Synthesis of 5-substituted pipecolic acid derivatives as new conformationally constrained ornithine and arginine analogues

Article abstract of DOI:10.1016/j.tetlet.2005.09.008

Two, orthogonally protected, constrained analogues of arginine have been synthesised in a diastereodivergent manner. The key step involved an electrophilic or radical functionalisation of methyl N-Boc-5,6- dehydropipecolate.

Full text of DOI:10.1016/j.tetlet.2005.09.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7495–7497
Synthesis of 5-substituted pipecolic acid derivatives as new
conformationally constrained ornithine and arginine analogues
Laurent Le Corre and Hamid Dhimane*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS/Universite´ Rene´ Descartes,
`
UFR Biome´dicale, 45, rue des Saints-Peres, 75270 Paris cedex 06, France
Received 18 July 2005; revised 25 August 2005; accepted 2 September 2005
Abstract—Two, orthogonally protected, constrained analogues of arginine have been synthesised in a diastereodivergent manner.
The key step involved an electrophilic or radical functionalisation of methyl N-Boc-5,6-dehydropipecolate.
Ó 2005 Elsevier Ltd. All rights reserved.
L-Arginine, a guanidino group-containing proteinogenic
amino acid, which is positively charged at neutral pH, is
involved in a large number of physiological and patho-
physiological processes. The arginine residue, alone or
as part of a peptide, constitutes an important compo-
nent of substrates or inhibitors of a variety of enzymes.
Various conformationally constrained analogues of
arginine have been described. Most of these analogues
involve a restriction by means of a bridge between the
side chain atoms.1 Little has been reported on the develop-
ment of arginine mimetics wherein simultaneous
restriction of vi and / torsion angles were achieved.
To the best of our knowledge, only four of such ana-
logues, which are proline-templated have been reported2
(Fig. 1).
The work disclosed in this letter describes a diastereo-
selective synthesis of racemic, orthogonally protected cis
and trans 5-guanidino-pipecolic acids as new constrained
analogues of arginine where four torsion angles (v1, v2, v3
and /) are restricted. Variously substituted pipecolic acid
derivatives have already been described;3 some of them
were designed for peptidomimetics purposes.4 Our strat-
egy towards the synthesis of protected 5-guanidino pipe-
colic acids 6 relies on diastereoselective functionalisation
of 5,6-dehydropipecolic acid derivative 2, via the corre-
sponding ornithine analogues 5 (Scheme 1).
We started our synthesis from 2, which we prepared in
quantitative yield, from racemic N-Boc methylpipecolate
χ3
χ2
H
H2N
ZNH
N
χ1
H
NTs
NTs
H2N
HN
H2N
N
NZ
N
CO2Me
H2N
N
CO2Me
N
H
HN
φ
Boc
Boc
H
5
H
6
CO2H
N
N
CO2H
N
CO2H
Boc
Boc
Boc
N
CO2Me
N
CO2Me
Figure 1. Proline-templated analogues of arginine.
Boc
2
Boc
1
Keywords: Arginine-mimetics; Constrained analogues; Pipecolic acid;
Stereoselective synthesis.
*
Scheme 1. Retrosynthesis of orthogonally protected 5-guanidino-
Corresponding author. Tel./fax: +33 (0) 142 862 265; e-mail:
piecolic acids.
hamid.dhimane@univ-paris5.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.008

