Stereoselective synthesis of swainsonines from pyridines

Article abstract of DOI:10.1016/j.tet.2004.10.086

An efficient synthesis of (-)-swainsonine and (-)-2,8a-di-epi-swainsonine was developed starting from readily available 2-pyridinecarbaldehyde and 3-hydroxypyridine. In particular, it was demonstrated that the mixture of simple indolizidines, i.e. lentigi

Full text of DOI:10.1016/j.tet.2004.10.086

Tetrahedron 61 (2005) 643–655
Stereoselective synthesis of swainsonines from pyridines
*
¨
Gerres Heimgartner, Dirk Raatz and Oliver Reiser
¨
¨
¨
Institut fur Organische Chemie, Universitat Regensburg, Universitatsstr. 31, D-93040, Germany
Received 7 September 2004; revised 27 October 2004; accepted 28 October 2004
Available online 23 November 2004
Abstract—An efficient synthesis of (K)-swainsonine and (K)-2,8a-di-epi-swainsonine was developed starting from readily available
2-pyridinecarbaldehyde and 3-hydroxypyridine. In particular, it was demonstrated that the mixture of simple indolizidines, i.e. lentiginosine
and epi-lentiginosine, being readily available by a number of different synthetic routes, can be directly converted to swainsonine.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the synthesis of (K)-lentiginosine (1a) and also of (K)-
swainsonine (1b).4
Indolizidines belong to an important class of alkaloids that
have received broad attention due to their biological
properties such as antimetastatic, antitumor-proliferative,
anticancer or immunoregulating activity.1 Most prominent,
(K)-swainsonine (1b) is a very potent a-mannosidase
inhibitor, being currently under clinical evaluation.2 Despite
their relative simple structure, the synthesis of indolizidines
has remained challenging, although a number of elegant
routes towards them have been reported3 (Fig. 1).
However, even the parent pipecolic acid (2a) is not readily
available in enantiomerically pure form since it is not
available from the chiral pool, and—despite contrary
announcements5—an efficient chemical large scale process
is yet to be developed.
An alternate approach towards indolizidines can be
envisioned from pyridines, requiring the efficient trans-
formation of the pyridine into a piperidine ring at some
point in the synthesis.6 Following our interest to use
heteroaromatic starting materials such as pyrrols,7 furans8
or pyridines9 for the synthesis of natural products and
analogs, we report here such a strategy that leads
stereoselectively to (K)-swainsonine (1b) and to the epimer
(K)-2,8a-di-epi-swainsonine.
We have reported that acrylates of pyridines cannot be used
as substrates in the Sharpless asymmetric aminohydroxyl-
ation (AA) due to poisoning of the osmium catalyst by the
pyridine nitrogen.10 However, we demonstrated that the
corresponding pyridine N-oxides 7 readily underwent this
transformation, which was applied to the enantioselective
synthesis of pyridine analogous side chains of paclitaxel.
Recently, this strategy was taken up for the synthesis of
(K)-lentiginosine (1a), using an asymmetric dihydroxyla-
tion of 7a as the key step,11 which prompts us to report our
own results for the synthesis of swainsonine epimers.
Figure 1. Retrosynthetic analysis of indolizidines.
One obvious approach towards indolizidines would be
construction of the five-membered ring by appropriate
functionalization of (hydroxylated) pipecolic acids, and
indeed, this approach was successfully developed for
2. Results and discussion
Keywords: Indolizidines; Swainsonine; 2,8a-Di-epi-swainsonine; Pyridine-
N-oxides; Asymmetric dihydroxylation.
Asymmetric dihydroxylations of pyridine N-oxides 7a–e,
which were readily prepared from pyridines 3 and 8
* Corresponding author. Tel.: C49 941 9434631; fax: C49 941 9434121;
e-mail: oliver.reiser@chemie.uni-regensburg.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.086

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
644
Scheme 1. Reagents and conditions: (a) (i) NaOEt, ethanol; (ii) DMSO, (4a: benzyl chloride; 4b: methyl iodide), 28–39%. (b) SeO2, dioxane, reflux, 83–84%.
(c) LiBr, acetonitrile, NEt3, (R1O)2POCH2COOR1, 62–84%. (d) Glacial acetic acid, hydrogen peroxide (30%), 60 8C, 77–97%. (e) LiBr, acetonitrile, NEt3,
(R1O)2POCH2COOR1, 62–86%.
(Scheme 1), were investigated using commercially available
AD-mix.
protecting group at the hydroxyl group in the 3-position on
the pyridine ring: while the benzyloxy derivative 7c gave
the diols 10c or (ent)-10c with only 53–66% ee, 7d,
substituted with the smaller methoxy group gave rise to the
diols 10d or (ent)-10d with excellent enantioselectivity.
Switching from the ethyl to the isopropyl esters 7b and 7e
considerably improved the yields by retaining the high
selectivities (93–98% ee) of the dihydroxylation reaction
due to the increased hydrolytic stability of the starting
materials and products.
7a gave the desired dihydroxylated products 10a, as
recently reported,11 or (ent)-10a, respectively, with high
enantioselectivity, either by employing AD-mix-a or
AD-mix-b (Table 1). Likewise, the alkoxy substituted
N-oxides 7c and 7d could be converted to the corresponding
diols with respectable yields, however, the enantioselec-
tivity of the reaction was distinctively dependent on the
Table 1. Asymmetric dihydroxylation of 7 to 10a–e (AD-mix-a) or (ent)-10a–e (AD-mix-b)a
AD-mix-a
AD-mix-b
% ee
Yield (%)
% ee
Yield (%)
7a
7b
7c
7d
7e
97
97
53
97
97
39
66
55
52
93
96
98
66
98
93
36
65
59
54
72
a Reagents and conditions: AD-Mix, MeSO2NH2, t-BuOH/H2O, room temperature, 24–72 h.

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
645
2.1. Synthesis of (K)-Swainsonine
alkoxylation17 has ample precedent. As a general rule it
was shown that bicyclic derivatives could be selectively
oxidized at the ring junction, while acyclic substituted
piperidines will be oxidized at the less substituted a-carbon.
Hydrogenation of (ent)-10b was achieved at ambient
pressure in methanol using platinum dioxide as catalyst.
Under these conditions, reduction of the pyridine N-oxide to
the piperidine with concurrent ring closure takes place,
giving rise directly to the bicyclic derivative 11. If
palladium on charcoal was used as the catalyst instead,
selective reduction of the pyridine-N-oxides to the
corresponding pyridines takes place in quantitative yield.
Compound 11 was obtained from (ent)-10b as an insepar-
able mixture of epimers (60:40) with respect to the
stereocenter at C-2 (Scheme 2).12 In order to invert the
stereocenter13 at C-1, this mixture was selectively benzoyl-
ated at C-2 to yield 12, followed by treatment with triflic
anhydride. The resulting 13 was debenzoylated to 1414 and
subsequently converted to the acetonide 15. If desired,
the major epimer 14a can be obtained in pure form by
recrystallization, and its X-ray structure15 analysis con-
firmed the successful establishment of the syn-stereo-
chemistry of the two hydroxy groups.
Treatment of the mixture of epimers 15 with ruthenium-
tetroxide, being generated in situ from rutheniumdioxide
and sodium hypochlorite, indeed resulted in a regioselective
oxidation to form 16 (Scheme 3). However, the two epimers
15 differ largely in their reactivity as well as in their
stereospecifity as could be shown by carrying out the
oxidation with the individual isomers: While 15a, having
the hydrogen to be oxidized oriented on the convex face
of the tricyclic ring system readily formed exclusively 16a
with retention of configuration, 15b reacted much more
sluggishly and unspecifically to a mixture of 16a and 16b,
which upon elimination gave rise to the known compound
17.18 Thus, when the epimeric mixture 15a/15b (60:40) is
used in this oxidation/elimination sequence, 17 is obtained
(50% yield) along with unreacted 15b (29%) which can
readily be separated and recovered by chromatography.
Compound 17 was subsequently converted to (K)-swain-
sonine (1b) as previously described in the literature.18
The a-oxidation of N-acylated piperidines by ruthenium-
(VIII)-catalyzed hydroxylation16 or electrochemical
Scheme 3. Reagents and conditions: (a1) (i) RuO2$H2O, 12% aqueous
NaOCl, ethyl acetate, 0 8C/10 8C; (ii) HOAc, CHCl3, 79% (2 steps). (a2)
(i) RuO2$H2O, 12% aqueous NaOCl solution, ethyl acetate, 0 8C;
(ii) HOAc, CHCl3, 50% (2 steps) 17 C 29% recovered 15b.
2.2. Synthesis of (K)-2,8a-di-epi-Swainsonine
Hydrogenation of 10e could be analogously carried out
under conditions as described for (ent)-10b. From the
possible four diastereomers, 18 was formed as the major one
(7:1:1:0.5) which could be obtained pure after recrystalliza-
tion (Scheme 4). The configuration of 18 was confirmed by
X-ray crystal analysis (not shown) as well as by subsequent
chemical transformation to the known (K)-2,8a-di-epi-
swainsonine (20).19 Thus, 18 was demethylated using
concentrated HBr, and the resulting crude 19 which
contained ammonium bromide as a byproduct was directly
reduced without purification to give rise to 20$HBr.
Recrystallization of 20$HBr gave suitable crystals for
X-ray structure analysis15 which confirmed the relative and
absolute (Flack parameterZ0.00(1)) stereochemical assign-
ment of the product. These crystals were converted to the
salt-free (K)-2,8a-di-epi-swainsonine (20) by ion exchange
chromatography, showing identical melting point and NMR
Scheme 2. Reagents and conditions: (a) PtO2$H2O, MeOH, H2, 89%.
(b) Benzoyl chloride, DMAP, pyridine, K30 8C, 84%. (c) Triflic anhydride,
pyridine, CH2Cl2, 53%. (d) NaOMe, MeOH, 78%. (e) 2,2-Dimethoxypro-
pane, p-TsOH, CH2Cl2, 98%.

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
646
3. Experimental
3.1. General
Reactions with moisture-sensitive chemicals were per-
formed under nitrogen in a flame-dried reaction flask.
Solvents were dried by standard methods.
Chromatography: Macherey–Nagel silica gel (0.03–
0.06 mm). Enantiomeric excesses were determined by
analytical HPLC using a Chiracel OD-H column (flow:
1 ml/min) and a UV detector at 254 nm. Diastereomeric
ratios were determined by integration of the respective
diastereomeric peaks in 1H NMR. TLC: commercially
precoated aluminum sheets 60 F 254 (Merck). Uncorrected
melting point: Bu¨chi SMP 20. IR: Mattson Genesis series
1
FT-IR, Perkin–Elmer 298, Bruker IFS 66, n in cmK1. H
NMR and 13C NMR: Bruker Avance 600, ARX 400,
Avance 300, AC 250 F, d in ppm, J in Hz. Multiplicities
were determined by DEPT (distortionless enhancement by
polarization transfer) measurements, C signifies a positive
signal (CH, CH3), K signifies a negative signal (CH2) in
DEPT 135. MS: Finnigan MAT 95, Varian MAT 311A.
Elemental analysis: Heraeus CHN-Rapid. XRD: Stoe
Imaging Plate System, Siemens Stoe AED2. Optical
rotation: Perkin–Elmer polarimeter PE 241.
3.1.1. 3-Benzyloxy-2-hydroxymethylpyridine (4a).
Sodium (4.60 g, 0.20 mol, 2.0 equiv) was added to ethanol
(80 ml). After 2 h of stirring 3-hydroxy-2-(hydroxymethyl)-
pyridine hydrochloride (16.2 g, 0.10 mol, 1.0 equiv) was
added and the solution was stirred further for 1 h at room
temperature. After addition of DMSO (125 ml), ethanol was
removed under reduced pressure. Benzyl chloride (12.55 g,
11.5 ml, 0.10 mol, 1.0 equiv) was added and stirred for 12 h
at room temperature. After addition of H2O (1.5 l), the
aqueous layer was extracted with CHCl3 (4!100 ml). The
combined organic layers were dried over MgSO4, and
the solution was concentrated under reduced pressure. The
crude product was extracted with hot hexane (3!250 ml),
and after removal of the solvent recrystallized from hexane
Scheme 4. Reagents and conditions: (a) Pt/C (5%), HOAc, H2, 47%.
(b) HBr (48%), 140 8C, 88%. (c) BH3$DMS, THF, 0 8C, 59%. (d) (i)
Recrystallization ethyl acetate/MeOH 1:1, 55%; (ii) Dowex 1!8, 100–200
mesh, 100%.
data, but a different value of optical rotation (K8.8) as
previously reported (K24.0) in literature.19
The greatly improved diastereoselectivity in the hydro-
genation of 10e compared to (ent)-10b clearly must be
attributable to the alkoxy substituent in the pyridine moiety.
The preferred formation of 18 from 10e can therefore be
rationalized by chelation of platinum by that group and a
side chain hydroxy group as depicted in Figure 2.
Restriction of the conformation in 10e by a hydrogen
bond of the second hydroxy group in the side chain with the
N-oxide might very well be an additional control factor in
this hydrogenation.
1
(500 ml) to give 4a (8.39 g, 0.04 mmol, 39%). H NMR
(250 MHz, CDCl3) d: 4.39 (br s, 1H), 4.82 (s, 2H), 5.11
(s, 2H), 7.16–7.17 (m, 2H), 7.34–7.40 (m, 5H), 8.15–8.17
(m, 1H). 13C NMR (62.9 MHz, CDCl3) d: 60.1 (K, CH2),
69.9 (K, CH2), 118.0 (C, Aryl-C), 122.2 (C, Aryl-C),
127.2 (C, 2C, Aryl-C), 128.3 (C, Aryl-C), 128.7 (C, 2C,
Aryl-C), 136.0 (quat C), 139.8 (C, Aryl-C), 148.8 (quat C),
151.4 (quat C).
3.1.2. 3-Methoxy-2-hydroxymethylpyridine (4b). Sodium
(11.5 g, 0.50 mol, 2.0 equiv) was added to ethanol (200 ml).
After 3 h of stirring, DMSO (300 ml) and 3-hydroxy-2-
(hydroxymethyl)-pyridine hydrochloride (40.4 g, 0.25 mol,
1.0 equiv) were added. Ethanol was removed under reduced
pressure. The mixture was cooled to 0 8C, methyl iodide
(35.5 g, 15.6 ml, 0.25 mol, 1.0 equiv) was added and stirred
for 12 h at room temperature. After addition of H2O (1.0 l)
the aqueous layer was extracted with CH2Cl2 (5!100 ml).
The combined organic layers were washed with brine
(300 ml), dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by
chromatography on silica to yield 4b (9.75 g, 0.07 mol,
Figure 2. Model for the stereoselective hydrogenation of 10e.
In conclusion, we have demonstrated that readily available
pyridines provide a convenient access to swainsonines in
diastereo- and enantiopure form.

