A straightforward synthesis of (S)-Anabasine via the catalytic, enantioselective vinylogous mukaiyama-Mannich reaction

Article abstract of DOI:10.1055/s-0029-1217026

The tobacco alkaloid (S)-anabasine was synthesized by a straightforward 4-step sequence with the catalytic enantioselective vinylogous Mannich reaction as a key step. Only 3 mol% of a structurally optimized chiral BINOL-based phosphoric acid was employed to control the absolute configuration of the natural product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217026

PAPER
3797
A Straightforward Synthesis of (S)-Anabasine via the Catalytic, Enantio-
selective Vinylogous Mukaiyama–Mannich Reaction
Synthesis of
(
S
)-A
a
nabasine vid S. Giera, Marcel Sickert, Christoph Schneider*
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: schneider@chemie.uni-leipzig.de
Received 19 May 2009; revised 13 July 2009
amides, respectively, in high yields and good to very good
enantioselectivities (Scheme 1).3,4 A chiral BINOL-based
phosphoric acid was employed to catalyze the reaction
and control the enantioselectivity of the carbon–carbon
bond-forming step. Such Brønsted acids had been previ-
ously introduced by Akiyama5 and Terada6 and their re-
spective groups independently into the field of
asymmetric organocatalysis in general and imine addition
reaction in particular. Subsequent to our report Carretero
and co-workers reported a silver-catalyzed vinylogous
Mannich reaction with sulfonyl imines, which was also
applicable to acyclic silyl dienolates and furnished the
products in good enantioselectivities.7 Other recently re-
ported and highly enantioselective protocols for the exe-
cution of the vinylogous Mannich reaction are limited to
silyloxyfurans8 and dicyanoalkenes9 as the nucleophilic
components.
Abstract: The tobacco alkaloid (S)-anabasine was synthesized by a
straightforward 4-step sequence with the catalytic enantioselective
vinylogous Mannich reaction as a key step. Only 3 mol% of a struc-
turally optimized chiral BINOL-based phosphoric acid was em-
ployed to control the absolute configuration of the natural product.
Key words: anabasine, piperidine, alkaloids, vinylogous Mannich
reaction, Brønsted acid catalysis
The tobacco alkaloid (–)-anabasine belongs to the large
group of piperidine alkaloids1 containing a 3-pyridyl sub-
stituent in the 2-position within the piperidine ring. Along
with nicotine it is the minor constituent of Nicotina
tabacum, the species most commonly used for the produc-
tion of cigarette tobacco. Although structurally not very
complex, only a limited number of stereocontrolled total
syntheses of this natural product have been reported,
which mainly rely on the use of chiral auxilaries for the es-
tablishment of the correct absolute configuration.2
We envisioned a particular vinylogous Mannich product
carrying a 3-pyridyl group at the stereogenic center as
suitable starting material for a straightforward conversion
into (S)-anabasine through reduction, cyclization, and
deprotection reactions. Accordingly, we investigated
phosphoric acid catalyzed vinylogous Mannich reactions
of silyl dienolates 2a and 2b with 3-pyridylimine 1a
(Table 1). It soon became apparent, however, that our pre-
viously optimized conditions for ester-based silyl dieno-
late 2a using phosphoric acid 3a (R = 2,4,6-Me3C6H2) as
the Brønsted acid catalyst did not give rise to a sufficiently
selective reaction and delivered the vinylogous Mannich
product 4a in good yield, but only with 70% ee (entry 1).
The enantioselectivity was increased to 79% ee by lower-
ing the reaction temperature to –50 °C (entry 2).
Thus, Kunz and co-workers employed a carbohydrate-de-
rived imine for the central ring-forming hetero Diels–
Alder reaction with Danishefsky’s diene in the first total
synthesis of (–)-anabasine.2a,b A very similar approach
was pursued by Yamamoto and co-workers who mediated
the cycloaddition reaction with a chiral boron complex.2c,d
Later Amat2i and Pedrosa2g and their respective co-work-
ers employed phenylglycinol as chiral auxiliary in cyclo-
dehydration and reductive ring-opening reactions to
arrive at the natural product. Asymmetric Brown allyla-
tion reactions were used by Lebreton and co-workers2e,f
and Breit and co-workers2k to establish the correct abso-
lute configuration of the stereogenic center of anabasine.
The only catalytic, enantioselective approach thus far
which furnished enantiomeric (+)-anabasine was reported
by the Kobayashi group. Following the Kunz synthesis
very closely they catalyzed the central hetero Diels–Alder
reaction with a chiral niobium complex to achieve 92%
ee.2j However, six additional steps had to be performed to
convert the cycloadduct into (+)-anabasine.
