6-alkynyl- and 6-aryl-substituted (R)-pipecolic acid derivatives

Article abstract of DOI:10.1021/ol4010728

(R)-α-Aminoadipic acid is a readily available enantiomerically pure starting material for the synthesis of (R)-pipecolic acid and its derivatives. Sonogashira or Suzuki cross-coupling reactions of an N-formyl pipecolate-derived vinyl bromide furnish 6-alkynyl or aryl derivatives. Reduction with sodium cyanoborohydride and subsequent N-deformylation provide 6-alkynyl substituted (R)-pipecolic acid derivatives, valuable building blocks for amino acid and peptide chemistry.

Full text of DOI:10.1021/ol4010728

ORGANIC
LETTERS
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Vol. XX, No. XX
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6‑Alkynyl- and 6‑Aryl-Substituted
(R)‑Pipecolic Acid Derivatives
Amina Sadiq and Norbert Sewald*
Department of Chemistry, Bielefeld University, P.O. Box 100131, 33501 Bielefeld,
Germany
norbert.sewald@uni-bielefeld.de
Received April 18, 2013
ABSTRACT
(R)-R-Aminoadipic acid is a readily available enantiomerically pure starting material for the synthesis of (R)-pipecolic acid and its derivatives.
Sonogashira or Suzuki cross-coupling reactions of an N-formyl pipecolate-derived vinyl bromide furnish 6-alkynyl or aryl derivatives. Reduction
with sodium cyanoborohydride and subsequent N-deformylation provide 6-alkynyl substituted (R)-pipecolic acid derivatives, valuable building
blocks for amino acid and peptide chemistry.
Amino acids are versatile chiral pool building blocks in
peptidechemistry, organicsynthesis, and organocatalysis.1
D-Amino acids are not as abundant in Nature as the
L-configured counterparts. However, D-amino acids signifi-
cantly influence the conformation of e.g. cyclic peptides.2
R-Aminoadipic acid, the homologue of glutamic acid, is a
naturally occurring amino acid found in green plants and
microorganisms.3,4 It is an intermediate in lysine meta-
bolism.5 (R)-R-Aminoadipic acid 1 constitutes the acyl
substituent present in penicillin N and cephalosporin
C. It is cleaved in the semisynthesis of β-lactam antibiotics
to give 7-aminocephalosporanic acid (7-ACA), which is
subsequently acylated in order to introduce different side
chains. Onlyrecently, anenzymaticprocesswasdeveloped,
which provides (R)-R-aminoadipic acid in large quantities
by cleavage from the fermentation product cephalosporin
C using cephalosporin acylase.6
(R)-R-Aminoadipic acid has been proven to be a con-
venient chiral pool starting material for the synthesis of
(R)-pipecolic acid and its derivatives.7 Pipecolic acid, also
known ashomoprolineorpiperidine-2-carboxylic acid, isa
component of several secondary metabolites in plants and
fungi. (S)-Pipecolic acid occurs in many natural products
with interesting biological activities, like the anticancer
agent VX710,8 the antibiotic sandramycin,9 the immuno-
suppressants FK 50610 and rapamycin,11 the histone de-
acetylase (HDAC) inhibitors WF-3161 and Cyl-2,12 and
the ATPase inhibiting efrapeptins and neo-efrapeptins.13
(R)-Pipecolic acid is a constituent of the HDAC inhi-
bitors trapoxin A and apicidin.14 Substituted derivatives
of pipecolic acid are valuable building blocks for
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r
10.1021/ol4010728
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structureÀactivity relationship studies. It is assumed that
6-substitutedderivativesofpipecolic acidcan act asmimics
of cis-prolyl peptide bonds as compared to the 5-substi-
tuted proline derivatives.15 They exhibit potential bioac-
tivity and also serve as starting material for the synthesis of
biologically active piperidine alkaloids.16 However, only a
few routes are available for the synthesis of 6-substituted
pipecolic acid derivatives.17 Therefore, it was of interest to
synthesize 6-substituted derivatives of pipecolic acid which
could be further incorporated into peptides for conforma-
tional studies.
reactions (Schemes 2 and 3). Sonogashira cross-coupling
combines, e.g., a vinyl bromide and a terminal alkyne. An
array of alkyne substituted derivatives of (R)-pipecolic
acid was prepared using catalytic amounts of PdCl2(PPh3)2
and CuI in the presence of Et3N as the base. The coupled
products were obtained in good-to-high yields.
Scheme 2. Synthesis of (R)-Pipecolic Acid Derivatives by
Sonogashira Cross-Coupling Reaction
Methyl 6-oxopipecolate 2 was prepared from (R)-R-
aminoadipic acid by esterification and subsequent lactam-
ization during Kugelrohr distillation in excellent yield
according to a protocol published for (S)-6-oxopipecolic
acid.18 VilsmeierÀHaack reaction of amides or lactams is
reported to give compounds like the 5-formyl-6-haloge-
nated derivative 4.7,19 Treatment of 2 with DMF and
POBr3 under different conditions gave 3 (Scheme 1).
Interestingly, similar compounds, e.g. triflates, are
