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Synthesis 2012; 44(13): 1935-1950
DOI: 10.1055/s-0031-1289767
review
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of Pipecolic Acid and Derivatives

Alastair A. Cant
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK , Fax: +44(141)3304888   Email: Andrew.Sutherland@glasgow.ac.uk
,
Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK , Fax: +44(141)3304888   Email: Andrew.Sutherland@glasgow.ac.uk
› Author Affiliations
Further Information

Publication History

Received: 13 March 2012

Accepted after revision: 10 April 2012

Publication Date:
25 May 2012 (online)

 
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Abstract

The nonproteinogenic α-amino acid, l-pipecolic acid and its derivatives are components of a wide range of pharmacologically active compounds. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review highlights these key methods as well as the application of these compounds for the preparation of enzyme inhibitors, conformationally restricted building blocks and peptidomimetics.

1 Introduction

2 Chiral Pool Approaches

2.1 From Amino Acids

2.2 From Carbohydrates

3 Asymmetric Reactions

3.1 Auxiliary-Based Approaches

3.2 Catalytic Asymmetric Methods

4 Chemoenzymatic Methods

4.1 Enzymatic Kinetic Resolution

4.2 Miscellaneous Enzymatic Methods

5 Synthesis of Pipecolic Acid Derivatives for Biological Applications

5.1 Synthesis of Novel Medicinal Agents

5.2 Synthesis of Conformationally Restricted Building Blocks (Peptide and Nucleic Acid Mimics)

6 Conclusions


#

Key words

amino acids - heterocycles - piperidines - asymmetric synthesis - asymmetric catalysis

Biographical Sketches

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Alastair Cant was born in 1984 in Alexandria, in the west of Scotland. He graduated with a first class MSci degree from the University of Edinburgh winning the Louis-Cohen, Hope, and Mackay-Smith prizes. He then carried out a PhD at the University of Edinburgh under the supervision of Dr Michael Greaney working on new methods for the generation of benzyne using C–H activation and its application in reactions such as σ-insertions and aza-Claisen reactions. In 2011, he joined the research group of Dr Andrew Sutherland at the University of Glasgow as a post-doctoral fellow and his current interests include the development of new transition-metal-mediated reactions for the preparation of aryl iodides as well as the stereoselective synthesis of novel pipecolic acid derivatives.

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Andrew Sutherland was born in 1972 in Wick, in the north of Scotland. After graduating with a first class B.Sc. degree in chemistry at the University of Edinburgh in 1994, he undertook a PhD at the University of Bristol under the supervision of Professor Christine Willis. In 1997, he joined the research group of Professor John Vederas at the University of Alberta where he studied diaminopimelate metabolism for the design of novel antibiotics. This was followed by a return to the University of Bristol as a junior research fellow working with Professor Timothy Gallagher on the design and synthesis of neuronal nicotinic receptors. In January 2003, he was appointed to a lectureship in the School of Chemistry at the University of Glasgow and in 2008 promoted to the position of senior lecturer. His research group’s interests are on the development of new synthetic methodology for the synthesis of chiral, biologically active and medicinally important compounds.

1

Introduction

l-Pipecolic acid (1; Figure [1]) is a cyclic nonproteinogenic α-amino acid metabolised via several putative pathways from l-lysine.[ 1 ] It is found in plants, fungi and human physiological fluids.[2] [3] Its role in humans is subject to some debate, but one theory suggests it has a functional role in the mammalian central nervous system in a manner similar to γ-aminobutyric acid (GABA).[ 2b,3 ] l-Pipecolic acid is also a component of a wide range of pharmacologically active compounds such as the local anaesthetic ­analogue, ropivacaine (2),[ 4 ] immunosuppressive agents rapamycin (3)[ 5 ] and FK506[ 6 ] as well as the antitumour antibiotic, sandramycin.[ 7 ] Derivatives of l-pipecolic acid, particularly hydroxylated variants, are also of considerable biological and medicinal interest. These derivatives are constituents of a wide range of pharmacologically active compounds such as the naturally occurring antitumour antibiotic, tetrazomine (4),[ 8 ] the tumour necrosis factor-α converting enzyme inhibitor 5 [ 9 ] and palinavir (6), a HIV protease inhibitor.[ 10 ] Due to their widespread presence in nature and their significant medicinal potential, there has been much interest in the development of new methods and approaches for the asymmetric synthesis of l-pipecolic acid and its derivatives. The aim of this article is to highlight key advances since the last major review in this area.[ 11 ] As well as describing approaches using the chiral pool, asymmetric reactions and biotransformations, the use of novel pipecolic acid derivatives for the preparation of conformationally restricted building blocks, peptide and nucleic acid mimetics is also discussed.

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Figure 1

# 2

Chiral Pool Approaches

The most common source of starting materials used for the asymmetric synthesis of pipecolic acid derivatives are linear proteinogenic α-amino acids. General strategies involve suitable functionalisation of the side-chain followed by a cyclisation reaction with the α-amino group. In a similar fashion, the chirality and functional groups of carbohydrates have been used in combination with key ring-forming reactions for the preparation of a range of hydroxylated pipecolic acid derivatives. The following sections (2.1 and 2.2) outline these general strategies according to type of ring-forming reaction.

2.1

From Amino Acids

l-Pipecolic acid and (2S,3R)-3-hydroxypipecolic acid, a component of tetrazomine (4) have been prepared from hydroxyproline and a serine derivative, respectively, using a ring-closing metathesis (RCM) reaction as the key step.[12] [13] Both syntheses used similar strategies involving the formation of an alkene side chain from a hydroxy group. Allylation of the α-amine followed by an RCM reaction gave the pipecolic acid rings. For example, serine derivative 7 was converted in two steps into alcohol 8 (Scheme [1]). This was subjected to a Swern oxidation and the resulting aldehyde was treated with vinylmagnesium bromide to give an inseparable mixture of syn- and anti-allylic alcohols 9 in an 87:13 ratio, respectively. Protection of the secondary alcohol as the methoxymethyl (MOM) ether and allylation of the tert-butyloxycarbonyl (Boc)-derived amine gave the RCM precursor 10, which at this stage could be separated from the minor anti-diastereomer. Reaction of diene 10 with Grubbs’ first-generation catalyst gave dihydropiperidine 11 in 84% yield. Hydrogenation, oxidation of the resulting primary alcohol followed by deprotection allowed the preparation of (2S,3R)-3-hydroxypipecolic acid 12 in good overall yield.

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Scheme 1 Synthesis of (2S,3R)-3-hydroxypipecolic acid 12 by ­Chattopadhyay and co-workers. Reagents and conditions: (i) DMSO, (COCl)2, Et3N, CH2Cl2; (ii) vinylmagnesium bromide, THF, 62% over two steps; (iii) MOMCl, DIPEA, CH2Cl2, 82%; (iv) NaH, allyl bromide, DMF, 90%; (v) Grubbs I catalyst, CH2Cl2, 84%.

A one-pot imine reduction and conjugate addition has been used for the preparation of 6-substituted 2,6-trans-4-hydroxy-l-pipecolic acids 18 (Scheme [2]).[ 14 ] Reaction of aspartic acid derivative 13 with the anion of dimethyl methylphosphonate gave phosphonate ester 14 in 84% yield. This was used in a Horner–Wadsworth–Emmons reaction with a range of alkyl- and aryl-substituted aldehydes to give a series of E-enones. A four-step, one-pot reaction process involving removal of the trityl protecting group, formation of imine 16 followed by chemoselective reduction and conjugate addition gave 4-oxo-l-pipecolic acids 17 in modest yields. The authors suggest that the 2,6-trans-geometry of the products of this one-pot process arises due to a Zimmerman–Traxler chair-like transition state. Reduction of the 4-oxo-l-pipecolic acids 17 and deprotection of the amine and carboxylic acid functional groups under standard conditions gave novel 6-substituted 4-hydroxy-l-pipecolic acids 18 in good overall yield.

