Synthesis of (+)-coniceine via reductive photocyclization of dienamides: an entry to indolizidines

Article abstract of DOI:10.1016/j.tetasy.2007.03.004

This paper describes the establishment of a new synthetic route to the hydrobromide salt of (+)-coniceine 1 with high enantiopurity in five steps and 8% overall yield. The key step is the reductive photocyclization of an acyclic chiral dienamide, for whic

Full text of DOI:10.1016/j.tetasy.2007.03.004

Tetrahedron: Asymmetry 18 (2007) 671–678
Synthesis of (+)-coniceine via reductive photocyclization
of dienamides: an entry to indolizidines
Thomas Hjelmgaard,a,b Daniel Gardette,a,* David Tannerb and David J. Aitkena,c
a
`
´
´
Departement de Chimie, Equipe de Synthese Organique et Modelisation Moleculaire, UMR SEESIB 6504, CNRS,
`
Universite´ Blaise Pascal, Clermont-Ferrand II, 24 avenue des Landais, 63170 Aubiere, France
bDepartment of Chemistry, Building 201, Technical University of Denmark, Kemitorvet, DK-2800 Kgs. Lyngby, Denmark
c
`
´ ´
Laboratoire de Synthese Organique et Methodologie, ICCMO—CNRS UMR 8182, Universite Paris-Sud XI,
15 rue Georges Cle´menceau, 91405 Orsay cedex, France
Received 12 February 2007; accepted 5 March 2007
Abstract—This paper describes the establishment of a new synthetic route to the hydrobromide salt of (+)-coniceine 1 with high enan-
tiopurity in five steps and 8% overall yield. The key step is the reductive photocyclization of an acyclic chiral dienamide, for which a
convenient one-pot synthesis is described.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
H
N
Simple indolizidine alkaloids (1-azabicyclo[4.3.0]nonanes),
which include 5-alkyl, 3,5- or 5,8-dialkyl and 5,6,8-trialkyl
indolizidines, are present in the skins of Central and South
American amphibians.1 Some of these natural products
have been shown to be non-competitive blockers of nico-
tinic acetylcholine receptor channels in the muscle and gan-
glia membranes,1 and are thus potentially useful for
studying the mechanisms of neuromuscular transmission.
Some examples of these alkylated indolizidine alkaloids
are shown in Figure 1 along with the simplest indolizidine,
coniceine 1. While currently not established as a natural
product, coniceine has attracted great interest from chem-
ists, usually as an illustrative target demonstrating the via-
bility of synthetic routes to indolizidine derivatives. This
has resulted in numerous successful syntheses of racemic2
and enantiomerically pure3 coniceine.
(+)-Coniceine 1
H
N
H
N
3
5
5
R
Indolizidine 167B 2
3
R = Me, Monomorine I
R = Pr, Indolizidine 223AB
4
H
8
H
8
6
N
N
R
5
5
Indolizidine 223A 7
5
R = CH=CH2, Indolizidine 207A
R =
H, Indolizidine 205A 6
Figure 1. Coniceine 1 and a selection of simple, naturally occurring
indolizidines 2–7.
Reductive photocyclization was first reported as a synthetic
tool in 1981,4 and has since been used in a number of total
syntheses of racemic indole,5 piperidine6 and ergoline-type7
alkaloids. Although a number of possibilities exist for
inducing stereoselectivity in photochemical reactions,8 little
attention has been paid to performing asymmetric synthe-
sis using reductive photocyclization. In a few early reports,
reductive photocyclization was carried out in the presence
of chiral metal hydride complexes, but both the chemical
yields and enantioselectivities were low.9 More recently,
we have developed a methodology for the synthesis of 2-
substituted piperidines in high enantioselectivity utilizing
*
Corresponding author. Tel.: +33 473 40 76 46; fax: +33 473 40 77 17;
e-mail: Daniel.GARDETTE@univ-bpclermont.fr
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.03.004

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T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
the reductive photocyclization of chiral dienamides.10 We
reasoned that the scope of this methodology could be ex-
tended to achieve a short synthesis of (+)-coniceine, thus
providing an entry to the indolizidine alkaloids.
NH2
Ph
8a
: R = CO2Et
8b: R = CH2OBn
+
O
R
+
a)
The overall retrosynthetic rationale is shown in Scheme 1.
Coniceine 1 should be accessible from piperidinone A1 in
which R is either CO2Et or CH2OBn. Piperidinone A1, in
turn, could be obtained by a stereoselective reductive
photocyclization of chiral dienamide A2. The stereoselec-
tivity of this reaction should originate from the selected
enantiomer of a-methylbenzylamine, used as a starting
material along with acryloyl chloride and ketone 8a (com-
mercially available) or 8b (readily available by benzylation
of the commercially available 5-hydroxy-pentan-2-one11).
Herein we report an original and efficient synthesis of enan-
tiomerically pure (+)-coniceine, based on this strategy.
O
N
R
O
N
R
Ph
Ph
10a: R = CO2Et
9a: R = CO2Et
9b
10b
: R = CH2OBn
: R = CH2OBn
˚
Scheme 2. One-pot synthesis of dienamides 9a and 9b. Key: (a) 4 A
molecular sieves, THF, rt; then H2C@CHCOCl, Et3N, THF, ꢀ15 ꢁC to rt.
9a/10a: 85% (9a/10a = 47:53), 9b/10b: 93% (9b/10b = 43:57).
extensively: under such conditions, facile isomerization to
10a and 10b, respectively, is observed.
Reductive
A series of reductive photocyclizations of dienamides 9a
and 9b were then performed, using benzene/MeOH as the
solvent and NaBH4 as a reducing agent,7,12 to give piperid-
inones 11a and 11b, respectively (Scheme 3). The reactor
type and reaction times were varied, and the results are
listed in Table 1. The reductive photocyclization of benzyl-
oxy dienamide 9b using a quartz reactor gave the highest
yield in the shortest reaction time (37%/2.5 h; entry 4).
Therefore, we retained this side chain and these conditions
for the chiral version of this reaction, described below.
photocyclization
*
*
N
O
N
R
*
H3C
Ph
1
Coniceine
H
A1
NH2
O
R
O
Cl
O
N
R
*
*
a)
H3C
Ph
H3C
Ph
8a
: R = CO2Et
H
H
A2
8b
: R = CH2OBn
O
N
R
O
N
R
Ph
: R = CO2Et
9b: R = CH2OBn
Ph
: R = CO2Et
11b: R = CH2OBn
Scheme 1. Retrosynthetic analysis for the indolizidine skeleton (coniceine
1) based on the reductive photocyclization of chiral dienamides.
