Enantioselective synthesis of (+)(R)- And (-)(S)-nicotine based on Ir-catalysed allylic amination

Article abstract of DOI:10.1039/b508634e

The synthesis of nicotine with enantiomeric excess of >99% ee was accomplished by asymmetric Ir-catalysed allylic amination followed by ring closing metathesis and racemisation-free double bond reduction. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b508634e

View Article Online / Journal Homepage / Table of Contents for this issue
C O M M U N I C A T I O N
Enantioselective synthesis of (+)(R)- and (−)(S)-nicotine based on
Ir-catalysed allylic amination†
Carolin Welter, Rosa M. Moreno, Stephane Streiff and Gu¨nter Helmchen*
Organisch-Chemisches Institut der Universita¨t Heidelberg, Im Neuenheimer Feld 270, D-69120
Heidelberg, Germany. E-mail: g.helmchen@urz.uni-heidelberg.de; Fax: 49 6221 544205;
Tel: 49 6221 8401
Received 20th June 2005, Accepted 1st August 2005
First published as an Advance Article on the web 11th August 2005
The synthesis of nicotine with enantiomeric excess of
>99% ee was accomplished by asymmetric Ir-catalysed
allylic amination followed by ring closing metathesis and
racemisation-free double bond reduction.
kaloids based on domino metathesis sequences starting with
cyclic allylamines, derived inter alia by Pd-catalysed allylic
substitution, have been reported by Blechert et al.3 Evans and
Robinson4 have described syntheses of dihydropyrroles based
on a combination of metathesis and stereospecific Rh-catalyzed
amination of enantiomerically pure allyl carbonates. Lebreton
and co-workers5 have used asymmetric allylboration of pyridine-
3-aldehyde as key step to yield allyl alcohols, which were
transformed into allyl amines serving as intermediates on the
way to tobacco alkaloids.
The Ir-catalysed asymmetric allylic substitution, cf. Scheme 1,
is well suited for the routes described above and offers new op-
portunities, as the precursors of the ring closing metathesis can
be assembled in a single step from simple components. Iridium-
catalysed intermolecular6 and intramolecular7 allylic aminations
of a variety of substrates have been studied intensively over
the past few years. The best results were achieved with allylic
carbonates as substrates and phosphorus amidites8 as chiral
ligands. A particularly active catalyst was obtained by treatment
of a solution of [Ir(COD)Cl]2 (0.02 mmol), L* (0.04 mmol) in
dry THF (0.5 mL) with the base 1,5,7-triazabicyclo-[4.4.0]dec-
5-ene (TBD) (0.08 mmol).7 This procedure was also used here.
In our laboratory, the phosphorus amidites L1–L3 (Fig. 2) are
routinely used as ligands, with a preference for ligand L2, which
was introduced by Alexakis and co-workers9
Nicotine is mainly known in connection with smoking as
an addictive substance. However, nicotine itself and several
analogues (Fig. 1) have shown therapeutic benefits for a number
of deseases caused by nervous system disorders. Examples are
Alzheimer’s and Parkinson’s disease and Tourette’s syndrom.1
Further positive effects of nicotine are pain relief and lowering
of anxiety and depression.
Fig. 1 Tobacco alkaloids.
The remarkable pharmacological profile has aroused interest
in the synthetic chemistry of piperidine and pyrrolidine deriva-
tives related to nicotine.2 As most of the pharmacologically
interesting compounds of these series are chiral, enantio- and
diastereoselectivity are important aspects. We have now devel-
oped new routes on the basis of Ir-catalysed allylic aminations
(Scheme 1), which proceed with unusually high regio- and
enantioselectivity.
Fig. 2 Ligands used in the allylic amination.
The results displayed in Table 1 demonstrate that excellent
results can be achieved with the (3-pyridyl)allyl derivatives.
While selectivities obtained upon use of ligands L1 and L3
are typical for allylic aminations,7a the selectivities induced by
ligand L2 are truly remarkable, for the N-allyl derivative 2a
regioselectivity of >98 : 2 and enantiomeric excess exceeding
99% ee, using either methyl carbonate 1a (entry 3) or tert-butyl
carbonate 1b (entry 8) as starting material. The N-homoallyl
derivative 2b was likewise obtained with excellent selectivity.
