Short syntheses of (S)-pipecolic acid, (R)-coniine, and (S)-δ-coniceine using biocatalytically-generated chiral building blocks

Article abstract of DOI:10.1016/S0957-4166(98)00178-5

The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2- (hydroxymethyl)piperidine [(±)-5] and (±)-N(tert-butoxycarbonyl)-2- (hydroxymethyl)piperidine [(±)-6] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks (S)-5 and (S)- 6, respectively; which were used for the syntheses of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2- 4 steps) and proceeded with satisfactory overall yield.

Full text of DOI:10.1016/S0957-4166(98)00178-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1951–1965
Short syntheses of (S)-pipecolic acid, (R)-coniine, and
(S)-δ-coniceine using biocatalytically-generated chiral building
blocks †,‡,§
Francisco Sánchez-Sancho and Bernardo Herradón ∗
Instituto de Química Orgánica General, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain
Received 23 April 1998; accepted 29 April 1998
Abstract
The kinetic resolutions of both (ꢀ)-N-(benzyloxycarbonyl-2-(hydroxymethyl)piperidine [(ꢀ)-5] and (ꢀ)-N-
(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine [(ꢀ)-6] catalyzed by the enzyme acylase I from Aspergillus
species (AA-I) afforded the chiral building blocks (S)-5 and (S)-6, respectively; which were used for the syntheses
of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2–4 steps) and
proceeded with satisfactory overall yield. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The piperidine ring is an ubiquitous structural feature in numerous secondary metabolites and bio-
logically active compounds. Some examples of natural products include alkaloids with the structure of
2-alkyl-piperidine2 [e.g.; (R)-coniine 1, Fig. 1], indolizidine alkaloids3 [e.g.; (S)-δ-coniceine 2], and
non-proteinogenic amino acids4 [e.g.; (S)-pipecolic acid 3]. This last compound, besides being a natural
product itself,5 it is a component of many natural peptides6 and immunosuppressor agents7 [e.g.; FK-506
and rapamycin], as well as an intermediate for their syntheses. Additionally, the piperidine nucleus is a
frequent structural moiety in many synthetic pharmaceuticals8 [e.g.; anesthetic (S)-bupivacaine 4].9 Due
to the known dependence between the biological activity of a molecule and its absolute configuration,10
it is convenient to have ready access to non-racemic functionalized piperidines.11
∗
†
‡
§
Corresponding author. Fax: 34-91-5644853; e-mail: herradon@fresno.csic.es
Part 10 in the series: ‘Biocatalysis in Organic Synthesis’; for Part 9, see Ref. 1.
Taken from the projected Ph.D. thesis of F. S.-S.
Dedicated to Professor Dieter Seebach on the occasion of his 60th birthday, and in recognition of his outstanding contribution
to Organic Chemistry.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00178-5

1952
F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
Fig. 1.
In connection with our ongoing project on synthetic applications of biocatalytically-generated chiral
building blocks,12 we have achieved efficient EPC-syntheses13 of derivatives of both enantiomers of 2-
(hydroxymethyl)piperidine [namely, (S)-5 and (S)-6, Fig. 1] through transesterifications catalyzed by the
enzyme acylase I from Aspergillus species (AA-I hereafter).14 The functionality existing in these N-
protected amino alcohols should make them useful intermediates for the syntheses of the above indicated
natural products and related compounds.15–17
In this paper we report full details on the kinetic resolutions of (ꢀ)-N-(benzyloxycarbonyl)-2-
(hydroxymethyl)piperidine (ꢀ)-5 and (ꢀ)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine (ꢀ)-6
catalyzed by AA-I, as well as the syntheses of (R)-coniine 1, (S)-δ-coniceine 2, and (S)-pipecolic acid
3, and its derivatives (S)-7 and (S)-8, from the chiral building blocks (S)-5 and (S)-6 (Fig. 1). Albeit the
structures of the target molecules are quite simple, they have attracted a great interest, especially to test
synthetic methodologies. Although many syntheses of these compounds have been reported,18–20 most
of them are not efficient; they are lengthy with low overall yield, and use non-readily available starting
materials.
2. Results and discussion
In our first experiments on transesterifications catalyzed by AA-I, we briefly studied the acetylation
of (ꢀ)-6 using vinyl acetate as the reagent.14 Although this kinetic resolution went with moderate
enantioselectivity21 (E=16), we were able to obtain enantiomerically pure (S)-6, albeit in modest
chemical yield. Recently we found that, in general, the butyrylations (using vinyl butyrate as the acylating
agent) are faster and more enantioselective than the cognate acetylations.1 We have also observed the
same effect in the kinetic resolution of both (ꢀ)-5 and (ꢀ)-6;22 thus, the butyrylations catalyzed by AA-
I of these substrates were more enantioselective than the acetylations, reaching values of E=25. With
this level of enantioselectivity, it was possible to get the N-protected amino alcohols (S)-5 and (S)-6
in high enantiomeric purities (>98% ee) if the kinetic resolutions were carried out at relatively high
conversions.23 A more convenient tactic is to run two consecutive reactions,25 that would allow us to
obtain the target molecules in enantiomerically pure form and in satisfactory overall yield.
Schemes 1 and 2 show representative resolution procedures to obtain enantiomerically pure (S)-5
and (S)-6, respectively.24,26 Racemic (ꢀ)-5 was butyrylated in wet toluene27 and catalyzed by AA-I
(Scheme 1).28 The reaction was carried out with up to ca. 50% conversion (1H-NMR evidence). The
butyrate29 (R)-9 and the alcohol (S)-5 (of 85% ee) were readily separated by flash-chromatography, and
the enantiomerically enriched alcohol was submitted to a second kinetic resolution, which was carried
out with up to ca. 15% conversion,30 to give enantiomerically pure (S)-5 in ca. 42% overall yield for the
two steps.31
Enantiomerically pure (S)-6 was obtained in an analogous manner (Scheme 2). In this case, the second

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1953
Scheme 1.
Scheme 2.
acylation was carried out in wet toluene, because we observed that the reaction in this solvent was slighty
faster than in toluene.
The transformations indicated in Schemes 1 and 2 were carried out up to an 80 mmol scale, and the
results were reproducible. Additionally, the enzyme could be recovered and reused, showing the same
enantioselectivity and nearly the same activity.
With a ready supply of the chiral building blocks (S)-5 and (S)-6 in hand, we applied them to the
syntheses of (S)-pipecolic acid 3, (R)-coniine 1, and (S)-δ-coniceine 2. The syntheses of (S)-pipecolic
acid 3 and its derivatives 7 and 8 are shown in Scheme 3. Swern oxidation32 of both 5 and 6 gave a high