9a
11a
Scheme 3. Reductive photocyclization of 9a and 9b giving piperidinones
11a and 11b. Key: (a) hm, NaBH4 (8 equiv), benzene/MeOH (9:1), rt.
Further conditions in Table 1.
2. Results and discussion
2.1. Model study
Initially, we carried out a model study using N-benzyl
derivatives, in order to identify the more convenient dien-
amide side chain (ester or protected alcohol). For the prep-
aration of the requisite dienamides 9a and 9b, a convenient
one pot procedure was developed, which avoided the isola-
tion of unstable imine intermediates (Scheme 2). Thus, ke-
tones 8a and 8b were reacted with benzylamine in the
Table 1. Reductive photocyclization of 9a and 9b giving piperidinones 11a
and 11b
Entry
R
Reactor
Time (h)
Yield (%)
1
2
3
4
CO2Et
CO2Et
CH2OBn
CH2OBn
Pyrex
Quartz
Pyrex
6
2.75
6
21
16
27
37
Quartz
2.5
˚
presence of 4 A molecular sieves in THF followed by the
addition of Et3N and acryloyl chloride to afford isomeric
mixtures 9a/10a and 9b/10b in 85% (9a/10a = 47:53) and
93% (9b/10b = 43:57) yield, respectively. The use of
2.2. Synthesis of (+)-coniceine
i
CH2Cl2 as the solvent, or of Pr2NEt as the base, or varia-
tion of the reaction temperature only decreased the yields
and/or selectivities. In each case, however, the structural
isomers could easily be separated by column chromatogra-
phy. Although the effective yields of dienamides 9a and 9b
are moderate, this one-pot methodology has the advantage
of being rapid and convenient. It should be noted that
dienamides 9a and 9b are unstable in the presence of trace
amounts of acids (for example, in CDCl3) or when heated
(S)-(ꢀ)-a-Methylbenzylamine was chosen as the chiral aux-
iliary. Our previous work on piperidine systems suggested
that reductive photocyclization using this antipode should
preferentially lead to a (6S)-piperidone derivative (A1,
Scheme 1).10 As shown in Scheme 4, the one-pot synthesis
of dienamides was employed successfully for the prepara-
tion of chiral dienamide 12. On a multigram scale, this
reaction affords the isomeric mixture 12/13 in 87% yield

T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
673
are listed in Table 2. When the reaction was performed in
benzene/MeOH (9:1) at rt (entry 1), the piperidinones were
obtained in a rather disappointing 39% combined yield and
54% de. We were satisfied to find that when benzene was
replaced by (less toxic) toluene, the yield rose to 56%,
although the de decreased to 42% (entry 2). This equates
to an increase in the effective yield of 15, from 30% to
40%. Changes in de were insignificant when the reaction
was performed at lower temperatures (entries 4–6). The
optimum temperature for high de was around ꢀ15 ꢁC (en-
try 5); however, when overall yields are taken into account,
the effective yield of 15 remains at 40–44% over the temper-
ature range examined. Satisfyingly, when scaled up, only a
slight decrease in overall yield was observed along with a
slight increase in de (entry 3).
NH2
(S)
+
O
H3C
Ph
OBn
H
8b
a)
+
OBn
O
N
O
N
(S)
(S)
OBn
H3C
Ph
H3C
Ph
H
12
H
13
˚
Scheme 4. One-pot synthesis of dienamide 12 and isomer 13. Key: (a) 4 A
molecular sieves, THF, rt; then H2C@CHCOCl, THF, ꢀ15 ꢁC to rt. 12/
13: 87% (12/13 = 53:47).
(12/13 = 53:47). Thus, as was the case in the model study,
the effective yield of the desired dienamide 12 is moderate,
but this pathway provides chiral dienamide 12 in a straight-
forward fashion with no isolation of the unstable interme-
diate imine being necessary; isomers 12 and 13 are easily
separated by column chromatography.
The reaction presumably proceeds via iminium ion 14 and
the anticipated (6S)-selectivity can be explained by the
nucleophilic addition of hydride on intermediate iminium
ion 14 from the less hindered of the two diastereotopic
faces.10,13 The diastereoselectivity was determined from
1H NMR spectra, in which chemical shift differences were
observed for the benzylic proton of the (S)-a-methylbenzyl
group and for the benzylic protons of the benzyloxy group
in each diastereoisomer (see Section 4). The unequivocal
attribution of the absolute configurations of the two diaste-
reoisomeric products was not possible from NMR data,
but this was achieved at a later stage.
Based on the results of the model study, the reductive
photocyclisation of dienamide 12 was performed using a
quartz reactor; other reaction conditions were varied.
Two diastereomeric piperidinones were obtained as an
inseparable mixture: the desired (10S,6S)-isomer 15 and
the undesired (10S,6R)-isomer 16 (Scheme 5); the results
Reduction of the amide function in the 15/16 mixtures
using LiAlH4 in refluxing THF gave a mixture of amines
17 and 18 (Scheme 6). This mixture was easily separated
by column chromatography, thus affording pure 17 in
around 61% yield and pure 18 in around 16% yield. Re-
moval of the two benzylic groups in 17 was accomplished
by hydrogenation over 10% Pd/C with HCOONH4 as the
hydrogen source.14 The desired amino alcohol 19 was iso-
lated simply by filtration and concentration, which pro-
vided an essentially pure product as judged by NMR.
Cyclization of crude 19 was achieved using CBr4 and
PPh3 in MeCN using a minor modification of a lit. proce-
dure.15 Aqueous workup gave (+)-coniceine hydrobromide
1ÆHBr in 58% yield for the last two steps.
a)
O
N
O
N
(
S
)
1'
H3C
S
OBn
OBn
H3C
Ph
Ph
H
H
12
14
6S
6R
O
N
O
N
1'
H3C
S
1'
H3C
S
OBn
OBn
Ph
Ph
H
H
15
16
The isolated (+)-coniceine hydrobromide 1ÆHBr showed
identical NMR spectral data and melting point to those re-
ported in the lit. for the racemic hydrobromide16 and had
Scheme 5. Reductive photocyclization of 12 yielding diastereomeric
piperidinones 15 and 16, via iminium ion 14. Key: (a) hm, NaBH4, quartz
reactor. Further conditions in Table 2.