Changing the Brønsted acid catalyst to 3b (R = SiPh3) sig-
nificantly enhanced the selectivity to 88% ee with the
amide-based silyl dienolate 2b while maintaining a good
yield of product 4b (entry 3). As previously observed this
reaction furnished the opposite enantiomer, however.3b In
order to further improve the enantioselectivity of the cen-
tral C–C bond forming event we then screened some ad-
ditional 3,3¢-substituted BINOL-phosphoric acids 3c–e as
catalysts. Indeed, more highly substituted 3,3¢-aryl groups
or larger substituents in the 3,3¢-aryl groups lead to en-
hanced enantioselectivities as compared to the mesityl-
substituted BINOL-phosphoric acid (entries 4–6).
We have recently established the first catalytic, enantiose-
lective vinylogous Mukaiyama–Mannich reaction of acy-
clic silyl dienolates and imines furnishing highly
functionalized d-amino a,b-unsaturated esters and
In particular, just 3 mol% of phosphoric acid 3e carrying
the 2,6-Me2-4-t-BuC6H2 group as 3,3¢-substituents in the
BINOL-backbone delivered the vinylogous Mannich
SYNTHESIS 2009, No. 22, pp 3797–3802
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217026; Art ID: T10309SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

3798
D. S. Giera et al.
PAPER
R
O
O
O
P
OH
R
PMP
PMP
R
OTBS
OEt
N
NH
O
3a R = Mes (5 mol%)
+
up to 92% ee
OEt
R
R
H
–30 °C
Solvent mixture
up to 94% yield
1
2a
4
4
PMP
R
PMP
H
NH
O
3b R = SiPh3 (1 mol%)
N
OTBS
+
N
up to 92% ee
up to 99% yield
–30 °C
Solvent mixture
N
1
2b
Scheme 1 Brønsted acid catalyzed, enantioselective, vinylogous Mukaiyama–Mannich reaction of acyclic silyl dienes
Table 1 Optimization of the Vinylogous Mukaiyama–Mannich Reactiona
R
O
O
O
P
OH
PMP
N
R
NH
O
OTBS
X
PMP
H
N
3 (3 mol%)
+
X
–50 °C
THF–t-BuOH–
2-methylbutan-2-ol
(1:1:1)
1a
2
4
N
4a: X = OEt
2a: X = OEt
N
4b: X =
N
2b: X =
Entry
Silyl dienolate
Catalyst
Product
4a
Time (h)
24
Yield (%)b
ee (%)c
1d
2
2a
2a
2b
2a
2a
2a
3a (R = 2,4,6-Me3C6H2)
3a (R = 2,4,6-Me3C6H2)
3b (R = SiPh3)
86
94
90
91
94
96
70
79
–88
86
89
92
4a
72
3d,e
4
4b
36
3c (R = Me5C6)
4a
72
5
3d (R = 2,4,6-Et3C6H2)
3e (R = 2,6-Me2-4-tBuC6H2)
4a
72
6
4a
60
a Reactions were performed with imine 1a (0.40 mmol) and silyl dienolates 2 (3.0 equiv) at –50 °C in a solvent mixture containing equal
amounts of THF, t-BuOH, and 2-methylbutan-2-ol with 1.0 equiv H2O and 3 mol% phosphoric acid 3 at 0.17 M concentration.
b Yields refer to chromatographically purified material.
c Enantiomeric excesses were determined by HPLC using Chiralcel OD or OD-H columns.
d This reaction was conducted at –30 °C.
e This reaction was conducted in a 0.2 mmol scale, solvent mixture: equal amounts of i-PrOH, t-BuOH, and 2-methylbutan-2-ol with 1.0 equiv
H2O, 1 mol% 3b, 0.1 M solution.
product 4a in excellent yield and 92% ee when the reac- dine, and silyl dienolate 2a as reaction partners giving
tion was conducted in our previously optimized solvent identical results and obviating the need for a separate syn-
system at –50 °C (entry 6). Further enhancement of the thesis of the imine.
steric size of the substituents in the 3,3¢-aryl groups, how-
Having established a highly efficient, direct, and enantio-
selective entry into the synthesis of (S)-anabasine we in-
vestigated the conversion of vinylogous Mannich product
4a into the natural product. In related studies we had
ever, resulted in a drop of selectivity as we had previously
observed in reactions with other imines and the TRIP-
phosphoric acid developed by List et al.10 The vinylogous
Mannich reaction with catalyst 3e could easily be run in a
three-component fashion with 3-pyridylaldehyde, p-anisi-
found LiBHEt3 to be a suitable reducing reagent for the
Synthesis 2009, No. 22, 3797–3802 © Thieme Stuttgart · New York

PAPER
Synthesis of (S)-Anabasine
3799
concomitant 1,4- and 1,2-reduction of a,b-unsaturated In conclusion we have reported a straightforward four-
carbonyl systems to the fully reduced alcohol.3b Presum- step synthesis of the tobacco alkaloid (S)-anabasine using
ably due to the presence of the readily reducible pyridine our recently developed vinylogous Mannich reaction as
ring in 4a, however, only low yields of the corresponding the key step. Only 3 mol% of a modified chiral Brønsted
saturated alcohol were obtained with this highly reactive acid catalyst was used to establish the absolute configura-
reductant. Accordingly, we slightly modified our strategy tion with high enantioselectivity. With a total yield of
and first reduced the conjugate double bond of 4a with the 55% our synthesis ranks among the most efficient synthe-
‘hot’-Stryker reagent developed by Lipshutz.11 This ses reported to date for this natural product.
proved to be a remarkably clean and efficient reaction and
furnished the saturated ester 5 in almost quantitative yield
(Scheme 2).