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
647
28%) as colorless solid. 1H NMR (300 MHz, CDCl3) d: 3.82
(s, 3H, OCH3), 4.72 (s, 2H, CH2), 7.10 (dd, JZ8, 1 Hz, 1H,
Aryl-H), 7.18 (dd, JZ8, 4 Hz, 1H, Aryl-H), 8.12 (dd, JZ4,
1 Hz, 1H, Aryl-H). 13C NMR (75 MHz, CDCl3) d: 55.1 (C,
CH3), 60.0 (K, CH2), 116.4 (C, Aryl-C), 122.6 (C, Aryl-
C), 139.3 (C, Aryl-C), 148.3 (quat C), 152.3 (quat C).
3.1.6. (E)- and (Z)-Ethyl 3-(3-methoxypyridin-2-yl)acryl-
ate (6b-Et). To a stirred suspension of LiBr (3.72 g,
42.7 mmol, 1.5 equiv) in dry acetonitrile (100 ml) was
added triethylamine (3.18 g, 4.4 ml, 31.4 mmol, 1.1 equiv),
triethyl phosphonoacetate (6.40 g, 28.5 mmol, 1.0 equiv)
and finally 3-methoxypyridine-2-carbaldehyde (3.92 g,
28.5 mmol, 1.0 equiv). The solution was stirred 18 h at
room temperature. H2O (40 ml) was added and the aqueous
layer was extracted with ethyl acetate (3!100 ml). The
combined organic layers were washed with brine (100 ml),
dried over MgSO4 and concentrated under reduced pressure.
The crude product (E/ZZ93:7) was purified by chroma-
tography on silica (ethyl acetate/hexanes 1:2) to yield
(E)-6b-Et (4.81 g, 23.2 mmol, 81%) as colorless solid and
(Z)-6b-Et (382 mg, 1.8 mmol, 6.5%) as yellow oil. (E)-6b-
3.1.3. 3-Benzyloxypyridine-2-carbaldehyde (5a).20 Com-
pound 4a (3.86 g, 17.9 mmol, 1.0 equiv) and SeO2 (1.99 g,
17.9 mmol, 1.0 equiv) were dissolved in 50 ml of dioxane.
The solution was refluxed, filtrated and concentrated. The
crude product was purified by chromatography on silica to
yield 5a (3.21 g, 15.1 mmol, 84%); Rf 0.26 (hexanes/ethyl
1
acetate 1:1). H NMR (250 MHz, CDCl3) d: 5.25 (s, 2H,
CH2Ph), 7.30–7.50 (m, 7H, Aryl-H), 8.40 (dd, JZ3.6 Hz,
2.0 Hz, 1H, Aryl-H), 10.44 (s, 1H, CHO).
1
Et: Rf 44 (hexanes/ethyl acetate 1:1). Mp 63 8C. H NMR
(250 MHz, CDCl3) d: 1.33 (t, JZ7.1 Hz, 3H, CH2CH3),
3.87 (s, 3H, OCH3), 4.27 (q, JZ7.1 Hz, 2H, CH2CH3), 7.01
(d, JZ15.8 Hz, 1H, CH]CHCO2Et), 7.18–7.29 (m, 2H,
Aryl-H), 8.07 (dd, JZ15.8, 0.46 Hz, 1H, CH]CHCO2Et),
8.21 (ddd, JZ3.9, 1.9, 0.42 Hz, 1H, Aryl-H). 13C NMR
(62.9 MHz, CDCl3) d: 14.2 (C, CH2CH3), 55.4 (C, OCH3),
60.3 (K, CH2CH3), 118.3 (C, Aryl-C), 122.1 (C, Aryl-C),
125.2 (C, CH]CHCO2Et), 137.8 (C, Aryl-C), 141.4 (C,
CH]CHCO2Et), 142.3 (quat, Aryl-C), 154.6 (quat, Aryl-
C), 167.1 (quat, CO2Et). IR (KBr) n: 3016, 2990, 2940,
2904, 1707, 1635, 1573, 1464, 1440, 1423, 1365, 1303,
1276, 1259, 1235, 1166, 1108, 1069, 1035, 1012, 980, 895,
876, 799, 774, 595, 574 cmK1. MS (EI, 70 eV) m/z (%):
207.0 (39.2 MC), 177.9 (30.4), 161.9 (100.0), 133.9 (50.2),
119.9 (28.1), 105.9 (19.0), 90.9 (11.5). Anal. Calcd for
C11H13NO3 (207.23) C 63.76, H 6.32, N 6.76. Found C
63.64, H 6.29, N 6.81. (Z)-6b-Et: Rf 0.30 (hexanes/ethyl
3.1.4. 3-Methoxypyridine-2-carbaldehyde (5b). Com-
pound 4b (9.00 g, 64.7 mmol, 1.0 equiv) and SeO2
(7.17 g, 64.7 mmol, 1.0 equiv) were dissolved in dioxane
(180 ml). The solution was refluxed (4 h), filtrated and
concentrated. The crude product was purified by chroma-
tography on silica to yield 5b (7.33 g, 53.5 mmol, 83%). Rf
0.32 (ethyl acetate). 1H NMR (250 MHz, CDCl3) d: 3.98 (s,
3H, OCH3), 7.43 (dd, JZ8.6 Hz, 1.4 Hz, 1H, Aryl-H), 7.50
(dd, JZ8.6 Hz, 4.3 Hz, 1H, Aryl-H), 8.41 (dd, JZ4.3 Hz,
1.4 Hz, 1H, Aryl-H), 10.35 (s, 1H, CHO). 13C NMR
(75 MHz, CDCl3) d: 55.8 (C, OCH3), 120.2 (C, Aryl-C),
128.8 (C, Aryl-C), 141.0 (C quat), 142.0 (C, Aryl-C),
157.9 (C quat), 190.3 (C quat).
3.1.5. (E)-Ethyl 3-(3-(benzyloxy)pyridin-2-yl)acrylate
(6a-Et). To a stirred suspension of LiBr (1.04 g,
12.0 mmol, 1.2 equiv) in dry acetonitrile (50 ml) was
added triethylamine (1.11 g, 1.5 ml, 11 mmol, 1.1 equiv),
triethyl phosphonoacetate (1.24 g, 10 mmol, 1.0 equiv) and
finally 3-benzyloxy-pyridine-2-carboxaldehyde (2.13 g,
10 mmol, 1.0 equiv). The solution was stirred 72 h at
room temperature. H2O (40 ml) was added and the aqueous
layer was extracted with ethyl acetate (3!30 ml). The
combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude product
was purified by chromatography on silica (ethyl acetate/
hexanes 1:3) to yield 6a-Et (2.39 g, 8.4 mmol, 84%, E/ZZ
99:1) as yellow solid. Rf 0.48 (hexanes/ethyl acetate 1:1). 1H
NMR (250 MHz, CDCl3) d: 1.32 (t, JZ7.1 Hz, 3H,
CH2CH3), 4.26 (q, JZ7.1 Hz, 2H, CH2CH3), 5.15 (s, 2H,
CH2Ph), 7.04 (d, JZ15.8 Hz, 1H, CH]CHCO2Et), 7.15–
7.45 (m, 7H, Aryl-H), 8.16 (dd, JZ15.8 Hz, JZ0.45 Hz,
1H, CH]CHCO2Et), 8.22 (ddd, JZ4.1 Hz, JZ1.6 Hz, JZ
0.45 Hz, 1H, Aryl-H). 13C NMR (62.9 MHz, CDCl3) d: 14.3
(C, CH2CH3), 60.5 (K, CH2CH3), 70.4 (K, CH2Ph), 120.0
(C, Aryl-C), 122.4 (C, Aryl-C), 125.1 (C, Aryl-C), 127.2
(C, 2C, Aryl-C), 128.3 (C, CH]CHCO2Et), 128.8 (C,
2C, Aryl-C), 135.8 (quat, Aryl-C), 137.8 (C, CH]CHCO2-
Et), 141.9 (C, Aryl-C), 142.9 (quat, Aryl-C), 153.7 (quat,
Aryl-C), 167.2 (quat, CO2Et). IR (KBr) n: 3056, 2982, 2937,
2877, 1684, 1573, 1444, 1391, 1365, 1297, 1274, 1245,
1169, 1108, 1048, 981, 927, 880, 859, 793, 773, 750, 705,
626, 598, 556 cmK1. MS (EI, 70 eV) m/z (%): 283.3 (3.7,
MC), 210.1 (28.9), 146.9 (1.1), 118.9 (2.7), 90.9 (100), 65.0
(7.6). Anal. Calcd for C17H17NO3 (283.32) C 72.07, H 6.05,
N 4.94. Found C 72.05, H 6.09, N 4.85.
1
acetate 1:1). H NMR (250 MHz, CDCl3) d: 1.20 (t, JZ
7.2 Hz, 3H, CH2CH3), 3.82 (s, 3H, OCH3), 4.18 (q, JZ
7.1 Hz, 2H, CH2CH3), 6.13 (d, JZ12.1 Hz, 1H,
CH]CHCO2Et), 7.09 (d, JZ12.1 Hz, 1H, CH]CHCO2-
Et), 7.12–7.22 (m, 2H, Aryl-H), 8.15 (ddd, JZ3.9, 2.1,
0.27 Hz, 1H, Aryl-H). 13C NMR (62.9 MHz, CDCl3) d: 14.0
(C, CH2CH3), 55.4 (C, OCH3), 60.3 (K, CH2CH3), 117.5
(C, Aryl-C), 123.90 (C, Aryl-C), 123.96 (C,
CH]CHCO2Et), 132.8 (C, CH]CHCO2Et), 140.7 (C,
Aryl-C), 143.9 (quat, Aryl-C), 153.4 (quat, Aryl-C), 167.6
(quat, CO2Et). IR (Film) n: 3059, 2982, 2941, 2840, 1724,
1637, 1580, 1462, 1432, 1398, 1277, 1189, 1118, 1069,
1029, 948, 858, 830, 798, 749 cmK1. MS (EI, 70 eV) m/z
(%): 207.1 (34.2, MC), 178.0 (32.1), 162.0 (100.0), 148.0
(14.4), 134.0 (44.4), 119.9 (26.4), 106.0 (17.8), 91.0 (11.5).
Anal. Calcd for C11H13NO3 (207.23) C 63.76, H 6.32, N
6.76. Found C 63.36, H 6.36, N 6.76.
3.1.7. (E)- and (Z)-Isopropyl 3-(3-methoxypyridin-2-
yl)acrylate (6b–iPr). To a stirred suspension of LiBr
(4.51 g, 51.9 mmol, 1.5 equiv) in dry acetonitrile (100 ml)
under nitrogen atmosphere was added at room temperature
triethylamine (3.85 g, 5.3 ml, 38.1 mmol, 1.1 equiv), triiso-
propyl phosphonoacetate (9.23 g, 34.6 mmol, 1.0 equiv)
and finally 3-methoxypyridine-2-carbaldehyde (4.75 g,
34.6 mmol, 1.0 equiv). The solution was stirred for 120 h
at room temperature. H2O (100 ml) was added and the
aqueous layer was extracted with ethyl acetate (3!50 ml).
The combined organic layers were washed with H2O
(100 ml) and brine (100 ml), dried over MgSO4 and