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F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
yield, affording the relatively unstable protected amino aldehydes 11 and 12, respectively;33,34 which, in
turn, were oxidized with potassium permanganate to the N-protected derivatives of (S)-pipecolic acid 7
and 8, respectively. Meanwhile the direct oxidation of 5 to 7 was achieved in satisfactory yield (77%)
with Jones reagent.35 We were unable to oxidize the N-tert-butoxycarbonyl derivative 6 to the acid 8,
probably reflecting a poor stability of this protecting group under the conditions of Jones oxidation. (S)-
Pipecolic acid 3 was obtained in high yield (94%) by the hydrolytic removal of the benzyloxycarbonyl
group in 7. We also tried the deprotection of the N-tert-butoxycarbonyl group from 8 (treatment with
trifluoroacetic acid); but, although the reaction was clean (t.l.c. evidence), we could not obtain a good
yield of (S)-pipecolic acid after ion-exchange chromatography. Since the synthesis of (S)-pipecolic acid
through the N-benzyloxycarbonyl derivative proceeded efficiently, we did not pursue its synthesis further
through compound 8.
Scheme 3.
The synthesis of (R)-coniine 1 is indicated in Scheme 4. The aldehyde 11 reacted with the ylide
formed from ethyl triphenylphosphonium bromide to give the olefin 13 as a single isomer,36 which was
hydrogenated to give volatile (R)-coniine,37 which was characterized as its hydrochloride.
Scheme 4.
We carried out two syntheses of (S)-δ-coniceine starting from both 11 and 12 (Scheme 5). The Wittig
reactions of both aldehydes 11 and 12 and the stabilized phosphorane 14 in methylene chloride were
totally stereoselective giving the (E)-α,β-unsaturated esters 15 and 16, respectively, in nearly quantitative
yield.38 The transformation of the N-Boc-derivative 16 to the indolizidinone 17 was performed in a three-
stage reaction sequence (saturation of the double bond, hydrolysis of the carbamate, and cyclization),

F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
1955
which was realized without purification of intermediates, in 82% overall yield. On the other hand,
the catalytic hydrogenation of 15 proceeded with N-deprotection, saturation of the double bond, and
cyclization, affording 17, along with a small and variable amount of the amino ester 18; this mixture
was heated at reflux in toluene to give 17 in 85% overall yield from 15. Although the reduction of 17
to volatile δ-coniceine has been disclosed several times,39 some of these reported procedures were not
reproducible in our hands. The best reagent to obtain (S)-δ-coniceine was the borane/dimethyl sulfide
complex, which gave the target molecule in good yield.37
Scheme 5.
Summarizing, we have demonstrated that the chiral building blocks 5 and 6 are useful for the syntheses
of enantiomerically pure piperidine derivatives. It is worth mentioning that the derivatives of pipecolic
acid 7 and 8, and their enantiomers,26,40 can be employed in the synthesis of analogues of FK-506,
rapamycin and other immunosuppressors,7 as well as for the preparation of pipecolic acid-containing
peptides.6,41,42 Additionally, the functionality of some of the chiral building blocks (e. g.; 11, 12, 13, 15,
16, and 17) reported in this paper make them suitable for the preparation of more complex molecules.
3. Experimental
All the reactions with sensitive materials were carried out using dry solvents under argon atmosphere.
All the solvents and chemicals were commercially available and, unless otherwise indicated, were used as
received. When necessary, THF and toluene were freshly dried over sodium/benzophenone ketyl. DMSO
was distilled from CaH2 under a reduced pressure of argon. Et3N was distilled from CaH2 or KOH
under an argon atmosphere. Commercially available CH2Cl2 (Fluka puriss quality) kept over molecular
sieves was used. The enzyme acylase I from Aspergillus species (AA-I) was purchased from Aldrich
or Sigma.28 1H-NMR and 13C-NMR spectra were measured in a Varian-UNITY-400, Varian-XL-300,
Varian-Gemini-200, or a Bruker AM-200; chemical shifts are reported in parts per million (δ), and the
coupling constants are indicated in Hz. Unless otherwise indicated, all the NMR spectra were measured
1
at room temperature (298 K). H-NMR spectra are referenced to the residual proton in the deuterated
solvent. 13C-NMR spectra are referenced to the chemical shift of the deuterated solvent. The multiplicity

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F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
of the signals in the 13C-NMR spectra were determined by APT or DEPT experiments. The IR spectra
were performed on a Perkin–Elmer-657 spectrometer, the frequencies in the IR spectra are indicated in
cm−1. All the mass spectra are low-resolution electron-impact mass spectra (70 eV), and were recorded
in a RMU-GMG spectrometer from Hitachi–Perkin–Elmer. Microanalysis were realized by E. Barbero
(Instituto de Química Orgánica, C. S. I. C.) on a Carlo Erba EA 1180-Elemental Analyzer. The optical
rotations were measured on a Perkin–Elmer 241 MC polarimeter; all the optical rotations were measured
at room temperature. All the preparative chromatographies were done with silica gel (40–63 mm) using
the technique of flash-chromatography.43
3.1. Synthesis of (ꢀ)-N-(benzyloxycarbonyl)-2-(hydroxymethyl)piperidine (ꢀ)-5
A solution of (ꢀ)-2-(hydroxymethyl)piperidine (20 g, 174 mmol) in THF (300 ml) was treated with
aqueous 1 M K2CO3 (500 ml, 500 mmol) and benzyl chloroformate (27 ml, 191 mmol). The mixture
was stirred at room temperature overnight, and then 5% aqueous HCl was added until pH=2. The
organic phase was separated and the aqueous phase was saturated with NaCl and extracted with AcOEt
(twice). The combined organic extracts were washed with water and dried over anhydrous MgSO4. After
evaporation of the solvent and chromatography using hexane:AcOEt mixtures (in the ratio of between
1
80:20 and 0:100), pure (ꢀ)-5 was obtained (39.8 g, 90% yield). White solid: m.p. 49–52°C. H-NMR
(200 MHz, CDCl3) δ 7.36–7.25 (m, 5H), 5.13 (s, 2H), 4.36 (m, 1H), 4.03 (br d, J=13.1, 1H), 3.83 (ddd,
J=11.1, 8.7, 6.1, 1H), 3.63 (distorted dt, J=11.3, 5.7, 1H), 2.95 (br distorted t, J=12.0, 1H), 2.20 (broad s,
1H), 1.86–1.39 (m, 6H). 13C-NMR (50.3 MHz, CDCl3) δ 156.2 (s), 136.5 (d), 128.2 (d, 2C), 127.7 (d),
127.5 (d, 2C), 66.9 (t), 60.6 (t), 52.5 (d), 39.9 (t), 25.0 (t), 24.8 (t), 19.2 (t). IR (KBr) ν 3450, 2950, 2880,
1680, 1430, 1360, 1270, 1170, 1140, 1050, 700. MS m/z 218 (M−31, 7), 174 (23), 140 (2) 128 (3), 91
(100), 84 (5), 83 (6), 65 (7), 57 (16), 55 (7), 45 (7), 41 (8). Anal. calcd for C14H19NO3: C, 67.45%; H,
7.68%; N, 5.62%. Found: C, 67.80%; H, 7.58%; N, 5.82%.
3.2. Synthesis of (ꢀ)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine (ꢀ)-6
A solution of (ꢀ)-2-(hydroxymethyl)piperidine (20 g, 174 mmol) in THF (300 ml) was treated with
aqueous 1 M K2CO3 (500 ml, 500 mmol) and di-tert-butyldicarbonate (44 ml, 191 mmol). The solution
was stirred at room temperature overnight, and then 5% aqueous HCl was added until pH=2. The
organic phase was separated and the aqueous phase was saturated with NaCl and extracted with AcOEt
(twice). The combined organic extracts were washed with water and dried over anhydrous MgSO4. After
evaporation of the solvent, a crude product was obtained, which was purified by crystallization from
MeOH–Et2O to give (ꢀ)-6 (35.5 g, 95% yield). White solid: m.p. 81–84°C. 1H-NMR (300 MHz, CDCl3)
δ 4.30 (m, 1H), 3.94 (br d, J=12.5, 1H), 3.83 (ddd, J=11.0, 9.3, 5.9, 1H), 3.61 (dt, J=11.0, 5.5, 1H), 2.89
(br t, J=12.5, 1H), 2.00 (broad s, 1H), 1.61 (m, 6H), 1.47 (s, 9H). 13C-NMR (50.3 MHz, CDCl3) δ 156.3
(s), 79.8 (s), 61.8 (t), 52.6 (d), 39.9 (t), 28.4 (q, 3C), 25.3 (t), 25.2 (t), 19.6 (t). IR (KBr) ν 3440, 2940,
2890, 1655, 1425, 1370, 1280, 1170, 1150, 1060, 1050, 870. MS m/z 184 (M+−31, 23), 128 (100), 84
(90), 57 (89), 56 (21), 55 (23), 41 (30). Anal. calcd for C11H21NO3: C, 61.37%; H, 9.83%; N, 6.51%.
Found: C, 61.36%; H, 10.13%; N, 6.64%.