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Scheme 2 Synthesis of 2,6-trans-6-substituted-4-hydroxy-l-pipecolic acids 18. Reagents and conditions: (i) (MeO)2P(O)Me, n-BuLi, THF, 84%; (ii) RCHO, K2CO3, MeCN, 57–96%; (iii) TFA, CH2Cl2 then PhCHO, Et3N, 4 Ǻ MS; (iv) NaBH3CN, 29–53% over the four steps.

A highly efficient and common strategy for preparing functionalised pipecolic acid ring systems involved the use of inter- and intramolecular reactions of amines with various carbonyl species.[15] [16] [17] Blaauw and co-workers used this strategy to good effect for the synthesis of (2S,5R)-5-hydroxypipecolic acid (22) and 6-substituted derivatives (Scheme [3]).[ 15 ] Acetal 19 was cyclised under acidic conditions to give enamine 20 in 98% yield. Epoxidation of 20 in the presence of methanol resulted in immediate ring-opening to give the N,O-acetal 21 in 98% yield and with 96:4 diasteroselectivity in favour of the 2S,5R-configured product. Hydrogenation and hydrolysis of the methyl ester gave (2S,5R)-5-hydroxypipecolic acid (22) in excellent overall yield. N,O-Acetal 21 proved to be an excellent intermediate for the preparation of 6-substituted derivatives using N-acyliminium chemistry. After protection of the 5-hydroxy group, the N-acyliminium ion was formed by treatment with a Lewis acid. In situ reaction with a series of π-silyl nucleophiles gave the 2,6-cis-substituted products 24 as single diastereomers in high yields. The formation of the 6S-configured products is due to nucleophilic attack of the N-acyliminium ion in a pseudoaxial fashion.

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Scheme 3 Synthesis of (2S,5R)-5-hydroxypipecolic acid (22) and 6-substituted derivatives 24. Reagents and conditions: (i) TsOH, DMF, toluene, 98%; (ii) Oxone®, NaHCO3, MeOH, 98%; (iii) H2, Pd/C; (iv) 6 M HCl, 93% over two steps; (v) Ac2O, Et3N, DMAP, 99%; (vi) TMS-R, Lewis acid, MeCN; (vii) H2, Pd/C, 82–92% over two steps.

Ene-type reactions performed under acidic or Lewis acid conditions have been used for the stereoselective synthesis of 4-hydroxypipecolic acids.[18] [19] For example, aldehyde 26, synthesised in six steps from l-homoserine (25) was subjected to a carbonyl ene reaction in the presence of methylaluminum dichloride (Scheme [4]).[ 19 ] At room temperature this gave the cis,cis-product which spontaneously lactonised to bicyclic pipecolic acid 27 in 79% yield. Alternatively, cyclisation of 26 in the presence of hydrochloric acid gave a mixture of lactonised and non-lactonised products as well as compounds where chlorination of the isopropenyl group had occurred.

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Scheme 4 Reagents and conditions: (i) MeAlCl2, CHCl3, 79%.

Cyclisation of diazo compounds derived from α-amino acids using either rhodium or ruthenium complexes have allowed the synthesis of 5-oxopipecolic acids in good yields.[20] [21] Ganesh and co-workers prepared diazoketone 29 under standard conditions from the orthogonally protected glutamic acid derivative 28 in 65% yield (Scheme [5]).[ 20 ] Formation of the rhodium carbene and subsequent N–H insertion gave 5-oxo-l-pipecolic acid 30 in 52% yield. Stereoselective reduction of 30 with sodium borohydride gave the (2S,5S)-5-hydroxypipecolic acid derivative 31 as the sole product and this was used as an intermediate for the preparation of a new class of peptide nucleic acid mimics.

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Scheme 5 Synthesis of (2S,5S)-5-hydroxypipecolic acid derivative 31. Reagents and conditions: (i) EtOCOCl, Et3N, THF, then CH2N2, Et2O, 65%; (ii) [Rh(OAc)2]2, benzene, 52%; (iii) NaBH4, MeOH, 93%.
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Scheme 6 Ring expansion of proline derivative 33. Reagents and conditions: (i) ethyl diazoacetate, BF3·OEt2, Et2O, 90%; (ii) NaCl, H2O (cat.), DMSO, 75%.

In contrast to previous examples that have used the cyclisation of linear amino acids to form the pipecolic acid ring, methods have also been developed involving ring expansion of cyclic amino acids.[22] [23] In particular, ring expansion of oxygenated analogues of proline have been used to generate functionalised pipecolic acids. Jung and Avery used 4-oxoproline derivative 33, easily prepared in three steps from (2S,4R)-4-hydroxyproline (32) in a ring-expansion reaction with ethyl diazoacetate (Scheme [6]).[ 22 ] In the presence of boron trifluoride–diethyl ether complex, this gave a 90% yield of the ring-expanded regioisomers 34 and 35 along with their keto tautomers. Without separation, decarboxylation was performed with sodium chloride at 140 ºC to give the 5-oxo- and 4-oxo derivatives 36 and 37 in a 1.5:1 ratio and in a combined 75% yield. After separation by flash column chromatography, 36 and 37 were reduced to the corresponding cis-hydroxy derivatives. After examining a range of reducing agents, sodium borohydride, as found in other studies, gave the highest yields and most stereoselective reduction of the oxopipecolic acid derivatives.


# 2.2

From Carbohydrates

In a similar manner to that of α-amino acids, carbohydrates have been used in combination with a range of cyclisation strategies for the stereoselective preparation of hydroxylated pipecolic acid derivatives. In general, the chirality of the furanoside or pyranoside motif is used to induce new stereogenic centres before the key cyclisation step, or used directly as a component of the pipecolic acid ring.

Carbohydrates have been converted into chiral dienes and utilised in RCM reactions.[24] [25] Using d-mannitol as a starting material, Chattopadhyay and co-workers prepared (R)-2,3-O-cyclohexylideneglyceraldehyde (39) as the key building block for the subsequent synthesis of a range of pipecolic acid derivatives (Scheme [7]).[24] [26] Aldehyde 39 was allowed to react with allylamine under anhydrous conditions to give imine 40 which was then treated with allylzinc bromide producing the addition products 41 and 42 in 19% and 47% yield, respectively. It should be noted that the selectivity of addition could be reversed by using allylmagnesium bromide as the nucleophile. Tosyl protection of the major product 42 from the zinc reaction was followed by a RCM reaction with Grubbs’ first-­generation catalyst which gave cyclic alkene 43 in high yield. Deprotection, hydrogenation and subsequent oxidation of the resulting diol gave N-tosyl pipecolic acid derivative 44 in good overall yield. Cyclic diene 43, formed from the RCM reaction, was also subjected to dihydroxylation with osmium tetroxide and N-methylmorpholine N-oxide (NMO), eventually yielding 4,5-dihydroxypipecolic acids.

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Scheme 7 Synthesis of pipecolic acid 44 using d-mannitol. Reagents and conditions: (i) allylamine, 4 Å MS, CH2Cl2, 95%; (ii) allylzinc bromide, THF, 66%; (iii) TsCl, Et3N, CH2Cl2, 91%; (iv) Grubbs I catalyst, CH2Cl2, 89%; (v) 6 M HCl, 91%; (vi) H2, Pd/C, EtOAc, 100%; (vii) NaIO4, RuCl3 (cat.), CCl4, MeCN, H2O, 73%.
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Scheme 8 Synthesis of glycosidase inhibitor 50 using d-glucose. ­Reagents and conditions: (i) Ph3P=CHCOMe, THF, 87%; (ii) H2, Pd/C, MeOH; (iii) CbzCl, NaHCO3, MeOH, H2O, 91% over two steps; (iv) TFA, H2O, then NaIO4, acetone, H2O; (v) NaClO2, NaH2PO4, 30% H2O2, aq MeCN, 87% over two steps; (vi) H2, Pd/C, MeOH, 80 psi, 97%.