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
648
concentrated under reduced pressure. The crude product
(E/ZZ86:14) was purified by chromatography on silica
(ethyl acetate/hexanes 1:2) to yield (E)-6b-iPr (4.76 g,
21.5 mmol, 62%) and (Z)-6b-iPr (567 mg, 2.6 mmol, 7%)
as colorless oils. (E)-6b-iPr: Rf 0.30 (ethyl acetate/hexanes
1:1). 1H NMR (300 MHz, CDCl3) d: 1.31 (d, JZ6.2 Hz, 6H,
CH(CH3)2), 3.90 (s, 3H, OCH3), 5.14 (hept, JZ6.2 Hz, 1H,
CH(CH3)2), 6.99 (d, JZ15.8 Hz, 1H, CH]CHCO2i-Pr),
7.23 (d, JZ1.7 Hz, 1H, Aryl-H), 7.24 (d, JZ4.2 Hz, 1H,
Aryl-H), 8.05 (d, JZ15.8 Hz, 1H, CH]CHCO2i-Pr), 8.22
(dd, JZ4.2, 1.7 Hz, 1H, Aryl-H). 13C NMR (75.5 MHz,
CDCl3) d: 21.9 (C, 2C, CH(CH3)2), 55.4 (C, OCH3), 67.7
(C, CH(CH3)2), 118.3 (C, CH]CHCO2i-Pr), 122.9 (C,
Aryl-C), 125.1 (C, Aryl-C), 137.7 (C, CH]CHCO2i-Pr),
141.5 (C, Aryl-C), 142.6 (quat, Aryl-C), 154.6 (quat, Aryl-
C), 166.7 (quat, CO2i-Pr). MS (DCI, NH3) m/z (%): 222.3
(100, MHC). IR (film) n: 3061, 2979, 2940, 2839, 1712,
1638, 1576, 1466, 1429, 1301, 1271, 1235, 1179, 1109,
1069, 1017, 986, 917, 879, 834, 799, 772 cmK1. Anal. Calcd
for C12H15NO3 (221.25) C 65.14, H 6.83, N 6.33. Found C
64.75, H 6.76, N 6.30. (E)-6b-iPr: Rf 0.22 (ethyl acetate/
3.1.9. (E)-Isopropyl 3-(N-oxypyridin-2-yl)acrylate (7b).
To a solution of (E)-9-iPr (4.39 g, 28.2 mmol, 1.0 equiv) in
glacial acid (10.9 g, 10.3 ml, 181 mmol, 6.4 equiv) was
added hydrogen peroxide (30%, 10.3 ml, 102 mmol,
3.6 equiv), and the mixture was heated for 12 h at 60 8C.
The resulting solution was concentrated under reduced
pressure to give a yellow oil, which was purified by
chromatography on silica (ethyl acetate) to give 7b (4.59 g,
22.1 mmol, 79%) as a yellow solid. Mp 98 8C. Rf 0.42
1
(CHCl3/MeOH 19:1). H NMR (250 MHz, CDCl3) d: 1.32
(d, JZ6.3 Hz, 6H, CH(CH3)2), 5.15 (hept, JZ6.3 Hz, 1H,
CH(CH3)2), 6.95 (d, JZ16.3 Hz, 1H, CH]CHCO2i-Pr),
7.26–7.34 (m, 2H, Aryl-H), 7.56–7.61 (m, 1H, Aryl-H), 8.07
(d, JZ16.3 Hz, 1H, CH]CHCO2i-Pr), 8.26–8.31 (m, 1H,
Aryl-H). 13C NMR (62.9 MHz, CDCl3) d: 21.8 (C, 2C,
CH(CH3)2), 68.4 (C, CH(CH3)2), 125.2 (C, Aryl-C), 125.4
(C, Aryl-C), 125.7 (C, Aryl-C), 125.8 (C, CH]CHCO2i-
Pr), 133.6 (C, CH]CHCO2i-Pr), 140.4 (C, Aryl-C), 145.3
(quat, Aryl-C), 165.6 (quat, CO2i-Pr). MS (EI, 70 eV) m/z
(%): 207.0 (3.4, MHC), 191.0 (5.36), 147.9 (23.3), 131.9
(23.2), 119.9 (100), 104.9 (11.9), 103.9 (10.4), 91.9 (84.4),
77.9 (16.7), 65.0 (23.9). IR (film) n: 3076, 2989, 1701, 1491,
1473, 1435, 1377, 1350, 1317, 1279, 1240, 1228, 1209,
1178, 1163, 1146, 1109, 989, 897, 876, 841, 812, 758, 569,
526 cmK1. Anal. Calcd for C11H13NO3 (207.23) C 63.76, H
6.32, N 6.76. Found C 63.64, H 6.25, N 6.70.
1
hexanes 1:1). H NMR (300 MHz, CDCl3) d: 1.21 (d, JZ
6.2 Hz, 6H, CH(CH3)2), 3.84 (s, 3H, OCH3), 5.09 (hept, JZ
6.2 Hz, 1H, CH(CH3)2), 6.12 (d, JZ12.1 Hz, 1H,
CH]CHCO2i-Pr), 7.07 (d, JZ12.1 Hz, 1H, CH]CHCO2-
i-Pr), 7.17 (d, JZ1.9 Hz, 1H, Aryl-H), 7.18 (d, JZ4.4 Hz,
1H, Aryl-H), 8.15 (dd, JZ4.2 Hz, 1.7 Hz, 1H, Aryl-H). 13C
NMR (75.5 MHz, CDCl3) d: 21.7 (C, 2C, CH(CH3)2), 55.3
(C, OCH3), 67.9 (C, CH(CH3)2), 117.4 (C, CH]CHCO2-
i-Pr), 123.8 (C, Aryl-C), 124.5 (C, Aryl-C), 132.1 (C,
CH]CHCO2i-Pr), 140.6 (C, Aryl-C), 144.0 (quat, Aryl-
C), 153.3 (quat, Aryl-C), 167.2 (quat, CO2i-Pr). MS (DCI,
NH3) m/z (%): 266.3 (13.2), 222.3 (100, MHC). IR (film) n:
3057, 2980, 2938, 2838, 1718, 1637, 1579, 1454, 1431,
1395, 1275, 1179, 1115, 1069, 961, 859, 828, 799, 782,
750 cmK1. Anal. Calcd for C12H15NO3 (221.25) C 65.14, H
6.83, N 6.33. Found C 64.65, H 6.81, N 6.33.
3.1.10. (E)-Ethyl 3-(3-(benzyloxy)-N-oxypyridin-2-yl)-
acrylate (7c). To a solution of (E)-6a-Et (3.41 g,
12.0 mmol, 1.0 equiv) in glacial acetic acid (4.62 g,
4.4 ml, 76.8 mmol, 6.4 equiv), hydrogen peroxide (30%,
4.90 g, 4.4 ml, 43.2 mmol, 3.6 equiv) was added, and the
mixture was heated for 12 h at 60 8C. The mixture was
concentrated under reduced pressure and the residue was
purified by chromatography on silica (ethyl acetate) to give
7c (2.77 g, 9.26 mmol, 77%) as a yellow solid. Mp 87 8C. Rf
1
0.35 (CHCl3/MeOH 19:1). H NMR (250 MHz, CDCl3) d:
1.32 (t, JZ7.1 Hz, 3H, CH2CH3), 4.26 (q, JZ7.1 Hz, 2H,
CH2CH3), 5.23 (s, 2H, CH2C6H5), 6.85 (ddd, JZ8.7, 0.92,
0.30 Hz, 1H, Aryl-H), 7.07 (dd, JZ8.7, 6.5 Hz, 1H, Aryl-
H), 7.29–7.46 (m, 5H, Aryl-H), 7.64 (d, JZ16.2 Hz, 1H.
CH]CHCO2Et), 7.94 (ddd, JZ6.54, 0.95, 0.46 Hz, 1H,
Aryl-H), 8.20 (d, JZ16.2 Hz, 1H, CH]CHCO2Et). 13C
NMR (62.9 MHz, CDCl3) d: 14.3 (C, CH2CH3), 60.7 (K,
CH2CH3), 71.5 (K, CH2C6H5), 109.0 (C, Aryl-C), 124.1
(C, Aryl-C), 126.4 (C, Aryl-C), 127.2 (C, 2C, Aryl-C),
128.6 (C, CH]CHCO2Et), 128.9 (C, 2C, Aryl-C), 129.2
(C, Aryl-C), 133.8 (C, CH]CHCO2Et), 134.9 (quat,
Aryl-C), 136.6 (quat, Aryl-C), 156.4 (quat, Aryl-C), 167.7
(quat, CO2Et). IR (KBr) n: 3121, 3074, 2983, 1714, 1696,
1627, 1558, 1499, 1463, 1434, 1394, 1367, 1312, 1282,
1257, 1233, 1212, 1177, 1146, 1088, 1045, 988, 869, 782,
743, 721, 689, 632, 583, 545 cmK1. MS (EI, 70 eV) 299.3
(1.02, MC), 283.3 (0.69), 226.1 (16.7), 210.1 (8.54), 107.9
(1.41), 90.9 (100.0). Anal. Calcd for C17H17NO4 (299.32) C
68.21, H 5.72, N 4.68. Found C 67.94, H 5.71, N 4.51.
3.1.8. (E)-Ethyl 3-(N-oxypyridin-2-yl)acrylate (7a). To a
cooled solution (0 8C) of 70% m-chlorperbenzoic acid
(1.45 g, 7.9 mmol, 1.1 equiv) in CH2Cl2 (50 ml) was added
a solution of (E)-9-Et (1.43 g, 8.1 mmol, 1.0 equiv) in
CH2Cl2 (10 ml). After 30 min the solution was refluxed for
20 h, cooled to room temperature and concentrated. The
crude product was purified by chromatography on neutral
aluminium oxide (CHCl3/MeOH 19:1) to give 7a (1.54 g,
8.0 mmol, 97%) as a yellow solid. Mp 71 8C. Rf 0.41
1
(CHCl3/MeOH 9:1). H NMR (300 MHz, CDCl3) d: 1.34
(t, JZ7.2 Hz, 3H, CH2CH3), 4.29 (q, JZ7.2 Hz, 2H,
CH2CH3), 6.98 (d, JZ16.3 Hz, 1H, CH]CHCO2Et),
7.23–7.29 (m, 2H, Aryl-H), 7.53–7.57 (m, 1H, Aryl-H),
8.07 (d, JZ16.3 Hz, 1H, CH]CHCO2Et), 8.25–8.28 (m,
1H, Aryl-H). 13C NMR (75.5 MHz, CDCl3) d: 14.3 (C,
CH2CH3), 61.0 (K, CH2CH3), 124.9 (C, CH]CHHCO2-
Et), 125.1 (C, Aryl-C), 125.7 (C, Aryl-C), 125.8 (C, Aryl-
C), 133.9 (C, Aryl-C), 140.4 (C, CH]CHCO2Et), 145.2
(quat, Aryl-C), 166.3 (quat, CO2Et). IR (KBr) n: 3090, 3042,
2980, 2440, 1700, 1625, 1480, 1425, 1365, 1305, 1230,
1180, 1020, 985, 875, 860, 832, 808, 740, 727, 580,
540 cmK1. MS (EI, 70 eV) m/z (%): 193.1 (6.1), 177.1 (5.7),
148.0 (21.3), 132.1 (19.9), 120.1 (100), 104.1 (7.7), 92.0
(74.8). Anal. Calcd for C10H11NO3 (193.20) C 62.17, H
5.74, N 7.25. Found C 61.97, H 5.65, N 7.18.
3.1.11. (E)-Ethyl 3-(3-(methoxy)-N-oxypyridin-2-yl)-
acrylate (7d). To the solution of (E)-6b-Et (2.07 g,
10.0 mmol, 1.0 equiv) in glacial acetic acid (4.08 g,
3.7 ml, 120.0 mmol, 12.0 equiv), hydrogen peroxide (30%,
3.85 g, 3.7 ml, 19.2 mmol, 1.9 equiv) was added, and the
mixture was heated for 12 h at 60 8C. The resulting solution