obtained in much more complicated procedures.22a
N-Formylated products have been reported20 as inter-
mediates that are deformylated upon addition of excess
POCl3. However, in our case the N-formyl compound 3
was formedastheonlyproductasconfirmedbyDEPTand
HSQC experiments.
The high enantiomeric purity (ee > 99%) of 5a was
verified by chiral HPLC (CHIRALPAK AD).
Scheme 1. Bromo-N-formylation vs VilsmeierÀHaack
Formylation of (R)-Methyl 6-Oxopipecolate
Scheme 3. Synthesis of (R)-Pipecolic Acid Derivatives via
Suzuki Cross-Coupling Reactions
The vinyl bromide 3 turned out to be a favorable starting
material for Sonogashira and Suzuki cross-coupling
Application of Suzuki cross-coupling reactions with
compound 3 and suitable boronic acids in the pre-
sence of PdCl2(PPh3)2 as the catalyst gave an array of
6-aryl or 6-trans-β-styryl substituted derivatives of
(R)-pipecolic acid under mild conditions in good yields
(Scheme 3). Exemplarily, compound 6a was shown to
be enantiomerically pure (ee > 99%) by chiral HPLC
(CHIRALPAK AD).
€
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Westerhoff, O.; Saak, W.; Martens, J. J. Chem. Soc., Perkin Trans. 1
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and pipecolic acid derivatives: Tools for stabilization of peptide second-
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Applications; Schmuck, C., Wennemers, H., Eds.; Wiley-VCH: Weinheim,
2004; pp 18À29.
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(17) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935–1950.
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The de was determined by 1H NMR to be >98%, while
the enantiomeric purity was complete according to chiral
HPLC (CHIRALPAK AD).
Scheme 4. Desilylation of 5c and Ester Hydrolysis of 5a and 6a
Cleavage of the N-formyl group in 10a was investigated
under both acidic23 and basic24 conditions. The N-formyl
group resisted basic conditions but was smoothly cleaved
under acidic conditions. Treatment with 6% HCl solution
in the presence of MeOH as solvent gave the target
(2R,6R)-pipecolic acid derivative 11a in 56% yield
(Scheme 5).
Desilylation of 5c was performed under basic conditions
using K2CO3 in MeOH to give 7 in 85% yield. Cleavage of
the methyl ester21 was carried out exemplarily on com-
pounds 5a and 6a using 10% aq NaOH in THF to give the
free carboxylic acids 8a and 9a (Scheme 4).
Scheme 5. Reduction of the N-Formyl Enamine and N-Defor-
mylation
N-Acyl substituted 2,3-dehydropiperidines can be
reduced with NaCNBH3 in the presence of TFA according
to Toyooka et al.22 The acyliminium salt initially formed
by protonation is attacked by the hydride. Likewise, the
6-alkynyl substituted N-formyl enamines of type 5 can be
reduced in the presence of 8 equiv of TFA and 4 equiv of
NaCNBH3 at ambient temperature to stereoselectively
give the 2,6-trans-disubstituted pipecolic acid derivatives
10 in 60À70% yield. Noteworthy, the reduction requires
higher TFA concentrations and reaction temperatures
than similar conversions described.22
In conclusion, we have developed an efficient protocol
for the synthesis of 6-substituted (2R,6R)-pipecolic acid
derivatives starting from (R)-R-aminoadipic acid by
Sonogashira and Suzuki cross-coupling reactions, respec-
tively, followed by diastereoselective N-formyl iminium
reduction with NaCNBH3 and N-deformylation.
The assignment of the NMR signals was achieved using
COSY and HMBC experiments, while the (2R,6R)-
configuration of 10 was established on the basis of 1H NMR
coupling constants and supported by NOESY experi-
ments. H-2 gives rise to a dd with very similar coupling
constants (10a: 5.9 Hz, 2.2 Hz; 11a: 4.0 Hz, 4.0 Hz, whereas
H-6 resonates as a dd with largely different coupling
constants (10a: 11.8 Hz, 3.2 Hz; 11a: 11.8 Hz, 3.2 Hz).
This supports an equatorialÀaxial and an equatorialÀ
equatorial relationship for H-2 and an axialÀaxial
relationship together with an axialÀequatorial one for
H-6, which establishes the trans-configuration for the
two protons and substituents, respectively (Scheme 5).
Acknowledgment. The authors acknowledge the German
Academic Exchange Service (DAAD) for the award
of a PhD fellowship to Amina Sadiq. Sandoz GmbH,
Kundl, Austria, and Trend Materials GmbH, Linz,
Austria, provided the starting material (R)-R-aminoadipic
acid.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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M.; Yamada, K.; Teranishi, S.; Sato, H.; Kaneko, C. Chem. Pharm. Bull.
2001, 49, 87–96.
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hedron 1989, 45, 4377–4382.
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H.; Spandec, T. F.; Daly, J. W. Tetrahedron 2005, 61, 1187–1198. (b)
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The authors declare no competing financial interest.
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