Table 2.
Entry
Solvent
Temperature (ꢁC)
Time (h)
Yield of 15/16 (%)
dee
Yield of 15 (%)
1a
2a
3b
4a
5a
6a
Benzene/MeOH 9:1
Toluene/MeOH 9:1
Toluene/MeOH 9:1
Toluene/MeOH 9:1
Toluene/MeOH 9:1
Toluene/MeOH 9:1
rt
rt
rt
2.5
2.5
2.5
2.5
2
39c
56c
46d
54c
50c
58c
54
42
50
54
62
52
30
40
35
42
41
44
5
ꢀ15
ꢀ30
2
a Approx. 1 mmol scale.
b 4.2 mmol scale.
c Corrected yields, after taking some 8b contained in the starting material into account (calculated from NMR).
d Corrected yield, reaction performed on a 12/13 89:11 mixture (NMR).
e Estimated from 1H NMR.

674
T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
chemicals obtained from commercial sources were, unless
otherwise stated, used without further purification.
a)
15/16
+
2
S
2R
N
N
1'
S
1'
S
OBn
OBn
Melting points were determined on Reichert microscope
apparatus and are uncorrected. Specific rotations were
measured on a Jasco DIP-370 polarimeter using a 10 cm
cell. IR spectra were recorded on a Perkin–Elmer 881 spec-
trometer and m are expressed in cmꢀ1. NMR spectra were
recorded on a 400 MHz Bruker AC 400 spectrometer;
chemical shifts are referenced to the residual solvent peak.
Where applicable, assignments were based on J-modula-
tion experiments: (ꢀ) designates a (C) or a (CH2); (+) des-
ignates a (CH) or a (CH3). GC–MS were recorded on
Agilent Technologies 6890N GC equipped with an Agilent
5973 Mass Selection Detector operating in EI mode
(70 eV); numbers in parentheses in MS spectral data are
relative abundances. HRMS were recorded on a Micro-
mass Q-Tof Micro (3000 V) apparatus in ESI mode. Ele-
mental analyses were determined on a Thermofinnigan
Flash EA 1112. TLC was performed on Merck TLC alumi-
num sheets, silicagel 60, F254. Visualisation of spots was ef-
fected with UV-light and/or ninhydrin in EtOH/AcOH.
Flash chromatography was performed with silica gel 60
(70–230 mesh ASTM). Unless otherwise stated, flash chro-
matography was performed in the eluent system for which
the Rf-values are given. Progressions of the reactions were,
when applicable, followed by NMR and/or TLC.
H3C
Ph
H3C
Ph
H
17
H
18
b)
H
c)
2
S
N
H
N
Br
H
OH
(+)-1.HBr
19
Scheme 6. Synthesis of (+)-coniceine hydrobromide 1ÆHBr from piperid-
inone mixture 15/16. Key: (a) LiAlH4, THF, D. 17: 61%, 18: 16%. (b)
HCOONH4, 10% Pd/C, MeOH, D. (c) CBr4, PPh3, MeCN, rt, 58% (for
two steps).
22
½aꢁD ¼ þ5:5 (c 0.88, EtOH). To the best of our knowledge,
there are no other reports that include the specific rotation
of (+)- or (ꢀ)-1ÆHBr, hence we liberated the free amine of 1
on a small scale. The sample showed spectral data identical
22
to those in the lit.3d,i and a specific rotation of ½aꢁD ¼ þ9:5
23
(c 1.13, EtOH) {lit.16 ½aꢁD ¼ þ9:3 ꢂ 0:6 (c 1.76, EtOH)}
which confirmed the structure to be (+)-coniceine 1, as ex-
pected. Our value for the specific rotation indicated a prod-
uct of high enantiopurity. Further verification was
obtained by adapting a lit. NMR method17 for the determi-
nation of enantiomeric ratios using an authentic sample of
( )-1ÆHBr as reference. Our synthesis provided (+)-conice-
ine hydrobromide 1ÆHBr in which only one enantiomer was
detected (>97% ee within detection limits).
4.2. 5-Benzyloxy-pentan-2-one 8b
5-Hydroxy-pentan-2-one (6.00 mL, 59.2 mmol) was added
dropwise over 5 min to a mixture of benzyl bromide
(15.5 mL, 130 mmol), Bu4NI (65 mg, 0.18 mmol) and NaI
(27 mg, 0.18 mmol) in 50 wt % aq NaOH (16 g, 200 mmol
NaOH) at rt. The resulting mixture was then stirred vigor-
ously for 18 h at 35 ꢁC. The mixture was diluted with Et2O
(100 mL) and water (40 mL) and the organic phase iso-
lated. The aqueous phase was extracted with Et2O
(2 · 100 mL) and the combined organic phases were dried
over MgSO4, filtered and concentrated under reduced pres-
sure. Residual benzyl bromide was distilled under reduced
pressure and flash chromatography of the residue yielded
8b (6.15 g, 54%) as a colorless oil: Rf (pentane/Et2O
75:25) = 0.26; bp = 91–93 ꢁC/0.3 mm Hg (lit.18 bp = 98–
100 ꢁC/0.7 mm Hg; lit.19 bp = 105–110 ꢁC/0.5 mm Hg);
1H NMR (400 MHz, CDCl3): d 7.41–7.26 (5H, m), 4.51
(2H, s), 3.51 (2H, t, J = 6.4 Hz), 2.58 (2H, t, J = 6.4 Hz),
2.16 (3H, s), 1.91 (2H, dt, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3): d 208.6 (ꢀ), 138.4 (ꢀ), 128.3 (2C, +),
127.6 (2C, +), 127.5 (+), 72.8 (ꢀ), 69.2 (ꢀ), 40.3 (ꢀ),
29.9 (+), 23.8 (ꢀ); IR (neat) 3031 (w), 2932 (m), 2860
(m), 1713 (s), 1453 (m), 1413 (m), 1362 (s), 1166 (m),
1107 (s), 738 (m), 699 (m); GC–MS (EI): m/z 164 (10),
107 (28), 101 (14), 92 (13), 91 (100), 85 (18), 65 (11), 58
(10). NMR spectra were in full accordance with those re-
ported in the lit.18,19
3. Conclusion
We have established a convenient new pathway to (+)-con-
iceine hydrobromide 1ÆHBr in highly enantiopure form in
only five steps and 8% overall yield. This is the first synthe-
sis that employs reductive photocyclization of a chiral
dienamide as the key step. An attractive feature of this
methodology is that the opposite enantiomer of the desired
indolizidine is equally accessible, in principle, simply by
using the opposite enantiomer of the chiral auxiliary. An
extension of this methodology for the total synthesis of
more complex indolizidine alkaloids can readily be
envisaged.