F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
1957
3.3. Kinetic resolution of N-(benzyloxycarbonyl)-2-(hydroxymethyl)piperidine (ꢀ)-5. Synthesis of (S)-
(−)-5 and (R)-(+)-9
AA-I (48 g, 300 U/mmol) was added to a solution of (ꢀ)-5 (20 g, 80.3 mmol) in wet toluene (500
ml). The mixture was stirred at room temperature for 5 minutes, and was then treated with vinyl butyrate
(10.4 ml, 80.3 mmol). The mixture was stirred at room temperature for 9 hours, and diluted with CH2Cl2
(ca. 200 ml). The enzyme was removed by filtration and washed with CH2Cl2. After evaporation of
the solvent, the crude product was chromatographed (hexane:AcOEt, ratios between 80:20 and 0:100)
to give (R)-9 (12.6 g, 49% yield) and (S)-5 (of 85% ee, as determined by g.l.c.; 9.8 g, 49% yield).
This enantiomerically enriched material was subjected to a second kinetic resolution using wet toluene
(300 ml), AA-I (23.5 g, 300 U/mmol), and vinyl butyrate (5.1 ml, 39.3 mmol). The mixture was stirred
at room temperature for 6 hours. The same work-up and purification procedure as in the first kinetic
resolution gave a small amount of the butyrate 9 and the enantiomerically pure alcohol (S)-5 (>99.8% ee,
as determined by g.l.c.; 8.3 g, 85% yield). The spectroscopic and analytical data of (S)-5 are identical to
that reported for (ꢀ)-5, having a specific rotation of: [α]D −30.2 (CHCl3, c=1.1).
The analytical and spectroscopic data of (R)-(+)-N-(benzyloxycarbonyl)-2-(butyryloxymethyl)piper-
idine [(R)-9] are as follows: thick oil; [α]D +20.7 (CHCl3, c=1.0; for a sample of ca. 70% ee).44 1H-NMR
(200 MHz, CDCl3, 313 K) δ 7.33 (m, 5H), 5.12 (s, 2H), 4.54 (m, 1H), 4.30 (dd, J=11.1, 8.3, 1H), 4.10
(dd, J=11.1, 6.4, 1H), 4.08 (m, 1H), 2.89 (m, 1H), 2.17 (t, J=7.5, 2H), 1.69–1.48 (m, 8H), 0.89 (t, J=7.4,
3H). 13C-NMR (50.3 MHz, CDCl3, 313 K) δ 172.4 (s), 155.0 (s), 136.5 (s), 127.9 (d, 2C), 127.3 (d),
127.2 (d, 2C), 66.4 (t), 60.9 (t), 48.9 (d), 38.2 (t), 35.4 (t), 25.8 (t), 24.7 (t), 19.8 (t), 17.7 (t), 13.0 (q). IR
(neat) ν 3040, 2940, 1740, 1700, 1500, 1260, 750, 700. MS m/z 292 (M−28, 31), 174 (57), 91 (100), 65
(9), 43 (10). Anal. calcd for C18H25NO4: C, 67.69%; H, 7.89%; N, 4.39%. Found: C, 67.95%; H, 8.02%;
N, 4.63%.
3.4. Kinetic resolution of N-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine (ꢀ)-6. Synthesis of (S)-
(−)-6 and (R)-(+)-10
AA-I (36 g, 300 U/mmol) was added to a solution of (ꢀ)-6 (13 g, 60.5 mmol) in toluene (400 ml). The
mixture was stirred at room temperature for 5 minutes, and then was treated with vinyl butyrate (7.8 ml,
60.5 mmol). The heterogeneous suspension was stirred at room temperature for 9 hours, and diluted with
CH2Cl2 (ca. 200 ml). The enzyme was removed by filtration and washed with CH2Cl2. After evaporation
of the solvent, the crude product was chromatographed (hexane:AcOEt, ratios between 80:20 and 0:100)
to give (R)-10 (88% ee, as determined by g.l.c.; 5.7 g, 33% yield) and (S)-6 (47% ee, as determined
by g.l.c.; 8.2 g, 63% yield). This enantiomerically enriched material was submitted to a second kinetic
resolution using wet toluene (200 ml), AA-I (23.0 g, 300 U/mmol), and vinyl butyrate (5.0 ml, 38.5
mmol). This mixture was stirred at room temperature for 8.5 hours. The same work-up and purification
procedure as in the first kinetic resolution gave the butyrate (R)-10 (ee not determined; 3.8 g, 35% yield)
and the enantiomerically pure alcohol (S)-6 (>99.6% ee, as determined by g.l.c.; 4.7 g, 58% yield). The
spectroscopic and analytical data of (S)-6 are identical to those reported for (ꢀ)-6. The specific rotation
is [α]D −40.5 (CHCl3, c=1.0).
The analytical and spectroscopic data of (R)-(+)-N-(tert-butoxycarbonyl)-2-(butyryloxymethyl)piper-
idine [(R)-10] are as follows: thick oil; [α]D +31.1 (CHCl3, c=0.3; for a sample of >98% ee). 1H-NMR
(200 MHz, CDCl3) δ 4.49 (broad m, 1H), 4.25 (dd, J=11.0, 8.1, 1H), 4.10 (dd, J=11.0, 6.8, 1H), 4.00
(broad d, J=13.0, 1H), 2.80 (m, 1H), 2.28 (t, J=7.4, 2H), 1.70–1.52 (m, 8H), 1.45 (s, 9H), 0.94 (t, J=7.4,
3H). 13C-NMR (50.3 MHz, CDCl3) δ 173.4 (s), 154.9 (s), 79.4 (s), 61.5 (t), 48.7 (d), 39.3 (t), 36.0 (t),