7496
L. Le Corre, H. Dhimane / Tetrahedron Letters 46 (2005) 7495–7497
1 in two steps; a-electromethoxylation and subsequent
b-elimination of methanol.5 Our initial attempts to
directly introduce the 5-amino group by hydrobora-
tion–amination sequence, based on literature examples,6
were unsuccessful. Therefore, we sought an alternative
stepwise approach to the ornithine mimetics 5 via the
corresponding 5-hydroxypipecolate. Although less reac-
tive than enamines, enecarbamates react with various
electophiles7 including boranes in the hydroboration–
oxidation sequence making possible the introduction
of the hydroxyl group into the b-position of the enecar-
This route provides the protected unnatural a-amino
acid ( )-cis-6 in high diastereomeric purity. To extend
this methodology to the trans isomer analogue, the alco-
hol cis-3 was required. This cis isomer was envisioned
by a stereoselective axial reduction with NaBH4 of the
corresponding ketone, which is taken to be locked in a
conformation with the 2-carbomethoxy group axially
oriented, due to the known A1,3 allylic strain present
in a-substituted N-acylpiperidines.8a,14 To this end, the
crude intermediate of the hydroboration step was sub-
jected to oxidation with various oxidants in order to
achieve the C–B oxidative cleavage and subsequent oxi-
dation of the resulting alcohol to the corresponding ke-
tone 7. The best yield (40%) of ketone 7 was obtained by
using 4 equiv of o-iodoxybenzoic acid (IBX)15 in reflux-
ing acetonitrile (Scheme 3). As anticipated, treatment of
7 with sodium borohydride gave selectively the alcohol
cis-3 (cis/trans > 97/3). Pure cis-3 was converted into
the azido compound trans-4 following the procedure
previously developed with the alcohol trans-3.
bamate nitrogen atom.7,8 As was pointed out by Plehiers
8a
´
and Hootele for 1-carbomethoxy-6-alkyl-2,3-dehydro-
piperidines, the hydroboration of 2 does not reach the
trialkylborane stage. On the other hand, even with
1 equiv of BH3ÆDMS the hydroboration of 2 was very
slow in THF (15 h for 1 mmol scale). Therefore, we
examined the solvent effects (toluene, Et2O, CH2Cl2)
and dichloromethane was found to be the most effective
solvent for the hydroboration step, which is completed
after 2.5 h.9 The oxidative cleavage of the C–B bond
was best achieved with trimethylamine N-oxide (TMO)
in refluxing THF. Under these conditions the desired
alcohol was isolated in 62% yield as a mixture of isomers
(trans/cis = 93/7)10 with respect to the ester function.
This mixture has been conveniently separated by column
chromatography, and each diastereomer was obtained
in a pure form.11 Mesylation of alcohol trans-3 provided
the corresponding mesylate, which was reacted with
sodium azide to give the azido derivative cis-4 in good
yield. This compound was then subjected to hydrogenoly-
sis using 10% palladium-on-charcoal in dichlorometh-
ane affording the corresponding primary amine cis-5.
To avoid lactamisation,12 the crude ornithine analogue
cis-5 was allowed to react with N,N-di-(benzyloxycar-
bonyl)-S-methylthiourea in presence of triethylamine
and mercury(II) chloride,13 to give the fully protected
cis isomer of arginine analogue cis-6 with 83% yield after
column chromatography (Scheme 2).
Beside this four-step route, we examined a two-step way.
The azidoalkoxylation of olefins, especially electron rich
ones, is a well established method for the introduction of
amino group.16 Thus, treatment of a mixture of our ene-
carbamate 2 and sodium azide, in acetonitrile–methanol,
with cerium(IV) ammonium nitrate (CAN) at 0 °C affor-
ded the desired a-methoxy-b-azido compound 8 in 76%
yield17 as a complex diastereomeric mixture.18 Subse-
quent reduction of the a-aminoether moiety, via the
corresponding iminium ion,5b,19 afforded the 5-azido-
pipecolate derivative 4 as a diastereomeric mixture
(trans/cis: 55/45). This ratio reflects the low selectivity
of the azidomethoxylation step. To optimise the stereo-
selectivity, we have studied the influence of various factors
and found that the diastereoselectivity in favor of the
desired trans isomer is strongly temperature dependent.
Best result (trans/cis: 92/8) was obtained when the azido-
methoxylation step was carried out in acetone at À95 °C
(Scheme 4). Finally, hydrogenolysis of trans-4 gave
quantitatively the ornithine analogue trans-5, which
HO
CO2Me
a, b
c
1
2
a
N
CO2Me
trans-3
2
N
Boc
O
Boc
7
d
H
N3
b
ZNH
N
e
f
CO2Me
NZ
N3
N
CO2Me
N
CO2Me
HO
Boc
cis-4
Boc
c
N
cis-6
N
CO2Me
Boc
H
Scheme 2. Reagents and conditions: (a) À2eÀ(C–C)–MeOH–n-
Bu4NBF4; (b) NH4Cl (1.4 equiv), toluene (reflux), (93% yield, two
steps); (c) (i) THF–2 M BH3ÆDMS (1 equiv), CH2Cl2, À78 °C then rt,
(ii) evaporation then TMOÆH2O (5.4 equiv), THF (reflux), 15 min (62%
yield); (d) (i) MsCl, NEt3 (82%), (ii) NaN3, DMF, 65 °C (90% yield);
(e) H2, 10% Pd–C, CH2Cl2, (f) ZN@C(SMe)NHZ, NEt3, HgCl2 (83%
yield, two steps).
Boc
cis-3
trans-4
Scheme 3. Reagents and conditions: (a) (i) THF–2 M BH3ÆDMS
(1 equiv), CH2Cl2, À78 °C then rt, (ii) evaporation then IBX (4 equiv),
CH3CN (reflux) (40% yield, two steps); (b) NaBH4, MeOH (85%, cis/
trans > 97/3); (c) (i) MsCl, NEt3 (78%), (ii) NaN3, DMF, 65 °C (91%).