4. Experimental
4.1. General
THF was distilled under N2 from potassium/benzophe-
none. CH2Cl2 was distilled under N2 from CaH2. Benzene
and toluene were dried over sodium. EtOAc and cyclohex-
ane for column chromatography were distilled before use.
Benzyl amine, benzyl bromide, MeOH and (S)-(ꢀ)-a-meth-
4.3. General procedure for the synthesis of dienamides
˚
˚
ylbenzylamine were distilled and dried over 4 A molecular
To a suspension of 4 A molecular sieves (ca. 12.5 g, dried
i
sieves. Et3N, ethyl levulinate, MeCN and Pr2NEt were
for 24 h at 180 ꢁC/2–4 mm Hg in flask to be used for reac-
tion) in THF (30 mL) at rt under Ar were added the ketone
˚
dried over 4 A molecular sieves. All other solvents and

T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
675
(5.2 mmol) and the amine (9a and 9b: 5.7 mmol; 12:
7.8 mmol). The mixture was then stirred vigorously for
ca. 40 h at rt under Ar. The mixture was cooled to
ꢀ15 ꢁC and Et3N (9a and 9b: 1.09 mL, 7.83 mmol; 12:
1.50 mL, 10.8 mmol) was added followed by acryloyl chlo-
ride (9a and 9b: 0.55 mL, 6.77 mmol; 12: 0.75 mL,
9.23 mmol) dropwise over 5 min. Stirring was continued
for 2.5 h while allowing the mixture to heat slowly to
0 ꢁC. After stirring for 1 h further at rt, the mixture was di-
luted with THF (20 mL), celite (ca. 20 mL) was added and
the resulting mixture filtered, washing the solids with THF
(2 · 25 mL). The filtrate was then concentrated and dried
in vacuo. Flash chromatography of the residue yielded
the dienamide and the isomer.
J = 6.5 Hz); 13C NMR (100 MHz, benzene-d6): d 164.9
(ꢀ), 147.3 (ꢀ), 139.2 (ꢀ), 138.6 (ꢀ), 129.4–127.3 (12C, +
and ꢀ), 114.2 (ꢀ), 73.0 (ꢀ), 69.3 (ꢀ), 49.1 (ꢀ), 31.3 (ꢀ),
27.4 (ꢀ); IR (neat) 3031 (w), 2935 (m), 2858 (m), 1651
(s), 1617 (m), 1410 (s), 1367 (m), 1258 (w), 1218 (w), 1105
(m), 735 (m), 699 (m); GC–MS (EI): m/z 244 (19), 201
(25), 200 (15), 91 (100). HRMS (TOF MS ES+) calcd for
C22H26NO2 [M+H]+ m/z 336.1964. Found: 336.1971;
Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18.
Found: C, 78.74; H, 7.57; N, 4.20. 10b: Rf (cyclohexane/
1
EtOAc 75:25) = 0.34; H NMR (400 MHz, benzene-d6): d
7.35–7.00 (10H, m), 6.71 (1H, dd, J = 16.8, 2.6 Hz), 6.52
(1H, dd, J = 16.8, 10.1 Hz), 5.34 (1H, dd, J = 10.1,
2.6 Hz), 4.95 (1H, t, J = 7.4 Hz), 4.66 (2H, s), 4.19 (2H,
s), 3.02 (2H, t, J = 6.5 Hz), 1.92 (2H, dt, J = 6.5 Hz),
1.42 (3H, s); 13C NMR (100 MHz, benzene-d6): d 164.7
(ꢀ), 139.0 (ꢀ), 138.9 (ꢀ), 136.5 (ꢀ), 129.6–127.0 (13C, +
and ꢀ), 73.0 (ꢀ), 69.2 (ꢀ), 49.4 (ꢀ), 28.8 (ꢀ), 16.4 (+);
IR (neat) 3031 (w), 2922 (w), 2858 (m), 1652 (s), 1615
(m), 1412 (s), 1362 (m), 1258 (m), 1102 (m), 736 (m), 700
(m); GC–MS (EI): m/z 244 (44), 214 (15), 201 (31), 200
(17), 160 (25), 91 (100), 55 (11). HRMS (TOF MS ES+)
calcd for C22H26NO2 [M+H]+ m/z 336.1964. Found:
336.1975; Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51;
N, 4.18. Found: C, 78.63; H, 7.61; N, 4.24.