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F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
28.3 (q, 3C), 25.3 (t), 25.2 (t), 19.2 (t), 18.3 (t), 13.6 (q). IR (neat) ν 2980, 1750, 1700, 1360, 1250. MS
m/z 285 (M+, <1), 184 (4), 128 (29), 111 (6), 98 (11), 97 (21), 84 (46), 83 (38), 71 (34), 69 (41), 57
(100), 55 (26), 43 (49), 41 (22).
3.5. General procedure for the Swern oxidation of 5 and 6. Syntheses of (S)-(−)-N-(benzyloxycarbonyl)-
2-(formyl)piperidine 11 and (S)-(−)-N-(tert-butoxycarbonyl)-2-(formyl)piperidine 12
Commercially available 2 M oxalyl chloride solution in CH2Cl2 (4.3 ml, 8.6 mmol) was diluted with
CH2Cl2 (15 ml) at −70°C under an argon atmosphere. A solution of dry DMSO (1.2 ml, 17.3 mmol) in
CH2Cl2 (5 ml) was slowly added dropwise at −70°C. After stirring for 30 minutes at this temperature, a
solution of the corresponding alcohol (7.2 mmol) in CH2Cl2 (10 ml) was added via cannula. The mixture
was stirred at −70°C for 90 minutes, and then dry Et3N (5 ml, 36.1 mmol) was added. Stirring was
maintained at −70°C while the formation of the aldehyde was monitored by t.l.c. When the reaction was
completed (ca. 0.5 hours), water was added at −70°C, the mixture was then allowed to warm slowly
to room temperature. The organic layer was then separated and the aqueous phase was extracted with
CH2Cl2 (three times). The combined organic extracts were washed with aqueous 5% HCl (twice), water
(twice), 1 M aqueous Na2CO3 (twice) and finally water (twice). After drying and solvent evaporation, a
chromatographically homogeneous product (either 11 or 12) was obtained. Analytically pure samples of
either 11 or 12 were obtained after flash-chromatography (hexane:AcOEt, 85:15). The spectroscopic and
analytical data of 11 and 12 are shown below.
3.5.1. (S)-(−)-N-(Benzyloxycarbonyl)-2-(formyl)piperidine 11
Compound 11 was obtained from alcohol (S)-5 in 92% yield: thick oil; [α]D −30.5 (CHCl3, c=1.4).
1H-NMR (300 MHz, CDCl3, 313 K) δ 9.61 (s, 1H), 7.35 (m, 5H), 5.17 (s, 2H), 4.70 (broad m, 1H), 4.12
(broad m, 1H), 3.00 (broad m, 1H), 2.22 (m, 1H), 1.75–1.23 (m, 5H). 13C-NMR (50.3 MHz, CDCl3) δ
200.5 (s), 172.5 (s), 136.2 (s), 128.2 (d, 2C), 127.8 (d), 127.6 (d, 2C), 67.1 (t), 60.8 (t), 42.4 (d), 24.3 (t),
23.2 (t), 20.4 (t). IR (neat) ν 3450, 3040, 2940, 2845, 1700, 1730, 1580, 1500, 1420, 1350, 1250, 1170,
1050, 700. MS m/z 247 (M+, <1), 218 (23), 174 (31), 91 (100). Anal. calcd for C14H17NO3: C, 67.98%;
H, 6.93%; N, 5.67%. Found: C, 67.82%; H, 7.12%; N, 5.78%.
3.5.2. (S)-(−)-N-(tert-Butoxycarbonyl)-2-(formyl)piperidine 12
Compound 12 was obtained from alcohol (S)-6 in 85% yield: thick oil; [α]D −77.4 (CHCl3, c=1.4).
1H-NMR (300 MHz, CDCl3) δ 9.59 (s, 1H), 4.55 (m, 1H), 3.95 (m, 1H), 2.90 (m, 1H), 2.15 (m, 1H),
1.70–1.20 (m, 5H), 1.47 (s, 9H). 13C-NMR (50.3 MHz, CDCl3) δ 201.1 (s), 156.3 (br s), 80.2 (s), 60.7
(very br d), 42.8 (very br, t), 28.1 (q, 3C), 24.5 (t), 23.4 (t), 20.7 (t). IR (neat) ν 2980, 2940, 2870, 1740,
1700, 1480, 1410, 1370, 1280, 1250, 1160, 1050, 1000, 1060, 870, 770. MS m/z 213 (M+, <1), 184 (4),
140 (3), 128 (53), 100 (3), 84 (41), 57 (100). Anal. calcd for C11H19NO3: C, 61.95%; H, 8.98%; N,
6.57%. Found: C, 61.72%; H, 9.10%; N, 6.65%.
3.6. Synthesis of (S)-(−)-N-(benzyloxycarbonyl)pipecolic acid 7
3.6.1. Method A
Jones reagent was added dropwise to a cooled (0°C) solution of the alcohol 5 (300 mg, 1.20 mmol)
in acetone (5 ml) until a brown–orange colour persisted. The mixture was stirred at this temperature for
an additional 15 minutes (the reaction was complete as shown by t.l.c.) and then excess isopropanol was
added, the solution turning to a dark-green colour. The solvent was evaporated and the residue partitioned

F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
1959
between AcOEt and water. The aqueous phase was extracted with AcOEt (twice). The organic layer
was washed with aqueous saturated NaHCO3. The combined aqueous phases were acidified with 10%
aqueous H2SO4 and extracted with AcOEt (twice). The combined organic extracts were dried (MgSO4)
and the solvent evaporated to give crude acid (S)-(−)-7, which was purified by crystallization from
Et2O/hexane (250 mg, 77% yield).
3.6.2. Method B
KMnO4 (125 mg, 0.79 mmol) was added in small portions, over 1 h, to a stirred suspension of aldehyde
11 (160 mg, 0.65 mmol) and MgSO4 (94 mg, 0.78 mmol) in acetone (5 ml) at room temperature. The
mixture was stirred at room temperature for another 30 minutes and then the solvent was removed in
vacuo. The residue was filtered using hot water as eluent. The solution was cooled to room temperature
and extracted with CHCl3 (twice), acidified with concentrated HCl, and extracted with CHCl3 (twice).
The combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated
to give the target molecule (S)-(−)-7 (137 mg, 76% yield). An analytically pure sample was obtained
by crystallization from Et2O/hexane. M.p. 106–109°C (lit.:45 m.p. 111–113°C). [α]D −53.0 (CH2Cl2,
1
c=1.0), [α]D −57.1 (AcOH, c=1.3) [lit.:45 [α]D +56.5, (AcOH, c=0.55) for the enantiomer]. H-NMR
(300 MHz, CDCl3) δ 10.00 (broad s, 1H), 7.33 (m, 5H), 5.16 (s, 2H), 4.95 (m, 1H), 4.10 (m, 1H), 3.05
(m, 1H), 2.25 (m, 1H), 1.80–1.22 (m, 5H). 13C-NMR (50.3 MHz, CDCl3) δ 176.6 (s), 156.6 (s), 136.3
(s), 128.3 (d, 2C), 127.8 (d), 127.6 (d, 2C), 67.4 (t), 54.1 (d), 41.7 (d), 26.5 (d), 24.5 (d), 20.5 (d). IR
(KBr) ν 3700–3000, 2970, 2860, 1730, 1650, 1470, 1430, 1350, 1320, 1280, 1260, 1200, 1160, 1120,
1080, 1070, 1040, 1000, 930, 860, 760, 700. MS m/z 263 (M+; <1), 218 (13), 174 (31), 128 (20), 91
(100), 65 (15), 55 (11). Anal. calcd for C14H17NO4: C, 63.87%; H, 6.51%; N, 5.32%. Found: C, 63.89%;
H, 6.54%; N, 5.35%.
3.7. Synthesis of (S)-(−)-N-(tert-butoxycarbonyl)pipecolic acid 8
KMnO4 (80 mg, 0.51 mmol) was added in small portions, over 1 h, to a stirred suspension of the
aldehyde 12 (90 mg, 0.42 mmol) and MgSO4 (60 mg, 0.50 mmol) in acetone (5 ml) at room temperature.
The mixture was stirred at room temperature for another 30 minutes and then the solvent was removed in
vacuo. The residue was filtered using hot water as eluent. The solution was cooled to room temperature
and extracted with CHCl3 (twice), acidified with concentrated HCl, and extracted with CHCl3 (twice).
The combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated
to give the N-protected amino acid (S)-(−)-8 (67 mg, 70% yield). An analytically pure sample was
obtained by crystallization from MeOH/Et2O. M.p. 120–123°C (lit.:46 m.p. 121–122°C). [α]D −52.4
(CHCl3, c=0.35), [α]D −55.7 (AcOH, c=0.6) [lit.:47 [α]D −56.0 (AcOH, c=1.0)]. 1H-NMR (300 MHz,
CDCl3, 313 K) δ 9.80 (broad s, 1H), 4.83 (broad m, 1H), 3.95 (broad s, 1H), 2.94 (broad s, 1H), 2.21
(m, 1H), 1.75–1.20 (m, 5H), 1.44 (s, 9C). 13C-NMR (50.3 MHz, CDCl3, 313 K) δ 177.6, 156.0 (broad),
80.3, 54.1 (very broad), 41.1 (very broad), 28.3 (3C), 26.6, 24.6, 20.7. IR (KBr) ν 3700–3000, 2980,
2945, 1755, 1630, 1480, 1440, 1400, 1370, 1320, 1280, 1260, 1200, 1160, 1140, 1100, 1040, 930, 860,
770, 740. MS m/z 229 (M+; <1), 184 (7), 156 (3), 128 (89), 84 (85), 57 (100), 41 (46). Anal. calcd for
C11H19NO4: C, 57.63%; H, 8.35%; N, 6.12%. Found: C, 57.48%; H, 8.46%; N, 6.12%.
3.8. Synthesis of (S)-(−)-pipecolic acid 3
A mixture of the benzyl carbamate 7 (80 mg, 0.30 mmol) and 10% Pd/C (16 mg) in MeOH (5 ml)
was hydrogenated at room temperature under a pressure of ca. 45 psi of H2 in a Parr shaker for 6 hours.