L. Le Corre, H. Dhimane / Tetrahedron Letters 46 (2005) 7495–7497
7497
6. (a) Brown, H. C.; Kim, K.-W.; Cole, T. E.; Singaram, B. J.
Am. Chem. Soc. 1986, 108, 6761–6764; (b) Rangaishenvi,
M. V.; Singaram, B.; Brown, H. C. J. Org. Chem. 1991, 56,
3286–3294.
N3
a
2
MeO
N
CO2Me
7. Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.-i.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc.
1982, 104, 6697–6703.
b
Boc
8
´
8. (a) Plehiers, M.; Hootele, C. Tetrahedron Lett. 1993, 34,
N3
H
N
7569–7570; (b) Martin-Lopez, M. J.; Bermejo-Gonzalez,
F. Tetrahedron Lett. 1994, 35, 8843–8845; (c) Oppolzer,
W.; Bochet, C. G. Tetrahedron Lett. 1995, 36, 2959–2962;
(d) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org.
Chem. 1997, 62, 746–748; (e) Herdeis, C.; Heller, E.
Tetrahedron: Asymmetry 1997, 8, 1115–1121; (f) Matsu-
mura, Y.; Ohishi, T.; Sonoda, C.; Maki, T.; Watanabe, M.
Tetrahedron 1997, 53, 4579–4592.
ZNH
c, d
NZ
N
CO2Me
N
CO2Me
Boc
trans-4
Boc
trans-6
Scheme 4. Reagents and conditions: (a) NaN3 (1.5 equiv), CAN
(3 equiv), acetone–MeOH, À95 °C; (b) Et3SiH (1 equiv), BF3ÆOEt2
(1 equiv), CH2Cl2, À80 °C, (60%, trans/cis: 92/8); (c) (i) 10% Pd–C, H2
(1 atm), CH2Cl2, (ii) ZN@C(SMe)NHZ, NEt3, HgCl2, CH2Cl2 (80%
yield, two steps).
9. Similar rate enhancement of hydroboration in chloro-
hydrocarbon solvents was reported, see: Kanth, J. V.;
Brown, H. C. Tetrahedron Lett. 2000, 41, 9361–9364.
10. Variable amounts (7–15%) of the unexpected C@C
reduction compound 1 were isolated. By using BD3 we
established that both introduced hydrogen atoms were
supplied by borane. We have previously observed similar
results with enelactams.5b
was then subjected to the guanylation procedure to
afford the arginine analogue trans-6 in 80% overall yield.
11. The assignment of relative stereochemistry of cis and trans
isomers is based on 1H NMR spectra recorded at variable
temperature in toluene.4a
12. When the hydrogenolysis was performed in methanol
lactamisation took place during the evaporation of the
solvent leading to a bicyclic lactam:
In summary, we have developed a diastereodivergent
synthesis of the orthogonally protected unknown
a-amino acid 5-guanidinopipecolic acid as new arginine
analogues. The biological evaluation of each fully
deprotected diastereomer (racemic) with NOS isoforms
will be the subject of a later report.
Boc
N
NH
O
References and notes
Therefore, we employed more volatile solvent, that is,
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stored at low temperature (À20 °C) to avoid its
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