The very high level of enantiomeric excess of 99% ee as well as
regioselectity of 99 : 1 was obtained with the tert-butyl carbonate
1b as substrate (entry 11).
Scheme 1 Iridium-catalysed allylic amination of 3-(3-pyridyl)allyl
carbonates (L* = L1, L2 or L3).
Allyl derivatives can often be transformed into heterocycles
by ring closing metathesis (RCM). Elegant syntheses of al-
Further steps towards tobacco alkaloids caused more dif-
ficulties than anticipated. The secondary amines 2 had to
† Electronic supplementary information (ESI) available: preparation of
carbonates 1a and 1b. See http://dx.doi.org/10.1039/b508634e
3 2 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 6 6 – 3 2 6 8
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
Table 1 Iridium-catalyzed allylic aminationa
Reaction
time/d
No
Reactant
Product
Ligand
Yieldb (%)
Ratio b : l isomerc
Ee (%)d
1
2e
3f
4
5
6
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2b
2b
2a
2a
2a
2b
2b
2b
L1
L1
L2
L3
L2
L3
L1
L2
L3
L1
L2
L3
1
1
1.1
3
0.7
4
4
4
3
4
87
78
69
91
68
77
59
69
53
59
70
68
96 : 4
99 : 1
98 : 2
92 : 8
86 : 14
99 : 1
99 : 1
>99 : 1
98 : 2
>99 : 1
99 : 1
>99 : 1
97
96
>99
97
99
95
97
>99
96
92
99
7
8f
9
10
11
12
1
1.7
96
a All reactions were carried out on a 0.5 mmol scale using 2 mol% of [Ir(COD)Cl]2, 4 mol% of ligand and 2 h of activation with TBD (8 mol%).
b Yield of isolated product. c The designations b and l refer to the branched (Scheme 1; 2a,b) and linear (formula not shown in Scheme 1) substitution
products, respectively. d Determined by HPLC {column: Daicel Chiralcel AD–H, eluent: n-hexane/i-PrOH 98 : 2, 250 × 4.6 mm, 5 lm, + guard
cartridge 10 × 4 mm, 5 lm, flow = 0.5 mL min−1), tR[(S)-2a] = 28.8 min, tR[(R)-2a] = 30.9 min, tR[(S)-2b] = 24.8 min, tR[(R)-2b] = 26.9 min}. e The
experiment was carried out with (R,R,R)-L1 as ligand. f These reactions were carried out on a 15 (entry 3) or 25 (entry 8) mmol scale.
be N-protected prior to RCM in order to prevent catalyst
deactivation. Unexpectedly, the reaction of CbzCl with amine 2a
was accompanied by polymerisation. A good yield was obtained
by carrying out the reaction in a suspension of potassium
carbonate in dichloromethane and addition of a polymerisation
inhibitor (5 mol% of 2,6-di-tert-butylbenzene-1,4-diol) to the
reaction mixture.10 The protected amine 3 was obtained in 66–
82% yield.11 RCM with the hydrochloride of 3 using Grubbs’
II catalyst12 was uneventful and yielded the 3,4-dihydropyrrole
derivative 4 in >90% yield. However, the seemingly simple
final reduction steps caused problems. Thus, reaction of 4
with lithium aluminium hydride (LAH) under a variety of
condititions produced mixtures of 3ꢀ,4ꢀ-dehydronicotine and
nicotine (GC/MS). We did not find conditions leading to either
of the pure compounds (Scheme 2).
The route described above was also used to prepare (+)(R)-
nicotine (cf. Table 1, entry 2). The enantiomeric purity (HPLC15)
of the final product 6 was identical to that of the starting material
2a, i.e. racemisation had not occurred in any of the steps.
In conclusion, we have developed a short route to prepare
nicotine of very high enantiomeric purity. The route can
be readily extended to a variety of other tobacco alcaloids,
for example anabasine, and analogs of interest in medicinal
chemistry.