1960
F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
The solid was then filtered off and washed. Evaporation of the solvent gave pure (S)-pipecolic acid (37
mg, 94% yield). An analytically pure sample was obtained by crystallization from MeOH/Et2O. M.p.
260–262°C (lit.:18c 256–261°C). [α]D −26.8 (H2O, c=0.5) [lit.:18c [α]D −25.9 (H2O, c=1.0)]. 1H-NMR
(200 MHz, D2O) δ 3.65 (m, 1H), 3.34 (m, 1H), 3.06–2.86 (m, 1H), 2.15 (m, 1H), 1.81–1.42 (m, 5H).
13C-NMR (50.3 MHz, D2O) δ 174.6 (s), 59.5 (d), 45.3 (t), 27.6 (t), 23.0 (2C, t). IR (KBr) ν 3430, 2970,
1675, 1625, 1400, 1060, 925. MS m/z 129 (M+; <1), 84 (100), 56 (37).
3.9. Synthesis of (S,Z)-(+)-N-(benzyloxycarbonyl)-2-(1-propenyl)piperidine 13
1.4 M BuLi in hexane (1.7 ml, 2.40 mmol) was slowly added to a stirred suspension of ethyl
triphenylphosphonium bromide (890 mg, 2.40 mmol) in dry THF (10 ml) at −70°C under argon. The
mixture was warmed at 0°C for 30 minutes. The solution was then cooled to −70°C and a solution of
the aldehyde 11 (377 mg, 1.53 mmol) in dry THF (5 ml) was added dropwise via cannula. The mixture
was left to reach room temperature overnight. The reaction was quenched by the addition of water and
extracted with Et2O (twice). The combined organic extracts were washed with brine, dried (MgSO4),
evaporated and chromatographed (hexane:AcOEt, 80:20) to give 13 as a single peak in g.l.c. (301 mg,
76% yield): thick oil; [α]D +14.6 (CHCl3, c=1.9). 1H-NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.72 (m,
1H), 5.58 (m, 1H), 5.16 (d, J=12.4, 1H), 5.10 (d, J=12.4, 1H), 4.02 (m, 1H), 2.96 (m, 1H), 1.72–1.42
(m, 10H). 13C-NMR (75 MHz, CDCl3) δ 155.0 (s), 136.8 (s), 128.2 (2C, d), 127.62 (d), 127.58 (2C, d),
127.3 (d), 126.3 (d), 66.7 (t), 47.8 (d), 39.8 (t), 30.1 (t), 25.3 (t), 19.2 (t), 13.0 (q). IR (neat) ν 3030, 2940,
2860, 2320, 1700, 1425, 1350, 1315, 1270, 1260, 1175, 1145, 1070, 1030, 765, 730, 700. MS m/z 259
(M+, 2), 174 (6), 168 (48), 158 (2), 128 (5), 124 (28), 91 (100), 82 (10), 65 (14).
3.10. Synthesis of (R)-(−)-coniine hydrochloride (1·HCl)
A mixture of the olefin 13 (100 mg, 0.39 mmol) and 10% Pd/C (20 mg) in MeOH (5 ml) was
hydrogenated at room temperature under a hydrogen pressure of ca. 45 psi in a Parr shaker for 6
hours. The solid was then filtered off and washed. Evaporation of the solvent gave a residue which was
dissolved in Et2O and treated with concentrated HCl at room temperature. After solvent evaporation and
crystallization from MeOH/Et2O, pure (R)-coniine hydrochloride (53 mg, 85% yield) was obtained. M.p.
213–215°C (lit.:19a m.p. 217–218°C). [α]D −6.2 (EtOH, c=0.48) [lit.:19a [α]D=−6.3 (EtOH, c=0.62)].
1H-NMR (200 MHz, CD3OD) δ 3.89–3.74 (m, 1H), 3.57 (m, 1H), 3.20 (m, 2H), 2.25–2.04 (m, 3H),
1.90–1.49 (m, 8H), 1.17 (t, J=7.0, 3H). 13C-NMR (50.3 MHz, CD3OD) δ 58.0 (d), 46.0 (t), 37.0 (t), 29.7
(t), 23.6 (t), 23.1 (t), 19.3 (t), 14.0 (q). IR (KBr) ν 3450, 2980, 1640, 1585, 1470, 1460, 1014, 1010. MS
m/z 163 (M+, <1) 127 (2), 112 (1), 98 (3), 85 (8), 84 (100), 70 (7), 56 (23), 43 (11), 41 (9).
3.11. Synthesis of (S,E)-(−)-methyl 3-[N-(benzyloxycarbonyl)-2-piperidyl]acrylate 15 by tandem
Swern–Wittig reaction
Commercially available 2 M oxalyl chloride solution in CH2Cl2 (4.8 ml, 9.6 mmol) was diluted with
CH2Cl2 (40 ml) at −70°C under an argon atmosphere. A solution of dry DMSO (1.35 ml, 19.3 mmol) in
CH2Cl2 (30 ml) was added slowly, dropwise, at −70°C. After stirring for 30 minutes at this temperature,
a solution of alcohol (S)-5 (2 g, 8.0 mmol) in CH2Cl2 (30 ml) was added via cannula. The mixture
was stirred at −70°C for 90 minutes, and then dry Et3N (5.5 ml, 40.2 mmol) was added. Stirring was
maintained at −70°C while the formation of the aldehyde was monitored by t.l.c. When the reaction was
completed (ca. 0.5 hours), solid Ph3P_CHCO2Me (7.6 g, 22.8 mmol). The temperature was allowed