All vinylogous Mannich reactions were carried out in oven-dried
glassware under air atmosphere. 1H and 13C NMR spectra were re-
corded in CDCl3 solutions using a Varian Gemini 2000 spectrome-
ter (200 or 300 MHz) and Bruker Avance DRX 400 (400 MHz). The
signals were referenced to residual CHCl3 (7.26 ppm, 1H, 77.0 ppm,
13C). Chemical shifts are reported in ppm. Melting points were de-
termined on a Boetius heating table and are uncorrected. IR spectra
were obtained with a FTIR spectrometer (Genesis ATI Mattson/
Unicam). UV spectra were recorded on a UV spectrometer (DU-
650 Beckmann). Optical rotations were measured using a Po-
larotronic polarimeter (Schmidt & Haensch). All ESI mass spectra
were recorded on a Bruker APEX II FT-ICR. All EI mass spectra
were recorded on a Finnigan MAT 8230. HPLC analyses were car-
ried out on a Jasco MD-2010 plus instrument with chiral stationary
phase column (Daicel Chiralcel OD column or Daicel Chiralcel
OD-H column).
PMP
NH
PMP
(BDP)CuH
PMHS
O
NH
O
r.t., 15 h
t-BuOH
toluene, 97%
OEt
OEt
N
N
4a (92% ee)
5
PMP
N
PMP
+
N
NH
DIBAL-H
OH
–60 °C, 1 h
THF
N
6 (65%)
7 (15%)
The solvents were distilled from indicated drying reagents: CH2Cl2
(CaH2), THF (Na, benzophenone), Et2O (Na, benzophenone), tolu-
ene (Na, benzophenone). Et2O, EtOAc, and petroleum ether (PE, bp
40–70 °C) were technical grade and distilled from KOH. All reac-
tions were monitored by HPLC. Flash column chromatography was
performed by using Merck silica gel 60 230–400 mesh (0.040–
0.063 mm). Spots were monitored by TLC on precoated silica gel
SIL G/UV254 plates (Machery-Nagel & Co.), were visualized by
UV and were treated with a solution of phosphomolybdic acid hy-
drate [5 g in 250 mL MeOH (dried over Mg), Acros, ACS]. The cor-
responding racemic products were prepared using achiral
diphenylphosporic acid (Alfa Aesar) as catalyst. All aldimines were
prepared analogous to literature procedures.12 The nucleophiles
1-(tert-butyldimethylsilyloxy)-1-ethoxybuta-1,3-diene (2a) and
(Z)-1-[1-(tert-butyldimethylsilyloxy)buta-1,3-dienyl]piperidine (2b)
were prepared according to the literature procedure of Denmark et
al.13 The preparation of chiral phosphoric acid catalysts 3 was done
following the procedure described by Akiyama et al.,14 Yamamoto
and co-workers,15 and MacMillan and co-workers.16 All other
chemicals like i-PrOH (HPLC-grade, VWR), t-BuOH (99.5%,
Acros), and 2-methylbutan-2-ol (>96%, Fluka) were used as re-
ceived from commercial suppliers.
Ph3P, DEAD
0–40 °C, 17 h
THF, 83%
HN
CAN
overall yield
(4 steps): 55%
0 °C, 3 h
MeCN–H2O
77%
N
8 (92% ee)
Scheme 2 Conversion of the vinylogous Mannich product 4a into
(S)-anabasine (8)
After some experimentation, it was found that DIBAL-H
reduction (3 equiv) of ester 5 at –60 °C in THF directly
delivered the desired piperidine 6 in 65% yield along with
some quantities (15% yield) of the saturated alcohol 7.
Apparently, the secondary amine was intercepted by the
in situ formed aldehyde and furnished a cyclic iminium
ion, which was further reduced to yield piperidine 6.
When this reduction was attempted at lower temperatures
the starting material could be recovered in high yield
whereas higher temperatures shifted the ratio of piperi-
dine 6 to alcohol 7 in favor of alcohol 7 in reduced yield.
