Enantioselective synthesis of lobeline via nonenzymatic desymmetrization

Article abstract of DOI:10.1021/ol071064i

Lobeline has been prepared in enantiopure form via desymmetrization of lobelanidine with use of BTM, a nonenzymatic enantioselective acyl transfer catalyst.

Full text of DOI:10.1021/ol071064i

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3237-3240
Enantioselective Synthesis of Lobeline
via Nonenzymatic Desymmetrization
Vladimir B. Birman,* Hui Jiang, and Ximin Li
Department of Chemistry, Washington UniVersity, Campus Box 1134,
One Brookings DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received May 7, 2007
ABSTRACT
Lobeline has been prepared in enantiopure form via desymmetrization of lobelanidine with use of BTM, a nonenzymatic enantioselective acyl
transfer catalyst.
Lobeline 1 (Figure 1) is the major alkaloid and the active
principle of Lobelia inflata, or Indian tobacco, which was
cholinergic receptors is comparable to that of nicotine itself,
despite the absence of any obvious structural resemblance
between the two alkaloids. In fact, lobeline mimics many of
the pharmacological effects of nicotine. Recent studies
suggest, however, that it may also act as a nicotinic antagonist
and some of its effects may be mediated by noncholinergic
pathways.2 It is noteworthy that lobeline’s symmetrical
natural congeners, lobelanine 2 and lobelanidine 3, and “one-
arm” analogues, sedamine 4 and sedaminone 6, are far less
biologically active.4 So far, pharmacological study of lo-
beline’s unnatural analogues has been limited mostly to its
semisynthetic derivatives.2,4 The availability of a flexible
asymmetric route to lobeline and its analogues would greatly
facilitate further exploration of their pharmacological po-
tential.
The first total syntheses of Lobelia alkaloidssracemic
lobeline 1, lobelanine 2, and lobelanidine 3swere achieved
simultaneously by Wieland5 and Scheuing6 in 1929. Subse-
quently, the elegant biomimetic approach of Scho¨pf in 1935
provided lobelanine 2 in one step.7 In 1959, Parker reported
another synthesis of this compound.8 Surprisingly, lobeline
Figure 1. Lobeline and related alkaloids.
among the most widely prescribed drugs in the 19th century.
Lobeline has been used as an anti-asthmatic, expectorant,
respiratory stimulant, and smoking-cessation aid.1 Recently,
it has received considerable attention as a potential treatment
for psychostimulant abuse.2,3 Lobeline’s affinity for nicotinic
(3) Thayer, A. M. Chem. Eng. News 2006, 84, 21.
(4) Flammia, D.; Dukat, M.; Damaj, M. I.; Martin, B.; Glennon, R. A.
J. Med. Chem. 1999, 42, 3726.
(5) (a) Wieland, H.; Drishaus, I. Annalen 1929, 473, 102. (b) Wieland,
H.; Koschara, W.; Dane, E. Annalen 1929, 473, 118.
(6) Scheuing, G.; Winterhalder, L. Annalen 1929, 473, 135.
(7) Scho¨pf, C.; Lehmann, G. Annalen 1935, 518, 1.
(1) For a review of history, chemistry, and biology of Lobelia alkaloids,
see: Felpin, F.-X.; Lebreton, J. Tetrahedron 2004, 60, 10127.
(2) Dwoskin, L. P.; Crooks, P. A. Biochem. Pharmacol. 2002, 63, 89.
10.1021/ol071064i CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/20/2007