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
649
was concentrated under reduced pressure and the residue
was purified by chromatography on silica (ethyl acetate/
MeOH 49:1) to give 7d (1.80 g, 8.05 mmol, 81%) as a
ethyl acetate (100 ml), and the solution was filtrated,
concentrated and distilled under reduced pressure to get
9-Et (15.2 g; 85.8 mmol, 86%, E/ZZ95:5) as colorless oil
1
1
yellow solid. Mp 100 8C. Rf 0.24 (CHCl3/MeOH 9:1). H
(bp0.1 80 8C), Rf 0.33 (hexanes/ethyl acetate 1:1). H NMR
NMR (250 MHz, CDCl3) d: 1.34 (t, JZ7.2 Hz, 3H,
CH2CH3), 3.97 (s, 3H, OCH3), 4.28 (q, JZ7.1 Hz, 2H,
CH2CH3), 6.87 (ddd, JZ8.6, 0.89, 0.38 Hz, 1H, Aryl-H),
7.16 (dd, JZ8.7, 6.6 Hz, 1H, Aryl-H), 7.57 (d, JZ16.2 Hz,
1H, CH]CHCO2Et), 7.95 (ddd, JZ6.6, 0.99, 0.43 Hz, 1H,
Aryl-H), 8.14 (d, JZ16.2 Hz, 1H, CH]CHCO2Et). 13C
NMR (62.9 MHz, CDCl3) d: 14.3 (C, CH2CH3), 56.6 (C,
OCH3), 60.7 (K, CH2CH3), 107.5 (C, Aryl-C), 124.3 (C,
Aryl-C), 126.0 (C, Aryl-C), 129.3 (C, CH]CHCO2Et),
133.4 (C, CH]CHCO2Et), 136.1 (quat, Aryl-C), 157.4
(quat, Aryl-C), 167.6 (quat, CO2Et). IR (KBr) n: 3123, 2991,
2901, 1719, 1623, 1555, 1458, 1447, 1424, 1362, 1291,
1235, 1186, 1170, 1084, 984, 951, 872, 843, 785, 746, 684,
653, 622, 576, 545, 535, 511 cmK1. MS (EI, 70 eV) 223.1
(3.16, MC), 207.1 (13.9), 178.0 (22.2), 162.1 (38.4), 150.0
(54.6), 134.0 (20.4), 122.0 (39.7), 106.0 (10.3), 92.0 (100.0).
Anal. Calcd for C11H13NO4 (223.23) C 59.19, H 5.87, N
6.27. Found C 59.08, H 5.90, N 6.17.
(300 MHz, CDCl3) d: 1.34 (t, JZ7.2 Hz, 3H, CH2CH3),
4.28 (q, JZ7.2 Hz, 2H, CH2CH3), 6.92 (d, JZ15.7 Hz, 1H,
CH]CHCO2Et), 7.25–7.74 (m, 3H, Aryl-H), 7.69 (d, JZ
15.7 Hz, 1H, CH]CHCO2Et), 8.58–8.66 (m, 1H, Aryl-H).
3.1.14. (E)- and (Z)-Isopropyl 3-(pyridin-2-yl)acrylate
((E)-9-iPr and (Z)-9-iPr). To a stirred suspension of LiBr
(5.21 g, 60 mmol, 1.2 equiv) in dry acetonitrile (150 ml)
under nitrogen atmosphere was added at room temperature
triethylamine (5.57 g, 7.6 ml, 55 mmol, 1.1 equiv), triiso-
propyl phosphonoacetate (13.3 g, 50 mmol, 1.0 equiv) and
finally pyridine-2-carbaldehyde (8) (5.36 g, 4.8 ml,
50 mmol). The solution was stirred 48 h at room tempera-
ture. H2O (200 ml) was added and the aqueous layer was
extracted with ethyl acetate (3!100 ml). The combined
organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica (ethyl acetate/hexanes 1:2) to
yield (E)-9-iPr (5.91 g, 30.9 mmol, 62%) and (Z)-9-iPr
(0.27 g, 1.4 mmol, 2.9%). (E)-9-iPr: Rf 0.52 (ethyl acetate/
3.1.12. (E)-Isopropyl 3-(3-(methoxy)-N-oxypyridin-2-
yl)acrylate (7e). To a solution of (E)-6b-iPr (3.06 g,
13.8 mmol, 1.0 equiv) in glacial acetic acid (5.63 g,
5.0 ml, 166 mmol, 12.0 equiv), hydrogen peroxide (30%,
5.31 g, 5.0 ml, 46.8 mmol, 3.4 equiv) was added, and the
mixture was heated for 12 h at 60 8C. The resulting solution
was concentrated under reduced pressure, and the residue
was purified by chromatography on silica (ethyl acetate/
methanol 30:1) to give 7e (2.93 g, 12.3 mmol, 90%) as a
yellow solid. Rf 0.33 (CHCl3/MeOH 9:1). 1H NMR
(250 MHz, CDCl3) d: 1.31 (d, JZ6.3 Hz, 6H, CH(CH3)2),
3.96 (s, 3H, OCH3), 5.15 (hept, JZ6.3 Hz, 1H, CH(CH3)2),
6.84 (ddd, JZ8.6, 0.48, 0.48 Hz, 1H, Aryl-H), 7.14 (dd, JZ
8.7, 6.6 Hz, 1H, Aryl-H), 7.55 (d, JZ16.2 Hz, 1H,
CH]CHCO2i-Pr), 7.96 (ddd, JZ6.6, 0.99, 0.46 Hz, 1H,
Aryl-H), 8.13 (ddd, JZ16.2, 0.45, 0.45 Hz, 1H,
CH]CHCO2i-Pr). 13C NMR (62.9 MHz, CDCl3) d: 21.9
(C, 2C, CH(CH3)2), 56.5 (C, OCH3), 68.1 (C, CH(CH3)2),
107.4 (C, Aryl-C), 124.1 (C, Aryl-C), 126.7 (C, Aryl-C),
129.0 (C, CH]CHCO2i-Pr), 133.5 (C, CH]CHCO2i-Pr),
136.3 (quat, Aryl-C), 157.4 (quat, Aryl-C), 167.2 (quat,
CO2i-Pr). IR (KBr) n: 3117, 3094, 3061, 2979, 2954, 2932,
1712, 1629, 1595, 1562, 1477, 1422, 1375, 1361, 1313,
1293, 1265, 1221, 1203, 1100, 1074, 985, 959, 911, 871,
789, 740, 545 cmK1. MS (DCI, NH3) m/z (%): 255.3 (4.1,
MCNHC4 ), 238.3 (10.7, MHC), 222.2 (100). Anal. Calcd
for C12H15NO4 (237.25): C 60.75, H 6.37, N 5.90. Found C
60.14, H 6.36, N 5.88.
1
hexane 1:1). H NMR (300 MHz, CDCl3) d: 1.31 (d, JZ
6.3 Hz, 6H, CH(CH3)2), 5.15 (hept, JZ6.3 Hz, 1H,
CH(CH3)2), 6.89 (d, JZ15.6 Hz, 1H, CH]CHCO2i-Pr),
7.23-7.73 (m, 3H, Aryl-H), 7.67 (d, JZ15.7 Hz, 1H,
CH]CHCO2i-Pr), 8.63–8.65 (m, 1H, Aryl-H). 13C NMR
(62.9 MHz, CDCl3) d: 21.9 (C, 2C, CH(CH3)2), 67.9 (C,
CH(CH3)2), 123.0 (C, Aryl-C), 123.9 (C, Aryl-C), 124.1
(C, Aryl-C), 136.7 (C, CH]CHCO2i-Pr), 143.0 (C,
CH]CHCO2i-Pr), 150.1 (C, Aryl-C), 153.1 (quat, Aryl-
C), 166.2 (quat, CO2i-Pr). MS (EI, 70 eV) m/z (%): 191.0
(19.6, MHC), 148.9 (21.4), 145.9 (14.6), 131.9 (100.0). IR
(film) n: 3051, 2981, 2937, 2875, 1721, 1647, 1581, 1468,
1433, 1373, 1350, 1315, 1296, 1275, 1109, 1049, 985, 916,
876, 823, 787, 744 cmK1. Anal. Calcd for C11H13NO2
(191.23): C 69.09, H 6.85, N 7.32. Found C 69.00, H 6.82, N
7.38. (Z)-9-iPr: Rf 0.40 (ethyl acetate/hexanes 1:1). 1H
NMR (300 MHz, CDCl3) d: 1.24 (d, JZ6.2 Hz, 6H,
CH(CH3)2), 5.10 (hept, JZ6.3 Hz, 1H, CH(CH3)2), 6.11
(d, JZ12.5 Hz, 1H, CH]CHCO2i-Pr), 6.91 (d, JZ12.5 Hz,
1H, CH]CHCO2i-Pr), 7.16–7.21 (m, 1H, Aryl-H), 7.59–
7.69 (m, 2H, Aryl-H), 8.58 (d, JZ4.8 Hz, 1H, Aryl-H). 13C
NMR (62.9 MHz, CDCl3) d: 21.7 (C, 2C, CH(CH3)2), 68.1
(C, CH(CH3)2), 122.9 (C, Aryl-C), 123.7 (C, Aryl-C),
124.3 (C, CH]CHCO2i-Pr), 135.9 (C, Aryl-C), 138.9 (C,
CH]CHCO2i-Pr), 149.1 (C, Aryl-C), 153.7 (quat, Aryl-
C), 166.3 (quat, CO2i-Pr). MS (EI, 70 eV) m/z (%): 191.0
(10.3, MHC), 247.9 (31.4), 131.9 (100.0), 104.9 (39.0), 77.9
(27.6). IR (film) n: 3053, 2981, 2935, 2877, 1720, 1637,
1585, 1566, 1468, 1435, 1387, 1373, 1244, 1211, 1178,
1147, 1109, 1049, 995, 960, 904, 835, 798, 746 cmK1. Anal.
Calcd for C11H13NO2 (191.23): C 69.09, H 6.85, N 7.32.
Found C 68.80, H 6.80, N 7.34.
3.1.13. (E)-Ethyl 3-(pyridin-2-yl)acrylate (9-Et).21 To a
stirred suspension of LiBr (10.4 g, 120 mmol, 1.2 equiv) in
dry acetonitrile (250 ml) was added triethylamine (11.1 g,
15.3 ml, 110 mmol, 1.1 equiv), triethyl phosphonoacetate
(22.4 g, 20.0 ml 100 mmol, 1.0 equiv) and finally pyridine-
2-carbaldehyde (8) (10.7 g, 9.7 ml, 100 mmol, 1.0 equiv).
The solution was stirred for 18 h at room temperature. H2O
(200 ml) was added and the aqueous layer was extracted
with ethyl acetate (5!50 ml). The combined organic layers
were dried over MgSO4 and the solution was concentrated
under reduced pressure. The crude product was dissolved in
3.2. General procedure GP1 for the dihydroxylation of 7
A mixture of AD-mix (1.40 g), methansulfonamide (95 mg,
1.0 mmol, 1.0 equiv) and 7 (1.0 mmol, 1.0 equiv) in tert-
butanol–water (15 ml, 1:1 v/v) was stirred vigorously at
room temperature. After 24 h water (5 ml) was added and