Chiral carbohydrate building blocks have been used to create new stereogenic centres during simple reductive amination reactions for the preparation of a wide range of substituted and bicyclic pipecolic acids.[27] [28] (2S,3R,6S)-6-Methyl-3-hydroxypipecolic acid (50), a new inhibitor of glycosidases, was prepared for the first time using such a strategy.[ 28 ] The known aldehyde 46 [ 29 ] was easily obtained from d-glucose (Scheme [8]). Wittig reaction of 46 with 1-(triphenylphosphoranylidene)-2-propanone gave the corresponding α,β-unsaturated methyl ketone 47 as a 91:9 mixture of Z and E isomers in 87% yield. High-pressure hydrogenation of 47 resulted in reduction of the alkene and azide moieties as well as effecting the key reductive amination reaction. After protection of the amine, 48 was isolated in 91% yield from 47. The acetonide group was removed using trifluoroacetic acid and the resulting anomeric mixture of hemiacetals was oxidatively cleaved using sodium periodate. This gave the unstable aldehyde 49 that was further oxidised, without purification, with sodium chlorite and hydrogen peroxide. Finally, hydrogenolysis gave (2S,3R,6S)-6-methyl-3-hydroxypipecolic acid (50) in 97% yield. Reduction of aldehyde 49 allowed access to the corresponding piperidinol. These new pipecolic acid derivatives were tested as glycosidase inhibitors and 50 was found to inhibit both an α-glucosidase from Baker’s yeast and an α-galactosidase.

The ring systems of 3-hydroxypipecolic acids have been synthesised via the intramolecular reaction of amines with esters followed by reduction of the resulting amide to give the piperidine ring.[30] [31] This approach was used by Kumar and Baskaran for the synthesis of a (2R,3S)-3-hydroxypipecolic acid derivative (Scheme [9]).[ 30 ] d-Glucose (45) was used as the chiral starting material and converted into the known benzylidene acetal 51.[ 32 ] Hydrogenation of the α,β-unsaturated ester followed by a Mitsunobu reaction gave the azido ester 52 in high yield. The cyclisation reaction was then implemented by reduction of the azide which gave lactam 53 in 95% yield. Lactam 53 was converted into the Boc-protected amine 54 under standard conditions. Compound 54 was then subjected to the second key reaction of this synthetic route, the regioselective reductive cleavage of the benzylidene acetal. This was performed using ethylaluminum dichloride as a Lewis acid in the presence of triethylsilane and gave solely the desired hydroxymethyl derivative 55 in 99% yield. The authors suggest that steric hindrance dictates the selective coordination of the Lewis acid to one of the acetal oxygen atoms resulting in the regioselective opening of the ring. Oxidation and removal of the benzyl protecting group completed the synthesis of Boc-protected (2R,3S)-3-hydroxypipecolic acid 56.

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Scheme 9 Synthesis of (2R,3S)-3-hydroxypipecolic acid derivative 56. Reagents and conditions: (i) H2, Pd/C, EtOH, 95%; (ii) DPPA, DEAD, Ph3P, THF, 71%; (iii) H2, Pd/C, EtOH, 95%; (iv) LiAlH4, Et2O, 88%; (v) Boc2O, MeCN, 88%; (vi) EtAlCl2, Et3SiH, CH2Cl2, 99%; (vii) RuCl3, NaIO4, CCl4, MeCN, H2O, 64%; (viii) H2, Pd(OH)2, EtOH, 70%.

More elaborate ring-forming reactions have been used to prepare highly functionalised pipecolic acid derivatives from carbohydrate-derived substrates.[33] [34] For example, Overkleeft and co-workers used a one-pot Staudinger, aza-Wittig and Ugi three-component reaction of ribose-based starting materials for the synthesis of a library of enantiomerically pure pipecolic acid amides (Scheme [10]).[ 33 ] The primary alcohol of the known d-ribose derivative 57 [ 35 ] was activated by tosylation and the anomeric hydroxy group was benzoylated. Displacement of the tosyl group with azide and removal of the benzoyl protecting group then gave key substrate 59 in 51% overall yield. The one-pot process was then initiated by reaction of 59 with trimethylphosphine. After completion of the Staudinger and aza-Wittig stage of the process to give imine 60, the addition of Boc-Ala-OH and cyclohexyl isocyanide allowed the Ugi reaction to take place, generating the pipecolic acid amide 61 as a single diastereomer in 34% yield.

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Scheme 10 Reagents and conditions: (i) TsCl, pyridine; (ii) BzCl, pyridine; (iii) NaN3, DMF; (iv) NaOMe (cat.), MeOH, 51% over four steps; (v) Me3P, MeOH, then Boc-Ala-OH, cyclohexyl-NC, 34%.

#
# 3

Asymmetric Reactions

A wide range of asymmetric reactions has been used to generate chiral intermediates for the synthesis of pipecolic acid derivatives. Despite advances in the development of highly efficient catalytic asymmetric methods, auxiliary-based approaches are still the most commonly used. Section 3.1 describes these approaches according to the type of chiral auxiliary used. Catalytic asymmetric methods involving processes such as transfer hydrogenation, asymmetric deprotonation with chiral bases as well as organocatalytic reactions have been used to prepare pipecolic acids and are described according to reaction type in section 3.2

3.1

Auxiliary-Based Approaches

The main strategy in auxiliary-based approaches involves the use of a chiral amine source which eventually becomes the amine of the pipecolic acid ring. Common auxiliaries include amino alcohols, α-methylbenzylamine, sulfinylamines as well as more classical auxiliaries such as pseudoephedrine and camphorsultam.

Amino alcohols such as valinol and phenylglycinol have been typically used as sources of chirality for the synthesis of l-pipecolic acid. Lemire and Charette used a valinol derivative for the asymmetric addition of organometallic reagents to N-pyridinium salts for the synthesis of l-pipecolic acid 1 (Scheme [11]).[ 36 ] Chiral N-iminopyridinium salt 63 was prepared by activation of valinol derivative 62 with triflate anhydride followed by reaction with pyridine. The resulting scaffold was then reacted with a range of organometallic reagents such as phenylmagnesium bromide which gave dihydropyridine 64 in 89% yield over the two steps and in a diastereoselective ratio of >98:2. High-­pressure hydrogenation yielded the piperidine ring system in good yield. The valinol auxiliary was then removed by alane reduction and the resulting amine was protected as the trifluoroacetate. Oxidation of the phenyl ring using the Sharpless procedure[ 37 ] afforded the carboxylic acid and l-pipecolic acid was subsequently isolated after hydrolysis of the amide protecting group under standard conditions. Dihydropyridine 64 was also used in a cycloaddition reaction with singlet oxygen for the synthesis of (2S,3S)-3-hydroxypipecolic acid.

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Scheme 11 Reagents and conditions: (i) Tf2O, pyridine, CH2Cl2; (ii) PhMgBr.LiBr, Et2O, 89% over two steps; (iii) H2, Pd/C, MeOH, 300 psi, 80%; (iv) AlH3, Et2O; (v) TFAA, Et2O, 79% over two steps; (vi) RuCl3, NaIO4, CCl4, MeCN, H2O; (vii) K2CO3, MeOH, 72% over two steps.

In a similar fashion, 2-phenylglycinols have been used for the asymmetric synthesis of a wide range of pipecolic ­acids with various substitution patterns and incorporating pharmacologically important groups such as trifluoromethyl.[38] [39] [40] [41] [42] [43] Hou and co-workers used (R)-2-phenylglycinol (67) for the preparation of both d- and l-pipecolic acid (Scheme [12]).[ 38 ] The chiral glycine enolate synthon, morpholin-2-one 68 was prepared from (R)-2-phenylglycinol using a well-established route. Alkylation with diiodobutane gave 69 as a single diastereomer and this was smoothly cyclised to 70 after removal of the Boc group. Hydrogenation with Pearlman’s catalyst gave d-pipecolic acid (71) in good overall yield. l-Pipecolic acid was also prepared from 70 using a deprotonation–protonation protocol that gave epimer 72 followed by hydrogenation. 2-Alkyl derivatives of d-pipecolic acid were also prepared in this programme using morpholin-2-one 68.

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Scheme 12 Synthesis of d- (71) and l-pipecolic acid (1) from (R)-2-phenylglycinol (67). Reagents and conditions: (i) BrCH2CO2Me; (ii) Boc2O; (iii) PTSA, 34% over three steps; (iv) I(CH2)4I, NaHMDS, HMPA, THF, 65%; (v) TFA, DCE then EtN(i-Pr)2, 65%; (vi) H2, Pd(OH)2, 99%; (vii) KHMDS, HMPA, THF then AcOH, H2O, 75%; (viii) H2, Pd(OH)2, 99%.

