No
background reaction was observed when acetone 9a
(pKa[DMSO] = 26.5) was employed as the nucleophile
7a
€
from rac-pelletierine by Kunding and co-workers or a
citrinadin B analog by Sorensen and co-workers.7b
The biosynthesis of these natural substances derives
from the metabolism of L-lysine 3, which is decarboxylated
to the achiral diamine cadaverine 4, cyclized to the unsatu-
rated heterocycle Δ1-piperideine 5a and then attacked by
acylacetyl-CoA 6. Subsequently, the side chain undergoes
further elaboration, to afford the simplest members of this
alkaloid family, pelletierine 1a or its superior homologues
1bꢀc. Reduction of the carbonyl function and N-methyla-
tion give a variety of naturally occurring molecules such as
compounds 2 or 8 (see Scheme 1).1b
(Table 1, entry 1). Ethyl acetoacetate 9b (pKa[DMSO]
=
14.2),12,13 which upon hydrolysis and decarboxylation
could lead to a one-pot, two-step synthesis of the alkaloid
pelletierine 1a, readily reacted with Δ1-piperideine 5a in the
absence of any additive (entry 2) because the unsaturated
heterocycle could itself act as the catalyst, suggesting that
the development of a tertiary amine asymmetric approach
to this peculiar reaction could be, at the state-of-the-art,
unfeasible.
Scheme 1. Biosynthesis of 2-Substituted Six-Membered Nitro-
gen Heterocyclic Natural Substances 1, 2, and 8
The reaction was therefore run with acetone 9a via
enamine activation14 employing organocatalysts IꢀV. In
particular, with TMS ether I15 none of the desired com-
pound could be obtained(entry 3). Onlycatalysts bearing a
deprotonable functional group such as II16ꢀV were effec-
tive in this transformation, leading to complete conversion
of Δ1-piperideine 5a, in moderate yield and with no
stereoselection employing catalyst II (entry 4) and in low
yield and 42% ee with catalyst III (entry 5). (L)-Proline IV
(entry 6) and azetidine V (entry 7) gave satisfactory yields
and good enantioselectivities.17 After aqueous workup, the
1H and 13C NMR spectra of the crude material showed the
formation of (þ)-pelletierine 1a2ꢀ4 with only some minor
Inspired by Nature’s approach, we envisaged that the
organocatalyzed Mannich-type addition reaction8 of acti-
vated ketones to Δ1-piperideine 5a could be the most
straightforward and direct synthesis possible for many of
these molecules, accessing them in a single step, in an
asymmetric way and without the need of protective groups.9
(11) (a) Rouchaud, A.; Braekman, J. C. Eur. J. Org. Chem. 2009,
2666. (b) Darwich, C.; Elkhatib, M.; Steinhauser, G.; Delalu, H. Helv.
Chim. Acta 2009, 92, 98.
(12) Racemic synthesis of pelletierine 1a exploiting this strategy:
ref 3d.
(13) Rouchaud and Braekman recently reported that ethyl acetoace-
tate 9b reacts with the dimer form of 5a to give the racemic skeleton of
tetraponerine-type alkaloids. With our conditions, we only observed the
reaction of monomer 5a with the nucleophile tested; see ref 11a.
(14) Modes of activation in organocatalysis; see: (a) Seayad, J.; List,
B. Org. Biomol. Chem. 2005, 3, 719. (b) List, B. Chem. Commun. 2006,
819. (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138. (d) Bertelsen, S.; Jørgensen, K. A. Chem.
Soc. Rev. 2009, 38, 2178.
(7) (a) Chausset-Boissarie, L.; Arvai, R.; Cumming, G. R.; Besnard,
€
C.; Kundig, E. P. Chem. Commun. 2010, 46, 6264. (b) Chadler, B. D.;
Roland, J. T.; Li, Y.; Sorensen, E. J. Org. Lett. 2010, 12, 2476.
(8) For reviews on the asymmetric organocatalytic Mannich reac-
tions, see: (a) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
(b) Verkade, J. M. M.; Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Ruties,
F. P. J. T. Chem. Soc. Rev. 2008, 37, 29.
(15) O-Silyl ethers of R,R-diarylprolinol as the catalyst; see:
(9) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193.
(a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 118, 7876.
(10) (a) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A.