Experimental
General procedure for the allylic amination of carbonates 1
Success with the following procedure requires dry THF (<35 lg
of H2O per mL, Karl Fischer titration). Under argon, a solution
of [Ir(COD)Cl]2 (0.02 mmol) and L* (0.04 mmol) in dry THF
(0.5 mL) was treated with TBD (0.08 mmol). After stirring for
2 h at room temperature the allylic carbonate 1 (1.0 mmol)
was added, and the mixture was stirred for 5 min at rt. Then
the nucleophile (1.1–5 mmol) was added and the mixture was
stirred until TLC indicated complete conversion. The solvent
was removed under reduced pressure and the residue analysed
with respect to the content of branched and linear product by
1H NMR. The pure reaction products were obtained by flash
chromatography.
(S)-Benzyl allyl(1-pyridin-3-ylprop-2-en-1-yl)carbamate (3)
A solution of amine (−)(S)-2a (1.15 g, 6.6 mmol, 99%ee) in dry
dichloromethane (50 mL) was treated with 5 mol% of 2,6-di-tert-
butylbenzene-1,4 diol and cooled to 0 ◦C. Then K2CO3 (1.82 g,
13.2 mmol) and CbzCl (1.46 g, 8.6 mmol) were added. The
mixture was allowed to warm to room temperature and air was
bubbled through for 2 min. After 24 h of stirring saturated aque-
ous NaHCO3 was added and the aqueous layer was extracted
three times with dichloromethane. The combined organic layers
were dried over MgSO4, and the solvent was removed under
reduced pressure. Flash chromatography (petroleum ether–ethyl
acetate 1 : 1) yielded carbamate (S)-3 (1.67 g, 82%) as a pale
yellow oil. 1H NMR (CDCl3, 250 MHz): d 3.72–3.91 (m, 2 H),
4.99–5.05 (m, 2 H), 5.17 (s, 2 H), 5.23 (d, J = 17.2 Hz, 1 H), 5.40
(d, J = 10.3 Hz, 1 H), 5.65–5.76 (m, 2 H), 6.18 (ddd, J = 17.0 Hz,
J = 3.8 Hz, J = 10.4 Hz, 1 H), 7.23–7.34 (m, 6 H), 7.58 (m, 1 H),
8.53–8.56 (m, 2 H). 13C NMR (CDCl3, 62.5 MHz): d 53.3, 60.5,
67.5, 116.2, 119.2, 123.2, 127.8, 128.0, 128.4, 134.2, 134.4, 135.0,
135.2, 136.3, 148.8, 149.4, 155.9. HRMS: m/z (FAB) calc. for
C19H21N2O2 (M + H+) 309.1603, found 309.1618.
Scheme 2 Synthesis of (−)(S)-nicotine (6).
Accordingly, we decided to reduce the double bond first. This
turned out to be another problematic step, in that transition
metal-catalysed hydrogenation is generally prone to induc-
ing epimerisation in an allylic position.13 We had previously
encountered this problem in conjunction with syntheses of
cyclopentanoid Archaea lipids and then solved it by using
diimide reduction.14 Gratifyingly, the reduction of 4 with diimide
generated from TsNHNH2 proceeded in 89% yield. Subsequent
reduction with LAH furnished (−)(S)-nicotine (6) in 95% yield.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 6 6 – 3 2 6 8
3 2 6 7

View Article Online
(S)-Benzyl 2-pyridin-3-yl-2,3-dihydro-1H-pyrrole-1-carboxylate
(4)
The hydrochloride 6·2HCl18 was prepared by treatment of
(S)-6 with an excess of 1 M HCl, concentration in vacuo
and crystallisation from EtOH–Et2O: mp 159–161 ◦C. The
same melting point was displayed by a sample prepared from
commercial (S)-nicotine.