Alcohol 7 could, however, be converted in good yield into
piperidine 6 using a Mitsunobu cyclization, which gave a
Ethyl (2E,5S)-5-(4-Methoxyphenylamino)-5-(pyridin-3-
yl)pent-2-enoate (4a)
An oven-dried, 5 mL flask containing a solution of N-p-methoxy-
phenylnicotinimine (1a; 42.4 mg, 0.20 mmol, 1.0 equiv) and chiral
phosphoric acid 3e (4.00 mg, 0.006 mmol, 0.03 equiv) in a freshly
prepared solvent mixture of THF, t-BuOH, and 2-methylbutan-2-ol
in H2O (1:1:1 and 1.0 equiv H2O, 1.2 mL) was cooled to –50 °C. Af-
total yield of 77% of piperidine 7 from ester 5. Finally, ter 1 min, 1-(tert-butyldimethylsilyloxy)-1-ethoxybuta-1,3-diene
(2a; 140 mg, 0.60 mmol, 3.0 equiv, E/Z = 1:2) was added in one por-
tion. The resulting mixture was stirred rapidly for 60 h at –50 °C
whereupon the solvent was removed in vacuo. The residue was pu-
rified by silica gel chromatography (EtOAc–PE, 1:2 → 2:1, 10%
Et3N) to afford 125 mg (96%; 92% ee) of 4a as a colorless oil; Rf =
0.2 (EtOAc–PE, 1:2, 10% Et3N); [a]D24 +22.9 (c = 1.00, CHCl3).
CAN-oxidation and removal of the PMP-group deprotect-
ed the piperidine and furnished (S)-anabasine (8) in 77%
yield. The analytical and spectroscopic data of the syn-
thetic material was in good agreement with the reported
data for (S)-anabasine. In addition, the corresponding p-
nitrobenzoate was prepared and its melting point and op-
tical rotation value matched the reported data.2a,b
HPLC: Chiralcel OD-H column, solvent: n-hexane–i-PrOH (4:1),
flow rate: 0.5 mL/min, UV detection at 250 nm, major enantiomer
tR = 67.3 min (4a), minor enantiomer tR = 77.0 min (ent-4a).
Synthesis 2009, No. 22, 3797–3802 © Thieme Stuttgart · New York

3800
D. S. Giera et al.
PAPER
IR (film): 3344, 2945, 1715, 1656, 1511, 1427, 1366, 1309, 1239,
1215, 1184, 1162, 1094, 982, 917, 818, 784, 760, 715 cm–1.
ized with K2CO3 and then extracted with CH2Cl2 (5 × 10 mL). The
combined organic phases were dried (MgSO4) and the solvent was
removed in vacuo to afford 194 mg (97%, 0.59 mmol) of 5 as a col-
orless oil, which did not require further purification; Rf = 0.2 (Et2O);
[a]D24 +5.7 (c = 1.06, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 2.70 (m, 2 H, H-4), 3.70 (s, 3 H, OCH3), 3.78 (s, 1 H,
NH), 4.19 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.49 (t, J = 6.5 Hz, 1 H,
H-5), 5.93 (dt, J = 15.5, 1.5 Hz, 1 H, H-2), 6.45 (mc, 2 Harom), 6.69
(mc, 2 Harom), 6.89 (dt, J = 15.5, 7.5 Hz, 1 H, H-3), 7.25 (ddd,
J = 8.0, 5.0, 1.0 Hz, 1 Harom), 7.66 (dt, J = 8.0, 2.0 Hz, 1 Harom), 8.51
(dd, J = 5.0, 2.0 Hz, 1 Harom), 8.63 (d, J = 2.0 Hz, 1 Harom).
13C NMR (100 MHz, CDCl3): d = 14.2, 41.0, 55.6, 55.7, 60.5,
114.8, 115.0, 123.7, 124.9, 133.9, 138.2, 140.3, 143.4, 148.6, 148.9,
152.6, 165.8.
HRMS (ESI): m/z calcd for C19H23N2O3 [M + H]+: 327.17032;
found: 327.17011; m/z calcd for C19H22N2O3 + Na [M + Na]+:
349.15226; found: 349.15222; m/z calcd for C38H45N4O6 [2 M +
H]+: 653.33336; found: 653.33335; m/z calcd for C38H44N4O6 + Na
[2 M + Na]+: 675.31531; found: 675.31519.
IR (film): 3379, 2934, 2832, 1729, 1619, 1578, 1513, 1426, 1384,
1298, 1238, 1181, 1120, 1037, 877, 821, 758, 717, 621, 524 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.67 (m, 1 H, CHH), 1.81 (m, 3 H, CHH, CH2), 2.33 (t,
J = 6.5 Hz, 2 H, H-2), 3.69 (s, 3 H, OCH3), 3.89 (br s, 1 H, NH),
4.12 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.30 (t, J = 5.0 Hz, H-5), 6.46
(mc, 2 Harom), 6.68 (mc, 2 Harom), 7.23 (dd, J = 8.0, 4.5 Hz, 1 Harom),
7.65 (d, J = 8.0 Hz, 1 Harom), 8.48 (d, J = 4.5 Hz, 1 Harom), 8.60 (s,
1 Harom).
13C NMR (75 MHz, CDCl3): d = 14.2, 21.5, 33.7, 37.9, 55.7, 56.6,
60.4, 114.6, 114.8, 123.6, 133.9, 139.3, 140.9, 148.5, 148.7, 152.2,
173.1.