Org. Lett. 2003, 5, 4301. (b) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata,
K.; Ohsawa, A. Org. Lett. 2006, 8, 1533. (c) Nagata, K.; Ishikawa, H.;
Tanaka, A.; Miyazaki, M.; Kanemitsu, T; Itoh, T. Heterocycles 2010,
81, 1791. (d) Schulz, K.; Ratjen, L.; Martens, J. Tetrahedron 2011, 67,
546.
ꢀ
(16) Longbottom, D. A.; Franckevicius, V.; Kumarn, S.; Oelke, A. J.;
Wascholowski, V.; Ley, S. V. Aldrichimica Acta 2008, 41, 3.
(17) Amino acids IIIꢀIV were employed in the pioneering paper
describing the asymmetric intermolecular aldol reaction: List, B.;
Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395.
Org. Lett., Vol. 13, No. 17, 2011
4547

impurities, but in order to perform HPLC analysis, the
secondary nitrogen moiety was protected in situ (Boc2O)
and the compound was purified by FC affording the
protected amine 10a.18
racemization. We believe that the superior reactivity of
organocatalysts IIꢀV presenting a free carboxyl group or
its isoster, with respect to catalyst I, is due to the deproto-
nation of the enamine 11b by the reagent or the product,
which, as documented recently,19 leads to the more acti-
vated intermediate 11c (Scheme 2, top). The absolute
configuration of 10a was determined by optical rotation
comparison with literature data,5 and the stereochemical
outcome is consistent with a ZimmermanꢀTraxler transi-
tion state (Scheme 2).17
Table 1. Optimization of Conditions for Organocatalytic
Synthesis of N-Boc-pelletierine 10a
Scheme 2. Activation of Enamines via Deprotonation (Top) and
Rationalization of the Stereochemical Outcome of the Reaction
(Bottom)
yield,
ee,
b
c
entrya
catalyst
solvent
T, °C
t
%
%
1d
none
none
I
DCM
rt
24 h
24 h
2 d
2 d
2 d
2 d
2 d
5 d
5 d
7 d
7 d
2 h
NR
95f
NR
60
22
67
65
68
65
45
82
92
ꢀ
ꢀ
2e
DCM
rt
3d
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
n-PrCN
PhCN
DMSO/
H2O g
rt
ꢀ
4d
II
rt
<5
42
79
85
87
87
93
95
76
5d
III
IV
V
rt
6d
rt
7d
rt
8d
IV
V
ꢀ20
ꢀ20
ꢀ20
ꢀ20
rt
9d
10d
11d
12d
IV
IV
IV
We then extended the scope of our reaction to different
combinations of unsaturated cyclic amines and ketones
(Table 2). First, we examined the electrophiles 5bꢀc, in the
reactionwith acetone. The cyclicimine5b, whichpresents a
protected carbonyl functionality, gave results comparable
to Δ1-piperideine 5a (Table 2, entry 1, 94% ee, 56% yield).
The isoquinoline-derived electrophile 5c allowed the pre-
paration of adduct 10c in good yield, but with low stereo-
selectivity (16% ee, entry 2).
a Reactions arerun employing50 mg (0.6 mmol) of Δ1-piperideine 5a,
nucleophile 9aꢀb, 0.85 mL of solvent, and 20 mol % catalyst IꢀV.
b Isolated yield of 9aꢀb determined after purification via FC. c Ee
determined by HPLC on chiral stationary phase, for 10a/hexane/
i-propanol 98.5:1.5, IA Chiralpack þ IB Chiralpack columns, flow 0.9
mL/min. d Acetone, R = Me, 9a, 6 equiv (0.3 mL). e Nucleophile: ethyl
acetoacetate, R = CO2Et, 9b, 2 equiv. f Yield of 1d. g 4 mL of DMSO/
H2O 8:1. rt = room temperature; NR = no reaction. ND = not
determined. See Supporting Information for a full list of conditions
and catalysts tested.