itself has not been prepared by asymmetric total synthesis
until recently. Although its structure suggests desymmetri-
zation9 as the most obvious synthetic strategy, the first two
asymmetric syntheses of lobelinesby Marazano (18 steps)10
and by Lebreton (17 steps)11sdid not take advantage of the
symmetry considerations, opting instead for the stepwise
construction of the three stereocenters. The first desym-
metrization-based route to lobelinesvia enantio- and stereo-
selective catalytic reduction of lobelaninesappeared in the
patent literature in 2006,12 shortly after we initiated the study
described herein.
Enantioselective acyl transfer catalyst BTM 7 recently
developed by our group proved to be highly effective for
the kinetic resolution of secondary benzylic alcohols.13
Desymmetrization of the meso-diol lobelanidine 3 (Scheme
1) presented an irresistible opportunity to apply BTM to the
Table 1. Acylation of Model Substratesa
catalyst
loading
(mol %)
temp
(°C)
%
convn
time
(h)
entry
substrate
s
1
2
9
9
rt
0
<1
51
50
50
50
44
19
50
52
54
50
49
48
8
2.9
12
40
5.5
10.5
0.73
0.83
3.5
3.7
7
8
93
3
4
5
6
7
8
10
10
10
10
10
4
rt
0
-20
0
-20
rt
8
8
8.2
ND
9
4
4
5
5
8
8
0
-20
rt
29
50
10
11
12
Scheme 1. Proposed Desymmetrization of Lobelanidine via
Enantioselective Acylation
8
0
4.6
a Conditions: 0.25 M substrate, (R)-7, 0.75 equiv of (EtCO)2O, 0.75
equiv of i-Pr2NEt, CDCl3.
(Table 1, entries 4 and 6). Further lowering the reaction
temperature to -20 °C led to greatly diminished reaction
rates of both the uncatalyzed and the catalyzed acylations
(Table 1, entries 5 and 7). The rapid uncatalyzed reaction of
10 was attributed to the strong hydrogen bond between the
hydroxyl and the dimethylamino group, which effectively
increased the nucleophilicity of the former.14
Despite this discouraging first result, we decided to
examine the enantioselective acylation of a more precise
model substrate: sedamine 4 having the same relative
configuration as lobelanidine 3. The short sequence shown
in Scheme 315-18 provided us with racemic sedamine (()-4
as well as its naturally occurring epimer allo-sedamine (()-
5.19
synthesis of natural products. Despite the simplicity of the
proposed synthetic scheme, there was one potential prob-
lem: since none of the substrates employed in our previous
studies contained basic functionality, we did not know
whether the tertiary amino group present in lobelanidine
would be compatible with the enantioselective acylation.
An experiment with the simplest model substrate 10
confirmed our misgivings. In contrast to the structurally
similar alcohol 9 lacking the basic amine moiety, 10 was
rapidly acylated with propionic anhydride in the absence of
any catalyst at room temperature (Scheme 2; Table 1, entries
Both (()-sedamine 4 and (()-allo-sedamine 5 underwent
rapid uncatalyzed acylation (entries 8 and 11). To our delight,
however, the kinetic resolution of sedamine 4 proceeded with
(8) Parker, W.; Raphael, R. A.; Wilkinson, D. I. J. Chem. Soc. 1959,
2433.
(9) (a) Rovis, T. In New Frontiers in Asymmetric Catalysis; Mikami,
K., Lautens, M., Eds.; Wiley: Hoboken, NJ, 2007; 275-311. (b) Garcia-
Urdiales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313.
(10) Compere, D.; Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64,
4528
Scheme 2. Influence of an Amino Group on the Rate of
Uncatalyzed Acylation
(11) Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192.
(12) Klingler, F.-D.; Sobotta, R. (Boehringer Ingelheim) US 2006014791.
(13) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351.
(14) A similar effect was recently utilized in the design of asymmetric
organocatalysts: (a) Wayman, K. A.; Sammakia, T. Org. Lett. 2003, 5,
4105. (b) Notte, G. T.; Sammakia, T.; Steel, P. J. J. Am. Chem. Soc. 2005,
127, 13502.
(15) Solladie-Cavallo, A.; Roje, M.; Isarno, T.; Sunjic, V.; Vinkovic,
V.; Eur. J. Org. Chem. 2000, 6, 1077.
(16) Yu, C.-Y.; Meth-Cohn, O. Tetrahedron Lett. 1999, 40, 6665.
(17) Pilli, R. A.; Dias, L. C. Synth. Commun. 1991, 21, 2213.
(18) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002,
67, 1982.
(19) For a review of syntheses of Sedum alkaloids, see: Bates, R. W.;
Sa-Ei, K. Tetrahedron 2002, 58, 5957.
1 and 3). The low selectivity factor obtained in its kinetic
resolution was tentatively ascribed to the interference from
the background reaction, which was still significant at 0 °C
3238
Org. Lett., Vol. 9, No. 17, 2007