A 1 M solution of HCl in Et2O (3 mL) was added to a solution
of amine (S)-3 (300 mg, 0.97 mmol) in dry Et2O (6 mL). After
10 min the solvent was evaporated, and the colourless, oily
residue was dissolved in dry, degassed CH2Cl2 (13 mL) and the
solution added to a solution of Grubbs’ II catalyst16 (43 mg,
0.05 mmol) in dry, degassed CH2Cl2 (7 mL). The resulting
mixture was heated at reflux under argon. After 4 h, saturated
aqueous NaHCO3 was added. The aqueous layer was extracted
with CH2Cl2 and the combined organic layers were concentrated
in vacuo. The residue was subjected to flash chromatography
(petroleum ether–ethyl acetate 1 : 1) to give (S)-4 (250 mg, 92%)
as a yellow oil. 1H NMR (CDCl3, 250 MHz):17 d 4.26–4.44 (m,
2 H), 5.02 (s, 2 H), 5.53–5.61 (m, 1 H), 5.74–5.83 (m, 1 H), 5.98–
6.04 (m, 1 H), 7.02–7.04 (m, 1 H), 7.18–7.65 (m, 6 H), 8.49–8.59
(m, 2 H). 13C NMR (CDCl3, 62.5 MHz):17 d 53.5, 54.0, 65.4,
65.9, 66.7, 66.9, 123.2, 123.2, 125.5, 125.7, 127.6, 127.7, 127.8,
128.1, 128.3, 129.6, 129.8, 134.2, 134.6, 135.9, 136.0, 136.6,
136.8, 148.5, 148.7, 148.8, 154.1. HRMS: m/z (FAB) calc. for
C17H17N2O2 (M + H+) 281.129, found 281.1317.
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (SFB 623) and by the EC (RTN HPRN-CT-2001-00172).
We thank Dr G. Egri (Reuter Chemischer Apparatebau KG), for
(S)-BINOL and Dr K. Ditrich (BASF AG) for enantiomerically
pure 2-arylethylamines. Successful scale-up experiments were
carried out by Nikolaus Meyerbro¨ker and Markus Krauter.
Notes and references
1 J. A. Rosecrans, Chem. Ind. (London), 1998, 525; M. W. Holladay,
M. J. Dart and J. K. Lynch, J. Med. Chem., 1997, 40, 4769.
2 Reviews: F.-X. Felpin and A. Lebreton, Eur. J. Org. Chem., 2003,
3693; I. R. Baxendale, G. Brusotti, M. Matsuoka and S. V. Ley,
J. Chem. Soc., Perkin Trans. 1, 2002, 143.
3 R. Stragies and S. Blechert, J. Am. Chem. Soc., 2000, 122, 9584; H.
Ovaa, R. Strategies, G. A. van der Marel, J. H. van Boom and S.
Blechert, Chem. Commun., 2000, 1501.
(S)-3-(1-Methyl-2,3-dihydro-1H-pyrrol-2-yl)pyridine (5)
4 P. A. Evans and J. E. Robinson, Org. Lett., 1999, 1, 1929.
5 F.-X. Felpin, S. Girard, G. Vo-Thanh, R. J. Robins, J. Villie´ras and J.
Lebreton, J. Org. Chem., 2001, 66, 6305.
6 G. Lipowsky and G. Helmchen, Chem. Commun, 2004, 116; C. A.
Kiener, C. Shu, C. Incarvito and J. F. Hartwig, J. Am. Chem.
Soc, 2003, 125, 14 272; H. Miyabe, K. Yoshida, Y. Kobayashi, A.
Matsumura and Y. Takemoto, Synlett, 2003, 1031; R. Takeuchi,
Synlett, 2002, 1954; K. Tissot-Croset, D. Polet and A. Alexakis,
Angew. Chem., Int. Ed., 2004, 43, 2426; A. Leitner, C. Shu and J. F.
Hartwig, Proc. Natl. Acad. Sci., 2004, 101, 5830.
7 (a) C. Welter, A. Dahnz, B. Brunner, S. Streiff, P. Du¨bon and G.
Helmchen, Org. Lett, 2005, 7, 1239; (b) C. Welter, O. Koch, G.
Lipowsky and G. Helmchen, Chem. Commun., 2004, 896.
8 B. Feringa, Acc. Chem. Res., 2000, 33, 346.
9 K. Tissot-Croset, D. Polet, S. Gille, C. Hawner and A. Alexakis,
Synthesis, 2004, 2586.
A solution of (S)-4 (118 mg, 0.42 mmol) and TsNHNH2
(3.91 g, 21 mmol) in dimethylformamide (8 mL) was stirred
at 96 ◦C. After 30 min a solution of sodium acetate (3.44 g,
42 mmol) in water (24 mL) was added slowly. After 20 h
the reaction mixture was cooled to room temperature. Water
was added and the mixture was extracted four times with
ethyl acetate. The combined organic layers were dried over
MgSO4 and the solvents were removed under reduced pressure.
