Straightforward entry to the pipecolic acid nucleus. Enantioselective synthesis of baikiain

Article abstract of DOI:10.1016/S0040-4039(01)02271-7

New enantioselective syntheses of N-protected baikiain and pipecolic acid have been developed. The starting material is 2,3-epoxy-5-hexen-1-ol (4) readily available in high ee by Sharpless epoxidation. The regio- and stereoselective epoxide ring-opening by allylamine afforded a doubly unsaturated amine that was converted into a carbamate (Boc) and submitted to ring-closing metathesis. The resulting cyclic amino diol 6 is a key intermediate that was converted into N-Boc-baikiain and several pipecolic acid derivatives.

Full text of DOI:10.1016/S0040-4039(01)02271-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 779–782
Straightforward entry to the pipecolic acid nucleus.
Enantioselective synthesis of baikiain
Xavier Ginesta, Miquel A. Perica`s* and Antoni Riera*
Departament de Qu´ımica Orga`nica, Mart´ı i Franque`s, 1-11, Barcelona E-08028, Spain
Received 15 November 2001; accepted 29 November 2001
Abstract—New enantioselective syntheses of N-protected baikiain and pipecolic acid have been developed. The starting material
is 2,3-epoxy-5-hexen-1-ol (4) readily available in high ee by Sharpless epoxidation. The regio- and stereoselective epoxide
ring-opening by allylamine afforded a doubly unsaturated amine that was converted into a carbamate (Boc) and submitted to
ring-closing metathesis. The resulting cyclic amino diol 6 is a key intermediate that was converted into N-Boc-baikiain and several
pipecolic acid derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
2-Piperidine carboxylic acid (pipecolic acid, 1) is a
nonproteinogenic amino acid present in several natural
products, some of them with important pharmaceutical
interest such as the immunosupresants FK5061 and
rapamicin2 (Scheme 1). As a proline analogue (homo-
proline) it has been used in many modified peptides and
synthetic drugs.3 The importance of pipecolic acid as a
starting material for those compounds3,4 has fostered
the development of many synthetic approaches involv-
ing enzymatic reactions,5 alkylation of chiral glycine
enolates,6 derivatization of natural amino acids,7 enan-
tioselective reactions8 and resolution.9 On the other
hand, 4,5-dehydropipecolic acid (baikiain, 2) is a natu-
ral product isolated from Baikiaea plurijuga and other
plants.10 Few syntheses of baikiain have been described
up to now, featuring glycine synthons or ring-closing
metathesis of allyl glycine derivatives.11 Nevertheless,
the use of baikiain as a synthetic precursor has been
very limited,12 hampered by lack of simple synthetic
methods for its preparation in high enantiomeric purity.
In the last decade we have been involved13 in a project
devoted to the synthesis of several structural types of
amino acids using the catalytic Sharpless epoxidation14
as a source of chirality. The amazing potential of the
ring-closing metathesis (RCM) reactions15 drove our
attention to the possible use of unsaturated epoxy
alcohols in the preparation of heterocyclic amino acids.
In this context we envisaged a new entry to 2-piperidine
carboxylic acids by RCM of a bis-olefinic compound,
potentially accessible by nucleophilic ring-opening of an
unsaturated epoxy alcohol by an unsaturated amine
(Fig. 1). We report here a new enantioselective synthe-
sis of baikiain and of several pipecolic acid derivatives
based on this strategy.
Our synthesis started with the preparation of the
known allyl alcohol 3 from propargyl alcohol.16 The
catalytic Sharpless epoxidation of 3 was initially per-
formed as described,17 using D-DIPT in the preparation
of the catalyst, to afford epoxy alcohol 4 in 82% yield
and 87–92% ee.18 As we have found in similar cases,13g
this enantioselectivity could be slightly improved (up to
93% ee) by using DET instead of DIPT. Then, enan-
N
H
N
H
COOH
COOH
OH
N
H
N
H
COOH
1
2
OH
Scheme 1.
O
OH
* Corresponding authors. Tel.: 34 934021245; fax: 34 933397878;
e-mail: a.riera@qo.ub.es; mapericas@qo.ub.es
Figure 1. Retrosynthetic analysis for baikiain.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02271-7