The enhanced reactivity of carbonyl compounds
in these conditions rendered possible extending this reac-
tion to several ketones different from acetone (entries
3ꢀ11).20
After the reaction temperature was lowered to ꢀ20 °C,
N-Boc pelletierine 10a was obtained in very good enantios-
electivity (89ꢀ95% ee, entries 8ꢀ11). The reaction condi-
tions originally developed by Ohsawa and Itoh10aꢀc
(DMSO/H2O, entry 12) for their analogous Mannich
reaction afforded the desired compound in shorter reac-
tion times and good yield; however, in these specific
conditions we observed racemization of the product 1a
(see Supporting Information (SI) for details; Table 3). It is
well-knownthatcompounds suchas1aracemize througha
retro aza-Michael process.1b Nitriles as solvents led to
longer reaction times, but they significantly prevented
These reactions were high yielding at room temperature
but proceeded in poor enantioselectivity (compound 10e,
(19) (a) Bella, M.; Scarpino Schietroma, D. M.; Cusella, P. P.;
Gasperi, T.; Visca, V. Chem. Commun. 2009, 597. (b) Blackmond,
D. G.; Moran, A.; Hughes, M.; Armstrong, A. J. Am. Chem. Soc.
2010, 132, 7598.
(20) Ketones activationin organocatalysis: (a) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701. (b) List, B. Tetrahedron 2002, 58, 5573. (c) Notz,
W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. For
examples of acetophenone or acetone in organocatalysis, see: (d) Yue,
L.; Du, W.; Liu, Y.-K.; Chen, Y.-C. Tetrahedron Lett. 2008, 49, 3881.
(e) Jiang, X.; Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2009, 11,
153. (f) Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2009, 351, 1355.
(g) Liu, K.; Cur, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923. (h) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew.
Chem., Int. Ed. 2010, 49, 9460.
(18) The Boc protection reaction, although necessary for analytical
purposes and compound purification via FC, has a yield e 80% and is
responsible for the moderate overall yield reported in Table 2.
4548
Org. Lett., Vol. 13, No. 17, 2011

8 entry 4a, 71% yield but only 36% ee). The lowering of the
temperature to 4 °C led to excellent enantiomeric excesses,
but at the expense of the yield (see Table 2, entries 3ꢀ11,
low conversion after few days). This dilemma was solved
employing in some cases a higher catalyst loading of the
cheap and widely available (L)-proline IV. For ketones
different from acetone, DMSO/H2O mixtures as solvent
led to better yields but to low enantioselectivity due to
racemization (see SI). With these improved conditions
and the usage of benzonitrile as solvent which pre-
vented racemization, it was finally possible to obtain
in moderate yields but excellent enantioselectivity the
desired adducts. Cyclic ketones such as 9g reacted in high
enantioselectivity (entries 7 and 11) without significant
diastereoselection.
Table 2. Synthesis of Pelletierine Analogues 10bꢀl by the Combina-
tion of Cyclic Imines 5aꢀc and Ketones 9a,cꢀg
IV,
t,
yield,
ee,
c
b
entrya
reagents
product mol % day
%
%
1
9a
9a
9c
9d
5b
5c
5a
5a
10b
10c
10d
10e
20
20
20
20
20
45
20
45
20
45
20
45
45
100
100
20
7
7
56
54
25
71
12
35
22
33
15
49
39
25
72
36
14
37
94
In conclusion, herein we report a new synthetic metho-
dology for the direct and asymmetric introduction of
six-membered heterocycles in ketones. Reactions pro-
ceed in good yield and elevated stereoselectivity em-
ploying as a chiral mediator the cheap organocatalyst
(L)-proline IV. We prepared (þ)-pelletierine 1a in a
single step. We strongly believe that electrophiles 5
could be successfully exploited in several other asym-
metric reactions.
2
3
4
16
7
97
ad
b
7
36
10
30
7
90
c
84
5
6
7
a
9e
9f
5a
5a
5a
10f
88
b
20
10
30
14
7
92
a
10g
10h
92
b
92
ae
b
9g
92/99f
87/94f
86
8
9c
9d
9e
9g
5b
5b
5b
5b
10i
10j
10k
10l
30
30
30
7
9
93
Acknowledgment. Financial support for this work
was provided by “Sapienza” University of Roma
(“Finanziamento di Ateneo” 2009).
10
11
96
g
90/ꢀ
a Reactions are run employing 0.6 mmol of electrophiles 5aꢀc, 6 equiv of
nucleophile 9a,cꢀg, 0.85 mL of PhCN, and catalyst IV. b Isolated yield
of 10bꢀl determined after purification via FC. c Ee determined by HPLC
on chiral stationary phase; see Supporting Information. d Reaction run
at rt. e Reaction run at ꢀ20 °C. f Dr = 1:1 stereochemistry not determined.
g Dr = 2:1, ee of major diastereoisomer; stereochemistry not determined. See
Supporting Information for details.
Supporting Information Available. Characterization of
new compounds and chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 17, 2011
4549