Scheme 3. Synthesis of (()-Sedamine and (()-allo-Sedamine
Table 2. Acylation of Lobelanidine
catalyst
loading
entry (mol %) condna
% 8b
(% ee)
time
% 3b
% 14b
a synthetically useful selectivity factor of 29 (entry 9).
Furthermore, the catalyzed acylation of 4 proved to be much
more rapid than that of any previously studied alcohols.
Therefore, we were able to lower the temperature to -20
°C and improve the enantioselectivity even further (entry
10). Clearly, the presence of the amino group accelerated
both the catalyzed and the uncatalyzed acylations to com-
parable extents in this case. At the same time, the catalyzed
acylation of allo-sedamine 5 produced a rather disappointing
result (entry 12), indicating that the influence of the amino
group is strongly affected by its spatial orientation.
Encouraged by the success in the kinetic resolution of
sedamine 4, we initiated the asymmetric synthesis of (-)-
lobeline 1. Preparation of lobelanine 2 was accomplished
by using the classical biomimetic Mannich reaction of
glutaraldehyde, methylamine hydrochloride, and benzoyl-
acetic acid developed by Scho¨pf and Lehmann7 (Scheme 4).
Lobelanine hydrochloride was obtained in 45% (unopti-
mized) yield as an 85/15 mixture of cis/trans isomers (by
1H NMR). Borohydride reduction of the mixture afforded
an 85/15 mixture of diastereomeric diols, from which the
major isomer, lobelanidine 3, was efficiently isolated in pure
form by recrystallization. The high stereoselectivity observed
in the reduction of each of the diastereomers of lobelanine
is in contrast to the reduction of sedaminone 6 with NaBH4
reported to give a 1:1 mixture of 4 and 5.15 We also obtained
lobelanidine as the major product of borohydride reduction
of commercial (-)-lobeline hydrochloride.20
1
2
3
4
5
6e
7
8
A
A
A
B
C
D
A
A
60 min 57
60 min 38
60 min 26
60 min 21
42
58 (89)
1
4
3
3
8d
e4
NDc
NDc
10
20
20
20
20
71 (>99)
76 (>99)
2 d
NDc 92d (>99)
2 d
8d
99
85
88d (>99)
1
1 min
1 min
20
15 (91)
a Conditions: (A) 1.0 equiv of (EtCO)2O, 1.0 equiv of i-Pr2NEt; (B)
1.0 equiv of (EtCO)2O, no base added; (C) 1.1 equiv of (EtCO)2O, no base
added; (D) 1.0 equiv of (EtCO)2O, 1.0 equiv of i-Pr2NEt. b Yields were
estimated by 1H NMR unless stated otherwise. c Not detected. d Isolated
yields are given. e (R)-BTM was used resulting in the opposite enantiomer
of 8a.
slower than the first one (cf. entry 1, Table 2). In fact,
addition of the second equivalent of propionic anhydride led
to only slow conversion of 8 to 14, despite the obvious
similarity of the monoester 8 to sedamine 4, which is rapidly
acylated under similar conditions (vide supra).
Desymmetrization of lobelanidine was examined next. We
were pleased to obtain high enantiomeric excess (89%) at
room temperature using 10 mol % of (S)-BTM, which is
equivalent to 5 mol % in kinetic resolutions (Table 2, entry
2). At 20 mol % catalyst loading, the monoester product was
enantiomerically pure within the limits of detection by HPLC
(entry 3). In the absence of Hu¨nig’s base, the reaction was
found to proceed with essentially the same rate and enan-
tioselectivity (entry 4). Conducting desymmetrization of 3
for 2 days, 8 was isolated in an excellent yield and
enantiopurity, in addition to small amounts of diester 14
(entry 5). Similar results were produced in the presence or
absence of Hu¨nig’s base (cf. entries 5 and 6).
Uncatalyzed acylation of lobelanidine 3 with 1 equiv of
propionic anhydride at room temperature rapidly gave rise
to the monoester (8), with only negligible diester formation
(14), which indicated that the second acylation step was much
The high ee of monoester 8 and the low yield of diester
14 obtained in the above experiments seemed surprising at
first glance, given the significant rate of the background
reaction. Thus, an additional control study was carried out.21
By stopping the reactions at low conversions, we estimated
the initial rate of the reaction catalyzed by 20 mol % BTM
to be ca. 15 times higher than that of the background reaction
(entries 7 and 8). Furthermore, the ee of 8 was found to
increase during the first hour of the reaction (cf. entries 8
and 3) indicating that the “wrong” (R,S)-enantiomer of 8
produced by the background reaction was consumed by the
BTM-catalyzed acylation to the diester. Finally, we estab-
Scheme 4. Preparation of Lobelanidine 3
Org. Lett., Vol. 9, No. 17, 2007
3239

lished that (S,R)-monoester 8 was rapidly acylated in the
presence of 20 mol % of (R)-BTM, but did not undergo any
appreciable reaction in its absence. These additional data lend
support to the overall scheme of the desymmetrization
processs depicted below (Scheme 5) and account, within
experimental error, for its surprising efficiency.
Scheme 6. Preparation of (-)-Lobeline
enantiomer (+)-lobeline was obtained by using (R)-BTM in
the key desymmetrization step (Table 2, entry 6).
Scheme 5. Catalyzed vs Background Acylationa
In conclusion, we have achieved a concise asymmetric
synthesis of (-)- and (+)-lobeline via desymmetrization of
lobelanidine. The synthetic route is expected to be suitable
for the preparation of unnatural lobeline analogues in
nonracemic form.
a Relative order of reaction rates: kBTM(S1) > kbg(S1) ) kbg(R1)
≈
kBTM(S2) > kBTM(R2) ≈ kbg(S2) ) kbg(R2) (kBTM ) rate of catalyzed
acylation; kbg ) rate of background acylation).
Acknowledgment. The authors thank Ms. Erica L. Flor
(Rice University) for her contributions to the early phase of
this project. The financial support of this study by NIGMS
(NIH R01 GM072682) is gratefully acknowledged. Mass
spectrometry was provided by the Washington University
Mass Spectrometry Resource, an NIH Research Resource
(Grant No. P41RR0954).
Monoester 8 underwent smooth oxidation with the Jones
reagent affording lobeline propionate 15 (Scheme 6). Trans-
esterification of the crude 15 with methanol in the presence
of HCl was chosen for its deprotection due to the known
facile epimerization of lobeline base.10 (-)-Lobeline hydro-
chloride was obtained in 71% yield after recrystallization.
Its spectral data and optical rotation matched those of a
commercial sample. In the same manner, the unnatural
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Reduction of lobelanine and lobeline with LiAlH4 was reported to
give lower selectivities: Ebnother, A. HelV. Chim. Acta 1958, 41, 386.
(21) See the Supporting Information for details.
OL071064I
3240
Org. Lett., Vol. 9, No. 17, 2007