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
650
the aqueous layer was extracted ten times with CHCl3/
MeOH (9:1 v/v, 20 ml each). The combined organic layers
were dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by chromato-
graphy on silica to give 10.
226.1 (65), 224.1 (24), 208 (6.9), 125.0 (4.1), 108.0 (30).
HRMS (C11H16NO5) calcd 242.1028, found 242.1028.
Determination of the enantiomeric excess by chiral HPLC:
Kontron HPLC 325, det.: UV (250 nm), Daicel Chiralcel
OD-H, hexane/ethanol 95:5, 0.8 ml/min, 20 8C, ret.-times:
51.4 min (10b), 62.9 min ((ent)-10b).
3.2.1. (2R,3S)-Ethyl 2,3-dihydroxy-3-(N-oxypyridin-2-
yl)propanoate (10a). According to GP1 10a (86 mg,
0.39 mmol, 39%) was obtained as colorless solid. Rf 0.24
3.2.4. (2S,3R)-Isopropyl 2,3-dihydroxy-3-(N-oxypyridin-
2-yl)propanoate ((ent)-10b). According to GP1 (ent)-10b
(157 mg, 0.65 mmol, 65%) was obtained as colorless solid.
Analytical data according to 10b; [a]2D0ZK21.2 (cZ0.99,
CHCl3). Determination of the enantiomeric excess by chiral
HPLC: Kontron HPLC 325, det.: UV (250 nm), Daicel
Chiralcel OD-H, hexane/ethanol 95:5, 0.8 ml/min, 20 8C,
ret.-times: 49.4 min (10b), 53.9 min ((ent)-10b).
1
(CHCl3/MeOH 9:1). [a]2D0ZC14.1 (cZ0.69, CHCl3). H
NMR (250 MHz, [D6]-DMSO) d: 1.20 (t, JZ7.1 Hz, 3H,
CH2CH3), 4.14 (q, JZ7.1 Hz, 2H, CH2CH3), 4.69 (dd, JZ
7.9, 2.4 Hz, 1H, CHOHCO2Et), 5.30 (d, JZ7.9 Hz, 1H,
CHOHCO2Et), 5.39 (dd, JZ6.9 Hz, 1H, CHOHCHOHCO2-
Et), 5.94 (d, JZ6.9 Hz, 1H, CHOHCHOHCO2Et), 7.33
(ddd, JZ7.6, 6.0, 2.3 Hz, 1H, Aryl-H), 7.39 (ddd, JZ7.7,
7.6, 1.4 Hz, 1H, Aryl-H), 7.57 (dd, JZ7.5, 2.3 Hz, 1H,
Aryl-H), 8.22 (ddd, JZ5.9, 1.5, 0.44 Hz, 1H, Aryl-H). 13C
NMR (75.5 MHz, D2O) d: 13.5 (C, CH2CH3), 62.9 (K,
CH2CH3), 69.4 (C, CHOHCHOHCO2Et), 70.8 (C,
CHOHCHOHCO2Et), 125.9 (C, Aryl-C), 126.1 (C, Aryl-
C), 131.6 (C, Aryl-C), 139.6 (C, Aryl-C), 150.4 (quat,
Aryl-C), 173.3 (quat, CO2Et). IR (KBr) n: 3411, 3235, 2993,
1920, 2852, 1723, 1489, 1437, 1283, 1248, 1224, 1128,
1068, 831, 772, 682, 552 cmK1. MS (DCI) m/z (%): 228.2
(42.5, MHC), 212.2 (100.0), 210.2 (26.6), 194.1 (19.8),
178.1 (7.2), 125.1 (12.6), 108.1 (58.1). Anal. Calcd for
C10H13NO5 (227.21): C 52.86, H 5.77, N 6.16. Found C
52.53, H 5.70, N 6.11. Determination of the enantiomeric
excess by chiral HPLC: Kontron HPLC 325, det.: UV
(250 nm), Daicel Chiralcel OD-H, hexane/ethanol
90:10, 1 ml/min, 20 8C, ret.-times: 18.6 min (10a),
20.9 min ((ent)-10a).
3.2.5. (2R,3S)-Ethyl 3-(3-(benzyloxy)N-oxypyridin-2-yl)-
2,3-dihydroxypropanoate (10c). According to GP1 10c
(185 mg, 0.55 mmol, 55%) was obtained as colorless solid.
Rf 0.12 (ethyl acetate/MeOH 50:1). [a]2D0ZK39.0 (cZ1.23,
CHCl3). 1H NMR (250 MHz, CDCl3) d: 1.23 (t, JZ7.2 Hz,
3H, CH2CH3), 4.14–4.29 (m, 2H, CH2CH3), 4.60 (d, JZ
3.7 Hz, 1H, CHOHCO2Et), 5.03 (bs, 1H, OH), 5.12–5.24
(m, 2H, CH2Ph), 5.71 (d, JZ3.7 Hz, 1H, CHOHCHOHCO2-
Et), 7.10 (dd, JZ8.7, 0.7 Hz, 1H, Aryl-H, 7.24 (ddd, JZ8.7,
6.4, 0.2 Hz, 1H, Aryl-H), 7.33–7.42 (m, 5H, Aryl-H), 7.66
(bs, 1H, OH), 7.92 (ddd, JZ6.4, 0.74, 0.24 Hz, 1H, Aryl-H).
13C NMR (75.5 MHz, CDCl3) d: 14.1 (C, CH2CH3), 61.4
(K, CH2CH3), 70.0 (C, CHOHCHOHCO2Et), 71.4 (K,
CH2Ph), 74.9 (C, CHOHCO2Et), 112.8 (C, Aryl-C), 124.7
(C, Aryl-C), 127.0 (C, 2C, Aryl-C), 128.6 (C, Aryl-C),
128.9 (C, 2C, Aryl-C), 133.3 (C, Aryl-C), 134.7 (quat,
Aryl-C), 139.2 (quat, Aryl-C), 154.1 (quat, Aryl-C), 171.4
(quat, CO2Et). IR (KBr) n: 3335, 3094, 2981, 1746, 1569,
1438, 1388, 1289, 1199, 1128, 1062, 862, 791, 741,
697 cmK1. MS (FAB, pos) m/z (%): 667.2 (3.9), 334.1
(100, MHC), 318.1 (8.4), 230.0 (9.1). HRMS (C17H20NO6)
calcd 334.1291, found 334.1287. Determination of the
enantiomeric excess by chiral HPLC: Kontron HPLC 325,
det.: UV (260 nm), Daicel Chiralcel OD-H, hexane/ethanol
90:10, 1 ml/min, 20 8C, ret.-times: 52.7 min (10c), 58.1 min
((ent)-10c).
3.2.2. (2S,3R)-Ethyl 2,3-dihydroxy-3-(N-oxypyridin-2-
yl)propanoate ((ent)-10a). According to GP1 (ent)-10a
(82 mg, 0.36 mmol, 36%) was obtained as colorless solid.
Analytical data according to 10a; [a]2D0ZK25.3 (cZ1.03,
CHCl3). Determination of the enantiomeric excess by chiral
HPLC: Kontron HPLC 325, det.: UV (250 nm), Daicel
Chiralcel OD-H, hexane/ethanol 90:10, 1 ml/min, 20 8C,
ret.-times: 18.0 min (10a), 19.7 min ((ent)-10a).
3.2.6. (2S,3R)-Ethyl 3-(3-(benzyloxy)N-oxypyridin-2-yl)-
2,3-dihydroxypropanoate ((ent)-10c). According to GP1
(ent)-10c (197 mg, 0.59 mmol, 59%) was obtained as
colorless solid. Analytical data according to 10c;
[a]2D0ZC44.7 (cZ0.97, CHCl3). Determination of the
enantiomeric excess by chiral HPLC: Kontron HPLC 325,
det.: UV (260 nm), Daicel Chiralcel OD-H, hexane/ethanol
90:10, 1 ml/min, 20 8C, ret.-times: 53.9 min (10c), 57.2 min
((ent)-10c).
3.2.3. (2R,3S)-Isopropyl 2,3-dihydroxy-3-(N-oxypyridin-
2-yl)propanoate (10b). According to GP1 10b (158 mg,
0.66 mmol, 66%) was obtained as colorless solid. Rf 0.24
1
(CHCl3/MeOH 9:1). [a]2D0ZC26.7 (cZ0.88, CHCl3). H
NMR (250 MHz, [D6]-DMSO) d: 1.21 (dd, JZ6.2, 3.8 Hz,
6H, CH(CH3)2), 4.56 (dd, JZ7.9, 2.5 Hz, 1H, CHOHCO2i-
Pr), 4.96 (hept, JZ6.3 Hz, 1H, CH(CH3)2), 5.23 (d, JZ
7.9 Hz, 1H, CHOHCO2i-Pr), 5.36 (dd, JZ6.9, 2.4 Hz,
1H, CHOHCHOHCO2i-Pr), 5.89 (d, JZ6.9 Hz, 1H,
CHOHCHOHCO2i-Pr), 7.28–7.44 (m, 2H, Aryl-H), 7.55
(dd, JZ7.6, 2.5 Hz, 1H, Aryl-H), 8.22 (ddd, JZ5.8, 1.6,
0.66 Hz, 1H, Aryl-H). 13C NMR (75.5 MHz, CDCl3) d:
21.57, 21.67 (C, 2C, CH(CH3)2), 67.8, 69.2, 69.8 (C, 3C,
CHOHCHOHCO2i-Pr, CHOHCO2i-Pr and CH(CH3)2),
124.6 (C, Aryl-C), 125.1 (C, Aryl-C), 125.4 (C, Aryl-
C), 138.7 (C, Aryl-C), 151.2 (quat, Aryl-C) 171.7 (quat,
CO2i-Pr). IR (film) n: 3386, 3203, 3120, 2983, 2937, 1747,
1726, 1637, 1489, 1437, 1375, 1321, 1277, 1261, 1199,
1132, 1105, 1068, 970, 914, 827, 769, 682 cmK1. MS (DCI,
NH3) m/z (%): 483.3 (2.0), 467.3 (0.4), 242.1 (100, MHC),
3.2.7. (2R,3S)-Ethyl 3-(3-(methoxy)N-oxypyridin-2-yl)-
2,3-dihydroxypropanoate (10d). According to GP1 10d
(134 mg, 0.52 mmol, 52%) was obtained as colorless solid.
Mp 103 8C. Rf 0.30 (CHCl3/MeOH 9:1). [a]2D0ZK122.0
1
(cZ0.86, CHCl3). H NMR (250 MHz, CDCl3) d: 1.29 (t,
JZ7.1 Hz, 3H, CH2CH3), 3.94 (s, 3H, OCH3), 4.27 (q, JZ
7.1 Hz, 2H, CH2CH3), 4.56 (dd, JZ6.1, 4.1 Hz, 1H,
CHOHCO2Et), 5.04 (d, JZ6.8 Hz, 1H, OH), 5.59 (dd, JZ
11.0, 4.0 Hz, 1H, CHOHCHOHCO2Et), 7.07 (dd, JZ8.8,
0.81 Hz, 1H, Aryl-H), 7.31 (dd, JZ8.8, 6.6 Hz, 1H,