Both enantiomers of α-methylbenzylamine have been used as the source of chirality as well as for the pipecolic acid amine. The general strategy typically involves an asymmetric ring-forming reaction to generate the piperidine ring, followed by removal of the α-methylbenzyl group by hydrogenation.[ 44 ] A number of pericyclic reactions including 1,3-dipolar cycloadditions[ 45 ] and imino-Diels–Alder reactions[46] [47] [48] have been used in such a strategy for the rapid generation of pipecolic acids. Diels–­Alder reaction of imine 74 derived from (S)-α-methylbenzylamine with freshly distilled 2-methylbutadiene gave piperidine 75 and the minor 1′S,2S-diastereomer in an 82:18 ratio (Scheme [13]).[ 48 ] Hydrogenation with a norbornadiene (nbd)-derived rhodium catalyst in the presence of chiral ferrocenyl phosphine ligand 76 gave the trans-hydrogenated product 77 in 96% diastereomeric excess. It should be noted that hydrogenation of 75 under standard conditions (Pt/C) gave the corresponding cis-product. A second hydrogenation, this time with Pearlman’s catalyst, removed the α-methylbenzyl group to give the ethyl ester of (2R,4R)-4-methylpipecolic acid, an important constituent of argatroban, a synthetic inhibitor of thrombin.

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Scheme 13 Reagents and conditions: (i) TFA, DMF, 33%; (ii) H2, Rh(nbd)2BF4, 76, MeSO3H, 87%; (iii) H2, Pd(OH)2/C, EtOH, 45%.

(R)-α-Methylbenzylamine (80) was used in an asymmetric Strecker reaction with 3,4-dihydro-2H-pyran (79) and sodium cyanide for the synthesis of d-pipecolic acid (Scheme [14]).[ 49 ] Amino nitrile 81 was isolated in 86% yield and >96% de from this process. Cyclisation of 81 was initially attempted by mesylation; however, this led to substantial racemisation at the 2-position. This problem was circumvented by acidic hydrolysis of the nitrile to amide 82 followed by a one-pot activation of the primary alcohol and cyclisation which gave pipecolinamide 83. Hydrogenation of the α-methylbenzyl group and further acid hydrolysis of the amide gave d-pipecolic acid (71) in good overall yield and in >98% ee.

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Scheme 14 Synthesis of d-pipecolic acid (71) using an asymmetric Strecker reaction. Reagents and conditions: (i) 0.2 M HCl, then NaCN and 80 in 1 M HCl, 86%; (ii) 18 M H2SO4, CH2Cl2, 58%; (iii) I2, Ph3P, imidazole, toluene, 97%; (iv) H2, Pd(OH)2/C, AcOH, 85%; (v) 6 M HCl, 91%.
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Scheme 15 Synthesis of (2S,3S)-3-hydroxypipecolic acid (89). ­Reagents and conditions: (i) SmI2, THF, 65%; (ii) HCl, MeOH; (iii) Boc2O, CH2Cl2, 88% over two steps; (iv) TBDMSCl, imidazole, DMF, 93%; (v) K2CO3, MeOH; (vi) MsCl, Et3N, CH2Cl2; (vii) t-BuOK, THF, 79% over three steps; (viii) H2, Pd/C, MeOH, 98%; (ix) RuCl3, NaIO4, CCl4, MeCN, H2O; (x) 6 M HCl, 74% over two steps.

Chiral sulfinylamines have been used in a similar fashion to α-methylbenzylamines for the asymmetric preparation of a wide range of pipecolic acid derivatives incorporating various substitution patterns and functionality.[50] [51] [52] [53] Wang and Liu utilised a chiral tert-butylsulfinyl imine in an asymmetric pinacol-type reductive coupling for the synthesis of (2S,3S)-3-hydroxypipecolic acid (89; Scheme [15]).[ 53 ] Reaction of imine 84 with aldehyde 85 in the presence of samarium iodide gave anti-vicinal amino alcohol 86 in 65% yield and >98% ee. A three-step sequence of reactions was then performed to remove the sulfinyl auxiliary, reprotect the amine as the Boc-carbamate and protect the secondary alcohol as a silyl ether. Cyclisation to give the piperidine ring was then implemented by hydrolysis of the pivaloyl protecting group, activation of the resulting alcohol as the mesylate and treatment with potassium tert-butoxide. This gave piperidine 88 in 79% over three steps. A Mitsunobu reaction was also examined for this cyclisation, but this approach proved less efficient. Hydrogenation of the benzyl ether, oxidation using the Sharpless protocol[ 37 ] and acid-mediated removal of the silyl ether gave (2S,3S)-3-hydroxypipecolic acid (89) in good overall yield. Inversion of the 3-hydroxy stereogenic centre of 86 and a similar sequence of reactions gave (2S,3R)-3-hydroxypipecolic acid.

A range of more traditional chiral auxiliaries such as 8-phenylmenthol,[ 54 ] (1S,2S)-pseudoephedrine[ 55 ] and camphor-derived auxiliaries[ 56 ] have all been used for the asymmetric synthesis of pipecolic acid derivatives. Seebach’s imidazolidinone auxiliaries[ 57 ] have been utilised in a novel acid-mediated rearrangement for the synthesis of 6-substituted 4-hydroxypipecolic acids (Scheme [16]).[58] [59] The Boc-protected imidazolidinone 90 was alkylated under standard conditions with 2-fluoroallyltosylate which gave the alkylated product 91 in 95% yield and in excellent dia­stereoselectivity (99%). Reaction of 91 under acidic conditions led to the formation of cis-pipecolinamide 92 in a 57% yield. Attempted cyclisation of analogous chloro and bromo derivatives gave only the product of hydrolysis of the imidazolidinone ring. A mechanism was suggested for the formation of 92 involving a carbocation which is stabilised by the fluorine atom. Reduction of the ketone with sodium borohydride (92% de) and hydrolysis of the amide gave (2S,4R,6R)-6-tert-butyl-4-hydroxypipecolic acid (93) in good overall yield. Further work in this programme of research utilised pipecolic acid scaffold 92 for the preparation of a series of conformationally rigid, cyclic α-amino acids.[ 59 ]

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Scheme 16 Synthesis of (2S,4R,6R)-6-tert-butyl-4-hydroxypipecolic acid (93). Reagents and conditions: (i) CH2=C(F)CH2OTs, LDA, DMPU, THF, 95%; (ii) 4 M HCl, MeOH, 57%; (iii) NaBH4, MeOH, 86%; (iv) 6 M HCl, 65%.

# 3.2

Catalytic Asymmetric Methods

Several catalytic asymmetric processes involving transition-metal catalysts have been used for the synthesis of pipecolic acid derivatives. For example, an eight-step synthesis of (2R,4R)-4-methylpipecolic acid (100), a component of antitumour agents and thrombin inhibitors has been prepared using a catalytic asymmetric Sharpless epoxidation (Scheme [17]).[ 60 ] Epoxidation of 94 using (+)-diethyl tartrate gave epoxide 95 in 83% yield and 93% ee. Ring opening with allylamine followed by Boc-protection of the resulting amine gave 96 as the major regioisomer. Oxidation of the diol and reduction of the intermediate aldehyde gave alcohol 97 which was subjected to an RCM reaction with Grubbs’ first-generation catalyst. Hydrogenation of the alkene followed by oxidation and deprotection under standard conditions gave 100. A similar approach was utilised for the synthesis of cis-4- and trans-3-hydroxypipecolic acids.[ 60b ]

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Scheme 17 Synthesis of (2R,4R)-4-methylpipecolic acid (100). ­Reagents and conditions: (i) (+)-DET, Ti(Oi-Pr)4, 3 M t-BuOOH, 4 Å MS, CH2Cl2, 83%; (ii) allylamine, LiClO4 then Boc2O, MeOH; (iii) NaIO4, THF, H2O; (iv) NaBH4, MeOH, 46% over four steps; (v) Grubbs I catalyst, CH2Cl2, 88%; (vi) H2, PtO2, EtOAc, 88%; (vii) NaClO2, NaClO, TEMPO, 63%; (viii) HCl, MeOH, 74%.