F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
1961
to warm slowly to ambient temperature (overnight). The solvent was removed under vacuum and the
residue was dissolved in the minimum amount of CH2Cl2, added to the top of a column of silica gel
and chromatographed (hexane:AcOEt, 80:20) to give diastereoisomerically pure α,β-unsaturated ester
1
15 (2.21 g, 91% yield): thick oil; [α]D −71.1 (CHCl3, c=1.1). H-NMR (300 MHz, CDCl3) δ 7.32 (m,
5H), 6.89 (dd, J=16.0, 4.1, 1H), 5.84 (dd, J=16.0, 2.1, 1H), 5.14 (s, 2H), 5.04 (m, 1H), 4.09 (m, 1H), 3.74
(s, 3H), 2.89 (m, 1H), 1.85–1.40 (m, 6H). 13C-NMR (50.3 MHz, CDCl3) δ 165.6 (s), 154.8 (s), 146.5 (d),
136.1 (s), 127.8 (d, 2C), 127.3 (d), 127.1 (d, 2C), 121.4 (d), 66.5 (t), 51.3 (d), 50.8 (q), 39.7 (t), 28.2 (t),
24.5 (t), 19.1 (t). IR (neat) ν 2940, 2860, 1730, 1700, 1660, 1590, 1500, 1420, 1310, 1260, 1170, 1140,
1100, 1050, 700. MS m/z 303 (M+; 1), 212 (10), 168 (63), 136 (17), 108 (11), 91 (100), 65 (13). Anal.
calcd for C17H21NO4: C, 67.31%; H, 6.98%; N, 4.62%. Found: C, 67.60%; H, 7.02%; N, 4.69%.
3.12. Synthesis of (S,E)-(−)-methyl 3-[N-(tert-butoxycarbonyl)-2-piperidyl]acrylate 16
Ph3P_CHCO2Me (5.3 g, 15.9 mmol) was added to a solution of the N-protected amino aldehyde 16
(1.13 g, 5.3 mmol) in dry CH2Cl2 (50 ml). The mixture was stirred at room temperature overnight. The
solvent was then evaporated to give a residue which was dissolved in the minimum amount of CH2Cl2
and added to the top of a column of silica gel and chromatographed (hexane:AcOEt, 80:20) to give 16 as
a single isomer (1.35 g, 95% yield): thick oil; [α]D −90.1 (CHCl3, c=1.0). 1H-NMR (300 MHz, CDCl3)
δ 6.90 (dd, J=15.9, 4.0, 1H), 5.82 (dd, J=15.9, 2.2, 1H), 4.95 (m, 1H), 4.00 (m, 1H), 3.74 (s, 3H), 2.81
(m, 1H), 1.80–1.40 (m, 6H), 1.45 (s, 9H). 13C-NMR (50.3 MHz, CDCl3) δ 166.3 (s), 154.7 (s), 147.5 (d),
121.4 (d), 79.5 (s), 51.4 (d), 51.3 (q), 39.8 (t), 28.7 (t), 28.1 (q, 3C), 25.0 (t), 19.6 (t). IR (neat) ν 2980,
2940, 2860, 1730, 1700, 1660, 1440, 1410, 1370, 1310, 1280, 1270, 1160, 1050, 870, 770. MS m/z 269
(M+; 1), 213 (8), 196 (3), 169 (14), 154 (39), 128 (22), 110 (31), 84 (30), 57 (100).
3.13. Synthesis of (S)-(+)-indolizidin-3-one 17
3.13.1. Method A. From (S,E)-methyl 3-[N-(benzyloxycarbonyl)-2-piperidyl]acrylate 15
A mixture of the α,β-unsaturated ester 15 (1.0 g, 3.30 mmol) and 10% Pd/C (200 mg) in MeOH (15
ml) was hydrogenated at room temperature under a pressure of ca. 45 psi of H2 in a Parr shaker for 6
hours. The solid was then filtered off and washed. The solvent was removed to give a residue consisting
of an inseparable mixture of the target compound 17 and a small amount of the γ-amino ester 18. The
crude product was dissolved in toluene and heated at reflux for 12 hours. After solvent evaporation and
filtration through a short pad of silica gel, using acetone as eluent, pure lactam 17 was obtained (390 mg,
85% yield).
3.13.2. Method B. From (S,E)-methyl 3-[N-(tert-butoxycarbonyl)-2-piperidyl]acrylate 16
A mixture of the α,β-unsaturated ester 16 (700 mg, 2.60 mmol) and 10% Pd/C (70 mg) in MeOH
(13 ml) was hydrogenated at atmospheric pressure (using a balloon filled with H2) at room temperature
for 30 minutes. The solid was then filtered off and washed. Evaporation of the solvent gave (S)-methyl
3-[N-(tert-butoxycarbonyl)-2-piperidyl]propionate (650 mg, 92% yield). This compound was dissolved
in AcOEt (15 ml) and treated with a 4 M solution of HCl in dioxane (6.5 ml, 26 mmol). The mixture was
stirred overnight and then the solvent was removed under vacuum. The residue was triturated with Et2O
to obtain (S)-methyl 2-(piperidyl)propionate hydrochloride (496 mg, >98% yield). This hydrochloride
was dissolved in EtOH (25 ml), treated with NaOAc (982 mg, 12.0 mmol), and heated at reflux for 6
hours. After solvent evaporation, the residue was filtered through a short pad of silica gel eluting with
AcOEt, to give pure 17 (one peak in chiral g.l.c., 302 mg, 91% yield; 84% overall yield from 16): oil;