HRMS (ESI): m/z calcd for C19H25N2O3 [M + H]+: 329.18597;
found: 329.18623; m/z calcd for C19H24N2O3 + Na [M + Na]+:
351.16791; found: 351.16809; m/z calcd for C38H48N4O6 + Na
[2 M + Na]+: 679.34661; found: 679.34633.
(2E,5R)-5-(4-Methoxyphenylamino)-1-(piperidin-1-yl)-5-(pyri-
din-3-yl)pent-2-en-1-one (4b)
An oven-dried, 10 mL flask containing a solution of N-p-methoxy-
phenylnicotinimine (1a; 42.4 mg 0.20 mmol, 1.0 equiv) and chiral
phosphoric acid 3b (1.70 mg, 0.002 mmol, 0.01 equiv) in a freshly
prepared solvent mixture of i-PrOH, t-BuOH, and 2-methylbutan-2-
ol in H2O (1:1:1 and 1.0 equiv H2O, 2 mL) was cooled to –30 °C.
3-[(2S)-1-(4-Methoxyphenyl)piperidin-2-yl]pyridine (6) and
(5S)-5-(4-Methoxyphenylamino)-5-(pyridin-3-yl)pentan-1-ol
(7)
After
1 min, (Z)-1-[1-(tert-butyldimethylsilyloxy)buta-1,3-di-
A flame-dried 50 mL flask containing a solution of 5 (75.0 mg, 0.23
mmol, 1.0 equiv) in anhyd THF (25 mL) was cooled to –60 °C.
DIBAL-H (0.73 mL, 1 M solution in hexane, 0.73 mmol, 3.2 equiv)
was added dropwise and the resulting solution was stirred for 1 h at
–60 °C. The reaction was quenched by the addition of sat. aq Roch-
elle salt (15 mL), and the mixture was allowed to warm to r.t. After
30 min, the mixture was diluted with H2O (30 mL) and extracted
with CH2Cl2 (5 × 10 mL). The combined organic phases were dried
(MgSO4) and the solvent was removed in vacuo. The residue was
purified by silica gel chromatography (EtOAc–PE, 1:1 → 1:0) to af-
ford 40.0 mg (65%, 0.15 mmol) of 6 and 10.0 mg (15%, 0.035
mmol) of 7, both as colorless oils.
enyl]piperidine (2b; 160 mg, 0.60 mmol, 3.0 equiv) was added drop-
wise. The resulting mixture was stirred rapidly for 36 h at –30 °C
whereupon the solvent was removed in vacuo. The residue was pu-
rified by silica gel chromatography (Et2O–EtOAc, 3:1) to afford
66 mg (90%; 88% ee) 4b as a colorless oil; Rf = 0.1 (Et2O–EtOAc,
3:1); [a]D24 –24.0 (c = 1.00, CHCl3).
HPLC: Chiralcel OD column, solvent: n-hexane–i-PrOH (4:1),
flow rate: 1.0 mL/min, UV detection at 250 nm, major enantiomer
tR = 34.3 min (4b), minor enantiomer tR = 53.9 min (ent-4b).
IR (film): 3329, 2997, 2936, 2855, 1657, 1606, 1512, 1442, 1384,
1238, 1180, 1139, 1125, 1037, 975, 852, 821, 755, 717, 665, 621,
524 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.54 (m, 4 H, CH2), 1.63 (m, 2 H,
CH2), 2.70 (m, 2 H, H-4), 3.37 (m, 2 H, NCH2), 3.57 (m, 2 H,
NCH2), 3.69 (s, 3 H, OCH3), 3.84 (br s, 1 H, NH), 4.48 (t, J = 6.5
Hz, 1 H, H-5), 6.29 (dt, J = 15.0, 1.5 Hz, 1 H, H-2), 6.44 (mc, 2
6
Rf (Et2O) = 0.3; [a]D24 +39.6 (c = 1.52, CHCl3).
IR (film): 2933, 2853, 2720, 1876, 1674, 1578, 1510, 1425, 1385,
1326, 1245, 1182, 1103, 1036, 933, 900, 877, 830, 803, 715, 640,
619, 578, 558, 535 cm–1.
Harom), 6.68 (mc, 2 Harom), 6.74 (dt, J = 15.0, 7.5 Hz, 1 H, H-3), 7.23
(dd, J = 8.0, 5.0 Hz, 1 Harom), 7.66 (dt, J = 8.0, 2.0 Hz, 1 Harom),
8.49 (dd, J = 5.0, 2.0 Hz, 1 Harom), 8.63 (d, J = 2.0 Hz, 1 Harom).