Rhodium-catalysed asymmetric transfer hydrogenation of itaconic acid monoesters was used for the synthesis of α,β-dehydropipecolic acids (Scheme [18]).[ 61 ] Itaconic acid monoesters such as 101 were hydrogenated with [Rh(cod)2]BF4 in the presence of chiral phosphoramidite ligands such as (S)-PipPhos (102) to give chiral succinic acid derivatives in high yields and excellent enantioselectivities (e.g., 99% ee for 103).[ 61a ] These chiral building blocks were smoothly converted into iodides such as 104 and coupled with Boc-protected dihydroalanine 105.[ 61b ] An RCM reaction with Grubbs’ second-generation catalyst gave (4S)-4-methyl-α,β-dehydropipecolic acid 107 in 81% yield. Using various substituted itaconic acid monoesters, a series of optically active 4-alkyl- and 4-aryl-α,β-dehydropipecolic acids could be prepared using this approach.

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Scheme 18 Asymmetric synthesis of α,β-dehydropipecolic acid derivative 107. Reagents and conditions: (i) H2, [Rh(cod)2]BF4, 102, CH2Cl2, 92%; (ii) NaH, DMF, 58%; (iii) Grubbs II catalyst, toluene, 81%.

A number of organocatalytic methods have been developed for the asymmetric synthesis of pipecolic acids. The research group of Lasne and Rouden have prepared enantioenriched pipecolic esters by the asymmetric decarboxylation of piperidino-hemimalonates catalysed by cinchona alkaloids.[ 62a ] Further work by this group showed that lithium enolates of pipecolinamides could be protonated by commercially available ephedrines to give optically active pipecolic acid amides with excellent enantioselectivity, although requiring stoichiometric amounts of the chiral protonating agent.[ 62b ] Phase-transfer-catalysed asymmetric alkylation of glycine esters using chiral quaternary ammonium salts provided functionalised α-amino acids that were easily transformed into a range of pipecolic acid derivatives with various substitution patterns including selfotel, a potent N-methyl-d-aspartate (NMDA) receptor antagonist.[ 63 ] A five-step synthesis of d-pipecolic acid (71) involving organocatalytic electrophilic amination was reported by Greck and co-workers (Scheme [19]).[ 64 ] Amination of 6,6-dimethoxyhexanal (108) with dibenzyl azodicarboxylate (DBAD) using l-proline as a catalyst gave, after reduction of the aldehyde, 109 in 76% yield and 94% ee. A three-step hydrogenation sequence was then used to remove the benzylcarbamates, cleave the nitrogen–nitrogen bond and effect cyclisation via a reductive amination. This generated piperidinium salt 110 in 95% yield. Oxidation with potassium permanganate then completed this short synthesis of d-pipecolic acid (71).

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Scheme 19 Reagents and conditions: (i) l-Pro, DBAD, MeCN; (ii) NaBH4, EtOH, 76% over two steps; (iii) H2, Pd/C, MeOH then Raney nickel; (iv) H2, PtO2·H2O, TFA, H2O, 95% over three steps; (v) KMnO4, 3 N H2SO4, 69%.

N-Boc-d-pipecolic acid (114) has been prepared using a catalytic dynamic resolution of N-Boc-2-lithiopiperidine (112) in the presence of a chiral ligand (Scheme [20]).[ 65 ] The racemic lithium salt 112 was prepared by deprotonation of 111 in the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA). Catalytic dynamic resolution was then performed by the addition of dilithiodiaminoalkoxide 113. Using carbon dioxide as an electrophile gave 114 in 78% yield and with an enantiomeric ratio of 98:2. When methyl chloroformate was used as the electrophile, the enantiopure ester was isolated. A diastereomer of 113 was also used to prepare the corresponding l-pipecolic acid derivatives.

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Scheme 20 Synthesis of N-Boc-d-pipecolic acid (114) using a catalytic dynamic resolution. Reagents and conditions: (i) s-BuLi, ­TMEDA, Et2O; (ii) 113, CO2, 78%.

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# 4

Chemoenzymatic Methods

Like other naturally occurring α-amino acids,[ 66 ] optically active pipecolic acid has been prepared using enzymatic transformations. As with other compound classes, the most well developed methods involve kinetic resolution using hydrolytic enzymes. However, other methods including reductive aminations and enzymatic hydroxylations have been reported for the synthesis of functionalised enantiomerically pure pipecolic acid derivatives. The following sections (4.1 and 4.2) outline these transformations according to type of enzyme reaction.

4.1

Enzymatic Kinetic Resolution

A number of hydrolytic enzymes such as nitrilases,[ 67 ] proteases[ 68 ] and aminoacylases[ 69 ] have been used for the kinetic resolution of various substrates for the asymmetric synthesis of pipecolic acid derivatives. For example, Nishino and co-workers utilised Aspergillus genus aminoacylase for the kinetic resolution of acetyl d,l-2-amino-6-bromohexanoic acid.[ 69 ] Hydrolysis of only the l-enantiomer, followed by spontaneous cyclisation under the reaction conditions, gave l-pipecolic acid in 40% yield. However, the main class of enzyme used for the preparation of optically active pipecolic acid compounds are lipases. Takahata and co-workers used a lipase-catalysed kinetic resolution for the synthesis of a small library of hydroxylated pipecolic acids.[ 70 ] The substrate for the enzymatic resolution was prepared in two steps from N-Boc-allylglycine ethyl ester (115) by alkylation with acrolein followed by an RCM reaction with Grubbs’ first-generation catalyst (Scheme [21]). This gave a 4:1 racemic mixture of the trans-isomer 117 and the cis-isomer, respectively, in 86% overall yield. The major trans-isomer 117 was then subjected to acetylation by Pseudomonas cepacia lipase immobilised on ceramic particles. The optimal solvent was found to be diisopropyl ether which gave acetate 118 in 47% yield and 97% ee and returned alcohol 119 in 47% yield and 99% ee. Hydrogenation of 119 followed by acid-mediated removal of the protecting groups gave (2S,3S)-3-hydroxypipecolic acid in excellent yield. Epoxidation and dihydroxylation of 119 and its stereoisomers, generated from further lipase-catalysed kinetic resolutions, allowed the asymmetric preparation of a number of trihydroxylated pipecolic acids.

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Scheme 21 Reagents and conditions: (i) acrolein, LiHMDS, THF, 87%; (ii) Grubbs I catalyst, CH2Cl2, 99%; (iii) lipase, vinyl acetate, i-Pr2O, 47% for 118, 47% for 119; (iv) H2, Pd/C, EtOAc, 99%; (v) 5 M HCl, 84%.

In a similar fashion, Occhiato and co-workers have shown that lipase-catalysed kinetic resolution of α,β-dehydro­pipecolic acids can be used for the preparation of enantiomerically pure 4-hydroxylated derivatives (Scheme [22]).[ 71 ] The substrate for the resolution, 122, was prepared in a short reaction sequence from commercially available δ-valerolactam 121. When lipase from Candida antarctica (CAL-B) supported on acrylic resin was used in toluene with acylating agents such as vinyl acetate, the R-enantiomer was preferentially acetylated, returning (S)-alcohol 124 in excellent enantiomeric excess (99% ee). Protection of the hydroxy group as a silyl ether followed by hydrogenation gave the cis-isomer as the sole product in quantitative yield. Removal of the protecting groups under acidic conditions gave (2R,4S)-4-hydroxypipecolic acid (125). In a separate report, optically active substrates similar to 124 were generated from lipase-catalysed kinetic resolutions and used in cyclopropanation reactions for the preparation of conformationally constrained pipecolic acid derivatives.[ 72 ]

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Scheme 22 Reagents and conditions: (i) CAL-B, vinyl acetate, toluene, 64% conversion; (ii) TIPSCl, DMF, 91%; (iii) H2, Pd/C, EtOAc, 100%; (iv) 2 M HCl, 100%.