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1
[α]D +35.4 (CHCl3, c=0.2). H-NMR (300 MHz, CDCl3) δ 4.11 (m, 1H), 3.39 (m, 1H), 2.61 (m, 1H),
2.35 (m, 2H), 2.19 (m, 1H), 1.86 (m, 2H), 1.72–1.51 (m, 2H), 1.45–1.25 (m, 2H), 1.17 (m, 1H). 13C-
NMR (50.3 MHz, CDCl3) δ 172.7 (s), 56.5 (d), 39.4 (t), 32.8 (t), 29.7 (t), 24.6 (t), 23.8 (t), 23.0 (t). IR
(neat) ν 3700–3200, 2940, 2860, 1680, 1450, 1425, 1370, 1310, 1270, 1140, 1060, 835. MS m/z 139
(M+, 36), 138 (100), 124 (11), 112 (16), 98 (84), 84 (40), 55 (47).
3.14. Synthesis of (S)-(+)-δ-coniceine 2
A BH3/SMe2 complex (0.43 ml, 4.74 mmol) was added dropwise to a solution of the lactam 17 (220
mg, 1.58 mmol) in dry THF (15 ml) at room temperature under argon. Stirring was maintained at room
temperature overnight. The excess of borane was removed by the slow addition of MeOH. The solvent
was removed under vacuum to give a δ-coniceine/borane complex [13C-NMR (50.3 MHz, CDCl3) δ 65.3
(d), 60.2 (t), 53.5 (t), 26.9 (t), 24.0 (t), 20.9 (t), 19.3 (t), 18.5 (t)], which was stirred with 60% aqueous
CF3CO2H for 20 minutes at room temperature. After solvent evaporation, the residue was dissolved in
EtOH and passed through a Dowex 1X8-200 column (OH− form) to obtain pure (S)-(+)-δ-coniceine (145
mg, 80% yield), identical to that reported in the literature:20 oil; [α]D +9.2 (EtOH, c=0.5) [lit.:20a [α]D
+9.3ꢀ0.6 (EtOH, c=1.77)]. 13C-NMR (50.3 MHz, CDCl3) δ 62.1 (d), 57.6 (t), 50.0 (t), 26.6 (t), 23.9 (t),
20.4 (t), 19.4 (t), 18.1 (t).
(S)-(+)-δ-Coniceine was further characterized as its picrate. The alkaloid was dissolved in EtOH and
treated with excess picric acid. The mixture was heated until a clear solution was obtained and then
allowed to reach room temperature slowly to obtain yellow needles of (S)-(+)-δ-coniceine picrate which
1
were recrystalized from MeOH. M.p. 228–232°C (lit.:19i 226–228°C). H-NMR (200 MHz, CDCl3)
δ 10.30 (br s, 1H), 8.90 (s, 2H), 3.90 (m, 2H), 2.84 (m, 3H), 2.28–1.84 (m, 10H). Anal. calcd for
C14H18N4O7: C, 47.46%; H, 5.12%; N, 15.81%. Found: C, 47.30%; H, 5.02%; N, 15.76%.
Acknowledgements
Financial support from DGICYT (Project number PB94-0104) is gratefully acknowledged. F. S.-S.
thanks the Spanish Ministry of Education for a fellowship.
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13. For a definition and discussion, see: Seebach, D.; Hungerbühler, E. In Modern Synthetic Methods; Scheffold, R., Ed.; Salle
and Sauerländer: Berlin; 1980; Vol. 2, pp 91–171.
14. The acetylation of (ꢀ)-6 catalyzed by AA-I was briefly mentioned in our first paper on transesterifications catalyzed by
AA-I, see: Herradón, B.; Valverde, S. Synlett 1995, 599–602.
15. (a) Derivatives of chiral 2-(hydroxymethyl)piperidine have been prepared by reduction of derivatives of chiral pipecolic
acid; although both enantiomers of pipecolic acid are commercially available, they are very expensive; sometimes this
inconvenience has hampered planned syntheses of natural products, see: Wong, P. L.; Moeller, K. D. J. Am. Chem. Soc.
1993, 115, 11434–11445 (especially footnote #16 in that paper!). (b) Racemic pipecolic acid was originally resolved
by crystallization of the tartrate salt, see: Yamada, S.; Hohgo, C.; Chibata, I. Agric. Biol. Chem. 1977, 41, 2413–2416.
(c) For recent EPC-syntheses of pipecolic acid, see Ref. 18 cited below. (d) Recently (S)-2-(hydroxymethyl)piperidine
has been synthesized, in several steps with moderate diastereoselectivity, using (R)-phenylglycine as an auto-immolative
chiral auxiliary, see: Lingibé, O.; Graffe, B.; Sacquet, M.-C.; Lhommet, G. Heterocycles 1995, 41, 1931–1934. (e)
Previous attempts to obtain chiral derivatives of 2-(hydroxymethyl)piperidine by lipase-catalyzed transformations were

1964
F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
unsuccessful, see: Toone, E. J.; Jones, J. B. Can. J. Chem. 1987, 65, 2722–2726. (f) Asensio, G.; Andreu, C.; Marco, J. A.
Tetrahedron Lett. 1991, 32, 4197–4198.
16. For recent applications of racemic 2-(hydroxymethyl)piperidine and/or racemic pipecolic acid, see: (a) Genin, M. J.;
Gleason, W. B.; Johnson, R. L. J. Org. Chem. 1993, 58, 860–866. (b) Berkes, D.; Decroix, B. Bull. Soc. Chim. Fr. 1994,
131, 986–991. (c) Martín-López, M. J.; Bermejo-González, F. Tetrahedron Lett. 1994, 35, 4235–4238. (d) Martín-López,
M. J.; Bermejo-González, F. Tetrahedron Lett. 1994, 35, 8843–8846. (e) Molander, G. A.; Nichols, P. J. J. Org. Chem. 1996,
61, 6040–6043. (f) Doll, M. K.-H.; Guggisberg, A.; Hesse, M. Helv. Chim. Acta 1996, 79, 1379–1386. (g) Laschat, S.;
Grehl, M. Chem. Ber. 1994, 127, 2023–2034. (h) Ezquerra, J.; Pedregal, C.; Escribano, A.; Carreño, M. C.; García-Ruano,
J. L. Tetrahedron Lett. 1995, 36, 3247–3250. (i) Wright, D. L.; Weekly, R. M.; Groff, R.; McMills, M. C. Tetrahedron Lett.
1996, 37, 2165–2168. (j) Ref. 15a cited above.
17. For synthetic applications of chiral 2-(hydroxymethyl)piperidine, see: (a) Gurjar, M. K.; Ghosh, L.; Syamala, M.; Jayasree,
V. Tetrahedron Lett. 1994, 35, 8871–8872. (b) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995, 117,
9369–9370.
18. For recent EPC-syntheses of pipecolic acid and derivatives, see: (a) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett.
1993, 34, 4473–4476. (b) Ng-Youn-Chen, M. C.; Serrequi, A. N.; Huang, Q.; Kazlauskas, R. J. Org. Chem. 1994, 59,
2075–2081. (c) Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994, 59, 3769–3774. (d) Pauly, R.; Sasaki, N. A.;
Potier, P. Tetrahedron Lett. 1994, 35, 237–240. (e) Fernández-García, C.; McKervey, M. A. Tetrahedron: Asymmetry 1995,
6, 2905–2906. (f) Hockless, D. C. R.; Mayadunne, R. C.; Wild, S. B. Tetrahedron: Asymmetry 1995, 6, 3031–3037. (g)
Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656–2657.
19. For recent EPC-syntheses of coniine, see: (a) Enders, D.; Tiebes, J. Liebigs Ann. 1993, 173–177. (b) Al-awar, R. S.;
Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993, 58, 7732–7739. (c) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49,
1749–1760. (d) Hirai, Y.; Nagatsu, M. Chem. Lett 1994, 21–22. (e) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994,
35, 2223–2226. (f) Oppolzer, W.; Bochet, C. G.; Merifield, E. Tetrahedron Lett. 1994, 35, 7015–7018. (g) Fréville, S.;
Célérier, J. P.; Thuy, V. M.; Llohmmet, G. Tetrahedron: Asymmetry 1995, 6, 2651–2654. (h) Munchhof, M. J.; Meyers, A.
I. J. Org. Chem. 1995, 60, 7084–7085. (i) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron: Asymmetry
1996, 7, 3047–3054. (j) Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543–5546. (k) Pandey, G.; Das, P. Tetrahedron
Lett. 1997, 38, 9073–9076. (l) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746–748. (m)
Weymann, M.; Pfrengle, W.; Schollmeyer, W.; Kunz, H. Synthesis 1997, 1151–1160.
20. For EPC-syntheses of δ-coniceine, see: (a) Ringdahl, B.; Pinder, A.; Pereira, W.; Oppenheimer, N.; Craig, J. J. Chem. Soc.,
Perkin Trans. 1 1984, 1–4. (b) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.; Panangadan, J. A. K.; Hung,
M.-H.; Bravo, A. A.; Erpelding, A. M. J. Org. Chem. 1989, 54, 5659–5662. (c) Sibi, M. P.; Christensen, J. W. Tetrahedron
Lett. 1990, 31, 5689–5692. (d) Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444–4451. (e) Nukui, S.; Sodeoka, M.;
Shibasaki, M. Tetrahedron Lett. 1993, 34, 4965–4968. (f) Arai, Y.; Kontani, T.; Koizumi, T. J. Chem. Soc., Perkin Trans.
1 1994, 15–23. (g) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett 1997, 1179–1180; and Refs.
19h and 19i cited above.
21. The efficiency of a kinetic resolution is indicated by the value of the enantioselectivity E, as defined in: Chen, C.-S.;
Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
22. Compounds (ꢀ)-5 and (ꢀ)-6 were prepared, in a nearly quantitative yield, from commercially available (ꢀ)-2-
(hydroxymethyl)piperidine using standard procedures (see Experimental part).
23. Some typical results of kinetic resolutions at high conversion are the following: (a) (ꢀ)-5/vinyl butyrate (1.0 mol
equiv.)/AA-I (300 U/mmol)/toluene/r.t./16 hours/c=60% (as determined by 1H-NMR) gave the butyrate (R)-9 (59% yield,
ee not determined) and the alcohol (S)-5 (35% yield, 98% ee). (b) (ꢀ)-6/vinyl butyrate (0.6 mol equiv.)/AA-I (300
U/mmol)/toluene/r.t./24 hours/c=58% gave the butyrate (R)-10 (55% yield, 72% ee) and the alcohol (S)-6 (37% yield,
98% ee).24
24. Unless otherwise indicated, all the enantiomeric excesses were determined by capillary gas-liquid chromatography using
cyclodextrin-based chiral stationary phases, which were prepared by Mrs. Mp Isabel Jiménez-Vacas (Centro de Química
Orgánica, C. S. I. C.), to whom we thank for her assistance.
25. For a discussion of this strategy, see: Sih, C. J.; Wu, S. H. Topics Stereochem. 1989, 19, 63–125.
26. (a) In principle, it is possible to access to the enantiomers [i.e.; (R)-5 and (R)-6] by hydrolysis of the butyrate. We
were unable to achieve this goal by chemical methods: neither basic nor acidic hydrolysis of 9 or 10 gave the expected
alcohols, but the corresponding bicyclic 2-oxazolidinone, which was formed by nucleophilic attack of the hydroxy group
(or alcoxide) to the carbamoyl carbonyl group. Acyl-migration is quite common in this kind of amino alcohols; for a
discussion, see: Morcuende, A.; Ors, M.; Valverde, S.; Herradón, B. J. Org. Chem. 1996, 61, 5264–5270. (b) On the other
hand, we have carried out some preliminary experiments on the hydrolysis of the esters (R)-9 and (R)-10 catalyzed by AA-