13C NMR (100 MHz, CDCl3): d = 24.5, 25.5, 26.6, 41.3, 43.1, 46.9,
55.7, 55.7, 114.8, 115.0, 123.6, 124.3, 134.1, 138.5, 139.4, 140.5,
148.6, 148.7, 152.5, 164.6.
HRMS (ESI): m/z calcd for C22H28N3O2 [M + H]+: 366.21760;
found: 366.21730; m/z calcd for C22H27N3O2 + Na [M + Na]+:
388.19955; found: 388.19934; m/z calcd for C44H55N6O4 [2 M +
H]+: 731.42793; found: 731.42740; m/z calcd for C44H55N6O4 + Na
[2 M + Na]+: 753.40988; found: 753.40932.
1H NMR (300 MHz, CDCl3): d = 1.44–1.57 (m, 1 H, H-4a), 1.64–
1.94 (m, 5 H, H-3, H-4b, H-5), 2.82 (ddd, J = 12.0, 10.0, 4.0 Hz, 1
H, H-6a), 3.33 (dtd, J = 12.0, 3.0, 1.0 Hz, 1 H, H-6b), 3.67 (s, 3 H,
OCH3), 4.01 (dd, J = 10.0, 2.5, Hz, 1 H, H-2), 6.64 (mc, 2 Harom),
6.89 (mc, 2 Harom), 7.06 (ddd, J = 8.0, 4.5, 0.5 Hz, 1 Harom), 7.55
(ddd, J = 8.0, 2.0, 2.0 Hz, 1 Harom), 8.30 (dd, J = 4.5, 2.0 Hz, 1
Harom), 8.46 (d, J = 2.0 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3,): d = 24.3, 26.4, 36.4, 55.2, 57.1, 62.6,
113.9, 123.2, 124.7, 135.0, 140.1, 145.6, 147.7, 149.3, 155.3.
HRMS (ESI): m/z calcd for C17H21N2O [M + H]+: 269.16484;
found: 269.16483; m/z calcd for C17H20N2O + Na [M + Na]+:
291.14678; found: 291.14675; m/z calcd for C34H40N4O2 + Na
[2 M + Na]+: 559.30435; found: 559.30449.
Ethyl (5S)-5-(4-Methoxyphenylamino)-5-(pyridin-3-yl)penta-
noate (5)10
To a flame-dried 20 mL flask, containing a solution of 4a (200 mg,
0.61 mmol, 1.0 equiv) in degassed anhyd toluene (8 mL) was added
t-BuOH (175mL, 3.0 equiv). After the addition of (BDP)CuH solu-
tion (0.74 mL, 1.0 mM in toluene, prepared following the literature
procedure11), the resulting red solution was stirred at r.t. for 12 h.
The reaction was quenched by addition of sat. aq NH4Cl (6.0 mL).
After dilution with Et2O (30 mL), the solution was extracted with aq
1 N HCl (5 × 10 mL). The combined aqueous phases were neutral-
7
Rf (Et2O) = 0.1; [a]D24 +8.7 (c = 1.60, CHCl3).
IR (film): 3373, 2929, 1592, 1511, 1428, 1385, 1237, 1039, 877,
786, 762, 714 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38–1.63 (m, 4 H, H-2, H-3),
1.72–1.90 (m, 2 H, H-4), 3.63 (t, J = 6.0 Hz, 2 H, H-1), 3.68 (s, 3
Synthesis 2009, No. 22, 3797–3802 © Thieme Stuttgart · New York

PAPER
Synthesis of (S)-Anabasine
3801
H, OCH3), 4.29 (t, J = 6.5 Hz, 1 H, H-5), 6.44 (mc, 2 Harom), 6.68
(mc, 2 Harom), 7.23 (dd, J = 8.0, 5.0 Hz, 1 Harom), 7.65 (dt, J = 8.0,
2.0 Hz, 1 Harom), 8.47 (dd, J = 5.0, 2.0 Hz, 1 Harom), 8.59 (d, J = 2.0
Hz, 1 Harom).
13C NMR (50 MHz, CDCl3): d = 22.5, 32.7, 38.5, 55.7, 56.8, 62.4,
114.6, 114.8, 123.7, 134.0, 139.7, 141.0, 148.3, 148.6, 152.2.
HPLC: Chiralcel OD column, solvent: n-hexane–i-PrOH (4:1),
flow rate: 1.0 mL/min, UV-detection at 210 nm, minor enantiomer
tR = 33.5 min (ent-9), major enantiomer tR = 57.8 min (9).
IR (film): 2943, 2859, 1930, 1715, 1638, 1601, 1526, 1494, 1479,
1429, 1384, 1347, 1277, 1238, 1178, 1125, 1106, 1024, 999, 968,
862, 851, 787, 762, 713, 700, 644, 579 cm–1.
HRMS (ESI): m/z calcd for C17H23N2O2 [M + H]+: 287.17540;
found: 287.17520; m/z calcd for C34H45N4O4 [2 M + H]+:
573.34353; found: 573.34333.