# 4.2

Miscellaneous Enzymatic Methods

In nature, the main metabolic pathways for the formation of α-amino acids include the use of dehydrogenase and oxidase enzymes. These have been commonly used as reagents for the synthesis of isotopically labeled and non-proteinogenic α-amino acids including pipecolic acid.[66] [73] In particular, a combination of amino acid oxidases and dehydrogenases have been used for the synthesis of l-pipecolic acid from d- or l-lysine.[74] [75] For example, l-lysine oxidase was used to convert l-lysine (126) into its corresponding α-keto acid 127 (Scheme [23]).[ 75 ] Under the reaction conditions, 127 was in equilibrium with cyclic imine 128. The addition of N-methyl-l-amino acid dehydrogenase (NMAADH) from Pseudomonas putida ATCC12633 resulted in reduction of the imine to give l-pipecolic acid (1) in 98% overall yield as a single enantiomer.

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Scheme 23 Chemoenzymatic synthesis of l-pipecolic acid (1). ­Reagents and conditions: (i) l-lysine oxidase; (ii) NMAADH, 98%.

Optically active 4-chloro-3-hydroxybutanoates such as 129, compounds that can be prepared by enzymatic reduction[ 76 ] of the corresponding ketones, have been readily converted into 4-hydroxypipecolic acids (Scheme [24]).[77] [78] The general strategy involved conversion of the 4-chloro-3-hydroxybutanoates into piperidin-2-ones (e.g., 131) and use of these in palladium-catalysed carbonylations for the preparation of α,β-dehydropiperidines. Hydrogenation and deprotection then gave the optically active 4-hydroxypipecolic acids in good overall yield.

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Scheme 24 Reagents and conditions: (i) NaI, acetone; (ii) NaCN, EtOH, H2O, 81% over two steps; (iii) PMBOC(=NH)CCl3, BF3·OEt2, CH2Cl2, cyclohexane, 99%; (iv) NaBH4, NiCl2·6H2O, EtOH, 74%; (v) n-BuLi, MeOCOCl, THF, 89%; (vi) KHMDS, THF then PhNTf2; (vii) Pd(OAc)2 Ph3P, CO, MeOH, Et3N, DMF, 62% over two steps; (viii) DDQ, H2O, CH2Cl2, 73%; (ix) TBDPSCl, imidazole, DMF, 88%; (x) H2, Pd/C, EtOAc, 98%; (xi) 2 M HCl, 95%.

Various isomers of 3- and 5-hydroxypipecolic acid have been prepared from l-pipecolic acid (1) using proline ­hydroxylases (Scheme [25]).[ 79 ] In vivo hydroxylation of 1 using an E. coli strain producing trans-4-proline hydroxylase (trans-P4H) gave (2S,5R)-5-hydroxypipecolic acid (135) in 61% isolated yield. A small amount of endogenously produced l-proline was also hydroxylated and isolated from the reaction mixture.

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Scheme 25 Chemoenzymatic synthesis of (2S,5R)-5-hydroxypipecolic acid (135). Reagents and conditions: (i) trans-P4H, 61%.

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# 5

Synthesis of Pipecolic Acid Derivatives for Biological Applications

As highlighted at the beginning of this review, cyclic α-amino acids and in particular pipecolic acid, are found in a diverse library of natural products and medicinally important compounds (see Figure [1]). Due to the rigidity of the piperidine ring and the ease in preparing functionalised derivatives, there has been significant recent interest in generating novel compounds with a pipecolic acid core for a wide range of biological applications. The following two sections describe the synthetic methods used for the preparation of pipecolic acid derived compounds as new drug-like structures (5.1), as well as for the generation of novel, conformationally restricted motifs for application as peptide and nucleic acid mimetics (5.2).

5.1

Synthesis of Novel Medicinal Agents

The tetrazole derived pipecolic acid, LY233053 (142; Scheme [26]) is a well-known selective and potent antagonist of the NMDA receptor.[ 80 ] This structure has inspired the development of new synthetic approaches for the preparation of novel triazole[ 81a ] and tetrazole derivatives.[ 81b ] A small library of these compounds was prepared in five steps from dimethyl meso-2,5-dibromoadipate (137; Scheme [26]).[ 81 ] For example, a substitution reaction with 5-phenyl-1H-tetrazole gave 138 in 70% yield. Displacement of the second bromide atom with sodium azide followed by hydrogenation led to cyclisation and isolation of lactam 140 in a 5:1 mixture of cis- and trans-diastereomers, respectively. The major cis-diastereomer was reduced using borane and converted into the cis-5-(5′-phenyltetrazolyl)pipecolic acid (141) after acid hydrolysis. While these compounds are racemic, this approach does allow a rapid and efficient diastereoselective route to a small library of unique structures.

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Scheme 26 Racemic synthesis of tetrazole derivative 141. Reagents and conditions: (i) 5-phenyl-1H-tetrazole, Et3N, acetone, 70%; (ii) NaN3, acetone, 90%; (iii) H2, Pd/C, MeOH, 80%; (iv) BH3·THF, THF; (v) 6 M HCl, propylene oxide, CH2Cl2, 80% over two steps.

A derivative of pipecolic acid containing macrolactams such as the immunomodulatory natural product ascomycin and the structurally related pimecrolimus, a compound with high therapeutic efficacy for inflammatory skin diseases, has been used for the total synthesis of novel analogues.[ 82 ] In particular, a derivative of ascomycin has undergone an eight-step synthesis to give the 6-vinyl derivative 143 (Figure [2]). A 6-methoxypipecolinate derivative was subjected to ring opening, producing an aldehyde which was reacted with vinylmagnesium bromide. Subsequent steps involved reformation of the piperidine ring to give 143. Due to the complexity of the 1H NMR spectrum, the stereochemistry of the 6-vinyl group could not be assigned.

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Figure 2

Hanessian and co-workers have used a 6-oxo-4,5-dehydro-d-pipecolic acid ester to prepare a series of azacyclic phosphonic acids as potential inhibitors of endothelin converting enzyme (ECE).[ 83 ] Conjugate addition followed by an alkylation led to the stereoselective functionalisation of the C4- and C5-positions. Incorporation of a phosphonate group at C-6 and a tryptophan residue led to compounds such as 144 (Figure [2]) which showed promising inhibitory results with ECE.


# 5.2

Synthesis of Conformationally Restricted Building Blocks (Peptide and Nucleic Acid Mimics)

Like most cyclic α-amino acids, the relative rigidity of the piperidine ring of pipecolic acid has meant that it can be used for the preparation of conformationally restricted building blocks. This, combined with the facile, stereoselective functionalisation of the ring system, has resulted in the preparation of a variety of pipecolic acid derivatives for application in a number of biological studies. A common motif used for the synthesis of both peptide and nucleic acid mimics is amino-substituted pipecolic acids. These are generally prepared by activation of a hydroxy group of a pipecolic acid derivative as a sulfonate, followed by SN2 displacement with azide (e.g., Scheme [27]).[ 84 ] Reduction of the azide and protection of the resulting amine gives the building block. 4-Aminopipecolic ­acids have been generated in this way and used to prepare conformationally restricted peptides,[ 84 ] while 5-aminopipecolic acids have been prepared in a similar manner and used to prepare nucleic acid mimics as well as conformationally constrained ornithine and arginine analogues.[85] [86]

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Scheme 27 General strategy for the synthesis of amino-substituted pipecolic acids. Reagents and conditions: (i) MsCl, DMAP, pyridine, 90%; (ii) NaN3, DMF, 80%; (iii) H2, 20% Pd/C, MeOH, 90%; (iv) CbzCl, Et3N, CH2Cl2, 95%.

Functionalised pipecolic acid motifs have also been utilised to prepare a spiro ladder oligomer (Scheme [28]).[ 87 ] 5-Oxopipecolic acid 36 was subjected to a Bucherer–Bergs reaction which gave, after Boc protection, hydantoin 148 as the major diastereomer. Hydrolysis with potassium hydroxide gave bis-amino acid 149 and this was used to assemble the spiro oligomer ladder 150. Two-dimensional NMR studies revealed that each monomer unit adopts a chair conformation, while the whole oligomer forms a left-handed helix.