F. Sánchez-Sancho, B. Herradón / Tetrahedron: Asymmetry 9 (1998) 1951–1965
1965
I, both in buffer solution (pH 7) and in an acetone-containing buffer. The reactions are chemoselective, giving the alcohols
of (R)-configuration [i.e.; (R)-5 and (R)-6, depending on the structure of the substrate]. Although the enantioselectivity of
the hydrolysis was lower than the acylation, it allowed an entry to the enantiomers of the compounds reported in this paper
(Faraldos, J.; Herradón, B. unpublished observations).
27. Wet toluene is water-saturated toluene, whose water-content is ca. 0.03%, as determined by the modified Karl Fischer
method.
28. The enzyme acylase I from Aspergillus species (AA-I) was purchased from Aldrich or Sigma. Its specific activity is ca. 0.5
U/mg (as defined in the Sigma catalog: one unit can hydrolyze 1.0 mmol of N-acetyl-L-methionine per hour at pH 7.0 and
25°C). For the sake of uniformity, the amount of AA-I used in any experiment is indicated in units per mmol of substrate.
29. The enantiomeric excess of the butyrate (R)-9 could not be determined by capillary g.l.c.
30. We observed that when this conversion degree was achieved [that is, all the (R)-enantiomer had reacted], the reaction
practically stopped.
31. (a) It must be remembered that the theoretical yield of a kinetic resolution is 50%. (b) When the slow reacting enantiomer
racemizes rapidly (Dynamic Kinetic Resolution), it is possible to get a higher yield than the theoretical one; for a recent
overview, see: Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 25, 447–456.
32. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
33. Other attempts at oxidation include (a) PCC oxidation [Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647–2650]
of (S)-6 gave a complex mixture. (b) The oxidations of (S)-5 and (S)-6 with tetra(n-propyl)ammonium perruthenate
(TPAP)/N-methylmorpholine N-oxide (NMO) in CH2Cl2 gave 11 and 12 in 61% and 86% yield, respectively, but with
considerable racemization. (c) Oxidation of (S)-6 with PDC/DMF [Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1980, 21,
731–734] gave a low yield of 8.
34. (a) Although analytically pure samples of both 11 and 12 could be obtained by flash-chromatography on silica gel,
we observed racemization during this procedure; it was more convenient to use the crude aldehydes in the next steps.
The enantiomeric excesses of samples of 11 and 12 were roughly determined by optical rotation and ascertained by
conversion to the indolizidinone 17, whose enantiomeric excess could be directly determined by capillary gas-liquid
chromatography.24 (b) For reviews on the synthesis and reactivity of N-protected α-amino aldehydes, see: Jurczak, J.;
Golebiowski, A. Chem. Rev. 1989, 89, 149–164. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531–1546.
35. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley & Sons, Inc: New York; 1967, pp 142–143.
36. Only one peak was observed on t.l.c. and chiral g.l.c. Although the 1H-NMR spectrum of 13 is complex due to nitrogen
inversion, we tentatively assigned the Z configuration to the double bond based in the coupling constant (J=12.4 Hz) of
the olefinic protons.
37. We have observed variable isolated yields of coniine (and hence its hydrochloride) and of δ-coniceine due to the high
volatility of these alkaloids.
38. Although we carried out a Wittig reaction of isolated aldehydes 11 and 12, it was more convenient to use the tandem
Swern–Wittig reaction, without isolating the aldehydes (see Experimental part) [Ireland, R. E.; Norbeck, D. W. J. Org.
Chem. 1985, 50, 2198–2200].
39. (a) Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J.; Weinreb, S. M. J. Am. Chem. Soc. 1981, 103, 6387–6393. (b)
Jung, M. E.; Choi, Y. M. J. Org. Chem. 1991, 56, 6729–6730; and references 16c, 20d, and 20f cited above.
40. For a discussion on the biological activity of unnatural alkaloid enantiomers, see: Brossi, A.; Pei, X.-F. In The Alkaloids.
Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic Press: San Diego; 1998, Vol. 50, pp 109–139.
41. Pipecolic acid has been used as a surrogate for proline in biologically active compounds,42 for some recent examples, see:
(a) Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B.
K.; Kay, J.; Kröhn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.
L.; Thomas, G. J.; Machin, P. J. Science 1990, 248, 358–361. (b) Zhao, Z.; Liu, X.; Shi, Z.; Danley, L.; Huang, B.; Jiang,
R.-T.; Tsai, M.-D. J. Am. Chem. Soc. 1996, 118, 3535–3536. (c) Rist, B.; Entzeroth, M.; Beck-Sickinger, A. G. J. Med.
Chem. 1998, 41, 117–123.
42. Recently there has been a great interest in proline-containing peptides, for some leading references, see: (a) Dalcol, I.;
Pons, M.; Ludevid, M.-D.; Giralt, E. J. Org. Chem. 1996, 61, 6775–6782. (b) Kern, D.; Schutkowski, M.; Drakenberg, T.
J. Am. Chem. Soc. 1997, 119, 8403–8408, and references cited in these papers.
43. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
44. The enantiomeric excess of (R)-(+)-9 could not be determined directly by g.l.c., but it may be approximately deduced from
the the degree of conversion and the enantiomeric excess of the remaining alcohol (S)-5.
45. Suzuki, H.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1995, 60, 6114–6122.
46. Johnson, R. L.; Rajakumar, G.; Yu, K.-L.; Mishra, R. K. J. Med. Chem. 1986, 29, 2104–2107.
47. Baláspiri, L.; Penke, B.; Petres, J.; Kovács, K. Monatsh. Chem. 1970, 101, 1177–1183.