1H NMR (200 MHz, CDCl3): d = 1.45–1.71 (m, 5 H, H-3a, H-4, H-
5), 1.79 (m, 1 H, H-3b), 2.04 (m, 1 H, H-6a), 2.46 (mc, 1 H, H-6b),
2.94 (m, 1 H, H-2), 7.36 (dd, J = 8.0, 4.5 Hz, 1 Harom), 7.64 (m, 3
Harom), 8.29 (mc, 2 Harom), 8.59 (m, 2 Harom).
3-[(2S)-1-(4-Methoxyphenyl)piperidin-2-yl]pyridine (6)
A flame-dried 10 mL flask containing a solution of 7 (18.0 mg,
0.063 mmol, 1.0 equiv) and Ph3P (24.7 mg, 0.094 mmol, 1.5 equiv)
in anhyd THF (5 mL) was cooled to 0 °C. Diethyl azodicarboxylate
(17 mL 0.094 mmol, 1.5 equiv) was added dropwise and the result-
ing solution was warmed to 40 °C and stirred for 17 h. The solvent
was removed in vacuo and the residue was purified by silica gel
chromatography (Et2O–PE, 1:1) to afford 6 (14.1 mg, 83%, 0.053
mmol) as a colorless oil.
13C NMR (50 MHz, CDCl3): d = 25.9, 27.2, 29.7, 47.5, 52.0, 123.8,
124.0, 127.6, 134.1, 134.7, 142.1, 148.2, 148.3, 148.4, 169.1.
HRMS (ESI): m/z calcd for C17H18N3O3 [M + H]+: 312.13427;
found: 312.13416; m/z calcd for C17H17N3O3 + Na [M + Na]+:
334.11621; found: 334.11598; m/z calcd for C34H34N6O6 + Na
[2 M + Na]+: 645.24321; found: 645.24321.
Acknowledgment
(S)-Anabasine (8)2j
We are grateful to the Deutsche Forschungsgemeinschaft for ge-
nerous financial support of this work (SPP 1179 ‘Organokatalyse’,
Schn 441/7-1) and to Wacker AG for the donation of chemicals.
3-[(2S)-1-(4-methoxyphenyl)piperidin-2-yl]pyridine (6; 15.0 mg,
0.056 mmol, 1.0 equiv) was dissolved in a solvent mixture of
MeCN and H2O (4:1, 1.5 mL) and the mixture was cooled to 0 °C.
After the addition of cerium ammonium nitrate (184.0 mg, 0.336
mmol, 6.0 equiv), the reaction mixture was stirred for 3 h at 0 °C.
The mixture was partitioned between H2O (3 mL) and EtOAc (20
mL), and the aqueous phase was basified with solid K2CO3. The
mixture was filtered through a pad of Celite and the aqueous phase
was extracted with EtOAc (5 mL). The combined organic layers
were dried (Na2SO4) and the solvent was removed in vacuo. The
crude product was purified by silica gel chromatography (CH2Cl2–
MeOH, 10:1 → 6:1) to afford 7.0 mg (77%, 0.043 mmol) of (S)-ana-
References
(1) Strunz, G. M.; Findlay, J. A. In The Alkaloids, Vol. 26;
Brossi, A., Ed.; Academic Press: New York, 1985, 89.
(2) (a) Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261.
(b) Pfrengle, W.; Kunz, H. Angew. Chem., Int. Ed. Engl.
1989, 28, 1067; Angew. Chem. 1989, 101, 1041. (c)Hattori,
K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(d) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749.
(e) Felpin, F.-X.; Vo-Thanh, G.; Robins, R. J.; Villieras, J.;
Lebreton, J. Synlett 2000, 1646. (f) Felpin, F.-X.; Girand,
S.; Vo-Thanh, G.; Robins, R. J.; Villieras, J.; Lebreton, J.
J. Org. Chem 2001, 66, 6305. (g) Andres, J. M.; Herraiz-
Sierra, I.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem.
2000, 1719. (h) Barco, A.; Benetti, S.; De Risi, C.;
Marchetti, P.; Pollini, G. P.; Zanirato, V. Eur. J. Org. Chem.
2001, 975. (i) Amat, M.; Canto, M.; Llor, N.; Bosch, J.
Chem. Commun. 2002, 526. (j) Jurčík, V.; Arai, K.; Salter,
M. M.; Yamashita, Y.; Kobayashi, S. Adv. Synth. Catal.
2008, 350, 647. (k) Spangenberg, T.; Breit, B.; Mann, A.
Org. Lett. 2009, 11, 261.
(3) (a) Sickert, M.; Schneider, C. Angew. Chem. Int. Ed. 2008,
47, 3631; Angew. Chem. 2008, 120, 3687. (b) Giera, D. S.;
Sickert, M.; Schneider, C. Org. Lett. 2008, 10, 4259.