4.3.1. 4-(Acryloyl-benzyl-amino)-pent-4-enoic acid ethyl
ester 9a and 4-(acryloyl-benzyl-amino)-pent-3-enoic acid
ethyl ester 10a. Reaction of ethyl levulinate (0.74 mL,
5.19 mmol) with benzyl amine (0.62 mL, 5.68 mmol) fol-
lowing the general procedure yielded 9a (603 mg, 40%)
and 10a (674 mg, 45%) as colorless oils. 9a: Rf (cyclohex-
1
ane/EtOAc 70:30) = 0.43; H NMR (400 MHz, benzene-
d6): d 7.32–7.27 (2H, m), 7.12–7.00 (3H, m), 6.66 (1H,
dd, J = 16.8, 2.5 Hz), 6.50 (1H, dd, J = 16.8, 10.1 Hz),
5.35 (1H, dd, J = 10.1, 2.5 Hz), 4.64 (2H, s), 4.58 (1H, s),
4.39 (1H, s), 3.91 (2H, q, J = 7.1 Hz), 2.20 (2H, t, J =
7.2 Hz), 2.03 (2H, t, J = 7.2 Hz), 0.94 (3H, t, J = 7.1 Hz);
13C NMR (100 MHz, benzene-d6): d 171.8 (ꢀ), 164.9 (ꢀ),
146.0 (ꢀ), 138.5 (ꢀ), 129.3–127.4 (7C, + and ꢀ), 114.9
(ꢀ), 60.4 (ꢀ), 49.0 (ꢀ), 31.3 (ꢀ), 29.5 (ꢀ), 14.2 (+); IR
(neat) 3030 (w), 2982 (m), 2935 (w), 1734 (s), 1652 (s),
1618 (m), 1411 (s), 1372 (m), 1161 (m), 1106 (m), 730
(m), 701 (m); GC–MS (EI): m/z 287 (1, M+), 214 (10),
196 (40), 186 (12), 158 (10), 150 (28), 122 (17), 91 (100),
55 (19). HRMS (TOF MS ES+) calcd for C17H22NO3
[M+H]+ m/z 288.1600. Found: 288.1591. 10a: Rf (cyclo-
4.3.3. N-(4-(Benzyloxy-1-methylene-butyl)-N-(1-(S)-phenyl-
ethyl)-acrylamide 12 and N-(4-(benzyloxy-1-methyl-but-1-
enyl)-N-(1-(S)-phenyl-ethyl)-acrylamide 13. Reaction of
8b (2.00 g, 10.4 mmol) with (S)-(ꢀ)-a-methylbenzylamine
(2.00 mL, 15.7 mmol) following the general procedure
yielded a 12/13 = 89:11 mixture as a pale yellowish oil
(1.59 g, 44%) and a 12/13 = 17:83 mixture as a pale yellow-
ish oil (1.58 g, 43%). The following characterization of 12
was carried out on the sample containing 11% 13 as judged
by NMR: Rf (cyclohexane/EtOAc 75:25) = 0.43;
22
1
1
hexane/EtOAc 70:30) = 0.34; H NMR (400 MHz, benz-
½aꢁD ¼ ꢀ82:8 (c 1.50, MeOH); H NMR (400 MHz, ben-
zene-d6): d 7.37–6.95 (10H, m), 6.70 (1H, d, J = 16.7 Hz),
6.45 (1H, dd, J = 16.7, 10.2 Hz), 6.25 (1H, q, J = 6.9 Hz),
5.34 (1H, d, J = 10.2 Hz), 4.74 (1H, s), 4.52 (1H, s), 4.20
(2H, s), 3.05–2.93 (2H, m), 1.81–1.64 (2H, m), 1.47–1.34
(2H, m), 1.37 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz,
benzene-d6): d 164.4 (ꢀ), 146.5 (ꢀ), 142.0 (ꢀ), 139.2 (ꢀ),
130.1–127.2 (12C, + and ꢀ), 116.0 (ꢀ), 72.9 (ꢀ), 69.4
(ꢀ), 51.9 (+), 33.9 (ꢀ), 27.4 (ꢀ), 17.2 (+); IR (neat) 3031
(w), 2937 (m), 2859 (m), 1650 (s), 1613 (m), 1407 (s),
1366 (m), 1322 (m), 1264 (m), 1107 (s), 739 (m), 700 (m);
GC–MS (EI): m/z 294 (20), 244 (18), 215 (17), 154 (10),
136 (11), 111 (16), 106 (10), 105 (100), 103 (11), 91 (62),
79 (12), 77 (11), 55 (14); HRMS (TOF MS ES+) calcd
for C23H27NO2Na [M+Na]+ m/z 372.1939. Found:
372.1935. The following characterization of 13 was carried
ene-d6): d 7.33–7.28 (2H, m), 7.13–7.00 (3H, m), 6.70
(1H, dd, J = 16.8, 2.6 Hz), 6.57 (1H, dd, J = 16.8,
10.0 Hz), 5.40 (1H, dd, J = 10.0, 2.6 Hz), 5.12 (1H, t,
J = 7.5 Hz), 4.64 (2H, s), 3.85 (2H, q, J = 7.1 Hz), 2.54
(2H, d, J = 7.5 Hz), 1.32 (3H, s), 0.89 (3H, t, J = 7.1 Hz);
13C NMR (100 MHz, benzene-d6): d 170.0 (ꢀ), 164.6 (ꢀ),
138.6 (ꢀ), 138.5 (ꢀ), 129.4–123.4 (8C, + and ꢀ), 60.6
(ꢀ), 49.5 (ꢀ), 33.3 (ꢀ), 16.4 (+), 14.2 (+); IR (neat) 3031
(w), 2983 (m), 2935 (w), 1736 (s), 1652 (s), 1616 (m), 1412
(s), 1369 (m), 1257 (m), 1175 (m), 1030 (m), 731 (w), 702
(m); GC–MS (EI): m/z 287 (2, M+), 214 (18), 200 (58),
160 (13), 91 (100), 55 (12). HRMS (TOF MS ES+) calcd
for C17H22NO3 [M+H]+ m/z 288.1600. Found: 288.1612.
4.3.2. N-Benzyl-N-(4-benzyloxy-1-methylene-butyl)-acryl-
amide 9b and N-benzyl-N-(4-benzyloxy-1-methyl-but-1-
enyl)-acrylamide 10b. Reaction of 8b (1.00 g, 5.20 mmol)
with benzyl amine (0.62 mL, 5.68 mmol) following the gen-
eral procedure yielded 9b (698 mg, 40%) as a colorless oil
and 10b (930 mg, 53%) as a pale yellowish oil 9b: Rf (cyclo-
out on the sample containing 17% 12 as judged by NMR:
22
Rf (cyclohexane/EtOAc 75:25) = 0.41; ½aꢁD ¼ ꢀ60:7
(c 1.45, MeOH); 1H NMR (400 MHz, benzene-d6): d
7.37–6.95 (10H, m), 6.72 (1H, dd, J = 16.7, 2.6 Hz), 6.45
(1H, dd, J = 16.7, 10.2 Hz), 6.33 (1H, q, J = 6.9 Hz), 5.34
(1H, dd, J = 10.2, 2.6 Hz), 5.29–4.79 (1H, m), 4.23 (2H,
s), 3.19–2.98 (2H, m), 1.90 (2H, m), 1.49–1.05 (3H, m),
1.36 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, benzene-
d6): d 164.4 (ꢀ), 142.1 (ꢀ), 139.0 (ꢀ), 134.7 (ꢀ), 130.9–
127.1 (13C, + and ꢀ), 73.1 (ꢀ), 69.2 (ꢀ), 52.0 (+), 29.0
1
hexane/EtOAc 75:25) = 0.43; H NMR (400 MHz, benz-
ene-d6): d 7.32–7.00 (10H, m), 6.68 (1H, d, J = 16.8),
6.49 (1H, dd, J = 16.8, 10.1 Hz), 5.33 (1H, d, J = 10.1),
4.68 (2H, s), 4.59 (1H, s), 4.42 (1H, s), 4.26 (2H, s), 3.12
(2H, t, J = 6.5 Hz), 2.04 (2H, t, J = 6.5 Hz), 1.46 (2H, dt,

676
T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
(ꢀ), 19.4 (+), 17.3 (+); IR (neat) 3031 (w), 2936 (m), 2859
(m), 1659 (s), 1612 (m), 1409 (s), 1367 (m), 1322 (m), 1267
(m), 1101 (s), 741 (m), 700 (m); GC–MS (EI): m/z 258 (10),
244 (16), 215 (11), 154 (22), 138 (10), 124 (26), 111 (23), 106
(10), 105 (100), 103 (10), 91 (53), 84 (11), 79 (12), 77 (11),
70 (12), 55 (14); HRMS (TOF MS ES+) calcd for
C23H27NO2Na [M+Na]+ m/z 372.1939. Found 372.1919.