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Scheme 28 Preparation of oligomer ladder 150. Reagents and conditions: (i) (NH4)2CO3, KCN, DMF, H2O; (ii) Boc2O, DMAP, THF, 49% over two steps; (iii) KOH, THF, H2O, 91%.

Other spirocyclic pipecolic acids have been generated through a variety of methods for biological applications. For example, O’Neil and co-workers used a Cope elimination and intramolecular cycloaddition process for the synthesis of pipecolic acid derived spirocyclic lactams,[ 88 ] while Somu and Johnson have synthesised bicyclic spiro pipecolic lactam scaffolds as type II β-turn mimics (Scheme [29]).[ 89 ] In this programme of research, racemic 2-allyl pipecolic acid (151) was subjected to oxidative cleavage and in situ cyclisation to give hydroxy lactone 152 in 55% yield. Condensation of 152 with the methyl ester of d-cysteine gave pipecolyl thiazolidine 153 as a mixture of diastereomers. Cyclisation was then performed using Mukaiyama’s reagent, and this gave a mixture of four diastereomeric spiro[6.5.5]bicyclic lactam scaffolds. One of the stereoisomers separated from this mixture, (3′S,6′R,7′aR)-lactam 154, was converted into an analogue of the dopamine receptor modulating peptide, l-prolyl-l-leucyl-glycinamide in a three-step sequence involving removal of the Boc protecting group, coupling with Boc-Pro-OH using Mukaiyama’s reagent and finally aminolysis of the methyl ester. Investigation of both 154 and 155 by X-ray crystallography showed both compounds displayed constrained torsion angles similar to that found in an ideal type II β-turn.

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Scheme 29 Reagents and conditions: (i) OsO4, NaIO4, THF, H2O, 55%; (ii) d-Cys-OMe·HCl, NaHCO3, EtOH, H2O, 75%; (iii) 2-chloro-1-methylpyridinium iodide, Et3N, CH2Cl2, 18%; (iv) HCl, dioxane; (v) Boc-Pro-OH, 2-chloro-1-methylpyridinium iodide, DIPEA, DMF, 70% yield over two steps; (vi) NH3, MeOH, 81%.

A number of bridged bicyclic pipecolic acid compounds have been prepared as building blocks for use in conformationally restricted peptidomimetics. Casabona and ­Cativiela have used a Bucherer–Bergs reaction as the key step for the preparation of a 2-azabicyclo[2.2.2]octane-1-carboxylic acid.[ 90 ] Grygorenko and co-workers have prepared a series of conformationally restricted bridged pipecolic acids using a tandem Strecker reaction and intramolecular cyclisation as the key step (Scheme [30]).[ 91 ] Reaction of cyclic ketones such as 156 with benzylamine and acetone cyanohydrin effected the tandem process to give the bridged pipecolic nitriles (157) in good yields. Hydrolysis and deprotection then gave the corresponding α-amino acids. As well as the 2-azabicyclo[2.2.2]octane-1-carboxylic acid analogue 158, 2-azabicyclo[3.1.1]heptane-1-carboxylic and 2-azabicyclo[3.3.1]nonane-1-carboxylic acids were also prepared using this approach. While these compounds are racemic, incorporation of these into peptides would allow their diastereomeric separation.

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Scheme 30 Synthesis of bridged pipecolic acid 158. Reagents and conditions: (i) acetone cyanohydrin, BnNH2, MeCN, 69%; (ii) 6 M HCl; (iii) H2, Pd/C, H2O, 54% over two steps.

#
# 6

Conclusions

The widespread occurrence of the pipecolic acid motif in natural products and medicinally important agents has stimulated the development of a number of elegant stereo­selective methods for its synthesis and the preparation of functionalised derivatives. As demonstrated by this review, the main and most effective approach to these compounds involves the traditional strategy of utilising the chiral pool for starting materials or chiral auxiliaries to induce asymmetric bond-forming reactions. As these compounds find more applications, either as enzyme inhibitors for the treatment of disease or as mimics for understanding biological processes, the drive to prepare more complex and highly substituted derivatives will provide an ongoing challenge for organic synthesis.


#
#

Acknowledgment

The Scottish Funding Council, SINAPSE and the University of Glasgow is gratefully acknowledged for financial support.