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
651
Aryl-H), 7.59 (d, JZ11.1 Hz, 1H, OH), 7.94 (dd, JZ6.5,
0.84 Hz, 1H, Aryl-H). 13C NMR (75.5 MHz, CDCl3) d: 14.2
(C, CH2CH3), 56.8 (C, OCH3), 61.5 (K, CH2CH3), 69.8
(C, CHOHCHOHCO2Et), 75.0 (C, CHOHCO2Et), 111.4
(C, Aryl-C), 124.8 (C, Aryl-C), 133.1 (C, Aryl-C), 138.9
(quat, Aryl-C), 155.1 (quat, Aryl-C), 171.4 (quat, CO2Et).
IR (film) n: 3392, 3097, 2990, 2938, 1756, 1739, 1604,
1570, 1467, 1430, 1364, 1339, 1280, 1196, 1131, 1079,
1057, 1029, 967, 877, 784, 767, 693, 680, 647, 597, 562,
519 cmK1. MS (DCI, NH3) m/z (%): 258.2 (100.0, MHC),
242.2 (75.4), 224.2 (12.8), 138.1 (59.6). Anal. Calcd for
C11H15NO6 (257.24): C 51.36, H 5.88, N 5.45. Found C
GP1 (ent)-10e (138 mg, 0.54 mmol, 54%) was obtained
as colorless solid. Analytical data according to 10e;
[a]2D0ZC105.9 (cZ1.16, CHCl3). Chiral shift 1H NMR
spectroscopy using (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol
indicated an enantiomeric excess O93%.
3.2.11. Measurement of the enantiomeric excess of 10d–e
and (ent)-10d-e. The measurement of the enantiomeric
excess of 10d and 10e was performed by NMR utilizing
the solvating agent (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol
(Pirkle alcohol) in CDCl3. For this purpose, 10d–e (4 mg)
was dissolved in 1.0 ml of CDCl3. To this solution was
added (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol (10 mg for
10e, 21 mg for 10d). The 1H NMR spectrum of this mixture
was run in order to determine the ee. A similar analysis was
performed on racemic mixture of 10d and 10e.
1
51.39, H 5.83, N 5.41. Chiral shift H NMR spectroscopy
using (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol indicated an
enantiomeric excess O97%.
3.2.8. (2S,3R)-Ethyl 3-(3-(methoxy)N-oxypyridin-2-yl)-
2,3-dihydroxypropanoate ((ent)-10d). According to GP1
(ent)-10d (138 mg, 0.54 mmol, 54%) was obtained as
colorless solid. Analytical data according to 10d;
[a]2D0ZC122.7 (cZ1.21, CHCl3). Chiral shift 1H NMR
spectroscopy using (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol
indicated an enantiomeric excess O98%.
3.3. Synthesis of swainsonine (1b)
3.3.1. (1R,2S,8aS)- and (1R,2S,8aR)-1,2-Dihydroxy-hexa-
hydroindolizin-3(5H)-one (11a and 11b). A solution of
(ent)-10b (8.06 g, 33.4 mmol, 1.0 equiv) in MeOH (50 ml)
was stirred at room temperature in the presence of
PtO2$H2O (82 mg, 0.33 mmol, 0.01 equiv) under an
atmospheric pressure of hydrogen for 14 d. After removal
of the catalyst by filtration through a celite pad, the solvent
was removed under reduced pressure. The residue was
purified by chromatography on silica (CHCl3/MeOH 9:1) to
give 11 as a mixture of epimers (5.08 g, 29.7 mmol, 89%,
11a:11bZ60:40). For analytical purposes, a small sample
of 11 was separated by converting the diol to the
corresponding bis-OTBDMS ether followed by chromato-
graphy on silica. Subsequent cleavage with TBAF resulted
in pure samples of 11a or 11b, respectively. 11a: Rf 0.15
3.2.9. (2R,3S)-Isopropyl 3-(3-(methoxy)N-oxypyridin-2-
yl)-2,3-dihydroxypropanoate (10e). A mixture of AD-mix
a (11.0 g) and methansulfonamide (0.75 g, 7.88 mmol,
1.0 equiv) in tert-butanol–water (120 ml, 1:1 v/v) was
stirred vigorously at room temperature. After 30 min the
(E)-7e (1.87 g, 7.88 mmol, 1.0 equiv) was added and
stirring was continued for 18 h. H2O (30 ml) was added
and the aqueous layer was extracted five times with CHCl3/
MeOH (9:1 v/v, 25 ml each). The combined organic layers
were dried over MgSO4. Evaporation of the solvent at
reduced pressure afforded a yellow oil, which was
fractionated by chromatography on silica gel (CHCl3/
MeOH 19:1) to give 10e (1.99 g, 7.32 mmol, 93%) as a
colorless solid. Rf10.42 (CHCl3/MeOH 9:1). [a]2D0ZK101.7
(c 1.16, CHCl3). H NMR (300 MHz, CDCl3) d: 1.29 (dd,
JZ8.6, 6.3 Hz, 6H, CH(CH3)2), 3.94 (s, 3H, OCH3), 4.54
(dd, JZ6.9, 4.1 Hz, 1H, CHOHCO2i-Pr), 4.97 (d, JZ
6.9 Hz, 1H, CHOHCO2i-Pr), 5.14 (hept, JZ6.3 Hz, 1H,
CH(CH3)2), 5.57 (dd, JZ11.2, 4.1 Hz, 1H,
CHOHCHOHCO2i-Pr), 7.00 (dd, JZ8.7, 0.82 Hz, 1H,
Aryl-H), 7.27 (dd, JZ8.7, 6.5 Hz, 1H, Aryl-H), 7.51 (d,
JZ11.2 Hz, 1H, CHOHCHOHCO2i-Pr), 7.92 (dd, JZ6.5,
0.74 Hz, 1H, Aryl-H). 13C NMR (75.5 MHz, CDCl3) d:
21.7, 21.8 (C, 2C, CH(CH3)2), 56.7 (C, OCH3), 69.4 (C,
CH), 69.8 (C, CH), 74.9 (C, CH), 111.1 (C, Aryl-C),
124.6 (C, Aryl-C), 133.1 (C, Aryl-C), 139.1 (quat, Aryl-
C), 155.1 (quat, Aryl-C), 171.0 (quat, CO2i-Pr). MS (DCI,
NH3) m/z (%): 272.2 (7.6, MHC), 152.1 (10.2), 138.0 (100),
124.0 (16.7), 110.0 (28.0), 96.0 (6.2). IR (film) n: 3369,
3281, 3103, 3011, 2985, 2919, 2852, 1744, 1603, 1571,
1473, 1435, 1375, 1355, 1291, 1218, 1193, 1134, 1110,
1093, 1080, 1055, 968, 915, 874, 826, 787, 760, 695,
648 cmK1. Anal. Calcd for C12H17NO6 (271.27): C 53.15, H
6.32, N 5.16. Found C 53.10, H 6.44, N 5.30. Chiral shift 1H
NMR spectroscopy using (S)-2,2,2-trifluoro-1-(9-anthryl)-
ethanol indicated an enantiomeric excess O97%.
(CHCl3/MeOH 9:1). [a]2D0ZK61.4 (cZ1.04, CHCl3) H
1
NMR (250 MHz, CD3OD) d: 1.03–1.52 (m, 3H, Piperidin-
H), 1.64–1.76 (m, 1H, Piperidin-H), 1.80–1.92 (m, 1H,
Piperidin-H), 2.04–2.16 (m, 1H, Piperidin-H), 2.64 (dddd,
JZ13.0, 12.7, 3.7, 1.7 Hz, 1H, CH2N), 3.07 (ddd, JZ11.5,
6.5, 3.8 Hz, 1H, NCH), 3.65 (dd, JZ7.4, 6.5 Hz, 1H,
NCHCHOH), 3.92–4.02 (m, 1H, CH2N), 4.02 (dd, JZ7.4,
1.7 Hz, 1H, N(CO)CHOH). 13C NMR (250 MHz, CD3OD)
d: 24.1 (K, NCHCH2CH2), 25.3 (K, CH2), 31.7 (K,CH2),
40.7 (K, NCH2), 60.5 (C, NCH), 77.6 (C, NCHCHOH),
80.9 (C, N(CO)CHOH), 173.0 (quat, N(CO)). IR (KBr) n:
3444, 3347, 3256, 2963, 2932, 1871, 1686, 1460, 1425,
1278, 1253, 1151, 1080, 1026, 838, 654, 611, 555 cmK1
.
Anal. Calcd for C8H13NO3 (171.19): C 56.13, H 7.56, N
8.18. Found C 55.79, H 7.62, N 8.08. 11b: Rf 0.15 (CHCl3/
MeOH 9:1). [a]D20ZK58.4 (cZ0.93, CHCl3) 1H NMR
(250 MHz, CDCl3) d: 1.13–153 (m, 3H, Piperidin-H), 1.53–
1.72 (m, 1H, Piperidin-H), 1.73–2.05 (m, 2H, Piperidin-H),
2.51–2.76 (m, 1H, NCH2), 3.40–3.64 (m, 1H, NCH), 3.94–
4.13 (m, 1H, N(CO)CHOH), 4.20–4.39 (m, 2H,
NCHCHOH, NCH2). 13C NMR (62.9 MHz, CDCl3) d:
23.7 (K, NCHCH2CH2), 24.9 (K, NCH2CH2), 25.9 (K,
NCHCH2), 41.0 (K, NCH2), 58.7 (C, NCH), 73.1 (C,
NCHCHOH), 76.3 (C, N(CO)CHOH), 171.2 (quat,
N(CO)). IR (film) n: 3362, 2926, 2856, 1676, 1446, 1357,
1281, 1227, 1152, 1103, 1004, 855, 804 cmK1. MS (DCI,
NH3) m/z (%): 343.2 (5.2), 189.1 (100, MHC), 172.1 (42),
155.1 (6.7), 138.0 (5.9). HRMS (C8H13NO3) calcd
171.0895, found 171.0897.
3.2.10. (2S,3R)-Isopropyl 3-(3-(methoxy)N-oxypyridin-2-
yl)-2,3-dihydroxypropanoate ((ent)-10e). According to

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
652
3.3.2. (1R,2S,8aS)- and (1R,2S,8aR)-1-Hydroxy-3-oxo-
octahydroindolizin-2-yl benzoate (12a and 12b). To a
stirred solution of the epimeric mixture of 11 (11a:11bZ
60:40, 1.10 g, 6.43 mmol, 1.0 equiv) in pyridine (30.0 ml)
and DMAP (0.01 g, 0.06 mmol, 0.01 equiv) was added
dropwise with a syringe pump a solution of benzoyl chloride
(0.81 g, 5.78 mmol, 0.9 equiv) in pyridine (5.0 ml) at
K30 8C during 1 h. The mixture was stirred for an
additional 80 min at K30 8C and was then allowed to
warm up during 2 h to 0 8C and subsequently kept in the
refrigerator (C4 8C) for 12 h. Ethyl acetate was added
(50 ml) and the mixture was washed with 2 N HCl (20 ml).
The aqueous layer was washed twice with ethyl acetate
(50 ml) and the combined organic layers were washed with
brine (50 ml) and then again with 2 N HCl (10 ml). The
organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
chromatography on silica (ethyl acetate/hexanes 5:1) to
give 12 as a mixture of epimers (12a:12bZ60:40, 1.49 g,
5.41 mmol, 84%). IR (KBr) n: 3334, 3244, 2950, 2870,
1678, 1455, 1335, 1304, 1240, 1167, 1123, 1106, 1001, 915,
829, 731, 663, 507, 3464, 2940, 2859, 1693, 1445, 1372,
1317, 1287, 1267, 1219, 1147, 1107, 1080, 978, 930, 912,
867, 837, 799, 731, 573, 503, 436, 3505, 3065, 2943, 2858,
1698, 1601, 1447, 1341, 1318, 1273, 1157, 1113, 1105, 984,
860, 802, 708, 586, 449 cmK1. (EI, 70 eV) m/z (%): 275.1
(4.9, MC$), 257.1 (5.1), 154.1 (30.7), 153.0 (92.0), 122.0
(13.1), 105.0 (100.0), 84.0 (63.6), 83.0 (21.7), 77.0 (47.5),
51.0 (13.0). HRMS (C15H17NO4) calcd 275.1158, found
275.1158. For analytical purposes, a small sample of 12 was
separated by column chromatography. 12a: Rf 0.41 (ethyl
acetate/hexanes 5:1). 1H NMR (300 MHz, CDCl3) d: 1.13–
1.77 (m, 4H, CH2), 1.90–2.08 (m, 2H, CH2), 2.69–2.81 (m,
1H), 3.63–3.75 (m, 1H), 4.22–4.31 (m, 1H), 4.47 (dd, JZ
8.1, 5.7 Hz, 1H), 5.21 (d, JZ5.7 Hz, 1H), 7.41–7.50 (m, 2H,
Aryl-H), 7.60–7.64 (m, 1H, Aryl-H), 8.08–8.13 (m, 2H,
Aryl-H). 13C NMR (75 MHz, CDCl3) d: 23.8 (K, CH2),
24.9 (K, CH2), 26.7 (K, CH2), 41.1 (K, CH2), 58.5 (C,
CH), 72.4 (C, CH), 80.6 (C, CH), 128.5 (C, 2C, Aryl-C),
128.6 (quat, Aryl-C), 130.23 (C, 2C, Aryl-C), 133.91 (C,
Aryl-C), 165.5 (quat, COPh), 168.2 (quat, NCO). 12b: Rf
0.36 (ethyl acetate/hexanes 5:1). 1H NMR (300 MHz,
CDCl3) d: 1.17–1.50 (m, 3H), 1.73–1.81 (m, 1H), 1.90–
1.99 (m, 1H), 2.18–2.27 (m, 1H), 2.67–2.97 (m, 1H), 3.29–
3.38 (m, 1H), 4.03 (t, JZ6.2 Hz, 1H), 4.16–4.25 (m, 1H),
5.29 (dd, JZ6.2, 1.5 Hz, 1H), 7.41–7.49 (m, 2H), 7.57–7.64
(m, 1H), 8.09–8.14 (m, 2H). 13C NMR (75 MHz, CDCl3) d:
23.1 (K, CH2), 23.9 (K, CH2), 31.1 (K, CH2), 40.1 (K,
CH2), 59.5 (C, CH), 78.8 (C, CH), 80.9 (C, CH), 128.5
(C, 2C, Aryl-C), 128.6 (quat, Aryl-C), 130.3 (C, 2C, Aryl-
C), 133.9 (C, Aryl-C), 165.8 (quat, CO), 168.3 (quat, CO).
with CH2Cl2 (4!15 ml). The combined organic layers were
extracted with aqueous NaHCO3 (20 ml), dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography on silica (ethyl
acetate/hexane 5:1) to yield 13 as a mixture of epimers
(0.58 g, 2.11 mmol, 53% yield). (EI, 70 eV) m/z (%): 275.1
(3.6, MC$), 153.0 (100.0), 105.0 (69.3), 84.0 (36.4), 77.0
(37.1). HRMS (C15H17NO4) calcd 275.1158, found
275.1158. For analytical purposes, a small sample of 13
was separated by column chromatography: 13a: Rf 0.12
(hexanes/ethyl acetate 1:5). [a]2D0ZK15.4 (cZ1.3, CHCl3).
1H NMR (300 MHz, CDCl3) d: 1.18–1.53 (m, 3H), 1.63–
1.73 (m, 1H), 1.88–1.99 (m, 1H), 2.04–2.13 (m, 1H), 2.74
(dt, JZ35, 12.9 Hz, 1H), 3.55–2.63 (m, 1H), 4.12–4.20 (m,
1H), 4.53 (d, JZ6.4 Hz, 1H), 5.23 (dd, JZ6.4, 2.4 Hz, 1H),
7.28–7.45 (m, 2H), 7.52–7.59 (m, 1H), 8.05–8.10 (m, 2H).
13C NMR (75 MHz, CDCl3) d: 23.6 (K, CH2), 24.4 (K,
CH2), 29.5 (K, CH2), 40.8 (K, CH2), 61.0 (C, CH), 69.3
(C, CH), 72.5 (C, CH), 128.4 (C, 2C, Aryl-C), 129.4
(quat, Aryl-C), 130.0 (C, 2C, Aryl-C), 133.4 (C, Aryl-C),
166.2 (quat, CO), 170.5 (quat, CO). 13b: Rf 0.21 (hexanes/
ethyl acetate 1:5). [a]2D0ZK24.7 (cZ1.5, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 1.38–1.57 (m, 3H), 1.70–1.82 (m,
2H), 1.90–1.97 (m, 1H), 2.67–2.79 (m, 1H), 2.8–2.99 (bs,
1H, OH), 3.63–3.70 (m, 1H), 4.13–4.22 (m, 1H), 4.47 (dd,
JZ5.6, 1.7 Hz, 1H), 5.78 (dd, JZ5.6, 4.2 Hz, 1H), 7.41–
7.48 (m, 1H), 7.54–7.61 (m, 1H), 8.02–8.07 (m, 2H). 13C
NMR (75 MHz, CDCl3) d: 22.9 (K, CH2), 24.0 (K, CH2),
24.9 (K, CH2), 40.4 (K, CH2), 56.6 (C, CH), 69.8 (C,
CH), 70.7 (C, CH), 128.5 (C, 2C, Aryl-C), 129.2 (quat,
Aryl-C), 129.9 (C, 2C, Aryl-C), 133.5 (C, Aryl-C), 165.9
(quat, CO), 171.4 (quat, CO).
3.3.4. (1S,2S,8aS)- and (1S,2S,8aR)-1,2-Dihydroxyhexa-
hydroindolizin-3-one (14a and 14b). To a solution of 13
(0.52 g, 1.89 mmol) in anhydrous methanol (10 ml) was
added under stirring 0.1 N MeONa (2 ml) at room
temperature. Stirring was continued for 3 h (TLC control),
subsequently a small piece of dry ice was added, and the
mixture was concentrated under reduced pressure. The
residue was purified by chromatography on silica (CHCl3/
MeOH 9:1) to give 14 (0.25 g, 1.48 mmol, 78% yield).
IR (KBr) n: 3334, 3244, 2950, 2870, 1678, 1455, 1335,
1304, 1240, 1167, 1123, 1106, 1001, 915, 829, 731, 663,
507 cmK1. MS (EI, 70 eV) m/z (%). 171.0 (47, MC$), 142.0
(34.0), 128.0 (16), 127.0 (10), 126.0 (40), 110.0 (14), 84
(100), 83.0 (26), 82.0 (12), 70.0 (11), 60.0 (24), 56.0 (16),
55.0 (29), 41.0 (19.3). HRMS (C8H13NO3) calcd 171.0895,
found 171.0896. For analytical purposes, a small sample of
14 was separated by column chromatography. 14a14: Rf 0.43
(CHCl3/MeOH 9:1). [a]2D0ZK15.0 (cZ1.07, MeOH). H
1
NMR (600 MHz, [D6]-DMSO) d: 1.00–1.15 (m, 2H), 1.33–
1.41 (m, 1H), 1.55–1.61 (m, 1H), 1.74–1.79 (m, 1H), 1.83–
1.88 (m, 1H), 2.60 (dt, JZ12.9, 3.52 Hz, 1H), 5.15 (dt, JZ
12.0, 3.3 Hz, 1H), 3.69–3.73 (m, 1H), 3.87 (dd, JZ12.9,
4.8 Hz, 1H), 3.91 (t, JZ5.4 Hz, 1H), 4.84 (d, JZ5.4 Hz,
1H), 5.37 (d, JZ6.4 Hz, 1H). 13C NMR (75 MHz, [D6]-
DMSO) d: 22.9 (K, CH2), 24.1 (K, CH2), 29.0 (K, CH2),
39.3 (K, CH2), 61.5 (C, CH), 69.6 (C, CH), 70.7 (C, CH),
170.4 (quat, CO). 14b: Rf 0.38 (CHCl3/MeOH 9:1).
[a]2D0ZK60.0 (cZ1.30, MeOH). 1H NMR (600 MHz,
[D6]-DMSO) d: 1.16–1.24 (m, 1H), 1.32–1.41 (m, 1H),
1.46–1.51 (m, 1H), 1.53–1.60 (m, 1H), 1.61–1.66 (m, 1H),
3.3.3. (1S,2S,8aS)- and (1S,2S,8aR)-2-Hydroxy-3-oxo-
octahydroindolizin-1-yl benzoate (13a and 13b). A
vigorously stirred solution of 12 (12a:12bZ60:40, 1.10 g,
3.99 mmol, 1.0 equiv) and pyridine (0.63 g, 7.98 mmol,
2.0 equiv) in dry CH2Cl2 under nitrogen atmosphere was
cooled to K30 8C. To this solution triflic anhydride (1.80 g,
6.38 mmol, 1.6 equiv) was added dropwise and the mixture
was slowly allowed to reach room temperature. Stirring was
continued for 1H, subsequently water (2.0 ml) was added
and the reaction mixture was further stirred overnight.
Water (15 ml) was added, and the mixture was extracted