(m); GC–MS (EI): m/z 337 (4, M+), 246 (29), 218 (20),
189 (13), 188 (72), 160 (15), 91 (100). NMR spectra were
in full accordance with those reported in the lit.20
4.4.3.
(S)-6-(3-Benzyloxy-propyl)-1-(10-(S)-phenyl-ethyl)-
piperidin-2-one 15 and (R)-6-(3-benzyloxy-propyl)-1-(10-
(S)-phenyl-ethyl)-piperidin-2-one 16. Irradiation of 12
(1.74 g of a 12/13 = 89:11 mixture; thus effectively 1.31 g,
3.74 mmol 12) in toluene/MeOH 9:1 (1 L) at rt for 2.5 h
in a quartz reactor following the general procedure yielded
15/16 as an inseparable 75:25 mixture (611 mg, 46%) as a
colorless oil. The following characterization of 15/16 was
4.4. General procedure for reductive photocyclization of
dienamides
To a stirred solution of the dienamide (1.25 mmol) in benz-
ene/MeOH 9:1 or toluene/MeOH 9:1 (250 mL) at rt under
Ar was added NaBH4 (380 mg, 10.0 mmol) and Ar was
bubbled through the resulting suspension for 15 min. The
resulting clear solution was irradiated under Ar in a quartz
or a pyrex reactor equipped with a medium pressure mer-
cury lamp (400 W) until TLC showed the reaction to be
complete. The solvents were then evaporated and the resi-
due dissolved in CH2Cl2 (30 mL) and water (20 mL). The
organic phase was isolated and the aqueous phase was ex-
tracted with CH2Cl2 (2 · 30 mL). The combined organic
phases were dried over MgSO4, filtered, concentrated and
dried in vacuo. Flash chromatography of the residue
yielded the piperidinone(s).
carried out on a 79:21 mixture, as judged by NMR: Rf
22
(cyclohexane/EtOAc 25:75) = 0.48; ½aꢁD ¼ ꢀ90:4 (c 0.50,
1
MeOH); H NMR (400 MHz, CDCl3): d 7.41–7.20 (10H,
m), 5.94 (0.21H, q, J = 7.1 Hz, CH3CHN, 16), 5.74
(0.79H, q, J = 7.1 Hz, CH3CHN, 15), 4.50 (0.42H, s,
OCH2Ph, 16), 4.40 (1.58H, s, OCH2Ph, 15) 3.49–3.41
(1.24H, m, NCH, 16 and OCH2CH2, 15), 3.19–3.08
(1.76H, m, NCH, 15 and OCH2CH2, 16), 2.54–2.43 (2H,
m), 1.94–0.82 (8H, m), 1.59 (3H, d, J = 7.1 Hz, CH3CHN);
13C NMR (100 MHz, CDCl3): d 170.2 (ꢀ, 16), 169.8
(ꢀ,15), 141.0 (ꢀ), 140.7 (ꢀ), 138.3 (ꢀ), 128.2–127.0 (10C,
+), 72.8 (ꢀ, 16), 72.7 (ꢀ, 15), 69.7 (ꢀ, 15), 69.6 (ꢀ, 16),
53.3 (+, 15), 52.5 (+, 15), 52.2 (+, 16), 51.8 (+,16), 31.1
(ꢀ, 15), 30.8 (ꢀ, 16), 30.4 (ꢀ, 16), 29.4 (ꢀ, 15), 26.6 (ꢀ,
16), 26.5 (ꢀ, 15), 25.8 (ꢀ, 15), 25.2 (ꢀ, 16), 15.9 (ꢀ, 15),
15.9 (ꢀ, 16), 17.4 (+, 16), 16.3 (+, 15); IR (neat) 3030
(w), 2946 (m), 2866 (m), 1635 (s), 1452 (m), 1362 (w),
1292 (w), 1101 (m), 739 (m), 700 (m); GC–MS (EI): m/z
351 (35, M+), 260 (20), 232 (11), 202 (22), 156 (18), 138
(16), 120 (39), 106 (11), 105 (100), 104 (13), 103 (10), 98
(89), 91 (72), 79 (14), 77 (13), 55 (10). HRMS (TOF MS
ES+) calcd for C23H30NO2 [M+H]+ m/z 352.2277. Found:
352.2281.