The residue was subjected to flash chromatography (petroleum
ether–ethyl acetate 2 : 1) to give (S)-5 (60 mg, 89%) as a colourless
1
oil. H NMR (CDCl3, 250 MHz): d 1.85–2.01 (m, 3 H), 2.39–
2.45 (m, 1 H), 3.50–3.71 (m, 2 H), 5.02–5.13 (m, 3 H), 6.91–7.00
(m, 1 H), 7.23–7.48 (m, 6 H), 7.81 (d, J = 4.8 Hz, 2 H). 13C
NMR (CDCl3, 62.5 MHz): d 21.4, 35.1, 36.8, 60.5, 68.0, 125.2,
127.2, 128.6, 128.9, 129.3, 129.5, 130.5, 135.6, 148.0, 148.5.
10 It is important to note that the reaction must be run in the presence
of dry air; under inert gas the inhibitor is not active.
11 In contrast, the formation of the N-formyl derivative of 2a by reaction
with DCC and formic acid proceeded without polymerisation in 85%
yield.
(S)-3-(1-Methylpyrrolidine-2-yl)pyridine, (S)-nicotine (6)
Under an atmosphere of argon, a solution of (S)-5 (87 mg,
0.54 mmol) in dry THF (6 mL) was added dropwise with a
syringe to a cold (0 ◦C) suspension of lithium aluminium hydride
(1.09 g, 28.7 mmol) in dry diethyl ether (17 mL). The mixture
was stirred for 4 h at room temperature, then cooled to 0 ◦C and
dropwise treated with water (1.1 mL), NaOH solution (1.1 mL,
15% in water) and again water (3.3 mL). The mixture was
stirred until the precipitate could be conveniently filtered off. The
filtrate was concentrated under reduced pressure. The residue
was subjected to flash chromatography (silica, CH2Cl2–MeOH
95 : 5) to give 6 (79 mg, 90%) as colourless oil. [a]2D0 = −127 (c 1.0,
EtOH). 1H NMR (CDCl3, 250 MHz): d 1.68–1.92 (m, 4 H), 2.20
(s, 3 H), 2.32–2.45 (m, 1 H), 3.10 (t, J = 9.0 Hz, 1 H), 3.27 (dt,
J = 2.4 Hz, J = 11.2 Hz, 1 H), 7.25–7.30 (m, 1 H), 7.67–7.73 (m,
1 H), 8.51–8.55 (m, 2 H). 13C NMR (CDCl3, 62.5 MHz): d 22.6,
35.2, 40.4, 57.0, 68.9, 123.6, 134.9, 138.6, 148.7, 149.5. HRMS:
m/z (EI), calc. for C10H14N2 (M+) 162.1157, found 162.1152.
12 M. Scholl, T. M. Trnka, J. P. Morgan and R. H. Grubbs, Tetrahedron
Lett., 1999, 40, 2247.
13 Concerning racemisation in the catalytic hydrogenation of dehydron-
icotine, cf.: C. D. Chavdarian, J. Org. Chem, 1983, 48, 1529.
14 E. Montenegro, B. Gabler, G. Paradies, M. Seemann and G.
Helmchen, Angew. Chem., Int. Ed., 2003, 42, 2419; D. J. Pasto and
R. T. Taylor, Org. React., 1991, 40, 91.
15 Column: CHIRACEL OD-H, 250 × 4.6 mm, 5 lm, + guard cartridge
10 × 4 mm, 5 lm; flow = 0.5 mL min−1; eluent: n-hexane–i-PrOH 98 :
2), tR[(S)-6] = 19.8 min, tR[(R)-6] = 24.1 min. Ee values found for
nicotine were equal to those of the precursor 2a: 96% ee for (R)-6 and
99% ee for (S)-6 obtained from 2a, which was prepared according to
entry 2 and entry 3, respectively, of Table 1.
16 Benzylidene(dichloro)(1,3-dimesitylimidazolidin-2-yl)(tricyclohexyl-
phosphino)ruthenate; prepared according to: S. B. Garber, J. S.
Kingsbury, B. L. Gray and A. Hoveyda, J. Am. Chem. Soc., 2000,
122, 8168.
17 Signals of a ca. 1 : 1 mixture of amide rotamers.
18 W. Windus and C. S. Marvel, J. Am. Chem. Soc., 1930, 52, 2543.
3 2 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 6 6 – 3 2 6 8