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
653
1.79–1.85 (m, 1H), 2.50–2.56 (m, 1H), 3.27 (dt, JZ11.4,
3.7 Hz, 1H), 3.80 (dd, JZ12.9, 4.8 Hz, 1H), 3.96–4.00 (m,
2H), 4.68 (d, JZ4.2 Hz, 1H), 5.20 (d, JZ6.6 Hz, 1H). 13C
NMR (75 MHz, [D6]-DMSO) d: 22.6 (K, CH2), 23.8 (K,
CH2), 23.8 (K, CH2), 38.9 (K, CH2), 56.3 (C, CH), 67.2
(C, CH), 71.1 (C, CH), 171.4 (quat, CO).
0.055 mmol, 29%). Analogously 15a was converted to 17
via 16a in 79% yield. 16a: Rf 0.51 (CHCl3/MeOH 9:1). 1H
NMR (300 MHz, CDCl3) d: 1.21–1.28 (m, 1H), 1.38 (s, 3H),
1.41 (s, 3H), 1.70–1.95 (m, 5H), 2.84–2.96 (m, 1H), 3.80–
3.89 (m, 1H), 3.91–4.04 (br s, 1H, OH), 4.47 (d, JZ5.8 Hz,
1H), 4.86 (dd, JZ1.0, 5.8 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d: 18.9 (K, CH2), 24.0 (K, CH2), 26.0 (C, CH3),
27.2 (C, CH3), 30.2 (K, CH2), 37.0 (K, CH2) 77.1 (C,
CH), 81.3 (C, CH), 87.7 (quat C), 113.4 (quat C), 170.6
(quat, CO). 17. Mp 67–69 8C. Rf 0.57 (ethyl acetate/hexanes
3.3.5. (1S,2S,8aS)- and (1S,2S,8aR)-1,2-(Isopropylidene-
dioxy)-1,5,6,7,8,8a-hexahydro-3(2H)-indolizinone (15a
and 15b). To a stirred solution of the diol 14 (0.20 g,
1.17 mmol, 1.0 equiv) in dry CH2Cl2 (10 ml) was added
2,2-dimethoxypropane (0.72 ml, 5.84 mmol, 5.0 equiv)
followed by p-TsOH (0.01 g, 0.05 mmol, 0.04 equiv). The
solution was stirred at room temperature for 2 h, concen-
trated under reduced pressure, and the residue was purified
by chromatography on silica (CHCl3/MeOH 9:1) to afford
15 (0.24 g, 0.14 mmol, 98%). IR (KBr) n: 3334, 3244, 2950,
2870, 1678, 1455, 1335, 1304, 1240, 1167, 1123, 1106,
1001, 915, 829, 731, 663, 507, 3464, 2940, 2859, 1693,
1445, 1372, 1317, 1287, 1267, 1219, 1147, 1107, 1080, 978,
930, 912, 867, 837, 799, 731, 573, 503, 436 cmK1. MS (EI,
70 eV) m/z (%): 211.0 (17.1, MC$), 197.0 (10.5), 196.0
(100.0), 154.0 (13.2), 153.0 (16.9), 136.0 (69.9), 100.0
(29.5), 84.9 (22.5), 84.0 (16.9), 83.0 (51.3), 55.0 (11.6),
42.9 (14.2). HRMS (C11H17NO3) calcd 211.1208, found
211.1212. For analytical purposes, a small sample of 15 was
separated by column chromatography. 15a (colorless
solid)14. Mp 106–107 8C. Rf 0.32 (ethyl acetate/hexanes
1
5:1). [a]2D0ZC25.5 (cZ1.1, CHCl3). H NMR (300 MHz,
CDCl3) d: 1.42 (s, 3H), 1.44 (s, 3H), 1.66–1.78 (m, 1H),
1.83–1.95 (m, 1H), 2.16–2.24 (m, 2H), 3.36–3.46 (m, 1H),
3.69–3.78 (m, 1H), 4.67 (d, JZ6.4 Hz, 1H), 4.96 (d, JZ
6.4 Hz, 1H), 5.25 (t, JZ4.1 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d: 20.0 (K, CH2), 21.5 (K, CH2), 25.6 (C, CH3),
26.9 (C, CH3), 39.0 (K, CH2), 73.7 (C, CH), 76.5 (C,
CH), 104.6 (C, CH), 113.2 (C, CH), 136.0 (quat,
C(CH3)2), 169.7 (quat, CO). IR (KBr) n: 2984, 2940,
2893, 1722, 1686, 1458, 1414, 1378, 1314, 1252, 1213,
1153, 1093, 1067, 1041, 1010, 972, 930, 899, 868, 779, 710,
644, 617, 563, 519 cmK1. MS (EI, 70 eV) m/z (%): 209.1
(59.1, MC$), 194.1 (26.1), 166.1 (14.1), 152.1 (100.0), 43.0
(10.3). HRMS (C11H15NO3) calcd 209.1052, found
209.1053.
3.3.7. Swainsonine (1b). 17 was converted in two steps into
swainsonine (1b) in 77% overall yield as described17 in the
literature. The spectroscopic data obtained for 1b was
1
5:1). [a]2D0ZC24 (cZ1.0, CHCl3). H NMR (300 MHz,
1
identical to those described in the literature3d: H NMR
CDCl3) d: 1.07 (dddd, JZ3.5, 12.7, 12.7, 12.7 Hz, 1H),
1.20–1.33 (m, 1H), 1.36 (s, 3H), 1.44 (s, 3H), 1.45–1.59 (m,
1H), 1.62–1.72 (m, 1H), 1.87–2.01 (m, 2H), 2.70 (ddd, JZ
3.5, 12.9, 12.9 Hz, 1H), 3.46 (dd, JZ2.7, 12.5 Hz, 1H),
4.13–4.21 (m, 1H), 4.34 (d, JZ6.6 Hz, 1H), 4.62 (d, JZ
6.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) dZ23.8 (K,
CH2), 24.6 (K, CH2), 25.3 (C, CH3), 26.8 (C, CH3), 30.8
(K, CH2), 40.5 (K, CH2), 62.2 (C, CH), 77.4 (C, 2C, CH),
112.6 (quat C), 168.5 (quat, CO). 15b (viscous oil) Rf 0.20
(ethyl acetate/hexanes 5:1). [a]2D0ZK15 (cZ1.0, CHCl3).
1H NMR (300 MHz, CDCl3) d: 1.21–1.48 (m, 2H), 1.39 (s,
3H), 1.44 (s, 3H), 1.62–1.81 (m, 3H), 1.91–2.00 (m, 1H),
2.63 (dt, JZ3.4, 12.8 Hz, 1H), 3.42–3.51 (m, 1H), 4.10–
4.18 (m, 1H), 4.64 (d, JZ2.6 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d: 23.3 (K, CH2), 24.1 (K, CH2), 25.1 (K, CH2),
26.0 (C, CH3), 27.1 (C, CH3), 40.1 (K, CH2), 57.8 (C,
CH), 74.4 (C, CH), 78.0 (C, CH), 112.6 (quat, C(CH3)2),
169.6 (quat, CO).
(300 MHz, D2O): dZ1.02–1.13 (m, 1H), 1.29–1.47 (m,
1H), 1.53–1.64 (m, 1H), 1.75–1.84 (m, 2H), 1.88–1.98 (m,
1H), 2.42 (dd, JZ11, 4 Hz, 1H), 2.72–2.78 (m, 2H), 3.67
(ddd, JZ11, 10, 5 Hz, 1H), 4.12 (dd, JZ6, 4 Hz, 1H), 4.22
(ddd, JZ8, 6, 3 Hz, 1H). 13C NMR (75.5 MHz, D2O): dZ
22.8 (K, CH2), 32.1 (K, CH2), 51.2 (K, CH2), 60.2 (K,
CH2), 65.9 (C, CH), 68.6 (C, CH), 69.2 (C, CH), 72.4 (C,
CH).
3.4. Synthesis of 2,8a-di-epi-swainsonine
3.4.1. (1S,2R,8R,8aR)-1,2-Dihydroxy-8-methoxy-hexa-
hydroindolizin-3(5H)-one (18). A solution of 10e (1.58 g,
5.82 mmol, 1.0 equiv) in glacial acetic acid (60 ml) was
stirred in the presence of platinum on carbon (470 mg, 5%
Pt/C, 0.24 mmol, 0.02 equiv) under an atmospheric pressure
of hydrogen for 7 d. After removal of the catalyst by
filtration through a celite pad, the solvent was removed
under reduced pressure. To the crude product CHCl3
(50 ml) and NEt3 (2 ml) was added and the solution was
stirred for 24 h at room temperature. Evaporation of the
solvent at reduced pressure afforded a yellow oil, which was
purified by chromatography on silica (chloroform/methanol
9:1). The crude product was recrystallized from ethyl
acetate/methanol (4:1) to give 18 (551 mg, 2.74 mmol,
47%) as white crystals. Mp 181 8C. Rf10.16 (CHCl3/MeOH
9:1). [a]2D0ZC33.7 (c 0.99, MeOH). H NMR (300 MHz,
[D6]-DMSO) d: 1.30–1.51 (m, 3H, Piperidine-H), 2.08–2.17
(m, 1H, Piperidine-H), 2.53–2.64 (m, 1H, CH2N), 3.08 (dd,
JZ6.8, 2.5 Hz, 1H, CHN), 3.26 (s, 3H, OCH3), 3.43–3.48
(m, 1H, CHOMe), 3.73–3.78 (m, 1H, CH2N), 3.78–3.86
(m, 1H, NCHCHOH), 3.97–4.06 (m, 1H, NCOCHOH), 5.47
(d, JZ5.8 Hz, 1H, NCHCHOH), 5.56 (d, JZ6.0 Hz, 1H,
3.3.6. (1S,2S)-1,2-Isopropylidenedioxy-1,2,6,7-tetrahy-
droindolizin-3(5H)-one (17).17 Aqueous NaOCl solution
(3 ml, 12%) was added dropwise during 9 h to a stirred
suspension of 15 (40.0 mg, 0.189 mmol) in ethyl acetate
(3 ml) and RuO2$H2O (5 mg) under cooling at 0 8C.
Isopropanol (1 ml) was added to the reaction mixture and
the organic layer was separated. The aqueous layer was
extracted with ethyl acetate (2!2 ml), and the combined
organic layers were dried over anhydrous Na2SO4 and
concentrated. The crude product was dissolved in CHCl3
(2 ml) and a small amount of HOAc was added. The
solution was stirred for 1 h at room temperature, concen-
trated under reduced pressure and the residue was purified
by chromatography on silica (hexanes/ethyl acetate 1:5) to
afford 17 (19.8 mg, 0.094 mmol, 50%) and 15b (11.6 mg,