4.4.1. 3-(1-Benzyl-6-oxo-piperidin-2-yl)-propionic acid ethyl
ester 11a. Irradiation of 9a (360 mg, 1.25 mmol) in benz-
ene/MeOH 9:1 at rt for 2.75 h in a quartz reactor follow-
ing the general procedure yielded 11a (56 mg, 16%) as a
colorless oil: Rf (cyclohexane/EtOAc 25:75) = 0.33; 1H
NMR (400 MHz, CDCl3): d 7.36–7.23 (5H, m), 5.43 (1H,
d, J = 15.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 3.98 (1H, d,
J = 15.1 Hz), 3.37–3.29 (1H, m), 2.54–2.47 (2H, m), 2.38–
1.68 (8H, m), 1.26 (3H, t, J = 7.1 Hz); 13C NMR
(100 MHz, CDCl3): d 172.6 (ꢀ), 170.2 (ꢀ), 137.5 (ꢀ),
128.4 (2C, +), 127.7 (2C, +), 127.1 (+), 60.6 (ꢀ), 47.3
(ꢀ), 54.4 (+), 31.8 (ꢀ), 30.5 (ꢀ), 26.9 (ꢀ), 25.9 (ꢀ), 17.1
(ꢀ), 14.1 (+); IR (neat) 3029 (w), 2949 (m), 1732 (s),
1638 (s), 1452 (m), 1417 (w), 1334 (w), 1260 (m), 1185
(m), 1030 (w), 731 (w), 703 (m); GC–MS (EI): m/z 289
(17, M+), 189 (16), 188 (71), 160 (29), 106 (11), 91 (100).
HRMS (TOF MS ES+) calcd for C17H23NO3Na
[M+Na]+ m/z 312.1576. Found: 312.1562; Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.59; H, 8.02; N, 4.87.
4.5. (S)-2-(3-Benzyloxy-propyl)-1-(10-(S)-phenyl-ethyl)-
piperidine 17 and (R)-2-(3-benzyloxy-propyl)-1-(10-(S)-phen-
yl-ethyl)-piperidine 18
To a stirred suspension of LiAlH4 (104 mg, 2.74 mmol) in
THF (35 mL) under Ar at 0 ꢁC was added dropwise a solu-
tion of 15/16 (383 mg, 1.09 mmol) in THF (5 mL). The
resulting mixture was then refluxed for 4 h, until TLC
(cyclohexane/EtOAc 25:75) showed the reaction to be com-
plete. The mixture was cooled to 0 ꢁC and the reaction was
quenched by the dropwise addition of water (ca. 10 drops).
The mixture was then dried over MgSO4 and filtered
through celite, washing the solids with THF (ca. 75 mL).
The clear filtrate was concentrated and dried in vacuo
and flash chromatography of the residue yielded 18
(58 mg, 16%) as an orange oil and 17 (223 mg, 61%) as a
4.4.2. 1-Benzyl-6-(3-benzyloxy-propyl)-piperidin-2-one 11b.
Irradiation of 9b (420 mg of a mixture of 68.0 mol %/
78.8 wt % 9b and 32.0 mol %/21.2 wt % 8b as judged by
NMR; thus effectively 331 mg, 0.99 mmol 9b) in benzene/
MeOH 9:1 at rt for 2.5 h in a quartz reactor following
the general procedure yielded 11b (127 mg, 37%) as a color-
less oil; Rf (EtOAc) = 0.64; 1H NMR (400 MHz, CDCl3): d
7.41–7.20 (10H, m), 5.41 (1H, d, J = 15.1 Hz), 4.50 (2H, s),
3.95 (1H, d, J = 15.1 Hz), 3.45 (2H, t, J = 6.5 Hz), 3.37–
3.28 (1H, m), 2.55–2.45 (2H, m), 2.30–1.42 (8H, m); 13C
NMR (100 MHz, CDCl3): d 170.1 (ꢀ), 138.1 (ꢀ), 137.5
(ꢀ), 128.3–126.9 (10C, +), 72.8 (ꢀ), 69.6 (ꢀ), 55.0 (+),
47.2 (ꢀ), 31.8 (ꢀ), 28.6 (ꢀ), 26.0 (ꢀ), 25.9 (ꢀ), 17.1 (ꢀ);
IR (neat) 3030 (w), 2946 (m), 2865 (m), 1636 (s), 1453
(m), 1415 (w), 1358 (m), 1259 (w), 1100 (m), 738 (m), 701
yellowish oil. 17: Rf (cyclohexane/EtOAc 1:1) = 0.25;
22
½aꢁD ¼ ꢀ68:4 (c 1.00, MeOH); 1H NMR (400 MHz,
CDCl3): d 7.41–7.20 (10H, m), 4.52 (2H, s), 4.06 (1H, q,
J = 6.4 Hz), 3.47 (2H, t, J = 6.3 Hz), 2.81–2.69 (1H, m),
2.51–2.40 (1H, m), 2.36–2.35 (1H, m), 1.82–1.20 (10H,
m), 1.38 (3H, d, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3):
d 143.5 (ꢀ), 138.7 (ꢀ), 128.2–126.5 (10C, +), 72.7 (ꢀ), 70.7
(ꢀ), 57.4 (+), 55.4 (+), 44.2 (ꢀ), 28.9 (ꢀ), 26.1 (ꢀ), 25.3
(ꢀ), 24.6 (ꢀ), 21.5 (ꢀ), 20.9 (+); IR (neat) 3028 (w), 2932
(s), 2856 (m), 1453 (m), 1363 (w), 1104 (s), 735 (m), 700

T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
677
(s); GC–MS (EI): m/z 246 (19), 189 (16), 188 (100), 105
J = 10.4 Hz), 3.00–2.86 (1H, m), 2.77–2.59 (2H, m), 2.38–
1.93 (8H, m), 1.87 (1H, br d, J = 14.7 Hz), 1.56–1.41
(1H, m); 13C NMR (100 MHz, CDCl3): d 67.2 (+), 52.4
(ꢀ), 51.9 (ꢀ), 28.3 (ꢀ), 27.3 (ꢀ), 22.6 (ꢀ), 22.5 (ꢀ), 19.4
(ꢀ). NMR spectra were in full accordance with those re-
ported in the lit. for ( )-1ÆHBr.16
(46), 91 (21), 84 (48). HRMS (TOF MS ES+) calcd for
C23H32NO [M+H]+ m/z 338.2484. Found: 338.2499. 18:
21
Rf (cyclohexane/EtOAc 1:1) = 0.48; ½aꢁD ¼ ꢀ6:4 (c 0.50,
1
MeOH); H NMR (400 MHz, CDCl3): d 7.47–7.20 (10H,
m), 4.53 (2H, s), 4.05 (1H, q, J = 6.6 Hz), 3.51 (2H, t,
J = 6.0 Hz), 2.83–2.72 (1H, m), 2.46–2.37 (1H, m), 2.32–
2.19 (1H, m), 1.82–1.24 (10H, m), 1.28 (3H, d,
J = 6.6 Hz); 13C NMR (100 MHz, CDCl3): d 146.1 (ꢀ),
138.6 (ꢀ), 128.3–126.2 (10C, +), 72.8 (ꢀ), 70.8 (ꢀ), 56.7
(+), 55.5 (+), 44.9 (ꢀ), 29.4 (ꢀ), 25.7 (ꢀ), 25.6 (ꢀ), 25.2
(ꢀ), 22.6 (ꢀ), 14.5 (+); IR (neat) 3029 (w), 2933 (s), 2856
(m), 1452 (m), 1364 (w), 1104 (s), 734 (m), 699 (s); GC–
MS (EI): m/z 246 (18), 189 (16), 188 (100), 105 (47), 91
(20), 84 (50). HRMS (TOF MS ES+) calcd for
C23H32NO [M+H]+ m/z 338.2484. Found: 338.2480.