(4) For reviews on the vinylogous Mannich reaction, see:
(a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (b) Bur,
S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(5) Review: Akiyama, T. Chem. Rev. 2007, 107, 5744; and
references cited therein.
(6) Review: Terada, M. Chem. Commun. 2008, 4097; and
references cited therein.
(7) Gonzalez, A. S.; Arrayas, R. G.; Rivero, M. R.; Carretero,
J. C. Org. Lett. 2008, 10, 4335.
(8) (a) Martin, S. F.; Lopez, O. D. Tetrahedron Lett. 1999, 40,
8949. (b) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2006, 45, 7230; Angew. Chem. 2006,
118, 7388. (c) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K.
Adv. Synth. Catal. 2008, 350, 399. (d) For a direct
vinylogous Mannich reaction of g-butenolides, see:
Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2008, 10, 2319.
24
basine (8) as a colorless oil; Rf = 0.2 (CH2Cl2–MeOH, 3:1); [a]D
–78.7 (c = 0.13, MeOH).2f
IR (film): 3407, 2926, 2854, 1735, 1432, 1385, 1109, 877, 786, 762
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48–1.92 (m, 7 H, H-3, H-4, H-
5, NH), 2.81 (td, J = 11.5, 3.0 Hz, 1 H, H-6a), 3.21 (mc, 1 H, H-6b),
3.64 (m, 1 H, H-2), 7.24 (dd, J = 8.0, 4.5 Hz, 1 Harom), 7.72 (dt,
J = 8.0, 2.0 Hz, 1 Harom), 8.49 (d, J = 4.5 Hz, 1 Harom), 8.59 (s, 1
Harom).
13C NMR (100 MHz, CDCl3): d = 22.3, 23.4, 30.4, 46.2, 59.0,
123.8, 135.2, 143.0, 149.0, 150.0.
HRMS (EI): m/z calcd for C10H14N2 [M]+: 162.11570; found:
162.11553.
(2S)-N-(4-Nitrobenzoyl)-2-(3-pyridyl)piperidine
To a solution of (S)-anabasine (8; 10.0 mg, 0.062 mmol, 1.0 equiv)
in anhyd THF (5 mL) at 0 °C, were added Et3N (35 mL, 4.0 equiv)
and 4-nitrobenzoyl chloride (40.0 mg, 3.5 equiv), and the resulting
solution was stirred for 2 h. Additional amounts of Et3N (35 mL, 4.0
equiv) and 4-nitrobenzoyl chloride (40.0 mg, 3.5 equiv) were added
and the solution was stirred for 12 h. The reaction was quenched
with H2O (2 mL), diluted with EtOAc (20 mL) and the organic layer
was washed with sat. aq NaHCO3 (5 mL) and brine (5 mL). The or-
ganic layer was dried (Na2SO4) and the solvent was removed in vac-
uo. The crude product was purified by silica gel chromatography
(EtOAc–PE, 1:2 → 2:1) to afford (2S)-N-(4-nitrobenzoyl)-2-(3-py-
ridyl)piperidine
(11.6 mg, 60%, 0.037 mmol as a white solid; mp 125–126 °C; Rf =
24
0.2 (EtOAc–PE, 3:1); [a]D –116.5 (c = 0.24, MeOH).
Synthesis 2009, No. 22, 3797–3802 © Thieme Stuttgart · New York

3802
D. S. Giera et al.
PAPER
(9) (a) Liu, T. Y.; Cui, H. L.; Long, J.; Li, B. J.; Wu, Y.; Ding,
L. S.; Chen, Y. C. J. Am. Chem. Soc. 2007, 129, 1878.
(b) Niess, B.; Jørgensen, K. A. Chem. Commun. 2007, 1620.
(10) Review: Adair, G.; Mukherjee, S.; List, B. Aldrichimica
Acta 2008, 41, 31.
(13) (a) Denmark, S. E.; Heemstra, J. R. J. r. J. Org. Chem. 2007,
72, 5668. (b) Denmark, S. E.; Beutner, G. L. J. Am. Chem.
Soc. 2003, 125, 7800.
(14) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566; Angew. Chem. 2004, 116,
1592. (b) Akiyama, T. PCT Int. Appl. WO 200409675,
2004; Chem. Abstr. 2004, 11, 11.
(11) Baker, B. A.; Bošković, V.; Lipshutz, B. H. Org. Lett. 2008,
10, 289.
(12) (a) Wang, M.; Yang, X.-F.; Li, C.-J. Eur. J. Org. Chem.
2003, 998. (b) Neuvonen, H.; Neuvonen, K.; Fülöp, F.
J. Org. Chem. 2006, 71, 3141.
(15) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto,
H. Bull. Chem. Soc. Jpn. 1988, 61, 2975.
(16) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 84.
Synthesis 2009, No. 22, 3797–3802 © Thieme Stuttgart · New York