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Figure 1
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Scheme 1 Synthesis of (2S,3R)-3-hydroxypipecolic acid 12 by ­Chattopadhyay and co-workers. Reagents and conditions: (i) DMSO, (COCl)2, Et3N, CH2Cl2; (ii) vinylmagnesium bromide, THF, 62% over two steps; (iii) MOMCl, DIPEA, CH2Cl2, 82%; (iv) NaH, allyl bromide, DMF, 90%; (v) Grubbs I catalyst, CH2Cl2, 84%.
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Scheme 2 Synthesis of 2,6-trans-6-substituted-4-hydroxy-l-pipecolic acids 18. Reagents and conditions: (i) (MeO)2P(O)Me, n-BuLi, THF, 84%; (ii) RCHO, K2CO3, MeCN, 57–96%; (iii) TFA, CH2Cl2 then PhCHO, Et3N, 4 Ǻ MS; (iv) NaBH3CN, 29–53% over the four steps.
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Scheme 3 Synthesis of (2S,5R)-5-hydroxypipecolic acid (22) and 6-substituted derivatives 24. Reagents and conditions: (i) TsOH, DMF, toluene, 98%; (ii) Oxone®, NaHCO3, MeOH, 98%; (iii) H2, Pd/C; (iv) 6 M HCl, 93% over two steps; (v) Ac2O, Et3N, DMAP, 99%; (vi) TMS-R, Lewis acid, MeCN; (vii) H2, Pd/C, 82–92% over two steps.
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Scheme 4 Reagents and conditions: (i) MeAlCl2, CHCl3, 79%.
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Scheme 5 Synthesis of (2S,5S)-5-hydroxypipecolic acid derivative 31. Reagents and conditions: (i) EtOCOCl, Et3N, THF, then CH2N2, Et2O, 65%; (ii) [Rh(OAc)2]2, benzene, 52%; (iii) NaBH4, MeOH, 93%.
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Scheme 6 Ring expansion of proline derivative 33. Reagents and conditions: (i) ethyl diazoacetate, BF3·OEt2, Et2O, 90%; (ii) NaCl, H2O (cat.), DMSO, 75%.
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Scheme 7 Synthesis of pipecolic acid 44 using d-mannitol. Reagents and conditions: (i) allylamine, 4 Å MS, CH2Cl2, 95%; (ii) allylzinc bromide, THF, 66%; (iii) TsCl, Et3N, CH2Cl2, 91%; (iv) Grubbs I catalyst, CH2Cl2, 89%; (v) 6 M HCl, 91%; (vi) H2, Pd/C, EtOAc, 100%; (vii) NaIO4, RuCl3 (cat.), CCl4, MeCN, H2O, 73%.
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Scheme 8 Synthesis of glycosidase inhibitor 50 using d-glucose. ­Reagents and conditions: (i) Ph3P=CHCOMe, THF, 87%; (ii) H2, Pd/C, MeOH; (iii) CbzCl, NaHCO3, MeOH, H2O, 91% over two steps; (iv) TFA, H2O, then NaIO4, acetone, H2O; (v) NaClO2, NaH2PO4, 30% H2O2, aq MeCN, 87% over two steps; (vi) H2, Pd/C, MeOH, 80 psi, 97%.
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Scheme 9 Synthesis of (2R,3S)-3-hydroxypipecolic acid derivative 56. Reagents and conditions: (i) H2, Pd/C, EtOH, 95%; (ii) DPPA, DEAD, Ph3P, THF, 71%; (iii) H2, Pd/C, EtOH, 95%; (iv) LiAlH4, Et2O, 88%; (v) Boc2O, MeCN, 88%; (vi) EtAlCl2, Et3SiH, CH2Cl2, 99%; (vii) RuCl3, NaIO4, CCl4, MeCN, H2O, 64%; (viii) H2, Pd(OH)2, EtOH, 70%.
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Scheme 10 Reagents and conditions: (i) TsCl, pyridine; (ii) BzCl, pyridine; (iii) NaN3, DMF; (iv) NaOMe (cat.), MeOH, 51% over four steps; (v) Me3P, MeOH, then Boc-Ala-OH, cyclohexyl-NC, 34%.
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Scheme 11 Reagents and conditions: (i) Tf2O, pyridine, CH2Cl2; (ii) PhMgBr.LiBr, Et2O, 89% over two steps; (iii) H2, Pd/C, MeOH, 300 psi, 80%; (iv) AlH3, Et2O; (v) TFAA, Et2O, 79% over two steps; (vi) RuCl3, NaIO4, CCl4, MeCN, H2O; (vii) K2CO3, MeOH, 72% over two steps.
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Scheme 12 Synthesis of d- (71) and l-pipecolic acid (1) from (R)-2-phenylglycinol (67). Reagents and conditions: (i) BrCH2CO2Me; (ii) Boc2O; (iii) PTSA, 34% over three steps; (iv) I(CH2)4I, NaHMDS, HMPA, THF, 65%; (v) TFA, DCE then EtN(i-Pr)2, 65%; (vi) H2, Pd(OH)2, 99%; (vii) KHMDS, HMPA, THF then AcOH, H2O, 75%; (viii) H2, Pd(OH)2, 99%.
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Scheme 13 Reagents and conditions: (i) TFA, DMF, 33%; (ii) H2, Rh(nbd)2BF4, 76, MeSO3H, 87%; (iii) H2, Pd(OH)2/C, EtOH, 45%.
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Scheme 14 Synthesis of d-pipecolic acid (71) using an asymmetric Strecker reaction. Reagents and conditions: (i) 0.2 M HCl, then NaCN and 80 in 1 M HCl, 86%; (ii) 18 M H2SO4, CH2Cl2, 58%; (iii) I2, Ph3P, imidazole, toluene, 97%; (iv) H2, Pd(OH)2/C, AcOH, 85%; (v) 6 M HCl, 91%.
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Scheme 15 Synthesis of (2S,3S)-3-hydroxypipecolic acid (89). ­Reagents and conditions: (i) SmI2, THF, 65%; (ii) HCl, MeOH; (iii) Boc2O, CH2Cl2, 88% over two steps; (iv) TBDMSCl, imidazole, DMF, 93%; (v) K2CO3, MeOH; (vi) MsCl, Et3N, CH2Cl2; (vii) t-BuOK, THF, 79% over three steps; (viii) H2, Pd/C, MeOH, 98%; (ix) RuCl3, NaIO4, CCl4, MeCN, H2O; (x) 6 M HCl, 74% over two steps.
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Scheme 16 Synthesis of (2S,4R,6R)-6-tert-butyl-4-hydroxypipecolic acid (93). Reagents and conditions: (i) CH2=C(F)CH2OTs, LDA, DMPU, THF, 95%; (ii) 4 M HCl, MeOH, 57%; (iii) NaBH4, MeOH, 86%; (iv) 6 M HCl, 65%.
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Scheme 17 Synthesis of (2R,4R)-4-methylpipecolic acid (100). ­Reagents and conditions: (i) (+)-DET, Ti(Oi-Pr)4, 3 M t-BuOOH, 4 Å MS, CH2Cl2, 83%; (ii) allylamine, LiClO4 then Boc2O, MeOH; (iii) NaIO4, THF, H2O; (iv) NaBH4, MeOH, 46% over four steps; (v) Grubbs I catalyst, CH2Cl2, 88%; (vi) H2, PtO2, EtOAc, 88%; (vii) NaClO2, NaClO, TEMPO, 63%; (viii) HCl, MeOH, 74%.
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Scheme 18 Asymmetric synthesis of α,β-dehydropipecolic acid derivative 107. Reagents and conditions: (i) H2, [Rh(cod)2]BF4, 102, CH2Cl2, 92%; (ii) NaH, DMF, 58%; (iii) Grubbs II catalyst, toluene, 81%.
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Scheme 19 Reagents and conditions: (i) l-Pro, DBAD, MeCN; (ii) NaBH4, EtOH, 76% over two steps; (iii) H2, Pd/C, MeOH then Raney nickel; (iv) H2, PtO2·H2O, TFA, H2O, 95% over three steps; (v) KMnO4, 3 N H2SO4, 69%.
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Scheme 20 Synthesis of N-Boc-d-pipecolic acid (114) using a catalytic dynamic resolution. Reagents and conditions: (i) s-BuLi, ­TMEDA, Et2O; (ii) 113, CO2, 78%.
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Scheme 21 Reagents and conditions: (i) acrolein, LiHMDS, THF, 87%; (ii) Grubbs I catalyst, CH2Cl2, 99%; (iii) lipase, vinyl acetate, i-Pr2O, 47% for 118, 47% for 119; (iv) H2, Pd/C, EtOAc, 99%; (v) 5 M HCl, 84%.
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Scheme 22 Reagents and conditions: (i) CAL-B, vinyl acetate, toluene, 64% conversion; (ii) TIPSCl, DMF, 91%; (iii) H2, Pd/C, EtOAc, 100%; (iv) 2 M HCl, 100%.
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Scheme 23 Chemoenzymatic synthesis of l-pipecolic acid (1). ­Reagents and conditions: (i) l-lysine oxidase; (ii) NMAADH, 98%.
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Scheme 24 Reagents and conditions: (i) NaI, acetone; (ii) NaCN, EtOH, H2O, 81% over two steps; (iii) PMBOC(=NH)CCl3, BF3·OEt2, CH2Cl2, cyclohexane, 99%; (iv) NaBH4, NiCl2·6H2O, EtOH, 74%; (v) n-BuLi, MeOCOCl, THF, 89%; (vi) KHMDS, THF then PhNTf2; (vii) Pd(OAc)2 Ph3P, CO, MeOH, Et3N, DMF, 62% over two steps; (viii) DDQ, H2O, CH2Cl2, 73%; (ix) TBDPSCl, imidazole, DMF, 88%; (x) H2, Pd/C, EtOAc, 98%; (xi) 2 M HCl, 95%.
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Scheme 25 Chemoenzymatic synthesis of (2S,5R)-5-hydroxypipecolic acid (135). Reagents and conditions: (i) trans-P4H, 61%.
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Scheme 26 Racemic synthesis of tetrazole derivative 141. Reagents and conditions: (i) 5-phenyl-1H-tetrazole, Et3N, acetone, 70%; (ii) NaN3, acetone, 90%; (iii) H2, Pd/C, MeOH, 80%; (iv) BH3·THF, THF; (v) 6 M HCl, propylene oxide, CH2Cl2, 80% over two steps.
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Figure 2
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Scheme 27 General strategy for the synthesis of amino-substituted pipecolic acids. Reagents and conditions: (i) MsCl, DMAP, pyridine, 90%; (ii) NaN3, DMF, 80%; (iii) H2, 20% Pd/C, MeOH, 90%; (iv) CbzCl, Et3N, CH2Cl2, 95%.
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Scheme 28 Preparation of oligomer ladder 150. Reagents and conditions: (i) (NH4)2CO3, KCN, DMF, H2O; (ii) Boc2O, DMAP, THF, 49% over two steps; (iii) KOH, THF, H2O, 91%.
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Scheme 29 Reagents and conditions: (i) OsO4, NaIO4, THF, H2O, 55%; (ii) d-Cys-OMe·HCl, NaHCO3, EtOH, H2O, 75%; (iii) 2-chloro-1-methylpyridinium iodide, Et3N, CH2Cl2, 18%; (iv) HCl, dioxane; (v) Boc-Pro-OH, 2-chloro-1-methylpyridinium iodide, DIPEA, DMF, 70% yield over two steps; (vi) NH3, MeOH, 81%.
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Scheme 30 Synthesis of bridged pipecolic acid 158. Reagents and conditions: (i) acetone cyanohydrin, BnNH2, MeCN, 69%; (ii) 6 M HCl; (iii) H2, Pd/C, H2O, 54% over two steps.