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X. Ginesta et al. / Tetrahedron Letters 43 (2002) 779–782
HPLC (Chiralcel OD) analysis of the N-Boc pipecolic
acid methyl ester. Starting from an epoxy alcohol 4 of
90% ee, a simple crystallization of 7, followed by the
previously described sequence, afforded the protected
pipecolic acid 8 in 94% ee. As expected, starting from
an epoxy alcohol of 93% ee and crystallizing intermedi-
ate 7, it was easy to achieve enantiomerically pure
pipecolic acid (>99% by HPLC).
tiomerically enriched 4 was subjected to nucleophilic
epoxide ring-opening using allylamine (Scheme 2).
Under Sharpless conditions19 [Ti(OiPr)4, CH2Cl2,
reflux], the reaction took place uneventfully affording a
crude aminodiol that, since free amino groups have a
deleterious effect in RCM, was treated without purifica-
tion with Boc2O in order to block the secondary amine.
In this way N-Boc-protected doubly-unsaturated
aminodiol 5 was obtained in 60% overall yield (two
steps).20 Although the reaction was completely regiose-
lective, the product had to be carefully purified by
chromatography. Application of Crotti’s conditions21
(LiClO4, CH3CN) also followed by Boc-protection
afforded aminodiol 5 in the same yield. In this case the
reaction was not completely regioselective (10:1) but the
crude was cleaner and the regioisomer (6%) was easily
removed by chromatography.
Oxidation of dehydropiperidine 6 was anticipated to be
a more difficult task due to the presence of the double
bond. According to our experience in the synthesis of
unsaturated amino acids,17 the diol fragment in 6 was
first oxidatively cleaved by NaIO4 to give aldehyde 9 in
excellent yield. This aldehyde was immediately oxidized
to N-Boc-baikiain 10 by sodium chlorite22 also in excel-
lent yield. At this point it was crucial to measure the
enantiomeric excess of the final product in order to
check both the possible racemization of the aldehyde
and the possibility of enantiomeric enrichment by crys-
tallization of aminodiol 6.
Using 2×4% mol of Grubbs’s catalyst in CH2Cl2 at
room temperature, the RCM of the doubly unsaturated
amine 5 took place in 72% yield affording N-Boc-tetra-
hydropyridinyletandiol 6. This is the key intermediate
in our approach, since hydrogenation of the double
bond would lead to pipecolic acid derivatives, whereas
oxidation of the diol fragment would give N-protected
baikiain. Gratifyingly enough, compound 6 was a crys-
talline compound [mp 92–3°C; [h]D=+39.5 (1.0,
Thus, (S)-Boc-baikiain (10) was hydrogenated to
pipecolic acid 8 and the corresponding methyl ester was
analyzed by HPLC (Chiralcel OD). Starting from an
epoxy alcohol 4 of 93% ee, without any crystallization
along the sequence, the observed enantiomeric purity of
the product (91% ee) showed that none or very little
racemization had taken place and proved the viability
of the present approach. The same reaction sequence
was subsequently performed starting from recrystallized
aminodiol 6. To our satisfaction, it provided (S)-Boc-
baikiain (10) in 99% ee (by HPLC) (Scheme 3).
CHCl3)], providing
enrichment.
a possibility for enantiomeric
Firstly, we studied the access to the saturated pipecolic
acid nucleus. To this end, dehydropiperidine 6 was
hydrogenated to give aminodiol 7 in 89% yield. This
compound was also nicely crystalline [mp 108–9°C;
[h]D=−59.5 (0.9, CHCl3)]. Subsequent oxidation of the
diol fragment of 7 afforded N-Boc-pipecolic acid 8 in
98% yield. The possibility of increasing the enan-
tiomeric purity by crystallization was checked by
The high enantiomeric purity of amino acids 8 and 10
and the configurational stability of aldehyde 9, convert
them in valuable synthetic intermediates. To start
exploring this possibility, 9 was reduced with sodium
borohydride to afford tetrahydropiridylmethanol 11 in
Boc
N
ButOOH
CH2Cl2, –20ºC
O
OH
OH
OH
OH
Ti(OiPr)4
D-(-)DET, 4Å,
4
H2, Pd/C
AcOEt
3
6
NaIO4
THF/H2O
84% yield, 93% ee
Boc
Boc
NH2
H
N
N
N
Boc2O
OH
CHO
92%
NaHCO3
MeOH, )))
LiClO4
CH3CN
OH
OH
7
9
89%
OH
NaIO4, KMnO4
Na2CO3
dioxane/H2O
NaClO2
tBuOH/H2O
NaH2PO4
PCy3
Ru
Cl
Cl
Boc
OH
Boc
N
N
Ph
PCy3
H2, Pd/C
AcOEt
Boc
Boc
N
OH
OH
OH
N
CH2Cl2
90%
COOH
98%
5
COOH
6
72%
60% two steps
8
10
81%
Scheme 3.
Scheme 2.

X. Ginesta et al. / Tetrahedron Letters 43 (2002) 779–782
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CHO
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NaBH4
EtOH
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In summary, we have developed a new enantioselective
entry to the synthesis of N-protected baikiain and
pipecolic acid. The present approach is based in the
regio- and stereoselective epoxide ring-opening of
unsaturated epoxy alcohol 4, followed by ring-closing
metathesis and oxidation. In this way, (S)-Boc-baikiain
has been prepared in only five steps (two of them
without purification of the product) in 32% overall
yield. The final products can be obtained in any
configuration in very high enantiomeric purity (99%
ee). This approach can be used in the synthesis of other
heterocyclic rings, possibility that is currently being
explored in our group.
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Acknowledgements
We thank financial support from MEC (grant PB98-
1246) and DURSI (grant 2000SGR00019). X.G. thanks
the University of Barcelona for a fellowship.
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