The free amine 1 was obtained by dissolving (+)-1ÆHBr (ca.
80 mg) in satd aq Na2CO3 (0.75 mL). The mixture was ex-
tracted with Et2O (4 · 0.75 mL) and the combined organic
phases were distilled over K2CO3 in a Kugelrohr appara-
tus, yielding (+)-1 (ca. 40 mg) as a colorless oil: bp =
100–105 ꢁC/140 mm Hg (lit.16 bp = 59–60 ꢁC/19 mm Hg;
22
lit.21 bp = 75–80 ꢁC/25 mm Hg); ½aꢁD ¼ þ9:5 (c 1.13,
23
1
EtOH) {lit.16 ½aꢁD ¼ 9:3 ꢂ 0:6 (c 1.76, EtOH)}; H NMR
(400 MHz, CDCl3): d 3.15–3.02 (2H, m), 2.08 (1H, q,
J = 9.0 Hz), 1.98 (1H, dt, J = 11.2, 3.5 Hz), 1.92–1.52
(8H, m), 1.48–1.36 (1H, m), 1.30–1.16 (2H, m); 13C
NMR (100 MHz, CDCl3): d 64.5 (+), 54.2 (ꢀ), 53.0 (ꢀ),
30.9 (ꢀ), 30.4 (ꢀ), 25.3 (ꢀ), 24.4 (ꢀ), 20.6 (ꢀ); GC–MS
(EI): m/z 125 (47, M+), 124 (100), 97 (53), 96 (57), 83
(33), 82 (10), 69 (27), 68 (11), 55 (10). NMR spectra were
in full accordance with those reported in the lit.3d,i
4.6. (S)-3-Piperidin-2-yl-propan-1-ol (19) and (+)-coniceine
hydrobromide 1ÆHBr
To a solution of 17 (304 mg, 0.901 mmol) in MeOH
(40 mL) under Ar at rt was added ammonium formate
(568 mg, 9.01 mmol) and 10% Pd/C (205 mg). The resulting
mixture was then refluxed for 16.5 h. The mixture was fil-
tered through Celite, washing the filter cake with a little
MeOH. The filtrate was concentrated and dried in vacuo.
The residual oil, which contained some solids, was then
redissolved in CH2Cl2 (5 mL) and the suspension filtered
though a cellulose plug, washing the plug with a little
CH2Cl2. The filtrate was concentrated and dried in vacuo,
yielding the crude amino alcohol 19 (143 mg) as a pale yel-
lowish oil, which showed NMR spectra in full accordance
with those reported in the lit. for the racemate2a: 1H NMR
(400 MHz, CDCl3): d 3.61–3.54 (1H, m), 3.53–2.46 (1H,
m), 3.08–3.01 (1H, m, J = 12.5 Hz), 2.58 (1H, ddd,
J = 12.5, 12.5, 2.9 Hz), 2.50–2.42 (1H, m), 1.84–1.66 (2H,
m), 1.65–1.51 (4H, m), 1.47–1.08 (4H, m); 13C NMR
(100 MHz, CDCl3): d 62.2 (ꢀ), 56.5 (+), 46.1 (ꢀ), 35.1
(ꢀ), 32.5 (ꢀ), 29.9 (ꢀ), 25.9 (ꢀ), 24.3 (ꢀ); GC–MS (EI):
m/z 143 (1, M+) 84 (100), 56 (11). The crude amino alcohol
was dissolved in MeCN (9 mL) at rt under Ar and PPh3
(445 mg, 1.697 mmol) and CBr4 (660 mg, 1.990 mmol) were
added. The resulting mixture was stirred at rt for 15 h and
was then poured into 5% aq HBr (25 mL) and the mixture
was washed with EtOAc (20 mL and 4 · 10 mL). The aque-
ous phase was basified by addition an excess of Na2CO3
and was then extracted with Et2O (8 · 10 mL). The com-
bined organic phases were extracted with 5% aq HBr (5.0
and 2.5 mL) and the combined aqueous phases were con-
centrated and dried in vacuo yielding a pale tan paste
(ca. 255 mg) containing chloroform-insoluble salts. The
residue was suspended in CHCl3 (10 mL) and the superna-
tant was filtered through a cellulose plug and the filtrate
was concentrated and dried in vacuo. The residue
(170 mg, pale tan paste) was dissolved in EtOH (0.5 mL)
and Et2O (ca. 15 mL) was added dropwise until precipita-
tion was complete. The supernatant was removed and the
residual solids were dried in vacuo, yielding (+)-1ÆHBr
4.7. Determination of enantiomeric purity using NMR
When adapting the lit. NMR method17 for determination
of enantiomeric ratios of organic ammonium halides, the
peak originally at 28.31 ppm in the 13C NMR spectrum
for ( )-1ÆHBr split into two separate, equally intense peaks
at 28.22 and 28.15 ppm. When an identical experiment was
performed on (+)-1ÆHBr only the peak at 28.15 ppm was
visible. This latter sample was therefore deduced as having
ee >97% (detection limit of the analytical technique).
Acknowledgement
We thank the Technical University of Denmark for finan-
cial support.
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Garraffo, H. M.; Spande, T. F. In The Alkaloids: Chemistry
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22
(lit.16 mp = 198–199 ꢁC for ( )-1ÆHBr); ½aꢁD ¼ þ5:5 (c
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T. Hjelmgaard et al. / Tetrahedron: Asymmetry 18 (2007) 671–678
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