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
654
NCOCHOH). 13C NMR (75.5 MHz, [D6]-DMSO) d: 16.8
(K, CH2), 24.5 (K, CH2), 38.1 (K, CH2), 55.8 (C, OCH3),
61.5 (C, NCH), 70.2 (C, CHOCH3), 71.5 (C,
NCHCHOH), 75.7 (C, NCOCHOH), 170.7 (quat, CO).
MS (DCI, NH3) m/z (%): 403.1 (5.17, 2MHC), 219.0 (100.0,
MCNHC4 ), 202.0 (100, MHC), 185.9 (3.3). IR (film) n:
3409, 3243, 2977, 2953, 1894, 2866, 2835, 1686, 1462,
1439, 1366, 1282, 1263, 1253, 1219, 1197, 1152, 1107,
1083, 1030, 976 cmK1. Anal. Calcd for C9H15NO4
(201.22): C 53.72, H 7.51, N 6.96. Found C 53.74, H
7.38, N 6.83.
2.48 (dd, JZ11.0, 7.3 Hz, 1H), 2.70–2.75 (m, 1H), 2.77–
2.84 (m, 1H), 3.86 (dd, JZ8.7, 3.6 Hz, 1H), 3.92–3.98 (m,
2H). 13C NMR (75.5 MHz, D2O) d: 18.5 (K, CH2), 29.6
(K, CH2), 52.3 (K, CH2), 60.3 (K, CH2), 62.8 (C, CH),
71.5 (C, CH), 75.6 (C, CH), 77.7 (C, CH). IR (KBr) n:
3415, 2922, 2822, 2297, 1334, 1240, 1209, 1154, 1105,
1006, 891, 812, 693 cmK1. HRMS (EI, 70 eV) calcd
173.1052, found 173.1052.
Acknowledgements
3.4.2. (1S,2S,8R,8aS)-Octahydroindolizine-1,2,8-triol
((K)-2,8a-di-epi-swainsonine) (20). A mixture of 18
(0.25 g, 1.24 mmol) and HBr (48%, 0.6 ml) was heated at
140 8C for 30 min. The solution was evaporated to dryness
under reduced pressure and evaporation was repeated after
addition of ethanol (3.5 ml). The crude product was purified
by chromatography on silica (CH2Cl2/MeOH/NH3 40:8:1)
to give crude 19, which was contaminated with ammonium
bromide (0.31 g, 1.08 mmol, 88%) as a brownish solid,
which was used in the next step without further purification.
Analytical pure 19 can be obtained by recrystallization form
ethyl acetate/methanol (2:1). 19. Mp 181–184 8C, Rf 0.28
(CH2Cl2/MeOH/NH3 40:8:1), [a]2D0ZC56 (c 1.10, MeOH).
1H NMR (300 MHz, [D6]-DMSO) d: 1.29–1.88 (m, 4H),
2.52–2.64 (m, 1H), 2.99 (dd, JZ6.5, 2.2 Hz, 1H), 3.74–3.87
(m, 3H), 3.98–4.06 (m, 1H), 4.80 (d, JZ4.3 Hz, 1H), 5.32
(d, JZ5.8 Hz, 1H), 5.52 (d, JZ5.9 Hz, 1H). 13C NMR
(75.5 MHz, [D6]-DMSO) d: 16.7 (K, CH2), 29.9 (K, CH2),
38.2 (K, CH2), 60.5 (C, CH), 62.1 (C, CH), 71.8 (C, CH),
76.0 (C, CH), 170.9 (quat, CO). IR (KBr) n: 3406, 3246,
1684, 1463, 1366, 1281, 1255, 1215, 1197, 1153, 1105,
1081, 1030, 976, 873, 851, 814, 753, 658, 600, 555,
448 cmK1. To a stirred solution of crude 19 (98 mg) in THF
(5 ml) was added BH3$Me2S complex (150 ml) at 0 8C
under nitrogen atmosphere. After warming to room
temperature, the mixture was stirred for 12 h, and additional
BH3$Me2S complex (100 ml) was added. After further
stirring for 20 h, ethanol and water were added to the
mixture. The aqueous layer was extracted with ethyl acetate
(3!5 ml) and the combined organic layers were dried over
MgSO4. The mixture was concentrated, and the residue was
purified by chromatography on silica (CH2Cl2/MeOH/NH3
40:8:1) to give 20$HBr (51 mg, 0.20 mmol, 59%) as a
colorless solid, which was recrystallized from ethyl acetate/
methanol 1:1 to give 20$HBr (28 mg, 0.11 mmol, 32%) to
obtain crystals suitable for X-ray analysis. Treatment of
20$HBr (28 mg, 0.11 mmol) on an ion exchange column
(Dowex 1!8; 100–200 mesh, eluent water) yielded 20
(19 mg, 0.11 mmol, 32% yield starting from 18). 20$HBr:
Rf 0.35 (CH2Cl2/Me OH/NH3 40:8:1). [a]2D0ZK12.7 (cZ
This work was supported by the Deutsche Forschungsge-
meinschaft (RE 948-3/2) and the Fonds der Chemischen
Industrie.
References and notes
1. (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520–542.
(b) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579–602.
2. Leading Review: el Nemr, A. Tetrahedron 2000, 56,
8579–8629.
3. Leading examples: (a) Lindsay, K. B.; Pyne, S. G. Aus.
J. Chem. 2004, 57, 669–672. (b) Raghavan, S.; Sreekanth, T.
Tetrahedron: Asymmetry 2004, 15, 565–570. (c) Fujita, T.;
Nagasawa, H.; Uto, Y.; Hashimoto, T.; Asakawa, Y.; Hori, H.
Org. Lett. 2004, 6, 827. (d) Buschmann, N.; Rueckert, A.;
Blechert, S. J. Org. Chem. 2002, 67, 4325–4329. (e) Lindsay,
K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774–7780.
(f) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R.
Eur. J. Org. Chem. 2002, 4137–4142.
4. (a) Gurjur, M. K. Tetrahedron Lett. 1993, 35, 8871.
(b) Ferreira, F.; Greck, C.; Genet, J.-P. Bull. Soc. Chim.
1997, 134, 615.
5. Stinson, S. C. Chem. Eng. News 2001, 79(28), 65–84.
6. Recent developments: Glorius, F.; Spielkamp, N.; Holle, S.;
Goddard, R.; Lehmann, C. W. Angew. Chem., Int. Ed. Engl.
2004, 43, 2850–2852.
7. (a) De Pol, S.; Zorn, C.; Klein, C.; Zerbe, O.; Reiser, O.
Angew. Chem., Int. Ed. Engl. 2004, 43, 511–514. (b) Koglin,
N.; Zorn, C.; Beumer, R.; Cabrele, C.; Bubert, C.; Sewald, N.;
Reiser, O.; Beck-Sickinger, A. G. Angew. Chem., Int. Ed. Engl.
2003, 42, 202–205. (c) Zorn, C.; Gnad, F.; Salmen, S.; Herpin,
T.; Reiser, O. Tetrahedron Lett. 2001, 42, 7049–7053.
(d) Beumer, R.; Reiser, O. Tetrahedron 2001, 45,
6497–6503. (e) Beumer, R.; Bubert, C.; Cabrele, C.;
Vielhauer, O.; Pietzsch, M.; Reiser, O. J. Org. Chem. 2000,
65, 8960–8969.
1
¨
8. (a) Nosse, B.; Chhor, R. B.; Jeong, W. B.; Bohm, C.; Reiser, O.
Org. Lett. 2003, 5, 941–944. (b) Chhor, R. B.; Nosse, B.;
1.28, MeOH). H NMR (400 MHz, D2O) d: 1.60–1.79 (m,
2H), 1.87–2.01 (m, 2H), 2.93–3.02 (m, 1H), 3.17 (d, JZ
9.4 Hz, 1H), 3.37 (dd, JZ12.6, 4.5 Hz, 1H), 3.40–3.52 (m,
2H), 4.08 (dd, JZ9.4, 3.7 Hz, 1H), 4.27–4.31 (m, 2H). 13C
NMR (75.5 MHz, D2O) d: 17.1 (K, CH2), 28.1 (K, CH2),
52.5 (K, CH2), 58.7 (K, CH2), 61.1 (C, CH), 71.3 (C,
CH), 73.0 (C, CH), 75.3 (C, CH). MS (DCI, NH3) m/z (%):
174.1 (100.0, MHC). 2018. Mp 138–142 8C (lit.19 mp 138–
142 8C). [a]D20ZK8.8 (cZ0.91, MeOH) (lit.19 [a]2D6Z
¨ ¨
Sorgel, S.; Bohm, C.; Seitz, M.; Reiser, O. Chem. Eur. J. 2003,
¨
9, 260–270. (c) Bohm, C.; Schinnerl, M.; Bubert, C.; Zabel,
M.; Labahn, T.; Parisini, E.; Reiser, O. Eur. J. Org. Chem.
2000, 2955–2965.
9. Gnad, F.; Polschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
4277–4280.
10. Raatz, D.; Innertsberger, C.; Reiser, O. Synlett 1999,
1907–1910.
11. (a) Feng, Z.-X.; Zhou, W.-S. Tetrahedon Lett. 2003, 44,
1
K24.0 (cZ1.14, MeOH)). H NMR (400 MHz, D2O) d:
1.32–1.45 (m, 2H), 1.53–1.81 (m, 2H), 1.87–1.99 (m, 2H),

¨
G. Heimgartner et al. / Tetrahedron 61 (2005) 643–655
655
493–495. (b) Feng, Z.-X.; Zhou, W.-S. Tetrahedon Lett. 2003,
44, 497–498.
1991. (b) Dhimane, H.; Vanucci, C.; Lhommet, G.
Tetrahedron Lett. 1997, 38, 1415–1418. (c) Dhimane, H.;
Vanucci-Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org.
Chem. 1998, 1955–1964.
12. In contrast, the hydrogenation of the related pyridine 10a was
reported (cf. Ref. 11b) to yield upon hydrogenation at 10 atm
hydrogen in methanol/triethylamine with palladium as catalyst
(ent)-11 with a 3.2:1 preference of the a-epimer. The major
diastereomer was obtained after recrystallization in 43% yield.
13. Cf. Kaluza, Z.; Mostowicz, D. Tetrahedron: Asymmetry 2003,
14, 225–232.
18. (a) Martin-Lopez, M. J.; Rodriguez, R.; Bermejo, F.
Tetrahedron 1998, 54, 11623–11636. (b) Rodriguez, R.;
Bermejo, F. Tetrahedron Lett. 1996, 37, 5581–5584.
19. Tadano, K.; Morita, M.; Hotta, Y.; Ogawa, S.; Winchester, B.;
Cenci di Bello, I. J. Org. Chem. 1988, 53, 5209–5215.
20. (a) Desideri, N.; Sestili, I.; Manarini, S.; Cerletti, C.; Stein,
M. L. Eur. J. Med. Chem. 1991, 26, 455–460. (b) Manna, F.;
Bolasco, A.; Bizzarri, B.; Lena, R.; Chimenti, F.; Fillippelli,
A.; Pallad, A.; Fontana, M. Farmaco 1996, 51, 579–587.
21. (a) Kempf, D. J.; Codacovi, L.; Wang, X. C.; Kohlbrenner,
W. E.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; Marsh,
K. C.; Bryant, P. J. Med. Chem. 1993, 36, 320–330.
(b) Robinson, C. N.; Wiseman, L. J., Jr.; Slater, C. D.
Tetrahedron 1989, 45, 4103–4112.
14. The synthesis of 14a and 15a has been reported before:
Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem.
2001, 66, 5438–5443.
15. Details on the X-ray structures can be obtained from the
Cambridge Crystallographic Data Centre: 14a (CCDC
244657); 20$HBr (CCDC 244656).
16. Shigeyuki, Y.; Yukimi, A.; Yoshihiro, N. Chem. Pharm. Bull.
1985, 33, 5042–5047.
17. (a) Shono, T. Electroorganic Synthesis; Academic: London,